Treatments for Flaviviridae virus infection

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 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

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 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.

5. The method of claim 1 wherein the compound is represented by a structural formula selected from the group consisting of:

6. 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

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.

7. A composition which is represented by a structural formula selected from the group consisting of:

in association with one or more further chemotherapeutic agents.

8. The composition of claim 6 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,

athiazolidine 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.

9. The composition of claim 6 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′-[(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.

10. The composition of 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.

11. The composition of claim 7 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.