2′,4′-bridged nucleosides for HCV infection
Provided herein are compounds, compositions and methods for the treatment of Flaviviridae infections, 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. In certain embodiments, the compounds are 2′,4′-bridged nucleosides which display remarkable efficacy and bioavailability for the treatment of, for example, HCV infection in a human. In certain embodiments, the 2′,4′-bridged nucleosides are of Formula 3001: or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form or polymorphic form thereof, where PD, B, W, X, R A , R B , R C and R D are as described herein.
1. A compound according to Formula 3001:
or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form or polymorphic form thereof, wherein:
PD is
B is
R 5 is independently hydrogen, hydroxyl, hydroxylamine, halogen, sulfanyl, amino or alkoxyl;
R 6 is hydrogen or halogen;
W is —O—, —NH—, —CHF—, —CF 2 — or —CH 2 —;
X is —C(O)—, —NH—, —CR E R E — or —C(═CRR)—;
A is O or S;
each of Y and Z is independently —OR 1 , —SR 1 , —NR 1 R 2 , an N-linked or O-linked amino acid residue, wherein said amino acid is a naturally occurring or synthetic α, β, γ or δ amino acid that is in either the D or L-configuration;
R B is hydrogen, hydroxyl, fluoro, azido, amino, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, or thiol;
R A is hydrogen or cyano;
R C is alkyl, alkoxyl, or halo;
R D is hydrogen or alkyl;
each R E is independently hydrogen, fluoro, alkyl, cycloalkyl, aryl, or heteroaryl;
each R 1 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl, alkylcarbonylthioalkyl, alkoxylcarbonylalkyl, alkoxylcarbonylthioalkyl or hydroxylalkylcarbonylthioalkyl;
each R 2 is independently hydrogen or alkyl; or R 1 and R 2 , together with the atoms to which they are attached, combine to form a 3-10 membered heterocyclic ring; and
each R is independently hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl.
2. The compound of claim 1 according to formula II:
3. The compound of claim 2 , wherein B cytosine, uracil, or 5′-fluorouracil.
4. The compound of claim 1 , according to any of formulas III or IV:
or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form or polymorphic form thereof, wherein:
each Ar 1 is independently aryl or heteroaryl; and
R 3 is alkyl or branched hydroxyalkyl.
5. The compound of claim 4 , wherein R 3 is —C(CH 3 ) 2 CH 2 OH.
6. The compound of claim 1 , according to any of the following formulas:
or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form or polymorphic form thereof.
7. The compound of claim 1 according to any of the following formulas:
or a pharmaceutically acceptable salt, solvate, phosphate, stereoisomeric form, tautomeric form or polymorphic form thereof.
8. The compound of claim 1 , according to any of the following structures:
or a pharmaceutically acceptable salt, solvate, phosphate, stereoisomeric form, tautomeric form or polymorphic form thereof.
9. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient, carrier or diluent.
10. The pharmaceutical composition of claim 9 , wherein the composition is an oral formulation.
11. A method for the treatment of a host infected with a hepatitis C virus, comprising the administration of an effective treatment amount of the compound of claim 1 .
12. The method of claim 11 , wherein the host is a human.
13. The method of claim 11 , wherein the administration directs a substantial amount of the compound, or pharmaceutically acceptable salt or stereoisomer thereof, to a liver of the host.
14. The method of claim 11 , 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.
15. The method of claim 14 , wherein the second anti-viral agent is selected from the group consisting of telaprevir, bocepravir, interferon alfacon-1, interferon alfa-2b, pegylated interferon alpha 2a, pegylated interferon alpha 2b, ribavirin, and combinations thereof.
16. The method of claim 14 , wherein the second anti-viral agent is selected from the group consisting of telaprevir, bocepravir, interferon alfacon-1, interferon alfa-2b, pegylated interferon alpha 2a, pegylated interferon alpha 2b, and combinations thereof; and wherein the second anti-viral agent is administered in combination or alternation in the absence of ribavirin.