Claims for Patent: RE36520

Summary for Patent: RE36520

Title:	HMG-CoA reductase inhibitors
Abstract:	Novel 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are useful as antihypercholesterolemic agents and are represented by the following general structural formula (II): ##STR1##
Inventor(s):	Smith; Robert L. (Lansdale, PA), Halczenko; Wasyl (Lansdale, PA), Hartman; George D. (Lansdale, PA), Stokker; Gerald E. (Gwynedd Valley, PA), Inamine; Edward S. (Rahway, NJ), Hensens; Otto D. (Red Bank, NJ), Houck; David R. (Los Alamos, NM), Lee; Ta Jyh (Lansdale, PA)
Assignee:	Merck & Co., Inc. (Rahway, NJ)
Application Number:	09/188,155
Patent Claims:	1. A compound represented by the following structural formula II: ##STR48## wherein: R is ##STR49## R.sup.1 and R.sup.5 are independently: (1) C.sub.1-10 alkyl; (2) substituted C.sub.1-10 alkyl in which one or more substituent(s) is: (a) halogen, (b) hydroxy, (c) C.sub.1-10 alkoxy, (d) C.sub.1-5 alkoxycarbonyl, (e) C.sub.1-5 acyloxy, (f) C.sub.3-8 cycloalkyl, (g) phenyl, (h) substituted phenyl in which the substituents are X and Y, (i) C.sub.1-10 alkylS(O).sub.n in which n is 0 to 2, (j) C.sub.3-8 cycloalkylS(O).sub.n, (k) phenylS(O).sub.n, (l) substituted phenylS(O).sub.n in which the substituents are X and Y, and (m) oxo; (3) C.sub.1-10 alkoxy; (4) C.sub.2-10 alkenyl; (5) C.sub.3-8 cycloalkyl; (6) substituted C.sub.3-8 cycloalkyl in which one substituent is: (a) C.sub.1-10 alkyl (b) substituted C.sub.1-10 alkyl in which the substituent is selected from (i) halogen, (ii) hydroxy, (iii) C.sub.1-10 alkoxy, (iv) C.sub.1-5 alkoxycarbonyl, (v) C.sub.1-5 acyloxy, (vi) phenyl, (vii) substituted phenyl in which the substituents are X and Y (viii) C.sub.1-10 alkylS(O).sub.n, (ix) C.sub.3-8 cycloalkylS(O).sub.n, (x) phenylS(O).sub.n, (xi) substituted phenylS(O).sub.n in which the substituents are X and Y, and (xii) oxo, (c) C.sub.1-10 alkylS(O).sub.n, (d) C.sub.3-8 cycloalkylS(O).sub.n, (e) phenylS(O).sub.n, (f) substituted phenylS(O).sub.n in which the substituents are X and Y, (g) halogen, (h) hydroxy, (i) C.sub.1-10 alkoxy, (j) C.sub.1-5 alkoxycarbonyl, (k) C.sub.1-5 acyloxy, (l) phenyl, and (m) substituted phenyl in which the substituents are X and Y; (7) phenyl; (8) substituted phenyl in which the substituents are X and Y; (9) amino; (10) C.sub.1-5 alkylamino; (11) di(C.sub.1-5 alkyl)amino; (12) phenylamino; (13) substituted phenylamino in which the substituents are X and Y; (14) phenyl C.sub.1-10 alkylamino; (15) substituted phenyl C.sub.1-10 alkylamino in which the substituents are X and Y; (16) R.sup.9 S in which R.sup.9 is selected from (a) C.sub.1-10 alkyl, (b) phenyl, and (c) substituted phenyl in which the substituents are X and Y; R.sup.2 and R.sup.6 are independently: (1) hydrogen; (2) C.sub.1- 5 alkyl; (3) substituted C.sub.1-5 alkyl in which the substituent is: (a) phenyl, (b) dimethylamino, and (c) acetylamino, and (4) 2,3-dihydroxypropyl; R.sup.3 and R.sup.4 are independently: (1) hydrogen; (2) C.sub.1-10 alkyl; (3) substituted C.sub.1-10 alkyl in which one or more substituent(s) is: (a) halogen, (b) hydroxy, (c) C.sub.1-10 alkoxy, (d) C.sub.1-5 alkoxycarbonyl, (e) C.sub.1-5 acyloxy, (f) C.sub.3-8 cycloalkyl, (g) phenyl, (h) substituted phenyl in which the substituents are X and Y. (i) C.sub.1-10 alkylS(O).sub.n, (j) C.sub.3-8 cycloalkylS(O).sub.n, (k) phenylS(O).sub.n, (l) substituted phenylS(O).sub.n in which the substituents are X and Y, and (m) oxo; (4) C.sub.2-10 alkenyl; (5) substituted C.sub.2-10 alkenyl in which one or more substituent(s) is: (a) halogen, (b) hydroxy, (c) C.sub.1-10 alkoxy, (d) C.sub.1-5 alkoxycarbonyl, (e) C.sub.1-5 acyloxy, (f) C.sub.3-8 cycloalkyl, (g) phenyl, (h) substituted phenyl in which the substituents are X and Y, (i) C.sub.1-10 alkylS(O).sub.n, (j) C.sub.3-8 cycloalkylS(O).sub.n, (k) phenylS(O).sub.n, (l) substituted phenylS(O).sub.n in which the substituents are X and Y, and (m) oxo; (6) C.sub.3-8 cycloalkyl; (7) substituted C.sub.3-8 cycloalkyl in which one substituent is: (a) C.sub.1-10 alkyl (b) substituted C.sub.1-10 alkyl in which the substituent is (i) halogen, (ii) hydroxy, (iii) C.sub.1-10 alkoxy, (iv) C.sub.1-5 alkoxycarbonyl, (v) C.sub.1-5 acyloxy (vi) phenyl, (vii) substituted phenyl in which the substituents are X and Y (viii) C.sub.1-10 alkylS(O).sub.n, (ix) C.sub.3-8 cycloalkylS(O).sub.n, (x) phenylS(O).sub.n, (xi) substituted phenylS(O).sub.n in which the substituents are X and Y, and (xii) oxo, (c) C.sub.1-10 alkylS(O).sub.n, (d) C.sub.3-8 cycloalkylS(O).sub.n, (e) phenylS(O).sub.n, (f) substituted phenylS(O).sub.n in which the substituents are X and Y, (g) halogen, (h) hydroxy, (i) C.sub.1-10 alkoxy, (j) C.sub.1-5 alkoxycarbonyl, (k) C.sub.1-5 acyloxy, (l) phenyl, and (m) substituted phenyl in which the substituents are X and Y; (8) phenyl; (9) substituted phenyl in which the substituents are X and Y; R.sup.7 and R.sup.8 are independently: (1) hydrogen; (2) C.sub.1-10 alkyl; (3) substituted C.sub.1-10 alkyl in which one or more substituent(s) is: (a) halogen, (b) hydroxy, (c) C.sub.1-10 alkoxy, (d) C.sub.1-10 alkoxycarbonyl, (e) C.sub.1-5 acyloxy, (f) C.sub.3-8 cycloalkyl, (g) phenyl, (h) substituted phenyl in which the substituents are X and Y, (i) C.sub.1-10 alkyl S(O).sub.n in which n is 0 to 2, (j) C.sub.3-8 cycloalkyl S(O).sub.n, (k) phenyl S(O).sub.n ; (l) substituted phenyl S(O).sub.n in which the substituents are X and Y, and (m) oxo; (4) C.sub.2-10 alkenyl; (5) C.sub.3-8 cycloalkyl; (6) aminocarbonyl; (7) substituted aminocarbonyl in which one or more substituent(s) is: (a) C.sub.1-5 alkyl, (b) C.sub.3-8 cycloalkyl, (c) phenyl, (d) substituted phenyl in which the substituents are X and Y; (8) phenyl; (9) substituted phenyl in which the substituents are X and Y; (10) C.sub.1-10 alkylcarbonyl; (11) C.sub.3-8 cycloalkylcarbonyl; (12) phenylcarbonyl; (13) substituted phenylcarbonyl in which the substituents are X and Y; and X and Y independently are hydrogen, halogen, trifluoromethyl, C.sub.1-3 alkyl, nitro, cyano or a group selected from: (1) R.sup.10 O(CH.sub.2).sub.m in which m is 0 to 3 and R.sup.10 is hydrogen, C.sub.1-3 alkyl or hydroxy-C.sub.2-3 alkyl; (2) ##STR50## in which R.sup.11 is hydrogen, C.sub.1-3 alkyl, hydroxy-C.sub.2-3 alkyl, phenyl, naphthyl, amino-C.sub.1-3 alkyl, C.sub.1-3 alkylamino C.sub.1-3 alkyl, di(C.sub.1-3 alkyl)amino-C.sub.1-3 alkyl, hydroxy-C.sub.2-3 -alkylamino-C.sub.1-3 alkyl or di(hydroxy C.sub.2-3 alkyl) amino-C.sub.1-3 alkyl; (3) ##STR51## in which R.sup.12 is hydrogen, C.sub.1-3 alkyl, hydroxy-C.sub.2-3 alkyl, C.sub.1-3 alkoxy-C.sub.1-3 alkyl, phenyl or naphthyl; (4) ##STR52## in which R.sup.13 and R.sup.14 independently are hydrogen, C.sub.1-3 alkyl, hydroxy-C.sub.2-3 alkyl; (5) R.sup.15 S(O).sub.n (CH.sub.2).sub.m in which R.sup.15 is hydrogen, C.sub.1-3 alkyl, amino, C.sub.1-3 alkylamino or di(C.sub.1-3 alkyl)amino; and a, b and c each represent single bonds or one of a, b and c represents a double bond or both a and c represent double bonds; or a pharmaceutically acceptable salt thereof. 2. A compound of claim 1 wherein: R.sup.1 and R.sup.5 are independently: (1) C.sub.1-10 alkyl; (2) substituted C.sub.1-10 alkyl in which one or more substituent(s) is: (a) halogen, (b) hydroxy, (c) C.sub.1-10 alkoxy, (d) C.sub.1-5 alkoxycarbonyl, (e) C.sub.1-5 acyloxy, (f) C.sub.3-8 cycloalkyl, (g) phenyl, (h) substituted phenyl in which the substituents are X and Y, and (i) oxo; (3) C.sub.3-8 cycloalkyl; (4) substituted C.sub.3-8 cycloalkyl in which one substituent is: (a) C.sub.1-10 alkyl, (b) substituted C.sub.1-10 alkyl in which the substituent is (i) halogen, (ii) hydroxy, (iii) C.sub.1-10 alkoxy (iv) C.sub.1-5 acyloxy, (v) C.sub.1-5 alkoxycarbonyl, (vi) phenyl, (vii) substituted phenyl in which the substituents are X and Y, and (viii) oxo, (c) halogen, (d) hydroxy, (e) C.sub.1-10 alkoxy, (f) C.sub.1-5 alkoxycarbonyl, (g) C.sub.1-5 acyloxy, (h) phenyl, (i) substituted phenyl in which the substituents are X and Y; (5) phenylamino; (6) substituted phenylamino in which the substituents are X and Y; (7) phenyl C.sub.1-10 alkylamino; and (8) substituted phenyl C.sub.1-10 alkylamino in which the substituents are X and Y. 3. A compound of claim 2 wherein: R.sup.1 and R.sup.5 are independently: (1) C.sub.1-10 alkyl; (2) C.sub.3-8 cycloalkyl; (3) phenylamino; and (4) substituted phenylamino in which the substituents are X and Y. 4. A compound of claim 3 wherein: R.sup.3 and R.sup.4 are independently: (1) hydrogen; (2) C.sub.1-10 alkyl; (3) C.sub.3-8 cycloalkyl; and (4) phenyl. 5. A compound of claim 4 wherein: R.sup.7 and R.sup.8 are independently: (1) hydrogen; (2) C.sub.1-10 alkyl; (3) C.sub.3-8 cycloalkyl; (4) aminocarbonyl; (5) substituted aminocarbonyl in which one or more substituent(s) is: (a) C.sub.1-5 alkyl, (b) C.sub.3-8 cycloalkyl, (c) phenyl, (d) substituted phenyl in which the substituents are X and Y. 6. A compound of claim 5 wherein R.sup.1 is 1,1-dimethylpropyl or sec-butyl. 7. A compound of claim 6 wherein R.sup.3 and R.sup.4 are independently selected from: (1) hydrogen; (2) C.sub.1-5 alkyl; and (3) phenyl. 8. The compound of claim 7 wherein a and c represent double bonds. 9. The compound of claim 8 wherein R is ##STR53## 10. 10. The compound of claim 9 selected from the group consisting of: .[.(1) 7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(S)-hydroxymethyl-8(S)-(2,2-dime thylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid; (2) 7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(S)-hydroxymethyl-8(S)-(2-methyl butyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid;.]. .[.(3).]. .Iadd.(1) .Iaddend.7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(R)-hydroxymethyl-8(S)- (2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid; .Iadd.and .Iaddend. .[.(4).]. .Iadd.(2) .Iaddend.7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(S)-phenylaminocarbonyl oxymethyl-8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyh eptanoic acid. 11. The compound of claim 8 wherein R is CO.sub.2 R.sup.6 or ##STR54## 12. The compound of claim 11 selected from the group consisting of: .[.(1) 7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(S)-carboxy-8(S)-(2,2-dimethylbu tyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid; (2) 7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(S)-carboxy-8(S)-(2-methylbutyry loxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid;.]. .[.(3).]. .Iadd.(1) .Iaddend.7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(R)-carboxy-8(S)-(2,2-d imethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid; .[.(4).]. .Iadd.(2) .Iaddend.7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(S)-(N,N-dimethyl)amino carbonyl-8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyhe ptanoic acid; .[.(5).]. .Iadd.(3) .Iaddend.7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(R)-aminocarbonyl-8(S)- (2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid; .Iadd.and .Iaddend. .[.(6).]. .Iadd.(4) .Iaddend.7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(S)-aminocarbonyl-8(S)- (2-methylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid. 13. The compound of claim 9 selected from the group consisting of: (1) 7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(S)-(1-hydroxyethyl)-8(S)-(2,2-d imethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid; (2) 7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(R)-(1-hydroxyethyl)-8(S)-(2,2-d imethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid; (3) 7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(S)-(1-hydroxyethyl)-8(S)-(2-met hylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid; (4) 7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(R)-(1,hydroxyethyl)-8(S)-(2-met hylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid. 14. The compound of claim 7 wherein a, b and c represent single bonds. 15. The compound of claim 13 wherein R is ##STR55## 16. The compound of claim 15 selected from the group consisting of: (1) 7-[1,2,3,4,4a(S),5,6,7,8,8a(R)-decahydro-2(S)-methyl-6(S)-(1-hydroxymethyl )-8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid; (2) 7-[1,2,3,4,4a(S),5,6,7,8,8a(R)-decahydro-2(S)-methyl-6(S)-(2,2-dimethylbut yryloxymethyl)-8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihyd roxyheptanoic acid; (3) 7-[1,2,3,4,4a(S),5,6,7,8,8a(R)-decahydro-2(S)-methyl-6(R)-(1-hydroxyethyl) -8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid; (4) 7-[1,2,3,4,4a(S),5,6,7,8,8a(R)-decahydro-2(S)-methyl-6(S)-(1-hydroxyethyl) -8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid; (5) 7-[1,2,3,4,4a(S),5,6,7,8,8a(R)-decahydro-2(S)-methyl-6(S)-(1-hydroxyphenyl methyl)-8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyhep tanoic acid. 17. The compound of claim 14 wherein R is CO.sub.2 R.sup.6 or ##STR56## 18. The compound of claim 17 selected from the group consisting of: (1) 7-[1,2,3,4,4a(S),5,6,7,8,8a(R)-decahydro-2(S)-methyl-6(S)-carboxy-8(S)-(2, 2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid; (2) 7-[1,2,3,4,4a(S),5,6,7,8,8a(R)-decahydro-2(S)-methyl-6(S)-ethoxycarbonyl-8 (S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid; (3) 7-[1,2,3,4,4a(S),5,6,7,8,8a(R)-decahydro-2(S)-methyl-6(S)-aminocarbonyl)-8 (S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid; (4) 7-[1,2,3,4,4a(S),5,6,7,8,8a(R)-decahydro-2(S)-methyl-6(S)-(N-cyclohexylami nocarbonyl)-8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydrox yheptanoic acid. 19. The compound of claim 14 wherein R is ##STR57## 20. 20. The compound of claim 19 which is: 7-[1,2,3,4,4a(S),5,6,7,8,8a(R)-decahydro-2(S)-methyl-6(S)-(1-oxoethyl)-8(S )-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid. 21. The compound of claim 7 wherein one of a, b and c represents a double bond. 22. The compound of claim 21 wherein R is ##STR58## 23. The compound of claim 22 selected from the group consisting of: (1) 7-[1,2,3,4,6,7,8,8a(R)-octahydro-2(S)-methyl-6(R)-hydroxymethyl-8(S)-(2,2- dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid; (2) 7-[1,2,3,4,6,7,8,8a(R)-octahydro-2(S)-methyl-6(R)-(2,2-dimethylbutyryloxym ethyl)-8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyhept anoic acid; (3) 7-[1,2,3,4,6,7,8,8a(R)-octahydro-2(S)-methyl-6(R)-(1-hydroxyethyl)-8(S)-(2 ,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid. 24. A hypocholesterolemic, hypolipidemic pharmaceutical composition comprising a pharmaceutically acceptable carrier and a nontoxic effective amount of a compound as defined in claim 1. 25. A method of inhibiting cholesterol biosynthesis comprising the administration to a subject in need of such treatment a nontoxic therapeutically effective amount of a compound of claim 1. .Iadd. 26. The compound of claim 9 which is 7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(S)-hydroxymethyl-8(S)-(2,2-dime thylbutyryloxy)-1(S)-naphthyl]-3(R), 5(R)-dihydroxyheptanoic acid. .Iaddend..Iadd.27. The compound of claim 9 which is 7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(S)-hydroxymethyl-8(S)-(2-methyl butyryloxy)-1(S)-naphthyl]-3(R), 5(R)-dihydroxyheptanoic acid. .Iaddend..Iadd.28. The compound of claim 11 which is 7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(S)-carboxy-8(S)-(2,2-dimethylbu tyryloxy)-1(S)-naphthyl]-3(R), 5(R)-dihydroxyheptanoic acid. .Iaddend..Iadd.29. The compound of claim 11 which is 7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(S)-carboxy-8(S)-(2-methylbutyry loxy)-1(S)-naphthyl]-3(R), 5(R)-dihydroxyheptanoic acid. .Iaddend.