Title of Invention	AN ALKYL ETHER DERIVATIVE AND A PROCESS FOR PREPARING THE SAME.
Abstract	TITLE: AN ALKYL ETHER DERIVATIVE AND A PROCESS FOR PREPARING THE SAME. An alkyl ether derivative represented by the general formula; FIGURE. wherein each of R1 and R2 represents one or more groups selected from a hydrogen atom, a halogen atom,an alkyl group, an aryl group, an aralkyl group, an alkoxy group, an aryloxy group, an alkythio group, an arylthio group, an alkenyl group, an aklenyloxy group, an amino group, an alkylsulfonyl group, an arylsulfonyl group, a carbamoyl group, a heterocyclic group, a hydroxyl group, a carboxyl group, a nitro group, an oxo group and the like; R3 is an alkylamino group, an amino group, a hydroxyl group or the like; the ring A is a 5-membered or 6-membered heteroaromatic ring or a benzene ring; each of m and n is an integer of 1 to 6; and p is 1, or its salt has activity to protect neurons, activity to accelerate nerve regeneration and activity to accelerate neurite extension and hence is useful as a therapeutic agent for diseases in central and peripheral nerves.

Title of Invention

AN ALKYL ETHER DERIVATIVE AND A PROCESS FOR PREPARING THE SAME.

Abstract

TITLE: AN ALKYL ETHER DERIVATIVE AND A PROCESS FOR PREPARING THE SAME. An alkyl ether derivative represented by the general formula; FIGURE. wherein each of R1 and R2 represents one or more groups selected from a hydrogen atom, a halogen atom,an alkyl group, an aryl group, an aralkyl group, an alkoxy group, an aryloxy group, an alkythio group, an arylthio group, an alkenyl group, an aklenyloxy group, an amino group, an alkylsulfonyl group, an arylsulfonyl group, a carbamoyl group, a heterocyclic group, a hydroxyl group, a carboxyl group, a nitro group, an oxo group and the like; R3 is an alkylamino group, an amino group, a hydroxyl group or the like; the ring A is a 5-membered or 6-membered heteroaromatic ring or a benzene ring; each of m and n is an integer of 1 to 6; and p is 1, or its salt has activity to protect neurons, activity to accelerate nerve regeneration and activity to accelerate neurite extension and hence is useful as a therapeutic agent for diseases in central and peripheral nerves.

Full Text	TECHNICAL FIELD The present invention relates to novel alkyl ether derivatives or their salts, a process for production thereof, intermediates thereof and a therapeutic agent for central and peripheral nerves. BACKGROUND ART Dementia is divided into cerebrovascular dementia and neurodegenerative dementia, and various agents such as cerebral blood flow improvers and nootropics are used for treating these dementias. Senile plaques characteristic of Alzheimer"s disease, which is most typical as neurodegenerative dementia, are mainly composed of amyloid ß protein (Ap) derived from (3 amyloid precursor protein. Aß is considered as a substance that is deposited on the neurons or blood vessels of brain to cause a disease such as dementia. In addition, it has been reported that Aß itself injures neurons. Inhibitors of neurotoxicity induced by Aß are investigated as therapeutic agents for Alzheimer"s disease. As compounds having inhibitory activity against neurotoxicity induced by Aß, there are known, for example, the 1,2-ethanediol derivatives disclosed in JP-A-3-232830 and JP-A-4-95070, and the N- alkoxyalkyl-N,N-dialkylamine derivatives disclosed in International Publication WO 00/76957. The 1,2-ethanediol derivatives disclosed in JP-A-3-232830 and JP-A-4-95070, in particular, (R)-1- (benzo[b]thiophen-5-yl)-2-[2-(N,N-diethylamino)- ethoxy]ethanol hydrochloride has protective activity against the neuronal death caused by Aß (SOCIETY FOR NEUROSCIENCE, Abstracts, Vol. 24, Part 1, p. 228, 1998) and activity to enhance the activity of nerve growth factor (NGF) (WO 96/12717) and hence is useful as a therapeutic agent for diseases in central and peripheral nerves. However, there is desired the development of a compound possessing properties such as a higher activity to protect neurons and a higher activity to accelerate nerve regeneration, which are required as a therapeutic agent for diseases in central and peripheral nerves. DISCLOSURE OF THE INVENTION The present inventors earnestly investigated in order to solve the above problem, and consequently found that there are compounds having not only calcium- antagonistic activity but also inhibitory activity against neurotoxicity induced by A(3, among the alkyl ether derivatives with calcium-antagonistic activity disclosed in WO 99/31C56. The present inventors further investigated, and consequently found that an alkyl ether derivative represented by the following general formula [1]: wherein each of R1 and R2 represents one or more groups selected from a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an aralkyl group, an alkoxy group, an aryloxy group, an alkythio group, an arylthio group, an alkenyl group, an alkenyloxy group, an amino group, an alkylsulfonyl group, an arylsulfonyl group, a carbamoyl group, a heterocyclic group, a hydroxyl group, a carboxyl group, a nitro group, an oxo group and the like; R3 is an alkylamino group, an amino group, a hydroxyl group or the like; the ring A is a 5-membered or 6-membered heteroaromatic ring or a benzene ring; each of m and n is an integer of 1 to 6; and p is 1, or its salt has activity to protect neurons, activity to accelerate nerve regeneration and activity to accelerate neurite extension and hence is useful as a therapeutic agent for diseases in central and peripheral nerves, whereby the present invention has been accomplished. The present invention is explained below in detail. The terms used in the present specification have the following meanings unless otherwise specified. The term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; the term "alkyl group" means a straight chain or branched chain C1-12alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl or the like; the term "lower alkyl group" means a straight chain or branched chain C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl or the like; the term "alkoxy group" means a straight chain or branched chain C1-12alkyloxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy or the like; the term "lower alkoxy group" means a straight chain or branched chain C1-6alkyloxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert- butoxy, pentyloxy, hexyloxy or the like; the term "alkenyl group" means a C2-12alkenyl group such as vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl or the like; the term "lower alkenyl group" means a C2- 6alkenyl group such as vinyl, propenyl, butenyl, pentenyl, hexenyl or the like; the term "alkenyloxy group" means a C2-12alkenyloxy group such as vinyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy heptenyloxy, octenyloxy or the like; the term "lower alkenyloxy group" means a C2-6alkenyloxy group such as vinyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy or the like; the term "alkynyl group" means a C2-6alkynyl group such as ethynyl, 2-propynyl, 2- bytynyl or the like; the term "cycloalkyl group" means a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group; the term "alkylthio group" means a C1-12alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio, heptylthio, octylthio or the like; the term "lower alkylthio group" means a C1-6alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio or the like; the term "aryl group" means a phenyl, naphthyl, indanyl or indenyl group; the term "aryloxy group" means a phenyloxy, naphthyloxy, indanyloxy or indenyloxy group; the term "aralkyl group" means an ar-C1-6alkyl group such as benzyl, diphenylmethyl, trityl, phenethyl or the like; the term "arylthio group" means a phenylthio, naphthylthio, indanylthio or indenylthio group; the term "acyl group" means a formyl group, a C2-12alkanoyl group such as acetyl, isovaleryl, propionyl, pivaloyl or the like, an aralkylcarbonyl group such as benzylcarbonyl or the like, or an aroyl group such as benzoyl, naphthoyl or the like; the term "alkylsulfonyl group" means a C1-12alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, heptylsulfonyl, octylsulfonyl or the like; the term "lower alkylsulfonyl group" means a C1-6alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl or the like; the term "arylsulfonyl group" means a phenylsulfonyl, p- toluenesulfonyl or naphthylsulfonyl group or the like; the term "lower alkylsulfonyloxy group" means a C1- 6alkylsulfonyloxy group such as methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy, tert- butylsulf onyloxy, pentylsulfonyloxy or the like; the term "arylsulfonyloxy group" means a phenylsulfonyloxy, p-toluenesulfonyloxy or naphthylsulfonyloxy group or the like; the term "alkylamino group" means a mono- or di-C1-6galkylamino group such as a methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, diisopropylamino, dibutylamino or the like; the term "monoalkylamino group" means a mono-C1-6galkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino or the like; the term "dialkylamino group" means a di-C1-6galkylamino group such as dimethylamino, diethylamino, diisopropylamino, dibutylamino or the like; the term "heterccyclic group" means a 5-membered or 6-membered heterocyclic group containing at least one heteroatom selected from nitrogen, oxygen and sulfur atoms or a condensed or crosslinked heterocyclic group thereof, such as pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, homopiperidinyl, morpholyl, thiomorpholyl, tetrahydroquinolyl, tetrahydroisoquinolyl, quinuclidinyl, imidazolinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, quinolyl, quinolizinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, purinyl, furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, isoxazolyl, benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinoxalyl, dihydroquinoxalyl, 2,3- dihydrobenzothienyl, 2,3-dihydrobenzopyrrolyl, 2,3-4H- 1-thianaphthyl, 2,3-dihydrobenzofuranyl, benzo[b]dioxanyl, imidazo[2,3-a]pyridyl, benzo[b]piperazinyl, chromenyl, isothiazolyl, isoxazolyl, oxadiazolyl, pyridazinyl, isoindolyl, isoquinolyl, 1,3-benzodioxonyl, 1,4-benzodioxanyl or the like; and the term "cyclic amino group" means a 5- membered, 6-membered or 7-membered cyclic amino group which contains one or more nitrogen atoms as the heteroatoms forming the ring and may further contain one or more oxygen atoms or sulfur atoms or a condensed or crosslinked cyclic amino group thereof, such as pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, homopiperidinyl, morpholyl, thiomorpholyl, tetrahydroquinolyl, tetrahydroisoquinolyl, imidazolidinyl or the like. As the 5-membered or 6-membered heteroaromatic ring as the ring A, there are exemplified 5-membered or 6-membered heteroaromatic rings which contain at least one heteroatom selected from oxygen, nitrogen and sulfur atoms as the heteroatom forming the ring, such as triazine, pyridazine, pyrimidine, pyrazine, pyridine, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, isoxazole, isothiazole, pyrazole, pyran, and the like. As the substituent of each of the alkyl group, aryl group, aralkyl group, alkoxy group, aryloxy group, alkylthio group, arylthio group, alkenyl group, alkenyloxy group, amino group, alkylsulfonyl group, arylsulfonyl group, carbamoyl group and heterocyclic group for each of R1 and R2 and the alkylamino group for R3, there are exemplified groups selected from halogen atoms, lower alkyl groups, cycloalkyl groups, aryl groups, lower alkoxy groups, aryloxy groups, lower alkylthio groups, arylthio groups, lower alkenyl groups, lower alkylsulfonyl groups, arylsulfonyl groups, alkylamino groups, protected or unprotected amino groups, protected or unprotected hydroxyl groups, protected or unprotected carboxyl groups, acyl groups, heterocyclic groups, etc. The protecting group for the carboxyl group includes all conventional groups usable as carboxyl- protecting groups, for example, lower alkyl groups such as methyl, ethyl, propyl, isopropyl, 1,1- dimethylpropyl, butyl, tert-butyl and the like; aryl groups such as phenyl, naphthyl and the like; ar-lower alkyl groups such as benzyl, diphenylmethyl, trityl, 4- nitrobenzyl, 4-methoxybenzyl, bis(4-methoxyphenyl)- methyl and the like; acyl-lower alkyl groups such as acetylmethyl, benzoylmethyl, 4-nitrobenzoylmethyl, 4- bromobenzoylmethyl, 4-methanesulfonylbenzoylmethyl and the like; oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl, 2-tetrahydrofuranyl and the like; halogeno-lower alkyl groups such as 2,2,2- trichloroethyl and the like; lower alkylsilyl-lower alkyl groups such as 2-(trimethylsilyl)ethyl and the like; acyloxy-lower alkyl groups such as acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl and the like; nitrogen-containing heterocyclic lower alkyl groups such as phthalimidomethyl, succinimidomethyl and the like; cycloalkyl groups such as cyclohexyl and the like; lower alkoxy-lower alkyl groups such as methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)- ethoxymethyl and the like; ar-lower alkoxy-lower alkyl groups such as benzyloxymethyl and the like; lower alkylthio-lower alkyl groups such as methylthiomethyl, 2-methylthioethyl and the like; arylthio-lower alkyl groups such as phenylthiomethyl and the like; lower alkenyl groups such as 1,l-dimethyl-2-propenyl, 3- methyl-3-butenyl, allyl and the like; and substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert- butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, tert-butylmethoxyphenylsilyl and the like. The protecting group for the hydroxyl group includes all conventional groups usable as hydroxyl- protecting groups, for example, alkoxy- and alkylthio- carbonyl groups such as benzyloxycarbonyl, 4- nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxy- carbonyl, 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, 4-ethoxy-l- naphthyloxycarbonyl, 8-quinolyloxycarbonyl, S- benzylthiocarbonyl and the like; acyl groups such as acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl and the like; lower alkyl groups such as methyl, tert-butyl, 2,2,2- trichloroethyl, 2-trimethylsilylethyl and the like; lower alkenyl groups such as allyl and the like; lower alkynyl groups such as propargyl and the like; ar-lower alkyl groups such as benzyl, 4-methoxybenzyl, 3,4- dimethoxybenzyl, diphenylmethyl, trityl and the like; oxygen-containing or sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and the like; lower alkoxy- or lower alkylthio-lower alkyl groups such as methoxymethyl, methylthiomethyl, benzyloxymethyl, 2- methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, 1-methyl- 1-methoxyethyl and the like; lower alkyl- or aryl- sulfonyl groups such as methanesulfonyl, p- toluenesulfonyl and the like; and substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert- butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, tert-butylmethoxyphenylsilyl and the like. The protecting group for the amino group includes all conventional groups usable as amino- protecting groups, for example, alkoxycarbonyl groups such as methoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-trimethylsilylethoxy- carbonyl, 1,1-dimethylpropoxycarbonyl, tert- butoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 1- adamantyloxycarbonyl, benzyloxycarbonyl, 4- nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, 2,4- dichlorobenzyloxycarbonyl, diphenylmethoxycarbonyl, 4- (phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, 8- quinolyloxycarbonyl and the like; acyl groups such as (mono-, di- or tri-)chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, phthaloyl, succinyl, alanyl, leucyl and the like; ar-lower alkyl groups such as benzyl, diphenylmethyl, trityl and the like; arylthio groups such as 2-nitrophenylthio, 2,4- dinitrophenylthio and the like; alkyl- or aryl-sulfonyl groups such as methanesulfonyl, p-toluenesulfonyl and the like; di-lower alkylamino-lower alkylidene groups such as N,N-dimethylaminomethylene and the like; ar- lower alkylidene groups such as benzylidene, 2- hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2- hydroxy-1-naphthylmethylene and the like; nitrogen- containing heterocyclic alkylidene groups such as 3- hydroxy-4-pyridylmethylene and the like; cycloalkylidene groups such as cyclohexylidene, 2- ethoxycarbonylcyclohexylidene, 2- ethoxycarbonylcyclopentylidene, 2- acetylcyclohexylidene, 3,3-dimethyl-5- oxycyclohexylidene and the like; diaryl- or diar-lower alkylphosphoryl groups such as diphenylphosphoryl, dibenzylphosphoryl and the like; oxygen-containing heterocyclic alkyl groups such as 5-methyl-2-oxo-2H- 1,3-dioxol-4-yl-methyl and the like; and substituted silyl groups such as trimethylsilyl and the like. The salt of the compound of the general formula [1] includes usually known salts at basic groups such as amino group and the like and salts at acidic groups such as hydroxyl group, carboxyl group and the like. The salts at the basic groups include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and the like; salts with organic carboxylic acids such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, tartaric acid, aspartic acid, trichloroacetic acid, trifluoroacetic acid and the like; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid and the like. The salts at the acidic groups include, for example, salts with alkali metals such as sodium, potassium and the like; salts with alkaline earth metals such as calcium, magnesium and the like; ammonium salts; and salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-ß- phenethylamine, 1-ephenamine, N,N"- dibenzylethylenediamine and the like. Of the above-exemplified salts, preferable salts are pharmacologically acceptable salts. When the alkyl ether derivative of the general formula [1] or its salt has isomers (for example, optical isomers, geometrical isomers and tautomers), the present invention includes all of these isomers, and the derivative or its salt may be in the form of a hydrate or solvate or in any crystal form. Preferable examples of the alkyl ether derivative of the general formula[1]or salt thereof of the present invention are compounds of the general formula [1] in which the portion represented by Of such compounds, preferable examples of the derivative or salt thereof of the present invention are compounds in which R~ is a hydrogen atom; and R2 is a hydrogen atom, a halogen atom or an alkoxy group. In addition, compounds of the general formula [1] in which m = 2 and n = 2 ~ 3 are preferable. Of such compounds, compounds of the general formula [1] in which p = 1 ~ 2 are more preferable. The most preferable examples of the derivative or salt thereof of the present invention are compounds in which each of R1 and R2 in the above group (A) is a hydrogen atom; R3 is a hydroxyl group; m = 2; n = 3; and p = 1. Processes for producing the alkyl ether derivative of the general formula [1] or its salt are explained below. The alkyl ether derivative of the general formula [1] or its salt can be produced, for example, by any of the following production processes by adopting one or a proper combination of per se well- known methods. Production process 1 wherein R1, R2, R3, A, m, n and p are as defined above; R3a is a dialkylamino group, a protected monoalkylamino group, a protected amino group or a protected or unprotected hydroxyl group; R3b is a dialkylamino group, a protected monoalkylamino group, a protected amino group or a protected hydroxyl group; R3c is a protected hydroxyl group; R3d is a monoalkylamino group, an amino group or a hydroxyl group; and each of X1, X2 and X3 is a leaving group. The leaving group includes, for example, halogen atoms, lower alkylsulfonyloxy groups and arylsulfonyloxy groups. The individual production processes are explained below. Production process 1. (1-1) A compound of the general formula [4] can be produced by reacting a compound of the general formula [2] or its reactive derivative with a compound of the general formula [3]. This reaction may be carried out by a per se well-known method, for example, the method described in Japanese Chemical Association, "Jikken Kagaku Koza" vol. 22, pages 137-173 (1992), Maruzen Co., Ltd. or a method based thereon. The reactive derivative of the compound of the general formula [2] includes, for example, acid halides, acid anhydrides, activated amides and activated esters. When the compound of the general formula [2] is used in the form of a free acid, the reaction is preferably carried out in the presence of a condensing agent. The condensing agent includes, for example, N,N"-dialkylcarbodiimides such as N,N"-dicyclohexyl- carbodiimide and the like; halogenating agents such as thionyl chloride, oxalyl chloride and the like; acid halides such as ethoxycarbonyl chloride and the like; agents for conversion to an activated amide, such as carbonyldiimidazole and the like; and agent for conversion to an azide, such as diphenylphosphoryl azide and the like. The amount of the condensing agent used is 1 mole or more, preferably 1 to 5 moles, per mole of the compound of the general formula [2]. In the reaction, any solvent may be used so long as it has no undesirable influence on the reaction. The solvent includes, for example, water; halogenated hydrocarbons such as methylene chloride, chloroform and the like; ethers such as tetrahydro- furan, dioxane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; sulfoxides such as dimethyl sulfoxide and the like; amides such as N,N-dimethylformamide and the like; esters such as ethyl acetate and the like; ketones such as acetone, methyl ethyl ketone and the like; nitriles such as acetonitrile and the like; and heteroaromatic compounds such as pyridine and the like. These solvents may be used singly or as a mixture thereof. The reaction may be carried out in the presence of a base. The base includes, for example, organic or inorganic bases such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undec-7- ene (DBU), pyridine, potassium tert-butoxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, sodium hydroxide and the like. The amount of the base used is 0.5 mole or more, preferably 1 to 10 moles, per mole of the compound of the general formula [2]. The amount of the compound of the general formula [3] is 1 mole or more, preferably 1 to 20 moles, per mole of the compound of the general formula [2]. The reaction is carried out at usually -100°C to 200°C, preferably -60°C to 100°C, for 10 minutes to 20 hours. The compound of the general formula [4] obtained may be used as it is in the subsequent reaction without isolation. (1-2) When R3a is an unprotected hydroxyl group in the compound of the general formula [4], this compound can be converted to a compound of the general formula [4a] by subjecting it to a conventional reaction for protecting the hydroxyl group. This reaction may be carried out by a per se well-known method, for example, the method described in Theodora W. Green, "Protective Groups in Organic Synthesis" pages 10-118 (1991), John Wiley & Sons. Inc., or a method based thereon. A compound used in the reaction for protecting the hydroxyl group includes, for example, acid anhydrides such as acetic anhydride and the like; acid halides such as benzoyl chloride, pivaloyl chloride, methoxycarbonyl chloride, ethoxycarbonyl chloride and the like; halides such as methoxymethyl chloride, benzyloxymethyl chloride, benzyl chloride, benzyl bromide, trityl chloride, triethylsilyl chloride and the like; organic carboxylic acid compounds such as benzoic acid and the like; dialkoxyalkyl compounds such as dimethoxymethane and the like; and acyclic or cyclic alkoxyvinyl compounds such as 2-methoxypropene, 3,4- dihydro-2H-pyran and the like. The amount of the compound used in the reaction for protecting the hydroxyl group is 1 mole or more, preferably 1 to 2 moles, per mole of the compound of the general formula [4a]. The reaction for protecting the hydroxyl group by the use of any of the acid anhydrides, the acid halides and the halides is usually carried out in the presence of a base or a dehalogenating agent. The base used includes, for example, organic or inorganic bases such as triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), pyridine, 4- dimethylaminopyridine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and the like. The dehalogenating agent includes silver compounds such as silver oxide and the like. The reaction for protecting the hydroxyl group by the use of the organic carboxylic acid compound is carried out in the presence of a dehydrating agent. The dehydrating agent used includes, for example triphenylphosphine- diisopropyl=azodicarboxylate. The reaction for protecting the hydroxyl group by the use of any of the acid anhydrides, the dialkoxyalkyl compounds and the acyclic or cyclic alkoxyvinyl compounds is usually carried out in the presence of an acid catalyst. The acid used includes organic sulfonic acids such as p-toluenesulfonic acid and the like; inorganic acids such as hydrochloric acid, sulfuric acid and the like; and Lewis acids such as boron trifluoride, boron trifluoride diethyl ether complex, boron trifluoride tetrahydrofuran complex and the like. The amount of the base, dehalogenating agent or dehydrating agent used in the reaction is 1 mole or more, preferably 1 to 2 moles, per mole of the compound used in the reaction for protecting the hydroxyl group. The amount of the acid used as catalyst is 0.001 to 10 moles, preferably 0.01 to 1 mole, per mole of the compound of the general formula [4a]. In the reaction, any solvent may be used so long as it has no undesirable influence on the reaction. The solvent includes, for example, halogenated hydrocarbons such as methylene chloride, chloroform and the like; ethers such as tetrahydrofuran, dioxane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; sulfoxides such as dimethyl sulfoxide and the like; amides such as N,N-dimethylformamide and the like; esters such as ethyl acetate and the like; ketones such as acetone, methyl ethyl ketone and the like; nitriles such as acetonitrile and the like; and heteroaromatic compounds such as pyridine and the like. These solvents may be used singly or as a mixture thereof. The reaction is carried out at usually -100°C to 200°C, preferably -60°C to 100°C, for 10 minutes to 30 hours. The reactants or base used in each of the above production methods may be used also as a solvent, depending on their properties. The compound of the general formula [4a] obtained may be used as it is in the subsequent reaction without isolation. (1-3) A compound of the general formula [1] can be produced by subjecting the compound of the general formula [4] or the general formula [4a] to a conventional reduction. This reduction may be carried out by a per se well-known method, for example, the method described in Japanese Chemical Association, "Shin Jikken Kagaku Koza" vol. 15, [II], pages 29-244 (1977), Maruzen Co., Ltd. or a method based thereon. In the reaction, any solvent may be used so long as it has no undesirable influence on the reac- tion. The solvent includes, for example, halogenated hydrocarbons such as methylene chloride, chloroform and the like; ethers such as tetrahydrofuran, dioxane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; and alcohols such as methanol, ethanol, isopropanol and the like. These solvents may be used singly or as a mixture thereof. As a reducing agent, there are exemplified aluminum hydrides such as lithium aluminum hydride and the like; and boron hydrides such as diborane, borane- tetrahydrofuran complexes, borane-dimethyl sulfide complexes, sodium borohydride and the like. When sodium borohydride is used as the reducing agent, the reaction is preferably carried out in the presence of a Lewis acid such as boron trifluoride, boron trifluoride diethyl ether complex, boron trifluoride tetrahydrofuran complex or the like. The amount of the redacing agent used is 0.2 mole or more, preferably 0.5 to 10 moles, per mole of the compound of the general formula [4] or the general formula [4a]. The amount of the Lewis acid used is 1 mole or more, preferably 4/3 to 2 moles, per mole of the reducing agent. The reaction is carried out at usually -50°C to 200°C, preferably 0°C to 110°C, for 10 minutes to 20 hours. Production process 2. A compound of the general formula [la] can be produced by reacting a compound of the general formula [5] with a compound of the general formula [3] in the presence or absence of a base. In this reaction, any solvent may be used so long as it has no undesirable influence on the reaction. The solvent includes,, for example, water; halogenated hydrocarbons such as methylene chloride, chloroform and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol and the like; nitriles such as acetonitrile and the like; amides such as N,N- dimethylformamide and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents may be used singly or as a mixture thereof. The base optionally used includes, for example, organic or inorganic bases such as triethylamine, diisopropylethylamine, 1,8- diazabicyclo[5,4,0]undec-7-ene (DBU), pyridine, potassium tert-butoxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, sodium hydroxide and the like. The amount of the base used is 0.5 mole or more, preferably 1 to 20 moles, per mole of the compound of the general formula [5], In addition, the reaction may be carried out in the presence of a catalyst. The catalyst includes, for example, potassium iodide and sodium iodide. The amount of the catalyst used is 0.01 to 10 moles, preferably 0.1 to 1 mole, per mole of the compound of the general formula [5]. The amount of the compound of the general formula [3] used is 1 mole or more, preferably 1 to 20 moles, per mole of the compound of the general formula [5] . The reaction is carried out at usually 0°C to 200°C, preferably 20°C to 150°C, for 10 minutes to 20 hours. The reactants or base used in the above production process may be used also as a solvent, depending on their properties. Production process 3. A compound of the general formula [lb] can be produced by reacting a compound of the general formula [6] with a compound of the general formula [7] in the presence of a base. This reaction may be carried out by a per se well-known method, for example, the method described in Tetrahedron Letters, vol. 38, pages 3251-3254 (1975) and Japanese Chemical Association, "Shin Jikken Kagaku Koza" vol. 14, [I], pages 567-611 (1977), Maruzen Co., Ltd. or a method based thereon. The base includes, for example, sodium hydride, sodium hydroxide, potassium hydroxide and potassium tert-butoxide. In the reaction, any solvent may be used so long as it has no undesirable influence on the reaction. The solvent includes, for example, halogenated hydrocarbons such as methylene chloride, chloroform and the like; ethers such as tetrahydrofuran, dioxane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; sulfoxides such as dimethyl sulfoxide and the like; amides such as N,N-dimethylformamide and the like; and water. These solvents may be used singly or as a mixture thereof. The reaction may be carried out in the presence or absence of a catalyst. The catalyst used includes usually known phase transfer catalysts composed of a quaternary ammonium salt, and preferable examples thereof are tetra-n-butylammonium hydrogensulfate and tetra-n- butylammonium bromide. The amount of each of the compound of the general formula [7] and the base used in the reaction is 1 mole or more, preferably 1 to 20 moles, per mole of the compound of the general formula [6]. The amount of the catalyst is 0.001 to 1 mole per mole of the compound of the general formula [6]. The reaction is carried out at usually -50°C to 200°C, preferably 0°C to 150°C, for 10 minutes to 20 hours. Production process 4. A compound of the general formula [lb] can be produced by reacting a compound of the general formula [8] with a compound of the general formula [9] in the presence or absence of a base. This reaction may be carried out by a per se well-known method, for example, the same method as in production process 3. Production process 5. (5-1) A compound of the general formula [lc] can be produced by subjecting a compound of the general formula [la] and a compound of rhe general formula [lb] to a conventional deprotecting reaction. This reaction may be carried out by a per se well-known method, for example, the method described in Theodora W. Green, "Protective Groups in Organic Synthesis" pages 10-118 and 309-405 (1991), John Wiley & Sons. Inc., or a method based thereon. The deprotecting reaction is carried out under conditions for, for example, hydrolysis and transesterification reaction in the presence of an acid or a base, substitution and elimination reaction in the presence of an acid catalyst, or hydrogenolysis in the presence of a metal catalyst. The base used includes, for example, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydride and the like. The acid includes organic sulfonic acids such as p- toluenesulfonic acid and the like; organic carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid and the like; inorganic acids such as hydrochloric acid, sulfuric acid and the likes; and Lewis acids such as boron trifluoride, boron trifluoride diethyl ether complex, boron trifluoride tetrahydrofuran complex and the like. The metal catalyst includes, for example, transition metals such as platinum, palladium, palladium-carbon, palladium hydroxide and the like. The base used in the reaction may be used in an amount of 1 mole or more, preferably 1 to 5 moles, per mole of a combination of the compounds of the general formulas [la] and [lb]. The amount of the acid used is 1 mole or more, preferably 1.1 to 100 moles, per mole of a combination of the compounds of the general formulas [la] and [lb]. The amount of the metal catalyst used is a catalytic amount, preferably 0.01 to 30% by weight, relative to a combination of the compounds of the general formulas [la] and [lb]. In the reaction, any solvent may be used so long as it has no undesirable influence on the reaction. The solvent includes, for example, halogenated hydrocarbons such as methylene chloride, chloroform and the like; ethers such as tetrahydrofuran, dioxane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; sulfoxides such as dimethyl sulfoxide and the like; amides such as N,N-dimethylformamide and the like; esters such as ethyl acetate and the like; ketones such as acetone, methyl ethyl ketone and the like; nitriles such as acetonitrile and the like; alcohols such as methanol, ethanol and the like; organic carboxylic acids such as formic acid, acetic acid and the like; and water. These solvents may be used singly or as a mixture thereof. The reaction is carried out at usually -100°C to 200°C, preferably -60°C to 120°C, for 10 minutes to 20 hours. The acid used in each of the above production methods may be used also as a solvent, depending on its properties. (5-2) The compound of the general formula [lc] can be converted to the compound of the general formula [lb] by subjecting it to any of conventional reactions for protection of a hydroxyl group and an amino group and the alkylation of an amino group. The reaction for protecting a hydroxyl group may be carried out by a per se well-known method, for example, the method described ir, Theodora W. Green, "Protective Groups in Organic Synthesis" pages 10-118 (1991), John Wiley & Sons. Inc., or a method based thereon, namely, the reaction may be carried out by the same method as in the above item (1-2). The reaction for protecting an amino group may be carried out by a per se well-known method, for example, the method described in Theodora W. Green, "Protective Groups in Organic Synthesis" pages 309-405 (1991), John Wiley & Sons. Inc., or a method based thereon. A compound used in the reaction for protecting an amino group includes, for example, acid anhydrides such as acetic anhydride and the like; and acid halides such as acetyl chloride, benzoyl chloride, mesyl chloride, tosyl chloride and the like. The amount of the compound used is 1 mole or more, preferably 1 to 2 moles, per mole of the compound of the general formula [lc]. This reaction is usually carried out in the presence of a base, and the base includes, for example, organic or inorganic bases such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undec-7- ene (DBU), pyridine, potassium tert-butoxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, sodium hydride and the like. The amount of the base used is 0.5 mole or more, preferably 1 to 10 moles, per mole of the compound of the general formula [1c]. In the reaction, any solvent may be used so long as it has no undesirable influence on the reaction. The solvent includes, for example, halogenated hydrocarbons such as methylene chloride, chloroform and the like; ethers such as tetrahydrofuran, dicxane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; sulfoxides such as dimethyl sulfoxide and the like; amides such as N,N-dimethylformamide and the like; esters such as ethyl acetate and the like; ketones such as acetone, methyl ethyl ketone and the like; nitriles such as acetonitrile and the like; alcohols such as methanol, ethanol and the like; and water. These solvents may be used singly or as a mixture thereof. The reaction is carried out at usually -100°C to 200°C, preferably -60°C to 100°C, for 10 minutes to 20 hours. The alkylation of an amino group may be carried out by a per se well-known method, for example, the method described in Japanese Chemical Association, "Shin Jikken Kagaku Koza" vol. 14, [III], pages 1332- 1399 (1977), Maruzen Co., Ltd. or a method based thereon. A compound used in the alkylation of an amino group includes, for example, carbonyl compounds such as formaldehyde, paraformaldehyde, acetaldehyde, acetone and the like. The amount of this compound used is 1 mole or more, preferably 1 to 5 moles, per mole of the compound of the general formula [lc]. This reaction is usually carried out in the presence of a reducing agent, and the reducing agent includes boron hydrides such as sodium borohydride and the like. The amount of the reducing agent used is 0.5 mole or more, preferably 1 to 10 moles, per mole of the carbonyl compound. In the reaction, any solvent may be used so long as it has no undesirable influence on the reaction. The solvent includes, for example, water; halogenated hydrocarbons such as methylene chloride, chloroform and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, dioxane and the like; and alcohols such as methanol, ethanol and the like. These solvents may be used singly or as a mixture thereof. The reaction is carried out at usually -100°C to 200°C, preferably 0°C to 100°C, for 10 minutes to 30 hours. The reactants used in each of the above production methods may be used also as a solvent, depending on their properties. In the above production processes, each of the compounds of the general formulas [2] to [9] can be used in the form of a salt. As the salt, there are exemplified the same salts as in the case of the compound of the general formula [1]. As salts of the compounds of the general formulas [la], [lb] and [lc], there are exemplified the same salts as in the case of the compound of the general formula [1]. When any cf the compounds of the general formulas [la], [lb], [lc] and [2] to [9] has isomers (for example, optical isomers, geometrical isomers and tautomers), each of these isomers can be used. In addition, any of the: compounds may be used in the form of a hydrate or solvate or in any crystal form. Each of the compounds of the general formulas [la], [lb], [lc] and [2] to [9] may be used as it is in the subsequent reaction without isolation. When any of the compounds of the general formulas [1], [la], [lb] , [lc] and [2] to [9] has a hydroxyl group, an amino group or a carboxyl group, it is possible to previously protect the hydroxyl group, the amino group or the carboxyl group with a conventional protecting group and, if necessary, remove the protecting group by a per se well-known method after completion of the reaction. In addition, each of the alkyl ether derivatives of the general formulas [1], [la], [lb] and [lc] or its salt can be converted to another alkyl ether derivative of the general formula [1] or its salt by a proper combination of per se well-known methods such as oxidation, reduction, alkylation, halogenation, sulfonylation, substitution, dehydration, hydrolysis and the like. The alkyl ether derivatives of the general formulas [1], [la], [lb] and [lc] or their salts can be isolated and separated according to one or more conventional operations which may be selected from extraction, crystallization, distillation, column chromatography and the like. Processes for producing each of the compounds of the general formulas [2] and [5], which is a starting material for producing the compound of the present invention, are explained below. The compound of the general formula [2] can be produced, for example, by the following production process A by adopting one or a proper combination of per se well-known methods. wherein R1, R2, A, X3, m and n are as defined above; R4 is a cyano group, a lower alkoxycarbonyl group, a dialkylaminocarbonyl group or a cyclic aminocarbonyl group; and X4 is a leaving group. (A-l) A compound of the general formula [11] can be produced by reacting a compound of the general formula [6] with a compound of the general formula [10] in the presence of a base. This reaction may be carried out by a per se well-known method, for example, the method described in Japanese Chemical Association, "Shin Jikken Kagaku Koza" vol. 14, [I], pages 567-611 (1977), Maruzen Co., Ltd. or a method based thereon. (A-2) A compound of the general formula [11] can be produced by reacting a compound of the general formula [8] with a compound of the general formula [12] in the presence of a base. This reaction may be carried out by a per se well-known method, for example, the same method as in the production process (A-l). (A-3) The compound of the general formula [2] can be produced by subjecting the compound of the general formula [11] to a conventional hydrolysis of nitrile, ester or amide. This reaction may be carried out by a per se well-known method, for example, the method described in Japanese Chemical Association, "Shin Jikken Kagaku Koza" vol. 14, [II], pages 930-950 (1977), Maruzen Co., Ltd. and Theodora W. Green, "Protective Groups in Organic Synthesis" pages 152-192 (1981), John Wiley & Sons. Inc. or a method based thereon. (A-4) A compound of the general formula [11a] can be produced by subjecting a compound of the general formula [6] to Michael addition with a compound of the general formula [16] in the presence of a base. This reaction may be carried out by a per se well-known method, for example, the method described in any of "Chemical & Pharmaceutical Bulletin" vol. 41, pages 1659-1663 (1993), Japanese Chemical Association, "Shin Jikken Kagaku Koza" vol. 14, [I], pages 585-587 (1977), Maruzen Co., Ltd. and JP-A-3-99038, or a method based thereon. (A-5) A compound of the general formula [2a] can be produced by subjecting the compound of the general formula [11a] to a conventional hydrolysis of nitrile, ester or amide. This reaction may be carried out by a per se well-known method, for example, the same method as in (A-3). The compound of the general formula [5] can be produced, for example, by the following production process B by adopting one or a proper combination of per se well-known methods. wherein R1, R2, X1, A, m and n are as defined above; R4a is an alkoxycarbonyl group; R5 is a hydroxyl-protecting group which is stable under basic conditions; and each of X5 and X6 is a leaving group. The hydroxyl-protecting group stable under basic conditions includes, for example, lower alkyl groups such as tert-butyl and the like; lower alkenyl groups such as allyl and the like; ar-lower alkyl groups such as benzyl, 4-methoxybenzyl, 3,4- dimethoxybenzyl, diphenylmethyl, trityl and the like; oxygen-containing or sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and the like; lower alkoxy-lower alkyl groups such as methoxymethyl, 2- (trimethylsilyl)ethoxymethyl, 1-methyl-l-methoxyethyl and the like; and substituted silyl groups such as tert-butyldimethylsilyl, diphenylmethylsilyl and the like. (B-l) The compound of the general formula [5] can be produced by reacting a compound of the general formula [6] with a compound of the general formula [13]. This reaction may be carried out by a per se well-known method, for example, the method described in Tetrahedron Letters, vol. 38, pages 3251-3254 (1975) and Japanese Chemical Association, "Shin Jikken Kagaku Koza" vol. 14, [I], pages 567-611 (1977), Maruzen Co., Ltd. or a method based thereon. (B-2) A compound of the general formula [15] can be produced by reacting a compound of the general formula [6] with a compound of the general formula [14], and then removing the protecting group. This reaction may be carried out by a per se well-known method, for example, the same method as in production process 3, and then the protecting group may be removed. (B-3) A compound of the general formula [15] can be produced by subjecting a compound of the general formula [2] or a compound of the general formula [l1b] to a conventional reduction. This reduction may be carried out by a per se well-known method, for example, the method described in "Shin Jikken Kagaku Koza" vol. 15, pages 26-244 (1977), Maruzen Co., Ltd. or a method based thereon. (B-4) The compound of the general formula [5] can be produced by reacting the compound of the general formula [15] with a halogenating agent or a sulfonylating agent in the presence or absence of a base. A solvent used in this reaction includes, for example, halogenated hydrocarbons such as methylene chloride, chloroform and the like; ethers such as tetrahydrofuran, dioxane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; sulfoxides such as dimethyl sulfoxide and the like; amides such as N,N-dimethylformamide and the like; esters such as ethyl acetate and the like; and nitriles such as acetonitrile and the like. These solvents may be used singly or as a mixture thereof. The base optionally used includes, for example, organic or inorganic bases such as triethylamine, diisopropylethylamine, 1,8- diazabicyclo[5,4,0]undec-7-ene, pyridine, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydride and the like. The halogenating agent includes, for example, phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus pentachloride, carbon tetrabromide-triphenylphosphine, and thionyl chloride. The sulfonylating agent includes, for example, methanesulfonyl chloride and p-toluenesulfonyl chloride. The amount of each of the halogenating agent or sulfonylating agent and the base used is 1 mole or more, preferably 1 to 2 moles, per mole of the compound of the general formula [15]. The reaction is carried out at usually -50°C to 200°C, preferably 0°C to 50°C, for 10 minutes to 30 hours. When any of the compounds of the general formulas [2], [2a], [6], [8], [10] to [16], [11a] and [l1b] in production processes A and B has a hydroxyl group, an amino group or a carboxyl group, it is possible to previously protect the hydroxyl group, the amino group or the carboxyl group with a conventional protecting group and, if necessary, remove the protecting group by a per se well-known method after completion of the reaction. When any of the compounds of the general formulas [2], [2a], [6], [8], [20] to [16], [11a] and [l1b] has isomers (for example, optical isomers, geometrical isomers and tautomers), each of these isomers can be used. In addition, any of the compounds may be used in the form of a hydrate or solvate or in any crystal form. Each of the compounds of the general formulas [2], [2a], [6], [8], [10] to [16], [11a] and [11b] may be used as it is in the subsequent reaction without isolation. The compound of the present invention can be formulated into pharmaceutical preparations such as oral preparations (e.g. tablets, capsules, powders, granules, fine granules, pills, suspensions, emulsions, solutions and syrups), injections, suppositories, external preparations (e.g. ointments and patches), aerosols and the like by blending therewith various pharmaceutical additives such as excipients, binders, disintegrators, disintegration inhibitors, consolidation•adhes:.on inhibitors, lubricants, absorption•adsorption carriers, solvents, fillers, isotonicity agents, solubilizers, emulsifying agents, suspending agents, thickening agents, coating agents, absorption accelerators, gelation•coagulation accelerators, light stabilizers, preservatives, dehumidifiers, emulsion•suspension•dispersion stabilizers, color protectors, deoxygenation»oxidation inhibitors, sweetening•flavoring agents, coloring agents, foaming agents, defoaming agents, soothing agents, antistatic agents, buffering and pH-adjusting agents, etc. The above various Pharmaceuticals are prepared by conventional methods. The oral solid Pharmaceuticals such as tablets, powders and granules are prepared by a conventional method by using pharmaceutical additives for solid preparation, for example, excipients such as lactose, sucrose, scdium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, anhydrous calcium secondary phosphate, partly pregelatinized starch, corn starch, alginic acid and the like; binders such as simple syrup, a glucose solution, a starch solution, a gelatin solution, polyvinyl alcohols, polyvinyl ethers, polyvinylpyrrolidones, carboxymethyl cellulose, shellac, methyl cellulose, ethyl cellulose, sodium alginate, gum arabic, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, water, ethanol and the like; disintegrators such as dried starch, alginic acid, agar powder, starch, crosslinked polyvinylpyrrolidones, crosslinked carboxymethyl cellulose sodium salt, carboxymethyl cellulose calcium salt, starch sodium glycolate and the like; disintegration inhibitors such as stearyl alcohol, stearic acid, cacao butter, hydrogenated oil and the like; consolidatiorradhesion inhibitors such as aluminum silicate, calcium hydrogenphosphate, magnesium oxide, talc, silicic acic anhydride and the like; lubricants such as carnauba wax, light silicic acid anhydride, aluminum silicate, magnesium silicate, hydrogenated oil, hydrogenated vegetable oil derivatives, sesame oil, white beeswax, titanium oxide, dried aluminum hydroxide gel, stearic acid, calcium stearate, magnesium stearate, talc, calcium hydrogenphosphate, sodium lauryl sulfate, polyethylene glycols and the like; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate, urea, enzymes and the like; and absorption•adsorption carriers such as starch, lactose kaolin, bentonite, silicic acid anhydride, hydrated silicon dioxide, magnesium aluminate metasilicate, colloidal silica and the like. If necessary, tablets can be made into tablets having a conventional coating, such as sugar coated tablets, gelatin coated tablets, gastric coated tablets, enteric coated tablets and water-soluble-film coated tablets. The capsules are prepared by mixing the compound of the present invention with the above- exemplified various pharmaceutical additives and packing the resulting mixture into hard gelatin capsules, soft capsules or the like. The compound of the present invention can be formulated into an aqueous or oily suspension, solution, syrup or elixir by a conventional method by using the above-exemplified various additives for liquid preparation, such as solvents, fillers, isotonicity agents, solubilizers, emulsifying agents, suspending agents, thickening agents and the like. The suppositories are prepared by adding a suitable absorption accelerator to, for example, a polyethylene glycol, cacao butter, lanolin, a higher alcohol, a higher alcohol ester, gelatin, a semi- synthesized glyceride or Witepsol. The injections are prepared by a conventional method by using pharmaceutical additives for liquid preparation, for example, diluents such as water, ethanol, Macrogol, propylene glycol, citric acid, acetic acid, phosphoric acid, lactic acid, sodium lactate, sulfuric acid, sodium hydroxide and the like; pH adjustors and buffers, such as sodium citrate, sodium acetate, sodium phosphate and the like; stabilizers such as sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid, thiolactic acid and the like; isotonicity agents such as sodium chloride, glucose, mannitol, glycerol and the like; solubilizers such as carboxymethyl cellulose sodium salt, propylene glycol, sodium benzoate, benzyl benzoate, urethane, ethanolamine, glycerol and the like; soothing agents such as calcium gluconate, chlorobutanol, glucose, benzyl alcohol and the like; and local anesthetics. The ointments in the form of paste, cream or gel are prepared by mixing and formulation according to a conventional method by using pharmaceutical additives, for example, base ingredients such as white soft paraffin, polyethylenes, paraffin, glycerol, cellulose derivatives, polyethylene glycols, silicone, bentonite and the like; preservatives such as methyl p- oxybenzoate, ethyl p-oxybenzoate, propyl p-oxybenzoate and the like; stabilizers; and wetting agents. When the patch is prepared, the above- mentioned ointment, cream, gel or paste is applied on a conventional support by a conventional method. As the support, there can be used woven or nonwoven fabrics made of cotton, staple fiber or chemical fiber; and films or foamed sheets of soft vinyl chloride, a polyethylene, a polyurethane or the like. A method for administering the above- mentioned pharmaceutical preparation is not particularly limited and is properly determined depending on the pharmaceutical form, the age, sex and other conditions of a patient, and the symptom of the patient. The dose of active ingredient of the pharmaceutical preparation of the present invention is properly chosen depending on administration route, the age, sex and pathosis of a patient, and other conditions. Usually, the active ingredient may be administered to an adult in a dose of 0.1 to 500 nag per day in one portion or several portions. BEST MODE FOR CARRYING OUT THE INVENTION The present invention is illustrated with reference to the following examples, reference examples and test examples, which should not be construed as limiting the scope of the invention. In the examples and reference examples, the mixing ratios in the eluents are all by volume, and B.W. Silica gel, BW-127ZH or FL-100DX (mfd. by FUJI SILYSIA CHEMICAL LTD.) was used as a carrier in the column chromatography. The symbols used in the reaction schemes have the following meanings: Ac: acetyl, Boc: tert-butoxycarbonyl, Bz: benzoyl, Piv: pivaloyl, Bn: benzyl, Tr: trityl, MOM: methoxymethyl, BOM: benzyloxymethyl, TES: triethylsilyl, THP: tetrahydropyranyl, Ms: mesyl, Me: methyl, Et: ethyl, Ph: phenyl, t-Bu: tert-butyl. Example 1 Production of 1-{2-[2-(1-benzothiophen-5- yl)ethoxy]ethyl}-3-azetidinol (1) In 12 mL of methylene chloride was dissolved 1.20 g of 2-[2-(1-benzothiophen-5-yl)ethoxy]acetic acid, and 2.3 mL of triethylamine and 0.38 g of imidazole were added to the solution. The resulting mixture was cooled to 5°C and 0.41 mL of thionyl chloride was added dropwise thereto, followed by stirring at the same temperature for 1 hour. After the reaction mixture was cooled to -60°C, 0.82 mL of triethylamine and 0.72 g of 3-azetidinol hydrochloride were added thereto, and the resulting mixture was stirred at the same temperature for 1 hour and then at room temperature for 1.5 hours. Water was added to the reaction mixture and the pH was adjusted to 1.0 with 6 mol/L hydrochloric acid, after which the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2- [2-(l-benzothiophen-5-yl)ethoxy]-1-(3-hydroxy-1- azetidinyl)-1-ethanone as a yellow oil. (2) The aforesaid 2-[2-(l-benzothiophen-5- yl)ethoxy]-1-(3-hydroxy-1-azetidinyl)-1-ethanone was dissolved in 12 mL of tetrahydrofuran and the resulting solution was cooled to 5°C, after which 12.7 mL of a 1 mol/L solution of a borane-tetrahydrofuran complex in tetrahydrofuran was added dropwise thereto and the resulting mixture was stirred at room temperature for 17 hours. To the reaction mixture was added 10 mL of acetone, and stirred for 30 minutes, followed by adding thereto 6.0 mL of 6 mol/L hydrochloric acid, and the resulting mixture was heated under reflux for 2 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the pH was adjusted to 13 with a 2 mol/L aqueous sodium hydroxide solution, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.13 g of 1-(2-[2-(1-benzothiophen- 5-yl)ethoxy]ethyl}-3-azetidinol as a yellow oil. IR(neat)cm"1: 3 378,2943,1438,1198,1119,703 NMR(CDCl3)d values: 2 . 66 (2H, t, J=6Hz), 2.9-3.1(2H,m), 2.99(2H,t,J=7Hz), 3.46(2H,t,J=6Hz), 3.6-3.7(2H,m), 3.67(2H,t,J=7Hz), 4.41(lH,qn,J=6Hz), 7.20(1H,dd,J=2,8Hz), 7.27(lH,d,J=5Hz), 7.41(1H,d,J=5Hz), 7.66(1H, d, J=2Hz), 7.78(lH,d,J=8Hz) Example 2 Production of 1-{2-[2-(l-benzothiophen-5- yl)ethoxy]ethyl}-3-azetidinol hydrochloride In 4.2 mL of ethyl acetate was dissolved 1.03 g of l-{2-[2-(l-benzothiophen-5-yl)ethoxy]ethyl}-3- azetidinol, and to the solution was added 0.86 mL of a 4.76 mol/L dried hydrogen chloride-ethyl acetate solution. The resulting mixture was stirred at room temperature for 1 hour and then at 5°C for 1 hour. The crystals precipitated were collected by filtration, washed with ethyl acetate and then dried to obtain 0.98 g of l-{2-[2-(l-benzothiophen-5-yl)ethoxy]ethyl}-3- azetidinol hydrochloride. Melting point: 101-102°C. IR(KBr) cm-1: 3132,2952,1423,1340,1158,814,7 01 NMR(CDC13)d values: 2.97(2H,t,J=7Hz) , 3.2- 3.3(2H,m), 3.69(2H,t,J=7Hz), 3.6-3.8(2H,m), 3.9- 4.1(2H,m), 4.2-4.4(2H,m), 4.6-4.8(lH,m), 7.18(lH,dd,J=l,8Hz), 7.29(lH,d,J=5Hz), 7.41(lH,d,J=5Hz), 7.65(lH,d,J=lHz), 7.78(lH,d,J=8Hz) Example 3 Production of l-{3-[2-(l-benzothiophen-6- yl)ethoxy]propyl}-3-azetidinol In 5 mL of dimethyl sulfoxide was dissolved 1.00 g of 6-[2-(3-chloropropoxy)ethyl]-l- benzothiophene, and 0.86 g of 3-azetidinol hydrochloride and 1.63 g of potassium carbonate were added to the solution. The resulting mixture was stirred at 75°C for 2.5 hours and then at 95°C for 1.5 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the pH was adjusted to 1 with 6 mol/L hydrochloric acid, and the aqueous layer was separated. Ethyl acetate was added to the aqueous layer and the pH was adjusted to 10 with a 2 mol/L aqueous sodium hydroxide solution, after which the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform : methanol =30 : 1 to 5 : 1) to obtain 0.28 g of l-{3-[2-(1-benzothiophen-6-yl)ethoxy]propyl}-3- azetidinol as a colorless oil. IR(neat) cm-1: 3398, 2 94 0, 28 67, 1197, 1107, 820, 7 57 NMR(CDC13)6 values: 1. 60 (2H, qn, J=7Hz) , 2.45(2H,t,J=7Hz), 2.7-2.8(2H,m), 2.99(2H,t,J=7Hz), 3.45(2H,t,J=7Hz), 3.5-3.6(2H,m), 3.66(2H,t,J=7Hz), 4.37(lH,qn,J=6Hz), 7.23(1H,dd,J=l,8Hz), 7.29(lH,d,J=5Hz), 7.37(lH,d,J=5Hz), 7.73(1H,d,J=1Hz), 7.74(1H,d,J=8Hz) Example 4 Production of l-{3-[2-(1-benzothiophen-6- yl)ethoxy]propyl}-3-azetidinol hydrochloride In 3.0 mL of ethyl acetate was dissolved 0.28 g of l-{3-[2-(1-benzothiophen-6-yl)ethoxy]propyl}-3- azetidinol, and to the solution was added 0.35 mL of a 3.25 mol/L dried hydrogen chloride-ethyl acetate solution, after which the resulting mixture was stirred at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure to obtain 0.30 g of l-{3-[2-(1-benzothiophen-6-yl)ethoxy]propyl}-3- azetidinol hydrochloride as a light-yellow oil. IR (neat) cm-1: 32 64, 2866, 2596, 1398, 1109, 1048, 821 NMR(CDC13)5 values: 1. 81 (2H, qn, J=6Hz) , 2.92(2H,tfJ=6Hz), 2.98(2H,t,J=6Hz), 3.46(2H,t,J=6Hz), 3.68(2H,t,J=6Hz), 3.8-3.9(2H,m), 3.8-4.0(2H,m), 4.4-4.6(1H,m), 7.23(1H,dd,J=l,8Hz), 7.31(1H,d,J=5Hz), 7.39 (1H,d,J=5Hz), 7.74(1H,d,J=1Hz), 7.76(lH,d,J=8Hz) Example 5 Production of 1-{3-[2-(l-benzothiophen-2- yl)ethoxy]propyl}-3-azetidinol In the same manner as in Example 3, 1-{3-[2- (l-benzothiophen-2-yl)ethoxy]propyl}-3-azetidinol was obtained as a colorless oil. IR (neat) cm"1: 3366, 2 942, 2856, 14 58,1436, 1113, 750 NMR(CDC13)5 values: 1. 64 (2H, qn=7Hz) , 2.49(2H,t,J=7Hz), 2.7-2.8(2H,m), 3.15(2H,t,J=7Hz), 3.50(2H,t,J=7Hz), 3.5-3.7(2H,m), 3.71(2H,t,J=7Hz), 4.3-4.4(lH,m), 7.06(lH,s), 7.2-7.4(2H,m), 7.67(lH,dd,J=l,7Hz), 7.7 7(1H,dd,J=l,7Hz) Example 6 Production of 1-{3-[2-(l-benzothiophen-2- yl)ethoxy]propyl}-3-azetidinol hydrochloride In the same manner as in Example 4, l-{3-[2- (1-benzothiophen-2-yl)ethoxy]propyl}-3-azetidinol hydrochloride was obtained as a light-yellow oil. IR (neat) cm"1: 3290, 28 68, 1457, 1436, 1113, 751 NMR(CDC13)5 values: 1. 83 (2H, qn, J=6Hz) , 2.91(2H,t,J=6Hz), 3.16(2H,t,J=6Hz), 3.52(2H,t,J=6Hz) , 3.7 4(2H,t,J=6Hz), 3.7-3.8(2H,m), 3.7-3.9(2H,m), 4.3-4.5(1H,m), 7.09(lH,s), 7.27(lH,dt,J=l,8Hz), 7.33(lH,dt,J=l,8Hz), 7.69(1H,dd,J=l,8Hz), 7.78(lH,dd,J=l,8Hz) Example 7 Production of 1-{3-[2-(l-benzothiophen-7- yl)ethoxy]propyl}-3-azetidinol In the same manner as in Example 3, l-{3-[2- (1-benzothiophen-7-yl)ethoxy]propyl}-3-azetidinol was obtained as a colorless oil. IR(neat)cm-2: 338 6,2 942,2 8 56,14 58,1105,7 96,755,700 NMR(CDC13)5 values: 1. 61 (2H, qn, J=7Hz) , 2.45(2H,t,J=7Hz), 2.7-2.8(2H,m), 3.17(2H,t,J=7Hz), 3.48(2H,t,J=7Hz), 3.5-3.7(2H,m), 3.79(2H,t,J=7Hz), 4.3-4.5(lH,m), 7.20(lH,dd,J=l,8Hz), 7.32(lH,t,J=8Hz), 7.36(1H,d,J=5Hz), 7.43 (lH,d, J=5Hz) , 7.70 (1H,dd,J=l, 8Hz) Example 8 Production of l-{3-[2-(1-benzothiophen-7- yl)ethoxy]propyl}-3-azetidinol hydrochloride In the same manner as in Example 2, l-{3-[2- (1-benzothiophen-7-yl)ethoxy]propyl}-3-azetidinol hydrochloride was obtained as colorless crystals. Melting point: 105-106°C. IR (KBr)cm-1: 3252, 2806, 2 620, 1398, 1130, 1106, 811, 708 NMR(CDC13) 8 values: 1. 82(2H,qn,J=6Hz), 2.8- 3.0(2H,m), 3.16(2H,t,J=6Hz), 3.47(2H,t,J=6Hz), 3.83(2H,t,J=6Hz), 3.7-4.1(4H,m), 4.5-4.7(lH,m), 7.21(lH,d,J=8Hz), 7.36(lH,t,J=8Hz), 7.38 (1H,d,J=5Hz), 7.4 6(1H,d,J=5Hz), 7.73 (lH,d,J=8Hz) Example 9 (a) Production of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinol In 30 mL of dimethyl sulfoxide was dissolved 6.50 g of 5-[2-(3-chloropropoxy)ethyl]-1- benzothiophene, and to the solution were added 5.60 g of 3-azetidinol hydrochloride anc 15.3 mL of a 5 mol/L aqueous sodium hydroxide solution, after which the resulting mixture was stirred at 65°C for 3.5 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the pH was adjusted to 1 with 6 mol/L hydrochloric acid, and the aqueous layer was separated. Ethyl acetate was added to the aqueous layer and the pH was adjusted to 10 with a 5 mol/L aqueous sodium hydroxide solution, after which the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform : methanol = 30 : 1 to 10 : 1) to obtain 4.77 g of l-{3-[2-(1- benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol. (b) Production of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinol 2 (1) In 300 mL of tetrahydrofuran was dissolved 100 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]propionic acid, and 0.1 mL of N,N-dimethylformamide was added thereto, after which 41.8 mL of oxalyl chloride was added thereto over a period of 10 minutes and the resulting mixture was stirred at room temperature for 1.5 hours. The resulting solution was added dropwise to a solution of 65.7 g of 3-hydroxyazetidine hydrochloride and 59.5 g of sodium hydroxide in 600 mL of water at 10°C, followed by stirring at room temperature for 1 hour. To the reaction solution were added 600 mL of water, 500 mL of ethyl acetate and sodium chloride, and the organic layer was separated. To the aqueous layer was added 100 mL of ethyl acetate and the organic layer was separated. The organic layers thus obtained were combined. To the combined organic layer was added 100 mL of water and the pH was adjusted to 3.5 with 6 mol/L hydrochloric acid, after which the organic layer was separated. The organic layer was concentrated to a volume of about 200 mL, washed with a saturated aqueous sodium hydrogen- carbonate solution and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. To the residue was added 300 mL of toluene, and the resulting mixture was heated at 50°C to effect dissolution, after which seed crystals were added at 40°C and the resulting mixture was slowly cooled and then stirred under ice-cooling for 30 minutes. The crystals precipitated were collected by filtration to obtain 96.6 g of 3-[2-(l-benzothiophen-5- yl)ethoxy]-1-(3-hydroxy-l-azetid nyl)-1-propanone as light-brown crystals. (2) In 60 mL of tetrahydrofuran was dissolved 30.0 g of 3-[2-(l-benzothiophen-5-yl)ethoxy]-1-(3- hydroxy-1-azetidinyl)-1-propanone, followed by adding dropwise thereto 275 mL of a 1 mol/L solution of a borane-tetrahydrofuran complex in tetrahydrofuran, and the resulting mixture was stirred at room temperature for 5 hours. To the reaction solution was added dropwise 81.9 mL of 6 mol/L hydrochloric acid, and the resulting mixture was refluxed for 1.5 hours. After cooling, the solvent was concentrated to be reduced by about 290 mL, and the insoluble materials were filtered off. To the filtrate were added 120 mL of water and 60 mL of toluene, and the aqueous layer was separated and then washed with 60 mL of toluene. To the aqueous layer was added 90 mL of ethyl acetate, and the pH was adjusted to 9.5 with a 5 mol/L aqueous sodium hydroxide solution, after which the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and 5.35 g of fumaric acid and 54 mL of ethanol were added to the resulting residue. The resulting mixture was heated at 74°C to effect dissolution, and then 161 mL of ethyl acetate was added dropwise thereto. The mixture thus obtained was slowly cooled and then stirred at 5 to 10°C for 30 minutes, and the crystals precipitated were collected by filtration to obtain 22.7 g of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinol 1/2 fumarate as light- brown crystals. (3) In 45 mL of water was suspended 22.7 g of 1- {3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol 1/2 fumarate, and 68 mL of ethyl acetate was added thereto, after which the pH was adjusted to 9.5 with a 1 mol/L aqueous sodium hydroxide solution and then the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform : methanol =20 : 1 to 10 : 1) and crystallized from 40 mL of diisopropyl ether to obtain 16.0 g of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinol as a solid. Melting point: 60-62°C. IR(KBr)cm-1: 3095, 2 94 4 , 27 69, 13 61, 1191, 1098 , 810, 70 9 NMR(CDC13)6 values: 1.61(2H,qn,J=7Hz), 2.45(2H,t,J=7Hzi, 2.7-2.9(2H,m), 2.99(2H,t,J=7Hz), 3.45(2H,t,J=7Hz), 3.5-3.6(2H,m), 3.66(2H,t,J=7Hz), 4.3-4.4(lH,m), 7.22(lH,dd,J=l,8Hz), 7.28(1H,d,J=5Hz), 7.41(1H,d,J=5Hz), 7.67(1H,d,J=1Hz), 7.7 9(lH,d,J=8Hz) Example 10 Production of l-{3-[2-(l-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinol hydrochloride In the same manner as in Example 2, l-{3-[2- (1-benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol hydrochloride was obtained as colorless crystals. Melting point: 71-73°C. IR(KBr)cm"1: 3301,2 937,28 09,2 631, 112 5, 1099, 818, 765,710 NMR(CDC13)5 values: 1. 8-1. 9 (2H, m) , 2.98 (2H,t, J=7Hz) ,r 2 . 9-3 . 1 (2H,m) , 3 . 48 (2H, t, J=6Hz) , 3.69(2H,t,J=7Hz)„ 3.6-4.4(4H,m), 4.5-4.7(lH,m), 7.22(lH,dd,J=l,8Hz), 7.31(1H,d,J=5Hz), 7.4 4(1H,d,J=5Hz), 7.68(1H,d,J=1Hz), 7.81(lH,d,J=8Hz) Example 11 Production of 1-{3-[2-(l-benzothiophen-4- yl)ethoxy]propyl}-3-azetidinol In the same manner as in Example 3, l-{3-[2- (l-benzothiophen-4-yl)ethoxy]propyl}-3-azetidinol was obtained as a colorless oil. IR (neat) cm"1: 33 68, 2 94 6, 285 6, 1457, 1107, 759 NMR(CDC13)5 values: 1.60(2Hrqn,J=7Hz), 2.44(2H,t,J=7Hz), 2.7-2.9(2H,m), 3.22(2H,t,J=7Hz) , 3.45(2H,t,J=7Hz), 3.5-3.6(2H,m), 3.70(2H,t,J=7Hz), 4.3-4.5(lH,m), 7.19(1H,d,J=7Hz), 7.28(1H,t,J=7Hz), 7.4 4(lH,d,J=6Hz), 7.4 6(lH,d,J=6Hz), 7.76(lH,d,J=7Hz) Example 12 Production of 1-{3-[2-(l-benzothiophen-4- yl)ethoxy]propyl}-3-azetidinol hydrochloride In the same manner as in Example 4, l-{3-[2- (l-benzothiophen-4-yl)ethoxy]propyl}-3-azetidinol hydrochloride was obtained as a light-yellow oil. IR (neat) cm-1: 3 302,2 966,2877,2594,1412,1108,7 66 NMR(CDC13)5 values: 1. 78(2H,qn,J=6Hz), 2.82(2H,t,J=7Hz), 3.21(2H,t,J=6Hz), 3.43(2H,t,J=6Hz), 3.73(2H,t,J=6Hz), 3.7-3.9(2H,m), 3.8-4.0(2H,m), 4.5-4.7(lH,m), 7.21(1H,d,J=7Hz), 7.30(lH,t,J=7Hz), 7.49(2H,s), 7.78(1H,d,J=7Hz) Example 13 Production of l-{3-[2-(l-benzothiophen-3- yl)ethoxy]propyl}-3-azetidinol In 5 mL of dimethyl sulfoxide was dissolved 1.00 g of 3-[2-(3-chloropropoxy)ethyl]-1- benzothiophene, and 1.10 g of 3-azetidinol trifluoroacetate and 1.63 g of potassium carbonate were added to the solution, after which the resulting mixture was stirred at 70°C for 2 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the pH was adjusted to 1 with 6 mol/L hydrochloric acid, and the aqueous layer was separated. Ethyl acetate was added to the aqueous layer and the pH was adjusted to 10 with a 2 mol/L aqueous sodium hydroxide solution, after which the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform : methanol = 30 : 1 to 10 : 1) to obtain 0.55 g of l-{3-[2-(l- benzothiophen-3-yl)ethoxy]propyl}-3-azetidinol as a colorless oil. IR (neat) cm"1: 3368,2942,2845, 1427,1191,1109,759 NMR(CDC13)5 values: 1. 62(2H,qn,J=7Hz), 2.47(2H,t,J=7Hz), 2.7-2.9(2H,m), 3.11(2H,t,J=7Hz), 3.48(2H,t,J=6Hz), 3.5-3.7(2H,m), 3.74(2H,t,J=7Hz), 4.3-4.5(lH,m), 7.18(lH,s), 7.33(1H,dt,J=l,7Hz), 7.39(lH,dt,J=l,7Hz), 7.77(1H,dd,J=l,7Hz), 7.86(lH,dd,J=l,7Hz) Example 14 Production of 1-{3-[2-(l-benzothiophen-3- yl)ethoxy]propyl}-3-azetidinol hydrochloride In the same manner as in Example 4, l-{3-[2- (1-benzothiophen-3-yl)ethoxy]prcpyl}-3-azetidinol hydrochloride was obtained as a light-yellow oil. IR (neat) cm-1: 3284, 2966, 2596, 1428, 1112, 1049, 765, 734 NMR(CDC13)5 values: 1.83(2H,qn,J=6Hz), 2.96(2H,t,J=6Hz), 3.12(2H,t,J=6Hz), 3.48(2H,t,J=6Hz), 3.76(2H,t,J=6Hz), 3.8-3.9(2H,m), 3.9-4.1(2H,m), 4.5-4.7(lH,m), 7.21(lH,s), 7.35(lH,dt,J=l,7Hz), 7.4 0(1H,dt,J=l,7Hz), 7.78(lH,dd,J=1.7Hz), 7.86(1H, dd,J=l,7Hz) Example 15 Production of N-(l-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinyl)acetamide In 8 mL of N,N-dimethylformamide was dissolved 0.80 g of 5-[2-(3-chloropropoxy)ethyl]-1- benzothiophene, and 1.20 g of N-(3-azetidinyl)acetamide was added to the solution, after which the resulting mixture was stirred at 90°C for 12 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform : methanol =7:1) to obtain 0.39 g of N- (l-{3- [2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- azetidinyl)acetamide as a light-yellow oil. IR (neat) cm"1: 3276,2941,28 60,1654,1559,1111,756,703 NMR(CDC13) 8 values: 1. 59 (2H, qn, J=7Hz) , 1.97(3H,s), 2.42(2H,t,J=7Hz), 2.7-2.9(2H,m), 2.98(2H,t,J=7Hz), 3.45(2H,t,J=7Hz), 3.4-3.6(2H,m), 3.66(2H,t,J=7Hz), 4.4-4.5(lH,m), 7.22 (1H,dd,J=l,8Hz), 7.29(1H,d,J=5Hz), 7.42(lH,d, J=5Hz) , 7.67(1H,d,J=1Hz), 7.8 0(lH,d,J=8Hz) Example 16 Production of 1-{2-[2-(1-benzothiophen-6- yl)ethoxy]ethyl}-3-pyrrolidinol (1) In 7.4 mL of methylene chloride was dissolved 0.74 g of 2-[2-(1-benzothiophen-6-yl)ethoxy]acetic acid, and 1.36 mL of triethylamine and 0.22 g of imidazole were added to the solution. Then, the resulting mixture was cooled to 5°C, after which 0.24 mL of thionyl chloride was added dropwise thereto, followed by stirring at the same temperature for 1 hour. After the reaction mixture was cooled to -50°C, 0.45 mL of triethylamine and 0.32 mL of 3-pyrrolidinol were added thereto, and the resulting mixture was stirred at the same temperature for 1 hour and then at room temperature for 1 hour. Water was added to the reaction mixture and the organic layer was separated. The organic layer was washed successively with 1 mol/L hydrochloric acid, a 2 mol/L aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Subsequently, the solvent was distilled off under reduced pressure to obtain 2-[2-(1-benzothiophen- 6-yl)ethoxy]-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanone as a light-yellow oil. IR (neat) cm"1: 3386, 2 942,1636, 1106, 758 (2) The aforesaid 2- [2-(l-benzothiophen-6- yl)ethoxy]-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanone was dissolved in 7.4 mL of tetrahydrofuran, and 7.4 mL of a 1 mol/L solution of a borane-tetrahydrofuran complex in tetrahydrofuran was added dropwise thereto under ice- cooling, followed by stirring at room temperature for 17 hours. To the reaction mixture was added 10 mL of acetone, and stirred for 30 minutes, after which 1.5 mL of 6 mol/L hydrochloric acid was added thereto and the resulting mixture was heated under reflux for 2 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the aqueous layer was separated. Ethyl acetate was added to the aqueous layer and the pH was adjusted to 9.5 with a 2 mol/L aqueous sodium hydroxide solution, after which the organic layer was separated. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform : methanol = 30 : 1 to 20 : 1) to obtain 0.53 g of l-{2-[2-(l- benzothiophen-6-yl)ethoxy]ethyl}-3-pyrrolidinol as a yellow oil. IR (neat) cm-1: 3386,2 94 0,28 67,1110,820,756 NMR(CDC13)d values: 1. 6-1. 8 (lH,m) , 2 . 0-2 . 2 (lH,m) , 2.31(lH,dt,J=7,9Hz), 2.53(1H,dd,J=5,lOHz), 2.6- 2.7(3H,m), 2.85(lH,dt,J=5,9Hz), 3.01(2H,t,J=7Hz), 3.58(2H,t,J=6Hz), 3.71(2H,t,J=7Hz), 4.2-4.3(lH,m), 7.23(lH,d,J=8Hz), 7.29(1H,d,J=5Hz), 7.37(1H,d,J=5Hz), 7.73(1H,d,J=8Hz), 7.73(lH,s) Example 17 Production of l-{2-[2-(L-benzothiophen-6- yl)ethoxy]ethyl}-3-pyrrolidinol oxalate In 2.0 mL of ethyl acetate was dissolved 0.48 g of 1-{2-[2-(1-benzothiophen-6-yl)ethoxy]ethyl}-3- pyrrolidinol, and to the solution was added a solution of 0.15 g of oxalic acid in 2.8 mL of ethyl acetate. The resulting mixture was stirred at room temperature for 1 hour and then at 5°C for 1 hour. The crystals precipitated were collected by filtration, washed with ethyl acetate and then dried to obtain 0.42 g of l-{2- [2-(1-benzothiophen-6-yl)ethoxy]ethyl}-3-pyrrolidinol oxalate as colorless crystals. IR(KBr)cm-1: 3384 , 28 62, 2 687, 1717, 163 6, 14 00, 1200, 1114,720 NMR(DMSO-d6)d values: 1. 7-1. 8 (1H,m) , 1. 9-2 . 1 (lH,m) , 2.96(2H,t,J=7Hz), 3.0-3.2(lH,m), 3.1-3.4(5H,m), 3.6-3.8(4H,m), 4.3-4.4(1H,m), 7.29(1H,d,J=8Hz), 7.41(1H,d,J=5Hz), 7.68(1H,d,J=5Hz), 7.80(1H,d,J=8Hz), 7.87(1H,s) Example 18 Production of 1-{2-[2-(l-benzothiophen-5- yl)ethoxy]ethyl}-3-pyrrolidinol In the same manner as in Example 16 (1), 2- [2- (1-benzothiophen-5-yl)ethoxy1-1-(3-hydroxy-l- pyrrolidinyl)-1-ethanone was obtained. NMR(CDC13) 5 values: 1. 6-2 . 2 (2H, m) , 2 . 9-4 . 0 (8H,m) , 4.0-4.2(2H,m), 4.2-4.5(1H,m), 7.1-7.4(2H,m), 7.42(1H,d,J=5Hz), 7.69(lH,s), 7.79(1H,d,J=8Hz) Then, l-{2-[2-(l-benzothiophen-5- yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a light-yellow oil in the same manner as in Example 16 (2) . IR (neat) cm-1: 3386, 2941,2864, 1438, 1112, 755, 702 NMR(CDC13) 6 values: 1. 5-2 . 0 (lH,m) , 2 . 0-2 . 9 (7H,m) , 3.00(2H,t,J=7Hz), 3.58(2H,t,J=6Hz), 3.71(2H,t,J=7Hz), 4.2-4.4(lH,m), 7.21(1H,d,J=8Hz), 7.28(1H,d,J=5Hz), 7.42(1H,d,J=5Hz), 7.67(lH,s), 7.79(lH,d,J=8Hz) Example 19 Production of l-{2-[2-(1-benzothiophen-5- yl)ethoxy]ethyl}-3-pyrrolidinol oxalate In the same manner as in Example 17, l-{2-[2- (1-benzothiophen-5-yl)ethoxy]ethyl}-3-pyrrolidinol oxalate was obtained as colorless crystals. IR (KBr)cm-1: 3347, 2943, 2687, 1719, 1404, 1119, 72 0 NMR(CDC13) 8 values: 1.7-2.2(2H,m), 2.9-3.8(6H,m), 2.94 (2H,t, J=6Hz.) , 3 . 68 (4H, t, J=6Hz) , 4 . 2-4 . 5 (1H,m) , 7.17(lH,d,J=8Hz), 7.26(1H,d,J=5Hz), 7.42(1H,d,J=5Hz), 7.62{lH,s), 7.78(1H,d,J=8Hz) Example 20 Production of 1-{2-[2-(l-benzothiophen-4- yl)ethoxy]ethyl}-3-pyrrolidinol In the same manner as in Example 16 (1), 2- [2-(l-benzothiophen-4-yl)ethoxy]-1-(3-hydroxy-1- pyrrolidinyl)-1-ethanone was obtained as an oil. IR (neat) cm"1: 3374,294 4,1637, 1107,7 61 Then, l-{2-[2-(1-benzothiophen-4- yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a light-yellow oil in the same manner as in Example 16 (2) . IR (neat) cm-1: 337 6,2939,28 67,1452,1413,1111,7 60 NMR(CDC13) 8 values: 1. 6-1. 8 (1H,m) , 2 . 1-2 . 2 (1H,m) , 2.30(lH,dt,J=6,9Hz), 2.53(1H,dd,J=5,lOHz), 2.6- 2.7(3H,m), 2.85(lH,dt,J=5,9Hz), 3.25(2H,t,J=7Hz), 3.58(2H,t,J=6Hz), 3.75(2H,t,J=7Hz), 4.2-4.4(1H,m), 7.20(lH,d,J-7Hz), 7.27(lH,t,J=7Hz), 7.4 4(lH,d,J=6Hz), 7.4 6(lH,d,J=6Hz), 7.75 (lH,d,J=7Hz) Example 21 Production of 1-{2-[2-(l-benzothiophen-4- yl)ethoxy]ethyl}-3-pyrrolidinol hydrochloride In 5.0 mL of ethyl acetate was dissolved 0.63 g of l-{2- [2-(l-benzothiophen-4-yl)ethoxy]ethyl}-3- pyrrolidinol, and to the solution was added 0.80 mL of a 3.25 mol/L dried hydrogen chloride-ethyl acetate solution. The resulting mixture was stirred at room temperature for 1 hour and then at 5°C for 1 hour, after which the crystals precipitated were collected by filtration. The crystals precipitated were washed with ethyl acetate and then dried to obtain 0.43 g of l-{2- [2- (l-benzothiophen-4-yl)ethoxy]ethyl}-3-pyrrolidinol hydrochloride as colorless crystals. IR(KBr)cm-1: 322 9,2872,2 625,14 51,1413,1119,771 NMR(DMSO-d6)d values: 1.7-2.2(2H,m), 2 . 9-3.6(6H,m) , 3.22(2H,t,J=7Hz), 3.74(4H,t,J=7Hz), 4 . 3-4.4(1H,m), 7.27(lH,d,J=8Hz), 7.30(1H,t,J=8Hz), 7.61(1H,d,J=5Hz), 7.77(1H,d,J=5Hz), 7.86(lH,d,J=8Hz) Example 22 Production of 1-{2-[2-(l-benzothiophen-7- yl)ethoxy]ethyl}-3-pyrrolidinol In the same manner as in Example 16 (1), 2- [2- (l-benzothiophen-7-yl)ethoxy]-1-(3-hydroxy-l- pyrrolidinyl)-1-ethanone was obtained as an oil. NMR(CDC13) 8 values: 1. 8-2 . 0 (2H,m) , 3 .1-3 . 3 (3H,m) , 3.3-3.6(3H,m) 3.8-4.0(2H,m), 4.0-4.2(2H,m), 4.3-4.5(1H,m), 7.23(lH,d,J=7Hz),7.3-7.4(2H,m), 7.4-7.5(1H,m), 7.6-7.8(1H,m) Then, l-{2-[2-(l-benzothiophen-7- yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a colorless oil in the same manner as in Example 16 (2). IR (neat) cm"1: 3385, 2941, 28 67 , 1459, 1395, 1106, 7 95, 754,701 NMR(CDC13) 5 values: 1. 6-1. 8 (1H,m) , 2 . 1-2 . 2 (1H,m) , 2.30(lH,dt,J=7,9Hz), 2 . 52(1H,dd,J=5,lOHz), 2.6- 2.7(3H,m), 2.85(lH,dt,J=5,9Hz), 3.19(2H,t,J=7Hz), 3.59(2H,t,J=6Hz], 3.84(2H,t,J=7Hz), 4.2-4.4(1H,m), 7.20(lH,d,J=8Hz), 7.32(lH,t,J=8Hz), 7.35(lH,d,J=5Hz,), 7.42(1H,d,J=5Hz), 7.69(lH,d,J=8Hz) Example 23 Production of l-{2-[2-(l-benzothiophen-7- yl)ethoxy]ethyl}-3-pyrrolidinol hydrochloride In the same manner as in Example 21, l-{2-[2- (1-benzothiophen-7-yl)ethoxy]ethyl}-3-pyrrolidinol hydrochloride was obtained as colorless crystals. IRtKBrJcnf1: 3283,2 938,270 6, 1395, 1358, 1125, 810, 720 NMR(DMSO-d6) 5 values: 1. 7-2 . 2 (2H,m) , 2 . 8-3 . 7 ( 6H,m) , 3.12(2H,t,J=7Hz), 3.7-3.8(2H,m), 3.82(2H,t,J=7Hz), 4.3-4.4(1H,m), 7.29 (1H,d,J=7Hz), 7.36(1H,t,J=7Hz), 7.49(1H,d,J=5Hz), 7.76(1H,d,J=5Hz), 7.77(lH,d,J=7Hz) Example 24 Production of 1-{2-[2-(l-benzothiophen-2- yl)ethoxy]ethyl}-3-pyrrolidinol In the same manner as in Example 16 (1), 2- [2- (1-benzothiophen-2-yl)ethoxy]-1-(3-hydroxy-l- pyrrolidinyl)-1-ethanone was obtained. NMR(CDC13) 8 values: 1.8-2.0(2H,m), 3 .1-3 . 3 (3H,m) , 3.3-3.7(3H,m), 3.8-4.0(2H,m), 4.1-4.2(2H,m), 4.2-4.5(1H,m), 7.10(lH,s), 7.2-7.4(2H,m), 7.6- 7.7(1H,m), 7.7-7.8(1H,m) Then, l-{2-[2-(l-benzothiophen-2- yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a light-yellow oil in the same manner as in Example 16 (2) . IR (neat) cm-1: 33 96, 2 939, 1458, 1438, 1113, 747, 727 NMR(CDC13)d values: 1.6-1.8(1H,m) , 2.1-2.2(1H,m), 2.34(lH,dt,J=6,9Hz), 2.55(lH,dd,J=5,lOHz), 2.6-2.8(3H,m), 2.85(lH,dt,J=5,9Hz), 3.18 (2H,dt,J=l,7Kz), 3.62(2H,t,J=6Hz), 3.77(2H,t,J=7Hz), 4.2-4.4(1H,m), 7.07(lH,s), 7.26(lH,dt,J=l,8Hz), 7.31(lH,dt,J=l,8Hz), 7.67(lH,dd,J=l,8Hz) , 7.7 6(1H,dd,J=l,8Hz) Example 25 Production of 1-{2-[2-(1-benzothiophen-2- yl)ethoxy]ethyl}-3-pyrrolidinol oxalate In the same manner as in Example 17, l-{2-[2- (1-benzothiophen-2-yl)ethoxy]ethyl}-3-pyrrolidinol oxalate was obtained as colorless crystals. IR(KBr)cm-1: 3432,2871,1716,1436,1127,827,7 60,706 NMR(DMSO-d6) 5 values: 1. 7-1. 8 (1H,m) , 1. 9-2 . 2 (1H,m) , 3.0-3.4(8H,m), 3.73(4H,t,J=6Hz), 4.2-4.4(1H,m), 7.23(lH,s), 7.28(1H,t,J=7Hz), 7.33(1H,t,J=7Hz), 7.7 4(lH,d,J-7Hz), 7.87(lH,d,J=7Hz) Example 26 Production of l-{2-[2-(l-benzothiophen-3- yl)ethoxy]ethyl}-3-pyrrolidinol In the same manner as in Example 16 (1), 2- [2-(1-benzothiophen-3-yl)ethoxy]-1-(3-hydroxy-1- pyrrolidinyl)-1-ethanone was obtained as an oil. NMR(CDC13) 5 values: 1. 8-1. 9 f lH,m) , 1. 9-2 . 0 (1H,m) , 3.1-3.6(6H,m), 3 . 8-4 . 0 (2H,m) , 4.09(lH,s), 4.13(lH,s), 4.3-4.5(1H,m), 7.26(lH,s), 7.3- 7.4(2H,m), 7.77(1H,d,J=8Hz), 7.85(1H,d,J=8Hz) Then, l-{2-[2-(l-benzothiophen-3- yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a light-yellow oil in the same manner as in Example 16 (2) . IR (neat) cm"1: 3388,2 934,1426,1112,761,7 33 NMR(CDC13) 5 values: 1.6-1.8(1H,m), 2.1-2.2 (1H,m), 2.33(lH,dt,J=6,9Hz) , 2.56(1H,dd,J=5,lOHz), 2.6- 2.8(3H,m), 2.87 (lH,dt,J=5,9Hz), 3.14(2H,dt,J=l,7Hz), 3.61(2H,t,J=6Hz), 3.80(2H,t,J=7Hz), 4.3-4.4(1H,m), 7.20(lH,s), 7.34(lH,dt,J=l,7Hz) , 7.38(lH,dt,J=l,7Hz) , 7.77(lH,dd,J=l,7Hz), 7.85(1H,dd,J=l,7Hz) Example 27 Production of 1-{2-[2-(l-benzothiophen-3- yl)ethoxy]ethyl}-3-pyrrolidinol oxalate In the same manner as in Example 17, l-{2-[2- (1-benzothiophen-3-yl)ethoxy]ethyl}-3-pyrrolidinol oxalate was obtained as colorless crystals. IR (KBr)cm-1: 3363,2 922,2 691, 1718, 163 6, 1427, 1404, 1119,767,721 NMR(DMSO-d6)d values: 1. 7-1. 8 (1H,m) , 2 . 0-2 . 2 (1H,m) , 3.10(2H,t,J=7Hz), 3.1-3.4(6H,m), 3.72(2H,t,J=5Hz), 3.78(2H,t,J=7Hz), 4.3-4.4(1H,m), 7.37(1H,t,J=8Hz), 7.42(lH,t,J=8Hz), 7.51(lH,s), 7.85(1H,d,J=8Hz), 7.98(lH,d,J=8Hz) Example 28 Production of 1-{2-[2-(1-naphthyl)ethoxy]- ethyl}-3-pyrrolidinol In the same manner as in Example 16 (1), 2- [2-(1-naphthyl)ethoxyl-1-(3-hydroxy-1-pyrrolidinyl)-1- ethanone was obtained as a yellow oil. IR (neat) cm-1: 3392,2 94 6,164 5,1133,8 00,77 9 Then, l-{2-[2-(1-naphthyl)ethoxy]ethyl}-3- pyrrolidinol was obtained as a light-yellow oil in the same manner as in Example 16 (2). IR (neat Jem-1: 3395,2944,1107,778 NMR(CDC13) 5 values: 1. 5-1. 9 (1H, m) , 2 . 0-2 . 5 (3H,m) , 2.5-3.0(4H,m), 3.37(2H,t, J=7Hz), 3.59(2H, t, J=6Hz) , 3.80(2H,t,J=7Hz), 4.2-4.4(1H,m), 7.4-7.6(4H,m), 7.6-8.0(2H,m), 6.0-8.2(lH,m; Example 2 9 Production of l-{2-[2-(1-naphthyl)ethoxy]- ethyl}-3-pyrrolidinol oxalate In the same manner as in Example 17, l-{2-[2- (1-naphthyl)ethoxy]ethyl}-3-pyrrolidinol oxalate was obtained as colorless crystals. IR (KBr)cm-1: 3366,14 00,1116,7 8 0,720 NMR(DMSO-d6)d values: 1. 6-2 . 3 (2H,m) , 2 . 7-3 . 5 (8H,m) , 3.5-3.9(4H,m), 4.2-4.5(1H,m), 7.4-7.6(4H,m), 7.7- 8.0(2H,m), 8.0-8.2(1H,m) Example 30 Production of (3S)-l-{2-[2-(1-benzothiophen- 5-yl)ethoxy]ethyl}-3-pyrrolidinol In the same manner as in Example 16 (1), 2- [2-(1-benzothiophen-5-yl)ethoxy]-1-[(3S)-3-hydroxy-l- pyrrolidinyl]-1-ethanone was obtained as a light-yellow oil. Then, (3S)-1-{2-[2-(l-benzothiophen-5- yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a light-yellow oil in the same manner as in Example 16 (2) . IR (neat Jem-1: 338 6, 2 936, 28 67 , 14 38, 1111, 755, 702 NMR(CDC13)d values: 1. 5-2 . 0 (1H,m) , 2 . 0-3 . 0 (5H,m) , 2.66(2H,t,J=6Hz), 3.00(2H,t,J=7Hz), 3.58(2H,t,J=6Hz), 3.71(2H,t,J=7Hz), 4.2-4.4(1H,m), 7.21(lH,d,J=8Hz), 7.28(lH,d,t=5Hz), 7.42(1H,d,J=5Hz), 7.67(lH,s), 7.79(1H,d,J=8Hz) Example 31 Production of (3S)-1-{2-[2-(l-benzothiophen- 5-yl) ethoxy]ethyl}-3-pyrrolidinol oxalate In the same manner as in Example 17, (3S)-1- {2-[2- (1-benzothiophen-5-yl)ethoxy]ethyl}-3- pyrrolidinol oxalate was obtained as colorless crystals. IR(KBr)cm-1: 33 66, 2 941, 28 67, 2 68 6, 1718, 1701, 14 04 , 1114,720 NMR(DMSO-d6)d values: 1.5-2.2(2H,m), 2.8-3.5(8H,m), 3.70(4H,t,J=6Hz), 4.2-4.5(1H,m), 7.28(1H,d,J=8Hz), 7.40 (1H,d,J=5Hz) , 7.73(1H,d,J=5Hz), 7.76(lH,s), 7.91(lH,d,J=8Hz) Example 32 Production of (3R)-1-{2-[2-(1-benzothiophen- 5-yl)ethoxy]ethyl}-3-pyrrolidinol In the same manner as in Example 16 (1), 2- [2-(1-benzothiophen-5-yl)ethoxy]-1-[(3R)-3-hydroxy-l- pyrrolidinyl]-1-ethanone was obtained as colorless crystals. IR(KBr)cm"1: 3408 , 2 937, 1637, 1137, 1108, 812, 703 Then, (3R)-l-{2-[2-(l-benzothiophen-5- yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a light-yellow oil in the same manner as in Example 16 (2) . IR (neat) cm-1: 3373, 294 0, 14 38, 1111, 7 55, 702 NMR(CDC13) 8 values: 1. 5-2 . 0 (1H, m) , 2 . 0-3 . 0 ( 5H,m) , 2.68(2H,t,J=6Hz), 3.01(2H,t,J=7Hz), 3.59(2H,t,J=6Hz), 3.71(2H,t,J=7Hz), 4 . 2-4.4(1H,m), 7.21(lH,d,J=8Hz), 7.28(1H,d,J=5Hz), 7.42(1H,d,J=5Hz), 7.67(1H,s), 7.79(1H,d,J=8Hz) Example 33 Production of (3R)-l-{2-[2-(1-benzothiophen- 5-yl) ethoxy] ethyl }-3--pyrrolidinol oxalate In the same manner as in Example 17, (3R)-1- {2-[2-(1-benzothiophen-5-yl)ethoxy]ethyl}-3- pyrrolidinol oxalate was obtained as colorless crystals. IR(KBr)cm-1: 3318,2870,1718,1114,720 NMR(DMSO-d6) d values: 1. 5-2 . 2 (2H,m) , 2.8-3.5(8H,m) , 3.70(4H,t,J=6Hz) , 4.2-4.5(1H,m), 7.28(1H, d, J=8Hz) , 7.40(1H,d,J=5Hz) , 7.73(1H,d,J=5Hz), 7.76(lH,s), 7.91(1H,d,J=8Hz) Example 34 Production of (3S)-1-{2-[2-(1-benzothiophen- 6-yl)ethoxy]ethyl}-3~pyrrolidinol In the same manner as in Example 16 (1), 2- [2- (1-benzothiophen-6-yl)ethoxy]-1-[(3S)-3-hydroxy-l- pyrrolidinyl]-1-ethanone was obtained as a colorless oil. IR(neat)cm-1: 338 5,294 4,1637, 1133, 820, 699 Then, (3S)-L-{2-[2-(l-benzothiophen-6- yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a colorless oil in the same manner as in Example 16 (2). IR(neat)cm-1: 3385,294 0,28 67, 1110, 820, 757 NMR(CDC13) 5 values: 1. 6-1. 8 (1H,m) , 2 .1-2 . 2 (1H,m) , 2.32(lH,dt,J=6,9Hz), 2.54(1H,dd,J=5,lOHz), 2.6- 2.7(3H,m), 2.85(lH,dt,J=5,9Hz), 3.01(2H,t,J=7Hz), 3.58(2H,t,J=6Hz), 3.71(2H,t,J=7Hz), 4.2-4.3(1H,m), 7.23(lH,d,J=8Hz), 7.29(1H,d,J=5Hz), 7.37(1H,d,J=5Hz), 7.73(1H,d,J=8Hz), 7.74(lH,s) Example 35 Production of (3S)-l-{2-[2-(1-benzothiophen- 6-yl)ethoxy]ethyl}-3-pyrrolidinol oxalate In the same manner as in Example 17, (3S)-1- {2-[2-(1-benzothiophen-6-yl)ethoxy]ethyl}-3- pyrrolidinol oxalate was obtained as colorless crystals. IR(KBr)cm-1: 3364,2 938,2692, 1718, 1400, 1201, 1114, 72 0 NMR(DMSO-d6)d values: 1.7-1.8(1H,m) , 1. 9-2 . 1 (1H,m) , 2.96(2H,t,J=7Hz) 3.0-3.1(1H,m), 3.1-3.3(5H,m), 3.70(4H,t,J=7HZ),4.2-4.3(1H,m) , 7.29(1H,d,J=8Hz), 7.41(1H,d,J=5Hz), 7.68(1H,d,J=5Hz), 7.80(lH,d,J=8Hz), 7.87(lH,s) Example 36 Production of (3R)-1-{2-[2-(l-benzothiophen- 6-yl) ethoxy]ethyl}-3-pyrrolidinol In the same manner as in Example 16 (1), 2- [2-(1-benzothiophen-6-yl)ethoxy]-L-[(3R)-3-hydroxy-l- pyrrolidinyl]-1-ethanone was obtained as an oil. IR (neat Jem-1: 338 6,294 0,1637,1107,820,758 Then, (3R)-l-{2-[2- (l-benzothiophen-6- yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a colorless oil in the same manner as in Example 16 (2). IR (neat) cm"1: 3385,294 0,28 67, 1110, 820, 757 NMR(CDC13) 5 values: 1. 6-1. 8 (1H,m) , 2 .1-2 . 2 (1H,m) , 2.32(lH,dt,J=6,9Hz), 2.54(1H,dd,J=5,lOHz), 2.6- 2.7(3H,m), 2.85(lH,dt,J=5,9Hz), 3.01(2H,t,J=7Hz), 3.58(2H,t,J=6Hz), 3.71(2H,t,J=7Hz), 4.2-4.3(1H,m), 7.23(lH,d,J=8Hz), 7.29(1H,d,J=5Hz), 7.37(1H,d,J=5Hz), 7.73(1H,d,J=8Hz), 7.74(lH,s) Example 37 Production of (3R)-l-{2-[2-(1-benzothiophen- 6-yl)ethoxy]ethyl}-3-pyrrolidinol oxalate In the same manner as in Example 17, (3R)-1- {2-[2-(1-benzothiophen-6-yl)ethoxy]ethyl}-3- pyrrolidinol oxalate v/as obtained as colorless crystals. IR(KBr)cm-1: 3364 , 2 938 , 2 688 , 1718 , 14 00, 1201, 1114 , 720 NMR(DMSO-d6) 5 values: 1. 7-1. 8 (1H,m) , 1. 9-2 . 1 (1H,m) , 2.96(2H,t,J=7Hz), 3.0-3.1(1H,m), 3.1-3.3(5H,m), 3.70(4H,t,J=7Hz),4.2-4.3(1H,m), 7.29(1H,d,J=8Hz), 7.41(1H,d,J=5Hz), 7.68(1H,d,J=5Hz), 7.80(lH,d,J=8Hz), 7.87(lH,s) Example 38 Production of (3R)-l-{2-[2-(1-benzothiophen- 3-yl)ethoxy]ethyl}-3-pyrrolidinol In the same manner as in Example 16 (1), 2- [2-(1-benzothiophen-3-yl)ethoxy]-1-[(3R)-3-hydroxy-l- pyrrolidinyl]-1-ethanone was obtained. NMR(CDC13) d values: 1.8-1.9(1H,m), 1.9-2.0(1H,m), 3.1-3.4(3H,m), 3.3-3.7(3H,m), 3.8-4.0(2H,m), 4.0-4.2(2H,m), 4.3-4.5(1H,m), 7.27(1/2H,s), 7.28(l/2H,s), 7.3-7.5(2H,m), 7.7-7.8(1H,m), 7.8- 7.9(1H,m) Then, (3R)-l-{2-[2-(l-benzothiophen-3- yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a yellow oil in the same manner as in Example 16 (2). IR (neat) cm-1: 338 6,2942,1458,142 9,1113,759,733 NMR(CDC13) 6 values: 1. 6-1. 8 (1H,m) , 2 . 1-2 . 2 (1H,m) , 2.34(lH,dt,J=6,9Hz), 2.55(1H,dd,J=5,lOHz), 2.6- 2.8(3H,m), 2.85(lH,dt,J=5,9Hz), 3.14(2H,t,J=7Hz), 3.61(2H,t,J=6Hz), 3.80(2H,t,J=7Hz), 4.2-4.4(1H,m), 7.21(lH,s), 7.34(lH,dt,J=l,7Hz), 7.38(lH,dt,J=l,7Hz), 7.7 6(1H,dd,J=l,7Hz), 7.85(lH,dd,J=l,7Hz) Example 39 Production of (3R)-l-{2-[2-(1-benzothiophen- 3-yl)ethoxy]ethyl}-3-pyrrolidinol hydrochloride In 5.0 mL of ethyl acetate was dissolved 0.99 g of (3R) -l-{2-[2-(1-benzothiophen-3-yl)ethoxy]ethyl}- 3-pyrrolidinol, and to the solution was added 1.10 mL of a 3.25 mol/L dried hydrogen chloride-ethyl acetate solution, after which the resulting mixture was stirred at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure to obtain 1.05 g of (3R)-l-{2-[2-(1-benzothiophen-3-yl)ethoxy]ethyl}-3- pyrrolidinol hydrochloride as a light-yellow oil. IR (neat Jem-1: 3368,294 6,1560,1430,1121,7 65,734 NMR(CDC13) 5 values: 1. 9-2 .1 (1H,m) , 2 .1-2 . 3 (1H,m) , 2.8-3.0(2H,m), 3.1-3.2(4H,m), 3.29(1H,d,J=12Hz), 3.3-3.5(1H,m), 3.8-3.9(4H,m), 4.3-4.4(1H,m), 7.24{lH,s), 7.35(lH,t,J=8Hz), 7.40(1H,t,J=8Hz), 7.76(lH,d,J=8Hz), 7.86(lH,d,J=8Hz) Example 4 0 Production of l-{2-[2-(l-benzothiophen-5- yl)ethoxy]ethyl}-4-piperidinol In the same manner as in Example 16 (1), 2- [2- (1-benzothiophen-5-yl)ethoxy]-1-(4-hydroxy-l- piperidinyl)-1-ethanone was obtained as an oil. Then, l-{2-[2-(l-benzothiophen-5- yl)ethoxy]ethyl}-4-piperidinol was obtained as a yellow oil in the same manner as in Example 16 (2). IR (neat)cm-1: 3386, 2 93 9, 1110, 1071, 754, 701 NMR(CDC13)d values: 1.5-2.3(6H,m), 2.5-3.0(2H,m), 2.56(2H,t,J=6Hz), 3.00(2H,t,J=7Hz), 3.5-3.9(1H,m), 3.58(2H,t,J=6Hz), 3.70(2H,t,J=7Hz), 7.19(lH,d,J=8Hz), 7.27(1H,d,J=5Hz), 7.41(1H,d,J=5Hz), 7.65(lH,s), 7.78(1H,d,J=8Hz) Example 41 Production of l-{2-[2-(1-benzothiophen-5- yl)ethoxy]ethyl}-4-piperidinol hydrochloride In the same manner as in Example 21, l-{2-[2- (1-benzothiophen-5-yl)ethoxy]ethyl}-4-piperidinol hydrochloride was obtained as light-brown crystals. IR(KBr)cm-1: 3312, 294 6, 2691, 14 57 , 1124 , 104 3, 7 69, 712 NMR(CDC13) 8 values: 1.5-2.5(4H,m), 2.8-3.2(6H,m), 2.99(2H,t,J=6Hz), 3.76(2H,t,J=6Hz), 3.8-4.2(3H,m), 7.19(lH,d,J=8Hz), 7.30(1H,d,J=5Hz), 7.44(1H,d,J=5Hz), 7.67(lH,s), 7.80(1H,d,J=8Hz) Example 42 Production of 1-{2-[2-(l-benzothiophen-5- yl)ethoxy]ethyl}-3-piperidinol In the same manner as in Example 16 (1), 2- [2-(1-benzothiophen-5-yl)ethoxy]-1-(3-hydroxy-l- piperidinyl)-1-ethanone was obtained as a yellow oil. IR (neat) cm"1: 3408, 2938, 1637, 1114, 704 Then, l-{2-[2-(l-benzothiophen-5- yl)ethoxy]ethyl}-3-piperidinol was obtained as a yellow oil in the same manner as in Example 16 (2). IR (neat) cm"1: 3387, 2937, 14 38, 1109, 703 NMR(CDC13) 5 values: 1. 4-2 . 0 (4H,m) , 2 . 0-2 . 7 (6H,m) , 2.57(2H,t,J=6Hz), 3.00(2H,t,J=7Hz), 3.56(2H,t,J=6Hz), 3.6-3.9(1H,m), 3.70(2H,t,J=7Hz), 7.20(lH,d,J=8Hz), 7.28(1H,d,J=5Hz), 7.42(1H,d,J=5Hz), 7.66(lH,s), 7.79(1H,d,J=8Hz) Example 4 3 Production of l-{2-[2-(l-benzothiophen-5- yl)ethoxy]ethyl}-3-piperidinol hydrochloride In the same manner as in Example 21, l-{2-[2- (1-benzothiophen-5-yl)ethoxy]ethyl}-3-piperidinol hydrochloride was obtained as colorless crystals. IR(KBr)cm-1: 32 60,2 94 9,2 638,14 33,112 9,1045,702,668 NMR(CDC13)d values: 1. 5-2 . 0 (4H,m) , 2 . 1-2 . 8 (2H,m) , 2.99(2H,t,J=6Hz), 3.1-3.6(4H,m), 3.76(2H,t,J=6Hz), 3.8-4.1(3H,m), 7.20(1H,d,J=8Hz), 7.30(1H,d,J=5Hz), 7.44(1H,d,J=5Hz), 7.67(lH,s),7.8 0(1H,d,J=8Hz) Example 4 4 Production of l-{2-[2-(1-benzofuran-5- yl)ethoxy]ethyl}-4-piperidinol In the same manner as in Example 16 (1), 2- [2- (l-benzofuran-5-yl)ethoxy]-1-(4-hydroxy-l- piperidinyl)-1-ethancne was obtained. IR (neat )cm-1: 34 06,2 931, 163 6, 1110, 771, 740 Then, l-{2-[2-(1-benzofuran-5- yl)ethoxy]ethyl}-4-piperidinol was obtained as a colorless oil in the same manner as in Example 16 (2). IR (neat) cm"1: 3359,2 939,14 68,1111,1073,882,7 68,739 NMR(CDC13)d values: 1. 5-2 . 3 (6H,m) , 2 . 5-3 . 0 (2H,m) , 2.57(2H,t,J=6Hz), 2 . 97(2H,t,J=7Hz), 3.5-3.8(1H,m), 3.58(2H,t,J=6Hz) , 3.68(2H,t,J=7Hz), 6.71(lH,dd, J=l,2Hz) , 7.13(1H,dd,J=2,8Hz), 7.4 0(lH,d, J=8Hz) , 7.42(1H, dd, J=l, 2), 7.55(lH,d,J=2Hz) Example 45 Production of l-{2-[2-(1-benzofuran-5- yl)ethoxy]ethyl}-4-piperidinol hydrochloride In the same: manner as in Example 21, l-{2-[2- (l-benzofuran-5-yl)ethoxy]ethyl}-4-piperidinol hydrochloride was obtained as a light-yellow oil. IR (neat) cm"1: 3366, 2938, 2638, 1458, 1126, 776, 742 NMR(CDC13) 8 values: 1. 6-2 . 4 (4H,m) , 2 . 8-3 . 2 (8H,m) , 3.71(2H,t,J=6Hz), 3.7-4.1(3H,m) , 6.72(lH,dd,J=l,2Hz), 7.12(1H,dd,J=2,8Hz), 7.4 4(lH,d, J=8Hz) , 7.42(1H, dd,J=l,2), 7.60(lH,d,J=2Hz) Example 4 6 Production of l-{2-[2-(1-benzofuran-5- yl)ethoxy]ethyl}-3-pyrrolidinol (1) In 13.0 mL of tetrahydrofuran was dissolved 1.28 g of 2-[2-(1-benzofuran-5-yl)ethoxy]acetic acid and the solution was cooled to 5°C, after which 1.41 g of 1,l"-carbonyldiimidazole was added thereto and the resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture were added 1.22 mL of triethylamine and 0.72 mL of 3-pyrrolidinol, followed by stirring at room temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture and the pH was adjusted to 1 with 6 mol/L hydrochloric acid, after which the organic layer was separated. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and then a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 1.39 g of 2-[2-(1-benzofuran-5-yl)ethoxy]-1-(3-hydroxy-l- pyrrolidinyl)-1-ethanone as a colorless oil. IR (neat) cm"1: 3398,2 943,1637, 14 67, 112 8, 103 0, 7 71, 741 (2) In 14.0 mL of tetrahydrofuran was dissolved 1.39 g of 2-[2-(1-benzofuran-5-yl)ethoxy]-1-(3-hydroxy- 1-pyrrolidinyl)-1-ethanone, and 14.4 mL of a 1 mol/L solution of a borane-tetrahydrofuran complex in tetrahydrofuran was added dropwise thereto under ice- cooling, after which the resulting mixture was stirred at room temperature for 17 hours. To the reaction mixture was added 8.0 mL of 6 mol/L hydrochloric acid, and the resulting mixture was heated under reflux for 1 hour. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the pH was adjusted to 10 with a 2 mol/L aqueous sodium hydroxide solution, and then the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform : methanol =30 : 1 to 10 : 1) to obtain 0.96 g of l-{2-[2-(l-benzofuran-5-yl)ethoxy]ethyl}-3- pyrrolidinol as a colorless oil. IR( neat)cm-1: 3386,2 941,14 68, 12 61, 1110, 1030, 882, 769,738 NMR(CDC13) 5 values: 1. 5-2 . 0 (1H,m) , 1. 9-3 . 0 (5H,m) , 2.68(2H,t,J=6Hz), 2.98(2H,t,J=7Hz), 3.58(2H,t,J=6Hz), 3.70(2H,t,J=7Hz), 4.2-4.4(1H,m), 6.71(lH,dd,J=l,2Hz), 7.14(lH,d,J=8Hz), 7.42(lH,d,J=8Hz), 7.4-7.5(1H,m), 7.59(1H,d,J=2Hz) Example 4 7 Production of l-{2-[2-(I-benzofuran-5- yl)ethoxy]ethyl}-3-pyrrolidinol oxalate In the same manner as in Example 17, l-{2-[2- (1-benzofuran-5-yl)ethoxy]ethyl}-3-pyrrolidinol oxalate was obtained as colorless crystals. IR(KBr)cm-1: 3413,294 5,2698, 1715, 1197, 1111, 720 NMR(DMSO-d6)d values: 1. 6-2 . 3 (2H,m) , 2.92 (2H,t, J=7Hz) , 3. 0-3. 5 (6.4,m) , 3 . 5-3 . 8 (4H,m) , 4.2-4.5(1H,m), 6.89(lH,dd,J=l,2Hz), 7.19(lH,dd,J=l,8Hz), 7.50(1H,d,J=8Hz), 7.5- 7.6(1H,m), 7.94(lH,d,J=2Hz) Example 4 8 Production of (3R,4R)-1-{2-[2-(1- benzothiophen-5-yl)ethoxy]ethyl}-3,4-pyrrolidinediol In the same manner as in Example 46 (1), 2- [2-(1-benzothiophen-5-yl)ethoxy]-1-[(3R,4R)-3,4- dihydroxy-1-pyrrolidinyl]-1-ethanone was obtained as a yellow oil. IR (neat)cm-1: 3370,2935,2874,1636,1131,756,7 01 Then, (3R,4R)-l-{2-[2-(l-benzothiophen-5- yl)ethoxy]ethyl}-3,4-pyrrolidinediol was obtained as a yellow oil in the same manner as in Example 46 (2). IR (neat) cm-1: 338 6,2938,28 66,14 38,1113,756,703 NMR(CDC13)6 values: 2.5-3.0(5H,m), 3.00(2H,t,J=7Hz), 3.2-3.7(1H,m), 3.56(2H,t,J=6Hz), 3.71(2H,t,J=7Hz), 3.9-4.4(2H,m), 7.20(1H,d,J=8Hz), 7.28(1H,d,J=5Hz), 7.43(1H,d,J=5Hz), 7.66(lH,s), 7.80(1H,d,J=8Hz) Example 4 9 Production of (3R,4R)-l-{2-[2-(1- benzothiophen-5-yl)ethoxy]ethyl}-3,4-pyrrolidinediol oxalate In the same manner as in Example 17, (3R, 4R)-l-{2-[2-(1-benzothiophen-5-yl)ethoxy]ethyl}- 3,4-pyrrolidinediol oxalate was obtained as colorless crystals. IR(KBr)cm-1: 3309,292 9,1718,1617,1199,1104,702 NMR(DMSO-d6)d values: 2.8-3.2(6H,m) , 3.2-3.8(6H,m), 4.1-4.4(2H,m), 7.26(1H,d,J=8Hz), 7.39(1H, d, J=5Hz) , 7.72(1H,d,J=5Hz), 7.75(lH,s), 7.90(1H,d,J=8Hz) Example 50 Production of l-{2-[2-(5-methoxy-l- benzofuran-6-yl)ethoxy]ethyl}-3-pyrrolidinol In the same manner as in Example 46 (1), 2- [2-(5-methoxy-l-benzofuran-6-yl)ethoxy]-1-(3-hydroxy-l- pyrrolidinyl)-1-ethanone was obtained as a colorless oil. IR (neat)cm-1: 3394,2 941,1637, 14 65, 1197,1131,1015, 841,759 Then, l-{2-[2-(5-methoxy-l-benzofuran-6- yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a colorless oil in the same manner as in Example 46 (2). IR (neat)cm-1: 338 6, 2 94 0, 14 66, 1430, 1198, 1131,1015, 837,762 NMR(CDC13)d values: 1. 5-2 . 4 (3H,m) , 2 . 5-3 . 0 (5H,m) , 2.99(2H,t,J=7Hz), 3.59(2H,t,J=6Hz), 3.67(2H,t,J=7Hz), 3.85(3H,s),4.2-4.4(1H,m), 6.68(1H,d,J=2Hz), 6.99(lH,s), 7.34(lH,s), 7.54(1H,d,J=2Hz) Example 51 Production of 1-{2-[2-(5-methoxy-1- benzofuran-6-yl)ethoxy]ethyl}-3-pyrrolidinol oxalate In the same manner as in Example 17, l-{2-[2- (5-methoxy-l-benzofuran-6-yl)ethoxy]ethyl}-3- pyrrolidinol oxalate was obtained as colorless crystals. IR(KBr)cm-1: 3396,2 942,2 691, 1718,1636,14 65,1198, 1130,720 NMR(DMSO-d6)d values: 1. 7-2 . 3 (2H,m) , 2 . 8-3. 6 (6H,m) , 2.91(2H,t,J=6Hz), 3.5-3.9(4H,m), 3.83(3H,s), 4.2- 4.5(1H,m), 6.86(LH,d,J=2Hz), 7.17(lH,s), 7.43(lH,s), 7.88(lH,d,J=2Hz) Example 52 Production of 1-{2-[2-(6-methoxy-l- benzofuran-5-yl)ethoxy]ethyl}-3-pyrrolidinol In the same manner as in Example 46 (1), 2- [2-(6-methoxy-l-benzofuran-5-yl)ethoxy]-1-(3-hydroxy-l- pyrrolidinyl)-1-ethanone was obtained as a colorless oil. IR (neat) cm-1: 3381,2944, 1638, 1475, 1201, 1125, 1011,758 Then, l-{2-[2-(6-methoxy-1-benzofuran-5- yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a colorless oil in the same manner as in Example 46 (2). IR(neat)cm-1: 3398,2938,1475,1202,1094,757,730 NMR(CDC13)d values: 1.5-2.4(3H,m), 2.5-3.0(5H,m), 2.98(2H,t,J=7Hz), 3.59(2H,t,J=6Hz), 3.68(2H,t,J=7Hz), 3.86(3H,s),4.2-4.4(1H,m), 6.65(lH,d,J=2Hz), 7.00(lH,s), 7.35(lH,s), 7.50(lH,d,J=2Hz) Example 53 Production of 1-{2-[2-(6-methoxy-l- benzof uran-5-yl )ethoxy]ethyl}-3-pyrrolidinol hydrochloride In the same manner as in Example 21, 1-{2-[2- (6-methoxy-l-benzofuran-5-yl)ethoKy]ethyl}-3- pyrrolidinol hydrochloride was obtained as a colorless oil. IR(neat) cm-1: 3377, 2938, 2694, 1475, 12 02, 1124, 1093,1011 NMR(CDC13) 8 values: 1. 7-2 . 2 (2H,m) , 2 . 8-3 . 6 ( 6H,m) , 2.96(2H,t,J=6Hz), 3.5-4.2(4H,m), 3.86(3H,s), 4.3-4.6(1H,m), 6.6-6.7(1H,m), 7.01(lH,s), 7.34 (lH,d, J=lHz) , 7.51 (1H, d,, J=2Hz) Example 54 Production of 1-{2-[2-(1-benzothiophen-5- yl)ethoxy]ethyl}-3-pyrrolidinamine (1) In 10.0 mL of tetrahydrofuran was dissolved 1.00 g of 2-[2-(1-benzothiophen-5-yl)ethoxy]acetic acid, and the solution was cooled to 5°C, after which 1.03 g of 1,1"-carbonyldiimidazole was added thereto and the resulting mixture was stirred at room temperature for 1 hour. After the reaction mixture was cooled to 5°C, 0.88 mL of triethylamine and 1.18 g of tert-butyl=3-pyrrolidinylcarbamate were added thereto, followed by stirring at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture and the pH was adjusted to 4 with 6 mol/L hydrochloric acid, after which the organic layer was separated. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and then a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 2.00 g of tert-butyl=l-{2-[2-(1-benzothiophen-5- yl)ethoxy]acetyl}-3-pyrrolidinylcarbamate as a light- yellow oil. (2) In 2.0 mL of tetrahydrofuran was dissolved 2.00 g of the aforesaid tert-butyl=l-{2-[2-(1- benzothiophen-5-yl)ethoxy]acetyl}-3-pyrrolidinyl- carbamate, and the resulting solution was cooled to 5°C, after which 10.6 mL of a 1 mol/L solution of a borane- tetrahydrofuran complex in tetrahydrofuran was added dropwise thereto and the resulting mixture was stirred at room temperature for 17 hours. To the reaction mixture was added 3.5 mL of 6 mol/L hydrochloric acid, and the resulting mixture was headed under reflux for 3 « hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the pH was adjusted to 10 with a 5 mol/L aqueous sodium hydroxide solution, and then the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform : methanol = 30 : 1 to 15 : 1) to obtain 1.01 g of l-{2-[2-(1-benzothiophen-5-yl)ethoxy]ethyl}- 3-pyrrolidinamine as a light-yellow oil. IR(neat)cm-1: 3358,2938,2861,1438,1112,1052,755,703 NMR(CDC13) 5 values: 1. 2-1. 7 (1H,m) , 1. 9-3 . 0 (7H,m) , 2.01(2H,s), 3.00(2H,t,J=7Hz), 3.3-3.7(1H,m), 3.57(2H,t,J=6Hz), 3.71(2H,t,J=7Hz), 7.20(lH,d, J=8Hz), 7.28(1H,d,J=5Hz), 7.41(1H,d,J=5Hz) , 7.66(lH,s), 7.78(lH,d,J=8Hz) Example 55 Production of l-{2-[2-(l-Benzothiophen-5- yl)ethoxy]ethyl}-3-pyrrolidinamine dioxalate In 3.0 mL of ethyl acetate was dissolved 0.71 g of l-{2-[2-(1-benzothiophen-5-yl)ethoxy]ethyl}-3- pyrrolidinaraine, and to the solution was added a solution of 0.44 g of oxalic acid in 4.0 mL of ethyl acetate. The resulting mixture was stirred at room temperature for 1 hour and then at 5°C for 1 hour. The crystals precipitated were collected by filtration, washed with ethyl acetate and then dried to obtain 1.03 g of 1-{2-[2-(1-benzothiophen-5-yl)ethoxy]ethyl}-3- pyrrolidinamine dioxalate as colorless crystals. IR(KBr)cm-1: 344 7,2938,1406,127 9,1115,720 NMR(DMSO-d6)d values: 1. 7-2 . 5 (2H, m) , 2 . 8-3. 5 (8H,m) , 3.5-4.0(5H,m), 7.27(1H, d, J=8Hz), 7.40(1H,d,J=5Hz), 7.72(1H,d,J=5Hz), 7.75(lH,s), 7.90 (1H,d,J=8Hz) Example 5 6 Production of 1-{2-[2-(1-benzofuran-5- yl)ethoxy]ethyl}-3-pyrrolidinamine In the same manner as in Example 54 (1), tert-butyl=l-{2-[2-(l-benzofuran-5-yl)ethoxy]acetyl}-3- pyrrolidinylcarbamate was obtained. Then, 1-{2-[2-(1-benzofuran-5- yl)ethoxy]ethyl}-3-pyrrolidinamine was obtained as a yellow oil in the same manner as in Example 54 (2). IR(neat)cm-1: 3356, 2 938, 14 67, 12 61, 1111, 1030, 882, 7 69,740 NMR(CDC13) 5 values: 1.2-1.7(1H,m), 2.02(2H,s), 2.1- 3.0(7H,m), 2.98(2H,t,J=7Hz), 3.3-3.7(1H,m), 3.57(2H,t,J=6Hz), 3.69(2H,t,J=7Hz), 6.71(lH,dd,J=l,2Hz), 7.15(1H,dd,J=l,7Hz), 7.40(lH,d,J=7Hz), 7.4-7.5(1H,m), 7.59(1H,d,J=2Kz) Example 57 Production of 1-{2-[2-(1-benzofuran-5- yl)ethoxy]ethyl}-3-pyrrolidinamine oxalate In the same manner as in Example 17, l-{2-[2- (1-benzofuran-5-yl)ethoxy]ethyl}-3-pyrrolidinamine oxalate was obtained as colorless crystals. IR(KBr)cm-1: 34 08,2 952, 1615, 1311, 1127, 769 NMR(DMSO-d6) 5 values: 1. 5-1 . 9 (1H,m) , 1. 8-2 . 4 (1H,m) , 2.1-3.0(6H,m), 2.89(2H,t,J=7Hz), 3.4-3.8(5H,m), 6.89(lH,dd,J=l,2Hz), 7.18(lH,d,J=8Hz), 7.50(lH,d,J=8Hz), 7.4-7.6(1H,m), 7.94(1H,d,J=2Hz) Example 58 Production of 1-{3-[2-(l-benzothiophen-5- yl)ethoxy]propyl}-3-pyrrolidinol In 12 mL of N,N-dimethylformamide was dissolved 1.20 g of 5-[2-(3-chloropropoxy)ethyl]-1- benzothiophene, and 0.82 g of 3-pyrrolidinol and 1.30 g of potassium carbonate were added to the solution, after which the resulting mixture was stirred at 85°C for 2.5 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform : methanol = 20 : 1 to 10 : 1) to obtain 0.78 g of l-{3-[2-(1- benzothiophen-5-yl)ethoxy]propyl}-3-pyrrolidinol as a colorless oil. IR (neat) cm-1: 338 6,2 94 3,1438,110 6, 1052,755,701 NMR(CDC13) 5 values: 1. 5-2 . 0 ( 3H,m) , 2 . 0-3 . 0 (7H,m) , 2.98(2H,t,J=7Hz), 3.49(2H,t,J=6Hz), 3.67(2H,t,J=7Hz), 4.2-4.4(1H,m), 7.1-7.3(2H,m), 7.41(lH,d,J=6Hz), 7.66(lH,s), 7.78(1H,d,J=8Hz) Example 59 Production of l-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-pyrrolidinol hydrochloride In the same manner as in Example 21, 1-{3-[2- (1-benzothiophen-5-yl)ethoxy]propyl}-3-pyrrolidinol hydrochloride was obtained as colorless crystals. IR(KBr)cm-1: 33 68, 2 937, 2 695, 1438, 1108 , 821, 7 64 , 7 08 NMR(CDC13)d values: 1.8-2.3(4H,m) , 2.3-3.6(6H,m), 2.96(2H,t,J=6Hz), 3.50(2H,t,J=6Hz), 3.68(2H,t,J=7Hz), 4.3-4.7(1H,m), 7.21(1H,d,J=8Hz), 7.30(1H,d,J=5Hz), 7.43(1H,d,J=5Hz), 7.67(lH,s), 7.80(lH,d,J=8Hz) Example 60 Production of 1-{3-[2-(1-benzofuran-5- yl)ethoxy]propyl}-3-pyrrolidinol In the same manner as in Example 58, l-{3-[2- (1-benzofuran-5-yl)ethoxy]propyl}-3-pyrrolidinol was obtained as a light-yellow oil. IR(neat) cm-1: 3386, 2942, 14 67, 12 61, 1108, 1030, 883, 740 NMR(CDC13) 8 values: 1. 5-2 . 0 (3H,m) , 2 . 0-3 . 0 (7H,m) , 2.95(2H,t,J=7Hz), 3 . 4 9(2H,z,J=6Hz), 3.65(2H, t, J=7Hz) , 4.2-4.4(1H,m), 6.71(lH,dd,J=l,2Hz), 7.14(1H,dd,J=l,8Hz), 7.3- 7.5(2H,m), 7.58 (lH,d,J=2Hz) Example 61 Production of l-{3-[2-(1-benzofuran-5- yl)ethoxy]propyl}-3-pyrrolidinoi hydrochloride In the same manner as in Example 39, l-{3-[2- (1-benzofuran-5-yl)ethoxy]propyl}-3-pyrrolidinol hydrochloride was obtained as a light-yellow oil. IR (neat) cm"1: 3339, 2941, 2605, 14 68, 12 62, 1110, 773, 742 NMR(CDC13) 5 values: 1. 6-2 . 4 (4H,m) , 2 . 4-4 . 0 (12H,m) , 4.4-4.8(1H,m), 6.72(1H,d,J=2Hz), 7.12(1H,d,J=8Hz), 7.3-7.6(2H,m), 7.59(1H,d,J=2Hz) Example 62 Production of 1-{3-[2-(6-fluoro-1- benzothiophen-5-yl)ethoxy]propyl}-3-pyrrolidinol In the same manner as in Example 58, 1-{3-[2- (6-fluoro-1-benzothiophen-5-yl)ethoxy]propyl}-3- pyrrolidinol was obtained as a yellow oil. IR (neat) cm-1: 3422,2 952,1458, 1257,1106,838,747,711 NMR(CDC13)d values: 1. 5-3 . 0 (10H,m) , 3.00(2H,t,J=7Hz), 3.4-3.6(2H,m), 3.68(2H,t,J=7Hz), 4.2-4.4(1H,m), 7.23(1H,d,J=5Hz), 7.36(1H,d,J=5Hz), 7.51 (lH,d, J=10.4z) , 7.66(lH,d, J=7Hz) Example 63 Production of l-{3-[2-(6-fluoro-1- benzothiophen-5-yl)ethoxy]propyl}-3-pyrrolidinol hydrochloride In the same manner as in Example 39, l-{3-[2- (6-fluoro-1-benzothiophen-5-yl)ethoxy]propyl} -3- pyrrolidinol hydrochloride was obtained as a yellow oil. IR(neat)cm-1: 3377,2 954,27 02,14 58,1257,1107,7 50,712 NMR(CDC13)d values: 1. 8-2 . 3 ( 4H,m) , 2 . 8-3 . 6 (8H,m) , 3.53(2H,t,J=6Hz), 3.69(2H,t,J=7Hz), 4.3-4.4(1H,m), 7.2 7(1H,d,J=5Hz), 7.39(1H,d,J=5Hz), 7.52(lH,d,J=10Hz), 7.67(lH,d,J=7Hz) Example 64 Production of (3R,4S)-l-{3-[2-(1- benzothiophen-5-yl)ethoxy]propyl}-3,4-pyrrolidinediol In the same manner as in Example 58, (3R,4S)- 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3,4- pyrrolidinediol was obtained as a colorless oil. IR(neat) cm-1: 3387, 2 94 0, 1438, 1159,1108, 1051, 703 NMR(CDC13)d values: 1. 5-1. 9 (2H,m) , 2 . 4-2 . 8 ( 6H,m) , 2.98(2H,t,J=7Hz), 3.4 7(2H,t,J=6Hz), 3.67(2H,t,J=7Hz), 4.1-4.3(2H,m), 7.20(lH,dd,J=l,8Hz), 7.2 7(1H,d,J=5Hz), 7.42(1H,d,J=5Hz), 7.65(1H,d,J=1Hz), 7.79(lH,d,J=8Hz) Example 65 Production of (3R,4S)-1-{3-[2- (1- benzothiophen-5-yl)ethoxy]propyl}-3,4-pyrrolidinediol hydrochloride In the same manner as in Example 21, (3R,4S)- l-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3,4- pyrrolidinediol hydrochloride was obtained as colorless crystals. IR(KBr)cm-1: 3381, 28 71, 2 602 , 112 0, 808 , 768 , 718 NMR(DMSO-d6) 5 values: 1. 8-2 . 0 (2H,m) , 2.8- 3.8(12H,m), 3.9-4.3(2H,m), 7.25(1H,dd,J=2,8Hz), 7.39(1H,d,J=5Hz), 7.72(1H,d,J=5Hz), 7.7 3(lH,d,J=2Hz), 7.90(lH,d,J=8Hz) Example 66 Production of l-{3-[2-(l-benzothiophen-5- yl)ethoxy]propyl}-4-piperidinol In the same manner as in Example 58, l-{3-[2- (1-benzothiophen-5-yl)ethoxy]propyl}-4-piperidinol was obtained as a light-yellow oil. IR (neat)cm-1: 3385, 2 935, 14 38, 1364 , 1111, 755, 7 01 NMR(CDC13)d values: 1. 4-2 . 2 ( 8H,m) , 2 . 1-2 . 5 (2H, m) , 2.5-3.0(2H,m), 2.98(2H,t,J=7Hz), 3.48(2H,t,J=6Hz), 3.5-3.8(1H,m), 3.67(2H,t,J=7Hz), 7.1-7.3(2H,m), 7.42(1H,d,J=5Hz), @@@7.66(lH,s), 7.79(1H,d,J=8Hz) Example 67 Production of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-4-piperidinol oxalate In the same manner as in Example 17, 1-{3-[2- (1-benzothiophen-5-yl)ethoxy]propyl}-4-piperidinol oxalate was obtained as colorless crystals. IR(KBr) cm-1: 3420,2866, 1718, 1616, 1190, 1120,705 NMR(DMSO-d6) 5 values: 1. 5-2 . 0 (6H,m) , 2 . 8-3 .1 (8H,m) , 3.4-3.8(1H,m), 3.44(2H,t,J=6Hz), 3.64(2H,t,J=6Hz), 7.24(lH,d,J=8Hz), 7.40(1H,d,J=5Hz), 7.6-7.8(2H,m), 7.91(lH,d,J=8Hz) Example 68 Production of l-{2-[2-(2- naphthyl)ethoxy]ethyl}-3-pyrrolidinol In 8 mL of N,N-dimethylformamide was dissolved 0.80 g of 2-[2-(2-naphthyl)ethoxy]- ethyl=methanesulfonate, and 0.45 mL of 3-pyrroiidinol and 0.75 g of potassium carbonate were added to the solution, after which the resulting mixture was stirred at 90°C for 2 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform : methanol = 8 : 1 to 5 : 1) to obtain 0.51 g of l-{2-[2-(2- naphthyl)ethoxy]ethyl}-3-pyrrolidinol as a colorless oil. IR (neat) cm-1: 3422,2 938,1112,820,74 9 NMR(CDC13)d values: 1. 5-1. 9 (1H, m) , 2 . 0-2 . 5 (3H,m) , 2.5-3.0(4H,m), 3.05(2H,t,J=7Hz), 3.59(2H,t,J=6Hz), 3.75(2H,t,J=7Hz), 4.2-4.4(1H,m), 7.2-7.6(4H,m), 7.6-8.0(3H,m) Example 69 Production of 1-{2-[2-(2- naphthyl)ethoxy]ethyl}-3-pyrrolidinol oxalate In the same manner as in Example 17, 1-{2-[2- (2-naphthyl)ethoxy]ethyl}-3-pyrrolidinol oxalate was obtained as colorless crystals. IR(KBr)cm-1: 33 66, 2 94 5, 14 05, 1113, 820, 720 NMR(DMSO-d6)d values: 1. 6-2 . 3 (2H,m) , 2. 7-3. 5 (8H,m) , 3.5-3.9(4H,m), 4.2-4.5(1H,m), 7.4-7.6(3H,m), 7.7- 8.0(4H,m) Example 70 Production of (3R,4S)-1-{2-[2-(1- benzothiophen-5-yl)ethoxy]ethyl}-3,4-pyrrolidinediol In 25 mL of N,N-dimethylformamide was dissolved 2.50 g of 2-[2-(l-benzothiophen-5- yl)ethoxy]ethyl=methanesulfonate, and 1.40 g of (3R,4S)-3,4-pyrrolidinediol hydrochloride and 4.70 mL of triethylamine were added to the solution, after which the resulting mixture was stirred at 90°C for 1 hour. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the pH was adjusted to 10 with a 2 mol/L aqueous sodium hydroxide solution, and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by a cclumn chromatography (eluent; chloroform : methanol = 8 : 1 to 5 : 1) to obtain 0.84 g of (3R,4S)-l-{2-[2-(l-benzothiophen-5- yl)ethoxy]ethyl}-3,4-pyrrolidinediol as a yellow oil. IR(neat)cm-1: 3390,2940,1438,1111,1050,703 NMR(CDC13)d values: 2 . 5-3 . 0 ( 6H,m) , 3.00(2H,t,J=7Hz), 3.55(2H,t,J=6Hz), 3.70(2H,t,J=7Hz), 4.0-4.3(2H,m), 7.21(lH,dd,J=l,8Hz), 7.28(1H,d,J=5Hz), 7.4 3(lH,d,J=5Hz], 7.66(1H,d,J=lHz), 7.80(lH,d,J=8Hz) Example 71 Production of (3R,4S)-I-{2-[2-(1- benzothiophen-5-yl)ethoxy]ethyl}-3,4-pyrrolidinediol hydrochloride In the same manner as in Example 21, (3R,4S)- l-{2-[2-(1-benzothiophen-5-yl)ethoxy]ethyl}-3,4- pyrrolidinediol hydrochloride was obtained as colorless crystals. IR(KBr)cm-1: 3194 , 2854 , 13 65, 134 8, 1130, 1111, 820, 712 NMR(DMSO-d5)d values: 2 . 8-4 . 0 (12H, m) , 3.9-4.3(2H,m), 7.2-7.5(2H,m), 7.7-8.2(3H,m) Example 72 Production of tert-butyl=1-{3-[2-(1- benzothiophen-5-yl)ethoxy]propyl}-3-pyrrolidinyl- carbamate In 7 mL of N,N-dimethylformamide was dissolved 0.70 g of 3- [2-(1-benzothiophen-5- yl)ethoxy]propyl=methanesulfonate, and 1.03 g of tert- butyl=3-pyrrolidinylcarbamate carbonate and 1.8 6 mL of triethylamine were added to the solution, after which the resulting mixture was stirred at 90°C for 2 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the pH was adjusted to 10 with 6 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was distilled off under reduced pressure to obtain 1.12 g of tert-butyl=1-{3- [2- (1-benzothiophen-5-yl)ethoxy]propyl}-3-pyrrolidinyl- carbamate as a yellow oil. NMR(CDC13)d values: 1. 2-1. 9 (3H, m) , 1.44(9H,s), 1.9- 3.0(7H,m), 2.99(2H,t,J=7Hz), 3.49(2H,t,J=6Hz), 3.67(2H,t,J=7Hz), 4.0-4.3(1H,m), 7.19(1H,d, J=8Hz) , 7.27(1H,d,J=5Hz), 7.42(1H,c,J=5Hz) , 7.66(lH,s), 7.79(lH,d,J=8Hz) Example 73 Production of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-pyrrolidinamine In 7.0 mL of ethyl acetate was dissolved 1.12 g of tert-butyl=1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-pyrrolidinylcarbamate, and 1.86 mL of 6 mol/L hydrochloric acid was added to the solution, after which the resulting mixture was heated under reflux for 1 hour. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the pH was adjusted to 10 with a 2 mol/L aqueous sodium hydroxide solution, and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform : methanol = 30 : 1 to 20 : 1) to obtain 0.38 g of 1-{3-[2-(l-benzothiophen-5- yl)ethoxy]propyl}-3-pyrrolidinamine as a light-yellow oil. IR(neat) cm-1: 3357,2937,2 8 61,27 96, 1146, 1108, 755, 701 NMR(CDCl3)d values: 1. 2-1. 9 (4H, m) , 1. 9-2 . 8 (7H,m) , 2.97(2H,t,J=7Hz), 3.4 8(2H,t,J=6Hz), 3.66(2H,t,J=7Hz), 7.19(1H,d,J=8Hz), 7.23(1H,d,J=5Hz), 7.39(1H,d,J=5Hz), 7.64(lH,s), 7.77(lH,d,J=8Hz) Example 7 4 Production of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-pyrrolidinamine oxalate In the same manner as in Example 17, l-{3-[2- (1-benzothiophen-5-yl)ethoxy]propyl}-3-pyrrolidinamine oxalate was obtained as colorless crystals. IR(KBr)cm-1: 3390,2871, 1614 , 1310, 1122 , 7 66 NMR(DMSO-d6)d values: 1.5-1.9(2H,m), 1.9-2.9(8H,m), 2.92(2H,t,J=7Hz), 3.3-3.7(1H,m), 3.43(2H,t,J=6Hz), 3.62(2H,t,J=7Hz), 7.25(lH,d,J=8Hz), 7.39(1H,d,J=5Hz), 7.12 (1H,d,J=5Hz), 7.73(lH,s), 7.90(lH,d,J=8Hz) Example 75 Production of N-(1-{3-[2-(l-benzothiophen-5- yl)ethoxy]propyl}-3-pyrrolidinyl)acetamide In 5 mL of methylene chloride was dissolved 0.50 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}- 3-pyrrolidinamine, and the solution was cooled to -60°C, after which 0.27 mL of triethylamine and 0.14 mL of acetyl chloride were added to the solution and the resulting mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform : methanol = 50 : 1 to 10 : 1) to obtain 0.55 g of N-(l-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-pyrrolidinyl)acetamide as a yellow oil. IR (neat) cm-1: 3292,2946,1654, 1560, 1110, 757, 702 NMR(CDC13)d values: 1. 5-1. 7 (1H,m) , 1. 7-1. 8 (2H,m) , 1.94(3H,s), 2.13(lH,q,J=9Hz), 2.2-2.3(1H,m), 2.4-2.5(3H,m), 2.59(1H,dd,J=2,lOHz), 2.86(lH,dt,J=4,9Hz), 2.99(2H,t,J=7Hz), 3.49(2H,t,J=6Hz), 3.67(2H,t,J=7Hz), 4.3-4.5(1H,m), 5.8-5.9(1H,m), 7.22(1H,dd,J=l,8Hz), 7.28(1H,d,J=5Hz), 7.42(1H,d,J=5Hz), 7.67(1H,d,J=1Hz), 7.7 9(lH,d,J=8Hz) Example 7 6 Production of N-(1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-pyrrolidinyl)acetamide hydrochloride In the same manner as in Example 21, N-(l-{3- [2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- pyrrolidinyl)acetamide hydrochloride was obtained as light-brown crystals. IR(KBr)cm-1: 3422,2 8 68,2475, 1664,1542,1343,1117,711 NMR(CDC13)d values: 1. 9-2 . 1 (3H,m) , 2.05(3H,s), 2.3-2.4(1H,m), 2.4-2.5(1H,m), 2.6-2.7(1H,m), 2.8-2.9(2H,m), 2.97(2H,t,J=6Hz), 3.4-3.4(1H,m), 3.51(2H,t,J=6Hz), 3.6-3.7(IH,m), 3.70(2H,t, J=6Hz) , 4.6-4.8(1H,m) , 7.22(1H,dd,J=l,8Hz), 7.31 (1H,d,J=5Hz), 7.46(1H,d,J=5Hz), 7.67(lH,s), 7.81(lH,d,J=8Hz) Example 77 Production of N-(1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-pyrrolidinyl)methanesulfonamide In the same manner as in Example 75, N-(l-{3- [2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- pyrrolidinyl)methanesulfonamide was obtained as a yellow oil. IR(neat) cm-1: 327 0,2 927,285 6,1320,1148,1110,7 56 NMR(CDC13)d values: 1. 6-1. 8 (3H,m) , 2 .1-2 . 3 (2H,m) , 2.4 4(2H,t,J=7Hz), 2.5 0(lH,dd,J=6,lOHz), 2.60(lH,dd,J=3,lOHz), 2.77(1H,dt,J=4,9Hz), 2.94(3H,s), 2.99(2H,t,J=7Hz), 3.48(2H,t,J=6Hz), 3.68(2H,t,J=7Hz), 3.9-4.0(1H,m), 4.6-4.8(1H,m), 7.22 (lH,dd,J=l,8Hz), 7.2 8 (1H,d,J=5Hz), 7.42 (1H,d,J=5Hz), 7.67(1H,d,J=1Hz), 7.79(lH,d,J=8Hz) Example 7 8 Production of N-(1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-pyrrolidinyl)methanesulfonamide oxalate In the same manner as in Example 17, N-(1-{3- [2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- pyrrolidinyl)methanesulfonamide oxalate was obtained as colorless crystals. IR(KBr)cm-1: 3250,28 68,1718, 1314, 1165, 1119,7 07 NMR(DMSO-d6) 8 values: 1.8-2 . 0 (3H, m) , 2 . 2-2 . 3 (1H,m) , 2.93(2H,t,J=7Hz), 2.97(3H,s), 3.0-3.1(3H,m), 3.1-3.2(1H,m), 3.2-3.3(1H,m), 3.4-3.5(1H,m), 3.45(2H,t,J=6Hz), 3.63(2H,t,J=7Hz), 4.0-4.1(1H,m), 7.2 6(lH,dd,J=l,8Hz), 7.4 0(1H,d,J=5Hz), 7.4-7.6(1H,m), 7.72(1H,d,J=5Hz), 7.74(1H,d,J=lHz) , 7.90(lH,d,J=8Hz) Example 7 9 Production of 1-{3-[2- (1-benzothiophen-5- yl)ethoxy]propyl}-N,N-dimethyl-3-pyrrolidinamine In 8.6 mL of methanol was dissolved 0.43 g of l-{3- [2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- pyrrolidinamine, and the solution was cooled to 5°C, after which 0.35 mL of 37% formalin and 0.09 g of sodium borohydride were added to the solution and the resulting mixture was stirred at room temperature for 17 hours. Under ice-cooling, 2.6 mL of 2 mol/L hydrochloric acid was added to the reaction mixture, followed by stirring at room temperature for 30 minutes, after which water and ethyl acetate were added thereto and the aqueous layer was separated. Ethyl acetate was added to "he aqueous layer and the pH was adjusted to 9.5 with a 2 mol/L aqueous sodium hydroxide solution, after which the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform : methanol =50 : 1 to 10 : 1) to obtain 0.39 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}- N,N-dimethyl-3-pyrrolidinamine as a yellow oil. IR(neat) cm-1: 2945, 28 62, 2 7 86, 1458, 1111, 700 NMR(CDC13)d values: 1. 6-1. 8 (3H,m) , 1. 9-2 . 0 (1H,m) , 2.20(6H,s), 2.2-2.3(1H,m), 2.3-2.5(2H,m), 2.50(lH,dt,J=8,12Hz), 2.7-2.8(2H,m), 2.8-2.9(1H,m), 2.99(2H,t,J=7Hz), 3.49(2H,t,J=7Hz) , 3.67(2H,t,J=7Hz;, 7.22(1H,dd,J=l,8Hz), 7.2 8 (1H,d,J=5Hz), 7.41(1H,d,J=5Hz), 7.67(1H,d,J=1Hz), 7.7 9(lH,d,J=8Hz) Example 8 0 Production of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-N,N-dimethyl-3-pyrrolidinamine dihydrochloride In 4.0 mL of ethyl acetate was dissolved 0.39 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-N,N- dimethyl-3-pyrrolidinamine, and to the solution was added 0.80 mL of a 3.25 mol/L dried hydrogen chloride- ethyl acetate solution. The resulting mixture was stirred at room temperature for 1 hour and then at 5°C for 1 hour. The crystals precipitated were collected by filtration, washed with ethyl acetate and then dried to obtain 0.32 g of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-N,N-dimethyl-3-pyrrolidinamine dihydrochloride as colorless crystals. IR(KBr)cm-1: 2936,1437,1101,701 NMR(CDC13)d values: 1. 9-2 .1 (2H,m) , 2 . 4-2 . 6 (2H, m) , 2.84(6H,s), 2.98(2H,t,J=7Hz), 3.1-3.2(2H,m), 3.4- 3.9(4H,m), 3.54(2H,t,J=5Hz), 3.72(2H,dt,J=3,7Hz), 4.2-4.3(1H,m), 7.24(1H,d,J=8Hz), 7.35(1H,d,J=5Hz), 7.43(1H,d,J=5Hz), 7.71(lH,s), 7.84(1H,d,J=8Hz) Example 81 Production of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinol 1/2 fumarate In 10.0 mL of ethanol was dissolved 5.00 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- azetidinol, and the solution was heated at 70°C, after which 0.99 g of fumaric acid was added to the solution and stirred for 30 minutes. To the resulting solution was added dropwise 30.0 mL of ethyl acetate, and the resulting mixture was stirred at 60°C for 15 minutes, cooled to 5°C over a period of 1 hour and then stirred at the same temperature for 1 hour. The crystals precipitated were collected by filtration, washed with ethyl acetate and then dried to obtain 5.83 g of 1—{3— [2- (1-benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol 1/2 fumarate as colorless crystals. IR(KBr)cm-1: 3258, 2 93 6, 28 62, 1578, 1360, 1114,1109, 707,665 NMR(DMSO-d6)d values: 1. 5-1. 6 (2H,m) , 2.60(2H,t,J=7Hz), 2.91(2H,t,J=7Hz), 2.9-3.1(2H,m), 3.39(2H,t,J=7Hz), 3.60(2H,t,J=7Hz), 3.6-3.8(2H,m), 4.1-4.3(1H,m), 6.50(lH,s), 7.25 (1H,dd,J=l,8Hz), 7.3 9(1H,d,J=5Hz), 7.72(1H,d,J=5Hz), 7.73(1H,d,J=1Hz), 7.89(lH,d,J=8Hz) Example 82 Production of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinol (1) In 12.5 mL of toluene was suspended 5.00 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]propionic acid, and 0.1 mL of N,N-dimethylformamide was added thereto, after which 1.68 mL of thionyl chloride was added dropwise thereto at 15°C and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was added dropwise to a solution of 4.44 g of 3-hydroxyazetidine 1/2 tartrate and 3.76 g of sodium hydroxide in 25 mL of water at 10°C, and stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture and the organic layer was separated. The organic layer was washed with diluted hydrochloric acid and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform : acetone = 3 : 1 to 1 : 1) and crystallized from diisopropyl ether to obtain 5.48 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-1- (3-hydroxy-l-azetidinyl)-1-propanone as colorless crystals. IR(KBr)cm-1: 3316, 2875, 1610, 1481, 1112, 992, 706 NMR(CDC13)d values: 2 . 2-2 . 4 (2H,m) , 2.98(2H,t,J=7Hz), 3.6-3.8(5H,m), 3.8-4.0(1H,m), 4.1-4.3(2H,m), 4.4-4.4(1H,m), 7.20(1H,dd,J=l,8Hz), 7.28(lH,dd,J=l,5Hz), 7.41(1H,d,J=5Hz), 7.6-7.7(1H,m), 7.79(1H,d,J=8Hz) (2) In 20 mL of tetrahydrofuran was dissolved 5.00 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-1-(3- hydroxy-1-azetidinyl)-1-propanone, and 1.09 g of sodium borohydride was added thereto, after which 4.25 mL of a boron trifluoride-tetrahydrofuran complex was added dropwise thereto at 10°C and the resulting mixture was stirred at the same temperature for 1 hour and then at 40°C for 3 hours. After the reaction mixture was cooled to 10°C, 30 mL of 6 mol/L hydrochloric acid was added dropwise thereto and the resulting mixture was refluxed for 1 hour. After cooling, the solvent was concentrated under reduced pressure, and ethyl acetate was added. The pH was adjusted to 9.4 with a 20% aqueous sodium hydroxide solution and then the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The resulting residue was purified by a column chromatography (eluent; chloroform : methanol = 20 : 1 to 10 : 1) and crystallized from toluene- diisopropyl ether (1 : 3, 14 mL) to obtain 2.31 g of 1- {3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- azetidinol. Example 83 Production of l-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinol maleate In 56 mL of acetone was dissolved 8.00 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- azetidinol, followed by adding thereto 3.19 g of maleic acid, and the resulting mixture was heated at 60°C to effect dissolution. The reaction mixture was slowly cooled and then stirred at 5°C for 30 minutes. The crystals precipitated were collected by filtration to obtain 9.89 g of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinol maleate as colorless crystals. NMR(DMSO-d6)d values: 1. 6-1. 8 (2H,m) , 2.93(2H,t,J=7Hz), 3.13(2H,t,J=7Hz), 3.43(2H, t, J=6Hz) , 3.63(2H,t,J=7Hz), 3.7-3.9(2H,m), 4.1-4.3(2H,m), 4.4-4.5(1H,m), 6.04(2H,s), 7.26(lH,dd,J=l,8Hz), 7.40(1H,d,J=5Hz), 7.7- 7.8(1H,m), 7.74(1H,d,J=5Hz), 7.92(1H,d,J=8Hz) Example 84 Production of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinol nitrate In 20 mL of ethyl acetate was dissolved 10.0 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- azetidinol, and 20 mL of isopropanol was added thereto, after which 2.60 mL of concentrated nitric acid (61%) was added dropwise thereto at room temperature. To the reaction mixture was added dropwise 60 mL of ethyl acetate, and the resulting mixture was stirred at the same temperature for 1 hour and then at 5°C for 1 hour. The crystals precipitated were collected by filtration to obtain 11.3 g of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinol nitrate as colorless crystals. IR(KBr) cm-1: 3354, 2880, 1385, 1107, 712 NMR(DMSO-d6)d values: 1. 6-1. 8 (2H,m) , 2.93(2H,t,J=7Hz), 3.1-3.2(2H,m), 3.44(2H,t,J=6Hz), 3.64(2H,t,J=7Hz), 3.7-3.9(2H,m), 4.0-4.4(2H,m), 4.4-4.5(1H,m), 7.27(1H,d,J=8Hz), 7.41(1H,d,J=5Hz), 7.74(1H,d,J=5Hz), 7.74(lH,s), 7.92(1H,d,J=8Hz) Example 8 5 Production of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinol L-tartrate In 40 mL of ethyl acetate was dissolved 10.0 g of l-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- azetidinol, and 5.15 g of L-tartaric acid and 40 mL of ethanol were added thereto, after which the resulting mixture was heated at 65°C to effect dissolution. After the resulting solution was stirred at 50°C for 20 minutes, 40 mL of ethyl acetate was added dropwise thereto at the same temperature and the resulting mixture was stirred at 20 to 30°C for 1 hour. The crystals precipitated were collected by filtration to obtain 13.9 g of 1-{3- [2- (1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinol L-tartrate as colorless crystals. IR(KBr) cm-1: 3318, 2807, 1305, 112 6, 67 9, 483 NMR(DMSO-d6)d values: 1. 5-1. 7 (2H, m) , 2.82(2H,t,J=7Hz), 2.92(2H,t,J=7Hz), 3.2-3.4(2H,m), 3.41(2H,t,J=6Hz), 3.61(2H,t,J=7Hz), 3.8-4.0(2H,m), 4.02(2H,s), 4.2-4.4(1H,m), 7.26(1H,dd,J=2,8Hz), 7.40(1H,d,J=5Hz), 7.73(1H,d,J=5Hz), 7.7-7.8(1H,m), 7.91(lH,d,J=8Hz) Example 8 6 Production of l-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinol 1/2 succinate In 30 mL of ethyl acetate was dissolved 10.0 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- azetidinol, and 2.03 g of succinic acid and 35 mL of isopropanol were added thereto, after which the resulting mixture was refluxed to effect dissolution. After 40 mL of ethyl acetate was added dropwise ro the reaction mixture, the resulting mixture was slowly cooled and then stirred at 5°C for 30 minutes. The crystals precipitated were collected by filtration to obtain 11.1 g of l-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinol 1/2 succinate as colorless crystals. IR(KBr)cm"1: 3250,2 93 6,157 6,1361, 1109,707, 652 NMR(DMSO-d6)d values: 1. 4-1. 6 (2H,m) , 2.35(2H,s), 2.46(2H,t,J=7Hz), 2.7-2.9(2H,m), 2.91(2H,t,J=7Hz), 3.38(2H,t,J=6Hz), 3.5-3.6(2H,m), 3.59(2H,t,J=7Hz), 4.1-4.2(1H,m), 7.2 5(1H,dd,J=2,8Hz), 7.39(1H,d,J=5Hz), 7.72(1H,d,J=5Hz), 7.7-7.8(1H,m), 7.90(lH,d,J=8Hz) Example 87 Production of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinol citrate In 14.4 mL of ethanol was dissolved 10.0 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- azetidinol, followed by adding thereto 7.21 g of citric acid monohydrate, and the resulting mixture was heated at 50°C to effect dissolution. To the resulting solution were added 35 mL of ethyl acetate and 5.6 mL of ethanol at 50°C, and stirred at 25°C. The reaction mixture was heated at 40°C, after which ethyl acetate (45 mL) was added dropwise thereto and the resulting mixture was stirred at 40°C for 10 minutes and then at 10 to 20°C for 1 hour. The crystals precipitated were collected by filtration to obtain 14.9 g of l-{3-[2-(l- benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol citrate as colorless crystals. IR(KBr)cm-1: 3374, 2 94 3, 1720, 1224 , 1104 , 706 NMR(DMSO-d6)d values: 1. 6-1. 7 (2H,m) , 2.50(2H,d,J=15Hz), 2.58(2H,d,J=15Hz), 93(2H,t,J=7Hz), 2.99(2H,t,J=7Hz), 3.42(2H,t,J=6Hz), 3.5-3.6(2K,m), 3.63(2K,t,J=7Hz), 4.0-4.1(2H,m), 4.3-4.4(1H,m), 7.26(1H,d,J=8Hz), 7.40(1H,d,J=5Hz), 7.73(1H,d,J=5Hz), 7.7-7.8(1H,m), 7.91 (lH,d,J=8Hz) Example 8 8 Production of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinyl=benzoate (1) in 7 mL of methylene chloride was dissolved 0.70 g of 3-[2- (1-benzothiophen-5-yl)ethoxy]-1-(3- nydroxy-1-azetidinyl)-1-propanone, and 0.57 mL of triethylamine was added to the solution. After the resulting mixture was cooled to 5°C, 0.42 mL of benzoyl chloride was added thereto, followed by stirring at the same temperature for 1 hour. Water was added to the reaction mixture and the pH was adjusted to 1 with 2 mol/L hydrochloric acid, after which the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; toluene : ethyl acetate =5 : 1 to 2 : 1) to obtain 0.45 g of l-{3-[2-(1-benzothiophen-5- yl)ethoxy]propanoyl}-3-azetidinyl=benzoate as a colorless oil. IR (neat)cm-1: 2873, 1719, 1654 , 1451, 1274 , 1117 , 714 NMR(CDC13)8 values: 2 . 3-2 . 4 (2H,m) , 2.99(2H,t,J=7Hz), 3.72(2H,t,J=7Hz), 3.7-3.8(2H,m), 4.0-4.3(2H,m), 4.3-4.4(1H,m), 4.4-4.6(1H,m), 5.2-5.4(1H,m), 7,1-7.3(2K,m), 7.41(1H,d,J=5Hz), 7.46(2H,t,J=8Hz), 7.5-7.7(2H,m), 7 . 78(1H,d,J=8Hz), 8.0-8.1(2H,m) (2) In 1 mL of tetrahydrofuran was dissolved 0.51 g of l-{3-[2-(1-benzothiophen-5-yl)ethoxy]propanoyl}-3- azetidinyl=benzoate, and 6.8 mL of a 1 mol/L solution of a borane-tetrahydrcfuran complex in tetrahydrofuran was added dropwise thereto under ice-cooling, after which the resulting mixture was stirred at room temperature for 22 hours. To the reaction mixture was added 6.2 mL of ethaaol, and the resulting mixture was refluxed for 4 hours. After cooling, the solvent was distilled off under reduced pressure and water and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; toluene : ethyl acetate =5:1 - chloroform) to obtain 0.33 g of l-{3-[2-(l- benzothiophen-5-yl)ethoxy]propyl}-3-azetidinyl=benzoate as a colorless oil. IR (neat) cm-1: 2941, 1718 , 127 4 , 1115, 755, 713 NMR(CDC13)d values: 1. 6-1. 7 (2H,m) , 2.54(2H,t,J=7Hz), 3.00(2H,t,J=7Hz), 3.0-3.2(2H,m), 3.49(2H,t,J=6Hz), 3.67(2H,t,J=7Hz), 3.7-3.8(2H,m), 5.2-5.3(1H,m), 7.22(1H,dd,J=2,8Hz), 7.2 8(1H,d,J=5Hz), 7.4 0(1H,d,J=5Hz), 7.45(2H,t, J=8Hz) ,, 7.5-7.6(1H,m), 7 . 6-7 . 7 (1H, m) , 7.79(lH,d,J=8Hz), 8.0-8.1(2H,m) Example 8 9 Production of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinyl=benzoate maleate In 3 mL of ethyl acetate was dissolved 0.25 g of l-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- azetidinyl=benzoate, and 0.07 g of maleic acid was added thereto, after which the resulting mixture was heated to effect dissolution. The reaction mixture was cooled and the crystals precipitated were collected by filtration to obtain 0.15 g of l-{3-[2-(l- benzothiophen-5-yl)ethoxy]propyl}-3-azetidinyl=benzoate maleate. IR(KBr)cm-1: 2872,17 32,1454,1358, 1270,1119 NMR(DMSO-d6)8 values: 1. 6-1. 8 (2H, m) , 2.94(2H,t,J=7Hz), 3.1-3.3(2H,m), 3.46(2H,t,J=6Hz), 3.65(2H,t,J=7Hz), 4.1-4.3(2H,m), 4.4-4.6(2H,m), 5.3-5.5(1H,m), 6.04(2H,s), 7.26(1H,d,J=8Hz), 7.39(1H,d,J=5Hz), 7.58(2H,t,J=8Hz), 7.7-7.8(3H,m), 7.91(lH,d, J=8Hz), 8.0-8.1(2H,m) Example 90 Production of l-{3-[2-(l-benzothiophen-5- yl)ethoxy]propyi}-3-azetidinyl=pivalate (1) In 8 mL of methylene chloride was dissolved 1.00 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-l-(3- hydroxy-1-azetidinyl)-1-propanone, and 0.40 mL of pyridine was added to the solution, after which 0.48 mL of pivaloyl chloride was added thereto under ice- cooling and the resulting mixture was stirred at room temperature for 22 hours. Water was added to the reaction mixture and the resulting mixture was acidified with 6 mol/L hydrochloric acid, after which the organic layer was separated. The organic layer was washed with a 2 mol/L aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; toluene : ethyl acetate = 3 : 1 to 2 : 1) to obtain 1.20 g of l-{3-[2-(1-benzothiophen-5-yl)ethoxy] - propanoyl}-3-azetidinyl=pivalate as a colorless oil. IR (neat) cm-1: 2 972,1730,1655,14 58,1282,1151, 1112,703 NMR(CDC13)d values: 1.21(9H,s), 2 .2-2 . 4 (2H,m) , 2.99(2H,t,J=7Hz), 3.6-3.8(4H,m), 3.8-4.1(2H,m), 4.2-4.3(1H,m), 4.3-4.5(1H,m), 4.9-5.1(1H,m), 7.1- 7.3(2H,m), 7.42(1H,d,J=5Hz), 7.6-7.7(1H,m), 7.80(lH,d,J=8Hz) (2) In the same manner as in Example 88 (2), 1- {3- [2- (1-benzothiophen-5-yl)ethoxy]propyl}-3- azetidinyl=pivalate was obtained. IR (neat) cm-1: 293 8, 1727, 12 83, 1156, 1110, 756, 702 NMR(CDC13)d values: 1.20(9H,s), 1. 5-1. 7 (2H,m) , 2.50(2H,t,J=7Hz), 2.8-3.0(2H,m), 2.99(2H,t,J=7Hz), 3.47(2H,t,J=6Hz), 3.6-3.8(4H,m), 4.9-5.1(1H,m), 7.22(lH,dd,J=2,8Hz), 7.2-7.3(1H,m), 7.42(lH,d,J=6Hz), 7.6-7.7(1H,m), 7.79(1H,d,J=8Hz) Example 91 Production of l-{3-[2-(l-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinyl=pivalate maleate In the same manner as in Example 89, l-{3-[2- (1-benzothiophen-5-yl)ethoxy]propyl} -3- azetidinyl=pivalate maleate was obtained. IR(KBr)cm-1: 28 66, 174 0, 157 8, 14 52, 1356, 1165, 1120, 8 70 NMR(DMSO-d6)d values: 1.18(9H,s), 1.6-1.8(2H,m), 2.8-3.0(2H,m), 3.0-3.3(2H,m), 3.3-3.6(2H,m), 3.5- 3.7(2H,m), 3.9-4.1(2H,m), 4.3-4.5(2H,m), 5.0- 5.2(1H,m), 6.05(2H,s), 7.26(1H,d,J=8Hz), 7.40(1H,d,J=5Hz), 7.7-7.8(2H,m), 7.91(1H,d,J=8Hz) Example 92 Production of 1-{3-[2-(l-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinyl=methyl=carbonate (1) In the same manner as in Example 90 (1), 1- {3-[2-(1-benzothiophen-5-yl)ethoxy]propanoyl}-3- azetidinyl=methyl=carbonate was obtained. IR (neat) cm-1: 2943,17 51,1272,1110,7 91,705 NMR(CDC13)d values: 2 . 2-2 . 4 (2H, m) , 2.99(2H,t,J=7Hz), 3.7-3.8(2H,m), 3.71(2H,t,J=7Hz), 3.82(3H,s), 3.9-4.0(1H,m), 4.0-4.3(2H,m), 4.3-4.4(1H,m), 4.9-5.1(1H,m), 7.21(1H,dd,J=l,8Hz), 7.29(1H,d,J=5Hz)„ 7.42(1H,d,J=5Hz), 7.6-7.7(1H,m), 7.80(lH,d,J=8Hz) (2) In the sane manner as in Example 88 (2), 1- {3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- azetidinyl=methyl=carbonate was obtained. IR(neat)cm-1: 2 952,2858,174 9, 14 42, 1271, 1109, 7 92, 704 NMR(CDC13)d values: 1. 5-1. 7 (2H,m) , 2.49(2H,t,J=7Hz), 2.9-3.1(4H,m), 3.46(2H,t,J=6Hz), 3.6-3.7(4H,m), 3.78(3H,s), 4.9-5.1(1H,m) , 7.21(lH,dd, J=2, 8Hz) , 7.2 8(1H,dd,J=l,5Hz), 7.42 (1H,d,J=5Hz), 7.6-7.7(1H,m), 7 . 