2′-C-methyl-3′-O-L-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections
View Patent ↗The 3′-L-valine ester of β-D-2′-C-methyl-ribofuranosyl cytidine provides superior results against flaviviruses and pestiviruses, including hepatitis C virus. Based on this discovery, compounds, compositions, methods and uses are provided for the treatment of flaviviridae, including HCV, that include the administration of an effective amount of val-mCyd or its salt, ester, prodrug or derivative, optionally in a pharmaceutically acceptable carrier. In an alternative embodiment, val-mCyd is used to treat any virus that replicates through an RNA-dependent RNA polymerase.
1. A compound of the formula:
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein the pharmaceutically acceptable salt is a hydrochloride salt.
3. The compound of claim 1 , wherein the pharmaceutically acceptable salt is the dihydrochloride salt.
4. A pharmaceutical composition comprising an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof to treat a Flaviviridae infection, in a pharmaceutically acceptable carrier.
5. The pharmaceutical composition of claim 4 wherein the pharmaceutically acceptable salt is a hydrochloride salt.
6. The pharmaceutical composition of claim 4 wherein the pharmaceutically acceptable salt is a dihydrochloride salt.
7. The pharmaceutical composition of claim 6 , wherein the pharmaceutically acceptable carrier is suitable for oral delivery.
8. The pharmaceutical composition of claim 6 , wherein the compound is in the form of a dosage unit.
9. The composition of claim 8 , wherein the dosage unit contains 50 mg to 1000 mg of the compound.
10. The composition of claim 8 , wherein said dosage unit is a tablet or capsule.
11. The composition of claim 6 , wherein the compound is in substantially pure form.
12. The compound of any of claims 1 – 3 , wherein the compound is at least 90% by weight the β-D-isomer.
13. The compound of any of claims 1 – 3 , wherein the compound is at least 95% by weight of the β-D-isomer.
14. A compound of the formula:
wherein R is mono, di or triphosphate; a stabilized phosphate prodrug; acyl; sulfonate ester; or benzyl, wherein the phenyl group is optionally substituted; an amino acid; a carbohydrate; or other pharmaceutical acceptable leaving group which when administered in vivo provides a compound wherein R is independently H or phosphate.
15. A pharmaceutical composition that comprises the compound of claim 1 , 2 , or 3 in a pharmaceutically acceptable carrier, wherein the 5′-hydroxyl group is replaced with a 5′-OR group, wherein R is mono, di or triphosphate; a stabilized phosphate prodrug; acyl; sulfonate ester; or benzyl, wherein the phenyl group is optionally substituted; an amino acid; a carbohydrate; or other pharmaceutical acceptable leaving group which when administered in vivo provides a compound wherein R is independently H or phosphate.
16. The compound of claim 1 , wherein the pharmaceutically acceptable salt is selected from tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate, formate, fumarate, propionate, glycolate, lactate, pyruvate, oxalate, maleate, salicyate, sulfate, sulfonate, nitrate, hydrobromate, hydrobromide, hydroiodide, and phosphoric acid salts.
17. The composition of claim 4 , wherein the pharmaceutically acceptable salt is selected from tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate, formate, fumarate, propionate, glycolate, lactate, pyruvate, oxalate, maleate, salicyate, sulfate, sulfonate, nitrate, hydrobromate, hydrobromide, hydroiodide, and phosphoric acid salts.
18. The composition of claim 8 , wherein the dosage unit contains 70 mg to 1400 mg of the compound.
19. The composition of claim 8 , wherein the dosage unit contains 50 mg of the compound.
20. The composition of claim 8 , wherein the dosage unit contains 100 mg of the compound.
21. The composition of claim 8 , wherein the dosage unit contains 200 mg of the compound.
22. The composition of claim 8 , wherein the dosage unit contains 400 mg of the compound.
23. The composition of claim 8 , wherein the dosage unit contains 800 mg of the compound.
24. The composition of claim 8 , wherein the dosage unit contains 1000 mg of the compound.
25. The pharmaceutical composition of claim 4 , wherein the pharmaceutically acceptable carrier is suitable for oral delivery.
26. The pharmaceutical composition of claim 4 , wherein the compound is in the form of a dosage unit.
27. The composition of claim 4 , wherein the compound is in substantially pure form.
28. The composition of claim 4 , wherein the dosage unit contains 50 mg to 1000 mg of the compound.
29. The composition of claim 4 , wherein the dosage unit contains 70 mg to 1400 mg of the compound.
30. The composition of claim 4 , wherein the dosage unit contains 50 mg of the compound.
31. The composition of claim 4 , wherein the dosage unit contains 100 mg of the compound.
32. The composition of claim 4 , wherein the dosage unit contains 200 mg of the compound.
33. The composition of claim 4 , wherein the dosage unit contains 400 mg of the compound.
34. The composition of claim 4 , wherein the dosage unit contains 800 mg of the compound.
35. The composition of claim 4 , wherein the dosage unit contains 1000 mg of the compound.
36. The pharmaceutical composition of claim 4 , wherein the Flaviviridae infection is hepatitis C.
37. The pharmaceutical composition of claim 5 , wherein the Flaviviridae infection is hepatitis C.
38. The pharmaceutical composition of claim 6 , wherein the Flaviviridae infection is hepatitis C.
39. The pharmaceutical composition of claim 7 , wherein the Flaviviridae infection is hepatitis C.