1-OXYBENZIMIDAZOLES

摘要

1322117 Benzimidazole derivatives MERCK & CO Inc 19 April 1971 [27 Feb 1970] 22284/71 Headings C2C and C2P Novel benzimidazole derivatives have the general formula in which R is an aryl or orthohaloaryl radical or a heteroaromatic radical in which the heteroatoms are nitrogen, oxygen and/or sulphur and do not exceed three in number; each of R 5 and R 6 is a hydrogen or halogen atom, an alkyl, alkoxy, alkylthio, phenoxy, phenylthio, phenyl, halophenyl, amino, alkylamino or dialkylamino radical or a heteroaromatic radical in which the heteroatoms are nitrogen, oxygen and/or sulphur and do not exceed three in number provided that when R 5 and R 6 are other than halogen at least one of R 6 and R 6 is hydrogen; and R 1 is phosphonoalkoxy or an alkyl ester thereof, phosphato-alkoxy or an alkyl ester thereof, alkylthioalkoxy or a sulphoxide or sulphone derivative thereof, sulphoalkoxy, C-amidinoalkoxy or an N 1 - and/or N 2 -alkyl derivative thereof, N-amidinoalkoxy in which the amidino residue is derived from a (C 1 -C 8 ) alkanoic acid or an N-alkyl derivative thereof, biguanidoalkoxy, guanidinoalkoxy or an N 1 , N 2 and/or N 3 alkyl derivative thereof, aminoguanidinoalkoxy or an N1, N 1 , N 2 and/or N 3 alkyl derivative thereof, imidazolylaminoalkoxy or a 1-alkyl derivative thereof, 1,4,5,6 - tetrahydropyrimidinylaminoalkoxy or a 1 - alkyl derivative thereof, thiazolinylaminoalkoxy, thiazinylaminoalkoxy, imidazolinoalkoxy or a 1-alkyl derivative thereof, 1,4,5,6-tetrahydropyrimidinoalkoxy or a 1-alkyl derivative thereof, alkanoyloxy, α-aminocarboxyalkoxy, glycosyloxy, p-alkylphenacyloxy or p-alkoxyphenacyloxy; and alkali metal, alkaline earth metal and pharmaceutically acceptable amine salts thereof when R 1 is sulphoalkoxy phosphonoalkoxy, phosphatoalkoxy or α-aminocarboxyalkoxy; and salts thereof with pharmaceutically acceptable acids when R 1 is C-amidinoalkoxy, N - amidinoalkoxy, biguanidoalkoxy, guanidinoalkoxy, aminoguanidinoalkoxy, imidazolinylaminoalkoxy, tetrahydropyrimidinylaminoalkoxy, thiazolinylaminoalkoxy, thiazinylaminoalkoxy, imidazolinoalkoxy, tetrahydropyrimidinoalkoxy or α-aminocarboxyalkoxy, and all the alkyl, alkoxy and alkanoyloxy residues mentioned in the foregoing definitions of R 1 , R 5 and R 6 are straight or branched-chain alkyl, alkoxy and alkanoyloxy residues containing from 1 to 8 carbon atoms. Compounds in which R 1 is phosphonoalkoxy or an alkyl ester thereof, alkylthioalkoxy, sulphoalkoxy, guanidinoalkoxy, imidazolinoalkoxy or a 1-alkyl derivative thereof, 1,4,5,6-tetrahydropyrimidinoalkoxy or a 1-alkyl derivative thereof, alkanoyloxy, α-aminocarboxyalkoxy, glycosyloxy, palkylphenacyloxy or p-alkoxyphenacyloxy, are prepared by reacting a 1-hydroxy benzimidazole of the formula in which R, R 5 and R 6 are as defined above in the presence of a base with a haloalkylphosphonic acid, an alkylester of a haloalkylphosphonic acid, a haloalkylsulphonic acid, an alkylthioalkyl halide, an imidazolinoalkyl halide, a 1-alkylimidazolinoalkyl halide, a 1,4,5,6-tetrahydropyrimidinoalkyl halide, a 1-alkyl-1,4,5,6- tetrahydropyrimidinoalkyl halide, an alkanoic acid halide, an α-aminocarboxyalkyl halide, a glycosyl halide, an α-halo-p-alkoxy acetophenone or an α-halo-p-alkylacetophenone. Compounds in which R 1 is imidazolylaminoalkoxy or a 1-alkyl derivative thereof, 1,4,5,6- tetrahydropyrimidinylaminoalkoxy or a 1-alkyl derivative thereof, thiazolinylaminoalkoxy, thiazinylaminoalkoxy or guanidino alkoxy, are prepared by reacting a compound of the formula in which R, R 5 and R 6 are as defined above and R 2 is alkylene with a compound of the formula: in which R 3 is 2-imidazolino, 1-alkyl-2-imidazolino, 2-(1,4,5,6-tetrahydropyrimidino), 1-alkyl- 2 - (1,4,5,6 - tetrahydropyrimidino), 2 - thiazolino, 2-thiazino or amidino. Compounds in which R 1 is biguanidoalkoxy are prepared by reacting a compound of the Formula II shown above, in which R 2 is alkylene, with dicyandiamide in an aqueous acidic solvent. Compounds in which R 1 is aminoguanidinoalkoxy are prepared by reacting a compound of the Formula II shown above in which R, R 5 and R 6 are as defined above and R 2 is alkylene, with nitroguanidine to produce the corresponding 1-nitroguanidinoalkoxybenzimidazole and reducing the nitro group catalytically. Compounds in which R 1 is a radical of formula where R 2 , R 7 , R 8 and R 9 are as defined above, are prepared by reacting an imino ether of the formula in which R, R 5 and R 6 are as defined above, R 7 is hydrogen or alkyl, R 2 is alkylene and R 10 is alkyl, in the presence of a catalytic quantity of hydrochloric acid with a compound of the formula: in which each of R 8 and R 9 is hydrogen or alkyl. Compounds in which R 1 is a radical of the formula wherein R 2 , R 11 and R 12 are as defined above, are prepared by reacting a compound of the formula in which R, R 5 and R 6 are as defined above, R 2 is alkylene and R 11 is hydrogen or alkyl, with an alkyl imino ester hydrochloride of the formula in which R 12 is hydrogen or alkyl and R 13 is alkyl. Compounds in which R 1 is a radical of the formula wherein R 2 and R 15 are as defined above, are prepared by reacting an imino ester hydrochloride of the formula in which R, R 5 and R 6 are as defined above and R 2 is alkylene with a compound of the formula in which each of R 14 and R 15 is hydrogen or alkyl. Compounds in which R 1 is phosphatoalkoxy are prepared by reacting a compound of the formula in which R, R 5 and R 6 are as defined above and R 2 is lower alkylene, with orthophosphoric acid in the presence of phosphoric acid anhydride. The novel compounds possess anthelmintic and anti-fungal properties.