Nucleoside phosphoramidate prodrugs
View Patent ↗Disclosed herein are phosphoramidate prodrugs of nucleoside derivatives for the treatment of viral infections in mammals, which is a compound, its stereoisomer, salt (acid or basic addition salt), hydrate, solvate, or crystalline form thereof, represented by the following structure: Also disclosed are methods of treatment, uses, and processes for preparing each of which utilize the compound represented by formula I.
1. A compound represented by formula:
wherein
R 1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, or a substituted or unsubstituted phenyl, where the substitutent of the substituted phenyl is CH 3 , OCH 3 , F, Cl, Br, I, nitro, cyano, or a CH 3-q X q , where X is F, Cl, Br, or I, and q is 1-3;
R 2 is hydrogen or CH 3;
R 3a is H and R 3b is H, CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 -phenyl, 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)-phenyl), CH 2 SH, or lower cycloalkyl, or
R 3a is CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 -phenyl, 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)-phenyl), CH 2 SH, or lower cycloalkyl and R 3b is H;
R 4 is hydrogen, CH 3 , ethyl, i-propyl, n-propyl, n-butyl, 2-butyl, tert-butyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl; and
R 7 and R 8 are independently H, F, Cl, Br, I, OH, OCH 3 , SH, SCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , CH 3 , CH 3-q X q , where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO 2 H, CO 2 CH 3 , CONH 2 , CONHCH 3 , or CON(CH 3 ) 2 .
2. The compound according to claim 1 , wherein:
R 1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromophenyl, p-chlorophenyl, or p-fluorophenyl;
R 3a is H; and
R 3b is H, CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 -phenyl, 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)-phenyl), CH 2 SH, or lower cycloalkyl.
3. The compound according to claim 1 , wherein:
R 1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromophenyl, p-chlorophenyl, or p-fluorophenyl;
R 3a is H;
R 3b is H, CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 -phenyl, or lower cycloalkyl; and
R 7 and R 8 are independently H, F, Br, SCH 3 , CH 3 , CH 3-q X q , where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO 2 CH 3 , CONH 2 , CONHCH 3 , or CON(CH 3 ) 2 .
4. The compound according to claim 1 , wherein:
R 1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromophenyl, p-chlorophenyl, or p-fluorophenyl;
R 2 is hydrogen;
R 3a is H;
R 3b is H, CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 -phenyl, or lower cycloalkyl; and
R 7 and R 8 are independently H, F, Br, SCH 3 , CH 3 , CH 3-q X q , where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO 2 CH 3 , CONH 2 , CONHCH 3 , or CON(CH 3 ) 2 .
5. The compound according to claim 1 , wherein:
R 1 is hydrogen, methyl, phenyl, p-bromophenyl, p-chlorophenyl, or p-fluorophenyl;
R 2 is hydrogen;
R 3a is H;
R 3b is H, CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 -phenyl, or lower cycloalkyl; and
R 7 and R 8 are independently H, F, Br, SCH 3 , CH 3 , CH 3-q X q , where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO 2 CH 3 , CONH 2 , CONHCH 3 , or CON(CH 3 ) 2 .
6. A composition comprising the compound according to claim 1 .
7. A composition comprising the compound according to claim 1 and a pharmaceutically acceptable medium.
8. A composition comprising an effective amount of the compound according to claim 1 to treat a hepatitis C virus infection and a pharmaceutically acceptable medium.
9. A method of treating a subject infected by a virus selected from among hepatitis C virus, West Nile virus, yellow fever virus, dengue virus, rhinovirus, polio virus, hepatitis A virus, bovine viral diarrhea virus or Japanese encephalitis virus, which comprises administering to the subject an effective amount of the compound according to claim 1 .
10. The method of claim 9 , wherein the virus is hepatitis C virus.
11. The method of claim 10 , which further comprises administering to the subject an effective amount of another antiviral agent.
12. The method of claim 10 , wherein the subject is a human.
13. The method of claim 11 , wherein:
R 1 is phenyl;
R 2 is hydrogen;
R 3a is H;
R 3b is CH 3 ;
R 4 is i-propyl; and
R 7 and R 8 are both H.
