Monocyclic diazodioxide based Bcl-2 protein antagonists related applications

• US 20040242886A1
• Filed: 04/30/2004
• Published: 12/02/2004
• Est. Priority Date: 04/30/2003
• Status: Abandoned Application

• Current Assignee: Ricerca Biosciences, LLC (Hangzhou Tigermed Consulting Co., Ltd.)
• Original Assignee: Ricerca Biosciences, LLC (Hangzhou Tigermed Consulting Co., Ltd.)
• Inventors: Fernandes, Prabhavathi, Carrig, David Michael, Gupta, Sandeep
• Application Number:
  US10/836,912
• Publication Number:
  US 20040242886A1
• Time in Patent Office: Days
• US Class Current: 546/117
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 213/89 with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 231/14 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 237/12 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 237/16 Two oxygen atoms
• CPC Class Codes: C07D 237/18 Sulfur atoms
• CPC Class Codes: C07D 237/30 Phthalazines

Abstract

Compounds and compositions containing compounds given by the structural Formula 8, for tumor therapeutic applications are disclosed.

A and B are each independently selected from

C is selected from

D is selected from —N—, —NO—, —NR¹⁰, —CR¹¹R¹²—, —CR¹³—, —S—, —SO—, and —SO₂—;

E is selected from single bond, —CR¹⁴R¹⁵, —NR¹⁶, —O—, —S—, —SO—, and —SO₂;

R¹ to R⁵, and R⁷ to R¹⁶ are appropriately selected to optimize physicochemical and/or biological properties. These compounds are expected to induce apoptosis in tumor cells mediated through Bcl-2 family of proteins.

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 R^2a 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 R^2a 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 R^2a 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 R^2a 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

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 E^a are each independently selected from a single bond, —

CR¹⁴R¹⁵, —

NR¹⁶, —

O—

, —

S—

, —

SO—

, and —

SO₂—

.

25. The compound of claim 1, where E^a 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 E^a 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 R^x and R^y 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 R^x 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 R^y 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

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.

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-X_L.

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-X_L.

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-X_L.

100. A method of inducing apoptosis, comprising administering to a subject in need thereof an effective amount of a compound of claim 1.

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 R^2a 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 R^2a 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 R^2a 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 R^2a 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

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 E^a are each independently selected from a single bond, —

CR¹⁴R¹⁵, —

NR¹⁶, —

O—

, —

S—

, —

SO—

, and —

SO₂—

.

68. The pharmaceutical composition of claim 44, where E^a 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 E^a 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 R^x and R^y 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 R^x 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 R^y 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

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.

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.

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: