Title of Invention	NOVEL BENZOPHENONE DERIVATIVES OR SALTS THEREOF
Abstract	A benzophenone derivative represented by the following formula: wherein R1 represents, for example, an optionally substituted heterocyclic group, or a substituted phenyl group; Z represents, for example, an alkylene group; R2 represents, for example, a carboxyl group optionally protected with alkyl; R3 represents, for example, an optionally protected hydroxyl group; R4 represents, for example, an optionally substituted cycloalkyloxy group; and R5 represents, for example, a hydrogen atom, or a salt thereof has anti-arthritic activity, inhibits bone destruction caused by arthritis, and provides high safety and excellent pharmacokinetics and thus is useful as therapeutic agent for arthritis. These compounds have inhibitory effect on AP-1 activity and are useful as preventive or therapeutic agent for diseases in which excessive expression of AP-1 is involved.

Title of Invention

NOVEL BENZOPHENONE DERIVATIVES OR SALTS THEREOF

Abstract

A benzophenone derivative represented by the following formula: wherein R1 represents, for example, an optionally substituted heterocyclic group, or a substituted phenyl group; Z represents, for example, an alkylene group; R2 represents, for example, a carboxyl group optionally protected with alkyl; R3 represents, for example, an optionally protected hydroxyl group; R4 represents, for example, an optionally substituted cycloalkyloxy group; and R5 represents, for example, a hydrogen atom, or a salt thereof has anti-arthritic activity, inhibits bone destruction caused by arthritis, and provides high safety and excellent pharmacokinetics and thus is useful as therapeutic agent for arthritis. These compounds have inhibitory effect on AP-1 activity and are useful as preventive or therapeutic agent for diseases in which excessive expression of AP-1 is involved.

