Claims for Patent: 5,656,650

Summary for Patent: 5,656,650

Title:	Angiotensin II receptor blocking compositions
Abstract:	This invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier, an angiotensin II receptor antagonist and a second agent selected from a diuretic, a calcium channel blocker, a β-adrenoceptor blocker, a renin inhibitor, or an angiotensin converting enzyme inhibitor and a method of treating hypertension.
Inventor(s):	Joseph Weinstock
Assignee:	SmithKline Beecham Corp
Application Number:	US08/444,121
Patent Claims:	1. A pharmaceutical composition comprising a diuretic, a pharmaceutically acceptable carrier and an angiotensin II receptor antagonist of the formula (I): ##STR10## 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, PO(OR7)2, NR7 R7, NR7 COH, NR7 COC1 -C6 alkyl, NR7 CON(R7)2, NR7 COW, W, or 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, wherein m is 0-4; and R8 is hydrogen, C1 -C6 alkyl, or 2-di(C1 -C6 alkyl)amino-2-oxoethyl;or a pharmaceutically acceptable salt thereof. 2. The pharmaceutical composition of claim 1 wherein the angiotensin II receptor antagonist 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. 3. The pharmaceutical composition of claim 2 wherein the angiotensin II receptor antagonist is (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate. 4. The pharmaceutical composition of claim 3 wherein the diuretic is hydrochlorothiazide or furosemide. 5. The pharmaceutical composition of claim 1 wherein the angiotensin II receptor antagonist is (E)-3-[2-n-butyl-1-{(4-carboxynapthy-1-yl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid or a pharmaceutically acceptable salt thereof. 6. The pharmaceutical composition of claim 5 wherein the diuretic is hydrochlorothiazide or furosemide. 7. A pharmaceutical composition comprising a calcium channel blocker, a pharmaceutically acceptable carrier and an angiotensin II receptor antagonist of the formula (I), as described in claim 1. 8. A pharmaceutical composition comprising a β-adrenoceptor blocker, a pharmaceutically acceptable carrier and an angiotensin II receptor antagonist of the formula (I), as described in claim 1. 9. A pharmaceutical composition comprising a renin inhibitor, a pharmaceutically acceptable carrier and an angiotensin II receptor antagonist of the formula (I), as described in claim 1. 10. A pharmaceutical composition comprising an angiotensin converting enzyme inhibitor, a pharmaceutically acceptable carrier and an angiotensin II receptor antagonist of the formula (I), as described in claim 1. 11. A method of treating hypertension which comprises administering stepwise or in physical combination a diuretic and an angiotensin II receptor antagonist of the formula (I), as described in claim 1. 12. The method of claim 11 wherein the angiotensin II receptor antagonist 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. 13. The method of claim 12 wherein the angiotensin II receptor antagonist is (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)-methyl-2-propenoic acid methanesulfonate. 14. The method of claim 13 wherein the diuretic is hydrochlorothiazide or furosemide. 15. The method of claim 11 wherein the angiotensin II receptor antagonist is (E)-3-[2-n-butyl-1-{(4-carboxynaphth-1-yl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid or a pharmaceutically acceptable salt thereof. 16. The method of claim 15 wherein the diuretic is hydrochlorothiazide or furosemide. 17. A method of treating hypertension which comprises administering stepwise or in physical combination a calcium channel blocker and an angiotensin II receptor antagonist of formula (I), as described in claim 1. 18. A method of treating hypertension which comprises administering stepwise or in physical combination a β-adrenoceptor blocker and an angiotensin II receptor antagonist of formula (I), as described in claim 1. 19. A method of treating hypertension which comprises administering stepwise or in physical combination a renin inhibitor and an angiotensin II receptor antagonist of formula (I), as described in claim 1. 20. A method of treating hypertension which comprises administering stepwise or in physical combination an angiotensin converting enzyme inhibitor and an angiotensin II receptor antagonist of formula (I), as described in claim 1.