Claims
- 1. A compound of Formula 8,
- 2. The compound of claim 1, or a pharmaceutically acceptable derivative thereof, wherein:
A and B are each independently —NO—, or —N—; C is a double bond; D is selected from the group consisting of: single bond, 53E and F are each independently selected from the group consisting of single bond, double bond, —NR9—, —CR10R11—, and —O—; m and n are each independently and integer from 0 to 6; R1 to R8, R10, and R11 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, C1-C10 alkoxyl, amino, C1-C10 aminoalkyl, C1-C10 alkylaminoalkyl, hydroxyl, C1-C10 hydroxyalkyl, carboxyl, C1-C10 carboxyalkyl, C1-C10 alkoxylcarbonyl, C1-C10 alkoxycarbonylalkyl, halogen, mono- or polyfluroalkyl, mono- or polyfluroalkoxyl, cyano, nitro, C1-C10 thioalkyl, C1-C10 sulfonylalkyl, and C1-C10 alkylsulfonylalkyl; and R9 is selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 acyl, C5-C10 aryl, C1-C10 alkoxyalkyl, C1-C10 hydroxyalkyl, C1-C10 carboxyalkyl, C1-C10 alkoxylcarbonyl, and C1-C10 alkoxycarbonylalkyl, with the proviso that if E is a single bond, A and B are both —NO— and m and n are both 1, and (i) if R1, R2, R4, R5, R7 and R8 are H, then R3 and R6 both are not hydrogen, hydroxyl, halo, alkoxyl, phenoxyl, or trifluoromethoxyl and (ii) if R1, R3-R6 and R8 are H, then R2 and R7 both are not methyl, halo, and methoxycarbonyl.
- 3. The compound of claim 1, or a pharmaceutically acceptable derivative thereof, wherein:
A and B are —NO—; C is a double bond; D is selected from the group consisting of: single bond, 54E and F are each independently single bond, double bond, —NR9—, or —O—; m and n are each independently and integer from 0 to 6; R1 to R8, R10, and R11 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, C1-C10 alkoxyl, amino, hydroxyl, C1-C10 hydroxyalkyl, carboxyl, C1-C10 alkoxylcarbonyl, mono- or polyfluroalkyl, mono- or polyfluroalkoxyl, cyano, nitro, C1-C10 thioalkyl, and C1-C10 sulfonylalkyl; and R9 is selected from the group consisting of hydrogen, C1-C1 alkyl, C3-C10 cycloalkyl, C1-C10 acyl, C5-C10 aryl, carboxyalkyl, C1-C10 alkoxylcarbonyl, and C1-C10 alkoxycarbonylalkyl, with the proviso that if E is a single bond, A and B are both —NO— and m and n are both 1, and (i) if R1, R2, R1, R5, R7 and R8 are H, then R3 and R6 both are not hydrogen, hydroxyl, alkoxyl or trifluoromethoxyl and (ii) if R1, R3-R6 and R8 are H, then R2 and R7 both are not methyl.
- 4. The compound of claim 1, or a pharmaceutically acceptable derivative thereof, wherein:
A and B are —NO—; C is a double bond; D is selected from the group consisting of: single bond, 55E and F are each independently single bond, double bond, —NR9—, or —O—; m and n are each independently an integer from 0 to 6; R1 to R8, R10, and R11 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl, C1-C10 alkoxyl, mono- or polyfluroalkyl, and mono- or polyfluroalkoxyl; and R9 is selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 acyl, and C5-C10 aryl, and C1-C10 alkoxylcarbonyl, with the proviso that if E is a single bond, A and B are both —NO— and m and n are both 1, and (i) if R1, R2, R4, R5, R7 and R8 are H, then R3 and R6 both are hydrogen, alkoxyl, or trifluoromethoxyl and (ii) if R1, R3-R6 and R8 are H, then R2 and R7 both are not methyl.
- 5. The compound of claim 1, or a pharmaceutically acceptable derivative thereof, wherein A and B are —SO—; C is a single bond;
D is selected from the group consisting of: single bond, 56E and F are each independently single bond, double bond, —NR9—, or —O—; m and n are each independently an integer from 0 to 6; R1 to R8, R10, and R11 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl, C1-C10 alkoxyl, mono- or polyfluroalkyl, and mono- or polyfluroalkoxyl; and R9 is selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 acyl, and C5-C10 aryl, and C1-C10 alkoxylcarbonyl.
- 6. The compound of claim 1, or a pharmaceutically acceptable derivative thereof, wherein at least one of R1-R8 is electron withdrawing substituents.
- 7. The compound of claim 1, or a pharmaceutically acceptable derivative thereof, wherein at least two of R1-R8 are electron withdrawing substituents.
- 8. The compound of claim 1, or a pharmaceutically acceptable derivative thereof, wherein at least one of R1-R8 is selected from haloalkoxy, alkylsulfonyl and haloamido groups.
- 9. The compound of claim 1, or a pharmaceutically acceptable derivative thereof, wherein at least two of R1-R8 are selected from haloalkoxy, alkylsulfonyl and haloamido groups.
- 10. The compound of claim 1, or a pharmaceutically acceptable derivative thereof, wherein R1, R4, R5 and R8 are each hydrogen.
- 11. The compound of claim 1, or a pharmaceutically acceptable derivative thereof, wherein, -A-C—B— is —NO═NO—.
- 12. The compound of claim 1, wherein D is alkylene or a single bond.
- 13. The compound of claim 1, wherein D is ethylene or a single bond.
- 14. The compound of claim 1, wherein R2 and R7 are each independently hydrogen or C1-C10 polyhaloalkylcarbonylamino.
- 15. The compound of claim 1, wherein R2 and R7 are each independently hydrogen or trifluoromethylcarbonylamino.
- 16. The compound of claim 1, wherein R2 and R7 are each hydrogen.
- 17. The compound of claim 1, wherein R2 and R7 are each trifluoromethylcarbonylamino.
- 18. The compound of claim 1, wherein R3 and R6 are each independently hydrogen, polyhaloalkoxy, halo, aralkoxy, alkylsulfonyl or polyhaloalkylheteroaryloxy.
- 19. The compound of claim 1, wherein R3 and R6 are each independently hydrogen, difluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2-trifluoro-2-chloroethoxy, 1,1,2,3,3,3-hexafluoropropoxy, fluoro, benzyloxy, ethanesulfonyl or 5-trifluoromethyl-2-pyridyloxy.
- 20. The compound of claim 1, wherein R3 and R6 are each independently polyhaloalkoxy, halo, aralkoxy, alkylsulfonyl or polyhaloalkylheteroaryloxy.
- 21. The compound of claim 1, wherein R3 and R6 are each independently difluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2-trifluoro-2-chloroethoxy, 1,1,2,3,3,3-hexafluoropropoxy, fluoro, benzyloxy, ethanesulfonyl or 5-trifluoromethyl-2-pyridyloxy.
- 22. The compound of claim 1, wherein the compound has formula:
- 23. The compound of claim 22, wherein the compound has formula:
- 24. An article of manufacture, comprising packaging material, a compound of formula 8:
- 25. A pharmaceutical composition, comprising, in a pharmaceutically acceptable carrier, a compound of formula 8:
- 26. The composition of claim 25, wherein:
A and B are each independently —NO—, or —N—; C is a double bond; D is selected from the group consisting of: single bond, 63E and F are each independently selected from the group consisting of single bond, double bond, —NR9—, —CR10R11—, and —O—; m and n are each independently and integer from 0 to 6; R1 to R8, R10, and R11 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, C1-C10 alkoxyl, amino, C1-C10 aminoalkyl, C1-C10 alkylaminoalkyl, hydroxyl, C1-C10 hydroxyalkyl, carboxyl, C1-C10 carboxyalkyl, C1-C10 alkoxylcarbonyl, C1-C10 alkoxycarbonylalkyl, halogen, mono- or polyfluroalkyl, mono- or polyfluroalkoxyl, cyano, nitro, C1-C10 thioalkyl, C1-C10 sulfonylalkyl, and C1-C10 alkylsulfonylalkyl; and R9 is selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 acyl, C5-C10 aryl, C1-C10 alkoxyalkyl, C1-C10 hydroxyalkyl, C1-C10 carboxyalkyl, C1-C10 alkoxylcarbonyl, and C1-C10 alkoxycarbonylalkyl, with the proviso that if E is a single bond, A and B are both —NO— and m and n are both 1, and (i) if R1, R2, R4, R5, R7 and R8 are H, then R3 and R6 both are not hydrogen, hydroxyl, halo, alkoxyl, phenoxyl, or trifluoromethoxyl and (ii) if R1, R3-R6 and R8 are H, then R2 and R7 both are not methyl, halo, and methoxycarbonyl.
- 27. The composition of claim 25, wherein:
A and B are —NO—; C is a double bond; D is selected from the group consisting of: single bond, 64E and F are each independently single bond, double bond, —NR9—, or —O—; m and n are each independently and integer from 0 to 6; R1 to R8, R10, and R11 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl, C5-C10 aryl, C1-C10 alkoxyl, amino, hydroxyl, C1-C10 hydroxyalkyl, carboxyl, C1-C10 alkoxylcarbonyl, mono- or polyfluroalkyl, mono- or polyfluroalkoxyl, cyano, nitro, C1-C10 thioalkyl, and C1-C10 sulfonylalkyl; and R9 is selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 acyl, C5-C10 aryl, carboxyalkyl, C1-C10 alkoxylcarbonyl, and C1-C10 alkoxycarbonylalkyl, with the proviso that if E is a single bond, A and B are both —NO— and m and n are both 1, and (i) if R1, R2, R4, R5, R7 and R8 are H, then R3 and R6 both are not hydrogen, hydroxyl, alkoxyl, or trifluoromethoxyl and (ii) if R1, R3-R6 and R8 are H, then R2 and R7 both are not methyl.
- 28. The composition of claim 25, wherein:
A and B are —NO—; C is a double bond; D is selected from the group consisting of: single bond, 65E and F are each independently single bond, double bond, —NR9—, or —O—; m and n are each independently an integer from 0 to 6; R1 to R8, R10, and R11 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl, C1-C10 alkoxyl, mono- or polyfluroalkyl, and mono- or polyfluroalkoxyl; and R9 is selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 acyl, and C5-C10 aryl, and C1-C10 alkoxylcarbonyl, with the proviso that if E is a single bond, A and B are both —NO— and m and n are both 1, and (i) if R1, R2, R4, R5, R7 and R8 are H, then R3 and R both are not hydrogen, hydroxyl, alkoxyl, or trifluoromethoxyl and (ii) if R1, R3-R6 and R8 are H, then R2 and R7 both are not methyl.
- 29. The composition of claim 25, wherein A and B are —SO—; C is a single bond;
D is selected from the group consisting of: single bond, 66E and F are each independently single bond, double bond, —NR9—, or —O—; m and n are each independently an integer from 0 to 6; R1 to R8, R10, and R11 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl, C1-C10 alkoxyl, mono- or polyfluroalkyl, and mono- or polyfluroalkoxyl; and R9 is selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 acyl, and C5-C10 aryl, and C1-C10 alkoxylcarbonyl.
- 30. The composition of claim 25, or a pharmaceutically acceptable derivative thereof, wherein at least one of R1-R8 is electron withdrawing substituents.
- 31. The composition of claim 25, wherein at least two of R1-R8 are electron withdrawing substituents.
- 32. The composition of claim 25, wherein at least one of R1-R8 is selected from haloalkoxy, alkylsulfonyl and haloamido groups.
- 33. The composition of claim 25, wherein at least two of R1-R8 are selected from haloalkoxy, alkylsulfonyl and haloamido groups.
