JPH1149718A - New cyclopentanone derivative and its use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new derivative useful as a therapeutic agent for the central neuropathy or peripheral neuropathy. SOLUTION: This derivative is represented by formula I (A-ring has one double bond conjugated with oxo group; X is O, S or the like; Y is a 1-6C aliphatic hydrocarbon group or the like; Z1 to Z3 are each carboxyl or the like), e. g. 5-[(2R)-(2-acetylamino-2carboxy)ethylthio] methyl-2-cyclopenten-1-ol. The derivative is obtained by carrying out the condensation reaction of, e.g. a derivative represented by formula II (U is an eliminable group; Z1' to Z3' are each carboxyl or the like) with a compound represented by formula III (X2 is S or the like; Y' is a 1-6C aliphatic hydrocarbon group or the like) [e.g. (2R)-2-acetylamino-2-carboxyethanethiol] in a molar amount of preferable 1-2 times based on the derivative represented by formula II under basic conditions in a molar amount of 0.1-20 times based on the derivative represented by formula II at 0-100 deg.C for 0.1-200 hr and, as necessary, removing protecting groups.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention belongs to the technical field of medicine, and more particularly to a nerve cell differentiation promoting agent.

[0002]

2. Description of the Related Art Neurotrophic factors induce the differentiation of neurons,
A group of proteinaceous compounds involved in the maintenance of survival, nerve growth factor (hereinafter abbreviated as NGF) is known as a typical substance (Ann. Neuro., Vol. 10, vol.
499-503 (1981)). NGF is the central nervous system,
It has been revealed that all peripheral nerves are deeply involved in neuronal differentiation, survival maintenance and repair.

[0003] When neurons are damaged by aging, internal factors and external factors, pathological symptoms appear. For example, in the central nervous system, dementia due to Alzheimer's disease, impaired consciousness due to brain contusion, tremor or stiffness due to Parkinson's disease, and in the peripheral nerve, movement impairment due to amyotrophic lateral sclerosis or spinal cord injury, administration of anticancer drugs or diabetes Paresthesia is well known (clinical examination, volume 40, 760-766 (19
96))). In addition, neurons cannot regenerate, so it has been considered difficult to recover from injury. Therefore, attention has been paid to the action of the above-mentioned neurotrophic factor on neurons, and it is suggested that it may be used as a therapeutic agent for neuropathy (Sci).
ence, 264 volumes, 772-774 (199
4)). For example, NGF has been clinically applied to Alzheimer's disease, peripheral neuropathy, or spinal cord injury.

[0004] However, NGF is a protein having a molecular weight of about 50,000 and has a long period of time for treating neuropathy. Therefore, it is not easy to develop an administration method and a formulation. Gene therapy by introducing the gene is also being studied, but the effect is unknown.

[0005] PC12 cells, a cell line cloned from rat adrenal medulla pheochromocytoma, are known to stop cell proliferation and to differentiate into neurite-containing neural-like cells by the addition of NGF. ing. This method makes it possible to screen for a substance having an NGF-like neuronal differentiation promoting action. For example, it has been shown that the antibiotic staurosporine also has a PC12 cell differentiation promoting action (Neurochemistry, Vol. 26). , 200-22
0 (1987)). Recently, the microorganism Streptomyces sp. NK175203 strain FERMBP-4372 produced a physiologically active substance NK175203 (hereinafter referred to as cystacyclin), which has a similar differentiation promoting effect (WO95 / 31992).

[0006]

However, the above-mentioned staurosporine is difficult to apply as a pharmaceutical because of toxicity and pharmacokinetics, has a nerve cell differentiation promoting action, is low toxic, and is a synthetic low molecular weight compound which is easy to manufacture. Is strongly expected.

[0007]

Means for Solving the Problems The present inventors have made intensive studies on derivatives of cystacyclin, and as a result, newly obtained a cyclopentanone derivative represented by the following general formula [1] or a pharmacologically acceptable salt thereof. The present invention has been completed. That is, the present invention relates to the following inventions.

(1) The present invention provides a compound represented by the general formula [1]:

[0009]

Embedded image (Wherein, ring A represents one double bond conjugated to an oxo group, X represents O, S, SO, SO2 or NH, and Y represents a substituted or unsubstituted C 1-6 carbon atom. An aliphatic hydrocarbon group, or a substituted or unsubstituted aromatic hydrocarbon group having 3 to 6 carbon atoms or a heteroaromatic monocyclic ring;
And Z3 are the same or independently of each other, a carboxyl group or a group derived therefrom, a hydroxyl group or a group derived therefrom, an amino group or a group derived therefrom, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms or It represents an alkenyl group, a heteroaromatic monocyclic ring, a halogen atom, or a hydrogen atom. Provided that when Z1 is a hydrogen atom, X is limited to S or SO), or a pharmacologically acceptable salt thereof.

(2) In the general formula [1] described in the above (1), a double bond in which the ring A is conjugated to an oxo group is CH2-X
X represents S, O or SO, and Y represents an aliphatic hydrocarbon group having 1 to 6 carbon atoms (a carboxyl group or a group derived therefrom). Wherein one or more hydrogen atoms are substituted with a group derived from an amino group, or a hydroxyl group or a group derived therefrom, wherein Z1, Z2 and Z3 are the same or each independently a carboxyl group or a group derived therefrom. Group, a hydroxyl group or a group derived therefrom, an amino group or a group derived therefrom, a substituted or unsubstituted alkyl or alkenyl group having 1 to 4 carbon atoms, a heteroaromatic monocyclic ring,
Or a pharmacologically acceptable salt thereof according to the above (1), which represents a halogen atom or a hydrogen atom).

(3) In the general formula [1] described in the above (1), the double bond in which the ring A is conjugated to an oxo group is CH2-X
-Y includes a bonded carbon atom, X represents S, O or SO, and Y is an aliphatic hydrocarbon group having 1 to 6 carbon atoms [carboxy group, COOR1 (R
1 represents a substituted or unsubstituted alkyl or alkenyl group having 1 to 4 carbon atoms), CONR2R3 (wherein R2,
R3 is the same or each independently a hydrogen atom, carbon number 1
To 4 unsubstituted or substituted alkyl groups), COW
(Wherein W represents an unsubstituted heterocyclic ring substituted with a carboxy group or a group derived therefrom, or an amino group or a group derived therefrom), NR4R5 (wherein R4, R4
5 is the same or each independently a hydrogen atom, 1 carbon atom;
4 unsubstituted or substituted alkyl groups, or 1 to 1 carbon atoms
5 represents an unsubstituted or substituted acyl group), or OR
6 (wherein R6 represents a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms, or an unsubstituted or substituted acyl group having 1 to 5 carbon atoms), wherein at least one hydrogen atom is substituted Wherein Z1, Z2 and Z3 are carboxy groups, COOR7 (wherein R7 represents an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms), CONR8R9 (wherein R8 and R9 are the same or each Independently represents a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms),
A cyano group, CH2OR10 (wherein R10 represents a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms, or an unsubstituted or substituted acyl group having 1 to 5 carbon atoms), a hydroxyl group, OCOR11 ( Wherein R11 is carbon number
4 represents an unsubstituted or substituted alkyl group), NR12
R13 (in the formula, R12 and R13 are the same or each independently represent a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms, or an unsubstituted or substituted acyl group having 1 to 5 carbon atoms), The cyclopentenone derivative or the pharmaceutically acceptable salt thereof according to the above (2), which represents a 5-tetrazolyl group, a chlorine atom, a fluorine atom, or a hydrogen atom.

(4) In the general formula [1] described in the above (1), the double bond in which the ring A is conjugated to an oxo group is CH2-X
-Y is formed including a carbon atom to which it is bonded, X represents S, and Y is an aliphatic hydrocarbon group having 1 to 6 carbon atoms ｛carboxy group, COOR1 ′ (wherein R1 ′ is carbon Represents an alkyl group or an alkenyl group of the formulas 1 to 4), NH
COR14 (wherein R14 represents an alkyl group having 1 to 4 carbon atoms, the hydrogen atom of which may be substituted with a fluorine atom), a hydroxyl group, or OCOR15 (wherein R15 represents an alkyl group having 1 to 4 carbon atoms) ) Represents｝ wherein at least two or more hydrogen atoms are substituted, Z1, Z2, and Z3 are carboxy groups, and COOR7 '(wherein R7' has 1 to 4 carbon atoms).
Or CH2OR10 '(wherein R10' represents a hydrogen atom or an acyl group having 1 to 5 carbon atoms) or the cyclopentenone derivative according to the above (3) or a pharmaceutically acceptable salt thereof. Salt obtained.

(5) In the general formula [1] described in the above (1), the double bond in which the ring A is conjugated to an oxo group is CH2-X
-Y indicates formation including a carbon atom bonded thereto, X indicates S, Y indicates a 2-acetylamino-2-carboxylethyl group, and either Z1 or Z2 indicates a hydroxy group And the cyclopentenone derivative or the pharmaceutically acceptable salt thereof according to the above (4), wherein Z1, Z2 and Z3 each represent a hydrogen atom.

(6) In the general formula [1] described in the above (1), a double bond in which ring A is conjugated to an oxo group is CH2-X
-Y indicates that it is formed without including the carbon atom to which it is bonded, X indicates S, O or SO, and Y indicates 1 to 6 carbon atoms
Wherein at least one hydrogen atom is substituted with a carboxy group or a group derived therefrom, an amino group or a group derived therefrom, or a hydroxyl group or a group derived therefrom; Z1, Z2 and Z3 each represent a carboxy group or a group derived therefrom; an unsubstituted or substituted alkyl or alkenyl group having 1 to 4 carbon atoms; a hydroxyl group or a group derived therefrom; an amino group or a group derived therefrom; The cyclopentenone derivative according to the above (1), which represents a ring, a halogen atom or a hydrogen atom, or a pharmaceutically acceptable salt thereof.

(7) In the general formula [1] according to the above (1), the double bond in which the ring A is conjugated to an oxo group is CH2-X
-Y indicates that it is formed without including the carbon atom to which it is bonded, X indicates S, O or SO, and Y indicates 1 to 6 carbon atoms
An aliphatic hydrocarbon group [carboxy group, COOR1 (wherein R1 represents a substituted or unsubstituted alkyl group or alkenyl group having 1 to 4 carbon atoms), CONR2R3 (wherein R
2, R3 are the same or each independently represent a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms),
OW (wherein W represents an unsubstituted, carboxy group or a group derived therefrom, or a heterocyclic ring substituted with an amino group or a group derived therefrom) NR4R5 (wherein R4,
R5 is the same or each independently a hydrogen atom, carbon number 1
4 to 4 unsubstituted or substituted alkyl groups, or 1 carbon atom
To 5 unsubstituted or substituted acyl groups), or O
R6 (wherein R6 represents a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms, or an unsubstituted or substituted acyl group having 1 to 5 carbon atoms), and at least one hydrogen atom is substituted Wherein Z1, Z2 and Z3 are carboxy groups, COOR7 (wherein R7 represents an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms), CONR8R9 (wherein R8 and R9 are the same or each Independently a hydrogen atom,
A substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a cyano group, CH2OR10 (wherein R10 is a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms, or a 1 to 5 carbon atom) An unsubstituted or substituted acyl group is shown), a hydroxyl group, OCOR11 (wherein R11 represents an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms), NR
12R13 (wherein R12 and R13 are the same or independently represent a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms, or an unsubstituted or substituted acyl group having 1 to 5 carbon atoms), The cyclopentenone derivative or the pharmaceutically acceptable salt thereof according to the above (6), which represents a 5-tetrazolyl group, a chlorine atom, a fluorine atom, or a hydrogen atom.

(8) In the general formula [1] according to the above (1), the double bond in which the ring A is conjugated to an oxo group is CH2-X
-Y indicates that it does not include the carbon atom to which it is bonded, X indicates S, and Y is an aliphatic hydrocarbon group having 1 to 6 carbon atoms ｛carboxy group, COOR1 ′ (where R1 ′ is An alkyl group or an alkenyl group having 1 to 4 carbon atoms), or NHCOR14 (wherein R14 represents an alkyl group having 1 to 4 carbon atoms, the hydrogen atom of which may be substituted with a fluorine atom), a hydroxyl group, or In OCOR15 (wherein R15 represents an alkyl group having 1 to 4 carbon atoms), at least two or more hydrogen atoms are substituted, and Z1, Z2, Z3
Is a carboxy group, COOR7 ′ (wherein R7 ′ has 1 carbon atom)
Or CH2OR10 '.
(Wherein R10 ′ represents a hydrogen atom or an acyl group having 1 to 5 carbon atoms). The cyclopentenone derivative according to the above (7), or a pharmaceutically acceptable salt thereof.

(9) In the general formula [1] described in the above (1), the double bond in which the ring A is conjugated to an oxo group is CH2-X
-Y indicates that it does not include the carbon atom to which it is bonded, X indicates S, Y indicates a 2-acetylamino-2-carboxylethyl group, and Z1, Z2 and Z3 all represent a hydrogen atom. Or the pharmacologically acceptable salt thereof according to the above (8).

(10) The cyclopentenone derivative according to any one of the above (1) to (9) (however, when Z1 is a hydrogen atom, the case where X represents NH, O or SO2 is also included) or A medicament comprising a pharmaceutically acceptable salt thereof as an active ingredient.

(11) The cyclopentenone derivative according to any of the above (1) to (9) (provided that when Z1 is a hydrogen atom, X includes NH, O or SO2) or A therapeutic agent for central nervous system comprising a pharmaceutically acceptable salt thereof as an active ingredient.

(12) The cyclopentenone derivative according to any one of the above (1) to (9) (however, when Z1 is a hydrogen atom, the case where X represents NH, O or SO2 is also included) or A therapeutic agent for peripheral nerves comprising a pharmaceutically acceptable salt thereof as an active ingredient.

(13) The cyclopentenone derivative according to any one of claims 1 to 9 (provided that when Z1 is a hydrogen atom, X also includes NH, O or SO2) or its pharmacological properties. A nerve cell differentiation promoting agent comprising a salt acceptable to the active ingredient as an active ingredient.

The agent for promoting neuronal differentiation in the present invention can be used for patients as a therapeutic agent for central nervous system disorders or peripheral nerve disorders.

[0023]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, ring A of the general formula [1] represents a 2-cyclopenten-1-one ring, and YX
There are a case where the —CH 2 group is bonded to a carbon having a double bond and a case where it is bonded to a carbon having a single bond.

In X in the general formula [1], S, O or SO is preferred, and S is most preferred.

The aliphatic hydrocarbon group having 1 to 6 carbon atoms for Y in the general formula [1] means an alkyl group or an alkenyl group having 1 to 6 carbon atoms. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, and n
-Pentyl group, n-hexyl group, isopropyl group, te
rt-butyl group and the like. Examples of the alkenyl group include a vinyl group, a 2-propenyl group, an isopropenyl group, and a 2-butenyl group. Preferably it is a C1-C4 alkyl group, More preferably, an ethyl group. This hydrocarbon group may be unsubstituted or substituted. When it has a substituent, it may have 1 to 6, preferably 1 to 4 substituents. Examples of the type of the substituent include a carboxy group or a group derived therefrom, an amino group or a group derived therefrom, or a hydroxyl group or a group derived therefrom. An aromatic hydrocarbon group having 3 to 6 carbon atoms or a heteroaromatic monocyclic ring means, for example, a benzene ring as the aromatic hydrocarbon group, and a nitrogen atom, oxygen atom or sulfur atom as the heterocyclic aromatic monocyclic ring. And a 5- or 6-membered ring. The substituent in the case of having a substituent is the same as in the case of the aliphatic hydrocarbon group.

The group derived from the carboxy group includes
For example, a carboxy group is esterified or amidated functional group, a cyano group, or a hydroxylmethyl group, an aminomethyl group in which these functional groups are reduced, or an acylation or alkylation of these reduced functional groups. Modified functional groups may be mentioned. Preferably, a carboxy group, COOR1 (wherein R1 represents an unsubstituted or substituted alkyl or alkenyl group having 1 to 4 carbon atoms), COOR1
NR2R3 (wherein R2 and R3 are the same or each independently represent a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms), COW (W represents an unsubstituted or substituted heterocycle) is there. Here, the alkyl group in R1 may be any of a chain, a chain, and a ring. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group and a cyclobutyl group. Preferred alkyl groups are a methyl group, an ethyl group, and an n-propyl group, and more preferably a methyl group. Examples of the alkenyl group include a vinyl group, a 2-propenyl group, an isopropenyl group, and a 2-butenyl group. When it has a substituent, it may have, for example, 1 to 6, preferably 1 to 3 substituents. Examples of the type of the substituent include a halogen atom, a hydroxyl group, a thiol group, a carboxy group, a methoxycarbonyl group, an acetyloxy group, an acetylthio group, a cyano group, and an acetylamino group. Examples of the halogen atom include a bromine atom, a chlorine atom, and a fluorine atom. Preferred substituents for R1 are unsubstituted.

The substituents of R2 and R3 having an alkyl group and a substituent are the same as those of R1. W is preferably a heterosaturated ring, more preferably an azetidine ring, a piperidine ring, a pyrrolidine ring, a piperazine ring, a piperazine ring, or a morpholine ring. Further, these rings can be bonded to a carbonyl group with a carbon atom or a nitrogen atom, and are preferably bonded to a carbonyl group with a nitrogen atom to form an amide bond. When it has a substituent, it may have 1 to 4 and preferably 1 to 2 substituents, and as the type of the substituent, a carboxy group or a group derived therefrom, or an amino group or a derivative thereof Group. Each is as described herein.

Examples of the group derived from the amino group include a functional group in which the amino group is alkylated or acylated,
Examples include a nitro group, a hydroxyamino group, an imino group, and a heterocyclic ring containing a nitrogen atom of an amino group. Preferably NR
4R5 (wherein R4 and R5 are the same or each independently represent a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms, or an unsubstituted or substituted acyl group having 1 to 5 carbon atoms) can give. Here, as for the alkyl group in R4 and R5, and the substituent when it has a substituent,
The same as in the case of 1. The acyl group is chain-like, branched,
It may be cyclic, saturated or unsaturated. Examples of the acyl group include an acetyl group, a propionyl group, an acroyl group, a propioyl group, an n-butyryl group, an isobutyryl group, a crotonoyl group, a valeryl group, an isovaleryl group, and a pivaloyl group. In the case of having a substituent, the substituent is the same as in the case of R1. Preferably NHCOR14 (wherein R14 has 1 to 4 carbon atoms)
Represents an alkyl group whose hydrogen atom may be substituted by a fluorine atom, and the alkyl group is the same as in R1). The number of fluorine atoms which may be substituted is 1
-9, preferably 1-7. Most preferred R14 is a methyl group.

Examples of the group derived from a hydroxyl group include a functional group in which a hydroxyl group is alkylated or acylated, a keto group, and a halogen atom. Preferably OCOR1
5 (in the formula, R15 represents an alkyl group having 1 to 4 carbon atoms, and the alkyl group is the same as in the case of R1).

