Claims for Patent: 10,005,779

Summary for Patent: 10,005,779

Title:	1\',4\'-thio nucleosides for the treatment of HCV
Abstract:	Provided herein are compounds, compositions and methods for the treatment of Flaviviridae infections, including HCV infections. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents. In certain embodiments, the compounds are 1\',4\'-thio nucleoside compounds which display remarkable efficacy and bioavailability for the treatment of, for example, HCV infection in a human. In certain embodiments, the compounds are of Formula 3001: ##STR00001## or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof; wherein Base, R.sup.A, R.sup.B, W, X, Y, and Z are as described herein.
Inventor(s):	Dukhan; David (Saint Gely du Fesc, FR), Gosselin; Gilles (Montpellier, FR), Dousson; Cyril B. (Canet, FR)
Assignee:	IDENIX PHARMACEUTICALS LLC (Cambridge, MA)
Application Number:	14/296,122
Patent Claims:	1. A compound according to Formula 3001: ##STR00054## or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof, wherein: Base is ##STR00055## or tautomeric form thereof, wherein: R.sup.4 is hydrogen, hydroxyl, alkoxyl, or amino; R.sup.5 is hydrogen, hydroxyl, amino, or alkoxyl; R.sup.6 is hydrogen, halogen, or alkyl; and R.sup.7 is hydrogen, amino, or hydroxyl; W is S or O; each of X and Y is independently hydrogen, --OR.sup.1, --SR.sup.1, --NR.sup.1R.sup.2, or an N-linked or O-linked amino acid residue, or derivative thereof; each N-linked amino acid residue or derivative thereof is --NR.sup.X-G(S.sub.C)--C(O)-Q.sup.1; each O-linked amino acid residue or derivative thereof is independently --OC(O)G(S.sub.C)-Q or --O--C(O)-G(S.sub.C)--NH-Q.sup.2; each G is independently unsubstituted C.sub.1-C.sub.2 alkylene; each S.sub.C is independently a side chain of a naturally occurring amino acid or S.sub.C is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted arylalkyl, unsubstituted heterocycloalkyl, -(unsubstituted alkyl)-C(O)OH, unsubstituted heteroarylalkyl, -(unsubstituted alkyl)-NH.sub.2, -(unsubstituted alkyl)-NH-(unsubstituted alkyl), -(unsubstituted alkyl)-N-(unsubstituted alkyl).sub.2, hydroxylalkyl, -alkyl-NH--C(NH)--NH.sub.2, -(unsubstituted alkyl)-SH, -(unsubstituted alkyl)-C(O)--NH.sub.2, -(unsubstituted alkyl)-C(O)--NH-(unsubstituted alkyl), -(unsubstituted alkyl)-C(O)--N-(unsubstituted alkyl).sub.2, -(unsubstituted alkyl)-S-(unsubstituted alkyl) and -(unsubstituted alkyl)-(unsubstituted aryl)-OH; each Q is independently --SR, --NRR or alkoxyl, each R is independently hydrogen or alkyl; each Q.sup.1 is independently --SR.sup.Y, --NR.sup.YR.sup.Y or alkoxyl; R.sup.Y is hydrogen or alkyl; each R.sup.X is hydrogen; each Q.sup.2 is independently hydrogen or alkoxyl; Z is hydrogen, hydroxyl, or halo; or, in the alternative, Y and Z, together with the atoms to which they are attached, combine to form a six-membered heterocyclic ring wherein Y and Z together represent a single divalent --O--; R.sup.A is hydrogen, methyl, or halo; R.sup.B is hydrogen, hydroxyl, or halo; each R.sup.1 is independently unsubstituted alkyl, substituted alkyl, unsubstituted aryl, substituted aryl, unsubstituted arylalkyl, substituted arylalkyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted -alkyl-S--C(O)-alkyl, or substituted -alkyl-S--C(O)-alkyl; and each R.sup.2 is independently hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted arylalkyl, or substituted arylalkyl; and wherein each substituted alkyl is independently alkyl substituted with a moiety(ies) selected from the group consisting of halogen; oxo; epoxy; hydroxyl; unsubstituted cycloalkyl; unsubstituted aralkyl; sulfanyl; --NR.sup.1'R.sup.2' wherein R.sup.1' and R.sup.2' are independently hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl, or unsubstituted heteroaryl; --O-(unsubstituted alkyl); --O-(unsubstituted cycloalkyl); unsubstituted aryloxy; nitro; cyano; sulfonic acid; sulfate; phosphonic acid; and phosphate; wherein each substituted aryl, either alone or as part of another group, is independently aryl substituted with one or more moieties selected from the group consisting of halogen; unsubstituted alkyl; haloalkyl; hydroxyl; --NR.sup.1'R.sup.2' wherein R.sup.1' and R.sup.2' are independently hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl, or unsubstituted heteroaryl; --O-(unsubstituted alkyl); --O-(unsubstituted cycloalkyl); unsubstituted aryloxy; nitro; cyano; sulfonic acid; sulfate; phosphonic acid; and phosphate; wherein each substituted cycloalkyl is independently cycloalkyl substituted with a moiety(ies) selected from the group consisting of halogen; oxo; epoxy; hydroxyl; sulfanyl; --NR.sup.1'R.sup.2' wherein R.sup.1' and R.sup.2' are independently hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl, or unsubstituted heteroaryl; --O-(unsubstituted alkyl); --O-(unsubstituted cycloalkyl); unsubstituted aryloxy; nitro; cyano; sulfonic acid; sulfate; phosphonic acid; and phosphate; and wherein each substituted heterocycloalkyl is independently heterocycloalkyl substituted with a moiety(ies) selected from the group consisting of halogen; oxo; epoxy; hydroxyl; alkoxycarbonyl; alkoxycarbonylalkyl; --NR.sup.1'R.sup.2' wherein R.sup.1' and R.sup.2' are independently hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl, or unsubstituted heteroaryl; --O-(unsubstituted alkyl); --O-(unsubstituted cycloalkyl); unsubstituted aryloxy; nitro; cyano; sulfonic acid; sulfate; phosphonic acid; and phosphate. 2. The compound of claim 1, wherein: X is --NH-G(S.sub.C)--C(O)-Q.sup.1; and S.sub.C is a side chain of a naturally occurring amino acid. 3. The compound of claim 1, wherein: X is --OR.sup.1; and R.sup.1 is unsubstituted -alkyl-S--C(O)-alkyl. 4. The compound of claim 1, wherein: Y is hydrogen, --OR.sup.1, --SR.sup.1, --NR.sup.1R.sup.2, or an N-linked or O-linked amino acid residue, or derivative thereof; and Z is hydrogen, hydroxyl, or halo. 5. The compound of claim 1, wherein W is O. 6. The compound of claim 1 according to any of Formulas II-IV, or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof: ##STR00056## 7. The compound of claim 1, wherein Base is: ##STR00057## or a tautomeric form thereof, wherein: R.sup.4 is hydrogen, hydroxyl, unsubstituted alkoxyl, --NH.sub.2, --NH(unsubstituted alkyl), or --N(unsubstituted alkyl).sub.2; R.sup.5 is hydrogen, hydroxyl, --NH.sub.2, --NH(unsubstituted alkyl), --N(unsubstituted alkyl).sub.2 or unsubstituted alkoxyl; R.sup.6 is hydrogen, halogen, unsubstituted alkyl, or substituted alkyl; and R.sup.7 is hydrogen, hydroxyl, --NH.sub.2, --NH(unsubstituted alkyl), or --N(unsubstituted alkyl).sub.2. 8. The compound of claim 7 wherein Base is: ##STR00058## wherein Y is hydrogen, --OR.sup.1, --SR.sup.1, --NR.sup.1R.sup.2, or an N-linked or O-linked amino acid residue, or derivative thereof; and R.sup.1 is unsubstituted alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or unsubstituted -alkyl-S--C(O)-- alkyl; X is --NH-G(S.sub.C)--C(O)-Q.sup.1; S.sub.C is a side chain of a naturally occurring amino acid; G is methylene, and Q.sup.1 is unsubstituted alkoxyl. 9. The compound of claim 1, wherein Base is uracil. 10. The compound of claim 1, wherein R.sup.A is hydrogen or methyl. 11. The compound of claim 1, wherein Z is hydroxyl. 12. The compound of claim 1, wherein R.sup.B is hydroxyl. 13. The compound of claim 1 according to any of Formulas 1-4, or a pharmaceutically acceptable salt, solvate, tautomeric form, or polymorphic form thereof: ##STR00059## 14. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient, carrier, or diluent. 15. The pharmaceutical composition of claim 14, wherein the composition is an oral formulation. 16. A method for the treatment of a human host infected with a hepatitis C virus, comprising administering to the host an effective amount of a compound of claim 1. 17. The method of claim 16 comprising administering a second anti-viral agent in combination or alternation with the compound, wherein the second anti-viral agent is an interferon, a nucleotide analogue, a polymerase inhibitor, an NS3 protease inhibitor, an NS5A inhibitor, an entry inhibitor, a non-nucleoside polymerase inhibitor, a cyclosporine immune inhibitor, an NS4A antagonist, an NS4B-RNA binding inhibitor, a locked nucleic acid mRNA inhibitor, a cyclophilin inhibitor, or a combination thereof. 18. The method of claim 17, wherein the second anti-viral agent is samatasvir, simeprevir, sofosbuvir, telaprevir, boceprevir, interferon alfacon-1, interferon alfa-2b, pegylated interferon alpha 2a, pegylated interferon alpha 2b, or a combination thereof. 