DK2362218T3 - Fremgangsmåder til overvågning af effektiviteten af farnesyltransferaseinhibitorer - Google Patents

Fremgangsmåder til overvågning af effektiviteten af farnesyltransferaseinhibitorer Download PDF

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DK2362218T3
DK2362218T3 DK11158145.0T DK11158145T DK2362218T3 DK 2362218 T3 DK2362218 T3 DK 2362218T3 DK 11158145 T DK11158145 T DK 11158145T DK 2362218 T3 DK2362218 T3 DK 2362218T3
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Anne Fourie
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Janssen Pharmaceutica Nv
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Claims (15)

1. Fremgangsmåde til bestemmelse af et respons fra et individ, der lider af sepsis eller septisk chok til behandling med en farnesyltransferaseinhibitor, omfattende de følgende trin: (i) måling af et niveau af mindst én markør, der er udvalgt fra gruppen bestående af de proteiner, der er identificeret i Tabel 4, og af transskriptioner af de gener, som identificeres i Tabel 2 og 3 i en ubehandlet blodprøve, der er opnået fra individet inden behandling med farnesyltransferaseinhibitoren, og (ii) måling af et niveau af markøren i en behandlet blodprøve, der er opnået fra individet mindst ét tidspunkt efter behandling med farnesyltransferaseinhibitoren er begyndt, og (iii) sammenligning af niveauerne af markøren, hvor en formindskelse i niveauet af markøren, der er målt i den ubehandlede blodprøve, til niveauet af markøren, der er målt i den behandlede blodprøve, angiver et respons til behandlingen.
2. Fremgangsmåde ifølge krav 1, hvor fremgangsmåden omfatter de følgende trin: (a) (i) isolering af celler eller plasma fra den ubehandlede blodprøve for at opnå en ubehandlet prøveekstrakt, og (ii) isolering af celler eller plasma fra den behandlede blodprøve for at opnå en behandlet prøveekstrakt; (b) (i) måling af et niveau af mindst én af IL-6, MCP-1, IL-1 β, MMP-9 og TNF-α i den ubehandlede prøveekstrakt, og (ii) måling af et niveau af mindst én af IL-6, MCP-1, IL-1 β, MMP-9 og TNF-α i hver behandlet prøveekstrakt, og (iii) sammenligning af niveauerne af mindst én af IL-6, MCP-1, IL-1 β, MMP-9, MIP-1a og TNF-α, hvor en formindskelse af niveauet af mindst én af IL-6, MCP-1, IL-1 β, MMP-9, MIP-1a og TNF-α målt i den ubehandlede prøveekstrakt, til niveauet af mindst én af IL-6, MCP-1, IL-1 β, MMP-9, MIP-1 α og TNF-α målt i den behandlede prøveekstrakt, angiver et respons til behandlingen.
3. Fremgangsmåde ifølge krav 1, hvor fremgangsmåden omfatter de følgende trin: (a) (i) isolering af mononukleære celler af perifært blod fra den ubehandlede blodprøve for at opnå en ubehandlet PBMC-prøve, og (ii) isolering af mono- nukleære celler af perifært blod fra hver behandlet blodprøve for at opnå en behandlet PBMC-prøve; (b) (i) stimulering af den ubehandlede PBMC-prøve med lipopolysaccharid for at opnå en LPS-stimuleret ubehandlet PBMC-prøve, og (ii) stimulering af hver behandlet PBMC-prøve med lipopolysaccharid for at opnå LPS-stimuleret, behandlet PBMC-prøve; (c) (i) isolering af RNA af den ubehandlede LPS-stimulerede PBMC-prøve, og (ii) isolering af RNA af hver behandlet LPS-stimulerede PBMC-prøve; (d) (i) måling af ekspressionen af mindst én af IL-1 β, MCP-1, MMP-9, MyD88, STAT1 og IL-6 i RNA af det ubehandlede LPS-stimulerede PBMC-prøve, og (ii) måling af ekspressionen af mindst én af IL-1 β, MCP-1, MMP-9, MyD88, STAT1 og IL-6 i RNA af hver behandlet LPS-stimulerede PBMC-prøve, og (iii) sammenligning af ekspressionsmålingerne af mindst én af IL-1β, MCP-1, MMP-9, MyD88, STAT1 og IL-6, hvor en formindskelse angiver et respons til behandlingen.
