Methods and compositions for treating hepatitis C virus using 4'-modified nucleosides
View Patent ↗A compound, method and composition for treating a host infected with a hepatitis C viral comprising administering an effective hepatitis C treatment amount of a described 4′-disubstituted nucleoside or a pharmaceutically acceptable salt or prodrug thereof, is provided.
1. A compound of Formula I:
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R 1 is alkyl; a, a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol
R 2 and R 3 are independently H, mono-phosphate, di-phosphate, tri-phosphate; a stabilized phosphate prodrug; acyl; alkyl; sulfonate ester; a phospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 2 and R 3 are independently H or phosphate;
Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , NR 4 R 5 or SR 4 ;
X 1 and X 2 are independently selected from the group consisting of H, alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR 4 , NR 4 NR 5 or SR 4 ; and
R 4 and R 5 are independently hydrogen, acyl, or alkyl.
2. A compound of Formula II:
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R 1 is alkyl; a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol
R 2 and R 3 are independently H, mono-phosphate, di-phosphate, tri-phosphate; a stabilized phosphate prodrug; acyl; alkyl; sulfonate ester; a phospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 2 and R 3 are independently H or phosnhate;
Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , NR 4 R 5 or SR 4 ;
X 1 is selected from the group consisting of H, alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR 4 , NR 4 NR 5 or SR 4 ; and
R 4 and R 5 are independently hydrogen, acyl, or alkyl.
3. A compound of Formula III, IV or V, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
wherein:
Base is a purine or pyrimidine base;
R 1 , R 2 and R 3 are independently H; mono-phosphate, di-phosphate, tri-phosphate, a stabilized phosphate prodrug; acyl; alkyl; sulfonate ester; a lipid, a phospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 1 , R 2 or R 3 is independently H or phosphate;
R 6 is hydroxy, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkenyl), NH(acyl), —N(lower alkyl) 2 , —N(acyl) 2 ; and
X is O, S, SO 2 or CH 2 .
4. A compound of Formula III, IV or V, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
wherein:
Base is a purine or pyrimidine base;
R 1 , R 2 and R 3 are independently hydrogen or phosphate;
R 6 is Br-vinyl; and
X is O, S, SO 2 or CH 2 .
5. A compound of Formula III, IV or V, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
wherein:
Base is a purine or pyrimidine base;
R 1 , R 2 and R 3 are hydrogens;
R 6 is Br-vinyl; and
X is O, S, SO 2 or CH 2 .
6. A compound of Formula III, IV or V, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
wherein:
Base is a purine or pyrimidine base;
R 1 , R 2 and R 3 are independently hydrogen or phosphate;
R 6 is Br-vinyl; and
X is O.
7. A compound of Formula IV, or its pharmaceutically acceptable salt or prodrug, is provided:
wherein:
Base is a purine or pyrimidine base; optionally substituted with an amine or cyclopropyl; and
R 1 and R 2 are independently mono-phosphate, di-phosphate, tri-phosphate, a stabilized phosphate prodrug; sulfonate ester; a lipid, a phospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 1 or R 2 is independently H or phosphate.
8. A compound of Formula VI, or a pharmaceutically acceptable salt or prodrug thereof:
wherein:
Base is a purine or pyrimidine base;
R 1 and R 2 are independently H; mono-phosphate, di-phosphate, tri-phosphate, a stabilized phosphate prodrug; acyl; alkyl; sulfonate ester; a lipid, a phospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 1 or R 2 independently H or phosphate;
R 6 is hydroxy, alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chloro, bromo, fluoro, iodo, NO 2 , NH 2 , —NH(lower alkyl), —NH(acyl), —N(lower alkyl) 2 , —N(acyl) 2 ;
R 7 and R 9 are independently OR 2 , hydroxy, azido, cyano, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chlorine, bromine, iodine, NO 2 , NH 2 , —NH(lower alkyl), —NH(acyl), —N(lower alkyl) 2 , —N(acyl) 2 ;
R 8 is chlorine, bromine or iodine;
R 10 is H, alkyl, chlorine, bromine or iodine; and
X is O, S, SO 2 or CH 2 .
