JPH09194476A - Thiophene alkanoic acid derivative - Google Patents

Abstract

(57) [Summary] [Objective] The present invention aims to provide a therapeutic agent for autoimmune diseases such as rheumatoid arthritis. [Structure] Formula [Chemical Formula 1] (In the formula, n represents an integer of 0 or 1, and Y represents a hydrogen atom or a lower alkyl group. Provided that when n = 1,
R ¹ and R ² are hydrogen atoms, X is a hydrogen atom, a halogen atom or a lower alkyl group, and when n = 0, at least one of R ¹ or R ² is a methyl group, X is a hydrogen atom, It represents a halogen atom or a lower alkyl group, Y represents a hydrogen atom, and R ³ represents a hydrogen atom or a methyl group. ) A thiophene alkanoic acid derivative and a formula, (In the formula, R ¹ and R ² represent a hydrogen atom, R ³ represents a hydrogen atom or a methyl group. X represents a hydroxyl group, a thioalkyl group, a phenoxy group, a phenyl group, a trifluoromethyl group, a halogen substituted at the 2-position or the 3-position. Represents an atom or a lower alkyl group, Y
Represents a hydrogen atom, or X and Y represent simultaneously or differently a halogen atom or a lower alkyl group. ) The thiophene alkanoic acid derivative represented by.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel thiophene acetic acid derivative, and more particularly to a thiophene alkanoic acid derivative effective for treating self-disease diseases such as rheumatoid arthritis.

[0002]

BACKGROUND OF THE INVENTION There are several therapeutic agents for rheumatoid arthritis, which is one of the autoimmune diseases. Among them are anti-inflammatory agents (diclofenac, piroxicam, etc.) and immunomodulators (bucilamine, D-penicillamine, gold). Formulation, Lobenzarit, etc.) Although anti-inflammatory agents are used to control pain and inflammation, they cannot prevent joint destruction that results from inflammation. On the other hand, immunomodulators are attracting attention as causative agents, but none of these agents are necessarily satisfactory in terms of their efficacy and side effects.

[0003]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a therapeutic agent for autoimmune diseases such as rheumatoid arthritis.

[0004]

Means for Solving the Problems As a result of intensive studies aimed at solving the above problems, the present inventors have found that the thiophene alkanoic acid derivatives shown below can achieve the objects, and have completed the present invention.

That is, the present invention provides formula I

[0006]

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(In the formula, n represents an integer of 0 or 1, and Y
Represents a hydrogen atom or a lower alkyl group. However, n = 1
R ¹ and R ² are hydrogen atoms, X is a hydrogen atom, a halogen atom or a lower alkyl group, and when n = 0, at least one of R ¹ or R ² is a methyl group and X is A hydrogen atom, a halogen atom and a lower alkyl group are shown, Y is a hydrogen atom and R ³ is a hydrogen atom or a lower alkyl group. ) And a thiophene alkanoic acid derivative represented by formula II

[0008]

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(Wherein R ¹ and R ² are hydrogen atoms, R ³ is a hydrogen atom or a lower alkyl group. X is a hydroxyl group, thioalkyl group, phenoxy group, phenyl group, trifluoromethyl group, 2-position or 3 A thiophene alkanoic acid derivative represented by a position-substituted halogen atom or a lower alkyl group and Y is a hydrogen atom, or X and Y are simultaneously or differently a halogen atom or a lower alkyl group.

In the present invention, the halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and the lower alkyl group is a carbon number such as methyl group, ethyl group, propyl group, isopropyl group, butyl group and isobutyl group. 1 to
It is four alkyl groups. The compound represented by the formula (I) can be produced, for example, by the method shown in the following production scheme I. (Manufacturing scheme I)

[0011]

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(In the production scheme, X represents a hydrogen atom, a halogen atom, or a lower alkyl group having 1 to 4 carbon atoms. R ³ represents a hydrogen atom or a lower alkyl group.) That is, JP-A-2- The thiophenecarboxylic acid derivative represented by the formula (1) described in Japanese Patent No. 193990 is reduced to give a 5-phenylthiophene-3-methanol derivative (2). Next, the hydroxyl group of the compound of formula (2) is converted into a halogen by a halogenating agent to obtain a methyl halide compound represented by formula (3).

The compound of the present invention in which R ³ is a lower alkyl group according to the decarboxylation reaction of the diester body (4) after replacing the halogen atom of the compound of formula (3) with diethyl malonate to form the diester body (4) (7) can be manufactured.

In the present production method, the reduction reaction can be carried out under the usual reduction reaction conditions in which a carboxylic acid or ester is reduced to an alcohol.

For example, reduction using lithium aluminum hydride, sodium borohydride, sodium metal and the like can be mentioned, and it is used in an amount of 1 to 5 molar equivalents relative to the compound (1). The solvent used in this reaction may be arbitrarily selected depending on the reducing agent, and generally diethyl ether,
Tetrahydrofuran, methanol, ethanol, toluene and the like can be used. The reaction temperature is 0 ° C to the reflux temperature of the solvent, preferably 0 ° C to room temperature, and the reaction time is generally 1 to 2 hours.

For the halogenation reaction, usual reaction conditions for halogenating a hydroxyl group can be applied. For example, the formula (2)
To an organic solvent (for example, tetrahydrofuran, benzene, carbon tetrachloride, N, N-dimethylformamide,
Dimethyl sulfoxide, hexamethylphosphoric triamide, etc., or a mixed solvent thereof, in a halogenating agent (eg, thionyl chloride, phosphorus pentachloride, thionyl bromide,
(Phosphorus tribromide, etc.) is added in an amount of 1 to 5 molar equivalents and the mixture is stirred at 0 ° C to the reflux temperature of the solvent for 1 to 5 hours.

The reaction between the methyl halide represented by formula (3) and diethyl malonate is carried out in an organic solvent (methanol, ethanol, etc.) using, for example, sodium methoxide, sodium ethoxide, etc. at room temperature to the solvent. The desired product is obtained by reacting at the reflux temperature of 1 to 5 hours.

The decarboxylation reaction is carried out according to A. By the method of Paul Krapcho et al. [Tetrahedron Letters, p. 957, 1973], the compound (4) was added to an organic solvent (dimethyl sulfoxide, dimethylformamide) in an amount of 1 to 2 equivalents of sodium chloride and 1 to 5 equivalents of water for 1 to 5 hours. The reaction proceeds by heating under reflux to obtain an ethyl 5-phenylthiophene-3-propionate derivative (5).

By hydrolyzing the compound of formula (5), the carboxylic acid type compound (6) of the present invention can be produced.

In this reaction, usual reaction conditions for hydrolyzing an ester to a carboxylic acid can be applied.

That is, for example, in the case of alkali hydrolysis, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide can be used, and in the case of acid hydrolysis, hydrochloric acid, sulfuric acid or bromide can be used. Mineral acids such as hydrogen acid, organic acids such as formic acid, acetic acid, p-toluenesulfonic acid, and mixtures thereof can be used.

Then, the carboxylic acid type compound (9) is subjected to an ordinary esterification reaction to form an ester type compound (1
It can be converted to the compound of 0).

There are various esterification reactions, for example, a method of reacting an alkylating agent corresponding to a carboxylic acid compound in the presence of a base in an organic solvent, or an alcohol (corresponding to an alcohol (corresponding to the carboxylic acid compound) under an acid catalyst). R ³ —OH) and the like.

Here, the organic solvent is acetone, N, N
-Dimethylformamide, dimethylsulfoxide and the like, and the base includes sodium carbonate, potassium carbonate and the like. The alkylating agent is an alkyl halide such as methyl iodide or isopropyl bromide, or a dialkyl sulfuric acid such as dimethyl sulfuric acid or diethyl sulfuric acid. Further, the compound represented by the formula (I), which is a mineral acid such as sulfuric acid or hydrochloric acid or an organic acid such as p-toluenesulfonic acid as the acid catalyst, can be produced, for example, by the method shown in the following Production Scheme II. . (Manufacturing scheme II)

[0025]

[Chemical 6]

(In the production scheme, X represents a hydrogen atom, a halogen atom, or a lower alkyl group having 1 to 4 carbon atoms. At least one of R ^{1 and} R ² represents a methyl group, and R ³ represents hydrogen. That is, an atom or a lower alkyl group is shown.) That is, the thiophenecarboxylic acid derivative represented by the formula (1) is reduced to a 5-phenylthiophene-3-methanol derivative (2). Next, the hydroxyl group of (2) is converted into halogen by a halogenating agent to obtain a halogenated methyl compound represented by the formula (3). By reacting the compound of formula (3) with a cyanating agent, the compound of formula (8) can be obtained.

In the present production method, the reduction reaction can be carried out under the usual reduction reaction conditions in which a carboxylic acid or ester is reduced to an alcohol.

For example, reduction using lithium aluminum hydride, sodium borohydride, metallic sodium or the like can be mentioned, and it is used in an amount of 1 to 5 molar equivalents relative to the compound (1). The solvent used in this reaction may be arbitrarily selected depending on the reducing agent, and generally diethyl ether,
Tetrahydrofuran, methanol, ethanol, toluene and the like can be used. The reaction temperature is 0 ° C to the reflux temperature of the solvent, preferably 0 ° C to room temperature, and the reaction time is generally 1 to 2 hours.

For the halogenation reaction, usual reaction conditions for halogenating a hydroxyl group can be applied. For example, the formula (2)
To an organic solvent (for example, tetrahydrofuran, benzene, carbon tetrachloride, N, N-dimethylformamide,
Dimethyl sulfoxide, hexamethylphosphoric triamide, etc., or a mixed solvent thereof, in a halogenating agent (eg, thionyl chloride, phosphorus pentachloride, thionyl bromide,
(Phosphorus tribromide, etc.) is added in an amount of 1 to 5 molar equivalents and the mixture is stirred at 0 ° C to the reflux temperature of the solvent for 1 to 5 hours.

In the cyanation reaction, a conventional cyanating agent (sodium cyanide, potassium cyanide, copper cyanide, etc.) is used in an amount of 1 to 5 molar equivalents relative to the compound of formula (3).
2 in a reaction solvent (dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile, etc.) at room temperature to 60 ° C.
Proceed by stirring for ~ 5 hours.

The carboxylic acid compound of the formula (9) can be produced by hydrolyzing the compound of the formula (8). In this reaction, usual reaction conditions for hydrolyzing a nitrile to a carboxylic acid can be applied.

That is, for example, in the case of alkali hydrolysis, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide can be used. In the case of acid hydrolysis, hydrochloric acid, sulfuric acid or bromide can be used. Mineral acids such as hydrogen acid, organic acids such as formic acid, acetic acid, p-toluenesulfonic acid, and mixtures thereof can be used.

The compound of formula (9) can be converted into an ester in which R ³ is a lower alkyl group by a conventional esterification reaction. There are various esterification reactions, for example, in an organic solvent, in the presence of a base, a method of acting an alkylating agent corresponding to a carboxylic acid compound, or under an acid catalyst,
Carboxylic acid compound and corresponding alcohol (R ³ -OH)
And a method of heating and the like.

Here, the organic solvent is acetone, N, N
-Dimethylformamide, dimethylsulfoxide and the like, and the base includes sodium carbonate, potassium carbonate and the like. The alkylating agent is an alkyl halide such as methyl iodide or isopropyl bromide, or a dialkyl sulfuric acid such as dimethyl sulfuric acid or diethyl sulfuric acid. As the acid catalyst, a thiopheneacetic acid derivative represented by the compound (10), which is a mineral acid such as sulfuric acid or hydrochloric acid or an organic acid such as p-toluenesulfonic acid, is methylated with an appropriate methylating agent in an organic solvent. By doing so, the compound of the present invention of formula (11) can be obtained.

The methylation reaction may be carried out by using a conventional methylating agent (methyl iodide, dimethylsulfate, etc.) in the formula (10).
1 to 2 molar equivalents relative to the compound of
0 in dimethylformamide, tetrahydrofuran, etc.)
Proceed by stirring at ~ 5 ° C for 1-5 hours.

The compound of formula (11) is hydrolyzed in the same manner as described above to give a carboxylic acid of formula (1).
The compound of the present invention represented by 2) can be produced.

The compound represented by the formula (II) can be produced, for example, by the method shown in the following production scheme III. The compound of formula (15) that is the starting material is, for example,
R, E, Lutz et al.'S method (Journal of A
Merchanic Chemical Society,
Vol. 75, p. 5039, 1953) or a method similar thereto, and a benzene derivative represented by the general formula X-Ph (III) (wherein X has the same meaning as described above) and itaconic anhydride. And can be produced by reacting with Friedel-Crafts.

(Production Scheme III)

[0039]

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(In the production scheme, X represents a halogen atom, a hydroxyl group, a thioalkyl group, a phenoxy group or a phenyl group, and R ³ is a hydrogen atom or a lower alkyl group.) That is, in the compound represented by the formula (15) Addition of thiocarboxylic acid gives formula (16). The obtained compound of formula (16) is subjected to a cyclization reaction with a base or an acid, and then a dehydrogenation reaction is performed to obtain a 5-phenylthiophene-3-carboxylic acid derivative (1).

The addition reaction with thiocarboxylic acid is carried out in an organic solvent (ether, tetrahydrofuran, benzene, toluene, ethyl acetate, N, N-dimethylformamide, etc.)
In the presence or absence of 0.01 to 1.5 molar equivalents of a base catalyst (sodium carbonate, potassium carbonate, lithium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, diisopropylethylamine, pyridine, etc.) in the formula ( Thioacetic acid is added in an amount of 1 to 2 molar equivalents to the compound of 13), and the reaction proceeds at room temperature to 50 ° C for 0.5 to 24 hours.

When a base is used in the cyclization reaction, the base includes alkali metal compounds such as sodium hydroxide, potassium hydroxide and lithium hydroxide, organic primary amines such as ammonia, methylamine, ethylamine and hydrazine. Which is 1 to 5 molar equivalents relative to the compound of formula (14).

The reaction solvent is methanol, ethanol, acetone, dioxane, tetrahydrofuran, dimethylformamide or a mixed solvent thereof with water. The reaction temperature is 0 ° C to the reflux temperature of the solvent, and the reaction temperature is 1 to 24 hours. When an acid is used, the acid is a mineral acid such as sulfuric acid or hydrochloric acid or an organic acid such as paratoluenesulfonic acid, and is used in an amount of 1 to 10 molar equivalents relative to the compound of formula (14). The reaction solvent used is water, methanol, propanol, isopropanol or the like, the reaction temperature is 20 ° C to the reflux temperature of the solvent, and the reaction temperature is 1 to 24 hours.

The dehydrogenation reaction may be carried out by any dehydrogenating agent used in the same reaction, for example, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (D
DQ) tetrachlorobenzoquinone and the like. The reaction solvent is benzene, toluene, tetrahydrofuran, dioxane, acetone or the like. The reaction temperature is 0 ° C to the reflux temperature of the solvent, and the reaction time is 0.5 to 24 hours.

The compound of formula (1) can be converted into the compound of the present invention of formula (17).

That is, the thiophenecarboxylic acid derivative is reduced to give the 5-phenylthiophene-3-methanol derivative of the formula (2). Next, the hydroxyl group of the compound of formula (2) is converted into a halogen by a halogenating agent to obtain a methyl halide compound represented by formula (3). By reacting the compound of formula (3) with a cyanating agent, the compound of formula (5) can be obtained.

In the present production method, the reduction reaction can be carried out under the usual reduction reaction conditions in which a carboxylic acid or ester is reduced to an alcohol.

For example, reduction using lithium aluminum hydride, sodium borohydride, metallic sodium and the like can be mentioned, and it is used in an amount of 1 to 5 molar equivalents relative to the compound (1). The solvent used in this reaction may be arbitrarily selected depending on the reducing agent, and generally diethyl ether,
Tetrahydrofuran, methanol, ethanol, toluene and the like can be used. The reaction temperature is 0 ° C to the reflux temperature of the solvent, preferably 0 ° C to room temperature, and the reaction time is generally 1 to 2 hours.

For the halogenation reaction, usual reaction conditions for halogenating a hydroxyl group can be applied. For example, the formula (2)
To an organic solvent (for example, tetrahydrofuran, benzene, carbon tetrachloride, N, N-dimethylformamide,
Dimethyl sulfoxide, hexamethylphosphoric triamide, etc., or a mixed solvent thereof, in a halogenating agent (eg, thionyl chloride, phosphorus pentachloride, thionyl bromide,
(Phosphorus tribromide, etc.) is added in an amount of 1 to 5 molar equivalents and the mixture is stirred at 0 ° C to the reflux temperature of the solvent for 1 to 5 hours.

In the cyanation reaction, a conventional cyanating agent (sodium cyanide, potassium cyanide, copper cyanide, etc.) is used in an amount of 1 to 5 molar equivalents relative to the compound of formula (3).
2 in a reaction solvent (dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile, etc.) at room temperature to 60 ° C.
Proceed by stirring for ~ 5 hours.

By hydrolyzing the compound of formula (8), a carboxylic acid type compound of the present invention of formula (9) can be prepared. In this reaction, usual reaction conditions for hydrolyzing a nitrile to a carboxylic acid can be applied.

That is, for example, in the case of alkali hydrolysis, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide can be used, and in the case of acid hydrolysis, hydrochloric acid, sulfuric acid or bromide can be used. Mineral acids such as hydrogen acid, organic acids such as formic acid, acetic acid, p-toluenesulfonic acid, and mixtures thereof can be used.

The compound of formula (9) can be converted to the ester type compound of the present invention of formula (15) by a conventional esterification reaction.

There are various esterification reactions, for example, a method of reacting an alkylating agent corresponding to a carboxylic acid compound in the presence of a base in an organic solvent, or an alcohol (corresponding to an alcohol (corresponding to a carboxylic acid compound under an acid catalyst)). R ³ —OH) and the like.

Here, the organic solvent is acetone, N, N
-Dimethylformamide, dimethylsulfoxide and the like, and the base includes sodium carbonate, potassium carbonate and the like. The alkylating agent is an alkyl halide such as methyl iodide or isopropyl bromide, or a dialkyl sulfuric acid such as dimethyl sulfuric acid or diethyl sulfuric acid. The acid catalyst is a mineral acid such as sulfuric acid or hydrochloric acid or an organic acid such as p-toluenesulfonic acid.

The compound represented by the formula (I) can be produced, for example, by the method shown in the following production scheme IV. (Manufacturing scheme IV)

[0057]

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(In the production scheme, X represents a hydrogen atom, a halogen atom, or a lower alkyl group having 1 to 4 carbon atoms. At least one of R ^{1 and} R ² represents a methyl group, and R ³ represents Indicates a hydrogen atom or a lower alkyl group.).