79 (1H,d,J=8Hz) Example 93 Production of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinyl=methyl=carbonate oxalate In 7 mL of ethyl acetate was dissolved 0.31 g of l-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- azetidinyl=methyl=carbonate, and to the solution was added a solution of 0.10 g of oxalic acid in 1 mL of ethyl acetate, after which the resulting mixture was stirred at room temperature. The crystals precipitated were collected by filtration to obtain 0.34 g of l-{3- [2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- azetidinyl=methyl=carbonate oxalate. IR(KBr) cm-1: 28 63, 2594, 17 53, 1444, 1278, 1112, 719 NMR(DMSO-d6)d values: 1. 6-1. 8 (2H,m) , 2.92(2H,t,J=7Hz), 3.0-3.1(2H,m) , 3.42(2H,t,J=6Hz), 3.62(2H,t,J=7Hz), 3.74(3H,s), 3.9-4.0(2H,m), 4.2- 4.3(2H,m), 5.0-5.2(1H,m), 7.26(1H, dd, J=l, 8Hz), 7.40(lH,dd,J=l,5Hz), 7.7-7.8(2H,m), 7.90(lH,d,J=8Hz) Example 94 Production of l-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinyl=ethyl=carbonate (1) In the same manner as in Example 90 (1), 1- {3-[2-(1-benzothiophen-5-yl)ethoxy]propanoyl}-3- azetidinyl=ethyl=carbonate was obtained. IR (neat)cm-1: 2942, 2873, 1747, 1654, 14 50, 12 60, 1111, 791,704 NMR(CDC13)d values: 1. 32 ( 3H, t, J=7Hz) , 2.2-2.4(2H,m), 2.99(2H,t,J=7Hz), 3.7-3.8(2H,m), 3.71 (2H,t,J=7Hz), 3.9-4.0(IK,m), 4.0-4.2(1H,m), 4.2-4.3(1H,m), 4.22(2H,q,J=7Hz), 4.3-4.4(1H,m), 4.9-5.1(1H,m), 7.21(lH,dd,J=2,8Hz), 7.29(1H,d,J=5Hz) , 7.42(1H,d,J=5Hz), 7.6-7.7(1H,m), 7.80(lH,d,J=8Hz) (2) In the same manner as in Example 88 (2), 1- {3- [2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- azetidinyl=ethyl=carbonate was obtained. IR (neat) cm-1: 2941,1750,12 62,1110,1049,7 92,704 NMR(CDC13)d values: 1.31(3H,t,J=7Hz) , 1.5-1.7(2H,m), 2.50(2H,t,J=7Hz), 2.9-3.1(4H,m), 3.46(2H,t,J=6Hz), 3.6-3.7(4H,m), 4.19(2H,q,J=7Hz), 4.9-5.1(1H,m), 7.21(1H,dd,J=2,8Hz), 7.28(lH,dd,J=l,5Hz) , 7.42(1H,d,J=5Hz), 7.6-7.7(1H,m), 7.79(1H,d,J=8Hz) Example 95 Production of 1-{3-[2-(l-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinyl=ethyl=carbonate oxalate In the same manner as in Example 93, l-{3-[2- (1-benzothiophen-5-yl)ethoxy]propyl}-3- azetidinyl=ethyl=carbonate oxalate was obtained. IR(KBr)cm-1: 2 932,2864,2583, 1748,789,719 NMR(DMSO-d6)d values: 1.23(3H,t,J=7Hz) , 1.6-1.8(2H,m), 2.92(2H,t,J=7Hz), 3.0-3.1(2H,m), 3.43(2H,t,J=6Hz), 3.62(2H,t,J=7Hz), 3.9-4.0(2H,m), 4.16(2H,q,J=7Hz), 4.2-4.3(2H,m), 5.0-5.2(1H,m), 7.26(lH,dd,J=2,8Hz) , 7.4 0(1H,d,J=6Hz), 7.7-7.8(2H,m), 7.90(1H,d,J=8Hz) Example 96 Production of l-{3-[2-(l-benzothiophen-5- yl)ethoxy]propyl}-3-[methoxymethoxy)azetidine (1) In 8.5 mL of methylene chloride was dissolved 1.52 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-l-(3- hydroxy-1-azetidinyl)-1-propanone, and 2.6 mL of N,N- diisopropylethyl-amine was added to the solution. After the resulting mixture was cooled to 5°C, 1.0 mL of chloromethyl methyl ether was added thereto, followed by stirring at room temperature for 17 hours. Water and ethyl acetate were added to the reaction mixture and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; toluene : ethyl acetate =3:1 to 1 : 1) to obtain 1.40 g of 3-[2-(l-benzothiophen-5- yl)ethoxy]-1-[3-(methoxymethoxy)-1-azetidinyl]-1- propanone as an oil. IR (neat) cm-1: 2941,2867,1654,1112, 1055,919,704 NMR(CDC13)d values: 2.3-2.4(2H,m) , 2.99(2H,t,J=7Hz), 3.37(3H,s), 3.7-3.8(2H,m), 3.72(2H,t,J=7Hz), 3.8-4.1(2H,m), 4.1-4.4(3H,m), 4.60(2H,s), 7.21(lH,dd,J=2, 8Hz), 7.29(1H,d,J=5Hz), 7.42(1H,d,J=5Hz), 7.6-7.7(1H,m), 7.79(1H,d,J=8Hz) (2) In the same manner as in Example 88 (2), 1- {3- [2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- (methoxymethoxy)azetidine was obtained. IR(neat) cm"1: 2 94 3, 1113, 1059, 1012, 919, 703 NMR(CDC13)8 values: 1. 5-1. 7 (2H,m) , 2.49(2H,t,J=7Hz), 2.8-2.9(2H,m), 2.99(2H,t,J=7Hz), 3.36(3H,s), 3.47(2H,t,J=6Hz), 3.5-3.7(4H,m), 4.2- 4.3(1H,m), 4.59(2H,s), 7.22(1H, dd,J=l,8Hz), 7.28(lH,dd,J=l,5Hz), 7.42(1H,d,J=5Hz), 7.6- 7.7(1H,m), 7.79(lH,d,J=8Hz) Example 97 Production of l-{3-[2-(l-benzothiophen-5- yl)ethoxy]propyl}-3-(methoxymethoxy)azetidine oxalate In the same manner as in Example 93, l-{3-[2- (1-benzothiophen-5-yl)ethoxy]propyi}-3- (methoxymethoxy) azetidine oxalate v/as obtained. IR(KBr)cm-1: 28 66, 1719, 1624, 1112, 98 9, 920, 707 NMR(DMSO-d6)d values: 1. 6-1. 8 (2H,m) , 2.93(2H,t,J=7Hz), 3.0-3.1(2H,m), 3.29(3H,s), 3.43(2H,t,J=6Hz), 3.63(2H, t, J=7Hz) , 3.7-3.9(2H,m), 4.1-4.3(2H,m), 4.3-4.5(1H,m), 4.60(2H,s), 7.26(lH,dd,J=2,3Hz), 7.4 0(1H,d,J=5Hz), 7.7-7.8(2H,m), 7.90(1H,d,J=8Hz) Example 98 Production of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-[(benzyloxy)methoxy]azetidine (1) In the same manner as in Example 96 (1), 3- [2- (1-benzothiophen-5-yl)ethoxy]-1-{3- [(benzyloxy)methoxy]-1-azetidinyl}-1-propanone was obtained. IR(neat)cm-1: 2872, 1654, 1112, 700 NMR(CDC13)5 values: 2 . 3-2 . 4 (2H,m) , 2.99(2H,t,J=7Hz), 3.7-3.8(2H,m), 3.71(2H,t,J=7Hz) , 3.8-4.3(4H,m) , 4.3-4.4(1H,m), 4.60(2H,s), 4.73(2H,s), 7.21(lH,dd,J=l,8Hz), 7.2-7.4(6H,m), 7.40(1H,d,J=5Hz), 7.6-7.7(1H,m), 7,79(1H,d,J=8Hz) (2) In the same manner as in Example 88 (2), 1- {3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- [(benzyloxy)methoxy]azetidine was obtained. IR (neat) cm-1: 2 942, 1196, 1115, 10 60, 700 NMR(CDC13)6 values: 1. 5-1. 7 (2H,m) , 2.49(2H,t,J=7Hz), 2.8-3.0(2H,m), 2.99(2H,t,J=7Hz), 3.47(2H,t,J=6Hz), 3.5-3.7(2H,m), 3.66(2H,t,J=7Hz), 4.2-4.4(1H,m), 4.60(2H,s), 4.72(2H,s), 7.2-7.4(6H,m), 7.22(1H,dd,J=l,8Hz), 7.41(lH,d,J=6Hz), 7.6-7.7(1H,m), 7.79(1H,d,J=8Hz) Example 99 Production of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-(trityloxy)azetidine (1) In 6.8 mL of toluene was dissolved 0.85 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-1-(3-hydroxy-l- azetidinyl)-1-propanone, and to the solution were added 0.34 mL of pyridine, 0.02 g of 4-(dimethylamino)- pyridine and 0.93 g of trityl chloride, after which the resulting mixture was stirred at 50°C for 3 hours. To the mixture was added 0.85 mL of N,N-dimethylformamide, followed by stirring at 50°C for another 24 hours. Water and ethyl acetate were added to the reaction mixture and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; toluene : ethyl acetate = 5 : 1 to 3 : 1) to obtain 1.15 g of 3- [2-(1-benzothiophen-5-yl)ethoxy]-1-[3-(trityloxy)-1- azetidinyl]-1-propanone as an oil. IR (neat) cm-1: 2940,2870, 1654, 1116, 762, 707 NMR(CDC13)d values: 2.18(2H,t,J=6Hz), 2.94(2H,t,J=7Hz), 3.5-3.8(8H,m), 4.2-4.4(1H,m), 7.1-7.5(18H,m), 7.6-7.7(1H,m), 7.73(1H,d,J=8Hz) (2) In the same manner as in Example 88 (2), 1- {3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- (trityloxy)azetidine was obtained. IR(neat)cm-1: 2 943,14 92,1449,1104,706 NMR(CDC13)d values: 1. 4-1. 6 (2H,m) , 2 . 3-2 . 4 (2H,m) , 2.5-2.7(2H,m), 2.95(2H,t,J=7Hz), 3.0-3.1(2H,m), 3.37(2H,t,J=7Hz), 3.61(2H,t,J=7Hz), 4.1-4.3(1H,m), 7.1-7.3 (HH,m) , 7 .3-7.5 (7H,m) , 7 . 6-7 . 7 (1H,m) , 7.77(lH,d,J=8Hz) Example 100 Production of 1-{3-[2-(l-benzothiophen-5- yl)ethoxy]propyl}-3-(trityloxy)azetidine oxalate In the same; manner as in Example 93, l-{3-[2- (1-benzothiophen-5-yl)ethoxy]propyl}-3-(trityloxy)- azetidine oxalate was obtained. IR(KBr)cm-1: 2866, 1491, 1451, 1155, 1110, 704 NMR(DMSO-d6)d values: 1. 4-1. 6 (2H, m) , 2 . 8-3 . 0 (4H,m) , 3.34(2H,t,J=6Hz), 3.4-3.6(6H,m), 4.2-4.4(1H,m), 7.23(lH,d,J=8Hz), 7.3-7.5(16H,m), 7.6-7.8(2H,m), 7.88(lH,d,J=8Hz) Example 101 Production of l-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-[(triethylsilyl)oxy]azetidine (1) In the same manner as in Example 99 (1), 3- [2- (1-benzothiophen-5-yl)ethoxy]-1-{3- [(triethylsilyl)oxy]-1-azetidinyl}-1-propanone was obtained. IR (neat) cm-1: 2 954 , 2875, 1654 , 1458, 1113,1004 , 750 NMR(CDC13)d values: 0.57 (6H,q,J=8Hz) , 0.94(9H,t,J=8Hz), 2.2-2.4(2H,m), 2.99(2H,t,J=7Hz), 3.6-3.9(5H,m), 3.9-4.0(1H,m), 4.1-4.3(2H,m), 4.4- 4.6(1H,m), 7.21(lH,dd,J=2,8Hz), 7.29(1H,d,J=5Hz), 7.42(1H,d,J=5Hz), 7.6-7.7(1H,m), 7.79(1H,d,J=8Hz) (2) In the same manner as in Example 88 (2), 1- {3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- [(triethylsilyl)oxy]azetidine was obtained. IR(neat) cm-1: 2 951, 1380, 12 01, 1114, 8 65, 747, 701 NMR(CDC13)d values: 0.57(6H,q,J=8Hz), 0.94(9H,t,J=8Hz), 1.5-1.7(2H,m), 2.48(2H,t,J=7Hz) , 2.7-2.8(2H,m), 2.99(2H,t,J=7Hz), 3.46(2H,t,J=6Hz), 3.5-3.7(2H,m), 3.66(2H,t,J=7Hz), 4.3-4.5(1H,m), 7.21(lH,dd,J=2,8Hz), 7.28(1H,dd,J=l,8), 7.41(lH,d,J=6Hz), 7.6-7.7(1H,m), 7.79(1H,d,J=8Hz) Example 102 Production of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-(benzyloxy)azetidine (1) In 8 mL of N,N-dimethylformamide was dissolved 1.00 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]- 1-(3-hydroxy-1-azetidinyl)-1-propanone, and 1.90 g of silver(I) oxide and 0.97 mL of benzyl bromide were added to the solution, after which the resulting mixture was stirred at room temperature for 31 hours. The insoluble materials were filtered off and water and ethyl acetate were added to the residue, after which the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; toluene : ethyl acetate =3:1 to 1 : 4) to obtain 1.00 g of 3-[2-(1-benzothiophen-5- yl)ethoxy]-1-[3-(benzyloxy)-1-azetidinyl]-1-propanone as an oil. IR(neat) cm-1: 28 69, 1654, 1112,754,700 NMR(CDC13)d values: 2 . 2-2 . 4 (2H,m) , 2.98(2H,t,J=7Hz), 3.6-3.8(4H,m), 3.8-3.9(1H,m), 3.9-4.0(1H,m), 4.0-4.1(1H,m), 4.1-4.3(2H,m), 4.4 0(lH,d,J=12Hz), 4.4 4(1H,d,J=12Hz), 7.20(lH,dd,J=l,8Hz), 7.2-7.5(7H,m), 7.6-7.7(1H,m), 7.78(lH,d,J=8Hz) (2) In the same manner as in Example 1 (2), 1-{3- [2- (1-benzothiophen-5-yl)ethoxy]propyl}-3- (benzyloxy)azetidine was obtained. IR(neat) cm-1: 2 93 9, 1355, 1194, 1110, 754, 700 NMR(CDC13)5 values: 1. 5-1. 7 (2H,m) , 2.48(2H,t,J=7Hz), 2.8-2.9(2H,m), 2.98 (2H,t,J=7Hz), 3.46(2H,t,J=6Hz), 3.5-3.7(2H,m), 3.65 (2H,t,J=7Hz) , 4.1-4.3(1H,m), 4.42(2H,s), 7.21(1H,dd,J=l,8Hz), 7.2-7.4(6H,m), 7.41(1H,d,J=5Hz), 7.6-7.7(1H,m), 7.79(lH,d,J=8Hz) Example 103 Production of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-(benzyloxy)azetidine oxalate In the same manner as in Example 93, l-{3-[2- (1-benzothiophen-5-yl)ethoxy]propyl}-3- (benzyloxy)azetidine oxalate was obtained. IR(KBr)cm-1: 2855,1111,700 NMR(DMSO-d6)d values: 1. 6-1. 8 (2H,m) , 2.92(2H,t,J=7Hz) , 3 . 06(2H,t,J=7Hz) , 3.42(2H,t,J=6Hz), 3.62(2H,t,J=7Hz), 3.7-3.9(2H,m), 4.1-4.2(2H,m), 4.3-4.4(1H,m), 4.46(2H,s), 7.26(lH,d,J=8Hz), 7.3-7.5(6H,m), 7.7-7.8(2H,m), 7.90(lH,d,J=8Hz) Example 104 Production of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-(trityloxy)azetidine In a mixture of 0.4 mL of toluene and 7 mL of a 50% (W/V) aqueous sodium hydroxide solution was suspended 0.54 g of 2-(1-benzothiophen-5-yl)-1-ethanol, followed by adding thereto 1.45 g of l-(3- chloropropyl)-3-(trityloxy)azetidine oxalate and 0.03 g of tetra-n-butylammonium bromide, and the resulting mixture was refluxed for 7 hours. After the reaction mixture was cooled, water and toluene were added thereto and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform : methanol =75 : 1) to obtain 0.59 g of 1- {3- [2- (1-benzothiophen-5-yl)ethoxy]propyl}-3- (tzityloxy)azetidine as a light-yellow oil. Example 105 Production of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-(trityloxy)azetidine maleate In the same manner as in Example 89, l-{3-[2 (1-benzothiophen-5-yl)ethoxy]propyl}-3-(trityloxy)- azetidine maleate was obtained. IR(KBr)cm"1: 3059,1346,1119,871,706 NMR(CDC13) 6 values: 1. 6-1. 8 (2H,m) , 2.8-3.0(4H,m), 3.1-3.3(2H,m), 3.40(2H,t,J=6Hz), 3.63(2H,t,J=7Hz) 3.8-4.0(2H,m), 4.4-4.6(1H,m), 6.23(2H,s), 7.18(lH,d,J=8Hz), 7.2-7.5(17H,m), 7.64(lH,s), 7.79(lH,d,J=8Hz) Example 10 6 Production of 1-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-(tetrahydro-2H-pyran-2- yloxy)azetidine In the same manner as in Example 104, l-{3- [2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-(tetrahydro- 2H-pyran-2-yloxy)azetidine was obtained from 2-(l- benzothiophen-5-yl)-1-ethanol and 1-(3-chloropropyl)-3- (tetrahydro-2H-pyran-2-yloxy)azetidine. IR (neat)cm-1: 2943,2853,1201,1115,1037,975,7 03 NMR(CDC13)d values: 1. 4-1. 9 (8H,m) , 2.49(2H,t,J=7Hz), 2.8-3.0(2H,m), 2.98(2H,t,J=7Hz), 3.4-3.6(1H,m), 3.46(2H,t,J=6Hz), 3.5-3.7(4H,m), 3.8-3.9(1H,m), 4.2-4.4(1H,m), 4.5-4.6(1H,m), 7.21(lH,dd,J=2,8Hz), 7.28(1H,dd,J=l,6Hz), 7.41(lH,d,J=6Hz), 7.6-7.7(1H,m), 7.78(1H,d,J=8Hz) Example 107 Production of l-{3-[2-(l-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinyl=pivalate In 3.75 mL of dimethyl sulfoxide was dissolved 0.75 g of 5-[2-(3-bromopropoxy)ethyl]-1- benzothiophene, and 0.63 g of sodium hydrogencarbonate and 0.73 g of 3-azetidinyl=pivalate hydrochloride were added to the solution, after which the resulting mixture was stirred at 70°C for 4 hours. After the reaction mixture was cooled, 20 mL of water and 15 mL of ethyl acetate were added thereto and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; toluene : ethyl acetate =1:1 to 1 : 5) to obtain 0.78 g of l-{3-[2-(1-benzothiophen- 5-yl)ethoxy]propyl}-3-azetidinyl=pivalate as a light- yellow oil. Example 108 Production of l-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-(trityloxy)azetidine In 15 mL of water was suspended 2.69 g of 3- (trityloxy)azetidine hydrochloride, and 20 mL of ethyl acetate was added thereto, after which the pH was adjusted to 9 with a 2 mol/1 aqueous sodium hydroxide solution and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The resulting residue was dissolved in 10 mL of dimethyl sulfoxide, and to the resulting solution were added 0.80 g of sodium hydrogencarbonate and 2.00 g of 3-[2-(l- benzothiophen-5-yl)ethoxy]propyl=methanesulfonate, followed by stirring at 50°C for 3 hours. To the reaction mixture were added 20 mL of water and 20 mL of ethyl acetate, and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a cclumn chromatography (eluent; toluene : ethyl acetate = 3 : 1 to 1 : 3) to obtain 2.89 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}- 3-(trityloxy)azetidine as a light-yellow oil. Example 10 9 Production of l-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinyl=acetate In 15 mL of tetrahydrofuran was dissolved 1.50 g of l-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}- 3-azetidinol, and 0.73 mL of acetic anhydride and 0.06 mL of a boron trifluoride-diethyl ether complex were added thereto under ice-cooling, after which the resulting mixture was stirred at room temperature for 1 hour. Ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform : methanol = 100 : 1 to 50 : 1) to obtain 1.63 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}- 3-azetidinyl=acetate as a light-yellow oil. IR (neat) cm-1: 2 941, 2859, 1741, 1375, 1239, 1109, 756, 703 NMR(CDC13)d values: 1. 5-1. 7 (2H, m) , 2.06(3H,s), 2.49(2H,t,J=7Hz), 2.9-3.1(4H,m), 3.46(2H,t,J=6Hz), 3.5-3.7(2H,m), 3.66(2H,t,J=7Hz), 4.9-5.1(1H,m), 7.21(lH,dd,J=l,8Hz), 7.28(1H,d,J=5Hz), 7.42(1H,d,J=5Hz), 7.6-7.7(1H,m), 7.79(1H,d,J=8Hz) Example 110 Production of 1-{3-[2-(l-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinyl=acetate oxalate In the same manner as in Example 93, l-{3-[2- (1-benzothiophen-5-yl)ethoxy]propyl}-3- azetidinyl=acetate oxalate was obtained. IR(KBr)cm-1: 28 62, 1745, 1253, 1108, 711 NMR(DMSO-d6)d values: 1. 6-1. 8 (2H,m) , 2.06(3H,s), 2.92(2H,t,J=7Hz), 3.05(2H,t,J=7Hz), 3.43(2H,t,J=6Hz), 3.62(2H,t,J=7Hz), 3.8-4.0(2H,m), 4.2-4.3(2H,m), 5.0-5.2(1H,m), 7.26(1H,dd,J=l,8Hz), 7.40(lH,d,J=6Hz), 7.7-7.8(2H,m), 7.91(1H,d,J=8Hz) Example 111 Production of l-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinol maleate In 2.6 mL of isopropanol was suspended 1.30 g of l-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- azetidinyl=pivalate maleate, and 2.1 mL of a 5 mol/L aqueous sodium hydroxide solution was added thereto at 20°C, after which the resulting mixture was stirred at room temperature for 6 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated and then washed successively with water and a saturated aqueous sodium chloride solution. To the organic layer was added 0.29 g of maleic acid, and the resulting mixture was heated to effect dissolution, after which the solvent was distilled off under reduced pressure. To the resulting residue were added 5.2 mL of ethyl acetate and 1.3 mL of isopropanol, and the resulting mixture was stirred at room temperature for 30 minutes and then under ice- cooling for 1 hour. The crystals precipitated were collected by filtration to obtain 0.76 g of l-{3-[2-(l- benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol maleate as colorless crystals. Example 112 Production of l-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinol maleate In 10 mL of isopropanol was suspended 2.00 g of l-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- azetidinyl=benzoate maleate, and 7.82 mL of a 2 mol/L aqueous sodium hydroxide solution was added thereto, after which the resulting mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. To the residue was added 0.43 g of maleic acid, and crystallization from ethyl acetate-isopropanol (4 : 1, 10 mL) was carried out to obtain 1.29 g of l-{3-[2-(l- benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol maleate as colorless crystals. Example 113 Production of l-{3-[2-(1-benzothiophen-5- yl)ethoxy]propyl}-3-azetidinol maleate In 4 mL of chloroform was dissolved 0.83 g of l-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3- (trityloxy)azetidine, and 1.66 mL of a 4.75 mol/L dried hydrogen chloride-ethanol solution was added thereto, after which the resulting mixture was stirred at room temperature for 6 hours. Water and chloroform were added to the reaction mixture and the aqueous layer was separated. Ethyl acetate was added to the aqueous layer and the pH was adjusted to 10 with a 5 mol/L aqueous sodium hydroxide solution, after which the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. To the residue was added 0.11 g of maleic acid, and crystallization from ethyl acetate- isopropanol (4 : 1, 5 mL) was carried out to obtain 0.33 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}- 3-azetidinol maleate as colorless crystals. Reference Example 1 Production of 3-[2-(l-benzothiophen-4- yl)ethoxy]-1-propanol In a mixture of 2.2 mL of toluene and 8.8 mL of a 50% (W/V) aqueous sodium hydroxide solution was suspended 2.2 g of 2-(l-benzothiophen-4-yl)-1-ethanol, followed by adding thereto 4.41 g of 2-(3- chloropropoxy)tetrahydro-2H-pyran and 0.42 g of tetra- n-butylammonium hydrogensulfate, and the resulting mixture was heated under reflux for 2 hours. After the reaction mixture was cooled, water and toluene were added thereto and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 6.50 g of a mixture of 2-{3-[2-(1-benzothiophen-4- yl)ethoxy]propoxy}tetrahydro-2H-pyran and 2-(3- chloropropoxy)tetrahydro-2H-pyran as a light-brown oil. In 8.0 mL of methanol was dissolved 6.50 g of this mixture, followed by adding thereto 8.0 mL of water and 0.70 g of p-toluenesulfonic acid monohydrate, and the resulting mixture was stirred at room temperature for 12 hours. Ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; toluene : ethyl acetate =4:1 to 3 : 1) to obtain 1.42 g of 3-[2-(1-benzothiophen-4- yl)ethoxy]-1-propanol as an oil. IR (neat) cm-1: 3394,2 943,28 67,1413,1110,7 61 NMR(CDC13)d values: 1. 81 (2H, qn, J=6Hz) , 2.1(lH,brs), 3.2 6(2H,t,J=7Hz), 3.63(2H,t,J=6Hz), 3.69(2H,t,J=7Hz), 3.76(2H,t,J=6Hz), 7.0-7.4(2H,m), 7.45(2H,s), 7.77(lH,dd,J=2,7Hz) Reference Example 2 The following compounds were obtained in the same manner as in Reference Example 1. 3-[2-(l-Benzothiophen-2-yl)ethoxy]-1-propanol NMR(CDC13)d values: 1. 68 (1H, brs) , 1.86(2H,qn,J=6Hz), 3.17(2H,t,J=6Hz), 3.67(2H,t,J=6Hz), 3.76(4H,t,J=6Hz), 7.07(lH,s), 7.2-7.4 (2H,m) , 7 .. 67 (1H, d, J=8Hz) , 7.77(1H,d,J=8Hz) • 3-[2-(1-Benzothiophen-3-yl)ethoxy]-1-propanol IR(neat) cm-1: 3395, 2942, 28 67, 1427, 1113, 762, 732 NMR(CDC13)d values: 1. 83 (2H, qn, J=6Hz) , 2.27(lH,t,J=6Hz), 3.13(2H,t,J=7Hz), 3.65 (2H,t, J=6Hz.) , 3.74 (2H,t, J=6Hz) , 3.78(2H,t,J=7Hz), 7.18(lH,s), 7.34(1H,dt,J=l,7Hz), 7.39(lH,dt,J=l,7Hz), 7.76(lH,dd,J=l,7Hz), 7.86(lH,dd,J=l,7Hz) • 3-[2-(l-Benzothiopben-5-yl)ethoxy]-1-propanol IR (neat) cm-1: 3398, 2 93 9, 2866, 1438, 1110, 704 NMR(CDC13)d values: 1. 82 (2H, qn, J=6Hz) , 2.29(1H,t,J=6Hz), 3.00(2H,t,J=7Hz), 3.64(2H,t,J=6Hz), 3.71(2H,t,J=7Hz), 3.7 3(2H,q,J=6Hz), 7.22(1H,dd,J=l,8Hz), 7.2 8(1H,d,J=5Hz), 7.42(1H,d,J=5Hz), 7.66(1H,d,J=1Hz), 7.80(lH,d,J=8Hz) • 3-[2-(l-Benzothiophen-6-yl)ethoxy]-1-propanol IR (neat) cm-1: 3389,2942,28 65,1397,1111,819,693 NMR(CDC13)d values: 1. 82(2H,qn,J=6Hz), 2.24(1H,t,J=6Hz), 3.00(2H,t, J=7Hz), 3.64(2H,t,J=6Hz), 3.71(2H,t,J=7Hz), 3.7 4(2H,q,J=6Hz), 7.21(lH,d,J=8Hz), 7.28(1H,d,J=5Hz), 7.38(1H,d,J=5Hz), 7.70(lH,s), 7.75(1H,d,J=8Hz) • 3-[2-(l-Benzothiophen-7-yl)ethoxy]-1-propanol Reference Example 3 Production of 4-[2-(3-chloropropoxy)ethyl]-1- benzothiophene In 7.0 mL of methylene chloride was dissolved 1.40 g of 3-[2-(l-benzothiophen-4-yl)ethoxy]-l- propanol, followed by adding thereto 1.10 mL of thionyl chloride and 0.05 mL of N,N-dimethylformamide, and the resulting mixture was heated under reflux for 5 hours. Then, the solvent was distilled off under reduced pressure. The residue was purified by a column chromatography (eluent; hexane : ethyl acetate = 20 : 1) to obtain 1.43 g of 4-[2-(3-chloropropoxy)ethyl]-1- benzothiophene as a yellow oil. IR (neat) cm-1: 28 67, 1413, 1113, 7 60 NMR(CDC13)5 values: 1.99 (2H,qn, J=6Hz) , 3.23(2H,t,J=7Hz), 3.58(2H,t,J=6Hz), 3.59(2H,t,J=6Hz), 3.75(2H,t,J=7Hz), 7.18(lH,dd,J=2,7Hz), 7.29(1H,t,J=7Hz), 7.1-7.3(2H,m), 7.45(2H,s), 7.76(1H,dd,J=2,8Hz) Reference Example 4 The following compounds were obtained in the same manner as in Reference Example 3. • 2-[2-(3-Chloropropoxy)ethyl]-1-benzothiophene NMR(CDC13)5 values: 2 . 04 (2H, qn, J=6Hz) , 3.16(2H,t,J=7Hz), 3.62(2H,t,J=6Hz), 3.66(2H,t,J=6Hz), 3.75(2H,t,J=7Hz), 7.06(lH,s), 7.25(lH,dt,J=l,7Hz), 7.30(1H,dt,J=l,7Hz), 7.67(lH,dd,J=l,7Hz), 7.77(1H,dd,J=l,7Hz) • 3-[2-(3-Chloropropoxy)ethyl]-1-benzothiophene IR(neat) cm-1: 28 65,1427,1115,7 62,732 NMR(CDC13)d values: 2 . 02 (2H, qn, J=6Hz) , 3.13(2H,t,J=7Hz), 3.61(2H,t,J=6Hz), 3.62(2H,t,J=6Hz), 3.79(2H,t,J=7Hz), 7.19(lH,s), 7.34(1H,dt,J=1,7Hz), 7.39(1H,dt,J=1,7Hz), 7.7 7(1H,dd,J=1,7Hz), 7.86(1H,dd,J=1,7Hz) • 5-[2-(3-Chloropropoxy)ethyl]-1-benzothiophene IR(neat) cm"1: 28 64, 1438, 1113, 755, 701 NMR(CDC13)8 values: 2.01(2H,qn,J=6Hz), 3.00(2H,t,J=7Hz), 3.59(2H,t,J=6Hz), 3.61(2H,t,J=6Hz), 3.7 0(2H,t,J=7Hz), 7.22(lH,dd,J=l,8Hz), 7.28(1H,d,J=5Hz), 7.42(1H,d,J=5Hz), 7.68(1H,d,J=1Hz), 7.79(lH,d,J=8Hz) • 6- [2-(3-Chloropropoxy)ethyl]-1-benzothiophene IR(neat) cm-1: 28 64, 1113, 820, 7 61, 695, 652 NMR(CDC13)d values: 2 . 00 (2H, qn, J=6Hz) , 3.00(2H,t,J=7Hz), 3.58(2H,t,J=6Hz), 3.61(2H,t,J=6Hz), 3.70(2H,t,J=7Hz), 7.21(1H,d,J=8Hz), 7.28(1H,d,J=5Hz), 7.37(1H,d,J=5Hz), 7.72(1H,s), 7.73(1H,d,J=8Hz) • 7-[2-(3-Chloropropoxy)ethyl]-1-benzothiophene IR(neat)cm~1: 28 66,14 60,1395,1115,7 95,701 NMR(CDC13)d values: 2.00 (2H, qn, J=6Hz) , 3.17(2H,t,J=7Hz), 3.60(4H,t,J=6Hz), 3.82 (2H,t,J=7Hz), 7.20(1H,d,J=8Hz), 7.33 (1H,t,J=8Hz), 7.35(1H,d,J=5Hz), 7.42(1H,d, J=5Hz), 7.7 0(1H,d,J=8Hz) Reference Example 5 Production of 3-[2-(l-benzothiophen-5- yl)ethoxy]propyl=methanesulfonate In 16.8 mL of methylene chloride was dissolved 2.03 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]- 1-propanol, and to the solution were added 2.43 mL of methanesulfonyl chloride, 4.37 mL of triethylamine and 0.10 g of 4-(dimethylamino)pyridine under ice-cooling, after which the resulting mixture was stirred at the same temperature for 30 minutes and then at room temperature for 12 hours. Methylene chloride and water were added to the reaction mixture and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; hexane : ethyl acetate =5:1) to obtain 1.40 g of 3-[2-(1-benzothiophen-5- yl)ethoxy]propyl=methanesulfonate. IR(neat)cm-1: 2937,2866, 1352, 1174, 1114, 943, 705, 529 NMR(CDC13) d values: 1.97(2H,qn,J=6Hz), 2.81(3H,s), 2.98(2H,t,J=7Hz), 3.54(2H,t,J=6Hz), 3.7 0(2H,t,J=6Hz), 4.2 6(2H,t,J=7Hz), 7.20(1H,dd,J=1,8Hz), 7.28(1H,d,J=5Hz), 7.42(1H,d,J=5Hz), 7.65(1H,d,J=lHz), 7.79(1H,d,J=8Hz) Reference Example 6 Production of 2-[2-(6-methoxy-l-benzofuran-5- yl)ethoxy]acetic acid and 2-[2-(5-methoxy-l-benzofuran- 6-yl)ethoxy]acetic acid (1) Production of 2,4-dimethoxyphenethyl=acetate In 150 mL of methylene chloride was dissolved 15.0 g of 2-(2,4-dimethoxyphenyl)-1-ethanol, and to the solution were added 9.32 mL of acetic anhydride, 13.8 mL of triethylamine and 0.10 g of 4-(dimethylamino)- pyridine under ice-cooling, after which the resulting mixture was stirred at the same temperature for 30 minutes and then at rcom temperature for 12 hours. Water was added to the reaction mixture and the pH was adjusted to 1.5 with 6 mol/L hydrochloric acid, after which the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; hexane : ethyl acetate =5:1) to obtain 17.2 g of 2,4- dimethoxyphenethyl=acetate as a colorless oil. IR(neat) cm-1: 2 958, 1736, 1509, 1243, 1035, 834 NMR(CDC13)d values: 2.03(3H,s), 2.87(2H,t,J=7Hz), 3.80(6H,s), 4.22(2H,t,J=7Hz), 6.41(1H,d,J=9Hz), 6.46(lH,s), 7.05 (lH,d,J=9Hz) In the same manner as above, 2,5-dimethoxy- phenethyl=acetate was obtained. IR (neat) cm-1: 2952,1736,1502, 122 6,104 8,802,710 NMR(CDC13)d values: 2.01(3H,s), 2 . 90 (2H, t, J=7Hz) , 3.74(3H,s), 3.76(3H,s), 4.25(2H,t,J=7Hz), 6.74 (3H,s) (2) Production of 5-acetyl-2,4- dimethoxyphenethyl=acetate In 170 mL of methylene chloride was dissolved 17.0 g of 2,4-dimethoxyphenethyl=acetate, and 5.93 mL of acetyl chloride and 12.1 g of aluminum chloride were added to the solution under ice-cooling, after which the resulting mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into ice water and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. Diisopropyl ether was added to the residue and the crystals precipitated were collected by filtration, washed with diisopropyl ether and then dried to obtain 13.9 g of 5-acetyl-2,4-dimethoxy-phenethyl=acetate as yellow crystals. NMR(CDC13)d values: 2.01(3H,s), 2.57(3H,s), 2.88(2H,t,J=7Hz), 3.90(3H,s), 3.93(3H,s), 4.21(2H,t,J=7Hz), 6.42(lH,s), 7.68(lH,s) In the same manner as above, 4-acetyl-2,5- dimethoxyphenethyl=acetate was obtained. (3) Production of 5-acetyl-4-hydroxy-2-methoxy- phenethyl=acetate In 70 mL of acetonitrile was dissolved 13.9 g of 5-acetyl-2,4-dimethoxyphenethyl=acetate, and 13.9 g of aluminum chloride and 7.82 g of sodium iodide were added to the solution under ice-cooling, after which the resulting mixture was stirred at 50°C for 3 hours. The reaction mixture was poured into ice water and to the resulting mixture was added ethyl acetate, after which the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 13.3 g of 5- acetyl-4-hydroxy-2-methoxyphenethyl=acetate as a yellow oil. In the same manner as above, 4-acetyl-5- hydroxy-2-methoxyphenethyl=acetate was obtained. (4) Production of 1-[2-hydroxy-5-(2-hydroxyethyl)-4- methoxyphenyl]-1-ethanone In 30 mL of ethanol was dissolved 13.3 g of the aforesaid 5-acetyl-4-hydroxy-2- methoxyphenethyl=acetate, and to the solution was addec 21 mL of a 5 mol/L aqueous sodium hydroxide solution, after which the resulting mixture was stirred at room temperature for 17 hours. Water and ethyl acetate were added to the reaction mixture and the pH was adjusted to 1 with 6 mol/L hydrochloric acid, after which the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. Diisopropyl ether was added to the residue, and the crystals precipitated were collected by filtration, washed with diisopropyl ether and then dried to obtain 8.30 g of 1-[2-hydroxy-5-(2- hydroxyethyl)-4-methoxyphenyl]-1-ethanone as yellow crystals. In the same manner as above, 1-[2-hydroxy-4- (2-hydroxyethyl)-5-methoxyphenyl]-1-ethanone was obtained. NMR(CDC13)d values: 1. 6-1. 8 (1H,m) , 2.61(3H,s), 2.90(2H,t,J=7Hz), 3.8-4.1(2H,m), 3.84(3H,s), 6.84(lH,s), 7.06(lH,s), 11.98(lH,s) (5) Production of 2-bromo-l-[2-hydroxy-5-(2- hydroxyethyl)-4-methoxyphenyl]-1-ethanone In 100 mL of methylene chloride was dissolved 10.0 g of l-[2-hydroxy-5-(2-hydroxyethyl)-4- methoxyphenyl]-1-ethanone, and 2.94 mL of bromine was added dropwise to the solution, after which the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 16.4 g of 2-bromo-l-[2- hydroxy-5-(2-hydroxyethyl)-4-methoxyphenyl]-1-ethanone as a yellow oil. In the same manner as above, 2-bromo-l-[2- hydroxy-4-(2-hydroxyethyl)-5-methoxyphenyl]-1-ethanone was obtained. IR (neat) cm-1: 337 6,2 941,164 4,14 96,124 3,1034,757, 690 NMR(CDC13)d values: 1. 5-1. 8 (1H, m) , 2.91(2H,t, J=7Hz.) , 3.8-4.1(2H,m), 3.85(3H,s) 4.40(2H,s), 6.89(lH,s), 7.07(lH,s) 11.51(lH,s) (6) Production of 2-(6-methoxy-l-benzofuran-5-yl)-1- ethanol In 70 mL of methanol was dissolved 16.4 g of the aforesaid 2-bromo-l-[2-hydroxy-5-(2-hydroxyethyl)- 4-methoxyphenyl]-1-ethanone, and 17.3 g of sodium acetate was added to "he solution, after which the resulting mixture was heated under reflux for 5 minutes. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was dissolved in 150 mL of methanol and to the resulting solution was added 6.30 g of sodium borohydride in small portions, after which the resulting mixture was stirred at room temperature for 1 hour. Then, the resulting solution was adjusted to pH 1 with 6 mol/L hydrochloric acid and stirred at room temperature for another 1 hour. The reaction mixture was concentrated under reduced pressure and water and ethyl acetate were added thereto, after which the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; hexane : ethyl acetate = 4 : 1) to obtain 1.48 g of 2-(6-methoxy-l-benzofuran-5- yl)-1-ethanol as light-yellow crystals. NMR(CDCl3)d values: 1. 79 (1H, brs) , 2 . 97 (2H, t, J=7Hz) , 3.84(2H,t,J=7Hz), 3.86(3H,s), 6.66(1H,d,J=3Hz), 7.03(lH,s), 7.35(1H,s), 7.51(1H,d,J=3Hz) In the same manner as above, 2-(5-methoxy-l- benzofuran-6-yl)-1-ethanol was obtained. NMR(CDC13)d values: 2.04(1H,brs), 2 . 98 (2H,t,J=6Hz), 3.86(2H,t,J=6Hz), 3.86(3H,s), 6.68(1H,d,J=2Hz), 7.02(lH,s), 7.31;1H,s), 7.55(1H,d,J=2Hz) (7) Production of 2-[2-(6-methoxy-l-benzofuran-5- yl)ethoxy]acetic acid In a mixture of 7.0 mL of tert-butanol and 1.75 mL of N,N-dimethylformamide was dissolved 1.75 g of 2-(6-methoxy-l-benzofuran-5-yl)-1-ethanol, and 2.2 g of 1-chloroacetylpiperidine and 1.54 g of potassium tert-butoxide were added to the solution under ice- cooling, after which the resulting mixture was stirred at the same temperature for 30 minutes and then at the room temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture and the pH was adjusted to 1 with 6 mol/L hydrochloric acid, after which the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was dissolved in 10.5 mL of a 90% aqueous ethanol solution, followed by adding thereto 0.91 g of sodium hydroxide, and the resulting mixture was heated under reflux for 3 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the pH was adjusted to 1 with 6 mol/L hydrochloric acid, after which the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. Diisopropyl ether was added to the residue, and the crystals precipitated were collected by filtration, washed with diisopropyl ether and then dried to obtain 1.42 g of 2-[2-(6- methoxy-l-benzofuran-5-yl)ethoxy]acetic acid as yellow crystals. IR (neat) cm-1: 2 939,1734,142 6,1252,1200,1148,1094, 1022,771 NMR(DMSO-d6)d values: 2.88(2H,t,J=7Hz), 3.64(2H,t,J=7Hz), 3.82(3H,s), 4.01(2H,s), 6.81(1H,d,J=2Hz), 7.22(lH,s), 7.44(lH,s), 7.82(1H,d,J=2Hz) In the same manner as above, 2-[2-(5-methoxy- 1-benzofuran-6-yl)ethoxy]acetic acid was obtained. IR(neat) cm-1: 2 942,1731,14 66,14 31,124 9,1132,1013, 955,832,760 NMR(DMSO-d6)d values: 2.90 (2H,t,J=7Hz), 3.66(2H,t,J=7Hz), 3.82(3H,s), 4.02(2H,s), 6.86(1H,d,J=2Hz), 7.15(lH,s), 7.46(lH,s), 7.88(1H,d,J=2Hz) Reference Example 7 Production of 3-[2-(1-benzothiophen-5- yl)ethoxy]propionic acid (1) To 4.60 g of 2-(1-benzothiophen-5-yl)-1- ethanol were added 29 mg of potassium hydroxide, 83 mg of tetra-n-butylammonium bromide and 5.67 mL of tert- butyl acrylate, and the resulting mixture was stirred at 45 to 50°C for 2 hours. After the reaction mixture was cooled, water and toluene were added thereto and the pH was adjusted to 1 with 6 mol/L hydrochloric acid, and the organic: layer was separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; hexane : ethyl acetate = 5 : 1) to obtain 7.70 g of tert-butyl 3-[2-(1-benzothiophen-5-yl)ethoxy]propionate as a colorless oil. IR (neat) cm-1: 2978,2867,1729,1368,1159, 1112,702 NMR(CDC13)d values: 1.43(9H,s), 2 . 49 (2H, t, J=6Hz) , 2.99(2H,t,J=7Hz), 3.70(2H,t,J=6Hz), 3.70(2H,t,J=7Hz), 7.21(1H,dd,J=2,8Hz), 7.27 (lH,dd,J=l,5Hz), 7.41(1H,d,J=5Hz), 7.6-7.7(1H,m) , 7 .. 78 (1H, d, J=8Hz) (2) In 22.8 mL of toluene was dissolved 7.60 g of tert-butyl 3- [2- (1-benzothiophen-5-yl) ethoxy]propionate, and 94 mg of p-toluenesulfonic acid monohydrate was added thereto, after which the resulting mixture was refluxed for 6 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was crystallized from a toluene-cyclohexane mixture (1:4, 23 mL) to obtain 5.30 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]propionic acid as light-red crystals., IR(KBr)cm-1: 28 60, 1719, 1273, 1128, 706 NMR(CDC13)d values: 2 . 63 (2H, t, J=6Hz) , 3.0 0(2H,t,J=7Hz), 3.7 3(2H,t,J=7Hz), 3.7 4(2H,t,J=6Hz), 7.20(1H,dd,J=l,8Hz), 7.28(lH,dd,J=l,5Hz) , 7.41(1H,d,J=5Hz), 7. 6-7.7 (1H,m) , 7 .. 79 (1H, d, J=8Hz) Reference Example 8 Production of 3-[2-(l-benzothiophen-5- yl)ethoxy]propionic acid (1) To 2.00 g of 2-(1-benzothiophen-5-yl)-1- ethanol were added 13 mg of potassium hydroxide, 36 mg of tetra-n-butylammorium bromide and 1.11 mL of acrylonitrile, and the resulting mixture was stirred at 45°C for 3 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the pH was adjusted to 1 with 2 mol/L hydrochloric acid. The insoluble materials were removed and then the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; hexane : ethyl acetate = 3 : 1) to obtain 2.46 g of 3-[2-(l-benzothiophen-5- yl)ethoxy]propiono-nierile as a colorless oil. IR( neat)cm-1: 2870,2251, 1114, 757, 704 NMR(CDC13)d values: 2 . 58 (2H, t, J=6Hz) , 3.02(2H,t,J=7Hz), 3.66(2H,t,J=6Hz), 3.7 5(2H,t,J=7Hz), 7.22(lH,d,J=8Hz), 7.29(1H,d,J=5Hz), 7.42(1H,d,J=5Hz), 7.68(lH,s), 7.80(1H,d,J=8Hz) (2) In 0.6 mL of acetic acid was dissolved 200 mg of 3-[2-(1-benzothiophen-5-yl)ethoxy]propiononitrile, followed by adding thereto 0.4 mL of water and 0.184 mL of sulfuric acid, and the resulting mixture was stirred at 90 to 100°C for 1 hour. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; toluene : ethyl acetate = 3 : 1) to obtain 140 mg of 3-[2-(l- benzothiophen-5-yl)ethoxy]propionic acid as colorless crystals. Reference Example 9 Production of 3-[2-(l-benzothiophen-5- yl)ethoxy]-1-propanol In 8 mL of cetrahydrofuran was dissolved 2.00 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-1-propionic acid, and 1.31 mL of triethylamine was added thereto. Then, the resulting solution was cooled to -25°C, after which a solution of 0.88 mL of ethyl chloroformate in 2 mL of tetrahydrofuran was added dropwise thereto, and the resulting mixture was stirred at 5°C for 1 hour. To the reaction mixture were added 15 mL of ethyl acetate and 10 mL of a saturated aqueous sodium chloride solution, and the organic layer was separated. After the organic layer was cooled to 5°C, 0.36 g of sodium borohydride was added thereto and the resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture were added 20 mL of water and 10 mL of ethyl acetate, and the organic layer was separated. The organic layer was washed successively with a 1 mol/L aqueous sodium hydroxide solution, water and a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.89 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-1-propanol as a yellow oil. Reference Example 10 Production of 5-[2-(3-bromopropoxy)ethyl]-1- benzothiophene In 40 mL of methylene chloride was dissolved 2.00 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-1- propanol, and 5.55 g of triphenylphosphine was added to the solution, after which a solution of 8.42 g of carbon tetrabromide in 10 mL of methylene chloride was added dropwise thereto under ice-cooling and the resulting mixture was stirred at room temperature for 20 minutes. To the reaction mixture was added 20 mL of water, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. Diethyl ether was added to the residue and the insoluble materials were filtered off, after which the solvent was distilled off under reduced pressure. The residue was purified by a column chromatography (eluent; hexane : ethyl acetate = 20 : 1 to 10 : 1) to obtain 1.93 g of 5-[2-(3- bromopropoxy)ethyl]-1-benzothiophene as a colorless oil. IR (neat) cm-1: 28 63,14 37,1112,1051,701 NMR(CDC13)d values: 2 . 0-2 . 2 (2H,m) , 3.00(2H,t,J=7Hz), 3.4 8(2H,t,J=6Hz), 3.58 (2H,t,J=6Hz) , 3.7 0(2H,t,J=7Hz) , 7.22(1H,dd,J=l,8Hz), 7.2 8(1H,dd,J=l,5Hz), 7.42(1H,d,J=5Hz), 7.6-7.7 (1H,m) , 7 .. 79 (1H, d, J=8Hz) Reference Example 11 Production of 3-azetidinyl=pivalate hydrochloride (1) In a mixture of 200 mL of toluene and 100 mL of tert-butanol was cissolved 50.0 g of 1-[(1R)-1- phenylethyl]azetidin-3-ol, and 41.2 g of potassium tert-butoxide was added thereto in small portions under ice-cooling, after which the resulting mixture was stirred at the same temperature for 1.5 hours. Under ice-cooling, 41.7 mL of pivaloyl chloride was added dropwise to the reaction mixture and stirred at the same temperature for 30 minutes. The reaction mixture was poured into 300 mL of water and the insoluble materials were filtered off, after which the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The oil thus obtained was dissolved in 200 mL of ethyl acetate, and 258 mL of a 1.15 mol/L dried hydrogen chloride-ethyl acetate solution was added thereto at 10°C and stirred at the same temperature for 20 minutes. The crystals precipitated were collected by filtration to obtain 70.8 g of 1-[(1R)-1- phenylethyl]-3-azetidinyl=pivalate hydrochloride as colorless crystals. IR(KBr)cm-1: 2963, 2509, 2436, 1731, 12 84, 1161, 699 NMR(DMSO-d6)d values: 1.16(9H,s), 1. 49 (3H,d,J=7Hz) , 3.6-4.3(3H,m), 4.4-4.7(2H,m), 4.9-5.2(1H,m), 7.3-7.5(3H,m), 7.6-7.7(2H,m) (2) To a solution of 50.0 g of 1-[(1R)-1- phenylethyl]-3-azetidinyl=pivalate hydrochloride in 250 mL of ethanol was added 5 g of 10% palladium-activated carbon, and the resulting mixture was stirred for 9 hours at 50°C and atmospheric pressure under a hydrogen atmosphere. After cooling, the insoluble materials were filtered off and the solvent was distilled off under reduced pressure. A mixture of ethyl acetate and hexane (1 : 2) was added to the residue and the crystals precipitated were collected by filtration to obtain 23.1 g of 3-azetidinyl=pivalate hydrochloride as colorless crystals. IR(KBr)cm-1: 2 988, 1718, 1156, 877, 789 NMR(CDC13)d values: 1.23(9H,s), 4 . 0-4 . 2 (2H, m) , 4.3-4.5(2H,m), 5.2-5.4(1H,m) Reference Example 12 Production of 3-(trityloxy)azetidine hydrochloride (1) In 50 mL of methylene chloride was dissolved 10.0 g of 1-(3-hydroxy-1-azetidinyl)-1-ethanone, and 31.2 mL of 1,8-diazabicyclo[5,4,0]undec-7-ene and 29.1 g of trityl chloride were added thereto under ice- cooling, after which the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 100 mL of ice water and the organic layer was separated. The organic layer was washed with diluted hydrochloric acid, water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. Diisopropyl ether was added to the residue and the crystals precipitated were collected by filtration to obtain 21.7 g of l-[3- (trityloxy)-1-azetidinyl]-1-ethanone as light-yellow crystals. IR(KBr)cm-1: 164 6,1450,112 4,750,711 NMR(CDC13)d values: 1.74(3H,s), 3 . 6-3 . 8 (4H, m) , 4.4-4.5(lH.m), 7.2-7.5(15H,m) (2) In 88 mL of methanol was suspended 22.0 g of 1-[3-(trityloxy)-1-azetidinyl]-1-ethanone, followed by adding thereto 66 mL of a 5 mol/L aqueous sodium hydroxide solution, and the resulting mixture was refluxed for 9 hours. The reaction mixture was distilled under reduced pressure to remove the solvent, and 110 mL of water and 220 mL of ethyl acetate were added to the residue, after which the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The oil thus obtained was dissolved in 154 mL of ethyl acetate, and to the resulting solution was added 25 mL of a 2.95 mol/L dried hydrogen chloride-ethyl acetate solution, after which the resulting mixture was stirred at room temperature. The crystals precipitated were collected by filtration to obtain 13.7 g of 3- (trityloxy)azetidine hydrochloride as colorless crystals. IR(KBr)cm-1: 2 90 0, 2 620, 1447, 751, 700 NMR(DMSO-d6)d values: 3 . 4-3 . 6 (4H,m) , 4 . 3-4 . 5 (1H,m) , 7.2-7.5(15H,m) Reference Example 13 Production of 3-(tetrahydro-2H-pyran-2- yloxy)azetidine hydrochloride (1) In 10 mL of methylene chloride was dissolved 1.00 g of 1-(3-hydroxy-1-azetidinyl)-1-ethanone, and 1.19 mL of 3,4-dihydro-2H-pyran and 0.08 g of p- toluenesulfonic acid monohydrate were added to the solution, after which the resulting mixture was stirred overnight at room temperature. To the reaction mixture was added 10 mL of water and the pH was adjusted to 8 with a saturated aqueous sodium hydrogencarbonate solution, after which the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform-chloroform : methanol = 25 : 1) to obtain 1.79 g of l-[3- (tetrahydro-2H-pyran-2-yloxy)-1-azetidinyl]-1-ethanone as a yellow oil. IR(neat) cm-1: 2 94 5, 2875, 1654, 1458, 1138, 103 6, 971 NMR(CDC13) 8 values: 1. 5-1.9(6H,m), 1.87(3H,s) 3.4-3.6(1H,m), 3.8-4.4(5H,m), 4.5-4.7(2H,m) (2) In the same manner as in Reference Example 12 (2), 3-(tetrahydro-2H-pyran-2-yloxy)azetidine hydrochloride was obtained from 1-[3-(tetrahydro-2H- pyran-2-yloxy)-1-azetidinyl]-1-ethanone. IR(KBr)cm-1: 2 95 6, 2627 , 103 6, 97 6, 915 NMR(DMSO-d6)d values: 1.4-1.8(6H,m), 3.3-3.5(1H,m), 3.7-4.2(5H,m), 4.4-4.7(2H,m) Reference Example 14 Production of 1-(3-chloropropyl)-3- (trityloxy)azetidine oxalate (1) In 5 mL of dimethyl sulfoxide was dissolved 0.50 g of 3-(trityloxy)azetidine hydrochloride, and to the solution were added 0.49 g of potassium carbonate, 0.35 g of potassium iodide and 0.22 mL of l-bromo-3- chloropropane, after which the resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture were added 15 mL of water and 10 mL of ethyl acetate, and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain l-(3- chloropropyl)-3-(trityloxy)azetidine. (2)In 10 mL of ethyl acetate was dissolved l-(3- chloropropyl)-3-(trityloxy)azetidine, and to the resulting solution was added 0.15 g of oxalic acid, after which the resulting mixture was stirred at room temperature. The crystals precipitated were collected by filtration to obtain 0.39 g of 1-(3-chloropropyl)-3- (trityloxy)azetidine oxalate. IR(KBr) cm-1: 30 33, 1491, 1449, 1139, 706 NMR(DMSO-d6)d values: 1. 7-1. 9 (2H, m),3.0-3.1(2H,m) , 3.5-3.7 (6H,m) ,4 ..3-4.5(1H,m),7.2-7.4(15H,m) Reference Example 15 Production of 1-(3-chloropropyl)-3- (tetrahydro-2H-pyran-2-yloxy)azetidine In the same manner as in Reference Example 14 (1), 1-(3-chloropropyl)-3-(tetrahydro-2H-pyran-2- yloxy)azetidine was obtained from 3-(tetrahydro-2H- pyran-2-yloxy)azetidine hydrochloride. IR(neat) cm-1: 2943, 2834, 1203, 1038, 975, 914, 871 NMR(CDC13)d values:1.4-1.8(6H,m),1.8-1.9(2H,m), 2.59(2H,t,J=7Hz),2.8-3.0(2H,m),3.4-3.5(1H,m), 3.57(2H,t,J=7Hz),3.6-3.7(2H,m),3.8-3.9(1H,m), 4.3-4.4(1H,m), 4.5-4.6(1H,m) Test Example 1 [Activity to accelerate neurite outgrowth] PC12 cells [rat adrenomedullary chromaffinoma (NGF responders)] were cultured in an incubator (5% CO2, 37°C) by using RPMI1640 medium (available from Nissui Pharmaceutical Co., Ltd.) containing 5% heat inactivated (56°C, 30 minutes) horse serum (available from Bio-Whittaker Inc.), 5% heat inactivated (56°C, 30 minutes) fetal calf serum (available from Sigma Chemical Co.) and 25 µg/ml gemamicin (available from GIBCO BRL). The cultured PC12 cells were incubated at 37°C for 30 minutes in phosphate-buffered physiological saline containing 1 mM EDTA, to be detached from a culture flask. The concentration of the cultured PC12 cells was adjusted to 5 x 104 cells/mL with RPMI1640 medium containing 1.5% heat inactivated horse serum, 1.5% heat inactivated fetal calf serum and 25 µg/ml gentamicin, and the resulting cell suspension was dispensed in 2 ml portions into 35-mm tissue culture dishes (mfd. by Falcon Inc.) coated with 0.01% polyornithine [dissolved in 150 mM borate buffer (pH 8.4)]. Then, 2.5s-NGF (available from Wako Pure Chemical Industries, Ltd.) [dissolved in phosphate- buffered physiological saline containing 0.1% bovine serum albumin] and each test compound were added to the medium at the same time so as to adjust their final concentrations to 40 ng/mL and 10 µM, respectively, followed by culturing under conditions of 5% CO2 and 37°C. After 48 hours of the culturing, cells were fixed in a 10% neutral formalin solution for 30 minutes, washed with phosphate-buffered physiological saline and distilled water, and then dried. Any four fields of view were selected under a phase contrast microscope, and 50 or more cells were observed in each field of view. The percentage of the number of cells having an neutrite extended to a length longer than the diameter of the cell body relative to the total number of cells observed (neutrite outgrowth rate) was calculated. The activity to accelerate neutrite outgrowth was calculated according to the following expression as a neutrite outgrowth acceleration rate attained by the addition of each test compound, by taking a neutrite outgrowth rate due to NGF as 100%: (neutrite outgrowth rate attained by addition of each test compound) / (neutrite outgrowth rate due to NGF) x 100 (%) As a result, the neutrite outgrowth acceleration rate was found to be as follows: the compound of Example 2: 2 65%, the compound of Example 6: 300%, the compound of Example 12: 299%, the compound of Example 14: 207%, the compound of Example 29: 212%, the compound of Example 51: 216%, the compound of Example 59: 241%, the compound of Example 69: 233%, the compound of Example 71: 183%, the compound of Example 74: 246%, the compound of Example 80: 190%, and the compound of Example 81: 190%. Test Example 2 [Activity to accelerate nerve regeneration] The test was carried out according to the method described in J. Pharmaco. Exp. Ther., Vol. 290, page 348 (1999) and Neuroscience, vol. 88, page 257 (1999). SD strain rats (male, aged 6 to 7 weeks, and weighing 170 to 280 g) were anesthetized with pentobarbital, and the left sciatic nerve of each rat was exposed in the femoral region, separated from the surrounding connective tissue, and then cut at a distal position which was about 1 cm apart from the gluteus. The ends of the nerve were inserted into a sterilized silicone tube with a length of 8 mm (inside diameter 1.3 mm, and outside diameter 1.8mm) to a depth of 3.5 mm so that a space of 1 mm might be formed in the middle of the tube. The ends of the nerve were fixed and the nerve was put back to the muscular tissue together with the tube, after which the incised part was sutured. On the seventh day, each test compound dissolved in distilled water was orally administered in a dose of 1 mg/kg, and thereafter the test compound was administered once a day for 13 days in the same manner as above. Twenty-one days after cutting the nerve, the sciatic nerve was exposed again under pentobarbital anesthesia, and the nerve in the femoral region and the crural region was separated from the surrounding connective tissues, after which the silicone tube at the cut part was removed. A stimulation electrode was set on the proximal side with respect to the cut position, and a recording electrode was set at the most distal position in the crural region. An electric stimulus (voltage: 2 V, delay: 1 msec, and duration: 100 fisec) was given, and an action potential induced by the stimulus was recorded. The recording electrode was gradually moved toward the proximal, and the distance between the cut position and the most distal position at which an action potential had been obtained was measured as regeneration distance. Only distilled water was administered to a control group. The sciatic nerve regeneration rate of the test compound was calculated according to the following expression: (regeneration distance of drug-treated group) (regeneration distance of control group) x 100 (%) As a result, the sciatic nerve regeneration rate was found to be as follows: the compound of Example 4: 167%, the compound of Example 10: 186%, the compound of Example 12: 142%, the compound of Example 14: 150%, the compound of Example 31: 155%, and the compound of Example 33: 161%. Test Example 3 [Activity to inhibit the neuronal death induced by Aß] Inhibitory effect on the death of cultured neurons induced by Aß was investigated by modifying the method described in Brain Res., vol. 639, page 240 (1994) . Cerebral cortices isolated from the brains of embryos (aged 17 to 19 days) of Wistar strain rats were sliced, and then neurons were dissociated by trypsin treatment. The cells were seeded into a 48-well tissue culture plate at a density of 1 x 105 cells per well and cultured under conditions of 5% CO2, and 37°C on Dulbecco"s modified Eagle"s medium added B27 supplement (available from GIBCO BRL) and 3.6 mg/mL glucose. On the 12th to 13th day of the culture, a potassium chloride solution was added to the medium to adjust the final concentration of potassium chloride to 25 mmol/L. Immediately after this addition, each test compound was added to the medium. After 24 hours, Aß (a peptides comprising 25 to 35 residues) dissolved in distilled water was added to the medium at a final concentration of 20 µmol/L. After another 24 hours, the medium was replaced with Dulbecco"s modified Eagle"s medium added B27 supplement and 3.6 mg/mL glucose and test compound. The inhibitory activity of the test compound against the death of cultured neurons was determined by inhibition against the decrease of reducing ability of MMT. That is, MTT assay [J. Immuno. Methods, vol. 65, page 55 (1983)] developed by Mosmann was carried out 48 hours after the medium replacement, and the inhibition rate (%) of the test compound against a decrease of a MTT assay value induced by A(3 was calculated. Inhibition rate = [(MTT assay value of a group treated with Aß and the drug) - (MTT assay value of a group treated with Aß)] / [MTT assay value of an untreated group - MTT assay value of a group treated with Aß] x 100 (%). As a result, the inhibition rate at a concentration of 1 µM was found to be as follows: the compound of Example 4: 63%, the compound of Example 6: 48%, the compound of Example 10: 42%, the compound of Example 14: 48%, the compound of Example 31: 50%, the compound of Example 33: 54%, the compound of Example 61: 52%, the compound of Example 69: 70%, the compound of Example 74: 50%, and the compound of Example 80: 75%. Test Example 4 [Metabolism in human liver microsomes] In a test tube were placed 50 µL of 100 mmol/L potassium phosphate buffer (pH 7.4) and 25 µL of 3 mg protein/mL pooled human liver microsomes (available from Gentest Inc.), and a solution prepared by blending 10 µL of 66 mmol/L sodium glucose 6- phosphate, 10 µL of 10 units/mL glucose 6-phosphate dehydrogenase, 10 µL of 26 mmol/L nicotinamide adenine dinucleotide phosphate oxidized form, 10 )µL of 66 mmol/L magnesium chloride and 135 µL of 100 mmol/L potassium phosphate buffer (pH 7.4) was added thereto, followed by preincubation for 5 minutes. Thereto was added 50 µL of each test compound to a concentration of 6 µmol/L to initiate the reaction, and incubation was carried out at 37°C for 60 minutes (final volume: 300 µL). The reaction was terminated by the addition of 600 µL of acetonitrile, followed by centrifugation at 12000 x g and at 4°C for 15 minutes. The supernatant was separated, concentrated by centrifugation under reduced pressure, and then subjected to high performance liquid chromatography, and the amount of the residual test compound after the metabolic reaction was determined. The residual rate was calculated by the following equation: Residual rate (%) = [(peak area due to the test compound after 60 minutes of the reaction) / (peak area due to the test compound in the case of stopping the reaction by adding acetonitrile simultaneously with the addition of the test compound after the preincubation)] x 100 As a result, the residual rate was found to be as follows: the compound of Example 4: 80%, the compound of Example 10: 70%, the compound of Example 12: 83%, the compound of Example 14: 75%, the compound of Example 61: 74%, the compound of Example 69: 74%, the compound of Example 71: 80%, and the compound of Example 74: 71%. INDUSTRIAL APPLICABILITY The alkyl ether derivative of the general formula [1] or salt thereof of the present invention has excellent activity to accelerate neurite outgrowth, activity to accelerate nerve regeneration and activity to protect neurons, is excellent also in stability to metabolism, and is useful as a therapeutic agent for diseases in central and peripheral nerves. WE CLAIM: 1. An. alkyl ether derivative represented by the general formula, or its salts: wherein each of R1 and R2, which may be the same or different, represents one or more groups selected from a hydrogen atoms, a halogen atom,aC1-12 alkyl, phenyl, naphthyl, indanyl, indenyl, benzyl, diphenylmethyl, trityi, phenethyl, C1-12 alkoxy, phenyloxy, naphthyloxy, indanyloxy, indenyloxy, C1-12 alkylthio, phenyltbio, naphthylthio, indanylthio, indenylthio, C2-12 alkenyl, C2-12 alkenyloxy, amino, C1-12 alkylsulfonyl, phenylsulfonyl, p-toluenesulfonyl, naphthylsulfonyl, carbamoyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, homopiperidinyl, morpholyl, thiomorpholyl, tetrahydroquinolyl, tetrahydroiaoquinolyl, quinuclidinyl, tmidazolinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, quinolyl, quin.olidin.yl, thiazoiyl, tetrazolyl, thiadiazolyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, purinyl, furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazoiyl, isoxazolyl, benzofuranyl, indolyl, heaasdxnidazoiyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quiaoxalyl, dihydroquinoxalyl, 2,3-dih.ydrobenzothienyl, 2,3- dihydrobenzopyrrotyl,2-3-4H- 1-thianaphthyl,2,3- dihydrobenzofuranyl, betnzo [b] dioxanyl, imidazo [2,3-a] pyridyl, beonzo [b] piperazinyl, chiomenyl, isotbiazolyl, isoxazolyl, oxadiazolyl, pyridazinyl, isoindolyl, isoquinolyl, 1,3-benzodiaxonyl or 1,4- benzodioxonyl group, a protected or unprotected amino, hydroxyl or carboxyl group, a nitro group, and an oxo group; R3 is a substituted or unsubstituted mono-or di- C1-6 alkylamino group, or a protected or unprotected amino or hydroxyl group; the ring A is a triazine, pyridazine, pyrimidine, pyrazine, pyridine, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, iaoxazole, isothiazole, pyrazole, pyran or a benzene ring; each of m and n is an integer of 1 to 6; and p is 1. 2. The alkyl ether derivative or its salts as claimed in Claim 1, wherein the portion represented by in the general formula in Claim 1 is any of the following (A), (B) and (C): 3. The alkyl ether derivative or its salts as claimed in Claim 1 or 2, wherein R1 is a hydrogen atom; and R2 is a hydrogen atom, a halogen atom or an C1-12 alkoxy group. 4. The alkyl ether derivative or its salts as claimed in Claims 1 to 3, wherein m is 2, n is an integer of 2 to 3, and p is 1. 5, A process for producing an alkyl ether derivative represented by the general formula: wherein R3 is a substituted or unsubstituted mono-or di- C1-6 alkylamino group, or a protected or unprotected amino or hydroxyl group; and R1, R2 , the ring A, m, n and p are as defined below, or its salt, which comprises reacting a carboxylic acid derivative represented by the general formula: wherein each of R1 and R2, which may be the same or different, represents one or more groups selected from a hydrogen atom, a halogen atom, C1-12 alkyl, phenyl, naphthyl, indanyl, indenyl, benzyl, diphenylmethyl, trityl, phenethyl, C1-12 alkoxy, phenyloxy, naphthyloxy, indanyloxy, indeayloxy, C1-12 atkylthio, pnenylthio, naphthylthio, indanylthio, indenylthio, C2-12 alkenyl, C2-12 alkenyloxy, amino, C1-12 alkylsulfonyl, phenybmlfonyl, p-toluenesulfonyl, naphthylsulfonyl, carbamoyl, pyrrolidinyl, piperidinyl, pipetrazinyl, homopiperazinyl, homopiperidinyl, morpholyl, thiomorpholyl, tetrahydroquinolyl, tetrahydroisoquinolyl, quimiclidinyl, imidazoliayl, pyrrolyl, tmidazolyl, pyrazolyl, pyridyl, pyrimidyl, quinolyl, quinolidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, purinyl, furyl, thienyl, benzotMenyl, pyranyl, isohenzofuranyl, oxazolyl, isoxazolyl, benzofuranyl, indolyl, benziiuidazolyl, benzoxazolyl, benzisoxazolyl, beozothiazolyl, quinoxalyl, dthydroquiaoxalyl, 2,3-dthydrobenzothien.yl, 2,3- dihydrobenzopyrrolyl,2,3-4H-1thianaphthyl,2,3- dihydrobenzofuranyl, benzo [b] dioxanyl, imidazo [2,3-a] pyridyl, benzo [b] piperazinyi, cliromenyl, isothiazolyl, isoxazolyl, oxadiazolyl, pyridazinyl, isoiadolyl, isoquinolyl, 1,3-benzodioxonyl or 1,4- benzodioxonyl group, a protected or unprotected amino, hydroxyl or carboxyl group, a nitro group, and an oxo group; the ring A is a triazine, pyridazine, pyrimidine, pyrazine, pyridine, furan, thiophetie, pyrrole, oxazole, thiazole, imidazol, isoxazole, isothiazole, pyrazole, pyran or a benzene ring; an each of m and n is an integer of 1 to 6, or its salt with a compound represented by the general formula: wherein R36 is di- C1-6 alkylamino group, a protected mono- C1-6 alkylamino group, a protected amino group or a protected or unprotected hydroxyl group; and p is 1 or its salt to obtain an alkylamide derivative represented by the general formula: wherein R1, R2, R3a, the ring A,m, n and p are as defined above, or its salt, optionally subjecting the alkylamide derivative or salt thereof to a hydroxyl group protection reaction in the case of R3a being a hydroxyl group, to obtain an alkylamide derivative in which R3a is a protected hydroxyl group, or its salt, and then subjecting the obtained alkylamide derivative to reduction reaction. 6. An alkylamide derivative represented by the general formula, or its salt: wherein each of R1 and R2, which may be the same or different, represents one or more groups selected from a hydrogen atom, a halogen atom, a C1-12 alkyl, phenyl, naphthyl, indanyl, indenyl, benzyl, diphenylmethyl, trityl, phenethyl, C1-12 alkoxy, phenyloxy, naphthyloxy, indanyloxy, indenyloxy, C1-12 alkylthio, phenylthio, naphthylthio, indanylthio, indenylthio, C2-12 alkenyl, C2-12 alkenyloxy, amino, C1-12 alkylsulfonyl, phenylaulfonyl, p-toluenesulfonyl, naphthylsulfonyl, carbamoyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazanyl, homopiperidinyl, morpholyl, thiomorpholyl, tetrahydroquinolyl, tetrahydroisoquinolyl, quinuctidinylt imidazoKnyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, quinolyl, quinolidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, purinyl, furyl, thienyl, benzothienyl, pyranyl, iaobenzofuranyl, oxazolyl, iaoxazolyl, benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinoxalyl, dihydroquinoxalyl, 2,3-dihydrobnenzothienyl, 2,3- dihydrobenzopyrroiyl,2,3-4H-1-thianaphthyl,2,3- dihydrobenzofuraayl, benzo[b] dioxanyl, imidazo [2,3-a] pyridyl, benzo [b] piperazinyl, chromenyl, isothiazolyl, isoxazolyl, oxadiazolyl, pyridazinyl, isoindolyl, isoquinolyl, 1,3-beozodioxonyl or 1,4- benzodioxonyl group, a protected or unprotected amino, hydroxyl or carboxyl group, a nitro group, and an oxo group; substituted or unsubstituted mono- or di- C1-6 alkylatnino group, a protected amino group, or a protected or unprotected hydroxy group; R 3a is a di- C1-6 alkylamino group, a protected mono- C1-6 alkyiamino group, a protected amino group or a proto. cted or unprotected hydroxyl group; the ring A is a triazine, pyridazine, pyrimidine, pyrazane, pyridine, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, isoxazole, isothiazole, pyrazole, pyrari or a benzene ring; each of m and n is an integer of 1 to 6; and p is 1. 7. A process for producing an alkyl ether derivative represented by the general formula: wherein R1, R2, R3a, the ring A, m , n and p are as defined below, or its salt, which comprises reacting an ether derivative represented by the general formula: wherein each of R1 and R2, which may be the same or different, represents one or more groups selected from a hydrogen atom, a halogen atom, a C1-12 alkyl, phenyl, naphthyl, indanyl, indenyl, benzyl, diphenylmethyl, trityl, phenethyl, C1-12 alkoxy, phenyloxy, naphthyloxy, indanyloxy, indenyloxy, C1-12 alkylthio, phenyltbio, naphthyltbio, indanylthio, indenylthio, C2-12 alkenyl, C 2-12 alkenyloxy, amino, C1-12 alkylsulfonyl, phenylsulfonyl, p-toluenesulfonyl, naphthylaulfonyl, carbatnoyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, hotnopiperidinyl, morpholyl, thiomorpholyl, tetrahydrogquinolyl,tetrahydroisoquinolyl,quinuclidinyl, imidazolinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridmidyl, quinolyl, quinolidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, purinyl, furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, isoxazolyl, benzofiiranyl, indofyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quiaoxalyl, dihydroquinoxalyl, 2,3-dihydrobenzotbienyl, 2,3- dihydrobenzopyrrolyl,2,3-4H-1-thianaphthyl,2,3- dihydrobenzofuranyl, benzo [b] dioxanyl, imidazo [2,3-a] pyridyl, benzo [b] piperazinyl, chromenyl, iaothiazolyl, iaoxazolyl, oxadiazolyl, pyridazinyl, iaoindolyl, iaoquinolyl, 1,3-benzodioxonyl or 1,4- benzodioxonyl group, a protected or unprotected amino, hydroxyl or carboxyl group, a nitro group, and an oxo group; the ring A is a triazine, pyridazine, pyrimidine, pyraztne, pyridine, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, isoxazole, isothiazole, pyrazole, pyran or a benzene ring, x1 is a leaving group; and each of m and n is an integer of 1 to 6, or its salt with a carboxylic acid derivative represented by the general formula: wherein R3a is a di- C1-6 alksylamino group, a protected mono- C1-6 alkylamino group, a protected amino group or a protected or unprotected hydroxyl group; and p is 1 or its salt. 8. A process for producing an alkyl ether derivative represented by the general formula: wherein R1, R2, R3b, the ring A, m, n and p are as defined below, or its salt, which comprises reacting an alcohol derivative represented by the general formula: wherein each of R1 and R2, which may be the same or different, represents one or more groups selected from a hydrogen atom, a halogen atom, a C1-12 alkyl, phenyl, naphthyl, indanyl, indenyl, benzyl, diphenylmethyl, trityl, phenethyl, C1-12 alkoxy, phenyloxy, naphthyloxy, indanyloxy, indenyloxy, C1-12 alkylthio, phenylthio, naphthylthio, indanylthio, indenylthio, C2-12 alkenyl, C 2-12 alkenyloxy, amino, C1-12 alkylsulfonyl, phenylsulfonyl, p-toluenesulfonyl, naphthylsulfonyl, carbamoyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, homopiperidinyl, morpholyl, thiomorpholyl, tetrahydroquinolyl, tetrahydroisoquitiolyl, quinuclidinyl, imidazolinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, quinolyl, quinolidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, purinyl, furyl, thienyl, benzothienyl, pyranyl, isobenzofiiranyl, oxazolyl, isoxazolyl , benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, bensdaoxazolyl, benzothiazoryl, quinoxalyl, dihydroquinoxalyl, 2,3-dihydrobenzothienyl, 2,3- dihydrobeozopyrrolyl,2,3-4H-l-thianaphth.yl,2,3- dihydrobenzofuranyl, benzo [b] dioxanyl, imidazo [2,3-a] pyridyl, benzo [b] piperazinyl, chromenyl, isothiazolyl, isoxazolyl, oxadiazolyl, pyridazinyl, isoindolyl, iaoquinolyl, 1,3-benzodioxonyl or 1,4- benzodioxonyl group, a protected or unprotected amino, hydroxyl or carboxyl group, a nitro group, and an oxo group; the ring A is a triazine, pyridazine, pyranidine, pyrazine, pyridine, furan, thiophene, pyrrole, oxazole, thiazole, ixnidazole, isoxazole, isothiazole, pyrazole, pyran or a benzene ring, m is an integer of 1 to 6, or its salt, with an N-alkyl cyclic amino derivative represented by the general formula: wherein R3b is a di- C 1-6 atkylamino group, a protected mono- C 1-6 alkylamino group, a protected amino group or a protected hydroxyl group; X2 is a leaving group; n is an integer of 1 to 6; and p is 1. 9. The alkyl ether derivative or its salts as claimed in claims 1 to 4, wherein the alkyl ether derivative is l-{3-[2-(l-benzothiopeh-5- y l)ethoxy]propy 1} -3-azeti dinol. An alkyl ether derivative represented by the general formula: wherein each of R1 and R2 represents one or more groups selected from a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an aralkyl group, an alkoxy group, an aryloxy group, an alkythio group, an arylthio group, an alkenyl group, an alkenyloxy group, an amino group, an alkylsulfonyl group, an arylsulfonyl group, a carbamoyl group, a heterocyclic group, a hydroxyl group, a carboxyl group, a nitro group, an oxo group and the like; R3 is an alkylamino group, an amino group, a hydroxyl group or the like; the ring A is a 5-membered or 6-membered heteroaromatic ring or a benzene ring; each of m and n is an integer of 1 to 6; and p is 1, or its salt has activity to protect neurons, activity to accelerate nerve regeneration and activity to accelerate neurite extension and hence is useful as a therapeutic agent for diseases in central and peripheral nerves.