19. The method of claim 17, wherein the second anti-viral agent is samatasvir, simeprevir, sofosbuvir, telaprevir, boceprevir, interferon alfacon-1, interferon alfa-2b, pegylated interferon alpha 2a, pegylated interferon alpha 2b, or a combination thereof, and further wherein the administration is not in combination or alternation with ribavirin. 20. A pharmaceutical composition comprising the compound of claim 8 and a pharmaceutically acceptable excipient, carrier, or diluent. 21. The pharmaceutical composition of claim 20, wherein the composition is an oral formulation. 22. A method for the treatment of a human host infected with a hepatitis C virus, comprising administering to the host an effective amount of a compound of claim 8. 23. The method of claim 22 comprising administering a second anti-viral agent in combination or alternation with the compound, wherein the second anti-viral agent is an interferon, a nucleotide analogue, a polymerase inhibitor, an NS3 protease inhibitor, an NS5A inhibitor, an entry inhibitor, a non-nucleoside polymerase inhibitor, a cyclosporine immune inhibitor, an NS4A antagonist, an NS4B-RNA binding inhibitor, a locked nucleic acid mRNA inhibitor, a cyclophilin inhibitor, or a combination thereof. 24. A compound according to Formula (3001) ##STR00060## or a pharmaceutically acceptable salt, solvate tautomeric form or polymorphic form thereof; wherein: Base is ##STR00061## or a tautomeric form thereof; R.sup.4 is hydrogen, hydroxyl, unsubstituted alkoxyl, --NH.sub.2, --NH(unsubstituted alkyl), or --N(unsubstituted alkyl).sub.2; R.sup.5 is hydrogen, hydroxyl, --NH.sub.2, --NH(unsubstituted alkyl), --N(unsubstituted alkyl).sub.2 or unsubstituted alkoxyl; R.sup.6 is hydrogen, halogen, unsubstituted alkyl; R.sup.7 is hydrogen, hydroxyl, --NH.sub.2, --NH(unsubstituted alkyl), or --N(unsubstituted alkyl).sub.2; W is S or O; each of X and Y is independently hydrogen, --OR.sup.1, --SR.sup.1, --NR.sup.1R.sup.2, or an N-linked or O-linked amino acid residue, or derivative thereof; each N-linked amino acid residue or derivative thereof is --NR.sup.X-G(S.sub.C)--C(O)-Q.sup.1; each O-linked amino acid residue or derivative thereof is independently --OC(O)G(S.sub.C)-Q or --O--C(O)-G(S.sub.C)--NH-Q.sup.2; each G is independently unsubstituted C.sub.1-C.sub.2 alkylene; each S.sub.C is independently a side chain of a naturally occurring amino acid or S.sub.C is selected from the group consisting of hydrogen, unsubstituted alkyl, unsubstituted arylalkyl, unsubstituted heterocycloalkyl, -(unsubstituted alkyl)-C(O)OH, unsubstituted heteroarylalkyl, -(unsubstituted alkyl)-NH.sub.2, -(unsubstituted alkyl)-NH-(unsubstituted alkyl), -(unsubstituted alkyl)-N-(unsubstituted alkyl).sub.2, hydroxylalkyl, -alkyl-NH--C(NH)--NH.sub.2, -(unsubstituted alkyl)-SH, -(unsubstituted alkyl)-C(O)--NH.sub.2, -(unsubstituted alkyl)-C(O)--NH-(unsubstituted alkyl), -(unsubstituted alkyl)-C(O)--N-(unsubstituted alkyl).sub.2, -(unsubstituted alkyl)-S-(unsubstituted alkyl) and -(unsubstituted alkyl)-(unsubstituted aryl)-OH; each Q is independently --SR, --NRR or alkoxyl, each R is independently hydrogen or alkyl; each Q.sup.1 is independently --SR.sup.Y, --NR.sup.YR.sup.Y or alkoxyl; each R.sup.Y is independently hydrogen or alkyl; each R.sup.X is hydrogen; each Q.sup.2 is independently hydrogen or alkoxyl; Z is hydrogen, hydroxyl, or halo; or, in the alternative, Y and Z, together with the atoms to which they are attached, combine to form a six-membered heterocyclic ring wherein Y and Z together represent a single divalent --O--, and X is --OR.sup.1, --SR.sup.1, --NR.sup.1R.sup.2, or an N-linked or O-linked amino acid residue, or derivative thereof; R.sup.A is hydrogen, methyl, or halo; R.sup.B is hydrogen, hydroxyl, or halo; each R.sup.1 is independently unsubstituted alkyl, substituted alkyl, unsubstituted aryl, substituted aryl, unsubstituted arylalkyl, substituted arylalkyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted -alkyl-S--C(O)-alkyl, or substituted -alkyl-S--C(O)-alkyl; each R.sup.2 is independently hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted arylalkyl, or substituted arylalkyl; each alkyl is independently a saturated straight or branched hydrocarbon having one to ten carbon atoms; and when