Claims for Patent: RE36481

Summary for Patent: RE36481

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 formulae (I) and (II): ##STR1##
Inventor(s):	Inamine; Edward S. (Rahway, NJ), Hensens; Otto D. (Red Bank, NJ), Houck; David R. (Los Alamos, NM), Lee; Ta J. (Lansdale, PA), Smith; Robert L. (Lansdale, PA), Halczenko; Wasyl (Hatfield, PA), Hartman; George D. (Lansdale, PA), Stokker; Gerald E. (Gwynedd Valley, PA)
Assignee:	Merck & Co., Inc. (Rahway, NJ)
Application Number:	09/188,158
Patent Claims:	1. A compound represented by the following structural formula (I): ##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; and 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.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 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.2-3 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, and hydroxy-C.sub.2-3 alkyl; (5) R.sup.15 S(O).sub.n (CH.sub.2)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. A compound of claim 7 wherein a and c represent double bonds. 9. A compound of claim 8 wherein R is ##STR54## 10. 10. A compound of claim 9 selected from the group consisting of: .[.(1) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(S)-hydroxymethyl-1,2, 6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2 H-pyran-2-one; (2) 6(R)-[2-[8(S)-(2-methylbutyryloxy)-(S)-methyl-6(S)-hydroxymethyl-1,2,6,7,8 ,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyr an-2-one; (3).]. .Iadd.(1) .Iaddend.6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(R)-hydroxyme thyl-1,2,6,7,8,8a-(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-te trahydro-2H-pyran-2-one; .Iadd.and (2) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-6(S)-phenylaminocarbonyloxymethyl-2 (S)-methyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5 ,6-tetrahydro-2H-pyran-2-one .Iaddend. .[.(4) 6(R)-[2-[B(S)-(2,2-dimethylbutyryloxy)-(S)-methyl-6(S)--phenylaminocarbony loxymethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5 ,6-tetrahydro-2H-pyran-2-one.].. 11. A compound of claim 8 wherein R is CO.sub.2 R.sup.6 or ##STR55## 12. A compound of claim 11 selected from the group consisting of: .[.(1) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-(S)-methyl-6(S)-carboxy-1,2,6,7,8,8 a(R)-hexahydro-naphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-H-pyran -2-one; (2) 6(R)-[2-[8(S)-(2-methylbutyryloxy)-2(S)-methyl-6(S)-carboxy-1,2,6,7,8,8a(R )-hexahydronaphthyl-(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-H-pyran-2-on e; (3).]. .Iadd.(1) .Iaddend.6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-.Iadd.2.Iaddend.(S)-methyl -6(R)-carboxy-1,2,6,7,8,8- a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-.Iadd.2 .Iaddend.H-pyran-2-one; .[.(4).]. .Iadd.(2) .Iaddend.6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(S)-(N,N.Iadd .-.Iaddend.dimethyl)aminocarbonyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]et hyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; .[.(5).]. .Iadd.(3) .Iaddend.6(R)-[2-(8(S)-(2,2-dimethylbutyryloxy)-.Iadd.2.Iaddend.(S)-methyl -6(R)-aminocarbonyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydr oxy-3,4,5,6-tetrahydro-2H-pyran-2-one; .Iadd.and .Iaddend. .[.(6).]. .Iadd.(4) .Iaddend.6(R)-[2-(8(S)-(2-methylbutyryloxy)-2(S)-methyl-6(S)-aminocarbonyl -1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahy dro-2H-pyran-2-one.[.; and the corresponding dihydroxy acids, and esters thereof.].. 13. A compound of claim 9 selected from the group consisting of: (1) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(S)-(1-hydroxyethyl) 1 ,2,6,7,8,8a-(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahyd ro-2H-pyran-2-one; (2) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(R)-(1-hydroxyethyl) 1 ,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydr o-2H-pyran-2-one; (3) 6(R)-[2-[8(S)-(2 -methylbutyryloxy)-2(S)-methyl-6(S)-(1-hydroxyethyl) 1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahy dro-2H-pyran-2-one; (4) 6(R)-[2-[8(S)-(2-methylbutyryloxy)-2(S)-methyl-6(R)-(1-hydroxyethyl)-1,2,6 ,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl,]4(R)-hydroxy-3,4,5,6-tetrahydro-2H -pyran-2-one. 14. A compound of claim 7 wherein a, b and c represent single bonds. 