2′-substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases

• US 9,061,041 B2
• Filed: 04/11/2012
• Issued: 06/23/2015
• Est. Priority Date: 04/13/2011
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Girijavallabhan, Vinay, Njoroge, F. George, Bogen, Stephane, Verma, Vishal, Bennett, Frank, Kerekes, Angela, Arasappan, Ashok, Pissarnitski, Dmitri, Dang, Qun, Davies, Ian, Olsen, David B., Stamford, Andrew, Vacca, Joseph P.
• Primary Examiner(s): McIntosh, III, Traviss C
• Application Number:
  US14/111,687
• Publication Number:
  US 20140154211A1
• Time in Patent Office: 1,168 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A01N 2300/00 Combinations or mixtures of active ingredients covered by classes A01N27/00 - A01N65/48 with other active or formulation relevant ingredients, e.g. specific carrier materials or surfactants, covered by classes A01N25/00 - A01N65/48
• CPC Class Codes: A01N 43/54 1,3-Diazines; Hydrogenated 1,3-diazines
• CPC Class Codes: A01N 43/56 1,2-Diazoles; Hydrogenated 1,2-diazoles
• CPC Class Codes: A01N 43/653 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: A01N 43/76 1,3-Oxazoles; Hydrogenated 1,3-oxazoles
• CPC Class Codes: A01N 43/82 five-membered rings with three ring hetero atoms
• CPC Class Codes: A01N 43/84 six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4
• CPC Class Codes: A01N 43/90 having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
• CPC Class Codes: A01N 47/36 containing the group >N—CO—N< directly attached to at least one heterocyclic ring; Thio analogues thereof
• CPC Class Codes: A61K 31/7042 Compounds having saccharide radicals and heterocyclic rings
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• 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: A61P 31/14 for RNA viruses
• CPC Class Codes: C07H 17/02 Heterocyclic radicals containing only nitrogen as ring hetero atoms
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/11 containing cyclic phosphate
• 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
• CPC Class Codes: C07H 19/213 containing cyclic phosphate

Abstract

The present invention relates to 2′-Substituted Nucleoside Derivatives of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, B, X, R¹, R² and R³ are as defined herein. The present invention also relates to compositions comprising at least one 2′-Substituted Nucleoside Derivative, and methods of using the 2′-Substituted Nucleoside Derivatives for treating or preventing HCV infection in a patient.

Claims

1. A compound having the structure:

2. The compound of claim 1, wherein X is O.

3. The compound of claim 1, wherein R³ is methyl.

4. The compound of claim 1 having the formula:

5. The compound of claim 1 having the formula:

6. The compound of claim 1, wherein A is —

NH₂.

7. The compound of claim 1, wherein B is:

8. The compound of claim 1 having the formula:

9. The compound of claim 1, wherein R¹⁴ is phenyl.

10. The compound of claim 1, wherein R¹⁷ is ethyl or isopropyl.

11. The compound of claim 1 having the formula:

12. The compound of claim 11, wherein R¹⁸ is isopropyl.

13. The compound of claim 1 having the formula:

14. The compound of claim 1, wherein B is

15. The compound of claim 1, wherein B is

16. The compound of claim 1, wherein B is

17. The compound of claim 1, being any one of the compounds numbered 1-99 in the above specification, or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1, having the structure:

19. A pharmaceutical composition comprising an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition according to claim 19, further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.

21. The pharmaceutical composition according to claim 20, further comprising a third therapeutic agent selected from the group consisting of HCV protease inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.

22. A method of treating a patient infected with HCV comprising the step of administering an amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, effective to treat infection by HCV in said patient.

23. The method according to claim 22, further comprising the step of administering pegylated-interferon alpha and an HCV protease inhibitor to said patient.

24. A compound having the structure:

25. The compound of claim 24 having the structure:

26. The compound of claim 24 having the structure:

27. The compound of claim 24 having the structure:

28. A pharmaceutically acceptable salt of the compound of claim 24 having the structure:

29. A pharmaceutically acceptable salt of the compound of claim 24 having the structure:

30. A pharmaceutically acceptable salt of the compound of claim 24 having the structure:

31. A pharmaceutical composition comprising (i) an amount of a compound of claim 25, effective for inhibition of HCV viral replication, and (ii) a pharmaceutically acceptable carrier.

32. A pharmaceutical composition comprising (i) an amount of a compound of claim 26, effective for inhibition of HCV viral replication, and (ii) a pharmaceutically acceptable carrier.

33. A pharmaceutical composition comprising (i) an amount of a compound of claim 27, effective for inhibition of HCV viral replication, and (ii) a pharmaceutically acceptable carrier.

34. A pharmaceutical composition comprising (i) an amount of the pharmaceutically acceptable salt of the compound of claim 28, effective for inhibition of HCV viral replication, and (ii) a pharmaceutically acceptable carrier.

35. A pharmaceutical composition comprising (i) an amount of the pharmaceutically acceptable salt of the compound of claim 29, effective for inhibition of HCV viral replication, and (ii) a pharmaceutically acceptable carrier.

36. A pharmaceutical composition comprising (i) an amount of the pharmaceutically acceptable salt of the compound of claim 30, effective for inhibition of HCV viral replication, and (ii) a pharmaceutically acceptable carrier.

37. A pharmaceutical composition comprising (i) a compound of claim 24 or a pharmaceutically acceptable salt thereof, and (ii) one or more additional therapeutic agents selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors.

38. A method of treating a patient infected with HCV comprising the step of administering the compound of claim 25, in an amount effective to treat infection by HCV in said patient.

39. A method of treating a patient infected with HCV comprising the step of administering the compound of claim 26, in an amount effective to treat infection by HCV in said patient.

40. A method of treating a patient infected with HCV comprising the step of administering the compound of claim 27, in an amount effective to treat infection by HCV in said patient.

41. A method of treating a patient infected with HCV comprising the step of administering a pharmaceutically acceptable salt of the compound of claim 28, in an amount effective to treat infection by HCV in said patient.

42. A method of treating a patient infected with HCV comprising the step of administering a pharmaceutically acceptable salt of the compound of claim 29, in an amount effective to treat infection by HCV in said patient.

43. A method of treating a patient infected with HCV comprising the step of administering a pharmaceutically acceptable salt of the compound of claim 30, in an amount effective to treat infection by HCV in said patient.