Thiazolidinone derivatives, pharmaceutical compositions containi

Details Thiazolidinone derivatives, pharmaceutical compositions containi Thiazolidinone derivatives, pharmaceutical compositions containi

1991-07-18

1992-12-08

Gerstl, Robert

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

548182, 548186, 548189, C07D27714, A01K 31425

Patent

active

051698595

DESCRIPTION:

BRIEF SUMMARY
This invention relates to novel 2-thiazolidinone derivatives of the formula (I), ##STR2## wherein R means hydrogen or a C.sub.1-4 alkyl; and group
The compounds of formula (I) possess a significant gastric acid secretion-inhibiting effect. They bear a high therapeutic importance since the number of patients suffering from gastric or duodenal ulcer is continuously increasing both in the absolute and relative sense as well.
Compounds, which are structurally similar to those of the formula (I) and exert a similar gastric acid secretion-inhibiting action, have been published in the Hungarian patent specification No. 198,915. The compounds being within the scope of this invention are substantially different from the known substances due to the nature of their substituents bound to the aromatic nuclei.
According to an other aspect of the invention, there is provided a process for the preparation of compounds of the formula (I) ##STR3## wherein R means hydrogen or C.sub.1-4 alkyl group; and group ##STR4## wherein R and Y are as defined above and X represents halogen, mesyloxy or tosyloxy group, with 2-thiazolidinone.
The reaction according to the process of the invention is carried out in a solvent, preferably in a C.sub.3-8 ketone such as e.g. methyl isobutyl ketone, or in an aqueous ketone, dimethylformamide or dimethylsulfoxide, in the presence of an acid binding agent, preferably an alkaline metal carbonate or hydrogen carbonate. After filtering off or washing out the inorganic precipitate with water, the product obtained from the reaction is separated by filtration or, after removing the solvent, it is purified by recrystallization or column chromatography.
2-Thiazolidinone used as starting compound is known and can be prepared according to the literature [J. Am. Chem. Soc. 78, 5349 (1956); and J. Chem. Soc. 1952, 3094].
From the compounds of formula (II), the substance containing halogen as X is a commercially available fine chemical (see the concerning booklet of Aldrich); the substances containing mesyloxy group as X can be prepared from the corresponding alcohols by using a method described in the Hungarian patent specification No. 163,399.
Based on the pharmacological investigations 3-(2-cyanophenylmethyl)-2-thiazolidinone is an outstanding member of the compound class of formula (I). This compound shows a gastric acid secretion-inhibiting effect on the so-called Shay's rat [Shay: Gastroenterology 5, 43 (1945)] with an oral ED.sub.50 value of 1.7 mg/kg. This compound is effective even against the indomethacin-induced gastric ulcer with an oral ED.sub.50 value of 1.2 mg/kg; it is active also against gastric laesions induced by acid-containing alcohol [Robert: Gastroenterology 77, 761 (1979)], i.e. it exhibits a so-called cytoprotective effect with an oral ED.sub.50 value of 3.7 mg/kg.
On the basis of our preliminary investigations, the expected human daily dose of the above compounds according to the invention amounts of 10-100 mg for one patient.
The preparation of the novel compounds according to the invention is illustrated by the general process described hereinafter:
To a mixture containing 3.09 g (0.03 mol) of 2-thiazolidinone, 11.2 g of potassium carbonate, 1.8 g of potassium hydrogen carbonate, 0.5 ml of water and 30 ml of methyl isobutyl ketone, 0.033 mol of a benzyl halide or benzyl alcohol mesylate or tosylate derivative of the formula (II) is added then the mixture is boiled under reflux till the complete consumption of the starting 2-thiazolidinone which is controlled by thin layer chromatography (TLC) by using a developing system of benzene/methanol/glacial acetic acid in a 10:3:1 ratio. After cooling down the reaction mixture is stirred with 30 ml of water for 30 minutes. An eventually remaining insoluble part is filtered off, washed with water, dried and purified by recrystallization. The filtrate as a second generation can be worked up in the following way:
When two clear phases appear on the effect of water, the organic layer is separated, washed with 30 ml of water, the organic phase i

REFERENCES:
patent: 4937252 (1990-06-01), Szabadkai

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