Agonists of hedgehog signaling pathways and uses related thereto

• US 6,683,108 B1
• Filed: 11/28/2000
• Issued: 01/27/2004
• Est. Priority Date: 03/30/2000
• Status: Expired due to Term

• Current Assignee: Curis, Inc.
• Original Assignee: Curis, Inc.
• Inventors: Rubin, Lee, Price, Stephen, Guicherit, Oivin M., Porter, Jeffrey, Boyd, Edward Andrew, Baxter, Anthony David
• Primary Examiner(s): Criares, Theodore J.
• Assistant Examiner(s): JIANG, SHAOJIA A
• Application Number:
  US09/724,492
• Time in Patent Office: 1,155 Days
• Field of Search: 514/183, 514/210, 514/247, 514/395, 514/708, 514/488, 514/443, 514/438, 514/448, 514/277, 514/252.01, 514/256
• US Class Current: 514/443
• 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 method for agonizing the hedgehog pathway in a cell, comprising contacting the cell with a hedgehog agonist represented in general formula (II):

wherein

Ar and Ar′

independently represent substituted or unsubstituted aryl or heteroaryl rings;

Y, independently for each occurrence, is absent or represents —

N(R)—

, —

O—

, —

S—

, or —

Se—

;

X is selected from —

C(═

O)—

, —

C(═

S)—

, —

S(O₂)—

, —

S(O)—

, —

C(═

NCN)—

, —

P(═

O)(OR)—

, and a methylene group optionally substituted with 1-2 groups selected from lower alkyl, alkenyl, and alkynyl groups;

M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two adjacent M taken together represent substituted or unsubstituted ethene or ethyne, wherein some or all occurrences of M in M_j form all or part of a cyclic ring;

R represents, independently for each occurrence, H or substituted or unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, heteroaralkyl, alkynyl, alkenyl, or alkyl, or two R taken together may form a 4- to 8-membered ring;

Cy′

represents substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or cycloalkyl;

j represents, independently for each occurrence, an integer from 0 to 10; and

i represents, independently for each occurrence, an integer from 0 to 5.

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

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

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

C(═

O)—

, —

C(═

S)—

, and —

S(O₂)—

.

5. The method of claim 1, wherein NR₂ represents a primary amine or a secondary or tertiary amine substituted with one or two lower alkyl groups.

6. The method of claim 1, wherein Cy′

is a substituted or unsubstituted aryl or heteroaryl.

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

M or less.

9. The method of claim 1, wherein the hedgehog agonist agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 nM or less.

10. The method of claim 1, where in the cell is contacted with the hedgehog agonist in vitro.

11. The method of claim 1, wherein the cell is contacted with the hedgehog agonist in vivo.

12. The method of claim 1, wherein the hedgehog agonist is administered as part of a therapeutic or cosmetic application.

13. The method of claim 12, wherein the therapeutic or cosmetic application is selected from the group consisting of 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, regulation of skin and hair growth.

14. The method of claim 1, wherein j represents an integer between 2 and 7, and i represents an integer between 0 and 2.

15. The method of claim 14 wherein M represents, independently for each occurrence, a substituted or unsubstituted methylene group.

16. The method of claim 1, wherein at least one of Ar and Ar′

represents a phenyl ring.

17. The method of claim 1, wherein at least one of Ar and Ar′

represents a heteroaryl ring.

18. The method of claim 1, wherein the Y and Ar′

are attached to Ar in a 1,3-relationship.

19. The method of claim 1, wherein if Y is present in a position, i represents an integer from 1-2 in an adjacent M_i if i=0 would result in two occurrences of Y being directly attached or an occurrence of Y being directly attached to N.

20. The method of claim 1, wherein Cy′

is directly attached to X.

21. The method of claim 1, wherein Cy′

represents a substituted or unsubstituted bicyclic or biaryl ring.

22. The method of claim 21, wherein Cy′

represents a bicyclic heteroaryl.

23. The method of claim 22, wherein Cy′

is selected from benzothiophene, benzofuran, benzopyrrole, and benzopyridine.

24. The method of claim 1, wherein Cy′

is a monocyclic aryl or heteroaryl ring substituted at least with a substituted or unsubstituted aryl or heteroaryl ring.

25. The method of claim 21, wherein up to 4 occurrences of M in Mj form part of a cyclic ring.

26. The method of claim 5, wherein NR₂ represents a primary amine.

27. The method of claim 5, wherein NR₂ represents a secondary amine.

28. The method of claim 1, wherein substituents on Ar or Ar′

are selected from halogen, lower alkyl, lower alkenyl, aryl, heteroaryl, carbonyl, thiocarbonyl, ketone, aldehyde, amino, acylamino, cyano, nitro, hydroxyl, azido, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, sulfonamido, phosphoryl, phosphonate, phosphinate, —

(CH₂)_palkyl, —

(CH₂)_palkenyl, —

(CH₂)_palkynyl, —

(CH₂)_paryl, —

(CH₂)_paralkyl, —

(CH₂)_pOH, —

(CH₂)_pO-lower alkyl, —

(CH₂)_pO-lower alkenyl, —

O(CH₂)_nR, —

(CH₂)_pSH, —

(CH₂)_pS-lower alkyl, —

(CH₂)_pS-lower alkenyl, —

S(CH₂)_nR, —

(CH₂)_pN(R)₂, —

(CH₂)_pNR-lower alkyl, —

(CH₂)_pNR-lower alkenyl, —

NR(CH₂)_nR, and protected forms of the above; and

p, independently for each occurrence, represents an integer from 0 to 10.

29. The method of claim 1, wherein Y is absent and 4 occurrences of M in M_j form part of a ring.

30. The method of claim 29, wherein M represents, independently for each occurrence, a substituted or unsubstituted methylene group.

31. The method of claim 29, wherein X is selected from —

C(═

O)—

, —

C(═

S)—

, and —

S(O₂)—

.

32. The method of claim 29, wherein NR₂ represents a primary amine or a secondary or tertiary amine substituted with one or two lower alkyl groups.

33. The method of claim 29, wherein Cy′

is a substituted or unsubstituted aryl or heteroaryl.

34. The method of claim 33, wherein Cy′

is bicyclic.

35. The method of claim 34, wherein Cy′

represents a substituted or unsubstituted benzothiophene.

36. The method of claim 35, wherein the benzothiophene is substituted with one or more hydrogen, methyl, ethyl, fluorine, chlorine, methoxy, or cyano groups.

37. The method of claim 36, wherein the ring is a cyclohexyl ring.

38. The method of claim 36, wherein each R independently represents H or a lower alkyl.

39. The method of claim 38, wherein NR₂ represents a secondary amine.

40. The method of claim 37, wherein each R independently represents H or a lower alkyl.

41. The method of claim 40, wherein NR₂ represents a secondary amine.

42. The method of claim 38, wherein

i is zero except for M_i between Ar and N;

and

all Y are absent.

43. The method of claim 40, wherein

i is zero except for M_i between Ar and N;

and

all Y are absent.

44. The method of claim 29, wherein the ring is a cyclohexyl ring.

45. The method of claim 44, wherein Cy′

represents a substituted or unsubstituted benzothiophene.

46. The method of claim 45, wherein the benzothiophene is substituted with one or more hydrogen, methyl, ethyl, fluorine, chlorine, methoxy, or cyano groups.

47. The method of claim 44, wherein each R independently represents H or a lower alkyl.

48. The method of claim 47, wherein NR₂ represents a secondary amine.

49. The method of claim 46, wherein each R independently represents H or a lower alkyl.

50. The method of claim 49, wherein NR₂ represents a secondary amine.

51. The method of claim 47, wherein

i is zero except for M_i between Ar and N;

and

all Y are absent.

52. The method of claim 49, wherein

i is zero except for M_i between Ar and N;

4 occurrences of M in M_j form part of a ring; and

all Y are absent.

53. The method of claim 32, wherein each R independently represents H or a lower alkyl.

54. The method of claim 53, wherein NR₂ represents a secondary amine.

55. The method of claim 53, wherein Cy′

represents a substituted or unsubstituted benzothiophene.

56. The method of claim 55, wherein the benzothiophene is substituted with one or more hydrogen, methyl, ethyl, fluorine, chlorine, methoxy, or cyano groups.

57. The method of claim 52, wherein the ring is a cyclohexyl ring.

58. The method of claim 56, wherein

i is zero except for M_i between Ar and N;

and all Y are absent.

59. The method of claim 57, wherein

i is zero except for M_i between Ar and N;

and

all Y are absent.

60. The method of claim 29, wherein

4 occurrences of M in M_j form part of a ring;

X is selected from —

C(═

O)—

or —

C(═

S)—

; and

Cy′

is a substituted or unsubstituted aryl or heteroaryl ring.

61. The method of claim 60, wherein Cy′

is heteroaryl.

62. The method of claim 60, wherein Cy′

is bicyclic.

63. The method of claim 60, wherein the ring is a cycloalkyl ring.

64. The method of claim 63, wherein the ring is a cyclohexyl ring.

65. The method of claim 64, wherein Cy′

represents a substituted or unsubstituted benzothiophene.

66. The method of claim 65, wherein the benzothiophene is substituted with one or more hydrogen, methyl, ethyl, fluorine, chlorine, methoxy, or cyano groups.

67. The method of claim 64, wherein each R independently represents H or a lower alkyl group.

68. The method of claim 65, wherein NR₂ represents a secondary amine.

69. The method of claim 66, wherein each R independently represents H or a lower alkyl group.

70. The method of claim 62, wherein Cy′

represents a substituted or unsubstituted benzothiophene.

71. The method of claim 70, wherein the benzothiophene is substituted with one or more hydrogen, methyl, ethyl, fluorine, chlorine, methoxy, or cyano groups.

72. The method of claim 71, wherein the ring is a cyclohexyl ring.

73. The method of claim 71, wherein each R independently represents H or a lower alkyl group.

74. The method of claim 72, wherein each R independently represents H or a lower alkyl group.

75. The method of claim 12, wherein the therapeutic or cosmetic application is promoting hair growth.

7. The method of claim wherein the hedgehog agonist agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 mM or less.