Claims
- 1. The compound of Formula 8,
- 2. The compound of claim 1, wherein
- 3. The compound of claim 1, wherein
- 4. The compound of claim 1, wherein
- 5. The compound of claim 1, wherein A is
- 6. The compound of claim 1, wherein B is
- 7. The compound of claim 1, where R2 and R2a are each independently selected from halogen, C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 hydroxyalkyl, C1-C10 alkoxycarbonylalkyl, C1-C10 alkylcarbonylaminoC1-C10alkyl, C3-C20 heterocyclyl, C3-C20 heterocyclylalkyl, C5-C20 aralkyl, C5-C20 aryl, C5-C20 heteroaralkyl and C5-C20 heteroaryl, where the aryl and heteroaryl groups are optionally substituted with one or more groups selected from alkyl, haloalkyl, halogen, alkoxycarbonyl, carboxy, hydroxy, alkylsulfonylamino, alkoxy and nitro.
- 8. The compound of claim 1, where R2 and R2a are each independently selected from chloro, methyl, ethyl, n-butyl, tert-butyl, hydroxyethyl, methoxycarbonylethyl, methylcarbonylaminoethyl, cyclopentyl, cyclohexyl, benzyl, phenyl, naphthyl, N-morpholinyl, 2-pyridinyl and 4-pyridinyl, where the phenyl and pyridinyl rings are optionally substituted with one or more groups selected from methyl, trifluoromethyl, chloro, methoxycarbonyl, carboxy, hydroxy, methylsulfonylamino, methoxy and nitro.
- 9. The compound of claim 1, where R2 and R2a are each independently selected from chloro, methyl, ethyl, n-butyl, tert-butyl, hydroxyethyl, methoxycarbonylethyl, methylcarbonylaminoethyl cyclopentyl, cyclohexyl, N-morpholinyl, 4-pyridinyl, benzyl, phenyl, 2-pyridinyl, 4-nitrophenyl, 4-methoxyphenyl, p-tolyl, 4-trifluoromethyl, m-tolyl, o-tolyl, 3-methoxyphenyl, 2-methoxyphenyl, 2-chlorophenyl, naphthyl, 2-methoxycarbonylphenyl, 2-carboxyphenyl, 4-hydroxyphenyl, 4-methoxycarbonylphenyl, 4-aminophenyl, 4-carboxyphenyl and 4-methylsulfonylaminophenyl.
- 10. The compound of claim 1, where R2 is chloro, methyl, ethyl, n-butyl, tert-butyl, hydroxyethyl, acetoxyethyl, methylcarbonylaminoethyl cyclopentyl, cyclohexyl, N-morpholinyl, 4-pyridinyl, benzyl, phenyl, 2-pyridinyl, 4-nitrophenyl, 4-methoxyphenyl, p-tolyl, 4-trifluoromethyl, m-tolyl, o-tolyl, 3-methoxyphenyl, 2-methoxyphenyl, 2-chlorophenyl, naphthyl, 2-methoxycarbonylphenyl, 2-carboxyphenyl, 4-hydroxyphenyl, 4-methoxycarbonylphenyl, 4-aminophenyl, 4-carboxyphenyl and 4-, methylsulfonylaminophenyl.
- 11. The compound of claim 1, where R2a is chloro, methyl, ethyl, n-butyl, tert-butyl, hydroxyethyl, methoxycarbonylethyl, methylcarbonylaminoethyl cyclopentyl, cyclohexyl, N-morpholinyl, 4-pyridinyl, benzyl, phenyl, 2-pyridinyl, 4-nitrophenyl, 4-methoxyphenyl, p-tolyl, 4-trifluoromethyl, m-tolyl, o-tolyl, 3-methoxyphenyl, 2-methoxyphenyl, 2-chlorophenyl, naphthyl, 2-methoxycarbonylphenyl, 2-carboxyphenyl, 4-hydroxyphenyl, 4-methoxycarbonylphenyl, 4-aminophenyl, 4-carboxyphenyl and 4-methylsulfonylaminophenyl.
- 12. The compound of claim 1, where C is selected from a group consisting of
- 13. The compound of claim 1, where C is
- 14. The compound of claim 1, where R4 and R5 are each independently selected from hydrogen and C1-C10 alkyl.
- 15. The compound of claim 1, where R4 and R5 are each independently hydrogen or methyl.
- 16. The compound of claim 1, where R4 is hydrogen or methyl.
- 17. The compound of claim 1, where R4 is methyl.
- 18. The compound of claim 1, where R5is hydrogen.
