Therapeutic uses of di-aryl acid derivatives

• US RE40,558 E1
• Filed: 10/20/2005
• Issued: 10/28/2008
• Est. Priority Date: 04/28/1999
• Status: Expired due to Term

• Current Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Original Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Inventors: McGarry, Daniel G., Groneberg, Robert D., Labaudiniere, Richard F., Bobko, Mark, Caulfield, Thomas J., Kelley, Michael F., McGeehan, Gerard M., Minnich, Anne, Jayyosi, Zaid, Zhang, Litao
• Primary Examiner(s): BALASUBRAMANIAN, VENKATARAMAN
• Application Number:
  US11/254,215
• Time in Patent Office: 1,104 Days
• Field of Search: 546/152, 548/235, 514/311, 514/374
• US Class Current: 514/311
• CPC Class Codes: C07C 233/11 with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 235/06 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 235/34 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 311/51 Y being a hydrogen or a carbon atom
• CPC Class Codes: C07C 323/12 the carbon skeleton being acyclic and saturated
• CPC Class Codes: C07C 323/52 the carbon skeleton being acyclic and saturated
• CPC Class Codes: C07C 59/66 the non-carboxylic part of the ether containing six-membered aromatic rings
• CPC Class Codes: C07C 59/68 the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
• CPC Class Codes: C07C 65/24 polycyclic
• CPC Class Codes: C07C 69/94 of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07D 209/18 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/34 in position 2
• CPC Class Codes: C07D 213/643 2-Phenoxypyridines; Derivatives thereof
• CPC Class Codes: C07D 215/12 with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 215/14 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 215/18 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 215/233 only one oxygen atom which is attached in position 4
• CPC Class Codes: C07D 215/38 Nitrogen atoms nitro radicals C07D215/18
• CPC Class Codes: C07D 215/60 N-oxides
• CPC Class Codes: C07D 217/04 with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 231/56 : Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 239/90 : with acyclic radicals attached in position 2 or 3
• CPC Class Codes: C07D 241/44 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 257/04 : Five-membered rings
• CPC Class Codes: C07D 263/32 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 307/81 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 333/28 : Halogen atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• 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 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: Y10S 514/824 : Arteriosclerosis
• CPC Class Codes: Y10S 514/866 : Diabetes
• CPC Class Codes: Y10S 514/884 : Hypoglycemia

Abstract

The use of diaryl acid derivatives of formula (I)
or pharmaceutically acceptable salts, N-oxides, hydrates or solvates thereof, wherein the variables shown are defined in the disclosure, and their pharmaceutical compositions as PPAR ligand receptor binders. The PPAR ligand receptor binders of this invention are useful as agonists or antagonists of the PPAR receptor.

Claims

1. A compound of formula (I)

wherein:

is oxazolyl or quinolinyl, which are optionally substituted by one or more ring system substituents;

is phenyl, which is optionally substituted by one or more ring system substituents, in addition to being substituted by group Z;

A is

B and E are a chemical bond;

a is 1;

b is 0 or 1;

c is 0;

d is 0;

g is 1-5;

R₁, R₂, R₃ and R₄ are, independently, hydrogen, halogen or alkyl, wherein alkyl is optionally substituted by one or more alkyl group substituents;

Z is R₂₁O₂C—

, R₂₁OC—

, —

CN, R₂₁O₂SHNCO—

, R₂₁O₂SHN—

, (R₂₁)₂NCO—

or R₂₁O—

;

R₂₁ is independently

hydrogen,

alkyl, which is optionally substituted by one or more alkyl group substituents,

aryl, which is optionally substituted by one or more ring system substituents,

cycloalkyl, which is optionally substituted by one or more ring system substituents, or

aralkyl, wherein the aryl portion is optionally substituted by one or more ring system substituents and the alkyl portion is optionally substituted by one or more alkyl group substituents;

R₁₅, R₁₆ are independently

hydrogen,

alkyl, which is optionally substituted by one or more alkyl group substituents,

aralkyl, wherein the aryl portion is optionally substituted by one or more ring system substituents and the alkyl portion is optionally substituted by one or more alkyl group substituents, or

alkoxycarbonyl, wherein the alkyl portion is optionally substituted by one or more alkyl group substituents;

or a pharmaceutically acceptable salt thereof, or an N-oxide thereof, a hydrate thereof or a solvate thereof,

wherein

alkyl is an aliphatic hydrocarbon group which is straight or branched having 1 to about 20 carbon atoms;

aryl is an aromatic monocyclic or multicyclic ring system of about 6 to about 14 carbon atoms;

a ring system substituent is halo, unsubstituted lower alkyl of 1 to about 4 carbon atoms, unsubstituted alkoxy, unsubstituted aryloxy, unsubstituted aralkyloxy or unsubstituted cycloalkylalkyloxy; and

an alkyl group substituent is unsubstituted acyl, carboxyl, unsubstituted carboxymethyl, unsubstituted methoxycarbonylethyl, unsubstituted benzyloxycarbonylmethyl, unsubstituted pyridylmethyloxycarbonylmethyl or unsubstituted alkoxycarbonyl.

2. A compound according to claim 1 wherein a=0;

R₁₅ and R₁₆ are hydrogen;

g is 1, 2, 3 or 4; and

b=0.

3. A compound according to claim 1 wherein Z is R₂₁O₂SHNCO—

, and R₂₁ is phenyl, wherein phenyl is optionally substituted by one or more ring system substituents.