4. Fremgangsmåde ifølge et af kravene 1, 2 eller 3, hvor farnesyltransferase-inhibitoren omfatter en forbindelse med formelen (I):
en stereoisomerisk form deraf, et farmaceutisk acceptabelt syre- eller baseadditionssalt deraf, hvor den punkterede line står for en eventuel binding; X er oxygen eller sulfur; R1 er hydrogen, Ci-i2alkyl, Ar1, Ar2Ci.6alkyl, quinolinylCi.6alkyl, pyridylCi. 6alkyl, hydroxyCi_6alkyl, Ci-6alkyloxyCi-6alkyl, mono- eller di(Ci_ 6alkyl)aminoCi-6alkyl, aminoCi_6alkyl eller en rest med formelen -Alk1-C(=0)-R9, -Alk1-S(0)-R9 eller -Alk1-S(0)2-R9, hvor Alk1 er Ci_6alkanediyl, R9 er hydroxy, Ci-6alkyl, Ci-6alkyloxy, amino, Ci-salkylamino eller Ci-salkylamino substitueret med Ci-6alkyloxycarbonyl; R2, R3 og R16 hver især uafhængigt er hydrogen, hydroxy, halo, cyano, Ci- 6alkyl, Ci.6alkyloxy, hydroxyCi.6alkyloxy, Ci-6alkyloxyCi-6alkyloxy, amino-Ci. ealkyloxy, mono- eller di(Ci-6alkyl)aminoCi-6alkyloxy, Ar1, Ai^Ci-ealkyl, Ai^oxy, Ar2Ci.6alkyloxy, hydroxycarbonyl, Ci.6alkyloxycarbonyl, trihalomethyl, triha-lomethoxy, C^ealkenyl, 4,4-dimethyloxazolyl; eller når de befinder sig på tilgrænsende positioner, R2 og R3 tilsammen kan danne en bivalent rest med formlen -O-CH2-O- (a-1), -O-CH2-CH2-O- (a-2), -0-CH=CH- (a-3), -O-CH2-CH2- (a-4), -O-CH2-CH2-CH2- (a-5), eller -CH=CH-CH=CH- (a-6); R4 og R5 hver især uafhængigt er hydrogen, halo, Ar1, Ci_6alkyl, hydroxy-Ci. 6alkyl, Ci-6alkyloxyCi-6alkyl, Ci-6alkyloxy, Ci-6alkylthio, amino, hydroxycarbonyl, Ci-6alkyloxycarbonyl, Ci-6alkylS(0)Ci-6alkyl eller Ci-6alkylS(0)2Ci. ealkyl; R6 og R7 hver især uafhængigt er hydrogen, halo, cyano, Ci-6alkyl, Ci_ ealkyloxy, Ar2oxy, trihalomethyl, Ci-6alkylthio, di(Ci.6alkyl)amino, eller når de befinder sig på tilgrænsende positioner, R6 og R7 tilsammen kan danne en bivalent rest med formlen -O-CH2-O- (c-1), eller -CH=CH-CH=CH- (c-2); R8 er hydrogen, Ci-6alkyl, cyano, hydroxycarbonyl, Ci-6alkyloxycarbonyl, Ci. 6alkylcarbonylCi-6alkyl, cyanoCi-6alkyl, Ci-6alkyloxycarbonylCi-6alkyl, car-boxyCi-6alkyl, hydroxyCi-ealkyl, aminoCi-6alkyl, mono- or di(Ci-6alkyl)-aminoCi-6alkyl, imidazolyl, haloCi-6alkyl, Ci-6alkyloxyCi-6alkyl, aminocar-bonylCi-6alkyl eller en rest med formelen -O-R10 (b-1), -S-R10 (b-2), -N-R11R12 (b-3), hvor R10 er hydrogen, Ci-6alkyl, Ci-6alkylcarbonyl, Ar1, Ar^Ci-ealkyl, Ci-6alkyloxycarbonylCi-6alkyl, en rest med formelen -Alk2-OR13 eller -Alk2-NR14R15; R11 er hydrogen, Ci-^alkyl, Ar1 eller Ar^Ci-ealkyl; R12 er hydrogen, Ci-6alkyl, Ci-i6alkylcarbonyl, Ci-6alkyloxycarbonyl, Ci-6alkylaminocarbonyl, Ar1, Ar^Ci-ealkyl, Ci-6alkylcarbonylCi-6alkyl, en naturlig aminosyre, Ar1carbonyl, Ar2Ci_6alkylcarbonyl, aminocarbonylcarbonyl, Ci-6alkyloxyCi-6alkylcarbonyl, hydroxy, Ci_6alkyloxy, aminocarbonyl, di(Ci_ 6alkyl)aminoCi-6 alkylcarbonyl, amino, Ci-6alkylamino, Ci-6alkylcarbonylamino, eller en rest med formelen -Alk2-OR13 eller -Alk2-NR14R15; hvor Alk2 er Ci-6alkanediyl; R13 er hydrogen, Ci-6alkyl, Ci-6alkylcarbonyl, hydroxyCi_6alkyl, Ar1 eller Ar2Ci-6alkyl; R14 er hydrogen, Ci-6alkyl, Ar1 eller Ar2Ci_6alkyl; R15 er hydrogen, Ci-6alkyl, Ci-6alkylcarbonyl, Ar1 eller Ar2Ci_6alkyl; R17 er hydrogen, halo, cyano, Ci-ealkyl, Ci-6alkyloxycarbonyl, Ar1; R18 er hydrogen, Ci-6alkyl, Ci.6alkyloxy eller halo; R19 er hydrogen eller Ci_6alkyl; Ar1 er phenyl eller phenyl substitueret med C^alkyl, hydroxy, amino, Ci-6alkyloxy eller halo; og Ar2 er phenyl eller phenyl substitueret med C^alkyl, hydroxy, amino, Ci-6alkyloxy eller halo.
5. Fremgangsmåde ifølge krav 4, hvorfarnesyltransferaseinhibitoren er: (a) en forbindelse med formelen (I), hvor X er oxygen, og den punkterede linje står for en binding; eller (b) en forbindelse med formelen (I), hvor R1 er hydrogen, Ci-ealkyl, Ci_ 6alkyloxy-Ci-6alkyl eller mono- eller di(Ci-6alkyl)aminoCi-6alkyl; R2 er halo, Ci-ealkyl, C2-6alkenyl, Ci-6alkyloxy, trihalomethoxy eller hydroxyCi-6alkyloxy; og R3 er hydrogen; eller (c) (+)-6-[amino(4-chlorophenyl)(1 -methyl-1 H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1/-/)-quinolinon; eller et farmaceutisk acceptabelt additionssalt deraf.
6. Fremgangsmåde ifølge krav 4, hvor R8 er hydrogen, hydroxy, haloCi-6alkyl, hydroxyCi-6alkyl, cyanoCi-6alkyl, Ci-6alkyloxycarbonylCi-6alkyl, imida-zolyl, eller en rest med formelen NR11R12 hvor R11 er hydrogen eller Ci_i2alkyl og R12 er hydrogen, Ci-ealkyl, Ci-6alkyloxy, Ci-6alkyloxyCi-6alkylcarbonyl, hydroxy eller en rest med formelen -Alk2-OR13 hvor R13 er hydrogen eller Ci-ealkyl.
7. Fremgangsmåde ifølge krav 1, hvor den mindst én markør er udvalgt fra gruppen bestående af IL-6, MCP-1, IL-1 β, MMP-9 og TNF-a.
8. Fremgangsmåde ifølge et af kravene 1 eller 2, hvor der i undertrin (ii) anvendes et flertal af behandlede blodprøver fra individet, som blev taget med periodiske tidsintervaller, efter behandling med farnesyltransferaseinhibitoren var begyndt.
9. Fremgangsmåde ifølge krav 1, hvor blodprøven er helblod, plasma, serum, samlede celler eller mononukleære celler af perifært blod.
10. Fremgangsmåde ifølge krav 2, hvor undertrinnene (b)(i) og (b)(ii) omfatter: (i) isolering af plasma fra den ubehandlede blodprøve ved centrifugering for at opnå en ubehandlet prøveekstrakt, og (ii) isolering af plasma fra hver behandlet blodprøve ved centrifugering for at opnå en behandlet prøveekstrakt.
11. Fremgangsmåde ifølge krav 2, hvor undertrinnene (b)(i) og (b)(ii) omfatter: (i) isolering af mononukleære celler af perifært blod fra den ubehandlede blodprøve ved Ficoll-Paque-gradient-separation for at opnå den ubehandlede prøveekstrakt, og (ii) isolering af mononukleære celler af perifært blod ved Ficoll-Paque-gradient-separation fra hver behandlet blodprøve for at opnå den behandlede prøveekstrakt.
12. Fremgangsmåde ifølge krav 2, som yderligere omfatter: (i) stimulering af den ubehandlede prøveekstrakt med lipopolysaccharid, og (ii) stimulering af den behandlede prøveekstrakt med lipopolysaccharid.
13. Fremgangsmåde ifølge krav 3, hvor undertrinnene (b)(i) og (b)(ii) hver især omfatter isolering af mononukleære celler af perifært blod under anvendelse af Ficoll-Paque-gradient-separation.
14. Fremgangsmåde ifølge krav 13, hvor individet er en patient i et klinisk forsøg.
15. Fremgangsmåde ifølge krav 1 eller 14, hvor farnesyltransferaseinhibito-ren, der anvendes til at behandle individet, er tipifarnib.
DK11158145.0T 2004-11-05 2005-11-02 Fremgangsmåder til overvågning af effektiviteten af farnesyltransferaseinhibitorer DK2362218T3 (da)

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