4′-fluoro nucleosides for the treatment of HCV
AssigneesIdenix Pharmaceuticals, Inc., Centre National De La Recherche Scientifique, Universite Montpellier 2 Sciences Et Techniques
InventorsBenjamin Alexander Mayes, Adel M. Moussa, Alistair James Stewart, Gilles Gosselin
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Abstract
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 according to Formula 1501: or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form or polymorphic form thereof, wherein B, PD, RA, RB, RC, L, M and Z are as described herein.
Claims23
A compound according to Formula 1501:
- or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof, wherein:
- B is a nucleobase;
- PD is
- W is S or O;
- X Y is hydrogen, —OR1, —SR1, —NR1R2, an N-linked or O-linked amino acid residue, or an N-linked or O-linked residue of an amino acid derivative;
- Z is —H or —OH;
- or, in the alternative, X and Z, together with the atoms to which they are attached, combine to form a six-membered heterocyclic ring wherein X and Z together represent a single divalent —O—;
- Y is hydrogen, —OR1, —SR1, —NR1R2, an N-linked or O-linked amino acid residue, or an N-linked or O-linked residue of an amino acid derivative;
- RA is hydrogen, hydroxyl, alkyl, chloro, bromo, iodo, cyano, azide, alkoxyl, or thiol;
- RB is hydrogen, hydroxyl, alkyl, halo, cyano, azide, alkoxyl, or thiol;
- or, in the alternative, RA and RB, together with the atoms to which they are attached, combine to form a 3-10 membered carbocyclic or heterocyclic ring;
- RC is hydrogen or alkyl;
- L is —O— or —CH2—;
- M is —CH2—, —O—, or —S—;
- R1 at each occurrence is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
- and
- R2 at each occurrence is independently hydrogen or alkyl;
- provided that when B is uracil;
- Z and RA are each hydroxyl;
- L and M are each —O—;
- RB is methyl;
- and RC is hydrogen, then PD is other than
- and
- provided that when B is uracil or cytosine;
- Z and RA are each hydroxyl;
- L and M are each —O—;
- and RB and RC are hydrogen, then PD is other than
A method for the treatment of a host infected with a hepatitis C virus comprising administering an effective amount of a compound according to Formula 1501:
- or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof, wherein:
- B is a nucleobase;
- PD is
- W is S or O;
- X is hydrogen, —OR1, —NR1R2, an N-linked or O-linked amino acid residue, or an N-linked or O-linked residue of an amino acid derivative;
- Z is —H or —OH;
- or, in the alternative, X and Z, together with the atoms to which they are attached, combine to form a six-membered heterocyclic ring wherein X and Z together represent a single divalent —O—;
- Y is hydrogen, —OR1, —NR1R2, an N-linked or O-linked amino acid residue, or an N-linked or O-linked residue of an amino acid derivative;
- RA is hydrogen, hydroxyl, alkyl, chloro, bromo, iodo, cyano, azide, alkoxyl, or thiol;
- RB is hydrogen, hydroxyl, alkyl, halo, cyano, azide, alkoxyl, or thiol;
- or, in the alternative, RA and RB, together with the atoms to which they are attached, combine to form a 3-10 membered carbocyclic or heterocyclic ring;
- RC is hydrogen or alkyl;
- L is —O— or —CH2—;
- M is —CH2—, —O—, or —S—;
- R1 at each occurrence is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
- and
- R2 at each occurrence is hydrogen or alkyl;
- and
- provided that when:
- B is uracil or cytosine;
- Z and RA are each hydroxyl;
- L and M are each —O—;
- and RB and RC are hydrogen, then PD is other than
A compound according to Formula 1501:
- or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, wherein:
- B is a nucleobase;
- PD is
- W is S or O;
- X is hydrogen, —OR1, —SR1, —NR1R2, an N-linked or O-linked amino acid residue, or an N-linked or O-linked residue of an amino acid derivative;
- Z is —H or —OH;
- or, in the alternative, X and Z, together with the atoms to which they are attached, combine to form a six-membered heterocyclic ring wherein X and Z together represent a single divalent —O—,
- Y is hydrogen, —OR1, —SR1, —NR1R2, or an N-linked or O-linked amino acid residue or an N-linked or O-linked residue of an amino acid derivative;
- RA is hydroxyl;
- RB is hydrogen or methyl;
- RC is hydrogen or alkyl;
- L is —O— or —CH2—;
- M is —CH2—, —O— or —S—;
- R1 at each occurrence is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
- and
- R2 at each occurrence is independently hydrogen or alkyl;
- provided that when:
- B is uracil;
- Z and RA are hydroxyl;
- RB is methyl;
- and RC is hydrogen, then PD is other than
- and
- provided that when:
- B is uracil or cytosine;
- Z and RA are hydroxyl;
- and RB and RC are hydrogen, then PD is other than
Dependencies are inferred from the claim text.