Heterocyclic cyclopamine analogs and methods of use thereof

• US 7,648,994 B2
• Filed: 03/07/2008
• Issued: 01/19/2010
• 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:
  US12/044,817
• Publication Number:
  US 20080293755A1
• Time in Patent Office: 683 Days
• Field of Search: 514/278, 514/302, 546/15, 546/115
• US Class Current: 514/278
• 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 compound of Formula 1a or 1b:

2. The compound of claim 1, wherein R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ are each independently H or alkyl.

3. The compound of claim 1, wherein R² and R³ taken together form a bond.

4. The compound of claim 1, wherein R⁴ and R⁵ are each H;

or R⁴ and R⁵ taken together form ═

O or ═

S.

5. The compound of claim 1, wherein Y is —

O—

or —

N(R²⁴)—

.

6. The compound of 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.

20. A pharmaceutical composition comprising a compound of claim 1, or a tautomer or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

21. The compound of claim 1, wherein X is a bond or —

CH₂—

.

22. The compound of claim 1, wherein X is —

CH₂—

.

23. The compound of claim 1, wherein R⁴ and R⁵ are each H.

24. The compound of 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.

25. The compound of claim 1, wherein R¹ is H, alkyl, hydroxyl, —

C(O)R²⁰, —

CO₂R²⁰ or —

S(O)₂R²⁰.

26. The compound of claim 1, wherein R⁶, R⁸, R⁹, R¹⁰, and R¹¹ are each H.

27. The compound of claim 1, wherein Y is —

N(R²⁴)—

.

28. The compound of 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.

29. The compound of claim 28, wherein R²⁴ is H, alkyl, or —

S(O)₂R²⁰.

30. The compound of claim 6, wherein R²⁴ is H, alkyl, or —

S(O)₂R²⁰.

7. A compound of formula 6a:

8. The compound of claim 7, wherein X is a bond or —

CH₂—

.

9. The compound of claim 7, wherein Y is —

O—

or —

N(R²⁴)—

.

10. The compound of claim 7, 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.

11. The compound of claim 10, wherein R²⁴ is H, alkyl, or —

S(O)₂R²⁰.

12. The compound of claim 7, 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.

31. The compound of claim 7, wherein X is —

CH₂—

.

32. The compound of claim 7, wherein R⁴ and R⁵ are each H.

33. The compound of claim 7, wherein R¹ is H, alkyl, hydroxyl, —

C(O)R²⁰, —

CO₂R²⁰ or —

S(O)₂R²⁰.

34. The compound of claim 7, wherein Y is —

N(R²⁴)—

.

35. The compound of claim 7, 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.

36. The compound of claim 35, wherein R²⁴ is H, alkyl, or —

S(O)₂R²⁰.

37. A pharmaceutical composition comprising a compound of claim 7, or a tautomer or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

13. A compound of formula 11b:

14. The compound of claim 13, wherein X is a bond or —

CH₂—

.

15. The compound of claim 13, wherein Y is —

O—

or —

N(R²⁴)—

.

16. The compound of claim 13, 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 CR^{23 and Y is NR24}.

17. The compound of claim 16, wherein R²⁴ is H, alkyl, or —

S(O)₂R²⁰.

18. The compound of claim 13, 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.

38. The compound of claim 13, wherein X is —

CH₂—

.

39. The compound of claim 13, wherein R⁴ and R⁵ are each H.

40. The compound of claim 13, wherein R¹ is H, alkyl, hydroxyl, —

C(O)R²⁰, —

CO₂R²⁰ or —

S(O)₂R²⁰.

41. The compound of claim 13, wherein Y is —

N(R²⁴)—

.

42. The compound of claim 13, 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.

43. The compound of claim 42, wherein R²⁴ is H, alkyl, or —

S(O)₂R²⁰.

44. A pharmaceutical composition comprising a compound of claim 13, or a tautomer or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

19. A compound selected from the group consisting of: