Dibenzyl Amine Compounds and Derivatives

Abstract

Dibenzyl amine compounds and derivatives, pharmaceutical compositions containing such compounds and the use of such compounds to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in some mammals, including humans.

Description

Claims

1. A compound of Formula I

2. A compound according to claim 1, wherein A is —COO(C1-C4)alkyl, —CO(C1-C4)alkyl or Q wherein Q is a five or six membered fully unsaturated ring wherein each ring atom, except for the atom connected to N of Formula I, may be replaced by a nitrogen, oxygen or sulfur atom, and wherein each ring atom may optionally be substituted by cyano, a fully saturated, partially unsaturated or fully unsaturated straight or branched chain having 1 to 6 carbon atoms, or a fully saturated, partially unsaturated or fully unsaturated ring having 3 to 8 carbon atoms, wherein each carbon atom of said chain or ring is optionally replaced by a heteroatom selected from nitrogen, oxygen or sulfur, and said carbon atom of said chain or ring is optionally mono-, di- or tri-substituted with amino, halo, cyano, hydroxy, oxo, carboxyl, (C1-C6)alkoxycarbonyl, or ((C1-C6)alkoxy optionally substituted with one to nine halo or one or two hydroxyl), and said nitrogen atom of said chain or ring is optionally mono- or disubstituted with (C1-C6)alkoxycarbonyl or ((C1-C6)alkyl optionally substituted with one to nine halo or one or two hydroxyl), said sulfur atom of said chain or ring is substituted with one or two oxo;R1 and R6 are each hydrogen;R4 is absent or is hydrogen;R11 is a fully saturated, partially unsaturated or fully unsaturated chain having 1 to 2 carbon atoms, or a fully saturated, partially unsaturated or fully unsaturated mono- or bi-cyclic ring having 3 to 10 carbon atoms, wherein said ring is optionally bicyclic, and wherein each carbon atom of said ring is optionally replaced by a heteroatom selected from nitrogen, oxygen or sulfur, and said carbon atom of said chain or ring is optionally mono di- or tri-substituted with R19, and wherein R11 and R12 are not attached to the carbon of Y at a heteroatom, and wherein R11 and R12 are not both hydrogen;R12 is hydrogen; andR2, R3, R5, and R7 are each independently hydrogen, cyano, ((C1-C6)alkyl optionally substituted with one to nine fluorines) or ((C1-C6)alkoxy optionally substituted with one to nine fluorines).

3. A compound according to claim 2, wherein X is C; and R2, R3, R5, and R7 are each hydrogen, methyl, cyano, or CF3.

4. A compound according to claim 3, wherein R11 is a 6-membered fully saturated ring optionally mono- or di-substituted with R19 and R19 is —(C0-C6)alkyl-aryl, —(C0-C6)alkyl-heteroaryl, —(C0-C6)alkyl-heterocycle, —(C0-C6)alkyl-(C3-C6)cycloalkyl, halo, (C2-C6)alkynyl, (C2-C6)alkenyl, (C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, nitro, cyano, oxo, or —CO—(C1-C6)alkyl, wherein said aryl, heteroaryl, heterocycle, cycloalkyl, alkynyl, alkenyl, alkyl and alkoxy groups are each optionally substituted independently with one to nine halo, one or two hydroxy, one to three (C1-C6)alkyl, one to three (C1-C6)haloalkyl, one to three (C1-C6)alkoxy, one to three (C1-C6)haloalkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy.

5. A compound according to claim 1, wherein A is —COO(C1-C4)alkyl, —CO(C1-C4)alkyl or Q wherein Q is a five or six membered fully unsaturated ring wherein each ring atom, except for the atom connected to N of Formula I, may be replaced by a nitrogen, oxygen or sulfur atom, and wherein each ring atom may optionally be substituted by cyano, a fully saturated, partially unsaturated or fully unsaturated straight or branched chain having 1 to 6 carbon atoms, or a fully saturated, partially unsaturated or fully unsaturated ring having 3 to 8 carbon atoms, wherein each carbon atom of said chain or ring is optionally replaced by a heteroatom selected from nitrogen, oxygen or sulfur, and said carbon atom of said chain or ring is optionally mono-, di- or tri-substituted with amino, halo, cyano, hydroxy, oxo, carboxyl, (C1-C6)alkoxycarbonyl, or ((C1-C6)alkoxy optionally substituted with one to nine halo or one or two hydroxyl), and said nitrogen atom of said chain or ring is optionally mono- or disubstituted with (C1-C6)alkoxycarbonyl or ((C1-C6)alkyl optionally substituted with one to nine halo or one or two hydroxyl), said sulfur atom of said chain or ring is substituted with one or two oxo;X is C;R1, R2, R3, R5, R6, and R7 are each hydrogen, methyl, cyano, or CF3 R4 is absent or is hydrogen;R11 is a 6-membered fully saturated ring optionally mono- or di-substituted with R19 and R19 is —(C0-C6)alkyl-aryl, —(C0-C6)alkyl-heteroaryl, —(C0-C6)alkyl-heterocycle, —(C0-C6)alkyl-(C3-C6)cycloalkyl, halo, (C2-C6)alkynyl, (C2-C6)alkenyl, (C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, nitro, cyano, oxo, or —CO—(C1-C6)alkyl, wherein said aryl, heteroaryl, heterocycle, cycloalkyl, alkynyl, alkenyl, alkyl and alkoxy groups are each optionally substituted independently with one to nine halo, one or two hydroxy, one to three (C1-C6)alkyl, one to three (C1-C6)haloalkyl, one to three (C1-C10-6)alkoxy, one to three (C1-C6)haloalkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy; andR12 is a fully saturated, partially unsaturated or fully unsaturated chain having 1 to 2 carbon atoms, or a fully saturated, partially unsaturated or fully unsaturated mono- or bi-cyclic ring having 3 to 10 carbon atoms, wherein said ring is optionally bicyclic, and wherein each carbon atom of said ring is optionally replaced by a heteroatom selected from nitrogen, oxygen or sulfur, and said carbon atom of said chain or ring is optionally mono-, di- or tri-substituted with R19,wherein R11 and R12 are not attached to the carbon of Y at a heteroatom, and wherein R11 and R12 are not both hydrogen.

6. A compound according to claim 1, wherein A is —COO(C1-C4)alkyl, —CO(C1-C4)alkyl or Q wherein Q is a five or six membered fully unsaturated ring wherein each ring atom, except for the atom connected to N of Formula I, may be replaced by a nitrogen, oxygen or sulfur atom, and wherein each ring atom may optionally be substituted by cyano, a fully saturated, partially unsaturated or fully unsaturated straight or branched chain having 1 to 6 carbon atoms, or a fully saturated, partially unsaturated or fully unsaturated ring having 3 to 8 carbon atoms, wherein each carbon atom of said chain or ring is optionally replaced by a heteroatom selected from nitrogen, oxygen or sulfur, and said carbon atom of said chain or ring is optionally mono-, di- or tri-substituted with amino, halo, cyano, hydroxy, oxo, carboxyl, (C1-C6)alkoxycarbonyl, or ((C1-C6)alkoxy optionally substituted with one to nine halo or one or two hydroxyl), and said nitrogen atom of said chain or ring is optionally mono- or disubstituted with (C1-C6)alkoxycarbonyl or ((C1-C6)alkyl optionally substituted with one to nine halo or one or two hydroxyl), said sulfur atom of said chain or ring is substituted with one or two oxo;X is C;R1, R2, R3, R5, R6, and R7 are each hydrogen, methyl, cyano, or CF3 R4 is absent or is hydrogen; andR11 and R12 are taken together to form a 6- or 7-membered fully saturated or partially unsaturated mono-cyclic ring, wherein the ring is optionally mono-, di- or tri-substitued with R19 and R19 is —(C0-C6)alkyl-aryl, —(C0-C6)alkyl-heteroaryl, —(C0-C6)alkyl-heterocycle, —(C0-C6)alkyl-(C3-C6)cycloalkyl, halo, C2-C6)alkynyl, (C2-C6)alkenyl, (C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, nitro, cyano, oxo, or —CO—(C1-C6)alkyl, wherein said aryl, heteroaryl, heterocycle, cycloalkenyl, cycloalkyl, alkynyl, alkenyl, alkyl and alkoxy groups are each optionally substituted independently with one to nine halo, one or two hydroxy, one to three (C1-C6)alkyl, one to three (C1-C5)haloalkyl, one to three (C1-C6)alkoxy, one to three (C1-C6)haloalkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy.

7. A compound according to claim 1, 4, 5 or 6 wherein X is C; R1, R4 and R6 are each hydrogen; R2, R3, R5, and R7 are each hydrogen, methyl, cyano, or CF3, and A is —COOCH2CH3, —COOCH3, —COCH2CH3, —COCH3, or Q wherein Q is triazolyl, tetrazolyl, oxadiazolyl, isoxazolyl, or pyrazolyl, and wherein Q is optionally substituted with halo, ((C1-C6)alkyl optionally substituted with one or two oxo, one or two hydroxyl or one to nine halo), hydroxy, ((C1-C6)alkoxy optionally substituted with one or two oxo, one or two hydroxyl or one to nine halo), amino, amido, oxo, cyano, carboxy, or ((C1-C6)alkyloxycarbonyl optionally substituted with one or two oxo, one or two hydroxyl and one to nine halo).

8. A compound according to claim 7, wherein Q is

9. A compound according to claim 8, wherein Q is

10. A compound according to claim 9, wherein B is —OR17 and R17 is —(C1-C6)alkyl-aryl, —(C1-C6)alkyl-heteroaryl, —(C0-C6)alkyl-heterocycle, —(C0-C6)alkyl-(C3-C6)cycloalkyl, (C1-C6)alkyl, wherein said aryl, heteroaryl, heterocycle, cycloalkyl, and alkyl substituents are each optionally substituted independently with one to nine halo, one or two hydroxy, one to three (C1-C6)alkyl, one to three (C1-C6)haloalkyl, one to three (C1-C6)alkoxy, one to three (C1-C6)haloalkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy.

11. A compound selected from the group consisting of:

12. A method for treating atherosclerosis, coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia or myocardial infarction in a mammal by administering to a mammal in need of such treatment an atherosclerosis, coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia or myocardial infarction treating amount of a compound of claim 1 or 11 or a pharmaceutically acceptable salt of said compound.

13. A pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 1 or 11, or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable vehicle, diluent or carrier.

14. A pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a compound of claim 1 or 11, or a pharmaceutically acceptable salt of said compound;a second compound, said second compound being an HMG CoA reductase inhibitor, an MTP/Apo B secretion inhibitor, a PPAR modulator, a bile acid reuptake inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, a combination of niacin and lovastatin, a combination of niacin and simvastatin, a combination of niacin and atorvastatin, a combination of amlodipine and atorvastatin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant; anda pharmaceutical vehicle, diluent or carrier.

15. A pharmaceutical combination composition according to claim 14 wherein the second compound is an HMG-CoA reductase inhibitor, a PPAR modulator, or niacin.

16. A pharmaceutical combination composition according to claim 15 wherein the second compound is fenofibrate, gemfibrozil, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, rosuvastatin or pitavastatin.