Patent CS-195292-B2 (CS)
Title: Method of producing novel derivatives of pyridazine
Inventor: AUSTEL VOLKHARD
IPC: C07D235/04
Filed: 1975-06-05
Abstract: 1466547 5(6) - Pyridazin - 6 - yl - benzimidazole derivatives DR KARL THOMAE GmbH 23 May 1975 [10 June 1974 12 April 1975] 22834/75 Heading C2C Novel compounds of the Formula I wherein R 1  is hydrogen, trifluoromethyl, C 1-5  alkyl, mercapto or alkylmercapto, or phenyl optionally substituted by one fluorine, methyl, hydroxy, methylmercapto, methylsulphinyl, methylsulphonyl or dimethylamino radical or by one to three methoxy groups; either A is hydrogen and B is hydrogen or C 1-3  alkyl or A and B together represent a C-C bond; and either R 2  is hydrogen or C 1-3  alkyl and R 3  and R together are oxo, or R 3  is chlorine, methylamino, morpholino or 4-methylpiperazino and R 2  and R together represent a C-N-bond; and tautomers and acid addition salts thereof, may be prepared (1) when R 3  and R together represent oxo, (a) reacting a compound of the Formula II with a compound R 1 COOH or a functional derivative, thereof, (b) cyclizing a compound of the Formula IV wherein one of X and Y is R 1 CO and the other is hydrogen, (c) reacting a compound of the Formula V or an ester thereof with a compound NH 2 NHR 2 ; (2) when R 3  is chlorine and R 2  and R together are a C-N bond, heating a compound of the Formula I wherein R 2  is hydrogen and R 3  and R together are oxo with phosphorus pentachloride, phosphorus oxychloride or thionyl chloride; (3) when R 3  is methylamino, morpholino, or 4-methylpiperazino and R 2  and R together are a C-N bond, heating the product of process (2) with an appropriate amine; (4) effecting the reverse of process (2) by hydrolysis; (5) when A and B together are a C-C bond; dehydrogenating a compound I in which A and B each represent hydrogen; (6) when R 1  is a phenyl substituted by methylsulphinyl or methylsulphonyl, oxidizing the corresponding methylmercaptophenyl substituent; (7) when R 1  is a phenyl substituted by a methoxy, methylating the corresponding hydroxyphenyl substituent; (8) when R 1  is alkylmercapto, alkylating the corresponding mercapto group and optionally forming acid addition salts thereof. Intermediates of the Formulae IV are prepared by reduction of a nitro group to an amino group, wherein the starting material is formed by a cyclization process similar to 1(c) to form the pyridazine ring or acylation of an amine. Intermediates of the Formula II are also prepared by reduction of a nitro group to an amino group. Intermediates of the Formula V are prepared by a process corresponding to (1)(b) above to form the benzimidazole ring, wherein the starting material is formed by reduction of the corresponding nitro compound to the amino starting material, 2 - (4 - Methylmercaptophenyl) - 5(6) - (3- methoxy carbonylpropanoyl) - benzimidazole hydrochloride is prepared by reducing 6-[3- nitro - 4 - (4 - methyl mercaptobenzoylamino)- phenyl] - 4,5 - dihydro - 2H - pyridazin - 3 - one to 6 - [3 - amino - 4 - (4 - methyl mercaptobenzoylamino) - phenyl] - 4,5 - dihydro - 2H- pyridazin - 3 - one followed by treatment with methanol. Pharmaceutical compositions of the compounds I with the usual excipients show hypotensive, antithrombotic and cardiotonic activity when administered orally, parenterally or rectally.