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, or a stereoisomer thereof, represented by formula (I):
wherein P* is a chiral phosphorous atom,
and wherein
(a) R 1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, or a substituted or unsubstituted phenyl, where the substitutent of the substituted phenyl is at least one of a CH 3 , OCH 3 , F, Cl, Br, I, nitro, cyano, and a CH 3-q X q , where X is F, Cl, Br, or I, and q is 1-3;
(b) R 2 is hydrogen or CH 3 ;
(c-i) 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 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, or
(c-ii) R 3a is 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 and R 3b is H;
(d) R 4 is hydrogen, CH 3 , Et, i Pr, n Pr, n Bu, 2-butyl, t Bu, 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
(e) 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 , wherein R′ is a C 1-20 alkyl; a C 1-20 cycloalkyl; a C 2 -C 6 alkenyl, a C 2 -C 6 alkynyl.
2. The compound according to claim 1 , wherein:
(a) R 1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl; and
(c-i) 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 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.
3. The compound according to claim 1 , wherein:
(a) R 1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(c-i) 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 Ph, or lower cycloalkyl; and
(e) 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:
(a) R 1 is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R 2 is hydrogen;
(c-i) 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 Ph, or lower cycloalkyl; and
(e) 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:
(a) R 1 is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;
(b) R 2 is hydrogen;
(c-i) 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 Ph, or lower cycloalkyl; and
(e) 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. A process for preparing the compound according to claim 1 comprising reacting a compound 4″ with a nucleoside analog 5′:
wherein
(f) X′ is a leaving group.
14. The method of claim 11 , wherein the subject is human.