Mediators of hedgehog signaling pathways, compositions and uses related thereto

• US 20020165221A1
• Filed: 10/12/2001
• Published: 11/07/2002
• Est. Priority Date: 10/13/2000
• Status: Abandoned Application

• Current Assignee: Curis, Inc.
• Original Assignee: Curis, Inc.
• Inventors: Price, Stephen, Guicherit, Oivin M., Boyd, Edward Andrew, Rubin, Lee L., Baxter, Anthony David
• Application Number:
  US09/977,096
• Publication Number:
  US 20020165221A1
• Time in Patent Office: Days
• US Class Current: 514/210.17
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: C07J 69/00 Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by contraction of only one ring by one atom and expansion of only one ring by one atom
• CPC Class Codes: C07J 71/0005 Oxygen-containing hetero ring
• CPC Class Codes: C07J 71/0068 at position 16(17)
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/30 from tumour cells
• CPC Class Codes: G01N 33/574 for cancer

Abstract

The present invention makes available methods and reagents for inhibiting aberrant growth states resulting from hedgehog gain-of-function, ptc loss-of-function or smoothened gain-of-function comprising contacting the cell with a hedgehog antagonist, such as a small molecule, in a sufficient amount to aberrant growth state, e.g., to agonize a normal ptc pathway or antagonize smoothened or hedgehog activity.

Claims

1. A pharmaceutical formulation comprising an aqueous solution of a pharmaceutically acceptable salt of a compound represented in the general formula (I):

2. The formulation of claim 1, wherein Y and Z each represent O.

3. The formulation of claim 1, wherein the sum of q and r is less than 4.

4. The formulation of claim 1, wherein D represents an aralkyl- or heteroaralkyl-substituted amine.

5. The formulation of claim 1, wherein R₁ represents a branched alkyl, a cycloalkyl, or a cycloalkylalkyl.

6. The formulation of claim 1, wherein L attached to R₁ represents O, S, or NR₈.

8. The formulation of claim 1, wherein X is included in a ring.

9. The formulation of claim 1, wherein XLR₄ includes a cyclic amine.

10. The formulation of claim 1, wherein the salt is a chloride, bromide, iodide, succinate, tartrate, lactate, mesylate, or maleate salt.

11. The formulation of claim 1, wherein the solution includes a dissolved physiologically acceptable salt.

12. The formulation of claim 11, wherein the physiologically salt is sodium acetate.

13. The formulation of claim 1, wherein the aqueous solution further includes a solute selected from dextrose, lactose, mannitol, or another polyhydroxylated compound.

14. The formulation of claim 1, wherein the aqueous solution has an osmolarity between 200 and 400 mOsm.

15. The formulation of claim 1, wherein the solution has a pH in the range of 3 to 6.

16. The formulation of claim 1, wherein the formulation is suitable for topical administration.

18. The formulation of claim 17, wherein Y and Z each represent O.

19. The formulation of claim 17, wherein the sum of q, r, and s is less than 4.

20. The formulation of claim 17, wherein at least one of R₁, R₂, and R₃ includes an aryl group.

21. The formulation of claim 17, wherein XLR₄ includes a cyclic diamine.

22. The formulation of claim 17, wherein X is included in a diazacarbocycle.

23. The formulation of claim 17, wherein R₁ represents a branched alkyl, a cycloalkyl, or a cycloalkylalkyl.

24. The formulation of claim 17, wherein L attached to R₁ represents O, S, or NR₈.

25. The formulation of claim 17, wherein the salt is a chloride, bromide, iodide, succinate, tartrate, lactate, mesylate, or maleate salt.

26. The formulation of claim 17, wherein the solution includes a dissolved physiologically acceptable salt.

27. The formulation of claim 26, wherein physiologically the salt is sodium acetate.

28. The formulation of claim 17, wherein the aqueous solution further includes a solute selected from dextrose, lactose, mannitol, or another polyhydroxylated compound.

29. The formulation of claim 17, wherein the aqueous solution has an osmolarity between 200 and 400 mOsm.

30. The formulation of claim 17, wherein the solution has a pH in the range of 3 to 6.

31. The formulation of claim 17, wherein the formulation is suitable for topical administration.

32. A method for inhibiting activation of a hedgehog pathway in a cell, comprising contacting the cell with the formulation of claim 1.

33. A method for inhibiting activation of a hedgehog pathway in a cell, comprising contacting the cell with the formulation of claim 17.

34. A method for treating or preventing basal cell carcinoma, comprising administering the formulation of claim 1 to a patient in an amount sufficient to inhibit progression of basal cell carcinoma.

35. A method for treating or preventing basal cell carcinoma, comprising administering the formulation of claim 17 to a patient in an amount sufficient to inhibit progression of basal cell carcinoma.

37. The formulation of claim 36, wherein the sum of q and r is less than 4.

38. The formulation of claim 36, wherein R₁ represents a branched alkyl, a cycloalkyl, or a cycloalkylalkyl.

39. The formulation of claim 36, wherein XLR₄ includes a cyclic amine.

40. The formulation of claim 36, wherein the salt is a chloride, bromide, iodide, succinate, tartrate, lactate, mesylate, or maleate salt.

41. The formulation of claim 36, wherein the solution includes a dissolved physiologically acceptable salt.

42. The formulation of claim 41, wherein physiologically the salt is sodium acetate.

43. The formulation of claim 36, wherein the aqueous solution further includes a solute selected from dextrose, lactose, mannitol, or another polyhydroxylated compound.

