Modified 2′ and 3′-nucleoside prodrugs for treating
View Patent ↗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.
1. A method for the treatment of a host infected with a hepatitis C virus, comprising administering to the host infected with a hepatitis C virus an effective amount of a compound having the formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H; mono-, di- or triphosphate; acyl; an amino acid ester; a carbohydrate; a peptide; or a pharmaceutically acceptable leaving group which when administered in vivo provides a compound wherein R 1 is H or phosphate;
R 2 is H; acyl; an amino acid ester; a carbohydrate; a peptide; or a pharmaceutically acceptable leaving group which when administered in vivo provides a compound wherein R 2 is H;
Base* is selected from the group consisting of adenine, N 6 -alkylpurine, N 6 -acylpurine, N 6 -benzylpurine, N 6 -halopurine, N 6 -vinylpurine, N 6 -acetylenic purine, N 6 -acyl purine, N 6 -hydroxyalkyl purine, N 6 -alkylaminopurine, N 6 -thioalkyl purine, N 2 -alkylpurine, N 2 -alkyl-6-thiopurine, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, 6-azacytosine, 2- and/or 4-mercaptopyrimidine, uracil, 5-halouracil, 5-fluorouracil, C 5 -alkylpyrimidine, C 5 -benzylpyrimidine, C 5 -halopyrimidine, C 5 -vinylpyrimidine, C 5 -acetylenic pyrimidine, C 5 -acyl pyrimidine, C 5 -hydroxyalkyl purine, C 5 -amidopyrimidine, C 5 -cyanopyrimidine, C 5 -iodopyrimidine, C 6 -iodo-pyrimidine, C 5 -Br-vinyl pyrimidine, C 6 -Br-vinyl pyrimidine, C 5 -nitropyrimidine, C 6 -amino-pyrimidine, N 2 -alkylpurine, N 2 -alkyl-6-thiopurine, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, guanine, hypoxanthine, 2,6-diaminopurine, and 6-choropurine;
R 12 is C(Y 3 ) 3 ; and
Y 3 is independently H or F.
2. The method of claim 1 , wherein R 2 is H.
3. The method of claim 1 , wherein the compound or pharmaceutically acceptable salt thereof is in the form of a dosage unit.
4. The method of claim 3 wherein the dosage unit contains 50 to 1000 mg.
5. The method of claim 3 wherein the dosage unit is a tablet or capsule.
6. The method of claim 1 , wherein the host is a human.
7. The method of claim 1 , wherein the compound or pharmaceutically acceptable salt thereof is at least 85% by weight of the β-D-isomer.
8. The method of claim 1 , wherein the compound or pharmaceutically acceptable salt thereof is at least 90% by weight of the β-D-isomer.
9. The method of claim 1 , wherein the compound or pharmaceutically acceptable salt thereof is at least 95% by weight of the β-D-isomer.
10. The method of claim 1 , 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.
11. The method of claim 10 , wherein the pharmaceutically acceptable salt is a hydrochloride salt.
12. The method of claim 1 , wherein Y 3 is H.
13. The method of claim 1 , wherein R 2 is acyl.
14. The method of claim 1 , wherein R 2 is an amino acid ester.
15. The method of claim 1 , wherein R 2 is a peptide.
16. The method of claim 1 , wherein R 2 is a carbohydrate.
17. The method of claim 1 , wherein R 1 is hydrogen.
18. The method of claim 1 , wherein Base* is cytosine.
19. The method of claim 1 , wherein Base* is thymine.
20. The method of claim 1 , wherein Base* is uracil.
21. The method of claim 1 , wherein Base* is adenine.
22. The method of claim 1 , wherein Base* is guanine.
23. The method of claim 13 , wherein acyl is of the formula C(O)R′, wherein R′ is a straight, branched, or cyclic alkyl.
24. The method of claim 13 , wherein acyl is of the formula C(O)R′, wherein R′ is aryl, alkaryl, aralkyl, alkoxyalkyl or aryloxyalkyl.
25. The method of claim 13 , wherein acyl is of the formula C(O)R′, wherein R′ is aryl.
26. The method of claim 13 , wherein R 2 is acetyl.
27. The method of claim 13 , wherein R 2 is propionyl, butyryl, hexanoyl, or 2-propenyl.
28. The method of claim 1 , wherein R 2 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.
29. The method of claim 1 , wherein R 2 is an ester of a naturally occurring or synthetic α, β, γ, or δ amino acid.
30. The method of claim 1 , wherein R 2 is an ester of an amino acid in the L configuration.
31. The method of claim 1 , wherein R 2 is an ester of valine.
32. The method of claim 28 , wherein host is human.
33. The method of claim 1 , wherein:
R 1 is H;
R 2 is H, acyl or an amino acid ester; and
Y 3 is H.
34. The method of claim 33 , wherein Base* is cytosine.
35. The method of claim 33 , wherein Base* is thymine.
36. The method of claim 33 , wherein Base* is uracil.
37. The method of claim 33 , wherein R 2 is acyl.
38. The method of claim 33 , wherein R 2 is H.
39. The method of claim 33 , wherein R 2 is an amino acid ester.
40. The method of claim 37 , wherein acyl is of the formula C(O)R′, wherein R′ is a straight, branched, or cyclic alkyl.
41. The method of claim 37 , wherein acyl is of the formula C(O)R′, wherein R′ is aryl, alkaryl, aralkyl alkoxyalkyl or aryloxyalkyl.
