AZIDO PURINE NUCLEOSIDES FOR TREATMENT OF VIRAL INFECTIONS
The present invention is directed to compounds, compositions and methods for treating or preventing viral infections, in particular, HIV, HBV, and HCV, in human patients or other animal hosts. The compounds are 3′-azido-2′,3′-dideoxy purine nucleosides or phosphonates, and pharmaceutically acceptable, salts, prodrugs, and other derivatives thereof. In particular, the compounds show potent antiviral activity against HIV-1 resistance mutants including HIV-1 K65R , HTV-1 K70E , HIV-1 L74V , HIV-1 M184V , HIV-1 Q151M and inhibitory activity against HIV-1 RT harboring TAMS or insertion mutations including HIV-1 AZT3 , HIV-1 AZT7 , HIV-1 AZT9 , HIV-1 Q151M , or HIV-1 69insertion . In one embodiment, the compounds are 3′-azido-ddA, 3′-azido-ddG, or combinations thereof, administered with one or more additional antiviral agents that select for TAM mutations and/or the M 184V mutation, along with a pharmaceutically acceptable carrier.
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
X is O, CH 2 , S, SO 2 , NH, P═O(OH), C═CH 2 , C═CHF, or C═CF 2 ;
R 1 is hydrogen, alkyl, haloalkyl (including CH 2 F, CF 3 ), halo, azido, cyano, nitro, amino, alkylamino, dialkylamino, alkenyl, alkynyl, haloalkenyl (including Br-vinyl), alkoxy, alkenoxy, alkylthio, acyloxy, alkyloxyacyl, alkylcarbonyl, acylthio, or acylamino;
R 2 is H, phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug), phosphothioate, carbonyl substituted with an alkyl (including C 1 -C 6 ), alkenyl (including C 2 -C 6 ), alkynyl (including C 2 -C 6 ), aryl (including C 6 -C 10 ), or other pharmaceutically acceptable leaving group, which, when administered in vivo, is capable of providing a compound wherein R 2 is H or phosphate, sulfonate ester (including alkyl or arylalkyl sulfonyl), benzyl (wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl given above), a lipid (including a phospholipid), an amino acid, a peptide, or cholesterol,
wherein the Base is purine or modified purine of the general formula (III):
wherein:
each W, W 1 , W 2 and W 3 is independently N, CH, CF, CCl, CBr, CI, CCN, CCH 3 , CCF 3 , CC(O)NH 2 , CC(O)NHR′, CC(O)N(R′) 2 , CC(O)OH, CC(O)OR′ or CR 5 ;
each R 5 and R 6 is chosen independently from H, halogen, CN, N 3 , NO 2 , OH, NH 2 , SH, OR′, NHR′, N(R′) 2 , SR′, OCOR′, NHCOR′, N(COR′)COR′, SCOR′, OCOOR′, NHCOR′, CH 2 OH, CH 2 CN, CH 2 N 3 , COOH, COOR′, CONH 2 , CONHR, CON(R′) 2 , CH 2 COOH, CH 2 COOR′, CH 2 CONH 2 , CH 2 CONHR′, CH 2 CON(R′) 2 , C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, heteroaryl, acyl, arylalkyl, and alkylaryl;
with the proviso that if R 1 and R 2 are H, W is CH, W 1 , W 2 and W 3 are N, and R 6 is NH 2 or NHR 7 where R 7 is acyl then R 5 cannot be Cl, Br, I, C 1-6 alkyloxy, C 3-6 cycloalkyloxy, aryloxy, arylalkoxy, amino which is substituted by one or two substituents independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, or 4 to 6 membered heterocyclic ring containing at least one nitrogen atom which ring is bonded to the purine base via the nitrogen atom; and
with the proviso wherein for formula (I) where base is formula (III), R 6 cannot be NH 2 when R 5 is OH and R 6 cannot be H when R 5 is NH 2 , if R 1 and R 2 are H, W is CH, W 1 , W 2 and W 3 are N; and
each R′ is independently a lower alkyl (C 1 -C 6 alkyl), lower alkenyl, lower alkynyl, lower cycloalkyl (C 3 -C 6 cycloalkyl) aryl, alkylaryl, or arylalkyl, wherein the groups can be substituted with one or more substituents as defined above, for example, hydroxyalkyl, aminoalkyl, and alkoxyalkyl, or
Base is a purine or modified purine of the general formula (IV):
wherein:
each W, W 2 and W 3 is independently N, CCF 3 , CC(O)NH 2 , CC(O)NHR′, CC(O)N(R′) 2 , CC(O)OH, CC(O)OR′ or CR 5 ;
W 4 is independently O, S, NH or NR′;
each R 5 and R 6 is chosen independently from H, halogen, CN, N 3 , NO 2 , OH, NH 2 , SH, OR′, NHR′, N(R′) 2 , SR′, OCOR′, NHCOR′, N(COR′)COR′, SCOR′, OCOOR′, NHCOR′, CH 2 OH, CH 2 CN, CH 2 N 3 , COOH, COOR′, CONH 2 , CONHR, CON(R′) 2 , CH 2 COOH, CH 2 COOR′, CH 2 CONH 2 , CH 2 CONHR′, CH 2 CON(R′) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, heteroaryl, acyl, arylalkyl, and alkylaryl; and
each R′ is independently a C 1-6 alkyl, C 3-6 cycloalkyl, aryl, alkylaryl, or arylalkyl.
