Novel HMG-CoA reductase inhibitors

Claim 2

A compound represented by structural formula (I'): ##STR18## R is ##STR19## R 1 is C 1-3 alkyl, C 1-3 alkoxy, chlorine or bromine, CF 3 , or C 1-3 alkylthio; R 2 is H, C 1-3 alkyl or C 2-4 alkoxy; R 3 is C 1-5 alkyl, phenyl, or phenyl substituted with W; R 4 is H, C 1-3 alkyl, phenylC 1-3 alkyl or phenyl C 1-3 alkyl in which the phenyl is substituted with W; R 5 and R 6 are independently selected from hydrogen, C 1-3 alkyl, phenyl or substituted phenyl in which the substituent is W; a, b, c are all single bonds or a and c are double bonds; and W is H, C 1-3 alkyl, chlorine, bromine, fluorine, C 1-3 alkyl, hydroxy or hydroxyC 1-3 alkyl.

Claim 3

A compound of claim 1, wherein R is methyl, or CH 2 OH, CO 2 H,.

Claim 4

A compound of claim 2 wherein R is methyl.

Claim 5

A compound of claim 3 wherein a and c are double bonds.

Claim 6

A compound of claim 4 wherein R 1 is C 1-3 alkyl, chlorine, CF 3 or C 1-3 alkylthio.

Claim 7

A compound of claim 5 wherein R 2 is H or methyl.

Claim 8

A compound of claim 6 wherein R 2 is hydrogen.

Claim 9

A compound of claim 7 which is 6(R)-[2-[(8(S)-(2-chlorobenzoyloxy)-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.

Claim 10

A compound of claim 7 which is 6(R)-[2-[8(S)-(2-trifluoromethylbenzoyloxy)-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.

Claim 11

A compound of claim 7 which is 6(R)-[2-[(S)-(2-methylbenzoyloxy)-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.

Claim 12

A compound of claim 7 which is 6(R) -2-[(S)-(2-methylthiobenzoyloxy)-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.

Claim 13

A compound of claim 7 which is 6(R)-[2-[(S)-(2-isopropylbenzoyloxy)-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.

Claim 14

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

Claim 15

A composition according to claim 13 wherein R is CH 3 , CH 2 OH or CO 2 H.

Claim 16

A composition of claim 14 wherein R is CH 3 .

Claim 17

A composition of claim 15 wherein R 2 is hydrogen and R 1 is C 1-3 alkyl, chlorine, CF 3 or C 1-3 alkylthio.

Claim 18

A composition according to claim 16 in which the therapeutically active ingredient is selected from: a. 6(R)-[2-[(8(S)-(2-chlorobenzoyloxy)-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; b. 6(R)-[2-[(S)-(2-trifluoromethylbenzoyloxy)-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-[(S)-(2-methylbenzoyloxy)-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 d. 6(R)-[2-[(S)-(2-methylthiobenzoyloxy)-2(S), 6(R)-dimethyl-1,2,6,7,8,8a(R)-hexhydronaphthyl-1(S)]-ethyl]-4(R)- hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, e. 6(R)-[2-[(S)-(2-isopropylbenzoyloxy)-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

Claim 19

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

Claim 20

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.

Claim 21

A method according to claim 19 wherein R is CH 3 , CH 2 OH or CO 2 H.

Claim 22

A method according to claim 20 wherein R is CH 3 .

Claim 23

A method according to claim 21 wherein R 2 is hydrogen and R 1 is C 1-3 alkyl, chlorine, CF 3 or C 1-3 alkylthio.

Claim 24

A method according to claim 22 wherein the therapeutically effective ingredient is selected from: a. 6(R)-[2-[(8(S)-(2-chlorobenzoyloxy)-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; b. 6(R)-[2-[8(S)-(2-trifluoromethylbenzoyloxy)-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-methylbenzoyloxy-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; d. 6(R)-[2-[8(S)-(2-methylthiobenzoyloxy)-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; e. 6(R)-[2-[8(S)-(2-isopropylbenzoyloxy)-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.

Claim 25

A compound of claim 6 which is: 6(R)-[2-[8(S)-(2,5-dimethylbenzoyloxy)-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.

Claim 26

A composition according to claim 15 in which the therapeutically active ingredient is: 6(R)-[2-[8(S)-(2,5-dimethylbenzoyloxy)-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.

Claim 27

A method according to claim 21 wherein the therapeutically effective ingredient is: 6(R)-[2[8(S)-(2,5-dimethylbenzoyloxy)-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.