Claims for Patent: 7,816,339

Summary for Patent: 7,816,339

Title:	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.
Inventor(s):	Malcolm; Bruce A. (Paoli, PA), Palermo; Robert (Seattle, WA), Tong; Xiao (Short Hills, NJ), Feld; Boris (New Milford, NJ), Le; Hung (Rockaway, NJ)
Assignee:	Schering Corporation (Kenilworth, NJ)
Application Number:	12/412,967
Patent Claims:	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 ##STR00079## or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof which composition comprises a pharmaceutically acceptable carrier; wherein R.sup.3 and R.sup.4 are independently --OH or a pharmaceutically acceptable leaving group, wherein R.sup.5 is --OH, a straight or branched chain C.sub.9 to C.sub.24 alkylphosphate or a straight or branched chain C.sub.9 to C.sub.24 alkenylphosphate group or a pharmaceutically acceptable leaving group and wherein R.sup.1 and R.sup.2 are independently C.sub.1 to C.sub.10 alkyl or wherein R.sup.1 and R.sup.2 taken together with N form a C.sub.3 to C.sub.7 ring represented by the following structural formula: ##STR00080## wherein n and m are independently 0, 1, 2 or 3 and Q is CH.sub.2, NR, O, S, SO or SO.sub.2; and R is independently H, C.sub.1 to C.sub.6 alkyl or C.sub.1 to C.sub.6 acyl or wherein R.sup.1 and R.sup.2, taken together with the N, are represented by the structural formula: ##STR00081## and wherein said pharmaceutically acceptable leaving groups are capable of being converted to --OH, -phosphate, --F or --CH.sub.3 when the compound of structural formula IV is administered in vivo and are independently represented by structural formula ##STR00082## wherein Y.dbd.H, CH.sub.3, CH.sub.3CH.sub.2--, CH.sub.3CH.sub.2CH.sub.2--, Me.sub.2CH--, Me.sub.2CH.sub.2CH.sub.2--, CH.sub.3CH.sub.2CH(Me)-, PhCH.sub.2--, HOOCCH.sub.2CH.sub.2--, HSCH.sub.2--, HOOCCH.sub.2--, MeSCH.sub.2CH.sub.2--, HOCH.sub.2--, ##STR00083## H.sub.2N(CH.sub.2).sub.4--, or CH.sub.3CH(OH)--, or a pharmaceutically acceptable salt thereof, or Y, taken together with the alpha-carbon and N, form ##STR00084## wherein the pharmaceutically acceptable leaving groups are capable of being converted to --OH, -phosphate, --F or --CH.sub.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: ##STR00085## 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, ##STR00086## gliotoxin, RD3-4082, RD3-4078, ##STR00087## 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-.alpha.-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, ##STR00088## 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: ##STR00089## ##STR00090## ##STR00091## ##STR00092## ##STR00093## ##STR00094## 6. A composition represented by structural formula IV ##STR00095## or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof which composition comprises a pharmaceutically acceptable carrier; wherein R.sup.3 and R.sup.4 are independently --OH or a pharmaceutically acceptable leaving group, wherein R.sup.5 is a straight or branched chain C.sub.9 to C.sub.24 alkylphosphate or a straight or branched chain C.sub.9 to C.sub.24 alkenylphosphate group and wherein R.sup.1 and R.sup.2 are independently C.sub.1 to C.sub.10 alkyl or wherein R.sup.1 and R.sup.2 taken together with N form a C.sub.3 to C.sub.7 ring represented by the following structural formula: ##STR00096## wherein n and m are independently 0, 1, 2 or 3 and Q is CH.sub.2, NR, O, S, SO or SO.sub.2; and R is independently H, C.sub.1 to C.sub.6 alkyl or C.sub.1 to C.sub.6 acyl or wherein R.sup.1 and R.sup.2, taken together with the N, are represented by the structural formula: ##STR00097## and wherein said pharmaceutically acceptable leaving groups are capable of being converted to --OH, -phosphate, --F or --CH.sub.3 when the compound of structural formula IV is administered in vivo and are independently represented by the structural formula ##STR00098## wherein Y.dbd.H, CH.sub.3, CH.sub.3CH.sub.2--, CH.sub.3CH.sub.2CH.sub.2--, Me.sub.2CH--, Me.sub.2CH.sub.2CH.sub.2--, CH.sub.3CH.sub.2CH (Me)-, PhCH.sub.2--, HOOCCH.sub.2CH.sub.2--, HSCH.sub.2--, HOOCCH.sub.2--, MeSCH.sub.2CH.sub.2--, HOCH.sub.2--, ##STR00099## H.sub.2N(CH.sub.2).sub.4--, or CH.sub.3CH(OH)--, or a pharmaceutically acceptable salt thereof, or Y, taken together with the alpha-carbon and N, form ##STR00100## wherein said pharmaceutically acceptable leaving groups are capable of being converted to --OH, -phosphate, --F or --CH.sub.3 when the compound of structural formula IV is administered in vivo and are independently represented by a structural formula ##STR00101## ##STR00102## 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: ##STR00103## ##STR00104## ##STR00105## 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, ##STR00106## gliotoxin, RD3-4082, RD3-4078, ##STR00107## 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-.alpha.-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, ##STR00108## 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.

Details for Patent 7,816,339

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132	06/04/1986		2025-03-02
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132			2025-03-02
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	Injection	103132			2025-03-02