15. A compound of claim 14 wherein R is ##STR56## 16. A compound of claim 15 selected from the group consisting of: (1) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(S)-hydroxymethyl-1,2, 3,4,4a(S),5,6,7,8,8a(S)-decahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6- tetrahydro-2H-pyran-2-one; (2) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-.Iadd.2.Iaddend.(S)-methyl-6(S)-(2, 2-dimethylbutyryloxymethyl)-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydronaphthyl-1 (S)]-ethyl]-4(R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (3) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-.Iadd.2.Iaddend.(S)-methyl-6(R)-(1- hydroxyethyl)-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydronaphthyl-1(S)]ethyl]-4(R )-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (4) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-.Iadd.2.Iaddend.(S)-methyl-6(S)-(1- hydroxyethyl) 1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4 ,5,6-tetrahydro-2H-pyran-2-one; (5) .[.6(R)-[2 (8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(S)-(1-hydroxyphenylmethyl)-1, 2,3,4,4a-(S),5,6,7,8,8a(S)-decahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5 ,6-tetrahydro-2H-pyran-2-one.].6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)- methyl-6(S)-(1-hydroxyphenylmethyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydronap hthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one. 17. A compound of claim 14 wherein R is ##STR57## 18. A compound of claim 17 selected from the group consisting of: (1) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-.Iadd.2(S)-methyl-.Iaddend.6(S)-car boxy-1,2,3,4,4a(S),5,6,7,8,.Iadd.8.Iaddend.a(S)-decahydronaphthyl-1(S)]ethy l]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (2) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-.Iadd.2.Iaddend.(S)-methyl-6(S)-eth oxycarbonyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydronaphthyl-1(S)]ethyl]-4(R)- hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (3) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(S)-aminocarbonyl-1,2, 3,4,4a(S),5,6,7,8,8a(S)-decahydronaphthyl-(S)]ethyl]-4(R)-hydroxy-3,4,5,6-t etrahydro-2H-pyran-2-one; .Iadd.and .Iaddend. (4) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(S)-(N-cyclohexylamino carbonyl,N-cyclohexyl)aminocarbonyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydrona phthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.[.; and the corresponding ring opened dihydroxy acids, and esters thereof.].. 19. A compound of claim 14 wherein R is ##STR58## 20. 20. A compound of claim 19 which is: .[.6(R)-[2 (8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(S)-(1 oxoethyl) 1,2,3,4,4a(S),5,6,7,8,a(S)-decahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4, 5,6-tetrahydro-2H-pyran-2-one and the corresponding ring opened dihydroxy acid, and esters thereof.]. .Iadd.6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(S)-(1-oxoethyl) -1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4 ,5,6-tetrahydro-2H-pyran-2-one.Iaddend.. 21. A compound of claim 7 wherein one of a, b and c represents a double bond. 22. A compound of claim 21 wherein R is ##STR59## 23. A compound of claim 22 selected from the group consisting of: (1) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(R)-hydroxymethyl-1,2, 3,4,6,7,8,8a-(R)-octahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahy dro-2H-pyran-2-one; (2) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(R)-(2,2-dimethylbutyr yloxymethyl)-1,2,3,4,6,7,8,8a(R)-octahydronaphthyl-(S)]ethyl]-4(R)-hydroxy- 3,4,5,6-tetrahydro-2H-pyran-2-one; (3) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(R)-(1 hydroxyethyl) 1.2.3,4,6,7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4(R)-hydro xy3,4,5,6-tetrahydro-2H-pyran-2-one. 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 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(S)-hydroxymethyl-1,2, 3,4,4a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H- pyran-2-one. .Iaddend..Iadd.27. The compound of claim 9 which is 6(R)-[2-[8(S)-(2-methylbutyryloxy)-2(S)-methyl-6(S)-hydroxymethyl-1,2,6,7, 8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-py ran-2-one. .Iaddend..Iadd.28. The compound of claim 11 which is 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(S)-carboxy-1,2,6,7,8, 8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyra n-2-one. .Iaddend..Iadd.29. The compound of claim 11 which is 6(R)-[2-[8(S)-(2-methylbutyryloxy)-2(S)-methyl-6(S)-carboxy--1,2,6,7,8,8a( R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2 -one. .Iaddend.