That is, T. H. Chan et al. [Tetr
ahedron Letters, 1991, p. 7017] or a method similar thereto, and an alcohol represented by the formula (16) which can be easily produced by an addition reaction between a benzaldehyde derivative (X is a halogen atom or a lower alkyl group) and bromomethylacrylic acid. The derivative is oxidized by an oxidant to give formula (17)
Benzoylpropionic acid derivative of

Then, a compound of formula (18) is obtained by adding a thiocarboxylic acid to the compound of formula (17). The resulting compound of formula (18) is subjected to a cyclization reaction with a base or an acid, followed by dehydrogenation to give 5-phenylthiophene-
A 3-carboxylic acid can be obtained.

The addition reaction of the above-mentioned benzaldehyde derivative with bromomethylacrylic acid is carried out, for example, by using a metal such as zinc, tin or indium in tetrahydrofuran, diethyl ether, benzene, toluene, dioxane and 2-bromomethylacrylic acid at room temperature to 0.5 to at the reflux temperature of the solvent
Proceed by stirring for 5 hours.

The oxidation reaction uses oxalyl chloride dimethyl sulfoxide triethylamine as an oxidant,
The reaction solvent is ether, tetrahydrofuran, methylene chloride, dioxane or the like and is obtained by reacting at -60 to -45 ° C for 2 to 5 hours.

The addition reaction with thiocarboxylic acid is carried out in an organic solvent (ether, tetrahydrofuran, benzene, toluene, ethyl acetate, N, N-dimethylformamide, etc.)
In the presence or absence of 0.01 to 1.5 molar equivalents of a base catalyst (sodium carbonate, potassium carbonate, lithium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, diisopropylethylamine, pyridine, etc.). 1 to 2 molar equivalents are added, and the reaction proceeds at room temperature to 50 ° C. for 0.5 to 24 hours.

When a base is used in the cyclization reaction, the base is an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, an organic primary such as ammonia, methylamine, ethylamine or hydrazine. It is an amine or the like and is used at 1 to 5 molar equivalents relative to the compound of formula (18). The reaction solvent is methanol, ethanol, acetone, dioxane, tetrahydrofuran, N, N-dimethylformamide or a mixed solvent thereof with water.
The reaction temperature is 0 to the reflux temperature of the solvent, and the reaction time is 1 to
24 hours. When an acid is used, the acid is a mineral acid such as sulfuric acid or hydrochloric acid or an organic acid such as paratoluenesulfonic acid, and is used in an amount of 1 to 10 molar equivalents relative to the compound of formula (18). The reaction solvent is water, methanol, ethanol,
Examples include propanol and isopropanol. The reaction temperature is 20 ° C to the reflux temperature of the solvent, and the reaction time is 1 to 24 hours.

The dehydrogenating agent used in the dehydrogenation reaction is
Any dehydrogenating agent used in the same reaction may be used, for example, 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) tetrachlorobenzoquinone and the like can be mentioned.

The reaction solvent is benzene, toluene, tetrahydrofuran, dioxane, acetone or the like. The reaction temperature is 0 ° C to the reflux temperature of the solvent, and the reaction time is 0.5 to
24 hours.

The compound of formula (19) can be converted to the compound of the present invention represented by formula (24).

That is, the thiophenecarboxylic acid derivative of the formula (19) is reduced to give the 5-phenylthiophene-3-methanol derivative of the formula (20). Next, equation (20)
The hydroxyl group of the compound (1) is converted to halogen by a halogenating agent to obtain a halogenated methyl compound represented by the formula (21). By reacting the compound of formula (21) with a cyanating agent, the cyano compound of formula (22) can be obtained.

In the present production method, the reduction reaction can be carried out under the usual reduction reaction conditions in which a carboxylic acid or ester is reduced to an alcohol.

For example, reduction using lithium aluminum hydride, sodium borohydride, metallic sodium and the like can be mentioned, and 1 to 5 molar equivalents relative to the compound (19) are used. The solvent used in this reaction may be arbitrarily selected depending on the reducing agent, and generally diethyl ether, tetrahydrofuran, methanol, ethanol, toluene or the like can be used. Reaction temperature is 0 ° C ~
At the reflux temperature of the solvent, it is preferably 0 ° C. to room temperature, and the reaction time is usually 1 to 2 hours.

For the halogenation reaction, usual reaction conditions for halogenating a hydroxyl group can be applied.
0) in an organic solvent (for example, tetrahydrofuran, benzene, carbon tetrachloride, N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc., or a mixed solvent thereof) with a halogenating agent (for example, (Thionyl chloride, phosphorus pentachloride, thionyl bromide, phosphorus tribromide, etc.) are added in an amount of 1 to 5 molar equivalents, and the mixture is stirred at 0 ° C. to the reflux temperature of the solvent for 1 to 5 hours.

In the cyanation reaction, a conventional cyanating agent (sodium cyanide, potassium cyanide, copper cyanide, etc.) is used in an amount of 1 to 5 molar equivalents with respect to the compound of the formula (21), and a reaction solvent (dimethyl sulfoxide, N 2 , N-dimethylformamide, acetonitrile, etc.) at room temperature to 60 ° C.
By stirring for 2 to 5 hours.

By hydrolyzing the compound of formula (22), the carboxylic acid type compound of the present invention of formula (23) can be produced. In this reaction, usual reaction conditions for hydrolyzing a nitrile to a carboxylic acid can be applied.

That is, for example, in the case of alkali hydrolysis, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide can be used, and in the case of acid hydrolysis, hydrochloric acid, sulfuric acid or bromide can be used. Mineral acids such as hydrogen acid, organic acids such as formic acid, acetic acid, p-toluenesulfonic acid, and mixtures thereof can be used.

The carboxylic acid type compound of formula (23) can be converted to the ester type compound of formula (24) by a conventional esterification reaction.

There are various esterification reactions, for example, a method of reacting an alkylating agent corresponding to a carboxylic acid compound in the presence of a base in an organic solvent, or an alcohol (corresponding to an alcohol (corresponding to the carboxylic acid compound under an acid catalyst)). R ³ —OH) and the like.

Here, the organic solvent is acetone, N, N
-Dimethylformamide, dimethylsulfoxide and the like, and the base includes sodium carbonate, potassium carbonate and the like. The alkylating agent is an alkyl halide such as methyl iodide or isopropyl bromide, or a dialkyl sulfuric acid such as dimethyl sulfuric acid or diethyl sulfuric acid. Further, the compound represented by the formula (II), which is a mineral acid such as sulfuric acid or hydrochloric acid or an organic acid such as p-toluenesulfonic acid as the acid catalyst, can also be produced, for example, by the method shown in the following Production Scheme V. it can. (Manufacturing scheme V)

[0078]

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(In the scheme, X and Y represent a halogen atom and R3 represents a hydrogen atom or a lower alkyl group.) That is, the thiophenecarboxylic acid derivative represented by the formula (27) is reduced to give 5-phenyl. This is a thiophen-3-methanol derivative (28). Next, the hydroxyl group of (28) is converted to halogen by a halogenating agent to obtain a halogenated methyl compound represented by the formula (29) (wherein Y represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom). Represent.). By reacting the compound of formula (29) with a cyanating agent, the compound of formula (30) can be obtained.

In the production method of the present invention, the reduction reaction can be carried out under the usual reduction reaction conditions in which a carboxylic acid or ester is reduced to an alcohol.

For example, reduction using lithium aluminum hydride, sodium borohydride, metallic sodium and the like can be mentioned, and it is used in an amount of 1 to 5 molar equivalents relative to the compound of formula (27). The solvent used in this reaction may be arbitrarily selected depending on the reducing agent and is generally diethyl ether.
Tellurium, tetrahydrofuran, methanol, ethanol,
Toluene or the like can be used. Reaction temperature is 0 ° C
~ The reflux temperature of the solvent is preferably 0 ° C to room temperature, and the reaction time is generally 1 to 2 hours.

For the halogenation reaction, usual reaction conditions for halogenating a hydroxyl group can be applied.
8) a halogenating agent (for example, tetrahydrofuran, benzene, carbon tetrachloride, N, N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, etc., or a mixed solvent thereof) in an organic solvent (Thionyl chloride, phosphorus pentachloride, thionyl bromide, phosphorus tribromide, etc.) are added in an amount of 1 to 5 molar equivalents, and the mixture is stirred at 0 ° C. to the reflux temperature of the solvent for 1 to 5 hours.

In the cyanation reaction, a conventional cyanating agent (sodium cyanide, potassium cyanide, copper cyanide, etc.) is used in an amount of 1 to 5 molar equivalents with respect to the compound of formula (29), and the reaction solvent (dimethyl sulfoxide, N 2 , N-dimethylformamide, acetonitrile, etc.) at room temperature to 60 ° C.
By stirring for 2 to 5 hours.

By hydrolyzing the compound of formula (30), the carboxylic acid type compound of the present invention of formula (31) can be produced. In this reaction, usual reaction conditions for hydrolyzing a nitrile to a carboxylic acid can be applied.

That is, for example, in the case of alkali hydrolysis, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide can be used, and in the case of acid hydrolysis, hydrochloric acid, sulfuric acid or bromide can be used. Mineral acids such as hydrogen acid, organic acids such as formic acid, acetic acid, p-toluenesulfonic acid, and mixtures thereof can be used.

The compound of formula (31) can be converted to the ester type compound of formula (32) by a conventional esterification reaction. There are various esterification reactions, for example, a method of reacting an alkylating agent corresponding to a carboxylic acid compound in the presence of a base in an organic solvent, or an alcohol (R ^3- O
And the method of heating H) and the like.

