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 formula (XIX), (XX), (XXI) (XXII) or (XXIII):
or a pharmaceutically acceptable salt thereof, wherein:
A is selected from the group consisting of 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;
Y is 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 ) n CONHR;
R is H, alkyl or acyl;
X is selected from the group consisting of-OH, optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, —O-alkyl, —O-alkenyl, —O-alkynyl, —O-aryl, —O-aralkyl, —O-cycloalkyl-, O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO 2 , NH 2 , N 3 , NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aryl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aryl, S-aralkyl, S-acyl, S-cycloalkyl, CO 2 -alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, 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 , (CH 2 ) m CONHR, an optionally substituted 3-7 membered carbocyclic, and an optionally substituted 3-7 membered heterocyclic ring having O, S and/or N independently as a heteroatom taken alone or in combination;
m is 0 or 1;
R 3 is selected from the group consisting of H; mono-, di-, and tri-phosphate or a stabilized phosphate prodrug; substituted or unsubstituted alkyl; acyl; a sulfonate ester; optionally substituted alkyl sulfonyl; optionally substituted arylsulfonyl; a lipid; an amino acid; a carbohydrate; a peptide; cholesterol; and a pharmaceutically acceptable leaving group which when administered in vivo is capable of providing a compound wherein R 3 is independently H, or mono-, di- or triphosphate; and
Base is a non-natural base selected from the group of:
wherein:
each R′, R″, R′″ and R″″ is independently selected from the group consisting of H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, 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, F, Cl, Br, I, CN, 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 and (CH 2 ) m CONH 2 ;
m is 0 or 1;
W is C—R″ or N;
T and V independently are CH or N;
Q is CH, —CCl, —CBr, —CF, —CI, —CCN, —C—COOH, —C—CONH 2 , or N;
Q 1 and Q 2 independently are N or C—R″″; and
Q 3 , Q 4 , Q 5 and Q 6 independently are N or CH;
with the proviso that in bases (g) and (i), R′, R″″ are not H, OH, or NH 2 ; and Q, T, V, Q 2 , Q 5 and Q 6 are not N.
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.