Small organic molecule regulators of cell proliferation

• US 20060287385A1
• Filed: 04/27/2006
• Published: 12/21/2006
• Est. Priority Date: 03/30/2000
• Status: Active Grant

• Current Assignee: Curis, Inc.
• Original Assignee: Curis, Inc.
• Inventors: Price, Stephen, Rubin, Lee, Boyd, Edward Andrew, Frank-Kamenetsky, Maria, Stibbard, John Harry Alexander, Porter, Jeffery, Baxter, Anthony David, Guicherit, Oivin
• Granted Patent: US 8,129,425 B2
• Time in Patent Office: Days
• 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 31/4436 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

1-23. -23. (canceled)

24. A method for modulating proliferation survival, or differentiation of a cell, comprising contacting the cell with a compound represented in general Formula (IX):

25. The method of claim 24, wherein the compound agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 μ

M or less.

26. The method of claim 25, wherein the compound agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 nM or less.

27. The method of claim 24, wherein the compound 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.

75. The method of any one of claims 24, 69, or 71, wherein Ar is selected from substituted or unsubstituted phenyl, pyridyl, thienyl, and furyl.

76. The method of claim 75, wherein Ar is a substituted or unsubstituted phenyl ring.

77. The method of any one of claims 24, 69, or 71 wherein Cy is a heterocyclyl ring that includes a secondary or tertiary amine.

78. The method of any one of claims 24, 69, or 71, wherein Cy is a cycloalkyl ring substituted with a primary or secondary amine.

79. The method of claim 78, wherein Cy is a cyclohexyl ring substituted with a primary amino or methylamino group.

80. The method of claim 79, wherein Cy is substituted with a methylamino group.

81. The method of claim 79, wherein the amino group is located at the 4 position of the ring relative to N-M_i-Y.

82. The method of claim 79, wherein the amino group on the cyclohexyl ring is disposed trans relative to N-M_i-Y.

83. The method of any one of claims 24, 69, or 71, wherein Cy′

represents a 3-chloro-benzo(b)thien-2-yl, wherein the benzo ring is substituted with from 1-4 substituents selected from halogen, nitro, cyano, methyl, and ethyl.

84. The method of any one of claims 24, 69, or 71, wherein the benzo ring is substituted with from 1-4 substituents selected from halogen and methyl.

85. The method of claim 84, wherein the benzo ring is substituted with from 1-4 fluoro substituents.

86. The method of claim 85, wherein the benzothiophene is substituted with fluorine at the 4-position and at the 7-position.

87. The method of claim 85, wherein the benzo ring is a 1,4-difluorobenzene ring.

88. The method of any one of claims 24, 69, or 71, wherein Z is selected from substituted or unsubstituted phenyl, thienyl, furyl, pyridyl, pyrimidyl, and pyrazinyl.

89. The method of any one of claims 24, 69, or 71, wherein M is unsubstituted methylene.

90. The method of any one of claims 28 or 62, wherein the therapeutic or cosmetic application is selected from regulation of skin and hair growth.

29-59. -59. (canceled)

60. A method for modulating proliferation, survival, or differentiation of a cell, comprising contacting the cell with a preparation comprising a pharmaceutical excipient and a compound represented in general Formula (I):

61. The method of claim 60, wherein the compound 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.

63-68. -68. (canceled)

69. A method for treating or preventing a condition of the central nervous system, comprising orally administering to a patient a compound represented in general Formula (IX):

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

71. A method for modulating proliferation, differentiation, or survival of a cell in vitro, comprising contacting the cell with orally a compound represented in general Formula (IX):

72. A method for treating or preventing a condition of the central nervous system, comprising orally administering to a patient a preparation comprising a pharmaceutical excipient and a compound represented in general Formula (I):

73. The method of claim 72, wherein the condition is Parkinson'"'"'s disease, Huntington'"'"'s disease, or ischemia.

74. A method for modulating proliferation, differentiation, or survival of a cell in vitro, comprising contacting the cell with a compound represented in general Formula (I):