Z1, Z2 and Z3 in the derivative are carboxy groups or groups derived therefrom, unsubstituted or substituted alkyl or alkenyl groups having 1 to 4 carbon atoms, hydroxyl groups or groups derived therefrom, amino groups. Or a group derived therefrom, a heteroaromatic monocyclic ring, a halogen atom, or a hydrogen atom. The groups derived from a carboxy group, an amino group and a hydroxyl group are the same as described above. The alkyl group, the alkenyl group and the substituent when they have a substituent are the same as those in the case of A. Preferred examples of Z1, Z2 and Z3 include a carboxy group, COOR7 (wherein R7 represents an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms), CONR8R9 (wherein
8, R9 are the same or each independently a hydrogen atom or each independently represent an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms), a cyano group, a hydroxyl group, CH2OR10 (wherein R10 is a hydrogen atom, a carbon atom An unsubstituted or substituted alkyl group having 1 to 4 carbon atoms, or an unsubstituted or substituted acyl group having 1 to 5 carbon atoms, OCOR11 (wherein R11 is an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms) ), N
R12R13 (wherein R12 and R13 are the same or independently and independently represent a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms, or an unsubstituted or substituted acyl group having 1 to 5 carbon atoms); -A tetrazolyl group, a chlorine atom, a fluorine atom, or a hydrogen atom. Where R7,
For the alkyl group of R8, R9, R10, R11, R12 and R13, and the substituent having a substituent, R
The same as in the case of 1. Further, R10, R12 and R1
The acyl group in 3 and the substituent when they have a substituent are the same as those in R4. R12,
A preferable combination of R13 is a case where R12 is a hydrogen atom and R13 is an acetyl group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a fluorine atom and a chlorine atom are preferred.
Preferred substituents for Z1, Z2, and Z3 are all hydrogen atoms, or one or two substituents other than hydrogen atoms. More preferred Z1, Z2, and Z3 other than a hydrogen atom include a carboxy group, COOR
7 '(wherein R7' represents an alkyl group having 1 to 4 carbon atoms), or CH2OR10 '(wherein R10' represents a hydrogen atom or an acyl group having 1 to 5 carbon atoms). Here, the alkyl group of R7 'is the same as that of R1. Further, the acyl group for R10 'is the same as that for R4. Particularly preferred are a carboxy group, a methoxycarbonyl group, a hydroxymethyl group, and an acetyloxymethyl group.

Specific cyclopentanone derivatives of the present invention include: (1) 5-[(2R)-(2-acetylamino-2-carboxy) ethylthio] methyl-2-cyclopentene-
1-one (2) (4R) -2-[(2R)-(2-acetylamino-2-carboxy) ethylthio] methyl-4-hydroxy-2-cyclopenten-1-one (3) 2-[(2R )-(2-Acetylamino-2-carboxy) ethylthio] methyl-3-hydroxy-2-
Cyclopenten-1-one (4) 5-[(2R)-(2-acetylamino-2-carboxy) ethylthio] methyl-4-carboxy-2-
Cyclopenten-1-one (5) 5-[(2R)-(2-acetylamino-2-carboxy) ethylthio] methyl-4-methoxycarbonyl-2-cyclopenten-1-one (6) 5-[(2R) -(2-acetylamino-2-carboxy) ethylthio] methyl-4-hydroxymethyl-2-cyclopenten-1-one (7) 5-[(2R)-(2-acetylamino-2-carboxy) ethylthio] methyl -4-acetoxymethyl-2-cyclopenten-1-one

(8) 5-[(2R)-(2-acetylamino-2-methoxycarbonyl) ethylthio] methyl-
4-carboxy-2-cyclopenten-1-one (9) 5-[(2-acetylamino) ethylthio] methyl-4-carboxy-2-cyclopenten-1-one (10) 2-[(2R)-(2 -Acetylamino-2-
Carboxy) ethylthio] methyl-3-carboxy-2
-Cyclopenten-1-one (11) 2-[(2R)-(2-acetylamino-2-
(Carboxy) ethylthio] methyl-3-methoxycarbonyl-2-cyclopenten-1-one (12) 2-[(2R)-(2-acetylamino-2-
(Carboxy) ethylthio] methyl-3-hydroxymethyl-2-cyclopenten-1-one (13) 2-[(2R)-(2-acetylamino-2-
(Carboxy) ethylthio] methyl-3-acetoxymethyl-2-cyclopenten-1-one (14) 2-[(2R)-(2-acetylamino-2-
Methoxycarbonyl) ethylthio] methyl-3-carboxy-2-cyclopenten-1-one (15) 2-[(2-methoxycarbonyl) ethylthio] methyl-3-carboxy-2-cyclopenten-1
-One (16) 2-[(2-acetylamino) ethylthio] methyl-3-carboxy-2-cyclopenten-1-one and the like.

The cyclopentenone derivative used in the present invention has stereoisomers or optical isomers.
The present invention includes all of these isomers. For example, geometric isomers and mixtures thereof, diastereomeric isomers and mixtures thereof, optically active isomers and racemates are all included in the present invention.

The compound of the present invention forms a salt with an acid or a base,
Examples of the salt with an acid include inorganic salts such as hydrochloride, sulfate and phosphate, and organic salts such as p-toluenesulfonate. Examples of the salt with a base include alkali metal salts such as sodium and potassium, alkaline earth metal salts with calcium and the like, and organic salts such as methylamine and the like. These are prepared by a conventional method.

A typical method for producing the cyclopentenone derivative of the present invention will be described below. The method for synthesizing the cyclopentenone derivative of the present invention is not limited to the following method. The compounds of the present invention and intermediates thereof are isolated by a conventional isolation method such as extraction, recrystallization, or chromatography.

In the general formula [1] of the present invention, X is S,
The compound representing O or NH has the general formula [2]

[0037]

Embedded image

(Wherein U represents a leaving group, Z1 ′, Z2 ′
And Z3 ′ have the same meaning as Z1, Z2 and Z3,
When there is a functional group, the functional group may be protected as necessary) (the carbonyl group at position 1 may be protected as necessary) (hereinafter simply referred to as A reactive derivative), the following general formula [3]

[Image Omitted] wherein X2 represents S, O or NH, and Y ′ has the same meaning as Y, but if there is a functional group, the functional group is protected if necessary. May be reacted to remove the protecting group, if necessary. Preferred examples of the reactive derivative include, for example, the following general formulas [4], [5], [6] [7],
And the compound of [8].

[0039]

Embedded image

(Wherein, R 16 represents a hydrocarbon group having 1 to 10 carbon atoms, such as an alkyl group, an alkenyl group, and an allyl group).
And these groups may be substituted or unsubstituted. When the substituent is a functional group, it may be protected with a protecting group, if necessary. R17 and R18 represent a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, for example, an alkyl group, an alkenyl group, an aryl group, etc.
These groups may be substituted or unsubstituted. When the substituent is a functional group, it may be protected with a protecting group, if necessary. Z1 ', Z2' and Z3 'have the same meaning as described above.

