Modified 2' and 3'-nucleoside prodrugs for treating Flaviviridae infections
2′ and/or 3′ prodrugs of 1′, 2′, 3′ or 4′-branched nucleosides, and their pharmaceutically acceptable salts and derivatives are described. These prodrugs are useful in the prevention and treatment of Flaviviridae infections, including HCV infection, and other related conditions. Compounds and compositions of the prodrugs of the present invention are described. Methods and uses are also provided that include the administration of an effective amount of the prodrugs of the present invention, or their pharmaceutically acceptable salts or derivatives. These drugs may optionally be administered in combination or alteration with further anti-viral agents to prevent or treat Flaviviridae infections and other related conditions.
1 . A compound of the formula (III), (IV) or (V) or its pharmaceutically acceptable salt:
wherein:
R 1 , R 2 and R 3 are independently H; phosphate; straight chained, branched or cyclic alkyl; acyl; CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate ester; benzyl, wherein the phenyl group is optionally substituted with one or more substituents; alkylsulfonyl; arylsulfonyl; aralkylsulfonyl; a lipid; an amino acid; an amino acid residue; a carbohydrate; a peptide; cholesterol; or pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 1 , R 2 and/or R 3 is independently H or phosphate;
wherein at least one of R 2 and R 3 is not hydrogen; and
wherein:
Base is selected from the group consisting of
each R 4 and R 5 is independently hydrogen, acyl, alkyl, lower alkyl, alkenyl, alkynyl or cycloalkyl;
each W 1 , W 2 , W 3 and W 4 is independently N, CH, CF, CI, CBr, CCl, CCN, CCH 3 , CCF 3 , CCH 2 CH 3 , CC(O)NH 2 , CC(O)NHR 4 , CC(O)N(R 4 ) 2 , CC(O)OH, CC(O)OR 4 or CX 3 ;
each W* is independently O, S, NH or NR 4 ;
X is O, S, SO 2 , CH 2 , CH 2 OH, CHF, CF 2 , C(Y 3 ) 2 , CHCN, C(CN) 2 , CHR 4 or C(R 4 ) 2 ;
X* is CH, CF, CY 3 or CR 4 ;
X 2 is H, straight chained, branched or cyclic optionally substituted alkyl, CH 3 , CF 3 , C(Y 3 ) 3 , 2-Br-ethyl, CH 2 F, CH 2 Cl, CH 2 CF 3 , CF 2 CF 3 , C(Y 3 ) 2 C(Y 3 ) 3 , CH 2 OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR 4 , COO-alkyl, COO-aryl, CO-Oalkoxyalkyl, CONH 2 , CONHR 4 , CON(R 4 ) 2 , chloro, bromo, fluoro, iodo, CN, N 3 , OH, OR 4 , NH 2 , NHR 4 , NR 4 R 5 , SH or SR 5 ;
each X 3 is independently a straight chained, branched or cyclic optionally substituted alkyl, CH 3 , CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , CH 2 OH, halogenated alkyl, CF 3 , C(Y 3 ) 3 , 2-Br-ethyl, CH 2 F, CH 2 Cl, CH 2 CF 3 , CF 2 CF 3 , C(Y 3 ) 2 C(Y 3 ) 3 , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, N 3 , CN, —C(O)OH, —C(O)OR 4 , —C(O)O(lower alkyl), —C(O)NH 2 , —C(O)NHR 4 , —C(O)NH(lower alkyl), —C(O)N(R 4 ) 2 , —C(O)N(lower alkyl) 2 , OH, OR 4 , —O(acyl), —O(lower acyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), —O(alkynyl), —O(aralkyl), —O(cycloalkyl), —S(acyl), —S(lower acyl), —S(R 4 ), —S(lower alkyl), —S(alkenyl), —S(alkynyl), —S(aralkyl), —S(cycloalkyl), chloro, bromo, fluoro, iodo, NH 2 , —NH(lower alkyl), —NHR 4 , —NR 4 R 5 , —NH(acyl), —N(lower alkyl) 2 , —NH(alkenyl), —NH(alkynyl), —NH(aralkyl), —NH(cycloalkyl), or —N(acyl) 2 ;
each Y is independently selected from the group consisting of H, optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH 2 OH, CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , CH 2 F, CH 2 Cl, CH 2 N 3 , CH 2 CN, CH 2 CF 3 , CF 3 ,CF 2 CF 3 , CH 2 CO 2 R, (CH 2 ) m COOH, (CH 2 ) m COOR, (CH 2 ) m CONH 2 , (CH 2 ) m CONR 2 , and (CH 2 ) m CONHR;
R is H, alkyl or acyl;
Y 1 is hydrogen, bromo, chloro, fluoro, iodo, CN, OH, OR 4 , NH 2 , NHR 4 , NR 4 R 5 , SH or SR 4 ;
each Y 2 is independently O, S, NH or NR 4 ; and
each Y 3 is independently H, F, Cl, Br or I;
wherein for Base (B), W 4 cannot be CH if W 1 , W 2 and W 3 are N;
wherein for Base (E), (F), (K), (L), (W) and (X), W 4 cannot be CH if W 1 is N;
each R 6 is independently an optionally substituted alkyl, CH 3 , CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , CH 2 OH, halogenated alkyl, CF 3 , C(Y 3 ) 3 , 2-Br-ethyl, CH 2 F, CH 2 Cl, CH 2 CF 3 , CF 2 CF 3 , C(Y 3 ) 2 C(Y 3 ) 3 , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, —CH 2 C(O)OH, —CH 2 C(O)OR 4 , —CH 2 C(O)O(lower alkyl), —CH 2 C(O)NH 2 , —CH 2 C(O)NHR 4 , —CH 2 C(O)NH(lower alkyl), —CH 2 C(O)N(R 4 ) 2 , —CH 2 C(O)N(lower alkyl) 2 , —(CH 2 ) m C(O)OH, —(CH 2 ) m C(O)OR 4 , —(CH 2 ) m C(O)O(lower alkyl), —(CH 2 ) m C(O)NH 2 , —(CH 2 ) m C(O)NHR 4 , —(CH 2 ) m C(O)NH(lower alkyl), —(CH 2 ) m C(O)N(R 4 ) 2 , —(CH 2 ) m C(O)N(lower alkyl) 2 , —C(O)OH, —C(O)OR 4 , —C(O)O(lower alkyl), —C(O)NH 2 , —C(O)NHR 4 , —C(O)NH(lower alkyl), —C(O)N(R 4 ) 2 , —C(O)N(lower alkyl) 2 or cyano;
each R 7 is independently OH, OR 2 , optionally substituted alkyl, CH 3 , CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , CH 2 OH, halogenated alkyl, CF 3 , C(Y 3 ) 3 , 2-Br-ethyl, CH 2 F, CH 2 Cl, CH 2 CF 3 , CF 2 CF 3 , C(Y 3 ) 2 C(Y 3 ) 3 , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted heteroaryl, —CH 2 C(O)OH, —CH 2 C(O)OR 4 , —CH 2 C(O)O(lower alkyl), —CH 2 C(O)SH, —CH 2 C(O)SR 4 , —CH 2 C(O)S(lower alkyl), —CH 2 C(O)NH 2 , —CH 2 C(O)NHR 4 , —CH 2 C(O)NH(lower alkyl), —CH 2 C(O)N(R 4 ) 2 , —CH 2 C(O)N(lower alkyl) 2 , —(CH 2 ) m C(O)OH, —(CH 2 ) m C(O)OR 4 , —(CH 2 ) m C(O)O(lower alkyl), —(CH 2 ) m C(O)SH, —(CH 2 ) m C(O)SR 4 , —(CH 2 ) m C(O)S(lower alkyl), —(CH 2 ) m C(O)NH 2 , —(CH 2 ) m C(O)NHR 4 , —(CH 2 ) m C(O)NH(lower alkyl), —(CH 2 ) m C(O)N(R 4 ) 2 , —(CH 2 ) m C(O)N(lower alkyl) 2 , —C(O)OH, —C(O)OR 4 , —C(O)O(lower alkyl), —C(O)SH, —C(O)SR 4 , —C(O)S(lower alkyl), —C(O)NH 2 , —C(O)NHR 4 , —C(O)NH(lower alkyl), —C(O)N(R 4 ) 2 , —C(O)N(lower alkyl) 2 , —O(acyl), —O(lower acyl), —O(R 4 ), —O(alkyl), —O(lower alkyl), —O(alkenyl), —O(alkynyl), —O(aralkyl), —O(cycloalkyl), —S(acyl), —S(lower acyl), —S(R 4 ), —S(lower alkyl), —S(alkenyl), —S(alkynyl), —S(aralkyl), —S(cycloalkyl), NO 2 , NH 2 , —NH(lower alkyl), —NHR 4 , —NR 4 R 5 , —NH(acyl), —N(lower alkyl) 2 , —NH(alkenyl), —NH(alkynyl), —NH(aralkyl), —NH(cycloalkyl), —N(acyl) 2 , azido, cyano, SCN, OCN, NCO or halo;