- 19. The compound of claim 1, where C is
- 20. The compound of claim 1, where
C is 129
- 21. The compound of claim 1, where D is selected from —N—, —NO—, —NR10, —CR11R12—, —CR13—, —S—, —SO—, and —SO2.
- 22. The compound of claim 1, where D is —N— or —NO—.
- 23. The compound of claim 1, where D is —N—.
- 24. The compound of claim 1, where E and Ea are each independently selected from a single bond, —CR14R15, —NR16, —O—, —S—, —SO—, and —SO2—.
- 25. The compound of claim 1, where Ea is single bond, —O—, —SO—, or —SO2—.
- 26. The compound of claim 1, where E is single bond, —O—, —SO—, or —SO2—.
- 27. The compound of claim 1, where Ea is —SO2—.
- 28. The compound of claim 1, where E is —SO2—.
- 29. The compound of claim 1, where R6 is hydrogen.
- 30. The compound of claim 1 that has formula:
- 31. The compound of claim 30, where E1 is chloro, —O— or —SO2—.
- 32. The compound of claim 30, where E2 is chloro, —O— or —SO2—.
- 33. The compound of claim 30, where Rx and Ry are each independently selected from chloro, methyl, ethyl, n-butyl, tert-butyl, hydroxyethyl, methoxycarbonylethyl, methylcarbonylaminoethyl, cyclopentyl, cyclohexyl, benzyl, phenyl, naphthyl, N-morpholinyl, 2-pyridinyl and 4-pyridinyl, where the phenyl and pyridinyl rings are optionally substituted with one or more groups selected from methyl, trifluoromethyl, chloro, methoxycarbonyl, carboxy, hydroxy, methylsulfonylamino, methoxy and nitro.
- 34. The compound of claim 30, where Rx is phenyl, optionally substituted with one or more methyl, trifluoromethyl, chloro, methoxycarbonyl, carboxy, hydroxy, methylsulfonylamino, methoxy or nitro.
- 35. The compound of claim 30, where Ry is phenyl, optionally substituted with one or more methyl, trifluoromethyl, chloro, methoxycarbonyl, carboxy, hydroxy, methylsulfonylamino, methoxy or nitro.
- 36. The compound of claim 30 that has formula:
- 37. The compound of claim 36 that has formula:
- 38. The compound of claim 30 that is selected from
- 39. The compound of claim 38 wherein m is 0 or 1.
- 40. The compound of claim 38 wherein n is 0 or 1.
- 41. The compound of claim 36 that has formula
- 42. The compound of claim 30 that has formula selected from
- 43. A compound of claim 1 that is selected from
- 44. A pharmaceutical composition, comprising, in a pharmaceutically acceptable carrier, a compound of formula 8,
- 45. The pharmaceutical composition of claim 44, wherein
- 46. The pharmaceutical composition of claim 44, wherein
- 47. The pharmaceutical composition of claim 44, wherein
- 48. The pharmaceutical composition of claim 44, wherein A is
- 49. The pharmaceutical composition of claim 44, wherein B is
- 50. The pharmaceutical composition of claim 44, where R2 and R2a are each independently selected from halogen, C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 hydroxyalkyl, C1-C10 alkoxycarbonylalkyl, C1-C10 alkylcarbonylaminoC1-C10alkyl, C3-C20 heterocyclyl, C3-C20 heterocyclylalkyl, C5-C20 aralkyl, C5-C20 aryl, C5-C20 heteroaralkyl and C5-C20 heteroaryl, where the aryl and heteroaryl groups are optionally substituted with one or more groups selected from alkyl, haloalkyl, halogen, alkoxycarbonyl, carboxy, hydroxy, alkylsulfonylamino, alkoxy and nitro.
- 51. The pharmaceutical composition of claim 44, where R2 and R2a are each independently selected from chloro, methyl, ethyl, n-butyl, tert-butyl, hydroxyethyl, methoxycarbonylethyl, methylcarbonylaminoethyl, cyclopentyl, cyclohexyl, benzyl, phenyl, naphthyl, N-morpholinyl, 2-pyridinyl and 4-pyridinyl, where the phenyl and pyridinyl rings are optionally substituted with one or more groups selected from methyl, trifluoromethyl, chloro, methoxycarbonyl, carboxy, hydroxy, methylsulfonylamino, methoxy and nitro.
