Phosphonates with reduced toxicity for treatment of viral infections
There are provided, inter alia, acyclic nucleoside phosphonate compounds having reduced toxicity and enhanced antiviral activity, and pharmaceutically accepted salts and solvates thereof. There are also provided methods of using the disclosed compounds for inhibiting viral RNA-dependent RNA polymerase, inhibiting viral reverse transcriptase, inhibiting replication of virus, including hepatitis C virus or a human retrovirus, and treating a subject infected with a virus, including hepatitis C virus or a human retrovirus.
1. A compound having the structure of Formula (I):
wherein
B N is a substituted or unsubstituted nucleobase;
L 1 is a bond or —O—;
R 1 is halogen, —CF 3 , unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl;
provided that, if L 1 is a bond, then R 1 is halogen, and if L 1 is —O—, then R 1 is —CF 3 , unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl;
R 2 is
L 2 -O—R 3 (II),
wherein L 2 is a substituted or unsubstituted alkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted arylene; and
R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl;
or pharmaceutically accepted salt or solvate thereof.
2. The compound of claim 1 , wherein B N is unsubstituted adenine, substituted adenine, unsubstituted thymine, substituted thymine, unsubstituted guanine, substituted guanine, unsubstituted cytosine, substituted cytosine, unsubstituted uracil, substituted uracil, 2,6-diaminopurine, 6-methoxypurine, or 6-O-methylguanine.
3. The compound of claim 1 , with structure of Formula (Ia):
wherein
R 1 is —CF 3 , unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl.
4. The compound of claim 1 , wherein R 1 is unsubstituted alkyl, unsubstituted cycloalkyl, or unsubstituted aryl.
5. The compound of claim 1 , wherein R 1 is unsubstituted C 1 -C 10 alkyl.
6. The compound of claim 5 , wherein R 1 is methyl, ethyl or isopropyl.
7. The compound of claim 1 , wherein R 1 is unsubstituted cycloalkyl.
8. The compound of claim 1 , wherein R 1 is unsubstituted aryl.
9. The compound of claim 8 , wherein R 1 is phenyl.
10. The compound of claim 1 , wherein R 1 is unsubstituted alkyl, substituted cycloalkyl, or substituted aryl.
11. The compound of claim 1 , with structure of Formula (Ib):
wherein L 1 is a bond, and R 1 is halogen.
12. The compound of claim 11 , wherein R 1 is fluoro.
13. The compound of claim 1 , with the structure of Formulae (Ia1) to (Ia7):
14. The compound of claim 1 , wherein R 2 is octadecyloxyethyl, hexadecyloxyethyl, hexadecyloxypropyl, 15-methyl-hexadecyloxypropyl, 15-methyl-hexadecyloxyethyl, 14-methyl-tetradecyloxypropyl, 14-methyl-tetradecyloxyethyl, 14-cyclopropyl-tetradecyloxypropyl, 14-cyclopropyl-tetradecyloxyethyl, or 1-O-octadecyl-2-O-benzyl-sn-glyceryl.
15. A compound with structure:
16. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
17. A method of inhibiting a viral reverse transcriptase comprising contacting a cell comprising a viral reverse transcriptase with an effective amount of a compound of claim 1 , thereby inhibiting said viral reverse transcriptase, wherein said viral reverse transcriptase is an HIV reverse transcriptase.