Full Text

TECHNICAL FIELD
The present invention relates to novel alkyl
ether derivatives or their salts, a process for
production thereof, intermediates thereof and a
therapeutic agent for central and peripheral nerves.
BACKGROUND ART
Dementia is divided into cerebrovascular
dementia and neurodegenerative dementia, and various
agents such as cerebral blood flow improvers and
nootropics are used for treating these dementias.
Senile plaques characteristic of Alzheimer"s
disease, which is most typical as neurodegenerative
dementia, are mainly composed of amyloid ß protein (Ap)
derived from (3 amyloid precursor protein. Aß is
considered as a substance that is deposited on the
neurons or blood vessels of brain to cause a disease
such as dementia. In addition, it has been reported
that Aß itself injures neurons. Inhibitors of
neurotoxicity induced by Aß are investigated as
therapeutic agents for Alzheimer"s disease.
As compounds having inhibitory activity
against neurotoxicity induced by Aß, there are known,
for example, the 1,2-ethanediol derivatives disclosed
in JP-A-3-232830 and JP-A-4-95070, and the N-
alkoxyalkyl-N,N-dialkylamine derivatives disclosed in
International Publication WO 00/76957.
The 1,2-ethanediol derivatives disclosed in
JP-A-3-232830 and JP-A-4-95070, in particular, (R)-1-
(benzo[b]thiophen-5-yl)-2-[2-(N,N-diethylamino)-
ethoxy]ethanol hydrochloride has protective activity
against the neuronal death caused by Aß (SOCIETY FOR
NEUROSCIENCE, Abstracts, Vol. 24, Part 1, p. 228, 1998)
and activity to enhance the activity of nerve growth
factor (NGF) (WO 96/12717) and hence is useful as a
therapeutic agent for diseases in central and
peripheral nerves. However, there is desired the
development of a compound possessing properties such as
a higher activity to protect neurons and a higher
activity to accelerate nerve regeneration, which are
required as a therapeutic agent for diseases in central
and peripheral nerves.
DISCLOSURE OF THE INVENTION
The present inventors earnestly investigated
in order to solve the above problem, and consequently
found that there are compounds having not only calcium-
antagonistic activity but also inhibitory activity
against neurotoxicity induced by A(3, among the alkyl
ether derivatives with calcium-antagonistic activity
disclosed in WO 99/31C56.
The present inventors further investigated,
and consequently found that an alkyl ether derivative represented by the
following general formula [1]:
wherein each of R1 and R2 represents one or more groups selected from a
hydrogen atom, a halogen atom, an alkyl group, an aryl group, an aralkyl
group, an alkoxy group, an aryloxy group, an alkythio group, an arylthio
group, an alkenyl group, an alkenyloxy group, an amino group, an
alkylsulfonyl group, an arylsulfonyl group, a carbamoyl group, a
heterocyclic group, a hydroxyl group, a carboxyl group, a nitro group, an
oxo group and the like; R3 is an alkylamino group, an amino group, a
hydroxyl group or the like; the ring A is a 5-membered or 6-membered
heteroaromatic ring or a benzene ring; each of m and n is an integer of 1 to
6; and p is 1, or its salt has activity to protect neurons, activity to accelerate
nerve regeneration and activity to accelerate neurite extension and hence is
useful as a therapeutic agent for diseases in central and peripheral nerves,
whereby the present invention has been accomplished.
The present invention is explained below in detail.
The terms used in the present specification
have the following meanings unless otherwise specified.
The term "halogen atom" means a fluorine atom, a
chlorine atom, a bromine atom or an iodine atom; the
term "alkyl group" means a straight chain or branched
chain C1-12alkyl group such as methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl,
heptyl, octyl or the like; the term "lower alkyl group"
means a straight chain or branched chain C1-6 alkyl group
such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, tert-butyl, pentyl, hexyl or the like; the
term "alkoxy group" means a straight chain or branched
chain C1-12alkyloxy group such as methoxy, ethoxy,
propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy,
pentyloxy, hexyloxy, heptyloxy, octyloxy or the like;
the term "lower alkoxy group" means a straight chain or
branched chain C1-6alkyloxy group such as methoxy,
ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-
butoxy, pentyloxy, hexyloxy or the like; the term
"alkenyl group" means a C2-12alkenyl group such as vinyl,
propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl
or the like; the term "lower alkenyl group" means a C2-
6alkenyl group such as vinyl, propenyl, butenyl,
pentenyl, hexenyl or the like; the term "alkenyloxy
group" means a C2-12alkenyloxy group such as vinyloxy,
propenyloxy, butenyloxy, pentenyloxy, hexenyloxy
heptenyloxy, octenyloxy or the like; the term "lower
alkenyloxy group" means a C2-6alkenyloxy group such as
vinyloxy, propenyloxy, butenyloxy, pentenyloxy,
hexenyloxy or the like; the term "alkynyl group" means
a C2-6alkynyl group such as ethynyl, 2-propynyl, 2-
bytynyl or the like; the term "cycloalkyl group" means
a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
group; the term "alkylthio group" means a C1-12alkylthio
group such as methylthio, ethylthio, propylthio,
isopropylthio, butylthio, isobutylthio, tert-butylthio,
pentylthio, hexylthio, heptylthio, octylthio or the
like; the term "lower alkylthio group" means a
C1-6alkylthio group such as methylthio, ethylthio,
propylthio, isopropylthio, butylthio, isobutylthio,
tert-butylthio, pentylthio, hexylthio or the like; the
term "aryl group" means a phenyl, naphthyl, indanyl or
indenyl group; the term "aryloxy group" means a
phenyloxy, naphthyloxy, indanyloxy or indenyloxy group;
the term "aralkyl group" means an ar-C1-6alkyl group such
as benzyl, diphenylmethyl, trityl, phenethyl or the
like; the term "arylthio group" means a phenylthio,
naphthylthio, indanylthio or indenylthio group; the
term "acyl group" means a formyl group, a C2-12alkanoyl
group such as acetyl, isovaleryl, propionyl, pivaloyl
or the like, an aralkylcarbonyl group such as
benzylcarbonyl or the like, or an aroyl group such as
benzoyl, naphthoyl or the like; the term "alkylsulfonyl
group" means a C1-12alkylsulfonyl group such as
methylsulfonyl, ethylsulfonyl, propylsulfonyl,
isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl,
sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl,
hexylsulfonyl, heptylsulfonyl, octylsulfonyl or the
like; the term "lower alkylsulfonyl group" means a
C1-6alkylsulfonyl group such as methylsulfonyl,
ethylsulfonyl, propylsulfonyl, isopropylsulfonyl,
butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl,
tert-butylsulfonyl, pentylsulfonyl or the like; the
term "arylsulfonyl group" means a phenylsulfonyl, p-
toluenesulfonyl or naphthylsulfonyl group or the like;
the term "lower alkylsulfonyloxy group" means a C1-
6alkylsulfonyloxy group such as methylsulfonyloxy,
ethylsulfonyloxy, propylsulfonyloxy,
isopropylsulfonyloxy, butylsulfonyloxy,
isobutylsulfonyloxy, sec-butylsulfonyloxy, tert-
butylsulf onyloxy, pentylsulfonyloxy or the like; the
term "arylsulfonyloxy group" means a phenylsulfonyloxy,
p-toluenesulfonyloxy or naphthylsulfonyloxy group or
the like; the term "alkylamino group" means a mono- or
di-C1-6galkylamino group such as a methylamino,
ethylamino, propylamino, isopropylamino, butylamino,
dimethylamino, diethylamino, diisopropylamino,
dibutylamino or the like; the term "monoalkylamino
group" means a mono-C1-6galkylamino group such as
methylamino, ethylamino, propylamino, isopropylamino,
butylamino or the like; the term "dialkylamino group"
means a di-C1-6galkylamino group such as dimethylamino,
diethylamino, diisopropylamino, dibutylamino or the
like; the term "heterccyclic group" means a 5-membered
or 6-membered heterocyclic group containing at least
one heteroatom selected from nitrogen, oxygen and
sulfur atoms or a condensed or crosslinked heterocyclic
group thereof, such as pyrrolidinyl, piperidinyl,
piperazinyl, homopiperazinyl, homopiperidinyl,
morpholyl, thiomorpholyl, tetrahydroquinolyl,
tetrahydroisoquinolyl, quinuclidinyl, imidazolinyl,
pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl,
quinolyl, quinolizinyl, thiazolyl, tetrazolyl,
thiadiazolyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl,
purinyl, furyl, thienyl, benzothienyl, pyranyl,
isobenzofuranyl, oxazolyl, isoxazolyl, benzofuranyl,
indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,
benzothiazolyl, quinoxalyl, dihydroquinoxalyl, 2,3-
dihydrobenzothienyl, 2,3-dihydrobenzopyrrolyl, 2,3-4H-
1-thianaphthyl, 2,3-dihydrobenzofuranyl,
benzo[b]dioxanyl, imidazo[2,3-a]pyridyl,
benzo[b]piperazinyl, chromenyl, isothiazolyl,
isoxazolyl, oxadiazolyl, pyridazinyl, isoindolyl,
isoquinolyl, 1,3-benzodioxonyl, 1,4-benzodioxanyl or
the like; and the term "cyclic amino group" means a 5-
membered, 6-membered or 7-membered cyclic amino group
which contains one or more nitrogen atoms as the
heteroatoms forming the ring and may further contain
one or more oxygen atoms or sulfur atoms or a condensed
or crosslinked cyclic amino group thereof, such as
pyrrolidinyl, piperidinyl, piperazinyl,
homopiperazinyl, homopiperidinyl, morpholyl,
thiomorpholyl, tetrahydroquinolyl,
tetrahydroisoquinolyl, imidazolidinyl or the like.
As the 5-membered or 6-membered
heteroaromatic ring as the ring A, there are
exemplified 5-membered or 6-membered heteroaromatic
rings which contain at least one heteroatom selected
from oxygen, nitrogen and sulfur atoms as the
heteroatom forming the ring, such as triazine,
pyridazine, pyrimidine, pyrazine, pyridine, furan,
thiophene, pyrrole, oxazole, thiazole, imidazole,
isoxazole, isothiazole, pyrazole, pyran, and the like.
As the substituent of each of the alkyl
group, aryl group, aralkyl group, alkoxy group, aryloxy
group, alkylthio group, arylthio group, alkenyl group,
alkenyloxy group, amino group, alkylsulfonyl group,
arylsulfonyl group, carbamoyl group and heterocyclic
group for each of R1 and R2 and the alkylamino group for
R3, there are exemplified groups selected from halogen
atoms, lower alkyl groups, cycloalkyl groups, aryl
groups, lower alkoxy groups, aryloxy groups, lower
alkylthio groups, arylthio groups, lower alkenyl
groups, lower alkylsulfonyl groups, arylsulfonyl
groups, alkylamino groups, protected or unprotected
amino groups, protected or unprotected hydroxyl groups,
protected or unprotected carboxyl groups, acyl groups,
heterocyclic groups, etc.
The protecting group for the carboxyl group
includes all conventional groups usable as carboxyl-
protecting groups, for example, lower alkyl groups such
as methyl, ethyl, propyl, isopropyl, 1,1-
dimethylpropyl, butyl, tert-butyl and the like; aryl
groups such as phenyl, naphthyl and the like; ar-lower
alkyl groups such as benzyl, diphenylmethyl, trityl, 4-
nitrobenzyl, 4-methoxybenzyl, bis(4-methoxyphenyl)-
methyl and the like; acyl-lower alkyl groups such as
acetylmethyl, benzoylmethyl, 4-nitrobenzoylmethyl, 4-
bromobenzoylmethyl, 4-methanesulfonylbenzoylmethyl and
the like; oxygen-containing heterocyclic groups such as
2-tetrahydropyranyl, 2-tetrahydrofuranyl and the like;
halogeno-lower alkyl groups such as 2,2,2-
trichloroethyl and the like; lower alkylsilyl-lower
alkyl groups such as 2-(trimethylsilyl)ethyl and the
like; acyloxy-lower alkyl groups such as acetoxymethyl,
propionyloxymethyl, pivaloyloxymethyl and the like;
nitrogen-containing heterocyclic lower alkyl groups
such as phthalimidomethyl, succinimidomethyl and the
like; cycloalkyl groups such as cyclohexyl and the
like; lower alkoxy-lower alkyl groups such as
methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)-
ethoxymethyl and the like; ar-lower alkoxy-lower alkyl
groups such as benzyloxymethyl and the like; lower
alkylthio-lower alkyl groups such as methylthiomethyl,
2-methylthioethyl and the like; arylthio-lower alkyl
groups such as phenylthiomethyl and the like; lower
alkenyl groups such as 1,l-dimethyl-2-propenyl, 3-
methyl-3-butenyl, allyl and the like; and substituted
silyl groups such as trimethylsilyl, triethylsilyl,
triisopropylsilyl, diethylisopropylsilyl, tert-
butyldimethylsilyl, tert-butyldiphenylsilyl,
diphenylmethylsilyl, tert-butylmethoxyphenylsilyl and
the like.
The protecting group for the hydroxyl group
includes all conventional groups usable as hydroxyl-
protecting groups, for example, alkoxy- and alkylthio-
carbonyl groups such as benzyloxycarbonyl, 4-
nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-
methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxy-
carbonyl, 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, 4-ethoxy-l-
naphthyloxycarbonyl, 8-quinolyloxycarbonyl, S-
benzylthiocarbonyl and the like; acyl groups such as
acetyl, formyl, chloroacetyl, dichloroacetyl,
trichloroacetyl, trifluoroacetyl, methoxyacetyl,
phenoxyacetyl, pivaloyl, benzoyl and the like; lower
alkyl groups such as methyl, tert-butyl, 2,2,2-
trichloroethyl, 2-trimethylsilylethyl and the like;
lower alkenyl groups such as allyl and the like; lower
alkynyl groups such as propargyl and the like; ar-lower
alkyl groups such as benzyl, 4-methoxybenzyl, 3,4-
dimethoxybenzyl, diphenylmethyl, trityl and the like;
oxygen-containing or sulfur-containing heterocyclic
groups such as tetrahydrofuryl, tetrahydropyranyl,
tetrahydrothiopyranyl and the like; lower alkoxy- or
lower alkylthio-lower alkyl groups such as
methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-
methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2-
(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, 1-methyl-
1-methoxyethyl and the like; lower alkyl- or aryl-
sulfonyl groups such as methanesulfonyl, p-
toluenesulfonyl and the like; and substituted silyl
groups such as trimethylsilyl, triethylsilyl,
triisopropylsilyl, diethylisopropylsilyl, tert-
butyldimethylsilyl, tert-butyldiphenylsilyl,
diphenylmethylsilyl, tert-butylmethoxyphenylsilyl and
the like.
The protecting group for the amino group
includes all conventional groups usable as amino-
protecting groups, for example, alkoxycarbonyl groups
such as methoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,
2,2,2-tribromoethoxycarbonyl, 2-trimethylsilylethoxy-
carbonyl, 1,1-dimethylpropoxycarbonyl, tert-
butoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 1-
adamantyloxycarbonyl, benzyloxycarbonyl, 4-
nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 4-
methoxybenzyloxycarbonyl, 2,4-
dichlorobenzyloxycarbonyl, diphenylmethoxycarbonyl, 4-
(phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, 8-
quinolyloxycarbonyl and the like; acyl groups such as
(mono-, di- or tri-)chloroacetyl, trifluoroacetyl,
phenylacetyl, formyl, acetyl, benzoyl, phthaloyl,
succinyl, alanyl, leucyl and the like; ar-lower alkyl
groups such as benzyl, diphenylmethyl, trityl and the
like; arylthio groups such as 2-nitrophenylthio, 2,4-
dinitrophenylthio and the like; alkyl- or aryl-sulfonyl
groups such as methanesulfonyl, p-toluenesulfonyl and
the like; di-lower alkylamino-lower alkylidene groups
such as N,N-dimethylaminomethylene and the like; ar-
lower alkylidene groups such as benzylidene, 2-
hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-
hydroxy-1-naphthylmethylene and the like; nitrogen-
containing heterocyclic alkylidene groups such as 3-
hydroxy-4-pyridylmethylene and the like;
cycloalkylidene groups such as cyclohexylidene, 2-
ethoxycarbonylcyclohexylidene, 2-
ethoxycarbonylcyclopentylidene, 2-
acetylcyclohexylidene, 3,3-dimethyl-5-
oxycyclohexylidene and the like; diaryl- or diar-lower
alkylphosphoryl groups such as diphenylphosphoryl,
dibenzylphosphoryl and the like; oxygen-containing
heterocyclic alkyl groups such as 5-methyl-2-oxo-2H-
1,3-dioxol-4-yl-methyl and the like; and substituted
silyl groups such as trimethylsilyl and the like.
The salt of the compound of the general
formula [1] includes usually known salts at basic
groups such as amino group and the like and salts at
acidic groups such as hydroxyl group, carboxyl group
and the like.
The salts at the basic groups include, for
example, salts with mineral acids such as hydrochloric
acid, hydrobromic acid, nitric acid, sulfuric acid and
the like; salts with organic carboxylic acids such as
formic acid, acetic acid, citric acid, oxalic acid,
fumaric acid, maleic acid, succinic acid, malic acid,
tartaric acid, aspartic acid, trichloroacetic acid,
trifluoroacetic acid and the like; and salts with
sulfonic acids such as methanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid,
mesitylenesulfonic acid, naphthalenesulfonic acid and
the like.
The salts at the acidic groups include, for
example, salts with alkali metals such as sodium,
potassium and the like; salts with alkaline earth
metals such as calcium, magnesium and the like;
ammonium salts; and salts with nitrogen-containing
organic bases such as trimethylamine, triethylamine,
tributylamine, pyridine, N,N-dimethylaniline, N-
methylpiperidine, N-methylmorpholine, diethylamine,
dicyclohexylamine, procaine, dibenzylamine, N-benzyl-ß-
phenethylamine, 1-ephenamine, N,N"-
dibenzylethylenediamine and the like.
Of the above-exemplified salts, preferable
salts are pharmacologically acceptable salts.
When the alkyl ether derivative of the
general formula [1] or its salt has isomers (for
example, optical isomers, geometrical isomers and
tautomers), the present invention includes all of these
isomers, and the derivative or its salt may be in the
form of a hydrate or solvate or in any crystal form.
Preferable examples of the alkyl ether
derivative of the general formula[1]or salt thereof
of the present invention are compounds of the general
formula [1] in which the portion represented by
Of such compounds, preferable examples of the
derivative or salt thereof of the present invention are
compounds in which R~ is a hydrogen atom; and R2 is a
hydrogen atom, a halogen atom or an alkoxy group.
In addition, compounds of the general formula
[1] in which m = 2 and n = 2 ~ 3 are preferable. Of
such compounds, compounds of the general formula [1] in
which p = 1 ~ 2 are more preferable.
The most preferable examples of the
derivative or salt thereof of the present invention are
compounds in which each of R1 and R2 in the above group
(A) is a hydrogen atom; R3 is a hydroxyl group; m = 2;
n = 3; and p = 1.
Processes for producing the alkyl ether
derivative of the general formula [1] or its salt are
explained below.
The alkyl ether derivative of the general
formula [1] or its salt can be produced, for example,
by any of the following production processes by
adopting one or a proper combination of per se well-
known methods.
Production process 1
wherein R1, R2, R3, A, m, n and p are as defined above;
R3a is a dialkylamino group, a protected monoalkylamino
group, a protected amino group or a protected or
unprotected hydroxyl group; R3b is a dialkylamino group,
a protected monoalkylamino group, a protected amino
group or a protected hydroxyl group; R3c is a protected
hydroxyl group; R3d is a monoalkylamino group, an amino
group or a hydroxyl group; and each of X1, X2 and X3 is a
leaving group.
The leaving group includes, for example,
halogen atoms, lower alkylsulfonyloxy groups and
arylsulfonyloxy groups.
The individual production processes are
explained below.
Production process 1.
(1-1) A compound of the general formula [4] can be
produced by reacting a compound of the general formula
[2] or its reactive derivative with a compound of the
general formula [3].
This reaction may be carried out by a per se
well-known method, for example, the method described in
Japanese Chemical Association, "Jikken Kagaku Koza"
vol. 22, pages 137-173 (1992), Maruzen Co., Ltd. or a
method based thereon.
The reactive derivative of the compound of
the general formula [2] includes, for example, acid
halides, acid anhydrides, activated amides and
activated esters.
When the compound of the general formula [2]
is used in the form of a free acid, the reaction is
preferably carried out in the presence of a condensing
agent.
The condensing agent includes, for example,
N,N"-dialkylcarbodiimides such as N,N"-dicyclohexyl-
carbodiimide and the like; halogenating agents such as
thionyl chloride, oxalyl chloride and the like; acid
halides such as ethoxycarbonyl chloride and the like;
agents for conversion to an activated amide, such as
carbonyldiimidazole and the like; and agent for
conversion to an azide, such as diphenylphosphoryl
azide and the like.
The amount of the condensing agent used is 1
mole or more, preferably 1 to 5 moles, per mole of the
compound of the general formula [2].
In the reaction, any solvent may be used so
long as it has no undesirable influence on the
reaction. The solvent includes, for example, water;
halogenated hydrocarbons such as methylene chloride,
chloroform and the like; ethers such as tetrahydro-
furan, dioxane and the like; aromatic hydrocarbons such
as benzene, toluene, xylene and the like; sulfoxides
such as dimethyl sulfoxide and the like; amides such as
N,N-dimethylformamide and the like; esters such as
ethyl acetate and the like; ketones such as acetone,
methyl ethyl ketone and the like; nitriles such as
acetonitrile and the like; and heteroaromatic compounds
such as pyridine and the like. These solvents may be
used singly or as a mixture thereof.
The reaction may be carried out in the
presence of a base.
The base includes, for example, organic or
inorganic bases such as triethylamine,
diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undec-7-
ene (DBU), pyridine, potassium tert-butoxide, sodium
carbonate, sodium hydrogencarbonate, potassium
carbonate, sodium hydroxide and the like.
The amount of the base used is 0.5 mole or
more, preferably 1 to 10 moles, per mole of the
compound of the general formula [2].
The amount of the compound of the general
formula [3] is 1 mole or more, preferably 1 to 20
moles, per mole of the compound of the general formula
[2].
The reaction is carried out at usually -100°C
to 200°C, preferably -60°C to 100°C, for 10 minutes to
20 hours.
The compound of the general formula [4]
obtained may be used as it is in the subsequent
reaction without isolation.
(1-2) When R3a is an unprotected hydroxyl group in
the compound of the general formula [4], this compound
can be converted to a compound of the general formula
[4a] by subjecting it to a conventional reaction for
protecting the hydroxyl group.
This reaction may be carried out by a per se
well-known method, for example, the method described in
Theodora W. Green, "Protective Groups in Organic
Synthesis" pages 10-118 (1991), John Wiley & Sons.
Inc., or a method based thereon.
A compound used in the reaction for
protecting the hydroxyl group includes, for example,
acid anhydrides such as acetic anhydride and the like;
acid halides such as benzoyl chloride, pivaloyl
chloride, methoxycarbonyl chloride, ethoxycarbonyl
chloride and the like; halides such as methoxymethyl
chloride, benzyloxymethyl chloride, benzyl chloride,
benzyl bromide, trityl chloride, triethylsilyl chloride
and the like; organic carboxylic acid compounds such as
benzoic acid and the like; dialkoxyalkyl compounds such
as dimethoxymethane and the like; and acyclic or cyclic
alkoxyvinyl compounds such as 2-methoxypropene, 3,4-
dihydro-2H-pyran and the like.
The amount of the compound used in the
reaction for protecting the hydroxyl group is 1 mole or
more, preferably 1 to 2 moles, per mole of the compound
of the general formula [4a].
The reaction for protecting the hydroxyl
group by the use of any of the acid anhydrides, the
acid halides and the halides is usually carried out in
the presence of a base or a dehalogenating agent. The
base used includes, for example, organic or inorganic
bases such as triethylamine, N,N-diisopropylethylamine,
1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), pyridine, 4-
dimethylaminopyridine, potassium tert-butoxide, sodium
hydroxide, potassium hydroxide, sodium hydride and the
like. The dehalogenating agent includes silver
compounds such as silver oxide and the like.
The reaction for protecting the hydroxyl
group by the use of the organic carboxylic acid
compound is carried out in the presence of a
dehydrating agent. The dehydrating agent used
includes, for example triphenylphosphine-
diisopropyl=azodicarboxylate.
The reaction for protecting the hydroxyl
group by the use of any of the acid anhydrides, the
dialkoxyalkyl compounds and the acyclic or cyclic
alkoxyvinyl compounds is usually carried out in the
presence of an acid catalyst. The acid used includes
organic sulfonic acids such as p-toluenesulfonic acid
and the like; inorganic acids such as hydrochloric
acid, sulfuric acid and the like; and Lewis acids such
as boron trifluoride, boron trifluoride diethyl ether
complex, boron trifluoride tetrahydrofuran complex and
the like.
The amount of the base, dehalogenating agent
or dehydrating agent used in the reaction is 1 mole or
more, preferably 1 to 2 moles, per mole of the compound
used in the reaction for protecting the hydroxyl group.
The amount of the acid used as catalyst is 0.001 to 10
moles, preferably 0.01 to 1 mole, per mole of the
compound of the general formula [4a].
In the reaction, any solvent may be used so
long as it has no undesirable influence on the
reaction. The solvent includes, for example,
halogenated hydrocarbons such as methylene chloride,
chloroform and the like; ethers such as
tetrahydrofuran, dioxane and the like; aromatic
hydrocarbons such as benzene, toluene, xylene and the
like; sulfoxides such as dimethyl sulfoxide and the
like; amides such as N,N-dimethylformamide and the
like; esters such as ethyl acetate and the like;
ketones such as acetone, methyl ethyl ketone and the
like; nitriles such as acetonitrile and the like; and
heteroaromatic compounds such as pyridine and the like.
These solvents may be used singly or as a mixture
thereof.
The reaction is carried out at usually -100°C
to 200°C, preferably -60°C to 100°C, for 10 minutes to
30 hours.
The reactants or base used in each of the
above production methods may be used also as a solvent,
depending on their properties.
The compound of the general formula [4a]
obtained may be used as it is in the subsequent
reaction without isolation.
(1-3) A compound of the general formula [1] can be
produced by subjecting the compound of the general
formula [4] or the general formula [4a] to a
conventional reduction.
This reduction may be carried out by a per se
well-known method, for example, the method described in
Japanese Chemical Association, "Shin Jikken Kagaku
Koza" vol. 15, [II], pages 29-244 (1977), Maruzen Co.,
Ltd. or a method based thereon.
In the reaction, any solvent may be used so
long as it has no undesirable influence on the reac-
tion. The solvent includes, for example, halogenated
hydrocarbons such as methylene chloride, chloroform and
the like; ethers such as tetrahydrofuran, dioxane and
the like; aromatic hydrocarbons such as benzene,
toluene, xylene and the like; and alcohols such as
methanol, ethanol, isopropanol and the like. These
solvents may be used singly or as a mixture thereof.
As a reducing agent, there are exemplified
aluminum hydrides such as lithium aluminum hydride and
the like; and boron hydrides such as diborane, borane-
tetrahydrofuran complexes, borane-dimethyl sulfide
complexes, sodium borohydride and the like.
When sodium borohydride is used as the
reducing agent, the reaction is preferably carried out
in the presence of a Lewis acid such as boron
trifluoride, boron trifluoride diethyl ether complex,
boron trifluoride tetrahydrofuran complex or the like.
The amount of the redacing agent used is 0.2
mole or more, preferably 0.5 to 10 moles, per mole of
the compound of the general formula [4] or the general
formula [4a].
The amount of the Lewis acid used is 1 mole
or more, preferably 4/3 to 2 moles, per mole of the
reducing agent.
The reaction is carried out at usually -50°C
to 200°C, preferably 0°C to 110°C, for 10 minutes to 20
hours.
Production process 2.
A compound of the general formula [la] can be
produced by reacting a compound of the general formula
[5] with a compound of the general formula [3] in the
presence or absence of a base.
In this reaction, any solvent may be used so
long as it has no undesirable influence on the
reaction. The solvent includes,, for example, water;
halogenated hydrocarbons such as methylene chloride,
chloroform and the like; aromatic hydrocarbons such as
benzene, toluene, xylene and the like; ethers such as
tetrahydrofuran, dioxane and the like; alcohols such as
methanol, ethanol and the like; nitriles such as
acetonitrile and the like; amides such as N,N-
dimethylformamide and the like; and sulfoxides such as
dimethyl sulfoxide and the like. These solvents may be
used singly or as a mixture thereof.
The base optionally used includes, for
example, organic or inorganic bases such as
triethylamine, diisopropylethylamine, 1,8-
diazabicyclo[5,4,0]undec-7-ene (DBU), pyridine,
potassium tert-butoxide, sodium carbonate, sodium
hydrogencarbonate, potassium carbonate, sodium
hydroxide and the like.
The amount of the base used is 0.5 mole or
more, preferably 1 to 20 moles, per mole of the
compound of the general formula [5],
In addition, the reaction may be carried out
in the presence of a catalyst.
The catalyst includes, for example, potassium
iodide and sodium iodide.
The amount of the catalyst used is 0.01 to 10
moles, preferably 0.1 to 1 mole, per mole of the
compound of the general formula [5].
The amount of the compound of the general
formula [3] used is 1 mole or more, preferably 1 to 20
moles, per mole of the compound of the general formula
[5] .
The reaction is carried out at usually 0°C to
200°C, preferably 20°C to 150°C, for 10 minutes to 20
hours.
The reactants or base used in the above
production process may be used also as a solvent,
depending on their properties.
Production process 3.
A compound of the general formula [lb] can be
produced by reacting a compound of the general formula
[6] with a compound of the general formula [7] in the
presence of a base.
This reaction may be carried out by a per se
well-known method, for example, the method described in
Tetrahedron Letters, vol. 38, pages 3251-3254 (1975)
and Japanese Chemical Association, "Shin Jikken Kagaku
Koza" vol. 14, [I], pages 567-611 (1977), Maruzen Co.,
Ltd. or a method based thereon.
The base includes, for example, sodium
hydride, sodium hydroxide, potassium hydroxide and
potassium tert-butoxide.
In the reaction, any solvent may be used so
long as it has no undesirable influence on the
reaction. The solvent includes, for example,
halogenated hydrocarbons such as methylene chloride,
chloroform and the like; ethers such as
tetrahydrofuran, dioxane and the like; aromatic
hydrocarbons such as benzene, toluene, xylene and the
like; sulfoxides such as dimethyl sulfoxide and the
like; amides such as N,N-dimethylformamide and the
like; and water. These solvents may be used singly or
as a mixture thereof.
The reaction may be carried out in the
presence or absence of a catalyst.
The catalyst used includes usually known
phase transfer catalysts composed of a quaternary
ammonium salt, and preferable examples thereof are
tetra-n-butylammonium hydrogensulfate and tetra-n-
butylammonium bromide.
The amount of each of the compound of the
general formula [7] and the base used in the reaction
is 1 mole or more, preferably 1 to 20 moles, per mole
of the compound of the general formula [6]. The amount
of the catalyst is 0.001 to 1 mole per mole of the
compound of the general formula [6].
The reaction is carried out at usually -50°C
to 200°C, preferably 0°C to 150°C, for 10 minutes to 20
hours.
Production process 4.
A compound of the general formula [lb] can be
produced by reacting a compound of the general formula
[8] with a compound of the general formula [9] in the
presence or absence of a base.
This reaction may be carried out by a per se
well-known method, for example, the same method as in
production process 3.
Production process 5.
(5-1) A compound of the general formula [lc] can be
produced by subjecting a compound of the general
formula [la] and a compound of rhe general formula [lb]
to a conventional deprotecting reaction.
This reaction may be carried out by a per se
well-known method, for example, the method described in
Theodora W. Green, "Protective Groups in Organic
Synthesis" pages 10-118 and 309-405 (1991), John Wiley
& Sons. Inc., or a method based thereon.
The deprotecting reaction is carried out
under conditions for, for example, hydrolysis and
transesterification reaction in the presence of an acid
or a base, substitution and elimination reaction in the
presence of an acid catalyst, or hydrogenolysis in the
presence of a metal catalyst. The base used includes,
for example, inorganic bases such as sodium hydroxide,
potassium hydroxide, sodium hydride and the like. The
acid includes organic sulfonic acids such as p-
toluenesulfonic acid and the like; organic carboxylic
acids such as formic acid, acetic acid, trifluoroacetic
acid and the like; inorganic acids such as hydrochloric
acid, sulfuric acid and the likes; and Lewis acids such
as boron trifluoride, boron trifluoride diethyl ether
complex, boron trifluoride tetrahydrofuran complex and
the like. The metal catalyst includes, for example,
transition metals such as platinum, palladium,
palladium-carbon, palladium hydroxide and the like.
The base used in the reaction may be used in
an amount of 1 mole or more, preferably 1 to 5 moles,
per mole of a combination of the compounds of the
general formulas [la] and [lb]. The amount of the acid
used is 1 mole or more, preferably 1.1 to 100 moles,
per mole of a combination of the compounds of the
general formulas [la] and [lb]. The amount of the
metal catalyst used is a catalytic amount, preferably
0.01 to 30% by weight, relative to a combination of the
compounds of the general formulas [la] and [lb].
In the reaction, any solvent may be used so
long as it has no undesirable influence on the
reaction. The solvent includes, for example,
halogenated hydrocarbons such as methylene chloride,
chloroform and the like; ethers such as
tetrahydrofuran, dioxane and the like; aromatic
hydrocarbons such as benzene, toluene, xylene and the
like; sulfoxides such as dimethyl sulfoxide and the
like; amides such as N,N-dimethylformamide and the
like; esters such as ethyl acetate and the like;
ketones such as acetone, methyl ethyl ketone and the
like; nitriles such as acetonitrile and the like;
alcohols such as methanol, ethanol and the like;
organic carboxylic acids such as formic acid, acetic
acid and the like; and water. These solvents may be
used singly or as a mixture thereof.
The reaction is carried out at usually -100°C
to 200°C, preferably -60°C to 120°C, for 10 minutes to
20 hours.
The acid used in each of the above production
methods may be used also as a solvent, depending on its
properties.
(5-2) The compound of the general formula [lc] can
be converted to the compound of the general formula
[lb] by subjecting it to any of conventional reactions
for protection of a hydroxyl group and an amino group
and the alkylation of an amino group.
The reaction for protecting a hydroxyl group
may be carried out by a per se well-known method, for
example, the method described ir, Theodora W. Green,
"Protective Groups in Organic Synthesis" pages 10-118
(1991), John Wiley & Sons. Inc., or a method based
thereon, namely, the reaction may be carried out by the
same method as in the above item (1-2).
The reaction for protecting an amino group
may be carried out by a per se well-known method, for
example, the method described in Theodora W. Green,
"Protective Groups in Organic Synthesis" pages 309-405
(1991), John Wiley & Sons. Inc., or a method based
thereon.
A compound used in the reaction for
protecting an amino group includes, for example, acid
anhydrides such as acetic anhydride and the like; and
acid halides such as acetyl chloride, benzoyl chloride,
mesyl chloride, tosyl chloride and the like. The
amount of the compound used is 1 mole or more,
preferably 1 to 2 moles, per mole of the compound of
the general formula [lc].
This reaction is usually carried out in the
presence of a base, and the base includes, for example,
organic or inorganic bases such as triethylamine,
diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undec-7-
ene (DBU), pyridine, potassium tert-butoxide, sodium
carbonate, sodium hydrogencarbonate, potassium
carbonate, sodium hydride and the like.
The amount of the base used is 0.5 mole or
more, preferably 1 to 10 moles, per mole of the
compound of the general formula [1c].
In the reaction, any solvent may be used so
long as it has no undesirable influence on the
reaction. The solvent includes, for example,
halogenated hydrocarbons such as methylene chloride,
chloroform and the like; ethers such as
tetrahydrofuran, dicxane and the like; aromatic
hydrocarbons such as benzene, toluene, xylene and the
like; sulfoxides such as dimethyl sulfoxide and the
like; amides such as N,N-dimethylformamide and the
like; esters such as ethyl acetate and the like;
ketones such as acetone, methyl ethyl ketone and the
like; nitriles such as acetonitrile and the like;
alcohols such as methanol, ethanol and the like; and
water. These solvents may be used singly or as a
mixture thereof.
The reaction is carried out at usually -100°C
to 200°C, preferably -60°C to 100°C, for 10 minutes to
20 hours.
The alkylation of an amino group may be
carried out by a per se well-known method, for example,
the method described in Japanese Chemical Association,
"Shin Jikken Kagaku Koza" vol. 14, [III], pages 1332-
1399 (1977), Maruzen Co., Ltd. or a method based
thereon.
A compound used in the alkylation of an amino
group includes, for example, carbonyl compounds such as
formaldehyde, paraformaldehyde, acetaldehyde, acetone
and the like.
The amount of this compound used is 1 mole or
more, preferably 1 to 5 moles, per mole of the compound
of the general formula [lc].
This reaction is usually carried out in the
presence of a reducing agent, and the reducing agent
includes boron hydrides such as sodium borohydride and
the like.
The amount of the reducing agent used is 0.5
mole or more, preferably 1 to 10 moles, per mole of the
carbonyl compound.
In the reaction, any solvent may be used so
long as it has no undesirable influence on the
reaction. The solvent includes, for example, water;
halogenated hydrocarbons such as methylene chloride,
chloroform and the like; aromatic hydrocarbons such as
benzene, toluene, xylene and the like; ethers such as
tetrahydrofuran, dioxane and the like; and alcohols
such as methanol, ethanol and the like. These solvents
may be used singly or as a mixture thereof.
The reaction is carried out at usually -100°C
to 200°C, preferably 0°C to 100°C, for 10 minutes to 30
hours.
The reactants used in each of the above
production methods may be used also as a solvent,
depending on their properties.
In the above production processes, each of
the compounds of the general formulas [2] to [9] can be
used in the form of a salt. As the salt, there are
exemplified the same salts as in the case of the
compound of the general formula [1]. As salts of the
compounds of the general formulas [la], [lb] and [lc],
there are exemplified the same salts as in the case of
the compound of the general formula [1].
When any cf the compounds of the general
formulas [la], [lb], [lc] and [2] to [9] has isomers
(for example, optical isomers, geometrical isomers and
tautomers), each of these isomers can be used. In
addition, any of the: compounds may be used in the form
of a hydrate or solvate or in any crystal form.
Each of the compounds of the general formulas
[la], [lb], [lc] and [2] to [9] may be used as it is in
the subsequent reaction without isolation.
When any of the compounds of the general
formulas [1], [la], [lb] , [lc] and [2] to [9] has a
hydroxyl group, an amino group or a carboxyl group, it
is possible to previously protect the hydroxyl group,
the amino group or the carboxyl group with a
conventional protecting group and, if necessary, remove
the protecting group by a per se well-known method
after completion of the reaction.
In addition, each of the alkyl ether
derivatives of the general formulas [1], [la], [lb] and
[lc] or its salt can be converted to another alkyl
ether derivative of the general formula [1] or its salt
by a proper combination of per se well-known methods
such as oxidation, reduction, alkylation, halogenation,
sulfonylation, substitution, dehydration, hydrolysis
and the like.
The alkyl ether derivatives of the general
formulas [1], [la], [lb] and [lc] or their salts can be
isolated and separated according to one or more
conventional operations which may be selected from
extraction, crystallization, distillation, column
chromatography and the like.
Processes for producing each of the compounds
of the general formulas [2] and [5], which is a
starting material for producing the compound of the
present invention, are explained below.
The compound of the general formula [2] can
be produced, for example, by the following production
process A by adopting one or a proper combination of
per se well-known methods.
wherein R1, R2, A, X3, m and n are as defined above; R4
is a cyano group, a lower alkoxycarbonyl group, a
dialkylaminocarbonyl group or a cyclic aminocarbonyl
group; and X4 is a leaving group.
(A-l) A compound of the general formula [11] can be
produced by reacting a compound of the general formula
[6] with a compound of the general formula [10] in the
presence of a base.
This reaction may be carried out by a per se
well-known method, for example, the method described in
Japanese Chemical Association, "Shin Jikken Kagaku
Koza" vol. 14, [I], pages 567-611 (1977), Maruzen Co.,
Ltd. or a method based thereon.
(A-2) A compound of the general formula [11] can be
produced by reacting a compound of the general formula
[8] with a compound of the general formula [12] in the
presence of a base.
This reaction may be carried out by a per se
well-known method, for example, the same method as in
the production process (A-l).
(A-3) The compound of the general formula [2] can
be produced by subjecting the compound of the general
formula [11] to a conventional hydrolysis of nitrile,
ester or amide.
This reaction may be carried out by a per se
well-known method, for example, the method described in
Japanese Chemical Association, "Shin Jikken Kagaku
Koza" vol. 14, [II], pages 930-950 (1977), Maruzen Co.,
Ltd. and Theodora W. Green, "Protective Groups in
Organic Synthesis" pages 152-192 (1981), John Wiley &
Sons. Inc. or a method based thereon.
(A-4) A compound of the general formula [11a] can
be produced by subjecting a compound of the general
formula [6] to Michael addition with a compound of the
general formula [16] in the presence of a base.
This reaction may be carried out by a per se
well-known method, for example, the method described in
any of "Chemical & Pharmaceutical Bulletin" vol. 41,
pages 1659-1663 (1993), Japanese Chemical Association,
"Shin Jikken Kagaku Koza" vol. 14, [I], pages 585-587
(1977), Maruzen Co., Ltd. and JP-A-3-99038, or a method
based thereon.
(A-5) A compound of the general formula [2a] can be
produced by subjecting the compound of the general
formula [11a] to a conventional hydrolysis of nitrile,
ester or amide.
This reaction may be carried out by a per se
well-known method, for example, the same method as in
(A-3).
The compound of the general formula [5] can
be produced, for example, by the following production
process B by adopting one or a proper combination of
per se well-known methods.
wherein R1, R2, X1, A, m and n are as defined above; R4a
is an alkoxycarbonyl group; R5 is a hydroxyl-protecting
group which is stable under basic conditions; and each
of X5 and X6 is a leaving group.
The hydroxyl-protecting group stable under
basic conditions includes, for example, lower alkyl
groups such as tert-butyl and the like; lower alkenyl
groups such as allyl and the like; ar-lower alkyl
groups such as benzyl, 4-methoxybenzyl, 3,4-
dimethoxybenzyl, diphenylmethyl, trityl and the like;
oxygen-containing or sulfur-containing heterocyclic
groups such as tetrahydrofuryl, tetrahydropyranyl,
tetrahydrothiopyranyl and the like; lower alkoxy-lower
alkyl groups such as methoxymethyl, 2-
(trimethylsilyl)ethoxymethyl, 1-methyl-l-methoxyethyl
and the like; and substituted silyl groups such as
tert-butyldimethylsilyl, diphenylmethylsilyl and the
like.
(B-l) The compound of the general formula [5] can
be produced by reacting a compound of the general
formula [6] with a compound of the general formula
[13].
This reaction may be carried out by a per se
well-known method, for example, the method described in
Tetrahedron Letters, vol. 38, pages 3251-3254 (1975)
and Japanese Chemical Association, "Shin Jikken Kagaku
Koza" vol. 14, [I], pages 567-611 (1977), Maruzen Co.,
Ltd. or a method based thereon.
(B-2) A compound of the general formula [15] can be
produced by reacting a compound of the general formula
[6] with a compound of the general formula [14], and
then removing the protecting group.
This reaction may be carried out by a per se
well-known method, for example, the same method as in
production process 3, and then the protecting group may
be removed.
(B-3) A compound of the general formula [15] can be
produced by subjecting a compound of the general
formula [2] or a compound of the general formula [l1b]
to a conventional reduction.
This reduction may be carried out by a per se
well-known method, for example, the method described in
"Shin Jikken Kagaku Koza" vol. 15, pages 26-244 (1977),
Maruzen Co., Ltd. or a method based thereon.
(B-4) The compound of the general formula [5] can
be produced by reacting the compound of the general
formula [15] with a halogenating agent or a
sulfonylating agent in the presence or absence of a
base.
A solvent used in this reaction includes, for
example, halogenated hydrocarbons such as methylene
chloride, chloroform and the like; ethers such as
tetrahydrofuran, dioxane and the like; aromatic
hydrocarbons such as benzene, toluene, xylene and the
like; sulfoxides such as dimethyl sulfoxide and the
like; amides such as N,N-dimethylformamide and the
like; esters such as ethyl acetate and the like; and
nitriles such as acetonitrile and the like. These
solvents may be used singly or as a mixture thereof.
The base optionally used includes, for
example, organic or inorganic bases such as
triethylamine, diisopropylethylamine, 1,8-
diazabicyclo[5,4,0]undec-7-ene, pyridine, potassium
tert-butoxide, sodium carbonate, potassium carbonate,
sodium hydride and the like.
The halogenating agent includes, for example,
phosphorus oxychloride, phosphorus oxybromide,
phosphorus trichloride, phosphorus pentachloride,
carbon tetrabromide-triphenylphosphine, and thionyl
chloride.
The sulfonylating agent includes, for
example, methanesulfonyl chloride and p-toluenesulfonyl
chloride.
The amount of each of the halogenating agent
or sulfonylating agent and the base used is 1 mole or
more, preferably 1 to 2 moles, per mole of the compound
of the general formula [15].
The reaction is carried out at usually -50°C
to 200°C, preferably 0°C to 50°C, for 10 minutes to 30
hours.
When any of the compounds of the general
formulas [2], [2a], [6], [8], [10] to [16], [11a] and
[l1b] in production processes A and B has a hydroxyl
group, an amino group or a carboxyl group, it is
possible to previously protect the hydroxyl group, the
amino group or the carboxyl group with a conventional
protecting group and, if necessary, remove the
protecting group by a per se well-known method after
completion of the reaction.
When any of the compounds of the general
formulas [2], [2a], [6], [8], [20] to [16], [11a] and
[l1b] has isomers (for example, optical isomers,
geometrical isomers and tautomers), each of these
isomers can be used. In addition, any of the compounds
may be used in the form of a hydrate or solvate or in
any crystal form.
Each of the compounds of the general formulas
[2], [2a], [6], [8], [10] to [16], [11a] and [11b] may
be used as it is in the subsequent reaction without
isolation.
The compound of the present invention can be
formulated into pharmaceutical preparations such as
oral preparations (e.g. tablets, capsules, powders,
granules, fine granules, pills, suspensions, emulsions,
solutions and syrups), injections, suppositories,
external preparations (e.g. ointments and patches),
aerosols and the like by blending therewith various
pharmaceutical additives such as excipients, binders,
disintegrators, disintegration inhibitors,
consolidation•adhes:.on inhibitors, lubricants,
absorption•adsorption carriers, solvents, fillers,
isotonicity agents, solubilizers, emulsifying agents,
suspending agents, thickening agents, coating agents,
absorption accelerators, gelation•coagulation
accelerators, light stabilizers, preservatives,
dehumidifiers, emulsion•suspension•dispersion
stabilizers, color protectors, deoxygenation»oxidation
inhibitors, sweetening•flavoring agents, coloring
agents, foaming agents, defoaming agents, soothing
agents, antistatic agents, buffering and pH-adjusting
agents, etc.
The above various Pharmaceuticals are
prepared by conventional methods.
The oral solid Pharmaceuticals such as
tablets, powders and granules are prepared by a
conventional method by using pharmaceutical additives
for solid preparation, for example, excipients such as
lactose, sucrose, scdium chloride, glucose, starch,
calcium carbonate, kaolin, crystalline cellulose,
anhydrous calcium secondary phosphate, partly
pregelatinized starch, corn starch, alginic acid and
the like; binders such as simple syrup, a glucose
solution, a starch solution, a gelatin solution,
polyvinyl alcohols, polyvinyl ethers,
polyvinylpyrrolidones, carboxymethyl cellulose,
shellac, methyl cellulose, ethyl cellulose, sodium
alginate, gum arabic, hydroxypropylmethyl cellulose,
hydroxypropyl cellulose, water, ethanol and the like;
disintegrators such as dried starch, alginic acid, agar
powder, starch, crosslinked polyvinylpyrrolidones,
crosslinked carboxymethyl cellulose sodium salt,
carboxymethyl cellulose calcium salt, starch sodium
glycolate and the like; disintegration inhibitors such
as stearyl alcohol, stearic acid, cacao butter,
hydrogenated oil and the like; consolidatiorradhesion
inhibitors such as aluminum silicate, calcium
hydrogenphosphate, magnesium oxide, talc, silicic acic
anhydride and the like; lubricants such as carnauba
wax, light silicic acid anhydride, aluminum silicate,
magnesium silicate, hydrogenated oil, hydrogenated
vegetable oil derivatives, sesame oil, white beeswax,
titanium oxide, dried aluminum hydroxide gel, stearic
acid, calcium stearate, magnesium stearate, talc,
calcium hydrogenphosphate, sodium lauryl sulfate,
polyethylene glycols and the like; absorption
accelerators such as quaternary ammonium salts, sodium
lauryl sulfate, urea, enzymes and the like; and
absorption•adsorption carriers such as starch, lactose
kaolin, bentonite, silicic acid anhydride, hydrated
silicon dioxide, magnesium aluminate metasilicate,
colloidal silica and the like.
If necessary, tablets can be made into
tablets having a conventional coating, such as sugar
coated tablets, gelatin coated tablets, gastric coated
tablets, enteric coated tablets and water-soluble-film
coated tablets.
The capsules are prepared by mixing the
compound of the present invention with the above-
exemplified various pharmaceutical additives and
packing the resulting mixture into hard gelatin
capsules, soft capsules or the like.
The compound of the present invention can be
formulated into an aqueous or oily suspension,
solution, syrup or elixir by a conventional method by
using the above-exemplified various additives for
liquid preparation, such as solvents, fillers,
isotonicity agents, solubilizers, emulsifying agents,
suspending agents, thickening agents and the like.
The suppositories are prepared by adding a
suitable absorption accelerator to, for example, a
polyethylene glycol, cacao butter, lanolin, a higher
alcohol, a higher alcohol ester, gelatin, a semi-
synthesized glyceride or Witepsol.
The injections are prepared by a conventional
method by using pharmaceutical additives for liquid
preparation, for example, diluents such as water,
ethanol, Macrogol, propylene glycol, citric acid,
acetic acid, phosphoric acid, lactic acid, sodium
lactate, sulfuric acid, sodium hydroxide and the like;
pH adjustors and buffers, such as sodium citrate,
sodium acetate, sodium phosphate and the like;
stabilizers such as sodium pyrosulfite,
ethylenediaminetetraacetic acid, thioglycolic acid,
thiolactic acid and the like; isotonicity agents such
as sodium chloride, glucose, mannitol, glycerol and the
like; solubilizers such as carboxymethyl cellulose
sodium salt, propylene glycol, sodium benzoate, benzyl
benzoate, urethane, ethanolamine, glycerol and the
like; soothing agents such as calcium gluconate,
chlorobutanol, glucose, benzyl alcohol and the like;
and local anesthetics.
The ointments in the form of paste, cream or
gel are prepared by mixing and formulation according to
a conventional method by using pharmaceutical
additives, for example, base ingredients such as white
soft paraffin, polyethylenes, paraffin, glycerol,
cellulose derivatives, polyethylene glycols, silicone,
bentonite and the like; preservatives such as methyl p-
oxybenzoate, ethyl p-oxybenzoate, propyl p-oxybenzoate
and the like; stabilizers; and wetting agents.
When the patch is prepared, the above-
mentioned ointment, cream, gel or paste is applied on a
conventional support by a conventional method. As the
support, there can be used woven or nonwoven fabrics
made of cotton, staple fiber or chemical fiber; and
films or foamed sheets of soft vinyl chloride, a
polyethylene, a polyurethane or the like.
A method for administering the above-
mentioned pharmaceutical preparation is not
particularly limited and is properly determined
depending on the pharmaceutical form, the age, sex and
other conditions of a patient, and the symptom of the
patient.
The dose of active ingredient of the
pharmaceutical preparation of the present invention is
properly chosen depending on administration route, the
age, sex and pathosis of a patient, and other
conditions. Usually, the active ingredient may be
administered to an adult in a dose of 0.1 to 500 nag per
day in one portion or several portions.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention is illustrated with
reference to the following examples, reference examples
and test examples, which should not be construed as
limiting the scope of the invention.
In the examples and reference examples, the
mixing ratios in the eluents are all by volume, and
B.W. Silica gel, BW-127ZH or FL-100DX (mfd. by FUJI
SILYSIA CHEMICAL LTD.) was used as a carrier in the
column chromatography.
The symbols used in the reaction schemes have
the following meanings:
Ac: acetyl, Boc: tert-butoxycarbonyl,
Bz: benzoyl,
Piv: pivaloyl, Bn: benzyl, Tr: trityl,
MOM: methoxymethyl, BOM: benzyloxymethyl,
TES: triethylsilyl, THP: tetrahydropyranyl,
Ms: mesyl, Me: methyl, Et: ethyl, Ph: phenyl,
t-Bu: tert-butyl.
Example 1
Production of 1-{2-[2-(1-benzothiophen-5-
yl)ethoxy]ethyl}-3-azetidinol
(1) In 12 mL of methylene chloride was dissolved
1.20 g of 2-[2-(1-benzothiophen-5-yl)ethoxy]acetic
acid, and 2.3 mL of triethylamine and 0.38 g of
imidazole were added to the solution. The resulting
mixture was cooled to 5°C and 0.41 mL of thionyl
chloride was added dropwise thereto, followed by
stirring at the same temperature for 1 hour. After the
reaction mixture was cooled to -60°C, 0.82 mL of
triethylamine and 0.72 g of 3-azetidinol hydrochloride
were added thereto, and the resulting mixture was
stirred at the same temperature for 1 hour and then at
room temperature for 1.5 hours. Water was added to the
reaction mixture and the pH was adjusted to 1.0 with 6
mol/L hydrochloric acid, after which the organic layer
was separated. The organic layer was washed with a
saturated aqueous sodium chloride solution and then
dried over anhydrous magnesium sulfate. The solvent
was distilled off under reduced pressure to obtain 2-
[2-(l-benzothiophen-5-yl)ethoxy]-1-(3-hydroxy-1-
azetidinyl)-1-ethanone as a yellow oil.
(2) The aforesaid 2-[2-(l-benzothiophen-5-
yl)ethoxy]-1-(3-hydroxy-1-azetidinyl)-1-ethanone was
dissolved in 12 mL of tetrahydrofuran and the resulting
solution was cooled to 5°C, after which 12.7 mL of a 1
mol/L solution of a borane-tetrahydrofuran complex in
tetrahydrofuran was added dropwise thereto and the
resulting mixture was stirred at room temperature for
17 hours. To the reaction mixture was added 10 mL of
acetone, and stirred for 30 minutes, followed by adding
thereto 6.0 mL of 6 mol/L hydrochloric acid, and the
resulting mixture was heated under reflux for 2 hours.
After the reaction mixture was cooled, water and ethyl
acetate were added thereto and the pH was adjusted to
13 with a 2 mol/L aqueous sodium hydroxide solution,
and the organic layer was separated. The organic layer
was washed with a saturated aqueous sodium chloride
solution and then dried over anhydrous magnesium
sulfate. The solvent was distilled off under reduced
pressure to obtain 1.13 g of 1-(2-[2-(1-benzothiophen-
5-yl)ethoxy]ethyl}-3-azetidinol as a yellow oil.
IR(neat)cm"1: 3 378,2943,1438,1198,1119,703
NMR(CDCl3)d values: 2 . 66 (2H, t, J=6Hz),
2.9-3.1(2H,m), 2.99(2H,t,J=7Hz), 3.46(2H,t,J=6Hz),
3.6-3.7(2H,m), 3.67(2H,t,J=7Hz),
4.41(lH,qn,J=6Hz), 7.20(1H,dd,J=2,8Hz),
7.27(lH,d,J=5Hz), 7.41(1H,d,J=5Hz), 7.66(1H, d,
J=2Hz), 7.78(lH,d,J=8Hz)
Example 2
Production of 1-{2-[2-(l-benzothiophen-5-
yl)ethoxy]ethyl}-3-azetidinol hydrochloride
In 4.2 mL of ethyl acetate was dissolved 1.03
g of l-{2-[2-(l-benzothiophen-5-yl)ethoxy]ethyl}-3-
azetidinol, and to the solution was added 0.86 mL of a
4.76 mol/L dried hydrogen chloride-ethyl acetate
solution. The resulting mixture was stirred at room
temperature for 1 hour and then at 5°C for 1 hour. The
crystals precipitated were collected by filtration,
washed with ethyl acetate and then dried to obtain 0.98
g of l-{2-[2-(l-benzothiophen-5-yl)ethoxy]ethyl}-3-
azetidinol hydrochloride.
Melting point: 101-102°C.
IR(KBr) cm-1: 3132,2952,1423,1340,1158,814,7 01
NMR(CDC13)d values: 2.97(2H,t,J=7Hz) , 3.2-
3.3(2H,m), 3.69(2H,t,J=7Hz), 3.6-3.8(2H,m), 3.9-
4.1(2H,m), 4.2-4.4(2H,m), 4.6-4.8(lH,m),
7.18(lH,dd,J=l,8Hz), 7.29(lH,d,J=5Hz),
7.41(lH,d,J=5Hz), 7.65(lH,d,J=lHz),
7.78(lH,d,J=8Hz)
Example 3
Production of l-{3-[2-(l-benzothiophen-6-
yl)ethoxy]propyl}-3-azetidinol
In 5 mL of dimethyl sulfoxide was dissolved
1.00 g of 6-[2-(3-chloropropoxy)ethyl]-l-
benzothiophene, and 0.86 g of 3-azetidinol
hydrochloride and 1.63 g of potassium carbonate were
added to the solution. The resulting mixture was
stirred at 75°C for 2.5 hours and then at 95°C for 1.5
hours. After the reaction mixture was cooled, water
and ethyl acetate were added thereto and the pH was
adjusted to 1 with 6 mol/L hydrochloric acid, and the
aqueous layer was separated. Ethyl acetate was added
to the aqueous layer and the pH was adjusted to 10 with
a 2 mol/L aqueous sodium hydroxide solution, after
which the organic layer was separated. The organic
layer was washed with water and then a saturated
aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, and then distilled under reduced
pressure to remove the solvent. The residue was
purified by a column chromatography (eluent;
chloroform : methanol =30 : 1 to 5 : 1) to obtain 0.28
g of l-{3-[2-(1-benzothiophen-6-yl)ethoxy]propyl}-3-
azetidinol as a colorless oil.
IR(neat) cm-1: 3398, 2 94 0, 28 67, 1197, 1107, 820, 7 57
NMR(CDC13)6 values: 1. 60 (2H, qn, J=7Hz) ,
2.45(2H,t,J=7Hz), 2.7-2.8(2H,m), 2.99(2H,t,J=7Hz),
3.45(2H,t,J=7Hz), 3.5-3.6(2H,m), 3.66(2H,t,J=7Hz),
4.37(lH,qn,J=6Hz), 7.23(1H,dd,J=l,8Hz),
7.29(lH,d,J=5Hz), 7.37(lH,d,J=5Hz),
7.73(1H,d,J=1Hz), 7.74(1H,d,J=8Hz)
Example 4
Production of l-{3-[2-(1-benzothiophen-6-
yl)ethoxy]propyl}-3-azetidinol hydrochloride
In 3.0 mL of ethyl acetate was dissolved 0.28
g of l-{3-[2-(1-benzothiophen-6-yl)ethoxy]propyl}-3-
azetidinol, and to the solution was added 0.35 mL of a
3.25 mol/L dried hydrogen chloride-ethyl acetate
solution, after which the resulting mixture was stirred
at room temperature for 1 hour. Then, the solvent was
distilled off under reduced pressure to obtain 0.30 g
of l-{3-[2-(1-benzothiophen-6-yl)ethoxy]propyl}-3-
azetidinol hydrochloride as a light-yellow oil.
IR (neat) cm-1: 32 64, 2866, 2596, 1398, 1109, 1048, 821
NMR(CDC13)5 values: 1. 81 (2H, qn, J=6Hz) ,
2.92(2H,tfJ=6Hz), 2.98(2H,t,J=6Hz),
3.46(2H,t,J=6Hz), 3.68(2H,t,J=6Hz), 3.8-3.9(2H,m),
3.8-4.0(2H,m), 4.4-4.6(1H,m), 7.23(1H,dd,J=l,8Hz),
7.31(1H,d,J=5Hz), 7.39 (1H,d,J=5Hz),
7.74(1H,d,J=1Hz), 7.76(lH,d,J=8Hz)
Example 5
Production of 1-{3-[2-(l-benzothiophen-2-
yl)ethoxy]propyl}-3-azetidinol
In the same manner as in Example 3, 1-{3-[2-
(l-benzothiophen-2-yl)ethoxy]propyl}-3-azetidinol was
obtained as a colorless oil.
IR (neat) cm"1: 3366, 2 942, 2856, 14 58,1436, 1113, 750
NMR(CDC13)5 values: 1. 64 (2H, qn=7Hz) ,
2.49(2H,t,J=7Hz), 2.7-2.8(2H,m), 3.15(2H,t,J=7Hz),
3.50(2H,t,J=7Hz), 3.5-3.7(2H,m), 3.71(2H,t,J=7Hz),
4.3-4.4(lH,m), 7.06(lH,s), 7.2-7.4(2H,m),
7.67(lH,dd,J=l,7Hz), 7.7 7(1H,dd,J=l,7Hz)
Example 6
Production of 1-{3-[2-(l-benzothiophen-2-
yl)ethoxy]propyl}-3-azetidinol hydrochloride
In the same manner as in Example 4, l-{3-[2-
(1-benzothiophen-2-yl)ethoxy]propyl}-3-azetidinol
hydrochloride was obtained as a light-yellow oil.
IR (neat) cm"1: 3290, 28 68, 1457, 1436, 1113, 751
NMR(CDC13)5 values: 1. 83 (2H, qn, J=6Hz) ,
2.91(2H,t,J=6Hz), 3.16(2H,t,J=6Hz),
3.52(2H,t,J=6Hz) , 3.7 4(2H,t,J=6Hz),
3.7-3.8(2H,m), 3.7-3.9(2H,m), 4.3-4.5(1H,m),
7.09(lH,s), 7.27(lH,dt,J=l,8Hz),
7.33(lH,dt,J=l,8Hz), 7.69(1H,dd,J=l,8Hz),
7.78(lH,dd,J=l,8Hz)
Example 7
Production of 1-{3-[2-(l-benzothiophen-7-
yl)ethoxy]propyl}-3-azetidinol
In the same manner as in Example 3, l-{3-[2-
(1-benzothiophen-7-yl)ethoxy]propyl}-3-azetidinol was
obtained as a colorless oil.
IR(neat)cm-2: 338 6,2 942,2 8 56,14 58,1105,7 96,755,700
NMR(CDC13)5 values: 1. 61 (2H, qn, J=7Hz) ,
2.45(2H,t,J=7Hz), 2.7-2.8(2H,m), 3.17(2H,t,J=7Hz),
3.48(2H,t,J=7Hz), 3.5-3.7(2H,m), 3.79(2H,t,J=7Hz),
4.3-4.5(lH,m), 7.20(lH,dd,J=l,8Hz),
7.32(lH,t,J=8Hz), 7.36(1H,d,J=5Hz),
7.43 (lH,d, J=5Hz) , 7.70 (1H,dd,J=l, 8Hz)
Example 8
Production of l-{3-[2-(1-benzothiophen-7-
yl)ethoxy]propyl}-3-azetidinol hydrochloride
In the same manner as in Example 2, l-{3-[2-
(1-benzothiophen-7-yl)ethoxy]propyl}-3-azetidinol
hydrochloride was obtained as colorless crystals.
Melting point: 105-106°C.
IR (KBr)cm-1: 3252, 2806, 2 620, 1398, 1130, 1106, 811, 708
NMR(CDC13) 8 values: 1. 82(2H,qn,J=6Hz), 2.8-
3.0(2H,m), 3.16(2H,t,J=6Hz), 3.47(2H,t,J=6Hz),
3.83(2H,t,J=6Hz), 3.7-4.1(4H,m), 4.5-4.7(lH,m),
7.21(lH,d,J=8Hz), 7.36(lH,t,J=8Hz),
7.38 (1H,d,J=5Hz), 7.4 6(1H,d,J=5Hz),
7.73 (lH,d,J=8Hz)
Example 9
(a) Production of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinol
In 30 mL of dimethyl sulfoxide was dissolved
6.50 g of 5-[2-(3-chloropropoxy)ethyl]-1-
benzothiophene, and to the solution were added 5.60 g
of 3-azetidinol hydrochloride anc 15.3 mL of a 5 mol/L
aqueous sodium hydroxide solution, after which the
resulting mixture was stirred at 65°C for 3.5 hours.
After the reaction mixture was cooled, water and ethyl
acetate were added thereto and the pH was adjusted to 1
with 6 mol/L hydrochloric acid, and the aqueous layer
was separated. Ethyl acetate was added to the aqueous
layer and the pH was adjusted to 10 with a 5 mol/L
aqueous sodium hydroxide solution, after which the
organic layer was separated. The organic layer was
washed with water and then a saturated aqueous sodium
chloride solution, dried over anhydrous magnesium
sulfate, and then distilled under reduced pressure to
remove the solvent. The residue was purified by a
column chromatography (eluent; chloroform : methanol =
30 : 1 to 10 : 1) to obtain 4.77 g of l-{3-[2-(1-
benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol.
(b) Production of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinol 2
(1) In 300 mL of tetrahydrofuran was dissolved
100 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]propionic
acid, and 0.1 mL of N,N-dimethylformamide was added
thereto, after which 41.8 mL of oxalyl chloride was
added thereto over a period of 10 minutes and the
resulting mixture was stirred at room temperature for
1.5 hours. The resulting solution was added dropwise
to a solution of 65.7 g of 3-hydroxyazetidine
hydrochloride and 59.5 g of sodium hydroxide in 600 mL
of water at 10°C, followed by stirring at room
temperature for 1 hour. To the reaction solution were
added 600 mL of water, 500 mL of ethyl acetate and
sodium chloride, and the organic layer was separated.
To the aqueous layer was added 100 mL of ethyl acetate
and the organic layer was separated. The organic
layers thus obtained were combined. To the combined
organic layer was added 100 mL of water and the pH was
adjusted to 3.5 with 6 mol/L hydrochloric acid, after
which the organic layer was separated. The organic
layer was concentrated to a volume of about 200 mL,
washed with a saturated aqueous sodium hydrogen-
carbonate solution and then a saturated aqueous sodium
chloride solution, dried over anhydrous magnesium
sulfate, and then distilled under reduced pressure to
remove the solvent. To the residue was added 300 mL of
toluene, and the resulting mixture was heated at 50°C to
effect dissolution, after which seed crystals were
added at 40°C and the resulting mixture was slowly
cooled and then stirred under ice-cooling for 30
minutes. The crystals precipitated were collected by
filtration to obtain 96.6 g of 3-[2-(l-benzothiophen-5-
yl)ethoxy]-1-(3-hydroxy-l-azetid nyl)-1-propanone as
light-brown crystals.
(2) In 60 mL of tetrahydrofuran was dissolved
30.0 g of 3-[2-(l-benzothiophen-5-yl)ethoxy]-1-(3-
hydroxy-1-azetidinyl)-1-propanone, followed by adding
dropwise thereto 275 mL of a 1 mol/L solution of a
borane-tetrahydrofuran complex in tetrahydrofuran, and
the resulting mixture was stirred at room temperature
for 5 hours. To the reaction solution was added
dropwise 81.9 mL of 6 mol/L hydrochloric acid, and the
resulting mixture was refluxed for 1.5 hours. After
cooling, the solvent was concentrated to be reduced by
about 290 mL, and the insoluble materials were filtered
off. To the filtrate were added 120 mL of water and 60
mL of toluene, and the aqueous layer was separated and
then washed with 60 mL of toluene. To the aqueous
layer was added 90 mL of ethyl acetate, and the pH was
adjusted to 9.5 with a 5 mol/L aqueous sodium hydroxide
solution, after which the organic layer was separated.
The organic layer was washed with a saturated aqueous
sodium chloride solution and dried over anhydrous
magnesium sulfate. The solvent was distilled off under
reduced pressure and 5.35 g of fumaric acid and 54 mL
of ethanol were added to the resulting residue. The
resulting mixture was heated at 74°C to effect
dissolution, and then 161 mL of ethyl acetate was added
dropwise thereto. The mixture thus obtained was slowly
cooled and then stirred at 5 to 10°C for 30 minutes, and
the crystals precipitated were collected by filtration
to obtain 22.7 g of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinol 1/2 fumarate as light-
brown crystals.
(3) In 45 mL of water was suspended 22.7 g of 1-
{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol
1/2 fumarate, and 68 mL of ethyl acetate was added
thereto, after which the pH was adjusted to 9.5 with a
1 mol/L aqueous sodium hydroxide solution and then the
organic layer was separated. The organic layer was
washed with a saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate, and
then distilled under reduced pressure to remove the
solvent. The residue was purified by a column
chromatography (eluent; chloroform : methanol =20 : 1
to 10 : 1) and crystallized from 40 mL of diisopropyl
ether to obtain 16.0 g of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinol as a solid.
Melting point: 60-62°C.
IR(KBr)cm-1: 3095, 2 94 4 , 27 69, 13 61, 1191, 1098 , 810, 70 9
NMR(CDC13)6 values: 1.61(2H,qn,J=7Hz),
2.45(2H,t,J=7Hzi, 2.7-2.9(2H,m), 2.99(2H,t,J=7Hz),
3.45(2H,t,J=7Hz), 3.5-3.6(2H,m), 3.66(2H,t,J=7Hz),
4.3-4.4(lH,m), 7.22(lH,dd,J=l,8Hz),
7.28(1H,d,J=5Hz), 7.41(1H,d,J=5Hz),
7.67(1H,d,J=1Hz), 7.7 9(lH,d,J=8Hz)
Example 10
Production of l-{3-[2-(l-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinol hydrochloride
In the same manner as in Example 2, l-{3-[2-
(1-benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol
hydrochloride was obtained as colorless crystals.
Melting point: 71-73°C.
IR(KBr)cm"1: 3301,2 937,28 09,2 631, 112 5, 1099, 818,
765,710
NMR(CDC13)5 values: 1. 8-1. 9 (2H, m) ,
2.98 (2H,t, J=7Hz) ,r 2 . 9-3 . 1 (2H,m) , 3 . 48 (2H, t, J=6Hz) ,
3.69(2H,t,J=7Hz)„ 3.6-4.4(4H,m), 4.5-4.7(lH,m),
7.22(lH,dd,J=l,8Hz), 7.31(1H,d,J=5Hz),
7.4 4(1H,d,J=5Hz), 7.68(1H,d,J=1Hz),
7.81(lH,d,J=8Hz)
Example 11
Production of 1-{3-[2-(l-benzothiophen-4-
yl)ethoxy]propyl}-3-azetidinol
In the same manner as in Example 3, l-{3-[2-
(l-benzothiophen-4-yl)ethoxy]propyl}-3-azetidinol was
obtained as a colorless oil.
IR (neat) cm"1: 33 68, 2 94 6, 285 6, 1457, 1107, 759
NMR(CDC13)5 values: 1.60(2Hrqn,J=7Hz),
2.44(2H,t,J=7Hz), 2.7-2.9(2H,m), 3.22(2H,t,J=7Hz) ,
3.45(2H,t,J=7Hz), 3.5-3.6(2H,m), 3.70(2H,t,J=7Hz),
4.3-4.5(lH,m), 7.19(1H,d,J=7Hz), 7.28(1H,t,J=7Hz),
7.4 4(lH,d,J=6Hz), 7.4 6(lH,d,J=6Hz),
7.76(lH,d,J=7Hz)
Example 12
Production of 1-{3-[2-(l-benzothiophen-4-
yl)ethoxy]propyl}-3-azetidinol hydrochloride
In the same manner as in Example 4, l-{3-[2-
(l-benzothiophen-4-yl)ethoxy]propyl}-3-azetidinol
hydrochloride was obtained as a light-yellow oil.
IR (neat) cm-1: 3 302,2 966,2877,2594,1412,1108,7 66
NMR(CDC13)5 values: 1. 78(2H,qn,J=6Hz),
2.82(2H,t,J=7Hz), 3.21(2H,t,J=6Hz),
3.43(2H,t,J=6Hz), 3.73(2H,t,J=6Hz), 3.7-3.9(2H,m),
3.8-4.0(2H,m), 4.5-4.7(lH,m), 7.21(1H,d,J=7Hz),
7.30(lH,t,J=7Hz), 7.49(2H,s), 7.78(1H,d,J=7Hz)
Example 13
Production of l-{3-[2-(l-benzothiophen-3-
yl)ethoxy]propyl}-3-azetidinol
In 5 mL of dimethyl sulfoxide was dissolved
1.00 g of 3-[2-(3-chloropropoxy)ethyl]-1-
benzothiophene, and 1.10 g of 3-azetidinol
trifluoroacetate and 1.63 g of potassium carbonate were
added to the solution, after which the resulting
mixture was stirred at 70°C for 2 hours. After the
reaction mixture was cooled, water and ethyl acetate
were added thereto and the pH was adjusted to 1 with 6
mol/L hydrochloric acid, and the aqueous layer was
separated. Ethyl acetate was added to the aqueous
layer and the pH was adjusted to 10 with a 2 mol/L
aqueous sodium hydroxide solution, after which the
organic layer was separated. The organic layer was
washed with water and then a saturated aqueous sodium
chloride solution, dried over anhydrous magnesium
sulfate, and then distilled under reduced pressure to
remove the solvent. The residue was purified by a
column chromatography (eluent; chloroform : methanol =
30 : 1 to 10 : 1) to obtain 0.55 g of l-{3-[2-(l-
benzothiophen-3-yl)ethoxy]propyl}-3-azetidinol as a
colorless oil.
IR (neat) cm"1: 3368,2942,2845, 1427,1191,1109,759
NMR(CDC13)5 values: 1. 62(2H,qn,J=7Hz),
2.47(2H,t,J=7Hz), 2.7-2.9(2H,m), 3.11(2H,t,J=7Hz),
3.48(2H,t,J=6Hz), 3.5-3.7(2H,m), 3.74(2H,t,J=7Hz),
4.3-4.5(lH,m), 7.18(lH,s), 7.33(1H,dt,J=l,7Hz),
7.39(lH,dt,J=l,7Hz), 7.77(1H,dd,J=l,7Hz),
7.86(lH,dd,J=l,7Hz)
Example 14
Production of 1-{3-[2-(l-benzothiophen-3-
yl)ethoxy]propyl}-3-azetidinol hydrochloride
In the same manner as in Example 4, l-{3-[2-
(1-benzothiophen-3-yl)ethoxy]prcpyl}-3-azetidinol
hydrochloride was obtained as a light-yellow oil.
IR (neat) cm-1: 3284, 2966, 2596, 1428, 1112, 1049, 765, 734
NMR(CDC13)5 values: 1.83(2H,qn,J=6Hz),
2.96(2H,t,J=6Hz), 3.12(2H,t,J=6Hz),
3.48(2H,t,J=6Hz), 3.76(2H,t,J=6Hz), 3.8-3.9(2H,m),
3.9-4.1(2H,m), 4.5-4.7(lH,m), 7.21(lH,s),
7.35(lH,dt,J=l,7Hz), 7.4 0(1H,dt,J=l,7Hz),
7.78(lH,dd,J=1.7Hz), 7.86(1H, dd,J=l,7Hz)
Example 15
Production of N-(l-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinyl)acetamide
In 8 mL of N,N-dimethylformamide was
dissolved 0.80 g of 5-[2-(3-chloropropoxy)ethyl]-1-
benzothiophene, and 1.20 g of N-(3-azetidinyl)acetamide
was added to the solution, after which the resulting
mixture was stirred at 90°C for 12 hours. After the
reaction mixture was cooled, water and ethyl acetate
were added thereto and the organic layer was separated.
The organic layer was washed with water and then a
saturated aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate, and then distilled under
reduced pressure to remove the solvent. The residue
was purified by a column chromatography (eluent;
chloroform : methanol =7:1) to obtain 0.39 g of N-
(l-{3- [2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
azetidinyl)acetamide as a light-yellow oil.
IR (neat) cm"1: 3276,2941,28 60,1654,1559,1111,756,703
NMR(CDC13) 8 values: 1. 59 (2H, qn, J=7Hz) , 1.97(3H,s),
2.42(2H,t,J=7Hz), 2.7-2.9(2H,m), 2.98(2H,t,J=7Hz),
3.45(2H,t,J=7Hz), 3.4-3.6(2H,m), 3.66(2H,t,J=7Hz),
4.4-4.5(lH,m), 7.22 (1H,dd,J=l,8Hz),
7.29(1H,d,J=5Hz), 7.42(lH,d, J=5Hz) ,
7.67(1H,d,J=1Hz), 7.8 0(lH,d,J=8Hz)
Example 16
Production of 1-{2-[2-(1-benzothiophen-6-
yl)ethoxy]ethyl}-3-pyrrolidinol
(1) In 7.4 mL of methylene chloride was dissolved
0.74 g of 2-[2-(1-benzothiophen-6-yl)ethoxy]acetic
acid, and 1.36 mL of triethylamine and 0.22 g of
imidazole were added to the solution. Then, the
resulting mixture was cooled to 5°C, after which 0.24 mL
of thionyl chloride was added dropwise thereto,
followed by stirring at the same temperature for 1
hour. After the reaction mixture was cooled to -50°C,
0.45 mL of triethylamine and 0.32 mL of 3-pyrrolidinol
were added thereto, and the resulting mixture was
stirred at the same temperature for 1 hour and then at
room temperature for 1 hour. Water was added to the
reaction mixture and the organic layer was separated.
The organic layer was washed successively with 1 mol/L
hydrochloric acid, a 2 mol/L aqueous sodium hydroxide
solution and a saturated aqueous sodium chloride
solution, and then dried over anhydrous magnesium
sulfate. Subsequently, the solvent was distilled off
under reduced pressure to obtain 2-[2-(1-benzothiophen-
6-yl)ethoxy]-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanone as
a light-yellow oil.
IR (neat) cm"1: 3386, 2 942,1636, 1106, 758
(2) The aforesaid 2- [2-(l-benzothiophen-6-
yl)ethoxy]-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanone was
dissolved in 7.4 mL of tetrahydrofuran, and 7.4 mL of a
1 mol/L solution of a borane-tetrahydrofuran complex in
tetrahydrofuran was added dropwise thereto under ice-
cooling, followed by stirring at room temperature for
17 hours. To the reaction mixture was added 10 mL of
acetone, and stirred for 30 minutes, after which 1.5 mL
of 6 mol/L hydrochloric acid was added thereto and the
resulting mixture was heated under reflux for 2 hours.
After the reaction mixture was cooled, water and ethyl
acetate were added thereto and the aqueous layer was
separated. Ethyl acetate was added to the aqueous
layer and the pH was adjusted to 9.5 with a 2 mol/L
aqueous sodium hydroxide solution, after which the
organic layer was separated. The organic layer was
washed with water and a saturated aqueous sodium
chloride solution, dried over anhydrous magnesium
sulfate, and then distilled under reduced pressure to
remove the solvent. The residue was purified by a
column chromatography (eluent; chloroform : methanol =
30 : 1 to 20 : 1) to obtain 0.53 g of l-{2-[2-(l-
benzothiophen-6-yl)ethoxy]ethyl}-3-pyrrolidinol as a
yellow oil.
IR (neat) cm-1: 3386,2 94 0,28 67,1110,820,756
NMR(CDC13)d values: 1. 6-1. 8 (lH,m) , 2 . 0-2 . 2 (lH,m) ,
2.31(lH,dt,J=7,9Hz), 2.53(1H,dd,J=5,lOHz), 2.6-
2.7(3H,m), 2.85(lH,dt,J=5,9Hz), 3.01(2H,t,J=7Hz),
3.58(2H,t,J=6Hz), 3.71(2H,t,J=7Hz), 4.2-4.3(lH,m),
7.23(lH,d,J=8Hz), 7.29(1H,d,J=5Hz),
7.37(1H,d,J=5Hz), 7.73(1H,d,J=8Hz), 7.73(lH,s)
Example 17
Production of l-{2-[2-(L-benzothiophen-6-
yl)ethoxy]ethyl}-3-pyrrolidinol oxalate
In 2.0 mL of ethyl acetate was dissolved 0.48
g of 1-{2-[2-(1-benzothiophen-6-yl)ethoxy]ethyl}-3-
pyrrolidinol, and to the solution was added a solution
of 0.15 g of oxalic acid in 2.8 mL of ethyl acetate.
The resulting mixture was stirred at room temperature
for 1 hour and then at 5°C for 1 hour. The crystals
precipitated were collected by filtration, washed with
ethyl acetate and then dried to obtain 0.42 g of l-{2-
[2-(1-benzothiophen-6-yl)ethoxy]ethyl}-3-pyrrolidinol
oxalate as colorless crystals.
IR(KBr)cm-1: 3384 , 28 62, 2 687, 1717, 163 6, 14 00, 1200,
1114,720
NMR(DMSO-d6)d values: 1. 7-1. 8 (1H,m) , 1. 9-2 . 1 (lH,m) ,
2.96(2H,t,J=7Hz), 3.0-3.2(lH,m), 3.1-3.4(5H,m),
3.6-3.8(4H,m), 4.3-4.4(1H,m), 7.29(1H,d,J=8Hz),
7.41(1H,d,J=5Hz), 7.68(1H,d,J=5Hz),
7.80(1H,d,J=8Hz), 7.87(1H,s)
Example 18
Production of 1-{2-[2-(l-benzothiophen-5-
yl)ethoxy]ethyl}-3-pyrrolidinol
In the same manner as in Example 16 (1), 2-
[2- (1-benzothiophen-5-yl)ethoxy1-1-(3-hydroxy-l-
pyrrolidinyl)-1-ethanone was obtained.
NMR(CDC13) 5 values: 1. 6-2 . 2 (2H, m) , 2 . 9-4 . 0 (8H,m) ,
4.0-4.2(2H,m), 4.2-4.5(1H,m), 7.1-7.4(2H,m),
7.42(1H,d,J=5Hz), 7.69(lH,s), 7.79(1H,d,J=8Hz)
Then, l-{2-[2-(l-benzothiophen-5-
yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a
light-yellow oil in the same manner as in Example 16
(2) .
IR (neat) cm-1: 3386, 2941,2864, 1438, 1112, 755, 702
NMR(CDC13) 6 values: 1. 5-2 . 0 (lH,m) , 2 . 0-2 . 9 (7H,m) ,
3.00(2H,t,J=7Hz), 3.58(2H,t,J=6Hz),
3.71(2H,t,J=7Hz), 4.2-4.4(lH,m), 7.21(1H,d,J=8Hz),
7.28(1H,d,J=5Hz), 7.42(1H,d,J=5Hz), 7.67(lH,s),
7.79(lH,d,J=8Hz)
Example 19
Production of l-{2-[2-(1-benzothiophen-5-
yl)ethoxy]ethyl}-3-pyrrolidinol oxalate
In the same manner as in Example 17, l-{2-[2-
(1-benzothiophen-5-yl)ethoxy]ethyl}-3-pyrrolidinol
oxalate was obtained as colorless crystals.
IR (KBr)cm-1: 3347, 2943, 2687, 1719, 1404, 1119, 72 0
NMR(CDC13) 8 values: 1.7-2.2(2H,m), 2.9-3.8(6H,m),
2.94 (2H,t, J=6Hz.) , 3 . 68 (4H, t, J=6Hz) , 4 . 2-4 . 5 (1H,m) ,
7.17(lH,d,J=8Hz), 7.26(1H,d,J=5Hz),
7.42(1H,d,J=5Hz), 7.62{lH,s), 7.78(1H,d,J=8Hz)
Example 20
Production of 1-{2-[2-(l-benzothiophen-4-
yl)ethoxy]ethyl}-3-pyrrolidinol
In the same manner as in Example 16 (1), 2-
[2-(l-benzothiophen-4-yl)ethoxy]-1-(3-hydroxy-1-
pyrrolidinyl)-1-ethanone was obtained as an oil.
IR (neat) cm"1: 3374,294 4,1637, 1107,7 61
Then, l-{2-[2-(1-benzothiophen-4-
yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a
light-yellow oil in the same manner as in Example 16
(2) .
IR (neat) cm-1: 337 6,2939,28 67,1452,1413,1111,7 60
NMR(CDC13) 8 values: 1. 6-1. 8 (1H,m) , 2 . 1-2 . 2 (1H,m) ,
2.30(lH,dt,J=6,9Hz), 2.53(1H,dd,J=5,lOHz), 2.6-
2.7(3H,m), 2.85(lH,dt,J=5,9Hz), 3.25(2H,t,J=7Hz),
3.58(2H,t,J=6Hz), 3.75(2H,t,J=7Hz), 4.2-4.4(1H,m),
7.20(lH,d,J-7Hz), 7.27(lH,t,J=7Hz),
7.4 4(lH,d,J=6Hz), 7.4 6(lH,d,J=6Hz),
7.75 (lH,d,J=7Hz)
Example 21
Production of 1-{2-[2-(l-benzothiophen-4-
yl)ethoxy]ethyl}-3-pyrrolidinol hydrochloride
In 5.0 mL of ethyl acetate was dissolved 0.63
g of l-{2- [2-(l-benzothiophen-4-yl)ethoxy]ethyl}-3-
pyrrolidinol, and to the solution was added 0.80 mL of
a 3.25 mol/L dried hydrogen chloride-ethyl acetate
solution. The resulting mixture was stirred at room
temperature for 1 hour and then at 5°C for 1 hour, after
which the crystals precipitated were collected by
filtration. The crystals precipitated were washed with
ethyl acetate and then dried to obtain 0.43 g of l-{2-
[2- (l-benzothiophen-4-yl)ethoxy]ethyl}-3-pyrrolidinol
hydrochloride as colorless crystals.
IR(KBr)cm-1: 322 9,2872,2 625,14 51,1413,1119,771
NMR(DMSO-d6)d values: 1.7-2.2(2H,m), 2 . 9-3.6(6H,m) ,
3.22(2H,t,J=7Hz), 3.74(4H,t,J=7Hz), 4 . 3-4.4(1H,m),
7.27(lH,d,J=8Hz), 7.30(1H,t,J=8Hz),
7.61(1H,d,J=5Hz), 7.77(1H,d,J=5Hz),
7.86(lH,d,J=8Hz)
Example 22
Production of 1-{2-[2-(l-benzothiophen-7-
yl)ethoxy]ethyl}-3-pyrrolidinol
In the same manner as in Example 16 (1), 2-
[2- (l-benzothiophen-7-yl)ethoxy]-1-(3-hydroxy-l-
pyrrolidinyl)-1-ethanone was obtained as an oil.
NMR(CDC13) 8 values: 1. 8-2 . 0 (2H,m) , 3 .1-3 . 3 (3H,m) ,
3.3-3.6(3H,m) 3.8-4.0(2H,m), 4.0-4.2(2H,m),
4.3-4.5(1H,m), 7.23(lH,d,J=7Hz),7.3-7.4(2H,m),
7.4-7.5(1H,m), 7.6-7.8(1H,m)
Then, l-{2-[2-(l-benzothiophen-7-
yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a
colorless oil in the same manner as in Example 16 (2).
IR (neat) cm"1: 3385, 2941, 28 67 , 1459, 1395, 1106, 7 95,
754,701
NMR(CDC13) 5 values: 1. 6-1. 8 (1H,m) , 2 . 1-2 . 2 (1H,m) ,
2.30(lH,dt,J=7,9Hz), 2 . 52(1H,dd,J=5,lOHz), 2.6-
2.7(3H,m), 2.85(lH,dt,J=5,9Hz), 3.19(2H,t,J=7Hz),
3.59(2H,t,J=6Hz], 3.84(2H,t,J=7Hz), 4.2-4.4(1H,m),
7.20(lH,d,J=8Hz), 7.32(lH,t,J=8Hz),
7.35(lH,d,J=5Hz,), 7.42(1H,d,J=5Hz),
7.69(lH,d,J=8Hz)
Example 23
Production of l-{2-[2-(l-benzothiophen-7-
yl)ethoxy]ethyl}-3-pyrrolidinol hydrochloride
In the same manner as in Example 21, l-{2-[2-
(1-benzothiophen-7-yl)ethoxy]ethyl}-3-pyrrolidinol
hydrochloride was obtained as colorless crystals.
IRtKBrJcnf1: 3283,2 938,270 6, 1395, 1358, 1125, 810, 720
NMR(DMSO-d6) 5 values: 1. 7-2 . 2 (2H,m) , 2 . 8-3 . 7 ( 6H,m) ,
3.12(2H,t,J=7Hz), 3.7-3.8(2H,m), 3.82(2H,t,J=7Hz),
4.3-4.4(1H,m), 7.29 (1H,d,J=7Hz), 7.36(1H,t,J=7Hz),
7.49(1H,d,J=5Hz), 7.76(1H,d,J=5Hz),
7.77(lH,d,J=7Hz)
Example 24
Production of 1-{2-[2-(l-benzothiophen-2-
yl)ethoxy]ethyl}-3-pyrrolidinol
In the same manner as in Example 16 (1), 2-
[2- (1-benzothiophen-2-yl)ethoxy]-1-(3-hydroxy-l-
pyrrolidinyl)-1-ethanone was obtained.
NMR(CDC13) 8 values: 1.8-2.0(2H,m), 3 .1-3 . 3 (3H,m) ,
3.3-3.7(3H,m), 3.8-4.0(2H,m), 4.1-4.2(2H,m),
4.2-4.5(1H,m), 7.10(lH,s), 7.2-7.4(2H,m), 7.6-
7.7(1H,m), 7.7-7.8(1H,m)
Then, l-{2-[2-(l-benzothiophen-2-
yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a
light-yellow oil in the same manner as in Example 16
(2) .
IR (neat) cm-1: 33 96, 2 939, 1458, 1438, 1113, 747, 727
NMR(CDC13)d values: 1.6-1.8(1H,m) , 2.1-2.2(1H,m),
2.34(lH,dt,J=6,9Hz), 2.55(lH,dd,J=5,lOHz),
2.6-2.8(3H,m), 2.85(lH,dt,J=5,9Hz),
3.18 (2H,dt,J=l,7Kz), 3.62(2H,t,J=6Hz),
3.77(2H,t,J=7Hz), 4.2-4.4(1H,m), 7.07(lH,s),
7.26(lH,dt,J=l,8Hz), 7.31(lH,dt,J=l,8Hz),
7.67(lH,dd,J=l,8Hz) , 7.7 6(1H,dd,J=l,8Hz)
Example 25
Production of 1-{2-[2-(1-benzothiophen-2-
yl)ethoxy]ethyl}-3-pyrrolidinol oxalate
In the same manner as in Example 17, l-{2-[2-
(1-benzothiophen-2-yl)ethoxy]ethyl}-3-pyrrolidinol
oxalate was obtained as colorless crystals.
IR(KBr)cm-1: 3432,2871,1716,1436,1127,827,7 60,706
NMR(DMSO-d6) 5 values: 1. 7-1. 8 (1H,m) , 1. 9-2 . 2 (1H,m) ,
3.0-3.4(8H,m), 3.73(4H,t,J=6Hz), 4.2-4.4(1H,m),
7.23(lH,s), 7.28(1H,t,J=7Hz), 7.33(1H,t,J=7Hz),
7.7 4(lH,d,J-7Hz), 7.87(lH,d,J=7Hz)
Example 26
Production of l-{2-[2-(l-benzothiophen-3-
yl)ethoxy]ethyl}-3-pyrrolidinol
In the same manner as in Example 16 (1), 2-
[2-(1-benzothiophen-3-yl)ethoxy]-1-(3-hydroxy-1-
pyrrolidinyl)-1-ethanone was obtained as an oil.
NMR(CDC13) 5 values: 1. 8-1. 9 f lH,m) , 1. 9-2 . 0 (1H,m) ,
3.1-3.6(6H,m), 3 . 8-4 . 0 (2H,m) , 4.09(lH,s),
4.13(lH,s), 4.3-4.5(1H,m), 7.26(lH,s), 7.3-
7.4(2H,m), 7.77(1H,d,J=8Hz), 7.85(1H,d,J=8Hz)
Then, l-{2-[2-(l-benzothiophen-3-
yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a
light-yellow oil in the same manner as in Example 16
(2) .
IR (neat) cm"1: 3388,2 934,1426,1112,761,7 33
NMR(CDC13) 5 values: 1.6-1.8(1H,m), 2.1-2.2 (1H,m),
2.33(lH,dt,J=6,9Hz) , 2.56(1H,dd,J=5,lOHz), 2.6-
2.8(3H,m), 2.87 (lH,dt,J=5,9Hz),
3.14(2H,dt,J=l,7Hz), 3.61(2H,t,J=6Hz),
3.80(2H,t,J=7Hz), 4.3-4.4(1H,m), 7.20(lH,s),
7.34(lH,dt,J=l,7Hz) , 7.38(lH,dt,J=l,7Hz) ,
7.77(lH,dd,J=l,7Hz), 7.85(1H,dd,J=l,7Hz)
Example 27
Production of 1-{2-[2-(l-benzothiophen-3-
yl)ethoxy]ethyl}-3-pyrrolidinol oxalate
In the same manner as in Example 17, l-{2-[2-
(1-benzothiophen-3-yl)ethoxy]ethyl}-3-pyrrolidinol
oxalate was obtained as colorless crystals.
IR (KBr)cm-1: 3363,2 922,2 691, 1718, 163 6, 1427, 1404,
1119,767,721
NMR(DMSO-d6)d values: 1. 7-1. 8 (1H,m) , 2 . 0-2 . 2 (1H,m) ,
3.10(2H,t,J=7Hz), 3.1-3.4(6H,m), 3.72(2H,t,J=5Hz),
3.78(2H,t,J=7Hz), 4.3-4.4(1H,m), 7.37(1H,t,J=8Hz),
7.42(lH,t,J=8Hz), 7.51(lH,s), 7.85(1H,d,J=8Hz),
7.98(lH,d,J=8Hz)
Example 28
Production of 1-{2-[2-(1-naphthyl)ethoxy]-
ethyl}-3-pyrrolidinol
In the same manner as in Example 16 (1), 2-
[2-(1-naphthyl)ethoxyl-1-(3-hydroxy-1-pyrrolidinyl)-1-
ethanone was obtained as a yellow oil.
IR (neat) cm-1: 3392,2 94 6,164 5,1133,8 00,77 9
Then, l-{2-[2-(1-naphthyl)ethoxy]ethyl}-3-
pyrrolidinol was obtained as a light-yellow oil in the
same manner as in Example 16 (2).
IR (neat Jem-1: 3395,2944,1107,778
NMR(CDC13) 5 values: 1. 5-1. 9 (1H, m) , 2 . 0-2 . 5 (3H,m) ,
2.5-3.0(4H,m), 3.37(2H,t, J=7Hz), 3.59(2H, t, J=6Hz) ,
3.80(2H,t,J=7Hz), 4.2-4.4(1H,m), 7.4-7.6(4H,m),
7.6-8.0(2H,m), 6.0-8.2(lH,m;
Example 2 9
Production of l-{2-[2-(1-naphthyl)ethoxy]-
ethyl}-3-pyrrolidinol oxalate
In the same manner as in Example 17, l-{2-[2-
(1-naphthyl)ethoxy]ethyl}-3-pyrrolidinol oxalate was
obtained as colorless crystals.
IR (KBr)cm-1: 3366,14 00,1116,7 8 0,720
NMR(DMSO-d6)d values: 1. 6-2 . 3 (2H,m) , 2 . 7-3 . 5 (8H,m) ,
3.5-3.9(4H,m), 4.2-4.5(1H,m), 7.4-7.6(4H,m), 7.7-
8.0(2H,m), 8.0-8.2(1H,m)
Example 30
Production of (3S)-l-{2-[2-(1-benzothiophen-
5-yl)ethoxy]ethyl}-3-pyrrolidinol
In the same manner as in Example 16 (1), 2-
[2-(1-benzothiophen-5-yl)ethoxy]-1-[(3S)-3-hydroxy-l-
pyrrolidinyl]-1-ethanone was obtained as a light-yellow
oil.
Then, (3S)-1-{2-[2-(l-benzothiophen-5-
yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a
light-yellow oil in the same manner as in Example 16
(2) .
IR (neat Jem-1: 338 6, 2 936, 28 67 , 14 38, 1111, 755, 702
NMR(CDC13)d values: 1. 5-2 . 0 (1H,m) , 2 . 0-3 . 0 (5H,m) ,
2.66(2H,t,J=6Hz), 3.00(2H,t,J=7Hz),
3.58(2H,t,J=6Hz), 3.71(2H,t,J=7Hz), 4.2-4.4(1H,m),
7.21(lH,d,J=8Hz), 7.28(lH,d,t=5Hz),
7.42(1H,d,J=5Hz), 7.67(lH,s), 7.79(1H,d,J=8Hz)
Example 31
Production of (3S)-1-{2-[2-(l-benzothiophen-
5-yl) ethoxy]ethyl}-3-pyrrolidinol oxalate
In the same manner as in Example 17, (3S)-1-
{2-[2- (1-benzothiophen-5-yl)ethoxy]ethyl}-3-
pyrrolidinol oxalate was obtained as colorless
crystals.
IR(KBr)cm-1: 33 66, 2 941, 28 67, 2 68 6, 1718, 1701, 14 04 ,
1114,720
NMR(DMSO-d6)d values: 1.5-2.2(2H,m), 2.8-3.5(8H,m),
3.70(4H,t,J=6Hz), 4.2-4.5(1H,m), 7.28(1H,d,J=8Hz),
7.40 (1H,d,J=5Hz) , 7.73(1H,d,J=5Hz), 7.76(lH,s),
7.91(lH,d,J=8Hz)
Example 32
Production of (3R)-1-{2-[2-(1-benzothiophen-
5-yl)ethoxy]ethyl}-3-pyrrolidinol
In the same manner as in Example 16 (1), 2-
[2-(1-benzothiophen-5-yl)ethoxy]-1-[(3R)-3-hydroxy-l-
pyrrolidinyl]-1-ethanone was obtained as colorless
crystals.
IR(KBr)cm"1: 3408 , 2 937, 1637, 1137, 1108, 812, 703
Then, (3R)-l-{2-[2-(l-benzothiophen-5-
yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a
light-yellow oil in the same manner as in Example 16
(2) .
IR (neat) cm-1: 3373, 294 0, 14 38, 1111, 7 55, 702
NMR(CDC13) 8 values: 1. 5-2 . 0 (1H, m) , 2 . 0-3 . 0 ( 5H,m) ,
2.68(2H,t,J=6Hz), 3.01(2H,t,J=7Hz),
3.59(2H,t,J=6Hz), 3.71(2H,t,J=7Hz), 4 . 2-4.4(1H,m),
7.21(lH,d,J=8Hz), 7.28(1H,d,J=5Hz),
7.42(1H,d,J=5Hz), 7.67(1H,s), 7.79(1H,d,J=8Hz)
Example 33
Production of (3R)-l-{2-[2-(1-benzothiophen-
5-yl) ethoxy] ethyl }-3--pyrrolidinol oxalate
In the same manner as in Example 17, (3R)-1-
{2-[2-(1-benzothiophen-5-yl)ethoxy]ethyl}-3-
pyrrolidinol oxalate was obtained as colorless
crystals.
IR(KBr)cm-1: 3318,2870,1718,1114,720
NMR(DMSO-d6) d values: 1. 5-2 . 2 (2H,m) , 2.8-3.5(8H,m) ,
3.70(4H,t,J=6Hz) , 4.2-4.5(1H,m), 7.28(1H, d, J=8Hz) ,
7.40(1H,d,J=5Hz) , 7.73(1H,d,J=5Hz), 7.76(lH,s),
7.91(1H,d,J=8Hz)
Example 34
Production of (3S)-1-{2-[2-(1-benzothiophen-
6-yl)ethoxy]ethyl}-3~pyrrolidinol
In the same manner as in Example 16 (1), 2-
[2- (1-benzothiophen-6-yl)ethoxy]-1-[(3S)-3-hydroxy-l-
pyrrolidinyl]-1-ethanone was obtained as a colorless
oil.
IR(neat)cm-1: 338 5,294 4,1637, 1133, 820, 699
Then, (3S)-L-{2-[2-(l-benzothiophen-6-
yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a
colorless oil in the same manner as in Example 16 (2).
IR(neat)cm-1: 3385,294 0,28 67, 1110, 820, 757
NMR(CDC13) 5 values: 1. 6-1. 8 (1H,m) , 2 .1-2 . 2 (1H,m) ,
2.32(lH,dt,J=6,9Hz), 2.54(1H,dd,J=5,lOHz), 2.6-
2.7(3H,m), 2.85(lH,dt,J=5,9Hz), 3.01(2H,t,J=7Hz),
3.58(2H,t,J=6Hz), 3.71(2H,t,J=7Hz), 4.2-4.3(1H,m),
7.23(lH,d,J=8Hz), 7.29(1H,d,J=5Hz),
7.37(1H,d,J=5Hz), 7.73(1H,d,J=8Hz), 7.74(lH,s)
Example 35
Production of (3S)-l-{2-[2-(1-benzothiophen-
6-yl)ethoxy]ethyl}-3-pyrrolidinol oxalate
In the same manner as in Example 17, (3S)-1-
{2-[2-(1-benzothiophen-6-yl)ethoxy]ethyl}-3-
pyrrolidinol oxalate was obtained as colorless
crystals.
IR(KBr)cm-1: 3364,2 938,2692, 1718, 1400, 1201, 1114, 72 0
NMR(DMSO-d6)d values: 1.7-1.8(1H,m) , 1. 9-2 . 1 (1H,m) ,
2.96(2H,t,J=7Hz) 3.0-3.1(1H,m), 3.1-3.3(5H,m),
3.70(4H,t,J=7HZ),4.2-4.3(1H,m) , 7.29(1H,d,J=8Hz),
7.41(1H,d,J=5Hz), 7.68(1H,d,J=5Hz),
7.80(lH,d,J=8Hz), 7.87(lH,s)
Example 36
Production of (3R)-1-{2-[2-(l-benzothiophen-
6-yl) ethoxy]ethyl}-3-pyrrolidinol
In the same manner as in Example 16 (1), 2-
[2-(1-benzothiophen-6-yl)ethoxy]-L-[(3R)-3-hydroxy-l-
pyrrolidinyl]-1-ethanone was obtained as an oil.
IR (neat Jem-1: 338 6,294 0,1637,1107,820,758
Then, (3R)-l-{2-[2- (l-benzothiophen-6-
yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a
colorless oil in the same manner as in Example 16 (2).
IR (neat) cm"1: 3385,294 0,28 67, 1110, 820, 757
NMR(CDC13) 5 values: 1. 6-1. 8 (1H,m) , 2 .1-2 . 2 (1H,m) ,
2.32(lH,dt,J=6,9Hz), 2.54(1H,dd,J=5,lOHz), 2.6-
2.7(3H,m), 2.85(lH,dt,J=5,9Hz), 3.01(2H,t,J=7Hz),
3.58(2H,t,J=6Hz), 3.71(2H,t,J=7Hz), 4.2-4.3(1H,m),
7.23(lH,d,J=8Hz), 7.29(1H,d,J=5Hz),
7.37(1H,d,J=5Hz), 7.73(1H,d,J=8Hz), 7.74(lH,s)
Example 37
Production of (3R)-l-{2-[2-(1-benzothiophen-
6-yl)ethoxy]ethyl}-3-pyrrolidinol oxalate
In the same manner as in Example 17, (3R)-1-
{2-[2-(1-benzothiophen-6-yl)ethoxy]ethyl}-3-
pyrrolidinol oxalate v/as obtained as colorless
crystals.
IR(KBr)cm-1: 3364 , 2 938 , 2 688 , 1718 , 14 00, 1201, 1114 , 720
NMR(DMSO-d6) 5 values: 1. 7-1. 8 (1H,m) , 1. 9-2 . 1 (1H,m) ,
2.96(2H,t,J=7Hz), 3.0-3.1(1H,m), 3.1-3.3(5H,m),
3.70(4H,t,J=7Hz),4.2-4.3(1H,m), 7.29(1H,d,J=8Hz),
7.41(1H,d,J=5Hz), 7.68(1H,d,J=5Hz),
7.80(lH,d,J=8Hz), 7.87(lH,s)
Example 38
Production of (3R)-l-{2-[2-(1-benzothiophen-
3-yl)ethoxy]ethyl}-3-pyrrolidinol
In the same manner as in Example 16 (1), 2-
[2-(1-benzothiophen-3-yl)ethoxy]-1-[(3R)-3-hydroxy-l-
pyrrolidinyl]-1-ethanone was obtained.
NMR(CDC13) d values: 1.8-1.9(1H,m), 1.9-2.0(1H,m),
3.1-3.4(3H,m), 3.3-3.7(3H,m), 3.8-4.0(2H,m),
4.0-4.2(2H,m), 4.3-4.5(1H,m), 7.27(1/2H,s),
7.28(l/2H,s), 7.3-7.5(2H,m), 7.7-7.8(1H,m), 7.8-
7.9(1H,m)
Then, (3R)-l-{2-[2-(l-benzothiophen-3-
yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a
yellow oil in the same manner as in Example 16 (2).
IR (neat) cm-1: 338 6,2942,1458,142 9,1113,759,733
NMR(CDC13) 6 values: 1. 6-1. 8 (1H,m) , 2 . 1-2 . 2 (1H,m) ,
2.34(lH,dt,J=6,9Hz), 2.55(1H,dd,J=5,lOHz), 2.6-
2.8(3H,m), 2.85(lH,dt,J=5,9Hz), 3.14(2H,t,J=7Hz),
3.61(2H,t,J=6Hz), 3.80(2H,t,J=7Hz), 4.2-4.4(1H,m),
7.21(lH,s), 7.34(lH,dt,J=l,7Hz),
7.38(lH,dt,J=l,7Hz), 7.7 6(1H,dd,J=l,7Hz),
7.85(lH,dd,J=l,7Hz)
Example 39
Production of (3R)-l-{2-[2-(1-benzothiophen-
3-yl)ethoxy]ethyl}-3-pyrrolidinol hydrochloride
In 5.0 mL of ethyl acetate was dissolved 0.99
g of (3R) -l-{2-[2-(1-benzothiophen-3-yl)ethoxy]ethyl}-
3-pyrrolidinol, and to the solution was added 1.10 mL
of a 3.25 mol/L dried hydrogen chloride-ethyl acetate
solution, after which the resulting mixture was stirred
at room temperature for 1 hour. Then, the solvent was
distilled off under reduced pressure to obtain 1.05 g
of (3R)-l-{2-[2-(1-benzothiophen-3-yl)ethoxy]ethyl}-3-
pyrrolidinol hydrochloride as a light-yellow oil.
IR (neat Jem-1: 3368,294 6,1560,1430,1121,7 65,734
NMR(CDC13) 5 values: 1. 9-2 .1 (1H,m) , 2 .1-2 . 3 (1H,m) ,
2.8-3.0(2H,m), 3.1-3.2(4H,m), 3.29(1H,d,J=12Hz),
3.3-3.5(1H,m), 3.8-3.9(4H,m), 4.3-4.4(1H,m),
7.24{lH,s), 7.35(lH,t,J=8Hz), 7.40(1H,t,J=8Hz),
7.76(lH,d,J=8Hz), 7.86(lH,d,J=8Hz)
Example 4 0
Production of l-{2-[2-(l-benzothiophen-5-
yl)ethoxy]ethyl}-4-piperidinol
In the same manner as in Example 16 (1), 2-
[2- (1-benzothiophen-5-yl)ethoxy]-1-(4-hydroxy-l-
piperidinyl)-1-ethanone was obtained as an oil.
Then, l-{2-[2-(l-benzothiophen-5-
yl)ethoxy]ethyl}-4-piperidinol was obtained as a yellow
oil in the same manner as in Example 16 (2).
IR (neat)cm-1: 3386, 2 93 9, 1110, 1071, 754, 701
NMR(CDC13)d values: 1.5-2.3(6H,m), 2.5-3.0(2H,m),
2.56(2H,t,J=6Hz), 3.00(2H,t,J=7Hz), 3.5-3.9(1H,m),
3.58(2H,t,J=6Hz), 3.70(2H,t,J=7Hz),
7.19(lH,d,J=8Hz), 7.27(1H,d,J=5Hz),
7.41(1H,d,J=5Hz), 7.65(lH,s), 7.78(1H,d,J=8Hz)
Example 41
Production of l-{2-[2-(1-benzothiophen-5-
yl)ethoxy]ethyl}-4-piperidinol hydrochloride
In the same manner as in Example 21, l-{2-[2-
(1-benzothiophen-5-yl)ethoxy]ethyl}-4-piperidinol
hydrochloride was obtained as light-brown crystals.
IR(KBr)cm-1: 3312, 294 6, 2691, 14 57 , 1124 , 104 3, 7 69, 712
NMR(CDC13) 8 values: 1.5-2.5(4H,m), 2.8-3.2(6H,m),
2.99(2H,t,J=6Hz), 3.76(2H,t,J=6Hz), 3.8-4.2(3H,m),
7.19(lH,d,J=8Hz), 7.30(1H,d,J=5Hz),
7.44(1H,d,J=5Hz), 7.67(lH,s), 7.80(1H,d,J=8Hz)
Example 42
Production of 1-{2-[2-(l-benzothiophen-5-
yl)ethoxy]ethyl}-3-piperidinol
In the same manner as in Example 16 (1), 2-
[2-(1-benzothiophen-5-yl)ethoxy]-1-(3-hydroxy-l-
piperidinyl)-1-ethanone was obtained as a yellow oil.
IR (neat) cm"1: 3408, 2938, 1637, 1114, 704
Then, l-{2-[2-(l-benzothiophen-5-
yl)ethoxy]ethyl}-3-piperidinol was obtained as a yellow
oil in the same manner as in Example 16 (2).
IR (neat) cm"1: 3387, 2937, 14 38, 1109, 703
NMR(CDC13) 5 values: 1. 4-2 . 0 (4H,m) , 2 . 0-2 . 7 (6H,m) ,
2.57(2H,t,J=6Hz), 3.00(2H,t,J=7Hz),
3.56(2H,t,J=6Hz), 3.6-3.9(1H,m), 3.70(2H,t,J=7Hz),
7.20(lH,d,J=8Hz), 7.28(1H,d,J=5Hz),
7.42(1H,d,J=5Hz), 7.66(lH,s), 7.79(1H,d,J=8Hz)
Example 4 3
Production of l-{2-[2-(l-benzothiophen-5-
yl)ethoxy]ethyl}-3-piperidinol hydrochloride
In the same manner as in Example 21, l-{2-[2-
(1-benzothiophen-5-yl)ethoxy]ethyl}-3-piperidinol
hydrochloride was obtained as colorless crystals.
IR(KBr)cm-1: 32 60,2 94 9,2 638,14 33,112 9,1045,702,668
NMR(CDC13)d values: 1. 5-2 . 0 (4H,m) , 2 . 1-2 . 8 (2H,m) ,
2.99(2H,t,J=6Hz), 3.1-3.6(4H,m), 3.76(2H,t,J=6Hz),
3.8-4.1(3H,m), 7.20(1H,d,J=8Hz), 7.30(1H,d,J=5Hz),
7.44(1H,d,J=5Hz), 7.67(lH,s),7.8 0(1H,d,J=8Hz)
Example 4 4
Production of l-{2-[2-(1-benzofuran-5-
yl)ethoxy]ethyl}-4-piperidinol
In the same manner as in Example 16 (1), 2-
[2- (l-benzofuran-5-yl)ethoxy]-1-(4-hydroxy-l-
piperidinyl)-1-ethancne was obtained.
IR (neat )cm-1: 34 06,2 931, 163 6, 1110, 771, 740
Then, l-{2-[2-(1-benzofuran-5-
yl)ethoxy]ethyl}-4-piperidinol was obtained as a
colorless oil in the same manner as in Example 16 (2).
IR (neat) cm"1: 3359,2 939,14 68,1111,1073,882,7 68,739
NMR(CDC13)d values: 1. 5-2 . 3 (6H,m) , 2 . 5-3 . 0 (2H,m) ,
2.57(2H,t,J=6Hz), 2 . 97(2H,t,J=7Hz), 3.5-3.8(1H,m),
3.58(2H,t,J=6Hz) , 3.68(2H,t,J=7Hz),
6.71(lH,dd, J=l,2Hz) , 7.13(1H,dd,J=2,8Hz),
7.4 0(lH,d, J=8Hz) , 7.42(1H, dd, J=l, 2),
7.55(lH,d,J=2Hz)
Example 45
Production of l-{2-[2-(1-benzofuran-5-
yl)ethoxy]ethyl}-4-piperidinol hydrochloride
In the same: manner as in Example 21, l-{2-[2-
(l-benzofuran-5-yl)ethoxy]ethyl}-4-piperidinol
hydrochloride was obtained as a light-yellow oil.
IR (neat) cm"1: 3366, 2938, 2638, 1458, 1126, 776, 742
NMR(CDC13) 8 values: 1. 6-2 . 4 (4H,m) , 2 . 8-3 . 2 (8H,m) ,
3.71(2H,t,J=6Hz), 3.7-4.1(3H,m) ,
6.72(lH,dd,J=l,2Hz), 7.12(1H,dd,J=2,8Hz),
7.4 4(lH,d, J=8Hz) , 7.42(1H, dd,J=l,2),
7.60(lH,d,J=2Hz)
Example 4 6
Production of l-{2-[2-(1-benzofuran-5-
yl)ethoxy]ethyl}-3-pyrrolidinol
(1) In 13.0 mL of tetrahydrofuran was dissolved
1.28 g of 2-[2-(1-benzofuran-5-yl)ethoxy]acetic acid
and the solution was cooled to 5°C, after which 1.41 g
of 1,l"-carbonyldiimidazole was added thereto and the
resulting mixture was stirred at room temperature for 2
hours. To the reaction mixture were added 1.22 mL of
triethylamine and 0.72 mL of 3-pyrrolidinol, followed
by stirring at room temperature for 2 hours. Water and
ethyl acetate were added to the reaction mixture and
the pH was adjusted to 1 with 6 mol/L hydrochloric
acid, after which the organic layer was separated. The
organic layer was washed with a saturated aqueous
sodium hydrogencarbonate solution and then a saturated
aqueous sodium chloride solution, and dried over
anhydrous magnesium sulfate. Then, the solvent was
distilled off under reduced pressure to obtain 1.39 g
of 2-[2-(1-benzofuran-5-yl)ethoxy]-1-(3-hydroxy-l-
pyrrolidinyl)-1-ethanone as a colorless oil.
IR (neat) cm"1: 3398,2 943,1637, 14 67, 112 8, 103 0, 7 71, 741
(2) In 14.0 mL of tetrahydrofuran was dissolved
1.39 g of 2-[2-(1-benzofuran-5-yl)ethoxy]-1-(3-hydroxy-
1-pyrrolidinyl)-1-ethanone, and 14.4 mL of a 1 mol/L
solution of a borane-tetrahydrofuran complex in
tetrahydrofuran was added dropwise thereto under ice-
cooling, after which the resulting mixture was stirred
at room temperature for 17 hours. To the reaction
mixture was added 8.0 mL of 6 mol/L hydrochloric acid,
and the resulting mixture was heated under reflux for 1
hour. After the reaction mixture was cooled, water and
ethyl acetate were added thereto and the pH was
adjusted to 10 with a 2 mol/L aqueous sodium hydroxide
solution, and then the organic layer was separated.
The organic layer was washed with water and then a
saturated aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate, and then distilled under
reduced pressure to remove the solvent. The residue
was purified by a column chromatography (eluent;
chloroform : methanol =30 : 1 to 10 : 1) to obtain
0.96 g of l-{2-[2-(l-benzofuran-5-yl)ethoxy]ethyl}-3-
pyrrolidinol as a colorless oil.
IR( neat)cm-1: 3386,2 941,14 68, 12 61, 1110, 1030, 882,
769,738
NMR(CDC13) 5 values: 1. 5-2 . 0 (1H,m) , 1. 9-3 . 0 (5H,m) ,
2.68(2H,t,J=6Hz), 2.98(2H,t,J=7Hz),
3.58(2H,t,J=6Hz), 3.70(2H,t,J=7Hz), 4.2-4.4(1H,m),
6.71(lH,dd,J=l,2Hz), 7.14(lH,d,J=8Hz),
7.42(lH,d,J=8Hz), 7.4-7.5(1H,m), 7.59(1H,d,J=2Hz)
Example 4 7
Production of l-{2-[2-(I-benzofuran-5-
yl)ethoxy]ethyl}-3-pyrrolidinol oxalate
In the same manner as in Example 17, l-{2-[2-
(1-benzofuran-5-yl)ethoxy]ethyl}-3-pyrrolidinol oxalate
was obtained as colorless crystals.
IR(KBr)cm-1: 3413,294 5,2698, 1715, 1197, 1111, 720
NMR(DMSO-d6)d values: 1. 6-2 . 3 (2H,m) ,
2.92 (2H,t, J=7Hz) , 3. 0-3. 5 (6.4,m) , 3 . 5-3 . 8 (4H,m) ,
4.2-4.5(1H,m), 6.89(lH,dd,J=l,2Hz),
7.19(lH,dd,J=l,8Hz), 7.50(1H,d,J=8Hz), 7.5-
7.6(1H,m), 7.94(lH,d,J=2Hz)
Example 4 8
Production of (3R*,4R*)-1-{2-[2-(1-
benzothiophen-5-yl)ethoxy]ethyl}-3,4-pyrrolidinediol
In the same manner as in Example 46 (1), 2-
[2-(1-benzothiophen-5-yl)ethoxy]-1-[(3R*,4R*)-3,4-
dihydroxy-1-pyrrolidinyl]-1-ethanone was obtained as a
yellow oil.
IR (neat)cm-1: 3370,2935,2874,1636,1131,756,7 01
Then, (3R*,4R*)-l-{2-[2-(l-benzothiophen-5-
yl)ethoxy]ethyl}-3,4-pyrrolidinediol was obtained as a
yellow oil in the same manner as in Example 46 (2).
IR (neat) cm-1: 338 6,2938,28 66,14 38,1113,756,703
NMR(CDC13)6 values: 2.5-3.0(5H,m),
3.00(2H,t,J=7Hz), 3.2-3.7(1H,m), 3.56(2H,t,J=6Hz),
3.71(2H,t,J=7Hz), 3.9-4.4(2H,m), 7.20(1H,d,J=8Hz),
7.28(1H,d,J=5Hz), 7.43(1H,d,J=5Hz), 7.66(lH,s),
7.80(1H,d,J=8Hz)
Example 4 9
Production of (3R*,4R*)-l-{2-[2-(1-
benzothiophen-5-yl)ethoxy]ethyl}-3,4-pyrrolidinediol
oxalate
In the same manner as in Example 17,
(3R*, 4R*)-l-{2-[2-(1-benzothiophen-5-yl)ethoxy]ethyl}-
3,4-pyrrolidinediol oxalate was obtained as colorless
crystals.
IR(KBr)cm-1: 3309,292 9,1718,1617,1199,1104,702
NMR(DMSO-d6)d values: 2.8-3.2(6H,m) , 3.2-3.8(6H,m),
4.1-4.4(2H,m), 7.26(1H,d,J=8Hz), 7.39(1H, d, J=5Hz) ,
7.72(1H,d,J=5Hz), 7.75(lH,s), 7.90(1H,d,J=8Hz)
Example 50
Production of l-{2-[2-(5-methoxy-l-
benzofuran-6-yl)ethoxy]ethyl}-3-pyrrolidinol
In the same manner as in Example 46 (1), 2-
[2-(5-methoxy-l-benzofuran-6-yl)ethoxy]-1-(3-hydroxy-l-
pyrrolidinyl)-1-ethanone was obtained as a colorless
oil.
IR (neat)cm-1: 3394,2 941,1637, 14 65, 1197,1131,1015,
841,759
Then, l-{2-[2-(5-methoxy-l-benzofuran-6-
yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a
colorless oil in the same manner as in Example 46 (2).
IR (neat)cm-1: 338 6, 2 94 0, 14 66, 1430, 1198, 1131,1015,
837,762
NMR(CDC13)d values: 1. 5-2 . 4 (3H,m) , 2 . 5-3 . 0 (5H,m) ,
2.99(2H,t,J=7Hz), 3.59(2H,t,J=6Hz),
3.67(2H,t,J=7Hz), 3.85(3H,s),4.2-4.4(1H,m),
6.68(1H,d,J=2Hz), 6.99(lH,s), 7.34(lH,s),
7.54(1H,d,J=2Hz)
Example 51
Production of 1-{2-[2-(5-methoxy-1-
benzofuran-6-yl)ethoxy]ethyl}-3-pyrrolidinol oxalate
In the same manner as in Example 17, l-{2-[2-
(5-methoxy-l-benzofuran-6-yl)ethoxy]ethyl}-3-
pyrrolidinol oxalate was obtained as colorless
crystals.
IR(KBr)cm-1: 3396,2 942,2 691, 1718,1636,14 65,1198,
1130,720
NMR(DMSO-d6)d values: 1. 7-2 . 3 (2H,m) , 2 . 8-3. 6 (6H,m) ,
2.91(2H,t,J=6Hz), 3.5-3.9(4H,m), 3.83(3H,s), 4.2-
4.5(1H,m), 6.86(LH,d,J=2Hz), 7.17(lH,s),
7.43(lH,s), 7.88(lH,d,J=2Hz)
Example 52
Production of 1-{2-[2-(6-methoxy-l-
benzofuran-5-yl)ethoxy]ethyl}-3-pyrrolidinol
In the same manner as in Example 46 (1), 2-
[2-(6-methoxy-l-benzofuran-5-yl)ethoxy]-1-(3-hydroxy-l-
pyrrolidinyl)-1-ethanone was obtained as a colorless
oil.
IR (neat) cm-1: 3381,2944, 1638, 1475, 1201, 1125,
1011,758
Then, l-{2-[2-(6-methoxy-1-benzofuran-5-
yl)ethoxy]ethyl}-3-pyrrolidinol was obtained as a
colorless oil in the same manner as in Example 46 (2).
IR(neat)cm-1: 3398,2938,1475,1202,1094,757,730
NMR(CDC13)d values: 1.5-2.4(3H,m), 2.5-3.0(5H,m),
2.98(2H,t,J=7Hz), 3.59(2H,t,J=6Hz),
3.68(2H,t,J=7Hz), 3.86(3H,s),4.2-4.4(1H,m),
6.65(lH,d,J=2Hz), 7.00(lH,s), 7.35(lH,s),
7.50(lH,d,J=2Hz)
Example 53
Production of 1-{2-[2-(6-methoxy-l-
benzof uran-5-yl )ethoxy]ethyl}-3-pyrrolidinol
hydrochloride
In the same manner as in Example 21, 1-{2-[2-
(6-methoxy-l-benzofuran-5-yl)ethoKy]ethyl}-3-
pyrrolidinol hydrochloride was obtained as a colorless
oil.
IR(neat) cm-1: 3377, 2938, 2694, 1475, 12 02, 1124,
1093,1011
NMR(CDC13) 8 values: 1. 7-2 . 2 (2H,m) , 2 . 8-3 . 6 ( 6H,m) ,
2.96(2H,t,J=6Hz), 3.5-4.2(4H,m), 3.86(3H,s),
4.3-4.6(1H,m), 6.6-6.7(1H,m), 7.01(lH,s),
7.34 (lH,d, J=lHz) , 7.51 (1H, d,, J=2Hz)
Example 54
Production of 1-{2-[2-(1-benzothiophen-5-
yl)ethoxy]ethyl}-3-pyrrolidinamine
(1) In 10.0 mL of tetrahydrofuran was dissolved
1.00 g of 2-[2-(1-benzothiophen-5-yl)ethoxy]acetic
acid, and the solution was cooled to 5°C, after which
1.03 g of 1,1"-carbonyldiimidazole was added thereto
and the resulting mixture was stirred at room
temperature for 1 hour. After the reaction mixture was
cooled to 5°C, 0.88 mL of triethylamine and 1.18 g of
tert-butyl=3-pyrrolidinylcarbamate were added thereto,
followed by stirring at room temperature for 1 hour.
Water and ethyl acetate were added to the reaction
mixture and the pH was adjusted to 4 with 6 mol/L
hydrochloric acid, after which the organic layer was
separated. The organic layer was washed with a
saturated aqueous sodium hydrogencarbonate solution and
then a saturated aqueous sodium chloride solution, and
dried over anhydrous magnesium sulfate. Then, the
solvent was distilled off under reduced pressure to
obtain 2.00 g of tert-butyl=l-{2-[2-(1-benzothiophen-5-
yl)ethoxy]acetyl}-3-pyrrolidinylcarbamate as a light-
yellow oil.
(2) In 2.0 mL of tetrahydrofuran was dissolved
2.00 g of the aforesaid tert-butyl=l-{2-[2-(1-
benzothiophen-5-yl)ethoxy]acetyl}-3-pyrrolidinyl-
carbamate, and the resulting solution was cooled to 5°C,
after which 10.6 mL of a 1 mol/L solution of a borane-
tetrahydrofuran complex in tetrahydrofuran was added
dropwise thereto and the resulting mixture was stirred
at room temperature for 17 hours. To the reaction
mixture was added 3.5 mL of 6 mol/L hydrochloric acid,
and the resulting mixture was headed under reflux for 3
«
hours. After the reaction mixture was cooled, water
and ethyl acetate were added thereto and the pH was
adjusted to 10 with a 5 mol/L aqueous sodium hydroxide
solution, and then the organic layer was separated.
The organic layer was washed with a saturated aqueous
sodium chloride solution, dried over anhydrous
magnesium sulfate, and then distilled under reduced
pressure to remove the solvent. The residue was
purified by a column chromatography (eluent;
chloroform : methanol = 30 : 1 to 15 : 1) to obtain
1.01 g of l-{2-[2-(1-benzothiophen-5-yl)ethoxy]ethyl}-
3-pyrrolidinamine as a light-yellow oil.
IR(neat)cm-1: 3358,2938,2861,1438,1112,1052,755,703
NMR(CDC13) 5 values: 1. 2-1. 7 (1H,m) , 1. 9-3 . 0 (7H,m) ,
2.01(2H,s), 3.00(2H,t,J=7Hz), 3.3-3.7(1H,m),
3.57(2H,t,J=6Hz), 3.71(2H,t,J=7Hz), 7.20(lH,d,
J=8Hz), 7.28(1H,d,J=5Hz), 7.41(1H,d,J=5Hz) ,
7.66(lH,s), 7.78(lH,d,J=8Hz)
Example 55
Production of l-{2-[2-(l-Benzothiophen-5-
yl)ethoxy]ethyl}-3-pyrrolidinamine dioxalate
In 3.0 mL of ethyl acetate was dissolved 0.71
g of l-{2-[2-(1-benzothiophen-5-yl)ethoxy]ethyl}-3-
pyrrolidinaraine, and to the solution was added a
solution of 0.44 g of oxalic acid in 4.0 mL of ethyl
acetate. The resulting mixture was stirred at room
temperature for 1 hour and then at 5°C for 1 hour. The
crystals precipitated were collected by filtration,
washed with ethyl acetate and then dried to obtain 1.03
g of 1-{2-[2-(1-benzothiophen-5-yl)ethoxy]ethyl}-3-
pyrrolidinamine dioxalate as colorless crystals.
IR(KBr)cm-1: 344 7,2938,1406,127 9,1115,720
NMR(DMSO-d6)d values: 1. 7-2 . 5 (2H, m) , 2 . 8-3. 5 (8H,m) ,
3.5-4.0(5H,m), 7.27(1H, d, J=8Hz), 7.40(1H,d,J=5Hz),
7.72(1H,d,J=5Hz), 7.75(lH,s), 7.90 (1H,d,J=8Hz)
Example 5 6
Production of 1-{2-[2-(1-benzofuran-5-
yl)ethoxy]ethyl}-3-pyrrolidinamine
In the same manner as in Example 54 (1),
tert-butyl=l-{2-[2-(l-benzofuran-5-yl)ethoxy]acetyl}-3-
pyrrolidinylcarbamate was obtained.
Then, 1-{2-[2-(1-benzofuran-5-
yl)ethoxy]ethyl}-3-pyrrolidinamine was obtained as a
yellow oil in the same manner as in Example 54 (2).
IR(neat)cm-1: 3356, 2 938, 14 67, 12 61, 1111, 1030, 882,
7 69,740
NMR(CDC13) 5 values: 1.2-1.7(1H,m), 2.02(2H,s), 2.1-
3.0(7H,m), 2.98(2H,t,J=7Hz), 3.3-3.7(1H,m),
3.57(2H,t,J=6Hz), 3.69(2H,t,J=7Hz),
6.71(lH,dd,J=l,2Hz), 7.15(1H,dd,J=l,7Hz),
7.40(lH,d,J=7Hz), 7.4-7.5(1H,m), 7.59(1H,d,J=2Kz)
Example 57
Production of 1-{2-[2-(1-benzofuran-5-
yl)ethoxy]ethyl}-3-pyrrolidinamine oxalate
In the same manner as in Example 17, l-{2-[2-
(1-benzofuran-5-yl)ethoxy]ethyl}-3-pyrrolidinamine
oxalate was obtained as colorless crystals.
IR(KBr)cm-1: 34 08,2 952, 1615, 1311, 1127, 769
NMR(DMSO-d6) 5 values: 1. 5-1 . 9 (1H,m) , 1. 8-2 . 4 (1H,m) ,
2.1-3.0(6H,m), 2.89(2H,t,J=7Hz), 3.4-3.8(5H,m),
6.89(lH,dd,J=l,2Hz), 7.18(lH,d,J=8Hz),
7.50(lH,d,J=8Hz), 7.4-7.6(1H,m), 7.94(1H,d,J=2Hz)
Example 58
Production of 1-{3-[2-(l-benzothiophen-5-
yl)ethoxy]propyl}-3-pyrrolidinol
In 12 mL of N,N-dimethylformamide was
dissolved 1.20 g of 5-[2-(3-chloropropoxy)ethyl]-1-
benzothiophene, and 0.82 g of 3-pyrrolidinol and 1.30 g
of potassium carbonate were added to the solution,
after which the resulting mixture was stirred at 85°C
for 2.5 hours. After the reaction mixture was cooled,
water and ethyl acetate were added thereto and the
organic layer was separated. The organic layer was
washed with water and then a saturated aqueous sodium
chloride solution, dried over anhydrous magnesium
sulfate, and then distilled under reduced pressure to
remove the solvent. The residue was purified by a
column chromatography (eluent; chloroform : methanol =
20 : 1 to 10 : 1) to obtain 0.78 g of l-{3-[2-(1-
benzothiophen-5-yl)ethoxy]propyl}-3-pyrrolidinol as a
colorless oil.
IR (neat) cm-1: 338 6,2 94 3,1438,110 6, 1052,755,701
NMR(CDC13) 5 values: 1. 5-2 . 0 ( 3H,m) , 2 . 0-3 . 0 (7H,m) ,
2.98(2H,t,J=7Hz), 3.49(2H,t,J=6Hz),
3.67(2H,t,J=7Hz), 4.2-4.4(1H,m), 7.1-7.3(2H,m),
7.41(lH,d,J=6Hz), 7.66(lH,s), 7.78(1H,d,J=8Hz)
Example 59
Production of l-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-pyrrolidinol hydrochloride
In the same manner as in Example 21, 1-{3-[2-
(1-benzothiophen-5-yl)ethoxy]propyl}-3-pyrrolidinol
hydrochloride was obtained as colorless crystals.
IR(KBr)cm-1: 33 68, 2 937, 2 695, 1438, 1108 , 821, 7 64 , 7 08
NMR(CDC13)d values: 1.8-2.3(4H,m) , 2.3-3.6(6H,m),
2.96(2H,t,J=6Hz), 3.50(2H,t,J=6Hz),
3.68(2H,t,J=7Hz), 4.3-4.7(1H,m), 7.21(1H,d,J=8Hz),
7.30(1H,d,J=5Hz), 7.43(1H,d,J=5Hz), 7.67(lH,s),
7.80(lH,d,J=8Hz)
Example 60
Production of 1-{3-[2-(1-benzofuran-5-
yl)ethoxy]propyl}-3-pyrrolidinol
In the same manner as in Example 58, l-{3-[2-
(1-benzofuran-5-yl)ethoxy]propyl}-3-pyrrolidinol was
obtained as a light-yellow oil.
IR(neat) cm-1: 3386, 2942, 14 67, 12 61, 1108, 1030, 883, 740
NMR(CDC13) 8 values: 1. 5-2 . 0 (3H,m) , 2 . 0-3 . 0 (7H,m) ,
2.95(2H,t,J=7Hz), 3 . 4 9(2H,z,J=6Hz),
3.65(2H, t, J=7Hz) , 4.2-4.4(1H,m),
6.71(lH,dd,J=l,2Hz), 7.14(1H,dd,J=l,8Hz), 7.3-
7.5(2H,m), 7.58 (lH,d,J=2Hz)
Example 61
Production of l-{3-[2-(1-benzofuran-5-
yl)ethoxy]propyl}-3-pyrrolidinoi hydrochloride
In the same manner as in Example 39, l-{3-[2-
(1-benzofuran-5-yl)ethoxy]propyl}-3-pyrrolidinol
hydrochloride was obtained as a light-yellow oil.
IR (neat) cm"1: 3339, 2941, 2605, 14 68, 12 62, 1110, 773, 742
NMR(CDC13) 5 values: 1. 6-2 . 4 (4H,m) , 2 . 4-4 . 0 (12H,m) ,
4.4-4.8(1H,m), 6.72(1H,d,J=2Hz), 7.12(1H,d,J=8Hz),
7.3-7.6(2H,m), 7.59(1H,d,J=2Hz)
Example 62
Production of 1-{3-[2-(6-fluoro-1-
benzothiophen-5-yl)ethoxy]propyl}-3-pyrrolidinol
In the same manner as in Example 58, 1-{3-[2-
(6-fluoro-1-benzothiophen-5-yl)ethoxy]propyl}-3-
pyrrolidinol was obtained as a yellow oil.
IR (neat) cm-1: 3422,2 952,1458, 1257,1106,838,747,711
NMR(CDC13)d values: 1. 5-3 . 0 (10H,m) ,
3.00(2H,t,J=7Hz), 3.4-3.6(2H,m), 3.68(2H,t,J=7Hz),
4.2-4.4(1H,m), 7.23(1H,d,J=5Hz), 7.36(1H,d,J=5Hz),
7.51 (lH,d, J=10.4z) , 7.66(lH,d, J=7Hz)
Example 63
Production of l-{3-[2-(6-fluoro-1-
benzothiophen-5-yl)ethoxy]propyl}-3-pyrrolidinol
hydrochloride
In the same manner as in Example 39, l-{3-[2-
(6-fluoro-1-benzothiophen-5-yl)ethoxy]propyl} -3-
pyrrolidinol hydrochloride was obtained as a yellow
oil.
IR(neat)cm-1: 3377,2 954,27 02,14 58,1257,1107,7 50,712
NMR(CDC13)d values: 1. 8-2 . 3 ( 4H,m) , 2 . 8-3 . 6 (8H,m) ,
3.53(2H,t,J=6Hz), 3.69(2H,t,J=7Hz), 4.3-4.4(1H,m),
7.2 7(1H,d,J=5Hz), 7.39(1H,d,J=5Hz),
7.52(lH,d,J=10Hz), 7.67(lH,d,J=7Hz)
Example 64
Production of (3R,4S)-l-{3-[2-(1-
benzothiophen-5-yl)ethoxy]propyl}-3,4-pyrrolidinediol
In the same manner as in Example 58, (3R,4S)-
1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3,4-
pyrrolidinediol was obtained as a colorless oil.
IR(neat) cm-1: 3387, 2 94 0, 1438, 1159,1108, 1051, 703
NMR(CDC13)d values: 1. 5-1. 9 (2H,m) , 2 . 4-2 . 8 ( 6H,m) ,
2.98(2H,t,J=7Hz), 3.4 7(2H,t,J=6Hz),
3.67(2H,t,J=7Hz), 4.1-4.3(2H,m),
7.20(lH,dd,J=l,8Hz), 7.2 7(1H,d,J=5Hz),
7.42(1H,d,J=5Hz), 7.65(1H,d,J=1Hz),
7.79(lH,d,J=8Hz)
Example 65
Production of (3R,4S)-1-{3-[2- (1-
benzothiophen-5-yl)ethoxy]propyl}-3,4-pyrrolidinediol
hydrochloride
In the same manner as in Example 21, (3R,4S)-
l-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3,4-
pyrrolidinediol hydrochloride was obtained as colorless
crystals.
IR(KBr)cm-1: 3381, 28 71, 2 602 , 112 0, 808 , 768 , 718
NMR(DMSO-d6) 5 values: 1. 8-2 . 0 (2H,m) , 2.8-
3.8(12H,m), 3.9-4.3(2H,m), 7.25(1H,dd,J=2,8Hz),
7.39(1H,d,J=5Hz), 7.72(1H,d,J=5Hz),
7.7 3(lH,d,J=2Hz), 7.90(lH,d,J=8Hz)
Example 66
Production of l-{3-[2-(l-benzothiophen-5-
yl)ethoxy]propyl}-4-piperidinol
In the same manner as in Example 58, l-{3-[2-
(1-benzothiophen-5-yl)ethoxy]propyl}-4-piperidinol was
obtained as a light-yellow oil.
IR (neat)cm-1: 3385, 2 935, 14 38, 1364 , 1111, 755, 7 01
NMR(CDC13)d values: 1. 4-2 . 2 ( 8H,m) , 2 . 1-2 . 5 (2H, m) ,
2.5-3.0(2H,m), 2.98(2H,t,J=7Hz), 3.48(2H,t,J=6Hz),
3.5-3.8(1H,m), 3.67(2H,t,J=7Hz), 7.1-7.3(2H,m),
7.42(1H,d,J=5Hz), @@@7.66(lH,s), 7.79(1H,d,J=8Hz)
Example 67
Production of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-4-piperidinol oxalate
In the same manner as in Example 17, 1-{3-[2-
(1-benzothiophen-5-yl)ethoxy]propyl}-4-piperidinol
oxalate was obtained as colorless crystals.
IR(KBr) cm-1: 3420,2866, 1718, 1616, 1190, 1120,705
NMR(DMSO-d6) 5 values: 1. 5-2 . 0 (6H,m) , 2 . 8-3 .1 (8H,m) ,
3.4-3.8(1H,m), 3.44(2H,t,J=6Hz), 3.64(2H,t,J=6Hz),
7.24(lH,d,J=8Hz), 7.40(1H,d,J=5Hz), 7.6-7.8(2H,m),
7.91(lH,d,J=8Hz)
Example 68
Production of l-{2-[2-(2-
naphthyl)ethoxy]ethyl}-3-pyrrolidinol
In 8 mL of N,N-dimethylformamide was
dissolved 0.80 g of 2-[2-(2-naphthyl)ethoxy]-
ethyl=methanesulfonate, and 0.45 mL of 3-pyrroiidinol
and 0.75 g of potassium carbonate were added to the
solution, after which the resulting mixture was stirred
at 90°C for 2 hours. After the reaction mixture was
cooled, water and ethyl acetate were added thereto and
the organic layer was separated. The organic layer was
washed with water and then a saturated aqueous sodium
chloride solution, dried over anhydrous magnesium
sulfate, and then distilled under reduced pressure to
remove the solvent. The residue was purified by a
column chromatography (eluent; chloroform : methanol =
8 : 1 to 5 : 1) to obtain 0.51 g of l-{2-[2-(2-
naphthyl)ethoxy]ethyl}-3-pyrrolidinol as a colorless
oil.
IR (neat) cm-1: 3422,2 938,1112,820,74 9
NMR(CDC13)d values: 1. 5-1. 9 (1H, m) , 2 . 0-2 . 5 (3H,m) ,
2.5-3.0(4H,m), 3.05(2H,t,J=7Hz), 3.59(2H,t,J=6Hz),
3.75(2H,t,J=7Hz), 4.2-4.4(1H,m), 7.2-7.6(4H,m),
7.6-8.0(3H,m)
Example 69
Production of 1-{2-[2-(2-
naphthyl)ethoxy]ethyl}-3-pyrrolidinol oxalate
In the same manner as in Example 17, 1-{2-[2-
(2-naphthyl)ethoxy]ethyl}-3-pyrrolidinol oxalate was
obtained as colorless crystals.
IR(KBr)cm-1: 33 66, 2 94 5, 14 05, 1113, 820, 720
NMR(DMSO-d6)d values: 1. 6-2 . 3 (2H,m) , 2. 7-3. 5 (8H,m) ,
3.5-3.9(4H,m), 4.2-4.5(1H,m), 7.4-7.6(3H,m), 7.7-
8.0(4H,m)
Example 70
Production of (3R,4S)-1-{2-[2-(1-
benzothiophen-5-yl)ethoxy]ethyl}-3,4-pyrrolidinediol
In 25 mL of N,N-dimethylformamide was
dissolved 2.50 g of 2-[2-(l-benzothiophen-5-
yl)ethoxy]ethyl=methanesulfonate, and 1.40 g of
(3R,4S)-3,4-pyrrolidinediol hydrochloride and 4.70 mL
of triethylamine were added to the solution, after
which the resulting mixture was stirred at 90°C for 1
hour. After the reaction mixture was cooled, water and
ethyl acetate were added thereto and the pH was
adjusted to 10 with a 2 mol/L aqueous sodium hydroxide
solution, and the organic layer was separated. The
organic layer was washed with water and then a
saturated aqueous sodium chloride solution, and dried
over anhydrous magnesium sulfate. The solvent was
distilled off under reduced pressure and the residue
was purified by a cclumn chromatography (eluent;
chloroform : methanol = 8 : 1 to 5 : 1) to obtain
0.84 g of (3R,4S)-l-{2-[2-(l-benzothiophen-5-
yl)ethoxy]ethyl}-3,4-pyrrolidinediol as a yellow oil.
IR(neat)cm-1: 3390,2940,1438,1111,1050,703
NMR(CDC13)d values: 2 . 5-3 . 0 ( 6H,m) ,
3.00(2H,t,J=7Hz), 3.55(2H,t,J=6Hz),
3.70(2H,t,J=7Hz), 4.0-4.3(2H,m),
7.21(lH,dd,J=l,8Hz), 7.28(1H,d,J=5Hz),
7.4 3(lH,d,J=5Hz], 7.66(1H,d,J=lHz),
7.80(lH,d,J=8Hz)
Example 71
Production of (3R,4S)-I-{2-[2-(1-
benzothiophen-5-yl)ethoxy]ethyl}-3,4-pyrrolidinediol
hydrochloride
In the same manner as in Example 21, (3R,4S)-
l-{2-[2-(1-benzothiophen-5-yl)ethoxy]ethyl}-3,4-
pyrrolidinediol hydrochloride was obtained as colorless
crystals.
IR(KBr)cm-1: 3194 , 2854 , 13 65, 134 8, 1130, 1111, 820, 712
NMR(DMSO-d5)d values: 2 . 8-4 . 0 (12H, m) ,
3.9-4.3(2H,m), 7.2-7.5(2H,m), 7.7-8.2(3H,m)
Example 72
Production of tert-butyl=1-{3-[2-(1-
benzothiophen-5-yl)ethoxy]propyl}-3-pyrrolidinyl-
carbamate
In 7 mL of N,N-dimethylformamide was
dissolved 0.70 g of 3- [2-(1-benzothiophen-5-
yl)ethoxy]propyl=methanesulfonate, and 1.03 g of tert-
butyl=3-pyrrolidinylcarbamate carbonate and 1.8 6 mL of
triethylamine were added to the solution, after which
the resulting mixture was stirred at 90°C for 2 hours.
After the reaction mixture was cooled, water and ethyl
acetate were added thereto and the pH was adjusted to
10 with 6 mol/L hydrochloric acid, and the organic
layer was separated. The organic layer was washed with
water and then a saturated aqueous sodium chloride
solution, and dried over anhydrous magnesium sulfate.
Subsequently, the solvent was distilled off under
reduced pressure to obtain 1.12 g of tert-butyl=1-{3-
[2- (1-benzothiophen-5-yl)ethoxy]propyl}-3-pyrrolidinyl-
carbamate as a yellow oil.
NMR(CDC13)d values: 1. 2-1. 9 (3H, m) , 1.44(9H,s), 1.9-
3.0(7H,m), 2.99(2H,t,J=7Hz), 3.49(2H,t,J=6Hz),
3.67(2H,t,J=7Hz), 4.0-4.3(1H,m), 7.19(1H,d, J=8Hz) ,
7.27(1H,d,J=5Hz), 7.42(1H,c,J=5Hz) , 7.66(lH,s),
7.79(lH,d,J=8Hz)
Example 73
Production of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-pyrrolidinamine
In 7.0 mL of ethyl acetate was dissolved 1.12
g of tert-butyl=1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-pyrrolidinylcarbamate, and 1.86 mL
of 6 mol/L hydrochloric acid was added to the solution,
after which the resulting mixture was heated under
reflux for 1 hour. After the reaction mixture was
cooled, water and ethyl acetate were added thereto and
the pH was adjusted to 10 with a 2 mol/L aqueous sodium
hydroxide solution, and the organic layer was
separated. The organic layer was washed with water and
then a saturated aqueous sodium chloride solution,
dried over anhydrous magnesium sulfate, and then
distilled under reduced pressure to remove the solvent.
The residue was purified by a column chromatography
(eluent; chloroform : methanol = 30 : 1 to 20 : 1) to
obtain 0.38 g of 1-{3-[2-(l-benzothiophen-5-
yl)ethoxy]propyl}-3-pyrrolidinamine as a light-yellow
oil.
IR(neat) cm-1: 3357,2937,2 8 61,27 96, 1146, 1108, 755, 701
NMR(CDCl3)d values: 1. 2-1. 9 (4H, m) , 1. 9-2 . 8 (7H,m) ,
2.97(2H,t,J=7Hz), 3.4 8(2H,t,J=6Hz),
3.66(2H,t,J=7Hz), 7.19(1H,d,J=8Hz),
7.23(1H,d,J=5Hz), 7.39(1H,d,J=5Hz), 7.64(lH,s),
7.77(lH,d,J=8Hz)
Example 7 4
Production of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-pyrrolidinamine oxalate
In the same manner as in Example 17, l-{3-[2-
(1-benzothiophen-5-yl)ethoxy]propyl}-3-pyrrolidinamine
oxalate was obtained as colorless crystals.
IR(KBr)cm-1: 3390,2871, 1614 , 1310, 1122 , 7 66
NMR(DMSO-d6)d values: 1.5-1.9(2H,m), 1.9-2.9(8H,m),
2.92(2H,t,J=7Hz), 3.3-3.7(1H,m), 3.43(2H,t,J=6Hz),
3.62(2H,t,J=7Hz), 7.25(lH,d,J=8Hz),
7.39(1H,d,J=5Hz), 7.12 (1H,d,J=5Hz), 7.73(lH,s),
7.90(lH,d,J=8Hz)
Example 75
Production of N-(1-{3-[2-(l-benzothiophen-5-
yl)ethoxy]propyl}-3-pyrrolidinyl)acetamide
In 5 mL of methylene chloride was dissolved
0.50 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-
3-pyrrolidinamine, and the solution was cooled to -60°C,
after which 0.27 mL of triethylamine and 0.14 mL of
acetyl chloride were added to the solution and the
resulting mixture was stirred at room temperature for 1
hour. Water and ethyl acetate were added to the
reaction mixture and the organic layer was separated.
The organic layer was washed with a saturated aqueous
sodium chloride solution, dried over anhydrous
magnesium sulfate, and then distilled under reduced
pressure to remove the solvent. The residue was
purified by a column chromatography (eluent;
chloroform : methanol = 50 : 1 to 10 : 1) to obtain
0.55 g of N-(l-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-pyrrolidinyl)acetamide as a yellow
oil.
IR (neat) cm-1: 3292,2946,1654, 1560, 1110, 757, 702
NMR(CDC13)d values: 1. 5-1. 7 (1H,m) , 1. 7-1. 8 (2H,m) ,
1.94(3H,s), 2.13(lH,q,J=9Hz), 2.2-2.3(1H,m),
2.4-2.5(3H,m), 2.59(1H,dd,J=2,lOHz),
2.86(lH,dt,J=4,9Hz), 2.99(2H,t,J=7Hz),
3.49(2H,t,J=6Hz), 3.67(2H,t,J=7Hz), 4.3-4.5(1H,m),
5.8-5.9(1H,m), 7.22(1H,dd,J=l,8Hz),
7.28(1H,d,J=5Hz), 7.42(1H,d,J=5Hz),
7.67(1H,d,J=1Hz), 7.7 9(lH,d,J=8Hz)
Example 7 6
Production of N-(1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-pyrrolidinyl)acetamide
hydrochloride
In the same manner as in Example 21, N-(l-{3-
[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
pyrrolidinyl)acetamide hydrochloride was obtained as
light-brown crystals.
IR(KBr)cm-1: 3422,2 8 68,2475, 1664,1542,1343,1117,711
NMR(CDC13)d values: 1. 9-2 . 1 (3H,m) , 2.05(3H,s),
2.3-2.4(1H,m), 2.4-2.5(1H,m), 2.6-2.7(1H,m),
2.8-2.9(2H,m), 2.97(2H,t,J=6Hz), 3.4-3.4(1H,m),
3.51(2H,t,J=6Hz), 3.6-3.7(IH,m), 3.70(2H,t, J=6Hz) ,
4.6-4.8(1H,m) , 7.22(1H,dd,J=l,8Hz),
7.31 (1H,d,J=5Hz), 7.46(1H,d,J=5Hz), 7.67(lH,s),
7.81(lH,d,J=8Hz)
Example 77
Production of N-(1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-pyrrolidinyl)methanesulfonamide
In the same manner as in Example 75, N-(l-{3-
[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
pyrrolidinyl)methanesulfonamide was obtained as a
yellow oil.
IR(neat) cm-1: 327 0,2 927,285 6,1320,1148,1110,7 56
NMR(CDC13)d values: 1. 6-1. 8 (3H,m) , 2 .1-2 . 3 (2H,m) ,
2.4 4(2H,t,J=7Hz), 2.5 0(lH,dd,J=6,lOHz),
2.60(lH,dd,J=3,lOHz), 2.77(1H,dt,J=4,9Hz),
2.94(3H,s), 2.99(2H,t,J=7Hz), 3.48(2H,t,J=6Hz),
3.68(2H,t,J=7Hz), 3.9-4.0(1H,m), 4.6-4.8(1H,m),
7.22 (lH,dd,J=l,8Hz), 7.2 8 (1H,d,J=5Hz),
7.42 (1H,d,J=5Hz), 7.67(1H,d,J=1Hz),
7.79(lH,d,J=8Hz)
Example 7 8
Production of N-(1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-pyrrolidinyl)methanesulfonamide
oxalate
In the same manner as in Example 17, N-(1-{3-
[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
pyrrolidinyl)methanesulfonamide oxalate was obtained as
colorless crystals.
IR(KBr)cm-1: 3250,28 68,1718, 1314, 1165, 1119,7 07
NMR(DMSO-d6) 8 values: 1.8-2 . 0 (3H, m) , 2 . 2-2 . 3 (1H,m) ,
2.93(2H,t,J=7Hz), 2.97(3H,s), 3.0-3.1(3H,m),
3.1-3.2(1H,m), 3.2-3.3(1H,m), 3.4-3.5(1H,m),
3.45(2H,t,J=6Hz), 3.63(2H,t,J=7Hz), 4.0-4.1(1H,m),
7.2 6(lH,dd,J=l,8Hz), 7.4 0(1H,d,J=5Hz),
7.4-7.6(1H,m), 7.72(1H,d,J=5Hz), 7.74(1H,d,J=lHz) ,
7.90(lH,d,J=8Hz)
Example 7 9
Production of 1-{3-[2- (1-benzothiophen-5-
yl)ethoxy]propyl}-N,N-dimethyl-3-pyrrolidinamine
In 8.6 mL of methanol was dissolved 0.43 g of
l-{3- [2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
pyrrolidinamine, and the solution was cooled to 5°C,
after which 0.35 mL of 37% formalin and 0.09 g of
sodium borohydride were added to the solution and the
resulting mixture was stirred at room temperature for
17 hours. Under ice-cooling, 2.6 mL of 2 mol/L
hydrochloric acid was added to the reaction mixture,
followed by stirring at room temperature for 30
minutes, after which water and ethyl acetate were added
thereto and the aqueous layer was separated. Ethyl
acetate was added to "he aqueous layer and the pH was
adjusted to 9.5 with a 2 mol/L aqueous sodium hydroxide
solution, after which the organic layer was separated.
The organic layer was washed with a saturated aqueous
sodium chloride solution, dried over anhydrous
magnesium sulfate, and then distilled under reduced
pressure to remove the solvent. The residue was
purified by a column chromatography (eluent;
chloroform : methanol =50 : 1 to 10 : 1) to obtain
0.39 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-
N,N-dimethyl-3-pyrrolidinamine as a yellow oil.
IR(neat) cm-1: 2945, 28 62, 2 7 86, 1458, 1111, 700
NMR(CDC13)d values: 1. 6-1. 8 (3H,m) , 1. 9-2 . 0 (1H,m) ,
2.20(6H,s), 2.2-2.3(1H,m), 2.3-2.5(2H,m),
2.50(lH,dt,J=8,12Hz), 2.7-2.8(2H,m),
2.8-2.9(1H,m), 2.99(2H,t,J=7Hz), 3.49(2H,t,J=7Hz) ,
3.67(2H,t,J=7Hz;, 7.22(1H,dd,J=l,8Hz),
7.2 8 (1H,d,J=5Hz), 7.41(1H,d,J=5Hz),
7.67(1H,d,J=1Hz), 7.7 9(lH,d,J=8Hz)
Example 8 0
Production of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-N,N-dimethyl-3-pyrrolidinamine
dihydrochloride
In 4.0 mL of ethyl acetate was dissolved 0.39
g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-N,N-
dimethyl-3-pyrrolidinamine, and to the solution was
added 0.80 mL of a 3.25 mol/L dried hydrogen chloride-
ethyl acetate solution. The resulting mixture was
stirred at room temperature for 1 hour and then at 5°C
for 1 hour. The crystals precipitated were collected
by filtration, washed with ethyl acetate and then dried
to obtain 0.32 g of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-N,N-dimethyl-3-pyrrolidinamine
dihydrochloride as colorless crystals.
IR(KBr)cm-1: 2936,1437,1101,701
NMR(CDC13)d values: 1. 9-2 .1 (2H,m) , 2 . 4-2 . 6 (2H, m) ,
2.84(6H,s), 2.98(2H,t,J=7Hz), 3.1-3.2(2H,m), 3.4-
3.9(4H,m), 3.54(2H,t,J=5Hz), 3.72(2H,dt,J=3,7Hz),
4.2-4.3(1H,m), 7.24(1H,d,J=8Hz), 7.35(1H,d,J=5Hz),
7.43(1H,d,J=5Hz), 7.71(lH,s), 7.84(1H,d,J=8Hz)
Example 81
Production of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinol 1/2 fumarate
In 10.0 mL of ethanol was dissolved 5.00 g of
1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
azetidinol, and the solution was heated at 70°C, after
which 0.99 g of fumaric acid was added to the solution
and stirred for 30 minutes. To the resulting solution
was added dropwise 30.0 mL of ethyl acetate, and the
resulting mixture was stirred at 60°C for 15 minutes,
cooled to 5°C over a period of 1 hour and then stirred
at the same temperature for 1 hour. The crystals
precipitated were collected by filtration, washed with
ethyl acetate and then dried to obtain 5.83 g of 1—{3—
[2- (1-benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol
1/2 fumarate as colorless crystals.
IR(KBr)cm-1: 3258, 2 93 6, 28 62, 1578, 1360, 1114,1109,
707,665
NMR(DMSO-d6)d values: 1. 5-1. 6 (2H,m) ,
2.60(2H,t,J=7Hz), 2.91(2H,t,J=7Hz), 2.9-3.1(2H,m),
3.39(2H,t,J=7Hz), 3.60(2H,t,J=7Hz), 3.6-3.8(2H,m),
4.1-4.3(1H,m), 6.50(lH,s), 7.25 (1H,dd,J=l,8Hz),
7.3 9(1H,d,J=5Hz), 7.72(1H,d,J=5Hz),
7.73(1H,d,J=1Hz), 7.89(lH,d,J=8Hz)
Example 82
Production of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinol
(1) In 12.5 mL of toluene was suspended 5.00 g of
3-[2-(1-benzothiophen-5-yl)ethoxy]propionic acid, and
0.1 mL of N,N-dimethylformamide was added thereto,
after which 1.68 mL of thionyl chloride was added
dropwise thereto at 15°C and the resulting mixture was
stirred at room temperature for 1 hour. The reaction
mixture was added dropwise to a solution of 4.44 g of
3-hydroxyazetidine 1/2 tartrate and 3.76 g of sodium
hydroxide in 25 mL of water at 10°C, and stirred at room
temperature for 1 hour. Ethyl acetate was added to the
reaction mixture and the organic layer was separated.
The organic layer was washed with diluted hydrochloric
acid and then a saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate, and
then distilled under reduced pressure to remove the
solvent. The residue was purified by a column
chromatography (eluent; chloroform : acetone = 3 : 1 to
1 : 1) and crystallized from diisopropyl ether to
obtain 5.48 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-1-
(3-hydroxy-l-azetidinyl)-1-propanone as colorless
crystals.
IR(KBr)cm-1: 3316, 2875, 1610, 1481, 1112, 992, 706
NMR(CDC13)d values: 2 . 2-2 . 4 (2H,m) ,
2.98(2H,t,J=7Hz), 3.6-3.8(5H,m), 3.8-4.0(1H,m),
4.1-4.3(2H,m), 4.4-4.4(1H,m), 7.20(1H,dd,J=l,8Hz),
7.28(lH,dd,J=l,5Hz), 7.41(1H,d,J=5Hz),
7.6-7.7(1H,m), 7.79(1H,d,J=8Hz)
(2) In 20 mL of tetrahydrofuran was dissolved
5.00 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-1-(3-
hydroxy-1-azetidinyl)-1-propanone, and 1.09 g of sodium
borohydride was added thereto, after which 4.25 mL of a
boron trifluoride-tetrahydrofuran complex was added
dropwise thereto at 10°C and the resulting mixture was
stirred at the same temperature for 1 hour and then at
40°C for 3 hours. After the reaction mixture was cooled
to 10°C, 30 mL of 6 mol/L hydrochloric acid was added
dropwise thereto and the resulting mixture was refluxed
for 1 hour. After cooling, the solvent was
concentrated under reduced pressure, and ethyl acetate
was added. The pH was adjusted to 9.4 with a 20%
aqueous sodium hydroxide solution and then the organic
layer was separated. The organic layer was washed with
water and then a saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate, and
then distilled under reduced pressure to remove the
solvent. The resulting residue was purified by a
column chromatography (eluent; chloroform : methanol =
20 : 1 to 10 : 1) and crystallized from toluene-
diisopropyl ether (1 : 3, 14 mL) to obtain 2.31 g of 1-
{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
azetidinol.
Example 83
Production of l-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinol maleate
In 56 mL of acetone was dissolved 8.00 g of
1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
azetidinol, followed by adding thereto 3.19 g of maleic
acid, and the resulting mixture was heated at 60°C to
effect dissolution. The reaction mixture was slowly
cooled and then stirred at 5°C for 30 minutes. The
crystals precipitated were collected by filtration to
obtain 9.89 g of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinol maleate as colorless
crystals.
NMR(DMSO-d6)d values: 1. 6-1. 8 (2H,m) ,
2.93(2H,t,J=7Hz), 3.13(2H,t,J=7Hz),
3.43(2H, t, J=6Hz) , 3.63(2H,t,J=7Hz), 3.7-3.9(2H,m),
4.1-4.3(2H,m), 4.4-4.5(1H,m), 6.04(2H,s),
7.26(lH,dd,J=l,8Hz), 7.40(1H,d,J=5Hz), 7.7-
7.8(1H,m), 7.74(1H,d,J=5Hz), 7.92(1H,d,J=8Hz)
Example 84
Production of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinol nitrate
In 20 mL of ethyl acetate was dissolved 10.0
g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
azetidinol, and 20 mL of isopropanol was added thereto,
after which 2.60 mL of concentrated nitric acid (61%)
was added dropwise thereto at room temperature. To the
reaction mixture was added dropwise 60 mL of ethyl
acetate, and the resulting mixture was stirred at the
same temperature for 1 hour and then at 5°C for 1 hour.
The crystals precipitated were collected by filtration
to obtain 11.3 g of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinol nitrate as colorless
crystals.
IR(KBr) cm-1: 3354, 2880, 1385, 1107, 712
NMR(DMSO-d6)d values: 1. 6-1. 8 (2H,m) ,
2.93(2H,t,J=7Hz), 3.1-3.2(2H,m), 3.44(2H,t,J=6Hz),
3.64(2H,t,J=7Hz), 3.7-3.9(2H,m), 4.0-4.4(2H,m),
4.4-4.5(1H,m), 7.27(1H,d,J=8Hz), 7.41(1H,d,J=5Hz),
7.74(1H,d,J=5Hz), 7.74(lH,s), 7.92(1H,d,J=8Hz)
Example 8 5
Production of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinol L-tartrate
In 40 mL of ethyl acetate was dissolved 10.0
g of l-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
azetidinol, and 5.15 g of L-tartaric acid and 40 mL of
ethanol were added thereto, after which the resulting
mixture was heated at 65°C to effect dissolution. After
the resulting solution was stirred at 50°C for 20
minutes, 40 mL of ethyl acetate was added dropwise
thereto at the same temperature and the resulting
mixture was stirred at 20 to 30°C for 1 hour. The
crystals precipitated were collected by filtration to
obtain 13.9 g of 1-{3- [2- (1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinol L-tartrate as colorless
crystals.
IR(KBr) cm-1: 3318, 2807, 1305, 112 6, 67 9, 483
NMR(DMSO-d6)d values: 1. 5-1. 7 (2H, m) ,
2.82(2H,t,J=7Hz), 2.92(2H,t,J=7Hz), 3.2-3.4(2H,m),
3.41(2H,t,J=6Hz), 3.61(2H,t,J=7Hz), 3.8-4.0(2H,m),
4.02(2H,s), 4.2-4.4(1H,m), 7.26(1H,dd,J=2,8Hz),
7.40(1H,d,J=5Hz), 7.73(1H,d,J=5Hz), 7.7-7.8(1H,m),
7.91(lH,d,J=8Hz)
Example 8 6
Production of l-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinol 1/2 succinate
In 30 mL of ethyl acetate was dissolved 10.0
g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
azetidinol, and 2.03 g of succinic acid and 35 mL of
isopropanol were added thereto, after which the
resulting mixture was refluxed to effect dissolution.
After 40 mL of ethyl acetate was added dropwise ro the
reaction mixture, the resulting mixture was slowly
cooled and then stirred at 5°C for 30 minutes. The
crystals precipitated were collected by filtration to
obtain 11.1 g of l-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinol 1/2 succinate as
colorless crystals.
IR(KBr)cm"1: 3250,2 93 6,157 6,1361, 1109,707, 652
NMR(DMSO-d6)d values: 1. 4-1. 6 (2H,m) , 2.35(2H,s),
2.46(2H,t,J=7Hz), 2.7-2.9(2H,m), 2.91(2H,t,J=7Hz),
3.38(2H,t,J=6Hz), 3.5-3.6(2H,m), 3.59(2H,t,J=7Hz),
4.1-4.2(1H,m), 7.2 5(1H,dd,J=2,8Hz),
7.39(1H,d,J=5Hz), 7.72(1H,d,J=5Hz), 7.7-7.8(1H,m),
7.90(lH,d,J=8Hz)
Example 87
Production of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinol citrate
In 14.4 mL of ethanol was dissolved 10.0 g of
1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
azetidinol, followed by adding thereto 7.21 g of citric
acid monohydrate, and the resulting mixture was heated
at 50°C to effect dissolution. To the resulting
solution were added 35 mL of ethyl acetate and 5.6 mL
of ethanol at 50°C, and stirred at 25°C. The reaction
mixture was heated at 40°C, after which ethyl acetate
(45 mL) was added dropwise thereto and the resulting
mixture was stirred at 40°C for 10 minutes and then at
10 to 20°C for 1 hour. The crystals precipitated were
collected by filtration to obtain 14.9 g of l-{3-[2-(l-
benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol citrate
as colorless crystals.
IR(KBr)cm-1: 3374, 2 94 3, 1720, 1224 , 1104 , 706
NMR(DMSO-d6)d values: 1. 6-1. 7 (2H,m) ,
2.50(2H,d,J=15Hz), 2.58(2H,d,J=15Hz),
93(2H,t,J=7Hz), 2.99(2H,t,J=7Hz),
3.42(2H,t,J=6Hz), 3.5-3.6(2K,m), 3.63(2K,t,J=7Hz),
4.0-4.1(2H,m), 4.3-4.4(1H,m), 7.26(1H,d,J=8Hz),
7.40(1H,d,J=5Hz), 7.73(1H,d,J=5Hz), 7.7-7.8(1H,m),
7.91 (lH,d,J=8Hz)
Example 8 8
Production of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinyl=benzoate
(1) in 7 mL of methylene chloride was dissolved
0.70 g of 3-[2- (1-benzothiophen-5-yl)ethoxy]-1-(3-
nydroxy-1-azetidinyl)-1-propanone, and 0.57 mL of
triethylamine was added to the solution. After the
resulting mixture was cooled to 5°C, 0.42 mL of benzoyl
chloride was added thereto, followed by stirring at the
same temperature for 1 hour. Water was added to the
reaction mixture and the pH was adjusted to 1 with 2
mol/L hydrochloric acid, after which the organic layer
was separated. The organic layer was washed with a
saturated aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate, and then distilled under
reduced pressure to remove the solvent. The residue
was purified by a column chromatography (eluent;
toluene : ethyl acetate =5 : 1 to 2 : 1) to obtain
0.45 g of l-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propanoyl}-3-azetidinyl=benzoate as a
colorless oil.
IR (neat)cm-1: 2873, 1719, 1654 , 1451, 1274 , 1117 , 714
NMR(CDC13)8 values: 2 . 3-2 . 4 (2H,m) ,
2.99(2H,t,J=7Hz), 3.72(2H,t,J=7Hz), 3.7-3.8(2H,m),
4.0-4.3(2H,m), 4.3-4.4(1H,m), 4.4-4.6(1H,m),
5.2-5.4(1H,m), 7,1-7.3(2K,m), 7.41(1H,d,J=5Hz),
7.46(2H,t,J=8Hz), 7.5-7.7(2H,m), 7 . 78(1H,d,J=8Hz),
8.0-8.1(2H,m)
(2) In 1 mL of tetrahydrofuran was dissolved 0.51
g of l-{3-[2-(1-benzothiophen-5-yl)ethoxy]propanoyl}-3-
azetidinyl=benzoate, and 6.8 mL of a 1 mol/L solution
of a borane-tetrahydrcfuran complex in tetrahydrofuran
was added dropwise thereto under ice-cooling, after
which the resulting mixture was stirred at room
temperature for 22 hours. To the reaction mixture was
added 6.2 mL of ethaaol, and the resulting mixture was
refluxed for 4 hours. After cooling, the solvent was
distilled off under reduced pressure and water and
ethyl acetate were added to the residue, and the
organic layer was separated. The organic layer was
washed with a saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate, and
then distilled under reduced pressure to remove the
solvent. The residue was purified by a column
chromatography (eluent; toluene : ethyl acetate =5:1
- chloroform) to obtain 0.33 g of l-{3-[2-(l-
benzothiophen-5-yl)ethoxy]propyl}-3-azetidinyl=benzoate
as a colorless oil.
IR (neat) cm-1: 2941, 1718 , 127 4 , 1115, 755, 713
NMR(CDC13)d values: 1. 6-1. 7 (2H,m) ,
2.54(2H,t,J=7Hz), 3.00(2H,t,J=7Hz), 3.0-3.2(2H,m),
3.49(2H,t,J=6Hz), 3.67(2H,t,J=7Hz), 3.7-3.8(2H,m),
5.2-5.3(1H,m), 7.22(1H,dd,J=2,8Hz),
7.2 8(1H,d,J=5Hz), 7.4 0(1H,d,J=5Hz),
7.45(2H,t, J=8Hz) ,, 7.5-7.6(1H,m), 7 . 6-7 . 7 (1H, m) ,
7.79(lH,d,J=8Hz), 8.0-8.1(2H,m)
Example 8 9
Production of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinyl=benzoate maleate
In 3 mL of ethyl acetate was dissolved 0.25 g
of l-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
azetidinyl=benzoate, and 0.07 g of maleic acid was
added thereto, after which the resulting mixture was
heated to effect dissolution. The reaction mixture was
cooled and the crystals precipitated were collected by
filtration to obtain 0.15 g of l-{3-[2-(l-
benzothiophen-5-yl)ethoxy]propyl}-3-azetidinyl=benzoate
maleate.
IR(KBr)cm-1: 2872,17 32,1454,1358, 1270,1119
NMR(DMSO-d6)8 values: 1. 6-1. 8 (2H, m) ,
2.94(2H,t,J=7Hz), 3.1-3.3(2H,m), 3.46(2H,t,J=6Hz),
3.65(2H,t,J=7Hz), 4.1-4.3(2H,m), 4.4-4.6(2H,m),
5.3-5.5(1H,m), 6.04(2H,s), 7.26(1H,d,J=8Hz),
7.39(1H,d,J=5Hz), 7.58(2H,t,J=8Hz), 7.7-7.8(3H,m),
7.91(lH,d, J=8Hz), 8.0-8.1(2H,m)
Example 90
Production of l-{3-[2-(l-benzothiophen-5-
yl)ethoxy]propyi}-3-azetidinyl=pivalate
(1) In 8 mL of methylene chloride was dissolved
1.00 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-l-(3-
hydroxy-1-azetidinyl)-1-propanone, and 0.40 mL of
pyridine was added to the solution, after which 0.48 mL
of pivaloyl chloride was added thereto under ice-
cooling and the resulting mixture was stirred at room
temperature for 22 hours. Water was added to the
reaction mixture and the resulting mixture was
acidified with 6 mol/L hydrochloric acid, after which
the organic layer was separated. The organic layer was
washed with a 2 mol/L aqueous sodium hydroxide solution
and a saturated aqueous sodium chloride solution, dried
over anhydrous magnesium sulfate, and then distilled
under reduced pressure to remove the solvent. The
residue was purified by a column chromatography
(eluent; toluene : ethyl acetate = 3 : 1 to 2 : 1) to
obtain 1.20 g of l-{3-[2-(1-benzothiophen-5-yl)ethoxy] -
propanoyl}-3-azetidinyl=pivalate as a colorless oil.
IR (neat) cm-1: 2 972,1730,1655,14 58,1282,1151,
1112,703
NMR(CDC13)d values: 1.21(9H,s), 2 .2-2 . 4 (2H,m) ,
2.99(2H,t,J=7Hz), 3.6-3.8(4H,m), 3.8-4.1(2H,m),
4.2-4.3(1H,m), 4.3-4.5(1H,m), 4.9-5.1(1H,m), 7.1-
7.3(2H,m), 7.42(1H,d,J=5Hz), 7.6-7.7(1H,m),
7.80(lH,d,J=8Hz)
(2) In the same manner as in Example 88 (2), 1-
{3- [2- (1-benzothiophen-5-yl)ethoxy]propyl}-3-
azetidinyl=pivalate was obtained.
IR (neat) cm-1: 293 8, 1727, 12 83, 1156, 1110, 756, 702
NMR(CDC13)d values: 1.20(9H,s), 1. 5-1. 7 (2H,m) ,
2.50(2H,t,J=7Hz), 2.8-3.0(2H,m), 2.99(2H,t,J=7Hz),
3.47(2H,t,J=6Hz), 3.6-3.8(4H,m), 4.9-5.1(1H,m),
7.22(lH,dd,J=2,8Hz), 7.2-7.3(1H,m),
7.42(lH,d,J=6Hz), 7.6-7.7(1H,m), 7.79(1H,d,J=8Hz)
Example 91
Production of l-{3-[2-(l-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinyl=pivalate maleate
In the same manner as in Example 89, l-{3-[2-
(1-benzothiophen-5-yl)ethoxy]propyl} -3-
azetidinyl=pivalate maleate was obtained.
IR(KBr)cm-1: 28 66, 174 0, 157 8, 14 52, 1356, 1165, 1120, 8 70
NMR(DMSO-d6)d values: 1.18(9H,s), 1.6-1.8(2H,m),
2.8-3.0(2H,m), 3.0-3.3(2H,m), 3.3-3.6(2H,m), 3.5-
3.7(2H,m), 3.9-4.1(2H,m), 4.3-4.5(2H,m), 5.0-
5.2(1H,m), 6.05(2H,s), 7.26(1H,d,J=8Hz),
7.40(1H,d,J=5Hz), 7.7-7.8(2H,m), 7.91(1H,d,J=8Hz)
Example 92
Production of 1-{3-[2-(l-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinyl=methyl=carbonate
(1) In the same manner as in Example 90 (1), 1-
{3-[2-(1-benzothiophen-5-yl)ethoxy]propanoyl}-3-
azetidinyl=methyl=carbonate was obtained.
IR (neat) cm-1: 2943,17 51,1272,1110,7 91,705
NMR(CDC13)d values: 2 . 2-2 . 4 (2H, m) ,
2.99(2H,t,J=7Hz), 3.7-3.8(2H,m), 3.71(2H,t,J=7Hz),
3.82(3H,s), 3.9-4.0(1H,m), 4.0-4.3(2H,m),
4.3-4.4(1H,m), 4.9-5.1(1H,m), 7.21(1H,dd,J=l,8Hz),
7.29(1H,d,J=5Hz)„ 7.42(1H,d,J=5Hz), 7.6-7.7(1H,m),
7.80(lH,d,J=8Hz)
(2) In the sane manner as in Example 88 (2), 1-
{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
azetidinyl=methyl=carbonate was obtained.
IR(neat)cm-1: 2 952,2858,174 9, 14 42, 1271, 1109, 7 92, 704
NMR(CDC13)d values: 1. 5-1. 7 (2H,m) ,
2.49(2H,t,J=7Hz), 2.9-3.1(4H,m), 3.46(2H,t,J=6Hz),
3.6-3.7(4H,m), 3.78(3H,s), 4.9-5.1(1H,m) ,
7.21(lH,dd, J=2, 8Hz) , 7.2 8(1H,dd,J=l,5Hz),
7.42 (1H,d,J=5Hz), 7.6-7.7(1H,m), 7 . 79 (1H,d,J=8Hz)
Example 93
Production of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinyl=methyl=carbonate oxalate
In 7 mL of ethyl acetate was dissolved 0.31 g
of l-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
azetidinyl=methyl=carbonate, and to the solution was
added a solution of 0.10 g of oxalic acid in 1 mL of
ethyl acetate, after which the resulting mixture was
stirred at room temperature. The crystals precipitated
were collected by filtration to obtain 0.34 g of l-{3-
[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
azetidinyl=methyl=carbonate oxalate.
IR(KBr) cm-1: 28 63, 2594, 17 53, 1444, 1278, 1112, 719
NMR(DMSO-d6)d values: 1. 6-1. 8 (2H,m) ,
2.92(2H,t,J=7Hz), 3.0-3.1(2H,m) , 3.42(2H,t,J=6Hz),
3.62(2H,t,J=7Hz), 3.74(3H,s), 3.9-4.0(2H,m), 4.2-
4.3(2H,m), 5.0-5.2(1H,m), 7.26(1H, dd, J=l, 8Hz),
7.40(lH,dd,J=l,5Hz), 7.7-7.8(2H,m),
7.90(lH,d,J=8Hz)
Example 94
Production of l-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinyl=ethyl=carbonate
(1) In the same manner as in Example 90 (1), 1-
{3-[2-(1-benzothiophen-5-yl)ethoxy]propanoyl}-3-
azetidinyl=ethyl=carbonate was obtained.
IR (neat)cm-1: 2942, 2873, 1747, 1654, 14 50, 12 60, 1111,
791,704
NMR(CDC13)d values: 1. 32 ( 3H, t, J=7Hz) ,
2.2-2.4(2H,m), 2.99(2H,t,J=7Hz), 3.7-3.8(2H,m),
3.71 (2H,t,J=7Hz), 3.9-4.0(IK,m), 4.0-4.2(1H,m),
4.2-4.3(1H,m), 4.22(2H,q,J=7Hz), 4.3-4.4(1H,m),
4.9-5.1(1H,m), 7.21(lH,dd,J=2,8Hz),
7.29(1H,d,J=5Hz) , 7.42(1H,d,J=5Hz), 7.6-7.7(1H,m),
7.80(lH,d,J=8Hz)
(2) In the same manner as in Example 88 (2), 1-
{3- [2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
azetidinyl=ethyl=carbonate was obtained.
IR (neat) cm-1: 2941,1750,12 62,1110,1049,7 92,704
NMR(CDC13)d values: 1.31(3H,t,J=7Hz) ,
1.5-1.7(2H,m), 2.50(2H,t,J=7Hz), 2.9-3.1(4H,m),
3.46(2H,t,J=6Hz), 3.6-3.7(4H,m), 4.19(2H,q,J=7Hz),
4.9-5.1(1H,m), 7.21(1H,dd,J=2,8Hz),
7.28(lH,dd,J=l,5Hz) , 7.42(1H,d,J=5Hz),
7.6-7.7(1H,m), 7.79(1H,d,J=8Hz)
Example 95
Production of 1-{3-[2-(l-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinyl=ethyl=carbonate oxalate
In the same manner as in Example 93, l-{3-[2-
(1-benzothiophen-5-yl)ethoxy]propyl}-3-
azetidinyl=ethyl=carbonate oxalate was obtained.
IR(KBr)cm-1: 2 932,2864,2583, 1748,789,719
NMR(DMSO-d6)d values: 1.23(3H,t,J=7Hz) ,
1.6-1.8(2H,m), 2.92(2H,t,J=7Hz), 3.0-3.1(2H,m),
3.43(2H,t,J=6Hz), 3.62(2H,t,J=7Hz), 3.9-4.0(2H,m),
4.16(2H,q,J=7Hz), 4.2-4.3(2H,m), 5.0-5.2(1H,m),
7.26(lH,dd,J=2,8Hz) , 7.4 0(1H,d,J=6Hz),
7.7-7.8(2H,m), 7.90(1H,d,J=8Hz)
Example 96
Production of l-{3-[2-(l-benzothiophen-5-
yl)ethoxy]propyl}-3-[methoxymethoxy)azetidine
(1) In 8.5 mL of methylene chloride was dissolved
1.52 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-l-(3-
hydroxy-1-azetidinyl)-1-propanone, and 2.6 mL of N,N-
diisopropylethyl-amine was added to the solution.
After the resulting mixture was cooled to 5°C, 1.0 mL of
chloromethyl methyl ether was added thereto, followed
by stirring at room temperature for 17 hours. Water
and ethyl acetate were added to the reaction mixture
and the organic layer was separated. The organic layer
was washed with a saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate, and
then distilled under reduced pressure to remove the
solvent. The residue was purified by a column
chromatography (eluent; toluene : ethyl acetate =3:1
to 1 : 1) to obtain 1.40 g of 3-[2-(l-benzothiophen-5-
yl)ethoxy]-1-[3-(methoxymethoxy)-1-azetidinyl]-1-
propanone as an oil.
IR (neat) cm-1: 2941,2867,1654,1112, 1055,919,704
NMR(CDC13)d values: 2.3-2.4(2H,m) ,
2.99(2H,t,J=7Hz), 3.37(3H,s), 3.7-3.8(2H,m),
3.72(2H,t,J=7Hz), 3.8-4.1(2H,m), 4.1-4.4(3H,m),
4.60(2H,s), 7.21(lH,dd,J=2, 8Hz), 7.29(1H,d,J=5Hz),
7.42(1H,d,J=5Hz), 7.6-7.7(1H,m), 7.79(1H,d,J=8Hz)
(2) In the same manner as in Example 88 (2), 1-
{3- [2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
(methoxymethoxy)azetidine was obtained.
IR(neat) cm"1: 2 94 3, 1113, 1059, 1012, 919, 703
NMR(CDC13)8 values: 1. 5-1. 7 (2H,m) ,
2.49(2H,t,J=7Hz), 2.8-2.9(2H,m), 2.99(2H,t,J=7Hz),
3.36(3H,s), 3.47(2H,t,J=6Hz), 3.5-3.7(4H,m), 4.2-
4.3(1H,m), 4.59(2H,s), 7.22(1H, dd,J=l,8Hz),
7.28(lH,dd,J=l,5Hz), 7.42(1H,d,J=5Hz), 7.6-
7.7(1H,m), 7.79(lH,d,J=8Hz)
Example 97
Production of l-{3-[2-(l-benzothiophen-5-
yl)ethoxy]propyl}-3-(methoxymethoxy)azetidine oxalate
In the same manner as in Example 93, l-{3-[2-
(1-benzothiophen-5-yl)ethoxy]propyi}-3-
(methoxymethoxy) azetidine oxalate v/as obtained.
IR(KBr)cm-1: 28 66, 1719, 1624, 1112, 98 9, 920, 707
NMR(DMSO-d6)d values: 1. 6-1. 8 (2H,m) ,
2.93(2H,t,J=7Hz), 3.0-3.1(2H,m), 3.29(3H,s),
3.43(2H,t,J=6Hz), 3.63(2H, t, J=7Hz) , 3.7-3.9(2H,m),
4.1-4.3(2H,m), 4.3-4.5(1H,m), 4.60(2H,s),
7.26(lH,dd,J=2,3Hz), 7.4 0(1H,d,J=5Hz),
7.7-7.8(2H,m), 7.90(1H,d,J=8Hz)
Example 98
Production of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-[(benzyloxy)methoxy]azetidine
(1) In the same manner as in Example 96 (1), 3-
[2- (1-benzothiophen-5-yl)ethoxy]-1-{3-
[(benzyloxy)methoxy]-1-azetidinyl}-1-propanone was
obtained.
IR(neat)cm-1: 2872, 1654, 1112, 700
NMR(CDC13)5 values: 2 . 3-2 . 4 (2H,m) ,
2.99(2H,t,J=7Hz), 3.7-3.8(2H,m), 3.71(2H,t,J=7Hz) ,
3.8-4.3(4H,m) , 4.3-4.4(1H,m), 4.60(2H,s),
4.73(2H,s), 7.21(lH,dd,J=l,8Hz), 7.2-7.4(6H,m),
7.40(1H,d,J=5Hz), 7.6-7.7(1H,m), 7,79(1H,d,J=8Hz)
(2) In the same manner as in Example 88 (2), 1-
{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
[(benzyloxy)methoxy]azetidine was obtained.
IR (neat) cm-1: 2 942, 1196, 1115, 10 60, 700
NMR(CDC13)6 values: 1. 5-1. 7 (2H,m) ,
2.49(2H,t,J=7Hz), 2.8-3.0(2H,m), 2.99(2H,t,J=7Hz),
3.47(2H,t,J=6Hz), 3.5-3.7(2H,m), 3.66(2H,t,J=7Hz),
4.2-4.4(1H,m), 4.60(2H,s), 4.72(2H,s),
7.2-7.4(6H,m), 7.22(1H,dd,J=l,8Hz),
7.41(lH,d,J=6Hz), 7.6-7.7(1H,m), 7.79(1H,d,J=8Hz)
Example 99
Production of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-(trityloxy)azetidine
(1) In 6.8 mL of toluene was dissolved 0.85 g of
3-[2-(1-benzothiophen-5-yl)ethoxy]-1-(3-hydroxy-l-
azetidinyl)-1-propanone, and to the solution were added
0.34 mL of pyridine, 0.02 g of 4-(dimethylamino)-
pyridine and 0.93 g of trityl chloride, after which the
resulting mixture was stirred at 50°C for 3 hours. To
the mixture was added 0.85 mL of N,N-dimethylformamide,
followed by stirring at 50°C for another 24 hours.
Water and ethyl acetate were added to the reaction
mixture and the organic layer was separated. The
organic layer was washed with a saturated aqueous
sodium chloride solution, dried over anhydrous
magnesium sulfate, and then distilled under reduced
pressure to remove the solvent. The residue was
purified by a column chromatography (eluent; toluene :
ethyl acetate = 5 : 1 to 3 : 1) to obtain 1.15 g of 3-
[2-(1-benzothiophen-5-yl)ethoxy]-1-[3-(trityloxy)-1-
azetidinyl]-1-propanone as an oil.
IR (neat) cm-1: 2940,2870, 1654, 1116, 762, 707
NMR(CDC13)d values: 2.18(2H,t,J=6Hz),
2.94(2H,t,J=7Hz), 3.5-3.8(8H,m), 4.2-4.4(1H,m),
7.1-7.5(18H,m), 7.6-7.7(1H,m), 7.73(1H,d,J=8Hz)
(2) In the same manner as in Example 88 (2), 1-
{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
(trityloxy)azetidine was obtained.
IR(neat)cm-1: 2 943,14 92,1449,1104,706
NMR(CDC13)d values: 1. 4-1. 6 (2H,m) , 2 . 3-2 . 4 (2H,m) ,
2.5-2.7(2H,m), 2.95(2H,t,J=7Hz), 3.0-3.1(2H,m),
3.37(2H,t,J=7Hz), 3.61(2H,t,J=7Hz), 4.1-4.3(1H,m),
7.1-7.3 (HH,m) , 7 .3-7.5 (7H,m) , 7 . 6-7 . 7 (1H,m) ,
7.77(lH,d,J=8Hz)
Example 100
Production of 1-{3-[2-(l-benzothiophen-5-
yl)ethoxy]propyl}-3-(trityloxy)azetidine oxalate
In the same; manner as in Example 93, l-{3-[2-
(1-benzothiophen-5-yl)ethoxy]propyl}-3-(trityloxy)-
azetidine oxalate was obtained.
IR(KBr)cm-1: 2866, 1491, 1451, 1155, 1110, 704
NMR(DMSO-d6)d values: 1. 4-1. 6 (2H, m) , 2 . 8-3 . 0 (4H,m) ,
3.34(2H,t,J=6Hz), 3.4-3.6(6H,m), 4.2-4.4(1H,m),
7.23(lH,d,J=8Hz), 7.3-7.5(16H,m), 7.6-7.8(2H,m),
7.88(lH,d,J=8Hz)
Example 101
Production of l-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-[(triethylsilyl)oxy]azetidine
(1) In the same manner as in Example 99 (1), 3-
[2- (1-benzothiophen-5-yl)ethoxy]-1-{3-
[(triethylsilyl)oxy]-1-azetidinyl}-1-propanone was
obtained.
IR (neat) cm-1: 2 954 , 2875, 1654 , 1458, 1113,1004 , 750
NMR(CDC13)d values: 0.57 (6H,q,J=8Hz) ,
0.94(9H,t,J=8Hz), 2.2-2.4(2H,m), 2.99(2H,t,J=7Hz),
3.6-3.9(5H,m), 3.9-4.0(1H,m), 4.1-4.3(2H,m), 4.4-
4.6(1H,m), 7.21(lH,dd,J=2,8Hz), 7.29(1H,d,J=5Hz),
7.42(1H,d,J=5Hz), 7.6-7.7(1H,m), 7.79(1H,d,J=8Hz)
(2) In the same manner as in Example 88 (2), 1-
{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
[(triethylsilyl)oxy]azetidine was obtained.
IR(neat) cm-1: 2 951, 1380, 12 01, 1114, 8 65, 747, 701
NMR(CDC13)d values: 0.57(6H,q,J=8Hz),
0.94(9H,t,J=8Hz), 1.5-1.7(2H,m), 2.48(2H,t,J=7Hz) ,
2.7-2.8(2H,m), 2.99(2H,t,J=7Hz), 3.46(2H,t,J=6Hz),
3.5-3.7(2H,m), 3.66(2H,t,J=7Hz), 4.3-4.5(1H,m),
7.21(lH,dd,J=2,8Hz), 7.28(1H,dd,J=l,8),
7.41(lH,d,J=6Hz), 7.6-7.7(1H,m), 7.79(1H,d,J=8Hz)
Example 102
Production of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-(benzyloxy)azetidine
(1) In 8 mL of N,N-dimethylformamide was
dissolved 1.00 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-
1-(3-hydroxy-1-azetidinyl)-1-propanone, and 1.90 g of
silver(I) oxide and 0.97 mL of benzyl bromide were
added to the solution, after which the resulting
mixture was stirred at room temperature for 31 hours.
The insoluble materials were filtered off and water and
ethyl acetate were added to the residue, after which
the organic layer was separated. The organic layer was
washed with a saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate, and
then distilled under reduced pressure to remove the
solvent. The residue was purified by a column
chromatography (eluent; toluene : ethyl acetate =3:1
to 1 : 4) to obtain 1.00 g of 3-[2-(1-benzothiophen-5-
yl)ethoxy]-1-[3-(benzyloxy)-1-azetidinyl]-1-propanone
as an oil.
IR(neat) cm-1: 28 69, 1654, 1112,754,700
NMR(CDC13)d values: 2 . 2-2 . 4 (2H,m) ,
2.98(2H,t,J=7Hz), 3.6-3.8(4H,m), 3.8-3.9(1H,m),
3.9-4.0(1H,m), 4.0-4.1(1H,m), 4.1-4.3(2H,m),
4.4 0(lH,d,J=12Hz), 4.4 4(1H,d,J=12Hz),
7.20(lH,dd,J=l,8Hz), 7.2-7.5(7H,m), 7.6-7.7(1H,m),
7.78(lH,d,J=8Hz)
(2) In the same manner as in Example 1 (2), 1-{3-
[2- (1-benzothiophen-5-yl)ethoxy]propyl}-3-
(benzyloxy)azetidine was obtained.
IR(neat) cm-1: 2 93 9, 1355, 1194, 1110, 754, 700
NMR(CDC13)5 values: 1. 5-1. 7 (2H,m) ,
2.48(2H,t,J=7Hz), 2.8-2.9(2H,m), 2.98 (2H,t,J=7Hz),
3.46(2H,t,J=6Hz), 3.5-3.7(2H,m), 3.65 (2H,t,J=7Hz) ,
4.1-4.3(1H,m), 4.42(2H,s), 7.21(1H,dd,J=l,8Hz),
7.2-7.4(6H,m), 7.41(1H,d,J=5Hz), 7.6-7.7(1H,m),
7.79(lH,d,J=8Hz)
Example 103
Production of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-(benzyloxy)azetidine oxalate
In the same manner as in Example 93, l-{3-[2-
(1-benzothiophen-5-yl)ethoxy]propyl}-3-
(benzyloxy)azetidine oxalate was obtained.
IR(KBr)cm-1: 2855,1111,700
NMR(DMSO-d6)d values: 1. 6-1. 8 (2H,m) ,
2.92(2H,t,J=7Hz) , 3 . 06(2H,t,J=7Hz) ,
3.42(2H,t,J=6Hz), 3.62(2H,t,J=7Hz), 3.7-3.9(2H,m),
4.1-4.2(2H,m), 4.3-4.4(1H,m), 4.46(2H,s),
7.26(lH,d,J=8Hz), 7.3-7.5(6H,m), 7.7-7.8(2H,m),
7.90(lH,d,J=8Hz)
Example 104
Production of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-(trityloxy)azetidine
In a mixture of 0.4 mL of toluene and 7 mL of
a 50% (W/V) aqueous sodium hydroxide solution was
suspended 0.54 g of 2-(1-benzothiophen-5-yl)-1-ethanol,
followed by adding thereto 1.45 g of l-(3-
chloropropyl)-3-(trityloxy)azetidine oxalate and 0.03 g
of tetra-n-butylammonium bromide, and the resulting
mixture was refluxed for 7 hours. After the reaction
mixture was cooled, water and toluene were added
thereto and the organic layer was separated. The
organic layer was washed with a saturated aqueous
sodium chloride solution, dried over anhydrous
magnesium sulfate, and then distilled under reduced
pressure to remove the solvent. The residue was
purified by a column chromatography (eluent;
chloroform : methanol =75 : 1) to obtain 0.59 g of 1-
{3- [2- (1-benzothiophen-5-yl)ethoxy]propyl}-3-
(tzityloxy)azetidine as a light-yellow oil.
Example 105
Production of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-(trityloxy)azetidine maleate
In the same manner as in Example 89, l-{3-[2
(1-benzothiophen-5-yl)ethoxy]propyl}-3-(trityloxy)-
azetidine maleate was obtained.
IR(KBr)cm"1: 3059,1346,1119,871,706
NMR(CDC13) 6 values: 1. 6-1. 8 (2H,m) , 2.8-3.0(4H,m),
3.1-3.3(2H,m), 3.40(2H,t,J=6Hz), 3.63(2H,t,J=7Hz)
3.8-4.0(2H,m), 4.4-4.6(1H,m), 6.23(2H,s),
7.18(lH,d,J=8Hz), 7.2-7.5(17H,m), 7.64(lH,s),
7.79(lH,d,J=8Hz)
Example 10 6
Production of 1-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-(tetrahydro-2H-pyran-2-
yloxy)azetidine
In the same manner as in Example 104, l-{3-
[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-(tetrahydro-
2H-pyran-2-yloxy)azetidine was obtained from 2-(l-
benzothiophen-5-yl)-1-ethanol and 1-(3-chloropropyl)-3-
(tetrahydro-2H-pyran-2-yloxy)azetidine.
IR (neat)cm-1: 2943,2853,1201,1115,1037,975,7 03
NMR(CDC13)d values: 1. 4-1. 9 (8H,m) ,
2.49(2H,t,J=7Hz), 2.8-3.0(2H,m), 2.98(2H,t,J=7Hz),
3.4-3.6(1H,m), 3.46(2H,t,J=6Hz), 3.5-3.7(4H,m),
3.8-3.9(1H,m), 4.2-4.4(1H,m), 4.5-4.6(1H,m),
7.21(lH,dd,J=2,8Hz), 7.28(1H,dd,J=l,6Hz),
7.41(lH,d,J=6Hz), 7.6-7.7(1H,m), 7.78(1H,d,J=8Hz)
Example 107
Production of l-{3-[2-(l-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinyl=pivalate
In 3.75 mL of dimethyl sulfoxide was
dissolved 0.75 g of 5-[2-(3-bromopropoxy)ethyl]-1-
benzothiophene, and 0.63 g of sodium hydrogencarbonate
and 0.73 g of 3-azetidinyl=pivalate hydrochloride were
added to the solution, after which the resulting
mixture was stirred at 70°C for 4 hours. After the
reaction mixture was cooled, 20 mL of water and 15 mL
of ethyl acetate were added thereto and the organic
layer was separated. The organic layer was washed with
water and then a saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate, and
then distilled under reduced pressure to remove the
solvent. The residue was purified by a column
chromatography (eluent; toluene : ethyl acetate =1:1
to 1 : 5) to obtain 0.78 g of l-{3-[2-(1-benzothiophen-
5-yl)ethoxy]propyl}-3-azetidinyl=pivalate as a light-
yellow oil.
Example 108
Production of l-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-(trityloxy)azetidine
In 15 mL of water was suspended 2.69 g of 3-
(trityloxy)azetidine hydrochloride, and 20 mL of ethyl
acetate was added thereto, after which the pH was
adjusted to 9 with a 2 mol/1 aqueous sodium hydroxide
solution and the organic layer was separated. The
organic layer was washed with water and then a
saturated aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate, and then distilled under
reduced pressure to remove the solvent. The resulting
residue was dissolved in 10 mL of dimethyl sulfoxide,
and to the resulting solution were added 0.80 g of
sodium hydrogencarbonate and 2.00 g of 3-[2-(l-
benzothiophen-5-yl)ethoxy]propyl=methanesulfonate,
followed by stirring at 50°C for 3 hours. To the
reaction mixture were added 20 mL of water and 20 mL of
ethyl acetate, and the organic layer was separated.
The organic layer was washed with water and then a
saturated aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate, and then distilled under
reduced pressure to remove the solvent. The residue
was purified by a cclumn chromatography (eluent;
toluene : ethyl acetate = 3 : 1 to 1 : 3) to obtain
2.89 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-
3-(trityloxy)azetidine as a light-yellow oil.
Example 10 9
Production of l-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinyl=acetate
In 15 mL of tetrahydrofuran was dissolved
1.50 g of l-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-
3-azetidinol, and 0.73 mL of acetic anhydride and 0.06
mL of a boron trifluoride-diethyl ether complex were
added thereto under ice-cooling, after which the
resulting mixture was stirred at room temperature for 1
hour. Ethyl acetate and a saturated aqueous sodium
hydrogencarbonate solution were added to the reaction
mixture and the organic layer was separated. The
organic layer was washed with water and then a
saturated aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate, and then distilled under
reduced pressure to remove the solvent. The residue
was purified by a column chromatography (eluent;
chloroform : methanol = 100 : 1 to 50 : 1) to obtain
1.63 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-
3-azetidinyl=acetate as a light-yellow oil.
IR (neat) cm-1: 2 941, 2859, 1741, 1375, 1239, 1109, 756, 703
NMR(CDC13)d values: 1. 5-1. 7 (2H, m) , 2.06(3H,s),
2.49(2H,t,J=7Hz), 2.9-3.1(4H,m), 3.46(2H,t,J=6Hz),
3.5-3.7(2H,m), 3.66(2H,t,J=7Hz), 4.9-5.1(1H,m),
7.21(lH,dd,J=l,8Hz), 7.28(1H,d,J=5Hz),
7.42(1H,d,J=5Hz), 7.6-7.7(1H,m), 7.79(1H,d,J=8Hz)
Example 110
Production of 1-{3-[2-(l-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinyl=acetate oxalate
In the same manner as in Example 93, l-{3-[2-
(1-benzothiophen-5-yl)ethoxy]propyl}-3-
azetidinyl=acetate oxalate was obtained.
IR(KBr)cm-1: 28 62, 1745, 1253, 1108, 711
NMR(DMSO-d6)d values: 1. 6-1. 8 (2H,m) , 2.06(3H,s),
2.92(2H,t,J=7Hz), 3.05(2H,t,J=7Hz),
3.43(2H,t,J=6Hz), 3.62(2H,t,J=7Hz), 3.8-4.0(2H,m),
4.2-4.3(2H,m), 5.0-5.2(1H,m), 7.26(1H,dd,J=l,8Hz),
7.40(lH,d,J=6Hz), 7.7-7.8(2H,m), 7.91(1H,d,J=8Hz)
Example 111
Production of l-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinol maleate
In 2.6 mL of isopropanol was suspended 1.30 g
of l-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
azetidinyl=pivalate maleate, and 2.1 mL of a 5 mol/L
aqueous sodium hydroxide solution was added thereto at
20°C, after which the resulting mixture was stirred at
room temperature for 6 hours. Water and ethyl acetate
were added to the reaction mixture, and the organic
layer was separated and then washed successively with
water and a saturated aqueous sodium chloride solution.
To the organic layer was added 0.29 g of maleic acid,
and the resulting mixture was heated to effect
dissolution, after which the solvent was distilled off
under reduced pressure. To the resulting residue were
added 5.2 mL of ethyl acetate and 1.3 mL of
isopropanol, and the resulting mixture was stirred at
room temperature for 30 minutes and then under ice-
cooling for 1 hour. The crystals precipitated were
collected by filtration to obtain 0.76 g of l-{3-[2-(l-
benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol maleate
as colorless crystals.
Example 112
Production of l-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinol maleate
In 10 mL of isopropanol was suspended 2.00 g
of l-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
azetidinyl=benzoate maleate, and 7.82 mL of a 2 mol/L
aqueous sodium hydroxide solution was added thereto,
after which the resulting mixture was stirred at room
temperature for 1 hour. Water and ethyl acetate were
added to the reaction mixture and the organic layer was
separated. The organic layer was washed with water and
then a saturated aqueous sodium chloride solution,
dried over anhydrous magnesium sulfate, and then
distilled under reduced pressure to remove the solvent.
To the residue was added 0.43 g of maleic acid, and
crystallization from ethyl acetate-isopropanol (4 : 1,
10 mL) was carried out to obtain 1.29 g of l-{3-[2-(l-
benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol maleate
as colorless crystals.
Example 113
Production of l-{3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl}-3-azetidinol maleate
In 4 mL of chloroform was dissolved 0.83 g of
l-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-
(trityloxy)azetidine, and 1.66 mL of a 4.75 mol/L dried
hydrogen chloride-ethanol solution was added thereto,
after which the resulting mixture was stirred at room
temperature for 6 hours. Water and chloroform were
added to the reaction mixture and the aqueous layer was
separated. Ethyl acetate was added to the aqueous
layer and the pH was adjusted to 10 with a 5 mol/L
aqueous sodium hydroxide solution, after which the
organic layer was separated. The organic layer was
washed with water and then a saturated aqueous sodium
chloride solution, dried over anhydrous magnesium
sulfate, and then distilled under reduced pressure to
remove the solvent. To the residue was added 0.11 g of
maleic acid, and crystallization from ethyl acetate-
isopropanol (4 : 1, 5 mL) was carried out to obtain
0.33 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-
3-azetidinol maleate as colorless crystals.
Reference Example 1
Production of 3-[2-(l-benzothiophen-4-
yl)ethoxy]-1-propanol
In a mixture of 2.2 mL of toluene and 8.8 mL
of a 50% (W/V) aqueous sodium hydroxide solution was
suspended 2.2 g of 2-(l-benzothiophen-4-yl)-1-ethanol,
followed by adding thereto 4.41 g of 2-(3-
chloropropoxy)tetrahydro-2H-pyran and 0.42 g of tetra-
n-butylammonium hydrogensulfate, and the resulting
mixture was heated under reflux for 2 hours. After the
reaction mixture was cooled, water and toluene were
added thereto and the organic layer was separated. The
organic layer was washed with water and then a
saturated aqueous sodium chloride solution, and dried
over anhydrous magnesium sulfate. Then, the solvent
was distilled off under reduced pressure to obtain
6.50 g of a mixture of 2-{3-[2-(1-benzothiophen-4-
yl)ethoxy]propoxy}tetrahydro-2H-pyran and 2-(3-
chloropropoxy)tetrahydro-2H-pyran as a light-brown oil.
In 8.0 mL of methanol was dissolved 6.50 g of
this mixture, followed by adding thereto 8.0 mL of
water and 0.70 g of p-toluenesulfonic acid monohydrate,
and the resulting mixture was stirred at room
temperature for 12 hours. Ethyl acetate and a
saturated aqueous sodium hydrogencarbonate solution
were added to the reaction mixture and the organic
layer was separated. The organic layer was washed with
water and then a saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate, and
then distilled under reduced pressure to remove the
solvent. The residue was purified by a column
chromatography (eluent; toluene : ethyl acetate =4:1
to 3 : 1) to obtain 1.42 g of 3-[2-(1-benzothiophen-4-
yl)ethoxy]-1-propanol as an oil.
IR (neat) cm-1: 3394,2 943,28 67,1413,1110,7 61
NMR(CDC13)d values: 1. 81 (2H, qn, J=6Hz) , 2.1(lH,brs),
3.2 6(2H,t,J=7Hz), 3.63(2H,t,J=6Hz),
3.69(2H,t,J=7Hz), 3.76(2H,t,J=6Hz), 7.0-7.4(2H,m),
7.45(2H,s), 7.77(lH,dd,J=2,7Hz)
Reference Example 2
The following compounds were obtained in the
same manner as in Reference Example 1.
3-[2-(l-Benzothiophen-2-yl)ethoxy]-1-propanol
NMR(CDC13)d values: 1. 68 (1H, brs) ,
1.86(2H,qn,J=6Hz), 3.17(2H,t,J=6Hz),
3.67(2H,t,J=6Hz), 3.76(4H,t,J=6Hz), 7.07(lH,s),
7.2-7.4 (2H,m) , 7 .. 67 (1H, d, J=8Hz) , 7.77(1H,d,J=8Hz)
• 3-[2-(1-Benzothiophen-3-yl)ethoxy]-1-propanol
IR(neat) cm-1: 3395, 2942, 28 67, 1427, 1113, 762, 732
NMR(CDC13)d values: 1. 83 (2H, qn, J=6Hz) ,
2.27(lH,t,J=6Hz), 3.13(2H,t,J=7Hz),
3.65 (2H,t, J=6Hz.) , 3.74 (2H,t, J=6Hz) ,
3.78(2H,t,J=7Hz), 7.18(lH,s), 7.34(1H,dt,J=l,7Hz),
7.39(lH,dt,J=l,7Hz), 7.76(lH,dd,J=l,7Hz),
7.86(lH,dd,J=l,7Hz)
• 3-[2-(l-Benzothiopben-5-yl)ethoxy]-1-propanol
IR (neat) cm-1: 3398, 2 93 9, 2866, 1438, 1110, 704
NMR(CDC13)d values: 1. 82 (2H, qn, J=6Hz) ,
2.29(1H,t,J=6Hz), 3.00(2H,t,J=7Hz),
3.64(2H,t,J=6Hz), 3.71(2H,t,J=7Hz),
3.7 3(2H,q,J=6Hz), 7.22(1H,dd,J=l,8Hz),
7.2 8(1H,d,J=5Hz), 7.42(1H,d,J=5Hz),
7.66(1H,d,J=1Hz), 7.80(lH,d,J=8Hz)
• 3-[2-(l-Benzothiophen-6-yl)ethoxy]-1-propanol
IR (neat) cm-1: 3389,2942,28 65,1397,1111,819,693
NMR(CDC13)d values: 1. 82(2H,qn,J=6Hz),
2.24(1H,t,J=6Hz), 3.00(2H,t, J=7Hz),
3.64(2H,t,J=6Hz), 3.71(2H,t,J=7Hz),
3.7 4(2H,q,J=6Hz), 7.21(lH,d,J=8Hz),
7.28(1H,d,J=5Hz), 7.38(1H,d,J=5Hz), 7.70(lH,s),
7.75(1H,d,J=8Hz)
• 3-[2-(l-Benzothiophen-7-yl)ethoxy]-1-propanol
Reference Example 3
Production of 4-[2-(3-chloropropoxy)ethyl]-1-
benzothiophene
In 7.0 mL of methylene chloride was dissolved
1.40 g of 3-[2-(l-benzothiophen-4-yl)ethoxy]-l-
propanol, followed by adding thereto 1.10 mL of thionyl
chloride and 0.05 mL of N,N-dimethylformamide, and the
resulting mixture was heated under reflux for 5 hours.
Then, the solvent was distilled off under reduced
pressure. The residue was purified by a column
chromatography (eluent; hexane : ethyl acetate = 20 :
1) to obtain 1.43 g of 4-[2-(3-chloropropoxy)ethyl]-1-
benzothiophene as a yellow oil.
IR (neat) cm-1: 28 67, 1413, 1113, 7 60
NMR(CDC13)5 values: 1.99 (2H,qn, J=6Hz) ,
3.23(2H,t,J=7Hz), 3.58(2H,t,J=6Hz),
3.59(2H,t,J=6Hz), 3.75(2H,t,J=7Hz),
7.18(lH,dd,J=2,7Hz), 7.29(1H,t,J=7Hz),
7.1-7.3(2H,m), 7.45(2H,s), 7.76(1H,dd,J=2,8Hz)
Reference Example 4
The following compounds were obtained in the
same manner as in Reference Example 3.
• 2-[2-(3-Chloropropoxy)ethyl]-1-benzothiophene
NMR(CDC13)5 values: 2 . 04 (2H, qn, J=6Hz) ,
3.16(2H,t,J=7Hz), 3.62(2H,t,J=6Hz),
3.66(2H,t,J=6Hz), 3.75(2H,t,J=7Hz), 7.06(lH,s),
7.25(lH,dt,J=l,7Hz), 7.30(1H,dt,J=l,7Hz),
7.67(lH,dd,J=l,7Hz), 7.77(1H,dd,J=l,7Hz)
• 3-[2-(3-Chloropropoxy)ethyl]-1-benzothiophene
IR(neat) cm-1: 28 65,1427,1115,7 62,732
NMR(CDC13)d values: 2 . 02 (2H, qn, J=6Hz) ,
3.13(2H,t,J=7Hz), 3.61(2H,t,J=6Hz),
3.62(2H,t,J=6Hz), 3.79(2H,t,J=7Hz), 7.19(lH,s),
7.34(1H,dt,J=1,7Hz), 7.39(1H,dt,J=1,7Hz),
7.7 7(1H,dd,J=1,7Hz), 7.86(1H,dd,J=1,7Hz)
• 5-[2-(3-Chloropropoxy)ethyl]-1-benzothiophene
IR(neat) cm"1: 28 64, 1438, 1113, 755, 701
NMR(CDC13)8 values: 2.01(2H,qn,J=6Hz),
3.00(2H,t,J=7Hz), 3.59(2H,t,J=6Hz),
3.61(2H,t,J=6Hz), 3.7 0(2H,t,J=7Hz),
7.22(lH,dd,J=l,8Hz), 7.28(1H,d,J=5Hz),
7.42(1H,d,J=5Hz), 7.68(1H,d,J=1Hz),
7.79(lH,d,J=8Hz)
• 6- [2-(3-Chloropropoxy)ethyl]-1-benzothiophene
IR(neat) cm-1: 28 64, 1113, 820, 7 61, 695, 652
NMR(CDC13)d values: 2 . 00 (2H, qn, J=6Hz) ,
3.00(2H,t,J=7Hz), 3.58(2H,t,J=6Hz),
3.61(2H,t,J=6Hz), 3.70(2H,t,J=7Hz),
7.21(1H,d,J=8Hz), 7.28(1H,d,J=5Hz),
7.37(1H,d,J=5Hz), 7.72(1H,s), 7.73(1H,d,J=8Hz)
• 7-[2-(3-Chloropropoxy)ethyl]-1-benzothiophene
IR(neat)cm~1: 28 66,14 60,1395,1115,7 95,701
NMR(CDC13)d values: 2.00 (2H, qn, J=6Hz) ,
3.17(2H,t,J=7Hz), 3.60(4H,t,J=6Hz),
3.82 (2H,t,J=7Hz), 7.20(1H,d,J=8Hz),
7.33 (1H,t,J=8Hz), 7.35(1H,d,J=5Hz),
7.42(1H,d, J=5Hz), 7.7 0(1H,d,J=8Hz)
Reference Example 5
Production of 3-[2-(l-benzothiophen-5-
yl)ethoxy]propyl=methanesulfonate
In 16.8 mL of methylene chloride was
dissolved 2.03 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-
1-propanol, and to the solution were added 2.43 mL of
methanesulfonyl chloride, 4.37 mL of triethylamine and
0.10 g of 4-(dimethylamino)pyridine under ice-cooling,
after which the resulting mixture was stirred at the
same temperature for 30 minutes and then at room
temperature for 12 hours. Methylene chloride and water
were added to the reaction mixture and the organic
layer was separated. The organic layer was washed with
water and then a saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate, and
then distilled under reduced pressure to remove the
solvent. The residue was purified by a column
chromatography (eluent; hexane : ethyl acetate =5:1)
to obtain 1.40 g of 3-[2-(1-benzothiophen-5-
yl)ethoxy]propyl=methanesulfonate.
IR(neat)cm-1: 2937,2866, 1352, 1174, 1114, 943, 705, 529
NMR(CDC13) d values: 1.97(2H,qn,J=6Hz), 2.81(3H,s),
2.98(2H,t,J=7Hz), 3.54(2H,t,J=6Hz),
3.7 0(2H,t,J=6Hz), 4.2 6(2H,t,J=7Hz),
7.20(1H,dd,J=1,8Hz), 7.28(1H,d,J=5Hz),
7.42(1H,d,J=5Hz), 7.65(1H,d,J=lHz),
7.79(1H,d,J=8Hz)
Reference Example 6
Production of 2-[2-(6-methoxy-l-benzofuran-5-
yl)ethoxy]acetic acid and 2-[2-(5-methoxy-l-benzofuran-
6-yl)ethoxy]acetic acid
(1) Production of 2,4-dimethoxyphenethyl=acetate
In 150 mL of methylene chloride was dissolved
15.0 g of 2-(2,4-dimethoxyphenyl)-1-ethanol, and to the
solution were added 9.32 mL of acetic anhydride, 13.8
mL of triethylamine and 0.10 g of 4-(dimethylamino)-
pyridine under ice-cooling, after which the resulting
mixture was stirred at the same temperature for 30
minutes and then at rcom temperature for 12 hours.
Water was added to the reaction mixture and the pH was
adjusted to 1.5 with 6 mol/L hydrochloric acid, after
which the organic layer was separated. The organic
layer was washed with water and then a saturated
aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, and then distilled under reduced
pressure to remove the solvent. The residue was
purified by a column chromatography (eluent; hexane :
ethyl acetate =5:1) to obtain 17.2 g of 2,4-
dimethoxyphenethyl=acetate as a colorless oil.
IR(neat) cm-1: 2 958, 1736, 1509, 1243, 1035, 834
NMR(CDC13)d values: 2.03(3H,s), 2.87(2H,t,J=7Hz),
3.80(6H,s), 4.22(2H,t,J=7Hz), 6.41(1H,d,J=9Hz),
6.46(lH,s), 7.05 (lH,d,J=9Hz)
In the same manner as above, 2,5-dimethoxy-
phenethyl=acetate was obtained.
IR (neat) cm-1: 2952,1736,1502, 122 6,104 8,802,710
NMR(CDC13)d values: 2.01(3H,s), 2 . 90 (2H, t, J=7Hz) ,
3.74(3H,s), 3.76(3H,s), 4.25(2H,t,J=7Hz),
6.74 (3H,s)
(2) Production of 5-acetyl-2,4-
dimethoxyphenethyl=acetate
In 170 mL of methylene chloride was dissolved
17.0 g of 2,4-dimethoxyphenethyl=acetate, and 5.93 mL
of acetyl chloride and 12.1 g of aluminum chloride were
added to the solution under ice-cooling, after which
the resulting mixture was stirred at the same
temperature for 1 hour. The reaction mixture was
poured into ice water and the organic layer was
separated. The organic layer was washed with water and
then a saturated aqueous sodium chloride solution,
dried over anhydrous magnesium sulfate, and then
distilled under reduced pressure to remove the solvent.
Diisopropyl ether was added to the residue and the
crystals precipitated were collected by filtration,
washed with diisopropyl ether and then dried to obtain
13.9 g of 5-acetyl-2,4-dimethoxy-phenethyl=acetate as
yellow crystals.
NMR(CDC13)d values: 2.01(3H,s), 2.57(3H,s),
2.88(2H,t,J=7Hz), 3.90(3H,s), 3.93(3H,s),
4.21(2H,t,J=7Hz), 6.42(lH,s), 7.68(lH,s)
In the same manner as above, 4-acetyl-2,5-
dimethoxyphenethyl=acetate was obtained.
(3) Production of 5-acetyl-4-hydroxy-2-methoxy-
phenethyl=acetate
In 70 mL of acetonitrile was dissolved 13.9 g
of 5-acetyl-2,4-dimethoxyphenethyl=acetate, and 13.9 g
of aluminum chloride and 7.82 g of sodium iodide were
added to the solution under ice-cooling, after which
the resulting mixture was stirred at 50°C for 3 hours.
The reaction mixture was poured into ice water and to
the resulting mixture was added ethyl acetate, after
which the organic layer was separated. The organic
layer was washed with water and then a saturated
aqueous sodium chloride solution, and dried over
anhydrous magnesium sulfate. The solvent was distilled
off under reduced pressure to obtain 13.3 g of 5-
acetyl-4-hydroxy-2-methoxyphenethyl=acetate as a yellow
oil.
In the same manner as above, 4-acetyl-5-
hydroxy-2-methoxyphenethyl=acetate was obtained.
(4) Production of 1-[2-hydroxy-5-(2-hydroxyethyl)-4-
methoxyphenyl]-1-ethanone
In 30 mL of ethanol was dissolved 13.3 g of the
aforesaid 5-acetyl-4-hydroxy-2-
methoxyphenethyl=acetate, and to the solution was addec
21 mL of a 5 mol/L aqueous sodium hydroxide solution,
after which the resulting mixture was stirred at room
temperature for 17 hours. Water and ethyl acetate were
added to the reaction mixture and the pH was adjusted
to 1 with 6 mol/L hydrochloric acid, after which the
organic layer was separated. The organic layer was
washed with water and then a saturated aqueous sodium
chloride solution, dried over anhydrous magnesium
sulfate, and then distilled under reduced pressure to
remove the solvent. Diisopropyl ether was added to the
residue, and the crystals precipitated were collected
by filtration, washed with diisopropyl ether and then
dried to obtain 8.30 g of 1-[2-hydroxy-5-(2-
hydroxyethyl)-4-methoxyphenyl]-1-ethanone as yellow
crystals.
In the same manner as above, 1-[2-hydroxy-4-
(2-hydroxyethyl)-5-methoxyphenyl]-1-ethanone was
obtained.
NMR(CDC13)d values: 1. 6-1. 8 (1H,m) , 2.61(3H,s),
2.90(2H,t,J=7Hz), 3.8-4.1(2H,m), 3.84(3H,s),
6.84(lH,s), 7.06(lH,s), 11.98(lH,s)
(5) Production of 2-bromo-l-[2-hydroxy-5-(2-
hydroxyethyl)-4-methoxyphenyl]-1-ethanone
In 100 mL of methylene chloride was dissolved
10.0 g of l-[2-hydroxy-5-(2-hydroxyethyl)-4-
methoxyphenyl]-1-ethanone, and 2.94 mL of bromine was
added dropwise to the solution, after which the
resulting mixture was stirred at room temperature for 1
hour. The reaction mixture was poured into ice water
and the organic layer was separated. The organic layer
was washed with water and then a saturated aqueous
sodium chloride solution, and dried over anhydrous
magnesium sulfate. The solvent was distilled off under
reduced pressure to obtain 16.4 g of 2-bromo-l-[2-
hydroxy-5-(2-hydroxyethyl)-4-methoxyphenyl]-1-ethanone
as a yellow oil.
In the same manner as above, 2-bromo-l-[2-
hydroxy-4-(2-hydroxyethyl)-5-methoxyphenyl]-1-ethanone
was obtained.
IR (neat) cm-1: 337 6,2 941,164 4,14 96,124 3,1034,757,
690
NMR(CDC13)d values: 1. 5-1. 8 (1H, m) ,
2.91(2H,t, J=7Hz.) , 3.8-4.1(2H,m), 3.85(3H,s)
4.40(2H,s), 6.89(lH,s), 7.07(lH,s) 11.51(lH,s)
(6) Production of 2-(6-methoxy-l-benzofuran-5-yl)-1-
ethanol
In 70 mL of methanol was dissolved 16.4 g of
the aforesaid 2-bromo-l-[2-hydroxy-5-(2-hydroxyethyl)-
4-methoxyphenyl]-1-ethanone, and 17.3 g of sodium
acetate was added to "he solution, after which the
resulting mixture was heated under reflux for 5
minutes. After the reaction mixture was cooled, water
and ethyl acetate were added thereto and the organic
layer was separated. The organic layer was washed with
water and then a saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate, and
then distilled under reduced pressure to remove the
solvent. The residue was dissolved in 150 mL of
methanol and to the resulting solution was added 6.30 g
of sodium borohydride in small portions, after which
the resulting mixture was stirred at room temperature
for 1 hour. Then, the resulting solution was adjusted
to pH 1 with 6 mol/L hydrochloric acid and stirred at
room temperature for another 1 hour. The reaction
mixture was concentrated under reduced pressure and
water and ethyl acetate were added thereto, after which
the organic layer was separated. The organic layer was
washed with water and then a saturated aqueous sodium
chloride solution, dried over anhydrous magnesium
sulfate, and then distilled under reduced pressure to
remove the solvent. The residue was purified by a
column chromatography (eluent; hexane : ethyl acetate =
4 : 1) to obtain 1.48 g of 2-(6-methoxy-l-benzofuran-5-
yl)-1-ethanol as light-yellow crystals.
NMR(CDCl3)d values: 1. 79 (1H, brs) , 2 . 97 (2H, t, J=7Hz) ,
3.84(2H,t,J=7Hz), 3.86(3H,s), 6.66(1H,d,J=3Hz),
7.03(lH,s), 7.35(1H,s), 7.51(1H,d,J=3Hz)
In the same manner as above, 2-(5-methoxy-l-
benzofuran-6-yl)-1-ethanol was obtained.
NMR(CDC13)d values: 2.04(1H,brs), 2 . 98 (2H,t,J=6Hz),
3.86(2H,t,J=6Hz), 3.86(3H,s), 6.68(1H,d,J=2Hz),
7.02(lH,s), 7.31;1H,s), 7.55(1H,d,J=2Hz)
(7) Production of 2-[2-(6-methoxy-l-benzofuran-5-
yl)ethoxy]acetic acid
In a mixture of 7.0 mL of tert-butanol and
1.75 mL of N,N-dimethylformamide was dissolved 1.75 g
of 2-(6-methoxy-l-benzofuran-5-yl)-1-ethanol, and 2.2 g
of 1-chloroacetylpiperidine and 1.54 g of potassium
tert-butoxide were added to the solution under ice-
cooling, after which the resulting mixture was stirred
at the same temperature for 30 minutes and then at the
room temperature for 2 hours. Water and ethyl acetate
were added to the reaction mixture and the pH was
adjusted to 1 with 6 mol/L hydrochloric acid, after
which the organic layer was separated. The organic
layer was washed with water and then a saturated
aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, and then distilled under reduced
pressure to remove the solvent. The residue was
dissolved in 10.5 mL of a 90% aqueous ethanol solution,
followed by adding thereto 0.91 g of sodium hydroxide,
and the resulting mixture was heated under reflux for 3
hours. After the reaction mixture was cooled, water
and ethyl acetate were added thereto and the pH was
adjusted to 1 with 6 mol/L hydrochloric acid, after
which the organic layer was separated. The organic
layer was washed with water and then a saturated
aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, and then distilled under reduced
pressure to remove the solvent. Diisopropyl ether was
added to the residue, and the crystals precipitated
were collected by filtration, washed with diisopropyl
ether and then dried to obtain 1.42 g of 2-[2-(6-
methoxy-l-benzofuran-5-yl)ethoxy]acetic acid as yellow
crystals.
IR (neat) cm-1: 2 939,1734,142 6,1252,1200,1148,1094,
1022,771
NMR(DMSO-d6)d values: 2.88(2H,t,J=7Hz),
3.64(2H,t,J=7Hz), 3.82(3H,s), 4.01(2H,s),
6.81(1H,d,J=2Hz), 7.22(lH,s), 7.44(lH,s),
7.82(1H,d,J=2Hz)
In the same manner as above, 2-[2-(5-methoxy-
1-benzofuran-6-yl)ethoxy]acetic acid was obtained.
IR(neat) cm-1: 2 942,1731,14 66,14 31,124 9,1132,1013,
955,832,760
NMR(DMSO-d6)d values: 2.90 (2H,t,J=7Hz),
3.66(2H,t,J=7Hz), 3.82(3H,s), 4.02(2H,s),
6.86(1H,d,J=2Hz), 7.15(lH,s), 7.46(lH,s),
7.88(1H,d,J=2Hz)
Reference Example 7
Production of 3-[2-(1-benzothiophen-5-
yl)ethoxy]propionic acid
(1) To 4.60 g of 2-(1-benzothiophen-5-yl)-1-
ethanol were added 29 mg of potassium hydroxide, 83 mg
of tetra-n-butylammonium bromide and 5.67 mL of tert-
butyl acrylate, and the resulting mixture was stirred
at 45 to 50°C for 2 hours. After the reaction mixture
was cooled, water and toluene were added thereto and
the pH was adjusted to 1 with 6 mol/L hydrochloric
acid, and the organic: layer was separated. The organic
layer was washed with water, dried over anhydrous
magnesium sulfate, and then distilled under reduced
pressure to remove the solvent. The residue was
purified by a column chromatography (eluent; hexane :
ethyl acetate = 5 : 1) to obtain 7.70 g of tert-butyl
3-[2-(1-benzothiophen-5-yl)ethoxy]propionate as a
colorless oil.
IR (neat) cm-1: 2978,2867,1729,1368,1159, 1112,702
NMR(CDC13)d values: 1.43(9H,s), 2 . 49 (2H, t, J=6Hz) ,
2.99(2H,t,J=7Hz), 3.70(2H,t,J=6Hz),
3.70(2H,t,J=7Hz), 7.21(1H,dd,J=2,8Hz),
7.27 (lH,dd,J=l,5Hz), 7.41(1H,d,J=5Hz),
7.6-7.7(1H,m) , 7 .. 78 (1H, d, J=8Hz)
(2) In 22.8 mL of toluene was dissolved 7.60 g of
tert-butyl 3- [2- (1-benzothiophen-5-yl)
ethoxy]propionate, and 94 mg of p-toluenesulfonic acid
monohydrate was added thereto, after which the
resulting mixture was refluxed for 6 hours. After the
reaction mixture was cooled, water and ethyl acetate
were added thereto and the organic layer was separated.
The organic layer was dried over anhydrous magnesium
sulfate and distilled under reduced pressure to remove
the solvent. The residue was crystallized from a
toluene-cyclohexane mixture (1:4, 23 mL) to obtain 5.30
g of 3-[2-(1-benzothiophen-5-yl)ethoxy]propionic acid
as light-red crystals.,
IR(KBr)cm-1: 28 60, 1719, 1273, 1128, 706
NMR(CDC13)d values: 2 . 63 (2H, t, J=6Hz) ,
3.0 0(2H,t,J=7Hz), 3.7 3(2H,t,J=7Hz),
3.7 4(2H,t,J=6Hz), 7.20(1H,dd,J=l,8Hz),
7.28(lH,dd,J=l,5Hz) , 7.41(1H,d,J=5Hz),
7. 6-7.7 (1H,m) , 7 .. 79 (1H, d, J=8Hz)
Reference Example 8
Production of 3-[2-(l-benzothiophen-5-
yl)ethoxy]propionic acid
(1) To 2.00 g of 2-(1-benzothiophen-5-yl)-1-
ethanol were added 13 mg of potassium hydroxide, 36 mg
of tetra-n-butylammorium bromide and 1.11 mL of
acrylonitrile, and the resulting mixture was stirred at
45°C for 3 hours. After the reaction mixture was
cooled, water and ethyl acetate were added thereto and
the pH was adjusted to 1 with 2 mol/L hydrochloric
acid. The insoluble materials were removed and then
the organic layer was separated. The organic layer was
washed with water and then a saturated aqueous sodium
chloride solution, dried over anhydrous magnesium
sulfate, and then distilled under reduced pressure to
remove the solvent. The residue was purified by a
column chromatography (eluent; hexane : ethyl acetate =
3 : 1) to obtain 2.46 g of 3-[2-(l-benzothiophen-5-
yl)ethoxy]propiono-nierile as a colorless oil.
IR( neat)cm-1: 2870,2251, 1114, 757, 704
NMR(CDC13)d values: 2 . 58 (2H, t, J=6Hz) ,
3.02(2H,t,J=7Hz), 3.66(2H,t,J=6Hz),
3.7 5(2H,t,J=7Hz), 7.22(lH,d,J=8Hz),
7.29(1H,d,J=5Hz), 7.42(1H,d,J=5Hz), 7.68(lH,s),
7.80(1H,d,J=8Hz)
(2) In 0.6 mL of acetic acid was dissolved 200 mg
of 3-[2-(1-benzothiophen-5-yl)ethoxy]propiononitrile,
followed by adding thereto 0.4 mL of water and 0.184 mL
of sulfuric acid, and the resulting mixture was stirred
at 90 to 100°C for 1 hour. After the reaction mixture
was cooled, water and ethyl acetate were added thereto
and the organic layer was separated. The organic layer
was washed with water and then a saturated aqueous
sodium chloride solution, dried over anhydrous
magnesium sulfate, and then distilled under reduced
pressure to remove the solvent. The residue was
purified by a column chromatography (eluent; toluene :
ethyl acetate = 3 : 1) to obtain 140 mg of 3-[2-(l-
benzothiophen-5-yl)ethoxy]propionic acid as colorless
crystals.
Reference Example 9
Production of 3-[2-(l-benzothiophen-5-
yl)ethoxy]-1-propanol
In 8 mL of cetrahydrofuran was dissolved 2.00
g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-1-propionic
acid, and 1.31 mL of triethylamine was added thereto.
Then, the resulting solution was cooled to -25°C, after
which a solution of 0.88 mL of ethyl chloroformate in 2
mL of tetrahydrofuran was added dropwise thereto, and
the resulting mixture was stirred at 5°C for 1 hour. To
the reaction mixture were added 15 mL of ethyl acetate
and 10 mL of a saturated aqueous sodium chloride
solution, and the organic layer was separated. After
the organic layer was cooled to 5°C, 0.36 g of sodium
borohydride was added thereto and the resulting mixture
was stirred at room temperature for 1 hour. To the
reaction mixture were added 20 mL of water and 10 mL of
ethyl acetate, and the organic layer was separated.
The organic layer was washed successively with a 1
mol/L aqueous sodium hydroxide solution, water and a
saturated aqueous sodium chloride solution, and then
dried over anhydrous magnesium sulfate. The solvent
was distilled off under reduced pressure to obtain 1.89
g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-1-propanol as a
yellow oil.
Reference Example 10
Production of 5-[2-(3-bromopropoxy)ethyl]-1-
benzothiophene
In 40 mL of methylene chloride was dissolved
2.00 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-1-
propanol, and 5.55 g of triphenylphosphine was added to
the solution, after which a solution of 8.42 g of
carbon tetrabromide in 10 mL of methylene chloride was
added dropwise thereto under ice-cooling and the
resulting mixture was stirred at room temperature for
20 minutes. To the reaction mixture was added 20 mL of
water, and the organic layer was separated. The
organic layer was washed with a saturated aqueous
sodium hydrogencarbonate solution and then a saturated
aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, and then distilled under reduced
pressure to remove the solvent. Diethyl ether was
added to the residue and the insoluble materials were
filtered off, after which the solvent was distilled off
under reduced pressure. The residue was purified by a
column chromatography (eluent; hexane : ethyl acetate =
20 : 1 to 10 : 1) to obtain 1.93 g of 5-[2-(3-
bromopropoxy)ethyl]-1-benzothiophene as a colorless
oil.
IR (neat) cm-1: 28 63,14 37,1112,1051,701
NMR(CDC13)d values: 2 . 0-2 . 2 (2H,m) ,
3.00(2H,t,J=7Hz), 3.4 8(2H,t,J=6Hz),
3.58 (2H,t,J=6Hz) , 3.7 0(2H,t,J=7Hz) ,
7.22(1H,dd,J=l,8Hz), 7.2 8(1H,dd,J=l,5Hz),
7.42(1H,d,J=5Hz),
7.6-7.7 (1H,m) , 7 .. 79 (1H, d, J=8Hz)
Reference Example 11
Production of 3-azetidinyl=pivalate
hydrochloride
(1) In a mixture of 200 mL of toluene and 100 mL
of tert-butanol was cissolved 50.0 g of 1-[(1R)-1-
phenylethyl]azetidin-3-ol, and 41.2 g of potassium
tert-butoxide was added thereto in small portions under
ice-cooling, after which the resulting mixture was
stirred at the same temperature for 1.5 hours. Under
ice-cooling, 41.7 mL of pivaloyl chloride was added
dropwise to the reaction mixture and stirred at the
same temperature for 30 minutes. The reaction mixture
was poured into 300 mL of water and the insoluble
materials were filtered off, after which the organic
layer was separated. The organic layer was washed with
water and then a saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate, and
then distilled under reduced pressure to remove the
solvent. The oil thus obtained was dissolved in 200 mL
of ethyl acetate, and 258 mL of a 1.15 mol/L dried
hydrogen chloride-ethyl acetate solution was added
thereto at 10°C and stirred at the same temperature for
20 minutes. The crystals precipitated were collected
by filtration to obtain 70.8 g of 1-[(1R)-1-
phenylethyl]-3-azetidinyl=pivalate hydrochloride as
colorless crystals.
IR(KBr)cm-1: 2963, 2509, 2436, 1731, 12 84, 1161, 699
NMR(DMSO-d6)d values: 1.16(9H,s), 1. 49 (3H,d,J=7Hz) ,
3.6-4.3(3H,m), 4.4-4.7(2H,m), 4.9-5.2(1H,m),
7.3-7.5(3H,m), 7.6-7.7(2H,m)
(2) To a solution of 50.0 g of 1-[(1R)-1-
phenylethyl]-3-azetidinyl=pivalate hydrochloride in 250
mL of ethanol was added 5 g of 10% palladium-activated
carbon, and the resulting mixture was stirred for 9
hours at 50°C and atmospheric pressure under a hydrogen
atmosphere. After cooling, the insoluble materials
were filtered off and the solvent was distilled off
under reduced pressure. A mixture of ethyl acetate and
hexane (1 : 2) was added to the residue and the
crystals precipitated were collected by filtration to
obtain 23.1 g of 3-azetidinyl=pivalate hydrochloride as
colorless crystals.
IR(KBr)cm-1: 2 988, 1718, 1156, 877, 789
NMR(CDC13)d values: 1.23(9H,s), 4 . 0-4 . 2 (2H, m) ,
4.3-4.5(2H,m), 5.2-5.4(1H,m)
Reference Example 12
Production of 3-(trityloxy)azetidine
hydrochloride
(1) In 50 mL of methylene chloride was dissolved
10.0 g of 1-(3-hydroxy-1-azetidinyl)-1-ethanone, and
31.2 mL of 1,8-diazabicyclo[5,4,0]undec-7-ene and 29.1
g of trityl chloride were added thereto under ice-
cooling, after which the resulting mixture was stirred
at room temperature for 1 hour. The reaction mixture
was poured into 100 mL of ice water and the organic
layer was separated. The organic layer was washed with
diluted hydrochloric acid, water and a saturated
aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, and then distilled under reduced
pressure to remove the solvent. Diisopropyl ether was
added to the residue and the crystals precipitated were
collected by filtration to obtain 21.7 g of l-[3-
(trityloxy)-1-azetidinyl]-1-ethanone as light-yellow
crystals.
IR(KBr)cm-1: 164 6,1450,112 4,750,711
NMR(CDC13)d values: 1.74(3H,s), 3 . 6-3 . 8 (4H, m) ,
4.4-4.5(lH.m), 7.2-7.5(15H,m)
(2) In 88 mL of methanol was suspended 22.0 g of
1-[3-(trityloxy)-1-azetidinyl]-1-ethanone, followed by
adding thereto 66 mL of a 5 mol/L aqueous sodium
hydroxide solution, and the resulting mixture was
refluxed for 9 hours. The reaction mixture was
distilled under reduced pressure to remove the solvent,
and 110 mL of water and 220 mL of ethyl acetate were
added to the residue, after which the organic layer was
separated. The organic layer was washed with water and
then a saturated aqueous sodium chloride solution,
dried over anhydrous magnesium sulfate, and then
distilled under reduced pressure to remove the solvent.
The oil thus obtained was dissolved in 154 mL of ethyl
acetate, and to the resulting solution was added 25 mL
of a 2.95 mol/L dried hydrogen chloride-ethyl acetate
solution, after which the resulting mixture was stirred
at room temperature. The crystals precipitated were
collected by filtration to obtain 13.7 g of 3-
(trityloxy)azetidine hydrochloride as colorless
crystals.
IR(KBr)cm-1: 2 90 0, 2 620, 1447, 751, 700
NMR(DMSO-d6)d values: 3 . 4-3 . 6 (4H,m) , 4 . 3-4 . 5 (1H,m) ,
7.2-7.5(15H,m)
Reference Example 13
Production of 3-(tetrahydro-2H-pyran-2-
yloxy)azetidine hydrochloride
(1) In 10 mL of methylene chloride was dissolved
1.00 g of 1-(3-hydroxy-1-azetidinyl)-1-ethanone, and
1.19 mL of 3,4-dihydro-2H-pyran and 0.08 g of p-
toluenesulfonic acid monohydrate were added to the
solution, after which the resulting mixture was stirred
overnight at room temperature. To the reaction mixture
was added 10 mL of water and the pH was adjusted to 8
with a saturated aqueous sodium hydrogencarbonate
solution, after which the organic layer was separated.
The organic layer was dried over anhydrous magnesium
sulfate and distilled under reduced pressure to remove
the solvent. The residue was purified by a column
chromatography (eluent; chloroform-chloroform :
methanol = 25 : 1) to obtain 1.79 g of l-[3-
(tetrahydro-2H-pyran-2-yloxy)-1-azetidinyl]-1-ethanone
as a yellow oil.
IR(neat) cm-1: 2 94 5, 2875, 1654, 1458, 1138, 103 6, 971
NMR(CDC13) 8 values: 1. 5-1.9(6H,m), 1.87(3H,s)
3.4-3.6(1H,m), 3.8-4.4(5H,m), 4.5-4.7(2H,m)
(2) In the same manner as in Reference Example 12
(2), 3-(tetrahydro-2H-pyran-2-yloxy)azetidine
hydrochloride was obtained from 1-[3-(tetrahydro-2H-
pyran-2-yloxy)-1-azetidinyl]-1-ethanone.
IR(KBr)cm-1: 2 95 6, 2627 , 103 6, 97 6, 915
NMR(DMSO-d6)d values: 1.4-1.8(6H,m), 3.3-3.5(1H,m),
3.7-4.2(5H,m), 4.4-4.7(2H,m)
Reference Example 14
Production of 1-(3-chloropropyl)-3-
(trityloxy)azetidine oxalate
(1) In 5 mL of dimethyl sulfoxide was dissolved
0.50 g of 3-(trityloxy)azetidine hydrochloride, and to
the solution were added 0.49 g of potassium carbonate,
0.35 g of potassium iodide and 0.22 mL of l-bromo-3-
chloropropane, after which the resulting mixture was
stirred at room temperature for 2 hours. To the
reaction mixture were added 15 mL of water and 10 mL of
ethyl acetate, and the organic layer was separated.
The organic layer was washed with water and then a
saturated aqueous sodium chloride solution, and dried
over anhydrous magnesium sulfate. The solvent was
distilled off under reduced pressure to obtain l-(3-
chloropropyl)-3-(trityloxy)azetidine.
(2)In 10 mL of ethyl acetate was dissolved l-(3-
chloropropyl)-3-(trityloxy)azetidine, and to the
resulting solution was added 0.15 g of oxalic acid,
after which the resulting mixture was stirred at room
temperature. The crystals precipitated were collected
by filtration to obtain 0.39 g of 1-(3-chloropropyl)-3-
(trityloxy)azetidine oxalate.
IR(KBr) cm-1: 30 33, 1491, 1449, 1139, 706
NMR(DMSO-d6)d values: 1. 7-1. 9 (2H, m),3.0-3.1(2H,m) ,
3.5-3.7 (6H,m) ,4 ..3-4.5(1H,m),7.2-7.4(15H,m)
Reference Example 15
Production of 1-(3-chloropropyl)-3-
(tetrahydro-2H-pyran-2-yloxy)azetidine
In the same manner as in Reference Example 14
(1), 1-(3-chloropropyl)-3-(tetrahydro-2H-pyran-2-
yloxy)azetidine was obtained from 3-(tetrahydro-2H-
pyran-2-yloxy)azetidine hydrochloride.
IR(neat) cm-1: 2943, 2834, 1203, 1038, 975, 914, 871
NMR(CDC13)d values:1.4-1.8(6H,m),1.8-1.9(2H,m),
2.59(2H,t,J=7Hz),2.8-3.0(2H,m),3.4-3.5(1H,m),
3.57(2H,t,J=7Hz),3.6-3.7(2H,m),3.8-3.9(1H,m),
4.3-4.4(1H,m), 4.5-4.6(1H,m)
Test Example 1
[Activity to accelerate neurite outgrowth]
PC12 cells [rat adrenomedullary chromaffinoma
(NGF responders)] were cultured in an incubator (5% CO2,
37°C) by using RPMI1640 medium (available from Nissui
Pharmaceutical Co., Ltd.) containing 5% heat
inactivated (56°C, 30 minutes) horse serum (available
from Bio-Whittaker Inc.), 5% heat inactivated (56°C, 30
minutes) fetal calf serum (available from Sigma
Chemical Co.) and 25 µg/ml gemamicin (available from
GIBCO BRL).
The cultured PC12 cells were incubated at 37°C
for 30 minutes in phosphate-buffered physiological
saline containing 1 mM EDTA, to be detached from a
culture flask. The concentration of the cultured PC12
cells was adjusted to 5 x 104 cells/mL with RPMI1640
medium containing 1.5% heat inactivated horse serum,
1.5% heat inactivated fetal calf serum and 25 µg/ml
gentamicin, and the resulting cell suspension was
dispensed in 2 ml portions into 35-mm tissue culture
dishes (mfd. by Falcon Inc.) coated with 0.01%
polyornithine [dissolved in 150 mM borate buffer (pH
8.4)]. Then, 2.5s-NGF (available from Wako Pure
Chemical Industries, Ltd.) [dissolved in phosphate-
buffered physiological saline containing 0.1% bovine
serum albumin] and each test compound were added to the
medium at the same time so as to adjust their final
concentrations to 40 ng/mL and 10 µM, respectively,
followed by culturing under conditions of 5% CO2 and
37°C. After 48 hours of the culturing, cells were fixed
in a 10% neutral formalin solution for 30 minutes,
washed with phosphate-buffered physiological saline and
distilled water, and then dried. Any four fields of
view were selected under a phase contrast microscope,
and 50 or more cells were observed in each field of
view. The percentage of the number of cells having an
neutrite extended to a length longer than the diameter
of the cell body relative to the total number of cells
observed (neutrite outgrowth rate) was calculated.
The activity to accelerate neutrite outgrowth
was calculated according to the following expression as
a neutrite outgrowth acceleration rate attained by the
addition of each test compound, by taking a neutrite
outgrowth rate due to NGF as 100%:
(neutrite outgrowth rate attained by addition
of each test compound) / (neutrite outgrowth rate due
to NGF) x 100 (%)
As a result, the neutrite outgrowth
acceleration rate was found to be as follows: the
compound of Example 2: 2 65%, the compound of Example 6:
300%, the compound of Example 12: 299%, the compound of
Example 14: 207%, the compound of Example 29: 212%, the
compound of Example 51: 216%, the compound of Example
59: 241%, the compound of Example 69: 233%, the
compound of Example 71: 183%, the compound of Example
74: 246%, the compound of Example 80: 190%, and the
compound of Example 81: 190%.
Test Example 2
[Activity to accelerate nerve regeneration]
The test was carried out according to the
method described in J. Pharmaco. Exp. Ther., Vol. 290,
page 348 (1999) and Neuroscience, vol. 88, page 257
(1999).
SD strain rats (male, aged 6 to 7 weeks, and
weighing 170 to 280 g) were anesthetized with
pentobarbital, and the left sciatic nerve of each rat
was exposed in the femoral region, separated from the
surrounding connective tissue, and then cut at a distal
position which was about 1 cm apart from the gluteus.
The ends of the nerve were inserted into a sterilized
silicone tube with a length of 8 mm (inside diameter
1.3 mm, and outside diameter 1.8mm) to a depth of 3.5
mm so that a space of 1 mm might be formed in the
middle of the tube. The ends of the nerve were fixed
and the nerve was put back to the muscular tissue
together with the tube, after which the incised part
was sutured. On the seventh day, each test compound
dissolved in distilled water was orally administered in
a dose of 1 mg/kg, and thereafter the test compound was
administered once a day for 13 days in the same manner
as above.
Twenty-one days after cutting the nerve, the
sciatic nerve was exposed again under pentobarbital
anesthesia, and the nerve in the femoral region and the
crural region was separated from the surrounding
connective tissues, after which the silicone tube at
the cut part was removed. A stimulation electrode was
set on the proximal side with respect to the cut
position, and a recording electrode was set at the most
distal position in the crural region. An electric
stimulus (voltage: 2 V, delay: 1 msec, and duration:
100 fisec) was given, and an action potential induced by
the stimulus was recorded. The recording electrode was
gradually moved toward the proximal, and the distance
between the cut position and the most distal position
at which an action potential had been obtained was
measured as regeneration distance. Only distilled
water was administered to a control group.
The sciatic nerve regeneration rate of the
test compound was calculated according to the following
expression:
(regeneration distance of drug-treated group)
(regeneration distance of control group) x 100 (%)
As a result, the sciatic nerve regeneration
rate was found to be as follows: the compound of
Example 4: 167%, the compound of Example 10: 186%, the
compound of Example 12: 142%, the compound of Example
14: 150%, the compound of Example 31: 155%, and the
compound of Example 33: 161%.
Test Example 3
[Activity to inhibit the neuronal death induced by Aß]
Inhibitory effect on the death of cultured
neurons induced by Aß was investigated by modifying the
method described in Brain Res., vol. 639, page 240
(1994) .
Cerebral cortices isolated from the brains of
embryos (aged 17 to 19 days) of Wistar strain rats were
sliced, and then neurons were dissociated by trypsin
treatment. The cells were seeded into a 48-well tissue
culture plate at a density of 1 x 105 cells per well and
cultured under conditions of 5% CO2, and 37°C on
Dulbecco"s modified Eagle"s medium added B27 supplement
(available from GIBCO BRL) and 3.6 mg/mL glucose.
On the 12th to 13th day of the culture, a
potassium chloride solution was added to the medium to
adjust the final concentration of potassium chloride to
25 mmol/L. Immediately after this addition, each test
compound was added to the medium. After 24 hours, Aß
(a peptides comprising 25 to 35 residues) dissolved in
distilled water was added to the medium at a final
concentration of 20 µmol/L. After another 24 hours,
the medium was replaced with Dulbecco"s modified
Eagle"s medium added B27 supplement and 3.6 mg/mL
glucose and test compound.
The inhibitory activity of the test compound
against the death of cultured neurons was determined by
inhibition against the decrease of reducing ability of
MMT. That is, MTT assay [J. Immuno. Methods, vol. 65,
page 55 (1983)] developed by Mosmann was carried out 48
hours after the medium replacement, and the inhibition
rate (%) of the test compound against a decrease of a
MTT assay value induced by A(3 was calculated.
Inhibition rate = [(MTT assay value of a
group treated with Aß and the drug) - (MTT assay value
of a group treated with Aß)] / [MTT assay value of an
untreated group - MTT assay value of a group treated
with Aß] x 100 (%).
As a result, the inhibition rate at a
concentration of 1 µM was found to be as follows: the
compound of Example 4: 63%, the compound of Example 6:
48%, the compound of Example 10: 42%, the compound of
Example 14: 48%, the compound of Example 31: 50%, the
compound of Example 33: 54%, the compound of Example
61: 52%, the compound of Example 69: 70%, the compound
of Example 74: 50%, and the compound of Example 80:
75%.
Test Example 4
[Metabolism in human liver microsomes]
In a test tube were placed 50 µL of 100
mmol/L potassium phosphate buffer (pH 7.4) and 25 µL of
3 mg protein/mL pooled human liver microsomes
(available from Gentest Inc.), and a solution prepared
by blending 10 µL of 66 mmol/L sodium glucose 6-
phosphate, 10 µL of 10 units/mL glucose 6-phosphate
dehydrogenase, 10 µL of 26 mmol/L nicotinamide adenine
dinucleotide phosphate oxidized form, 10 )µL of 66
mmol/L magnesium chloride and 135 µL of 100 mmol/L
potassium phosphate buffer (pH 7.4) was added thereto,
followed by preincubation for 5 minutes. Thereto was
added 50 µL of each test compound to a concentration of
6 µmol/L to initiate the reaction, and incubation was
carried out at 37°C for 60 minutes (final volume:
300 µL). The reaction was terminated by the addition
of 600 µL of acetonitrile, followed by centrifugation
at 12000 x g and at 4°C for 15 minutes. The supernatant
was separated, concentrated by centrifugation under
reduced pressure, and then subjected to high
performance liquid chromatography, and the amount of
the residual test compound after the metabolic reaction
was determined.
The residual rate was calculated by the
following equation:
Residual rate (%) = [(peak area due to the
test compound after 60 minutes of the reaction) / (peak
area due to the test compound in the case of stopping
the reaction by adding acetonitrile simultaneously with
the addition of the test compound after the
preincubation)] x 100
As a result, the residual rate was found to
be as follows: the compound of Example 4: 80%, the
compound of Example 10: 70%, the compound of Example
12: 83%, the compound of Example 14: 75%, the compound
of Example 61: 74%, the compound of Example 69: 74%,
the compound of Example 71: 80%, and the compound of
Example 74: 71%.
INDUSTRIAL APPLICABILITY
The alkyl ether derivative of the general
formula [1] or salt thereof of the present invention
has excellent activity to accelerate neurite outgrowth,
activity to accelerate nerve regeneration and activity
to protect neurons, is excellent also in stability to
metabolism, and is useful as a therapeutic agent for
diseases in central and peripheral nerves.
WE CLAIM:
1. An. alkyl ether derivative represented by the general formula, or
its salts:
wherein each of R1 and R2, which may be the same or different,
represents one or more groups selected from a hydrogen atoms, a
halogen atom,aC1-12 alkyl, phenyl, naphthyl, indanyl, indenyl, benzyl,
diphenylmethyl, trityi, phenethyl, C1-12 alkoxy, phenyloxy,
naphthyloxy, indanyloxy, indenyloxy, C1-12 alkylthio, phenyltbio,
naphthylthio, indanylthio, indenylthio, C2-12 alkenyl, C2-12 alkenyloxy,
amino, C1-12 alkylsulfonyl, phenylsulfonyl, p-toluenesulfonyl,
naphthylsulfonyl, carbamoyl, pyrrolidinyl, piperidinyl, piperazinyl,
homopiperazinyl, homopiperidinyl, morpholyl, thiomorpholyl,
tetrahydroquinolyl, tetrahydroiaoquinolyl, quinuclidinyl, tmidazolinyl,
pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, quinolyl,
quin.olidin.yl, thiazoiyl, tetrazolyl, thiadiazolyl, pyrrolinyl, pyrazolinyl,
pyrazolidinyl, purinyl, furyl, thienyl, benzothienyl, pyranyl,
isobenzofuranyl, oxazoiyl, isoxazolyl, benzofuranyl, indolyl,
heaasdxnidazoiyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,
quiaoxalyl, dihydroquinoxalyl, 2,3-dih.ydrobenzothienyl, 2,3-
dihydrobenzopyrrotyl,2-3-4H- 1-thianaphthyl,2,3-
dihydrobenzofuranyl, betnzo [b] dioxanyl, imidazo [2,3-a] pyridyl,
beonzo [b] piperazinyl, chiomenyl, isotbiazolyl, isoxazolyl, oxadiazolyl,
pyridazinyl, isoindolyl, isoquinolyl, 1,3-benzodiaxonyl or 1,4-
benzodioxonyl group, a protected or unprotected amino, hydroxyl or
carboxyl group, a nitro group, and an oxo group; R3 is a substituted
or unsubstituted mono-or di- C1-6 alkylamino group, or a protected or
unprotected amino or hydroxyl group; the ring A is a triazine,
pyridazine, pyrimidine, pyrazine, pyridine, furan, thiophene, pyrrole,
oxazole, thiazole, imidazole, iaoxazole, isothiazole, pyrazole, pyran or a
benzene ring; each of m and n is an integer of 1 to 6; and p is 1.
2. The alkyl ether derivative or its salts as claimed in Claim 1,
wherein the portion represented by
in the general formula in Claim 1 is any of the following (A), (B) and
(C):
3. The alkyl ether derivative or its salts as claimed in Claim 1 or 2,
wherein R1 is a hydrogen atom; and R2 is a hydrogen atom, a halogen
atom or an C1-12 alkoxy group.
4. The alkyl ether derivative or its salts as claimed in Claims 1 to
3, wherein m is 2, n is an integer of 2 to 3, and p is 1.
5, A process for producing an alkyl ether derivative represented by
the general formula:
wherein R3 is a substituted or unsubstituted mono-or di- C1-6
alkylamino group, or a protected or unprotected amino or hydroxyl
group; and R1, R2 , the ring A, m, n and p are as defined below, or its
salt, which comprises
reacting a carboxylic acid derivative represented by the
general formula:
wherein each of R1 and R2, which may be the same or different,
represents one or more groups selected from a hydrogen atom, a
halogen atom, C1-12 alkyl, phenyl, naphthyl, indanyl, indenyl, benzyl,
diphenylmethyl, trityl, phenethyl, C1-12 alkoxy, phenyloxy,
naphthyloxy, indanyloxy, indeayloxy, C1-12 atkylthio, pnenylthio,
naphthylthio, indanylthio, indenylthio, C2-12 alkenyl, C2-12 alkenyloxy,
amino, C1-12 alkylsulfonyl, phenybmlfonyl, p-toluenesulfonyl,
naphthylsulfonyl, carbamoyl, pyrrolidinyl, piperidinyl, pipetrazinyl,
homopiperazinyl, homopiperidinyl, morpholyl, thiomorpholyl,
tetrahydroquinolyl, tetrahydroisoquinolyl, quimiclidinyl, imidazoliayl,
pyrrolyl, tmidazolyl, pyrazolyl, pyridyl, pyrimidyl, quinolyl,
quinolidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, pyrazolinyl,
pyrazolidinyl, purinyl, furyl, thienyl, benzotMenyl, pyranyl,
isohenzofuranyl, oxazolyl, isoxazolyl, benzofuranyl, indolyl,
benziiuidazolyl, benzoxazolyl, benzisoxazolyl, beozothiazolyl,
quinoxalyl, dthydroquiaoxalyl, 2,3-dthydrobenzothien.yl, 2,3-
dihydrobenzopyrrolyl,2,3-4H-1thianaphthyl,2,3-
dihydrobenzofuranyl, benzo [b] dioxanyl, imidazo [2,3-a] pyridyl,
benzo [b] piperazinyi, cliromenyl, isothiazolyl, isoxazolyl, oxadiazolyl,
pyridazinyl, isoiadolyl, isoquinolyl, 1,3-benzodioxonyl or 1,4-
benzodioxonyl group, a protected or unprotected amino, hydroxyl or
carboxyl group, a nitro group, and an oxo group; the ring A is a
triazine, pyridazine, pyrimidine, pyrazine, pyridine, furan, thiophetie,
pyrrole, oxazole, thiazole, imidazol, isoxazole, isothiazole, pyrazole,
pyran or a benzene ring; an each of m and n is an integer of 1 to 6, or
its salt with a compound represented by the general formula:
wherein R36 is di- C1-6 alkylamino group, a protected mono- C1-6
alkylamino group, a protected amino group or a protected or
unprotected hydroxyl group; and p is 1 or its salt to obtain an
alkylamide derivative represented by the general formula:
wherein R1, R2, R3a, the ring A,m, n and p are as defined above, or its
salt, optionally subjecting the alkylamide derivative or salt thereof to
a hydroxyl group protection reaction in the case of R3a being a
hydroxyl group, to obtain an alkylamide derivative in which R3a is a
protected hydroxyl group, or its salt, and
then subjecting the obtained alkylamide derivative to reduction
reaction.
6. An alkylamide derivative represented by the general formula, or
its salt:
wherein each of R1 and R2, which may be the same or different,
represents one or more groups selected from a hydrogen atom, a
halogen atom, a C1-12 alkyl, phenyl, naphthyl, indanyl, indenyl,
benzyl, diphenylmethyl, trityl, phenethyl, C1-12 alkoxy, phenyloxy,
naphthyloxy, indanyloxy, indenyloxy, C1-12 alkylthio, phenylthio,
naphthylthio, indanylthio, indenylthio, C2-12 alkenyl, C2-12 alkenyloxy,
amino, C1-12 alkylsulfonyl, phenylaulfonyl, p-toluenesulfonyl,
naphthylsulfonyl, carbamoyl, pyrrolidinyl, piperidinyl, piperazinyl,
homopiperazanyl, homopiperidinyl, morpholyl, thiomorpholyl,
tetrahydroquinolyl, tetrahydroisoquinolyl, quinuctidinylt imidazoKnyl,
pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, quinolyl,
quinolidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, pyrazolinyl,
pyrazolidinyl, purinyl, furyl, thienyl, benzothienyl, pyranyl,
iaobenzofuranyl, oxazolyl, iaoxazolyl, benzofuranyl, indolyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,
quinoxalyl, dihydroquinoxalyl, 2,3-dihydrobnenzothienyl, 2,3-
dihydrobenzopyrroiyl,2,3-4H-1-thianaphthyl,2,3-
dihydrobenzofuraayl, benzo[b] dioxanyl, imidazo [2,3-a] pyridyl, benzo
[b] piperazinyl, chromenyl, isothiazolyl, isoxazolyl, oxadiazolyl,
pyridazinyl, isoindolyl, isoquinolyl, 1,3-beozodioxonyl or 1,4-
benzodioxonyl group, a protected or unprotected amino, hydroxyl or
carboxyl group, a nitro group, and an oxo group; substituted or
unsubstituted mono- or di- C1-6 alkylatnino group, a protected amino
group, or a protected or unprotected hydroxy group; R 3a is a di- C1-6
alkylamino group, a protected mono- C1-6 alkyiamino group, a
protected amino group or a proto. cted or unprotected hydroxyl group;
the ring A is a triazine, pyridazine, pyrimidine, pyrazane, pyridine,
furan, thiophene, pyrrole, oxazole, thiazole, imidazole, isoxazole,
isothiazole, pyrazole, pyrari or a benzene ring; each of m and n is an
integer of 1 to 6; and p is 1.
7. A process for producing an alkyl ether derivative represented by
the general formula:
wherein R1, R2, R3a, the ring A, m , n and p are as defined below, or its
salt, which comprises reacting an ether derivative represented by the
general formula:
wherein each of R1 and R2, which may be the same or different,
represents one or more groups selected from a hydrogen atom, a
halogen atom, a C1-12 alkyl, phenyl, naphthyl, indanyl, indenyl,
benzyl, diphenylmethyl, trityl, phenethyl, C1-12 alkoxy, phenyloxy,
naphthyloxy, indanyloxy, indenyloxy, C1-12 alkylthio, phenyltbio,
naphthyltbio, indanylthio, indenylthio, C2-12 alkenyl, C 2-12 alkenyloxy,
amino, C1-12 alkylsulfonyl, phenylsulfonyl, p-toluenesulfonyl,
naphthylaulfonyl, carbatnoyl, pyrrolidinyl, piperidinyl, piperazinyl,
homopiperazinyl, hotnopiperidinyl, morpholyl, thiomorpholyl,
tetrahydrogquinolyl,tetrahydroisoquinolyl,quinuclidinyl,
imidazolinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridmidyl,
quinolyl, quinolidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl,
pyrazolinyl, pyrazolidinyl, purinyl, furyl, thienyl, benzothienyl,
pyranyl, isobenzofuranyl, oxazolyl, isoxazolyl, benzofiiranyl, indofyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,
quiaoxalyl, dihydroquinoxalyl, 2,3-dihydrobenzotbienyl, 2,3-
dihydrobenzopyrrolyl,2,3-4H-1-thianaphthyl,2,3-
dihydrobenzofuranyl, benzo [b] dioxanyl, imidazo [2,3-a] pyridyl,
benzo [b] piperazinyl, chromenyl, iaothiazolyl, iaoxazolyl, oxadiazolyl,
pyridazinyl, iaoindolyl, iaoquinolyl, 1,3-benzodioxonyl or 1,4-
benzodioxonyl group, a protected or unprotected amino, hydroxyl or
carboxyl group, a nitro group, and an oxo group; the ring A is a
triazine, pyridazine, pyrimidine, pyraztne, pyridine, furan, thiophene,
pyrrole, oxazole, thiazole, imidazole, isoxazole, isothiazole, pyrazole,
pyran or a benzene ring, x1 is a leaving group; and each of m and n is
an integer of 1 to 6, or its salt with a carboxylic acid derivative
represented by the general formula:
wherein R3a is a di- C1-6 alksylamino group, a protected mono- C1-6
alkylamino group, a protected amino group or a protected or
unprotected hydroxyl group; and p is 1 or its salt.
8. A process for producing an alkyl ether derivative represented by
the general formula:
wherein R1, R2, R3b, the ring A, m, n and p are as defined below, or its
salt, which comprises reacting an alcohol derivative represented by
the general formula:
wherein each of R1 and R2, which may be the same or different,
represents one or more groups selected from a hydrogen atom, a
halogen atom, a C1-12 alkyl, phenyl, naphthyl, indanyl, indenyl,
benzyl, diphenylmethyl, trityl, phenethyl, C1-12 alkoxy, phenyloxy,
naphthyloxy, indanyloxy, indenyloxy, C1-12 alkylthio, phenylthio,
naphthylthio, indanylthio, indenylthio, C2-12 alkenyl, C 2-12 alkenyloxy,
amino, C1-12 alkylsulfonyl, phenylsulfonyl, p-toluenesulfonyl,
naphthylsulfonyl, carbamoyl, pyrrolidinyl, piperidinyl, piperazinyl,
homopiperazinyl, homopiperidinyl, morpholyl, thiomorpholyl,
tetrahydroquinolyl, tetrahydroisoquitiolyl, quinuclidinyl, imidazolinyl,
pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, quinolyl,
quinolidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, pyrazolinyl,
pyrazolidinyl, purinyl, furyl, thienyl, benzothienyl, pyranyl,
isobenzofiiranyl, oxazolyl, isoxazolyl , benzofuranyl, indolyl,
benzimidazolyl, benzoxazolyl, bensdaoxazolyl, benzothiazoryl,
quinoxalyl, dihydroquinoxalyl, 2,3-dihydrobenzothienyl, 2,3-
dihydrobeozopyrrolyl,2,3-4H-l-thianaphth.yl,2,3-
dihydrobenzofuranyl, benzo [b] dioxanyl, imidazo [2,3-a] pyridyl,
benzo [b] piperazinyl, chromenyl, isothiazolyl, isoxazolyl, oxadiazolyl,
pyridazinyl, isoindolyl, iaoquinolyl, 1,3-benzodioxonyl or 1,4-
benzodioxonyl group, a protected or unprotected amino, hydroxyl or
carboxyl group, a nitro group, and an oxo group; the ring A is a
triazine, pyridazine, pyranidine, pyrazine, pyridine, furan, thiophene,
pyrrole, oxazole, thiazole, ixnidazole, isoxazole, isothiazole, pyrazole,
pyran or a benzene ring, m is an integer of 1 to 6, or its salt, with an
N-alkyl cyclic amino derivative represented by the general formula:
wherein R3b is a di- C 1-6 atkylamino group, a protected mono- C 1-6
alkylamino group, a protected amino group or a protected hydroxyl
group; X2 is a leaving group; n is an integer of 1 to 6; and p is 1.
9. The alkyl ether derivative or its salts as claimed in claims 1 to 4,
wherein the alkyl ether derivative is l-{3-[2-(l-benzothiopeh-5-
y l)ethoxy]propy 1} -3-azeti dinol.
An alkyl ether derivative represented by the general formula:
wherein each of R1 and R2 represents one or more groups selected from a
hydrogen atom, a halogen atom, an alkyl group, an aryl group, an aralkyl
group, an alkoxy group, an aryloxy group, an alkythio group, an arylthio
group, an alkenyl group, an alkenyloxy group, an amino group, an
alkylsulfonyl group, an arylsulfonyl group, a carbamoyl group, a
heterocyclic group, a hydroxyl group, a carboxyl group, a nitro group, an
oxo group and the like; R3 is an alkylamino group, an amino group, a
hydroxyl group or the like; the ring A is a 5-membered or 6-membered
heteroaromatic ring or a benzene ring; each of m and n is an integer of 1 to
6; and p is 1, or its salt has activity to protect neurons, activity to accelerate
nerve regeneration and activity to accelerate neurite extension and hence is
useful as a therapeutic agent for diseases in central and peripheral nerves.

