Treatments for flaviviridae virus infection

Abstract

The present invention provides methods for treating infections, in a host, by viruses belonging to the Flaviviridae family, such as HCV, comprising administering an Ara-C homologue to the host.

1 . A method for treating an infection by a virus which is a member of the Flaviviridae family of viruses, in a mammalian host, comprising administering to said host a therapeutically effective amount of a compound represented by structural formula IV 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof which composition comprises a pharmaceutically acceptable carrier; 
         wherein R 3  and R 4  are independently —OH or a pharmaceutically acceptable leaving group, wherein R 5  is —OH, a straight or branched chain C 9  to C 24  alkylphosphate or a straight or branched chain C 9  to C 24  alkenylphosphate group or a pharmaceutically acceptable leaving group and wherein R 1  and R 2  are independently C 1  to C 10  alkyl or wherein R 1  and R 2  taken together with N form a C 3  to C 7  ring represented by the following structural formula: 
       
       
         
           
           
               
               
           
         
         wherein n and m are independently 0, 1, 2 or 3 and Q is CH 2 , NR, O, S, SO or SO 2 ; and R is independently H, C 1  to C 6  alkyl or C 1  to C 6  acyl or wherein R 1  and R 2 , taken together with the N, are represented by the structural formula: 
       
       
         
           
           
               
               
           
         
       
       and wherein said pharmaceutically acceptable leaving groups groups are capable of being converted to —OH, -phosphate, —F or —CH 3  when the compound of structural formula IV is administered in vivo and are independently represented by structural formula 
       
         
           
           
               
               
           
         
         wherein Y═H, CH 3 , CH 3 CH 2 —, CH 3 CH 2 CH 2 —, Me 2 CH—, Me 2 CH 2 CH 2 —, CH 3 CH 2 CH(Me)—, PhCH 2 —, HOOCCH 2 CH 2 —, HSCH 2 —, HOOCCH 2 —, MeSCH 2 CH 2 —, HOCH 2 —, 
       
       
         
           
           
               
               
           
         
         H 2 N(CH 2 ) 4 —, or CH 3 CH(OH)—, or a pharmaceutically acceptable salt thereof, or Y, taken together with the alpha-carbon and N, form 
       
       
         
           
           
               
               
           
         
       
       or wherein the pharmaceutically acceptable leaving groups are capable of being converted to —OH, -phosphate, —F or —CH 3  when the compound of structural formula IV is administered in vivo and are independently represented by a structural formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       in association with one or more further chemotherapeutic agents. 
     
     
         2 . The method of  claim 1  wherein the further chemotherapeutic agent is:
 a ribonucleoside analogue, 
 an IMPDH inhibitor, 
 an N-glycosylation inhibitor, 
 an N3 protease inhibitor, 
 an NS5B inhibitor, 
 an immunomodulatory compound, 
 a CTP synthase inhibitor, 
 a thiazolidine derivative, 
 a benzanilide, 
 a phenanthrenequinone, 
 a helicase inhibitor, 
 a polymerase inhibitor, 
 an antisense phosphothioate oligodeoxynucleotide, 
 an IRES-dependent translation inhibitor, 
 a nuclease resistant ribozyme, 
 a 1-amino-alkyloyclohexane, 
 an alkyl lipid, 
 an antioxidant, 
 squalene, 
 amantadine, 
 a bile acid, 
 N-(phosphonoacetyl)-L-aspartic acid, 
 a benzenedicarboxamide, 
 a polyadenylic acid, 
 2′,3′ dideoxyinosine, or 
 a benzimidazole. 
 
     
     
         3 . The method of  claim 1  wherein the further chemotherapeutic agent is one or more members selected from the group consisting of: gemcitabine, VX497, mycophenolate mofetil, EICAR, tiazofurin, deoxynojirimycin, N-nonyl-deoxynojirimycin, n-butyl deoxynojirimycin albumin-interferon alpha, BILN-2061, thymalfasin, isatoribine, NM283, NM107, 
       
         
           
           
               
               
           
         
       
       gliotoxin, RD3-4082, RD3-4078, 
       
         
           
           
               
               
           
         
       
       RD4-6205, cerulenin, ceplene, amantadine, IDN-6556, naphthoquinone, 2-methylnaphthoquinone, 2-hydroxynaphthoquinone, 5-hydroxynaphthoquinone, 5,8-dihydroxynaphthoquinone, alkannin, or shikonin, 1-amino-1,3,5-trimethylcyclohexane; 1-amino-1(trans),3(trans),5-trimethylcyclohexane; 1-amino-1(cis),3(cis),5-trimethylcyclohexane; 1-amino-1,3,3,5-tetramethylcyclohexane; 1-amino-1,3,3,5,5-pentamethylcyclohexane; 1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane; 1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane; 1-amino-1,5,5-trimethyl-cis-3-ethylcyclohexane; 1-amino-(1S,5S)cis-3-ethyl-1,5,5-trimethylcyclohexane; 1-amino-1,5,5-trimethyl-trans-3-ethylcyclohexane; 1-amino-(1R,5S)trans-3-ethyl-1,5,5-trimethylcyclohexane; 1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane; 1-amino-1-propyl-3,3,5,5-tetramethylcyclohexane; N-methyl-1-amino-1,3,3,5,5-pentamethylcyclohexane; N-ethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane; N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine, d-α-tocopherol, tauroursodeoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, free bile acid; 1,1′-[1,4-phenylenebis(methylene)]bis(4,4′-trans-(4,5,6,7,8,9-hexahydro) benzimidazoyl)piperidine; 1,1′-[1,4-phenylenebis(methylene)]bis(4,4′-benzimidazoyl)piperidine; N,N′-4-[(2-benzimidazole)phenyl]-1,4-butanedicarboxamide; N,N′-4-[(2-benzimidazole)phenyl]-1,6-hexanedicarboxamide; N,N′-4-[(2-benzimidazole)phenyl]-1,8-octanedicarboxamide; N,N′-4-[(2-benzimidazole)phenyl]-1,9-nonanedicarboxamide; N,N′-4-[(2-benzimidazole)phenyl]-1,10-decanedicarboxamide; N,N′-4-[(2-benzimidazole)phenyl]-1,4-butenedicarboxamide; 2′,3′-dideoxyinosine 
       
         
           
           
               
               
           
         
       
       VX-950, viramidine and levovirin. 
     
     
         4 . The method  claim 1  wherein the virus is hepatitis C virus, the host is human and the compound represented by structural formula IV is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The method  claim 2  wherein the virus is hepatitis C virus, the host is human and the compound represented by structural formula IV is 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method  claim 3  wherein the virus is hepatitis C virus, the host is human and the compound represented by structural formula IV is 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method  claim 4  wherein the further chemotherapeutic agent is one or more members selected from the group consisting of:
 ribavirin, 
 interferon alfa-2a, 
 interferon alfa-2b, 
 PEGylated Interferon alfa-2a, and 
 PEGylated Interferon alfa-2b. 
 
     
     
         8 . The method  claim 5  wherein the further chemotherapeutic agent is one or more members selected from the group consisting of:
 ribavirin, 
 interferon alfa-2a, 
 interferon alfa-2b, 
 PEGylated Interferon alfa-2a, and 
 PEGylated Interferon alfa-2b. 
 
     
     
         9 . The method  claim 6  wherein the further chemotherapeutic agent is one or more members selected from the group consisting of:
 ribavirin, 
 interferon alfa-2a, 
 interferon alfa-2b, 
 PEGylated Interferon alfa-2a, and 
 PEGylated Interferon alfa-2b. 
 
     
     
         10 . The method of  claim 1  wherein the host is administered the compound represented by structural formula IV following transplantation of a liver into said host or transfusion of blood into said host. 
     
     
         11 . The method of  claim 1  wherein the compound represented by structural formula IV is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . A composition represented by structural formula IV 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof which composition comprises a pharmaceutically acceptable carrier; 
         wherein R 3  and R 4  are independently —OH or a pharmaceutically acceptable leaving group, wherein R 5  is a straight or branched chain C 9  to C 24  alkylphosphate or a straight or branched chain C 9  to C 24  alkenylphosphate group and wherein R 1  and R 2  are independently C 1  to C 10  alkyl or wherein R 1  and R 2  taken together with N form a C 3  to C 7  ring represented by the following structural formula: 
       
       
         
           
           
               
               
           
         
         wherein n and m are independently 0, 1, 2 or 3 and Q is CH 2 , NR, O, S, SO or SO 2 ; and R is independently H, C 1  to C 6  alkyl or C 1  to C 6  acyl or wherein R 1  and R 2 , taken together with the N, are represented by the structural formula: 
       
       
         
           
           
               
               
           
         
       
       and wherein said pharmaceutically acceptable leaving groups are capable of being converted to —OH, -phosphate, —F or —CH 3  when the compound of structural formula IV is administered in vivo and are independently represented by the structural formula 
       
         
           
           
               
               
           
         
         wherein Y═H, CH 3 , CH 3 CH 2 —, CH 3 CH 2 CH 2 —, Me 2 CH—, Me 2 CH 2 CH 2 —, CH 3 CH 2 CH(Me)—, PhCH 2 —, HOOCCH 2 CH 2 —, HSCH 2 —, HOOCCH 2 —, MeSCH 2 CH 2 —, HOCH 2 —, 
       
       
         
           
           
               
               
           
         
         —H 2 N(CH 2 ) 4 —, or CH 3 CH(OH)—, or a pharmaceutically acceptable salt thereof, 
         or Y, taken together with the alpha-carbon and N, form 
       
       
         
           
           
               
               
           
         
       
       or wherein said pharmaceutically acceptable leaving groups are capable of being converted to —OH, -phosphate, —F or —CH 3  when the compound of structural formula IV is administered in vivo and are independently represented by a structural formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       in association with one or more further chemotherapeutic agents. 
     
