Imidazolyl-alkenoic acids

Claim 1

A process for preparing a compound of the formula (I): in which: R¹ is phenyl, biphenyl, naphthyl, or adamantylmethyl, which are unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C₁-C₄alkyl, nitro, CO₂R⁷, tetrazol-5-yl, C₁-C₄alkoxy, hydroxy, SC₁-C₄alkyl, SO₂NHR⁷, NHSO₂R⁷, SO₃H, CONR⁷R⁷, CN, SO₂C₁-C₄alkyl, or C n F 2n+1 , wherein n is 1-3; R² is C₂-C₁₀alkyl, C₃-C₁₀alkenyl, C₃-C₁₀alkynyl, C₃-C₆cycloalkyl, or (CH₂)₀₋₈phenyl unsubstituted or substituted by one to three substituents selected from C₁-C₄alkyl, nitro, Cl, Br, F, I, hydroxy, C₁-C₄alkoxy, NR⁷R⁷, CO₂R⁷, CN, or CONR⁷R⁷; X is a single bond, S, or O; R³ is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, COOR⁷, CONR⁷R⁷, NO₂, or C n F 2n+1 where n is 1-3; R⁴ and R⁵ are independently hydrogen, C₁-C₆alkyl, thienyl-Y-, pyrazolyl-Y-, imidazolyl-Y-, thiazolyl-Y-, furyl-Y-, pyrrolyl-Y-, triazolyl-Y-, oxazolyl-Y-, isoxazolyl-Y, pyridyl-Y-, or tetrazolyl-Y-, except that R⁴ and R⁵ are not both selected from hydrogen and C₁-C₆alkyl and each heterocyclic ring is unsubstituted or substituted by C₁-C₄alkyl, C₁-C₄alkoxy, Cl, Br, F, I, NR⁷R⁷, CO₂R⁷, SO₂NHR⁷, SO₃H, or CONR⁷R⁷; Y is a single bond, S, O, or C₁-C₆alkyl which is straight or branched or optionally substituted by phenyl or benzyl, wherein each of the aryl groups is unsubstituted or substituted by halo, NO₂, CF₃, C₁-C₄alkyl, C₁-C₄alkoxy, CN, or CO₂R⁷; R⁶ is -Z-COOR⁸ or -Z-CONR⁷R⁷; Z is a single bond, vinyl, -CH₂-O-CH₂-, methylene optionally substituted by C₁-C₄alkyl, one or two benzyl groups, thienylmethyl, or furylmethyl, or -C(O)NHCHR⁹-, wherein R⁹ is H, C₁-C₄alkyl, phenyl, benzyl thienylmethyl, or furylmethyl; each R⁷ independently is hydrogen, C₁-C₄alkyl, or (CH₂) m phenyl, wherein m is 0-4; and R⁸ is hydrogen, C₁-C₆alkyl, or 2-di(C₁-C₄alkyl)­amino-2-oxoethyl; or a pharmaceutically acceptable salt thereof, which process comprises: a) reacting a compound of the formula (II): wherein R², R³, and X are as defined in claim 1, and R¹′ is R¹ as defined in claim 1, except that the substituents on the R¹′ do not include tetrazol-5-yl, OH, or CO₂H, with (C₁-C₄alkoxy)₂-­P(O)CH(R⁵)COOC₁-C₆alkyl, wherein R⁵ is as defined in claim 1, in the presence of a base; or b) reacting a compound of the formula (III): wherein R², R³, R⁴, R⁵, and X are as defined in claim 1, with a compound of the formula (IV): wherein W is Cl, Br, F, I, C₁-C₄alkyl, nitro, CO₂C₁-C₄alkyl, C₁-C₄alkoxy, SC₁-C₄alkyl, CN, SO₂C₁-C₄alkyl, SO₂NHR⁷, NHSO₂C₁-C₄alkyl, or C n F 2n+1 , n is 1-3, p is 0-3, and R⁷ is hydrogen, C₁-C₄alkyl, or (CH₂)₀₋₄phenyl; or c) reacting a compound of the formula (II) as hereinbefore defined with a compound of the formula (V): wherein R⁵ is as defined in claim 1, in the presence of a base; or d) reacting a compound of the formula (VI): wherein R², R³, R⁵, and X are as defined in claim 1, R¹′ is R¹ as defined in claim 1, except that the substituents on the R¹′ group do not include tetrazol-5-yl, OH, or CO₂H and R¹¹ is COCH₃ or SO₂CH₃, with a base; or e) reacting a compound of the formula (II) as hereinbefore defined with an appropriate heterocyclic acetic acid in acetic anhydride in the presence of a base; and thereafter: (i) for formula (I) compounds in which Z is -CH₂-O-CH₂-, reducing the formula (I) ester hereinbefore prepared, followed by reaction with a C₁-C₆alkyl haloacetate or; (ii) for formula (I) compounds in which Z is -C(O)NHCHR⁹- wherein R⁹ is H, C₁-C₄ alkyl, phenyl, benzyl, thienylmethyl, or furylmethyl, hydrolyzing the formula (I) ester compounds hereinbefore prepared, followed by reaction with an appropriately substituted amino acid, in the presence of an amide-forming reagent; or (iii) for formula (I) compounds in which Z is a methylene group, reducing the formula (I) ester compounds hereinbefore prepared, followed by reaction with a C₁-C₆alkyl chloroformate and then reaction with carbon monoxide in the presence of a phosphine ligand; or (iv) for formula (I) compounds in which Z is a methylene group substituted by C₁-C₄alkyl, benzyl, thienylmethyl, or furylmethyl, reacting the formula (I) ester compounds wherein Z is a methylene group prepared above with a lithium dialkylamide followed by reaction with an alkylating agent; and thereafter where necessary: (i) for formula (I) compounds in which the R¹ group is substituted by hydroxy, deprotecting the formula (I) compounds in which the R¹ group is substituted by C₁-C₄alkoxy; or (ii) for formula (I) compounds in which the R¹ group is substituted by carboxy, hydrolyzing the formula (I) compounds in which the R¹ group is substituted by CO₂C₁₋₄alkyl; or (iii) for formula (I) compounds in which R¹ group is substituted by a tetrazol-5-yl group, treating the formula (I) compound in which the R¹ group is substituted by carboxy, with a halogenating agent, followed by conversion to the priary amide in a reaction with ammonia, dehydration with oxalylchloride/dimethylformamide and reaction with azide; or (iv) for formula (I) compounds in which R⁶ is -Z-COOH, hydrolyzing the formula (I) compounds in which R⁶ is -Z-COOC₁-C₆alkyl; or (v) for formula (I) compounds in which R⁶ is -Z-CONR⁷R⁷ wherein R⁷ is hydrogen, C₁-C₄alkyl, or (CH₂)₀₋₄phenyl, treating the formula (I) compounds in which R⁶ is -Z-COOH with a halogenating agent, followed by reaction with an appropriately substituted amine; and thereafter optionally forming a pharmaceutically acceptable salt.