METABOLITES OF THE JANUS KINASE INHIBITOR (R)-3-(4-(7H-PYRROLO[2,3-d]PYRIMIDIN-4-YL)-1H-PYRAZOL-1-YL)-3-CYCLOPENTYL-PROPANENITRILE

• US 20080312258A1
• Filed: 06/12/2008
• Published: 12/18/2008
• Est. Priority Date: 06/13/2007
• Status: Active Grant

• Current Assignee: Incyte Holdings Corporation And Incyte Corporation
• Original Assignee: Incyte Corporation
• Inventors: Rodgers, James D., Arvanitis, Argyrios G., Shi, Jack Guoen
• Granted Patent: US 7,834,022 B2
• Time in Patent Office: Days
• US Class Current: 514/265.1
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C12N 9/99 Enzyme inactivation by chemical treatment

Abstract

The present invention provides active metablites of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile that modulate the activity of Janus kinases and are useful in the treatment of diseases related to activity of Janus kinases including, for example, immune-related diseases, skin disorders, myeloid proliferative disorders, cancer, and other diseases.

Claims

1. A compound selected from:

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(3-hydroxycyclopentyl)propanenitrile;

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(2-hydroxycyclopentyl)propanenitrile; and

3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(3-oxocyclopentyl)propanenitrile,

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, or pharmaceutically acceptable salt thereof, which is substantially isolated.

3. A composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

4. The composition of claim 3 which is suitable for oral administration.

5. A method of modulating an activity of JAK comprising contacting JAK with a compound of claim 1, or pharmaceutically acceptable salt thereof.

6. The method of claim 5 wherein said modulating is inhibiting.

7. A method of treating a disease in a patient, wherein said disease is associated with JAK activity, comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

8. The method of claim 7 wherein said disease is allograft rejection or graft versus host disease.

9. The method of claim 7 wherein said disease is an autoimmune disease.

10. The method of claim 9 wherein said autoimmune disease is a skin disorder, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type I diabetes, lupus, inflammatory bowel disease, Crohn'"'"'s disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, or autoimmune thyroid disorder.

11. The method of claim 9 wherein said autoimmune disease is bullous skin disorder.

12. The method of claim 11 wherein said bullous skin disorder is pemphigus vulgaris (PV) or bullous pemphigoid (BP).

13. The method of claim 7 wherein said disease is a skin disorder.

14. The method of claim 13 wherein said skin disorder is atopic dermatitis, psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization.

15. The method of claim 7 wherein said disease is a viral disease.

16. The method of claim 15 wherein said viral disease is Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicell-Zoster Virus (VZV) or Human Papilloma Virus (HPV).

17. The method of claim 7 wherein said disease is cancer.

18. The method of claim 17 wherein said cancer is a solid tumor

19. The method of claim 18 wherein said cancer is prostate cancer, renal cancer, hepatic cancer, breast cancer, lung cancer, thyroid cancer, Kaposi'"'"'s sarcoma, Castleman'"'"'s disease or pancreatic cancer.

20. The method of claim 18 wherein said cancer is prostate cancer.

21. The method of claim 17 wherein said cancer is hematological.

22. The method of claim 21 wherein said cancer is lymphoma, leukemia, or multiple myeloma.

23. The method of claim 17 wherein said cancer is a skin cancer.

24. The method of claim 23 wherein said skin cancer is cutaneous T-cell lymphoma or cutaneous B-cell lymphoma.

25. The method of claim 21 wherein said cancer is multiple myeloma.

26. The method of claim 7 wherein said disease is characterized by a mutant JAK2.

27. The method of claim 26 wherein at least one mutation of said mutant JAK2 resides in the pseudo-kinase domain of said JAK2.

28. The method of claim 7 wherein said disease is a myeloproliferative disorder.

29. The method of claim 28 wherein said myeloproliferative disorder (MPD) is polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), or systemic mast cell disease (SMCD).

30. The method of claim 7 wherein said disease is an inflammatory disease.

31. The method of claim 30 wherein said disease is an inflammatory disease of the eye.

32. The method of claim 31 wherein said disease is iritis, uveitis, scleritis, or conjunctivitis.

33. The method of claim 30 wherein said disease is an inflammatory disease of the respiratory tract.

34. The method of claim 33 wherein said inflammatory disease concerns the upper respiratory tract.

35. The method of claim 33 wherein said inflammatory disease concerns the lower respiratory tract.

36. The method of claim 7 wherein said inflammatory disease is an inflammatory myopathy.

37. The method of claim 36 wherein said inflammatory disease is myocarditis.

38. The method of claim 7 wherein said disease is ischemia reperfusion or related to an ischemic event.

39. The method of claim 7 wherein said disease is anorexia or cachexia resulting from or associated with cancer.

40. The method of claim 7 wherein said disease is fatigue resulting from or associated with cancer.

41. A method of treating cancer in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

42. A method of treating rheumatoid arthritis in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

43. A method of treating prostate cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

44. A method of treating psoriasis in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

45. A method of treating multiple myeloma in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

46. A method of treating myeloid metaplasia with myelofibrosis (MMM) in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

47. A method of treating polycythemia vera (PV) in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

48. A method of treating essential thrombocythemia (ET) in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

49. A method of treating mycosis fungoides in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

50. A method of treating a hematological cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

51. A method of treating chronic myelogenous leukemia (CML) in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

52. A method of treating acute lymphoblastic leukemia (ALL) in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

53. A method of treating chronic myelomonocytic leukemia (CMML) in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof