GB1101149A - Benzimidazoles and process for their preparation - Google Patents

Abstract

Novel benzimidazoles of the formula <FORM:1101149/C2/1> (wherein Ph is 1,2-phenylene which may be alkyl, etherified hydroxy, alkylenedioxy, halogen, CF3, NO2, NH2, dialkylamino, alkanoyl, benzoyl, toluoyl, pyridoyl or sulphamoyl substituted; R is an aliphatic, araliphatic, aryl or heterocyclic aryl group; A is an alkylene group and Am is a primary, secondary or tertiary amino group), N-oxides thereof, and acid-addition salts and quaternary ammonium derivatives of these compounds are prepared (1) from the free N-hydroxy-benzimidazoles and reactive esters of the compounds Am-A-OH; (2) from the N-(O-A-X) benzimidazoles in which X is a reactively esterified hydroxy group and the compounds H-Am; and (3) by reduction with a light metal hydride of the N-(O-Ac-Am) benzimidazoles in which Ac is alkanoylene. Products may be interconverted, e.g. substituents may be introduced into or removed from an amino group, and amino groups and their N-oxides may be interconverted. 1 - Hydoxy - 2 - R - benzimidazole starting materials are prepared (1) by reacting a compound of the formula NO2-Ph-NHCH2R with a strong base; (2) by reducing a compound of the formula NO2-Ph-NH-COR with an alkaline sodium dithionite solution; and (3) for N-oxides, by adding a compound R-NO to a compound H-Ph-CN-->O. The products, with halogeno-hydrins, give 1-hydroxy - alkyl - 2 - R - benzimidazoles which may be converted to reactive esters, e.g. 1-haloalkyl -2-R-benzimidazoles. N - (4-Chlorobenzyl) - 2 - nitro - aniline is prepared from 2-chloro-nitrobenzene and 4-chloro - benzylamine. N - benzyl - 4 - chloro-2 - nitro - aniline; and N - benzyl - 5 - chloro-2 -nitro-aniline are prepared similarly. (2 - Phenyl - 1 - benzimidazolyl) - oxy - acetylamide and -N-ethylamide and -N,N-dimethylamide are prepared by reacting 1-hydroxy-2-phenyl -benzimidazole with ethyl bromacetate to give the N-ethoxycarbonylmethoxy derivative, hydrolysing this to the free acid, converting this to the acid chloride, and reacting this with ammonia or ethylamine or dimethylamine. The benzimidazoles of the invention, which are stated to be useful as c.n.s. depressants, skeletal muscle relaxants and tranquillizers, may be made up into pharmaceutical and veterinary compositions for parenteral or enteral administration or as feedstuffs with suitable carriers and additives.