Full Text	DESCRIPTION NOVEL BENZOPHENONE DERIVATIVES OR SALTS THEREOF TECHNICAL FIELD The present invention relates to novel benzophenone derivatives or the salts thereof that have anti-arthritic activities and inhibitory effect on bone destruction caused by arthritis and provide preventive, therapeutic and improving effect against arthritic diseases. Further, the invention relates to preventive/therapeutic agent for diseases, in which excessive expression of AP-1 is involved, and inhibitors against AP-1 activity, which contain the above benzophenone derivatives or the salts thereof. BACKGROUND ART Arthritic disease such as connective tissue diseases, represented by rheumatoid arthritis, and osteoarthritis brings on joint dysfunction by the progression of cartilage/bone destruction and has a large effect on patients' daily life. Up until now, for drug treatment for rheumatoid arthritis and other arthritis, have been used non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and indomethacin, disease modifying antirheumatic drugs (DMARDs) such as gold preparation and D~penicillamine, immunosuppressive drugs such as methotrexate, and adrenocorticoids. However, therapies currently in use cannot completely inhibit the progress of bone destruction, which is the most important problem of concern with arthritis, and are difficult to apply to patients for a long period of time because of adverse effects occurring in association with the drugs used and thereby satisfactory treatment has not been given to patients to date. To overcome the above problem, studies have been performed; for example, Japanese Patent Laid-Open No. 2000-336063 discloses benzophenone derivatives that are effective in the treatment for mouse collagen- induced arthritis. However, it is still expected that the benzophenone derivatives having anti-arthritic activities provide a further improvement in anti- arthritic activities and inhibitory effect on bone destruction caused by arthritis, safety, and pharmacokinetics. Further, it has been hoped that preventive/therapeutic agent for diseases, in which excessive expression of AP-1 is involved, are developed which provide inhibitory effect on the activity of transcription factor AP-1, suppress excessive expression of a variety of genes based on their inhibitory effect on AP-1, and produce less adverse effects. DISCLOSURE OF THE INVENTION Under these conditions, the inventors of this invention directed tremendous research effort toward coming up to the above expectation and hope, and they have found that benzophenone derivatives represented by the following general formula: wherein R1 represents a substituted or unsubstituted heterocyclic group, a substituted phenyl group or a substituted or unsubstituted alkyl group; Z represents a substituted or unsubstituted alkylene group; R2 represents a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted heterocyclic carbonyl group or a protected or unprotected carboxyl group; R3 represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a protected or unprotected carboxyl group, a protected or unprotected hydroxyl group, a protected or unprotected amino group, a mercapto group, a carbamoyl group or a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group; R4 represents a substituted or unsubstituted alkoxy, cycloalkyloxy, cycloalkenyloxy, alkyl, cycloalkyl, heterocyclic-oxy or heterocyclic group; R5 represents a hydrogen atom, a halogen atom or a hydroxyl group; provided that, when R1 represents a substituted or unsubstituted alkyl group, R4 represents a substituted or unsubstituted cycloalkyloxy group, an alkoxy group substituted with a substituted or unsubstituted phenyl or heterocyclic group, or a substituted or unsubstituted heterocyclic-oxy group, or the salts thereof have excellent anti- arthritic action as well as inhibitory action against bone destruction caused by arthritis, and moreover, high safety and excellent pharmacokinetics. They also have found that the compounds of this invention provide AP-1 inhibitory action and are useful as preventive/therapeutic agent for diseases, in which excessive expression of AP-1 is involved. And they have finally accomplished this invention. The compounds of this invention are expected to have AP-1 inhibitory action and be effective in the treatment and the prevention of diseases in which AP-1 related genes are involved. In the following the compounds of this invention will be described in detail. In this specification, unless otherwise specified, halogen atoms mean fluorine, chlorine, bromine and iodine atoms; alkyl groups mean straight- or branched-chain C1_12 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl and octyl groups; lower alkyl groups mean straight- or branched-chain C1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl and isopentyl groups; halogeno lower alkyl groups mean straight- or branched-chain halogeno- C1-6 alkyl groups such as fluoromethyl, chloromethyl, bromomethyl, dichloromethyl, trifluoromethyl, trichloromethyl, chloroethyl, dichloroethyl, trichloroethyl and chloropropyl groups; lower alkoxy lower alkyl groups mean straight- or branched-chain C1-6 alkoxy-C1-6 alkyl groups such as methoxymethyl, ethoxymethyl, n-propoxymethyl, methoxyethyl and ethoxyethyl groups; hydroxy lower alkyl groups mean straight- or branched-chain hydroxy-C1-6 alkyl groups such as hydroxymethyl, hydroxyethyl and hydroxypropyl groups; amino lower alkyl groups mean amino-C1-6 alkyl groups such as aminomethyl, aminoethyl and aminopropyl groups; alkenyl groups mean straight- or branched-chain C2-12 alkenyl groups such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl and octenyl groups; lower alkenyl groups mean straight- or branched-chain C2-6 alkenyl groups such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl and pentenyl groups; cycloalkyl groups mean C3-7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group; cycloalkyloxy groups mean C3-7 cycloalkyloxy groups such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cyclopentyloxy group; cycloalkenyloxy groups mean C5-7 cycloalkenyloxy groups such as cyclopentenyloxy and cyclohexenyloxy groups; aryl groups mean, for example, phenyl, tolyl and naphthyl groups; aralkyl groups mean ar- C1-12 alkyl groups such as benzyl, diphenylmethyl, trityl, phenethyl, 4- methylbenzyl and naphthylmethyl groups; ar- lower alkyl groups mean ar- C1-6 alkyl groups such as benzyl, diphenylmethyl, trityl and phenethyl groups; aryloxy groups mean, for example, phenoxy and naphthoxy groups; aryloxycarbonyl groups mean, for example, phenoxycarbonyl and naphthoxycarbonyl groups; alkoxy groups mean straight- or branched-chain C1-12 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy and octyloxy groups; lower alkoxy groups mean straight- or branched-chain C1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert- butoxy, pentyloxy and isopentyloxy groups; alkylene groups mean straight- or branched-chain C1-12 alkylene groups such as methylene, ethylene and propylene groups; alkoxycarbonyl groups mean straight- or branched-chain C1-12 alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and pentyloxycarbonyl groups; lower alkoxycarbonyl groups mean straight- or branched-chain C1-6 alkyloxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl groups; lower alkoxycarbonyl lower alkyl groups mean straight- or branched-chain C1-6 alkoxycarbonyl-C1-6 alkyl groups such as methoxycarbonylmethyl, ethoxycarbonylmethyl, n- propoxycarbonylmethyl, methoxycarbonylethyl and ethoxycarbonylethyl groups; lower alkoxyimino groups mean straight- or branched-chain C1-6 alkoxyimino groups such as methoxyimino and ethoxyimino groups; alkylamino groups mean straight- or branched-chain C1-l2 alkylamino groups such as methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, heptylamino and octylamino groups; lower alkylamino groups mean straight- or branched-chain mono- or di- C1-6 alkylamino groups such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino and methylethylamino groups; lower alkylamino lower alkyl groups mean mono- or di- C1-6 alkylamino C1-6 alkyl groups such as methylaminomethyl, methylaminoethyl, ethylaminomethyl, methylaminopropyl, propylaminoethyl, dimethylaminomethyl, diethylaminomethyl, diethylaminoethyl and dimethylaminopropyl groups; lower alkylidene groups mean C1-6 alkylidene groups such as methylene, ethylidene, propylidene and isopropylidene groups; nitrogen-containing heterocyclic groups mean 5- or 6-membered-ring, condensed-ring or bridged-ring heterocyclic groups each of which contains one or more nitrogen atoms as hetero atoms forming the ring and optionally one or more oxygen atoms or sulfur atoms, such as pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl, quinolizinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinuclidinyl, quinazolyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, purinyl and indazolyl groups; heterocyclic rings mean the above described nitrogen- containing heterocyclic groups and 5- or 6-membered- ring, condensed-ring or bridged-ring heterocyclic groups each of which contains at least one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms and optionally one or more oxygen and sulfur atoms as heteroatoms forming the ring, such as furyl, thienyl, 4-methyl-2-oxo-l,3-dioxol, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinoxalyl, dihydroquinoxalinyl, 2,3-dihydrobenzothienyl, 2,3- dihydrobenzopyrrolyl, 2,3-dihydro-4H-l-thianaphthyl, 2,3-dihydrobenzofuranyl, benzo[b]dioxanyl, imidazo[2,3- a]pyridyl, benzo[b]piperazinyl, chromenyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, isoindolyl and isoquinolyl groups; heterocyclic carbonyl groups mean heterocyclic -CO- groups such as 4-hydroxy-2-(5H)-furanocarbonyl, morpholinocarbonyl, piperazinocarbonyl or pyrrolidinocarbonyl group; acyl groups mean, for example, formyl group, straight- or branched-chain C2-12 alkanoyl groups such as acetyl, isovaleryl, propionyl and pivaloyl, aralkylcarbonyl groups such as benzylcarbonyl group, aroyl groups such as benzoyl and naphthoyl groups, and heterocyclic carbonyl groups such as nicotinoyl, thenoyl, pyrrolidinocarbonyl and furoyl groups; acylamino groups mean C1-6 acylamino groups such as formylamino, acetylamino, propionylamino and butyrylamino groups; alkanoyloxy groups mean C2-12 alkanoyloxy groups such as acetyloxy, propionyloxy and pivaloyloxy groups; cyclic amino groups mean both saturated and unsaturated cyclic amino groups, each of which optionally contains, in the ring, one or more heteroatoms such as nitrogen, oxygen and sulfur atoms and carbonyl-carbons and may be monocyclic or di- to tricyclic, in more particular, saturated or unsaturated 3- to 7-membered-ring monocyclic amino groups containing one nitrogen atom, such as aziridin-1-yl, azetizin-1-yl, pyrrolidin-1-yl, pyrrolin-1-yl, pyrrol-1-yl, dihydropyridin-1-yl, piperidin-1-yl, dihydroazepin-1-yl and perhydroazepin- 1-yl groups, saturated or unsaturated 3- to 7-membered- ring monocyclic amino groups containing two nitrogen atoms, such as imidazol-1-yl, imidazolidin-1-yl, imidazolin-1-yl, pyrazolidin-1-yl, piperazin-1-yl, 1,4- dihydropyrazin-1-yl, 1,2-dihydropyrimidin-l-yl, perhydropyrazin-1-yl and homopiperazin-1-yl groups, saturated or unsaturated 3- to 7-membered-ring monocyclic amino groups containing 3 or more nitrogen atoms, such as 1,2,4-triazol-l-yl, 1,2,3-triazol-l-yl, 1,2-dihydro-l,2,4-triazin-l-yl and perhydro-S-triazin- 1-yl, saturated or unsaturated 3- to 7-membered-ring monocyclic amino groups containing 1 to 4 heteroatoms selected from the group consisting of oxygen and sulfur atoms, besides nitrogen atoms, such as oxazolidin-3-yl, isoxazolidin-2-yl, morpholin-4-yl, thiazolidin-3-yl, isothiazolidin-2-yl, thiomorpholin-4-yl, homothiomorpholin-4-yl and 1,2,4-thiaziazolin-2-yl groups, saturated or unsaturated di- to tricyclic amino groups such as isoindolin-2-yl, indolin-1-yl, 1H- indazol-1-yl, purin-7-yl and tetrahydroquinolin-1-yl groups, and spiro or bridged saturated or unsaturated 5- to 12-membered cyclic amino groups such as 5- azaspiro[2.4]heptan-5-yl, 2,8-diazabicyclo[4.3.0]nonan- 8-yl, 3-azabicyclo[3.1.0]hexan-3-yl, 2-oxa-5,8- diazabicyclo[4.3.0]nonan-8-yl, 2,8- diazaspiro[4.4]nonan-2-yl and 7- azabicyclo[2.2.1]heptan-7-yl groups; alkylthio groups mean straight- or branched-chain Cx_12 alkylthio groups such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, hexylthio, heptylthio and octylthio groups; lower alkylthio groups mean straight- or branched-chain C1_6 alkylthio groups such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio and isopentylthio groups; alkylsulfinyl groups mean straight- or branched-chain C1-12 alkylsulf inyl groups such as methylsulf inyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n- butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl, isopentylsulfinyl, hexylsulfinyl, heptylsulfinyl and octylsulfinyl groups; alkylsulfonyl groups mean straight- or branched-chain C1-12 alkylsulf onyl groups such as methylsulf onyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n- butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, hexylsulfonyl, heptylsulfonyl and octylsulfonyl groups; alkylsulfonylamino groups mean straight- or branched- chain C1-12 alkylsulfonylamino groups such as methylsulfonylamino, ethylsulfonylamino, n- propylsulfonylamino, isopropylsulfonylamino, n- butylsulfonylamino, isobutylsulfonylamino, sec- butylsulfonylamino, tert-butylsulfonylamino, pentylsulfonylamino, isopentylsulfonylamino, hexylsulfonylamino, heptylsulfonylamino and octylsulfonylamino groups; arylsulfonylamino groups mean aryl-S02NH-groups such as phenylsulfonylamino and naphthylsulfonylamino groups; lower alkylsulfinyl groups mean straight- or branched-chain C1-6 alkylsulfinyl groups such as methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n- butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl and hexylsulfinyl groups; lower alkylsulfonyl groups mean straight- or branched-chain C1-6 alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl and pentylsulfonyl; lower alkylcarbamoyl groups mean mono- or di- C1-6 alkylcarbamoyl groups such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and methylethylcarbamoyl groups; lower alkylsulfonylamino groups mean straight- or branched- chain C1-6 alkylsulfonylamino groups such as methylsulfonylamino, ethylsulfonylamino, n- propylsulfonylamino, isopropylsulfonylamino, n- butylsulfonylamino, isobutylsulfonylamino, sec- butylsulfonylamino, tert-butylsulfonylamino and pentylsulfonylamino groups; lower alkylsulfonylcarbamoyl groups mean straight- or branched-chain C1-6 alkylsulf onylcarbamoyl groups such as methylsulfonylcarbamoyl, ethylsulfonylcarbamoyl, n- propylsulfonylcarbamoyl, isopropylsulfonylcarbamoyl, n- butylsulfonylcarbamoyl, isobutylsulfonylcarbamoyl, sec- butylsulfonylcarbamoyl, tert-butylsulfonylcarbamoyl and pentylsulfonylcarbamoyl groups; lower alkylaminosulfonyl groups mean mono- or di- C1-6 alkylaminosulfonyl groups such as methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, dimethylaminosulfonyl, diethylaminosulfonyl and methylethylaminosulfonyl groups; carboxyl-lower alkenyl groups mean, for example, straight- or branched-chain carboxyl-substituted C2-6 alkenyl groups; hydroxyl- heterocyclic groups mean, for example, hydroxyl- substituted heterocyclyl groups; lower alkyl- heterocyclic groups mean, for example, heterocyclic groups each having been substituted with a straight- or branched-chain lower alkyl group; lower alkoxy-lower alkoxy groups mean straight- or branched-chain C1-6 alkoxy groups each having been substituted with a lower alkoxy group; heterocyclic-lower alkyl groups mean heterocyclic -CH2- groups such as pyrrolidinylmethyl, piperidylmethyl, piperazinylmethyl, pyrazolylmethyl, tetrahydropyridylmethyl, morpholinylmethyl, thiomorpholinylmethyl, tetrahydroquinolinylmethyl, tetrahydroisoquinolinylmethyl, quinuclidinylmethyl, tetrazolylmethyl, thiadiazolylmethyl, pyrazolidinylmethyl, purinylmethyl, indazolylmethyl, 2- thienylmethyl, furfuryl, 2-pyranylmethyl, 1- isobenzofurylmethyl, 2-pyrrolylmethyl, 1- imidazolylmethyl, 1- pyrazolylmethyl, 3- isothiazolylmethyl, 3-isoxazolylmethyl, 2-pyridylmethyl, 2-pyrazinylmethyl, 2-pyrimidinylmethyl, 2- pyridazinylmethyl, 1-isoindolylmethyl, 2-indolylmethyl, 1-isoquinolylmethyl, 2-quinolylmethyl, 1- phthalazinylmethyl, 2-naphthyridinylmethyl, 2- quinoxalinylmethyl, 2-quinazolinylmethyl, 3- cinnolinylmethyl, 2-oxazolylmethyl, 2-thiazolylmethyl, 2-benzo[b]furylmethyl, 2-benzo[b]thienylmethyl, 2- benz[d]imidazolylmethyl and 2-benz[d]oxazolylmethyl groups; leaving groups mean halogen atoms such as fluorine, chlorine, bromine and iodine atoms, alkoxysulfonyloxy groups such as methoxysulfonyloxy group, alkylsulfonyloxy groups such as methylsulfonyloxy group, and arylsulfonyloxy groups such as p-toluenesulfonyloxy and benzenesulfonyloxy groups; and heterocyclic oxy groups mean groups represented by heterocyclic-O- each of which binds via an oxygen atom, such as pyrrolidinyloxy, piperidinyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy and tetrahydrothiopyranyloxy groups. Carboxyl-protecting groups include all the groups that can be used as ordinary carboxyl-protecting groups. Concrete examples are alkyl such as methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, and tert-butyl; aryl such as phenyl and naphthyl; aralkyl such as benzyl, diphenylmethyl, trityl, p- nitrobenzyl, p-methoxybenzyl, and bis(p- methoxyphenyl)methyl; acyl-alkyl such as acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p- bromobenzoylmethyl, and p-methanesulfonylbenzoylmethyl; oxygen-containing heterocyclyl such as 2- tetrahydropyranyl and 2-tetrahydrofuranyl; halogeno- alkyl such as 2,2,2-trichloroethyl; alkylsilylalkyl such as 2-(trimethylsilyl)ethyl; acyloxyalkyl such as acetoxymethyl, propionyloxymethyl, and pivaloyloxymethyl; nitrogen-containing heterocyclic alkyl such as phthalimidomethyl and succinimidomethyl; cycloalkyl such as cyclohexyl; alkoxyalkyl such as methoxymethyl, methoxyethoxymethyl, and 2- (trimethylsilyl)ethoxymethyl; ar-alkoxy-alkyl such as benzyloxymethyl; alkylthio-alkyl such as methylthiomethyl and 2-methylthioethyl; arylthio-alkyl such as phenylthiomethyl; alkenyl such as 1,1-dimethyl- 2-propenyl, 3-methyl-3-butenyl, and allyl; and substituted silyl such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert- butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl. Of the above carboxyl-protecting groups, are preferred alkyl groups such as methyl, ethyl, isopropyl and isobutyl groups; aralkyl groups such as benzyl group; and substituted silyl groups such as trimethylsilyl group. Amino-protecting groups include all the groups that can be used as ordinary amino-protecting groups. Concrete examples are acyl such as trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, 2-ethylhexyloxycarbonyl, p- nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, (mono-, di-, tri-)chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert- pentyloxycarbonyl, tert-butoxycarbonyl, p- methoxybenzyloxycarbonyl, 3,4- dimethoxybenzyloxycarbonyl, 4- (phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl, and 8-quinolyloxycarbonyl; aralkyl such as benzyl, diphenylmethyl, and trityl; alkoxy-alkyl such as methoxymethyl, benzyloxymethyl, 2- methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl)ethoxymethyl, and 1-ethoxyethyl; alkylthio-alkyl such as methylthiomethyl; arylthio such as 2-nitrophenylthio and 2,4-dinitrophenylthio; alkyl- or aryl-sulfonyl such as methanesulfonyl and p- toluenesulfonyl; dialkylamino-alkylidene such as N,N- dimethylaminomethylene; aralkylidene such as benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5- chlorobenzylidene, and 2-hydroxy-l-naphthylmethylene; nitrogen-containing heterocyclic alkylidene such as 3- hydroxy-4-pyridylmethylene; cycloalkylidene such as cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2- ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, and 3,3-dimethyl-5-oxycyclohexylidene; diaryl- or diaralkylphosphoryl such as diphenylphosphoryl and dibenzylphosphoryl; oxygen-containing heterocyclic alkyl such as 5-methyl-2-oxo~2H-l,3-dioxol-4-yl-methyl; substituted silyl such as trimethylsilyl; hydroxylamino; and nitroso and nitro. Of the above amino-protecting groups, are preferred acyl groups such as tert-butoxycarbonyl and 2-ethylhexyloxycarbonyl groups; aralkyl groups such as trityl group; alkoxyalkyl groups such as methoxymethyl group; alkyl- or aryl-sulfonyl groups such as methanesulfonyl and p- toluenesulfonyl groups; substituted silyl groups such as trimethylsilyl group; hydroxylamino group; nitroso group; and nitro group. Hydroxyl-protecting groups include all the groups that can be used as ordinary hydroxyl-protecting groups. Concrete examples are acyl such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4- bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1- dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2- trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2- (phenylsulfonyl)ethoxycarbonyl, 2- (triphenylphosphonio)ethoxycarbonyl, 2- furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, S- benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8- quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, and benzoyl; alkyl such as methyl, isopropyl, isobutyl, tert-butyl, 2,2,2-trichloroethyl, and 2-trimethylsilylethyl; alkenyl such as allyl; aralkyl such as benzyl, p- methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, and trityl; oxygen-containing and sulfur-containing heterocyclyl such as tetrahydrofuryl, tetrahydropyranyl, and tetrahydrothiopyranyl; alkoxy-alkyl such as methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl)ethoxymethyl, and 1-ethoxyethyl; alkylthio-alkyl such as methylthiomethyl; alkyl- and aryl-sulfonyl such as methanesulfonyl and p- toluenesulfonyl; and substituted silyl such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert- butyldiphenylsilyl, diphenylmethylsilyl, and tert- butylmethoxyphenylsilyl. Of the above hydroxyl- protecting groups, are preferred acyl groups such as acetyl group; alkyl groups such as methyl, isopropyl and isobutyl groups; aralkyl groups such as benzyl group; oxygen-containing heterocyclic groups such as tetrahydropyranyl group; alkoxyalkyl groups such as methoxymethyl group; and arylsulfonyl groups such as p- toluenesulfonyl group. Phenolic hydroxyl-protecting groups include all the groups that can be used as ordinary phenol- protecting groups. Concrete examples are acyl such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4- bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1- dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2- trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2- (phenylsulfonyl)ethoxycarbonyl, 2- (triphenylphosphonio)ethoxycarbonyl, 2- furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, S- benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8- quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, and benzoyl; alkyl such as methyl, isopropyl, isobutyl, tert-butyl, 2,2,2-trichloroethyl, and 2-trimethylsilylethyl; alkenyl such as allyl; aralkyl such as benzyl, p- methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, and trityl; oxygen-containing and sulfur-containing heterocyclyl such as tetrahydrofuryl, tetrahydropyranyl, and tetrahydrothiopyranyl; alkoxy-alkyl such as methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2, 2, 2-trichloroethoxymethyl, 2- (trimethylsilyl)ethoxymethyl, and 1-ethoxyethyl; alkylthio-alkyl such as methylthiomethyl; alkyl-, and aryl-sulfonyl such as methanesulfonyl and p- toluenesulfonyl; and substituted silyl such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert- butyldiphenylsilyl, diphenylmethylsilyl, and tert- butylmethoxyphenylsilyl. Of the above phenolic hydroxyl-protecting groups, are preferred acyl groups such as acetyl group; alkyl groups such as methyl, isopropyl and isobutyl groups; aralkyl groups such as benzyl group; oxygen-containing heterocyclic groups such as tetrahydropyranyl group; alkoxyalkyl groups such as methoxymethyl group; and arylsulfonyl groups such as p-toluenesulfonyl group. Phosphoryl-protecting groups include all the groups that can be used as ordinary phosphoryl- protecting groups. Concrete examples are alkyl such as methyl, ethyl, isopropyl, tert-butyl, 2-cyanoethyl, 2- (trimethylsilyl)ethyl, 2-(4-nitrophenyl)ethyl, 2- (benzylsulfonyl)ethyl, and 2,2,2-trichloroethyl; alkenyl such as allyl; aralkyl such as benzyl, 4- nitrobenzyl, and diphenylmethyl; aryl such as phenyl, 2-methylphenyl, 4-chlorophenyl, and 4-nitrophenyl; and amino such as anilino and isopropylamino. Sulfo-protecting groups include all the groups that can be used as ordinary sulfonyloxy- protecting groups. Concrete examples are aryl groups such as phenyl and 2,4-dinitrophenyl groups; alkyl groups such as tert-butyl, neopentyl, isopropyl and isobutyl groups; and 1-adamantyl group. In this invention, the improvement in pharmacokinetics means, for example, the reduction in enzyme inhibitory effect of cytochrome P450 and the improvement in metabolic stability, in more particular, the reduction in enzyme inhibitory effect of CYP2C9 etc. and the decrease of in vivo metabolite ratio. Salts of the compounds represented by general formula [1] include, for example, commonly known salts produced in the compounds' basic groups such as amino group and produced in the compounds' acidic groups such as hydroxyl and carboxyl groups. Salts produced in the compounds' basic groups include, for example, salts produced with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; salts produced with organic carboxylic acids such as tartaric acid, formic acid, citric acid, trichloroacetic acid and trifluoroacetic acid; and salts produced with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. Salts produced in the compounds' acidic groups include, for example, salts produced with alkaline metals such as sodium and potassium; salts produced with alkaline earth metals such as calcium and magnesium; ammonium salts; and salts produced with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N- methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-p-phenethylamine and N,N'-dibenzylethylenediamine. Of the above salts of the compounds represented by the general formula [1], preferable are pharmacologically acceptable salts. Each substituent of the groups R1, R2, R3 and R4 is optionally substituted with one or more groups selected from the group consisting of cyano, nitro, halogen, carboxyl that may be protected, phosphoryl, hydroxyl, amino, carbamoyl, hydroxycarbamoyl, aminosulfonyl, sulfo, hydroxy lower alkyl, amino lower alkyl, cyclic amino, lower alkylamino and lower alkylamino lower alkyl, lower alkyl, lower alkenyl, lower alkoxy, lower alkoxycarbonyl, acyl, aryl, heterocyclyl, cycloalkyl, aralkyl, lower alkylidene, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkylsulfonylcarbamoyl, lower alkylcarbamoyl, lower alkylsulfonylamino, lower alkylaminosulfonyl, carboxyl lower alkenyl, hydroxyheterocyclyl, lower alkyl heterocyclyl, lower alkoxy lower alkoxy, halogeno lower alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl, and lower alkoxyimino. The alkylene group of Z is optionally substituted with one or more groups selected from the group consisting of cyano, nitro, halogen, carboxyl that may be protected, carbamoyl, hydroxycarbamoyl, hydroxy lower alkyl, amino lower alkyl and lower alkylamino lower alkyl, lower alkyl, lower alkoxycarbonyl, acyl, aryl, heterocyclyl, cycloalkyl, lower alkenyl, aralkyl, lower alkylsulfonylcarbamoyl, lower alkylcarbamoyl, halogeno lower alkyl, lower alkoxy lower alkyl, and lower alkoxycarbonyl lower alkyl. The substituents of the above described substituents are further optionally substituted with the groups exemplified above as substituents. The heterocyclic groups and cyclic amino groups of the substituents of the above described substituents are optionally substituted with keto groups. Preferable substituents of the compounds of this invention are as follows. In the compounds of this invention, R1 is preferably an optionally substituted heterocyclyl group or a substituted phenyl group, more preferably an optionally substituted heterocyclyl group, much more preferably an optionally substituted benzisoxazolyl group, and most preferably hydroxyl-substituted benzisoxazolyl group. In the compounds of this invention, R2 is preferably a heterocyclic carbonyl group optionally substituted with a hydroxyl group or an alkyl group or a carboxyl group optionally protected with an alkyl group, more preferably a carboxyl group optionally protected with an alkyl group, much more preferably a carboxyl group optionally protected with an ethyl group, and most preferably a carboxyl group. Further, in the compounds of this invention, R2 is preferably a carboxyl group protected with a substituted alkyl group and more preferably a carboxyl group protected with an alkyl group that has been substituted with a 4-morpholinyl group. In the compounds of this invention, R3 is preferably a halogen atom, a lower alkyl group, or an optionally protected hydroxyl group, more preferably an optionally protected hydroxyl group, and much more preferably a hydroxyl group. In the compounds of this invention, R4 is preferably an optionally substituted cycloalkyloxy group, more preferably a cycloalkyloxy group optionally substituted with an alkyl, alkoxy or optionally protected hydroxyl group, and much more preferably a cycloalkyloxy group. In the compounds of this invention, R5 is preferably a hydrogen atom. In the compounds of this invention, Z is preferably an alkylene group optionally substituted with a lower alkyl group, more preferably an alkylene group, and much more preferably a methylene group. When the substituent of R2 is a carboxyl group, any one of commonly used carboxyl-protecting groups can be used as a carboxyl-protecting group. Examples of such carboxyl-protecting groups are the above described carboxyl-protecting groups. Specifically, the carboxyl-protecting groups include, for example, alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl groups; alkoxycarbonyloxyalkyl groups such as 1- [(methoxycarbonyl)oxy]ethyl, 1- [ (ethoxycarbonyl)oxy]ethyl and 1- [ (isopropoxycarbonyl)oxy]ethyl groups; cycloalkyloxycarbonyloxyalkyl groups such as 1- {[(cyclopentyloxy)carbonyl]oxy}ethyl and 1- {[(cyclohexyloxy)carbonyl]oxy}ethyl groups; heterocyclic-alkyl groups such as 2-(4- morpholinyl)ethyl, (5-methyl-2-oxo-l,3-dioxol-4- yl)methyl and (5-phenyl-2-oxo-1,3-dioxol-4-yl)methyl groups; and acyloxyalkyl groups such as acetoxymethyl, propionyloxymethyl and pivaloyloxymethyl groups. Of the above carboxyl-protecting groups, are preferably used alkyl groups such as methyl and ethyl groups; alkoxycarbonyloxyalkyl groups such as 1- [(ethoxycarbonyl)oxy]ethyl group; cycloalkyloxycarbonyloxyalkyl groups such as 1- {[(cyclohexyloxy)carbonyl]oxyjethyl group; heterocyclic-alkyl groups such as 2-(4- morpholinyl)ethyl and (5-methyl-2-oxo-l,3-dioxol-4- yl)methyl groups; and acyloxyalkyl groups such as pivaloyloxymethyl group, and 2-(4-morpholinyl)ethyl group is more preferably used. In the compounds of this invention, a preferable combination of substituents is such that R1 is an optionally substituted heterocyclyl group, R2 is a carboxyl group optionally protected with an optionally substituted alkyl group, R3 is an optionally protected hydroxyl group, R4 is a cycloalkyloxy group optionally substituted with an alkyl, alkoxy or optionally protected hydroxyl group, R5 is a hydrogen atom, and Z is an alkylene group. A more preferable combination of substituents is such that R1 is an optionally substituted benzisoxazolyl group, R2 is a carboxyl group protected with an optionally substituted alkyl group, R3 is a hydroxyl group, R4 is a cycloalkyloxy group, R5 is a hydrogen atom, and Z is an alkylene group. Another more preferable combination of substituents is such that R1 is an optionally substituted benzisoxazolyl group, R2 is a carboxyl group, R3 is a hydroxyl group, R4 is a cycloalkyloxy group, R5 is a hydrogen atom, and Z is an alkylene group. Diseases in which AP-1-related genes are involved include, for example, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Behcet's disease, rheumatic fever, polymyositis, periarteritis nodosa, Sjogren's syndrome, active chronic hepatitis and glomerulonephritis; a variety of intractable diseases based on inflammation such as osteoarthritis, gout, atherosclerosis, psoriasis, atopic dermatitis and encephalitis; pulmonary diseases accompanied by granuloma such as interstitial pneumonia; endotoxin shock; sepsis; inflammatory colitis; diabetes mellitus; acute myeloblast leukemia; meningitis; hepatitis; hepatic disorder; jaundice; liver cirrhosis; liver failure; atrialmyxoma; Castleman's syndrome; multiple myeloma; cancer; metastasis of cancer; AIDS; epilepsy; ischemic heart disease; endothelial proliferative disease (arteriosclerosis); Alzheimer's disease and ischemic neuronal death; allograft rejection in transplantation. The compounds of this invention are particularly suitably used for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Behcet's disease, rheumatic fever, polymyositis, periarteritis nodosa, Sjogren's syndrome, active chronic hepatitis and glomerulonephritis and more suitably used for rheumatoid arthritis. Representative compounds of this invention include, for example, compounds shown in Table 1 to Table 11 below. In the tables abbreviations represent the following meanings. BTP: benzothiophene, TZ: tetrazole, ODN: oxadiazolone, TDN: thiadiazolone, BOZ: benzisoxazole, BTZ: benzisothiazole, QN: quinazolidione, IOZ: isoxazolole, ITZ: isothiazolole, PZ: pyrazolole, c- Pent: cyclopentyl, Ms: methanesulfonyl, Ts: toluenesulfonyl, Ac: acetyl, Py: pyridyl, Me: methyl, Et: ethyl, Pr: propyl, Bu: butyl, Ph: phenyl, Bn: benzyl, Moe: 2-(4-morpholinyl)ethyl, Eoe: 1- [(ethoxycarbonyl)oxy]ethyl, Hoe: 1- {[(cyclohexyloxy)carbonyl]oxy}ethyl, Pvm: (pivaloyloxy)methyl, Dom: (5-methyl-2-oxo-l,3-dioxol-4- yl)methyl, i: iso When isomers (e.g. optical isomers, geometrical isomers and tautomers) are present in compounds represented by the general formula [1] or the salts thereof, this invention embraces the isomers. This invention also embraces the solvates, the hydrates and the crystals in various forms of the compound or the salt thereof. Then the process of producing the compounds of this invention will be described. The compounds of this invention are produced by combining known processes; for example, they can be synthesized in accordance with the production processes A to Q shown below. wherein R2a and R2aa each represent a carboxyl-protecting group; Rla represents a group represented by R1 - Z (wherein R1 and Z represent the same meanings as above); R4a and R4aa each represent optionally substituted alkyl, cycloalkyl, heterocyclic, optionally substituted phenyl, or heterocyclyl-substituted alkyl; R5 represents the same meaning as above; and X represents a leaving group. A compound represented by the general formula [3] can be obtained by dehydrating a compound represented by the general formula [4]. This dehydration reaction is an ordinary dehydration reaction, and the reaction processes include, for example, processes in which dehydration is carried out in the presence or absence of acid or dehydrating agent, in which dehydration is carried out using base, condensing agent and additive, in which dehydration is carried out via acid chloride, and in which dehydration is carried out via acid anhydride. Acids used in this reaction as the need arises include, for example, mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid; organic acids such as p- toluenesulfonic acid and trifluoroacetic acid; and tin tetrachloride, aluminium chloride and boron trifluoride. The amount of acid used can be 0.01- to 100-fold of the mole of a compound represented by the general formula [4] and preferably 0.01- to 50-fold of the mole of the same. Dehydrating agents used in this reaction as the need arises include, for example, phosphorus pentoxide and polyphosphoric acid. The amount of dehydrating agent used can be 1- to 1000-fold of the mole of a compound represented by the general formula [4] and preferably 1- to 100-fold of the mole of the same. When using base, condensing agent and additive in this reaction, bases used in the reaction include, for example, organic amines such as dimethylaminopyridine, triethylamine, pyridine and N- methylmorpholine; and alkaline metal carbonates such as potassium carbonate and sodium carbonate. The amount of base used can be 0.5- to 10-fold of the mole of a compound represented by the general formula [4] and preferably 1- to 3-fold of the mole of the same. Condensing agents used in the reaction include, for example, N,N'-dicyclohexylcarbodiimide, 1,1'- carbonyldiimidazole, 2-chloro-1-methylpyridinium iodide, 2,2'-dipyridyl disulfide and diphenylphosphoryl azide. The amount of condensing agent used can be 0.5- to 10- fold of the mole of a compound represented by the general formula [4] and preferably 1- to 3-fold of the mole of the same. Additives used in the reaction include, for example, 1-hydroxybenzotriazole, N- hydroxysuccinimide and triphenylphosphine. The amount of additive used can be 0.5- to 10-fold of the mole of a compound represented by the general formula [4] and preferably 1- to 3-fold of the mole of the same. When using the processes via acid chloride or acid anhydride, the acid chloride or the acid anhydride of a compound represented by the general formula [4] can be obtained by reacting the compound represented by the general formula [4] with activating agent such as thionyl chloride, oxalyl chloride, phosphorus pentachloride, acetic anhydride or ethyl chloroformate. The amount of activating agent used can be 1- to 20- fold of the mole of a compound represented by the general formula [4] and preferably 1- to 5-fold of the mole of the same. In the reaction for obtaining the acid chloride of a compound represented by the general formula [4], N,N-dimethylformamide, as a catalyst, may be added in amounts of 0.001- to 10-fold of the mole of the compound represented by the general formula [4] and preferably 0.01- to 1-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene and toluene; ethers such as 1,4-dioxane, tetrahydrofuran and diethyl ether; esters such as ethyl acetate and butyl acetate; nitriles such as acetonitrile; amides such as N,N-dimethylformamide and N,N'- dimethylacetamide; halogenated hydrocarbons such as chloroform and methylene chloride; sulfones such as sulfolane; and sulfoxides such as dimethyl sulfoxide. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at - 78°C to the reflux temperature of the solvent used and preferably 0 to 150 °C for 30 minutes to 24 hours. The reaction can also be performed in an atmosphere of inert gas (e.g. argon, nitrogen). The reaction for obtaining a compound represented by the general formula [3] from a compound represented by the general formula [2] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [3] from a compound represented by the general formula [4] in the production process A. Preferably the reaction is carried out in the presence or absence of acid. A compound represented by the general formula [5] can be obtained by subjecting a compound represented by the general formula [3] and a compound represented by the general formula [R1a] to Mitsunobu reaction. This reaction can be carried out using an azodicarbonyl compound such as diethyl azodicarboxylate, diisopropyl azodicarboxylate or azodicarbonyldipiperidine; and triarylphosphine such as triphenylphosphine or trialkylphosphine such as tri-n- butylphosphine. The amount of the compound represented by the general formula [Rla] used can be 1- to 5-fold of the mole of the compound represented by the general formula [3] and preferably 1- to 3-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile; amides such as N,N-dimethylformamide and N,N'-dimethylacetamide; and halogenated hydrocarbons such as chloroform and methylene chloride. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at - 20 to 120°C and preferably 0 to 50 °C for 30 minutes to 24 hours. A compound represented by the general formula [5] can be obtained by reacting a compound represented by the general formula [3] and a compound represented by the general formula [R1b] in the presence of base. The amount of the compound represented by the general formula [R1b] used can be 1- to 20-fold of the mole of the compound represented by the general formula [3] and preferably 1- to 5-fold of the mole of the same. Bases used in this reaction include, for example, organic amines such as dimethylaminopyridine, triethylamine and pyridine; alkaline metal hydrides such as sodium hydride; and alkaline metal carbonates such as potassium carbonate and sodium carbonate. The amount of base used can be 1- to 20-fold of the mole of the compound represented by the general formula [3] and preferably 1- to 5-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile; amides such as N,N-dimethylformamide; halogenated hydrocarbons such as chloroform and methylene chloride; and sulfoxides such as dimethyl sulfoxide. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at 0 to 200°C and preferably 25 to 150 °C for 10 minutes to 24 hours. A compound represented by the general formula [6] can be obtained by reacting a compound represented by the general formula [R1c] and a compound represented by the general formula [5] in the presence of acid or base. The compound represented by the general formula [Rlc] used in this reaction can be used as a solvent in appropriate amount; however, when using some other solvent, the amount of the compound used can be 1- to 20-fold of the mole of the compound represented by the general formula [5] and preferably 1- to 5-fold of the mole of the same. Acids used in this reaction include, for example, hydrochloric acid, sulfuric acid, trimethylsilyl chloride and boron trifluoride. The amount of acid used can be 1- to 20-fold of the mole of the compound represented by the general formula [5] and preferably 1- to 5-fold of the mole of the same. Bases used in this reaction include, for example, alkaline metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; organic amines such as dimethylaminopyridine, triethylamine and pyridine; alkaline metal hydrides such as sodium hydride; and alkaline metal carbonates such as potassium carbonate and sodium carbonate. The amount of base used can be 1- to 20-fold of the mole of the compound represented by the general formula [5] and preferably 1- to 5-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; nitriles such as acetonitrile; amides such as N,N-dimethylformamide; halogenated hydrocarbons such as chloroform and methylene chloride; and sulfoxides such as dimethyl sulfoxide. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at -20 to 200°C and preferably -10 to 150°C for 10 minutes to 24 hours. The reaction for obtaining a compound represented by the general formula [la-1] from a compound represented by the general formula [6] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [5] from a compound represented by the general formula [3] in the production process A. A compound represented by the general formula [1a-2] can be obtained by subjecting a compound represented by the general formula [la-1] to deprotection reaction such as hydrolysis reaction in the presence of acid or base, dealkylation reaction using salt, or reductive dealkylation reaction including metal catalyst hydrogen addition reaction. Acids used in this reaction include, for example, formic acid, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, aluminium chloride and trimethylsilyl iodide. The amount of acid used can be 1- to 1000-fold of the mole of the compound represented by the general formula [la-1] and preferably 1- to 100-fold of the mole of the same. Bases used in this reaction include, for example, alkali hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; alkaline metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkaline metal carbonates such as potassium carbonate and sodium carbonate; and tetrabutylarnmonium fluoride. The amount of base used can be 1- to 1000-fold of the mole of the compound represented by the general formula [1a-1] and preferably 1- to 50-fold of the mole of the same. Salts used in this reaction include, for example, lithium iodide and sodium chloride. The amount of salt used can be 1- to 100-fold of the mole of the compound represented by the general formula [la-1] and preferably 1- to 10-fold of the mole of the same. Catalysts used in the reductive dealkylation reaction include, for example, palladium-carbon, palladium-black and palladium hydroxide. The amount of catalyst used can be 0.1- to 100% (w/w) the weight of the compound represented by the general formula [la-1] and preferably 1- to 50% (w/w) the weight of the same. Reducing agents used in this reaction include, for example, hydrogen, formic acid, cyclohexene and zinc. The amount of reducing agent used can be 1- to 100-fold of the mole of the compound represented by the general formula [la-1] and preferably 1- to 10-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, alcohols such as methanol, ethanol and isopropyl alcohol; ethers such as tetrahydrofuran, diethyl ether, 1,4-dioxane and anisole; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; nitriles such as acetonitrile; aliphatic hydrocarbons such as n-hexane and cyclohexane; esters such as ethyl acetate; aromatic hydrocarbons such as toluene, benzene and xylene; dimethyl sulfoxide, N,N-dimethylformamide, nitromethane, pyridine and water. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at -78 to 100°C and preferably 0 to 80°C for 10 minutes to 24 hours. When the substituent R1a, R43 or R5 has a protecting group, the reaction can be carried out while appropriately deprotecting the substituent by conventional procedure. A compound represented by the general formula [7] can be obtained by subjecting a compound represented by the general formula [1a-1] to reaction in the presence of acid, base or salt. Acids used in this reaction include, for example, mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid; organic acids such as trifluoroacetic acid; trimethylsilyl iodide, aluminium chloride, boron tribromide; and zinc chloride. These may be used in combination with each other. Bases used in this reaction include, for example, ethylmercaptan-sodium salt and lithium diisopropylamide. Salts used in this reaction include, for example, sodium cyanide, lithium iodide and pyridine hydrochloride. The amounts of acid, base and salt used each can be 1- to 100-fold of the mole of the compound represented by the general formula [1a-1] and preferably 2- to 50-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile; alcohols such as methanol, ethanol and isopropyl alcohol; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and halogenated hydrocarbons such as chloroform and methylene chloride; and sulfoxides such as dimethyl sulfoxide. When using a mineral acid, water may also be used. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at - 78°C to 150°C and preferably 20 to 110°C for 1 to 48 hours. The reaction for obtaining a compound represented by the general formula [1a-3] from a compound represented by the general formula [7] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [5] from a compound represented by the general formula [3] in the production process A. The reaction for obtaining a compound represented by the general formula [1a-4] from a compound represented by the general formula [1a-3] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1a-2] from a compound represented by the general formula [1a-1] in the production process A. When the substituent R5, R1a or R4aa has a protecting group, the reaction can be carried out while appropriately deprotecting the substituent by conventional procedure. wherein R2D represents a carboxyl-protecting group; R1b represents the same meaning as Rla; R2bb, R3b and R4b each represent the same meaning as R4t!; and R5 and X represent the same meaning as above. A compound represented by the general formula [8] can be obtained by subjecting the acid chloride or acid anhydride of a compound represented by the general formula [8A] and a compound represented by the general formula [8B] to Friedel-Crafts reaction in the presence of acid. The acid chloride or acid anhydride of a compound represented by the general formula [8A] used in the reaction can be obtained by allowing the compound represented by the general formula [8A] to react with activating agent such as thionyl chloride, oxalyl chloride, phosphorus pentachloride, acetic anhydride and ethyl chloroformate. The amount of activating agent used can be 1- to 10-fold of the mole of the compound represented by the general formula [8A] and preferably 1- to 3-fold of the mole of the same. In the reaction for obtaining the acid chloride of a compound represented by the general formula [8A], N,N- dimethylformamide as a catalyst may be added in amounts of 0.001- to 1-fold of the mole of the compound represented by the general formula [8A] and preferably 0.001- to 0.5-fold of the mole of the same. Acids used in this reaction include, for example, tin tetrachloride, aluminium chloride, boron trifluoride and zinc chloride. The amount of acid used can be 1- to 10-fold of the mole of a compound represented by the general formula [8A] and preferably 1- to 5-fold of the mole of the same. The amount of a compound represented by the general formula [8B] used can be 1 to 10-fold of the mole of a compound represented by the general formula [8A] and preferably 1- to 2-fold of the mole of the same. Solvents used in this reaction include, for example, halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane and carbon tetrachloride; aliphatic hydrocarbons such as n-hexane and cyclohexane; nitromethane and nitrobenzene; and carbon disulfide. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at - 78°C to 100°C and preferably -50°C to 30°C for 10 minutes to 24 hours. A compound represented by the general formula [9] can be obtained by subjecting a compound represented by the general formula [8] to reaction in the presence of acid, base or salt. Acids used in this reaction include, for example, mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid; organic acids such as trifluoroacetic acid; trimethylsilyl iodide, aluminium chloride, boron tribromide; and zinc chloride. These may be used in combination with each other. Bases used in this reaction include, for example, ethylmercaptan-sodium salt and lithium diisopropylamide. Salts used in this reaction include, for example, sodium cyanide, lithium iodide and pyridine hydrochloride. The amounts of acid, base and salt used each can be 2- to 100-fold of the mole of the compound represented by the general formula [8] and preferably 2- to 50-fold of the mole of the same. In this reaction, additives such as 2'-hydroxyacetophenone, anisole and ethyl acetate may be used. The amount of additive used can be 1- to 10-fold of the mole of the compound represented by the general formula [8] and preferably 1- to 5-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile; alcohols such as methanol, ethanol and isopropyl alcohol; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and halogenated hydrocarbons such as chloroform and methylene chloride; and sulfoxides such as dimethyl sulfoxide. When using a mineral acid, water may also be used. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at - 78°C to 150°C and preferably 20 to 110°C for 1 to 48 hours. A compound represented by the general formula [9] can also be obtained not by isolating a compound represented by the general formula [8] from a compound represented by the general formula [8A], but by carrying out the reactions continuously. The reaction for obtaining a compound represented by the general formula [1b-1] from a compound represented by the general formula [9] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [5] from a compound represented by the general formula [3] in the production process A. The reaction for obtaining a compound represented by the general formula [1b-2] from a compound represented by the general formula [1b-1] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1a-2] from a compound represented by the general formula [1a-1] in the production process A. When the substituent Rlb or R4b has a protecting group, the reaction can be carried out while appropriately deprotecting the substituent by conventional procedure. wherein R2c represents a carboxyl-protecting group; Rlc represents the same meaning as Rla; R3c, R4c and R4cc each represent the same meaning as R4a; and R5 and X represent the same meaning as above. The reaction for obtaining a compound represented by the general formula [10] from a compound represented by the general formula [10A] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [8] from a compound represented by the general formula [8A] in the production process B. A compound represented by the general formula [11] can also be obtained not by isolating a compound represented by the general formula [10] from a compound represented by the general formula [10A], but by carrying out the reactions continuously. The reaction for obtaining a compound represented by the general formula [11] from a compound represented by the general formula [10] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [9] from a compound represented by the general formula [8] in the production process B. The reaction for obtaining a compound represented by the general formula [1c-1] from a compound represented by the general formula [11] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [5] from a compound represented by the general formula [3] in the production process A. The reaction for obtaining a compound represented by the general formula [1c-2] from a compound represented by the general formula [1c-1] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1a-2] from a compound represented by the general formula [1a-1] in the production process A. When the substituent Rlc or R4c has a protecting group, the reaction can be carried out while appropriately deprotecting the substituent by conventional procedure. wherein R2d represents a carboxyl-protecting group; Rld, R3d and R4d each represent the same meaning as R4a; and X represents the same meaning as above. The reaction for obtaining a compound represented by the general formula [12d] from a compound represented by the formula [12] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [6] from a compound represented by the general formula [5] in the production process A. The reaction for obtaining a compound represented by the general formula [13] from a compound represented by the general formula [12d] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [5] from a compound represented by the general formula [3] in the production process A. A compound represented by the general formula [13] can be obtained from a compound represented by the formula [12] via a compound represented by the general formula [12d] by carrying out the reactions continuously. A compound represented by the general formula [15] can be obtained by subjecting the acid chloride or acid anhydride of a compound represented by the general formula [14] and a compound represented by the general formula [13] to Friedel-Crafts reaction in the presence of acid. The acid chloride or the acid anhydride of a compound represented by the general formula [14] can be obtained by reacting the compound represented by the general formula [14] with activating agent such as thionyl chloride, oxalyl chloride, phosphorus pentachloride, acetic anhydride or ethyl chloroformate. The amount of activating agent used can be 1- to 10- fold of the mole of a compound represented by the general formula [14] and preferably 1- to 3-fold of the mole of the same. In the reaction for obtaining the acid chloride of a compound represented by the general formula [14], N,N-dimethylformamide, as a catalyst, may be added in amounts of 0.001- to 1-fold of the mole of the compound and preferably 0.001- to 0.5-fold of the mole of the same. Acids used in this reaction include, for example, tin tetrachloride, aluminium chloride, boron trifluoride and zinc chloride. The amount of acid used can be 1- to 10-fold of the mole of a compound represented by the general formula [14] and preferably 1- to 5-fold of the mole of the same. The amount of a compound represented by the general formula [13] used can be 1- to 10-fold of the mole of a compound represented by the general formula [14] and preferably 1- to 2-fold of the mole of the same. Solvents used in this reaction include, for example, halogenated hydrocarbons such as methylene chloride, chloroform 1,2-dichlorohexane and carbon tetrachloride; aliphatic hydrocarbons such as n-hexane and cyclohexane; nitromethane, nitrobenzene; and carbon disulfide. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at - 78°C to 100°C and preferably -50°C to 30°C for 10 minutes to 24 hours. A compound represented by the general formula [16] can be obtained by subjecting a compound represented by the general formula [15] to reaction in the presence of acid, base or salt. Acids used in this reaction include, for example, mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid; organic acids such as trifluoroacetic acid and thiophenol; trimethylsilyl iodide, aluminium chloride, boron tribromide; and zinc chloride. Bases used in this reaction include, for example, ethylmercaptan-sodium salt and lithium diisopropylamide. Salts used in this reaction include, for example, sodium cyanide, lithium iodide and pyridine hydrochloride. The amounts of acid, base and salt used each can be 3- to 100-fold of the mole of the compound represented by the general formula [15] and preferably 3- to 50-fold of the mole of the same. In this reaction, additives such as 2'-hydroxyacetophenone, anisole and ethyl acetate may be used. The amount of additive used can be 1- to 10-fold of the mole of the compound represented by the general formula [14] and preferably 1- to 5-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile; alcohols such as methanol, ethanol and isopropyl alcohol; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and halogenated hydrocarbons such as chloroform and methylene chloride; and sulfoxides such as dimethyl sulfoxide. When using a mineral acid, water may also be used. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at - 78°C to 150°C and preferably 20 to 110°C for 10 minutes to 48 hours. A compound represented by the general formula [16] can also be obtained from a compound represented by the general formula [14] via a compound represented by the general formula [15] by carrying out the reactions continuously. wherein R2e represents a carboxyl-protecting group; Rle, R3e and R4e each represent the same meaning as R4a, and R5 represents the same meaning as above. A compound represented by the general formula [18] can be obtained by reacting a compound represented by the general formula [17] with a formylating agent in the presence of acid. Acids used in this reaction include, for example, titanium tetrachloride, tin tetrachloride, aluminium chloride and phosphorus oxychloride. The amount of acid used can be 1- to 10-fold of the mole of the compound represented by the general formula [17] and preferably 1- to 3-fold of the mole of the same. Formylating agents used in this reaction include, for example, α,α-dichloromethyl methyl ether, N,N- dimethylformamide and ethyl orthoformate. The amount of formylating agent used can be 1- to 10-fold of the mole of the compound represented by the general formula [17] and preferably 1- to 5-fold of the mole of the same. Solvents used in this reaction include, for example, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; and aliphatic hydrocarbons such as n-hexane and cyclohexane. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at - 78°C to 150°C and preferably -50°C to 100°C for 30 minutes to 24 hours. A compound represented by the general formula [20] can be obtained by reacting a compound represented by the general formula [18] with an oxidizing agent in the presence or absence of acid or base. Acids used in this reaction as the need arises include, for example, sodium dihydrogenphosphate, hydrochloric acid, sulfuric acid, acetic acid and sulfamic acid. The amount of acid used can be 1- to 1000-fold of the mole of a compound represented by the general formula [18] and preferably 1- to 100-fold of the mole of the same. Bases used in this reaction as the need arises include, for example, alkali hydroxides such as sodium hydroxide and potassium hydroxide; and pyridine. The amount of base used can be 1- to 1000- fold of the mole of a compound represented by the general formula [18] and preferably 1- to 100-fold of the mole of the same. Oxidizing agents used in this reaction include, for example, sodium chlorite, sodium hypochlorite, chromic acid, potassium permanganate, hydrogen peroxide, ruthenium oxide, nickel oxide, silver oxide and silver nitrate. The amount of oxidizing agent used can be 1- to 10-fold of the mole of a compound represented by the general formula [18] and preferably 1- to 5-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, ethers such as tetrahydrofuran, diethyl ether and 1,4-dioxane; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; nitriles such as acetonitrile; aliphatic hydrocarbons such as n-hexane and cyclohexane; aromatic hydrocarbons such as toluene and benzene; dimethyl sulfoxide, pyridine; and water. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at 0°C to 100°C and preferably 0°C to 50°C for 10 minutes to 24 hours. A compound represented by the general formula [20] can also be obtained by reacting a compound represented by the general formula [19] with an oxidizing agent in the presence or absence of acid or base. Acids used in this reaction as the need arises include, for example, sulfuric acid and acetic acid. The amount of acid used can be 1- to 1000-fold of the mole of a compound represented by the general formula [19] and preferably 1- to 100-fold of the mole of the same. Bases used in this reaction as the need arises include, for example, alkali hydroxides such as sodium hydroxide and potassium hydroxide; and pyridine. The amount of base used can be 1- to 1000-fold of the mole of a compound represented by the general formula [19] and preferably 1- to 100-fold of the mole of the same. Oxidizing agents used in this reaction include, for example, chromic acid and potassium permanganate. The amount of oxidizing agent used can be 1- to 50-fold of the mole of a compound represented by the general formula [19] and preferably 1- to 10-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; aliphatic hydrocarbons such as n-hexane and cyclohexane; pyridine; and water. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at 0°C to 150°C and preferably 20°C to 100°C for 30 minutes to 24 hours. The reaction for obtaining a compound represented by the general formula [22] from a compound represented by the general formula [20] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [15] from a compound represented by the general formula [14] in the production process D. The reaction for obtaining a compound represented by the general formula [23] from a compound represented by the general formula [22] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [16] from a compound represented by the general formula [15] in the production process D. A compound represented by the general formula [23] can be obtained from a compound represented by the general formula [20] via a compound represented by the general formula [22] by carrying out the reactions wherein R2f represents a carboxyl-protecting group; Rlf represents the same meaning as Rla; Rlff and RJf each represent the same meaning as R4a; and R4 and X represent the same meaning as above. The reaction for obtaining a compound represented by the general formula [12f] from a compound represented by the formula [12] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [12d] from a compound represented by the formula [12] in the production process D. The reaction for obtaining a compound represented by the general formula [24] from a compound represented by the general formula [12f] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [13] from a compound represented by the general formula [12d] in the production process D. A compound represented by the general formula [24] can be obtained from a compound represented by the formula [12] via a compound represented by the general formula [12f] by carrying out the reaction for obtaining the compound represented by the general formula [12f] and the reaction of alkylating the same continuously. The reaction for obtaining a compound represented by the general formula [26] from a compound represented by the general formula [25] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [15] from a compound represented by the general formula [14] in the production process D. The reaction for obtaining a compound represented by the general formula [27] from a compound represented by the general formula [26] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [9] from a compound represented by the general formula [8] in the production process B. A compound represented by the general formula [27] can also be obtained not by isolating a compound represented by the general formula [26] from a compound represented by the general formula [25], but by carrying out the reactions continuously. The reaction for obtaining a compound represented by the general formula [1f-1] from a compound represented by the general formula [27] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [5] from a compound represented by the general formula [3] in the production process A. The reaction for obtaining a compound represented by the general formula [1f-2] from a compound represented by the general formula [1f-1] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1a-2] from a compound represented by the general formula [1a-1] in the production process A. When the substituent Rlf or R"1 has a protecting group, the reaction can be carried out while appropriately deprotecting the substituent by conventional procedure. wherein R2g represents a carboxyl-protecting group; R1g represnts the same meaning as Rla; R4g represents the same meaning as R4a; R5 and X represent the same meaning as above; and R4gg represents a phenol-protecting group. A compound represented by the general formula [28] can be obtained by, for example, the process described in Greene et al., Protective Groups in Organic Synthesis, 3rd edition, 1999, 249-280. Specifically, when R4gg is a tetrahydropyranyl group, for example, a compound represented by the general formula [28] can be obtained by reacting a compound represented by the general formula [3] with 3,4-dihydro-2H-pyran in the presence of catalyst. The amount of 3,4-dihydro-2H-pyran used can be 1- to 20- fold of the mole of a compound represented by the general formula [3] and preferably 1- to 5-fold of the mole of the same. Catalysts used in this reaction include, for example, acids such as dry hydrogen chloride and p-toluenesulfonic acid; and salts such as pyridinium p-toluenesulfonate. The amount of catalyst used can be 0.01- to 10-fold of the mole of a compound represented by the general formula [3] and preferably 0.05- to 3-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4- dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and halogenated hydrocarbons such as chloroform and methylene chloride. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at 0°C to 100°C and preferably 0°C to 50°C for 10 minutes to 24 hours. The reaction for obtaining a compound represented by the general formula [29] from a compound represented by the general formula [28] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [6] from a compound represented by the general formula [5] in the production process A. The reaction for obtaining a compound represented by the general formula [30] from a compound represented by the general formula [29] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1a-1] from a compound represented by the general formula [6] in the production process A. A compound represented by the general formula [31] can be obtained from a compound represented by the general formula [30] by ordinary deprotection. Specifically, when R4" of a compound represented by the general formula [30] is tetrahydropyran, for example, a compound represented by the general formula [31] can be obtained by carrying out the reaction in the presence of acid. Acids used in this reaction include, for example, mineral acids such as hydrochloric acid; and organic acids such as p- toluenesulfonic acid and oxalic acid. The amount of acid used can be 0.01- to 100-fold of the mole of a compound represented by the general formula [30] and preferably 0.05- to 10-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; alcohols such as methanol and ethanol; esters such as butyl acetate and ethyl acetate; nitriles such as acetonitrile; amides such as N,N- dimethylformamide and N,N-dimethylacetamide; halogenated hydrocarbons such as chloroform and methylene chloride; and water. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at 0°C to the reflux temperature of the solvent used and preferably 5 to 100°C for 10 minutes to 24 hours. The reaction for obtaining a compound represented by the general formula [lg-1] from a compound represented by the general formula [31] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [5] from a compound represented by the general formula [3] in the production process A. The reaction for obtaining a compound represented by the general formula [1g-2] from a compound represented by the general formula [1g-1] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1a-2] from a compound represented by the general formula [1a-1] in the production process A. wherein R4h represents the same meaning as R4a; R2h, R2hh and R11 each represent a carboxyl-protecting group; R12, R13, R14 and R15 each represent hydrogen, optionally substituted alkyl or an amino-protecting group; and X represent the same meaning as above. The reaction for obtaining a compound represented by the general formula [1h-1] from a compound represented by the general formula [32] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [5] from a compound represented by the general formula [3] in the production process A. The reaction for obtaining a compound represented by the general formula [1h-2] from a compound represented by the general formula [1h-1] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1a-2] from a compound represented by the general formula [1a-1] in the production process A. When the substituent R4h or R11 has a protecting group, the reaction can be carried out while appropriately deprotecting the substituent by conventional procedure. The reaction for obtaining a compound represented by the general formula [1h-3] from a compound represented by the general formula [1h-1] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1a-2] from a compound represented by the general formula [1a-1] in the production process A. A compound represented by the general formula [1h-4] can be obtained by esterifying a compound represented by the general formula [1h-3]. In this reaction, common esterification methods can be used. Processes of esterification include: for example, processes in which an acid catalyst-additive combination is used, in which esterification is carried out via acid chloride, in which esterification is carried out via acid anhydride, in which a compound represented by the general formula [R8g] is used with a base and in which a condensing agent-additive combination is used. For example, in the process in which an acid catalyst-additive combination is used, acid catalysts used include, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trimethylsilyl chloride, aluminium chloride, boron trifluoride and trifluoroacetic acid. The amount of catalyst used can be 0.01- to 100-fold of the mole of a compound represented by the general formula [1h-3] and preferably 0.5- to 50-fold of the mole of the same. Additives used include, for example, 2,2- dimethoxypropane and ethyl orthoformate. The amount of the additive used can be 0.1- to 100-fold of the mole of a compound represented by the general formula [1h-3] and preferably 1- to 50-fold of the mole of the same. A compound represented by the general formula [R8c] can be used as a solvent in an appropriate amount; however, when some other solvent is used, the amount of the compound used can be 1- to 100-fold of the mole of a compound represented by the general formula [1h-3] and preferably 1- to 50-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile; amides such as N,N-dimethylformamide; halogenated hydrocarbons such as chloroform and methylene chloride; and sulfoxides such as dimethyl sulfoxide. Usually this reaction can be performed at 0 to 200°C and preferably 5 to 100°C for 10 minutes to 24 hours. In the process in which a base and a compound represented by the general formula [R8g] are used, bases used in this reaction include, for example, organic amines such as dimethylaminopyridine, triethylamine, pyridine and N-methylmorpholine; and alkaline metal carbonates such as potassium carbonate and sodium carbonate. The amount of base used can be 0.5- to 10-fold of the mole of a compound represented by the general formula [1h-3] and preferably 1- to 3- fold of the mole of the same. Compounds represented by the general formula [R8g] used in this reaction include, for example, methyl iodide, ethyl iodide and benzyl bromide. The amount of the compound used can be 0.5- to 10-fold of the mole of a compound represented by the general formula [1h-3] and preferably 1- to 3-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile; amides such as N,N-dimethylformamide; halogenated hydrocarbons such as chloroform and methylene chloride; and sulfoxides such as dimethyl sulfoxide. Usually this reaction can be performed at 0 to 200°C and preferably 5 to 100°C for 10 minutes to 24 hours. In the process in which a condensing agent and an additive are used, a compound represented by the general formula [1h-4] can be obtained by subjecting a compound represented by the general formula [R8c] together with the condensing agent and the additive to condensation reaction. Condensing agents used in this reaction include, for example, 1,1'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-ethyl-N'-3-dimethylaminopropylcarbodiimide and diphenylphosphoryl azide. Additives used in this reaction include, for example, 1-hydroxybenzotriazole and N-hydroxysuccinimide. The amounts of the alcohol, the condensing agent and the additive used in this reaction each can be 0.5- to 10-fold of the mole of a compound represented by the general formula [1h-3] and preferably 1- to 3-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile; amides such as N,N-dimethylformamide; halogenated hydrocarbons such as chloroform and methylene chloride; and sulfoxides such as dimethyl sulfoxide. Usually this reaction can be performed at 0 to 200°C and preferably 5 to 100°C for 10 minutes to 24 hours. A compound represented by the general formula [1h-5] can be obtained by subjecting a compound represented by the general formula [1h-4] together with a compound represented by the general formula [R8d] to amidation. This amidation is commonly used amidation. And processes of amidation include: for example, processes in which amidation is carried out via acid chloride, in which amidation is carried out via acid anhydride, and in which base, condensing agent and additive are used. For example, in the process in which a base, a condensing agent and an additive are used, amines represented by the general formula [R8d] used in this reaction include, for example, ammonia and hydroxylamine; primary amines such as methyl amine, benzyl amine, aniline, phenethylamine, isopropylamine and aminothiazole; and secondary amines such as dimethyl amine, diethyl amine and di-n-propylamine and sulfonamides include, for example, methanesulfonamide. The amount of amine used can be 0.5- to 10-fold of the mole of a compound represented by the general formula [1h-4] and preferably 1- to 3-fold of the mole of the same. Bases used in this reaction include, for example, organic amines such as dimethylaminopyridine, triethylamine, pyridine, N-methylmorpholine and 1,8- diazabicyclo[5.4.0]undec-7-ene; and alkaline metal carbonates such as potassium carbonate and sodium carbonate. The amount of base used can be 0.5- to 10- fold of the mole of a compound represented by the general formula [1h-4] and preferably 1- to 5-fold of the mole of the same. Condensing agents used in this reaction include, for example, N,N'- dicyclohexylcarbodiimide, diisopropylcarbodiimide, N- ethyl-N'-3-dimethylaminopropylcarbodiimide and diphenylphosphoryl azide. The amount of the condensing agent used in this reaction can be 0.5- to 10-fold of the mole of a compound represented by the general formula [1h-4] and preferably 1- to 3-fold of the mole of the same. Additives used in this reaction include, for example, 1-hydroxybenzotriazole and N- hydroxysuccinimide. The amount of the additive used can be 0.5- to 10-fold of the mole of a compound represented by the general formula [1h-4] and preferably 1- to 3-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile; amides such as N,N-dimethylformamide; halogenated hydrocarbons such as chloroform and methylene chloride; and sulfoxides such as dimethyl sulfoxide. Usually this reaction can be performed at -20 to 150°C and preferably 0 to 120°C for 10 minutes to 24 hours. The reaction for obtaining a compound represented by the general formula [1h-6] from a compound represented by the general formula [1h-5] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1a-2] from a compound represented by the general formula [1a-1] in the production process A. When the substituent R12 or R13 is an amino-protecting group or the substituent R41' has a protecting group, the reaction can be carried out while appropriately deprotecting the substituent by conventional procedure. The reaction for obtaining a compound represented by the general formula [1h-7] from a compound represented by the general formula [32] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [5] from a compound represented by the general formula [3] in the production process A. The reaction for obtaining a compound represented by the general formula [1h-8] from a compound represented by the general formula [1h-7] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1a-2] from a compound represented by the general formula [1a-1] in the production process A. When the substituent R14 or R15 is an amino-protecting group or the substituent R4h has a protecting group, the reaction can be carried out while appropriately deprotecting the substituent by conventional procedure. wherein R11 represents the same meaning as Rla; and R41 represents the same meaning as R4a. A compound represented by the general formula [1i-2] can be obtained by reacting a compound represented by the general formula [1i-1] with a compound having the formula [R9] in accordance with the process described in Chemical and Pharmaceutical Bulletin, Vol. 34, 5188-5190, 1986. This reaction can be carried out, for example, by the process in which condensing agent and additive are used, in which the compound is obtained via acid chloride, or in which the compound is obtained via acid anhydride. For example, in the process in which condensing agent and additive are used, condensing agents used in this reaction include, for example, N,N'-dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-ethyl-N'-3-dimethylaminopropylcarbodiimide and diphenylphosphoryl azide. The amount of condensing agent used in this reaction can be 0.5- to 10-fold of the mole of a compound represented by the general formula [1i-1] and preferably 1- to 3-fold of the mole of the same. Additives used in this reaction include, for example, 1-hydroxybenzotriazole and N- hydroxysuccinimide. The amount of additive used can be 0.5- to 10-fold of the mole of a compound represented by the general formula [1i-1] and preferably 1- to 3- fold of the mole of the same. The amount of a compound represented by the formula [R9] used in this reaction can be 1- to 10-fold of the mole of a compound represented by the general formula [1i-1] and preferably 1- to 2-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile; amides such as N,N-dimethylformamide; halogenated hydrocarbons such as chloroform and methylene chloride; and sulfoxides such as dimethyl sulfoxide. Usually this reaction can be performed at -20 to 150°C and preferably 0 to 120°C for 10 minutes to 24 hours. In the process in which a compound represented by the general formula [1i-2] is obtained via acid chloride or via acid anhydride, the compound can be obtained by reacting the acid chloride or acid anhydride of a compound represented by the general formula [1i-1] with a compound represented by the formula [R9] in the presence of base. The acid chloride or acid anhydride of a compound represented by the general formula [1i-1] used in this reaction can be obtained by reacting the compound represented by the general formula [1i-1] with activating agent such as thionyl chloride, oxalyl chloride, phosphorus pentachloride, acetic anhydride or ethyl chloroformate. The amount of activating agent used can be 1- to 10- fold of the mole of a compound represented by the general formula [1i-1] and preferably 1- to 2-fold of the mole of the same. The amount of a compound represented by the formula [R9] used can be 1- to 20- fold of the mole of a compound represented by the general formula [1i-1] and preferably 1- to 5-fold of the mole of the same. Bases used in this reaction include, for example, organic amines such as dimethylaminopyridine, trimethylamine, pyridine and N- methylmorpholine; and alkaline metal carbonates such as potassium carbonate and sodium carbonate; organic lithiums such as n-butyllithium, methyllithium and lithium diisopropylamide; and organic magnesiums such as methylmagnesium bromide. The amount of base used can be 1- to 20-fold of the mole of a compound represented by the general formula [1i-1] and preferably 1- to 5-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform and methylene chloride; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; and aliphatic hydrocarbons such as hexane and cyclohexane. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at -78 to 150°C and preferably -78 to 120°C for 10 minutes to 24 hours. When the substituent R11 or R41 has a protecting group, the reaction can be carried out while appropriately deprotecting the substituent by conventional procedure. The reaction for obtaining a compound represented by the general formula [33] from a compound represented by the general formula [1i-1] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1h-5] from a compound represented by the general formula [1h-4] in the production process H. A compound represented by the general formula [34] can be obtained by dehydrating a compound represented by the general formula [33] in the presence or absence of dehydrating agent and bases. Dehydrating agents used in this reaction as the need arises include, for example, phosphorus pentoxide, phosphorus pentachloride, phosphoryl chloride and thionyl chloride. The amount of dehydrating agent used can be 1- to 50-fold of the mole of a compound represented by the general formula [33] and preferably 1- to 10-fold of the mole of the same. Salts used in this reaction as the need arises include, for example, sodium chloride. The amount of salt used can be 1- to 50-fold of the mole of a compound represented by the general formula [33] and preferably 1- to 5-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4- dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; aliphatic hydrocarbons such as hexane and cyclohexane; halogenated hydrocarbons such as chloroform and methylene chloride; esters such as methyl acetate and ethyl acetate; and amides such as N,N-dimethylformamide and N,N-dimethylacetamide. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at -20 to 300°C and preferably 0 to 220°C for 30 minutes to 24 hours. A compound represented by the general formula [1i-4] can be synthesized from a compound represented by the general formula [34] in accordance with the process described in Journal of Medicinal Chemistry, Vol. 39, 5228-5235, 1996. Specifically, amidoxime can be obtained by reacting a compound represented by the general formula [34] with hydroxylamine in the presence of base. The amount of hydroxylamine used can be 1- to 20-fold of the mole of a compound represented by the general formula [34] and preferably 1- to 10-fold of the mole of the same. Bases used in this reaction include, for example, organic amines such as dimethylaminopyridine, triethylamine, pyridine and N-methylmorpholine; metal alkoxides such as sodium methoxide; and alkaline metal carbonates such as potassium carbonate and sodium carbonate. The amount of base used can be 1- to 10- fold of the mole of a compound represented by the general formula [34] and preferably 1- to 5-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, alcohols such as methanol and ethanol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; aliphatic hydrocarbons such as hexane and cyclohexane; halogenated hydrocarbons such as chloroform and methylene chloride; esters such as methyl acetate and ethyl acetate; sulfoxides such as dimethyl sulfoxide; and amides such as N,N- dimethylformamide and N,N-dimethylacetamide. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at -20 to 200°C and preferably 0 to 100°C for 30 minutes to 24 hours. The amidoxime compound obtained by the above method is then reacted with halogenated carbonate in the presence of base. Bases used in this reaction include, for example, organic amines such as dimethylaminopyridine, triethylamine, pyridine and N- methylmorpholine; alkaline metal carbonates such as potassium carbonate and sodium carbonate; and metal alkoxides such as potassium tert-butoxide. The amount of base used can be 1- to 10-fold of the mole of a compound represented by the general formula [34] and preferably 1- to 3-fold of the mole of the same. Halogenated carbonate used in this reaction include, for example, ethyl chloroformate, butyl chloroformate and 2-ethylhexyl chloroformate. The amount of halogenated carbonate used can be 1- to 10-fold of the mole of a compound represented by the general formula [34] and preferably 1- to 3-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, nitriles such as acetonitrile; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; aliphatic hydrocarbons such as hexane and cyclohexane; halogenated hydrocarbons such as chloroform and methylene chloride; esters such as methyl acetate and ethyl acetate; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at -20 to 200°C and preferably 0 to 100°C for 5 minutes to 24 hours. Then the reaction product is heated in the presence or absence of solvent to give a compound represented by the general formula [1i-4]. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, nitriles such as acetonitrile; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; aliphatic hydrocarbons such as hexane and cyclohexane; halogenated hydrocarbons such as chloroform and methylene chloride; esters such as methyl acetate and ethyl acetate; amides such as N,N-dimethylformamide and N,N- dimethylacetamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at 0 °C to the reflux temperature of the solvent used and preferably 0 to 150°C for 30 minutes to 24 hours and preferably 30 minutes to 10 hours. When the substituent R11 or R41 has a protecting group, the reaction can be carried out while appropriately deprotecting the substituent by conventional procedure. A compound represented by the general formula [1i-3] can be obtained by reacting a compound represented by the general formula [34] and an azide compound in the presence or absence of salts. Azide compounds used in this reaction include, for example, sodium azide, trimethyltin azide and trimethylsilyl azide. The amount of azide compound used can be 1- to 30-fold of the mole of a compound represented by the general formula [34] and preferably 1- to 10-fold of the mole of the same. Salts used in this reaction as the need arises include, for example, triethylamine hydrochloride and ammonium chloride. The amount of salt used can be 1- to 30-fold of the mole of a compound represented by the general formula [34] and preferably 1- to 10-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; aliphatic hydrocarbons such as hexane and cyclohexane; halogenated hydrocarbons such as chloroform and methylene chloride; esters such as butyl acetate and ethyl acetate; amides such as N,N- dimethylformamide and N,N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at -20 to 250°C and preferably 0 to 150°C for 30 minutes to 24 hours. When the substituent R11 or R41 has a protecting group, the reaction can be carried out while appropriately deprotecting the substituent by conventional procedure. wherein R2j and R2jj each represent a carboxyl-protecting group; Rlj, Rljj and Rljjj each represent the same meaning as Rla; R3 and X represent the same meaning as above; R4D and R4jj each represent the same meaning as R4a. The reaction for obtaining a compound represented by the general formula [12j] from a compound represented by the formula [12] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [12d] from a compound represented by the formula [12] in the production process D. The reaction for obtaining a compound represented by the general formula [35] from a compound represented by the general formula [12j] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [13] from a compound represented by the general formula [12d] in the production process D. The reaction for obtaining a compound represented by the general formula [37] from a compound represented by the general formula [36] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [15] from a compound represented by the general formula [14] in the production process D. The reaction for obtaining a compound represented by the general formula [38] from a compound represented by the general formula [37] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1] from a compound represented by the general formula [1a-l] in the production process A. A compound represented by the general formula [38] can also be obtained not by isolating a compound represented by the general formula [37] from a compound represented by the general formula [36], but by continuously carrying out Friedel-Crafts reaction and dealkylation. The reaction for obtaining a compound represented by the general formula [1j-1] from a compound represented by the general formula [38] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [5] from a compound represented by the general formula [3] in the production process A. The reaction for obtaining a compound represented by the general formula [1j-2] from a compound represented by the general formula [1j-1] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1a-2] from a compound represented by the general formula [1a-1] in the production process A. When the substituent Rlj, R4j or R3 has a protecting group, the reaction can be carried out while appropriately deprotecting the substituent by conventional procedure. The reaction for obtaining a compound represented by the general formula [39] from a compound represented by the general formula [37] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [9] from a compound represented by the general formula [8] in the production process B. The reaction for obtaining a compound represented by the general formula [40] from a compound represented by the general formula [39] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [3] from a compound represented by the general formula [2] in the production process A. A compound represented by the general formula [40] can also be obtained from a compound represented by the general formula [36] by continuously carrying out Friedel-Crafts reaction, dealkylation and dehydration. The reaction for obtaining a compound represented by the general formula [41] from a compound represented by the general formula [40] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [5] from a compound represented by the general formula [3] in the production process A. The reaction for obtaining a compound represented by the general formula [42] from a compound represented by the general formula [41] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [6] from a compound represented by the general formula [5] in the production process A. The reaction for obtaining a compound represented by the general formula [1j-3] from a compound represented by the general formula [42] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [5] from a compound represented by the general formula [3] in the production process A. The reaction for obtaining a compound represented by the general formula [1j-4] from a compound represented by the general formula [1j-3] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1a-2] from a compound represented by the general formula [1a-1] in the production process A. When the substituent R13j, R4)3 or R3 has a protecting group, the reaction can be carried out while appropriately deprotecting the substituent by conventional procedure. [Production Process K] [Formula 14] wherein R2k represents a carboxyl-protecting group; R1k represents the same meaning as R1a; R3k represents optionally substituted alkyl; R4k represents the same meaning as R4a; and X represents the same meaning as above. The reaction for obtaining a compound represented by the general formula [1k-2] from a compound represented by the general formula [1k-1] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [5] from a compound represented by the general formula [3] in the production process A. The reaction for obtaining a compound represented by the general formula [1k-3] from a compound represented by the general formula [1k-2] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1a-2] from a compound represented by the general formula [1a-1] in the production process A. When the substituent Rlk, R3k or R4k has a protecting group, the reaction can be carried out while appropriately deprotecting the substituent by conventional procedure. wherein R21 represents a carboxyl-protecting group; R11 and RU1 each represent the same meaning as Rla; R41 represents the same meaning as R4a; and X represents the same meaning as above. The reaction for obtaining a compound represented by the general formula [44] from a compound represented by the general formula [43] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [15] from a compound represented by the general formula [14] in the production process D. The reaction for obtaining a compound represented by the general formula [45] from a compound represented by the general formula [44] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [7] from a compound represented by the general formula [1a-1] in the production process A. The reaction for obtaining a compound represented by the general formula [11-1] from a compound represented by the general formula [45] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [5] from a compound represented by the general formula [3] in the production process A. The reaction for obtaining a compound represented by the general formula [11-2] from a compound represented by the general formula [11-1] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1a-2] from a compound represented by the general formula [1a-1] in the production process A. When the substituent R11 or R41 has a protecting group, the reaction can be carried out while appropriately deprotecting the substituent by conventional procedure. wherein R2m represents a carboxyl-protecting group; R4m represents the same meaning as R4a; and X represents the same meaning as above. The reaction for obtaining a compound represented by the general formula [1m-1] from a compound represented by the general formula [47] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [5] from a compound represented by the general formula [3] in the production process A. The reaction for obtaining a compound represented by the general formula [1m-2] from a compound represented by the general formula [1m-1] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1i-3] from a compound represented by the general formula [34] in the production process I. The reaction for obtaining a compound represented by the general formula [1m-3] from a compound represented by the general formula [1m-2] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1a-2] from a compound represented by the general formula [1a-1] in the production process A. When the substituent R4m has a protecting group, the reaction can be carried out while appropriately deprotecting the substituent by conventional procedure. The reaction for obtaining a compound represented by the general formula [1m-4] from a compound represented by the general formula [1m-1] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1i-4] from a compound represented by the general formula [34] in the production process I. The reaction for obtaining a compound represented by the general formula [1m-5] from a compound represented by the general formula [1m-4] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1a-2] from a compound represented by the general formula [1a-1] in the production process A. When the substituent R4m has a protecting group, the reaction can be carried out while appropriately deprotecting the substituent by conventional procedure. wherein R2n represents a carboxyl-protecting group; R4n represents the same meaning as R4a; R16 is optionally substituted alkyl or aryl; and X represents the same meaning as above. The reaction for obtaining a compound represented by the general formula [1n-1] from a compound represented by the general formula [48] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [5] from a compound represented by the general formula [3] in the production process A. A compound represented by the general formula [1n-2] can be obtained by oxidizing a compound represented by the general formula [1n-1]. Oxidizing agents used in this reaction include, for example, organic peroxides such as peracetic acid, trifluoroperacetic acid, perbenzoic acid and m-chloroperbenzoic acid; hydrogen peroxide; chromic acid and potassium permanganate. The amount of oxidizing agent used can be 0.5- to 5-fold of the mole of a compound represented by the general formula [1n-1] and preferably 1- to 3-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; alcohols such as methanol and ethanol; esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile; amides such as N,N- dimethylformamide and N,N-dimethylacetamide; halogenated hydrocarbons such as chloroform and methylene chloride; water; and sulfoxides such as dimethyl sulfoxide. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at - 78°C to the reflux temperature of the solvent used and preferably -10 to 30°C for 10 minutes to 24 hours. The reaction for obtaining a compound represented by the general formula [1n-3] from a compound represented by the general formula [1n-2] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1a-2] from a compound represented by the general formula [1a-1] in the production process A. A compound represented by the general formula [1n-4] can be obtained by oxidizing a compound represented by the general formula [1n-3]. Oxidizing agents used in this reaction include, for example, organic peroxides such as peracetic acid, trifluoroperacetic acid, perbenzoic acid and m-chloroperbenzoic acid; hydrogen peroxide; chromic acid and potassium permanganate. The amount of oxidizing agent used can be 1- to 5-fold of the mole of a compound represented by the general formula [1n-3] and preferably 1- to 3-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; alcohols such as methanol and ethanol; esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile; amides such as N,N- dimethylformamide and N,N-dimethylacetamide; halogenated hydrocarbons such as chloroform and methylene chloride; and water. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at - 78°C to the reflux temperature of the solvent used and preferably -10 to 30°C for 10 minutes to 2 4 hours. The reaction for obtaining a compound represented by the general formula [1n-5] from a compound represented by the general formula [1n-2] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1n-4] from a compound represented by the general formula [1n-3] in the production process N. When the substituent R4n or R16 has a protecting group, the reaction can be carried out while appropriately deprotecting the substituent by conventional procedure. A compound represented by the general formula [1n-5] can also be obtained by oxidizing a compound represented by the general formula [1n-1]. Oxidizing agents used in this reaction include, for example, organic peroxides such as peracetic acid, trifluoroperacetic acid, perbenzoic acid and m-chloroperbenzoic acid; hydrogen peroxide; chromic acid and potassium permanganate. The amount of oxidizing agent used can be 2- to 10-fold of the mole of a compound represented by the general formula [1n-1] and preferably 2- to 3-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; alcohols such as methanol and ethanol; esters such as butyl acetate and ethyl acetate; nitriles such as acetonitrile; amides such as N,N- dimethylformamide and N,N-dimethylacetamide; halogenated hydrocarbons such as chloroform and methylene chloride; and water. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at - 78°C to the reflux temperature of the solvent used and preferably -10 to 30°C for 10 minutes to 24 hours. The reaction for obtaining a compound represented by the general formula [1n-4] from a compound represented by the general formula [1n-5] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1a-2] from a compound represented by the general formula [1a-1] in the production process A. When the substituent R4n or R16 has a protecting group, the reaction can be carried out while appropriately deprotecting the substituent by conventional procedure. wherein R20 represents a carboxyl-protecting group; RlD represents the same meaning as R1a; R100 and R30 are optionally substituted alkyl; R° is a phenol-protecting group; RHet is optionally substituted heterocyclyl; X1 is a leaving group; and X represents the same meaning as above. The reaction for obtaining a compound represented by the general formula [12o] from a compound represented by the formula [12] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [12d] from a compound represented by the formula [12] in the production process D. The reaction for obtaining a compound represented by the general formula [49] from a compound represented by the general formula [12o] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [13] from a compound represented by the general formula [12d] in the production process D. The reaction for obtaining a compound represented by the general formula [51] from a compound represented by the general formula [50] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [15] from a compound represented by the general formula [14] in the production process D. The reaction for obtaining a compound represented by the general formula [52] from a compound represented by the general formula [51] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [9] from a compound represented by the general formula [8] in the production process B. A compound represented by the general formula [52] can be obtained from a compound represented by the general formula [50] not by isolating a compound represented by the general formula [51], but by continuously carrying out E'riedel-Crafts reaction and dealkylation reaction. A compound represented by the general formula [53] can be obtained by the process disclosed in Greene et al., Protective Groups in Organic Synthesis, 3rd edition, 1999, 249-280. Specifically, when R° is an acetyl group, for example, a compound represented by the general formula [53] can be obtained by reacting a compound represented by the general formula [52] with acetic anhydride in the presence of base. In this reaction, acetic anhydride can be used as a solvent; however, when some other solvent is used, the amount of acetic anhydride used can be 2- to 20-fold of the mole of a compound represented by the general formula [52] and preferably 2- to 3-fold of the mole of the same. Bases used in this reaction include, for example, organic amines such as dimethylaminopyridine, triethylamine, pyridine and N- methylmorpholine; and alkaline metal carbonates such as potassium carbonate and sodium carbonate. The amount of base used can be 2- to 10-fold of the mole of a compound represented by the general formula [52] and preferably 2- to 3-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, nitriles such as acetonitrile; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; aliphatic hydrocarbons such as hexane and cyclohexane; halogenated hydrocarbons such as chloroform and methylene chloride; esters such as methyl acetate and ethyl acetate; amides such as N,N-dimethylformamide and N,N- dimethylacetamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at -20 to 200°C and preferably 0 to 100°C for 5 minutes to 24 hours. When R° is a tetrahydropyranyl group, for example, a compound represented by the general formula [53] can be obtained by reacting a compound represented by the general formula [52] with 3,4-dihydro-2H-pyran in the presence of a catalyst. The amount of the catalyst used in this reaction can be 2- to 20-fold of the mole of a compound represented by the general formula [52] and preferably 2- to 5-fold of the mole of the same. The catalysts used in this reaction include, for example, acids such as dry hydrogen chloride and p-toluenesulfonic acid; and salts such as pyridinium p-toluenesulfonate. The amount of catalyst used can be 0.01- to 10-fold of the mole of a compound represented by the general formula [52] and preferably 0.05- to 3-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and halogenated hydrocarbons such as chloroform and methylene chloride. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at 0°C to 100°C and preferably 0 to 50°C for 10 minutes to 24 hours. A compound represented by the general formula [54] can be obtained, for example, by the process described in Tetrahedron Letters, Vol. 28, 5093-5096, 1987. Specifically, a compound represented by the general formula [54] can be obtained by reacting a compound represented by the general formula [53] and a compound represented by the general formula [R15d] in the presence of base and a palladium coordination compound as a catalyst. Palladium coordination compounds used in this reaction include, for example, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, benzyl(chloro)bis(triphenylphosphine)palladium(II) and palladium(II) acetate. The amount of catalyst used can be 0.001- to 1 mole per mole of a compound represented by the general formula [53] and preferably 0.01- to 0.1-fold of the mole of the same. Bases used in this reaction include, for example, alkali carbonates such as sodium hydrogencarbonate and sodium carbonate; alkali hydroxides such as sodium hydroxide and potassium hydroxide; alkaline metal alkoxides such as sodium methoxide and sodium tert-butoxide; and organic bases such as triethylamine and pyridine. The amount of base used can be 1- to 10-fold of the mole of a compound represented by the general formula [53] and preferably 2- to 4-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane and tetrahydrofuran; halogenated hydrocarbons such as chloroform and methylene chloride; alcohols such as methanol and ethanol; esters such as ethyl acetate; amides such as N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; and water. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at 20°C to the reflux temperature of the solvent used and preferably 30 to 120°C for 30 minutes to 72 hours and preferably 30 minutes to 5 hours. A compound represented by the general formula [54] can be obtained, for example, by the process described in Nippon Kagaku Kaishi, No.3, 520-526, 1985. Specifically, a compound represented by the general formula [54] can also be obtained by reacting a compound represented by the general formula [53] with a compound represented by the general formula [Rl5e] in the presence or absence of a palladium coordination compound as a catalyst. Palladium coordination compounds used in this reaction include, for example, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, benzyl(chloro)bis(triphenylphosphine)palladium(II) and palladium(II) acetate. The amount of catalyst used can be 0.001- to 1-fold of the mole of a compound represented by the general formula [53] and preferably 0.01- to 0.1-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane and tetrahydrofuran; halogenated hydrocarbons such as chloroform and methylene chloride; alcohols such as methanol and ethanol; esters such as ethyl acetate; amides such as N,N-dimethylformamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at 20°C to the reflux temperature of the solvent used and preferably 30 to 120°C for 30 minutes to 72 hours and preferably 30 minutes to 5 hours. A compound represented by the general formula [55] can be obtained from a compound represented by the general formula [54] by carrying out ordinary deprotection. Specifically, when R° of a compound represented by the general formula [54] is acetyl, a compound represented by the general formula [55] can be obtained by deprotecting the substituents protected with R° in the presence of base. Bases used in this reaction include, for example, alkaline metal carbonates such as potassium carbonate and sodium carbonate; and alkaline metal alkoxides such as potassium tert-butoxide and sodium methoxide. The amount of base used can be 2- to 10- fold of the mole of a compound represented by the general formula [54] and preferably 2- to 3-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane and tetrahydrofuran; halogenated hydrocarbons such as chloroform and methylene chloride; alcohols such as methanol and ethanol; amides such as N,N- dimethylformamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at - 10°C to 100°C and preferably 0 to 30°C for 5 minutes to 24 hours and preferably 10 minutes to 10 hours. When R° of a compound represented by the general formula [54] is tetrahydropyran, for example, elimination thereof can be accomplished in the presence of acid. Acids used in this reaction include, for example, mineral acids such as hydrochloric acid; and organic acids such as p-toluenesulfonic acid and oxalic acid. The amount of acid used can be 0.01- to 100-fold of the mole of a compound represented by the general formula [54] and preferably 0.05- to 10-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; alcohols such as methanol and ethanol; esters such as butyl acetate and ethyl acetate; nitriles such as acetonitrile; amides such as N,N- dimethylformamide and N,N-dimethylacetamide; halogenated hydrocarbons such as chloroform and methylene chloride; and water. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at 0°C to the reflux temperature of the solvent used and preferably 5 to 100°C for 10 minutes to 24 hours. The reaction for obtaining a compound represented by the general formula [1o-1] from a compound represented by the general formula [55] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [5] from a compound represented by the general formula [3] in the production process A. The reaction for obtaining a compound represented by the general formula [1o-2] from a compound represented by the general formula [1o-1] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1a-2] from a compound represented by the general formula [1a-1] in the production process A. When the substituent R10 or RHet has a protecting group, the reaction can be carried out while appropriately deprotecting the substituent by conventional procedure. wherein R1p represents a hydroxyl- or amino-protecting group; R2p and R2pp each represent optionally substituted alkyl; R3p is hydrogen, halogen, cyano, nitro, optionally protected hydroxyl, optionally protected amino, mercapto, carbamoyl, or optionally substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclyl; R4, R5 and X represent the same meaning as above (Rlp represents a group substituted for oxygen of a hydroxyl group as a substituent of benzisoxazole or nitrogen of benzisoxazole). A compound represented by the general formula [1p-2] can be obtained by subjecting a compound represented by the general formula [1p-1] to deprotection reaction such as (1) hydrolysis with acid or base, (2) dealkylation with salt or (3) reductive dealkylation including hydrogen addition reaction with metal catalyst. Acids used in the reaction (1) include, for example, mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid; organic acids such as formic acid and trifluoroacetic acid; and Lewis acids such as aluminium chloride and trimethylsilyl iodide. The amount of acid used in the reaction can be 1- to 100-fold of the mole of a compound represented by the general formula [1p-1] and preferably 1- to 10-fold of the mole of the same. Bases used in the reaction (1) include, for example, alkali hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; alkaline metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkaline metal carbonates such as potassium carbonate and sodium carbonate; and tetrabutylammonium fluoride. The amount of base used can be 1- to 100-fold of the mole of a compound represented by the general formula [1p-1] and preferably 1- to 10-fold of the mole of the same. Salts used in the reaction (2) include, for example, lithium iodide and sodium chloride. The amount of salt used can be 1- to 100-fold of the mole of a compound represented by the general formula [1p-1] and preferably 1- to 10-fold of the mole of the same. Catalysts used in the reaction (3) include, for example, palladium carbon, palladium black and palladium hydroxide. The amount of catalyst used can be 0.1- to 100% (w/w) the weight of the compound represented by the general formula [1p-1] and preferably 1- to 50% (w/w) the weight of the same. Reducing agents used in the reaction (3) include, for example, hydrogen, formic acid, cyclohexene and zinc. The amount of reducing agent used can be 1- to 100-fold of the mole of a compound represented by the general formula [1p-1] and preferably 1- to 10-fold of the mole of the same. Solvents used in these reactions are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, alcohols such as methanol, ethanol and isopropyl alcohol; ethers such as tetrahydrofuran, diethyl ether; 1,4-dioxane and anisole; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; nitriles such as acetonitrile; aliphatic hydrocarbons such as n-hexane and cyclohexane; esters such as ethyl acetate; aromatic hydrocarbons such as toluene, benzene and xylene; dimethyl sulfoxide, N,N-dimethylformamide, nitromethane, pyridine and water. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually these reaction can be performed at - 78 to 100°C and preferably 0 to 80°C for 10 minutes to 24 hours. A compound represented by the general formula [1p-3] can be obtained by subjecting a compound represented by the general formula [1p-2] to esterification. This can be carried out using ordinary esterification reaction, and the processes of esterification include, for example, processes (1) in which acid catalyst and additive are used, (2) in which esterification is carried out via acid chloride in the presence or absence of catalyst, (3) in which esterification is carried out via acid anhydride in the presence or absence of base, (4) in which base and a compound represented by the general formula [R2p] are used and (5) in which a compound represented by the general formula [R1p] together with condensing agent and additive is subjected to condensation reaction. Acid catalysts used in the reaction (1) include, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trimethylsilyl chloride, aluminium chloride, boron trifluoride and trifluoroacetic acid. The amount of acid catalyst used in the reaction can be 0.01- to 100-fold of the mole of a compound represented by the general formula [1p-2] and preferably 0.5- to 50-fold of the mole of the same. Additives used in the reaction include, for example, 2,2-dimethoxypropane and ethyl orthoformate. The amount of additive used in the reaction can be 0.1- to 100-fold of the mole of a compound represented by the general formula [1p-2] and preferably 1- to 50-fold of the mole of the same. Compounds represented by the general formula [R1p] include, for example, methanol, ethanol, benzyl alcohol, N-(2-hydroxyethyl)morpholine and 4- hydroxymethyl-5-methyl-l,3-dioxol-2-one. These compounds can be used as a solvent in appropriate amount; however, when some other solvent is used, the amount of such a compound used can be 1- to 100-fold of the mole of a compound represented by the general formula [1p-2] and preferably 1- to 50-fold of the mole of the same. Solvents used in the reaction (1) are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, and dimethyl cellosolve; esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile; amides such as N,N-dimethylformamide; halogenated hydrocarbons such as chloroform and methylene chloride; and sulfoxides such as dimethyl sulfoxide. Usually these reaction can be performed at 0 to 200°C and preferably 5 to 100°C for 10 minutes to 2 4 hours. Carboxylic-activating agents used in the reaction (2) include, for example, oxalyl chloride and thionyl chloride. The amount of the agent used in the reaction can be 1- to 10-fold of the mole of a compound represented by the general formula [1p-2] and preferably 1- to 5-fold of the mole of the same. Catalysts used in the reaction (2) as the need arises include, for example, N,N-dimethylformamide, and the amount of catalyst used in the reaction can be 0.001- to 1-fold of the mole of a compound represented by the general formula [1p-2] and preferably 0.01- to 0.5-fold of the mole of the same. Solvents used in the reaction (2) are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, and dimethyl cellosolve; esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile; amides such as N,N-dimethylformamide; and halogenated hydrocarbons such as chloroform and methylene chloride. Usually these reaction can be performed at 0 to 200°C and preferably 5 to 100°C for 10 minutes to 24 hours. Activating agents used in the reaction (3) include, for example, acetic anhydride and ethyl chloroformate, and the amount of activating agent used in the reaction can be 1- to 10-fold of the mole of a compound represented by the general formula [1p-2] and preferably 1- to 5-fold of the mole of the same. Bases used in the reaction (3) as the need arises include, for example, organic amines such as dimethylaminopyridine, triethylamine, pyridine, N- methylmorpholine and N-ethyldiisopropylamine; and alkaline metal carbonates such as potassium carbonate and sodium carbonate. The amount of base used can be 1- to 10-fold of the mole of a compound represented by the general formula [1p-2] and preferably 1- to 5-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile; amides such as N,N-dimethylformamide; and halogenated hydrocarbons such as chloroform and methylene chloride. Usually this reaction can be performed at 0 to 200°C and preferably 5 to 100°C for 10 minutes to 24 hours. Bases used in the reaction (4) include, for example, organic amines such as dimethylaminopyridine, triethylamine, pyridine and N-methylmorpholine; and alkaline metal carbonates such as potassium carbonate and sodium carbonate. The amount of base used can be 0.5- to 10-fold of the mole of a compound represented by the general formula [1p-2] and preferably 1- to 5- fold of the mole of the same. Compounds represented by the general formula [R2p] used in the reaction (4) include, for example, methyl iodide, ethyl iodide, benzyl bromide, ethyl carbonate 1-ethyl iodide, cyclohexyl carbonate 1-ethyl iodide, 4-bromomethyl-5-methyl-1,3-dioxol-2-one, N-(2- chloroethyl)morpholine and chloromethyl pivalate. The amount of such a compound used can be 0.5- to 10-fold of the mole of a compound represented by the general formula [1p-2] and preferably 1- to 3-fold of the mole of the same. Solvents used in the reaction (4) are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile; amides such as N,N-dimethylformamide; halogenated hydrocarbons such as chloroform and methylene chloride; and sulfoxides such as dimethyl sulfoxide. Usually this reaction can be performed at 0 to 200°C and preferably 5 to 100°C for 10 minutes to 24 hours. Condensing agents used in the reaction (5) include, for example, 1,1'-carbonyldiimidazole, N,N'- dicyclohexylcarbodiimide, diisopropylcarbodiimide, N- ethyl-N'-3-dimethylaminopropylcarbodiimide, diisopropyl azodicarboxylate and diphenylphosphoryl azide. Additives used in the reaction (5) include, for example, 1-hydroxybenzotriazole, triphenylphosphine and N-hydroxysuccinimide. The amounts of a compound represented by the general formula [R1p], condensing agent and additive used in the reaction (5) each can be 0.01- to 10-fold of the mole of a compound represented by the general formula [1p-2] and preferably 0.1- to 3-fold of the mole of the same. Solvents used in the reaction (5) are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile; amides such as N,N-dimethylformamide; and halogenated hydrocarbons such as chloroform and methylene chloride. Usually this reaction can be performed at 0 to 200°C and preferably 5 to 100°C for 10 minutes to 24 hours. A compound represented by the general formula [1p-3] can also be obtained from a compound represented by the general formula [1p-1] by continuously carrying out deprotection and esterification. A compound represented by the general formula [1p-3] can also be obtained by reacting a compound represented by the general formula [1p-1] with a compound represented by the general formula [R1p] in the presence of acid or base. Compounds represented by the general formula [R1p] used in this reaction include, for example, methanol, ethanol, benzyl alcohol, N-(2- hydroxyethyl)morpholine and 4-hydroxymethyl-5-methyl- 1,3-dioxole-2-one. These compounds can be used as a solvent in appropriate amount; however, when some other solvent is used, the amount of such a compound used can be 1- to 100-fold of the mole of a compound represented by the general formula [1p-1] and preferably 1- to 10- fold of the mole of the same. Acids used in this reaction include, for example, hydrochloric acid, sulfuric acid, p- toluenesulfonic acid, trimethylsilyl chloride and boron trifluoride. The amount of acid used in the reaction can be 0.01- to 100-fold of the mole of a compound represented by the general formula [1p-1] and preferably 0.1- to 10-fold of the mole of the same. Bases used in this reaction include, for example, alkaline metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; organic amines such as dimethylaminopyridine, triethylamine and pyridine; alkaline metal hydrides such as sodium hydride; and alkaline metal carbonates such as potassium carbonate and sodium carbonate. The amount of base used can be 1- to 100-fold of the mole of a compound represented by the general formula [1p-1] and preferably 1- to 10-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, and dimethyl cellosolve; nitriles such as acetonitrile; amides such as N,N-dimethylformamide; halogenated hydrocarbons such as chloroform and methylene chloride; and sulfoxides such as dimethyl sulfoxide. These solvents are used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at -50 to 200°C and preferably -30 to 150°C for 10 minutes to 24 hours. A compound represented by the general formula [1p-4] can be obtained from a compound represented by the general formula [1p-3] by carrying out ordinary deprotection. For example, when Rlp of a compound represented by the general formula [1p-3] is tert- butoxycarbonyl, deprotection can be carried out in the presence of acid. Acids used in this reaction include, for example, mineral acids such as hydrochloric acid and sulfuric acid; and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid and trifluoroacetic acid. The amount of acid used in the reaction can be 0.01- to 100-fold of the mole of a compound represented by the general formula [1p-3] and preferably 1- to 10-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, and dimethyl cellosolve; alcohols such as methanol, ethanol and isopropyl alcohol; esters such as butyl acetate and ethyl acetate; nitriles such as acetonitrile; amides such as N,N-dimethylformamide and N,N- dimethylacetamide; halogenated hydrocarbons such as chloroform and methylene chloride; and water. These solvents are used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at 0°C to the reflux temperature of the solvent used and preferably 0 to 120°C for 10 minutes to 24 hours. For example, when Rlp of a compound represented by the general formula [1p-3] is methoxymethyl or trityl, deprotection can be carried out in the presence of acid. Acids used in this reaction include, for example, mineral acids such as hydrochloric acid and sulfuric acid; and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid and trifluoroacetic acid. The amount of acid used in the reaction can be 0.01- to 100-fold of the mole of a compound represented by the general formula [1p-3] and preferably 1- to 10-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, and dimethyl cellosolve; alcohols such as methanol, ethanol and isopropyl alcohol; esters such as butyl acetate and ethyl acetate; nitriles such as acetonitrile; amides such as N,N-dimethylformamide and N,N- dimethylacetamide; halogenated hydrocarbons such as chloroform and methylene chloride; and water. These solvents are used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at 0°C to the reflux temperature of the solvent used and preferably 0 to 120°C for 10 minutes to 24 hours. A compound represented by the general formula [1p-4] can also be obtained from a compound represented by the general formula [1p-2] by continuously carrying out esterification and deprotection. wherein R1q represents the same meaning as Rlp; R2q represents the same meaning as R2p; R3q represents the same meaning as R3p; and R4, R5 and X represent the same meaning as above (Rlq represents a group substituted for oxygen of an oxo group as a substituent of benzisoxazole or nitrogen of benzisoxazole). A compound represented by the general formula [1q-2] can be obtained, for example, by the process disclosed in Greene et al., Protective Groups in Organic Synthesis, 3rd edition, 1999, 17-292, 494-653. Specifically, when Rlq is a trityl group, for example, a compound represented by the general formula [1q-2] can be obtained by reacting a compound represented by the general formula [1q-1] with trityl chloride in the presence of base. The amount of trityl chloride used can be 1- to 10-fold of the mole of a compound represented by the general formula [1q-1] and preferably 1- to 3-fold of the mole of the same. Bases used in this reaction include, for example, organic amines such as dimethylaminopyridine, triethylamine, pyridine and N-methylmorpholine; and alkaline metal carbonates such as potassium carbonate and sodium carbonate. The amount of base used can be 1- to 20-fold of the mole of a compound represented by the general formula [1q-1] and preferably 3- to 10-fold of the mole of the same. Solvents used in this reaction are not limited to any specific ones as long as they do not adversely affect the reaction. They include, for example, nitriles such as acetonitrile; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; aliphatic hydrocarbons such as hexane and cyclohexane; halogenated hydrocarbons such as chloroform and methylene chloride; esters such as methyl acetate and ethyl acetate; amides such as N,N- dimethylformamide and N,N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be used independently or in the form of a mixture of two or more kinds. Usually this reaction can be performed at -50 to 150°C and preferably -30 to 100°C for 5 minutes to 24 hours. The reaction for obtaining a compound represented by the general formula [1q-3] from a compound represented by the general formula [1q-2] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1p-3] from a compound represented by the general formula [1p-2] in the production process P. The reaction for obtaining a compound represented by the general formula [1q-4] from a compound represented by the general formula [1q-1] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1p-3] from a compound represented by the general formula [1p-2] in the production process P. The reaction for obtaining a compound represented by the general formula [1q-4] from a compound represented by the general formula [1q-3] can be carried out in the same manner as in the reaction for obtaining a compound represented by the general formula [1p-4] from a compound represented by the general formula [1p-3] in the production process P. In the compounds used in the above described production processes, those capable of taking the form of salts can be used as salts. Such salts include, for example, the same salts as described in the salts of compounds represented by the general formula [1]. When isomers (e.g. optical isomers, geometrical isomers and tautomers) are present in the compounds used in the above described production processes, the isomers can also be used. When solvates, hydrates and crystals in various forms are present in the compounds, the solvates, hydrates and crystals in various forms can also be used. In the compounds used in the above described production processes, for those having substituents that can be protected, such as amino, hydroxyl or carboxyl, the substituents can be protected with ordinary protecting groups in advance and deprotected by known processes after reaction. Subjecting the compounds represented by the general formula [1] thus obtained to known reaction, such as oxidation, reduction, substitution, rearrangement, halogenation, dehydration or hydrolysis, or the combination thereof enables other compounds represented by the general formula [1] to be derived. Compounds represented by the general formula [1] or the salts thereof can be isolated and purified by conventional procedure such as extraction, crystallization and/or column chromatography. When using the compounds of this invention as drugs, additives commonly used in preparation of drugs, such as excipient, carrier and diluent, can be appropriately mixed with the compounds. The resultant drugs can be administered orally or parenterally in a dosage form of tablet, capsule, powder, syrup, granule, pill, suspension, emulsion, solution, powder preparations, suppository, ointment or parenteral injection. The dosage, administration and dosing can be appropriately selected depending on the age, body weight and symptoms of patients. For adults, usually they can be administered orally or parenterally (e.g. injection, drip infusion, or administration into rectum) in a daily dose of 0.1 to 100 mg/kg in one to several divided portions. [Test Methods] Test Example 1 Effect on AP-1 binding activity to AP-1 recognition sequence (ELISA) Jun peptide and Fos peptide with its N- terminal labeled with biotin via 4 glycine residues containing a DNA binding site [Nature, Vol. 373, 1995, 257-261] were synthesized. Each of the peptides was dissolved in Tris buffer [20 mM Tris-hydrochloric acid (pH 7.5), 50 mM potassium chloride, 1 mM ethylenediaminetetraacetic acid, 10 mM magnesium chloride, 1 mM dithiothreitol, 0.5 M guanidinohydrochloric acid, 30% glycerol], and equimolar amounts of the peptide solutions were mixed with each other to be used as an AP-1 complex (Fos/Jun peptide). The AP-1 complex was added onto a 96-well avidin-coated ELISA plate (10 pmol/well). The plate was washed, blocked by bovine serum albumin, and used for binding assay. Digoxigenin-labeled double-stranded oligonucleotide (22mer) that contained AP-1 binding sequence (3'-TGAGTCA-5') synthesized by conventional procedure was reacted in binding reaction solution [25 mM tris-hydrochloric acid (pH 7.9), 0.5 mM ethylenediaminetetraacetic acid, 0.05% Nonidet P-40, 10% glycerol] for 30 minutes at room temperature in the presence or absence of samples. After the reaction, unbound labeled oligonucleotide was removed by washing with HEPES buffer containing 0.05% Tween-20. Then peroxidase-labeled anti-digoxigenin antibody was added to react with the labeled oligonucleotide bound to AP-1. After removing excess antibody by washing with HEPES buffer containing 0.05% Tween-20, incubation was conducted for a certain period with o-phenylene diamine as a substrate in 100 mM citric acid buffer (pH 5.0) containing hydrogen peroxide, sulfuric acid solution was added to each well, and the absorbance (492 nm) was measured. Inhibition rate of each sample was calculated from the absorbance obtained in the binding assay carried out in the presence of the sample, taking the absorbance obtained in the absence of the sample = 100%. The results are shown in Table 12. mouse Male DBA/1J mice aged 8 weeks (Charles River Japan) were used. To a solution of 2 mg/mL bovine type II collagen in 0.1 mol/L acetic acid (Koken), an equimolar amount of Freund's complete adjuvant (DIFCO) was added to prepare an emulsion, and 0.2 ml of the emulsion was subcutaneously injected in the tail root region of each mouse. The same treatment was given 21 days after the initial inoculation to induce arthritis in the mice. Test compounds were each suspended in 0.5% methylcellulose solution, and 10 mg/kg of each test compound was given orally to mice once a day from 21 to 35 days after the initial inoculation. To a control group (a negative control group), 0.5% methylcellulose solution was given in the same manner. Taking the maximum score as 12, the arthritis score was calculated to evaluate the severity of arthritis that was evaluated in the following manner: score 0: no change; score 1: swelling on one or two toes, or slight swelling in the carpal and tarsal joints; score 2: swelling and rubor in more joints; score 3: extensive swelling over whole foreleg or hindleg; and total of the four legs was calculated. X-ray photographs of four paws were taken 36 days after the initial inoculation, and the severity of bone destruction was evaluated as bone destruction score on a maximum scale, the sum of the points for extremities, of 105 points: 0 or 0.5 points in accordance with presence or absence of osteoporosis in the joints and their vicinity, and for bone erosion, no change at 0 point; "partial bone destruction" at 1 point and "complete bone destruction" at 2 points in the second to fifth interdigital joints, the first to fifth metacarpal and metatarsal joints, and carpal, tarsal and calcaneal regions. Inhibition rate was calculated using the following equation: Inhibition rate (%) = 100 - (score of the group given the test compound / score of the control group) x 100 Table 13 shows the arthritis inhibition rate and the bone destruction inhibition rate of each test compound on 36 days after initial inoculation. the Examples have meanings as follows, respectively. Me: methyl, Et: ethyl, i-Pr: isopropyl, i-Bu: isobutyl, MOM: methoxymethyl, Bn: benzyl, Tr: trityl, Ph: phenyl, Boc: tert-butoxycarbonyl, CDC13: deuterated chloroform, DMSO-d6: deuterated dimethylsulfoxide M represents a unit "mol/L". Every mixing ratio of components used for the eluent is expressed by volume. In addition, Silica gel BW-127ZH (produced by Fuji Silysia Chemical Ltd.) was used as a support for silica gel chromatography. Example 1 Two grams of ethyl 3-[5-(2,4- diisopropoxybenzoyl)-2-isobutoxyphenyl] propanoate was dissolve in 20 mL of methylene chloride, and after the addition of 1.42 g of aluminum chloride at room temperature, the resultant mixture was stirred for 30 minutes at room temperature. This reaction mixture was added to ice water for the separation of an organic phase therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=2:l] to yield 585 mg of ethyl 3-[5-(2-hydroxy-4- isopropoxybenzoyl)-2-isobutoxyphenyl] propanoate as light yellow oil. NMR(90MHz,CDCl3) 5 value: 1. 07 ( 6H, d, J=6 . 8Hz) , 1.23(3H,t,J=7.3Hz), 1.38(6H,d,J=6.1Hz), 1.92-2.40(1H,m), 2.61-2.72(2H,m), 2.92-3.12(2H,m), 3.82(2H,d,J=6.1Hz), 4.13(2H,q,J=7.1Hz), 4.50-4.77(1H,m), 6.34-6.50(2H,m), 6.88(1H,d,J=9.3Hz), 7.49-7.58(3H,m), 12.70(1H,s) Example 2 545 mg of ethyl 3-[5-(2-hydroxy-4- isopropoxybenzoyl)-2-isobutoxyphenyl] propanoate was dissolve in 2.5 mL of ethanol, and after the addition of 1.5 mL of 5M sodium hydroxide thereto, the resultant mixture was stirred for 2.5 hours at room temperature. Following the addition of chloroform and water to the reaction mixture, which is then adjusted to pH 2 with 6M hydrochloric acid, and the organic phase was separate therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. Consequently, 444 mg of 3-[5-(2-hydroxy-4- isopropoxybenzoyl)-2-isobutoxyphenyl] propanoic acid was obtained as light yellow solid. NMR(90MHz, CDC13) 8 value: 1.07(6H,d,J=6.6Hz), 1.36(6H,d,J=6.1Hz), 1.95-2.31(1H,m), 2.61-3.12(4H,m), 3.82(2H,d,J=6.1Hz), 4.50-4.77(1H,m), 6.32-6.49(2H,m), 6.89(1H,d,J=9.3Hz), 7.48-7.62(3H,m), 10.00(1H,br), 12.68(1H,s) Example 3 Isopropyl 3-[5-(2-hydroxy-4- isopropoxybenzoyl)-2-isopropoxyphenyl] propanoate was obtained in a similar manner as in Example 1. NMR(90MHz,CDCl3) 5 value: 1.19(6H,d,J=6.4Hz), 1.38(6H,d,J=6.1Hz), 1.39(6H,d,J=6.1Hz), 2.56-2.66(2H,m), 2.88-3.06(2H,m), 4.42-5.13(3H,m), 6.33-6.49(2H,m), 6.89(1H,d,J=9.3Hz), 7.50-7.60(3H,m), 12.70(1H,s) Example 4 3-[5-(2-hydroxy-4-isopropoxybenzoyl)-2- isopropoxyphenyl] propanoic acid was obtained in a similar manner as in Example 2. NMR(90MHz,CDCI3) 5 value: 1.36(6H,d,J=6.1Hz), 1.39(6H,d,J=5.9Hz), 2.61-3.08(4H,m), 4.49-4.74(2H,m), 6.33-6.49(2H,m), 6 . 90(1H,d,J=9.3Hz), 7.50-7.60(3H,m), 11.18(1H,br), 12.69(1H,s) Example 5 5.0 g of methyl 3-[5-(2,4-dihydroxybenzoyl)- 2-hydroxyphenyl] propanoate, 9.6 g of potassium carbonate, and 6.4 mL of isopropyl iodide were suspended in 50 mL of N,N-dimethylformamide, and stirred for 2 hours at temperatures of 50 to 60°C. This reaction mixture was added to a mixture of ethyl acetate and water, which is then adjusted to pH 2 with 6M hydrochloric acid, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=5:l] to yield 4.7 g of methyl 3-[5-(2~hydroxy-4- isopropoxybenzoyl)-2-isopropoxyphenyl] propanoate as yellow oil. NMR(90MHz,CDCl3) 5 value: 1.36(6H,d,J=6.1Hz) , 1.38 (6H,d,J=6.1Hz), 2.52-3.06(4H,m), 3.66(3H,s), 4.49- 4.80(2H,m), 6.30-6.48(2H,m), 6.88(1H,d,J=9.3Hz), 7.49- 7.58(3H,m), 12.69(1H,s) Example 6 6.5 g of methyl 3-[5-(2-hydroxy-4- isopropoxybenzoyl)-2-isopropoxyphenyl] propanoate was dissolved in 65 mL of methanol, and after the addition of 6.5 mL of 5M sodium hydroxide thereto, the resultant mixture was stirred for 4 hours at the temperature of 60°C. Ethyl acetate and water were added to the reaction mixture, which is then adjusted to pH 2 with 6M hydrochloric acid, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure, followed by purification with silica gel column chromatography to yield 4.3 g of 3-[5-(2-hydroxy-4-isopropoxybenzoyl)- 2-isopropoxyphenyl] propanoic acid as light yellow solid. NMR(90MHz,CDCl3) δ value: 1.36 (6H,d,J=6.1Hz), 1.39(6H,d,J=5.9Hz), 2.61-3.08(4H,m), 4.49-4.74(2H,m), 6.33-6.49(2H,m), 6.90(1H,d,J=9.3Hz), 7.50-7.60(3H,m), 11.18 (1H,br), 12.69(1H,s) Example 7 5.12 g of 4-isobutoxy-3-(3-ethoxy-3- oxopropyl)benzoic acid was dissolved in 51 mL of methylene chloride, and after the consecutive addition thereto of 1.8 mL of oxalyl chloride and 20 (0.L of N,N- dimethylformamide at room temperature, the resultant mixture was stirred for one hour at room temperature. Then, 4.64 g of aluminum chloride and 3.30 g of 1,3- diisopropoxybenzene were successively added to the reaction mixture at temperatures of -30 to -20°C, followed by raising the temperature to 5°C, where the mixture was stirred for one hour. This reaction mixture was added to ice water for the separation of the organic phase therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=5:l] to yield 5.05 g of ethyl 3-[5-(2,4- diisopropoxybenzoyl)-2-isobutoxyphenyl] propanoate as light yellow oil. NMR(90MHz,CDCl3) 5 value: 1.06(6H,d,J=6.6Hz), 1.10(6H,d,J=6.1Hz), 1.23(3H,t,J=7.1Hz), 1.38(6H,d,J=6.1Hz), 1.91-2.38(1H,m), 2.47-2.69(2H,ra), 2.87-3.07(2H,m), 3.80(2H,d,J=6.4Hz), 4.00-4.81(4H,m), 6.46-6.58(2H,m), 6.79(1H,d,J=9.3Hz), 7.33(1H,d,J=8.6Hz), 7.58-7.71(2H,m) Example 8 Isopropyl 3-[5-(2,4-diisopropoxybenzoyl)-2- isopropoxyphenyl] propanoate was obtained in a similar manner as in Example 7. NMR(90MHz, CDC13) 8 value: 1.10(6H,d,J=6.1Hz), 1.20(6H,d,J=6.4Hz), 1.37(12H,d,J=6.1Hz), 2.43- 2.62(2H,m), 2.83-3.03(2H,m), 4.02-5.20(4H,m), 6.46- 6.58(2H,m), 6.80(1H, d, J=9.3Hz) , 7.33(1H,d,J=8.1Hz), 7.55-7.67(2H,m) Example 9 15.0 g of 2,4-dimethoxybenzoic acid was dissolved in 150 mL of methylene chloride, and after the consecutive addition thereto of 8.6 mL of oxalyl chloride and 20 µL of N, N-dimethylf ormamide at room temperature, the resultant mixture was stirred for 4 hours at room temperature. After 32.9 g of aluminum chloride was added thereto at temperatures of -45 to - 40°C, 19.2 g of methyl 3-(2-methoxyphenyl) propanoate was added dropwise at temperatures of -45 to -15°C, and then the temperature was raised to an ambient temperature over 3 hours. This reaction mixture was added to ice water for the separation of the organic phase therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=l:2] to yield 15.1 g of methyl 3-[5-(2,4-dimethoxybenzoyl)-2- methoxyphenyl] propanoate as yellow oil. NMR(90MHz,CDCl3) 5 value: 2.48-2.68(2H,m), 2.89- 3.03(2H,m), 3.66(3H,s), 3.72(3H,s), 3.86(3H,s), 3.88(3H,s), 6.47-6.57(2H,m), 6.83(1H,d,J=9.0Hz), 7.32(1H,d,J=9.0Hz), 7.64-7.72(2H,m) Example 10 After 0.5 mL of 2'-hydroxyacetophenone and 1.8 6 g of aluminum chloride were added to a solution of 500 mg of methyl 3-[5-(2,4-dimethoxybenzoyl)-2- methoxyphenyl] propanoate in 5 mL of 1,2-dichloroethane, the resultant mixture was stirred for two hours at temperatures 35 to 55°C. The reaction mixture was added to ice water for the separation of the organic phase therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:1] to yield 316 mg of methyl 3-[5-(2,4-dihydroxybenzoyl)-2- hydroxyphenyl] propanoate as light yellow solid. Example 11 80.0 g of 2,4-dimethoxybenzoic acid was dissolved in 1040 mL of methylene chloride, and after the consecutive addition thereto of 0.7 mL of N,N- dimethylformamide and 4 6 mL of oxalyl chloride at room temperature, the resultant mixture was stirred for 2 hours at room temperature. After a solution of 102.3 g of methyl 3-(2-methoxyphenyl) propanoate in 80 mL of methylene chloride was added thereto, this solution was cooled to -30 °C, followed by the addition of 146.4 g of aluminum chloride, and then stirred for one hour in an ice bath. Subsequently, 129 mL of ethyl acetate was added dropwise thereto, followed by the addition of 322.0 g of aluminum chloride in small portions at temperatures of 5 to 20°C, and then this solution was stirred for four hours while heating it under reflux. The reaction mixture was poured into a mixture of ice water, 6M hydrochloric acid, and methanol, then the organic phase was separated therefrom. After the resultant organic phase was washed with 6M hydrochloric acid, water was added thereto, and this phase was adjusted to pH 10 with a 10% aqueous solution of sodium hydroxide for separation of the aqueous phase. The aqueous phase was combined with ethyl acetate and then adjusted to pH 8 with 6M hydrochloric acid for the separation of the organic phase therefrom. After the resultant organic phase was washed with a saturated sodium chloride solution, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=4:3] to yield 74.5 g of methyl 3-[5-(2,4-dihydroxybenzoyl)-2- hydroxyphenyl] propanoate as light yellow solid. NMR (400MHz, CDC13) 5 value: 2 . 77 (2H, t, J=6 . 8Hz) , 2.96(2H,t,J=6.8Hz), 3.73(3H,s), 5.78(1H,s), 6.36(1H,dd,J=8.8,2.4Hz), 6.46(1H,d,J=2.4Hz), 6.96(1H,d,J=8.0Hz), 7.45-7.49(2H,m), 7.54(1H,d,J=8.8Hz) , 7.90(1H,s), 12.59(1H,s) Example 12 Compounds listed in Table 14 were obtained in a similar manner as in Example 11. 12(1) NMR(400MHz,CDCl3) 5 value: 1.27(6H,d, J=6.8Hz), 2.76- 2.79(2H,m), 2.89-2.98(3H,m), 3.73(3H,s), 6.75(1H,dd,J=8.2,2.0Hz), 6.92(1H,d,J=l.6Hz), 6.97(1H,d,J=9.2Hz), 7.51-7.55(3H,m), 7.92(1H,s), 12.07 (1H,s) 12 (2) NMR(400MHz,CDC13) 5 value: 0.93(3H,s), 1.31-1.38(2H,m), 1.52-1.57(2H,m), 1.66-1.70(4H,m), 2.61(2H,s), 2.77- 2.80(2H,m), 2.95-2.98(2H,m), 3.73(3H,s), 6.68(1H,dd, J=8.0, 1.2Hz) , 6.8 6(1H,d,J=l.2Hz), 6.97(1H,d,J=8.4Hz), 7.50-7.53(3H,m), 7.93(1H,s), 12.07(1H,s) 12(3) NMR(400MHz,CDC13) 5 value: 1.57-1.75(4H,m) , 1.78- 1.84(2H,m), 2.07-2.11(2H,m), 2.76-2.79(2H,m), 2.95- 3.03(3H,m), 3.73(3H,s), 6.76(1H,dd,J=8.4,1.6Hz), 6.93- 6.98(2H,m), 7.50-7.54(3H,m), 7.90(1H,s), 12.06(1H,s) 12(4) NMR( 4 00MHz, DMSO-d6) 5 value: 2.16(3H,s), 2.58(2H,t,J=7.6Hz), 2.81(2H,t,J=7.6Hz), 3.57(3H,s), 6.65(1H,dd,J=8.4,2.4Hz), 6.71(1H,d,J=2.0Hz), 6.8 8(1H,d,J=8.4Hz), 7.12(1H,d,J=8.OHz), 7.42(1H,dd,J=8.0,2.4Hz), 7.46(1H,d,J=2.OHz), 9.87 (1H,brs), 10.44(1H,brs) 12(5) NMR(400MHz,CDCl3) 5 value: 1. 18-1.23(2H,m), 1.52- 1.75(6H,m), 2.08-2.16(1H,m), 2.62(2H,d,J=7.6Hz), 2.76- 2.79(2H,m), 2.95-2.98(2H,m), 3.73(3H,s), 6.69(1H,dd,J-8.2,1.6Hz), 6.8 7(1H,d,J=l.6Hz), 6.97(1H,d,J=8.8Hz), 7.51-7.53(3H,m), 7.91(1H,s), 12.08 (1H,s) 12(6) NMR(400MHz,CDCl3) 8 value: 2 . 78 (2H, t, J=6 . OHz) , 2.96(2H,t,J=6.0Hz), 3.73(3H,s), 6.98(1H,d,J=8.4Hz), 7.03(1H,dd,J=8.4,2.0Hz), 7.47-7.52(4H,m), 8.02(1H,brs), 12.06(1H,s) Example 13 5.00 g of 2-fluoro-4-methoxybenzoic acid was dissolved in 50 mL of methylene chloride, and after the consecutive addition thereto of 20 µL of N,N- dimethylformamide and 3.9 mL of oxalyl chloride at room temperature, the resultant mixture was stirred for 2.5 hours at room temperature. After 8.23 g of aluminum chloride and 6.28 g of methyl 3-(2-methoxyphenyl) propanoate were successively added thereto in an ice bath, this solution was stirred for two hours in an ice bath. Further, 19.64 g of aluminum chloride was added thereto, and then this solution was stirred for two hours while heating it under reflux. After ethyl acetate was added to the reaction mixture, this mixture was poured into the icecooled 6M hydrochloric acid for the separation of the organic phase therefrom. After the resultant organic phase was washed with 6M hydrochloric acid, water, and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=l:2] to yield 2.52 g of 6-(2-fluoro-4-hydroxybenzoyl)-2- chromanone as yellow oil. NMR(400MHz,CDC13) 5 value: 2.85(2H,dd,J=8.2,7.6Hz) , 3.08 (2H,t,J=7.6Hz), 6.55(1H,brs) , 6.66(1H,dd,J=l1.4,2.0Hz), 6.7 5(1H,dd,J=8.6,2.4Hz), 7.12(1H,d,J=8.4Hz), 7.52(1H,t,J=8.4Hz), 7.68-7.73(2H,m) Example 14 3.50 g of 4-isopropoxy-3- (3-isopropoxy-3- oxopropyl) benzoic acid was dissolved in 35 mL of methylene chloride, and after the consecutive addition thereto of 20 µL of N,N-dimethylf ormamide and 1.6 mL of oxalyl chloride at room temperature, the resultant mixture was stirred for 30 minutes at room temperature. The reaction mixture was cooled to -50 °C, and 3.17 g of aluminum chloride and 2.91 g of 1,3-diisobutoxybenzene were successively added thereto, followed by raising its temperature to an ambient temperature over 30 minutes. Then this mixture was stirred for one hour while heating it under reflux. Further, 0.790 g of aluminum chloride was added thereto, and then this mixture was stirred for one hour while heating it under reflux. The reaction mixture was poured into a mixture of ice water and methanol for the separation of the organic phase therefrom. After the resultant organic phase was washed with 6M hydrochloric acid and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=3:l] to yield 4.01 g of isopropyl 3-[2-hydroxy- 5-(2-hydroxy-4-isobutoxybenzoyl)phenyl] propanoate as yellow oil. NMR(90MHz,CDC13) 5 value: 1.03(6H,d,J=6.6Hz), 1.23(6H,d,J=6.1Hz), 1.97-2.26(1H,m), 2.71-2.92(4H,m), 3.78(2H,d,J=6.7Hz), 4.91-5.18(1H,m), 6.38-6.48(2H,m), 6.95 (1H,d, J==9.0Hz) , 7 . 40-7 . 59 (3H,m) , 8 . 18 (1H, brs) , 12.65(1H,s) Example 15 The following compounds were obtained in a similar manner as in Example 14. (1) isobutyl 3-[5-(2,4-dihydroxybenzoyl)-2- isobutoxyphenyl] propanoate NMR(90MHz,CDC13) 6 value: 0.89(6H,d,J=6.6Hz) , 1.07(6H,d,J=6.8Hz), 1.6-2.4(2H,m), 2.6-3.2(4H,m), 3.82(2H,d,J=6.1Hz), 3.87(2H,d,J=6.6Hz), 6.3-6.5(2H,m), 6.88(1H,d,J=9.3Hz), 7.0-7.6(4H,m), 12.63(1H,s) (2) isopropyl 3-[2-hydroxy-5-(4- isobutoxybenzoyl)phenyl] propanoate NMR(90MHz,CDCI3) 5 value: 1.05(6H,d,J=6.6Hz) , 1.22(6H,d,J=6.4Hz), 1.90-2.35(1H,m), 2.62-3.05(4H,m), 3.80(2H,d,J=6.4Hz), 4.90-5.18(1H,m), 6.89-7.00(3Hrm), 7.51-7.85(4H,m), 8.34(1H,brs) Example 16 6.00 g of 4-isobutoxy-3-(3-methoxy-3- oxopropyl) benzoic acid was dissolved in 60 mL of methylene chloride, and after the consecutive addition thereto of 20 µL of N, N-dimethylformamide and 2.8 mL of oxalyl chloride at room temperature, the resultant mixture was stirred for 3 hours at room temperature. After the reaction mixture was cooled to -30 °C, followed by the consecutive addition thereto of 5.17 g of aluminum chloride and 3.68 g of l-fluoro-3,5- dimethoxybenzene, this mixture was stirred for 30 minutes in an ice bath. The reaction mixture was poured into an iced 6M hydrochloric acid for the separation of the organic phase therefrom. After the resultant organic phase was washed with 6M hydrochloric acid, water, and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexanerethyl acetate=3:l] to yield 5.40 g of methyl 3-[5-(2-fluoro-4,6-dimethoxybenzoyl)-2- isobutoxyphenyl] propanoate as colorless oil. NMR(400MHz,CDCl3) 5 value: 1.05(6H,d,J=6.8Hz), 2.10- 2.17(1H,m), 2.61(2H,t,J=7.8Hz), 2.96(2H,t,J=7.8Hz), 3.66(3H,s), 3.72(3H,s), 3.80(2H,d,J=6.4Hz), 3.85(3H,s), 6.28-6.32(2H,m), 6.82(1H,d,J=8.4Hz), 7.69-7.73(2H,m) Example 17 5.00 g of methyl 3-[5-(2-fluoro-4,6- dimethoxybenzoyl)-2-isobutoxyphenyl] propanoate was dissolved in a mixed solvent of 50 mL of methylene chloride and 3.5 mL of ethyl acetate, and after the addition thereto of 12.7 g of aluminum chloride, the resultant mixture was stirred for 5 hours while heating it under reflux. The reaction mixture was poured into an iced 6M hydrochloric acid for the separation of the organic phase therefrom. After the resultant organic phase was washed with 6M hydrochloric acid, water, and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography feluent; hexane:ethyl acetate=2:l] to yield 2.82 g of methyl 3-[5- (2-fluoro- 4,6-dihydroxybenzoyl)-2-hydroxyphenyl] propanoate as yellowish foam. NMR(400MHz,CDCl3) 5 value: 2 . 75 (2H,t,J=6.0Hz), 2.95(2H,t,J=6.8Hz), 3.72(3H,s), 6.13(1H,dd,J=12.0,2.4Hz), 6.2 9-6.30(1H,m), 6.89(1H,d,J=8.4Hz), 7.26 (1H,brs), 7.46-7.49(2H,m), 7.95(1H,brs), 11.82(1H,s) Example 18 74.2 g of methyl 3-[5-(2,4-dihydroxybenzoyl)- 2-hydroxyphenyl] propanoate was suspended in 742 mL of toluene, and then 2.23 g of p-toluenesulfonic acid monohydrate was added thereto. This suspension was stirred for four hours while heating it under reflux. This reaction mixture was cooled to room temperature, followed by the consecutive addition thereto of ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was solidified with diisopropyl ether and washed with ethanol to yield 56.3 g of 6-(2,4- dihydroxybenzoyl)-2-chromanone as light yellow solid. NMR (4 00MHz, DMSO-d6) 8 value: 2 . 85 (2H, t, J=6 . 8Hz) , 3.08(2H,t,J=6.8Hz), 6.37(1H,d,J=2.2Hz), 6.4 0(1H,dd,J=8.6,2.2Hz), 7.2 0(1H,d,J=8.3Hz), 7.41(1H,d,J=8.6Hz), 7.56 (1H,dd,J=8.4,2.2Hz), 7.62(1H,d,J=2.0Hz), 10.70(1H,s), 12.06(1H,s) Example 19 The following compounds were obtained in a similar manner as in Example 18. (1) 6-(4-hydroxy-2-methylbenzoyl)-2- chromanone NMR(400MHz,CDCl3) 8 value: 2.36(3H,s), 2.8 4(2H,t,J=7.4Hz), 3.07(2H,t,J=7.4Hz), 6.71(1H,dd,J=8.4,2.4Hz), 6.7 8(1H,d,J=2.4Hz), 6.88 (1H,brs), 7.09(1H,d,J=8.0Hz), 7.25(1H,d,J=8.4Hz), 7.66(1H,dd,J=8.0, 2.0Hz), 7.67(1H,s) (2) 6-(2-fluoro-4,6-dihydroxybenzoyl)-2- chromanone NMR(400MHz,CDCl3) 8 value: 2 . 83-2 . 87 (2H,m) , 3.08(2H,t,J=8.0Hz), 5.98(1H,brs), 6.15(1H,dd,J=12.2,2.4Hz), 6.30-6.31(1H,m), 7.11(1H,d,J=8.4Hz), 7.54-7.57(2H,m), 11.89(1H,s) Example 2 0 50.0 g of 6-(2,4-dihydroxybenzoyl)-2- chromanone, 17.6 mL of cyclopentanol, and 55.4 g of triphenylphosphine were dissolved in 500 mL of tetrahydrofuran, to which 41.6 mL of diisopropyl azodicarboxylate was added dropwise at temperatures of 15 to 32°C, and this solution was stirred for 30 minutes at room temperature. The reaction mixture was poured into a mixture of ethyl acetate and water for the separation of the organic phase therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=3:l] to yield 54.7 g of 6-[4-(cyclopentyloxy)- 2-hydroxybenzoyl]-2-chromanone as light yellow solid. NMR(90MHz,CDC13) 5 value: 1.42-2.20(8H,m), 2.74- 3.10(4H,m), 4.60-5.03(1H,m), 6.31-6.48(2H,m), 7.12(1H,d,J=9.0Hz), 7.30-7.58(3H,m), 12.55(1H,s) Example 21 Compounds listed in Table 15 were obtained in a similar manner as in Example 20. 21(1) NMR (400MHz, CDC13) 8 value: 1.64-1. 71 (2H,m) , 1.78- 1.99(6H,m), 2.82-2.86(2H,m), 3.06-3.09(2H,m), 4.79- 4.82(1H,m), 6.62(1H,dd,J=12.2,2.0Hz), 6.76(1H,dd,J=8.6,2.4Hz), 7.11(1H,d,J=8.4Hz), 7.55(1H,t,J=8.8Hz), 7.68-7.72(2H,m) 21(2) NMR (400MHz, CDC13) 8 value: 0.95(6H,d,J=6.4Hz), 1.68(2H,q,J=6.8Hz), 1.78-1.84(1H,m), 2.82-2.85(2H,m), 3.07(2H,t,J=7.6Hz), 4.04(2H,t,J=6.8Hz), 6.4 0(1H,dd,J=9.2,2.4Hz), 6.4 9(1H,d,J=2.0Hz), 7.13(1H,d,J=8.8Hz), 7.45(1H,d,J=8.8Hz), 7.53-7.55(2H,m), 12.53(1H,s) 21(3) NMR(4 00MHz,CDC13) 5 value: 1.05(9H,s), 2.84-2.88(2H,m), 3.08-3.11(2H,m), 3.66(2H,s), 6.44(1H,dd,J=8.8,3.6Hz), 6.51(1H,d,J=2.4Hz), 7.16(1H,d,J=8.8Hz), 7.45-7.57(3H,m), 12.54(1H,s) 21(4) NMR(90MHz,CDCI3) 5 value: 1.1-2.2(10H,m), 2.7-3.2(4H,m), 4.1-4.5(1H,m), 6.3-6.5(2H,m), 7.14(1H,d,J=8.8Hz), 7.4- 7.6(3H,m), 12.54(1H,s) 21(5) NMR(400MHz,CDCl3) 8 value: 1. 59-1.71(2H,m), 1.75- 1.98(6H,m), 2.82-2.86(2H,m), 3.06-3.09(2H,m), 4.79- 4.81(1H,m), 6.13(1H,dd,J=13.2,2.4Hz), 6.32(1H,t,J=1.2Hz), 7.11(1H,d,J=8.0Hz), 7.53-7.57(2H,m), 12.03(1H,s) 21(6) NMR(400MHz,CDCl3) 8 value: 1.6-1.7(2H,m), 1.7-2.0(6H,m), 2.39(3H,s), 2.83(2H,t,J=7.4Hz), 3.06(2H,t,J=7.4Hz), 4.80-4.85(1H,m), 6.71(1H,dd,J=8.8, 2.4Hz), 6.7 9 (1H,d,J=2.4Hz), 7.09(1H,d,J=8.8Hz), 7.29(1H,d,J=8.4Hz), 7.66(1H,dd,J=8.4,2.0Hz), 7.70(1H,d,J=2.0Hz) 21(7) NMR(90MHz,CDCl3) 5 value: 0.96 (6H, t, J=7 . 2Hz), 1.5- 1.9(4H,m), 2.7-3.2(4H,m), 4.0-4.4(1H,m), 6.4-6.5(2H,m), 7.15(1H,d,J=9.0Hz), 7.4-7.6(3H,m), 12.55(1H,s) 5 21(8) NMR(90MHz,CDCl3) 5 value: 0 . 8-2 . 0 (HH,m) , 2 . 7-3.2(4H,m), 3.82(2H,d,J=5.9Hz), 6.3-6.5(2H,m), 7.14(1H,d,J=8.8Hz), 7.4-7.6(3H,m), 12.54(1H,s) 21(9) D NMR(90MHz, CDC13) 8 value: 0.3-0.8(4H,m), 1.1-1.4(1H,m), 2.7-3.2(4H,m), 3 . 87(2H,d,J=6.8Hz), 6.4-6.5(2H,m), 7.13 (1H,d,J=9.0Hz) , 7.4-7.6(3H,m), 12.53(1H,s) 21 (10) NMR(90MHz, CDCl3) 5 value: 1.2-2.2(12H,m) , 2.7-3.2(4H,m) , 3 4.4-4.7(1H,m), 6.3-6.5(2H,m), 7.14(1H,d,J=9.0Hz), 7.4- 7.7(3H,m), 12.55(1H,s) 21(11) NMR(400MHz,CDCl3) 5 value: 1.33-1.41(2H,m), 1.57- 1.68(4H,m), 1.81-1.89(2H,m), 2.35-2.42(1H,m), 2.84- D 2.87(2H,m), 3.09(2H,t,J=7.6Hz), 3.90(2H,d,J=6.8Hz), 6.42(1H,dd,J=9.2,2.4Hz), 6.51(1H,d,J=2.4Hz), 7.l6(1H,d,J=8.8Hz), 7.47(1H,d,J=9.2Hz), 7.55-7.57(2H,m), 12.55(1H,s) 21(12) 5 NMR(90MHz, CDCI3) 8 value: 2.70-3.20(4H,m), 5.15(2H,s), 6.40-6.60(2H,m), 7.10-7.90(6H,m), 8.60-8.70(2H,m), 12.51 (1H,s) 21 (13) NMR(400MHz,CDCl3) 8 value: 1. 69-1.77(1H,m), 1.87- 1.94(1H,m), 2.18-2.23(2H,m), 2.48-2.51(2H,m), 2.83- 2.87(2H,m), 3.09(2H,t,J=6.8Hz), 4.69-4.73(1H,m), 6.36(1H,dd, J=9.0,2.4Hz) , 6.4 0(1H,d,J=2.4Hz), 7.15(1H,d,J=8.5Hz), 7.47(1H,d,J=9.0Hz), 7.54-7.57(2H,m), 12.54(1H,s) 21(14) NMR (400MHz, CDC13) 8 value: 2 . 83-2 . 87 (2H,m) , 3.10(2H,t,J=8.0Hz), 5.13(2H,s), 6.51(1H,dd,J=9.2,2.4Hz), 6.61(1H,d,J=2.4Hz), 7.16(1H,d,J=8.4Hz) , 7.34-7.57(8H,m), 12.53(1H,s) Example 22 54.7 g of 6-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-chromanone was suspended in 274 mL of methanol, to which 71.9 g of a 28% solution of sodium methoxide in methanol was added dropwise at temperatures of 0 to 4°C, and this suspension was stirred for one hour at temperatures of 2 to 4°C. The reaction mixture was poured into a mixture of ethyl acetate and 6M hydrochloric acid, to which water was added, for the separation of the organic phase therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was solidified with a mixed solvent of diisopropylether and hexane (1:1) to yield 45.3 g of methyl 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2- hydroxyphenyl} propanoate as white solid. NMR( 90MHz, CDC13) 5 value: 1. 43-2 . 12 (8H,m) , 2.73- 2.96(4H,m), 3.70(3H,s), 4.68-4.92(1H,m), 6.31- 6.46(2H,m), 6.89(1H,d,J=8.1Hz), 7.24-7.58(3H,m), 9.90(2H,brs) Example 23 Compounds listed in Table 16 were obtained in a similar manner as in Example 22. 23(1) NMR(400MHz,CDCl3) 6 value: 1.63-1.69(2H,m), 1.78- 1.98(6H,m), 2.74-2.77(2H,m), 2.92-2.95(2H,m), 3.72(3H,s), 4.78-4.82(1H,m), 6.61(1H,dd,J=12.2,2.4Hz), 6.73(1H,dd,J=8.8,2.4Hz), 6.91(1H,d,J=8.4Hz), 7.48(1H,t,J=8.4Hz), 7.58-7.61(1H,m), 7.67(1H,d,J=l.2Hz), 7.98 (1H,s) 23(2) NMR(400MHz, CDC13) 5 value: 0.95(6H,d,J=6.6Hz), 1.68 (2H, q, J=6.6Hz), 1.76-1.86 (1H,m), 2.73-2.76(2H,m), 2.92-2.95(2H,m) , 3.70(3H,s), 4.03(2H,t,J=6.6Hz), 6.38(1H,dd,J=6.3,2.4Hz), 6.4 7 (1H, d, J=l.7Hz), 6.94 (1H,d,J=8.1Hz), 7.32-7.52(3H,m), 7.82(1H,s), 12.64 (1H,s) 23(3) NMR(400MHz,CDCl3) 5 value: 1.04(9H,s), 2 . 76-2 . 79 (2H, m), 2.90-2.97(2H,m), 3.67(2H,s), 3.70(3H,s), 6.43(1H,dd, J=9.0,2.8Hz), 6.50(1H,d,J=2.4Hz), 6.96(1H,d, J=8.4Hz), 7.46-7.49(2H,m), 7.53(1H,d,J=9.2Hz), 7.87(1H,s), 12.64(1H,s) 23(4) NMR(90MHz,CDCl3) 5 value: 1. 1-2 . 2 (10H,m) , 2 . 6-3 .1 (4H,m) , 3.70(3H,s), 4.1-4.5(1H,m), 6.3-6.5(2H,m), 6.90(1H,d,J=8.5Hz), 7.3-7.6(3H,m), 8.12(1H,s), 12.69(1H,s) 23(5) NMR (400MHz, CDCl3) 5 value: 1. 61-1. 68 (2H,m) , 1.78- 1.95(6H,m), 2.76(2H,t,J=5.6Hz), 2.93(2H,t,J=6.4Hz), 3.72(3H,s), 4.77-4.80(1H,m), 6.13(1H, dd,J=13.2,2.4Hz), 6.31(1H,t,J=1.2Hz), 6.92(1H,d,J=8.8Hz), 7.48-7.52(2H,m), 7.90(1H,s), 11.90(1H,s) 23(6) NMR(400MHz,CDCl3) 8 value: 1. 6-2. 0 (8H,m) , 2.34(3H,s), 2.73(2H,t,J=6.4Hz), 2.93(2H,t,J=6.4Hz), 3.68(3H,s), 4.79-4.83(1H,m), 6.70(1H,dd,J=8.4, 2.4Hz), 6.7 7(1H,d,J=2.4Hz), 6.8 9(1H,d,J=8.8Hz), 7.26(1H,d,J=8.4Hz), 7.53 (1H,dd,J=8.4,2.OHz), 7.64(1H,d,J=2.4Hz), 8.13(1H,s) 23(7) I NMR(90MHz,CDC13) 8 value: 0.96(6H,t,J=7.2Hz) , 1.5- 1.9(4H,m), 2.7-3.1(4H,m), 3.72(3H,s), 4.1-4.4(1H,m), 6.3-6.5(2H,m), 6.95(1H,d,J=9.OHz), 7.4-7.6(3H,m), 7.86(1H,s), 12.67(1H,s) 23(8) NMR(90MHz,CDCI3) 8 value: 0.7-2.1(11H,m), 2.6-3.1(4H,m), 3.72(3H,s), 3.82(2H,d,J=5.9Hz), 6.3-6.5(2H,m), 6.93(1H,d,J=9.OHz), 7.4-7.6(3H,m), 7.96(1H,brs), 12.67(1H,s) 23(9) NMR(90MHz,CDCl3) 8 value: 0.2-1.6(5H,m), 2.6-3.2(4H,m), 3.71(3H,s), 3.86(2H,d,J=6.8Hz), 6.3-6.5(2H,m), 6.92(1H,d,J=9.OHz), 7.2-7.7(4H,m), 8.8-10.6(1H,br) 23(10) NMR(90MHz,CDCl3) 8 value: 1. 2-2 . 2 (12H,m) , 2 . 6-3 . 1 (4H,m) , 3.72(3H,s), 4.3-4.7(1H,m), 6.3-6.4(2H,m), 6.94(1H,d,J=9.OHz), 7.4-7.6(3H,m), 7.89(1H,s), 12.67 (1H,s) 23(11) light yellow solid NMR(90MHz,CDCl3) 8 value: 1.03(6H,d,J=6.6Hz), 1.8- 2.3(1H,m), 2.6-3.7(4H,m), 3.72(3H,s), 3.78(2H,d,J=6.6Hz), 6.35-6.51(2H,m), 6.92(1H,d,J=9.OHz), 7.40-7.59(3H,m), 7.8-8.2(1H,br), 12.66(1H,s) 23(12) NMR(400MHz,CDC13) 5 value: 1. 33-1.38(2H,m), 1.57- 1.68(4H,m), 1.81-1.88(2H,m), 2.34-2.41(1H,m), 2.76- 2.79(2H,m), 2.95(2H,t,J=6.6Hz), 3.72(3H,s), 3.89(2H,d,J=6.9Hz), 6.41(1H,dd,J=8.8,2.4Hz), 6.49(1H,d,J=2.4Hz), 6.96(1H,d,J=8.3Hz), 7.45-7.54(3H,m), 7.85(1H,s), 12.64(1H,s) 23(13) NMR(90MHz,CDC13) 8 value: 2.60-3.10(4H,m), 3.70(3H,s), 5.15(2H,s), 6.40-6.60(2H,m), 6. 93(1H,d,J=8.3Hz), 7.20- 7.90(6H,m), 8.60-8.70(2H,m), 12.65(1H,s) 23(14) NMR(400MHz,CDCl3) 5 value: 1. 66-1.78(1H,m), 1.86- 1.94(1H,m), 2.17-2.22(2H,m), 2.45-2.52(2H,m), 2.77(2H,t,J=6.8Hz), 2.96(2H,t,J=6.8Hz), 3.73(3H,s), 4.68-4.72(1H,m), 6.35(1H,dd,J=8.8,2.4Hz), 6.38(1H,d,J=2.4Hz), 6.96(1H,d,J=8.4Hz), 7.45-7.48(2H,m), 7.53(1H,d,J=8.8Hz), 7.85(1H,s), 12.65(1H,s) 23(15) NMR (400MHz, CDCI3) 8 value: 2 . 76-2 . 79 (2H,m) , 2.96(2H,t,J=6.4Hz), 3.73(3H,s), 5.12(2H,s), 6.49(1H,dd,J=9.0,2.8Hz), 6.5 9(1H,d,J=2.8Hz), 6.96(1H,d,J=8.0Hz), 7.33-7.49(7H,m), 7.56(1H,d,J=8.8Hz) , 7.86(1H,s), 12.64(1H,s) Example 24 2.00 g of 6-(2,4-dihydroxybenzoyl)-2- chromanone was dissolved in 20 mL of tetrahydrofuran, to which 0.65 mL of 2-propanol and 2.21 g of triphenylphosphine were added and to which a solution of 1.7 mL of diisopropyl azodicarboxylate in 2 mL of tetrahydrofuran were added dropwise at 18-37°C, and the this mixture was stirred for one hour at room temperature. The reaction mixture was poured into a mixture of ethyl acetate and water, for the separation of the organic phase therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was dissolved in 20 mL of methanol, to which 3.39 g of a 28% solution of sodium methoxide in methanol was added dropwise in an ice bath, and then this mixture was stirred for one hour at temperatures of 5 to 10°C. The reaction mixture was poured into a mixture of chloroform and aqueous diluted hydrochloric acid. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; toluene:ethyl acetate=4:l] and solidified with hexane to yield 2.36 g of methyl 3-[2- hydroxy-5-(2-hydroxy-4-isopropoxybenzoyl)phenyl] propanoate as light yellow solid. NMR(400MHz,DMS0-d6) 8 value: 1.36(6H,d,J=6.0Hz), 2.61(2H,t,J=7.6Hz), 2.84(2H,t,J=7.6Hz), 3.59(3H,s), 4.7 0-4.76(1H,m), 6.4 8(1H,dd,J=8.8,2.OHz), 6.52(1H,d,J=2.4Hz), 6.93(1H,d,J=8.4Hz), 7.43-7.48(3H,m), 10.42(1H,brs), 12.08(1H,brs) Example 25 10.0 g of 6-(2,4-dihydroxybenzoyl)-2- chromanone was suspended in 100 mL of methylene chloride, to which 3.53 mL of 3,4-dihydro-2H-pyran and 0.884 g of pyridinium p-toluenesulfonate were added, and this mixture was stirred for 18 hours at room temperature. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=3:l] to yield 6.99 g of 6-[2-hydroxy-4- (tetrahydro-2H-pyran-2-yloxy)benzoyl]-2-chromanon as light yellow solid. NMR(400MHz,CDCl3) 5 value: 1. 5-2 .1 ( 6H, m) , 2.86(2H,t,J=7.6Hz), 3.10(2H,t,J=7.6Hz), 3.6-3.7(1H,m), 3.8-3.9(1H,m), 5.52(1H,t,J=3.2Hz), 6.55(1H,dd,J=9.2,2.4Hz), 6.72(1H,d,J=2.4Hz) , 7.14(1H,d,J=8.4Hz), 7.4-7.6(3H,m), 12.39(1H,s) Example 2 6 3.20 g of 6-[2-hydroxy-4-(tetrahydro-2H- pyran-2-yloxy)benzoyl]-2-chromanone was suspended in 18.6 mL of methanol and was cooled to 0°C, to which 4.02 g of a 28% solution of sodium methoxide in methanol was added dropwise, and then this mixture was stirred for one hour at temperatures of -5 to 0°C. The reaction mixture was poured into a mixture of ethyl acetate and 6M hydrochloric acid, to which water was added, and the organic phase was separated therefrom. After the resultant organic phase was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=3:l] to yield 3.29 g of methyl 3- {2-hydroxy-5- [2-hydroxy-4- (tetrahydro-2H-pyran-2- yloxy)benzoyl]phenyl} propanoate as light yellow oil. NMR(400MHz,CDCl3) 5 value: 1.5-2.1( 6H, m), 2.77(2H,t,J=6.0Hz), 2.96(2H,t,J=6.2Hz), 3.6-3.7(1H,m), 3.73(3H,s), 3.8-3.9(1H,m), 5.51(1H,t,J=3.2Hz), 6.54(1H,dd,J=8.8,2.4Hz), 6.71(1H,d,J=2.4Hz), 6.96(1H,d,J=8.8Hz), 7.4-7.6(3H,m), 7.87(1H,s), 12.50(1H,s) Example 27 3.20 g of methyl 3-{2-hydroxy-5-[2-hydroxy-4- (tetrahydro-2H-pyran-2-yloxy)benzoyl]phenyl} propanoate, 1.83 g of methyl 4-(bromomethyl)benzoate, and 1.33 g of potassium carbonate were suspended in 32 mL of N,N- dimethylformamide, and this mixture was stirred for one hour at temperatures of 60 to 70°C. After the reaction mixture was cooled to room temperature, this mixture was added to a mixture of ethyl acetate and ice water, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=3:l] to yield 2.75 g of methyl 4- {[4-[2-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)benzoyl]- 2-(3-methoxy-3-oxopropyl)phenoxy]methyl} benzoate as light yellow solid. NMR(400MHz,CDCl3) δ value: 1. 5-2 .1 ( 6H,m) , 2.69(2H,t,J=7.2Hz), 3.08(2H,t,J=7.2Hz), 3.6-3.7(1H,m), 3.67(3H,s), 3.8-3.9(1H,m), 3.93(3H,s), 5.24(2H,s), 5.4- 5.6(1H,m), 6.54(1H,d,J=8.0Hz), 6.71(1H,s), 6.93(1H,d,J=8.0Hz), 7.4-7.6(5H,m), 8.09 (2 H,d,J=7.6Hz), 12.51 (1H,s) Example 2 8 2.70 g of methyl 4-{ [4-[2-hydroxy-4- (tetrahydro-2H-pyran-2-yloxy)benzoyl]-2-(3-methoxy-3- oxopropyl)phenoxy]methyl} benzoate was suspended in 27 mL of tetrahydrofuran, to which 27 mL of 1M hydrochloric acid was added, and this suspension was stirred for 3 hours at room temperature and then for another one hour at temperatures of 30 to 40°C. After the reaction mixture was cooled to room temperature, this mixture was added to a mixture of ethyl acetate and water, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was solidified with diisopropyl ether, and the solid filtered out was washed with diisopropyl ether to yield 2.28 g of methyl 4-{[4-(2,4- dihydroxybenzoyl)-2-(3-methoxy-3- oxopropyl)phenoxy]methyl} benzoate as white solid. NMR (400MHz, CDC13) 8 value: 2 . 70 (2H, t, J=7 . 6Hz) , 3.08(2H,t,J=7.6Hz), 3.67(3H,s), 3.94(3H,s), 5.24(2H,s), 6.36(1H,dd,J=8.8,2.4Hz), 6.4 5(1H,d,J=2.4Hz), 6.58(1H,brs), 6.93(1H,d,J=8.4Hz), 7.49-7.55(5H,m), 8.09(2H,dd,J=6.8,1.6Hz), 12.60(1H,s) Example 2 9 32.0 g of methyl 3-{5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-hydroxyphenyl} propanoate and 23.0 g of potassium carbonate were suspended in 320 mL of N,N- dimethylformamide, and a temperature of this suspension was raised to 50°C. 28.5 g of 6-(bromomethyl)-3- (methoxymethoxy)-1,2-berizisoxazole was further added to this suspension, and which was stirred for one hour at 50°C. After the reaction mixture was cooled to room temperature, this mixture was added to a mixture of ethyl acetate and water, and was adjusted to pH 7 with 6M hydrochloric acid, then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=2:l] to yield 32.5 g of methyl 3-(5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2- benzisoxazol-6-yl]methoxy}phenyl)propanoate as yellow oil. NMR(4 00MHz, CDC13) 5 value: 1.60-1.66(2H,m), 1.74- 1.99(6H,m), 2.70 (2H,t,J=7.6Hz) , 3.09(2H,t,J=7.6Hz) , 3.65(3H,s), 3.68(3H,s), 4.80-4.83(1H,m), 5.33(2H,s), 5.57(2H,s), 6.37(1H,dd,J=9.0,2.8Hz), 6.48(1H,d,J=2.8Hz) , 6.95(1H,d,J=8.4Hz), 7.36(1H,d,J=8.0Hz), 7.45-7.57(4H,m), 7.72(1H,d,J=8.0Hz), 12.69(1H,s) Example 30 32.0 g of methyl 3-(5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2- benzisoxazol-6-yl]methoxy}phenyl) propanoate was dissolved in a mixed solvent of 96 mL of methanol and 96 mL of 1,4-dioxane, to which 32 mL of 6M hydrochloric acid was added at room temperature, and then this mixture was stirred for 30 minutes at the same temperature. The resulting precipitate was filtered and solid was washed with water and diisopropyl ether successively to yield 26.3 g of methyl 3-{5-[4- (cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-l,2- benzisoxazol-6-yl)methoxy]phenyl}propanoate as light yellow solid. NMR(4 00MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.93- 1.96(2H,m), 2.67(2H,t,J=7.6Hz), 2.96(2H,t,J=7.6Hz), 3.58{3H,s), 4.90-4.93(1H,m), 5.42(2H,s), 6.47- 6.51(2H,m), 7.20(1H,d,J=8.4Hz), 7.43-7.45(2H,m), 7.55- 7.57(2H,m), 7.68(1H,s), 7.79(1H,d,J=8.4Hz), 12.02(1H,s), 12.41(1H,brs) Example 31 0.66 g of methyl 3-[5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-({4-[3-(methoxymethoxy)-5- isoxazolyl]benzyl}oxy)phenyl] propanoate was dissolved in a mixed solvent of 4 mL of methanol and 4 mL of 1,4- dioxane, to which 3 mL of 6M hydrochloric acid was added at room temperature, and then this mixture was stirred for 20 minutes at the same temperature and for another 20 minutes while heating it under reflux. Resultant precipitate was filtered out, and the resultant solid was washed with diisopropyl ether to yield 0.40 g of methyl 3-(5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-{[4-(3-hydroxy-5- isoxazolyl)benzyl]oxy}phenyl)propanoate as light yellow solid. NMR(4 00MHz,DMSO-d6) 8 value: 1. 5-1.8(6H,m), 1.9- 2.0(2H,m), 2.66(2H,t,J=7.6Hz), 2.95(2H,t,J=7.6Hz), 3.57(3H,s), 4.92(1H,m), 5.33(2H,s), 6.48 (1H,dd,J=8.8,2.4Hz), 6. 51(1H,d,J=2.0Hz), 6.58(1H,s), 7.19(1H,d,J=8.4Hz), 7.44(1H,d,J=8.8Hz), 7.5-7.6(2H,m), 7.62(2H,d,J=8.0Hz), 7.85(2H,d,J=8.4Hz), 11.41(1H,br), 12.01(1H,S) Example 32 The following compounds were obtained in a similar manner as in Example 31. (1) 4-({2-(2-carboxyethyl)-4-[4- (cyclopentyloxy)-2-hydroxybenzoyl]phenoxy}methyl)-3- hydroxybenzoic acid NMR(4 00MHz,DMSO-d6) 5 value: 1.60-1.74(6H,m), 1.90- 2.00(2H,m), 2.57(2H,t,J=7.6Hz) , 2.89(2H,t,J=7.6Hz), 4.90-4.93(1H,m), 5.23(2H,s), 6.48-6.50(2H,m), 7.17(1H,d,J=8.4Hz), 7.41-7.49(4H,m), 7.54-7.57(2H,m), 10.20(1H,s), 12.05(1H,s), 12.48(2H,brs) (2) methyl 3-{5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-[(3-hydroxy-l,2-benzisoxazol-5- yl)methoxy]phenyl} propanoate NMR(400MHz,CDCl3) 6 value: 1.62-1.68(2H,m), 1.78- 1.98(6H,m), 2.70(2H,t,J=7.6Hz), 2.75(1H,brs), 3.08(2H,t,J=7.6Hz), 3.68(3H,s), 4.81-4.84(1H,m), 5.29(2H,s), 6.37(1H,dd,J=8.8,2.4Hz) , 6.48(1H,d, J=2.4Hz) , 6.99(1H,d,J=8.8Hz), 7.4 8(1H,d,J=8.4Hz), 7.51(1H,d,J=8.8Hz), 7.54-7.57(2H,m), 7.68(1H,dd,J=8.4,2.0Hz), 7.91(1H,s), 12.69(1H,s) Example 33 3.00 g of methyl 3-{5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-hydroxyphenyl} propanoate and 2.16 g of potassium carbonate were suspended in 30 mL of N,N- dimethylformamide, and after this suspension was stirred for 30 minutes at room temperature, 2.55 g of 6-(bromomethyl)-2-(methoxymethyl)-1,2-benzisoxazol- 3(2H)-one was added thereto at the same temperature and this mixture was stirred for 30 minutes at 50°C. The reaction mixture was cooled to room temperature, and was added to a mixture of ethyl acetate and water, which was adjusted to pH 5 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=l:l] to yield 3.90 g of methyl 3- (5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-{[2- (methoxymethyl)-3-oxo-2,3-dihydro-l,2-benzisoxazol-6- yl]methoxy}phenyl)propanoate as yellow oil. NMR(400MHz,CDCl3) 8 value: 1.62-1.66(2H,m), 1.78- 1.96(6H,m), 2.70(2H,t,J=7.6Hz), 3.10(2H,t,J=7.6Hz), 3.47(3H,s), 3.68(3H,s), 4.81-4.83(1H,m), 5.31(2H,s), 5.35(2H,s), 6.37(1H,dd,J=9.0,2.4Hz), 6.48(1H,d,J=2.4Hz), 6.93(1H,d,J=8.4Hz), 7 . 35(1H,d,J=8.4Hz), 7.39(1H,s), 7.49-7.57(3H,m), 7.90(1H,d,J=8.4Hz), 12.68(1H,s) Example 34 3.65 g of methyl 3-(5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-{[2-(methoxymethyl)-3-oxo-2,3- dihydro-1,2-benzisoxazol-6-yl]methoxy}phenyl) propanoate was dissolved in a mixed solvent of 40 mL of methanol and 40 mL of 1,4-dioxane, to which 30 mL of 6M hydrochloric acid was added at room temperature, and then this mixture was stirred for 4 hours while heating it under reflux. The reaction mixture was cooled to room temperature, to which chloroform and water were added, and then the organic phase was separated therefrom. After the resultant organic phase was washed with a saturated sodium chloride solution, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; chloroform:ethanol=50:1] to yield 1.90 g of methyl 3- {5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3- hydroxyl-1,2-benzisoxazol-6-yl)methoxy]phenyl}- propanoate as light yellow solid. NMR(400MHz,DMSO-d6) 5 value: 1.60-1.74(6H,m), 1.93- 1.96(2H,m), 2.67(2H,t,J=7.6Hz), 2.96(2H,t,J=7.6Hz), 3.58(3H,s), 4.90-4.93(1H,m), 5.42(2H,s), 6.47- 6.51(2H,m), 7.20(1H,d,J=8.4Hz), 7.43-7.45(2H,m), 7.55- 7.57(2H,m), 7.68(1H,s), 7.79(1H,d,J=8.4Hz), 12.02(1H,s), 12.41(1H,brs) Example 35 26.0 g of methyl 3-{5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-[(3-hydroxy-l,2-benzisoxazol-6- yl)methoxy]phenyl} propanoate was suspended in 182 mL of methanol, to which a solution of 10.5 g of sodium hydroxide in 78 mL of water was added dropwise at room temperature, and then this mixture was stirred for 30 minutes at the same temperature. The reaction mixture was added to water, which was then adjusted to pH 1.5 with 6M hydrochloric acid, and resultant precipitate was filtered out. The resultant solid was dissolved in a mixed solvent of chloroform and methanol, and washed with water, and subsequently, a solvent in the separated organic phase was distilled out under reduced pressure. The resultant residue was washed with hexane to yield 22.5 g of 3-{5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-[(3-hydroxy1-1,2-benzisoxazol-6- yl)methoxy]phenyl}propanoic acid as light yellow solid. NMR (400MHz,DMSO-d5) 5 value: 1.60-1.74(6H,m), 1.95- 1.97(2H,m), 2.59(2H,t,J=7.2Hz), 2.94(2H,t,J=7.2Hz), 4.88-4.95(1H,m), 5.42(2H,s), 6.48-6.51(2H,m), 7.20(1H,d,J=9.2Hz), 7.43-7.47(2H,m), 7.55-7.57(2H,m), 7.69(1H,s), 7.80(1H,d,J=8.0Hz), 12.06(1H,s), 12.30 (2H,brs) Example 3 6 40.0 g of methyl 3-{5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-hydroxyphenyl} propanoate, 23.8 g of methyl 4-(bromomethyl) benzoate, and 17.3 g of potassium carbonate were suspended in 400 mL of N,N- dimethylformamide, and this mixture was stirred for one hour at 60°C. The reaction mixture was cooled to room temperature, which was then added to a mixture of ethyl acetate and ice water, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was solidified with diisopropyl ether and filtered out. Crude crystals thus obtained were recrystallized from methanol to yield 40.1 g of methyl 4-{[4-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-(3- methoxy-3-oxopropyl)phenoxy]methyl} benzoate as light yellow crystals. NMR(90MHz,CDCl3) 5 value: 1.50-2.04(8H,m), 2.58- 3.18(4H,m), 3.67(3H,s), 3.93(3H,s), 4.71-4.93(1H,m), 5.24(2H,s), 6.30-6.49(2H,m), 6.93(1H,d,J=9.0Hz), 7.47- 7.56(5H,m), 8.09(2H,d,J=8.1Hz), 12.68(1H,s) Example 37 1.00 g of methyl 3-{5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-hydroxyphenyl}propanoate, 0.809 g of methyl 4-(bromomethyl)-2-methoxy benzoate, and 0.539 g of potassium carbonate were suspended in 10 mL of N,N- dimethylformamide, and this suspension was stirred for 30 minutes at temperatures of 50 to 60°C. The reaction mixture was cooled to room temperature, which was then added to a mixture of ethyl acetate and water, and this mixture was adjusted to pH 2 with 6M hydrochloric acid for the separation of the organic phase therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=2:l] to yield 1.08 g of methyl 4- {[4-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-methoxy- 3-oxopropyl)phenoxy]methyl}-2-methoxybenzoate as yellow oil. NMR(400MHz,CDC13) 8 value: 1.59-1.66(2H,m), 1.76- 1.98(6H,m), 2.69(2H,t,J=7.6Hz), 3.08(2H,t, J=7.6Hz) , 3.66(3H,s), 3.90(3H,s), 3.94(3H,s), 4.80-4.83{lH,m), 5.20(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.48(1H,d,J=2.4Hz), 6.93(1H,d,J=8.4Hz), 7.03(1H,d,J=8.0Hz), 7.09(1H,s), 7.50(1H,d,J=8.8Hz), 7.52-7.55(2H,m), 7 . 84(1H,d,J=8.0Hz), 12.68 (1H,s) Example 38 1.36 g of methyl 3-{5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-hydroxyphenyl} propanoate, 1.43 g of 5-[4-(bromomethyl)phenyl]-3-isoxazolyl methoxymethyl ether, and 0.975 g of potassium carbonate were suspended in 12 mL of N,N-dimethylformamide, and this suspension was stirred for 30 minutes at 60°C. The reaction mixture was cooled to room temperature, which was then added to a mixture of ethyl acetate and water, and this mixture was adjusted to pH 2 with 6M hydrochloric acid for the separation of the organic phase therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; ethyl acetate] to yield 0.76 g of methyl 3-[5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2- ({4- [3-(methoxymethoxy)-5-isoxazolyl]benzyl}oxy)phenyl] propanoate as yellow oil. NMR(400MHz,CDCl3) 5 value: 1. 5-2 .1 (8H,m) , 2.69(2H,t,J=7.6Hz), 3.07(2H,t,J=7.6Hz), 3.59(3H,s), 3.67(3H,s), 4.7-4.9(1H,m), 5.22(2H,s), 5.38(2H,s), 6.26(1H,s), 6.37(1H,dd,J=9.0, 2.4Hz), 6.48(1H,d,J=2.4Hz), 6.95(1H,d,J=8.4Hz), 7.5-7.6(5H,m), 7.78 (2H,d,J=8.4Hz) , 12.70(1H,s) Example 39 Compounds listed in Tables 17 to 21 were obtained in a similar manner as in Example 36. Each of the compounds 39(47) and 39(61) to 39(64) in these tables was synthesized from a compound having a hydroxyl group as R4, for the purpose of substitution of R4. 39(1) NMR(4 00MHz,CDCl3) 5 value: 2.70(2H,t,J=7.6Hz), 3.09(2H,t,J=7.6Hz), 3.68(3H,s), 3.94(3H,s), 5.26(2H,s), 6.96(1H,d,J=8.4Hz) , 7.1-7.2(2H,m), 7.31(1H,d,J=2.0Hz), 7.40(1H,dd,J=4.8,0.8Hz), 7.47(1H,dd,J=3.6, 0.8Hz), 7.52(2H,d,J=8.0Hz), 7.5-7.7(3H,m), 8.10(2H,d,J=8.4Hz), 12.18(1H,s) 39(2) NMR(400MHz,CDCl3) 5 value: 1. 62-1. 71 (2H,m) , 1.77- 1.98 (6H,m), 2.64-2.68(2H,m), 3 . 03-3.07(2H,m), 3.66 (3H,s), 3.93(3H,s), 4.78-4.82(1H,m), 5.23(2H,s), 6.61 (1H,dd,J=12.4,2.4Hz), 6.7 3(1H,dd,J=8.8,2.4Hz), 6.90(1H,d,J=8.4Hz), 7.47-7.51(3H,m), 7.67-7.70(2H,m), 8.06-8.09(2H,m) 39(3) NMR(400MHz,CDCl3) 5 value: 0.97(6H,d,J=6.8Hz) , 1.70(2H,q,J=6.8Hz), 1.79-1.87(1H,m), 2 . 69(2H,t,J=7.6Hz), 3.07 (2H,t,J=8.0Hz) , 3.67(3H,s), 3.94(3H,s), 4.05 (2H,t,J=6.8Hz), 5.24(2H,s), 6.40(1H,dd,J=8.8,2.4Hz), 6.50(1H,d,J=2.4Hz), 6.93(1H,d,J=8.0Hz), 7.51-7.55(5H,m), 8.09(2H,d,J=8.0Hz), 12.67(1H,s) 39(4) NMR(400MHz,CDCl3) 5 value: 1.04(9H,s), 2.69(2H,t,J=7.6Hz), 3.07(2H,t,J=7.6Hz), 3.65(2H,s), 3.67(3H,s), 3.94(3H,s), 5.25(2H,s), 6.4 3(1H,dd,J=9.0,2.8Hz), 6.5 0(1H, d, J=2.8Hz) , 6.94(1H,d,J=8.4Hz), 7.51-7.56(5H,m), 8.09(2H,d,J=8.0Hz), 12.65(1H,s) 39(5) NMR (90MHz, CDCl3) 8 value: 1.1-2.2(10H,m), 2.68 (2H,t,J=6.8Hz), 3.08 (2H, t, J=6.6Hz), 3.67(3H,s), 3.93 (3H,s), 4.1-4.5(1H,m), 5.24(2H,s), 6.3-6.5 (2H,m), 6.93 (1H,d, J=9.0Hz) , 7.4-7.6 (5H,m), 8.09 (2H,d,J=8.3Hz), 12.67 (1H,s) 39 (6) NMR(400MHz,CDCl3) 5 value: 1. 58-1.64(2H,m), 1.76- 1.98(6H,m), 2.70(2H,t,J=7.6Hz), 3.08(2H,t,J=7.6Hz), 3.41(3H,s), 3.52(3H,s), 3.67(3H,s), 3.93(3H,s), 4.81- 4.82(1H,m), 5.27(2H,s), 5.32(2H,s), 6.37(1H,dd, J=8.8,2.0Hz) , 6.4 8(1H,d,J=2.0Hz), 6.99(1H,d,J=8.4Hz), 7.51-7.56(4H,m), 7.75(1H,d,J=8.0Hz), 7.80(1H,s), 12.70(1H,S) 39(7) NMR(400MHz,CDCl3) 8 value: 1.17-1.26(2H,m), 1.52- 1.75(6H,m), 2.04-2.16(1H,m), 2.62(2H,d,J=7.6Hz), 2.69(2H,t,J=7.3Hz), 3.08(2H,t,J=7.8Hz), 3.67(3H,s), 3.94(3H,s), 5.25(2H,s), 6.69(1H,dd,J=8.2,1.5Hz), 6.87 (1H,d,J=1.5Hz), 6.94(1H,d,J=8.3Hz), 7.49-7.52(3H,m), 7.56-7.59(2H,m), 8.09(2H,d,J=8.3Hz), 12.09(1H,s) 39(8) NMR(400MHz,CDCl3) 5 value: 1.49(18H,s), 1.63-1.68(2H,m), 1.78-1.97(6H,m), 2.69(2H,t,J=7.6Hz), 3.08(2H,t,J=8.0Hz), 3.67(3H,s), 4.80-4.82(1H,m), 5.28(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.4 8(1H,d,J=2.0Hz), 6.91(1H,d,J=8.4Hz), 7.49-7.56(3H,m), 7.63(2H,d,J=8.4Hz), 8.14(2H,d,J=8.8Hz), 12.68(1H,s) 39(9) NMR(400MHz,CDCl3) 8 value: 1.61-1.69(2H,m), 1.76- 1.98(6H,m), 2.68(2H,t,J=7.6Hz), 3.08(2H,t,J=7.6Hz), 3.67(3H,s), 4.80-4.84(1H,m), 5.24(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.4 8(1H,d,J=2.4Hz), 6.91(1H,d,J=8.4Hz), 7.49(1H,d,J=8.8Hz), 7.53-7.58(4H,m), 7.72(2H,d,J=8.4Hz), 12.69(1H,s) 39(10) NMR(90MHz, CDCI3) 8 value: 1.03(6H,d,J=6.6Hz), 1.90- 2.33(1H,m), 2.60-2.75(2H,m), 2.99-3.20(2H,m), 3.67(3H,s), 3.78(2H,d,J=6.6Hz), 5.24(2H,s), 6.35- 6.51(2H,m), 6.92(1H,d,J=9.3Hz), 7.46-7.77(7H,m), 12.64(1H,s) 39(11) NMR(90MHz, CDCl3) 8 value: 1.03(6H,d,J=6.6Hz), 1.20(6H,d,J=6.lHz), 1.8-2.4(1H,m), 2.64(2H,t,J=7.2Hz), 3.09(2H,t,J=7.2Hz), 3.79(2H,d,J=6.6Hz), 4.8-5.2(1H,m), 5.30(2H,s), 6.3-6.6(2H,m), 6.92(1H,d,J=9.0Hz), 7.4- 7.8(5H,m), 8.29(2 H,d,J=8.6Hz), 12.64(1H,s) 39(12) NMR(400MHz,CDCl3) 5 value: 1. 27 ( 6H, d, J=6 . 8Hz) , 2.69(2H,t,J=7.6Hz), 2.88-2.95(1H,m), 3.08(2H,t,J=8.OHz), 3.67(3H,s), 3.94(3H,s), 5.25(2H,s), 6.7 5(1H,dd,J=8.2,1.6Hz), 6.92(1H,d,J=2.OHz), 6.94(1H,d,J=8.0Hz), 7.51-7.59(5H,m), 8.09(2H,d,J=8.OHz), 12.09(1H,s) 39(13) NMR(400MHz,CDCl3) 5 value: 0.93(3H,s), 1. 31-1. 36 (2H, m) , 1.50-1.55(2H,m), 1.66-1.69(4H,m), 2.61(2H,s), 2. 69(2H,t,J=7.6Hz), 3.08(2H,t,J=7.6Hz), 3.67(3H,s), 3.94(3H,s), 5.25(2H,s), 6.67(1H,dd,J=8.4,1.6Hz) , 6.86(1H,d,J=2.0Hz), 6.94(1H,d,J=8.4Hz), 7.48-7.60(5H,m), 8.09(2H,d,J=8.OHz), 12.08(1H,s) 39(14) NMR(400MHz,CDCl3) 5 value: 1.62-1.69(2H,m), 1.78- 1.98(6H,m), 2.70(2H,t,J=7.6Hz), 2.75(6H,s), 3.09(2H,t,J=8.0Hz) , 3.68(3H,s), 4.80-4.84(1H,m), 5.26(2H,s), 6.38(1H,dd,J=9.0,2.4Hz), 6.48(1H,d,J=2.4Hz), 6.94(1H,d,J=8.4Hz), 7.50(1H,d,J=8.8Hz), 7.54-7.56(2H,m) , 7.62(2H,d,J=8.4Hz), 7.84(2H,d,J=8.4Hz), 12.68(1H,s) 39(15) NMR(400MHz, CDC13) 8 value: 1.33-1.38(2H,m), 1.57- 1.66(4H,m), 1.82-1.87(2H,m), 2.35-2.41(1H,m), 2.69(2H,t,J=7.6Hz), 3.07(2H,t,J=7.6Hz), 3.67(3H,s), 3.89(2H,d,J=6.8Hz), 3.94(3H,s), 5.24(2H,s), 6.41(1H,dd,J=8.8,2.4Hz), 6.50(1H,d,J=2.4Hz), 6.93(1H,d,J=8.4Hz), 7.51-7.56(5H,m), 8.09(2H,d,J=8.4Hz), 12.66(1H,s) 39(16) NMR(90MHz,CDCl3) 5 value: 2 . 60-3 . 20 (4H,m) , 3.67(3H,s), 3.94(3H,s), 5.14(2H,s), 5.25(2H,s), 6.40-6.70(2H,m), 6.94(1H,d,J=9.3Hz), 7.30-7.90(7H,m), 8.10(2H,d,J=8.1Hz), 8.60-8.80(2H,m), 12.64(1H,s) 39(17) NMR (400MHz, CDC13) 5 value: 1. 62-1. 68 (2H,m) , 1.76- 1.98(6H,m), 2.69(2H,t,J=8.1Hz), 3.07(2H,t,J=8.1Hz), 3.65(3H,s), 3.84(6H,s), 3.92(3H,s), 4.80-4.83(1H,m), 5.15(2H,s), 6.38(1H,dd,J=9.0,2.4Hz) , 6.48(1H,d,J=2.4Hz) , 6.65(2H,s), 6.92(1H,d,J=8.6Hz) , 7.50-7.55(3H,m), 12.68(1H,s) 39(18) NMR(400MHz,CDCl3) 5 value: 1.27(3H,t,J=7.1Hz), 1.56- 1.64(2H,m), 1.78-1.96(6H,m), 2.68(2H,t,J=7.6Hz), 3.05(2H,t,J=7.6Hz), 3.64(2H,s), 3.66(3H,s), 4.17(2H,q,J=7.1Hz), 4.81-4.82(1H,m), 5.16(2H,s), 6.37(1H,dd,J=8.8,2.1Hz), 6.4 7(1H,d,J=2.0Hz), 6.96(1H,d,J=9.0Hz), 7.33(2H,d,J=7.8Hz), 7.39(2H,d,J=7.8Hz), 7.50-7.54(3H,m), 12.71(1H,s) 39(19) NMR(400MHz,CDCl3) 6 value: 1.68-1.76(1H,m), 1.86- 1.92(1H,m), 2.15-2.25(2H,m), 2.45-2.53(2H,m), 2.69(2H,t,J=7.6Hz), 3 . 07(2H,t,J=7.6Hz), 3.67(3H,s), 3.94(3H,s), 4.69-4.72(1H,m), 5.24(2H,s), 6.33- 6.39(2H,m), 6.93(1H,d,J=8.4Hz), 7.50-7.55(5H,m), 8.09(2H,d,J=8.4Hz), 12.66(1H,s) 39(20) NMR (400MHz, CDC13) 5 value: 2 . 69 (2H, t, J=8 . 0Hz) , 3.07(2H,t,J=8.0Hz), 3.66(3H,s), 3.94(3H,s), 5.12(2H,s), 5.24(2H,s), 6.49(1H,dd,J=8.8,2.4Hz), 6.60(1H,d,J=2.4Hz), 6.93(1H,d,J=8.4Hz), 7.35-7.44(5H,m), 7.50-7.55(5H,m), 8.09(2H,d,J=8.0Hz), 12.65(1H,s) 39(21) NMR(400MHz,CDCl3) 5 value: 1.35(9H,s), 1.62-1.66(2H,m), 1.76-1.96(6H,m), 2.68(2H,t,J=7.6Hz), 3.08(2H,t, J=7.6Hz) , 3.36(3H,s), 3.67(3H,s), 4.80-4.83(1H,m), 5.27(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.4 8(1H,d,J=2.4Hz), 6.91(1H,d,J=8.4Hz), 7.48-7.61(5H,m), 7.95(2H,d,J=8.4Hz), 12.67(1H,s) 39(22) NMR(400MHz,CDCl3) 8 value: 1.62-1.68(2H,m), 1.77- 1.98(6H,m), 2.68(2H,t,J=7.6Hz), 3 . 01 (3H,brs), 3.06(2H,t,J=7.6Hz), 3.13(3H,brs), 3.67(3H,s), 4.80- 4.83(1H,m), 5.21(2H,s), 6.37(1H,dd,J=9.2, 2.4Hz) , 6.48(1H,d,J=2.4Hz), 6.94(1H,d,J=8.4Hz), 7.47-7.55(7H,m), 12.69(1H,s) 39 (23) NMR (4 00MHz, CDCI3) 8 value: 1.48(9H,s), 1. 60-1. 66 (2H,m) , 1.81-1.96(6H,m), 2.69(2H,t,J=8.0Hz), 3.07(2H,t,J=8.0Hz), 3.45(3H,s), 3.66(3H,s), 4.81-4.83(1H,m), 5.21(2H,s), 6.37 (1H,dd,J=8.8,2.4Hz), 6.4 8(1H,d,J=2.4Hz), 6.95 (1H,d,J=8.4Hz), 7.29(2H,d,J=8.4Hz), 7.49-7.55(5H,m), 12.69(1H,s) 39(24) NMR(400MHz,CDCl3) 5 value: 1.17(9H,s), 1. 60-1. 68 (2H,m) , 1.77-1.98(6H,m), 2.67(2H,t,J=7.2Hz), 3.05(2H,t,J=7.6Hz), 3.32(3H,s), 3.66(3H,s), 4.80-4.83(1H,m), 5.22(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.4 8(1H,d,J=2.4Hz), 6.94(1H,d,J=8.0Hz), 7.46-7.57(7H,m), 12.69(1H,s) 39(25) NMR(400MHz,CDCl3) 8 value: 1. 58-1. 73 (4H,m) , 1.79- 1.84(2H,m), 2.05-2.11(2H,m), 2.69(2H,t,J=7.6Hz), 2.97- 3.05(1H,m), 3.08(2H,t,J=8.0Hz), 3.67(3H,s), 3.94(3H,s), 5.25(2H,s), 6.76(1H,dd,J=8.4,1.6Hz), 6.93-6.95(2H,m), 7.51-7.59(5H,m), 8.09(2H,d,J=8.0Hz), 12.09(1H,s) 39(28) NMR(400MHz,CDCl3) 5 value: 1. 62-1. 