2'-SUBSTITUTED NUCLEOSIDE DERIVATIVES AND METHODS OF USE THEREOF FOR THE TREATMENT OF VIRAL DISEASES

• US 20140154211A1
• Filed: 04/11/2012
• Published: 06/05/2014
• 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: Njoroge, F. George, Bogen, Stephane, Bennett, Frank, Arasappan, Ashok, Pissarnitski, Dmitri, Dang, Qun, Davies, Ian, Olsen, David B., Stamford, Andrew, Vacca, Joseph P., Girijavallabhan, Vinay, Verma, Vishal, Kereles, Angela
• Granted Patent: US 9,061,041 B2
• Time in Patent Office: Days
• US Class Current: 424/85.7
• 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 or 2, 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 any of claims 1-4, wherein A is —

NH₂.

7. The compound of any one of claims 1-6, wherein B is:

8. The compound of claim 1 having the formula:

9. The compound of any one of claim 1-4 or 6-8, wherein R¹⁴ is phenyl.

10. The compound of any one of claim 1-4 or 6-9, 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 any of claims 1-13, wherein B is

15. The compound of any of claims 1-13, wherein B is

16. The compound of any of claims 1-13, 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 any of claims 1 to 18, 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 19, further comprising a third therapeutic agent selected from the group consisting of HCV protease inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.

22. The use of the compound according to any of claims 1 to 18, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for inhibiting HCV NS5A activity or for preventing and/or treating infection by HCV in a patient in need thereof.

23. A method of treating a patient infected with HCV comprising the step of administering an amount of (i) the compound according to any of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or (ii) the composition according to any of claims 19-21 effective to prevent and/or treat infection by HCV in said patient.

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

25. The method according to claim 23 or 24, further comprising the step of administering ribavirin to said patient.

26. The use of the compound according to any of claims 1 to 18, or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition for inhibiting HCV NS5A activity or for preventing and/or treating infection by HCV in a patient in need thereof.