AR040079A1 - 3-aminopirazoles n-sustituidos como inhibidores para el tratamiento de los desordenes proliferativos de las celulas, composicion farmaceutica y metodos de preparacion - Google Patents

3-aminopirazoles n-sustituidos como inhibidores para el tratamiento de los desordenes proliferativos de las celulas, composicion farmaceutica y metodos de preparacion

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AR040079A1
AR040079A1 ARP030101696A ARP030101696A AR040079A1 AR 040079 A1 AR040079 A1 AR 040079A1 AR P030101696 A ARP030101696 A AR P030101696A AR P030101696 A ARP030101696 A AR P030101696A AR 040079 A1 AR040079 A1 AR 040079A1
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Argentina
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alkyl
nhc
group
benzo
fused
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ARP030101696A
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Janssen Pharmaceutica Nv
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Abstract

La presente está dirigida a derivados 3-aminopirazol tricíclicos N-sustituidos, que son utilizados como inhibidores de la quinasa de receptor del factor de crecimiento derivado de plaquetas (PDGF-R), y los métodos para la preparación de dichos derivados. La presente está dirigida además a las composiciones farmacéuticas que comprenden los compuestos de la presente, a los métodos para tratar las afecciones tales como tumores y otros desórdenes proliferativos de células, a los procesos de preparación del compuesto y de las composiciones farmacéuticas y a un dispositivo para administración de la droga Reivindicación 1: Un compuesto de fórmula (1): en la cual, n es un número entero de 1 a 4; R1 está seleccionado del grupo que consiste en hidrógeno, alquilo inferior, -OH-alcoxi, -oxo, -NH2, -NH(alquilo) y -N(alquilo)2; el anillo A está seleccionado del grupo que consiste en un arilo, un heteroarilo monocíclico de cinco a seis miembros, un heteroarilo benzo-fusionado de nueve a diez miembros, un grupo heterocicloalquilo benzo-fusionado de nueve a diez miembros, y un grupo cicloalquilo benzo-fusionado de nueve a diez miembros; donde el heteroarilo benzo-fusionado, el heterocicloalquilo benzo-fusionado o el grupo cicloalquilo benzo-fusionado está adherido a la molécula de manera que el anillo fenilo está directamente ligado a la porción de fórmula (2) de la molécula; p es un número entero de 0 a 2; R2 está seleccionado del grupo que consiste en: un resto de fórmula (3), y -X-A1-Y-A2; en la cual, X e Y están cada uno independientemente ausentes o están seleccionados del grupo que consiste en -O-, -NH-, -N(alquilo)-, S-, -SO-, -SO2-, -OC(=O), -C(=O)O-, -NHC(=O)-, -N(alquilo)C(=O)-, -C(=O)NH-, -C(=O)N(alquilo)-, -OC(=O)O-, -NHC(=O)O-, -OC(=O)NH-, -N(alquilo)C(=O)O-, -OC(=O)N(alquilo)-, -NHC(=O)NH-, -NHC(=O)N(alquilo)-, -N(alquilo)C(=O)NH-, -N(alquilo)C(=O)N(alquilo)-, -NHSO2-, -SO2NH-, -N(alquilo)SO2- y -SO2N(alquilo)-; A1 está ausente o está seleccionado entre alquilo o alquenilo; A2 está seleccionado entre alquilo, alquenilo, o H; donde, cuando A1 o A2 es alquilo o alquenilo, el grupo alquilo o alquenilo puede estar opcionalmente sustituido con uno o más grupos independientemente seleccionados de halógeno, ciano, hidroxi, alcoxi, tio, alcoxi halogenado, -OC(=O)alquilo, -OC(=O)Oalquilo, amino, alquilamino, -NHC(=O)alquilo, -N(alquilo)C(=O)alquilo, dialquilamino, -NHC(=O)NH2, -NHC(=O)NHalquilo, -N(alquilo)C(=O)NHalquilo, -(alquilo)C(=O)NH2, -OC(=O)NHalquilo, -NHC(=O)Oalquilo, -N(alquilo)C(=O)Oalquilo, -NHSO2alquilo, -N(alquilo)SO2alquilo, tioalquilo, tioalquilo