Synthetic triterpenoids and methods of use in the treatment of disease

• US 8,129,429 B2
• Filed: 01/12/2009
• Issued: 03/06/2012
• Est. Priority Date: 01/11/2008
• Status: Active Grant

• Current Assignee: The Trustees of Dartmounth College (Dartmouth College), Reata Pharmaceuticals Holdings LLC (Reata Pharmaceuticals, Inc.)
• Original Assignee: The Trustees of Dartmounth College (Dartmouth College), Reata Pharmaceuticals, Inc.
• Inventors: Sporn, Michael B., Liby, Karen T., Gribble, Gordon W., Honda, Tadashi, Kral, Robert M., Meyer, Colin J.
• Primary Examiner(s): Lundgren, Jeffrey S.
• Assistant Examiner(s): Bori, Ibrahim D
• Application Number:
  US12/352,473
• Publication Number:
  US 20090326063A1
• Time in Patent Office: 1,149 Days
• Field of Search: 514/510, 514/511, 514/512, 514/506, 514/519, 558/431, 558/429, 558/430, 558/440, 558/443
• US Class Current: 514/510
• 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 31/275 Nitriles; Isonitriles
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/4174 Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 5/50 : for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• 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: A61P 9/12 : Antihypertensives
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Abstract

The present invention concerns methods for treating and preventing renal/kidney disease, insulin resistance/diabetes, fatty liver disease, and/or endothelial dysfunction/cardiovascular disease using synthetic triterpenoids, optionally in combination with a second treatment or prophylaxis.

Claims

1. A method of improving kidney function in a subject in need thereof comprising administering to the subject a compound of the formula,

2. The method of claim 1, where the subject has chronic kidney disease (CKD) or exhibits one or more symptoms of CKD.

3. The method of claim 2, where the subject has been identified as having CKD.

4. The method of claim 2, where the CKD is characterized by a serum creatinine level of 1.3-3.0 mg/DL where the subject is a human female or a serum creatinine level of 1.5-3.0 mg/DL where the subject is a human male.

5. The method of claim 2, where the CKD is stage 4.

6. The method of claim 1, where the subject has diabetic nephropathy (DN) or exhibits one or more symptoms of DN.

7. The method of claim 6, where the subject has been identified as having DN.

8. The method of claim 1, where the administering results in an improvement in estimated glomerular filtration rate (eGFR) of the subject.

9. The method of claim 8, where the administering reduces the level of serum creatinine in the subject.

10. The method of claim 9, where the level of serum creatinine in the blood of the subject has been measured.

11. The method of claim 1, where the level of blood urea nitrogen (BUN) in the subject has been measured.

12. The method of claim 1, where the level of Adiponectin in the blood of the subject has been measured.

13. The method of claim 1, where the level of Angiotensin II in the subject has been measured.

14. The method of claim 1, where the subject has insulin resistance or exhibits one or more symptoms of insulin resistance.

15. The method of claim 14, where the subject has been identified as having insulin resistance.

16. The method of claim 14, where the level of hemoglobin Alc in the subject has been measured.

17. The method of claim 14, where a blood sugar level of the subject has been measured.

18. The method of claim 14, where the administering reduces the level of hemoglobin Alc or fasting blood glucose in the subject.

19. The method of claim 17, where a fasting glucose level of the subject has been measured.

20. The method of claim 14, where the insulin sensitivity of the subject has been measured by a hyperinsulinemic euglycemic clamp test.

21. The method of claim 14, where a glucose disposal rate (GDR) in the subject has been measured.

22. The method of claim 1, where the subject has cardiovascular disease (CVD) or exhibits one or more symptoms of CVD.

23. The method of claim 22, where the subject has been identified as having CVD.

24. The method of claim 22, where the level of a marker of CVD in the subject has been measured.

25. The method of claim 22, where the number of circulating endothelial cells (CFCs) in the blood of the subject has been measured.

26. The method of claim 25, where the CECs are iNOS-positive circulating endothelial cells.

27. The method of claim 22, where the administering reduces the level of circulating endothelial cells in the subject.

28. The method of claim 27, where the administering reduces the level of hemoglobin Alc or fasting blood glucose in the subject.

29. The method of claim 1, wherein the subject is a human.

30. The method of claim 1, wherein at least a portion of the compound is present as a crystalline form having an X-ray diffraction pattern (CuKα

) comprising significant diffraction peaks at about 8.8, 12.9, 13.4, 14.2 and 17.4 °

2θ

.

31. The method of claim 30, wherein the X-ray diffraction pattern (CuKα

) is substantially as shown in FIG. 12A or FIG. 12B.

32. The method of claim 30, wherein the pharmaceutically effective amount is a daily dose of about 10 mg to about 200 mg of the compound.

33. The method of claim 1, wherein at least a portion of the compound is present as an amorphous form having an X-ray diffraction pattern (CuKα

) with a halo peak at approximately 13.5 °

2θ

, substantially as shown in FIG. 12C, and a T_g from about 120 °

C. to about 135 °

C.

34. The method of claim 33, wherein the T_g is from about 125 °

C. to about 130 °

C.

35. The method of claim 33, wherein the pharmaceutically effective amount is a daily dose from about 0.1 mg to about 30 mg of the compound.

36. The method of claim 1, where the compound is administered orally, intraarterially or intravenously.

37. The method of claim 1, where the compound is formulated as a hard or soft capsule or a tablet.

38. The method of claim 1, wherein the compound is formulated as a solid dispersion comprising (i) the compound and (ii) an excipient.

39. The method of claim 38, wherein the excipient is a methacrylic acid-ethyl acrylate copolymer (1:

1).

40. A method of improving kidney function in a subject comprising administering to the subject a compound of the formula,