9. A pharmaceutical composition for the treatment of a hepatitis C virus in a host, comprising an effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent, wherein:
R 1 is alkyl; a phospholipid; a carbohydrate; a peptide; an amino acid or cholesterol
R 2 and R 3 are independently H, mono-phosphate, di-phosphate, tri-phosphate; a stabilized phosphate prodrug; acyl; alkyl; sulfonate ester; a lipid a phospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 2 and R 3 are independently H or phosphate;
Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , NR 4 R 5 or SR 4 ;
X 1 and X 2 are independently selected from the group consisting of hydrogen, alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR 4 , NR 4 NR 5 or SR 4 ; and
R 4 and R 5 are independently hydrogen, acyl, or alkyl.
10. A pharmaceutical composition for the treatment of a hepatitis C virus in a host, comprising an effective amount of a compound of Formula II:
or a pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent, wherein:
R 1 is alkyl; a phospholipid; an amino acid; a carbohydrate; a peptide or cholesterol;
R 2 and R 3 are independently H, mono-phosphate, di-phosphate, tri-phosphate; a stabilized phosphate prodrug; acyl; alkyl; sulfonate ester; a lipid, a phospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 2 and R 3 are independently H or phosphate;
Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , NR 4 R 5 or SR 4 ;
X 1 is selected from the group consisting of H, alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR 4 , NR 4 NR 5 or SR 4 ; and
R 4 and R 5 are independently hydrogen, acyl, or alkyl.
11. A pharmaceutical composition for the treatment of a hepatitis C virus in a host, comprising an effective amount of a compound selected from Formulas III, IV and V, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
together with a pharmaceutically acceptable carrier or diluent, wherein:
Base is a purine or pyrimidine base;
R 1 , R 2 and R 3 are independently H; mono-phosphate, di-phosphate, tri-phosphate, a stabilized phosphate prodrug; acyl; alkyl; sulfonate ester, a lipid, a phospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 1 , R 2 or R 3 independently H or phosphate;
R 6 is hydroxy, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkenyl), NO 2 , NH 2 , —NH(lower alkyl), —NH(acyl), —N(lower alkyl) 2 , —N(acyl) 2 ; and
X is O, S, SO 2 or CH 2 .
12. A pharmaceutical composition for the treatment of a hepatitis C virus in a host, comprising an effective amount of a compound of Formula VI, or a pharmaceutically acceptable salt or prodrug thereof:
together with a pharmaceutically acceptable carrier or diluent, wherein:
Base is a purine or pyrimidine base;
R 1 and R 2 are independently H; mono-phosphate, di-phosphate, tri-phosphate, a stabilized phosphate prodrug; acyl; alkyl; sulfonate ester, a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group when administered in vivo provides a compound wherein R 1 or R 2 is independently H or phosphate;
R 6 is hydroxy, alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chloro, bromo, fluoro, iodo, NO 2 , NH 2 , —NH(lower alkyl), —NH(acyl), —N(lower alkyl) 2 , —N(acyl) 2 ;
R 7 and R 9 are independently OR 2 , hydroxy, azido, cyano, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chlorine, bromine, iodine, NO 2 , NH 2 , —NH(lower alkyl), —NH(acyl), —N(lower alkyl) 2 , —N(acyl) 2 ;
R 8 is chlorine, bromine or iodine; —R 10 is H, alkyl, chlorine, bromine or iodine; and
X is O, S, SO 2 or CH 2 .
13. A pharmaceutical composition for the treatment of a hepatitis C virus in a host, comprising an effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent, in combination with one or more other antivirally effective agents, wherein:
R 1 is alkyl; a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol;
R 2 and R 3 are independently H, mono-phosphate, di-phosphate, tri-phosphate; a stabilized phosphate prodrug; acyl; alkyl; sulfonate ester; a lipid, a phospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 2 and R 3 are independently H or phosphate;
Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , NR 4 R 5 or SR 4 ;
X 1 and X 2 are independently selected from the group consisting of H, alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chioro, bromo, fluoro, iodo, OR 4 , NR 4 NR 5 or SR 4 ; and
R 4 and R 5 are independently hydrogen, acyl, or alkyl.
14. A pharmaceutical composition for the treatment of a hepatitis C virus in a host, comprising an effective amount of a compound of Formula IV:
or a pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent, in combination with one or more other antivirally effective agents, wherein:
R 1 is alkyl; a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol
R 2 and R 3 are independently H, mono-phosphate, di-phosphate, tri-phosphate; a stabilized phosphate prodrug; acyl; alkyl; sulfonate ester; a lipid, a phospholipid; an amino acid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 2 and R 3 are independently H or phosphate;
Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , NR 4 R 5 or SR 4 ;
X 1 is selected from the group consisting of H, alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR 4 , NR 4 NR 5 or SR 4 ; and
R 4 and R 5 are independently hydrogen, acyl, or alkyl.
15. A pharmaceutical composition for the treatment of a hepatitis C virus in a host, comprising an effective amount of a compound of Formula III, IV or V, or a pharmaceutically acceptable salt or prodrug thereof, is provided:
together with a pharmaceutically acceptable carrier or diluent, in combination with one or more other antivirally effective agents wherein:
Base is a purine or pyrimidine base;
R 1 , R 2 and R 3 are independently H; phosphate mono-phosphate, di-phosphate, tr-iphosphate, a stabilized phosphate prodrug; acyl; alkyl; sulfonate ester, a lipid, a phospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 1, R 2 or R 3 is independently H or phosphate;
R 6 is hydroxy Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkenyl), NO 2 , NH 2 , —NH(lower alkyl), —NH(acyl), —N(lower alkyl) 2 , —N(acyl) 2 ; and
X is O, S, SO 2 or CH 2 .
16. A pharmaceutical composition for the treatment of a hepatitis C virus in a host, comprising an effective amount of a compound of Formula VI, or a pharmaceutically acceptable salt or prodrug thereof:
together with a pharmaceutically acceptable carrier or diluent, in combination with one or more other antivirally effective agents wherein:
Base is a purine or pyrimidine base;
R 1 and R 2 are independently H; phosphate mono-phosphate, di-phosphate, tri-phosphate, a stabilized phosphate prodrug; acyl; alkyl; sulfonate ester; a lipid, a phospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 1 or R 2 independently H or phosphate;
R 6 is hydroxy, alkyl, azido, cyano, alkenyl, alkynyl, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chloro, bromo, fluoro, iodo, NO 2 , NH 2 , —NH(lower alkyl), —NH(acyl), —N(lower alkyl) 2 , —N(acyl) 2 ;
R 7 and R 9 are independently OR 2 , hydroxy, azido, cyano, Br-vinyl, —C(O)O(alkyl), —C(O)O(lower alkyl), —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), chlorine, bromine, iodine, NO 2 , NH 2 , —NH(lower alkyl), —NH(acyl), —N(lower alkyl) 2 , —N(acyl) 2 ;
R 8 is chlorine, bromine or iodine;
R 10 is H, alkyl, chlorine, bromine or iodine; and
X is O, S, SO 2 or CH 2 .
17. The compound as described in any of the preceding claims 1 – 8 , wherein the said compound is in the form of a dosage unit.
18. The compound as described in claim 17 , wherein the dosage unit contains 10 to 1500 mg of said compound.
19. The compound as described in claim 17 or 18 , wherein said dosage unit is a tablet or capsule.
20. A compound as in claims 3 , 4 , 5 , 6 , 7 , or 8 , in which the purine or pyrimidine base is selected from the group consisting of
wherein, and L are each independently CH or N;
D is N, CH, C—CN, C—NO 2 , C—C 1-3 alkyl, C—NHCONH 2 , C—CONQ 11 Q 11 , C—CSNQ 11 Q 11 , CCOOQ 11 , C—C(═NH)NH 2 , C-hydroxy, C—C 1-3 alkoxy, C-amino, C—C 1-4 alkylamino, C—di(C 1-4 alkyl)amino, C-halogen, C—(1,3-oxazol-2-yl), C—(1,3-thiazol-2-yl), or C—(imidazol-2-yl); wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and C 1-3 alkoxy;
E is N or CQ 5 ;
W is O, S, or NR;
R is H, OH, alkyl;
Q 5 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkylamino, CF 3 , halogen, N, CN, NO 2 , NHCONH 2 , CONQ 11 Q 11 , CSNQ 11 Q 11 , COOQ 11 , C(═NH)NH 2 , hydroxy, C 1-3 alkoxy, amino, C 1-4 alkylamino, di(C 1-4 alkyl) amino, halogen, 1,3-oxazol-2-yl, 1,3-thiazol-2-yl, or imidazol-2-yl; wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and C 1-3 alkoxy;
Q 6 is H, OH, SH, NH 2 , C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 3-6 cycloalkylamino, halogen, C 1-4 alkyl, C 1-4 alkoxy, or CF 3 ;
Q 7 and Q 14 are each independently selected from the group consisting of H, CF 3 , OH, SH, OR, SR C 1-4 alkyl, amino, C 1-4 alkylamino, C 3-6 cycloalkylanilno, and di(C 1-4 alkyl)amino;
Q 11 is independently H or C 1-6 alkyl;
Q 8 is H, halogen, CN, carboxy, C 1-4 alkyloxycarbonyl, N 3 , amino, C 1-4 alkylaniino, di(C 1-4 alkyl)amino, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfonyl, (C 1-4 alkyl)0–2 aminomethyl, N, CN, NO 2 , C 1-3 alkyl, NHCONH 2 , CONQ 11 Q 11 , CSNQ 11 Q 11 , COOQ 11 , C(═NH)NH 2 , 1,3-oxazol-2-yl, 1,3-thiazol-2-yl, or imidazol-2-yl, wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and C 1-3 alkoxy.
21. A compound as in claims 3 , 4 , 5 , 6 , 7 , or 8 , in which the purine or pyrimidine base is selected from the group consisting of:
wherein:
T 1 and T 2 are independently selected from N, CH, or C-Q 16 ;
Q 16 , U, and Y are independently selected from O, H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR 4 , NR 4 R 5 or SR 5 , Br-vinyl, —O-alkyl, —O-alkenyl, —O-alkynyl, —O-aryl, —O-aralkyl, —O-acyl, —O-cycloalkyl, NH 2 , NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, CN, N 3 , COOH, CONH 2 , CO 2 -alkyl, CONH-alkyl, CON-dialkyl, OH, CF 3 , CH 2 OH, (CH 2 ) m OH, (CH 2 ) m NH 2 , (CH 2 ) m COOH, (CH 2 ) m CN, (CH 2 ) m NO 2 , (CH 2 ) m CONH 2 , C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 3-6 cycloalkylamino, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, C 1-6 alkylthio, C 1-6 alkylsulfonyl, (C 1-4 alkyl) 0-2 aminomethyl, or-NHC(═NH)NH 2 ;
R 4 and R 5 are independently selected from hydrogen, acyl, or alkyl;
m is 0–10;
Z is S, SO, SO2, C═O, or NQ 20 ;
Q 20 is H or alkyl; and
V 1 and V 2 are independently selected from CH or N.
22. A compound as in claims 3 , 4 , 5 , 6 , 7 , or 8 , in which the purine or pyrimidine base is selected from the group consiting of:
wherein:
T 3 and T 4 are independently selected from N or CQ 22 ;
Q 22 is independently selected from O, H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR 4 , NR 4 R 5 or SR 5 , Br-vinyl,—O-alkyl, —O-alkenyl, —O-alkynyl, —O-aryl, —O-aralkyl, —O-acyl, —O-cycloalkyl, NH 2 , NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, CN, N 3 , COOGH, CONH 2 , CO 2 -alkyl, CONH-alkyl, CON-dialkyl, OH, CF 3 , CH 2 OH, (CH 2 ) m OH, (CH 2 ) m NH 2 , (CH 2 ) m COOH, (CH 2 ) m CN, (CH 2 ) m NO 2 , (CH 2 ) m CONH 2 , C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 3-6 cycloalkylamino, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, C 1-6 alkylthio, C 1-6 alkylsulfonyl, (C 1-4 alkyl) 0-2 aminomethyl, or —NHC(=NH)NH 2 ;
R 4 and R 5 are independently selected from hydrogen, acyl, or alkyl;
m is 0–10;
T 5 , T 6 , T 7 , T 8 , T 9 , T 10 , T 11 , and T 12 are independently selected from N or CH;
U 2 is H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR 4 , NR 4 R 5 or SR 5 ;
Y 2 is O, S, NH, NR or CQ 24 Q 26 where R is H, OH, or alkyl;
Q 24 and Q 26 are independently selected from H, alkyl, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR 4 , NR 4 R 5 or SR 5 .
23. The pharmaceutical composition as described in any of the preceding claims 9 12 and 13 16 , wherein the said compound is in the form of a dosage unit.
24. The pharmaceutical composition as described in claim 23 , wherein the dosage unit contains 10 to 1500 mg of said compound.
25. The pharmaceutical composition as described in claim 23 , wherein said dosage unit is a tablet or capsule.
26. A compound of Formula I:
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R 1 H, mono-phosphate, di-phosphate, tri-phosphate; a stabilized phosphate prodrug; acyl; alkyl; sulfonate ester; a lipid, a phospholipid; an amino acid; a carbohydrate; a peptide; cholesterol ; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 1 is independently H or phosphate;
R 2 and R 3 are independently mono-phosphate, di-phosphate, tri-phosphate; a stabilized phosphate prodrug; a lipid, a phospholipid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 2 and R 3 are phosphate;
Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , NR 4 R 5 or SR 4 ;
X 1 and X 2 are independently selected from the group consisting of H, alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR 4 , NR 4 NR 5 or SR 4 ; and
R 4 and R 5 are independently hydrogen, acyl, or alkyl.
