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Last Updated: March 28, 2024

Claims for Patent: 9,339,541


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Summary for Patent: 9,339,541
Title:Thiophosphate 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, the compounds are according to Formula 2001: ##STR00001## where PD, Base, R.sup.A and R.sup.B are as provided herein. 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.
Inventor(s): Dousson; Cyril B. (Canet, FR), Mayes; Benjamin Alexander (Boston, MA), Dukhan; David (Saint Gely du Fesc, FR), Moussa; Adel M. (Burlington, MA), Stewart; Alistair James (Lincoln, MA)
Assignee: Merck Sharp & Dohme Corp. (Rahway, NJ)
Application Number:14/195,635
Patent Claims:1. A compound according to Formula I: ##STR00147## or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein: Base is a nucleobase; R.sup.A is hydroxyl or fluoro; R.sup.B is methyl or halo; PD is ##STR00148## X is alkyl, alkoxycarbonylalkyl, (alkoxycarbonyl)(alkoxycarbonylamino)alkyl, cycloalkyl, heterocycloalkyl, hydantoinylalkyl, or aryl; Y is --NR.sup.1R.sup.2 or an N-linked amino acid, or ester thereof; Z is alkyl, alkoxycarbonyl or alkoxyalkylcarbonyl; A is --CHR.sup.10--, --CHR.sup.10CHR.sup.11--, or --CHR.sup.10CHR.sup.11CHR.sup.12--; R.sup.1 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; R.sup.2 is hydrogen or alkyl; R is hydrogen or alkyl; and each of R.sup.10, R.sup.11, and R.sup.12 is independently hydrogen or alkyl; or R.sup.10 and R.sup.11, together with the carbon atoms to which they are attached, combine to form a five-, six-, or seven-membered ring.

2. The compound of claim 1 according to Formula III: ##STR00149## or a pharmaceutically acceptable salt, solvate, stereoisomeric form,-tautomeric form, or polymorphic form thereof.

3. The compound of claim 1 according to Formula II: ##STR00150## or a pharmaceutically acceptable salt, solvate, stereoisomeric form,-tautomeric form, or polymorphic form thereof.

4. The compound of claim 1 according to any of Formulas IV-VI: ##STR00151## or a pharmaceutically acceptable salt, solvate, stereoisomeric form,-tautomeric form, or polymorphic form thereof.

5. The compound of claim 1 according to Formula VII or VIII: ##STR00152## or a pharmaceutically acceptable salt, solvate, stereoisomeric form,-tautomeric form, or polymorphic form thereof.

6. The compound of claim 1, wherein Base is: ##STR00153## or tautomeric form thereof, wherein: R.sup.4 is hydrogen, hydroxyl, unsubstituted alkoxyl, --NR.sup.1'R.sup.2' or alkyl substituted with --NR.sup.1'R.sup.2'; where each R.sup.1' and R.sup.2' are independently selected from hydrogen, unsubstituted alkyl and unsubstituted cycloalkyl; R.sup.5 is hydrogen, hydroxyl, --NR.sup.1' R.sup.2' (where R.sup.1' and R.sup.2' are independently selected from hydrogen, unsubstituted alkyl and unsubstituted cycloalkyl), or unsubstituted alkoxyl; R.sup.6 is hydrogen, halogen, or unsubstituted alkyl; and R.sup.7 is hydrogen or --NH.sub.2.

7. The compound of claim 6 according to any of Formulas (IX)-(XII): ##STR00154## or a pharmaceutically acceptable salt, solvate, stereoisomeric form,-tautomeric form, or polymorphic form thereof.

8. The compound of claim 1 according to any of Formulas XIII-XVII: ##STR00155## or a pharmaceutically acceptable salt, solvate, stereoisomeric form,-tautomeric form, or polymorphic form thereof.

9. A compound according to any of Formulas 1-23: ##STR00156## ##STR00157## ##STR00158## ##STR00159## ##STR00160## ##STR00161## or a pharmaceutically acceptable salt, solvate, stereoisomeric form,-tautomeric form, or polymorphic form thereof.

10. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient, carrier, or diluent.

11. The pharmaceutical composition of claim 10, wherein the composition is an oral formulation.

12. A method for the treatment of a host infected with a hepatitis C virus, comprising the administration of an effective treatment amount of a compound of claim 1.

13. The method of claim 12, wherein the host is a human.

14. The method of claim 12, wherein the administration directs a substantial amount of the compound, or pharmaceutically acceptable salt or stereoisomer thereof, to a liver of the host.

15. The method of claim 12, wherein the compound is administered in combination or alternation with a second anti-viral agent, 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 combination thereof.

16. The method of claim 15, wherein the second anti-viral agent is IDX-719, TMC435, PSI-7977, telaprevir, boceprevir, interferon alfacon-1, interferon alfa-2b, pegylated interferon alpha 2a, pegylated interferon alpha 2b, ribavirin, and combinations thereof.

17. The method of claim 15, wherein the second anti-viral agent is IDX-719, TMC435, PSI-7977, telaprevir, boceprevir, interferon alfacon-1, interferon alfa-2b, pegylated interferon alpha 2a, pegylated interferon alpha 2b, and combinations thereof, and further wherein the administration is not in combination or alternation with ribavirin.

18. The compound of claim 1, wherein: Base is ##STR00162## or a tautomeric form thereof; R.sup.4 is hydrogen, hydroxyl, unsubstituted alkoxyl, --NR.sup.1'R.sup.2' or alkyl substituted with --NR.sup.1'R.sup.2'; where each R.sup.1' and R.sup.2' are independently selected from hydrogen, unsubstituted alkyl and unsubstituted cycloalkyl; R.sup.5 is hydrogen; hydroxyl; --NR.sup.1'R.sup.2' where R.sup.1' and R.sup.2' are independently selected from hydrogen, unsubstituted alkyl and unsubstituted cycloalkyl; or unsubstituted alkoxyl; R.sup.6 is hydrogen, halogen, or unsubstituted alkyl; and R.sup.7 is hydrogen or --NH.sub.2; R.sup.A is hydroxyl or fluoro; R.sup.B is methyl or halo; PD is ##STR00163## X is unsubstituted alkyl; substituted alkyl; alkoxycarbonylalkyl; (alkoxycarbonyl)(alkoxycarbonylamino)alkyl; cycloalkyl; heterocycloalkyl; ##STR00164## where R.sup.XX and R.sup.YY each independently hydrogen or unsubstituted lower alkyl; or aryl; Y is --NR.sup.1R.sup.2, --NR.sup.X-G(S.sub.C)--C(O)-Q.sup.1, or --O--C(O)-G(S.sub.C)--NH-Q.sup.2; R.sup.1 is hydrogen, unsubstituted alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, -alkyl-(unsubstituted aryl), -alkyl-(substituted aryl), or heteroarylalkyl; R.sup.2 is hydrogen or unsubstituted alkyl; Q.sup.1 is --SR.sup.Y, --NR.sup.YR.sup.Y or unsubstituted alkoxyl; R.sup.Y is hydrogen or unsubstituted alkyl; S.sub.C is a side chain of a naturally occurring or non-naturally occurring amino acid; or S.sub.C is hydrogen, unsubstituted alkyl, substituted alkyl, -alkyl-(unsubstituted aryl), -alkyl-(substituted aryl), heterocycloalkyl, carboxylalkyl, heteroarylalkyl, alkyl substituted with --NR.sup.1'R.sup.2' (where each R.sup.1' and R.sup.2' are independently selected from hydrogen, unsubstituted alkyl and unsubstituted cycloalkyl), hydroxylalkyl, -alkyl-NH--C(NH)--NH.sub.2, -alkyl-C(O)NH.sub.2, sulfanylalkyl, alkylsulfanylalkyl, or hydroxylarylalkyl; G is C.sub.1-C.sub.2 alkyl; R.sup.X is hydrogen or R.sup.X and S.sub.C, together with the atoms to which they are attached, combine to form a five-membered heterocyclic ring; Q.sup.2 is hydrogen or unsubstituted alkoxyl; or Q.sup.2 and S.sub.C, together with the atoms to which they are attached, combine to form a five-membered heterocyclic ring; Z is unsubstituted alkyl, substituted alkyl, alkoxycarbonyl or alkoxyalkylcarbonyl; A is --CHR.sup.10--, --CHR.sup.10CHR.sup.11--, or --CHR.sup.10CHR.sup.11CHR.sup.12--; R is hydrogen or unsubstituted alkyl; each of R.sup.10, R.sup.11, and R.sup.12 is independently hydrogen or unsubstituted alkyl; or R.sup.10 and R.sup.11, together with the carbon atoms to which they are attached, combine to form a five-, six-, or seven-membered ring; each "alkyl," unless specified otherwise, is unsubstituted; each alkoxy is --OR' where R' is unsubstituted alkyl or unsubstituted cycloalkyl; each "substituted alkyl" is independently alkyl substituted with moiety(ies) selected from halogen; hydroxyl; sulfanyl; --NR.sup.1'R.sup.2' where each R.sup.1' and R.sup.2' are independently selected from hydrogen, unsubstituted alkyl and unsubstituted cycloalkyl; --NH (unsubstituted aryl), --N(unsubstituted aryl).sub.2; --OR' where R' is unsubstituted alkyl or unsubstituted cycloalkyl; --O-(unsubstituted aryl); nitro; cyano; sulfonic acid; sulfate; phosphonic acid; and phosphate; each cycloalkyl is a saturated, monocyclic hydrocarbon or a bridged or fused bicyclic