2 . A compound of Formula (II):
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
X is O, CH 2 , S, SO 2 , NH, P═O(OH), C═CH 2 , C═CHF, or C═CF 2 ;
Y is O or S;
Z is CH 2 , CH 2 CH 2 , CH 2 O, CH 2 S, or CH 2 NH (wherein a carbon atom is connected to a phosphorus atom);
R 1 is hydrogen, alkyl, haloalkyl, halo, azido, cyano, nitro, amino, alkylamino, dialkylamino, alkenyl, alkynyl, haloalkenyl, alkoxy, alkenoxy, alkylthio, acyloxy, alkyloxyacyl, alkylcarbonyl, acylthio, or acylamino;
R 3 and R 4 are, independently, hydrogen, phosphate, diphosphate, or a group that is preferentially removed in a hepatocyte to yield the corresponding H group, wherein the term “preferentially removed in a hepatocyte” means that at least part of the group is removed in a hepatocyte at a rate higher than the rate of removal of the same group in a non-hepatocytic cell, or the removable group is a pharmaceutically acceptable group that can be removed by a reductase, esterase, cytochrome P450 or other enzyme;
wherein the Base is purine or modified purine of the general formula (III):
wherein:
each W, W 1 , W 2 and W 3 is independently N, CH, CF, CCl, CBr, CI, CCN, CCH 3 , CCF 3 , CC(O)NH 2 , CC(O)NHR′, CC(O)N(R′) 2 , CC(O)OH, CC(O)OR′ or CR 5 ;
each R 5 and R 6 is chosen independently from H, halogen (F, Cl, Br, I), CN, N 3 , NO 2 , OH, NH 2 , SH, OR′, NHR′, N(R′) 2 , SR′, OCOR′, NHCOR′, N(COR′)COR′, SCOR′, OCOOR′, NHCOR′, CH 2 OH, CH 2 CN, CH 2 N 3 , COOH, COOR′, CONH 2 , CONHR, CON(R′) 2 , CH 2 COOH, CH 2 COOR′, CH 2 CONH 2 , CH 2 CONHR′, CH 2 CON(R′) 2 , C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, heteroaryl, acyl, arylalkyl, and alkylaryl;
each R′ is independently a C 1-6 alkyl, C 3-6 cycloalkyl, aryl, alkylaryl, or arylalkyl, or
wherein the Base is purine or modified purine of the general formula (IV):
wherein:
each W, W 2 and W 3 is independently N, CH, CF, CCl, CBr, CI, CCN, CCH 3 , CCF 3 , CC(O)NH 2 , CC(O)NHR′, CC(O)N(R′) 2 , CC(O)OH, CC(O)OR′ or CR 5 ;
W 4 is independently O, S, NH or NR′;
each R 5 and R 6 is chosen independently from H, halogen, CN, N 3 , NO 2 , OH, NH 2 , SH, OR′, NHR′, N(R′) 2 , SR′, OCOR′, NHCOR′, N(COR′)COR′, SCOR′, OCOOR′, NHCOR′, CH 2 OH, CH 2 CN, CH 2 N 3 , COOH, COOR′, CONH 2 , CONHR, CON(R′) 2 , CH 2 COOH, CH 2 COOR′, CH 2 CONH 2 , CH 2 CONHR′, CH 2 CON(R′) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, heteroaryl, acyl, arylalkyl, and alkylaryl;
each R′ is independently a C 1-6 alkyl, C 3-6 cycloalkyl, aryl, alkylaryl, or arylalkyl.
3 . The compound of claim 1 , wherein the compound is in the β-L- or β-D configuration, or a racemic mixture thereof.
4 . A method for treating a host infected with HIV-1 or HIV-2, comprising administering an effective amount of a compound of claim 1 to a patient in need of treatment thereof.
5 . A method for treating an HIV-1 or HIV-2 infection, comprising administering an effective amount of a compound of claim 2 to a patient in need of treatment thereof.
6 . The method of claim 4 , wherein the HIV-1 or HIV-2 infection is caused by a virus comprising a mutation selected from the group consisting of TAM mutations and the M184V mutation.
7 . The method of claim 5 , wherein the HIV-1 or HIV-2 infection is caused by a virus comprising a mutation selected from the group consisting of TAM mutations and the M184V mutation.
8 . The method of claim 4 , wherein the compound of claim 1 is administered in a pharmaceutically acceptable carrier in combination with another anti-HIV agent.
9 . The method of claim 5 , wherein the compound of claim 2 is administered in a pharmaceutically acceptable carrier in combination with another anti-HIV agent.
10 . The compound of claim 2 , wherein the compound is in the β-L- or β-D configuration, or a racemic mixture thereof.
11 . A method for treating a host infected with HBV, comprising administering an effective amount of a compound of claim 1 to a patient in need of treatment thereof.
12 . A method for treating an HBV infection, comprising administering a phrophylactically effective amount of a compound of claim 2 to a patient in need of treatment thereof.
13 . The method of claim 11 , wherein the compound is administered in a pharmaceutically acceptable carrier in combination with another anti-HBV agent.
14 . The method of claim 12 , wherein the compound is administered in a pharmaceutically acceptable carrier in combination with another anti-HBV agent.
15 - 18 . (canceled)
19 . A method of treating an HIV-1 of HIV-2 infection, comprising administering an effective treatment amount of 3′-azido-ddA, 3′-azido-ddG, or combinations thereof, in combination with one or more additional antiviral agents, where the one or more additional antiviral agents select for TAM mutations and/or for the M184V mutation.
20 . A pharmaceutical composition, comprising 3′-azido-ddA, 3′-azido-ddG, or combinations thereof, and one or more additional antiviral agents that select for TAM mutations and/or the M184V mutation, along with a pharmaceutically acceptable carrier.