METHODS AND COMPOSITIONS FOR TREATING HEPATITIS C VIRUS

• US 20090280086A1
• Filed: 07/16/2009
• Published: 11/12/2009
• Est. Priority Date: 05/23/2000
• Status: Active Grant

• Current Assignee: Idenix Pharmaceuticals LLC (Merck & Co., Inc.)
• Original Assignee: Jean-Pierre Sommadossi, Paulo Lacolla
• Inventors: LaColla, Paulo, Sommadossi, Jean-Pierre
• Granted Patent: US 8,299,038 B2
• Time in Patent Office: Days
• US Class Current: 424/85.400
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• 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 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 38/21 Interferons [IFN]
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: G03C 1/0051 Tabular grain emulsions

Abstract

A method and composition for treating a host infected with hepatitis C comprising administering an effective hepatitis C treatment amount of a described 1′, 2′ or 3′-modified nucleoside or a pharmaceutically acceptable salt or prodrug thereof, is provided.

Claims

1. A method for the treatment of a hepatitis C virus infection in a host, comprising contacting a cell infected with a hepatitis C virus an effective amount of a compound of the formula:

or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof, wherein

R¹, R² and R³ are each independently H;

phosphate or a stabilized phosphate prodrug;

acyl;

or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R¹, R² or R³ is independently H or phosphate;

Y is hydrogen;

bromo;

chloro, fluoro;

iodo;

OR⁴;

NR⁴R⁵ or SR⁴;

X¹ and X² are each independently H;

straight chained, branched or cyclic alkyl;

CO-alkyl;

CO-aryl;

CO-alkoxyalkyl;

chloro;

bromo;

fluoro;

iodo;

OR⁴;

NR⁴NR⁵ or SR⁵; and

R⁴ and R⁵ are independently hydrogen;

acyl;

or alkyl.

3. The method of claim 1, wherein the compound has the structure:

or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof.

4. The method of claim 1, wherein the compound has the structure:

or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof.

5. The method of claim 1, wherein the compound has the structure:

or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof.

2. A method for the treatment of a hepatitis C virus infection in a host, comprising contacting a cell infected with a hepatitis C virus an effective amount of a compound of the formula:

or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof, wherein

R¹, R² and R³ are each independently H;

phosphate or a stabilized phosphate prodrug;

acyl;

or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R¹, R² or R³ is independently H or phosphate;

Y is hydrogen;

bromo;

chloro, fluoro;

iodo;

OR⁴;

NR⁴R⁵ or SR⁴;

X¹ is H;

straight chained alkyl;

branched alkyl;

cyclic alkyl;

CO-alkyl;

CO-aryl;

CO-alkoxyalkyl;

chloro;

bromo;

fluoro;

iodo;

OR⁴;

NR⁴NR⁵ or SR⁵; and

R⁴ and R⁵ are independently hydrogen;

acyl;

or alkyl.

6. The method of claim 2, wherein the compound has the structure:

or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof.

7. The method of claim 2, wherein the compound has the structure:

or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof.

8. The method of claim 2, wherein the compound has the structure:

or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof.

9. A pharmaceutical composition comprising a compound of the formula:

or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof, in combination with one or more other antiviral agents, and one or more pharmaceutically acceptable carriers, excipients or diluents, wherein

R¹, R² and R³ are each independently H;

phosphate or a stabilized phosphate prodrug;

acyl;

or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R¹, R² or R³ is independently H or phosphate;

Y is hydrogen;

bromo;

chloro, fluoro;

iodo;

OR⁴;

NR⁴R⁵ or SR⁴;

X¹ and X² are each independently H;

straight chained;

branched or cyclic alkyl;

CO-alkyl;

CO-aryl;

CO-alkoxyalkyl;

chloro;

bromo;

fluoro;

iodo;

OR⁴;

NR⁴NR⁵ or SR⁵; and

R⁴ and R⁵ are independently hydrogen;

acyl;

or alkyl.

11. The pharmaceutical composition of claim 9, wherein the compound has the structure:

or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof.

12. The pharmaceutical composition of claim 9, wherein the compound has the structure:

or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof.

17. The pharmaceutical composition of claim 9, wherein the compound is in the form of a dosage unit.

18. The pharmaceutical composition of claim 17, wherein the dosage unit contains 10 to 1500 mg of said compound.

19. The pharmaceutical composition of claim 18, wherein said dosage unit is a tablet or capsule.

20. The pharmaceutical composition of claim 9, wherein the carrier is suitable for oral delivery.

21. The pharmaceutical composition of claim 9, wherein the carrier is suitable for intravenous, parenteral, intradermal, subcutaneous or topical delivery.

27. The pharmaceutical composition of claim 9, wherein the other antiviral agent is ribavirin.

29. The pharmaceutical composition of claim 9, wherein the other antiviral agent is an interferon.

10. A pharmaceutical composition comprising a compound of the formula:

or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof, in combination with one or more other antiviral agents, and one or more pharmaceutically acceptable carriers, excipients or diluents, wherein

R¹, R² and R³ are each independently H;

phosphate or a stabilized phosphate prodrug;

acyl;

or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R¹, R² or R³ is independently H or phosphate;

Y is hydrogen;

bromo;

chloro, fluoro;

iodo;

OR⁴;

NR⁴R⁵ or SR⁴;

X¹ is H;

straight chained;

branched alkyl;

cyclic alkyl;

CO-alkyl;

CO-aryl;

CO-alkoxyalkyl;

chloro;

bromo;

fluoro;

iodo;

OR⁴;

NR⁴NR⁵ or SR⁵; and

R⁴ and R⁵ are independently hydrogen;

acyl;

or alkyl.

13. The pharmaceutical composition of claim 10, wherein the compound has the structure:

or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof.

14. The pharmaceutical composition of claim 10, wherein the compound has the structure:

or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof.

15. The pharmaceutical composition of claim 10, wherein the compound has the structure:

or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof.

16. The pharmaceutical composition of claim 10, wherein the compound has the structure:

or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof.

22. The pharmaceutical composition of claim 10, wherein the compound is in the form of a dosage unit.

23. The pharmaceutical composition of claim 22, wherein the dosage unit contains 10 to 1500 mg of said compound.

24. The pharmaceutical composition of claim 22, wherein said dosage unit is a tablet or capsule.

25. The pharmaceutical composition of claim 10, wherein the carrier is suitable for oral delivery.

26. The pharmaceutical composition of claim 10, wherein the carrier is suitable for intravenous, parenteral, intradermal, subcutaneous or topical delivery.

28. The pharmaceutical composition of claim 10, wherein the other antiviral agent is ribavirin.

30. The pharmaceutical composition of claim 10, wherein the other antiviral agent is an interferon.

31. An acyl ester prodrug of the compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein;

Base is a purine or pyrimidine base;

R¹, R² and R³ are each hydrogen or phosphate;

R⁶ is alkyl; and

X is O.

32. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein R⁶ is methyl.

33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein the acyl ester is a lower acyl ester.

34. A pharmaceutical composition comprising a compound of claim 32, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

35. A method for the treatment of a hepatitis C virus infection in a host, comprising administering a compound of claim 31 or a pharmaceutically acceptable salt thereof.

36. A method for the treatment of a hepatitis C virus infection in a host, comprising contacting a cell in the host infected with a hepatitis C virus with a compound of claim 31 or a pharmaceutically acceptable salt thereof.

37. A method for the treatment of a hepatitis C virus infection in a host, comprising administering to the host infected with a hepatitis C virus an effective amount of a compound of the formula:

or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof, wherein

R¹, R² and R³ are each independently H;

phosphate or a stabilized phosphate prodrug;

acyl;

or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R¹, R² or R³ is independently H or phosphate;

Y is hydrogen;

bromo;

chloro, fluoro;

iodo;

OR⁴;

NR⁴R⁵ or SR⁴;

X¹ is H;

straight chained alkyl;

branched alkyl;

cyclic alkyl;

CO-alkyl;

CO-aryl;

CO-alkoxyalkyl;

chloro;

bromo;

fluoro;

iodo;

OR⁴;

NR⁴NR⁵ or SR⁵; and

R⁴ and R⁵ are independently hydrogen;

acyl;

or alkyl.

38. The method of claim 37, wherein

R¹, R² and R³ are each independently H or phosphate;

X¹ is H or CH₃; and

Y is hydrogen;

bromo;

chloro, fluoro;

iodo;

—

NH₂ or —

OH.

39. The method of claim 38, wherein R¹, R² and R³ are each H.