DK2471786T3 - Aminopyrazolderivat - Google Patents

Aminopyrazolderivat Download PDF

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DK2471786T3
DK2471786T3 DK10806527.7T DK10806527T DK2471786T3 DK 2471786 T3 DK2471786 T3 DK 2471786T3 DK 10806527 T DK10806527 T DK 10806527T DK 2471786 T3 DK2471786 T3 DK 2471786T3
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Prior art keywords
methyl
amino
alkyl
benzimidazol
pyrazol
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DK10806527.7T
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Inventor
Naoki Taka
Masayuki Ohmori
Kyoko Takami
Masayuki Matsushita
Tadakatsu Hayase
Ikumi Hyodo
Masami Kochi
Hiroki Nishii
Hirosato Ebiike
Yoshito Nakanishi
Toshiyuki Mio
Lisha Wang
Weili Zhao
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Chugai Pharmaceutical Co Ltd
Hoffmann La Roche
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    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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Claims (11)

1. Forbindelse med følgende almene formel (I) eller et farmaceutisk acceptabelt salt deraf:
( I ) hvori Ri, R2, R3 og R4 hver især indbyrdes uafhængigt betyder den nedenfor opregnede gruppe: Ri betyder hydrogen, hydroxy, halogen, cyano, nitro, Ci-4halogenalkyl, Ci-6alkyl, C2-ealkenyl, C2-ealkynyl, C3-7cycloalkyl, C6-ioaryl-Ci-4alkyl, -OR5, -NR6R7, -(CReR9)nZi, -C(0)NRi2Ri3, -SR14, -SOR15, -SO2R16, -NR17SO2R18, COOH, C6-ioaryl, som eventuelt er substitueret med en eller flere grupper indbyrdes uafhængigt valgt blandt gruppe P, 5- til 10-leddet heteroaryl eller 3- til 10-leddet heterocyclyl, som eventuelt er substitueret med en eller flere grupper indbyrdes uafhængigt valgt blandt gruppe Q, -COR19, -COOR20, -0C(0)R2i, -NR22C(0)R23, -NR24C(S)R25, -C(S)NR26R27, -SO2NR28R29, -OSO2R30, -SO3R31 eller-Si(R32)3! R2 betyder hydrogen, hydroxy, halogen, cyano, nitro, Ci-4halogenalkyl, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C6-ioaryl-Ci-4alkyl, -OR5, -NR6R7, -(CR8R9)nZi, -C(0)NRi2Ri3, -SR14, -SOR15, -SO2R16, -NR17SO2R18, COOH, C6-ioaryl, som eventuelt er substitueret med en eller flere grupper indbyrdes uafhængigt valgt blandt gruppe P, 5- til 10-leddet heteroaryl eller 3- til 10-leddet heterocyclyl, som eventuelt er substitueret med en eller flere grupper indbyrdes uafhængigt valgt blandt gruppe Q, -COR19, -COOR20, -0C(0)R2i, -NR22C(0)R23, -NR24C(S)R25, -C(S)NR26R27, -SO2NR28R29, -OSO2R30, -SO3R31 eller-Si(R32)3! eller Ri og R2 sammen med et dertil bundet atom danner 3- til 10-leddet heterocyclyl eller 5- til 10-leddet heteroaryl, hvori heterocyclyl eller heteroaryl eventuelt er substitueret med halogen; R3 betyder hydrogen, Ci-salkyl, C6-ioaryl-Ci-6alkyl eller Ci-4halogenalkyl; R4 betyder hydrogen, halogen, Ci-3alkyl, Ci-3perfluoralkyl, cyano, methansulfonyl, hydroxyl, alkoxy eller amino; A betyder indol eller pyrrol; Rs betyder Ci-salkyl, C3-7cycloalkyl, C3-7cycloalkyl-Ci-3alkyl, C2-6alkenyl, C2-6alkynyl, Ci-4halogenalkyl, Ci-3alkoxy-Ci-4alkyl, Ci-3alkoxy-Ci-4alkoxy-Ci-4alkyl, Ci-4aminoalkyl, Ci-4alkylamino-Ci-4alkyl, di(Ci-4alkyl)amino-Ci-4alkyl, C6-ioaryl, C6-ioaryl-Ci-3alkyl eller 3-til 10-leddet heterocyclyl-Ci-3alkyl, 3- til 10-leddet heterocyclyl, 5- til 10-leddet heteroaryl, 5- til 10-leddet heteroaryl-Ci-3alkyl, Ci-6monohydroxyalkyl, Ci-6dihydroxy-alkyl eller Ci-6trihydroxyalkyl, som eventuelt er substitueret med en eller flere grupper indbyrdes uafhængigt valgt blandt gruppe Q; R6 og R7, som er ens eller forskellige, hver især betyder hydrogen, Ci-4alkyl, C2-6alkenyl, C2-6alkynyl, Ci-4halogenalkyl, Ci-3alkoxy-Ci-4alkyl, C6-ioaryl-Ci-3alkyl, 3- til 10-leddet heterocyclyl-Ci-3alkyl, 5- til 10-leddet heteroaryl-Ci-3alkyl, Ci-6monohydroxy-alkyl, Ci-6dihydroxyalkyl, Ci-6trihydroxyalkyl, 3- til 10-leddet heterocyclyl, C-Mamino-alkyl, Ci-4alkylamino-Ci-4alkyl, di(Ci-4alkyl)amino-Ci-4alkyl eller cyano-(Ci-3alkyl); eller R6 og R7 sammen med et dertil bundet nitrogenatom danner 3- til 10-leddet heterocyclyl eller 5- til 10-leddet heteroaryl; n betyder 1 til 3; Re og Rg, som er ens eller forskellige, hver især betyder hydrogen, Ci-4alkyl eller halogen; eller Re og Rg alternativt sammen med et dertil bundet carbonatom danner en cycloalifatisk ring; Zi betyder hydrogen, NR10R11, -OH eller 3- til 10-leddet heterocyclyl eller 5- til 10-leddet heteroaryl, som eventuelt er substitueret med en eller flere grupper indbyrdes uafhængigt valgt blandt gruppe Q; R10 og Ru, som er ens eller forskellige, hver især betyder Ci-4alkyl, C2-6alkenyl, C2-6alkynyl, Ci-4halogenalkyl, Ci-3alkoxy-Ci-4alkyl, cyano-(Ci-3alkyl) eller Ci-3alkyl-sulfonyl-Ci-4alkyl; eller R10 og Ru alternativt sammen med et dertil bundet nitrogenatom danner 3- til 10-leddet heterocyclyl eller 5- til 10-leddet heteroaryl; R12 og R13, som er ens eller forskellige, hver især betyder hydrogen, Ci-4alkyl, C2-6alkenyl, C2-6alkynyl, Ci-4halogenalkyl, Ci-3alkoxy-Ci-4alkyl, C6-ioaryl, 5- til 10-leddet heteroaryl, 3- til 10-leddet heterocyclyl, C6-ioaryl-Ci-4alkyl, 3- til 10-leddet heterocyclyl-Ci-3alkyl, 5- til 10-leddet heteroaryl-Ci-3alkyl, cyano-(Ci-3alkyl), Ci-3alkylsulfonyl-Ci-4alkyl, en 3- til 10-leddet cycloalifatisk ring, 5- til 10-leddet heteroaryl eller 3- til 10-leddet heterocyclyl; eller R12 og R13 alternativt sammen med et dertil bundet nitrogenatom danner 3- til 10-leddet heterocyclyl eller 5- til 10-leddet heteroaryl, som eventuelt er substitueret med en eller flere grupper indbyrdes uafhængigt valgt blandt gruppe Q; R14 betyder Ci-4alkyl, C2-6alkenyl, C2-6alkynyl, Ci-4halogenalkyl, C6-ioaryl. som eventuelt er substitueret med en eller flere grupper indbyrdes uafhængigt valgt blandt gruppe P, eller 5- til 10-leddet heteroaryl eller 3- til 10-leddet heterocyclyl, som eventuelt er substitueret med en eller flere grupper indbyrdes uafhængigt valgt blandt gruppe Q; Ris betyder Ci-4alkyl, C2-6alkenyl, C2-6alkynyl, Ci-4halogenalkyl, C6-ioaryl, som eventuelt er substitueret med en eller flere grupper indbyrdes uafhængigt valgt blandt gruppe P, eller 5- til 10-leddet heteroaryl eller 3- til 10-leddet heterocyclyl, som eventuelt er substitueret med en eller flere grupper indbyrdes uafhængigt valgt blandt gruppe Q; Ri6 betyder Ci-4alkyl, C2-6alkenyl, C2-6alkynyl, Ci-4halogenalkyl, C6-ioaryl, som eventuelt er substitueret med en eller flere grupper indbyrdes uafhængigt valgt blandt gruppe P. eller 5- til 10-leddet heteroaryl eller 3- til 10-leddet heterocyclyl. som eventuelt er substitueret med en eller flere grupper indbyrdes uafhængigt valgt blandt gruppe Q; R17 betyder hydrogen eller Ci-4alkyl; Rie betyder Ci^alkyl, C2-6alkenyl, C2-6alkynyl, Ci-4halogenalkyl, C6-ioaryl, som eventuelt er substitueret med en eller flere grupper indbyrdes uafhængigt valgt blandt gruppe P, eller 5- til 10-leddet heteroaryl eller 3- til 10-leddet heterocyclyl, som eventuelt er substitueret med en eller flere grupper indbyrdes uafhængigt valgt blandt gruppe Q; R19 betyder hydrogen, Ci^alkyl, C3-7cycloalkyl, Ci-4halogenalkyl, C6-ioaryl eller 5- til 10-leddet heteroaryl eller 3- til 10-leddet heterocyclyl, som eventuelt er substitueret med en eller flere grupper indbyrdes uafhængigt valgt blandt gruppe Q; R20 betyder Ci-4alkyl, C3-7cycloalkyl, Ci-4halogenalkyl, C6-ioaryl, 5- til 10-leddet heteroaryl eller 3- til 10-leddet heterocyclyl; R21 betyder Ci-4alkyl, C3-7cycloalkyl, Ci-4halogenalkyl, C6-ioaryl, 5- til 10-leddet heteroaryl eller 3- til 10-leddet heterocyclyl; R22 betyder hydrogen, Ci^alkyl eller Ci-4halogenalkyl; R23 betyder hydrogen, Ci-4alkyl, C3-7cycloalkyl, Ci-4halogenalkyl, C6-ioaryl, 5- til 10-leddet heteroaryl eller 3- til 10-leddet heterocyclyl; R24 betyder hydrogen, Ci^alkyl eller Ci-4halogenalkyl; R25 betyder Ci-4alkyl, C3-7cycloalkyl, Ci-4halogenalkyl, C6-ioaryl, 5- til 10-leddet heteroaryl eller 3- til 10-leddet heterocyclyl; R26 og R27, som er ens eller forskellige, hver især betyder hydrogen, Ci^alkyl, C2-6alkenyl, C2-6alkynyl, Ci-4halogenalkyl, Ci-3alkoxyl-Ci-4alkyl, C6-ioaryl, 5- til 10-leddet heteroaryl, 3-til 10-leddet heterocyclyl, C6-ioaryl-Ci-4alkyl, 3- til 10-leddet heterocyclyl-Ci-3alkyl, 5-til 10-leddet heteroaryl-Ci-3alkyl, cyano-(Ci-3alkyl), Ci-3alkylsulfonyl-Ci-4alkyl eller en 3- til 10-leddet cycloalifatisk ring; eller R26 og R27 alternativt sammen med et dertil bundet nitrogenatom danner 3- til 10-leddet heterocyclyl eller 5- til 10-leddet heteroaryl; R28 og R29, som er ens eller forskellige, hver især betyder hydrogen, Ci-4alkyl, C2-6alkenyl, C2-6alkynyl, Ci-4halogenalkyl, Ci-3alkoxyl-Ci-4alkyl, C6-ioaryl, 5- til 10-leddet heteroaryl, 3- til 10-leddet heterocyclyl, C6-ioaryl-Ci-4alkyl, 3- til 10-leddet heterocyclyl-Ci-3alkyl, 5-til 10-leddet heteroaryl-Ci-3alkyl, cyano-(Ci-3alkyl), Ci-3alkylsulfonyl-Ci-4alkyl eller en 3- til 10-leddet cycloalifatisk ring; eller R28 og R29 alternativt sammen med et dertil bundet nitrogenatom danner 3- til 10-leddet heterocyclyl eller 5- til 10-leddet heteroaryl; R30 betyder Ci-4alkyl, C3-7cycloalkyl, Ci-4halogenalkyl, C6-ioaryl, 5- til 10-leddet heteroaryl eller 3- til 10-leddet heterocyclyl; R31 betyder Ci-4alkyl, C3-7cycloalkyl, Ci-4halogenalkyl, C6-ioaryl, 5- til 10-leddet heteroaryl eller 3- til 10-leddet heterocyclyl; R32 betyder Ci-4alkyl eller C6-ioaryl; <gruppe P> halogen, Ci-4alkyl, Ci-4halogenalkyl, -OH, Ci-3alkoxy, Ci-3halogenalkoxy, 3- til 10-leddet heterocyclylamino, -SO2R16, -CN, -NO2 og 3- til 