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 (XIII) or (XIV):
or a pharmaceutically acceptable salt thereof, wherein:
R 3 is selected from the group consisting of H; mono-, di-, and tri-phosphate or a stabilized phosphate prodrug; 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;
B indicates a spiro compound selected from the group consisting of optionally substituted carbocycle or optionally substituted heterocycle;
Base is selected from the group consisting of:
wherein
each R′, R″, R″′ and R″″ are 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, —Cl, —CCN, —C—COOH, —C—CONH 2 , or N;
Q 1 and Q 2 independently are N or C—R;
R is H, alkyl, or acyl; and
Q 3 , Q 4 , Q 5 and Q 6 independently are N or CH.
2 . A compound of claim 1 , wherein B is a 3-7 membered carbocyclic ring.
3 . A compound of claim 1 , wherein B is a 3-7 membered heterocyclic ring having one or more O, S and/or N atoms.
4 . A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.
5 . A method for the treatment of a host infected with a hepatitis C virus, comprising administering an effective treatment amount of a compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof.
6 . The method of claim 5 , wherein the compound or pharmaceutically acceptable salt thereof is administered in combination or alternation with a second anti-viral agent.
7 . The method of claim 6 , 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.
8 . The method of claim 7 , wherein the second anti-viral agent is an interferon.
9 . The method of claim 8 , wherein the second anti-viral 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.
10 . The method of claim 5 , wherein the compound or pharmaceutically acceptable salt thereof is in the form of a dosage unit.
11 . The method of claim 10 , wherein the dosage unit contains 50 to 1000 mg or 0.1 to 50 mg of the compound.
12 . The method of claim 10 , wherein the dosage unit is a tablet or capsule.
13 . The method of claim 5 , wherein the host is a human.