Guanine analogs as telomerase substrates and telomere length affectors

• US 9,593,137 B2
• Filed: 12/21/2012
• Issued: 03/14/2017
• Est. Priority Date: 12/22/2011
• Status: Active Grant

• Current Assignee: Geron Corporation
• Original Assignee: Geron Corporation
• Inventors: Gryaznov, Sergei M., Pruzan, Ronald A., Pongracz, Krisztina
• Primary Examiner(s): Shameem, Golam M M
• Assistant Examiner(s): DANIEL, LAURA M
• Application Number:
  US14/366,218
• Publication Number:
  US 20150299232A1
• Time in Patent Office: 1,544 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 473/18 one oxygen and one nitrogen atom, e.g. guanine
• CPC Class Codes: C07F 9/65616 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Abstract

This invention relates to compounds useful for inhibiting telomere elongation. More specifically, the invention provides nucleotide analogs that are incorporated into telomeres by telomerase thereby inhibiting elongation of telomeres. The compounds are useful in treating cancer and other cell proliferative diseases.

Claims

1. A compound of formula (I):

2. The compound of claim 1, wherein one of R¹ and R² carries a positive charge and the other carries a negative charge.

3. The compound of claim 1, wherein the compound of formula (I) is the enriched or isolated (R) enantiomer at the stereocenter bearing R⁴.

4. The compound of claim 1, wherein one of R^1a and R^1b is —

CH(R^1d)—

C(O)OR^1e, and R² is OH.

5. The compound of claim 1, wherein R⁴ is C_1-2 alkyl, wherein alkyl is optionally substituted with —

OH, —

NH₂, or N₃.

6. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

7. A method of treating breast or pancreatic cancer in an individual by administering an effective amount of the compound of claim 1.

16. The compound of claim 1, wherein R¹ is —

NR^1aR^1b and R² is OR^1c.

17. The compound of claim 16, wherein one of R^1a and R^1b is C_1-20alkyl;

and R² is OH.

18. The compound of claim 4, wherein R^1d is selected from hydrogen, alkyl, substituted alkyl, heteroaryl, and substituted heteroaryl.

19. The compound of claim 4, wherein —

CH(R^1d)—

C(O)OR^1e, when taken with the nitrogen to which —

CH(R^1d)—

C(O)OR^1e is connected, is an amino acid selected from lysine, arginine, and histidine.

20. The compound of claim 1, wherein R^3a and R^3b are hydrogen.

21. The compound of claim 1, wherein W is O.

22. The compound of claim 1, wherein R⁴ is —

OH.

23. The compound of claim 1, wherein R⁴ is —

CH═

CH₂.

24. The compound of claim 1, wherein R^5a and R^5b are hydrogen.

25. The compound of claim 1, wherein X is O.

26. The method of claim 7, wherein the cancer is breast cancer.

27. The method of claim 7, wherein the cancer is pancreatic cancer.

28. The method of claim 7, wherein the compound or pharmaceutical composition is administered orally, intra-arterially, intranasally, intraperitoneally, intravenously, intramuscularly, subcutaneously, or transdermally.

8. A compound of formula (II):

9. The compound of claim 8, wherein X¹ and X² are O.

10. The compound of claim 8, wherein R¹ carries a positive charge or a negative charge.

11. The compound of claim 8, wherein the compound of formula (II) is the enriched or isolated (R) enantiomer at the stereocenter bearing R⁴.

12. The compound of claim 8, wherein R¹ is —

NR^1aR^1b.

13. A pharmaceutical composition comprising the compound of claim 8 and a pharmaceutically acceptable excipient.

14. A method of treating breast or pancreatic cancer in an individual by administering an effective amount of the compound of claim 8.

29. The compound of claim 8, wherein R³⁰ is C_1-20 alkyl.

30. The compound of claim 12, wherein one of R^1a and R^1b is C_1-20alkyl.

31. The compound of claim 12, wherein one of R^1a and R^1b is —

(CH₂)_nNH(CH₂)_nNHR^x;

wherein R^x is hydrogen or —

(CH₂)_nNH₂; and

n is independently a number from 2 to 4.

32. The compound of claim 12, wherein one of R^1a and R^1b is —

(CH₂)_nNHR^x;

wherein R^x is hydrogen or —

(CH₂)_nNH₂; and

n is independently a number from 2 to 4.

33. The compound of claim 12, wherein one of R^1a and R^1b is —

CH(R^1d)—

C(O)OR^1e.

34. The compound of claim 8, wherein W is O.

35. The compound of claim 8, wherein R⁴ is —

CH═

CH₂.

36. The compound of claim 8, wherein R⁴ is C_1-2 alkyl.

37. The compound of claim 8, wherein R^5a and R^5b are hydrogen.

38. The compound of claim 8, wherein R⁷ is hydrogen.

39. The compound of claim 8, wherein X is O.

40. The method of claim 14, wherein the cancer is breast cancer.

60. The method of claim 14, wherein the cancer is pancreatic cancer.

15. A method of treating breast or pancreatic cancer in an individual by administering an effective amount of a compound of formula (V):

41. The method of claim 15, wherein the cancer is breast cancer.

61. The method of claim 15, wherein the cancer is pancreatic cancer.

42. A compound of formula (I):

43. The compound of claim 42, wherein R¹ is —

NR^1aR^1b and R² is OR^1c.

44. A pharmaceutical composition comprising the compound of claim 42 and a pharmaceutically acceptable excipient.

45. A method of treating breast or pancreatic cancer in an individual by administering an effective amount of the compound of claim 42.

62. The method of claim 45, wherein the cancer is breast cancer.

63. The method of claim 45, wherein the cancer is pancreatic cancer.

46. A compound of formula (I):

47. The compound of claim 46, wherein the compound of formula (I) is the enriched or isolated (R) enantiomer at the stereocenter bearing R⁴.

48. The compound of claim 46, wherein R¹ is —

NR^1aR^1b and R² is OR^1c.

49. The compound of claim 48, wherein one of R^1a and R^1b is —

(CH₂)_nNH(CH₂)_nNHR^x;

wherein R^x is hydrogen or —

(CH₂)_nNH₂; and

n is independently a number from 2 to 4.

50. The compound of claim 48, wherein one of R^1a and R^1b is —

(CH₂)_nNHR^x;

wherein R^x is hydrogen or —

(CH₂)_nNH₂; and

n is independently a number from 2 to 4.

51. The compound of claim 46, wherein W is O.

52. The compound of claim 46, wherein R⁴ is —

OH.

53. The compound of claim 46, wherein R⁴ is —

CH═

CH₂.

54. The compound of claim 46, wherein R⁴ is C_1-2 alkyl, wherein alkyl is optionally substituted with —

OH, —

NH₂, or N₃.

55. The compound of claim 46, wherein X is O.

56. A pharmaceutical composition comprising the compound of claim 46 and a pharmaceutically acceptable excipient.

57. A method of treating breast or pancreatic cancer in an individual by administering an effective amount of the compound of claim 46.

58. The method of claim 57, wherein the cancer is breast cancer.

59. The method of claim 57, wherein the cancer is pancreatic cancer.