substituted is substituted with a moiety(ies) selected from the group consisting of halogen; oxo; epoxy; hydroxyl; unsubstituted cycloalkyl; unsubstituted aralkyl; sulfanyl; --NR.sup.1'R.sup.2' wherein R.sup.1' and R.sup.2' are independently hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl, or unsubstituted heteroaryl; --O-(unsubstituted alkyl); --O-(unsubstituted cycloalkyl); unsubstituted aryloxy; nitro; cyano; sulfonic acid; sulfate; phosphonic acid; and phosphate; each alkenyl is independently an unsubstituted monovalent olefinically unsaturated, straight-chained or branched hydrocarbon group having 2 to 11 carbon atoms and having at least 1 site of olefinic unsaturation; each alkynyl is independently an unsubstituted acetylenically unsaturated, straight-chained or branched hydrocarbon group having 2 to 11 carbon atoms and having at least 1 alkynyl unsaturation; each aryl, either alone or as part of another group, is independently a C6-C12 aromatic ring; and when substituted is substituted with one or more moieties selected from the group consisting of halogen; unsubstituted alkyl; haloalkyl; hydroxyl; --NR.sup.1'R.sup.2' wherein R.sup.1' and R.sup.2' are independently hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl, or unsubstituted heteroaryl; --O-(unsubstituted alkyl); --O-(unsubstituted cycloalkyl); unsubstituted aryloxy; nitro; cyano; sulfonic acid; sulfate; phosphonic acid; and phosphate; each arylalkyl is independently an unsubstituted alkyl group with an unsubstituted or substituted aryl substituent; each cycloalkyl is independently a saturated cyclic C.sub.3-15 hydrocarbon which can be a bridged, non-bridged, and fused bicyclic group; and when substituted is substituted with a moiety(ies) selected from the group consisting of halogen; oxo; epoxy; hydroxyl; sulfanyl; NR.sup.1'R.sup.2' wherein R.sup.1' and R.sup.2' are independently hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl, or unsubstituted heteroaryl; --O-(unsubstituted alkyl); --O-(unsubstituted cycloalkyl); unsubstituted aryloxy; nitro; cyano; sulfonic acid; sulfate; phosphonic acid; and phosphate; each heterocyclic or heterocyclo is independently a monovalent monocyclic non-aromatic ring system having 3 to 20 ring atoms or a bicyclic, tricyclic, or tetracyclic ring system that contains at least one non-aromatic ring and which can be fused or bridged having 3 to 20 ring atoms; wherein one or more of the non-aromatic ring atoms is a heteroatom independently selected from O, S, and N and the remaining ring atoms are carbon atoms and in which the nitrogen or sulfur atoms are optionally oxidized and the nitrogen atoms are optionally quaternized; where the heterocyclic and heterocyclo are attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound; and when substituted is substituted with a moiety(ies) selected from the group consisting of halogen; oxo; epoxy; hydroxyl; alkoxycarbonyl; alkoxycarbonylalkyl; --NR.sup.1'R.sup.2' wherein R.sup.1' and R.sup.2' are independently hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocyclic, unsubstituted aryl, or unsubstituted heteroaryl; --O-(unsubstituted alkyl); --O-(unsubstituted cycloalkyl); unsubstituted aryloxy; nitro; cyano; sulfonic acid; sulfate; phosphonic acid; and phosphate; each heterocycloalkyl is independently an unsubstituted alkyl group with an unsubstituted or substituted heterocyclo substituent; each heteroaryl, either alone or as part of another group, is independently a monovalent monocyclic aromatic group or a multicyclic aromatic group that contains at least one aromatic ring; wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S and N in the ring provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom; wherein the heteroaryl is bonded to the rest of the molecule through the aromatic ring; and wherein the ring has 5 to 20 ring atoms; and each heteroarylalkyl is independently an alkyl group with an heteroaryl substituent.

Details for Patent 10,005,779

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		2039-02-26
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132			2039-02-26
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	Injection	103132			2039-02-26
Kadmon Pharmaceuticals Llc	INFERGEN	interferon alfacon-1	Injection	103663	10/06/1997		2039-02-26