CS261333B1 - Indomethacin esters and their production method - Google Patents

Abstract

Indomethacin esters of general formula I, where R denotes 1,2:5,6-di-O-isopropylidene- -afla-D-glucofuranos-3-yl, 1,2:3,4-di-O- -isopropylidene-alpha-D-galactopyranos-6-yl, 1,2:4,5-di-O-isopropylidene-beta-D-fructopyranos-3-yl, expand the range of nonsteroidal anti-inflammatory drugs. Their production method consists in treating the acid halide of formula II with 1,2:5,6-di-O- -isopropylidene-alpha-D-glucofuranose or 1,2:3,4-di-O-isopropylidene-alpha-D- -galactopyranose or 1,2:4,5-di-O-isopropylidene-beta-D-fructopyranose at a temperature of 0 to 50 °C in a tertiary amine environment, preferably pyridine or triethylamine, or a catalytic amount of 4-dimethylaminopyridine for 1 to 12 hours, after which, after diluting the reaction mixture with water, the ester of general formula I is isolated by extraction with an organic solvent.

Description

The present invention relates to indomethacin esters of formula I wherein R is 1,2: 5,6-di-O-isopropylidene-alpha-D-glucofuranos-3-yl, 1,2: 3,4-di-O-isopropylidene- alpha-D-galactopyranps-6-yl

1,2: 4,5-di-O-isopropylidene-t-D-fructopyranos-3-yl.

Said esters of formula I belong to the group of non-steroidal anti-inflammatory drugs / Cs. Pharmacy 29, 309, 1980, J. Pharm. Sci. 73, 579 (1984)]. In many cases, 2-arylalkanoic acid esters have been shown to exhibit higher analgesic and anti-inflammatory activity than free acids. Indomethacin ethoxycarbonylmethyl ester / Ger. Offen. 3 347 721

J. Pharm. Pharmacol. 35, 398 (1983)] shows a high anti-inflammatory effect at a higher selectivity than indomethacin. Likewise, butoxycarbonylmethyl ester / Euro. Pat. 144 845 /. Japanese Patent Specifications Jpn. Kokai Tokkyo Koho 5,885,820 and 5,872,560 protect indomethacin salicylester, which exhibits lower ulcerogenic effects with higher anti-inflammatory activity than indomethacin.

Recently / Folia Pharmacol. japon. 88, 33, 77, 205 (1986) introduced a substituted piperazinylethyl ester with an anti-inflammatory activity of the free acid (indomethacin) but with a significantly lower ulcerogenic effect (1/7 to 1/10 indomethacin) in addition to a lesser inhibitory effect on prostaglandin biosynthesis. .

A process for the preparation of the indomethacin esters of the formula I wherein R is as defined hereinabove is characterized by treating the readily available acid chloride of the formula II with 1,2: 5,6-di-O-isopropylidene-alpha-D-glucofuranose, or 1,2: 3,4-di-O-isopropylidene-α-β-D-galactopyranose or 1,2: 5,4-di-O-isopropylidene-beta-D-fructopyranose with stirring at 0 to 50 ° C in a tertiary amine environment, preferably pyridine, triethylamine, optionally in the presence of a catalytic amount of 4-dimethylaminopyridine for 1 to 12 hours, the progress of the reaction being monitored by thin layer chromatography. After completion of the reaction, the reaction mixture is diluted with water, washed with an organic solvent such as dichloromethane, chloroform, 1,2-dichloroethane, toluene, the combined organics are washed with water, saturated sodium chloride solution, dried and evaporated. An ester of the general formula is thus obtained.

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

Example 1

A mixture of 35.7 g of indomethacin, 24 g of thionyl chloride, 0.5 ml of dimethylformamide and 200 ml of toluene was heated under reflux for 1 h and evaporated in vacuo. The residue was dissolved in 250 mL of dichloromethane, cooled with ice to 0 ° C, and a mixture of 11.9 g of pyridine and 0.1 g of 4-dimethylaminopyridine was added dropwise over 5 minutes with stirring. A solution of 26.0 g of 1,2: 5,6-di-O-isopropylidene-alpha-D-glucofuranose in 50 ml of pyridine was then added dropwise with stirring and cooling. After 6 h at 20 ° C, the reaction mixture was diluted with water, the organic layer was washed with water, 5% sulfuric acid, water, brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent afforded 46.8 g (78%) of the ester of Formula I wherein R is 1,2: 5,6-di-O-isopropylidene-alpha-D-glucofuranos-3-yl as a non-volatile oil. For C 5 ^H H ^ClNOg (6000) calculated: 62.05% C, 5.71% H, 2.33% N, 5.91% Cl; found; % C, 62.20;% H, 5.86;% N, 2.40. IR spectrum / CHC1 _3, cm ^-1 /: 3020, 2990, 2930, 1740, 1675, 1590, 1450, 1 060th

Example 2

In the same manner as in Example 1, crystallization of a crude product of 49.8 g was obtained from 35.7 g of indomethacin and 26.1 g of 1,2: 3,4-di-O-isopropylidene-alpha-D-galactopyranose in 200 ml of pyridine. 83%) of an ester of formula I wherein R is 1,2: 3,4-di-O-isopropylidene-alpha-D-galactopyranos-6-yl, mp 157-158 ° C. For C 5 ^H HClNONO (600.0) calculated: 62.05% C, 5.71% H, 2.33% N, 5.91% Cl; Found: C 62.24, H 5.70, N 2.57, Cl 6.07. IR spectrum (CHCl3, cm ^-1 ): 3,020, 2,990, 2,940, 1,735, 1680, 1590, 1455, 1285, 1060.

Example 3

In the same manner as in Example 1, from 35.7 g of indomethacin and 26 h of 1,2: 4,5-di-O-isopropylidene-beta-D-fructopyranose in a mixture of 200 ml of 1,2-dichloroethane and 50 ml of triethylamine was crystallized by crude 44.4 g (74%) of the ester of formula I is obtained, wherein R is 1,2,2,5,5-di-O-isopropylidene-beta-D-fructopyranos-3-yl, mp 136-138 ° C. For C ₃₁ H ₃₄ C1NC> ₉ / 600.0 / calculated: 62.05% C 5.71% H 2.33% N 5.91% Cl; Found: C 62.35, H 5.77, N 2.50, Cl 6.00. IR spectrum (CHCl3, cm &^lt; -1 ^> ): 3,010, 2980, 2930, 1740, 1680, 1590,

452, 1285, 1060.

Claims (2)

object of the invention Indomethacin esters of general formula I, wherein R is 1,2: 5,6-di-O-isopropylidene-alpha-D-glucofuranos-3-yl, 1,2: 3,4-di-O-isopropylidene-alpha -D-galactopyranos-6-yl, 1,2: 4,5-di-O-isopropylidene-beta-D-fructopyranos-3-yl. 2. A process for the preparation of indomethacin esters according to claim 1, characterized in that the acid halide of the formula II is treated with 1,2,2,6,6-di-O-isopropylidene-alpha-D-glucofuranose or 1,2,2,4-di -O-isopropylidene-alpha-D-galactopyranose or 1,2: 4,5-di-O-isopropylidene-beta-D-fructopyranose at 0 to 50 ° C in a tertiary amine environment, preferably pyridine or triethylamine, respectively. a catalytic amount of 4-dimethylaminopyridine for 1 to 12 hours, and after diluting the reaction mixture with water, the ester of formula I is isolated by extraction with an organic solvent.