JPS59161331A - Novel phenylacetic ester derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A phenylacetic ester derivative shown by the formula I [R is H, COR1 (R1 is alkyl, or phenyl), group shown by the formula II (R2 is H, halogen, cyano, lower alkyl, or phenyl; R3 is H, lower alkyl, or phenyl; R4 is phenyl which may be replaced with lower alkyl, lower alkyloxy, acyloxy, or group shown by the formula III (A is single bond, 1-2C alkylene, 1-2C alkyleneoxy; R5 is phenyl which may be replaced with lower alkyl, lower alkyloxy, etc.)]. USE:Having antiphlogistic analgesic action, useful as a drug. Having extremely low side effect such as gastrointestinal disorder followed by occurrence of ulcer. PREPARATION:A compound shown by the formula IV or its reactive derivative is reacted with 2,3-butanediol shown by the formula V or its reactive derivative in the presence of a deoxidizer such as pyridine, alkyli carbonate, etc. in a solvent to give a compound shown by the formula I wherein R is H. This compound is further reacted with a compound shown by the formula R6COOH (R6 is R1, group shown by the formula VI, or A-R5), to give the compound shown by the formula I wherein R is other than H.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel phenylacetic acid ester derivative, and more particularly to a novel phenylacetic acid ester derivative represented by the following general formula (1) [wherein R is a hydrogen atom and a group COR1 (where R1 is an alkyl group or an alkenyl group] ), Gen atom, cyano group, lower alkyl group, phenyl group,
R3 is a hydrogen atom, a lower alkyl group, a phenyl group, R4
represents a lower alkyl group, a lower alkyloxy group, an acyloxy group, a hydroxyl group, or a phenyl group optionally substituted with a halogen atom), a group -Co-A-R5 (where A is a single bond, and an alkylene group of 01 to 2) group, 01-2 alkyleneoxy group, R5 is phenyl optionally substituted with lower alkyl group, lower alkyloxy group, acyloxy group, hydroxyl group, halogen atom, nido tetragroup, benzoyl group, or alkylenedioxy group The present invention relates to a phenylacetate derivative represented by the following formula and a method for producing the same.

Currently, ketoprofen is a non-steroidal anti-inflammatory analgesic that is frequently used as a medicine for the treatment of headaches, toothaches, lower back pains, muscle pains, rheumatic diseases, etc.

However, it has been known that when ketoprofen is administered through a gag, side effects such as gastrointestinal disorders accompanied by the development of ulcers occur. In other words, ketoprofen often causes unpleasant symptoms such as gastric congestion and bleeding, not only when long-term administration is required, such as in the treatment of rheumatoid isthmus, but even when administered for a short period of time. Currently, there are restrictions on the administration method and dosage.

Therefore, the present inventors conducted intensive research to reduce the above-mentioned side effects of ketoprofen, and as a result, the above-mentioned formula (
The inventors have completed the present invention by discovering that the phenylacetate derivative represented by I) has an anti-inflammatory and analgesic effect equivalent to that of ketoprofen, but its side effects are much smaller than that of ketoprofen.

That is, the object of the present invention is to obtain a standard phenylacetate derivative (11) useful as a nonsteroidal anti-inflammatory analgesic.
We are trying to provide the following.

Another object of the present invention is to provide a method for producing a novel phenylacetate derivative (11).

Compound (1) of the present invention can be produced using a known esterification reaction, for example, by any of the following methods.

■ Ketoprofen (ID or its reactive derivative) with 2.
Phenyl acetate (Ia) is produced by reacting 3-butanediol 1) or its reactive derivative.

(■・) Product - ■ A phenylacetate derivative (lb) is produced by reacting the phenylacetate (1,) obtained in step (■) with carboxylic acid (IV) or a reactive derivative thereof in the presence of a condensing agent.

-A-R5) ■ 2,3-butanediol monoester derivative (9)
is reacted with ketoprofen (Il''l or a reactive derivative thereof) to produce a phenylacetate derivative (Ib).

Below margin (Ib) Product.

(In the formula, R6 is the same as above.) In the vaporization method, examples of the reactive derivatives of ketoprofen (II) and carboxylic acid (IV) include acid halides, acid anhydrides, mixed acid 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-mentioned 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.

Reactions using condensing agents include 2-halo 1- as the condensing agent.
carried out in the presence of an alkylpyridinium salt and a tertiary amine such as pyridine, triethylamine, tributylamine, or
Alternatively, it is preferable to carry out the reaction in the presence of diethyl azodicarboxylate and triphenylphosphine as condensing agents. Further, the above condensation reaction is preferably carried out in a suitable reaction solvent, and the reaction solvent is ether, tetrahydrone,
Benzene, toluene, acetonitrile, chloroform,
A solvent that does not participate in the reaction, such as dichloromethane, is preferred.

The results of testing the anti-inflammatory effect of the compound (1) of the present invention thus obtained are shown.

A group of 7 male Donryu rats weighing around 2,001 kg were fasted for 48 hours, and the unplugging compound was suspended in a 1% sodium carboxymethyl cellulose aqueous solution and orally administered.

60 minutes after administration of the test compound, the foot jump volume of 2 tons was measured using a volumetric device, and then 1% carrageenan saline solution 0.111+7! was injected subcutaneously into the footprint of the right hind leg, and the edema intensity after 3 hours was compared with a control group administered with a 1% carboxymethyl cellulose sodium aqueous solution to determine the edema suppression rate.

The results are shown in Table 1.

As is clear from Table 1, the compounds of the present invention showed a high inhibitory effect on carakenin edema.

Furthermore, the compounds of the present invention caused less ulcer formation, which is a side effect of non-steroidal anti-inflammatory analgesic substances, than ketoprofen.

Next, embodiments of the present invention will be explained in detail.

Example 1 (Synthesis of Compound 1) Ketoprofen so and sor were suspended in 60° of benzene, 80° 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 acid chloride of ketoprofen as a pale yellow liquid.

Dissolve this acid chloride in anhydrous ether 2C,0-
, 18 g of 3-butanediol, 20 g of pyridine! f! and anhydrous ether 500-ml dropwise.

After the dropwise addition, the reaction solution was stirred at room temperature for 5 hours, and then diluted with water for 10 hours.
% 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 colorless liquid compound 1 40.10f (
61.5% of vehicles were collected).

Example 2 (Synthesis of Compound 2) Compound 1.632 was dissolved in anhydrous ether/L-20m, 1 pyridine was added, and 5 tn1 of an ether solution of 0.71 f of caproic acid chloride was added dropwise with stirring while cooling with water. . 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 colorless liquid compound 21.701 (yield: 80.0%) listed in Table 2.

Example 3 (Synthesis of Compound 32) 1,807 2.3-butanediol was dissolved in 40πE of tetrahydrofuran, 2 ml of pyridine was added thereto, and after cooling with water and stirring, 2.42 ml of α-7-enylcinnamic acid chloride was dissolved.
10 ml of a solution of F in 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 remaining liquid 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 a colorless liquid monoester 2.01? (
A yield of 67.6% was obtained. This monoester was dissolved in anhydrous ether 20-, pyridine 1- was added, and an ether solution 5- of ketoprofen acid chloride 1.85 f was added dropwise while stirring while cooling with water. After stirring at the same temperature for 30 minutes and then returning to room temperature 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 Compound 32 3.12f (yield 86.8) listed in Table 2 as a pale yellow liquid.
%) was obtained.

Example 4 (Synthesis of Compound 28) Compound 1 1.6: M,) Riphenylphosphine 2.6
2f% p-acetoxytinic acid 2. o6t was dissolved in 60ml of tetrahydrofuran, and a solution of 1.742 (diethyl azodicarboxylene) in tetrahydrofuran was added to the solution.
- was added dropwise. 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 tear fluid was distilled off under reduced pressure, and the remaining liquid was purified by column chromatography (silica gel) to obtain Compound 282.25F (yield: 87.5%) listed in Table 2 as a pale yellow liquid.

Example 5 (Synthesis of compound 26) 2-chloro-1-methylpyridium iodide 0.7
79 was suspended in 10d of toluene, and compound 10.8 was added to this.
Add a solution of 0.41r of 2P, p-metallic acid, and 1,1r of tributylamine in 10-toluene, and add 3
After heating and stirring for an hour, the solvent was distilled off under reduced pressure and the residue was purified by column chromatography (silica gel) to obtain a pale yellow liquid compound 26 listed in Table 2, yield 3: 0.36 fC.
0.6%) was obtained.

bottom margin

Claims (1)

[Claims] 1. The following general formula (1)) % formula % [In the formula, R is a hydrogen atom, a group COR1 (here, R1 represents an alkyl group or an alkenyl group), '1' 7 atoms, Cyan group, lower alkyl group, phenyl group, R3 is a hydrogen atom, lower alkyl group, phenyl group, R4 is a lower alkyl group, lower alkyloxy group, acyloxy group, hydroxyl group, or... Even if substituted with a loken atom ), the group -CO-A-R5 ( shows a good phenyl group),
Here, people are single bonds, alkylene groups of cl-2, 01-2
R5 represents a lower alkyl group, a lower alkyloxy group, an acyloxy group, a hydroxyl group, a halogen atom, a nitro group, a benzoyl group, or a phenyl group optionally substituted with an alkylenedioxy group). ] A phenylacetic acid ester derivative represented by 2. The compound represented by the general formula (11) or its reactive derivative has a general formula value of 2,3-butanediol or its general formula (1)
,) A method for producing phenylacetic acid ester represented by CH3. 3. General formula (IV) R2OOOH (Iv) is added to the phenylacetic acid ester represented by the general formula (1,) CH3 or its reactive derivative [wherein, R6 is an alkyl group, an alkenyl group, an atom, a cyano group, a lower alkyl group] group, phenyl group, R3 is a hydrogen atom, lower alkyl group, phenyl group, R4 is a phenyl group optionally substituted with a lower alkyl group, lower alkyloxy group, acyloxy group, hydroxyl group or halogen atom), Group A -R5 (Here, people use a single bond, an alkylene group of 01-2, an alkyleneoxy group of 01-2, R5
represents an ifenyl group which may be substituted with a lower alkyl group, a lower alkinooxy group, an acyloxy group, a hydroxyl group, a halogen atom, a nitro group, a benzoyl group, or an alkylene dioxy group] A method for producing a phenylacetate derivative represented by the general formula (1b) CH3 (wherein R6 is the same as above), which comprises reacting an acid or a reactive derivative thereof. 4. General formula ■ CH3-CH-Cu-CH5CVI OH0COR6 [In the formula, R6 is an alkyl group, alkenyl group, atom, cyano group, lower alkyl group, or phenyl group, and R3 is a hydrogen atom, lower alkyl group, or phenyl group. , -R4 represents a lower alkyl group, a lower alkyloxy group, an acyloxy group, a hydroxyl group, or a phenyl group optionally substituted with a halogen atom), a group A -Fi5 (where A is a single bond, C1-2
alkylene group, C1-2 alkyleneoxy group, R
5 represents a phenyl group optionally substituted with a lower alkyl group, a lower alkyloxy group, an acyloxy group, a hydroxyl group, a halogen atom, a nitro group, a benzoyl group, or an alkylenedioxy group] , General formula (Ib)+1, characterized in that a 3-butanediol monoester derivative is reacted with a compound represented by General formula (n) or a reactive derivative thereof.
A method for producing a phenylacetate derivative represented by 1 o CHOCOR6 H3 (wherein R6 is the same as above).