2-THIAZOLONE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND PROCESS FOR PREPARING SAME

Abstract: The present invention relates to novel 2-thiazolone derivatives of general formula (I), wherein X stands for -CN, -CONH2, -CO2H or -CO2R group, wherein R is a C1-5 alkyl group; and n is 0, 1 or 2, with the proviso, that when X stands for CO2H, CO2R, n is other than 0. The compounds according to the invention possess advantageous cytoprotective and gastric acid secretion-inhibiting effects and thus, they may be used in the therapy of gastric ulcer.

Description: 2-THIAZOLONE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND PROCESS FOR PREPARING SAME This invention relates to novel 2-thiazolαπe derivatives of the general formula (I), wherein X stands for -CN, -C0NH 2 ,-C0 2 H or -C0 2 R group, wherein R is a C, calkyl group; and n is 0, 1 or 2, with the proviso, that when X stands for C0 2 H, C0 2 R, π is other than 0, as well as the pharmaceutical compositions containing these compounds. When X stands for a -C0 2 group, then R preferab¬ ly means a methyl, ethyl or prαpyl group. The compounds of the general formula (I) possess advantageous cytoprotective and gastric acid secretion- -inhibitiπg effects. Compounds of the class of general formula (I) have till now been unknown in the literature; however, the iso erizing cyclization of o -thiocyaπato ketones, which may be improved by acidic or basic catalysis, is known see e.g. J. Am. Che . Soc. _7___. . 1719 (1972); or J. Chem. Soc. 1949, 28987. According to our know¬ ledge, this reaction type has not been used for the synthesis of o£,o£.'-bis derivatives. The invention is based on the recognition that 1,3-bis(thiocyaπato)acetone of the formula (II), can be cyclized by using the method cited above and thereafter, the side chain of the resulting thiazole compound can further be modified in a preferable way. According to an other aspect of the invention, there is provided a process for the preparation of new compounds of the general formula (I), ^.S - |CH 2 | n - X II 0 wherein X stands for -CN, -C0NH 2 , -C0 2 H or -C0 2 R group, wherein R is a C, ,-alkyl group; and n is 0, 1 or 2, with the proviso, that when X stands for C0 2 H, C0 2 R, n is other than 0, which comprises cyclizing a compound of the formula (II) then, if desired, transforming the resulting compound of the formula (la), S~CN 0 to the carbarπoy preparing therefrom by alkaline hydrolysis and S- -alkylation a compound of the general formula (I), wherein π is 1 or 2 and, if desired, subjecting the side chain of the compounds thus obtained to further transformations in a known manner. According to the process of the invention, the compound of the formula (II) is transformed to the compound of formula (la) or (lb) depending on the strength of the reaction of (II) with methanol contain¬ ing hydrogen chloride. The compound of the formula (lb) is S-decarbamoylated by alkali in an aqueous alkaπolic medium and then, the in situ obtained mercaptan compound is S-alkylated in a manner known per se. The nitrile compound is further reacted by known transformations of the cyano group. In this way carboxylic acid, carboxylic acid esters, amides and other nitrogen-containing carboxylic acid derivatives (e.g. hydrazides, amidines and substituted amidines) may be prepared which in turn may be further modified. The compound of the formula (II) used as start¬ ing substance is known /_Acta Univ. Voroπegieπsis S_, 167 (1937_V7; it was prepared by reacting 1,3-dichloro- acetone with potassium rhodaπide in an aqueous-alco¬ holic medium. The compound of the formula (la), chemically 4- -thiocyanatomethyl-2(3H)-thiazolone proved to posses outstanding effects: it showed an oral EDcn value of 0.7 mg/kg in the acidic alcohol test /A. Robert: Gastroeπterology Tl_, 761 (197927 " ; and it inhibited even the gastric acid secretion with a higher oral ED_- n value of 40 mg/kg in the Shay test /_Shay: Gastroeπterology 1, 43 (1945X7. 4-Carbamoylthiomethy1-2(3H)-thiazolone, 4-(2- -cianoethyl)thiomethyl-2(3H)-thiazolone and 4-carbamoyl- methylthiomethyl-2(3H)-thiazoloπe also showed an advantageous effect. Thus, the compounds according to the invention may be used as active ingredients of pharmaceutical compositions for the therapy of gastric ulcer. The invention is illustrated in detail by the following non-limiting Examples. Example 1 Preparation of 4-thiocyanatomethyl-2(3H)-thiazα- loπe _c " ompouπd of the formula (Ia2 * a) 17.22 g (0.10 ol) of l,3-bis(thiocyanato)acetone (m.p.: 94-96 °C) are added to the stirred solution of 10 g of potassium hydrogen carbonate in 100 ml of water. The reaction mixture, which becomes mildly warm at the beginning, is stirred for 16 hours. After filtration and washing with ethaπol and then with acetone and drying, 9.0 g (52.3%) of the title product are obtained, m.p.: 140-143 °C (with decomposition). The active ingredient content of the substance is 99.1% based on the potentiometric titration with sodium hydroxide. X H-NMR (DMS0-d 6 , & ppm) : CH 2 4.1 s Ar-H 6.5 s X-H 11.5 b* The sulfur content of the substance is 37.5% (calculated 37.2%). b) After absorbing 7.3 g (0.20 mol) of gaseous hyd¬ rogen chloride in 100 ml of anhydrous methaπol, 17.22 g (0.10 mol) of 1,3-bis(thiocyaπato)-acetoπe are added and the mixture is stirred at 45 to 50 °C for 4 hours. Then, the reaction mixture is evaporated under reduced pressure until a crystalline precipitate begins to separate. After cooling down the residue, the precipi¬ tate is filtered off. After washing with methanol and drying, 8.3 g (48.3%) of the title compound are obtain¬ ed with the same quality characteristics as described in Example la). The active ingredient content of the substance obtained is 99.0%. Example 2 Preparation of 4-carbamoylmercaptomethyl-2(3H)- -thiazolone /_c ~ ompound of the formula (Ib27 a) After absorbing 36.5 g (1.0 mol) of gaseous hydrogen chloride in 100 ml of methaπol, 17.22 g (0.10 mol) of 1,3-bis(thiocyanato)acetone are portionwise added. After ceasing of the exothermic reaction, the mixture is stirred at 4Q to 42 °C for 24 hours. The evolution of methyl chloride which is violent at the beginning, slowly ceases and then completely stops. After filtration at room temperature, washing with ethanol and drying, 16.05 g (84.5%) of the title product are obtained, m.p.: 234-246 °C (with decomposition). The active ingredient content of the substance is 98.9% based on the. poteπtiometric titration with sodium hydroxide. IR: 3170 cm "1 / ~ V (N-H)7 1688 cm 1 /_ v (C=0) lactajn7 1635 cm - ■ y (C=0) amide_7 Analysis calculated: C 31.55; H 3.16; N 14.74%; found: C 31.66; H 3.21; N 14.77. b) The process of Example 2a) is followed, except that the compound of the formula (la) is used as start¬ ing substance instead of the compound of the formula (II). Thus, 16.0 g (84.2%) of the title compound are obtained. Example 3 Preparation of 4-(2-cyanoethyl)thiomethyl-2(3H)- -thiazolαne 60 ml (0.60 mol) of ION sodium hydroxide solution are added dropwise to a suspension containing 57 g (0.30 mol) of 4-carbamoylmercaptomethyl-2(3H)-thiazolone cfompαuπd of the formula (Ib27 in 150 ml of water and 90 ml of ethanol under stirring while bubbling an inert gas through the mixture. After 5 minutes, 17.5 g (0.33 mol) of acrylnitrile are added dropwise to the result¬ ing solution at 25 to 30 °C. The mixture is stirred for additional 4 hours, then filtered to obtain a sharply clear solution which is then acidified by adding 27 m l of glacial acetic acid. The crystalline precipitate is filtered off at 15 to 20 °C, washed with water and then with isopropaπol and dried to give 45.8 g (76.5%) of the title compound, m.p.: 108-111 C. The active ingredient content of the substance is 99.6%. actam7 ppm) Example 4 Preparation of 4-carbamoylmethylthiomethyl-2(3H)- -thiazolone 9.0 ml of ION (40%) sodium hydroxide solution are added dropwise to a suspension containing 5.7 g (0.03 mol) of 4-carbamoylmercaptomethyl-2(3H)-thiazolone compound of the formula (Ib27 in 27 ml of water and 18 ml of ethanol at 25 to 30 °C while bubbling an inert gas through the mixture. After 15 minutes, 3.0 g (0.032 mol) of chloroacetamide are added to the reaction mixture which is then stirred far 16 hours. After fil¬ tering off the insoluble material, the filtrate is acidi¬ fied by adding 5 ml of glacial acetic acid. The crystalline product is filtered, washed with isopropanol and dried to obtain 4.04 g (66.0%) of the title compound, m.p.: 151-153 °C. The active ingredient content of the substance is 99.4% based on titration with alkaline metal hydroxide. IR: 3390 cm "1 /_ ~ V NH-, J 1665 cm "1 ~ y (C=0) 1630 cm "1 /~V (C=0) 1 H-NMR (DMSO-d,, <f ppm) Example 5 Preparation of 3-(2-oxothiazolin-4-ylmethylthio)- propioπic acid A solution containing 6.01 g (0.03 mol) of 4-(2- -cyanoethyl)thiomethyl-2(3H)-thiazolone in 27 g