Compounds and pharmaceutical compositions for the treatment of viral infections
Provided herein are compounds, compositions and methods for the treatment of liver disorder, including HCV and/or HBV infections. Specifically, compound and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents.
1. A compound of the formula:
or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof, wherein:
R y is optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, hydroxyalkyl, amino, heterocyclyl or heteroaryl;
R a and R b are selected as follows:
i) R a and R b are each independently hydrogen or optionally substituted alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heterocyclyl; or
ii) R a and R b together with the nitrogen atom on which they are substituted form a 3-7 membered heterocyclic or heteroaryl ring; and
R 1 is selected from the group consisting of ribavirin, viramidine, valopicitabine, PSI-6130, MK-0608, resiquimod and celgosivir, lamivudine, entecavir, telbivudine, racivir, emtricitabine, clevudine, amdoxovir, valtorcitabine, tenofovir and adefovir.
2. The compound of claim 1 having the formula:
or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof.
3. The compound of claim 1 having the formula:
or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof.
4. The compound of claim 1 having the formula:
or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof.
5. The compound of claim 1 having the formula:
wherein R 2 and R 3 are each independently H, or R 2 and R 3 are linked to form a cyclic group by an alkyl, ester or carbamate linkage;
or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof.
6. The compound of claim 1 having the formula:
wherein R d is hydrogen, methyl or methoxy;
each R L is independently H, carbamyl, straight chained, branched or cyclic alkyl; acyl; CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate ester, a lipid, an amino acid; an amino acid residue; or a carbohydrate;
or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof.
7. The compound of claim 1 having the formula:
or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof.
8. The compound of claim 1 , wherein R y is substituted alkyl; and R a and R b are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl.
9. The compound of claim 8 , wherein R y is hydroxyalkyl or aminoalkyl.
10. The compound of claim 1 , wherein R y is —OR c , —C(R c ) 3 or —NHR c , where each R c is independently alkyl, substituted alkyl, aryl or substituted aryl; and R a and R b are independently hydrogen, alkyl, substituted alkyl, benzyl or substituted benzyl.
11. The compound of claim 1 , wherein R a and R b are independently hydrogen, benzyl or substituted alkyl.
12. The compound of claim 1 , wherein R y is selected from the group consisting of alkyl and hydroxyalkyl.
13. The compound of claim 1 , wherein R y is —C(CH 3 ) 2 CH 2 OH.
14. The compound of claim 1 , wherein R 2 and R 3 are each hydrogen, R a is hydrogen, R b is benzyl and R y is —C(CH 3 ) 2 CH 2 OH.
15. The compound of claim 1 selected from:
16. The compound of claim 1 having the structure:
17. A pharmecutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient, carrier or diluent.
18. The composition of claim 17 , wherein the compound is selected from
and pharmaceutically acceptable salts and stereoisomers thereof.
19. The composition of claim 17 , wherein the composition is an oral formulation.
20. The composition of claim 18 , wherein the composition is an oral formulation.
21. A kit comprising a combination, wherein the combination comprises a compound and ribavirin, wherein the compound has formula:
or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof, wherein:
R y is optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, hydroxyalkyl, amino, heterocyclyl or heteroaryl;
R a and R b are selected as follows:
i) R a and R b are each independently hydrogen or optionally substituted alkyl, carboxyalkyl, hydroxyalkyl, hydroxyarylalkyl, acyloxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heterocyclyl; or
ii) R a and R b together with the nitrogen atom on which they are substituted form a 3-7 membered heterocyclic or heteroaryl ring; and
R 1 is selected from the group consisting of ribavirin, viramidine, valopicitabine, PSI-6130, MK-0608, resiquimod and celgosivir, lamivudine, entecavir, telbivudine, racivir, emtricitabine, clevudine, amdoxovir, valtorcitabine, tenofovir and adefovir.