66 (2H,m) , 1.74- 1.98(6H,m), 2.69(2H,t,J=7.6Hz), 3.08(2H,t,J=7.6Hz), 3.68(3H,s), 3.98(3H,s), 4.80-4.83(1H,m), 5.21(2H,s), 6.37(1H,dd,J=9.0,2.2Hz), 6.4 7(1H,d,J=2.2Hz), 6.90(1H,d,J=8.3Hz), 7.24-7.28(2H,m), 7.49(1H,d,J=9.0Hz), 7.51-7.55(2H,m), 7.99(1H,t,J=7.8Hz), 12.68(1H,s) 39(29) NMR(400MHz,CDCl3) 8 value: 1.60-1.65(2H,m), 1.80- 1.95(6H,m), 2.68(2H,t,J=7.6Hz), 3.07(2H,t,J=7.6Hz), 3.67(3H,s), 3.93(3H,s), 3.94(3H,s), 4.78-4.83(1H,m), 5.24(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.48(1H,d,J=2.4Hz), 6.91(1H,d,J=8.4Hz), 7.50(1H,d,J=8.8Hz), 7.51-7.56(2H,m), 7.62-7.64(1H,m), 7.79(2H,d,J=8.0Hz), 12.68(1H,s) 39(30) NMR( 90MHz, CDC13) 8 value: 1. 05 ( 6H, d, J=6 . 6Hz) , 1.19(6H,d,J=6.3Hz), 1.90-2.36(1H,m), 2.52-2.77(2H,m), 2.86-3.16(2H,m), 3.80(2H,d,J=6.6Hz), 3.93(3H,s), 4.86- 5.14(1H,m), 5.25(2H,s), 6.86-7.02(3H,m), 7.47- 7.81(6H,m), 8.09(2H,d,J=8.3Hz) 39 (31) NMR(90MHz,CDCl3) 5 value: 1. 03 ( 6H, d, J=6 . 6Hz) , 1.38(6H,d,J=6.4Hz), 1.40(6H,d,J=6.1Hz), 1.9-2.4(1H,m), 2.6-2.8(2H,m), 3.0-3.2(2H,m), 3.68(3H,s), 3.79(2H,d,J=6.4Hz), 4.5-5.0(1H,m), 5.1-5.5(1H,m), 5.25(2H,s), 6.3-6.5(2H,m), 6.97(1H,d,J=9.3Hz), 7.5- 7.7(6H,m), 12.68(1H,s) 39(32) NMR (4 00MHz, CDCI3) 5 value: 1 . 01 ( 6H, d, J=6 . 6Hz ) , 1.06(6H,d,J=6.6Hz), 1.64-1.73(2H,m), 1.78-1.96(6H,m), 2.08(1H,sep,J=6.6Hz), 2.15(1H,sep,J=6.6Hz), 2.69(2H,t,J=7.6Hz), 3.07(2H,t,J=7.6Hz), 3.66(3H,s), 3.82(2H,d,J=6.6Hz), 4.10(2H,d,J=6.6Hz), 4.79-4.84(1H,m), 5.18(2H,s), 6.37(1H,dd,J=8.8,1.7Hz), 6.48(1H,d,J=l.7Hz), 6.92(1H,d,J=8.3Hz), 7.00-7.03(2H,m), 7.49-7.55(3H,m), 7.82(1H,d,J=7.8Hz), 12.69(1H,s) 39(33) NMR(90MHz,CDCl3) 8 value: 1. 03(6H, d,J=6.6Hz), 1.95- 2.23(1H,m), 2.69(2H,t,J=7.1Hz), 3.09(2H,t,J=7.1Hz), 3.67(3H,s), 3.79(2H,d,J=6.1Hz), 3.94(3H,s), 5.25(2H,s), 6.35-6.48(2H,m), 6.93(1H,d,J=8.5Hz), 7.47-7.57(5H,m), nitrogen atoms as hetero atoms forming the ring and optionally one or more oxygen atoms or sulfur atoms, such as pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl, quinolizinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinuclidinyl, quinazolyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, purinyl and indazolyl groups; [0011] heterocyclic groups mean the above described nitrogen-containing heterocyclic groups and 5- or 6- membered-ring, condensed-ring or bridged-ring heterocyclic groups each of which contains at least one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms and optionally one or more oxygen or sulfur atoms as heteroatoms forming the ring, such as furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinoxalyl, dihydroquinoxalinyl, 2,3- dihydrobenzothienyl, 2,3-dihydrobenzopyrrolyl, 2,3- dihydro-4H-1-thianaphthyl, 2,3-dihydrobenzofuranyl, benzo[b]dioxanyl, imidazo[2,3-a]pyridyl, benzo[b]piperazinyl, chromenyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, isoindolyl and isoquinolyl groups; organic layer was separated therefrom. After the resultant organic layer was washed with water and a saturated sodium chloride solution successively, the washed layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was washed with hexane to yield 0.64 g of 4-({2-(2-carboxyethyl)-4-[4- (cyclopentyloxy)-2-hydroxybenzoyl]phenoxy}methyl) benzoic acid as light yellow solid. NMR(90MHz,DMSO-ds) 8 value: 1.21-3.02 (12H,m), 4.77- 5.03(1H,m), 5.35(2H,s), 6 . 44-6. 52 (2H,m) , 7.17(1H,d,J=9.3Hz), 7.41-7.89(5H,m), 8.00(2H,d,J=8.3Hz), 12.09(3H,brs) [0236] Example 4 5 1.15 g of methyl 3-{[4-[4-(cyclopeniyloxy)-2- hydroxybenzoyl]-2-(3-methoxy-3- oxopropyl)phenoxy]methyl}-1-benzothiophene-7-carboxylate was dissolved in a mixed solvent of 10 mL of methanol and 10 mL of tetrahydrofuran, 2 mL of a 5M aqueous solution of sodium hydroxide was added at room temperature, and then this mixture was stirred for 30 minutes at the same temperature, followed by addition of 2 mL of water, and this mixture was stirred for 30 minutes at 50 to 60°C. The reaction mixture was returned to room temperature, water was added, and the mixture was adjusted to pH 2 with 6M hydrochloric acid. Chloroform was added, and then the organic layer was 3.67(3H,s), 3.94(3H,s), 4.1-4.3(1H,m), 5.25(2H,s), 6.3- 6.5(2H,m), 6.93(1H,d,J=9.0Hz), 7.4-7.6(5H,m), 8.10(2H,d,J=8.1Hz), 12.67(1H,s) 39(42) NMR(90MHz,CDCl3) 5 value: 0.7-2.0(llH,m), 2.68(2H,t,J=7.7Hz), 3.08(2H,t,J=8.1Hz), 3.67(3H,s), 3.81(2H,d,J=5.9Hz), 3.93(3H,s), 5.24(2H,s), 6.3- 6.5(2H,m), 6.93(1H,d,J=9.0Hz), 7.4-7.6(5H,m), 8.09(2H,d,J=8.5Hz), 12.67(1H,s) 39(43) NMR(90MHz,CDCl3) 8 value: 0 . 3-0 . 8 (4H,m) , 1.1-1. 5 (1H,m) , 2.6-2.8(2H,m), 3.0-3.2(2H,m), 3.67(3H,s), 3.86(2H,d,J=6.8Hz), 3.94(3H,s), 5.24(2H,s), 6.3- 6.5(2H,m), 6.93(1H,d,J=9.0Hz), 7.4-7.6(5H,m), 8.09(2H,d,J=8.3Hz), 12.67(1H,s) 39(44) NMR(90MHz,CDCl3) 8 value: 1.3-2.0(12H,m), 2.68 (2H,t,J=6.8Hz), 3.08(2H,t,J=6.8Hz), 3.67(3H,s), 3.93(3H,s), 4.3-4.6(1H,m), 5.24(2H,s), 6.3-6.4(2H,m), 6.93(1H,d,J=9.3Hz), 7.5-7.6(5H,m), 8.09(2H,d,J=8.3Hz), 12.68(1H,s) 39(45) NMR(400MHz,CDCl3) 8 value: 1.34(6H,t,J=7.6Hz), 1.60- 1.98(8H,m), 2.69(2H,t,J=7.2Hz), 3.08(2H,t,J=8.0Hz), 3.67(3H,s), 4.10-4.19(4H,m), 4.80-4.82(1H,m), 5.23(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.48(1H,d,J=2.4Hz), 6.93(1H,d,J=8.4Hz), 7.50-7.56(5H,m), 7.84-7.89(2H,m), 12.69(1H,s) 39(46) NMR(90MHz,CDCl3) 5 value: 1.03(6H,d,J=6.6Hz), 1.19(6H,d,J=6.1Hz), 1.96-2.20(1H,m), 2.55-2.71(2H,m), 2.99-3.17(2H/m), 3.79(2H,d,J=6.3Hz), 4.86-5.14(1H,m), 5.24(2H,s), 6.37-6.48(2H,m), 6.90(1H,d,J=9.3Hz), 7.46- 7.77(7H,m), 12.63(1H,s) 39(47) NMR(400MHz,CDCl3) 5 value: 2.69(2H,t,J=7.2Hz), 3.08(2H,t,J=7.6Hz), 3.67(3H,s), 3.94(3H,s), 5.25(2H,s), 5.30(2H,s), 6.54(1H,dd,J=8.8,2.8Hz), 6.62(1H,d,J=2.4Hz), 6.94(1H,d,J=8.4Hz) , 7.51-7.60(5H,m) , 8.09(2H,d,J=8.4Hz), 8.58-8.60(2H,m), 8.82(1H,s), 12.62(1H,s) 39(48) NMR(400MHz,CDCl3) 5 value : 1. 61-1. 68 (2H, m) , 1.78- 1.98(6H,m), 2.67(2H,t,J=7.6Hz), 3.05(2H,t,J=7.6Hz), 3.65(3H,s), 3.66(3H,s), 4.81-4.84(1H,m), 5.27(2H,s), 5.57(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.48(1H,d,J=2.4Hz), 6.99(1H,d,J=8.8Hz), 7.50-7.57(4H,m), 7.64(1H,dd,J=8.8,1.6Hz), 7.75(1H,s), 12.70(1H,s) 39(49) NMR(4 00MHz, CDC13) 5 value: 1.60-1.66(2H,m), 1.67- 1.98(6H,m), 2.67(3H,s), 2 . 70 (2H, t, J=7 . 6Hz) , 3.08(2H,t,J=7.6Hz), 3.67(3H,s), 4.80-4.83(1H,m), 5.25(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.48(1H,d,J=2.4Hz), 6.96(1H,d,J=8.4Hz), 7.48-7.57(5H,m), 8.11(2H,d,J=8.0Hz), 12.70 (1H,s) 39(50) NMR(400MHz,CDCl3) 5 value: 1. 63-1. 67 (2H,m) , 1.67(9H,s), 1.78-1.96(6H,m), 2.63(2H,t,J=7.6Hz), 3.00(2H,t,J=7.6Hz) , 3.66(3H,s), 4.81-4.83(1H,m), 5.09(2H,s), 6.38(1H,dd,J=9.0,2.4Hz), 6.4 8(1H,d,J=2.4Hz), 6.97(1H,d,J=8.6Hz), 7.50(1H,d,J=8.8Hz), 7.53-7.57(2H,m), 7.80(1H,s), 8.18(1H,s), 12.69(1H,s) 39(51) NMR (400MHz, CDC13) 5 value: 1. 62-1. 67 (2H,m) , 1.76- 1.98(6H,m), 2.67(2H,t,J=7.6Hz), 3.04(2H,t,J=7.6Hz), 3.39(6H,s), 3.66(3H,s), 4.80-4.83(1H,m), 5.20(2H,s), 5.32(2H,s), 5.34(2H,s), 6.37(1H,dd,J=9.2,2.4Hz), 6.48(1H,d,J=2.4Hz), 6. 99(1H,d,J=8.8Hz), 7.18-7.32(3H,m), 7.50-7.56(3H,m), 12.70(1H,s) 39(52) NMR(400MHz,CDCI3) 5 value: 1.63-1.68(2H,m), 1.76- 1.98(6H,m), 2.70(2H,t,J=7.6Hz) , 3.09(2H, t, J=7.6Hz) , 3.36(3H,s), 3.68(3H,s), 4.80-4.84(1H,m), 5.28(2H,s), 6.37(1H,dd, J=8.8,2.4Hz) , 6.4 8(1H,d,J=2.4Hz), 6.95(1H,d,J=8.0Hz), 7.50(1H,d,J=9.2Hz), 7.54-7.56(2H,m), 7.64-7.70(4H,m), 12.68(1H,s) 39(53) NMR(400MHz,CDCl3) 5 value: 1.60-1.68(11H,m), 1.77- 1.98(6H,m), 2.69(2H,t,J=7.2Hz), 3.09(2H,t,J=7.6Hz), 3.68(3H,s), 4.81-4.84(1H,m), 5.33(2H,s), 6.38(1H,dd,J=8.8,2.4Hz), 6.4 8(1H, d, J=2.4Hz) , 6.92(1H,d,J=8.8Hz), 7.48-7.57(3H,m), 7.90(1H,d,J=7.6Hz), 8.00(2H,d,J=8.0Hz), 12.67(1H,s) 39(54) NMR(400MHz,CDCl3) 6 value: 1. 62-1. 68 (2H, m) , 1.76- 1.98(6H,m), 2.70(2H,t,J=7.8Hz), 3.09(2H,t,J=7.6Hz), 3.68(3H,s), 3.69(3H,s), 4.80-4.83(1H,m), 5.30(2H,s), 6.37(1H,dd,J=9.0,2.4Hz), 6.4 8(1H,d,J=2.4Hz), 6.93(1H,d,J=8.4Hz) , 7.31-7.35(2H,m), 7.49-7.57(3H,m), 7.87(1H,d,J=7.6Hz), 12.67(1H,s) 39(55) NMR (400MHz, CDC13) 5 value: 1. 64-1. 96 (8H,m) , 2.70(2H,t,J=7.6Hz), 3.09(2H,t,J=7.6Hz), 3.68(3H,s), 4.18(3H,s), 4.80-4.83(1H,m), 5.32(2H,s), 6.37(1H,dd,J=9.0,2.8Hz), 6.4 8(1H,d,J=2.8Hz), 6.95(1H,d,J=8.4Hz), 7.33(1H,d,J=7.2Hz), 7.49-7.56(4H,m), 7.66(1H,d,J=8.0Hz), 12.69(1H,s) 39(56) NMR(400MHz,CDCI3) 5 value: 1.66(9H,s), 1.75(9H,s), 1.77- 1.98(8H,m), 2.66(2H,t,J=7.6Hz), 3.04(2H,t,J=8.0Hz), 3.66(3H,s), 4.80-4.83(1H,m), 5.19(2H,s), 6.37(1H,dd,J=9.0, 2.4Hz) , 6.4 8 (1H,d,J=2.4Hz), 6.95(1H,d,J=9.2Hz), 7.06(1H,d,J=8.4Hz), 7.51(1H,d,J=9.2Hz) , 7.52-7.54(2H,m), 7.66(1H,dd,J=8.4,2.0Hz) , 8.11(1H,d,J=2.0Hz), 12.69(1H,s) 39(57) NMR ( 90MHz, CDCI3) 5 value: 1. 04 ( 6H, d, J=6 . 6Hz) , 1.18(6H,d,J=6.4Hz), 1.86-2.34(1H,m), 2.53-2.70(2H,m), 2.97-3.14(2H,m), 3.79(2H,d,J=6.4Hz), 4.80-5.30(1H,m), 5.21(2H,s), 6.38-6.49(2H,m), 6.98(1H,d,J=9.0Hz), 7.28- 7.58(4H,m), 7.81(1H,d,J=7.3Hz), 8.63(1H,d,J=4.6Hz), 8.71(1H,s), 12.66(1H,s) 39(58) NMR(400MHz,CDCl3) 5 value: 1. 48(3H,t,J=7.3Hz), 1.63- 1.67(2H,m), 1.76-1.98(6H,m), 2.70(2H,t,J=7.6Hz), 3.10(2H,t,J=7.6Hz), 3.68(3H,s), 4.53(2H,q,J=7.2Hz), 4.80-4.84(1H,m), 5.43(2H,s), 6.37(1H,dd,J=8.8,2.4Hz) , 6.4 8(1H,d,J=2.4Hz), 6.97(1H,d,J=8.4Hz), 7.49(1H,d,J=8.8Hz), 7.54-7.57(2H,m), 8.98(1H,s), 9.31(1H,d,J=1.2Hz), 12.66(1H,s) 39(59) NMR(90MHz, CDC13) 8 value: 1.39(3H,t,J=7.1Hz), 1.5- 2.1(8H,m), 2.6-2.7(2H,m), 2.9-3.1(2H,m), 3.66(3H,s), 4.38(2H,q,J=7.1Hz), 4.7-4.9(1H,m), 5.19(2H,s), 6.3- 6.6(3H,m), 6.93(1H,d,J=9.0Hz), 7.17(1H,d,J=3.4Hz), 7.4- 7.6(3H,m), 12.67(1H,s) 39(60) NMR( 90MHz, CDCl3) 6 value: 1. 2-2 .1 ( HH,m) , 2.71 (2H,t,J=6.8Hz), 3.11(2H,t,J=8.0Hz), 3.68(3H,s), 4.46(2H,q,J=7.1Hz), 4.7-5.0(1H,m), 5.52(2H,s), 6.3- 6.5(2H,m), 6.98(1H,d,J=9.0Hz), 7.4-7.6(3H,m), 8.24(1H,s), 12.65(1H,s) 39(61) NMR(90MHz,CDCl3) 5 value: 0.90(6H,d,J=6.6Hz), 1.08(6H,d,J=6.6Hz), 1.6-3.1(6H,m), 2.74(3H,s), 3.83(2H,d,J=6.4Hz), 3.86(2H,d,J=6.6Hz), 5.20(2H,s), 6.4-6.7(2H,m), 6.89(1H,d,J=9.3Hz), 7.18(1H,s), 7.4- 7.6(3H,m), 12.67(1H,s) 39(62) NMR(90MHz,CDCl3) 5 value: 0.90(6H,d,J=6.6Hz) , 1.08(6H,d,J=6.6Hz), 1.63-2.40(2H,m), 2.63-2.74(2H,m) , 2. 94-3.12(2H,m), 3.83(2H,d,J=6.4Hz), 3.86(2H,d,J=6.6Hz), 5.14(2H,s), 6.46-6.61(2H,m), 6.89(1H,d,J=9.3Hz), 7.33- 7.82(5H,m), 8.58-8.69(2H,m), 12.67(1H,s) 39(63) NMR(90MHz,CDCl3) 8 value: 0 . 90 ( 6H, d, J=6 . 6Hz) , 1.08(6H,d,J=6.6Hz), 1.68-2.32(2H,m), 2.55-2.74(2H,m), 2.94-3.13(2H,m), 3.83(2H,d, J=6.4Hz) , 3.86(2H,d,J=6.6Hz), 3.93(3H,s), 5.18(2H,s), 6.43-6.56(2H,m), 6.89(1H,d,J=9.0Hz), 7.45-7.63(5H,m), 8.08(2H,d,J=8.3Hz), 12.66(1H,s) 39(64) NMR( 90MHz, CDC13) 8 value : 0.90(6H,d,J=6.6Hz), 1.08(6H,d,J=6.6Hz), 1.6-2.4(2H,m), 2.5-2.8(2H,m), 2.9- 3.1(2H,m), 3.83(2H,d,J=6.lHz), 3.86(2H, d, J=6.6Hz) , 5.27(2H,s), 6.4-6.6(2H,m), 6.89(1H,d,J=9.0Hz), 7.2- 7.9(6H,m), 8.61(1H,d,J=4.6Hz), 12.64(1H,s) Example 4 0 1.50 g of methyl 3-{5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-hydroxyphenyl} propanoate, 1.04 g of methyl 3-(hydroxymethyl)-1-benzothiophene-7-carboxylate, and 1.23 g of triphenylphosphine were dissolved in 15 mL of tetrahydrofuran, to which 0.92 mL of diisopropyl azodicarboxylate was added dropwise at temperatures of 19 to 32°C, and this mixture was stirred for one hour at room temperature. The reaction mixture was poured into a mixture of ethyl acetate and water, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=3:l] to yield 1.70 g of methyl 3-{[4-[4- (cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-methoxy-3- oxopropyl)phenoxy]methyl}-1-benzothiophene-7- carboxylate as light yellow solid. NMR(400MHz,CDCl3) 5 value: 1. 61-1. 68 (2H,m) , 1.76- 1.98(6H,m), 2.61(2H,t,J=7.6Hz), 3.00(2H,t,J=7.6Hz), 3.62(3H,s), 4.04(3H,s), 4.80-4.84(1H,m), 5.43(2H,s), 6.38(1H,dd,J=9.2,2.4Hz), 6.4 8(1H,d,J=2.0Hz), 7.10(1H,d,J=8.4Hz), 7.51-7.59(4H,m), 7.67(1H,s), 8.08(1H,d,J=7.6Hz), 8.18(1H,d,J=7.6Hz), 12.70(1H,s) Example 41 1.20 g of methyl 3-{5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-hydroxyphenyl} propanoate, 0.773 g of ethyl(E)-3-[4-(hydroxymethyl)phenyl]-2-propenoate, and 0.984 g of triphenylphosphine were dissolved in 12 mL of tetrahydrofuran, to which 0.74 mL of diisopropyl azodicarboxylate was added dropwise at temperatures of 20 to 31°C, and this mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into a mixture of ethyl acetate and water, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=3:1] to yield 1.33 g of ethyl (E)-3-(4-{[4-[4- (cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-methoxy-3- oxopropyl)phenoxy]methyl}phenyl)-2-propenoate as yellow oil. NMR(4 00MHz,CDC13) 5 value: 1.35(3H,t,J=7.1Hz), 1.57- 1.64(2H,m), 1.76-1.98(6H,m), 2.68(2H,t,J=7.6Hz), 3.06(2H,t,J=7.6Hz), 3.67(3H,s), 4.28(2H,q,J=7.1Hz), 4.81-4.82(1H,m), 5.20(2H,s), 6.37(1H,dd,J=8.8,2.2Hz) , 6.46(1H,d,J=15.6Hz), 6.4 8(1H,d,J=2.4Hz), 6.94(1H,d,J=8.0Hz), 7.46(2H,d,J=8.0Hz), 7.50-7.55(3H,m), 7.57(2H,d,J=8.0Hz), 7.70(1H,d,J=16.0Hz), 12.69(1H,s) Example 42 Compounds listed in Tables 22 to 25 and Table 25-2 were obtained in a similar manner to in Example 40. Each of the compounds 42(6) and 42(22) to 42(25) in these Tables were synthesized from a compound having a hydrogen atom as R4z, in order to replace the hydrogen by another R4Z group. 1.66(2H,m), 1.76-1.98(6H,m), 2.64(2H,t,J=7.6Hz), 2.67(2H,t,J=7.6Hz), 2.98(2H,t,J=7.6Hz), 3.04(2H,t,J=7.6Hz) , 3.66(3H,s), 4.13(2H,q,J=7.2Hz), 4.80-4.83(1H,m), 5.15(2H,s), 6.37(1H,dd,J=8.8,2.4Hz) , 6.4 7(1H,d,J=2.4Hz), 6.96(1H,d,J=9.0Hz), 7.22(2H,d,J=8.0Hz), 7.36(2H,d,J=8.OHz), 7.50-7.54(3H,m), 12.70 (1H,s) 42(2) NMR (400MHz, CDC13) 5 value: 1 . 5-2 . 0 (8H,m) , 2.43(3H,s), 2.66(2H,t,J=7.6Hz), 3.06(2H,t,J=7.6Hz), 3.66(3H,s), 3.93(3H,s), 4.8-4.9(1H,m), 5.19(2H,s), 6.37 (1H,dd,J=9.2,2.4Hz), 6.4 8(1H,d,J=2.4Hz), 6.97(1H,d,J=9.2Hz), 7.4-7.6(4H,m), 7.91-7.92(2H,m), 12.70 (1H,S) 42(3) NMR(90MHz,CDCl3) 8 value: 1. 03(6H,d,J=6.6Hz), 1.19(6H,d,J=6.4Hz), 1.98-2.28(1H,m), 2.50-2.70(5H,m), 2.93-3.11(2H,m), 3.78(2H,d,J=6.6Hz), 4.92-5.14(3H,m), 6.35-6.50(2H,m), 6.95(1H,d,J=9.4Hz), 7.32-7.57(7H,m), 12.67(1H,s) 42 (4) NMR (400MHz,CDCl3) 5 value: 1.24(3H,t,J=7.1Hz) , 1.60- 1.67(2H,m), 1.78-1.96(6H,m), 2.61(2H,t,J=7.8Hz), 2.69(2H,t,J=7.6Hz), 2.95(2H,t,J=7.8Hz), 3.05(2H,t,J=7.6Hz), 3.65(3H,s), 3.85(3H,s), 4.13 (2H,q,J=7.1Hz), 4.81-4.82(1H,m), 5.14(2H,s), 6.37(1H,dd,J=8.8,2.2Hz), 6.47(1H,d,J=2.OHz), 6.91- 6.98(3H,m), 7.17(1H,d,J=7.3Hz), 7.50-7.54(3H,m), 12.70 (1H,s) 42(5) NMR(400MHz,CDCl3) 8 value: 1. 57-1. 63 (2H,m) , 1.70(3H,d,J=6.4Hz), 1.75-1.95(6H,m), 2.73(2H,dt, J=7.6,2.8Hz), 3.10(2H,dt,J=7.6,2.8Hz), 3.70(3H,s), 3.91(3H,s), 4.79-4.81(1H,m), 5.45(1H,q,J=6.4Hz), 6.34(1H,dd,J=8.8,2.4Hz), 6.4 5(1H,d,J=2.4Hz), 6.68(1H,d,J=8.8Hz), 7.37(1H,dd,J=8.4,2.0Hz), 7.43- 7.47(3H,m), 7.51(1H,d,J=l.6Hz), 8.04(2H,d,J=8.4Hz), 12.72 (1H,s) 42(6) NMR(400MHz,CDCl3) 5 value: 2.59(2H,d,J=17.6Hz), 2.69(2H,t,J=7.6Hz), 2.85(2H,dd,J=16.4,6.4Hz), 3.08(2H,t,J=7.6Hz), 3.67(3H,s), 3.94(3H,s), 5.0- 5.1(1H,m), 5.24(2H,s), 5.77(2H,s), 6.38(1H,dd,J=9.0,2.4Hz), 6.4 8(1H,d,J=2.4Hz), 6.93(1H,d,J=8.8Hz), 7.5-7.6(5H,m), 8.09(2H,d,J=8.0Hz), 12.70(1H,s) 42(7) NMR(90MHz,CDCl3) 5 value: 1. 03 ( 6H, d, J=6 . 6Hz) , 1.20(6H,d,J=6.4Hz), 1.97-2.25(1H,m), 2.48-2.56(2H,m), 2.85-3.28(4H,m), 3.78(2H,d,J=6.1Hz), 3.92(3H,s), 4.30(2H,t,J=6.7Hz), 4.88-5.15(1H,m), 6.36-6.48(2H,m), 6.82-6.95(1H,m), 7.40-7.64(5H,m), 7.90-8.00(2H,m), 12.66(1H,s) 42 (8) NMR(90MHz,CDCl3) 8 value: 1. 03 ( 6H, d, J=6 . 6Hz) , 1.22(6H,d,J=6.4Hz), 1.98-2.25(1H,m), 2.40-2.56(2H,m), 2.85-3.03(2H,m), 3.15-3.28(2H,m), 3.78(2H,d,J=6.4Hz), 3.91(3H,s), 4.23-4.37(2H,m), 4.94-5.08(1H,m), 6.36- 6.48(2H,m), 6.88(1H,d,J=9.1Hz), 7.34-7.55(5H,m), 8.01(2H,d,J=8.1Hz), 12.65(1H,s) 42 (9) NMR(400MHz,CDCl3) 8 value: 1. 60-1. 68 (2H,m) , 1.78- 1.96(6H,m), 2.63(2H,t,J=7.6Hz), 2.66(2H, t,J=7.6Hz), 2.96(2H,t,J=7.6Hz), 3.02(2H,t,J=7.6Hz), 3.65(3H,s), 3.66(3H,s), 3.85(3H,s), 4.79-4.84(1H,m), 5.08(2H,s), 6.37(1H,d,J=9.3Hz), 6.47(1H,s), 6.87(1H,d,J=8.3Hz), 6.97(1H,d,J=8.6Hz), 7.22-7.28(2H,m), 7.51-7.55(3H,m), 12.71(1H,s) 42(10) R1 is a 1-trityl-lH-benzimidazol-6-yl substituent. NMR(400MHz, CDCl3) 5 value: 1.62-1.66(2H,m), 1.78- 1.95(6H,m), 2.66(2H,t,J=7.6Hz), 3.03(2H,t,J=7.6Hz), 3.63(3H,s), 4.80-4.83(1H,m), 5.21(2H,s), 6.37(1H,dd,J=9.0, 2.4Hz), 6.47-6.53(2H,m), 6.96- 7.00(1H,m), 7.14-7.35(16H,m), 7.40(1H,dd,J=8.4, 2.4Hz), 7.47-7.53(2H,m), 7.85(1H,s), 7.92(1H,s), 12.72(1H,s) R1 is a l-trityl-1H-benzimidazol-5-yl substituent. NMR(400MHz,CDCl3) 5 value: 1.62-1.66(2H,m), 1.78- 1.95(6H,m), 2.44(2H,t,J=7.6Hz), 2.84(2H, t, J=7.6Hz) , 3.66(3H,s), 4.80-4.83(1H,m), 5.00(2H,s), 6.37(1H,dd,J=9.0, 2.4Hz), 6.47-6.49(1H,m), 6.63(1H,d,J=8.8Hz), 6.96-7.00(1H,m), 7.14-7.35(16H,m), 7.47-7.53(3H,m), 7.80(1H,d,J=8.4Hz), 7.89(1H,s), 12.74 (1H,s) 42(11) NMR(400MHz,CDCl3) 5 value: 1. 62-1. 67 (2H,m) , 1.76- 1.98(6H,m), 2.68(2H,t,J=7.6Hz), 3.05(2H,t,J=7.6Hz), 3.18(3H,s), 3.67(3H,s), 3.72(2H,t,J=5.6Hz), 4.01 (2H,t,J=5.6Hz), 4.80-4.83(1H,m), 5.18(2H,s), 6.37(1H,dd,J=9.0,2.4Hz), 6.4 8(1H,d,J=2.4Hz), 6.95(1H,d,J=9.2Hz), 7.40(2H,d,J=8.4Hz), 7.48-7.54(5H,m), 12.69(1H,s) 42 (12) NMR(400MHz,CDCl3) 8 value: 1. 62-1. 67 (2H,m) , 1.76- 1.98(6H,m), 2.76(2H,t,J=7.6Hz), 3.14(2H,t,J=7.6Hz), 3.70(3H,s), 3.99(3H,s), 4.79-4.83(1H,m), 5.60(2H,s), 6.37(1H,dd,J=9.2,2.4Hz), 6.4 8(1H,d,J=2.4Hz), 7.03(1H,d,J=8.8Hz), 7.49(1H,d,J=8.8Hz), 7.52-7.59(2H,m), 7.98(1H,d,J=8.4Hz), 8.11(1H,dd,J=8.6,2.4Hz), 8.72(1H,d,J=1.2Hz), 12.66(1H,s) 42(13) NMR(400MHz,CDCl3) 5 value: 1. 60-1.68 (2H,m) , 1.76- 1.98(6H,m), 2.66(2H,t,J=7.8Hz), 3.03(2H,t,J=7.8Hz), 3.66(3H,s), 4.80-4.84(1H,m), 5.07(2H,s), 5.99(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.4 8(1H,d,J=2.4Hz), 6.83(1H,d,J=8.0Hz), 6.88-6.97(3H,m), 7.50-7.55(3H,m), 12.71 (1H,s) 42 (14) NMR (4 00MHz,CDC13) 5 value: 1.62-1.68(2H,m), 1.76- 1.98(6H,m), 2.67(2H,t,J=7.6Hz), 3.04(2H,t,J=7.6Hz), 3.66(3H,s), 4.09(2H,t,J=8.0Hz), 4.51(2H,t,J=8.OHz), 4.80-4.83(1H,m), 5.16(2H,s), 6.37(1H, dd,J=8.8,2.4Hz) , 6.4 8(1H,d,J=2.0Hz), 6.96(1H,d,J=8.8Hz), 7.45(2H,d,J=8.8Hz), 7.50-7.56(3H,m), 7.60(2H,d,J=8.8Hz), 12.70(1H,s) 42 (15) NMR(400MHz,CDCl3) 5 value: 1.62-1.68(2H,m), 1.78- 1.98(6H,m), 2.64(2H,t,J=7.6Hz), 3.03(2H,t,J=7.6Hz), 3.61(3H,s), 3.97(3H,s), 4.80-4.84(1H,m), 5.45(2H,s), 6.38(1H,dd,J=9.2,2.4Hz) , 6.4 8(1H,d,J=2.4Hz), 7.09(1H,d,J=8.4Hz), 7.52-7.61(4H,m), 7.95(1H,d,J=8.4Hz), 8.07(1H,dd,J=8.6,1.4Hz), 8.56(1H,s), 12.70(1H,s) 42(16) NMR(400MHz,CDCl3) 5 value: 1. 03 ( 6H, d, J=6 . 4Hz) , 1.18(6H,d,J=6.4Hz), 2.06-2.16(1H,m), 2.66(2H,t,J=7.6Hz), 3.06(2H,t,J=7.6Hz) , 3.78(2H,d,J=6.8Hz) , 3.96(3H,s), 4.95-5.04(1H,m), 5.45(2H,s), 6.42(1H,dd,J=9.2,2.4Hz), 6.49(1H,d,J=2.4Hz), 7.02(1H,d,J=8.8Hz), 7.42(1H,s), 7.51-7.57(3H,m), 7.88(1H,d,J=8.4Hz), 8.01(1H,dd,J=8.4 ,1.6Hz) , 8.4 8(1H,d,J=l.6Hz), 12.66(1H,s) 42 (17) NMR(400MHz,CDCl3) 5 value: 1.38(6H,d,J=6.0Hz), 2.71(2H,t,J=7.6Hz), 3.06(2H, t, J=7.6Hz) , 3.66(3H,s), 3.97(3H,s), 4.60-4.66(1H,m), 5.45(2H,s), 6.38(1H,dd,J=8.8,2.4Hz), 6.4 8(1H,d,J=2.4Hz), 7.03(1H,d,J=8.8Hz), 7.43(1H,s), 7.50-7.56(3H,m), 7.88(1H,d,J=8.4Hz), 8.01(1H,dd,J=8.4,1.6Hz), 8.48(1H,d,J=1.6Hz), 12.67(1H,s) 42(18) NMR(400MHz,CDCl3) 5 value: 1.62-1.67(2H,m), 1.76- 1.98(6H,m), 2.71 (2H,t,J=7.6Hz) , 3.06(2H,t,J=7.6Hz), 3.66(3H,s), 3.96(3H,s), 4.79-4.83(1H,m), 5.45(2H,s), 6.37(1H,dd,J=9.2,2.4Hz), 6.4 8(1H,d,J=2.4Hz), 7.02(1H,d,J=9.2Hz), 7.42(1H,s), 7.50(1H,d,J=9.2Hz), 7.54-7.56(2H,m), 7.8 8(1H,d,J=8.8Hz), 8.01 (1H,dd,J=8.4,1.6Hz), 8.4 8(1H,d,J=l.6Hz), 12.68(1H,s) 42 (19) NMR(90MHz,CDC13) 5 value: 1.03(6H,d,J=6.6Hz), 1.9- 2.4(1H,m), 2.6-3.2(4H,m), 3.67(3H,s), 3.78(2H,d,J=6.6Hz), 3.89(3H,s), 5.34(2H,s), 6.3- 6.5(2H,m), 6.97(1H,d,J=9.0Hz), 7.10(1H,d,J=3.9Hz), 7.4- 7.6(3H,m), 7.72(1H,d,J=3.9Hz), 12.68(1H,s) 42 (20) NMR(90MHz,CDCl3) 5 value: 1.03(6H,d,J=6.7Hz), 1.46(3H,t,J=7.lHz), 1.98-2.15(1H,m), 2.64-2.73(2H,m), 2.97-3.06(2H,m), 3.66(3H,s), 3.79(2H,d,J=6.6Hz), 4.51(2H,q,J=7.1Hz), 5.28(2H,s), 6.38-6.51(2H,m), 6.96(1H,d,J=9.3Hz), 7.46-7.60(3H,m), 7.9-8.0(1H,m), 8.21(1H,d,J=7.6Hz), 8.85(1H,d,J=l.5Hz), 12.63(1H,s) 42 (21) NMR(400MHz,CDCl3) 5 value: 1. 42 (3H, t, J=7 . 2Hz) , 1.62- 1.66(2H,m), 1.76-1.97(6H,m), 2.69(2H,t,J=7.6Hz), 3.07(2H,t,J=7.6Hz), 3.66(3H,s), 4.42(2H,q,J=7.2Hz), 4.80-4.83(1H,m), 5.29(2H,s), 6.37(1H,dd,J=8.8,2.0Hz), 6.48(1H,d,J=2.0Hz), 6.99(1H,d,J=8.4Hz), 7.50-7.55(4H,m), 7.90(1H,d,J=8.4Hz), 7.94(1H,s), 8.07(1H,s), 12.70(1H,s) 42 (22) NMR(90MHz,CDC13) 8 value: 0 . 90(6H,d,J=6.6Hz), 1.08(6H,d,J=6.8Hz), 1.48(9H,s), 1.7-2.4(4H,m), 2.5- 2.8(2H,m), 2.9-3.2(2H,m), 3.4-4.0(4H,m), 3.83(2H,d,J=6.4Hz), 3.86(2H, d, J=6.6Hz) , 4.9-5.1(1H,m), 6.3-6.5(2H,m), 6.89(1H,d,J=9.3Hz), 7.5-7.6(3H,m), 12.67(1H,brs) 42 (23) NMR(90MHz,CDCl3) 5 value: 0.89(6H,d,J=6.6Hz), 1.08(6H,d,J=6.6Hz), 1.7-2.4(2H,m), 2.5-2.8(2H,m), 2.9- 3.3(4H,m), 3.83(2H,d,J=6.4Hz), 3.85(2H, d,J=6.6Hz), 4.29(2H,t,J=6.4Hz), 6.3-6.5(2H,m), 6.88(1H, d, J=9.3Hz) , 7.4-7.6(5H,m), 8.19(2H,d,J=8.8Hz), 12.66(1H,s) 42 (24) NMR (90MHz, CDCl3) 8 value: 0.90 (6H, d, J=6 . 6Hz), 1.08 (6H,d,J=6.6Hz), 1.4-2.3(10H,m), 2.5-2.8(2H,m), 2.9- 3.2(2H,m), 3.83(2H,d, J=6.4Hz) , 3.86(2H,d,J=6.6Hz), 4.7- 4.9(1H,m), 6.3-6.5(2H,m), 6.88(1H,d,J=9.3Hz), 7.2- 7.6(3H,m), 12.71(1H,s) 42 (25) NMR(90MHz,CDCl3) 8 value: 0 . 7-1. 2 (12H,m) , 1.46(3H,t,J=7.1Hz), 1.7-2.5(2H,m), 2.4-3.2(4H,m), 3.7- 4.0(4H,m), 4.54(2H,q,J=7.1Hz), 5.22(2H,s), 6.4- 6.7(2H,m), 6.8-7.0(1H,m), 7.4-7.7(3H,m), 7.8-8.0(1H,m), 8.19(1H,d,J=7.3Hz), 8.82(1H,d,J=l.5Hz), 12.65(1H,s) 42 (26) NMR (400MHz, CDC13) 5 value: 2.69(2H,t,J=7.6Hz), 3.08(2H,t,J=8.0Hz), 3.66(3H,s), 3.94(3H,s), 5.06(2H,s), 5.25(2H,s), 6.40-6.41(1H,m), 6.47-6.50(2H,m), 6.62(1H,d,J=2.8Hz), 6.93(1H,d,J=8.4Hz), 7.47-7.56(6H,m), 8.09(2H,d,J=8.0Hz), 12.66(1H,s) 42 (27) NMR(400MHz, CDC13) 5 value: 2.69(2H,t,J=7.6Hz), 3.08(2H,t,J=7.6Hz), 3.67(3H,s), 3.94(3H,s), 5.25(2H,s), 5.28(2H,s), 6.49(1H,dd,J=8.8,2.8Hz), 6.61(1H, d,J=2.4Hz) , 6.93(1H,d,J=8.4Hz), 7.02-7.04(1H,m), 7.15(1H,d,J=3.6Hz), 7.36(1H,dd,J=5.2,1.2Hz), 7.5 0-7.56(5H,m), 8.09(2H,d,J=8.4Hz), 12.65(1H,s) Example 43 Isopropyl 3-(5-(2-hydroxy-4- isobutoxybenzoyl)-2-{ [ (2S)-5- oxopyrrolizinyl]methoxy}phenylpropanoate was obtained in a similar manner as in Example 40. NMR(90MHz, CDC13) 5 value: 0 . 6-1. 6 (12H,m) , 1. 6-3 . 3 (9H,m) , 3.4-4.4(5H,m), 4.7-5.3(1H,m), 6.2-7.8(6H,m), 12.30(1H,s), 12.63(1H,s) Example 4 4 1.16 g of methyl 4-{[4-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-(3-methoxy-3- oxopropyl)phenoxy]methyl} benzoate was dissolved in 10 mL of methanol, to which 2.6 mL of a 20% aqueous solution of sodium hydroxide was added at room temperature, and this mixture was stirred for 30 minutes at the same temperature. Water and chloroform were successively added to the reaction mixture which was adjusted to pH 2 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was washed with hexane to yield 0.64 g of 4-({2-(2-carboxyethyl)-4-[4- (cyclopentyloxy)-2-hydroxybenzoyl]phenoxy}methyl) benzoic acid as light yellow solid. NMR(90MHz,DMSO-d6) δ value: 1.21-3.02(12H,m), 4.77- 5.03(1H,m), 5.35(2H,s), 6.44-6.52(2H,m), 7.17(1H,d,J=9.3Hz), 7.41-7.89(5H,m), 8.00(2H,d,J=8.3Hz), 12.09(3H,br) Example 4 5 1.15 g of methyl 3-{[4-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-(3-methoxy-3- oxopropyl)phenoxy]methyl}-1-benzothiophene-7- carboxylate was dissolved in a mixed solvent of 10 mL of methanol and 10 mL of tetrahydrofuran, to which 2 mL of a 5M aqueous solution of sodium hydroxide was added at room temperature, and then this mixture was stirred for 30 minutes at the same temperature, followed by addition thereto of 2 mL of water, and this mixture was stirred for another 30 minutes at temperatures of 50 to 60°C. The reaction mixture was cooled to room temperature, to which water was added, and then adjusted to pH 2 with 6M hydrochloric acid. Chloroform was added to this reaction mixture, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water, the organic phase was separated and the solvent was distilled out thereof under reduced pressure. The resultant residue was washed with hexane to yield 1.00 g of 3-({2-(2-carboxyethyl)-4-[4-(cyclopentyloxy)-2- hydroxybenzoyl]phenoxy}methyl)-1-benzothiophene-7- carboxilic acid as light yellow solid. NMR(4 00MHz,DMSO-d6) 8 value: 1.60-1.76(6H,m), 1.91- 1.96(2H,m), 2.50(2H,t,J=8.0Hz), 2.84(2H,t,J=7.6Hz), 4.86-4.91(1H,m), 5.56(2H,s), 6.48-6.51(2H,m), 7.38(1H,d,J=8.8Hz), 7.4 7(1H,d,J=8.8Hz), 7.54(1H,d,J=1.6Hz), 7.58-7.61(2H,m), 8.02(1H,s), 8.10(1H,d,J=7.6Hz), 8.22(1H,d,J=7.6Hz), 12.07(1H,brs) Example 4 6 1.20 g of ethyl (E)-3-(4-{ [4-[4- (cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-methoxy-3- oxopropyl)phenoxy]methyl}phenyl)-2-propenoate was dissolved in a mixed solvent of 12 mL of methanol and 12 mL of tetrahydrofuran, to which 2.4 mL of a 20% aqueous solution of sodium hydroxide was added at room temperature, and then this mixture was stirred for one hour at the same temperature. The reaction mixture was concentrated under reduced pressure, to which water was added, and then adjusted to pH 2 with 6M hydrochloric acid. The resultant precipitate was filtered out and washed with water to yield 0.841 g of (E)-3-(4-{ [4-[4- (cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-hydroxy-3- oxopropyl)phenoxy]methyl}phenyl)-2-propenoic acid as light yellow solid. NMR(4 00MHz, DMSO-d6) 5 value: 1. 60-1.74(6H,m) , 1.93- 1.96(2H,m), 2.57(2H,t,J=7.3Hz), 2.91(2H,t,J=7.3Hz), 4.89-4.92(1H,m), 5.29(2H,s), 6 . 48-6 . 50 (2H,m) , 6.56(1H,d,J=l6.1Hz), 7.18(1H,d,J=9.3Hz), 7.46(1H,d,J=8.6Hz), 7.52-7.56(4H,m), 7.60(1H,d,J=15.9Hz), 7.74 (2H,d,J=8.0Hz), 12.07(3H,brs) Example 4 7 16.5 g of methyl 3-(5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-{ [4- (3-hydroxy-5- isoxoazolyl)benzyl]oxy}phenyl) propanoate was dissolved in a mixed solvent of 160 mL of methanol and 160 mL of tetrahydrofuran, to which 20 mL of a 20% aqueous solution of sodium hydroxide was added at room temperature, and then this mixture was stirred for 2 hours at the same temperature. Water was added to the reaction mixture, and then adjusted to pH 1 with 6M hydrochloric acid. This mixture was concentrated under reduced pressure, then resultant precipitate was filtered out. The resultant precipitate was dissolved in a mixed solvent of chloroform and methanol, and washed with water. The solvent was distilled out under reduced pressure to yield 14.3 g of 3-(5-[4- (cyclopentyloxy)-2-hydroxybenzoyl]-2-{[4-(3-hydroxy-5- isoxazolyl)benzyl]oxy}phenyl) propanoic acid as light yellow solid. NMR (400MHz,DMSO-d6) 8 value: 1. 5-1.8( 6H,m) , 1.9- 2.0(2H,m), 2.58 (2 H,t,J=7.6Hz), 2.91(2H,t,J=7.6Hz), 4.8-5.0(1H,m), 5.33(2H,s), 6.49(1H,dd,J=8.8, 2.4Hz), 6.52(1H,d,J=2.4Hz), 6.59(1H,s), 7.19(1H,m), 7.44(1H,d,J=8.4Hz), 7.5-7.6(2H,m), 7.62(2H,d,J=8.4Hz), 7.85(2H,d,J=8.0Hz), 11.45(1H,brs), 11.97(2H,brs) Example 4 8 0.98 g of methyl 4-{[4-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-(3-methoxy-3- oxopropyl)phenoxy]methyl}-2-methoxybenzoate was dissolved in a mixed solvent of 10 mL of methanol and 10 mL of tetrahydrofuran, to which 2 mL of a 20% aqueous solution of sodium hydroxide was added at room temperature, and then this mixture was stirred for one hour at the same temperature. The reaction mixture to which water was added was adjusted to pH 2 with 6M hydrochloric acid, followed by the addition of ethyl acetate thereto, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, this washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out under reduced pressure. The resultant residue was recrystallized from ethanol to yield 0.42 g of 4-({2-(2-carboxyethyl)-4-[4-(cyclopentyloxy)-2- hydroxybenzoyl]phenoxy}methyl)-2-methoxybenzoic acid as light yellow solid. NMR(4 00MHz,DMSO-d6) 5 value: 1.60-1.74 (6H,m), 1.93- 1.96(2H,m), 2.59 (2H,t,J=7.6Hz) , 2.93(2H,t,J=7.6Hz), 3.84(3H,s), 4.90-4.93(1H,m), 5.30(2H,s), 6.48- 6.50(2H,m), 7.10(1H,d,J=9.0Hz) , 7.18(1H,d,J=9.2Hz), 7.27(1H,s), 7.46(1H,d,J=8.4Hz), 7.55-7.57(2H,m), 7.68 (1H,d,J=8.0Hz), 12.04(1H,s), 12.39(2H,brs) Example 4 9 Compounds listed in Tables 26 to 32 were obtained in a similar manner as in Example 44. 49(1) NMR(400MHz,DMSO-d6) 5 value: 1.60-1.74(6H,m), 1.93- 1.96(2H,m), 2.55(4H,t,J=7 .6Hz), 2.84(2H,t,J=7.6Hz), 2.88(2H,t,J=7.6Hz), 4.90-4.91(1H,m), 5.21(2H,s), 6.47- 6.50(2H,m), 7.19(1H,d,J=8.4Hz), 7.27(2H,d,J=8.0Hz), 7.40(2H,d,J=8.0Hz), 7.46(1H, d, J=8.8Hz) , 7.53-7.55(2H,m), 12.05(1H,s), 12.13(2H,brs) 49(2) NMR(400MHz,DMSO-d6) δ value: 1.60-1.76(6H,m), 1.94- 1.96(2H,m), 2.55(3H,s), 2 . 58 (2H,t,J=7.2Hz) , 2.92(2H,t,J=7.6Hz), 4.89-4.91(1H,m), 5.29(2H,s), 6.48- 6.50(2H,m), 7.16-7.19(1H,m), 7.39 (1H,d,J=8.0Hz), 7.42(1H,s), 7.46(1H,d, J=8.4Hz), 7.54-7.56(2H,m), 7.87(1H,d,J=8.0Hz), 12.05(1H,s), 12.47(2H,brs) 49(3) NMR(400MHz,DMSO-d6) δ value: 1.5-1.8(6H,m), 1.8- 2.0(2H,m), 2.41(3H,s), 2.55(2H,t,J=7.6Hz), 2.90 (2H,t,J=7.6Hz) , 4.8-5.0(1H,m), 5.30(2H,s), 6.48- 6.50(2H,m), 7.25(1H,d,J=8.4Hz), 7.47(1H,d,J=8.4Hz), 7.5-7.6(3H,m), 7.79(1H,d,J=7.6Hz), 7.82(1H,s), 12.07 (3H,brs) 49(4) NMR(90MHz,CDCl3) 5 value: 1.01 ( 6H,d,J=6.6Hz), 1.95- 2.24(1H,m), 2.49(3H,s), 2.63-2.79(2H,m), 2.95- 3.10(2H,m), 3.77(2H,d,J=6.7Hz), 5.12(2H,s), 6.36- 6.50(2H,m), 6.95(1H, d, J=9.1Hz) , 7.20-7.59(7H,m), 12.66(2H,brs) 49(5) NMR(90MHz,CDCl3) 5 value: 1.02(6H,d,J=6.6Hz) , 1.95- 2.30(1H,m), 2.70-2.81(5H,m), 3.00-3.20(2H,m), 3.78(2H,d,J=6.4Hz) , 5.24(2H,s), 6.39-6.48(2H,m), 6.95(1H,d,J=9.3Hz), 7.46-7.77(7H,m), 12.63(2H,brs) 49(6) NMR(90MHz,CDC13) 8 value: 1.02(6H,d,J=6.8Hz), 1.95- 2.30(1H,m), 2.62-2.82(2H,m), 2.96-3.16(5H,m), 3.78(2H,d,J=6.6Hz), 5.27(2H,s), 6.36-6.48(2H,m), 6.93(1H,d,J=9.3Hz), 7.43-7.69(5H,m), 8.00(2H,d,J=8.4Hz), 12.63(2H,brs) 49(7) NMR(400MHz,DMSO-d6) 8 value: 0.98(6H,d,J=6.8Hz), 1.99- 2.07(1H,m), 2.57(2H,t,J=7.6Hz), 2.91(2H,t,J=7.6Hz), 3.83(2H,d,J=6.6Hz), 5.32(2H,s), 6.52-6.55(2H,m), 7.18(1H,d,J=9.3Hz), 7.38(1H,brs), 7.47(1H,d,J=9.5Hz), 7.54-7.57(4H,m), 7.91(2H,d,J=8.3Hz), 7.99(1H,brs), 12.00(1H,brs), 12.15(1H,brs) 49(8) NMR ( 90MHz,DMSO-d6) δ value: 0.99 ( 6H,d,J=6.6Hz), 1.90- 2.19(1H,m), 2.50-2.64(2H,m), 2.82-2.98(2H,m), 3.32(3H,s), 3.84(2H,d,J=6.6Hz), 5.36(2H,s), 6.50- 6.57(2H,m), 7.13-7.68(7H,m), 8.00(2H,d,J=8.3Hz), 11.99(1H,s), 12.14(1H,brs) 49(9) NMR(90MHz,DMSO-d6) δ value: 0.67(6H,d,J=6.8Hz), 1.05(6H,d,J=6.7Hz) , 1.60-1.88(1H,m), 1.98-2.25(1H,m), 2.67-2.75(2H,m), 3.01-3.20(2H,m), 3.61(2H,d,J=6.3Hz), 3.78(2H,d,J=6.3Hz), 5.22(2H,s), 5.98(2H,brs), 6.45- 6.59(2H,m), 6.87(1H,d,J=9.3Hz), 7.34-7.69(5H,m), 8.12(2H,d,J=8.1Hz) 49(10) NMR (400MHz, DMSO-d6) δ value: 1. 5-1. 8 ( 6H,m) , 1.8- 2.1(2H,m), 2.53(2H,t, J=7.6Hz) , 2.88(2H, t, J=7.6Hz) , 3.65(3H,s), 4.91-4.93(1H,m), 5.33(2H,s), 6.5-6.7(2H,m), 7.11(1H,d,J=8.8Hz), 7.21(1H,d,J=8.4Hz), 7.51(1H,dd,J=8.4,2.4Hz), 7.5 8-7.60(3H,m), 7.8 9(2H,d,J=8.4Hz), 12.5 6(2H,brs) 49(11) NMR(400MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.94- 1.96(2H,m), 2.48 (2H,t,J=7.3Hz) , 2.58(2H,t,J=7.6Hz), 2.78(2H,t,J=7.6Hz), 2.90(2H,t,J=7.3Hz), 3.82(3H,s), 4.90-4.93(1H,m), 5.21(2H,s), 6.48-6.50(2H,m), 6.98(1H,d,J=7.3Hz), 7.10(1H,s), 7.16-7.21(2H,m), 7.46(1H,d,J=8.8Hz), 7.54-7.57(2H,m), 12.04(1H,s), 12.13 (2H,brs) 49(12) NMR(400MHz,CDCl3) δ value: 1. 58-1. 66 (2H,m) , 1.71(3H,d,J=6.4Hz),1.7 4-1.96(6H,m), 2.8 4-2.8 8(2H,m), 2.91-2.98(1H,m), 3.33-3.41(1H,m), 4.76-4.81(1H,m), 5.51(1H,q,J=6.4Hz), 6.34(1H,dd,J=8.8,2.0Hz), 6.44(1H,d,J=2.4Hz), 6.69(1H,d,J=8.8Hz), 7.37(1H,dd,J=8.4,1.2Hz), 7.4 4(1H,d,J=8.8Hz), 7.51(2H,d,J=8.4Hz), 7.54(1H,d,J=l.2Hz), 8.12 (2H,d,J=8.0Hz), 12.64(1H,s) 49(13) NMR (400MHz,DMSO-d6) δ value: 2.42(2H,d,J=17.6Hz), 2.57(2H,t,J=7.6Hz), 2.84(2H,dd,J=16.8,6.8Hz), 2.92(2H,t,J=7.6Hz), 5.13-5.16(1H,m), 5.35(2H,s), 5.77(2H,s), 6.48-6.52(2H,m), 7.18(1H,d,J=9.2Hz), 7.46(1H,d,J=8.4Hz), 7.55-7.61(4H,m), 7.98(2H,d,J=8.0Hz), 12.02 (3H,brs) 49(14) NMR(90MHz,DMSO-d6) δ value: 0.98(6H,d,J=6.6Hz), 1.88- 2.10(1H,m), 2.38-2.52(2H,m), 2.68-2.76(2H,m), 3.09- 3.23(2H,m), 3.83(2H,d,J=6.4Hz), 4.26-4.33(2H,m), 6.48- 6.54(2H,m), 7.12(1H,d,J=9.5Hz), 7.40-7.57(5H,m), 7.77- 7.94(2H,m), 11.99(1H,s), 12.46(2H,brs) 49(15) NMR(90MHz,DMSO-d6) δ value: 0.98(6H,d,J=6.7Hz), 1.90- 2.18(1H,m), 2.30-2.50(2H,m), 2.67-2.86(2H,m), 3.09- 3.28(2H,m), 3.83(2H,d,J=6.4Hz), 4.27-4.40(2H,m), 6.50- 6.54(2H,m), 7.11(1H,d,J=8.4Hz), 7.40-7.58(5H,m), 7.90(2H,d,J=7.8Hz), 11.99(1H,s), 12.44(2H,brs) 49(16) NMR(400MHz,DMSO-d6) δ value: 2.90(2H,t,J=7.6Hz), 3.25(2H,t,J=7.6Hz), 5.69(2H,s), 7.4-7.7(4H,m), 7.75(1H,d,J=8.4Hz), 7.9-8.1(6H,m), 8.31(2H,d,J=8.0Hz), 10.81(1H,brs) 49(17) NMR(400MHz,DMSO-d6) δ value: 1.61-1.76(6H,m), 1.96- 1.98(2H,m), 2.55(2H,t,J=7.2Hz), 2.90(2H,t,J=7.2Hz), 4.93-4.94(1H,m), 5.35(2H,s), 6.85-6.91(2H,m), 7.16(1H,d,J=8.8Hz), 7.45(1H,t,J=8.8Hz), 7.59-7.65(4H,m), 7.98(2H,d,J=8.0Hz), 12.57(2H,brs) 49(18) NMR(400MHz,DMSO-d6) δ value: 0.94(6H,d,J=6.8Hz), 1.63(2H,q,J=6.6Hz), 1.74-1.79(1H,m), 2.57(2H,t,J=7.6Hz), 2.92(2H,t,J=7.6Hz), 4.08(2H,t,J=6.8Hz), 5.35(2H,s), 6.51-6.55(2H,m), 7.18(1H,d,J=9.3Hz), 7.46(1H,d,J=8.8Hz) , 7.54-7.56(2H,m), 7.61(2H,d,J=8.3Hz), 7.99(2H,d,J=8.3Hz) , 12.02(3H,brs) 49(19) NMR (400MHz, DMSO-d6) δ value: 1.00(9H,s), 2.57(2H,t,J=7.6Hz), 2.92(2H,t,J=7.6Hz), 3.72(2H,s), 5.35(2H,s), 6.53-6.55(2H,m), 7.18(1H,d,J=9.2Hz), 7.47(1H,d,J=9.6Hz), 7.54-7.56(2H,m), 7.60(2H,d,J=8.0Hz), 7.98(2H,d,J=8.0Hz), 12.00(3H,brs) 49(20) NMR(90MHz,DMSO-d6) δ value: 1.0-2.2 (10H,m), 2.4- 3.1(4H,m), 4.3-4.7(1H,m), 5.35(2H,s), 6.4-6.6(2H,m), 7.17(1H,d,J=9.3Hz) , 7.4-7.7(5H,m), 8.00 (2H,d,J=8.1Hz) , 11.6-12.9(3H,br) 49(21) NMR (4 00MHz,DMSO-d6) δ value: 1.60-1.74(6H,m) , 1.94- 2.09(2H,m), 2.56(2H, t, J=7.6Hz) , 2.90(2H,t,J=7.6Hz), 3.43(3H,s), 4.90-4.93(1H,m), 5.30(2H,s), 5.34(2H,s), 6.48-6.50(2H,m), 7.20(1H,d,J=8.4Hz) , 7.47(1H,d,J=8.4Hz) , 7.55-7.61(3H,m), 7.64(1H,dd,J=7.6,1.2Hz), 7.72(1H,d,J=1.2Hz), 12.05(1H,s), 12.62(2H,brs) 49(22) NMR(400MHz,DMSO-d6) δ value: 1.16-1.21(2H,m), 1.49- 1.52(2H,m), 1.60-1.68(4H,m), 2.05-2.13(1H,m), 2.54- 2.59(4H,m), 2.91(2H,t,J=7.2Hz), 5.35(2H,s), 6.78(1H,d, J=7.6Hz) , 6.81(1H,s), 7.16(1H,d,J=8.4Hz), 7.32(1H,d,J=8.0Hz), 7.55(1H,dd,J=8.4,2.4Hz), 7.59- 7.62(3H,m), 7.98(2H,d,J=8.4Hz), 10.81(3H,brs) 49(23) NMR(400MHz,DMSO-d6) δ value: 1. 57-1.74(6H,m), 1.80- 1.98(2H,m), 2.37(2H,t,J=8.0Hz), 2.85(2H,t,J=7.6Hz), 3.39(2H,brs), 4 . 88-4.91(1H,m), 5.33(2H,s), 6.47- 6.50(2H,m), 7.14(1H,d,J=8.4Hz), 7.38(2H,brs), 7.45(1H,d,J=8.8Hz), 7.51-7.54(2H,m), 7.67(2H,d,J=8.4Hz), 7.86(2H,d,J=8.4Hz) 49 (24) NMR(90MHz,CDC13) δ value: 1.02(6H,d,J=6.6Hz), 1.86- 2.24(1H,m), 2.64-3.18(4H,m), 3.77(2H,d,J=6.3Hz), 5.23(2H,s), 6.36-6.48(2H,m), 6.92(1H,d,J=9.0Hz), 7.45- 7.76(7H,m), 8.74 (1H,brs), 12.62(1H,s) 49(25) NMR(90MHz,CDCl3) δ value: 1.02(6H,d,J=6.6Hz), 1.9- 2.4(1H,m), 2.75(2H,t, J=6.8Hz) , 3.09(2H,t,J=6.8Hz), 3.77(2H,d,J=6.3Hz), 5.28(2H,s), 6.3-6.6(2H,m), 6.92(1H,d,J=9.3Hz) , 7.4-7.8(5H,m) , 8.27(2H,d,J=8.3Hz) , 12.6K2H, brs) 49(26) NMR(400MHz,DMSO-d6) δ value: 1. 22 ( 6H,d,J=6.8Hz), 2.56(2H,t,J=7.6Hz) , 2.86-2.93(3H,m), 5.35(2H,s), 6.83- 6.86(2H,m), 7.16(1H,d,J=8.8Hz), 7.35(1H,d,J=8.0Hz), 7.56(1H,dd,J=8.4,2.4Hz), 7.60-7.63(3H,m), 7.98(2H,d,J=8.4Hz), 10.8 3(3H,brs) 49(27) NMR(400MHz,DMSO-d6) δ value: 0.90(3H,s), 1.24-1.31(2H,m), 1.48-1.55(2H,m), 1.60-1.67(4H,m), 2.54-2.58(4H,m), 2.91(2H,t,J=7.6Hz) , 5.34(2H,s), 6.75(1H, d, J=8.0Hz) , 6.79(1H,s), 7.16(1H,d,J=8.8Hz) , 7.31(1H,d,J=8.0Hz), 7.55(1H,dd,J=8.4,2.0Hz), 7.60(2H,d,J=8.4Hz), 7.63(1H,d,J=2.0Hz), 7.98(2H,d,J=8.4Hz), 10.73 (3H,brs) 49(28) NMR(400MHz,DMSO-d6) δ value: 1.57-1.78(6H,m), 1.91- 2.00(2H,m), 2.58(2H,t,J=7.6Hz), 2.63(6H,s), 2.94(2H,t,J=7.2Hz), 4.89-4.93(1H,m), 5.40(2H,s), 6.48- 6.51(2H,m), 7.19(1H,d,J=9.6Hz), 7.46 (1H,d,J=8.4Hz), 7.56(2H,s), 7.77(2H,d,J=8.4Hz), 7.81(2H,d,J=8.4Hz), 12.08(2H,brs) 49(29) NMR(400MHz,DMSO-d6) δ value: 1.30-1.35(2H,m), 1.54- 1.62(4H,m), 1.74-1.80(2H,m), 2.28-2.35(1H,m), 2.57(2H,t,J=7.6Hz), 2.92(2H,t,J=7.6Hz), 3.93(2H,d,J=7.2Hz), 5.35(2H,s), 6.51-6.54(2H,m), 7.18(1H,d,J=9.2Hz), 7.46(1H,d,J=9.2Hz), 7.54-7.56(2H,m), 7.61(2H,d,J=8.4Hz), 7.99(2H,d,J=8.4Hz), 12.00(3H,brs) 49(30) NMR(90MHz,DMSO-d6) δ value: 2.40-3.10(4H,m), 5.25(2H,s), 5.35(2H,s), 6.40-6.70(2H,m), 7.17(1H,d,J=9.3Hz), 7.4- 7.7(6H,m), 7.80-8.10(3H,m), 8.50-8.80(2H,m), 11.5- 12.9(3H,br) 49(31) NMR(400MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.94- 1.99(2H,m), 2.60(2H,t,J=7.6Hz), 2.93(2H,t,J=7.6Hz), 3.78(6H,s), 4.90-4.91(1H,m), 5.25(2H,s), 6.49(1H,dd,J=7.6,2.2Hz), 6.51(1H,s), 6.84(2H,s), 7.19(1H,d,J=9.3Hz), 7.46(1H,d,J=9.3Hz), 7.56-7.58(2H,m), 12.02(1H,s), 49(32) NMR(400MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.93- 1.96(2H,m), 2.56(2H,t,J=7.3Hz) , 2 . 88(2H,t,J=7.3Hz), 3.59(2H,s), 4.90-4.93(1H,m), 5.23(2H,s), 6.48- 6.50(2H,m), 7.19(1H,d,J=8.3Hz), 7.30(2H,d,J=8.0Hz), 7.43(2H,d,J=8.0Hz), 7.46(1H,d,J=9.0Hz), 7.54-7.56(2H,m), 12.05(1H,s), 12.25(2H,brs) 49(33) NMR(400MHz,DMSO-d6) δ value: 1.60-1.70(1H,m), 1.77- 1.83(1H,m), 2.04-2.09(2H,m), 2.42-2.50(2H,m), 2.57(2H,t,J=7.6Hz), 2.91(2H,t,J=7.6Hz), 4.77-4.80(1H,m), 5.35(2H,s), 6.42(1H,d,J=2.4Hz), 6.45(1H,dd,J=8.8,2.4Hz) , 7.17(1H,d,J=9.2Hz), 7.45(1H,d,J=8.8Hz), 7.54-7.56(2H,m), 7.60(2H,d,J=8.4Hz), 7.98(2H,d,J=8.4Hz), 11.92(3H,brs) 49(34) NMR(400MHz,DMSO-d6) δ value: 2.57(2H,t,J=7.6Hz), 2.92(2H,t,J=7.6Hz), 5.20(2H,s), 5.35(2H,s), 6.60- 6.64(2H,m), 7.18(1H,d,J=9.2Hz), 7.34-7.49(6H,m), 7.55- 7.62(4H,m), 7.99(2H,d,J=8.8Hz), 11.93(3H,brs) 49(35) NMR(400MHz,DMSO-d6) δ value: 1.56-1.78(6H,m), 1.90- 1.99(2H,m), 2.43(3H,d,J=4.8Hz), 2.58(2H,t,J=7.2Hz), 2.93(2H,t,J=7.2Hz), 4.90-4.93(1H,m), 5.37(2H,s), 6.48- 6.50(2H,m), 7.18(1H,t,J=4.4Hz), 7.45-7.50(2H,m), 7.55- 7.57(2H,m), 7.72(2H,d,J=8.4Hz), 7.83(2H,d,J=8.0Hz), 12.05(1H,s), 12.17(1H,brs) 49(36) NMR(400MHz,DMSO-d6) 6 value: 1.57-1.75(6H,m) , 1.90- 2.00(2H,m), 2.58(2H,t,J=7.6Hz), 2.90-2.99(8H,m), 4.89- 4.93(1H,m), 5.31(2H,s), 6.48-6.50(2H,m), 7.20(1H,d,J=9.2Hz), 7.44-7.47(3H,m), 7.54-7.57(4H,m), 12.06(1H,s), 12.15(1H,brs) 49(37) NMR(4 00MHz,DMSO-d5) δ value: 1.60-1.70(2H,m), 1.71- 1.75(4H,m), 1.93-1.99(2H,m), 2.56(2H,t,J=6.8Hz), 2.88(2H,t,J=6.8Hz), 3.02(3H,s), 4.91(1H,m), 5.20(2H,s), 6.48-6.50(2H,m), 7.19(1H,d,J=8.OHz), 7.25(2H,d,J=8.OHz), 7.46(2H,d,J=8.4Hz), 7.47(1H,s), 7.55(2H,d,J=8.OHz), 9.85(1H,brs), 12.07(1H,s) 49(38) NMR(400MHz,CDCl3) δ value: 1.59-1.66(2H,m), 1.75- 1.97(6H,m), 2.73(2H,t,J=7.6Hz), 3.02(3H,d,J=5.2Hz), 3.06(2H,t,J=7.6Hz), 4.79-4.82(1H,m), 5.22(2H,s), 6.23(1H,brs), 6.38(1H,dd,J=9.2,2.4Hz) , 6.47(1H,d,J=2.4Hz), 6.94(1H,d,J=8.4Hz), 7.49-7.56(5H,m), 7.8 0(2H,d,J=8.0Hz), 12.68 (2H,brs) 49(39) NMR(400MHz,DMSO-d6) δ value: 1.52-1.59(2H,m), 1.64- 1.70(2H,m), 1.75-1.79(2H,m), 1.99-2.03(2H,m), 2.55(2H,t,J=7.6Hz), 2.90(2H,t,J=7.6Hz), 2.94-3.03(1H,m), 3.34(3H,brs), 5.32(2H,s), 6.84(1H,d,J=8.4Hz), 6.87(1H,s), 7.15(1H,d,J=8.4Hz) , 7.34(1H,d,J=8.OHz), 7.53-7.57(3H,m), 7.62(1H,d,J=2.4Hz), 7.95(2H,d,J=8.OHz) 49(40) NMR(400MHz,DMSO-d6) δ value: 2.57(2H,t,J=7.6Hz), 2.91(2H,t,J=6.8Hz), 5.15(2H,s), 5.33(2H,s), 6.48- 6.52(1H,m), 6.60(1H,d,J=8.4Hz), 6.64(1H,d,J=3.6Hz), 6.68(1H,d,J=2.4Hz), 7.18(1H,d,J=9.2Hz), 7.47(1H,d,J=8.8Hz), 7.55-7.58(7H,m), 7.72-7.73(1H,m), 7.96(2H,d,J=8.0Hz) 49(41) NMR(400MHz, DMSO-d6) δ value: 2.57(2H,t,J=7.6Hz), 2.92(2H,t,J=7.6Hz), 5.35(2H,s), 5.39(2H,s), 6.61(1H,dd,J=9.2,2.8Hz), 6.67(1H,d,J=2.0Hz), 7.05- 7.07(1H,m), 7.18(1H,d,J=9.6Hz), 7.26(1H,d,J=3.6Hz), 7.47(1H,d,J=8.8Hz), 7.55-7.62(5H,m), 7.99(2H,d,J=8.0Hz), 11.90(3H,brs) 49(42) NMR(4 00MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.93- 1.99(2H,m), 2.58(2H,t,J=7.6Hz), 2.93(2H,t, J=7.6Hz), 4.90-4.93(1H,m), 5.35(2H,s), 6.48-6.50(2H,m), 7.16(1H,d,J=9.2Hz), 7.40-7.47(3H,m), 7.55-7.56(2H,m), 7.91(1H,t,J=8.0Hz), 12.03(1H,s) 49(43) NMR(400MHz,DMSO-d6) δ value: 1.59-1.79(6H, m), 1.83- 2.00(2H,m), 2.57(2H,t,J=7.2Hz), 2.91(2H,t,J=7.2Hz) , 4.88-4.93(1H,m), 5.36(2H,s), 6.48-6.50(2H,m), 7.16(1H,d,J=9.2Hz), 7.45(1H,d,J=9.2Hz), 7.55(2H,s), 7.68-7.77(3H,m), 12.06(1H,s) 49(44) NMR(90MHz, CDC13) δ value: 1.05(6H,d,J=6.6Hz), 1.90- 2.35(1H,m), 2.56-3.14(4H,m), 3.81(2H,d,J=6.6Hz), 5.26(2H,s), 6.91-7.01(4H,m), 7.41-7.80(7H,m), 8.07(2H,d,J=8.lHz) 49 (45) NMR (90MHz, DMSO-d6) δ value: 0 . 99 (6H, d, J=6 . 6Hz) , 1.33(6H,d,J=6.lHz), 1.8-2.3(1H,m), 2.5-3.0(4H,m), 3.42(2H,brs), 3.84(2H,d,J=6.4Hz), 4.6-4.9(1H,m), 5.24(2H,s), 6.4-6.6(2H,m), 7.17(1H,d,J=8.8Hz), 7.4- 7.6(6H,m), 12.05(1H,s) 49(46) NMR (400MHz, DMSO-d6) δ value: 0.99(6H,d,J=6.6Hz), 1.60- 1.74(6H,m), 1.86-2.06(3H,m), 2.58(2H,t,J=7.6Hz), 2.92(2H,t,J=7.6Hz), 3.83(2H,d,J-6.4Hz), 4.90-4.93(1H,m), 5.29(2H,s), 6.48-6.50(2H,m), 7.08(1H,d,J=8.0Hz), 7.16(1H,d, J=9.2Hz) , 7.23(1H,s), 7.45(1H,d,J=9.0Hz), 7.54-7.56(2H,m), 7.65(1H,d,J=7.8Hz), 12.04(1H,s), 12.36(2H,brs) 49(47) NMR(90MHz,DMSO-d6) δ value: 0 . 99 ( 6H,d,J=6.6Hz) , 1.82- 3.02(5H,m), 3.83(2H,d,J=6.3Hz), 5.35(2H,s), 6.47- 6.55(2H,m), 7.17(1H,d,J=9.3Hz), 7.42-7.66(5H,m), 8.00(2H,d,J-8.3HZ), 12.03(1H,s), 12.55(2H,brs) 49(48) NMR (90MHz,DMSO-d6) δ value: 0.99(6H,d,J6.7Hz), 1.90- 2.19(1H,m), 2.48-2.64(2H,m), 2.83-2.99(2H,m), 3.84(2H,d,J=6.7Hz) , 5.32(2H,s), 6.47-6.57(2H,m), 7.17 (1H,d,J=9.5Hz) , 7.42-7.70(5H,m), 7.80(2H,d,J-8.1Hz), 9.02(1H,brs), 11.20(1H,brs), 11.96(2H,brs) 49(49) NMR(90MHz,CDCl3) δ value: 1.04(6H,d,J=6. 6Hz) , 1.90- 2.35(1H,m), 2.57-2.72(2H,m), 2.98-3.13(2H,m), 3.80(2H,d,J=6.2Hz) , 5.25(2H,s), 6.39-6.49(2H,m), 7.00(1H,d,J=9.2Hz), 7.40-7.72(6H,m), 7.98-8.12(3H,m), 12.64(1H,s) 49(50) NMR{90MHz,DMSO-d6) δ value: 0.99(6H,d,J=6.6Hz) , 1.90- 2.95(5H,m), 3.84(2H,d,J=6.4Hz), 5.59(2H,s), 6.50- 6.55(2H,m), 7.10(1H,d,J=8.6Hz), 7.44-7.68(6H,m), 7.98(1H,d,J=7.1Hz), 12.03(1H,s), 12.62 (2H,brs) 49(51) NMR(400MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.93- 1.96(2H,m), 2.54(2H,t,J=7.6Hz) , 2.88(2H,t,J=7.6Hz), 4.90-4.93(1H,m), 5.38(2H,s), 6.48-6.50(2H,m), 7.25(1H,d,J=8.8Hz), 7.46(1H,d,J=8.8Hz), 7.55-7.58(2H,m), 7.72-7.75(2H,m), 7.83(1H,dd,J=8.0,1.2Hz), 12.03(1H,s), 12.55(2H,brs) 4 9(52) NMR(400MHz,DMSO-d6) δ value: 1.54-1.75(6H,m), 1.88- 1.96(2H,m), 2.50(2H,t,J=7.6Hz), 2.89(2H,t,J=7.6Hz), 4.78-4.81(1H,m), 5.33(2H,s), 6.28(1H,s), 6.33(1H,dd,J=11.6,2.0Hz), 7 . 13(1H,d,J=8.4Hz), 7.54(1H,dd,J=8.8,2.0Hz), 7.59(2H,d,J=8.0Hz), 7.68(1H,d,J=2.0Hz), 7.97(2H,d,J=8.4Hz), 10.23(3H,brs) 49(53) NMR(400MHz,DMSO-d6) S value: 1.5-1.8(6H,m), 1.9- 2.0(2H,m), 2.25(3H,s), 2.55(2H,t,J=7.4Hz), 2.90(2H,t,J=7.4Hz), 4.8-5.0(1H,m), 5.34(2H,s), 6.8 0(1H,dd,J=8.4,2.4Hz), 6.86(1H,d,J=2.4Hz), 7.15(1H,d,J=8.4Hz), 7.22(1H,d,J=8.4Hz), 7.52(1H,dd,J=8.4,2.4Hz), 7.59-7.62(3H,m), 7.98(2H,d,J=8.4Hz), 12.56(2H,brs) 49(54) NMR(400MHz,DMSO-d6) δ value: 1.55-1.75(6H,m), 1.90- 1.98(2H,m), 2.56(2H,t,J=7.6Hz), 2.89(2H,t,J=7.2Hz) , 4.31(3H,brs), 4.89-4.92(1H,m), 5.26(2H,s), 6.48- 6.50(2H,m), 7 . 17(1H,d,J=9.6Hz), 7.43-7.47(3H,m), 7.53- 7.55(2H,m), 7.63(2H,d,J=8.0Hz) 49(55) NMR(90MHz,DMSO-d6) δ value: 0.91(6H,t,J=7.1Hz), 1.5- 1.8(4H,m), 2.5-3.0(4H,m), 4.2-4.5(1H,m), 5.36(2H,s), 6.4-6.6(2H,m), 7.17(1H,d,J=9.0Hz), 7.4-7.7(5H,m), 8.00(2H,d,J=8.0Hz), 12.08(1H,s), 12.55(2H,brs) 49(56) NMR ( 90MHz, DMSO-d6) δ value: 0 . 8-2 . 0 (llH,m) , 2.4- 3.1(4H,m), 3.86(2H,d,J=5.1Hz), 5.35(2H,s), 6.4- 6.6(2H,m), 7.1-7.7(6H,m), 7.99(2H, d,J=8.1Hz) , 11.4- 12.9(3H,br) 49(57) NMR(90MHz,DMSO-d6) δ value: 0.3-0.7(4H,m), 1.0-1.4(1H,m), 2.5-3.0(4H,m), 3.90(2H,d,J=6.8Hz), 5.35(2H,s), 6.5- 6.6(2H,m), 7.17(1H,d,J=9.0Hz), 7.4-7.7(5H,m), 7.99(2H,d,J=7.8Hz), 11.4-13.0(3H,br) 49(58) NMR(90MHz, DMSO-d6) δ value: 1.2-1.9(12H,m), 2.5- 3.0(4H,m), 4.5-4.8(1H,m), 5.35(2H,s), 6.4-6.5(2H,m), 7.1-7.7(6H,m), 8.00(2H,d,J=8.4Hz), 11.4-13.0 (3H,br) 49(59) NMR(400MHz,CDCl3) δ value: 1.34(6H,t,J=7.2Hz) , 1.60- 1.98(8H,m), 2.74(2H,t,J=7.6Hz), 3.08(2H,t,J=7.6Hz), 4.10-4.18(4H,m), 4.80-4.83(1H,m), 5.23(2H,s), 6.38(1H,dd,J=8.8,2.4Hz), 6.4 8(1H,d,J=2.4Hz), 6.94(1H,d,J=8.8Hz), 7.49-7.57(5H,m), 7.84-7.89(2H,m), 12.68(2H,brs) 49(60) NMR(400MHz,DMSO-d6) δ value: 2.57(2H,t,J=7.6Hz), 2.91(2H,t,J=7.6Hz), 5.35(4H,s), 6.66(1H,dd,J=8.8,2.8Hz), 6.6?(1H,d,J=2.4Hz), 7.18(1H,d,J=8.4Hz), 7.48(1H,d,J=8.4Hz), 7.55-7.61(4H,m), 7.98(2H,d,J=8.4Hz), 8.66-8.70(2H,m), 8.84(1H,s), 11.82(3H,brs) 49 (61) NMR(4 00MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.93- 1.96(2H,m), 2.46-2.56(4H,m), 2.80(2H,t,J=7.6Hz), 2.85(2H,t,J=7.6Hz), 3.81(3H,s), 4.90-4.93(1H,m), 5.13(2H,s), 6.48-6.50(2H,m), 6.99(1H,d,J=8.6Hz), 7.20(1H,d,J=8.6Hz), 7.28-7.33(2H,m), 7.46(1H,d,J=8.8Hz), 7.52-7.56(2H,m), 12.06(1H,s), 12.10(2H,brs) 49 (62) NMR(4 00MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.95- 1.96(2H,m), 2.58(2H,t,J=7.2Hz), 2.92(2H, t, J=7.2Hz), 3.39(3H,s), 4.87-4.95(1H,m), 5.36(2H,s), 6.48- 6.50(2H,m), 7.17(1H,d,J=8.8Hz), 7.46(1H,d,J=8.8Hz), 7.54-7.56(2H,m), 7.63 (2H,d,J=8.0Hz), 7.99(2H,d,J=8.OHz), 12.05(1H,s), 12.17(2H,brs) 49 (63) NMR(400MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.91- 1.99(2H,m), 2.56(2H,t,J=7.6Hz), 2.89(2H,t,J=7.6Hz), 3.42(1H,brs), 4.90-4.93(1H,m), 5.36(2H,s), 6.48- 6.50(2H,m), 7.23(1H,d,J=8.0Hz), 7.46(1H,d,J=8.4Hz), 7.55-7.58(2H,m), 7.62(1H,d,J=8.4Hz), 7.74(1H,dd,J=8.8,1.6Hz), 7.88(1H,s), 12.06(1H,s), 12.30(1H,brs) 49(64) NMR(400MHz,DMSO-d6) δ value: 1. 60-1.74(6H,m), 1.93- 1.99(2H,m), 2.59(2H,t,J=7.6Hz), 2.68(3H,s), 2.93(2H,t,J=7.6Hz), 4.90-4.91(1H,m), 5.36(2H,s), 6.48- 6.50(2H,m), 7.20(1H,d,J=8.4Hz), 7.46(1H,d,J=8.4Hz), 7.56-7.57(2H,m), 7.67(2H,d,J=8.4Hz), 8.04(2H,d,J=8.0Hz), 12.07(1H,s), 12.18(1H,brs) 49(65) NMR(400MHz,CDCl3) δ value: 1.63-1.95(8H,m), 2.71(2H,t,J=7.2Hz), 3.07(2H,t,J=7.2Hz), 3.38(3H,s), 3.39(3H,s), 4.77-4.85(1H,m), 5.21(2H,s), 5.31(2H,s), 5.35(2H,s), 6.38(1H,d,J=8.8Hz), 6.47(1H,d,J=2.0Hz), 6.97(1H,d,J=8.0Hz), 7.17-7.19(2H,m), 7.33(1H,s), 7.49- 7.55(3H,m), 12.67(2H,brs) 49(66) NMR(400MHz,DMSO-d6) δ value: 1.58-1.74(6H,m), 1.94- 1.99(2H,m), 2.59(2H,t,J= 7.6 Hz), 2.94(2H, t, J=7.6Hz) , 3.24(3H,s), 4.90-4.93(1H,m), 5.39(2H,s), 6.48- 6.50(2H,m), 7.20(1H,d,J=9.2Hz), 7.46(1H,d,J=8.4Hz), 7.56-7.58(2H,m), 7.72(2H,d,J=8.4Hz), 7.80(2H,d,8.4), 12.06(1H,s), 12.17(1H,brs) 49(67) NMR(400MHz,DMSO-d6) δ value: 1.59-1.78(6H,m), 1.90- 2.01(2H,m), 2.58(2H,t,J=7.6Hz), 2.92 (2H,t,J=7.2Hz), 4.90-4.93(1H,m), 5.45(2H,s), 6.48-6.50(2H,m), 7.19(1H,d,J=9.2Hz), 7.45(1H,d,J=-8.8Hz), 7.56- 7.57(2H,m), 7.87-7.89(1H,m), 7.92-7.95(2H,m), 11.39(1H,brs), 12.03(1H,brs), 12.15 (1H,brs) 49(68) NMR(400MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.94- 1.96{2H,m), 2.58(2H,t,J=7.4Hz), 2.94(2H,t,J=7.4Hz), 3.59(3H,s), 4.90-4.93(1H,m), 5.42(2H,s), 6.48- 6.53(2H,m), 7.10(1H,d,J=8.4Hz), 7.45(2H,d,J=8.4Hz), 7.55-7.61(3H,m), 7.83(1H,d,J=7.6Hz), 12.04(1H,s) 12.16(1H,brs) 49(69) NMR(400MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.93- 1.96(2H,m), 2.58(2H,t,J=7.2Hz), 2.93(2H,t,J-7.2Hz), 4.12(3H,s), 4.90-4.93(1H,m), 5.43 6.50(2H,m), 7.13-7,27(2H,m), 7.46(1H,d,J=8.4Hz), 7.48(1H,d,J=8.8Hz), 7.55-7.60(2H,m), 7.75(1H,s), 7.79(1H,d,J=8.0Hz), 12.05 (1H,brs) 49(70) NMR(400MHz, DMSO-d6) δ value: 1.53-1.75(6H,m), 1.90- 1.98(2H,m)f 2.47(2H,t,J=7.6Hz), 2.84(2H,t,J=7.6Hz), 4.87-4.91(1H,m), 5.26(2H,s), 6.47-6.50(2H,m), 7.17- 7.23(2H,m), 7.45(1H,d,J=8.8Hz), 7.53-7.55(2H,m), 7.76(1H,d,J=8.4Hz), 8.00(1H,s), 11.32(4H,brs) 49(71) NMR(90MHz,CDCl3) δ value: 1. 04(6H, d, J=6.6Hz), 1.90- 2.32(1H,m), 2.54-2.70(2H,m) , 2.96-3.12(2H,m), 3.80(2H,d,J=6.6Hz), 5.24(2H,s), 6.41-6.49(2H,m), 7.03(1H,d,J=9.0Hz), 7.36-7.88(6H,m), 8 . 61 (1H, d, J=4 . 6Hz) , 8.72(1H,s), 12.63(1H,s) 49(72) NMR(400MHz,DMSO-d6) δ value: 1.58-1.75(6H,m), 1.92- 1.98(2H,m), 2.60(2H,t,J=7.6Hz) , 2.93(2H, t,J=7.6Hz) , 4.89-4.92(1H,m), 5.44(2H,s), 6.48-6.50(2H,m), 7.22(1H,d,J=8.0Hz) , 7.46(1H,d,J=8.8Hz), 7.54-7.56(2H,m), 8.77(1H,s), 9.06(1H,s), 12.04(3H,brs) 49(73) NMR( 90MHz, DMSO-d6) δ value: 1. 4-2 . 1 (8H,m) , 2 . 4-3 . 0 (4H,m) , 4.8-5.0(1H,m), 5.31(2H,s), 6.4-6.6(2H,m), 6.77(1H,d,J=3.4Hz), 7.20(1H,d,J=3.4Hz), 7.3-7.6(4H,m), 12.06(1H,brs), 12.2-13.0(2H,br) 49(74) NMR ( 90MHz, DMSO-d6) δ value: 1. 5-2 . 2 (8H,m) , 2 . 5-3 . 0 (4H,m) , 4.8-5.0(1H,m), 5.62(2H,s), 6.4-6.6(2H,m), 7.2-7.6(4H,m), 8.54(1H,s), 12.06(1H,brs), 12.62(2H,brs) 49(75) NMR(400MHz,DMSO-d6) δ value: 1.59-1.74(6H,m), 1.93- 1.99(2H,m), 2.57(2H,t,J=7.6Hz), 2.89(2H,t,J=7.6Hz), 3.53(1H,brs), 4.89-4.92(1H,m), 5.36(2H,s), 6.47- 6.51(2H,m), 7.25(1H,d,J=8.8Hz), 7.35(1H,dd,J=8.3,1.5Hz), 7.47(1H,d,J=8.5Hz) , 7.52-7.57(2H,m), 7.64(1H, d, J=8.0Hz) , 7.74(1H,s), 8.29(1H,s), 12.08(1H,s) 49(76) NMR(400MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.95- 1.96(2H,m), 2.57(2H,t,J=7.8Hz), 2.90(2H,t,J=7.4Hz), 3.00(3H,s), 3.68(2H,t,J=5.6Hz), 3 . 97(2H,t,J=5.6Hz), 4.88-4.95(1H,m), 5.26(2H,s), 6.48-6.50(2H,m), 7.20(1H,d,J=8.4Hz) , 7.44-7.75(7H,m), 12.06(1H,s), 12.12(1H,brs) 49(77) NMR(4 00MHz,DMSO-d6) 6 value: 1.60-1.76(6H,m), 1.94- 1.96(2H,m), 2.66(2H,t,J=7.6Hz), 2.99(2H,t,J=7.6Hz), 4.90-4.92(1H,m), 5.79(2H,s), 6.49-6.51(2H,m), 7.29 (1H,d,J=8.4Hz) , 7.46(1H,d,J=8.4Hz), 7.56-7.60(2H,m), 8.02 (1H,dd,J=8.6,1.6Hz), 8.29(1H,d,J=8.0Hz), 8.53(1H,d,J=1.6Hz), 12.03(3H,brs) 49(78) NMR(400MHz,CDCl3) δ value: 1.59-1.67(2H,m), 1.75- 1.97(6H,m), 2.72(2H,t,J=7.6Hz), 3.03(2H,t,J=7.6Hz), 4.78-4.83(1H,m), 5.06(2H,s), 5.98(2H,s), 6.38(1H,dd,J=9.0, 2.4Hz), 6.4 7(1H,d,J=2.4Hz), 6.82(1H,d, J=8.0Hz) , 6.87-6.90(2H,m), 6.96(1H,d,J=9.2Hz), 7.50(1H,d,J=9.2Hz), 7.52-7.56(2H,m), 12.69(2H,brs) 49(79) NMR(4 00MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.93- 1.98(2H,m), 2.55(2H,t,J=7.6Hz), 2.87(2H,t,J=7.2Hz), 4.08(2H,t,J=8.2Hz), 4.45(2H,t,J=8.0Hz), 4.90-4.93(1H,m), 5.23(2H,s), 6.48-6.50(2H,m), 7.20(1H,d,J=8.4Hz), 7.52(1H,d,J=8.8Hz), 7.54-7.56(4H,m), 7.62(2H,d,J=8.8Hz) , 12.05(1H,s), 12.14(1H,brs) 49(80) NMR(400MHz, DMSO-d6) δ value: 1.60-1.77(6H,m), 1.94- 1.97(2H,m), 2.51(2H,t,J=7.6Hz), 2.86(2H, t, J=7.6Hz) , 4.90-4.92(1H,m), 5.59(2H,s), 6.49-6.51(2H,m), 7.40(1H,d,J=8.4Hz), 7.49(1H, d, J=8.4Hz) , 7.55(1H,s), 7.60(1H,dd,J=8.4,1.6Hz), 7.97(1H,d,J=8.8Hz), 8.02(1H,s), 8.16(1H,d,J=8.8Hz), 8.56(1H,s), 12.07(1H,s), 12.54 (2H,brs) 49(81) NMR(4 00MHz,DMSO-d6) 6 value: 0 . 98(6H,d,J=6.8Hz), 1.98- 2.09(1H,m), 2.59(2H,t, J=7.6Hz) , 2 . 90(2H,t,J=7.6Hz), 3.83(2H,d,J=6.4Hz), 5.62(2H,s), 6.52-6.54(2H,m), 7.29(1H,d,J=8.8Hz), 7.46(1H,d,J=9.5Hz), 7.50-7.60(2H,m), 7.71(1H,s), 7.90(1H,dd,J=8.5,1.7Hz), 8 . 10(1H, d,J=8.6Hz), 8.47(1H,s), 11.99(1H,s), 12.58(2H,brs) 49(82) NMR(400MHz,DMSO-d6) δ value: 1. 30(6H,d,J=6.1Hz) , 2.59(2H,t,J=7.5Hz), 2.90(2H,t,J=7.5Hz), 4.69-4.76(1H,m), 5.62(2H,s), 6.48-6.52(2H,m), 7.29(1H,d,J=8.8Hz), 7.45(1H,d,J=8.8Hz), 7.55-7.58(2H,m), 7.71(1H,s), 7.90(1H,dd,J=8.4,1.7Hz) , 8.0 9(1H,d,J=8.5Hz), 8.47(1H,d,J=1.0Hz), 12.02(1H,s), 12.58(2H,brs) 49(83) NMR (400MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.93- 1.96(2H,m), 2.59 (2H,t,J=7.6Hz) , 2.91(2H,t,J=7.6Hz), 4.88-4.94(1H,m), 5.62(2H,s), 6.47-6.50(2H,m), 7.29(1H,d,J=8.8Hz), 7.46(1H,d,J=8.8Hz), 7.56-7.58(2H,m), 7.72(1H,s), 7.90(1H,dd,J=8.8,1.6Hz), 8.10(1H,d,J=8.4Hz), 8.47(1H,d,J=1.2Hz), 12.04(1H,s), 12.56(2H,brs) 49(84) NMR(90MHz,DMSO-d6) δ value: 0.99(6H,d,J=6.6Hz), 1.8- 3.0(5H,m), 3.84(2H,d,J=6.6Hz), 5.50(2H,s), 6.4- 6.5(2H,m), 7.2-7.8(6H,m), 12.00(1H,s), 11.7-13.2 (2H,br) 49(85) NMR(90MHz,DMSO-d6) δ value: 0.98(6H,d,J=6.7Hz), 1.90- 2.18(1H,m), 2.48-2.61(2H,m), 2.83-2.90(2H,m), 3.84(2H,d,J=6.7Hz), 5.41(2H,s), 6.49-6.55(2H,m), 7.16- 7.54(4H,m), 8.08(2H,s), 8.83(1H,s), 11.98(3H,brs) 49(86) NMR(400MHz,DMSO-d6) δ value: 1.59-1.74(6H,m), 1.93- 1.96(2H,m), 2.58(2H,t,J=7.4Hz), 2.91(2H,t,J=7.4Hz), 4.89-4.91 (1H,m) , 5.38(2H,s), 6 . 47-6 . 50.(2H,m) , 7.23(1H,d,J=9.2Hz), 7.46(1H,d,J=8.8Hz), 7.55-7.61(3H,m), 8.07(2H,d,J=8.8Hz), 8.11(1H,s), 12.05(3H,brs) 49(87) NMR (400MHz,DMSO-d6) δ value: 1. 60-1.74(6H,m) , 1.94- 1.99(2H,m), 2.58(2H,t,J=7.6Hz) , 2.93(2H,t,J=7.6Hz) , 4.90-4.91(1H,m), 5.36(2H,s), 6.48-6.50(2H,m), 7.18(1H,d,J=9.2Hz), 7.46(1H,d,J=8.4Hz), 7.55-7.56(2H,m), 7.69(2H,d,J=8.0Hz) , 7.87(2H,d,J=8.4Hz) , 12.06(1H,s), 12.17(1H,brs), 12.99(1H,brs) 49(88) NMR(90MHz,CDCl3) δ value: 0 . 2-3 .1 (15H,m) , 3 . 1-4 . 5 (4H,m) , 4.7-5.3(1H,m), 6.0-8.0(6H,m), 8.83(1H,s), 12.2- 12.4(1H,br), 12.63(1H,s) 49(89) NMR(90MHz,DMSO-d6) δ value: 0.99 ( 6H,d,J=6.4Hz), 1.90- 2.19(1H,m), 3.13-3.20(4H,m), 3.84(2H,d,J=6.4Hz), 5.36(2H,s), 6.47-6.55(2H,m), 7.15-7.66(6H,m), 8.0 0(2H,d,J=7.9Hz), 11.95(3H,brs) 49(90) NMR(90MHz,DMSO-d6) δ value: 0.99(6H,d,J=6.8Hz), 1.92- 2.20(1H,m), 2.50-2.66(2H,m), 2 . 85-3.03(2H,m), 3.84 (2H,d,J=6.8Hz), 5.38(2H,s), 6.50-6.57(2H,m), 7.22(1H,d,J=8.2Hz), 7.42-7.77(5H,m), 8.10(2H,d,J=8.0Hz), 12.01(1H,s), 12.14(2H,brs) 49(91) NMR(90MHz,DMSO-d6) 8 value: 1.02 ( 6H,d,J=6.6Hz) , 1.6- 3.4(llH,m), 3.85(2H,d,J=5.6Hz), 4.2-5.4(4H,br), 6.4- 6.5(2H,m), 7.04(1H,d,J=9.0Hz), 7.4-7.5(3H,m) 49(92) NMR(90MHz,CDC13) 5 value: 1.06(6H,d,J=6.8Hz), 1.9- 2.4(1H,m), 2.6-3.1(6H,m), 3.82(2H,d,J=6.4Hz), 4.15(2H,t,J=7.0Hz), 4.5-5.9(4H,br), 6.3-6.5(2H,m), 6.63(2H,d,J=8.3Hz), 6.8 8(1H,d,J=9.3Hz), 7.05(2H,d,J=8.5Hz), 7.4-7.6(3H,m) 49(93) NMR(90MHz,CDCl3) 5 value: 1.07(6H,d,J=6.6Hz), 1.4- 2.3(9H,m), 2.6-3.1(4H,m), 3.82(2H,d,J=6.1Hz), 4.7- 4.9(1H,m), 6.3-6.5(2H,m), 6.89(1H,d, J=9.3Hz) , 7.4- 7.6(3H,m), 8.3-9.6(1H,br), 12.69(1H,brs) 49(94) NMR(90MHz,DMSO-dg) δ value: 1.03(6H,d,J=6.6Hz), 1.8- 5.0(10H,m), 5.30(2H,s), 6.5-6.8(2H,m), 6.9-7.3(1H,m), 7.4-7.8(3H,m), 8.01(2H,s), 8.71(1H,s) 49(95) NMR(90MHz,CDCl3) 5 value: 1.07(6H,d,J=6.6Hz), 1.9- 3.1(5H,m), 2.73(3H,s), 3.82(2H,d,J=6.1Hz), 5.0- 6.2(1H,br), 5.20(2H,s), 6.4-6.8(2H,m), 6.89(1H,d,J=9.3Hz), 7.17(1H,s), 7.5-7.7(3H,m), 12.64(1H,s) 49 (96) NMR(90MHz,CDCl3) 5 value: 1. 07 ( 6H,d,J=6.6Hz), 1.90- 2.43(1H,m), 2.61-3.10(4H,m), 3.82(2H,d,J=6.4Hz), 5.10(2H,s), 6.43(1H,dd,J=8.8,2.4Hz) , 6.56(1H,d,J=2.4Hz), 6.89(1H,d,J=9.0Hz), 7.34-7.76(5H,m), 8.57-8.68(2H,m), 9.0-10.0(1H,br), 12.32 (2H,brs) 49 (97) NMR(90MHz,CDC13) δ value: 1.08(6H,d,J=6.8Hz), 2.03- 2.32(1H,m), 2.51-2.69(2H,m), 2.91-3.06(2H,m), 3.85(2H,d,J=6.1Hz), 5.22(2H,s), 5.63(2H,brs), 6.48- 6.58(2H,m), 6.93(1H,d,J=9.0Hz), 7.47-7.65(5H,m), 8.07(2H,d,J=8.1Hz), 12.61(1H,s) 49(98) NMR(90MHz,DMSO-d5) δ value: 1.03(6H,d,J=6.6Hz), 1.9- 3.0(5H,m), 3.88(2H,d,J=6.1Hz), 5.27(2H,s), 6.5- 6.7(2H,m), 7.07(1H,d,J=9.3Hz), 7.3-8.0(6H,m), 8.60(1H,d,J=4.9Hz), 11.4-12.4(2H,br) Example 50 0.13 g of hydroxylamine hydrochloride was dissolved in 3 mL of methanol, to which 0.36 g of a 28% solution of sodium methoxide in methanol was added at room temperature, and then this mixture was stirred for 30 minutes. The mixture thus obtained was added to 0.31 g of methyl 3-{2-[(4-cyanobenzyl)oxy]-5-[4- (cyclopentyloxy)-2-hydroxybenzoyl]phenyl}propanoate which was dissolved in a mixed solution of 5 mL of methanol and 5 mL of tetrahydrofuran, and then stirred for 14 hours at room temperature and subsequently for another one hour at 50°C. The reaction mixture was cooled to room temperature, to which water and ethyl acetate were successively added, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, this washed phase was dried over anhydrous sodium sulfate and the solvent was distilled out under reduced pressure. 0.42 g of the resultant residue was dissolved in 2 mL of N,N- dimethylformamide, to which 55 mg of pyridine and 0.12 g of 2-ethylhexyl chloroformate were added at room temperature, then this mixture was stirred for 5 minutes at the same temperature. The reaction mixture was added to a mixed solution of water and ethyl acetate, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, this washed phase was dried over anhydrous sodium sulfate and the solvent was distilled out under reduced pressure. The resultant residue to which 4 mL of xylene was added was stirred for one hour while heating it under reflux. The reaction mixture was cooled to room temperature, and purified by silica gel column chromatography [eluent; hexanerethyl acetate=1:1] to yield 0.19 g of methyl 3-(5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-{[4-(5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl)benzyl]oxy}phenyl)propanoate as yellow solid. NMR(400MHz,CDCl3) δ value: 1. 61-1. 98 ( 8H, m) , 2.70(2H,t,J=7.6Hz), 3.09(2H,t,J=7.6Hz), 3.68(3H,s), 4.81-4.84(1H,m), 5.27(2H,s), 6.37(1H,dd,J=8.8,2.4Hz) , 6.48(1H,d,J=2.4Hz), 6 . 94(1H, d,J=8.0Hz), 7.49-7.56(3H,m), 7.62(2H,d,J=8.8Hz), 7.84(2H,d,J=8.4Hz), 11.01(1H,brs), 12.68(1H,s) Example 51 1.85 g of 4-({2-(2-carboxyethyl)-4-[4- (cyclopentyloxy)-2-hydroxybenzoyl]phenoxy}methyl) benzoic acid was dissolved in a mixed solvent of 19 mL of methylene chloride and 0.1 mL of N,N- dimethylformamide, to which 1.6 mL of oxalyl chloride was added dropwise over 10 minutes at room temperature, and then this mixture was stirred for one hour at room temperature. After 19 mL of ethanol was added dropwise to the reaction mixture over 10 minutes and this mixture was stirred for one hour at room temperature and for another 30 minutes at 50°C, the reaction mixture was cooled to room temperature to which water was added, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, this washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=4:l] to yield 2.00 g of ethyl 4-{[4-[4- (cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-ethoxy-3- oxopropyl)phenoxy]methyl} benzoate as yellow oil. NMR(400MHz,CDCl3) δ value: 1. 22 (3H, t, J=7 .2Hz) , 1.41(3H,t,J=7.2Hz), 1.62-1.67(2H,m), 1.78-1.98(6H,m), 2.67(2H,t,J=7.6Hz), 3.07(2H,t,J=7.6Hz), 4.12(2H,q,J=7.2Hz), 4.40(2H,q,J=7.2Hz), 4.80-4.83(1H,m), 5.25(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.48(1H,d,J=2.4Hz), 6.93(1H,d,J=8.4Hz), 7.49-7.56(5H,m), 8.09(2H,d,J=8.0Hz), 12.69(1H,s) Example 52 The following compounds were obtained in a similar manner as in Example 51. (1) ethyl 4-{[2-(3-ethoxy-3-oxopropyl)-4-(2- hydroxy-4-isobutoxybenzoyl)phenoxy]methyl} benzoate NMR(90MHz,CDCl3) δ value: 1. 03 ( 6H, d, J=6 . 6Hz) , 1.22(3H,t,J=7.4Hz), 1.40(3H,t,J=7.4Hz), 1. 98-2.25(1H,m), 2.58-2.74(2H,m), 3.00-3.16(2H,m), 3.78(2H,d,J=6.7Hz), 4.12(2H,q,J=7.4Hz) , 4.39(2H,q,J=7.4Hz) , 5.24(2H,s), 6.34-6.48(2H,m), 6.93(1H,d,J=8.8Hz), 7.47-7.57(5H,m), 8.09(2H,d,J=8.lHz), 12.65(1H,s) (2) ethyl 4-{[4-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-(3-ethoxy-3- oxopropyl)phenoxy]methyl}-2-methoxybenzoate NMR(400MHz,CDCl3) δ value: 1. 22 (3H, t, J=7 . 2Hz) , 1.39(3H,t,J=7.2Hz), 1.61-1.66(2H,m), 1.78-1.96(6H,m), 2.68(2H,t,J=7.8Hz), 3.08(2H,t,J=7.8Hz) , 3.93(3H,s), 4.11(2H,q,J=7.2Hz), 4.37(2H,q,J=7.2Hz), 4.80-4.82(1H,m), 5.21(2H,s), 6.37(1H,dd,J=9.2,2.4Hz), 6.48(1H,d, J=2.8Hz), 6.92(1H,d,J=8.4Hz), 7.03(1H,dd,J=8.0,1.2Hz), 7.09(1H,s), 7.49-7.56(3H,m), 7.83(1H,d,J=7.6Hz), 12.69(1H,s) Example 53 1.90 g of ethyl 4-{[4-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-(3-ethoxy-3-oxopropyl)phenoxy]methyl} benzoate was dissolved in 25 mL of ethanol, to which 0.14 g of lithium hydroxide monohydrate dissolved in 5 mL of water was added dropwise over 5 minutes at room temperature, and then this mixture was stirred for 1.5 hour at the same temperature. Another 0.14 g of lithium hydroxide monohydrate dissolved in 5 mL of water was added dropwise over 5 minutes, then this mixture was stirred for 20 hours. The reaction mixture to which water and chloroform were successively added was adjusted to pH 2 with 6M hydrochloric acid, then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, this washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=l:l] to yield 0.70 g of 3-(5-[4- (cyclopentyloxy)-2-hydroxybenzoyl]-2-{[4- (ethoxycarbonyl)benzyl]oxy}phenyl) propanoic acid as light yellow solid. NMR(400MHz,CDCl3) δ value: 1.40(3H,t,J=7.2Hz), 1.55- 1.66(2H,m), 1.74-1.98(6H,m), 2.75(2H,t,J=7.6Hz), 3.07 (2H,t,J=7.6Hz), 4.39(2H,q,J=7.2Hz), 4.78-4.81(1H,m), 5.23(2H,s), 6.38(1H,dd,J=9.0,2.8Hz), 6.47(1H,d,J=2.8Hz), 6.93(1H,d,J=8.4Hz), 7.48-7.57(5H,m), 8.08(2H,d,J=8.4Hz), 12.68 (2H,brs) Example 54 The following compounds were obtained in a similar manner as in Example 53. (1) 3-(5-(2-hydroxy-4-isobutoxybenzoyl)-2- {[4-(methoxycarbonyl)benzyl]oxy}phenyl) propanoic acid NMR( 90MHz,CDC13) δ value: 1.02(6H,d,J=6.7Hz), 1.98- 2.24(1H,m), 2.72-2.83(2H,m), 3.00-3.18(2H,m), 3.77(2H,d,J=6.3Hz), 3.93(3H,s), 5.24(2H,s), 6.38- 6.48(2H,m), 6.93(1H,d,J=9.3Hz), 7.46-7.58(5H,m), 8.0 9(2H,d,J=8.3Hz), 12.64(2H,brs) (2) 3-(5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-{[4-(ethoxycarbonyl)-3- methoxybenzyl]oxy}phenyl) propanoic acid NMR(400MHz,CDCl3) δ value: 1.38(3H,t,J=6.8Hz), 1.61- 1.66(2H,m), 1.77-1.95(6H,m), 2.75(2H,t, J=7.6Hz), 3.08 (2H,t,J=7.6Hz) , 3.92(3H,s), 4.36 (2H,q,J=6.8Hz), 4.79-4.82(1H,m), 5.20(2H,s), 6.38(1H,dd,J=8.8,2.4Hz), 6.4 7(1H,d,J=2.4Hz), 6.93(1H,d,J=8.4Hz), 7.02(1H,d,J=8.0Hz), 7.08(1H,s), 7.48-7.57(3H,m), 7.8 3(1H,d,J=7.6Hz), 12.67(2H,brs) (3) 3-[2-{[4-(ethoxycarbonyl)benzyl]oxy}-5- (2-hydroxy-4-isobutoxybenzoyl)phenyl] propanoic acid NMR( 90MHz, CDCl3) δ value: 1.02(6H,d,J=6.8Hz), 1.40(3H,t,J=7.1Hz), 1.96-2.26(1H,m), 2 . 71-2.82(2H,m), 3.00-3.08(2H,m), 3.77(2H,d,J=6.4Hz), 4.39(2H,q,J=7.1Hz), 5.24(2H,s), 6.38-6.48(2H,m), 6 . 93(1H,d,J=9.3Hz), 7.44- 7.58(5H,m), 8.09(2H,d,J=3.4Hz), 12.64(2H,brs) Example 55 1.00 g of methyl 3-{5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-hydroxyphenyl} propanoate, 0.56 g of methyl 4-(hydroxymethyl)-2-methylbenzoate, and 0.82 g of triphenylphosphine were dissolved in 10 mL of tetrahydrofuran, to which a solution of 0.6 mL of diisopropyl azodicarboxylate in 1 mL of tetrahydrofuran was added dropwise at room temperature, and then this mixture was stirred for one hour at the same temperature. The reaction mixture was added to a mixture of ethyl acetate and water, then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, this washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=4:l] to yield 1.12 g of methyl 4-{ [4-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-(3-methoxy-3-oxopropyl)- phenoxy]methyl}-2-methylbenzoate as yellow oil. NMR(400MHz,CDCl3) δ value: 1. 61-1. 67 (2H,m) , 1.76- 1.98(6H,m), 2.64(3H,s), 2.69(2H,t,J=7.6Hz), 3.07(2H,t,J=7.6Hz), 3.67(3H,s), 3.91(3H,s), 4.80- 4.83(1H,m), 5.19(2H,s), 6.37(1H,dd,J=9.2,2.4Hz), 6.48(1H,d,J=2.4Hz), 6.92(1H,d,J=8.4Hz), 7.30-7.32(2H,m), 7.50-7.55(3H,m), 7.96(1H,d,J=8.8Hz), 12.70(1H,s) Example 5 6 0.95 g of tert-butyl 4-{[4-[4- (cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-methoxy-3- oxopropyl)phenoxy]methyl}-IH-pyrazole-1-carboxylate was dissolved in 4.8 rtiL of chloroform, to which 10 mL of 4M hydrogen chloride/ethanol was added dropwise at room temperature, and then this mixture was stirred for one hour at the same temperature. The reaction mixture was added to water, then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, this washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexanerethyl acetate=l:l] to yield 0.67 g of ethyl 3-[5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-(1H-pyrazol-4-ylmethoxy)phenyl] propanoate as light yellow oil. NMR(400MHz,CDC13) δ value: 1.22(3H,t,J=7.2Hz), 1.62- 1.66(2H,m), 1.78-1.96(6H,m), 2.61(2H,t,J=7.6Hz), 2.99(2H,t,J=7.6Hz), 4.11(2H,q,J=7.2Hz), 4.81-4.83(1H,m), 5.13(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.48(1H,d,J=2.4Hz) , 7.00(1H,d,J=8.3Hz), 7.52-7.57(3H,m), 7.71(2H,s), 12.71 (2H,brs) Example 57 The following compounds were obtained in a similar manner as in Example 56. (1) methyl 3-{2-{[4- (aminosulfonyl)benzyl]oxy}-5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]phenyl] propanoate NMR(400MHz,CDCl3) 6 value: 1.62-1.68(2H,m), 1.77- 1.98(6H,m), 2.68(2H,t,J=7.2Hz), 3.07(2H,t,J=8.0Hz), 3.68(3H,s), 4.81(3H,brs), 5.26(2H,s), 6.37(1H,dd,J=9.2,2.4Hz), 6.4 8(1H,d,J=2.4Hz), 6.92(1H,d,J=8.4Hz), 7.49-7.55(3H,m), 7.61(2H,d,J=8.4Hz), 7.99(2H,d,J=8.4Hz), 12.67(1H,s) (2) methyl 3-[5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-({4- [(methylsulfonyl)amino]benzyl}oxy)phenyl] propanoate NMR(4 00MHz,CDC13) δ value: 1.55-1.65(2H,m), 1.78- 2.05(6H,m), 2.67(2H,t,J=7.2Hz), 3.05(3H,s), 3.02(2H,t,J=7.2Hz), 3.67(3H,s), 4.80-4.83(1H,m), 5.30(2H,s), 6.37(1H,dd,J=9.2,2.4Hz), 6.48(1H,d,J=2.4Hz), 6.53(1H,s), 6.96(1H,d,J=9.2Hz), 7.26(2H,d,J=8.4Hz), 7.43(2H,d,J=8.4Hz), 7.50-7.55(3H,m), 12.69 (1H,s) (3) ethyl 3-{2-(1H-benzimidazol-5- ylmethoxy)-5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]phenyl} propanoate was obtained. NMR(4 00MHz,DMSO-d6) δ value: 1.10(3H,t,J=7.2Hz), 1.60- 1.71(6H,m), 1.93-1.98(2H,m), 2.63(2H,t,J=7.6Hz), 2.93(2H,t,J=7.6Hz), 4.01(2H,q,J=7.2Hz), 4.89-4.92(1H,m), 5.45(2H,s), 6.47(1H,dd,J=8.8,2.4Hz), 6.51(1H, d, J=2.4Hz) , 7.24(1H,d,J=8.4Hz), 7.43(1H,d,J=8.8Hz), 7.54-7.58(2H,m), 7.69(1H,d,J=7.6Hz), 7.90(1H,d,J=8.4Hz), 7.96(1H,s), 8.33(1H,s), 9.49(1H,s), 11.98(1H,s) (4) methyl 3-{5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-[(2,4-dioxo-l,2,3,4-tetrahydro-6- quinazolinyl)methoxy]phenyl} propanoate was obtained. NMR(400MHz, CDC13) δ value: 1.61-1.67(2H,m), 1.77- 1.98(6H,m), 2.67(2H,t,J=7.2Hz), 3.05(2H,t,J=7.6Hz), 3.66(3H,s), 4.80-4.83(1H,m), 5.21(2H,s), 6.37(1H,dd,J=9.0,2.4Hz), 6.4 8(1H,d,J=2.4Hz), 6.96(1H,d,J=9.2Hz) , 7.13(1H,d,J=8.4Hz), 7.50(1H,d,J=9.2Hz) , 7.53-7.55(2H,m), 7.76(1H,d,J=6.4Hz) , 8.18(1H,s), 8.27(1H,brs), 8.52(1H,brs), 12.69(1H,s) (5) methyl 3-[5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-({4- [(methylamino)sulfonyl]benzyl}oxy)phenyl} propanoate NMR(400MHz,CDCl3) δ value: 1. 63-1'. 68 (2H,m) , 1.76- 1.98(6H,m), 2.68-2.71(5H,m), 2.88(2H,brs) , 3.08(2H,t,J=7.6Hz), 3.68(3H,s), 4.80-4.84(1H,m), 5.26(2H,s), 6.38(1H,dd,J=9.0,2.4Hz), 6.49(1H,d,J=2.4Hz), 6.93 (1H,d,J=8.4Hz), 7.49-7.55(3H,m), 7.61(2H,d,J=8.4Hz), 7.92(2H,d,J=8.8Hz) (6) methyl 3-[5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-({ 4- [(methylamino)carbonyl]benzyl}oxy)phenyl] propanoate NMR(400MHz,CDCl3) δ value: 1.62-1.66(2H,m), 1.78- 1.96(6H,m), 2.68(2H,t,J=7.6Hz), 3.05-3.08(5H,m), 3.38(1H,brs), 3.67(3H,s), 4.80-4.84(1H,m), 5.23(2H,s), 6.33 (1H,brs), 6.37(1H,dd,J=9.0,2.4Hz), 6.48(1H,d,J=2.4Hz), 6.93(1H,d,J=8.4Hz), 7.49-7.54(5H,m), 7.79(2H,d,J=8.0Hz) (7) methyl 3-{5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-[(l,3-dioxo-2,3-dihydro-lH-isoindol- 5-yl)methoxy]phenyl} propanoate NMR(400MHz,CDCl3) δ value: 1. 62-1. 67 (2H,m) , 1.77- 2.00(6H,m), 2.70(2H,t,J=7.6Hz), 3.09(2H,t,J=7.6Hz), 3.68(3H,s), 4.81-4.84(1H,m), 5.33(2H,s), 6.38(1H,dd,J=9.0,2.4Hz), 6.4 8(1H,d,J=2.4Hz), 6.93(1H,d,J=8.4Hz), 7.49-7.56(3H,m), 7.72(2H,brs), 7.86(1H,d,J=7.6Hz), 7.92-7.95(2H,m) Example 58 0.50 g of methyl 3-[5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-(1H-pyrazol-4-ylmethoxy)phenyl] propanoate was dissolved in 5 mL of 1,4-dioxane, to which 5 mL of 6M hydrochloric acid was added at room temperature, and then this mixture was stirred for 7 hours at the same temperature. The reaction mixture was added to a mixture of ethyl acetate and water, then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, this washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; chloroform:ethanol=20:1] to yield 0.33 g of 3-[5-[4- (cyclopentyloxy)-2-hydroxybenzoyl]-2-(1H-pyrazol-4- ylmethoxy)phenyl] propanoic acid as yellow oil. NMR(400MHz,CDCl3) δ value: 1.60-1.67(2H,m), 1.76- 1.98(6H,m), 2.66(2H,t,J=7.6Hz), 3.02(2H,t,J=7.6Hz), 4.80-4.83(1H,m) , 5.11(2H,s), 5.7 5(2H,brs),6.38(1H,dd,J=8.8,2.4Hz), 6.4 8(1H,d,J=2.4Hz), 7.01(1H,d,J=8.0Hz), 7.52(1H,d,J=8.8Hz), 7.55-7.58(2H,m), 7.71(2H,s) Example 5 9 1.00 g of 4-{[4-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-(3-ethoxy-3-oxopropyl)phenoxy]methyl} benzoic acid was dissolved in 12 mL of tetrahydrofuran, to which 1.03 g of 1,1'-carbonyldiimidazole was added at room temperature, and then this mixture was stirred for one hour while heating it under reflux. After the reaction mixture was cooled to room temperature, 1.07 g of methanesulfonamide and 1.7 mL of 1,8- diazabicyclo[5.4.0]undec-7-ene were added to this mixture, which was stirred for 30 minutes at room temperature and for another 30 minutes at 50°C. The reaction mixture which was cooled to room temperature was added to a mixture of methylene chloride and water, and adjusted to pH 2 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, this washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=l:2] to yield 0.65 g of ethyl 3-{5-[4- (cyclopentyloxy)-2-hydroxybenzoyl]-2-[(4- {[(methylsulfonyl)amino]carbonyl}benzyl)oxy]phenyl} propanoate as light yellow solid. NMR(400MHz,CDCl3) δ value: 1.23 (3H,t,J=7.2Hz), 1.63- 1.68(2H,m), 1.76-1.96(6H,m), 2.67(2H,t,J=7.6Hz), 3.07(2H,t,J=7.6Hz) , 3.46(3H,s), 4.13(2H,q, J=7.2Hz) , 4.81-4.83(1H,m), 5.26(2H,s), 6.37(1H, dd, J=9.2, 2.4Hz) , 6.48(1H,d,J=2.4Hz), 6.92(1H,d,J=8.0Hz), 7.48-7.61(5H,m), 7.89(2H,d,J=8.4Hz) , 8.57(1H,brs), 12.67(1H,s) Example 60 The following compounds were obtained in a similar manner as in Example 59. (1) methyl 3-{5-(2-hydroxy-4- isobutoxybenzoyl)-2-[(4-{[(methylsulfonyl)- amino]carbonyl}benzyl)oxy]phenyl} propanoate NMR(90MHz, CDC13) δ value: 1.03(6H,d,J=6.6Hz), 1.96- 2.26(1H,m), 2.60-2.75(2H,m), 2.98-3.15(2H,m), 3.45(3H,s), 3.67(3H,s), 3.79(2H,d,J=6.3Hz), 5.25(2H,s), 6.38-6.51(2H,m), 6.92(1H,d,J=9.4Hz), 7.46-7.62(5H,m), 7.92 (2H,d,J=8.6Hz), 9.00(1H,brs), 12.63(1H,s) (2) ethyl 3-[2-({4-[(hydroxyamino)- carbonyl]benzyl}oxy)-5-(2-hydroxy-4- isobutoxybenzoyl)phenyl]propanoate NMR(90MHz,DMSO-d6) δ value: 0.95-1.20(9H,m), 1.92- 2.16(1H,m), 2.47-2.63(2H,m), 2.82-2.94(2H,m), 3.80- 4.06(4H,m), 5.32(2H,s), 6.52-6.56(2H,m), 7.23- 7.85(8H,m), 9.05(1H,s), 11.24(1H,s), 11.93(1H,s) (3) methyl 3-[2-{[4- (aminocarbonyl)benzyl]oxy}-5-(2-hydroxy-4- isobutoxybenzoyl)phenyl]propanoate NMR(90MHz,DMSO-d6) δ value: 0.99(6H,d,J=6.6Hz) , 1.85- 2.23(1H,m), 2.46-2.95(4H,m), 3.58(3H,s), 3.83(2H,d,J=6.4Hz), 5.32(2H,s), 6.53-6.56(2H,m), 7.13- 7.60(8H,m), 7.92(2H,d,J=7.8Hz), 11.96 (1H,brs) Example 61 1.85 g of methyl 3-[5-(4-bromo-2- hydroxybenzoyl)-2-hydroxyphenyl] propanoate was dissolved in 20 mL of methylene chloride, to which 1.5 mL of triethylamine and 1.0 mL of acetic anhydride were successively added at 5 to 10°C, and then this mixture was stirred for 2 hours at room temperature. Then, water and a saturated aqueous solution of sodium hydrogen carbonate were added to this mixture, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and 1M hydrochloric acid successively, this washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 2.46 g of methyl 3-{2-(acetyloxy)-5-[2-(acetyloxy)-4- bromobenzoyl]phenyl} propanoate as brown oil. NMR(400MHz,CDCl3) δ value: 1.96(3H,s), 2.37(3H,s), 2.59(2 H,t,J=7.8Hz), 2.90(2H,t,J=7.8Hz), 3.67(3H,s), 7.14(1H,d,J=8.0Hz), 7.39-7.51(3H,m), 7.62-7.66(2H,m) Example 62 4-{[4-[2-(acetyloxy)-4-isobutoxybenzoyl]-2- (3-methoxy-3-oxopropyl)phenoxy]methyl} benzoic acid was obtained in a similar manner as in Example 61. NMR(90MHz,CDC13) δ value: 1.04(6H,d,J=6.7Hz), 1.86- 2.25(4H,m), 2.65-2.75(2H,m), 2.99-3.14(2H,m), 3.67(3H,s), 3.78(2H,d,J=6.4Hz), 5.25(2H,s), 6.67- 6.94(3H,m), 7.42-7.65(5H,m), 8.15(2H,d,J=7.8Hz), 12.65 (1H,brs) Example 63 1.20 g of methyl 3-{2-(acetyloxy)-5-[2- (acetyloxy)-4-bromobenzoyl]phenyl}propanoate was dissolved in 12 mL of toluene, to which 0.33 g of 2- thienylboronic acid, 0.69 g of potassium carbonate, and 0.10 g of bis(triphenylphosphine)palladium (II)dichloride were added at room temperature in a stream of nitrogen, and then this mixture was stirred for 3.5 hours while heating it under reflux. The reaction mixture was cooled to room temperature, followed by the addition thereto of ethyl acetate and water, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, this washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=3:l] to yield 0.64 g of methyl 3- {2-(acetyloxy)-5-[2-(acetyloxy)-4-(2- thienyl)benzoyl]phenyl} propanoate as light yellow oil. NMR (4 00MHz, CDC13) δ value: 2.00(3H,s), 2.37(3H,s), 2.60(2H,t,J=8.0Hz), 2.91(2H,t,J=8.0Hz), 3.67(3H,s), 7.1-7.2(2H,m), 7.3-7.5(3H,m), 7.57(2H,s), 7.6-7.7(2H,m) Example 64 0.72 g of methyl 3-{2-(acetyloxy)-5-[2- (acetyloxy)-4-(2-thienyl)benzoyl]phenyl}propanoate was suspended in 8 mL of methanol, to which 0.66 g of a 28% solution of sodium methoxide in methanol was added dropwise at 5 to 7°C, and then this suspension was stirred for 30 minutes in an ice bath. The reaction mixture was added to a mixture of ethyl acetate and ice water, and adjusted to pH 3 with 1M hydrochloric acid, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, this washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant solid was recrystallized from a mixed solvent of diisopropyl ether-hexane to yield 0.50 g of methyl 3-{2-hydroxy-5-[2-hydroxy-4-(2- thienyl)benzoyl]phenyl} propanoate as light yellow crystals. NMR(400MHz,CDCl3) δ value: 2 . 79 (2H, t, J=6 . 2Hz) , 2.98(2H,t,J=6.2Hz) , 3.74(3H,s), 6.99(1H,d,J=8.8Hz), 7.1-7.2(2H,m), 7.31(1H,d,J=l.6Hz), 7.39(1H,dd,J=5.0,J=1.2Hz), 7.4 6(1H,dd,J=3.6,1.2Hz), 7.46-7.62(2H,m), 7.63(1H,d, J=8.4Hz) , 7.99(1H,s), 12.16(1H,s) Example 65 1.00 g of methyl 4-{[4-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-(3-methoxy-3- oxopropyl)phenoxy]methyl)benzoate was dissolved in 10 mL of N,N-dimethylformamide, to which 0.52 g of potassium carbonate and 0.23 mL of iodomethane were added at 5 to 10°C, and then this mixture was stirred for 4 hours at room temperature. The reaction mixture was added to a mixture of ethyl acetate and ice water, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, this washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant solid was recrystallized from a mixed solvent of diisopropyl ether-hexane to yield 0.98 g of methyl 4-{ [4-[4-(cyclopentyloxy)-2- methoxybenzoyl]-2-(3-methoxy-3- oxopropyl)phenoxy]methyl} benzoate as light yellow crystals. NMR(400MHz,CDCl3) δ value: 1. 6-1. 7 (2H, m) , 1. 7-2 . 0 ( 6H,m) , 2.64(2H,t,J=7.8Hz), 3.03(2H,t,J=7.8Hz), 3.65(3H,s), 3.70(3H,s), 3.93(3H,s), 4.7-4.9(1H,m), 5.22(2H,s), 6.4- 6.6(2H,m), 6.86(1H,d, J=8.4Hz) , 7.30(1H,d,J=8.0Hz), 7.50(2H,d,J=8.4Hz) , 7.64-7.68(2H,m) , 8.07(2H,d,J=8.0Hz) Example 66 1.00 g of isopropyl 3-(5-(2-hydroxy-4- isobutoxybenzoyl)-2-{[4- (methylsulfanyl)benzyl]oxylphenyl) propanoate was dissolved in 10 mL of methylene chloride, to which 0.69 g of 70% m-chloroperbenzoic acid was added in small portions in an ice bath, and then this mixture was stirred for 1.5 hours at room temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, this washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; ethyl acetate] to yield 0.50 g of isopropyl 3-(5-(2-hydroxy-4-isobutoxybenzoyl)-2-{[4- (methylsulfonyl)benzyl]oxylphenyl) propanoate as yellow oil and 0.54 g of isopropyl 3-(5-(2-hydroxy-4- isobutoxybenzoyl)-2-{[4- (methylsulfinyl)benzyl]oxylphenyl) propanoate as yellow oil. isopropyl 3-(5-(2-hydroxy-4- isobutoxybenzoyl)-2-{[4- (methylsulfinyl)benzyl]oxy(phenyl) propanoate NMR(90MHz,CDCl3) δ value: 1. 03 ( 6H, d, J=6 . 6Hz) , 1.19(6H,d,J=6.3Hz), 1.98-2.30(1H,m), 2.64-2.76(5H,m), 2.99-3.17 (2H,m) , 3. 79 (2H, d, J=6. 6Hz) , 4 . 80-5.15 (1H,m), 5.25(2H,s), 6.38-6.51{2H,mJ, 6.94 (1H, d, J=9.1Hz), 7.48- 7.77{7H,m}, 12.64(1H,s) isopropyl 3-(5-(2-hydroxy-4- isobutoxybenzoyl)-2-{[4- (methylsulfonyl)benzyl]oxyjphenyl) propanoate NMR(9QMHz,CDCl3) δ value: 1.03(6H,d,J=6.6Hz), 1.20(6H,d,J=6.4Hz), 1.98-2.18(1H,m), 2.56-2.72(2H,m), 2.98-3.18(5H,m), 3.79(2H, d, J=6.4Hz), 4.86-5.15(1H,m), 5.28{2H,s), 6.35-6.51(2H,m), 6.92(1H,d,J=9.3Hz), 7.47- 7.71(5H,m), 8.01(2H,d,J=8.6Hz), 12.63£lH,s) Example 67 0.93 g of 3-(5~(2-hydroxy~4- isobutoxybenzoyl)-2-{[4- (methoxycarbonyl)benzyl]oxy}phenyl) propanoic acid was dissolved in 9.3 mL of tetrahydrofuran, to which 0.19 mL of oxalyl chloride and 20 fiL of N,N- dimethylformamide were added at room temperature, and after this mixture was stirred for one hour, the reaction mixture was added dropwise to a 25% aqueous ammonia in an ice bath over 15 minutes. The reaction mixture was adjusted to pH 6 with 6M hydrochloric acid, to which ethyl acetate was added, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, this washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was dissolved in 18.6 mL of tetrahydrofuran, to which 0.27 mL of thionyl chloride was added, and this mixture was stirred for 6.5 hours while heating it under reflux. The reaction mixture was added to a mixture of ethyl acetate and ice water, followed by the separation of the organic phase therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, this washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; ethyl acetate:hexane=2:1] to yield 0.36 g of methyl 4-{[2-(2-cyanoethyl)-4-(2- hydroxy-4-isobutoxybenzoyl)phenoxy]methyl} benzoate as light orange solid. NMR(90MHz,CDCl3) δ value: 1.03(6H,d,J=6.7Hz), 1.98- 2.26(1H,m), 2.68-2.77(2H,m), 3.00-3.08(2H,m), 3.67- 3.94(5H,m), 5.25(2H,s), 6.39-6.49(2H,m), 6.99(1H,d,J=9.0Hz), 7.43-7.66(5H,m), 8.11(2H,d,J=8.1Hz), 12.57 (1H,S) Example 68 0.35 g of methyl 4-{[2-(2-cyanoethyl)-4-(2- hydroxy-4-isobutoxybenzoyl)phenoxy]methyl} benzoate, 0.42 g of sodium azide, and 0.89g of triethylamine hydrochloride were suspended in 3.5 mL of xylene, and stirred for 7 hours at 110°C. The reaction mixture was cooled to room temperature, to which methylene chloride and water were added, and after this mixture was adjusted to pH 2 with 6M hydrochloric acid, the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, this washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The residue was purified by silica gel column chromatography [eluent; chloroform:ethanol=10:1] to yield 0.19 g of methyl 4-({4-(2-hydroxy-4- isobutoxybenzoyl)-2-[2-(1H-1,2,3,4-tetrazol-5- yl)ethyl]phenoxy}methyl) benzoate as light yellow solid. NMR(90MHz,CDC13) δ value: 1.02(6H,d,J=6.5Hz), 1.98- 2.24(1H,m), 3.23-3.34(4H,m), 3.76(2H,d,J=6.7Hz), 3.91(3H,s), 5.16(2H,s), 6.38-6.46(2H,m), 6.87(1H,d,J=9.5Hz), 7.29-7.50(5H,m), 8.03(2H,d,J=8.3Hz), 12.49(2H,brs) Example 69 isopropyl 3-(5-(2-hydroxy-4- isobutoxybenzoyl)-2-{[4-(1H-1,2,3,4-tetrazol-5- yl)benzyl]oxy}phenyl) propanoate was obtained in a similar manner as in Example 68. NMR( 90MHz, CDCl3) δ value: 1. 03 ( 6H, d, J=6 . 8Hz) , 1.20(6H,d,J=6.4Hz), 1.90-2.18(1H,m), 2.62-2.98(2H,m), 3.00-3.18(2H,m), 3.78(2H,d,J=6.4Hz), 4.95-5.09(2H,m), 5.21(2H,s), 6.35-6.48(2H,m), 6.91(1H,d,J=7.4Hz), 7.48- 7.57(5H,m), 8.10(2H,d,J=8.3Hz), 12.63 (1H,brs) Example 7 0 0.580 g of isobutyl 3-(5-{2-hydroxy-4-[ (4- nitrophenethyl)oxy]benzoyl}-2-isobutoxyphenyl) propanoate was dissolved in a mixed solvent of 3 mL of ethanol and 3 mL of tetrahydrofuran, to which 58 mg of 5% palladium-carbon was added, and this mixture was stirred for 3 hours at room temperature in a stream of hydrogen. After the reaction mixture was filtered through Celite, the solvent was distilled out under reduced pressure, and then the resultant residue was purified by silica gel column chromatography [eluent; hexanerethyl acetate=2:l] to yield 0.515 g of isobutyl 3- (5-{4-[(4-aminophenethyl)oxy]-2-hydroxybenzoyl} -2- isobutoxyphenyl) propanoate as light yellow oil. NMR( 90MHz, CDC13) δ value: 0 . 8 9 ( 6H, d, J=6 . 6Hz ) , 1.07(6H,d, J=6.6Hz) , 1.7-2.3(2H,m), 2.5-2.8(2H,m), 2.9- 3.1(4H,m), 3.60(2H,brs), 3.82(2H,d,J=6.3Hz), 3.85 (2H,d,J=6.6Hz), 4.17(2H,t,J=7.1Hz), 6.3-6.5(2H,m), 6.65(2H,d,J=8.5Hz), 6.88(1H,d,J=9.3Hz), 7.07(2H,d,J=8.3Hz), 7.4-7.6(3H,m), 12.66(1H,s) Example 71 3.32 g of 4-({2-(2-carboxyethyl)-4-[4- (cyclopentyloxy)-2-hydroxybenzoyl]phenoxy}- methyl)benzoic acid was suspended in 3.3 mL of methylene chloride, to which 3.3 mL of 4M hydrogen chloride-ethanol was added, and this mixture was stirred for 7 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and then the resultant residue was purified by silica gel column chromatography [eluent; chloroform:ethanol=10:1] to yield 1.76 g of 4-{[4-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-(3-ethoxy-3-oxopropyl)phenoxy]methyl} benzoic acid as white solid. NMR(400MHz,CDCl3) δ value: 1.23(3H,t,J=7.6Hz) , 1.62- 1.66(2H,m), 1.78-1.96(6H,m), 2 . 69(2H,t,J=7.6Hz), 3.09(2H,t,J=7.6Hz), 4.13(2H,q,J=7.2Hz), 4 . 80-4.83(1H,m), 5.27(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.48(1H,d,J=2.4Hz), 6.94(1H,d,J=8.4Hz), 7.50-7.57(5H,m), 8.16(2H,d,J=8.4Hz), 12.69(2H,brs) Example 72 The following compounds were obtained in a similar manner as in Example 71. (1) 4-{[2-(3-ethoxy-3-oxopropyl)-4-(2- hydroxy-4-isobutoxybenzoyl)phenoxy]methyl} benzoic acid NMR(90MHz,CDCl3) δ value: 1.03(6H,d,J=6.8Hz), 1.23(3H,t,J=7.1Hz), 1.98-2.27(1H,m), 2 . 66-2.76(2H,m), 3.00-3.09(2H,m), 3.79(2H,d,J=6.6Hz), 4.13(2H,q,J=7.1Hz), 5.27(2H,s), 6.35-6.51(2H,m), 6.94(1H,d,J=9.4Hz), 7.48- 7.61(5H,m), 8.17(2H,d,J=8.1Hz), 12.65(2H,brs) (2) 4-{[4-(2-hydroxy-4-isobutoxybenzoyl)-2- (3-methoxy-3-oxopropyl)phenoxy]methyl} benzoic acid NMR(90MHz,DMSO-d6) δ value: 0.99(6H,d,J=6.7Hz), 1.92- 2.19(1H,m), 2.62-2.73(2H,m), 2.86-3.14(2H,m), 3.57(3H,s), 3.84(2H,d,J=5.9Hz), 5.35(2H,s), 6.48- 6.55(2H,m), 7.16-7.65(6H,m), 8.00(2H,d,J=7.8Hz), 11.96(1H,s), 12.80(1H,brs) Example 73 0.50 g of 4-{[2-(2-carboxyethyl)~4-(2- hydroxy-4-isobutoxybenzoyl)phenoxy]methyl} benzoic acid was dissolved in 15 mL of N,N-dimethylformamide, to which 1.54 g of potassium carbonate and 1.2 mL of isobutyl bromide were added at room temperature, and this mixture was stirred for one hour at 100°C. The reaction mixture was added to a mixture of chloroform and water, and adjusted to pH 3 with 6M hydrochloric acid, and then followed by separation of the organic phase therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, this washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; chloroform:ethanol=10:1] to yield 0.64 g of isobutyl 4-{[4-(2,4- diisobutoxybenzoyl)-2-(3-isobutoxy-3- oxopropyl)phenoxy]methyl} benzoate as yellow oil. NMR(90MHz,CDC13) δ value: 0.68(6H,d,J=6.8Hz), 0.86- 1.09(18H,m), 1.75-2.25(4H,m), 2.56-2.70(2H,m), 2.93- 3.12{2H,m), 3.57-3.88(6H,m), 4.12(2H,d,J=6.4Hz), 5.22(2H,s), 6.46-6.55(2H,m), 6.83(1H,d,J=9.1Hz) , 7.32- 7.66(5H,m), 8.07(2H,d,J=8.3Hz) Example 7 4 72.1 g of methyl 3-(5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2- benzisoxazol-6-yl]methoxy}phenyl) propanoate was dissolved in 220 mL of tetrahydrofuran and 140 mL of methanol, to which 125 g of a 20% aqueous solution of sodium hydroxide and 360 mL of water were added, and this mixture was stirred for 2 hours at room temperature. The reaction mixture to which water was added was adjusted to pH 2 with 6M hydrochloric acid, and then resultant precipitate was filtered out thereof. The precipitates thus obtained were washed with water and diisopropyl ether successively to yield 69.7 g of 3-(5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-{[3- (methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl) propanoic acid as light yellow solid. NMR(400MHz,DMSO-d6) δ value: 1.54-1.78(6H,m), 1.89- 2.02(2H,m), 2.58(2H,t,J=7.6Hz), 2.93(2H,t,J=7.6Hz), 3.54(3H,s), 4.87-4.94(1H,m), 5.44(2H,s), 5.55(2H,s), 6.46-6.52(2H,m), 7.20(1H,d,J=9.2Hz), 7.45(1H,d,J=8.8Hz), 7.51(1H,d,J=8.0Hz), 7.53-7.58(2H,m), 7.78(1H,s), 7.84(1H,d,J=8.0Hz), 11.93-12.34(1H,br), 12.04(1H,brs). Example 7 5 69.7 g of 3-(5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2- benzisoxazol-6-yl]methoxy}phenyl) propanoic acid was dissolved in 700 mL of tetrahydrofuran, to which 16.5 mL of N-(2-hydroxyethyl)morpholine and 39.1 g of triphenylphosphine were added at room temperature followed by addition of diisopropyl azodicarboxylate, and this mixture was stirred for 20 minutes at the same temperature. The reaction mixture was added to a mixture of ethyl acetate and water, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, this washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue to which toluene was added was stirred in an ice bath, and resultant precipitate was filtered out thereof. The filtrate was concentrated under reduced pressure, and the resultant residue was purified by silica gel column chromatography [eluent; ethyl acetate] to yield 91.0 g of 2-(4-morpholinyl)ethyl 3-(5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2- benzisoxazol-6-yl]methoxy}phenyl) propanoate as yellow oil. NMR(400MHz,CDCl3) δ value: 1. 58-1. 70 (2H,m) , 1.74- 2.01(6H,m), 2.45(4H,t,J=4.8Hz), 2.58(2H,t,J=6.4Hz), 2.72(2H,t,J=7.6Hz), 3.09(2H,t,J=7.6Hz), 3.63-3.68(4H,m), 3.65(3H,s), 4.21(2H,t,J=6.4Hz), 4.77-4.85(1H,m), 5.33(2H,s), 5.57(2H,s), 6.37(1H,dd,J=9.3,2.4Hz), 6.4 8(1H,d,J=2.4Hz), 6.95(1H,d,J=8.3Hz), 7.36(1H,d,J=7.6Hz), 7.48-7.58(4H,m), 7.72(1H,d,J=8.3Hz), 12.69(1H,s). Example 7 6 86.7 g of 2-(4-morpholinyl)ethyl 3-(5-[4- (cyclopentyloxy)-2-hydroxybenzoyl]-2-{[3- (methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl) propanoate was dissolved in 200 mL of methylene chloride and 610 mL of isopropyl alcohol, to which 18.8 mL of methanesulfonic acid was added at room temperature, and this mixture was stirred for 30 minutes at the same temperature. The reaction mixture was added to a mixture of ice water and chloroform, followed by adjustment thereof to pH 6 with a saturated aqueous solution of sodium hydrogen carbonate, and the organic phase was separated therefrom. After the resultant organic phase was washed with a saturated sodium chloride solution, this washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; chloroform:methanol=20:1] to yield 69.9 g of light yellow solid, which was recrystallized from acetone to yield 46.2 g of 2-(4- morpholinyl)ethyl 3-{5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-[(3-hydroxy-l,2-benzisoxazol-6- yl)methoxy]phenyl} propanoate as colorless crystals. NMR(400MHz,CDCl3) δ value: 1. 58-1. 70 (2H,m) , 1.74- 2.01(6H,m), 2.61(2H,t,J=8.0Hz), 2.68-2.78(4H,m), 2.8 4(2H,t,J=5.4Hz), 3.00(2H,t,J=8.0Hz), 3.77(4H,t,J=4.4Hz), 4.32(2H,t,J=5.4Hz), 4.78-4.84(1H,m), 5.23(2H,s), 6.20-7.00(1H,br), 6.36(1H,dd,J=9.6,2.4Hz), 6.47(1H,d,J=2.4Hz), 6.90-6.93(1H,m), 7.22(1H,d,J=8.0Hz), 7.40(1H,s), 7.44-7.52(3H,m), 7.74(1H,d,J=8.4Hz). Example 77 5.80 g of 3-{5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-[(3-hydroxy-l,2-benzisoxazol-6- yl)methoxy]phenyl} propanoic acid was suspended in 58 mL of methylene chloride, to which 6.2 mL of triethylamine was added at room temperature followed by addition of 3.44 g of trityl chloride in an ice bath, and this mixture was stirred for 30 minutes at room temperature. The reaction mixture to which water was added was adjusted to pH 3 with 6M hydrochloric acid, and the organic phase was separated therefrom. After the resultant organic phase was washed with water, the solvent was distilled out under reduced pressure. The resultant residue was washed with hexane and then purified by silica gel column chromatography [eluent; chloroform:ethanol=50:1] to yield 6.83 g of 3~{5-[4- (cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-oxo-2-trityl- 2,3-dihydro-l,2-benzisoxazol-6-yl)methoxy]phenyl} propanoic acid as yellow solid. NMR (400MHz, CDC13) δ value: 1. 5-2 .1 (8H,m) , 2.72(2H,t,J=7.4Hz), 3.06(2H,t,J=7.4Hz), 4.75-4.85(1H,mj, 5.20(2H,s), 6.37(1H,dd,J=9.4,2.6Hz), 6.47(1H,d,J=2.4Hz), 6.87 (1H,d, J=8.0Hz) , 7 . 15-7 . 35 (HH,m) , 7.45-7.60(10H,m), 7.66(1H,d,J=8.0Hz), 12.67(1H,s). Example 7 8 50.0 g of 3-{5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-[(3-oxo-2-trityl-2,3-dihydro-l,2- benzisoxazol-6-yl)methoxy]phenyl} propanoic acid was dissolved in 500 mL of tetrahydrofuran, to which 8.8 mL of N-(2-hydroxyethyl)morpholine and 20.7 g of triphenylphosphine were added at room temperature followed by dropwise addition of 15.5 mL of diisopropyl azodicarboxylate, and this mixture was stirred for one hour at the same temperature. Then, water, ethyl acetate, and a saturated sodium chloride solution were added to the reaction mixture, and the organic phase was separated therefrom. After the resultant organic phase was washed with a saturated sodium chloride solution, this washed phase was dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; ethyl acetate] to yield 59.0 g of 2-(4-morpholinyl)ethyl 3- {5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-oxo-2- trityl-2,3-dihydro-l,2-benzisoxazol-6- yl)methoxy]phenyl} propanoate as yellow oil. NMR(400MHz,CDCl3) δ value: 1. 5-2 . 1 ( 8H,m) , 2.4 4(4H,t,J=4.4Hz), 2.55(2H,t,J=6.0Hz), 2.69(2H,t,J=7.6Hz), 3.0 6(2H,t,J=7.6Hz),3.65(4H,t,J=4.6Hz), 4.17(2H,t,J=5.8Hz), 4.7-4.9(1H,m), 5.22(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.4 8(1H,d,J=2.4Hz), 6.88(1H,d,J=8.4Hz),7.16-7.34(llH,m), 7.4 3-7.5 9(9H,m), 7.67(1H,d,J=8.4Hz), 12.68(1H,s). Example 7 9 134 g of 2-(4-morpholinyl)ethyl 3-{5-[4- (cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-oxo-2-trityl- 2,3-dihydro-1,2-benzisoxazol-6-yl)methoxy]phenyl} propanoate was dissolved in 1.3 L of 1,4-dioxane, to which 670 mL of 3M hydrochloric acid was added at room temperature, and this mixture was stirred for 1.5 hour at 40°C. The reaction mixture to which chloroform was added was adjusted to pH 5 with a saturated aqueous solution of sodium hydrogen carbonate, and the organic phase was separated therefrom. An aqueous phase was extracted with chloroform, and after the combined organic phases were washed with a saturated sodium chloride solution, the washed phases was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; chloroform:methanol=40:1] to yield 38.6 g of 2-(4-morpholinyl)ethyl 3-{5-[4- (cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-l,2- benzisoxazol-6-yl)methoxy]phenyl} propanoate as colorless crystals. NMR(400MHz,CDCl3) δ value: 1. 58-2 . 00 ( 8H, m) , 2.60(2H,t,J=7.6Hz), 2.71(4H,brs), 2.82(2H,t,J=5.6Hz), 3.00(2H,t,J=7.6Hz), 3.7 7(4H,t,J=4.6Hz), 4.31(2H,t,J=5.6Hz), 4.78-4.84(1H,m), 5.24(2H,s), 5.7.- 6.2(1H,br), 6.36(1H,dd,J=9.4,2.6Hz), 6.47(1H,d,J=2.4Hz) , 6.92(1H,d,J=8.8Hz), 7.24(1H,d,J=8.4Hz), 7.40(1H,s), 7.46-7.52(3H,m), 7.74(1H,d,J=8.0Hz), 12.4-13.0(1H,br) Example 7 9 (2) 280 g of 2-(4-morpholinyl)ethyl 3-{5-[4- (cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-oxo-2-trityl- 2,3-dihydro-l,2-benzisoxazol-6-yl)methoxy]phenyl} propanoate was suspended in 560 mL of 1,4-dioxane, to which 92.5 g of methanesulfonic acid was added dropwise at 12 to 15°C, and this mixture was stirred for 15 minutes at 15°C. 20 mL of water was added to the reaction mixture, which was then stirred for one hour at 12 to 15°C, and the resultant precipitate was filtered out thereof. The filtrate was ice-cooled, to which methylene chloride and water were added, and was adjusted to pH 4.5 with a 20% aqueous solution of sodium hydroxide, and then the organic phase was separated therefrom. An aqueous phase was extracted with methylene chloride, and after the combined organic phases were washed with a saturated sodium chloride solution followed by filtration thereof through Celite, the organic phase was separated. The resultant organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue, to which diisopropyl ether and ethyl acetate were added, was stirred for 30 minutes at room temperature, and then resultant precipitate was filtered out thereof to yield 180 g of light yellow solid. Then, 170 g of the resultant solid was recrystallized from acetone to yield 142 g of 2-(4- morpholinyl)ethyl 3-{5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-[(3-hydroxy-l,2-benzisoxazol-6- yl)methoxy]phenyl} propanoate as light yellow needle crystals. melting point: 131 - 132.5°C IR(KBr) : 1742, 1625 cm-1 NMR (400MHz, CDCl3) δ value: 1. 6-2 . 0 (8H, m) , 2.61(2H,t,J=7.5Hz) , 2.74(4H,brs) , 2.85(2H,t,J=5.6Hz) , 3.00(2H,t,J=7.5Hz), 3.7 8 (4H,t,J=4.6Hz), 4.32(2H,t,J=5.6Hz), 4.78-4.84(1H,m), 5.23(2H,s), 6.36(1H,dd,J=9.2,2.4Hz), 6.4 7(1H,d,J=2.4Hz), 6.91 (1H,d,J=9.2Hz), 7.23(1H,dd,J=8.0,1.2Hz), 7.40(1H,s), 7.4 7-7.52(3H,m), 7.7 4(1H,d,J=8.0Hz) Example 8 0 (1) 3.00 g of 1-chloroethyl ethyl carbonate was dissolved in 90 mL of acetonitrile, to which 13.3 g of sodium iodide was added, and this mixture was stirred for 1.5 hours at 60°C. This mixture was cooled to room temperature, followed by concentration thereof under reduced pressure, and then insoluble substances were filtered out thereof by adding diethyl ether to the residue. The resultant filtrate was concentrated under reduced pressure to yield 4.60 g of ethyl 1- iodoethyl carbonate as orange oil. (2) 1.50 g of 3-(5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2- benzisoxazol-6-yl]methoxy}phenyl) propanoic acid and 1.85 g of potassium carbonate were suspended in 15 mL of N,N-dimethylformamide, to which 2.00 g of 1- iodoethyl ethyl carbonate prepared in (1) was added, and this mixture was stirred for one hour at room temperature. The reaction mixture, to which water and ethyl acetate were added, was adjusted to pH 5 with 6M hydrochloric acid, and the organic phase was separated therefrom. After the resultant organic phases was washed with an aqueous solution of sodium thiosulfate and a saturated sodium chloride solution, the washed phase was dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=4:l] to yield 1.42 g of 1-[(ethoxycarbonyl)oxy]ethyl 3—{5— [4- (cyclopentyloxy)-2-hydroxybenzoyl]-2-{[3- (methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl) propanoate as yellow oil. NMR(400MHz,CDC13) δ value: 1.28(3H,t,J=7.0Hz), 1.49(3H,d,J=5.6Hz), 1.6-2.1(8H,m), 2.70-2.76(2H,m), 3.09(2H,t,J=7.6Hz), 3.65(3H,s), 4.14-4.23(2H,m), 4.79- 4.86(1H,m), 5.33(2H,s), 5.57(2H,s), 6.38(1H,dd,J=8.8,2.8Hz), 6 . 48(1H,d,J=2.4Hz), 6.74- 6.80(1H,m), 6.94(1H,d,J=8.4Hz), 7.37(1H,dd,J=8.2,1.0Hz), 7.48-7.59(4H,m), 7.72(1H,d,J=8.4Hz), 12.68(1H,s). Example 81 1.40 g of 1-[(ethoxycarbonyl)oxy]ethyl 3-(5- [4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-{[3- (methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl) propanoate was dissolved in 28 mL of 1,4-dioxane, to which 6 mL of 3M hydrochloric acid was added, and this mixture was stirred for 3.5 hours at room temperature. Then, water and ethyl acetate were added to the reaction mixture, and the organic phase was separated therefrom. After the resultant organic phases was washed with water and a saturated sodium chloride solution, the washed phase was dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; chloroform] to yield 1.12 g of 1- [(ethoxycarbonyl)oxy]ethyl 3-{5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6- yl)methoxy]phenyl} propanoate as light yellow solid. NMR(400MHz,CDCl3) δ value: 1 . 29 ( 3H, t, J=7 . 2Hz ), 1.49(3H,d,J=5.4Hz), 1.5-2.0(8H,m), 2.70-2.80(2H,m), 3.10(2H,t,J=7.6Hz), 4.1-4.3(2H,m), 4.8-4.9(1H,m), 5.33(2H,s), 6.39(1H,dd,J=9.2,2.4Hz), 6.47(1H,d,J=2.2Hz), 6.75-6.85(1H,m), 6.95(1H,d,J=8.4Hz), 7.39(1H,d,J=8.4Hz) , 7.47-7.62(4H,m), 7.82(1H,d,J=8.0Hz), 9.5-10.0(1H,br), 12.69(1H,brs). Example 82 (1) 9.15 g of cyclohexanol was dissolved in 150 mL of methylene chloride, to which 7.4 mL of pyridine was added followed by dropwise addition of 10 mL of 1-chloroethyl chloroformate in an ice bath, and this mixture was stirred for 2 hours at room temperature. Then, a sodium chloride solution was added to the reaction mixture and the organic phase was separated therefrom. After the resultant organic phase was dried over anhydrous magnesium sulfate, the solvent was distilled out under reduced pressure to yield 18.6 g of 1-chloroethyl cyclohexyl carbonate as colorless oil. 5.00 g of this 1-chloroethyl cyclohexyl carbonate was dissolved in 150 mL of acetonitrile, to which 16.3 g of sodium iodide was added, and this mixture was stirred for one hour at 60°C. The mixture was cooled to room temperature, followed by concentration thereof under reduced pressure, and then insoluble substances were filtered out therefrom by adding diethyl ether to the residue. The resultant filtrate was concentrated under reduced pressure to yield 5.90 g of cyclohexyl 1- iodoethyl carbonate as red oil. (2) 1.50 g of 3-(5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2- benzisoxazol-6-yl]methoxy}phenyl) propanoic acid and 1.85 g of potassium carbonate were suspended in 15 mL of N,N-dimethylformamide, to which 4.00 g of 1- iodoethyl cyclohexyl carbonate prepared in (1) was added, and this mixture was stirred for one hour at room temperature. The reaction mixture, to which water and ethyl acetate were added, was adjusted to pH 5 with 6M hydrochloric acid, and the organic phase was separated therefrom. An aqueous phase was extracted with ethyl acetate, and then after the combined organic phases were washed with an aqueous solution of sodium thiosulfate and a saturated sodium chloride solution, the washed phase was dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=5:l] to yield 1.47 g of 1- { [(cyclohexyloxy)carbonyl]oxy}ethyl 3- (5-[4- (cyclopentyloxy)-2-hydroxybenzoyl]-2-{[3- (methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl) propanoate as red oil. (3) 1.40 g of the resultant oil was dissolved in 42 mL of 1,4-dioxane, to which 9 mL of 3M hydrochloric acid was added, and this mixture was stirred for one hour at room temperature. Then, water and ethyl acetate were added to the reaction mixture and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution, the washed phase was dried over anhydrous sodium sulfate, the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; chloroform:ethyl acetate=l:l] to yield 1.04 g of 1- { [(cyclohexyloxy)carbonyl]oxy}ethyl 3-{5- [4- (cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2- benzisoxazol-6-yl)methoxy]phenyl} propanoate as yellow solid. NMR (400MHz, CDCl3) δ value: 1.1-2.0(21H,m) , 2.7-2.8(2H,m), 3.10(2H,t,J=7.4Hz), 4.55-4.65(1H,m), 4.78-4.86(1H,m), 5.34(2H,s), 6.39(1H,dd,J=9.0,2.6Hz), 6.48(1H,d,J=2.4Hz) , 6.74-6.82(1H,m), 6.95(1H,d,J=8.8Hz), 7.40(1H,d,J=8.0Hz), 7.45-7.65(4H,m), 7.83(1H,d,J=8.OHz), 8.0-9.0(1H,br), 5 12.68(1H,brs). Example 83 1.04 g of 3-(5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2- benzisoxazol-6-yl]methoxy}phenyl) propanoic acid and ) 512 mg of potassium carbonate were suspended in 10 mL of N,N-dimethylformamide, to which 0.29 mL of chloromethyl pivalate was added, and this mixture was stirred for 2 hours at 40°C. Then, water and ethyl acetate were added to the reaction mixture, and the 3 organic phase was separated therefrom. The remaining aqueous phase was extracted with ethyl acetate, and organic phases were combined together. After the resultant organic phase was washed with a saturated sodium chloride solution, the washed phase was dried ) over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=3:l] to yield 1.02 g of {[3-(5-[4-(cyclopentyloxy)-2- j hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2- benzisoxazol-6-yl]methoxy}phenyl) propanoyl]oxy}methyl pivalate as light yellow oil. NMR(400MHz,CDCl3) δ value: 1.16(9H,s), 1.58-2.02(8H,m), 2.75(2H,t,J=7.6Hz), 3.09(2H,t,J=7.6Hz), 3.65(3H,s), 4.75-4.85(1H,m), 5.32(2H,s), 5.57(2H,s), 5.75(2H,s), 6.38(1H,dd,J=9.2,2.4Hz), 6.4 8(1H,d,J=2.8Hz), 6.95 (1H,d,J=8.4Hz), 7.36(1H,d,J=8.0Hz), 7.45-7.60(4H,m), 7.72(1H,d,J=8.4Hz), 12.68(1H,s). Example 8 4 1.02 g of {[3-(5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2- benzisoxazol-6-yl]methoxy}phenyl) propanoyl]oxy}methyl pivalate was dissolved in 8 mL of 1,4-dioxane and 8 mL of methanol, to which 6 mL of 6M hydrochloric acid was added at room temperature, and this mixture was stirred for 50 minutes at the same temperature. The reaction mixture, to which water was added, was adjusted to pH 7 with an aqueous solution of sodium hydroxide, and then ethyl acetate was added to this mixture and the organic phase was separated therefrom. The remaining aqueous phase was extracted with ethyl acetate, and organic phases were combined together. After the resultant organic phase was washed with a saturated sodium chloride solution, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue, to which a mixture of hexane and ethyl acetate [3:1] was added, was filtered out to yield 0.56 g of [ (3-{5-[4-(eye1opentyloxy)-2-hydroxybenzoyl]-2-[(3- hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl} propanoyl)oxy]methyl pivalate as white solid. NMR (400MHz, DMSO-d6) δ value: 1.04(9H,s), 1.53-1.80(6H,m), 1.89-2.00(2H,m), 2.74(2H,t, J=7.2Hz) , 2.96(2H,t,J=7.2Hz), 3.1-3.7(1H,br) , 4.88-4.94(1H,m), 5.38(2H,s), 5.67(2H,s), 6.4-6.6(2H,m), 7.20 (1H,d,J=8.4Hz), 7 . 35(1H,d,J=8.0Hz), 7.45(1H,d, J=8.4Hz) , 7.50-7.35(3H,m), 7.80(1H,d,J=8.0Hz), 12.10(1H,brs). Example 8 5 1.80 g of 3- (5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2- benzisoxazol-6-yl]methoxy}phenyl) propanoic acid was dissolved in 20 mL of N,N-dimethylformamide, to which 0.9 g of potassium carbonate and 0.3 mL of ethyl iodide were added at room temperature, and this mixture was stirred for one hour at 30 to 35°C. The reaction mixture was added to a mixture of ethyl acetate and ice water, and adjusted to pH 3 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=30:1] to yield 1.50 g of ethyl 3- (5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-{ [3- (methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl) propanoate as light yellow solid. NMR(400MHz,CDCl3) δ value: 1.23 (3H,t,J=7.1Hz), 1.58- 1.72(2H,m), 1.75-2.02(6H,m), 2.69(2H,t,J=7.7Hz), 3.09(2H,t,J=7.7Hz), 3.65(3H,s), 4.13(2H,q,J=7.1Hz), 4.78-4.86(1H,m), 5.33(2H,s), 5.57(2H,s), 6.37(1H,dd,J=9.2,2.4Hz), 6.4 8(1H,d,J=2.8Hz), 6.94(1H,d,J=8.8Hz), 7.36(1H,d,J=8.4Hz), 7.48-7.60(4H,m), 7.71(1H,d,J=8.4Hz), 12.68(1H,s). Example 8 6 0.70 g of ethyl 3-(5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2- benzisoxazol-6-yl]methoxyJphenyl) propanoate was dissolved in 5 mL of 1,4-dioxane, to which 5 mL of 3M hydrochloric acid was added in an ice bath, and further, 7 mL of ethanol, 5 mL of 1,4-dioxane and 2 mL of 3M hydrochloric acid were added to the mixture, which was stirred for 2 hours at room temperature. The reaction mixture was added to a mixture of ice water and ethyl acetate, and the organic phase was separated therefrom. After the resultant organic phase was washed with a saturated sodium chloride solution, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue, to which diisopropyl ether was added, was filtered out to yield 0.56 g of ethyl 3-{5-[4- (cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-l, 2- benzisoxazol-6-yl)methoxy]phenyl} propanoate as white solid. NMR(400MHz,CDCl3) δ value: 1.23(3H,t,J=7.1Hz), 1.58- 1.72(2H,m), 1.74-2.04(6H,m), 2.70(2H,t,J=7.9Hz), 3.10(2H,t,J=7.9Hz), 4 . 14(2H, q,J=7.1Hz), 4.78-4.90(1H,m), 5.34(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.48(1H,d,J=2.4Hz), 6.95(1H,d,J=8.8Hz), 7.39(1H,d,J=8.0Hz), 7.48-7.63(4H,m), 7.83(1H,d,J=7.6Hz), 12.68(2H,brs). Example 87 5.50 g of methyl 3-(5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2- benzisoxazol-6-yl]methoxy}phenyl) propanoate was dissolved in 17 mL of 1,4-dioxane and 17 mL of methanol, to which 5.5 mL of 6M hydrochloric acid was added at room temperature, and this mixture was stirred for 20 minutes at the same temperature. Then, water was added to the reaction mixture, and resultant precipitate was filtered out therefrom. The precipitate thus obtained was washed with water to yield 4.99 g of methyl 3-{5- [4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy- 1,2-benzisoxazol-6-yl)methoxy]phenyl} propanoate as white solid. NMR (400MHz, CDC13) δ value: 1. 57-1. 71 (2H,m) , 1.74- 2.01(6H,m), 2.71(2H,t, J=7.6Hz) , 3.11(2H,t,J=7.6Hz), 3.69(3H,s), 4.77-4.85(1H,m), 5.34(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.4 8(1H,d,J=2.4Hz), 6.95(1H,d,J=8.8Hz), 7.39(1H,dd,J=8.0,0.8Hz) , 7.48- 7.58(4H,m), 7.83(1H,d,J=8.0Hz), 12.68(1H,s). Example 8 8 (1) 2.08 g of 4,5-dimethyl-l,3-dioxol-2-one was dissolved in 24 mL of benzene, to which 3.25 g of N-bromosuccinimide and 8 6 mg of 2,2'- azobis(isobutyronitrile) were added at room temperature, and this mixture was stirred for 30 minutes while heating it under reflux. The reaction mixture was cooled to room temperature, and consequently, a solution of 4-bromomethyl-5-methyl-l,3-dioxol-2-one in benzene was obtained. (2) 3.00 g of methyl 3-(5-[4- (cyclopentyloxy)-2-hydroxybenzoyl]-2-{[3- (methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl) propanoate was dissolved in 15 mL of methanol and 15 mL of tetrahydrofuran, to which a solution of 1.08 g of potassium hydroxide in 4.5 mL of water was added, and this mixture was stirred for one hour at room temperature, and then the solvent was distilled out under reduced pressure. The resultant residue was dissolved in 40 mL of N,N-dimethylformamide, to which 3.60 g of potassium carbonate was added. Then, the benzene solution prepared in (1) was added thereto, and was stirred for one hour at room temperature. The reaction mixture was poured into a mixture of ethyl acetate and water, and adjusted to pH 7 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; toluene:ethyl acetate=5:1 to yield 1.58 g of (5- methyl-2-oxo-1,3-dioxol-4-yl)methyl 3- (5-[4- (cyclopentyloxy)-2-hydroxybenzoyl]-2-{[3- (methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl) propanoate as yellow oil. NMR(4 00MHz, CDCl) δ value: 1.5-2.0(8H,m), 2.16(3H,s), 2.75(2H,t,J=7.6Hz) , 3.10(2H,t,J=7.6Hz), 3.65(3H,s), 4.5-5.0(3H,m), 5.33(2H,s), 5.57(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.4 7(1H,d,J=2.4Hz), 6.95(1H,d,J=8.4Hz), 7.35(1H,dd,J=8.4,1.2Hz), 7.4- 7.6(4H,m), 7.72(1H,d,J=8.0Hz), 12.67(1H,s). Example 8 9 1.40 g of (5-methyl-2-oxo-1,3-dioxol-4- yl)methyl 3-(5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2- {[3-(methoxymethoxy)-1,2-benzisoxazol-6- yl]methoxy}phenyl) propanoate was dissolved in 28 mL of 1,4-dioxane, to which 14 mL of 3M hydrochloric acid was added, and this mixture was stirred for 2 hours at room temperature. Then, water and chloroform were added to the reaction mixture, and the organic phase was separated therefrom. After the resultant organic phase was washed with a saturated sodium chloride solution, the washed phase was dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue, to which 15 mL of methylene chloride and 45 mL of hexane were added, was stirred for 30 minutes at room temperature and then filtered out to yield 1.20 g of (5-methyl-2-oxo-1,3- dioxol-4-yl)methyl 3-{5-[4-(cyclopentyloxy)-2- hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6- yl)methoxy]phenyl} propanoate as light yellow solid. NMR(4 00MHz,CDC13) δ value: 1.5-2.1(8H,m), 2.15(3H,s), 2.76(2H,t,J=7.6Hz), 3.11(2H,t,J=7.6Hz), 4.7-5.0(3H,m), 5.35(2H,s), 6.37(1H,dd,J=9.2,2.4Hz), 6.48(1H,d,J=2.0Hz), 6.96(1H,d,J=8.4Hz), 7.38(1H,d,J=7.6Hz), 7.4-7.7(4H,m), 7.83(1H,d,J=8.4Hz), 12.6 6(2H,brs) Reference Example 1 5.0 g of 3-(2-hydroxyphenyl) propanoic acid, 12.5 g of potassium carbonate, and 7.5 mL of isopropyl iodide were suspended in 50 mL of N,N-dimethylformamide, and this suspension was stirred for 5 hours at 80 to 120°C. After the reaction mixture was filtered out, 10.4 g of potassium carbonate and 6 mL of isopropyl iodide were added to the filtrate, and this mixture was stirred for 3 hours at 80 to 120°C. The reaction mixture was added to a mixture of ethyl acetate and water, and adjusted to pH 2 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=10:1] to yield 4.55 g of isopropyl 3-(2-isopropoxyphenyl) propanoate as colorless oil. NMR(90MHz,CDCl3) δ value: 1.20(6H,d,J=6.1Hz), 1.34 (6H,d,J=6.1Hz), 2.46-2.68(2H,m), 2.84-3.01(2H,m), 4.42-4.69(1H,m), 4.85-5.14(1H,m), 6.74-6.89(2H,m), 7.10-7.25(2H,m) Reference Example 2 4.38 g of isopropyl 3-(2-isopropoxyphenyl) propanoate was dissolved in 44 mL of methylene chloride, followed by successive dropwise addition of 3.84 mL of titanium tetrachloride at -5°C and 1.9 mL of α,α- dichloromethyl methyl ether at 0 to 15°C, and this mixture was stirred for one hour at -5 to -3°C. The reaction mixture was added to a mixture of chloroform and water, then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was dissolved in 20 mL of acetonitrile, to which 7.34 g of sodium dihydrogen phosphate dihydrate dissolved in 9 mL of water and 3.17 g of a 80% sodium chlorite dissolved in 5.6 mL of water and 2.9 mL of a 30% hydrogen peroxide solution were successively added at 5 to 10°C, and this mixture was stirred for one hour at room temperature. Then, ethyl acetate and water were added to the reaction mixture, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:1] to yield 2.69 g of 4-isopropoxy-3-(3-isopropoxy-3- oxopropyl) benzoic acid as light yellowish brown solid. NMR( 90MHz, CDC13) δ value: 1. 22 ( 6H, d, J=6.1Hz) , 1.38(6H,d,J=5.9Hz), 2.49-2.67(2H,m), 2.87-3.03(2H,m), 4.50-5.23(2H,m), 6.87(1H,d,J=9.3Hz), 7.92-8.03(2H,m), 10.88 (1H,br) Reference Example 3 10.0 g of resorcin, 87.8 g of potassium carbonate, and 54 mL of isopropyl iodide were suspended in 100 mL of N,N-dimethylformamide, and this suspension was stirred for 10 hours at 90 to 110°C. After the reaction mixture was filtered out, 43.9 g of potassium carbonate and 27 mL of isopropyl iodide were added to the filtrate, and this mixture was stirred for 3 hours at 120 to 130°C. The reaction mixture was added to a mixture of ethyl acetate and water, and adjusted to pH 2 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=10:1] to yield 6.68 g of 1,3-diisopropoxybenzene as light brown oil. NMR(90MHz,CDC13) δ value: 1.32 (12H,d,J=6.1Hz) , 4.30- 4.72(2H,m), 6.42-6.51(3H,m), 7.03-7.23(1H,m) Reference Example 4 70.0 g of salicylaldehyde and 158.5 g of potassium carbonate were suspended in 700 mL of N,N- dimethylformamide, to which 68 mL of 3-chloro-2-methyl- 1-propene was added dropwise over 30 minutes at 70°C, and this mixture was stirred for 30 minutes at the same temperature. Then, the reaction mixture was added to a mixture of ethyl acetate and water, and adjusted to pH 3 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was dissolved in 350 mL of ethanol, to which 7.0 g of 5% palladium-carbon was added, and this mixture was stirred for 4 hours at 35°C in a stream of hydrogen. After the reaction mixture was filtered through Celite, the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:toluene=2:1] to yield 92.4 g of 2- isobutoxybenzaldehyde as light yellow oil. NMR(90MHz,CDCl3) δ value: 1.07(6H,d,J=6.6Hz), 2.0- 2.2(1H,m), 3.85(2H,d,J=6.4Hz), 6.9-7.1(2H,m), 7.4- 7.7(1H,m), 7.83(1H, dd, J=8 . 1,2.0Hz), 10.55(1H,s) Reference Example 5 0.92 g of 60% sodium hydride was suspended in 30 mL of tetrahydrofuran, to which 5.0 mL of ethyl diethylphosphonoacetate was added dropwise over 5 minutes at room temperature, and this mixture was stirred for 30 minutes at 40°C. Then, after 3.40 g of 2-isobutoxybenzaldehyde dissolved in 20 mL of tetrahydrofuran was added to the mixture dropwise over 20 minutes at room temperature, this mixture was stirred for one hour at the same temperature. The reaction mixture was added to a mixture of ethyl acetate and water, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=9:l] to yield 4.30 g of ethyl (E)-3-(2-isobutoxyphenyl)-2- propenoate as light yellow oil. NMR(90MHz,CDCl3) δ value: 1.06(6H,d,J=6.6Hz), 1.32(3H,t,J=7.1Hz), 1.8-2.4(1H,m), 3.78(2H,d,J=6.4Hz), 4.25(2H,q,J=7.1Hz), 6.53(1H,d,J=16.4Hz), 6.8-7.6(4H,m), 8.10(1H,d,J=16.1Hz) Reference Example 6 1.50 g of ethyl (E)-3-(2-isobutoxyphenyl)-2- propenoate was dissolved in 15 mL of ethanol, to which 0.30 g of 5% palladium-carbon was added, and this mixture was stirred for one hour at room temperature in a stream of hydrogen. After the reaction mixture was filtered through Celite, the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=9:l] to yield 0.76 g of ethyl 3- (2-isobutoxyphenyl) propanoate as colorless oil. NMR( 90MHz, CDCl3) δ value: 1.04(6H,d,J=6 .6Hz), 1.22(3H,t,J=7.1Hz), 1.9-2.3(1H,m), 2.5-2.7(2H,m),2.9- 3.1(2H,m), 3.73(2H,d,J=6.4Hz), 4.12(2H,q,J=6.8Hz), 6.7- 7.3(4H,m) Reference Example 7 12.8 g of ethyl 3-(2-isobutoxyphenyl)-2- propanoate was dissolved in 128 mL of methylene chloride, to which 11.2 mL of titanium tetrachloride and 5.1 mL of α,α-dichloromethyl methyl ether were successively added dropwise at 5 to 10°C, and this mixture was stirred for 30 minutes at room temperature. The reaction mixture was added to a mixture of methylene chloride and water, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=10:1] to yield 13.4 g of ethyl 3-(5-formyl-2-isobutoxyphenyl) propanoate as light yellow oil. NMR(90MHz, CDCl3) δ value: 1.07(6H,d,J=6.6Hz) , 1.23(3H,t,J=7.1Hz), 2.0-2.4(1H,m), 2.5-2.8(2H,m), 2.9- 3.1(2H,m), 3.84(2H,d,J=6.4Hz), 4.13(2H,q,J=7.1Hz), 6.93(1H,d,J=9.0Hz), 7.7-7.9(2H,m), 9.85(1H,s) Reference Example 8 13.9 g of ethyl 3-(5-formyl-2- isobutoxyphenyl) propanoate was dissolved in 139 mL of acetonitrile, to which 21.0 g of sodium dihydrogen phosphate dihydrate dissolved in 100 mL of water and 11.3 g of a 80% sodium chlorite dissolved in 39 mL of water and 11.3 mL of a 30% aq. hydrogen peroxide solution were successively added at 5 to 10°C, and this mixture was stirred for 4 hours at room temperature. Then, chloroform and water were added to the reaction mixture, and the organic phase was separated therefrom. After the resultant organic phase was washed with a 5% aqueous solution of sodium thiosulfate, water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 13.2 g of 4-isobutoxy-3-(3-ethoxy-3- oxopropyl) benzoic acid as light yellow solid. NMR( 90MHz, CDCl3) δ value: 1.07( 6H, d, J=6 . 6Hz) , 1.25(3H,t,J=7.3Hz), 2.0-2.4(1H,m), 2.5-2.8(2H,m), 2.9- 3.1(2H,m), 3.82(2H,d,J=6.1Hz), 4.14(2H,q,J=7.1Hz), 6.8 5 (1H,d,J=8.0Hz), 7.9-8.1(2H,m) Reference Example 9 50 g of 2,4-dihydroxybenzoic acid, 269 g of potassium carbonate, 123 mL of dimethyl sulfate, and 500 mL of N, N-dimethylformamide were suspended together, and this suspension was stirred for 6.5 hours at 70 to 80°C. Further, 90 g of potassium carbonate and 61 mL of dimethyl sulfate were added to this suspension, which was stirred for another 4 hours at 110 to 115°C. This reaction mixture was added to a mixture of ethyl acetate and water, and adjusted to pH 2 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=l:2] to yield 54 g of methyl 2,4-dimethoxybenzoate as yellow oil. NMR(90MHz,CDCl3) 6 value: 3.85(6H,s), 3.89(3H,s), 6.42- 6.55(2H,m), 7.85(1H,d,J=9.3Hz) Reference Example 10 53 g of methyl 2,4-dimethoxybenzoate was dissolved in 160 mL of ethanol, to which 104 mL of a 5M aqueous solution of sodium hydroxide was added, and this mixture was stirred for 2 hours at 25 to 40°C. Then, chloroform and water were added to the reaction mixture, which was adjusted to pH 2 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 45 g of 2,4-dimethoxybenzoic acid as white solid. NMR(90MHz,CDCl3) δ value: 3.88(3H,s), 4.04(3H,s), 6.53- 6.69(2H,m), 8 .11(1H,d,J=8.5Hz), 10.34(1H,br) Reference Example 11 78 g of a 28% solution of sodium methoxide in methanol was added to 150 mL of a solution of 50 g of 3,4-dihydrocoumarin in methanol at room temperature, and then this mixture was stirred for 10 minutes at the same temperature. Then, 96 mL of dimethyl sulfate and 78 g of a 28% solution of sodium methoxide in methanol were successively added to the mixture, which was stirred for another 30 minutes at 20 to 40°C. The reaction mixture was added to a mixture of methylene chloride and water, and adjusted to pH 2 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:1] to yield 61 g of methyl 3-(2-methoxyphenyl) propanoate as colorless oil. NMR (90MHz, CDCl3) δ value: 2.50-2.69(2H,m), 2.86- 3.04(2H,m), 3.66(3H,s), 3.82(3H,s), 6.79-6.94(2H,m), 7.11-7.30(2H,m) Reference Example 12 9.05 g of hydroxylamine hydrochloride was dissolved in 84 mL of methanol, to which 40.64 g of a 28% solution of sodium methoxide in methanol was added at room temperature, and then this mixture was stirred for 10 minutes. Then, 21 mL of a solution of 7.00 g of methyl 2-hydroxy-4-methylsalicylate in methanol was added dropwise to the reaction mixture, which was stirred for one hour at room temperature and then another four hours while heating it under reflux. The reaction mixture was added to water, and adjusted to pH 5 with 6M hydrochloric acid, and then resultant precipitate was filtered out thereof. The resultant solid was washed with water and diisopropyl ether successively to yield 5.95 g of N,2-dihydroxy-4- methylbenzamide as light yellow solid. NMR(4 00MHz,DMS0-d6) δ value: 2.26(3H,s), 6.68(1H,d,J=8.8Hz), 6.72(1H,s), 7.57(1H,d,J=8.4Hz), 9.27(1H,s), 11.38 (1H,brs), 12.29 (1H,brs) Reference Example 13 N,2-dihydroxy-5-methylbenzamide was obtained in a similar manner as in Reference Example 12. NMR(4 00MHz,DMSO-d6) δ value: 2.22(3H,s), 6.79(1H,d,J=8.4Hz), 7.20(1H,d,J=8.4Hz), 7.50(1H,s), 9.29(1H,brs), 11.33 (1H,brs), 11.95 (1H,brs) Reference Example 14 44.0 g of N,2-dihydroxy-4-methylbenzamide was suspended in 880 mL of tetrahydrofuran, to which 147 mL of triethylamine was added dropwise at room temperature and then 28.7 mL of thionyl chloride was added dropwise at 5 to 10°C successively, and this mixture was stirred for one hour at room temperature. The reaction mixture was added to water, and adjusted to pH 1 with 12M hydrochloric acid, and then resultant precipitate was filtered out thereof. The resultant solid was washed with water to yield 35.2 g of 6-methyl-1,2- benzisoxazol-3-ol as light yellow solid. NMR (400MHz, DMSO-d6) δ value: 2.45(3H,s), 7.14(1H,d,J=8.0Hz), 7.36(1H,s), 7.59(1H,d,J=8.4Hz), 12.24(1H,brs) Reference Example 15 5-methyl-1,2-benzisoxazol-3-ol was obtained in a similar manner as in Reference Example 14. NMR (400MHz, CDC13) δ value: 2.47(3H,s), 7.30(1H,d,J=8.8Hz), 7.42(1H,d,J=8.8Hz), 7.56(1H,s) Reference Example 16 20.0 g of methoxymethyl 6-methyl-1,2- benzisoxazol-3-yl ether was dissolved in 200 mL of benzene, to which 20.3 g of N-bromosuccinimide and 1.7 g of 2,2'-azobisisobutyronitrile were successively added at room temperature, and this mixture was stirred for 30 minutes while heating it under reflux. The reaction mixture was cooled to room temperature, and added to a mixture of ethyl acetate and water, and then the organic phase was separated therefrom. After the resultant organic phase was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 28.5 g of 6-(bromomethyl)-3- (methoxymethoxy)-1,2-benzisoxazole as light brown oil. NMR(400MHz,CDC13) δ value: 3.63(3H,s), 4.59(2H,s), 5.56(2H,s), 7.33(1H,dd,J=8.2,0.8Hz), 7.48(1H,s), 7.65(1H,d,J=8.0Hz) Reference Example 17 Compounds listed in Table 33 were obtained in a similar manner as in Reference Example 16. 17(1) yellow oil 17(2) yellow oil 17(3) NMR(400MHz,CDCl3) δ value: 1.49(18H,s), 4.50(2H,s), 7.56(2H,d,J=8.4Hz), 8.0 6(2H,d,J=8.4Hz) 17(4) NMR(400MHz,CDCl3) 6 value: 4.49(2H,s), 6 . 97-7 . 02 (2H,m) , 7.22-7.34(3H,m), 7.54(2H,d,J=8.4Hz), 7.80-7.86(2H,m) 17(5) NMR(4 00MHz, CDC13) δ value: 1.31-1.36(6H,m), 4.08- 4.16(4H,m), 4.49(2H,s), 7.48-7.51(2H,m), 7.77- 7.82(2H,m) 17(6) colorless oil 17(7) light yellow oil 17 (8) yellow oil NMR (400MHz, CDCl3) δ value: 3.89(3H,s), 3.93(3H,s), 4.47(2H,s), 6.99-7.01(2H,m), 7.77(1H,d,J=8.4Hz) 17(9) NMR(400MHz,CDCl3) δ value: 3.90(3H,s), 3.91(3H,s), 4.47(2H,s), 7.55(1H,dd,J=8.0,2.0Hz) 7.70(1H,d,J=8.0Hz), 7.73(1H,d,J=2.0Hz) 17(10) yellow oil 17(11) NMR (90MHz,CDCl3) δ value: 1. 36 ( 6H, d, J=6 . 3Hz) , 1.40(6H,d,J=5.9Hz), 4.54(2H,s), 4.5-5.0(1H,m), 5.0- 5.5(1H,m), 7.3-7.7(3H,m) 17(12) yellow oil 17(13) NMR(400MHz,CDCl3) δ value: 1.47(9H,s), 3.43(3H,s), 4.48(2H,s), 7.21(2H,d,J=8.4Hz), 7.44(2H,d,J=8.4Hz) 17(14) yellow oil 17(15) yellow oil 17(16) NMR(400MHz,CDCl3) δ value: 3.93(3H,s), 4.61(2H,s), 7.53 (1H,d,J=8.0Hz), 7.96(1H,dd,J=8.0,1.6Hz), 8.25 (1H,d,J=1.6Hz) 17 (17) NMR(400MHz,CDCl3) 5 value: 3.53(3H,s), 3.91(3H,s), 4.56(2H,s), 5.33(2H,s), 7.40(1H,d,J=8.0Hz), 7.66(1H,d,J=8.0Hz), 7.74(1H,s) Reference Example 18 The following compounds were obtained in a similar manner as in Reference Example 16. (1) 2-(chloromethyl)pyrazine NMR(400MHz,CDCl3) δ value: 4.71(2H,s), 8 . 55-8 . 58 (2H,m) , 8.77(1H,d,J=1.2Hz) (2) 5-[4-(bromomethyl)phenyl]-3-isoxazole methoxymethyl ether NMR (400MHz, CDC13) δ value: 3.58(3H,s), 4.51(2H,s), 5.37(2H,s), 6.25(1H,s), 7.48(2H,d,J=8.8Hz), 7.71 (2H,d,J=8.8Hz) (3) 3-[4-(bromomethyl)phenyl]-5-methyl- 1,2,4-oxadiazole NMR (4 00MHz, CDC13) δ value: 2.66(3H,s), 4.52(2H,s), 7.51(2H,d,J=8.4Hz), 8.04(2H,d,J=8.4Hz) (4) 5-(bromomethyl)-1,3-bis(methoxymethyl)- 1,3-dihydro-2H-benzimidazol-2-one light yellow solid (5) 6-(bromomethyl)-1,2-benzisoxazol-3-yl methyl ether NMR (400MHz, CDC13) δ value: 4.19(3H,s), 4.58(2H,s), 7.31(1H,dd,J=8.4,1.2Hz), 7.4 5(1H,d,J=0.8Hz), 7.60(1H,d,J=8.0Hz) (6) 6-(bromomethyl)-2-methyl-l,2- benzisoxazol-3(2H)-one NMR(400MHz,CDCl3) δ value: 3.67(3H,s), 4.54(2H,s), 7.26- 7.31(2H,m), 7.80(1H,d,J=8.0Hz) (7) 6-(bromomethyl)-2-(methoxymethoxy)-1,2- benzisoxazol-3(2H)-one NMR (400MHz, CDCl3) δ value: 3.50(3H,s), 4.54(2H,s), 5.33(2H,s), 7.30-7.33(2H,m), 7.83(1H,d,J=8.0Hz) (8) 5-(bromomethyl)-3-(methoxymethoxy)-1,2- benzisoxazole NMR (400MHz, CDCl3) δ value: 3.64(3H,s), 4.61(2H,s), 5.55(2H,s), 7.44(1H,d,J=8.8Hz), 7.59(1H,dd,J=8.8, 2.0Hz) , 7.70(1H,d,J=2.0Hz) (9) tert-butyl 4-(bromomethyl)-lH-pyrazole- 1-carboxylate NMR(400MHz,CDCl3) δ value: 1.65(9H,s), 4.39(2H,s), 7.74(1H,s), 8.10(1H,s) (10) ethyl 2-(bromomethyl)-1,3-thiazole-4- carboxylate NMR(90MHz,CDCl3) δ value: 1.41(3H,t,J=7.1Hz) , 4.44(2H,q,J=7.1Hz), 4.77(2H,s), 8.23(1H,s) (11) ethyl 5-(chloromethyl)-2- pyrazinecarboxylate NMR(400MHz,CDCl3) δ value: 1.47(3H,t,J=7.2Hz) , 4.53(2H,q,J=7.2Hz), 4.77(2H,s), 8.88(1H,d,J=l.5Hz), 9.26(1H,d,J=1.5Hz) (12) tert-butyl 5-(bromomethyl)-1,3-dioxo- 1,3-dihydro-2H-isoindole-2-carboxylate NMR( 4 00MHz, CDC13) δ value: 1.63(9H,s), 4.57(2H,s), 7.81(1H,dd,J=7.6,1.6Hz), 7.91-7.95(2H,m) (13) di(tert-butyl) 6-(bromomethyl)-2,4- dioxo-1,3(2H,4H)-quinazolinedicarboxylate NMR(400MHz,CDCl3) δ value: 1.65(9H,s), 1.73(9H,s), 4.51(2H,s), 7.00(1H,d,J=8.4Hz), 7.59(1H,dd,J=8.6,2.4Hz), 8.07(1H,d,J=2.0Hz) (14) 3-[4-(bromomethyl)phenyl]-4-methyl- 1,2,4-oxadiazol-5(4H)-one NMR(400MHz,CDCl3) δ value: 3.34(3H,s), 4.53(2H,s), 7.59(2H,d,J=8.8Hz), 7.61(2H,d,J=8.8Hz) Reference Example 19 3.50 g of methyl 1H-benzimidazole-5- carboxylate hydrochloride and 6.9 mL of triethylamine were suspended in 35 mL of methylene chloride, to which 5.05 g of trityl chloride was added in small portions at 5 to 10°C, and this mixture was stirred for one hour at the same temperature. The reaction mixture was added to a mixture of ethyl acetate and water, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=3:l] to yield 3.55 g of a mixture of methyl 1- trityl-lH-benzimidazole-5-carboxylate and methyl 3- trityl-3H-benzimidazole-5-carboxylate as white foam. methyl 1-trityl-1H-benzimidazole-5- carboxylate NMR(400MHz,CDCl3) δ value: 3.90(3H,s), 6.49(1H,d,J=8.8Hz), 7.15-7.19(6H,m), 7.31-7.34(9H,m), 7.61(1H,d,J=8.4Hz), 7.97(1H,s), 8.49(1H,s) methyl 3-trityl-3H-benzimidazole-5- carboxylate NMR(4 00MHz,CDC13) δ value: 3.75(3H,s), 7.15-7.19(7H,m), 7.31-7.34(9H,m), 7.77(1H,d,J=8.4Hz), 7.87(1H,d,J=8.4Hz), 8.02(1H,s) Reference Example 20 The following compounds were obtained in a similar manner as in Reference Example 5. (1) benzyl 4-[ (E)-3-ethoxy-3-oxo-1- propenyl]-3-methoxybenzoate NMR(400MHz,CDCl3) δ value: 1.34(3H,t,J=7.1Hz), 3.94(3H,s), 4.27(2H,q,J=7.1Hz), 5.38(2H,s), 6.5 9(1H,d,J=l6.0Hz), 7.33-7.46(5H,m), 7.54(1H,d,J=8.0Hz), 7.60(1H,d,J=l.5Hz), 7.66(1H,dd,J=8.0,1.5Hz), 7.97(1H,d,J=16.0Hz) (2) ethyl (E)-3-(4-formylphenyl)-2- propenoate NMR(400MHz,CDCl3) δ value: 1.35(3H,t,J=7.2Hz), 4.2 9 (2H,q,J=7.2Hz) , 6.55(1H,d,J=16.0Hz), 7.68 (2H,d,J=8.4Hz), 7.71(1H,d,J=16.0Hz), 7.90(2H,d,J=8.4Hz), 10.03(1H,s) Reference Example 21 The following compounds were obtained in a similar manner as in Reference Example 6. (1) 2-[4-(methoxycarbonyl)phenyl]acetic acid NMR(90MHz,CDCl3) δ value: 3.71(2H,s), 3.91(3H,s), 7.36(2H,d,J=8.1Hz), 8.01(2H,d,J=8.4Hz) (2) ethyl 3-(4-formylphenyl)propanoate light yellow oil NMR (4 00MHz, CDC13) δ value:1.23(3H,t,J=7.2Hz), 2.66(2H,t,J=7.8Hz), 3.04(2H,t,J=7.6Hz), 4.13(2H,q,J=7.2Hz), 7.38(2H,d,J=7.8Hz), 7.81(2H,d,J=8.0Hz), 9.98(1H,s) (3) 3-cyclopentylphenol NMR(400MHz,CDCl3) δ value: 1.54-1.81(6H,m), 2.01- 2.08(2H,m), 2.89-2.99(1H,m), 4.64(1H,brs), 6.62- 6.65(1H,m), 6.72(1H,t,J=2.0Hz), 6.82(1H,d,J=7.6Hz), 7.15 (1H,t,J=7.6Hz) (4) 3-(cyclopentylmethyl)phenol NMR(400MHz,CDCl3) δ value: 1. 15-1. 20 (2H,m) , 1.49- 1.73(6H,m), 2.03-2.11(1H,m), 2.56(2H,d,J=7.2Hz), 4.59(1H,s), 6.63-6.66(2H,m), 6.74-6.76(1H,m), 7.11- 7.15(1H,m) (5) 4- (3-ethoxy-3-oxopropyl)-3- methoxybenzoic acid NMR(4 00MHz,CDC13) 6 value: 1.24 (3H,t,J=7.1Hz), 2.62 (2H,t,J=7.6Hz), 2.99(2H,t,J=7.6Hz), 3.90(3H,s), 4.14(2H,q,J=7.lHz) , 7.2 5(1H,d,J=7.8Hz), 7.55(1H,d,J=1.5Hz), 7 . 66 (1H,dd,J=7.8,1.5Hz) Reference Example 22 The following compounds were obtained in a similar manner as in Reference Example 7. (1) methyl 3-formyl-1-benzothiophene-7- carboxylate NMR(400MHz,CDCl3) δ value: 4.05(3H,s), 7.62(1H,dd,J=8.0,7.6Hz), 8.22(1H,dd,J=7.6,1.2Hz), 8.46(1H,s), 8.95(1H,dd,J=8.0,1.2Hz) , 10.18(1H,s) (2) methyl 3-formyl-1-benzothiophene-5- carboxylate NMR(400MHz,CDCl3) δ value: 3.99(3H,s), 7.95(1H,dd,J=8.6,0.8Hz), 8.15(1H,dd,J=8.6,2.0Hz), 8.40(1H,s), 9.33(1H,dd,J=2.0,0.8Hz), 10.19(1H,s) (3) methyl 2-(4-formylphenyl)acetate NMR(90MHz,CDCl3) δ value: 3.6-3.8(2H,m), 3.72(3H,s), 7.46(2H,d,J=8.4Hz), 7.86(2H,d,J=8.0Hz), 10.01(1H,s) (4) methyl 3-(5-formyl-2- methoxyphenyl)propanoate NMR(400MHz,CDCl3) δ value: 2.63(2H,t,J=7.6Hz), 2.99 (2H,t,J=7.6Hz), 3.68(3H,s), 3.92(3H,s), 6.96(1H,d,J=8.6Hz), 7.7 0(1H,d,J=2.0Hz), 7.75(1H,dd,J=8.6,2.0Hz), 9.86(1H,s) Reference Example 23 The following compounds were obtained in a similar manner as in Reference Example 8. (1) 4-(cyclopentylmethyl)-2-methoxybenzoic acid NMR (400MHz, CDCl3) δ value: 1. 17-1. 27 (2H,m) , 1.52- 1.74(6H,m), 2.06-2.14(1H,m), 2.67(2H,d,J=7.6Hz), 4.07(3H,s), 6.85(1H,s), 6.96(1H,d,J=8.4Hz), 8.08(1H,d,J=8.0Hz), 10.68(1H,brs) (2) 4-isopropyl-2-methoxybenzoic acid NMR(4 00MHz,CDCl3) δ value: 1.28(6H,d,J=7.2Hz), 2.93- 3.00(1H,m), 4.08(3H,s), 6.89(1H,d,J=l.6Hz) , 7.02(1H,dd,J=8.2,2.0Hz), 8.10(1H,d,J=8.0Hz), 10.72 (1H,brs) (3) 4-cyclopentyl-2-methoxybenzoic acid NMR(400MHz,CDCl3) δ value: 1.56-1.87(6H,m), 2.07- 2.14(2H,m), 3.01-3.09(1H,m), 4.08(3H,s), 6.90(1H,d,J=1.2Hz), 7.02(1H,dd,J=8.2,1.6Hz), 8.09(1H,d,J=8.0Hz), 10.68(1H,brs) Reference Example 24 0.770 g of 4-cyclopentyl-2- hydroxybenzaldehyde, 0.38 mL of iodomethane, and 0.839 g of potassium carbonate were suspended in 7.7 mL of N,N-dimethylformamide, and this mixture was stirred for 2 hours at 75°C. The reaction mixture, which was cooled to room temperature, was added to a mixture of ethyl acetate and water, and then adjusted to pH 3 with 6M hydrochloric acid, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 0.777 g of 4-cyclopentyl-2-methoxybenzaldehyde as yellow oil. NMR(400MHz,CDCl3) δ value: 1. 58-1. 87 ( 6H,m) , 2.05- 2.13(2H,m), 2.99-3.07(1H,m), 3.93(3H,s), 6.84(1H,d,J=1.2Hz), 6.91(1H,dd,J=8.6,1.2Hz), 7.75 (1H,d,J=8.0Hz) , 10.40(1H,s) Reference Example 25 The following compounds were obtained in a similar manner as in Reference Example 24. (1) 1-(benzyloxy)-3-bromobenzene NMR (4 00MHz, CDC13) δ value: 5.04(2H,s), 6 . 89-6 . 91 (1H,m) , 7.08-7.16(3H,m), 7.31-7.43(5H,m) (2) 4-isopropyl-2-methoxybenzaldehyde NMR(400MHz, CDCl3) δ value: 1.28(6H,d,J=7.2Hz), 2.91- 2.98(1H,m), 3.93(3H,s), 6.82(1H,s), 6.90(1H,d,J=8.0Hz), 7.76(1H,d,J=8.0Hz), 10.40(1H,s) (3) 4-(cyclopentylmethyl)-2- methoxybenzaldehyde NMR(400MHz,CDCl3) δ value: 1.17-1.24(2H,m), 1.53- 1.74(6H,m), 2.07-2.14(1H,m), 2.65(2H,d,J=7.2Hz), 3.92(3H,s), 6.78(1H,s), 6.85(1H,d,J=7.6Hz), 7.74 (1H,d,J=8.0Hz) , 10.41(1H,s) (4) 3-(benzyloxy)benzaldehyde NMR(400MHz,CDCl3) δ value: 5.13(2H,s), 7 . 23-7 . 49 ( 9H,m) , 9.98(1H,s) (5) 4-methyl-3-(4-methylphenyl)-1,2,4- oxadiazol-5(4H)-one NMR(4 00MHz,CDC13) δ value: 2.46(3H,s), 3.32(3H,s), 7.37(2H,d,J=8.4Hz), 7.50(2H,d,J=8.4Hz) (6) 3-methoxy-6-methyl-l,2-benzisoxazole NMR(400MHz,CDCl3) δ value: 2.48(3H,s), 4.11(3H,s), 7.07(1H,dd,J=8.2,0.4Hz), 7.22(1H,d,J=0.4Hz), 7.48(1H,d,J=8.0Hz) (7) 2,6-dimethyl-1,2-benzisoxazol-3(2H)-one NMR (400MHz, CDCl3) δ value: 2.47(3H,s), 3.68(3H,s), 7.00(1H,s), 7.07(1H,d,J=8.0Hz), 7.68(1H,d,J=8.4Hz) Reference Example 26 Compounds listed in Table 34 were obtained in a similar manner as in Reference Example 9. 26(1) NMR(400MHz,CDCl3) 8 value: 2.39(3H,s), 3.91(3H,s), 6.94(1H,d,J=11.7Hz), 6 . 99(1H,d,J=7.8Hz), 7.83(1H,t,J=7.8Hz) 26(2) NMR(400MHz,CDCl3) δ value: 2.38(3H,s), 3.87(3H,s), 3.90(3H,s), 6.78(1H,s), 6.79(1H,d,J=8.4Hz), 7.72(1H,d,J=8.4Hz) 26(3) NMR(4 00MHz,CDC13) δ value: 1.00(6H,d,J=6.8Hz), 1.05(6H,d,J=6.8Hz) , 2.0 6(1H,sep,J=6.6Hz), 2.14(1H,sep,J=6.6Hz), 2.36(3H,s), 3.77(2H,d,J=6.6Hz) , 4.06(2H,d,J=6.8Hz), 6.75(1H,s), 6.76(1H, d, J=8.0Hz) , 7.71(1H,d,J=8.0Hz) 26(4) NMR(400MHz,CDCl3) 8 value: 2.34(3H,s), 3.93(3H,s), 6.69(1H,dd,J=8.2,1.0Hz), 6.79(1H,s), 7.71(1H,d,J=8.0Hz), 10.70(1H,s) 26(5) NMR(400MHz,CDCl3) 8 value: 2.35(3H,s), 3.80(6H,s), 3.89(3H,s), 6.37(2H,s) 26(6) NMR(400MHz,CDCl3) 8 value: 2.30(3H,s), 3.91(3H,s), 5.67(1H,s), 7.18(1H,d,J=8.0Hz), 7 . 51(1H,dd,J=7.6,2.0Hz), 7.56(1H,s) 26(7) NMR(400MHz,CDCl3) 8 value: 2.44(3H,s), 3.90(3H,s), 7.2 9(1H,d,J=7.6Hz), 7.86(1H,dd,J=7.6,2.0Hz), 8.19 (1H,d,J=2.0Hz) 26(8) NMR(400MHz,CDCl3) 8 value: 3.99(3H,s), 5.39(2H,s), 7.34- 7.47(5H,m), 7.69(1H,d,J=l.2Hz), 7.71(1H,d,J=8.0Hz) , 7.87 (1H,d,J=8.0Hz), 10.51(1H,s) 26(9) NMR(4 00MHz,CDCl3) δ value: 2 . 33 (3H, d, J=l. 7Hz) , 3.91(3H,s), 7.25(1H,t,J=8.0Hz), 7.65(1H,dd,J=10.0,1.6Hz), 7.72(1H,dd,J=8.0,1.6Hz), 26(10) NMR( 90MHz, CDC13) δ value: 1. 36 (12H, d, J=6. 4Hz) , 2.24(3H,s), 4.4-4.9(1H,m), 5.0-5.5(1H,m), 7.16(1H,d,J=8.1Hz), 7.5-7.6(2H,m) 26(11) NMR(400MHz,CDCl3) δ value: 2.28(3H,s), 3.94(3H,s), 6.89(1H,d,J=8.8Hz), 7.26(1H,d,J=8.8Hz), 7.63(1H,s), 10.56(1H,s) 26(12) NMR(400MHz,CDCl3) δ value: 2.44(3H,s), 3.91(3H,s), 7.60(1H,d,J=8.4Hz), 7.7 0(1H, dd,J=8.2,2.4Hz), 7.90(1H,d,J=2.4Hz) 26(13) NMR(90MHz,CDC13) δ value: 3.97(3H,s), 7.63(1H,t,J=7.8Hz), 8.10(1H,dt, J=8.1, 1.4Hz) , 8.31(1H,dt,J=7.2,1.4Hz), 8.54(1H,t,J=1.4Hz), 10.09(1H,s) 26(14) NMR(400MHz,CDCl3) δ value: 3.99(3H,s), 5.39(2H,s), 7.34- 7.47(5H,m), 7.69(1H,d,J=l.2Hz), 7.71(1H,d,J=8.0Hz), 7.87(1H,d,J=8.0Hz), 10.51(1H,s) Reference Example 27 The following compounds were obtained in a similar manner as in Reference Example 9. (1) methyl 5-formyl-2-thiophenecarboxylate NMR(90MHz,CDC13) δ value: 3.94(3H,s), 7.74(1H,d,J=3.9Hz), 7.85(1H,d,J=3.9Hz), 9.98(1H,s) (2) diethyl 2,5-pyridinedicarboxylate NMR(90MHz,CDC13) δ value: 1.43(3H,t,J=7.1Hz), 1.4 7(3H,t,J=7.lHz) , 4.4 6(2H,q,J=7.1Hz) , 4.52(2H,q,J=7.1Hz), 8.20(1H,d,J=8.4Hz) , 8.45(1H,dd,J=8.2,2.0Hz), 9.33(1H,d,J=2.0Hz) Reference Example 28 5.66 g of cyclopentyltriphenylphosphonim bromide was suspended in 25 mL of diethyl ether, to which 8.8 mL of a solution of n~butyllithium in n- hexane (1.56 M) was added dropwise at -30°C. After the reaction mixture was stirred for one hour at 5°C, 2.67 g of 3-(benzyloxy)benzaldehyde dissolved in 5 mL of diethyl ether was added to the reaction mixture, which was then stirred another one hour at room temperature. The reaction mixture was added to a mixture of methylene chloride and dilute hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=5:l] to yield 1.06 g of 1-(benzyloxy)-3- (cyclopentylidenemethyl)benzene as light yellow solid. NMR (400MHz, CDC13) δ value: 1.62-1.69(2H,m), 1.73- 1.78(2H,m), 2.46-2.53(4H,m), S.07(2H,s), 6.32(1H,d,J=2.4Hz), 6.79(1H,d,J=8.0Hz), 6.90-6.94(2H,m), 7.20-7.45(6H,m) Reference Example 29 9.10 g of (4-bromo-3-methylphenyl)methanol was dissolved in 91 mL of methylene chloride and cooled to 5°C, to which 19.7 mL of N-ethyldiisopropylamine and 6.9 mL of chloromethyl methyl ether were successively added dropwise at 5 to 10°C, and then this mixture was stirred for 2.5 hours at room temperature. Water was added to the reaction mixture and adjusted to pH 7 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=5:l] to yield 10.44 g of 1-bromo- 4-[(methoxymethoxy)methyl]-2-methylbenzene as yellow oil. NMR (400MHz, CDC13) δ value: 2.40(3H,s), 3.41(3H,s), 4.52(2H,s), 4.71(2H,s), 7.04(1H,dd,J=8.2,2.0Hz), 7.23(1H,d,J=1.6Hz), 7.50(1H,d,J=8.0Hz) Reference Example 30 The following compounds were obtained in a similar manner as in Reference Example 29. (1) 1,3-bis(methoxymethyl)-5-methyl-l,3- dihydro-2H-benzimidazol-2-one NMR(400MHz,CDCl3) δ value: 2.41(3H,s), 3.36(3H,s), 3.37(3H,s), 5.33(2H,s), 5.34(2H,s), 6.94(1H,d,J=7.2Hz), 6.96(1H,d,J=0.8Hz), 7.05(1H,d,J=8.0Hz) (2) methoxymethyl 6-methyl-l,2-benzisoxazol- 3-yl ether NMR(400MHz,CDCl3) δ value: 2.50(3H,s), 3.63(3H,s), 5.54(2H,s), 7.11(1H,dd,J=8.0,0.8Hz), 7.25(1H,s), 7.54(1H,d,J=8.0Hz) (3) methoxymethyl 5-methyl-l,2-benzisoxazol- 3-yl ether NMR(400MHz,CDCl3) δ value: 2.46(3H,s), 3.63(3H,s), 5.54(2H,s), 7.33(1H,d,J=8.8Hz), 7.36(1H,d,J=8.8Hz) , 7.45 (1H,s) (4) 2-(methoxymethyl)-6-methyl-l, 2- benzisoxazol-3(2H)-one NMR(400MHz,CDCl3) δ value: 2.49(3H,s), 3.44(3H,s), 5.31(2H,s), 7.05(1H,d,J=0.8Hz), 7.10(1H,dd,J=8.0,0.8Hz), 7.72(1H,d,J=8.0Hz) (5) (l-benzothiophen-5-ylmethoxy)methyl methyl ether NMR (4 00MHz,CDCl3) 6 value: 3.42(3H,s), 4.71(2H,s), 4.73(2H,s), 7.31-7.36(2H,m), 7.44(1H,d,J=5.4Hz), 7.81(1H,s), 7.86(1H,d,J=8.3Hz) (6) methyl 3-(methoxymethoxy)-4- methylbenzoate NMR(400MHz,CDCl3) 6 value: 2.30(3H,s), 3.50(3H,s), 3.89(3H,s), 5.25(2H,s), 7.20(1H,d,J=8.0Hz), 7.61(1H,dd,J=8.0,1.6Hz), 7.68(1H,d,J=l.6Hz), (7) 3-(methoxymethoxy)-5-(4- methylphenyl)isoxazole NMR(400MHz,CDCl3) δ value: 2.38(3H,s), 3.57(3H,s), 5.35(2H,s), 6.17(1H,s), 7.23(2H,d,J=8.0Hz), 7.61(2H,d,J=8.0Hz) Reference Example 31 4.00 g of 1-bromo-4-[(methoxymethoxy)methyl]- 2-methylbenzene was dissolved in 40 mL of tetrahydrofuran, to which 11.5 mL of a solution of n- butyllithium in n-hexane (1.56 M) was added dropwise at -65 to -60°C, and then this mixture was stirred for 30 minutes at -65°C. Then, 20 mL of N,N-dimethylformamide was added dropwise thereto at -65 to -40°C, and a temperature of this reaction mixture was raised to room temperature over one hour and was stirred for another one hour at room temperature. Water was added to the reaction mixture and adjusted to pH 5 with 6M hydrochloric acid, followed by addition thereto of ethyl acetate, and then the organic phase was separated therefrom. After the resultant organic phase was washed with.water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=5:l] to yield 1.54 g of 4-[(methoxymethoxy)methyl]-2- methylbenzaldehyde as colorless oil. NMR (4 00MHz, CDC13) δ value: 2.68(3H,s), 3.43(3H,s), 4.63(2H,s), 4.76(2H,s), 7.26(1H,s), 7.35(1H,d,J=7.6Hz), 7.79(1H,d,J=7.6Hz), 10.26(1H,s) Reference Example 32 The following compounds were obtained in a similar manner as in Reference Example 31. (1) diethyl 4-methylphenylphosphonate NMR(400MHz,CDC13) 6 value: 1.30-1.36(6H,m), 2.40(3H,s), 4.07-4.16(4H,m), 7.26-7.29(2H,m), 7.68-7.73(2H,m) (2) 2-(hydroxymethyl)-1-benzothiophene-5- carboaldehyde NMR(400MHz,CDCl3) δ value: 2.12(1H,brs), 4.98(2H,s), 7.34(1H,s), 7.83(1H,dd,J=8.4,1.6Hz), 7.94(1H,d,J=8.0Hz), 8.20(1H,d,J=1.2Hz), 10.08(1H,s) (3) ethyl 5-(hydroxymethyl)-1- benzothiophene-2-carboxylate NMR(400MHz,CDCl3) δ value: 1.42(3H,t,J=7.1Hz), 1.80(1H,brs), 4.41(2H,q,J=7.1Hz), 4.82(2H,d,J=5.1Hz), 7.46(1H,dd, J=8.6,1.6Hz) , 7.83-7.86(2H,m), 8.03(1H,s) (4) 2-fluoro-4-methylbenzoic acid NMR (400MHz, CDCl3) δ value: 2.42(3H,s), 6.98(1H,d,J=12.0Hz), 7.04(1H,d,J=7.8Hz), 7.92(1H,t,J=7.8Hz) Reference Example 33 2.90 g of 3-cyclopentylphenol was dissolved in 14.5 mL of toluene, to which 0.21 mL of tin tetrachloride and 1.7 mL of tri-n-butylamine were added at room temperature in a stream of nitrogen, and then this mixture was stirred for 30 minutes at room temperature followed by addition thereto of 1.18 g of paraformaldehyde, and this mixture was stirred for 1.5 hours at 80°C. Then, the reaction mixture was cooled to room temperature and poured into water, to which methylene chloride was added, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=10:1] to yield 0.77 g of 4-cyclopentyl-2-hydroxybenzaldehyde as yellow oil. NMR(4 00MHz,CDCl3) δ value: 1.57-1.84(6H,m), 2.04- 2.11(2H,m), 2.97-3.05(1H,m), 6.86(1H,s), 6.90 (1H,dd,J=7.8,1.6Hz) , 7.45(1H,d,J=8.0Hz), 9.83(1H,s), 11.04(1H,s) Reference Example 34 The following compounds were obtained in a similar manner as in Reference Example 33. (1) 2-hydroxy-4-isopropylbenzaldehyde NMR(90MHz,CDCl3) δ value: 1.26(6H,d,J=6.8Hz), 2.79- 3.06(1H,m), 6.85-6.94(2H,m), 7.47(1H,d,J=8.5Hz), 9.84(1H,s), 11.03(1H,s) (2) 4-(cyclopentylmethyl)-2- hydroxybenzaldehyde NMR(400MHz,CDCl3) 6 value: 1.16-1.21(2H,m), 1.52- 1.73(6H,m), 2.06-2.14(1H,m), 2.62(2H,d,J=7.6Hz), 6.80(1H,s), 6.83(1H,dd,J=8.0,1.6Hz), 7.44(1H,d,J=8.0Hz), 9.83(1H,s), 11.04(1H,s) Reference Example 35 1.61 mL of cyclopentanecarboxylic acid was dissolved in 5 mL of tetrahydrofuran, and this mixture was added dropwise to 50 mL of solution of lithium diisopropylamide in tetrahydrofuran prepared from 20.9 mL of n-butyllithium in n-hexane (1.56 M) and 4.58 mL of diisopropylamine at -30°C, and then this mixture was stirred for one hour at 5°C and for another one hour at room temperature. After the reaction mixture was cooled to -30°C, a solution of 5.00 g of methyl 4- (bromomethyl)-2-methoxybenzoate in 5 mL of tetrahydrofuran was added dropwise to this mixture, which was then stirred for 1.5 hours at -10°C and for another 1.5 hours at room temperature. A saturated aqueous solution of ammonium chloride and diethyl ether were successively added to the reaction mixture, and the organic phase was separated therefrom. A saturated aqueous solution of sodium hydrogen carbonate was added to the resultant organic phase, from which an aqueous phase was separated, followed by adjustment to pH 2 with 6M hydrochloric acid, and then the organic layer was separated therefrom by adding chloroform thereto. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=3:2] to yield 0.718 g of l-[3- methoxy-4-(methoxycarbonyl)benzyl]- cyclopentanecarboxylic acid as colorless oil. NMR(400MHz,CDCl3) δ value: 1.62-1.72(6H,m), 2.05- 2.12(2H,m), 3.00(2H,s), 3.84(3H,s), 3.87(3H,s), 6.78- 6.80(3H,m), 7.71(1H,d,J=8.0Hz) Reference Example 36 1.50 g of 1-[3-methoxy-4-(methoxycarbonyl) - benzyl]cyclopentanecarboxylic acid was dissolved in 15 mL of tetrahydrofuran, to which 10.3 mL of a 1M solution of borane in tetrahydrofuran was added dropwise at 5 to 10°C, and then this mixture was stirred for one hour at room temperature. Then, acetone and water were successively added dropwise to the reaction mixture, which was added to a mixture of ethyl acetate and water, and the organic phase was separated therefrom. After the resultant organic phase was washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=l:l] to yield 0.564 g of methyl 4-{[1-(hydroxymethyl) cyclopentyl]methyl}-2-methoxybenzoate as colorless oil. NMR(400MHz,CDCl3) 6 value: 1. 38-1. 66 ( 9H, m) , 2.74(2H,s), 3.32(2H,s), 3.88(3H,s), 3.90(3H,s), 6.83-6.86(2H,m), 7.72(1H,d,J=8.4Hz) Reference Example 37 1.16 g of methyl 4-{[1-(hydroxymethyl) cyclopentyl]methyl}-2-methoxybenzoate and 0.764 g of 4- (dimethylamino)pyridine were dissolved in 10 mL of methylene chloride, to which a solution of 0.953 g of para-toluenesulfonyl chloride in 10 mL of methylene chloride was added dropwise at 0°C, and then this mixture was stirred for one hour at room temperature. Further, 1.53 g of 4-(dimethylamino)pyridine and a solution of 1.91 g of para-toluenesulfonyl chloride in 15 mL of methylene chloride was added thereto, and this mixture was stirred for another one hour at room temperature. The reaction mixture was added to water, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=2:l] to yield 1.58 g of methyl 2-methoxy-4- {[1-({[(4-methylphenyl)sulfonyl]oxy}methyl)- cyclopentyl]methyl} benzoate as colorless oil. NMR(400MHz,CDCl3) δ value: 1.33-1.36(2H,m), 1.47- 1.53(4H,m), 1.59-1.63(2H,m), 2.46(3H,s), 2.71(2H,s), 3.66(2H,s), 3.88(6H,s), 6.64(1H,dd,J=8.0,1.6Hz), 6.80(1H,d,J=1.6Hz), 7.35(2H,d,J=8.0Hz), 7.61(1H,d,J=8.0Hz), 7.7 7-7.80(2H,m) Reference Example 38 Phenyl 4-methylbenzenesulfonate was obtained in a similar manner as in Reference Example 37. NMR(400MHz,CDCl3) δ value: 2.45(3H,s), 6.96-6.99(2H,m), 7.22-7.32(5H,m), 7.7 0(2H,d,J=8.8Hz) Reference Example 39 1.58 g of methyl 2-methoxy-4-{[1-({[(4- methylphenyl)sulfonyl]oxy}methyl)cyclopentyl]methyl} benzoate, 0.716 g of zinc dust, and 1.64 g of sodium iodide were suspended in 16 mL of N,N-dimethylformamide, and this mixture was stirred for 2.5 hours at 115°C. The reaction mixture was cooled to room temperature, to which diethyl ether was added, and filtered through Celite. The filtrate was added to a mixture of ethyl acetate and dilute hydrochloric acid, and the organic phase was separated therefrom. After the resultant organic phase was washed with an aqueous solution of sodium thiosulfate, water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=2:l] to yield 0.725 g of methyl 2-methoxy-4-[(1- methylcyclopentyl)methyl] benzoate as colorless oil. NMR(4 00MHz,CDC13) δ value: 0.90(3H,s), 1.30-1.34(2H,m), 1.49-1.55(2H,m), 1.65-1.68(4H,m), 2.62(2H,s), 3.88(3H,s), 3.90(3H,s), 6 . 75-6.79(2H,m), 7.71 (1H,d,J=8.0Hz) Reference Example 40 8.75 g of copper (II) bromide was suspended in 40 mL of acetonitrile, to which a solution of 5.82 mL of tert-butyl nitrite in 5 mL of acetonitrile was added dropwise at room temperature in a stream of nitrogen and then a suspension of 5.00 g of 4-amino-2- hydroxybenzoic acid in 100 mL of acetonitrile was added dropwise in an ice bath, and this suspension was stirred for 2 hours at 5 to 10°C. The reaction mixture was added dropwise to a mixture of ice and 6M hydrochloric acid, to which diethyl ether was added, and the organic phase was separated therefrom. After the resultant organic phase was washed with 6M hydrochloric acid, water, and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 7.84 g of 4-bromo-2-hydroxybenzoic acid as black solid. NMR(4 00MHz,DMSO-d6) δ value: 7.13 (1H,dd,J=8.4,2.0Hz), 7.22 (1H,d,J=2.0Hz), 7.71(1H,d,J=8.4Hz), 10.5- 10.7(1H,br), ll.l-11.5(1H,br) Reference Example 41 1.85 g of magnesium was suspended in 15 mL of diethyl ether, to which a catalytic amount of iodine was added and then a solution of 20.00 g of 1- (benzyloxy)-3-bromobenzene in 40 mL of diethyl ether was added dropwise and this mixture was stirred for 8 hours while heating it under reflux. The reaction mixture was cooled to 5°C, to which a solution of 6.72 mL of cyclopentanone in 20 mL of diethyl ether was added dropwise, and this mixture was stirred for one hour at room temperature. Then an aqueous solution of ammonia chloride was added to the ice-cooled reaction mixture, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=10:1] to yield 7.65 g of l-[3- (benzyloxy)phenyl] cyclopentanol as yellow oil. NMR( 4 00MHz, CDCl3) δ value: 1.52(1H,s), 1. 79-1. 88 (2H, m) , 1.93-2.04(6H,m), 5.08(2H,s), 6.8 5(1H,ddd,J=8.4,2.8,1.2Hz), 7.08(1H,ddd,J=7.6,1.6,0.8Hz), 7.16-7.17(1H,m), 7.24- 7.46(6H,m) Reference Example 42 10.55 g of methyl 4-bromo-3-methylbenzoate was dissolved in 110 mL of tetrahydrofuran, to which 1.31 g of lithium aluminium hydride was added dropwise in small portions at -30 to -20°C, and this mixture was stirred for 15 minutes at -20°C. Then a mixed solution of methanol and water (4:1) was added dropwise to the reaction mixture, and this mixture was stirred for 30 minutes at room temperature. The reaction mixture, to which water was added, was adjusted to pH 7 with 6M hydrochloric acid followed by addition of ethyl acetate, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 9.20 g of (4-bromo-3- methylphenyl)methanol as brown oil. NMR(4 00MHz,CDCl3) δ value: 1.74(1H,brs), 2.40(3H,s), 4.62(2H,s), 7.04(1H,dd,J=8.2,2.0Hz), 7.23(1H,d,J=2.0Hz) , 7.50(1H,d,J=8.0Hz) Reference Example 4 3 A mixture of (l-trityl-lH-benzimidazol-5- yl)methanol and (l-trityl-lH-benzimidazol-6-yl)methanol was obtained in a similar manner as in Reference Example 42. (l-trityl-lH-benzimidazol-5-yl)methanol NMR(400MHz,CDCl3) δ value: 2 . 05 (1H, brs) , 4.71(2H,s), 6.46(1H,d,J=8.4Hz) , 6 . 94(1H, dd,J=8.4,1. 6Hz) , 7.16- 7.19(6H,m), 7.31-7.32(9H,m), 7.73(1H,d,J=l.6Hz), 7.88(1H,s) (l-trityl-lH-benzimidazol-6-yl)methanol NMR(400MHz,CDCl3) δ value: 1. 56 (1H, brs) , 4.45(2H,s), 6.44(1H,s), 7.16-7.19(6H,m), 7.31-7.32(10H,m), 7.73(1H,d,J=1.6Hz), 7.88(1H,s) Reference Example 44 4.00 g of 2-amino-5-methylbenzoic acid was dissolved in 40 mL of 1,4-dioxane, to which 5.5 mL of triethylamine and 6.8 mL of diphenylphosphoryl azide were successively added, and this mixture was stirred for 1.5 hours while heating it under reflux. The reaction mixture, to which a mixture of ethyl acetate and water was added, was adjusted to pH 7 with 1M hydrochloric acid, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure to yield 2.96 g of 5-methyl- 1,3-dihydro-2H-benzimidazol-2-one as light yellow solid. NMR(400MHz,DMSO-d6) δ value: 2.27(3H,s), 6.72-6.75(2H,m), 6.80 (1H,d,J=8.0Hz) , 10.47(1H,s), 10.51(1H,s) Reference Example 45 1.00 g of methyl 3-formyl-1-benzothiophene-7- carboxylate was dissolved in a mixed solution of 15 mL of ethanol and 15 mL of tetrahydrofuran, to which 86 mg of sodium borohydride was added at room temperature, and this solution was stirred for one hour at the same temperature. After acetone was added dropwise to the reaction mixture, from which the solvent was distilled out under reduced pressure, followed by addition of ethyl acetate and water, and this mixture was adjusted to pH 6 with 6M hydrochloric acid, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 0.97 g of methyl 3-(hydroxymethyl)-1- benzothiophene-7-carboxylate as light yellow solid. NMR(400MHz,CDCl3) δ value: 1. 73 (1H,brs), 4.03(3H,s), 4.97(2H,s), 7.47-7.53(2H,m), 8.11(1H,d,J=8.0Hz), 8.14(1H,d,J=8.0Hz) Reference Example 4 6 Compounds listed in Table 35 were obtained in a similar manner as in Reference Example 45. [Table 35] 46(1) NMR(400MHz,CDCl3) δ value: 1.24(3H,t,J=7.2Hz) , 1.69(1H,brs), 2.61(2H,t,J=7.6Hz), 2.95(2H,t,J=7.6Hz), 4.12(2H,q,J=7.2Hz), 4.66(2H,s), 7.20(2H,d,J=8.OHz), 7.29(2H,d,J=8.0Hz) 46(2) NMR(4 00MHz,CDCl3) δ value: 1. 34(3H,t,J=7.1Hz), 2.00(1H,brs), 4.26(2H,q,J=7.1Hz), 4.72(2H,s), 6.42(1H,d,J=l6.1Hz), 7.38(2H,d,J=8.1Hz), 7.51(2H,d,J=8.1Hz), 7.66(1H,d,J=16.1Hz) 46(3) NMR(90MHz,CDCl3) δ value: 2.02(1H,brs), 3.92(3H,s), 4.75(2H,s), 7.34-7.62(2H,m), 7.90-8.02(2H,m) 46(4) NMR(90MHz, CDCl3) δ value: 1.77 (1H,brs), 2.48(3H,s), 4.64(2H,s), 7.16-7.38(4H,m) 46(5) NMR(400MHz,CDCl3) 6 value: 1. 71 (1H, brs ) , 2.61(2H,t,J=7.6Hz), 2.93(2H,t,J=7.6Hz), 3.67(3H,s), 3.82(3H,s), 4.59(2H,s), 6.82(1H,d,J=8.3Hz), 7.15(1H,d,J=2.2Hz), 7.19(1H,dd,J=8.3,2.2Hz) 46(6) NMR(400MHz,CDCl3) δ value : 1. 58-1. 63 (1H, m) , 4.58 (2H,d,J=6.OHz) , 5.96(2H,s), 6.78(1H,d,J=8.OHz), 6.82(1H,dd,J=8.0,1.6Hz), 6.8 7(1H,d,J=l.6Hz) Reference Example 4 7 The following compounds were obtained in a similar manner as in Reference Example 45. (1) 1-[4-(hydroxymethyl)phenyl]-4-methyl- 2,3-piperazinedione NMR (400MHz, DMSO-d6) δ value: 2.99(3H,s), 3.67(2H,dd,J=6.8,4.8Hz), 3.92(2H,dd,J=6.8,4.8Hz), 4.50(2H,d, J=5.6Hz) , 5.22(1H,t,J=5.8Hz), 7.31-7.36(4H,m) (2) 3-[4-(hydroxymethyl)phenyl]-1,3- oxazolidin-2-one NMR (400MHz,DMSO-d6) δ value: 4.05(2H,t,J=8.2Hz), 4.41- 4.47(4H,m), 5.14(1H,t,J=5.8Hz), 7.32(2H,d,J=8.0Hz) , 7.51 (1H,dd,J=9.0,2.2Hz), 7.52(1H,dd,J=9.0,2.2Hz) (3) methyl 3-(hydroxymethyl)-1- benzothiophene-5-carboxylate NMR(400MHz, CDC13) 6 value: 2.01 (1H,brs), 3.96(3H,s), 4.99(2H,s), 7.47(1H,s), 7.89(1H,d,J=8.4Hz), 8.01(1H,dd,J=8.4,1.6Hz) , 8.54(1H,d,J=l.2Hz) (4) methyl 5-(hydroxymethyl)-2- thiophenecarboxylate NMR(90MHz,CDCl3) δ value: 2.3-2.5(1H,m), 3.87(3H,s), 4.85(2H,d,J=4.9Hz), 6.98(1H,dd,J=3.7,0.7Hz), 7.66(1H,d,J=3.7Hz) (5) l-benzothiophen-5-ylmethanol NMR(400MHz,CDCl3) δ value: 1.78(1H,brs), 4.80(2H,s), 7.31-7.36(2H,m), 7.45(1H,d,J=5.6Hz), 7.81(1H,s), 7.86(1H,d,J=8.4Hz) Reference Example 4 8 Benzyl 2-(4-formylphenyl)acetate was obtained in a similar manner as in Reference Example 9. NMR (90MHz, CDCl3) 6 value: 3.76(2H,s), 5.15(2H,s), 7.16- 7.55(7H,m), 7.76-7.89(2H,m), 10.00(1H,s) Reference Example 4 9 29.7 g of hydroxylamine hydrochloride was dissolved in 100 mL of methanol, to which 82.4 g of a 28% solution of sodium methoxide in methanol was added at room temperature, and this solution was stirred for one hour at the same temperature. 10.0 g of 4- methylbenzonitrile was added to this mixture, which was then stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure, to which water was added, and adjusted to pH 8 with 6M hydrochloric acid, followed by addition thereto of ethyl acetate, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 11.6 g of N'-hydroxy-4-methylbenzenecarboxyimidamide as white solid. NMR (400MHz, CDC13) δ value: 2.37(3H,s), 4 . 87 (2H, brs) , 8.31(1H,brs), 7.20(2H,d,J=8.0Hz), 7.51(2H,d,J=8.0Hz) Reference Example 50 1.00 g of N'-hydroxy-4- methylbenzenecarboxyimidamide was dissolved in 14 mL of N,N-dimethylformamide, to which 0.59 mL of pyridine was added at room temperature and then 1.28 g of 2- ethylhexyl chloroformate was added at 5°C, this solution was stirred for one hour at the same temperature. The reaction mixture was added to a mixture of water and ethyl acetate, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure. 14 mL of xylene was added to the resultant residue, and which was stirred for one hour while heating it under reflux. The reaction mixture was cooled to room temperature, from which resultant precipitate was filtered out, and the resultant precipitate was washed with hexane and then with diisopropyl ether to yield 0.78 g of 3-(4- methylphenyl)-1,2,4-oxadiazol-5(4H)-one as white solid. NMR(4 00MHz,DMSO-d6) δ value: 2.38(3H,s), 7.39(2H,d,J=8.4Hz), 7.70(2H,d,J=8.4Hz), 12.90(1H,brs) Reference Example 51 2.00 g of N'-hydroxy-4- methylbenzenecarboxyimidamide was dissolved in 40 mL of acetic anhydride, and this solution was stirred for 1.5 hours while heating it under reflux. After the reaction mixture was cooled to room temperature, the solvent was distilled out thereof under reduced pressure, and then the resultant residue was purified by silica gel column chromatography to yield 1.20 g of 5-methyl-3-(4-methylphenyl)-1,2,4-oxadiazole as yellow solid. NMR (400MHz, CDCl3) δ value: 2.41(3H,s), 2.65(3H,s), 7.28(2H,d,J=8.0Hz), 7.94(2H,d,J=8.0Hz) Reference Example 52 1.00 g of 4-methyl-1H-pyrazole and 2.5 mL of triethylamine were dissolved in 10 mL of tetrahydrofuran, to which 3.1 mL of di-tert-butyl dicarbonate and 73 mg of 4-(dimethylamino)pyridine were successively added, and this solution was stirred for 30 minutes at room temperature. The reaction mixture was added to a mixture of water and ethyl acetate, and adjusted to pH 7 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 2.23 g of tert-butyl 4-methyl-1H- pyrazole-1-carboxylate as light yellow oil. NMR(4 00MHz,CDCl3) δ value: 1.64(9H,s), 2.09(3H,s), 7.54(1H,s), 7.84(1H,s) Reference Example 53 The following compounds were obtained in a similar manner as in Reference Example 52. (1) di-tert-butyl 6-methyl-2,4-dioxo-1,3- (2H,4H)-quinazolinedicarboxylate NMR (400MHz, CDCl3) δ value: 1.64(9H,s), 1.73(9H,s), 2.38(3H,s), 6.90(1H,d,J=8.0Hz), 7.36(1H,dd,J=8.4,2.0Hz), 7.85(1H,d,J=2.0Hz) (2) tert-butyl methyl[(4- methylphenyl)sulfonyl]carbamate NMR(400MHz,CDCl3) δ value: 1.35(9H,s), 2.44(3H,s), 3.35(3H,s), 7.31(2H,d,J=8.0Hz), 7.78(2H,d,J=8.4Hz) (3) tert-butyl methyl(4-methylbenzoyl)- carbamate NMR (4 00MHz, CDCl3) δ value: 1.19(9H,s), 2.39(3H,s), 3.29(3H,s), 7.19(2H,d,J=8.0Hz), 7.42(2H,d,J=8.4Hz) (4) tert-butyl 4-methylphenyl- (methylsulfonyl)carbamate NMR (4 00MHz, CDCl3) δ value: 1.48(9H,s), 2.37(3H,s), 3.41(3H,s), 7.11(2H,d,J=7.6Hz), 7.20(2H,d,J=7.6Hz) (5) tert-butyl 5-methyl-l,3-dioxo-1,3- dihydro-2H-isoindole-2-carboxylate NMR(400MHz,CDCl3) δ value: 1.63(9H,s), 2.54(3H,s), 7.59(1H,dd,J=7.6,0.8Hz), 7.7 3(1H,d,J=0.8Hz), 7.82(1H,d,J=7.6Hz) (6) tert-butyl 3-hydroy-1- pyrrolidinecarboxylate NMR(90MHz,CDCl3) δ value: 1.46(9H,s), 1.8-2.1(3H,m), 3.2-3.6(4H,m), 4.3-4.6(1H,m) Reference Example 54 16.5 g of l-benzothiophene-5-carbaldehyde and 49.5 mL of ethylene glycol were dissolved in 165 mL of toluene, to which 0.30 g of para-toluenesulfonic acid monohydrate was added, and this solution was stirred for 7 hours while heating it under reflux. The reaction mixture was cooled to room temperature, to which an aqueous solution of sodium hydroxide was added, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=5:l] to yield 15.8 g of 2-(l- benzothiophen-5-yl)-1,3-dioxolane as yellow oil. NMR( 4 00MHz, CDCl3) δ value: 4 . 03-4 .18 (4H,m) , 5.95(1H,s), 7.34(1H,d,J=5.6Hz), 7.45-7.48(2H,m), 7.89(1H,d,J=8.4Hz), 7.94 (1H,s) Reference Example 55 3.83 g of silver nitrate was dissolved in 10 mL of water, to which a solution of 1.81 g of sodium hydroxide in 10 mL of water was added dropwise and then a solution of 2.00 g of 2-methyl-1,3-benzothiazole-5- carbaldehyde in 20 mL of tetrahydrofuran was added dropwise at room temperature, and this solution was stirred for 30 minutes at the same temperature. The reaction mixture was filtered through Celite, and 6M hydrochloric acid was added to the filtrate to adjust its pH value to 3.5 followed by addition of ethyl acetate, and then the organic phase was separated therefrom. After the resultant organic phase was washed with a saturated sodium chloride solution, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was dissolved in 30 mL of methylene chloride, to which 20 µL of N,N- dimethylformamide and 1.5 mL of oxalyl chloride were added successively, and this solution was stirred for 30 minutes at room temperature. The reaction mixture, 5 to which 20 mL of methanol was added dropwise, was stirred for 30 minutes at room temperature, and after water was added thereto, the pH value of this mixture was adjusted to 7 with a 5M solution of sodium hydroxide in water, and then the organic phase was D separated therefrom. After the resultant organic phase was washed with a saturated sodium chloride solution, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 1.90 g of methyl 2-methyl- 5 1,3-benzothiazole-5-carboxylate as light yellow solid. NMR(400MHz,CDCl3) δ value: 2.87(3H,s), 3.97(3H,s), 7.88(1H,d,J=8.4Hz), 8.03(1H,dd,J=8.4,1.6Hz), 8.61(1H,d,J=1.6Hz) Reference Example 56 ) The following compounds were obtained in a similar manner as in Reference Example 55. (1) methyl l-benzothiophene-5-carboxylate NMR(400MHz,CDCl3) δ value: 3.96(3H,s), 7.43(1H,dd,J=5.6,0.8Hz), 7.52(1H,d,J=5.6Hz), 7.92(1H,dd,J=8.6,0.8Hz), 8.01(1H,dd,J=8.6,1.6Hz), 8.54(1H,d,J=1.2Hz) (2) methyl 4-[2-(benzyloxy)-2-oxoethyl] benzoate NMR(90MHz,CDCl3) δ value: 3.72(2H,s), 3.91(3H,s), 5.14(2H,s), 7.33-7.46(7H,m), 7.90-8.04(2H,m) Reference Example 57 10.85 g of methyl 3-bromo-4- (bromomethyl)benzoate was dissolved in 108 mL of N,N- dimethylformamide, to which 3.4 6 g of potassium acetate was added at room temperature, and this solution was stirred for 17.5 hours at the same temperature. The reaction mixture was added to a mixture of water and ethyl acetate, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=10:1] to yield 6.43 g of methyl 4- [(acetyloxy)methyl]-3-bromobenzoate as white solid. NMR(400MHz,CDCl3) δ value: 2.18(3H,s), 3.93(3H,s), 5.22(2H,s), 7.47(1H,d,J=8.0Hz), 7.98(1H,dd,J=8.0,1.2Hz), 8.24(1H,d,J=1.2Hz) Reference Example 58 5.30 g of methyl 4-[(acetyloxy)methyl]-3- bromobenzoate was dissolved in 50 mL of hexamethylphosphoramide, to which 6.6 mL of tetramethyltin and 0.26 g of bis(triphenylphosphine)- palladium(II) dichloride were added at room temperature in a stream of nitrogen, and this solution was stirred for 3 hours at 70°C. The reaction mixture was cooled to room temperature, and was added to a mixture of water and diethyl ether, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=5:l] to yield 4.17 g of methyl 4- [(acetyloxy)methyl]-3-methylbenzoate as brown oil. NMR(400MHz,CDCl3) δ value: 2.13(3H,s), 2.38(3H,s), 3.91(3H,s), 5.15(2H,s), 7.8-7.9(2H,m), 7.40(1H,d,J=8.4Hz) Reference Example 59 1.00 g of methyl 4-[(acetyloxy)methyl]-3- methylbenzoate was dissolved in 10 mL of methanol, to which a solution of 0.365 g of sodium methoxide in 7 mL of methanol was added dropwise at 5 to 7°C, and this solution was stirred for 30 minutes at 5°C. The reaction mixture was concentrated under reduced pressure, followed by successive addition of ethyl acetate and water, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 0.79 g of methyl 4- (hydroxymethyl)-3-methylbenzoate as yellow oil. NMR(400MHz, CDCl3) δ value: 1. 78 (1H,brs), 2.36(3H,s), 3.91(3H,s), 4.75(2H,s), 7.48(1H,d,J=8.0Hz), 7.84(1H,s), 7.87 (1H,d,J=8.0Hz) Reference Example 60 Methyl 2-(hydroxymethyl)-1,3-benzothiazole-5- carboxylate was obtained in a similar manner as in Reference Example 59. NMR(400MHz,CDCl3) δ value: 3.97(4H,brs), 5.11(2H,s), 7.94(1H,d,J=8.0Hz), 8.06(1H,dd,J=8.4,1.6Hz), 8.63(1H,d,J=1.6Hz) Reference Example 61 1.00 g of 5-methyl-2-benzofuran-1,3-dione was suspended in 10 mL of chlorobenzene, to which 1.3 mL of 1,1,1,3,3,3-hexamethyldisilazane was added at room temperature, and this suspension was stirred for 10.5 hours while heating it under reflux. The reaction mixture was cooled to room temperature, and resultant precipitate was filtered out therefrom to yield 0.169 g of 5-methyl-1H-isoindole-1,3(2H)-dione as light yellow solid. NMR(400MHz,CDCl3) δ value: 2.53(3H,s), 7.49(1H,brs), 7.55(1H,dd,J=7.8,0.8Hz) , 7.67(1H,d,J=0.8Hz), 7.75(1H,d,J=8.0Hz) Reference Example 62 1.00 g of lH-benzimidazole-5-carboxylic acid was suspended in a mixed solvent of 10 mL of tetrahydrofuran and 20 µL of N,N-dimethylformamide, to which 1.6 mL of oxalyl chloride was added dropwise at room temperature, and this suspension was stirred for one hour at room temperature. The reaction mixture, to which 10 mL of methanol was added, was stirred for another one hour at room temperature and then for 30 minutes at 50°C, and this mixture was concentrated under reduced pressure. The resultant solid was washed with diisopropyl ether to yield 1.25 g of methyl 1H- benzimidazole-5-carboxylate hydrochloride as gray solid. NMR (4 00MHz, DMSO-d6) δ value: 3.92(3H,s), 7.95(1H,d,J=8.4Hz), 8.11(1H,d,J=8.4Hz), 8.39(1H,s), 9.56(1H,s) Reference Example 63 3.00 g of 5-methyl-2-benzofuran-l,3-dione was suspended in 30 mL of methanol, to which 0.2 mL of sulfuric acid was added at room temperature, and this suspension was stirred for 2.5 hours while heating it under reflux. The reaction mixture was cooled to room temperature, and poured into ice water followed by addition of ethyl acetate, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and then the solvent was distilled out under reduced pressure to yield 2.95 g of dimethyl 4-methylphthalate as light yellow oil. NMR(400MHz,CDCl3) δ value: 2.42(3H,s), 3.88(3H,s), 3.91(3H,s), 7.33(1H,d,J=8.0Hz) 7.47(1H,s), 7.67(1H,d,J=8.0Hz) Reference Example 64 The following compounds were obtained in a similar manner as in Reference Example 63. (1) ethyl 5-methyl-2-pyrazinecarboxylate NMR(400MHz,CDCl3) δ value: 1.46(3H,t,J=7.2Hz), 2.67(3H,s), 4.51(2H,q,J=7.2Hz) , 8.59(1H,d,J=l- 2Hz), 9.19(1H,d,J=1.2Hz) (2) methyl 3-(2-methoxy-2-oxoethyl)benzoate NMR(90MHz,CDCl3) δ value: 3.68(2H,s), 3.70(3H,s), 3.92(3H,s), 7.39-7.47(2H,m), 7.91-7.96(2H,m) Reference Example 65 0.34 g of 60% sodium hydride was added to a solution of 1.00 g of l-methyl-2,3-piperazinedione in 10 mL of N,N-dimethylformamide, and this mixture was stirred for 10 minutes at 50°C. Then, 0.88 mL of 4- fluorobenzaldehyde was added thereto and the mixture was stirred for 30 minutes at 120°C. The mixture was cooled to room temperature, and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; chloroform:ethanol=15:1] to yield 0.80 g of 4-(4-methyl-2,3-dioxo-1- piperazinyl)benzaldehyde as white solid. NMR(400MHz,DMSO-d6) δ value: 3.01(3H,s), 3.7 0(2H,t,J=5.8Hz), 4.05(2H,t,J=5.6Hz), 7.65(2H,d,J=8.4Hz), 7.96(2H,d,J=7.6Hz), 9.99(1H,s) Reference Example 66 4-(2-oxo-1,3-oxazolidin-3-yl)benzaldehyde was obtained in a similar manner as in Reference Example 65. NMR (4 00MHz, CDC13) δ value: 4 .14 (2H, t, J=8 . 0Hz) , 4.55 (2H,t,J=8.0Hz), 7.7 4(2H,dd,J=9.0,2.2Hz), 7.91 (2H,dd,J=9.2,2.2Hz), 9.96 (1H,s) Reference Example 67 7.00 g of 4-methylbenzenesulfonyl chloride was dissolved in 70 mL of methylene chloride, to which 3.59 g of dimethylamine hydrochloride was added at room temperature and 12.8 mL of triethylamine was added dropwise in an ice bath, and then this solution was stirred for one hour at room temperature. The reaction mixture, to which water was added, was adjusted to pH 3 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out thereof under reduced pressure to yield 6.75 g of N,N,4-trimethylbenzenesulfonamide as white solid. NMR(400MHz,CDCl3) δ value: 2.44(3H,s), 2.68(6H,s), 7.34 (2H,d,J=8.4Hz) , 7.66(2H,d,J=8.4Hz) Reference Example 68 The following compounds were obtained in a similar manner as in Reference Example 67. (1) N-(4-methylphenyl)methanesulfonamide NMR(400MHz, DMSO-d6) δ value: 2.23(3H,s), 2.89(3H,s), 7.10(2H,d,J=8.8Hz), 7.14(2H,d,J=8.8Hz), 9.53(1H,s) (2) [bis(tert-butoxycarbonyl)amino](4- methylphenyl) dioxo-A,6-sulf ane NMR(400MHz,CDCl3) 6 value: 1.48(18H,s), 2.45(3H,s), 7.3 3(2H,d,J=8.0Hz), 7.96(2H,d,J=8.4Hz) (3) N,4-dimethylbenzenesulfonamide NMR(400MHz,CDCl3) δ value: 2.43(3H,s), 2.65(3H,d,J=5.6Hz), 4.47(1H,d,J=4.8Hz), 7.32(2H,d,J=8.4Hz), 7.7 5(2H,d,J=8.4Hz) Reference Example 69 99.3 g of ethyl (E)-3-(4-methylphenyl)-2- propenoate was dissolved in 400 mL of chloroform, to which a solution of 21.7 mL of bromine in 100 mL of chloroform was added dropwise in an ice bath, and then this solution was stirred for 30 minutes at room temperature. An aqueous solution of sodium thiosulfate was then added to the reaction mixture, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out therefrom under reduced pressure to yield 146.34 g of ethyl 2,3-dibromo-3-(4- methylphenyl)propanoate as light yellow solid. NMR(400MHz,CDCl3) δ value: 1.37(3H,t,J=6.8Hz), 2.36(3H,s), 4.35(2H,q,J=6.8Hz), 4.83(1H,d,J=12.0Hz), 5.33(1H,d,J=12.0Hz), 7.19(2H,d,J=7.8Hz), 7.29(2H,d,J=7.8Hz) Reference Example 70 0.35 g of ethyl 2,3-dibromo-3-(4- methylphenyl)propanoate and 0.083 g of hydroxylamine hydrochloride was suspended in 7 mL of methanol, to which 0.19 g of a 28% solution of sodium methoxide in methanol was added at room temperature, and then this solution was stirred for 12 hours at the same temperature. The reaction mixture, to which water was added, was adjusted to pH 1 with 6M hydrochloric acid followed by addition of ethyl acetate, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out therefrom under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=4:l] to yield 0.12 g of 5-(4-methylphenyl)-3- isoxazolol as yellow oil. NMR(400MHz,CDCl3) δ value: 2.41(3H,s), 6.16(1H,s), 7.2- 7.3(3H,m), 7.62(2H,d,J=8.0Hz) Reference Example 71 2.50 g of methyl 3-methoxy-4-methylbenzoate was dissolved in 25 mL of benzene, to which 2.72 g of N-bromosuccinimide and 0.23 g of 2,2'- azobisisobutyronitrile were successively added at room temperature, and this solution was stirred for one hour while heating it under reflux. After 3.90 g of hexamethylenetetramine dissolved in 7.8 mL of acetic acid and 7.8 mL of water was added dropwise to the reaction mixture, benzene was distilled out therefrom, and then the mixture was stirred for one hour while heating it under reflux. The reaction mixture, which was cooled to room temperature, was added to a mixture of chloroform and water and then adjusted to pH 7 with a 20% aqueous solution of sodium hydroxide, and the organic phase was separated therefrom. After the resultant organic phase was successively washed with water, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated sodium chloride solution, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=3:l] to yield 1.74 g of methyl 4- formyl-3-methoxybenzoate as white solid. NMR(400MHz,CDCl3) δ value: 3.96(3H,s), 4.00(3H,s), 7.67(1H,s), 7.68(1H,d,J=7.8Hz), 7.88(1H,d,J=7.8Hz), 10.52(1H,s) Reference Example 72 2-methyl-1,3-benzothiazole-5-carboaldehyde was obtained in a similar manner as in Reference Example 71. NMR(400MHz,CDCl3) δ value: 2.89(3H,s), 7.90(1H,dd,J=8.4,1.6Hz), 7.97(1H,d,J=8.4Hz), 8.40(1H,d,J=1.2Hz), 10.13(1H,s) Reference Example 7 3 1.72 g of methyl 4-formyl-3-methoxybenzoate was dissolved in 8.6 mL of methanol, to which 2.6 mL of a 20% aqueous solution of sodium hydroxide was added at room temperature, and this solution was stirred for one hour at the same temperature. The reaction mixture, to which water was added, was adjusted to pH 2 with 6M hydrochloric acid, and resultant precipitate was filtered out therefrom and washed with water to yield 1.49 g of 4-formyl-3-methoxybenzoic acid as light yellow solid. NMR(400MHz, DMSO-d6) δ value: 3.99(3H,s), 7.62(1H,d,J=8.0Hz), 7.68(1H,d,J=l.2Hz), 7.79(1H,d,J=8.0Hz), 10.40(1H,s), 13.51 (1H,brs) Reference Example 74 The following compounds were obtained in a similar manner as in Reference Example 73. (1) 5-(ethoxycarbonyl)-2-pyridinecarboxylic acid NMR(90MHz,DMSO-d6) δ value: 1.36(3H,t,J=7.1Hz) , 3.60(1H,brs), 4.39(2H,q,J=7.1Hz), 8.16(1H,d,J=8.1Hz), 8.46(1H,dd,J=8.2,2.3Hz), 9.16-9.18(1H,m) (2) 2-[3-(methoxycarbonyl)phenyl]acetic acid NMR(90MHz,CDCl3) δ value: 3.71(2H,s), 3.96(3H,s), 7.39- 7.54(2H,m), 7.93-8.01(2H,m), 9.52(1H,brs) (3) 2-(4-formylphenyl)acetic acid light yellow oil (4) 2-methoxy-4-[(1-methylcyclopentyl)- methyl]benzoic acid NMR(400MHz,CDCl3) 6 value: 0.91(3H,s), 1.32-1.37(2H,m), 1.49-1.56(2H,m), 1.67-1.70(4H,m), 2.67(2H,s), 4.07(3H,s), 6.82(1H,s), 6 . 94(1H,d,J=8.0Hz) , 8.08(1H,d,J=7.6Hz), 10.70 (1H,brs) Reference Example 75 1.58 g of 4-(3-ethoxy-3-oxopropyl)-3- methoxybenzoic acid was dissolved in 16 mL of tetrahydrofuran, to which 0.96 mL of triethylamine was added dropwise at -10°C and then 0.63 mL of ethyl chloroformate was added dropwise at -20°C, followed by addition thereto of 0.47 g of sodium borohydride in an ice bath, and this solution was stirred for 30 minutes at the same temperature. The reaction mixture, to which water was added dropwise before adding ethyl acetate and water thereto, was adjusted to pH 2 with 6M hydrochloric acid, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 1.49 g of ethyl 3-[4-(hydroxymethyl)-2-methoxyphenyl]propanoate as white solid. NMR(400MHz,CDCl3) δ value: 1.24 (3H,t,J=7.1Hz) , 2.58(2H,t,J=7.6Hz), 2.85(1H,brs), 2.92(2H,t,J=7.6Hz), 3.83(3H,s), 4.11(2H,q,J=7.1Hz), 4.65(2H,s), 6.84(1H,d,J=7.6Hz), 6.88(1H,s), 7.11 (1H, d, J=7 . 6Hz) Reference Example 76 The following compounds were obtained in a similar manner as in Reference Example 75. (1) methyl 4-(2-hydroxyethyl)benzoate NMR(90MHz,CDCl3) δ value: 1.55 (1H,brs), 2.92(2H,t,J=6.7Hz), 3.77-4.03(2H,m), 3.91(3H,s), 7.30(2H,d,J=7.7Hz), 7.98(2H,d,J=8.1Hz) (2) methyl 3-(2-hydroxyethyl)benzoate NMR(90MHz, CDC13) δ value: 1.42(1H,t,J=5.9Hz), 2.93(2H,t,J=6.7Hz), 3.80-4.00(2H,m), 3.92(3H,s), 7.37- 7.44(2H,m), 7.85-7.96(2H,m) Reference Example 77 5.00 g of 4-bromobenzaldehyde was dissolved in 100 mL of N,N-dimethylformamide, to which 2.9 mL of ethyl acrylate, 0.30 g of palladium(II) acetate, 0.35 g of triphenylphosphine, 13.20 g of potassium acetate, and 8.70 g of tetra-n-butylammonium bromide were added, and this solution was stirred for 2.5 hours at 90°C. The reaction mixture was added to a mixture of ethyl acetate and water, and adjusted to pH 2 with 6M hydrochloric acid, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=2:l] to yield 4.75 g of ethyl (E)-3-(4-formylphenyl)-2- propenoate as yellow solid. NMR (400MHz,CDC13) δ value: 1.35(3H,t,J=7.2Hz), 4.2 9 (2H,q,J=7.2Hz), 6.55(1H,d,J=16.0Hz) , 7.68(2H,d,J=8.4Hz), 7.71(1H,d,J=16.0Hz), 7.90(2H,d,J=8.4Hz), 10.03(1H,s) Reference Example 78 4.00 g of methyl 3-(hydroxymethyl)benzoate was dissolved in 80 mL of methylene chloride, to which 9.47 g of triphenylphosphine was added in small portions in an ice bath followed by addition of 12.00 g of carbon tetrabromide in small portions, and this solution was stirred for one hour at room temperature. The reaction mixture was concentrated under reduced pressure, and the resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=2:l] to yield 5.02 g of methyl 3- (bromomethyl)benzoate as colorless oil. NMR(90MHz,CDCl3) δ value: 3.93(3H,s), 4.52(2H,s), 7.42- 8.07(4H,m) Reference Example 7 9 0.924 g of sodium cyanide was dissolved in 15 mL of dimethylsulfoxide, to which a solution of 4.00 g of methyl 3-(bromomethyl)benzoate in 5 mL of dimethylsulfoxide was added in an ice bath, and this solution was stirred for 2 hours at room temperature. The reaction mixture was added to a mixture of ethyl acetate and water, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield 3.00 g of methyl 3- (cyanomethyl)benzoate as orange oil. NMR(90MHz,CDCl3) δ value: 3.81(2H,s), 3.94(3H,s), 7.46- 7.54(2H,m), 7 . 99-8 . 06 (2H,m) Reference Example 80 12.2 mL of (S)-(-)-a-pinene was dissolved in 30 mL of tetrahydrofuran, to which a 1M solution of borane in tetrahydrofuran was added dropwise in an ice bath, and this solution was stirred for 2 hours at 5 to 10°C. Then, after a solution of 4.59 g of 1,3- cyclopentadiene in 4 mL of tetrahydrofuran was added dropwise thereto in an ice bath, the solution was stirred for 14 hours at room temperature. The reaction mixture was ice-cooled, to which 1.2 mL of water, 6.9 mL of 20% sodium hydroxide, and 6.9 mL of a 30% aqueous solution of hydrogen peroxide were successively added dropwise, and then the reaction mixture was cooled to room temperature followed by addition of sodium chloride, and the organic phase was separated therefrom. The resultant organic phase was concentrated under reduced pressure, to which diethyl ether and a 1M aqueous solution of silver nitrate were added, and after this mixture was stirred for 30 minutes at room temperature, the reaction mixture was permitted to stand and the organic phase was separated therefrom. The resultant organic phase was washed with a 1M aqueous solution of silver nitrate followed by addition of sodium chloride, and then filtered. The filtrate was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 0.83 g of 3-cyclopenten-1-ol as light yellow oil. NMR(4 00MHz, CDCl3) δ value: 1.73(1H,brs), 2.29-2.36(2H,m), 2.61-2.69(2H,m), 4.51-4.54(1H,m), 5.72(2H,s) Reference Example 81 2.00 g of 2-amino-5-methylbenzoic acid was suspended in 20 mL of water, to which 1.18 g of potassium cyanate was added and a mixture of 0.23 mL of acetic acid and 1 mL of water were added dropwise, and this suspension was stirred for 1.5 hours at 50°C. Then, after a solution of 1.42 g of sodium hydroxide in 2 mL of water was added drowise, to which 40 mL of water and 20 mL of 1,4-dioxane were added, and this solution was stirred for 3.5 hours while heating it under reflux. The reaction mixture was ice-cooled, from which precipitated solid was filtered, and then 30 mL of water and 3 mL of 6M of hydrochloric acid were added to the resultant solid, which was then stirred for 1.5 hours while heating it under reflux. The reaction mixture was cooled to room temperature, from which resultant precipitate was filtered and washed with water to yield 1.17 g of 6-methyl-2,4-(1H,3H)- quinazolinedione as white solid. NMR(400MHz, DMSO-d6) δ value: 2.32(3H,s), 7.07(1H,d,J=8.4Hz), 7.4 6(1H,dd,J=8.4,2.0Hz), 7.69(1H,d,J=0.8Hz), 11.09 (1H,brs), 11.18(1H,brs) Reference Example 82 0.636 g of sodium borohydride was added to 22 mL of ice-cooled ethanol, to which a solution of 1.09 g of calcium chloride in 14 mL of ethanol was added dropwise, followed by addition of 1.20 g of 5- (ethoxycarbonyl)-2-pyridinecarboxylic acid 1/2 calcium salt, and this mixture was stirred for one hour at room temperature. The reaction mixture, to which 2.8 mL of concentrated sulfuric acid was added, was stirred for 6 hours while heating it under reflux. The reaction mixture was cooled to room temperature and concentrated under reduced pressure followed by successive addition of a saturated aqueous solution of sodium hydrogen carbonate and chloroform, and then the organic phase was separated therefrom. The resultant organic phase was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 0.34 g of ethyl 5-(hydroxymethyl)-2- pyridinecarboxylate as light yellow solid. NMR ( 90MHz, CDC13) δ value: 1. 45 (3H, t, J=7 . 1Hz) , 2.32(1H,brs), 4.48(2H,q,J=7.1Hz), 4.84(2H,s), 7.86(1H,dd,J=8.1,2.0Hz), 8.13(1H,d,J=7.9Hz), 8.71(1H,d,J=1.3Hz) Reference Example 83 23.30 g of sodium hydroxide was dissolved in 118 mL of water and was ice-cooled, to which 9.23 mL of bromine was added dropwise over 20 minutes and then a solution of 9.80 g of 1-(2-fluoro-4-methoxyphenyl)-1- ethanone in 88 mL of 1,4-dioxane was added dropwise over one hour at -10°C. The resultant reaction mixture was cooled to room temperature, to which water was added, and then an aqueous phase was separated therefrom. A solution of 7.23 g of sodium thiosulfate in 100 mL of water was added to the aqueous phase, and then 12M hydrochloric acid was further added until the pH value of this aqueous phase reached 2. The resultant precipitate was filtered therefrom and washed with water to yield 8.20 g of 2-fluoro-4-methoxybenzoic acid as white solid. NMR(4 00MHz,DMSO-d6) δ value: 3.83(3H,s), 6. 84-6 . 92 (2H,m) , 7.83(1H,t,J=8.8Hz), 12.86(1H,brs) Reference Example 84 1.70 g of 4-(methoxymethoxymethyl)-2- methylbenzaldehyde was dissolved in 10 mL of acetonitrile, to which 3.69 g of sodium dihydrogen phosphate dihydrate dissolved in 7 mL of water and 1.58 g of a 80% sodium chlorite dissolved in 3 mL of water and a 1.5 mL of 30% aqueous solution of hydrogen peroxide were successively added at 5 to 10°C, and then this solution was stirred for 20 minutes at room temperature. Then, ethyl acetate and water were added to the reaction mixture, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was dissolved in 18 mL of methanol, to which 9 mL of 6M hydrochloric acid was added, and this mixture was stirred for 4.5 hours while heating it under reflux. The reaction mixture was cooled to room temperature, and poured into a mixture of chloroform and water, then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=l:l] to yield 1.30 g of methyl 4- (hydroxymethyl)-2-methylbenzoate as light yellow oil. NMR (400MHz, CDC13) δ value: 1.89(1H,brs), 2.61(3H,s), 3.87(3H,s), 4.71(2H,s), 7.22-7.26(2H,m), 7.91(1H,d,J=8.0Hz) Reference Example 85 14.17 g of 4-bromo-2-hydroxybenzoic acid, 16.3 mL of iodomethane, and 27.07 g of potassium carbonate were suspended in 142 mL of N,N- dimethylformamide, and this suspension was stirred for 5 hours at 75°C. In addition, 4.1 mL of iodomethane and 9.02 g of potassium carbonate were added thereto, and the mixture was stirred for 30 minutes at 105°C. The reaction mixture was cooled to room temperature, added to a mixture of ethyl acetate and ice cooled water, and adjusted to pH 2 with 6M hydrochloric acid for separation of the organic phase. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=3:l] to yield 5.62 g of yellow oil. The resultant oil was dissolved in 30 mL of methanol, to which 10 mL of a 20% aqueous solution of sodium hydroxide was added, and this mixture was stirred for one hour at room temperature. The reaction mixture, to which water was added, was adjusted to pH 2 with 6M hydrochloric acid followed by addition of chloroform, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; toluene:ethyl acetate=5:l] to yield 5.62 g of 4-bromo-2-methoxybenzoic acid as light yellow solid. NMR(4 00MHz, DMSO-d6) δ value: 3.84(3H,s), 7.20(1H,dd,J=8.0,1.6Hz), 7.33(1H,d,J=1.6Hz), 7.58 (1H,d,J=8.0Hz), 12.81(1H,brs) Reference Example 8 6 4-isobutoxy-2-methylbenzoic acid was obtained in a similar manner as in Reference Example 85. NMR(90MHz,DMSO-d6) δ value: 0.98(6H,d,J=6.6Hz), 1.7- 2.3(1H,m), 2.52(3H,s), 3.79(2H,d,J=6.4Hz), 6.77- 6.84(2H,m), 7.84(1H,d,J=9.3Hz) Reference Example 87 2.20 g of methyl 2-methyl-1,3-benzothiazole- 5-carboxylate was dissolved in 165 mL of benzene, to which 16.63 g of N-bromosuccinimide and 1.22 g of 2,2'- azobisisobutyronitrile were successively added at room temperature, and this solution was stirred for 15 hours while heating it under reflux. The reaction mixture was cooled to room temperature, and then the solvent was distilled out under reduced pressure. The resultant residue was dissolved in 22 mL of N,N- dimethylformamide, to which 5.21 g of potassium acetate was added at room temperature, and this solution was stirred for 30 minutes at the same temperature. The reaction mixture was added to a mixture of water and ethyl acetate, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=5:l] to yield 0.64 g of methyl 2-[(acetyloxy)methyl]-1,3- benzothiazole-5-carboxylate as yellow solid. NMR(400MHz,CDCl3) δ value: 2.22(3H,s), 3.98(3H,s), 5.51(2H,s), 7.95(1H,d, J=8.4Hz), 8.10 (1H, dd, J==8 . 4, 1. 6Hz) , 8.70(1H,d,J=1.6Hz) Reference Example 8 8 3.00 g of 4-methylbenzoic acid was suspended in a mixed solvent of 30 mL of methylene chloride and 20 µL of N,N-dimethylformamide, to which 2.9 mL of oxalyl chloride was added dropwise at room temperature, and this suspension was stirred for 5.5 hours at room temperature. Then, 1.7 9 g of monomethylamine hydrochloride was added to the reaction mixture, to which 15.4 mL of triethylamine was added dropwise in an ice bath, and the mixture was stirred for one hour at room temperature. The reaction mixture, to which water was added, was adjusted to pH 3 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; chloroform:acetone=5:1] to yield 2.11 g of N,4-dimethylbenzamide as light orange solid. NMR (400MHz, CDCl3) 6 value: 2.39(3H,s), 3.01(3H,d,J=4.8Hz), 6.11(1H,brs), 7.23(2H,d,J=7.6Hz), 7.66(2H,d,J=8.0Hz) Reference Example 8 9 N,N,4-trimethylbenzamide was obtained in a similar manner as in Reference Example 88. NMR(400MHz,CDCl3) δ value: 2.37(3H,s), 2.99(3H,brs), 3.10(3H,brs), 7.19(2H,d,J=7.6Hz), 7.32(2H,d,J=8.0Hz) Reference Example 90 1.00 g of 2-[4-(bromomethyl)phenyl]acetic acid was suspended in 5 mL of a 4M solution of hydrogen chloride in ethanol, and this suspension was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure to yield 0.954 g of ethyl 2-[4-(bromomethyl)phenyl]acetate as light brown oil. NMR(400MHz,CDCl3) δ value: 1. 25(3H,t,J=7.2Hz), 3.61(2H,s), 4.15(2H,q,J=7.2Hz), 4.57(2H,s), 7.28(2H,d,J=7.8Hz), 7.34(2H,d,J=7.9Hz) Reference Example 91 5.00 g of ethanethioamide was suspended in 50 mL of ethanol, to which 9.3 mL of ethyl 3-bromo-2- oxopropanoate was added dropwise at room temperature, and this suspension was stirred for one hour while heating it under reflux. The reaction mixture was cooled to room temperature and added to a mixture of ethyl acetate and water, followed by separation of the organic phase therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent. was distilled out under reduced pressure to yield 2.30 g of ethyl 2-methyl-1,3-thiazole-4-carboxylate as white solid. NMR( 90MHz, CDCl3) δ value: 1. 40 (3H, t, J=7 . 1Hz) , 2.77(3H,s), 4.42(2H,q,J=7.1Hz), 8.04(1H,s) Reference Example 92 25.0 g of 2-sulfanylbenzoic acid was suspended in 125 mL of ethanol, to which 14.3 g of sodium hydroxide and 31.7 mL of 2-bromo-l,1- diethoxyethane was successively added and this suspension was stirred for 3.5 hours while heating it under reflux. The reaction mixture was concentrated under reduced pressure, and the resultant residue was dissolved in 250 mL of N,N-dimethylformamide, to which 15.1 mL of iodomethane and 67.2 g of potassium carbonate were added, and then this mixture was stirred for one hour at room temperature. The reaction mixture was added to a mixture of ethyl acetate and water, from which the organic phase was separated. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=2:1] to yield yellow oil. This product was dissolved in 250 mL of toluene, to which 100 mL of a 85% phosphoric acid was added, and this solution was stirred for 4.5 hours while heating it under reflux. The reaction mixture was cooled to room temperature, to which water was added, and filtered through Celite to separate the organic phase therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. Purification by silica gel column chromatography [eluent; hexanerethyl acetate=10:1] to yield 20.5 g of methyl l-benzothiophene-7-carboxylate as yellow oil. NMR(400MHz,CDCl3) δ value: 4.03(3H,s), 7.40(1H,d,J=5.6Hz), 7.4 5(1H,t,J=7.6Hz), 7.58(1H,d,J=5.6Hz), 8.03(1H,dd,J=8.2,0.8Hz), 8.11- 8.13(1H,m) Reference Example 93 4.42 g of 2-(hydroxymethyl)-1-benzothiophene- 5-carbaldehyde was suspended in 44 mL of methylene chloride, to which 20.0 mL of N-ethyldiisopropylamine and 5.2 mL of chloromethyl methyl ether were successively added dropwise at 25 to 30°C, and this mixture was stirred for one hour at room temperature. The reaction mixture was poured into water, and adjusted to pH 7.5 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure to yield 5.40 g of brown oil. The resultant oil was dissolved in 20 mL of tetrahydrofuran, and this solution was added dropwise to 40 mL of an aqueous suspension of silver oxide prepared from 7.62 g of silver nitrate and 3.78 g of sodium hydroxide in an ice bath, and then this mixture was stirred for 1.5 hours at room temperature. The reaction mixture was filtered through Celite, and the filtrate to which 6M hydrochloric acid was added was adjusted to pH 2 followed by addition thereto of ethyl acetate, and then the organic phase was separated therefrom. After the resultant organic phase was washed with a saturated sodium chloride solution, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. 6.00 g of the resultant yellow solid was dissolved in 60 mL of N,N- dimethylformamide, to which 7.90 g of potassium carbonate and 2.1 mL of iodomethane were added, and this mixture was stirred for 30 minutes at room temperature. The reaction mixture was added to a mixture of ethyl acetate and water, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield yellow solid. The resultant solid was dissolved in 50 mL of methanol, to which 10 mL of 6M hydrochloric acid was added, and this mixture was stirred for 30 minutes while heating it under reflux. The reaction mixture was cooled to room temperature and poured into a mixture of ethyl acetate and water for separation of the organic phase. After the resultant organic phase was washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 3.50 g of methyl 2-(hydroxymethyl)-1- benzothiophene-5-carboxylate as yellow solid. NMR(4 00MHz,CDC13) δ value: 2.03(1H,t,J=5.4Hz), 3.96(3H,s), 4.96(2H,d,J=4.8Hz), 7.29(1H,s), 7.86(1H,d,J=8.8Hz), 7.97(1H,dd,J=8.8,1.6Hz), 8.43 (1H,d,J=1.6Hz) INDUSTRIAL APPLICABILITY The novel benzophenone derivatives and the salts thereof in accordance with this invention have excellent anti-arthritic activities and inhibitory effect on bone destruction caused by arthritis, and moreover, provide high safety as well as excellent pharmacokinetics in vivo and thus are useful as therapeutic agent for arthritis. The preventive/ therapeutic agent for diseases in which excessive expression of AP-1 is involved and inhibitors against AP-1 activity, which contain the above benzophenone derivatives or the salts thereof, are useful as preventive/therapeutic agent for diseases in which excessive expression of AP-1 is involved because of their inhibitory activity on AP-1 activity. CLAIMS 1. A benzophenone derivative represented by the following general formula: wherein R1 represents a substituted or unsubstituted heterocyclic group, a substituted phenyl group, or a substituted or unsubstituted alkyl group; Z represents a substituted or unsubstituted alkylene group; R2 represents a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted heterocyclic carbonyl group or a protected or unprotected carboxyl group; R3 represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a protected or unprotected carboxyl group, a protected or unprotected hydroxyl group, a protected or unprotected amino group, a mercapto group, a carbamoyl group or a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group; R4 represents a substituted or unsubstituted alkoxy, cycloalkyloxy, cycloalkenyloxy, alkyl, cycloalkyl, heterocyclic-oxy or heterocyclic group; R5 represents a hydrogen atom, a halogen atom or a hydroxyl group, provided that, when R1 represents a substituted or unsubstituted alkyl group, R4 represents a substituted or unsubstituted cycloalkyloxy group, an alkoxy group substituted with a substituted or unsubstituted phenyl or heterocyclic group or a substituted or unsubstituted heterocyclic-oxy group, or a salt thereof. 2. The benzophenone derivative or a salt thereof according to claim 1, wherein R1 is a substituted or unsubstituted heterocyclic group or a substituted phenyl group; R2 is a carboxyl group protected or unprotected with an alkyl group; R3 is a protected or unprotected hydroxyl group; R4 is a substituted or unsubstituted cycloalkyloxy group; R5 is a hydrogen atom; and Z is an alkylene group. 3. The benzophenone derivative or a salt thereof according to claim 1 or 2, wherein R1 is a substituted or unsubstituted heterocyclic group; R2 is a carboxyl group; and R3 a is hydroxyl group. 4. The benzophenone derivative or a salt thereof according to claim 1, wherein R1 is a substituted or unsubstituted heterocyclic group or a substituted phenyl group; R2 is a carboxyl group protected with a substituted alkyl group; R3 is a protected or unprotected hydroxyl group; R4 is a substituted or unsubstituted cycloalkyloxy group; R5 is a hydrogen group; and z is an alkylene group. 5. The benzophenone derivative or a salt thereof as claimed in claim 1 or 4, wherein R1 is a substituted or unsubstituted heterocyclic group; R2 is a carboxyl group protected with a substituted alkyl group; and R3 is a hydroxyl group. Dated this 5th day of May 2004 A benzophenone derivative represented by the following formula: wherein R1 represents, for example, an optionally substituted heterocyclic group, or a substituted phenyl group; Z represents, for example, an alkylene group; R2 represents, for example, a carboxyl group optionally protected with alkyl; R3 represents, for example, an optionally protected hydroxyl group; R4 represents, for example, an optionally substituted cycloalkyloxy group; and R5 represents, for example, a hydrogen atom, or a salt thereof has anti-arthritic activity, inhibits bone destruction caused by arthritis, and provides high safety and excellent pharmacokinetics and thus is useful as therapeutic agent for arthritis. These compounds have inhibitory effect on AP-1 activity and are useful as preventive or therapeutic agent for diseases in which excessive expression of AP-1 is involved.

Full Text

DESCRIPTION
NOVEL BENZOPHENONE DERIVATIVES OR SALTS THEREOF
TECHNICAL FIELD
The present invention relates to novel
benzophenone derivatives or the salts thereof that have
anti-arthritic activities and inhibitory effect on bone
destruction caused by arthritis and provide preventive,
therapeutic and improving effect against arthritic
diseases. Further, the invention relates to
preventive/therapeutic agent for diseases, in which
excessive expression of AP-1 is involved, and
inhibitors against AP-1 activity, which contain the
above benzophenone derivatives or the salts thereof.
BACKGROUND ART
Arthritic disease such as connective tissue
diseases, represented by rheumatoid arthritis, and
osteoarthritis brings on joint dysfunction by the
progression of cartilage/bone destruction and has a
large effect on patients' daily life.
Up until now, for drug treatment for
rheumatoid arthritis and other arthritis, have been
used non-steroidal anti-inflammatory drugs (NSAIDs)
such as aspirin and indomethacin, disease modifying
antirheumatic drugs (DMARDs) such as gold preparation
and D~penicillamine, immunosuppressive drugs such as

methotrexate, and adrenocorticoids. However, therapies
currently in use cannot completely inhibit the progress
of bone destruction, which is the most important
problem of concern with arthritis, and are difficult to
apply to patients for a long period of time because of
adverse effects occurring in association with the drugs
used and thereby satisfactory treatment has not been
given to patients to date.
To overcome the above problem, studies have
been performed; for example, Japanese Patent Laid-Open
No. 2000-336063 discloses benzophenone derivatives that
are effective in the treatment for mouse collagen-
induced arthritis. However, it is still expected that
the benzophenone derivatives having anti-arthritic
activities provide a further improvement in anti-
arthritic activities and inhibitory effect on bone
destruction caused by arthritis, safety, and
pharmacokinetics.
Further, it has been hoped that
preventive/therapeutic agent for diseases, in which
excessive expression of AP-1 is involved, are developed
which provide inhibitory effect on the activity of
transcription factor AP-1, suppress excessive
expression of a variety of genes based on their
inhibitory effect on AP-1, and produce less adverse
effects.

DISCLOSURE OF THE INVENTION
Under these conditions, the inventors of this
invention directed tremendous research effort toward
coming up to the above expectation and hope, and they
have found that benzophenone derivatives represented by
the following general formula:

wherein
R1 represents a substituted or unsubstituted
heterocyclic group, a substituted phenyl group or a
substituted or unsubstituted alkyl group;
Z represents a substituted or unsubstituted
alkylene group;
R2 represents a substituted or unsubstituted
heterocyclic group, a substituted or unsubstituted
heterocyclic carbonyl group or a protected or
unprotected carboxyl group;
R3 represents a hydrogen atom, a halogen atom,
a cyano group, a nitro group, a protected or
unprotected carboxyl group, a protected or unprotected
hydroxyl group, a protected or unprotected amino group,
a mercapto group, a carbamoyl group or a substituted

or unsubstituted alkyl, alkenyl, cycloalkyl, aryl,
aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl,
aryloxycarbonyl, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkylamino, acylamino,
alkylsulfonylamino, arylsulfonylamino or heterocyclic
group;
R4 represents a substituted or unsubstituted
alkoxy, cycloalkyloxy, cycloalkenyloxy, alkyl,
cycloalkyl, heterocyclic-oxy or heterocyclic group;
R5 represents a hydrogen atom, a halogen atom
or a hydroxyl group;
provided that, when R1 represents a
substituted or unsubstituted alkyl group, R4 represents
a substituted or unsubstituted cycloalkyloxy group, an
alkoxy group substituted with a substituted or
unsubstituted phenyl or heterocyclic group, or a
substituted or unsubstituted heterocyclic-oxy group,
or the salts thereof have excellent anti-
arthritic action as well as inhibitory action against
bone destruction caused by arthritis, and moreover,
high safety and excellent pharmacokinetics. They also
have found that the compounds of this invention provide
AP-1 inhibitory action and are useful as
preventive/therapeutic agent for diseases, in which
excessive expression of AP-1 is involved. And they
have finally accomplished this invention.
The compounds of this invention are expected
to have AP-1 inhibitory action and be effective in the

treatment and the prevention of diseases in which AP-1
related genes are involved.
In the following the compounds of this
invention will be described in detail.
In this specification, unless otherwise
specified, halogen atoms mean fluorine, chlorine,
bromine and iodine atoms; alkyl groups mean straight-
or branched-chain C1_12 alkyl groups such as methyl,
ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,
isobutyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl
and octyl groups; lower alkyl groups mean straight- or
branched-chain C1-6 alkyl groups such as methyl, ethyl,
n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,
tert-butyl, pentyl and isopentyl groups; halogeno lower
alkyl groups mean straight- or branched-chain halogeno-
C1-6 alkyl groups such as fluoromethyl, chloromethyl,
bromomethyl, dichloromethyl, trifluoromethyl,
trichloromethyl, chloroethyl, dichloroethyl,
trichloroethyl and chloropropyl groups; lower alkoxy
lower alkyl groups mean straight- or branched-chain C1-6
alkoxy-C1-6 alkyl groups such as methoxymethyl,
ethoxymethyl, n-propoxymethyl, methoxyethyl and
ethoxyethyl groups; hydroxy lower alkyl groups mean
straight- or branched-chain hydroxy-C1-6 alkyl groups
such as hydroxymethyl, hydroxyethyl and hydroxypropyl
groups; amino lower alkyl groups mean amino-C1-6 alkyl
groups such as aminomethyl, aminoethyl and aminopropyl
groups; alkenyl groups mean straight- or branched-chain

C2-12 alkenyl groups such as vinyl, allyl, propenyl,
isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl,
heptenyl and octenyl groups; lower alkenyl groups mean
straight- or branched-chain C2-6 alkenyl groups such as
vinyl, allyl, propenyl, isopropenyl, butenyl,
isobutenyl and pentenyl groups; cycloalkyl groups mean
C3-7 cycloalkyl groups such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl group;
cycloalkyloxy groups mean C3-7 cycloalkyloxy groups such
as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,
cyclohexyloxy or cyclopentyloxy group; cycloalkenyloxy
groups mean C5-7 cycloalkenyloxy groups such as
cyclopentenyloxy and cyclohexenyloxy groups; aryl
groups mean, for example, phenyl, tolyl and naphthyl
groups; aralkyl groups mean ar- C1-12 alkyl groups such
as benzyl, diphenylmethyl, trityl, phenethyl, 4-
methylbenzyl and naphthylmethyl groups; ar- lower alkyl
groups mean ar- C1-6 alkyl groups such as benzyl,
diphenylmethyl, trityl and phenethyl groups; aryloxy
groups mean, for example, phenoxy and naphthoxy groups;
aryloxycarbonyl groups mean, for example,
phenoxycarbonyl and naphthoxycarbonyl groups; alkoxy
groups mean straight- or branched-chain C1-12 alkoxy
groups such as methoxy, ethoxy, n-propoxy, isopropoxy,
n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy,
isopentyloxy, hexyloxy, heptyloxy and octyloxy groups;
lower alkoxy groups mean straight- or branched-chain C1-6
alkoxy groups such as methoxy, ethoxy, n-propoxy,

isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-
butoxy, pentyloxy and isopentyloxy groups; alkylene
groups mean straight- or branched-chain C1-12 alkylene
groups such as methylene, ethylene and propylene
groups; alkoxycarbonyl groups mean straight- or
branched-chain C1-12 alkoxycarbonyl groups such as
methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,
isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl,
sec-butoxycarbonyl, tert-butoxycarbonyl and
pentyloxycarbonyl groups; lower alkoxycarbonyl groups
mean straight- or branched-chain C1-6 alkyloxycarbonyl
groups such as methoxycarbonyl, ethoxycarbonyl and
propoxycarbonyl groups; lower alkoxycarbonyl lower
alkyl groups mean straight- or branched-chain C1-6
alkoxycarbonyl-C1-6 alkyl groups such as
methoxycarbonylmethyl, ethoxycarbonylmethyl, n-
propoxycarbonylmethyl, methoxycarbonylethyl and
ethoxycarbonylethyl groups; lower alkoxyimino groups
mean straight- or branched-chain C1-6 alkoxyimino groups
such as methoxyimino and ethoxyimino groups; alkylamino
groups mean straight- or branched-chain C1-l2 alkylamino
groups such as methylamino, ethylamino, propylamino,
butylamino, pentylamino, hexylamino, heptylamino and
octylamino groups; lower alkylamino groups mean
straight- or branched-chain mono- or di- C1-6 alkylamino
groups such as methylamino, ethylamino, propylamino,
dimethylamino, diethylamino and methylethylamino
groups; lower alkylamino lower alkyl groups mean mono-

or di- C1-6 alkylamino C1-6 alkyl groups such as
methylaminomethyl, methylaminoethyl, ethylaminomethyl,
methylaminopropyl, propylaminoethyl,
dimethylaminomethyl, diethylaminomethyl,
diethylaminoethyl and dimethylaminopropyl groups; lower
alkylidene groups mean C1-6 alkylidene groups such as
methylene, ethylidene, propylidene and isopropylidene
groups; nitrogen-containing heterocyclic groups mean 5-
or 6-membered-ring, condensed-ring or bridged-ring
heterocyclic groups each of which contains one or more
nitrogen atoms as hetero atoms forming the ring and
optionally one or more oxygen atoms or sulfur atoms,
such as pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl,
imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl,
pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl,
quinolizinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, quinuclidinyl, quinazolyl,
thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl,
imidazolinyl, imidazolidinyl, pyrazolinyl,
pyrazolidinyl, purinyl and indazolyl groups;
heterocyclic rings mean the above described nitrogen-
containing heterocyclic groups and 5- or 6-membered-
ring, condensed-ring or bridged-ring heterocyclic
groups each of which contains at least one or more
heteroatoms selected from the group consisting of
nitrogen, oxygen and sulfur atoms and optionally one or
more oxygen and sulfur atoms as heteroatoms forming the
ring, such as furyl, thienyl, 4-methyl-2-oxo-l,3-dioxol,

benzothienyl, pyranyl, isobenzofuranyl, oxazolyl,
benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl,
benzisoxazolyl, benzothiazolyl, quinoxalyl,
dihydroquinoxalinyl, 2,3-dihydrobenzothienyl, 2,3-
dihydrobenzopyrrolyl, 2,3-dihydro-4H-l-thianaphthyl,
2,3-dihydrobenzofuranyl, benzo[b]dioxanyl, imidazo[2,3-
a]pyridyl, benzo[b]piperazinyl, chromenyl, isothiazolyl,
isoxazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl,
isoindolyl and isoquinolyl groups; heterocyclic
carbonyl groups mean heterocyclic -CO- groups such as
4-hydroxy-2-(5H)-furanocarbonyl, morpholinocarbonyl,
piperazinocarbonyl or pyrrolidinocarbonyl group; acyl
groups mean, for example, formyl group, straight- or
branched-chain C2-12 alkanoyl groups such as acetyl,
isovaleryl, propionyl and pivaloyl, aralkylcarbonyl
groups such as benzylcarbonyl group, aroyl groups such
as benzoyl and naphthoyl groups, and heterocyclic
carbonyl groups such as nicotinoyl, thenoyl,
pyrrolidinocarbonyl and furoyl groups; acylamino groups
mean C1-6 acylamino groups such as formylamino,
acetylamino, propionylamino and butyrylamino groups;
alkanoyloxy groups mean C2-12 alkanoyloxy groups such as
acetyloxy, propionyloxy and pivaloyloxy groups; cyclic
amino groups mean both saturated and unsaturated cyclic
amino groups, each of which optionally contains, in the
ring, one or more heteroatoms such as nitrogen, oxygen
and sulfur atoms and carbonyl-carbons and may be
monocyclic or di- to tricyclic, in more particular,

saturated or unsaturated 3- to 7-membered-ring
monocyclic amino groups containing one nitrogen atom,
such as aziridin-1-yl, azetizin-1-yl, pyrrolidin-1-yl,
pyrrolin-1-yl, pyrrol-1-yl, dihydropyridin-1-yl,
piperidin-1-yl, dihydroazepin-1-yl and perhydroazepin-
1-yl groups, saturated or unsaturated 3- to 7-membered-
ring monocyclic amino groups containing two nitrogen
atoms, such as imidazol-1-yl, imidazolidin-1-yl,
imidazolin-1-yl, pyrazolidin-1-yl, piperazin-1-yl, 1,4-
dihydropyrazin-1-yl, 1,2-dihydropyrimidin-l-yl,
perhydropyrazin-1-yl and homopiperazin-1-yl groups,
saturated or unsaturated 3- to 7-membered-ring
monocyclic amino groups containing 3 or more nitrogen
atoms, such as 1,2,4-triazol-l-yl, 1,2,3-triazol-l-yl,
1,2-dihydro-l,2,4-triazin-l-yl and perhydro-S-triazin-
1-yl, saturated or unsaturated 3- to 7-membered-ring
monocyclic amino groups containing 1 to 4 heteroatoms
selected from the group consisting of oxygen and sulfur
atoms, besides nitrogen atoms, such as oxazolidin-3-yl,
isoxazolidin-2-yl, morpholin-4-yl, thiazolidin-3-yl,
isothiazolidin-2-yl, thiomorpholin-4-yl,
homothiomorpholin-4-yl and 1,2,4-thiaziazolin-2-yl
groups, saturated or unsaturated di- to tricyclic amino
groups such as isoindolin-2-yl, indolin-1-yl, 1H-
indazol-1-yl, purin-7-yl and tetrahydroquinolin-1-yl
groups, and spiro or bridged saturated or unsaturated
5- to 12-membered cyclic amino groups such as 5-
azaspiro[2.4]heptan-5-yl, 2,8-diazabicyclo[4.3.0]nonan-

8-yl, 3-azabicyclo[3.1.0]hexan-3-yl, 2-oxa-5,8-
diazabicyclo[4.3.0]nonan-8-yl, 2,8-
diazaspiro[4.4]nonan-2-yl and 7-
azabicyclo[2.2.1]heptan-7-yl groups; alkylthio groups
mean straight- or branched-chain Cx_12 alkylthio groups
such as methylthio, ethylthio, n-propylthio,
isopropylthio, n-butylthio, isobutylthio, sec-butylthio,
tert-butylthio, pentylthio, isopentylthio, hexylthio,
heptylthio and octylthio groups; lower alkylthio groups
mean straight- or branched-chain C1_6 alkylthio groups
such as methylthio, ethylthio, n-propylthio,
isopropylthio, n-butylthio, isobutylthio, sec-butylthio,
tert-butylthio, pentylthio and isopentylthio groups;
alkylsulfinyl groups mean straight- or branched-chain
C1-12 alkylsulf inyl groups such as methylsulf inyl,
ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-
butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl,
tert-butylsulfinyl, pentylsulfinyl, isopentylsulfinyl,
hexylsulfinyl, heptylsulfinyl and octylsulfinyl groups;
alkylsulfonyl groups mean straight- or branched-chain
C1-12 alkylsulf onyl groups such as methylsulf onyl,
ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-
butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl,
tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl,
hexylsulfonyl, heptylsulfonyl and octylsulfonyl groups;
alkylsulfonylamino groups mean straight- or branched-
chain C1-12 alkylsulfonylamino groups such as
methylsulfonylamino, ethylsulfonylamino, n-

propylsulfonylamino, isopropylsulfonylamino, n-
butylsulfonylamino, isobutylsulfonylamino, sec-
butylsulfonylamino, tert-butylsulfonylamino,
pentylsulfonylamino, isopentylsulfonylamino,
hexylsulfonylamino, heptylsulfonylamino and
octylsulfonylamino groups; arylsulfonylamino groups
mean aryl-S02NH-groups such as phenylsulfonylamino and
naphthylsulfonylamino groups; lower alkylsulfinyl
groups mean straight- or branched-chain C1-6
alkylsulfinyl groups such as methylsulfinyl,
ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-
butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl,
tert-butylsulfinyl, pentylsulfinyl and hexylsulfinyl
groups; lower alkylsulfonyl groups mean straight- or
branched-chain C1-6 alkylsulfonyl groups such as
methylsulfonyl, ethylsulfonyl, n-propylsulfonyl,
isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl,
sec-butylsulfonyl, tert-butylsulfonyl and
pentylsulfonyl; lower alkylcarbamoyl groups mean mono-
or di- C1-6 alkylcarbamoyl groups such as methylcarbamoyl,
ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl,
diethylcarbamoyl and methylethylcarbamoyl groups; lower
alkylsulfonylamino groups mean straight- or branched-
chain C1-6 alkylsulfonylamino groups such as
methylsulfonylamino, ethylsulfonylamino, n-
propylsulfonylamino, isopropylsulfonylamino, n-
butylsulfonylamino, isobutylsulfonylamino, sec-
butylsulfonylamino, tert-butylsulfonylamino and

pentylsulfonylamino groups; lower
alkylsulfonylcarbamoyl groups mean straight- or
branched-chain C1-6 alkylsulf onylcarbamoyl groups such as
methylsulfonylcarbamoyl, ethylsulfonylcarbamoyl, n-
propylsulfonylcarbamoyl, isopropylsulfonylcarbamoyl, n-
butylsulfonylcarbamoyl, isobutylsulfonylcarbamoyl, sec-
butylsulfonylcarbamoyl, tert-butylsulfonylcarbamoyl and
pentylsulfonylcarbamoyl groups; lower
alkylaminosulfonyl groups mean mono- or di- C1-6
alkylaminosulfonyl groups such as methylaminosulfonyl,
ethylaminosulfonyl, propylaminosulfonyl,
dimethylaminosulfonyl, diethylaminosulfonyl and
methylethylaminosulfonyl groups; carboxyl-lower alkenyl
groups mean, for example, straight- or branched-chain
carboxyl-substituted C2-6 alkenyl groups; hydroxyl-
heterocyclic groups mean, for example, hydroxyl-
substituted heterocyclyl groups; lower alkyl-
heterocyclic groups mean, for example, heterocyclic
groups each having been substituted with a straight- or
branched-chain lower alkyl group; lower alkoxy-lower
alkoxy groups mean straight- or branched-chain C1-6
alkoxy groups each having been substituted with a lower
alkoxy group; heterocyclic-lower alkyl groups mean
heterocyclic -CH2- groups such as pyrrolidinylmethyl,
piperidylmethyl, piperazinylmethyl, pyrazolylmethyl,
tetrahydropyridylmethyl, morpholinylmethyl,
thiomorpholinylmethyl, tetrahydroquinolinylmethyl,
tetrahydroisoquinolinylmethyl, quinuclidinylmethyl,

tetrazolylmethyl, thiadiazolylmethyl,
pyrazolidinylmethyl, purinylmethyl, indazolylmethyl, 2-
thienylmethyl, furfuryl, 2-pyranylmethyl, 1-
isobenzofurylmethyl, 2-pyrrolylmethyl, 1-
imidazolylmethyl, 1- pyrazolylmethyl, 3-
isothiazolylmethyl, 3-isoxazolylmethyl, 2-pyridylmethyl,
2-pyrazinylmethyl, 2-pyrimidinylmethyl, 2-
pyridazinylmethyl, 1-isoindolylmethyl, 2-indolylmethyl,
1-isoquinolylmethyl, 2-quinolylmethyl, 1-
phthalazinylmethyl, 2-naphthyridinylmethyl, 2-
quinoxalinylmethyl, 2-quinazolinylmethyl, 3-
cinnolinylmethyl, 2-oxazolylmethyl, 2-thiazolylmethyl,
2-benzo[b]furylmethyl, 2-benzo[b]thienylmethyl, 2-
benz[d]imidazolylmethyl and 2-benz[d]oxazolylmethyl
groups; leaving groups mean halogen atoms such as
fluorine, chlorine, bromine and iodine atoms,
alkoxysulfonyloxy groups such as methoxysulfonyloxy
group, alkylsulfonyloxy groups such as
methylsulfonyloxy group, and arylsulfonyloxy groups
such as p-toluenesulfonyloxy and benzenesulfonyloxy
groups; and heterocyclic oxy groups mean groups
represented by heterocyclic-O- each of which binds via
an oxygen atom, such as pyrrolidinyloxy, piperidinyloxy,
tetrahydrofuranyloxy, tetrahydropyranyloxy and
tetrahydrothiopyranyloxy groups.
Carboxyl-protecting groups include all the
groups that can be used as ordinary carboxyl-protecting
groups. Concrete examples are alkyl such as methyl,

ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl,
and tert-butyl; aryl such as phenyl and naphthyl;
aralkyl such as benzyl, diphenylmethyl, trityl, p-
nitrobenzyl, p-methoxybenzyl, and bis(p-
methoxyphenyl)methyl; acyl-alkyl such as acetylmethyl,
benzoylmethyl, p-nitrobenzoylmethyl, p-
bromobenzoylmethyl, and p-methanesulfonylbenzoylmethyl;
oxygen-containing heterocyclyl such as 2-
tetrahydropyranyl and 2-tetrahydrofuranyl; halogeno-
alkyl such as 2,2,2-trichloroethyl; alkylsilylalkyl
such as 2-(trimethylsilyl)ethyl; acyloxyalkyl such as
acetoxymethyl, propionyloxymethyl, and
pivaloyloxymethyl; nitrogen-containing heterocyclic
alkyl such as phthalimidomethyl and succinimidomethyl;
cycloalkyl such as cyclohexyl; alkoxyalkyl such as
methoxymethyl, methoxyethoxymethyl, and 2-
(trimethylsilyl)ethoxymethyl; ar-alkoxy-alkyl such as
benzyloxymethyl; alkylthio-alkyl such as
methylthiomethyl and 2-methylthioethyl; arylthio-alkyl
such as phenylthiomethyl; alkenyl such as 1,1-dimethyl-
2-propenyl, 3-methyl-3-butenyl, and allyl; and
substituted silyl such as trimethylsilyl, triethylsilyl,
triisopropylsilyl, diethylisopropylsilyl, tert-
butyldimethylsilyl, tert-butyldiphenylsilyl,
diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.
Of the above carboxyl-protecting groups, are preferred
alkyl groups such as methyl, ethyl, isopropyl and
isobutyl groups; aralkyl groups such as benzyl group;

and substituted silyl groups such as trimethylsilyl
group.
Amino-protecting groups include all the
groups that can be used as ordinary amino-protecting
groups. Concrete examples are acyl such as
trichloroethoxycarbonyl, tribromoethoxycarbonyl,
benzyloxycarbonyl, 2-ethylhexyloxycarbonyl, p-
nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl,
(mono-, di-, tri-)chloroacetyl, trifluoroacetyl,
phenylacetyl, formyl, acetyl, benzoyl, tert-
pentyloxycarbonyl, tert-butoxycarbonyl, p-
methoxybenzyloxycarbonyl, 3,4-
dimethoxybenzyloxycarbonyl, 4-
(phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl,
diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl,
isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl,
1-adamantyloxycarbonyl, and 8-quinolyloxycarbonyl;
aralkyl such as benzyl, diphenylmethyl, and trityl;
alkoxy-alkyl such as methoxymethyl, benzyloxymethyl, 2-
methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2-
(trimethylsilyl)ethoxymethyl, and 1-ethoxyethyl;
alkylthio-alkyl such as methylthiomethyl; arylthio such
as 2-nitrophenylthio and 2,4-dinitrophenylthio; alkyl-
or aryl-sulfonyl such as methanesulfonyl and p-
toluenesulfonyl; dialkylamino-alkylidene such as N,N-
dimethylaminomethylene; aralkylidene such as
benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-
chlorobenzylidene, and 2-hydroxy-l-naphthylmethylene;

nitrogen-containing heterocyclic alkylidene such as 3-
hydroxy-4-pyridylmethylene; cycloalkylidene such as
cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-
ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene,
and 3,3-dimethyl-5-oxycyclohexylidene; diaryl- or
diaralkylphosphoryl such as diphenylphosphoryl and
dibenzylphosphoryl; oxygen-containing heterocyclic
alkyl such as 5-methyl-2-oxo~2H-l,3-dioxol-4-yl-methyl;
substituted silyl such as trimethylsilyl;
hydroxylamino; and nitroso and nitro. Of the above
amino-protecting groups, are preferred acyl groups such
as tert-butoxycarbonyl and 2-ethylhexyloxycarbonyl
groups; aralkyl groups such as trityl group;
alkoxyalkyl groups such as methoxymethyl group; alkyl-
or aryl-sulfonyl groups such as methanesulfonyl and p-
toluenesulfonyl groups; substituted silyl groups such
as trimethylsilyl group; hydroxylamino group; nitroso
group; and nitro group.
Hydroxyl-protecting groups include all the
groups that can be used as ordinary hydroxyl-protecting
groups. Concrete examples are acyl such as
benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-
bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl,
ethoxycarbonyl, tert-butoxycarbonyl, 1,1-
dimethylpropoxycarbonyl, isopropoxycarbonyl,
isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-
trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl,

2-(trimethylsilyl)ethoxycarbonyl, 2-
(phenylsulfonyl)ethoxycarbonyl, 2-
(triphenylphosphonio)ethoxycarbonyl, 2-
furfuryloxycarbonyl, 1-adamantyloxycarbonyl,
vinyloxycarbonyl, allyloxycarbonyl, S-
benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-
quinolyloxycarbonyl, acetyl, formyl, chloroacetyl,
dichloroacetyl, trichloroacetyl, trifluoroacetyl,
methoxyacetyl, phenoxyacetyl, pivaloyl, and benzoyl;
alkyl such as methyl, isopropyl, isobutyl, tert-butyl,
2,2,2-trichloroethyl, and 2-trimethylsilylethyl;
alkenyl such as allyl; aralkyl such as benzyl, p-
methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, and
trityl; oxygen-containing and sulfur-containing
heterocyclyl such as tetrahydrofuryl, tetrahydropyranyl,
and tetrahydrothiopyranyl; alkoxy-alkyl such as
methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl,
2,2,2-trichloroethoxymethyl, 2-
(trimethylsilyl)ethoxymethyl, and 1-ethoxyethyl;
alkylthio-alkyl such as methylthiomethyl; alkyl- and
aryl-sulfonyl such as methanesulfonyl and p-
toluenesulfonyl; and substituted silyl such as
trimethylsilyl, triethylsilyl, triisopropylsilyl,
diethylisopropylsilyl, tert-butyldimethylsilyl, tert-
butyldiphenylsilyl, diphenylmethylsilyl, and tert-
butylmethoxyphenylsilyl. Of the above hydroxyl-
protecting groups, are preferred acyl groups such as
acetyl group; alkyl groups such as methyl, isopropyl

and isobutyl groups; aralkyl groups such as benzyl
group; oxygen-containing heterocyclic groups such as
tetrahydropyranyl group; alkoxyalkyl groups such as
methoxymethyl group; and arylsulfonyl groups such as p-
toluenesulfonyl group.
Phenolic hydroxyl-protecting groups include
all the groups that can be used as ordinary phenol-
protecting groups. Concrete examples are acyl such as
benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-
bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl,
ethoxycarbonyl, tert-butoxycarbonyl, 1,1-
dimethylpropoxycarbonyl, isopropoxycarbonyl,
isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-
trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl,
2-(trimethylsilyl)ethoxycarbonyl, 2-
(phenylsulfonyl)ethoxycarbonyl, 2-
(triphenylphosphonio)ethoxycarbonyl, 2-
furfuryloxycarbonyl, 1-adamantyloxycarbonyl,
vinyloxycarbonyl, allyloxycarbonyl, S-
benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-
quinolyloxycarbonyl, acetyl, formyl, chloroacetyl,
dichloroacetyl, trichloroacetyl, trifluoroacetyl,
methoxyacetyl, phenoxyacetyl, pivaloyl, and benzoyl;
alkyl such as methyl, isopropyl, isobutyl, tert-butyl,
2,2,2-trichloroethyl, and 2-trimethylsilylethyl;
alkenyl such as allyl; aralkyl such as benzyl, p-
methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, and

trityl; oxygen-containing and sulfur-containing
heterocyclyl such as tetrahydrofuryl, tetrahydropyranyl,
and tetrahydrothiopyranyl; alkoxy-alkyl such as
methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl,
2, 2, 2-trichloroethoxymethyl, 2-
(trimethylsilyl)ethoxymethyl, and 1-ethoxyethyl;
alkylthio-alkyl such as methylthiomethyl; alkyl-, and
aryl-sulfonyl such as methanesulfonyl and p-
toluenesulfonyl; and substituted silyl such as
trimethylsilyl, triethylsilyl, triisopropylsilyl,
diethylisopropylsilyl, tert-butyldimethylsilyl, tert-
butyldiphenylsilyl, diphenylmethylsilyl, and tert-
butylmethoxyphenylsilyl. Of the above phenolic
hydroxyl-protecting groups, are preferred acyl groups
such as acetyl group; alkyl groups such as methyl,
isopropyl and isobutyl groups; aralkyl groups such as
benzyl group; oxygen-containing heterocyclic groups
such as tetrahydropyranyl group; alkoxyalkyl groups
such as methoxymethyl group; and arylsulfonyl groups
such as p-toluenesulfonyl group.
Phosphoryl-protecting groups include all the
groups that can be used as ordinary phosphoryl-
protecting groups. Concrete examples are alkyl such as
methyl, ethyl, isopropyl, tert-butyl, 2-cyanoethyl, 2-
(trimethylsilyl)ethyl, 2-(4-nitrophenyl)ethyl, 2-
(benzylsulfonyl)ethyl, and 2,2,2-trichloroethyl;
alkenyl such as allyl; aralkyl such as benzyl, 4-
nitrobenzyl, and diphenylmethyl; aryl such as phenyl,

2-methylphenyl, 4-chlorophenyl, and 4-nitrophenyl; and
amino such as anilino and isopropylamino.
Sulfo-protecting groups include all the
groups that can be used as ordinary sulfonyloxy-
protecting groups. Concrete examples are aryl groups
such as phenyl and 2,4-dinitrophenyl groups; alkyl
groups such as tert-butyl, neopentyl, isopropyl and
isobutyl groups; and 1-adamantyl group.
In this invention, the improvement in
pharmacokinetics means, for example, the reduction in
enzyme inhibitory effect of cytochrome P450 and the
improvement in metabolic stability, in more particular,
the reduction in enzyme inhibitory effect of CYP2C9 etc.
and the decrease of in vivo metabolite ratio.
Salts of the compounds represented by general
formula [1] include, for example, commonly known salts
produced in the compounds' basic groups such as amino
group and produced in the compounds' acidic groups such
as hydroxyl and carboxyl groups. Salts produced in the
compounds' basic groups include, for example, salts
produced with mineral acids such as hydrochloric acid,
hydrobromic acid and sulfuric acid; salts produced with
organic carboxylic acids such as tartaric acid, formic
acid, citric acid, trichloroacetic acid and
trifluoroacetic acid; and salts produced with sulfonic
acids such as methanesulfonic acid, benzenesulfonic
acid, p-toluenesulfonic acid, mesitylenesulfonic acid
and naphthalenesulfonic acid. Salts produced in the

compounds' acidic groups include, for example, salts
produced with alkaline metals such as sodium and
potassium; salts produced with alkaline earth metals
such as calcium and magnesium; ammonium salts; and
salts produced with nitrogen-containing organic bases
such as trimethylamine, triethylamine, tributylamine,
pyridine, N,N-dimethylaniline, N-methylpiperidine, N-
methylmorpholine, diethylamine, dicyclohexylamine,
procaine, dibenzylamine, N-benzyl-p-phenethylamine and
N,N'-dibenzylethylenediamine. Of the above salts of
the compounds represented by the general formula [1],
preferable are pharmacologically acceptable salts.
Each substituent of the groups R1, R2, R3 and
R4 is optionally substituted with one or more groups
selected from the group consisting of cyano, nitro,
halogen, carboxyl that may be protected, phosphoryl,
hydroxyl, amino, carbamoyl, hydroxycarbamoyl,
aminosulfonyl, sulfo, hydroxy lower alkyl, amino lower
alkyl, cyclic amino, lower alkylamino and lower
alkylamino lower alkyl, lower alkyl, lower alkenyl,
lower alkoxy, lower alkoxycarbonyl, acyl, aryl,
heterocyclyl, cycloalkyl, aralkyl, lower alkylidene,
mercapto, lower alkylthio, lower alkylsulfinyl, lower
alkylsulfonyl, lower alkylsulfonylcarbamoyl, lower
alkylcarbamoyl, lower alkylsulfonylamino, lower
alkylaminosulfonyl, carboxyl lower alkenyl,
hydroxyheterocyclyl, lower alkyl heterocyclyl, lower
alkoxy lower alkoxy, halogeno lower alkyl, lower alkoxy

lower alkyl, lower alkoxycarbonyl lower alkyl, and
lower alkoxyimino.
The alkylene group of Z is optionally
substituted with one or more groups selected from the
group consisting of cyano, nitro, halogen, carboxyl
that may be protected, carbamoyl, hydroxycarbamoyl,
hydroxy lower alkyl, amino lower alkyl and lower
alkylamino lower alkyl, lower alkyl, lower
alkoxycarbonyl, acyl, aryl, heterocyclyl, cycloalkyl,
lower alkenyl, aralkyl, lower alkylsulfonylcarbamoyl,
lower alkylcarbamoyl, halogeno lower alkyl, lower
alkoxy lower alkyl, and lower alkoxycarbonyl lower
alkyl.
The substituents of the above described
substituents are further optionally substituted with
the groups exemplified above as substituents.
The heterocyclic groups and cyclic amino
groups of the substituents of the above described
substituents are optionally substituted with keto
groups.
Preferable substituents of the compounds of
this invention are as follows.
In the compounds of this invention, R1 is
preferably an optionally substituted heterocyclyl group
or a substituted phenyl group, more preferably an
optionally substituted heterocyclyl group, much more
preferably an optionally substituted benzisoxazolyl
group, and most preferably hydroxyl-substituted

benzisoxazolyl group.
In the compounds of this invention, R2 is
preferably a heterocyclic carbonyl group optionally
substituted with a hydroxyl group or an alkyl group or
a carboxyl group optionally protected with an alkyl
group, more preferably a carboxyl group optionally
protected with an alkyl group, much more preferably a
carboxyl group optionally protected with an ethyl group,
and most preferably a carboxyl group.
Further, in the compounds of this invention,
R2 is preferably a carboxyl group protected with a
substituted alkyl group and more preferably a carboxyl
group protected with an alkyl group that has been
substituted with a 4-morpholinyl group.
In the compounds of this invention, R3 is
preferably a halogen atom, a lower alkyl group, or an
optionally protected hydroxyl group, more preferably an
optionally protected hydroxyl group, and much more
preferably a hydroxyl group.
In the compounds of this invention, R4 is
preferably an optionally substituted cycloalkyloxy
group, more preferably a cycloalkyloxy group optionally
substituted with an alkyl, alkoxy or optionally
protected hydroxyl group, and much more preferably a
cycloalkyloxy group.
In the compounds of this invention, R5 is
preferably a hydrogen atom.
In the compounds of this invention, Z is

preferably an alkylene group optionally substituted
with a lower alkyl group, more preferably an alkylene
group, and much more preferably a methylene group.
When the substituent of R2 is a carboxyl group,
any one of commonly used carboxyl-protecting groups can
be used as a carboxyl-protecting group. Examples of
such carboxyl-protecting groups are the above described
carboxyl-protecting groups.
Specifically, the carboxyl-protecting groups
include, for example, alkyl groups such as methyl,
ethyl, n-propyl, isopropyl, n-butyl and tert-butyl
groups; alkoxycarbonyloxyalkyl groups such as 1-
[(methoxycarbonyl)oxy]ethyl, 1-
[ (ethoxycarbonyl)oxy]ethyl and 1-
[ (isopropoxycarbonyl)oxy]ethyl groups;
cycloalkyloxycarbonyloxyalkyl groups such as 1-
{[(cyclopentyloxy)carbonyl]oxy}ethyl and 1-
{[(cyclohexyloxy)carbonyl]oxy}ethyl groups;
heterocyclic-alkyl groups such as 2-(4-
morpholinyl)ethyl, (5-methyl-2-oxo-l,3-dioxol-4-
yl)methyl and (5-phenyl-2-oxo-1,3-dioxol-4-yl)methyl
groups; and acyloxyalkyl groups such as acetoxymethyl,
propionyloxymethyl and pivaloyloxymethyl groups. Of
the above carboxyl-protecting groups, are preferably
used alkyl groups such as methyl and ethyl groups;
alkoxycarbonyloxyalkyl groups such as 1-
[(ethoxycarbonyl)oxy]ethyl group;
cycloalkyloxycarbonyloxyalkyl groups such as 1-

{[(cyclohexyloxy)carbonyl]oxyjethyl group;
heterocyclic-alkyl groups such as 2-(4-
morpholinyl)ethyl and (5-methyl-2-oxo-l,3-dioxol-4-
yl)methyl groups; and acyloxyalkyl groups such as
pivaloyloxymethyl group, and 2-(4-morpholinyl)ethyl
group is more preferably used.
In the compounds of this invention, a
preferable combination of substituents is such that R1
is an optionally substituted heterocyclyl group, R2 is a
carboxyl group optionally protected with an optionally
substituted alkyl group, R3 is an optionally protected
hydroxyl group, R4 is a cycloalkyloxy group optionally
substituted with an alkyl, alkoxy or optionally
protected hydroxyl group, R5 is a hydrogen atom, and Z
is an alkylene group.
A more preferable combination of substituents
is such that R1 is an optionally substituted
benzisoxazolyl group, R2 is a carboxyl group protected
with an optionally substituted alkyl group, R3 is a
hydroxyl group, R4 is a cycloalkyloxy group, R5 is a
hydrogen atom, and Z is an alkylene group.
Another more preferable combination of
substituents is such that R1 is an optionally
substituted benzisoxazolyl group, R2 is a carboxyl group,
R3 is a hydroxyl group, R4 is a cycloalkyloxy group, R5
is a hydrogen atom, and Z is an alkylene group.
Diseases in which AP-1-related genes are
involved include, for example, autoimmune diseases such

as rheumatoid arthritis, systemic lupus erythematosus,
scleroderma, Behcet's disease, rheumatic fever,
polymyositis, periarteritis nodosa, Sjogren's syndrome,
active chronic hepatitis and glomerulonephritis; a
variety of intractable diseases based on inflammation
such as osteoarthritis, gout, atherosclerosis,
psoriasis, atopic dermatitis and encephalitis;
pulmonary diseases accompanied by granuloma such as
interstitial pneumonia; endotoxin shock; sepsis;
inflammatory colitis; diabetes mellitus; acute
myeloblast leukemia; meningitis; hepatitis; hepatic
disorder; jaundice; liver cirrhosis; liver failure;
atrialmyxoma; Castleman's syndrome; multiple myeloma;
cancer; metastasis of cancer; AIDS; epilepsy; ischemic
heart disease; endothelial proliferative disease
(arteriosclerosis); Alzheimer's disease and ischemic
neuronal death; allograft rejection in transplantation.
The compounds of this invention are particularly
suitably used for autoimmune diseases such as
rheumatoid arthritis, systemic lupus erythematosus,
scleroderma, Behcet's disease, rheumatic fever,
polymyositis, periarteritis nodosa, Sjogren's syndrome,
active chronic hepatitis and glomerulonephritis and
more suitably used for rheumatoid arthritis.
Representative compounds of this invention
include, for example, compounds shown in Table 1 to
Table 11 below. In the tables abbreviations represent
the following meanings.

BTP: benzothiophene, TZ: tetrazole, ODN:
oxadiazolone, TDN: thiadiazolone, BOZ: benzisoxazole,
BTZ: benzisothiazole, QN: quinazolidione, IOZ:
isoxazolole, ITZ: isothiazolole, PZ: pyrazolole, c-
Pent: cyclopentyl, Ms: methanesulfonyl, Ts:
toluenesulfonyl, Ac: acetyl, Py: pyridyl, Me: methyl,
Et: ethyl, Pr: propyl, Bu: butyl, Ph: phenyl, Bn:
benzyl, Moe: 2-(4-morpholinyl)ethyl, Eoe: 1-
[(ethoxycarbonyl)oxy]ethyl, Hoe: 1-
{[(cyclohexyloxy)carbonyl]oxy}ethyl, Pvm:
(pivaloyloxy)methyl, Dom: (5-methyl-2-oxo-l,3-dioxol-4-
yl)methyl, i: iso

When isomers (e.g. optical isomers, geometrical isomers
and tautomers) are present in compounds represented by
the general formula [1] or the salts thereof, this
invention embraces the isomers. This invention also
embraces the solvates, the hydrates and the crystals in
various forms of the compound or the salt thereof.
Then the process of producing the compounds
of this invention will be described.

The compounds of this invention are produced
by combining known processes; for example, they can be
synthesized in accordance with the production processes
A to Q shown below.

wherein R2a and R2aa each represent a carboxyl-protecting
group; Rla represents a group represented by R1 - Z
(wherein R1 and Z represent the same meanings as above);
R4a and R4aa each represent optionally substituted alkyl,
cycloalkyl, heterocyclic, optionally substituted phenyl,

or heterocyclyl-substituted alkyl; R5 represents the
same meaning as above; and X represents a leaving group.
A compound represented by the general formula
[3] can be obtained by dehydrating a compound
represented by the general formula [4]. This
dehydration reaction is an ordinary dehydration
reaction, and the reaction processes include, for
example, processes in which dehydration is carried out
in the presence or absence of acid or dehydrating agent,
in which dehydration is carried out using base,
condensing agent and additive, in which dehydration is
carried out via acid chloride, and in which dehydration
is carried out via acid anhydride.
Acids used in this reaction as the need
arises include, for example, mineral acids such as
hydrochloric acid, sulfuric acid, phosphoric acid and
hydrobromic acid; organic acids such as p-
toluenesulfonic acid and trifluoroacetic acid; and tin
tetrachloride, aluminium chloride and boron trifluoride.
The amount of acid used can be 0.01- to 100-fold of the
mole of a compound represented by the general formula
[4] and preferably 0.01- to 50-fold of the mole of the
same. Dehydrating agents used in this reaction as the
need arises include, for example, phosphorus pentoxide
and polyphosphoric acid. The amount of dehydrating
agent used can be 1- to 1000-fold of the mole of a
compound represented by the general formula [4] and
preferably 1- to 100-fold of the mole of the same.

When using base, condensing agent and
additive in this reaction, bases used in the reaction
include, for example, organic amines such as
dimethylaminopyridine, triethylamine, pyridine and N-
methylmorpholine; and alkaline metal carbonates such as
potassium carbonate and sodium carbonate. The amount
of base used can be 0.5- to 10-fold of the mole of a
compound represented by the general formula [4] and
preferably 1- to 3-fold of the mole of the same.
Condensing agents used in the reaction include, for
example, N,N'-dicyclohexylcarbodiimide, 1,1'-
carbonyldiimidazole, 2-chloro-1-methylpyridinium iodide,
2,2'-dipyridyl disulfide and diphenylphosphoryl azide.
The amount of condensing agent used can be 0.5- to 10-
fold of the mole of a compound represented by the
general formula [4] and preferably 1- to 3-fold of the
mole of the same. Additives used in the reaction
include, for example, 1-hydroxybenzotriazole, N-
hydroxysuccinimide and triphenylphosphine. The amount
of additive used can be 0.5- to 10-fold of the mole of
a compound represented by the general formula [4] and
preferably 1- to 3-fold of the mole of the same.
When using the processes via acid chloride or
acid anhydride, the acid chloride or the acid anhydride
of a compound represented by the general formula [4]
can be obtained by reacting the compound represented by
the general formula [4] with activating agent such as
thionyl chloride, oxalyl chloride, phosphorus

pentachloride, acetic anhydride or ethyl chloroformate.
The amount of activating agent used can be 1- to 20-
fold of the mole of a compound represented by the
general formula [4] and preferably 1- to 5-fold of the
mole of the same. In the reaction for obtaining the
acid chloride of a compound represented by the general
formula [4], N,N-dimethylformamide, as a catalyst, may
be added in amounts of 0.001- to 10-fold of the mole of
the compound represented by the general formula [4] and
preferably 0.01- to 1-fold of the mole of the same.
Solvents used in this reaction are not
limited to any specific ones as long as they do not
adversely affect the reaction. They include, for
example, aromatic hydrocarbons such as benzene and
toluene; ethers such as 1,4-dioxane, tetrahydrofuran
and diethyl ether; esters such as ethyl acetate and
butyl acetate; nitriles such as acetonitrile; amides
such as N,N-dimethylformamide and N,N'-
dimethylacetamide; halogenated hydrocarbons such as
chloroform and methylene chloride; sulfones such as
sulfolane; and sulfoxides such as dimethyl sulfoxide.
These solvents may be used independently or in the form
of a mixture of two or more kinds.
Usually this reaction can be performed at -
78°C to the reflux temperature of the solvent used and
preferably 0 to 150 °C for 30 minutes to 24 hours. The
reaction can also be performed in an atmosphere of
inert gas (e.g. argon, nitrogen).

The reaction for obtaining a compound
represented by the general formula [3] from a compound
represented by the general formula [2] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [3] from
a compound represented by the general formula [4] in
the production process A. Preferably the reaction is
carried out in the presence or absence of acid.
A compound represented by the general formula
[5] can be obtained by subjecting a compound
represented by the general formula [3] and a compound
represented by the general formula [R1a] to Mitsunobu
reaction.
This reaction can be carried out using an
azodicarbonyl compound such as diethyl azodicarboxylate,
diisopropyl azodicarboxylate or
azodicarbonyldipiperidine; and triarylphosphine such as
triphenylphosphine or trialkylphosphine such as tri-n-
butylphosphine. The amount of the compound represented
by the general formula [Rla] used can be 1- to 5-fold
of the mole of the compound represented by the general
formula [3] and preferably 1- to 3-fold of the mole of
the same.
Solvents used in this reaction are not
limited to any specific ones as long as they do not
adversely affect the reaction. They include, for
example, aromatic hydrocarbons such as benzene, toluene
and xylene; ethers such as 1,4-dioxane, tetrahydrofuran,

anisole, diethylene glycol diethyl ether and dimethyl
cellosolve; esters such as methyl acetate and ethyl
acetate; nitriles such as acetonitrile; amides such as
N,N-dimethylformamide and N,N'-dimethylacetamide; and
halogenated hydrocarbons such as chloroform and
methylene chloride. These solvents may be used
independently or in the form of a mixture of two or
more kinds.
Usually this reaction can be performed at -
20 to 120°C and preferably 0 to 50 °C for 30 minutes to
24 hours.
A compound represented by the general formula
[5] can be obtained by reacting a compound represented
by the general formula [3] and a compound represented
by the general formula [R1b] in the presence of base.
The amount of the compound represented by the
general formula [R1b] used can be 1- to 20-fold of the
mole of the compound represented by the general formula
[3] and preferably 1- to 5-fold of the mole of the same.
Bases used in this reaction include, for example,
organic amines such as dimethylaminopyridine,
triethylamine and pyridine; alkaline metal hydrides
such as sodium hydride; and alkaline metal carbonates
such as potassium carbonate and sodium carbonate. The
amount of base used can be 1- to 20-fold of the mole of
the compound represented by the general formula [3] and
preferably 1- to 5-fold of the mole of the same.
Solvents used in this reaction are not limited to any

specific ones as long as they do not adversely affect
the reaction. They include, for example, aromatic
hydrocarbons such as benzene, toluene and xylene;
ethers such as 1,4-dioxane, tetrahydrofuran, anisole,
diethylene glycol diethyl ether and dimethyl
cellosolve; esters such as methyl acetate and ethyl
acetate; nitriles such as acetonitrile; amides such as
N,N-dimethylformamide; halogenated hydrocarbons such as
chloroform and methylene chloride; and sulfoxides such
as dimethyl sulfoxide. These solvents may be used
independently or in the form of a mixture of two or
more kinds.
Usually this reaction can be performed at 0
to 200°C and preferably 25 to 150 °C for 10 minutes to
24 hours.
A compound represented by the general formula
[6] can be obtained by reacting a compound represented
by the general formula [R1c] and a compound represented
by the general formula [5] in the presence of acid or
base.
The compound represented by the general
formula [Rlc] used in this reaction can be used as a
solvent in appropriate amount; however, when using some
other solvent, the amount of the compound used can be
1- to 20-fold of the mole of the compound represented
by the general formula [5] and preferably 1- to 5-fold
of the mole of the same. Acids used in this reaction
include, for example, hydrochloric acid, sulfuric acid,

trimethylsilyl chloride and boron trifluoride. The
amount of acid used can be 1- to 20-fold of the mole of
the compound represented by the general formula [5] and
preferably 1- to 5-fold of the mole of the same. Bases
used in this reaction include, for example, alkaline
metal alkoxides such as sodium methoxide, sodium
ethoxide and potassium tert-butoxide; organic amines
such as dimethylaminopyridine, triethylamine and
pyridine; alkaline metal hydrides such as sodium
hydride; and alkaline metal carbonates such as
potassium carbonate and sodium carbonate. The amount
of base used can be 1- to 20-fold of the mole of the
compound represented by the general formula [5] and
preferably 1- to 5-fold of the mole of the same.
Solvents used in this reaction are not limited to any
specific ones as long as they do not adversely affect
the reaction. They include, for example, aromatic
hydrocarbons such as benzene, toluene and xylene;
ethers such as 1,4-dioxane, tetrahydrofuran, anisole,
diethylene glycol diethyl ether and dimethyl
cellosolve; nitriles such as acetonitrile; amides such
as N,N-dimethylformamide; halogenated hydrocarbons such
as chloroform and methylene chloride; and sulfoxides
such as dimethyl sulfoxide. These solvents may be used
independently or in the form of a mixture of two or
more kinds.
Usually this reaction can be performed at -20
to 200°C and preferably -10 to 150°C for 10 minutes to

24 hours.
The reaction for obtaining a compound
represented by the general formula [la-1] from a
compound represented by the general formula [6] can be
carried out in the same manner as in the reaction for
obtaining a compound represented by the general formula
[5] from a compound represented by the general formula
[3] in the production process A.
A compound represented by the general formula
[1a-2] can be obtained by subjecting a compound
represented by the general formula [la-1] to
deprotection reaction such as hydrolysis reaction in
the presence of acid or base, dealkylation reaction
using salt, or reductive dealkylation reaction
including metal catalyst hydrogen addition reaction.
Acids used in this reaction include, for example,
formic acid, hydrochloric acid, sulfuric acid,
hydrobromic acid, trifluoroacetic acid, aluminium
chloride and trimethylsilyl iodide. The amount of acid
used can be 1- to 1000-fold of the mole of the compound
represented by the general formula [la-1] and
preferably 1- to 100-fold of the mole of the same.
Bases used in this reaction include, for example,
alkali hydroxides such as sodium hydroxide, potassium
hydroxide and lithium hydroxide; alkaline metal
alkoxides such as sodium methoxide, sodium ethoxide and
potassium tert-butoxide; alkaline metal carbonates such
as potassium carbonate and sodium carbonate; and

tetrabutylarnmonium fluoride. The amount of base used
can be 1- to 1000-fold of the mole of the compound
represented by the general formula [1a-1] and
preferably 1- to 50-fold of the mole of the same.
Salts used in this reaction include, for example,
lithium iodide and sodium chloride. The amount of salt
used can be 1- to 100-fold of the mole of the compound
represented by the general formula [la-1] and
preferably 1- to 10-fold of the mole of the same.
Catalysts used in the reductive dealkylation reaction
include, for example, palladium-carbon, palladium-black
and palladium hydroxide. The amount of catalyst used
can be 0.1- to 100% (w/w) the weight of the compound
represented by the general formula [la-1] and
preferably 1- to 50% (w/w) the weight of the same.
Reducing agents used in this reaction include, for
example, hydrogen, formic acid, cyclohexene and zinc.
The amount of reducing agent used can be 1- to 100-fold
of the mole of the compound represented by the general
formula [la-1] and preferably 1- to 10-fold of the mole
of the same. Solvents used in this reaction are not
limited to any specific ones as long as they do not
adversely affect the reaction. They include, for
example, alcohols such as methanol, ethanol and
isopropyl alcohol; ethers such as tetrahydrofuran,
diethyl ether, 1,4-dioxane and anisole; halogenated
hydrocarbons such as methylene chloride, chloroform and
carbon tetrachloride; nitriles such as acetonitrile;

aliphatic hydrocarbons such as n-hexane and
cyclohexane; esters such as ethyl acetate; aromatic
hydrocarbons such as toluene, benzene and xylene;
dimethyl sulfoxide, N,N-dimethylformamide, nitromethane,
pyridine and water. These solvents may be used
independently or in the form of a mixture of two or
more kinds.
Usually this reaction can be performed at -78
to 100°C and preferably 0 to 80°C for 10 minutes to 24
hours.
When the substituent R1a, R43 or R5 has a
protecting group, the reaction can be carried out while
appropriately deprotecting the substituent by
conventional procedure.
A compound represented by the general formula
[7] can be obtained by subjecting a compound
represented by the general formula [1a-1] to reaction
in the presence of acid, base or salt.
Acids used in this reaction include, for
example, mineral acids such as hydrochloric acid,
sulfuric acid and hydrobromic acid; organic acids such
as trifluoroacetic acid; trimethylsilyl iodide,
aluminium chloride, boron tribromide; and zinc chloride.
These may be used in combination with each other.
Bases used in this reaction include, for example,
ethylmercaptan-sodium salt and lithium diisopropylamide.
Salts used in this reaction include, for example,
sodium cyanide, lithium iodide and pyridine

hydrochloride.
The amounts of acid, base and salt used each
can be 1- to 100-fold of the mole of the compound
represented by the general formula [1a-1] and
preferably 2- to 50-fold of the mole of the same.
Solvents used in this reaction are not limited to any
specific ones as long as they do not adversely affect
the reaction. They include, for example, aromatic
hydrocarbons such as benzene, toluene and xylene;
ethers such as 1,4-dioxane, tetrahydrofuran, anisole,
diethylene glycol diethyl ether and dimethyl
cellosolve; esters such as methyl acetate and ethyl
acetate; nitriles such as acetonitrile; alcohols such
as methanol, ethanol and isopropyl alcohol; amides such
as N,N-dimethylformamide and N,N-dimethylacetamide; and
halogenated hydrocarbons such as chloroform and
methylene chloride; and sulfoxides such as dimethyl
sulfoxide. When using a mineral acid, water may also
be used. These solvents may be used independently or
in the form of a mixture of two or more kinds.
Usually this reaction can be performed at -
78°C to 150°C and preferably 20 to 110°C for 1 to 48
hours.
The reaction for obtaining a compound
represented by the general formula [1a-3] from a
compound represented by the general formula [7] can be
carried out in the same manner as in the reaction for
obtaining a compound represented by the general formula

[5] from a compound represented by the general formula
[3] in the production process A.
The reaction for obtaining a compound
represented by the general formula [1a-4] from a
compound represented by the general formula [1a-3] can
be carried out in the same manner as in the reaction
for obtaining a compound represented by the general
formula [1a-2] from a compound represented by the
general formula [1a-1] in the production process A.
When the substituent R5, R1a or R4aa has a protecting
group, the reaction can be carried out while
appropriately deprotecting the substituent by
conventional procedure.

wherein R2D represents a carboxyl-protecting group; R1b
represents the same meaning as Rla; R2bb, R3b and R4b each
represent the same meaning as R4t!; and R5 and X represent
the same meaning as above.

A compound represented by the general formula
[8] can be obtained by subjecting the acid chloride or
acid anhydride of a compound represented by the general
formula [8A] and a compound represented by the general
formula [8B] to Friedel-Crafts reaction in the presence
of acid.
The acid chloride or acid anhydride of a
compound represented by the general formula [8A] used
in the reaction can be obtained by allowing the
compound represented by the general formula [8A] to
react with activating agent such as thionyl chloride,
oxalyl chloride, phosphorus pentachloride, acetic
anhydride and ethyl chloroformate. The amount of
activating agent used can be 1- to 10-fold of the mole
of the compound represented by the general formula [8A]
and preferably 1- to 3-fold of the mole of the same.
In the reaction for obtaining the acid chloride of a
compound represented by the general formula [8A], N,N-
dimethylformamide as a catalyst may be added in amounts
of 0.001- to 1-fold of the mole of the compound
represented by the general formula [8A] and preferably
0.001- to 0.5-fold of the mole of the same. Acids used
in this reaction include, for example, tin
tetrachloride, aluminium chloride, boron trifluoride
and zinc chloride. The amount of acid used can be 1-
to 10-fold of the mole of a compound represented by the
general formula [8A] and preferably 1- to 5-fold of the
mole of the same. The amount of a compound represented

by the general formula [8B] used can be 1 to 10-fold of
the mole of a compound represented by the general
formula [8A] and preferably 1- to 2-fold of the mole of
the same. Solvents used in this reaction include, for
example, halogenated hydrocarbons such as methylene
chloride, chloroform, 1,2-dichloroethane and carbon
tetrachloride; aliphatic hydrocarbons such as n-hexane
and cyclohexane; nitromethane and nitrobenzene; and
carbon disulfide. These solvents may be used
independently or in the form of a mixture of two or
more kinds.
Usually this reaction can be performed at -
78°C to 100°C and preferably -50°C to 30°C for 10 minutes
to 24 hours.
A compound represented by the general formula
[9] can be obtained by subjecting a compound
represented by the general formula [8] to reaction in
the presence of acid, base or salt.
Acids used in this reaction include, for
example, mineral acids such as hydrochloric acid,
sulfuric acid and hydrobromic acid; organic acids such
as trifluoroacetic acid; trimethylsilyl iodide,
aluminium chloride, boron tribromide; and zinc chloride.
These may be used in combination with each other.
Bases used in this reaction include, for example,
ethylmercaptan-sodium salt and lithium diisopropylamide.
Salts used in this reaction include, for example,
sodium cyanide, lithium iodide and pyridine

hydrochloride. The amounts of acid, base and salt used
each can be 2- to 100-fold of the mole of the compound
represented by the general formula [8] and preferably
2- to 50-fold of the mole of the same. In this
reaction, additives such as 2'-hydroxyacetophenone,
anisole and ethyl acetate may be used. The amount of
additive used can be 1- to 10-fold of the mole of the
compound represented by the general formula [8] and
preferably 1- to 5-fold of the mole of the same.
Solvents used in this reaction are not limited to any
specific ones as long as they do not adversely affect
the reaction. They include, for example, aromatic
hydrocarbons such as benzene, toluene and xylene;
ethers such as 1,4-dioxane, tetrahydrofuran, anisole,
diethylene glycol diethyl ether and dimethyl
cellosolve; esters such as methyl acetate and ethyl
acetate; nitriles such as acetonitrile; alcohols such
as methanol, ethanol and isopropyl alcohol; amides such
as N,N-dimethylformamide and N,N-dimethylacetamide; and
halogenated hydrocarbons such as chloroform and
methylene chloride; and sulfoxides such as dimethyl
sulfoxide. When using a mineral acid, water may also
be used. These solvents may be used independently or
in the form of a mixture of two or more kinds.
Usually this reaction can be performed at -
78°C to 150°C and preferably 20 to 110°C for 1 to 48
hours.
A compound represented by the general formula

[9] can also be obtained not by isolating a compound
represented by the general formula [8] from a compound
represented by the general formula [8A], but by
carrying out the reactions continuously.
The reaction for obtaining a compound
represented by the general formula [1b-1] from a
compound represented by the general formula [9] can be
carried out in the same manner as in the reaction for
obtaining a compound represented by the general formula
[5] from a compound represented by the general formula
[3] in the production process A.
The reaction for obtaining a compound
represented by the general formula [1b-2] from a
compound represented by the general formula [1b-1] can
be carried out in the same manner as in the reaction
for obtaining a compound represented by the general
formula [1a-2] from a compound represented by the
general formula [1a-1] in the production process A.
When the substituent Rlb or R4b has a protecting group,
the reaction can be carried out while appropriately
deprotecting the substituent by conventional procedure.

wherein R2c represents a carboxyl-protecting group; Rlc
represents the same meaning as Rla; R3c, R4c and R4cc each
represent the same meaning as R4a; and R5 and X represent

the same meaning as above.
The reaction for obtaining a compound
represented by the general formula [10] from a compound
represented by the general formula [10A] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [8] from
a compound represented by the general formula [8A] in
the production process B.
A compound represented by the general formula
[11] can also be obtained not by isolating a compound
represented by the general formula [10] from a compound
represented by the general formula [10A], but by
carrying out the reactions continuously.
The reaction for obtaining a compound
represented by the general formula [11] from a compound
represented by the general formula [10] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [9] from
a compound represented by the general formula [8] in
the production process B.
The reaction for obtaining a compound
represented by the general formula [1c-1] from a
compound represented by the general formula [11] can be
carried out in the same manner as in the reaction for
obtaining a compound represented by the general formula
[5] from a compound represented by the general formula
[3] in the production process A.
The reaction for obtaining a compound

represented by the general formula [1c-2] from a
compound represented by the general formula [1c-1] can
be carried out in the same manner as in the reaction
for obtaining a compound represented by the general
formula [1a-2] from a compound represented by the
general formula [1a-1] in the production process A.
When the substituent Rlc or R4c has a
protecting group, the reaction can be carried out while
appropriately deprotecting the substituent by
conventional procedure.

wherein R2d represents a carboxyl-protecting group; Rld,
R3d and R4d each represent the same meaning as R4a; and X
represents the same meaning as above.

The reaction for obtaining a compound
represented by the general formula [12d] from a
compound represented by the formula [12] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [6] from
a compound represented by the general formula [5] in
the production process A.
The reaction for obtaining a compound
represented by the general formula [13] from a compound
represented by the general formula [12d] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [5] from
a compound represented by the general formula [3] in
the production process A.
A compound represented by the general formula
[13] can be obtained from a compound represented by the
formula [12] via a compound represented by the general
formula [12d] by carrying out the reactions
continuously.
A compound represented by the general formula
[15] can be obtained by subjecting the acid chloride or
acid anhydride of a compound represented by the general
formula [14] and a compound represented by the general
formula [13] to Friedel-Crafts reaction in the presence
of acid.
The acid chloride or the acid anhydride of a
compound represented by the general formula [14] can be
obtained by reacting the compound represented by the

general formula [14] with activating agent such as
thionyl chloride, oxalyl chloride, phosphorus
pentachloride, acetic anhydride or ethyl chloroformate.
The amount of activating agent used can be 1- to 10-
fold of the mole of a compound represented by the
general formula [14] and preferably 1- to 3-fold of the
mole of the same. In the reaction for obtaining the
acid chloride of a compound represented by the general
formula [14], N,N-dimethylformamide, as a catalyst, may
be added in amounts of 0.001- to 1-fold of the mole of
the compound and preferably 0.001- to 0.5-fold of the
mole of the same. Acids used in this reaction include,
for example, tin tetrachloride, aluminium chloride,
boron trifluoride and zinc chloride. The amount of
acid used can be 1- to 10-fold of the mole of a
compound represented by the general formula [14] and
preferably 1- to 5-fold of the mole of the same. The
amount of a compound represented by the general formula
[13] used can be 1- to 10-fold of the mole of a
compound represented by the general formula [14] and
preferably 1- to 2-fold of the mole of the same.
Solvents used in this reaction include, for example,
halogenated hydrocarbons such as methylene chloride,
chloroform 1,2-dichlorohexane and carbon tetrachloride;
aliphatic hydrocarbons such as n-hexane and
cyclohexane; nitromethane, nitrobenzene; and carbon
disulfide. These solvents may be used independently or
in the form of a mixture of two or more kinds.

Usually this reaction can be performed at -
78°C to 100°C and preferably -50°C to 30°C for 10 minutes
to 24 hours.
A compound represented by the general formula
[16] can be obtained by subjecting a compound
represented by the general formula [15] to reaction in
the presence of acid, base or salt.
Acids used in this reaction include, for
example, mineral acids such as hydrochloric acid,
sulfuric acid and hydrobromic acid; organic acids such
as trifluoroacetic acid and thiophenol; trimethylsilyl
iodide, aluminium chloride, boron tribromide; and zinc
chloride. Bases used in this reaction include, for
example, ethylmercaptan-sodium salt and lithium
diisopropylamide. Salts used in this reaction include,
for example, sodium cyanide, lithium iodide and
pyridine hydrochloride. The amounts of acid, base and
salt used each can be 3- to 100-fold of the mole of the
compound represented by the general formula [15] and
preferably 3- to 50-fold of the mole of the same. In
this reaction, additives such as 2'-hydroxyacetophenone,
anisole and ethyl acetate may be used. The amount of
additive used can be 1- to 10-fold of the mole of the
compound represented by the general formula [14] and
preferably 1- to 5-fold of the mole of the same.
Solvents used in this reaction are not limited to any
specific ones as long as they do not adversely affect
the reaction. They include, for example, aromatic

hydrocarbons such as benzene, toluene and xylene;
ethers such as 1,4-dioxane, tetrahydrofuran, anisole,
diethylene glycol diethyl ether and dimethyl
cellosolve; esters such as methyl acetate and ethyl
acetate; nitriles such as acetonitrile; alcohols such
as methanol, ethanol and isopropyl alcohol; amides such
as N,N-dimethylformamide and N,N-dimethylacetamide; and
halogenated hydrocarbons such as chloroform and
methylene chloride; and sulfoxides such as dimethyl
sulfoxide. When using a mineral acid, water may also
be used. These solvents may be used independently or
in the form of a mixture of two or more kinds.
Usually this reaction can be performed at -
78°C to 150°C and preferably 20 to 110°C for 10 minutes
to 48 hours.
A compound represented by the general formula
[16] can also be obtained from a compound represented
by the general formula [14] via a compound represented
by the general formula [15] by carrying out the
reactions continuously.

wherein R2e represents a carboxyl-protecting group; Rle,
R3e and R4e each represent the same meaning as R4a, and R5
represents the same meaning as above.
A compound represented by the general formula
[18] can be obtained by reacting a compound represented

by the general formula [17] with a formylating agent in
the presence of acid.
Acids used in this reaction include, for
example, titanium tetrachloride, tin tetrachloride,
aluminium chloride and phosphorus oxychloride. The
amount of acid used can be 1- to 10-fold of the mole of
the compound represented by the general formula [17]
and preferably 1- to 3-fold of the mole of the same.
Formylating agents used in this reaction include, for
example, α,α-dichloromethyl methyl ether, N,N-
dimethylformamide and ethyl orthoformate. The amount
of formylating agent used can be 1- to 10-fold of the
mole of the compound represented by the general formula
[17] and preferably 1- to 5-fold of the mole of the
same. Solvents used in this reaction include, for
example, halogenated hydrocarbons such as methylene
chloride, chloroform and carbon tetrachloride; and
aliphatic hydrocarbons such as n-hexane and cyclohexane.
These solvents may be used independently or in the form
of a mixture of two or more kinds.
Usually this reaction can be performed at -
78°C to 150°C and preferably -50°C to 100°C for 30
minutes to 24 hours.
A compound represented by the general formula
[20] can be obtained by reacting a compound represented
by the general formula [18] with an oxidizing agent in
the presence or absence of acid or base.
Acids used in this reaction as the need

arises include, for example, sodium dihydrogenphosphate,
hydrochloric acid, sulfuric acid, acetic acid and
sulfamic acid. The amount of acid used can be 1- to
1000-fold of the mole of a compound represented by the
general formula [18] and preferably 1- to 100-fold of
the mole of the same. Bases used in this reaction as
the need arises include, for example, alkali hydroxides
such as sodium hydroxide and potassium hydroxide; and
pyridine. The amount of base used can be 1- to 1000-
fold of the mole of a compound represented by the
general formula [18] and preferably 1- to 100-fold of
the mole of the same. Oxidizing agents used in this
reaction include, for example, sodium chlorite, sodium
hypochlorite, chromic acid, potassium permanganate,
hydrogen peroxide, ruthenium oxide, nickel oxide,
silver oxide and silver nitrate. The amount of
oxidizing agent used can be 1- to 10-fold of the mole
of a compound represented by the general formula [18]
and preferably 1- to 5-fold of the mole of the same.
Solvents used in this reaction are not limited to any
specific ones as long as they do not adversely affect
the reaction. They include, for example, ethers such
as tetrahydrofuran, diethyl ether and 1,4-dioxane;
halogenated hydrocarbons such as methylene chloride,
chloroform and carbon tetrachloride; nitriles such as
acetonitrile; aliphatic hydrocarbons such as n-hexane
and cyclohexane; aromatic hydrocarbons such as toluene
and benzene; dimethyl sulfoxide, pyridine; and water.

These solvents may be used independently or in the form
of a mixture of two or more kinds.
Usually this reaction can be performed at 0°C
to 100°C and preferably 0°C to 50°C for 10 minutes to 24
hours.
A compound represented by the general formula
[20] can also be obtained by reacting a compound
represented by the general formula [19] with an
oxidizing agent in the presence or absence of acid or
base.
Acids used in this reaction as the need
arises include, for example, sulfuric acid and acetic
acid. The amount of acid used can be 1- to 1000-fold
of the mole of a compound represented by the general
formula [19] and preferably 1- to 100-fold of the mole
of the same. Bases used in this reaction as the need
arises include, for example, alkali hydroxides such as
sodium hydroxide and potassium hydroxide; and pyridine.
The amount of base used can be 1- to 1000-fold of the
mole of a compound represented by the general formula
[19] and preferably 1- to 100-fold of the mole of the
same. Oxidizing agents used in this reaction include,
for example, chromic acid and potassium permanganate.
The amount of oxidizing agent used can be 1- to 50-fold
of the mole of a compound represented by the general
formula [19] and preferably 1- to 10-fold of the mole
of the same. Solvents used in this reaction are not
limited to any specific ones as long as they do not

adversely affect the reaction. They include, for
example, halogenated hydrocarbons such as methylene
chloride, chloroform and carbon tetrachloride;
aliphatic hydrocarbons such as n-hexane and
cyclohexane; pyridine; and water. These solvents may
be used independently or in the form of a mixture of
two or more kinds.
Usually this reaction can be performed at 0°C
to 150°C and preferably 20°C to 100°C for 30 minutes to
24 hours.
The reaction for obtaining a compound
represented by the general formula [22] from a compound
represented by the general formula [20] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [15] from
a compound represented by the general formula [14] in
the production process D.
The reaction for obtaining a compound
represented by the general formula [23] from a compound
represented by the general formula [22] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [16] from
a compound represented by the general formula [15] in
the production process D.
A compound represented by the general formula
[23] can be obtained from a compound represented by the
general formula [20] via a compound represented by the
general formula [22] by carrying out the reactions

wherein R2f represents a carboxyl-protecting group; Rlf
represents the same meaning as Rla; Rlff and RJf each
represent the same meaning as R4a; and R4 and X represent
the same meaning as above.
The reaction for obtaining a compound
represented by the general formula [12f] from a
compound represented by the formula [12] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [12d]
from a compound represented by the formula [12] in the
production process D.
The reaction for obtaining a compound
represented by the general formula [24] from a compound
represented by the general formula [12f] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [13] from
a compound represented by the general formula [12d] in
the production process D.
A compound represented by the general formula
[24] can be obtained from a compound represented by the
formula [12] via a compound represented by the general
formula [12f] by carrying out the reaction for
obtaining the compound represented by the general
formula [12f] and the reaction of alkylating the same
continuously.
The reaction for obtaining a compound
represented by the general formula [26] from a compound
represented by the general formula [25] can be carried

out in the same manner as in the reaction for obtaining
a compound represented by the general formula [15] from
a compound represented by the general formula [14] in
the production process D.
The reaction for obtaining a compound
represented by the general formula [27] from a compound
represented by the general formula [26] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [9] from
a compound represented by the general formula [8] in
the production process B.
A compound represented by the general formula
[27] can also be obtained not by isolating a compound
represented by the general formula [26] from a compound
represented by the general formula [25], but by
carrying out the reactions continuously.
The reaction for obtaining a compound
represented by the general formula [1f-1] from a
compound represented by the general formula [27] can be
carried out in the same manner as in the reaction for
obtaining a compound represented by the general formula
[5] from a compound represented by the general formula
[3] in the production process A.
The reaction for obtaining a compound
represented by the general formula [1f-2] from a
compound represented by the general formula [1f-1] can
be carried out in the same manner as in the reaction
for obtaining a compound represented by the general

formula [1a-2] from a compound represented by the
general formula [1a-1] in the production process A.
When the substituent Rlf or R"1 has a protecting group,
the reaction can be carried out while appropriately
deprotecting the substituent by conventional procedure.

wherein R2g represents a carboxyl-protecting group; R1g
represnts the same meaning as Rla; R4g represents the

same meaning as R4a; R5 and X represent the same meaning
as above; and R4gg represents a phenol-protecting group.
A compound represented by the general formula
[28] can be obtained by, for example, the process
described in Greene et al., Protective Groups in
Organic Synthesis, 3rd edition, 1999, 249-280.
Specifically, when R4gg is a tetrahydropyranyl
group, for example, a compound represented by the
general formula [28] can be obtained by reacting a
compound represented by the general formula [3] with
3,4-dihydro-2H-pyran in the presence of catalyst. The
amount of 3,4-dihydro-2H-pyran used can be 1- to 20-
fold of the mole of a compound represented by the
general formula [3] and preferably 1- to 5-fold of the
mole of the same. Catalysts used in this reaction
include, for example, acids such as dry hydrogen
chloride and p-toluenesulfonic acid; and salts such as
pyridinium p-toluenesulfonate. The amount of catalyst
used can be 0.01- to 10-fold of the mole of a compound
represented by the general formula [3] and preferably
0.05- to 3-fold of the mole of the same. Solvents used
in this reaction are not limited to any specific ones
as long as they do not adversely affect the reaction.
They include, for example, aromatic hydrocarbons such
as benzene, toluene and xylene; ethers such as 1,4-
dioxane, tetrahydrofuran, anisole, diethylene glycol
diethyl ether and dimethyl cellosolve; esters such as
methyl acetate and ethyl acetate; nitriles such as

acetonitrile; amides such as N,N-dimethylformamide and
N,N-dimethylacetamide; and halogenated hydrocarbons
such as chloroform and methylene chloride. These
solvents may be used independently or in the form of a
mixture of two or more kinds.
Usually this reaction can be performed at 0°C
to 100°C and preferably 0°C to 50°C for 10 minutes to 24
hours.
The reaction for obtaining a compound
represented by the general formula [29] from a compound
represented by the general formula [28] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [6] from
a compound represented by the general formula [5] in
the production process A.
The reaction for obtaining a compound
represented by the general formula [30] from a compound
represented by the general formula [29] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [1a-1]
from a compound represented by the general formula [6]
in the production process A.
A compound represented by the general formula
[31] can be obtained from a compound represented by the
general formula [30] by ordinary deprotection.
Specifically, when R4" of a compound
represented by the general formula [30] is
tetrahydropyran, for example, a compound represented by

the general formula [31] can be obtained by carrying
out the reaction in the presence of acid. Acids used
in this reaction include, for example, mineral acids
such as hydrochloric acid; and organic acids such as p-
toluenesulfonic acid and oxalic acid. The amount of
acid used can be 0.01- to 100-fold of the mole of a
compound represented by the general formula [30] and
preferably 0.05- to 10-fold of the mole of the same.
Solvents used in this reaction are not limited to any
specific ones as long as they do not adversely affect
the reaction. They include, for example, aromatic
hydrocarbons such as benzene, toluene and xylene;
ethers such as 1,4-dioxane, tetrahydrofuran, anisole,
diethylene glycol diethyl ether and dimethyl
cellosolve; alcohols such as methanol and ethanol;
esters such as butyl acetate and ethyl acetate;
nitriles such as acetonitrile; amides such as N,N-
dimethylformamide and N,N-dimethylacetamide;
halogenated hydrocarbons such as chloroform and
methylene chloride; and water. These solvents may be
used independently or in the form of a mixture of two
or more kinds.
Usually this reaction can be performed at 0°C
to the reflux temperature of the solvent used and
preferably 5 to 100°C for 10 minutes to 24 hours.
The reaction for obtaining a compound
represented by the general formula [lg-1] from a
compound represented by the general formula [31] can be

carried out in the same manner as in the reaction for
obtaining a compound represented by the general formula
[5] from a compound represented by the general formula
[3] in the production process A.
The reaction for obtaining a compound
represented by the general formula [1g-2] from a
compound represented by the general formula [1g-1] can
be carried out in the same manner as in the reaction
for obtaining a compound represented by the general
formula [1a-2] from a compound represented by the
general formula [1a-1] in the production process A.

wherein R4h represents the same meaning as R4a; R2h, R2hh
and R11 each represent a carboxyl-protecting group; R12,
R13, R14 and R15 each represent hydrogen, optionally
substituted alkyl or an amino-protecting group; and X
represent the same meaning as above.

The reaction for obtaining a compound
represented by the general formula [1h-1] from a
compound represented by the general formula [32] can be
carried out in the same manner as in the reaction for
obtaining a compound represented by the general formula
[5] from a compound represented by the general formula
[3] in the production process A.
The reaction for obtaining a compound
represented by the general formula [1h-2] from a
compound represented by the general formula [1h-1] can
be carried out in the same manner as in the reaction
for obtaining a compound represented by the general
formula [1a-2] from a compound represented by the
general formula [1a-1] in the production process A.
When the substituent R4h or R11 has a protecting group,
the reaction can be carried out while appropriately
deprotecting the substituent by conventional procedure.
The reaction for obtaining a compound
represented by the general formula [1h-3] from a
compound represented by the general formula [1h-1] can
be carried out in the same manner as in the reaction
for obtaining a compound represented by the general
formula [1a-2] from a compound represented by the
general formula [1a-1] in the production process A.
A compound represented by the general formula
[1h-4] can be obtained by esterifying a compound
represented by the general formula [1h-3].
In this reaction, common esterification

methods can be used. Processes of esterification
include: for example, processes in which an acid
catalyst-additive combination is used, in which
esterification is carried out via acid chloride, in
which esterification is carried out via acid anhydride,
in which a compound represented by the general formula
[R8g] is used with a base and in which a condensing
agent-additive combination is used. For example, in
the process in which an acid catalyst-additive
combination is used, acid catalysts used include, for
example, hydrochloric acid, sulfuric acid, hydrobromic
acid, trimethylsilyl chloride, aluminium chloride,
boron trifluoride and trifluoroacetic acid. The amount
of catalyst used can be 0.01- to 100-fold of the mole
of a compound represented by the general formula [1h-3]
and preferably 0.5- to 50-fold of the mole of the same.
Additives used include, for example, 2,2-
dimethoxypropane and ethyl orthoformate. The amount of
the additive used can be 0.1- to 100-fold of the mole
of a compound represented by the general formula [1h-3]
and preferably 1- to 50-fold of the mole of the same.
A compound represented by the general formula [R8c] can
be used as a solvent in an appropriate amount; however,
when some other solvent is used, the amount of the
compound used can be 1- to 100-fold of the mole of a
compound represented by the general formula [1h-3] and
preferably 1- to 50-fold of the mole of the same.
Solvents used in this reaction are not limited to any

specific ones as long as they do not adversely affect
the reaction. They include, for example, aromatic
hydrocarbons such as benzene, toluene and xylene;
ethers such as 1,4-dioxane, tetrahydrofuran, anisole,
diethylene glycol diethyl ether and dimethyl
cellosolve; esters such as methyl acetate and ethyl
acetate; nitriles such as acetonitrile; amides such as
N,N-dimethylformamide; halogenated hydrocarbons such as
chloroform and methylene chloride; and sulfoxides such
as dimethyl sulfoxide. Usually this reaction can be
performed at 0 to 200°C and preferably 5 to 100°C for 10
minutes to 24 hours.
In the process in which a base and a compound
represented by the general formula [R8g] are used,
bases used in this reaction include, for example,
organic amines such as dimethylaminopyridine,
triethylamine, pyridine and N-methylmorpholine; and
alkaline metal carbonates such as potassium carbonate
and sodium carbonate. The amount of base used can be
0.5- to 10-fold of the mole of a compound represented
by the general formula [1h-3] and preferably 1- to 3-
fold of the mole of the same. Compounds represented by
the general formula [R8g] used in this reaction include,
for example, methyl iodide, ethyl iodide and benzyl
bromide. The amount of the compound used can be 0.5-
to 10-fold of the mole of a compound represented by the
general formula [1h-3] and preferably 1- to 3-fold of
the mole of the same. Solvents used in this reaction

are not limited to any specific ones as long as they do
not adversely affect the reaction. They include, for
example, aromatic hydrocarbons such as benzene, toluene
and xylene; ethers such as 1,4-dioxane, tetrahydrofuran,
anisole, diethylene glycol diethyl ether and dimethyl
cellosolve; esters such as methyl acetate and ethyl
acetate; nitriles such as acetonitrile; amides such as
N,N-dimethylformamide; halogenated hydrocarbons such as
chloroform and methylene chloride; and sulfoxides such
as dimethyl sulfoxide. Usually this reaction can be
performed at 0 to 200°C and preferably 5 to 100°C for 10
minutes to 24 hours.
In the process in which a condensing agent
and an additive are used, a compound represented by the
general formula [1h-4] can be obtained by subjecting a
compound represented by the general formula [R8c]
together with the condensing agent and the additive to
condensation reaction. Condensing agents used in this
reaction include, for example, 1,1'-carbonyldiimidazole,
N,N'-dicyclohexylcarbodiimide, diisopropylcarbodiimide,
N-ethyl-N'-3-dimethylaminopropylcarbodiimide and
diphenylphosphoryl azide. Additives used in this
reaction include, for example, 1-hydroxybenzotriazole
and N-hydroxysuccinimide. The amounts of the alcohol,
the condensing agent and the additive used in this
reaction each can be 0.5- to 10-fold of the mole of a
compound represented by the general formula [1h-3] and
preferably 1- to 3-fold of the mole of the same.

Solvents used in this reaction are not limited to any
specific ones as long as they do not adversely affect
the reaction. They include, for example, aromatic
hydrocarbons such as benzene, toluene and xylene;
ethers such as 1,4-dioxane, tetrahydrofuran, anisole,
diethylene glycol diethyl ether and dimethyl
cellosolve; esters such as methyl acetate and ethyl
acetate; nitriles such as acetonitrile; amides such as
N,N-dimethylformamide; halogenated hydrocarbons such as
chloroform and methylene chloride; and sulfoxides such
as dimethyl sulfoxide.
Usually this reaction can be performed at 0
to 200°C and preferably 5 to 100°C for 10 minutes to 24
hours.
A compound represented by the general formula
[1h-5] can be obtained by subjecting a compound
represented by the general formula [1h-4] together with
a compound represented by the general formula [R8d] to
amidation. This amidation is commonly used amidation.
And processes of amidation include: for example,
processes in which amidation is carried out via acid
chloride, in which amidation is carried out via acid
anhydride, and in which base, condensing agent and
additive are used.
For example, in the process in which a base,
a condensing agent and an additive are used, amines
represented by the general formula [R8d] used in this
reaction include, for example, ammonia and

hydroxylamine; primary amines such as methyl amine,
benzyl amine, aniline, phenethylamine, isopropylamine
and aminothiazole; and secondary amines such as
dimethyl amine, diethyl amine and di-n-propylamine and
sulfonamides include, for example, methanesulfonamide.
The amount of amine used can be 0.5- to 10-fold of the
mole of a compound represented by the general formula
[1h-4] and preferably 1- to 3-fold of the mole of the
same. Bases used in this reaction include, for example,
organic amines such as dimethylaminopyridine,
triethylamine, pyridine, N-methylmorpholine and 1,8-
diazabicyclo[5.4.0]undec-7-ene; and alkaline metal
carbonates such as potassium carbonate and sodium
carbonate. The amount of base used can be 0.5- to 10-
fold of the mole of a compound represented by the
general formula [1h-4] and preferably 1- to 5-fold of
the mole of the same. Condensing agents used in this
reaction include, for example, N,N'-
dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-
ethyl-N'-3-dimethylaminopropylcarbodiimide and
diphenylphosphoryl azide. The amount of the condensing
agent used in this reaction can be 0.5- to 10-fold of
the mole of a compound represented by the general
formula [1h-4] and preferably 1- to 3-fold of the mole
of the same. Additives used in this reaction include,
for example, 1-hydroxybenzotriazole and N-
hydroxysuccinimide. The amount of the additive used
can be 0.5- to 10-fold of the mole of a compound

represented by the general formula [1h-4] and
preferably 1- to 3-fold of the mole of the same.
Solvents used in this reaction are not limited to any
specific ones as long as they do not adversely affect
the reaction. They include, for example, aromatic
hydrocarbons such as benzene, toluene and xylene;
ethers such as 1,4-dioxane, tetrahydrofuran, anisole,
diethylene glycol diethyl ether and dimethyl
cellosolve; esters such as methyl acetate and ethyl
acetate; nitriles such as acetonitrile; amides such as
N,N-dimethylformamide; halogenated hydrocarbons such as
chloroform and methylene chloride; and sulfoxides such
as dimethyl sulfoxide.
Usually this reaction can be performed at -20
to 150°C and preferably 0 to 120°C for 10 minutes to 24
hours.
The reaction for obtaining a compound
represented by the general formula [1h-6] from a
compound represented by the general formula [1h-5] can
be carried out in the same manner as in the reaction
for obtaining a compound represented by the general
formula [1a-2] from a compound represented by the
general formula [1a-1] in the production process A.
When the substituent R12 or R13 is an amino-protecting
group or the substituent R41' has a protecting group, the
reaction can be carried out while appropriately
deprotecting the substituent by conventional procedure.
The reaction for obtaining a compound

represented by the general formula [1h-7] from a
compound represented by the general formula [32] can be
carried out in the same manner as in the reaction for
obtaining a compound represented by the general formula
[5] from a compound represented by the general formula
[3] in the production process A.
The reaction for obtaining a compound
represented by the general formula [1h-8] from a
compound represented by the general formula [1h-7] can
be carried out in the same manner as in the reaction
for obtaining a compound represented by the general
formula [1a-2] from a compound represented by the
general formula [1a-1] in the production process A.
When the substituent R14 or R15 is an amino-protecting
group or the substituent R4h has a protecting group, the
reaction can be carried out while appropriately
deprotecting the substituent by conventional procedure.

wherein R11 represents the same meaning as Rla; and R41
represents the same meaning as R4a.
A compound represented by the general formula

[1i-2] can be obtained by reacting a compound
represented by the general formula [1i-1] with a
compound having the formula [R9] in accordance with the
process described in Chemical and Pharmaceutical
Bulletin, Vol. 34, 5188-5190, 1986. This reaction can
be carried out, for example, by the process in which
condensing agent and additive are used, in which the
compound is obtained via acid chloride, or in which the
compound is obtained via acid anhydride.
For example, in the process in which
condensing agent and additive are used, condensing
agents used in this reaction include, for example,
N,N'-dicyclohexylcarbodiimide, diisopropylcarbodiimide,
N-ethyl-N'-3-dimethylaminopropylcarbodiimide and
diphenylphosphoryl azide. The amount of condensing
agent used in this reaction can be 0.5- to 10-fold of
the mole of a compound represented by the general
formula [1i-1] and preferably 1- to 3-fold of the mole
of the same. Additives used in this reaction include,
for example, 1-hydroxybenzotriazole and N-
hydroxysuccinimide. The amount of additive used can be
0.5- to 10-fold of the mole of a compound represented
by the general formula [1i-1] and preferably 1- to 3-
fold of the mole of the same. The amount of a compound
represented by the formula [R9] used in this reaction
can be 1- to 10-fold of the mole of a compound
represented by the general formula [1i-1] and
preferably 1- to 2-fold of the mole of the same.

Solvents used in this reaction are not limited to any
specific ones as long as they do not adversely affect
the reaction. They include, for example, aromatic
hydrocarbons such as benzene, toluene and xylene;
ethers such as 1,4-dioxane, tetrahydrofuran, anisole,
diethylene glycol diethyl ether and dimethyl
cellosolve; esters such as methyl acetate and ethyl
acetate; nitriles such as acetonitrile; amides such as
N,N-dimethylformamide; halogenated hydrocarbons such as
chloroform and methylene chloride; and sulfoxides such
as dimethyl sulfoxide.
Usually this reaction can be performed at -20
to 150°C and preferably 0 to 120°C for 10 minutes to 24
hours.
In the process in which a compound
represented by the general formula [1i-2] is obtained
via acid chloride or via acid anhydride, the compound
can be obtained by reacting the acid chloride or acid
anhydride of a compound represented by the general
formula [1i-1] with a compound represented by the
formula [R9] in the presence of base. The acid
chloride or acid anhydride of a compound represented by
the general formula [1i-1] used in this reaction can be
obtained by reacting the compound represented by the
general formula [1i-1] with activating agent such as
thionyl chloride, oxalyl chloride, phosphorus
pentachloride, acetic anhydride or ethyl chloroformate.
The amount of activating agent used can be 1- to 10-

fold of the mole of a compound represented by the
general formula [1i-1] and preferably 1- to 2-fold of
the mole of the same. The amount of a compound
represented by the formula [R9] used can be 1- to 20-
fold of the mole of a compound represented by the
general formula [1i-1] and preferably 1- to 5-fold of
the mole of the same. Bases used in this reaction
include, for example, organic amines such as
dimethylaminopyridine, trimethylamine, pyridine and N-
methylmorpholine; and alkaline metal carbonates such as
potassium carbonate and sodium carbonate; organic
lithiums such as n-butyllithium, methyllithium and
lithium diisopropylamide; and organic magnesiums such
as methylmagnesium bromide. The amount of base used
can be 1- to 20-fold of the mole of a compound
represented by the general formula [1i-1] and
preferably 1- to 5-fold of the mole of the same.
Solvents used in this reaction are not limited to any
specific ones as long as they do not adversely affect
the reaction. They include, for example, aromatic
hydrocarbons such as benzene, toluene and xylene;
halogenated hydrocarbons such as chloroform and
methylene chloride; ethers such as 1,4-dioxane,
tetrahydrofuran, anisole, diethylene glycol diethyl
ether and dimethyl cellosolve; and aliphatic
hydrocarbons such as hexane and cyclohexane. These
solvents may be used independently or in the form of a
mixture of two or more kinds.

Usually this reaction can be performed at -78
to 150°C and preferably -78 to 120°C for 10 minutes to
24 hours. When the substituent R11 or R41 has a
protecting group, the reaction can be carried out while
appropriately deprotecting the substituent by
conventional procedure.
The reaction for obtaining a compound
represented by the general formula [33] from a compound
represented by the general formula [1i-1] can be
carried out in the same manner as in the reaction for
obtaining a compound represented by the general formula
[1h-5] from a compound represented by the general
formula [1h-4] in the production process H.
A compound represented by the general formula
[34] can be obtained by dehydrating a compound
represented by the general formula [33] in the presence
or absence of dehydrating agent and bases.
Dehydrating agents used in this reaction as
the need arises include, for example, phosphorus
pentoxide, phosphorus pentachloride, phosphoryl
chloride and thionyl chloride. The amount of
dehydrating agent used can be 1- to 50-fold of the mole
of a compound represented by the general formula [33]
and preferably 1- to 10-fold of the mole of the same.
Salts used in this reaction as the need arises include,
for example, sodium chloride. The amount of salt used
can be 1- to 50-fold of the mole of a compound
represented by the general formula [33] and preferably

1- to 5-fold of the mole of the same. Solvents used in
this reaction are not limited to any specific ones as
long as they do not adversely affect the reaction.
They include, for example, aromatic hydrocarbons such
as benzene, toluene and xylene; ethers such as 1,4-
dioxane, tetrahydrofuran, anisole, diethylene glycol
diethyl ether and dimethyl cellosolve; aliphatic
hydrocarbons such as hexane and cyclohexane;
halogenated hydrocarbons such as chloroform and
methylene chloride; esters such as methyl acetate and
ethyl acetate; and amides such as N,N-dimethylformamide
and N,N-dimethylacetamide. These solvents may be used
independently or in the form of a mixture of two or
more kinds.
Usually this reaction can be performed at -20
to 300°C and preferably 0 to 220°C for 30 minutes to 24
hours.
A compound represented by the general formula
[1i-4] can be synthesized from a compound represented
by the general formula [34] in accordance with the
process described in Journal of Medicinal Chemistry,
Vol. 39, 5228-5235, 1996.
Specifically, amidoxime can be obtained by
reacting a compound represented by the general formula
[34] with hydroxylamine in the presence of base. The
amount of hydroxylamine used can be 1- to 20-fold of
the mole of a compound represented by the general
formula [34] and preferably 1- to 10-fold of the mole

of the same. Bases used in this reaction include, for
example, organic amines such as dimethylaminopyridine,
triethylamine, pyridine and N-methylmorpholine; metal
alkoxides such as sodium methoxide; and alkaline metal
carbonates such as potassium carbonate and sodium
carbonate. The amount of base used can be 1- to 10-
fold of the mole of a compound represented by the
general formula [34] and preferably 1- to 5-fold of the
mole of the same. Solvents used in this reaction are
not limited to any specific ones as long as they do not
adversely affect the reaction. They include, for
example, alcohols such as methanol and ethanol;
aromatic hydrocarbons such as benzene, toluene and
xylene; ethers such as 1,4-dioxane, tetrahydrofuran,
anisole, diethylene glycol diethyl ether and dimethyl
cellosolve; aliphatic hydrocarbons such as hexane and
cyclohexane; halogenated hydrocarbons such as
chloroform and methylene chloride; esters such as
methyl acetate and ethyl acetate; sulfoxides such as
dimethyl sulfoxide; and amides such as N,N-
dimethylformamide and N,N-dimethylacetamide. These
solvents may be used independently or in the form of a
mixture of two or more kinds.
Usually this reaction can be performed at -20
to 200°C and preferably 0 to 100°C for 30 minutes to 24
hours.
The amidoxime compound obtained by the above
method is then reacted with halogenated carbonate in

the presence of base. Bases used in this reaction
include, for example, organic amines such as
dimethylaminopyridine, triethylamine, pyridine and N-
methylmorpholine; alkaline metal carbonates such as
potassium carbonate and sodium carbonate; and metal
alkoxides such as potassium tert-butoxide. The amount
of base used can be 1- to 10-fold of the mole of a
compound represented by the general formula [34] and
preferably 1- to 3-fold of the mole of the same.
Halogenated carbonate used in this reaction include,
for example, ethyl chloroformate, butyl chloroformate
and 2-ethylhexyl chloroformate. The amount of
halogenated carbonate used can be 1- to 10-fold of the
mole of a compound represented by the general formula
[34] and preferably 1- to 3-fold of the mole of the
same. Solvents used in this reaction are not limited
to any specific ones as long as they do not adversely
affect the reaction. They include, for example,
nitriles such as acetonitrile; aromatic hydrocarbons
such as benzene, toluene and xylene; ethers such as
1,4-dioxane, tetrahydrofuran, anisole, diethylene
glycol diethyl ether and dimethyl cellosolve; aliphatic
hydrocarbons such as hexane and cyclohexane;
halogenated hydrocarbons such as chloroform and
methylene chloride; esters such as methyl acetate and
ethyl acetate; amides such as N,N-dimethylformamide and
N,N-dimethylacetamide; and sulfoxides such as dimethyl
sulfoxide. These solvents may be used independently or

in the form of a mixture of two or more kinds.
Usually this reaction can be performed at -20
to 200°C and preferably 0 to 100°C for 5 minutes to 24
hours.
Then the reaction product is heated in the
presence or absence of solvent to give a compound
represented by the general formula [1i-4]. Solvents
used in this reaction are not limited to any specific
ones as long as they do not adversely affect the
reaction. They include, for example, nitriles such as
acetonitrile; aromatic hydrocarbons such as benzene,
toluene and xylene; ethers such as 1,4-dioxane,
tetrahydrofuran, anisole, diethylene glycol diethyl
ether and dimethyl cellosolve; aliphatic hydrocarbons
such as hexane and cyclohexane; halogenated
hydrocarbons such as chloroform and methylene chloride;
esters such as methyl acetate and ethyl acetate; amides
such as N,N-dimethylformamide and N,N-
dimethylacetamide; and sulfoxides such as dimethyl
sulfoxide. These solvents may be used independently or
in the form of a mixture of two or more kinds.
Usually this reaction can be performed at 0 °C
to the reflux temperature of the solvent used and
preferably 0 to 150°C for 30 minutes to 24 hours and
preferably 30 minutes to 10 hours. When the
substituent R11 or R41 has a protecting group, the
reaction can be carried out while appropriately
deprotecting the substituent by conventional procedure.

A compound represented by the general formula
[1i-3] can be obtained by reacting a compound
represented by the general formula [34] and an azide
compound in the presence or absence of salts.
Azide compounds used in this reaction include,
for example, sodium azide, trimethyltin azide and
trimethylsilyl azide. The amount of azide compound
used can be 1- to 30-fold of the mole of a compound
represented by the general formula [34] and preferably
1- to 10-fold of the mole of the same. Salts used in
this reaction as the need arises include, for example,
triethylamine hydrochloride and ammonium chloride. The
amount of salt used can be 1- to 30-fold of the mole of
a compound represented by the general formula [34] and
preferably 1- to 10-fold of the mole of the same.
Solvents used in this reaction are not limited to any
specific ones as long as they do not adversely affect
the reaction. They include, for example, aromatic
hydrocarbons such as benzene, toluene and xylene;
ethers such as 1,4-dioxane, tetrahydrofuran, anisole,
diethylene glycol diethyl ether and dimethyl
cellosolve; aliphatic hydrocarbons such as hexane and
cyclohexane; halogenated hydrocarbons such as
chloroform and methylene chloride; esters such as butyl
acetate and ethyl acetate; amides such as N,N-
dimethylformamide and N,N-dimethylacetamide; and
sulfoxides such as dimethyl sulfoxide. These solvents
may be used independently or in the form of a mixture

of two or more kinds.
Usually this reaction can be performed at -20
to 250°C and preferably 0 to 150°C for 30 minutes to 24
hours. When the substituent R11 or R41 has a protecting
group, the reaction can be carried out while
appropriately deprotecting the substituent by
conventional procedure.

wherein R2j and R2jj each represent a carboxyl-protecting
group; Rlj, Rljj and Rljjj each represent the same meaning
as Rla; R3 and X represent the same meaning as above; R4D
and R4jj each represent the same meaning as R4a.
The reaction for obtaining a compound

represented by the general formula [12j] from a
compound represented by the formula [12] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [12d]
from a compound represented by the formula [12] in the
production process D.
The reaction for obtaining a compound
represented by the general formula [35] from a compound
represented by the general formula [12j] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [13] from
a compound represented by the general formula [12d] in
the production process D.
The reaction for obtaining a compound
represented by the general formula [37] from a compound
represented by the general formula [36] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [15] from
a compound represented by the general formula [14] in
the production process D.
The reaction for obtaining a compound
represented by the general formula [38] from a compound
represented by the general formula [37] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [1] from
a compound represented by the general formula [1a-l] in
the production process A.
A compound represented by the general formula

[38] can also be obtained not by isolating a compound
represented by the general formula [37] from a compound
represented by the general formula [36], but by
continuously carrying out Friedel-Crafts reaction and
dealkylation.
The reaction for obtaining a compound
represented by the general formula [1j-1] from a
compound represented by the general formula [38] can be
carried out in the same manner as in the reaction for
obtaining a compound represented by the general formula
[5] from a compound represented by the general formula
[3] in the production process A.
The reaction for obtaining a compound
represented by the general formula [1j-2] from a
compound represented by the general formula [1j-1] can
be carried out in the same manner as in the reaction
for obtaining a compound represented by the general
formula [1a-2] from a compound represented by the
general formula [1a-1] in the production process A.
When the substituent Rlj, R4j or R3 has a protecting group,
the reaction can be carried out while appropriately
deprotecting the substituent by conventional procedure.
The reaction for obtaining a compound
represented by the general formula [39] from a compound
represented by the general formula [37] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [9] from
a compound represented by the general formula [8] in

the production process B.
The reaction for obtaining a compound
represented by the general formula [40] from a compound
represented by the general formula [39] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [3] from
a compound represented by the general formula [2] in
the production process A.
A compound represented by the general formula
[40] can also be obtained from a compound represented
by the general formula [36] by continuously carrying
out Friedel-Crafts reaction, dealkylation and
dehydration.
The reaction for obtaining a compound
represented by the general formula [41] from a compound
represented by the general formula [40] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [5] from
a compound represented by the general formula [3] in
the production process A.
The reaction for obtaining a compound
represented by the general formula [42] from a compound
represented by the general formula [41] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [6] from
a compound represented by the general formula [5] in
the production process A.
The reaction for obtaining a compound

represented by the general formula [1j-3] from a
compound represented by the general formula [42] can be
carried out in the same manner as in the reaction for
obtaining a compound represented by the general formula
[5] from a compound represented by the general formula
[3] in the production process A.
The reaction for obtaining a compound
represented by the general formula [1j-4] from a
compound represented by the general formula [1j-3] can
be carried out in the same manner as in the reaction
for obtaining a compound represented by the general
formula [1a-2] from a compound represented by the
general formula [1a-1] in the production process A.
When the substituent R13j, R4)3 or R3 has a protecting
group, the reaction can be carried out while
appropriately deprotecting the substituent by
conventional procedure.
[Production Process K]
[Formula 14]

wherein R2k represents a carboxyl-protecting group; R1k
represents the same meaning as R1a; R3k represents
optionally substituted alkyl; R4k represents the same
meaning as R4a; and X represents the same meaning as
above.
The reaction for obtaining a compound
represented by the general formula [1k-2] from a
compound represented by the general formula [1k-1] can
be carried out in the same manner as in the reaction
for obtaining a compound represented by the general
formula [5] from a compound represented by the general
formula [3] in the production process A.
The reaction for obtaining a compound
represented by the general formula [1k-3] from a

compound represented by the general formula [1k-2] can
be carried out in the same manner as in the reaction
for obtaining a compound represented by the general
formula [1a-2] from a compound represented by the
general formula [1a-1] in the production process A.
When the substituent Rlk, R3k or R4k has a protecting
group, the reaction can be carried out while
appropriately deprotecting the substituent by
conventional procedure.

wherein R21 represents a carboxyl-protecting group; R11
and RU1 each represent the same meaning as Rla; R41
represents the same meaning as R4a; and X represents the
same meaning as above.
The reaction for obtaining a compound

represented by the general formula [44] from a compound
represented by the general formula [43] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [15] from
a compound represented by the general formula [14] in
the production process D.
The reaction for obtaining a compound
represented by the general formula [45] from a compound
represented by the general formula [44] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [7] from
a compound represented by the general formula [1a-1] in
the production process A.
The reaction for obtaining a compound
represented by the general formula [11-1] from a
compound represented by the general formula [45] can be
carried out in the same manner as in the reaction for
obtaining a compound represented by the general formula
[5] from a compound represented by the general formula
[3] in the production process A.
The reaction for obtaining a compound
represented by the general formula [11-2] from a
compound represented by the general formula [11-1] can
be carried out in the same manner as in the reaction
for obtaining a compound represented by the general
formula [1a-2] from a compound represented by the
general formula [1a-1] in the production process A.
When the substituent R11 or R41 has a protecting group,

the reaction can be carried out while appropriately
deprotecting the substituent by conventional procedure.

wherein R2m represents a carboxyl-protecting group; R4m
represents the same meaning as R4a; and X represents the
same meaning as above.
The reaction for obtaining a compound
represented by the general formula [1m-1] from a
compound represented by the general formula [47] can be

carried out in the same manner as in the reaction for
obtaining a compound represented by the general formula
[5] from a compound represented by the general formula
[3] in the production process A.
The reaction for obtaining a compound
represented by the general formula [1m-2] from a
compound represented by the general formula [1m-1] can
be carried out in the same manner as in the reaction
for obtaining a compound represented by the general
formula [1i-3] from a compound represented by the
general formula [34] in the production process I.
The reaction for obtaining a compound
represented by the general formula [1m-3] from a
compound represented by the general formula [1m-2] can
be carried out in the same manner as in the reaction
for obtaining a compound represented by the general
formula [1a-2] from a compound represented by the
general formula [1a-1] in the production process A.
When the substituent R4m has a protecting group, the
reaction can be carried out while appropriately
deprotecting the substituent by conventional procedure.
The reaction for obtaining a compound
represented by the general formula [1m-4] from a
compound represented by the general formula [1m-1] can
be carried out in the same manner as in the reaction
for obtaining a compound represented by the general
formula [1i-4] from a compound represented by the
general formula [34] in the production process I.

The reaction for obtaining a compound
represented by the general formula [1m-5] from a
compound represented by the general formula [1m-4] can
be carried out in the same manner as in the reaction
for obtaining a compound represented by the general
formula [1a-2] from a compound represented by the
general formula [1a-1] in the production process A.
When the substituent R4m has a protecting group, the
reaction can be carried out while appropriately
deprotecting the substituent by conventional procedure.

wherein R2n represents a carboxyl-protecting group; R4n
represents the same meaning as R4a; R16 is optionally
substituted alkyl or aryl; and X represents the same
meaning as above.
The reaction for obtaining a compound

represented by the general formula [1n-1] from a
compound represented by the general formula [48] can be
carried out in the same manner as in the reaction for
obtaining a compound represented by the general formula
[5] from a compound represented by the general formula
[3] in the production process A.
A compound represented by the general formula
[1n-2] can be obtained by oxidizing a compound
represented by the general formula [1n-1].
Oxidizing agents used in this reaction
include, for example, organic peroxides such as
peracetic acid, trifluoroperacetic acid, perbenzoic
acid and m-chloroperbenzoic acid; hydrogen peroxide;
chromic acid and potassium permanganate. The amount of
oxidizing agent used can be 0.5- to 5-fold of the mole
of a compound represented by the general formula [1n-1]
and preferably 1- to 3-fold of the mole of the same.
Solvents used in this reaction are not limited to any
specific ones as long as they do not adversely affect
the reaction. They include, for example, aromatic
hydrocarbons such as benzene, toluene and xylene;
ethers such as 1,4-dioxane, tetrahydrofuran, anisole,
diethylene glycol diethyl ether and dimethyl
cellosolve; alcohols such as methanol and ethanol;
esters such as methyl acetate and ethyl acetate;
nitriles such as acetonitrile; amides such as N,N-
dimethylformamide and N,N-dimethylacetamide;
halogenated hydrocarbons such as chloroform and

methylene chloride; water; and sulfoxides such as
dimethyl sulfoxide. These solvents may be used
independently or in the form of a mixture of two or
more kinds.
Usually this reaction can be performed at -
78°C to the reflux temperature of the solvent used and
preferably -10 to 30°C for 10 minutes to 24 hours.
The reaction for obtaining a compound
represented by the general formula [1n-3] from a
compound represented by the general formula [1n-2] can
be carried out in the same manner as in the reaction
for obtaining a compound represented by the general
formula [1a-2] from a compound represented by the
general formula [1a-1] in the production process A.
A compound represented by the general formula
[1n-4] can be obtained by oxidizing a compound
represented by the general formula [1n-3].
Oxidizing agents used in this reaction
include, for example, organic peroxides such as
peracetic acid, trifluoroperacetic acid, perbenzoic
acid and m-chloroperbenzoic acid; hydrogen peroxide;
chromic acid and potassium permanganate. The amount of
oxidizing agent used can be 1- to 5-fold of the mole of
a compound represented by the general formula [1n-3]
and preferably 1- to 3-fold of the mole of the same.
Solvents used in this reaction are not limited to any
specific ones as long as they do not adversely affect
the reaction. They include, for example, aromatic

hydrocarbons such as benzene, toluene and xylene;
ethers such as 1,4-dioxane, tetrahydrofuran, anisole,
diethylene glycol diethyl ether and dimethyl
cellosolve; alcohols such as methanol and ethanol;
esters such as methyl acetate and ethyl acetate;
nitriles such as acetonitrile; amides such as N,N-
dimethylformamide and N,N-dimethylacetamide;
halogenated hydrocarbons such as chloroform and
methylene chloride; and water. These solvents may be
used independently or in the form of a mixture of two
or more kinds.
Usually this reaction can be performed at -
78°C to the reflux temperature of the solvent used and
preferably -10 to 30°C for 10 minutes to 2 4 hours.
The reaction for obtaining a compound
represented by the general formula [1n-5] from a
compound represented by the general formula [1n-2] can
be carried out in the same manner as in the reaction
for obtaining a compound represented by the general
formula [1n-4] from a compound represented by the
general formula [1n-3] in the production process N.
When the substituent R4n or R16 has a protecting group,
the reaction can be carried out while appropriately
deprotecting the substituent by conventional procedure.
A compound represented by the general formula
[1n-5] can also be obtained by oxidizing a compound
represented by the general formula [1n-1].
Oxidizing agents used in this reaction

include, for example, organic peroxides such as
peracetic acid, trifluoroperacetic acid, perbenzoic
acid and m-chloroperbenzoic acid; hydrogen peroxide;
chromic acid and potassium permanganate. The amount of
oxidizing agent used can be 2- to 10-fold of the mole
of a compound represented by the general formula [1n-1]
and preferably 2- to 3-fold of the mole of the same.
Solvents used in this reaction are not limited to any
specific ones as long as they do not adversely affect
the reaction. They include, for example, aromatic
hydrocarbons such as benzene, toluene and xylene;
ethers such as 1,4-dioxane, tetrahydrofuran, anisole,
diethylene glycol diethyl ether and dimethyl
cellosolve; alcohols such as methanol and ethanol;
esters such as butyl acetate and ethyl acetate;
nitriles such as acetonitrile; amides such as N,N-
dimethylformamide and N,N-dimethylacetamide;
halogenated hydrocarbons such as chloroform and
methylene chloride; and water. These solvents may be
used independently or in the form of a mixture of two
or more kinds.
Usually this reaction can be performed at -
78°C to the reflux temperature of the solvent used and
preferably -10 to 30°C for 10 minutes to 24 hours.
The reaction for obtaining a compound
represented by the general formula [1n-4] from a
compound represented by the general formula [1n-5] can
be carried out in the same manner as in the reaction

for obtaining a compound represented by the general
formula [1a-2] from a compound represented by the
general formula [1a-1] in the production process A.
When the substituent R4n or R16 has a protecting group,
the reaction can be carried out while appropriately
deprotecting the substituent by conventional procedure.

wherein R20 represents a carboxyl-protecting group; RlD
represents the same meaning as R1a; R100 and R30 are
optionally substituted alkyl; R° is a phenol-protecting
group; RHet is optionally substituted heterocyclyl; X1 is
a leaving group; and X represents the same meaning as
above.
The reaction for obtaining a compound
represented by the general formula [12o] from a
compound represented by the formula [12] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [12d]

from a compound represented by the formula [12] in the
production process D.
The reaction for obtaining a compound
represented by the general formula [49] from a compound
represented by the general formula [12o] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [13] from
a compound represented by the general formula [12d] in
the production process D.
The reaction for obtaining a compound
represented by the general formula [51] from a compound
represented by the general formula [50] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [15] from
a compound represented by the general formula [14] in
the production process D.
The reaction for obtaining a compound
represented by the general formula [52] from a compound
represented by the general formula [51] can be carried
out in the same manner as in the reaction for obtaining
a compound represented by the general formula [9] from
a compound represented by the general formula [8] in
the production process B.
A compound represented by the general formula
[52] can be obtained from a compound represented by the
general formula [50] not by isolating a compound
represented by the general formula [51], but by
continuously carrying out E'riedel-Crafts reaction and

dealkylation reaction.
A compound represented by the general formula
[53] can be obtained by the process disclosed in Greene
et al., Protective Groups in Organic Synthesis, 3rd
edition, 1999, 249-280.
Specifically, when R° is an acetyl group, for
example, a compound represented by the general formula
[53] can be obtained by reacting a compound represented
by the general formula [52] with acetic anhydride in
the presence of base.
In this reaction, acetic anhydride can be
used as a solvent; however, when some other solvent is
used, the amount of acetic anhydride used can be 2- to
20-fold of the mole of a compound represented by the
general formula [52] and preferably 2- to 3-fold of the
mole of the same. Bases used in this reaction include,
for example, organic amines such as
dimethylaminopyridine, triethylamine, pyridine and N-
methylmorpholine; and alkaline metal carbonates such as
potassium carbonate and sodium carbonate. The amount
of base used can be 2- to 10-fold of the mole of a
compound represented by the general formula [52] and
preferably 2- to 3-fold of the mole of the same.
Solvents used in this reaction are not limited to any
specific ones as long as they do not adversely affect
the reaction. They include, for example, nitriles such
as acetonitrile; aromatic hydrocarbons such as benzene,
toluene and xylene; ethers such as 1,4-dioxane,

tetrahydrofuran, anisole, diethylene glycol diethyl
ether and dimethyl cellosolve; aliphatic hydrocarbons
such as hexane and cyclohexane; halogenated
hydrocarbons such as chloroform and methylene chloride;
esters such as methyl acetate and ethyl acetate; amides
such as N,N-dimethylformamide and N,N-
dimethylacetamide; and sulfoxides such as dimethyl
sulfoxide. These solvents may be used independently or
in the form of a mixture of two or more kinds.
Usually this reaction can be performed at -20
to 200°C and preferably 0 to 100°C for 5 minutes to 24
hours.
When R° is a tetrahydropyranyl group, for
example, a compound represented by the general formula
[53] can be obtained by reacting a compound represented
by the general formula [52] with 3,4-dihydro-2H-pyran
in the presence of a catalyst.
The amount of the catalyst used in this
reaction can be 2- to 20-fold of the mole of a compound
represented by the general formula [52] and preferably
2- to 5-fold of the mole of the same. The catalysts
used in this reaction include, for example, acids such
as dry hydrogen chloride and p-toluenesulfonic acid;
and salts such as pyridinium p-toluenesulfonate. The
amount of catalyst used can be 0.01- to 10-fold of the
mole of a compound represented by the general formula
[52] and preferably 0.05- to 3-fold of the mole of the
same. Solvents used in this reaction are not limited

to any specific ones as long as they do not adversely
affect the reaction. They include, for example,
aromatic hydrocarbons such as benzene, toluene and
xylene; ethers such as 1,4-dioxane, tetrahydrofuran,
anisole, diethylene glycol diethyl ether and dimethyl
cellosolve; esters such as methyl acetate and ethyl
acetate; nitriles such as acetonitrile; amides such as
N,N-dimethylformamide and N,N-dimethylacetamide; and
halogenated hydrocarbons such as chloroform and
methylene chloride. These solvents may be used
independently or in the form of a mixture of two or
more kinds.
Usually this reaction can be performed at 0°C
to 100°C and preferably 0 to 50°C for 10 minutes to 24
hours.
A compound represented by the general formula
[54] can be obtained, for example, by the process
described in Tetrahedron Letters, Vol. 28, 5093-5096,
1987.
Specifically, a compound represented by the
general formula [54] can be obtained by reacting a
compound represented by the general formula [53] and a
compound represented by the general formula [R15d] in
the presence of base and a palladium coordination
compound as a catalyst.
Palladium coordination compounds used in this
reaction include, for example,
tetrakis(triphenylphosphine)palladium(0),

bis(triphenylphosphine)palladium(II) chloride,
benzyl(chloro)bis(triphenylphosphine)palladium(II) and
palladium(II) acetate. The amount of catalyst used can
be 0.001- to 1 mole per mole of a compound represented
by the general formula [53] and preferably 0.01- to
0.1-fold of the mole of the same. Bases used in this
reaction include, for example, alkali carbonates such
as sodium hydrogencarbonate and sodium carbonate;
alkali hydroxides such as sodium hydroxide and
potassium hydroxide; alkaline metal alkoxides such as
sodium methoxide and sodium tert-butoxide; and organic
bases such as triethylamine and pyridine. The amount
of base used can be 1- to 10-fold of the mole of a
compound represented by the general formula [53] and
preferably 2- to 4-fold of the mole of the same.
Solvents used in this reaction are not limited to any
specific ones as long as they do not adversely affect
the reaction. They include, for example, aromatic
hydrocarbons such as benzene, toluene and xylene;
ethers such as 1,4-dioxane and tetrahydrofuran;
halogenated hydrocarbons such as chloroform and
methylene chloride; alcohols such as methanol and
ethanol; esters such as ethyl acetate; amides such as
N,N-dimethylformamide; sulfoxides such as dimethyl
sulfoxide; and water. These solvents may be used
independently or in the form of a mixture of two or
more kinds.
Usually this reaction can be performed at 20°C

to the reflux temperature of the solvent used and
preferably 30 to 120°C for 30 minutes to 72 hours and
preferably 30 minutes to 5 hours.
A compound represented by the general formula
[54] can be obtained, for example, by the process
described in Nippon Kagaku Kaishi, No.3, 520-526, 1985.
Specifically, a compound represented by the
general formula [54] can also be obtained by reacting a
compound represented by the general formula [53] with a
compound represented by the general formula [Rl5e] in
the presence or absence of a palladium coordination
compound as a catalyst.
Palladium coordination compounds used in this
reaction include, for example,
tetrakis(triphenylphosphine)palladium(0),
bis(triphenylphosphine)palladium(II) chloride,
benzyl(chloro)bis(triphenylphosphine)palladium(II) and
palladium(II) acetate. The amount of catalyst used can
be 0.001- to 1-fold of the mole of a compound
represented by the general formula [53] and preferably
0.01- to 0.1-fold of the mole of the same. Solvents
used in this reaction are not limited to any specific
ones as long as they do not adversely affect the
reaction. They include, for example, aromatic
hydrocarbons such as benzene, toluene and xylene;
ethers such as 1,4-dioxane and tetrahydrofuran;
halogenated hydrocarbons such as chloroform and
methylene chloride; alcohols such as methanol and

ethanol; esters such as ethyl acetate; amides such as
N,N-dimethylformamide; and sulfoxides such as dimethyl
sulfoxide. These solvents may be used independently or
in the form of a mixture of two or more kinds.
Usually this reaction can be performed at 20°C
to the reflux temperature of the solvent used and
preferably 30 to 120°C for 30 minutes to 72 hours and
preferably 30 minutes to 5 hours.
A compound represented by the general formula
[55] can be obtained from a compound represented by the
general formula [54] by carrying out ordinary
deprotection.
Specifically, when R° of a compound
represented by the general formula [54] is acetyl, a
compound represented by the general formula [55] can be
obtained by deprotecting the substituents protected
with R° in the presence of base.
Bases used in this reaction include, for
example, alkaline metal carbonates such as potassium
carbonate and sodium carbonate; and alkaline metal
alkoxides such as potassium tert-butoxide and sodium
methoxide. The amount of base used can be 2- to 10-
fold of the mole of a compound represented by the
general formula [54] and preferably 2- to 3-fold of the
mole of the same. Solvents used in this reaction are
not limited to any specific ones as long as they do not
adversely affect the reaction. They include, for
example, aromatic hydrocarbons such as benzene, toluene

and xylene; ethers such as 1,4-dioxane and
tetrahydrofuran; halogenated hydrocarbons such as
chloroform and methylene chloride; alcohols such as
methanol and ethanol; amides such as N,N-
dimethylformamide; and sulfoxides such as dimethyl
sulfoxide. These solvents may be used independently or
in the form of a mixture of two or more kinds.
Usually this reaction can be performed at -
10°C to 100°C and preferably 0 to 30°C for 5 minutes to
24 hours and preferably 10 minutes to 10 hours.
When R° of a compound represented by the
general formula [54] is tetrahydropyran, for example,
elimination thereof can be accomplished in the presence
of acid. Acids used in this reaction include, for
example, mineral acids such as hydrochloric acid; and
organic acids such as p-toluenesulfonic acid and oxalic
acid. The amount of acid used can be 0.01- to 100-fold
of the mole of a compound represented by the general
formula [54] and preferably 0.05- to 10-fold of the
mole of the same. Solvents used in this reaction are
not limited to any specific ones as long as they do not
adversely affect the reaction. They include, for
example, aromatic hydrocarbons such as benzene, toluene
and xylene; ethers such as 1,4-dioxane, tetrahydrofuran,
anisole, diethylene glycol diethyl ether and dimethyl
cellosolve; alcohols such as methanol and ethanol;
esters such as butyl acetate and ethyl acetate;
nitriles such as acetonitrile; amides such as N,N-

dimethylformamide and N,N-dimethylacetamide;
halogenated hydrocarbons such as chloroform and
methylene chloride; and water. These solvents may be
used independently or in the form of a mixture of two
or more kinds.
Usually this reaction can be performed at 0°C
to the reflux temperature of the solvent used and
preferably 5 to 100°C for 10 minutes to 24 hours.
The reaction for obtaining a compound
represented by the general formula [1o-1] from a
compound represented by the general formula [55] can be
carried out in the same manner as in the reaction for
obtaining a compound represented by the general formula
[5] from a compound represented by the general formula
[3] in the production process A.
The reaction for obtaining a compound
represented by the general formula [1o-2] from a
compound represented by the general formula [1o-1] can
be carried out in the same manner as in the reaction
for obtaining a compound represented by the general
formula [1a-2] from a compound represented by the
general formula [1a-1] in the production process A.
When the substituent R10 or RHet has a protecting group,
the reaction can be carried out while appropriately
deprotecting the substituent by conventional procedure.

wherein R1p represents a hydroxyl- or amino-protecting
group; R2p and R2pp each represent optionally substituted
alkyl; R3p is hydrogen, halogen, cyano, nitro,
optionally protected hydroxyl, optionally protected
amino, mercapto, carbamoyl, or optionally substituted

alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy,
aryloxy, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylamino, acylamino, alkylsulfonylamino,
arylsulfonylamino or heterocyclyl; R4, R5 and X
represent the same meaning as above (Rlp represents a
group substituted for oxygen of a hydroxyl group as a
substituent of benzisoxazole or nitrogen of
benzisoxazole).
A compound represented by the general formula
[1p-2] can be obtained by subjecting a compound
represented by the general formula [1p-1] to
deprotection reaction such as (1) hydrolysis with acid
or base, (2) dealkylation with salt or (3) reductive
dealkylation including hydrogen addition reaction with
metal catalyst.
Acids used in the reaction (1) include, for
example, mineral acids such as hydrochloric acid,
sulfuric acid and hydrobromic acid; organic acids such
as formic acid and trifluoroacetic acid; and Lewis
acids such as aluminium chloride and trimethylsilyl
iodide. The amount of acid used in the reaction can be
1- to 100-fold of the mole of a compound represented by
the general formula [1p-1] and preferably 1- to 10-fold
of the mole of the same.
Bases used in the reaction (1) include, for
example, alkali hydroxides such as sodium hydroxide,
potassium hydroxide and lithium hydroxide; alkaline
metal alkoxides such as sodium methoxide, sodium

ethoxide and potassium tert-butoxide; alkaline metal
carbonates such as potassium carbonate and sodium
carbonate; and tetrabutylammonium fluoride. The amount
of base used can be 1- to 100-fold of the mole of a
compound represented by the general formula [1p-1] and
preferably 1- to 10-fold of the mole of the same.
Salts used in the reaction (2) include, for
example, lithium iodide and sodium chloride. The
amount of salt used can be 1- to 100-fold of the mole
of a compound represented by the general formula [1p-1]
and preferably 1- to 10-fold of the mole of the same.
Catalysts used in the reaction (3) include,
for example, palladium carbon, palladium black and
palladium hydroxide. The amount of catalyst used can
be 0.1- to 100% (w/w) the weight of the compound
represented by the general formula [1p-1] and
preferably 1- to 50% (w/w) the weight of the same.
Reducing agents used in the reaction (3)
include, for example, hydrogen, formic acid,
cyclohexene and zinc. The amount of reducing agent
used can be 1- to 100-fold of the mole of a compound
represented by the general formula [1p-1] and
preferably 1- to 10-fold of the mole of the same.
Solvents used in these reactions are not
limited to any specific ones as long as they do not
adversely affect the reaction. They include, for
example, alcohols such as methanol, ethanol and
isopropyl alcohol; ethers such as tetrahydrofuran,

diethyl ether; 1,4-dioxane and anisole; halogenated
hydrocarbons such as methylene chloride, chloroform and
carbon tetrachloride; nitriles such as acetonitrile;
aliphatic hydrocarbons such as n-hexane and
cyclohexane; esters such as ethyl acetate; aromatic
hydrocarbons such as toluene, benzene and xylene;
dimethyl sulfoxide, N,N-dimethylformamide, nitromethane,
pyridine and water. These solvents may be used
independently or in the form of a mixture of two or
more kinds.
Usually these reaction can be performed at -
78 to 100°C and preferably 0 to 80°C for 10 minutes to
24 hours.
A compound represented by the general formula
[1p-3] can be obtained by subjecting a compound
represented by the general formula [1p-2] to
esterification.
This can be carried out using ordinary
esterification reaction, and the processes of
esterification include, for example, processes (1) in
which acid catalyst and additive are used, (2) in which
esterification is carried out via acid chloride in the
presence or absence of catalyst, (3) in which
esterification is carried out via acid anhydride in the
presence or absence of base, (4) in which base and a
compound represented by the general formula [R2p] are
used and (5) in which a compound represented by the
general formula [R1p] together with condensing agent

and additive is subjected to condensation reaction.
Acid catalysts used in the reaction (1)
include, for example, hydrochloric acid, sulfuric acid,
hydrobromic acid, trimethylsilyl chloride, aluminium
chloride, boron trifluoride and trifluoroacetic acid.
The amount of acid catalyst used in the reaction can be
0.01- to 100-fold of the mole of a compound represented
by the general formula [1p-2] and preferably 0.5- to
50-fold of the mole of the same. Additives used in the
reaction include, for example, 2,2-dimethoxypropane and
ethyl orthoformate. The amount of additive used in the
reaction can be 0.1- to 100-fold of the mole of a
compound represented by the general formula [1p-2] and
preferably 1- to 50-fold of the mole of the same.
Compounds represented by the general formula
[R1p] include, for example, methanol, ethanol, benzyl
alcohol, N-(2-hydroxyethyl)morpholine and 4-
hydroxymethyl-5-methyl-l,3-dioxol-2-one. These
compounds can be used as a solvent in appropriate
amount; however, when some other solvent is used, the
amount of such a compound used can be 1- to 100-fold of
the mole of a compound represented by the general
formula [1p-2] and preferably 1- to 50-fold of the mole
of the same.
Solvents used in the reaction (1) are not
limited to any specific ones as long as they do not
adversely affect the reaction. They include, for
example, aromatic hydrocarbons such as benzene, toluene

and xylene; ethers such as 1,4-dioxane, tetrahydrofuran,
anisole, diethylene glycol diethyl ether, and dimethyl
cellosolve; esters such as methyl acetate and ethyl
acetate; nitriles such as acetonitrile; amides such as
N,N-dimethylformamide; halogenated hydrocarbons such as
chloroform and methylene chloride; and sulfoxides such
as dimethyl sulfoxide. Usually these reaction can be
performed at 0 to 200°C and preferably 5 to 100°C for 10
minutes to 2 4 hours.
Carboxylic-activating agents used in the
reaction (2) include, for example, oxalyl chloride and
thionyl chloride. The amount of the agent used in the
reaction can be 1- to 10-fold of the mole of a compound
represented by the general formula [1p-2] and
preferably 1- to 5-fold of the mole of the same.
Catalysts used in the reaction (2) as the
need arises include, for example, N,N-dimethylformamide,
and the amount of catalyst used in the reaction can be
0.001- to 1-fold of the mole of a compound represented
by the general formula [1p-2] and preferably 0.01- to
0.5-fold of the mole of the same.
Solvents used in the reaction (2) are not
limited to any specific ones as long as they do not
adversely affect the reaction. They include, for
example, aromatic hydrocarbons such as benzene, toluene
and xylene; ethers such as 1,4-dioxane, tetrahydrofuran,
anisole, diethylene glycol diethyl ether, and dimethyl
cellosolve; esters such as methyl acetate and ethyl

acetate; nitriles such as acetonitrile; amides such as
N,N-dimethylformamide; and halogenated hydrocarbons
such as chloroform and methylene chloride. Usually
these reaction can be performed at 0 to 200°C and
preferably 5 to 100°C for 10 minutes to 24 hours.
Activating agents used in the reaction (3)
include, for example, acetic anhydride and ethyl
chloroformate, and the amount of activating agent used
in the reaction can be 1- to 10-fold of the mole of a
compound represented by the general formula [1p-2] and
preferably 1- to 5-fold of the mole of the same.
Bases used in the reaction (3) as the need
arises include, for example, organic amines such as
dimethylaminopyridine, triethylamine, pyridine, N-
methylmorpholine and N-ethyldiisopropylamine; and
alkaline metal carbonates such as potassium carbonate
and sodium carbonate. The amount of base used can be
1- to 10-fold of the mole of a compound represented by
the general formula [1p-2] and preferably 1- to 5-fold
of the mole of the same. Solvents used in this
reaction are not limited to any specific ones as long
as they do not adversely affect the reaction. They
include, for example, aromatic hydrocarbons such as
benzene, toluene and xylene; ethers such as 1,4-dioxane,
tetrahydrofuran, anisole, diethylene glycol diethyl
ether and dimethyl cellosolve; esters such as methyl
acetate and ethyl acetate; nitriles such as
acetonitrile; amides such as N,N-dimethylformamide; and

halogenated hydrocarbons such as chloroform and
methylene chloride. Usually this reaction can be
performed at 0 to 200°C and preferably 5 to 100°C for 10
minutes to 24 hours.
Bases used in the reaction (4) include, for
example, organic amines such as dimethylaminopyridine,
triethylamine, pyridine and N-methylmorpholine; and
alkaline metal carbonates such as potassium carbonate
and sodium carbonate. The amount of base used can be
0.5- to 10-fold of the mole of a compound represented
by the general formula [1p-2] and preferably 1- to 5-
fold of the mole of the same.
Compounds represented by the general formula
[R2p] used in the reaction (4) include, for example,
methyl iodide, ethyl iodide, benzyl bromide, ethyl
carbonate 1-ethyl iodide, cyclohexyl carbonate 1-ethyl
iodide, 4-bromomethyl-5-methyl-1,3-dioxol-2-one, N-(2-
chloroethyl)morpholine and chloromethyl pivalate. The
amount of such a compound used can be 0.5- to 10-fold
of the mole of a compound represented by the general
formula [1p-2] and preferably 1- to 3-fold of the mole
of the same.
Solvents used in the reaction (4) are not
limited to any specific ones as long as they do not
adversely affect the reaction. They include, for
example, aromatic hydrocarbons such as benzene, toluene
and xylene; ethers such as 1,4-dioxane, tetrahydrofuran,
anisole, diethylene glycol diethyl ether and dimethyl

cellosolve; esters such as methyl acetate and ethyl
acetate; nitriles such as acetonitrile; amides such as
N,N-dimethylformamide; halogenated hydrocarbons such as
chloroform and methylene chloride; and sulfoxides such
as dimethyl sulfoxide. Usually this reaction can be
performed at 0 to 200°C and preferably 5 to 100°C for 10
minutes to 24 hours.
Condensing agents used in the reaction (5)
include, for example, 1,1'-carbonyldiimidazole, N,N'-
dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-
ethyl-N'-3-dimethylaminopropylcarbodiimide, diisopropyl
azodicarboxylate and diphenylphosphoryl azide.
Additives used in the reaction (5) include,
for example, 1-hydroxybenzotriazole, triphenylphosphine
and N-hydroxysuccinimide.
The amounts of a compound represented by the
general formula [R1p], condensing agent and additive
used in the reaction (5) each can be 0.01- to 10-fold
of the mole of a compound represented by the general
formula [1p-2] and preferably 0.1- to 3-fold of the
mole of the same.
Solvents used in the reaction (5) are not
limited to any specific ones as long as they do not
adversely affect the reaction. They include, for
example, aromatic hydrocarbons such as benzene, toluene
and xylene; ethers such as 1,4-dioxane, tetrahydrofuran,
anisole, diethylene glycol diethyl ether and dimethyl
cellosolve; esters such as methyl acetate and ethyl

acetate; nitriles such as acetonitrile; amides such as
N,N-dimethylformamide; and halogenated hydrocarbons
such as chloroform and methylene chloride. Usually
this reaction can be performed at 0 to 200°C and
preferably 5 to 100°C for 10 minutes to 24 hours.
A compound represented by the general formula
[1p-3] can also be obtained from a compound represented
by the general formula [1p-1] by continuously carrying
out deprotection and esterification.
A compound represented by the general formula
[1p-3] can also be obtained by reacting a compound
represented by the general formula [1p-1] with a
compound represented by the general formula [R1p] in
the presence of acid or base.
Compounds represented by the general formula
[R1p] used in this reaction include, for example,
methanol, ethanol, benzyl alcohol, N-(2-
hydroxyethyl)morpholine and 4-hydroxymethyl-5-methyl-
1,3-dioxole-2-one. These compounds can be used as a
solvent in appropriate amount; however, when some other
solvent is used, the amount of such a compound used can
be 1- to 100-fold of the mole of a compound represented
by the general formula [1p-1] and preferably 1- to 10-
fold of the mole of the same.
Acids used in this reaction include, for
example, hydrochloric acid, sulfuric acid, p-
toluenesulfonic acid, trimethylsilyl chloride and boron
trifluoride. The amount of acid used in the reaction

can be 0.01- to 100-fold of the mole of a compound
represented by the general formula [1p-1] and
preferably 0.1- to 10-fold of the mole of the same.
Bases used in this reaction include, for
example, alkaline metal alkoxides such as sodium
methoxide, sodium ethoxide and potassium tert-butoxide;
organic amines such as dimethylaminopyridine,
triethylamine and pyridine; alkaline metal hydrides
such as sodium hydride; and alkaline metal carbonates
such as potassium carbonate and sodium carbonate. The
amount of base used can be 1- to 100-fold of the mole
of a compound represented by the general formula [1p-1]
and preferably 1- to 10-fold of the mole of the same.
Solvents used in this reaction are not
limited to any specific ones as long as they do not
adversely affect the reaction. They include, for
example, aromatic hydrocarbons such as benzene, toluene
and xylene; ethers such as 1,4-dioxane, tetrahydrofuran,
anisole, diethylene glycol diethyl ether, and dimethyl
cellosolve; nitriles such as acetonitrile; amides such
as N,N-dimethylformamide; halogenated hydrocarbons such
as chloroform and methylene chloride; and sulfoxides
such as dimethyl sulfoxide. These solvents are used
independently or in the form of a mixture of two or
more kinds.
Usually this reaction can be performed at -50
to 200°C and preferably -30 to 150°C for 10 minutes to
24 hours.

A compound represented by the general formula
[1p-4] can be obtained from a compound represented by
the general formula [1p-3] by carrying out ordinary
deprotection.
For example, when Rlp of a compound
represented by the general formula [1p-3] is tert-
butoxycarbonyl, deprotection can be carried out in the
presence of acid. Acids used in this reaction include,
for example, mineral acids such as hydrochloric acid
and sulfuric acid; and organic acids such as
methanesulfonic acid, p-toluenesulfonic acid, acetic
acid and trifluoroacetic acid. The amount of acid used
in the reaction can be 0.01- to 100-fold of the mole of
a compound represented by the general formula [1p-3]
and preferably 1- to 10-fold of the mole of the same.
Solvents used in this reaction are not limited to any
specific ones as long as they do not adversely affect
the reaction. They include, for example, aromatic
hydrocarbons such as benzene, toluene and xylene;
ethers such as 1,4-dioxane, tetrahydrofuran, anisole,
diethylene glycol diethyl ether, and dimethyl
cellosolve; alcohols such as methanol, ethanol and
isopropyl alcohol; esters such as butyl acetate and
ethyl acetate; nitriles such as acetonitrile; amides
such as N,N-dimethylformamide and N,N-
dimethylacetamide; halogenated hydrocarbons such as
chloroform and methylene chloride; and water. These
solvents are used independently or in the form of a

mixture of two or more kinds. Usually this reaction
can be performed at 0°C to the reflux temperature of the
solvent used and preferably 0 to 120°C for 10 minutes to
24 hours.
For example, when Rlp of a compound
represented by the general formula [1p-3] is
methoxymethyl or trityl, deprotection can be carried
out in the presence of acid. Acids used in this
reaction include, for example, mineral acids such as
hydrochloric acid and sulfuric acid; and organic acids
such as methanesulfonic acid, p-toluenesulfonic acid,
acetic acid and trifluoroacetic acid. The amount of
acid used in the reaction can be 0.01- to 100-fold of
the mole of a compound represented by the general
formula [1p-3] and preferably 1- to 10-fold of the mole
of the same. Solvents used in this reaction are not
limited to any specific ones as long as they do not
adversely affect the reaction. They include, for
example, aromatic hydrocarbons such as benzene, toluene
and xylene; ethers such as 1,4-dioxane, tetrahydrofuran,
anisole, diethylene glycol diethyl ether, and dimethyl
cellosolve; alcohols such as methanol, ethanol and
isopropyl alcohol; esters such as butyl acetate and
ethyl acetate; nitriles such as acetonitrile; amides
such as N,N-dimethylformamide and N,N-
dimethylacetamide; halogenated hydrocarbons such as
chloroform and methylene chloride; and water. These
solvents are used independently or in the form of a

mixture of two or more kinds. Usually this reaction
can be performed at 0°C to the reflux temperature of the
solvent used and preferably 0 to 120°C for 10 minutes to
24 hours.
A compound represented by the general formula
[1p-4] can also be obtained from a compound represented
by the general formula [1p-2] by continuously carrying
out esterification and deprotection.

wherein R1q represents the same meaning as Rlp; R2q
represents the same meaning as R2p; R3q represents the
same meaning as R3p; and R4, R5 and X represent the same
meaning as above (Rlq represents a group substituted for
oxygen of an oxo group as a substituent of

benzisoxazole or nitrogen of benzisoxazole).
A compound represented by the general formula
[1q-2] can be obtained, for example, by the process
disclosed in Greene et al., Protective Groups in
Organic Synthesis, 3rd edition, 1999, 17-292, 494-653.
Specifically, when Rlq is a trityl group, for
example, a compound represented by the general formula
[1q-2] can be obtained by reacting a compound
represented by the general formula [1q-1] with trityl
chloride in the presence of base. The amount of trityl
chloride used can be 1- to 10-fold of the mole of a
compound represented by the general formula [1q-1] and
preferably 1- to 3-fold of the mole of the same.
Bases used in this reaction include, for
example, organic amines such as dimethylaminopyridine,
triethylamine, pyridine and N-methylmorpholine; and
alkaline metal carbonates such as potassium carbonate
and sodium carbonate. The amount of base used can be
1- to 20-fold of the mole of a compound represented by
the general formula [1q-1] and preferably 3- to 10-fold
of the mole of the same.
Solvents used in this reaction are not
limited to any specific ones as long as they do not
adversely affect the reaction. They include, for
example, nitriles such as acetonitrile; aromatic
hydrocarbons such as benzene, toluene and xylene;
ethers such as 1,4-dioxane, tetrahydrofuran, anisole,
diethylene glycol diethyl ether and dimethyl

cellosolve; aliphatic hydrocarbons such as hexane and
cyclohexane; halogenated hydrocarbons such as
chloroform and methylene chloride; esters such as
methyl acetate and ethyl acetate; amides such as N,N-
dimethylformamide and N,N-dimethylacetamide; and
sulfoxides such as dimethyl sulfoxide. These solvents
may be used independently or in the form of a mixture
of two or more kinds.
Usually this reaction can be performed at -50
to 150°C and preferably -30 to 100°C for 5 minutes to 24
hours.
The reaction for obtaining a compound
represented by the general formula [1q-3] from a
compound represented by the general formula [1q-2] can
be carried out in the same manner as in the reaction
for obtaining a compound represented by the general
formula [1p-3] from a compound represented by the
general formula [1p-2] in the production process P.
The reaction for obtaining a compound
represented by the general formula [1q-4] from a
compound represented by the general formula [1q-1] can
be carried out in the same manner as in the reaction
for obtaining a compound represented by the general
formula [1p-3] from a compound represented by the
general formula [1p-2] in the production process P.
The reaction for obtaining a compound
represented by the general formula [1q-4] from a
compound represented by the general formula [1q-3] can

be carried out in the same manner as in the reaction
for obtaining a compound represented by the general
formula [1p-4] from a compound represented by the
general formula [1p-3] in the production process P.
In the compounds used in the above described
production processes, those capable of taking the form
of salts can be used as salts. Such salts include, for
example, the same salts as described in the salts of
compounds represented by the general formula [1].
When isomers (e.g. optical isomers,
geometrical isomers and tautomers) are present in the
compounds used in the above described production
processes, the isomers can also be used. When solvates,
hydrates and crystals in various forms are present in
the compounds, the solvates, hydrates and crystals in
various forms can also be used. In the compounds used
in the above described production processes, for those
having substituents that can be protected, such as
amino, hydroxyl or carboxyl, the substituents can be
protected with ordinary protecting groups in advance
and deprotected by known processes after reaction.
Subjecting the compounds represented by the
general formula [1] thus obtained to known reaction,
such as oxidation, reduction, substitution,
rearrangement, halogenation, dehydration or hydrolysis,
or the combination thereof enables other compounds
represented by the general formula [1] to be derived.
Compounds represented by the general formula [1] or the

salts thereof can be isolated and purified by
conventional procedure such as extraction,
crystallization and/or column chromatography.
When using the compounds of this invention as
drugs, additives commonly used in preparation of drugs,
such as excipient, carrier and diluent, can be
appropriately mixed with the compounds. The resultant
drugs can be administered orally or parenterally in a
dosage form of tablet, capsule, powder, syrup, granule,
pill, suspension, emulsion, solution, powder
preparations, suppository, ointment or parenteral
injection. The dosage, administration and dosing can
be appropriately selected depending on the age, body
weight and symptoms of patients. For adults, usually
they can be administered orally or parenterally (e.g.
injection, drip infusion, or administration into
rectum) in a daily dose of 0.1 to 100 mg/kg in one to
several divided portions.
[Test Methods]
Test Example 1 Effect on AP-1 binding activity to AP-1
recognition sequence (ELISA)
Jun peptide and Fos peptide with its N-
terminal labeled with biotin via 4 glycine residues
containing a DNA binding site [Nature, Vol. 373, 1995,
257-261] were synthesized. Each of the peptides was
dissolved in Tris buffer [20 mM Tris-hydrochloric acid
(pH 7.5), 50 mM potassium chloride, 1 mM
ethylenediaminetetraacetic acid, 10 mM magnesium

chloride, 1 mM dithiothreitol, 0.5 M
guanidinohydrochloric acid, 30% glycerol], and
equimolar amounts of the peptide solutions were mixed
with each other to be used as an AP-1 complex (Fos/Jun
peptide). The AP-1 complex was added onto a 96-well
avidin-coated ELISA plate (10 pmol/well). The plate
was washed, blocked by bovine serum albumin, and used
for binding assay.
Digoxigenin-labeled double-stranded
oligonucleotide (22mer) that contained AP-1 binding
sequence (3'-TGAGTCA-5') synthesized by conventional
procedure was reacted in binding reaction solution [25
mM tris-hydrochloric acid (pH 7.9), 0.5 mM
ethylenediaminetetraacetic acid, 0.05% Nonidet P-40,
10% glycerol] for 30 minutes at room temperature in the
presence or absence of samples. After the reaction,
unbound labeled oligonucleotide was removed by washing
with HEPES buffer containing 0.05% Tween-20. Then
peroxidase-labeled anti-digoxigenin antibody was added
to react with the labeled oligonucleotide bound to AP-1.
After removing excess antibody by washing with HEPES
buffer containing 0.05% Tween-20, incubation was
conducted for a certain period with o-phenylene diamine
as a substrate in 100 mM citric acid buffer (pH 5.0)
containing hydrogen peroxide, sulfuric acid solution
was added to each well, and the absorbance (492 nm) was
measured. Inhibition rate of each sample was
calculated from the absorbance obtained in the binding

assay carried out in the presence of the sample, taking
the absorbance obtained in the absence of the sample =
100%.
The results are shown in Table 12.

mouse
Male DBA/1J mice aged 8 weeks (Charles River
Japan) were used. To a solution of 2 mg/mL bovine type
II collagen in 0.1 mol/L acetic acid (Koken), an
equimolar amount of Freund's complete adjuvant (DIFCO)
was added to prepare an emulsion, and 0.2 ml of the
emulsion was subcutaneously injected in the tail root
region of each mouse. The same treatment was given 21
days after the initial inoculation to induce arthritis
in the mice. Test compounds were each suspended in
0.5% methylcellulose solution, and 10 mg/kg of each
test compound was given orally to mice once a day from
21 to 35 days after the initial inoculation. To a
control group (a negative control group), 0.5%
methylcellulose solution was given in the same manner.
Taking the maximum score as 12, the arthritis
score was calculated to evaluate the severity of
arthritis that was evaluated in the following manner:
score 0: no change; score 1: swelling on one or two
toes, or slight swelling in the carpal and tarsal
joints; score 2: swelling and rubor in more joints;
score 3: extensive swelling over whole foreleg or
hindleg; and total of the four legs was calculated.
X-ray photographs of four paws were taken 36
days after the initial inoculation, and the severity of
bone destruction was evaluated as bone destruction
score on a maximum scale, the sum of the points for
extremities, of 105 points: 0 or 0.5 points in

accordance with presence or absence of osteoporosis in
the joints and their vicinity, and for bone erosion, no
change at 0 point; "partial bone destruction" at 1
point and "complete bone destruction" at 2 points in
the second to fifth interdigital joints, the first to
fifth metacarpal and metatarsal joints, and carpal,
tarsal and calcaneal regions. Inhibition rate was
calculated using the following equation:
Inhibition rate (%) = 100 - (score of the
group given the test compound / score of the control
group) x 100
Table 13 shows the arthritis inhibition rate
and the bone destruction inhibition rate of each test
compound on 36 days after initial inoculation.

the Examples have meanings as follows, respectively.
Me: methyl, Et: ethyl, i-Pr: isopropyl, i-Bu:
isobutyl, MOM: methoxymethyl, Bn: benzyl, Tr: trityl,
Ph: phenyl, Boc: tert-butoxycarbonyl, CDC13: deuterated
chloroform, DMSO-d6: deuterated dimethylsulfoxide
M represents a unit "mol/L".
Every mixing ratio of components used for the
eluent is expressed by volume.
In addition, Silica gel BW-127ZH (produced by
Fuji Silysia Chemical Ltd.) was used as a support for
silica gel chromatography.
Example 1
Two grams of ethyl 3-[5-(2,4-
diisopropoxybenzoyl)-2-isobutoxyphenyl] propanoate was
dissolve in 20 mL of methylene chloride, and after the
addition of 1.42 g of aluminum chloride at room
temperature, the resultant mixture was stirred for 30
minutes at room temperature. This reaction mixture was
added to ice water for the separation of an organic
phase therefrom. After the resultant organic phase was
washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous magnesium sulfate and the solvent was
distilled out thereof under reduced pressure. The
resultant residue was purified by silica gel column
chromatography [eluent; hexane:ethyl acetate=2:l] to
yield 585 mg of ethyl 3-[5-(2-hydroxy-4-
isopropoxybenzoyl)-2-isobutoxyphenyl] propanoate as

light yellow oil.
NMR(90MHz,CDCl3) 5 value: 1. 07 ( 6H, d, J=6 . 8Hz) ,
1.23(3H,t,J=7.3Hz), 1.38(6H,d,J=6.1Hz), 1.92-2.40(1H,m),
2.61-2.72(2H,m), 2.92-3.12(2H,m), 3.82(2H,d,J=6.1Hz),
4.13(2H,q,J=7.1Hz), 4.50-4.77(1H,m), 6.34-6.50(2H,m),
6.88(1H,d,J=9.3Hz), 7.49-7.58(3H,m), 12.70(1H,s)
Example 2
545 mg of ethyl 3-[5-(2-hydroxy-4-
isopropoxybenzoyl)-2-isobutoxyphenyl] propanoate was
dissolve in 2.5 mL of ethanol, and after the addition
of 1.5 mL of 5M sodium hydroxide thereto, the resultant
mixture was stirred for 2.5 hours at room temperature.
Following the addition of chloroform and water to the
reaction mixture, which is then adjusted to pH 2 with
6M hydrochloric acid, and the organic phase was
separate therefrom. After the resultant organic phase
was washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous magnesium sulfate and the solvent was
distilled out thereof under reduced pressure.
Consequently, 444 mg of 3-[5-(2-hydroxy-4-
isopropoxybenzoyl)-2-isobutoxyphenyl] propanoic acid
was obtained as light yellow solid.
NMR(90MHz, CDC13) 8 value: 1.07(6H,d,J=6.6Hz),
1.36(6H,d,J=6.1Hz), 1.95-2.31(1H,m), 2.61-3.12(4H,m),
3.82(2H,d,J=6.1Hz), 4.50-4.77(1H,m), 6.32-6.49(2H,m),
6.89(1H,d,J=9.3Hz), 7.48-7.62(3H,m), 10.00(1H,br),
12.68(1H,s)

Example 3
Isopropyl 3-[5-(2-hydroxy-4-
isopropoxybenzoyl)-2-isopropoxyphenyl] propanoate was
obtained in a similar manner as in Example 1.
NMR(90MHz,CDCl3) 5 value: 1.19(6H,d,J=6.4Hz),
1.38(6H,d,J=6.1Hz), 1.39(6H,d,J=6.1Hz), 2.56-2.66(2H,m),
2.88-3.06(2H,m), 4.42-5.13(3H,m), 6.33-6.49(2H,m),
6.89(1H,d,J=9.3Hz), 7.50-7.60(3H,m), 12.70(1H,s)
Example 4
3-[5-(2-hydroxy-4-isopropoxybenzoyl)-2-
isopropoxyphenyl] propanoic acid was obtained in a
similar manner as in Example 2.
NMR(90MHz,CDCI3) 5 value: 1.36(6H,d,J=6.1Hz),
1.39(6H,d,J=5.9Hz), 2.61-3.08(4H,m), 4.49-4.74(2H,m),
6.33-6.49(2H,m), 6 . 90(1H,d,J=9.3Hz), 7.50-7.60(3H,m),
11.18(1H,br), 12.69(1H,s)
Example 5
5.0 g of methyl 3-[5-(2,4-dihydroxybenzoyl)-
2-hydroxyphenyl] propanoate, 9.6 g of potassium
carbonate, and 6.4 mL of isopropyl iodide were
suspended in 50 mL of N,N-dimethylformamide, and
stirred for 2 hours at temperatures of 50 to 60°C. This
reaction mixture was added to a mixture of ethyl
acetate and water, which is then adjusted to pH 2 with
6M hydrochloric acid, and the organic phase was
separated therefrom. After the resultant organic phase
was washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over

anhydrous magnesium sulfate and the solvent was
distilled out thereof under reduced pressure. The
resultant residue was purified by silica gel column
chromatography [eluent; hexane:ethyl acetate=5:l] to
yield 4.7 g of methyl 3-[5-(2~hydroxy-4-
isopropoxybenzoyl)-2-isopropoxyphenyl] propanoate as
yellow oil.
NMR(90MHz,CDCl3) 5 value: 1.36(6H,d,J=6.1Hz) ,
1.38 (6H,d,J=6.1Hz), 2.52-3.06(4H,m), 3.66(3H,s), 4.49-
4.80(2H,m), 6.30-6.48(2H,m), 6.88(1H,d,J=9.3Hz), 7.49-
7.58(3H,m), 12.69(1H,s)
Example 6
6.5 g of methyl 3-[5-(2-hydroxy-4-
isopropoxybenzoyl)-2-isopropoxyphenyl] propanoate was
dissolved in 65 mL of methanol, and after the addition
of 6.5 mL of 5M sodium hydroxide thereto, the resultant
mixture was stirred for 4 hours at the temperature of
60°C. Ethyl acetate and water were added to the
reaction mixture, which is then adjusted to pH 2 with
6M hydrochloric acid, and the organic phase was
separated therefrom. After the resultant organic phase
was washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous magnesium sulfate and the solvent was
distilled out thereof under reduced pressure, followed
by purification with silica gel column chromatography
to yield 4.3 g of 3-[5-(2-hydroxy-4-isopropoxybenzoyl)-
2-isopropoxyphenyl] propanoic acid as light yellow

solid.
NMR(90MHz,CDCl3) δ value: 1.36 (6H,d,J=6.1Hz),
1.39(6H,d,J=5.9Hz), 2.61-3.08(4H,m), 4.49-4.74(2H,m),
6.33-6.49(2H,m), 6.90(1H,d,J=9.3Hz), 7.50-7.60(3H,m),
11.18 (1H,br), 12.69(1H,s)
Example 7
5.12 g of 4-isobutoxy-3-(3-ethoxy-3-
oxopropyl)benzoic acid was dissolved in 51 mL of
methylene chloride, and after the consecutive addition
thereto of 1.8 mL of oxalyl chloride and 20 (0.L of N,N-
dimethylformamide at room temperature, the resultant
mixture was stirred for one hour at room temperature.
Then, 4.64 g of aluminum chloride and 3.30 g of 1,3-
diisopropoxybenzene were successively added to the
reaction mixture at temperatures of -30 to -20°C,
followed by raising the temperature to 5°C, where the
mixture was stirred for one hour. This reaction
mixture was added to ice water for the separation of
the organic phase therefrom. After the resultant
organic phase was washed with water and a saturated
sodium chloride solution successively, the washed phase
was dried over anhydrous magnesium sulfate and the
solvent was distilled out thereof under reduced
pressure. The resultant residue was purified by silica
gel column chromatography [eluent; hexane:ethyl
acetate=5:l] to yield 5.05 g of ethyl 3-[5-(2,4-
diisopropoxybenzoyl)-2-isobutoxyphenyl] propanoate as
light yellow oil.

NMR(90MHz,CDCl3) 5 value: 1.06(6H,d,J=6.6Hz),
1.10(6H,d,J=6.1Hz), 1.23(3H,t,J=7.1Hz),
1.38(6H,d,J=6.1Hz), 1.91-2.38(1H,m), 2.47-2.69(2H,ra),
2.87-3.07(2H,m), 3.80(2H,d,J=6.4Hz), 4.00-4.81(4H,m),
6.46-6.58(2H,m), 6.79(1H,d,J=9.3Hz), 7.33(1H,d,J=8.6Hz),
7.58-7.71(2H,m)
Example 8
Isopropyl 3-[5-(2,4-diisopropoxybenzoyl)-2-
isopropoxyphenyl] propanoate was obtained in a similar
manner as in Example 7.
NMR(90MHz, CDC13) 8 value: 1.10(6H,d,J=6.1Hz),
1.20(6H,d,J=6.4Hz), 1.37(12H,d,J=6.1Hz), 2.43-
2.62(2H,m), 2.83-3.03(2H,m), 4.02-5.20(4H,m), 6.46-
6.58(2H,m), 6.80(1H, d, J=9.3Hz) , 7.33(1H,d,J=8.1Hz),
7.55-7.67(2H,m)
Example 9
15.0 g of 2,4-dimethoxybenzoic acid was
dissolved in 150 mL of methylene chloride, and after
the consecutive addition thereto of 8.6 mL of oxalyl
chloride and 20 µL of N, N-dimethylf ormamide at room
temperature, the resultant mixture was stirred for 4
hours at room temperature. After 32.9 g of aluminum
chloride was added thereto at temperatures of -45 to -
40°C, 19.2 g of methyl 3-(2-methoxyphenyl) propanoate
was added dropwise at temperatures of -45 to -15°C, and
then the temperature was raised to an ambient
temperature over 3 hours. This reaction mixture was
added to ice water for the separation of the organic

phase therefrom. After the resultant organic phase was
washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous magnesium sulfate and the solvent was
distilled out thereof under reduced pressure. The
resultant residue was purified by silica gel column
chromatography [eluent; hexane:ethyl acetate=l:2] to
yield 15.1 g of methyl 3-[5-(2,4-dimethoxybenzoyl)-2-
methoxyphenyl] propanoate as yellow oil.
NMR(90MHz,CDCl3) 5 value: 2.48-2.68(2H,m), 2.89-
3.03(2H,m), 3.66(3H,s), 3.72(3H,s), 3.86(3H,s),
3.88(3H,s), 6.47-6.57(2H,m), 6.83(1H,d,J=9.0Hz),
7.32(1H,d,J=9.0Hz), 7.64-7.72(2H,m)
Example 10
After 0.5 mL of 2'-hydroxyacetophenone and
1.8 6 g of aluminum chloride were added to a solution of
500 mg of methyl 3-[5-(2,4-dimethoxybenzoyl)-2-
methoxyphenyl] propanoate in 5 mL of 1,2-dichloroethane,
the resultant mixture was stirred for two hours at
temperatures 35 to 55°C. The reaction mixture was added
to ice water for the separation of the organic phase
therefrom. After the resultant organic phase was
washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous magnesium sulfate and the solvent was
distilled out thereof under reduced pressure. The
resultant residue was purified by silica gel column
chromatography [eluent; hexane:ethyl acetate=1:1] to

yield 316 mg of methyl 3-[5-(2,4-dihydroxybenzoyl)-2-
hydroxyphenyl] propanoate as light yellow solid.
Example 11
80.0 g of 2,4-dimethoxybenzoic acid was
dissolved in 1040 mL of methylene chloride, and after
the consecutive addition thereto of 0.7 mL of N,N-
dimethylformamide and 4 6 mL of oxalyl chloride at room
temperature, the resultant mixture was stirred for 2
hours at room temperature. After a solution of 102.3 g
of methyl 3-(2-methoxyphenyl) propanoate in 80 mL of
methylene chloride was added thereto, this solution was
cooled to -30 °C, followed by the addition of 146.4 g of
aluminum chloride, and then stirred for one hour in an
ice bath. Subsequently, 129 mL of ethyl acetate was
added dropwise thereto, followed by the addition of
322.0 g of aluminum chloride in small portions at
temperatures of 5 to 20°C, and then this solution was
stirred for four hours while heating it under reflux.
The reaction mixture was poured into a mixture of ice
water, 6M hydrochloric acid, and methanol, then the
organic phase was separated therefrom. After the
resultant organic phase was washed with 6M hydrochloric
acid, water was added thereto, and this phase was
adjusted to pH 10 with a 10% aqueous solution of sodium
hydroxide for separation of the aqueous phase. The
aqueous phase was combined with ethyl acetate and then
adjusted to pH 8 with 6M hydrochloric acid for the
separation of the organic phase therefrom. After the

resultant organic phase was washed with a saturated
sodium chloride solution, the washed phase was dried
over anhydrous magnesium sulfate and the solvent was
distilled out thereof under reduced pressure. The
resultant residue was purified by silica gel column
chromatography [eluent; hexane:ethyl acetate=4:3] to
yield 74.5 g of methyl 3-[5-(2,4-dihydroxybenzoyl)-2-
hydroxyphenyl] propanoate as light yellow solid.
NMR (400MHz, CDC13) 5 value: 2 . 77 (2H, t, J=6 . 8Hz) ,
2.96(2H,t,J=6.8Hz), 3.73(3H,s), 5.78(1H,s),
6.36(1H,dd,J=8.8,2.4Hz), 6.46(1H,d,J=2.4Hz),
6.96(1H,d,J=8.0Hz), 7.45-7.49(2H,m), 7.54(1H,d,J=8.8Hz) ,
7.90(1H,s), 12.59(1H,s)
Example 12
Compounds listed in Table 14 were obtained in
a similar manner as in Example 11.

