Title of Invention	A PROCESS FOR PREPARING OPTICALLY ACTIVE COMPOUND
Abstract	A process for preparing an optically active sulfoxide derivative (I) having CCR5 antagonism without causing side reactions such as racemization and Pummerer rearrangement, which comprises reacting a compound (II) with a compound (III) as shown by the following scheme: wherein R1 represents hydrogen, an aliphatic hydrocarbon group or an aromatic group; R2 represents halogeno, alkyl, hydroxyl, amino, an aromatic group, etc.; R3 represents a 5- or 6-membered ring; R4 represents hydrogen, alkyl, alkoxy or halogeno; R5 represents hydrogen, a hydrocarbon group, a heterocyclic group, acyl, etc.; ring A represents an optionally substituted benzene ring; X represents a bond or divalent group comprising a linear part constituted of 1 to 4 atoms; m represents an integer of 1 to 5; n represents an integer of 0 to 3; p represents an integer of 0 to 2; and *1 represents an asymmetric center.

Title of Invention

A PROCESS FOR PREPARING OPTICALLY ACTIVE COMPOUND

Abstract

A process for preparing an optically active sulfoxide derivative (I) having CCR5 antagonism without causing side reactions such as racemization and Pummerer rearrangement, which comprises reacting a compound (II) with a compound (III) as shown by the following scheme: wherein R1 represents hydrogen, an aliphatic hydrocarbon group or an aromatic group; R2 represents halogeno, alkyl, hydroxyl, amino, an aromatic group, etc.; R3 represents a 5- or 6-membered ring; R4 represents hydrogen, alkyl, alkoxy or halogeno; R5 represents hydrogen, a hydrocarbon group, a heterocyclic group, acyl, etc.; ring A represents an optionally substituted benzene ring; X represents a bond or divalent group comprising a linear part constituted of 1 to 4 atoms; m represents an integer of 1 to 5; n represents an integer of 0 to 3; p represents an integer of 0 to 2; and *1 represents an asymmetric center.

