Nucleotide hemi-sulfate salt for the treatment of hepatitis C virus

• US 10,519,186 B2
• Filed: 01/31/2018
• Issued: 12/31/2019
• Est. Priority Date: 02/01/2017
• Status: Active Grant

• Current Assignee: Atea Pharmaceuticals, Inc.
• Original Assignee: Atea Pharmaceuticals, Inc.
• Inventors: Moussa, Adel, Sommadossi, Jean-Pierre
• Primary Examiner(s): McIntosh, III, Traviss C
• Application Number:
  US15/885,630
• Publication Number:
  US 20180215776A1
• Time in Patent Office: 699 Days
• Field of Search: None
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 31/708 having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
• 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: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

A hemi-sulfate salt of the structure:

to treat a host infected with hepatitis C, as well as pharmaceutical compositions and dosage forms, including solid dosage forms, thereof.

Claims

1. A compound of the formula:

2. A solid dosage form comprising a compound of the formula

3. The solid dosage form of claim 2, wherein the steady-state trough plasma level (C_24,ss) is between approximately 20-50 ng/mL.

4. The solid dosage form of claim 2, wherein the steady-state trough plasma level (C_24,ss) is between approximately 20-45 ng/mL.

5. The solid dosage form of claim 2, wherein the steady-state trough plasma level (C_24,ss) is between approximately 20-30 ng/mL.

6. The solid dosage form of claim 2, wherein the steady-state trough plasma level (C_24,ss) is between approximately 20-25 ng/mL.

7. The solid dosage form of claim 2, wherein the area under the curve of metabolite

8. The solid dosage form of claim 7, wherein the area under the curve is between approximately 1,800 ng*h/mL and 3,000 ng*h/mL.

9. The solid dosage form of claim 7, wherein the area under the curve is between approximately 2,100 ng*h/mL and 3,000 ng*h/mL.

10. The solid dosage form of claim 7, wherein the area under the curve is between approximately 2,400 ng*h/mL and 3,000 ng*h/mL.

11. The solid dosage form of claim 7, wherein the area under the curve is between approximately 2,700 ng*h/mL and 3,000 ng*h/mL.

12. The solid dosage form of claim 7, wherein the area under the curve is between approximately 2,000 ng*h/mL and 2,200 ng*h/mL.

13. A pharmaceutical composition comprising an anti-HCV effective amount of a compound of the formula

14. The pharmaceutical composition of claim 13, in a solid dosage form that delivers at least 300 mg of the compound.

15. The pharmaceutical composition of claim 13, in a solid dosage form that delivers at least 400 mg of the compound.

16. The pharmaceutical composition of claim 13, in a solid dosage form that delivers at least 500 mg of the compound.

17. The pharmaceutical composition of claim 13, in a solid dosage form that delivers at least 600 mg of the compound.

18. The pharmaceutical composition of claim 17, wherein the solid dosage form provides a steady-state trough plasma level (C_24,ss) of metabolite

19. The pharmaceutical composition of claim 18, wherein the steady-state trough plasma level (C_24,ss) is between approximately 40-60 ng/mL.

20. The pharmaceutical composition of claim 13, in a solid dosage form that delivers at least 700 mg of the compound.

21. The pharmaceutical composition of claim 13, in a solid dosage form that delivers approximately 600 mg of the compound.

22. The pharmaceutical composition of claim 13, wherein the solid dosage form provides a steady-state trough plasma level (C_24,ss) of metabolite

23. The pharmaceutical composition of claim 22, wherein the solid steady-state trough plasma level (C_24,ss) is between approximately 20-50 ng/mL.

24. The pharmaceutical composition of claim 22, wherein the solid steady-state trough plasma level (C_24,ss) is between approximately 20-45 ng/mL.

25. The pharmaceutical composition of claim 22, wherein the solid steady-state trough plasma level (C_24,ss) is between approximately 20-30 ng/mL.

26. The pharmaceutical composition of claim 22, wherein the solid steady-state trough plasma level (C_24,ss) is between approximately 20-25 ng/mL.

27. The pharmaceutical composition of claim 13, wherein the pharmaceutically acceptable carrier is suitable for oral delivery.

28. The pharmaceutical composition of claim 27, wherein the pharmaceutically acceptable carrier is in the form of a tablet.

29. A method to treat a hepatitis C infection, in a human in need thereof, comprising administering an effective amount of a compound of the formula

30. The method of claim 29, wherein the compound is administered orally.

31. The method of claim 29, wherein the compound is administered parenterally.

32. The method of claim 29, wherein at least 300 mg of the compound is administered.

33. The method of claim 29, wherein at least 400 mg of the compound is administered.

34. The method of claim 29, wherein at least 500 mg of the compound is administered.

35. The method of claim 29, wherein at least 600 mg of the compound is administered.

36. The method of claim 29, wherein at least 700 mg of the compound is administered.

37. The method of claim 29, wherein at least 800 mg of the compound is administered.

38. The method of claim 29, wherein the compound is administered for up to 12 weeks.

39. The method of claim 38, wherein the compound is administered once a day.

40. The method of claim 38, wherein the compound is administered every other day.

41. The method of claim 29, wherein the compound is administered for up to 8 weeks.

42. The method of claim 29, wherein the compound is administered for up to 6 weeks.

43. The method of claim 29, wherein the compound is administered for at least 6 weeks.

44. The method of claim 29, wherein the compound is administered for at least 8 weeks.

45. The method of claim 29, wherein the compound is administered for at least 12 weeks.

46. The method of claim 29, wherein the hepatitis C virus is Genotype 1a, 1b, 2a, 2b, 3a, 4a, 4d, 5a, or 6.

47. The method of claim 46, wherein the hepatitis C virus is Genotype 1a or 1b.

48. The method of claim 46, wherein the hepatitis C virus is Genotype 2a or 2b.

49. The method of claim 46, wherein the hepatitis C virus is Genotype 3a.

50. The method of claim 46, wherein the hepatitis C virus is Genotype 4a or 4b.

51. The method of claim 46, wherein the hepatitis C virus is Genotype 5a.

52. A solid dosage form comprising a compound of the formula