Documents:

509-kolnp-2004-granted-abstract.pdf

509-kolnp-2004-granted-claims.pdf

509-kolnp-2004-granted-correspondence.pdf

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

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

509-kolnp-2004-granted-form 13.pdf

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

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

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

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

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

509-kolnp-2004-granted-letter patent.pdf

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

509-kolnp-2004-granted-specification.pdf

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Patent Number

218676

Indian Patent Application Number

00509/KOLNP/2004

PG Journal Number

15/2008

Publication Date

11-Apr-2008

Grant Date

09-Apr-2008

Date of Filing

19-Apr-2004

Name of Patentee

TOYAMA CHEMICAL CO., LTD.

Applicant Address

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

Inventors:

#	Inventor's Name	Inventor's Address
1	AKIHITO SAITOH	1-21, TOYOSHIROCHO, TOYAMA-SHI, TOYAMA-JAPAN.
2	NOBORU IWAKAMI	3-20, SENGOKUMACHI, TAKAOKA-SHI, TOYAMA, JAPAN.
3	TAMOTSU TAKAMATSU	29-19, NAKAGAWARA, TOYAMA-SHI, TOYAMA, JAPAN.

PCT International Classification Number

C07D409/12

PCT International Application Number

PCT/JP02/10827

PCT International Filing date

2002-10-18

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	2001-321381	2001-10-19	Japan