CS261049B1 - Arylpropionic acid monosaccharide esters - Google Patents

Abstract

Esters of monosaccharides of 2-arylpropionic acids of the general formula I Ar-CH-COOR 1 (i) where Ar denotes 4-isobutylphenyl, 2-fluoro- -4-biphenylyl, 6-methoxy-2-naphthyl, R denotes 1,2:3,4-di-O-isopropylidene-beta-D-galactopyranos-6-yl or 1,2:4,5-di-O-isopropylidene-beta-D-fructopyranos-3-yl have anti-inflammatory and analgesic effects. The method of their production consists in reacting the acid halide of the general formula II Ar-CH-COOH i (ii) where Ar has the meaning given above with a di-O-isopropylidene monosaccharide, for example 1,2:3,4-di-O-isopropylidene-beta-D-galactopyranose or 1,2:4,5-di-O-isopropylidene-beta-D-fructopyranose at a temperature of 0 to 40 °C in a tertiary amine environment, preferably pyridine, triethylamine, ethyldiisopropylamine, optionally in the presence of a catalytic amount of 4-dimethylaminopyridine for a period of 1 to 24 hours, after which the racemic mixture of esters of the general formula I is isolated after evaporation of the organic solvent.

Description

The present invention relates to 2-arylpropionic acid monosaccharides esters of formula (I)

Ar-CH-COOR (1) wherein Ar is 4-isobutylphenyl, 2-fluoro-4-biphenylyl, 6-methoxy-2-naphthyl, R is 1,2,2,4-di-O-isopropylidene-beta-D -galactopyranos-6-yl or 1,2: 4,5-di-O-isopropylidene-beta-D-fructopyranos-3-yl. The compounds of formula (I) according to the invention are novel substances from the series of 2-arylpropionic acid esters, many of which have significant anti-inflammatory effects.

Ger. Offen. 3,043,712 protects arylalkanoic acid phthalyl esters 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) -methyl- 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 / Euro pat. 166,135) has been shown in 4- (2-hydroxy-2-propyl) -1-cyclohexen-1-yl) methyl 2- (6-methoxy-2-naphthyl) propionate, which in addition exhibits a 3-fold higher tolerance to 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 the parent acids but with protracted effects. 2,3,4,6-tetraacetyl-1- (2-4-isobutylphenyl) propionyl] -beta-D-glucopyranose and 2,3,4,6-tetraacetyl-1- (2- / 6) belong to the same group. -methoxy-2-naphthyl (propionyl) -beta-D-glucopyranose / Indian. J. Chem., Sec. Β 25B,

337 (1986). For these reasons, they are classified as non-steroidal anti-inflammatory. of drugs / J. Pharm. Soi. 73, 579 (1984)]. The broadening of the indication field represents use in the treatment of acute respiratory syndrome / Eur. Pat. 70, 717].

The present invention provides novel esters of 2-arylpropionic acid monosaccharides of formula I,

Ar-CH-COOR (1) wherein Ar and R are as defined above. The invention also relates to a process for their production. The essence of the process according to the invention consists in the readily available acid halide of the formula II

Ar-CH-COOH (11) wherein Ar is as defined above, acts with di-O-isopropylidene monosaccharide, for example 1,2: 3,4-di-O-isopropylidene-beta-D-galactopyranose or 1,2: 4,5 di-O-isopropylidene-beta-D-fructopyranose with stirring at 0 to 40 ° C in a tertiary amine, preferably pyridine, triethylamine, ethyldiisopropylamine, optionally in the presence of a catalytic amount of 4-dimethylaminopyridine for 1 to 24 hours. The progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mixture is diluted with water, washed with an organic solvent such as chloroform, dichloromethane, 1,2-dichloroethane, toluene, and the combined organics are washed with water, dilute mineral acid, preferably sulfuric acid, dried and evaporated. A diastereomeric mixture of the ester of formula (I) is thus obtained.

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

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

Example 1

A mixture of 8.25 g of 2- (4-isobutylphenyl) propionic acid of formula II wherein Ar is 4-isobutylphenyl, 10.25 g of oxalyl chloride and 60 ml of toluene was heated to boiling for 1 h, evaporated to dryness and the residue diluted with 50 ml of dry dichloromethane. The solution was cooled to 0 ° C and 5.05 g of triethanolamine and 0.1 g of dimethylaminopyridine were added with stirring. A solution of 10.2 g of 1,2: 3,4-di-isopropylidene-beta-D-galactopyranose in 30 ml of dichloromethane was then added dropwise over 1 h. After 3 h at 20 ° C, the reaction mixture was diluted with 100 mL of water, the organic layer was separated, washed with water, 5% sulfuric acid, water, and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 15.3 g (88%) of the ester of formula I wherein Ar is as defined above and R is 1,2: 3,4-di-O-isopropylidene-beta-D-galactopyranos-6-yl a residue such as a non-volatile viscous oil.

Example 2

In the same manner as in Example 1, the corresponding acid chloride of formula II wherein Ar is as defined above was prepared from 6.1 g of an acid of formula II wherein Ar is 2-fluoro-4-biphenylyl, 8 g of oxalyl chloride in 50 ml of toluene. A solution of chloride in 30 ml of 1,2-dichloroethane was added dropwise to a solution of 6.5 g of 2: 4,5-di-O-isopropylidene-beta-D-fructopyranose, 2.0 g with stirring over a period of 30 minutes at 10 ° C. pyridine in 50 ml 1,2-dichloroethane. After stirring at 20 ° C for 24 h, the reaction mixture was worked up in the same manner as in Example 1. 11.8 g (97%) of the ester of formula I was obtained, wherein Ar is as defined above and R is 1.2: 4.5 a di-O-isopropylidene-beta-D-fructopyranos-3-yl residue, m.p. Mp 100-115 ° C.

Claims (2)

SUBJECT OF THE INVENTION 1. Esters of 2-arylpropionic acid monosaccharides of the general formula I, Ar-CH-COOR (1) wherein Ar is 4-isobutylphenyl, 2-fluoro-4-biphenylyl, 6-methoxy-2-naphthyl, R is 1,2,2,4-di-O-isopropylidene-beta-D -galactopyranos-6-yl or 1,2: 4,5-di-O-isopropylidene-beta-D-fructopyranos-3-yl. 2. A process for the preparation of 2-arylpropionic acid monosaccharides according to claim 1, characterized in that the acid halide of the formula II Ar-CH-COOH (11) wherein Ar is as defined above, acts with di-O-isopropylidene monosaccharide, for example 1,2,2,4-di-O-isopropylidene-beta-D-galactopyranose or 1,2: 4,5 di-O-isopropylidene-beta-D-fructopyranose at 0 to 40 ° C in a tertiary amine, preferably pyridine, triethylamine, ethyldiisopropylamine, optionally in the presence of a catalytic amount of 4-dimethylaminopyridine for 1 to 24 hours, after which Dilution of the reaction mixture with water isolates the racemic mixture of the monosaccharide esters of formula I after evaporation of the organic solvent.