Guanine analogs as telomerase substrates and telomere length affectors

• US 10,035,814 B2
• Filed: 01/30/2017
• Issued: 07/31/2018
• 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): Shameen, Golam M
• Assistant Examiner(s): Daniel, Laura M
• Application Number:
  US15/419,559
• Publication Number:
  US 20170233419A1
• Time in Patent Office: 547 Days
• Field of Search: None
• 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 use in treating cancer and other cell proliferative diseases.

Claims

1. A compound of formula (III):

2. The compound of claim 1, wherein:

R¹ is different from R²;

or

one of R¹ and R² carries a positive charge and the other carries a negative charge;

or

R¹ is —

NR^1aR^1b and R² is OR^1c.

3. The compound of claim 1, wherein:

one of R^1a and R^1b is C_1-20alkyl and R² is OH;

or

one of R^1a and R^1b is a polyamine and R² is OH;

or

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;

or

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;

or

one of R^1a and R^1b is —

CH(R^1d)—

C(O)OR^1e and R² is OH.

4. The compound of claim 1, wherein:

R^1d is selected from hydrogen, alkyl, substituted alkyl, heteroaryl, and substituted heteroaryl;

or

R^1d is a positively charged amino acid side chain.

5. The compound of claim 1, wherein:

R^3a and R^3b are hydrogen;

or

one of R^3a and R^3b is halo.

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

7. The compound of claim 1, wherein R^4a and R^4b are hydrogen.

8. The compound of claim 1, wherein:

one of R^5a and R^5b is —

OH;

or

one of R^5a and R^5b is selected from —

NH₂ and N₃;

or

one of R^5a and R^5b is —

CH═

CH₂;

or

one of R^5a and R^5b is C_1-2 alkyl;

or

one of R^5a and R^5b is C_1-2 alkyl, substituted with —

OH, —

NH₂, or N₃.

9. The compound of claim 1, wherein R^6a and R^6b are hydrogen.

10. The compound of claim 1, wherein R⁷ is hydrogen.

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

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

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

14. The method of claim 13, wherein the cancer is pancreatic cancer.

15. The method of claim 13, wherein the cancer is breast cancer.

16. A compound of formula (IV):

17. The compound of claim 16, wherein X¹ and X² are O.

18. The compound of claim 16, wherein R³⁰ is C_1-20alkyl.

19. The compound of claim 16, wherein:

R¹ carries a positive charge or a negative charge;

or

R¹ is —

NR^1aR^1b.

20. The compound of claim 19, wherein:

one of R^1a and R^1b is C_1-20alkyl; and

R² is OH;

or

one of R^1a and R^1b is a polyamine and R² is OH;

or

one of R^1a and R^1b is —

(CH₂)_nNH(CH₂)_nNHR^x, wherein R^x is hydrogen or —

(CH₂)—

NH₂ and n is independently a number from 2 to 4;

or

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;

or

one of R^1a and R^1b is —

CH(R^1d)—

C(O)OR^1e, and R² is OH.

21. The compound of claim 16, wherein;

R^1d is selected from hydrogen, alkyl, substituted alkyl, heteroaryl, and substituted heteroaryl;

or

R^1d is a positively charged amino acid side chain.

22. The compound of claim 16, wherein:

R^3a and R^3b are hydrogen;

or

one of R^3a and R^3b is halo.

23. The compound of claim 16, wherein W is O.

24. The compound of claim 16, wherein R^4a and R^4b are hydrogen.

25. The compound of claim 16, wherein:

one of R^5a and R^5b is —

OH;

or

one of R^5a and R^5b is selected from —

NH₂ and N₃;

or

one of R^5a and R^5b is —

CH═

CH₂;

or

one of R^5a and R^5b is C_1-2 alkyl;

or

one of R^5a and R^5b is C_1-2 alkyl, substituted with —

OH, —

NH₂, or N₃.

26. The compound of claim 16, wherein R^6a and R^6b are hydrogen.

27. The compound of claim 16, wherein R⁷ is hydrogen.

28. A pharmaceutical composition comprising the compound of claim 16.

29. A method of treating breast or pancreatic cancer in an individual by administering an effective amount of the compound of claim 16.

30. The method of claim 29, wherein the cancer is pancreatic cancer.

31. The method of claim 29, wherein the cancer is breast cancer.

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

33. The method of claim 32, wherein the cancer is pancreatic cancer.

34. The method of claim 32, wherein the cancer is breast cancer.