CS262009B1 - Triglycerides of 2-arylpropionic acids - Google Patents

Abstract

Triglycerides of 2-arylpropionic acids of Formula I wherein Ar is 4-isobutylphenyl, 2-fluoro-4-biphenylyl, 6-methoxy-2-naphthyl, 4- (2-thenoyl) phenyl, 5-benzoyl-2-thienyl-1, 1α-phthalic acid; exhibit anti-inflammatory and analgesic effects effects. Process for preparing 2-arylpropionic esters the kyeelin of the formula I is based in that the acid halide is of formula II wherein Ar is as defined above meaning glycerol at 0 up to 50 ° C in a tertiary amine environment as pyridine or triethylamine, preferably in the presence of a catalytic amount 4-dimethylaminopyridine or i-benzylimidazole for 1 to 24 hours, whereupon after diluting the reaction mixture with water extraction with an organic solvent triglyceride of formula (1).

Description

The present invention provides triglycerides of the 2-arylpropionic acids of formula (I)

Ar-CH-CH-C00 _2/1 /

wherein Ar is 4-isobutylphenyl, 2-fluoro-4-biphenylyl, 6-methoxy-2-naphthyl, 4- (2-thenoyl) phenyl, 5-benzoyl-2-thienyl. 2-Arylpuepionic acids are therapeutically used in the treatment of inflammatory diseases, especially rheumatoid arthritis, osteoerthritis, Schill disease / MS. Pharmacy 29, 309 (1980); Chronicles of Drug Discovery, J., iley, New York 1981; J. Pharm. Sci. 73, 579 (1984)]. It has been shown that esters of said arylpropionic acids exhibit more advantageous pharmacological effects, particularly anti-inflammatory and analgesic. Ger. Cffen, 5,043,712 protects phthalidyl esters of arylalkanoic acids such as phthalidyl-2- (4-isobutylphenyl) propionate, phthalidyl-2- (6-methoxy-2-naphthyl) propionate, phthalidyl 2- (3-benzoylphenyl) propionate and others . These substances have been shown to have higher anti-inflammatory and analgesic efficacy than the corresponding parent acids, even in dosage forms. In Swiss Patent Specifications 579,051 and 594,625, (2-pyridyl) oethyl- are protected; (3-pyridyl) methyl-; (4-pyridyl) methyl-; 3- (4-pyridyl) propyl esters of o- (2,6-dichloroanilino) phenylacetic acid and other related acids, which, in addition to anti-inflammatory and analgesic effects, have proved to be filters against dangerous shortwave solar radiation. Particularly pronounced analgesic efficacy / Buro pat. 166,135 (b) has been demonstrated in 4- (2-hydroxy-2-pro2)

282 009 2- [6-methoxy-2-naphthyl] propionic acid methyl [1- (cyclohexen-1-yl) methyl], which, moreover, exhibits a 3-fold higher tolerance to the gastrointestinal tract. In belg. U.S. Pat. U.S. Pat. No. 887,460 discloses esters of polyethylene glycols with arylpropionic acids with comparable potency of parent acids but with protracted effects. 2,3,4,6-tetraacetyl-11- [2- (4-isobutylphenyl) propionyl] -D-glucopyranose and 2,3,4,6-tetraacetyl-1- (2- / 6) belong to the same group. -methoxy-2-naphthyl (propionyl) - D-glucopyranose (Indian J. Chem., Sec. Β 25B, 337 A986 /. In Eur. Pat. 70, 717, their indication is further extended to the treatment of acute respiratory syndrome.

The present invention also relates to a process for the preparation of the 2-arylpropionic acid triglycerides of the general formula (I).

Ar-CH-COOH ^'CH3 / IX / a wherein Ar has the meaning given above, is reacted with anhydrous glycerol of the formula III, CK ₂ -CH = CH _2/111 /

OH OH OH with stirring at 0 to 50 ° C in a tertiary amine environment, preferably pyridine or triethylamine. A particularly preferred embodiment of the esterification reaction can be achieved by adding a catalytic amount of 4-dimethylaminopyridine or N-benzylimidazole, which substantially accelerates the progress of the reaction, which is monitored by thin layer chromatography. Upon achieving a preferred conversion, the reaction mixture is diluted with water and the product extracted with an organic solvent such as dichloromethane, chloroform, 1,2-dichloroethane or toluene, the combined organics are washed with a dilute mineral acid solution, preferably hydrochloric or sulfuric acid, dried and evaporated. An ester of formula I is thus obtained.

