2′-Fluoronucleosides

• US 6,348,587 B1
• Filed: 02/25/1999
• Issued: 02/19/2002
• Est. Priority Date: 02/25/1998
• Status: Expired due to Term

• Current Assignee: Emory University, The University of Georgia Research Foundation, Inc.
• Original Assignee: Emory University, The University of Georgia Research Foundation, Inc.
• Inventors: Lee, Kyeong, Hong, Joon H., McAtee, J. Jeffrey, Shi, Junxing, Choi, Yongseok, Schinazi, Raymond F., Chu, Chung K., Liotta, Dennis C.
• Primary Examiner(s): Riley, Jezia
• Application Number:
  US09/257,130
• Time in Patent Office: 1,090 Days
• Field of Search: 435/6, 514/1, 514/44, 536/1.11, 536/4.1, 536/22.1, 536/23.1, 536/25.3
• US Class Current: 536/25.3
• CPC Class Codes: A61K 31/706 containing six-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7064 containing condensed or non-condensed pyrimidines
• 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: A61P 31/12 Antivirals
• 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: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 473/00 Heterocyclic compounds containing purine ring systems
• 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

Abstract

A class of 2′-fluoro-nucleoside compounds are disclosed which are useful in the treatment of hepatitis B infection, hepatitis C infection, HIV and abnormal cellular proliferation, including tumors and cancer. The compounds have the general formulae:

wherein

Base is a purine or pyrimidine base; R¹ is OH, H, OR³, N₃, CN, halogen, including F, or CF₃, lower alkyl, amino, loweralkylamino, di(lower)alkylamino, or alkoxy, and base refers to a purine or pyrimidine base;

R² is H, phosphate, including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug; acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate; sulfonate ester including alkyl or arylalkyl sulfonyl including methanesulfonyl, benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given above, a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof.

Claims

1. A method for the treatment of hepatitis B infection in humans, comprising administering to a patient in need thereof an effective treatment amount of a 2′

-fluoro-β

-D nucleoside of the formula;

wherein

Base is a purine base;

R¹ is OH, H, OR³, N₃, CN, halogen, CF₃, lower alkyl, amino, loweralkylamino, di(lower)alkylamino;

R¹ is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

2. A method for the treatment of hepatitis C infection in humans, comprising administering to a patient in need thereof an effective treatment amount of the compound of the formula:

wherein

Base is a purine or pyrimidine base;

R¹ is OH, H, OR³, N₃, CN, halogen, CF₃, lower alkyl, amino, loweralkylamino, di(lower)alkylamino, or alkoxy, and base refers to a purine or pyrimidine base;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more subsituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

3. A method for the treatment of abnormal cell proliferation in humans, comprising administering to a patient in need thereof an effective treatment amount of a 2′

-fluoro-α

-L nucleoside of the formula;

wherein

Base is a purine or pyrimidine base;

R¹ is OH, H, OR³, N₃, CN, halogen, CF₃, lower alkyl, amino, loweralkylamino, di(lower)alkylamino;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

4. A 2′

-fluoro-(β

-D or β

-L)-nucleoside of the formula;

wherein

Base is a purine base;

R¹ is H, OR³, N₃, CN, halogen, CF₃, lower alkyl, amino, loweralkylamino or di(lower)-alkylamino;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

5. The compound of claim 4, wherein the base is a purine base, R² is H, monophosphate, diphosphate, triphosphate or acyl, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 4, wherein the purine base is selected from the group consisting of guanine, adenine, hypoxanthine, 2,6-diaminopurine and 6-chloropurine, or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising an effective treatment amount of a 2′

-fluoro-(β

-D or β

-L)-nucleoside of the formula;

wherein

Base is a purine base;

R¹ is H, OR³, N₃, CN, halogen, CF₃, lower alkyl, amino, loweralkylamino or di(lower)-alkylamino;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

8. The composition of claim 7, wherein the base is a purine base selected from the group consisting of guanine, adenine, hypoxanthine, 2,6-diaminopurine and 6-chloropurine, or a pharmaceutically acceptable salt thereof.

9. A method for the treatment of hepatitis B infection comprising administering to a host in need thereof an effective treatment amount of a 2′

-fluoro-(β

-D or β

-L)-nucleoside of the formula;

wherein

Base is a purine base;

R¹ is H, OR³, N₃, CN, halogen, CF₃, lower alkyl, amino, loweralkylamino or di(lower)-alkylamino;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

10. A method for the treatment of hepatitis C infection comprising administering to a host in need thereof an effective treatment amount of a 2′

-fluoro-nucleoside of the formula;

wherein

Base is a purine or pyrimidine base;

R¹ is H, OR³, N₃, CN, halogen, CF₃, lower alkyl, amino, loweralkylamino or di(lower)-alkylamino;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

11. A method for inhibiting the replication of HIV comprising administering to a host in need thereof an effective treatment amount of a 2′

-fluoro-(β

-D or β

-L)-nucleoside of the formula;

wherein

Base is a purine base;

R¹ is H, OR³, N₃, CN, halogen, CF₃, lower alkyl, amino, loweralkylamino or di(lower)-alkylamino;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

12. A method for the treatment of abnormal cell proliferation in humans comprising administering to a host in need thereof an effective treatment amount of a 2′

-fluoro-nucleoside of the formula;

wherein

Base is a purine or pyrimidine base;

R¹ is H, OR³, N₃, CN, halogen, CF₃, lower alkyl, amino, loweralkylamino or di(lower)-alkylamino;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

13. A 2′

-fluoro-β

-L-nucleoside of the formula;

wherein

X is S;

Base is a purine base;

R¹ is OH, H, OR³, N₃, CN, halogen, CF₃, lower alkyl, amino, loweralkylamino, di(lower)alkylamino;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

14. The compound of claim 13, wherein the base is a purine base, R² is H, monophosphate, diphosphate, triphosphate or acyl, or a pharmaceutically acceptable salt thereof.

15. The compound of claim 14, wherein the purine base is selected from the group consisting of guanine, adenine, hypoxanthine, 2,6-diaminopurine and 6-chloropurine, or a pharmaceutically acceptable salt thereof.

39. The 2′

-fluoro-β

-D or β

-L-nucleoside of claim 13, (wherein R¹ and R² are hydrogen.

49. The 2′

-fluoro-β

-D or β

-L-nucleoside of claim 13, wherein R¹ is OH or OR³.

16. A pharmaceutical composition comprising an effective treatment amount of a 2′

-fluoro-β

-L-nucleoside of the formula;

wherein

Base is a purine base;

R¹ is OH, H, OR³, N₃, CN, halogen, CF₃, lower alkyl, amino, loweralkylamino, di(lower)alkylamino;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

17. The composition of claim 16, wherein the base is a purine base selected from the group consisting of guanine, adenine, hypoxanthine, 2,6-diaminopurine and 6-chloropurine, or a pharmaceutically acceptable salt thereof.

40. The pharmaceutical composition of claim 16, wherein R¹ and R² of the 2′

-fluoro-β

-L-nucleoside are hydrogen.

50. The pharmaceutical composition of claim 16, wherein R¹ of the 2′

-fluoro-β

-L-nucleoside is OH or OR³.

18. A method for the treatment of hepatitis B infection comprising administering to a patient in need thereof an effective treatment amount of a 2′

-fluoro-β

-L-nucleoside of the formula;

wherein

Base is a purine base;

R¹ is OH, H, OR³, N₃, CN, halogen, CF₃, lower alkyl, amino, loweralkylamino, di(lower)alkylamino;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodru&

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

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

41. The method of claim 18, wherein R¹ and R² of the 2′

-fluoro-β

-L-nucleoside are hydrogen.

51. The method of claim 18, wherein R¹ of the 2′

-fluoro-β

-L-nucleoside is OH or OR³.

19. A method for the treatment of hepatitis C infection comprising administering to a host in need thereof an effective treatment amount of a 2′

-fluoro-(β

-D or β

-L)-nucleoside of the formula;

wherein

Base is a purine or pyrimidine base;

R¹ is OH, H, OR³, N₃, CN, halogen, CF₃, lower alkyl, amino, loweralkylamino or di(lower)alkylamino;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

20. A method for the inhibition of HIV comprising administering to a host in need thereof an effective treatment amount of a 2′

-fluoro-β

-L-nucleoside of the formula;

wherein

Base is a purine base;

R¹ is OH, H, OR³, N₃, CN, halogen, CF₃, lower alkyl, amino, loweralkylamino, or di(lower)alkylamino;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

42. The method of claim 20, wherein R¹ and R² of the 2′

-fluoro-β

-L-nucleoside are hydrogen.

52. The method of claim 20, wherein R¹ of the 2′

-fluoro-β

-L-nucleoside is OH or OR³.

21. A method for the treatment of abnormal cellular proliferation in humans comprising administering to a host in need thereof an effective treatment amount of a 2′

-fluoro-nucleoside of the formula;

wherein

Base is a purine or pyrimidine base;

R¹ is OH, H, OR³, N₃, CN, halogen, CF₃, lower alkyl, amino, loweralkylamino or di(lower)alkylamino;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

43. The method of claim 21, wherein X of the 2′

-fluoro-nucleoside is S.

22. A 2′

-fluoro-nucleosidel 2′

-fluoro-β

-L-nucleoside of the formula;

wherein

Base is a purine base;

R¹ is H, OR³, N₃, CN, halogen, CF₃, lower alkyl, amino, loweralkylamino, di(lower)alkylamino;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodru&

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

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof, optionally in combination with a phannaceutically acceptable carner.

23. The compound of claim 22, wherein the base is a purine base, R² is H, monophosphate, diphosphate, triphosphate or acyl, or a pharmaceutically acceptable salt thereof.

24. The compound of claim 23, wherein the purine base is selected from the group consisting of guanine, adenine, hypoxanthine, 2,6-diaminopurine and 6-chloropurine, or a pharmaceutically acceptable salt thereof.

44. The 2′

-fluoro-β

-L-nucleoside of claim 22, wherein R¹ and R² are hydrogen.

53. The 2′

-fluoro-β

-L-nucleoside of claim 22, wherein R¹ is OH or OR³.

25. A pharmaceutical composition comprising an effective treatment amount of a 2′

-fluoro-β

-L-nucleoside of the formula;

wherein

Base is a purine base;

R¹ is H, OR³, N₃, CN, halogen, CF₃, lower alkyl, amino, loweralkylamino, di(lower)alkylamino;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

26. The composition of claim 25, wherein the base is a purine base selected from the group consisting of guanine, adenine, hypoxanthine, 2,6-diaminopurine and 6-chloropurine, or a pharmaceutically acceptable salt thereof.

45. The pharmaceutical composition of claim 25, wherein R¹ and R² of the 2′

-fluoro-β

-L-nucleoside are hydrogen.

54. The pharmaceutical composition of claim 25, wherein R¹ of the 2′

-fluoro-β

-L-nucleoside is OH or OR³.

27. A method for the treatment of hepatitis B infection comprising administering to a host in need thereof an effective treatment amount of a 2′

-β

-fluoro-β

-L-nucleoside of the formula;

wherein

Base is a purine base;

R¹ is OH, H, OR³, N₃, CN, halogen, CF₃, lower alkyl, amino, loweralkylamino or di(lower)alkylamino;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

47. The method of claim 27, wherein R¹ and R² of the 2′

-fluoro-β

-L-arabinonucleoside are hydrogen.

55. The method of claim 27, wherein R¹ of the 2′

-fluoro-β

-L-arabinonucleoside is OH or OR³.

28. A method for the treatment of hepatitis C infection comprising administering to a patient in need thereof an effective treatment amount of a 2-fluoro-β

-L nucleoside of the formula;

wherein

Base is a purine or pyrimidine base;

R¹ is OH, H, OR³, N₃, CN, halogen, CF₃, lower alkyl, amino, loweralkylamino, di(lower)alkylamino;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

29. A method for the inhibition of HIV comprising administering to a host in need thereof an effective treatment amount of a 2′

-fluoro-β

-L-nucleoside of the formula;

wherein

Base is a purine base;

R¹ is OH, H, OR³, N₃, CN, halogen, CF₃, lower alkyl, amino, loweralkylamino or di(lower)alkylamino;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

46. The method of claim 29, wherein R¹ and R² of the 2′

-fluoro-β

-L-arabinonucleoside are hydrogen.

56. The method of claim 29, wherein R¹ of the 2′

-fluoro-β

-L-arabinonucleoside is OH or OR³.

30. A method for the treatment of abnormal cellular proliferation in humans comprising administering to a host in need thereof an effective treatment amount of a 2′

-fluoro-β

-L-nucleoside of the formula;

wherein

Base is a purine or pyrimidine base;

R¹ is H, OR³, N₃, CN, halogen, CF₃, lower alkyl, amino, loweralkylamino or di(lower)alkylamino;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

48. The method of claim 30, wherein X of the 2′

-fluoro-β

-L-arabinonucleoside is CH₂.

31. A 2′

-fluoro-β

-L-nucleoside of the formula;

wherein

Base is a purine base;

R¹ is OR³, N₃, CN, CF₃, lower alkyl, amino, loweralkylamino, or di(lower)alkylamino;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof.

32. The 2′

-fluoronucleoside of claim 31, wherein the base is a purine base, R² is hydrogen, monophosphate, diphosphate, triphosphate or acyl, or a pharmaceutically acceptable salt thereof.

33. The 2′

-fluoronucleoside of claim 31, wherein the purine base is selected from the group consisting of guanine, adenine, hypoxanthine, 2,6-diaminopurine and 6-chloropurine, or a pharmaceutically acceptable salt thereof.

34. A pharmaceutical composition comprising an effective treatment amount of a 2′

-fluoro-β

-L-nucleoside of the formula;

wherein

Base is a purine base;

R¹ is OR³, N₃, CN, CF₃, lower alkyl, amino, loweralkylamino, or di(lower)alkylamino;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

35. The composition of claim 34, wherein the purine base is selected from the group consisting of guanine, adenine, hypoxanthine, 2,6-diaminopurine and 6-chloropurine, or a pharmaceutically acceptable salt thereof.

36. A method for the treatment of hepatitis B infection comprising administering to a patient in need thereof an effective treatment amount of a 2′

-fluoro-(β

-D or β

-L)-nucleoside of the formula;

wherein

Base is a purine base;

R¹ is OR³, N₃, CN, CF₃, lower alkyl, amino, loweralkylamino, or di(lower)alkylamino;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof.

37. A method for the treatment of hepatitis C infection comprising administering to a patient in need thereof an effective treatment amount of a 2′

-fluoro-nucleoside of the formula;

wherein

Base is a purine or pyrimidine base;

R¹ is OH, OR³, N₃, CN, CF₃, lower alkyl, amino, loweralkylamino, di(lower)alkylamino, or alkoxy, and base refers to a purine or pyrimidine base;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof.

38. A method for inhibiting the replication of HIV comprising administering to a patient in need thereof an effective treatment amount of a 2′

-fluoro-β

-L-nucleoside of the formula;

wherein

Base is a purine base;

R¹ is OR³, N₃, CN, CF₃, lower alkyl, amino, loweralkylamino, or di(lower)alkylamino;

R² is H, monophosphate, diphosphate, triphosphate, a stabilized phosphate prodrug, acyl, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of providing a compound wherein R² is H or phosphate;

sulfonate ester, benzyl, wherein the phenyl group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

a lipid, an amino acid, peptide, or cholesterol; and

R³ is acyl, alkyl, phosphate, or other pharmaceutically acceptable leaving group which when administered in vivo, is capable of being cleaved to the parent compound, or a pharmaceutically acceptable salt thereof.