Squalene synthetase inhibitors

Claim 3

The method of claim 1 wherein: R 1 is hydrogen; R 2 is --H, or --CH 3 ; R 3 is --H, --OH, or --OCH 3 ; R 4 is --H, --CH 3 , or --CH 2 --CH═CH 2 ; R 5 is hydrogen, fluorine, or methyl; and R 6 and R 7 together represent ═0, or R 6 and R 7 are independently selected from hydrogen, hydroxyl, methyl, ethyl, ethenyl, 2-naphthyl, acetoxy, phenyl, and 4-substituted phenyl wherein the substituent is fluoro or hydroxyl.

Claim 4

The method of claim 1 wherein the squalene synthetase inhibitor is: a) 3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]-1-azabicyclo[2.2.2]octane; b) 3-[3-(1-phenylethyl-1,2,4-oxadiazol-5-yl]-1-azabicyclo[2.2.2]octane; c) 3-[3-(1-methyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl]-1-azabicyclo[2.2.2]octane; d) 3-[3-(5-fluoro-1-methyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl]-1-azabicyclo[2.2.2]octane; e) α-methyl-α-phenyl-5-(1-azabicyclo[2.2.2]-oct-3-yl)-1,2,4-oxadiazole-3-methanol; f) 3-[3-(1-acetoxy-1-phenylmethyl)-1,2,4-oxadia-zol-5-yl]-quinuclidine; g) α-phenyl-5-(1-azabicyclo[2.2.2]oct-3-yl)-1,2,4-oxadiazole-3-methanol h) 3-[3-(1-methyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl]-1-azabicyclo[2.2.2]octane)boron; i) α-ethyl-α-phenyl-5-(1-azabicyclo[2.2.2]oct-3-yl)-1,2,4-oxadiazole-3-methanol; j) α-ethenyl-α-phenyl-5-(1-azabicyclo[2.2.2]oct-3-yl)-1,2,4-oxadiazole-3-methanol; k) 3-[3-(diphenylmethyl)-1,2,4-oxadiazol-5-yl]-1-azabicyclo[2.2.2]octane; l) α-(4-fluorophenyl)-α-phenyl-5-(1-azabicyclo[2.2.2]oct-3-yl)-1,2,4-oxadiazole-3-methanol; m) α-(4-methoxyphenyl)-α-phenyl-5-(1-azabicyclo[2.2.2]oct-3-yl)-1,2,4-oxadiazole-3-methanol; n) α-2-naphthalenyl-α-phenyl-5-(1-azabicyclo[2.2.2]oct-3-yl)-1,2,4-oxadiazole-3-methanol; o) 3-[3-(1-methyl-1H-indol-2-yl)-1,2,4-oxadiazol-5-yl]-1-azabicyclo[2.2.2]octane; p) 2-methoxy-3-[3-(1-methyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl]-1-azabicyclo[2.2.2]octane; q) 3-[3-(1H-indazol-3-yl)-1,2,4-oxadiazol-5-yl]-1-azabicyclo[2.2.2]octane; r) 3-[3-(1,7-dimethyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl]-1-azabicyclo[2.2.2]octane; s) 3-[3-(1,5-dimethyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl]-1-azabicyclo[2.2.2]octane; t) 3-[3-(1H-indol-3-yl)-1,2,4-oxadizol-5-yl]-1-azabicyclo[2.2.2]octane; u) (+)-3-[3-(1-methyl-1H-indol-3-yl)-1,2,4-oxadi-azol-5-yl]-1-azabicyclo[2.2.2]octane; v) (-)-3-[3-(1-methyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl]-1-azabicyclo[2.2.2]octane; w) 3-[3-(2-naphthalenyl)-1,2,4-oxadiazol-5-yl]-1-azabicyclo[2.2.2]octane; x) 3-[3-phenyl-1,2,4-oxadiazol-5-yl]-1-azabicyclo[2.2.2]octane; y) 3-[3-(1-(2-propenyl)-1H-indol-3-yl]-1,2,4-oxadiazol-5-yl)-1-azabicyclo[2.2.2]octane; z) 3-[3-(3-pyridinyl)-1,2,4-oxadiazol-5-yl]-1-azabicyclo[2.2.2]octane; aa) 3-[3-(1-naphthalenyl)-1,2,4-oxadiazol-5-yl]-1-azabicyclo[2.2.2]octane; bb) 3-[3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-azabicyclo[2.2.2]octane; cc) 3-[3-(2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-azabicyclo[2.2.2]octane; dd) 3-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-azabicyclo[2.2.2]octane; ee) 2-[5-(1-azabicyclo[2.2.2]oct-3-yl)-1,2,4-oxadiazol-5-yl]-phenol; ff) 3-[5-(1-azabicyclo[2.2.2]oct-3-yl)-1,2,4-oxadiazol-5-yl]-phenol; gg) 4-[5-(1-azabicyclo[2.2.2]oct-3-yl)-1,2,4-oxadiazol-5-yl]-phenol; hh) 3-[3-(1,1-diphenyl-1-hydroxymethyl)-1,2,4-oxadiazol-5-yl]-quinuclidine; ii) 3-[3-(1H-indol-3-yl)-1,2,4-oxadiazol-5-yl]-1-azabicyclo[2.2.2]octane; jj) 3-[3-(3-quinolyl)-1,2,4-oxadiazol-5-yl]-1-azabicyclo[2.2.2]octane; or kk) 3-(3-benzoyl-1,2,4-oxadiazol-5-yl)quinuclidine; or a pharmaceutically acceptable salt thereof.

Claim 5

A method of treating hypercholesterolemia comprising administration to a subject in need of such treatment of 10 to 400 mg per day of a squalene synthetase inhibitor of claim 1.

Claim 6

A method of treating hypercholesterolemia comprising administration to a subject in need of such treatment of 10 to 400 mg per day of a squalene synthetase inhibitor of claim 2.

Claim 7

A method of treating hypercholesterolemia comprising administration to a subject in need of such treatment of 10 to 400 mg per day of a squalene synthetase inhibitor of claim 3.

Claim 8

The method of claim 1, wherein the amount of the squalene synthetase inhibitor administered per day is from 20 to 200 mg.

Claim 9

The method of claim 2, wherein the amount of the squalene synthetase inhibitor administered per day is from 20 to 200 mg.

Claim 10

The method of claim 3, wherein the amount of the squalene synthetase inhibitor administered per day is from 20 to 200 mg.

Claim 11

The method of claim 4, wherein the amount of the squalene synthetase inhibitor administered per day is from 20 to 200 mg.

Claim 12

The method of claim 5, wherein the amount of the squalene synthetase inhibitor administered per day is from 20 to 200 mg.

Claim 13

The method of claim 6, wherein the amount of the squalene synthetase inhibitor administered per day is from 20 to 200 mg.

Claim 14

The method of claim 1 wherein the compound of formula (I) is administered as the hydrochloride, oxalate or citrate salt.

Claim 15

The method of claim 2 wherein the compound of formula (I) is administered as the hydrochloride, oxalate or citrate salt.

Claim 16

The method of claim 3 wherein the compound of formula (I) is administered as the hydrochloride, oxalate or citrate salt.

Claim 17

The method of claim 4 wherein the compound of formula (I) is administered as the hydrochloride, oxalate or citrate salt.

Claim 18

The method of claim 5 wherein the compound of formula (I) is administered as the hydrochloride, oxalate or citrate salt.

Claim 19

The method of claim 6 wherein the compound of formula (I) is administered as the hydrochloride, oxalate or citrate salt.

Claim 20

A pharmaceutical composition comprising 1 to 400 mg of a compound of claim 1 in combination with a pharmaceutically acceptable nontoxic cationic polymer capable of binding bile acids in a non-resorbable form in the gastrointestinal tract and a pharmaceutically acceptable carrier.

Claim 21

A pharmaceutical composition comprising 1 to 400 mg of a compound of claim 1 in combination with a nontoxic therapeutically effective amount of a cholesterol lowering agent selected from the group consisting of: (a) HMG-CoA reductase inhibitor; (b) HMG-CoA synthase inhibitor; (c) Squalene epoxidase inhibitor; (d) Probucol; (e) Niacin; (f) Gemfibrozil; (g) Clofibrate; and (h) LDL-receptor gene inducer.

Claim 22

A pharmaceutical composition comprising 1 to 400 mg of a compound of claim 1 and a nontoxic therapeutically effective amount of an HMG-CoA reductase inhibitor.

Claim 23

A composition of claim 21 wherein the HMG-CoA reductase inhibitor is selected from lovastatin, simvastatin, pravastatin and fluvastatin.

Claim 24

A pharmaceutical composition comprising 1 to 400 mg of a compound of claim 3 in combination with a pharmaceutically acceptable nontoxic cationic polymer capable of binding bile acids in a non-resorbable form in the gastrointestinal tract and a pharmaceutically acceptable carrier.

Claim 25

A pharmaceutical composition comprising 1 to 400 mg of a compound of claim 3 in combination with a nontoxic therapeutically effective amount of a cholesterol lowering agent selected from the group consisting of: (a) HMG-CoA reductase inhibitor; (b) HMG-CoA synthase inhibitor; (c) Squalene epoxidase inhibitor; (d) Probucol; (e) Niacin; (f) Gemfibrozil; (g) Clofibrate; and (h) LDL-receptor gene inducer.