3-[4-(7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)-1H-PYRAZOL-1-YL]OCTANE- OR HEPTANE-NITRILE AS JAK INHIBITORS

• US 20100298355A1
• Filed: 05/21/2010
• Published: 11/25/2010
• Est. Priority Date: 05/22/2009
• Status: Active Grant

• Current Assignee: Incyte Holdings Corporation And Incyte Corporation
• Original Assignee: Incyte Corporation
• Inventors: Rodgers, Jame D., Li, Yun-Lon
• Granted Patent: US 8,604,043 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 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• 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: C07D 487/04 : Ortho-condensed systems

Abstract

The present invention relates to the Janus kinase (JAK) inhibitors 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]octanenitrile or 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]heptanenitrile, as well as its compositions and methods of use, which is useful in the treatment of JAK-associated diseases including, for example, inflammatory and autoimmune disorders, skin disorders, cancer, and other diseases.

Claims

1. A compound, which is selected from:

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

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

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, which is 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]octanenitrile, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, which is (3R)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]octanenitrile, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, which is (3S)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]octanenitrile, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, which is 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]octanenitrile phosphoric acid salt.

6. The compound of claim 1, which is (3R)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]octanenitrile phosphoric acid salt.

7. The compound of claim 1, which is (3S)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]octanenitrile phosphoric acid salt.

8. The compound of claim 1, which is 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]heptanenitrile, or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1, which is (3R)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]heptanenitrile, or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1, which is (3S)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]heptanenitrile, or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1, which is 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]heptanenitrile phosphoric acid salt.

12. The compound of claim 1, which is (3R)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]heptanenitrile phosphoric acid salt.

13. The compound of claim 1, which is (3S)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]heptanenitrile phosphoric acid salt.

14. A composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

15. The composition of claim 14 which is suitable for topical administration.

16. The composition of claim 14 which is suitable for transdermal administration.

17. The composition of claim 16 which is in the form of a transdermal patch, ointment, lotion, cream, or gel.

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

19. A method of treating an autoimmune disease in a patient comprising administering to said patient a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

20. The method of claim 19 wherein said autoimmune disease is a skin disorder, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, Crohn'"'"'s disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, or autoimmune thyroid disorder.

21. The method of claim 19 wherein said autoimmune disease is a bullous skin disorder.

22. The method of claim 21 wherein said bullous skin disorder is pemphigus vulgaris (PV) or bullous pemphigoid (BP).

23. The method of claim 19 wherein said autoimmune disease is rheumatoid arthritis.

24. The method of claim 19 wherein said autoimmune disease is a skin disorder.

25. The method of claim 24 wherein said skin disorder is atopic dermatitis or psoriasis.

26. The method of claim 24 wherein said skin disorder is skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization.

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

28. The method of claim 27 wherein said cancer is a solid tumor.

29. The method of claim 27 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.

30. The method of claim 27 wherein said cancer is lymphoma, leukemia, or multiple myeloma.

31. The method of claim 27 wherein said cancer is cutaneous T-cell lymphoma or cutaneous B-cell lymphoma.

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

33. The method of claim 32 wherein said myeloproliferative disorder is polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), or systemic mast cell disease (SMCD).

34. A method of treating an inflammatory disease in a patient comprising administering to said patient a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

35. The method of claim 34 wherein said inflammatory disease is iritis, uveitis, scleritis, conjuctivitis, inflammatory disease of the respiratory tract, inflammatory myopathy, or myocarditis.

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

37. The method of claim 36 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).

38. A method of treating organ transplant rejection in a patient comprising administering to said patient a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

39. A method of treating ischemia reperfusion or a disease related to an ischemic event in a patient comprising administering to said patient a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

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

41. A method of treating fatigue in a patient comprising administering to said patient a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the fatigue is resulting from or associated with cancer.

42. A method of treating allograft rejection or graft versus host disease in a patient comprising administering to said patient a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

50. A process for preparing a phosphoric acid salt of a compound of Formula III:

51. The process of claim 50 wherein said process is a process of preparing 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]octanenitrile phosphoric acid salt.

52. The process of claim 50 wherein said process is a process of preparing 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]heptanenitrile phosphoric acid salt.

53. The process of claim 50, wherein said combining is carried out in the presence of an organic solvent.

54. The process of claim 53 wherein the organic solvent is an alcohol.

55. The process of claim 54 wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, and butanol.

56. The process of claim 50, wherein the combining is performed at a temperature of greater than about 20°

C.

57. The process of claim 50, wherein the combining is performed at a temperature of about 60°

C.