27. A compound of Formula II:
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R 1 is H, mono-phosphate, di-phosphate, tri-phosphate; a stabilized phosphate prodrug; acyl; alkyl; sulfonate ester; a lipid, a phospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 1 is H or phosphate;
R 2 and R 3 are independently mono-phosphate, di-phosphate, tri-phosphate; a stabilized phosphate prodrug; a lipid, a phospholipid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 2 and R 3 are phosphate;
Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , NR 4 R 5 or SR 4 ;
X 1 is selected from the group consisting of H, alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR 4 , NR 4 NR 5 or SR 4 ; and
R 4 and R 5 are independently hydrogen, acyl, or alkyl.
28. A pharmaceutical composition for the treatment of a hepatitis C virus in a host, comprising an effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent, wherein:
R 1 is H, mono-phosphate, di-phosphate, tri-phosphate; a stabilized phosphate prodrug; acyl; alkyl; sulfonate ester; a lipid, a phospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 1 is independently H or phosphate;
R 2 and R 3 are independently mono-phosphate, di-phosphate, tri-phosphate; a stabilized phosphate prodrug; a lipid, a phospholipid; a carbohydrate; a peptide; a cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 2 and R 3 are phosphate;
Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , NR 4 R 5 or SR 4 ;
X 1 and X 2 are independently selected from the group consisting of H, alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR 4 , NR 4 NR 5 or SR 4 ; and
R 4 and R 5 are independently hydrogen, acyl, or alkyl.
29. A pharmaceutical composition for the treatment of a hepatitis C virus in a host, comprising an effective amount of a compound of Formula II:
or a pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent, wherein:
R 1 is H, mono-phosphate, di-phosphate, tri-phosphate; a stabilized phosphate prodrug; acyl; alkyl; sulfonate ester; a lipid, a phospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 1 is H or phosphate;
R 2 and R 3 are independently mono-phosphate, di-phosphate, tri-phosphate; a stabilized phosphate prodrug; a lipid, a phospholipid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 2 and R 3 are phosphate;
Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , NR 4 R 5 or SR 4 ;
X 1 is selected from the group consisting of H, alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR 4 , NR 4 NR 5 or SR 4 ; and
R 4 and R 5 are independently hydrogen, acyl, or alkyl.
30. A pharmaceutical composition for the treatment of a hepatitis C virus in a host, comprising an effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent, in combination with one or more other antivirally effective agents, wherein:
R 1 is H, mono-phosphate, di-phosphate, tri-phosphate; a stabilized phosphate prodrug; acyl; alkyl; sulfonate ester; a lipid, a phospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 1 is independently H or phosphate;
R 2 and R 3 are independently mono-phosphate, di-phosphate, tri-phosphate; a stabilized phosphate prodrug; a lipid, a phospholipid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 2 and R 3 are phosphate;
Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , NR 4 R 5 or SR 4 ;
X 1 and X 2 are independently selected from the group consisting of H, alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR 4 , NR 4 NR 5 or SR 4 ; and
R 4 and R 5 are independently hydrogen, acyl, or alkyl.
31. A pharmaceutical composition for the treatment of a hepatitis C virus in a host, comprising an effective amount of a compound of Formula II:
or a pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent, in combination with one or more other antivirally effective agents, wherein:
R 1 is H, mono-phosphate, di-phosphate, tri-phosphate; a stabilized phosphate prodrug; acyl; alkyl; sulfonate ester; a lipid, a phospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 1 is H or phosphate;
R 2 and R 3 are independently mono-phosphate, di-phosphate, tri-phosphate; a stabilized phosphate prodrug; a lipid, a phospholipid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group that when administered in vivo provides a compound wherein R 2 and R 3 are phosphate;
Y is hydrogen, bromo, chloro, fluoro, iodo, OR 4 , NR 4 R 5 or SR 4 ;
X 1 is selected from the group consisting of H, alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, chloro, bromo, fluoro, iodo, OR 4 , NR 4 NR 5 or SR 4 ; and
R 4 and R 5 are independently hydrogen, acyl, or alkyl.