Full Text	PROCESS FOR PREPARING OPTICALLY ACTIVE SULFOXIDE DERIVATIVE Technical Field The present invention relates to an industrially advantageous process for preparing an optically active sulfoxide derivative having CCR5 antagonism, or a salt thereof. Background Art Prior Art Conventionally, as a process for preparing an optically active sulfoxide derivative, separation by a chiral column is generally employed, except for special cases. However, such a process is not a fully satisfactory one from an industrial point of view, because it requires a special apparatus such as SMB (Simulated moving bed). Disclosure of Prior Art The prior art documents related to the present invention are as follows: [Patent Document 1] WO96/01267 A [Patent Document 2] WO99/32468 A [Patent Document 3] WO99/32100 A [Patent Document 4] WO00/10965 A [Patent Document 5] WO00/37455 A [Patent Document 6] WO00/68203 A [Patent Document 7] WO00/76993 A [Patent Document 8] GB Patent No. 1579270 [Patent Document 9] JP 62-265270 A [Patent Document 10] JP 2002-521408 A [Patent Document 11] WO01/46203 A [Non-Patent Document 1] Proc. Natl. Acad. Sci. (USA), Volume 96, pp. 5698-5703 (May, 1999) Problems to be Solved by the Invention The present invention provides an industrially advantageous process for preparing an optically active sulfoxide derivative or a salt thereof, by acylating an optically active sulfoxide derivative having an amino group in the molecule without causing side reactions such as racemization and Pummerer rearrangement. Brief Disclosure of the Invention The present inventors have studied a process for preparing an optically active sulfoxide derivative having CCR5 antagonism or a salt thereof, intensively, and as a result, they have found an industrially advantageous process for preparing an optically active sulfoxide derivative or a salt thereof without causing side reactions such as racemization and Pummerer rearrangement. Namely, the present invention relates to: (1) A process for preparing an optically active compound represented by the formula (I): wherein R1 represents a hydrogen atom, an optionally substituted aliphatic hydrocarbon group or an optionally substituted aromatic group; R2 represents a halogen atom, a nitro group, a cyano group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group (the sulfur atom may be oxidized to form a sulfinyl group that may be substituted or a sulfonyl group that may be substituted), an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified carboxyl group or an optionally substituted aromatic group; R3 represents an optionally substituted 5- or 6- membered ring; R4 represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group or a halogen atom; R5 represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted sulfonyl group, an esterified or amidated carboxyl group or an optionally substituted acyl group; X represents a bond or a divalent group comprising a linear part constituted of 1 to 4 atoms; the ring A represents a benzene ring which may be substituted with a halogen atom, a C1-4 alkyl group which may be substituted with a halogen atom or a C1-4 alkoxy group which may be substituted with a halogen atom; m is an integer of 1 to 5; n represents an integer of 0 to 3; p represents an integer of 0 to 2; 1 represents an asymmetric center; and the SO to which 1 is given represents an asymmetric sulfoxide group, or a salt thereof, which comprises reacting an optically active compound represented by the formula (II): wherein each symbol is as defined above, or a salt thereof, with a compound represented by the formula (III): wherein each symbol is as defined above, a salt thereof or a reactive derivative thereof; (2) A process for preparing an optically active compound represented by the formula (I) or a salt thereof, which comprises reacting an optically active compound represented by the formula (XIa): wherein R6 represents a methyl group, a phenyl group, a 4-methylphenyl group or a a-naphthyl group; 2 represents an asymmetric center; and the other symbols are as defined above, or an optically active compound represented by the formula (XIb): wherein R7 represents a hydrogen atom, a chlorine atom or a nitro group; and the other symbols are as defined above, with a compound represented by the formula (III), a salt thereof or a reactive derivative thereof; (3) An optically active compound represented by the formula (II) or a salt thereof; (4) The optically active compound as described in the above (3), wherein R1 and R2 each represents a C1-6 alkyl group, and n represents 1 or 2, or a salt thereof; (5) The optically active compound as described in the above (3) , wherein R1 represents a C1-6 alkyl group, p represents 0; n represents 1, and (6) A process for preparing an optically active compound represented by the formula (II) or a salt thereof, which comprises subjecting an optically active compound represented by the formula (XIa) or the formula (XIb) to a metathesis reaction; (7) An optically active compound represented by the formula (XIa) or the formula (XIb); (8) The optically active compound as described in the above (7) , wherein R1 and R2 each represents a C1-6 alkyl group, n represents 1 or 2, and R6 represents a 4- methylphenyl group or R1 represents a nitro group; (9) The optically active compound as described in the above (7), wherein R1 represents a C1-6 alkyl group, p (10) A process for preparing an optically active compound represented by the formula (XIa) or the formula (XIb), which comprises subjecting a compound represented by the formula (IX): wherein each symbol is as defined above, or a salt thereof, to optical resolution with an optically active acid represented by the formula (XIIa): wherein each symbol is as defined above, or the formula (XIIb): wherein each symbol is as defined above; (11) A process for preparing an optically active compound represented by the formula (II) or a salt thereof, which comprises oxidizing a compound represented by the formula (X): wherein each symbol is as defined above, or a salt thereof, in the presence of the formula (XIIa), or an acid which is optically active with respect to axial asymmetry and represented by the formula (XIIc): (12) A compound represented by the formula (IX) or a salt thereof; (13) A process for preparing a compound represented by the formula (IX) or a salt thereof, which comprises subjecting a compound represented by the formula (VIII): wherein R8 represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group or - OR10 wherein R10 represents an optionally substituted lower alkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group, and the other symbols are as defined above, or a salt thereof, to a deprotection reaction; (14) A process for preparing a compound represented by the formula (IX) or a salt thereof, which comprises oxidizing a compound represented by the formula (X) or a salt thereof; (15) A compound represented by the formula (VIII) or a salt thereof; (16) A process for preparing a compound represented by the formula (VIII) or a salt thereof, which comprises oxidizing a compound represented by the formula (VII): wherein each symbol is as defined above, or a salt thereof; (17) A compound represented by the formula (VII1): wherein R2' represents a halogen atom, a cyano group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group (the sulfur atom may be oxidized to form a sulfinyl group that may be substituted or a sulfonyl group that may be substituted), an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified carboxyl group or an optionally substituted aromatic group, and the other symbols are as defined above, or a salt thereof; (18) A process for preparing a compound represented by the formula (VII) or a salt thereof, which comprises reacting a compound represented by the formula (V): wherein each symbol is as defined above, or a salt thereof, with a compound represented by the formula (VI): wherein Y represents a halogen atom or a group represented by the formula -OSO2-R9 wherein R9 represents a lower alkyl group or an optionally substituted aryl group, and the other symbols are as defined above, or a salt thereof; (19) A compound represented by the formula (X'): wherein each symbol is as defined above, or a salt thereof; and (20) A process for preparing a compound represented by the formula (X) or a salt thereof, which comprises reacting a compound represented by the formula (IV): wherein the ring A is as defined above, or a salt thereof, with a compound represented by the formula (VI), or a salt thereof. Detailed Description of the Invention Hereinafter, the present invention will be explained in detail. A halogen atom which is the substituent of the ring A includes, for example, fluorine, chloride and bromine; a C1-4 alkyl group which may be substituted with a halogen atom includes, for example, methyl, ethyl, trifluoromethyl and trifluoroethyl; and a C1-4 alkoxy group which may be substituted with a halogen atom includes, for example, methoxy, ethoxy, propoxy, trifluoromethoxy and trifluoroethoxy. An optionally substituted aliphatic hydrocarbon group represented by R1 includes an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group and an optionally substituted cycloalkenyl group. The alkyl group in the optionally substituted alkyl group includes a straight-chain or branched C1-10 alkyl group, for example, a C1-10 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl and decyl, preferably a lower C1-6 alkyl group; the alkenyl group in the optionally substituted alkenyl group includes, for example, a straight-chain or branched C2-10 alkenyl group having 1 to 5 double bonds, for example, a C1-10 alkenyl group such as ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, noneyl and decenyl, preferably a lower C1-6 alkenyl group; the alkynyl group in the optionally substituted alkynyl group includes, for example, a straight-chain or branched C2-10 alkynyl group having 1 to 5 double bonds, for example, a C1-10 alkynyl group such as ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl, preferably a lower C1-6 alkynyl group, repectively. The substituent in the optionally substituted alkyl group, the optionally substituted alkenyl group or the optionally substituted alkynyl group, includes a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, an optionally substituted hydroxyl group (e.g., a hydroxyl group, C1-4 alkoxy, etc.), an optionally substituted thiol group (e.g., thiol, C1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group such as, pyrrolidine, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally halogenated C1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), a formyl group, a C2-4 alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl, etc.). The number of the substituents is preferably 1 to 3. The cycloalkyl group in the optionally substituted cycloalkyl group includes, for example, a C3-7 cycloalkyl group, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and the cycloalkenyl group in the optionally substituted cycloalkenyl group includes, for example, a C3-7 cycloalkenyl group, etc. such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. The substituent in the optionally substituted cycloalkyl group and the optionally substituted cycloalkynyl group includes a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, a hydroxyl group, an optionally substituted thiol group (e.g., thiol, C1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally halogenated C1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), formyl, a C2-4 alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl, etc.). The number of the substituents is preferably 1 to 3. The aromatic group in the optionally substituted aromatic group represented by R1 includes a 5- or 6- membered homo- or heterocyclic aromatic group such as phenyl, pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazolyl; and a condensed heterocyclic aromatic group such as benzofuran, indole, benzothiophene, benzoxazole, benzothiazole, indazole, benzimidazole, quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline and imidazopyridine. The substituent in the aromatic group includes a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, a hydroxyl group, an optionally substituted thiol group (e.g., thiol, C1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5- or 6- membered cyclic amino group such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-Ci-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally halogenated C1-4 alkyl group (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), a formyl group, a C2-4 alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl, etc.). The number of the substituents is preferably 1 to 3. The "substituent" which may be contained in the "aromatic group" of the "optionally substituted aromatic 'group" represented by R1 preferably includes, in particular, a halogen atom, an optionally halogenated or lower-(C1-4) alkoxylated lower (C1-4) alkyl group (e.g., methyl, ethyl, t-butyl, trifluoromethyl, methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, butoxyethyl, etc.), a lower (C1-4) alkyl group which may be substituted with a hydroxyl group or a cyano group (e.g., hydroxy C1-4 alkyl, cyano C1-4 alkyl, etc.), a lower (C1-4) alkyl group which may be substituted with an optionally esterified or amidated carboxyl group (e.g., carboxyl C1-4 alkyl, C1-4 alkoxycarbonyl C1-4 alkyl, carbamoyl C1-4 alkyl, mono-C1-4 alkylcarbamoyl C1-4 alkyl, di-C1-4 alkylcarbamoyl C1-4 alkyl, pyrrolidinocarbonyl C1-4 alkyl, piperidinocarbonyl C1-4 alkyl, morpholinocarbonyl C1-4 alkyl, thiomorpholinocarbonyl C1-4 alkyl, etc.), an optionally halogenated or lower- (C1-4) alkoxylated lower (C1-4) alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, t-butoxy, trifluoromethoxy, methoxymethoxy, ethoxymethoxy, propoxymethoxy, butoxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, butoxyethoxy, methoxypropoxy, ethoxypropoxy, propoxypropoxy, butoxypropoxy, etc.), a halogen atom (e.g., fluorine, chlorine, etc.), a nitro group, a cyano group and 1 or 2 of a lower (C1-4) alkyl group, and more preferably an optionally halogenated lower (C1-4) alkyl group. The "optionally substituted alkyl group", the "optionally substituted cycloalkyl group" and the "optionally substituted aromatic group" represented by R2 are as defined in R1. The substituent in the optionally substituted hydroxyl group represented by R2 includes (1) an optionally substituted alkyl group (e.g., a C1-10 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl and decyl, preferably a lower (C1-6) alkyl group , or the like is exemplified); (2) a cycloalkyl group that may be substituted and may contain heteroatoms (e.g., C3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; a saturated 5- to 6-membered heterocyclic ring group containing 1 to 2 heteroatoms such as tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl and tetrahydrothiopyranyl (preferably, tetrahydropyranyl, etc.); or the like is exemplified); (3) an optionally substituted alkenyl group (e.g., a C2-10 alkenyl group such as allyl, crotyl, 2-pentenyl and 3-hexenyl, preferably a lower (C2-6) alkenyl group , or the like is exemplified) ; (4) an optionally substituted cycloalkenyl group (e.g., a C3-7 cycloalkenyl group such as 2-cyclopentenyl, 2- cyclohexenyl, 2-cyclopentenylmethyl and 2- cyclohexenylmethyl, or the like is exemplified); (5) an optionally substituted aralkyl group (e.g., phenyl-C1-4 alkyl (e.g., benzyl, phenethyl, etc.), or the like is exemplified); (6) a formyl group or an optionally substituted acyl group (e.g., a C2-4 alkanoyl group such as acetyl, propionyl, butyryl and isobutyryl, and a C1-4 alkylsulfonyl group such as methanesulfonyl and ethanesulfonyl, or the like is exemplified); and (7) an optionally substituted aryl group (e.g., phenyl, naphthyl, or the like is exemplified). The substituent which may be contained in (1) an optionally substituted alkyl group, (2) an optionally substituted cycloalkyl group, (3) an optionally substituted alkenyl group, (4) an optionally substituted cycloalkenyl group, (5) an optionally substituted aralkyl group, (6) an optionally substituted acyl group, and (7) an optionally substituted aryl group, includes a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, a hydroxyl group, an optionally substituted thiol group (e.g., thiol, C1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally halogenated C1-4 alkyl group (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1-6 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.; preferably optionally halogenated C1-4 alkoxy), a formyl group, a C2-4 alkanoyl group (e.g., acetyl, propionyl, etc.), a C1-4 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl, etc.), a 5- to 6-membered aromatic heterocycle that may be substituted [e.g., a 5- to 6- membered aromatic heterocycle, which contains 1 to 4 heteroatoms of 1 to 2 kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom, such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine and triazole; the substituent that may be contained in the heterocycle, includes a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, a hydroxyl group, a thiol group, an amino group, a carboxyl group, an optionally halogenated C1-4 alkyl group (e.g., trif luoromethyl, methyl, ethyl, etc.), an optionally substituted C1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), a formyl group, a C2-4 alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl, etc.), and the number of the substituents is preferably 1 to 3. The substituent in the optionally substituted thiol group represented by R2 includes the same as the "substituent in the optionally substituted hydroxyl group" as described above. Among them, it preferably includes: (1) an optionally substituted alkyl group (e.g., a C1- 10 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl and decyl, preferably a lower (C1-6) alkyl group , or the like is exemplified); (2) an optionally substituted cycloalkyl group (e.g., C3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, or the like is exemplified); (3) an optionally substituted aralkyl group (e.g., a phenyl-C1-4 alkyl group (e.g., benzyl, phenethyl, etc.), or the like is exemplified); and (4) an optionally substituted aryl (e.g., phenyl, naphthyl, or the like is exemplified). The substituent which may be contained in (1) an optionally substituted alkyl group, (2) an optionally substituted cycloalkyl group, (3) an optionally substituted aralkyl group and (4) an optionally substituted aryl group as describe above includes a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, a hydroxyl group, an optionally substituted thiol group (e.g., thiol, C1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-Ci-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally halogenated C1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc. ) , a formyl group, a C2-4 alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl, etc.). The number of the substituents is preferably 1 to 3. The substituent of the optionally substituted amino group represented by R2 includes an amino group which may contain 1 or 2 of the same substituents as in the "optionally substituted hydroxyl group" as described above. Among them, it preferably includes: (1) an optionally substituted alkyl group (e.g., a C1- 10 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl, preferably a lower (C1-6) alkyl group , or the like is exemplified); (2) an optionally substituted cycloalkyl group (e.g., a C3-7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, or the like is exemplified); (3) an optionally substituted alkenyl group (e.g., a C2-10 alkeny group such as allyl, crotyl, 2- pentenyl and 3-hexenyl, preferably a lower (C2-6) alkenyl group, or the like is exemplified); (4) an optionally substituted cycloalkenyl group (e.g., a C3-7 cycloalkenyl group such as 2-cyclopentenyl, 2-cyclohexenyl, 2- cyclopentenylmethyl and 2-cyclohexenylmethyl, or the like is exemplified); (5) a formyl group or an optionally substituted acyl group (e.g., a C2-4 alkanoyl group such as acetyl, propionyl, butyryl and isobutyryl, and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl and ethanesulfonyl) , or the like is exemplified); and (6) an optionally substituted aryl group (e.g., phenyl, naphthyl, or the like is exemplified). The substituent which may be contained in (1) an optionally substituted alkyl group, (2) an optionally substituted cycloalkyl group, (3) an optionally substituted alkenyl group, (4) an optionally substituted cycloalkenyl group, (5) an optionally substituted acyl group and (6) an optionally substituted aryl group as describe above, includes a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, a hydroxyl group, an optionally substituted thiol group (e.g., thiol, C1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally halogenated C1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethqxyethoxy, trifluoroethoxyethoxy, etc.), a formyl group, a C2-4 alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl, etc.). The number of the substituents is preferably 1 to 3. In the optionally substituted amino group represented by R2, the substituents of the amino group may bond each other to form a cyclic amino group (e.g., a cyclic amino group that is formed by removing one hydrogen atom from the nitrogen atom which constitutes a 5- or 6-membered ring such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole, and has a bond on the nitrogen atom). The cyclic amino group may contain substituents, and the substituents include a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, a hydroxyl group, an optionally substituted thiol group (e.g., thiol, C1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, mono- C1-4 alkylamino, di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally halogenated C1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), a formyl group, a C2-4 alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl, etc.). The number of the substituents is preferably 1 to 3, The optionally substituted acyl group represented by R2 includes the groups which (1) hydrogen; (2) an optionally substituted alkyl group (e.g., a C1-10 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl and decyl, preferably a lower (C1-6) alkyl group , or the like is exemplified); (3) an optionally substituted cycloalkyl group (e.g., a C3-7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl , or the like is exemplified); (4) an optionally substituted alkenyl group (e.g., a C2-10 alkenyl group such as allyl, crotyl, 2-pentenyl and 3-hexenyl, preferably a lower (C2-6) alkenyl group , or the like is exemplified); (5) an optionally substituted cycloalkenyl group (e.g., a C3-7 cycloalkenyl group such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl and 2-cyclohexenylmethyl , or the like is exemplified); (6) an optionally substituted 5- to 6-membered monocycle aromatic group (e.g., phenyl, pyridyl or the like is exemplified); or the like is bonded with the carbonyl group or the sulfonyl group, (e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2- cyclohexenecarbonyl, benzoyl, nicotinoyl, methanesulfonyl, ethanesulfonyl, etc.). The substituent which may be contained in (2) an optionally substituted alkyl group, (3) an optionally substituted cycloalkyl group, (4) an optionally substituted alkenyl group, (5) an optionally substituted cycloalkenyl group and (6) an optionally substituted 5- or 6-membered monocycle aromatic group as describe above, includes a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, a hydroxyl group, an optionally substituted thiol group (e.g., thiol, C1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally halogenated C1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), a formyl group, a C2-4 alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl, etc.). The number of the substituents is preferably 1 to 3. The optionally esterified carboxyl group represented by R2 includes the groups which (1) hydrogen; (2) an optionally substituted alkyl group (e.g., a C1-10 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl and decyl, preferably a lower (C1-6) alkyl group, or the like is exemplified); (3) an optionally substituted cycloalkyl group (e.g., a C3-7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, or the like is exemplified); (4) an optionally substituted alkenyl group (e.g., a C2-10 alkenyl group such as allyl, crotyl, 2- pentenyl and 3-hexenyl, preferably a lower (C2-6) alkenyl group, or the like is exemplified); (5) an optionally substituted cycloalkenyl group (e.g., a C3-7 cycloalkenyl group such as 2-cyclopentenyl, 2-cyclohexenyl, 2- cyclopentenylmethyl and 2-cyclohexenylmethyl, or the like is exemplified); (6) an optionally substituted aryl group (e.g., phenyl, naphthyl, etc.); or the like is bonded with a carbonyloxy group, preferably includes a carboxyl group, a lower (C1-6) alkoxycarbonyl group, an aryloxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, phenoxycarbonyl, naphthoxycarbonyl, etc.). The substituent which may be contained in (2) an optionally substituted alkyl group, (3) an optionally substituted cycloalkyl group, (4) an optionally substituted alkenyl group, (5) an optionally substituted cycloalkenyl group and (6) an optionally substituted aryl group as describe above, includes a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, a hydroxyl group, an optionally substituted thiol group (e.g., thiol, C1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally halogenated C1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), a formyl group, a C2-4 alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl, etc.). The number of the substituents is preferably 1 to 3. R2 preferably includes, in particular, a halogen atom, a cyano group, a hydroxyl group, a nitro group, an optionally esterified or amidated carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, etc.), an optionally halogenated or lower-(C1-4) alkoxylated lower (C1-4) alkyl group (e.g., methyl, ethyl, t-butyl, trifluoromethyl, methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, butoxyethyl, etc.), a lower (C1- 4) alkyl group which may be substituted with a hydroxyl group or a cyano group (e.g., hydroxy C1-4 alkyl, cyano C1-4 alkyl, etc.), a lower (C1-4) alkyl group which may be substituted with an optionally esterified or amidated carboxyl group (e.g., carboxyl C1-4 alkyl, C1-4 alkoxycarbonyl C1-4 alkyl, carbamoyl C1-4 alkyl, mono-C1-4 alkylcarbamoyl C1-4 alkyl, di-C1-4 alkylcarbamoyl C1-4 alkyl, pyrrolidinocarbonyl C1-4 alkyl, piperidinocarbonyl C1-4 alkyl, morpholinocarbonyl C1-4 alkyl, thiomorpholinocarbonyl C1-4 alkyl, etc.), an optionally halogenated and lower-(C1-4) alkoxylated lower (C1-4) alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, t-butoxy, trifluoromethoxy, methoxymethoxy, ethoxymethoxy, propoxymethoxy, butoxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, butoxyethoxy, methoxypropoxy, ethoxypropoxy, propoxypropoxy, butoxypropoxy, etc.), a halogen atom (e.g., fluorine, chlorine, etc.), a nitro group, a cyano group, an amino group which may be substituted with 1 or 2 of a lower (C1-4) alkyl group, formyl or a lower (C2-4) alkanoyl group (e.g., amino, methylamino, dimethylamino, formylamino, acetylamino, etc.) and a 5- or 6-membered cyclic amino group (e.g, 1- pyrrolidinyl, 1-piperazinyl, 1-piperidinyl, 4-morpholino, 4-thiomorpholino, 1-imidazolyl, 4-tetrahydropyranyl, etc.). For R2, more particularly preferred is an optionally halogenated lower (C1-4) alkyl group. Definitions of each of the substituents represented by R2' are the same as in R2. A "5- or 6-membered cyclic ring" in an "optionally substituted 5- or 6-membered cyclic ring group" represented by R3 includes a group that is formed by removing one hydrogen atom from a 6-membered aromatic hydrocarbon such as benzene, a 5- to 6-membered aliphatic hydrocarbon such as cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, and cyclohexadiene, a 5- to 6-membered aromatic heterocycle containing 1 to 4 heteroatoms of 1 to 2 kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom, such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine and triazole, a 5- to 6-membered non-aromatic heterocycle containing 1 to 4 heteroatoms of 1 to 2 kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom, such as tetrahydrofuran, tetrahydrothiophene, dithiolane, oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, pyran, tetrahydropyran, and tetrahydrothiopyran, or the like. Among them, as for the "5- to 6-membered cyclic ring" is preferably benzene, furan, thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran (preferably, a 6-membered cyclic ring) or the like, particularly benzene. The substituent which may be contained in the "5- or 6-membered cyclic ring" of the "optionally substituted 5- or 6-membered cyclic ring group" represented by R3 includes, for example, a halogen atom, nitro, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, an optionally substituted hydroxyl group, an optionally substituted thiol group (the sulfur atom may be oxidized to form a sulfinyl group that may be substituted or a sulfonyl group that may be substituted), an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified carboxyl group or an optionally substituted aromatic group. Halogen as the substituent of R3 includes fluorine, chlorine, bromine and iodine, and in particular preferably fluorine and chlorine. An alkyl group in the optionally substituted alkyl group as the substituent of R3 includes a straight-chain or branched C1-10 alkyl group, for example, a C1-10 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl and decyl, preferably a lower C1-6 alkyl group. The substituent in the optionally substituted alkyl group includes a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, a hydroxyl group, an optionally substituted thiol group (e.g., thiol, C1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally halogenated C1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), a formyl group, a C2-4 alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl, etc.). The number of the substituents is preferably 1 to 3. The cycloalkyl group in the optionally substituted cycloalkyl group as the substituent of R3 includes, for example, a C3-7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The substituent in the optionally substituted cycloalkyl group includes a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, a hydroxyl group, an optionally substituted thiol group (e.g., thiol, C1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally halogenated C1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), a formyl group, a C2-4 alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl, etc.). The number of the substituents is preferably 1 to 3 The substituent in the optionally substituted hydroxyl group as the substituent of R3 includes (1) an optionally substituted alkyl group (e.g., a C1-10 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl and decyl, preferably a lower (C1-6) alkyl group, or the like is exemplified); (2) a cycloalkyl group that may be substituted and may contain heteroatoms (e.g., C3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; a saturated 5- to 6-membered heterocyclic group containing 1 to 2 heteroatoms such as tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl and tetrahydrothiopyranyl (preferably, tetrahydropyranyl, etc.); or the like is exemplified); (3) an optionally substituted alkenyl group (e.g., a C2-10 alkenyl group such as allyl, crotyl, 2-pentenyl and 3-hexenyl, preferably a lower (C2-6) alkenyl group, or the like is exemplified); (4) an optionally substituted cycloalkenyl group (e.g., a C3-7 cycloalkenyl group such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl and 2-cyclohexenylmethyl, or the like is exemplified); (5) an optionally substituted aralkyl group (e.g., phenyl-C1-4 alkyl (e.g., benzyl, phenethyl, etc.) or the like is exemplified); (6) a formyl group or an optionally substituted acyl group (e.g., a C2-4 alkanoyl group such as acetyl, propionyl, butyryl and isobutyryl, and a C1-4 alkylsulfonyl group such as methanesulfonyl and ethanesulfonyl, or the like is exemplified); and (7) an optionally substituted aryl group (e.g., phenyl, naphthyl, or the like is exemplified). The substituent which may be contained in (1) an optionally substituted alkyl group, (2) an optionally substituted cycloalkyl group, (3) an optionally substituted alkenyl group, (4) an optionally substituted cycloalkenyl group, (5) an optionally substituted aralkyl group, (6) an optionally substituted acyl group, and (7) an optionally substituted aryl group as described above, includes a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, a hydroxyl group, an optionally substituted thiol group (e.g., thiol, C1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally halogenated C1-4 alkyl group (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1-6 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.; preferably an optionally halogenated C1-4 alkoxy group) , a formyl group, a C2-4 alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl, etc.), a 5- to 6-membered aromatic heterocycle that may be substituted [for example, an 5- to 6-membered aromatic heterocycle containing 1 to 4 heteroatoms of 1 to 2 kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom, such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine and triazole, etc.; the substituent that may be contained in the heterocycle, includes a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, a hydroxyl group, a thiol group, an amino group, a carboxyl group, an optionally halogenated C1-4 alkyl group (e.g., trif luoromethyl, methyl, ethyl, etc. ) , a C1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), a formyl group, a C2-4 alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl, etc.), and the number of the substituents is preferably 1 to 3]. The number of the substituents is preferably 1 to 3. Further, the substituent in the optionally substituted thiol group as the substituent of R3 includes the same as the "substituents in the optionally substituted hydroxyl group as the substituent of R1" as described above. Among them, it preferably includes: (1) an optionally substituted alkyl group (e.g., a C1- 10 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl and decyl, preferably a lower (C1-4) alkyl group, or the like is exemplified); (2) an optionally substituted cycloalkyl group (e.g., C3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, or the like is exemplified); (3) an optionally substituted aralkyl group (e.g., a phenyl-C1-4 alkyl group (e.g., benzyl, phenethyl, etc.) or the like is exemplified); and (4) an optionally substituted aryl group (e.g., phenyl, naphthyl or the like is exemplified). The substituent which may be contained in (1) an optionally substituted alkyl group, (2) an optionally substituted cycloalkyl group, (3) an optionally substituted aralkyl group and (4) an optionally substituted aryl group as describe above, includes a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, a hydroxyl group, an optionally substituted thiol group (e.g., thiol, C1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole, etc.) , an optionally esterified or amidated carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally halogenated C1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), a formyl group, a C2-4 alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl, etc.). The number of the substituents is preferably 1 to 3. The substituent of the optionally substituted amino group as the substituent of R3 includes an amino group which may contain 1 or 2 substituents of the same as the "substituent of the optionally substituted hydroxyl group as the substituent of R1". Among them, it preferably includes: (1) an optionally substituted alkyl group (e.g., a C1- i 10 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl and decyl, preferably a lower (C1-6) alkyl group, or the like is exemplified); (2) an optionally substituted cycloalkyl group (e.g., a C3-7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, or the like is exemplified); (3) an optionally substituted alkenyl group (e.g., a C2-10 alkenyl group such as allyl, crotyl, 2- pentenyl and 3-hexenyl, preferably a lower (C2-6) alkenyl group, or the like is exemplified); (4) an optionally substituted cycloalkenyl group (e.g., a C3-7 cycloalkenyl group such as 2-cyclopentenyl, 2-cyclohexenyl, 2- cyclopentenylmethyl and 2-cyclohexenylmethyl, or the like is exemplified); (5) a formyl group or an optionally substituted acyl group (e.g., a C2-4 alkanoyl group such as acetyl, propionyl, butyryl and isobutyryl), a C1-4 alkylsulfonyl group (e.g., methanesulfonyl and ethanesulfonyl), or the like is exemplified); and (6) an optionally substituted aryl group (e.g., phenyl, naphthyl, or the like is exemplified). The substituent which may be contained in (1) an optionally substituted alkyl group, (2) an optionally substituted cycloalkyl group, (3) an optionally substituted alkenyl group, (4) an optionally substituted cycloalkenyl group, (5) an optionally substituted acyl group and (6) an optionally substituted aryl group as describe above, includes a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, a hydroxyl group, an optionally substituted thiol group (e.g., thiol, C1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally halogenated C1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), a formyl group, a C2-4 alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl, etc.). The number of the substituents is preferably 1 to 3. Further, in the optionally substituted amino group as the substituent of R3, the substituents of the amino group may bond each other to form a cyclic amino group (for example, a cyclic amino group that is formed by removing one hydrogen from the nitrogen atom constituting the ring of a 5- to 6-membered cyclic ring such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole, and has a bond on the nitrogen atom). The cyclic amino group may contain a substituent, and the substituent includes a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, a hydroxyl group, an optionally substituted thiol group (e.g., thiol, C1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally halogenated C1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), a formyl group, a C2-4 alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl, etc.). The number of the substituents is preferably 1 to 3. The optionally substituted acyl group as the substituent of R3 includes those which (1) hydrogen; (2) an optionally substituted alkyl group (e.g., a C1-10 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl and decyl, preferably a lower (C1-6) alkyl group, or the like is exemplified); (3) an optionally substituted cycloalkyl group (e.g., a C3-7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, or the like is exemplified); (4) an optionally substituted alkenyl group (e.g., a C2-10 alkenyl group such as allyl, crotyl, 2- pentenyl and 3-hexenyl, preferably a lower (C2-6) alkenyl group, or the like is exemplified); (5) an optionally substituted cycloalkenyl group (e.g., a C3-7 cycloalkenyl group such as 2-cyclopentenyl, 2-cyclohexenyl, 2- cyclopentenylmethyl and 2-cyclohexenylmethyl, or the like is exemplified); (6) a 5- to 6-membered monocycle aromatic group (for example, phenyl, pyridyl or the like is exemplified) ; or the like is bonded with the carbonyl group or the sulfonyl group, (for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, methanesulfonyl, ethanesulfonyl or the like). The substituent which may be contained in (2) an optionally substituted alkyl group, (3) an optionally substituted cycloalkyl group, (4) an optionally substituted alkenyl group, (5) an optionally substituted cycloalkenyl group and (6) an optionally substituted aromatic group of a 5- or 6-rnembered monocycle as describe above, includes a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, a hydroxyl group, an optionally substituted thiol group (e.g., thiol, C1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally halogenated C1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), a formyl group, a C2-4 alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl, etc.). The number of the substituents is preferably 1 to 3. The optionally esterified carboxyl group as the substituent of R3 includes those which (1) hydrogen; (2) an optionally substituted alkyl group (e.g., a C1-10 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl and decyl, preferably a lower (C1-6) alkyl group, or the like is exemplified); (3) an optionally substituted cycloalkyl group (e.g., a C3-7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, or the like is exemplified); (4) an optionally substituted alkenyl group (e.g., a C2-10 alkenyl group such as allyl, crotyl, 2- pentenyl and 3-hexenyl, preferably a lower (C2-6) alkenyl group, or the like is exemplified); (5) an optionally substituted cycloalkenyl group (e.g., a C3-7 cycloalkenyl group such as 2-cyclopentenyl, 2-cyclohexenyl, 2- cyclopentenylmethyl and 2-cyclohexenylmethyl, or the like is exemplified); (6) an optionally substituted aryl group (e.g., phenyl, naphthyl, etc.); or the like is bonded with a carbonyloxy group, preferably includes a carboxyl group, a lower (C1-6) alkoxycarbonyl group and an aryloxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, phenoxycarbonyl, naphthoxycarbonyl, etc.). The substituent which may be contained in (2) an optionally substituted alkyl group, (3) an optionally substituted cycloalkyl group, (4) an optionally substituted alkenyl group, (5) an optionally substituted cycloalkenyl group and (6) an optionally substituted aryl group as describe above, includes a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, a hydroxyl group, an optionally substituted thiol group (e.g., thiol, C1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally halogenated C1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), a formyl group, a C2-4 alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl, etc.). The number of the substituents is preferably 1 to 3. The aromatic group in the optionally substituted aromatic group as the substituent of R3 includes a 5- or 6- membered homo- or heterocyclic aromatic group such as phenyl, pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazolyl; and a condensed heterocyclic aromatic group such as benzofuran, indole, benzothiophene, benzoxazole, benzothiazole, indazole, benzimidazole, quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline and imidazopyridine. The substituent in the aromatic group includes a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, a hydroxyl group, an optionally substituted thiol group (e.g., thiol, C1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally halogenated C1-4 alkyl group (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc. ) , a formyl group, a C2-4 alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl, etc.). The number of the substituents is preferably 1 to 3. Such a substituent of R3 may be substituted at any position of 1 to 4 (preferably, 1 to 2) of the same or different cyclic rings. Further, in the case where the "5- or 6-membered cyclic ring" of the "optionally substituted 5- or 6-membered cyclic ring" represented by R3 contains at least 2 substituents, two substituents among them may bond each other to form, for example, a lower (C1-6) alkylene group (e.g., trimethylene, tetramethylene, etc.), a lower (C1-6) alkyleneoxy group (e.g., -CH2-O-CH2-, -O-CH2-CH2-, -O- CH2-CH2-CH2-, -O-CH2-CH2-CH2-CH2-, -O-C(CH3) (CH3)-CH2-CH2-, etc.), a lower (C1-6) alkylene thio group (e.g., -CH2-S-CH2-, -S-CH2-CH2-, -S-CH2-CH2-CH2-, -S-CH2-CH2-CH2-CH2-, -S- C(CH3) (CH3)-CH2-CH2-, etc.), a lower (C1-6) alkylenedioxy group (e.g., -O-CH2-O-, -O-CH2-CH2-O-, -O-CH2-CH2-CH2-O-, etc.), a lower (C1-6) alkylenedithio group (e.g., -S-CH2-S-, -S-CH2-CH2-S-, -S-CH2-CH2-CH2-S-, etc.), an oxy-lower (C1-6) alkylene amino group (e.g., -O-CH2-NH-, -O-CH2-CH2-NH-, etc.), an oxy-lower (C1-6) alkylene thio group (e.g., -O- CH2-S-, -O-CH2-CH2-S-, etc.), a lower (C1-6) alkylene amino group (e.g., -NH-CH2-CH2-, -NH-CH2-CH2-CH2-, etc.), a lower (C1-6) alkylene diamino group (e.g., -NH-CH2-NH- and -NH- CH2-CH2-NH-) , a thia-lower (C1-6) alkylene amino group (e.g., -S-CH2-NH-, -S-CH2-CH2-NH-, etc.), a lower (C2-6) alkenylene group (e.g., -CH2-CH=CH-, -CH2-CH2-CH=CH-, -CH2-CH=CH-CH2-, etc.) and a lower (C4-6) alkadienylene group (e.g., -CH=CH- CH=CH-, etc.). In addition, the divalent group formed by bonding two substituents of R3 each other may contain the same 1 to 3 substituents as those which may be contained in the "5- or 6-membered cyclic ring" of the "optionally substituted 5- or 6-membered cyclic ring" represented by R3 [a halogen atom, a nitro group, a cyano group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group (the sulfur atom may be oxidized to form a sulfinyl group that may be substituted or a sulfonyl group that may be substituted), an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified or amidated carboxyl group or an optionally substituted aromatic group]. The substituent which may be contained in the "5- or 6-membered cyclic ring" of the "optionally substituted 5- or 6-membered cyclic ring" represented by R3, includes in particular an optionally halogenated or lower-(C1-4) alkoxylated lower (C1-4) alkyl group (e.g., methyl, ethyl, t-butyl, trifluoromethyl, methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, butoxyethyl, etc.), an optionally halogenated or lower-(C1-4) alkoxylated lower (C 1-4) alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, t-butoxy, trifluoromethoxy, methoxymethoxy, ethoxymethoxy, propoxymethoxy, butoxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, butoxyethoxy, methoxypropoxy, ethoxypropoxy, propoxypropoxy, butoxypropoxy, etc.), a halogen atom (e.g., fluorine, chlorine, etc.), a nitro group, a cyano group, an amino group which may be substituted with 1 or 2 lower (C1- 4) alkyl groups, formyl or lower (C2-4) alkanoyl (e.g., amino, methylamino, dimethylamino, formylamino and acetylamino), and a 5- or 6-membered cyclic amino group (e.g., 1-pyrrolidinyl, 1-piperadinyl, 1-piperidinyl, 4- morpholino, 4-thiomorpholino, 1-imidazolyl and 4- tetrahydropyranyl). The "divalent group comprising a linear part constituted of 1 to 4 atoms" represented by X includes, for example, - (CH2)a'- [a1 is an integer of 1 to 4 (preferably 1 or 2)], -(CH2)b'-X1- [b1 is an integer of 0 to 3 (preferably 0 or 1), X1 is an optionally substituted imino group (e.g., an imino group which may be substituted with lower (C1-6) alkyl, lower (C3-7) cycloalkyl, formyl, lower (C2-7) alkanoyl and lower (C1-6) alkoxycarbonyl), a carbonyl group, an oxygen atom or an optionally oxidized sulfur atom (e.g., - S(O)m- (m is an integer of 0 to 2) or the like)], -CH=CH-, -C = C-, -CO-NH- and -SO2-NH-. Such group may bond with a condensed ring by either of a bond on the left and a bond on the right, but preferably it binds with a condensed ring by a bond on the right. X is preferably a bond, -(CH2)b'-O- [b' is an integer of 0, 1 or 2 (preferably 0 or 1)] and -C=C-, and more preferably a bond. The lower alkyl group of the "optionally substituted lower alkyl group" represented by R4 as described above includes, for example, a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, isopentyl, neopentyl and hexyl. The lower alkoxy group of the "optionally substituted lower alkoxy group" represented by R4 as described above includes a C1-6 alkoxy group such as methoxy, ethoxy, propoxy and butoxy. The substituent which may be contained in the "optionally substituted lower alkyl group" and "the optionally substituted lower alkoxy group" includes, for example, a halogen atom (e.g., fluorine, chlorine, bromine and iodine), a hydroxyl group, an amino group, a mono- flower alkyl) amino group, a di-(lower alkyl) amino group and a lower alkanoyl group. The lower alkyl which is contained in the mono-(lower alkyl) amino group and the di-(lower alkyl) amino group includes, for example, the same lower alkyl group as in the "optionally substituted lower alkyl group" represented by R4 as described above. The lower alkanoyl group includes, for example, a C2-6 alkanoyl group such as acetyl, propionyl, butyryl and isobutyryl. The "halogen atoms" represented by R4 as described above includes fluorine, chlorine, bromine and iodine. Among them, R4 is preferably an optionally substituted lower C1-6 alkyl group, preferably a halogen atom, and in particular preferably an optionally substituted methyl group and a halogen atom. The "hydrocarbon group" of the "optionally substituted hydrocarbon group" represented by R5 includes, for example, (1) an alkyl group (e.g., a C1-10 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl and decyl, preferably a lower (C1-6) alkyl group, more preferably a lower (C1-4) alkyl group, or the like is exemplified); (2) a cycloalkyl group (e.g., a C3-7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, or the like is exemplified); (3) an alkenyl group (e.g., a C2-10 alkenyl group such as allyl, crotyl, 2-pentenyl and 3-hexenyl, preferably a lower (C2-6) alkenyl group, or the like is exemplified); (4) a cycloalkenyl group (e.g., a C3-7 cycloalkenyl group such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl and 2-cyclohexenylmethyl, or the like is exemplified); (5) an alkynyl group (e.g., a C2-10 alkynyl group such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-pentynyl and 3-hexynyl, preferably a lower a C2-6 alkynyl group, or the like is exemplified), (6) an aralkyl group (e.g., phenyl-C1-4 alkyl (e.g., benzyl, phenethyl, etc.), or the like is exemplified), (7) an aryl group (e.g., phenyl, naphthyl, or the like is exemplified), and (8) a cycloalkyl-alkyl group (e.g., a C3-7 cycloalkyl-C1-4 alkyl group such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptyl methyl, or the like is exemplified). The substituent which may be contained in (1) an alkyl group, (2) a cycloalkyl group, (3) an alkenyl group, (4) a cycloalkenyl group, (5) an alkynyl group, (6) an aralkyl group, (7) an aryl group and (8) a cycloalkyl-alkyl group as described above, includes a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, a hydroxyl group, an optionally substituted thiol group (e.g., thiol, C1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally halogenated C1-4 alkyl group (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), a C1-4 alkylenedioxy group (e.g., -O-CH2-O-, -O-CH2-CH2-O-, etc.), an optionally substituted sulfonamide group [e.g, a group formed by bonding an optionally substituted amino group (e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole and imidazole, etc.) with -SO2-, etc.], a formyl group, a C2-4 alkanoyl group (e.g., acetyl and propionyl) , a C1-4 alkylsulfonyl group (e.g., methanesulfonyl and ethanesulfonyl) and an optionally substituted heterocyclic group. The number of the substituents is preferably 1 to 3. The "optionally substituted heterocyclic group" represented by R5 includes, for example, a group formed by removing one hydrogen atom from an aromatic heterocycle or a non-aromatic heterocycle. The aromatic heterocycle includes a 5- or 6-membered, aromatic heterocycle 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, oxadiazole, thiadiazole, etc., and the non-aromatic heterocycle includes, for example, a 5- or 6-membered non-aromatic heterocycle containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and a non-aromatic heterocycle which a part or all of the bonds of the above-described aromatic heterocycle is saturated bonds, such as tetrahydrofuran, tetrahydrothiophene, dioxolane, dithiolane, oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, pyran and tetrahydropyran (preferably an aromatic heterocycle such as pyrazole, thiazole, oxazole and tetrazole). The substitutent of the "optionally substituted sulfonyl group" represented by R5 includes the same substituents as that in the "optionally substituted thiol group" described as the substituent of R3. The "optionally esterified carboxyl group" and the "optionally substituted acyl group" represented by R5 include the same substituents as those described as the substituent of R3. The preferable examples of R5 includes a hydrogen atom, an optionally substituted hydrocarbon group and an optionally substituted acyl group, more preferably a C1-6 alkyl group, a C1-4 alkylsulfonyl group, a formyl group and a C2-5 alkanoyl group, even more preferably a C1-4 alkyl group, a formyl group, a C2-5 alkanoyl group, and even more preferably a propyl group or an isobutyl group. The halogen atom represented by Y includes a chlorine atom and a bromine atom. A lower alkyl group represented by R9 in -OSO2-R9 which is represented by Y includes a C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2- dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl. The aryl group in the optionally substituted aryl group represented by R9 includes, for example, phenyl and naphthyl, and the substituent in the optionally substituted aryl group includes, for example, a C1-6 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, etc.), a C1-6 alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.), a halogen atom (e.g., chlorine, bromine, iodine, fluorine, etc.), a nitro group and a cyano group. A preferable example of the group represented by the formula -OSO2-R9 includes a methanesulfonyloxy group and a p-toluenesulfonyloxy group. m is an integer of 1 to 5, preferably 2 to 4. n is an integer of 0 to 3, preferably 0 or 1. 1 and 2 mean that the atom to which 1 or 2 is attached is an asymmetric atom, respectively. R6 represents a methyl group, a phenyl group, a 4- methylphenyl group or a-naphthyl group. R7 represents a chlorine atom or a nitro group. The lower alkyl group in the optionally substituted lower alkyl group represented by R8 includes, for example, a halogen atom (e.g., fluorine, chlorine, bromine and iodine), a hydroxyl group, an amino group, a mono-(lower alkyl) amino group, a di-(lower alkyl) amino group and a lower alkanoyl group. The aryl group in the optionally substituted aryl group represented by R8 includes, for example, a C6-10 aryl group such as a phenyl group and a naphthyl group, and the substituent in the optionally substituted aryl group includes, for example, a halogen atom (e.g., fluorine, chlorine, bromine and iodine), a hydroxyl group, an amino group, a mono-(lower alkyl) amino group, a di-(lower alkyl) amino group and a lower alkanoyl group. The aralkyl group in the optionally substituted aralkyl group represented by R8 includes, for example, a C7- 10 aralkyl group such as a benzyl group and a phenethyl group, and the substituent in the optionally substituted aralkyl group includes, for example, a halogen atom (e.g., fluorine, chlorine, bromine and iodine), a hydroxyl group, an amino group, a mono-(lower alkyl) amino group, a di- (lower alkyl) amino group and a lower alkanoyl group. The optionally substituted lower alkyl group, the optionally substituted aryl group and the optionally substituted aralkyl group represented by R10 in -OR10 which is represented by R8, includes those described as the optionally substituted lower alkyl group, the optionally substituted aryl group and the optionally substituted aralkyl group represented by R8, respectively. Best Mode for Carrying Out the Invention Hereinafter, each of the reaction processes of the present invention will be described in detail. As described below, each of the compounds represented by the formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XIa) and (XIb) can form a salt thereof. The salts include, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, and a salt with a basic or acidic amino acid. A preferable example of a salt with an inorganic base includes, for example, an alkali metal salt such as a sodium salt and a potassium salt; an alkaline earth metal salt such as a calcium salt and a magnesium salt; an aluminum salt; and an ammonium salt. A preferable example of a salt with an organic base includes, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine and N,N'- dibenzylethylenediamine. A preferable example of a salt with an inorganic acid includes, for example, a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid. A preferable example of a salt with an organic acid includes, for example, a salt with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. A preferable example of a salt with a basic amino acid includes, for example, a salt wit^h arginine, lysine, and ornithine, and a preferable example of a salt with an acidic amino acid includes, for example, a salt with asparagic acid, and glutamic acid. The compound (I) thus obtained can be isolated and purified by a well-known separation-purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, solution conversion and chromatography. Hereinafter, a compound represented by the formula' (I) and a salt thereof are simply referred to as Compound (I). Similarly, a compound represented by the formula (II), a compound represented by the formula (III), a compound represented by the formula (IV), a compound represented by the formula (V), a compound represented by the formula (VI), a compound represented by the formula (VII), a compound represented by the formula (VIII), a compound represented by the formula (IX), a compound represented by the formula (X), a compound represented by the formula (XIa) and a compound represented by the formula (XIb), including salts thereof, are simply referred to as Compounds (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XIa) and (XIb), respectively. In addition, a compound represented by the formula (XIIa), a compound represented by the formula (XIIb), and a compound represented by the formula (XIIc) are also referred to as the compound (XIIa), the compound (XIIb) and the compound (XIIc), respectively. These compounds can be isolated by a general isolation-production means after the reaction in each process, but they may be also used for the next reaction without isolation. The compound (V) can be prepared by reacting the compound (IV), for example, with an acylating agent (e.g., acid chloride, acid bromide, a mixed acid anhydride and active ester). This reaction is performed in an appropriate solvent. The solvent includes, for example, aromatic hydrocarbons (e.g., benzene, toluene and xylene), ethers (e.g., dioxane, tetrahydrofuran (THF) and dimethoxyethane), esters (e.g., ethyl acetate), nitriles (e.g., acetonitrile), ketones (e.g., acetone, 2-butanone, 2-pentanone, 3-pentanone, 2-hexanone, 3-hexanone and methyl isobutyl ketone), tertiary amines (e.g., pyridine), N,N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), N- methylpyrrolidone (NMP), halogenated hydrocarbons (e.g., chloroform, dichloromethane, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane) and a mixed solvent thereof. The amount of the acylating agent used is preferably about 1 to 5 mole equivalents, based on the compound (IV). In addition, this reaction may be also performed in the presence of a base. The base includes an alkali metal salt (e.g., potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate), amines (e.g., trimethylamine, triethylamine, diisopropyl ethylamine, N- methylmorpholine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) and 1,4-diazabicyclo[2,2,2]octane (DABCO)) and aromatic amines (e.g., N,N-dimethylaminopyridine, N, N-diethylamino pyridine, pyridine, 4-dimethylaminopyridine, picoline and quinoline). This reaction is performed generally at -20°C to 200°C, preferably at about -10°C to 150°C. Process 2 The compound (VII) can be prepared by reacting the compound (V) with the compound (VI). The reaction is performed in an appropriate solvent. The solvent includes, for example, aromatic hydrocarbons (e.g., benzene, toluene and xylene), ethers (e.g., dioxane, tetrahydrofuran (THF) and dimethoxyethane), alcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol and tert-butanol), esters (e.g., ethyl acetate), nitriles (e.g., acetonitrile), ketones (e.g., acetone, 2-butanone, 2- pentanone, 3-pentanone, 2-hexanone, 3-hexanone and methyl isobutyl ketone), pyridine, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), halogenated hydrocarbons (e.g., chloroform, dichloromethane, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane), water and a mixed solvent thereof. This reaction may be performed in the presence of a base. The base includes an alkali metal salt (e.g., potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate), a metal hydride (e.g., potassium hydride, sodium hydride and calcium hydride), amines (e.g., trimethylamine, triethylamine, diisopropyl ethylamine, N-methylmorpholine, 1, 8-diazabicyclo[5.4.0]-7-undecene (DBU), 1,4- diazabicyclo[2,2,2]octane (DABCO)) and aromatic amines (e.g., N,N-dimethylaminopyridine, N,N-diethylaminopyridine, pyridine, 4-dimethylaminopyridine, picoline and quinoline). The amount of the compound (VI) used is about 1 to 5 mole equivalents, preferably about 1 to 3 mole equivalents, based on Compound (V). In addition, the amount of the base used is preferably about 1 to 5 mole equivalents, based on the compound (V). This reaction is performed generally at -20°C to 200°C, preferably at about -10°C to 150°C. Process 3 The compounds (VIII) can be prepared by oxidizing the compound (VII). The reaction is performed in an appropriate solvent. The solvent includes, for example, carbohydrates (e.g., benzene, toluene and xylene), ethers (e.g., dioxane, tetrahydrofuran (THF) and dimethoxyethane), alcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol and tert-butanol), esters (e.g., ethyl acetate), nitriles (e.g., acetonitrile), ketones (e.g., acetone, 2-butanone, 2-pentanone, 3- pentanone, 2-hexanone, 3-hexanone and methyl isobutyl ketone), pyridine, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), halogenated hydrocarbons (e.g., chloroform, dichloromethane, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane), organic carboxylic acids (e.g., formic acid and acetic acid) and a mixed solvent thereof. The oxidant used includes, for example, hydrogen peroxide, organic peroxy acids such as performic acid, peracetic acid, pertrifluoroacetic acid, perbenzoic acid, m-chloroperbenzoic acid and monoperoxyphthalic acid, cumene hydroperoxide, N- halocarboxylic amides such as N-bromoacetamide, N- bromosuccinimide and N-chlorosuccinimide, tert-butyl hypochloride, manganese dioxide, and periodates such as orthoperiodic acid, sodium metaperiodate and potassium metaperiodate. In addition, this reaction may be performed in the presence of an acid catalyst. The acid catalyst includes, for example, organic acids such as formic acid, acetic acid and propionic, acid, and mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and perchloric acid. In addition, the metal catalyst includes, for example, vanadium oxide, vanadium oxide acetyl acetate, manganese oxide, molybdenum chloride and tungsten chloride. The amount of the oxidant used varies depending on the reaction conditions, but it is generally 1 to 100 mole equivalents, preferably 1 to 20 mole equivalents, based on the compound (VII). The reaction temperature is -50 to 200°C, preferably -30 to 150°C. The amount of the acid or metal catalyst used is 1/1000 to 100 mole equivalents, preferably 1/500 to 50 mole equivalents, based on the compound (VII). Process 4 The compound (IX) can be prepared by subjecting the compound (VIII) to deprotection reaction. The deprotection means include the hydrolysis and the hydrogenolysis. The hydrolysis is usually performed in a solvent in the presence of an acid or a base. The solvent includes, for example, ethers (e.g., dioxane, tetrahydrofuran (THF) and dimethoxyethane), alcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol and tert-butanol), ketones (e.g., acetone, 2-butanone, 2- pentanone, 3-pentanone, 2-hexanone, 3-hexanone and methyl isobutyl ketone), pyridine, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), water and a mixed solvent thereof. In the case where an acid is used, the acid includes organic acids such as formic acid, acetic acid and propionic acid, and mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and perchloric acid. In the case where a base is used, the base includes an alkali metal salt (e.g., potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, calcium carbonate, cesium carbonate, potassium hydrogencarbonate and sodium hydrogen carbonate). The amount of the acid or base used is 0.01 to 200 mole equivalents, preferably 0.1 to 100 mole equivalents, based on the compound (VIII). The reaction temperature is -20 to 200°C, preferably -10 to 100°C. The hydrogenolysis reaction is usually performed in a solvent in the presence of a catalyst. The solvent includes, for example, aromatic hydrocarbons (e.g., benzene, toluene and xylene), ethers (e.g., dioxane, tetrahydrofuran (THF) and dimethoxyethane), esters (e.g., ethyl acetate, etc.), nitriles (e.g., acetonitrile, etc.), tertiary amines (e.g., pyridine, etc.), alcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, tert-butanol, etc.), ketones (e.g., acetone, 2-butanone (MEK), methyl isobutyl ketone (MIBK), etc.), N,N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), N- methylpyrrolidone (NMP), halogenated hydrocarbons (e.g., chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2- tetrachloroethane, etc.), water and a mixed solvent thereof. As the catalyst, for example, palladiums such as palladium chloride, palladium black and palladium carbon, platinums such as platinum oxide, platinum black and platinum carbon, rhodiums such as rhodium carbon, Raney nickel and Raney cobalt are used. As the hydrogen source, hydrogen, formic acid, ammonium formate, isopropanol, etc. are used. The reaction temperature is -70 to 200°C, preferably 0 to 100°C. The reaction pressure is 0 to 10 MPa, preferably 0 to 5 MPa. The amount of the catalyst used is 1/10000 to 100 mole equivalents, preferably 1/1000 to 50 mole equivalents, based on the compound (VIII). For this hydrogenolysis reaction, an acid or a base may be added, if necessary. As the acid, organic acids such as formic acid, acetic acid and propionic acid, mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and perchloric acid, etc. are used, and as the base, an alkali metal salt (e.g., potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc.), amines (e.g., trimethylamine, triethylamine, diisopropyl ethylamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 1,4- diazabicyclo[2,2,2]octane (DABCO), etc.), aromatic amines (e.g., N,N-dimethylaminopyridine, N,N-diethylamino pyridine, pyridine, 4-dimethylaminopyridine, picoline, quinoline, etc.), etc. are used. Process 5 Using the compound (IX) and the optically active acid represented by the formula (XIIa) or (XIIb), optical resolution is performed via a diastereomeric salt. In the process of preparing a diastereomeric salt, the reaction is performed in an appropriate solvent. The solvent includes, for example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran (THF) and dimethoxyethane, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol and tert-butanol, ethyl acetate, acetonitrile, ketones (e.g., acetone, 2-butanone, 2-pentanone, 3-pentanone, 2-hexanone, 3-hexanone, methyl isobutyl ketone, etc.), pyridine, N,N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), N- methylpyrrolidone (NMP), water, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane and a mixed solvent thereof. The acidic optical resolution agent includes, for example, tartaric acid and the derivative thereof [diacyl tartaric acid (diacetyl tartaric acid, dibenzoyl tartaric acid, di-p- toluoyl tartaric acid, di-1- naphthoyl tartaric acid, etc.), etc.], amino acid (pyroglutaric acid, aspartic acid and a-phenylglycine) and the derivative thereof [N-acylamino acid (N-acetylleucine, N-acetylvaline, N-(3,5-dinitro)benzoylphenylglycine, etc.), etc.] and (+) or (-) phosphoric acid such as a cyclic phosphate derivative (2,2'-(1,1'-binaphthyl)phosphoric acid and 4-phenyl-2-hydroxy-5,5-dimethyl-1,3,2- dioxaphosphorinan-2-oxide. The optical resolution agent used is preferably dibenzoyl tartaric acid, di-p-toluoyl tartaric acid, di-1-naphthoyl tartaric acid and N-(3,5- dinitro)benzoylphenylglycine, and the amount used thereof is 0.1 to 10 mole equivalents, preferably 0.5 to 5 mole equivalents, based on the compound (IX). The reaction temperature is -20 to 200°C, preferably -10 to 100°C. Process 6 The compound (X) can be prepared by reacting the compound (IV) with the compound (VI). For this reaction, the same reaction conditions as those in Process 2 can be employed. Process 7 The reaction for derivating the compound (II) from the compound (X) is performed by reacting the compound (X) with an oxidant in the presence of the optically active acid represented by the formula (XIIa) or the formula (XIIc). This reaction is performed in an appropriate solvent. The solvent includes, for example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran (THF) and dimethoxyethane, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol and tert-butanol, ethyl acetate, acetonitrile, ketones (e.g., acetone, 2-butanone, 2- pentanone, 3-pentanone, 2-hexanone, 3-hexanone, methyl isobutyl ketone, etc.), pyridine, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) , water, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, organic carboxylic acids (e.g., formic acid, acetic acid, etc.) and a mixed solvent thereof. The oxidant used includes, for example, hydrogen peroxide, organic peroxy acids such as performic acid, peracetic acid, pertrifluoroacetic acid, perbenzoic acid, m- chloroperbenzoic acid and monoperoxyphthalic acid, cumene hydroperoxide, N-halocarboxylic acids such as N- bromoacetamide, N-bromosuccinimide and N-chlorosuccinimide, tert-butyl hypochloride, manganese dioxide, periodates such as orthoperiodic acid, sodium metaperiodate and potassium metaperiodate. In addition, this reaction may be performed in the presence of an acid catalyst. The acid catalyst includes, for example, a tartaric acid derivative [diacyl tartaric acid (dibenzoyl tartaric acid, di-p-toluoyl tartaric acid, di-1-naphthoyl tartaric acid, etc.), etc.], and (+) or (-) phosphoric acid such as a cyclic phosphate derivative (2,2'-(1,1'-binaphthyl)phosphoric acid and 4- phenyl-2-hydroxy-5, 5-dimethyl-1,3,2-dioxaphosphorinan-2- oxide. Preferably, dibenzoyl tartaric acid, di-p-toluoyl tartaric acid, di-1-naphthoyl tartaric acid and 2,2'-(1,1'- binaphthyl)phosphoric acid are used. The amount of the optically active acid used is 0.5 to 10 mole equivalents, preferably 0.5 to 5 mole equivalents, based on 1 mole of the compound (X). The amount of the oxidant used is 1 to 100 mole equivalents, preferably 1 to 50 mole equivalents, based on 1 mole of the compound (X). The amount of the acid used is 0.1 to 10 mole equivalents, preferably 0.5 to 5 mole equivalents, based on 1 mole of the compound (X). The reaction temperature is -50 to 200°C, preferably -30 to 50°C. Process 8 The compound (IX) is prepared by oxidizing the compound (X). For this reaction, the same reaction conditions as those in Process 3 can be employed. Process 9 Metathesis reaction of the compound (XI) is performed in an appropriate solvent by contacting it with an acid or a base. The solvent includes, for example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran (THF) and dimethoxyethane, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol and tert-butanol, ethyl acetate, acetonitrile, ketones (e.g., acetone, 2-butanone, 2-pentanone, 3-pentanone, 2-hexanone, 3-hexanone, methyl isobutyl ketone, etc.), N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), water, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2- tetrachloroethane and a mixed solvent thereof. As the acid, organic acids such as formic acid, acetic acid and propionic acid, and mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and perchloric acid are used, and as the base, an alkali metal salt (e.g., potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogen carbonate, etc.), amines (e.g., trimethylamine, triethylamine, diisopropyl ethylamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 1,4- diazabicyclo[2,2,2]octane (DABCO), etc.) and aromatic amines (e.g., N,N-dimethylaminopyridine, N,N-diethylamino pyridine, pyridine, 4-dimethylaminopyridine, picoline, quinoline, etc.) are used. The reaction temperature is -30 to 150°C, preferably -10 to 100°C. The amount of the acid used or base used is 1 to 200 mole equivalents, preferably 1 to 100 mole equivalents, based on 1 mole of the compound (XI) . Process 10 The compound (I) can be prepared by reacting the compound (II) with the compound (III) or a reactive derivative thereof. This reaction is usually performed in a solvent. Any solvent can be used if it does not inhibit the reaction, but it includes for example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran (THF) and dimethoxyethane, ethyl acetate, acetonitrile, ketones (e.g., acetone, 2- butanone, 2-pentanone, 3-pentanone, 2-hexanone, 3-hexanone, methyl isobutyl ketone, etc.), pyridine, N,N- dimethylformamide (DMF), N,N-dimethylacetoamide (DMA), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2- tetrachloroethane, and a mixed solvent thereof. The reactive derivative means the reactive derivative in the carboxyl group of the compound represented by the formula (III). The reactive derivative includes, for example, those which are well-known in the field of peptide such as acid chloride, acid bromide, mixed acid anhydride and active ester. In addition, in the case where the reactive derivative is used, the reaction may be performed in the presence of a base. The base includes an alkali metal salt (e.g., potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate), amines (e.g., trimethylamine, triethylamine, diisopropyl ethylamine, N- methylmorpholine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 1,4-diazabicyclo[2,2,2]octane (DABCO), etc.) and aromatic amines (e.g., N,N-dimethylaminopyridine, N, N-diethylamino pyridine, pyridine, 4-dimethylaminopyridine, picoline, quinoline, etc.). The amount of the base used is preferably about 1 to 5 mole equivalents, based on the compound (III) or a reactive derivative thereof. In addition, the amount of the compound (III) or a reactive derivative used is preferably about 1 to 5 mole equivalents, based on Compound (II). The reaction temperature is usually -20 to 150°C, preferably -10 to 100°C. The reaction time is about 1 to 100 hours. The compound (III) which is used as a starting material in the reaction can be prepared according to the method as described in WO01-17947 (corresponding to JP 2001-151741 A). Examples and Reference Examples The present invention is hereinafter described in more detail by means of the following Examples and Reference Examples, but the present invention is not limited thereto. Reference Example 1 1-Isobutylpiperidin-2-one To a suspension of potassium hydroxide (482 g) in toluene (700 ml) was added dropwise a solution of 2- piperidone (181 g) in toluene (100 ml) at 50°C or lower. Then, to the reaction mixture was added tetrabutylammonium bromide (5.88 g) and further added dropwise a solution of isobutyl bromide (500 g) in toluene (100 ml). The mixture was stirred at 50 to 60°C for 3 hours and then allowed to cool to room temperature. Water (500 ml) was added to the reaction mixture and the resulting solution was neutralized with concentrated hydrochloric acid (460 ml) under ice- cooling (pH 8) and separated into layers. The aqueous layer was reextracted with toluene (450 ml), the organic layers were combined and washed with saturated brine, and then the solvent was distilled off. The residue was distilled under reduced pressure and a fraction of b.p. 98°C was collected at 8 mmHg to obtain 23.5 g (yield: 83.1%) of the title compound as a colorless oily matter. 1H-NMR (300MHz, CDCl3, d): 0.86 (6H, d, J = 6.7Hz), 1.73- 1.78 (4H, m), 1.85-2.05 (1H, m) , 2.34-2.38 (2H, m), 3.16 (2H, d, J = 7.7HZ), 3.20-3.25 (2H, m). Reference Example 2 8-Bromo-l-isobutyl-l,2,3,4-tetrahydro-l-benzazocinee-5- carboxylic acid To l-isobutylpiperidin-2-one (10 g) were added methanesulfonic acid (16.7 ml) and water (35 ml), and the mixture was stirred under reflux for 24 hours to form 5- isobutylaminopentanoic acid. The reaction solution was cooled to 50°C and neutralized with sodium carbonate (13.7 g). The neutralized solution was slowly added dropwise at 110 to 115°C to a mixture of 2-fluoro-5-bromobenzaldehyde (8.2 g), sodium carbonate (11.1 g), and DMSO (65 ml), and the mixture was, stirred with heating under reflux for 4 hours. The mixture was cooled to 50°C, water (30 ml) and toluene (40 ml) were added thereto, and the resulting solution was adjusted to pH 3.5 with 6 N hydrochloric acid. The toluene layer was separated and the aqueous layer was reextracted with toluene (40 ml). The organic layers were combined and washed with 10% brine and water. The solvent was distilled off to obtain 5-[(4-bromo-2- formylphenyl)(isobutyl)amino]pentanoic acid of a brown oily matter. This compound was dissolved in N,N- dimethylformamide (24.6 ml), and to the solution was added potassium carbonate (56.7 g) and then added dropwise methyl iodide (3 ml). The mixture was stirred at room temperature for 4 hours, thereto was added dimethyl carbonate (49.2 ml) and then added dropwise a solution of 28% sodium methoxide in methanol (15.6 g) , and the mixture was stirred at 60°C for 1.5 hours. Water was added to the reaction solution and the mixture was extracted with toluene. The organic layer was washed with 10% brine and then water. The solvent was distilled off to obtain methyl 8-bromo-1- isobutyl-1,2,3,4-tetrahydro-l-benzazocinee-5-carboxylate of a brown oily matter. To a solution of methyl 8-bromo-1-isobutyl-1,2,3,4- tetrahydro-1-benzazocinee-5-carboxylate in tetrahydrofuran - methanol (2 : 1, 45 ml) was added an aqueous 2 N sodium hydroxide solution (40 ml) and the reaction mixture was stirred at 60°C for 2.5 hours. The mixture was allowed to cool to room temperature and adjusted to pH 3.5 with concentrated hydrochloric acid, and the mixture was extracted with toluene. The organic layer was washed with water, activated carbon (0.8 g) was added thereto, and the mixture was stirred for 10 minutes. The activated carbon was filtered off and the solvent was then distilled off. The residue was dissolved in methanol (24 ml) at 60°C and to the solution was added dropwise water (6 ml). The mixture was stirred at room temperature for 1 hour and crystallized. The crystals were collected by filtration, washed with methanol - water (5 : 2), and then dissolved in methanol (24 ml) with heating under reflux. To the solution was added dropwise water (4.8 ml) at the same temperature, and the mixture was stirred at room temperature for 1 hour and crystallized. The crystals were collected by filtration, washed with methanol - water (5 : 1), and dried at 40°C under reduced pressure to obtain 6.2 g (yield: 45%) of the title compound as yellow powder. 1H-NMR (300MHz, CDCl3, d): 0.97 (6H, d, J = 6.7Hz), 1.43- 1.47 (2H, m) , 2.05-2.25 (1H, m), 2.45-2.55 (2H, m), 3.00 (2H, d, J = 7.3HZ), 3.40-3.50 (2H, m), 6.63 (1H, d, J =8.9Hz), 7.15-7.30 (2H, m), 7.83 (1H, s). Elemental analysis value: in terms of C16H20NO2Br Calcd. value: C, 56.82; H, 5.96; N, 4.14; Br, 23.62 Found value: C, 56.63; H, 5.88; N, 3.92; Br, 23.41 IR (KBr, cm-1) : 1664, 1604, 1494 Melting point: 153.3 - 154.0°C Reference Example 3 8-[4-(2-Butoxyethoxy)phenyl]-1-isobutyl-12,3,4-tetrahydro- 1-benzazocine-5-carboxylic acid Under an argon atmosphere, to a suspension of magnesium (1.3 g) in tetrahydrofuran (100 ml) was slowly added dropwise one third of a solution of 1-bromo-4-(2- butoxyethoxy)benzene (14.2 g) in THF (30 ml) with heating under reflux. After confirming that the reaction was initiated, to the solution were added dropwise the other two thirds thereof, and the mixture was stirred for 1 hour under reflux. To the mixture was added dropwise a solution of trimethyl borate (5.7 ml) in tetrahydrofuran (30 ml) while keeping the temperature at -10°C or lower and the reaction mixture was stirred for 1 hour. The reaction mixture was warmed to room temperature, thereto were added palladium acetate (20 mg) and triphenylphosphine (93 mg), and the mixture was stirred for 30 minutes. To the mixture were added 8-bromo-1-isobutyl-1,2,3,4-tetrahydro-1- benzazocine-5-carboxylic acid (10 g), tripotassium phosphate (39.3 g) and distilled water (80 ml), and the resulting mixture was stirred for 3 hours with heating under reflux. After allowing to cool the mixture, water (100 ml) was added thereto, and the resulting mixture was adjusted to pH 3 with 6 N hydrochloric acid under ice- cooling and separated into layers. The aqueous layer was further extracted with ethyl acetate. The organic layers were combined and washed with saturated brine, activated carbon (1 g) and tributylphosphine (1 ml) were added thereto, and the mixture was stirred at room temperature for 20 minutes. The activated carbon was filtered off and the solvent was then distilled off. To the residue was added isopropyl ether (50 ml) and dissolved therein at 60°C. The mixture was stirred at room temperature for 2 hours and then stirred for 1 hour under ice-cooling, and the crystals were collected by filtration (12.6 g). The crystals were dissolved in isopropanol (55 ml) at 60°C, to the solution was added activated carbon (1 g), and the mixture was stirred for 20 minutes. The activated carbon was filtered off while the mixture was hot, and the mixture was stirred at 60°C for 30 minutes, stirred for 1 hour at room temperature and then stirred for 1 hour under ice-cooling. The crystals were collected by filtration, washed with cold isopropanol (10 ml) and dried at 4 0°C under reduced pressure to obtain 5.30 g (yield: 89%) of the title compound as yellow powder. 1H-NMR (300MHz, CDCl3, d): 0.94 (3H, t, J = 7.3Hz), 1.00 (6H, d, J = 6.6HZ), 1.35-1.65 (6H, m) , 2.10-2.30 (1H, m) , 2.55-2.60 (2H, m), 3.08 (2H, d, J = 7.2Hz), 3.45-3.75 (4H, m) , 3.80-3.85 (2H, m), 4.15-4.20 (2H, m), 6.83 (1H, d, J= 8.8HZ), 6.96 (2H, d, J=8.7Hz), 7.30-7.40 (2H, m), 7.43 (2H, d, J = 8.7Hz), 8.01 (1H, s). Elemental analysis value: in terms of C28H37NO4 Calcd. value: C, 74.47; H, 8.26; N, 3.10 Found value: C, 74.53; H, 8.51; N, 3.03 IR (KBr, cm-1): 1666, 1604, 1494 Melting point: 119.6 - 120.1°C Reference Example 4 8-[4-(2-Butoxyethoxy)phenyl]-1-isobutyl-1,2,3,4-tetrahydro- 1-benzazocine-5-carboxylic acid Under an argon atmosphere, to a suspension of magnesium (650 mg) in tetrahydrofuran (50 ml) was added trimethylsilyl chloride (0.07 ml) and the reaction mixture was stirred at room temperature for 10 minutes. To the mixture was added dropwise one third of a solution of 1- bromo-4-(2-butoxyethoxy)benzene (7.08 g) in tetrahydrofuran (15 ml) . The mixture was slowly warmed (23°C ? 32°C). After confirming that the reaction was initiated by coloration in about 30 minutes, to the reaction solution were added dropwise the other two thirds thereof and after completion of addition, the mixture was stirred at 4 5 to 50°C for 0.5 hours. The mixture was allowed to cool to room temperature, thereto was added dropwise a solution of trimethyl borate (2.9 ml) in tetrahydrofuran (15 ml) while keeping the temperature at -10°C or lower, and the reaction mixture was stirred for 1 hour. The reaction mixture was warmed to room temperature, thereto were added palladium acetate (10 mg) and triphenylphosphine (47 mg), and the mixture was stirred for 30 minutes. To the mixture were added 8-bromo-1-isobutyl-1,2,3,4-tetrahydro-1-benzazocine- 5-carboxylic acid (5 g) , tripotassium phosphate (19.63 g) and distilled water (40 ml) , and the resulting mixture was stirred for 2 hours with heating under reflux. The mixture was allowed to cool, water (50 ml) was added thereto, and the resulting mixture was adjusted to pH 3 with 6 N hydrochloric acid and separated into layers. The aqueous layer was extracted with ethyl acetate (50 ml) . The organic layers were combined and washed with saturated brine, activated carbon (0.5 g) and tributylphosphine (0.5 ml) were added thereto, and the mixture was stirred at room temperature for 20 minutes. The activated carbon was filtered off and the solvent was then distilled off. To the residue was added isopropyl ether (25 ml), and the mixture was heated at 60°C and slowly returned to room temperature, and stirred at room temperature for two hours and then stirred for 1 hour under ice-cooling. The crystals were collected by filtration (6.0 g) and washed with cold isopropyl ether (10 ml) . The crystals were dissolved in isopropanol (60 ml) at 60°C, to the solution was added activated carbon (0.5 g) , and the mixture was stirred for 20 minutes. The activated carbon was filtered off and the solvent was then distilled off. To the residue was added isopropanol (30 ml) , followed by dissolving therein at 60°C. The mixture was stirred at room temperature for 3 hours and then stirred for 1 hour under ice-cooling. The crystals were collected by filtration, washed with cold isopropanol (10 ml) and dried at 40°C under reduced pressure to obtain 5.38 g (yield: 80.5%) of the title compound as yellow powder. Reference Example 5 1-Isobutylpyrrolidin-2-one To a solution of 2-pyrrolidone (60 g) in tetrahydrofuran (300 ml) were added potassium hydroxide (59.3 g) and tetrabutylammonium bromide (2.5 g) and then added dropwise isobutyl bromide (144.9 g) at 50°C or lower. The resulting mixture was stirred at 50 to 60°C for 3 hours and allowed to cool to room temperature. Insoluble materials were filtered off and washed with toluene (300 ml). The filtrate was washed with saturated brine (150 ml), and then the solvent was distilled off. The residue was distilled under reduced pressure and a fraction of b.p. 97 to 102°C was collected at 3 mmHg to obtain 73 g (yield: 73%) of the title compound as a colorless oily matter. Reference Example 6 7-Bromo-1-isobutyl-2,3-dihydro-lH-1-benzazepine-4- carboxylic acid To 1-isobutylpyrrolidin-2-one (28 g) were added water (66 ml) and methanesulfonic acid (26 ml) and the resulting mixture was stirred for 24 hours under reflux. After allowing to cool the mixture, thereto were added water (30 ml) and sodium carbonate (84.8 g) (vigorously foamed), and the mixture was stirred for 1 hour. To the reaction solution was added dimethylsulfoxide (30 ml) and added dropwise a solution of 5-bromo-2-fluorobenzaldehyde (12.2 g) in dimethylsulfoxide (66 ml). After completion of addition, the mixture was heated under reflux for 9 hours. After allowing to cool, the mixture was adjusted to pH 3 with 6 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with 20% brine and the product was extracted with an aqueous 1 N sodium hydroxide solution (100 ml). The aqueous layer was adjusted to pH 3 with 6 N hydrochloric acid and extracted with ethyl acetate. The solvent was distilled off to obtain 4-[(4-bromo-2- formylphenyl)(isobutyl)amino]butanoic acid as a brown oily matter. To a solution of 4-[(4-bromo-2- formylphenyl)(isobutyl)amino]butanoic acid in N,N- dimethylformamide (50 ml) was added potassium carbonate (9.12 g) and added dropwise a solution of methyl iodide (10.22 g) in N,N-dimethylformamide (10 ml). After stirring for 1 hour at room temperature, to the resulting solution was added dimethyl carbonate (120 ml) and added dropwise 28% sodium methoxide (27.8 g) , and the mixture was stirred at 60°C for 1 hour. The mixture was adjusted to pH 3 with 2 N hydrochloric acid (100 ml) under ice-cooling. Then, the mixture was adjusted to pH 6.5 with an aqueous 6 N sodium hydroxide solution and the solvent was distilled off. The residue was extracted with toluene. The toluene layer was sequentially washed with an aqueous 1 N sodium hydroxide solution, 2% brine and water. The solvent was distilled off to obtain methyl 7-bromo-1-isobutyl-2,3- dihydro-1H-1-benzazepine-4-carboxylate as a brown oily matter. To a solution of the oily matter in tetrahydrofuran - methanol (1 : 1, 190 ml) was added an aqueous 1 N sodium hydroxide solution (120 ml) and the reaction mixture was stirred at 50°C for 1.5 hours. After distilling off about half of the solvent, the residue was washed with toluene. The aqueous layer was adjusted to pH 3 with 6 N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with 2% brine and the solvent was then distilled off to pbtain a brown oily matter. The oily matter was dissolved in methanol (120 ml), thereto was added activated carbon (1.2 g) , and the mixture was stirred 60°C for 20 minutes. The activated carbon was filtered off and the solvent was then distilled off. The residue was dissolved in methanol (45 ml) at 60°C, to the solution was added water (9 ml), and the crystals were precipitated. The mixture was stirred for 8 hours at room temperature and then stirred for 1 hour under ice-cooling. The crystals were collected by filtration, washed with cold methanol - water (1 : 1, 30 ml) and dried at 40°C under reduced pressure to obtain 10.13 g (yield: 52.1%) of the title compound. 1H-NMR (300MHz, CDCl3, d): 0.91 (6H, d, J = 6.6Hz), 1.90- 2.25 (1H, m), 2.75-2.85 (2H, m), 3.12 (2H, d, J = 7.4Hz), 3.20-3.30 (2H, m), 6.72 (1H, d, J = 9.0Hz), 7.20-7.30 (1H, m), 7.44 (1H, s), 7.70 (1H, s). Elemental analysis value: in terms of C15H18NO2Br Calcd. value: C, 55.57; H, 5.60; N, 4.32; Br, 24.65 Found value: C, 55.52; H, 5.59; N, 4.13; Br, 24.39 IR (KBr, cm-1) : 1677, 1614, 1490 Melting point: 144.8 - 145.5°C Reference Example 7 7-[4-(2-Butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1- benzazepine-4-carboxylic acid Under an argon atmosphere, a suspension of magnesium (2.25 g) in tetrahydrofuran (140 ml) was heated under reflux and to the mixture was slowly added dropwise one third of a solution of 1-bromo-4-(2-butoxyethoxy)benzene (24.6 g) in tetrahydrofuran (40 ml). After confirming that the reaction was initiated (the reaction solution was clouded), to the solution were added dropwise the other two thirds thereof, and the mixture was stirred for 1 hour under reflux. After allowing cool the reaction solution to room temperature, thereto was added dropwise a solution of trimethyl borate (10 ml) in tetrahydrofuran (40 ml) while keeping the temperature at -10°C or lower and the reaction solution was stirred for 1 hour. The reaction solution was warmed to room temperature, thereto were added palladium acetate (27 mg) and triphenylphosphine (126 mg), and the mixture was stirred for 30 minutes. To the mixture were added 7-bromo-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4- carboxylic acid (19.45 g), tripotassium phosphate (79.6 g) and distilled water (100 ml), and the resulting solution was stirred for 2 hours with heating under reflux. After allowing to cool the mixture, water (150 ml) was added thereto, and the resulting solution was adjusted to pH 3 with 6 N hydrochloric acid (150 ml) and separated into layers. The aqueous layer was extracted with toluene (14 0 ml). The organic layer was sequentially washed with an aqueous 1 N sodium hydroxide solution, 1 N hydrochloric acid and 20% brine. Activated carbon (2 g) and tributylphosphine (2 ml) were added to the organic layer and the mixture was stirred for 20 minutes at room temperature. The activated carbon was filtered off and the solvent was then distilled off. To the residue was added isopropyl ether (80 ml), followed by heating. The mixture was stirred for 1 hour at room temperature and stirred for 1 hour under ice-cooling, and the crystals were collected by filtration. The crystals were washed with isopropyl ether (30 ml) and dried at 40°C under reduced pressure to obtain 23.72 g (yield: 90.3%) of yellow crystals. The crystals (2 g) were dissolved in isopropanol (10 ml) with heating under reflux, to the resulting solution was added tributylphosphine (0.2 ml), and the mixture was stirred for 2 hours at room temperature and stirred for 1 hour under ice-cooling. The crystals were collected by filtration, washed with cold isopropanol (5 ml) and dried at 40°C under reduced pressure to obtain 1.92 g (yield: 96.0%) of the pure title compound as yellow crystals. 1H-NMR (300MHz, CDCl3, d): 0.90-1.10 (9H, m) , 1.35-1.50 (2H, m), 1.55-1.70 (2H, m), 2.00-2.15 (1H, m), 2.85-2.90 (2H, m), 3.20 (2H, d, J = 7.3HZ), 3.30-3.35 (2H, m), 3.58 (2H, d, J = 6.7HZ), 3.80-3.85 (2H, m) , 4.15-4.20 (2H, m), 6.92 (1H, d, J = 8.8HZ), 7.01 (2H, d, J = 8.8Hz), 7.40-7.55 (4H, m), 7.91 (1H, s). Elemental analysis value: in terms of C27H35NO4 Calcd. value: C, 74.11; H, 8.06; N, 3.20 Found value: C, 74.18; H, 8.33; N, 2.95 IR (KBr, cm-1): 1668, 1608, 1500 Melting point: 126.4 - 127.0°C Reference Example 8 1-Propylpiperidin-2-one To toluene (750 ml) were added potassium hydroxide (254 g) and then added tetrabutylammonium bromide (4.87 g) and to the resulting mixture was slowly added dropwise a solution of 2-piperidone (150 g) in toluene (150 ml) at 50 to 60°C. The mixture was stirred at the same temperature for 1 hour. To the mixture was added dropwise propyl bromide (371 g) at the same temperature. The mixture was stirred at the same temperature for 1 hour and thereto was added water (450 ml) while keeping the temperature at 30°C or lower. The mixture was adjusted to pH 7.2 by adding dropwise 48% hydrobromic acid and then the organic layer was separated. The aqueous layer was extracted with toluene (450 ml). The organic layers were combined and concentrated under reduced pressure. The residue was distilled under reduced pressure and a fraction of b.p. 91 to 93°C was collected at 6 mmHg to obtain 169.3 g (yield: 79%) of the title compound as a colorless oily matter. 1H-NMR (CDCl3, d, 300MHz): 0.88 (3H, t, J = 7.4Hz), 1.48- 1.61 (2H, m), 1.74-2.00 (4H, m), 2.33-2.38 (2H, m), 3.22- 3.33 (4H, m). Reference Example 9 8-Bromo-1-propyl-1,2,3,4-tetrahydro-1-benzazocine-5- carboxylic acid 1-Propylpiperidin-2-one (55.6 g) was added to 4 N sodium hydroxide (197 ml) and the resulting mixture was refluxed for 4 hours. The mixture was cooled to room temperature and adjusted to pH 6.1 with adding concentrated hydrochloric acid. To the mixture were added sodium carbonate (83.5 g), water (255 ml), dimethylsulfoxide (520 ml), and 5-bromo-2-fluorobenzaldehyde (40 g). After refluxing for 5 hours, the mixture was cooled to 50°C and adjusted to pH 3.1 with 6 N hydrochloric acid. The mixture was cooled to room temperature and extracted with ethyl acetate. The organic layers were combined, washed with 5% brine and the product was extracted with an aqueous 5% sodium carbonate solution (440 ml). The aqueous layer was adjusted to pH 3.3 with 6 N hydrochloric acid and extracted with a mixed solution of toluene (400 ml) and tetrahydrofuran (150 ml). The organic layer was sequentially washed with 5% brine and water, and the solvent was distilled off to obtain 5-[(4-bromo-2- formylphenyl)(propyl)amino]valeric acid as a brown oily matter. The obtained 5-[(4-bromo-2- formylphenyl)(propyl)amino]valeric acid was dissolved in N,N-dimethylformamide (120 ml), thereto was added potassium carbonate (30 g) and further added methyl iodide (33.6 g) , and the resulting mixture was stirred at room temperature for 2 hours. To the mixture was added dimethyl carbonate (240 ml) and then added dropwise a solution of 28% sodium methoxide in methanol (91.2 g), and the mixture was stirred at 60°C for 1 hour. The mixture was cooled to room temperature, thereto was added water (4 00 ml) and the mixture was extracted with toluene. The organic layer was washed with 5% brine and concentrated under reduced pressure to obtain methyl 8-bromo-1-propyl-1,2,3,4- tetrahydro-1-benzazocine-5-carboxylate as an oily matter. The obtained methyl 8-bromo-1-propyl-1,2,3,4-tetrahydro-1- benzazocine-5-carboxylate was dissolved in a mixed solution of tetrahydrofuran (100 ml) and methanol (100 ml). To the solution was added 2 N sodium hydroxide (197 ml) and the reaction mixture was refluxed for 1 hour. The mixture was cooled to room temperature and adjusted to pH 3.2 with adding 6 N hydrochloric acid. The resulting mixture was extracted with ethyl acetate and the extract was washed with 5% brine. To the extract was added activated carbon (2 g), the resulting mixture was stirred for 30 minutes and then filtered, and the mixture was washed with ethyl acetate (80 ml). The filtrates were combined and concentrated under reduced pressure, and to the obtained crystals were added methanol (90 ml). The resulting mixture was refluxed for 30 minutes, and stirred at room temperature for 1 hour and stirred for 2 hours under ice- cooling. The obtained crystals were collected by filtration to obtain 29.76 g of the title compound (yield: 47%) 1H-NMR (CDCl3, d, 300MHz): 0.96 (3H, t, J= 7.4Hz), 1.40- 1.49 (2H, m), 1.59-1.71 (2H, m) , 2.53 (2H, t, J = 6.0Hz), 3.12 (2H, t, J = 7.9HZ), 3.44 (2H, t, J = 5.3Hz), 6.56-6.60 (1H, m) , 7.19-7.23 (2H, m), 7.81 (1H, s). Reference Example 10 8-[4-(2-Butoxyethoxy)phenyl]-1-propyl-1,2,3,4-tetrahydro-1- benzazocine-5-carboxylic acid Under an argon atmosphere, magnesium (675 mg) was added to tetrahydrofuran (50 ml). To the resulting suspension was slowly added dropwise a solution of 1-bromo- 4-(2-butoxyethoxy)benzene (7.37 g) in tetrahydrofuran (15 ml) under reflux and the mixture was refluxed for 1 hour. To the mixture was added dropwise a solution of trimethyl borate (2.79 g) in tetrahydrofuran (15 ml) at -15 to -10°C and the mixture was stirred at the same temperature for 30 minutes. The mixture was warmed to room temperature, thereto were added palladium acetate (13 mg) and triphenylphosphine (63 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture were sequentially added 8-bromo-1-propyl-l, 2,3,4-tetrahydro-1- benzazocine-S-carboxylic acid (5.0 g) , potassium phosphate (20.5 g) and distilled water (40 ml), and the resulting mixture was refluxed with stirring for 2.5 hours. To the reaction solution were added palladium acetate (13 mg) and triphenylphosphine (63 mg), and then the mixture was refluxed for 50 minutes. The mixture was cooled to room temperature and water (40 ml) was added thereto. The resulting solution was adjusted to pH 3.3 with 6 N hydrochloric acid under ice-cooling and the organic layer was separated. The aqueous layer was extracted with toluene. The organic layers were combined and washed with water and 1 N sodium hydroxide. To the organic layer was added 0.3 N hydrochloric acid (120 ml) and further added ethyl acetate, and then insoluble materials was filtered and the filtrate was separated . The organic layer was washed with water, thereto were added tributylphosphine (0.5 ml) and then activated carbon (250 mg), and the mixture was stirred at room temperature for 30 minutes. The mixture was filtered, washed with ethyl acetate and concentrated under reduced pressure. To the obtained crystals were added ethyl acetate (25 ml) and the mixture was stirred under reflux. Then, the mixture was stirred for 1 hour under ice-cooling. The obtained crystals were filtered and washed with the ice-cooled ethyl acetate (10 ml) to obtain 5.63 g (yield: 83%) of the title compound as reddish yellow crystals. 1H-NMR (CDCl3, d, 300MHz): 0.90-1.01 (6H, m) , 1.35-1.72 (8H, m) , 2.57 (2H, t, J = 5.3Hz), 3.19 (2H, t, J = 7.7Hz), 3.48- 3.57 (4H, m), 3.80 (2H, t, J = 4.9Hz), 4.15 (2H, t, J = 4.9HZ), 6.76 (1H, d, J = 8.9Hz), 6.95 (2H, d, J = 8.7Hz), 7.32-7.45 (4H, m), 8.00 (1H, s). Reference Example 11 5-(Chloromethyl)-1-propyl-1H-imidazole monohydrochloride To a mixture of 1-butanol (900 ml) and acetic acid (120 ml) was added dropwise n-propylamine (103 ml) and further added dropwise methanesulfonic acid (81 ml) at 30°C or lower. The reaction mixture was returned to room temperature, thereto were added 1,3-dihydroxyacetone dimer (90.1 g) and potassium thiocyanate (145.8 g), and the resulting mixture was stirred at the same temperature for 24 hours. To the mixture was added water (250 ml), the reaction mixture was stirred at room temperature 2 hours, and then the precipitated crystals were collected by filtration. The obtained crystals were washed with water (100 ml) to obtain (2-mercapto-1-propyl-1H-imidazol-5- yl)methanol. The solution of sodium nitrite (1.7 g) in water (5 ml) was added dropwise to 5 M nitric acid (600 ml) at 20°C or lower. To the solution was first added dropwise a solution of all of the above-obtained (2-mercapto-1-propyl-1H- imidazol-5-yl)methanol in aqueous 3.5 N sodium hydroxide (215 ml) at 20°C or lower and then the mixture was stirred at room temperature for 2 hours. Further, to the reaction mixture was added dropwise at 20°C or lower an aqueous 6 N sodium hydroxide solution (370 ml) (pH = about 6.5) and then added dropwise an aqueous 2 M sodium carbonate solution (370 ml) (pH = about 9) at 20°C or lower. The mixture was extracted with ethyl acetate - isopropanol (2 : 1, 450 ml) and again, extracted twice with ethyl acetate - isopropanol (3 : 1, 400 ml). The organic layers were combined, washed with 10% brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain (l-propyl-1H-imidazol-5-yl)methanol as an oily matter. To all of the above (1-propyl-1H-imidazol-5- yl)methanol was added DMF (375 ml)and the remaining ethyl acetate was distilled off under reduced pressure. Then, toluene (100 ml) was added thereto and the mixture was distilled off under reduced pressure. After carrying out this operation twice, to the residue was added dropwise thionyl chloride (40.1 ml) at 30°C or lower. The mixture was returned to room temperature and stirred for two hours. To the reaction mixture was added toluene (700 ml) and the resulting mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed with toluene (100 ml), and dried at 40°C under reduced pressure to obtain 63.7 g of the title compound as white crystals. 1H-NMR (300MHz, CDCl3, d): 0.88 (3H, t, J = 7.35Hz), 1.80- 2.00 (2H, m), 4.21 (2H, t, J = 7.35Hz), 5.05 (2H, s), 7.83 (1H, s), 9.33 (1H, s). Elemental analysis value: in terms of C7H11ClN2•HCl Calcd. value: C, 43.10; H, 6.20; N, 14.36 Found value: C, 43.12; H, 5.95; N, 14.28 IR (KBr, cm-1) : 1600 Melting point: 164.8 - 166.4°C Example 1 2,2,2-Trifluoro-N-(4-{[(1-propyl-1H-imidazol-5- yl)methyl]thiojphenyl)acetamide Triethylamine (27.9 ml) was added dropwise to a solution of 4-aminobenzenethiol (12.5 g) in tetrahydrofuran (180 ml) at 0 to 10°C. Subsequently, to the reaction mixture was added dropwise trifluoroacetic anhydride (28.2 ml) at 0 to 10°C and the reaction mixture was stirred at the same temperature for 0.5 hours. To the reaction solution was added water (30 ml) and the mixture was stirred at room temperature for 0.5 hours. To the mixture was added 20 w/w% brine (30 ml) and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (180 ml) . The organic layers were combined and water (30 ml) was added thereto. The resulting solution was adjusted to about pH 9 with adding sodium hydrogen carbonate. After separation into layers, the organic layer was washed with water (30 ml) and concentrated. To the precipitated crystals were added n-hexane (120 ml) and the resulting solution was stirred at room temperature for 17 hours. The crystals were collected by filtration and washed with n-hexane (20 ml) . The crystals were dried under reduced pressure to obtain 26.1 g of 2,2,2-trifluoro- N-(4-mercaptophenyl)acetamide as white crystals. 1H-NMR (CDCl3, 300MHz) d: 3.45 (1H, s) , 7.18 (2H, d, J = 9.4HZ), 7.51 (2H, d, J = 9.4Hz), 9.97 (1H, brs) Under a nitrogen atmosphere, to a solution of the above obtained 2,2,2-trifluoro-N-(4- mercaptophenyl)acetamide (24.8 g) in methanol (99 ml) was added dropwise triethylamine (29.0 ml) at 0 to 10°C under ice-cooling. Subsequently, to the reaction mixture was added dropwise at 0 to 20°C a solution of 5-(chloromethyl)- 1-propyl-1H-imidazole hydrochloride (20.4 g) in distilled water (21 ml) and the resulting solution was stirred at 20 to 30°C for 0.5 hours. Ethyl acetate (200 ml) was added to the reaction solution and the organic layer was separated. Subsequently, after washing with an aqueous 7 w/w% sodium hydrogen carbonate (50 ml) and water (50 ml), the organic layer was concentrated. To the precipitated crystals were added diisopropyl ether (250 ml) and the resulting mixture was stirred for 0.5 hours with heating under reflux, and then allowed to cool to room temperature and stirred for 3 hours. The precipitated crystals were collected by filtration and washed with diisopropyl ether (20 ml) . The crystals were dried under reduced pressure to obtain 23.8 g (yield: 73%, calculated from the amount of 4- aminobenzenethiol) of the title compound as white crystals. Melting point: 82 - 84°C Elemental analysis value: in terms of C15H16N3OSF3 • 0. 5 H2O Calcd. value: C, 51.13; H, 4.86; N, 11.92 Found value: C, 51.41; H, 4.55; N, 11.75 1H-NMR (CDCl3, 300MHz) d: 0.99 (3H, t, J = 7.4Hz), 1.67 (1H, brs), 1.82-1.94 (2H, m), 3.77 (2H, t, J = 6.6Hz), 3.99 (2H, s), 6.67 (1H, s), 6.96-7.31 (2H, m) , 7.47 (1H, m), 7.51- 7.59 (2H, m) IR (KBr, cm-1): 1704, 1504, 1247, 1195, 1160, 1145, 1108 Example 2 2,2,2-Trifluoro-N-(4-{[(1-propyl-1H-imidazol-5- yl)methyl]thio}phenyl)acetamide (one-pot reaction) Under a nitrogen atmosphere, triethylamine (27.9 ml) was added dropwise to a solution of 4-aminobenzenethiol (12.5 g) in tetrahydrofuran (180 ml) at 0 to 10°C. Subsequently, to the reaction mixture was added dropwise trifluoroacetic anhydride (28.2 ml) at 0 to 10°C and the reaction mixture was stirred at the same temperature for 1 hour. To the reaction solution was added water (30 ml) and the mixture was stirred at room temperature for 1 hour. To the solution was added dropwise triethylamine (41.8 ml) at 0 to 10°C. Subsequently, to the reaction solution was added dropwise at 0 to 20°C a solution of 5-(chloromethyl)- 1-propyl-1H-imidazol'e hydrochloride (19.5 g) in distilled water (19 ml) and the resulting solution was stirred at the same temperature for 1 hour. Ethyl acetate (120 ml) was added to the reaction solution and the organic layer was separated. Subsequently, after washing with an aqueous 7 w/w% sodium hydrogen carbonate (60 ml) and city water (60 ml), the organic layer was concentrated. To the concentrate was added diisopropyl ether (150 ml) and the resulting mixture was stirred at 20 to 30°C for 2 hours. The precipitated crystals were collected by filtration and washed with diisopropyl ether (20 ml) . The crystals were dried under reduced pressure to obtain 33.1 g (yield: 96%, calculated from the amount of 4-aminobenzenethiol) of the title compound as white crystals. Example 3 4-{[(1-Propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenylamine At 20 to 30°C, 30 w/w% hydrogen peroxide (16.4 g) was added to a solution of 2,2,2-trifluoro-N-(4-{[(1-propyl-1H- imidazol-5-yi)methyl]thio)phenyl)acetamide (33.1 g) in acetic acid (49.7 ml) and the reaction mixture was stirred at the same temperature for 3 hours. To the reaction was added ethyl acetate (330 ml), thereto were added dropwise sodium thiosulfate pentahydrate (35.9 g) and an aqueous 6 N sodium hydroxide solution (144.6 ml) at 0 to 10°C, and the reaction mixture was stirred at the same temperature for 0.5 hours. To the mixture was added tetrahydrofuran (330 ml) and the organic layer was separated. The aqueous layer was again extracted with ethyl acetate/tetrahydrofuran (160 ml/160 ml). The organic layers were combined, washed with 10w/w% brine (80 ml x 2) and concentrated. To the organic layers was added methanol (330 ml), the organic layers were dissolved therein and again concentrated. The concentrate was dissolved in methanol (198.6 ml) and thereto was added a solution of potassium carbonate (40.0 g) in water (99.3 ml) at room temperature. The mixture was warmed to 50°C and stirred for 2.5 hours. After cooling to 20 to 30°C, the organic layer was separated and the aqueous layer was extracted with ethyl acetate (330 ml). The organic layers were combined and washed with 20 w/w% brine (100 ml), thereto were added anhydrous magnesium sulfate (5 g) and activated carbon (3 g), and the mixture was stirred at 20 to 30ºC for 0.5 hours. The solids were filtered off, the filtrate was washed with ethyl acetate (64 ml) and the organic layer was concentrated. Ethyl acetate (160 ml) was added to the concentrate and the product was again concentrated. Ethyl acetate (132 ml) was added to the concentrate and the mixture was stirred at 50°C for 1 hour, and then allowed to cool to 20 to 30°C and stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration and washed with ethyl acetate (33 ml). The obtained crystals were dried under reduced pressure to obtain 18.5 g (yield: 73%) of the title compound as white crystals. Melting point: 143°C (decomposition) 1H-NMR (CDCl3, 300MHz) d: 0.90 (3H, t, J = 7.4Hz), 1.68- 1.78 (2H, m), 3.74 (2H, t, J = 6.5Hz), 3.95-4.08 (4H, m), 6.60 (1H, s), 6.69 (2H, d, J = 6.8Hz), 7.17 (2H, d, J = 6.8HZ), 7.43 (1H, s) IR (KBr, cm-1): 3397, 3334, 3216, 1650, 1596, 1419, 1018 Example 4 4-{[(l-Propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenylamine (one-pot reaction) At 20 to 30°C, 30 w/w% hydrogen peroxide (35.4 g) was added to a solution of 2,2,2-trifluoro-N-(4-{[(1-propyl-1H- imidazol-5-yl)methyl]thio}phenyl)acetamide (71.5 g) in acetic acid (107.3 ml) and the reaction mixture was stirred at the same temperature for 3 hours. To the reaction mixture was added methanol (429 ml), thereto were added dropwise sodium thiosulfate pentahydrate (11. 4 g) and an aqueous 6 N sodium hydroxide solution (312.2 ml) at 0 to 10°C, and the reaction mixture was stirred at the same temperature for 1 hour. Subsequently, to the mixture was added potassium carbonate (86.2 g), the resulting mixture was warmed to 50°C and stirred for 3 hours. After cooling to 20 to 30°C, the organic layer was separated and the aqueous layer was extracted with ethyl acetate (710 ml). The organic layer was washed with 20 w/w% brine (200 ml), thereto were added anhydrous magnesium sulfate (10 g) and activated carbon (7.1 g), and the mixture was stirred at 20 to 30°C for 0.5 hours. The solids were filtered off, the filtrate was washed with ethyl acetate (200 ml) and the organic layer was concentrated. Ethyl acetate (358 ml) was added to concentrate and the mixture was stirred at 50°C for 2 hours, and then allowed to cool to 20 to 30°C and stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration and washed with ethyl acetate (72 ml). The obtained crystals were dried under reduced pressure to obtain 36.3 g (yield: 66%) of the title compound as white crystals. Example 5 4-{[(1-Propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenylamine A solution of 5-(chloromethyl)-1-propyl-1H-imidazole hydrochloride (10.7 g) in distilled water (6 ml) was added dropwise to a mixed solution of 4-aminobenzenethiol (6.3 g) and triethylamine (15.3 ml) in 2-propanol (25.2 ml) at 10 to 30°C and the resulting solution was stirred under the same condition for 1 hour. To the solution was added water (20 ml) and the mixture was extracted with ethyl acetate (50 ml x 2). The organic layer was washed with 20 w/w% brine (20 ml) and concentrated. The concentrate was dissolved in acetic acid (12.6 ml), thereto was added 30 w/w% hydrogen peroxide (8.5 g) at 20 to 30°C, and the resulting mixture was stirred at the same temperature for 2 hours. Thereto were added dropwise sodium thiosulfate pentahydrate (9.3 g) and an aqueous 6 N sodium hydroxide solution (36 ml) at 0 to 10°C, and the reaction mixture was stirred at the same temperature for 1 hour. The mixture was extracted with ethyl acetate/2- propanol (4/1, 180 ml). The organic layer was washed with 20 w/w% brine (30 ml), to the organic layer were added anhydrous sodium sulfate and activated carbon (0.6 g) , and the mixture was stirred at 20 to 30°C for 1 hour. The solids were filtered off, the filtrate was washed with ethyl acetate (10 ml) and the organic layer was concentrated. To the concentrate was added 2-propanol (18 ml) and the concentrate was dissolved therein, and then the resulting solution was stirred at 20 to 30°C for 0.5 hours. Subsequently, to the solution was added n-heptane (36 ml) and the mixture was stirred at 20 to 30°C for 1 hour. The precipitated crystals were collected by filtration and washed with 2-propanol/n-heptane (4 ml/2 ml). The obtained crystals were dried under reduced pressure to obtain 10.2 g (yield: 73%) of the title compound as white crystals. Example 6 4-{[(l-Propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenylamine (one-pot reaction) A solution of 5-(chloromethyl)-1-propyl-1H-imidazole hydrochloride (0.78 g) in distilled water (0.5 ml) was added dropwise to a mixed solution of 4-aminobenzenethiol (0.46 g) and triethylamine (1.1 ml) in methanol (2 ml) at 10 to 30°C and the resulting solution was stirred under the same conditions for 1 hour. Subsequently, to the solution were added acetic acid (1 ml) and 30 w/w% hydrogen peroxide (0.62 g) at 20 to 30°C, and the resulting mixture was stirred at the same temperature for 17 hours. Thereto were added dropwise sodium sulfite (0.69 g) and an aqueous 6 N sodium hydroxide solution (3 ml) at 0 to 10°C, and the reaction mixture was stirred at the same temperature for 1 hour. The mixture was extracted with ethyl acetate/2- propanol. The organic layer was washed with 20 w/w% brine, to the organic layer were added anhydrous sodium sulfate and activated carbon (40 mg), and the product was stirred at 20 to 30°C for 1 hour. The solids were filtered off, the filtrate was washed with ethyl acetate (10 ml) and the organic layer was concentrated. To the concentrate was added ethyl acetate (4 ml) and the concentrate was dissolved therein, and then the resulting solution was stirred at 20 to 30°C for 1 hour. The precipitated crystals were collected by filtration and washed with ethyl acetate (2 ml). The obtained crystals were dried under reduced pressure to obtain 0.73 g (yield: 71%) of the title compound as white crystals. Example 7 (-)-4- [ [(1-Propyl-1H-imidazol-5- yl)methyl]sulfinyl]phenylamine(2S,3S)-di(1- naphthoyl)tartrate The racemate (50 mg) of 4-[[(1-propyl-1-H-imidazol-5- yl)methyl]sulfinyl]phenylamine and (2S, 3S)-di(1- naphthoyl)tartaric acid monohydrate (45.2 mg) were dissolved in methanol (1.0 ml) and the resulting solution was stirred at room temperature overnight. The precipitate was filtered to obtain 56.2 mg of the crystals. As a result of HPLC analysis, the excess rate of the diastereomers was 88%de. These crystals (55 mg) were heated under reflux in ethanol (1.5 ml) for 0.5 hours and the mixture was stirred at room temperature overnight. The precipitate was filtered to obtain 48.1 mg of the crystals. As a result of HPLC analysis, the excess rate of the diastereomers was 95%de. These crystals (47 mg) were heated under reflux in methanol (2 ml) and water (1 ml) for 0.5 hours and the mixture was stirred at room temperature overnight. The precipitate was filtered to obtain 41.8 mg of the crystals. As a result of HPLC analysis, the excess rate of the diastereomers was 99%de. Specific rotation; [a]27D = -45.5 (c = 0.2 MeOH) Melting point: 178°C (decomposition) Elemental analysis value: in terms of C13H17N3OS • C26H18O8 Calcd. value: C, 64.90; H, 4.89; N, 5.84; S, 4.44 Found value: C, 64.65; H, 4.63; N, 5.65; S, 4.31 Example 8 (-)-4-{[(1-Propyl-1H-imidazol-5- yl)methyl]sulfinyl}phenylamine The racemate (200 mg) of (-)-4-{[(1-propyl-1H- imidazol-5-yl)methyl]sulfinyl)phenylamine and (2S, 3S)- di(1-naphthoyl)tartaric acid monohydrate (180.8 mg) were heated under reflux in ethyl acetate (1.5 ml) and methanol (4 ml) for about 0.5 hours and the resulting solution as such was allowed to stand at room temperature. The precipitate was filtered to obtain 223.6 mg of the crystals, As a result of HPLC analysis, the excess rate of the diastereomers was 92%de. These crystals (223 mg) were heated under reflux in methanol (13 ml) for 0.5 hours and the mixture was stirred at room temperature overnight. The precipitate was filtered to obtain 188.1 mg of the crystals. As a result of HPLC analysis, the excess rate of the diastereomers was 99%de. These crystals (187 mg) were metathesized in saturated sodium bicarbonate solution (5 ml) and water (5 ml) and the mixture was extracted three times with chloroform (about 15 ml). The chloroform layer was dried over anhydrous magnesium sulfate, and then concentrated to obtain 62.4 mg (yield: 31%) of the crystals, As a result of HPLC analysis, the excess rate of the enantiomers was 99%ee. H1-NMR (DMSO-d6) d; 0.78-0.82 (3H, t, J = 7.3Hz), 1.58-1.67 (2H, m), 3.72-3.76 (2H, t, J = 7.0Hz), 4.05-4.14 (2H, m) , 5.71 (2H, s), 6.54 (1H, s), 6.61-6.63 (2H, d, J = 7.6Hz), 7.14-7.16 (2H, d, J = 7.6Hz), 7.59 (1H, s) Melting point: 137 - 138°C Example 9 (-)-4-{[(1-Propyl-1H-imidazol-5- yl)methyl]sulfinyl}phenylamine • di-p-toluoyl-D-tartrate • monohydrate To a mixed solution of (2S, 3S)-2,3-bis[(4- methylbenzoyl)oxy]butane dicarboxylic acid (15.1 g) and 4- {[(1-propyl-1H-imidazole-5-yl) methyl] sulfinyl}phenylamine (10.3 g) in 1,2-dimethoxyethane (90 ml) was added dropwise water (90 ml) and the resulting mixture was stirred at room temperature overnight. The precipitated crystals were collected by filtration, washed with 50 v/v% aqueous 1,2- dimethoxyethane (30 ml), and dried under reduced pressure. The crystals were dissolved in 50v/v% aqueous acetonitrile (84 ml) with heating at 70°C and thereto was added water (42 ml) while keeping at the same temperature. The mixture was allowed to cool to room temperature, and stirred at room temperature overnight and subsequently at 0°C for 1 hour. The precipitated crystals were collected by filtration and washed with 75% aqueous acetonitrile (30 ml) that was cooled to 0°C. The obtained crystals were dried under reduced pressure to obtain 10.9 g (yield: 41.6%, 99.6%de) of the title compound as white crystals. Melting point: 134 - 136°C Elemental analysis value: in terms of C33H35N3O9S •1 H2O Theoretical value: C, 59.36; H, 5.59; N, 6.29; S, 4.80 Analytical value: C, 59.26; H, 5.67; N, 6.18; S, 4.77 Example 10 (-)-4-{[(1-Propyl-1H-imidazol-5- yl)methyl]sulfinyl}phenylamine (-)-4-{[(1-Propyl-1H-imidazol-5- yl)methyl]sulfinyl}phenylamine • di-p-toluoyl-D-tartrate monohydrate (5 g) was dissolved in a mixture of 3 N hydrochloric acid (10 ml) and ethyl acetate (20ml) and the aqueous layer was separated. The aqueous layer was adjusted to pH 9 with 6 N aqueous sodium hydroxide solution (5 ml), crystallized by adding seed crystals and the mixture was stirred at room temperature. The crystals were collected by filtration to obtain 1.88 g (yield: 95.4%) of the title compound as white powder. Example 11 (-)-4-{[(1-Propyl-1-H-imidazol-5- yl)methyl]sulfinyl}phenylamine and (R)-N-(3,5- dinitrobenzoyl)phenylglycine salt The racemate (50 mg) of 4-[[(l-propyl-1-H-imidazol-5- yl)methyl]sulfinyl]phenylamine and (R)-N-(3,5- dinitrobenzoyl)phenylglycine (65.6 mg) were dissolved in methanol (1.0 ml) and the resulting solution was allowed to stand at room temperature overnight. The precipitate was filtered to obtain 57.9 mg of the crystals. As a result of HPLC analysis, the excess rate of the diastereomers was 51%de. These crystals (57 mg) were dissolved in ethanol (1.5 ml) and the product was stirred at room temperature overnight. The precipitate was filtered to obtain 27.9 mg of the crystals. As a result of HPLC analysis, the excess rate of the diastereomers was 80%de. Example 12 (-)-4-{[(1-Propyl-1H-imidazol-5- yl)methyl]sulfenyl}phenylamine • di-p-toluoyl-D-tartrate • monohydrate 4-Aminothiophenol (2.5 g) was dissolved in water (2.5 ml) and isopropanol (10 ml), to the resulting solution was added triethylamine (5.5 ml) and the mixture was cooled to -15 to -10°C. To the mixture was added dropwise a solution of 5- (chloromethyl)-1-propyl-1H-imidazole hydrochloride (3.9 g) in water (2.5 ml) at -15 to -10°C and the resulting mixture was stirred at the same temperature for 1 hour. The isopropanol was distilled off under reduced pressure and to the residue was added methyl isobutyl ketone (25 ml) and the organic layer was washed with water. Activated carbon (0.1 g) was added to the organic layer and the mixture was stirred at room temperature for 10 minutes. The organic layer was concentrated and the concentrate was dissolved in methyl isobutyl ketone (30 ml). Separately, di-p-toluoyl-(D)-tartaric acid (7.7 g) was dissolved in a mixed solution of toluene (90 ml) and methyl isobutyl ketone (60 ml) and to the resulting solution was added water (3.6 ml). Subsequently, to the solution was slowly added dropwise the above-mentioned methyl isobutyl ketone solution over 2 hours. After stirring for 1 hour, to the mixture was added 30% hydrogen peroxide (6.8 g) and the resulting mixture was stirred at room temperature for 24 hours. To the mixture was added methanol (30 ml) and the resulting solution was stirred at 50°C for 8 hours. To the solution was added water (30 ml) and the resulting mixture was stirred at room temperature for 5 hours. The precipitated crystals were collected by filtration and washed with water (30 ml) to obtain 7.1 g (yield: 53%) of the title compound. Example 13 (-)-7-[4-(2-Butoxyethoxy)phenyl]-1-isobutyl-N-(4-{[(1- propyl-lH-imidazol-5-yl)methyl]sulfinyl}phenyl)-2,3- dihydro-1H-1-benzazepine-4-carboxamide (-)-4-{[(1-Propyl-1H-imidazol-5- yl)methyl]sulfinyl}phenylamine • di-p~toluoyl-D-tartrate • monohydrate (5 g) was dissolved in a mixture of 1 N hydrochloric acid (25 ml) and ethyl acetate (15 ml) and the aqueous layer was separated. The aqueous layer were made pH 9 by adding an aqueous 25% potassium carbonate (25 ml) and extracted three times with ethyl acetate - 2-propanol (4:1) (25 ml). The organic layer was washed with saturated brine (25 ml) and dried over magnesium sulfate. The solvent was distilled off to obtain (-)-4-{[(1-propyl- 1H-imidazol-5-yl)methyl]sulfinyl}phenylamine. Separately, to a solution of 7-[4-(2- butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1- benzazepine-4-carboxylic acid (2.56 g) in tetrahydrofuran (7.5 ml) was added N,N-dimethylformamide (one drop), and added dropwise oxalyl chloride (0.56 ml) at room temperature and the resulting solution was stirred for 1 hour to prepare an acid chloride. To a solution of (-)-4-{[(1-propyl-1H-imidazol-5- yl)methyl]sulfinyl)phenylamine in tetrahydrofuran (17.5 ml) was added triethylamine (2.85 ml)(the solution was almost clear) and added dropwise an acid chloride solution at room temperature, and the resulting solution was stirred for 1 hour. To the solution was added water (15 ml) and the mixture was extracted with ethyl acetate. The extract was sequentially washed with an aqueous 10% acetic acid solution, saturated sodium bicarbonate solution and 10% brine, and thereto were added basic silica gel (4 g), activated carbon (0.4 g) and sodium sulfate (2 g) and the mixture was stirred for 10 minutes and filtered, and the solvent was distilled off. To the residue was added tert- butyl methyl ether (20 ml) and added water (4 ml), and the resulting mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration to obtain tert-butyl methyl ether solvate (3.62 g, 80.3%) of the title compound. To the resulting product was added ethanol (3.5 ml) and dissolved therein at 40°C, and thereto was added tert-butyl methyl ether (31.5 ml) and the mixture was stirred for 14 hours under room temperature and stirred for 1 hour under ice-cooling. The crystals were collected by filtration to obtain tert-butyl methyl ether solvate (3.52 g, 78%, 99%ee) of the title compound as yellow powder. 1H-NMR (CDCl3, 300MHz) d; title compound : tert-butyl methyl ether =1 : 0.94; title compound: 0.84-0.97 (12H, m) , 1.28-1.42 (2H, m) , 1.53-1.75 (4H, m) 2.02-2.11 (1H, m), 2.88-2.94 (2H, m) , 3.17-3.21 (2H, m) , 3.33-3.37 (2H, m), 3.53 (2H, t, J = 6.6HZ), 3.71-3.81 (4H, m), 3.95-4.10 (2H, m), 4.13-4.16 (2H, m), 6.55 (1H, s), 6.90-6.98 (3H, m), 7.32 (2H, d, J = 8.7HZ), 7.43-7.47 (5H, m), 7.75 (2H, d, J = 8.7Hz), 8.32 (1H, s), NH undetected, tert-butyl methyl ether: 1.19 (9H, s), 3.21 (3H, s). Example 14 (-) -7-[4-(2-Butoxyethoxy)phenyl]-1-isobutyl-N-(4-{[(1- propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-2,3- dihydro-1H-1-benzazepine-4-carboxamide To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1- isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (2.56 g) in tetrahydrofuran (8 ml) was added N,N- dimethylformamide (one drop), and added dropwise oxalyl chloride (0.56 ml) under ice-cooling and the resulting solution was stirred for 1 hour to prepare an acid chloride To a solution of (-)-4-{[(1-propyl-1H-imidazol-5- yl)methyl]sulfinyl}phenylamine in tetrahydrofuran (18 ml) was added diisopropylethylamine (3.5 ml) and added dropwise the acid chloride solution at 10°C or lower, and the resulting solution was stirred for 2 hours. To the solution was added water (15 ml) and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with 10% aqueous acetic acid solution, saturated sodium bicarbonate solution and 10% brine, and thereto were added basic silica gel (4 g), activated carbon (0.4 g) and sodium sulfate (2 g) and the mixture was stirred for 10 minutes and filtered, and the solvent was distilled off. To the residue was added isopropyl acetate (15 ml) and the residue was dissolved therein with stirring at 40°C, and the resulting solution was stirred for 14 hours at room temperature. To the solution was added heptane (15 ml) and the mixture was stirred for 1 hour at room temperature, and then ice-cooled. The crystals were collected by filtration to obtain isopropyl acetate solvate (2.93 g) of the title compound. Subsequently, thereto was added isopropyl acetate (10 ml). After dissolution at 40°C, the solution was stirred for 4 hours at room temperature and stirred for 1 hour under ice-cooling. The crystals were collected by filtration, washed with isopropyl acetate (15 ml) and dried under reduced pressure to obtain isopropyl acetate solvate (2.8 g, 77.1%) of the title compound as yellow powder. 1H-NMR (CDCl3, 300MHz) 8; title compound : isopropyl acetate = 1 : 0.80; title compound: 0.84-0.97 (12H, m), 1.28-1.42 (2H, m), 1.53-1.75 (4H, m) 2.02-2.11 (1H, m) , 2.88-2.94 (2H, m) , 3.17-3.21 (2H, m) , 3.33-3.37 (2H, m), 3.53 (2H, t, J = 6.6HZ), 3.71-3.81 (4H, m), 3.95-4.10 (2H, m), 4.13-4.16 (2H, m), 6.55 (1H, s), 6.90-6.98 (3H, m), 7.32 (2H, d, J = 8.7HZ), 7.43-7.47 (5H, m), 7.75 (2H, d, J = 8.7Hz), 8.32 (1H, s), isopropyl acetate: 1.27 (6H, d, J = 6.3HZ), 2.06 (3H, s), 4.99-5.08 (1H, m) . Example 15 (-)-8-[4-(2-Butoxyethoxy)phenyl]-1-isobutyl-N-(4-{[(1- propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-1,2,3,4- tetrahydro-1-benzazocine-5-carboxamide • methanesulfonate 8-[4-(2-Butoxyethoxy)phenyl]-1-isobutyl-1,2,3,4- tetrahydro-1-benzazocine-5-carboxylic acid (986 mg) was dissolved in tetrahydrofuran (3 ml) and thereto was added N,N-dimethylformamide (one drop). Subsequently, to the resulting solution was added dropwise oxalyl chloride (0.2 ml, 2.29 mmol) under ice-cooling and the mixture was stirred for 80 minutes under ice-cooling to prepare an acid chloride. Separately, (-)-4-{[(1-propyl-1H-imidazol-5- yl)methyl]sulfinyl}phenylamine (689 mg) was added to tetrahydrofuran (7 ml) and the resulting solution was cooled to 5ºC. To the solution was added dropwise pyridine (0.62 ml) and added dropwise the acid chloride solution at 3 to 5°C, and the mixture was stirred for 2 hours under ice-cooling. To the mixture was added water (20 ml) at 10°C or lower and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water, saturated sodium bicarbonate solution and water, and concentrated under reduced pressure. Thereto was added toluene and the mixture was concentrated under reduced pressure. Thereto was added acetonitrile and the mixture was concentrated under reduced pressure. The residue was dissolved in acetonitrile (7 ml) and acetone (7 ml), thereto was added dropwise methanesulfonic acid (209 mg) , and added seed crystals and the mixture was stirred at room temperature for 100 minutes. Subsequently, to the mixture was added acetone - acetonitrile (1 : 1, 5 ml) . After stirring at room temperature overnight, the mixture was stirred for 2.5 hours under ice-cooling. The precipitated crystals were collected by filtration and washed with the ice-cooled acetone (9 ml). The crystals were dried at 40°C under reduced pressure to obtain 1.51 g (yield: 87%) of the title compound as yellow crystals. 1H-NMR (300MHz, DMSO-d6, d): 0.78-0.96 (12H, m) , 1.25-1.40 (2H, m), 1.41-1.51 (4H, m), 1.65-1.85 (2H, m), 2.05-2.15 (1H, m), 2.30 (3H, s), 2.35-2.50 (2H, m), 3.05-3.15 (2H, m) , 3.30-3.55 (4H, m) , 3.65-3.70 (2H, m), 3.90-4.05 (2H, m), 4.05-4.10 (2H, m), 4.30 (1H, d, J = 14.73Hz), 4.65 (1H, d, J = 14.73HZ), 6.85 (1H, d, J = 8.97Hz), 6.97 (1H, d, J = 8.79HZ), 7.17 (1H, s), 7.35-7.75 (6H, m), 7.92 (2H, d, J= 8.79HZ), 9.08 (1H, s), 10.15 (1H, s). Elemental analysis value: in terms of C41H52N4O4S • CH4SO3 Calcd. value: C, 63.61; H, 7.12; N, 7.06; S, 8.09 Found value: C, 63.65; H, 7.23; N, 7.05; S, 8.08 Example 16 (-)-8-[4-(2-Butoxyethoxy)]phenyl]-1-isobutyl-N-(4-{[(1- propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-1,2,3,4- tetrahydro-1-benzazocine-5-carboxamide • methanesulfonate To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1- isobutyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylic acid (5 g) in tetrahydrofuran (15 ml) was added N,N- dimethylformamide (one drop), added dropwise oxalyl chloride (1.1 ml) under ice-cooling and the mixture was stirred for 1 hour to prepare an acid chloride. Separately, to a solution of (-)-4-{[(1-propyl-1H- imidazol-5-yl)methyl]sulfinyl}phenylamine (3.22 g) in tetrahydrofuran (35 ml) was added diisopropylethylamine (6.7 ml) and added dropwise the acid chloride solution at 10°C or lower, and the resulting mixture was stirred for 1 hour. To the mixture were added water (50 ml) and toluene (50 ml), and the mixture was adjusted to about pH 4 by adding acetic acid (about 8 ml) and separated into layers. The organic layer was washed with saturated sodium bicarbonate solution to adjust to pH 7 to 8, washed with 10% brine, and then thereto were added basic silica gel (4 g), activated carbon (0.5 g) and sodium sulfate (2 g) and the mixture was stirred for 10 minutes and filtered, and washed with toluene (20 ml). The solvent was distilled off and the residue was dissolved in methyl isobutyl ketone (15 ml) and thereto was added methanesulfonic acid (0.65 ml), and added seed crystals (80 mg) and the mixture was stirred for 16 hours. To the mixture was added methyl isobutyl ketone - ethyl acetate (1 : 1, 50 ml), and the resulting mixture was stirred for 2 hours under ice-cooling. The crystals were collected by filtration and dried at 40°C under reduced pressure to obtain 6.62 g of yellow powder. These crystals were suspended in methyl isobutyl ketone (40 ml) and the suspension was stirred for 16 hours, and then thereto was added ethyl acetate (40 ml) and the resulting solution was stirred at room temperature for 1 hour and stirred for 2 hours under ice-cooling. The crystals were collected by filtration to obtain 6.05 g (yield: 68.7%) of the title compound as yellow powder. Example 17 (-)-4-{[(1-Propyl-1H-imidazol-5- yl)methyl] sulfinyl}phenylamine • di-p-toluoyl-D-tartrate • monohydrate To a solution of di-p-toluoyl-D-tartaric acid (1.9 g) in toluene (15 ml) and methyl isobutyl ketone (30 ml) was added a solution of 4-{[(1-propyl-1H-imidazol-5- yl)methyl]thio}phenylamine (1.2 g) in methyl isobutyl ketone (15 ml). Subsequently, to the resulting mixture was added 30% hydrogen peroxide (1.7 g) and the mixture was stirred at room temperature for 3 weeks. The precipitated crystals were collected by filtration. The obtained crystals were dried until they became constant weight to obtain 2.9 g (yield: 87%, 82.7%de) of the title compound. The crystals were added to acetonitrile/water (9 ml/9 ml) and the mixture was stirred at 60°C for 0.5 hours, and thereto was added dropwise water (9 ml). The mixture was stirred at the same temperature for 0.5 hours, stirred at room temperature for 1 hour, and stirred for 1 hour under ice-cooling. The precipitated crystals were collected by filtration and washed with ice-cooled acetonitrile/water (4 ml/2 ml). The obtained crystals were dried until they became constant weight to obtain 2.4 g (yield: 72%, 98.1%de) of the title compound. Example 18 (+)-4-{[(1-Propyl-1H-imidazol-5- yl)methyl]sulfinyl}phenylamine To a mixture of 4-{[(1-propyl-1H-imidazol-5- yl)methyl]thio}phenylamine (0.99 g) and (R) - (-)-1, 1'- binapthyl-2,2'-diyl hydrogenphosphate (0.14 g) in dichloromethane (5 ml) was added 30% hydrogen peroxide (0.14 g) and the mixture was stirred at room temperature for 6 hours. A portion of the reaction solution was sampled and analyzed by high performance liquid chromatography (HPLC). Conversion rate: 52%, Optical purity: 35.0%ee. HPLC condition: Column: Chiralcel (Daicel) OD Mobile phase: Hexane - ethanol (85 : 15) Flow rate: 1 ml/min Temperature: 35°C (+)-isomer: 21 min, (-)-isomer: 27 min Example 19 (-)-8-[4-(2-Butoxyethoxy)phenyl]-1-isobutyl-N-(4-{[(1- propy1-1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-1,2,3,4- tetrahydro-1-benzazocine-5- carboxamide • methanesulfonate To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1- isobutyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylic acid (90 g) in tetrahydrofuran (7.5 ml) was added N,N- dimethylformamide (4 60 mg) and then added dropwise thionyl chloride (24.9 g) at 10 to 15°C, and the resulting solution was stirred at the same temperature for 40 minutes to prepare an acid chloride. Separately, to a solution of (-)-4-{[(1-propyl-1H- imidazol-5-yl)methyl]sulfinyl}phenylamine in tetrahydrofuran (540 ml) was added pyridine (55.18 g) , the resulting solution was adjusted to 5°C or lower, and then thereto was added dropwise the acid chloride solution at 5°C or lower, and the resulting mixture was stirred at the same temperature for 2.8 hours. To the mixture were added water (540 ml) and 20% aqueous citric acid solution (360 ml), tetrahydrofuran was distilled off under reduced pressure and the residue was extracted with ethyl acetate. The extract was sequentially washed with water, saturated sodium bicarbonate solution and water, and then the solvent was distilled off. To the residue was added acetonitrile (720 ml) and ethyl acetate (720 ml) and added dropwise methanesulfonic acid (18.2 g), and the resulting mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration to obtain 141.8 g (yield: 94.4%) of the title compound as yellow crystals. Example 20 (-)-8-[4-(2-Butoxyethoxy)phenyl]-1-propyl-N-(4-{[(1-propyl- 1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-1,2,3,4- tetrahydro-1-benzazocine-5-carboxamide • methanesulfonate According to the same method as that described in Example 15, the title compound was produced from 8-[4-(2- butoxyethoxy)phenyl]-1-propyl-1,2,3,4-tetrahydro-1- benzazocine-5-carboxylic acid and (-)-4-{[(1-propyl-1H- imidazol-5-yl) methyl]sulfinyl}phenylamine. 1H-NMR (CDCl3, d, 300MHz) 0.88-1.01 (9H, m), 1.37-1.42 (2H, m), 1.57-1.80 (8H, m), 2.63 (2H, br) , 2.77 (3H, s), 3.27 (2H, br), 3.51-3.57 (4H, m), 3.77-3.86 (4H, m), 3.90-4.05 (1H, m), 4.14 (2H, t, J = 4.6Hz), 4.25 (1H, d, J = 14.6Hz), 6.73 (1H, s), 6.84 (1H, d, J = 8.7Hz), 6.93 (2H, d, J = 8.8HZ), 7.21 (2H, d, J = 8.7Hz), 7.40-7.48 (4H, m), 7.61 (1H, s), 7.89 (2H, d, J = 8.7HZ), 8.65 (1H, s) , 9.27 (1H, br) Elemental analysis value: in terms of C41H54N4O7S2 Calcd. value: C, 63.21; H, 6.99; N, 7.19; S, 8.23 Analytical value: C, 63.00; H, 7.09; N, 7.41;, S, 8.25 Example 21 (-)-8-[4-(2-Butoxyethoxy)phenyl]-1-isobutyl-N-(4-{[(1- propyl -1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-1,2,3,4- tetrahydro-1-benzazocine-5-carboxamide To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1- isobutyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylic acid (45 g) in tetrahydrofuran (135 ml) was added N,N- dimethylformamide (230 mg) and added dropwise thionyl chloride (12.45 g) at 10 to 15°C, and the resulting solution was stirred at the same temperature for 4 0 minutes to prepare an acid chloride. Separately, to a solution of (-)-4-{[(1-propyl-1H- imidazol-5-yl)methyl]sulfinylJphenylamine in tetrahydrofuran (270 ml) was added pyridine (27.59 g), the resulting mixture was adjusted to 5°C or lower, and then thereto was added dropwise the acid chloride solution at 5°C or less, and the resulting mixture was stirred at the same temperature for 2 hours. To the mixture were added water (270 ml) and 20% aqueous citric acid solution (180 ml) , tetrahydrofuran was distilled off under reduced pressure and the residue was extracted with ethyl acetate. The extract was sequentially washed with water, saturated sodium bicarbonate solution and water, and then the solvent was distilled off. To the residue was added ethyl acetate (360 ml) , added heptane (360 ml) at 40°C and added seed crystals of (-)-8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N- (4-{[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenyl)- 1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide (10 mg) , and the mixture was stirred at 25°C for 2 hours and stirred at 5°C for 1 hour. The precipitated crystals were collected by filtration to obtain 63.97 g (yield: 92.1%) of the title compound. Melting point: 120 - 122°C. Elemental analysis value: in terms of C41H52N4O4S Calcd. value: C, 70.66; H, 7.52; N, 8.04 Analytical value: C, 70.42; H, 7.52; N, 8.01 Industrial Applicability According to the present invention, an optically active sulfoxide derivative having CCR5 antagonism or an intermediate compound thereof can be prepared without causing side reactions such as racemization and Pummerer rearrangement. In particular, Process 7 is industrially advantageous since it is possible to prepare an optically active Compound (II) by asymmetric oxidization in the presence of an optically active acid. WE CLAIM; 1. A process for preparing an optically active compound represented by the formula (I): wherein R1 represents a hydrogen atom, an aliphatic hydrocarbon group selected from the group consisting of a C1-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, a C3-7 cycloalkyl group and a C3-7 cycloalkenyl group, each of said alkyl, alkenyl and alkynyl groups optionally being substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a C1-4 alkoxy group, a thiol group, a C1-4 alkylthio group, an amino group, a mono-C1-4 alkylamino group, a di-C1- 4 alkylamino group, a 5- or 6-membered cyclic amino group, imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkoxy group, an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group, and each of said cycloalkyl and cycloalkenyl groups optionally being substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, a C1-4 alkylthio group, an amino group, a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6-membered cyclic amino group, imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkoxy group, an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group, or an aromatic group selected from the group consisting of a 5- or 6-membered homo- or heterocyclic aromatic group and a condensed heterocyclic aromatic group which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, a C1-4 alkylthio group, an amino group, a mono-C1-4 alkylamino group, a di-C1- 4 alkylamino group, a 5- or 6- membered cyclic amino group, imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkyl group, an optionally halogenated C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group; R2 represents (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) a C1-10 alkyl group which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a C1-4 alkoxy group, a thiol group, a C1-4 alkylthio group, an amino group, a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6- membered cyclic amino group, imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkoxy group, an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group, (5) a C3-7 cycloalkyl group which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, a C1-4 alkylthio group, an amino group, a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6-membered cyclic amino group, imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkoxy group, an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group, (6) hydroxyl group which may be substituted with a substituent selected from the group consisting of a C1-10 alkyl group a C3-7 cycloalkyl group, a saturated 5- to 6- membered heterocyclic ring group containing 1 to 2 heteroatoms, a C2-10 alkenyl group, a C3-7 cycloalkenyl group, a phenyl-C1-4 alkyl group, a formyl group, a C2-4 alkanoyl group, a C1-4 alkylsulfonyl group, a phenyl group, and a naphthyl group each of which may be substituted with a substituent selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, a C1-4 alkylthio group, an amino group, a mono- C1-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6- membered cyclic amino group, imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkyl group, an optionally halogenated C1-6 alkoxy group, a formyl group, a C2-4 alkanoyl group, a C1-4 alkylsulfonyl group, and a 5- to 6- membered aromatic heterocycle, which contains 1 to 4 heteroatoms of 1 to 2 kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom and may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, an amino group, a carboxyl group, an optionally halogenated C1-4 alkyl group, an optionally substituted C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group, (7) a thiol group (the sulfur atom may be oxidized to form a sulfinyl group or a sulfonyl group) which may be substituted with a substituent selected from the group consisting of a C1-10 alkyl group a C3-7 cycloalkyl group, a saturated 5- to 6- membered heterocyclic ring group containing 1 to 2 heteroatoms, a C2-10 alkenyl group, a C3-7 cycloalkenyl group, a phenyl-C1-4 alkyl group, a formyl group, a C2-4 alkanoyl group, a C1-4 alkylsulfonyl group, a phenyl group, and a naphthyl group each of which may be substituted with a substituent selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, a C1-4 alkylthio group, an amino group, a mono- C1-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6- membered cyclic amino group, imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbaraoyl group, an optionally halogenated C1-4 alkyl group, an optionally halogenated C1-6 alkoxy group, a formyl group, a C2-4 alkanoyl group, a C1-4 alkylsulfonyl group, and a 5- to 6- membered aromatic heterocycle, which contains 1 to 4 heteroatoms of 1 to 2 kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom and may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, an amino group, a carboxyl group, an optionally halogenated C1-4 alkyl group, an optionally substituted C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group, (8) an amino group which may be substituted with 1 or 2 substituents selected from the group consisting of a C1-10 alkyl group, a C3-7 cycloalkyl group, a saturated 5- to 6-membered heterocyclic ring group containing 1 to 2 heteroatoms, a C2- 10 alkenyl group, a C3-7 cycloalkenyl group, a phenyl-C1-4 alkyl group, a formyl group, a C2-4 alkanoyl group, a C1-4 alkylsulfonyl group, a phenyl group, and a naphthyl group each of which may be substituted with a substituent selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, a C1-4 alkylthio group, an amino group, a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6- membered cyclic amino group, imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkyl group, an optionally halogenated C1-6 alkoxy group, a formyl group, a C2-4 alkanoyl group, a C1-4 alkylsulfonyl group, and a 5- to 6- membered aromatic heterocycle, which contains 1 to 4 heteroatoms of 1 to 2 kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom and may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, an amino group, a carboxyl group, an optionally halogenated C1-4 alkyl group, an optionally substituted C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group, or these two substituents may bond each other to form a 5- or 6-membered cyclic amino group or imidazole having a bond on the nitrogen atom and optionally substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, a C1-4 alkylthio group, an amino group, a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6-membered cyclic amino group, imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkoxy group, an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group, (9) an acyl group formed by bonding (a) hydrogen, (b) a C1-10 alkyl group, (c) a C3-7 cycloalkyl group, (d) a C2-10 alkenyl group, (e) a C3-7 cycloalkenyl group, or (f) a 5- to 6-membered monocycle aromatic group with a carbonyl group or a sulfonyl group which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, a C1-4 alkylthio group, an amino group, a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6-membered cyclic amino group, imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkoxy group, an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group, (10) a group formed by bonding (a) hydrogen; (b) a C1-10 alkyl group, (c) a C3-7 cycloalkyl group, (d) a C2-10 alkenyl group, (e) a C3-7 cycloalkenyl group, (6) phenyl or (7) naphthyl with a carbonyloxy group which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, a C1-4 alkylthio group, an amino group, a mono-C1-4 alkylamino group, a di-1- 4 alkylamino group, a 5- or 6-membered cyclic amino group, imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkoxy group, an optionally halogenated C1-4 alkoxy-Ci_4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group, or (12) an aromatic group selected from the group consisting of a 5- or 6-membered homo- or heterocyclic aromatic group and a condensed heterocyclic aromatic group which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, a C1-4 alkylthio group, an amino group, a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6- membered cyclic amino group, imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkyl group, an optionally halogenated C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group; R3 represents a 5- or 6-membered cyclic ring formed by removing one hydrogen atom from a 6-membered aromatic hydrocarbon, a 5- to 6-membered aliphatic hydrocarbon, a 5- to 6-membered aromatic heterocycle containing 1 to 4 heteroatoms of 1 to 2 kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom, or a 5- to 6-membered non-aromatic heterocycle containing 1 to 4 heteroatoms of 1 to 2 kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom, which may be substituted with 1 to 3 substituents selected from the group consisting of (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) a C1-10 alkyl group which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, a C1-4 alkylthio group, an amino group, a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6-membered cyclic amino group, imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkoxy group, an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group, (5) a C3-7 cycloalkyl group which may be substituted with 1 to 3 substituents selected from a group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, a C1-4 alkylthio group, an amino group, a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6-membered cyclic amino group, imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkoxy group, an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group, (6) a hydroxyl group which may be substituted with a substituent selected from the group consisting of (a) a C1-10 alkyl group, (b) a C3-7 cycloalkyl group,, (c) a saturated 5- to 6-membered heterocyclic group containing 1 to 2 heteroatoms, (d) a C2-10 alkenyl group, (e) a C3-7 cycloalkenyl group, (f) a phenyl-C1-4 alkyl group, (g) a formyl group, (h) a C2-4 alkanoyl group, (i) a C1-4 alkylsulfonyl group, (j) a phenyl group and (k) a naphthyl group, each of which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, a C1-4 alkylthio group, an amino group, a mono-Ci-4 alkylamino group, a di-C1-4 alkylamino grouop, a 5- or 6-membered cyclic amino group, imidazole, a carboxyl group, a c1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkyl group, an optionally halogenated C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group, a C1-4 alkylsulfonyl group, and a 5- to 6-membered aromatic heterocycle containing 1 to 4 heteroatoms of 1 to 2 kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom and may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, an amino group, a carboxyl group, an optionally halogenated C1-4 alkyl group, a C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group (7) a thiol group (the sulfur atom may be oxidized to form a sulfinyl group or a sulfonyl group) which may be substituted with a substituent selected from the group consisting of a C1-10 alkyl group a C3-7 cycloalkyl group, a saturated 5- to 6-membered heterocyclic ring group containing 1 to 2 heteroatoms, a C2-10 alkenyl group, a C3-7 cycloalkenyl group, a phenyl-C1-4 alkyl group, a formyl group, a C2-4 alkanoyl group, a C1-4 alkylsulfonyl group, a phenyl group, and a naphthyl group each of which may be substituted with a substituent selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, a C1-4 alkylthio group, an amino group, a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6-membered cyclic amino group, imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkyl group, an optionally halogenated C1-6 alkoxy group, a formyl group, a C2-4 alkanoyl group, a C1-4 alkylsulfonyl group, and a 5- to 6-membered aromatic heterocycle, which contains 1 to 4 heteroatoms of 1 to 2 kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom and may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, an amino group, a carboxyl group, an optionally halogenated C1-4 alkyl group, an optionally substituted C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group, (8) an amino group which may be substituted with 1 or 2 substituents selected from the group consisting of a C1-10 alkyl group, a C3-7 cycloalkyl group, a saturated 5- to 6- membered heterocyclic ring group containing 1 to 2 heteroatoms, a C2-10 alkenyl group, a C3-7 cycloalkenyl group, a phenyl-C1-4 alkyl group, a formyl group, a C2-4 alkanoyl group, a C1-4 alkylsulfonyl group, a phenyl group, and a naphthyl group each of which may be substituted with a substituent selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, a C1-4 alkylthio group, an amino group, a mono- C1-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6- membered cyclic amino group, imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkyl group, an optionally halogenated C1-6 alkoxy group, a formyl group, a C2-4 alkanoyl group, a C1-4 alkylsulfonyl group, and a 5- to 6- membered aromatic heterocycle, which contains 1 to 4 heteroatoms of 1 to 2 kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom and may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, an amino group, a carboxyl group, an optionally halogenated C1-4 alkyl group, an optionally substituted C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group, or these two substituents may bond each other to form a 5- or 6-membered cyclic amino group or imidazole having a bond on the nitrogen atom and optionally substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, a C1-4 alkylthio group, an amino group, a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6-membered cyclic amino group, imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkoxy group, an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group, (9) an acyl group formed by bonding (a) hydrogen, (b) a C1-10 alkyl group, (c) a C3-7 cycloalkyl group, (d) a C2-10 alkenyl group, (e) a C3-7 cycloalkenyl group, or (f) a 5- to 6-membered monocycle aromatic group with a carbonyl group or a sulfonyl group which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, a C1-4 alkylthio group, an amino group, a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6-membered cyclic amino group, imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkoxy group, an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group, (10) a group formed by bonding (a) hydrogen; (b) a C1-10 alkyl group, (c) a C3-7 cycloalkyl group, (d) a C2-10 alkenyl group, (e) a C3-7 cycloalkenyl group, (f) phenyl or (g) naphthyl with a carbonyloxy group which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, a C1-4 alkylthio group, an amino group, a mono-C1-4 alkylamino group, a di-C1- 4 alkylamino group, a 5- or 6-membered cyclic amino group, imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkoxy group, an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group, or (11) an aromatic group selected from the group consisting of a 5- or 6-membered homo- or heterocyclic aromatic group and a condensed heterocyclic aromatic group which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, a C1-4 alkylthio group, an amino group, a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6- membered cyclic amino group, imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkyl group, an optionally halogenated C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group, or two of these substituents may bond each other to form a C1-6 alkylene group, a C1-6 alkyleneoxy group, a C1-6 alkylene thio group, a C1-6 alkylenedioxy group, a C1-6 alkylenedithio group, an oxy-C1-6 alkylene amino group, an oxy-C1-6 alkylene thio group, a C1-6 alkylene amino group, a C1-6 alkylene diamino group, a thia-C1-6 alkylene amino group, a C2-6 alkenylene group or a C4-6 alkadienylene group, which may be substituted with the same 1 to 3 substituents as the above substituents (1) to (11); R4 represents a hydrogen atom, a C1-4 alkyl group, a C1-6 alkoxy group or a halogen atom, said alkyl or alkoxy group being optionally substituted with a halogen atom, a hydroxyl group, an amino group, a mono-(C1-6 alkyl) amino group, a di-(C1-6 alkyl) amino group and a C2-6 alkanoyl group; R5 represents a hydrogen atom, a hydrocarbon group selected from the group consisting of (1) a C1-10 alkyl group, (2) a C3-7 cycloalkyl group, (3) a C2-10 alkenyl group, (4) a C3-7 cycloalkenyl group, (5) a C2-10 alkynyl group, (6) a phenyl-C1-4 alkyl group, (7) a phenyl group, (8) a naphthyl group and (9) a C3-7 cycloalkyl-C1-4 alkyl group, each of which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, a C1-4 alkylthio group, an amino group, a mono-C1-4 alkylaitiino group, a di-C1- 4 alkylamino group, a 5- or 6-membered cyclic amino group, imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkyl group, an optionally halogenated C1-4 alkoxy group, a C1-4 alkylenedioxy group, a group formed by bonding an amino group, a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6-membered cyclic amino group or imidazole - SO2-, a formyl group, a C2-4 alkanoyl group, a C1-4 alkylsulfonyl and a heterocyclic group, a group formed by removing one hydrogen atom from a 5- or 6-membered, aromatic heterocycle 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, a 5- or 6-membered non- aromatic heterocycle containing 1 to 4 of 1 or 2 kinds of hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, or a non-aromatic heterocycle which a part or all of the bonds of the above-described aromatic heterocycle is saturated bonds, a sulfonyl group which may be substituted with a substituent selected from the group consisting of a C1-10 alkyl group a C3-7 cycloalkyl group, a saturated 5- to 6- membered heterocyclic ring group containing 1 to 2 heteroatoms, a C2-10 alkenyl group, a C3-7 cycloalkenyl group, a phenyl-C1-4 alkyl group, a formyl group, a C2-4 alkanoyl group, a C1-4 alkylsulfonyl group, a phenyl group, and a naphthyl group each of which may be substituted with a substituent selected from the group consisting of a halogen atom,- a nitro group, a cyano group, a hydroxyl group, a thiol group, a C1-4 alkylthio group, an amino group, a mono- Ci-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6- membered cyclic amino group, imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkyl group, an optionally halogenated C1-6 alkoxy group, a formyl group, a C2-4 alkanoyl group, a C1-4 alkylsulfonyl group, and a 5- to 6- membered aromatic heterocycle, which contains 1 to 4 heteroatoms of 1 to 2 kinds selected from a nitrogen atom, a sulfur atom and an oxygen atom and may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, an amino group, a carboxyl group, an optionally halogenated C1-4 alkyl group, an optionally substituted C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group, a group formed by bonding (a) hydrogen; (b) a C1-10 alkyl group, (c) a C3-7 cycloalkyl group, (d) a C2-10 alkenyl group, (e) a C3-7 cycloalkenyl group, (f) phenyl or (g) naphthyl with a carbonyloxy group which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, a C1-4 alkylthio group, an amino group, a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6-membered cyclic amino group, imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkoxy group, an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group, or an acyl group formed by bonding (a) hydrogen, (b) a C1-10 alkyl group, (c) a C3-7 cycloalkyl group, (d) a C2-10 alkenyl group, (e) a C3-7 cycloalkenyl group, or (f) a 5- to 6-membered monocycle aromatic group with a carbonyl group or a sulfonyl group which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a nitro group, a cyano group, a hydroxyl group, a thiol group, a C1-4 alkylthio group, an amino group, a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6-membered cyclic amino group, imidazole, a carboxyl group, a 1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an optionally halogenated C1-4 alkoxy group, an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group, a formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group; X represents (1) a bond, (2) a group represented by - (CH2)a'- , wherein a' is an integer of 1 to 4, (3) a group represented by - (CH2)b'-x1-, wherein b' is an integer of 0 to 3, and X1 is an imino group which may be substituted with C1-6 alkyl, C3-7 cycloalkyl, formyl, C2-7 alkanoyl or C1-6 alkoxycarbonyl, a carbonyl group, an oxygen atom or -S(O)m-, wherein m is an integer of 0 to 2, (4) -CH=CH-, (5) -C=C-, (6) -CO-NH- or (6) -SO2-NH-, such group may bond with a condensed ring by either of a bond on the left and a bond on the right; the ring A represents a benzene ring which may be substituted with a halogen atom, a C1-4 alkyl group which may be substituted with a halogen atom or a C1-4 alkoxy group which may be substituted with a halogen atom; m is an integer of 1 to 5; n represents an integer of 0 to 3; p represents an integer of 0 to 2; and 1 represents an asymmetric center, or a salt thereof, which comprises reacting a compound represented by the formula (IV): wherein the ring A is as defined above, or a salt thereof, with a compound represented by the formula (VI): wherein Y represents a halogen atom or a group represented by the formula -OSO2-R9 wherein R9 represents a lower alkyl group or an optionally substituted aryl group; and the other symbols are as defined above, or a salt thereof, to obtain a compound represented by the formula (X) oxidizing the compound represented by the formula (X) or a salt in the presence of an optically active compound represented by the formula (XIIa): wherein R6 represents a methyl group, a phenyl group, a 4-methylphenyl group or a a-naphthyl group; and 2 represents an asymmetric center, or an acid which is optically active with respect to axial asymmetry, and represented by the formula (XIIc): to obtain an optically active compound represented by the formula (II) wherein each symbol is as defined above, reacting the compound represented by the formula II or a salt thereof, with a compound represented by the formula (III) : wherein each symbol is as defined above, a salt thereof, or a reactive derivative thereof. 2. An optically active compound represented by the formula (II): wherein R1 represents a hydrogen atom, an optionally substituted aliphatic hydrocarbon group or an optionally substituted aromatic group; R2 represents a halogen atom, a nitro group, a cyano group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group (the sulfur atom may be oxidized to form a sulfinyl group that may be substituted or a sulfonyl group that may be substituted), an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified carboxyl group or an optionally substituted aromatic group; the ring A represents a benzene ring which may be substituted with a halogen atom, a C1-4 alkyl group which may be substituted with a halogen atom or a C1-4 alkoxy group which may be substituted with a halogen atom; n represents an integer of 0 to 3; p represents an integer of 0 to 2; and 1 represents an asymmetric center, or a salt thereof. 3. The optically active compound according to claim 2, wherein R1 and R2 each represents a C1-6 alkyl group; and n represents 1 or 2, or a salt thereof. 4. The optically active compound according to claim 2, wherein R1 represents a C1-6 alkyl group; p represents 0; n represents 1; and 5. Process as claimed in claim 1 wherein the optically active compound, represented by the formula (II), wherein R1 represents a hydrogen atom/ an optionally substituted aliphatic hydrocarbon group or an optionally substituted aromatic group; R2 represents a halogen atom, a nitro group, a cyano group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group (the sulfur atom may be oxidized to form a sulfinyl group that may be substituted or a sulfonyl group that may be substituted), an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified carboxyl group or an optionally substituted aromatic group; the ring A represents a benzene ring which may be substituted with a halogen atom, a C1-4 alkyl group which may be substituted with a halogen atom or a C1-4 alkoxy group which may be substituted with a halogen atom; n represents an integer of 0 to 3; p represents an integer of 0 to 2; and 1 represents an asymmetric center, or a salt thereof is prepared by a process which comprises subjecting an optically active compound represented by the formula (XIa) wherein R6 represents a methyl group, a phenyl group, a 4-methylphenyl group or a a-naphthyl group; 2 represents an asymmetric center; and the other symbols are as defined above, or an optically active compound represented by the formula (XIb): wherein R7 represents a hydrogen atom, a chlorine atom or a nitro group; and the other symbols are as defined above, to a metathesis reaction. 6. An optically active compound represented by the formula (XIa) : wherein R represents a hydrogen atom, an optionally substituted aliphatic hydrocarbon group or an optionally substituted aromatic group; R2 represents a halogen atom, a nitro group, a cyano group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group (the sulfur atom may be oxidized to form a sulfinyl group that may be substituted or a sulfonyl group that may be substituted), an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified carboxyl group or an optionally substituted aromatic group; R6 represents a methyl group, a phenyl group, a 4- methylphenyl group or a a-naphthyl group; the ring A represents a benzene ring which may be substituted with a halogen atom, a C1-4 alkyl group which may be substituted with a halogen atom or a C1-4 alkoxy group which may be substituted with a halogen atom; n represents an integer of 0 to 3; p represents an integer of 0 to 2; and 1 and 2 each represents an asymmetric center, or an optically active compound represented by the formula (XIb): wherein R7 represents a hydrogen atom, a chlorine atom or a nitro group; and the other symbols are as defined above. 7. The optically active compound according to 6, wherein R1 and R2 each represents a C1-6 alkyl group; n represents 1 or 2; and R6 represents a 4-methylphenyl group or R7 represents a nitro group. 8. The optically active compound according to 7, wherein R1 represents a C1-6 alkyl group; p represents 0; n represents 1; 9. A process as claimed in claim 1 wherein the optically active compound represented by the formula (II): wherein R1 represents a hydrogen atom, an optionally substituted aliphatic hydrocarbon group or an optionally substituted aromatic group; R2 represents a halogen atom, a nitro group, a cyano group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group (the sulfur atom may be oxidized to form a sulfinyl group that may be substituted or a sulfonyl group that may be substituted), an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified carboxyl group or an optionally substituted aromatic group; the ring A represents a benzene ring which may be substituted with a halogen atom, a C1-4 alkyl group which may be substituted with a halogen atom or a C1-4 alkoxy group which may be substituted with a halogen atom; n represents an integer of 0 to 3; p represents an integer of 0 to 2; and 1 represents an asymmetric center, or a salt thereof, is prepared by subjecting a compound represented by the formula (X): wherein each symbol is as defined above, or a salt thereof to oxidation to obtain a compound representated by the formula (IX) wherein each symbol is as defined above, and subjecting the compound of formula IX or a salt thereof, to optical resolution with an optically active compound represented by the formula (XIIa): wherein each symbol is as defined above,and R6 represents a methyl group, a phenyl group, a 4- methylphenyl group or a a-naphthyl group;and 2 represents an asymmetric center, or an optically active acid represented by the formula (XIIb): wherein each symbol is as defined above and wherein R7 represents a hydrogen atom, a chlorine atom or a nitro group; to obtain a compound represented by the formula (XIa) : followed by subjecting the compound represented by the formula (XIa)or (XIb)to a metathesis reaction. 10. A compound represented by the formula (IX'): wherein R1' represents an optionally substituted aliphatic hydrocarbon group or an optionally substituted aromatic group; R2 represents a halogen atom, a nitro group, a cyano group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group (the sulfur atom may be oxidized to form a sulfinyl group that may be substituted or a sulfonyl group that may be substituted) , an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified carboxyl group or an optionally substituted aromatic group; the ring A represents a benzene ring which may be substituted with a halogen atom, a C1-4 alkyl group which may be substituted with a halogen atom or a C1-4 alkoxy group which may be substituted with a halogen atom; n represents an integer of 0 to 3; and p represents an integer of 0 to 2, or a salt thereof. 11. A process as claimed in claim 9 wherein the compound represented by the formula (IX): wherein R1 represents a hydrogen atom, an optionally substituted aliphatic hydrocarbon group or an optionally substituted aromatic group; R2 represents a halogen atom, a nitro group, a cyano group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group (the sulfur atom may be oxidized to form a sulfinyl group that may be substituted or a sulfonyl group that may be substituted) , an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified carboxyl group or an optionally substituted aromatic group; the ring A represents a benzene ring which may be substituted with a halogen atom, a C1-4 alkyl group which may be substituted with a halogen atom or a C1-4 alkoxy group which may be substituted with a halogen atom; n represents an integer of 0 to 3; and p represents an integer of 0 to 2, or a salt thereof, is prepared by reacting a compound represented by the formula (V): wherein R8 represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group or -OR10 wherein R10 represents an optionally substituted lower alkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group; and the other symbols are as defined above,or a salt thereof, with a compound represented by the formula (VI): wherein Y represents a halogen atom or a group represented by the formula -OSO2-R9 wherein R9 represents a lower alkyl group or an optionally substituted aryl group; and the other symbols are as defined above, or a salt thereof to obtain a compound represented by the formula (VII) oxidizing the compound represented by the formula (VII) or a salt thereof to obtain a compound represented by the formula (VIII): wherein R8 represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group or -OR10 wherein R10 represents an optionally substituted lower alkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group; and the other symbols are as defined above, or a salt thereof, to a deprotection reaction. 12. A compound represented by the formula (VIII): wherein R1 represents a hydrogen atom, an optionally substituted aliphatic hydrocarbon group or an optionally substituted aromatic group; R2 represents a halogen atom, a nitro group, a cyano group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group (the sulfur atom may be oxidized to form a sulfinyl group that may be substituted or a sulfonyl group that may be substituted), an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified carboxyl group or an optionally substituted aromatic group; R8 represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group or -OR10 wherein R10 represents an optionally substituted lower alkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group; the ring A represents a benzene ring which may be substituted with a halogen atom, a C1-4 alkyl group which may be substituted with a halogen atom or a C1-4 alkoxy group which may be substituted with a halogen atom; n represents an integer of 0 to 3; and p represents an integer of 0 to 2, or a salt thereof. 13. A process as claimed in claim 11 wherein the compound represented by the formula (VIII): wherein R1 represents a hydrogen atom, an optionally substituted aliphatic hydrocarbon group or an optionally substituted aromatic group; R2 represents a halogen atom, a nitro group, a cyano group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group (the sulfur atom may be oxidized to form a sulfinyl group that may be substituted or a sulfonyl group that may be substituted), an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified carboxyl group or an optionally substituted aromatic group; R8 represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group or -OR10 wherein R10 represents an optionally substituted lower alkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group; the ring A represents a benzene ring which may be substituted with a halogen atom, a C1-4 alkyl group which may be substituted with a halogen atom or a C1-4 alkoxy group which may be substituted with a halogen atom; n represents an integer of 0 to 3; and p represents an integer of 0 to 2, or a salt thereof, is prepared by oxidizing a compound represented by the formula (VII): wherein each symbol is as defined above, or a salt thereof. 14.A compound represented by the formula (VII1): wherein R1 represents a hydrogen atom, an optionally substituted aliphatic hydrocarbon group or an optionally substituted aromatic group; R2' represents a halogen atom, a cyano group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group (the sulfur atom may be oxidized to form a sulfinyl group that may be substituted or a sulfonyl group that may be substituted), an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified carboxyl group or an optionally substituted aromatic group; R8 represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group or -OR10 wherein R10 represents an optionally substituted lower alkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group; the ring A represents a benzene ring which may be substituted with a halogen atom, a C1-4 alkyl group which may be substituted with a halogen atom or a C1-4 alkoxy group which may be substituted with a halogen atom; n represents an integer of 0 to 3; and p represents an integer of 0 to 2, or a salt thereof. 15.A compound represented by the formula (X'): wherein R1' represents an optionally substituted aliphatic hydrocarbon group or an optionally substituted aromatic group; R2' represents a halogen atom, a cyano group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group (the sulfur atom may be oxidized to form a sulfinyl group that may be substituted or a sulfonyl group that may be substituted) , an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified carboxyl group or an optionally substituted aromatic group; the ring A represents a benzene ring which may be substituted with a halogen atom, a C1-4 alkyl group which may be substituted with a halogen atom or a C1-4 alkoxy group which may be substituted with a halogen atom; n represents an integer of 0 to 3; and p represents an integer of 0 to 2, or a salt thereof. A process for preparing an optically active sulfoxide derivative (I) having CCR5 antagonism without causing side reactions such as racemization and Pummerer rearrangement, which comprises reacting a compound (II) with a compound (III) as shown by the following scheme: wherein R1 represents hydrogen, an aliphatic hydrocarbon group or an aromatic group; R2 represents halogeno, alkyl, hydroxyl, amino, an aromatic group, etc.; R3 represents a 5- or 6-membered ring; R4 represents hydrogen, alkyl, alkoxy or halogeno; R5 represents hydrogen, a hydrocarbon group, a heterocyclic group, acyl, etc.; ring A represents an optionally substituted benzene ring; X represents a bond or divalent group comprising a linear part constituted of 1 to 4 atoms; m represents an integer of 1 to 5; n represents an integer of 0 to 3; p represents an integer of 0 to 2; and *1 represents an asymmetric center.