4. A compound according to claim 1 wherein Z is —

CO₂H or —

CN.

5. A compound according to claim 1 wherein

is unsubstituted quinolin-2-yl, 3-substituted quinolin-2-yl, 4-substituted quinolin-2-yl, 6-substituted quinolin-2-yl or 7 substituted quinolin-2-yl; or 2-substituted-oxazol4-yl or 2,5 disubstituted-oxazol4-yl;

4-substituted oxazol-2-yl or 4,5-disubstituted-oxazol-2-yl;

wherein an indicated substituent is a ring system substituent.

6. A compound as claimed in claim 1, wherein the compound is 2-methyl-6-[3-(quinolin-2-ylmethoxy)-propoxymethyl]-benzoic acid.

7. A compound as claimed in claim 1, which is of formula

wherein

b=0;

R₁, R₂, R₃, R₄ are hydrogen

R₁₅, R₁₆ are hydrogen;

g=2, 3, 4 or 5;

Z is R₂₁O₂C—

, R₂₁OC—

, or R₂₁O—

;

R′

is hydrogen, halo, unsubstituted lower alkyl of 1 to about 4 carbon atoms, unsubstituted alkoxy, unsubstituted aryloxy or unsubstituted aralkyloxy; and

R″

is hydrogen, halo, unsubstituted lower alkyl of 1 to about 4 carbon atoms, unsubstituted alkoxy, unsubstituted aralkyloxy or unsubstituted cycloalkylalkyloxy, or

a pharmaceutically acceptable salt thereof, or an N-oxide thereof, a hydrate thereof or a solvate thereof .

8. A compound according to claim 7, wherein Z is —

CO₂H.

9. A compound according to claim 7, wherein R′

is hydrogen; and

R″

is lower alkyl of 1 to about 4 carbon atoms.

10. A compound according to claim 7, wherein

is 2-substituted-oxazol-4-yl, wherein the substituent is a ring system substituent.

11. A compound according to claim 1, wherein the compound is

12. A compound according to claim 1, wherein the compound is

13. A compound according to claim 1 , wherein the compound is

14. A pharmaceutical composition comprising a pharmaceutically acceptable amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.

15. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound wherein the disorder is associated with a physiological detrimental blood level of insulin, glucose, free fatty acids, or triglycerides.

16. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is hyperglycemia.

17. The method according to claim 16, wherein the hyperglycemia is diabetes.

18. The method according to claim 16, wherein the hyperglycemia is A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the disorder is Type II diabetes.

19. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is hyperinsulinism.

20. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is insulin resistance.

21. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is a cardiovascular condition.

22. The method according to claim 21, wherein the cardiovascular condition is atherosclerosis.

23. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is hyperlipidemia.

24. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is hypertension.

25. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is an eating disorder.

26. A compound of formula (I)

27. A compound according to claim 26 wherein R₁₅ and R₁₆ are hydrogen;

and g is 1, 2, 3 or 4.

28. A compound according to claim 26 wherein Z is R₂₁O₂SHNCO—

, and R₂₁ is phenyl, wherein phenyl is optionally substituted by one or more ring system substituents.

29. A compound according to claim 26 wherein Z is —

CO₂H or —

CN.

30. A compound according to claim 26 wherein

is unsubstituted quinolin-2-yl, 3-substituted quinolin-2-yl, 4-substituted quinolin-2-yl, 6-substituted quinolin-2-yl or 7 substituted quinolin-2-yl;

or 2-substituted-oxazol-4-yl or 2,5 disubstituted-oxazol-4-yl;

4-substituted oxazol-2-yl or 4,5-disubstituted-oxazol-2-yl;

wherein an indicated substituent is selected from phenyl optionally substituted by one or more ring system substituents, thienyl optionally substituted by one or more ring system substituents, cycloalkyl optionally substituted by one or more ring system substituents, lower alkyl optionally substituted by one or more alkyl group substituents, branched alkyl optionally substituted by one or more alkyl group substituents, fluoro, chloro, alkoxy wherein the alkyl portion is optionally substituted by one or more alkyl group substituents, aralkyloxy wherein the aryl portion is optionally substituted with one or more ring system substituents and the alkyl portion is optionally substituted with one or more alkyl group substituents, trifluoromethyl and trifluoromethyloxy.

31. A compound as claimed in claim 26, which is of formula

32. A compound according to claim 31, wherein Z is —

CO₂H.

33. A compound according to claim 31, wherein R′

is hydrogen; and

R″

is lower alkyl of 1 to about 4 carbon atoms.

34. A compound according to claim 31, wherein

is 2-substituted-oxazol-4-yl, wherein the substituent is unsubstituted phenyl.

35. A compound according to claim 26, wherein

37. A compound according to claim 26, wherein the compound is

or a pharmaceutically acceptable salt thereof, or an N-oxide thereof.

39. A pharmaceutical composition comprising a pharmaceutically acceptable amount of the compound according to claim 26 and a pharmaceutically acceptable carrier.

40. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 26 having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the disorder is Type II diabetes.

41. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 26 having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is hypertension.

42. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 26 having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the physiological disorder is an eating disorder.

36. A compound, wherein the compound is

or a pharmaceutically acceptable salt thereof, or an N-oxide thereof.

38. A compound, wherein the compound is

or a pharmaceutically acceptable salt thereof, or an N-oxide thereof.