JPS584699B2 - Substituted phenylacetic acid derivatives and their production method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel substituted phenic acid derivative having the general formula, a salt thereof, and a process for producing the same.

In the above formula, R1 represents a hydrogen atom or a lower alkyl group, and n represents an integer of 1 to 2.

In the general formula (■), R1 is preferably a hydrogen atom or methyl, ethyl, n-propyl, isopropyl, n
- It represents a linear or branched alkyl group having 1 to 4 carbon atoms such as butyl and isobutyl, and particularly preferred compounds include R1 representing a hydrogen atom or a methyl group, and n representing 1 or 2 Examples include compounds that exhibit the following.

Further, the substituted phenylacetic acid derivative having the general formula (■) can be converted into a pharmacologically acceptable salt form if necessary.

Pharmaceutically acceptable salt forms include alkali metal or alkali metal salts such as sodium and calcium, aluminum salts, ammonium salts, triethylamine, dicyclohexylamine, dibenzylamine, morpholine, piperidine and N-ethylpiperidine. Salts of organic bases such as or basic amino acids such as lysine and arginine can be mentioned.

In addition, since an asymmetric carbon atom exists in the compound having the general formula (■), optical isomers and diastereoismers exist.

Therefore, when the compound having the above general formula (■) is obtained as a mixture of these optical isomers and diastereoisomers, each isomer can be obtained by optical resolution or diastereoisomer separation using conventional methods. I can do it.

In the compound having the general formula (■), all optical isomers, diastereoisomers, and mixtures of these isomers are represented by a single formula, but this does not limit the scope of the description of the present invention. It's not something you can do.

As a result of repeated research on the synthesis and pharmacological activity of phenylacetic acid derivatives for the purpose of developing anti-inflammatory agents, the present inventors have found that a novel substituted phenylacetic acid derivative represented by the general formula (■) has anti-inflammatory, analgesic, and antipyretic properties. The present invention was completed by discovering that the compound is a useful compound as a medicine.

Examples of the compound having the general formula (■) obtained by the present invention include the compounds described below.

(1) 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propionic acid (2) 4-(2-oxocyclopentan-1-ylmethyl)phenylacetic acid (3) 2-[4-( 2-Oxocyclohexan-1-ylmethyl)phenyl]propionic acid (4) 4-(2-oxocyclohexan-1-ylmethyl)phenylacetate (5) 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl ] Propionic acid arginine salt (6) 4-(2-oxocyclohexan-1-ylmethyl)phenylacetic acid lysine salt The novel compound according to the present invention can be synthesized by the method shown below.

Method 1 The substituted phenylacetic acid derivative having the above general formula (■) is a substituted phenylacetic acid derivative having the general formula (wherein R1 and n have the same meanings as described above, and R2 and R3 are methyl, ethyl, n-propyl, isopropyl, etc.). Indicates a lower alkyl group.

) is obtained by hydrolyzing a ketodicarboxylic acid ester derivative having the following formula and then subjecting it to a decarboxylation reaction.

In carrying out this method, the first hydrolysis reaction is carried out by bringing the compound having the general formula (■) into contact with an acid or base as a hydrolysis reagent.

As the acid or base used, acids or bases used in ordinary hydrolysis reactions can be used without particular limitation.
Suitable acids or bases include mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide.

The reaction is usually suitably carried out in the presence of a solvent, and the solvents used include water, methanol, ethanol,
Alcohols such as n-propanol, glycols such as ethylene glycol and diethylene glycol,
Organic solvents such as fatty acid dialkylamides such as dimethylformamide and dimethylacetamide, and mixed solvents of these organic solvents and water are suitable.

There is no particular limitation on the reaction temperature, but it is usually between room temperature and about 15
Performed at 0°C.

The reaction time varies mainly depending on the reaction temperature, the hydrolysis reagent used, etc., but is about 1 to 12 hours.

After the reaction is completed, the target compound of the hydrolysis reaction is collected from the reaction mixture according to a conventional method.

For example, if a base is used as the hydrolysis agent, the reaction mixture is washed with an organic solvent such as ether,
The aqueous layer is made acidic by adding an acid such as hydrochloric acid, and then extracted using an organic solvent such as ether.

It can be obtained by washing the extract with water, drying it, and then distilling off the solvent from the extract, but the following decarboxylation reaction can be carried out using the acidified aqueous suspension.

The reaction of decarboxylating the hydrolysis product thus obtained is then carried out by heating in the presence or absence of a solvent.

When heating in the presence of a solvent, water, aromatic hydrocarbons such as benzene, toluene, xylene, cymene, dioxane, etc. are preferably heated in the presence of an acid such as hydrochloric acid or p-toluenesulfonic acid. Organic solvents such as ethers and mixed solvents of these organic solvents and water are used.

When heating in the absence of a solvent, it is desirable to carry out the heating under reduced pressure or in a stream of inert gas such as nitrogen gas in order to suppress side reactions.

The heating reaction temperature is preferably about 50 to 200°C, and the reaction time is about 15 minutes to 3 hours, although it varies mainly depending on the type of raw material compound and reaction temperature.

When an acid is used for hydrolysis in the method of the present invention,
A decarboxylation reaction can also be carried out at the same time.

In such cases, the ester compound having the general formula (■) is preferably heated in an ether such as dioxane in the presence of a mineral acid such as hydrochloric acid, hydrobromic acid, or sulfuric acid. be able to.

The reaction temperature is usually 100 to 150°C, preferably around the boiling point of the solvent used.

Reaction time is about 1 to 20 hours.

After the reaction is completed, the target compound having the general formula (■) is collected from the reaction mixture according to a conventional method.

For example, it can be obtained by extracting the reaction mixture using a suitable organic solvent, washing the resulting organic solvent layer with water and drying it, and then distilling off the solvent from the extract.

If necessary, the target compound in each of the above steps can be further purified by conventional methods, such as vacuum distillation or column chromatography for oily products, and recrystallization for crystals or salts.

In carrying out the method of the present invention, the novel compound having the general formula (■) used as a raw material can be synthesized, for example, by the reaction shown below.

In the above formula, R1, R2, R3 and n have the same meanings as defined above, and X represents a halogen atom such as chlorine or bromine.

That is, the reaction for synthesizing the compound having the general formula (■I) involves reacting a benzyl halide derivative having the general formula (■) with a cycloalkanone carboxylic acid ester derivative having the general formula (■) in the presence of a base. It is done by letting

The base used is not particularly limited to the base used in the alkylation reaction of normal active methylene groups, but alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium amide, potassium Suitable bases include alkali metal amides such as amides, alkali metal hydrides such as sodium hydride and potassium hydride, and the like.

The reaction is preferably carried out in the presence of a solvent, and the solvents used include alcohols such as methanol, ethanol, and tertiary butanol, fatty acid dialkylamides such as dimethylformamide, dimethyl sulfoxide,
Ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane are preferred.

Although the reaction temperature is not particularly limited, it is usually carried out at room temperature or around the reflux temperature of the solvent.

The reaction time varies depending on the type of base used, reaction temperature, etc., but is usually 1 to 5 hours.

After the reaction is completed, the target compound having the general formula (■) can be obtained by treating the reaction mixture according to a conventional method.

The obtained target compound can be further purified, if necessary, using conventional methods such as vacuum distillation and column chromatography.

Method 2 A substituted phenylacetic acid derivative having the above general formula (■) is prepared by the above general formula (where R1, R2 and X have the same meanings as defined above).

) is a benzyl halide derivative having the general formula (wherein R
4 and R5 are lower alkyl groups such as methyl, ethyl, n-propyl, inpropyl, n-butyl, and isobutyl, or R4 and R5 together represent adjacent nitrogen groups such as 1-pyrrolidinylpiperidino and morpholino. It represents a group that forms a cyclic amine group together with an oxygen atom, and n has the same meaning as described above.

) to obtain a general formula (wherein R1, R2, R4, R5, X and n have the same meanings as described above).

) can be obtained by hydrolyzing a compound having

In carrying out this method, the condensation reaction between the initial halide compound (■) and the enamine compound (■) is carried out by heating in the presence of a solvent.

Preferred solvents include aromatic hydrocarbons such as benzene, toluene and xylene, and ethers such as dioxane.

The reaction temperature is around 80 to 140°C, preferably the reflux temperature of the commonly used solvent.

The reaction time varies depending on the reaction temperature, etc., but is usually 1 to 30 hours.

After the reaction is completed, the solvent can be distilled off from the reaction mixture according to a conventional method, and the resulting residue can be used to carry out the next hydrolysis reaction.

The hydrolysis reaction is carried out using the above general formula (■
) is brought into contact with an acid or base as a hydrolysis agent.

As the acid or base used, acids or bases used in ordinary hydrolysis reactions can be used without particular limitation.
Suitable acids or bases include mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide.

The reaction is usually suitably carried out in the presence of a solvent.

Suitable solvents to be used include water, organic solvents such as alcohols such as methanol, ethanol, and n-propanol, and glycols such as ethylene glycol and diethylene glycol, and mixed solvents of these organic solvents and water.

There is no particular limitation on the reaction temperature, but it is usually room temperature to about 11
Performed at 0°C.

The reaction time varies mainly depending on the reaction temperature, the hydrolysis reagent used, etc., but is approximately 10 minutes to 6 hours.

After completion of the reaction, the target compound having the general formula (■) is collected from the reaction mixture according to a conventional method, and the collection method can be, for example, similar to the method described for the hydrolysis reaction in Method 1 above. .

The obtained target compound can be purified by conventional methods, such as vacuum distillation or column chromatography for oily products, if necessary.
The crystal or salt form can be further purified by recrystallization.

The substituted phenylacetic acid derivatives of the present invention having the general formula (■) have shown excellent anti-inflammatory, analgesic and antipyretic effects in pharmacological tests, and the results of these pharmacological tests are illustrated below.

In addition, the pharmacological test was conducted by the following method.

Anti-inflammatory activity was tested using the carrageenan edema method using Wistar rats.

[C. A. Winter, E. A. Risley, G.
W. Nuss;J. Pharmacol. Exp. Th
erap. , 141, 369 (1963)] Analgesic effect was tested using the heat inflammatory pain method using Wistar rats.

[Yoshio Iizuka, Kiichiro Tanaka; Japanese Pharmacological Journal, 70, 697 (1
974)] As is clear from the results of the above pharmacological tests, the compound having the general formula (■) and its pharmacologically acceptable salts are useful as analgesic and anti-inflammatory agents. , oral administration in the form of capsules, granules, powders, syrups, etc., or enteral administration in the form of suppositories.

The amount used varies depending on symptoms, age, body weight, etc., but is usually about 50 ml to 2000 mg per day for adults, and can be administered once or in divided doses.

Next, the present invention will be explained in more detail with reference to Examples and Reference Examples.

Example 1 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propionic acid 2-[4-(1-ethoxycarbonyl-2-oxocyclopentan-1-ylmethyl)phenyl]propionic acid ethyl ester 20g was dissolved in 30ml of dioxane and 100ml of 47% hydrogen bromide water, heated under reflux for 6 hours, extracted with ether, washed the extract with water, dried over anhydrous sodium sulfate, and distilled off the ether to give a yellow oily substance. can get.

When this is subjected to vacuum distillation, the boiling point is 190-195°C/0.
Target compound 13 as colorless oil with 3 mmHg (bath temperature)
．． 1 g is obtained.

After cooling, this product solidifies, and when recrystallized from ether-n-hexane, it becomes crystals with a melting point of 108.5-111°C.

Elemental analysis value Calculated value as C15H18O3 C, 73.14; H, 7.37 Actual value C, 73.19; H, 7.28 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propion Acid sodium salt 2.46 g of 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propionic acid is dissolved in 10 ml of a 7.6% aqueous sodium hydroxide solution and stirred for 1 hour at room temperature.

After acidifying with hydrochloric acid, extract with ether, wash the extract with water,
After drying over anhydrous sodium sulfate, the solvent is distilled off.

The resulting residue was dissolved in 10 ml of ethanol, 5 mg of a 7.6% aqueous sodium hydroxide solution was added dropwise under ice cooling, and after stirring at room temperature for 2 hours, the solvent was distilled off to obtain crystals. Recrystallization from the ether mixture yields 2.5 g of the desired sodium salt as white crystals with a melting point of 194-198°C.

Elemental analysis value Calculated value as C15H17O3Na C, 67.10; H, 6.38 Actual value C, 67.07; H, 6.43 Example 2 4-(2-oxocyclopentan-1-ylmethyl)phenyl acetic acid 4 -(1-ethoxycarbonyl-2-oxo-cyclopentan-1-ylmethyl)phenyl acetic acid ethyl ester (9.2 g), 20 ml of 47% hydrobromic acid, dioxane 1
After refluxing with 5 ml of the mixture for 6 hours, the solvent was distilled off, the residue was poured into ice water, and extracted with ether.

After washing the extract with water, it was dried over anhydrous sodium sulfate, the ether was distilled off, and the obtained oily substance was distilled under reduced pressure. .0g Obtained elemental analysis value C14H16O3
Calculated value C, 72.39; H, 6.94: Actual value C, 72.08; H, 6.55 Example 3 2-(4-(2-oxocyclohexan-1-ylmethyl)phenyl]propionic acid 80 containing 13 g of 2-[4-(1-ethoxycarbonyl-2-okynecyclohexan-1-ylmethyl)phenyl]propionate ethyl ester and 5 g of potassium hydroxide.
% ethanol, heated under reflux for 2 hours, distilled off the ethanol, added 100 ml of water, extracted with ether, added 100 ml of concentrated hydrochloric acid to the aqueous layer, heated and stirred at 50-60°C for 1 hour, and then diluted with ether. After washing the extract with water and drying, the ether was distilled off, and the obtained yellow oil was subjected to silica gel column chromatography to obtain a colorless oil from the eluate of benzene:acetic acid ethyl ester = 5:1, When this is subjected to vacuum distillation, the boiling point is 190-195℃/
4.1 g of the target compound are obtained as a colorless oil having a bath temperature of 0.4 mmHg.

After cooling, this product solidifies into crystals having a melting point of 84 to 86°C.

Calculated value as elemental analysis value C16H20O3 C, 73.82; H, 7.74 Actual value C, 73.72; H, 7.58 Example 4 4-(2-oxocyclohexan-1-ylmethyl)-
Phenylacetic acid P-chloromethylphenyl acetate ethyl ester 6.39
A mixed solution of 4.53 g of cyclohexanone pyrrolidine enamine and 110 ml of toluene was refluxed for 21 hours.

After cooling, the solvent was distilled off, ether was added, and 5% hydrochloric acid 100%
ml and stirred for 1 hour at room temperature.

After extraction with ether, washing with water and drying over anhydrous sodium sulfate, the solvent is distilled off to obtain an oily substance.

When subjected to vacuum distillation, the boiling point is 165-180℃/0.5mm
1.7 g of ester of the target compound with Hg (bath temperature)
can get.

Add 1.7 g of the obtained ester to 20 ml of alcohol.
, and 20 ml of 10% caustic soda and heated under reflux for 5 hours.

After cooling, acidify with hydrochloric acid and extract with ether.

After washing with water and drying with anhydrous sodium sulfate, the ether is distilled off to obtain an oily substance.

When this is subjected to vacuum distillation, the boiling point is 190-195°C/0.
1.3 g of the target compound having a bath temperature of 3 mmHg is obtained.

After cooling, this product solidifies into crystals having a melting point of 71.5 to 72.5°C.

Calculated value as elemental analysis value C15H18O3 C, 73.14; H, 7.37 Actual value C, 73.09; H, 7.40 Example 5 2-[4-(2-oxocyclopentan-1-ylmethyl) Phenyl]propionic acid L-arginine salt 1.23 g of 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propionic acid was dissolved in 1.2 g of acetone.
2 ml of water containing 0.87 g of L-arginine was dissolved in a mixture of 6 ml and 0.5 ml of water, and 2 ml of water containing 0.87 g of L-arginine was added dropwise with stirring. After stirring for 1 hour, acetone and water were distilled off under reduced pressure to obtain the target compound 2. 1 g is obtained.

Melting point 101-110°C Elemental analysis value Calculated value as C21H32O5N4 C, 59.98; H, 7.67; N, 13.33 Actual value C, 59.69; H, 7.88; N, 13.26 Reference example 1 2-[4-(1-Ethoxycarbonyl-2-oxocyclopentan-1-ylmethyl)phenyl]propionate ethyl ester dimethylformamide 6 potassium hydroxide
．． After adding 0g of 2-carboethoxycyclopentanone at room temperature with stirring to become a homogeneous solution, 25g of 2-(P-chloromethylphenyl)propionic acid ethyl ester was added under ice cooling. was added dropwise, and then heated and stirred at 80°C for 2 hours.

After the reaction was completed, the reaction mixture was poured into ice water, extracted with ether, the extract was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and 28 g of the obtained oil was subjected to vacuum distillation. 21 g of the target compound having a boiling point of 175-178° C./0.5 mmHg are obtained.

Calculated value as elemental analysis value C20H26O5 C, 69.34; H, 7.57 Actual value C, 69.10; H, 7.20 Reference example 2 2-[4-(1-ethoxycarbonyl-2-oxynecyclohexane) 34 g of 2-cyclohexanonecarboxylic acid ethyl ester was added dropwise to 9.6 g of 50% sodium hydride and 200 ml of dimethylformamide under ice cooling, and the mixture was heated to 50°C.
The mixture was stirred for 30 minutes, and 45.3 g of 2-(P-chloromethylphenyl)propionate ethyl ester was added dropwise under ice-cooling again, followed by heating and stirring at 50 to 60° C. for 1 hour.

After the reaction is complete, the reaction mixture is poured into ice water and extracted with ether.

After washing with water and drying with anhydrous sodium sulfate, the solvent was distilled off and 69.5 g of the obtained oil was subjected to vacuum distillation.
57 g of the target compound are obtained as a colorless oil having a temperature of 0-205 DEG C./0.4 mmHg.

Calculated value C, 69.97; H, 7.83 as elemental analysis value C21H28O5; Actual value C, 69.85; H, 7.78. Reference Example 3 2-[4-(1-ethoxycarbonyl-2oxocyclopentan-1-ylmethyl)phenyl]acetic acid ethyl ester 2-cyclopentanonecarboxylic acid ethyl ester 9.4
g, P-chloromethylphenylacetic acid ethyl ester 10
．． After stirring a mixture of 6g of potassium hydroxide, 3.58g of potassium hydroxide, and 60ml of dimethylformamide at room temperature for 5 hours,
Stir at 0° C. for 1 hour and then at room temperature overnight.

After that, acetic acid was added and dimethylformamide was distilled off.
Add water to the residue and extract with ether.

After washing with water, drying with anhydrous sodium sulfate and distilling off the solvent gives an oily substance.

When subjected to vacuum distillation, the boiling point is 180-190℃/0.8mm
12 g of the target compound containing Hg are obtained.

As elemental analysis value C19H24O5 Calculated value C, 68.65; H, 7.28 Actual value C, 68.41; H, 7.33

Claims (1)

[Claims] 1 General formula (wherein R1 represents a hydrogen atom or a lower alkyl group,
n represents an integer of 1 to 2. ) and its salts. 2. The substituted phenylacetic acid derivative and its salt according to claim 1, having the general formula (wherein n represents an integer of 1 to 2). 3. The substituted phenylacetic acid derivative and its salt according to claim 1, having the general formula (wherein n represents an integer of 1 to 2). 4 General formula (wherein R1 represents a hydrogen atom or a lower alkyl group,
R2 and R3 represent a lower alkyl group, and n is 1 to 2
indicates an integer. ) is hydrolyzed and then subjected to a decarboxylation reaction to form a salt if necessary. ) and a method for producing a substituted phenylacetic acid derivative and a salt thereof. 5 General formula (wherein R1 represents a hydrogen atom or a lower alkyl group,
R2 represents a lower alkyl group, and X represents a halogen atom. ) is a benzyl halide derivative having the general formula (wherein R4 and R5 are lower alkyl groups or R4
and R5 together represent a group that together with the adjacent nitrogen atom form a cyclic amino group which may include an oxygen atom, and n represents an integer of 1 to 2. ), and the resulting compound is hydrolyzed to form a salt if necessary (wherein R1 and n have the same meanings as described above). A method for producing a substituted phenylacetic acid derivative and a salt thereof.