Synthesis of purine nucleosides

• US 8,716,263 B2
• Filed: 12/23/2009
• Issued: 05/06/2014
• Est. Priority Date: 12/23/2008
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Pharmasset LLC (Gilead Sciences Inc.)
• Inventors: Chun, Byoung-Kwon, Du, Jinfa, Rachakonda, Suguna, Ross, Bruce, Sofia, Michael Joseph, Pamulapati, Ganapati Reddy, Chang, Wonsuk, Zhang, Hai-Ren, Nagarathnam, Dhanapalan
• Primary Examiner(s): McIntosh, III, Traviss C
• Application Number:
  US12/645,821
• Publication Number:
  US 20100279973A1
• Time in Patent Office: 1,595 Days
• Field of Search: None
• US Class Current: 514/48
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07H 1/00 Processes for the preparation of sugar derivatives
• CPC Class Codes: C07H 15/04 attached to an oxygen atom of the saccharide radical
• CPC Class Codes: C07H 19/167 with ribosyl as the saccharide radical
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/213 containing cyclic phosphate
• CPC Class Codes: C07H 5/02 to halogen
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

A process for preparing phosphoramidate prodrugs or cyclic phosphate prodrugs of nucleoside derivatives, which is a compound, its stereoisomers, salts (acid or basic addition salts), hydrates, solvates, or crystalline forms thereof.

Claims

1. A compound or salt thereof having the structure:

2. The compound or salt thereof of claim 1, wherein R⁷ is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or cyclopentyl and R⁸ is methoxy, ethoxy, isopropyloxy, —

O-cyclopropyl, —

O-cyclobutyl, or —

O-cyclopentyl.

3. A compound or salt thereof of claim 2 having the structure:

4. A compound or salt thereof of claim 2 having the structure:

5. A compound or salt thereof of claim 2 having the structure:

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

11. A composition comprising:

an effective amount of the compound or a salt thereof of claim 1;

an effective amount of at least one agent selected from an HCV NS3 protease inhibitor, an HCV NS5B inhibitor, an HCV NS4A inhibitor, an HCV NS4B inhibitor, and an HCV NS5a inhibitor; and

a pharmaceutically acceptable medium.

12. A composition comprising:

an effective amount of the compound or a salt thereof of claim 1;

an effective amount of at least one agent selected from an HCV NS3 protease inhibitor, an HCV NS5B inhibitor, and an HCV NS5a inhibitor; and

a pharmaceutically acceptable medium.

13. A composition comprising:

an effective amount of the compound or a salt thereof of claim 1;

an effective amount of at least one agent selected from an HCV NS3 protease inhibitor and an HCV NS5B inhibitor; and

a pharmaceutically acceptable medium.

14. A composition comprising:

an effective amount of the compound or a salt thereof of claim 1;

an effective amount of at least one agent selected from an HCV NS3 protease inhibitor and an HCV NS5a inhibitor; and

a pharmaceutically acceptable medium.

15. A composition comprising:

an effective amount of the compound or a salt thereof of claim 1;

an effective amount of at least one agent selected from an HCV NS5B inhibitor, and an HCV NS5a inhibitor; and

a pharmaceutically acceptable medium.

16. A composition comprising:

an effective amount of the compound or a salt thereof of claim 1;

an effective amount of an HCV NS3 protease inhibitor; and

a pharmaceutically acceptable medium.

17. A composition comprising:

an effective amount of the compound or a salt thereof of claim 1;

an effective amount of an HCV NS5B inhibitor; and

a pharmaceutically acceptable medium.

18. A composition comprising:

an effective amount of the compound or a salt thereof of claim 1;

an effective amount of an HCV NS4A inhibitor; and

a pharmaceutically acceptable medium.

19. A composition comprising:

an effective amount of the compound or a salt thereof of claim 1;

an effective amount of an HCV NS4B inhibitor; and

a pharmaceutically acceptable medium.

20. A composition comprising:

an effective amount of the compound or a salt thereof of claim 1;

an effective amount an HCV NS5a inhibitor; and

a pharmaceutically acceptable medium.

21. A method of treating hepatitis C virus infection in a subject in need thereof, which comprises administering to the subject an effective amount of the compound or salt thereof of claim 1.

22. The method of claim 21, wherein the subject is a human.

23. A method of treating a hepatitis C virus infection in a subject in need thereof, which comprises:

administering to the subject the composition as claimed in any one of claims 11-20.

24. The method of claim 23, wherein the subject is a human.

6. A compound having the structure:

7. A compound having the structure:

8. A compound having the structure:

9. The compound of claim 8 having an FT-IR peak at about 999 cm⁻

1.