Heterocyclic cyclopamine analogs and methods of use thereof

• US 7,994,191 B2
• Filed: 12/02/2009
• Issued: 08/09/2011
• Est. Priority Date: 03/07/2007
• Status: Expired due to Fees

• Current Assignee: Royalty Security, LLC
• Original Assignee: Infinity Discovery, Inc. (Infinity Pharmaceuticals, Inc.)
• Inventors: Grogan, Michael J., Castro, Alfredo C., Tremblay, Martin
• Primary Examiner(s): Aulakh; Charanjit
• Application Number:
  US12/629,382
• Publication Number:
  US 20100144775A1
• Time in Patent Office: 615 Days
• Field of Search: 514/278, 514/302
• US Class Current: 514/302
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 491/14 Ortho-condensed systems
• CPC Class Codes: C07D 513/14 Ortho-condensed systems

Abstract

The present invention relates to steroidal alkaloids that can be used in the treatment of hedgehog pathway related disorders, particularly cancer.

Claims

1. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 1a or 1b:

2. The method according to claim 1, wherein R¹ is H, alkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, —

OR²⁰, —

C(O)R²⁰, —

CO₂R²⁰, —

C(O)N(R²⁰)(R²⁰), —

S(O)₂R²⁰, —

S(O)₂N(R²⁰)(R²⁰), —

[(W)—

C(O)]_pR²⁰, —

[(W)—

C(O)O]_pR²⁰, —

[(W)—

OC(O)]_pR²⁰, —

[(W)—

SO₂]_pR²⁰, —

[(W)—

N(R²⁰)SO₂]_pR²⁰, —

[(W)—

C(O)N(R²⁰)]_pR²⁰, —

[(W)—

O]_pR²⁰, —

[(W)—

N(R²⁰)]_pR²⁰, or —

[(W)—

S]_pR²⁰.

3. The method according to claim 2, wherein R¹ is H, alkyl, hydroxyl, —

C(O)R²⁰, —

CO₂R²⁰ or —

S(O)₂R²⁰.

4. The method according to claim 1, wherein R² and R³ taken together form a bond.

5. The method according to claim 1, wherein R⁴ and R⁵ are each H;

or R⁴ and R⁵ taken together form ═

O or ═

S.

6. The method according to claim 5, wherein R⁴ and R⁵ are each H.

7. The method according to claim 1, wherein R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are each independently H or alkyl.

8. The method according to claim 1, wherein R⁶, R⁸, R⁹, R¹⁰, and R¹¹ are each H.

9. The method according to claim 1, wherein X is a bond or —

CH₂—

.

10. The method according to claim 9, wherein X is —

CH₂—

.

11. The method according to claim 1, wherein Y is —

O—

or —

N(R²⁴)—

.

12. The method according to claim 11, wherein Y is —

N(R²⁴)—

.

13. The method according to claim 1, wherein -T¹-T²-T³- is A-B—

Y, A is CR²³, B is N and Y is NR²⁴;

or -T¹-T²-T³- is B—

Y-A, A is N, B is CR²³ and Y is NR²⁴.

14. The method according to claim 1, wherein -T¹-T²-T³- is B—

Y-A, A is CR²³, B is N and Y is NR²⁴;

or -T¹-T²-T³- is B—

Y-A, A is N, B is CR²³ and Y is O;

or -T¹-T²-T³- is Y—

B-A, A is N, B is CR²³ and Y is S.

15. The method according to claim 1, wherein R²⁴ is H, alkyl, or —

S(O)₂R²⁰.

16. The method according to claim 1, wherein the compound of Formula 1a is a compound of the Formula 6a:

17. The method according to claim 16, wherein R¹ is H, alkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, —

OR²⁰, —

C(O)R²⁰, —

CO₂R²⁰, —

C(O)N(R²⁰)(R²⁰), —

S(O)₂R²⁰, —

S(O)₂N(R²⁰)(R²⁰), —

[(W)—

C(O)]_pR²⁰, —

[(W)—

C(O)O]_pR²⁰, —

[(W)—

OC(O)]_pR²⁰, —

[(W)—

SO₂]_pR²⁰, —

[(W)—

N(R²⁰)SO₂]_pR²⁰, —

[(W)—

C(O)N(R²⁰)]_pR²⁰, —

[(W)—

O]_pR²⁰, —

[(W)—

N(R²⁰)]_pR²⁰, or —

[(W)—

S]_pR²⁰.

18. The method according to claim 17, wherein R¹ is H, alkyl, hydroxyl, —

C(O)R²⁰, —

CO₂R²⁰ or —

S(O)₂R²⁰.

19. The method according to claim 16, wherein R⁴ and R³ are each H.

20. The method according to claim 16, wherein X is a bond or —

CH₂—

.

21. The method according to claim 20, wherein X is —

CH₂—

.

22. The method according to claim 16, wherein Y is —

O—

or —

N(R²⁴)—

.

