Imidazole derivatives and salts thereof, their synthesis, and pharmaceutical formulations

Claim 1

A pharmaceutical formulation which comprises an imidazole of formula (IA) wherein (i) A is a straight or branched alkylene or alkepylene group having 1,2, 3 or 4 carbon, atoms, and R is a naphthyl, tetrahydronaphthyl, heterocyclyl, arylthio, arylalkylthio, aryloxy, arylalkyloxy, arylhydroxymethylene, arylcarbonyl, arylalkylcarbonyl, alkyloxy, alkylthio group or a cycloalkyl or cycloalkenyl group of from 4 to 9 carbon atoms suhstituted by a group other than a hydrocarbon group, (ii) A is an -SO 2 - group, and R is an aryl or heterocyclyl group, (iii) A is a chemical bond and R is a heterocyclyl or suhstituted phenyl group, or (iv) A is a straight or branched alkylene group having 1, 2 or 3 carbon atoms and R is a halo-substituted phenyl group; or a pharmaceutically acceptable acid addition salt of such an imidazole, and a pharmaceutically acceptable carrier for the imidazole or salt thereof.

Claim 11

A method of preparing a pharmaceutical formulation according to any one of claims 1 to 9 which comprises admixing the imidazole or its salts with the pharmaceutically acceptable carrier.

Claim 18

A method of preparing a 1-substituted imidazole of formula (I) as defined in any of claims 11 to 15 or an acid addition salt thereof characterised in that one (a) reacts imidazole or a salt thereof with an agent of the formula Z-A-R wherein A and R are defined in formula (I) and Z is a leaving group; (b) converts a substituted imidazole of the formula: wherein A and R are as defined in formula (I) and Q 1 , Q 2 and Q 3 etc. are the same or different, at least one being a radical capable of removal by reduction or oxidation, the other being a radical having the same or other removable function or is hydrogen, with the proviso that when R is, or includes, aryl or aromatic heterocyclyl, the removable groups Q etc may be, or may also be, on aryl or heterocyclyl ring(s) in R; (c) decarboxylates a carboxyimidazole derivative of the formula: wherein A and R are as defined in formula (I), one of R 1 , R 2 and R 4 is carboxyl or a derivative thereof, and the other is hydrogen, carboxyl or a derivative thereof with the proviso that, when R is, or includes, aryl or aromatic heterocyclyl, the removable groups R 1 , R 2 etc. may be, or may also be, on the aryl or heterocyclyl ring(s); (d) converts a precursor of the formula: wherein N is 1-imidazoline, 1-imidazole or 1-pyrazole, A is a straight or branched saturated or unsaturated acyclic hydrocarbon radical which may include a keto group and R 3 is as defined in formula (I), or provided that at least one of N, A and R 3 is other than 1-imidazole, a saturated acyclic hydrocarbon group and R of the product of formula (I); (e) alkylates or acylates a compound of formula (X): wherein A is as defined for formula (I) and R a is an aryl or aromatic heterocyclyl R(R being as defined for formula (I)) with a compound of formula QZ 1 wherein Q is an alkyl or acyl group and Z 1 is a leaving group; (f) cyclises a compound of formula (XI): wherein A and R are as defined for formula (I) and X 2 is a leaving group; (g) reacts a compound of formula (XII): wherein A and R are as defined for formula (I) with a compound of formula (XIII): wherein either of X 3 and Y 3 is a leaving group and the other is hydrogen, or X 3 and Y 3 are both halo or, together with the CH group to which they are attached form an aldehyde group or an acetal derivative thereof, and X 4 and Y 4 are as defined for X 3 and y3 , being the same as or different from X 3 and Y 3 ; or (h) reduces an amino salt of formula (XIIIa): wherein R is defined as for formula (I), X is an anion, A 2 is a chemical bond or a straight or branching, saturated or unsaturated acyclic hydrocarbon radical, which may include a keto group, A3 is hydrogen or a saturated or unsaturated acyclic hydrocarbon radical, which may include a keto group, with the proviso that A 2 and A3 together contain no more than 3 carbon atoms; (i) reacts a compound in which R as defined for formula (I) is replaced by a cycloalkenyl or cycloalkynyl group containing one or more carbon to carbon double or triple bonds with an electrophilic reagent capable of adding across the double or triple bond(s) so as to provide the substituents in the cycloalkyl or cycloalkenyl ring of the compound of formula (I); (j) when R is heterocyclyl reacts imidazole with an aldehyde and a heterocyclyl compound containing an -NH-group in the heterocyclyl ring(s). (k) reacts imidazole with a Mannich base which may be prepared from (i) an aldehyde A 4 C HO, wherein A4 is hydrogen or contains less carbon atom than A as defined for formula (I), (ii) a heterocyclyl compound RH, R being a heterocyclyl group as defined for formula (I) to which the hydrogen atom is attached to form a ring -NH-group and (iii) a cyclic or acyclic secondary amine or (1) reacts a heterocyclyl compound RH, R being a heterocyclyl group as defined for formula (I) to which the hydrogen atom is attached to form a ring -NH-group, with a Mannich base which may be prepared from (i) an aldehyde A 4 CHO, wherein A 4 is hydrogen or contains 1 less carbon atom than A as defined for formula (I) , (ii) imidazole and (iii) a cyclic or acyclic secondary amine (other than RH).