Here, the organic solvent is acetone, N, N
-Dimethylformamide, dimethylsulfoxide and the like, and the base includes sodium carbonate, potassium carbonate and the like. The alkylating agent is an alkyl halide such as methyl iodide or isopropyl bromide, or a dialkyl sulfuric acid such as dimethyl sulfuric acid or diethyl sulfuric acid. The acid catalyst is a mineral acid such as sulfuric acid or hydrochloric acid or an organic acid such as p-toluenesulfonic acid.

[0088]

The compound of the formula (I), which is the object of the present invention, has an excellent effect on adjuvant arthritis in rats and further suppresses the production of interleukin 1 which is one of inflammatory cytokines. It also has anti-inflammatory and analgesic effects, and is therefore effective in treating autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus.

(Test Example 1) [Effect on Adjuvant Arthritis (Rheumatoid Arthritis Pathological Model)] 7-week-old Sprague-Dawley rats (body weight: 160 to 1)
90 g) 10 animals were used as a group.

0.6 mg of killed Mycobacterium tuberculosis (bovine type)
A liquid suspended in 1 ml of liquid paraffin was intradermally injected into the tail of each group of rats for sensitization. As a test drug, various compounds of the formula (I) were suspended in a 5% gum arabic solution, and this was used as a compound of the formula (I) at 10 mg / Kg (or 1
(00 mg / kg, 50 mg / kg), 1 day a day after sensitization
Orally administered to rats in separate groups once or twice for 16 consecutive days. In the control group, only 5% gum arabic was used and orally administered to rats in the same manner. On the last day of the experiment, the volume of edema of the hind limbs was measured, and the edema inhibition rate for the drug administration group was calculated.
The results on the 17th day after the sensitization are shown in Table 1.

[0091]

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[0092]

[Table 1]

[0093]

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[0094]

[Table 2]

(Test Example 2) [IL-1 production inhibitory effect] Heparin-treated normal human peripheral blood was layered on Lymphoprep (Daiichi Pharmaceutical Co., Ltd.) under sterile conditions to remove red blood cells, and then the cells were fetal bovine serum 10%, Penicillin 100 U / ml, streptomycin 100 / ml, Hepes buffer 10 mM and L-glutamine 2 mM were added to the suspension, and the cells were suspended in RPMI-1640 medium (Gibco) to obtain 2 × 10 ⁶ cells.
s / ml.

500 μl of the prepared cell suspension, ConA
(Sigma, 8.0 μg / ml solution) and the above-mentioned medium solution of the test compound (compound of the present invention) (250 μl each) were added to a microplate (flat bottom 24 holes, manufactured by Iwaki Glass Co., Ltd.), and 5% CO ₂ incubate was added. The cells were cultured for 48 hours.

A culture medium solution of the test compound was prepared by dissolving the sample in ethanol and then diluting the culture medium solution so that the final concentration of ethanol was 0.05%. After culture, ELISA is performed with IL-1β (pg / ml) in the cell supernatant.
Measured with a kit (Amersham), 50% inhibition rate (IC
₅₀ values, μM) were calculated.

[0098]

Embedded image

[0099]

[Table 3]

[0100]

[Examples] Hereinafter, the method for producing the compound of the present invention will be described in detail with reference to Examples. Example 1 5- (4-Bromophenyl) thiophene-3
-Propionic acid 1) 5- (4-bromophenyl) thiophene-3-meta
In a suspension of 4.8 g of lithium aluminum aluminum hydride in ether at room temperature, 5- (4-bromophenyl) thiophene-3-
After 50.0 g of methyl carboxylate was added little by little, the mixture was stirred for 3 hours at room temperature. The reaction solution was decomposed with isopropyl alcohol and diluted hydrochloric acid, and then extracted with ether. The extract was washed with sodium hydrogen carbonate and water in this order, dried (magnesium sulfate), evaporated to remove the solvent, and recrystallized from ethyl acetate-n-hexane to give 5- (4-bromophenyl) thiophene-3-methanol. 42.1 g was obtained.

NMR (CDCl ₃ ) δ (ppm);
70 (2H, S), 7.19 (1H, d, J = 1.0H
z), 7.30 (1H, d, J = 1.0 Hz), 7.4
0-7.55 (4H, m).

2) 3-chloromethyl-5- (4-bromo
Phenyl) thiophene 5- (4-bromophenyl) thiophene-3-methanol (40.0 g) was dissolved in tetrahydrofuran (400 ml) -hexamethylphosphoric triamide (40 ml) and thionyl chloride (21.7 ml) was added dropwise at room temperature.
After stirring for an hour, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried (magnesium sulfate) and the solvent was distilled off to give crude 3-chloromethyl-5- (4-bromophenyl) thiophene (40%). 0.0 g was obtained.

NMR (CDCl ₃ ) δ (ppm);
60 (2H, S), 7.23 (1H, d, J = 1.0H
z), 7.30 (1H, d, J = 1.0 Hz), 7.4
0 to 7.15 (4H, m). 3) 3-diethylmalonylmethyl-5- (4-bromophenyl)
Phenyl) thiophene sodium 2.8g is dissolved in ethanol 350ml,
After 27.7 ml of diethyl malonate was added dropwise at room temperature, 35.0 g of 3-chloromethyl-5- (4-bromophenyl) thiophene was slowly added with heating under reflux, and further 1.
The mixture was heated under reflux for 5 hours. Ethanol was evaporated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (magnesium sulfate), and the solvent was evaporated. The residue was purified by silica gel chromatography to obtain 36.5 g of the desired product.

NMR (CDCl ₃ ) δ (ppm);
20-1.35 (6H, m), 3.21 (2H, d, J
= 7.5 Hz), 3.65 (1H, t, J = 7.5H)
z), 4.10 to 4.30 (4H, m), 7.00 (1
H, d, J = 1.0 Hz), 7.15 (1H, d, J =
1.0 Hz), 7.30 to 7.60 (4H, m).

4) 5- (4-bromophenyl) thiophene
Ethyl 3 -propionate 3-diethylmalonylmethyl-5- (4-bromophenyl) thiophene 30.0 g was added to dimethyl sulfoxide 15
It was dissolved in 0 ml, sodium chloride 8.8 g and water 4.8 ml were added at room temperature, and the mixture was heated under reflux for 5 hours. The reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried (magnesium sulfate).
The after-solvent was distilled off, and the residue was purified by silica gel chromatography to obtain ethyl 5- (4-bromophenyl) thiophene-3-propionate (21.7 g). NMR (CDCl ₃ ) δ (ppm); 1.25 (3H,
td, J = 7.5, 1.3 Hz), 2.65 (2H,
t, J = 7.5 Hz), 2.95 (2H, t, J = 7.
5 Hz), 4.07 to 4.21 (2H, m), 6.95
(1H, d, J = 1.0 Hz), 7.15 (1H, d,
J = 1.0 Hz), 7.40 to 7.60 (4H, m).

5) 5- (4-bromophenyl) thiophe
Down-3-propionic acid 5- (4-bromophenyl) thiophene-3-propionate 20.0g was dissolved in methanol 400 ml, water 100ml at room temperature with sodium hydroxide 14.1g
The solution was added and stirred at room temperature for 1 hour. After distilling off methanol and washing with ether, the mixture was poured into concentrated hydrochloric acid-ice and extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, dried (magnesium sulfate) and then the solvent was distilled off. Recrystallized from ethyl acetate-n-hexane to give 5- (4-bromophenyl)
14.9 g of thiophen-3-propionic acid was obtained.

NMR (CDCl ₃ ) δ (ppm); 2.
73 (2H, t, J = 7.5Hz), 2.98 (2H,
t, J = 7.5 Hz), 6.95 (1H, d, J = 1.
0Hz), 7.15 (1H, d, J = 1.0Hz),
7.30-7.60 (4H, m).

Example 2 The following compounds of the present invention were obtained according to Example 1 using the various compounds (1) shown in the above Production Scheme I.

5-Phenylthiophene-3-propionic acid m.p. p. 133.9 ° C. 5- (4-methylphenyl) thiophene-3-propionic acid m.p. p. 121.7 ° C. 5- (4-chlorophenyl) thiophene-3-propionic acid m.p. p. 128.2 ° C.

Example 3 5- (4-Bromophenyl) thiophene-3-propio
Methyl acid 5- (4-bromophenyl) thiophene-3-propionic acid (6.0 g), concentrated sulfuric acid (3.1 ml), methanol (62 ml)
The solution was added and the mixture was heated under reflux for 6 hours. After methanol was distilled off under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (magnesium sulfate) and the solvent was distilled off. The residue was recrystallized from ethyl acetate-n-hexane to obtain methyl 5- (4-bromophenyl) thiophene-3-propionate (4.8 g).

NMR (CDCl ₃ ) δ (ppm); 2.
66 (2H, t, J = 7.5 Hz), 2.95 (2H,
t, J = 7.5 Hz), 3.70 (3H, s), 6.
95 (1H, d, J = 1.0 Hz), 7.14 (1H,
d, J = 1.0 Hz), 7.38 to 7.53 (4H,
m).

Example 4 The following compounds of the present invention were obtained according to Example 1 using the various compounds (6) shown in the above Production Scheme I.

Methyl 5-phenylthiophene-3-propionate m.p. p. 66.8 ° C. Methyl 5- (4-methylphenyl) thiophene-3-propionate m.p. p. 59.6 ° C. Methyl 5- (4-chlorophenyl) thiophene-3-propionate m.p. p. 85.4 ° C.

Example 5 2- [5- (4-bromophenyi
Methyl) -3-thiophene) propionate 1) 5- (4-bromophenylthiophene) -3-meta
It was produced in the same manner as in No. 1-1).

2) 3-chloromethyl-5- (4-bromo
Phenyl) thiophene Prepared as in Example 1-2).

3) 5- (4-bromophenyl) thiophene
3- (3 -acetonitrile) 3 -chloromethyl-5- (4-bromophenyl) thiophene (3.6 g) was dissolved in dimethylsulfoxide (50 ml), sodium cyanide (920 mg) was added, and the mixture was stirred at 50 ° C for 1 hr. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (magnesium sulfate), and then the solvent was distilled off. Recrystallize from ethyl acetate-n-hexane 5
2.8 g of-(4-bromophenyl) thiophene-3-acetonitrile was obtained.

NMR (CDCl ₃ ) δ (ppm); 3.
74 (2H, s), 7.21 (2H, s), 7.45
(2H, d, J = 9.0 Hz), 7.52 (2H, d,
J = 9.0 Hz).

4) 5- (4-bromophenyl) thiophene
To 2.8 g of 5- (4-bromophenyl) thiophene-3-acetonitrile- 3-acetic acid was added 100 ml of ethanol and 100 ml of 5N potassium hydroxide, and the mixture was heated under reflux for 1 hour. After cooling the reaction solution, ethanol was distilled off under reduced pressure, water was added, and the mixture was poured into concentrated hydrochloric acid-ice and extracted with ethyl acetate. The extract was washed with water and dried (magnesium sulfate), and then the solvent was distilled off. The residue was recrystallized from ethyl acetate-n-hexane to obtain 3.0 g of the desired product.

NMR (CDCl ₃ ) δ (ppm); 3.
69 (2H, s), 7.12 (1H, m), 7.23
(1H, d, J = 2.0Hz), 7.43 (2H, d,
J = 8.0 Hz), 7.50 (2H, d, J = 8.0H)
z).

5) 5- (4-bromophenyl) thiophene
Methyl - 3-acetate 5- (4-bromophenyl) thiophene-3-acetic acid,
A solution of concentrated sulfuric acid 3.8 ml in methanol 38 ml was added to 7.0 g, and the mixture was heated under reflux for 2 hours. After distilling off methanol under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and dried (magnesium sulfate), and then the solvent was distilled off. The residue was recrystallized from ethyl acetate-n-hexane to obtain 6.4 g of the desired product.

NMR (CDCl ₃ ) δ (ppm); 3.
64 (2H, s), 3.72 (3H, s), 7.10
(1H, m), 7.24 (1H, d, J = 2.0H
z), 7.43 (2H, d, J = 8.0 Hz), 7.4
8 (2H, d, J = 8.0 Hz).

6) 2- [5- (4-bromophenyl)-
Methyl 3-thiophene] propionate 5- (4-bromophenyl) thiophene-3-acetate Methyl acetate (5.2 g) was added to a solution of dimethylformamide (40 ml) in an amount of 672 mg of sodium hydride (60% oily) and cooled under ice-cooling.
Stirred for 0 minutes. 1.1 ml of methyl iodide was added dropwise to this, and the mixture was stirred at the same temperature for 3 hours, ice water was added, and the mixture was extracted with ethyl acetate. Wash the organic layer with water and dry (magnesium sulfate)
Thereafter, the solvent was distilled off. The residue was purified by silica gel chromatography to obtain 3.4 g of the desired product.

NMR (CDCl ₃ ) δ (ppm);
53 (3H, d, J = 7.0Hz), 3.70 (3H,
s), 3.82 (1H, q, J = 7.0Hz) m),
7.05 to 7.55 (6H, m).

Example 6 The following compounds of the present invention were obtained according to Example 5 using the various compounds (1) shown in the above Production Scheme II.

Methyl 2- (5-phenyl-3-thiophene) propionate NMR (CDCl ₃ ) δ (ppm); 1.53 (3H,
d, J = 7.0 Hz), 3.70 (3H, s), 3.8
2 (1H, q, J = 7.0Hz), 7.05 to 7.65
(7H, m).

2- [5- (4-methylphenyl) -3-
Thiophene] methyl propionate NMR (CDCl ₃ )
δ (ppm); 1.53 (3H, d, J = 7.0H
z), 2.36 (3H, s), 3.70 (3H, s),
3.82 (1H, q, J = 7.0Hz), 7.00
7.52 (6H, m).

2- [5- (4-chlorophenyl) -3-
Thiophene] methyl propionate NMR (CDCl ₃ )
δ (ppm); 1.52 (3H, d, J = 7.0H
z), 3.70 (3H, s), 3.82 (1H, q, J
= 7.0 Hz), 7.05 to 7.56 (6H, m).

Example 7 2- [5- (4-bromophenyi
Ru) -3-thiophene] propionic acid 2- [5- (4-bromophenyl) -3-thiophene]
Sodium hydroxide was added to a solution of 2.9 g of methyl propionate in 30 ml of methanol and 15 ml of tetrahydrofuran.
A 35 ml solution of 5 g of water was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, diluted with dilute hydrochloric acid to make it acidic, and extracted with ethyl acetate. The organic layer was washed with water, dried (magnesium sulfate), and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to obtain 2.5 g of the desired product.

M. p. 128.3 ° C NMR (CDCl ₃ ) δ (ppm); 1.55 (3H,
d, J = 7.0 Hz), 3.84 (1H, q, J = 7.
0 Hz), 7.10 to 7.55 (6H, m).

Example 8 The following compounds of the present invention were obtained according to Example 7 using the various compounds (11) shown in the above production scheme II.

2- (5-phenyl-3-thiophene) propionic acid m.p. p. 97.1 ° C. 2- [5- (4-methylphenyl) -3-thiophene]
Methyl propionate m. p. 174.9 ° C. 2- [5- (4-chlorophenyl) -3-thiophene]
Methyl propionate m. p. 117.7 ° C. Example 9 2- [5- (4-bromophenyl) -3-thi
[Ophen] methyl - 2-methylpropionate 2- [5- (4-bromophenyl) -3-thiophene]
Dimethylformamide 1 containing 0.5 g of methyl propionate
61 mg of sodium hydride (60% oily) in 0 ml solution
Was added and the mixture was stirred for 30 minutes under ice cooling. Methyl iodide (0.1 ml) was added dropwise to this, and the mixture was stirred at the same temperature for 3 hours, ice water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried (magnesium sulfate), and then the solvent was distilled off. The residue was purified by silica gel chromatography to obtain 0.5 g of the desired product.

NMR (CDCl ₃ ) δ (ppm);
60 (6H, s), 3.68 (3H, s), 7.06
(1H, d, J = 2.0 Hz), 7.26 (1H, d,
J = 2.0 Hz), 7.44 (2H, d, J = 8.0H
z), 7.48 (2H, d, J = 8.0 Hz).

Example 10 The following compounds of the present invention were obtained according to Example 9 using various compounds (10) shown in the above Production Scheme II.

2- [5- (4-chlorophenyl) -3-
Thiophene] methyl 2-methylpropionate NMR (CDCl ₃ ) δ (ppm); 1.60 (6H,
s), 3.69 (3H, s), 7.05 (1H, d, J
= 2.0 Hz), 7.25 (1H, d, J = 2.0H
z), 7.32 (2H, d, J = 8.0 Hz), 7.5
0 (2H, d, J = 8.0 Hz).

Example 11 2- [5- (4-bromophen
Nyl) -3-thiophene] -2-methylpropionic acid 2- [5- (4-bromophenyl) -3-thiophene]
To a solution of 0.3 g of methyl-2-methylpropionate in 3 ml of methanol and 1.5 ml of tetrahydrofuran was added a solution of 0.9 g of sodium hydroxide in 4 ml of water, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, diluted with dilute hydrochloric acid to make it acidic, and extracted with ethyl acetate. The organic layer was washed with water, dried (magnesium sulfate), and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to obtain 0.2 g of the desired product.

M. p. 152-153 ° C NMR (CDCl ₃ ) δ (ppm); 1.62 (6H,
s), 7.12 (1H, d, J = 2.0 Hz), 7.3
2 (1H, d, J = 2.0Hz), 7.44 (2H,
d, J = 8.0 Hz), 7.49 (2H, d, J = 8.
0 Hz), 10.3 (1H, bs).

Example 12 Using the various compounds (13) shown in the above Production Scheme II, the following compounds of the present invention were obtained according to Example 11.

2- [5- (4-chlorophenyl) -3-
Thiophene] -2-methylpropionic acid m. p. 148-149 ° C NMR (CDCl ₃ ) δ (ppm); 1.62 (6H,
s), 7.11 (1H, d, J = 2.0 Hz), 7.3
0 (1H, d, J = 2.0Hz), 7.33 (2H,
d, J = 8.0 Hz), 7.50 (2H, d, J = 8.
0 Hz).

Reference Example 1 3- (4-thiomethylbenzoyl)
50 g of thioanisole- 2-methylpropionate and 49.6 g of itaconic anhydride were dissolved in 200 ml of nitroethane, and 118.1 g of anhydrous aluminum chloride was gradually added with stirring under ice cooling, followed by stirring at room temperature for 5 hours. To react. After completion of the reaction, the reaction solution was concentrated under reduced pressure, poured into concentrated hydrochloric acid-ice, and extracted with ethyl acetate. The extract was washed with water and dried (magnesium sulfate), the solvent was distilled off, and the residue was recrystallized from isopropyl ether to give 3- (4thiomethylbenzoyl) -2-methylenepropionic acid (in the above formula, a compound of X = SCH3). ) 1
4.4 g were obtained.

