Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1989-07-21
1991-02-05
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
598186, 598187, A61K 31425, C07D77734
Patent
active
049905244
DESCRIPTION:
BRIEF SUMMARY
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a national phase application of PCT/HU No. 88/00079 filed 13 Dec. 1988 and based, under the International Convention, on Hungarian national application No. 5633/87 field 14 Dec. 1987.
FIELD OF THE INVENTION
This invention relates to novel 2-thiazolone derivatives of the formula (I), ##STR2## wherein X is a --CN, --CONH.sub.2, --CO.sub.2 H or --CO.sub.2 R, wherein R is a C.sub.1-5 alkyl group; and CO.sub.2 R, n is other than 0,
When X stands for a --CO.sub.2 R group, then R preferably is a methyl, ethyl or propyl group.
The compounds of the formula (I) possess advantageous cytoprotective and gastric acid secretion-inhibiting effects.
BACKGROUND OF THE INVENTION
Compounds of the class of formula (I) have until now been unknown in the literature; however, the isomerizing cyclization of .alpha.-thiocyanato ketones, which may be improved by acidic or basic catalysis, is known [see e.g. J. Am. Chem. Soc. 74, 1719 (1972); or J. Chem. Soc. 1949, 2898]. According to our knowledge, this reaction type has not been used for the synthesis of .alpha.,.alpha.'-bis derivatives.
DESCRIPTION OF THE INVENTION
The invention is based on the recognition that 1,3-bis(thiocyanato)acetone of the formula (II). ##STR3## 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 another aspect of the invention, there is provided a process for the preparation of new compounds of the formula (I), ##STR4## wherein X is a --CN, --CONH.sub.2, --CO.sub.2 H or --CO.sub.2 R group, wherein R is a C.sub.1-5 alkyl group; and R, n is other than 0, transforming the resulting compound of the formula (Ia), ##STR5## to the carbamoyl derivative of the formula (Ib), ##STR6## preparing therefrom by alkaline hydrolysis and S-alkylation, a compound of the 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.
According to the process of the invention, the compound of the formula (II) is transformed to the compound of formula (Ia) or (Ib) depending on the strength of the reaction of (II) with methanol containing hydrogen chloride. The compound of the formula (Ib) is S-decarbamoylated by alkali in an aqueous alkanolic 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 the starting substance is known [Acta Univ. Voronegiensis 9, 167 (1937)]; it was prepared by reacting 1,3-dichloroacetone with potassium rhodanide in an aqueous-alcoholic medium.
The compound of the formula (Ia), chemically 4-thiocyanatomethyl-2(3H)-thiazolone proved to posses outstanding effects: it showed an oral ED.sub.50 value of 0.7 mg/kg in the acidic alcohol test [A. Robert: Gastroenterology 77, 761 (1979)]; and it inhibited gastric acid secretion with even a higher oral ED.sub.50 value of 40 mg/kg in the Shay test [Shay: Gastroenterology 5, 43 (1945)].
4-Carbamoylthiomethyl-2(3H)-thiazolone, 4-(2-cyanoethyl)thiomethyl-2(3H)-thiazolone and 4-carbamoylmethylthiomethyl-2(3H)-thiazolone 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.
SPECIFIC EXAMPLES
The invention is illustrated in detail by the following non-limiting Examples.
EXAMPLE 1
Preparation of 4-thiocyanatomethyl-2(3H)-thiazolone [compound of the
formula (Ia)]
(a) 17.22 g (0.10 mol) of 1,3-bis(thiocyanato)acetone (m.p.: 94.degree.-96.degree. C.) are added to the stirred solution of 10 g of potassium hydrogen carbonate in
REFERENCES:
patent: 4762849 (1988-08-01), Grisar
March, Advanced Organic Chemistry pp. 788-789 (1985).
Ganapathi, Proc. Ind. Acad Sci 22A 362(1945) Abstract.
Bod Peter
Ezer Elemer
Fekecs Eva
Hajos Gyorgy
Harsanyi Kalman
Dubno Herbert
Gerstl Robert
Myers Jonathan
Richter Gedeon Vegyeszeti Gyar Rt.
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