- 52. The pharmaceutical composition of claim 44, where R2 and R2a are each independently selected from chloro, methyl, ethyl, n-butyl, tert-butyl, hydroxyethyl, methoxycarbonylethyl, methylcarbonylaminoethyl cyclopentyl, cyclohexyl, N-morpholinyl, 4-pyridinyl, benzyl, phenyl, 2-pyridinyl, 4-nitrophenyl, 4-methoxyphenyl, p-tolyl, 4-trifluoromethyl, m-tolyl, o-tolyl, 3-methoxyphenyl, 2-methoxyphenyl, 2-chlorophenyl, naphthyl, 2-methoxycarbonylphenyl, 2-carboxyphenyl, 4-hydroxyphenyl, 4-methoxycarbonylphenyl, 4-aminophenyl, 4-carboxyphenyl and 4-methylsulfonylaminophenyl.
- 53. The pharmaceutical composition of claim 44, where R2 is chloro, methyl, ethyl, n-butyl, tert-butyl, hydroxyethyl, methoxycarbonylethyl, methylcarbonylaminoethyl cyclopentyl, cyclohexyl, N-morpholinyl, 4-pyridinyl, benzyl, phenyl, 2-pyridinyl, 4-nitrophenyl, 4-methoxyphenyl, p-tolyl, 4-trifluoromethyl, m-tolyl, o-tolyl, 3-methoxyphenyl, 2-methoxyphenyl, 2-chlorophenyl, naphthyl, 2-methoxycarbonylphenyl, 2-carboxyphenyl, 4-hydroxyphenyl, 4-methoxycarbonylphenyl, 4-aminophenyl, 4-carboxyphenyl and 4-methylsulfonylaminophenyl.
- 54. The pharmaceutical composition of claim 44, where R2a is chloro, methyl, ethyl, n-butyl, tert-butyl, hydroxyethyl, methoxycarbonylethyl, methylcarbonylaminoethyl cyclopentyl, cyclohexyl, N-morpholinyl, 4-pyridinyl, benzyl, phenyl, 2-pyridinyl, 4-nitrophenyl, 4-methoxyphenyl, p-tolyl, 4-trifluoromethyl, m-tolyl, o-tolyl, 3-methoxyphenyl, 2-methoxyphenyl, 2-chlorophenyl, naphthyl, 2-methoxycarbonylphenyl, 2-carboxyphenyl, 4-hydroxyphenyl, 4-methoxycarbonylphenyl, 4-aminophenyl, 4-carboxyphenyl and 4-methylsulfonylaminophenyl.
- 55. The pharmaceutical composition of claim 44, where C is selected from a group consisting of
- 56. The pharmaceutical composition of claim 44, where C is
- 57. The pharmaceutical composition of claim 44, where R4 and R5 are each independently selected from hydrogen and C1-C10 alkyl.
- 58. The pharmaceutical composition of claim 44, where R4 and R5 are each independently hydrogen or methyl.
- 59. The pharmaceutical composition of claim 44, where R4 is hydrogen or methyl.
- 60. The pharmaceutical composition of claim 44, where R4 is methyl.
- 61. The pharmaceutical composition of claim 44, where R5 is hydrogen.
- 62. The pharmaceutical composition of claim 44, where C is
- 63. The pharmaceutical composition of claim 44, where
C is 156
- 64. The pharmaceutical composition of claim 44, where D is selected from —N—, —NO—, —NR10, —CR11R12—, —CR13—, —S—, —SO—, and —SO2.
- 65. The pharmaceutical composition of claim 44, where D is —N—or —NO—.
- 66. The pharmaceutical composition of claim 44, where D is —N—.
- 67. The pharmaceutical composition of claim 44, where E and Ea are each independently selected from a single bond, —CR14R15, —NR16, —O—, —S—, —SO—, and —SO2—.
- 68. The pharmaceutical composition of claim 44, where Ea is single bond,—O—, —SO—, or —SO2—.
- 69. The pharmaceutical composition of claim 44, where E is single bond, —O—, —SO—, or —SO2—.
- 70. The pharmaceutical composition of claim 44, where Ea is —SO2—.
- 71. The pharmaceutical composition of claim 44, where E is —SO2—.
- 72. The pharmaceutical composition of claim 44, where R6 is hydrogen.
- 73. The pharmaceutical composition of claim 44 that has formula:
- 74. The pharmaceutical composition of claim 73, where E1 is chloro, —O— or —SO2—.
- 75. The pharmaceutical composition of claim 73, where E2 is chloro, —O— or —SO2—.
- 76. The pharmaceutical composition of claim 73, where Rx and Ry are each independently selected from chloro, methyl, ethyl, n-butyl, tert-butyl, hydroxyethyl, methoxycarbonylethyl, methylcarbonylaminoethyl, cyclopentyl, cyclohexyl, benzyl, phenyl, naphthyl, N-morpholinyl, 2-pyridinyl and 4-pyridinyl, where the phenyl and pyridinyl rings are optionally substituted with one or more groups selected from methyl, trifluoromethyl, chloro, methoxycarbonyl, carboxy, hydroxy, methylsulfonylamino, methoxy and nitro.
