Dibenzyl amine compounds and derivatives

• US 8,383,660 B2
• Filed: 01/03/2007
• Issued: 02/26/2013
• Est. Priority Date: 03/10/2006
• Status: Expired due to Fees

• Current Assignee: Pfizer Inc., Pfizer Products Incorporated (Pfizer Inc.)
• Original Assignee: Pfizer Inc.
• Inventors: Chang, George, Garigipati, Ravi S., Lefker, Bruce, Perry, David A.
• Primary Examiner(s): Kosack, Joseph
• Assistant Examiner(s): Coughlin, Matthew P
• Application Number:
  US11/619,299
• Publication Number:
  US 20070213314A1
• Time in Patent Office: 2,246 Days
• Field of Search: 514/381, 514/210.2, 514/238.8, 514/232.2, 514/326, 514/210.18, 514/278, 514/364, 514/256, 514/299, 514/300, 514/254.07, 514/253.09, 514/235.2, 514/316, 514/218, 514/340, 514/365, 514/227.8, 514/378, 540/575, 540/582, 544/60, 544/82, 544/130, 544/120, 544/129, 544/132, 544/364, 544/366, 546/16, 546/113, 546/186, 546/187, 546/193, 546/210, 546/209, 546/268.4, 548/131, 548/143, 548/202, 548/251, 548/207
• US Class Current: 514/381
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 257/06 with nitrogen atoms directly attached to the ring carbon atom
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 453/06 containing isoquinuclidine ring systems
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

Dibenzyl amine compounds and derivatives of Formula I, 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.

Claims

1. A compound or pharmaceutically acceptable derivative or variation 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; and

R², 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

6. A compound according to claim 4, 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.

11. 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.

12. 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; and

a pharmaceutically acceptable vehicle, diluent or carrier.

13. A pharmaceutical combination composition according to claim 12 wherein the second compound is an HMG-CoA reductase inhibitor, a PPAR modulator, or niacin.

14. A pharmaceutical combination composition according to claim 13 wherein the second compound is fenofibrate, gemfibrozil, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, rosuvastatin or pitavastatin.

5. A compound or pharmaceutically acceptable derivative or variation of Formula I

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 or pharmaceutically acceptable derivative or variation selected from the group consisting of:

N-[3,5-Bis(trifluoromethyl)benzyl]-2-methyl-N-[2-(1-morpholin-4-yl-propyl)-5-(trifluoromethyl)benzyl]-2H-tetrazol-5-yl-amine;

(R)-N-[3,5-Bis(trifluoromethyl)benzyl]-2-methyl-N-[2-(1-morpholin-4-yl-propyl)-5-(trifluoromethyl)benzyl]-2H-tetrazol-5-yl-amine;

(S)-N-[3,5-Bis(trifluoromethyl)benzyl]-2-methyl-N-[2-(1-morpholin-4-yl-propyl)-5-(trifluoromethyl)benzyl]-2H-tetrazol-5-yl-amine;

N-[3,5-Bis(trifluoromethyl)benzyl]-2-methyl-N-[2-(2-methyl-1-morpholin-4-ylpropyl)-5-(trifluoromethyl)benzyl]-2H-tetrazol-5-yl-amine;

(R)-N-[3,5-Bis(trifluoromethyl)benzyl]-2-methyl-N-[2-(2-methyl-1-morpholin-4-ylpropyl)-5-(trifluoromethyl)benzyl]-2H-tetrazol-5-yl-amine;

(S)-N-[3,5-Bis(trifluoromethyl)benzyl]-2-methyl-N-[2-(2-methyl-1-morpholin-4-ylpropyl)-5-(trifluoromethyl)benzyl]-2H-tetrazol-5-yl-amine;

N-[3,5-Bis(trifluoromethyl)benzyl]-2-methyl-N-[2-(1-piperidin-1-ylpropyl)-5-(trifluoromethyl)benzyl]-2H-tetrazol-5-yl-amine;

(R)-N-[3,5-Bis(trifluoromethyl)benzyl]-2-methyl-N-[2-(1-piperidin-1-ylpropyl)-5-(trifluoromethyl)benzyl]-2H-tetrazol-5-yl-amine;

(S)-N-[3,5-Bis(trifluoromethyl)benzyl]-2-methyl-N-[2-(1-piperidin-1-ylpropyl)-5-(trifluoromethyl)benzyl]-2H-tetrazol-5-yl-amine;

N-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-[2-(1-pyrrolidin-1-yl-propyl)-5-trifluoromethyl-benzyl]-amine;

(R)-N-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-[2-(1-pyrrolidin-1-yl-propyl)-5-trifluoromethyl-benzyl]-amine;

(S)-N-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-[2-(1-pyrrolidin-1-yl-propyl)-5-trifluoromethyl-benzyl]-amine;

(N-[3,5-bis(trifluoromethyl)benzyl]-N-[2-{1-[4-(ethoxymethyl)-4-fluoropiperidin-1-yl]-2-methylpropyl}-5-(trifluoromethyl)benzyl]-2-methyl-2H-tetrazol-5-amine);

(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);

(N-[3,5-bis(trifluoromethyl)benzyl]-N-[2-{(1S)-1-[4-(ethoxymethyl)-4-fluoropiperidin-1-yl]-2-methylpropyl}-5-(trifluoromethyl)benzyl]-2-methyl-2H-tetrazol-5-amine);

1-{1-[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-4-(trifluoromethyl)phenyl]-2-methylpropyl}piperidine-4-carboxylic acid;

(1R)-{1-[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-4-(trifluoromethyl)phenyl]-2-methylpropyl}piperidine-4-carboxylic acid;

(1S)-{1-[2-({[3,5-bis(trifluormethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-4-(trifluoromethyl)phenyl]-2-methylpropyl}piperidine-4-carboxylic acid;

1-{1-[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-4-(trifluoromethyl)phenyl]-propyl}piperidine-4-carboxylic acid;

(1R) {1-[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-4-(trifluoromethyl)phenyl]-propyl}piperidine-4-carboxylic acid;

(1S)-{1-[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-4-(trifluoromethyl)phenyl]-propyl}piperidine-4-carboxylic acid;

N-(2-(1-(3-fluoroazetidin-1-yl)-2-methylpropyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine;

(R)-N-(2-(1-(3-fluoroazetidin-1-yl)-2-methylpropyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine;

(S)-N-(2-(1-(3-fluoroazetidin-1-yl)-2-methylpropyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine;

1(1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-2-methylpropyl)piperidine-4-carbonitrile;

(R)-1-(1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl) amino)methyl)-4-(trifluoromethyl)phenyl)-2-methylpropyl)piperidine-4-carbonitrile;

(S)-1-(1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-2-methylpropyl)piperidine-4-carbonitrile;

1-(1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-2-methylpropyl)azetidine-3-carbonitrile;

(R)-1-(1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl amino)methyl)-4-(trifluoromethyl)phenyl)-2-methylpropyl)azetidine-3-carbonitrile;

(S)-1-[(1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl phenyl)-2-methylpropyl)azetidine-3-carbonitrile.

N-(2-(1-(3,3-difluoroazetidin-1-yl)-2-methylpropyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine

(R)-N-(2-(1-(3,3-difluoroazetidin-1-yl)-2-methylpropyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine;

(S)-N-(2-(1-(3,3-difluoroazetidin-1-yl)-2-methylpropyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine;

1-(1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-2-methylpropyl)piperidine-4-carboxamide;

(R)-1-(1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-2-methylpropyl)piperidine-4-carboxamide;

(S)-1-(1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-2-methylpropyl)piperidine-4-carboxamide;

(3,5-Bis-trifluoromethyl-benzyl)-{2-[1-(4-ethoxymethyl-4-fluoro-piperidin-1-yl)-propyl]-5-trifluoromethyl-benzyl}-(2-methyl-2H-tetrazol-5-yl)-amine;

(R)-(3,5-Bis-trifluoromethyl-benzyl)-{2-[1-(4-ethoxymethyl-4-fluoro-piperidin-1-yl)-propyl]-5-trifluoromethyl-benzyl}-(2-methyl-2H-tetrazol-5-yl)-amine;

(S)-(3,5-Bis-trifluoromethyl-benzyl)-{2-[1-(4-ethoxymethyl-4-fluoro-piperidin-1-yl)-propyl]-5-trifluoromethyl-benzyl}-(2-methyl-2H-tetrazol-5-yl)-amine;

2-(1-(1(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-2-methylpropyl)piperidin-4-yl)ethanol;

(R)-2-(1-(1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-2-methylpropyl)piperidin-4-yl)ethanol; and

(S)-2-(1-(1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-2-methylpropyl)piperidin-4-yl)ethanol;

or a pharmaceutically acceptable salt of said compound or pharmaceutically acceptable derivative or variation, wherein the pharmaceutically acceptable derivative or variation is selected from the group consisting of conformational isomers, optical isomers, mixtures of conformational isomers, mixtures of optical isomers, tautomers, esters, and prodrugs of said compound.

15. A compound selected from the group consisting of :

1-{1-[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-4-(trifluoromethyl)phenyl]-2-methylpropyl}piperidine-4-carboxylic acid; and

(1R)-{1-2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-4-(trifluoromethyl)phenyl]-2-methylpropyl}piperidine-4-carboxylic acid;

or a pharmaceutically acceptable salt thereof.

16. A compound (1R)-{1-[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H -tetrazol-5-yl)amino}methyl)-4-(trifluoromethy)phenyl]-2-methylpropyl}piperidine-4-carboxylic acid;

or a pharmaceutically acceptable salt thereof.