β-2′- or 3′-halonucleosides

• US 6,949,522 B2
• Filed: 06/24/2002
• Issued: 09/27/2005
• Est. Priority Date: 06/22/2001
• Status: Expired due to Fees

• Current Assignee: Pharmasset Incorporated (Gilead Sciences Inc.)
• Original Assignee: Emory University, Pharmasset Incorporated (Gilead Sciences Inc.), The University of Georgia Research Foundation, Inc.
• Inventors: Choi, Yongseok, Gumina, Giuseppe, Schinazi, Raymond F., Otto, Michael J., Chu, Chung K., Shi, Junxing, Chong, Youhoon
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): Lewis, Patrick T.
• Application Number:
  US10/179,612
• Publication Number:
  US 20050119286A1
• Time in Patent Office: 1,191 Days
• Field of Search: 514/42, 514/43, 514/45, 514/46, 514/47, 514/48
• US Class Current: 514/45
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 9/04 Cyclic acetals

Abstract

The present invention includes compounds and compositions of β-halonucleosides, as well as methods to treat HIV, HBV or abnormal cellular proliferation comprising administering said compounds or compositions.

Claims

1. A method for the treatment of an HIV infection in a host, comprising administering an effective treatment amount of a β

-D or β

-L-3′

-halonucleoside of the formula (II);

or its pharmaceutically acceptable salt, optionally in combination with a pharmaceutically acceptable carrier, wherein

X is S;

Y is fluoro, chloro, bromo or iodo;

R¹ is hydrogen, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, aryl, alkylsufonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di or triphosphate or a phosphate derivative;

Y¹ is OH, OR², NH₂, NHR², NR²R³, SH, SR² or halogen;

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, OH, OR⁴, NH₂, NHR², NR⁴R⁵, SH or SR⁴; and

R², R³, R⁴ and R⁵ are independently H, straight chained, branched or cyclic alkyl, dialkylaminoalkylene, dimethylaminomethylene), CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate.

16. The method of any of claims 3, 7, 1 or 2 wherein R¹ is hydrogen.

17. The method of any of claims 3, 7, 1 or 2 wherein Y¹ is OH.

18. The method of any of claims 1 or 2 wherein Y¹ is NH₂.

19. The method of any of claims 1 or 2 wherein Y¹ is NHR².

20. The method of any of claims 3, 7, 1 or 2 wherein Y¹ is Cl.

21. The method of any of claims 3, 7, 1 or 2 wherein X¹ and X² are independently H.

22. The method of any of claims 3, 7, 1 or 2 wherein X¹ and X² are independently OH.

23. The method of any of claims 3, 7, 1 or 2 wherein X¹ and X² are independently NH₂.

24. The method of any of claims 3, 7, 1 or 2 wherein R², R³, R⁴ and R⁵ are independently H.

25. The method of any of claims 3, 7, 1 or 2 wherein R², R³, R⁴ and R⁵ are independently alkyl.

26. The method of any of claims 3, 7, 1 or 2 wherein R², R³, R⁴ and R⁵ are independently amino acid residue.

27. The method of any of claims 3, 7, 1 or 2 wherein R², R³, R⁴ and R⁵ are independently mono-phosphate.

28. The method of any of claims 3, 7, 1 or 2 wherein R², R³, R⁴ and R⁵ are independently di-phosphate.

29. The method of any of claims 3, 7, 1 or 2 wherein R², R³, R⁴ and R⁵ are independently tri-phosphate.

32. The method of one of claims 1or 2 wherein Y is F.

33. The method of one of claims 1 or 2 wherein X¹ and X² are each H and Y¹ is NH₂.

34. The method of one of claims 3, 7, 1 or 2 wherein R¹ is CO-alkyl.

35. The method of one of claims 3, 7, 1 or 2 wherein wherein X² is NH₂.

36. The method of one of claims 3, 7, 1 or 2 wherein X² is F.

39. The method of claim 1 wherein the 3′

-halonucleoside is a β

-D nucleoside.

43. The method of claim 1 wherein the 3′

-halonucleoside is a β

-L nucleoside.

2. A method for the treatment of an HIV infection in a host, comprising administering an effective treatment amount of a β

-D or β

-L-3′

-halonucleoside of the formula (II);

or its pharmaceutically acceptable salt, in combination or alternation with one or more other effective anti-HIV agent, optionally in combination with a pharmaceutically acceptable carrier, wherein

X is S;

Y is fluoro, chloro, bromo or iodo;

R¹ is hydrogen, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, aryl, alkylsufonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di or triphosphate or a phosphate derivative;

Y¹ is OH, OR², NH₂, NHR², NR²R³, SH, SR² or halogen;

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, OH, OR⁴, NH₂, NHR², NR⁴R⁵, SH or SR⁴; and

R², R³, R⁴ and R⁵ are independently H, straight chained, branched or cyclic alkyl, dialkylaminoalkylene, dimethylaminomethylene), CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate.

31. The method of claim 7 or 2, wherein the other effective anti-HIV agent is selected from the group consisting of a protease inhibitor, cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC), the (−

)-enantiomer of 2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC), carbovir, acyclovir, foscarnet, interferon, AZT, DDI, DDC, D4T, CS-87 (3′

-azido-2′

,3′

-dideoxy-uridine), and β

-D-dioxolane nucleosides, and MKC-442 (6-benzyl-1-(ethoxymethyl)-5-isopropyl uracil.

40. The method of claim 2 wherein the 3′

-halonucleoside is a β

-D nucleoside.

44. The method of claim 2 wherein the 3′

-halonucleoside is a β

-L nucleoside.

3. A method for the treatment of an HIV infection in a host, comprising administering an effective treatment amount of a β

-D or β

-L-3′

-halonucleoside of the formula (II);

or its pharmaceutically acceptable salt, optionally in combination with a pharmaceutically acceptable carrier, wherein

X is O or S;

Y is fluoro, chloro, bromo or iodo;

R¹ is hydrogen, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO aryloxyalkyl, CO-substituted aryl, aryl, alkylsufonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di or triphosphate or a phosphate derivative;

Y¹ is OH, OR², SH, SR² or halogen;

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, OH, OR⁴, NH₂, NHR², NR⁴R⁵, SH or SR⁴; and

R², R³, R⁴ and R⁵ are independently H, straight chained, branched or cyclic alkyl, dialkylaminoalkylene, dimethylaminomethylene), CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate.

4. The method of claim 3 wherein X is O.

5. The method of claim 3 wherein X is S.

6. The method of claim 3 wherein Y is F.

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

-halonucleoside is a β

-D nucleoside.

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

-halonucleoside is a β

-L nucleoside.

7. A method for the treatment of an HIV infection in a host, comprising administering an effective treatment amount of a β

-D or β

-L-3′

-halonucleoside of the formula (II);

or its pharmaceutically acceptable salt, in combination or alternation with one or more other effective anti-HIV agent, optionally in combination with a pharmaceutically acceptable carrier, wherein

X is O or S;

Y is fluoro, chloro, bromo or iodo;

R¹ is hydrogen, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO aryloxyalkyl, CO-substituted aryl, aryl, alkylsufonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di or triphosphate or a phosphate derivative;

Y¹ is OH, OR², SH, SR² or halogen;

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 OH, OR⁴, NH₂, NHR², NR⁴R⁵, SH or SR⁴; and

R², R³, R⁴ and R⁵ are independently H, straight chained, branched or cyclic alkyl dialkylaminoalkylene, dimethylaminomethylene, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate.

8. The method of claim 7, wherein X is O.

9. The method of claim 7, wherein X is S.

10. The method of claim 7, wherein Y is F.

11. The method of any one of claims 3, 4-6, 7 or 8-10, wherein the host is a human.

38. The method of claim 7 wherein the 3′

-halonucleoside is a β

-D nucleoside.

42. The method of claim 7 wherein the 3′

-halonucleoside is a β

-L nucleoside.

12. A method for the treatment of an HBV infection in a host, comprising administering an effective treatment amount of a β

-D or β

-L-3′

-halonucleoside of the formula (II);

or its pharmaceutically acceptable salt, optionally in combination with a pharmaceutically acceptable carrier, wherein

X is O, S, SO₂;

Y is fluoro, chloro, bromo or iodo;

R¹ is hydrogen, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO aryloxyalkyl, CO-substituted aryl, aryl, alkylsufonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di or triphosphate or a phosphate derivative;

Y¹ is OH, OR², NH₂, NHR², NR²R³, SH, SR² or halogen;

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, OH, OR⁴, NH₂, NHR², NR⁴R⁵, SH or SR⁴; and

R², R³, R⁴ and R⁵ are indepcndently H, straight chained, branched or cyclic alkyl, dialkylaminoalkylene, dimethylaminomethylene), CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate.

14. The meihod of claim 12 or 13, wherein the host is a human.

15. The method of claim 12 or 13, wherein Y is F.

13. A method for the treatment of an HBV infection in a host, comprising administering an effective treatment amount of a β

-D or β

-L-3′

-halonucleoside of the formula (II);

or its pharmaceutically acceptable salt, in combination or alternation with one or more other effective anti-HBV agents optionally in combination with a pharmaceutically acceptable carrier, wherein

X is O, S, SO₂ or CH₂;

Y is fluoro, chloro, bromo or iodo;

R¹ is hydrogen, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO aryloxyalkyl, CO-substituted aryl, aryl, alkylsufonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di or triphosphate or a phosphate derivative

Y¹ is OH, OR², NH₂, NHR², NR²R³, SH, SR² or halogen;

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, OH, OR⁴, NH₂, NHR², NR⁴R⁵, SH or SR⁴; and

R², R³, R⁴ and R⁵ are independently H, straight chained, branched or cyclic alkyl, dialkylaminoalkylene, dimethylaminomethylene, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate.

30. The method of claim 13, wherein the other effective anti-HBV agent is selected from the group consisting of (−

)-enantiomer of 2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC), cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC), L-FMAU, interferon, β

-D-dioxolanyl-guanine (DXG), β

-D-dioxolanyl-2,6-diaminopurine (DAPD), and β

-D-dioxolanyl-6-chloropurine (ACP), famciclovir, penciclovir, BMS-200475, bis porn PMEA;

lobucavir, ganciclovir, and ribavarin.