hydrocarbon comprising 3 to 15 carbon atoms; the cycloalkyl is unsubstituted or substituted, unless otherwise specified, and when substituted is substituted with moiety(ies) selected from halogen; hydroxyl; sulfanyl; --NR.sup.1'R.sup.2' where each R.sup.1' and R.sup.2' are independently selected from hydrogen, unsubstituted alkyl and unsubstituted cycloalkyl; --NH(unsubstituted aryl), --N(unsubstituted aryl).sub.2; --OR' where R' is unsubstituted alkyl or unsubstituted cycloalkyl; --O-(unsubstituted aryl); nitro; cyano; sulfonic acid; sulfate; phosphonic acid; and phosphate; the heterocyclo in heterocycloalkyl is a monovalent, monocyclic, non-aromatic ring system or a fused or bridged, bicyclic, tricyclic, or tetracyclic ring system that is partially or fully saturated or aromatic provided that it contains at least one non-aromatic ring; wherein the heterocyclo comprises 3 to 20 ring atoms; wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, or N and the remaining ring atoms are carbon atoms and where the nitrogen or sulfur atoms may be optionally oxidized, and the nitrogen atoms may be optionally quaternized; and wherein the heterocyclo may be attached to the alkyl at any heteroatom or carbon atom which results in the creation of a stable compound; and wherein the heterocyclo ring is unsubstituted or substituted and when substituted is substituted with moiety(ies) selected from halogen; hydroxyl; alkoxycarbonyl; alkoxycarbonylalkyl; sulfanyl; --NR.sup.1'R.sup.2' where each R.sup.1' and R.sup.2' are independently selected from hydrogen, unsubstituted alkyl and unsubstituted cycloalkyl; --NH(unsubstituted aryl), --N(unsubstituted aryl).sub.2; --OR' where R' is unsubstituted alkyl or unsubstituted cycloalkyl; --O-(unsubstituted aryl); nitro; cyano; sulfonic acid; sulfate; phosphonic acid; and phosphate; each aryl is a C.sub.6-C.sub.12 aromatic group and is unsubstituted or substituted, unless otherwise specified, and when substituted is substituted with moiety(ies) selected from halogen; unsubstituted alkyl; substituted alkyl; haloalkyl; hydroxyl; --NR.sup.1'R.sup.2' where each R.sup.1' and R.sup.2' are independently selected from hydrogen, unsubstituted alkyl and unsubstituted cycloalkyl; --NH(unsubstituted aryl), --N(unsubstituted aryl).sub.2; --OR' where R' is unsubstituted alkyl or unsubstituted cycloalkyl; --O-(unsubstituted aryl); nitro; cyano; sulfonic acid; sulfate; phosphonic acid; and phosphate; and each heteroaryl is a monovalent monocyclic aromatic group or multicyclic aromatic group that contains at least one aromatic ring; wherein the ring comprises 5 to 20 ring atoms; wherein at least one aromatic ring contains one to four heteroatoms independently selected from O, S, and N, provided that the ring contains at least one carbon atom; and where the heteroaryl is bonded to the rest of the molecule through the aromatic ring.

19. A pharmaceutical composition comprising the compound of claim 18 and a pharmaceutically acceptable excipient, carrier, or diluent.

20. A method for the treatment of a host infected with a hepatitis C virus, comprising the administration of an effective treatment amount of a compound of claim 18.

Details for Patent 9,339,541

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 ⤷  Try a Trial 2039-03-29
Merck Sharp & Dohme Corp. INTRON A interferon alfa-2b For Injection 103132 ⤷  Try a Trial 2039-03-29
Merck Sharp & Dohme Corp. INTRON A interferon alfa-2b Injection 103132 ⤷  Try a Trial 2039-03-29
Kadmon Pharmaceuticals Llc INFERGEN interferon alfacon-1 Injection 103663 10/06/1997 ⤷  Try a Trial 2039-03-29
Hoffmann-la Roche Inc. PEGASYS COPEGUS COMBINATION PACK peginterferon alfa-2a and ribavirin 125083 06/04/2004 ⤷  Try a Trial 2039-03-29
Schering Corporation A Subsidiary Of Merck & Co., Inc. PEGINTRON/ REBETOL COMBO PACK peginterferon alfa-2b and ribavirin 125196 06/13/2008 ⤷  Try a Trial 2039-03-29
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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