2'-Fluoronucleosides

• US 20040254141A1
• Filed: 03/08/2004
• Published: 12/16/2004
• Est. Priority Date: 02/25/1998
• Status: Active Grant

• Current Assignee: Chung K. Chu, Dennis C. Liotta, Joon H. Hong, Junxing Shi, Kyeong Lee, Mcatee J. Jeffrey, Raymond F. Schinazi, Yongseok Choi
• Original Assignee: Chung K. Chu, Dennis C. Liotta, Joon H. Hong, Junxing Shi, Kyeong Lee, Mcatee J. Jeffrey, Raymond F. Schinazi, Yongseok Choi
• Inventors: Choi, Yongseok, Lee, Kyeong, Schinazi, Raymond F., Chu, Chung K., Liotta, Dennis C., Hong, Joon H., McAtee, J. Jeffrey, Shi, Junxing
• Granted Patent: US 7,307,065 B2
• Time in Patent Office: Days
• US Class Current: 514/47
• 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

1-38. -38. (cancelled)

39. :

A method for the treatment of a HCV infection in a host in need thereof comprising administering an effective treatment amount of a β

-D-2′

-fluoronucleoside, or a pharmaceutically acceptable salt or prodrug thereof, optionally in a pharmaceutically acceptable carrier or diluent.

40. :

The method of claim 39, wherein the β

-D-2′

-fluoronucleoside has a pyrimidine base.

41. :

The method of claim 40, wherein the pyrimidine base is selected from the group consisting of thymine, uracil, 5-halouracil, 5-fluorouracil, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-aza-pyrimidine, 6-azacytosine, 2- and/or 4-mercaptopyrmidine, C⁵-alkylpyrimidine, C⁵-benzylpyrimidine, C⁵-halopyrimidine, C⁵-vinylpyrimidine, C⁵-acetylenic pyrimidine, C⁵-acyl pyrimidine, C⁵-hydroxyalkyl purine, C⁵-amidopyrimidine, C⁵-cyanopyrimidine, C⁵-nitropyrimidine, and C⁵-aminopyrimidine.

42. :

The method of claim 40, wherein the pyrimidine base is thymine.

43. :

The method of claim 40, wherein the pyrimidine base is uracil.

44. :

The method of claim 40, wherein the pyrimidine base is 5-halouracil.

45. :

The method of claim 40, wherein the pyrimidine base is cytosine.

46. :

The method of claim 40, wherein the pyrimidine base is 5-fluorocytosine.

47. :

The method of claim 39, wherein the β

-D-2′

-fluoronucleoside has a purine base.

48. :

The method of claim 47, wherein the purine base is selected from the group consisting of N⁶-alkylpurine, N⁶-acylpurine (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N⁶-benzylpurine, N⁶-halopurine, N⁶-vinylpurine, N⁶-acetylenic purine, N⁶-acyl purine, N⁶-hydroxyalkyl purine, N⁶-thioalkyl purine, N²-alkylpurines, N²-alkyl-6-thiopurines, N²-alkylpurine, N²-alkyl-6-thiopurine, 5-azacytidinyl, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine.

49. :

The method of claim 39, wherein the β

-D-2′

-fluoronucleoside has a triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, or pyrazolopyrimidinyl base.

50. :

The method of claim 39, wherein the β

-D-2′

-fluoronucleoside is in substantially pure form.

51. :

The method of claim 39, wherein the β

-D-2′

-fluoronucleoside is at least 90% by weight of the β

-D-isomer.

52. :

The method of claim 39, wherein the β

-D-2′

-fluoronucleoside is at least 95% by weight of the β

-D-isomer.

53. :

The method of claim 39, wherein the β

-D-2′

-fluoronucleoside is administered in the form of a dosage unit.

54. :

The method of claim 53, wherein the dosage unit contains 50-1000 mg of the compound.

55. :

The method of claim 53, wherein the dosage unit is in the form of a tablet or capsule.

56. :

The method of claim 39, wherein the pharmaceutically acceptable carrier is suitable for oral delivery.

57. :

The method of claim 39, wherein the pharmaceutically acceptable carrier is suitable for intravenous delivery.

58. :

The method of claim 39, wherein the pharmaceutically acceptable carrier is suitable for parenteral delivery.

59. :

The method of claim 39, wherein the pharmaceutically acceptable carrier is suitable for intradermal delivery.

60. :

The method of claim 39, wherein the pharmaceutically acceptable carrier is suitable for subcutaneous delivery.

61. :

The method of claim 39, wherein the pharmaceutically acceptable carrier is suitable for topical delivery.

62. :

The method of any one of claims 39-49, wherein the host is a human.