The process according to the invention does not require expensive process equipment, operates with 8 cheap and available reagents and can be carried out without difficulty in large batches.

282 009

The invention and its effects are demonstrated in several exemplary embodiments, which are illustrative only and are not intended to limit the scope of the invention in any way.

Example 1

A mixture of 6.8 g of an acid of formula II wherein Ar is 4-isobutylphenyl, 5.9 g of thionyl chloride and 50 ml of toluene was heated to boiling for 2 hours, after evaporation the residue was dissolved in 20 ml of dichloromethane and cooled to 0 ° C. While stirring, 2.6 g of pyridine and 0.1 g of 4-dimethylaminopyridine were added and a mixture of 0.92 g of glycerol in 10 ml of dichloromethane was added dropwise over 0.5 hours. The mixture was stirred for 20 hours at 20 ° C, diluted with water, organic layer separated, aqueous washed with 20 mL of dichloromethane, the combined organics were washed with a 5 wt. sulfuric acid, water, brine and dried over anhydrous magnesium sulfate. After evaporation, 6.1 g (92%) of the ester of formula I, wherein Ar is as defined above, is isolated as a yellowish oil.

Example 2

4.88 g of an acid of formula II wherein Ar is 2-fluoro-4-biphenylyl were heated to boiling for 3 hours with 5.1 g of oxalyl chloride and 50 ml of benzene. After evaporation, the residue was dissolved in 30 ml of 1,2-dichloroethane and to this solution was added 2.02 g of triethylamine at 0 ° C. 0.55 g of glycerol of formula III dissolved in 15 ml of 1,2-dichloroethane was added dropwise over 30 minutes, the mixture was heated at 20 ° C for 12 hours and worked up as in the example.

1. 4.0 g (86%) of an ester of formula I wherein Ar is as defined above, m.p. 103-108 ° C, were obtained.

Example 3

A mixture of 5.2 g of an acid of formula II wherein Ar is 5-benzoyl-2-thienyl, 5.1 g of oxalyl chloride and 50 ml of toluene was heated to boiling for 3 hours, after evaporation the residue was dissolved in 50 ml of 1,2-dichloroethane. . 0.1 g of 4-dimethylaminopyridine and 2.02 g of triethylamine were added to the solution under ice-cooling to 0 ° C. While stirring, 0.55 g of glycerol dissolved in 15 ml of 1,2-dichloroethane was added over 30 minutes. The reaction mixture was stirred at 20 ° C for 4 hours and worked up as in Example 1. 4.45 g (91%) of the ester of formula I, wherein Ar is as defined above, was obtained as a viscous oil.

Claims (1)

SUBJECT OF THE INVENTION 1. Triglycerides of 2-arylpropionic acids of the general formula I, Ar-pH-COO-CH CH _5/1 / Ar-pH-COO-CHo CH3 wherein Ar is 4-isobutylphenyl, 2-fluoro-4-biphenylyl, 6-methoxy-2-naphthyl, 4- (2-thenoyl) phenyl, 5-benzoyl-2-thienyl. 2. A process for the preparation of a 2-arylpropionic acid triglyceride of the formula I as claimed in claim 1, Ar-CK-COOH CH? wherein Ar is as defined above acting with glycerol of formula III ch ₂ - 4 h-ch ₂ OH OH OH (111) at 0 to 50 ° C in a tertiary amine such as pyridine or triethylamine, preferably in the presence of a catalytic amount of 4-dimethylaminopyridine or N-benzylimidazole for 1 to 24 hours, after which the reaction mixture is diluted with water an organic solvent of the triglyceride of formula I. / 1 / 282 009 Ar CH, I ³ - CH - COOH - CH I Ar - CH - and CH-j COOH 1 - CH Ar - CH - l ₇ COOH - CH Ar Í ^H CH. C00H