23. The method according to claim 22, wherein Y is —

N(R²¹)—

.

24. The method according to claim 16, wherein -T¹-T²-T³- is A-B—

Y, A is CR²³, B is N and Y is NR²⁴;

or -T¹-T²-T³- is B—

Y-A, A is N, B is CR²³ and Y is NR²⁴.

25. The method according to claim 16, wherein -T¹-T²-T³- is B—

Y-A, A is CR²³, B is N and Y is NR²⁴;

or -T¹-T²-T³- is B—

Y-A, A is N, B is CR²³ and Y is O;

or -T¹-T²-T³- is Y—

B-A, A is N, B is CR²³ and Y is S.

26. The method according to claim 16, wherein R²⁴ is H, alkyl, or —

S(O)₂R²⁰.

27. The method according to claim 1, wherein the compound of Formula 1b is a compound of the Formula 11b:

28. The method according to claim 27, wherein R¹ is H, alkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, —

OR²⁰, —

C(O)R²⁰, —

CO₂R²⁰, —

C(O)N(R²⁰)(R²⁰), —

S(O)₂R²⁰, —

S(O)₂N(R²⁰)(R²⁰), —

[(W)—

C(O)]_pR²⁰, —

[(W)—

C(O)O]_pR²⁰, —

[(W)—

OC(O)]_pR²⁰, [(W)—

SO₂]_pR²⁰, —

[(W)—

N(R²⁰)SO₂]_pR²⁰, —

[(W)—

C(O)N(R²⁰)]_pR²⁰, —

[(W)—

O]_pR²⁰, —

[(W)—

N(R²⁰)]_pR²⁰, or —

[(W)—

S]_pR²⁰.

29. The method according to claim 28, wherein R¹ is H, alkyl, hydroxyl, —

C(O)R²⁰, —

CO₂R²⁰ or —

S(O)₂R²⁰.

30. The method according to claim 27, wherein R⁴ and R⁵ are each H.

31. The method according to claim 27, wherein X is a bond or —

CH₂—

.

32. The method according to claim 31, wherein X is —

CH₂—

.

33. The method according to claim 27, wherein Y is —

O—

or —

N(R²⁴)—

.

34. The method according to claim 33, wherein Y is —

N(R²⁴)—

.

35. The method according to claim 27, wherein -T¹-T²-T³- is A-B—

Y, A is CR²³, B is N and Y is NR²⁴;

or -T¹-T²-T³- is B—

Y-A, A is N, B is CR²³ and Y is NR²⁴.

36. The method according to claim 27, wherein -T¹-T²-T³- is B—

Y-A, A is CR²³, B is N and Y is NR²⁴;

or -T¹-T²-T³- is B—

Y-A, A is N, B is CR²³ and Y is O;

or -T¹-T²-T³- is Y—

B-A, A is N, B is CR²³ and Y is S.

37. The method according to claim 27, wherein R²⁴ is H, alkyl, or —

S(O)₂R²⁰.

39. The method according to claim 1, wherein the cancer is basal cell carcinoma, pancreatic cancer, prostate cancer, osteogenic sarcoma, chondrosarcoma, non-Hodgkin'"'"'s type lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, gastric cancer, esophageal cancer, multiple myeloma, lung cancer, glioma, breast cancer, hepatocellular cancer, ovarian cancer, colon cancer or medulloblastoma.

40. The method according to claim 1, wherein the cancer is pancreatic cancer.

41. The method according to claim 1, wherein the cancer is chondrosarcoma.

42. The method according to claim 1, wherein the cancer is lung cancer.

43. The method according to claim 42, wherein the lung cancer is small cell lung cancer.

44. The method according to claim 1, wherein the cancer is basal cell carcinoma.

45. The method according to claim 1, wherein the cancer is medulloblastoma.

46. The method according to claim 1, wherein the cancer is acute lymphocytic leukemia.

47. The method according to claim 1, wherein the cancer is chronic lymphocytic leukemia.

48. The method according to claim 1, wherein the cancer is ovarian cancer.

49. The method according to claim 1, wherein the cancer is osteogenic sarcoma.

50. The method according to claim 1, wherein the cancer is chronic myeloid leukemia.

51. The method according to claim 1, wherein the compound is used in combination with one or more chemotherapeutic or other anti-cancer agent.

52. The method according to claim 51, wherein the other anti-cancer agent is radiation.

53. The method according to claim 1, wherein the compound is administered locally to a tumor.

54. The method according to claim 1, wherein the compound is administered systemically.

55. The method according to claim 1, wherein the mode of administration of said compound is inhalation, oral, intravenous, sublingual, ocular, transdermal, rectal, vaginal, topical, intramuscular, intraperitoneal, epidural, subcutaneous, buccal, or nasal.

56. The method according to claim 55, wherein the mode of administration is oral, intravenous, or topical.

38. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of: