Treating NIDDM with RXR agonists

• US 5,972,881 A
• Filed: 11/26/1997
• Issued: 10/26/1999
• Est. Priority Date: 09/18/1995
• Status: Expired due to Term

• Current Assignee: Eisai Incorporated (Eisai Medical Research Incorporated)
• Original Assignee: Ligand Pharmaceuticals, Inc.
• Inventors: Heyman, Richard A., Mukherjee, Ranjan, Cesario, Rosemary
• Primary Examiner(s): Henley, III, Raymond
• Application Number:
  US08/979,725
• Time in Patent Office: 699 Days
• Field of Search: 514/3, 514/277, 514/299, 514/342, 514/367, 514/369, 514/370, 514/569, 514/725
• US Class Current: 514/5.9
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/425 Thiazoles
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4418 having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07C 251/48 with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 2602/10 the other ring being six-membered, e.g. tetraline
• CPC Class Codes: C07C 2603/24 Anthracenes; Hydrogenated anthracenes
• CPC Class Codes: C07C 57/50 containing condensed ring systems
• CPC Class Codes: C07C 59/72 containing six-membered aromatic rings and other rings
• CPC Class Codes: C07C 63/49 containing rings other than six-membered aromatic rings
• CPC Class Codes: C07C 63/66 Polycyclic acids with unsaturation outside the aromatic rings
• CPC Class Codes: C07C 65/28 having unsaturation outside the aromatic rings
• CPC Class Codes: C07C 65/36 containing rings other than six-membered aromatic rings
• CPC Class Codes: C07D 221/08 Aza-anthracenes
• CPC Class Codes: C07D 265/34 condensed with carbocyclic rings
• CPC Class Codes: C07D 311/92 Naphthopyrans; Hydrogenated naphthopyrans
• CPC Class Codes: C07D 317/30 : 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: G01N 2500/00 : Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 33/5008 : for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
• CPC Class Codes: G01N 33/502 : for testing non-proliferative effects
• CPC Class Codes: G01N 33/5038 : involving detection of metabolites per se
• CPC Class Codes: G01N 33/5044 : involving specific cell types
• CPC Class Codes: G01N 33/5073 : Stem cells

Abstract

This invention relates to methods and compositions for the treatment of non-insulin-dependent diabetes mellitus using an RXR agonist alone or in combination with a PPARγ agonist such as a thiazolidinedione compound.

Claims

1. A method of treating hypertriglyceridemia in a host suffering therefrom, comprising the step of administering to said host a pharmaceutically effective amount of an RXR agonist.

2. A method of increasing the level of HDL cholesterol in a host, comprising the step of administering to said host a pharmaceutically effective amount of an RXR specific agonist.

6. The method of claim 2, wherein said RXR agonist is an RXR specific agonist.

7. The method of claim 6, wherein said RXR specific agonist is 2-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-cyclopropyl]-pyridine-5-carboxylic acid or a pharmaceutically acceptable salt thereof.

8. The method of claim 6, wherein said RXR specific agonist is 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-carbonyl]-benzoic acid or a pharmaceutically acceptable salt thereof.

9. The method of claim 2, further comprising the step of administering to said host a pharmaceutically effective amount of a PPARγ

agonist.

10. The method of claim 9, wherein said PPARγ

agonist is a thiazolidinedione compound.

11. The method of claim 10, wherein said thiazolidinedione compound is selected from the group consisting of 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, troglitazone, pioglitazone, ciglitazone, WAY-120,744, englitazone, AD 5075, darglitazone, and their pharmaceutically acceptable salts.

12. The method of claim 2, further comprising the step of administering to said host a pharmaceutically effective amount of a compound selected from the group consisting of insulin, an insulin derivative, an insulin secretagogue, an insulin sensitizer, and an insulin mimetic.

13. The method of claim 9, further comprising the step of administering to said host a pharmaceutically effective amount of a compound selected from the group consisting of insulin, an insulin derivative, an insulin secretagogue, an insulin sensitizer, and an insulin mimetic.

14. The method of claim 2, wherein said RXR agonist is orally, topically, intravenously, transdermally, rectally, or parentally administered to said host.

15. The method of claim 2, wherein said RXR agonist is administered to said host in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

16. The method of claim 9, wherein said RXR agonist and said PPARγ

agonist are administered to said host in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

17. The method of claim 12, wherein said RXR agonist and said compound are administered to said host in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

18. The method of claim 12, wherein said RXR agonist, said PPARγ

agonist and said compound are administered to said host in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

19. The method of claim 15, 16, 17 or 18, wherein said pharmaceutical composition consists of a single dosage unit.

3. A method of preventing hypertriglyceridemia in a host, comprising the step of administering to said host a pharmaceutically effective amount of an RXR agonist.

4. A method of treating cardiovascular disease in a host suffering therefrom, comprising the step of administering to said host a pharmaceutically effective amount of an RXR specific agonist.

20. The method of claim 4, wherein said RXR agonist is an RXR specific agonist.

21. The method of claim 20, wherein said RXR specific agonist is 2-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-cyclopropyl]-pyridine-5-carboxylic acid or a pharmaceutically acceptable salt thereof.

22. The method of claim 20, wherein said RXR specific agonist is 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-carbonyl]-benzoic acid or a pharmaceutically acceptable salt thereof.

23. The method of claim 4, further comprising the step of administering to said host a pharmaceutically effective amount of a PPARγ

agonist.

24. The method of claim 23, wherein said PPARγ

agonist is a thiazolidinedione compound.

25. The method of claim 20, wherein said thiazolidinedione compound is selected from the group consisting of 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, troglitazone, pioglitazone, ciglitazone, WAY-120,744, englitazone, AD 5075, darglitazone, and their pharmaceutically acceptable salts.

26. The method of claim 4, further comprising the step of administering to said host a pharmaceutically effective amount of a compound selected from the group consisting of insulin, an insulin derivative, an insulin secretagogue, an insulin sensitizer, and an insulin mimetic.

27. The method of claim 23, further comprising the step of administering to said host a pharmaceutically effective amount of a compound selected from the group consisting of insulin, an insulin derivative, an insulin secretagogue, an insulin sensitizer, and an insulin mimetic.

28. The method of claim 4, wherein said RXR agonist is orally, topically, intravenously, transdermally, rectally, or parentally administered to said host.

29. The method of claim 4, wherein said RXR agonist is administered to said host in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

30. The method of claim 23, wherein said RXR agonist and said PPARγ

agonist are administered to said host in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

31. The method of claim 26, wherein said RXR agonist and said compound are administered to said host in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

32. The method of claim 27, wherein said RXR agonist, said PPARγ

agonist and said compound are administered to said host in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

33. The method of claim 29, 30, 31 or 32, wherein said pharmaceutical composition consists of a single dosage unit.

5. A method of preventing cardiovascular disease in a host, comprising the step of administering to said host a pharmaceutically effective amount of an RXR specific agonist.

34. The method of claim 5, wherein said RXR agonist is an RXR specific agonist.

35. The method of claim 34, wherein said RXR specific agonist is 2-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-cyclopropyl]-pyridine-5-carboxylic acid or a pharmaceutically acceptable salt thereof.

36. The method of claim 34, wherein said RXR specific agonist is 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-2-carbonyl]-benzoic acid or a pharmaceutically acceptable salt thereof.

37. The method of claim 5, further comprising the step of administering to said host a pharmaceutically effective amount of a PPARγ

agonist.

38. The method of claim 5, wherein said PPARγ

agonist is a thiazolidinedione compound.

39. The method of claim 38, wherein said thiazolidinedione compound is selected from the group consisting of 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, troglitazone, pioglitazone, ciglitazone, WAY-120,744, englitazone, AD 5075, darglitazone, and their pharmaceutically acceptable salts.

40. The method of claim 5, further comprising the step of administering to said host a pharmaceutically effective amount of a compound selected from the group consisting of insulin, an insulin derivative, an insulin secretagogue, an insulin sensitizer, and an insulin mimetic.

41. The method of claim 5, further comprising the step of administering to said host a pharmaceutically effective amount of a compound selected from the group consisting of insulin, an insulin derivative, an insulin secretagogue, an insulin sensitizer, and an insulin mimetic.

42. The method of claim 5, wherein said RXR agonist is orally, topically, intravenously, transdermally, rectally, or parentally administered to said host.

43. The method of claim 5, wherein said RXR agonist is administered to said host in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

44. The method of claim 5, wherein said RXR agonist and said PPARγ

agonist are administered to said host in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

45. The method of claim 40, wherein said RXR agonist and said compound are administered to said host in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

46. The method of claim 41, wherein said RXR agonist, said PPARγ

agonist and said compound are administered to said host in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

47. The method of claim 43, 44, 45 or 46, wherein said pharmaceutical composition consists of a single dosage unit.