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 compound of Formula (VI):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H; phosphate; acyl; an amino acid ester; a carbohydrate; a peptide; or pharmaceutically acceptable leaving group which when administered in vivo provides a compound wherein R 1 is 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 provides a compound wherein R 2 is H
Base is selected from the group consisting of
each R 4 and R 5 is independently hydrogen, acyl, alkyl, lower alkyl, alkenyl, alkynyl or cycloalkyl;
X is CH 2 , CHF, CF 2 , C(Y 3 ) 2 , CHCN, C(CN) 2 , CHR 4 or C(R 4 ) 2 ;
X 2 is H, straight chained, branched or cyclic alkyl, CH 3 , CF 3 , or fluoro;
X 3 is H or CH 3 ;
Y 3 is H, F, Cl, Br or I;
R 6 is alkyl, CF 3 , alkenyl, or alkynyl;
R 7 is OH, O(acyl), or halo;
R 8 and R 11 are hydrogen;
R 9 is OH or OR 2 ;
R 10 is hydrogen; and
wherein each alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate.
2. The compound of claim 1 , wherein the compound is at least 85% by weight of the β-D-isomer.
3. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.
4. The pharmaceutical composition of claim 3 , wherein the compound or pharmaceutically acceptable salt thereof, is in the form of a dosage unit.
5. The pharmaceutical composition of claim 4 wherein the dosage unit contains 50 to 1000 mg of the compound.
6. The pharmaceutical composition of claim 5 wherein said dosage unit is a tablet or capsule.
7. The pharmaceutical composition of claim 3 , or a pharmaceutically acceptable salt thereof is, wherein the compound is at least 85% by weight of the β-D isomer.
8. The pharmaceutical composition of claim 3 , further comprising a pharmaceutically acceptable carrier suitable for oral, parenteral, inhalant or intravenous delivery.
9. The compound of claim 1 , wherein Base has the formula P.
10. The compound of claim 1 , wherein Base has the formula AB.
11. The compound of claim 1 , wherein Base is selected from the group consisting of cytosine, thymine, uracil, 5-methylcytosine and 5-fluorocytosine.
12. The compound of claim 1 , wherein X 2 is CH 3 .
13. The compound of claim 1 , wherein X 2 is H.
14. The compound of claim 1 , wherein X 2 is fluoro.
15. The compound of claim 1 , wherein X 2 is CF 3 .
16. The compound of claim 1 , wherein X 3 is CH 3 .
17. The compound of claim 1 , wherein X 3 is H.
18. The compound of claim 1 , wherein X is CH 2 .
19. The compound of claim 1 , wherein X is CHF.
20. The compound of claim 1 , wherein X is CF 2 .
21. The compound of claim 1 , wherein X is CHR 4 .
22. The compound of claim 1 , wherein R 6 is CH 3 .
23. The compound of claim 1 , wherein R 6 is CF 3 .
24. The compound of claim 1 , wherein R 7 OR 2 .
25. The compound of claim 1 , wherein R 7 is fluoro.
26. The compound of claim 1 , wherein R 1 is a mono, di or triphosphate.
27. The compound of claim 1 , wherein R 1 is hydrogen.
28. The compound of claim 1 , wherein R 9 is OR 2 .
29. The compound of claim 28 , wherein R 2 is acyl.
30. The compound of claim 29 , wherein acyl is an amino acid ester.
31. The compound of claim 29 , wherein acyl is of the formula C(O)R′, wherein R′ is a straight, branched, or cyclic alkyl, or aryl.
32. The compound of claim 29 , wherein R 2 is acetyl.
33. The compound 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.
34. The compound of claim 1 , wherein R 2 is an ester of a naturally occurring or synthetic α, β, γ or δ amino acid.
35. The compound of claim 1 , wherein R 2 is an ester of an amino acid in the L configuration.
36. The compound of claim 1 , wherein R 2 is an ester of valine.
37. The compound of claim 1 , wherein:
X is CH 2 , or C(R 4 ) 2 ;
X 2 is H or CH 3 ;
X 3 is H;
R 9 is OR 2 ;
R 2 is acyl or an amino acid ester; and
R 1 is H.
38. The compound of claim 37 , wherein R 2 is an amino acid ester.
39. The compound of claim 38 , wherein R 2 is an ester of valine.
40. The compound of claim 37 , wherein Base is cytosine, uracil or thymine.