Inhibitors of Akt activity

• US 8,273,782 B2
• Filed: 02/07/2008
• Issued: 09/25/2012
• Est. Priority Date: 02/07/2007
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC)
• Inventors: Seefeld, Mark A., Rouse, Meagan B., Heerding, Dirk A.
• Primary Examiner(s): Padmanabhan, Sreeni
• Assistant Examiner(s): JEAN-LOUIS, SAMIRA JM
• Application Number:
  US12/027,454
• Publication Number:
  US 20090209607A1
• Time in Patent Office: 1,692 Days
• Field of Search: 514/406, 548/364.4, 548/365.7, 548/373.1
• US Class Current: 514/406
• CPC Class Codes: A61K 31/12 Ketones
• CPC Class Codes: A61K 31/4155 non condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 31/4192 1,2,3-Triazoles
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/48 Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings

Abstract

Invented are novel heterocyclic carboxamide compounds, the use of such compounds as inhibitors of protein kinase B activity and in the treatment of cancer and arthritis.

Claims

1. A compound:

N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 which is:

N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide.

3. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

4. A pharmaceutical composition comprising a compound according to claim 2 and a pharmaceutically acceptable carrier.

5. A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier and a compound of claim 1 which process comprises bringing the compound of claim 1 into association with a pharmaceutically acceptable carrier.

6. A method of inhibiting Akt activity in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of claim 1.

7. The method of claim 6 wherein the mammal is a human.

8. A pharmaceutical composition according to claim 3, wherein the composition is in tablet form.

9. A pharmaceutical composition according to claim 4, wherein the composition is in tablet form.

10. A method of treating or lessening the severity of cancer, wherein said cancer is selected from:

brain cancer (gliomas), glioblastomas, medulloblastoma, prostate cancer, breast cancer, inflammatory breast cancer, colon cancer, head and neck cancer, kidney cancer, Wilm'"'"'s tumor, renal cancer, lung cancer, endometrial cancer, gastric cancer, liver cancer and ovarian cancer,

in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

11. A method of treating or lessening the severity of cancer, wherein said cancer is selected from:

Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia and Erythroleukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

12. A method of treating or lessening the severity of cancer, wherein said cancer is selected from:

malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt'"'"'s lymphoma and follicular lymphoma,

in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

13. A method of treating or lessening the severity of cancer, wherein said cancer is selected from:

pancreatic cancer, Bannayan-Zonana syndrome, Cowden disease, and Lhermitte-Duclos disease,

in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

22. A method of treating or lessening the severity of cancer, wherein said cancer is selected from:

Multiple myeloma, melanoma, mesothelioma, sarcoma, Ewing'"'"'s sarcoma, Rhabdomyosarcoma, osteosarcoma, and thyroid cancer,

in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

24. A method of treating or lessening the severity of Lymphoblastic T cell leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

25. A method of treating or lessening the severity of Chronic myelogenous leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

26. A method of treating or lessening the severity of Chronic lymphocytic leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

27. A method of treating or lessening the severity of Hairy-cell leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

28. A method of treating or lessening the severity of acute lymphoblastic leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

29. A method of treating or lessening the severity of acute myelogenous leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

30. A method of treating or lessening the severity of Chronic neutrophilic leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

31. A method of treating or lessening the severity of Acute lymphoblastic T cell leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

32. A method of treating or lessening the severity of Plasmacytoma, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

33. A method of treating or lessening the severity of Immunoblastic large cell leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

34. A method of treating or lessening the severity of Mantle cell leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

35. A method of treating or lessening the severity of Megakaryoblastic leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

36. A method of treating or lessening the severity of multiple myeloma, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

37. A method of treating or lessening the severity of acute megakaryocytic leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

38. A method of treating or lessening the severity of promyelocytic leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

39. A method of treating or lessening the severity of Erythroleukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

56. A method of treating or lessening the severity of melanoma, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

57. A method of treating or lessening the severity of mesothelioma, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

58. A method of treating or lessening the severity of sarcoma, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

59. A method of treating or lessening the severity of thyroid cancer, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

60. A method of treating or lessening the severity of brain cancer, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

61. A method of treating or lessening the severity of breast cancer, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

62. A method of treating or lessening the severity of prostate cancer, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

63. A method of treating or lessening the severity of lung cancer, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

64. A method of treating or lessening the severity of colon cancer, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 1.

14. A pharmaceutically acceptable salt of the compound:

15. A pharmaceutical composition comprising a compound according to claim 14 and a pharmaceutically acceptable carrier.

16. A pharmaceutical composition according to claim 15, wherein the composition is in tablet form.

17. A method of treating or lessening the severity of cancer, wherein said cancer is selected from:

brain cancer (gliomas), glioblastomas, medulloblastoma, prostate cancer, breast cancer, inflammatory breast cancer, colon cancer, head and neck cancer, kidney cancer, Wilm'"'"'s tumor, renal cancer, lung cancer, endometrial cancer, gastric cancer, liver cancer and ovarian cancer,

in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 14.

18. A method of treating or lessening the severity of cancer, wherein said cancer is selected from:

Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia and Erythroleukemia,

in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 14.

19. A method of treating or lessening the severity of cancer, wherein said cancer is selected from:

malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt'"'"'s lymphoma and follicular lymphoma,

in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 14.

20. A method of treating or lessening the severity of cancer, wherein said cancer is selected from:

pancreatic cancer, Bannayan-Zonana syndrome, Cowden disease, and Lhermitte-Duclos disease,

in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 14.

21. A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier and a compound of claim 14 which process comprises bringing the compound of claim 14 into association with a pharmaceutically acceptable carrier.

23. A method of treating or lessening the severity of cancer, wherein said cancer is selected from:

Multiple myeloma, melanoma, mesothelioma, sarcoma, Ewing'"'"'s sarcoma, Rhabdomyosarcoma, osteosarcoma, and thyroid cancer,

in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 14.

40. A method of treating or lessening the severity of Lymphoblastic T cell leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 14.

41. A method of treating or lessening the severity of Chronic myelogenous leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 14.

42. A method of treating or lessening the severity of Chronic lymphocytic leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 14.

43. A method of treating or lessening the severity of Hairy-cell leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 14.

44. A method of treating or lessening the severity of acute lymphoblastic leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 14.

45. A method of treating or lessening the severity of acute myelogenous leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 14.

46. A method of treating or lessening the severity of Chronic neutrophilic leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 14.

47. A method of treating or lessening the severity of Acute lymphoblastic T cell leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 14.

48. A method of treating or lessening the severity of Plasmacytoma, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 14.

49. A method of treating or lessening the severity of Immunoblastic large cell leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 14.

50. A method of treating or lessening the severity of Mantle cell leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 14.

51. A method of treating or lessening the severity of Megakaryoblastic leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 14.

52. A method of treating or lessening the severity of multiple myeloma, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 14.

53. A method of treating or lessening the severity of acute megakaryocytic leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 14.

54. A method of treating or lessening the severity of promyelocytic leukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 14.

55. A method of treating or lessening the severity of Erythroleukemia, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of claim 14.