Full Text

PROCESS FOR PREPARING OPTICALLY ACTIVE SULFOXIDE DERIVATIVE
Technical Field
The present invention relates to an industrially
advantageous process for preparing an optically active
sulfoxide derivative having CCR5 antagonism, or a salt
thereof.
Background Art
Prior Art
Conventionally, as a process for preparing an
optically active sulfoxide derivative, separation by a
chiral column is generally employed, except for special
cases. However, such a process is not a fully satisfactory
one from an industrial point of view, because it requires a
special apparatus such as SMB (Simulated moving bed).
Disclosure of Prior Art
The prior art documents related to the present
invention are as follows:
[Patent Document 1]
WO96/01267 A
[Patent Document 2]
WO99/32468 A
[Patent Document 3]
WO99/32100 A
[Patent Document 4]
WO00/10965 A
[Patent Document 5]
WO00/37455 A
[Patent Document 6]
WO00/68203 A
[Patent Document 7]
WO00/76993 A
[Patent Document 8]
GB Patent No. 1579270
[Patent Document 9]
JP 62-265270 A
[Patent Document 10]
JP 2002-521408 A
[Patent Document 11]
WO01/46203 A
[Non-Patent Document 1]
Proc. Natl. Acad. Sci. (USA), Volume 96, pp. 5698-5703
(May, 1999)
Problems to be Solved by the Invention
The present invention provides an industrially
advantageous process for preparing an optically active
sulfoxide derivative or a salt thereof, by acylating an
optically active sulfoxide derivative having an amino group
in the molecule without causing side reactions such as
racemization and Pummerer rearrangement.
Brief Disclosure of the Invention
The present inventors have studied a process for
preparing an optically active sulfoxide derivative having
CCR5 antagonism or a salt thereof, intensively, and as a
result, they have found an industrially advantageous
process for preparing an optically active sulfoxide
derivative or a salt thereof without causing side reactions
such as racemization and Pummerer rearrangement.
Namely, the present invention relates to:
(1) A process for preparing an optically active
compound represented by the formula (I):
wherein R1 represents a hydrogen atom, an optionally
substituted aliphatic hydrocarbon group or an optionally
substituted aromatic group;
R2 represents a halogen atom, a nitro group, a cyano
group, an optionally substituted alkyl group, an optionally
substituted cycloalkyl group, an optionally substituted
hydroxyl group, an optionally substituted thiol group (the
sulfur atom may be oxidized to form a sulfinyl group that
may be substituted or a sulfonyl group that may be
substituted), an optionally substituted amino group, an
optionally substituted acyl group, an optionally esterified
carboxyl group or an optionally substituted aromatic group;
R3 represents an optionally substituted 5- or 6-
membered ring;
R4 represents a hydrogen atom, an optionally
substituted lower alkyl group, an optionally substituted
lower alkoxy group or a halogen atom;
R5 represents a hydrogen atom, an optionally
substituted hydrocarbon group, an optionally substituted
heterocyclic group, an optionally substituted sulfonyl
group, an esterified or amidated carboxyl group or an
optionally substituted acyl group;
X represents a bond or a divalent group comprising a
linear part constituted of 1 to 4 atoms;
the ring A represents a benzene ring which may be
substituted with a halogen atom, a C1-4 alkyl group which
may be substituted with a halogen atom or a C1-4 alkoxy
group which may be substituted with a halogen atom;
m is an integer of 1 to 5;
n represents an integer of 0 to 3;
p represents an integer of 0 to 2;
*1 represents an asymmetric center; and
the SO to which *1 is given represents an asymmetric
sulfoxide group,
or a salt thereof, which comprises reacting an optically
active compound represented by the formula (II):
wherein each symbol is as defined above,
or a salt thereof, with a compound represented by the
formula (III):
wherein each symbol is as defined above,
a salt thereof or a reactive derivative thereof;
(2) A process for preparing an optically active
compound represented by the formula (I) or a salt thereof,
which comprises reacting an optically active compound
represented by the formula (XIa):
wherein R6 represents a methyl group, a phenyl group,
a 4-methylphenyl group or a a-naphthyl group;
*2 represents an asymmetric center; and
the other symbols are as defined above,
or an optically active compound represented by the formula
(XIb):
wherein R7 represents a hydrogen atom, a chlorine atom
or a nitro group; and
the other symbols are as defined above,
with a compound represented by the formula (III), a salt
thereof or a reactive derivative thereof;
(3) An optically active compound represented by the
formula (II) or a salt thereof;
(4) The optically active compound as described in the
above (3), wherein R1 and R2 each represents a C1-6 alkyl
group, and n represents 1 or 2, or a salt thereof;
(5) The optically active compound as described in the
above (3) , wherein R1 represents a C1-6 alkyl group, p
represents 0; n represents 1, and
(6) A process for preparing an optically active
compound represented by the formula (II) or a salt thereof,
which comprises subjecting an optically active compound
represented by the formula (XIa) or the formula (XIb) to a
metathesis reaction;
(7) An optically active compound represented by the
formula (XIa) or the formula (XIb);
(8) The optically active compound as described in the
above (7) , wherein R1 and R2 each represents a C1-6 alkyl
group, n represents 1 or 2, and R6 represents a 4-
methylphenyl group or R1 represents a nitro group;
(9) The optically active compound as described in the
above (7), wherein R1 represents a C1-6 alkyl group, p
(10) A process for preparing an optically active
compound represented by the formula (XIa) or the formula
(XIb), which comprises subjecting a compound represented by
the formula (IX):
wherein each symbol is as defined above,
or a salt thereof, to optical resolution with an optically
active acid represented by the formula (XIIa):
wherein each symbol is as defined above,
or the formula (XIIb):
wherein each symbol is as defined above;
(11) A process for preparing an optically active
compound represented by the formula (II) or a salt thereof,
which comprises oxidizing a compound represented by the
formula (X):
wherein each symbol is as defined above,
or a salt thereof, in the presence of the formula (XIIa),
or an acid which is optically active with respect to axial
asymmetry and represented by the formula (XIIc):
(12) A compound represented by the formula (IX) or a
salt thereof;
(13) A process for preparing a compound represented by
the formula (IX) or a salt thereof, which comprises
subjecting a compound represented by the formula (VIII):

wherein R8 represents a hydrogen atom, an optionally
substituted lower alkyl group, an optionally substituted
aryl group, an optionally substituted aralkyl group or -
OR10 wherein R10 represents an optionally substituted lower
alkyl group, an optionally substituted aryl group or an
optionally substituted aralkyl group, and
the other symbols are as defined above,
or a salt thereof, to a deprotection reaction;
(14) A process for preparing a compound represented by
the formula (IX) or a salt thereof, which comprises
oxidizing a compound represented by the formula (X) or a
salt thereof;
(15) A compound represented by the formula (VIII) or a
salt thereof;
(16) A process for preparing a compound represented by
the formula (VIII) or a salt thereof, which comprises
oxidizing a compound represented by the formula (VII):
wherein each symbol is as defined above,
or a salt thereof;
(17) A compound represented by the formula (VII1):
wherein R2' represents a halogen atom, a cyano group,
an optionally substituted alkyl group, an optionally
substituted cycloalkyl group, an optionally substituted
hydroxyl group, an optionally substituted thiol group (the
sulfur atom may be oxidized to form a sulfinyl group that
may be substituted or a sulfonyl group that may be
substituted), an optionally substituted amino group, an
optionally substituted acyl group, an optionally esterified
carboxyl group or an optionally substituted aromatic group,
and
the other symbols are as defined above,
or a salt thereof;
(18) A process for preparing a compound represented by
the formula (VII) or a salt thereof, which comprises
reacting a compound represented by the formula (V):
wherein each symbol is as defined above,
or a salt thereof, with a compound represented by the
formula (VI):
wherein Y represents a halogen atom or a group
represented by the formula -OSO2-R9 wherein R9 represents a
lower alkyl group or an optionally substituted aryl group,
and
the other symbols are as defined above,
or a salt thereof;
(19) A compound represented by the formula (X'):
wherein each symbol is as defined above,
or a salt thereof; and
(20) A process for preparing a compound represented by
the formula (X) or a salt thereof, which comprises reacting
a compound represented by the formula (IV):
wherein the ring A is as defined above,
or a salt thereof, with a compound represented by the
formula (VI), or a salt thereof.
Detailed Description of the Invention
Hereinafter, the present invention will be explained
in detail.
A halogen atom which is the substituent of the ring A
includes, for example, fluorine, chloride and bromine; a
C1-4 alkyl group which may be substituted with a halogen
atom includes, for example, methyl, ethyl, trifluoromethyl
and trifluoroethyl; and a C1-4 alkoxy group which may be
substituted with a halogen atom includes, for example,
methoxy, ethoxy, propoxy, trifluoromethoxy and
trifluoroethoxy.
An optionally substituted aliphatic hydrocarbon group
represented by R1 includes an optionally substituted alkyl
group, an optionally substituted alkenyl group, an
optionally substituted alkynyl group, an optionally
substituted cycloalkyl group and an optionally substituted
cycloalkenyl group.
The alkyl group in the optionally substituted alkyl
group includes a straight-chain or branched C1-10 alkyl
group, for example, a C1-10 alkyl group such as methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-
butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,
nonyl and decyl, preferably a lower C1-6 alkyl group; the
alkenyl group in the optionally substituted alkenyl group
includes, for example, a straight-chain or branched C2-10
alkenyl group having 1 to 5 double bonds, for example, a
C1-10 alkenyl group such as ethenyl, propenyl, butenyl,
isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, noneyl
and decenyl, preferably a lower C1-6 alkenyl group; the
alkynyl group in the optionally substituted alkynyl group
includes, for example, a straight-chain or branched C2-10
alkynyl group having 1 to 5 double bonds, for example, a
C1-10 alkynyl group such as ethynyl, propynyl, butynyl,
isobutynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl
and decynyl, preferably a lower C1-6 alkynyl group,
repectively. The substituent in the optionally substituted
alkyl group, the optionally substituted alkenyl group or
the optionally substituted alkynyl group, includes a
halogen atom (e.g., fluorine, chlorine, bromine, iodine,
etc.), a nitro group, a cyano group, an optionally
substituted hydroxyl group (e.g., a hydroxyl group, C1-4
alkoxy, etc.), an optionally substituted thiol group (e.g.,
thiol, C1-4 alkylthio, etc.), an optionally substituted
amino group (e.g., amino, mono-C1-4 alkylamino, di-C1-4
alkylamino, a 5- or 6-membered cyclic amino group such as,
pyrrolidine, piperazine, piperidine, morpholine,
thiomorpholine, pyrrole and imidazole, etc.), an optionally
esterified or amidated carboxyl group (e.g., carboxyl, C1-4
alkoxycarbonyl, carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4
alkylcarbamoyl, etc.), an optionally halogenated C1-4 alkoxy
group (e.g., methoxy, ethoxy, propoxy, butoxy,
trifluoromethoxy, trifluoroethoxy, etc.), an optionally
halogenated C1-4 alkoxy-C1-4 alkoxy group (e.g.,
methoxymethoxy, methoxyethoxy, ethoxyethoxy,
trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), a
formyl group, a C2-4 alkanoyl group (e.g., acetyl, propionyl,
etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl,
ethanesulfonyl, etc.). The number of the substituents is
preferably 1 to 3.
The cycloalkyl group in the optionally substituted
cycloalkyl group includes, for example, a C3-7 cycloalkyl
group, etc. such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and cycloheptyl, and the cycloalkenyl group in
the optionally substituted cycloalkenyl group includes, for
example, a C3-7 cycloalkenyl group, etc. such as
cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl
and cycloheptenyl. The substituent in the optionally
substituted cycloalkyl group and the optionally substituted
cycloalkynyl group includes a halogen atom (e.g., fluorine,
chlorine, bromine, iodine, etc.), a nitro group, a cyano
group, a hydroxyl group, an optionally substituted thiol
group (e.g., thiol, C1-4 alkylthio, etc.), an optionally
substituted amino group (e.g., amino, mono-C1-4 alkylamino,
di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group
such as tetrahydropyrrole, piperazine, piperidine,
morpholine, thiomorpholine, pyrrole and imidazole, etc.),
an optionally esterified or amidated carboxyl group (e.g.,
carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4
alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally
halogenated C1-4 alkoxy group (e.g., methoxy, ethoxy,
propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.),
an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group (e.g.,
methoxymethoxy, methoxyethoxy, ethoxyethoxy,
trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.),
formyl, a C2-4 alkanoyl group (e.g., acetyl, propionyl,
etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl,
ethanesulfonyl, etc.). The number of the substituents is
preferably 1 to 3.
The aromatic group in the optionally substituted
aromatic group represented by R1 includes a 5- or 6-
membered homo- or heterocyclic aromatic group such as
phenyl, pyridyl, furyl, thienyl, pyrrolyl, imidazolyl,
pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl,
tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl and
triazolyl; and a condensed heterocyclic aromatic group such
as benzofuran, indole, benzothiophene, benzoxazole,
benzothiazole, indazole, benzimidazole, quinoline,
isoquinoline, quinoxaline, phthalazine, quinazoline,
cinnoline and imidazopyridine. The substituent in the
aromatic group includes a halogen atom (e.g., fluorine,
chlorine, bromine, iodine, etc.), a nitro group, a cyano
group, a hydroxyl group, an optionally substituted thiol
group (e.g., thiol, C1-4 alkylthio, etc.), an optionally
substituted amino group (e.g., amino, mono-C1-4 alkylamino,
di-C1-4 alkylamino, a 5- or 6- membered cyclic amino group
such as tetrahydropyrrole, piperazine, piperidine,
morpholine, thiomorpholine, pyrrole and imidazole, etc.),
an optionally esterified or amidated carboxyl group (e.g.,
carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-Ci-4
alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally
halogenated C1-4 alkyl group (e.g., trifluoromethyl, methyl,
ethyl, etc.), an optionally halogenated C1-4 alkoxy group
(e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,
trifluoroethoxy, etc.), a formyl group, a C2-4 alkanoyl
group (e.g., acetyl, propionyl, etc.) and a C1-4
alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl,
etc.). The number of the substituents is preferably 1 to 3.
The "substituent" which may be contained in the
"aromatic group" of the "optionally substituted aromatic
'group" represented by R1 preferably includes, in particular,
a halogen atom, an optionally halogenated or lower-(C1-4)
alkoxylated lower (C1-4) alkyl group (e.g., methyl, ethyl,
t-butyl, trifluoromethyl, methoxymethyl, ethoxymethyl,
propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl,
propoxyethyl, butoxyethyl, etc.), a lower (C1-4) alkyl group
which may be substituted with a hydroxyl group or a cyano
group (e.g., hydroxy C1-4 alkyl, cyano C1-4 alkyl, etc.), a
lower (C1-4) alkyl group which may be substituted with an
optionally esterified or amidated carboxyl group (e.g.,
carboxyl C1-4 alkyl, C1-4 alkoxycarbonyl C1-4 alkyl, carbamoyl
C1-4 alkyl, mono-C1-4 alkylcarbamoyl C1-4 alkyl, di-C1-4
alkylcarbamoyl C1-4 alkyl, pyrrolidinocarbonyl C1-4 alkyl,
piperidinocarbonyl C1-4 alkyl, morpholinocarbonyl C1-4 alkyl,
thiomorpholinocarbonyl C1-4 alkyl, etc.), an optionally
halogenated or lower- (C1-4) alkoxylated lower (C1-4) alkoxy
group (e.g., methoxy, ethoxy, propoxy, butoxy, t-butoxy,
trifluoromethoxy, methoxymethoxy, ethoxymethoxy,
propoxymethoxy, butoxymethoxy, methoxyethoxy, ethoxyethoxy,
propoxyethoxy, butoxyethoxy, methoxypropoxy, ethoxypropoxy,
propoxypropoxy, butoxypropoxy, etc.), a halogen atom (e.g.,
fluorine, chlorine, etc.), a nitro group, a cyano group and
1 or 2 of a lower (C1-4) alkyl group, and more preferably an
optionally halogenated lower (C1-4) alkyl group.
The "optionally substituted alkyl group", the
"optionally substituted cycloalkyl group" and the
"optionally substituted aromatic group" represented by R2
are as defined in R1.
The substituent in the optionally substituted hydroxyl
group represented by R2 includes (1) an optionally
substituted alkyl group (e.g., a C1-10 alkyl group such as
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-
butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl,
heptyl, octyl, nonyl and decyl, preferably a lower (C1-6)
alkyl group , or the like is exemplified); (2) a cycloalkyl
group that may be substituted and may contain heteroatoms
(e.g., C3-7 cycloalkyl such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and cycloheptyl; a saturated 5- to
6-membered heterocyclic ring group containing 1 to 2
heteroatoms such as tetrahydrofuranyl, tetrahydrothienyl,
pyrrolidinyl, pyrazolidinyl, piperidyl, piperazinyl,
morpholinyl, thiomorpholinyl, tetrahydropyranyl and
tetrahydrothiopyranyl (preferably, tetrahydropyranyl,
etc.); or the like is exemplified); (3) an optionally
substituted alkenyl group (e.g., a C2-10 alkenyl group such
as allyl, crotyl, 2-pentenyl and 3-hexenyl, preferably a
lower (C2-6) alkenyl group , or the like is exemplified) ;
(4) an optionally substituted cycloalkenyl group (e.g., a
C3-7 cycloalkenyl group such as 2-cyclopentenyl, 2-
cyclohexenyl, 2-cyclopentenylmethyl and 2-
cyclohexenylmethyl, or the like is exemplified); (5) an
optionally substituted aralkyl group (e.g., phenyl-C1-4
alkyl (e.g., benzyl, phenethyl, etc.), or the like is
exemplified); (6) a formyl group or an optionally
substituted acyl group (e.g., a C2-4 alkanoyl group such as
acetyl, propionyl, butyryl and isobutyryl, and a C1-4
alkylsulfonyl group such as methanesulfonyl and
ethanesulfonyl, or the like is exemplified); and (7) an
optionally substituted aryl group (e.g., phenyl, naphthyl,
or the like is exemplified). The substituent which may be
contained in (1) an optionally substituted alkyl group, (2)
an optionally substituted cycloalkyl group, (3) an
optionally substituted alkenyl group, (4) an optionally
substituted cycloalkenyl group, (5) an optionally
substituted aralkyl group, (6) an optionally substituted
acyl group, and (7) an optionally substituted aryl group,
includes a halogen atom (e.g., fluorine, chlorine, bromine,
iodine, etc.), a nitro group, a cyano group, a hydroxyl
group, an optionally substituted thiol group (e.g., thiol,
C1-4 alkylthio, etc.), an optionally substituted amino group
(e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5-
or 6-membered cyclic amino group such as tetrahydropyrrole,
piperazine, piperidine, morpholine, thiomorpholine, pyrrole
and imidazole, etc.), an optionally esterified or amidated
carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl,
carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl,
etc.), an optionally halogenated C1-4 alkyl group (e.g.,
trifluoromethyl, methyl, ethyl, etc.), an optionally
halogenated C1-6 alkoxy group (e.g., methoxy, ethoxy,
propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.;
preferably optionally halogenated C1-4 alkoxy), a formyl
group, a C2-4 alkanoyl group (e.g., acetyl, propionyl, etc.),
a C1-4 alkylsulfonyl group (e.g., methanesulfonyl,
ethanesulfonyl, etc.), a 5- to 6-membered aromatic
heterocycle that may be substituted [e.g., a 5- to 6-
membered aromatic heterocycle, which contains 1 to 4
heteroatoms of 1 to 2 kinds selected from a nitrogen atom,
a sulfur atom and an oxygen atom, such as furan, thiophene,
pyrrole, imidazole, pyrazole, thiazole, oxazole,
isothiazole, isoxazole, tetrazole, pyridine, pyrazine,
pyrimidine, pyridazine and triazole; the substituent that
may be contained in the heterocycle, includes a halogen
atom (e.g., fluorine, chlorine, bromine, iodine, etc.), a
nitro group, a cyano group, a hydroxyl group, a thiol group,
an amino group, a carboxyl group, an optionally halogenated
C1-4 alkyl group (e.g., trif luoromethyl, methyl, ethyl,
etc.), an optionally substituted C1-4 alkoxy group (e.g.,
methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,
trifluoroethoxy, etc.), a formyl group, a C2-4 alkanoyl
group (e.g., acetyl, propionyl, etc.) and a C1-4
alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl,
etc.), and the number of the substituents is preferably 1
to 3.
The substituent in the optionally substituted thiol
group represented by R2 includes the same as the
"substituent in the optionally substituted hydroxyl group"
as described above. Among them, it preferably includes:
(1) an optionally substituted alkyl group (e.g., a C1-
10 alkyl group such as methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,
neopentyl, hexyl, heptyl, octyl, nonyl and decyl,
preferably a lower (C1-6) alkyl group , or the like is
exemplified); (2) an optionally substituted cycloalkyl
group (e.g., C3-7 cycloalkyl such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and cycloheptyl, or the like is
exemplified); (3) an optionally substituted aralkyl group
(e.g., a phenyl-C1-4 alkyl group (e.g., benzyl, phenethyl,
etc.), or the like is exemplified); and (4) an optionally
substituted aryl (e.g., phenyl, naphthyl, or the like is
exemplified). The substituent which may be contained in
(1) an optionally substituted alkyl group, (2) an
optionally substituted cycloalkyl group, (3) an optionally
substituted aralkyl group and (4) an optionally substituted
aryl group as describe above includes a halogen atom (e.g.,
fluorine, chlorine, bromine, iodine, etc.), a nitro group,
a cyano group, a hydroxyl group, an optionally substituted
thiol group (e.g., thiol, C1-4 alkylthio, etc.), an
optionally substituted amino group (e.g., amino, mono-C1-4
alkylamino, di-C1-4 alkylamino, a 5- or 6-membered cyclic
amino group such as tetrahydropyrrole, piperazine,
piperidine, morpholine, thiomorpholine, pyrrole and
imidazole, etc.), an optionally esterified or amidated
carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl,
carbamoyl, mono-Ci-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl,
etc.), an optionally halogenated C1-4 alkoxy group (e.g.,
methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,
trifluoroethoxy, etc.), an optionally halogenated C1-4
alkoxy-C1-4 alkoxy group (e.g., methoxymethoxy,
methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy,
trifluoroethoxyethoxy, etc. ) , a formyl group, a C2-4
alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4
alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl,
etc.). The number of the substituents is preferably 1 to 3.
The substituent of the optionally substituted amino
group represented by R2 includes an amino group which may
contain 1 or 2 of the same substituents as in the
"optionally substituted hydroxyl group" as described above.
Among them, it preferably includes:
(1) an optionally substituted alkyl group (e.g., a C1-
10 alkyl group such as methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,
neopentyl, hexyl, heptyl, octyl, nonyl, and decyl,
preferably a lower (C1-6) alkyl group , or the like is
exemplified); (2) an optionally substituted cycloalkyl
group (e.g., a C3-7 cycloalkyl group such as cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, or the
like is exemplified); (3) an optionally substituted alkenyl
group (e.g., a C2-10 alkeny group such as allyl, crotyl, 2-
pentenyl and 3-hexenyl, preferably a lower (C2-6) alkenyl
group, or the like is exemplified); (4) an optionally
substituted cycloalkenyl group (e.g., a C3-7 cycloalkenyl
group such as 2-cyclopentenyl, 2-cyclohexenyl, 2-
cyclopentenylmethyl and 2-cyclohexenylmethyl, or the like
is exemplified); (5) a formyl group or an optionally
substituted acyl group (e.g., a C2-4 alkanoyl group such as
acetyl, propionyl, butyryl and isobutyryl, and a C1-4
alkylsulfonyl group (e.g., methanesulfonyl and
ethanesulfonyl) , or the like is exemplified); and (6) an
optionally substituted aryl group (e.g., phenyl, naphthyl,
or the like is exemplified). The substituent which may be
contained in (1) an optionally substituted alkyl group, (2)
an optionally substituted cycloalkyl group, (3) an
optionally substituted alkenyl group, (4) an optionally
substituted cycloalkenyl group, (5) an optionally
substituted acyl group and (6) an optionally substituted
aryl group as describe above, includes a halogen atom (e.g.,
fluorine, chlorine, bromine, iodine, etc.), a nitro group,
a cyano group, a hydroxyl group, an optionally substituted
thiol group (e.g., thiol, C1-4 alkylthio, etc.), an
optionally substituted amino group (e.g., amino, mono-C1-4
alkylamino, di-C1-4 alkylamino, a 5- or 6-membered cyclic
amino group such as tetrahydropyrrole, piperazine,
piperidine, morpholine, thiomorpholine, pyrrole and
imidazole, etc.), an optionally esterified or amidated
carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl,
carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl,
etc.), an optionally halogenated C1-4 alkoxy group (e.g.,
methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,
trifluoroethoxy, etc.), an optionally halogenated C1-4
alkoxy-C1-4 alkoxy group (e.g., methoxymethoxy,
methoxyethoxy, ethoxyethoxy, trifluoromethqxyethoxy,
trifluoroethoxyethoxy, etc.), a formyl group, a C2-4
alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4
alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl,
etc.). The number of the substituents is preferably 1 to 3.
In the optionally substituted amino group represented
by R2, the substituents of the amino group may bond each
other to form a cyclic amino group (e.g., a cyclic amino
group that is formed by removing one hydrogen atom from the
nitrogen atom which constitutes a 5- or 6-membered ring
such as tetrahydropyrrole, piperazine, piperidine,
morpholine, thiomorpholine, pyrrole and imidazole, and has
a bond on the nitrogen atom). The cyclic amino group may
contain substituents, and the substituents include a
halogen atom (e.g., fluorine, chlorine, bromine, iodine,
etc.), nitro, cyano, a hydroxyl group, an optionally
substituted thiol group (e.g., thiol, C1-4 alkylthio, etc.),
an optionally substituted amino group (e.g., amino, mono-
C1-4 alkylamino, di-C1-4 alkylamino, a 5- or 6-membered
cyclic amino group such as tetrahydropyrrole, piperazine,
piperidine, morpholine, thiomorpholine, pyrrole and
imidazole, etc.), an optionally esterified or amidated
carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl,
carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl,
etc.), an optionally halogenated C1-4 alkoxy group (e.g.,
methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,
trifluoroethoxy, etc.), an optionally halogenated C1-4
alkoxy-C1-4 alkoxy group (e.g., methoxymethoxy,
methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy,
trifluoroethoxyethoxy, etc.), a formyl group, a C2-4
alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4
alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl,
etc.). The number of the substituents is preferably 1 to 3,
The optionally substituted acyl group represented by
R2 includes the groups which (1) hydrogen; (2) an
optionally substituted alkyl group (e.g., a C1-10 alkyl
group such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,
neopentyl, hexyl, heptyl, octyl, nonyl and decyl,
preferably a lower (C1-6) alkyl group , or the like is
exemplified); (3) an optionally substituted cycloalkyl
group (e.g., a C3-7 cycloalkyl group such as cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl , or
the like is exemplified); (4) an optionally substituted
alkenyl group (e.g., a C2-10 alkenyl group such as allyl,
crotyl, 2-pentenyl and 3-hexenyl, preferably a lower (C2-6)
alkenyl group , or the like is exemplified); (5) an
optionally substituted cycloalkenyl group (e.g., a C3-7
cycloalkenyl group such as 2-cyclopentenyl, 2-cyclohexenyl,
2-cyclopentenylmethyl and 2-cyclohexenylmethyl , or the
like is exemplified); (6) an optionally substituted 5- to
6-membered monocycle aromatic group (e.g., phenyl, pyridyl
or the like is exemplified); or the like is bonded with the
carbonyl group or the sulfonyl group, (e.g., acetyl,
propionyl, butyryl, isobutyryl, valeryl, isovaleryl,
pivaloyl, hexanoyl, heptanoyl, octanoyl,
cyclobutanecarbonyl, cyclopentanecarbonyl,
cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-
cyclohexenecarbonyl, benzoyl, nicotinoyl, methanesulfonyl,
ethanesulfonyl, etc.). The substituent which may be
contained in (2) an optionally substituted alkyl group, (3)
an optionally substituted cycloalkyl group, (4) an
optionally substituted alkenyl group, (5) an optionally
substituted cycloalkenyl group and (6) an optionally
substituted 5- or 6-membered monocycle aromatic group as
describe above, includes a halogen atom (e.g., fluorine,
chlorine, bromine, iodine, etc.), a nitro group, a cyano
group, a hydroxyl group, an optionally substituted thiol
group (e.g., thiol, C1-4 alkylthio, etc.), an optionally
substituted amino group (e.g., amino, mono-C1-4 alkylamino,
di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group
such as tetrahydropyrrole, piperazine, piperidine,
morpholine, thiomorpholine, pyrrole and imidazole, etc.),
an optionally esterified or amidated carboxyl group (e.g.,
carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4
alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally
halogenated C1-4 alkoxy group (e.g., methoxy, ethoxy,
propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.),
an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group (e.g.,
methoxymethoxy, methoxyethoxy, ethoxyethoxy,
trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), a
formyl group, a C2-4 alkanoyl group (e.g., acetyl, propionyl,
etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl,
ethanesulfonyl, etc.). The number of the substituents is
preferably 1 to 3.
The optionally esterified carboxyl group represented
by R2 includes the groups which (1) hydrogen; (2) an
optionally substituted alkyl group (e.g., a C1-10 alkyl
group such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,
neopentyl, hexyl, heptyl, octyl, nonyl and decyl,
preferably a lower (C1-6) alkyl group, or the like is
exemplified); (3) an optionally substituted cycloalkyl
group (e.g., a C3-7 cycloalkyl group such as cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, or the
like is exemplified); (4) an optionally substituted alkenyl
group (e.g., a C2-10 alkenyl group such as allyl, crotyl, 2-
pentenyl and 3-hexenyl, preferably a lower (C2-6) alkenyl
group, or the like is exemplified); (5) an optionally
substituted cycloalkenyl group (e.g., a C3-7 cycloalkenyl
group such as 2-cyclopentenyl, 2-cyclohexenyl, 2-
cyclopentenylmethyl and 2-cyclohexenylmethyl, or the like
is exemplified); (6) an optionally substituted aryl group
(e.g., phenyl, naphthyl, etc.); or the like is bonded with
a carbonyloxy group, preferably includes a carboxyl group,
a lower (C1-6) alkoxycarbonyl group, an aryloxycarbonyl
group (e.g., methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, phenoxycarbonyl, naphthoxycarbonyl, etc.).
The substituent which may be contained in (2) an optionally
substituted alkyl group, (3) an optionally substituted
cycloalkyl group, (4) an optionally substituted alkenyl
group, (5) an optionally substituted cycloalkenyl group and
(6) an optionally substituted aryl group as describe above,
includes a halogen atom (e.g., fluorine, chlorine, bromine,
iodine, etc.), a nitro group, a cyano group, a hydroxyl
group, an optionally substituted thiol group (e.g., thiol,
C1-4 alkylthio, etc.), an optionally substituted amino group
(e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5-
or 6-membered cyclic amino group such as tetrahydropyrrole,
piperazine, piperidine, morpholine, thiomorpholine, pyrrole
and imidazole, etc.), an optionally esterified or amidated
carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl,
carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl,
etc.), an optionally halogenated C1-4 alkoxy group (e.g.,
methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,
trifluoroethoxy, etc.), an optionally halogenated C1-4
alkoxy-C1-4 alkoxy group (e.g., methoxymethoxy,
methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy,
trifluoroethoxyethoxy, etc.), a formyl group, a C2-4
alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4
alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl,
etc.). The number of the substituents is preferably 1 to 3.
R2 preferably includes, in particular, a halogen atom,
a cyano group, a hydroxyl group, a nitro group, an
optionally esterified or amidated carboxyl group (e.g.,
carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4
alkylcarbamoyl, di-C1-4 alkylcarbamoyl, pyrrolidinocarbonyl,
piperidinocarbonyl, morpholinocarbonyl,
thiomorpholinocarbonyl, etc.), an optionally halogenated or
lower-(C1-4) alkoxylated lower (C1-4) alkyl group (e.g.,
methyl, ethyl, t-butyl, trifluoromethyl, methoxymethyl,
ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl,
ethoxyethyl, propoxyethyl, butoxyethyl, etc.), a lower (C1-
4) alkyl group which may be substituted with a hydroxyl
group or a cyano group (e.g., hydroxy C1-4 alkyl, cyano C1-4
alkyl, etc.), a lower (C1-4) alkyl group which may be
substituted with an optionally esterified or amidated
carboxyl group (e.g., carboxyl C1-4 alkyl, C1-4
alkoxycarbonyl C1-4 alkyl, carbamoyl C1-4 alkyl, mono-C1-4
alkylcarbamoyl C1-4 alkyl, di-C1-4 alkylcarbamoyl C1-4 alkyl,
pyrrolidinocarbonyl C1-4 alkyl, piperidinocarbonyl C1-4 alkyl,
morpholinocarbonyl C1-4 alkyl, thiomorpholinocarbonyl C1-4
alkyl, etc.), an optionally halogenated and lower-(C1-4)
alkoxylated lower (C1-4) alkoxy group (e.g., methoxy, ethoxy,
propoxy, butoxy, t-butoxy, trifluoromethoxy, methoxymethoxy,
ethoxymethoxy, propoxymethoxy, butoxymethoxy, methoxyethoxy,
ethoxyethoxy, propoxyethoxy, butoxyethoxy, methoxypropoxy,
ethoxypropoxy, propoxypropoxy, butoxypropoxy, etc.), a
halogen atom (e.g., fluorine, chlorine, etc.), a nitro
group, a cyano group, an amino group which may be
substituted with 1 or 2 of a lower (C1-4) alkyl group,
formyl or a lower (C2-4) alkanoyl group (e.g., amino,
methylamino, dimethylamino, formylamino, acetylamino, etc.)
and a 5- or 6-membered cyclic amino group (e.g, 1-
pyrrolidinyl, 1-piperazinyl, 1-piperidinyl, 4-morpholino,
4-thiomorpholino, 1-imidazolyl, 4-tetrahydropyranyl, etc.).
For R2, more particularly preferred is an optionally
halogenated lower (C1-4) alkyl group.
Definitions of each of the substituents represented by
R2' are the same as in R2.
A "5- or 6-membered cyclic ring" in an "optionally
substituted 5- or 6-membered cyclic ring group" represented
by R3 includes a group that is formed by removing one
hydrogen atom from a 6-membered aromatic hydrocarbon such
as benzene, a 5- to 6-membered aliphatic hydrocarbon such
as cyclopentane, cyclohexane, cyclopentene, cyclohexene,
cyclopentadiene, and cyclohexadiene, a 5- to 6-membered
aromatic heterocycle containing 1 to 4 heteroatoms of 1 to
2 kinds selected from a nitrogen atom, a sulfur atom and an
oxygen atom, such as furan, thiophene, pyrrole, imidazole,
pyrazole, thiazole, oxazole, isothiazole, isoxazole,
tetrazole, pyridine, pyrazine, pyrimidine, pyridazine and
triazole, a 5- to 6-membered non-aromatic heterocycle
containing 1 to 4 heteroatoms of 1 to 2 kinds selected from
a nitrogen atom, a sulfur atom and an oxygen atom, such as
tetrahydrofuran, tetrahydrothiophene, dithiolane,
oxathiolane, pyrrolidine, pyrroline, imidazolidine,
imidazoline, pyrazolidine, pyrazoline, piperidine,
piperazine, oxazine, oxadiazine, thiazine, thiadiazine,
morpholine, thiomorpholine, pyran, tetrahydropyran, and
tetrahydrothiopyran, or the like. Among them, as for the
"5- to 6-membered cyclic ring" is preferably benzene, furan,
thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidine,
piperidine, piperazine, morpholine, thiomorpholine,
tetrahydropyran (preferably, a 6-membered cyclic ring) or
the like, particularly benzene.
The substituent which may be contained in the "5- or
6-membered cyclic ring" of the "optionally substituted 5-
or 6-membered cyclic ring group" represented by R3 includes,
for example, a halogen atom, nitro, cyano, optionally
substituted alkyl, optionally substituted cycloalkyl, an
optionally substituted hydroxyl group, an optionally
substituted thiol group (the sulfur atom may be oxidized to
form a sulfinyl group that may be substituted or a sulfonyl
group that may be substituted), an optionally substituted
amino group, an optionally substituted acyl group, an
optionally esterified carboxyl group or an optionally
substituted aromatic group.
Halogen as the substituent of R3 includes fluorine,
chlorine, bromine and iodine, and in particular preferably
fluorine and chlorine.
An alkyl group in the optionally substituted alkyl
group as the substituent of R3 includes a straight-chain or
branched C1-10 alkyl group, for example, a C1-10 alkyl group
such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl,
heptyl, octyl, nonyl and decyl, preferably a lower C1-6
alkyl group. The substituent in the optionally substituted
alkyl group includes a halogen atom (e.g., fluorine,
chlorine, bromine, iodine, etc.), a nitro group, a cyano
group, a hydroxyl group, an optionally substituted thiol
group (e.g., thiol, C1-4 alkylthio, etc.), an optionally
substituted amino group (e.g., amino, mono-C1-4 alkylamino,
di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group
such as tetrahydropyrrole, piperazine, piperidine,
morpholine, thiomorpholine, pyrrole and imidazole, etc.),
an optionally esterified or amidated carboxyl group (e.g.,
carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4
alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally
halogenated C1-4 alkoxy group (e.g., methoxy, ethoxy,
propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.),
an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group (e.g.,
methoxymethoxy, methoxyethoxy, ethoxyethoxy,
trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), a
formyl group, a C2-4 alkanoyl group (e.g., acetyl, propionyl,
etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl,
ethanesulfonyl, etc.). The number of the substituents is
preferably 1 to 3.
The cycloalkyl group in the optionally substituted
cycloalkyl group as the substituent of R3 includes, for
example, a C3-7 cycloalkyl group such as cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The
substituent in the optionally substituted cycloalkyl group
includes a halogen atom (e.g., fluorine, chlorine, bromine,
iodine, etc.), a nitro group, a cyano group, a hydroxyl
group, an optionally substituted thiol group (e.g., thiol,
C1-4 alkylthio, etc.), an optionally substituted amino group
(e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5-
or 6-membered cyclic amino group such as tetrahydropyrrole,
piperazine, piperidine, morpholine, thiomorpholine, pyrrole
and imidazole, etc.), an optionally esterified or amidated
carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl,
carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl,
etc.), an optionally halogenated C1-4 alkoxy group (e.g.,
methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,
trifluoroethoxy, etc.), an optionally halogenated C1-4
alkoxy-C1-4 alkoxy group (e.g., methoxymethoxy,
methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy,
trifluoroethoxyethoxy, etc.), a formyl group, a C2-4
alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4
alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl,
etc.). The number of the substituents is preferably 1 to 3
The substituent in the optionally substituted hydroxyl
group as the substituent of R3 includes (1) an optionally
substituted alkyl group (e.g., a C1-10 alkyl group such as
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-
butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl,
heptyl, octyl, nonyl and decyl, preferably a lower (C1-6)
alkyl group, or the like is exemplified); (2) a cycloalkyl
group that may be substituted and may contain heteroatoms
(e.g., C3-7 cycloalkyl such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and cycloheptyl; a saturated 5- to
6-membered heterocyclic group containing 1 to 2 heteroatoms
such as tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl,
pyrazolidinyl, piperidyl, piperazinyl, morpholinyl,
thiomorpholinyl, tetrahydropyranyl and
tetrahydrothiopyranyl (preferably, tetrahydropyranyl,
etc.); or the like is exemplified); (3) an optionally
substituted alkenyl group (e.g., a C2-10 alkenyl group such
as allyl, crotyl, 2-pentenyl and 3-hexenyl, preferably a
lower (C2-6) alkenyl group, or the like is exemplified); (4)
an optionally substituted cycloalkenyl group (e.g., a C3-7
cycloalkenyl group such as 2-cyclopentenyl, 2-cyclohexenyl,
2-cyclopentenylmethyl and 2-cyclohexenylmethyl, or the like
is exemplified); (5) an optionally substituted aralkyl
group (e.g., phenyl-C1-4 alkyl (e.g., benzyl, phenethyl,
etc.) or the like is exemplified); (6) a formyl group or an
optionally substituted acyl group (e.g., a C2-4 alkanoyl
group such as acetyl, propionyl, butyryl and isobutyryl,
and a C1-4 alkylsulfonyl group such as methanesulfonyl and
ethanesulfonyl, or the like is exemplified); and (7) an
optionally substituted aryl group (e.g., phenyl, naphthyl,
or the like is exemplified). The substituent which may be
contained in (1) an optionally substituted alkyl group, (2)
an optionally substituted cycloalkyl group, (3) an
optionally substituted alkenyl group, (4) an optionally
substituted cycloalkenyl group, (5) an optionally
substituted aralkyl group, (6) an optionally substituted
acyl group, and (7) an optionally substituted aryl group as
described above, includes a halogen atom (e.g., fluorine,
chlorine, bromine, iodine, etc.), a nitro group, a cyano
group, a hydroxyl group, an optionally substituted thiol
group (e.g., thiol, C1-4 alkylthio, etc.), an optionally
substituted amino group (e.g., amino, mono-C1-4 alkylamino,
di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group
such as tetrahydropyrrole, piperazine, piperidine,
morpholine, thiomorpholine, pyrrole and imidazole, etc.),
an optionally esterified or amidated carboxyl group (e.g.,
carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4
alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally
halogenated C1-4 alkyl group (e.g., trifluoromethyl, methyl,
ethyl, etc.), an optionally halogenated C1-6 alkoxy group
(e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,
trifluoroethoxy, etc.; preferably an optionally halogenated
C1-4 alkoxy group) , a formyl group, a C2-4 alkanoyl group
(e.g., acetyl, propionyl, etc.) and a C1-4 alkylsulfonyl
group (e.g., methanesulfonyl, ethanesulfonyl, etc.), a 5-
to 6-membered aromatic heterocycle that may be substituted
[for example, an 5- to 6-membered aromatic heterocycle
containing 1 to 4 heteroatoms of 1 to 2 kinds selected from
a nitrogen atom, a sulfur atom and an oxygen atom, such as
furan, thiophene, pyrrole, imidazole, pyrazole, thiazole,
oxazole, isothiazole, isoxazole, tetrazole, pyridine,
pyrazine, pyrimidine, pyridazine and triazole, etc.; the
substituent that may be contained in the heterocycle,
includes a halogen atom (e.g., fluorine, chlorine, bromine,
iodine, etc.), a nitro group, a cyano group, a hydroxyl
group, a thiol group, an amino group, a carboxyl group, an
optionally halogenated C1-4 alkyl group (e.g.,
trif luoromethyl, methyl, ethyl, etc. ) , a C1-4 alkoxy group
(e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,
trifluoroethoxy, etc.), a formyl group, a C2-4 alkanoyl
group (e.g., acetyl, propionyl, etc.) and a C1-4
alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl,
etc.), and the number of the substituents is preferably 1
to 3]. The number of the substituents is preferably 1 to 3.
Further, the substituent in the optionally substituted
thiol group as the substituent of R3 includes the same as
the "substituents in the optionally substituted hydroxyl
group as the substituent of R1" as described above. Among
them, it preferably includes:
(1) an optionally substituted alkyl group (e.g., a C1-
10 alkyl group such as methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,
neopentyl, hexyl, heptyl, octyl, nonyl and decyl,
preferably a lower (C1-4) alkyl group, or the like is
exemplified); (2) an optionally substituted cycloalkyl
group (e.g., C3-7 cycloalkyl such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and cycloheptyl, or the like is
exemplified); (3) an optionally substituted aralkyl group
(e.g., a phenyl-C1-4 alkyl group (e.g., benzyl, phenethyl,
etc.) or the like is exemplified); and (4) an optionally
substituted aryl group (e.g., phenyl, naphthyl or the like
is exemplified). The substituent which may be contained in
(1) an optionally substituted alkyl group, (2) an
optionally substituted cycloalkyl group, (3) an optionally
substituted aralkyl group and (4) an optionally substituted
aryl group as describe above, includes a halogen atom (e.g.,
fluorine, chlorine, bromine, iodine, etc.), a nitro group,
a cyano group, a hydroxyl group, an optionally substituted
thiol group (e.g., thiol, C1-4 alkylthio, etc.), an
optionally substituted amino group (e.g., amino, mono-C1-4
alkylamino, di-C1-4 alkylamino, a 5- or 6-membered cyclic
amino group such as tetrahydropyrrole, piperazine,
piperidine, morpholine, thiomorpholine, pyrrole and
imidazole, etc.) , an optionally esterified or amidated
carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl,
carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl,
etc.), an optionally halogenated C1-4 alkoxy group (e.g.,
methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,
trifluoroethoxy, etc.), an optionally halogenated C1-4
alkoxy-C1-4 alkoxy group (e.g., methoxymethoxy,
methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy,
trifluoroethoxyethoxy, etc.), a formyl group, a C2-4
alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4
alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl,
etc.). The number of the substituents is preferably 1 to 3.
The substituent of the optionally substituted amino
group as the substituent of R3 includes an amino group
which may contain 1 or 2 substituents of the same as the
"substituent of the optionally substituted hydroxyl group
as the substituent of R1". Among them, it preferably
includes:
(1) an optionally substituted alkyl group (e.g., a C1-
i
10 alkyl group such as methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,
neopentyl, hexyl, heptyl, octyl, nonyl and decyl,
preferably a lower (C1-6) alkyl group, or the like is
exemplified); (2) an optionally substituted cycloalkyl
group (e.g., a C3-7 cycloalkyl group such as cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, or the
like is exemplified); (3) an optionally substituted alkenyl
group (e.g., a C2-10 alkenyl group such as allyl, crotyl, 2-
pentenyl and 3-hexenyl, preferably a lower (C2-6) alkenyl
group, or the like is exemplified); (4) an optionally
substituted cycloalkenyl group (e.g., a C3-7 cycloalkenyl
group such as 2-cyclopentenyl, 2-cyclohexenyl, 2-
cyclopentenylmethyl and 2-cyclohexenylmethyl, or the like
is exemplified); (5) a formyl group or an optionally
substituted acyl group (e.g., a C2-4 alkanoyl group such as
acetyl, propionyl, butyryl and isobutyryl), a C1-4
alkylsulfonyl group (e.g., methanesulfonyl and
ethanesulfonyl), or the like is exemplified); and (6) an
optionally substituted aryl group (e.g., phenyl, naphthyl,
or the like is exemplified). The substituent which may be
contained in (1) an optionally substituted alkyl group, (2)
an optionally substituted cycloalkyl group, (3) an
optionally substituted alkenyl group, (4) an optionally
substituted cycloalkenyl group, (5) an optionally
substituted acyl group and (6) an optionally substituted
aryl group as describe above, includes a halogen atom (e.g.,
fluorine, chlorine, bromine, iodine, etc.), a nitro group,
a cyano group, a hydroxyl group, an optionally substituted
thiol group (e.g., thiol, C1-4 alkylthio, etc.), an
optionally substituted amino group (e.g., amino, mono-C1-4
alkylamino, di-C1-4 alkylamino, a 5- or 6-membered cyclic
amino group such as tetrahydropyrrole, piperazine,
piperidine, morpholine, thiomorpholine, pyrrole and
imidazole, etc.), an optionally esterified or amidated
carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl,
carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl,
etc.), an optionally halogenated C1-4 alkoxy group (e.g.,
methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,
trifluoroethoxy, etc.), an optionally halogenated C1-4
alkoxy-C1-4 alkoxy group (e.g., methoxymethoxy,
methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy,
trifluoroethoxyethoxy, etc.), a formyl group, a C2-4
alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4
alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl,
etc.). The number of the substituents is preferably 1 to 3.
Further, in the optionally substituted amino group as
the substituent of R3, the substituents of the amino group
may bond each other to form a cyclic amino group (for
example, a cyclic amino group that is formed by removing
one hydrogen from the nitrogen atom constituting the ring
of a 5- to 6-membered cyclic ring such as tetrahydropyrrole,
piperazine, piperidine, morpholine, thiomorpholine, pyrrole
and imidazole, and has a bond on the nitrogen atom). The
cyclic amino group may contain a substituent, and the
substituent includes a halogen atom (e.g., fluorine,
chlorine, bromine, iodine, etc.), a nitro group, a cyano
group, a hydroxyl group, an optionally substituted thiol
group (e.g., thiol, C1-4 alkylthio, etc.), an optionally
substituted amino group (e.g., amino, mono-C1-4 alkylamino,
di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group
such as tetrahydropyrrole, piperazine, piperidine,
morpholine, thiomorpholine, pyrrole and imidazole, etc.),
an optionally esterified or amidated carboxyl group (e.g.,
carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4
alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally
halogenated C1-4 alkoxy group (e.g., methoxy, ethoxy,
propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.),
an optionally halogenated C1-4 alkoxy-C1-4 alkoxy group (e.g.,
methoxymethoxy, methoxyethoxy, ethoxyethoxy,
trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), a
formyl group, a C2-4 alkanoyl group (e.g., acetyl, propionyl,
etc.) and a C1-4 alkylsulfonyl group (e.g., methanesulfonyl,
ethanesulfonyl, etc.). The number of the substituents is
preferably 1 to 3.
The optionally substituted acyl group as the
substituent of R3 includes those which (1) hydrogen; (2) an
optionally substituted alkyl group (e.g., a C1-10 alkyl
group such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,
neopentyl, hexyl, heptyl, octyl, nonyl and decyl,
preferably a lower (C1-6) alkyl group, or the like is
exemplified); (3) an optionally substituted cycloalkyl
group (e.g., a C3-7 cycloalkyl group such as cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, or the
like is exemplified); (4) an optionally substituted alkenyl
group (e.g., a C2-10 alkenyl group such as allyl, crotyl, 2-
pentenyl and 3-hexenyl, preferably a lower (C2-6) alkenyl
group, or the like is exemplified); (5) an optionally
substituted cycloalkenyl group (e.g., a C3-7 cycloalkenyl
group such as 2-cyclopentenyl, 2-cyclohexenyl, 2-
cyclopentenylmethyl and 2-cyclohexenylmethyl, or the like
is exemplified); (6) a 5- to 6-membered monocycle aromatic
group (for example, phenyl, pyridyl or the like is
exemplified) ; or the like is bonded with the carbonyl group
or the sulfonyl group, (for example, acetyl, propionyl,
butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl,
hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl,
cyclopentanecarbonyl, cyclohexanecarbonyl,
cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl,
benzoyl, nicotinoyl, methanesulfonyl, ethanesulfonyl or the
like). The substituent which may be contained in (2) an
optionally substituted alkyl group, (3) an optionally
substituted cycloalkyl group, (4) an optionally substituted
alkenyl group, (5) an optionally substituted cycloalkenyl
group and (6) an optionally substituted aromatic group of a
5- or 6-rnembered monocycle as describe above, includes a
halogen atom (e.g., fluorine, chlorine, bromine, iodine,
etc.), a nitro group, a cyano group, a hydroxyl group, an
optionally substituted thiol group (e.g., thiol, C1-4
alkylthio, etc.), an optionally substituted amino group
(e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5-
or 6-membered cyclic amino group such as tetrahydropyrrole,
piperazine, piperidine, morpholine, thiomorpholine, pyrrole
and imidazole, etc.), an optionally esterified or amidated
carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl,
carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl,
etc.), an optionally halogenated C1-4 alkoxy group (e.g.,
methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,
trifluoroethoxy, etc.), an optionally halogenated C1-4
alkoxy-C1-4 alkoxy group (e.g., methoxymethoxy,
methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy,
trifluoroethoxyethoxy, etc.), a formyl group, a C2-4
alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4
alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl,
etc.). The number of the substituents is preferably 1 to 3.
The optionally esterified carboxyl group as the
substituent of R3 includes those which (1) hydrogen; (2) an
optionally substituted alkyl group (e.g., a C1-10 alkyl
group such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,
neopentyl, hexyl, heptyl, octyl, nonyl and decyl,
preferably a lower (C1-6) alkyl group, or the like is
exemplified); (3) an optionally substituted cycloalkyl
group (e.g., a C3-7 cycloalkyl group such as cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, or the
like is exemplified); (4) an optionally substituted alkenyl
group (e.g., a C2-10 alkenyl group such as allyl, crotyl, 2-
pentenyl and 3-hexenyl, preferably a lower (C2-6) alkenyl
group, or the like is exemplified); (5) an optionally
substituted cycloalkenyl group (e.g., a C3-7 cycloalkenyl
group such as 2-cyclopentenyl, 2-cyclohexenyl, 2-
cyclopentenylmethyl and 2-cyclohexenylmethyl, or the like
is exemplified); (6) an optionally substituted aryl group
(e.g., phenyl, naphthyl, etc.); or the like is bonded with a
carbonyloxy group, preferably includes a carboxyl group, a
lower (C1-6) alkoxycarbonyl group and an aryloxycarbonyl
group (e.g., methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, phenoxycarbonyl, naphthoxycarbonyl, etc.).
The substituent which may be contained in (2) an optionally
substituted alkyl group, (3) an optionally substituted
cycloalkyl group, (4) an optionally substituted alkenyl
group, (5) an optionally substituted cycloalkenyl group and
(6) an optionally substituted aryl group as describe above,
includes a halogen atom (e.g., fluorine, chlorine, bromine,
iodine, etc.), a nitro group, a cyano group, a hydroxyl
group, an optionally substituted thiol group (e.g., thiol,
C1-4 alkylthio, etc.), an optionally substituted amino group
(e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5-
or 6-membered cyclic amino group such as tetrahydropyrrole,
piperazine, piperidine, morpholine, thiomorpholine, pyrrole
and imidazole, etc.), an optionally esterified or amidated
carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl,
carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl,
etc.), an optionally halogenated C1-4 alkoxy group (e.g.,
methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,
trifluoroethoxy, etc.), an optionally halogenated C1-4
alkoxy-C1-4 alkoxy group (e.g., methoxymethoxy,
methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy,
trifluoroethoxyethoxy, etc.), a formyl group, a C2-4
alkanoyl group (e.g., acetyl, propionyl, etc.) and a C1-4
alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl,
etc.). The number of the substituents is preferably 1 to 3.
The aromatic group in the optionally substituted
aromatic group as the substituent of R3 includes a 5- or 6-
membered homo- or heterocyclic aromatic group such as
phenyl, pyridyl, furyl, thienyl, pyrrolyl, imidazolyl,
pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl,
tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl and
triazolyl; and a condensed heterocyclic aromatic group such
as benzofuran, indole, benzothiophene, benzoxazole,
benzothiazole, indazole, benzimidazole, quinoline,
isoquinoline, quinoxaline, phthalazine, quinazoline,
cinnoline and imidazopyridine. The substituent in the
aromatic group includes a halogen atom (e.g., fluorine,
chlorine, bromine, iodine, etc.), a nitro group, a cyano
group, a hydroxyl group, an optionally substituted thiol
group (e.g., thiol, C1-4 alkylthio, etc.), an optionally
substituted amino group (e.g., amino, mono-C1-4 alkylamino,
di-C1-4 alkylamino, a 5- or 6-membered cyclic amino group
such as tetrahydropyrrole, piperazine, piperidine,
morpholine, thiomorpholine, pyrrole and imidazole, etc.),
an optionally esterified or amidated carboxyl group (e.g.,
carboxyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-4
alkylcarbamoyl, di-C1-4 alkylcarbamoyl, etc.), an optionally
halogenated C1-4 alkyl group (e.g., trifluoromethyl, methyl,
ethyl, etc.), an optionally halogenated C1-4 alkoxy group
(e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,
trifluoroethoxy, etc. ) , a formyl group, a C2-4 alkanoyl
group (e.g., acetyl, propionyl, etc.) and a C1-4
alkylsulfonyl group (e.g., methanesulfonyl, ethanesulfonyl,
etc.). The number of the substituents is preferably 1 to 3.
Such a substituent of R3 may be substituted at any
position of 1 to 4 (preferably, 1 to 2) of the same or
different cyclic rings. Further, in the case where the "5-
or 6-membered cyclic ring" of the "optionally substituted
5- or 6-membered cyclic ring" represented by R3 contains at
least 2 substituents, two substituents among them may bond
each other to form, for example, a lower (C1-6) alkylene
group (e.g., trimethylene, tetramethylene, etc.), a lower
(C1-6) alkyleneoxy group (e.g., -CH2-O-CH2-, -O-CH2-CH2-, -O-
CH2-CH2-CH2-, -O-CH2-CH2-CH2-CH2-, -O-C(CH3) (CH3)-CH2-CH2-,
etc.), a lower (C1-6) alkylene thio group (e.g., -CH2-S-CH2-,
-S-CH2-CH2-, -S-CH2-CH2-CH2-, -S-CH2-CH2-CH2-CH2-, -S-
C(CH3) (CH3)-CH2-CH2-, etc.), a lower (C1-6) alkylenedioxy
group (e.g., -O-CH2-O-, -O-CH2-CH2-O-, -O-CH2-CH2-CH2-O-,
etc.), a lower (C1-6) alkylenedithio group (e.g., -S-CH2-S-,
-S-CH2-CH2-S-, -S-CH2-CH2-CH2-S-, etc.), an oxy-lower (C1-6)
alkylene amino group (e.g., -O-CH2-NH-, -O-CH2-CH2-NH-,
etc.), an oxy-lower (C1-6) alkylene thio group (e.g., -O-
CH2-S-, -O-CH2-CH2-S-, etc.), a lower (C1-6) alkylene amino
group (e.g., -NH-CH2-CH2-, -NH-CH2-CH2-CH2-, etc.), a lower
(C1-6) alkylene diamino group (e.g., -NH-CH2-NH- and -NH-
CH2-CH2-NH-) , a thia-lower (C1-6) alkylene amino group (e.g.,
-S-CH2-NH-, -S-CH2-CH2-NH-, etc.), a lower (C2-6) alkenylene
group (e.g., -CH2-CH=CH-, -CH2-CH2-CH=CH-, -CH2-CH=CH-CH2-,
etc.) and a lower (C4-6) alkadienylene group (e.g., -CH=CH-
CH=CH-, etc.).
In addition, the divalent group formed by bonding two
substituents of R3 each other may contain the same 1 to 3
substituents as those which may be contained in the "5- or
6-membered cyclic ring" of the "optionally substituted 5-
or 6-membered cyclic ring" represented by R3 [a halogen
atom, a nitro group, a cyano group, an optionally
substituted alkyl group, an optionally substituted
cycloalkyl group, an optionally substituted hydroxyl group,
an optionally substituted thiol group (the sulfur atom may
be oxidized to form a sulfinyl group that may be
substituted or a sulfonyl group that may be substituted),
an optionally substituted amino group, an optionally
substituted acyl group, an optionally esterified or
amidated carboxyl group or an optionally substituted
aromatic group].
The substituent which may be contained in the "5- or
6-membered cyclic ring" of the "optionally substituted 5-
or 6-membered cyclic ring" represented by R3, includes in
particular an optionally halogenated or lower-(C1-4)
alkoxylated lower (C1-4) alkyl group (e.g., methyl, ethyl,
t-butyl, trifluoromethyl, methoxymethyl, ethoxymethyl,
propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl,
propoxyethyl, butoxyethyl, etc.), an optionally halogenated
or lower-(C1-4) alkoxylated lower (C 1-4) alkoxy group (e.g.,
methoxy, ethoxy, propoxy, butoxy, t-butoxy,
trifluoromethoxy, methoxymethoxy, ethoxymethoxy,
propoxymethoxy, butoxymethoxy, methoxyethoxy, ethoxyethoxy,
propoxyethoxy, butoxyethoxy, methoxypropoxy, ethoxypropoxy,
propoxypropoxy, butoxypropoxy, etc.), a halogen atom (e.g.,
fluorine, chlorine, etc.), a nitro group, a cyano group, an
amino group which may be substituted with 1 or 2 lower (C1-
4) alkyl groups, formyl or lower (C2-4) alkanoyl (e.g.,
amino, methylamino, dimethylamino, formylamino and
acetylamino), and a 5- or 6-membered cyclic amino group
(e.g., 1-pyrrolidinyl, 1-piperadinyl, 1-piperidinyl, 4-
morpholino, 4-thiomorpholino, 1-imidazolyl and 4-
tetrahydropyranyl).
The "divalent group comprising a linear part
constituted of 1 to 4 atoms" represented by X includes, for
example, - (CH2)a'- [a1 is an integer of 1 to 4 (preferably 1
or 2)], -(CH2)b'-X1- [b1 is an integer of 0 to 3 (preferably
0 or 1), X1 is an optionally substituted imino group (e.g.,
an imino group which may be substituted with lower (C1-6)
alkyl, lower (C3-7) cycloalkyl, formyl, lower (C2-7) alkanoyl
and lower (C1-6) alkoxycarbonyl), a carbonyl group, an
oxygen atom or an optionally oxidized sulfur atom (e.g., -
S(O)m- (m is an integer of 0 to 2) or the like)], -CH=CH-,
-C = C-, -CO-NH- and -SO2-NH-. Such group may bond with a
condensed ring by either of a bond on the left and a bond
on the right, but preferably it binds with a condensed ring
by a bond on the right.
X is preferably a bond, -(CH2)b'-O- [b' is an integer
of 0, 1 or 2 (preferably 0 or 1)] and -C=C-, and more
preferably a bond.
The lower alkyl group of the "optionally substituted
lower alkyl group" represented by R4 as described above
includes, for example, a C1-6 alkyl group such as methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-
butyl, pentyl, isopentyl, neopentyl and hexyl.
The lower alkoxy group of the "optionally substituted
lower alkoxy group" represented by R4 as described above
includes a C1-6 alkoxy group such as methoxy, ethoxy,
propoxy and butoxy.
The substituent which may be contained in the
"optionally substituted lower alkyl group" and "the
optionally substituted lower alkoxy group" includes, for
example, a halogen atom (e.g., fluorine, chlorine, bromine
and iodine), a hydroxyl group, an amino group, a mono-
flower alkyl) amino group, a di-(lower alkyl) amino group
and a lower alkanoyl group.
The lower alkyl which is contained in the mono-(lower
alkyl) amino group and the di-(lower alkyl) amino group
includes, for example, the same lower alkyl group as in the
"optionally substituted lower alkyl group" represented by
R4 as described above.
The lower alkanoyl group includes, for example, a C2-6
alkanoyl group such as acetyl, propionyl, butyryl and
isobutyryl.
The "halogen atoms" represented by R4 as described
above includes fluorine, chlorine, bromine and iodine.
Among them, R4 is preferably an optionally substituted
lower C1-6 alkyl group, preferably a halogen atom, and in
particular preferably an optionally substituted methyl
group and a halogen atom.
The "hydrocarbon group" of the "optionally substituted
hydrocarbon group" represented by R5 includes, for example,
(1) an alkyl group (e.g., a C1-10 alkyl group such as methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-
butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,
nonyl and decyl, preferably a lower (C1-6) alkyl group, more
preferably a lower (C1-4) alkyl group, or the like is
exemplified); (2) a cycloalkyl group (e.g., a C3-7
cycloalkyl group such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and cycloheptyl, or the like is
exemplified); (3) an alkenyl group (e.g., a C2-10 alkenyl
group such as allyl, crotyl, 2-pentenyl and 3-hexenyl,
preferably a lower (C2-6) alkenyl group, or the like is
exemplified); (4) a cycloalkenyl group (e.g., a C3-7
cycloalkenyl group such as 2-cyclopentenyl, 2-cyclohexenyl,
2-cyclopentenylmethyl and 2-cyclohexenylmethyl, or the like
is exemplified); (5) an alkynyl group (e.g., a C2-10 alkynyl
group such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,
2-pentynyl and 3-hexynyl, preferably a lower a C2-6 alkynyl
group, or the like is exemplified), (6) an aralkyl group
(e.g., phenyl-C1-4 alkyl (e.g., benzyl, phenethyl, etc.), or
the like is exemplified), (7) an aryl group (e.g., phenyl,
naphthyl, or the like is exemplified), and (8) a
cycloalkyl-alkyl group (e.g., a C3-7 cycloalkyl-C1-4 alkyl
group such as cyclopropylmethyl, cyclobutylmethyl,
cyclopentylmethyl, cyclohexylmethyl and cycloheptyl methyl,
or the like is exemplified). The substituent which may be
contained in (1) an alkyl group, (2) a cycloalkyl group,
(3) an alkenyl group, (4) a cycloalkenyl group, (5) an
alkynyl group, (6) an aralkyl group, (7) an aryl group and
(8) a cycloalkyl-alkyl group as described above, includes a
halogen atom (e.g., fluorine, chlorine, bromine, iodine,
etc.), a nitro group, a cyano group, a hydroxyl group, an
optionally substituted thiol group (e.g., thiol, C1-4
alkylthio, etc.), an optionally substituted amino group
(e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, a 5-
or 6-membered cyclic amino group such as tetrahydropyrrole,
piperazine, piperidine, morpholine, thiomorpholine, pyrrole
and imidazole, etc.), an optionally esterified or amidated
carboxyl group (e.g., carboxyl, C1-4 alkoxycarbonyl,
carbamoyl, mono-C1-4 alkylcarbamoyl, di-C1-4 alkylcarbamoyl,
etc.), an optionally halogenated C1-4 alkyl group (e.g.,
trifluoromethyl, methyl, ethyl, etc.), an optionally
halogenated C1-4 alkoxy group (e.g., methoxy, ethoxy,
propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.),
a C1-4 alkylenedioxy group (e.g., -O-CH2-O-, -O-CH2-CH2-O-,
etc.), an optionally substituted sulfonamide group [e.g, a
group formed by bonding an optionally substituted amino
group (e.g., amino, mono-C1-4 alkylamino, di-C1-4 alkylamino,
a 5- or 6-membered cyclic amino group such as
tetrahydropyrrole, piperazine, piperidine, morpholine,
thiomorpholine, pyrrole and imidazole, etc.) with -SO2-,
etc.], a formyl group, a C2-4 alkanoyl group (e.g., acetyl
and propionyl) , a C1-4 alkylsulfonyl group (e.g.,
methanesulfonyl and ethanesulfonyl) and an optionally
substituted heterocyclic group. The number of the
substituents is preferably 1 to 3.
The "optionally substituted heterocyclic group"
represented by R5 includes, for example, a group formed by
removing one hydrogen atom from an aromatic heterocycle or
a non-aromatic heterocycle. The aromatic heterocycle
includes a 5- or 6-membered, aromatic heterocycle 1 to 4 of
1 or 2 kinds of hetero atoms selected from a nitrogen atom,
a sulfur atom and an oxygen atom, such as furan, thiophene,
pyrrole, imidazole, pyrazole, thiazole, oxazole,
isothiazole, isoxazole, tetrazole, pyridine, pyrazine,
pyrimidine, pyridazine, triazole, oxadiazole, thiadiazole,
etc., and the non-aromatic heterocycle includes, for
example, a 5- or 6-membered non-aromatic heterocycle
containing 1 to 4 of 1 or 2 kinds of hetero atoms selected
from a nitrogen atom, a sulfur atom and an oxygen atom, and
a non-aromatic heterocycle which a part or all of the bonds
of the above-described aromatic heterocycle is saturated
bonds, such as tetrahydrofuran, tetrahydrothiophene,
dioxolane, dithiolane, oxathiolane, pyrrolidine, pyrroline,
imidazolidine, imidazoline, pyrazolidine, pyrazoline,
piperidine, piperazine, oxazine, oxadiazine, thiazine,
thiadiazine, morpholine, thiomorpholine, pyran and
tetrahydropyran (preferably an aromatic heterocycle such as
pyrazole, thiazole, oxazole and tetrazole).
The substitutent of the "optionally substituted
sulfonyl group" represented by R5 includes the same
substituents as that in the "optionally substituted thiol
group" described as the substituent of R3.
The "optionally esterified carboxyl group" and the
"optionally substituted acyl group" represented by R5
include the same substituents as those described as the
substituent of R3.
The preferable examples of R5 includes a hydrogen atom,
an optionally substituted hydrocarbon group and an
optionally substituted acyl group, more preferably a C1-6
alkyl group, a C1-4 alkylsulfonyl group, a formyl group and
a C2-5 alkanoyl group, even more preferably a C1-4 alkyl
group, a formyl group, a C2-5 alkanoyl group, and even more
preferably a propyl group or an isobutyl group.
The halogen atom represented by Y includes a chlorine
atom and a bromine atom. A lower alkyl group represented
by R9 in -OSO2-R9 which is represented by Y includes a C1-6
alkyl group such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl,
1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-
dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl. The
aryl group in the optionally substituted aryl group
represented by R9 includes, for example, phenyl and
naphthyl, and the substituent in the optionally substituted
aryl group includes, for example, a C1-6 alkyl group (e.g.,
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-
butyl, tert-butyl, pentyl, etc.), a C1-6 alkoxy group (e.g.,
methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
sec-butoxy, tert-butoxy, etc.), a halogen atom (e.g.,
chlorine, bromine, iodine, fluorine, etc.), a nitro group
and a cyano group. A preferable example of the group
represented by the formula -OSO2-R9 includes a
methanesulfonyloxy group and a p-toluenesulfonyloxy group.
m is an integer of 1 to 5, preferably 2 to 4.
n is an integer of 0 to 3, preferably 0 or 1.
*1 and *2 mean that the atom to which *1 or *2 is
attached is an asymmetric atom, respectively.
R6 represents a methyl group, a phenyl group, a 4-
methylphenyl group or a-naphthyl group. R7 represents a
chlorine atom or a nitro group.
The lower alkyl group in the optionally substituted
lower alkyl group represented by R8 includes, for example,
a halogen atom (e.g., fluorine, chlorine, bromine and
iodine), a hydroxyl group, an amino group, a mono-(lower
alkyl) amino group, a di-(lower alkyl) amino group and a
lower alkanoyl group.
The aryl group in the optionally substituted aryl
group represented by R8 includes, for example, a C6-10 aryl
group such as a phenyl group and a naphthyl group, and the
substituent in the optionally substituted aryl group
includes, for example, a halogen atom (e.g., fluorine,
chlorine, bromine and iodine), a hydroxyl group, an amino
group, a mono-(lower alkyl) amino group, a di-(lower alkyl)
amino group and a lower alkanoyl group.
The aralkyl group in the optionally substituted
aralkyl group represented by R8 includes, for example, a C7-
10 aralkyl group such as a benzyl group and a phenethyl
group, and the substituent in the optionally substituted
aralkyl group includes, for example, a halogen atom (e.g.,
fluorine, chlorine, bromine and iodine), a hydroxyl group,
an amino group, a mono-(lower alkyl) amino group, a di-
(lower alkyl) amino group and a lower alkanoyl group.
The optionally substituted lower alkyl group, the
optionally substituted aryl group and the optionally
substituted aralkyl group represented by R10 in -OR10 which
is represented by R8, includes those described as the
optionally substituted lower alkyl group, the optionally
substituted aryl group and the optionally substituted
aralkyl group represented by R8, respectively.
Best Mode for Carrying Out the Invention
Hereinafter, each of the reaction processes of the
present invention will be described in detail.
As described below, each of the compounds represented
by the formulas (I), (II), (III), (IV), (V), (VI), (VII),
(VIII), (IX), (X), (XIa) and (XIb) can form a salt thereof.
The salts include, for example, a salt with an inorganic
base, a salt with an organic base, a salt with an inorganic
acid, a salt with an organic acid, and a salt with a basic
or acidic amino acid. A preferable example of a salt with
an inorganic base includes, for example, an alkali metal
salt such as a sodium salt and a potassium salt; an
alkaline earth metal salt such as a calcium salt and a
magnesium salt; an aluminum salt; and an ammonium salt. A
preferable example of a salt with an organic base includes,
for example, salts with trimethylamine, triethylamine,
pyridine, picoline, ethanolamine, diethanolamine,
triethanolamine, dicyclohexylamine and N,N'-
dibenzylethylenediamine. A preferable example of a salt
with an inorganic acid includes, for example, a salt with
hydrochloric acid, hydrobromic acid, nitric acid, sulfuric
acid and phosphoric acid. A preferable example of a salt
with an organic acid includes, for example, a salt with
formic acid, acetic acid, trifluoroacetic acid, fumaric
acid, oxalic acid, tartaric acid, maleic acid, citric acid,
succinic acid, malic acid, methanesulfonic acid,
benzenesulfonic acid and p-toluenesulfonic acid. A
preferable example of a salt with a basic amino acid
includes, for example, a salt wit^h arginine, lysine, and
ornithine, and a preferable example of a salt with an
acidic amino acid includes, for example, a salt with
asparagic acid, and glutamic acid.
The compound (I) thus obtained can be isolated and
purified by a well-known separation-purification means, for
example, concentration, concentration under reduced
pressure, solvent extraction, crystallization,
recrystallization, solution conversion and chromatography.
Hereinafter, a compound represented by the formula' (I)
and a salt thereof are simply referred to as Compound (I).
Similarly, a compound represented by the formula (II), a
compound represented by the formula (III), a compound
represented by the formula (IV), a compound represented by
the formula (V), a compound represented by the formula (VI),
a compound represented by the formula (VII), a compound
represented by the formula (VIII), a compound represented
by the formula (IX), a compound represented by the formula
(X), a compound represented by the formula (XIa) and a
compound represented by the formula (XIb), including salts
thereof, are simply referred to as Compounds (I),
(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),
(XIa) and (XIb), respectively. In addition, a compound
represented by the formula (XIIa), a compound represented
by the formula (XIIb), and a compound represented by the
formula (XIIc) are also referred to as the compound (XIIa),
the compound (XIIb) and the compound (XIIc), respectively.
These compounds can be isolated by a general
isolation-production means after the reaction in each
process, but they may be also used for the next reaction
without isolation.
The compound (V) can be prepared by reacting the
compound (IV), for example, with an acylating agent (e.g.,
acid chloride, acid bromide, a mixed acid anhydride and
active ester). This reaction is performed in an
appropriate solvent. The solvent includes, for example,
aromatic hydrocarbons (e.g., benzene, toluene and xylene),
ethers (e.g., dioxane, tetrahydrofuran (THF) and
dimethoxyethane), esters (e.g., ethyl acetate), nitriles
(e.g., acetonitrile), ketones (e.g., acetone, 2-butanone,
2-pentanone, 3-pentanone, 2-hexanone, 3-hexanone and methyl
isobutyl ketone), tertiary amines (e.g., pyridine), N,N-
dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-
methylpyrrolidone (NMP), halogenated hydrocarbons (e.g.,
chloroform, dichloromethane, 1,2-dichloroethane and
1,1,2,2-tetrachloroethane) and a mixed solvent thereof.
The amount of the acylating agent used is preferably about
1 to 5 mole equivalents, based on the compound (IV). In
addition, this reaction may be also performed in the
presence of a base. The base includes an alkali metal salt
(e.g., potassium hydroxide, sodium hydroxide, potassium
carbonate, sodium carbonate, potassium hydrogen carbonate
and sodium hydrogen carbonate), amines (e.g.,
trimethylamine, triethylamine, diisopropyl ethylamine, N-
methylmorpholine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU)
and 1,4-diazabicyclo[2,2,2]octane (DABCO)) and aromatic
amines (e.g., N,N-dimethylaminopyridine, N, N-diethylamino
pyridine, pyridine, 4-dimethylaminopyridine, picoline and
quinoline). This reaction is performed generally at -20°C
to 200°C, preferably at about -10°C to 150°C.
Process 2
The compound (VII) can be prepared by reacting the
compound (V) with the compound (VI). The reaction is
performed in an appropriate solvent. The solvent includes,
for example, aromatic hydrocarbons (e.g., benzene, toluene
and xylene), ethers (e.g., dioxane, tetrahydrofuran (THF)
and dimethoxyethane), alcohols (e.g., methanol, ethanol,
propanol, isopropanol, butanol, isobutanol, sec-butanol and
tert-butanol), esters (e.g., ethyl acetate), nitriles (e.g.,
acetonitrile), ketones (e.g., acetone, 2-butanone, 2-
pentanone, 3-pentanone, 2-hexanone, 3-hexanone and methyl
isobutyl ketone), pyridine, N,N-dimethylformamide (DMF),
dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP),
halogenated hydrocarbons (e.g., chloroform, dichloromethane,
1,2-dichloroethane and 1,1,2,2-tetrachloroethane), water
and a mixed solvent thereof. This reaction may be
performed in the presence of a base. The base includes an
alkali metal salt (e.g., potassium hydroxide, sodium
hydroxide, potassium carbonate, sodium carbonate, potassium
hydrogen carbonate and sodium hydrogen carbonate), a metal
hydride (e.g., potassium hydride, sodium hydride and
calcium hydride), amines (e.g., trimethylamine,
triethylamine, diisopropyl ethylamine, N-methylmorpholine,
1, 8-diazabicyclo[5.4.0]-7-undecene (DBU), 1,4-
diazabicyclo[2,2,2]octane (DABCO)) and aromatic amines
(e.g., N,N-dimethylaminopyridine, N,N-diethylaminopyridine,
pyridine, 4-dimethylaminopyridine, picoline and quinoline).
The amount of the compound (VI) used is about 1 to 5 mole
equivalents, preferably about 1 to 3 mole equivalents,
based on Compound (V). In addition, the amount of the base
used is preferably about 1 to 5 mole equivalents, based on
the compound (V). This reaction is performed generally at
-20°C to 200°C, preferably at about -10°C to 150°C.
Process 3
The compounds (VIII) can be prepared by oxidizing the
compound (VII). The reaction is performed in an
appropriate solvent. The solvent includes, for example,
carbohydrates (e.g., benzene, toluene and xylene), ethers
(e.g., dioxane, tetrahydrofuran (THF) and dimethoxyethane),
alcohols (e.g., methanol, ethanol, propanol, isopropanol,
butanol, isobutanol, sec-butanol and tert-butanol), esters
(e.g., ethyl acetate), nitriles (e.g., acetonitrile),
ketones (e.g., acetone, 2-butanone, 2-pentanone, 3-
pentanone, 2-hexanone, 3-hexanone and methyl isobutyl
ketone), pyridine, N,N-dimethylformamide (DMF),
dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP),
halogenated hydrocarbons (e.g., chloroform, dichloromethane,
1,2-dichloroethane and 1,1,2,2-tetrachloroethane), organic
carboxylic acids (e.g., formic acid and acetic acid) and a
mixed solvent thereof. The oxidant used includes, for
example, hydrogen peroxide, organic peroxy acids such as
performic acid, peracetic acid, pertrifluoroacetic acid,
perbenzoic acid, m-chloroperbenzoic acid and
monoperoxyphthalic acid, cumene hydroperoxide, N-
halocarboxylic amides such as N-bromoacetamide, N-
bromosuccinimide and N-chlorosuccinimide, tert-butyl
hypochloride, manganese dioxide, and periodates such as
orthoperiodic acid, sodium metaperiodate and potassium
metaperiodate. In addition, this reaction may be performed
in the presence of an acid catalyst. The acid catalyst
includes, for example, organic acids such as formic acid,
acetic acid and propionic, acid, and mineral acids such as
hydrochloric acid, sulfuric acid, nitric acid and
perchloric acid. In addition, the metal catalyst includes,
for example, vanadium oxide, vanadium oxide acetyl acetate,
manganese oxide, molybdenum chloride and tungsten chloride.
The amount of the oxidant used varies depending on the
reaction conditions, but it is generally 1 to 100 mole
equivalents, preferably 1 to 20 mole equivalents, based on
the compound (VII). The reaction temperature is -50 to
200°C, preferably -30 to 150°C. The amount of the acid or
metal catalyst used is 1/1000 to 100 mole equivalents,
preferably 1/500 to 50 mole equivalents, based on the
compound (VII).
Process 4
The compound (IX) can be prepared by subjecting the
compound (VIII) to deprotection reaction. The deprotection
means include the hydrolysis and the hydrogenolysis. The
hydrolysis is usually performed in a solvent in the
presence of an acid or a base. The solvent includes, for
example, ethers (e.g., dioxane, tetrahydrofuran (THF) and
dimethoxyethane), alcohols (e.g., methanol, ethanol,
propanol, isopropanol, butanol, isobutanol, sec-butanol and
tert-butanol), ketones (e.g., acetone, 2-butanone, 2-
pentanone, 3-pentanone, 2-hexanone, 3-hexanone and methyl
isobutyl ketone), pyridine, N,N-dimethylformamide (DMF),
dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), water
and a mixed solvent thereof. In the case where an acid is
used, the acid includes organic acids such as formic acid,
acetic acid and propionic acid, and mineral acids such as
hydrochloric acid, sulfuric acid, nitric acid and
perchloric acid. In the case where a base is used, the
base includes an alkali metal salt (e.g., potassium
hydroxide, sodium hydroxide, potassium carbonate, sodium
carbonate, calcium carbonate, cesium carbonate, potassium
hydrogencarbonate and sodium hydrogen carbonate). The
amount of the acid or base used is 0.01 to 200 mole
equivalents, preferably 0.1 to 100 mole equivalents, based
on the compound (VIII). The reaction temperature is -20 to
200°C, preferably -10 to 100°C.
The hydrogenolysis reaction is usually performed in a
solvent in the presence of a catalyst. The solvent
includes, for example, aromatic hydrocarbons (e.g., benzene,
toluene and xylene), ethers (e.g., dioxane, tetrahydrofuran
(THF) and dimethoxyethane), esters (e.g., ethyl acetate,
etc.), nitriles (e.g., acetonitrile, etc.), tertiary amines
(e.g., pyridine, etc.), alcohols (e.g., methanol, ethanol,
propanol, isopropanol, butanol, isobutanol, sec-butanol,
tert-butanol, etc.), ketones (e.g., acetone, 2-butanone
(MEK), methyl isobutyl ketone (MIBK), etc.), N,N-
dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-
methylpyrrolidone (NMP), halogenated hydrocarbons (e.g.,
chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-
tetrachloroethane, etc.), water and a mixed solvent thereof.
As the catalyst, for example, palladiums such as palladium
chloride, palladium black and palladium carbon, platinums
such as platinum oxide, platinum black and platinum carbon,
rhodiums such as rhodium carbon, Raney nickel and Raney
cobalt are used. As the hydrogen source, hydrogen, formic
acid, ammonium formate, isopropanol, etc. are used. The
reaction temperature is -70 to 200°C, preferably 0 to 100°C.
The reaction pressure is 0 to 10 MPa, preferably 0 to 5 MPa.
The amount of the catalyst used is 1/10000 to 100 mole
equivalents, preferably 1/1000 to 50 mole equivalents,
based on the compound (VIII). For this hydrogenolysis
reaction, an acid or a base may be added, if necessary. As
the acid, organic acids such as formic acid, acetic acid
and propionic acid, mineral acids such as hydrochloric acid,
sulfuric acid, nitric acid and perchloric acid, etc. are
used, and as the base, an alkali metal salt (e.g.,
potassium hydroxide, sodium hydroxide, potassium carbonate,
sodium carbonate, potassium hydrogen carbonate, sodium
hydrogen carbonate, etc.), amines (e.g., trimethylamine,
triethylamine, diisopropyl ethylamine, N-methylmorpholine,
1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 1,4-
diazabicyclo[2,2,2]octane (DABCO), etc.), aromatic amines
(e.g., N,N-dimethylaminopyridine, N,N-diethylamino pyridine,
pyridine, 4-dimethylaminopyridine, picoline, quinoline,
etc.), etc. are used.
Process 5
Using the compound (IX) and the optically active acid
represented by the formula (XIIa) or (XIIb), optical
resolution is performed via a diastereomeric salt. In the
process of preparing a diastereomeric salt, the reaction is
performed in an appropriate solvent. The solvent includes,
for example, aromatic hydrocarbons such as benzene, toluene
and xylene, ethers such as dioxane, tetrahydrofuran (THF)
and dimethoxyethane, alcohols such as methanol, ethanol,
propanol, isopropanol, butanol, isobutanol, sec-butanol and
tert-butanol, ethyl acetate, acetonitrile, ketones (e.g.,
acetone, 2-butanone, 2-pentanone, 3-pentanone, 2-hexanone,
3-hexanone, methyl isobutyl ketone, etc.), pyridine, N,N-
dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-
methylpyrrolidone (NMP), water, chloroform, dichloromethane,
1,2-dichloroethane, 1,1,2,2-tetrachloroethane and a mixed
solvent thereof. The acidic optical resolution agent
includes, for example, tartaric acid and the derivative
thereof [diacyl tartaric acid (diacetyl tartaric acid,
dibenzoyl tartaric acid, di-p- toluoyl tartaric acid, di-1-
naphthoyl tartaric acid, etc.), etc.], amino acid
(pyroglutaric acid, aspartic acid and a-phenylglycine) and
the derivative thereof [N-acylamino acid (N-acetylleucine,
N-acetylvaline, N-(3,5-dinitro)benzoylphenylglycine, etc.),
etc.] and (+) or (-) phosphoric acid such as a cyclic
phosphate derivative (2,2'-(1,1'-binaphthyl)phosphoric acid
and 4-phenyl-2-hydroxy-5,5-dimethyl-1,3,2-
dioxaphosphorinan-2-oxide. The optical resolution agent
used is preferably dibenzoyl tartaric acid, di-p-toluoyl
tartaric acid, di-1-naphthoyl tartaric acid and N-(3,5-
dinitro)benzoylphenylglycine, and the amount used thereof
is 0.1 to 10 mole equivalents, preferably 0.5 to 5 mole
equivalents, based on the compound (IX). The reaction
temperature is -20 to 200°C, preferably -10 to 100°C.
Process 6
The compound (X) can be prepared by reacting the
compound (IV) with the compound (VI). For this reaction,
the same reaction conditions as those in Process 2 can be
employed.
Process 7
The reaction for derivating the compound (II) from the
compound (X) is performed by reacting the compound (X) with
an oxidant in the presence of the optically active acid
represented by the formula (XIIa) or the formula (XIIc).
This reaction is performed in an appropriate solvent. The
solvent includes, for example, aromatic hydrocarbons such
as benzene, toluene and xylene, ethers such as dioxane,
tetrahydrofuran (THF) and dimethoxyethane, alcohols such as
methanol, ethanol, propanol, isopropanol, butanol,
isobutanol, sec-butanol and tert-butanol, ethyl acetate,
acetonitrile, ketones (e.g., acetone, 2-butanone, 2-
pentanone, 3-pentanone, 2-hexanone, 3-hexanone, methyl
isobutyl ketone, etc.), pyridine, N,N-dimethylformamide
(DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) ,
water, chloroform, dichloromethane, 1,2-dichloroethane,
1,1,2,2-tetrachloroethane, organic carboxylic acids (e.g.,
formic acid, acetic acid, etc.) and a mixed solvent thereof.
The oxidant used includes, for example, hydrogen peroxide,
organic peroxy acids such as performic acid, peracetic acid,
pertrifluoroacetic acid, perbenzoic acid, m-
chloroperbenzoic acid and monoperoxyphthalic acid, cumene
hydroperoxide, N-halocarboxylic acids such as N-
bromoacetamide, N-bromosuccinimide and N-chlorosuccinimide,
tert-butyl hypochloride, manganese dioxide, periodates such
as orthoperiodic acid, sodium metaperiodate and potassium
metaperiodate. In addition, this reaction may be performed
in the presence of an acid catalyst. The acid catalyst
includes, for example, a tartaric acid derivative [diacyl
tartaric acid (dibenzoyl tartaric acid, di-p-toluoyl
tartaric acid, di-1-naphthoyl tartaric acid, etc.), etc.],
and (+) or (-) phosphoric acid such as a cyclic phosphate
derivative (2,2'-(1,1'-binaphthyl)phosphoric acid and 4-
phenyl-2-hydroxy-5, 5-dimethyl-1,3,2-dioxaphosphorinan-2-
oxide. Preferably, dibenzoyl tartaric acid, di-p-toluoyl
tartaric acid, di-1-naphthoyl tartaric acid and 2,2'-(1,1'-
binaphthyl)phosphoric acid are used. The amount of the
optically active acid used is 0.5 to 10 mole equivalents,
preferably 0.5 to 5 mole equivalents, based on 1 mole of
the compound (X). The amount of the oxidant used is 1 to
100 mole equivalents, preferably 1 to 50 mole equivalents,
based on 1 mole of the compound (X). The amount of the
acid used is 0.1 to 10 mole equivalents, preferably 0.5 to
5 mole equivalents, based on 1 mole of the compound (X).
The reaction temperature is -50 to 200°C, preferably -30 to
50°C.
Process 8
The compound (IX) is prepared by oxidizing the
compound (X). For this reaction, the same reaction
conditions as those in Process 3 can be employed.
Process 9
Metathesis reaction of the compound (XI) is performed
in an appropriate solvent by contacting it with an acid or
a base. The solvent includes, for example, aromatic
hydrocarbons such as benzene, toluene and xylene, ethers
such as dioxane, tetrahydrofuran (THF) and dimethoxyethane,
alcohols such as methanol, ethanol, propanol, isopropanol,
butanol, isobutanol, sec-butanol and tert-butanol, ethyl
acetate, acetonitrile, ketones (e.g., acetone, 2-butanone,
2-pentanone, 3-pentanone, 2-hexanone, 3-hexanone, methyl
isobutyl ketone, etc.), N,N-dimethylformamide (DMF),
dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), water,
chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-
tetrachloroethane and a mixed solvent thereof. As the acid,
organic acids such as formic acid, acetic acid and
propionic acid, and mineral acids such as hydrochloric acid,
sulfuric acid, nitric acid and perchloric acid are used,
and as the base, an alkali metal salt (e.g., potassium
hydroxide, sodium hydroxide, potassium carbonate, sodium
carbonate, potassium hydrogencarbonate, sodium hydrogen
carbonate, etc.), amines (e.g., trimethylamine,
triethylamine, diisopropyl ethylamine, N-methylmorpholine,
1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 1,4-
diazabicyclo[2,2,2]octane (DABCO), etc.) and aromatic
amines (e.g., N,N-dimethylaminopyridine, N,N-diethylamino
pyridine, pyridine, 4-dimethylaminopyridine, picoline,
quinoline, etc.) are used. The reaction temperature is -30
to 150°C, preferably -10 to 100°C. The amount of the acid
used or base used is 1 to 200 mole equivalents, preferably
1 to 100 mole equivalents, based on 1 mole of the compound
(XI) .
Process 10
The compound (I) can be prepared by reacting the
compound (II) with the compound (III) or a reactive
derivative thereof. This reaction is usually performed in
a solvent. Any solvent can be used if it does not inhibit
the reaction, but it includes for example, aromatic
hydrocarbons such as benzene, toluene and xylene, ethers
such as dioxane, tetrahydrofuran (THF) and dimethoxyethane,
ethyl acetate, acetonitrile, ketones (e.g., acetone, 2-
butanone, 2-pentanone, 3-pentanone, 2-hexanone, 3-hexanone,
methyl isobutyl ketone, etc.), pyridine, N,N-
dimethylformamide (DMF), N,N-dimethylacetoamide (DMA),
dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP),
chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-
tetrachloroethane, and a mixed solvent thereof. The
reactive derivative means the reactive derivative in the
carboxyl group of the compound represented by the formula
(III). The reactive derivative includes, for example,
those which are well-known in the field of peptide such as
acid chloride, acid bromide, mixed acid anhydride and
active ester. In addition, in the case where the reactive
derivative is used, the reaction may be performed in the
presence of a base. The base includes an alkali metal salt
(e.g., potassium hydroxide, sodium hydroxide, potassium
carbonate, sodium carbonate, potassium hydrogen carbonate
and sodium hydrogen carbonate), amines (e.g.,
trimethylamine, triethylamine, diisopropyl ethylamine, N-
methylmorpholine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU),
1,4-diazabicyclo[2,2,2]octane (DABCO), etc.) and aromatic
amines (e.g., N,N-dimethylaminopyridine, N, N-diethylamino
pyridine, pyridine, 4-dimethylaminopyridine, picoline,
quinoline, etc.). The amount of the base used is
preferably about 1 to 5 mole equivalents, based on the
compound (III) or a reactive derivative thereof.
In addition, the amount of the compound (III) or a
reactive derivative used is preferably about 1 to 5 mole
equivalents, based on Compound (II). The reaction
temperature is usually -20 to 150°C, preferably -10 to
100°C. The reaction time is about 1 to 100 hours.
The compound (III) which is used as a starting
material in the reaction can be prepared according to the
method as described in WO01-17947 (corresponding to JP
2001-151741 A).
Examples and Reference Examples
The present invention is hereinafter described in more
detail by means of the following Examples and Reference
Examples, but the present invention is not limited thereto.
Reference Example 1
1-Isobutylpiperidin-2-one
To a suspension of potassium hydroxide (482 g) in
toluene (700 ml) was added dropwise a solution of 2-
piperidone (181 g) in toluene (100 ml) at 50°C or lower.
Then, to the reaction mixture was added tetrabutylammonium
bromide (5.88 g) and further added dropwise a solution of
isobutyl bromide (500 g) in toluene (100 ml). The mixture
was stirred at 50 to 60°C for 3 hours and then allowed to
cool to room temperature. Water (500 ml) was added to the
reaction mixture and the resulting solution was neutralized
with concentrated hydrochloric acid (460 ml) under ice-
cooling (pH 8) and separated into layers. The aqueous
layer was reextracted with toluene (450 ml), the organic
layers were combined and washed with saturated brine, and
then the solvent was distilled off. The residue was
distilled under reduced pressure and a fraction of b.p.
98°C was collected at 8 mmHg to obtain 23.5 g (yield:
83.1%) of the title compound as a colorless oily matter.
1H-NMR (300MHz, CDCl3, d): 0.86 (6H, d, J = 6.7Hz), 1.73-
1.78 (4H, m), 1.85-2.05 (1H, m) , 2.34-2.38 (2H, m), 3.16
(2H, d, J = 7.7HZ), 3.20-3.25 (2H, m).
Reference Example 2
8-Bromo-l-isobutyl-l,2,3,4-tetrahydro-l-benzazocinee-5-
carboxylic acid
To l-isobutylpiperidin-2-one (10 g) were added
methanesulfonic acid (16.7 ml) and water (35 ml), and the
mixture was stirred under reflux for 24 hours to form 5-
isobutylaminopentanoic acid. The reaction solution was
cooled to 50°C and neutralized with sodium carbonate (13.7
g). The neutralized solution was slowly added dropwise at
110 to 115°C to a mixture of 2-fluoro-5-bromobenzaldehyde
(8.2 g), sodium carbonate (11.1 g), and DMSO (65 ml), and
the mixture was, stirred with heating under reflux for 4
hours. The mixture was cooled to 50°C, water (30 ml) and
toluene (40 ml) were added thereto, and the resulting
solution was adjusted to pH 3.5 with 6 N hydrochloric acid.
The toluene layer was separated and the aqueous layer was
reextracted with toluene (40 ml). The organic layers were
combined and washed with 10% brine and water. The solvent
was distilled off to obtain 5-[(4-bromo-2-
formylphenyl)(isobutyl)amino]pentanoic acid of a brown oily
matter. This compound was dissolved in N,N-
dimethylformamide (24.6 ml), and to the solution was added
potassium carbonate (56.7 g) and then added dropwise methyl
iodide (3 ml). The mixture was stirred at room temperature
for 4 hours, thereto was added dimethyl carbonate (49.2 ml)
and then added dropwise a solution of 28% sodium methoxide
in methanol (15.6 g) , and the mixture was stirred at 60°C
for 1.5 hours. Water was added to the reaction solution
and the mixture was extracted with toluene. The organic
layer was washed with 10% brine and then water. The
solvent was distilled off to obtain methyl 8-bromo-1-
isobutyl-1,2,3,4-tetrahydro-l-benzazocinee-5-carboxylate of
a brown oily matter.
To a solution of methyl 8-bromo-1-isobutyl-1,2,3,4-
tetrahydro-1-benzazocinee-5-carboxylate in tetrahydrofuran
- methanol (2 : 1, 45 ml) was added an aqueous 2 N sodium
hydroxide solution (40 ml) and the reaction mixture was
stirred at 60°C for 2.5 hours. The mixture was allowed to
cool to room temperature and adjusted to pH 3.5 with
concentrated hydrochloric acid, and the mixture was
extracted with toluene. The organic layer was washed with
water, activated carbon (0.8 g) was added thereto, and the
mixture was stirred for 10 minutes. The activated carbon
was filtered off and the solvent was then distilled off.
The residue was dissolved in methanol (24 ml) at 60°C and
to the solution was added dropwise water (6 ml). The
mixture was stirred at room temperature for 1 hour and
crystallized. The crystals were collected by filtration,
washed with methanol - water (5 : 2), and then dissolved in
methanol (24 ml) with heating under reflux. To the
solution was added dropwise water (4.8 ml) at the same
temperature, and the mixture was stirred at room
temperature for 1 hour and crystallized. The crystals were
collected by filtration, washed with methanol - water (5 :
1), and dried at 40°C under reduced pressure to obtain 6.2
g (yield: 45%) of the title compound as yellow powder.
1H-NMR (300MHz, CDCl3, d): 0.97 (6H, d, J = 6.7Hz), 1.43-
1.47 (2H, m) , 2.05-2.25 (1H, m), 2.45-2.55 (2H, m), 3.00
(2H, d, J = 7.3HZ), 3.40-3.50 (2H, m), 6.63 (1H, d, J
=8.9Hz), 7.15-7.30 (2H, m), 7.83 (1H, s).
Elemental analysis value: in terms of C16H20NO2Br
Calcd. value: C, 56.82; H, 5.96; N, 4.14; Br, 23.62
Found value: C, 56.63; H, 5.88; N, 3.92; Br, 23.41
IR (KBr, cm-1) : 1664, 1604, 1494
Melting point: 153.3 - 154.0°C
Reference Example 3
8-[4-(2-Butoxyethoxy)phenyl]-1-isobutyl-12,3,4-tetrahydro-
1-benzazocine-5-carboxylic acid
Under an argon atmosphere, to a suspension of
magnesium (1.3 g) in tetrahydrofuran (100 ml) was slowly
added dropwise one third of a solution of 1-bromo-4-(2-
butoxyethoxy)benzene (14.2 g) in THF (30 ml) with heating
under reflux. After confirming that the reaction was
initiated, to the solution were added dropwise the other
two thirds thereof, and the mixture was stirred for 1 hour
under reflux. To the mixture was added dropwise a solution
of trimethyl borate (5.7 ml) in tetrahydrofuran (30 ml)
while keeping the temperature at -10°C or lower and the
reaction mixture was stirred for 1 hour. The reaction
mixture was warmed to room temperature, thereto were added
palladium acetate (20 mg) and triphenylphosphine (93 mg),
and the mixture was stirred for 30 minutes. To the mixture
were added 8-bromo-1-isobutyl-1,2,3,4-tetrahydro-1-
benzazocine-5-carboxylic acid (10 g), tripotassium
phosphate (39.3 g) and distilled water (80 ml), and the
resulting mixture was stirred for 3 hours with heating
under reflux. After allowing to cool the mixture, water
(100 ml) was added thereto, and the resulting mixture was
adjusted to pH 3 with 6 N hydrochloric acid under ice-
cooling and separated into layers. The aqueous layer was
further extracted with ethyl acetate. The organic layers
were combined and washed with saturated brine, activated
carbon (1 g) and tributylphosphine (1 ml) were added
thereto, and the mixture was stirred at room temperature
for 20 minutes. The activated carbon was filtered off and
the solvent was then distilled off. To the residue was
added isopropyl ether (50 ml) and dissolved therein at 60°C.
The mixture was stirred at room temperature for 2 hours and
then stirred for 1 hour under ice-cooling, and the crystals
were collected by filtration (12.6 g). The crystals were
dissolved in isopropanol (55 ml) at 60°C, to the solution
was added activated carbon (1 g), and the mixture was
stirred for 20 minutes. The activated carbon was filtered
off while the mixture was hot, and the mixture was stirred
at 60°C for 30 minutes, stirred for 1 hour at room
temperature and then stirred for 1 hour under ice-cooling.
The crystals were collected by filtration, washed with cold
isopropanol (10 ml) and dried at 4 0°C under reduced
pressure to obtain 5.30 g (yield: 89%) of the title
compound as yellow powder.
1H-NMR (300MHz, CDCl3, d): 0.94 (3H, t, J = 7.3Hz), 1.00
(6H, d, J = 6.6HZ), 1.35-1.65 (6H, m) , 2.10-2.30 (1H, m) ,
2.55-2.60 (2H, m), 3.08 (2H, d, J = 7.2Hz), 3.45-3.75 (4H,
m) , 3.80-3.85 (2H, m), 4.15-4.20 (2H, m), 6.83 (1H, d, J=
8.8HZ), 6.96 (2H, d, J=8.7Hz), 7.30-7.40 (2H, m), 7.43
(2H, d, J = 8.7Hz), 8.01 (1H, s).
Elemental analysis value: in terms of C28H37NO4
Calcd. value: C, 74.47; H, 8.26; N, 3.10
Found value: C, 74.53; H, 8.51; N, 3.03
IR (KBr, cm-1): 1666, 1604, 1494
Melting point: 119.6 - 120.1°C
Reference Example 4
8-[4-(2-Butoxyethoxy)phenyl]-1-isobutyl-1,2,3,4-tetrahydro-
1-benzazocine-5-carboxylic acid
Under an argon atmosphere, to a suspension of
magnesium (650 mg) in tetrahydrofuran (50 ml) was added
trimethylsilyl chloride (0.07 ml) and the reaction mixture
was stirred at room temperature for 10 minutes. To the
mixture was added dropwise one third of a solution of 1-
bromo-4-(2-butoxyethoxy)benzene (7.08 g) in tetrahydrofuran
(15 ml) . The mixture was slowly warmed (23°C ? 32°C).
After confirming that the reaction was initiated by
coloration in about 30 minutes, to the reaction solution
were added dropwise the other two thirds thereof and after
completion of addition, the mixture was stirred at 4 5 to
50°C for 0.5 hours. The mixture was allowed to cool to
room temperature, thereto was added dropwise a solution of
trimethyl borate (2.9 ml) in tetrahydrofuran (15 ml) while
keeping the temperature at -10°C or lower, and the reaction
mixture was stirred for 1 hour. The reaction mixture was
warmed to room temperature, thereto were added palladium
acetate (10 mg) and triphenylphosphine (47 mg), and the
mixture was stirred for 30 minutes. To the mixture were
added 8-bromo-1-isobutyl-1,2,3,4-tetrahydro-1-benzazocine-
5-carboxylic acid (5 g) , tripotassium phosphate (19.63 g)
and distilled water (40 ml) , and the resulting mixture was
stirred for 2 hours with heating under reflux. The mixture
was allowed to cool, water (50 ml) was added thereto, and
the resulting mixture was adjusted to pH 3 with 6 N
hydrochloric acid and separated into layers. The aqueous
layer was extracted with ethyl acetate (50 ml) . The
organic layers were combined and washed with saturated
brine, activated carbon (0.5 g) and tributylphosphine (0.5
ml) were added thereto, and the mixture was stirred at room
temperature for 20 minutes. The activated carbon was
filtered off and the solvent was then distilled off. To
the residue was added isopropyl ether (25 ml), and the
mixture was heated at 60°C and slowly returned to room
temperature, and stirred at room temperature for two hours
and then stirred for 1 hour under ice-cooling. The
crystals were collected by filtration (6.0 g) and washed
with cold isopropyl ether (10 ml) . The crystals were
dissolved in isopropanol (60 ml) at 60°C, to the solution
was added activated carbon (0.5 g) , and the mixture was
stirred for 20 minutes. The activated carbon was filtered
off and the solvent was then distilled off. To the residue
was added isopropanol (30 ml) , followed by dissolving
therein at 60°C. The mixture was stirred at room
temperature for 3 hours and then stirred for 1 hour under
ice-cooling. The crystals were collected by filtration,
washed with cold isopropanol (10 ml) and dried at 40°C
under reduced pressure to obtain 5.38 g (yield: 80.5%) of
the title compound as yellow powder.
Reference Example 5
1-Isobutylpyrrolidin-2-one
To a solution of 2-pyrrolidone (60 g) in
tetrahydrofuran (300 ml) were added potassium hydroxide
(59.3 g) and tetrabutylammonium bromide (2.5 g) and then
added dropwise isobutyl bromide (144.9 g) at 50°C or lower.
The resulting mixture was stirred at 50 to 60°C for 3 hours
and allowed to cool to room temperature. Insoluble
materials were filtered off and washed with toluene (300
ml). The filtrate was washed with saturated brine (150 ml),
and then the solvent was distilled off. The residue was
distilled under reduced pressure and a fraction of b.p. 97
to 102°C was collected at 3 mmHg to obtain 73 g (yield:
73%) of the title compound as a colorless oily matter.
Reference Example 6
7-Bromo-1-isobutyl-2,3-dihydro-lH-1-benzazepine-4-
carboxylic acid
To 1-isobutylpyrrolidin-2-one (28 g) were added water
(66 ml) and methanesulfonic acid (26 ml) and the resulting
mixture was stirred for 24 hours under reflux. After
allowing to cool the mixture, thereto were added water (30
ml) and sodium carbonate (84.8 g) (vigorously foamed), and
the mixture was stirred for 1 hour. To the reaction
solution was added dimethylsulfoxide (30 ml) and added
dropwise a solution of 5-bromo-2-fluorobenzaldehyde (12.2
g) in dimethylsulfoxide (66 ml). After completion of
addition, the mixture was heated under reflux for 9 hours.
After allowing to cool, the mixture was adjusted to pH 3
with 6 N hydrochloric acid and extracted with ethyl acetate.
The organic layer was washed with 20% brine and the product
was extracted with an aqueous 1 N sodium hydroxide solution
(100 ml). The aqueous layer was adjusted to pH 3 with 6 N
hydrochloric acid and extracted with ethyl acetate. The
solvent was distilled off to obtain 4-[(4-bromo-2-
formylphenyl)(isobutyl)amino]butanoic acid as a brown oily
matter. To a solution of 4-[(4-bromo-2-
formylphenyl)(isobutyl)amino]butanoic acid in N,N-
dimethylformamide (50 ml) was added potassium carbonate
(9.12 g) and added dropwise a solution of methyl iodide
(10.22 g) in N,N-dimethylformamide (10 ml). After stirring
for 1 hour at room temperature, to the resulting solution
was added dimethyl carbonate (120 ml) and added dropwise
28% sodium methoxide (27.8 g) , and the mixture was stirred
at 60°C for 1 hour. The mixture was adjusted to pH 3 with
2 N hydrochloric acid (100 ml) under ice-cooling. Then,
the mixture was adjusted to pH 6.5 with an aqueous 6 N
sodium hydroxide solution and the solvent was distilled off.
The residue was extracted with toluene. The toluene layer
was sequentially washed with an aqueous 1 N sodium
hydroxide solution, 2% brine and water. The solvent was
distilled off to obtain methyl 7-bromo-1-isobutyl-2,3-
dihydro-1H-1-benzazepine-4-carboxylate as a brown oily
matter.
To a solution of the oily matter in tetrahydrofuran -
methanol (1 : 1, 190 ml) was added an aqueous 1 N sodium
hydroxide solution (120 ml) and the reaction mixture was
stirred at 50°C for 1.5 hours. After distilling off about
half of the solvent, the residue was washed with toluene.
The aqueous layer was adjusted to pH 3 with 6 N
hydrochloric acid and extracted with ethyl acetate. The
ethyl acetate layer was washed with 2% brine and the
solvent was then distilled off to pbtain a brown oily
matter. The oily matter was dissolved in methanol (120 ml),
thereto was added activated carbon (1.2 g) , and the mixture
was stirred 60°C for 20 minutes. The activated carbon was
filtered off and the solvent was then distilled off. The
residue was dissolved in methanol (45 ml) at 60°C, to the
solution was added water (9 ml), and the crystals were
precipitated. The mixture was stirred for 8 hours at room
temperature and then stirred for 1 hour under ice-cooling.
The crystals were collected by filtration, washed with cold
methanol - water (1 : 1, 30 ml) and dried at 40°C under
reduced pressure to obtain 10.13 g (yield: 52.1%) of the
title compound.
1H-NMR (300MHz, CDCl3, d): 0.91 (6H, d, J = 6.6Hz), 1.90-
2.25 (1H, m), 2.75-2.85 (2H, m), 3.12 (2H, d, J = 7.4Hz),
3.20-3.30 (2H, m), 6.72 (1H, d, J = 9.0Hz), 7.20-7.30 (1H,
m), 7.44 (1H, s), 7.70 (1H, s).
Elemental analysis value: in terms of C15H18NO2Br
Calcd. value: C, 55.57; H, 5.60; N, 4.32; Br, 24.65
Found value: C, 55.52; H, 5.59; N, 4.13; Br, 24.39
IR (KBr, cm-1) : 1677, 1614, 1490
Melting point: 144.8 - 145.5°C
Reference Example 7
7-[4-(2-Butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-
benzazepine-4-carboxylic acid
Under an argon atmosphere, a suspension of magnesium
(2.25 g) in tetrahydrofuran (140 ml) was heated under
reflux and to the mixture was slowly added dropwise one
third of a solution of 1-bromo-4-(2-butoxyethoxy)benzene
(24.6 g) in tetrahydrofuran (40 ml). After confirming that
the reaction was initiated (the reaction solution was
clouded), to the solution were added dropwise the other two
thirds thereof, and the mixture was stirred for 1 hour
under reflux. After allowing cool the reaction solution to
room temperature, thereto was added dropwise a solution of
trimethyl borate (10 ml) in tetrahydrofuran (40 ml) while
keeping the temperature at -10°C or lower and the reaction
solution was stirred for 1 hour. The reaction solution was
warmed to room temperature, thereto were added palladium
acetate (27 mg) and triphenylphosphine (126 mg), and the
mixture was stirred for 30 minutes. To the mixture were
added 7-bromo-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-
carboxylic acid (19.45 g), tripotassium phosphate (79.6 g)
and distilled water (100 ml), and the resulting solution
was stirred for 2 hours with heating under reflux. After
allowing to cool the mixture, water (150 ml) was added
thereto, and the resulting solution was adjusted to pH 3
with 6 N hydrochloric acid (150 ml) and separated into
layers. The aqueous layer was extracted with toluene (14 0
ml). The organic layer was sequentially washed with an
aqueous 1 N sodium hydroxide solution, 1 N hydrochloric
acid and 20% brine. Activated carbon (2 g) and
tributylphosphine (2 ml) were added to the organic layer
and the mixture was stirred for 20 minutes at room
temperature. The activated carbon was filtered off and the
solvent was then distilled off. To the residue was added
isopropyl ether (80 ml), followed by heating. The mixture
was stirred for 1 hour at room temperature and stirred for
1 hour under ice-cooling, and the crystals were collected
by filtration. The crystals were washed with isopropyl
ether (30 ml) and dried at 40°C under reduced pressure to
obtain 23.72 g (yield: 90.3%) of yellow crystals. The
crystals (2 g) were dissolved in isopropanol (10 ml) with
heating under reflux, to the resulting solution was added
tributylphosphine (0.2 ml), and the mixture was stirred for
2 hours at room temperature and stirred for 1 hour under
ice-cooling. The crystals were collected by filtration,
washed with cold isopropanol (5 ml) and dried at 40°C under
reduced pressure to obtain 1.92 g (yield: 96.0%) of the
pure title compound as yellow crystals.
1H-NMR (300MHz, CDCl3, d): 0.90-1.10 (9H, m) , 1.35-1.50 (2H,
m), 1.55-1.70 (2H, m), 2.00-2.15 (1H, m), 2.85-2.90 (2H, m),
3.20 (2H, d, J = 7.3HZ), 3.30-3.35 (2H, m), 3.58 (2H, d, J
= 6.7HZ), 3.80-3.85 (2H, m) , 4.15-4.20 (2H, m), 6.92 (1H, d,
J = 8.8HZ), 7.01 (2H, d, J = 8.8Hz), 7.40-7.55 (4H, m),
7.91 (1H, s).
Elemental analysis value: in terms of C27H35NO4
Calcd. value: C, 74.11; H, 8.06; N, 3.20
Found value: C, 74.18; H, 8.33; N, 2.95
IR (KBr, cm-1): 1668, 1608, 1500
Melting point: 126.4 - 127.0°C
Reference Example 8
1-Propylpiperidin-2-one
To toluene (750 ml) were added potassium hydroxide
(254 g) and then added tetrabutylammonium bromide (4.87 g)
and to the resulting mixture was slowly added dropwise a
solution of 2-piperidone (150 g) in toluene (150 ml) at 50
to 60°C. The mixture was stirred at the same temperature
for 1 hour. To the mixture was added dropwise propyl
bromide (371 g) at the same temperature. The mixture was
stirred at the same temperature for 1 hour and thereto was
added water (450 ml) while keeping the temperature at 30°C
or lower. The mixture was adjusted to pH 7.2 by adding
dropwise 48% hydrobromic acid and then the organic layer
was separated. The aqueous layer was extracted with
toluene (450 ml). The organic layers were combined and
concentrated under reduced pressure. The residue was
distilled under reduced pressure and a fraction of b.p. 91
to 93°C was collected at 6 mmHg to obtain 169.3 g (yield:
79%) of the title compound as a colorless oily matter.
1H-NMR (CDCl3, d, 300MHz): 0.88 (3H, t, J = 7.4Hz), 1.48-
1.61 (2H, m), 1.74-2.00 (4H, m), 2.33-2.38 (2H, m), 3.22-
3.33 (4H, m).
Reference Example 9
8-Bromo-1-propyl-1,2,3,4-tetrahydro-1-benzazocine-5-
carboxylic acid
1-Propylpiperidin-2-one (55.6 g) was added to 4 N
sodium hydroxide (197 ml) and the resulting mixture was
refluxed for 4 hours. The mixture was cooled to room
temperature and adjusted to pH 6.1 with adding concentrated
hydrochloric acid. To the mixture were added sodium
carbonate (83.5 g), water (255 ml), dimethylsulfoxide (520
ml), and 5-bromo-2-fluorobenzaldehyde (40 g). After
refluxing for 5 hours, the mixture was cooled to 50°C and
adjusted to pH 3.1 with 6 N hydrochloric acid. The mixture
was cooled to room temperature and extracted with ethyl
acetate. The organic layers were combined, washed with 5%
brine and the product was extracted with an aqueous 5%
sodium carbonate solution (440 ml). The aqueous layer was
adjusted to pH 3.3 with 6 N hydrochloric acid and extracted
with a mixed solution of toluene (400 ml) and
tetrahydrofuran (150 ml). The organic layer was
sequentially washed with 5% brine and water, and the
solvent was distilled off to obtain 5-[(4-bromo-2-
formylphenyl)(propyl)amino]valeric acid as a brown oily
matter. The obtained 5-[(4-bromo-2-
formylphenyl)(propyl)amino]valeric acid was dissolved in
N,N-dimethylformamide (120 ml), thereto was added potassium
carbonate (30 g) and further added methyl iodide (33.6 g) ,
and the resulting mixture was stirred at room temperature
for 2 hours. To the mixture was added dimethyl carbonate
(240 ml) and then added dropwise a solution of 28% sodium
methoxide in methanol (91.2 g), and the mixture was stirred
at 60°C for 1 hour. The mixture was cooled to room
temperature, thereto was added water (4 00 ml) and the
mixture was extracted with toluene. The organic layer was
washed with 5% brine and concentrated under reduced
pressure to obtain methyl 8-bromo-1-propyl-1,2,3,4-
tetrahydro-1-benzazocine-5-carboxylate as an oily matter.
The obtained methyl 8-bromo-1-propyl-1,2,3,4-tetrahydro-1-
benzazocine-5-carboxylate was dissolved in a mixed solution
of tetrahydrofuran (100 ml) and methanol (100 ml). To the
solution was added 2 N sodium hydroxide (197 ml) and the
reaction mixture was refluxed for 1 hour. The mixture was
cooled to room temperature and adjusted to pH 3.2 with
adding 6 N hydrochloric acid. The resulting mixture was
extracted with ethyl acetate and the extract was washed
with 5% brine. To the extract was added activated carbon
(2 g), the resulting mixture was stirred for 30 minutes and
then filtered, and the mixture was washed with ethyl
acetate (80 ml). The filtrates were combined and
concentrated under reduced pressure, and to the obtained
crystals were added methanol (90 ml). The resulting
mixture was refluxed for 30 minutes, and stirred at room
temperature for 1 hour and stirred for 2 hours under ice-
cooling. The obtained crystals were collected by
filtration to obtain 29.76 g of
the title compound (yield: 47%)
1H-NMR (CDCl3, d, 300MHz): 0.96 (3H, t, J= 7.4Hz), 1.40-
1.49 (2H, m), 1.59-1.71 (2H, m) , 2.53 (2H, t, J = 6.0Hz),
3.12 (2H, t, J = 7.9HZ), 3.44 (2H, t, J = 5.3Hz), 6.56-6.60
(1H, m) , 7.19-7.23 (2H, m), 7.81 (1H, s).
Reference Example 10
8-[4-(2-Butoxyethoxy)phenyl]-1-propyl-1,2,3,4-tetrahydro-1-
benzazocine-5-carboxylic acid
Under an argon atmosphere, magnesium (675 mg) was
added to tetrahydrofuran (50 ml). To the resulting
suspension was slowly added dropwise a solution of 1-bromo-
4-(2-butoxyethoxy)benzene (7.37 g) in tetrahydrofuran (15
ml) under reflux and the mixture was refluxed for 1 hour.
To the mixture was added dropwise a solution of trimethyl
borate (2.79 g) in tetrahydrofuran (15 ml) at -15 to -10°C
and the mixture was stirred at the same temperature for 30
minutes. The mixture was warmed to room temperature,
thereto were added palladium acetate (13 mg) and
triphenylphosphine (63 mg), and the mixture was stirred at
room temperature for 30 minutes. To the mixture were
sequentially added 8-bromo-1-propyl-l, 2,3,4-tetrahydro-1-
benzazocine-S-carboxylic acid (5.0 g) , potassium phosphate
(20.5 g) and distilled water (40 ml), and the resulting
mixture was refluxed with stirring for 2.5 hours. To the
reaction solution were added palladium acetate (13 mg) and
triphenylphosphine (63 mg), and then the mixture was
refluxed for 50 minutes. The mixture was cooled to room
temperature and water (40 ml) was added thereto. The
resulting solution was adjusted to pH 3.3 with 6 N
hydrochloric acid under ice-cooling and the organic layer
was separated. The aqueous layer was extracted with
toluene. The organic layers were combined and washed with
water and 1 N sodium hydroxide. To the organic layer was
added 0.3 N hydrochloric acid (120 ml) and further added
ethyl acetate, and then insoluble materials was filtered
and the filtrate was separated . The organic layer was
washed with water, thereto were added tributylphosphine
(0.5 ml) and then activated carbon (250 mg), and the
mixture was stirred at room temperature for 30 minutes.
The mixture was filtered, washed with ethyl acetate and
concentrated under reduced pressure. To the obtained
crystals were added ethyl acetate (25 ml) and the mixture
was stirred under reflux. Then, the mixture was stirred
for 1 hour under ice-cooling. The obtained crystals were
filtered and washed with the ice-cooled ethyl acetate (10
ml) to obtain 5.63 g (yield: 83%) of the title compound as
reddish yellow crystals.
1H-NMR (CDCl3, d, 300MHz): 0.90-1.01 (6H, m) , 1.35-1.72 (8H,
m) , 2.57 (2H, t, J = 5.3Hz), 3.19 (2H, t, J = 7.7Hz), 3.48-
3.57 (4H, m), 3.80 (2H, t, J = 4.9Hz), 4.15 (2H, t, J =
4.9HZ), 6.76 (1H, d, J = 8.9Hz), 6.95 (2H, d, J = 8.7Hz),
7.32-7.45 (4H, m), 8.00 (1H, s).
Reference Example 11
5-(Chloromethyl)-1-propyl-1H-imidazole monohydrochloride
To a mixture of 1-butanol (900 ml) and acetic acid
(120 ml) was added dropwise n-propylamine (103 ml) and
further added dropwise methanesulfonic acid (81 ml) at 30°C
or lower. The reaction mixture was returned to room
temperature, thereto were added 1,3-dihydroxyacetone dimer
(90.1 g) and potassium thiocyanate (145.8 g), and the
resulting mixture was stirred at the same temperature for
24 hours. To the mixture was added water (250 ml), the
reaction mixture was stirred at room temperature 2 hours,
and then the precipitated crystals were collected by
filtration. The obtained crystals were washed with water
(100 ml) to obtain (2-mercapto-1-propyl-1H-imidazol-5-
yl)methanol.
The solution of sodium nitrite (1.7 g) in water (5 ml)
was added dropwise to 5 M nitric acid (600 ml) at 20°C or
lower. To the solution was first added dropwise a solution
of all of the above-obtained (2-mercapto-1-propyl-1H-
imidazol-5-yl)methanol in aqueous 3.5 N sodium hydroxide
(215 ml) at 20°C or lower and then the mixture was stirred
at room temperature for 2 hours. Further, to the reaction
mixture was added dropwise at 20°C or lower an aqueous 6 N
sodium hydroxide solution (370 ml) (pH = about 6.5) and
then added dropwise an aqueous 2 M sodium carbonate
solution (370 ml) (pH = about 9) at 20°C or lower. The
mixture was extracted with ethyl acetate - isopropanol (2 :
1, 450 ml) and again, extracted twice with ethyl acetate -
isopropanol (3 : 1, 400 ml). The organic layers were
combined, washed with 10% brine, and dried over anhydrous
magnesium sulfate. The solvent was distilled off to obtain
(l-propyl-1H-imidazol-5-yl)methanol as an oily matter.
To all of the above (1-propyl-1H-imidazol-5-
yl)methanol was added DMF (375 ml)and the remaining ethyl
acetate was distilled off under reduced pressure. Then,
toluene (100 ml) was added thereto and the mixture was
distilled off under reduced pressure. After carrying out
this operation twice, to the residue was added dropwise
thionyl chloride (40.1 ml) at 30°C or lower. The mixture
was returned to room temperature and stirred for two hours.
To the reaction mixture was added toluene (700 ml) and the
resulting mixture was stirred at room temperature for 1
hour. The precipitated crystals were collected by
filtration, washed with toluene (100 ml), and dried at 40°C
under reduced pressure to obtain 63.7 g of the title
compound as white crystals.
1H-NMR (300MHz, CDCl3, d): 0.88 (3H, t, J = 7.35Hz), 1.80-
2.00 (2H, m), 4.21 (2H, t, J = 7.35Hz), 5.05 (2H, s), 7.83
(1H, s), 9.33 (1H, s).
Elemental analysis value: in terms of C7H11ClN2•HCl
Calcd. value: C, 43.10; H, 6.20; N, 14.36
Found value: C, 43.12; H, 5.95; N, 14.28
IR (KBr, cm-1) : 1600
Melting point: 164.8 - 166.4°C
Example 1
2,2,2-Trifluoro-N-(4-{[(1-propyl-1H-imidazol-5-
yl)methyl]thiojphenyl)acetamide
Triethylamine (27.9 ml) was added dropwise to a
solution of 4-aminobenzenethiol (12.5 g) in tetrahydrofuran
(180 ml) at 0 to 10°C. Subsequently, to the reaction
mixture was added dropwise trifluoroacetic anhydride (28.2
ml) at 0 to 10°C and the reaction mixture was stirred at
the same temperature for 0.5 hours. To the reaction
solution was added water (30 ml) and the mixture was
stirred at room temperature for 0.5 hours. To the mixture
was added 20 w/w% brine (30 ml) and the organic layer was
separated. The aqueous layer was extracted with ethyl
acetate (180 ml) . The organic layers were combined and
water (30 ml) was added thereto. The resulting solution
was adjusted to about pH 9 with adding sodium hydrogen
carbonate. After separation into layers, the organic layer
was washed with water (30 ml) and concentrated. To the
precipitated crystals were added n-hexane (120 ml) and the
resulting solution was stirred at room temperature for 17
hours. The crystals were collected by filtration and
washed with n-hexane (20 ml) . The crystals were dried
under reduced pressure to obtain 26.1 g of 2,2,2-trifluoro-
N-(4-mercaptophenyl)acetamide as white crystals.
1H-NMR (CDCl3, 300MHz) d: 3.45 (1H, s) , 7.18 (2H, d, J =
9.4HZ), 7.51 (2H, d, J = 9.4Hz), 9.97 (1H, brs)
Under a nitrogen atmosphere, to a solution of the
above obtained 2,2,2-trifluoro-N-(4-
mercaptophenyl)acetamide (24.8 g) in methanol (99 ml) was
added dropwise triethylamine (29.0 ml) at 0 to 10°C under
ice-cooling. Subsequently, to the reaction mixture was
added dropwise at 0 to 20°C a solution of 5-(chloromethyl)-
1-propyl-1H-imidazole hydrochloride (20.4 g) in distilled
water (21 ml) and the resulting solution was stirred at 20
to 30°C for 0.5 hours. Ethyl acetate (200 ml) was added to
the reaction solution and the organic layer was separated.
Subsequently, after washing with an aqueous 7 w/w% sodium
hydrogen carbonate (50 ml) and water (50 ml), the organic
layer was concentrated. To the precipitated crystals were
added diisopropyl ether (250 ml) and the resulting mixture
was stirred for 0.5 hours with heating under reflux, and
then allowed to cool to room temperature and stirred for 3
hours. The precipitated crystals were collected by
filtration and washed with diisopropyl ether (20 ml) . The
crystals were dried under reduced pressure to obtain 23.8 g
(yield: 73%, calculated from the amount of 4-
aminobenzenethiol) of the title compound as white crystals.
Melting point: 82 - 84°C
Elemental analysis value: in terms of C15H16N3OSF3 • 0. 5 H2O
Calcd. value: C, 51.13; H, 4.86; N, 11.92
Found value: C, 51.41; H, 4.55; N, 11.75
1H-NMR (CDCl3, 300MHz) d: 0.99 (3H, t, J = 7.4Hz), 1.67 (1H,
brs), 1.82-1.94 (2H, m), 3.77 (2H, t, J = 6.6Hz), 3.99 (2H,
s), 6.67 (1H, s), 6.96-7.31 (2H, m) , 7.47 (1H, m), 7.51-
7.59 (2H, m)
IR (KBr, cm-1): 1704, 1504, 1247, 1195, 1160, 1145, 1108
Example 2
2,2,2-Trifluoro-N-(4-{[(1-propyl-1H-imidazol-5-
yl)methyl]thio}phenyl)acetamide (one-pot reaction)
Under a nitrogen atmosphere, triethylamine (27.9 ml)
was added dropwise to a solution of 4-aminobenzenethiol
(12.5 g) in tetrahydrofuran (180 ml) at 0 to 10°C.
Subsequently, to the reaction mixture was added dropwise
trifluoroacetic anhydride (28.2 ml) at 0 to 10°C and the
reaction mixture was stirred at the same temperature for 1
hour. To the reaction solution was added water (30 ml) and
the mixture was stirred at room temperature for 1 hour. To
the solution was added dropwise triethylamine (41.8 ml) at
0 to 10°C. Subsequently, to the reaction solution was
added dropwise at 0 to 20°C a solution of 5-(chloromethyl)-
1-propyl-1H-imidazol'e hydrochloride (19.5 g) in distilled
water (19 ml) and the resulting solution was stirred at the
same temperature for 1 hour. Ethyl acetate (120 ml) was
added to the reaction solution and the organic layer was
separated. Subsequently, after washing with an aqueous 7
w/w% sodium hydrogen carbonate (60 ml) and city water (60
ml), the organic layer was concentrated. To the
concentrate was added diisopropyl ether (150 ml) and the
resulting mixture was stirred at 20 to 30°C for 2 hours.
The precipitated crystals were collected by filtration and
washed with diisopropyl ether (20 ml) . The crystals were
dried under reduced pressure to obtain 33.1 g (yield: 96%,
calculated from the amount of 4-aminobenzenethiol) of the
title compound as white crystals.
Example 3
4-{[(1-Propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenylamine
At 20 to 30°C, 30 w/w% hydrogen peroxide (16.4 g) was
added to a solution of 2,2,2-trifluoro-N-(4-{[(1-propyl-1H-
imidazol-5-yi)methyl]thio)phenyl)acetamide (33.1 g) in
acetic acid (49.7 ml) and the reaction mixture was stirred
at the same temperature for 3 hours. To the reaction was
added ethyl acetate (330 ml), thereto were added dropwise
sodium thiosulfate pentahydrate (35.9 g) and an aqueous 6 N
sodium hydroxide solution (144.6 ml) at 0 to 10°C, and the
reaction mixture was stirred at the same temperature for
0.5 hours. To the mixture was added tetrahydrofuran (330
ml) and the organic layer was separated. The aqueous layer
was again extracted with ethyl acetate/tetrahydrofuran (160
ml/160 ml). The organic layers were combined, washed with
10w/w% brine (80 ml x 2) and concentrated. To the organic
layers was added methanol (330 ml), the organic layers were
dissolved therein and again concentrated.
The concentrate was dissolved in methanol (198.6 ml)
and thereto was added a solution of potassium carbonate
(40.0 g) in water (99.3 ml) at room temperature. The
mixture was warmed to 50°C and stirred for 2.5 hours.
After cooling to 20 to 30°C, the organic layer was
separated and the aqueous layer was extracted with ethyl
acetate (330 ml). The organic layers were combined and
washed with 20 w/w% brine (100 ml), thereto were added
anhydrous magnesium sulfate (5 g) and activated carbon (3
g), and the mixture was stirred at 20 to 30ºC for 0.5 hours.
The solids were filtered off, the filtrate was washed with
ethyl acetate (64 ml) and the organic layer was
concentrated. Ethyl acetate (160 ml) was added to the
concentrate and the product was again concentrated. Ethyl
acetate (132 ml) was added to the concentrate and the
mixture was stirred at 50°C for 1 hour, and then allowed to
cool to 20 to 30°C and stirred at the same temperature for
1 hour. The precipitated crystals were collected by
filtration and washed with ethyl acetate (33 ml). The
obtained crystals were dried under reduced pressure to
obtain 18.5 g (yield: 73%) of the title compound as white
crystals.
Melting point: 143°C (decomposition)
1H-NMR (CDCl3, 300MHz) d: 0.90 (3H, t, J = 7.4Hz), 1.68-
1.78 (2H, m), 3.74 (2H, t, J = 6.5Hz), 3.95-4.08 (4H, m),
6.60 (1H, s), 6.69 (2H, d, J = 6.8Hz), 7.17 (2H, d, J =
6.8HZ), 7.43 (1H, s)
IR (KBr, cm-1): 3397, 3334, 3216, 1650, 1596, 1419, 1018
Example 4
4-{[(l-Propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenylamine
(one-pot reaction)
At 20 to 30°C, 30 w/w% hydrogen peroxide (35.4 g) was
added to a solution of 2,2,2-trifluoro-N-(4-{[(1-propyl-1H-
imidazol-5-yl)methyl]thio}phenyl)acetamide (71.5 g) in
acetic acid (107.3 ml) and the reaction mixture was stirred
at the same temperature for 3 hours. To the reaction
mixture was added methanol (429 ml), thereto were added
dropwise sodium thiosulfate pentahydrate (11. 4 g) and an
aqueous 6 N sodium hydroxide solution (312.2 ml) at 0 to
10°C, and the reaction mixture was stirred at the same
temperature for 1 hour. Subsequently, to the mixture was
added potassium carbonate (86.2 g), the resulting mixture
was warmed to 50°C and stirred for 3 hours. After cooling
to 20 to 30°C, the organic layer was separated and the
aqueous layer was extracted with ethyl acetate (710 ml).
The organic layer was washed with 20 w/w% brine (200 ml),
thereto were added anhydrous magnesium sulfate (10 g) and
activated carbon (7.1 g), and the mixture was stirred at 20
to 30°C for 0.5 hours. The solids were filtered off, the
filtrate was washed with ethyl acetate (200 ml) and the
organic layer was concentrated. Ethyl acetate (358 ml) was
added to concentrate and the mixture was stirred at 50°C
for 2 hours, and then allowed to cool to 20 to 30°C and
stirred at the same temperature for 1 hour. The
precipitated crystals were collected by filtration and
washed with ethyl acetate (72 ml). The obtained crystals
were dried under reduced pressure to obtain 36.3 g (yield:
66%) of the title compound as white crystals.
Example 5
4-{[(1-Propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenylamine
A solution of 5-(chloromethyl)-1-propyl-1H-imidazole
hydrochloride (10.7 g) in distilled water (6 ml) was added
dropwise to a mixed solution of 4-aminobenzenethiol (6.3 g)
and triethylamine (15.3 ml) in 2-propanol (25.2 ml) at 10
to 30°C and the resulting solution was stirred under the
same condition for 1 hour. To the solution was added water
(20 ml) and the mixture was extracted with ethyl acetate
(50 ml x 2). The organic layer was washed with 20 w/w%
brine (20 ml) and concentrated.
The concentrate was dissolved in acetic acid (12.6 ml),
thereto was added 30 w/w% hydrogen peroxide (8.5 g) at 20
to 30°C, and the resulting mixture was stirred at the same
temperature for 2 hours. Thereto were added dropwise
sodium thiosulfate pentahydrate (9.3 g) and an aqueous 6 N
sodium hydroxide solution (36 ml) at 0 to 10°C, and the
reaction mixture was stirred at the same temperature for 1
hour. The mixture was extracted with ethyl acetate/2-
propanol (4/1, 180 ml). The organic layer was washed with
20 w/w% brine (30 ml), to the organic layer were added
anhydrous sodium sulfate and activated carbon (0.6 g) , and
the mixture was stirred at 20 to 30°C for 1 hour. The
solids were filtered off, the filtrate was washed with
ethyl acetate (10 ml) and the organic layer was
concentrated. To the concentrate was added 2-propanol (18
ml) and the concentrate was dissolved therein, and then the
resulting solution was stirred at 20 to 30°C for 0.5 hours.
Subsequently, to the solution was added n-heptane (36 ml)
and the mixture was stirred at 20 to 30°C for 1 hour. The
precipitated crystals were collected by filtration and
washed with 2-propanol/n-heptane (4 ml/2 ml). The obtained
crystals were dried under reduced pressure to obtain 10.2 g
(yield: 73%) of the title compound as white crystals.
Example 6
4-{[(l-Propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenylamine
(one-pot reaction)
A solution of 5-(chloromethyl)-1-propyl-1H-imidazole
hydrochloride (0.78 g) in distilled water (0.5 ml) was
added dropwise to a mixed solution of 4-aminobenzenethiol
(0.46 g) and triethylamine (1.1 ml) in methanol (2 ml) at
10 to 30°C and the resulting solution was stirred under the
same conditions for 1 hour. Subsequently, to the solution
were added acetic acid (1 ml) and 30 w/w% hydrogen peroxide
(0.62 g) at 20 to 30°C, and the resulting mixture was
stirred at the same temperature for 17 hours. Thereto were
added dropwise sodium sulfite (0.69 g) and an aqueous 6 N
sodium hydroxide solution (3 ml) at 0 to 10°C, and the
reaction mixture was stirred at the same temperature for 1
hour. The mixture was extracted with ethyl acetate/2-
propanol. The organic layer was washed with 20 w/w% brine,
to the organic layer were added anhydrous sodium sulfate
and activated carbon (40 mg), and the product was stirred
at 20 to 30°C for 1 hour. The solids were filtered off,
the filtrate was washed with ethyl acetate (10 ml) and the
organic layer was concentrated. To the concentrate was
added ethyl acetate (4 ml) and the concentrate was
dissolved therein, and then the resulting solution was
stirred at 20 to 30°C for 1 hour. The precipitated
crystals were collected by filtration and washed with ethyl
acetate (2 ml). The obtained crystals were dried under
reduced pressure to obtain 0.73 g (yield: 71%) of the title
compound as white crystals.
Example 7
(-)-4- [ [(1-Propyl-1H-imidazol-5-
yl)methyl]sulfinyl]phenylamine(2S,3S)-di(1-
naphthoyl)tartrate
The racemate (50 mg) of 4-[[(1-propyl-1-H-imidazol-5-
yl)methyl]sulfinyl]phenylamine and (2S, 3S)-di(1-
naphthoyl)tartaric acid monohydrate (45.2 mg) were
dissolved in methanol (1.0 ml) and the resulting solution
was stirred at room temperature overnight. The precipitate
was filtered to obtain 56.2 mg of the crystals. As a
result of HPLC analysis, the excess rate of the
diastereomers was 88%de. These crystals (55 mg) were
heated under reflux in ethanol (1.5 ml) for 0.5 hours and
the mixture was stirred at room temperature overnight. The
precipitate was filtered to obtain 48.1 mg of the crystals.
As a result of HPLC analysis, the excess rate of the
diastereomers was 95%de. These crystals (47 mg) were heated
under reflux in methanol (2 ml) and water (1 ml) for 0.5
hours and the mixture was stirred at room temperature
overnight. The precipitate was filtered to obtain 41.8 mg
of the crystals. As a result of HPLC analysis, the excess
rate of the diastereomers was 99%de.
Specific rotation; [a]27D = -45.5 (c = 0.2 MeOH)
Melting point: 178°C (decomposition)
Elemental analysis value: in terms of C13H17N3OS • C26H18O8
Calcd. value: C, 64.90; H, 4.89; N, 5.84; S, 4.44
Found value: C, 64.65; H, 4.63; N, 5.65; S, 4.31
Example 8
(-)-4-{[(1-Propyl-1H-imidazol-5-
yl)methyl]sulfinyl}phenylamine
The racemate (200 mg) of (-)-4-{[(1-propyl-1H-
imidazol-5-yl)methyl]sulfinyl)phenylamine and (2S, 3S)-
di(1-naphthoyl)tartaric acid monohydrate (180.8 mg) were
heated under reflux in ethyl acetate (1.5 ml) and methanol
(4 ml) for about 0.5 hours and the resulting solution as
such was allowed to stand at room temperature. The
precipitate was filtered to obtain 223.6 mg of the crystals,
As a result of HPLC analysis, the excess rate of the
diastereomers was 92%de. These crystals (223 mg) were
heated under reflux in methanol (13 ml) for 0.5 hours and
the mixture was stirred at room temperature overnight. The
precipitate was filtered to obtain 188.1 mg of the crystals.
As a result of HPLC analysis, the excess rate of the
diastereomers was 99%de. These crystals (187 mg) were
metathesized in saturated sodium bicarbonate solution (5
ml) and water (5 ml) and the mixture was extracted three
times with chloroform (about 15 ml). The chloroform layer
was dried over anhydrous magnesium sulfate, and then
concentrated to obtain 62.4 mg (yield: 31%) of the crystals,
As a result of HPLC analysis, the excess rate of the
enantiomers was 99%ee.
H1-NMR (DMSO-d6) d; 0.78-0.82 (3H, t, J = 7.3Hz), 1.58-1.67
(2H, m), 3.72-3.76 (2H, t, J = 7.0Hz), 4.05-4.14 (2H, m) ,
5.71 (2H, s), 6.54 (1H, s), 6.61-6.63 (2H, d, J = 7.6Hz),
7.14-7.16 (2H, d, J = 7.6Hz), 7.59 (1H, s)
Melting point: 137 - 138°C
Example 9
(-)-4-{[(1-Propyl-1H-imidazol-5-
yl)methyl]sulfinyl}phenylamine • di-p-toluoyl-D-tartrate •
monohydrate
To a mixed solution of (2S, 3S)-2,3-bis[(4-
methylbenzoyl)oxy]butane dicarboxylic acid (15.1 g) and 4-
{[(1-propyl-1H-imidazole-5-yl) methyl] sulfinyl}phenylamine
(10.3 g) in 1,2-dimethoxyethane (90 ml) was added dropwise
water (90 ml) and the resulting mixture was stirred at room
temperature overnight. The precipitated crystals were
collected by filtration, washed with 50 v/v% aqueous 1,2-
dimethoxyethane (30 ml), and dried under reduced pressure.
The crystals were dissolved in 50v/v% aqueous acetonitrile
(84 ml) with heating at 70°C and thereto was added water
(42 ml) while keeping at the same temperature. The mixture
was allowed to cool to room temperature, and stirred at
room temperature overnight and subsequently at 0°C for 1
hour. The precipitated crystals were collected by
filtration and washed with 75% aqueous acetonitrile (30 ml)
that was cooled to 0°C. The obtained crystals were dried
under reduced pressure to obtain 10.9 g (yield: 41.6%,
99.6%de) of the title compound as white crystals.
Melting point: 134 - 136°C
Elemental analysis value: in terms of C33H35N3O9S •1 H2O
Theoretical value: C, 59.36; H, 5.59; N, 6.29; S, 4.80
Analytical value: C, 59.26; H, 5.67; N, 6.18; S, 4.77
Example 10
(-)-4-{[(1-Propyl-1H-imidazol-5-
yl)methyl]sulfinyl}phenylamine
(-)-4-{[(1-Propyl-1H-imidazol-5-
yl)methyl]sulfinyl}phenylamine • di-p-toluoyl-D-tartrate
monohydrate (5 g) was dissolved in a mixture of 3 N
hydrochloric acid (10 ml) and ethyl acetate (20ml) and the
aqueous layer was separated. The aqueous layer was
adjusted to pH 9 with 6 N aqueous sodium hydroxide solution
(5 ml), crystallized by adding seed crystals and the
mixture was stirred at room temperature. The crystals were
collected by filtration to obtain 1.88 g (yield: 95.4%) of
the title compound as white powder.
Example 11
(-)-4-{[(1-Propyl-1-H-imidazol-5-
yl)methyl]sulfinyl}phenylamine and (R)-N-(3,5-
dinitrobenzoyl)phenylglycine salt
The racemate (50 mg) of 4-[[(l-propyl-1-H-imidazol-5-
yl)methyl]sulfinyl]phenylamine and (R)-N-(3,5-
dinitrobenzoyl)phenylglycine (65.6 mg) were dissolved in
methanol (1.0 ml) and the resulting solution was allowed to
stand at room temperature overnight. The precipitate was
filtered to obtain 57.9 mg of the crystals. As a result of
HPLC analysis, the excess rate of the diastereomers was
51%de. These crystals (57 mg) were dissolved in ethanol
(1.5 ml) and the product was stirred at room temperature
overnight. The precipitate was filtered to obtain 27.9 mg
of the crystals. As a result of HPLC analysis, the excess
rate of the diastereomers was 80%de.
Example 12
(-)-4-{[(1-Propyl-1H-imidazol-5-
yl)methyl]sulfenyl}phenylamine • di-p-toluoyl-D-tartrate •
monohydrate
4-Aminothiophenol (2.5 g) was dissolved in water (2.5
ml) and isopropanol (10 ml), to the resulting solution was
added triethylamine (5.5 ml) and the mixture was cooled to
-15 to -10°C.
To the mixture was added dropwise a solution of 5-
(chloromethyl)-1-propyl-1H-imidazole hydrochloride (3.9 g)
in water (2.5 ml) at -15 to -10°C and the resulting mixture
was stirred at the same temperature for 1 hour. The
isopropanol was distilled off under reduced pressure and to
the residue was added methyl isobutyl ketone (25 ml) and
the organic layer was washed with water. Activated carbon
(0.1 g) was added to the organic layer and the mixture was
stirred at room temperature for 10 minutes. The organic
layer was concentrated and the concentrate was dissolved in
methyl isobutyl ketone (30 ml).
Separately, di-p-toluoyl-(D)-tartaric acid (7.7 g) was
dissolved in a mixed solution of toluene (90 ml) and methyl
isobutyl ketone (60 ml) and to the resulting solution was
added water (3.6 ml). Subsequently, to the solution was
slowly added dropwise the above-mentioned methyl isobutyl
ketone solution over 2 hours. After stirring for 1 hour,
to the mixture was added 30% hydrogen peroxide (6.8 g) and
the resulting mixture was stirred at room temperature for
24 hours. To the mixture was added methanol (30 ml) and
the resulting solution was stirred at 50°C for 8 hours. To
the solution was added water (30 ml) and the resulting
mixture was stirred at room temperature for 5 hours. The
precipitated crystals were collected by filtration and
washed with water (30 ml) to obtain 7.1 g (yield: 53%) of
the title compound.
Example 13
(-)-7-[4-(2-Butoxyethoxy)phenyl]-1-isobutyl-N-(4-{[(1-
propyl-lH-imidazol-5-yl)methyl]sulfinyl}phenyl)-2,3-
dihydro-1H-1-benzazepine-4-carboxamide
(-)-4-{[(1-Propyl-1H-imidazol-5-
yl)methyl]sulfinyl}phenylamine • di-p~toluoyl-D-tartrate •
monohydrate (5 g) was dissolved in a mixture of 1 N
hydrochloric acid (25 ml) and ethyl acetate (15 ml) and the
aqueous layer was separated. The aqueous layer were made
pH 9 by adding an aqueous 25% potassium carbonate (25 ml)
and extracted three times with ethyl acetate - 2-propanol
(4:1) (25 ml). The organic layer was washed with
saturated brine (25 ml) and dried over magnesium sulfate.
The solvent was distilled off to obtain (-)-4-{[(1-propyl-
1H-imidazol-5-yl)methyl]sulfinyl}phenylamine.
Separately, to a solution of 7-[4-(2-
butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-
benzazepine-4-carboxylic acid (2.56 g) in tetrahydrofuran
(7.5 ml) was added N,N-dimethylformamide (one drop), and
added dropwise oxalyl chloride (0.56 ml) at room
temperature and the resulting solution was stirred for 1
hour to prepare an acid chloride.
To a solution of (-)-4-{[(1-propyl-1H-imidazol-5-
yl)methyl]sulfinyl)phenylamine in tetrahydrofuran (17.5 ml)
was added triethylamine (2.85 ml)(the solution was almost
clear) and added dropwise an acid chloride solution at room
temperature, and the resulting solution was stirred for 1
hour. To the solution was added water (15 ml) and the
mixture was extracted with ethyl acetate. The extract was
sequentially washed with an aqueous 10% acetic acid
solution, saturated sodium bicarbonate solution and 10%
brine, and thereto were added basic silica gel (4 g),
activated carbon (0.4 g) and sodium sulfate (2 g) and the
mixture was stirred for 10 minutes and filtered, and the
solvent was distilled off. To the residue was added tert-
butyl methyl ether (20 ml) and added water (4 ml), and the
resulting mixture was stirred at room temperature for 1
hour. The precipitated crystals were collected by
filtration to obtain tert-butyl methyl ether solvate (3.62
g, 80.3%) of the title compound. To the resulting product
was added ethanol (3.5 ml) and dissolved therein at 40°C,
and thereto was added tert-butyl methyl ether (31.5 ml) and
the mixture was stirred for 14 hours under room temperature
and stirred for 1 hour under ice-cooling. The crystals
were collected by filtration to obtain tert-butyl methyl
ether solvate (3.52 g, 78%, 99%ee) of the title compound as
yellow powder.
1H-NMR (CDCl3, 300MHz) d; title compound : tert-butyl
methyl ether =1 : 0.94; title compound: 0.84-0.97 (12H, m) ,
1.28-1.42 (2H, m) , 1.53-1.75 (4H, m) 2.02-2.11 (1H, m),
2.88-2.94 (2H, m) , 3.17-3.21 (2H, m) , 3.33-3.37 (2H, m),
3.53 (2H, t, J = 6.6HZ), 3.71-3.81 (4H, m), 3.95-4.10 (2H,
m), 4.13-4.16 (2H, m), 6.55 (1H, s), 6.90-6.98 (3H, m),
7.32 (2H, d, J = 8.7HZ), 7.43-7.47 (5H, m), 7.75 (2H, d, J
= 8.7Hz), 8.32 (1H, s), NH undetected, tert-butyl methyl
ether: 1.19 (9H, s), 3.21 (3H, s).
Example 14
(-) -7-[4-(2-Butoxyethoxy)phenyl]-1-isobutyl-N-(4-{[(1-
propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-2,3-
dihydro-1H-1-benzazepine-4-carboxamide
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-
isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid
(2.56 g) in tetrahydrofuran (8 ml) was added N,N-
dimethylformamide (one drop), and added dropwise oxalyl
chloride (0.56 ml) under ice-cooling and the resulting
solution was stirred for 1 hour to prepare an acid chloride
To a solution of (-)-4-{[(1-propyl-1H-imidazol-5-
yl)methyl]sulfinyl}phenylamine in tetrahydrofuran (18 ml)
was added diisopropylethylamine (3.5 ml) and added dropwise
the acid chloride solution at 10°C or lower, and the
resulting solution was stirred for 2 hours. To the
solution was added water (15 ml) and the mixture was
extracted with ethyl acetate. The organic layer was
sequentially washed with 10% aqueous acetic acid solution,
saturated sodium bicarbonate solution and 10% brine, and
thereto were added basic silica gel (4 g), activated carbon
(0.4 g) and sodium sulfate (2 g) and the mixture was
stirred for 10 minutes and filtered, and the solvent was
distilled off. To the residue was added isopropyl acetate
(15 ml) and the residue was dissolved therein with stirring
at 40°C, and the resulting solution was stirred for 14
hours at room temperature. To the solution was added
heptane (15 ml) and the mixture was stirred for 1 hour at
room temperature, and then ice-cooled. The crystals were
collected by filtration to obtain isopropyl acetate solvate
(2.93 g) of the title compound. Subsequently, thereto was
added isopropyl acetate (10 ml). After dissolution at 40°C,
the solution was stirred for 4 hours at room temperature
and stirred for 1 hour under ice-cooling. The crystals
were collected by filtration, washed with isopropyl acetate
(15 ml) and dried under reduced pressure to obtain
isopropyl acetate solvate (2.8 g, 77.1%) of the title
compound as yellow powder.
1H-NMR (CDCl3, 300MHz) 8; title compound : isopropyl
acetate = 1 : 0.80; title compound: 0.84-0.97 (12H, m),
1.28-1.42 (2H, m), 1.53-1.75 (4H, m) 2.02-2.11 (1H, m) ,
2.88-2.94 (2H, m) , 3.17-3.21 (2H, m) , 3.33-3.37 (2H, m),
3.53 (2H, t, J = 6.6HZ), 3.71-3.81 (4H, m), 3.95-4.10 (2H,
m), 4.13-4.16 (2H, m), 6.55 (1H, s), 6.90-6.98 (3H, m),
7.32 (2H, d, J = 8.7HZ), 7.43-7.47 (5H, m), 7.75 (2H, d, J
= 8.7Hz), 8.32 (1H, s), isopropyl acetate: 1.27 (6H, d, J =
6.3HZ), 2.06 (3H, s), 4.99-5.08 (1H, m) .
Example 15
(-)-8-[4-(2-Butoxyethoxy)phenyl]-1-isobutyl-N-(4-{[(1-
propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-1,2,3,4-
tetrahydro-1-benzazocine-5-carboxamide • methanesulfonate
8-[4-(2-Butoxyethoxy)phenyl]-1-isobutyl-1,2,3,4-
tetrahydro-1-benzazocine-5-carboxylic acid (986 mg) was
dissolved in tetrahydrofuran (3 ml) and thereto was added
N,N-dimethylformamide (one drop). Subsequently, to the
resulting solution was added dropwise oxalyl chloride (0.2
ml, 2.29 mmol) under ice-cooling and the mixture was
stirred for 80 minutes under ice-cooling to prepare an acid
chloride.
Separately, (-)-4-{[(1-propyl-1H-imidazol-5-
yl)methyl]sulfinyl}phenylamine (689 mg) was added to
tetrahydrofuran (7 ml) and the resulting solution was
cooled to 5ºC. To the solution was added dropwise pyridine
(0.62 ml) and added dropwise the acid chloride solution at
3 to 5°C, and the mixture was stirred for 2 hours under
ice-cooling. To the mixture was added water (20 ml) at
10°C or lower and the mixture was extracted with ethyl
acetate. The organic layer was sequentially washed with
water, saturated sodium bicarbonate solution and water, and
concentrated under reduced pressure. Thereto was added
toluene and the mixture was concentrated under reduced
pressure. Thereto was added acetonitrile and the mixture
was concentrated under reduced pressure. The residue was
dissolved in acetonitrile (7 ml) and acetone (7 ml),
thereto was added dropwise methanesulfonic acid (209 mg) ,
and added seed crystals and the mixture was stirred at room
temperature for 100 minutes. Subsequently, to the mixture
was added acetone - acetonitrile (1 : 1, 5 ml) . After
stirring at room temperature overnight, the mixture was
stirred for 2.5 hours under ice-cooling. The precipitated
crystals were collected by filtration and washed with the
ice-cooled acetone (9 ml). The crystals were dried at 40°C
under reduced pressure to obtain 1.51 g (yield: 87%) of the
title compound as yellow crystals.
1H-NMR (300MHz, DMSO-d6, d): 0.78-0.96 (12H, m) , 1.25-1.40
(2H, m), 1.41-1.51 (4H, m), 1.65-1.85 (2H, m), 2.05-2.15
(1H, m), 2.30 (3H, s), 2.35-2.50 (2H, m), 3.05-3.15 (2H, m) ,
3.30-3.55 (4H, m) , 3.65-3.70 (2H, m), 3.90-4.05 (2H, m),
4.05-4.10 (2H, m), 4.30 (1H, d, J = 14.73Hz), 4.65 (1H, d,
J = 14.73HZ), 6.85 (1H, d, J = 8.97Hz), 6.97 (1H, d, J =
8.79HZ), 7.17 (1H, s), 7.35-7.75 (6H, m), 7.92 (2H, d, J=
8.79HZ), 9.08 (1H, s), 10.15 (1H, s).
Elemental analysis value: in terms of C41H52N4O4S • CH4SO3
Calcd. value: C, 63.61; H, 7.12; N, 7.06; S, 8.09
Found value: C, 63.65; H, 7.23; N, 7.05; S, 8.08
Example 16
(-)-8-[4-(2-Butoxyethoxy)]phenyl]-1-isobutyl-N-(4-{[(1-
propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-1,2,3,4-
tetrahydro-1-benzazocine-5-carboxamide • methanesulfonate
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-
isobutyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylic acid
(5 g) in tetrahydrofuran (15 ml) was added N,N-
dimethylformamide (one drop), added dropwise oxalyl
chloride (1.1 ml) under ice-cooling and the mixture was
stirred for 1 hour to prepare an acid chloride.
Separately, to a solution of (-)-4-{[(1-propyl-1H-
imidazol-5-yl)methyl]sulfinyl}phenylamine (3.22 g) in
tetrahydrofuran (35 ml) was added diisopropylethylamine
(6.7 ml) and added dropwise the acid chloride solution at
10°C or lower, and the resulting mixture was stirred for 1
hour. To the mixture were added water (50 ml) and toluene
(50 ml), and the mixture was adjusted to about pH 4 by
adding acetic acid (about 8 ml) and separated into layers.
The organic layer was washed with saturated sodium
bicarbonate solution to adjust to pH 7 to 8, washed with
10% brine, and then thereto were added basic silica gel (4
g), activated carbon (0.5 g) and sodium sulfate (2 g) and
the mixture was stirred for 10 minutes and filtered, and
washed with toluene (20 ml). The solvent was distilled off
and the residue was dissolved in methyl isobutyl ketone (15
ml) and thereto was added methanesulfonic acid (0.65 ml),
and added seed crystals (80 mg) and the mixture was stirred
for 16 hours. To the mixture was added methyl isobutyl
ketone - ethyl acetate (1 : 1, 50 ml), and the resulting
mixture was stirred for 2 hours under ice-cooling. The
crystals were collected by filtration and dried at 40°C
under reduced pressure to obtain 6.62 g of yellow powder.
These crystals were suspended in methyl isobutyl ketone (40
ml) and the suspension was stirred for 16 hours, and then
thereto was added ethyl acetate (40 ml) and the resulting
solution was stirred at room temperature for 1 hour and
stirred for 2 hours under ice-cooling. The crystals were
collected by filtration to obtain 6.05 g (yield: 68.7%) of
the title compound as yellow powder.
Example 17
(-)-4-{[(1-Propyl-1H-imidazol-5-
yl)methyl] sulfinyl}phenylamine • di-p-toluoyl-D-tartrate •
monohydrate
To a solution of di-p-toluoyl-D-tartaric acid (1.9 g)
in toluene (15 ml) and methyl isobutyl ketone (30 ml) was
added a solution of 4-{[(1-propyl-1H-imidazol-5-
yl)methyl]thio}phenylamine (1.2 g) in methyl isobutyl
ketone (15 ml). Subsequently, to the resulting mixture was
added 30% hydrogen peroxide (1.7 g) and the mixture was
stirred at room temperature for 3 weeks. The precipitated
crystals were collected by filtration. The obtained
crystals were dried until they became constant weight to
obtain 2.9 g (yield: 87%, 82.7%de) of the title compound.
The crystals were added to acetonitrile/water (9 ml/9 ml)
and the mixture was stirred at 60°C for 0.5 hours, and
thereto was added dropwise water (9 ml). The mixture was
stirred at the same temperature for 0.5 hours, stirred at
room temperature for 1 hour, and stirred for 1 hour under
ice-cooling. The precipitated crystals were collected by
filtration and washed with ice-cooled acetonitrile/water (4
ml/2 ml). The obtained crystals were dried until they
became constant weight to obtain 2.4 g (yield: 72%,
98.1%de) of the title compound.
Example 18
(+)-4-{[(1-Propyl-1H-imidazol-5-
yl)methyl]sulfinyl}phenylamine
To a mixture of 4-{[(1-propyl-1H-imidazol-5-
yl)methyl]thio}phenylamine (0.99 g) and (R) - (-)-1, 1'-
binapthyl-2,2'-diyl hydrogenphosphate (0.14 g) in
dichloromethane (5 ml) was added 30% hydrogen peroxide
(0.14 g) and the mixture was stirred at room temperature
for 6 hours. A portion of the reaction solution was
sampled and analyzed by high performance liquid
chromatography (HPLC). Conversion rate: 52%, Optical
purity: 35.0%ee.
HPLC condition:
Column: Chiralcel (Daicel) OD
Mobile phase: Hexane - ethanol (85 : 15)
Flow rate: 1 ml/min
Temperature: 35°C
(+)-isomer: 21 min, (-)-isomer: 27 min
Example 19
(-)-8-[4-(2-Butoxyethoxy)phenyl]-1-isobutyl-N-(4-{[(1-
propy1-1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-1,2,3,4-
tetrahydro-1-benzazocine-5- carboxamide • methanesulfonate
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-
isobutyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylic acid
(90 g) in tetrahydrofuran (7.5 ml) was added N,N-
dimethylformamide (4 60 mg) and then added dropwise thionyl
chloride (24.9 g) at 10 to 15°C, and the resulting solution
was stirred at the same temperature for 40 minutes to
prepare an acid chloride.
Separately, to a solution of (-)-4-{[(1-propyl-1H-
imidazol-5-yl)methyl]sulfinyl}phenylamine in
tetrahydrofuran (540 ml) was added pyridine (55.18 g) , the
resulting solution was adjusted to 5°C or lower, and then
thereto was added dropwise the acid chloride solution at
5°C or lower, and the resulting mixture was stirred at the
same temperature for 2.8 hours. To the mixture were added
water (540 ml) and 20% aqueous citric acid solution (360
ml), tetrahydrofuran was distilled off under reduced
pressure and the residue was extracted with ethyl acetate.
The extract was sequentially washed with water, saturated
sodium bicarbonate solution and water, and then the solvent
was distilled off. To the residue was added acetonitrile
(720 ml) and ethyl acetate (720 ml) and added dropwise
methanesulfonic acid (18.2 g), and the resulting mixture
was stirred at room temperature for 1 hour. The
precipitated crystals were collected by filtration to
obtain 141.8 g (yield: 94.4%) of the title compound as
yellow crystals.
Example 20
(-)-8-[4-(2-Butoxyethoxy)phenyl]-1-propyl-N-(4-{[(1-propyl-
1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-1,2,3,4-
tetrahydro-1-benzazocine-5-carboxamide • methanesulfonate
According to the same method as that described in
Example 15, the title compound was produced from 8-[4-(2-
butoxyethoxy)phenyl]-1-propyl-1,2,3,4-tetrahydro-1-
benzazocine-5-carboxylic acid and (-)-4-{[(1-propyl-1H-
imidazol-5-yl) methyl]sulfinyl}phenylamine.
1H-NMR (CDCl3, d, 300MHz) 0.88-1.01 (9H, m), 1.37-1.42 (2H,
m), 1.57-1.80 (8H, m), 2.63 (2H, br) , 2.77 (3H, s), 3.27
(2H, br), 3.51-3.57 (4H, m), 3.77-3.86 (4H, m), 3.90-4.05
(1H, m), 4.14 (2H, t, J = 4.6Hz), 4.25 (1H, d, J = 14.6Hz),
6.73 (1H, s), 6.84 (1H, d, J = 8.7Hz), 6.93 (2H, d, J =
8.8HZ), 7.21 (2H, d, J = 8.7Hz), 7.40-7.48 (4H, m), 7.61
(1H, s), 7.89 (2H, d, J = 8.7HZ), 8.65 (1H, s) , 9.27 (1H,
br)
Elemental analysis value: in terms of C41H54N4O7S2
Calcd. value: C, 63.21; H, 6.99; N, 7.19; S, 8.23
Analytical value: C, 63.00; H, 7.09; N, 7.41;, S, 8.25
Example 21
(-)-8-[4-(2-Butoxyethoxy)phenyl]-1-isobutyl-N-(4-{[(1-
propyl -1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-1,2,3,4-
tetrahydro-1-benzazocine-5-carboxamide
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-
isobutyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylic acid
(45 g) in tetrahydrofuran (135 ml) was added N,N-
dimethylformamide (230 mg) and added dropwise thionyl
chloride (12.45 g) at 10 to 15°C, and the resulting
solution was stirred at the same temperature for 4 0 minutes
to prepare an acid chloride.
Separately, to a solution of (-)-4-{[(1-propyl-1H-
imidazol-5-yl)methyl]sulfinylJphenylamine in
tetrahydrofuran (270 ml) was added pyridine (27.59 g), the
resulting mixture was adjusted to 5°C or lower, and then
thereto was added dropwise the acid chloride solution at
5°C or less, and the resulting mixture was stirred at the
same temperature for 2 hours. To the mixture were added
water (270 ml) and 20% aqueous citric acid solution (180
ml) , tetrahydrofuran was distilled off under reduced
pressure and the residue was extracted with ethyl acetate.
The extract was sequentially washed with water, saturated
sodium bicarbonate solution and water, and then the solvent
was distilled off. To the residue was added ethyl acetate
(360 ml) , added heptane (360 ml) at 40°C and added seed
crystals of (-)-8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-
(4-{[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-
1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide (10 mg) , and
the mixture was stirred at 25°C for 2 hours and stirred at
5°C for 1 hour. The precipitated crystals were collected
by filtration to obtain 63.97 g (yield: 92.1%) of the title
compound. Melting point: 120 - 122°C.
Elemental analysis value: in terms of C41H52N4O4S
Calcd. value: C, 70.66; H, 7.52; N, 8.04
Analytical value: C, 70.42; H, 7.52; N, 8.01
Industrial Applicability
According to the present invention, an optically
active sulfoxide derivative having CCR5 antagonism or an
intermediate compound thereof can be prepared without
causing side reactions such as racemization and Pummerer
rearrangement. In particular, Process 7 is industrially
advantageous since it is possible to prepare an optically
active Compound (II) by asymmetric oxidization in the
presence of an optically active acid.
WE CLAIM;
1. A process for preparing an optically active
compound represented by the formula (I):
wherein R1 represents a hydrogen atom,
an aliphatic hydrocarbon group selected from the
group consisting of a C1-10 alkyl group, a C2-10 alkenyl group,
a C2-10 alkynyl group, a C3-7 cycloalkyl group and a C3-7
cycloalkenyl group, each of said alkyl, alkenyl and alkynyl
groups optionally being substituted with 1 to 3
substituents selected from the group consisting of a
halogen atom, a nitro group, a cyano group, a hydroxyl
group, a C1-4 alkoxy group, a thiol group, a C1-4 alkylthio
group, an amino group, a mono-C1-4 alkylamino group, a di-C1-
4 alkylamino group, a 5- or 6-membered cyclic amino group,
imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a
carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4
alkylcarbamoyl group, an optionally halogenated C1-4 alkoxy
group, an optionally halogenated C1-4 alkoxy-C1-4 alkoxy
group, a formyl group, a C2-4 alkanoyl group and a C1-4
alkylsulfonyl group, and each of said cycloalkyl and
cycloalkenyl groups optionally being substituted with 1 to
3 substituents selected from the group consisting of a
halogen atom, a nitro group, a cyano group, a hydroxyl
group, a thiol group, a C1-4 alkylthio group, an amino group,
a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a
5- or 6-membered cyclic amino group, imidazole, a carboxyl
group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a
mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl
group, an optionally halogenated C1-4 alkoxy group, an
optionally halogenated C1-4 alkoxy-C1-4 alkoxy group, a
formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl
group, or
an aromatic group selected from the group consisting
of a 5- or 6-membered homo- or heterocyclic aromatic group
and a condensed heterocyclic aromatic group which may be
substituted with 1 to 3 substituents selected from the
group consisting of a halogen atom, a nitro group, a cyano
group, a hydroxyl group, a thiol group, a C1-4 alkylthio
group, an amino group, a mono-C1-4 alkylamino group, a di-C1-
4 alkylamino group, a 5- or 6- membered cyclic amino group,
imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a
carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4
alkylcarbamoyl group, an optionally halogenated C1-4 alkyl
group, an optionally halogenated C1-4 alkoxy group, a formyl
group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group;
R2 represents (1) a halogen atom, (2) a nitro group,
(3) a cyano group, (4) a C1-10 alkyl group which may be
substituted with 1 to 3 substituents selected from the
group consisting of a halogen atom, a nitro group, a cyano
group, a hydroxyl group, a C1-4 alkoxy group, a thiol group,
a C1-4 alkylthio group, an amino group, a mono-C1-4
alkylamino group, a di-C1-4 alkylamino group, a 5- or 6-
membered cyclic amino group, imidazole, a carboxyl group, a
C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4
alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an
optionally halogenated C1-4 alkoxy group, an optionally
halogenated C1-4 alkoxy-C1-4 alkoxy group, a formyl group, a
C2-4 alkanoyl group and a C1-4 alkylsulfonyl group, (5) a C3-7
cycloalkyl group which may be substituted with 1 to 3
substituents selected from the group consisting of a
halogen atom, a nitro group, a cyano group, a hydroxyl
group, a thiol group, a C1-4 alkylthio group, an amino group,
a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a
5- or 6-membered cyclic amino group, imidazole, a carboxyl
group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a
mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl
group, an optionally halogenated C1-4 alkoxy group, an
optionally halogenated C1-4 alkoxy-C1-4 alkoxy group, a
formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl
group, (6) hydroxyl group which may be substituted with a
substituent selected from the group consisting of a C1-10
alkyl group a C3-7 cycloalkyl group, a saturated 5- to 6-
membered heterocyclic ring group containing 1 to 2
heteroatoms, a C2-10 alkenyl group, a C3-7 cycloalkenyl group,
a phenyl-C1-4 alkyl group, a formyl group, a C2-4 alkanoyl
group, a C1-4 alkylsulfonyl group, a phenyl group, and a
naphthyl group each of which may be substituted with a
substituent selected from the group consisting of a halogen
atom, a nitro group, a cyano group, a hydroxyl group, a
thiol group, a C1-4 alkylthio group, an amino group, a mono-
C1-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6-
membered cyclic amino group, imidazole, a carboxyl group, a
C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4
alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an
optionally halogenated C1-4 alkyl group, an optionally
halogenated C1-6 alkoxy group, a formyl group, a C2-4
alkanoyl group, a C1-4 alkylsulfonyl group, and a 5- to 6-
membered aromatic heterocycle, which contains 1 to 4
heteroatoms of 1 to 2 kinds selected from a nitrogen atom,
a sulfur atom and an oxygen atom and may be substituted
with 1 to 3 substituents selected from the group consisting
of a halogen atom, a nitro group, a cyano group, a hydroxyl
group, a thiol group, an amino group, a carboxyl group, an
optionally halogenated C1-4 alkyl group, an optionally
substituted C1-4 alkoxy group, a formyl group, a C2-4
alkanoyl group and a C1-4 alkylsulfonyl group, (7) a thiol
group (the sulfur atom may be oxidized to form a sulfinyl
group or a sulfonyl group) which may be substituted with a
substituent selected from the group consisting of a C1-10
alkyl group a C3-7 cycloalkyl group, a saturated 5- to 6-
membered heterocyclic ring group containing 1 to 2
heteroatoms, a C2-10 alkenyl group, a C3-7 cycloalkenyl group,
a phenyl-C1-4 alkyl group, a formyl group, a C2-4 alkanoyl
group, a C1-4 alkylsulfonyl group, a phenyl group, and a
naphthyl group each of which may be substituted with a
substituent selected from the group consisting of a halogen
atom, a nitro group, a cyano group, a hydroxyl group, a
thiol group, a C1-4 alkylthio group, an amino group, a mono-
C1-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6-
membered cyclic amino group, imidazole, a carboxyl group, a
C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4
alkylcarbamoyl group, a di-C1-4 alkylcarbaraoyl group, an
optionally halogenated C1-4 alkyl group, an optionally
halogenated C1-6 alkoxy group, a formyl group, a C2-4
alkanoyl group, a C1-4 alkylsulfonyl group, and a 5- to 6-
membered aromatic heterocycle, which contains 1 to 4
heteroatoms of 1 to 2 kinds selected from a nitrogen atom,
a sulfur atom and an oxygen atom and may be substituted
with 1 to 3 substituents selected from the group consisting
of a halogen atom, a nitro group, a cyano group, a hydroxyl
group, a thiol group, an amino group, a carboxyl group, an
optionally halogenated C1-4 alkyl group, an optionally
substituted C1-4 alkoxy group, a formyl group, a C2-4
alkanoyl group and a C1-4 alkylsulfonyl group, (8) an amino
group which may be substituted with 1 or 2 substituents
selected from the group consisting of a C1-10 alkyl group, a
C3-7 cycloalkyl group, a saturated 5- to 6-membered
heterocyclic ring group containing 1 to 2 heteroatoms, a C2-
10 alkenyl group, a C3-7 cycloalkenyl group, a phenyl-C1-4
alkyl group, a formyl group, a C2-4 alkanoyl group, a C1-4
alkylsulfonyl group, a phenyl group, and a naphthyl group
each of which may be substituted with a substituent
selected from the group consisting of a halogen atom, a
nitro group, a cyano group, a hydroxyl group, a thiol group,
a C1-4 alkylthio group, an amino group, a mono-C1-4
alkylamino group, a di-C1-4 alkylamino group, a 5- or 6-
membered cyclic amino group, imidazole, a carboxyl group, a
C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4
alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an
optionally halogenated C1-4 alkyl group, an optionally
halogenated C1-6 alkoxy group, a formyl group, a C2-4
alkanoyl group, a C1-4 alkylsulfonyl group, and a 5- to 6-
membered aromatic heterocycle, which contains 1 to 4
heteroatoms of 1 to 2 kinds selected from a nitrogen atom,
a sulfur atom and an oxygen atom and may be substituted
with 1 to 3 substituents selected from the group consisting
of a halogen atom, a nitro group, a cyano group, a hydroxyl
group, a thiol group, an amino group, a carboxyl group, an
optionally halogenated C1-4 alkyl group, an optionally
substituted C1-4 alkoxy group, a formyl group, a C2-4
alkanoyl group and a C1-4 alkylsulfonyl group, or these two
substituents may bond each other to form a 5- or 6-membered
cyclic amino group or imidazole having a bond on the
nitrogen atom and optionally substituted with 1 to 3
substituents selected from the group consisting of a
halogen atom, a nitro group, a cyano group, a hydroxyl
group, a thiol group, a C1-4 alkylthio group, an amino group,
a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a
5- or 6-membered cyclic amino group, imidazole, a carboxyl
group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a
mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl
group, an optionally halogenated C1-4 alkoxy group, an
optionally halogenated C1-4 alkoxy-C1-4 alkoxy group, a
formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl
group, (9) an acyl group formed by bonding (a) hydrogen,
(b) a C1-10 alkyl group, (c) a C3-7 cycloalkyl group, (d) a
C2-10 alkenyl group, (e) a C3-7 cycloalkenyl group, or (f) a
5- to 6-membered monocycle aromatic group with a carbonyl
group or a sulfonyl group which may be substituted with 1
to 3 substituents selected from the group consisting of a
halogen atom, a nitro group, a cyano group, a hydroxyl
group, a thiol group, a C1-4 alkylthio group, an amino group,
a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a
5- or 6-membered cyclic amino group, imidazole, a carboxyl
group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a
mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl
group, an optionally halogenated C1-4 alkoxy group, an
optionally halogenated C1-4 alkoxy-C1-4 alkoxy group, a
formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl
group, (10) a group formed by bonding (a) hydrogen; (b) a
C1-10 alkyl group, (c) a C3-7 cycloalkyl group, (d) a C2-10
alkenyl group, (e) a C3-7 cycloalkenyl group, (6) phenyl or
(7) naphthyl with a carbonyloxy group which may be
substituted with 1 to 3 substituents selected from the
group consisting of a halogen atom, a nitro group, a cyano
group, a hydroxyl group, a thiol group, a C1-4 alkylthio
group, an amino group, a mono-C1-4 alkylamino group, a di-1-
4 alkylamino group, a 5- or 6-membered cyclic amino group,
imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a
carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4
alkylcarbamoyl group, an optionally halogenated C1-4 alkoxy
group, an optionally halogenated C1-4 alkoxy-Ci_4 alkoxy
group, a formyl group, a C2-4 alkanoyl group and a C1-4
alkylsulfonyl group, or (12) an aromatic group selected
from the group consisting of a 5- or 6-membered homo- or
heterocyclic aromatic group and a condensed heterocyclic
aromatic group which may be substituted with 1 to 3
substituents selected from the group consisting of a
halogen atom, a nitro group, a cyano group, a hydroxyl
group, a thiol group, a C1-4 alkylthio group, an amino group,
a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a
5- or 6- membered cyclic amino group, imidazole, a carboxyl
group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a
mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl
group, an optionally halogenated C1-4 alkyl group, an
optionally halogenated C1-4 alkoxy group, a formyl group, a
C2-4 alkanoyl group and a C1-4 alkylsulfonyl group;
R3 represents a 5- or 6-membered cyclic ring formed by
removing one hydrogen atom from a 6-membered aromatic
hydrocarbon, a 5- to 6-membered aliphatic hydrocarbon, a 5-
to 6-membered aromatic heterocycle containing 1 to 4
heteroatoms of 1 to 2 kinds selected from a nitrogen atom,
a sulfur atom and an oxygen atom, or a 5- to 6-membered
non-aromatic heterocycle containing 1 to 4 heteroatoms of 1
to 2 kinds selected from a nitrogen atom, a sulfur atom and
an oxygen atom, which may be substituted with 1 to 3
substituents selected from the group consisting of (1) a
halogen atom, (2) a nitro group, (3) a cyano group, (4) a
C1-10 alkyl group which may be substituted with 1 to 3
substituents selected from the group consisting of a
halogen atom, a nitro group, a cyano group, a hydroxyl
group, a thiol group, a C1-4 alkylthio group, an amino group,
a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a
5- or 6-membered cyclic amino group, imidazole, a carboxyl
group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a
mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl
group, an optionally halogenated C1-4 alkoxy group, an
optionally halogenated C1-4 alkoxy-C1-4 alkoxy group, a
formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl
group, (5) a C3-7 cycloalkyl group which may be substituted
with 1 to 3 substituents selected from a group consisting
of a halogen atom, a nitro group, a cyano group, a hydroxyl
group, a thiol group, a C1-4 alkylthio group, an amino group,
a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a
5- or 6-membered cyclic amino group, imidazole, a carboxyl
group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a
mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl
group, an optionally halogenated C1-4 alkoxy group, an
optionally halogenated C1-4 alkoxy-C1-4 alkoxy group, a
formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl
group, (6) a hydroxyl group which may be substituted with a
substituent selected from the group consisting of (a) a C1-10
alkyl group, (b) a C3-7 cycloalkyl group,, (c) a saturated
5- to 6-membered heterocyclic group containing 1 to 2
heteroatoms, (d) a C2-10 alkenyl group, (e) a C3-7
cycloalkenyl group, (f) a phenyl-C1-4 alkyl group, (g) a
formyl group, (h) a C2-4 alkanoyl group, (i) a C1-4
alkylsulfonyl group, (j) a phenyl group and (k) a naphthyl
group, each of which may be substituted with 1 to 3
substituents selected from the group consisting of a
halogen atom, a nitro group, a cyano group, a hydroxyl
group, a thiol group, a C1-4 alkylthio group, an amino group,
a mono-Ci-4 alkylamino group, a di-C1-4 alkylamino grouop, a
5- or 6-membered cyclic amino group, imidazole, a carboxyl
group, a c1-4 alkoxycarbonyl group, a carbamoyl group, a
mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl
group, an optionally halogenated C1-4 alkyl group, an
optionally halogenated C1-4 alkoxy group, a formyl group, a
C2-4 alkanoyl group, a C1-4 alkylsulfonyl group, and a 5- to
6-membered aromatic heterocycle containing 1 to 4
heteroatoms of 1 to 2 kinds selected from a nitrogen atom,
a sulfur atom and an oxygen atom and may be substituted
with 1 to 3 substituents selected from the group consisting
of a halogen atom, a nitro group, a cyano group, a hydroxyl
group, a thiol group, an amino group, a carboxyl group, an
optionally halogenated C1-4 alkyl group, a C1-4 alkoxy group,
a formyl group, a C2-4 alkanoyl group and a C1-4
alkylsulfonyl group (7) a thiol group (the sulfur atom may
be oxidized to form a sulfinyl group or a sulfonyl group)
which may be substituted with a substituent selected from
the group consisting of a C1-10 alkyl group a C3-7 cycloalkyl
group, a saturated 5- to 6-membered heterocyclic ring group
containing 1 to 2 heteroatoms, a C2-10 alkenyl group, a C3-7
cycloalkenyl group, a phenyl-C1-4 alkyl group, a formyl
group, a C2-4 alkanoyl group, a C1-4 alkylsulfonyl group, a
phenyl group, and a naphthyl group each of which may be
substituted with a substituent selected from the group
consisting of a halogen atom, a nitro group, a cyano group,
a hydroxyl group, a thiol group, a C1-4 alkylthio group, an
amino group, a mono-C1-4 alkylamino group, a di-C1-4
alkylamino group, a 5- or 6-membered cyclic amino group,
imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a
carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4
alkylcarbamoyl group, an optionally halogenated C1-4 alkyl
group, an optionally halogenated C1-6 alkoxy group, a formyl
group, a C2-4 alkanoyl group, a C1-4 alkylsulfonyl group, and
a 5- to 6-membered aromatic heterocycle, which contains 1
to 4 heteroatoms of 1 to 2 kinds selected from a nitrogen
atom, a sulfur atom and an oxygen atom and may be
substituted with 1 to 3 substituents selected from the
group consisting of a halogen atom, a nitro group, a cyano
group, a hydroxyl group, a thiol group, an amino group, a
carboxyl group, an optionally halogenated C1-4 alkyl group,
an optionally substituted C1-4 alkoxy group, a formyl group,
a C2-4 alkanoyl group and a C1-4 alkylsulfonyl group, (8) an
amino group which may be substituted with 1 or 2
substituents selected from the group consisting of a C1-10
alkyl group, a C3-7 cycloalkyl group, a saturated 5- to 6-
membered heterocyclic ring group containing 1 to 2
heteroatoms, a C2-10 alkenyl group, a C3-7 cycloalkenyl group,
a phenyl-C1-4 alkyl group, a formyl group, a C2-4 alkanoyl
group, a C1-4 alkylsulfonyl group, a phenyl group, and a
naphthyl group each of which may be substituted with a
substituent selected from the group consisting of a halogen
atom, a nitro group, a cyano group, a hydroxyl group, a
thiol group, a C1-4 alkylthio group, an amino group, a mono-
C1-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6-
membered cyclic amino group, imidazole, a carboxyl group, a
C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4
alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an
optionally halogenated C1-4 alkyl group, an optionally
halogenated C1-6 alkoxy group, a formyl group, a C2-4
alkanoyl group, a C1-4 alkylsulfonyl group, and a 5- to 6-
membered aromatic heterocycle, which contains 1 to 4
heteroatoms of 1 to 2 kinds selected from a nitrogen atom,
a sulfur atom and an oxygen atom and may be substituted
with 1 to 3 substituents selected from the group consisting
of a halogen atom, a nitro group, a cyano group, a hydroxyl
group, a thiol group, an amino group, a carboxyl group, an
optionally halogenated C1-4 alkyl group, an optionally
substituted C1-4 alkoxy group, a formyl group, a C2-4
alkanoyl group and a C1-4 alkylsulfonyl group, or these two
substituents may bond each other to form a 5- or 6-membered
cyclic amino group or imidazole having a bond on the
nitrogen atom and optionally substituted with 1 to 3
substituents selected from the group consisting of a
halogen atom, a nitro group, a cyano group, a hydroxyl
group, a thiol group, a C1-4 alkylthio group, an amino group,
a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a
5- or 6-membered cyclic amino group, imidazole, a carboxyl
group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a
mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl
group, an optionally halogenated C1-4 alkoxy group, an
optionally halogenated C1-4 alkoxy-C1-4 alkoxy group, a
formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl
group, (9) an acyl group formed by bonding (a) hydrogen,
(b) a C1-10 alkyl group, (c) a C3-7 cycloalkyl group, (d) a
C2-10 alkenyl group, (e) a C3-7 cycloalkenyl group, or (f) a
5- to 6-membered monocycle aromatic group with a carbonyl
group or a sulfonyl group which may be substituted with 1
to 3 substituents selected from the group consisting of a
halogen atom, a nitro group, a cyano group, a hydroxyl
group, a thiol group, a C1-4 alkylthio group, an amino group,
a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a
5- or 6-membered cyclic amino group, imidazole, a carboxyl
group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a
mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl
group, an optionally halogenated C1-4 alkoxy group, an
optionally halogenated C1-4 alkoxy-C1-4 alkoxy group, a
formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl
group, (10) a group formed by bonding (a) hydrogen; (b) a
C1-10 alkyl group, (c) a C3-7 cycloalkyl group, (d) a C2-10
alkenyl group, (e) a C3-7 cycloalkenyl group, (f) phenyl or
(g) naphthyl with a carbonyloxy group which may be
substituted with 1 to 3 substituents selected from the
group consisting of a halogen atom, a nitro group, a cyano
group, a hydroxyl group, a thiol group, a C1-4 alkylthio
group, an amino group, a mono-C1-4 alkylamino group, a di-C1-
4 alkylamino group, a 5- or 6-membered cyclic amino group,
imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a
carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4
alkylcarbamoyl group, an optionally halogenated C1-4 alkoxy
group, an optionally halogenated C1-4 alkoxy-C1-4 alkoxy
group, a formyl group, a C2-4 alkanoyl group and a C1-4
alkylsulfonyl group, or (11) an aromatic group selected
from the group consisting of a 5- or 6-membered homo- or
heterocyclic aromatic group and a condensed heterocyclic
aromatic group which may be substituted with 1 to 3
substituents selected from the group consisting of a
halogen atom, a nitro group, a cyano group, a hydroxyl
group, a thiol group, a C1-4 alkylthio group, an amino group,
a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a
5- or 6- membered cyclic amino group, imidazole, a carboxyl
group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a
mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl
group, an optionally halogenated C1-4 alkyl group, an
optionally halogenated C1-4 alkoxy group, a formyl group, a
C2-4 alkanoyl group and a C1-4 alkylsulfonyl group,
or two of these substituents may bond each other to
form a C1-6 alkylene group, a C1-6 alkyleneoxy group, a C1-6
alkylene thio group, a C1-6 alkylenedioxy group, a C1-6
alkylenedithio group, an oxy-C1-6 alkylene amino group, an
oxy-C1-6 alkylene thio group, a C1-6 alkylene amino group, a
C1-6 alkylene diamino group, a thia-C1-6 alkylene amino group,
a C2-6 alkenylene group or a C4-6 alkadienylene group, which
may be substituted with the same 1 to 3 substituents as the
above substituents (1) to (11);
R4 represents a hydrogen atom, a C1-4 alkyl group, a
C1-6 alkoxy group or a halogen atom, said alkyl or alkoxy
group being optionally substituted with a halogen atom, a
hydroxyl group, an amino group, a mono-(C1-6 alkyl) amino
group, a di-(C1-6 alkyl) amino group and a C2-6 alkanoyl
group;
R5 represents a hydrogen atom,
a hydrocarbon group selected from the group
consisting of (1) a C1-10 alkyl group, (2) a C3-7 cycloalkyl
group, (3) a C2-10 alkenyl group, (4) a C3-7 cycloalkenyl
group, (5) a C2-10 alkynyl group, (6) a phenyl-C1-4 alkyl
group, (7) a phenyl group, (8) a naphthyl group and (9) a
C3-7 cycloalkyl-C1-4 alkyl group, each of which may be
substituted with 1 to 3 substituents selected from the
group consisting of a halogen atom, a nitro group, a cyano
group, a hydroxyl group, a thiol group, a C1-4 alkylthio
group, an amino group, a mono-C1-4 alkylaitiino group, a di-C1-
4 alkylamino group, a 5- or 6-membered cyclic amino group,
imidazole, a carboxyl group, a C1-4 alkoxycarbonyl group, a
carbamoyl group, a mono-C1-4 alkylcarbamoyl group, a di-C1-4
alkylcarbamoyl group, an optionally halogenated C1-4 alkyl
group, an optionally halogenated C1-4 alkoxy group, a C1-4
alkylenedioxy group, a group formed by bonding an amino
group, a mono-C1-4 alkylamino group, a di-C1-4 alkylamino
group, a 5- or 6-membered cyclic amino group or imidazole -
SO2-, a formyl group, a C2-4 alkanoyl group, a C1-4
alkylsulfonyl and a heterocyclic group,
a group formed by removing one hydrogen atom from a
5- or 6-membered, aromatic heterocycle 1 to 4 of 1 or 2
kinds of hetero atoms selected from a nitrogen atom, a
sulfur atom and an oxygen atom, a 5- or 6-membered non-
aromatic heterocycle containing 1 to 4 of 1 or 2 kinds of
hetero atoms selected from a nitrogen atom, a sulfur atom
and an oxygen atom, or a non-aromatic heterocycle which a
part or all of the bonds of the above-described aromatic
heterocycle is saturated bonds,
a sulfonyl group which may be substituted with a
substituent selected from the group consisting of a C1-10
alkyl group a C3-7 cycloalkyl group, a saturated 5- to 6-
membered heterocyclic ring group containing 1 to 2
heteroatoms, a C2-10 alkenyl group, a C3-7 cycloalkenyl group,
a phenyl-C1-4 alkyl group, a formyl group, a C2-4 alkanoyl
group, a C1-4 alkylsulfonyl group, a phenyl group, and a
naphthyl group each of which may be substituted with a
substituent selected from the group consisting of a halogen
atom,- a nitro group, a cyano group, a hydroxyl group, a
thiol group, a C1-4 alkylthio group, an amino group, a mono-
Ci-4 alkylamino group, a di-C1-4 alkylamino group, a 5- or 6-
membered cyclic amino group, imidazole, a carboxyl group, a
C1-4 alkoxycarbonyl group, a carbamoyl group, a mono-C1-4
alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl group, an
optionally halogenated C1-4 alkyl group, an optionally
halogenated C1-6 alkoxy group, a formyl group, a C2-4
alkanoyl group, a C1-4 alkylsulfonyl group, and a 5- to 6-
membered aromatic heterocycle, which contains 1 to 4
heteroatoms of 1 to 2 kinds selected from a nitrogen atom,
a sulfur atom and an oxygen atom and may be substituted
with 1 to 3 substituents selected from the group consisting
of a halogen atom, a nitro group, a cyano group, a hydroxyl
group, a thiol group, an amino group, a carboxyl group, an
optionally halogenated C1-4 alkyl group, an optionally
substituted C1-4 alkoxy group, a formyl group, a C2-4
alkanoyl group and a C1-4 alkylsulfonyl group,
a group formed by bonding (a) hydrogen; (b) a C1-10
alkyl group, (c) a C3-7 cycloalkyl group, (d) a C2-10 alkenyl
group, (e) a C3-7 cycloalkenyl group, (f) phenyl or (g)
naphthyl with a carbonyloxy group which may be substituted
with 1 to 3 substituents selected from the group consisting
of a halogen atom, a nitro group, a cyano group, a hydroxyl
group, a thiol group, a C1-4 alkylthio group, an amino group,
a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a
5- or 6-membered cyclic amino group, imidazole, a carboxyl
group, a C1-4 alkoxycarbonyl group, a carbamoyl group, a
mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl
group, an optionally halogenated C1-4 alkoxy group, an
optionally halogenated C1-4 alkoxy-C1-4 alkoxy group, a
formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl
group, or
an acyl group formed by bonding (a) hydrogen, (b) a
C1-10 alkyl group, (c) a C3-7 cycloalkyl group, (d) a C2-10
alkenyl group, (e) a C3-7 cycloalkenyl group, or (f) a 5- to
6-membered monocycle aromatic group with a carbonyl group
or a sulfonyl group which may be substituted with 1 to 3
substituents selected from the group consisting of a
halogen atom, a nitro group, a cyano group, a hydroxyl
group, a thiol group, a C1-4 alkylthio group, an amino group,
a mono-C1-4 alkylamino group, a di-C1-4 alkylamino group, a
5- or 6-membered cyclic amino group, imidazole, a carboxyl
group, a 1-4 alkoxycarbonyl group, a carbamoyl group, a
mono-C1-4 alkylcarbamoyl group, a di-C1-4 alkylcarbamoyl
group, an optionally halogenated C1-4 alkoxy group, an
optionally halogenated C1-4 alkoxy-C1-4 alkoxy group, a
formyl group, a C2-4 alkanoyl group and a C1-4 alkylsulfonyl
group;
X represents (1) a bond, (2) a group represented by -
(CH2)a'- , wherein a' is an integer of 1 to 4, (3) a group
represented by - (CH2)b'-x1-, wherein b' is an integer of 0 to
3, and X1 is an imino group which may be substituted with
C1-6 alkyl, C3-7 cycloalkyl, formyl, C2-7 alkanoyl or C1-6
alkoxycarbonyl, a carbonyl group, an oxygen atom or -S(O)m-,
wherein m is an integer of 0 to 2, (4) -CH=CH-, (5) -C=C-,
(6) -CO-NH- or (6) -SO2-NH-, such group may bond with a
condensed ring by either of a bond on the left and a bond
on the right;
the ring A represents a benzene ring which may be
substituted with a halogen atom, a C1-4 alkyl group which
may be substituted with a halogen atom or a C1-4 alkoxy
group which may be substituted with a halogen atom;
m is an integer of 1 to 5;
n represents an integer of 0 to 3;
p represents an integer of 0 to 2; and
*1 represents an asymmetric center,
or a salt thereof, which comprises reacting a compound
represented by the formula (IV):
wherein the ring A is as defined above,
or a salt thereof, with a compound represented by the
formula (VI):
wherein Y represents a halogen atom or a group
represented by the formula -OSO2-R9 wherein R9 represents a
lower alkyl group or an optionally substituted aryl group;
and
the other symbols are as defined above,
or a salt thereof,
to obtain a compound represented by the formula (X)
oxidizing the compound represented by the formula (X) or a
salt in the presence of an optically active compound
represented by the formula (XIIa):
wherein R6 represents a methyl group, a phenyl group,
a 4-methylphenyl group or a a-naphthyl group; and
*2 represents an asymmetric center,
or an acid which is optically active with respect to axial
asymmetry, and represented by the formula (XIIc):
to obtain an optically active compound represented by the
formula (II)
wherein each symbol is as defined above,
reacting the compound represented by the formula II or a
salt thereof, with a compound represented by the formula
(III) :
wherein each symbol is as defined above, a salt
thereof, or a reactive derivative thereof.
2. An optically active compound represented by the
formula (II):
wherein R1 represents a hydrogen atom, an optionally
substituted aliphatic hydrocarbon group or an optionally
substituted aromatic group;
R2 represents a halogen atom, a nitro group, a cyano
group, an optionally substituted alkyl group, an optionally
substituted cycloalkyl group, an optionally substituted
hydroxyl group, an optionally substituted thiol group (the
sulfur atom may be oxidized to form a sulfinyl group that
may be substituted or a sulfonyl group that may be
substituted), an optionally substituted amino group, an
optionally substituted acyl group, an optionally esterified
carboxyl group or an optionally substituted aromatic group;
the ring A represents a benzene ring which may be
substituted with a halogen atom, a C1-4 alkyl group which
may be substituted with a halogen atom or a C1-4 alkoxy
group which may be substituted with a halogen atom;
n represents an integer of 0 to 3;
p represents an integer of 0 to 2; and
*1 represents an asymmetric center, or a salt thereof.
3. The optically active compound according to claim
2, wherein R1 and R2 each represents a C1-6 alkyl group; and
n represents 1 or 2, or a salt thereof.
4. The optically active compound according to claim
2, wherein R1 represents a C1-6 alkyl group; p represents 0;
n represents 1; and
5. Process as claimed in claim 1 wherein the
optically active compound, represented by the formula (II),
wherein R1 represents a hydrogen atom/ an optionally
substituted aliphatic hydrocarbon group or an optionally
substituted aromatic group;
R2 represents a halogen atom, a nitro group, a cyano
group, an optionally substituted alkyl group, an optionally
substituted cycloalkyl group, an optionally substituted
hydroxyl group, an optionally substituted thiol group (the
sulfur atom may be oxidized to form a sulfinyl group that
may be substituted or a sulfonyl group that may be
substituted), an optionally substituted amino group, an
optionally substituted acyl group, an optionally esterified
carboxyl group or an optionally substituted aromatic group;
the ring A represents a benzene ring which may be
substituted with a halogen atom, a C1-4 alkyl group which
may be substituted with a halogen atom or a C1-4 alkoxy
group which may be substituted with a halogen atom;
n represents an integer of 0 to 3;
p represents an integer of 0 to 2; and
*1 represents an asymmetric center,
or a salt thereof is prepared by a process which comprises
subjecting an optically active compound represented by the
formula (XIa)
wherein R6 represents a methyl group, a phenyl group, a
4-methylphenyl group or a a-naphthyl group;
*2 represents an asymmetric center; and
the other symbols are as defined above,
or an optically active compound represented by the formula
(XIb):
wherein R7 represents a hydrogen atom, a chlorine atom
or a nitro group; and
the other symbols are as defined above,
to a metathesis reaction.
6. An optically active compound represented by the
formula (XIa) :
wherein R represents a hydrogen atom, an optionally
substituted aliphatic hydrocarbon group or an optionally
substituted aromatic group;
R2 represents a halogen atom, a nitro group, a cyano
group, an optionally substituted alkyl group, an optionally
substituted cycloalkyl group, an optionally substituted
hydroxyl group, an optionally substituted thiol group (the
sulfur atom may be oxidized to form a sulfinyl group that
may be substituted or a sulfonyl group that may be
substituted), an optionally substituted amino group, an
optionally substituted acyl group, an optionally esterified
carboxyl group or an optionally substituted aromatic group;
R6 represents a methyl group, a phenyl group, a 4-
methylphenyl group or a a-naphthyl group;
the ring A represents a benzene ring which may be
substituted with a halogen atom, a C1-4 alkyl group which
may be substituted with a halogen atom or a C1-4 alkoxy
group which may be substituted with a halogen atom;
n represents an integer of 0 to 3;
p represents an integer of 0 to 2; and
*1 and *2 each represents an asymmetric center,
or an optically active compound represented by the formula
(XIb):
wherein R7 represents a hydrogen atom, a chlorine atom
or a nitro group; and
the other symbols are as defined above.
7. The optically active compound according to 6,
wherein R1 and R2 each represents a C1-6 alkyl group; n
represents 1 or 2; and R6 represents a 4-methylphenyl group
or R7 represents a nitro group.
8. The optically active compound according to 7,
wherein R1 represents a C1-6 alkyl group; p represents 0; n
represents 1;
9. A process as claimed in claim 1 wherein the
optically active compound represented by the formula (II):
wherein R1 represents a hydrogen atom, an optionally
substituted aliphatic hydrocarbon group or an optionally
substituted aromatic group;
R2 represents a halogen atom, a nitro group, a cyano
group, an optionally substituted alkyl group, an optionally
substituted cycloalkyl group, an optionally substituted
hydroxyl group, an optionally substituted thiol group (the
sulfur atom may be oxidized to form a sulfinyl group that
may be substituted or a sulfonyl group that may be
substituted), an optionally substituted amino group, an
optionally substituted acyl group, an optionally esterified
carboxyl group or an optionally substituted aromatic group;
the ring A represents a benzene ring which may be
substituted with a halogen atom, a C1-4 alkyl group which
may be substituted with a halogen atom or a C1-4 alkoxy
group which may be substituted with a halogen atom;
n represents an integer of 0 to 3;
p represents an integer of 0 to 2; and
*1 represents an asymmetric center,
or a salt thereof, is prepared by
subjecting a compound represented by the
formula (X):
wherein each symbol is as defined above,
or a salt thereof to oxidation to obtain a compound
representated by the formula (IX)
wherein each symbol is as defined above,
and subjecting the compound of formula IX
or a salt thereof, to optical resolution with an optically
active compound represented by the formula (XIIa):
wherein each symbol is as defined above,and
R6 represents a methyl group, a phenyl group, a 4-
methylphenyl group or a a-naphthyl group;and
*2 represents an asymmetric center,
or an optically active acid represented by the formula
(XIIb):
wherein each symbol is as defined above and
wherein R7 represents a hydrogen atom, a chlorine atom
or a nitro group; to obtain a compound represented by the
formula (XIa) :
followed by subjecting the compound represented by the
formula (XIa)or (XIb)to a metathesis reaction.
10. A compound represented by the formula (IX'):
wherein R1' represents an optionally substituted
aliphatic hydrocarbon group or an optionally substituted
aromatic group;
R2 represents a halogen atom, a nitro group, a cyano
group, an optionally substituted alkyl group, an optionally
substituted cycloalkyl group, an optionally substituted
hydroxyl group, an optionally substituted thiol group (the
sulfur atom may be oxidized to form a sulfinyl group that
may be substituted or a sulfonyl group that may be
substituted) , an optionally substituted amino group, an
optionally substituted acyl group, an optionally esterified
carboxyl group or an optionally substituted aromatic group;
the ring A represents a benzene ring which may be
substituted with a halogen atom, a C1-4 alkyl group which
may be substituted with a halogen atom or a C1-4 alkoxy
group which may be substituted with a halogen atom;
n represents an integer of 0 to 3; and
p represents an integer of 0 to 2,
or a salt thereof.
11. A process as claimed in claim 9 wherein the
compound represented by the formula (IX):
wherein R1 represents a hydrogen atom, an optionally
substituted aliphatic hydrocarbon group or an optionally
substituted aromatic group;
R2 represents a halogen atom, a nitro group, a cyano
group, an optionally substituted alkyl group, an optionally
substituted cycloalkyl group, an optionally substituted
hydroxyl group, an optionally substituted thiol group (the
sulfur atom may be oxidized to form a sulfinyl group that
may be substituted or a sulfonyl group that may be
substituted) , an optionally substituted amino group, an
optionally substituted acyl group, an optionally esterified
carboxyl group or an optionally substituted aromatic group;
the ring A represents a benzene ring which may be
substituted with a halogen atom, a C1-4 alkyl group which
may be substituted with a halogen atom or a C1-4 alkoxy
group which may be substituted with a halogen atom;
n represents an integer of 0 to 3; and
p represents an integer of 0 to 2,
or a salt thereof, is prepared by reacting a compound
represented by the formula (V):
wherein R8 represents a hydrogen atom, an optionally
substituted lower alkyl group, an optionally substituted
aryl group, an optionally substituted aralkyl group or -OR10
wherein R10 represents an optionally substituted lower alkyl
group, an optionally substituted aryl group or an
optionally substituted aralkyl group; and the other symbols
are as defined above,or a salt thereof, with a compound
represented by the formula (VI):
wherein Y represents a halogen atom or a group
represented by the formula -OSO2-R9 wherein R9 represents a
lower alkyl group or an optionally substituted aryl group;
and
the other symbols are as defined above,
or a salt thereof to obtain a compound represented by the
formula (VII)
oxidizing the compound represented by the formula (VII) or
a salt thereof to obtain a compound represented by the
formula (VIII):
wherein R8 represents a hydrogen atom, an optionally
substituted lower alkyl group, an optionally substituted
aryl group, an optionally substituted aralkyl group or -OR10
wherein R10 represents an optionally substituted lower alkyl
group, an optionally substituted aryl group or an
optionally substituted aralkyl group; and
the other symbols are as defined above,
or a salt thereof, to a deprotection reaction.
12. A compound represented by the formula (VIII):
wherein R1 represents a hydrogen atom, an optionally
substituted aliphatic hydrocarbon group or an optionally
substituted aromatic group;
R2 represents a halogen atom, a nitro group, a cyano
group, an optionally substituted alkyl group, an optionally
substituted cycloalkyl group, an optionally substituted
hydroxyl group, an optionally substituted thiol group (the
sulfur atom may be oxidized to form a sulfinyl group that
may be substituted or a sulfonyl group that may be
substituted), an optionally substituted amino group, an
optionally substituted acyl group, an optionally esterified
carboxyl group or an optionally substituted aromatic group;
R8 represents a hydrogen atom, an optionally
substituted lower alkyl group, an optionally substituted
aryl group, an optionally substituted aralkyl group or -OR10
wherein R10 represents an optionally substituted lower
alkyl group, an optionally substituted aryl group or an
optionally substituted aralkyl group;
the ring A represents a benzene ring which may be
substituted with a halogen atom, a C1-4 alkyl group which
may be substituted with a halogen atom or a C1-4 alkoxy
group which may be substituted with a halogen atom;
n represents an integer of 0 to 3; and
p represents an integer of 0 to 2,
or a salt thereof.
13. A process as claimed in claim 11 wherein the
compound represented by the formula (VIII):
wherein R1 represents a hydrogen atom, an optionally
substituted aliphatic hydrocarbon group or an optionally
substituted aromatic group;
R2 represents a halogen atom, a nitro group, a cyano
group, an optionally substituted alkyl group, an optionally
substituted cycloalkyl group, an optionally substituted
hydroxyl group, an optionally substituted thiol group (the
sulfur atom may be oxidized to form a sulfinyl group that
may be substituted or a sulfonyl group that may be
substituted), an optionally substituted amino group, an
optionally substituted acyl group, an optionally esterified
carboxyl group or an optionally substituted aromatic group;
R8 represents a hydrogen atom, an optionally
substituted lower alkyl group, an optionally substituted
aryl group, an optionally substituted aralkyl group or -OR10
wherein R10 represents an optionally substituted lower alkyl
group, an optionally substituted aryl group or an
optionally substituted aralkyl group;
the ring A represents a benzene ring which may be
substituted with a halogen atom, a C1-4 alkyl group which
may be substituted with a halogen atom or a C1-4 alkoxy
group which may be substituted with a halogen atom;
n represents an integer of 0 to 3; and
p represents an integer of 0 to 2,
or a salt thereof, is prepared by oxidizing a compound
represented by the formula (VII):
wherein each symbol is as defined above,
or a salt thereof.
14.A compound represented by the formula (VII1):
wherein R1 represents a hydrogen atom, an optionally
substituted aliphatic hydrocarbon group or an optionally
substituted aromatic group;
R2' represents a halogen atom, a cyano group, an
optionally substituted alkyl group, an optionally
substituted cycloalkyl group, an optionally substituted
hydroxyl group, an optionally substituted thiol group (the
sulfur atom may be oxidized to form a sulfinyl group that
may be substituted or a sulfonyl group that may be
substituted), an optionally substituted amino group, an
optionally substituted acyl group, an optionally esterified
carboxyl group or an optionally substituted aromatic group;
R8 represents a hydrogen atom, an optionally
substituted lower alkyl group, an optionally substituted
aryl group, an optionally substituted aralkyl group or -OR10
wherein R10 represents an optionally substituted lower alkyl
group, an optionally substituted aryl group or an
optionally substituted aralkyl group;
the ring A represents a benzene ring which may be
substituted with a halogen atom, a C1-4 alkyl group which
may be substituted with a halogen atom or a C1-4 alkoxy
group which may be substituted with a halogen atom;
n represents an integer of 0 to 3; and
p represents an integer of 0 to 2,
or a salt thereof.
15.A compound represented by the formula (X'):
wherein R1' represents an optionally substituted
aliphatic hydrocarbon group or an optionally substituted
aromatic group;
R2' represents a halogen atom, a cyano group, an
optionally substituted alkyl group, an optionally
substituted cycloalkyl group, an optionally substituted
hydroxyl group, an optionally substituted thiol group (the
sulfur atom may be oxidized to form a sulfinyl group that
may be substituted or a sulfonyl group that may be
substituted) , an optionally substituted amino group, an
optionally substituted acyl group, an optionally esterified
carboxyl group or an optionally substituted aromatic group;
the ring A represents a benzene ring which may be
substituted with a halogen atom, a C1-4 alkyl group which
may be substituted with a halogen atom or a C1-4 alkoxy
group which may be substituted with a halogen atom;
n represents an integer of 0 to 3; and
p represents an integer of 0 to 2,
or a salt thereof.
A process for preparing an optically active sulfoxide
derivative (I) having CCR5 antagonism without causing side
reactions such as racemization and Pummerer rearrangement,
which comprises reacting a compound (II) with a compound
(III) as shown by the following scheme:
wherein R1 represents hydrogen, an aliphatic hydrocarbon
group or an aromatic group; R2 represents halogeno, alkyl,
hydroxyl, amino, an aromatic group, etc.; R3 represents a
5- or 6-membered ring; R4 represents hydrogen, alkyl,
alkoxy or halogeno; R5 represents hydrogen, a hydrocarbon
group, a heterocyclic group, acyl, etc.; ring A represents
an optionally substituted benzene ring; X represents a bond
or divalent group comprising a linear part constituted of 1
to 4 atoms; m represents an integer of 1 to 5; n represents
an integer of 0 to 3; p represents an integer of 0 to 2;
and *1 represents an asymmetric center.

Documents:

1279-kolnp-2004-granted-abstract.pdf

1279-kolnp-2004-granted-claims.pdf

1279-kolnp-2004-granted-correspondence.pdf

1279-kolnp-2004-granted-description (complete).pdf

1279-kolnp-2004-granted-examination report.pdf

1279-kolnp-2004-granted-form 1.pdf

1279-kolnp-2004-granted-form 13.pdf

1279-kolnp-2004-granted-form 18.pdf

1279-kolnp-2004-granted-form 2.pdf

1279-kolnp-2004-granted-form 3.pdf

1279-kolnp-2004-granted-form 5.pdf

1279-kolnp-2004-granted-gpa.pdf

1279-kolnp-2004-granted-reply to examination report.pdf

1279-kolnp-2004-granted-specification.pdf

1279-kolnp-2004-granted-translated copy of priority document.pdf

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Patent Number

225210

Indian Patent Application Number

1279/KOLNP/2004

PG Journal Number

45/2008

Publication Date

07-Nov-2008

Grant Date

05-Nov-2008

Date of Filing

01-Sep-2004

Name of Patentee

TAKEDA PHARMACEUTICAL COMPANY LIMITED

Applicant Address

1-1 DOSHOMACHI 4-CHOME, CHUO-KU, OSAKA-SHI, OSAKA

Inventors:

#	Inventor's Name	Inventor's Address
1	ITO TATSUYA	117.1-7 ASAHIGAOKA-KUKAKUSEIRICHINAI, 1214, IMAIZUMI, KASHIBA-SHI, NARA
2	ADACHI MARI	2-3, MIHOGAOKA 4-CHOME, NISHI-KU, KOBE-SHI, HYOGO
3	TAWADA HIROYUKI	11-1, MIYANOKAWAHARA 1-CHOME, TAKATSUKI-SHI, OSAKA
4	IKEMOTO TOMOMI	11-5 YAMAMOTOMARYHASHI 2-CHOME, TAKARAZUKA-SHI, HYOGO
5	NISHIGUCHI ARSUKO	151, MINAMISUZUHARA 3-CHOME, ITAMI-SHI, HYOGO

PCT International Classification Number

C07D 233/64, 403/12

PCT International Application Number

PCT/JP03/02840

PCT International Filing date

2003-03-11

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	2002-066809	2002-03-12	Japan
2	2002-229802	2002-08-07	Japan