CS263921B1 - Esters of 2-arylpropionic acids - Google Patents

Abstract

Esters of 2-arylpropionic acids, where the aryl group denotes 4-isobutylphenyl, 6-methoxy-2-naphthyl or 2-fluoro-4-biphenylyl with diglycerides from natural sources, whose 1,2-:1,3-diglyceride ratio is 1:2 to 2.5 and the content of saturated fatty acids C1 to C18 is 3 to 50% by weight, and unsaturated fatty acids C1 to C22 is 30 to 97% by weight, are substances with potential anti-inflammatory effects. They are prepared by the action of a 2-arylpropionic acid halide, where the aryl group has the meaning given above, on a diglycerol of the composition given above, at a temperature of 0 to 50 °C in an organic solvent, preferably dichloromethane, 1,2-dichloroethane or toluene, in the presence of a tertiary amine, preferably pyridine or triethylamine, or in the presence of a catalytic amount of 4-dimethylaminopyridine, for a period of 1 to 12 h, after which the reaction mixture is diluted with water and the arylpropionic acid ester is isolated after evaporation of the organic solvent.

Description

The invention relates to esters of 2-arylpropionic acids wherein the aryl group represents 4-isobutylphenyl, 6-methoxy-2-naphthyl or 2-fluoro-4-biphenylyl with naturally occurring diglycerides having a ratio of 1,2-: 1,3-diglyceride being 1: 2 to 2.5, and the content of saturated fatty acids C 18 to C 18 is 3 to 50 wt. and the C16 to C22 unsaturated fatty acids is 30 to 97 why. wt. prepared by treatment with a 2-arylpropionic acid halide, wherein the aryl group is as defined above, on the diglyceride of the above composition, with stirring at 0 to 50 ° C in a tertiary amine, preferably pyridine, triethylamine, optionally in the presence of a catalytic amount of 4-dimethylaminopyridine. in an organic solvent, preferably dichloromethane, 1,2-dichloroethane, toluene for 1 to 12 hours. The progress of the reaction can be monitored by thin layer chromatography. Diglycerides which are derived from olive, rapeseed or sunflower oil, fish oil, lard or tallow are used as diglycerides. Especially preferred are diglycerides derived from rapeseed and sunflower oil, which contain an increased amount of bound essential unsaturated fatty acids. After completion of the reaction, the reaction mixture is diluted with water, the aqueous phase is washed with an organic solvent, the organic portions are washed with a dilute solution of a mineral acid, preferably hydrochloric or sulfuric acid, dried and the solvents are distilled off under reduced pressure. The arylalkanoic acid ester is obtained.

The presence of the substituted 2-arylpropionic acid moiety in these esters makes them a substance with potential anti-inflammatory effects. (Chronicles of Drug Discovery, J. Wiley, New York, 1981; J. Pharm. Sci. 73, 579 [1984]). In many cases, 2-arylpropionic acid esters have been shown to exhibit higher analgesic and anti-inflammatory efficacy than free acid. (6-methoxy-2-naphthyl) propionate, phthalidyl-2- (3-benzoylphenyl) propionate, etc. These compounds have a higher anti-inflammatory activity than the corresponding parent acids, even in dosage forms. (2-pyridyl) -methyl-, (3-pyridyl) methyl- and (4-pyridylmethyl) -, 3- (4-pyridyl) propyl (2,6-dichloroanilino) phenylacetic acid and other related acids protected anti-inflammatory and analgesic effects have proved to be filters against dangerous shortwave solar radiation, and particularly pronounced analgesic efficacy (European Patent Specification 166 135) has been shown in [4- (2-hydro 2- (6-methoxy-2-naphthyl) propionic acid xy-2-propyl-1-cyclohexenyl] methyl ester, which in addition exhibits a 3X higher tolerance to the gastrointestinal tract. In Belgian Pat. No. 887,460 discloses esters of polyethylene glycols with arylpropionic acids with comparable potency of the parent acids but with protracted effects. 2,3,4,6-tetraacetyl-1- (2- (4-isobutylphenyl) propionyl) - + D-glucopyranose and 2,3,4,6-tetraacetyl-1- [2- (6) (methoxy-2-maphthyl) propionyl] -? - D-glucopyranose (Indian J. Chem., Sec. B 25B, 337 [1986]), and other therapeutic uses (European Pat. No. 70,717) have also been found in the treatment of Recently (Folia pharmacol. japon. 88, 33-40, 77-84, 205-213 [1986]), new esters of 1- (4-chlorobenzoyl) -5-methoxy-2 have been introduced into clinical practice. -methylindol-3-ylacetic acids with the anti-inflammatory activity of the free acid (drug indomethacin), but with a significantly lower ulcerogenic effect (1/7 to 1/10) in addition to a lesser inhibitory effect on prostaglandin biosynthesis.