of 6N hydrochloric acid is refluxed under stirring for 4 hours. After filtration at room temperature, washing and drying, 5.16 g (78.5%) of the title compound are obtained, m.p.: 125-127 °C. The active ingredient content of the substan¬ ce is 97.0% based on titratioπ with sodium hydroxide. IR: 3400-2000 cm "1 / " V (X-H27 1720 cm "1 / ~ v> (C=0) lactaiπ/ 1600 cm -1 r \ ) (C=0) carboxyl/ X H-NMR (DMS0-d 6 , & ppm): SCH 2 CH 2 C00H 2.6 t Ar-CH 2 -S 3.5 s Ar-H 6.2 s X-H 11.3 b Example 6 Preparation of methyl 3-(2-αxothiazolin-4-yl- methylthio)prαpionate 4.39 g (0.02 mol) of 3-(2-oxothiazolin-4-yl- methylthio)propiαnic acid are refluxed with the mixture of 5 ml of methaπol and 0.5 g of concentrated sulfuric acid for 6 hours, then the reaction mixture is poured into- 10 g of ice water under stirring. The ctystalliπe precipitate is filtered, washed and dried to give 3.97 g (85%) of the title compound, m.p.: 70-73 °C. The active ingredient content of the substance is 98.8% based on potentiometric titratioπ with sodium hydroxide. IR: 1725 cm "1 /~y (C=0) ester/ 1660 cm "1 /~V (C=0) lactam7 -• ■ H-NMR (DMS0-d 6 , ό ppm) : S-CH 2 -CH 2 ~C0 2.6 t Ar-CH 2 -S 3.5 s 0-CH 3 4.0 s Ar-H 6.2 s X-H 11.2 b Example 7 Pharmaceutical composition Preparation of tablets containing 50 mg of active ingredient each For the preparation of 1000 tablets the following components are used: 4-thiocyanatomethyl-2(3H)-thiazolone 50 g Lactose 210 g Starch 30 g Magnesium stearate 3 g The components are mixed in a mixer equipment and then compressed to tablets in a tabletting machine.

Claims: Claims 1. 2-Thiazoloπe derivatives of the general formula (I), CH 2 ( i ) / 0 wherein X stands for -CN, -C0NH 2 , -C0 2 H or -C0 2 R group, wherein R is a C-,_ 5 alkyl group; and n is 0, 1 or 2, with the proviso that when X stands for C0 2 H, C0 2 R, n is other than 0. 2. 4-Thiocyaπatomethyl-2(3H)-thiazoloπe. 3. A process for the preparation of 2-thiazolone derivatives of the general formula (I), wherein X stands for -CN, -C0NH 2 , -C0 2 H or -C0 2 R group wherein R is a C,_ 5 alkyl group; and n is 0, 1 or 2, with the proviso that when X stands for C0 2 H, C0 2 R, π is other than 0, which comprises cyclizing a compound of the formula (II), then, if desired, transforming the resulting compound of the formula (la), c rjsj _<- to the carba oyl derivative of the formula (lb), / N NH 2 CH 2 0 l \ ( I ) N H S 1^1 - 0 preparing therefrom by alkaline hydrolysis and S-alkyla- tioπ a compound of the general formula (I), wherein n is 1 or 2 and, if desired, subjecting the side chain of the compounds thus obtained to further transformations in a known manner. 0 4. A process as claimed in claim 3 for the prepa¬ ration of 4-thiocyaπatomethyl-2(3H)-thiazolone of the formula (la) , 35 S-CN which comprises cyclizing the compound of the formula (II) in the presence of an acid or base. 5. A process as claimed in claim 3 for the preparation of 4-carbamoylthiomethyl-2(3H)-thiazolone which comprises cyclizing the compound of the formula (II) and treating the thus obtained compound of the formula (la) with methaπol containing hydrogen -chloride. 6. A pharmaceutical composition, which comprises as active ingredient a 2-thiazolone derivative of the general formula (I ) , 5—|CH } | — X If ( I ) 0 wherein X stands for -CN, -C0NH 2 , -C0 2 H or -C0 2 R group, R is a C, ,-alkyl group; and π is 0, 1 or 2, with the proviso, that when X stands for CO^H, C0 2 R, π is other than 0, in admixture with carriers and/or additives commonly used in the pharmaceutical industry. 7. A process for the preparation of a pharmaceu¬ tical composition, which comprises mixing as active ingredient a 2-thiazolone derivative of the general formula (I), wherein X and π are as defined in claim 3 prepared by using the process according to claim 3, with carriers and/or additives commonly used in the pharmaceutical industry and transforming them to a pharmaceutical composition.

Inventors: BOD PETER, EZER ELEMER, FEKECS EVA, HAJOS GYOERGY, HARSANYI KALMAN, HEGEDUES BELA, MATUZ JUDIT, SAGHY KATALIN, SZEKELY KRISZTINA, SZPORNY LASZLO, TRISCHLER FERENC, BOD, PETER, EZER, ELEMER, FEKECS, EVA, HAJOS, GYOERGY, HARSANYI, KALMAN, HEGEDUES, BELA, MATUZ, JUDIT, SAGHY, KATALIN, SZEKELY, KRISZTINA, SZPORNY, LASZLO, TRISCHLER, FERENC
Applicants: RICHTER GEDEON VEGYESZET, RICHTER GEDEON VEGYESZETI GYAR RT
Application year: 1988
Main classification: C07D277
IPC codes: A61K31, A61P1, C07D277