Nucleoside phosphoramidates
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.
1. A crystalline compound represented by the formula (S P -4):
having XRPD 2θ-reflections (°) at about: 6.1, 8.2, 10.4, 12.7, 17.2, 17.7, 18.0, 18.8, 19.4, 19.8, 20.1, 20.8, 21.8, and 23.3.
2. A crystalline compound represented by the formula (S P -4):
having 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.
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.
4. A crystalline compound represented by the formula (S P -4):
having an XRPD diffraction pattern substantially as shown in FIG. 21 .
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):
having an XRPD diffraction pattern substantially as shown in FIG. 3 or FIG. 4 to atmospheric humidity to provide a first composition.
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):
having an XRPD diffraction pattern substantially as shown in FIG. 3 or FIG. 4 in water to provide a suspension.
11. The process according to claim 10 further comprising heating the suspension.
12. The process according to claim 11 further comprising cooling the suspension.
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):
having an XRPD diffraction pattern substantially as shown in FIG. 3 or FIG. 4 to atmospheric humidity to provide a first composition.
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):
having an XRPD diffraction pattern substantially as shown in FIG. 3 or FIG. 4 in water to provide a suspension.
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):
having an XRPD diffraction pattern substantially as shown in FIG. 3 or FIG. 4 to atmospheric humidity to provide a first composition.
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):
having an XRPD diffraction pattern substantially as shown in FIG. 3 or FIG. 4 in water to provide a suspension.
27. The process according to claim 26 further comprising heating the suspension.
28. The process according to claim 27 further comprising cooling the suspension.
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):
having an XRPD diffraction pattern substantially as shown in FIG. 3 or FIG. 4 to atmospheric humidity to provide a first composition.
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):
having an XRPD diffraction pattern substantially as shown in FIG. 3 or FIG. 4 in water to provide a suspension.
35. The process according to claim 34 further comprising heating the suspension.
36. The process according to claim 35 further comprising cooling the suspension.