NMR (CDCl ₃ ) δ (ppm); 2.
53 (3H, s), 3.98 (2H, s), 5.72
(1H, d, J = 1.0 Hz), 6.20 (1H, d,
J = 1.0 Hz), 7.35 (2H, d, J = 7.3H)
z), 7.90 (2H, d, J = 7.3 Hz), 12.
5 (1H, bs).

Example 13 5- (4-thiomethylphenyi)
Methyl) thiophene-3-carboxylate 1) 2-acetylthiomethyl-3- (4-thiomethyl ester )
1- (4-thiomethylbenzoyl) -2-methylenepropionic acid (14.0 g) was dissolved in 100 ml of ethyl acetate,
To this, 5.1 ml of thioacetic acid was added, 1.7 ml of triethylamine was added dropwise with stirring at room temperature, and the mixture was further reacted at 50 ° C. for 1 hour. After the reaction was completed, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried (magnesium sulfate), the solvent was evaporated, the residue was recrystallized from isopropyl ether and 2-acetylthiomethyl-3- (4-thiomethylbenzoyl) propionic acid 1
2.0 g were obtained.

NMR (CDCl ₃ ) δ (ppm); 2.
35 (3H, s), 2.50 (3H, s), 3.15 ~
3.50 (5H, m), 7.27 (2H, d, J = 7.
3 Hz), 7.85 (2H, d, J = 7.3 Hz).

2) 5- (4-thiomethylphenyl) thio
Methyl phen-3-carboxylate 2-Acetylthiomethyl-3- (4-thiomethylbenzoyl) propionic acid 12.0 g was added with a solution of concentrated sulfuric acid 5.8 ml in methanol 58 ml and the mixture was heated under reflux for 1 hour. After methanol was distilled off under reduced pressure, water was added and the mixture was extracted with benzene. The benzene layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine in this order, and then 9.5 g of chloranil was added to the organic layer, and the mixture was heated under reflux for 1 hour. After cooling the reaction solution, the precipitate was collected by filtration and the filtrate was mixed with 5
% Aqueous sodium hydroxide solution was added and the mixture was extracted with benzene.
The organic layer was washed with saturated ammonium chloride and saturated sodium chloride in this order, dried (magnesium sulfate) and the solvent was distilled off.
The residue was recrystallized from isopropyl ether and 5- (4-
10.1 g of methyl thiomethylphenyl) thiophene-3-carboxylate was obtained.

NMR (CDCl ₃ ) δ (ppm); 2.
50 (3H, s), 3.88 (3H, s), 7.28
(2H, d, J = 7.3 Hz), 7.51 (2H, d,
J = 7.3 Hz), 7.68 (1H, d, J = 1.0H
z), 8.00 (1H, d, J = 1.0 Hz).

3) 5- (4-thiomethylphenyl) thio
To a tetrahydrofuran suspension of 860 mg of lithium aluminum hydride ofophen-3-methanol hydride, 8.0 g of methyl 5- (4-thiomethylphenyl) thiophene-3-carboxylate was added little by little under ice cooling, and then 1 hour at room temperature. It was stirred. The reaction solution was decomposed with isopropyl alcohol and dilute hydrochloric acid and then extracted with ethyl acetate. The extract was washed successively with sodium hydrogen carbonate and water, dried (magnesium sulfate), evaporated to remove the solvent, and recrystallized from ethyl acetate-n-hexane to give 5- (4-
6.9 g of thiomethylphenyl) thiophene-3-methanol was obtained.

NMR (CDCl ₃ ) δ (ppm); 2.
50 (3H, s), 4.65 (2H, s), 7.15
(1H, d, J = 1.0 Hz), 7.25 (2H, d,
J = 7.5 Hz), 7.27 (1H, d, J = 1.0H)
z), 7.50 (2H, d, J = 7.5Hz).

4) 3-chloromethyl-5- (4-thio
Methylphenyl) thiophene 5- (4-thiomethylphenyl) thiophene-3-methanol 6.9 g tetrahydrofuran 60 ml-N, N
-Dissolved in 20 ml of dimethylformamide, added dropwise 4.4 ml of thionyl chloride at room temperature, stirred for 2 hours at room temperature, poured the reaction solution into ice water, extracted with ethyl acetate, washed the organic layer with water, dried (magnesium sulfate), then removed the solvent. Distilled off, crude 3-
7.0 g of chloromethyl-5- (4-bromophenyl) thiophene was obtained.

NMR (CDCl ₃ ) δ (ppm); 2.
50 (2H, s), 4.60 (2H, s), 7.15 ~
7.32 (4H, m), 7.50 (2H, d, J = 7.
5 Hz).

5) 5- (4-thiomethylphenyl) thio
7.0 g of offen- 3 -acetonitrile 3-chloromethyl-5- (4-thiomethylphenyl) thiophene was dissolved in 30 ml of dimethyl sulfoxide, 2.2 g of sodium cyanide was added, and the mixture was stirred at 50 ° C for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (magnesium sulfate), and then the solvent was distilled off. After purifying the residue by silica gel chromatography,
Recrystallized from ethyl acetate-n-hexane and 5- (4-thiomethylphenyl) thiophene-3-acetonitrile 4.
5 g were obtained. NMR (CDCl ₃ ) δ (ppm); 2.50 (3H,
s), 3.70 (2H, s), 7.13 to 7.20 (2
H, m), 7.25 (2H, d, J = 7.5 Hz),
7.49 (2H, d, J = 7.5 Hz).

6) 5- (4-thiomethylphenyl) thio
40 ml of ethanol and 19.6 ml of 10N potassium hydroxide were added to 4.8 g of offene -3-acetic acid 5- (4-thiomethylphenyl) thiophene-3-acetonitrile, and the mixture was heated under reflux for 2 hours. After cooling the reaction solution, ethanol was distilled off under reduced pressure, water was added, and the mixture was poured into concentrated hydrochloric acid-ice and extracted with ethyl acetate. The extract was washed with water and dried (magnesium sulfate), and then the solvent was distilled off. The residue was recrystallized from ethyl acetate-isopropyl ether,
2.3 g of the target product was obtained.

NMR (CDCl ₃ ) δ (ppm); 1.
50 (3H, s), 3.58 (2H, s), 7.28
(2H, d, J = 10 Hz), 7.30 (1H, d,
J = 1.0 Hz), 7.37 (1H, d, J = 1.0H
z), 7.55 (2H, dd, J = 10, 2.0H
z), 12.4 (1H, bs).

Example 14 Using various compounds (15) shown in the above Production Scheme III, the following compound of the present invention was obtained according to Example 13.

5- (4-hydroxyphenyl) thiophene-3-acetic acid m.p. p. 185.0 ° C. 5- (4-phenoxyphenyl) thiophene-3-acetic acid NMR (CDCl ₃ ) δ (ppm); 3.59 (2H,
s), 6.95 to 7.48 (9H, m), 7.63 (2
H, d, J = 8.0 Hz), 12.4 (1H, s) 5- (4-biphenyl) thiophene-3-acetic acid m.p. p. 216.0-216.5 ° C.

Example 15 5- (4-thiomethylphenyi)
Methyl thiophene-3-acetate 5- (4-thiomethylphenyl) thiophene-3-acetic acid (3.0 g) was added with a solution of concentrated sulfuric acid (1.7 ml) in methanol (34 ml) and the mixture was heated under reflux for 2 hours. After distilling off methanol under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and dried (magnesium sulfate), and then the solvent was distilled off. The residue was recrystallized from ethyl acetate-n-hexane to obtain 3.0 g of the desired product.

NMR (CDCl ₃ ) δ (ppm); 1.
50 (3H, s), 3.65 (2H, s), 3.75
(3H, s), 7.07 (1H, d, J = 1.0H
z), 7.21 (1H, d, J = 1.0 Hz), 7.2
5 (2H, dd, J = 10, 1.0 Hz), 7.50
(2H, dd, J = 10, 1.0 Hz).

Example 16 The following compounds of the present invention were obtained according to Example 15 using the various compounds (16) shown in the above Production Scheme III.

Methyl 5- (4-hydroxyphenyl) thiophene-3-acetate m.p. p. 99.9 ° C. 5- (4-phenoxyphenyl) thiophene-3-ethyl acetate NMR (CDCl ₃ ) δ (ppm); 1.28 (3H,
t, J = 7.0 Hz), 3.62 (2H, s), 4.1
8 (2H, q, J = 7.0 Hz), 6.95 to 7.20
(7H, m), 7.30 to 7.41 (2H, m), 7.
55 (2H, d, J = 8.0 Hz).

5- (4-biphenyl) thiophene-3-
Methyl acetate m. p. 123.0-124.0 ° C.

Reference Example 2 4-hydroxy-4- (3-me
Cyclohexyl) -2-methylenepropionate 4-hydroxy-4- (3-methylphenyl) -2-methylenepropionate Indium 5.6 g was added to a tetrahydrofuran 100 ml suspension and bromomethylacrylic acid 1 was added.
0.0 g, 4.9 g of 3-methylbenzaldehyde are added, and the mixture is stirred at room temperature for 2 hours. After the reaction is complete, dilute hydrochloric acid is added and the mixture is extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, dried (sodium sulfate), and the solvent was evaporated to give crude 4-
Hydroxy-4- (3-methylphenyl) -2-methylenepropionic acid was obtained.

