CS260735B1 - Monoglycerides of arylpropionic acids - Google Patents

Description

The invention relates to 2-arylpropionic acid monoglycerides of the general formula I,

A i-, .r μ .... c.OO-C H _n - CH - CH _n - * (L)

2.3.4.6-tetraacetyl-1- (2- (4-isobutylphenyl) propionyl-D-glucopyranose, and

2.3.4.6-Tetraacetyl-1- (2- (6-methoxy-2-naphthyl) propionyl) -D-glucopyranose (Ind. J. Chem., Sec. 25B, 337 (1986)). Other therapeutic uses (Eur. Pat. No. 70, 717) have also been found in the treatment of acute respiratory syndrome.

The present invention provides monoglycerides

2-arylpropionic acids of the general formula I, in which Ar represents

4-isobutylphenyl,

2-fluoro-4-biphenylyl,

6-methoxy-2-naphthyl, (2-thenoyl) phenyl,

-, b enzoy 1-2-thienes 1.

Ar ~ C H- CO OC H. ~ CH-CH ₂ I 4 I><·

CH. ·

CH, CH

Said esters of formula (I) belong to the group of non-sterile anti-inflammatory drugs (Pharm. 29, 309 (1980)); Chronicles of Drug Discovery, J. Wiley, New York, 1981; J. Pharm. Scí. 73, 579 (1984)].

In many cases, 2-arylalkanoic acid esters have been shown to exhibit higher analgesic and anti-inflammatory activity than free acids. Ger. Offen. No. 3,043,712 protects phthalidyl esters of arylalkanoic acids such as:

wherein Ar is as defined above. The invention also relates to a process for their production. The essence of the process consists in converting the readily available halide (chloride) (Jpn. Kobai Tokkyo Koho 81, 95, 149) of the acids of the formula II, with phthalidyl-2- -isobutylphenyl) propionate, phthalidyl-2- (6-methoxy-2-naphthyl) propionate, phthalidyl-2- (3-benzoylphenyl) propionate and others.

C i ///) v /

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 Nos. 579,051 and 594,625, the following are protected:

(2-pyridyl) methyl-, (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. No. 166,135) has been shown for 2- (6-methoxy-2- (4- (2-hydroxy-2-propyl) -1-cyclohexan-1-yl) methyl ester). naphthyl jpropionic, which in addition shows a 3X higher tolerance to the gastrointestinal tract.

In belg. U.S. Pat. U.S. Patent No. 887,460 discloses esters of polyethylene glycols with arylpropionic acids with comparable potency of the parent acids but with protracted effects. The same group also includes:

wherein Ar is as defined above, reacts with 2,3-dimethyl-4-hydroxymethyl-1,3-dioxplan of formula III with stirring at 0 to 50 ° C in a tertiary amine, preferably pyridine, ethyldiisopropylamine or triethylamine, optionally in the presence of a catalytic amount of 4-dimethylaminopyridine for 1 to 12 hours (progress of the reaction was monitored by thin layer chromatography).

/ '>

r M (i''9 ", /’ ’’ \

v.- ’· And i i ·: · /

After completion of the reaction, the reaction mixture is diluted with water, extracted with an organic solvent such as:

dichloromethane, chloroform,

1,2-dichloroethane or toluene, the combined organics are washed with a dilute solution of mineral acid, preferably hydrochloric or sulfuric acid, dried, and evaporated. An ester of formula I is thus obtained.

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 20.6 g of an acid of formula II wherein Ar is 4-isobutylphenyl, 17.8 g of thionyl chloride and 100 ml of toluene was heated to boiling for 2 hours and then evaporated to dryness. The residue was dissolved in 100 ml 1,2-dichloroethane, cooled to 0 ° C with stirring, and 8.7 g pyridine was added dropwise. A solution of 13.2 g of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane of formula III in 50 ml of 1,2-dichloroethane was added dropwise over 1 hour, the mixture was stirred for 3 hours at 20 ° C and diluted with water. The organic layer was separated, the aqueous layer was washed with 20 mL of 1,2-dichloroethane. The combined organic solutions were washed with 5% HCl, water and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 13.0 g (96%) of the ester of formula I wherein Ar is 4-isobutylphenyl.

Claims (2)

pKedmet 1. Monoglycerides of 2-arylpropionic acids of the general formula I, Ar - cH - C 00-C ΐCH - Cl-1? l ^Λ I \ ch ₂ o_o ch ₃ ch ₃ (I) where Ar denotes 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 2-arylpropionic acid monoglycerides according to claim 1, characterized in that the acid halide of the formula II is Example 2 A mixture of 4.9 g of the acid of formula (I) wherein Ar is 2-fluoro-4-biphenylyl, 3.6 g of thionyl chloride and 20 ml of toluene was heated to boiling for 3 hours, evaporated to dryness and the residue dissolved in 30 ml of dichloromethane. To the solution cooled to 0 ° C was added dropwise 2.02 g of triethylamine, 0.1 g of 4-dimethylaminopyridine, and 2.64 g of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane of formula III was added dropwise over 30 minutes. . The mixture was stirred at 20 ° C for 3 hours and after dilution with water treated as in Example 1. 6.0 g (84%) of the ester of formula I wherein Ar is 2-fluoro-4-biphenylyl were obtained as a non-volatile oil. . Example 3 A mixture of 5.2 g of an acid of formula II wherein Ar is 4- (2-thenoyl) -phenyl, 5 g of oxalyl chloride and 50 ml of toluene was heated to boiling for 2 hours and after evaporation the residue was dissolved in 30 ml of toluene. 2.02 g of triethylamine were added to the solution at 0 ° C and a solution of 2.64 g of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane of formula III was added dropwise over 30 minutes. The mixture was stirred for 12 hours at 20 ° C and worked up as in Example 1. 6.81 g (91%) of the ester of formula I was isolated, k-de Ar being 4- (2-thenoyl) -phenyl. INVENTION It ^ _r -CH-COONa _CH3 (II) wherein Ar is as defined above, with 2,2-dimethyl-4-hydroxymethyl-l, 3-dioxolane -vzorce III HO C Λ o. ' 0¾ ^cK 3 (HI) at 0-50 ° C in an environment of a tertiary amine, preferably pyridine or triethyl mine or- ethyldiisopropylamine or 4-The amount of catalyst dimethylaminoipyridrnu for 1 to 12 hours and, after diluting the reaction mixture with water isolated by organic solvent extraction of the monoglyceride of the formula I.