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DK1576138T3 - 2'-methylnukleosider i kombination med interferon og flaviviridae-mutation - Google Patents

2'-methylnukleosider i kombination med interferon og flaviviridae-mutation Download PDF

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Publication number
DK1576138T3
DK1576138T3 DK03796412.9T DK03796412T DK1576138T3 DK 1576138 T3 DK1576138 T3 DK 1576138T3 DK 03796412 T DK03796412 T DK 03796412T DK 1576138 T3 DK1576138 T3 DK 1576138T3
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ester
virus
nucleoside
alkyl
amino acid
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DK03796412.9T
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Jean-Pierre Sommadossi
Colla Paolo La
David Standring
Vadim Bichko
Lin Qu
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Idenix Pharmaceuticals Llc
Univ Degli Studi Cagliari
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Claims (3)

1. 2'-methylnukleosid, eller dets farmaceutisk acceptable salt, eventuelt i en farmaceutisk acceptabel bærer eller fortynder, til anvendelse i en fremgangsmåde til behandling af hepatitis C-virus i en vært, hvor fremgangsmåden omfatter at administrere 2'-methylnukleosidet eller dets farmaceutisk acceptable salt, eventuelt i en farmaceutisk acceptabel bærer eller fortynder, og at administrere interferon, hvor 2'-methylnukleosidet har forårsaget en mutation ved nukleotid 8443 (G til C) af hepatitis C-virusgenomet eller fra aminosyre 282 Serin til Threonin af RNA-polymeraseregionen af hepatitis C-virus. 2. 2'-methylnukleosidet til anvendelse ifølge krav 1, hvor 2'-methylnukleosidet er af formlen:
eller dets farmaceutisk acceptable salt, hvor R1, R2, og R3 er uafhængigt H, phosphat (der inkluderer mono-, di- eller triphosphat og et stabiliseret phosphat); acyl; alkyl; sulfonatester (der inkluderer alkyl eller arylalkyl sulfonyl der inkluderer methanesulfonyl); benzyl, hvor phenylgruppen eventuelt er substitueret med en eller flere substituenter; lipid (der inkluderer et phospholipid); aminosyre; kulhydrat; peptid; kolesterol; eller en farmaceutisk acceptabel leaving group der tilvejebringer en forbindelse, hvor R1, R2 eller R3 er uafhængigt H eller phosphat når administreret in vivo; og R4 er methyl; og Base er en purin eller pyrimidin. 3. 2'-methylnukleosidet til anvendelse ifølge krav 2, hvor 2'-methylnukleosidet er af formlen:
eller dets farmaceutisk acceptable salt, hvor i R1 og R2 er uafhængigt H; mono-, di- eller triphosphat; acyl; sulfonatester; benzyl; en aminosyreester; et kulhydrat; et peptid; et kolesterol eller en farmaceutisk acceptabel leaving group, der tilvejebringer en forbindelse, hvor R1 eller R2 er uafhængigt H eller phosphat når administreret in vivo; R3 er hydrogen; i R4 er methyl; og Base er pyrimidin. 4. 2'-methylnukleosidet til anvendelse ifølge et hvilket som helst af de foregående krav, hvor R1, R2, eller R3 er en naturlig eller syntetisk D- eller L-aminosyreester. 5. 2'-methylnukleosidet til anvendelse ifølge et hvilket som helst af de foregående krav, hvor R1, R2, eller R3 er en naturlig eller syntetisk D- eller L-aminosyreester eller en alkylester. i 6. 2'-methylnukleosidet til anvendelse ifølge et hvilket som helst af de foregående krav, hvor 2'-methylnukleosidet er β-ϋ-2'-ΟΗ3-Γ^ο€. 7. 2'-methylnukleosidet til anvendelse ifølge krav 6, hvor R2 er en aminosyreester. 8. 2'-methylnukleosidet til anvendelse ifølge krav 7, hvor R2 er en L-valinylester. 9. 2'-methylnukleosidet til anvendelse ifølge et hvilket som helst af de foregående krav, hvor R1 er et mono-, di- eller triphosphat. 10. 2'-methylnukleosidet til anvendelse ifølge et hvilket som helst af de foregående krav, hvor 2'-methylnukleosidet er 3-D-2'-CH3-riboC og hvor fremgangsmåden yderligere omfatter trinnet at identificere virusresistens i værten. 11. 2'-methylnukleosidet til anvendelse ifølge et hvilket som helst af kravene 1 til 9, hvor fremgangsmåden yderligere omfatter trinnet at analysere blodet af værten for at teste for serokonversion fra vild-type til mutantvirus efter administration af 2'-methylnukleosidet til værten. 12. 2'-methylnukleosidet til anvendelse ifølge et hvilket som helst af kravene 1 til 9, hvor fremgangsmåden yderligere omfatter trinnene: (a) at opnå en virusprøve fra værten; (b) at bestemme replikationsfitness af virussen; (c) at bestemme hvorvidt replikationsfitness af virussen i prøven er mindre end replikationsfitness af vild-type virussen, hvilket indikerer resistens over for 2'-methylnukleosidet; efter administration af 2'-methylnukleosidet til værten. 13. 2'-methylnukleosidet til anvendelse ifølge et hvilket som helst af kravene 1 til 9, hvor fremgangsmåden yderligere omfatter trinnene: (a) at opnå en virusprøve fra værten; (b) at dyrke prøven og sammenligne plaquevæksten mellem prøven og vild-type virussen; (c) at bestemme hvorvidt plaquevæksten af prøven er mindre end plaquevæksten af vild-typen, hvilket indikerer resistens over for 2'-methylnukleosidet; efter administration af 2'-methylnukleosidet til værten.
14. Interferon til anvendelse i en fremgangsmåde til behandling af hepatitis C-virus i en vært, hvor værten har fået administreret et 2'-methylnukleosid, eller dets farmaceutisk acceptable salt, eventuelt i en farmaceutisk acceptabel bærer eller fortynder, hvilket har forårsaget en mutation ved nukleotid 8443 (G til C) af hepatitis C-virusgenomet eller fra aminosyre 282 Serin til Threonin af RNA-polymeraseregionen af hepatitis C-virus.
15. Interferon til anvendelse i en fremgangsmåde ifølge krav 14 yderligere omfattende en hvilken som helst af egenskaberne af kravene 2 til 13.
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US20140286900A1 (en) 2014-09-25
US7824851B2 (en) 2010-11-02
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