M. p. 107-108 ° C.

Example 17 5- (3-methylphenyl)
Thiophene-3-acetic acid 1) 3- (3-methylbenzoyl) -2-methylenepro
Acid oxalyl chloride 3.9ml of methylene chloride 100m
A solution of 5.8 ml of dimethylsulfoxide in 20 ml of methylene chloride was added dropwise to the 1 solution at -60 to -50 ° C, and then 4-
Hydroxy-4- (3-methylphenyl) -2-methylenepropionic acid 8.0 g tetrahydrofuran 50 ml
The solution was added little by little and stirred at -60 ° C for 30 minutes. Next, 19.9 ml of triethylamine was added at -60 to -50 ° C, and then the mixture was stirred at room temperature for 1 hour. The reaction solution is poured into concentrated hydrochloric acid-ice and extracted with chloroform. The organic layer was washed with water and saturated brine in that order, dried (sodium sulfate), and the solvent was evaporated to give 5.0 g of 3- (3-methylbenzoyl) -2-methylenepropionic acid.

NMR (CDCl ₃ ) δ (ppm); 2.
38 (3H, s), 4.03 (2H, s), 5.73
(1H, d, J = 1.0 Hz), 6.21 (1H, d,
J = 1.0 Hz), 7.36 to 7.52 (2H, m),
7.72 to 7.90 (2H, m), 12.3 to 12.7
(1H, br).

2) 2-Acetylthiomethyl-3- (3-
Methylbenzoyl) propionic acid 3- (3-methylbenzoyl) -2-methylenepropionic acid 5.0 g was dissolved in ethyl acetate 50 ml, thioacetic acid 1.9 ml was added thereto, and triethylamine 0.3 ml was added with stirring at room temperature. The mixture was added dropwise and further reacted at 50 ° C. for 2 hours. After the reaction was completed, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried (sodium sulfate), the solvent was evaporated, and crude acetyl-2-acetylthiomethyl-3- (3-methylbenzoyl) propionic acid (6.9 g) was used.
I got

NMR (CDCl ₃ ) δ (ppm); 2.
33 (3H, s), 2.40 (3H, s), 3.15-
3.55 (5H, m), 7.30 to 7.44 (2H,
m), 7.70-7.80 (2H, m).

3) 5- (3-methylphenyl) thiophene
Methyl - 3-carboxylate 2-acetylthiomethyl-3- (3-methylbenzoyl) propionic acid (6.9 g) was added with concentrated sulfuric acid (3.5 ml) in methanol (70 ml) and the mixture was heated under reflux for 2 hours. After methanol was distilled off under reduced pressure, water was added and the mixture was extracted with toluene. The toluene layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine in this order and dried (sodium sulfate). Sodium sulfate is filtered off,
DDQ (5.6 g) was added to the filtrate, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was filtered, toluene in the filtrate was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain methyl 5- (3-methylphenyl) thiophene-3-carboxylate 4.18 g.

NMR (CDCl ₃ ) δ (ppm); 2.
40 (3H, s), 3.88 (3H, s), 7.10
7.18 (1H, m), 7.23 to 7.34 (1H,
m), 7.37 to 7.45 (2H, m), 7.70 (1
H, d, J = 1.0 Hz), 8.01 (1H, d, J =
1.0 Hz).

4) 5- (3-methylphenyl) thiophene
-3-methanol lithium aluminum hydride 1.4 g ether 100
ml suspension A methyl 5- (3-methylphenyl) thiophene-3-carboxylate (4.2 g) was added little by little at 0 to 5 ° C, and the mixture was stirred at room temperature for 2 hours. The reaction solution was decomposed with isopropyl alcohol and dilute hydrochloric acid and then extracted with ethyl acetate. The extract was washed with sodium hydrogen carbonate and water in that order, dried (sodium sulfate), and the solvent was evaporated to give crude 5- (3
-Methylphenyl) thiophene-3-methanol.
7 g were obtained.

NMR (CDCl ₃ ) δ (ppm);
73 (1H, s), 2.38 (3H, s), 4.67
(2H, s), 7.06 to 7.45 (6H, m).

5) 3-chloromethyl-5- (3-methyl
Phenyl) thiophene 5- (3-methylphenyl) thiophene-3-methanol 3.7 g was dissolved in tetrahydrofuran 20 ml-N, N dimethylformamide 20 ml, and thionyl chloride 2.6 ml was added dropwise at room temperature, followed by stirring at room temperature for 2 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and dried (magnesium sulfate), and the solvent was evaporated to give crude 3-chloromethyl-5- (3-methylphenyl) thiophene (3.9).
g was obtained.

NMR (CDCl ₃ ) δ (ppm); 2.
38 (3H, s), 4.60 (2H, s), 7.06 ~
7.46 (6H, m).

6) 5- (3-methylphenyl) thiophene
-3-Acetonitrile 3-chloromethyl-5- (3-methylphenyl) thiophene (3.9 g) was dissolved in dimethyl sulfoxide (30 ml), sodium cyanide (1.7 g) was added, and the mixture was stirred at 50 ° C for 2 hr. The reaction solution was poured into water and extracted with ethyl acetate.
The organic layer was washed with water and dried (magnesium sulfate), and then the solvent was distilled off. The residue is purified by silica gel chromatography and 5- (3-
Methylphenyl) thiophene-3-acetonitrile 2.
1 g was obtained.

NMR (CDCl ₃ ) δ (ppm); 2.
39 (3H, s), 3.72 (2H, s), 7.10
7.45 (6H, m).

7) 5- (3-methylphenyl) thiophene
20 ml of ethanol and 9.8 ml of 10N potassium hydroxide were added to 2.1 g of 5- (3-methylphenyl) thiophene-3-acetonitrile-3 -acetic acid, and the mixture was heated under reflux for 2 hours. After cooling the reaction solution, ethanol was distilled off under reduced pressure, water was added, and the mixture was poured into concentrated hydrochloric acid-ice and extracted with ethyl acetate. The extract was washed with water and dried (sodium sulfate), and then the solvent was distilled off. The residue was recrystallized from isopropyl ether to obtain 1.0 g of the desired product.

NMR (CDCl ₃ ) δ (ppm); 2.
32 (3H, s), 3.58 (2H, s), 7.07-
7.50 (6H, m), 12.3 to 12.6 (1H, b
r).

Example 18 The following compounds of the present invention were obtained according to Example 17 by using the various compounds (18) shown in the above Production Scheme IV.

5- (3-Fluorophenyl) thiophene-3-acetic acid m.p. p. 148.0-149.0 ° C NMR (CDCl ₃ ) δ (ppm); 3.68 (2H,
s), 6.92 to 7.04 (1H, m), 7.14 (1
H, d, J = 2.0 Hz), 7.24 to 7.40 (4
H, m).

5- (3-chlorophenyl) thiophene-
3-Acetic acid NMR (CDCl ₃ ) δ (ppm); 3.68 (2H,
s), 7.15 (1H, d, J = 2.0 Hz), 7.2
1 to 7.36 (3H, m), 7.46 (1H, m),
7.58 (1H, m).

5- (3-Bromophenyl) thiophene-
3-Acetic acid NMR (CDCl ₃ ) δ (ppm); 3.68 (2H,
s), 7.14 (1H, d, J = 2.0 Hz), 7.1
8 to 7.28 (2H, m), 7.40 (1H, m),
7.49 (1H, m), 7.73 (1H, m).

5- (2-Fluorophenyl) thiophene-3-acetic acid NMR (CDCl ₃ ) δ (ppm); 3.71 (2H,
s), 7.05 to 7.30 (4H, m), 7.42 (1
H, m), 7.60 (1H, m).

5- (2-chlorophenyl) thiophene-
3-Acetic acid NMR (CDCl ₃ ) δ (ppm); 3.71 (2H,
s), 7.24 (3H, m), 7.31 (1H, d, J
= 2.0 Hz), 7.48 (2H, m).

5- (2-methylphenyl) thiophene-
3-Acetic acid NMR (CDCl ₃ ) δ (ppm); 2.43 (3H,
s), 3.70 (2H, s), 7.00 (1H, d, J
= 2.0 Hz), 7.16 (1 H, m), 7.23 (3
H, m), 7.38 (1H, m).

5- (4-trifluoromethylphenyl)
Thiophene-3-acetic acid NMR (CDCl ₃ ) δ (ppm); 3.62 (2H,
s), 7.43 (1H, d, J = 1.0 Hz), 7.5
8 (1H, d, J = 1.0 Hz), 7.75 (2H,
d, J = 8.0 Hz), 7.85 (2H, d, J = 8.
0 Hz), 12.7 to 12.1 (1H, br).

Example 19 5- (3-methylphenyl)
Methyl thiophene-3-acetate 5- (3-Methylphenyl) thiophene-3-acetic acid 1.
A solution of concentrated sulfuric acid 0.7 ml in methanol 15 ml was added to 0 g, and the mixture was heated under reflux for 5 hours. After cooling the reaction mixture, water was added and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated sodium chloride, dried (sodium sulfate), and the solvent was evaporated. The residue was purified by silica gel chromatography to obtain 0.9 g of the target methyl 5- (3-methylphenyl) thiophene-3-acetate.

