2' and 3'-nucleoside prodrugs for treating Flaviviridae infections
2′ and 3′-Prodrugs of 1′, 2′, 3′ or 4′-branched β-D or β-L nucleosides, or their pharmaceutically acceptable salts and derivatives are described, which are useful in the prevention and treatment of Flaviviridae infections and other related conditions. These modified nucleosides provide superior results against flaviviruses and pestiviruses, including hepatitis C virus and viruses generally that replicate through an RNA dependent RNA reverse transcriptase. Compounds, compositions, methods and uses are provided for the treatment of Flaviviridae infection, including HCV infection, 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 . (canceled)
2 . A method for the treatment of a host infected with a Flaviviridae virus, comprising administering an effective treatment amount of a compound of formula
or a pharmaceutically acceptable salt thereof
wherein:
Base is a pyrimidine base;
R 1 is hydrogen, mono, di or triphosphate or a stabilized phosphate; acyl; an amino acid ester; a carbohydrate; a peptide; or a pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 1 is independently H or phosphate;
R 2 is acyl; an amino acid ester; a carbohydrate; a peptide; or a pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 2 is hydrogen;
R 3 is hydrogen;
R 6 is CH 3 ; and
X is O;
in combination or alternation with a second antiviral agent.
3 . The method of claim 2 , 10 , 40 or 52 , wherein the virus is hepatitis C.
4 - 7 . (canceled)
8 . The method of claim 2 , wherein the compound or pharmaceutically acceptable salt thereof, is in the form of a dosage unit.
9 . The method of claim 8 , wherein the dosage unit is a tablet or capsule.
10 . The method of claim 2 , wherein the host is a human.
11 . The method of claim 2 , wherein the compound is in substantially pure form.
12 . The method of claim 2 , wherein the compound is at least 90% by weight of the β-D-isomer.
13 . The method of claim 2 , wherein the compound or a pharmaceutically acceptable salt thereof is in combination with a pharmaceutically acceptable carrier.
14 . The method of claim 13 , wherein the pharmaceutically acceptable carrier is suitable for oral delivery.
15 . The method of claim 13 , wherein the compound or a pharmaceutically acceptable salt thereof, is in the form of a dosage unit.
16 . The method of claim 15 , wherein the dosage unit contains 50 to 1000 mg of the compound.
17 . The method of claim 16 , wherein said dosage unit is a tablet or capsule.
18 . (canceled)
19 . The method of claim 13 , wherein the compound or pharmaceutically acceptable salt thereof is in substantially pure form.
20 . The method of claim 13 , wherein the pharmaceutically acceptable carrier is suitable for systemic, topical, parenteral, inhalant or intravenous delivery.
21 . The method of claim 2 , wherein R 1 is hydrogen, mono, di or triphosphate or a stabilized phosphate.
22 . The method of claim 2 , wherein R 2 is acyl.
23 . The method of claim 2 , wherein R 2 is an amino acid ester.
24 . The method of claim 2 , wherein the R 2 acyl is of the formula C(O)R′, wherein R′ is a straight, branched, or cyclic alkyl.
25 . The method of claim 2 , wherein R 1 is hydrogen.
26 . The method of claim 2 , wherein the R 2 is of the formula C(O)R′ wherein R′ is aryl, alkaryl, aralkyl, alkoxyalkyl or aryloxyalkyl.
27 . The method of claim 21 , wherein R 2 is acetyl.
28 . The method of claim 22 , wherein X is O.
29 . The method of claim 2 , wherein the base is thymine.
30 . The method of claim 2 , wherein the base is cytosine.
31 . The method of claim 2 , wherein the base is uracil.
32 . The method of claim 2 , wherein the base is 5-methylcytosine.
33 . The method of claim 2 , wherein the base is 5-fluorocytosine.
34 . The method of claim 2 , 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.
35 . The method of claim 2 , wherein R 2 is an ester of a naturally occurring or synthetic α, β, γ, or δ amino acid.
36 . The method of claim 2 , wherein R 2 is an ester of an amino acid in the L configuration.
37 . The method of claim 2 , wherein R 2 is an ester of valine.
38 . The method of claim 2 , wherein the host is human.
39 . The method of claim 34 , wherein the host is human.
40 . The method of claim 2 , wherein:
R 1 is H;
R 2 is acyl or an amino acid ester;
R 3 is H; and
X is O.
41 . The method of claim 40 , wherein R 2 is an amino acid ester.
42 . The method of claim 40 , wherein the base is thymine.
43 . The method of claim 40 , wherein the base is cytosine.
44 . The method of claim 40 , wherein the base is uracil.
45 . The method of claim 40 , wherein the base is 5-methylcytosine.
46 . The method of claim 40 , wherein the base is 5-fluorocytosine.
47 . The method of claim 40 , 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.
48 . The method of claim 40 , wherein R 2 is an ester of a naturally occurring or synthetic α, β, γ, or δ amino acid ester.
49 . The method of claim 40 , wherein R 2 is an ester of an amino acid in the L configuration.
50 . The method of claim 40 , wherein the host is a human.
51 . The method of claim 47 , wherein the host is a human.
52 . A method for the treatment of a host infected with a Flaviviridae virus, comprising administering an effective treatment amount of a compound of formula:
or a pharmaceutically acceptable salt thereof
wherein:
Base is a pyrimidine base;
R 1 is H or phosphate;
R 2 and R 3 are independently H, phosphate, acyl or an amino acid ester, wherein at least one of R 2 and R 3 is acyl or an amino acid ester;
R 6 is methyl; and
X is O;
in combination or alternation with a second anti-viral agent.
53 . The method of claim 2 , 3 , 10 , 40 , or 52 wherein the second anti-viral agent is selected from the group consisting of ribavirin, an interleukin, a helicase inhibitor, and an inhibitor of IRES-dependent translation.
54 . The method of claim 2 , 3 , 10 , 40 or 52 wherein the second anti-viral agent is a polymerase inhibitor.
55 . The method of claim 2 , 3 , 10 , 40 or 52 wherein the second anti-viral agent is a substrate based NS3 protease inhibitor.
56 . The method of claim 2 , 3 , 10 , 40 or 52 wherein the second ant-viral agent is an interferon.
57 . The method of claim 56 , wherein the second agent is selected from the group consisting of pegylated interferon alpha 2a, interferon alphacon-1, natural interferon, albuferon, interferon beta-1 a, omega interferon, interferon alpha, interferon gamma-1b.