NOVEL THIAZOLIDINONE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND PROCESS FOR PREPARING SAME

Abstract: The present invention relates to novel compounds of general formula (I), wherein R means hydrogen or C1-4alkyl group; and Y stands for cyano, trifluoromethyl, aryloxy or aryl(C1-4alkyl)oxy group. The compounds according to the invention show a gastric acid secretion-inhibiting effect and therefore, they are useful for the treatment of gastric and duodenal ulcers. In addition, they exert a cytoprotective action against gastric laesions induced, e.g. by indomethacin or acid-containing alcohol.

Description: NOVEL THIAZOLIDINONE DERIVATIVES, PHARMACEUTICAL COMPOSI TIONS CONTAINING THE M AND PROCE SS FOR PREPARI NG SAME Thi s inventi on rel ates to novel 2 -thi azol idinone deri vatives of the genera l f ormula ( I ) , ( I ) wherein R menas hydrogen or C- j ^ alkyl group; and Y stands for cyano, trifluoromehtyl , aryloxy or aryl(C, _ 4 alkyl)oxy group as well as the pharmaceutical compositions containing these compounds. The compounds of general 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 thos of the general 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 whithin the scope of this invention a 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 compou of the general formula (I) ( I ) wherein R means hydrogen or C,_ ^ alkyl group; and Y stands for cyano, trifluoromethyl, aryloxy or aryl(C, _.alkyDoxy group which comprises reacting a compound of the general formula (II) ( II ) 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 inven tion is carried out in a solvent, preferably in a C-,_ a 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 wit 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-Thiazolidinoπe used as starting compound is known and can be prepared according to the literature / ""j" . Am. Chem. Soc. 7J 5349 (1956); and J. Chem. Soc. 1952, 3094_7. From the compounds of general 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- -cyaπophenylmethyl)-2-thiazolidinone is an outstanding member of the compound class of general formula (I). This compound shows a gastric acid secretion-inhibiting effect on the so-called Shay's rat / " Shay: Gastroenterolog _5, 43 (1945) 7 with an oral ED,- n value of 1.7 mg/kg. This compound is effective even against the indo ethacin-induc- ed gastric ulcer with an oral ED,- n value of 1.2 mg/kg; it is active also against gastric laesioπs induced by acid -coπtaining alcohol / " Robert: Gastroenterology ]J_, 761 (1979)_7, i.e. it exhibits a so-called cytoprotective effect with an oral ED 50 value of 3.7 mg/kg. On the basis of our preliminary investigations, th expected human daily dose of the above compounds according to the invention amounts to 10 - 100 mg for one patient. The preparation of the novel compounds according to the invention is illustrated by the general process described hereinafter: jo 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 general formula (II) is added then the mixture is boiled under reflux till the complete comsumption of the start¬ ing 2-thiazolidinone which is controlled by thin layer chro atography (TLC) by using a developing system of beπzene/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 seco 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 is dried and evaporated. The residue is purified by column chromatography (on Kieselgel 60, 230 - 400 mesh, by using chloroform or ethy acetate as eluent) or by recrystallization. The compounds and their most important character tics prepared as described above are summarized in Table without any restriction of the scope of the invention to the Examples. The chemical names of compounds listed in Table I are as follows: 1/ 3-(2-cyanophenylmethyl)-2-thiazolidinone, 2/ 3-(4-cyaπophenylmethyl)-2-thiazolidinone, 3/ 3-(3-cyaπophenylmethyl)-2-thiazolidinone, 4/ 3-(l-phenyl-l-ethyl)-2-thiazolidiπone, 5/ 3-(3-phenoxyphenylmethyl)-2-thiazolidinone, 6/ 3-(4-benzyloxyphenylmethyl)-2-thiazolidinone, 7/ 3-(4-trifluorome hylphenylmethyl)-2-thiazolidinone, 8/ 3-(2-trifluoromethylphenylmethyl)-2-thiazolidinone an 9/ 3-(3-trifluoromethylphenylmethyl)-2-thiazolidinone. T a b l e Compound Empirical for- Yield Melting point IR NMR No. mula, OP C _ c_m-l ppm Molecular weight (cryst. solvent) 7. C n H ιn F 3 N0s 73 41-45 1665 3.0-3.7 /m,4H,2CH 1330 4.6 /s,2H,CH 2 1240 7.5 /q,4H,ArH 8 56 41-42 1670 3.1-3.7 /m,4H,2CH C 11 H 10 F 3 N0S 1417 4.7 /s,2H,CH 2 1311 7.2-7.8 /m,4H,ArH C n H 10 F 3 N0S 61 olaj* 1673 3.1-3.7 /m,4H,2CH 1408 4.6 /s,2H,CH 2 1331 7.6 /s,4H,ArH x = Purified by column chromatography with chloroform as eluent. The invention is illustrated in detail by the follo ing non-limiting Examples. Example 1 Preparation of 3-(2-cyanophenylmethyl)-2-thiazolidi none A mixture containing 3.09 g (0.03 mol) of 2-thiazol dinoπe, 11.2 g (0.081 mol) of potassium carbonate, 1.8 g (0.018 mol) of potassium hydrogen carbonate, 0.5 ml (0.027 mol) of water and 6.47 g (0.033 mol) of 2-bromo- methylbenzonitrile in 30 ml of methyl isobutyl ketone is refluxed for 5 hours, then cooled down. After adding 30 m of water the mixture is stirred for 30 minutes, the insoluble precipitate is filtered off, washed twice with 10 ml of water each and dried. After recrystallizing 4.71 of crude product from 20 ml of ethanol under simultaneous clarification with activated carbon 3.39 g (51.8 %) of white, crystalline title compound are obtained, m.p.: 116 - 117°C. Example 2 Preparation of a pharmaceutical composition contain¬ ing 3-(2-cyanophenylmehyl)-2-thiazolidinone as active ingredient Ingredients: g 3-(2-Cyanophenylmethyl)-2-thiazolidinone 40 Lactose 80 Starch 67 Talc 6 Polyvinylpyrrolidone 4 Magnesium stearate 2 Colloidal silicic acid 1 From the above composition 1000 tablets weighing 200 mg each with a diameter of 8 mm are prepared.

