D-amino acid compounds for liver disease
Provided herein are compounds, compositions and methods for the treatment of liver disease and conditions, including HCV infections. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents.
1. A compound according to formula (IIa) or (IIb), or a pharmaceutically acceptable salt thereof:
wherein
Y is independently —OR 1 or —SR 1 ;
Base is
or a tautomeric form thereof;
W is O;
R b1 is —CH 3 or —H;
R b2 is —OH, or —F;
R 1 is alkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkylcarbonylthioalkyl, alkoxycarbonylalkyl, arylalkoxycarbonylalkyl, alkylcarbonylalkoxy(arylalkyl), (alkoxycarbonyl)(alkoxycarbonylamino)alkyl, cycloalkylcarbonylalkoxyl, alkoxycarbonylaminoalkylcarbonylthioalkyl, hydroxylalkylcarbonylthioalkyl, aminoalkylcarbonylalkoxycarbonylthioalkyl, or hydantoinylalkyl;
R c is OH;
R d is —H or —F;
R e is —H;
R 10 is —CH 3 ; and
R 11 is ethyl, propyl, isopropyl, n-propyl, t-butyl, or cyclopentyl.
2. The compound of claim 1 , according to formula (IIa).
3. The compound of claim 1 , according to formula (IIb).
4. The compound of claim 1 wherein
Y is —OR 1 ;
R 1 is phenyl; and
R b2 is —OH or —F.
5. The compound of claim 1 which is according to
or a pharmaceutically acceptable salt or tautomeric form thereof.
6. A nucleoside composition comprising a compound according to Formula IIa or IIb:
or a pharmaceutically acceptable salt thereof,
wherein the composition is substantially free of other stereoisomers of the compound:
Y is —OR 1 or —SR 1 ;
Base is guanine, uracil, cytosine, or adenine, or a tautomeric form thereof;
W is O;
R b1 is —CH 3 or —H;
R b2 is —OH, or —F;
R 1 is alkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkylcarbonylthioalkyl, alkoxycarbonylalkyl, arylalkoxycarbonylalkyl, alkylcarbonylalkoxy(arylalkyl), (alkoxycarbonyl)(alkoxycarbonylamino)alkyl, cycloalkylcarbonylalkoxyl, alkoxycarbonylaminoalkylcarbonylthioalkyl, hydroxylalkylcarbonylthioalkyl, aminoalkylcarbonylalkoxycarbonylthioalkyl, or hydantoinylalkyl;
R c is OH;
R d is —H or —F;
R e is —H;
R 10 is —CH 3 ; and
R 11 is ethyl, propyl, isopropyl, n-propyl, t-butyl, or cyclopentyl.
7. The nucleoside composition of claim 6 , wherein
Y is —OR 1 ;
R d is —H;
R 1 is phenyl; and
R b2 is —OH or —F.
8. The nucleoside composition of claim 7 , wherein the composition provides a therapeutically effective amount of the compound for treating a human infected with HCV.
9. The nucleoside composition of claim 6 , wherein the compound is according to Formula (IIa).
10. The nucleoside composition of claim 6 , wherein the compound is according to Formula (IIb).
11. The nucleoside composition of claim 6 , wherein the compound is at least 90% by weight the compound according to Formula (IIa).
12. The nucleoside composition of claim 6 , wherein the compound is at least 90% by weight the compound according to Formula (IIb).
13. The nucleoside composition of claim 6 , comprising the compound
or a pharmaceutically acceptable salt thereof; wherein the composition is substantially free of other stereoisomers of the compound (804ai).
14. The nucleoside composition of claim 6 , comprising the compound
or a pharmaceutically acceptable salt thereof; wherein the composition is substantially free of other stereoisomers of the compound (804aii).
15. A pharmaceutical composition comprising a compound according to formula (II) or a pharmaceutically acceptable salt thereof:
Y is —OR 1 or —SR 1 ;
Base is guanine, uracil, cytosine, or adenine, or a tautomeric form thereof;
W is O;
R b1 is —CH 3 or —H;
R b2 is —OH, or —F;
R 1 is alkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkylcarbonylthioalkyl, alkoxycarbonylalkyl, arylalkoxycarbonylalkyl, alkylcarbonylalkoxy(arylalkyl), (alkoxycarbonyl)(alkoxycarbonylamino)alkyl, cycloalkylcarbonylalkoxyl, alkoxycarbonylaminoalkylcarbonylthioalkyl, hydroxylalkylcarbonylthioalkyl, aminoalkylcarbonylalkoxycarbonylthioalkyl, or hydantoinylalkyl;
R c is OH;
R d is —H or —F;
R e is —H;
R 10 is —CH 3 ; and
R 11 is ethyl, propyl, isopropyl, n-propyl, t-butyl, or cyclopentyl;
and a pharmaceutically acceptable carrier.
16. The pharmaceutical composition of claim 15 wherein
Y is —OR 1 ;
R 1 is phenyl; and
R b2 is —F or —OH.
17. The pharmaceutical composition of claim 16 , wherein the pharmaceutical composition provides a therapeutically effective amount of the compound for treating a human infected with HCV.
18. A method for the treatment of a human infected with a hepatitis C virus, comprising the administration to the human an effective amount of a nucleoside composition comprising a compound according to formula (IIa) or (IIb) or a pharmaceutically acceptable salt thereof:
wherein the composition is substantially free of other stereoisomers of the compound;
Y is —OR 1 or —SR 1 ;
Base is guanine, uracil, cytosine, or adenine, or a tautomeric form thereof;
W is O;
R b1 is —CH 3 or —H;
R b2 is —OH, or —F;
R 1 is alkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkylcarbonylthioalkyl, alkoxycarbonylalkyl, arylalkoxycarbonylalkyl, alkylcarbonylalkoxy(arylalkyl), (alkoxycarbonyl)(alkoxycarbonylamino)alkyl, cycloalkylcarbonylalkoxyl, alkoxycarbonylaminoalkylcarbonylthioalkyl, hydroxylalkylcarbonylthioalkyl, aminoalkylcarbonylalkoxycarbonylthioalkyl, or hydantoinylalkyl;
R c is OH;
R d is —H or —F;
R e is —H;
R 10 is —CH 3 ; and
R 11 is ethyl, propyl, isopropyl, n-propyl, t-butyl, or cyclopentyl.
19. The method of claim 18 , wherein
Y is —OR 1 ;
R 1 is phenyl; and
R b2 is —OH or —F.
20. The method of claim 18 , wherein the compound is administered in combination or alternation with a second anti-viral agent selected from the group consisting of an interferon, a nucleotide analogue, a polymerase inhibitor, an NS3 protease inhibitor, an NS5A inhibitor, an entry inhibitor, a non-nucleoside polymerase inhibitor, a cyclosporine immune inhibitor, an NS4A antagonist, an NS4B-RNA binding inhibitor, a locked nucleic acid mRNA inhibitor, a cyclophilin inhibitor, and combinations thereof.
21. The method of claim 20 , wherein the second anti-viral agent is an HCV NS3 protease inhibitor.
22. The method of claim 20 , wherein the second anti-viral agent is an HCV NS5A inhibitor.
23. The method of claim 18 , wherein the nucleoside composition comprises the compound
or a pharmaceutically acceptable salt thereof; and
wherein the composition is substantially free of other stereoisomers of the compound (804ai).
24. The method of claim 18 , wherein the nucleoside composition comprises the compound
or a pharmaceutically acceptable salt thereof; and
wherein the composition is substantially free of other stereoisomers of the compound (804aii).