The compounds represented by the general formulas [4], [5], [6], [7] and [8] include, for example, the following compounds. (A) 2-[(2R)-(2-acetylamino-2-methoxycarbonyl) ethylsulfonyl] methyl-4-t
tert-butyldimethylsiloxy-2-cyclopentan-1-one (b) 2-methylidene-4-tert-butyldimethylsiloxy-2-cyclopentan-1-one (c) 2-diethylaminomethyl-4-tert-butyl Dimethylsiloxy-2-cyclopenten-1-one (d) 3-acetoxy-2-benzenesulfonylmethyl-2-cyclopenten-1-one

In the general formula [3], when X is S, examples of the compound represented by the general formula [3] include the following compounds. (E) (2R) -2-acetylamino-2-carboxyethanethiol (f) (2R) -2-acetylamino-2-methoxycarbonylethanethiol

For this reaction, any method can be used as long as the compound of the general formula [2] and the compound of the general formula [3] can be condensed. Usually, the reaction is performed in an organic solvent, water or a mixed solvent thereof. Organic solvents include aromatic hydrocarbons such as benzene and toluene, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and diethyl ether, halogenated hydrocarbons such as methylene chloride and chloroform, acetone, methyl ethyl ketone and the like. Ketones, dimethyl sulfoxide, polar aprotic solvents such as dimethylformamide and the like are used, but ethers such as tetrahydrofuran and diethyl ether, halogenated hydrocarbons such as methylene chloride and chloroform, acetone, methyl ethyl ketone and the like are preferable. Polar aprotic solvents such as ketones, dimethylsulfoxide and dimethylformamide, or a mixed solvent of these solvents and water. The reaction generally proceeds in the presence of an acid or base or without a catalyst, but is preferably performed under basic conditions. As the reactant, for example, an inorganic base such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate sodium hydride, or triethylamine, 1,
Organic bases such as 8-diazabicyclo [5,4,0] -undec-7-ene are exemplified. These reactants are 0.1
It is used in an amount of about 20 to 20 times, preferably about 0.5 to 5 times. The reaction temperature is not particularly limited, and may be any of cooling, normal temperature, and heating, but is preferably 0 ° C.
~ 100 ° C is good. The compound of the general formula [2] and the compound of the general formula [3] may be reacted in an equal amount, but in an actual reaction, the compound of the general formula [3] is excessively added (for example, 1
２2 times). The reaction is carried out for 0.1 to 200 hours, preferably for 0.1 to 72 hours.

Compound (a) as compound of general formula [2]
In the case of using (b) and (b), the condensed compound can be derivatized to a desired cyclopentenone derivative by further performing a dehydration reaction after removing the protecting group of the hydroxyl group. Acids, acidic resins, as reactants for deprotection and dehydration reactions,
Lewis acids or fluorine reagents can be used. As the acid, inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as p-toluenesulfonic acid and acetic acid can be used. Dowex50 is preferred as the acidic resin. As the Lewis acid, boron fluoride etherate or the like can be used. Examples of the fluorine reagent include tetrabutylammonium fluoride, hydrogen fluoride and the like.

When X in the general formula [2] is N, that is, when the compound of the general formula [7] and the compound of the general formula [3] are condensed, the nitrogen atom of the general formula [7] is methylated. Alternatively, by reacting the compound of the general formula [3] after oxidation, the desired condensate can be produced. As the methylating agent, a methylating agent such as methyl halide or dimethyl sulfate is used. Preferred is methyl iodide. As the oxidizing agent, an organic peracid such as m-chloroperbenzoic acid, hydrogen peroxide, an organic peroxide or the like is used. Preferably m
Organic peracids such as chloroperbenzoic acid or hydrogen peroxide.

In the general formula [1], a compound in which X represents SO2 can be produced by oxidizing a compound in which X represents S in the general formula [1]. Examples of the oxidizing agent include organic peracids such as m-chloroperbenzoic acid, permanganates, chromic acid, and inorganic oxidizing agents such as ruthenium tetroxide;
Hydrogen peroxide, organic peroxide and the like are used. Preferred are organic peracids such as m-chloroperbenzoic acid.

In the general formula [1], a compound in which X represents SO can be produced by oxidizing a compound in which X represents S in the general formula [1]. Examples of the oxidizing agent include organic peracids such as m-chloroperbenzoic acid, inorganic oxidizing agents such as manganese dioxide, chromic acid and ruthenium tetroxide, and halogenated oxidizing agents such as hydrogen peroxide, organic peroxides and periodic acid. Agents and the like are used.

For example, the above compounds (a) and (b) can be produced as follows.

[0049]

Embedded image

The starting compound (c) is a known compound and can be purchased, for example, from Nissan Chemical Industries, Ltd. The conversion of the compound (c) to the compound (a-1) can be performed according to the condensation reaction when X is N in the general formula [2]. The following compound (a-2) can be produced according to the above-mentioned oxidation method to SO2. In the reduction reaction of the carbon-carbon double bond of the compound (a-2), the compound (a) can be obtained by using a conventional reducing agent. As the reducing agent, an alkali metal reducing agent, an organic tin reducing agent, an organic silicon reducing agent, a catalytic hydrogenation reducing agent, or the like is used. Preferred is a catalytic hydrogenation-reducing agent such as palladium-carbon. Furthermore, compound (b) can be obtained by subjecting compound (a) to basic conditions. Examples of the reactant include inorganic bases such as potassium hydroxide, sodium hydroxide, potassium carbonate and sodium carbonate, and organic bases such as triethylamine and 1,8-diazabicyclo [5,4,0] -undec-7-ene. Is raised. Preferably, an organic base such as triethylamine, 1,8-diazabicyclo [5,4,0] -undec-7-ene can be used.

[0051]

Embedded image

The compound (d-1) is a known compound. Org. Chem. , 58, 3953-39
It can be produced by the method described in Section 59 (1993). The compound (d) can be obtained by acetylating the compound (d-1) in a conventional manner. (A) to above
Compounds of the general formulas [4] to [8] other than (d) can be appropriately produced according to the method for producing the compounds of the above (a) to (d).

Compound (e) is easily available as a commercial product (for example, Tokyo Chemical Industry Co., Ltd.), and compound (f) can be easily produced by heating compound (e) in the presence of an acid catalyst in methanol. Examples of the acid catalyst include hydrochloric acid, inorganic acids such as sulfuric acid, organic acids such as p-toluenesulfonic acid, and Lewis acids such as boron fluoride etherate.
Preferred are organic acids such as p-toluenesulfonic acid.

When the cyclopentenone derivative of the present invention or a pharmaceutically acceptable salt thereof is used as a neuronal differentiation promoting agent, it may be used alone or as a pharmaceutically acceptable carrier, excipient, diluent, solubilizing agent and the like. Mix with additives to be used in the form of injections, drops, granules, tablets, fine granules, powders, capsules, inhalants, suppositories, eye drops, patches, ointments, sprays, etc. Oral administration or parenteral administration (systemic administration, local administration, etc.) can be selected as the administration route.