alternatively, R 6 and R 7 can come together to form a spiro compound selected from the group consisting of optionally substituted carbocycle or optionally substituted heterocycle; and
each m is independently 0, 1 or 2.
2 . A method for the treatment of a host infected with a Flaviviridae virus, comprising administering an effective treatment amount of a compound or a pharmaceutically acceptable salt thereof as claimed in any one of claim 1 .
3 . The method of claim 2 , wherein the virus is hepatitis C.
4 . The method of claim 2 , wherein the compound or pharmaceutically acceptable salt thereof, is administered in combination or alternation with a second anti-viral agent.
5 . The method of claim 2 wherein the second anti-viral agent is selected from the group consisting of an interferon, a ribavirin, an interleukin, a NS3 protease inhibitor, a cysteine protease inhibitor, a phenan-threnequinone, a thiazolidine derivative, a thiazolidine, a benzanilide, a phenan-threnequinone, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a gliotoxin, a cerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation, and a ribozyme.
6 . The method of claim 2 , wherein the second ant-viral agent is an interferon.
7 . The method of claim 6 , wherein the second agent is selected from the group consisting of pegylated interferon alpha 2a, interferon alphacon-1, natural interferon, albuferon, interferon beta-1a, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta and interferon gamma-1b.
8 . The method of claim 2 , wherein the compound or pharmaceutically acceptable salt thereof, is in the form of a dosage unit.
9 . The method of claim 8 , wherein the dosage unit is a tablet or capsule.
10 . The method of claim 2 , wherein the host is a human.
11 . The compound of claim 1 , in substantially pure form.
12 . The method of claim 2 , wherein the compound is at least 90% by weight of the β-D-isomer.
13 . A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.
14 . The pharmaceutical composition of claim 13 , comprising an effective amount of the compound or a pharmaceutically acceptable salt thereof, for the treatment of a host infected with a Flaviviridae virus.
15 . The pharmaceutical composition of claim 13 , wherein the compound or a pharmaceutically acceptable salt thereof, is in the form of a dosage unit.
16 . The pharmaceutical composition of claim 13 , wherein the dosage unit contains 50 to 1000 mg of the compound.
17 . The pharmaceutical composition of claim 16 , wherein said dosage unit is a tablet or capsule.
18 . The pharmaceutical composition of claim 13 , further comprising a second anti-viral agent.
19 . The pharmaceutical composition of claim 13 , or pharmaceutically acceptable salt thereof, is in substantially pure form.
20 . The pharmaceutical composition of claim 13 , further comprising a pharmaceutically acceptable carrier suitable for systemic, topical, parenteral, inhalant or intravenous delivery.