- 77. The pharmaceutical composition of claim 73, where Rx is phenyl, optionally substituted with one or more methyl, trifluoromethyl, chloro, methoxycarbonyl, carboxy, hydroxy, methylsulfonylamino, methoxy or nitro.
- 78. The pharmaceutical composition of claim 73, where Ry is phenyl, optionally substituted with one or more methyl, trifluoromethyl, chloro, methoxycarbonyl, carboxy, hydroxy, methylsulfonylamino, methoxy or nitro.
- 79. The pharmaceutical composition of claim 73 that has formula:
- 80. The pharmaceutical composition of claim 79 that has formula:
- 81. The pharmaceutical composition of claim 71 that is selected from
- 82. The pharmaceutical composition of claim 81 wherein m is 0 or 1.
- 83. The pharmaceutical composition of claim 81 wherein n is 0 or 1.
- 84. The pharmaceutical composition of claim 79 that has formula
- 85. The pharmaceutical composition of claim 71 that has formula selected from
- 86. A pharmaceutical composition, comprising, in a pharmaceutically acceptable carrier, a compound selected from
- 87. An article of manufacture, comprising packaging material, a compound of formula 8:
- 88. A method of treating, preventing, or ameliorating the symptoms of a disease or disorder that is modulated or otherwise affected by Bcl-2 protein or in which Bcl-2 protein is implicated, comprising administering to a subject in need thereof an effective amount of a compound of claim 1.
- 89. The method of claim 88, wherein the disease or disorder is a Bcl-2 or Bcl-XL mediated disease or disorder.
- 90. The method of claim 88, wherein the disease or disorder is characterized by overexpression of a Bcl-2 or Bcl-XL protein.
- 91. The method of claim 88, wherein the disease or disorder is selected from cancers, tumors, hyperproliferative diseases, acquired immune deficiency syndrome, degenerative conditions, and vascular diseases.
- 92. The method of claim 90, wherein the cancer is selected from B-cell lymphoma including B-cell lymphoma-2, B-cell leukemia, skin cancer, pancreatic cancer, ovarian cancer, liver cancer, bladder cancer, adrenal carcinoma, breast cancer, prostate cancer, and colorectal cancer.
- 93. A method of treating, preventing, or ameliorating the symptoms of a disease or disorder that is modulated or otherwise affected by Bcl-2 protein or in which Bcl-2 protein is implicated, comprising administering to a subject in need thereof an effective amount of a compound of claim 79.
- 94. A method of modulating the activity of a Bcl-2 protein, comprising administering to a subject in need thereof an effective amount of a compound of claim 1.
- 95. The method of claim 94, wherein the Bcl-2 protein is selected from anti-apoptotic Bcl-2 protein, Bcl-2 and Bcl-XL.
- 96. A method of antagonizing Bcl-2 protein, comprising administering to a subject in need thereof an effective amount of a compound of claim 1.
- 97. The method of claim 95, wherein the Bcl-2 protein is selected from anti-apoptotic Bcl-2 protein, Bcl-2 and BCl-XL.
- 98. A method of altering the interaction of an anti-apoptotic Bcl-2 protein, comprising administering to a subject in need thereof an effective amount of a compound of claim 1.
- 99. The method of claim 95, wherein the Bcl-2 protein is selected from anti-apoptotic Bcl-2 protein, Bcl-2 and BCl-XL.
- 100. A method of inducing apoptosis, comprising administering to a subject in need thereof an effective amount of a compound of claim 1.
- 101. A method of modulating the activity of a Bcl-2 protein, comprising administering to a subject in need thereof an effective amount of a compound of claim 79.
- 102. A method of antagonizing Bcl-2 protein, comprising administering to a subject in need thereof an effective amount of a compound of claim 79.
- 103. A method of altering the interaction of an anti-apoptotic Bcl-2 protein, comprising administering to a subject in need thereof an effective amount of a compound of claim 79.
- 104. A method of inducing apoptosis, comprising administering to a subject in need thereof an effective amount of a compound of claim 79.
RELATED APPLICATIONS
[0001] Priority is claimed herein to U.S. provisional patent application No. 60/466,203, to Gupta et al., filed Apr. 30, 2003, entitled “Novel Monocyclic Diazodioxide based Bcl-2 Protein Antagonists and Use Thereof”. The disclosure of the above-referenced application is incorporated by reference herein in its entirety.
Provisional Applications (1)
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Number |
Date |
Country |
|
60466203 |
Apr 2003 |
US |