Nucleoside phosphoramidates

• US 8,618,076 B2
• Filed: 03/31/2011
• Issued: 12/31/2013
• Est. Priority Date: 05/20/2009
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Pharmasset LLC (Gilead Sciences Inc.)
• Inventors: Ross, Bruce S., Sofia, Michael Joseph, Pamulapati, Ganapati Reddy, Rachakonda, Suguna, Zhang, Hai-Ren, Chun, Byoung-Kwon, Wang, Peiyuan
• Primary Examiner(s): OLSON, ERIC
• Assistant Examiner(s): Wang, Zhengfu
• Application Number:
  US13/076,552
• Publication Number:
  US 20110251152A1
• Time in Patent Office: 1,006 Days
• Field of Search: 514/51, 536/26.8
• US Class Current: 514/51
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07F 9/2479 Compounds containing the structure P(=X)n-N-acyl, P(=X)n-N-heteroatom, P(=X)n-N-CN (X = O, S, Se; n = 0, 1)
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 23/00 Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12 esters with inorganic acids C07H11/00; metal salts, see parent compounds

Abstract

Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.

Claims

1. A crystalline compound represented by the formula (S_P-4):

5. A pharmaceutical composition comprising the crystalline compound according to claim 1 and a pharmaceutically acceptable medium.

6. A method of treating a hepatitis C virus infection in a human comprising administering to the human an effective amount of the crystalline compound according to claim 1.

7. The method according to claim 6 further comprising administering to the human another antiviral agent.

8. A process for preparing the crystalline compound according to claim 1 comprising:

exposing a second crystalline compound represented by the formula (S_P-4);

9. The process according to claim 8 further comprising:

grinding the first composition into a powder; and

allowing the powder to stand in an open vessel.

10. A process for preparing the crystalline compound according to claim 1 comprising:

suspending a second crystalline compound represented by the formula (S_P-4);

11. The process according to claim 10 further comprising heating the suspension.

12. The process according to claim 11 further comprising cooling the suspension.

2. A crystalline compound represented by the formula (S_P-4):

3. The crystalline compound according to claim 2, wherein the XRPD 2θ

-reflections (°

) at about 6.08, 8.2, 10.38, 10.85, 12.17, 12.7, 13.73, 14.1, 15.91, 16.83, 17.17, 17.66, 17.95, 18.79, 19.1, 19.41, 19.8, 20.11, 20.82, 21.81, 22.03, 23.03, 23.26, 23.64, 23.89, and 24.73 have intensities (%) of 66.7, 62.1, 29.8, 10.4, 12.0, 66.4, 14.9, 13.8, 3.1, 8.7, 19.7, 56.2, 37.7, 59.0, 14.3, 37.2, 46.0, 68.8, 100.0, 36.8, 7.4, 14.2, 21.6, 6.3, 7.0, and 3.3, respectively.

13. A pharmaceutical composition comprising the crystalline compound according to claim 2 and a pharmaceutically acceptable medium.

14. A method of treating a hepatitis C virus infection in a human comprising administering to the human an effective amount of the crystalline compound according to claim 2.

15. The method according to claim 14 further comprising administering to the human another antiviral agent.

16. A process for preparing the crystalline compound according to claim 2 comprising:

exposing a second crystalline compound represented by the formula (S_P-4);

17. The process according to claim 16 further comprising:

grinding the first composition into a powder; and

allowing the powder to stand in an open vessel.

18. A process for preparing the crystalline compound according to claim 2 comprising:

suspending a second crystalline compound represented by the formula (S_P-4);

19. The process according to claim 18 further comprising heating the suspension.

20. The process according to claim 19 further comprising cooling the suspension.

21. A pharmaceutical composition comprising the crystalline compound according to claim 3 and a pharmaceutically acceptable medium.

22. A method of treating a hepatitis C virus infection in a human comprising administering to the human an effective amount of the crystalline compound according to claim 3.

23. The method according to claim 22 further comprising administering to the human another antiviral agent.

24. A process for preparing the crystalline compound according to claim 3 comprising:

exposing a second crystalline compound represented by the formula (S_P-4);

25. The process according to claim 24 further comprising:

grinding the first composition into a powder; and

allowing the powder to stand in an open vessel.

26. A process for preparing the crystalline compound according to claim 3 comprising:

suspending a second crystalline compound represented by the formula (S_P-4);

27. The process according to claim 26 further comprising heating the suspension.

28. The process according to claim 27 further comprising cooling the suspension.

4. A crystalline compound represented by the formula (S_P-4):

29. A pharmaceutical composition comprising the crystalline compound according to claim 4 and a pharmaceutically acceptable medium.

30. A method of treating a hepatitis C virus infection in a human comprising administering to the human an effective amount of the crystalline compound according to claim 4.

31. The method according to claim 30 further comprising administering to the human another antiviral agent.

32. A process for preparing the crystalline compound according to claim 4 comprising:

exposing a second crystalline compound represented by the formula (S_P-4);

33. The process according to claim 32 further comprising:

grinding the first composition into a powder; and

allowing the powder to stand in an open vessel.

34. A process for preparing the crystalline compound according to claim 4 comprising:

suspending a second crystalline compound represented by the formula (S_P-4);

35. The process according to claim 34 further comprising heating the suspension.

36. The process according to claim 35 further comprising cooling the suspension.