Substituted imidazole derivatives and their preparation and use

Claim 2

A process for the preparation of therapeutically active imidazole derivatives of the formula:

Claim 3

wherein each of R 1 , R 2 and R3, which can be the same or different, is hydrogen, chloro, bromo, fluro, methyl, ethyl, methoxy, amino, hydroxy or nitro; R 4 is hydrogen or an alkyl radical of 1 to 7 carbon atoms; R 5 is hydrogen or a straight or branched alkyl group of 1 to 5 carbon atoms or a phenyl group; R 6 is hydrogen or an alkyl group of 1 to 7 carbon atoms or a substituted or unsubstituted benzyl; X is -CH 2 -, -CHOH- or -CH=CH-; and n is 0-4, provided that R 5 and R 6 are simultaneously hydrogen only when n is 4 and X is -CH=CH-; when n is 0, X is -CH 2 - and R 1 , R 2 , R 3 and R 6 are all hydrogen, and R 4 is hydrogen or ethyl, then R 5 is other than methyl or phenyl;when n is 0, X is CHOH, and R 1 ,R 2 ,R 3 and R4 are all hydrogen, both of R 5 and R 6 are other than methyl; and when n is 2, X is CHOH, R 1 ,R 2 ,R 4 and R 5 are all hydrogen, and R 6 is methyl, then R 3 is other than 2-amino, and its non-toxic pharmaceutically acceptable acid addition salts, which comprises a) reacting an imidazole aldehyde of the formula or wherein R 4 , R 5 and R 6 are as defined above, with an arylalkylmagnesiumhalide of the formula wherein R 1 , R 2 and R 3 are as defined above and Hal is a halogen atom to give a compound of formula (I) wherein X is -CHOH-. b) reducing a compound of the formula: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and n are as defined above to give a compound of formula (I) wherein X is -CHOH-. c) hydrogenating a compound of the formula wherein R 1 , R 2 ,.R 3 , R 4 , R 5 and R 6 are as defined above and n is 0 to 3 to give a compound of formula (I) wherein X is -CH 2 -. d) hydrolysing a compound of the formula wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and n are as defined above to give a compound of formula (I) wherein X is -CH 2 - . e) hydrogenating a compound of the formula or wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and n are as defined above, and R 7 is an alkyl or an aryl group to give a compound of formula (I) wherein X is -CH 2 -. f) reacting a starting material of the formula wherein R 1 , R 2 , R 3 and n are as before; wherein Rg, R 10 , R 11 and R 12 , which can be the same or different, are each hydrogen, an alkyl of 1 to 7 carbon atoms, hydroxy, halogen, amino, -0-alkyl containing 1 to 7 carbon atoms or (wherein R 6 is as before); or wherein R 12 and R 10 can be combined to form a keto group, or R 9 and R 11 can be combined to form a keto group, or both R 12 and R 10 and R 9 and R 11 can simultaneously form keto groups; with a reagent capable of converting the said starting material to the corresponding imidazole to give a compound of formula (I) wherein X is -CH 2 - and R 4 is hydrogen reacting a starting material of the formula: wherein n is as before and the alkyl groups contain 1 to 7 carbon atoms each and R 1 , R 2 and R 3 are as defined in claim 1, with Wherein R 5 is as above to form the corresponding imidazole to give a compound of formula (I) wherein X is -CH 2 - and R 4 is hydrogen. reacting a N-trialkylsilylimidazole of the formula wherein R 4 and R 5 are as defined above and Y is an alkyl group, preferably methyl, with an arylalkylhalogenide of the formula wherein R 1 , R 2 , R3 and n are as before and Hal is a halogen atom, in the presence of a Lewis acid to give a compound of formula (I) wherein X is -CH 2 -. dehydration of a compound of the formula: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are as defined above and n is 1-5 to give a compound of formula (I) wherein X is -CH=CH-. comprises reacting an imidazole aldehyde of the formula wherein R 4 , R 5 and R 6 are the same as before, with an aralkylidene- triphenyl phosporane of the formula wherein R 1 , R 2 and R 3 are the same as before and n is 0-4 to give a compound of formula (I) wherein X is -CH=CH-. k ) hydrogenation of the benzyl group R 8 -CH 2 of a starting material of the formula wherein R 1 , R 2 , R 3 , R 4 , R 5 and n are as defined above and R 8 is a substituted or an uhsubstituted phenyl group to give a compound of formula (I) wherein X is -CH 2 - or CHOH-. 1) alkylation of a compound of the formula wherein R 1 , R 2 , R 3 , R 4 , R 5 , X and n are as defined above with a compound of the formula R 6 -Hal or wherein R 6 is defined as in claim 1, Hal is a halogen atom and R is for example p-tolyl to give a compound of formula (I) wherein R 6 is an alkyl of 1 to 7 carbon atoms or benzyl. m) reacting a compound of the formula wherein R 4 is as defined above with a primary amine of the formula R 6 NH 2 and an aldehyde of the formula or with an imine of the formula wherein R 1 , R 2 , R 3 , R 6 and n are as defined above to give a compound of formula (I) wherein R 6 is an alkyl group of 1 to 7 carbon atoms or a substituted or unsubstituted benzyl, R 5 is hydrogen and X is -CH 2 -.