DK2480552T3 - 2' -fluorsubstituerede carba-nukleosidanaloger til antiviral behandling - Google Patents

2' -fluorsubstituerede carba-nukleosidanaloger til antiviral behandling Download PDF

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DK2480552T3
DK2480552T3 DK10763083.2T DK10763083T DK2480552T3 DK 2480552 T3 DK2480552 T3 DK 2480552T3 DK 10763083 T DK10763083 T DK 10763083T DK 2480552 T3 DK2480552 T3 DK 2480552T3
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Aesop Cho
Choung U Kim
Samuel E Metobo
Adrian S Ray
Jie Xu
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Gilead Sciences Inc
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Claims (26)

  1. 2' -FLUORSUBSTITUEREDE CARBA-NUKLEOSIDANALOGER TIL ANTIVIRAL BEHANDLING PATENTKRAV
    1. Forbindelse med formel I:
    Formel I eller et farmaceutisk acceptabelt salt deraf; hvor: R1 er (Ci-C8)-alkyl, (C4-C8)-carbocyclylalkyl, (Ci-C8)-substitueret alkyl, (C2-C8)-alkenyl, (C2-C8)-substitueret alkenyl, (C2-C8)-alkynyl, (C2-C8)-substitueret alkynyl eller aryl(Ci-C8)-alkyl; R2 er F; hvert R3, R4 eller R5 uafhængigt er H, ORaN(Ra)2, N3, CN, N02, S(0)nRa, halogen, (Ci-C8)-alkyl, (C4-C8)-carbocyclylalkyl, (Ci-C8)-substitueret alkyl, (C2-C8)-alkenyl, (C2-C8)-substitueret alkenyl, (C2-C8)-alkynyl, (C2-C8)-substitueret alkynyl eller aryl(Ci-C8)-alkyl; eller hvilke som helst to af R3, R4 eller R5 på tilstødende carbonatomer, når de tages sammen, er -0(C0)0- eller når taget sammen med de ringcarbonatomer, hvortil de er bundet, danner en dobbelt binding; R6 er H, ORa, N(Ra)2, N3, CN, N02, S(0)nRa, -C(-())R", -Cf-OKtR1 , - C(-())NRMR12, -C(0)SRu -S(0)Rn, -S(0)2Rn, -S(0)(0Rn), -S(0)2(0Rn), -S02NRuR12, halogen, (Ci-C8)-alkyl, (C4-C8)-carbocyclylalkyl, (Ci-C8)-substitueret alkyl, (C2-C8)-alkenyl, (C2-C8)-substitueret alkenyl, (C2-C8)-alkynyl, (C2-C8)-substitueret alkynyl eller aryl(Ci-C8)-alkyl; hvert n uafhængigt er 0, 1 eller 2; hvert Ra uafhængigt er H, (СгС8)-а1ку1, (C2-C8)-alkenyl, (C2-C8)-alkynyl, aryl(Ci-C8)-alkyl, (C4-C8)-carbocyclylalkyl, -C(=0)R11 -C(=0)0Rn, -C(=0)NR11R12, -C(=0)SRn, -S(0)Rn, S(0)2Rn -S^COR11), -S(0)2(0Rn) eller -S02NR11R12’ R7 er H, -C(=0)Rn, -C(=0)0Ru, -C(=0)NR11R12, -C(=0)SRn, -S(0)Rn, - S(0)2R11, -S(0)(0R13), -S(0)2(0Rn), -S02NRuR12 eller
    hvert Y eller Y1 er, uafliængigt, O, S, NR, +N(0)(R), N(OR), +N(0)(0R) eller N-NR2; W1 og W2, når de tages sammen, er -Y3(C(Ry)2)3Y3-; eller en af W1 eller W2 sammen med enten R3 eller R4 er -Y3- og den anden af W1 eller W2 er formel la; eller W1 og W2 hver, uafhængigt, er en gruppe med formel la:
    Formel la hvor: hvert Y2 uafhængigt er en binding, O, CR2, NR, dSf(0)(R), N(OR), ^(0)(0R), N-NR2, S, S-S, S(O) eller S(0)2; hvert Y3 uafhængigt er O, S eller NR; M2 er 0, 1 eller 2; hvert Rx uafhængigt er Ry eller formlen:
    hvor: hvert Mia, Mlc, og Mld uafhængigt er 0 eller 1; M12c er 0, 1, 2, 3,4, 5, 6, 7, 8, 9,10, 11 eller 12; hvert Ry uafhængigt er H, F, Cl, Br, I, OH, R, -C(=Y')R, -C(=Y1)OR,-C(=Y1)N(R)2, -N(R)2, -4N(R)3, -SR, -S(0)R, -S(0)2R, -S(0)(0R), -S(0),(0R),-0C(=Y1)R, -OC(=Y1)OR, -OC(=Y1)(N(R)2), -SC(=Y‘)R, -SC(=Y1)OR,-SC(=Y1)(N(R)2), -N(R)C(=Y1)R, -N(R)C(=Y1)OR, -N(R)C(=Y1)N(R)2, -so2nr2, -CN, -N3, -N02, -OR eller W3; eller når de tages sammen, to Ry på det samme carbonatom danner en carbocyklisk ring på 3 til 7 carbonatomer; hvert R uafhængigt er H, (Ci-C8)-alkyl, (Ci-C8)-substitueret alkyl, (C2-C8)-alkenyl, (C2-C8)-substitueret alkenyl, (C2-C8) alkynyl, (C2-C8)-substitueret alkynyl, C6-C20-aryl, C6-C20-substitueret aryl, C2-C20-heterocyclyl, C2-C20-substitueret heterocyclyl, arylalkyl eller substitueret arylalkyl; W3 er W4 eller W5; W4 er R, -С(Ү^У, -С(Ү])\Ү5, -S02Ry eller -S02W5; og W5 er en carbocyklus eller et heterocyklus, hvor W5 uafhængigt er substitueret med 0 til 3 Ry-grupper; hvert X1 eller X2 uafhængigt er C-R10 eller N; hvert R8 er halogen, NRUR12, N(Rn)ORn, NRnNRnR12, N3, NO, NOz, CHO, CN, -CH(=NRn), -CH=NNHRU, -CH=N(ORn), -CH(ORn)2, -C(=0)NRnR12, -C(=S)NRnR12, -C(=0)0Rn, (CrC8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C4-C8)-carbocyclylalkyl, eventuelt substitueret aryl, eventuelt substitueret heteroaryl, -C(=0)(CrC8)-alkyl, -S(0)n(CrC8)-alkyl, aryl(CrC8)-alkyl, OR11 eller SR11; hvert R9 eller R10 uafhængigt er H, halogen, NRnR12, N(R1)OR11, NRnNRnR12, N3, NO, N02, CHO, CN, -CH(=NRn), -CH=NHNR1J, -CH=N(ORu), -CII(ORM)2, -C(=0)NR"r'2, -C(=S)NR"r'\ -C(=0)0Rn, R11, OR11 eller SR11; hvert R11 eller R12 uafhængigt er H, (C]-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C4-C8)-carbocyclylalkyl, eventuelt substitueret aryl, eventuelt substitueret heteroaryl, -C(=0)(Ci-C8)-alkyl, -S(0)n(Ci-C8)-alkyl eller aryl(Ci-C8)-alkyl; eller R11 og R12 taget sammen med et nitrogen til hvilket de begge er bundet, danner en 3- til 7-leddet heterocyklisk ring, hvor et hvilket som helst carbonatom fra den heterocykliske ring eventuelt kan erstattes med -O-, -S- eller -NRa-; hvor hvert (C!-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl eller агу1(С!-С8)-а1ку1 fra hvert R1, R3, R4, R5, R6, R11 eller R12 uafhængigt eventuelt er substitueret med en eller flere halo, hydroxy, CN, N3, N(Ra)2 eller ORa; og hvor et eller flere af de ikke-terminale carbonatomer fra hvert (Ci-C8)-alkyl eventuelt kan erstattes med -O-, -S- eller -NRa-, med det forbehold at forbindelsen med formel I ikke er en forbindelse, der er repræsenteret ved en hvilken som helst af de følgende formler, i hvilke R er H:
    eller % ынг J H0 'Г T, R<? \
  2. 2. Forbindelse ifølge krav 1, der er repræsenteret ved formel II
    Formel TT hvor hvert Y og Y1 er O; X1 er CR10 eller N og X2 er CH; eller et farmaceutisk acceptabelt salt eller ester deraf.
  3. 3. Forbindelse ifølge krav 1 eller 2, hvor R8 er halogen, NRnR12, N(Rn)ORn, NRnNRnR12, OR11 eller SR11.
  4. 4. Forbindelse ifølge et hvilket som helst af kravene 1-3, hvor R9 er H, halogen, SR11 eller NRnRu.
  5. 5. Forbindelse ifølge et hvilket som helst af kravene 1-4, hvor R6 er H, ORd, CN, methyl, ethenyl eller ethynyl.
  6. 6. Forbindelse ifølge et hvilket som helst af kravene 1-5, hvor R6 er H.
  7. 7. Forbindelse ifølge et hvilket som helst af kravene 1-5, hvor R6 er CN.
  8. 8. Forbindelse ifølge et hvilket som helst af kravene 1-7, hvor R4 er ORa.
  9. 9. Forbindelse ifølge et hvilket som helst af kravene 1 -8, der er repræsenteret ved formel TTI
    Formel III hvor R1 er methyl eller ethynyl; eller et farmaceutisk acceptabelt salt eller ester deraf.
  10. 10. Forbindelse ifølge et hvilket som helst af kravene 1-9, hvor R7 er H eller
  11. 11. Forbindelse ifølge et hvilket som helst af kravene
    1-10, hvor R7 er
  12. 12. Forbindelse ifølge et hvilket som helst af kravene 1-11, hvor R1 er CH3.
  13. 13. Forbindelse ifølge krav 1 med den følgende formel:
    eller
    eller et farmaceutisk acceptabelt salt eller ester deraf.
  14. 14. Forbindelse med den følgende formel: eller
    eller et farmaceutisk acceptabelt salt eller ester deraf.
  15. 15. Forbindelse anvendelig til fremstilling af en forbindelse med formel I udvalgt Ira gruppen bestående af
    - 10 -
    eller salte eller estere deraf.
  16. 16. Farmaceutisk sammensætning, der omfatter en terapeutisk effektiv mængde af en forbindelse ifølge krav 1 og en farmaceutisk acceptabel bærer.
  17. 17. Farmaceutisk sammensætning ifølge krav 16, hvilken sammensætning endvidere omfatter mindst ét yderligere terapeutisk middel udvalgt fra gruppen bestående af interferoner, ribavirin eller dets analoger, HCV NS3-proteaseinhibitorer, NS5a-inhibitorer, alpha-glucosidase 1-inhibitorer, leverbeskyttelsesmidler, mevalonatdecarboxylaseantagonister, antagonister af renin-angiotensinsystemet, endothelinantagonister, andre anti-fibrotiske midler, nukleosid- eller nukleotidinhibitorer af HCV NS5B-polymerase, ikke-nukleo sidinhibitorer af HCV NS5B-polymerase, HCV NS5A-inhibitorer, TLR-7-agonister, cyclophillinmhibitorer, HCV TRF.S-inhibitorer, pharmacokinetiske enhancere og andre lægemidler til behandling af I IC V; eller blandinger deraf.
  18. 18. Forbindelse ifølge et hvilket som helst af kravene 1 til 14 til anvendelse som et medikament.
  19. 19. Forbindelse ifølge et hvilket som helst af kravene 1 til 14 til anvendelse til behandling af en Flaviviridae-γ irusinfektion.
  20. 20. Forbindelse ifølge krav 19, hvor virusinfektionen er en hepatitis C-virusinfektion.
  21. 21. Forbindelse ifølge krav 19 eller 20, hvor virusinfektionen er forårsaget af en S282T-mutant af hepatitis C-virus.
  22. 22. Blanding til anvendelse til behandling af en Flaviviridae-vimsinfektion, hvilken blanding omfatter forbindelsen ifølge et hvilket som helst af kravene 19 til 21, der endvidere omfatter mindst ét yderligere terapeutisk middel udvalgt fra gruppen bestående af inteneroner, ribavirin eller dets analoger, HCV NS3-proteaseinhibitorer, NS5a-inhibitorer, alpha-glucosidase 1-inhibitorer, leverbeskyttelsesmidler, mevalonatdecarboxylaseantagonister, antagonister af renin-angiotensinsystemet, endothelinantagonister, andre anti-fibro tiske midler, nukleosid- eller nukleotidinhibitorer af HCV NS5B-polymerase, ikke-nukleo sidinhibitorer af HCV NS5B-polymerase, HCV NS5A-inhibitorer, TLR-7-agonister, cyclophillininhibitorer, HCV IRES-inhibitorer, farmakokinetiske enhancere og andre lægemidler til behandling af HCV; eller blandinger deraf.
  23. 23. Anvendelse af en forbindelse ifølge et hvilket som helst af kravene 1-14 til fremstilling af et lægemiddel til behandling af en Flaviviridae-virusinfektion.
  24. 24. Anvendelse ifølge krav 23, hvor A/avrøridae-virusinfektionen er forårsaget af hepatitis C-virus.
  25. 25. Anvendelse ifølge krav 23 eller 24, hvor Flaviviridae-vimsinfektionen er forårsaget af en S282T-mutant af hepatitis C-virus.
  26. 26. Anvendelse af en forbindelse ifølge et hvilket som helst af kravene 1-15 til fremstilling af et medikament til behandling eller forebyggelse af en Flaviviridae-v irusinfektion, hepatitis C-virusinfektion eller S282T-mutant af hepatitis C-virusinfektion.
DK10763083.2T 2009-09-21 2010-09-20 2' -fluorsubstituerede carba-nukleosidanaloger til antiviral behandling DK2480552T3 (da)

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