42. The method of claim 37 , wherein acyl is of the formula C(O)R′, wherein R′ is aryl.
43. The method of claim 37 , wherein R 2 is acetyl.
44. The method of claim 37 , wherein R 2 is propionyl, butyryl, hexanoyl, or 2-propenyl.
45. The method of claim 33 , wherein R 2 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.
46. The method of claim 33 , wherein R 2 is an ester of a naturally occurring or synthetic α, β, γ, or δ amino acid.
47. The method of claim 33 , wherein R 2 is an ester of an amino acid in the L configuration.
48. The method of claim 33 , wherein R 2 is an ester of valine.
49. The method of claim 33 wherein host is human.
50. A method for the treatment of a host infected with a hepatitis C virus, comprising contacting a cell infected with a hepatitis C virus in the host with a compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H; mono-, di- or triphosphate; acyl; an amino acid ester; a carbohydrate; a peptide; or a pharmaceutically acceptable leaving group which when administered in vivo provides a compound wherein R 1 is H or phosphate;
R 2 is H; acyl; an amino acid ester; a carbohydrate; a peptide; or a pharmaceutically acceptable leaving group which when administered in vivo provides a compound wherein R 2 is H;
Base* is selected from the group consisting of adenine, N 6 -alkylpurine, N 6 -acylpurine, N 6 -benzylpurine, N 6 -halopurine, N 6 -vinylpurine, N 2 -acetylenic purine, N 6 -acyl purine, N 6 -hydroxyalkyl purine, N 6 -alkylaminopurine, N 6 -thioalkyl purine, N 6 -alkylpurine, N 6 -alkyl-6-thiopurine, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, 6-azacytosine, 2- and/or 4-mercaptopyrimidine, uracil, 5-halouracil, 5-fluorouracil, C 5 -alkylpyrimidine, C 5 -benzylpyrimidine, C 5 -halopyrimidine, C 5 -vinylpyrimidine, C 5 -acetylenic pyrimidine, C 5 -acyl pyrimidine, C 5 -hydroxyalkyl purine, C 5 -amidopyrimidine, C 5 -cyanopyrimidine, , C 5 -iodopyrimidine, C 6 -iodo-pyrimidine, C 5 -Br-vinyl pyrimidine, C 6 -Br-vinyl pyrimidine, C 5 -nitropyrimidine, C 5 -amino-pyrimidine, N 2 -alkylpurine, N 2 -alkyl-6-thiopurine, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, guanine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine;
R 12 C(Y 3 ) 3 ; and
Y 3 is independently H or F.
51. The method of claim 50 , wherein R 1 is H.
52. The method of claim 50 , wherein R 2 is H.
53. The method of claim 51 , wherein R 2 is H.
54. The method claim 50 , wherein Y 3 is H.
55. The method claim 51 , wherein Y 3 is H.
56. The method of claim 52 , wherein Y 3 is H.
57. The method of claim 53 , wherein Y 3 is H.
58. The method of claim 50 , wherein R 2 is acyl.
59. The method of claim 50 , wherein R 2 is an amino acid ester.
60. The method of claim 50 , wherein R 2 is a peptide.
61. The method of claim 50 , wherein R 2 is a carbohydrate.
62. The method of claim 50 , wherein Base* is cytosine.
63. The method of claim 50 , wherein Base* is thymine.
64. The method of claim 50 , wherein Base* is uracil.
65. The method of claim 50 , wherein Base* is adenine.
66. The method of claim 50 , wherein Base* is guanine.
67. The method of claim 58 , wherein acyl is of the formula C(O)R′, wherein R′ is a straight, branched or cyclic alkyl.
68. The method of claim 58 , wherein acyl is of the formula C(O)R′, wherein R′ aryl, alkaryl, aralkyl, alkoxyalkyl or aryloxyalkyl.
69. The method of claim 58 , wherein acyl is of the formula C(O)R′, wherein R′ is aryl.
70. The method of claim 58 , wherein R 2 is acetyl.
71. The method of claim 58 , wherein R 2 is propionyl, butyryl, hexanoyl or 2-propenyl.
72. The method of claim 50 , wherein R 2 is 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.
73. The method of claim 50 , wherein R 2 is an ester of a naturally occurring or synthetic α, β, γ or δ amino acid.
74. The method of claim 50 , wherein R 2 is an ester of an amino acid in the L configuration.
75. The method of claim 50 , wherein R 2 is an ester of valine.
76. The method of claim 50 , wherein:
R 1 is H;
R 2 is H, acyl or an amino acid ester; and
Y 3 is H.
77. The method of claim 50 , wherein the compound or pharmaceutically acceptable salt thereof is in the form of a dosage unit.
78. The method of claim 77 wherein the dosage unit contains 50 to 1000 mg.
79. The method of claim 77 wherein the dosage unit is a tablet or capsule.
80. The method of claim 50 , wherein the host is a human.
81. The method of claim 50 , wherein the compound or pharmaceutically acceptable salt thereof is at least 85% by weight of the β-D-isomer.
82. The method of claim 50 , wherein the compound or pharmaceutically acceptable salt thereof is at least 90% by weight of the β-D-isomer.
83. The method of claim 50 , wherein the compound or pharmaceutically acceptable salt thereof is at least 95% by weight of the β-D-isomer.
84. The method of claim 50 , 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, ascorbate, α-ketoglutarate, α-glycerophosphate, formate, fumarate, propionate, glycolate, lactate, pyruvate, oxalate, maleate, salicylate, sulfate, nitrate, hydrobromate, hydrochloride, di-hydrochloride, and phosphoric acid salt.
85. The method of claim 84 , wherein the pharmaceutically acceptable salt is a hydrochloride salt.