10-leddet heterocyclyl; <gruppe Q> halogen, Ci-4alkyl, Ci-4halogenalkyl, -OH, Ci-3alkoxy, Ci-6monohydroxyalkyl, Ci-6dihydroxyalkyl, Ci-6trihydroxyalkyl, 3- til 10-leddet heterocyclylamin, -SO2R16, -CN, -NO2, C3-7cycloalkyl, -COR19 og 3- til 10-leddet heterocyclyl, som eventuelt er substitueret med Ci^alkyl; med det forbehold, at forbindelsen med den almene formel I ikke omfatter [5-amino-1-(2-methyl-1 H-benzimidazol-5-yl)-1 H-pyrazol-4-yl]-[5-(4-trifluormethyl-phenyl)-1 H-indol-2-yl]-methanon, og hvori cycloalkyl betegner en mættet eller delvis mættet cyclisk monovalent alifatisk carbonhydridgruppe.
2. Forbindelse eller et farmaceutisk acceptabelt salt deraf ifølge krav 1, hvori R3 betyder hydrogen, Ci-4alkyl, C6-ioaryl-Ci-4alkyl eller Ci-3perfluoralkyl.
3. Forbindelse eller et farmaceutisk acceptabelt salt deraf ifølge krav 1 eller 2, hvori forbindelsen har følgende formel:
4. Forbindelse valgt blandt: [5-amino-1-(2-methyl-3H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(1 H-indol-2-yl)-methanon-L-malat, [5-amino-1-(2-methyl-1 H-benzimidazol-5-yl)-1 H-pyrazol-4-yl]-(1 H-indol-2-yl)-methanon-hydrochlorid og [5-amino-1-(2-methyl-1 H-benzimidazol-5-yl)-1 H-pyrazol-4-yl]-(1 H-indol-2-yl)-methanon-1-methansulfonat-monohydrat.
5. Forbindelse eller farmaceutisk acceptabelt salt deraf ifølge et hvilket som helst af kravene 1-3, hvori det farmaceutisk acceptable salt er valgt blandt acetat, succinat, fumarat, maleinat, tartrat, citrat, lactat, malat, stearat, benzoat, methansulfonat og p-toluensulfonat.
6. Farmaceutisk sammensætning omfattende en forbindelse eller et et farmaceutisk acceptabelt salt deraf ifølge et hvilket som helst af kravene 1 til 5; og et bærestof.
7. Middel til anvendelse ved en fremgangsmåde til forebyggelse eller behandling af cancer, der som aktivt stof omfatter en forbindelse eller et farmaceutisk acceptabelt salt deraf ifølge et hvilket som helst af kravene 1 til 5.
8. Middel til anvendelse ved en fremgangsmåde til forebyggelse eller behandling af cancer ifølge krav 7, hvori canceren er mindst én valgt blandt: brystcancer, akut myelocytisk leukæmi, pankreascancer, blærecancer, prostatacancer, spiserørscancer, angiogenese, mavecancer, livmodercancer, ovariecancer, hjernetumor, coloncancer, multipelt myelom, hepatocarcinom, lungecancer og skjoldbruskkirtelcancer.
9. Sammensætning omfattende forbindelsen eller et farmaceutisk acceptabelt salt deraf ifølge et hvilket som helst af kravene 1 til 5 til anvendelse ved en fremgangsmåde til forebyggelse eller behandling af cancer omfattende indgivelse af en farmaceutisk effektiv mængde af sammensætningen til en patient med behov for forebyggelse eller behandling af cancer.
10. Anvendelse af en forbindelse eller et farmaceutisk acceptabelt salt deraf ifølge et hvilket som helst af kravene 1 til 5 ved fremstillingen af et middel til forebyggelse eller behandling af cancer.
11. Forbindelse eller farmaceutisk acceptabelt salt deraf ifølge et hvilket som helst af kravene 1 til 5 til anvendelse ved en fremgangsmåde til forebyggelse eller behandling af cancer.
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