12(1)
NMR(400MHz,CDCl3) 5 value: 1.27(6H,d, J=6.8Hz), 2.76-
2.79(2H,m), 2.89-2.98(3H,m), 3.73(3H,s),
6.75(1H,dd,J=8.2,2.0Hz), 6.92(1H,d,J=l.6Hz),
6.97(1H,d,J=9.2Hz), 7.51-7.55(3H,m), 7.92(1H,s),
12.07 (1H,s)
12 (2)
NMR(400MHz,CDC13) 5 value: 0.93(3H,s), 1.31-1.38(2H,m),
1.52-1.57(2H,m), 1.66-1.70(4H,m), 2.61(2H,s), 2.77-
2.80(2H,m), 2.95-2.98(2H,m), 3.73(3H,s),
6.68(1H,dd, J=8.0, 1.2Hz) , 6.8 6(1H,d,J=l.2Hz),
6.97(1H,d,J=8.4Hz), 7.50-7.53(3H,m), 7.93(1H,s),
12.07(1H,s)
12(3)

NMR(400MHz,CDC13) 5 value: 1.57-1.75(4H,m) , 1.78-
1.84(2H,m), 2.07-2.11(2H,m), 2.76-2.79(2H,m), 2.95-
3.03(3H,m), 3.73(3H,s), 6.76(1H,dd,J=8.4,1.6Hz), 6.93-
6.98(2H,m), 7.50-7.54(3H,m), 7.90(1H,s), 12.06(1H,s)
12(4)
NMR( 4 00MHz, DMSO-d6) 5 value: 2.16(3H,s),
2.58(2H,t,J=7.6Hz), 2.81(2H,t,J=7.6Hz), 3.57(3H,s),
6.65(1H,dd,J=8.4,2.4Hz), 6.71(1H,d,J=2.0Hz),
6.8 8(1H,d,J=8.4Hz), 7.12(1H,d,J=8.OHz),
7.42(1H,dd,J=8.0,2.4Hz), 7.46(1H,d,J=2.OHz),
9.87 (1H,brs), 10.44(1H,brs)
12(5)
NMR(400MHz,CDCl3) 5 value: 1. 18-1.23(2H,m), 1.52-
1.75(6H,m), 2.08-2.16(1H,m), 2.62(2H,d,J=7.6Hz), 2.76-
2.79(2H,m), 2.95-2.98(2H,m), 3.73(3H,s),
6.69(1H,dd,J-8.2,1.6Hz), 6.8 7(1H,d,J=l.6Hz),
6.97(1H,d,J=8.8Hz), 7.51-7.53(3H,m), 7.91(1H,s),
12.08 (1H,s)
12(6)
NMR(400MHz,CDCl3) 8 value: 2 . 78 (2H, t, J=6 . OHz) ,
2.96(2H,t,J=6.0Hz), 3.73(3H,s), 6.98(1H,d,J=8.4Hz),
7.03(1H,dd,J=8.4,2.0Hz), 7.47-7.52(4H,m), 8.02(1H,brs),
12.06(1H,s)
Example 13
5.00 g of 2-fluoro-4-methoxybenzoic acid was
dissolved in 50 mL of methylene chloride, and after the
consecutive addition thereto of 20 µL of N,N-
dimethylformamide and 3.9 mL of oxalyl chloride at room

temperature, the resultant mixture was stirred for 2.5
hours at room temperature. After 8.23 g of aluminum
chloride and 6.28 g of methyl 3-(2-methoxyphenyl)
propanoate were successively added thereto in an ice
bath, this solution was stirred for two hours in an ice
bath. Further, 19.64 g of aluminum chloride was added
thereto, and then this solution was stirred for two
hours while heating it under reflux. After ethyl
acetate was added to the reaction mixture, this mixture
was poured into the icecooled 6M hydrochloric acid for
the separation of the organic phase therefrom. After
the resultant organic phase was washed with 6M
hydrochloric acid, water, and a saturated sodium
chloride solution successively, the washed phase was
dried over anhydrous magnesium sulfate and the solvent
was distilled out thereof under reduced pressure. The
resultant residue was purified by silica gel column
chromatography [eluent; hexane:ethyl acetate=l:2] to
yield 2.52 g of 6-(2-fluoro-4-hydroxybenzoyl)-2-
chromanone as yellow oil.
NMR(400MHz,CDC13) 5 value: 2.85(2H,dd,J=8.2,7.6Hz) ,
3.08 (2H,t,J=7.6Hz), 6.55(1H,brs) ,
6.66(1H,dd,J=l1.4,2.0Hz), 6.7 5(1H,dd,J=8.6,2.4Hz),
7.12(1H,d,J=8.4Hz), 7.52(1H,t,J=8.4Hz), 7.68-7.73(2H,m)
Example 14
3.50 g of 4-isopropoxy-3- (3-isopropoxy-3-
oxopropyl) benzoic acid was dissolved in 35 mL of
methylene chloride, and after the consecutive addition

thereto of 20 µL of N,N-dimethylf ormamide and 1.6 mL of
oxalyl chloride at room temperature, the resultant
mixture was stirred for 30 minutes at room temperature.
The reaction mixture was cooled to -50 °C, and 3.17 g of
aluminum chloride and 2.91 g of 1,3-diisobutoxybenzene
were successively added thereto, followed by raising
its temperature to an ambient temperature over 30
minutes. Then this mixture was stirred for one hour
while heating it under reflux. Further, 0.790 g of
aluminum chloride was added thereto, and then this
mixture was stirred for one hour while heating it under
reflux. The reaction mixture was poured into a mixture
of ice water and methanol for the separation of the
organic phase therefrom. After the resultant organic
phase was washed with 6M hydrochloric acid and a
saturated sodium chloride solution successively, the
washed phase was dried over anhydrous magnesium sulfate
and the solvent was distilled out thereof under reduced
pressure. The resultant residue was purified by silica
gel column chromatography [eluent; hexane:ethyl
acetate=3:l] to yield 4.01 g of isopropyl 3-[2-hydroxy-
5-(2-hydroxy-4-isobutoxybenzoyl)phenyl] propanoate as
yellow oil.
NMR(90MHz,CDC13) 5 value: 1.03(6H,d,J=6.6Hz),
1.23(6H,d,J=6.1Hz), 1.97-2.26(1H,m), 2.71-2.92(4H,m),
3.78(2H,d,J=6.7Hz), 4.91-5.18(1H,m), 6.38-6.48(2H,m),
6.95 (1H,d, J==9.0Hz) , 7 . 40-7 . 59 (3H,m) , 8 . 18 (1H, brs) ,
12.65(1H,s)

Example 15
The following compounds were obtained in a
similar manner as in Example 14.
(1) isobutyl 3-[5-(2,4-dihydroxybenzoyl)-2-
isobutoxyphenyl] propanoate
NMR(90MHz,CDC13) 6 value: 0.89(6H,d,J=6.6Hz) ,
1.07(6H,d,J=6.8Hz), 1.6-2.4(2H,m), 2.6-3.2(4H,m),
3.82(2H,d,J=6.1Hz), 3.87(2H,d,J=6.6Hz), 6.3-6.5(2H,m),
6.88(1H,d,J=9.3Hz), 7.0-7.6(4H,m), 12.63(1H,s)
(2) isopropyl 3-[2-hydroxy-5-(4-
isobutoxybenzoyl)phenyl] propanoate
NMR(90MHz,CDCI3) 5 value: 1.05(6H,d,J=6.6Hz) ,
1.22(6H,d,J=6.4Hz), 1.90-2.35(1H,m), 2.62-3.05(4H,m),
3.80(2H,d,J=6.4Hz), 4.90-5.18(1H,m), 6.89-7.00(3Hrm),
7.51-7.85(4H,m), 8.34(1H,brs)
Example 16
6.00 g of 4-isobutoxy-3-(3-methoxy-3-
oxopropyl) benzoic acid was dissolved in 60 mL of
methylene chloride, and after the consecutive addition
thereto of 20 µL of N, N-dimethylformamide and 2.8 mL of
oxalyl chloride at room temperature, the resultant
mixture was stirred for 3 hours at room temperature.
After the reaction mixture was cooled to -30 °C,
followed by the consecutive addition thereto of 5.17 g
of aluminum chloride and 3.68 g of l-fluoro-3,5-
dimethoxybenzene, this mixture was stirred for 30
minutes in an ice bath. The reaction mixture was
poured into an iced 6M hydrochloric acid for the

separation of the organic phase therefrom. After the
resultant organic phase was washed with 6M hydrochloric
acid, water, and a saturated sodium chloride solution
successively, the washed phase was dried over anhydrous
magnesium sulfate and the solvent was distilled out
thereof under reduced pressure. The resultant residue
was purified by silica gel column chromatography
[eluent; hexanerethyl acetate=3:l] to yield 5.40 g of
methyl 3-[5-(2-fluoro-4,6-dimethoxybenzoyl)-2-
isobutoxyphenyl] propanoate as colorless oil.
NMR(400MHz,CDCl3) 5 value: 1.05(6H,d,J=6.8Hz), 2.10-
2.17(1H,m), 2.61(2H,t,J=7.8Hz), 2.96(2H,t,J=7.8Hz),
3.66(3H,s), 3.72(3H,s), 3.80(2H,d,J=6.4Hz), 3.85(3H,s),
6.28-6.32(2H,m), 6.82(1H,d,J=8.4Hz), 7.69-7.73(2H,m)
Example 17
5.00 g of methyl 3-[5-(2-fluoro-4,6-
dimethoxybenzoyl)-2-isobutoxyphenyl] propanoate was
dissolved in a mixed solvent of 50 mL of methylene
chloride and 3.5 mL of ethyl acetate, and after the
addition thereto of 12.7 g of aluminum chloride, the
resultant mixture was stirred for 5 hours while heating
it under reflux. The reaction mixture was poured into
an iced 6M hydrochloric acid for the separation of the
organic phase therefrom. After the resultant organic
phase was washed with 6M hydrochloric acid, water, and
a saturated sodium chloride solution successively, the
washed phase was dried over anhydrous magnesium sulfate
and the solvent was distilled out thereof under reduced

pressure. The resultant residue was purified by silica
gel column chromatography feluent; hexane:ethyl
acetate=2:l] to yield 2.82 g of methyl 3-[5- (2-fluoro-
4,6-dihydroxybenzoyl)-2-hydroxyphenyl] propanoate as
yellowish foam.
NMR(400MHz,CDCl3) 5 value: 2 . 75 (2H,t,J=6.0Hz),
2.95(2H,t,J=6.8Hz), 3.72(3H,s),
6.13(1H,dd,J=12.0,2.4Hz), 6.2 9-6.30(1H,m),
6.89(1H,d,J=8.4Hz), 7.26 (1H,brs), 7.46-7.49(2H,m),
7.95(1H,brs), 11.82(1H,s)
Example 18
74.2 g of methyl 3-[5-(2,4-dihydroxybenzoyl)-
2-hydroxyphenyl] propanoate was suspended in 742 mL of
toluene, and then 2.23 g of p-toluenesulfonic acid
monohydrate was added thereto. This suspension was
stirred for four hours while heating it under reflux.
This reaction mixture was cooled to room temperature,
followed by the consecutive addition thereto of ethyl
acetate and a saturated aqueous solution of sodium
hydrogen carbonate, and the organic phase was separated
therefrom. After the resultant organic phase was
washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous magnesium sulfate and the solvent was
distilled out thereof under reduced pressure. The
resultant residue was solidified with diisopropyl ether
and washed with ethanol to yield 56.3 g of 6-(2,4-
dihydroxybenzoyl)-2-chromanone as light yellow solid.

NMR (4 00MHz, DMSO-d6) 8 value: 2 . 85 (2H, t, J=6 . 8Hz) ,
3.08(2H,t,J=6.8Hz), 6.37(1H,d,J=2.2Hz),
6.4 0(1H,dd,J=8.6,2.2Hz), 7.2 0(1H,d,J=8.3Hz),
7.41(1H,d,J=8.6Hz), 7.56 (1H,dd,J=8.4,2.2Hz),
7.62(1H,d,J=2.0Hz), 10.70(1H,s), 12.06(1H,s)
Example 19
The following compounds were obtained in a
similar manner as in Example 18.
(1) 6-(4-hydroxy-2-methylbenzoyl)-2-
chromanone
NMR(400MHz,CDCl3) 8 value: 2.36(3H,s),
2.8 4(2H,t,J=7.4Hz), 3.07(2H,t,J=7.4Hz),
6.71(1H,dd,J=8.4,2.4Hz), 6.7 8(1H,d,J=2.4Hz),
6.88 (1H,brs), 7.09(1H,d,J=8.0Hz), 7.25(1H,d,J=8.4Hz),
7.66(1H,dd,J=8.0, 2.0Hz), 7.67(1H,s)
(2) 6-(2-fluoro-4,6-dihydroxybenzoyl)-2-
chromanone
NMR(400MHz,CDCl3) 8 value: 2 . 83-2 . 87 (2H,m) ,
3.08(2H,t,J=8.0Hz), 5.98(1H,brs),
6.15(1H,dd,J=12.2,2.4Hz), 6.30-6.31(1H,m),
7.11(1H,d,J=8.4Hz), 7.54-7.57(2H,m), 11.89(1H,s)
Example 2 0
50.0 g of 6-(2,4-dihydroxybenzoyl)-2-
chromanone, 17.6 mL of cyclopentanol, and 55.4 g of
triphenylphosphine were dissolved in 500 mL of
tetrahydrofuran, to which 41.6 mL of diisopropyl
azodicarboxylate was added dropwise at temperatures of
15 to 32°C, and this solution was stirred for 30 minutes

at room temperature. The reaction mixture was poured
into a mixture of ethyl acetate and water for the
separation of the organic phase therefrom. After the
resultant organic phase was washed with water and a
saturated sodium chloride solution successively, the
washed phase was dried over anhydrous magnesium sulfate
and the solvent was distilled out thereof under reduced
pressure. The resultant residue was purified by silica
gel column chromatography [eluent; hexane:ethyl
acetate=3:l] to yield 54.7 g of 6-[4-(cyclopentyloxy)-
2-hydroxybenzoyl]-2-chromanone as light yellow solid.
NMR(90MHz,CDC13) 5 value: 1.42-2.20(8H,m), 2.74-
3.10(4H,m), 4.60-5.03(1H,m), 6.31-6.48(2H,m),
7.12(1H,d,J=9.0Hz), 7.30-7.58(3H,m), 12.55(1H,s)
Example 21
Compounds listed in Table 15 were obtained in
a similar manner as in Example 20.

21(1)
NMR (400MHz, CDC13) 8 value: 1.64-1. 71 (2H,m) , 1.78-
1.99(6H,m), 2.82-2.86(2H,m), 3.06-3.09(2H,m), 4.79-
4.82(1H,m), 6.62(1H,dd,J=12.2,2.0Hz),
6.76(1H,dd,J=8.6,2.4Hz), 7.11(1H,d,J=8.4Hz),
7.55(1H,t,J=8.8Hz), 7.68-7.72(2H,m)
21(2)

NMR (400MHz, CDC13) 8 value: 0.95(6H,d,J=6.4Hz),
1.68(2H,q,J=6.8Hz), 1.78-1.84(1H,m), 2.82-2.85(2H,m),
3.07(2H,t,J=7.6Hz), 4.04(2H,t,J=6.8Hz),
6.4 0(1H,dd,J=9.2,2.4Hz), 6.4 9(1H,d,J=2.0Hz),
7.13(1H,d,J=8.8Hz), 7.45(1H,d,J=8.8Hz), 7.53-7.55(2H,m),
12.53(1H,s)
21(3)
NMR(4 00MHz,CDC13) 5 value: 1.05(9H,s), 2.84-2.88(2H,m),
3.08-3.11(2H,m), 3.66(2H,s), 6.44(1H,dd,J=8.8,3.6Hz),
6.51(1H,d,J=2.4Hz), 7.16(1H,d,J=8.8Hz), 7.45-7.57(3H,m),
12.54(1H,s)
21(4)
NMR(90MHz,CDCI3) 5 value: 1.1-2.2(10H,m), 2.7-3.2(4H,m),
4.1-4.5(1H,m), 6.3-6.5(2H,m), 7.14(1H,d,J=8.8Hz), 7.4-
7.6(3H,m), 12.54(1H,s)
21(5)
NMR(400MHz,CDCl3) 8 value: 1. 59-1.71(2H,m), 1.75-
1.98(6H,m), 2.82-2.86(2H,m), 3.06-3.09(2H,m), 4.79-
4.81(1H,m), 6.13(1H,dd,J=13.2,2.4Hz),
6.32(1H,t,J=1.2Hz), 7.11(1H,d,J=8.0Hz), 7.53-7.57(2H,m),
12.03(1H,s)
21(6)
NMR(400MHz,CDCl3) 8 value: 1.6-1.7(2H,m), 1.7-2.0(6H,m),
2.39(3H,s), 2.83(2H,t,J=7.4Hz), 3.06(2H,t,J=7.4Hz),
4.80-4.85(1H,m), 6.71(1H,dd,J=8.8, 2.4Hz),
6.7 9 (1H,d,J=2.4Hz), 7.09(1H,d,J=8.8Hz),
7.29(1H,d,J=8.4Hz), 7.66(1H,dd,J=8.4,2.0Hz),
7.70(1H,d,J=2.0Hz)

21(7)
NMR(90MHz,CDCl3) 5 value: 0.96 (6H, t, J=7 . 2Hz), 1.5-
1.9(4H,m), 2.7-3.2(4H,m), 4.0-4.4(1H,m), 6.4-6.5(2H,m),
7.15(1H,d,J=9.0Hz), 7.4-7.6(3H,m), 12.55(1H,s)
5 21(8)
NMR(90MHz,CDCl3) 5 value: 0 . 8-2 . 0 (HH,m) , 2 . 7-3.2(4H,m),
3.82(2H,d,J=5.9Hz), 6.3-6.5(2H,m), 7.14(1H,d,J=8.8Hz),
7.4-7.6(3H,m), 12.54(1H,s)
21(9)
D NMR(90MHz, CDC13) 8 value: 0.3-0.8(4H,m), 1.1-1.4(1H,m),
2.7-3.2(4H,m), 3 . 87(2H,d,J=6.8Hz), 6.4-6.5(2H,m),
7.13 (1H,d,J=9.0Hz) , 7.4-7.6(3H,m), 12.53(1H,s)
21 (10)
NMR(90MHz, CDCl3) 5 value: 1.2-2.2(12H,m) , 2.7-3.2(4H,m) ,
3 4.4-4.7(1H,m), 6.3-6.5(2H,m), 7.14(1H,d,J=9.0Hz), 7.4-
7.7(3H,m), 12.55(1H,s)
21(11)
NMR(400MHz,CDCl3) 5 value: 1.33-1.41(2H,m), 1.57-
1.68(4H,m), 1.81-1.89(2H,m), 2.35-2.42(1H,m), 2.84-
D 2.87(2H,m), 3.09(2H,t,J=7.6Hz), 3.90(2H,d,J=6.8Hz),
6.42(1H,dd,J=9.2,2.4Hz), 6.51(1H,d,J=2.4Hz),
7.l6(1H,d,J=8.8Hz), 7.47(1H,d,J=9.2Hz), 7.55-7.57(2H,m),
12.55(1H,s)
21(12)
5 NMR(90MHz, CDCI3) 8 value: 2.70-3.20(4H,m), 5.15(2H,s),
6.40-6.60(2H,m), 7.10-7.90(6H,m), 8.60-8.70(2H,m),
12.51 (1H,s)
21 (13)

NMR(400MHz,CDCl3) 8 value: 1. 69-1.77(1H,m), 1.87-
1.94(1H,m), 2.18-2.23(2H,m), 2.48-2.51(2H,m), 2.83-
2.87(2H,m), 3.09(2H,t,J=6.8Hz), 4.69-4.73(1H,m),
6.36(1H,dd, J=9.0,2.4Hz) , 6.4 0(1H,d,J=2.4Hz),
7.15(1H,d,J=8.5Hz), 7.47(1H,d,J=9.0Hz), 7.54-7.57(2H,m),
12.54(1H,s)
21(14)
NMR (400MHz, CDC13) 8 value: 2 . 83-2 . 87 (2H,m) ,
3.10(2H,t,J=8.0Hz), 5.13(2H,s), 6.51(1H,dd,J=9.2,2.4Hz),
6.61(1H,d,J=2.4Hz), 7.16(1H,d,J=8.4Hz) , 7.34-7.57(8H,m),
12.53(1H,s)
Example 22
54.7 g of 6-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-chromanone was suspended in 274 mL of
methanol, to which 71.9 g of a 28% solution of sodium
methoxide in methanol was added dropwise at
temperatures of 0 to 4°C, and this suspension was
stirred for one hour at temperatures of 2 to 4°C. The
reaction mixture was poured into a mixture of ethyl
acetate and 6M hydrochloric acid, to which water was
added, for the separation of the organic phase
therefrom. After the resultant organic phase was
washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous magnesium sulfate and the solvent was
distilled out thereof under reduced pressure. The
resultant residue was solidified with a mixed solvent
of diisopropylether and hexane (1:1) to yield 45.3 g of

methyl 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-
hydroxyphenyl} propanoate as white solid.
NMR( 90MHz, CDC13) 5 value: 1. 43-2 . 12 (8H,m) , 2.73-
2.96(4H,m), 3.70(3H,s), 4.68-4.92(1H,m), 6.31-
6.46(2H,m), 6.89(1H,d,J=8.1Hz), 7.24-7.58(3H,m),
9.90(2H,brs)
Example 23
Compounds listed in Table 16 were obtained in
a similar manner as in Example 22.

23(1)
NMR(400MHz,CDCl3) 6 value: 1.63-1.69(2H,m), 1.78-
1.98(6H,m), 2.74-2.77(2H,m), 2.92-2.95(2H,m),
3.72(3H,s), 4.78-4.82(1H,m), 6.61(1H,dd,J=12.2,2.4Hz),
6.73(1H,dd,J=8.8,2.4Hz), 6.91(1H,d,J=8.4Hz),
7.48(1H,t,J=8.4Hz), 7.58-7.61(1H,m), 7.67(1H,d,J=l.2Hz),
7.98 (1H,s)

23(2)
NMR(400MHz, CDC13) 5 value: 0.95(6H,d,J=6.6Hz),
1.68 (2H, q, J=6.6Hz), 1.76-1.86 (1H,m), 2.73-2.76(2H,m),
2.92-2.95(2H,m) , 3.70(3H,s), 4.03(2H,t,J=6.6Hz),
6.38(1H,dd,J=6.3,2.4Hz), 6.4 7 (1H, d, J=l.7Hz),
6.94 (1H,d,J=8.1Hz), 7.32-7.52(3H,m), 7.82(1H,s),
12.64 (1H,s)
23(3)
NMR(400MHz,CDCl3) 5 value: 1.04(9H,s), 2 . 76-2 . 79 (2H, m),
2.90-2.97(2H,m), 3.67(2H,s), 3.70(3H,s),
6.43(1H,dd, J=9.0,2.8Hz), 6.50(1H,d,J=2.4Hz),
6.96(1H,d, J=8.4Hz), 7.46-7.49(2H,m), 7.53(1H,d,J=9.2Hz),
7.87(1H,s), 12.64(1H,s)
23(4)
NMR(90MHz,CDCl3) 5 value: 1. 1-2 . 2 (10H,m) , 2 . 6-3 .1 (4H,m) ,
3.70(3H,s), 4.1-4.5(1H,m), 6.3-6.5(2H,m),
6.90(1H,d,J=8.5Hz), 7.3-7.6(3H,m), 8.12(1H,s),
12.69(1H,s)
23(5)
NMR (400MHz, CDCl3) 5 value: 1. 61-1. 68 (2H,m) , 1.78-
1.95(6H,m), 2.76(2H,t,J=5.6Hz), 2.93(2H,t,J=6.4Hz),
3.72(3H,s), 4.77-4.80(1H,m), 6.13(1H, dd,J=13.2,2.4Hz),
6.31(1H,t,J=1.2Hz), 6.92(1H,d,J=8.8Hz), 7.48-7.52(2H,m),
7.90(1H,s), 11.90(1H,s)
23(6)
NMR(400MHz,CDCl3) 8 value: 1. 6-2. 0 (8H,m) , 2.34(3H,s),
2.73(2H,t,J=6.4Hz), 2.93(2H,t,J=6.4Hz), 3.68(3H,s),
4.79-4.83(1H,m), 6.70(1H,dd,J=8.4, 2.4Hz),

6.7 7(1H,d,J=2.4Hz), 6.8 9(1H,d,J=8.8Hz),
7.26(1H,d,J=8.4Hz), 7.53 (1H,dd,J=8.4,2.OHz),
7.64(1H,d,J=2.4Hz), 8.13(1H,s)
23(7)
I
NMR(90MHz,CDC13) 8 value: 0.96(6H,t,J=7.2Hz) , 1.5-
1.9(4H,m), 2.7-3.1(4H,m), 3.72(3H,s), 4.1-4.4(1H,m),
6.3-6.5(2H,m), 6.95(1H,d,J=9.OHz), 7.4-7.6(3H,m),
7.86(1H,s), 12.67(1H,s)
23(8)
NMR(90MHz,CDCI3) 8 value: 0.7-2.1(11H,m), 2.6-3.1(4H,m),
3.72(3H,s), 3.82(2H,d,J=5.9Hz), 6.3-6.5(2H,m),
6.93(1H,d,J=9.OHz), 7.4-7.6(3H,m), 7.96(1H,brs),
12.67(1H,s)
23(9)
NMR(90MHz,CDCl3) 8 value: 0.2-1.6(5H,m), 2.6-3.2(4H,m),
3.71(3H,s), 3.86(2H,d,J=6.8Hz), 6.3-6.5(2H,m),
6.92(1H,d,J=9.OHz), 7.2-7.7(4H,m), 8.8-10.6(1H,br)
23(10)
NMR(90MHz,CDCl3) 8 value: 1. 2-2 . 2 (12H,m) , 2 . 6-3 . 1 (4H,m) ,
3.72(3H,s), 4.3-4.7(1H,m), 6.3-6.4(2H,m),
6.94(1H,d,J=9.OHz), 7.4-7.6(3H,m), 7.89(1H,s),
12.67 (1H,s)
23(11)
light yellow solid
NMR(90MHz,CDCl3) 8 value: 1.03(6H,d,J=6.6Hz), 1.8-
2.3(1H,m), 2.6-3.7(4H,m), 3.72(3H,s),
3.78(2H,d,J=6.6Hz), 6.35-6.51(2H,m), 6.92(1H,d,J=9.OHz),
7.40-7.59(3H,m), 7.8-8.2(1H,br), 12.66(1H,s)

23(12)
NMR(400MHz,CDC13) 5 value: 1. 33-1.38(2H,m), 1.57-
1.68(4H,m), 1.81-1.88(2H,m), 2.34-2.41(1H,m), 2.76-
2.79(2H,m), 2.95(2H,t,J=6.6Hz), 3.72(3H,s),
3.89(2H,d,J=6.9Hz), 6.41(1H,dd,J=8.8,2.4Hz),
6.49(1H,d,J=2.4Hz), 6.96(1H,d,J=8.3Hz), 7.45-7.54(3H,m),
7.85(1H,s), 12.64(1H,s)
23(13)
NMR(90MHz,CDC13) 8 value: 2.60-3.10(4H,m), 3.70(3H,s),
5.15(2H,s), 6.40-6.60(2H,m), 6. 93(1H,d,J=8.3Hz), 7.20-
7.90(6H,m), 8.60-8.70(2H,m), 12.65(1H,s)
23(14)
NMR(400MHz,CDCl3) 5 value: 1. 66-1.78(1H,m), 1.86-
1.94(1H,m), 2.17-2.22(2H,m), 2.45-2.52(2H,m),
2.77(2H,t,J=6.8Hz), 2.96(2H,t,J=6.8Hz), 3.73(3H,s),
4.68-4.72(1H,m), 6.35(1H,dd,J=8.8,2.4Hz),
6.38(1H,d,J=2.4Hz), 6.96(1H,d,J=8.4Hz), 7.45-7.48(2H,m),
7.53(1H,d,J=8.8Hz), 7.85(1H,s), 12.65(1H,s)
23(15)
NMR (400MHz, CDCI3) 8 value: 2 . 76-2 . 79 (2H,m) ,
2.96(2H,t,J=6.4Hz), 3.73(3H,s), 5.12(2H,s),
6.49(1H,dd,J=9.0,2.8Hz), 6.5 9(1H,d,J=2.8Hz),
6.96(1H,d,J=8.0Hz), 7.33-7.49(7H,m), 7.56(1H,d,J=8.8Hz) ,
7.86(1H,s), 12.64(1H,s)
Example 24
2.00 g of 6-(2,4-dihydroxybenzoyl)-2-
chromanone was dissolved in 20 mL of tetrahydrofuran,
to which 0.65 mL of 2-propanol and 2.21 g of

triphenylphosphine were added and to which a solution
of 1.7 mL of diisopropyl azodicarboxylate in 2 mL of
tetrahydrofuran were added dropwise at 18-37°C, and the
this mixture was stirred for one hour at room
temperature. The reaction mixture was poured into a
mixture of ethyl acetate and water, for the separation
of the organic phase therefrom. After the resultant
organic phase was washed with water and a saturated
sodium chloride solution successively, the washed phase
was dried over anhydrous magnesium sulfate and the
solvent was distilled out thereof under reduced
pressure. The resultant residue was dissolved in 20 mL
of methanol, to which 3.39 g of a 28% solution of
sodium methoxide in methanol was added dropwise in an
ice bath, and then this mixture was stirred for one
hour at temperatures of 5 to 10°C. The reaction mixture
was poured into a mixture of chloroform and aqueous
diluted hydrochloric acid. After the resultant organic
phase was washed with water and a saturated sodium
chloride solution successively, the washed phase was
dried over anhydrous magnesium sulfate and the solvent
was distilled out thereof under reduced pressure. The
resultant residue was purified by silica gel column
chromatography [eluent; toluene:ethyl acetate=4:l] and
solidified with hexane to yield 2.36 g of methyl 3-[2-
hydroxy-5-(2-hydroxy-4-isopropoxybenzoyl)phenyl]
propanoate as light yellow solid.
NMR(400MHz,DMS0-d6) 8 value: 1.36(6H,d,J=6.0Hz),

2.61(2H,t,J=7.6Hz), 2.84(2H,t,J=7.6Hz), 3.59(3H,s),
4.7 0-4.76(1H,m), 6.4 8(1H,dd,J=8.8,2.OHz),
6.52(1H,d,J=2.4Hz), 6.93(1H,d,J=8.4Hz), 7.43-7.48(3H,m),
10.42(1H,brs), 12.08(1H,brs)
Example 25
10.0 g of 6-(2,4-dihydroxybenzoyl)-2-
chromanone was suspended in 100 mL of methylene
chloride, to which 3.53 mL of 3,4-dihydro-2H-pyran and
0.884 g of pyridinium p-toluenesulfonate were added,
and this mixture was stirred for 18 hours at room
temperature. The reaction mixture was poured into a
saturated aqueous solution of sodium hydrogen carbonate,
and the organic phase was separated therefrom. After
the resultant organic phase was washed with water and a
saturated sodium chloride solution successively, the
washed phase was dried over anhydrous magnesium sulfate
and the solvent was distilled out thereof under reduced
pressure. The resultant residue was purified by silica
gel column chromatography [eluent; hexane:ethyl
acetate=3:l] to yield 6.99 g of 6-[2-hydroxy-4-
(tetrahydro-2H-pyran-2-yloxy)benzoyl]-2-chromanon as
light yellow solid.
NMR(400MHz,CDCl3) 5 value: 1. 5-2 .1 ( 6H, m) ,
2.86(2H,t,J=7.6Hz), 3.10(2H,t,J=7.6Hz), 3.6-3.7(1H,m),
3.8-3.9(1H,m), 5.52(1H,t,J=3.2Hz),
6.55(1H,dd,J=9.2,2.4Hz), 6.72(1H,d,J=2.4Hz) ,
7.14(1H,d,J=8.4Hz), 7.4-7.6(3H,m), 12.39(1H,s)
Example 2 6

3.20 g of 6-[2-hydroxy-4-(tetrahydro-2H-
pyran-2-yloxy)benzoyl]-2-chromanone was suspended in
18.6 mL of methanol and was cooled to 0°C, to which 4.02
g of a 28% solution of sodium methoxide in methanol was
added dropwise, and then this mixture was stirred for
one hour at temperatures of -5 to 0°C. The reaction
mixture was poured into a mixture of ethyl acetate and
6M hydrochloric acid, to which water was added, and the
organic phase was separated therefrom. After the
resultant organic phase was washed with water, a
saturated aqueous solution of sodium hydrogen carbonate,
and a saturated sodium chloride solution successively,
the washed phase was dried over anhydrous magnesium
sulfate and the solvent was distilled out thereof under
reduced pressure. The resultant residue was purified
by silica gel column chromatography [eluent;
hexane:ethyl acetate=3:l] to yield 3.29 g of methyl 3-
{2-hydroxy-5- [2-hydroxy-4- (tetrahydro-2H-pyran-2-
yloxy)benzoyl]phenyl} propanoate as light yellow oil.
NMR(400MHz,CDCl3) 5 value: 1.5-2.1( 6H, m),
2.77(2H,t,J=6.0Hz), 2.96(2H,t,J=6.2Hz), 3.6-3.7(1H,m),
3.73(3H,s), 3.8-3.9(1H,m), 5.51(1H,t,J=3.2Hz),
6.54(1H,dd,J=8.8,2.4Hz), 6.71(1H,d,J=2.4Hz),
6.96(1H,d,J=8.8Hz), 7.4-7.6(3H,m), 7.87(1H,s),
12.50(1H,s)
Example 27
3.20 g of methyl 3-{2-hydroxy-5-[2-hydroxy-4-
(tetrahydro-2H-pyran-2-yloxy)benzoyl]phenyl} propanoate,

1.83 g of methyl 4-(bromomethyl)benzoate, and 1.33 g of
potassium carbonate were suspended in 32 mL of N,N-
dimethylformamide, and this mixture was stirred for one
hour at temperatures of 60 to 70°C. After the reaction
mixture was cooled to room temperature, this mixture
was added to a mixture of ethyl acetate and ice water,
and then the organic phase was separated therefrom.
After the resultant organic phase was washed with water
and a saturated sodium chloride solution successively,
the washed phase was dried over anhydrous magnesium
sulfate and the solvent was distilled out thereof under
reduced pressure. The resultant residue was purified
by silica gel column chromatography [eluent;
hexane:ethyl acetate=3:l] to yield 2.75 g of methyl 4-
{[4-[2-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)benzoyl]-
2-(3-methoxy-3-oxopropyl)phenoxy]methyl} benzoate as
light yellow solid.
NMR(400MHz,CDCl3) δ value: 1. 5-2 .1 ( 6H,m) ,
2.69(2H,t,J=7.2Hz), 3.08(2H,t,J=7.2Hz), 3.6-3.7(1H,m),
3.67(3H,s), 3.8-3.9(1H,m), 3.93(3H,s), 5.24(2H,s), 5.4-
5.6(1H,m), 6.54(1H,d,J=8.0Hz), 6.71(1H,s),
6.93(1H,d,J=8.0Hz), 7.4-7.6(5H,m), 8.09 (2 H,d,J=7.6Hz),
12.51 (1H,s)
Example 2 8
2.70 g of methyl 4-{ [4-[2-hydroxy-4-
(tetrahydro-2H-pyran-2-yloxy)benzoyl]-2-(3-methoxy-3-
oxopropyl)phenoxy]methyl} benzoate was suspended in 27
mL of tetrahydrofuran, to which 27 mL of 1M

hydrochloric acid was added, and this suspension was
stirred for 3 hours at room temperature and then for
another one hour at temperatures of 30 to 40°C. After
the reaction mixture was cooled to room temperature,
this mixture was added to a mixture of ethyl acetate
and water, and the organic phase was separated
therefrom. After the resultant organic phase was
washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous magnesium sulfate and the solvent was
distilled out thereof under reduced pressure. The
resultant residue was solidified with diisopropyl ether,
and the solid filtered out was washed with diisopropyl
ether to yield 2.28 g of methyl 4-{[4-(2,4-
dihydroxybenzoyl)-2-(3-methoxy-3-
oxopropyl)phenoxy]methyl} benzoate as white solid.
NMR (400MHz, CDC13) 8 value: 2 . 70 (2H, t, J=7 . 6Hz) ,
3.08(2H,t,J=7.6Hz), 3.67(3H,s), 3.94(3H,s), 5.24(2H,s),
6.36(1H,dd,J=8.8,2.4Hz), 6.4 5(1H,d,J=2.4Hz),
6.58(1H,brs), 6.93(1H,d,J=8.4Hz), 7.49-7.55(5H,m),
8.09(2H,dd,J=6.8,1.6Hz), 12.60(1H,s)
Example 2 9
32.0 g of methyl 3-{5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-hydroxyphenyl} propanoate and 23.0 g
of potassium carbonate were suspended in 320 mL of N,N-
dimethylformamide, and a temperature of this suspension
was raised to 50°C. 28.5 g of 6-(bromomethyl)-3-
(methoxymethoxy)-1,2-berizisoxazole was further added to

this suspension, and which was stirred for one hour at
50°C. After the reaction mixture was cooled to room
temperature, this mixture was added to a mixture of
ethyl acetate and water, and was adjusted to pH 7 with
6M hydrochloric acid, then the organic phase was
separated therefrom. After the resultant organic phase
was washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous magnesium sulfate and the solvent was
distilled out thereof under reduced pressure. The
resultant residue was purified by silica gel column
chromatography [eluent; hexane:ethyl acetate=2:l] to
yield 32.5 g of methyl 3-(5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2-
benzisoxazol-6-yl]methoxy}phenyl)propanoate as yellow
oil.
NMR(4 00MHz, CDC13) 5 value: 1.60-1.66(2H,m), 1.74-
1.99(6H,m), 2.70 (2H,t,J=7.6Hz) , 3.09(2H,t,J=7.6Hz) ,
3.65(3H,s), 3.68(3H,s), 4.80-4.83(1H,m), 5.33(2H,s),
5.57(2H,s), 6.37(1H,dd,J=9.0,2.8Hz), 6.48(1H,d,J=2.8Hz) ,
6.95(1H,d,J=8.4Hz), 7.36(1H,d,J=8.0Hz), 7.45-7.57(4H,m),
7.72(1H,d,J=8.0Hz), 12.69(1H,s)
Example 30
32.0 g of methyl 3-(5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2-
benzisoxazol-6-yl]methoxy}phenyl) propanoate was
dissolved in a mixed solvent of 96 mL of methanol and
96 mL of 1,4-dioxane, to which 32 mL of 6M hydrochloric

acid was added at room temperature, and then this
mixture was stirred for 30 minutes at the same
temperature. The resulting precipitate was filtered
and solid was washed with water and diisopropyl ether
successively to yield 26.3 g of methyl 3-{5-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-l,2-
benzisoxazol-6-yl)methoxy]phenyl}propanoate as light
yellow solid.
NMR(4 00MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.93-
1.96(2H,m), 2.67(2H,t,J=7.6Hz), 2.96(2H,t,J=7.6Hz),
3.58{3H,s), 4.90-4.93(1H,m), 5.42(2H,s), 6.47-
6.51(2H,m), 7.20(1H,d,J=8.4Hz), 7.43-7.45(2H,m), 7.55-
7.57(2H,m), 7.68(1H,s), 7.79(1H,d,J=8.4Hz), 12.02(1H,s),
12.41(1H,brs)
Example 31
0.66 g of methyl 3-[5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-({4-[3-(methoxymethoxy)-5-
isoxazolyl]benzyl}oxy)phenyl] propanoate was dissolved
in a mixed solvent of 4 mL of methanol and 4 mL of 1,4-
dioxane, to which 3 mL of 6M hydrochloric acid was
added at room temperature, and then this mixture was
stirred for 20 minutes at the same temperature and for
another 20 minutes while heating it under reflux.
Resultant precipitate was filtered out, and the
resultant solid was washed with diisopropyl ether to
yield 0.40 g of methyl 3-(5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-{[4-(3-hydroxy-5-
isoxazolyl)benzyl]oxy}phenyl)propanoate as light yellow

solid.
NMR(4 00MHz,DMSO-d6) 8 value: 1. 5-1.8(6H,m), 1.9-
2.0(2H,m), 2.66(2H,t,J=7.6Hz), 2.95(2H,t,J=7.6Hz),
3.57(3H,s), 4.92(1H,m), 5.33(2H,s),
6.48 (1H,dd,J=8.8,2.4Hz), 6. 51(1H,d,J=2.0Hz), 6.58(1H,s),
7.19(1H,d,J=8.4Hz), 7.44(1H,d,J=8.8Hz), 7.5-7.6(2H,m),
7.62(2H,d,J=8.0Hz), 7.85(2H,d,J=8.4Hz), 11.41(1H,br),
12.01(1H,S)
Example 32
The following compounds were obtained in a
similar manner as in Example 31.
(1) 4-({2-(2-carboxyethyl)-4-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]phenoxy}methyl)-3-
hydroxybenzoic acid
NMR(4 00MHz,DMSO-d6) 5 value: 1.60-1.74(6H,m), 1.90-
2.00(2H,m), 2.57(2H,t,J=7.6Hz) , 2.89(2H,t,J=7.6Hz),
4.90-4.93(1H,m), 5.23(2H,s), 6.48-6.50(2H,m),
7.17(1H,d,J=8.4Hz), 7.41-7.49(4H,m), 7.54-7.57(2H,m),
10.20(1H,s), 12.05(1H,s), 12.48(2H,brs)
(2) methyl 3-{5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-[(3-hydroxy-l,2-benzisoxazol-5-
yl)methoxy]phenyl} propanoate
NMR(400MHz,CDCl3) 6 value: 1.62-1.68(2H,m), 1.78-
1.98(6H,m), 2.70(2H,t,J=7.6Hz), 2.75(1H,brs),
3.08(2H,t,J=7.6Hz), 3.68(3H,s), 4.81-4.84(1H,m),
5.29(2H,s), 6.37(1H,dd,J=8.8,2.4Hz) , 6.48(1H,d, J=2.4Hz) ,
6.99(1H,d,J=8.8Hz), 7.4 8(1H,d,J=8.4Hz),
7.51(1H,d,J=8.8Hz), 7.54-7.57(2H,m),

7.68(1H,dd,J=8.4,2.0Hz), 7.91(1H,s), 12.69(1H,s)
Example 33
3.00 g of methyl 3-{5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-hydroxyphenyl} propanoate and 2.16 g
of potassium carbonate were suspended in 30 mL of N,N-
dimethylformamide, and after this suspension was
stirred for 30 minutes at room temperature, 2.55 g of
6-(bromomethyl)-2-(methoxymethyl)-1,2-benzisoxazol-
3(2H)-one was added thereto at the same temperature and
this mixture was stirred for 30 minutes at 50°C. The
reaction mixture was cooled to room temperature, and
was added to a mixture of ethyl acetate and water,
which was adjusted to pH 5 with 6M hydrochloric acid,
and then the organic phase was separated therefrom.
After the resultant organic phase was washed with water
and a saturated sodium chloride solution successively,
the washed phase was dried over anhydrous magnesium
sulfate and the solvent was distilled out thereof under
reduced pressure. The resultant residue was purified
by silica gel column chromatography [eluent;
hexane:ethyl acetate=l:l] to yield 3.90 g of methyl 3-
(5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-{[2-
(methoxymethyl)-3-oxo-2,3-dihydro-l,2-benzisoxazol-6-
yl]methoxy}phenyl)propanoate as yellow oil.
NMR(400MHz,CDCl3) 8 value: 1.62-1.66(2H,m), 1.78-
1.96(6H,m), 2.70(2H,t,J=7.6Hz), 3.10(2H,t,J=7.6Hz),
3.47(3H,s), 3.68(3H,s), 4.81-4.83(1H,m), 5.31(2H,s),
5.35(2H,s), 6.37(1H,dd,J=9.0,2.4Hz), 6.48(1H,d,J=2.4Hz),

6.93(1H,d,J=8.4Hz), 7 . 35(1H,d,J=8.4Hz), 7.39(1H,s),
7.49-7.57(3H,m), 7.90(1H,d,J=8.4Hz), 12.68(1H,s)
Example 34
3.65 g of methyl 3-(5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-{[2-(methoxymethyl)-3-oxo-2,3-
dihydro-1,2-benzisoxazol-6-yl]methoxy}phenyl)
propanoate was dissolved in a mixed solvent of 40 mL of
methanol and 40 mL of 1,4-dioxane, to which 30 mL of 6M
hydrochloric acid was added at room temperature, and
then this mixture was stirred for 4 hours while heating
it under reflux. The reaction mixture was cooled to
room temperature, to which chloroform and water were
added, and then the organic phase was separated
therefrom. After the resultant organic phase was
washed with a saturated sodium chloride solution, the
washed phase was dried over anhydrous magnesium sulfate
and the solvent was distilled out thereof under reduced
pressure. The resultant residue was purified by silica
gel column chromatography [eluent;
chloroform:ethanol=50:1] to yield 1.90 g of methyl 3-
{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-
hydroxyl-1,2-benzisoxazol-6-yl)methoxy]phenyl}-
propanoate as light yellow solid.
NMR(400MHz,DMSO-d6) 5 value: 1.60-1.74(6H,m), 1.93-
1.96(2H,m), 2.67(2H,t,J=7.6Hz), 2.96(2H,t,J=7.6Hz),
3.58(3H,s), 4.90-4.93(1H,m), 5.42(2H,s), 6.47-
6.51(2H,m), 7.20(1H,d,J=8.4Hz), 7.43-7.45(2H,m), 7.55-
7.57(2H,m), 7.68(1H,s), 7.79(1H,d,J=8.4Hz), 12.02(1H,s),

12.41(1H,brs)
Example 35
26.0 g of methyl 3-{5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-[(3-hydroxy-l,2-benzisoxazol-6-
yl)methoxy]phenyl} propanoate was suspended in 182 mL
of methanol, to which a solution of 10.5 g of sodium
hydroxide in 78 mL of water was added dropwise at room
temperature, and then this mixture was stirred for 30
minutes at the same temperature. The reaction mixture
was added to water, which was then adjusted to pH 1.5
with 6M hydrochloric acid, and resultant precipitate
was filtered out. The resultant solid was dissolved in
a mixed solvent of chloroform and methanol, and washed
with water, and subsequently, a solvent in the
separated organic phase was distilled out under reduced
pressure. The resultant residue was washed with hexane
to yield 22.5 g of 3-{5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-[(3-hydroxy1-1,2-benzisoxazol-6-
yl)methoxy]phenyl}propanoic acid as light yellow solid.
NMR (400MHz,DMSO-d5) 5 value: 1.60-1.74(6H,m), 1.95-
1.97(2H,m), 2.59(2H,t,J=7.2Hz), 2.94(2H,t,J=7.2Hz),
4.88-4.95(1H,m), 5.42(2H,s), 6.48-6.51(2H,m),
7.20(1H,d,J=9.2Hz), 7.43-7.47(2H,m), 7.55-7.57(2H,m),
7.69(1H,s), 7.80(1H,d,J=8.0Hz), 12.06(1H,s),
12.30 (2H,brs)
Example 3 6
40.0 g of methyl 3-{5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-hydroxyphenyl} propanoate, 23.8 g of

methyl 4-(bromomethyl) benzoate, and 17.3 g of
potassium carbonate were suspended in 400 mL of N,N-
dimethylformamide, and this mixture was stirred for one
hour at 60°C. The reaction mixture was cooled to room
temperature, which was then added to a mixture of ethyl
acetate and ice water, and the organic phase was
separated therefrom. After the resultant organic phase
was washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous magnesium sulfate and the solvent was
distilled out thereof under reduced pressure. The
resultant residue was solidified with diisopropyl ether
and filtered out. Crude crystals thus obtained were
recrystallized from methanol to yield 40.1 g of methyl
4-{[4-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-
methoxy-3-oxopropyl)phenoxy]methyl} benzoate as light
yellow crystals.
NMR(90MHz,CDCl3) 5 value: 1.50-2.04(8H,m), 2.58-
3.18(4H,m), 3.67(3H,s), 3.93(3H,s), 4.71-4.93(1H,m),
5.24(2H,s), 6.30-6.49(2H,m), 6.93(1H,d,J=9.0Hz), 7.47-
7.56(5H,m), 8.09(2H,d,J=8.1Hz), 12.68(1H,s)
Example 37
1.00 g of methyl 3-{5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-hydroxyphenyl}propanoate, 0.809 g of
methyl 4-(bromomethyl)-2-methoxy benzoate, and 0.539 g
of potassium carbonate were suspended in 10 mL of N,N-
dimethylformamide, and this suspension was stirred for
30 minutes at temperatures of 50 to 60°C. The reaction

mixture was cooled to room temperature, which was then
added to a mixture of ethyl acetate and water, and this
mixture was adjusted to pH 2 with 6M hydrochloric acid
for the separation of the organic phase therefrom.
After the resultant organic phase was washed with water
and a saturated sodium chloride solution successively,
the washed phase was dried over anhydrous magnesium
sulfate and the solvent was distilled out thereof under
reduced pressure. The resultant residue was purified
by silica gel column chromatography [eluent;
hexane:ethyl acetate=2:l] to yield 1.08 g of methyl 4-
{[4-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-methoxy-
3-oxopropyl)phenoxy]methyl}-2-methoxybenzoate as yellow
oil.
NMR(400MHz,CDC13) 8 value: 1.59-1.66(2H,m), 1.76-
1.98(6H,m), 2.69(2H,t,J=7.6Hz), 3.08(2H,t, J=7.6Hz) ,
3.66(3H,s), 3.90(3H,s), 3.94(3H,s), 4.80-4.83{lH,m),
5.20(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.48(1H,d,J=2.4Hz),
6.93(1H,d,J=8.4Hz), 7.03(1H,d,J=8.0Hz), 7.09(1H,s),
7.50(1H,d,J=8.8Hz), 7.52-7.55(2H,m), 7 . 84(1H,d,J=8.0Hz),
12.68 (1H,s)
Example 38
1.36 g of methyl 3-{5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-hydroxyphenyl} propanoate, 1.43 g of
5-[4-(bromomethyl)phenyl]-3-isoxazolyl methoxymethyl
ether, and 0.975 g of potassium carbonate were
suspended in 12 mL of N,N-dimethylformamide, and this
suspension was stirred for 30 minutes at 60°C. The

reaction mixture was cooled to room temperature, which
was then added to a mixture of ethyl acetate and water,
and this mixture was adjusted to pH 2 with 6M
hydrochloric acid for the separation of the organic
phase therefrom. After the resultant organic phase was
washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous magnesium sulfate and the solvent was
distilled out thereof under reduced pressure. The
resultant residue was purified by silica gel column
chromatography [eluent; ethyl acetate] to yield 0.76 g
of methyl 3-[5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-
({4- [3-(methoxymethoxy)-5-isoxazolyl]benzyl}oxy)phenyl]
propanoate as yellow oil.
NMR(400MHz,CDCl3) 5 value: 1. 5-2 .1 (8H,m) ,
2.69(2H,t,J=7.6Hz), 3.07(2H,t,J=7.6Hz), 3.59(3H,s),
3.67(3H,s), 4.7-4.9(1H,m), 5.22(2H,s), 5.38(2H,s),
6.26(1H,s), 6.37(1H,dd,J=9.0, 2.4Hz),
6.48(1H,d,J=2.4Hz), 6.95(1H,d,J=8.4Hz), 7.5-7.6(5H,m),
7.78 (2H,d,J=8.4Hz) , 12.70(1H,s)
Example 39
Compounds listed in Tables 17 to 21 were
obtained in a similar manner as in Example 36.
Each of the compounds 39(47) and 39(61) to
39(64) in these tables was synthesized from a compound
having a hydroxyl group as R4, for the purpose of
substitution of R4.

39(1)
NMR(4 00MHz,CDCl3) 5 value: 2.70(2H,t,J=7.6Hz),
3.09(2H,t,J=7.6Hz), 3.68(3H,s), 3.94(3H,s), 5.26(2H,s),
6.96(1H,d,J=8.4Hz) , 7.1-7.2(2H,m), 7.31(1H,d,J=2.0Hz),
7.40(1H,dd,J=4.8,0.8Hz), 7.47(1H,dd,J=3.6, 0.8Hz),
7.52(2H,d,J=8.0Hz), 7.5-7.7(3H,m), 8.10(2H,d,J=8.4Hz),
12.18(1H,s)
39(2)
NMR(400MHz,CDCl3) 5 value: 1. 62-1. 71 (2H,m) , 1.77-
1.98 (6H,m), 2.64-2.68(2H,m), 3 . 03-3.07(2H,m),
3.66 (3H,s), 3.93(3H,s), 4.78-4.82(1H,m), 5.23(2H,s),
6.61 (1H,dd,J=12.4,2.4Hz), 6.7 3(1H,dd,J=8.8,2.4Hz),
6.90(1H,d,J=8.4Hz), 7.47-7.51(3H,m), 7.67-7.70(2H,m),
8.06-8.09(2H,m)
39(3)

NMR(400MHz,CDCl3) 5 value: 0.97(6H,d,J=6.8Hz) ,
1.70(2H,q,J=6.8Hz), 1.79-1.87(1H,m), 2 . 69(2H,t,J=7.6Hz),
3.07 (2H,t,J=8.0Hz) , 3.67(3H,s), 3.94(3H,s),
4.05 (2H,t,J=6.8Hz), 5.24(2H,s), 6.40(1H,dd,J=8.8,2.4Hz),
6.50(1H,d,J=2.4Hz), 6.93(1H,d,J=8.0Hz), 7.51-7.55(5H,m),
8.09(2H,d,J=8.0Hz), 12.67(1H,s)
39(4)
NMR(400MHz,CDCl3) 5 value: 1.04(9H,s),
2.69(2H,t,J=7.6Hz), 3.07(2H,t,J=7.6Hz), 3.65(2H,s),
3.67(3H,s), 3.94(3H,s), 5.25(2H,s),
6.4 3(1H,dd,J=9.0,2.8Hz), 6.5 0(1H, d, J=2.8Hz) ,
6.94(1H,d,J=8.4Hz), 7.51-7.56(5H,m), 8.09(2H,d,J=8.0Hz),
12.65(1H,s)
39(5)
NMR (90MHz, CDCl3) 8 value: 1.1-2.2(10H,m),
2.68 (2H,t,J=6.8Hz), 3.08 (2H, t, J=6.6Hz), 3.67(3H,s),
3.93 (3H,s), 4.1-4.5(1H,m), 5.24(2H,s), 6.3-6.5 (2H,m),
6.93 (1H,d, J=9.0Hz) , 7.4-7.6 (5H,m), 8.09 (2H,d,J=8.3Hz),
12.67 (1H,s)
39 (6)
NMR(400MHz,CDCl3) 5 value: 1. 58-1.64(2H,m), 1.76-
1.98(6H,m), 2.70(2H,t,J=7.6Hz), 3.08(2H,t,J=7.6Hz),
3.41(3H,s), 3.52(3H,s), 3.67(3H,s), 3.93(3H,s), 4.81-
4.82(1H,m), 5.27(2H,s), 5.32(2H,s),
6.37(1H,dd, J=8.8,2.0Hz) , 6.4 8(1H,d,J=2.0Hz),
6.99(1H,d,J=8.4Hz), 7.51-7.56(4H,m), 7.75(1H,d,J=8.0Hz),
7.80(1H,s), 12.70(1H,S)
39(7)

NMR(400MHz,CDCl3) 8 value: 1.17-1.26(2H,m), 1.52-
1.75(6H,m), 2.04-2.16(1H,m), 2.62(2H,d,J=7.6Hz),
2.69(2H,t,J=7.3Hz), 3.08(2H,t,J=7.8Hz), 3.67(3H,s),
3.94(3H,s), 5.25(2H,s), 6.69(1H,dd,J=8.2,1.5Hz),
6.87 (1H,d,J=1.5Hz), 6.94(1H,d,J=8.3Hz), 7.49-7.52(3H,m),
7.56-7.59(2H,m), 8.09(2H,d,J=8.3Hz), 12.09(1H,s)
39(8)
NMR(400MHz,CDCl3) 5 value: 1.49(18H,s), 1.63-1.68(2H,m),
1.78-1.97(6H,m), 2.69(2H,t,J=7.6Hz), 3.08(2H,t,J=8.0Hz),
3.67(3H,s), 4.80-4.82(1H,m), 5.28(2H,s),
6.37(1H,dd,J=8.8,2.4Hz), 6.4 8(1H,d,J=2.0Hz),
6.91(1H,d,J=8.4Hz), 7.49-7.56(3H,m), 7.63(2H,d,J=8.4Hz),
8.14(2H,d,J=8.8Hz), 12.68(1H,s)
39(9)
NMR(400MHz,CDCl3) 8 value: 1.61-1.69(2H,m), 1.76-
1.98(6H,m), 2.68(2H,t,J=7.6Hz), 3.08(2H,t,J=7.6Hz),
3.67(3H,s), 4.80-4.84(1H,m), 5.24(2H,s),
6.37(1H,dd,J=8.8,2.4Hz), 6.4 8(1H,d,J=2.4Hz),
6.91(1H,d,J=8.4Hz), 7.49(1H,d,J=8.8Hz), 7.53-7.58(4H,m),
7.72(2H,d,J=8.4Hz), 12.69(1H,s)
39(10)
NMR(90MHz, CDCI3) 8 value: 1.03(6H,d,J=6.6Hz), 1.90-
2.33(1H,m), 2.60-2.75(2H,m), 2.99-3.20(2H,m),
3.67(3H,s), 3.78(2H,d,J=6.6Hz), 5.24(2H,s), 6.35-
6.51(2H,m), 6.92(1H,d,J=9.3Hz), 7.46-7.77(7H,m),
12.64(1H,s)
39(11)
NMR(90MHz, CDCl3) 8 value: 1.03(6H,d,J=6.6Hz),

1.20(6H,d,J=6.lHz), 1.8-2.4(1H,m), 2.64(2H,t,J=7.2Hz),
3.09(2H,t,J=7.2Hz), 3.79(2H,d,J=6.6Hz), 4.8-5.2(1H,m),
5.30(2H,s), 6.3-6.6(2H,m), 6.92(1H,d,J=9.0Hz), 7.4-
7.8(5H,m), 8.29(2 H,d,J=8.6Hz), 12.64(1H,s)
39(12)
NMR(400MHz,CDCl3) 5 value: 1. 27 ( 6H, d, J=6 . 8Hz) ,
2.69(2H,t,J=7.6Hz), 2.88-2.95(1H,m), 3.08(2H,t,J=8.OHz),
3.67(3H,s), 3.94(3H,s), 5.25(2H,s),
6.7 5(1H,dd,J=8.2,1.6Hz), 6.92(1H,d,J=2.OHz),
6.94(1H,d,J=8.0Hz), 7.51-7.59(5H,m), 8.09(2H,d,J=8.OHz),
12.09(1H,s)
39(13)
NMR(400MHz,CDCl3) 5 value: 0.93(3H,s), 1. 31-1. 36 (2H, m) ,
1.50-1.55(2H,m), 1.66-1.69(4H,m), 2.61(2H,s),
2. 69(2H,t,J=7.6Hz), 3.08(2H,t,J=7.6Hz), 3.67(3H,s),
3.94(3H,s), 5.25(2H,s), 6.67(1H,dd,J=8.4,1.6Hz) ,
6.86(1H,d,J=2.0Hz), 6.94(1H,d,J=8.4Hz), 7.48-7.60(5H,m),
8.09(2H,d,J=8.OHz), 12.08(1H,s)
39(14)
NMR(400MHz,CDCl3) 5 value: 1.62-1.69(2H,m), 1.78-
1.98(6H,m), 2.70(2H,t,J=7.6Hz), 2.75(6H,s),
3.09(2H,t,J=8.0Hz) , 3.68(3H,s), 4.80-4.84(1H,m),
5.26(2H,s), 6.38(1H,dd,J=9.0,2.4Hz), 6.48(1H,d,J=2.4Hz),
6.94(1H,d,J=8.4Hz), 7.50(1H,d,J=8.8Hz), 7.54-7.56(2H,m) ,
7.62(2H,d,J=8.4Hz), 7.84(2H,d,J=8.4Hz), 12.68(1H,s)
39(15)
NMR(400MHz, CDC13) 8 value: 1.33-1.38(2H,m), 1.57-
1.66(4H,m), 1.82-1.87(2H,m), 2.35-2.41(1H,m),

2.69(2H,t,J=7.6Hz), 3.07(2H,t,J=7.6Hz), 3.67(3H,s),
3.89(2H,d,J=6.8Hz), 3.94(3H,s), 5.24(2H,s),
6.41(1H,dd,J=8.8,2.4Hz), 6.50(1H,d,J=2.4Hz),
6.93(1H,d,J=8.4Hz), 7.51-7.56(5H,m), 8.09(2H,d,J=8.4Hz),
12.66(1H,s)
39(16)
NMR(90MHz,CDCl3) 5 value: 2 . 60-3 . 20 (4H,m) , 3.67(3H,s),
3.94(3H,s), 5.14(2H,s), 5.25(2H,s), 6.40-6.70(2H,m),
6.94(1H,d,J=9.3Hz), 7.30-7.90(7H,m), 8.10(2H,d,J=8.1Hz),
8.60-8.80(2H,m), 12.64(1H,s)
39(17)
NMR (400MHz, CDC13) 5 value: 1. 62-1. 68 (2H,m) , 1.76-
1.98(6H,m), 2.69(2H,t,J=8.1Hz), 3.07(2H,t,J=8.1Hz),
3.65(3H,s), 3.84(6H,s), 3.92(3H,s), 4.80-4.83(1H,m),
5.15(2H,s), 6.38(1H,dd,J=9.0,2.4Hz) , 6.48(1H,d,J=2.4Hz) ,
6.65(2H,s), 6.92(1H,d,J=8.6Hz) , 7.50-7.55(3H,m),
12.68(1H,s)
39(18)
NMR(400MHz,CDCl3) 5 value: 1.27(3H,t,J=7.1Hz), 1.56-
1.64(2H,m), 1.78-1.96(6H,m), 2.68(2H,t,J=7.6Hz),
3.05(2H,t,J=7.6Hz), 3.64(2H,s), 3.66(3H,s),
4.17(2H,q,J=7.1Hz), 4.81-4.82(1H,m), 5.16(2H,s),
6.37(1H,dd,J=8.8,2.1Hz), 6.4 7(1H,d,J=2.0Hz),
6.96(1H,d,J=9.0Hz), 7.33(2H,d,J=7.8Hz),
7.39(2H,d,J=7.8Hz), 7.50-7.54(3H,m), 12.71(1H,s)
39(19)
NMR(400MHz,CDCl3) 6 value: 1.68-1.76(1H,m), 1.86-
1.92(1H,m), 2.15-2.25(2H,m), 2.45-2.53(2H,m),

2.69(2H,t,J=7.6Hz), 3 . 07(2H,t,J=7.6Hz), 3.67(3H,s),
3.94(3H,s), 4.69-4.72(1H,m), 5.24(2H,s), 6.33-
6.39(2H,m), 6.93(1H,d,J=8.4Hz), 7.50-7.55(5H,m),
8.09(2H,d,J=8.4Hz), 12.66(1H,s)
39(20)
NMR (400MHz, CDC13) 5 value: 2 . 69 (2H, t, J=8 . 0Hz) ,
3.07(2H,t,J=8.0Hz), 3.66(3H,s), 3.94(3H,s), 5.12(2H,s),
5.24(2H,s), 6.49(1H,dd,J=8.8,2.4Hz), 6.60(1H,d,J=2.4Hz),
6.93(1H,d,J=8.4Hz), 7.35-7.44(5H,m), 7.50-7.55(5H,m),
8.09(2H,d,J=8.0Hz), 12.65(1H,s)
39(21)
NMR(400MHz,CDCl3) 5 value: 1.35(9H,s), 1.62-1.66(2H,m),
1.76-1.96(6H,m), 2.68(2H,t,J=7.6Hz), 3.08(2H,t, J=7.6Hz) ,
3.36(3H,s), 3.67(3H,s), 4.80-4.83(1H,m), 5.27(2H,s),
6.37(1H,dd,J=8.8,2.4Hz), 6.4 8(1H,d,J=2.4Hz),
6.91(1H,d,J=8.4Hz), 7.48-7.61(5H,m), 7.95(2H,d,J=8.4Hz),
12.67(1H,s)
39(22)
NMR(400MHz,CDCl3) 8 value: 1.62-1.68(2H,m), 1.77-
1.98(6H,m), 2.68(2H,t,J=7.6Hz), 3 . 01 (3H,brs),
3.06(2H,t,J=7.6Hz), 3.13(3H,brs), 3.67(3H,s), 4.80-
4.83(1H,m), 5.21(2H,s), 6.37(1H,dd,J=9.2, 2.4Hz) ,
6.48(1H,d,J=2.4Hz), 6.94(1H,d,J=8.4Hz), 7.47-7.55(7H,m),
12.69(1H,s)
39 (23)
NMR (4 00MHz, CDCI3) 8 value: 1.48(9H,s), 1. 60-1. 66 (2H,m) ,
1.81-1.96(6H,m), 2.69(2H,t,J=8.0Hz), 3.07(2H,t,J=8.0Hz),
3.45(3H,s), 3.66(3H,s), 4.81-4.83(1H,m), 5.21(2H,s),

6.37 (1H,dd,J=8.8,2.4Hz), 6.4 8(1H,d,J=2.4Hz),
6.95 (1H,d,J=8.4Hz), 7.29(2H,d,J=8.4Hz), 7.49-7.55(5H,m),
12.69(1H,s)
39(24)
NMR(400MHz,CDCl3) 5 value: 1.17(9H,s), 1. 60-1. 68 (2H,m) ,
1.77-1.98(6H,m), 2.67(2H,t,J=7.2Hz), 3.05(2H,t,J=7.6Hz),
3.32(3H,s), 3.66(3H,s), 4.80-4.83(1H,m), 5.22(2H,s),
6.37(1H,dd,J=8.8,2.4Hz), 6.4 8(1H,d,J=2.4Hz),
6.94(1H,d,J=8.0Hz), 7.46-7.57(7H,m), 12.69(1H,s)
39(25)
NMR(400MHz,CDCl3) 8 value: 1. 58-1. 73 (4H,m) , 1.79-
1.84(2H,m), 2.05-2.11(2H,m), 2.69(2H,t,J=7.6Hz), 2.97-
3.05(1H,m), 3.08(2H,t,J=8.0Hz), 3.67(3H,s), 3.94(3H,s),
5.25(2H,s), 6.76(1H,dd,J=8.4,1.6Hz), 6.93-6.95(2H,m),
7.51-7.59(5H,m), 8.09(2H,d,J=8.0Hz), 12.09(1H,s)
39(28)
NMR(400MHz,CDCl3) 5 value: 1. 62-1. 66 (2H,m) , 1.74-
1.98(6H,m), 2.69(2H,t,J=7.6Hz), 3.08(2H,t,J=7.6Hz),
3.68(3H,s), 3.98(3H,s), 4.80-4.83(1H,m), 5.21(2H,s),
6.37(1H,dd,J=9.0,2.2Hz), 6.4 7(1H,d,J=2.2Hz),
6.90(1H,d,J=8.3Hz), 7.24-7.28(2H,m), 7.49(1H,d,J=9.0Hz),
7.51-7.55(2H,m), 7.99(1H,t,J=7.8Hz), 12.68(1H,s)
39(29)
NMR(400MHz,CDCl3) 8 value: 1.60-1.65(2H,m), 1.80-
1.95(6H,m), 2.68(2H,t,J=7.6Hz), 3.07(2H,t,J=7.6Hz),
3.67(3H,s), 3.93(3H,s), 3.94(3H,s), 4.78-4.83(1H,m),
5.24(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.48(1H,d,J=2.4Hz),
6.91(1H,d,J=8.4Hz), 7.50(1H,d,J=8.8Hz), 7.51-7.56(2H,m),

7.62-7.64(1H,m), 7.79(2H,d,J=8.0Hz), 12.68(1H,s)
39(30)
NMR( 90MHz, CDC13) 8 value: 1. 05 ( 6H, d, J=6 . 6Hz) ,
1.19(6H,d,J=6.3Hz), 1.90-2.36(1H,m), 2.52-2.77(2H,m),
2.86-3.16(2H,m), 3.80(2H,d,J=6.6Hz), 3.93(3H,s), 4.86-
5.14(1H,m), 5.25(2H,s), 6.86-7.02(3H,m), 7.47-
7.81(6H,m), 8.09(2H,d,J=8.3Hz)
39 (31)
NMR(90MHz,CDCl3) 5 value: 1. 03 ( 6H, d, J=6 . 6Hz) ,
1.38(6H,d,J=6.4Hz), 1.40(6H,d,J=6.1Hz), 1.9-2.4(1H,m),
2.6-2.8(2H,m), 3.0-3.2(2H,m), 3.68(3H,s),
3.79(2H,d,J=6.4Hz), 4.5-5.0(1H,m), 5.1-5.5(1H,m),
5.25(2H,s), 6.3-6.5(2H,m), 6.97(1H,d,J=9.3Hz), 7.5-
7.7(6H,m), 12.68(1H,s)
39(32)
NMR (4 00MHz, CDCI3) 5 value: 1 . 01 ( 6H, d, J=6 . 6Hz ) ,
1.06(6H,d,J=6.6Hz), 1.64-1.73(2H,m), 1.78-1.96(6H,m),
2.08(1H,sep,J=6.6Hz), 2.15(1H,sep,J=6.6Hz),
2.69(2H,t,J=7.6Hz), 3.07(2H,t,J=7.6Hz), 3.66(3H,s),
3.82(2H,d,J=6.6Hz), 4.10(2H,d,J=6.6Hz), 4.79-4.84(1H,m),
5.18(2H,s), 6.37(1H,dd,J=8.8,1.7Hz), 6.48(1H,d,J=l.7Hz),
6.92(1H,d,J=8.3Hz), 7.00-7.03(2H,m), 7.49-7.55(3H,m),
7.82(1H,d,J=7.8Hz), 12.69(1H,s)
39(33)
NMR(90MHz,CDCl3) 8 value: 1. 03(6H, d,J=6.6Hz), 1.95-
2.23(1H,m), 2.69(2H,t,J=7.1Hz), 3.09(2H,t,J=7.1Hz),
3.67(3H,s), 3.79(2H,d,J=6.1Hz), 3.94(3H,s), 5.25(2H,s),
6.35-6.48(2H,m), 6.93(1H,d,J=8.5Hz), 7.47-7.57(5H,m),

nitrogen atoms as hetero atoms forming the ring and
optionally one or more oxygen atoms or sulfur atoms,
such as pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl,
imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl,
pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl,
quinolizinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, quinuclidinyl, quinazolyl,
thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl,
imidazolinyl, imidazolidinyl, pyrazolinyl,
pyrazolidinyl, purinyl and indazolyl groups;
[0011]
heterocyclic groups mean the above described
nitrogen-containing heterocyclic groups and 5- or 6-
membered-ring, condensed-ring or bridged-ring
heterocyclic groups each of which contains at least one
or more heteroatoms selected from the group consisting
of nitrogen, oxygen and sulfur atoms and optionally one
or more oxygen or sulfur atoms as heteroatoms forming
the ring, such as furyl, thienyl, benzothienyl, pyranyl,
isobenzofuranyl, oxazolyl, benzofuranyl, indolyl,
benzimidazolyl, benzoxazolyl, benzothiazolyl,
quinoxalyl, dihydroquinoxalinyl, 2,3-
dihydrobenzothienyl, 2,3-dihydrobenzopyrrolyl, 2,3-
dihydro-4H-1-thianaphthyl, 2,3-dihydrobenzofuranyl,
benzo[b]dioxanyl, imidazo[2,3-a]pyridyl,
benzo[b]piperazinyl, chromenyl, isothiazolyl,
isoxazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl,
isoindolyl and isoquinolyl groups;

organic layer was separated therefrom. After the
resultant organic layer was washed with water and a
saturated sodium chloride solution successively, the
washed layer was dried over anhydrous magnesium sulfate,
and the solvent was distilled off under reduced
pressure. The resultant residue was washed with hexane
to yield 0.64 g of 4-({2-(2-carboxyethyl)-4-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]phenoxy}methyl)
benzoic acid as light yellow solid.
NMR(90MHz,DMSO-ds) 8 value: 1.21-3.02 (12H,m), 4.77-
5.03(1H,m), 5.35(2H,s), 6 . 44-6. 52 (2H,m) ,
7.17(1H,d,J=9.3Hz), 7.41-7.89(5H,m), 8.00(2H,d,J=8.3Hz),
12.09(3H,brs)
[0236]
Example 4 5
1.15 g of methyl 3-{[4-[4-(cyclopeniyloxy)-2-
hydroxybenzoyl]-2-(3-methoxy-3-
oxopropyl)phenoxy]methyl}-1-benzothiophene-7-carboxylate
was dissolved in a mixed solvent of 10 mL of methanol
and 10 mL of tetrahydrofuran, 2 mL of a 5M aqueous
solution of sodium hydroxide was added at room
temperature, and then this mixture was stirred for 30
minutes at the same temperature, followed by addition of
2 mL of water, and this mixture was stirred for 30
minutes at 50 to 60°C. The reaction mixture was returned
to room temperature, water was added, and the mixture
was adjusted to pH 2 with 6M hydrochloric acid.
Chloroform was added, and then the organic layer was

3.67(3H,s), 3.94(3H,s), 4.1-4.3(1H,m), 5.25(2H,s), 6.3-
6.5(2H,m), 6.93(1H,d,J=9.0Hz), 7.4-7.6(5H,m),
8.10(2H,d,J=8.1Hz), 12.67(1H,s)
39(42)
NMR(90MHz,CDCl3) 5 value: 0.7-2.0(llH,m),
2.68(2H,t,J=7.7Hz), 3.08(2H,t,J=8.1Hz), 3.67(3H,s),
3.81(2H,d,J=5.9Hz), 3.93(3H,s), 5.24(2H,s), 6.3-
6.5(2H,m), 6.93(1H,d,J=9.0Hz), 7.4-7.6(5H,m),
8.09(2H,d,J=8.5Hz), 12.67(1H,s)
39(43)
NMR(90MHz,CDCl3) 8 value: 0 . 3-0 . 8 (4H,m) , 1.1-1. 5 (1H,m) ,
2.6-2.8(2H,m), 3.0-3.2(2H,m), 3.67(3H,s),
3.86(2H,d,J=6.8Hz), 3.94(3H,s), 5.24(2H,s), 6.3-
6.5(2H,m), 6.93(1H,d,J=9.0Hz), 7.4-7.6(5H,m),
8.09(2H,d,J=8.3Hz), 12.67(1H,s)
39(44)
NMR(90MHz,CDCl3) 8 value: 1.3-2.0(12H,m),
2.68 (2H,t,J=6.8Hz), 3.08(2H,t,J=6.8Hz), 3.67(3H,s),
3.93(3H,s), 4.3-4.6(1H,m), 5.24(2H,s), 6.3-6.4(2H,m),
6.93(1H,d,J=9.3Hz), 7.5-7.6(5H,m), 8.09(2H,d,J=8.3Hz),
12.68(1H,s)
39(45)
NMR(400MHz,CDCl3) 8 value: 1.34(6H,t,J=7.6Hz), 1.60-
1.98(8H,m), 2.69(2H,t,J=7.2Hz), 3.08(2H,t,J=8.0Hz),
3.67(3H,s), 4.10-4.19(4H,m), 4.80-4.82(1H,m),
5.23(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.48(1H,d,J=2.4Hz),
6.93(1H,d,J=8.4Hz), 7.50-7.56(5H,m), 7.84-7.89(2H,m),
12.69(1H,s)

39(46)
NMR(90MHz,CDCl3) 5 value: 1.03(6H,d,J=6.6Hz),
1.19(6H,d,J=6.1Hz), 1.96-2.20(1H,m), 2.55-2.71(2H,m),
2.99-3.17(2H/m), 3.79(2H,d,J=6.3Hz), 4.86-5.14(1H,m),
5.24(2H,s), 6.37-6.48(2H,m), 6.90(1H,d,J=9.3Hz), 7.46-
7.77(7H,m), 12.63(1H,s)
39(47)
NMR(400MHz,CDCl3) 5 value: 2.69(2H,t,J=7.2Hz),
3.08(2H,t,J=7.6Hz), 3.67(3H,s), 3.94(3H,s), 5.25(2H,s),
5.30(2H,s), 6.54(1H,dd,J=8.8,2.8Hz), 6.62(1H,d,J=2.4Hz),
6.94(1H,d,J=8.4Hz) , 7.51-7.60(5H,m) , 8.09(2H,d,J=8.4Hz),
8.58-8.60(2H,m), 8.82(1H,s), 12.62(1H,s)
39(48)
NMR(400MHz,CDCl3) 5 value : 1. 61-1. 68 (2H, m) , 1.78-
1.98(6H,m), 2.67(2H,t,J=7.6Hz), 3.05(2H,t,J=7.6Hz),
3.65(3H,s), 3.66(3H,s), 4.81-4.84(1H,m), 5.27(2H,s),
5.57(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.48(1H,d,J=2.4Hz),
6.99(1H,d,J=8.8Hz), 7.50-7.57(4H,m),
7.64(1H,dd,J=8.8,1.6Hz), 7.75(1H,s), 12.70(1H,s)
39(49)
NMR(4 00MHz, CDC13) 5 value: 1.60-1.66(2H,m), 1.67-
1.98(6H,m), 2.67(3H,s), 2 . 70 (2H, t, J=7 . 6Hz) ,
3.08(2H,t,J=7.6Hz), 3.67(3H,s), 4.80-4.83(1H,m),
5.25(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.48(1H,d,J=2.4Hz),
6.96(1H,d,J=8.4Hz), 7.48-7.57(5H,m), 8.11(2H,d,J=8.0Hz),
12.70 (1H,s)
39(50)
NMR(400MHz,CDCl3) 5 value: 1. 63-1. 67 (2H,m) , 1.67(9H,s),

1.78-1.96(6H,m), 2.63(2H,t,J=7.6Hz), 3.00(2H,t,J=7.6Hz) ,
3.66(3H,s), 4.81-4.83(1H,m), 5.09(2H,s),
6.38(1H,dd,J=9.0,2.4Hz), 6.4 8(1H,d,J=2.4Hz),
6.97(1H,d,J=8.6Hz), 7.50(1H,d,J=8.8Hz), 7.53-7.57(2H,m),
7.80(1H,s), 8.18(1H,s), 12.69(1H,s)
39(51)
NMR (400MHz, CDC13) 5 value: 1. 62-1. 67 (2H,m) , 1.76-
1.98(6H,m), 2.67(2H,t,J=7.6Hz), 3.04(2H,t,J=7.6Hz),
3.39(6H,s), 3.66(3H,s), 4.80-4.83(1H,m), 5.20(2H,s),
5.32(2H,s), 5.34(2H,s), 6.37(1H,dd,J=9.2,2.4Hz),
6.48(1H,d,J=2.4Hz), 6. 99(1H,d,J=8.8Hz), 7.18-7.32(3H,m),
7.50-7.56(3H,m), 12.70(1H,s)
39(52)
NMR(400MHz,CDCI3) 5 value: 1.63-1.68(2H,m), 1.76-
1.98(6H,m), 2.70(2H,t,J=7.6Hz) , 3.09(2H, t, J=7.6Hz) ,
3.36(3H,s), 3.68(3H,s), 4.80-4.84(1H,m), 5.28(2H,s),
6.37(1H,dd, J=8.8,2.4Hz) , 6.4 8(1H,d,J=2.4Hz),
6.95(1H,d,J=8.0Hz), 7.50(1H,d,J=9.2Hz), 7.54-7.56(2H,m),
7.64-7.70(4H,m), 12.68(1H,s)
39(53)
NMR(400MHz,CDCl3) 5 value: 1.60-1.68(11H,m), 1.77-
1.98(6H,m), 2.69(2H,t,J=7.2Hz), 3.09(2H,t,J=7.6Hz),
3.68(3H,s), 4.81-4.84(1H,m), 5.33(2H,s),
6.38(1H,dd,J=8.8,2.4Hz), 6.4 8(1H, d, J=2.4Hz) ,
6.92(1H,d,J=8.8Hz), 7.48-7.57(3H,m), 7.90(1H,d,J=7.6Hz),
8.00(2H,d,J=8.0Hz), 12.67(1H,s)
39(54)
NMR(400MHz,CDCl3) 6 value: 1. 62-1. 68 (2H, m) , 1.76-

1.98(6H,m), 2.70(2H,t,J=7.8Hz), 3.09(2H,t,J=7.6Hz),
3.68(3H,s), 3.69(3H,s), 4.80-4.83(1H,m), 5.30(2H,s),
6.37(1H,dd,J=9.0,2.4Hz), 6.4 8(1H,d,J=2.4Hz),
6.93(1H,d,J=8.4Hz) , 7.31-7.35(2H,m), 7.49-7.57(3H,m),
7.87(1H,d,J=7.6Hz), 12.67(1H,s)
39(55)
NMR (400MHz, CDC13) 5 value: 1. 64-1. 96 (8H,m) ,
2.70(2H,t,J=7.6Hz), 3.09(2H,t,J=7.6Hz), 3.68(3H,s),
4.18(3H,s), 4.80-4.83(1H,m), 5.32(2H,s),
6.37(1H,dd,J=9.0,2.8Hz), 6.4 8(1H,d,J=2.8Hz),
6.95(1H,d,J=8.4Hz), 7.33(1H,d,J=7.2Hz), 7.49-7.56(4H,m),
7.66(1H,d,J=8.0Hz), 12.69(1H,s)
39(56)
NMR(400MHz,CDCI3) 5 value: 1.66(9H,s), 1.75(9H,s), 1.77-
1.98(8H,m), 2.66(2H,t,J=7.6Hz), 3.04(2H,t,J=8.0Hz),
3.66(3H,s), 4.80-4.83(1H,m), 5.19(2H,s),
6.37(1H,dd,J=9.0, 2.4Hz) , 6.4 8 (1H,d,J=2.4Hz),
6.95(1H,d,J=9.2Hz), 7.06(1H,d,J=8.4Hz),
7.51(1H,d,J=9.2Hz) , 7.52-7.54(2H,m),
7.66(1H,dd,J=8.4,2.0Hz) , 8.11(1H,d,J=2.0Hz),
12.69(1H,s)
39(57)
NMR ( 90MHz, CDCI3) 5 value: 1. 04 ( 6H, d, J=6 . 6Hz) ,
1.18(6H,d,J=6.4Hz), 1.86-2.34(1H,m), 2.53-2.70(2H,m),
2.97-3.14(2H,m), 3.79(2H,d,J=6.4Hz), 4.80-5.30(1H,m),
5.21(2H,s), 6.38-6.49(2H,m), 6.98(1H,d,J=9.0Hz), 7.28-
7.58(4H,m), 7.81(1H,d,J=7.3Hz), 8.63(1H,d,J=4.6Hz),
8.71(1H,s), 12.66(1H,s)

39(58)
NMR(400MHz,CDCl3) 5 value: 1. 48(3H,t,J=7.3Hz), 1.63-
1.67(2H,m), 1.76-1.98(6H,m), 2.70(2H,t,J=7.6Hz),
3.10(2H,t,J=7.6Hz), 3.68(3H,s), 4.53(2H,q,J=7.2Hz),
4.80-4.84(1H,m), 5.43(2H,s), 6.37(1H,dd,J=8.8,2.4Hz) ,
6.4 8(1H,d,J=2.4Hz), 6.97(1H,d,J=8.4Hz),
7.49(1H,d,J=8.8Hz), 7.54-7.57(2H,m), 8.98(1H,s),
9.31(1H,d,J=1.2Hz), 12.66(1H,s)
39(59)
NMR(90MHz, CDC13) 8 value: 1.39(3H,t,J=7.1Hz), 1.5-
2.1(8H,m), 2.6-2.7(2H,m), 2.9-3.1(2H,m), 3.66(3H,s),
4.38(2H,q,J=7.1Hz), 4.7-4.9(1H,m), 5.19(2H,s), 6.3-
6.6(3H,m), 6.93(1H,d,J=9.0Hz), 7.17(1H,d,J=3.4Hz), 7.4-
7.6(3H,m), 12.67(1H,s)
39(60)
NMR( 90MHz, CDCl3) 6 value: 1. 2-2 .1 ( HH,m) ,
2.71 (2H,t,J=6.8Hz), 3.11(2H,t,J=8.0Hz), 3.68(3H,s),
4.46(2H,q,J=7.1Hz), 4.7-5.0(1H,m), 5.52(2H,s), 6.3-
6.5(2H,m), 6.98(1H,d,J=9.0Hz), 7.4-7.6(3H,m),
8.24(1H,s), 12.65(1H,s)
39(61)
NMR(90MHz,CDCl3) 5 value: 0.90(6H,d,J=6.6Hz),
1.08(6H,d,J=6.6Hz), 1.6-3.1(6H,m), 2.74(3H,s),
3.83(2H,d,J=6.4Hz), 3.86(2H,d,J=6.6Hz), 5.20(2H,s),
6.4-6.7(2H,m), 6.89(1H,d,J=9.3Hz), 7.18(1H,s), 7.4-
7.6(3H,m), 12.67(1H,s)
39(62)
NMR(90MHz,CDCl3) 5 value: 0.90(6H,d,J=6.6Hz) ,

1.08(6H,d,J=6.6Hz), 1.63-2.40(2H,m), 2.63-2.74(2H,m) ,
2. 94-3.12(2H,m), 3.83(2H,d,J=6.4Hz), 3.86(2H,d,J=6.6Hz),
5.14(2H,s), 6.46-6.61(2H,m), 6.89(1H,d,J=9.3Hz), 7.33-
7.82(5H,m), 8.58-8.69(2H,m), 12.67(1H,s)
39(63)
NMR(90MHz,CDCl3) 8 value: 0 . 90 ( 6H, d, J=6 . 6Hz) ,
1.08(6H,d,J=6.6Hz), 1.68-2.32(2H,m), 2.55-2.74(2H,m),
2.94-3.13(2H,m), 3.83(2H,d, J=6.4Hz) , 3.86(2H,d,J=6.6Hz),
3.93(3H,s), 5.18(2H,s), 6.43-6.56(2H,m),
6.89(1H,d,J=9.0Hz), 7.45-7.63(5H,m), 8.08(2H,d,J=8.3Hz),
12.66(1H,s)
39(64)
NMR( 90MHz, CDC13) 8 value : 0.90(6H,d,J=6.6Hz),
1.08(6H,d,J=6.6Hz), 1.6-2.4(2H,m), 2.5-2.8(2H,m), 2.9-
3.1(2H,m), 3.83(2H,d,J=6.lHz), 3.86(2H, d, J=6.6Hz) ,
5.27(2H,s), 6.4-6.6(2H,m), 6.89(1H,d,J=9.0Hz), 7.2-
7.9(6H,m), 8.61(1H,d,J=4.6Hz), 12.64(1H,s)
Example 4 0
1.50 g of methyl 3-{5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-hydroxyphenyl} propanoate, 1.04 g of
methyl 3-(hydroxymethyl)-1-benzothiophene-7-carboxylate,
and 1.23 g of triphenylphosphine were dissolved in 15
mL of tetrahydrofuran, to which 0.92 mL of diisopropyl
azodicarboxylate was added dropwise at temperatures of
19 to 32°C, and this mixture was stirred for one hour at
room temperature. The reaction mixture was poured into
a mixture of ethyl acetate and water, and the organic
phase was separated therefrom. After the resultant

organic phase was washed with water and a saturated
sodium chloride solution successively, the washed phase
was dried over anhydrous magnesium sulfate and the
solvent was distilled out thereof under reduced
pressure. The resultant residue was purified by silica
gel column chromatography [eluent; hexane:ethyl
acetate=3:l] to yield 1.70 g of methyl 3-{[4-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-methoxy-3-
oxopropyl)phenoxy]methyl}-1-benzothiophene-7-
carboxylate as light yellow solid.
NMR(400MHz,CDCl3) 5 value: 1. 61-1. 68 (2H,m) , 1.76-
1.98(6H,m), 2.61(2H,t,J=7.6Hz), 3.00(2H,t,J=7.6Hz),
3.62(3H,s), 4.04(3H,s), 4.80-4.84(1H,m), 5.43(2H,s),
6.38(1H,dd,J=9.2,2.4Hz), 6.4 8(1H,d,J=2.0Hz),
7.10(1H,d,J=8.4Hz), 7.51-7.59(4H,m), 7.67(1H,s),
8.08(1H,d,J=7.6Hz), 8.18(1H,d,J=7.6Hz), 12.70(1H,s)
Example 41
1.20 g of methyl 3-{5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-hydroxyphenyl} propanoate, 0.773 g of
ethyl(E)-3-[4-(hydroxymethyl)phenyl]-2-propenoate, and
0.984 g of triphenylphosphine were dissolved in 12 mL
of tetrahydrofuran, to which 0.74 mL of diisopropyl
azodicarboxylate was added dropwise at temperatures of
20 to 31°C, and this mixture was stirred for 30 minutes
at room temperature. The reaction mixture was poured
into a mixture of ethyl acetate and water, and the
organic phase was separated therefrom. After the
resultant organic phase was washed with water and a

saturated sodium chloride solution successively, the
washed phase was dried over anhydrous magnesium sulfate
and the solvent was distilled out thereof under reduced
pressure. The resultant residue was purified by silica
gel column chromatography [eluent; hexane:ethyl
acetate=3:1] to yield 1.33 g of ethyl (E)-3-(4-{[4-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-methoxy-3-
oxopropyl)phenoxy]methyl}phenyl)-2-propenoate as yellow
oil.
NMR(4 00MHz,CDC13) 5 value: 1.35(3H,t,J=7.1Hz), 1.57-
1.64(2H,m), 1.76-1.98(6H,m), 2.68(2H,t,J=7.6Hz),
3.06(2H,t,J=7.6Hz), 3.67(3H,s), 4.28(2H,q,J=7.1Hz),
4.81-4.82(1H,m), 5.20(2H,s), 6.37(1H,dd,J=8.8,2.2Hz) ,
6.46(1H,d,J=15.6Hz), 6.4 8(1H,d,J=2.4Hz),
6.94(1H,d,J=8.0Hz), 7.46(2H,d,J=8.0Hz), 7.50-7.55(3H,m),
7.57(2H,d,J=8.0Hz), 7.70(1H,d,J=16.0Hz), 12.69(1H,s)
Example 42
Compounds listed in Tables 22 to 25 and Table
25-2 were obtained in a similar manner to in Example 40.
Each of the compounds 42(6) and 42(22) to
42(25) in these Tables were synthesized from a compound
having a hydrogen atom as R4z, in order to replace the
hydrogen by another R4Z group.

1.66(2H,m), 1.76-1.98(6H,m), 2.64(2H,t,J=7.6Hz),
2.67(2H,t,J=7.6Hz), 2.98(2H,t,J=7.6Hz),
3.04(2H,t,J=7.6Hz) , 3.66(3H,s), 4.13(2H,q,J=7.2Hz),
4.80-4.83(1H,m), 5.15(2H,s), 6.37(1H,dd,J=8.8,2.4Hz) ,
6.4 7(1H,d,J=2.4Hz), 6.96(1H,d,J=9.0Hz),
7.22(2H,d,J=8.0Hz), 7.36(2H,d,J=8.OHz), 7.50-7.54(3H,m),
12.70 (1H,s)
42(2)
NMR (400MHz, CDC13) 5 value: 1 . 5-2 . 0 (8H,m) , 2.43(3H,s),
2.66(2H,t,J=7.6Hz), 3.06(2H,t,J=7.6Hz), 3.66(3H,s),
3.93(3H,s), 4.8-4.9(1H,m), 5.19(2H,s),
6.37 (1H,dd,J=9.2,2.4Hz), 6.4 8(1H,d,J=2.4Hz),
6.97(1H,d,J=9.2Hz), 7.4-7.6(4H,m), 7.91-7.92(2H,m),
12.70 (1H,S)
42(3)
NMR(90MHz,CDCl3) 8 value: 1. 03(6H,d,J=6.6Hz),
1.19(6H,d,J=6.4Hz), 1.98-2.28(1H,m), 2.50-2.70(5H,m),
2.93-3.11(2H,m), 3.78(2H,d,J=6.6Hz), 4.92-5.14(3H,m),
6.35-6.50(2H,m), 6.95(1H,d,J=9.4Hz), 7.32-7.57(7H,m),
12.67(1H,s)
42 (4)
NMR (400MHz,CDCl3) 5 value: 1.24(3H,t,J=7.1Hz) , 1.60-
1.67(2H,m), 1.78-1.96(6H,m), 2.61(2H,t,J=7.8Hz),
2.69(2H,t,J=7.6Hz), 2.95(2H,t,J=7.8Hz),
3.05(2H,t,J=7.6Hz), 3.65(3H,s), 3.85(3H,s),
4.13 (2H,q,J=7.1Hz), 4.81-4.82(1H,m), 5.14(2H,s),
6.37(1H,dd,J=8.8,2.2Hz), 6.47(1H,d,J=2.OHz), 6.91-
6.98(3H,m), 7.17(1H,d,J=7.3Hz), 7.50-7.54(3H,m),

12.70 (1H,s)
42(5)
NMR(400MHz,CDCl3) 8 value: 1. 57-1. 63 (2H,m) ,
1.70(3H,d,J=6.4Hz), 1.75-1.95(6H,m), 2.73(2H,dt,
J=7.6,2.8Hz), 3.10(2H,dt,J=7.6,2.8Hz), 3.70(3H,s),
3.91(3H,s), 4.79-4.81(1H,m), 5.45(1H,q,J=6.4Hz),
6.34(1H,dd,J=8.8,2.4Hz), 6.4 5(1H,d,J=2.4Hz),
6.68(1H,d,J=8.8Hz), 7.37(1H,dd,J=8.4,2.0Hz), 7.43-
7.47(3H,m), 7.51(1H,d,J=l.6Hz), 8.04(2H,d,J=8.4Hz),
12.72 (1H,s)
42(6)
NMR(400MHz,CDCl3) 5 value: 2.59(2H,d,J=17.6Hz),
2.69(2H,t,J=7.6Hz), 2.85(2H,dd,J=16.4,6.4Hz),
3.08(2H,t,J=7.6Hz), 3.67(3H,s), 3.94(3H,s), 5.0-
5.1(1H,m), 5.24(2H,s), 5.77(2H,s),
6.38(1H,dd,J=9.0,2.4Hz), 6.4 8(1H,d,J=2.4Hz),
6.93(1H,d,J=8.8Hz), 7.5-7.6(5H,m), 8.09(2H,d,J=8.0Hz),
12.70(1H,s)
42(7)
NMR(90MHz,CDCl3) 5 value: 1. 03 ( 6H, d, J=6 . 6Hz) ,
1.20(6H,d,J=6.4Hz), 1.97-2.25(1H,m), 2.48-2.56(2H,m),
2.85-3.28(4H,m), 3.78(2H,d,J=6.1Hz), 3.92(3H,s),
4.30(2H,t,J=6.7Hz), 4.88-5.15(1H,m), 6.36-6.48(2H,m),
6.82-6.95(1H,m), 7.40-7.64(5H,m), 7.90-8.00(2H,m),
12.66(1H,s)
42 (8)
NMR(90MHz,CDCl3) 8 value: 1. 03 ( 6H, d, J=6 . 6Hz) ,
1.22(6H,d,J=6.4Hz), 1.98-2.25(1H,m), 2.40-2.56(2H,m),

2.85-3.03(2H,m), 3.15-3.28(2H,m), 3.78(2H,d,J=6.4Hz),
3.91(3H,s), 4.23-4.37(2H,m), 4.94-5.08(1H,m), 6.36-
6.48(2H,m), 6.88(1H,d,J=9.1Hz), 7.34-7.55(5H,m),
8.01(2H,d,J=8.1Hz), 12.65(1H,s)
42 (9)
NMR(400MHz,CDCl3) 8 value: 1. 60-1. 68 (2H,m) , 1.78-
1.96(6H,m), 2.63(2H,t,J=7.6Hz), 2.66(2H, t,J=7.6Hz),
2.96(2H,t,J=7.6Hz), 3.02(2H,t,J=7.6Hz), 3.65(3H,s),
3.66(3H,s), 3.85(3H,s), 4.79-4.84(1H,m), 5.08(2H,s),
6.37(1H,d,J=9.3Hz), 6.47(1H,s), 6.87(1H,d,J=8.3Hz),
6.97(1H,d,J=8.6Hz), 7.22-7.28(2H,m), 7.51-7.55(3H,m),
12.71(1H,s)
42(10)
R1 is a 1-trityl-lH-benzimidazol-6-yl
substituent.
NMR(400MHz, CDCl3) 5 value: 1.62-1.66(2H,m), 1.78-
1.95(6H,m), 2.66(2H,t,J=7.6Hz), 3.03(2H,t,J=7.6Hz),
3.63(3H,s), 4.80-4.83(1H,m), 5.21(2H,s),
6.37(1H,dd,J=9.0, 2.4Hz), 6.47-6.53(2H,m), 6.96-
7.00(1H,m), 7.14-7.35(16H,m), 7.40(1H,dd,J=8.4, 2.4Hz),
7.47-7.53(2H,m), 7.85(1H,s), 7.92(1H,s), 12.72(1H,s)
R1 is a l-trityl-1H-benzimidazol-5-yl
substituent.
NMR(400MHz,CDCl3) 5 value: 1.62-1.66(2H,m), 1.78-
1.95(6H,m), 2.44(2H,t,J=7.6Hz), 2.84(2H, t, J=7.6Hz) ,
3.66(3H,s), 4.80-4.83(1H,m), 5.00(2H,s),
6.37(1H,dd,J=9.0, 2.4Hz), 6.47-6.49(1H,m),
6.63(1H,d,J=8.8Hz), 6.96-7.00(1H,m), 7.14-7.35(16H,m),

7.47-7.53(3H,m), 7.80(1H,d,J=8.4Hz), 7.89(1H,s),
12.74 (1H,s)
42(11)
NMR(400MHz,CDCl3) 5 value: 1. 62-1. 67 (2H,m) , 1.76-
1.98(6H,m), 2.68(2H,t,J=7.6Hz), 3.05(2H,t,J=7.6Hz),
3.18(3H,s), 3.67(3H,s), 3.72(2H,t,J=5.6Hz),
4.01 (2H,t,J=5.6Hz), 4.80-4.83(1H,m), 5.18(2H,s),
6.37(1H,dd,J=9.0,2.4Hz), 6.4 8(1H,d,J=2.4Hz),
6.95(1H,d,J=9.2Hz), 7.40(2H,d,J=8.4Hz), 7.48-7.54(5H,m),
12.69(1H,s)
42 (12)
NMR(400MHz,CDCl3) 8 value: 1. 62-1. 67 (2H,m) , 1.76-
1.98(6H,m), 2.76(2H,t,J=7.6Hz), 3.14(2H,t,J=7.6Hz),
3.70(3H,s), 3.99(3H,s), 4.79-4.83(1H,m), 5.60(2H,s),
6.37(1H,dd,J=9.2,2.4Hz), 6.4 8(1H,d,J=2.4Hz),
7.03(1H,d,J=8.8Hz), 7.49(1H,d,J=8.8Hz), 7.52-7.59(2H,m),
7.98(1H,d,J=8.4Hz), 8.11(1H,dd,J=8.6,2.4Hz),
8.72(1H,d,J=1.2Hz), 12.66(1H,s)
42(13)
NMR(400MHz,CDCl3) 5 value: 1. 60-1.68 (2H,m) , 1.76-
1.98(6H,m), 2.66(2H,t,J=7.8Hz), 3.03(2H,t,J=7.8Hz),
3.66(3H,s), 4.80-4.84(1H,m), 5.07(2H,s), 5.99(2H,s),
6.37(1H,dd,J=8.8,2.4Hz), 6.4 8(1H,d,J=2.4Hz),
6.83(1H,d,J=8.0Hz), 6.88-6.97(3H,m), 7.50-7.55(3H,m),
12.71 (1H,s)
42 (14)
NMR (4 00MHz,CDC13) 5 value: 1.62-1.68(2H,m), 1.76-
1.98(6H,m), 2.67(2H,t,J=7.6Hz), 3.04(2H,t,J=7.6Hz),

3.66(3H,s), 4.09(2H,t,J=8.0Hz), 4.51(2H,t,J=8.OHz),
4.80-4.83(1H,m), 5.16(2H,s), 6.37(1H, dd,J=8.8,2.4Hz) ,
6.4 8(1H,d,J=2.0Hz), 6.96(1H,d,J=8.8Hz),
7.45(2H,d,J=8.8Hz), 7.50-7.56(3H,m), 7.60(2H,d,J=8.8Hz),
12.70(1H,s)
42 (15)
NMR(400MHz,CDCl3) 5 value: 1.62-1.68(2H,m), 1.78-
1.98(6H,m), 2.64(2H,t,J=7.6Hz), 3.03(2H,t,J=7.6Hz),
3.61(3H,s), 3.97(3H,s), 4.80-4.84(1H,m), 5.45(2H,s),
6.38(1H,dd,J=9.2,2.4Hz) , 6.4 8(1H,d,J=2.4Hz),
7.09(1H,d,J=8.4Hz), 7.52-7.61(4H,m), 7.95(1H,d,J=8.4Hz),
8.07(1H,dd,J=8.6,1.4Hz), 8.56(1H,s), 12.70(1H,s)
42(16)
NMR(400MHz,CDCl3) 5 value: 1. 03 ( 6H, d, J=6 . 4Hz) ,
1.18(6H,d,J=6.4Hz), 2.06-2.16(1H,m), 2.66(2H,t,J=7.6Hz),
3.06(2H,t,J=7.6Hz) , 3.78(2H,d,J=6.8Hz) , 3.96(3H,s),
4.95-5.04(1H,m), 5.45(2H,s), 6.42(1H,dd,J=9.2,2.4Hz),
6.49(1H,d,J=2.4Hz), 7.02(1H,d,J=8.8Hz), 7.42(1H,s),
7.51-7.57(3H,m), 7.88(1H,d,J=8.4Hz),
8.01(1H,dd,J=8.4 ,1.6Hz) , 8.4 8(1H,d,J=l.6Hz),
12.66(1H,s)
42 (17)
NMR(400MHz,CDCl3) 5 value: 1.38(6H,d,J=6.0Hz),
2.71(2H,t,J=7.6Hz), 3.06(2H, t, J=7.6Hz) , 3.66(3H,s),
3.97(3H,s), 4.60-4.66(1H,m), 5.45(2H,s),
6.38(1H,dd,J=8.8,2.4Hz), 6.4 8(1H,d,J=2.4Hz),
7.03(1H,d,J=8.8Hz), 7.43(1H,s), 7.50-7.56(3H,m),
7.88(1H,d,J=8.4Hz), 8.01(1H,dd,J=8.4,1.6Hz),

8.48(1H,d,J=1.6Hz), 12.67(1H,s)
42(18)
NMR(400MHz,CDCl3) 5 value: 1.62-1.67(2H,m), 1.76-
1.98(6H,m), 2.71 (2H,t,J=7.6Hz) , 3.06(2H,t,J=7.6Hz),
3.66(3H,s), 3.96(3H,s), 4.79-4.83(1H,m), 5.45(2H,s),
6.37(1H,dd,J=9.2,2.4Hz), 6.4 8(1H,d,J=2.4Hz),
7.02(1H,d,J=9.2Hz), 7.42(1H,s), 7.50(1H,d,J=9.2Hz),
7.54-7.56(2H,m), 7.8 8(1H,d,J=8.8Hz),
8.01 (1H,dd,J=8.4,1.6Hz), 8.4 8(1H,d,J=l.6Hz),
12.68(1H,s)
42 (19)
NMR(90MHz,CDC13) 5 value: 1.03(6H,d,J=6.6Hz), 1.9-
2.4(1H,m), 2.6-3.2(4H,m), 3.67(3H,s),
3.78(2H,d,J=6.6Hz), 3.89(3H,s), 5.34(2H,s), 6.3-
6.5(2H,m), 6.97(1H,d,J=9.0Hz), 7.10(1H,d,J=3.9Hz), 7.4-
7.6(3H,m), 7.72(1H,d,J=3.9Hz), 12.68(1H,s)
42 (20)
NMR(90MHz,CDCl3) 5 value: 1.03(6H,d,J=6.7Hz),
1.46(3H,t,J=7.lHz), 1.98-2.15(1H,m), 2.64-2.73(2H,m),
2.97-3.06(2H,m), 3.66(3H,s), 3.79(2H,d,J=6.6Hz),
4.51(2H,q,J=7.1Hz), 5.28(2H,s), 6.38-6.51(2H,m),
6.96(1H,d,J=9.3Hz), 7.46-7.60(3H,m), 7.9-8.0(1H,m),
8.21(1H,d,J=7.6Hz), 8.85(1H,d,J=l.5Hz), 12.63(1H,s)
42 (21)
NMR(400MHz,CDCl3) 5 value: 1. 42 (3H, t, J=7 . 2Hz) , 1.62-
1.66(2H,m), 1.76-1.97(6H,m), 2.69(2H,t,J=7.6Hz),
3.07(2H,t,J=7.6Hz), 3.66(3H,s), 4.42(2H,q,J=7.2Hz),
4.80-4.83(1H,m), 5.29(2H,s), 6.37(1H,dd,J=8.8,2.0Hz),

6.48(1H,d,J=2.0Hz), 6.99(1H,d,J=8.4Hz), 7.50-7.55(4H,m),
7.90(1H,d,J=8.4Hz), 7.94(1H,s), 8.07(1H,s), 12.70(1H,s)
42 (22)
NMR(90MHz,CDC13) 8 value: 0 . 90(6H,d,J=6.6Hz),
1.08(6H,d,J=6.8Hz), 1.48(9H,s), 1.7-2.4(4H,m), 2.5-
2.8(2H,m), 2.9-3.2(2H,m), 3.4-4.0(4H,m),
3.83(2H,d,J=6.4Hz), 3.86(2H, d, J=6.6Hz) , 4.9-5.1(1H,m),
6.3-6.5(2H,m), 6.89(1H,d,J=9.3Hz), 7.5-7.6(3H,m),
12.67(1H,brs)
42 (23)
NMR(90MHz,CDCl3) 5 value: 0.89(6H,d,J=6.6Hz),
1.08(6H,d,J=6.6Hz), 1.7-2.4(2H,m), 2.5-2.8(2H,m), 2.9-
3.3(4H,m), 3.83(2H,d,J=6.4Hz), 3.85(2H, d,J=6.6Hz),
4.29(2H,t,J=6.4Hz), 6.3-6.5(2H,m), 6.88(1H, d, J=9.3Hz) ,
7.4-7.6(5H,m), 8.19(2H,d,J=8.8Hz), 12.66(1H,s)
42 (24)
NMR (90MHz, CDCl3) 8 value: 0.90 (6H, d, J=6 . 6Hz),
1.08 (6H,d,J=6.6Hz), 1.4-2.3(10H,m), 2.5-2.8(2H,m), 2.9-
3.2(2H,m), 3.83(2H,d, J=6.4Hz) , 3.86(2H,d,J=6.6Hz), 4.7-
4.9(1H,m), 6.3-6.5(2H,m), 6.88(1H,d,J=9.3Hz), 7.2-
7.6(3H,m), 12.71(1H,s)
42 (25)
NMR(90MHz,CDCl3) 8 value: 0 . 7-1. 2 (12H,m) ,
1.46(3H,t,J=7.1Hz), 1.7-2.5(2H,m), 2.4-3.2(4H,m), 3.7-
4.0(4H,m), 4.54(2H,q,J=7.1Hz), 5.22(2H,s), 6.4-
6.7(2H,m), 6.8-7.0(1H,m), 7.4-7.7(3H,m), 7.8-8.0(1H,m),
8.19(1H,d,J=7.3Hz), 8.82(1H,d,J=l.5Hz), 12.65(1H,s)
42 (26)

NMR (400MHz, CDC13) 5 value: 2.69(2H,t,J=7.6Hz),
3.08(2H,t,J=8.0Hz), 3.66(3H,s), 3.94(3H,s), 5.06(2H,s),
5.25(2H,s), 6.40-6.41(1H,m), 6.47-6.50(2H,m),
6.62(1H,d,J=2.8Hz), 6.93(1H,d,J=8.4Hz), 7.47-7.56(6H,m),
8.09(2H,d,J=8.0Hz), 12.66(1H,s)
42 (27)
NMR(400MHz, CDC13) 5 value: 2.69(2H,t,J=7.6Hz),
3.08(2H,t,J=7.6Hz), 3.67(3H,s), 3.94(3H,s), 5.25(2H,s),
5.28(2H,s), 6.49(1H,dd,J=8.8,2.8Hz), 6.61(1H, d,J=2.4Hz) ,
6.93(1H,d,J=8.4Hz), 7.02-7.04(1H,m), 7.15(1H,d,J=3.6Hz),
7.36(1H,dd,J=5.2,1.2Hz), 7.5 0-7.56(5H,m),
8.09(2H,d,J=8.4Hz), 12.65(1H,s)
Example 43
Isopropyl 3-(5-(2-hydroxy-4-
isobutoxybenzoyl)-2-{ [ (2S)-5-
oxopyrrolizinyl]methoxy}phenylpropanoate was obtained
in a similar manner as in Example 40.
NMR(90MHz, CDC13) 5 value: 0 . 6-1. 6 (12H,m) , 1. 6-3 . 3 (9H,m) ,
3.4-4.4(5H,m), 4.7-5.3(1H,m), 6.2-7.8(6H,m),
12.30(1H,s), 12.63(1H,s)
Example 4 4
1.16 g of methyl 4-{[4-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-(3-methoxy-3-
oxopropyl)phenoxy]methyl} benzoate was dissolved in 10
mL of methanol, to which 2.6 mL of a 20% aqueous
solution of sodium hydroxide was added at room
temperature, and this mixture was stirred for 30
minutes at the same temperature. Water and chloroform

were successively added to the reaction mixture which
was adjusted to pH 2 with 6M hydrochloric acid, and
then the organic phase was separated therefrom. After
the resultant organic phase was washed with water and a
saturated sodium chloride solution successively, the
washed phase was dried over anhydrous magnesium sulfate
and the solvent was distilled out thereof under reduced
pressure. The resultant residue was washed with hexane
to yield 0.64 g of 4-({2-(2-carboxyethyl)-4-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]phenoxy}methyl)
benzoic acid as light yellow solid.
NMR(90MHz,DMSO-d6) δ value: 1.21-3.02(12H,m), 4.77-
5.03(1H,m), 5.35(2H,s), 6.44-6.52(2H,m),
7.17(1H,d,J=9.3Hz), 7.41-7.89(5H,m), 8.00(2H,d,J=8.3Hz),
12.09(3H,br)
Example 4 5
1.15 g of methyl 3-{[4-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-(3-methoxy-3-
oxopropyl)phenoxy]methyl}-1-benzothiophene-7-
carboxylate was dissolved in a mixed solvent of 10 mL
of methanol and 10 mL of tetrahydrofuran, to which 2 mL
of a 5M aqueous solution of sodium hydroxide was added
at room temperature, and then this mixture was stirred
for 30 minutes at the same temperature, followed by
addition thereto of 2 mL of water, and this mixture was
stirred for another 30 minutes at temperatures of 50 to
60°C. The reaction mixture was cooled to room
temperature, to which water was added, and then

adjusted to pH 2 with 6M hydrochloric acid. Chloroform
was added to this reaction mixture, and then the
organic phase was separated therefrom. After the
resultant organic phase was washed with water, the
organic phase was separated and the solvent was
distilled out thereof under reduced pressure. The
resultant residue was washed with hexane to yield 1.00
g of 3-({2-(2-carboxyethyl)-4-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]phenoxy}methyl)-1-benzothiophene-7-
carboxilic acid as light yellow solid.
NMR(4 00MHz,DMSO-d6) 8 value: 1.60-1.76(6H,m), 1.91-
1.96(2H,m), 2.50(2H,t,J=8.0Hz), 2.84(2H,t,J=7.6Hz),
4.86-4.91(1H,m), 5.56(2H,s), 6.48-6.51(2H,m),
7.38(1H,d,J=8.8Hz), 7.4 7(1H,d,J=8.8Hz),
7.54(1H,d,J=1.6Hz), 7.58-7.61(2H,m), 8.02(1H,s),
8.10(1H,d,J=7.6Hz), 8.22(1H,d,J=7.6Hz), 12.07(1H,brs)
Example 4 6
1.20 g of ethyl (E)-3-(4-{ [4-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-methoxy-3-
oxopropyl)phenoxy]methyl}phenyl)-2-propenoate was
dissolved in a mixed solvent of 12 mL of methanol and
12 mL of tetrahydrofuran, to which 2.4 mL of a 20%
aqueous solution of sodium hydroxide was added at room
temperature, and then this mixture was stirred for one
hour at the same temperature. The reaction mixture was
concentrated under reduced pressure, to which water was
added, and then adjusted to pH 2 with 6M hydrochloric
acid. The resultant precipitate was filtered out and

washed with water to yield 0.841 g of (E)-3-(4-{ [4-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-hydroxy-3-
oxopropyl)phenoxy]methyl}phenyl)-2-propenoic acid as
light yellow solid.
NMR(4 00MHz, DMSO-d6) 5 value: 1. 60-1.74(6H,m) , 1.93-
1.96(2H,m), 2.57(2H,t,J=7.3Hz), 2.91(2H,t,J=7.3Hz),
4.89-4.92(1H,m), 5.29(2H,s), 6 . 48-6 . 50 (2H,m) ,
6.56(1H,d,J=l6.1Hz), 7.18(1H,d,J=9.3Hz),
7.46(1H,d,J=8.6Hz), 7.52-7.56(4H,m),
7.60(1H,d,J=15.9Hz), 7.74 (2H,d,J=8.0Hz), 12.07(3H,brs)
Example 4 7
16.5 g of methyl 3-(5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-{ [4- (3-hydroxy-5-
isoxoazolyl)benzyl]oxy}phenyl) propanoate was dissolved
in a mixed solvent of 160 mL of methanol and 160 mL of
tetrahydrofuran, to which 20 mL of a 20% aqueous
solution of sodium hydroxide was added at room
temperature, and then this mixture was stirred for 2
hours at the same temperature. Water was added to the
reaction mixture, and then adjusted to pH 1 with 6M
hydrochloric acid. This mixture was concentrated under
reduced pressure, then resultant precipitate was
filtered out. The resultant precipitate was dissolved
in a mixed solvent of chloroform and methanol, and
washed with water. The solvent was distilled out under
reduced pressure to yield 14.3 g of 3-(5-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]-2-{[4-(3-hydroxy-5-
isoxazolyl)benzyl]oxy}phenyl) propanoic acid as light

yellow solid.
NMR (400MHz,DMSO-d6) 8 value: 1. 5-1.8( 6H,m) , 1.9-
2.0(2H,m), 2.58 (2 H,t,J=7.6Hz), 2.91(2H,t,J=7.6Hz),
4.8-5.0(1H,m), 5.33(2H,s), 6.49(1H,dd,J=8.8, 2.4Hz),
6.52(1H,d,J=2.4Hz), 6.59(1H,s), 7.19(1H,m),
7.44(1H,d,J=8.4Hz), 7.5-7.6(2H,m), 7.62(2H,d,J=8.4Hz),
7.85(2H,d,J=8.0Hz), 11.45(1H,brs), 11.97(2H,brs)
Example 4 8
0.98 g of methyl 4-{[4-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-(3-methoxy-3-
oxopropyl)phenoxy]methyl}-2-methoxybenzoate was
dissolved in a mixed solvent of 10 mL of methanol and
10 mL of tetrahydrofuran, to which 2 mL of a 20%
aqueous solution of sodium hydroxide was added at room
temperature, and then this mixture was stirred for one
hour at the same temperature. The reaction mixture to
which water was added was adjusted to pH 2 with 6M
hydrochloric acid, followed by the addition of ethyl
acetate thereto, and the organic phase was separated
therefrom. After the resultant organic phase was
washed with water and a saturated sodium chloride
solution successively, this washed phase was dried over
anhydrous magnesium sulfate and the solvent was
distilled out under reduced pressure. The resultant
residue was recrystallized from ethanol to yield 0.42 g
of 4-({2-(2-carboxyethyl)-4-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]phenoxy}methyl)-2-methoxybenzoic acid as
light yellow solid.

NMR(4 00MHz,DMSO-d6) 5 value: 1.60-1.74 (6H,m), 1.93-
1.96(2H,m), 2.59 (2H,t,J=7.6Hz) , 2.93(2H,t,J=7.6Hz),
3.84(3H,s), 4.90-4.93(1H,m), 5.30(2H,s), 6.48-
6.50(2H,m), 7.10(1H,d,J=9.0Hz) , 7.18(1H,d,J=9.2Hz),
7.27(1H,s), 7.46(1H,d,J=8.4Hz), 7.55-7.57(2H,m),
7.68 (1H,d,J=8.0Hz), 12.04(1H,s), 12.39(2H,brs)
Example 4 9
Compounds listed in Tables 26 to 32 were
obtained in a similar manner as in Example 44.

