Thionucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
View Patent ↗The present invention provides thionucleoside compounds and certain derivatives thereof which are inhibitors of RNA-dependent RNA viral polymerase. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such thionucleoside compounds alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the thionucleoside compounds of the present invention.
1. A compound of the structural formula I:
or a pharmaceutically acceptable salt thereof;
wherein R 1 is C 1-4 alkyl, wherein alkyl is unsubstituted or substituted with hydroxy, amino, C 1-4 alkoxy, C 1-4 alkylthio, or one to three fluorine atoms;
R 2 is amino, fluorine, hydroxy, mercapto, C 1-4 alkoxy, or C 1-10 alkylcarbonyloxy;
R 3 and R 4 are each independently selected from the group consisting of hydrogen, cyano, azido, halogen, hydroxy, mercapto, amino, C 1-4 alkoxy, C 1-10 alkylcarbonyloxy, C 2-4 alkenyl, C 2-4 alkynyl, and C 1-4 alkyl, wherein alkyl is unsubstituted or substituted with hydroxy, amino, C 1-4 alkoxy, C 1-4 alkylthio, or one to three fluorine atoms;
R 5 is hydrogen, C 1-10 alkylcarbonyl, P 3 O 9 H 4 , P 2 O 6 H 3 , or P(O)R 13 R 14 ;
R 6 and R 7 are each independently hydrogen, methyl, hydroxymethyl, or fluoromethyl;
R 8 is hydrogen, C 1-4 alkyl, C 2-4 alkynyl, halogen, cyano, carboxy, C 1-4 alkyloxycarbonyl, azido, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfonyl, or (C 1-4 alkyl) 0-2 aminomethyl;
R 9 is hydrogen, nitro, C 1-3 alkyl, NHCONH 2 , CONR 12 R 12 , CSNR 12 R 12 , COOR 12 , C(═NH)NH 2 , hydroxy, C 1-3 alkoxy, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, halogen, (1,3-oxazol-2-yl), (1,3-thiazol-2-yl), or (imidazol-2-yl); wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and C 1-3 alkoxy;
R 10 and R 11 are each independently hydrogen, hydroxy, halogen, C 1-4 alkoxy, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 3-6 cycloalkylamino, di(C 3-6 cycloalkyl)amino, or C 4-6 cycloheteroalkyl, unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, amino, C 1-4 alkyl, and C 1-4 alkoxy;
each R 12 is independently hydrogen or C 1-6 alkyl; and
R 13 and R 14 are each independently hydroxy, OCH 2 CH 2 SC(═O)C 1-4 alkyl, OCH 2 O(C═O)OC 1-4 alkyl, NHCHMeCO 2 Me, OCH(C 1-4 alkyl)O(C═O)C 1-4 alkyl,
2. The compound of claim 1 of the structural formula II:
or a pharmaceutically acceptable salt thereof;
wherein
R 1 is C 1-3 alkyl, wherein alkyl is unsubstituted or substituted with hydroxy, amino, C 1-3 alkoxy, C 1-3 alkylthio, or one to three fluorine atoms;
R 2 is hydroxy, fluoro, C 1-3 alkoxy, or C 1-8 alkylcarbonyloxy;
R 3 is hydrogen, halogen, hydroxy, amino, C 1-3 alkoxy, or C 1-8 alkylcarbonyloxy;
R 5 is hydrogen, C 1-8 alkylcarbonyl, P 3 O 9 H 4 , P 2 O 6 H 3 , or PO 3 H 2 ;
R 8 is hydrogen, amino, or C 1-4 alkylamino;
R 9 is hydrogen, methyl, halogen, or CONH 2 ; and
R 10 and R 11 are each independently hydrogen, halogen, hydroxy, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, or C 3-6 cycloalkylamino.
3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, or aminomethyl;
R 2 is hydroxy, fluoro, or methoxy;
R 3 is hydrogen, fluoro, hydroxy, amino, or methoxy;
R 5 is hydrogen or P 3 O 9 H 4 ;
R 8 is hydrogen or amino;
R 9 is hydrogen, methyl, halogen, or CONH 2 ; and
R 10 and R 11 are each independently hydrogen, fluoro, hydroxy, or amino.
4. The compound of claim 3 which is selected from the group consisting of:
4-amino-7-(2-C-methyl-4-thio-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;
2-amino-7-(2-C-methyl-4-thio-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one;
the corresponding 5′-triphosphates; and
pharmaceutically acceptable salts thereof.
5. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
6. The pharmaceutical composition of claim 5 useful for inhibiting RNA-dependent RNA viral polymerase, inhibiting RNA-dependent RNA replication, and/or treating RNA-dependent RNA viral infection.
7. The pharmaceutical composition of claim 6 wherein said RNA-dependent RNA viral polymerase is HCV NS5B polymerase, said RNA-dependent RNA viral replication is HCV replication, and said RNA-dependent RNA viral infection is HCV infection.
8. A method of inhibiting HCV NS5B RNA-dependent RNA viral polymerase and/or inhibiting HCV viral replication comprising administering to a mammal in need of such inhibition an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
9. A method of treating HCV infection comprising administering to a mammal in need of such treatment an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
10. The method of claim 9 in combination with a therapeutically effective amount of another agent active against HCV.
11. The method of claim 10 wherein said agent active against HCV is ribavirin; levovirin; thymosin alpha-1; interferon-β; an inhibitor of NS3 serine protease; an inhibitor of inosine monophosphate dehydrogenase; interferon-α or pegylated interferon-α, alone or in combination with ribavirin or levovirin.
12. The method of claim 11 wherein said agent active against HCV is interferon-α or pegylated interferon-α, alone or in combination with ribavirin.
13. A method of treating HCV infection which comprises administering to a mammal in need of such treatment an effective amount of a compound of structural formula II:
or a pharmaceutically acceptable salt thereof;
wherein
R 1 is C 1-3 alkyl, wherein alkyl is unsubstituted or substituted with hydroxy, amino, C 1-3 alkoxy, C 1-3 alkylthio, or one to three fluorine atoms;
R 2 is hydroxy, fluoro, C 1-3 alkoxy, or C 1-8 alkylcarbonyloxy;
R 3 is hydrogen, halogen, hydroxy, amino, C 1-3 alkoxy, or C 1-8 alkylcarbonyloxy;
R 5 is hydrogen, C 1-8 alkylcarbonyl, P 3 O 9 H 4 , P 2 O 6 H 3 , or PO 3 H 2 ;
R 8 is hydrogen, amino, or C 1-4 alkylamino;
R 9 is hydrogen, cyano, methyl, halogen, or CONH 2 ; and
R 10 and R 11 are each independently hydrogen, halogen, hydroxy, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, or C 3-6 cycloalkylamino.
14. The method according to claim 13 , wherein in the compound of formula II, or a pharmaceutically acceptable salt thereof:
R 1 is methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, or aminomethyl;
R 2 is hydroxy, fluoro, or methoxy;
R 3 is hydrogen, fluoro, hydroxy, amino, or methoxy;
R 5 is hydrogen or P 3 O 9 H 4 ;
R 8 is hydrogen or amino;
R 9 is hydrogen, cyano, methyl, halogen, or CONH 2 ; and
R 10 and R 11 are each independently hydrogen, fluoro, hydroxy, or amino.
15. The method according to claim 14 , wherein the compound is selected from the group consisting of:
4-amino-7-(2-C-methyl-4-thio-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;
2-amino-7-(2-C-methyl-4-thio-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one; corresponding 5′-triphosphates; and pharmaceutically acceptable salts thereof.