Benzimidazole derivatives

Claim 1

A process for the manufacture of a benzimidazole derivative of the formula I wherein R¹ is (1-8C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-4C)alkyl, phenyl or phenyl(1-4C)alkyl; R² is hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano or nitro; R³ and R⁴ are independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro; X is phenylene optionally bearing a substituent selected from (1-4C)alkyl, (1-4C)alkoxy and halogeno, or X is a direct bond between the adjacent phenyl and methylene moieties; and Z is 1 H -tetrazol-5-yl or a group of the formula -CO.OR⁵ or -CO.NH.SO₂.R⁶ in which R⁵ is hydrogen or a non-toxic, biodegradable residue of a physiologically acceptable alcohol or phenol, and R6 is (1-6C)alkyl, (3-8C)cycloalkyl or phenyl; and wherein any of said phenyl moieties may be unsubstituted or bear one or two substituents independently selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, cyano and trifluoromethyl; or a physiologically acceptable salt thereof except when R5 is other than hydrogen; which is characterised in that:- (a) for those compounds in which Z is carboxy, a carboxylic derivative of the formula II in which Q is a protected carboxy group selected from (1-6C)alkoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl and carbamoyl, is converted to carboxy; (b) for those compounds of formula I wherein Z is tetrazolyl, a compound of the formula III in which L is a suitable protecting group affixed to a nitrogen of the tetrazolyl moiety, is deprotected; (c) for those compounds of formula I wherein Z is a group of the formula -CO.OR⁵, a benzimidazole of the formula IV is reacted with a compound of the formula V wherein Hal. stands for a suitable leaving group; or (d) a 1,2-diamino derivative of the formula VII is reacted with a carboxylic acid of the formula R¹.CO₂H or a (1-4C)alkyl orthoester thereof; whereafter, when a compound of the formula I is required wherein Z is a group of the formula -CO.NH.SO₂R⁶ or a group of the formula -CO.OR⁵ in which R⁵ is other than hydrogen, a carboxylic acid of the formula I in which Z is carboxy (or a reactive derivative of said acid) is reacted with a sulphonamide of the formula NH₂.SO₂R⁶ or a hydroxy compound of the formula HO.R⁵ , or with a salt thereof; whereafter, when a salt of a compound of formula I is required, it is obtained by reaction with the appropriate base affording a physiologically acceptable ion, or by any other conventional salt formation procedure; and when an optically active form of a compound of formula I is required, one of the processes (a)-(d) is carried out using an optically active starting material, or the racemic form of a compound of formula I in which Z is an acidic group is resolved by reaction with an optically active form of a suitable organic base, followed by conventional separation of the diastereoisomeric mixture of salts thus obtained, and liberation of the required optically active form of said compound of formula I by conventional treatment with acid; and wherein R¹, R², R³, R⁴, X and Z have any of the meanings defined above unless otherwise stated.