49(1)
NMR(400MHz,DMSO-d6) 5 value: 1.60-1.74(6H,m), 1.93-
1.96(2H,m), 2.55(4H,t,J=7 .6Hz), 2.84(2H,t,J=7.6Hz),
2.88(2H,t,J=7.6Hz), 4.90-4.91(1H,m), 5.21(2H,s), 6.47-
6.50(2H,m), 7.19(1H,d,J=8.4Hz), 7.27(2H,d,J=8.0Hz),

7.40(2H,d,J=8.0Hz), 7.46(1H, d, J=8.8Hz) , 7.53-7.55(2H,m),
12.05(1H,s), 12.13(2H,brs)
49(2)
NMR(400MHz,DMSO-d6) δ value: 1.60-1.76(6H,m), 1.94-
1.96(2H,m), 2.55(3H,s), 2 . 58 (2H,t,J=7.2Hz) ,
2.92(2H,t,J=7.6Hz), 4.89-4.91(1H,m), 5.29(2H,s), 6.48-
6.50(2H,m), 7.16-7.19(1H,m), 7.39 (1H,d,J=8.0Hz),
7.42(1H,s), 7.46(1H,d, J=8.4Hz), 7.54-7.56(2H,m),
7.87(1H,d,J=8.0Hz), 12.05(1H,s), 12.47(2H,brs)
49(3)
NMR(400MHz,DMSO-d6) δ value: 1.5-1.8(6H,m), 1.8-
2.0(2H,m), 2.41(3H,s), 2.55(2H,t,J=7.6Hz),
2.90 (2H,t,J=7.6Hz) , 4.8-5.0(1H,m), 5.30(2H,s), 6.48-
6.50(2H,m), 7.25(1H,d,J=8.4Hz), 7.47(1H,d,J=8.4Hz),
7.5-7.6(3H,m), 7.79(1H,d,J=7.6Hz), 7.82(1H,s),
12.07 (3H,brs)
49(4)
NMR(90MHz,CDCl3) 5 value: 1.01 ( 6H,d,J=6.6Hz), 1.95-
2.24(1H,m), 2.49(3H,s), 2.63-2.79(2H,m), 2.95-
3.10(2H,m), 3.77(2H,d,J=6.7Hz), 5.12(2H,s), 6.36-
6.50(2H,m), 6.95(1H, d, J=9.1Hz) , 7.20-7.59(7H,m),
12.66(2H,brs)
49(5)
NMR(90MHz,CDCl3) 5 value: 1.02(6H,d,J=6.6Hz) , 1.95-
2.30(1H,m), 2.70-2.81(5H,m), 3.00-3.20(2H,m),
3.78(2H,d,J=6.4Hz) , 5.24(2H,s), 6.39-6.48(2H,m),
6.95(1H,d,J=9.3Hz), 7.46-7.77(7H,m), 12.63(2H,brs)
49(6)

NMR(90MHz,CDC13) 8 value: 1.02(6H,d,J=6.8Hz), 1.95-
2.30(1H,m), 2.62-2.82(2H,m), 2.96-3.16(5H,m),
3.78(2H,d,J=6.6Hz), 5.27(2H,s), 6.36-6.48(2H,m),
6.93(1H,d,J=9.3Hz), 7.43-7.69(5H,m), 8.00(2H,d,J=8.4Hz),
12.63(2H,brs)
49(7)
NMR(400MHz,DMSO-d6) 8 value: 0.98(6H,d,J=6.8Hz), 1.99-
2.07(1H,m), 2.57(2H,t,J=7.6Hz), 2.91(2H,t,J=7.6Hz),
3.83(2H,d,J=6.6Hz), 5.32(2H,s), 6.52-6.55(2H,m),
7.18(1H,d,J=9.3Hz), 7.38(1H,brs), 7.47(1H,d,J=9.5Hz),
7.54-7.57(4H,m), 7.91(2H,d,J=8.3Hz), 7.99(1H,brs),
12.00(1H,brs), 12.15(1H,brs)
49(8)
NMR ( 90MHz,DMSO-d6) δ value: 0.99 ( 6H,d,J=6.6Hz), 1.90-
2.19(1H,m), 2.50-2.64(2H,m), 2.82-2.98(2H,m),
3.32(3H,s), 3.84(2H,d,J=6.6Hz), 5.36(2H,s), 6.50-
6.57(2H,m), 7.13-7.68(7H,m), 8.00(2H,d,J=8.3Hz),
11.99(1H,s), 12.14(1H,brs)
49(9)
NMR(90MHz,DMSO-d6) δ value: 0.67(6H,d,J=6.8Hz),
1.05(6H,d,J=6.7Hz) , 1.60-1.88(1H,m), 1.98-2.25(1H,m),
2.67-2.75(2H,m), 3.01-3.20(2H,m), 3.61(2H,d,J=6.3Hz),
3.78(2H,d,J=6.3Hz), 5.22(2H,s), 5.98(2H,brs), 6.45-
6.59(2H,m), 6.87(1H,d,J=9.3Hz), 7.34-7.69(5H,m),
8.12(2H,d,J=8.1Hz)
49(10)
NMR (400MHz, DMSO-d6) δ value: 1. 5-1. 8 ( 6H,m) , 1.8-
2.1(2H,m), 2.53(2H,t, J=7.6Hz) , 2.88(2H, t, J=7.6Hz) ,

3.65(3H,s), 4.91-4.93(1H,m), 5.33(2H,s), 6.5-6.7(2H,m),
7.11(1H,d,J=8.8Hz), 7.21(1H,d,J=8.4Hz),
7.51(1H,dd,J=8.4,2.4Hz), 7.5 8-7.60(3H,m),
7.8 9(2H,d,J=8.4Hz), 12.5 6(2H,brs)
49(11)
NMR(400MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.94-
1.96(2H,m), 2.48 (2H,t,J=7.3Hz) , 2.58(2H,t,J=7.6Hz),
2.78(2H,t,J=7.6Hz), 2.90(2H,t,J=7.3Hz), 3.82(3H,s),
4.90-4.93(1H,m), 5.21(2H,s), 6.48-6.50(2H,m),
6.98(1H,d,J=7.3Hz), 7.10(1H,s), 7.16-7.21(2H,m),
7.46(1H,d,J=8.8Hz), 7.54-7.57(2H,m), 12.04(1H,s),
12.13 (2H,brs)
49(12)
NMR(400MHz,CDCl3) δ value: 1. 58-1. 66 (2H,m) ,
1.71(3H,d,J=6.4Hz),1.7 4-1.96(6H,m), 2.8 4-2.8 8(2H,m),
2.91-2.98(1H,m), 3.33-3.41(1H,m), 4.76-4.81(1H,m),
5.51(1H,q,J=6.4Hz), 6.34(1H,dd,J=8.8,2.0Hz),
6.44(1H,d,J=2.4Hz), 6.69(1H,d,J=8.8Hz),
7.37(1H,dd,J=8.4,1.2Hz), 7.4 4(1H,d,J=8.8Hz),
7.51(2H,d,J=8.4Hz), 7.54(1H,d,J=l.2Hz),
8.12 (2H,d,J=8.0Hz), 12.64(1H,s)
49(13)
NMR (400MHz,DMSO-d6) δ value: 2.42(2H,d,J=17.6Hz),
2.57(2H,t,J=7.6Hz), 2.84(2H,dd,J=16.8,6.8Hz),
2.92(2H,t,J=7.6Hz), 5.13-5.16(1H,m), 5.35(2H,s),
5.77(2H,s), 6.48-6.52(2H,m), 7.18(1H,d,J=9.2Hz),
7.46(1H,d,J=8.4Hz), 7.55-7.61(4H,m), 7.98(2H,d,J=8.0Hz),
12.02 (3H,brs)

49(14)
NMR(90MHz,DMSO-d6) δ value: 0.98(6H,d,J=6.6Hz), 1.88-
2.10(1H,m), 2.38-2.52(2H,m), 2.68-2.76(2H,m), 3.09-
3.23(2H,m), 3.83(2H,d,J=6.4Hz), 4.26-4.33(2H,m), 6.48-
6.54(2H,m), 7.12(1H,d,J=9.5Hz), 7.40-7.57(5H,m), 7.77-
7.94(2H,m), 11.99(1H,s), 12.46(2H,brs)
49(15)
NMR(90MHz,DMSO-d6) δ value: 0.98(6H,d,J=6.7Hz), 1.90-
2.18(1H,m), 2.30-2.50(2H,m), 2.67-2.86(2H,m), 3.09-
3.28(2H,m), 3.83(2H,d,J=6.4Hz), 4.27-4.40(2H,m), 6.50-
6.54(2H,m), 7.11(1H,d,J=8.4Hz), 7.40-7.58(5H,m),
7.90(2H,d,J=7.8Hz), 11.99(1H,s), 12.44(2H,brs)
49(16)
NMR(400MHz,DMSO-d6) δ value: 2.90(2H,t,J=7.6Hz),
3.25(2H,t,J=7.6Hz), 5.69(2H,s), 7.4-7.7(4H,m),
7.75(1H,d,J=8.4Hz), 7.9-8.1(6H,m), 8.31(2H,d,J=8.0Hz),
10.81(1H,brs)
49(17)
NMR(400MHz,DMSO-d6) δ value: 1.61-1.76(6H,m), 1.96-
1.98(2H,m), 2.55(2H,t,J=7.2Hz), 2.90(2H,t,J=7.2Hz),
4.93-4.94(1H,m), 5.35(2H,s), 6.85-6.91(2H,m),
7.16(1H,d,J=8.8Hz), 7.45(1H,t,J=8.8Hz), 7.59-7.65(4H,m),
7.98(2H,d,J=8.0Hz), 12.57(2H,brs)
49(18)
NMR(400MHz,DMSO-d6) δ value: 0.94(6H,d,J=6.8Hz),
1.63(2H,q,J=6.6Hz), 1.74-1.79(1H,m), 2.57(2H,t,J=7.6Hz),
2.92(2H,t,J=7.6Hz), 4.08(2H,t,J=6.8Hz), 5.35(2H,s),
6.51-6.55(2H,m), 7.18(1H,d,J=9.3Hz), 7.46(1H,d,J=8.8Hz) ,

7.54-7.56(2H,m), 7.61(2H,d,J=8.3Hz), 7.99(2H,d,J=8.3Hz) ,
12.02(3H,brs)
49(19)
NMR (400MHz, DMSO-d6) δ value: 1.00(9H,s),
2.57(2H,t,J=7.6Hz), 2.92(2H,t,J=7.6Hz), 3.72(2H,s),
5.35(2H,s), 6.53-6.55(2H,m), 7.18(1H,d,J=9.2Hz),
7.47(1H,d,J=9.6Hz), 7.54-7.56(2H,m), 7.60(2H,d,J=8.0Hz),
7.98(2H,d,J=8.0Hz), 12.00(3H,brs)
49(20)
NMR(90MHz,DMSO-d6) δ value: 1.0-2.2 (10H,m), 2.4-
3.1(4H,m), 4.3-4.7(1H,m), 5.35(2H,s), 6.4-6.6(2H,m),
7.17(1H,d,J=9.3Hz) , 7.4-7.7(5H,m), 8.00 (2H,d,J=8.1Hz) ,
11.6-12.9(3H,br)
49(21)
NMR (4 00MHz,DMSO-d6) δ value: 1.60-1.74(6H,m) , 1.94-
2.09(2H,m), 2.56(2H, t, J=7.6Hz) , 2.90(2H,t,J=7.6Hz),
3.43(3H,s), 4.90-4.93(1H,m), 5.30(2H,s), 5.34(2H,s),
6.48-6.50(2H,m), 7.20(1H,d,J=8.4Hz) , 7.47(1H,d,J=8.4Hz) ,
7.55-7.61(3H,m), 7.64(1H,dd,J=7.6,1.2Hz),
7.72(1H,d,J=1.2Hz), 12.05(1H,s), 12.62(2H,brs)
49(22)
NMR(400MHz,DMSO-d6) δ value: 1.16-1.21(2H,m), 1.49-
1.52(2H,m), 1.60-1.68(4H,m), 2.05-2.13(1H,m), 2.54-
2.59(4H,m), 2.91(2H,t,J=7.2Hz), 5.35(2H,s),
6.78(1H,d, J=7.6Hz) , 6.81(1H,s), 7.16(1H,d,J=8.4Hz),
7.32(1H,d,J=8.0Hz), 7.55(1H,dd,J=8.4,2.4Hz), 7.59-
7.62(3H,m), 7.98(2H,d,J=8.4Hz), 10.81(3H,brs)
49(23)

NMR(400MHz,DMSO-d6) δ value: 1. 57-1.74(6H,m), 1.80-
1.98(2H,m), 2.37(2H,t,J=8.0Hz), 2.85(2H,t,J=7.6Hz),
3.39(2H,brs), 4 . 88-4.91(1H,m), 5.33(2H,s), 6.47-
6.50(2H,m), 7.14(1H,d,J=8.4Hz), 7.38(2H,brs),
7.45(1H,d,J=8.8Hz), 7.51-7.54(2H,m), 7.67(2H,d,J=8.4Hz),
7.86(2H,d,J=8.4Hz)
49 (24)
NMR(90MHz,CDC13) δ value: 1.02(6H,d,J=6.6Hz), 1.86-
2.24(1H,m), 2.64-3.18(4H,m), 3.77(2H,d,J=6.3Hz),
5.23(2H,s), 6.36-6.48(2H,m), 6.92(1H,d,J=9.0Hz), 7.45-
7.76(7H,m), 8.74 (1H,brs), 12.62(1H,s)
49(25)
NMR(90MHz,CDCl3) δ value: 1.02(6H,d,J=6.6Hz), 1.9-
2.4(1H,m), 2.75(2H,t, J=6.8Hz) , 3.09(2H,t,J=6.8Hz),
3.77(2H,d,J=6.3Hz), 5.28(2H,s), 6.3-6.6(2H,m),
6.92(1H,d,J=9.3Hz) , 7.4-7.8(5H,m) , 8.27(2H,d,J=8.3Hz) ,
12.6K2H, brs)
49(26)
NMR(400MHz,DMSO-d6) δ value: 1. 22 ( 6H,d,J=6.8Hz),
2.56(2H,t,J=7.6Hz) , 2.86-2.93(3H,m), 5.35(2H,s), 6.83-
6.86(2H,m), 7.16(1H,d,J=8.8Hz), 7.35(1H,d,J=8.0Hz),
7.56(1H,dd,J=8.4,2.4Hz), 7.60-7.63(3H,m),
7.98(2H,d,J=8.4Hz), 10.8 3(3H,brs)
49(27)
NMR(400MHz,DMSO-d6) δ value: 0.90(3H,s), 1.24-1.31(2H,m),
1.48-1.55(2H,m), 1.60-1.67(4H,m), 2.54-2.58(4H,m),
2.91(2H,t,J=7.6Hz) , 5.34(2H,s), 6.75(1H, d, J=8.0Hz) ,
6.79(1H,s), 7.16(1H,d,J=8.8Hz) , 7.31(1H,d,J=8.0Hz),

7.55(1H,dd,J=8.4,2.0Hz), 7.60(2H,d,J=8.4Hz),
7.63(1H,d,J=2.0Hz), 7.98(2H,d,J=8.4Hz), 10.73 (3H,brs)
49(28)
NMR(400MHz,DMSO-d6) δ value: 1.57-1.78(6H,m), 1.91-
2.00(2H,m), 2.58(2H,t,J=7.6Hz), 2.63(6H,s),
2.94(2H,t,J=7.2Hz), 4.89-4.93(1H,m), 5.40(2H,s), 6.48-
6.51(2H,m), 7.19(1H,d,J=9.6Hz), 7.46 (1H,d,J=8.4Hz),
7.56(2H,s), 7.77(2H,d,J=8.4Hz), 7.81(2H,d,J=8.4Hz),
12.08(2H,brs)
49(29)
NMR(400MHz,DMSO-d6) δ value: 1.30-1.35(2H,m), 1.54-
1.62(4H,m), 1.74-1.80(2H,m), 2.28-2.35(1H,m),
2.57(2H,t,J=7.6Hz), 2.92(2H,t,J=7.6Hz),
3.93(2H,d,J=7.2Hz), 5.35(2H,s), 6.51-6.54(2H,m),
7.18(1H,d,J=9.2Hz), 7.46(1H,d,J=9.2Hz), 7.54-7.56(2H,m),
7.61(2H,d,J=8.4Hz), 7.99(2H,d,J=8.4Hz), 12.00(3H,brs)
49(30)
NMR(90MHz,DMSO-d6) δ value: 2.40-3.10(4H,m), 5.25(2H,s),
5.35(2H,s), 6.40-6.70(2H,m), 7.17(1H,d,J=9.3Hz), 7.4-
7.7(6H,m), 7.80-8.10(3H,m), 8.50-8.80(2H,m), 11.5-
12.9(3H,br)
49(31)
NMR(400MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.94-
1.99(2H,m), 2.60(2H,t,J=7.6Hz), 2.93(2H,t,J=7.6Hz),
3.78(6H,s), 4.90-4.91(1H,m), 5.25(2H,s),
6.49(1H,dd,J=7.6,2.2Hz), 6.51(1H,s), 6.84(2H,s),
7.19(1H,d,J=9.3Hz), 7.46(1H,d,J=9.3Hz), 7.56-7.58(2H,m),
12.02(1H,s), 49(32)

NMR(400MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.93-
1.96(2H,m), 2.56(2H,t,J=7.3Hz) , 2 . 88(2H,t,J=7.3Hz),
3.59(2H,s), 4.90-4.93(1H,m), 5.23(2H,s), 6.48-
6.50(2H,m), 7.19(1H,d,J=8.3Hz), 7.30(2H,d,J=8.0Hz),
7.43(2H,d,J=8.0Hz), 7.46(1H,d,J=9.0Hz), 7.54-7.56(2H,m),
12.05(1H,s), 12.25(2H,brs)
49(33)
NMR(400MHz,DMSO-d6) δ value: 1.60-1.70(1H,m), 1.77-
1.83(1H,m), 2.04-2.09(2H,m), 2.42-2.50(2H,m),
2.57(2H,t,J=7.6Hz), 2.91(2H,t,J=7.6Hz), 4.77-4.80(1H,m),
5.35(2H,s), 6.42(1H,d,J=2.4Hz), 6.45(1H,dd,J=8.8,2.4Hz) ,
7.17(1H,d,J=9.2Hz), 7.45(1H,d,J=8.8Hz), 7.54-7.56(2H,m),
7.60(2H,d,J=8.4Hz), 7.98(2H,d,J=8.4Hz), 11.92(3H,brs)
49(34)
NMR(400MHz,DMSO-d6) δ value: 2.57(2H,t,J=7.6Hz),
2.92(2H,t,J=7.6Hz), 5.20(2H,s), 5.35(2H,s), 6.60-
6.64(2H,m), 7.18(1H,d,J=9.2Hz), 7.34-7.49(6H,m), 7.55-
7.62(4H,m), 7.99(2H,d,J=8.8Hz), 11.93(3H,brs)
49(35)
NMR(400MHz,DMSO-d6) δ value: 1.56-1.78(6H,m), 1.90-
1.99(2H,m), 2.43(3H,d,J=4.8Hz), 2.58(2H,t,J=7.2Hz),
2.93(2H,t,J=7.2Hz), 4.90-4.93(1H,m), 5.37(2H,s), 6.48-
6.50(2H,m), 7.18(1H,t,J=4.4Hz), 7.45-7.50(2H,m), 7.55-
7.57(2H,m), 7.72(2H,d,J=8.4Hz), 7.83(2H,d,J=8.0Hz),
12.05(1H,s), 12.17(1H,brs)
49(36)
NMR(400MHz,DMSO-d6) 6 value: 1.57-1.75(6H,m) , 1.90-
2.00(2H,m), 2.58(2H,t,J=7.6Hz), 2.90-2.99(8H,m), 4.89-

4.93(1H,m), 5.31(2H,s), 6.48-6.50(2H,m),
7.20(1H,d,J=9.2Hz), 7.44-7.47(3H,m), 7.54-7.57(4H,m),
12.06(1H,s), 12.15(1H,brs)
49(37)
NMR(4 00MHz,DMSO-d5) δ value: 1.60-1.70(2H,m), 1.71-
1.75(4H,m), 1.93-1.99(2H,m), 2.56(2H,t,J=6.8Hz),
2.88(2H,t,J=6.8Hz), 3.02(3H,s), 4.91(1H,m), 5.20(2H,s),
6.48-6.50(2H,m), 7.19(1H,d,J=8.OHz), 7.25(2H,d,J=8.OHz),
7.46(2H,d,J=8.4Hz), 7.47(1H,s), 7.55(2H,d,J=8.OHz),
9.85(1H,brs), 12.07(1H,s)
49(38)
NMR(400MHz,CDCl3) δ value: 1.59-1.66(2H,m), 1.75-
1.97(6H,m), 2.73(2H,t,J=7.6Hz), 3.02(3H,d,J=5.2Hz),
3.06(2H,t,J=7.6Hz), 4.79-4.82(1H,m), 5.22(2H,s),
6.23(1H,brs), 6.38(1H,dd,J=9.2,2.4Hz) ,
6.47(1H,d,J=2.4Hz), 6.94(1H,d,J=8.4Hz), 7.49-7.56(5H,m),
7.8 0(2H,d,J=8.0Hz), 12.68 (2H,brs)
49(39)
NMR(400MHz,DMSO-d6) δ value: 1.52-1.59(2H,m), 1.64-
1.70(2H,m), 1.75-1.79(2H,m), 1.99-2.03(2H,m),
2.55(2H,t,J=7.6Hz), 2.90(2H,t,J=7.6Hz), 2.94-3.03(1H,m),
3.34(3H,brs), 5.32(2H,s), 6.84(1H,d,J=8.4Hz),
6.87(1H,s), 7.15(1H,d,J=8.4Hz) , 7.34(1H,d,J=8.OHz),
7.53-7.57(3H,m), 7.62(1H,d,J=2.4Hz), 7.95(2H,d,J=8.OHz)
49(40)
NMR(400MHz,DMSO-d6) δ value: 2.57(2H,t,J=7.6Hz),
2.91(2H,t,J=6.8Hz), 5.15(2H,s), 5.33(2H,s), 6.48-
6.52(1H,m), 6.60(1H,d,J=8.4Hz), 6.64(1H,d,J=3.6Hz),

6.68(1H,d,J=2.4Hz), 7.18(1H,d,J=9.2Hz),
7.47(1H,d,J=8.8Hz), 7.55-7.58(7H,m), 7.72-7.73(1H,m),
7.96(2H,d,J=8.0Hz)
49(41)
NMR(400MHz, DMSO-d6) δ value: 2.57(2H,t,J=7.6Hz),
2.92(2H,t,J=7.6Hz), 5.35(2H,s), 5.39(2H,s),
6.61(1H,dd,J=9.2,2.8Hz), 6.67(1H,d,J=2.0Hz), 7.05-
7.07(1H,m), 7.18(1H,d,J=9.6Hz), 7.26(1H,d,J=3.6Hz),
7.47(1H,d,J=8.8Hz), 7.55-7.62(5H,m), 7.99(2H,d,J=8.0Hz),
11.90(3H,brs)
49(42)
NMR(4 00MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.93-
1.99(2H,m), 2.58(2H,t,J=7.6Hz), 2.93(2H,t, J=7.6Hz),
4.90-4.93(1H,m), 5.35(2H,s), 6.48-6.50(2H,m),
7.16(1H,d,J=9.2Hz), 7.40-7.47(3H,m), 7.55-7.56(2H,m),
7.91(1H,t,J=8.0Hz), 12.03(1H,s)
49(43)
NMR(400MHz,DMSO-d6) δ value: 1.59-1.79(6H, m), 1.83-
2.00(2H,m), 2.57(2H,t,J=7.2Hz), 2.91(2H,t,J=7.2Hz) ,
4.88-4.93(1H,m), 5.36(2H,s), 6.48-6.50(2H,m),
7.16(1H,d,J=9.2Hz), 7.45(1H,d,J=9.2Hz), 7.55(2H,s),
7.68-7.77(3H,m), 12.06(1H,s)
49(44)
NMR(90MHz, CDC13) δ value: 1.05(6H,d,J=6.6Hz), 1.90-
2.35(1H,m), 2.56-3.14(4H,m), 3.81(2H,d,J=6.6Hz),
5.26(2H,s), 6.91-7.01(4H,m), 7.41-7.80(7H,m),
8.07(2H,d,J=8.lHz)
49 (45)

NMR (90MHz, DMSO-d6) δ value: 0 . 99 (6H, d, J=6 . 6Hz) ,
1.33(6H,d,J=6.lHz), 1.8-2.3(1H,m), 2.5-3.0(4H,m),
3.42(2H,brs), 3.84(2H,d,J=6.4Hz), 4.6-4.9(1H,m),
5.24(2H,s), 6.4-6.6(2H,m), 7.17(1H,d,J=8.8Hz), 7.4-
7.6(6H,m), 12.05(1H,s)
49(46)
NMR (400MHz, DMSO-d6) δ value: 0.99(6H,d,J=6.6Hz), 1.60-
1.74(6H,m), 1.86-2.06(3H,m), 2.58(2H,t,J=7.6Hz),
2.92(2H,t,J=7.6Hz), 3.83(2H,d,J-6.4Hz), 4.90-4.93(1H,m),
5.29(2H,s), 6.48-6.50(2H,m), 7.08(1H,d,J=8.0Hz),
7.16(1H,d, J*=9.2Hz) , 7.23(1H,s), 7.45(1H,d,J=9.0Hz),
7.54-7.56(2H,m), 7.65(1H,d,J=7.8Hz), 12.04(1H,s),
12.36(2H,brs)
49(47)
NMR(90MHz,DMSO-d6) δ value: 0 . 99 ( 6H,d,J=6.6Hz) , 1.82-
3.02(5H,m), 3.83(2H,d,J=6.3Hz), 5.35(2H,s), 6.47-
6.55(2H,m), 7.17(1H,d,J=9.3Hz), 7.42-7.66(5H,m),
8.00(2H,d,J-8.3HZ), 12.03(1H,s), 12.55(2H,brs)
49(48)
NMR (90MHz,DMSO-d6) δ value: 0.99(6H,d,J*6.7Hz), 1.90-
2.19(1H,m), 2.48-2.64(2H,m), 2.83-2.99(2H,m),
3.84(2H,d,J=6.7Hz) , 5.32(2H,s), 6.47-6.57(2H,m),
7.17 (1H,d,J=9.5Hz) , 7.42-7.70(5H,m), 7.80(2H,d,J-8.1Hz),
9.02(1H,brs), 11.20(1H,brs), 11.96(2H,brs)
49(49)
NMR(90MHz,CDCl3) δ value: 1.04(6H,d,J=6. 6Hz) , 1.90-
2.35(1H,m), 2.57-2.72(2H,m), 2.98-3.13(2H,m),
3.80(2H,d,J=6.2Hz) , 5.25(2H,s), 6.39-6.49(2H,m),

7.00(1H,d,J=9.2Hz), 7.40-7.72(6H,m), 7.98-8.12(3H,m),
12.64(1H,s)
49(50)
NMR{90MHz,DMSO-d6) δ value: 0.99(6H,d,J=6.6Hz) , 1.90-
2.95(5H,m), 3.84(2H,d,J=6.4Hz), 5.59(2H,s), 6.50-
6.55(2H,m), 7.10(1H,d,J=8.6Hz), 7.44-7.68(6H,m),
7.98(1H,d,J=7.1Hz), 12.03(1H,s), 12.62 (2H,brs)
49(51)
NMR(400MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.93-
1.96(2H,m), 2.54(2H,t,J=7.6Hz) , 2.88(2H,t,J=7.6Hz),
4.90-4.93(1H,m), 5.38(2H,s), 6.48-6.50(2H,m),
7.25(1H,d,J=8.8Hz), 7.46(1H,d,J=8.8Hz), 7.55-7.58(2H,m),
7.72-7.75(2H,m), 7.83(1H,dd,J=8.0,1.2Hz), 12.03(1H,s),
12.55(2H,brs)
4 9(52)
NMR(400MHz,DMSO-d6) δ value: 1.54-1.75(6H,m), 1.88-
1.96(2H,m), 2.50(2H,t,J=7.6Hz), 2.89(2H,t,J=7.6Hz),
4.78-4.81(1H,m), 5.33(2H,s), 6.28(1H,s),
6.33(1H,dd,J=11.6,2.0Hz), 7 . 13(1H,d,J=8.4Hz),
7.54(1H,dd,J=8.8,2.0Hz), 7.59(2H,d,J=8.0Hz),
7.68(1H,d,J=2.0Hz), 7.97(2H,d,J=8.4Hz), 10.23(3H,brs)
49(53)
NMR(400MHz,DMSO-d6) S value: 1.5-1.8(6H,m), 1.9-
2.0(2H,m), 2.25(3H,s), 2.55(2H,t,J=7.4Hz),
2.90(2H,t,J=7.4Hz), 4.8-5.0(1H,m), 5.34(2H,s),
6.8 0(1H,dd,J=8.4,2.4Hz), 6.86(1H,d,J=2.4Hz),
7.15(1H,d,J=8.4Hz), 7.22(1H,d,J=8.4Hz),
7.52(1H,dd,J=8.4,2.4Hz), 7.59-7.62(3H,m),

7.98(2H,d,J=8.4Hz), 12.56(2H,brs)
49(54)
NMR(400MHz,DMSO-d6) δ value: 1.55-1.75(6H,m), 1.90-
1.98(2H,m), 2.56(2H,t,J=7.6Hz), 2.89(2H,t,J=7.2Hz) ,
4.31(3H,brs), 4.89-4.92(1H,m), 5.26(2H,s), 6.48-
6.50(2H,m), 7 . 17(1H,d,J=9.6Hz), 7.43-7.47(3H,m), 7.53-
7.55(2H,m), 7.63(2H,d,J=8.0Hz)
49(55)
NMR(90MHz,DMSO-d6) δ value: 0.91(6H,t,J=7.1Hz), 1.5-
1.8(4H,m), 2.5-3.0(4H,m), 4.2-4.5(1H,m), 5.36(2H,s),
6.4-6.6(2H,m), 7.17(1H,d,J=9.0Hz), 7.4-7.7(5H,m),
8.00(2H,d,J=8.0Hz), 12.08(1H,s), 12.55(2H,brs)
49(56)
NMR ( 90MHz, DMSO-d6) δ value: 0 . 8-2 . 0 (llH,m) , 2.4-
3.1(4H,m), 3.86(2H,d,J=5.1Hz), 5.35(2H,s), 6.4-
6.6(2H,m), 7.1-7.7(6H,m), 7.99(2H, d,J=8.1Hz) , 11.4-
12.9(3H,br)
49(57)
NMR(90MHz,DMSO-d6) δ value: 0.3-0.7(4H,m), 1.0-1.4(1H,m),
2.5-3.0(4H,m), 3.90(2H,d,J=6.8Hz), 5.35(2H,s), 6.5-
6.6(2H,m), 7.17(1H,d,J=9.0Hz), 7.4-7.7(5H,m),
7.99(2H,d,J=7.8Hz), 11.4-13.0(3H,br)
49(58)
NMR(90MHz, DMSO-d6) δ value: 1.2-1.9(12H,m), 2.5-
3.0(4H,m), 4.5-4.8(1H,m), 5.35(2H,s), 6.4-6.5(2H,m),
7.1-7.7(6H,m), 8.00(2H,d,J=8.4Hz), 11.4-13.0 (3H,br)
49(59)
NMR(400MHz,CDCl3) δ value: 1.34(6H,t,J=7.2Hz) , 1.60-

1.98(8H,m), 2.74(2H,t,J=7.6Hz), 3.08(2H,t,J=7.6Hz),
4.10-4.18(4H,m), 4.80-4.83(1H,m), 5.23(2H,s),
6.38(1H,dd,J=8.8,2.4Hz), 6.4 8(1H,d,J=2.4Hz),
6.94(1H,d,J=8.8Hz), 7.49-7.57(5H,m), 7.84-7.89(2H,m),
12.68(2H,brs)
49(60)
NMR(400MHz,DMSO-d6) δ value: 2.57(2H,t,J=7.6Hz),
2.91(2H,t,J=7.6Hz), 5.35(4H,s), 6.66(1H,dd,J=8.8,2.8Hz),
6.6?(1H,d,J=2.4Hz), 7.18(1H,d,J=8.4Hz),
7.48(1H,d,J=8.4Hz), 7.55-7.61(4H,m), 7.98(2H,d,J=8.4Hz),
8.66-8.70(2H,m), 8.84(1H,s), 11.82(3H,brs)
49 (61)
NMR(4 00MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.93-
1.96(2H,m), 2.46-2.56(4H,m), 2.80(2H,t,J=7.6Hz),
2.85(2H,t,J=7.6Hz), 3.81(3H,s), 4.90-4.93(1H,m),
5.13(2H,s), 6.48-6.50(2H,m), 6.99(1H,d,J=8.6Hz),
7.20(1H,d,J=8.6Hz), 7.28-7.33(2H,m), 7.46(1H,d,J=8.8Hz),
7.52-7.56(2H,m), 12.06(1H,s), 12.10(2H,brs)
49 (62)
NMR(4 00MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.95-
1.96(2H,m), 2.58(2H,t,J=7.2Hz), 2.92(2H, t, J=7.2Hz),
3.39(3H,s), 4.87-4.95(1H,m), 5.36(2H,s), 6.48-
6.50(2H,m), 7.17(1H,d,J=8.8Hz), 7.46(1H,d,J=8.8Hz),
7.54-7.56(2H,m), 7.63 (2H,d,J=8.0Hz), 7.99(2H,d,J=8.OHz),
12.05(1H,s), 12.17(2H,brs)
49 (63)
NMR(400MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.91-
1.99(2H,m), 2.56(2H,t,J=7.6Hz), 2.89(2H,t,J=7.6Hz),

3.42(1H,brs), 4.90-4.93(1H,m), 5.36(2H,s), 6.48-
6.50(2H,m), 7.23(1H,d,J=8.0Hz), 7.46(1H,d,J=8.4Hz),
7.55-7.58(2H,m), 7.62(1H,d,J=8.4Hz),
7.74(1H,dd,J=8.8,1.6Hz), 7.88(1H,s), 12.06(1H,s),
12.30(1H,brs)
49(64)
NMR(400MHz,DMSO-d6) δ value: 1. 60-1.74(6H,m), 1.93-
1.99(2H,m), 2.59(2H,t,J=7.6Hz), 2.68(3H,s),
2.93(2H,t,J=7.6Hz), 4.90-4.91(1H,m), 5.36(2H,s), 6.48-
6.50(2H,m), 7.20(1H,d,J=8.4Hz), 7.46(1H,d,J=8.4Hz),
7.56-7.57(2H,m), 7.67(2H,d,J=8.4Hz), 8.04(2H,d,J=8.0Hz),
12.07(1H,s), 12.18(1H,brs)
49(65)
NMR(400MHz,CDCl3) δ value: 1.63-1.95(8H,m),
2.71(2H,t,J=7.2Hz), 3.07(2H,t,J=7.2Hz), 3.38(3H,s),
3.39(3H,s), 4.77-4.85(1H,m), 5.21(2H,s), 5.31(2H,s),
5.35(2H,s), 6.38(1H,d,J=8.8Hz), 6.47(1H,d,J=2.0Hz),
6.97(1H,d,J=8.0Hz), 7.17-7.19(2H,m), 7.33(1H,s), 7.49-
7.55(3H,m), 12.67(2H,brs)
49(66)
NMR(400MHz,DMSO-d6) δ value: 1.58-1.74(6H,m), 1.94-
1.99(2H,m), 2.59(2H,t,J= 7.6 Hz), 2.94(2H, t, J=7.6Hz) ,
3.24(3H,s), 4.90-4.93(1H,m), 5.39(2H,s), 6.48-
6.50(2H,m), 7.20(1H,d,J=9.2Hz), 7.46(1H,d,J=8.4Hz),
7.56-7.58(2H,m), 7.72(2H,d,J=8.4Hz), 7.80(2H,d,8.4),
12.06(1H,s), 12.17(1H,brs)
49(67)
NMR(400MHz,DMSO-d6) δ value: 1.59-1.78(6H,m), 1.90-

2.01(2H,m), 2.58(2H,t,J=7.6Hz), 2.92 (2H,t,J=7.2Hz),
4.90-4.93(1H,m), 5.45(2H,s), 6.48-6.50(2H,m),
7.19(1H,d,J=9.2Hz), 7.45(1H,d,J=-8.8Hz), 7.56-
7.57(2H,m), 7.87-7.89(1H,m), 7.92-7.95(2H,m),
11.39(1H,brs), 12.03(1H,brs), 12.15 (1H,brs)
49(68)
NMR(400MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.94-
1.96{2H,m), 2.58(2H,t,J=7.4Hz), 2.94(2H,t,J=7.4Hz),
3.59(3H,s), 4.90-4.93(1H,m), 5.42(2H,s), 6.48-
6.53(2H,m), 7.10(1H,d,J=8.4Hz), 7.45(2H,d,J=8.4Hz),
7.55-7.61(3H,m), 7.83(1H,d,J=7.6Hz), 12.04(1H,s)
12.16(1H,brs)
49(69)
NMR(400MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.93-
1.96(2H,m), 2.58(2H,t,J=7.2Hz), 2.93(2H,t,J-7.2Hz),
4.12(3H,s), 4.90-4.93(1H,m), 5.43 6.50(2H,m), 7.13-7,27(2H,m), 7.46(1H,d,J=8.4Hz),
7.48(1H,d,J=8.8Hz), 7.55-7.60(2H,m), 7.75(1H,s),
7.79(1H,d,J=8.0Hz), 12.05 (1H,brs)
49(70)
NMR(400MHz, DMSO-d6) δ value: 1.53-1.75(6H,m), 1.90-
1.98(2H,m)f 2.47(2H,t,J=7.6Hz), 2.84(2H,t,J=7.6Hz),
4.87-4.91(1H,m), 5.26(2H,s), 6.47-6.50(2H,m), 7.17-
7.23(2H,m), 7.45(1H,d,J=8.8Hz), 7.53-7.55(2H,m),
7.76(1H,d,J=8.4Hz), 8.00(1H,s), 11.32(4H,brs)
49(71)
NMR(90MHz,CDCl3) δ value: 1. 04(6H, d, J=6.6Hz), 1.90-
2.32(1H,m), 2.54-2.70(2H,m) , 2.96-3.12(2H,m),

3.80(2H,d,J=6.6Hz), 5.24(2H,s), 6.41-6.49(2H,m),
7.03(1H,d,J=9.0Hz), 7.36-7.88(6H,m), 8 . 61 (1H, d, J=4 . 6Hz) ,
8.72(1H,s), 12.63(1H,s)
49(72)
NMR(400MHz,DMSO-d6) δ value: 1.58-1.75(6H,m), 1.92-
1.98(2H,m), 2.60(2H,t,J=7.6Hz) , 2.93(2H, t,J=7.6Hz) ,
4.89-4.92(1H,m), 5.44(2H,s), 6.48-6.50(2H,m),
7.22(1H,d,J=8.0Hz) , 7.46(1H,d,J=8.8Hz), 7.54-7.56(2H,m),
8.77(1H,s), 9.06(1H,s), 12.04(3H,brs)
49(73)
NMR( 90MHz, DMSO-d6) δ value: 1. 4-2 . 1 (8H,m) , 2 . 4-3 . 0 (4H,m) ,
4.8-5.0(1H,m), 5.31(2H,s), 6.4-6.6(2H,m),
6.77(1H,d,J=3.4Hz), 7.20(1H,d,J=3.4Hz), 7.3-7.6(4H,m),
12.06(1H,brs), 12.2-13.0(2H,br)
49(74)
NMR ( 90MHz, DMSO-d6) δ value: 1. 5-2 . 2 (8H,m) , 2 . 5-3 . 0 (4H,m) ,
4.8-5.0(1H,m), 5.62(2H,s), 6.4-6.6(2H,m), 7.2-7.6(4H,m),
8.54(1H,s), 12.06(1H,brs), 12.62(2H,brs)
49(75)
NMR(400MHz,DMSO-d6) δ value: 1.59-1.74(6H,m), 1.93-
1.99(2H,m), 2.57(2H,t,J=7.6Hz), 2.89(2H,t,J=7.6Hz),
3.53(1H,brs), 4.89-4.92(1H,m), 5.36(2H,s), 6.47-
6.51(2H,m), 7.25(1H,d,J=8.8Hz), 7.35(1H,dd,J=8.3,1.5Hz),
7.47(1H,d,J=8.5Hz) , 7.52-7.57(2H,m), 7.64(1H, d, J=8.0Hz) ,
7.74(1H,s), 8.29(1H,s), 12.08(1H,s)
49(76)
NMR(400MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.95-
1.96(2H,m), 2.57(2H,t,J=7.8Hz), 2.90(2H,t,J=7.4Hz),

3.00(3H,s), 3.68(2H,t,J=5.6Hz), 3 . 97(2H,t,J=5.6Hz),
4.88-4.95(1H,m), 5.26(2H,s), 6.48-6.50(2H,m),
7.20(1H,d,J=8.4Hz) , 7.44-7.75(7H,m), 12.06(1H,s),
12.12(1H,brs)
49(77)
NMR(4 00MHz,DMSO-d6) 6 value: 1.60-1.76(6H,m), 1.94-
1.96(2H,m), 2.66(2H,t,J=7.6Hz), 2.99(2H,t,J=7.6Hz),
4.90-4.92(1H,m), 5.79(2H,s), 6.49-6.51(2H,m),
7.29 (1H,d,J=8.4Hz) , 7.46(1H,d,J=8.4Hz), 7.56-7.60(2H,m),
8.02 (1H,dd,J=8.6,1.6Hz), 8.29(1H,d,J=8.0Hz),
8.53(1H,d,J=1.6Hz), 12.03(3H,brs)
49(78)
NMR(400MHz,CDCl3) δ value: 1.59-1.67(2H,m), 1.75-
1.97(6H,m), 2.72(2H,t,J=7.6Hz), 3.03(2H,t,J=7.6Hz),
4.78-4.83(1H,m), 5.06(2H,s), 5.98(2H,s),
6.38(1H,dd,J=9.0, 2.4Hz), 6.4 7(1H,d,J=2.4Hz),
6.82(1H,d, J=8.0Hz) , 6.87-6.90(2H,m), 6.96(1H,d,J=9.2Hz),
7.50(1H,d,J=9.2Hz), 7.52-7.56(2H,m), 12.69(2H,brs)
49(79)
NMR(4 00MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.93-
1.98(2H,m), 2.55(2H,t,J=7.6Hz), 2.87(2H,t,J=7.2Hz),
4.08(2H,t,J=8.2Hz), 4.45(2H,t,J=8.0Hz), 4.90-4.93(1H,m),
5.23(2H,s), 6.48-6.50(2H,m), 7.20(1H,d,J=8.4Hz),
7.52(1H,d,J=8.8Hz), 7.54-7.56(4H,m), 7.62(2H,d,J=8.8Hz) ,
12.05(1H,s), 12.14(1H,brs)
49(80)
NMR(400MHz, DMSO-d6) δ value: 1.60-1.77(6H,m), 1.94-
1.97(2H,m), 2.51(2H,t,J=7.6Hz), 2.86(2H, t, J=7.6Hz) ,

4.90-4.92(1H,m), 5.59(2H,s), 6.49-6.51(2H,m),
7.40(1H,d,J=8.4Hz), 7.49(1H, d, J=8.4Hz) , 7.55(1H,s),
7.60(1H,dd,J=8.4,1.6Hz), 7.97(1H,d,J=8.8Hz), 8.02(1H,s),
8.16(1H,d,J=8.8Hz), 8.56(1H,s), 12.07(1H,s),
12.54 (2H,brs)
49(81)
NMR(4 00MHz,DMSO-d6) 6 value: 0 . 98(6H,d,J=6.8Hz), 1.98-
2.09(1H,m), 2.59(2H,t, J=7.6Hz) , 2 . 90(2H,t,J=7.6Hz),
3.83(2H,d,J=6.4Hz), 5.62(2H,s), 6.52-6.54(2H,m),
7.29(1H,d,J=8.8Hz), 7.46(1H,d,J=9.5Hz), 7.50-7.60(2H,m),
7.71(1H,s), 7.90(1H,dd,J=8.5,1.7Hz), 8 . 10(1H, d,J=8.6Hz),
8.47(1H,s), 11.99(1H,s), 12.58(2H,brs)
49(82)
NMR(400MHz,DMSO-d6) δ value: 1. 30(6H,d,J=6.1Hz) ,
2.59(2H,t,J=7.5Hz), 2.90(2H,t,J=7.5Hz), 4.69-4.76(1H,m),
5.62(2H,s), 6.48-6.52(2H,m), 7.29(1H,d,J=8.8Hz),
7.45(1H,d,J=8.8Hz), 7.55-7.58(2H,m), 7.71(1H,s),
7.90(1H,dd,J=8.4,1.7Hz) , 8.0 9(1H,d,J=8.5Hz),
8.47(1H,d,J=1.0Hz), 12.02(1H,s), 12.58(2H,brs)
49(83)
NMR (400MHz,DMSO-d6) δ value: 1.60-1.74(6H,m), 1.93-
1.96(2H,m), 2.59 (2H,t,J=7.6Hz) , 2.91(2H,t,J=7.6Hz),
4.88-4.94(1H,m), 5.62(2H,s), 6.47-6.50(2H,m),
7.29(1H,d,J=8.8Hz), 7.46(1H,d,J=8.8Hz), 7.56-7.58(2H,m),
7.72(1H,s), 7.90(1H,dd,J=8.8,1.6Hz), 8.10(1H,d,J=8.4Hz),
8.47(1H,d,J=1.2Hz), 12.04(1H,s), 12.56(2H,brs)
49(84)
NMR(90MHz,DMSO-d6) δ value: 0.99(6H,d,J=6.6Hz), 1.8-

3.0(5H,m), 3.84(2H,d,J=6.6Hz), 5.50(2H,s), 6.4-
6.5(2H,m), 7.2-7.8(6H,m), 12.00(1H,s), 11.7-13.2 (2H,br)
49(85)
NMR(90MHz,DMSO-d6) δ value: 0.98(6H,d,J=6.7Hz), 1.90-
2.18(1H,m), 2.48-2.61(2H,m), 2.83-2.90(2H,m),
3.84(2H,d,J=6.7Hz), 5.41(2H,s), 6.49-6.55(2H,m), 7.16-
7.54(4H,m), 8.08(2H,s), 8.83(1H,s), 11.98(3H,brs)
49(86)
NMR(400MHz,DMSO-d6) δ value: 1.59-1.74(6H,m), 1.93-
1.96(2H,m), 2.58(2H,t,J=7.4Hz), 2.91(2H,t,J=7.4Hz),
4.89-4.91 (1H,m) , 5.38(2H,s), 6 . 47-6 . 50.(2H,m) ,
7.23(1H,d,J=9.2Hz), 7.46(1H,d,J=8.8Hz), 7.55-7.61(3H,m),
8.07(2H,d,J=8.8Hz), 8.11(1H,s), 12.05(3H,brs)
49(87)
NMR (400MHz,DMSO-d6) δ value: 1. 60-1.74(6H,m) , 1.94-
1.99(2H,m), 2.58(2H,t,J=7.6Hz) , 2.93(2H,t,J=7.6Hz) ,
4.90-4.91(1H,m), 5.36(2H,s), 6.48-6.50(2H,m),
7.18(1H,d,J=9.2Hz), 7.46(1H,d,J=8.4Hz), 7.55-7.56(2H,m),
7.69(2H,d,J=8.0Hz) , 7.87(2H,d,J=8.4Hz) , 12.06(1H,s),
12.17(1H,brs), 12.99(1H,brs)
49(88)
NMR(90MHz,CDCl3) δ value: 0 . 2-3 .1 (15H,m) , 3 . 1-4 . 5 (4H,m) ,
4.7-5.3(1H,m), 6.0-8.0(6H,m), 8.83(1H,s), 12.2-
12.4(1H,br), 12.63(1H,s)
49(89)
NMR(90MHz,DMSO-d6) δ value: 0.99 ( 6H,d,J=6.4Hz), 1.90-
2.19(1H,m), 3.13-3.20(4H,m), 3.84(2H,d,J=6.4Hz),
5.36(2H,s), 6.47-6.55(2H,m), 7.15-7.66(6H,m),

8.0 0(2H,d,J=7.9Hz), 11.95(3H,brs)
49(90)
NMR(90MHz,DMSO-d6) δ value: 0.99(6H,d,J=6.8Hz), 1.92-
2.20(1H,m), 2.50-2.66(2H,m), 2 . 85-3.03(2H,m),
3.84 (2H,d,J=6.8Hz), 5.38(2H,s), 6.50-6.57(2H,m),
7.22(1H,d,J=8.2Hz), 7.42-7.77(5H,m), 8.10(2H,d,J=8.0Hz),
12.01(1H,s), 12.14(2H,brs)
49(91)
NMR(90MHz,DMSO-d6) 8 value: 1.02 ( 6H,d,J=6.6Hz) , 1.6-
3.4(llH,m), 3.85(2H,d,J=5.6Hz), 4.2-5.4(4H,br), 6.4-
6.5(2H,m), 7.04(1H,d,J=9.0Hz), 7.4-7.5(3H,m)
49(92)
NMR(90MHz,CDC13) 5 value: 1.06(6H,d,J=6.8Hz), 1.9-
2.4(1H,m), 2.6-3.1(6H,m), 3.82(2H,d,J=6.4Hz),
4.15(2H,t,J=7.0Hz), 4.5-5.9(4H,br), 6.3-6.5(2H,m),
6.63(2H,d,J=8.3Hz), 6.8 8(1H,d,J=9.3Hz),
7.05(2H,d,J=8.5Hz), 7.4-7.6(3H,m)
49(93)
NMR(90MHz,CDCl3) 5 value: 1.07(6H,d,J=6.6Hz), 1.4-
2.3(9H,m), 2.6-3.1(4H,m), 3.82(2H,d,J=6.1Hz), 4.7-
4.9(1H,m), 6.3-6.5(2H,m), 6.89(1H,d, J=9.3Hz) , 7.4-
7.6(3H,m), 8.3-9.6(1H,br), 12.69(1H,brs)
49(94)
NMR(90MHz,DMSO-dg) δ value: 1.03(6H,d,J=6.6Hz), 1.8-
5.0(10H,m), 5.30(2H,s), 6.5-6.8(2H,m), 6.9-7.3(1H,m),
7.4-7.8(3H,m), 8.01(2H,s), 8.71(1H,s)
49(95)
NMR(90MHz,CDCl3) 5 value: 1.07(6H,d,J=6.6Hz), 1.9-

3.1(5H,m), 2.73(3H,s), 3.82(2H,d,J=6.1Hz), 5.0-
6.2(1H,br), 5.20(2H,s), 6.4-6.8(2H,m),
6.89(1H,d,J=9.3Hz), 7.17(1H,s), 7.5-7.7(3H,m),
12.64(1H,s)
49 (96)
NMR(90MHz,CDCl3) 5 value: 1. 07 ( 6H,d,J=6.6Hz), 1.90-
2.43(1H,m), 2.61-3.10(4H,m), 3.82(2H,d,J=6.4Hz),
5.10(2H,s), 6.43(1H,dd,J=8.8,2.4Hz) , 6.56(1H,d,J=2.4Hz),
6.89(1H,d,J=9.0Hz), 7.34-7.76(5H,m), 8.57-8.68(2H,m),
9.0-10.0(1H,br), 12.32 (2H,brs)
49 (97)
NMR(90MHz,CDC13) δ value: 1.08(6H,d,J=6.8Hz), 2.03-
2.32(1H,m), 2.51-2.69(2H,m), 2.91-3.06(2H,m),
3.85(2H,d,J=6.1Hz), 5.22(2H,s), 5.63(2H,brs), 6.48-
6.58(2H,m), 6.93(1H,d,J=9.0Hz), 7.47-7.65(5H,m),
8.07(2H,d,J=8.1Hz), 12.61(1H,s)
49(98)
NMR(90MHz,DMSO-d5) δ value: 1.03(6H,d,J=6.6Hz), 1.9-
3.0(5H,m), 3.88(2H,d,J=6.1Hz), 5.27(2H,s), 6.5-
6.7(2H,m), 7.07(1H,d,J=9.3Hz), 7.3-8.0(6H,m),
8.60(1H,d,J=4.9Hz), 11.4-12.4(2H,br)
Example 50
0.13 g of hydroxylamine hydrochloride was
dissolved in 3 mL of methanol, to which 0.36 g of a 28%
solution of sodium methoxide in methanol was added at
room temperature, and then this mixture was stirred for
30 minutes. The mixture thus obtained was added to
0.31 g of methyl 3-{2-[(4-cyanobenzyl)oxy]-5-[4-

(cyclopentyloxy)-2-hydroxybenzoyl]phenyl}propanoate
which was dissolved in a mixed solution of 5 mL of
methanol and 5 mL of tetrahydrofuran, and then stirred
for 14 hours at room temperature and subsequently for
another one hour at 50°C. The reaction mixture was
cooled to room temperature, to which water and ethyl
acetate were successively added, and the organic phase
was separated therefrom. After the resultant organic
phase was washed with water and a saturated sodium
chloride solution successively, this washed phase was
dried over anhydrous sodium sulfate and the solvent was
distilled out under reduced pressure. 0.42 g of the
resultant residue was dissolved in 2 mL of N,N-
dimethylformamide, to which 55 mg of pyridine and 0.12
g of 2-ethylhexyl chloroformate were added at room
temperature, then this mixture was stirred for 5
minutes at the same temperature. The reaction mixture
was added to a mixed solution of water and ethyl
acetate, and the organic phase was separated therefrom.
After the resultant organic phase was washed with water
and a saturated sodium chloride solution successively,
this washed phase was dried over anhydrous sodium
sulfate and the solvent was distilled out under reduced
pressure. The resultant residue to which 4 mL of
xylene was added was stirred for one hour while heating
it under reflux. The reaction mixture was cooled to
room temperature, and purified by silica gel column
chromatography [eluent; hexanerethyl acetate=1:1] to

yield 0.19 g of methyl 3-(5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-{[4-(5-oxo-4,5-dihydro-l,2,4-
oxadiazol-3-yl)benzyl]oxy}phenyl)propanoate as yellow
solid.
NMR(400MHz,CDCl3) δ value: 1. 61-1. 98 ( 8H, m) ,
2.70(2H,t,J=7.6Hz), 3.09(2H,t,J=7.6Hz), 3.68(3H,s),
4.81-4.84(1H,m), 5.27(2H,s), 6.37(1H,dd,J=8.8,2.4Hz) ,
6.48(1H,d,J=2.4Hz), 6 . 94(1H, d,J=8.0Hz), 7.49-7.56(3H,m),
7.62(2H,d,J=8.8Hz), 7.84(2H,d,J=8.4Hz), 11.01(1H,brs),
12.68(1H,s)
Example 51
1.85 g of 4-({2-(2-carboxyethyl)-4-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]phenoxy}methyl)
benzoic acid was dissolved in a mixed solvent of 19 mL
of methylene chloride and 0.1 mL of N,N-
dimethylformamide, to which 1.6 mL of oxalyl chloride
was added dropwise over 10 minutes at room temperature,
and then this mixture was stirred for one hour at room
temperature. After 19 mL of ethanol was added dropwise
to the reaction mixture over 10 minutes and this
mixture was stirred for one hour at room temperature
and for another 30 minutes at 50°C, the reaction mixture
was cooled to room temperature to which water was added,
and then the organic phase was separated therefrom.
After the resultant organic phase was washed with water
and a saturated sodium chloride solution successively,
this washed phase was dried over anhydrous magnesium
sulfate and the solvent was distilled out under reduced

pressure. The resultant residue was purified by silica
gel column chromatography [eluent; hexane:ethyl
acetate=4:l] to yield 2.00 g of ethyl 4-{[4-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-ethoxy-3-
oxopropyl)phenoxy]methyl} benzoate as yellow oil.
NMR(400MHz,CDCl3) δ value: 1. 22 (3H, t, J=7 .2Hz) ,
1.41(3H,t,J=7.2Hz), 1.62-1.67(2H,m), 1.78-1.98(6H,m),
2.67(2H,t,J=7.6Hz), 3.07(2H,t,J=7.6Hz),
4.12(2H,q,J=7.2Hz), 4.40(2H,q,J=7.2Hz), 4.80-4.83(1H,m),
5.25(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.48(1H,d,J=2.4Hz),
6.93(1H,d,J=8.4Hz), 7.49-7.56(5H,m), 8.09(2H,d,J=8.0Hz),
12.69(1H,s)
Example 52
The following compounds were obtained in a
similar manner as in Example 51.
(1) ethyl 4-{[2-(3-ethoxy-3-oxopropyl)-4-(2-
hydroxy-4-isobutoxybenzoyl)phenoxy]methyl} benzoate
NMR(90MHz,CDCl3) δ value: 1. 03 ( 6H, d, J=6 . 6Hz) ,
1.22(3H,t,J=7.4Hz), 1.40(3H,t,J=7.4Hz), 1. 98-2.25(1H,m),
2.58-2.74(2H,m), 3.00-3.16(2H,m), 3.78(2H,d,J=6.7Hz),
4.12(2H,q,J=7.4Hz) , 4.39(2H,q,J=7.4Hz) , 5.24(2H,s),
6.34-6.48(2H,m), 6.93(1H,d,J=8.8Hz), 7.47-7.57(5H,m),
8.09(2H,d,J=8.lHz), 12.65(1H,s)
(2) ethyl 4-{[4-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-(3-ethoxy-3-
oxopropyl)phenoxy]methyl}-2-methoxybenzoate
NMR(400MHz,CDCl3) δ value: 1. 22 (3H, t, J=7 . 2Hz) ,
1.39(3H,t,J=7.2Hz), 1.61-1.66(2H,m), 1.78-1.96(6H,m),

2.68(2H,t,J=7.8Hz), 3.08(2H,t,J=7.8Hz) , 3.93(3H,s),
4.11(2H,q,J=7.2Hz), 4.37(2H,q,J=7.2Hz), 4.80-4.82(1H,m),
5.21(2H,s), 6.37(1H,dd,J=9.2,2.4Hz), 6.48(1H,d, J=2.8Hz),
6.92(1H,d,J=8.4Hz), 7.03(1H,dd,J=8.0,1.2Hz), 7.09(1H,s),
7.49-7.56(3H,m), 7.83(1H,d,J=7.6Hz), 12.69(1H,s)
Example 53
1.90 g of ethyl 4-{[4-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-(3-ethoxy-3-oxopropyl)phenoxy]methyl}
benzoate was dissolved in 25 mL of ethanol, to which
0.14 g of lithium hydroxide monohydrate dissolved in 5
mL of water was added dropwise over 5 minutes at room
temperature, and then this mixture was stirred for 1.5
hour at the same temperature. Another 0.14 g of
lithium hydroxide monohydrate dissolved in 5 mL of
water was added dropwise over 5 minutes, then this
mixture was stirred for 20 hours. The reaction mixture
to which water and chloroform were successively added
was adjusted to pH 2 with 6M hydrochloric acid, then
the organic phase was separated therefrom. After the
resultant organic phase was washed with water and a
saturated sodium chloride solution successively, this
washed phase was dried over anhydrous magnesium sulfate
and the solvent was distilled out under reduced
pressure. The resultant residue was purified by silica
gel column chromatography [eluent; hexane:ethyl
acetate=l:l] to yield 0.70 g of 3-(5-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]-2-{[4-
(ethoxycarbonyl)benzyl]oxy}phenyl) propanoic acid as

light yellow solid.
NMR(400MHz,CDCl3) δ value: 1.40(3H,t,J=7.2Hz), 1.55-
1.66(2H,m), 1.74-1.98(6H,m), 2.75(2H,t,J=7.6Hz),
3.07 (2H,t,J=7.6Hz), 4.39(2H,q,J=7.2Hz), 4.78-4.81(1H,m),
5.23(2H,s), 6.38(1H,dd,J=9.0,2.8Hz), 6.47(1H,d,J=2.8Hz),
6.93(1H,d,J=8.4Hz), 7.48-7.57(5H,m), 8.08(2H,d,J=8.4Hz),
12.68 (2H,brs)
Example 54
The following compounds were obtained in a
similar manner as in Example 53.
(1) 3-(5-(2-hydroxy-4-isobutoxybenzoyl)-2-
{[4-(methoxycarbonyl)benzyl]oxy}phenyl) propanoic acid
NMR( 90MHz,CDC13) δ value: 1.02(6H,d,J=6.7Hz), 1.98-
2.24(1H,m), 2.72-2.83(2H,m), 3.00-3.18(2H,m),
3.77(2H,d,J=6.3Hz), 3.93(3H,s), 5.24(2H,s), 6.38-
6.48(2H,m), 6.93(1H,d,J=9.3Hz), 7.46-7.58(5H,m),
8.0 9(2H,d,J=8.3Hz), 12.64(2H,brs)
(2) 3-(5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-{[4-(ethoxycarbonyl)-3-
methoxybenzyl]oxy}phenyl) propanoic acid
NMR(400MHz,CDCl3) δ value: 1.38(3H,t,J=6.8Hz), 1.61-
1.66(2H,m), 1.77-1.95(6H,m), 2.75(2H,t, J=7.6Hz),
3.08 (2H,t,J=7.6Hz) , 3.92(3H,s), 4.36 (2H,q,J=6.8Hz),
4.79-4.82(1H,m), 5.20(2H,s), 6.38(1H,dd,J=8.8,2.4Hz),
6.4 7(1H,d,J=2.4Hz), 6.93(1H,d,J=8.4Hz),
7.02(1H,d,J=8.0Hz), 7.08(1H,s), 7.48-7.57(3H,m),
7.8 3(1H,d,J=7.6Hz), 12.67(2H,brs)
(3) 3-[2-{[4-(ethoxycarbonyl)benzyl]oxy}-5-

(2-hydroxy-4-isobutoxybenzoyl)phenyl] propanoic acid
NMR( 90MHz, CDCl3) δ value: 1.02(6H,d,J=6.8Hz),
1.40(3H,t,J=7.1Hz), 1.96-2.26(1H,m), 2 . 71-2.82(2H,m),
3.00-3.08(2H,m), 3.77(2H,d,J=6.4Hz), 4.39(2H,q,J=7.1Hz),
5.24(2H,s), 6.38-6.48(2H,m), 6 . 93(1H,d,J=9.3Hz), 7.44-
7.58(5H,m), 8.09(2H,d,J=3.4Hz), 12.64(2H,brs)
Example 55
1.00 g of methyl 3-{5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-hydroxyphenyl} propanoate, 0.56 g of
methyl 4-(hydroxymethyl)-2-methylbenzoate, and 0.82 g
of triphenylphosphine were dissolved in 10 mL of
tetrahydrofuran, to which a solution of 0.6 mL of
diisopropyl azodicarboxylate in 1 mL of tetrahydrofuran
was added dropwise at room temperature, and then this
mixture was stirred for one hour at the same
temperature. The reaction mixture was added to a
mixture of ethyl acetate and water, then the organic
phase was separated therefrom. After the resultant
organic phase was washed with water and a saturated
sodium chloride solution successively, this washed
phase was dried over anhydrous magnesium sulfate and
the solvent was distilled out under reduced pressure.
The resultant residue was purified by silica gel column
chromatography [eluent; hexane:ethyl acetate=4:l] to
yield 1.12 g of methyl 4-{ [4-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-(3-methoxy-3-oxopropyl)-
phenoxy]methyl}-2-methylbenzoate as yellow oil.
NMR(400MHz,CDCl3) δ value: 1. 61-1. 67 (2H,m) , 1.76-

1.98(6H,m), 2.64(3H,s), 2.69(2H,t,J=7.6Hz),
3.07(2H,t,J=7.6Hz), 3.67(3H,s), 3.91(3H,s), 4.80-
4.83(1H,m), 5.19(2H,s), 6.37(1H,dd,J=9.2,2.4Hz),
6.48(1H,d,J=2.4Hz), 6.92(1H,d,J=8.4Hz), 7.30-7.32(2H,m),
7.50-7.55(3H,m), 7.96(1H,d,J=8.8Hz), 12.70(1H,s)
Example 5 6
0.95 g of tert-butyl 4-{[4-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-methoxy-3-
oxopropyl)phenoxy]methyl}-IH-pyrazole-1-carboxylate was
dissolved in 4.8 rtiL of chloroform, to which 10 mL of 4M
hydrogen chloride/ethanol was added dropwise at room
temperature, and then this mixture was stirred for one
hour at the same temperature. The reaction mixture was
added to water, then the organic phase was separated
therefrom. After the resultant organic phase was
washed with water and a saturated sodium chloride
solution successively, this washed phase was dried over
anhydrous magnesium sulfate and the solvent was
distilled out under reduced pressure. The resultant
residue was purified by silica gel column
chromatography [eluent; hexanerethyl acetate=l:l] to
yield 0.67 g of ethyl 3-[5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-(1H-pyrazol-4-ylmethoxy)phenyl]
propanoate as light yellow oil.
NMR(400MHz,CDC13) δ value: 1.22(3H,t,J=7.2Hz), 1.62-
1.66(2H,m), 1.78-1.96(6H,m), 2.61(2H,t,J=7.6Hz),
2.99(2H,t,J=7.6Hz), 4.11(2H,q,J=7.2Hz), 4.81-4.83(1H,m),
5.13(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.48(1H,d,J=2.4Hz) ,

7.00(1H,d,J=8.3Hz), 7.52-7.57(3H,m), 7.71(2H,s),
12.71 (2H,brs)
Example 57
The following compounds were obtained in a
similar manner as in Example 56.
(1) methyl 3-{2-{[4-
(aminosulfonyl)benzyl]oxy}-5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]phenyl] propanoate
NMR(400MHz,CDCl3) 6 value: 1.62-1.68(2H,m), 1.77-
1.98(6H,m), 2.68(2H,t,J=7.2Hz), 3.07(2H,t,J=8.0Hz),
3.68(3H,s), 4.81(3H,brs), 5.26(2H,s),
6.37(1H,dd,J=9.2,2.4Hz), 6.4 8(1H,d,J=2.4Hz),
6.92(1H,d,J=8.4Hz), 7.49-7.55(3H,m), 7.61(2H,d,J=8.4Hz),
7.99(2H,d,J=8.4Hz), 12.67(1H,s)
(2) methyl 3-[5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-({4-
[(methylsulfonyl)amino]benzyl}oxy)phenyl] propanoate
NMR(4 00MHz,CDC13) δ value: 1.55-1.65(2H,m), 1.78-
2.05(6H,m), 2.67(2H,t,J=7.2Hz), 3.05(3H,s),
3.02(2H,t,J=7.2Hz), 3.67(3H,s), 4.80-4.83(1H,m),
5.30(2H,s), 6.37(1H,dd,J=9.2,2.4Hz), 6.48(1H,d,J=2.4Hz),
6.53(1H,s), 6.96(1H,d,J=9.2Hz), 7.26(2H,d,J=8.4Hz),
7.43(2H,d,J=8.4Hz), 7.50-7.55(3H,m), 12.69 (1H,s)
(3) ethyl 3-{2-(1H-benzimidazol-5-
ylmethoxy)-5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]phenyl} propanoate was obtained.
NMR(4 00MHz,DMSO-d6) δ value: 1.10(3H,t,J=7.2Hz), 1.60-
1.71(6H,m), 1.93-1.98(2H,m), 2.63(2H,t,J=7.6Hz),

2.93(2H,t,J=7.6Hz), 4.01(2H,q,J=7.2Hz), 4.89-4.92(1H,m),
5.45(2H,s), 6.47(1H,dd,J=8.8,2.4Hz), 6.51(1H, d, J=2.4Hz) ,
7.24(1H,d,J=8.4Hz), 7.43(1H,d,J=8.8Hz), 7.54-7.58(2H,m),
7.69(1H,d,J=7.6Hz), 7.90(1H,d,J=8.4Hz), 7.96(1H,s),
8.33(1H,s), 9.49(1H,s), 11.98(1H,s)
(4) methyl 3-{5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-[(2,4-dioxo-l,2,3,4-tetrahydro-6-
quinazolinyl)methoxy]phenyl} propanoate was obtained.
NMR(400MHz, CDC13) δ value: 1.61-1.67(2H,m), 1.77-
1.98(6H,m), 2.67(2H,t,J=7.2Hz), 3.05(2H,t,J=7.6Hz),
3.66(3H,s), 4.80-4.83(1H,m), 5.21(2H,s),
6.37(1H,dd,J=9.0,2.4Hz), 6.4 8(1H,d,J=2.4Hz),
6.96(1H,d,J=9.2Hz) , 7.13(1H,d,J=8.4Hz),
7.50(1H,d,J=9.2Hz) , 7.53-7.55(2H,m), 7.76(1H,d,J=6.4Hz) ,
8.18(1H,s), 8.27(1H,brs), 8.52(1H,brs), 12.69(1H,s)
(5) methyl 3-[5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-({4-
[(methylamino)sulfonyl]benzyl}oxy)phenyl} propanoate
NMR(400MHz,CDCl3) δ value: 1. 63-1'. 68 (2H,m) , 1.76-
1.98(6H,m), 2.68-2.71(5H,m), 2.88(2H,brs) ,
3.08(2H,t,J=7.6Hz), 3.68(3H,s), 4.80-4.84(1H,m),
5.26(2H,s), 6.38(1H,dd,J=9.0,2.4Hz), 6.49(1H,d,J=2.4Hz),
6.93 (1H,d,J=8.4Hz), 7.49-7.55(3H,m), 7.61(2H,d,J=8.4Hz),
7.92(2H,d,J=8.8Hz)
(6) methyl 3-[5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-({ 4-
[(methylamino)carbonyl]benzyl}oxy)phenyl] propanoate
NMR(400MHz,CDCl3) δ value: 1.62-1.66(2H,m), 1.78-

1.96(6H,m), 2.68(2H,t,J=7.6Hz), 3.05-3.08(5H,m),
3.38(1H,brs), 3.67(3H,s), 4.80-4.84(1H,m), 5.23(2H,s),
6.33 (1H,brs), 6.37(1H,dd,J=9.0,2.4Hz),
6.48(1H,d,J=2.4Hz), 6.93(1H,d,J=8.4Hz), 7.49-7.54(5H,m),
7.79(2H,d,J=8.0Hz)
(7) methyl 3-{5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-[(l,3-dioxo-2,3-dihydro-lH-isoindol-
5-yl)methoxy]phenyl} propanoate
NMR(400MHz,CDCl3) δ value: 1. 62-1. 67 (2H,m) , 1.77-
2.00(6H,m), 2.70(2H,t,J=7.6Hz), 3.09(2H,t,J=7.6Hz),
3.68(3H,s), 4.81-4.84(1H,m), 5.33(2H,s),
6.38(1H,dd,J=9.0,2.4Hz), 6.4 8(1H,d,J=2.4Hz),
6.93(1H,d,J=8.4Hz), 7.49-7.56(3H,m), 7.72(2H,brs),
7.86(1H,d,J=7.6Hz), 7.92-7.95(2H,m)
Example 58
0.50 g of methyl 3-[5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-(1H-pyrazol-4-ylmethoxy)phenyl]
propanoate was dissolved in 5 mL of 1,4-dioxane, to
which 5 mL of 6M hydrochloric acid was added at room
temperature, and then this mixture was stirred for 7
hours at the same temperature. The reaction mixture
was added to a mixture of ethyl acetate and water, then
the organic phase was separated therefrom. After the
resultant organic phase was washed with water and a
saturated sodium chloride solution successively, this
washed phase was dried over anhydrous magnesium sulfate
and the solvent was distilled out under reduced
pressure. The resultant residue was purified by silica

gel column chromatography [eluent;
chloroform:ethanol=20:1] to yield 0.33 g of 3-[5-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]-2-(1H-pyrazol-4-
ylmethoxy)phenyl] propanoic acid as yellow oil.
NMR(400MHz,CDCl3) δ value: 1.60-1.67(2H,m), 1.76-
1.98(6H,m), 2.66(2H,t,J=7.6Hz), 3.02(2H,t,J=7.6Hz),
4.80-4.83(1H,m) , 5.11(2H,s),
5.7 5(2H,brs),6.38(1H,dd,J=8.8,2.4Hz),
6.4 8(1H,d,J=2.4Hz), 7.01(1H,d,J=8.0Hz),
7.52(1H,d,J=8.8Hz), 7.55-7.58(2H,m), 7.71(2H,s)
Example 5 9
1.00 g of 4-{[4-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-(3-ethoxy-3-oxopropyl)phenoxy]methyl}
benzoic acid was dissolved in 12 mL of tetrahydrofuran,
to which 1.03 g of 1,1'-carbonyldiimidazole was added
at room temperature, and then this mixture was stirred
for one hour while heating it under reflux. After the
reaction mixture was cooled to room temperature, 1.07 g
of methanesulfonamide and 1.7 mL of 1,8-
diazabicyclo[5.4.0]undec-7-ene were added to this
mixture, which was stirred for 30 minutes at room
temperature and for another 30 minutes at 50°C. The
reaction mixture which was cooled to room temperature
was added to a mixture of methylene chloride and water,
and adjusted to pH 2 with 6M hydrochloric acid, and
then the organic phase was separated therefrom. After
the resultant organic phase was washed with water and a
saturated sodium chloride solution successively, this

washed phase was dried over anhydrous magnesium sulfate
and the solvent was distilled out under reduced
pressure. The resultant residue was purified by silica
gel column chromatography [eluent; hexane:ethyl
acetate=l:2] to yield 0.65 g of ethyl 3-{5-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(4-
{[(methylsulfonyl)amino]carbonyl}benzyl)oxy]phenyl}
propanoate as light yellow solid.
NMR(400MHz,CDCl3) δ value: 1.23 (3H,t,J=7.2Hz), 1.63-
1.68(2H,m), 1.76-1.96(6H,m), 2.67(2H,t,J=7.6Hz),
3.07(2H,t,J=7.6Hz) , 3.46(3H,s), 4.13(2H,q, J=7.2Hz) ,
4.81-4.83(1H,m), 5.26(2H,s), 6.37(1H, dd, J=9.2, 2.4Hz) ,
6.48(1H,d,J=2.4Hz), 6.92(1H,d,J=8.0Hz), 7.48-7.61(5H,m),
7.89(2H,d,J=8.4Hz) , 8.57(1H,brs), 12.67(1H,s)
Example 60
The following compounds were obtained in a
similar manner as in Example 59.
(1) methyl 3-{5-(2-hydroxy-4-
isobutoxybenzoyl)-2-[(4-{[(methylsulfonyl)-
amino]carbonyl}benzyl)oxy]phenyl} propanoate
NMR(90MHz, CDC13) δ value: 1.03(6H,d,J=6.6Hz), 1.96-
2.26(1H,m), 2.60-2.75(2H,m), 2.98-3.15(2H,m),
3.45(3H,s), 3.67(3H,s), 3.79(2H,d,J=6.3Hz), 5.25(2H,s),
6.38-6.51(2H,m), 6.92(1H,d,J=9.4Hz), 7.46-7.62(5H,m),
7.92 (2H,d,J=8.6Hz), 9.00(1H,brs), 12.63(1H,s)
(2) ethyl 3-[2-({4-[(hydroxyamino)-
carbonyl]benzyl}oxy)-5-(2-hydroxy-4-
isobutoxybenzoyl)phenyl]propanoate

NMR(90MHz,DMSO-d6) δ value: 0.95-1.20(9H,m), 1.92-
2.16(1H,m), 2.47-2.63(2H,m), 2.82-2.94(2H,m), 3.80-
4.06(4H,m), 5.32(2H,s), 6.52-6.56(2H,m), 7.23-
7.85(8H,m), 9.05(1H,s), 11.24(1H,s), 11.93(1H,s)
(3) methyl 3-[2-{[4-
(aminocarbonyl)benzyl]oxy}-5-(2-hydroxy-4-
isobutoxybenzoyl)phenyl]propanoate
NMR(90MHz,DMSO-d6) δ value: 0.99(6H,d,J=6.6Hz) , 1.85-
2.23(1H,m), 2.46-2.95(4H,m), 3.58(3H,s),
3.83(2H,d,J=6.4Hz), 5.32(2H,s), 6.53-6.56(2H,m), 7.13-
7.60(8H,m), 7.92(2H,d,J=7.8Hz), 11.96 (1H,brs)
Example 61
1.85 g of methyl 3-[5-(4-bromo-2-
hydroxybenzoyl)-2-hydroxyphenyl] propanoate was
dissolved in 20 mL of methylene chloride, to which 1.5
mL of triethylamine and 1.0 mL of acetic anhydride were
successively added at 5 to 10°C, and then this mixture
was stirred for 2 hours at room temperature. Then,
water and a saturated aqueous solution of sodium
hydrogen carbonate were added to this mixture, and the
organic phase was separated therefrom. After the
resultant organic phase was washed with water and 1M
hydrochloric acid successively, this washed phase was
dried over anhydrous magnesium sulfate, and the solvent
was distilled out under reduced pressure to yield 2.46
g of methyl 3-{2-(acetyloxy)-5-[2-(acetyloxy)-4-
bromobenzoyl]phenyl} propanoate as brown oil.
NMR(400MHz,CDCl3) δ value: 1.96(3H,s), 2.37(3H,s),

2.59(2 H,t,J=7.8Hz), 2.90(2H,t,J=7.8Hz), 3.67(3H,s),
7.14(1H,d,J=8.0Hz), 7.39-7.51(3H,m), 7.62-7.66(2H,m)
Example 62
4-{[4-[2-(acetyloxy)-4-isobutoxybenzoyl]-2-
(3-methoxy-3-oxopropyl)phenoxy]methyl} benzoic acid was
obtained in a similar manner as in Example 61.
NMR(90MHz,CDC13) δ value: 1.04(6H,d,J=6.7Hz), 1.86-
2.25(4H,m), 2.65-2.75(2H,m), 2.99-3.14(2H,m),
3.67(3H,s), 3.78(2H,d,J=6.4Hz), 5.25(2H,s), 6.67-
6.94(3H,m), 7.42-7.65(5H,m), 8.15(2H,d,J=7.8Hz),
12.65 (1H,brs)
Example 63
1.20 g of methyl 3-{2-(acetyloxy)-5-[2-
(acetyloxy)-4-bromobenzoyl]phenyl}propanoate was
dissolved in 12 mL of toluene, to which 0.33 g of 2-
thienylboronic acid, 0.69 g of potassium carbonate, and
0.10 g of bis(triphenylphosphine)palladium
(II)dichloride were added at room temperature in a
stream of nitrogen, and then this mixture was stirred
for 3.5 hours while heating it under reflux. The
reaction mixture was cooled to room temperature,
followed by the addition thereto of ethyl acetate and
water, and the organic phase was separated therefrom.
After the resultant organic phase was washed with water
and a saturated sodium chloride solution successively,
this washed phase was dried over anhydrous magnesium
sulfate, and the solvent was distilled out under
reduced pressure. The resultant residue was purified

by silica gel column chromatography [eluent;
hexane:ethyl acetate=3:l] to yield 0.64 g of methyl 3-
{2-(acetyloxy)-5-[2-(acetyloxy)-4-(2-
thienyl)benzoyl]phenyl} propanoate as light yellow oil.
NMR (4 00MHz, CDC13) δ value: 2.00(3H,s), 2.37(3H,s),
2.60(2H,t,J=8.0Hz), 2.91(2H,t,J=8.0Hz), 3.67(3H,s),
7.1-7.2(2H,m), 7.3-7.5(3H,m), 7.57(2H,s), 7.6-7.7(2H,m)
Example 64
0.72 g of methyl 3-{2-(acetyloxy)-5-[2-
(acetyloxy)-4-(2-thienyl)benzoyl]phenyl}propanoate was
suspended in 8 mL of methanol, to which 0.66 g of a 28%
solution of sodium methoxide in methanol was added
dropwise at 5 to 7°C, and then this suspension was
stirred for 30 minutes in an ice bath. The reaction
mixture was added to a mixture of ethyl acetate and ice
water, and adjusted to pH 3 with 1M hydrochloric acid,
and the organic phase was separated therefrom. After
the resultant organic phase was washed with water and a
saturated sodium chloride solution successively, this
washed phase was dried over anhydrous magnesium sulfate,
and the solvent was distilled out under reduced
pressure. The resultant solid was recrystallized from
a mixed solvent of diisopropyl ether-hexane to yield
0.50 g of methyl 3-{2-hydroxy-5-[2-hydroxy-4-(2-
thienyl)benzoyl]phenyl} propanoate as light yellow
crystals.
NMR(400MHz,CDCl3) δ value: 2 . 79 (2H, t, J=6 . 2Hz) ,
2.98(2H,t,J=6.2Hz) , 3.74(3H,s), 6.99(1H,d,J=8.8Hz),

7.1-7.2(2H,m), 7.31(1H,d,J=l.6Hz),
7.39(1H,dd,J=5.0,J=1.2Hz), 7.4 6(1H,dd,J=3.6,1.2Hz),
7.46-7.62(2H,m), 7.63(1H,d, J=8.4Hz) , 7.99(1H,s),
12.16(1H,s)
Example 65
1.00 g of methyl 4-{[4-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-(3-methoxy-3-
oxopropyl)phenoxy]methyl)benzoate was dissolved in 10
mL of N,N-dimethylformamide, to which 0.52 g of
potassium carbonate and 0.23 mL of iodomethane were
added at 5 to 10°C, and then this mixture was stirred
for 4 hours at room temperature. The reaction mixture
was added to a mixture of ethyl acetate and ice water,
and the organic phase was separated therefrom. After
the resultant organic phase was washed with water and a
saturated sodium chloride solution successively, this
washed phase was dried over anhydrous magnesium sulfate,
and the solvent was distilled out under reduced
pressure. The resultant solid was recrystallized from
a mixed solvent of diisopropyl ether-hexane to yield
0.98 g of methyl 4-{ [4-[4-(cyclopentyloxy)-2-
methoxybenzoyl]-2-(3-methoxy-3-
oxopropyl)phenoxy]methyl} benzoate as light yellow
crystals.
NMR(400MHz,CDCl3) δ value: 1. 6-1. 7 (2H, m) , 1. 7-2 . 0 ( 6H,m) ,
2.64(2H,t,J=7.8Hz), 3.03(2H,t,J=7.8Hz), 3.65(3H,s),
3.70(3H,s), 3.93(3H,s), 4.7-4.9(1H,m), 5.22(2H,s), 6.4-
6.6(2H,m), 6.86(1H,d, J=8.4Hz) , 7.30(1H,d,J=8.0Hz),

7.50(2H,d,J=8.4Hz) , 7.64-7.68(2H,m) , 8.07(2H,d,J=8.0Hz)
Example 66
1.00 g of isopropyl 3-(5-(2-hydroxy-4-
isobutoxybenzoyl)-2-{[4-
(methylsulfanyl)benzyl]oxylphenyl) propanoate was
dissolved in 10 mL of methylene chloride, to which 0.69
g of 70% m-chloroperbenzoic acid was added in small
portions in an ice bath, and then this mixture was
stirred for 1.5 hours at room temperature. A saturated
aqueous solution of sodium hydrogen carbonate was added
to the reaction mixture, and the organic phase was
separated therefrom. After the resultant organic phase
was washed with water and a saturated sodium chloride
solution successively, this washed phase was dried over
anhydrous magnesium sulfate, and the solvent was
distilled out under reduced pressure. The resultant
residue was purified by silica gel column
chromatography [eluent; ethyl acetate] to yield 0.50 g
of isopropyl 3-(5-(2-hydroxy-4-isobutoxybenzoyl)-2-{[4-
(methylsulfonyl)benzyl]oxylphenyl) propanoate as yellow
oil and 0.54 g of isopropyl 3-(5-(2-hydroxy-4-
isobutoxybenzoyl)-2-{[4-
(methylsulfinyl)benzyl]oxylphenyl) propanoate as yellow
oil.
isopropyl 3-(5-(2-hydroxy-4-
isobutoxybenzoyl)-2-{[4-
(methylsulfinyl)benzyl]oxy(phenyl) propanoate
NMR(90MHz,CDCl3) δ value: 1. 03 ( 6H, d, J=6 . 6Hz) ,

1.19(6H,d,J=6.3Hz), 1.98-2.30(1H,m), 2.64-2.76(5H,m),
2.99-3.17 (2H,m) , 3. 79 (2H, d, J=6. 6Hz) , 4 . 80-5.15 (1H,m),
5.25(2H,s), 6.38-6.51{2H,mJ, 6.94 (1H, d, J=9.1Hz), 7.48-
7.77{7H,m}, 12.64(1H,s)
isopropyl 3-(5-(2-hydroxy-4-
isobutoxybenzoyl)-2-{[4-
(methylsulfonyl)benzyl]oxyjphenyl) propanoate
NMR(9QMHz,CDCl3) δ value: 1.03(6H,d,J=6.6Hz),
1.20(6H,d,J=6.4Hz), 1.98-2.18(1H,m), 2.56-2.72(2H,m),
2.98-3.18(5H,m), 3.79(2H, d, J=6.4Hz), 4.86-5.15(1H,m),
5.28{2H,s), 6.35-6.51(2H,m), 6.92(1H,d,J=9.3Hz), 7.47-
7.71(5H,m), 8.01(2H,d,J=8.6Hz), 12.63£lH,s)
Example 67
0.93 g of 3-(5~(2-hydroxy~4-
isobutoxybenzoyl)-2-{[4-
(methoxycarbonyl)benzyl]oxy}phenyl) propanoic acid was
dissolved in 9.3 mL of tetrahydrofuran, to which 0.19
mL of oxalyl chloride and 20 fiL of N,N-
dimethylformamide were added at room temperature, and
after this mixture was stirred for one hour, the
reaction mixture was added dropwise to a 25% aqueous
ammonia in an ice bath over 15 minutes. The reaction
mixture was adjusted to pH 6 with 6M hydrochloric acid,
to which ethyl acetate was added, and the organic phase
was separated therefrom. After the resultant organic
phase was washed with water and a saturated sodium
chloride solution successively, this washed phase was
dried over anhydrous magnesium sulfate, and the solvent

was distilled out under reduced pressure. The
resultant residue was dissolved in 18.6 mL of
tetrahydrofuran, to which 0.27 mL of thionyl chloride
was added, and this mixture was stirred for 6.5 hours
while heating it under reflux. The reaction mixture
was added to a mixture of ethyl acetate and ice water,
followed by the separation of the organic phase
therefrom. After the resultant organic phase was
washed with water and a saturated sodium chloride
solution successively, this washed phase was dried over
anhydrous magnesium sulfate, and the solvent was
distilled out under reduced pressure. The resultant
residue was purified by silica gel column
chromatography [eluent; ethyl acetate:hexane=2:1] to
yield 0.36 g of methyl 4-{[2-(2-cyanoethyl)-4-(2-
hydroxy-4-isobutoxybenzoyl)phenoxy]methyl} benzoate as
light orange solid.
NMR(90MHz,CDCl3) δ value: 1.03(6H,d,J=6.7Hz), 1.98-
2.26(1H,m), 2.68-2.77(2H,m), 3.00-3.08(2H,m), 3.67-
3.94(5H,m), 5.25(2H,s), 6.39-6.49(2H,m),
6.99(1H,d,J=9.0Hz), 7.43-7.66(5H,m), 8.11(2H,d,J=8.1Hz),
12.57 (1H,S)
Example 68
0.35 g of methyl 4-{[2-(2-cyanoethyl)-4-(2-
hydroxy-4-isobutoxybenzoyl)phenoxy]methyl} benzoate,
0.42 g of sodium azide, and 0.89g of triethylamine
hydrochloride were suspended in 3.5 mL of xylene, and
stirred for 7 hours at 110°C. The reaction mixture was

cooled to room temperature, to which methylene chloride
and water were added, and after this mixture was
adjusted to pH 2 with 6M hydrochloric acid, the organic
phase was separated therefrom. After the resultant
organic phase was washed with water and a saturated
sodium chloride solution successively, this washed
phase was dried over anhydrous magnesium sulfate, and
the solvent was distilled out under reduced pressure.
The residue was purified by silica gel column
chromatography [eluent; chloroform:ethanol=10:1] to
yield 0.19 g of methyl 4-({4-(2-hydroxy-4-
isobutoxybenzoyl)-2-[2-(1H-1,2,3,4-tetrazol-5-
yl)ethyl]phenoxy}methyl) benzoate as light yellow solid.
NMR(90MHz,CDC13) δ value: 1.02(6H,d,J=6.5Hz), 1.98-
2.24(1H,m), 3.23-3.34(4H,m), 3.76(2H,d,J=6.7Hz),
3.91(3H,s), 5.16(2H,s), 6.38-6.46(2H,m),
6.87(1H,d,J=9.5Hz), 7.29-7.50(5H,m), 8.03(2H,d,J=8.3Hz),
12.49(2H,brs)
Example 69
isopropyl 3-(5-(2-hydroxy-4-
isobutoxybenzoyl)-2-{[4-(1H-1,2,3,4-tetrazol-5-
yl)benzyl]oxy}phenyl) propanoate was obtained in a
similar manner as in Example 68.
NMR( 90MHz, CDCl3) δ value: 1. 03 ( 6H, d, J=6 . 8Hz) ,
1.20(6H,d,J=6.4Hz), 1.90-2.18(1H,m), 2.62-2.98(2H,m),
3.00-3.18(2H,m), 3.78(2H,d,J=6.4Hz), 4.95-5.09(2H,m),
5.21(2H,s), 6.35-6.48(2H,m), 6.91(1H,d,J=7.4Hz), 7.48-
7.57(5H,m), 8.10(2H,d,J=8.3Hz), 12.63 (1H,brs)

Example 7 0
0.580 g of isobutyl 3-(5-{2-hydroxy-4-[ (4-
nitrophenethyl)oxy]benzoyl}-2-isobutoxyphenyl)
propanoate was dissolved in a mixed solvent of 3 mL of
ethanol and 3 mL of tetrahydrofuran, to which 58 mg of
5% palladium-carbon was added, and this mixture was
stirred for 3 hours at room temperature in a stream of
hydrogen. After the reaction mixture was filtered
through Celite, the solvent was distilled out under
reduced pressure, and then the resultant residue was
purified by silica gel column chromatography [eluent;
hexanerethyl acetate=2:l] to yield 0.515 g of isobutyl
3- (5-{4-[(4-aminophenethyl)oxy]-2-hydroxybenzoyl} -2-
isobutoxyphenyl) propanoate as light yellow oil.
NMR( 90MHz, CDC13) δ value: 0 . 8 9 ( 6H, d, J=6 . 6Hz ) ,
1.07(6H,d, J=6.6Hz) , 1.7-2.3(2H,m), 2.5-2.8(2H,m), 2.9-
3.1(4H,m), 3.60(2H,brs), 3.82(2H,d,J=6.3Hz),
3.85 (2H,d,J=6.6Hz), 4.17(2H,t,J=7.1Hz), 6.3-6.5(2H,m),
6.65(2H,d,J=8.5Hz), 6.88(1H,d,J=9.3Hz),
7.07(2H,d,J=8.3Hz), 7.4-7.6(3H,m), 12.66(1H,s)
Example 71
3.32 g of 4-({2-(2-carboxyethyl)-4-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]phenoxy}-
methyl)benzoic acid was suspended in 3.3 mL of
methylene chloride, to which 3.3 mL of 4M hydrogen
chloride-ethanol was added, and this mixture was
stirred for 7 hours at room temperature. The reaction
mixture was concentrated under reduced pressure, and

then the resultant residue was purified by silica gel
column chromatography [eluent; chloroform:ethanol=10:1]
to yield 1.76 g of 4-{[4-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-(3-ethoxy-3-oxopropyl)phenoxy]methyl}
benzoic acid as white solid.
NMR(400MHz,CDCl3) δ value: 1.23(3H,t,J=7.6Hz) , 1.62-
1.66(2H,m), 1.78-1.96(6H,m), 2 . 69(2H,t,J=7.6Hz),
3.09(2H,t,J=7.6Hz), 4.13(2H,q,J=7.2Hz), 4 . 80-4.83(1H,m),
5.27(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.48(1H,d,J=2.4Hz),
6.94(1H,d,J=8.4Hz), 7.50-7.57(5H,m), 8.16(2H,d,J=8.4Hz),
12.69(2H,brs)
Example 72
The following compounds were obtained in a
similar manner as in Example 71.
(1) 4-{[2-(3-ethoxy-3-oxopropyl)-4-(2-
hydroxy-4-isobutoxybenzoyl)phenoxy]methyl} benzoic acid
NMR(90MHz,CDCl3) δ value: 1.03(6H,d,J=6.8Hz),
1.23(3H,t,J=7.1Hz), 1.98-2.27(1H,m), 2 . 66-2.76(2H,m),
3.00-3.09(2H,m), 3.79(2H,d,J=6.6Hz), 4.13(2H,q,J=7.1Hz),
5.27(2H,s), 6.35-6.51(2H,m), 6.94(1H,d,J=9.4Hz), 7.48-
7.61(5H,m), 8.17(2H,d,J=8.1Hz), 12.65(2H,brs)
(2) 4-{[4-(2-hydroxy-4-isobutoxybenzoyl)-2-
(3-methoxy-3-oxopropyl)phenoxy]methyl} benzoic acid
NMR(90MHz,DMSO-d6) δ value: 0.99(6H,d,J=6.7Hz), 1.92-
2.19(1H,m), 2.62-2.73(2H,m), 2.86-3.14(2H,m),
3.57(3H,s), 3.84(2H,d,J=5.9Hz), 5.35(2H,s), 6.48-
6.55(2H,m), 7.16-7.65(6H,m), 8.00(2H,d,J=7.8Hz),
11.96(1H,s), 12.80(1H,brs)

Example 73
0.50 g of 4-{[2-(2-carboxyethyl)~4-(2-
hydroxy-4-isobutoxybenzoyl)phenoxy]methyl} benzoic acid
was dissolved in 15 mL of N,N-dimethylformamide, to
which 1.54 g of potassium carbonate and 1.2 mL of
isobutyl bromide were added at room temperature, and
this mixture was stirred for one hour at 100°C. The
reaction mixture was added to a mixture of chloroform
and water, and adjusted to pH 3 with 6M hydrochloric
acid, and then followed by separation of the organic
phase therefrom. After the resultant organic phase was
washed with water and a saturated sodium chloride
solution successively, this washed phase was dried over
anhydrous magnesium sulfate, and the solvent was
distilled out under reduced pressure. The resultant
residue was purified by silica gel column
chromatography [eluent; chloroform:ethanol=10:1] to
yield 0.64 g of isobutyl 4-{[4-(2,4-
diisobutoxybenzoyl)-2-(3-isobutoxy-3-
oxopropyl)phenoxy]methyl} benzoate as yellow oil.
NMR(90MHz,CDC13) δ value: 0.68(6H,d,J=6.8Hz), 0.86-
1.09(18H,m), 1.75-2.25(4H,m), 2.56-2.70(2H,m), 2.93-
3.12{2H,m), 3.57-3.88(6H,m), 4.12(2H,d,J=6.4Hz),
5.22(2H,s), 6.46-6.55(2H,m), 6.83(1H,d,J=9.1Hz) , 7.32-
7.66(5H,m), 8.07(2H,d,J=8.3Hz)
Example 7 4
72.1 g of methyl 3-(5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2-

benzisoxazol-6-yl]methoxy}phenyl) propanoate was
dissolved in 220 mL of tetrahydrofuran and 140 mL of
methanol, to which 125 g of a 20% aqueous solution of
sodium hydroxide and 360 mL of water were added, and
this mixture was stirred for 2 hours at room
temperature. The reaction mixture to which water was
added was adjusted to pH 2 with 6M hydrochloric acid,
and then resultant precipitate was filtered out thereof.
The precipitates thus obtained were washed with water
and diisopropyl ether successively to yield 69.7 g of
3-(5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-{[3-
(methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl)
propanoic acid as light yellow solid.
NMR(400MHz,DMSO-d6) δ value: 1.54-1.78(6H,m), 1.89-
2.02(2H,m), 2.58(2H,t,J=7.6Hz), 2.93(2H,t,J=7.6Hz),
3.54(3H,s), 4.87-4.94(1H,m), 5.44(2H,s), 5.55(2H,s),
6.46-6.52(2H,m), 7.20(1H,d,J=9.2Hz), 7.45(1H,d,J=8.8Hz),
7.51(1H,d,J=8.0Hz), 7.53-7.58(2H,m), 7.78(1H,s),
7.84(1H,d,J=8.0Hz), 11.93-12.34(1H,br), 12.04(1H,brs).
Example 7 5
69.7 g of 3-(5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2-
benzisoxazol-6-yl]methoxy}phenyl) propanoic acid was
dissolved in 700 mL of tetrahydrofuran, to which 16.5
mL of N-(2-hydroxyethyl)morpholine and 39.1 g of
triphenylphosphine were added at room temperature
followed by addition of diisopropyl azodicarboxylate,
and this mixture was stirred for 20 minutes at the same

temperature. The reaction mixture was added to a
mixture of ethyl acetate and water, and then the
organic phase was separated therefrom. After the
resultant organic phase was washed with water and a
saturated sodium chloride solution successively, this
washed phase was dried over anhydrous magnesium sulfate,
and the solvent was distilled out under reduced
pressure. The resultant residue to which toluene was
added was stirred in an ice bath, and resultant
precipitate was filtered out thereof. The filtrate was
concentrated under reduced pressure, and the resultant
residue was purified by silica gel column
chromatography [eluent; ethyl acetate] to yield 91.0 g
of 2-(4-morpholinyl)ethyl 3-(5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2-
benzisoxazol-6-yl]methoxy}phenyl) propanoate as yellow
oil.
NMR(400MHz,CDCl3) δ value: 1. 58-1. 70 (2H,m) , 1.74-
2.01(6H,m), 2.45(4H,t,J=4.8Hz), 2.58(2H,t,J=6.4Hz),
2.72(2H,t,J=7.6Hz), 3.09(2H,t,J=7.6Hz), 3.63-3.68(4H,m),
3.65(3H,s), 4.21(2H,t,J=6.4Hz), 4.77-4.85(1H,m),
5.33(2H,s), 5.57(2H,s), 6.37(1H,dd,J=9.3,2.4Hz),
6.4 8(1H,d,J=2.4Hz), 6.95(1H,d,J=8.3Hz),
7.36(1H,d,J=7.6Hz), 7.48-7.58(4H,m), 7.72(1H,d,J=8.3Hz),
12.69(1H,s).
Example 7 6
86.7 g of 2-(4-morpholinyl)ethyl 3-(5-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]-2-{[3-

(methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl)
propanoate was dissolved in 200 mL of methylene
chloride and 610 mL of isopropyl alcohol, to which 18.8
mL of methanesulfonic acid was added at room
temperature, and this mixture was stirred for 30
minutes at the same temperature. The reaction mixture
was added to a mixture of ice water and chloroform,
followed by adjustment thereof to pH 6 with a saturated
aqueous solution of sodium hydrogen carbonate, and the
organic phase was separated therefrom. After the
resultant organic phase was washed with a saturated
sodium chloride solution, this washed phase was dried
over anhydrous magnesium sulfate, and the solvent was
distilled out under reduced pressure. The resultant
residue was purified by silica gel column
chromatography [eluent; chloroform:methanol=20:1] to
yield 69.9 g of light yellow solid, which was
recrystallized from acetone to yield 46.2 g of 2-(4-
morpholinyl)ethyl 3-{5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-[(3-hydroxy-l,2-benzisoxazol-6-
yl)methoxy]phenyl} propanoate as colorless crystals.
NMR(400MHz,CDCl3) δ value: 1. 58-1. 70 (2H,m) , 1.74-
2.01(6H,m), 2.61(2H,t,J=8.0Hz), 2.68-2.78(4H,m),
2.8 4(2H,t,J=5.4Hz), 3.00(2H,t,J=8.0Hz),
3.77(4H,t,J=4.4Hz), 4.32(2H,t,J=5.4Hz), 4.78-4.84(1H,m),
5.23(2H,s), 6.20-7.00(1H,br), 6.36(1H,dd,J=9.6,2.4Hz),
6.47(1H,d,J=2.4Hz), 6.90-6.93(1H,m), 7.22(1H,d,J=8.0Hz),
7.40(1H,s), 7.44-7.52(3H,m), 7.74(1H,d,J=8.4Hz).

Example 77
5.80 g of 3-{5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-[(3-hydroxy-l,2-benzisoxazol-6-
yl)methoxy]phenyl} propanoic acid was suspended in 58
mL of methylene chloride, to which 6.2 mL of
triethylamine was added at room temperature followed by
addition of 3.44 g of trityl chloride in an ice bath,
and this mixture was stirred for 30 minutes at room
temperature. The reaction mixture to which water was
added was adjusted to pH 3 with 6M hydrochloric acid,
and the organic phase was separated therefrom. After
the resultant organic phase was washed with water, the
solvent was distilled out under reduced pressure. The
resultant residue was washed with hexane and then
purified by silica gel column chromatography [eluent;
chloroform:ethanol=50:1] to yield 6.83 g of 3~{5-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-oxo-2-trityl-
2,3-dihydro-l,2-benzisoxazol-6-yl)methoxy]phenyl}
propanoic acid as yellow solid.
NMR (400MHz, CDC13) δ value: 1. 5-2 .1 (8H,m) ,
2.72(2H,t,J=7.4Hz), 3.06(2H,t,J=7.4Hz), 4.75-4.85(1H,mj,
5.20(2H,s), 6.37(1H,dd,J=9.4,2.6Hz), 6.47(1H,d,J=2.4Hz),
6.87 (1H,d, J=8.0Hz) , 7 . 15-7 . 35 (HH,m) , 7.45-7.60(10H,m),
7.66(1H,d,J=8.0Hz), 12.67(1H,s).
Example 7 8
50.0 g of 3-{5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-[(3-oxo-2-trityl-2,3-dihydro-l,2-
benzisoxazol-6-yl)methoxy]phenyl} propanoic acid was

dissolved in 500 mL of tetrahydrofuran, to which 8.8 mL
of N-(2-hydroxyethyl)morpholine and 20.7 g of
triphenylphosphine were added at room temperature
followed by dropwise addition of 15.5 mL of diisopropyl
azodicarboxylate, and this mixture was stirred for one
hour at the same temperature. Then, water, ethyl
acetate, and a saturated sodium chloride solution were
added to the reaction mixture, and the organic phase
was separated therefrom. After the resultant organic
phase was washed with a saturated sodium chloride
solution, this washed phase was dried over anhydrous
sodium sulfate, and the solvent was distilled out under
reduced pressure. The resultant residue was purified
by silica gel column chromatography [eluent; ethyl
acetate] to yield 59.0 g of 2-(4-morpholinyl)ethyl 3-
{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-oxo-2-
trityl-2,3-dihydro-l,2-benzisoxazol-6-
yl)methoxy]phenyl} propanoate as yellow oil.
NMR(400MHz,CDCl3) δ value: 1. 5-2 . 1 ( 8H,m) ,
2.4 4(4H,t,J=4.4Hz), 2.55(2H,t,J=6.0Hz),
2.69(2H,t,J=7.6Hz),
3.0 6(2H,t,J=7.6Hz),3.65(4H,t,J=4.6Hz),
4.17(2H,t,J=5.8Hz), 4.7-4.9(1H,m), 5.22(2H,s),
6.37(1H,dd,J=8.8,2.4Hz), 6.4 8(1H,d,J=2.4Hz),
6.88(1H,d,J=8.4Hz),7.16-7.34(llH,m), 7.4 3-7.5 9(9H,m),
7.67(1H,d,J=8.4Hz), 12.68(1H,s).
Example 7 9
134 g of 2-(4-morpholinyl)ethyl 3-{5-[4-

(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-oxo-2-trityl-
2,3-dihydro-1,2-benzisoxazol-6-yl)methoxy]phenyl}
propanoate was dissolved in 1.3 L of 1,4-dioxane, to
which 670 mL of 3M hydrochloric acid was added at room
temperature, and this mixture was stirred for 1.5 hour
at 40°C. The reaction mixture to which chloroform was
added was adjusted to pH 5 with a saturated aqueous
solution of sodium hydrogen carbonate, and the organic
phase was separated therefrom. An aqueous phase was
extracted with chloroform, and after the combined
organic phases were washed with a saturated sodium
chloride solution, the washed phases was dried over
anhydrous magnesium sulfate, and the solvent was
distilled out under reduced pressure. The resultant
residue was purified by silica gel column
chromatography [eluent; chloroform:methanol=40:1] to
yield 38.6 g of 2-(4-morpholinyl)ethyl 3-{5-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-l,2-
benzisoxazol-6-yl)methoxy]phenyl} propanoate as
colorless crystals.
NMR(400MHz,CDCl3) δ value: 1. 58-2 . 00 ( 8H, m) ,
2.60(2H,t,J=7.6Hz), 2.71(4H,brs), 2.82(2H,t,J=5.6Hz),
3.00(2H,t,J=7.6Hz), 3.7 7(4H,t,J=4.6Hz),
4.31(2H,t,J=5.6Hz), 4.78-4.84(1H,m), 5.24(2H,s), 5.7.-
6.2(1H,br), 6.36(1H,dd,J=9.4,2.6Hz), 6.47(1H,d,J=2.4Hz) ,
6.92(1H,d,J=8.8Hz), 7.24(1H,d,J=8.4Hz), 7.40(1H,s),
7.46-7.52(3H,m), 7.74(1H,d,J=8.0Hz), 12.4-13.0(1H,br)
Example 7 9 (2)

280 g of 2-(4-morpholinyl)ethyl 3-{5-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-oxo-2-trityl-
2,3-dihydro-l,2-benzisoxazol-6-yl)methoxy]phenyl}
propanoate was suspended in 560 mL of 1,4-dioxane, to
which 92.5 g of methanesulfonic acid was added dropwise
at 12 to 15°C, and this mixture was stirred for 15
minutes at 15°C. 20 mL of water was added to the
reaction mixture, which was then stirred for one hour
at 12 to 15°C, and the resultant precipitate was
filtered out thereof. The filtrate was ice-cooled, to
which methylene chloride and water were added, and was
adjusted to pH 4.5 with a 20% aqueous solution of
sodium hydroxide, and then the organic phase was
separated therefrom. An aqueous phase was extracted
with methylene chloride, and after the combined organic
phases were washed with a saturated sodium chloride
solution followed by filtration thereof through Celite,
the organic phase was separated. The resultant organic
phase was dried over anhydrous magnesium sulfate, and
the solvent was distilled out under reduced pressure.
The resultant residue, to which diisopropyl ether and
ethyl acetate were added, was stirred for 30 minutes at
room temperature, and then resultant precipitate was
filtered out thereof to yield 180 g of light yellow
solid.
Then, 170 g of the resultant solid was
recrystallized from acetone to yield 142 g of 2-(4-
morpholinyl)ethyl 3-{5-[4-(cyclopentyloxy)-2-

hydroxybenzoyl]-2-[(3-hydroxy-l,2-benzisoxazol-6-
yl)methoxy]phenyl} propanoate as light yellow needle
crystals.
melting point: 131 - 132.5°C
IR(KBr) : 1742, 1625 cm-1
NMR (400MHz, CDCl3) δ value: 1. 6-2 . 0 (8H, m) ,
2.61(2H,t,J=7.5Hz) , 2.74(4H,brs) , 2.85(2H,t,J=5.6Hz) ,
3.00(2H,t,J=7.5Hz), 3.7 8 (4H,t,J=4.6Hz),
4.32(2H,t,J=5.6Hz), 4.78-4.84(1H,m), 5.23(2H,s),
6.36(1H,dd,J=9.2,2.4Hz), 6.4 7(1H,d,J=2.4Hz),
6.91 (1H,d,J=9.2Hz), 7.23(1H,dd,J=8.0,1.2Hz), 7.40(1H,s),
7.4 7-7.52(3H,m), 7.7 4(1H,d,J=8.0Hz)
Example 8 0
(1) 3.00 g of 1-chloroethyl ethyl carbonate
was dissolved in 90 mL of acetonitrile, to which 13.3 g
of sodium iodide was added, and this mixture was
stirred for 1.5 hours at 60°C. This mixture was cooled
to room temperature, followed by concentration thereof
under reduced pressure, and then insoluble substances
were filtered out thereof by adding diethyl ether to
the residue. The resultant filtrate was concentrated
under reduced pressure to yield 4.60 g of ethyl 1-
iodoethyl carbonate as orange oil.
(2) 1.50 g of 3-(5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2-
benzisoxazol-6-yl]methoxy}phenyl) propanoic acid and
1.85 g of potassium carbonate were suspended in 15 mL
of N,N-dimethylformamide, to which 2.00 g of 1-

iodoethyl ethyl carbonate prepared in (1) was added,
and this mixture was stirred for one hour at room
temperature. The reaction mixture, to which water and
ethyl acetate were added, was adjusted to pH 5 with 6M
hydrochloric acid, and the organic phase was separated
therefrom. After the resultant organic phases was
washed with an aqueous solution of sodium thiosulfate
and a saturated sodium chloride solution, the washed
phase was dried over anhydrous sodium sulfate, and the
solvent was distilled out under reduced pressure. The
resultant residue was purified by silica gel column
chromatography [eluent; hexane:ethyl acetate=4:l] to
yield 1.42 g of 1-[(ethoxycarbonyl)oxy]ethyl 3—{5— [4-
(cyclopentyloxy)-2-hydroxybenzoyl]-2-{[3-
(methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl)
propanoate as yellow oil.
NMR(400MHz,CDC13) δ value: 1.28(3H,t,J=7.0Hz),
1.49(3H,d,J=5.6Hz), 1.6-2.1(8H,m), 2.70-2.76(2H,m),
3.09(2H,t,J=7.6Hz), 3.65(3H,s), 4.14-4.23(2H,m), 4.79-
4.86(1H,m), 5.33(2H,s), 5.57(2H,s),
6.38(1H,dd,J=8.8,2.8Hz), 6 . 48(1H,d,J=2.4Hz), 6.74-
6.80(1H,m), 6.94(1H,d,J=8.4Hz), 7.37(1H,dd,J=8.2,1.0Hz),
7.48-7.59(4H,m), 7.72(1H,d,J=8.4Hz), 12.68(1H,s).
Example 81
1.40 g of 1-[(ethoxycarbonyl)oxy]ethyl 3-(5-
[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-{[3-
(methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl)
propanoate was dissolved in 28 mL of 1,4-dioxane, to

which 6 mL of 3M hydrochloric acid was added, and this
mixture was stirred for 3.5 hours at room temperature.
Then, water and ethyl acetate were added to the
reaction mixture, and the organic phase was separated
therefrom. After the resultant organic phases was
washed with water and a saturated sodium chloride
solution, the washed phase was dried over anhydrous
sodium sulfate, and the solvent was distilled out under
reduced pressure. The resultant residue was purified
by silica gel column chromatography [eluent;
chloroform] to yield 1.12 g of 1-
[(ethoxycarbonyl)oxy]ethyl 3-{5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-
yl)methoxy]phenyl} propanoate as light yellow solid.
NMR(400MHz,CDCl3) δ value: 1 . 29 ( 3H, t, J=7 . 2Hz ),
1.49(3H,d,J=5.4Hz), 1.5-2.0(8H,m), 2.70-2.80(2H,m),
3.10(2H,t,J=7.6Hz), 4.1-4.3(2H,m), 4.8-4.9(1H,m),
5.33(2H,s), 6.39(1H,dd,J=9.2,2.4Hz), 6.47(1H,d,J=2.2Hz),
6.75-6.85(1H,m), 6.95(1H,d,J=8.4Hz), 7.39(1H,d,J=8.4Hz) ,
7.47-7.62(4H,m), 7.82(1H,d,J=8.0Hz), 9.5-10.0(1H,br),
12.69(1H,brs).
Example 82
(1) 9.15 g of cyclohexanol was dissolved in
150 mL of methylene chloride, to which 7.4 mL of
pyridine was added followed by dropwise addition of 10
mL of 1-chloroethyl chloroformate in an ice bath, and
this mixture was stirred for 2 hours at room
temperature. Then, a sodium chloride solution was

added to the reaction mixture and the organic phase was
separated therefrom. After the resultant organic phase
was dried over anhydrous magnesium sulfate, the solvent
was distilled out under reduced pressure to yield 18.6
g of 1-chloroethyl cyclohexyl carbonate as colorless
oil. 5.00 g of this 1-chloroethyl cyclohexyl carbonate
was dissolved in 150 mL of acetonitrile, to which 16.3
g of sodium iodide was added, and this mixture was
stirred for one hour at 60°C. The mixture was cooled to
room temperature, followed by concentration thereof
under reduced pressure, and then insoluble substances
were filtered out therefrom by adding diethyl ether to
the residue. The resultant filtrate was concentrated
under reduced pressure to yield 5.90 g of cyclohexyl 1-
iodoethyl carbonate as red oil.
(2) 1.50 g of 3-(5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2-
benzisoxazol-6-yl]methoxy}phenyl) propanoic acid and
1.85 g of potassium carbonate were suspended in 15 mL
of N,N-dimethylformamide, to which 4.00 g of 1-
iodoethyl cyclohexyl carbonate prepared in (1) was
added, and this mixture was stirred for one hour at
room temperature. The reaction mixture, to which water
and ethyl acetate were added, was adjusted to pH 5 with
6M hydrochloric acid, and the organic phase was
separated therefrom. An aqueous phase was extracted
with ethyl acetate, and then after the combined organic
phases were washed with an aqueous solution of sodium

thiosulfate and a saturated sodium chloride solution,
the washed phase was dried over anhydrous sodium
sulfate, and the solvent was distilled out under
reduced pressure. The resultant residue was purified
by silica gel column chromatography [eluent;
hexane:ethyl acetate=5:l] to yield 1.47 g of 1-
{ [(cyclohexyloxy)carbonyl]oxy}ethyl 3- (5-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]-2-{[3-
(methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl)
propanoate as red oil.
(3) 1.40 g of the resultant oil was
dissolved in 42 mL of 1,4-dioxane, to which 9 mL of 3M
hydrochloric acid was added, and this mixture was
stirred for one hour at room temperature. Then, water
and ethyl acetate were added to the reaction mixture
and the organic phase was separated therefrom. After
the resultant organic phase was washed with water and a
saturated sodium chloride solution, the washed phase
was dried over anhydrous sodium sulfate, the solvent
was distilled out under reduced pressure. The
resultant residue was purified by silica gel column
chromatography [eluent; chloroform:ethyl acetate=l:l]
to yield 1.04 g of 1-
{ [(cyclohexyloxy)carbonyl]oxy}ethyl 3-{5- [4-
(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-
benzisoxazol-6-yl)methoxy]phenyl} propanoate as yellow
solid.
NMR (400MHz, CDCl3) δ value: 1.1-2.0(21H,m) , 2.7-2.8(2H,m),

3.10(2H,t,J=7.4Hz), 4.55-4.65(1H,m), 4.78-4.86(1H,m),
5.34(2H,s), 6.39(1H,dd,J=9.0,2.6Hz), 6.48(1H,d,J=2.4Hz) ,
6.74-6.82(1H,m), 6.95(1H,d,J=8.8Hz), 7.40(1H,d,J=8.0Hz),
7.45-7.65(4H,m), 7.83(1H,d,J=8.OHz), 8.0-9.0(1H,br),
5 12.68(1H,brs).
Example 83
1.04 g of 3-(5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2-
benzisoxazol-6-yl]methoxy}phenyl) propanoic acid and
) 512 mg of potassium carbonate were suspended in 10 mL
of N,N-dimethylformamide, to which 0.29 mL of
chloromethyl pivalate was added, and this mixture was
stirred for 2 hours at 40°C. Then, water and ethyl
acetate were added to the reaction mixture, and the
3 organic phase was separated therefrom. The remaining
aqueous phase was extracted with ethyl acetate, and
organic phases were combined together. After the
resultant organic phase was washed with a saturated
sodium chloride solution, the washed phase was dried
) over anhydrous magnesium sulfate, and the solvent was
distilled out under reduced pressure. The resultant
residue was purified by silica gel column
chromatography [eluent; hexane:ethyl acetate=3:l] to
yield 1.02 g of {[3-(5-[4-(cyclopentyloxy)-2-
j hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2-
benzisoxazol-6-yl]methoxy}phenyl) propanoyl]oxy}methyl
pivalate as light yellow oil.
NMR(400MHz,CDCl3) δ value: 1.16(9H,s), 1.58-2.02(8H,m),

2.75(2H,t,J=7.6Hz), 3.09(2H,t,J=7.6Hz), 3.65(3H,s),
4.75-4.85(1H,m), 5.32(2H,s), 5.57(2H,s), 5.75(2H,s),
6.38(1H,dd,J=9.2,2.4Hz), 6.4 8(1H,d,J=2.8Hz),
6.95 (1H,d,J=8.4Hz), 7.36(1H,d,J=8.0Hz), 7.45-7.60(4H,m),
7.72(1H,d,J=8.4Hz), 12.68(1H,s).
Example 8 4
1.02 g of {[3-(5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2-
benzisoxazol-6-yl]methoxy}phenyl) propanoyl]oxy}methyl
pivalate was dissolved in 8 mL of 1,4-dioxane and 8 mL
of methanol, to which 6 mL of 6M hydrochloric acid was
added at room temperature, and this mixture was stirred
for 50 minutes at the same temperature. The reaction
mixture, to which water was added, was adjusted to pH 7
with an aqueous solution of sodium hydroxide, and then
ethyl acetate was added to this mixture and the organic
phase was separated therefrom. The remaining aqueous
phase was extracted with ethyl acetate, and organic
phases were combined together. After the resultant
organic phase was washed with a saturated sodium
chloride solution, the washed phase was dried over
anhydrous magnesium sulfate, and the solvent was
distilled out under reduced pressure. The resultant
residue, to which a mixture of hexane and ethyl acetate
[3:1] was added, was filtered out to yield 0.56 g of
[ (3-{5-[4-(eye1opentyloxy)-2-hydroxybenzoyl]-2-[(3-
hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl}
propanoyl)oxy]methyl pivalate as white solid.

NMR (400MHz, DMSO-d6) δ value: 1.04(9H,s), 1.53-1.80(6H,m),
1.89-2.00(2H,m), 2.74(2H,t, J=7.2Hz) , 2.96(2H,t,J=7.2Hz),
3.1-3.7(1H,br) , 4.88-4.94(1H,m), 5.38(2H,s), 5.67(2H,s),
6.4-6.6(2H,m), 7.20 (1H,d,J=8.4Hz), 7 . 35(1H,d,J=8.0Hz),
7.45(1H,d, J=8.4Hz) , 7.50-7.35(3H,m), 7.80(1H,d,J=8.0Hz),
12.10(1H,brs).
Example 8 5
1.80 g of 3- (5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2-
benzisoxazol-6-yl]methoxy}phenyl) propanoic acid was
dissolved in 20 mL of N,N-dimethylformamide, to which
0.9 g of potassium carbonate and 0.3 mL of ethyl iodide
were added at room temperature, and this mixture was
stirred for one hour at 30 to 35°C. The reaction
mixture was added to a mixture of ethyl acetate and ice
water, and adjusted to pH 3 with 6M hydrochloric acid,
and then the organic phase was separated therefrom.
After the resultant organic phase was washed with water,
a saturated aqueous solution of sodium hydrogen
carbonate, and a saturated sodium chloride solution
successively, the washed phase was dried over anhydrous
magnesium sulfate, and the solvent was distilled out
under reduced pressure. The resultant residue was
purified by silica gel column chromatography [eluent;
hexane:ethyl acetate=30:1] to yield 1.50 g of ethyl 3-
(5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-{ [3-
(methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl)
propanoate as light yellow solid.

NMR(400MHz,CDCl3) δ value: 1.23 (3H,t,J=7.1Hz), 1.58-
1.72(2H,m), 1.75-2.02(6H,m), 2.69(2H,t,J=7.7Hz),
3.09(2H,t,J=7.7Hz), 3.65(3H,s), 4.13(2H,q,J=7.1Hz),
4.78-4.86(1H,m), 5.33(2H,s), 5.57(2H,s),
6.37(1H,dd,J=9.2,2.4Hz), 6.4 8(1H,d,J=2.8Hz),
6.94(1H,d,J=8.8Hz), 7.36(1H,d,J=8.4Hz), 7.48-7.60(4H,m),
7.71(1H,d,J=8.4Hz), 12.68(1H,s).
Example 8 6
0.70 g of ethyl 3-(5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2-
benzisoxazol-6-yl]methoxyJphenyl) propanoate was
dissolved in 5 mL of 1,4-dioxane, to which 5 mL of 3M
hydrochloric acid was added in an ice bath, and further,
7 mL of ethanol, 5 mL of 1,4-dioxane and 2 mL of 3M
hydrochloric acid were added to the mixture, which was
stirred for 2 hours at room temperature. The reaction
mixture was added to a mixture of ice water and ethyl
acetate, and the organic phase was separated therefrom.
After the resultant organic phase was washed with a
saturated sodium chloride solution, the washed phase
was dried over anhydrous magnesium sulfate, and the
solvent was distilled out under reduced pressure. The
resultant residue, to which diisopropyl ether was added,
was filtered out to yield 0.56 g of ethyl 3-{5-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-l, 2-
benzisoxazol-6-yl)methoxy]phenyl} propanoate as white
solid.
NMR(400MHz,CDCl3) δ value: 1.23(3H,t,J=7.1Hz), 1.58-

1.72(2H,m), 1.74-2.04(6H,m), 2.70(2H,t,J=7.9Hz),
3.10(2H,t,J=7.9Hz), 4 . 14(2H, q,J=7.1Hz), 4.78-4.90(1H,m),
5.34(2H,s), 6.37(1H,dd,J=8.8,2.4Hz), 6.48(1H,d,J=2.4Hz),
6.95(1H,d,J=8.8Hz), 7.39(1H,d,J=8.0Hz), 7.48-7.63(4H,m),
7.83(1H,d,J=7.6Hz), 12.68(2H,brs).
Example 87
5.50 g of methyl 3-(5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-{[3-(methoxymethoxy)-1,2-
benzisoxazol-6-yl]methoxy}phenyl) propanoate was
dissolved in 17 mL of 1,4-dioxane and 17 mL of methanol,
to which 5.5 mL of 6M hydrochloric acid was added at
room temperature, and this mixture was stirred for 20
minutes at the same temperature. Then, water was added
to the reaction mixture, and resultant precipitate was
filtered out therefrom. The precipitate thus obtained
was washed with water to yield 4.99 g of methyl 3-{5-
[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-
1,2-benzisoxazol-6-yl)methoxy]phenyl} propanoate as
white solid.
NMR (400MHz, CDC13) δ value: 1. 57-1. 71 (2H,m) , 1.74-
2.01(6H,m), 2.71(2H,t, J=7.6Hz) , 3.11(2H,t,J=7.6Hz),
3.69(3H,s), 4.77-4.85(1H,m), 5.34(2H,s),
6.37(1H,dd,J=8.8,2.4Hz), 6.4 8(1H,d,J=2.4Hz),
6.95(1H,d,J=8.8Hz), 7.39(1H,dd,J=8.0,0.8Hz) , 7.48-
7.58(4H,m), 7.83(1H,d,J=8.0Hz), 12.68(1H,s).
Example 8 8
(1) 2.08 g of 4,5-dimethyl-l,3-dioxol-2-one
was dissolved in 24 mL of benzene, to which 3.25 g of

N-bromosuccinimide and 8 6 mg of 2,2'-
azobis(isobutyronitrile) were added at room temperature,
and this mixture was stirred for 30 minutes while
heating it under reflux. The reaction mixture was
cooled to room temperature, and consequently, a
solution of 4-bromomethyl-5-methyl-l,3-dioxol-2-one in
benzene was obtained.
(2) 3.00 g of methyl 3-(5-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]-2-{[3-
(methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl)
propanoate was dissolved in 15 mL of methanol and 15 mL
of tetrahydrofuran, to which a solution of 1.08 g of
potassium hydroxide in 4.5 mL of water was added, and
this mixture was stirred for one hour at room
temperature, and then the solvent was distilled out
under reduced pressure. The resultant residue was
dissolved in 40 mL of N,N-dimethylformamide, to which
3.60 g of potassium carbonate was added. Then, the
benzene solution prepared in (1) was added thereto, and
was stirred for one hour at room temperature. The
reaction mixture was poured into a mixture of ethyl
acetate and water, and adjusted to pH 7 with 6M
hydrochloric acid, and then the organic phase was
separated therefrom. After the resultant organic phase
was washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous sodium sulfate, and the solvent was distilled
out under reduced pressure. The resultant residue was

purified by silica gel column chromatography [eluent;
toluene:ethyl acetate=5:1 to yield 1.58 g of (5-
methyl-2-oxo-1,3-dioxol-4-yl)methyl 3- (5-[4-
(cyclopentyloxy)-2-hydroxybenzoyl]-2-{[3-
(methoxymethoxy)-1,2-benzisoxazol-6-yl]methoxy}phenyl)
propanoate as yellow oil.
NMR(4 00MHz, CDCl) δ value: 1.5-2.0(8H,m), 2.16(3H,s),
2.75(2H,t,J=7.6Hz) , 3.10(2H,t,J=7.6Hz), 3.65(3H,s),
4.5-5.0(3H,m), 5.33(2H,s), 5.57(2H,s),
6.37(1H,dd,J=8.8,2.4Hz), 6.4 7(1H,d,J=2.4Hz),
6.95(1H,d,J=8.4Hz), 7.35(1H,dd,J=8.4,1.2Hz), 7.4-
7.6(4H,m), 7.72(1H,d,J=8.0Hz), 12.67(1H,s).
Example 8 9
1.40 g of (5-methyl-2-oxo-1,3-dioxol-4-
yl)methyl 3-(5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-
{[3-(methoxymethoxy)-1,2-benzisoxazol-6-
yl]methoxy}phenyl) propanoate was dissolved in 28 mL of
1,4-dioxane, to which 14 mL of 3M hydrochloric acid was
added, and this mixture was stirred for 2 hours at room
temperature. Then, water and chloroform were added to
the reaction mixture, and the organic phase was
separated therefrom. After the resultant organic phase
was washed with a saturated sodium chloride solution,
the washed phase was dried over anhydrous sodium
sulfate, and the solvent was distilled out under
reduced pressure. The resultant residue, to which 15
mL of methylene chloride and 45 mL of hexane were added,
was stirred for 30 minutes at room temperature and then

filtered out to yield 1.20 g of (5-methyl-2-oxo-1,3-
dioxol-4-yl)methyl 3-{5-[4-(cyclopentyloxy)-2-
hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-
yl)methoxy]phenyl} propanoate as light yellow solid.
NMR(4 00MHz,CDC13) δ value: 1.5-2.1(8H,m), 2.15(3H,s),
2.76(2H,t,J=7.6Hz), 3.11(2H,t,J=7.6Hz), 4.7-5.0(3H,m),
5.35(2H,s), 6.37(1H,dd,J=9.2,2.4Hz), 6.48(1H,d,J=2.0Hz),
6.96(1H,d,J=8.4Hz), 7.38(1H,d,J=7.6Hz), 7.4-7.7(4H,m),
7.83(1H,d,J=8.4Hz), 12.6 6(2H,brs)
Reference Example 1
5.0 g of 3-(2-hydroxyphenyl) propanoic acid,
12.5 g of potassium carbonate, and 7.5 mL of isopropyl
iodide were suspended in 50 mL of N,N-dimethylformamide,
and this suspension was stirred for 5 hours at 80 to
120°C. After the reaction mixture was filtered out,
10.4 g of potassium carbonate and 6 mL of isopropyl
iodide were added to the filtrate, and this mixture was
stirred for 3 hours at 80 to 120°C. The reaction
mixture was added to a mixture of ethyl acetate and
water, and adjusted to pH 2 with 6M hydrochloric acid,
and then the organic phase was separated therefrom.
After the resultant organic phase was washed with water
and a saturated sodium chloride solution successively,
the washed phase was dried over anhydrous magnesium
sulfate, and the solvent was distilled out under
reduced pressure. The resultant residue was purified
by silica gel column chromatography [eluent;
hexane:ethyl acetate=10:1] to yield 4.55 g of isopropyl

3-(2-isopropoxyphenyl) propanoate as colorless oil.
NMR(90MHz,CDCl3) δ value: 1.20(6H,d,J=6.1Hz),
1.34 (6H,d,J=6.1Hz), 2.46-2.68(2H,m), 2.84-3.01(2H,m),
4.42-4.69(1H,m), 4.85-5.14(1H,m), 6.74-6.89(2H,m),
7.10-7.25(2H,m)
Reference Example 2
4.38 g of isopropyl 3-(2-isopropoxyphenyl)
propanoate was dissolved in 44 mL of methylene chloride,
followed by successive dropwise addition of 3.84 mL of
titanium tetrachloride at -5°C and 1.9 mL of α,α-
dichloromethyl methyl ether at 0 to 15°C, and this
mixture was stirred for one hour at -5 to -3°C. The
reaction mixture was added to a mixture of chloroform
and water, then the organic phase was separated
therefrom. After the resultant organic phase was
washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous magnesium sulfate, and the solvent was
distilled out under reduced pressure. The resultant
residue was dissolved in 20 mL of acetonitrile, to
which 7.34 g of sodium dihydrogen phosphate dihydrate
dissolved in 9 mL of water and 3.17 g of a 80% sodium
chlorite dissolved in 5.6 mL of water and 2.9 mL of a
30% hydrogen peroxide solution were successively added
at 5 to 10°C, and this mixture was stirred for one hour
at room temperature. Then, ethyl acetate and water
were added to the reaction mixture, and the organic
phase was separated therefrom. After the resultant

organic phase was washed with water and a saturated
sodium chloride solution successively, the washed phase
was dried over anhydrous magnesium sulfate, and the
solvent was distilled out under reduced pressure. The
resultant residue was purified by silica gel column
chromatography [eluent; hexane:ethyl acetate=1:1] to
yield 2.69 g of 4-isopropoxy-3-(3-isopropoxy-3-
oxopropyl) benzoic acid as light yellowish brown solid.
NMR( 90MHz, CDC13) δ value: 1. 22 ( 6H, d, J=6.1Hz) ,
1.38(6H,d,J=5.9Hz), 2.49-2.67(2H,m), 2.87-3.03(2H,m),
4.50-5.23(2H,m), 6.87(1H,d,J=9.3Hz), 7.92-8.03(2H,m),
10.88 (1H,br)
Reference Example 3
10.0 g of resorcin, 87.8 g of potassium
carbonate, and 54 mL of isopropyl iodide were suspended
in 100 mL of N,N-dimethylformamide, and this suspension
was stirred for 10 hours at 90 to 110°C. After the
reaction mixture was filtered out, 43.9 g of potassium
carbonate and 27 mL of isopropyl iodide were added to
the filtrate, and this mixture was stirred for 3 hours
at 120 to 130°C. The reaction mixture was added to a
mixture of ethyl acetate and water, and adjusted to pH
2 with 6M hydrochloric acid, and then the organic phase
was separated therefrom. After the resultant organic
phase was washed with water and a saturated sodium
chloride solution successively, the washed phase was
dried over anhydrous magnesium sulfate, and the solvent
was distilled out under reduced pressure. The

resultant residue was purified by silica gel column
chromatography [eluent; hexane:ethyl acetate=10:1] to
yield 6.68 g of 1,3-diisopropoxybenzene as light brown
oil.
NMR(90MHz,CDC13) δ value: 1.32 (12H,d,J=6.1Hz) , 4.30-
4.72(2H,m), 6.42-6.51(3H,m), 7.03-7.23(1H,m)
Reference Example 4
70.0 g of salicylaldehyde and 158.5 g of
potassium carbonate were suspended in 700 mL of N,N-
dimethylformamide, to which 68 mL of 3-chloro-2-methyl-
1-propene was added dropwise over 30 minutes at 70°C,
and this mixture was stirred for 30 minutes at the same
temperature. Then, the reaction mixture was added to a
mixture of ethyl acetate and water, and adjusted to pH
3 with 6M hydrochloric acid, and then the organic phase
was separated therefrom. After the resultant organic
phase was washed with water and a saturated sodium
chloride solution successively, the washed phase was
dried over anhydrous magnesium sulfate, and the solvent
was distilled out under reduced pressure. The
resultant residue was dissolved in 350 mL of ethanol,
to which 7.0 g of 5% palladium-carbon was added, and
this mixture was stirred for 4 hours at 35°C in a stream
of hydrogen. After the reaction mixture was filtered
through Celite, the solvent was distilled out under
reduced pressure. The resultant residue was purified
by silica gel column chromatography [eluent;
hexane:toluene=2:1] to yield 92.4 g of 2-

isobutoxybenzaldehyde as light yellow oil.
NMR(90MHz,CDCl3) δ value: 1.07(6H,d,J=6.6Hz), 2.0-
2.2(1H,m), 3.85(2H,d,J=6.4Hz), 6.9-7.1(2H,m), 7.4-
7.7(1H,m), 7.83(1H, dd, J=8 . 1,2.0Hz), 10.55(1H,s)
Reference Example 5
0.92 g of 60% sodium hydride was suspended in
30 mL of tetrahydrofuran, to which 5.0 mL of ethyl
diethylphosphonoacetate was added dropwise over 5
minutes at room temperature, and this mixture was
stirred for 30 minutes at 40°C. Then, after 3.40 g of
2-isobutoxybenzaldehyde dissolved in 20 mL of
tetrahydrofuran was added to the mixture dropwise over
20 minutes at room temperature, this mixture was
stirred for one hour at the same temperature. The
reaction mixture was added to a mixture of ethyl
acetate and water, and the organic phase was separated
therefrom. After the resultant organic phase was
washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous magnesium sulfate, and the solvent was
distilled out under reduced pressure. The resultant
residue was purified by silica gel column
chromatography [eluent; hexane:ethyl acetate=9:l] to
yield 4.30 g of ethyl (E)-3-(2-isobutoxyphenyl)-2-
propenoate as light yellow oil.
NMR(90MHz,CDCl3) δ value: 1.06(6H,d,J=6.6Hz),
1.32(3H,t,J=7.1Hz), 1.8-2.4(1H,m), 3.78(2H,d,J=6.4Hz),
4.25(2H,q,J=7.1Hz), 6.53(1H,d,J=16.4Hz), 6.8-7.6(4H,m),

8.10(1H,d,J=16.1Hz)
Reference Example 6
1.50 g of ethyl (E)-3-(2-isobutoxyphenyl)-2-
propenoate was dissolved in 15 mL of ethanol, to which
0.30 g of 5% palladium-carbon was added, and this
mixture was stirred for one hour at room temperature in
a stream of hydrogen. After the reaction mixture was
filtered through Celite, the solvent was distilled out
under reduced pressure. The resultant residue was
purified by silica gel column chromatography [eluent;
hexane:ethyl acetate=9:l] to yield 0.76 g of ethyl 3-
(2-isobutoxyphenyl) propanoate as colorless oil.
NMR( 90MHz, CDCl3) δ value: 1.04(6H,d,J=6 .6Hz),
1.22(3H,t,J=7.1Hz), 1.9-2.3(1H,m), 2.5-2.7(2H,m),2.9-
3.1(2H,m), 3.73(2H,d,J=6.4Hz), 4.12(2H,q,J=6.8Hz), 6.7-
7.3(4H,m)
Reference Example 7
12.8 g of ethyl 3-(2-isobutoxyphenyl)-2-
propanoate was dissolved in 128 mL of methylene
chloride, to which 11.2 mL of titanium tetrachloride
and 5.1 mL of α,α-dichloromethyl methyl ether were
successively added dropwise at 5 to 10°C, and this
mixture was stirred for 30 minutes at room temperature.
The reaction mixture was added to a mixture of
methylene chloride and water, and the organic phase was
separated therefrom. After the resultant organic phase
was washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over

anhydrous magnesium sulfate, and the solvent was
distilled out under reduced pressure. The resultant
residue was purified by silica gel column
chromatography [eluent; hexane:ethyl acetate=10:1] to
yield 13.4 g of ethyl 3-(5-formyl-2-isobutoxyphenyl)
propanoate as light yellow oil.
NMR(90MHz, CDCl3) δ value: 1.07(6H,d,J=6.6Hz) ,
1.23(3H,t,J=7.1Hz), 2.0-2.4(1H,m), 2.5-2.8(2H,m), 2.9-
3.1(2H,m), 3.84(2H,d,J=6.4Hz), 4.13(2H,q,J=7.1Hz),
6.93(1H,d,J=9.0Hz), 7.7-7.9(2H,m), 9.85(1H,s)
Reference Example 8
13.9 g of ethyl 3-(5-formyl-2-
isobutoxyphenyl) propanoate was dissolved in 139 mL of
acetonitrile, to which 21.0 g of sodium dihydrogen
phosphate dihydrate dissolved in 100 mL of water and
11.3 g of a 80% sodium chlorite dissolved in 39 mL of
water and 11.3 mL of a 30% aq. hydrogen peroxide
solution were successively added at 5 to 10°C, and this
mixture was stirred for 4 hours at room temperature.
Then, chloroform and water were added to the reaction
mixture, and the organic phase was separated therefrom.
After the resultant organic phase was washed with a 5%
aqueous solution of sodium thiosulfate, water and a
saturated sodium chloride solution successively, the
washed phase was dried over anhydrous magnesium sulfate,
and the solvent was distilled out under reduced
pressure to yield 13.2 g of 4-isobutoxy-3-(3-ethoxy-3-
oxopropyl) benzoic acid as light yellow solid.

NMR( 90MHz, CDCl3) δ value: 1.07( 6H, d, J=6 . 6Hz) ,
1.25(3H,t,J=7.3Hz), 2.0-2.4(1H,m), 2.5-2.8(2H,m), 2.9-
3.1(2H,m), 3.82(2H,d,J=6.1Hz), 4.14(2H,q,J=7.1Hz),
6.8 5 (1H,d,J=8.0Hz), 7.9-8.1(2H,m)
Reference Example 9
50 g of 2,4-dihydroxybenzoic acid, 269 g of
potassium carbonate, 123 mL of dimethyl sulfate, and
500 mL of N, N-dimethylformamide were suspended together,
and this suspension was stirred for 6.5 hours at 70 to
80°C. Further, 90 g of potassium carbonate and 61 mL of
dimethyl sulfate were added to this suspension, which
was stirred for another 4 hours at 110 to 115°C. This
reaction mixture was added to a mixture of ethyl
acetate and water, and adjusted to pH 2 with 6M
hydrochloric acid, and then the organic phase was
separated therefrom. After the resultant organic phase
was washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous magnesium sulfate, and the solvent was
distilled out under reduced pressure. The resultant
residue was purified by silica gel column
chromatography [eluent; hexane:ethyl acetate=l:2] to
yield 54 g of methyl 2,4-dimethoxybenzoate as yellow
oil.
NMR(90MHz,CDCl3) 6 value: 3.85(6H,s), 3.89(3H,s), 6.42-
6.55(2H,m), 7.85(1H,d,J=9.3Hz)
Reference Example 10
53 g of methyl 2,4-dimethoxybenzoate was

dissolved in 160 mL of ethanol, to which 104 mL of a 5M
aqueous solution of sodium hydroxide was added, and
this mixture was stirred for 2 hours at 25 to 40°C.
Then, chloroform and water were added to the reaction
mixture, which was adjusted to pH 2 with 6M
hydrochloric acid, and then the organic phase was
separated therefrom. After the resultant organic phase
was washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous magnesium sulfate, and the solvent was
distilled out under reduced pressure to yield 45 g of
2,4-dimethoxybenzoic acid as white solid.
NMR(90MHz,CDCl3) δ value: 3.88(3H,s), 4.04(3H,s), 6.53-
6.69(2H,m), 8 .11(1H,d,J=8.5Hz), 10.34(1H,br)
Reference Example 11
78 g of a 28% solution of sodium methoxide in
methanol was added to 150 mL of a solution of 50 g of
3,4-dihydrocoumarin in methanol at room temperature,
and then this mixture was stirred for 10 minutes at the
same temperature. Then, 96 mL of dimethyl sulfate and
78 g of a 28% solution of sodium methoxide in methanol
were successively added to the mixture, which was
stirred for another 30 minutes at 20 to 40°C. The
reaction mixture was added to a mixture of methylene
chloride and water, and adjusted to pH 2 with 6M
hydrochloric acid, and then the organic phase was
separated therefrom. After the resultant organic phase
was washed with water and a saturated sodium chloride

solution successively, the washed phase was dried over
anhydrous magnesium sulfate, and the solvent was
distilled out under reduced pressure. The resultant
residue was purified by silica gel column
chromatography [eluent; hexane:ethyl acetate=1:1] to
yield 61 g of methyl 3-(2-methoxyphenyl) propanoate as
colorless oil.
NMR (90MHz, CDCl3) δ value: 2.50-2.69(2H,m), 2.86-
3.04(2H,m), 3.66(3H,s), 3.82(3H,s), 6.79-6.94(2H,m),
7.11-7.30(2H,m)
Reference Example 12
9.05 g of hydroxylamine hydrochloride was
dissolved in 84 mL of methanol, to which 40.64 g of a
28% solution of sodium methoxide in methanol was added
at room temperature, and then this mixture was stirred
for 10 minutes. Then, 21 mL of a solution of 7.00 g of
methyl 2-hydroxy-4-methylsalicylate in methanol was
added dropwise to the reaction mixture, which was
stirred for one hour at room temperature and then
another four hours while heating it under reflux. The
reaction mixture was added to water, and adjusted to pH
5 with 6M hydrochloric acid, and then resultant
precipitate was filtered out thereof. The resultant
solid was washed with water and diisopropyl ether
successively to yield 5.95 g of N,2-dihydroxy-4-
methylbenzamide as light yellow solid.
NMR(4 00MHz,DMS0-d6) δ value: 2.26(3H,s),
6.68(1H,d,J=8.8Hz), 6.72(1H,s), 7.57(1H,d,J=8.4Hz),

9.27(1H,s), 11.38 (1H,brs), 12.29 (1H,brs)
Reference Example 13
N,2-dihydroxy-5-methylbenzamide was obtained
in a similar manner as in Reference Example 12.
NMR(4 00MHz,DMSO-d6) δ value: 2.22(3H,s),
6.79(1H,d,J=8.4Hz), 7.20(1H,d,J=8.4Hz), 7.50(1H,s),
9.29(1H,brs), 11.33 (1H,brs), 11.95 (1H,brs)
Reference Example 14
44.0 g of N,2-dihydroxy-4-methylbenzamide was
suspended in 880 mL of tetrahydrofuran, to which 147 mL
of triethylamine was added dropwise at room temperature
and then 28.7 mL of thionyl chloride was added dropwise
at 5 to 10°C successively, and this mixture was stirred
for one hour at room temperature. The reaction mixture
was added to water, and adjusted to pH 1 with 12M
hydrochloric acid, and then resultant precipitate was
filtered out thereof. The resultant solid was washed
with water to yield 35.2 g of 6-methyl-1,2-
benzisoxazol-3-ol as light yellow solid.
NMR (400MHz, DMSO-d6) δ value: 2.45(3H,s),
7.14(1H,d,J=8.0Hz), 7.36(1H,s), 7.59(1H,d,J=8.4Hz),
12.24(1H,brs)
Reference Example 15
5-methyl-1,2-benzisoxazol-3-ol was obtained
in a similar manner as in Reference Example 14.
NMR (400MHz, CDC13) δ value: 2.47(3H,s),
7.30(1H,d,J=8.8Hz), 7.42(1H,d,J=8.8Hz), 7.56(1H,s)

Reference Example 16
20.0 g of methoxymethyl 6-methyl-1,2-
benzisoxazol-3-yl ether was dissolved in 200 mL of
benzene, to which 20.3 g of N-bromosuccinimide and 1.7
g of 2,2'-azobisisobutyronitrile were successively
added at room temperature, and this mixture was stirred
for 30 minutes while heating it under reflux. The
reaction mixture was cooled to room temperature, and
added to a mixture of ethyl acetate and water, and then
the organic phase was separated therefrom. After the
resultant organic phase was washed with a saturated
aqueous solution of sodium hydrogen carbonate and a
saturated sodium chloride solution successively, the
washed phase was dried over anhydrous magnesium sulfate,
and the solvent was distilled out under reduced
pressure to yield 28.5 g of 6-(bromomethyl)-3-
(methoxymethoxy)-1,2-benzisoxazole as light brown oil.
NMR(400MHz,CDC13) δ value: 3.63(3H,s), 4.59(2H,s),
5.56(2H,s), 7.33(1H,dd,J=8.2,0.8Hz), 7.48(1H,s),
7.65(1H,d,J=8.0Hz)
Reference Example 17
Compounds listed in Table 33 were obtained in
a similar manner as in Reference Example 16.

17(1)
yellow oil
17(2)
yellow oil
17(3)
NMR(400MHz,CDCl3) δ value: 1.49(18H,s), 4.50(2H,s),
7.56(2H,d,J=8.4Hz), 8.0 6(2H,d,J=8.4Hz)

17(4)
NMR(400MHz,CDCl3) 6 value: 4.49(2H,s), 6 . 97-7 . 02 (2H,m) ,
7.22-7.34(3H,m), 7.54(2H,d,J=8.4Hz), 7.80-7.86(2H,m)
17(5)
NMR(4 00MHz, CDC13) δ value: 1.31-1.36(6H,m), 4.08-
4.16(4H,m), 4.49(2H,s), 7.48-7.51(2H,m), 7.77-
7.82(2H,m)
17(6)
colorless oil
17(7)
light yellow oil
17 (8)
yellow oil
NMR (400MHz, CDCl3) δ value: 3.89(3H,s), 3.93(3H,s),
4.47(2H,s), 6.99-7.01(2H,m), 7.77(1H,d,J=8.4Hz)
17(9)
NMR(400MHz,CDCl3) δ value: 3.90(3H,s), 3.91(3H,s),
4.47(2H,s), 7.55(1H,dd,J=8.0,2.0Hz) 7.70(1H,d,J=8.0Hz),
7.73(1H,d,J=2.0Hz)
17(10)
yellow oil
17(11)
NMR (90MHz,CDCl3) δ value: 1. 36 ( 6H, d, J=6 . 3Hz) ,
1.40(6H,d,J=5.9Hz), 4.54(2H,s), 4.5-5.0(1H,m), 5.0-
5.5(1H,m), 7.3-7.7(3H,m)
17(12)
yellow oil
17(13)

NMR(400MHz,CDCl3) δ value: 1.47(9H,s), 3.43(3H,s),
4.48(2H,s), 7.21(2H,d,J=8.4Hz), 7.44(2H,d,J=8.4Hz)
17(14)
yellow oil
17(15)
yellow oil
17(16)
NMR(400MHz,CDCl3) δ value: 3.93(3H,s), 4.61(2H,s),
7.53 (1H,d,J=8.0Hz), 7.96(1H,dd,J=8.0,1.6Hz),
8.25 (1H,d,J=1.6Hz)
17 (17)
NMR(400MHz,CDCl3) 5 value: 3.53(3H,s), 3.91(3H,s),
4.56(2H,s), 5.33(2H,s), 7.40(1H,d,J=8.0Hz),
7.66(1H,d,J=8.0Hz), 7.74(1H,s)
Reference Example 18
The following compounds were obtained in a
similar manner as in Reference Example 16.
(1) 2-(chloromethyl)pyrazine
NMR(400MHz,CDCl3) δ value: 4.71(2H,s), 8 . 55-8 . 58 (2H,m) ,
8.77(1H,d,J=1.2Hz)
(2) 5-[4-(bromomethyl)phenyl]-3-isoxazole
methoxymethyl ether
NMR (400MHz, CDC13) δ value: 3.58(3H,s), 4.51(2H,s),
5.37(2H,s), 6.25(1H,s), 7.48(2H,d,J=8.8Hz),
7.71 (2H,d,J=8.8Hz)
(3) 3-[4-(bromomethyl)phenyl]-5-methyl-
1,2,4-oxadiazole
NMR (4 00MHz, CDC13) δ value: 2.66(3H,s), 4.52(2H,s),

7.51(2H,d,J=8.4Hz), 8.04(2H,d,J=8.4Hz)
(4) 5-(bromomethyl)-1,3-bis(methoxymethyl)-
1,3-dihydro-2H-benzimidazol-2-one
light yellow solid
(5) 6-(bromomethyl)-1,2-benzisoxazol-3-yl
methyl ether
NMR (400MHz, CDC13) δ value: 4.19(3H,s), 4.58(2H,s),
7.31(1H,dd,J=8.4,1.2Hz), 7.4 5(1H,d,J=0.8Hz),
7.60(1H,d,J=8.0Hz)
(6) 6-(bromomethyl)-2-methyl-l,2-
benzisoxazol-3(2H)-one
NMR(400MHz,CDCl3) δ value: 3.67(3H,s), 4.54(2H,s), 7.26-
7.31(2H,m), 7.80(1H,d,J=8.0Hz)
(7) 6-(bromomethyl)-2-(methoxymethoxy)-1,2-
benzisoxazol-3(2H)-one
NMR (400MHz, CDCl3) δ value: 3.50(3H,s), 4.54(2H,s),
5.33(2H,s), 7.30-7.33(2H,m), 7.83(1H,d,J=8.0Hz)
(8) 5-(bromomethyl)-3-(methoxymethoxy)-1,2-
benzisoxazole
NMR (400MHz, CDCl3) δ value: 3.64(3H,s), 4.61(2H,s),
5.55(2H,s), 7.44(1H,d,J=8.8Hz), 7.59(1H,dd,J=8.8, 2.0Hz) ,
7.70(1H,d,J=2.0Hz)
(9) tert-butyl 4-(bromomethyl)-lH-pyrazole-
1-carboxylate
NMR(400MHz,CDCl3) δ value: 1.65(9H,s), 4.39(2H,s),
7.74(1H,s), 8.10(1H,s)
(10) ethyl 2-(bromomethyl)-1,3-thiazole-4-
carboxylate

NMR(90MHz,CDCl3) δ value: 1.41(3H,t,J=7.1Hz) ,
4.44(2H,q,J=7.1Hz), 4.77(2H,s), 8.23(1H,s)
(11) ethyl 5-(chloromethyl)-2-
pyrazinecarboxylate
NMR(400MHz,CDCl3) δ value: 1.47(3H,t,J=7.2Hz) ,
4.53(2H,q,J=7.2Hz), 4.77(2H,s), 8.88(1H,d,J=l.5Hz),
9.26(1H,d,J=1.5Hz)
(12) tert-butyl 5-(bromomethyl)-1,3-dioxo-
1,3-dihydro-2H-isoindole-2-carboxylate
NMR( 4 00MHz, CDC13) δ value: 1.63(9H,s), 4.57(2H,s),
7.81(1H,dd,J=7.6,1.6Hz), 7.91-7.95(2H,m)
(13) di(tert-butyl) 6-(bromomethyl)-2,4-
dioxo-1,3(2H,4H)-quinazolinedicarboxylate
NMR(400MHz,CDCl3) δ value: 1.65(9H,s), 1.73(9H,s),
4.51(2H,s), 7.00(1H,d,J=8.4Hz), 7.59(1H,dd,J=8.6,2.4Hz),
8.07(1H,d,J=2.0Hz)
(14) 3-[4-(bromomethyl)phenyl]-4-methyl-
1,2,4-oxadiazol-5(4H)-one
NMR(400MHz,CDCl3) δ value: 3.34(3H,s), 4.53(2H,s),
7.59(2H,d,J=8.8Hz), 7.61(2H,d,J=8.8Hz)
Reference Example 19
3.50 g of methyl 1H-benzimidazole-5-
carboxylate hydrochloride and 6.9 mL of triethylamine
were suspended in 35 mL of methylene chloride, to which
5.05 g of trityl chloride was added in small portions
at 5 to 10°C, and this mixture was stirred for one hour
at the same temperature. The reaction mixture was
added to a mixture of ethyl acetate and water, and then

the organic phase was separated therefrom. After the
resultant organic phase was washed with water and a
saturated sodium chloride solution successively, the
washed phase was dried over anhydrous sodium sulfate,
and the solvent was distilled out under reduced
pressure. The resultant residue was purified by silica
gel column chromatography [eluent; hexane:ethyl
acetate=3:l] to yield 3.55 g of a mixture of methyl 1-
trityl-lH-benzimidazole-5-carboxylate and methyl 3-
trityl-3H-benzimidazole-5-carboxylate as white foam.
methyl 1-trityl-1H-benzimidazole-5-
carboxylate
NMR(400MHz,CDCl3) δ value: 3.90(3H,s),
6.49(1H,d,J=8.8Hz), 7.15-7.19(6H,m), 7.31-7.34(9H,m),
7.61(1H,d,J=8.4Hz), 7.97(1H,s), 8.49(1H,s)
methyl 3-trityl-3H-benzimidazole-5-
carboxylate
NMR(4 00MHz,CDC13) δ value: 3.75(3H,s), 7.15-7.19(7H,m),
7.31-7.34(9H,m), 7.77(1H,d,J=8.4Hz), 7.87(1H,d,J=8.4Hz),
8.02(1H,s)
Reference Example 20
The following compounds were obtained in a
similar manner as in Reference Example 5.
(1) benzyl 4-[ (E)-3-ethoxy-3-oxo-1-
propenyl]-3-methoxybenzoate
NMR(400MHz,CDCl3) δ value: 1.34(3H,t,J=7.1Hz),
3.94(3H,s), 4.27(2H,q,J=7.1Hz), 5.38(2H,s),
6.5 9(1H,d,J=l6.0Hz), 7.33-7.46(5H,m),

7.54(1H,d,J=8.0Hz), 7.60(1H,d,J=l.5Hz),
7.66(1H,dd,J=8.0,1.5Hz), 7.97(1H,d,J=16.0Hz)
(2) ethyl (E)-3-(4-formylphenyl)-2-
propenoate
NMR(400MHz,CDCl3) δ value: 1.35(3H,t,J=7.2Hz),
4.2 9 (2H,q,J=7.2Hz) , 6.55(1H,d,J=16.0Hz),
7.68 (2H,d,J=8.4Hz), 7.71(1H,d,J=16.0Hz),
7.90(2H,d,J=8.4Hz), 10.03(1H,s)
Reference Example 21
The following compounds were obtained in a
similar manner as in Reference Example 6.
(1) 2-[4-(methoxycarbonyl)phenyl]acetic acid
NMR(90MHz,CDCl3) δ value: 3.71(2H,s), 3.91(3H,s),
7.36(2H,d,J=8.1Hz), 8.01(2H,d,J=8.4Hz)
(2) ethyl 3-(4-formylphenyl)propanoate
light yellow oil
NMR (4 00MHz, CDC13) δ value:1.23(3H,t,J=7.2Hz),
2.66(2H,t,J=7.8Hz), 3.04(2H,t,J=7.6Hz),
4.13(2H,q,J=7.2Hz), 7.38(2H,d,J=7.8Hz),
7.81(2H,d,J=8.0Hz), 9.98(1H,s)
(3) 3-cyclopentylphenol
NMR(400MHz,CDCl3) δ value: 1.54-1.81(6H,m), 2.01-
2.08(2H,m), 2.89-2.99(1H,m), 4.64(1H,brs), 6.62-
6.65(1H,m), 6.72(1H,t,J=2.0Hz), 6.82(1H,d,J=7.6Hz),
7.15 (1H,t,J=7.6Hz)
(4) 3-(cyclopentylmethyl)phenol
NMR(400MHz,CDCl3) δ value: 1. 15-1. 20 (2H,m) , 1.49-
1.73(6H,m), 2.03-2.11(1H,m), 2.56(2H,d,J=7.2Hz),

4.59(1H,s), 6.63-6.66(2H,m), 6.74-6.76(1H,m), 7.11-
7.15(1H,m)
(5) 4- (3-ethoxy-3-oxopropyl)-3-
methoxybenzoic acid
NMR(4 00MHz,CDC13) 6 value: 1.24 (3H,t,J=7.1Hz),
2.62 (2H,t,J=7.6Hz), 2.99(2H,t,J=7.6Hz), 3.90(3H,s),
4.14(2H,q,J=7.lHz) , 7.2 5(1H,d,J=7.8Hz),
7.55(1H,d,J=1.5Hz), 7 . 66 (1H,dd,J=7.8,1.5Hz)
Reference Example 22
The following compounds were obtained in a
similar manner as in Reference Example 7.
(1) methyl 3-formyl-1-benzothiophene-7-
carboxylate
NMR(400MHz,CDCl3) δ value: 4.05(3H,s),
7.62(1H,dd,J=8.0,7.6Hz), 8.22(1H,dd,J=7.6,1.2Hz),
8.46(1H,s), 8.95(1H,dd,J=8.0,1.2Hz) , 10.18(1H,s)
(2) methyl 3-formyl-1-benzothiophene-5-
carboxylate
NMR(400MHz,CDCl3) δ value: 3.99(3H,s),
7.95(1H,dd,J=8.6,0.8Hz), 8.15(1H,dd,J=8.6,2.0Hz),
8.40(1H,s), 9.33(1H,dd,J=2.0,0.8Hz), 10.19(1H,s)
(3) methyl 2-(4-formylphenyl)acetate
NMR(90MHz,CDCl3) δ value: 3.6-3.8(2H,m), 3.72(3H,s),
7.46(2H,d,J=8.4Hz), 7.86(2H,d,J=8.0Hz), 10.01(1H,s)
(4) methyl 3-(5-formyl-2-
methoxyphenyl)propanoate
NMR(400MHz,CDCl3) δ value: 2.63(2H,t,J=7.6Hz),
2.99 (2H,t,J=7.6Hz), 3.68(3H,s), 3.92(3H,s),

6.96(1H,d,J=8.6Hz), 7.7 0(1H,d,J=2.0Hz),
7.75(1H,dd,J=8.6,2.0Hz), 9.86(1H,s)
Reference Example 23
The following compounds were obtained in a
similar manner as in Reference Example 8.
(1) 4-(cyclopentylmethyl)-2-methoxybenzoic
acid
NMR (400MHz, CDCl3) δ value: 1. 17-1. 27 (2H,m) , 1.52-
1.74(6H,m), 2.06-2.14(1H,m), 2.67(2H,d,J=7.6Hz),
4.07(3H,s), 6.85(1H,s), 6.96(1H,d,J=8.4Hz),
8.08(1H,d,J=8.0Hz), 10.68(1H,brs)
(2) 4-isopropyl-2-methoxybenzoic acid
NMR(4 00MHz,CDCl3) δ value: 1.28(6H,d,J=7.2Hz), 2.93-
3.00(1H,m), 4.08(3H,s), 6.89(1H,d,J=l.6Hz) ,
7.02(1H,dd,J=8.2,2.0Hz), 8.10(1H,d,J=8.0Hz),
10.72 (1H,brs)
(3) 4-cyclopentyl-2-methoxybenzoic acid
NMR(400MHz,CDCl3) δ value: 1.56-1.87(6H,m), 2.07-
2.14(2H,m), 3.01-3.09(1H,m), 4.08(3H,s),
6.90(1H,d,J=1.2Hz), 7.02(1H,dd,J=8.2,1.6Hz),
8.09(1H,d,J=8.0Hz), 10.68(1H,brs)
Reference Example 24
0.770 g of 4-cyclopentyl-2-
hydroxybenzaldehyde, 0.38 mL of iodomethane, and 0.839
g of potassium carbonate were suspended in 7.7 mL of
N,N-dimethylformamide, and this mixture was stirred for
2 hours at 75°C. The reaction mixture, which was cooled
to room temperature, was added to a mixture of ethyl

acetate and water, and then adjusted to pH 3 with 6M
hydrochloric acid, and the organic phase was separated
therefrom. After the resultant organic phase was
washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous magnesium sulfate, and the solvent was
distilled out under reduced pressure to yield 0.777 g
of 4-cyclopentyl-2-methoxybenzaldehyde as yellow oil.
NMR(400MHz,CDCl3) δ value: 1. 58-1. 87 ( 6H,m) , 2.05-
2.13(2H,m), 2.99-3.07(1H,m), 3.93(3H,s),
6.84(1H,d,J=1.2Hz), 6.91(1H,dd,J=8.6,1.2Hz),
7.75 (1H,d,J=8.0Hz) , 10.40(1H,s)
Reference Example 25
The following compounds were obtained in a
similar manner as in Reference Example 24.
(1) 1-(benzyloxy)-3-bromobenzene
NMR (4 00MHz, CDC13) δ value: 5.04(2H,s), 6 . 89-6 . 91 (1H,m) ,
7.08-7.16(3H,m), 7.31-7.43(5H,m)
(2) 4-isopropyl-2-methoxybenzaldehyde
NMR(400MHz, CDCl3) δ value: 1.28(6H,d,J=7.2Hz), 2.91-
2.98(1H,m), 3.93(3H,s), 6.82(1H,s), 6.90(1H,d,J=8.0Hz),
7.76(1H,d,J=8.0Hz), 10.40(1H,s)
(3) 4-(cyclopentylmethyl)-2-
methoxybenzaldehyde
NMR(400MHz,CDCl3) δ value: 1.17-1.24(2H,m), 1.53-
1.74(6H,m), 2.07-2.14(1H,m), 2.65(2H,d,J=7.2Hz),
3.92(3H,s), 6.78(1H,s), 6.85(1H,d,J=7.6Hz),
7.74 (1H,d,J=8.0Hz) , 10.41(1H,s)

(4) 3-(benzyloxy)benzaldehyde
NMR(400MHz,CDCl3) δ value: 5.13(2H,s), 7 . 23-7 . 49 ( 9H,m) ,
9.98(1H,s)
(5) 4-methyl-3-(4-methylphenyl)-1,2,4-
oxadiazol-5(4H)-one
NMR(4 00MHz,CDC13) δ value: 2.46(3H,s), 3.32(3H,s),
7.37(2H,d,J=8.4Hz), 7.50(2H,d,J=8.4Hz)
(6) 3-methoxy-6-methyl-l,2-benzisoxazole
NMR(400MHz,CDCl3) δ value: 2.48(3H,s), 4.11(3H,s),
7.07(1H,dd,J=8.2,0.4Hz), 7.22(1H,d,J=0.4Hz),
7.48(1H,d,J=8.0Hz)
(7) 2,6-dimethyl-1,2-benzisoxazol-3(2H)-one
NMR (400MHz, CDCl3) δ value: 2.47(3H,s), 3.68(3H,s),
7.00(1H,s), 7.07(1H,d,J=8.0Hz), 7.68(1H,d,J=8.4Hz)
Reference Example 26
Compounds listed in Table 34 were obtained in
a similar manner as in Reference Example 9.

26(1)
NMR(400MHz,CDCl3) 8 value: 2.39(3H,s), 3.91(3H,s),
6.94(1H,d,J=11.7Hz), 6 . 99(1H,d,J=7.8Hz),
7.83(1H,t,J=7.8Hz)
26(2)
NMR(400MHz,CDCl3) δ value: 2.38(3H,s), 3.87(3H,s),
3.90(3H,s), 6.78(1H,s), 6.79(1H,d,J=8.4Hz),
7.72(1H,d,J=8.4Hz)
26(3)
NMR(4 00MHz,CDC13) δ value: 1.00(6H,d,J=6.8Hz),

1.05(6H,d,J=6.8Hz) , 2.0 6(1H,sep,J=6.6Hz),
2.14(1H,sep,J=6.6Hz), 2.36(3H,s), 3.77(2H,d,J=6.6Hz) ,
4.06(2H,d,J=6.8Hz), 6.75(1H,s), 6.76(1H, d, J=8.0Hz) ,
7.71(1H,d,J=8.0Hz)
26(4)
NMR(400MHz,CDCl3) 8 value: 2.34(3H,s), 3.93(3H,s),
6.69(1H,dd,J=8.2,1.0Hz), 6.79(1H,s), 7.71(1H,d,J=8.0Hz),
10.70(1H,s)
26(5)
NMR(400MHz,CDCl3) 8 value: 2.35(3H,s), 3.80(6H,s),
3.89(3H,s), 6.37(2H,s)
26(6)
NMR(400MHz,CDCl3) 8 value: 2.30(3H,s), 3.91(3H,s),
5.67(1H,s), 7.18(1H,d,J=8.0Hz), 7 . 51(1H,dd,J=7.6,2.0Hz),
7.56(1H,s)
26(7)
NMR(400MHz,CDCl3) 8 value: 2.44(3H,s), 3.90(3H,s),
7.2 9(1H,d,J=7.6Hz), 7.86(1H,dd,J=7.6,2.0Hz),
8.19 (1H,d,J=2.0Hz)
26(8)
NMR(400MHz,CDCl3) 8 value: 3.99(3H,s), 5.39(2H,s), 7.34-
7.47(5H,m), 7.69(1H,d,J=l.2Hz), 7.71(1H,d,J=8.0Hz) ,
7.87 (1H,d,J=8.0Hz), 10.51(1H,s)
26(9)
NMR(4 00MHz,CDCl3) δ value: 2 . 33 (3H, d, J=l. 7Hz) ,
3.91(3H,s), 7.25(1H,t,J=8.0Hz),
7.65(1H,dd,J=10.0,1.6Hz), 7.72(1H,dd,J=8.0,1.6Hz),
26(10)

NMR( 90MHz, CDC13) δ value: 1. 36 (12H, d, J=6. 4Hz) ,
2.24(3H,s), 4.4-4.9(1H,m), 5.0-5.5(1H,m),
7.16(1H,d,J=8.1Hz), 7.5-7.6(2H,m)
26(11)
NMR(400MHz,CDCl3) δ value: 2.28(3H,s), 3.94(3H,s),
6.89(1H,d,J=8.8Hz), 7.26(1H,d,J=8.8Hz), 7.63(1H,s),
10.56(1H,s)
26(12)
NMR(400MHz,CDCl3) δ value: 2.44(3H,s), 3.91(3H,s),
7.60(1H,d,J=8.4Hz), 7.7 0(1H, dd,J=8.2,2.4Hz),
7.90(1H,d,J=2.4Hz)
26(13)
NMR(90MHz,CDC13) δ value: 3.97(3H,s), 7.63(1H,t,J=7.8Hz),
8.10(1H,dt, J=8.1, 1.4Hz) , 8.31(1H,dt,J=7.2,1.4Hz),
8.54(1H,t,J=1.4Hz), 10.09(1H,s)
26(14)
NMR(400MHz,CDCl3) δ value: 3.99(3H,s), 5.39(2H,s), 7.34-
7.47(5H,m), 7.69(1H,d,J=l.2Hz), 7.71(1H,d,J=8.0Hz),
7.87(1H,d,J=8.0Hz), 10.51(1H,s)
Reference Example 27
The following compounds were obtained in a
similar manner as in Reference Example 9.
(1) methyl 5-formyl-2-thiophenecarboxylate
NMR(90MHz,CDC13) δ value: 3.94(3H,s), 7.74(1H,d,J=3.9Hz),
7.85(1H,d,J=3.9Hz), 9.98(1H,s)
(2) diethyl 2,5-pyridinedicarboxylate
NMR(90MHz,CDC13) δ value: 1.43(3H,t,J=7.1Hz),
1.4 7(3H,t,J=7.lHz) , 4.4 6(2H,q,J=7.1Hz) ,

4.52(2H,q,J=7.1Hz), 8.20(1H,d,J=8.4Hz) ,
8.45(1H,dd,J=8.2,2.0Hz), 9.33(1H,d,J=2.0Hz)
Reference Example 28
5.66 g of cyclopentyltriphenylphosphonim
bromide was suspended in 25 mL of diethyl ether, to
which 8.8 mL of a solution of n~butyllithium in n-
hexane (1.56 M) was added dropwise at -30°C. After the
reaction mixture was stirred for one hour at 5°C, 2.67 g
of 3-(benzyloxy)benzaldehyde dissolved in 5 mL of
diethyl ether was added to the reaction mixture, which
was then stirred another one hour at room temperature.
The reaction mixture was added to a mixture of
methylene chloride and dilute hydrochloric acid, and
then the organic phase was separated therefrom. After
the resultant organic phase was washed with water and a
saturated sodium chloride solution successively, the
washed phase was dried over anhydrous magnesium sulfate,
and the solvent was distilled out under reduced
pressure. The resultant residue was purified by silica
gel column chromatography [eluent; hexane:ethyl
acetate=5:l] to yield 1.06 g of 1-(benzyloxy)-3-
(cyclopentylidenemethyl)benzene as light yellow solid.
NMR (400MHz, CDC13) δ value: 1.62-1.69(2H,m), 1.73-
1.78(2H,m), 2.46-2.53(4H,m), S.07(2H,s),
6.32(1H,d,J=2.4Hz), 6.79(1H,d,J=8.0Hz), 6.90-6.94(2H,m),
7.20-7.45(6H,m)
Reference Example 29
9.10 g of (4-bromo-3-methylphenyl)methanol

was dissolved in 91 mL of methylene chloride and cooled
to 5°C, to which 19.7 mL of N-ethyldiisopropylamine and
6.9 mL of chloromethyl methyl ether were successively
added dropwise at 5 to 10°C, and then this mixture was
stirred for 2.5 hours at room temperature. Water was
added to the reaction mixture and adjusted to pH 7 with
6M hydrochloric acid, and then the organic phase was
separated therefrom. After the resultant organic phase
was washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous sodium sulfate, and the solvent was distilled
out under reduced pressure. The resultant residue was
purified by silica gel column chromatography [eluent;
hexane:ethyl acetate=5:l] to yield 10.44 g of 1-bromo-
4-[(methoxymethoxy)methyl]-2-methylbenzene as yellow
oil.
NMR (400MHz, CDC13) δ value: 2.40(3H,s), 3.41(3H,s),
4.52(2H,s), 4.71(2H,s), 7.04(1H,dd,J=8.2,2.0Hz),
7.23(1H,d,J=1.6Hz), 7.50(1H,d,J=8.0Hz)
Reference Example 30
The following compounds were obtained in a
similar manner as in Reference Example 29.
(1) 1,3-bis(methoxymethyl)-5-methyl-l,3-
dihydro-2H-benzimidazol-2-one
NMR(400MHz,CDCl3) δ value: 2.41(3H,s), 3.36(3H,s),
3.37(3H,s), 5.33(2H,s), 5.34(2H,s), 6.94(1H,d,J=7.2Hz),
6.96(1H,d,J=0.8Hz), 7.05(1H,d,J=8.0Hz)
(2) methoxymethyl 6-methyl-l,2-benzisoxazol-

3-yl ether
NMR(400MHz,CDCl3) δ value: 2.50(3H,s), 3.63(3H,s),
5.54(2H,s), 7.11(1H,dd,J=8.0,0.8Hz), 7.25(1H,s),
7.54(1H,d,J=8.0Hz)
(3) methoxymethyl 5-methyl-l,2-benzisoxazol-
3-yl ether
NMR(400MHz,CDCl3) δ value: 2.46(3H,s), 3.63(3H,s),
5.54(2H,s), 7.33(1H,d,J=8.8Hz), 7.36(1H,d,J=8.8Hz) ,
7.45 (1H,s)
(4) 2-(methoxymethyl)-6-methyl-l, 2-
benzisoxazol-3(2H)-one
NMR(400MHz,CDCl3) δ value: 2.49(3H,s), 3.44(3H,s),
5.31(2H,s), 7.05(1H,d,J=0.8Hz), 7.10(1H,dd,J=8.0,0.8Hz),
7.72(1H,d,J=8.0Hz)
(5) (l-benzothiophen-5-ylmethoxy)methyl
methyl ether
NMR (4 00MHz,CDCl3) 6 value: 3.42(3H,s), 4.71(2H,s),
4.73(2H,s), 7.31-7.36(2H,m), 7.44(1H,d,J=5.4Hz),
7.81(1H,s), 7.86(1H,d,J=8.3Hz)
(6) methyl 3-(methoxymethoxy)-4-
methylbenzoate
NMR(400MHz,CDCl3) 6 value: 2.30(3H,s), 3.50(3H,s),
3.89(3H,s), 5.25(2H,s), 7.20(1H,d,J=8.0Hz),
7.61(1H,dd,J=8.0,1.6Hz), 7.68(1H,d,J=l.6Hz),
(7) 3-(methoxymethoxy)-5-(4-
methylphenyl)isoxazole
NMR(400MHz,CDCl3) δ value: 2.38(3H,s), 3.57(3H,s),
5.35(2H,s), 6.17(1H,s), 7.23(2H,d,J=8.0Hz),

7.61(2H,d,J=8.0Hz)
Reference Example 31
4.00 g of 1-bromo-4-[(methoxymethoxy)methyl]-
2-methylbenzene was dissolved in 40 mL of
tetrahydrofuran, to which 11.5 mL of a solution of n-
butyllithium in n-hexane (1.56 M) was added dropwise at
-65 to -60°C, and then this mixture was stirred for 30
minutes at -65°C. Then, 20 mL of N,N-dimethylformamide
was added dropwise thereto at -65 to -40°C, and a
temperature of this reaction mixture was raised to room
temperature over one hour and was stirred for another
one hour at room temperature. Water was added to the
reaction mixture and adjusted to pH 5 with 6M
hydrochloric acid, followed by addition thereto of
ethyl acetate, and then the organic phase was separated
therefrom. After the resultant organic phase was
washed with.water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous magnesium sulfate, and the solvent was
distilled out under reduced pressure. The resultant
residue was purified by silica gel column
chromatography [eluent; hexane:ethyl acetate=5:l] to
yield 1.54 g of 4-[(methoxymethoxy)methyl]-2-
methylbenzaldehyde as colorless oil.
NMR (4 00MHz, CDC13) δ value: 2.68(3H,s), 3.43(3H,s),
4.63(2H,s), 4.76(2H,s), 7.26(1H,s), 7.35(1H,d,J=7.6Hz),
7.79(1H,d,J=7.6Hz), 10.26(1H,s)

Reference Example 32
The following compounds were obtained in a
similar manner as in Reference Example 31.
(1) diethyl 4-methylphenylphosphonate
NMR(400MHz,CDC13) 6 value: 1.30-1.36(6H,m), 2.40(3H,s),
4.07-4.16(4H,m), 7.26-7.29(2H,m), 7.68-7.73(2H,m)
(2) 2-(hydroxymethyl)-1-benzothiophene-5-
carboaldehyde
NMR(400MHz,CDCl3) δ value: 2.12(1H,brs), 4.98(2H,s),
7.34(1H,s), 7.83(1H,dd,J=8.4,1.6Hz), 7.94(1H,d,J=8.0Hz),
8.20(1H,d,J=1.2Hz), 10.08(1H,s)
(3) ethyl 5-(hydroxymethyl)-1-
benzothiophene-2-carboxylate
NMR(400MHz,CDCl3) δ value: 1.42(3H,t,J=7.1Hz),
1.80(1H,brs), 4.41(2H,q,J=7.1Hz), 4.82(2H,d,J=5.1Hz),
7.46(1H,dd, J=8.6,1.6Hz) , 7.83-7.86(2H,m), 8.03(1H,s)
(4) 2-fluoro-4-methylbenzoic acid
NMR (400MHz, CDCl3) δ value: 2.42(3H,s),
6.98(1H,d,J=12.0Hz), 7.04(1H,d,J=7.8Hz),
7.92(1H,t,J=7.8Hz)
Reference Example 33
2.90 g of 3-cyclopentylphenol was dissolved
in 14.5 mL of toluene, to which 0.21 mL of tin
tetrachloride and 1.7 mL of tri-n-butylamine were added
at room temperature in a stream of nitrogen, and then
this mixture was stirred for 30 minutes at room
temperature followed by addition thereto of 1.18 g of
paraformaldehyde, and this mixture was stirred for 1.5

hours at 80°C. Then, the reaction mixture was cooled to
room temperature and poured into water, to which
methylene chloride was added, and then the organic
phase was separated therefrom. After the resultant
organic phase was washed with water and a saturated
sodium chloride solution successively, the washed phase
was dried over anhydrous magnesium sulfate, and the
solvent was distilled out under reduced pressure. The
resultant residue was purified by silica gel column
chromatography [eluent; hexane:ethyl acetate=10:1] to
yield 0.77 g of 4-cyclopentyl-2-hydroxybenzaldehyde as
yellow oil.
NMR(4 00MHz,CDCl3) δ value: 1.57-1.84(6H,m), 2.04-
2.11(2H,m), 2.97-3.05(1H,m), 6.86(1H,s),
6.90 (1H,dd,J=7.8,1.6Hz) , 7.45(1H,d,J=8.0Hz), 9.83(1H,s),
11.04(1H,s)
Reference Example 34
The following compounds were obtained in a
similar manner as in Reference Example 33.
(1) 2-hydroxy-4-isopropylbenzaldehyde
NMR(90MHz,CDCl3) δ value: 1.26(6H,d,J=6.8Hz), 2.79-
3.06(1H,m), 6.85-6.94(2H,m), 7.47(1H,d,J=8.5Hz),
9.84(1H,s), 11.03(1H,s)
(2) 4-(cyclopentylmethyl)-2-
hydroxybenzaldehyde
NMR(400MHz,CDCl3) 6 value: 1.16-1.21(2H,m), 1.52-
1.73(6H,m), 2.06-2.14(1H,m), 2.62(2H,d,J=7.6Hz),
6.80(1H,s), 6.83(1H,dd,J=8.0,1.6Hz), 7.44(1H,d,J=8.0Hz),

9.83(1H,s), 11.04(1H,s)
Reference Example 35
1.61 mL of cyclopentanecarboxylic acid was
dissolved in 5 mL of tetrahydrofuran, and this mixture
was added dropwise to 50 mL of solution of lithium
diisopropylamide in tetrahydrofuran prepared from 20.9
mL of n-butyllithium in n-hexane (1.56 M) and 4.58 mL
of diisopropylamine at -30°C, and then this mixture was
stirred for one hour at 5°C and for another one hour at
room temperature. After the reaction mixture was
cooled to -30°C, a solution of 5.00 g of methyl 4-
(bromomethyl)-2-methoxybenzoate in 5 mL of
tetrahydrofuran was added dropwise to this mixture,
which was then stirred for 1.5 hours at -10°C and for
another 1.5 hours at room temperature. A saturated
aqueous solution of ammonium chloride and diethyl ether
were successively added to the reaction mixture, and
the organic phase was separated therefrom. A saturated
aqueous solution of sodium hydrogen carbonate was added
to the resultant organic phase, from which an aqueous
phase was separated, followed by adjustment to pH 2
with 6M hydrochloric acid, and then the organic layer
was separated therefrom by adding chloroform thereto.
After the resultant organic phase was washed with water
and a saturated sodium chloride solution successively,
the washed phase was dried over anhydrous magnesium
sulfate, and the solvent was distilled out under
reduced pressure. The resultant residue was purified

by silica gel column chromatography [eluent;
hexane:ethyl acetate=3:2] to yield 0.718 g of l-[3-
methoxy-4-(methoxycarbonyl)benzyl]-
cyclopentanecarboxylic acid as colorless oil.
NMR(400MHz,CDCl3) δ value: 1.62-1.72(6H,m), 2.05-
2.12(2H,m), 3.00(2H,s), 3.84(3H,s), 3.87(3H,s), 6.78-
6.80(3H,m), 7.71(1H,d,J=8.0Hz)
Reference Example 36
1.50 g of 1-[3-methoxy-4-(methoxycarbonyl) -
benzyl]cyclopentanecarboxylic acid was dissolved in 15
mL of tetrahydrofuran, to which 10.3 mL of a 1M
solution of borane in tetrahydrofuran was added
dropwise at 5 to 10°C, and then this mixture was stirred
for one hour at room temperature. Then, acetone and
water were successively added dropwise to the reaction
mixture, which was added to a mixture of ethyl acetate
and water, and the organic phase was separated
therefrom. After the resultant organic phase was
washed with a saturated aqueous solution of sodium
hydrogen carbonate, water, and a saturated sodium
chloride solution successively, the washed phase was
dried over anhydrous magnesium sulfate, and the solvent
was distilled out under reduced pressure. The
resultant residue was purified by silica gel column
chromatography [eluent; hexane:ethyl acetate=l:l] to
yield 0.564 g of methyl 4-{[1-(hydroxymethyl)
cyclopentyl]methyl}-2-methoxybenzoate as colorless oil.
NMR(400MHz,CDCl3) 6 value: 1. 38-1. 66 ( 9H, m) , 2.74(2H,s),

3.32(2H,s), 3.88(3H,s), 3.90(3H,s), 6.83-6.86(2H,m),
7.72(1H,d,J=8.4Hz)
Reference Example 37
1.16 g of methyl 4-{[1-(hydroxymethyl)
cyclopentyl]methyl}-2-methoxybenzoate and 0.764 g of 4-
(dimethylamino)pyridine were dissolved in 10 mL of
methylene chloride, to which a solution of 0.953 g of
para-toluenesulfonyl chloride in 10 mL of methylene
chloride was added dropwise at 0°C, and then this
mixture was stirred for one hour at room temperature.
Further, 1.53 g of 4-(dimethylamino)pyridine and a
solution of 1.91 g of para-toluenesulfonyl chloride in
15 mL of methylene chloride was added thereto, and this
mixture was stirred for another one hour at room
temperature. The reaction mixture was added to water,
and the organic phase was separated therefrom. After
the resultant organic phase was washed with water and a
saturated sodium chloride solution successively, the
washed phase was dried over anhydrous magnesium sulfate,
and the solvent was distilled out under reduced
pressure. The resultant residue was purified by silica
gel column chromatography [eluent; hexane:ethyl
acetate=2:l] to yield 1.58 g of methyl 2-methoxy-4-
{[1-({[(4-methylphenyl)sulfonyl]oxy}methyl)-
cyclopentyl]methyl} benzoate as colorless oil.
NMR(400MHz,CDCl3) δ value: 1.33-1.36(2H,m), 1.47-
1.53(4H,m), 1.59-1.63(2H,m), 2.46(3H,s), 2.71(2H,s),
3.66(2H,s), 3.88(6H,s), 6.64(1H,dd,J=8.0,1.6Hz),

6.80(1H,d,J=1.6Hz), 7.35(2H,d,J=8.0Hz),
7.61(1H,d,J=8.0Hz), 7.7 7-7.80(2H,m)
Reference Example 38
Phenyl 4-methylbenzenesulfonate was obtained
in a similar manner as in Reference Example 37.
NMR(400MHz,CDCl3) δ value: 2.45(3H,s), 6.96-6.99(2H,m),
7.22-7.32(5H,m), 7.7 0(2H,d,J=8.8Hz)
Reference Example 39
1.58 g of methyl 2-methoxy-4-{[1-({[(4-
methylphenyl)sulfonyl]oxy}methyl)cyclopentyl]methyl}
benzoate, 0.716 g of zinc dust, and 1.64 g of sodium
iodide were suspended in 16 mL of N,N-dimethylformamide,
and this mixture was stirred for 2.5 hours at 115°C.
The reaction mixture was cooled to room temperature, to
which diethyl ether was added, and filtered through
Celite. The filtrate was added to a mixture of ethyl
acetate and dilute hydrochloric acid, and the organic
phase was separated therefrom. After the resultant
organic phase was washed with an aqueous solution of
sodium thiosulfate, water and a saturated sodium
chloride solution successively, the washed phase was
dried over anhydrous magnesium sulfate, and the solvent
was distilled out under reduced pressure. The
resultant residue was purified by silica gel column
chromatography [eluent; hexane:ethyl acetate=2:l] to
yield 0.725 g of methyl 2-methoxy-4-[(1-
methylcyclopentyl)methyl] benzoate as colorless oil.
NMR(4 00MHz,CDC13) δ value: 0.90(3H,s), 1.30-1.34(2H,m),

1.49-1.55(2H,m), 1.65-1.68(4H,m), 2.62(2H,s),
3.88(3H,s), 3.90(3H,s), 6 . 75-6.79(2H,m),
7.71 (1H,d,J=8.0Hz)
Reference Example 40
8.75 g of copper (II) bromide was suspended
in 40 mL of acetonitrile, to which a solution of 5.82
mL of tert-butyl nitrite in 5 mL of acetonitrile was
added dropwise at room temperature in a stream of
nitrogen and then a suspension of 5.00 g of 4-amino-2-
hydroxybenzoic acid in 100 mL of acetonitrile was added
dropwise in an ice bath, and this suspension was
stirred for 2 hours at 5 to 10°C. The reaction mixture
was added dropwise to a mixture of ice and 6M
hydrochloric acid, to which diethyl ether was added,
and the organic phase was separated therefrom. After
the resultant organic phase was washed with 6M
hydrochloric acid, water, and a saturated sodium
chloride solution successively, the washed phase was
dried over anhydrous magnesium sulfate, and the solvent
was distilled out under reduced pressure to yield 7.84
g of 4-bromo-2-hydroxybenzoic acid as black solid.
NMR(4 00MHz,DMSO-d6) δ value: 7.13 (1H,dd,J=8.4,2.0Hz),
7.22 (1H,d,J=2.0Hz), 7.71(1H,d,J=8.4Hz), 10.5-
10.7(1H,br), ll.l-11.5(1H,br)
Reference Example 41
1.85 g of magnesium was suspended in 15 mL of
diethyl ether, to which a catalytic amount of iodine
was added and then a solution of 20.00 g of 1-

(benzyloxy)-3-bromobenzene in 40 mL of diethyl ether
was added dropwise and this mixture was stirred for 8
hours while heating it under reflux. The reaction
mixture was cooled to 5°C, to which a solution of 6.72
mL of cyclopentanone in 20 mL of diethyl ether was
added dropwise, and this mixture was stirred for one
hour at room temperature. Then an aqueous solution of
ammonia chloride was added to the ice-cooled reaction
mixture, and the organic phase was separated therefrom.
After the resultant organic phase was washed with water
and a saturated sodium chloride solution successively,
the washed phase was dried over anhydrous magnesium
sulfate, and the solvent was distilled out under
reduced pressure. The resultant residue was purified
by silica gel column chromatography [eluent;
hexane:ethyl acetate=10:1] to yield 7.65 g of l-[3-
(benzyloxy)phenyl] cyclopentanol as yellow oil.
NMR( 4 00MHz, CDCl3) δ value: 1.52(1H,s), 1. 79-1. 88 (2H, m) ,
1.93-2.04(6H,m), 5.08(2H,s),
6.8 5(1H,ddd,J=8.4,2.8,1.2Hz),
7.08(1H,ddd,J=7.6,1.6,0.8Hz), 7.16-7.17(1H,m), 7.24-
7.46(6H,m)
Reference Example 42
10.55 g of methyl 4-bromo-3-methylbenzoate
was dissolved in 110 mL of tetrahydrofuran, to which
1.31 g of lithium aluminium hydride was added dropwise
in small portions at -30 to -20°C, and this mixture was
stirred for 15 minutes at -20°C. Then a mixed solution

of methanol and water (4:1) was added dropwise to the
reaction mixture, and this mixture was stirred for 30
minutes at room temperature. The reaction mixture, to
which water was added, was adjusted to pH 7 with 6M
hydrochloric acid followed by addition of ethyl acetate,
and the organic phase was separated therefrom. After
the resultant organic phase was washed with water and a
saturated sodium chloride solution successively, the
washed phase was dried over anhydrous magnesium sulfate,
and the solvent was distilled out under reduced
pressure to yield 9.20 g of (4-bromo-3-
methylphenyl)methanol as brown oil.
NMR(4 00MHz,CDCl3) δ value: 1.74(1H,brs), 2.40(3H,s),
4.62(2H,s), 7.04(1H,dd,J=8.2,2.0Hz), 7.23(1H,d,J=2.0Hz) ,
7.50(1H,d,J=8.0Hz)
Reference Example 4 3
A mixture of (l-trityl-lH-benzimidazol-5-
yl)methanol and (l-trityl-lH-benzimidazol-6-yl)methanol
was obtained in a similar manner as in Reference
Example 42.
(l-trityl-lH-benzimidazol-5-yl)methanol
NMR(400MHz,CDCl3) δ value: 2 . 05 (1H, brs) , 4.71(2H,s),
6.46(1H,d,J=8.4Hz) , 6 . 94(1H, dd,J=8.4,1. 6Hz) , 7.16-
7.19(6H,m), 7.31-7.32(9H,m), 7.73(1H,d,J=l.6Hz),
7.88(1H,s)
(l-trityl-lH-benzimidazol-6-yl)methanol
NMR(400MHz,CDCl3) δ value: 1. 56 (1H, brs) , 4.45(2H,s),
6.44(1H,s), 7.16-7.19(6H,m), 7.31-7.32(10H,m),

7.73(1H,d,J=1.6Hz), 7.88(1H,s)
Reference Example 44
4.00 g of 2-amino-5-methylbenzoic acid was
dissolved in 40 mL of 1,4-dioxane, to which 5.5 mL of
triethylamine and 6.8 mL of diphenylphosphoryl azide
were successively added, and this mixture was stirred
for 1.5 hours while heating it under reflux. The
reaction mixture, to which a mixture of ethyl acetate
and water was added, was adjusted to pH 7 with 1M
hydrochloric acid, and the organic phase was separated
therefrom. After the resultant organic phase was
washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous sodium sulfate, and the solvent was distilled
out under reduced pressure to yield 2.96 g of 5-methyl-
1,3-dihydro-2H-benzimidazol-2-one as light yellow solid.
NMR(400MHz,DMSO-d6) δ value: 2.27(3H,s), 6.72-6.75(2H,m),
6.80 (1H,d,J=8.0Hz) , 10.47(1H,s), 10.51(1H,s)
Reference Example 45
1.00 g of methyl 3-formyl-1-benzothiophene-7-
carboxylate was dissolved in a mixed solution of 15 mL
of ethanol and 15 mL of tetrahydrofuran, to which 86 mg
of sodium borohydride was added at room temperature,
and this solution was stirred for one hour at the same
temperature. After acetone was added dropwise to the
reaction mixture, from which the solvent was distilled
out under reduced pressure, followed by addition of
ethyl acetate and water, and this mixture was adjusted

to pH 6 with 6M hydrochloric acid, and the organic
phase was separated therefrom. After the resultant
organic phase was washed with water and a saturated
sodium chloride solution successively, the washed phase
was dried over anhydrous magnesium sulfate, and the
solvent was distilled out under reduced pressure to
yield 0.97 g of methyl 3-(hydroxymethyl)-1-
benzothiophene-7-carboxylate as light yellow solid.
NMR(400MHz,CDCl3) δ value: 1. 73 (1H,brs), 4.03(3H,s),
4.97(2H,s), 7.47-7.53(2H,m), 8.11(1H,d,J=8.0Hz),
8.14(1H,d,J=8.0Hz)
Reference Example 4 6
Compounds listed in Table 35 were obtained in
a similar manner as in Reference Example 45.
[Table 35]

46(1)
NMR(400MHz,CDCl3) δ value: 1.24(3H,t,J=7.2Hz) ,
1.69(1H,brs), 2.61(2H,t,J=7.6Hz), 2.95(2H,t,J=7.6Hz),

4.12(2H,q,J=7.2Hz), 4.66(2H,s), 7.20(2H,d,J=8.OHz),
7.29(2H,d,J=8.0Hz)
46(2)
NMR(4 00MHz,CDCl3) δ value: 1. 34(3H,t,J=7.1Hz),
2.00(1H,brs), 4.26(2H,q,J=7.1Hz), 4.72(2H,s),
6.42(1H,d,J=l6.1Hz), 7.38(2H,d,J=8.1Hz),
7.51(2H,d,J=8.1Hz), 7.66(1H,d,J=16.1Hz)
46(3)
NMR(90MHz,CDCl3) δ value: 2.02(1H,brs), 3.92(3H,s),
4.75(2H,s), 7.34-7.62(2H,m), 7.90-8.02(2H,m)
46(4)
NMR(90MHz, CDCl3) δ value: 1.77 (1H,brs), 2.48(3H,s),
4.64(2H,s), 7.16-7.38(4H,m)
46(5)
NMR(400MHz,CDCl3) 6 value: 1. 71 (1H, brs ) ,
2.61(2H,t,J=7.6Hz), 2.93(2H,t,J=7.6Hz), 3.67(3H,s),
3.82(3H,s), 4.59(2H,s), 6.82(1H,d,J=8.3Hz),
7.15(1H,d,J=2.2Hz), 7.19(1H,dd,J=8.3,2.2Hz)
46(6)
NMR(400MHz,CDCl3) δ value : 1. 58-1. 63 (1H, m) ,
4.58 (2H,d,J=6.OHz) , 5.96(2H,s), 6.78(1H,d,J=8.OHz),
6.82(1H,dd,J=8.0,1.6Hz), 6.8 7(1H,d,J=l.6Hz)
Reference Example 4 7
The following compounds were obtained in a
similar manner as in Reference Example 45.
(1) 1-[4-(hydroxymethyl)phenyl]-4-methyl-
2,3-piperazinedione
NMR (400MHz, DMSO-d6) δ value: 2.99(3H,s),

3.67(2H,dd,J=6.8,4.8Hz), 3.92(2H,dd,J=6.8,4.8Hz),
4.50(2H,d, J=5.6Hz) , 5.22(1H,t,J=5.8Hz), 7.31-7.36(4H,m)
(2) 3-[4-(hydroxymethyl)phenyl]-1,3-
oxazolidin-2-one
NMR (400MHz,DMSO-d6) δ value: 4.05(2H,t,J=8.2Hz), 4.41-
4.47(4H,m), 5.14(1H,t,J=5.8Hz), 7.32(2H,d,J=8.0Hz) ,
7.51 (1H,dd,J=9.0,2.2Hz), 7.52(1H,dd,J=9.0,2.2Hz)
(3) methyl 3-(hydroxymethyl)-1-
benzothiophene-5-carboxylate
NMR(400MHz, CDC13) 6 value: 2.01 (1H,brs), 3.96(3H,s),
4.99(2H,s), 7.47(1H,s), 7.89(1H,d,J=8.4Hz),
8.01(1H,dd,J=8.4,1.6Hz) , 8.54(1H,d,J=l.2Hz)
(4) methyl 5-(hydroxymethyl)-2-
thiophenecarboxylate
NMR(90MHz,CDCl3) δ value: 2.3-2.5(1H,m), 3.87(3H,s),
4.85(2H,d,J=4.9Hz), 6.98(1H,dd,J=3.7,0.7Hz),
7.66(1H,d,J=3.7Hz)
(5) l-benzothiophen-5-ylmethanol
NMR(400MHz,CDCl3) δ value: 1.78(1H,brs), 4.80(2H,s),
7.31-7.36(2H,m), 7.45(1H,d,J=5.6Hz), 7.81(1H,s),
7.86(1H,d,J=8.4Hz)
Reference Example 4 8
Benzyl 2-(4-formylphenyl)acetate was obtained
in a similar manner as in Reference Example 9.
NMR (90MHz, CDCl3) 6 value: 3.76(2H,s), 5.15(2H,s), 7.16-
7.55(7H,m), 7.76-7.89(2H,m), 10.00(1H,s)
Reference Example 4 9
29.7 g of hydroxylamine hydrochloride was

dissolved in 100 mL of methanol, to which 82.4 g of a
28% solution of sodium methoxide in methanol was added
at room temperature, and this solution was stirred for
one hour at the same temperature. 10.0 g of 4-
methylbenzonitrile was added to this mixture, which was
then stirred for 2 hours at room temperature. The
reaction mixture was concentrated under reduced
pressure, to which water was added, and adjusted to pH
8 with 6M hydrochloric acid, followed by addition
thereto of ethyl acetate, and the organic phase was
separated therefrom. After the resultant organic phase
was washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous magnesium sulfate, and the solvent was
distilled out under reduced pressure to yield 11.6 g of
N'-hydroxy-4-methylbenzenecarboxyimidamide as white
solid.
NMR (400MHz, CDC13) δ value: 2.37(3H,s), 4 . 87 (2H, brs) ,
8.31(1H,brs), 7.20(2H,d,J=8.0Hz), 7.51(2H,d,J=8.0Hz)
Reference Example 50
1.00 g of N'-hydroxy-4-
methylbenzenecarboxyimidamide was dissolved in 14 mL of
N,N-dimethylformamide, to which 0.59 mL of pyridine was
added at room temperature and then 1.28 g of 2-
ethylhexyl chloroformate was added at 5°C, this solution
was stirred for one hour at the same temperature. The
reaction mixture was added to a mixture of water and
ethyl acetate, and the organic phase was separated

therefrom. After the resultant organic phase was
washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous sodium sulfate, and the solvent was distilled
out under reduced pressure. 14 mL of xylene was added
to the resultant residue, and which was stirred for one
hour while heating it under reflux. The reaction
mixture was cooled to room temperature, from which
resultant precipitate was filtered out, and the
resultant precipitate was washed with hexane and then
with diisopropyl ether to yield 0.78 g of 3-(4-
methylphenyl)-1,2,4-oxadiazol-5(4H)-one as white solid.
NMR(4 00MHz,DMSO-d6) δ value: 2.38(3H,s),
7.39(2H,d,J=8.4Hz), 7.70(2H,d,J=8.4Hz), 12.90(1H,brs)
Reference Example 51
2.00 g of N'-hydroxy-4-
methylbenzenecarboxyimidamide was dissolved in 40 mL of
acetic anhydride, and this solution was stirred for 1.5
hours while heating it under reflux. After the
reaction mixture was cooled to room temperature, the
solvent was distilled out thereof under reduced
pressure, and then the resultant residue was purified
by silica gel column chromatography to yield 1.20 g of
5-methyl-3-(4-methylphenyl)-1,2,4-oxadiazole as yellow
solid.
NMR (400MHz, CDCl3) δ value: 2.41(3H,s), 2.65(3H,s),
7.28(2H,d,J=8.0Hz), 7.94(2H,d,J=8.0Hz)

Reference Example 52
1.00 g of 4-methyl-1H-pyrazole and 2.5 mL of
triethylamine were dissolved in 10 mL of
tetrahydrofuran, to which 3.1 mL of di-tert-butyl
dicarbonate and 73 mg of 4-(dimethylamino)pyridine were
successively added, and this solution was stirred for
30 minutes at room temperature. The reaction mixture
was added to a mixture of water and ethyl acetate, and
adjusted to pH 7 with 6M hydrochloric acid, and then
the organic phase was separated therefrom. After the
resultant organic phase was washed with water and a
saturated sodium chloride solution successively, the
washed phase was dried over anhydrous magnesium sulfate,
and the solvent was distilled out under reduced
pressure to yield 2.23 g of tert-butyl 4-methyl-1H-
pyrazole-1-carboxylate as light yellow oil.
NMR(4 00MHz,CDCl3) δ value: 1.64(9H,s), 2.09(3H,s),
7.54(1H,s), 7.84(1H,s)
Reference Example 53
The following compounds were obtained in a
similar manner as in Reference Example 52.
(1) di-tert-butyl 6-methyl-2,4-dioxo-1,3-
(2H,4H)-quinazolinedicarboxylate
NMR (400MHz, CDCl3) δ value: 1.64(9H,s), 1.73(9H,s),
2.38(3H,s), 6.90(1H,d,J=8.0Hz), 7.36(1H,dd,J=8.4,2.0Hz),
7.85(1H,d,J=2.0Hz)
(2) tert-butyl methyl[(4-
methylphenyl)sulfonyl]carbamate

NMR(400MHz,CDCl3) δ value: 1.35(9H,s), 2.44(3H,s),
3.35(3H,s), 7.31(2H,d,J=8.0Hz), 7.78(2H,d,J=8.4Hz)
(3) tert-butyl methyl(4-methylbenzoyl)-
carbamate
NMR (4 00MHz, CDCl3) δ value: 1.19(9H,s), 2.39(3H,s),
3.29(3H,s), 7.19(2H,d,J=8.0Hz), 7.42(2H,d,J=8.4Hz)
(4) tert-butyl 4-methylphenyl-
(methylsulfonyl)carbamate
NMR (4 00MHz, CDCl3) δ value: 1.48(9H,s), 2.37(3H,s),
3.41(3H,s), 7.11(2H,d,J=7.6Hz), 7.20(2H,d,J=7.6Hz)
(5) tert-butyl 5-methyl-l,3-dioxo-1,3-
dihydro-2H-isoindole-2-carboxylate
NMR(400MHz,CDCl3) δ value: 1.63(9H,s), 2.54(3H,s),
7.59(1H,dd,J=7.6,0.8Hz), 7.7 3(1H,d,J=0.8Hz),
7.82(1H,d,J=7.6Hz)
(6) tert-butyl 3-hydroy-1-
pyrrolidinecarboxylate
NMR(90MHz,CDCl3) δ value: 1.46(9H,s), 1.8-2.1(3H,m),
3.2-3.6(4H,m), 4.3-4.6(1H,m)
Reference Example 54
16.5 g of l-benzothiophene-5-carbaldehyde and
49.5 mL of ethylene glycol were dissolved in 165 mL of
toluene, to which 0.30 g of para-toluenesulfonic acid
monohydrate was added, and this solution was stirred
for 7 hours while heating it under reflux. The
reaction mixture was cooled to room temperature, to
which an aqueous solution of sodium hydroxide was added,
and then the organic phase was separated therefrom.

After the resultant organic phase was washed with water
and a saturated sodium chloride solution successively,
the washed phase was dried over anhydrous magnesium
sulfate, and the solvent was distilled out under
reduced pressure. The resultant residue was purified
by silica gel column chromatography [eluent;
hexane:ethyl acetate=5:l] to yield 15.8 g of 2-(l-
benzothiophen-5-yl)-1,3-dioxolane as yellow oil.
NMR( 4 00MHz, CDCl3) δ value: 4 . 03-4 .18 (4H,m) , 5.95(1H,s),
7.34(1H,d,J=5.6Hz), 7.45-7.48(2H,m), 7.89(1H,d,J=8.4Hz),
7.94 (1H,s)
Reference Example 55
3.83 g of silver nitrate was dissolved in 10
mL of water, to which a solution of 1.81 g of sodium
hydroxide in 10 mL of water was added dropwise and then
a solution of 2.00 g of 2-methyl-1,3-benzothiazole-5-
carbaldehyde in 20 mL of tetrahydrofuran was added
dropwise at room temperature, and this solution was
stirred for 30 minutes at the same temperature. The
reaction mixture was filtered through Celite, and 6M
hydrochloric acid was added to the filtrate to adjust
its pH value to 3.5 followed by addition of ethyl
acetate, and then the organic phase was separated
therefrom. After the resultant organic phase was
washed with a saturated sodium chloride solution, the
washed phase was dried over anhydrous magnesium sulfate,
and the solvent was distilled out under reduced
pressure. The resultant residue was dissolved in 30 mL

of methylene chloride, to which 20 µL of N,N-
dimethylformamide and 1.5 mL of oxalyl chloride were
added successively, and this solution was stirred for
30 minutes at room temperature. The reaction mixture,
5 to which 20 mL of methanol was added dropwise, was
stirred for 30 minutes at room temperature, and after
water was added thereto, the pH value of this mixture
was adjusted to 7 with a 5M solution of sodium
hydroxide in water, and then the organic phase was
D separated therefrom. After the resultant organic phase
was washed with a saturated sodium chloride solution,
the washed phase was dried over anhydrous magnesium
sulfate, and the solvent was distilled out under
reduced pressure to yield 1.90 g of methyl 2-methyl-
5 1,3-benzothiazole-5-carboxylate as light yellow solid.
NMR(400MHz,CDCl3) δ value: 2.87(3H,s), 3.97(3H,s),
7.88(1H,d,J=8.4Hz), 8.03(1H,dd,J=8.4,1.6Hz),
8.61(1H,d,J=1.6Hz)
Reference Example 56
) The following compounds were obtained in a
similar manner as in Reference Example 55.
(1) methyl l-benzothiophene-5-carboxylate
NMR(400MHz,CDCl3) δ value: 3.96(3H,s),
7.43(1H,dd,J=5.6,0.8Hz), 7.52(1H,d,J=5.6Hz),
7.92(1H,dd,J=8.6,0.8Hz), 8.01(1H,dd,J=8.6,1.6Hz),
8.54(1H,d,J=1.2Hz)
(2) methyl 4-[2-(benzyloxy)-2-oxoethyl]
benzoate

NMR(90MHz,CDCl3) δ value: 3.72(2H,s), 3.91(3H,s),
5.14(2H,s), 7.33-7.46(7H,m), 7.90-8.04(2H,m)
Reference Example 57
10.85 g of methyl 3-bromo-4-
(bromomethyl)benzoate was dissolved in 108 mL of N,N-
dimethylformamide, to which 3.4 6 g of potassium acetate
was added at room temperature, and this solution was
stirred for 17.5 hours at the same temperature. The
reaction mixture was added to a mixture of water and
ethyl acetate, and then the organic phase was separated
therefrom. After the resultant organic phase was
washed with water and a saturated sodium chloride
solution, the washed phase was dried over anhydrous
magnesium sulfate, and the solvent was distilled out
under reduced pressure. The resultant residue was
purified by silica gel column chromatography [eluent;
hexane:ethyl acetate=10:1] to yield 6.43 g of methyl 4-
[(acetyloxy)methyl]-3-bromobenzoate as white solid.
NMR(400MHz,CDCl3) δ value: 2.18(3H,s), 3.93(3H,s),
5.22(2H,s), 7.47(1H,d,J=8.0Hz), 7.98(1H,dd,J=8.0,1.2Hz),
8.24(1H,d,J=1.2Hz)
Reference Example 58
5.30 g of methyl 4-[(acetyloxy)methyl]-3-
bromobenzoate was dissolved in 50 mL of
hexamethylphosphoramide, to which 6.6 mL of
tetramethyltin and 0.26 g of bis(triphenylphosphine)-
palladium(II) dichloride were added at room temperature
in a stream of nitrogen, and this solution was stirred

for 3 hours at 70°C. The reaction mixture was cooled to
room temperature, and was added to a mixture of water
and diethyl ether, and then the organic phase was
separated therefrom. After the resultant organic phase
was washed with water and a saturated sodium chloride
solution, the washed phase was dried over anhydrous
magnesium sulfate, and the solvent was distilled out
under reduced pressure. The resultant residue was
purified by silica gel column chromatography [eluent;
hexane:ethyl acetate=5:l] to yield 4.17 g of methyl 4-
[(acetyloxy)methyl]-3-methylbenzoate as brown oil.
NMR(400MHz,CDCl3) δ value: 2.13(3H,s), 2.38(3H,s),
3.91(3H,s), 5.15(2H,s), 7.8-7.9(2H,m),
7.40(1H,d,J=8.4Hz)
Reference Example 59
1.00 g of methyl 4-[(acetyloxy)methyl]-3-
methylbenzoate was dissolved in 10 mL of methanol, to
which a solution of 0.365 g of sodium methoxide in 7 mL
of methanol was added dropwise at 5 to 7°C, and this
solution was stirred for 30 minutes at 5°C. The
reaction mixture was concentrated under reduced
pressure, followed by successive addition of ethyl
acetate and water, and then the organic phase was
separated therefrom. After the resultant organic phase
was washed with water and a saturated sodium chloride
solution, the washed phase was dried over anhydrous
magnesium sulfate, and the solvent was distilled out
under reduced pressure to yield 0.79 g of methyl 4-

(hydroxymethyl)-3-methylbenzoate as yellow oil.
NMR(400MHz, CDCl3) δ value: 1. 78 (1H,brs), 2.36(3H,s),
3.91(3H,s), 4.75(2H,s), 7.48(1H,d,J=8.0Hz), 7.84(1H,s),
7.87 (1H,d,J=8.0Hz)
Reference Example 60
Methyl 2-(hydroxymethyl)-1,3-benzothiazole-5-
carboxylate was obtained in a similar manner as in
Reference Example 59.
NMR(400MHz,CDCl3) δ value: 3.97(4H,brs), 5.11(2H,s),
7.94(1H,d,J=8.0Hz), 8.06(1H,dd,J=8.4,1.6Hz),
8.63(1H,d,J=1.6Hz)
Reference Example 61
1.00 g of 5-methyl-2-benzofuran-1,3-dione was
suspended in 10 mL of chlorobenzene, to which 1.3 mL of
1,1,1,3,3,3-hexamethyldisilazane was added at room
temperature, and this suspension was stirred for 10.5
hours while heating it under reflux. The reaction
mixture was cooled to room temperature, and resultant
precipitate was filtered out therefrom to yield 0.169 g
of 5-methyl-1H-isoindole-1,3(2H)-dione as light yellow
solid.
NMR(400MHz,CDCl3) δ value: 2.53(3H,s), 7.49(1H,brs),
7.55(1H,dd,J=7.8,0.8Hz) , 7.67(1H,d,J=0.8Hz),
7.75(1H,d,J=8.0Hz)
Reference Example 62
1.00 g of lH-benzimidazole-5-carboxylic acid
was suspended in a mixed solvent of 10 mL of
tetrahydrofuran and 20 µL of N,N-dimethylformamide, to

which 1.6 mL of oxalyl chloride was added dropwise at
room temperature, and this suspension was stirred for
one hour at room temperature. The reaction mixture, to
which 10 mL of methanol was added, was stirred for
another one hour at room temperature and then for 30
minutes at 50°C, and this mixture was concentrated under
reduced pressure. The resultant solid was washed with
diisopropyl ether to yield 1.25 g of methyl 1H-
benzimidazole-5-carboxylate hydrochloride as gray solid.
NMR (4 00MHz, DMSO-d6) δ value: 3.92(3H,s),
7.95(1H,d,J=8.4Hz), 8.11(1H,d,J=8.4Hz), 8.39(1H,s),
9.56(1H,s)
Reference Example 63
3.00 g of 5-methyl-2-benzofuran-l,3-dione was
suspended in 30 mL of methanol, to which 0.2 mL of
sulfuric acid was added at room temperature, and this
suspension was stirred for 2.5 hours while heating it
under reflux. The reaction mixture was cooled to room
temperature, and poured into ice water followed by
addition of ethyl acetate, and then the organic phase
was separated therefrom. After the resultant organic
phase was washed with water and a saturated sodium
chloride solution successively, the washed phase was
dried over anhydrous magnesium sulfate, and then the
solvent was distilled out under reduced pressure to
yield 2.95 g of dimethyl 4-methylphthalate as light
yellow oil.
NMR(400MHz,CDCl3) δ value: 2.42(3H,s), 3.88(3H,s),

3.91(3H,s), 7.33(1H,d,J=8.0Hz) 7.47(1H,s),
7.67(1H,d,J=8.0Hz)
Reference Example 64
The following compounds were obtained in a
similar manner as in Reference Example 63.
(1) ethyl 5-methyl-2-pyrazinecarboxylate
NMR(400MHz,CDCl3) δ value: 1.46(3H,t,J=7.2Hz),
2.67(3H,s), 4.51(2H,q,J=7.2Hz) , 8.59(1H,d,J=l- 2Hz),
9.19(1H,d,J=1.2Hz)
(2) methyl 3-(2-methoxy-2-oxoethyl)benzoate
NMR(90MHz,CDCl3) δ value: 3.68(2H,s), 3.70(3H,s),
3.92(3H,s), 7.39-7.47(2H,m), 7.91-7.96(2H,m)
Reference Example 65
0.34 g of 60% sodium hydride was added to a
solution of 1.00 g of l-methyl-2,3-piperazinedione in
10 mL of N,N-dimethylformamide, and this mixture was
stirred for 10 minutes at 50°C. Then, 0.88 mL of 4-
fluorobenzaldehyde was added thereto and the mixture
was stirred for 30 minutes at 120°C. The mixture was
cooled to room temperature, and the solvent was
distilled out thereof under reduced pressure. The
resultant residue was purified by silica gel column
chromatography [eluent; chloroform:ethanol=15:1] to
yield 0.80 g of 4-(4-methyl-2,3-dioxo-1-
piperazinyl)benzaldehyde as white solid.
NMR(400MHz,DMSO-d6) δ value: 3.01(3H,s),
3.7 0(2H,t,J=5.8Hz), 4.05(2H,t,J=5.6Hz),
7.65(2H,d,J=8.4Hz), 7.96(2H,d,J=7.6Hz), 9.99(1H,s)

Reference Example 66
4-(2-oxo-1,3-oxazolidin-3-yl)benzaldehyde was obtained
in a similar manner as in Reference Example 65.
NMR (4 00MHz, CDC13) δ value: 4 .14 (2H, t, J=8 . 0Hz) ,
4.55 (2H,t,J=8.0Hz), 7.7 4(2H,dd,J=9.0,2.2Hz),
7.91 (2H,dd,J=9.2,2.2Hz), 9.96 (1H,s)
Reference Example 67
7.00 g of 4-methylbenzenesulfonyl chloride
was dissolved in 70 mL of methylene chloride, to which
3.59 g of dimethylamine hydrochloride was added at room
temperature and 12.8 mL of triethylamine was added
dropwise in an ice bath, and then this solution was
stirred for one hour at room temperature. The reaction
mixture, to which water was added, was adjusted to pH 3
with 6M hydrochloric acid, and then the organic phase
was separated therefrom. After the resultant organic
phase was washed with water and a saturated sodium
chloride solution successively, the washed phase was
dried over anhydrous magnesium sulfate, and the solvent
was distilled out thereof under reduced pressure to
yield 6.75 g of N,N,4-trimethylbenzenesulfonamide as
white solid.
NMR(400MHz,CDCl3) δ value: 2.44(3H,s), 2.68(6H,s),
7.34 (2H,d,J=8.4Hz) , 7.66(2H,d,J=8.4Hz)
Reference Example 68
The following compounds were obtained in a
similar manner as in Reference Example 67.
(1) N-(4-methylphenyl)methanesulfonamide

NMR(400MHz, DMSO-d6) δ value: 2.23(3H,s), 2.89(3H,s),
7.10(2H,d,J=8.8Hz), 7.14(2H,d,J=8.8Hz), 9.53(1H,s)
(2) [bis(tert-butoxycarbonyl)amino](4-
methylphenyl) dioxo-A,6-sulf ane
NMR(400MHz,CDCl3) 6 value: 1.48(18H,s), 2.45(3H,s),
7.3 3(2H,d,J=8.0Hz), 7.96(2H,d,J=8.4Hz)
(3) N,4-dimethylbenzenesulfonamide
NMR(400MHz,CDCl3) δ value: 2.43(3H,s),
2.65(3H,d,J=5.6Hz), 4.47(1H,d,J=4.8Hz),
7.32(2H,d,J=8.4Hz), 7.7 5(2H,d,J=8.4Hz)
Reference Example 69
99.3 g of ethyl (E)-3-(4-methylphenyl)-2-
propenoate was dissolved in 400 mL of chloroform, to
which a solution of 21.7 mL of bromine in 100 mL of
chloroform was added dropwise in an ice bath, and then
this solution was stirred for 30 minutes at room
temperature. An aqueous solution of sodium thiosulfate
was then added to the reaction mixture, and the organic
phase was separated therefrom. After the resultant
organic phase was washed with water and a saturated
sodium chloride solution successively, the washed phase
was dried over anhydrous magnesium sulfate, and the
solvent was distilled out therefrom under reduced
pressure to yield 146.34 g of ethyl 2,3-dibromo-3-(4-
methylphenyl)propanoate as light yellow solid.
NMR(400MHz,CDCl3) δ value: 1.37(3H,t,J=6.8Hz),
2.36(3H,s), 4.35(2H,q,J=6.8Hz), 4.83(1H,d,J=12.0Hz),
5.33(1H,d,J=12.0Hz), 7.19(2H,d,J=7.8Hz),

7.29(2H,d,J=7.8Hz)
Reference Example 70
0.35 g of ethyl 2,3-dibromo-3-(4-
methylphenyl)propanoate and 0.083 g of hydroxylamine
hydrochloride was suspended in 7 mL of methanol, to
which 0.19 g of a 28% solution of sodium methoxide in
methanol was added at room temperature, and then this
solution was stirred for 12 hours at the same
temperature. The reaction mixture, to which water was
added, was adjusted to pH 1 with 6M hydrochloric acid
followed by addition of ethyl acetate, and the organic
phase was separated therefrom. After the resultant
organic phase was washed with water and a saturated
sodium chloride solution successively, the washed phase
was dried over anhydrous magnesium sulfate, and the
solvent was distilled out therefrom under reduced
pressure. The resultant residue was purified by silica
gel column chromatography [eluent; hexane:ethyl
acetate=4:l] to yield 0.12 g of 5-(4-methylphenyl)-3-
isoxazolol as yellow oil.
NMR(400MHz,CDCl3) δ value: 2.41(3H,s), 6.16(1H,s), 7.2-
7.3(3H,m), 7.62(2H,d,J=8.0Hz)
Reference Example 71
2.50 g of methyl 3-methoxy-4-methylbenzoate
was dissolved in 25 mL of benzene, to which 2.72 g of
N-bromosuccinimide and 0.23 g of 2,2'-
azobisisobutyronitrile were successively added at room
temperature, and this solution was stirred for one hour

while heating it under reflux. After 3.90 g of
hexamethylenetetramine dissolved in 7.8 mL of acetic
acid and 7.8 mL of water was added dropwise to the
reaction mixture, benzene was distilled out therefrom,
and then the mixture was stirred for one hour while
heating it under reflux. The reaction mixture, which
was cooled to room temperature, was added to a mixture
of chloroform and water and then adjusted to pH 7 with
a 20% aqueous solution of sodium hydroxide, and the
organic phase was separated therefrom. After the
resultant organic phase was successively washed with
water, a saturated aqueous solution of sodium hydrogen
carbonate, and a saturated sodium chloride solution,
the washed phase was dried over anhydrous magnesium
sulfate, and the solvent was distilled out under
reduced pressure. The resultant residue was purified
by silica gel column chromatography [eluent;
hexane:ethyl acetate=3:l] to yield 1.74 g of methyl 4-
formyl-3-methoxybenzoate as white solid.
NMR(400MHz,CDCl3) δ value: 3.96(3H,s), 4.00(3H,s),
7.67(1H,s), 7.68(1H,d,J=7.8Hz), 7.88(1H,d,J=7.8Hz),
10.52(1H,s)
Reference Example 72
2-methyl-1,3-benzothiazole-5-carboaldehyde
was obtained in a similar manner as in Reference
Example 71.
NMR(400MHz,CDCl3) δ value: 2.89(3H,s),
7.90(1H,dd,J=8.4,1.6Hz), 7.97(1H,d,J=8.4Hz),

8.40(1H,d,J=1.2Hz), 10.13(1H,s)
Reference Example 7 3
1.72 g of methyl 4-formyl-3-methoxybenzoate
was dissolved in 8.6 mL of methanol, to which 2.6 mL of
a 20% aqueous solution of sodium hydroxide was added at
room temperature, and this solution was stirred for one
hour at the same temperature. The reaction mixture, to
which water was added, was adjusted to pH 2 with 6M
hydrochloric acid, and resultant precipitate was
filtered out therefrom and washed with water to yield
1.49 g of 4-formyl-3-methoxybenzoic acid as light
yellow solid.
NMR(400MHz, DMSO-d6) δ value: 3.99(3H,s),
7.62(1H,d,J=8.0Hz), 7.68(1H,d,J=l.2Hz),
7.79(1H,d,J=8.0Hz), 10.40(1H,s), 13.51 (1H,brs)
Reference Example 74
The following compounds were obtained in a
similar manner as in Reference Example 73.
(1) 5-(ethoxycarbonyl)-2-pyridinecarboxylic
acid
NMR(90MHz,DMSO-d6) δ value: 1.36(3H,t,J=7.1Hz) ,
3.60(1H,brs), 4.39(2H,q,J=7.1Hz), 8.16(1H,d,J=8.1Hz),
8.46(1H,dd,J=8.2,2.3Hz), 9.16-9.18(1H,m)
(2) 2-[3-(methoxycarbonyl)phenyl]acetic acid
NMR(90MHz,CDCl3) δ value: 3.71(2H,s), 3.96(3H,s), 7.39-
7.54(2H,m), 7.93-8.01(2H,m), 9.52(1H,brs)
(3) 2-(4-formylphenyl)acetic acid
light yellow oil

(4) 2-methoxy-4-[(1-methylcyclopentyl)-
methyl]benzoic acid
NMR(400MHz,CDCl3) 6 value: 0.91(3H,s), 1.32-1.37(2H,m),
1.49-1.56(2H,m), 1.67-1.70(4H,m), 2.67(2H,s),
4.07(3H,s), 6.82(1H,s), 6 . 94(1H,d,J=8.0Hz) ,
8.08(1H,d,J=7.6Hz), 10.70 (1H,brs)
Reference Example 75
1.58 g of 4-(3-ethoxy-3-oxopropyl)-3-
methoxybenzoic acid was dissolved in 16 mL of
tetrahydrofuran, to which 0.96 mL of triethylamine was
added dropwise at -10°C and then 0.63 mL of ethyl
chloroformate was added dropwise at -20°C, followed by
addition thereto of 0.47 g of sodium borohydride in an
ice bath, and this solution was stirred for 30 minutes
at the same temperature. The reaction mixture, to
which water was added dropwise before adding ethyl
acetate and water thereto, was adjusted to pH 2 with 6M
hydrochloric acid, and the organic phase was separated
therefrom. After the resultant organic phase was
washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous magnesium sulfate, and the solvent was
distilled out under reduced pressure to yield 1.49 g of
ethyl 3-[4-(hydroxymethyl)-2-methoxyphenyl]propanoate
as white solid.
NMR(400MHz,CDCl3) δ value: 1.24 (3H,t,J=7.1Hz) ,
2.58(2H,t,J=7.6Hz), 2.85(1H,brs), 2.92(2H,t,J=7.6Hz),
3.83(3H,s), 4.11(2H,q,J=7.1Hz), 4.65(2H,s),

6.84(1H,d,J=7.6Hz), 6.88(1H,s), 7.11 (1H, d, J=7 . 6Hz)
Reference Example 76
The following compounds were obtained in a
similar manner as in Reference Example 75.
(1) methyl 4-(2-hydroxyethyl)benzoate
NMR(90MHz,CDCl3) δ value: 1.55 (1H,brs),
2.92(2H,t,J=6.7Hz), 3.77-4.03(2H,m), 3.91(3H,s),
7.30(2H,d,J=7.7Hz), 7.98(2H,d,J=8.1Hz)
(2) methyl 3-(2-hydroxyethyl)benzoate
NMR(90MHz, CDC13) δ value: 1.42(1H,t,J=5.9Hz),
2.93(2H,t,J=6.7Hz), 3.80-4.00(2H,m), 3.92(3H,s), 7.37-
7.44(2H,m), 7.85-7.96(2H,m)
Reference Example 77
5.00 g of 4-bromobenzaldehyde was dissolved
in 100 mL of N,N-dimethylformamide, to which 2.9 mL of
ethyl acrylate, 0.30 g of palladium(II) acetate, 0.35 g
of triphenylphosphine, 13.20 g of potassium acetate,
and 8.70 g of tetra-n-butylammonium bromide were added,
and this solution was stirred for 2.5 hours at 90°C.
The reaction mixture was added to a mixture of ethyl
acetate and water, and adjusted to pH 2 with 6M
hydrochloric acid, and the organic phase was separated
therefrom. After the resultant organic phase was
washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous magnesium sulfate, and the solvent was
distilled out under reduced pressure. The resultant
residue was purified by silica gel column

chromatography [eluent; hexane:ethyl acetate=2:l] to
yield 4.75 g of ethyl (E)-3-(4-formylphenyl)-2-
propenoate as yellow solid.
NMR (400MHz,CDC13) δ value: 1.35(3H,t,J=7.2Hz),
4.2 9 (2H,q,J=7.2Hz), 6.55(1H,d,J=16.0Hz) ,
7.68(2H,d,J=8.4Hz), 7.71(1H,d,J=16.0Hz),
7.90(2H,d,J=8.4Hz), 10.03(1H,s)
Reference Example 78
4.00 g of methyl 3-(hydroxymethyl)benzoate
was dissolved in 80 mL of methylene chloride, to which
9.47 g of triphenylphosphine was added in small
portions in an ice bath followed by addition of 12.00 g
of carbon tetrabromide in small portions, and this
solution was stirred for one hour at room temperature.
The reaction mixture was concentrated under reduced
pressure, and the resultant residue was purified by
silica gel column chromatography [eluent; hexane:ethyl
acetate=2:l] to yield 5.02 g of methyl 3-
(bromomethyl)benzoate as colorless oil.
NMR(90MHz,CDCl3) δ value: 3.93(3H,s), 4.52(2H,s), 7.42-
8.07(4H,m)
Reference Example 7 9
0.924 g of sodium cyanide was dissolved in 15
mL of dimethylsulfoxide, to which a solution of 4.00 g
of methyl 3-(bromomethyl)benzoate in 5 mL of
dimethylsulfoxide was added in an ice bath, and this
solution was stirred for 2 hours at room temperature.
The reaction mixture was added to a mixture of ethyl

acetate and water, and the organic phase was separated
therefrom. After the resultant organic phase was
washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous magnesium sulfate, and concentrated under
reduced pressure to yield 3.00 g of methyl 3-
(cyanomethyl)benzoate as orange oil.
NMR(90MHz,CDCl3) δ value: 3.81(2H,s), 3.94(3H,s), 7.46-
7.54(2H,m), 7 . 99-8 . 06 (2H,m)
Reference Example 80
12.2 mL of (S)-(-)-a-pinene was dissolved in
30 mL of tetrahydrofuran, to which a 1M solution of
borane in tetrahydrofuran was added dropwise in an ice
bath, and this solution was stirred for 2 hours at 5 to
10°C. Then, after a solution of 4.59 g of 1,3-
cyclopentadiene in 4 mL of tetrahydrofuran was added
dropwise thereto in an ice bath, the solution was
stirred for 14 hours at room temperature. The reaction
mixture was ice-cooled, to which 1.2 mL of water, 6.9
mL of 20% sodium hydroxide, and 6.9 mL of a 30% aqueous
solution of hydrogen peroxide were successively added
dropwise, and then the reaction mixture was cooled to
room temperature followed by addition of sodium
chloride, and the organic phase was separated therefrom.
The resultant organic phase was concentrated under
reduced pressure, to which diethyl ether and a 1M
aqueous solution of silver nitrate were added, and
after this mixture was stirred for 30 minutes at room

temperature, the reaction mixture was permitted to
stand and the organic phase was separated therefrom.
The resultant organic phase was washed with a 1M
aqueous solution of silver nitrate followed by addition
of sodium chloride, and then filtered. The filtrate
was dried over anhydrous magnesium sulfate, and the
solvent was distilled out under reduced pressure to
yield 0.83 g of 3-cyclopenten-1-ol as light yellow oil.
NMR(4 00MHz, CDCl3) δ value: 1.73(1H,brs), 2.29-2.36(2H,m),
2.61-2.69(2H,m), 4.51-4.54(1H,m), 5.72(2H,s)
Reference Example 81
2.00 g of 2-amino-5-methylbenzoic acid was
suspended in 20 mL of water, to which 1.18 g of
potassium cyanate was added and a mixture of 0.23 mL of
acetic acid and 1 mL of water were added dropwise, and
this suspension was stirred for 1.5 hours at 50°C. Then,
after a solution of 1.42 g of sodium hydroxide in 2 mL
of water was added drowise, to which 40 mL of water and
20 mL of 1,4-dioxane were added, and this solution was
stirred for 3.5 hours while heating it under reflux.
The reaction mixture was ice-cooled, from which
precipitated solid was filtered, and then 30 mL of
water and 3 mL of 6M of hydrochloric acid were added to
the resultant solid, which was then stirred for 1.5
hours while heating it under reflux. The reaction
mixture was cooled to room temperature, from which
resultant precipitate was filtered and washed with
water to yield 1.17 g of 6-methyl-2,4-(1H,3H)-

quinazolinedione as white solid.
NMR(400MHz, DMSO-d6) δ value: 2.32(3H,s),
7.07(1H,d,J=8.4Hz), 7.4 6(1H,dd,J=8.4,2.0Hz),
7.69(1H,d,J=0.8Hz), 11.09 (1H,brs), 11.18(1H,brs)
Reference Example 82
0.636 g of sodium borohydride was added to 22
mL of ice-cooled ethanol, to which a solution of 1.09 g
of calcium chloride in 14 mL of ethanol was added
dropwise, followed by addition of 1.20 g of 5-
(ethoxycarbonyl)-2-pyridinecarboxylic acid 1/2 calcium
salt, and this mixture was stirred for one hour at room
temperature. The reaction mixture, to which 2.8 mL of
concentrated sulfuric acid was added, was stirred for 6
hours while heating it under reflux. The reaction
mixture was cooled to room temperature and concentrated
under reduced pressure followed by successive addition
of a saturated aqueous solution of sodium hydrogen
carbonate and chloroform, and then the organic phase
was separated therefrom. The resultant organic phase
was washed with a saturated sodium chloride solution
and dried over anhydrous magnesium sulfate, and the
solvent was distilled out under reduced pressure to
yield 0.34 g of ethyl 5-(hydroxymethyl)-2-
pyridinecarboxylate as light yellow solid.
NMR ( 90MHz, CDC13) δ value: 1. 45 (3H, t, J=7 . 1Hz) ,
2.32(1H,brs), 4.48(2H,q,J=7.1Hz), 4.84(2H,s),
7.86(1H,dd,J=8.1,2.0Hz), 8.13(1H,d,J=7.9Hz),
8.71(1H,d,J=1.3Hz)

Reference Example 83
23.30 g of sodium hydroxide was dissolved in
118 mL of water and was ice-cooled, to which 9.23 mL of
bromine was added dropwise over 20 minutes and then a
solution of 9.80 g of 1-(2-fluoro-4-methoxyphenyl)-1-
ethanone in 88 mL of 1,4-dioxane was added dropwise
over one hour at -10°C. The resultant reaction mixture
was cooled to room temperature, to which water was
added, and then an aqueous phase was separated
therefrom. A solution of 7.23 g of sodium thiosulfate
in 100 mL of water was added to the aqueous phase, and
then 12M hydrochloric acid was further added until the
pH value of this aqueous phase reached 2. The
resultant precipitate was filtered therefrom and washed
with water to yield 8.20 g of 2-fluoro-4-methoxybenzoic
acid as white solid.
NMR(4 00MHz,DMSO-d6) δ value: 3.83(3H,s), 6. 84-6 . 92 (2H,m) ,
7.83(1H,t,J=8.8Hz), 12.86(1H,brs)
Reference Example 84
1.70 g of 4-(methoxymethoxymethyl)-2-
methylbenzaldehyde was dissolved in 10 mL of
acetonitrile, to which 3.69 g of sodium dihydrogen
phosphate dihydrate dissolved in 7 mL of water and 1.58
g of a 80% sodium chlorite dissolved in 3 mL of water
and a 1.5 mL of 30% aqueous solution of hydrogen
peroxide were successively added at 5 to 10°C, and then
this solution was stirred for 20 minutes at room
temperature. Then, ethyl acetate and water were added

to the reaction mixture, and the organic phase was
separated therefrom. After the resultant organic phase
was washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous magnesium sulfate, and the solvent was
distilled out under reduced pressure. The resultant
residue was dissolved in 18 mL of methanol, to which 9
mL of 6M hydrochloric acid was added, and this mixture
was stirred for 4.5 hours while heating it under reflux.
The reaction mixture was cooled to room temperature,
and poured into a mixture of chloroform and water, then
the organic phase was separated therefrom. After the
resultant organic phase was washed with water and a
saturated sodium chloride solution successively, the
washed phase was dried over anhydrous magnesium sulfate,
and the solvent was distilled out under reduced
pressure. The resultant residue was purified by silica
gel column chromatography [eluent; hexane:ethyl
acetate=l:l] to yield 1.30 g of methyl 4-
(hydroxymethyl)-2-methylbenzoate as light yellow oil.
NMR (400MHz, CDC13) δ value: 1.89(1H,brs), 2.61(3H,s),
3.87(3H,s), 4.71(2H,s), 7.22-7.26(2H,m),
7.91(1H,d,J=8.0Hz)
Reference Example 85
14.17 g of 4-bromo-2-hydroxybenzoic acid,
16.3 mL of iodomethane, and 27.07 g of potassium
carbonate were suspended in 142 mL of N,N-
dimethylformamide, and this suspension was stirred for

5 hours at 75°C. In addition, 4.1 mL of iodomethane and
9.02 g of potassium carbonate were added thereto, and
the mixture was stirred for 30 minutes at 105°C. The
reaction mixture was cooled to room temperature, added
to a mixture of ethyl acetate and ice cooled water, and
adjusted to pH 2 with 6M hydrochloric acid for
separation of the organic phase. After the resultant
organic phase was washed with water and a saturated
sodium chloride solution successively, the washed phase
was dried over anhydrous magnesium sulfate, and the
solvent was distilled out under reduced pressure. The
resultant residue was purified by silica gel column
chromatography [eluent; hexane:ethyl acetate=3:l] to
yield 5.62 g of yellow oil. The resultant oil was
dissolved in 30 mL of methanol, to which 10 mL of a 20%
aqueous solution of sodium hydroxide was added, and
this mixture was stirred for one hour at room
temperature. The reaction mixture, to which water was
added, was adjusted to pH 2 with 6M hydrochloric acid
followed by addition of chloroform, and the organic
phase was separated therefrom. After the resultant
organic phase was washed with water and a saturated
sodium chloride solution successively, the washed phase
was dried over anhydrous magnesium sulfate, and the
solvent was distilled out under reduced pressure. The
resultant residue was purified by silica gel column
chromatography [eluent; toluene:ethyl acetate=5:l] to
yield 5.62 g of 4-bromo-2-methoxybenzoic acid as light

yellow solid.
NMR(4 00MHz, DMSO-d6) δ value: 3.84(3H,s),
7.20(1H,dd,J=8.0,1.6Hz), 7.33(1H,d,J=1.6Hz),
7.58 (1H,d,J=8.0Hz), 12.81(1H,brs)
Reference Example 8 6
4-isobutoxy-2-methylbenzoic acid was obtained
in a similar manner as in Reference Example 85.
NMR(90MHz,DMSO-d6) δ value: 0.98(6H,d,J=6.6Hz), 1.7-
2.3(1H,m), 2.52(3H,s), 3.79(2H,d,J=6.4Hz), 6.77-
6.84(2H,m), 7.84(1H,d,J=9.3Hz)
Reference Example 87
2.20 g of methyl 2-methyl-1,3-benzothiazole-
5-carboxylate was dissolved in 165 mL of benzene, to
which 16.63 g of N-bromosuccinimide and 1.22 g of 2,2'-
azobisisobutyronitrile were successively added at room
temperature, and this solution was stirred for 15 hours
while heating it under reflux. The reaction mixture
was cooled to room temperature, and then the solvent
was distilled out under reduced pressure. The
resultant residue was dissolved in 22 mL of N,N-
dimethylformamide, to which 5.21 g of potassium acetate
was added at room temperature, and this solution was
stirred for 30 minutes at the same temperature. The
reaction mixture was added to a mixture of water and
ethyl acetate, and then the organic phase was separated
therefrom. After the resultant organic phase was
washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over

anhydrous magnesium sulfate, and the solvent was
distilled out under reduced pressure. The resultant
residue was purified by silica gel column
chromatography [eluent; hexane:ethyl acetate=5:l] to
yield 0.64 g of methyl 2-[(acetyloxy)methyl]-1,3-
benzothiazole-5-carboxylate as yellow solid.
NMR(400MHz,CDCl3) δ value: 2.22(3H,s), 3.98(3H,s),
5.51(2H,s), 7.95(1H,d, J=8.4Hz), 8.10 (1H, dd, J==8 . 4, 1. 6Hz) ,
8.70(1H,d,J=1.6Hz)
Reference Example 8 8
3.00 g of 4-methylbenzoic acid was suspended
in a mixed solvent of 30 mL of methylene chloride and
20 µL of N,N-dimethylformamide, to which 2.9 mL of
oxalyl chloride was added dropwise at room temperature,
and this suspension was stirred for 5.5 hours at room
temperature. Then, 1.7 9 g of monomethylamine
hydrochloride was added to the reaction mixture, to
which 15.4 mL of triethylamine was added dropwise in an
ice bath, and the mixture was stirred for one hour at
room temperature. The reaction mixture, to which water
was added, was adjusted to pH 3 with 6M hydrochloric
acid, and then the organic phase was separated
therefrom. After the resultant organic phase was
washed with water and a saturated sodium chloride
solution successively, the washed phase was dried over
anhydrous magnesium sulfate, and the solvent was
distilled out under reduced pressure. The resultant
residue was purified by silica gel column

chromatography [eluent; chloroform:acetone=5:1] to
yield 2.11 g of N,4-dimethylbenzamide as light orange
solid.
NMR (400MHz, CDCl3) 6 value: 2.39(3H,s),
3.01(3H,d,J=4.8Hz), 6.11(1H,brs), 7.23(2H,d,J=7.6Hz),
7.66(2H,d,J=8.0Hz)
Reference Example 8 9
N,N,4-trimethylbenzamide was obtained in a
similar manner as in Reference Example 88.
NMR(400MHz,CDCl3) δ value: 2.37(3H,s), 2.99(3H,brs),
3.10(3H,brs), 7.19(2H,d,J=7.6Hz), 7.32(2H,d,J=8.0Hz)
Reference Example 90
1.00 g of 2-[4-(bromomethyl)phenyl]acetic
acid was suspended in 5 mL of a 4M solution of hydrogen
chloride in ethanol, and this suspension was stirred
for 2 hours at room temperature. The reaction mixture
was concentrated under reduced pressure to yield 0.954
g of ethyl 2-[4-(bromomethyl)phenyl]acetate as light
brown oil.
NMR(400MHz,CDCl3) δ value: 1. 25(3H,t,J=7.2Hz),
3.61(2H,s), 4.15(2H,q,J=7.2Hz), 4.57(2H,s),
7.28(2H,d,J=7.8Hz), 7.34(2H,d,J=7.9Hz)
Reference Example 91
5.00 g of ethanethioamide was suspended in 50
mL of ethanol, to which 9.3 mL of ethyl 3-bromo-2-
oxopropanoate was added dropwise at room temperature,
and this suspension was stirred for one hour while
heating it under reflux. The reaction mixture was

cooled to room temperature and added to a mixture of
ethyl acetate and water, followed by separation of the
organic phase therefrom. After the resultant organic
phase was washed with water and a saturated sodium
chloride solution successively, the washed phase was
dried over anhydrous magnesium sulfate, and the solvent.
was distilled out under reduced pressure to yield 2.30
g of ethyl 2-methyl-1,3-thiazole-4-carboxylate as white
solid.
NMR( 90MHz, CDCl3) δ value: 1. 40 (3H, t, J=7 . 1Hz) , 2.77(3H,s),
4.42(2H,q,J=7.1Hz), 8.04(1H,s)
Reference Example 92
25.0 g of 2-sulfanylbenzoic acid was
suspended in 125 mL of ethanol, to which 14.3 g of
sodium hydroxide and 31.7 mL of 2-bromo-l,1-
diethoxyethane was successively added and this
suspension was stirred for 3.5 hours while heating it
under reflux. The reaction mixture was concentrated
under reduced pressure, and the resultant residue was
dissolved in 250 mL of N,N-dimethylformamide, to which
15.1 mL of iodomethane and 67.2 g of potassium
carbonate were added, and then this mixture was stirred
for one hour at room temperature. The reaction mixture
was added to a mixture of ethyl acetate and water, from
which the organic phase was separated. After the
resultant organic phase was washed with water and a
saturated sodium chloride solution successively, the
washed phase was dried over anhydrous magnesium sulfate,

and the solvent was distilled out under reduced
pressure. The resultant residue was purified by silica
gel column chromatography [eluent; hexane:ethyl
acetate=2:1] to yield yellow oil. This product was
dissolved in 250 mL of toluene, to which 100 mL of a
85% phosphoric acid was added, and this solution was
stirred for 4.5 hours while heating it under reflux.
The reaction mixture was cooled to room temperature, to
which water was added, and filtered through Celite to
separate the organic phase therefrom. After the
resultant organic phase was washed with water and a
saturated sodium chloride solution successively, the
washed phase was dried over anhydrous magnesium sulfate,
and the solvent was distilled out under reduced
pressure. Purification by silica gel column
chromatography [eluent; hexanerethyl acetate=10:1] to
yield 20.5 g of methyl l-benzothiophene-7-carboxylate
as yellow oil.
NMR(400MHz,CDCl3) δ value: 4.03(3H,s),
7.40(1H,d,J=5.6Hz), 7.4 5(1H,t,J=7.6Hz),
7.58(1H,d,J=5.6Hz), 8.03(1H,dd,J=8.2,0.8Hz), 8.11-
8.13(1H,m)
Reference Example 93
4.42 g of 2-(hydroxymethyl)-1-benzothiophene-
5-carbaldehyde was suspended in 44 mL of methylene
chloride, to which 20.0 mL of N-ethyldiisopropylamine
and 5.2 mL of chloromethyl methyl ether were
successively added dropwise at 25 to 30°C, and this

mixture was stirred for one hour at room temperature.
The reaction mixture was poured into water, and
adjusted to pH 7.5 with 6M hydrochloric acid, and then
the organic phase was separated therefrom. After the
resultant organic phase was washed with water and a
saturated sodium chloride solution successively, the
washed phase was dried over anhydrous sodium sulfate,
and the solvent was distilled out under reduced
pressure to yield 5.40 g of brown oil. The resultant
oil was dissolved in 20 mL of tetrahydrofuran, and this
solution was added dropwise to 40 mL of an aqueous
suspension of silver oxide prepared from 7.62 g of
silver nitrate and 3.78 g of sodium hydroxide in an ice
bath, and then this mixture was stirred for 1.5 hours
at room temperature. The reaction mixture was filtered
through Celite, and the filtrate to which 6M
hydrochloric acid was added was adjusted to pH 2
followed by addition thereto of ethyl acetate, and then
the organic phase was separated therefrom. After the
resultant organic phase was washed with a saturated
sodium chloride solution, the washed phase was dried
over anhydrous magnesium sulfate, and the solvent was
distilled out under reduced pressure. 6.00 g of the
resultant yellow solid was dissolved in 60 mL of N,N-
dimethylformamide, to which 7.90 g of potassium
carbonate and 2.1 mL of iodomethane were added, and
this mixture was stirred for 30 minutes at room
temperature. The reaction mixture was added to a

mixture of ethyl acetate and water, and then the
organic phase was separated therefrom. After the
resultant organic phase was washed with water and a
saturated sodium chloride solution successively, the
washed phase was dried over anhydrous magnesium sulfate,
and the solvent was distilled out under reduced
pressure to yield yellow solid. The resultant solid
was dissolved in 50 mL of methanol, to which 10 mL of
6M hydrochloric acid was added, and this mixture was
stirred for 30 minutes while heating it under reflux.
The reaction mixture was cooled to room temperature and
poured into a mixture of ethyl acetate and water for
separation of the organic phase. After the resultant
organic phase was washed with a saturated aqueous
solution of sodium hydrogen carbonate, water, and a
saturated sodium chloride solution successively, the
washed phase was dried over anhydrous magnesium sulfate,
and the solvent was distilled out under reduced
pressure to yield 3.50 g of methyl 2-(hydroxymethyl)-1-
benzothiophene-5-carboxylate as yellow solid.
NMR(4 00MHz,CDC13) δ value: 2.03(1H,t,J=5.4Hz),
3.96(3H,s), 4.96(2H,d,J=4.8Hz), 7.29(1H,s),
7.86(1H,d,J=8.8Hz), 7.97(1H,dd,J=8.8,1.6Hz),
8.43 (1H,d,J=1.6Hz)
INDUSTRIAL APPLICABILITY
The novel benzophenone derivatives and the
salts thereof in accordance with this invention have

excellent anti-arthritic activities and inhibitory
effect on bone destruction caused by arthritis, and
moreover, provide high safety as well as excellent
pharmacokinetics in vivo and thus are useful as
therapeutic agent for arthritis. The preventive/
therapeutic agent for diseases in which excessive
expression of AP-1 is involved and inhibitors against
AP-1 activity, which contain the above benzophenone
derivatives or the salts thereof, are useful as
preventive/therapeutic agent for diseases in which
excessive expression of AP-1 is involved because of
their inhibitory activity on AP-1 activity.

CLAIMS
1. A benzophenone derivative represented by the
following general formula:

wherein
R1 represents a substituted or unsubstituted
heterocyclic group, a substituted phenyl group, or a
substituted or unsubstituted alkyl group;
Z represents a substituted or unsubstituted
alkylene group;
R2 represents a substituted or unsubstituted
heterocyclic group, a substituted or unsubstituted
heterocyclic carbonyl group or a protected or
unprotected carboxyl group;
R3 represents a hydrogen atom, a halogen atom,
a cyano group, a nitro group, a protected or
unprotected carboxyl group, a protected or unprotected
hydroxyl group, a protected or unprotected amino group,
a mercapto group, a carbamoyl group or a substituted or
unsubstituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl,
alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino,

acylamino, alkylsulfonylamino, arylsulfonylamino or
heterocyclic group;
R4 represents a substituted or unsubstituted
alkoxy, cycloalkyloxy, cycloalkenyloxy, alkyl,
cycloalkyl, heterocyclic-oxy or heterocyclic group;
R5 represents a hydrogen atom, a halogen atom
or a hydroxyl group,
provided that, when R1 represents a
substituted or unsubstituted alkyl group, R4 represents
a substituted or unsubstituted cycloalkyloxy group, an
alkoxy group substituted with a substituted or
unsubstituted phenyl or heterocyclic group or a
substituted or unsubstituted heterocyclic-oxy group,
or a salt thereof.
2. The benzophenone derivative or a salt thereof
according to claim 1, wherein R1 is a substituted or
unsubstituted heterocyclic group or a substituted
phenyl group; R2 is a carboxyl group protected or
unprotected with an alkyl group; R3 is a protected or
unprotected hydroxyl group; R4 is a substituted or
unsubstituted cycloalkyloxy group; R5 is a hydrogen
atom; and Z is an alkylene group.
3. The benzophenone derivative or a salt thereof
according to claim 1 or 2, wherein R1 is a substituted
or unsubstituted heterocyclic group; R2 is a carboxyl
group; and R3 a is hydroxyl group.
4. The benzophenone derivative or a salt thereof
according to claim 1, wherein R1 is a substituted or

unsubstituted heterocyclic group or a substituted phenyl group; R2 is a carboxyl
group protected with a substituted alkyl group; R3 is a protected or unprotected
hydroxyl group; R4 is a substituted or unsubstituted cycloalkyloxy group; R5 is a
hydrogen group; and z is an alkylene group.
5. The benzophenone derivative or a salt thereof as claimed in claim 1 or 4,
wherein R1 is a substituted or unsubstituted heterocyclic group; R2 is a
carboxyl group protected with a substituted alkyl group; and R3 is a
hydroxyl group.
Dated this 5th day of May 2004

A benzophenone derivative represented by the following formula:
wherein R1 represents, for example, an optionally substituted heterocyclic group,
or a substituted phenyl group; Z represents, for example, an alkylene group; R2
represents, for example, a carboxyl group optionally protected with alkyl;
R3 represents, for example, an optionally protected hydroxyl group; R4
represents, for example, an optionally substituted cycloalkyloxy group; and R5
represents, for example, a hydrogen atom, or a salt thereof has anti-arthritic
activity, inhibits bone destruction caused by arthritis, and provides high safety
and excellent pharmacokinetics and thus is useful as therapeutic agent for
arthritis. These compounds have inhibitory effect on AP-1 activity and are useful
as preventive or therapeutic agent for diseases in which excessive expression of
AP-1 is involved.

Documents:

591-KOLNP-2004-FORM-27.pdf

591-kolnp-2004-granted-abstract.pdf

591-kolnp-2004-granted-assignment.pdf

591-kolnp-2004-granted-claims.pdf

591-kolnp-2004-granted-correspondence.pdf

591-kolnp-2004-granted-description (complete).pdf

591-kolnp-2004-granted-examination report.pdf

591-kolnp-2004-granted-form 1.pdf

591-kolnp-2004-granted-form 18.pdf

591-kolnp-2004-granted-form 2.pdf

591-kolnp-2004-granted-form 26.pdf

591-kolnp-2004-granted-form 3.pdf

591-kolnp-2004-granted-form 5.pdf

591-kolnp-2004-granted-form 6.pdf

591-kolnp-2004-granted-others.pdf

591-kolnp-2004-granted-reply to examination report.pdf

591-kolnp-2004-granted-specification.pdf

591-kolnp-2004-granted-translated copy of priority document.pdf

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Patent Number

231471

Indian Patent Application Number

591/KOLNP/2004

PG Journal Number

10/2009

Publication Date

06-Mar-2009

Grant Date

04-Mar-2009

Date of Filing

05-May-2004

Name of Patentee

TOYAMA CHEMICAL CO. LTD.

Applicant Address

2-5, 3-CHOME NISHISHINJUKU, SHINJUKU-KU, TOKYO

Inventors:

#	Inventor's Name	Inventor's Address
1	HIRONORI KOTSUBO	44-7, NISHIASHIHARA, TATEYAMA-MACHI, NAKANIIKAWA-GUN, TOYAMA
2	TADASHI TANAKA	52-4-B-203, NAKAFUGO, TOYAMA-SHI, TOYAMA
3	YUKIHIKO AIKAWA	230, MIZUHASHINAKAMURAMACHI, TOYAMA-SHI, TOYAMA
4	SHUICHI HIRONO	16-29, AKATSUKASHINMACHI 3-CHOME, ITABASHI-KU, TOKYO
5	SHUNICHI SHIOZAWA	11-6, TAKENODAI 2-CHOME, NISHI-KU, KOBE-SHI, HYOGO
6	HISAAKI CHAKI	455-1, OHARAYA, OHYAMA-MACHI, KAMINIIKAWA-GUN, TOYAMA

PCT International Classification Number

C07C 59/90

PCT International Application Number

PCTJP02/11846

PCT International Filing date

2002-11-13

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	2001-351217	2001-11-16	Japan
2	2002-209382	2002-07-18	Japan