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

DESCRIPTION OF THE DRAWINGS

FIG. 1 reflects a refined structure of mesylate salt crystal of example 213 [(N-[3,5-bis(trifluoromethyl)benzyl]-N-[2-{(1R)-1-[4-(ethoxymethyl)-4-fluoropiperidin-1-yl]-2-methylpropyl}-5-trifluoromethyl)benzyl]-2-methyl-2H-tetrazol-5-amine)].

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 and 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, ((C1-C6)alkyl optionally substituted with one to nine halo or one or two hydroxyl), 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; andR2, R3, R5, and R7 are each independently hydrogen, cyano, (C1-C6)alkyl or (C1-C6)alkoxy wherein said alkyl and alkoxy substituents each are optionally substituted independently 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 1 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, cyano, —CHO, —CONH2, —COCH2CH3, —COCH3, or Q and Q is

5. A compound of Formula I

6. A compound according to claim 4 or 5, wherein B is —NR15R16 wherein R15 and R16 are each independently hydrogen, —(C1-C6)alkyl-NR8R9, —(C0-C6)alkyl-CO—OR10, —(C1-C6)alkyl-NR13—(C0-C6)alkyl-CO—O—R10, —(C1-C6)alkyl-O—CO—NR8R9, (C1-C6)alkyl, —(C0-C6)alkyl-heterocycle, —(C0-C6)alkyl-(C3-C6)cycloalkyl, —(C0-C6)alkyl-heteroaryl, —(C0-C6)alkyl-aryl, cyano, or —CO—(C1-C6)alkyl, wherein said alkyl substituents are each optionally substituted independently with one to four fluorines, one or two hydroxyl, or one or two (C1-C6)alkoxy; and said heterocycle, heteroaryl or aryl substituents are each optionally substituted with (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy, or halo, wherein said alkyl and alkoxy substituents each optionally substituted independently with one to four fluorines, one or two hydroxyl, or one or two (C1-C6)alkoxy.

7. A compound according to claim 4 or 5, wherein R11 is (C1-C6)alkyl optionally substituted with one to nine halo.

8. A compound according to claim 5, wherein B is an optionally substituted heterocycle selected from the group consisting of

9. A compound according to 8, wherein R20 is halo, —COOH, or (C1-C6)alkyl wherein said alkyl substituents are each optionally substituted independently with one to four fluorines, one or two hydroxyl, or one or two (C1-C6)alkoxy.

10. A compound selected from the group consisting of:

11. 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 10 or a pharmaceutically acceptable salt of said compound.

12. A pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 1 or 10, or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable vehicle, diluent or carrier.

13. 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 10, 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.

14. A pharmaceutical combination composition according to claim 13 wherein the second compound is an HMG-CoA reductase inhibitor, a PPAR modulator, or niacin.

15. A pharmaceutical combination composition according to claim 14 wherein the second compound is fenofibrate, gemfibrozil, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, rosuvastatin or pitavastatin.