Claims for Patent: 5,185,351

Summary for Patent: 5,185,351

Title:	Imidazolyl-alkenoic acids useful as angiotensin II receptor antagonists
Abstract:	Angiotensin II receptor antagonists having the formula: ##STR1## which are useful in regulating hypertension and in the treatment of congestive heart failure, renal failure, and glaucoma, pharmaceutical compositions including these antagonists, and methods of using these compounds to produce angiotensin II receptor antagonism in mammals.
Inventor(s):	Joseph A. Finkelstein, Richard M. Keenan, Joseph Weinstock
Assignee:	SmithKline Beecham Corp
Application Number:	US07/746,262
Patent Claims:	1. A compound of the formula: ##STR26## in which: R1 is adamantyl, phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C1 -C6 alkyl, nitro, A--CO2 R7, tetrazol-5-yl, C1 -C6 alkoxy, hydroxy, SC1 -C6 alkyl, SO2 NHR7, NHSO2 R7, SO3 H, CONR7 R7, CN, SO2 C1 -C6 alkyl, NHSO2 R7, PO(OR7)2, NR7 R7, NR7 COH, NR7 COC1 -C6 -alkyl, NR7 CON(R7)2, NR7 COW, W, SO2 W;m is 0-4; R2 is C2 -C10 alkyl, C3 -C10 alkenyl, C3 -C10 alkynyl, C3 -C6 cycloalkyl, or (CH2)0-8 phenyl unsubstituted or substituted by one to three substituents selected from C1 -C6 alkyl, nitro, Cl, Br, F, I, hydroxy, C1 -C6 alkoxy, NR7 R7, CO2 R7, CN, CONR7 R7, W, tetrazol-5-yl, NR7 COC1 -C6 alkyl, NR7 COW, SC1 -C6 alkyl, SO2 W, or SO2 C1 -C6 alkyl; X is a single bond, S, NR7, or O; R3 is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, COOR7, CONR7 R7, NO2, W, CN, NR7 R7, or phenyl; R4 and R5 are independently hydrogen, C1 -C6 alkyl, thienyl--Y--, furyl--Y--, pyrazolyl--Y--, imidazolyl--Y--, pyrrolyl--Y--, triazolyl--Y--, oxazolyl--Y--, isoxazolyl--Y--, thiazolyl--Y--, pyridyl--Y--, or tetrazolyl--Y--, except that R4 and R5 are not both selected from hydrogen and C1 -C6 alkyl and each heterocyclic ring is unsubstituted or substituted by C1 -C6 alkyl, C1 -C6 alkoxy, Cl, Br, F, I, NR7 R7, CO2 R7, SO2 NHR7, SO3 H, or CONR7 R7, OH, NO2, W, SO2 W, SC1 -C6 alkyl, SO2 C1 -C6 alkyl, NR7 COH, NR7 COW, or NR7 COC1 -C6 alkyl; Y is a single bond, O, S, or C1 -C6 alkyl 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 -C6 alkyl, C1 -C6 alkoxy, CN, or CO2 R7 ; R6 is --Z--COOR8 or --Z--CONR7 R7 ; Z is a single bond, vinyl, --CH2 --O--CH2 --, methylene optionally substituted by C1 -C6 alkyl, one or two benzyl groups, thienylmethyl, or furylmethyl, or --C(O)NHCHR9 --, wherein R9 is H, C1 -C6 alkyl, phenyl, benzyl, thienylmethyl, or furylmethyl; W is Cn F2n+1, wherein n is 1-3; A is --(CH2)m --, --CH═CH--, --O(CH2)n --, or --S(CH2)n --; each R7 independently is hydrogen, C1 -C6 alkyl, or (CH2)m phenyl; and R8 is hydrogen, C1 -C6 alkyl, or 2-di(C1 -C6 alkyl)-amino-2-oxoethyl; or a pharmaceutically acceptable salt thereof. 2. A compound of claim 1 in which one of R4 and R5 is hydrogen or C1 -C4 alkyl. 3. A compound of claim 2 in which R1 is phenyl or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from chloro, fluoro, trifluoromethyl, nitro, methyl, methoxy, hydroxy, sulfamyl, cyano, carboxy, --(CH2)1-2 carboxy, --CH═CH--carboxy, --OCH2 -carboxy, carboC1 -C6 alkoxy, carbamoyl, or tetrazol-5-yl, and m is 0-2. 4. A compound of claim 3 in which X is a single bond or S and R2 is C2 -C8 alkyl. 5. A compound of claim 4 in which R3 is hydrogen, chloro, fluoro, or trifluoromethyl and R4 is hydrogen or C1 -C4 alkyl. 6. A compound of claim 5 in which R6 is COOH, COOC1-2 alkyl or CONH2. 7. A compound of claim 6 in which R5 is thienylmethyl, thienylethyl, furylmethyl, imidazolylmethyl, or pyridylmethyl, each of which is optionally substituted by methyl or methoxy. 8. A compound of claim 7 which is the E isomer, wherein the R6 group and the imidazole are trans to each other. 9. A compound of claim 8 which is (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid or a pharmaceutically acceptable salt thereof. 10. A compound of claim 8 which is (E)-3-[2-n-butyl-1-{(4-carboxy-2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid or a pharmaceutically acceptable salt thereof. 11. A compound of claim 8 which is (E)-3-[2-n-butyl-1-{(4-carboxy-3-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid or a pharmaceutically acceptable salt thereof. 12. A compound of claim 8 which is (E)-3-[2-n-propyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid or a pharmaceutically acceptable salt thereof. 13. A compound of claim 8 which is (E)-3-[2-n-hexyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid or a pharmaceutically acceptable salt thereof. 14. A compound of claim 8 which is (E)-3-[2-n-butyl-1-{(4-carboxy-2,3-dichlorophenyl)methyl}-1H-imidazol-5-yl]-2-propenoic acid or a pharmaceutically acceptable salt thereof. 15. A compound of claim 8 which is (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid or a pharmaceutically acceptable salt thereof. 16. A compound of claim 15 which is (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate. 17. A compound of claim 8 which is:(E)-3-[2-n-butyl-1-{(2-nitrophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-furyl)methyl-2-propenoic acid (E)-3-[2-n-butyl-1-{(4-carbomethoxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(4-imidazolyl)methyl-2-propenoic acid; (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(3-thienyl)methyl-2-propenoic acid; (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(5-methyl-2-thienyl)methyl-2-propenoic acid; (E)-3-[2-n-butyl-1-{(2-cyanophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid; (E)-3-[2-n-butyl-1-{(4-methoxy-3-methylphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid; (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(4-pyridyl)methyl-2-propenoic acid; (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(5-methoxy-2-thienyl)methyl-2-propenoic acid; (E)-3-[2-butyl-1-{(2,3-dichlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid; (E)-3-[2-n-butyl-1-{(3,4-dicarboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid; (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)ethyl-2-propenoic acid; (E)-3-[2-n-butyl-1-{(4-carboxymethylphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid; (E)-3-[2-n-butyl-1-{(4-carboxy-3-hydroxyphenyl)methyl}1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid; or (E)-3-[2-n-butyl-1-{(2-trifluoromethylphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid; or a pharmaceutically acceptable salt thereof. 