IP Library › Granted Patent US 7,091,228
Granted Patent B2
US 7,091,228 · App. 10/839,833 · Granted Aug 15, 2006

Preparation and use of aryl alkyl acid derivatives for the treatment of obesity

View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 7,091,228
App. No.
10/839,833
Granted
Aug 15, 2006
Kind
B2
Abstract

This invention relates to certain aryl alkyl acid compounds, compositions, and methods for treating or preventing obesity and related diseases.

Claims (145)

1. A compound of Formula (I)

wherein

Q is S;

A is a linker selected from

wherein m is 0 and n is 1, 2, 3, or 4, or

m is 1 and n is 1, 2, or 3, and

 wherein said linker is optionally substituted by one or two R 8 groups;

R 1 and R 2 are independently selected from hydrogen, halo, (C 1 –C 6 )alkyl, and (C 1 –C 6 )alkoxy;

R 3 is selected from

hydrogen,

(C 1 –C 6 )alkyl optionally substituted by hydroxy, and

phenyl optionally substituted with (C 1 –C 6 )alkyl, (C 1 –C 6 )alkoxy, or halo;

R 4 is selected from hydrogen, nitro, and (C 1 –C 6 )alkyl; or

R 3 and R 4 may, when taken together with the carbon atoms to which they are attached, form a benzene ring optionally substituted with up to two substituents selected from

halo, (C 1 –C 6 )alkyl, (C 1 –C 6 )alkoxy, nitro, cyano, (C 1 –C 6 )haloalkyl, (C 1 –C 6 )haloalkoxy, aminocarbonyl, (C 1 –C 6 )alkylaminocarbonyl, bis[(C 1 –C 6 )alkyl]aminocarbonyl, aminosulfonyl, (C 1 –C 6 )alkylaminosulfonyl, bis[(C 1 –C 6 )alkyl]aminosulfonyl, (C 1 –C 6 )alkylcarbonylamino, (C 1 –C 6 )alkylsulfonylamino, and hydroxy-(C 2 –C 6 )alkylaminocarbonyl, and

 when two of said benzene ring substituents are (C 1 –C 6 )alkyl and are attached to adjacent carbon atoms of the benzene ring, they may be joined together to form a 5–7-membered carbocyclic ring;

R 8 is (C 1 –C 6 )alkyl;

or the pharmaceutically acceptable salts and esters thereof.

2. The compound of claim 1 , wherein

Q is S;

A is

wherein m is 0 and n is 1, 2, 3, or 4, or

m is 1 and n is 1, 2, or 3, and

 wherein said linker is optionally substituted by one or two R 8 groups;

R 3 and R 4 may, when taken together with the carbon atoms to which they are attached, form a benzene ring optionally substituted with up to two substituents selected from

halo, (C 1 –C 6 )alkyl, (C 1 –C 6 )alkoxy, nitro, cyano, (C 1 –C 6 )haloalkyl, (C 1 –C 6 )haloalkoxy, aminocarbonyl, (C 1 –C 6 )alkylaminocarbonyl, bis[(C 1 –C 6 )alkyl]aminocarbonyl, aminosulfonyl, (C 1 –C 6 )alkylaminosulfonyl, bis[(C 1 –C 6 )alkyl]aminosulfonyl, (C 1 –C 6 )alkylcarbonylamino, (C 1 –C 6 )alkylsulfonylamino, hydroxy-(C 2 –C 6 )alkylaminocarbonyl, and

R 1 , R 2 , R 5 , and R 8 are as defined in claim 1 .

3. The compound of claim 1 , wherein

Q is S;

A is

wherein

m is 1 and n is 1, 2, or 3, and

 wherein said linker is optionally substituted by one or two R 8 groups;

R 3 and R 4 may, when taken together with the carbon atoms to which they are attached, form a benzene ring optionally substituted with up to two substituents selected from

halo, (C 1 –C 6 )alkyl, (C 1 –C 6 )alkoxy, nitro, cyano, (C 1 –C 6 )haloalkyl, (C 1 –C 6 )haloalkoxy, aminocarbonyl, (C 1 –C 6 )alkylaminocarbonyl, bis[(C 1 –C 6 )alkyl]aminocarbonyl, aminosulfonyl, (C 1 –C 6 )alkylaminosulfonyl, bis[(C 1 –C 6 )alkyl]aminosulfonyl, (C 1 –C 6 )alkylcarbonylamino, (C 1 –C 6 )alkylsulfonylamino, and hydroxy-(C 2 –C 6 )alkylaminocarbonyl,

R 1 , R 2 , and R 8 are as defined in claim 1 .

4. The compound of claim 1 , wherein

Q is S;

A is

wherein m is 0 and n is 1, 2, 3, or 4, and

 wherein said linker is optionally substituted by one or two R 8 groups;

R 3 and R 4 may, when taken together with the carbon atoms to which they are attached, form a benzene ring optionally substituted with up to two substituents selected from

halo, (C 1 –C 6 )alkyl, (C 1 –C 6 )alkoxy, nitro, cyano, (C 1 –C 6 )haloalkyl, (C 1 –C 6 )haloalkoxy, aminocarbonyl, (C 1 –C 6 )alkylaminocarbonyl, bis[(C 1 –C 6 )alkyl]aminocarbonyl, aminosulfonyl, (C 1 –C 6 )alkylaminosulfonyl, bis[(C 1 –C 6 )alkyl]aminosulfonyl, (C 1 –C 6 )alkylcarbonylamino, (C 1 –C 6 )alkylsulfonylamino, hydroxy-(C 2 –C 6 )alkylaminocarbonyl,

R 1 , R 2 , and R 8 are as defined in claim 1 .

5. The compound of claim 1 selected from the group consisting of:

trans-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl) cyclopentane-carboxylic acid;

trans-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl) cyclopentane-carboxylic acid;

trans-(1R,2R)-2-{[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]carbonyl}cyclopentane-carboxylic acid;

trans-2-{[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]carbonyl}cyclopentane-carboxylic acid;

trans-2-({4′-[(5-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;

trans-2-({4′-[(6-nitro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;

trans-2-({4′-[(4-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl) cyclopentane-carboxylic acid;

trans-2-({4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;

trans-2-({4′-[(6-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;

trans-2-({4′-[(6-ethoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;

trans-2-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;

trans-(1R,2R)-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylic acid;

trans-(1S,2S)-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylic acid;

2,2-dimethyl-4-{4′-[(5-nitro-1,3-thiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-4-oxobutanoic acid;

trans-(1R,2R)-2-({4′-[(4,6-difluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;

trans-(1S,2S)-2-({4′-[(4,6-difluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;

cis-3-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclohexane-carboxylic acid;

cis-3-({4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclohexane-carboxylic acid;

trans-2-[(4′-{[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4-yl)carbonyl]cyclopentane-carboxylic acid;

trans-(1R,2R)-2-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylic acid;

trans-(1R,2R)-2-({4′-[(6-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylic acid;

trans-(1S,2S)-2-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylic acid;

trans-(1S,2S)-2-({4′-[(6-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylic acid;

trans-2-({4′-[(4,6-difluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;

trans-2-({4′-[(4-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;

trans-2-({4′-[(5-fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;

trans-2-[(4′-{[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4-yl)carbonyl]-cyclopentane-carboxylic acid;

trans-2-({4′-[(5-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;

trans-2-({4′-[(5,7-dimethyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;

trans-2-[(4′-{[6-(methylsulfonyl)-1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4-yl)carbonyl]-cyclopentane-carboxylic acid;

trans-2-({4′-[(5,6-dimethyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;

trans-2-({4′-[(5,7-difluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;

trans-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;

trans-(1R,2R)-2-[(4′-{[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4-yl)-carbonyl]cyclopentane-carboxylic acid;

trans-2-{[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]carbonyl}cyclopropane-carboxylic acid;

trans-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclohexane-carboxylic acid;

trans-2-({4′-[(4-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopropane-carboxylic acid;

trans-2-({4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopropane-carboxylic acid;

trans-2-({4′-[(5,7-difluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopropane-carboxylic acid;

trans-2-({4′-[(4,6-difluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopropane-carboxylic acid;

trans-2-{[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]carbonyl}cyclobutane-carboxylic acid;

trans-2-({4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclobutane-carboxylic acid;

trans-2-({4′-[(4-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclobutane-carboxylic acid;

trans-(1R,2R)-2-({4′-[(6-isopropyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;

trans-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-3′-fluoro-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylic acid;

trans-2-({3′-fluoro-4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylic acid;

trans-(1R,2R)-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-3′-fluoro-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylic acid

trans-(1R,2R)-2-({3′-fluoro-4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylic acid

trans-2-{[4′-(1,3-benzothiazol-2-ylamino)-3′-fluoro-1,1′-biphenyl-4-yl]carbonyl}cyclopentane-carboxylic acid;

trans-(1R,2R)-2-({4′-[(4,6-difluoro-1,3-benzothiazol-2-yl)amino]-3′-fluoro-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylic acid;

trans-(1S,2S)-2-({4′-[(4,6-difluoro-1,3-benzothiazol-2-yl)amino]-3′-fluoro-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylic acid;

trans-(1R,2R)-2-[(3′-fluoro-4′-{[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4-yl)carbonyl]cyclopentane-carboxylic acid;

trans-(1R,2R)-2-({3′-fluoro-4′-[(5-fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylic acid;

trans-(1R,2R)-2-({3′-fluoro-4′-[(4-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-carbonyl)cyclopentane-carboxylic acid;

trans-(1R,2R)-2-({4′-[(5-chloro-1,3-benzothiazol-2-yl)amino]-3′-fluoro-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;

trans-(1R,2R)-2-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;

trans-(1R,2R)-2-({3′-fluoro-4′-[(6-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-carbonyl)cyclopentane-carboxylic acid;

trans-(1R,2R)-2-({4′-[(5,7-dimethyl-1,3-benzothiazol-2-yl)amino]-3′-fluoro-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;

trans-(1R,2R)-2-({4′-[(5,7-difluoro-1,3-benzothiazol-2-yl)amino]-3′-fluoro-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid

trans-(1R,2R)-2-[(3′-fluoro-4′-{[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino)}-1,1′-biphenyl-4-yl)carbonyl]cyclopentane-carboxylic acid;

trans-(1R,2R)-2-[(3′-fluoro-4′-{[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4-yl)carbonyl]cyclopentane-carboxylic acid;

trans-2-({3′-fluoro-4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclobutane-carboxylic acid;

trans-2-{[4′-(1,3-benzothiazol-2-ylamino)-3′-fluoro-1,1′-biphenyl-4-yl]carbonyl}cyclobutane-carboxylic acid;

trans-2-{[4′-(1,3-benzothiazol-2-ylamino)-3′-fluoro-1,1′-biphenyl-4-yl]carbonyl}cyclopropane-carboxylic acid;

trans-2-({3′-fluoro-4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopropane-carboxylic acid

trans-(1R,2R)-2-({3′-fluoro-4′-[(6-isopropyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;

trans-2-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amnino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylic acid;

trans-2-[(3′-fluoro-4′-{[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4-yl)-carbonyl]cyclopentane-carboxylic acid;

(1R,2R)-2-[{3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}(hydroxy)-methyl]cyclopentanecarboxylic acid.

6. A therapeutic composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or ester, in combination with a pharmaceutically acceptable carrier.

7. A therapeutic composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or ester thereof, in combination with a pharmaceutically acceptable carrier and one or more pharmaceutical agents.

8. The therapeutic composition of claim 7 , wherein said pharmaceutical agent is an anti-obesity agent selected from the group consisting of β-3 agonists, CB-1 antagonists, neuropeptide Y5 inhibitors, appetite suppressants, and lipase inhibitors.

9. The therapeutic composition of claim 7 , wherein said pharmaceutical agent is an agent for the treatment of diabetes selected from the group consisting of insulin, insulin derivatives, PPAR ligands, sulfonylurea drugs, α-glucosidase inhibitors, biguanides, PTP-1B inhibitors, DPP-IV inhibitors, 11-beta-HSD inhibitors, GLP-1 and GLP-1 derivatives, GIP and GIP derivatives, PACAP and PACAP derivatives, and secretin and secretin derivatives.

10. The therapeutic composition of claim 7 , wherein said pharmaceutical agent is an agent for the treatment of lipid disorders selected from the group consisting of HMG-CoA inhibitors, nicotinic acid, fatty acid lowering compounds, lipid lowering drugs, ACAT inhibitors, bile sequestrants, bile acid reuptake inhibitors, microsomal triglyceride transport inhibitors, and fibric acid derivatives.

11. The therapeutic composition of claim 7 , wherein said pharmaceutical agent is an anti-hypertensive agent selected from the group consisting of β-blockers, calcium channel blockers, diuretics, renin inhibitors, ACE inhibitors, AT-1 receptor antagonists, ET receptor antagonists, and nitrates.

12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 5 , or, or a pharmaceutically acceptable salt or ester, in combination with a pharmaceutically acceptable carrier.

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 5 , or, or a pharmaceutically acceptable salt or ester thereof, in combination with a pharmaceutically acceptable carrier and one or more pharmaceutical agents.

14. A method of treating obesity comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a composition of claim 6 .

15. A method of inducing weight loss comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a composition of claim 6 .

16. A method of treating obesity comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 in combination with one or more therapeutic agents.

17. The method of claim 16 , wherein the compound of claim 1 and one or more therapeutic agents are administered as a single pharmaceutical dosage formulation.

18. A method of treating obesity comprising the step of administering to a subject in need thereof a therapeutically effective amount of a composition of claim 7 , 8 , 9 , 10 , or 11 .

19. A process for the preparation of a compound of Formula (VIII) comprising the steps of:

reacting a compound of Formula (II)

wherein

R is hydrogen or (C 1 –C 6 )alkyl;

X is Cl, Br, or I; and

R 1 and A are as defined in claim 1 ;

with a boronic ester reagent to give a compound of Formula (X)

wherein

R is hydrogen or (C 1 –C 6 )alkyl; and

R 1 and A are as defined in claim 1 ;

and coupling the compound of Formula (X) with a compound of Formula (IX)

wherein

R 2 , R 3 , R 4 , and Q are as defined in claim 1 ;

in the presence of a palladium catalyst, and optionally in the presence of a base, to give the compound of Formula (VIII)

wherein

R is hydrogen or (C 1 –C 6 )alkyl,

R 1 , R 2 , R 3 , R 4 , A, and Q are as defined in claim 1 .

20. The process of claim 19 , wherein the boronic ester reagent is pinnacol borane and the base is potassium carbonate.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 27, 2009
From: BAYER PHARMACEUTICALS CORPORATION
To: BAYER HEALTHCARE LLC
Reel/Frame 023027/0804 →