The content of the cyclopentenone derivative or a pharmaceutically acceptable salt thereof in the preparation varies depending on the preparation, but is usually preferably 0.1 to 100% by weight.
The dose is determined according to the age, sex, weight, symptoms, treatment purpose, etc. of the patient, and the dose is generally 0.001 to 500.
It is about 0 mg / kg / day.

[0056]

Next, the action of the cyclopentenone derivative of the present invention or a pharmaceutically acceptable salt thereof for promoting neuronal differentiation and a method for producing the same will be described in detail.

Test Example Neurite Outgrowth Effect of Compounds on PC12 Cells The method of Green et al. (Ann. Rev. Neurosc)
i. 3, 353 (1980), and the effect was determined based on the presence or absence and degree of morphological change of cells. That is, PC12 cells were added to a Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum and 10% horse serum at a concentration of about 100,000 cells / ml, and collagen-coated 96-well multiplate was placed at 37 ° C. under 5% CO 2. Overnight. In this state, the test substance was added, and the morphological change one day later was observed with a microscope. As a result, the minimum effective concentrations (MED, μg / ml) of each test substance that cause a neurite outgrowth effect on PC12 cells are as shown below.

Minimum effective concentration causing neurite outgrowth on PC12 cells

Example 1 Preparation of 5-[(2R)-(2-acetylamino-2-carboxy) ethylthio] methyl-2-cyclopenten-1-one [compound (1)] Part 1 (4R) -2- [(2R)-(2-acetylamino-2
-Methoxycarbonyl) ethylthio] methyl-4-te
rt-butyldimethylsiloxy-2-cyclopentene-
Method for producing 1-one [compound (a)] Compound (c) (370 mg, 1.24 mmol) was dissolved in methanol (4 ml), and iodomethane (0,
16 ml, 2,48 mmol) and stirred at room temperature for 2 hours. After concentrating the reaction mixture, the residue was treated with methanol (3 m
l), N-acetyl-L-cysteine methyl ester (220 mg, 1.24 mmol) was added, and the mixture was added at room temperature.
Stir for 5 hours. After concentrating the reaction solution, the residue was subjected to silica gel column chromatography (60 ml, dichloromethane:
(Methanol = 40: 1) to give compound (a-1)
(378 mg, yield 75.7%). 1H-NMR (200 MHz, CDCl3) [delta]: 0.1
2 (3H, s), 0.14 (3H, s), 0.92 (9
H, s), 2.07 (3H, s), 2.31 (1H, d
d, J = 2.11 Hz, 18.31 Hz) 2,80 (1
H, dd, J = 5, 99 Hz, 18.31 Hz), 2.
99 (2H, m), 3.30 (2H, m), 3,78
(3H, s), 4.86 (1H, m), 4.92 (1
H, m), 6.56 (1H, d, J = 7.69 Hz),
7.29 (1H, m) MS (FAB, POS) m / z: 402 (M + H) +

Part 2 (4R) -2-[(2R)-(2-acetylamino-2
-Methoxycarbonyl) ethylsulfonyl] methyl-4
Method for producing -tert-butyldimethylsiloxy-2-cyclopenten-1-one [compound (a-2)] Compound (a-1) (378 mg, 0.94 mmol) is dissolved in dichloromethane (30 ml), and cooled under ice-cooling. -Chloroperbenzoic acid (406 mg, 80% purity, 1.88 mm
ol) and stirred for 2 hours. Water (15 ml) and 20% sodium bisulfite (3 ml) were added to the reaction solution.
And saturated sodium bicarbonate is added until the aqueous layer is at pH 7.0. The dichloromethane layer was washed with saturated saline and concentrated, and the residue was subjected to silica gel column chromatography (50 ml, dichloromethane: methanol = 10: 1).
The compound (a-2) (355 mg, yield 87.
3%). 1H-NMR (200 MHz, CDCl3) [delta]: 0.1
3 (3H, s), 0.14 (3H, s), 0.96 (9
H, s), 2.08 (3H, s), 2.35 (1 Hd
d. J = 2.16 Hz, 18.52 Hz), 2.86
(1H, dd, J = 5.94 Hz, 18.52 Hz),
3.65 (2H, d, J = 4.97 Hz), 3.80
(3H, s), 3.81-4.16 (2H, m), 4.
89 to 5,09 (2H, m), 6.70 (1H, br
d, J = 7.41 Hz), 7.66 (1 Hm) MS (FAB, POS), m / z: 434 (M + H) +

Part 3 (4R) -2-[(2R)-(2-acetylamino-2
-Methoxycarbonyl) ethylsulfonyl] methyl-4
Method for producing -tert-butyldimethylsiloxy-2-cyclopentan-1-one [compound (a)] Compound (a-2) (355 mg, 0.82 mmol) is dissolved in ethanol (20 ml), and 10% Pd-C is dissolved. (8
0 mg, containing 50% water) at room temperature under a hydrogen atmosphere.
Stir for hours. The reaction solution is filtered, and the filtrate is concentrated to obtain a compound (a) (330 mg, yield 92.9%). MS (FAB, POS) m / z: 436 (M + H) +

Part 4 (4R) -2-[(2R)-(2-acetylamino-2
Production of -carbonyl) ethylthio] methyl-4-tert-butyldimethylsiloxy-2-cyclopentan-1-one [compound (a-3)] Compound (a) (330 mg, 0.76 mmol) was added to acetone (2 ml), Methanol [8 ml], N-acetyl-L-cysteine (123.9 mg, 0.76 mmol)
l) and 1N sodium hydroxide (1.52 ml) were added, and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction solution, Seph
Purification with adexLH-20 (200 ml, 80%, aqueous methanol) gives compound (a-3) (299 mg). This compound is subjected to the next reaction without further purification.

(5) Method for producing 5-[(2R)-(2-acetylamino-2-carboxy) ethylthio] methyl-2-cyclopenten-1-one [compound (1)] Compound (a-3) (299 mg) , 0.76 mmol) in methanol (15 ml), water (1 ml) and Dowex.
50 (H type, 300 mg) was added, and the mixture was stirred at room temperature for 20 hours. After filtration, silica gel (1 g) is added to the filtrate and concentrated. The residue was subjected to silica gel column chromatography (80
ml, dichloromethane: methanol: acetic acid = 5: 1:
0.1) to give Compound (1) (83 mg, yield 39).
%). 1H-NMR (200 MHz, D2O) [delta]: 2.00
(3H, s), 2.45-3.16 (7H, m), 4.
52 (1H, m), 6.20 (1H, m), 7, 98
(1H, m) MS (FAB, POS) m / z: 258 (M + H) +

Example 2 (4R) -2-[(2R)-(2-acetylamino-2
-Carboxy) ethylthio] methyl-4-hydroxy-
Production of 2-cyclopenten-1-one [compound (2)] (4R) -2-[(2R)-(2-acetylamino-2
-Methoxycarbonyl) ethylsulfonyl] methyl-4
-Tert-butyldimethylsiloxy-2-cyclopenten-1-one (165 mg, 0.38 mmol) in acetone (2 ml), methanol [4 ml], N-acetyl-L-cysteine (61.9 mg, 0.39 mmol)
l) and 1N sodium hydroxide (0.76 ml) were added, and the mixture was stirred at room temperature for 2 hours. After concentration of the reaction solution, methanol (5 ml), water (1 ml), Dowex 50
(Form H, 700 mg) and stirred at room temperature for 16 hours. After filtering the reaction solution, silica gel (500 mg) is added and concentrated. The residue was subjected to silica gel column chromatography (80 ml, dichloromethane: methanol: acetic acid = 5:
1: 0.1). After concentration, the residue was dissolved in water (10 ml), adjusted to pH 6.9 by adding 1 N sodium hydroxide, and sodium salt of compound (2) (61 mg, yield 5
4.4%). 1H-NMR (200 MHz, D20) δ: 2.00
(3H, s), 2.3 (1H, dd, J = 1.83H
z, 18.83 Hz), 2.75-3.07 (3H,
m), 3.32 (2H, s), 4,48 (1, dd, J
= 4.76 Hz, 8.01 Hz), 4.98 (1H,
m), 7.52 (1H, m) MS (ESI, NEG) m / z: 272 (M-Na)-

Example 3 Method for producing 2-[(2R)-(2-acetylamino-2-carboxy) ethylthio] methyl-3-hydroxy-2-cyclopenten-1-one [compound (3)] Compound (d) ) (347 mg, 1.18 mmol) with N-
Acetyl-L-cysteine (193 mg, 1.18 mm
ol), methanol (2 ml), acetone (4 ml) and 1 N sodium hydroxide (2.36 ml), and the mixture was stirred at room temperature. 1N sodium hydroxide is added in small portions until the reaction becomes neutral (4 hours). Silica gel (1.2 g) is added to the reaction solution and concentrated. The residue was subjected to silica gel column chromatography (100 ml, dichloromethane: methanol: acetic acid = 5: 1: 0.1 to 2.5: 1:
0.1) and purified by compound (3) (308 mg, yield 9).
5.6%). 1H-NMR (200 MHz, D2O) [delta]: 2.00
(1H, s), 2.49 (4H, s), 2.72-2.
99 (2H, s), 3.26 (2H, s), 4.38
(1H, dd, J = 4.68 Hz, 8.26 Hz) MS (FAB, NEG) m / z: 272 (M−H) −

[0066]

Industrial Applicability According to the present invention, it has been found that a cyclopentenone derivative or a pharmaceutically acceptable salt thereof has a strong neuronal differentiation promoting action. Therefore, a pharmaceutical composition containing the cyclopentenone derivative or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient is useful as a nerve cell differentiation promoter, and a medicament such as a therapeutic agent for central nervous system or a therapeutic agent for peripheral nerve. Application to the indicated.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07C 62/24 C07C 62/24 62/38 62/38 69/757 69/757 Z 225/14 225/14 225/20 225 / 20 317/24 317/24 317/28 317/28 317/44 317/44 323/22 323/22 323/24 323/24 323/51 323/51

Claims (13)

[Claims] 1. A compound of the general formula [1] (Wherein, ring A represents one double bond conjugated to an oxo group, X represents O, S, SO, SO2 or NH, and Y represents a substituted or unsubstituted C 1-6 carbon atom. An aliphatic hydrocarbon group, or a substituted or unsubstituted aromatic hydrocarbon group having 3 to 6 carbon atoms or a heteroaromatic monocyclic ring;
And Z3 are the same or independently of each other, a carboxyl group or a group derived therefrom, a hydroxyl group or a group derived therefrom, an amino group or a group derived therefrom, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms or It represents an alkenyl group, a heteroaromatic monocyclic ring, a halogen atom, or a hydrogen atom. Provided that when Z1 is a hydrogen atom, X is limited to S or SO), or a pharmacologically acceptable salt thereof. 2. In the general formula [1] according to claim 1, A
The ring forms a double bond conjugated to an oxo group including the carbon atom to which CH2-XY is bonded, X represents S, O or SO, and Y has 1 to 6 carbon atoms. An aliphatic hydrocarbon group (in which one or more hydrogen atoms are substituted with a carboxyl group or a group derived therefrom, a group derived from an amino group, or a hydroxyl group or a group derived therefrom), Z1, Z2 and Z3 is the same or each independently a carboxyl group or a group derived therefrom, a hydroxyl group or a group derived therefrom, an amino group or a group derived therefrom, a substituted or unsubstituted alkyl group or alkenyl having 1 to 4 carbon atoms A cyclopentenone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the cyclopentenone derivative represents a group, a heteroaromatic monocycle, a halogen atom or a hydrogen atom. 3. The method according to claim 1, wherein A is
The ring forms a double bond conjugated to an oxo group including the carbon atom to which CH2-XY is bonded, X represents S, O or SO, and Y has 1 to 6 carbon atoms. An aliphatic hydrocarbon group [carboxy group, COOR1 (wherein R1 represents a substituted or unsubstituted alkyl or alkenyl group having 1 to 4 carbon atoms), CONR2R3 (wherein R2 and R3 are the same or each independently A hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms, COW (W
Is unsubstituted, a carboxy group or a group derived therefrom,
Or a heterocyclic ring substituted with an amino group or a group derived therefrom; NR4R5 (wherein R4 and R5 are the same or each independently a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms) Or an unsubstituted or substituted acyl group having 1 to 5 carbon atoms) or OR6 (wherein R6 is a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms, or a 1 to 5 carbon atom) At least one hydrogen atom is substituted with an unsubstituted or substituted acyl group), and Z1, Z2, and Z3 are carboxy groups,
OOR7 (wherein R7 represents an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms), CONR8R9 (wherein R8, R
9 is the same or each independently represents a hydrogen atom,
4 represents a substituted or unsubstituted alkyl group), a cyano group, CH2OR10 (wherein R10 is a hydrogen atom,
4 to 4 unsubstituted or substituted alkyl groups, or 1 carbon atom
-5, an unsubstituted or substituted acyl group), a hydroxyl group, OCOR11 (wherein R11 represents an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms), NR12R13
(Wherein R12 and R13 are the same or independently represent a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms, or an unsubstituted or substituted acyl group having 1 to 5 carbon atoms). The cyclopentenone derivative according to claim 2, which represents a tetrazolyl group, a chlorine atom, a fluorine atom, or a hydrogen atom, or a pharmaceutically acceptable salt thereof. 4. In the general formula [1] according to claim 1, A
A ring conjugated to an oxo group to form a double bond containing a carbon atom to which CH2-XY is bonded, X represents S, and Y is an aliphatic hydrocarbon having 1 to 6 carbon atoms. Groups {carboxy group, COOR1 ′ (wherein R1 ′ represents an alkyl group or alkenyl group having 1 to 4 carbon atoms), NHCOR1
4 (wherein R14 represents an alkyl group having 1 to 4 carbon atoms, the hydrogen atom of which may be substituted with a fluorine atom), a hydroxyl group, or OCOR15 (wherein R15 represents an alkyl group having 1 to 4 carbon atoms) ) Represents｝ wherein at least two or more hydrogen atoms are substituted, Z1, Z2, and Z3 represent a carboxy group, COOR7 '(wherein R7' represents an alkyl group having 1 to 4 carbon atoms), or CH2OR10 '( Where R10 '
Represents a hydrogen atom or an acyl group having 1 to 5 carbon atoms). The cyclopentenone derivative or a pharmaceutically acceptable salt thereof according to claim 3, wherein 5. The method according to claim 1, wherein
A ring conjugated to an oxo group to form a double bond containing the carbon atom to which CH2-XY is bonded, X represents S, and Y represents a 2-acetylamino-2-carboxylethyl group The cyclopentenone derivative or a pharmaceutically acceptable salt thereof according to claim 4, wherein Z1 or Z2 represents a hydroxy group, and Z1, Z2 and Z3 represent a hydrogen atom. 6. In the general formula [1] according to claim 1, A is
X indicates that the ring forms a double bond conjugated to an oxo group without including the carbon atom to which CH2-XY is bonded;
Represents S, O or SO, and Y represents an aliphatic hydrocarbon group having 1 to 6 carbon atoms (a carboxy group or a group derived therefrom, an amino group or a group derived therefrom, or a hydroxyl group or a group derived therefrom) Wherein one or more hydrogen atoms are substituted), wherein Z1, Z2, and Z3 are carboxy groups or groups derived therefrom, unsubstituted or substituted alkyl or alkenyl groups having 1 to 4 carbon atoms, hydroxyl groups or groups derived therefrom. The cyclopentenone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the cyclopentenone derivative represents a group represented by the following formula, an amino group or a group derived therefrom, a heteroaromatic monocyclic ring, a halogen atom or a hydrogen atom. 7. The method according to claim 1, wherein
X indicates that the ring forms a double bond conjugated to an oxo group without including the carbon atom to which CH2-XY is bonded;
Represents S, O or SO, and Y represents an aliphatic hydrocarbon group having 1 to 6 carbon atoms [carboxy group, COOR1 (wherein R1 represents a substituted or unsubstituted alkyl or alkenyl group having 1 to 4 carbon atoms) ), CONR2R3 (wherein R2 and R3 are the same or each independently represent a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms), COW (wherein W is an unsubstituted, carboxy group or NR4R5 wherein R4 and R5 are the same or each independently represent a hydrogen atom, an unsubstituted or substituted carbon atom having 1 to 4 carbon atoms, or a group derived therefrom or a heterocyclic ring substituted with an amino group or a group derived therefrom; A substituted alkyl group or an unsubstituted or substituted acyl group having 1 to 5 carbon atoms, or OR6 (wherein R6 is a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms, or Indicates] at least one or more hydrogen atoms are replaced by indicating the unsubstituted or substituted acyl group of prime 1 to 5), Z1, Z2, Z3 is a carboxy group,
COOR7 (wherein R7 represents an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms), CONR8R9 (wherein R8,
R9 is the same or each independently hydrogen atom, carbon number 1
To 4 substituted or unsubstituted alkyl groups), cyano group, CH2OR10 (wherein R10 is a hydrogen atom,
4 to 4 unsubstituted or substituted alkyl groups, or 1 carbon atom
-5, an unsubstituted or substituted acyl group), a hydroxyl group, OCOR11 (wherein R11 represents an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms), NR12R13
(Wherein R12 and R13 are the same or independently represent a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms, or an unsubstituted or substituted acyl group having 1 to 5 carbon atoms). 7. The cyclopentenone derivative or a pharmaceutically acceptable salt thereof according to claim 6, which represents a tetrazolyl group, a chlorine atom, a fluorine atom, or a hydrogen atom. 8. In the general formula [1] according to claim 1, A is
X indicates that the ring forms a double bond conjugated to an oxo group without including the carbon atom to which CH2-XY is bonded;
Represents S, and Y represents an aliphatic hydrocarbon group having 1 to 6 carbon atoms ｛carboxy group, COOR1 ′ (wherein R1 ′ represents 1 to 4 carbon atoms)
Represents an alkyl group or an alkenyl group), or NH
COR14 (wherein R14 represents an alkyl group having 1 to 4 carbon atoms, the hydrogen atom of which may be substituted with a fluorine atom), a hydroxyl group, or OCOR15 (wherein R15 represents an alkyl group having 1 to 4 carbon atoms) ) Represents｝ wherein at least two or more hydrogen atoms are substituted, Z1, Z2, and Z3 are carboxy groups, and COOR7 '(wherein R7' has 1 to 4 carbon atoms).
Or a CH2OR10 ′ (wherein R10 ′ represents a hydrogen atom or an acyl group having 1 to 5 carbon atoms), or the cyclopentenone derivative according to claim 7, or a pharmaceutically acceptable salt thereof. salt. 9. The method according to claim 1, wherein A is
X indicates that the ring forms a double bond conjugated to an oxo group without including the carbon atom to which CH2-XY is bonded;
Represents S, Y represents a 2-acetylamino-2-carboxylethyl group, and Z1, Z2 and Z3 all represent a hydrogen atom, or a pharmacologically acceptable salt thereof. 10. The cyclopentenone derivative according to any one of claims 1 to 9 (however, when Z1 is a hydrogen atom, also when X represents NH, O or SO2) or a pharmacologically thereof. A medicament comprising an acceptable salt as an active ingredient. 11. The cyclopentenone derivative according to any one of claims 1 to 9 (provided that when Z1 is a hydrogen atom, X includes NH, O or SO2) or a pharmacologically active substance thereof. A therapeutic agent for central nervous system comprising an acceptable salt as an active ingredient. 12. The cyclopentenone derivative according to any one of claims 1 to 9 (provided that when Z1 is a hydrogen atom, X includes NH, O or SO2) or a pharmacologically active substance thereof. A therapeutic agent for peripheral nerves comprising an acceptable salt as an active ingredient. 13. The cyclopentenone derivative according to any one of claims 1 to 9 (however, when Z1 is a hydrogen atom, also when X represents NH, O or SO2) or a pharmacologically thereof. A nerve cell differentiation promoter comprising an acceptable salt as an active ingredient.