- 34. The composition of claim 25, wherein R1, R4, R5 and R8 are each hydrogen.
- 35. The composition of claim 25, wherein, -A-C—B— is —NO═NO—.
- 36. The composition of claim 25, wherein D is alkylene or a single bond.
- 37. The composition of claim 25, wherein D is ethylene or a single bond.
- 38. The composition of claim 25, wherein R2 and R7 are each independently hydrogen or C1-C10 polyhaloalkylcarbonylamino.
- 39. The composition of claim 25, wherein R2 and R7 are each independently hydrogen or trifluoromethylcarbonylamino.
- 40. The composition of claim 25, wherein R2 and R7 are each hydrogen.
- 41. The composition of claim 25, wherein R2 and R7 are each trifluoromethylcarbonylamino.
- 42. The composition of claim 25, wherein R3 and R6 are each independently hydrogen, polyhaloalkoxy, halo, aralkoxy, alkylsulfonyl or polyhaloalkylheteroaryloxy.
- 43. The composition of claim 25, wherein R3 and R6 are each independently hydrogen, difluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2-trifluoro-2-chloroethoxy, 1,1,2,3,3,3-hexafluoropropoxy, fluoro, benzyloxy, ethanesulfonyl or 5-trifluoromethyl-2-pyridyloxy.
- 44. The composition of claim 25, wherein R3 and R6 are each independently polyhaloalkoxy, halo, aralkoxy, alkylsulfonyl or polyhaloalkylheteroaryloxy.
- 45. The composition of claim 25, wherein R3 and R6 are each independently difluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2-trifluoro-2-chloroethoxy, 1,1,2,3,3,3-hexafluoropropoxy, fluoro, benzyloxy, ethanesulfonyl or 5-trifluoromethyl-2-pyridyloxy.
- 46. The composition of claim 25, wherein the compound has formula:
- 47. The composition of claim 46, wherein the compound has formula:
- 48. 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.
- 49. The method of claim 48, wherein the disease or disorder is a Bcl-2 or Bcl-XL mediated disease or disorder.
- 50. The method of claim 48, wherein the disease or disorder is characterized by overexpression of a Bcl-2 or Bcl-XL protein.
- 51. 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 23.
- 52. The method of claim 48, wherein the disease or disorder is selected from cancers, tumors, hyperproliferative diseases, acquired immune deficiency syndrome, degenerative conditions, and vascular diseases.
- 53. The method of claim 52, 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.
- 54. 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.
- 55. 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 23.
- 56. The method of claim 54, wherein the Bcl-2 protein is selected from anti-apoptotic Bcl-2 protein, Bcl-2 and Bcl-XL.
- 57. A method of antagonizing Bcl-2 protein, comprising administering to a subject in need thereof an effective amount of a compound of claim 1.
- 58. A method of antagonizing Bcl-2 protein, comprising administering to a subject in need thereof an effective amount of a compound of claim 23.
- 59. The method of claim 57, wherein the Bcl-2 protein is selected from anti-apoptotic Bcl-2 protein, Bcl-2 and Bcl-XL.
- 60. 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.
- 61. 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 23.
- 62. The method of claim 60, wherein the Bcl-2 protein is selected from anti-apoptotic Bcl-2 protein, Bcl-2 and Bcl-XL.
- 63. A method of inducing apoptosis, comprising administering to a subject in need thereof an effective amount of a compound of claim 1.
- 64. A method of inducing apoptosis, comprising administering to a subject in need thereof an effective amount of a compound of claim 23.
- 65. The compound of claim 1 that is selected from
- 66. The composition of claim 25, wherein the compound is selected from
RELATED APPLICATIONS
[0001] Priority is claimed herein to U.S. provisional patent application No. 60/466,344, to Gupta et al., filed Apr. 30, 2003, entitled “Novel Polycyclic Diazodioxide based Bcl-2 Protein Antagonists and the 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 |
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60466344 |
Apr 2003 |
US |