Small organic molecule regulators of cell proliferation

• US 20030139457A1
• Filed: 09/17/2002
• Published: 07/24/2003
• Est. Priority Date: 03/30/2000
• Status: Active Grant

• Current Assignee: Curis, Inc.
• Original Assignee: Curis, Inc.
• Inventors: Rubin, Lee, Price, Stephen, Boyd, Edward Andrew, Frank-Kamenetsky, Maria, Stibbard, John Harry Alexander, Porter, Jeffery, Baxter, Anthony David, Guicherit, Oivin
• Granted Patent: US 7,115,653 B2
• Time in Patent Office: Days
• US Class Current: 514/357
• 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 31/4436 containing a heterocyclic ring having sulfur as a ring hetero atom
• 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 modulating proliferation or differentiation in a cell or tissue comprising contacting the cell with a hedgehog agonist, such as the compounds depicted in FIGS. 32 and 33. 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 (IX):

2. The compound of claim 1, wherein Cy includes at least one sp³ hybridized atom.

3. The compound of claim 2, wherein Cy further includes at least one nitrogen atom in the ring, or an amino substituent on the ring.

4. The compound of claim 1, wherein Cy includes or is substituted with a primary, secondary, or tertiary amine.

5. The compound of claim 4, wherein Cy is a cyclohexyl ring substituted with a primary or secondary amine.

6. The compound of claim 5, wherein the amine is a methylamino group.

7. The compound of claim 1, wherein the benzo ring is substituted with from 1-4 substituents selected from halogen, and methyl.

8. The compound of claim 7, wherein the benzo ring is a 1,4-difluorobenzene ring.

21. A pharmaceutical composition comprising a sterile excipient and a compound according to claim 1.

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

25. The method of claim 21, wherein the hedgehog agonist agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 μ

M or less.

26. The method of claim 21, wherein the hedgehog agonist agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 nM or less.

27. The method of claim 24, wherein the hedgehog agonist is administered to a patient as part of a therapeutic or cosmetic application.

28. The method of claim 27, 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.

69. A method for treating or preventing a condition of the central nervous system, comprising orally administering to a patient a compound of claim 1, 9, or 16, or a preparation of claim 39, 46, or 53.

70. The method of claim 69, wherein the condition is Parkinson'"'"'s disease, Huntington'"'"'s disease, or ischemia.

71. A method for regulating the growth, differentiation, or survival of a cell in vitro, comprising orally administering to a patient a compound of claim 1, 9, or 16, or a preparation of claim 39, 46, or 53.

9. A compound represented in general formula (X):

10. The compound of claim 9, wherein M_j includes a cycloalkyl ring having 5-7 ring atoms.

11. The compound of claim 10, wherein NR₂ represents NHMe.

12. The compound of claim 9, wherein Cy is a cyclohexyl ring substituted with a primary or secondary amine.

13. The compound of claim 12, wherein the amine is a methylamino group.

14. The compound of claim 9, wherein the benzo ring is substituted with from 1-4 substituents selected from halogen, and methyl.

15. The compound of claim 14, wherein the benzo ring is a 1,4-difluorobenzene ring.

22. A pharmaceutical composition comprising a sterile excipient and a compound according to claim 9.

29. A method for modulating proliferation or differentiation of a cell, comprising contacting the cell with a compound of claim 9.

30. The method of claim 29, wherein the hedgehog agonist agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 μ

M or less.

31. The method of claim 29, wherein the hedgehog agonist agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 nM or less.

32. The method of claim 29, wherein the hedgehog agonist is administered to a patient as part of a therapeutic or cosmetic application.

33. The method of claim 32, 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.

16. A compound represented in general formula (XI):

17. The compound of claim 16, wherein Cy is a cyclohexyl ring substituted with a primary or secondary amine.

18. The compound of claim 17, wherein the amine is a methylamino group.

19. The compound of claim 16, wherein the benzo ring is substituted with from 1-4 substituents selected from halogen, and methyl.

20. The compound of claim 19, wherein the benzo ring is a 1,4-difluorobenzene ring.

23. A pharmaceutical composition comprising a sterile excipient and a compound according to claim 16.

34. A method for modulating proliferation or differentiation of a cell, comprising contacting the cell with a compound of claim 16.

35. The method of claim 34, wherein the hedgehog agonist agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 μ

M or less.

36. The method of claim 34, wherein the hedgehog agonist agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 nM or less.

37. The method of claim 34, wherein the hedgehog agonist is administered to a patient as part of a therapeutic or cosmetic application.

38. The method of claim 37, 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.

39. A pharmaceutical preparation comprising a sterile pharmaceutical excipient and a compound represented in general formula (I):

40. The pharmaceutical preparation of claim 39, wherein Y is absent from all positions.

41. The pharmaceutical preparation of claim 39, wherein M represents, independently for each occurrence, a substituted or unsubstituted methylene group.

42. The pharmaceutical preparation of claim 39, wherein X is selected from —

C(═

O)—

, —

C(═

S)—

, and —

S(O₂)—

.

43. The pharmaceutical preparation of claim 39, wherein Cy includes at least one sp³ hybridized atom.

44. The pharmaceutical preparation of claim 39, wherein Cy′

is a substituted or unsubstituted aryl or heteroaryl.

45. The pharmaceutical preparation of claim 39, wherein Cy includes or is substituted with a primary, secondary, or tertiary amine.

60. A method for modulating proliferation or differentiation of a cell, comprising contacting the cell with a preparation of claim 39.

61. The method of claim 60, wherein the hedgehog agonist is administered to a patient as part of a therapeutic or cosmetic application.

62. The method of claim 61, 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.

46. A pharmaceutical preparation comprising a sterile pharmaceutically acceptable excipient and an organic molecule represented in general formula (II):

47. The pharmaceutical preparation of claim 46, wherein Y is absent from all positions.

48. The pharmaceutical preparation of claim 46, wherein M represents, independently for each occurrence, a substituted or unsubstituted methylene group.

49. The pharmaceutical preparation of claim 46, wherein X is selected from —

C(═

O)—

, —

C(═

S)—

, and —

S(O₂)—

.

50. The pharmaceutical preparation of claim 46, wherein NR₂ represents a primary amine or a secondary or tertiary amine substituted with one or two lower alkyl groups, aryl groups, or aralkyl groups

51. The pharmaceutical preparation of claim 46, wherein Cy′

is a substituted or unsubstituted aryl or heteroaryl.

52. The pharmaceutical preparation of claim 46, wherein Cy′

is bicyclic.

63. A method for modulating proliferation or differentiation of a cell, comprising contacting the cell with a preparation of claim 46.

64. The method of claim 63, wherein the hedgehog agonist is administered to a patient as part of a therapeutic or cosmetic application.

65. The method of claim 64, 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.

53. A pharmaceutical preparation comprising a sterile pharmaceutically acceptable excipient and a compound represented in general formula (III):

54. The pharmaceutical preparation of claim 53, wherein Y is absent from all positions.

55. The pharmaceutical preparation of claim 53, wherein M represents, independently for each occurrence, a substituted or unsubstituted methylene group.

56. The pharmaceutical preparation of claim 53, wherein X is selected from —

C(═

O)—

, —

C(═

S)—

, and —

S(O₂)—

.

57. The pharmaceutical preparation of claim 53, wherein NR₂ represents a primary amine or a secondary or tertiary amine substituted with one or two lower alkyl groups, aryl groups, or aralkyl groups.

58. The pharmaceutical preparation of claim 53, wherein Cy′

is a substituted or unsubstituted aryl or heteroaryl.

59. The pharmaceutical preparation of claim 53, wherein Cy′

is bicyclic.

66. A method for modulating proliferation or differentiation of a cell, comprising contacting the cell with a preparation of claim 53.

67. The method of claim 66, wherein the hedgehog agonist is administered to a patient as part of a therapeutic or cosmetic application.

68. The method of claim 67, 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.