The advantage of using the mixed diglycerides of the invention is their ease of availability. They are easily metabolized in the human body and at the same time form an important part of the diet. Their abundance allows the synthesis of a number of biologically important catalysts, such as prostaglandins and leukotrienes. Furthermore, bound unsaturated acids are believed to act as a significant component against atherosclerosis.

The invention and its effects are illustrated by several examples, which are illustrative only and in no way limit the scope of the invention.

Example 1

A mixture of 1.15 g of 2-arylpropionic acid wherein the aryl group is 4-isobutylphenyl, 1.42 g of oxalyl chloride and 30 ml of toluene was heated to boiling for 3 hours, after evaporation to dryness the residue was dissolved in 30 ml of dichloromethane. This solution was within 30 min. dropwise at 0 ° C to a mixture of 0.61 g triethylamine, 0.1 g 4-dimethylaminopyridine, 1.85 g rapeseed oil diglycerides and 20 ml dichloromethane. The reaction mixture was stirred for 12 h at 20 ° C, diluted with water, the organic layer separated, aqueous washed with dichloromethane. The combined organic solutions were washed with 5% hydrochloric acid, water and dried over anhydrous magnesium sulfate. Evaporation gave 2.30 g (95%) of the 2-arylpropionic acid ester, wherein the aryl group is as defined above as an oil.

Infrared spectrum (chloroform, cm * ¹ ):

020 m, 2,940 s, 2,865 s, 1,740 s, 1,520 m,

472 m, 1170s, 1100m, 1034m.

Thin layer chromatography (silica gel

Merck, eluting with toluene ether 8: 2a toluene).

R _f 0.9 and 0.35,

Example 2 ____________

A mixture of 1.1 g of 2-arylpropionic acid wherein the aryl group is 2-fluoro-4-biphenylyl, 1.2 g of thionyl chloride and 30 ml of benzene was heated to boiling for 3 h, after evaporation the residue was dissolved in 10 ml of toluene. The solution was added dropwise to a cold solution of 0.4 g pyridine, 30 ml toluene, and 1.85 g sunflower oil diglyceride. The mixture was heated at 40 ° C for 6 h, diluted with water after cooling. The aqueous layer was washed with toluene, the combined organics were washed with sulfuric acid (5%), water, and dried over anhydrous magnesium sulfate. Evaporation gave 2.20 g (90%) of the 2-arylpropionic acid ester, wherein the aryl group is as defined above as an oil.

Infrared spectrum (chloroform, cm ^-1 ): 3 020 m, 2 940 s, 2 865 s, 1 740 s, 1 628 w, 1 588 w, 1 520 w, 1 488 m, 1 472 m, 1 425 m, 1,095 m, 1,075 m.

Thin layer chromatography (Merck silica gel) (toluene-ether 8: 2, toluene).

R _f 0.9 and 0.35.

Subject

Esters of 2-arylpropionic acids wherein the aryl group denotes 4-isobutylphenyl, 6-methoxy-2-naphthyl and 2-fluoro-4-biphenylyl with naturally occurring diglycerides having a ratio of 1,2-: 1,3-diglyceride of 1: 2 to 2.5 and the saturated fatty acid content of C 16 to C 16 is 3 to 50 why. wt. and the C16 to C22 unsaturated fatty acids are 30 to 97% by weight, obtainable by the action of a 2-arylpropionic acid halide, wherein the aryl group is as defined above, on the diglyceride at the front.

Claims (1)

at a temperature of 0 to 50 ° C in an organic solvent, preferably dichloromethane, 1,2-dichloroethane or toluene, in the presence of a tertiary amine, preferably pyridine or triethylamine, optionally in the presence of a catalytic amount of 4-dimethylaminopyridine for 1 to 12 h, diluting the reaction mixture with water and isolating the arylpropionic acid ester after evaporation of the organic solvent.