Polycyclic diazodioxide-based Bcl-2 protein antagonists and use thereof

• US 20040248877A1
• Filed: 04/30/2004
• Published: 12/09/2004
• 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: Rajagopalan, Raghavan, Gupta, Sandeep, Fernandes, Prabhavathi, Carrig, David Michael
• Application Number:
  US10/837,220
• Publication Number:
  US 20040248877A1
• Time in Patent Office: Days
• US Class Current: 514/211.08
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 245/04 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 339/00 Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links

Abstract

Compounds of Formula 8 are provided:

A and B are each independently selected from the group consisting of —NO—, —SO—, and —NR⁹—. C is a single bond or a double bond. D is selected from the group consisting of single bond,

E is selected from the group consisting of single bond, double bond, —NR⁹—, —O—, —S—, —SO—, and —SO₂—; and m and n are each independently an integer from 0 to 6. R¹ to R⁹ are appropriately selected to optimize physicochemical and/or biological properties such as lipophilicity, bioavailability, pharmacokinetics, Bcl-2 and Bcl-X_L activities, metabolism, and the like. R¹ and R², R² and R³, R³ and R⁴, R⁵ and R⁶, R⁶ and R⁷, or R⁷ and R⁸ may optionally be joined together to form an aromatic or heteroaromatic ring, including, but not limited to, naphthyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl and the like. The compounds are useful for tumor therapeutic applications. These compounds induce apoptosis in tumor cells mediated through Bcl-2 family of proteins.

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,

E 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,

E 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,

E 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,

E 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:

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-X_L.

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-X_L.

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-X_L.

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

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,

E 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,

E 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,

E 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,

E 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:

66. The composition of claim 25, wherein the compound is selected from