Modified 2' and 3'-nucleoside prodrugs for treating Flaviviridae infections

• US 20070087960A1
• Filed: 06/27/2003
• Published: 04/19/2007
• Est. Priority Date: 06/28/2002
• Status: Active Grant

• Current Assignee: Centre National De La Recherche Scientifique, Idenix Pharmaceuticals (Merck & Co., Inc.)
• Original Assignee: Centre National De La Recherche Scientifique, Idenix Pharmaceuticals (Merck & Co., Inc.), Universite Montpellier II, University of Calgary
• Inventors: Sommadossi, Jean-Pierre, Gosselin, Gilles, Storer, Richard
• Granted Patent: US 7,608,600 B2
• Time in Patent Office: Days
• 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 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• 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 38/212 IFN-alpha
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/48 Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07H 19/00 Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/048 Pyridine radicals
• CPC Class Codes: C07H 19/056 Triazole or tetrazole radicals
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 19/22 : Pteridine radicals

Abstract

2′ and/or 3′ prodrugs of 1′, 2′, 3′ or 4′-branched nucleosides, and their pharmaceutically acceptable salts and derivatives are described. These prodrugs are useful in the prevention and treatment of Flaviviridae infections, including HCV infection, and other related conditions. Compounds and compositions of the prodrugs of the present invention are described. Methods and uses are also provided that include the administration of an effective amount of the prodrugs of the present invention, or their pharmaceutically acceptable salts or derivatives. These drugs may optionally be administered in combination or alteration with further anti-viral agents to prevent or treat Flaviviridae infections and other related conditions.

Claims

1-11. -11. (canceled)

12. A method for the treatment of a host infected with a hepatitis C virus, comprising administering an effective treatment amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound has the formula:

13. The method of claim 12, wherein R² is H.

18. The method of claim 12, wherein the compound or pharmaceutically acceptable salt thereof is in the form of a dosage unit.

19. The method of claim 18 wherein the dosage unit contains 50 to 1000 mg.

20. The method of claim 18 wherein the dosage unit is a tablet or capsule.

21. The method of claim 12, wherein the host is a human.

22. The method of claim 12, wherein the compound or pharmaceutically acceptable salt thereof is in substantially pure form.

23. The method of claim 12, wherein the compound or pharmaceutically acceptable salt thereof is at least 90% by weight of the β

-D-isomer.

24. The method of claim 12, wherein the compound or pharmaceutically acceptable salt thereof is at least 95% by weight of the β

-D-isomer.

25. The method of claim 12, wherein the compound is in the form of a pharmaceutically acceptable salt selected from the group consisting of a tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorate, α

-ketoglutarate, α

-glycerophosphate, formate, fumarate, propionate, glycolate, lactate, pyruvate, oxalate, maleate, salicylate, sulfate, nitrate, hydrobromate, hydrochloride, di-hydrochloride, and phosphoric acid salt.

26. The method of claim 25, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

44. The method of claim 12, wherein Y³ is H.

45. The method of claim 12, wherein R² is acyl.

46. The method of claim 12, wherein R² is an amino acid ester.

47. The method of claim 12, wherein R² is a peptide.

48. The method of claim 12, wherein R² is a carbohydrate.

49. The method of claim 12, wherein R¹ is hydrogen.

50. The method of claim 12, wherein the base is a purine base.

51. The method of claim 12, wherein the base is a pyrimidine base.

52. The method of claim 51, wherein the pyrimidine base is cytosine.

53. The method of claim 51, wherein the pyrimidine base is thymine.

54. The method of claim 51, wherein the pyrimidine base is uracil.

55. The method of claim 50, wherein the purine base is adenine.

56. The method of claim 50, wherein the purine base is guanine.

57. The method of claim 45, wherein acyl is of the formula C(O)R′

, wherein R′

is a straight, branched, or cyclic alkyl.

58. The method of claim 45, wherein acyl is of the formula C(O)R′

, wherein R′

is aryl, alkaryl, aralkyl, alkoxyalkyl or aryloxyalkyl.

59. The method of claim 45, wherein acyl is of the formula C(O)R′

wherein R′

is aryl.

60. The method of claim 45, wherein R² is acetyl.

61. The method of claim 45, wherein R² is propionyl, butyryl, hexanoyl, or 2-propenyl.

62. The method of claim 12, wherein R² is an ester of an amino acid selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine.

63. The method of claim 12, wherein R² is an ester of a naturally occurring or synthetic α

, β

, γ

, or δ

amino acid.

64. The method of claim 12, wherein R² is an ester of an amino acid in the L configuration.

65. The method of claim 12, wherein R² is an ester of valine.

66. The method of claim 62, wherein host is human.

67. The method of claim 12, wherein:

Base is a pyrimidine base;

R¹ is H;

R² is H, acyl or an amino acid ester; and

Y³ is H.

68. The method of claim 67, wherein the pyrimidine base is cytosine.

69. The method of claim 67, wherein the pyrimidine base is thymine.

70. The method of claim 67, wherein the pyrimidine base is uracil.

71. The method of claim 67, wherein R² is acyl.

72. The method of claim 67, wherein R² is H.

73. The method of claim 67, wherein R² is an amino acid ester.

74. The method of claim 71, wherein acyl is of the formula C(O)R′

, wherein R′

is a straight, branched, or cyclic alkyl.

75. The method of claim 71, wherein acyl is of the formula C(O)R′

, wherein R′

is aryl, alkaryl, aralkyl alkoxyalkyl or aryloxyalkyl.

76. The method of claim 71, wherein acyl is of the formula C(O)R′

wherein R′

is aryl.

77. The method of claim 71, wherein R² is acetyl.

78. The method of claim 71, wherein R² is propionyl, butyryl, hexanoyl, or 2-propenyl.

79. The method of claim 67, wherein R² is an ester of an amino acid selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine.

80. The method of claim 67, wherein R² is an ester of a naturally occurring or synthetic α

, β

, γ

, or δ

amino acid.

81. The method of claim 67, wherein R² is an ester of an amino acid in the L configuration.

82. The method of claim 67, wherein R² is an ester of valine.

83. The method of claim 12, wherein the compound has the formula

84. The method of claim 67 or 83 wherein host is human.

14-17. -17. (canceled)

27-43. -43. (canceled)