Antiviral drugs for treatment of arenavirus infection
View Patent ↗Compounds, methods and pharmaceutical compositions for treating viral infections, by administering certain compounds in therapeutically effective amounts are disclosed. Methods for preparing the compounds and methods of using the compounds and pharmaceutical compositions thereof are also disclosed. In particular, the treatment and prophylaxis of viral infections such as caused by the Arenavirus family is disclosed.
1. A method of inhibiting or causing regression of an Arenavirus infection, comprising administering in a therapeutically effective amount to a mammal in need thereof, a compound of Formula I below or a pharmaceutically acceptable salt thereof:
wherein each of B, D, E, G, B′, D′, E′ and G′ is C—R and;
R is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, hydroxy, alkyloxy, aryloxy, heteroaryloxy, acyloxy, arylacyloxy, heteroarylacyloxy, alkylsulfonyloxy, arylsulfonyloxy, thio, alkylthio, amino, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, acylamino, arylacylamino, heteroarylacylamino, alkylsulfonylamino, arylsulfonylamino, acyl, arylacyl, heteroarylacyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, substituted aminosulfonyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl, substituted carbamoyl, halogen, cyano, isocyano and nitro; and
wherein each of X and X′ is N—R′ and R′ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, aryl, heteroaryl, acyl, arylacyl, heteroarylacyl, sulfonyl, aminosulfonyl, substituted aminosulfonyl, alkoxycarbonyl, cycloalkyloxycarbonyl, aryloxycarbonyl, carbamoyl and substituted carbamoyl.
2. The method of claim 1 , wherein that at least one of B, D, E, G, B′, D′, E′ and G′ is C—Y, wherein Y is halogen.
3. The method of claim 1 , wherein R is selected from the group consisting of hydrogen, alkyl, amino and halogen.
4. The method of claim 3 , wherein, R is hydrogen or methyl.
5. The method of claim 1 , wherein R′ is hydrogen or alkyl.
6. The method of claim 1 , wherein the compound of Formula I is selected from the group consisting of 1H,1′H-[2,2′]Bibenzoimidazolyl; 5,6,5′,6′-Tetramethyl-1H, 1′H-[2,2′]bibenzoimidazolyl; 1,1′-Dimethyl-1H, 1′H-[2,2′]bibenzoimidazolyl; 1,1′-Diethyl-1H, 1′H-[2,2′]bibenzoimidazolyl; 6,6′-Dinitro-1H,1′H-[2,2′]bibenzoimidazolyl; 4,4′-Difluoro-1H,1′H-[2,2′]bibenzoimidazolyl; 5,5′-Difluoro-1H,1′H-[2,2′]bibenzoimidazolyl; 5,5′-Dichloro-1H,1′H-[2,2′]bibenzoimidazolyl; 5,5′-Dibromo-1H,1′H-[2,2′]bibenzoimidazolyl; 4,4′-Dimethyl-1H,1′H-[2,2′]bibenzoimidazolyl; 5,5′-Dimethyl- 1H,1′H-[2,2′]bibenzoimidazolyl; 4,4′-Dimethoxy-1H,1′H[2,2′]bibenzoimidazolyl; 5,5′-Dimethoxy-1H,1′H[2,2′]bibenzoimidazolyl;
1H,1′H-[2,2′]Bibenzoimidazolyl-4,4′-dicarboxylic acid dimethyl ester; 1H,1′H-[2,2′]Bibenzoimidazolyl-5,5′-dicarboxylic acid dimethyl ester; 4,4′-Diphenyl-1H,1′H-[2,2′]bibenzoimidazolyl; 4,5,4′,5′-Tetrafluoro-1H,1′H-[2,2′]bibenzoimidazolyl; 4,6,4′,6′-Tetrafluoro-1H,1′H-[2,2′]bibenzoimidazolyl; 5,6,5′,6′-Tetrafluoro-1H,1′H-[2,2′]bibenzoimidazolyl; 4,7,4′,7′-Tetrafluoro-1H,1′H-[2,2′]bibenzoimidazolyl; and 4,4′-Dichloro-1H,1′H-[2,2′]bibenzoimidazolyl.
7. The method of claim 1 , wherein the compound of Formula I is selected from the group consisting 1H,1′H-[2,2′]Bibenzoimidazolyl; 4,4′-Difluoro-1H,1′H-[2,2′]bibenzoimidazolyl; 5,5′-Difluoro-1H,1′H-[2,2′]bibenzoimidazolyl; and 4,6,4′,6′-Tetrafluoro-1H,1′H-[2,2′]bibenzoimidazolyl.
8. The method of claim 1 , wherein the mammal is a human.
9. The method of claim 1 , wherein the Arenavirus is selected from the group consisting of Lassa, Junín, Machupo, Guanarito, Sabia, Whitewater Arroyo, Chapare, LCMV, and LCMV-like viruses.
10. The method of claim 9 , wherein said LCMV-like viruses are selected from the group consisting of Dandenong, Tacaribe, and Pichinde.
11. The method of claim 1 , wherein said viral infection is associated with a condition selected from the group consisting of viral hemorrhagic fever, meningitis, meningoencephalitis, encephalitis and arenavirus-mediated disease in organ transplant recipients.
12. The method of claim 1 , wherein said viral infection is associated with birth defects and natural abortions.
13. The method of claim 1 , which further comprises co-administration of at least one agent selected from the group consisting of antiviral agent, vaccine, and interferon.
14. The method of claim 13 , wherein said antiviral agent is Ribavirin.
15. The method of claim 13 , wherein said interferon is pegylated.
16. A method of inhibiting or causing regression of an Arenavirus infection, comprising administering in a therapeutically effective amount to a mammal in need thereof, a 1H, 1′H-[2,2′]bibenzoimidazolyl.
17. A method of inhibiting or causing regression of an Arenavirus infection, comprising administering in a therapeutically effective amount to a mammal in need thereof, a 4,4′-Difluro-1H, 1H′-[2,2′]bibenzoimidazolyl.
18. A method of inhibiting or causing regression of an Arenavirus infection, comprising administering in a therapeutically effective amount to a mammal in need thereof, a 4,6,4′,6′-Tetrafluoro-1H, 1′H-[2,2′]bibenzoimidazolyl.