3′-azido purine nucleotide prodrugs for treatment of viral infections
The present invention is directed to compounds, compositions and methods for treating or preventing viral infections, in particular, HIV, and HBV, in human patients or other animal hosts. The compounds are 3′-azido-2′,3′-dideoxy purine monophosphates, and pharmaceutically acceptable, salts, prodrugs, and other derivatives thereof. In particular, the compounds show potent antiviral activity against HIV-1 and HBV.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt, wherein:
R 5 is selected from the group consisting of halogen, N(R′) 2 , OCOR′, NHCOR′, N(COR′)COR′, SCOR′, OCOOR′, and NHCOOR′,
each R′ is independently H, a lower alkyl (C 1 -C 6 ), lower haloalkyl (C 1 -C 6 ), lower alkoxy (C 1 -C 6 ), lower alkenyl (C 2 -C 6 ), lower alkynyl (C 2 -C 6 ), lower cycloalkyl (C 3 -C 6 ) aryl, heteroaryl, alkylaryl, or arylalkyl, wherein the groups can be substituted with one or more hydroxyalkyl, aminoalkyl, or alkoxyalkyl substituents,
R 3 and R 4 are independently:
(a) OR 1 where R 1 is H, C 1-20 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, aryl, or heteroaryl optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, (CH 2 ) 1-6 CO 2 R 1a , halogen, C 1-6 haloalkyl, —N(R 1a ) 2 , C 1-6 acylamino, —NHSO 2 C 1-6 alkyl, —SO 2 N(R 1a ) 2 , —SO 2 C 1-6 alkyl, COR 1b , nitro and cyano;
R 1a is independently H or C 1-6 alkyl;
R 1b is —OR 1a or —N(R 1a ) 2 ;
(b)
where R 2a and R 2b are:
(i) independently selected from the group consisting of H, C 1-10 alkyl, —(CH 2 ) r NR 1a 2 , C 1-6 hydroxyalkyl, —CH 2 SH, —(CH 2 ) 2 S (O) p Me, —(CH 2 ) 3 NHC(═NH)NH 2 , (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, —(CH 2 ) m COR 1b , aryl and aryl-C 1-3 alkyl, said aryl groups optionally substituted with a group selected from the group consisting of hydroxyl, C 1-10 alkyl, C 1-6 alkoxy, halogen, nitro, and cyano;
(ii) R 2a is H and R 2b and R 8 together are (CH 2 ) 2-4 to form a ring that comprises the adjoining N and C atoms;
(iii) R 2a and R 2b together are (CH 2 ) n to form a ring;
(iv) R 2a and R 2b both are C 1-6 alkyl; or
(v) R 2a is H and R 2b is H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 Ph, CH 2 -indol-3-yl, —CH 2 CH 2 SCH 3 , CH 2 CO 2 H, CH 2 C(O)NH 2 , CH 2 CH 2 COOH, CH 2 CH 2 C(O)NH 2 , CH 2 CH 2 CH 2 CH 2 NH 2 , CH 2 CH 2 CH 2 NHC(NH)NH 2 , CH 2 -imidazol-4-yl, CH 2 OH, CH(OH)CH 3 , CH 2 ((4′-OH)-Ph), CH 2 SH, or lower cycloalkyl;
p is 0 to 2;
r is 1 to 6;
n is 4 or 5;
m is 0 to 3
R 7 is H, C 1-10 alkyl, C 1-10 alkyl optionally substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, halogen, C 3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl;
R 8 is H, C 1-3 alkyl, R 2a or R 2b and R 8 together are (CH 2 ) 2-4 so as to form a ring that comprises the adjoining N and C atoms;
(c) OH, an O attached lipid or phospholipid, an N or O attached peptide, an O attached cholesterol, or an O attached phytosterol;
(d) R 3 and R 4 may come together to form a ring
where W 2 is selected from the group consisting of phenyl, optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkyl, CF 3 , C 2-6 alkenyl, C 1-6 alkoxy, OW 1c , CO 2 R 1a , COR 1a , halogen, C 1-6 haloalkyl, —N(R 1a ) 2 , C 1-6 acylamino, CO 2 N(R 1a ) 2 , SR 1a , —NHSO 2 C 1-6 alkyl, —SO 2 N(R 1a ) 2 , —SO 2 C 1-6 alkyl, COR 1b , and cyano, and wherein said monocyclic heteroaryl and substituted monocyclic heteroaryl has 1-2 heteroatoms that are independently selected from the group consisting of N, O, and S with the provisos that:
a) when there are two heteroatoms and one is O, then the other can not be O or S, and
