Guanine analogs as telomerase substrates and telomere length affectors

• US 10,562,926 B2
• Filed: 06/22/2018
• Issued: 02/18/2020
• 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): Shibuya, Mark L
• Assistant Examiner(s): Daniel, Laura M
• Application Number:
  US16/016,071
• Publication Number:
  US 20190106447A1
• Time in Patent Office: 606 Days
• 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 method for inhibiting telomere elongation, comprising contacting a cell with a compound of formula (I):

2. The method of claim 1, wherein:

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

4. The method 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.

5. The method 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.

6. The method of claim 1, wherein:

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

or

R^3a is halo and R^3b is hydrogen.

7. The method of claim 1, wherein W is O.

8. The method of claim 1, wherein:

R⁴ is —

OH;

or

R⁴ is selected from —

NH₂ and N₃;

or

R⁴ is —

CH═

CH₂;

or

R⁴ is C_1-2alkyl;

or

R⁴ is optionally substituted C_1-2 alkyl, wherein alkyl optionally is substituted with —

OH, —

NH₂, or N₃.

9. The method of claim 1, wherein R^5a and R^5b are hydrogen.

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

11. The method of claim 1, wherein R⁷ is fluoro.

12. The method of claim 1, wherein X is O.

13. The method of claim 1, wherein the cell is a cancer cell.

14. A method for inhibiting telomere elongation, comprising contacting a cell with a compound of formula (II):

15. The method of claim 14, wherein X¹ and X² are O.

16. The method of claim 14, wherein R³⁰ is C_1-20alkyl.

17. The method of claim 14, wherein;

R¹ carries a positive charge or a negative charge;

or

R¹ is NR^1aR^1b.

18. The method of claim 14, wherein the compound of formula (II) is the enriched or isolated (R) enantiomer at the stereocenter bearing R⁴.

19. The method of claim 14, wherein:

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

or

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

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.

20. The method of claim 14, 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.

21. The method of claim 14, wherein;

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

or

R^3a is halo and R^3b is hydrogen.

22. The method of claim 14, wherein W is O.

23. The method of claim 14, wherein:

R⁴ is —

OH;

or

R⁴ is selected from —

NH₂ and N₃;

or

R⁴ is —

CH═

CH₂;

or

R⁴ is C_1-2alkyl;

or

R⁴ is optionally substituted C_1-2alkyl, wherein alkyl is optionally substituted with —

OH, —

NH₂, or N₃.

24. The method of claim 14, wherein R^5a and R^5b are hydrogen.

25. The method of claim 14, wherein R⁷ is hydrogen.

26. The method of claim 14, wherein R⁷ is fluoro.

27. The method of claim 14, wherein X is O.

28. The method of claim 14, wherein the cell is a cancer cell.

29. A method for inhibiting telomere elongation comprising contacting a cell with a compound of formula (V):

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