Claims: Claims 1. 2-Thiazolidinone derivatives of the general for¬ mula (I), ( I ) wherein R means hydrogen or C, .alkyl group; and Y stands for cyano, trifluoromethyl, aryloxy or aryl(C, .alkyDoxy group. 2. 3-(2-Cyanophenylmethyl)-2-thiazolidinoπe. 3. A process for the preparation of 2-thiazolidinone derivatives of the general formula (I) ( I ) wherein R means hydrogen or C,_.alkyl group; and Y stands for cyano, trifluoromethyl, aryloxy or aryl(C, _.alkyl)oxy group, which compr i ses reacting a compound of the general formula (II), ( II ) wherein R and Y arre as defined above, and X represents halogen, mesyloxy or tosyloxy group, with 2-thiazolidinone. 4. A process as claimed in claim 3, which comp ¬ ri se s carrying out the reaction in an organic solvent, preferably in a ketone-type solvent in the presence of an acid binding agent and water. 5. A process as claimed in claim 4, which comp¬ r i se s using an alkaline metal carbonate and/or alkaline metal hydrogen carbonate as acid binding agent and using water in an amount of 3 - 5 % by volume in the reaction mixture . 6. A pharmaceutical composition, which c ompr i s e as active ingredient a 2-thiazolidinoπe derivative of the general formula (I) ( I ) wherein R means hydrogen or C, * alkyl group; and stands for cyano, tri luoromethyl, aryloxy or aryl(C, .alkyDoxy group in admixture with carriers and/or additives commonly used in the pharmaceutical industry. 7. A pharmaceutical composition, which comp- r ise s as active ingredient 3-(2-cyanophenylmethyl)- -2-thiazolidinone in admixture with carriers and/or additives commonly used in the pharmaceutical industry. 8. A process for the preparation of a pharmaceutical composition, which compr is e s mixing as active ingredient a 2-thiazolidinone derivative of the general formula (I), wherein R and Y are as defined in claim 3, prepared by using a process according to claim 3, with carriers and/or additives commonly used in the pharmace¬ utical industry and transforming them to a pharmaceutical composition.

Inventors: BALOGH GABOR, CSEHI ATTILA, EZER ELEMER, HAJOS GYOERGY, HARSANYI KALMAN, HEGEDUES BELA, MATUZ JUDIT, SAGHY KATALIN, SZABADKAI ISTVAN, SZABO ZSOLTNE, SZPORNY LASZLO, BALOGH, GABOR, CSEHI, ATTILA, EZER, ELEMER, HAJOS, GYOERGY, HARSANYI, KALMAN, HEGEDUES, BELA, MATUZ, JUDIT, SAGHY, KATALIN, SZABADKAI, ISTVAN, SZABO, ZSOLTNE, SZPORNY, LASZLO
Applicants: RICHTER GEDEON VEGYESZET, RICHTER GEDEON VEGYESZETI GYAR RT
Application year: 1990
Main classification: C07D277
IPC codes: A61K31, A61P1, C07D277