44. The formulation of claim 36, wherein the aqueous solution has an osmolarity between 200 and 400 mOsm.

45. The formulation of claim 36, wherein the solution has a pH in the range of 3 to 6.

46. The formulation of claim 36, wherein the formulation is suitable for topical administration.

48. The formulation of claim 47, wherein R₁ represents a branched alkyl, a cycloalkyl, or a cycloalkylalkyl.

49. The formulation of claim 47, wherein at least one of R₁, R₂, and R₃ includes an aryl group.

50. The formulation of claim 47, wherein XLR₄ includes a cyclic amine.

51. The formulation of claim 47, wherein X is part of a diazacarbocycle.

52. The formulation of claim 47, wherein the salt is a chloride, bromide, iodide, succinate, tartrate, lactate, mesylate, or maleate salt.

53. The formulation of claim 47, wherein the solution includes a dissolved physiologically acceptable salt.

54. The formulation of claim 53, wherein physiologically the salt is sodium acetate.

55. The formulation of claim 47, wherein the aqueous solution further includes a solute selected from dextrose, lactose, mannitol, or another polyhydroxylated compound.

56. The formulation of claim 47, wherein the aqueous solution has an osmolarity between 200 and 400 mOsm.

57. The formulation of claim 47, wherein the solution has a pH in the range of 3 to 6.

58. The formulation of claim 47, wherein the formulation is suitable for topical administration.

59. A method for inhibiting activation of a hedgehog pathway in a cell, comprising contacting the cell with the formulation of claim 36.

60. A method for inhibiting activation of a hedgehog pathway in a cell, comprising contacting the cell with the formulation of claim 47.

61. A method for treating or preventing basal cell carcinoma, comprising administering the formulation of claim 36 to a patient in an amount sufficient to inhibit progression of basal cell carcinoma.

62. A method for treating or preventing basal cell carcinoma, comprising administering the formulation of claim 47 to a patient in an amount sufficient to inhibit progression of basal cell carcinoma.

17. A pharmaceutical formulation comprising an aqueous solution of a pharmaceutically acceptable salt of a compound represented in the general formula (II):

36. A pharmaceutical formulation comprising an aqueous solution of a pharmaceutically acceptable salt of a compound represented in the general formula (III):

47. A pharmaceutical formulation comprising an aqueous solution of a pharmaceutically acceptable salt of a compound represented in the general formula (IV):

63. A pharmaceutical formulation comprising an aqueous solution of a pharmaceutically acceptable salt of a compound represented by the general formula (V):

64. The formulation of claim 63, wherein Y and Z are O.

65. The formulation of claim 63, wherein the sum of q and r is less than 4.

66. The formulation of claim 63, wherein at least one occurrence of J is part of a heterocyclic ring having from 5 to 8 members.

67. The formulation of claim 63, wherein R₅ represents a branched alkyl, cycloalkyl, or cycloalkylalkyl.

68. The formulation of claim 63, wherein R₆ includes at least one heterocyclic ring.

69. The formulation of claim 63, wherein R₇ represents a phenyl alkyl.

70. The formulation of claim 63, wherein the salt is a chloride, bromide, iodide, succinate, tartrate, lactate, mesylate, or maleate salt.

71. The formulation of claim 63, wherein the solution includes a dissolved physiologically acceptable salt.

72. The formulation of claim 71, wherein physiologically the salt is sodium acetate.

73. The formulation of claim 63, wherein the aqueous solution further includes a solute selected from dextrose, lactose, mannitol, or another polyhydroxylated compound.

74. The formulation of claim 63, wherein the aqueous solution has an osmolarity between 200 and 400 mOsm.

75. The formulation of claim 63, wherein the solution has a pH in the range of 3 to 6.

76. The formulation of claim 63, wherein the formulation is suitable for topical administration.

77. A method for inhibiting activation of a hedgehog pathway in a cell, comprising contacting the cell with the formulation of claim 63.

78. A method for treating or preventing basal cell carcinoma, comprising administering the formulation of claim 63 to a patient in an amount sufficient to inhibit progression of basal cell carcinoma.

80. The preparation of claim 79, wherein Y and Z are O.

81. The preparation of claim 79, wherein at least one occurrence of J is part of a heterocyclic ring having from 5 to 8 members.

82. The preparation of claim 79, wherein R₅ represents a branched alkyl, cycloalkyl, or cycloalkylalkyl.

83. The preparation of claim 79, wherein R₆ includes at least one heterocyclic ring.

84. The preparation of claim 79, wherein R₇ represents a phenyl alkyl.

85. The formulation of claim 79, wherein the salt is a chloride, bromide, iodide, succinate, tartrate, lactate, mesylate, or maleate salt.

86. The formulation of claim 79, wherein the solution includes a dissolved physiologically acceptable salt.

87. The formulation of claim 86, wherein physiologically the salt is sodium acetate.

88. The formulation of claim 79, wherein the aqueous solution further includes a solute selected from dextrose, lactose, mannitol, or another polyhydroxylated compound.

89. The formulation of claim 79, wherein the aqueous solution has an osmolarity between 200 and 400 mOsm.

90. The formulation of claim 79, wherein the solution has a pH in the range of 3 to 6.

91. The formulation of claim 79, wherein the formulation is suitable for topical administration.

92. A method for inhibiting activation of a hedgehop pathway in a cell, comprising contacting the cell with the formulation of claim 79.

93. A method for treating or preventing basal cell carcinoma, comprising administering the formulation of claim 79 to a patient in an amount sufficient to inhibit progression of basal cell carcinoma.

79. A pharmaceutical formulation comprising an aqueous solution of a pharmaceutically acceptable salt of a compound represented by the general formula (VI):