18. A pharmaceutical composition comprising a pharmaceutical carrier and a compound of claim 1. 19. A pharmaceutical composition of claim 18 in which the compound is (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid. 20. A pharmaceutical composition of claim 18 in which the compound is (E)-3-[2-n-butyl-1-{(4-carboxy-2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid. 21. A pharmaceutical composition of claim 18 in which the compound is (E)-3-[2-n-butyl-1-{(4-carboxy-3-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid. 22. A pharmaceutical composition of claim 18 in which the compound is (E)-3-[2-n-propyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid. 23. A pharmaceutical composition of claim 18 in which the compound is (E)-3-[2-n-hexyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid. 24. A pharmaceutical composition of claim 18 in which the compound is (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid. 25. A pharmaceutical composition of claim 18 in which the compound is (E)-3-[2-n-butyl-1-{(4-carboxy-2,3-dichlorophenyl)methyl}-1H-imidazol-5-yl]-2-propenoic acid. 26. A pharmaceutical composition of claim 18 in which the compound is (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate. 27. A pharmaceutical composition of claim 18 in which the compound is:(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-furyl)methyl-2-propenoic acid (E)-3-[2-n-butyl-1-{(2-nitro-phenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)-methyl-2-propenoic acid (E)-3-[2-n-butyl-1-{(4-carbomethoxy-phenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)-methyl-2-propenoic acid (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(4-imidazoyl)methyl-2-propenoic acid; (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(3-thienyl)methyl-2-propenoic acid; (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(5-methyl-2-thienyl)methyl-2-propenoic acid; (E)-3-[2-n-butyl-1-{(2-cyanophenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid; (E)-3-[2-n-butyl-1-{(4-methoxy-3-methylphenyl)-methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid; (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl[-2-(4-pyridyl)methyl-2-propenoic acid; (E)-3-[2-n-butyl-1-(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(5-methoxy-2-thienyl)methyl-2-propenoic acid; (E)-3-[2-n-butyl-1-{(2,3-dichlorophenyl)-methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid; (E)-3-[2-n-butyl-1-{(2-trifluoromethylphenyl)-methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid (E)-3-[2-n-butyl-1-{(3,4-dicarboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid; (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)ethyl-2-propenoic acid; (E)-3-[2-n-butyl-1-{(4-carboxymethylphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid; or (E)-3-[2-n-butyl-1-{(4-carboxy-3-hydroxyphenyl)methyl}1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid. 28. A method of antagonizing angiotensin II receptors which comprises administering to a subject in need thereof an effective amount of a compound of claim 1. 29. A method of treating hypertension which comprises administering to a subject in need thereof an effective amount of a compound of claim 1. 30. A method of treating congestive heart failure which comprises administering to a subject in need thereof an effective amount of a compound of claim 1. 31. A method of treating renal failure which comprises administering to a subject in need thereof an effective amount of a compound of claim 1. 32. A method of treating glaucoma which comprises administering to a subject in need thereof an effective amount of a compound of claim 1. 33. The method of claim 28 wherein the compound is (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl-2-propanoic acid. 34. The method of claim 28 wherein the compound is (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl-2-propanoic acid methanesulfonate. 35. The method of claim 29 wherein the compound is (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl-2-propanoic acid. 36. The method of claim 29 wherein the compound is (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl-2-propanoic acid methanesulfonate. 37. The method of claim 30 wherein the compound is (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl-2-propanoic acid. 38. The method of claim 30 wherein the compound is (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl-2-propanoic acid methanesulfonate. 39. The method of claim 31 wherein the compound is (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl-2-propanoic acid. 40. The method of claim 31 wherein the compound is (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl-2-propanoic acid methanesulfonate. 41. The method of claim 32 wherein the compound is (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl-2-propanoic acid. 42. The method of claim 32 wherein the compound is (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl-2-propanoic acid methanesulfonate.