Methods and compounds for treating
Provided are methods for treating Paramyxoviridae virus infections by administering ribosides, riboside phosphates and prodrugs thereof, of Formula I: wherein the 1′ position of the nucleoside sugar is substituted. The compounds, compositions, and methods provided are particularly useful for the treatment of Human parainfluenza and Human respiratory syncytial virus infections.
1. A compound having the structure of Formula III or a pharmaceutically acceptable salt thereof:
wherein
R 2 and R 3 are each OR a ;
R 6 is CN;
R 7 is (C═O)R 11 or
R 8 is NH 2 ;
R 9 is H;
each occurrence of R a is independently H or (C═O)R 11 ;
each occurrence of R 11 is independently H or (C 1 -C 8 )alkyl which is optionally substituted by NH 2 ; and
each occurrence of R is independently H or (C 1 -C 8 )alkyl.
2. The compound of claim 1 , wherein R 7 is
3. The compound of claim 2 , wherein R is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl.
4. The compound of claim 1 , wherein R 2 and R 3 are each OH.
5. The compound of claim 4 , wherein R 7 is —(C═O)—(C 1 -C 8 )alkyl; wherein the (C 1 -C 8 )alkyl of R 7 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl, each of which is optionally substituted by NH 2 .
6. The compound of claim 5 , wherein R 7 is —(C═O)—CH(CH 3 ) 2 .
7. The compound of claim 5 , wherein R 7 is —(C═O)—CH(NH 2 )CH(CH 3 ) 2 .
8. The compound of claim 1 , wherein R 2 and R 3 are each —O(C═O)(C 1 -C 8 )alkyl, wherein the (C 1 -C 8 )alkyl groups of R 2 and R 3 are each optionally substituted with NH 2 .
9. The compound of claim 8 , wherein the (C 1 -C 8 )alkyl groups of R 2 and R 3 are each selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl, each of which is optionally substituted with NH 2 .
10. The compound of claim 9 , wherein each of R 2 and R 3 is selected from the group consisting of —O(C═O)—CH(CH 3 ) 2 and —O(C═O)—CH(NH 2 )CH(CH 3 ) 2 .
11. The compound of claim 10 , wherein R 2 and R 3 are —O(C═O)—CH(NH 2 )CH(CH 3 ) 2 and —O(C═O)—CH(CH 3 ) 2 , respectively; —O(C═O)—CH(CH 3 ) 2 and —O(C═O)—CH(NH 2 )CH(CH 3 ) 2 , respectively; or —O(C═O)—CH(NH 2 )CH(CH 3 ) 2 and —O(C═O)—CH(NH 2 )CH(CH 3 ) 2 , respectively.
12. The compound of claim 10 , wherein R 2 and R 3 are each —O(C═O)—CH(CH 3 ) 2 .
13. The compound of claim 8 , wherein R 7 is —(C═O)—(C 1 -C 8 )alkyl, wherein the (C 1 -C 8 )alkyl of R 7 is optionally substituted by NH 2 .
14. The compound of claim 13 , wherein the (C 1 -C 8 )alkyl of R 7 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl, each of which is optionally substituted by NH 2 .
15. The compound of claim 14 , wherein R 7 is —(C═O)—CH(CH 3 ) 2 .
16. The compound of claim 14 , wherein R 7 is —(C═O)—CH(NH 2 )CH(CH 3 ) 2 .
17. The compound of claim 8 , wherein R 2 is —O(C═O)—CH(CH 3 ) 2 , R 3 is —O(C═O)—CH(CH 3 ) 2 , and R 7 is —(C═O)—CH(CH 3 ) 2 .
18. The compound of claim 1 , wherein R 2 is OH and R 3 is —O(C═O)(C 1 -C 8 )alkyl, wherein the (C 1 -C 8 )alkyl of R 3 is optionally substituted by NH 2 .
19. The compound of claim 18 , wherein the (C 1 -C 8 )alkyl of R 3 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl, each of which is optionally substituted by NH 2 .
20. The compound of claim 19 , wherein R 3 is —O(C═O)—CH(CH 3 ) 2 .
21. The compound of claim 19 , wherein R 3 is —O(C═O)—CH(NH 2 )CH(CH 3 ) 2 .
22. The compound of claim 18 , wherein R 7 is —(C═O)—(C 1 -C 8 )alkyl; wherein the (C 1 -C 8 )alkyl of R 7 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl, each of which is optionally substituted by NH 2 .
23. The compound of claim 22 , wherein R 7 is —(C═O)—CH(CH 3 ) 2 .
24. The compound of claim 22 , wherein R 7 is —(C═O)—CH(NH 2 )CH(CH 3 ) 2 .
25. The compound of claim 1 , wherein R 3 is OH and R 2 is —O(C═O)(C 1 -C 8 )alkyl, wherein the (C 1 -C 8 )alkyl of R 2 is optionally substituted by NH 2 .
26. The compound of claim 25 , wherein the (C 1 -C 8 )alkyl of R 2 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, or 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl, each of which is optionally substituted by NH 2 .
27. The compound of claim 26 , wherein R 2 is —O(C═O)—CH(CH 3 ) 2 .
28. The compound of claim 26 , wherein R 2 is —O(C═O)—CH(NH 2 )CH(CH 3 ) 2 .
29. The compound of claim 25 , wherein R 7 is —(C═O)—(C 1 -C 8 )alkyl; wherein the (C 1 -C 8 )alkyl of R 7 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl, each of which is optionally substituted by NH 2 .
30. The compound of claim 29 , wherein R 7 is —(C═O)—CH(CH 3 ) 2 .
31. The compound of claim 29 , wherein R 7 is —(C═O)—CH(NH 2 )CH(CH 3 ) 2 .
32. The compound of claim 1 , wherein R 2 and R 3 are each —O(C═O)(C 1 -C 8 )alkyl.
33. The compound of claim 32 , wherein the (C 1 -C 8 )alkyl groups of R 2 and R 3 are each selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl.
34. The compound of claim 32 , wherein R 7 is —(C═O)—(C 1 -C 8 )alkyl.
35. The compound of claim 34 , wherein the (C 1 -C 8 )alkyl of R 7 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl.
36. The compound of claim 4 , wherein R 7 is —(C═O)—(C1-C8)alkyl.
37. The compound of claim 36 , wherein the (C1-C8)alkyl of R 7 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl.