Novel HMG-CoA reductase inhibitors

Claim 2

A compound represented by the following general structural formula (I) or (II): wherein: n is 1 to 5; R is hydrogen or R 1 is hydrogen or methyl; R 2 is hydrogen or methyl; and R 3 is hydrogen, C 1-5 alkyl or C 1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and the dotted lines at a, b and c represent optional double bonds or a pharmaceutically acceptable salt of the compound (II) in which R 3 is hydrogen.

Claim 3

A compound of Claim 1 wherein n is 1 to 3 and R 2 is methyl.

Claim 4

A compound of Claim 2 wherein one of the dotted lines at a, b or c represents a double bond or the dotted lines at a anc c represent double bonds.

Claim 5

A compound of Claim 3 wherein the dotted line at a and c represent double bonds.

Claim 6

A compound of Claim 4 which is 6(R)-[2-[8(S)-(2 methyl-4-hydroxybutyryloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-heaahydronaphthyl-1(S)] ethyl]-4(R)-hydroay-3,4,5,6-tetrahydro-2H-pyran-2- one and 7-[1,2,6,7,8,Sa-(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-(2-methyl-4-hydroxy-butyryloxy) naphthalenyl-l(S)]-3(R),5(R)-dihydroxyheptanoic acid.

Claim 7

A compound of Claim 4 wherein R is methyl.

Claim 8

A compound of Claim 6 which is 6(R)-[2-[8(S)-(2,2-dimethyl-4-hydroxybutyryloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-heaahydronaphthyl-1(S)] ethyl]-4(R)-hydroay-3,4,5,6-tetrahydro-2H-pyran-2- one and 7-[1,2,6,7,8,8a(R)-heaahydro-2(S).6(R)-dimethyl-8(S)-(2,2-dimethyl-4-hydroxybutyryloxy) naphthalenyl-l(S)]-3(R),5(R)-dihydroxyheptanoic acid; 6(R)-[2-[8(S)-(2,2-dimethyl-5-hydroxypentanoyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-heaahydronaphthyl-1(S)]ethyl]-4(R)-hydroay-3,4,5,6-tetrahydro-2H-pyran-2-one and 7-[1,2,6,7,8,8a(R)-heaahydro-2(S),6(R)-dimethyl-8(S)-(2,2-dimethyl-5-hydroxypentanoyloxy)-naphthalenyl-l(S)]-3(R),5(R)-dihydroxyheptanoic acid; 6(R)-[2-[8(S)-(2,2-dimethyl-3-hydroxypropionyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one and 7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-(2,2-dimethyl-3-hydroxypropionyloxy) naphthalenyl-l(S)]-3(R),5(R)-dihydroxyheptanoic acid.

Claim 9

A hypocholesterolemic, hypolipidemic pharmaceutical composition comprising a nontoxic therapeutically effective amount of a compound of Claim 1 and a pharmaceutically acceptable carrier.

Claim 10

A pharmaceutical composition of Claim 8 wherein the therapeutically active ingredient is selected from (a) 6(R)-[2-[8(S)-(2-methyl-4-hydroxybutyryloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-9(R)-hydroxy-3,4,5.6-tetrahydro-2H-pyran-2-one; (b) 6(R)-[2-[8(S)-(2,2-dimethyl-4-hydroxy- butyryloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (c) 6(R)-[2-[8(S)-(2,2-dimethyl-5-hydroxy- pentanoyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; and (d) 6(R)-[2-[8(S)-(2,2-dimethyl-3-hydroxypro- pionyloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-l(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one and the corresponding free hydroxy acids thereof.

Claim 11

A hypocholesterolemic, hypolipidemic pharmaceutical composition comprising a nontoxic therapeutically effective amount of a compound of Claim 1 in combination with a pharmaceutically acceptable nontoxic cationic polymer capable of binding bile acids in a non-reabsorbable form in the gastrointestinal tract and a pharmaceutically acceptable carrier.

Claim 12

A process for the preparation of a compound represented by the following general structural formula (I) or (II): wherein: n is 1 to 5; R is hydrogen or R is hydrogen or methyl; R 2 is hydrogen or methyl; and R 3 is hydrogen, C 1-5 alkyl or C 1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and the dotted lines at a, b and c represent optional double bonds or a pharmaceutically acceptable salt of the compound (II) in which R 3 is hydrogen which comprises: (a) treating a compound of the formula (4) wherein n, R 1 , R 2 , a, b and c are defined above and R' is with a tetra(C 1-5 alkyl) ammonium halide and an organic acid to form the compounds of the formula (II) in which R is and R 3 is H; and (b) optionally, treating the compounds from step (a) under acid conditions to form the compounds of the formula (II) wherein R and R 3 are H; and (c) optionally, treating the compounds from step (a) or step (b) to relactonize the dihydroxy acid to form the compounds of the formula (I); and (d) optionally, treating the compounds from step (a) or step (b) with a C 1-5 alkanol or a substituted C 1-5 alkanol to form the compounds of the formula (II) wherein R 3 is C 1-5 alkyl or C 1-5 alkyl substituted with a phenyl, dimethylamino or acetylamino group.

Claim 13

A process for the preparation of a compound represented by the following general structural formula (I) or (II): wherein: n is 1 to 5; R is hydrogen or R is hydrogen or methyl; R 2 is hydrogen or methyl; and R 3 is hydrogen, C 1-5 alkyl or C 1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and the dotted lines at a, b and c represent optional double bonds or a pharmaceutically acceptable salt of the compound (II) in which R 3 is hydrogen which comprises: (a) treating a compound of the formula (4) wherein n, R 1 , R 2 , a, b and c are defined above and R' is with a tetra(C 1-5 alkyl) ammonium halide and an organic acid to form the compounds of the formula (II) in which R is and R 3 is H; and (b) optionally, treating the compounds from step (a) under acid conditions to form the compounds of the formula (II) wherein R and R 3 are H; and (c) optionally, treating the compounds from step (a) or step (b) to relactonize the dihydroxy acid to form the compounds of the formula (I); and (d) optionally, treating the compounds from step (a) or step (b) with a C 1-5 alkanol or a substituted C 1-5 alkanol to form the compounds of the formula (II) wherein R 3 is C 1-5 alkyl or C 1-5 alkyl substituted with a phenyl, dimethylamino or acetylamino group.

Claim 14

A process for the preparation of a compound represented by the following general structural formula (I) or (II): wherein: n is 1 to 5; R is hydrogen or (C 1-5 alkyl)C-; R is hydrogen or methyl; R 2 is hydrogen or methyl; and R 3 is hydrogen, C 1-5 alkyl or C 1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and the dotted lines at a, b and c represent optional double bonds or a pharmaceutically acceptable salt of the compound (II) in which R 3 is hydrogen which comprises: (a) treating a compound of the formula (4) wherein n , R i , R 2 , a, b and c are defined above and R' is with a tetra(C 1-5 alkyl) ammonium halide and an organic acid to form the compounds of the formula (II) in which R is and R 3 is H; and (b) optionally, treating the compounds from step (a) under acid conditions to form the compounds of the formula (II) wherein R and R 3 are H; and (c) optionally, treating the compounds from step (a) or step (b) to relactonize the dihydroxy acid to form the compounds of the formula (I); and (d) optionally, treating the compounds from step (a) or step (b) with a C 1-5 alkanol or a substituted C 1-5 alkanol to form the compounds of the formula (II) wherein R 3 is C 1-5 alkyl or C 1-5 alkyl substituted with a phenyl, dimethylamino or acetylamino group.

Claim 15

A process for the preparation of a compound represented by the following general structural formula (I) or (II): wherein: n is 1 to 5; R is hydrogen or (C 1-5 alkyl)C-; R is hydrogen or methyl; R 2 is hydrogen or methyl; and R 3 is hydrogen, C 1-5 alkyl or C 1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and the dotted lines at a, b and c represent optional double bonds or a pharmaceutically acceptable salt of the compound (II) in which R 3 is hydrogen which comprises: (a) treating a compound of the formula (4) wherein n , R i , R 2 , a, b and c are defined above and R' is with a tetra(C 1-5 alkyl) ammonium halide and an organic acid to form the compounds of the formula (II) in which R is and R 3 is H; and (b) optionally, treating the compounds from step (a) under acid conditions to form the compounds of the formula (II) wherein R and R 3 are H; and (c) optionally, treating the compounds from step (a) or step (b) to relactonize the dihydroxy acid to form the compounds of the formula (I); and (d) optionally, treating the compounds from step (a) or step (b) with a C 1-5 alkanol or a substituted C 1-5 alkanol to form the compounds of the formula (II) wherein R 3 is C 1-5 alkyl or C 1-5 alkyl substituted with a phenyl, dimethylamino or acetylamino group.

Claim 16

A process of Claim 1 wherein n is 1 to 3 and R 2 is methyl.

Claim 17

A process of Claim 2 wherein one of the dotted lines at a, b or c'represents a double bond or the dotted lines at a anc c represent double bonds.

Claim 18

A process of Claim 3 wherein the dotted line at a and c represent double bonds.

Claim 19

A process of Claim 4 in which the compound prepared is 6(R)-[2-[8(S)-(2 methyl-4-hydroxybutyryloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)] ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2- one or 7-[1,2,6,7,8,8a-(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-(2-methyl-4-hydroxybutyryloxy) naphthalenyl-l(S)]-3(R),5(R)-dihydroxyheptanoic acid.

Claim 20

A process of Claim 4 wherein R 1 is methyl.

Claim 21

A process of Claim 6 in which the compound prepared is 6(R)-[2-[8(S)-(2,2-dimethyl-4-hydroxybutyryloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one and 7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-(2,2-dimethyl-4-hydroxybutyryloxy)naphthalenyl-l(S)]-3(R),5(R)-di- hydroxyheptanoic acid; 6(R)-[2-[8(S)-(2,2-dimethyl-5-hydroxypentanoyloxy)-2(S),6(R)-dimethyl-1,2.6,7,8,8a-(R)-hexahydronaphthyl-l(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one and 7-(1,2,6,7,8,8a(R)-hexa- hydro-2(S),6(R)-dimethyl-8(S)-(2,2-dimethyl-5-hydroxy- pentanoyloxy)naphthalenyl-l(S)]-3(R),5(R)-dihydroxy- heptanoic acid; or 6(R)-[2-[8(S)-(2,2-dimethyl-3-hydroxypropionyloxy)-2(S),6(R)-dimethyl-l,2,6,7,8,8a-(R)-hezahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one or 7-[1,2,6,7,8,8a(R)-hexa- hydro-2(S),6(R)-dimethyl-8(S)-(2,2-dimethyl-3-hydroxy- propionyloxy)naphthalenyl-l(S)]-3(R),5(R)-dihydroxy- heptanoic acid.