Spiro[2.4]heptanes for treatment of flaviviridae infections
View Patent ↗Compounds, methods, and compositions for the treatment of infections in or exposure to humans and other host animals of Flaviviridae viruses, including HCV, that includes the administration of an effective amount of a spiro[2.4]heptane as described herein or a pharmaceutically acceptable salt or prodrug thereof, optionally in a pharmaceutically acceptable carrier, are provided. The spiro[2.4]heptane compounds either possess antiviral activity, or are metabolized to a compound that exhibits such activity.
1. A spiro[2.4]heptane of the structure:
wherein:
R 1 is a natural or non-natural heteroaryl or heterocyclic moiety;
R 2 is methyl, F, Cl, N 3 , or OR 7 ;
R 3 is methyl, F, Cl, or N 3 ;
R 4 is OR 7 , H, methyl, F, Cl, or N 3 ;
R 5 is H, phosphate, a stabilized phosphate prodrug, phosphoramidate, acyl, alkyl, sulfonate ester, a lipid, a phospholipid, an amino acid, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 5 is H or mono, di, or tri-phosphate; and,
R 7 is H, acyl, phosphate, sulfate, amino acid, peptide, or an oxygen-protecting group;
or its pharmaceutically acceptable salt.
2. The spiro[2.4]heptane of claim 1 , wherein R 1 is a pyrimidine or purine.
3. The spiro[2.4]heptane of claim 2 , wherein the purine or pyrimidine is selected from the group consisting of cytosine, 5-halocytosine, uracil, 5-halouracil, 5-methylcytosine, thymine, adenine, thymine, guanine, xanthine, or hypoxanthine.
4. The spiro[2.4]heptane of claim 3 , wherein the pyrimidine is 5-fluorocytosine or 5-fluorouracil.
5. The spiro[2.4]heptane of claim 3 , wherein the pyrimidine is uracil.
6. The spiro[2.4]heptane of claim 3 , wherein the pyrimidine is cytosine.
7. The spiro[2.4]heptane of claim 1 , wherein R 5 is a phosphoramidate.
8. The spiro[2.4]heptane of claim 1 , wherein R 2 is methyl, R 3 is F, and R 4 is OR 7 .
9. The spiro[2.4]heptane of claim 8 , wherein R 1 is uracil.
10. The spiro[2.4]heptane of claim 9 , wherein R 5 is phosphoramidate.
11. The spiro[2.4]heptane of claim 1 , wherein R 3 is F or R 2 is F.
12. The spiro[2.4]heptane of claim 1 , wherein R 4 and R 5 together form a bridge.
13. The spiro[2.4]heptane of claim 12 , wherein the bridge is selected from a phosphoester, carbodiester, or a phosphoramidate.
14. Spiro[2.4]heptanes of the formula:
wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 7 are as defined in claim 1 , or a pharmaceutically acceptable salt thereof.
15. The spiro[2.4]heptane of claim 14 , wherein R 1 is a pyrimidine or purine.
16. The spiro[2.4]heptane of claim 15 , wherein the purine or pyrimidine is selected from the group consisting of cytosine, 5-halocytosine, uracil, 5-halouracil, 5-methylcytosine, thymine, adenine, thymine, guanine, xanthine, or hypoxanthine.
17. The spiro[2.4]heptane of claim 16 , wherein the pyrimidine is 5-fluorocytosine or 5-fluorouracil.
18. The spiro[2.4]heptane of claim 16 , wherein the pyrimidine is uracil.
19. The spiro[2.4]heptane of claim 16 , wherein the pyrimidine is cytosine.
20. The spiro[2.4]heptane of claim 15 , wherein R 5 is a phosphoramidate.
21. The spiro[2.4]heptane of claim 14 , wherein R 2 is methyl, R 3 is F, and R 4 is OR 7 .
22. The spiro[2.4]heptane of claim 21 , wherein R 1 is uracil.
23. A pharmaceutical composition, comprising an effective amount of the spiro[2.4]heptane of claim 1 , in a pharmaceutically acceptable carrier.
24. A pharmaceutical composition, comprising an effective amount of the spiro[2.4]heptane of claim 14 , in a pharmaceutically acceptable carrier.
25. The pharmaceutical composition of claim 23 , wherein the composition is suitable for oral delivery.
26. The spiro[2.4]heptane of claim 2 , wherein R 5 is a phosphoramidate.
27. The spiro[2.4]heptane of claim 3 , wherein R 5 is a phosphoramidate.