14. The method of claim 12 , wherein:
R 1 is phenyl;
R 2 is hydrogen;
R 3a is H;
R 3b is CH 3 ;
R 4 is i-propyl; and
R 7 and R 8 are both H.
15. A compound represented by formula:
wherein
R 1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, or a substituted or unsubstituted phenyl, where the substitutent of the substituted phenyl is CH 3 , OCH 3 , F, Cl, Br, I, nitro, cyano, or a CH 3-q X q , where X is F, Cl, Br, or I, and q is 1-3;
R 2 is hydrogen or CH 3 ;
R 3a is H and R 3b is H, CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 -phenyl, 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, or
R 3a is CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 -phenyl, 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)-phenyl), CH 2 SH, or lower cycloalkyl and R 3b is H;
R 4 is hydrogen, CH 3 , ethyl, i-propyl, n-propyl, n-butyl, 2-butyl, tert-butyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-lower alkyl; and
R 7 and R 8 are independently H, F, Cl, Br, I, OH, OCH 3 , SH, SCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , CH 3 , CH 3-q X q , where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO 2 H, CO 2 CH 3 , CONH 2 , CONHCH 3 , or CON(CH 3 ) 2 .
16. The compound according to claim 15 , wherein:
R 1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromophenyl, p-chlorophenyl, or p-fluorophenyl;
R 3a is H; and
R 3b is H, CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 -phenyl, 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)-phenyl), CH 2 SH, or lower cycloalkyl.
17. The compound according to claim 15 , wherein:
R 1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromophenyl, p-chlorophenyl, or p-fluorophenyl;
R 3a is H;
R 3b is H, CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 -phenyl, or lower cycloalkyl; and
R 7 and R 8 are independently H, F, Br, SCH 3 , CH 3 , CH 3-q , where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO 2 CH 3 , CONH 2 , CONHCH 3 , or CON(CH 3 ) 2 .
18. The compound according to claim 15 , wherein:
R 1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromophenyl, p-chlorophenyl, or p-fluorophenyl;
R 2 is hydrogen;
R 3a is H;
R 3b is H, CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 -phenyl, or lower cycloalkyl; and
R 7 and R 8 are independently H, F, Br, SCH 3 , CH 3 , CH 3-q X q , where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO 2 CH 3 , CONH 2 , CONHCH 3 , or CON(CH 3 ) 2 .
19. The compound according to claim 15 , wherein:
R 1 is hydrogen, methyl, phenyl, p-bromophenyl, p-chlorophenyl, or p-fluorophenyl;
R 2 is hydrogen;
R 3a is H;
R 3b is H, CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 -phenyl, or lower cycloalkyl; and
R 7 and R 8 are independently H, F, Br, SCH 3 , CH 3 , CH 3-q X q , where X is F, Cl, Br, or I and q is 1 to 3; vinyl, CO 2 CH 3 , CONH 2 , CONHCH 3 , or CON(CH 3 ) 2 .
20. A composition comprising the compound according to claim 15 .
21. A composition comprising the compound according to claim 15 and a pharmaceutically acceptable medium.
22. A composition comprising an effective amount of the compound according to claim 15 to treat a hepatitis C virus infection and a pharmaceutically acceptable medium.
23. A method of treating a subject infected by a virus selected from among hepatitis C virus, West Nile virus, yellow fever virus, dengue virus, rhinovirus, polio virus, hepatitis A virus, bovine viral diarrhea virus or Japanese encephalitis virus, which comprises administering to the subject an effective amount of the compound according to claim 15 .
24. The method of claim 23 , wherein the virus is hepatitis C virus.
25. The method of claim 24 , which further comprises administering to the subject an effective amount of another antiviral agent.
26. The method of claim 24 , wherein the subject is a human.
27. The method of claim 25 , wherein:
R 1 is phenyl;
R 2 is hydrogen;
R 3a is H;
R 3b is CH 3 ;
R 4 is i-propyl; and
R 7 and R 8 are both H.
28. The method of claim 26 , wherein:
R l is phenyl;
R 2 is hydrogen;
R 3a is H;
R 3b is CH 3 ;
R 4 is i-propyl; and
R 7 and R 8 are both H.