Mediators of hedgehog signaling pathways, compositions and uses related thereto

• US 20050014796A1
• Filed: 12/09/2003
• Published: 01/20/2005
• Est. Priority Date: 03/30/2000
• Status: Abandoned Application

• Current Assignee: Curis, Inc.
• Original Assignee: Curis, Inc.
• Inventors: Rubin, Lee, Price, Stephen, Guicherit, Oivin M., Boyd, Edward Andrew, Porter, Jeffrey, Baxter, Anthony David
• Application Number:
  US10/732,669
• Publication Number:
  US 20050014796A1
• Time in Patent Office: Days
• US Class Current: 514/332
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/422 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/50 Pyridazines; Hydrogenated pyridazines
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: C07D 333/70 attached in position 2
• 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

The present invention makes available methods and reagents for inducing activation of a hedgehog pathway in a cell or tissue comprising contacting the cell with a hedgehog agonist, such as a small molecule, in a sufficient amount to achieve a therapeutic result. In certain embodiments, the methods and reagents may be employed to correct or inhibit an aberrant or unwanted growth state, e.g., by antagonizing a normal ptc pathway or agonizing smoothened or hedgehog activity.

Claims

1. A compound represented in general formula (III):

2. The compound of claim 1, wherein Y is absent from all positions.

3. The compound of claim 1, wherein M represents, independently for each occurrence, a substituted or unsubstituted methylene group.

4. The compound of claim 1, wherein X is selected from —

C(═

O)—

, —

C(═

S)—

, and —

S(O<sub>2)—

.</sub>

5. The compound of claim 1, wherein NR₂ represents a primary amine, or a secondary amine substituted with one lower alkyl group.

6. The compound of claim 1, wherein Cy′

is a substituted or unsubstituted aryl or heteroaryl.

7. The compound of claim 1, wherein Cy′

is bicyclic.

8. The compound of claim 7, wherein Cy′

represents a substituted or unsubstituted benzothiophene.

9. The compound of claim 8, wherein the benzothiophene ring is substituted with one or more methyl, ethyl, fluorine, chlorine, methoxy or cyano groups.

10. The compound of claim 9, wherein each R independently represents H or a lower alkyl.

11. The compound of claim 9, wherein NR₂ represents a secondary amine.

12. The compound of claim 11, wherein each R independently represents H or a lower alkyl.

13. The compound of claim 10, wherein

i is zero except for M_i between Ar and N;

and all Y are absent.

14. The compound of claim 12, wherein

i is zero except for M_i between Ar and N;

and all Y are absent.

15. The compound of claim 14, wherein X is selected from —

C(═

O)—

, —

C(═

S)—

, and —

S(O₂)—

.

16. The compound of claim 11, wherein X is selected from —

C(═

O)—

, —

C(═

S)—

, and —

S(O₂)—

.

17. The compound of claim 10, wherein X is selected from —

C(═

O)—

, —

C(═

S)—

, and —

S(O₂)—

.

18. The compound of claim 8, wherein X is selected from —

C(═

O)—

, —

C(═

S)—

, and —

S(O₂)—

.

19. The compound of claim 18, wherein NR₂ represents a secondary amine.

20. The compound of claim 19, wherein each R independently represents H or a lower alkyl.

21. The compound of claim 8, wherein NR₂ represents a secondary amine.

22. The compound of claim 20, wherein

i is zero except for M_i between Ar and N;

and

all Y are absent.

23. The compound of claim 21, wherein

i is zero except for M, between Ar and N, and

all Y are absent.

24. The compound of claim 23, wherein each R independently represents H or a lower alkyl.

25. The compound of claim 24, wherein NR₂ represents a secondary amine.

26. The compound of claim 25, wherein Cy′

represents a substituted or unsubstituted benzothiophene.

27. The compound of claim 26, wherein X is selected from —

C(═

O)—

, —

C(═

S)—

, and —

S(O₂)—

.

28. The compound of claim 27, wherein the benzothiophene ring is substituted with one or more methyl, ethyl, fluorine, chlorine, methoxy or cyano groups.

29. The compound of claim 27, wherein the benzothiophene ring is substituted with one or more methyl, fluorine, or chlorine groups.

46. A method for modulating proliferation or differentiation of a cell, comprising contacting the cell with a compound of claim 1 or claim 30.

47. The method of claim 46, wherein the compound is a hedgehog agonist.

48. The method of claim 47, wherein the hedgehog agonist agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 μ

M or less.

49. The method of claim 47, wherein the hedgehog agonist is administered as part of a therapeutic or cosmetic application.

50. The method of claim 49, wherein the therapeutic or cosmetic application is selected from regulation of neural tissues, bone and cartilage formation and repair, regulation of spermatogenesis, regulation of smooth muscle, regulation of lung, liver and other organs arising from the primitive gut, regulation of hematopoietic function, and regulation of skin and hair growth.

51. A method for treating neurological conditions deriving from acute, subacute, or chronic injury to the nervous system:

aging of the nervous system;

chronic neurodegenerative diseases of the nervous system;

or chronic immunological diseases of the nervous system or affecting the nervous system, comprising administering to a subject the preparation of claim 1 or 30.

52. The method of claim 51, wherein the injury is ischemic injury resulting from stroke.

53. The method of claim 51, wherein the neurodegenerative disease is Parkinson'"'"'s disease.

54. The method of claim 51, wherein the neuromuscular disorders are selected from chronic or progressive atrophies and chronic peripheral neuropathy.

55. A method for treating or reducing the risk of developing Parkinson'"'"'s disease comprising administering to an animal a compound of claim 1 or 30.

56. The method of claim 55, wherein the hedgehog agonist increases the rate of survival of dopaminergic neurons.

57. A method for treating autonomic disorders of the peripheral nervous system comprising administering to an animal a compound of claim 1 or 30.

58. A method for treating neuronal damage due to ischemic events comprising administering to an animal a compound of claim 1 or 30.

59. A method of modulating the growth, differentiation, or survival of a cell, comprising contacting the cell with a compound of claim 1 or 30.

60. The method of claim 59, wherein the cell is contacted with the compound in vitro.

61. The method of claim 59, wherein the cell is contacted with the compound ex vivo.

30. A compound represented in general formula (Vet):

31. The compound of claim 30, wherein Ar is heteroaryl.

32. The compound of claim 30, wherein Ar is bicyclic.

33. The compound of claim 30, wherein NR₂ represents NH).

34. The compound of claim 33, wherein Ar represents a substituted or unsubstituted benzothiophene.

35. The compound of claim 34, wherein the benzothiophene ring is substituted with one or more methyl, ethyl, fluorine, chlorine, methoxy, or cyano groups.

36. The compound of claim 30, wherein each R independently represents H or a lower alkyl group.

37. The compound of claim 36, wherein NR₂ represents a secondary amine.

38. The compound of claim 36, wherein Ar represents a substituted or unsubstituted benzothiophene.

39. The compound of claim 38, wherein the benzothiophene ring is substituted with one or more methyl, ethyl, fluorine, chlorine, methoxy, or cyano groups.

40. The compound of claim 30, wherein Ar represents a substituted or unsubstituted benzothiophene.

41. The compound of claim 40, wherein the benzothiophene ring is substituted with one or more methyl, ethyl, fluorine, chlorine, methoxy, or cyano groups.

42. The compound of claim 40, wherein each R independently represents H or a lower alkyl group.

43. The compound of claim 42, wherein NR₂ represents a secondary amine.

44. The compound of claim 43, wherein the benzothiophene ring is substituted with one or more methyl, ethyl, fluorine, chlorine, methoxy, or cyano groups.

45. The compound of claim 43, wherein the benzothiophene ring is substituted with one or more methyl, fluorine, or chlorine groups.