Purine nucleoside phosphoramidate

• US 8,563,530 B2
• Filed: 03/31/2011
• Issued: 10/22/2013
• Est. Priority Date: 03/31/2010
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Pharmasset LLC (Gilead Sciences Inc.)
• Inventors: Chang, Wonsuk, Nagarathnam, Dhanapalan, Pamulapati, Ganapati Reddy, Ross, Bruce S., Sofia, Michael Joseph, Zhang, Hai-Ren, Naduthambi, Devan
• Primary Examiner(s): McIntosh, III, Traviss C
• Application Number:
  US13/076,718
• Publication Number:
  US 20110257121A1
• Time in Patent Office: 936 Days
• Field of Search: None
• US Class Current: 514/47
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07H 19/207 the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide

Abstract

Disclosed herein is a compound represented by formula 1 or its hydrate thereof in crystalline or crystal-like form.

Claims

1. A compound represented by formula 1, its hydrate or solvate thereof in crystalline or crystal-like form.

2. The compound of claim 1, represented by 1.mH₂O, wherein m varies in an integer or non-integer amount from about 0 to about 5 and is not 0.

3. The compound of claim 2, wherein m is about 1.

4. The compound of claim 2, wherein m is about ½

.

5. The compound of claim 2, wherein m is about 1, that further comprises an amount of adsorbed water.

6. The compound of claim 5, wherein the amount of adsorbed water ranges from about 0 wt. % to about 10 wt. % based on the weight of the 1.H₂O.

7. The compound of claim 2, wherein the compound is a monohydrate in crystalline form.

8. The compound of claim 7 having an XRPD 2θ

-reflection (°

) at about 14.8.

9. The compound of claim 8 having XRPD 2θ

-reflections (°

) at about 14.8 and about 17.6.

10. The compound of claim 9 having XRPD 2θ

-reflections (°

) at about 20.4.

11. The compound of claim 9 having XRPD 2θ

-reflections (°

) at about 8.7.

12. The compound of claim 9 having XRPD 2θ

-reflections (°

) at about 13.6.

13. The compound of claim 9 having XRPD 2θ

-reflections (°

) at about.

14. The compound of claim 9 having a pattern substantially as that shown in FIG. 1.

15. The compound of claim 7, wherein the compound is an orthorhombic crystalline.

16. The orthorhombic crystalline of claim 15, having the following unit cell parameters a˜

10.99 Å

, b˜

13.09 Å

, and c˜

20.36 Å

.

17. A composition comprising the compound of claim 1.

18. A method for treating HCV in a patient in need thereof, which comprises administering to the patient a therapeutically effective amount of the compound of claim 1.

19. A method for treating HCV in a patient in need thereof, which comprises administering to the patient a therapeutically effective amount of the compound of claim 7.

20. A method for treating HCV in a patient in need thereof, which comprises administering to the patient a therapeutically effective amount of the compound of claim 1 in combination or in alternation with a therapeutically effective amount of another antiviral.

21. The method of claim 20, wherein the other antiviral is selected from the group consisting of

22. A co-therapy method for treating HCV in a patient in need thereof, which comprises administering to the patient a therapeutically effective amount of the compound of claim 7 in combination or in alternation with a therapeutically effective amount of another antiviral.

23. The co-therapy method of claim 22, wherein the other antiviral is selected from the group consisting of

24. A process for preparing the compound of claim 1 in a crystalline form, which comprises crystallizing the compound of claim 1.

25. The process of claim 24, which further comprises dissolving or suspending the compound of claim 1 in a solvent or solvent mixture.

26. The process of claim 25, wherein the solvent or solvent mixture is selected from the group consisting of anisole, ethyl acetate;

xylenes;

toluene;

isopropanol;

acetone;

dichloromethane;

diethyl ether;

isopropyl acetate;

t-butyl methyl ether; and

combinations thereof.

27. The process of claim 25, wherein the solvent mixture is selected from the group consisting of anisole/ethyl acetate;

heptanes/ethyl acetate;

xylenes/ethyl acetate/water;

anisole/water;

ethyl acetate/xylenes;

isopropanol/xylenes;

acetone/xylenes;

dichloromethane/xylenes;

dichloromethane/hexanes;

ethyl acetate/toluene;

diethyl ether/xylenes;

isopropyl acetate/xylenes;

isopropyl acetate/heptanes;

ethyl acetate/water;

t-butyl methyl ether/water; and

t-butyl methyl ether/ethyl ether.

28. A method for determining the crystallinity of the compound of claim 1, which comprises analyzing the compound by XRPD or single-crystal X-ray crystallography.