b) when there are two heteroatoms and one is S, then the other can not be O or S;
R 1a is independently H or C 1-6 alkyl;
R 1b is —OR 1a or —N(R 1a ) 2 ;
(e)
where R 9 is selected from the group consisting of H, C 1-10 alkyl, and C 1-10 alkyl optionally substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, halogen, C 3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl;
R 1c is H or C 1-6 acyl; or
(f) R 3 and R 4 may come together to form a ring
where R 2b is: (i) independently selected from the group consisting of H, C 1-10 alkyl, —(CH 2 ) r NR 1a 2 , C 1-6 hydroxyalkyl, —CH 2 SH, —(CH 2 ) 2 S(O) p Me, —(CH 2 ) 3 NHC(═NH)NH 2 , (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, —(CH 2 ) m COR 1b , aryl and aryl-C 1-3 alkyl, said aryl groups optionally substituted with a group selected from the group consisting of hydroxyl, C 1-10 alkyl, C 1-6 alkoxy, halogen, nitro, and cyano; (ii) R 2b is H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 Ph, CH 2 -indol-3-yl, —CH 2 CH 2 SCH 3 , CH 2 CO 2 H, CH 2 C(O)NH 2 , CH 2 CH 2 COOH, CH 2 CH 2 C(O)NH 2 , CH 2 CH 2 CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , CH 2 -imidazol-4-yl, CH 2 OH, CH(OH)CH 3 , CH 2 ((4′-OH)-Ph), CH 2 SH, or lower cycloalkyl;
p is 0 to 2;
r is 1 to 6;
m is 0 to 3
A is NR 1a , O, or S
B is C 1-10 alkyl, C 1-6 hydroxyalkyl, aryl and aryl-C 1-3 alkyl, heteroaryl or heteroaryl-C 1-3 alkyl, said aryl and heteroaryl groups optionally substituted with a group selected from the group consisting of hydroxyl, C 1-10 alkyl, C 1-6 alkoxy, and halogen,
R 7 is H, C 1-10 alkyl, C 1-10 alkyl optionally substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, halogen, C 3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl;
R 8 is H, C 1-3 alkyl, R 2a or R 2b and R 8 together are (CH 2 ) 2-4 so as to form a ring that comprises the adjoining N and C atoms;
W is N, CH, CF, CCN, CC≡CH, or CC(O)N(R′) 2 ;
Y is O or S; and
Z is CH 2 CH 2 , CH 2 O, or OCH 2 .
2. The compounds of claim 1 , wherein R 5 is selected from the group consisting of NH 2 , dimethylamine, methyl-allyl-amine, methoxy, chloro, cyclopropylamine, 5-hydroxy-pentylamine, 1,1-dimethyl-ethanolamine, and 2-methoxy-ethylamine.
3. The compounds of claim 1 , wherein the compounds are 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 reducing the biological activity of an HIV-1 or HIV-2 infection in a host, comprising administering an effective amount of a compound of claim 1 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. A method for treating a host infected with HIV-1 or HIV-2 that includes administering an effective amount of a compound of claim 1 to a patient in need of treatment thereof in a pharmaceutically acceptable carrier in combination with another anti-HIV agent.
8. The method of claim 7 , 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.
9. 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.
10. A method for reducing the biological activity of an HBV infection in a host, comprising administering an effective amount of a compound of claim 1 to a patient in need of treatment thereof.
11. A method for treating a host infected with HBV that includes administering an effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier in combination with another anti-HBV agent.
12. The compound of claim 1 , having the formula:
or a pharmaceutically acceptable salt thereof.
13. A method for treating a host infected with HIV-1 or HIV-2, comprising administering an effective amount of a compound of claim 12 to a patient in need of treatment thereof.
14. The method of claim 13 , wherein the compound is administered in combination with another anti-HIV agent.