JPH0326180B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel phenyl acetate derivative, more specifically, the following general formula () [In the formula, R is a hydrogen atom, a group COR ₁ (here, R ₁ represents an alkyl group or an alkenyl group), a group

[Formula] (where R ₂ is a hydrogen atom, halogen atom, cyano group, lower alkyl group, phenyl group, R ₃ is a hydrogen atom, lower alkyl group, phenyl group, R ₄ is a lower alkyl group, lower alkyloxy group, acyloxy group, hydroxyl group, or phenyl group optionally substituted with a halogen atom), group -CO-A-R ₅ (where A is a single bond, C1 to
2 alkylene group, C1-2 alkyleneoxy group, R ₅ is lower alkyl group, lower alkyloxy group, acyloxy group, hydroxyl group, halogen atom,
Indicates a phenyl group that may be substituted with a nitro group, benzoyl group, or alkylenedioxy group)
It relates to a phenyl acetate derivative represented by: Currently, ketoprofen is a nonsteroidal anti-inflammatory analgesic drug that is frequently used to treat headaches, toothaches, lower back pains, muscle pains, rheumatic diseases, and the like. However, when ketoprofen is orally administered, it has been known that side effects such as gastrointestinal disorders accompanied by ulcer formation occur. In other words, ketoprofen often causes undesirable symptoms such as gastric congestion and bleeding, not only when long-term administration is required such as in the treatment of rheumatic diseases, but even when administered for a short period of time. Currently, the dosage is limited. Therefore, the present inventors conducted intensive research to reduce the above-mentioned side effects of ketoprofen, and as a result,
The present inventor discovered that the phenyl acetate derivative represented by the above formula () obtained by reacting ketoprofen with a butanediol compound has an anti-inflammatory and analgesic effect equivalent to that of ketoprofen, but its side effects are very minor compared to ketoprofen. Completed the invention. That is, an object of the present invention is to provide a novel phenylacetate derivative () useful as a non-steroidal anti-inflammatory analgesic agent. The compound () of the present invention can be produced using a known esterification reaction, for example, by any of the following methods. Phenyl acetate (a) is produced by reacting ketoprofen () or a reactive derivative thereof with 2,3-butanediol () or a reactive derivative thereof. Phenyl acetate (a) obtained in
Then, carboxylic acid () or a reactive derivative thereof is reacted in the presence of a condensing agent to produce a phenyl acetate derivative (b). (In the formula, R ₆ is the above-mentioned R ₁ ,

[Formula] and -A-R ₅ ) 2,3-butanediol monoester derivative () is reacted with ketoprofen () or a reactive derivative thereof to produce a phenyl acetate derivative (b). (In the formula, R ₆ is the same as above.) In the above method, examples of the reactive derivatives of ketoprofen ( ) and carboxylic acid ( ) include acid halogenides, acid anhydrides, mixed anhydrides, and the like. Further, the reaction is preferably carried out in the presence of a tertiary amine such as pyridine, trimethylamine, or triethylamine; or a deoxidizing agent such as an alkali carbonate, an alkali hydroxide, or an alkali hydride. Further, the above reaction is preferably carried out in a suitable reaction solvent, and the reaction solvent is preferably a solvent that does not participate in the reaction, such as ether, tetrahydrofuran, benzene, toluene, chloroform, or dichloromethane. The reaction using a condensing agent is carried out in the presence of a 2-halo-1-alkylpyridinium salt as a condensing agent and a tertiary amine such as pyridine, triethylamine, or tributylamine, or in the presence of a tertiary amine such as diethyl azodicarboxylate and tributylamine as a condensing agent. Preferably, the reaction is carried out in the presence of enylphosphine. Further, the above condensation reaction is preferably carried out in a suitable reaction solvent, and the reaction solvent is ether, tetrahydrofuran,
Solvents that do not participate in the reaction, such as benzene, toluene, acetonitrile, chloroform, and dichloromethane, are preferred. The results of testing the anti-inflammatory effect and ulcerative properties of the compound () of the present invention thus obtained are shown below. Anti-inflammatory effect A group of 7 male rats weighing around 200g were fasted for 48 hours, and then 1 dose of the test compound was administered.
% carboxymethylcellulose sodium aqueous solution and administered orally. 60 minutes after administration of the test compound, the rat's footpad volume was measured using a volumetric device.
Next, 0.1 ml of a 1% carrageenan saline solution was subcutaneously injected into the right hind footpad, and the edema intensity after 3 hours was compared with a control group administered with a 1% sodium carboxymethyl cellulose aqueous solution to determine the edema suppression rate. The results are shown in Table 1.

[Table] As is clear from Table 1, the compounds of the present invention exhibited a high inhibitory effect on carrageenan edema. Ulcerogenicity A group of 7 male Wistar rats weighing around 170 to 200 g were given 0.5 ml of the test compound after fasting for 24 hours.
% carboxymethylcellulose sodium aqueous solution and administered orally. After 3.5 hours, the rats were bludgeoned to death and the entire stomach was removed. Immediately after fixing the stomach wall by injecting 5% formalin solution, the stomach was incised and the occurrence of gastric ulcer was visually observed and determined. In addition, the control group
Only 0.5% sodium carboxymethyl cellulose aqueous solution was orally administered. The results are shown in Table 2.

[Table] As is clear from Table 2, no ulcer formation was observed with the compounds of the present invention, and it was confirmed that the side effects were lower than those of Comparative Compounds 1 and 2, which are known ketoprofen derivatives. Next, examples of the present invention will be described. Example 1 (Synthesis of Compound 1) 50.80 g of ketoprofen was suspended in 600 ml of benzene, 80 ml of thionyl chloride was added thereto, and the suspension was heated and stirred for 6 hours. After the reaction, excess thionyl chloride and benzene were distilled off under reduced pressure to obtain ketoprofen acid chloride as a pale yellow liquid. This acid chloride was dissolved in 200 ml of anhydrous ether and added dropwise into a mixed solution of 18 g of 2,3-butanediol, 20 ml of pyridine and 500 ml of anhydrous ether.
After the addition, the mixture was stirred at room temperature for 5 hours, and the reaction solution was washed with water, 10% hydrochloric acid, water, sodium carbonate solution, and water in this order, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the ether was purified by column chromatography (silica gel) to obtain 40.10 g (yield: 61.5%) of Compound 1 listed in Table 3 as a colorless liquid. Example 2 (Synthesis of Compound 2) 1.63 g of Compound 1 was dissolved in 20 ml of anhydrous ether, 1 ml of pyridine was added, and 5 ml of an ether solution containing 0.71 g of caproic acid chloride was added dropwise while stirring under ice cooling. After stirring at the same temperature for 30 minutes and further returning to room temperature for 4 hours, the reaction solution was washed with water, 10% hydrochloric acid, water, sodium carbonate test solution, and water in this order, and dried over anhydrous magnesium sulfate. After distilling off the ether under reduced pressure, the residue was purified by column chromatography (silica gel) to obtain 1.70 g of compound 2 listed in Table 3 as a colorless liquid.
(yield 80.0%). Example 3 (Synthesis of Compound 32) 1.80 g of 2,3-butanediol was dissolved in 40 ml of tetrahydrofuran, and 2 ml of pyridine was added thereto.
α-Phenylcinnamic acid chloride while stirring on ice.
A solution of 2.42 g in 10 ml of tetrahydrofuran was added dropwise. After stirring at the same temperature for 30 minutes and further returning to room temperature for 5 hours, the solvent was distilled off under reduced pressure, and the residue was dissolved in ether. The ether layer was washed with water, 10% hydrochloric acid, water, sodium carbonate test solution, and water in this order, and dried over anhydrous magnesium sulfate. The ether was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel) to obtain 2.01 g of a colorless liquid monoester (yield 67.6).
%) was obtained. This monoester is converted into anhydrous ether.
1 ml of pyridine was added, and 5 ml of an ether solution containing 1.85 g of ketoprofen acid chloride was added dropwise while stirring under ice cooling. After stirring at the same temperature for 30 minutes, and then returning to room temperature and stirring overnight, the reaction solution was washed with water, 10% hydrochloric acid, water, sodium carbonate test solution, and water in this order, and dried over anhydrous magnesium sulfate. The ether was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel) to obtain 3.12 g (yield: 86.8%) of Compound 32 listed in Table 3 as a pale yellow liquid. Example 4 (Synthesis of compound 28) Compound 1 1.63g, triphenylphosphine
2.62 g of p-acetoxycinnamic acid and 2.06 g of p-acetoxycinnamic acid were dissolved in 60 ml of tetrahydrofuran, and 10 ml of a solution of 1.74 g of diethyl azodicarboxylate in tetrahydrofuran was added dropwise thereto. After the dropwise addition, the mixture was stirred overnight at room temperature, the solvent was distilled off under reduced pressure, and ether was added to the residue to remove insoluble matter. The liquid was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel) to obtain compound 28 listed in Table 3 as a pale yellow liquid.
2.25g (yield 87.5%) was obtained. Example 5 (Synthesis of compound 26) 0.77 g of 2-chloro-1-methylpyridium iodide was suspended in 10 ml of toluene, and 0.82 g of compound 1, 0.41 g of p-methylcinnamic acid, and 1.1 g of tributylamine were added to 10 ml of toluene. After heating and stirring for 3 hours, the solvent was distilled off under reduced pressure and the residue was purified by column chromatography (silica gel) to obtain 0.36 g of the compound 26 listed in Table 3 as a pale yellow liquid (yield). rate of 30.6%).

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Claims (1)

[Claims] First-order general formula () [In the formula, R is a hydrogen atom, a group COR ₁ (where R ₁ represents an alkyl group or an alkenyl group), a group [formula] (where R ₂ is a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group, phenyl group, R ₃ represents a hydrogen atom, lower alkyl group, phenyl group, R ₄ represents a phenyl group optionally substituted with a lower alkyl group, lower alkyloxy group, acyloxy group, hydroxyl group or halogen atom), Group -CO-A-R ₅ (where A is a single bond, C1~
2 alkylene group, C1-2 alkyleneoxy group, R ₅ is lower alkyl group, lower alkyloxy group, acyloxy group, hydroxyl group, halogen atom,
Indicates a phenyl group that may be substituted with a nitro group, benzoyl group, or alkylenedioxy group)
A phenyl acetate derivative represented by