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Details for Patent: 5,116,870

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Details for Patent: 5,116,870

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 (Hatfield, 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 J. (Lansdale, PA)
Assignee: Merck & Co., Inc. (Rahway, NJ)
Filing Date:Jun 06, 1990
Application Number:07/533,744
Claims:1. A compound represented by the following structural formula II: ##STR49## wherein: R is ##STR50## 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) ##STR51## 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) ##STR52## 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) ##STR53## 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 ##STR54##

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) 7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(R)-hydroxymethyl-8(S)-(2,2-dime thylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid;

(4) 7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(S)-phenylaminocarbonyloxymethyl -8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid.

11. The compound of claim 8 wherein R is CO.sub.2 R.sup.6 or ##STR55##

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) 7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(R)-carboxy-8(S)-(2,2-dimethylbu tyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid;

(4) 7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(S)-(N,N-dimethyl)aminocarbonyl- 8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid;

(5) 7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(R)-aminocarbonyl-8(S)-(2,2-dime thylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid;

(6) 7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl-6(S)-aminocarbonyl-8(S)-(2-methyl butyryloxy)-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 ##STR56##

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 ##STR57##

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 ##STR58##

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 ##STR59##

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.
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