2′,3′-dideoxynucleoside analogues for the treatment or prevention of Flaviviridae infections
AssigneesPharmasset, Inc., Leland Stanford Junior University, Emory University
InventorsRaymond Schinazi, Robert Striker, Junxing Shi
Life of this patent
Estimating the term…
Abstract
A method for the treatment or prevention of Flaviviridae infections, in particular, hepatitis C virus infection, in a host, and in particular, a human, is provided that includes administering an effective amount of a β-L- or β-D-2′,3′-dideoxynucleoside or a pharmaceutically acceptable salt or prodrug thereof, optionally in a pharmaceutically acceptable diluent or excipient.
Claims26
A pharmaceutical composition for the treatment of an HCV infection in a host, comprising an effective treatment amount of a 2′,3′-dideoxynucleoside of the formula:
- or a pharmaceutically acceptable salt thereof, wherein
- (i) X is S═O, SO2, NR1, N+R1R2, CHF or CR3R4;
- R1 and R2 are independently C2-6 alkenyl, C2-6 alkynyl, or C3-8 cycloalkyl;
- R3 and R4 are independently hydrogen, halogen (F, Cl, Br, or I), OH or OR5, with the proviso that R3 and R4 are not both hydrogen;
- R5 is hydrogen, an alkyl, an acyl, or a silyl;
- (ii) Y is NH2, NHR6, NR6R7, OH or OR8
- each R6, R7 and R7 is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, cyclopropyl, or C2-6 acyl;
- (iii) Z is chosen from hydrogen, halogen (F, Cl, Br, or I), C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, CN, CF3, N3, NO2, aryl, heteroaryl and COR9;
- R9 is chosen from H, OH, SH, C1-6 alkyl, C1-6 aminoalkyl, C1-6 alkoxy and C1-6 thioalkyl;
- and
- (iv) R is phosphate;
- acyl;
- —C(O)R10, alkyl;
- sulfonate ester;
- sulfonyl;
- a lipid;
- an amino acid;
- a carbohydrate;
- a peptide;
- a cholesterol;
- or other pharmaceutically acceptable leaving group;
- R10 is a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, monophosphate, diphosphate, triphosphate, or —P(O)(OR11)2;
- each R11 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or a hydroxyl-protecting group;
- together with pharmaceutically acceptable carrier.
A pharmaceutical composition for the treatment of an HCV infection in a host, comprising an effective amount of a compound of the formula:
- or a pharmaceutically acceptable salt, wherein
- Z′ is CF3 or N3;
- together with a pharmaceutically acceptable carrier.
A pharmaceutical composition for the treatment of an HCV infection in a host, comprising an effective amount of a compound of the formula:
- or a pharmaceutically acceptable salt thereof, wherein
- (i) R6 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, cyclopropyl, or C2-6 acyl;
- and
- (ii) R is hydrogen, phosphate, acyl, —C(O)R10, alkyl, sulfonate ester, sulfonyl, a lipid, an amino acid, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group;
- (iii) Z′ is CF3 or N3;
- together with a pharmaceutically acceptable carrier.
A pharmaceutical composition for reducing the biological activity of a Flaviviridae viral infection in a host comprising an effective amount of a 2′,3′-dideoxynucleoside of the formula:
- or a pharmaceutically acceptable salt thereof, wherein
- (i) X is S═O, SO2, NR1, N+R1R2, CHF or CR3R4;
- R1 and R2 are independently C2-6 alkenyl, C2-6 alkynyl, or C3-8 cycloalkyl;
- R3 and R4 are independently hydrogen, halogen (F, Cl, Br, or I), OH or OR5, with the proviso that R3 and R4 are not both hydrogen;
- R5 is hydrogen, an alkyl, an acyl, or a silyl;
- (ii) Y is NH2, NHR6, NR6R7, OH or OR8
- each R6, R7 and R7 is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, cyclopropyl, or C2-6 acyl;
- (iii) Z is chosen from hydrogen, halogen (F, Cl, Br, or I), C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, CN, CF3, N3, NO2, aryl, heteroaryl and COR9;
- R9 is chosen from H, OH, SH, C1-6 alkyl, C1-6 aminoalkyl, C1-6 alkoxy and C1-6 thioalkyl;
- and
- (iv) R is phosphate;
- acyl;
- —C(O)R10, alkyl;
- sulfonate ester;
- sulfonyl;
- a lipid;
- an amino acid;
- a carbohydrate;
- a peptide;
- a cholesterol;
- or other pharmaceutically acceptable leaving group;
- R10 is a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, monophosphate, diphosphate, triphosphate, or —P(O)(OR11)2;
- each R11 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or a hydroxyl-protecting group;
- together with a pharmaceutically acceptable carrier.
A pharmaceutical composition for reducing the biological activity of a Flaviviridae viral infection in a host comprising an effective amount of a compound of the formula:
- or a pharmaceutically acceptable salt thereof, wherein
- Z′ is CF3 or N3;
- together with a pharmaceutically acceptable carrier.
A pharmaceutical composition for reducing the biological activity of a Flaviviridae viral infection in a host comprising an effective amount of a compound of the formula:
- or a pharmaceutically acceptable salt thereof, wherein
- (i) R6 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, cyclopropyl, or C2-6 acyl;
- and
- (ii) R is phosphate;
- acyl;
- —C(O)R10, alkyl;
- sulfonate ester;
- sulfonyl;
- a lipid;
- an amino acid;
- a carbohydrate;
- a peptide;
- a cholesterol;
- or other pharmaceutically acceptable leaving group;
- (iii) Z′ is CF3 or N3;
- together with a pharmaceutically acceptable carrier.
Dependencies are inferred from the claim text.