Methods of treating hepatitis delta virus infection with β-L-2′-deoxy-nucleosides

• US 6,787,526 B1
• Filed: 12/26/2002
• Issued: 09/07/2004
• Est. Priority Date: 05/26/2000
• Status: Expired due to Fees

• Current Assignee: Novartis Ag
• Original Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.)
• Inventors: Sommadossi, Jean-Pierre, Bryant, Martin L.
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): McIntosh, III, Traviss C.
• Application Number:
  US10/329,616
• Time in Patent Office: 621 Days
• Field of Search: 514/45, 514/46, 514/47, 514/48, 514/49, 514/50, 514/894
• US Class Current: 514/45
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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

Abstract

A method and composition for treating a host infected with hepatitis D comprising administering an effective hepatitis D treatment amount of a described 2′-deoxy-β-L-erythro-pentofuranonucleoside or a pharmaceutically acceptable salt or prodrug thereof.

Claims

1. A method for treating a host infected with hepatitis D virus comprising administering an effective hepatitis D treatment amount of a biologically active 2′

-deoxy-β

-L-erythro-pentofuranonucleoside or a pharmaceutically acceptable salt thereof in combination or alternation with interferon to a host in need thereof.

25. The method of any one of claims 1-24, wherein the host is a human.

2. A method for treating a host infected with hepatitis D virus comprising administering an effective hepatitis D treatment amount of 2′

-deoxy-β

-L-erythro-pentofuranonucleoside of the formula;

or a pharmaceutically acceptable salt thereof, wherein

R¹ is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate derivative; and

BASE is a purine or pyrimidine base that may optionally be substituted;

in combination or alternation with interferon to a host in need thereof.

3. The method of claim 2, wherein the 2′

-deoxy-β

-L-erythro-pentofuranonucleoside is a β

-L-2′

-deoxypurine of the formula;

or a pharmaceutically acceptable salt thereof, wherein

R¹ is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate derivative;

Y is OR³, NR³R⁴ or SR³; and

X¹ and X² are independently selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, halogen, OR⁵, NR⁵NR⁶ or SR⁵; and

R³, R⁴, R⁵ and R⁶ are independently H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate derivative.

4. The method of claim 3, wherein the 2′

-deoxy-β

-L-erythro-pentofuranonucleoside is a β

-L-2′

-deoxyadenosine of the formula;

or pharmaceutically acceptable salt thereof, wherein R¹ is H, mono, di or triphosphate, acyl, alkyl, or a stabilized phosphate derivative.

5. The method of claim 4, wherein R¹ is hydrogen.

6. The method of claim 5, wherein R¹ is acyl.

7. The method of claim 6, wherein the acyl is derived from an amino acid.

8. The method of claim 7, wherein the amino acid is valine.

9. The method of claim 3, wherein the 2′

-deoxy-β

-L-erythro-pentofuranonucleoside is a β

-L-2′

-deoxyguanosine of the formula;

or pharmaceutically acceptable salt thereof, wherein R¹ is H, mono, di or triphosphate, acyl, alkyl, or a stabilized phosphate derivative.

10. The method of claim 3, wherein the 2′

-deoxy-β

-L-erythro-pentofuranonucleoside is a β

-L-2′

-deoxyinosine of the formula;

or pharmaceutically acceptable salt thereof, wherein R¹ is H, mono, di or triphosphate, acyl, alkyl, or a stabilized phosphate derivative.

11. The method of claim 2, wherein the 2′

-deoxy-β

-L-erythro-pentofuranonucleoside is a β

-L-2′

-deoxypyrimidine of the formula;

or a pharmaceutically acceptable salt or prodrug thereof, wherein

R¹ is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate derivative;

Y is OR³, NR³R⁴ or SR³; and

X¹ is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, halogen, OR⁵, NR⁵NR⁶ or SR⁵; and

R³, R⁴, R⁵ and R⁶ are independently H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate derivative.

12. The method of claim 11, wherein the 2′

-deoxy-β

-L-erythro-pentofuranonucleoside is a β

-L-2′

-deoxyuridine of the formula;

or pharmaceutically acceptable salt thereof, wherein R¹ is H, mono, di or triphosphate, acyl, alkyl, or a stabilized phosphate derivative.

13. A method for treating a host infected with hepatitis D virus comprising administering an effective hepatitis D treatment amount of a β

-L-2′

-deoxycytidine of the formula;

or pharmaceutically acceptable salt thereof, wherein R¹ is H, mono, di or triphosphate, acyl, alkyl, or a stabilized phosphate derivative;

in combination or alternation with interferon to a host in need thereof.

14. The method of claim 13, wherein R¹ is hydrogen.

15. The method of claim 14, wherein R¹ is acyl.

16. The method of claim 15, wherein the acyl is derived from an amino acid.

17. The method of claim 16, wherein the amino acid is valine.

18. A method for treating a host infected with hepatitis D virus comprising administering an effective hepatitis D treatment amount of a β

-L-thymidine of the formula;

or pharmaceutically acceptable salt thereof, wherein R¹ is H, mono, di or triphosphate, acyl, alkyl or a stabilized phosphate derivative;

in combination or alternation with interferon to a host in need thereof.

19. The method of claim 18, wherein R¹ is hydrogen.

20. The method of claim 19, wherein R¹ is acyl.

21. The method of claim 20, wherein the acyl is derived from an amino acid.

22. The method of claim 21, wherein the amino acid is valine.

23. A method for treating a host infected with hepatitis D virus comprising administering an effective hepatitis D treatment amount of a β

-L-2′

-deoxycytidine of the formula;

or pharmaceutically acceptable salt thereof,

in combination or alternation with interferon.

24. A method for treating a host infected with hepatitis D virus comprising administering an effective hepatitis D treatment amount of a β

-L-thymidine of the formula;

or pharmaceutically acceptable salt thereof,

in combination or alternation with interferon.