     
         13 . A composition which is represented by a structural formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       in association with one or more further chemotherapeutic agents. 
     
     
         14 . The composition of  claim 12  wherein the further chemotherapeutic agent is:
 a ribonucleoside analogue, 
 an IMPDH inhibitor, 
 an N-glycosylation inhibitor, 
 an N3 protease inhibitor, 
 an NS5B inhibitor, 
 an immunomodulatory compound, 
 a CTP synthase inhibitor, 
 a thiazolidine derivative, 
 a benzanilide, 
 a phenanthrenequinone, 
 a helicase inhibitor, 
 a polymerase inhibitor, 
 an antisense phosphothioate oligodeoxynucleotide, 
 an IRES-dependent translation inhibitor, 
 A nuclease resistant ribozyme, 
 a 1-amino-alkyloyclohexane, 
 an alkyl lipid, 
 antioxidants, 
 squalene, 
 amantadine, 
 a bile acid, 
 N-(phosphonoacetyl)-L-aspartic acid, 
 a benzenedicarboxamide, 
 a polyadenylic acid derivative, 
 2′,3′ dideoxyinosine, or 
 a benzimidazole. 
 
     
     
         15 . The composition of  claim 12  wherein the further chemotherapeutic agent is one or more members selected from the group consisting of: gemcitabine, VX497, mycophenolate mofetil, EICAR, tiazofurin, deoxynojirimycin, N-nonyl-deoxynojirimycin, n-butyl deoxynojirimycin albumin-interferon alpha, BILN-2061, thymalfasin, isatoribine, NM283, NM107, 
       
         
           
           
               
               
           
         
       
       gliotoxin, RD3-4082, RD3-4078, 
       
         
           
           
               
               
           
         
       
       RD4-6205, cerulenin, ceplene, amantadine, IDN-6556, naphthoquinone, 2-methylnaphthoquinone, 2-hydroxynaphthoquinone, 5-hydroxynaphthoquinone, 5,8-dihydroxynaphthoquinone, alkannin, or shikonin, 1-amino-1,3,5-trimethylcyclohexane; 1-amino-1(trans),3(trans),5-trimethylcyclohexane; 1-amino-1(cis),3(cis),5-trimethylcyclohexane; 1-amino-1,3,3,5-tetramethylcyclohexane; 1-amino-1,3,3,5,5-pentamethylcyclohexane; 1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane; 1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane; 1-amino-1,5,5-trimethyl-cis-3-ethylcyclohexane; 1-amino-(1S,5S)cis-3-ethyl-1,5,5-trimethylcyclohexane; 1-amino-1,5,5-trimethyl-trans-3-ethylcyclohexane; 1-amino-(1R,5S)trans-3-ethyl-1,5,5-trimethylcyclohexane; 1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane; 1-amino-1-propyl-3,3,5,5-tetramethylcyclohexane; N-methyl-1-amino-1,3,3,5,5-pentamethylcyclohexane; N-ethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane; N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine, d-α-tocopherol, tauroursodeoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, free bile acid; 1,1′-[1,4-phenylenebis(methylene)]bis(4,4′-trans-(4,5,6,7,8,9-hexahydro) benzimidazoyl)piperidine; 1,1′-[4-phenylenebis(methylene)]bis(4,4′-benzimidazoyl)piperidine; N,N′-4-[(2-benzimidazole)phenyl]-1,4-butanedicarboxamide; N,N′-4-[(2-benzimidazole)phenyl]-1,6-hexanedicarboxamide; N,N′-4-[(2-benzimidazole)phenyl]-1,8-octanedicarboxamide; N,N′-4-[(2-benzimidazole)phenyl]-1,9-nonanedicarboxamide; N,N′-4-[(2-benzimidazole)phenyl]-1,10-decanedicarboxamide; N,N′-4-[(2-benzimidazole)phenyl]-1,4-butenedicarboxamide; 2′,3′-dideoxyinosine, 
       
         
           
           
               
               
           
         
       
       VX-950, viramidine and levovirin. 
     
     
         16 . The composition of  claim 12  wherein the further chemotherapeutic agent one or more members selected from the group consisting of:
 ribavirin, 
 interferon alfa-2a, 
 interferon alfa-2b, 
 PEGylated Interferon alfa-2a, and 
 PEGylated Interferon alfa-2b. 
 
     
     
         17 . The composition of  claim 13  wherein the further chemotherapeutic agent one or more members selected from the group consisting of:
 ribavirin, 
 interferon alfa-2a, 
 interferon alfa-2b, 
 PEGylated Interferon alfa-2a, and 
 PEGylated Interferon alfa-2b.