NMR (CDCl ₃ ) δ (ppm); 2.
38 (3H, s), 3.63 (2H, s), 3.73
(3H, s), 7.05 to 7.12 (2H, m), 7.
22 to 7.30 (2H, m), 7.36 to 7.43 (2
H, m).

Example 20 The following compounds of the present invention were obtained according to Example 19 using the various compounds (25) shown in the above Production Scheme IV.

Methyl 5- (3-fluorophenyl) thiophene-3-acetate NMR (CDCl ₃ ) δ (ppm); 3.65 (2H,
s), 3.74 (3H, s), 6.91 to 7.02 (1
H, m), 7.11 (1H, m), 7.23 to 7.39.
(4H, m).

5- (3-chlorophenyl) thiophene-
3-Methyl acetate NMR (CDCl ₃ ) δ (ppm); 3.59 (2H,
s), 3.69 (3H, s), 7.16 to 7.57 (6)
H, m).

5- (3-Bromophenyl) thiophene-
3-Methyl acetate NMR (CDCl ₃ ) δ (ppm); 3.59 (2H,
s), 3.68 (3H, s), 7.15 to 7.55 (5
H, m), 7.70 (1H, m).

5- (2-Fluorophenyl) thiophene-3-methyl acetate NMR (CDCl ₃ ) δ (ppm); 3.65 (2H,
s), 3.75 (3H, s), 7.05 to 7.30 (4
H, m), 7.40 (1H, m), 7.60 (1H,
m).

5- (2-chlorophenyl) thiophene-
3-Acetic acid NMR (CDCl ₃ ) δ (ppm); 3.67 (2H,
s), 3.72 (3H, s), 7.21 (1H, m),
7.25 (2H, m), 7.32 (1H, d, J = 2.
0 Hz), 7.49 (2H, m).

5- (2-methylphenyl) thiophene-
3-Acetic acid NMR (CDCl ₃ ) δ (ppm); 2.43 (3H,
s), 3.67 (2H, s), 3.73 (3H, s),
7.00 (1H, d, J = 2.0Hz), 7.14 (1
H, m), 7.25 (3H, m), 7.39 (1H,
m).

Example 21 5- (3,4-dimethylphene)
Nyl) thiophene-3-acetic acid 1) 5- (3,4-dimethylphenyl) thiophene-3
- ice-cooling in tetrahydrofuran 100ml suspension of methanol Lithium aluminum hydride 2.5g, 5- (3,4- dimethylphenyl) thiophene-3-carboxylate 22.
After adding 0 g of tetrahydrofuran solution at room temperature, 3
The mixture was stirred at 40 ° C. for 1 hour. The reaction solution was decomposed with isopropyl alcohol and dilute hydrochloric acid and then extracted with ethyl acetate. Wash the extract with sodium bicarbonate and water,
After drying (magnesium sulfate), the solvent was distilled off, and the residue was purified by silica gel chromatography to obtain 5- (3,4-dimethylphenyl) thiophene-3-methanol (16.1 g).

NMR (CDCl ₃ ) δ (ppm); 2.
26 (3H, s), 2.29 (3H, s), 4.68
(2H, s), 7.12 (1H, s), 7.13 (2
H, d, J = 8.0 Hz), 7.25 (1H, s),
7.29-7.40 (2H, m).

2) 5- (3,4-dimethylphenyl) thiophene-3-acetonitrile 5- (3,4-dimethylphenyl) thiophene-3-methanol (15.0 g) in tetrahydrofuran (100 ml)-
After dissolving in 10 ml of N, N-dimethylformamide and adding dropwise 7.5 ml of thionyl chloride at room temperature and stirring for 30 minutes at room temperature, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and dried (magnesium sulfate). After that, the solvent was distilled off to obtain 19.6 g of crude 3-chloromethyl-5- (3,4-dimethylphenyl) thiophene. The obtained chloride was dissolved in 100 ml of dimethyl sulfoxide, 5.0 g of sodium cyanide and 5 ml of water were added, and the mixture was stirred at 50 ° C. for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (magnesium sulfate), and then the solvent was distilled off. The residue was purified by silica gel chromatography to give crude 5-
9.9 g of (3,4-dimethylphenyl) thiophene-3-acetonitrile was obtained. NMR (CDCl ₃ ) δ (ppm); 2.28 (3H,
s), 2.29 (3H, s), 3.72 (2H, s),
7.08 to 7.20 (3H, m), 7.26 to 7.38
(2H, m).

3) 5- (3,4-dimethylphenyl) thio
Ofen-3-acetic acid 5- (3,4-dimethylphenyl) thiophene-3-acetonitrile 6.0 g ethanol 100 ml, 10N
26.4 ml of potassium hydroxide was added, and the mixture was heated under reflux for 2 hours. After cooling the reaction solution, ethanol was distilled off under reduced pressure, water was added, and the mixture was poured into concentrated hydrochloric acid-ice and extracted with ethyl acetate. The extract was washed with water and dried (magnesium sulfate), and then the solvent was distilled off. The residue was recrystallized from ethyl acetate-n-hexane to obtain 5.3 g of the desired product.

NMR (CDCl ₃ ) δ (ppm); 2.
27 (3H, s), 2.29 (3H, s), 3.68
(2H, s), 7.06 (1H, s), 7.11 (1
H, d, J = 7.5 Hz), 7.19 (1H, s),
7.28-7.40 (2H, m).

Example 22 Various compounds (2
Using 7), the following compound of the present invention was obtained according to Example 22.

5- (2,4-Dimethylphenyl) thiophene-3-acetic acid NMR (CDCl ₃ ) δ (ppm); 2.35 (3H,
s), 2.40 (3H, s), 3.70 (2H, s),
6.95 to 7.10 (3H, m), 7.15 (1H,
d, J = 1.0 Hz), 7.28 (1H, d, J = 1.
0 Hz).

5- (2,5-Dimethylphenyl) thiophene-3-acetic acid m.p. p. 86.0-87.0 ° C.

5- (3,4-dichlorophenyl) thiophene-3-acetic acid NMR (CDCl ₃ ) δ (ppm); 3.68 (2H,
s), 7.15 (1H, d, J = 2.0 Hz), 7.2
5 (1H, m), 7.41 (2H, m), 7.66 (1
H, m).

Example 23 5- (3,4-dimethylphene)
Nyl) thiophene-3-acetic acid methyl 5- (3,4-dimethylphenyl) thiophene-3-acetic acid (3.0 g) was added with concentrated sulfuric acid (1.7 ml) in 34 ml of methanol, and the mixture was heated under reflux for 2 hours. After distilling off the methanol under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water,
After drying (magnesium sulfate), the solvent was distilled off. The residue was recrystallized from ethyl acetate-n-hexane to give 3.0 g of the desired product.
I got

NMR (CDCl ₃ ) δ (ppm); 2.
23 (3H, s), 2.27 (3H, s), 3.62
(2H, s), 3.70 (3H, s), 7.02 (1
H, d, J = 1.0 Hz), 7.11 (1H, d, J =
7.5 Hz), 7.18 (1H, d, J = 1.0H
z), 7.30-7.38 (2H, m).

Example 24 Various compounds (3
Using 1) and according to Example 23, the following compounds of the present invention were obtained.

5- (2,4-Dimethylphenyl) thiophene-3-methyl acetate NMR (CDCl ₃ ) δ (ppm); 2.35 (3H,
s), 2.40 (3H, s), 3.65 (2H, s),
3.72 (3H, s), 6.95 to 7.10 (3H,
m), 7.11 (1H, d, J = 1.0 Hz), 7.2
7 (1H, d, J = 1.0 Hz).

5- (2,5-Dimethylphenyl) thiophene-3-methyl acetate NMR (CDCl ₃ ) δ (ppm); 2.32 (3H,
s), 2.37 (3H, s), 3.66 (2H, s),
3.72 (3H, s), 6.97 (1H, d, J = 2.
0Hz), 7.04 (1H, d, J = 8.0Hz),
7.11 (1H, s), 7.13 (1H, d, J =
8.0 Hz).

5- (3,4-Dichlorophenyl) thiophene-3-methyl acetate NMR (CDCl ₃ ) δ (ppm); 3.65 (2H,
s), 3.73 (3H, s), 7.13 (1H, d, J
= 2.0 Hz), 7.25 (1H, d, J = 2.0H
z), 7.41 (2H, m), 7.66 (1H, m).

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Katsuo Hatayama 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd.

Claims (2)

[Claims] (1) Formula (1) (In the formula, n represents an integer of 0 or 1, and Y represents a hydrogen atom or a lower alkyl group. Provided that when n = 1,
R ¹ and R ² are hydrogen atoms, X is a hydrogen atom, a halogen atom or a lower alkyl group, and when n = 0, at least one of R ^{1 and} R ² is a methyl group, and X is a hydrogen atom, It represents a halogen atom or a lower alkyl group, Y represents a hydrogen atom, and R ³ represents a hydrogen atom or a lower alkyl group. ) The thiophene alkanoic acid derivative represented by. 2. A compound of the formula (In the formula, R ¹ and R ² are hydrogen atoms, R ³ is a hydrogen atom or a lower alkyl group. X is a hydroxyl group, a thioalkyl group, a phenoxy group, a phenyl group, a trifluoromethyl group, a 2-position or a 3-position-substituted group. A halogen atom or a lower alkyl group is shown and Y is a hydrogen atom, or X and Y are simultaneously or differently a halogen atom or a lower alkyl group.)
A thiophene alkanoic acid derivative represented by.