halogenado, -SO2alquilo, -SO2alquilo halogenado, -NHC(=O)N(alquilo)2, -N(alquilo)C(=O)N(alquilo)2 o -OC(=O)N(alquilo)2; el anillo D está seleccionado del grupo que consiste en un arilo a cicloalquilo, un carbociclo parcialmente insaturado, un heteroarilo, un heterocicloalquilo, un cicloalquilo benzo-fusionado de nueve a diez miembros, y un heterocicloalquilo benzo-fusionado de nueve a diez miembros; donde el arilo, cicloalquilo, carbociclo parcialmente insaturado, heteroarilo, heterocicloalquilo, cicloalquilo, benzo-fusionado o heterocicloalquilo benzo-fusionado, está opcionalmente sustituido con uno o más sustituyentes independientemente seleccionados de halógeno, hidroxi, amino, tio, nitro, ciano, alquilo, alquilo halogenado, alcoxi, alcoxi halogenado, alquilamino, -NHC(=O)alquilo, -N(alquilo)C(=O)alquilo, o dialquilimino, -NHC(=O)NH2, -NHC(=O)NHalquilo, -N(alquilo)C(=O)NHalquilo, -OC(=O)NHalquilo, -NHC(=O)Oalquilo, -N(alquilo)C(=O)Oalquilo, -NHSO2alquilo, -N(alquilo)SO2alquilo, tioalquilo, tioalquilo halogenado, -SO2alquilo, halogenado, -SO2alquilo, -NHC(=O)N(alquilo)2, -N(alquilo)C(=O)N(alquilo)2 o OC(=O)N(alquilo)2; q es un número entero de 0 a 4; R3 está seleccionado del grupo que consiste en halogenado, hidroxi, amino, tio, nitro, ciano, alquilo, alquilo halogenado, alcoxi, alquiloxi halogenado, alquilamino, -NHC(=O)alquilo, -N(alquilo)C(=O)alquilo, o dialquilamino, -NHC(=O)NH2, -NHC(=O)NHalquilo, -N(alquilo)C(=O)NHalquilo, -OC(=O)NHalquilo, -NHC(=O)Oalquilo, -N(alquilo)C(=O)Oalquilo, -NHSO2alquilo, -N(alquilo)SO2alquilo, tioalquilo, tioalquilo halogenado, -SO2alquilo, -SO2alquilo halogenado, -NHC(=O)N(alquilo)2, -N(alquilo)C(=O)N(alquilo)2 y -OC(=O)N(alquilo)2; con la condición de que la suma p y q es un número entero de 0 a 4; L1 esta ausente o está seleccionado del grupo que consiste en alquilo; el anillo B está seleccionado del grupo que consiste en un arilo, un cicloalquilo, un carbociclo parcialmente insaturado, un heteroarilo, un heterocicloalquilo, un cicloalquilo benzo-fusionado de nueve a diez miembros, y un heterocicloalquilo benzo-fusionado de nueve a diez miembros; o un isómero óptico, un enantiómero, un diasterómero, un racemato o una sal farmacéuticamente aceptable del mismo. Reivindicación 71: Un procedimiento para la preparación de un compuesto de la fórmula (1): en la cual, n es un número entero de 1 a 4; R1 está seleccionado del grupo que consiste en hidrógeno, alquilo inferior, -OH, alcoxi, -oxo, -NH2, -NH(alquilo) y -N(alquilo)2; el anillo A está seleccionado del grupo que consiste en un arilo, un heteroarilo monocíclico de cinco a seis miembros, un heteroarilo benzo-fusionado de nueve a diez miembros, un grupo heterocicloalquilo benzo-fusionado de nueve a diez miembros, y un grupo cicloalquilo benzo-fusionado de nueve a diez miembros; donde el heteroarilo benzo-fusionado, el heterocicloalquilo benzo-fusionado o el grupo cicloalquilo benzo-fusionado está adherido a la molécula de manera que el anillo fenilo está directamente ligado a la porción de fórmula (2) de la molécula; p es un número entero de 0 a 2; R2 está seleccionado del grupo que consiste en: un resto de fórmula (3), y -X-A1-Y-A2; donde, X e Y están cada uno independientemente ausentes o están seleccionados del grupo que consiste en -O-, -NH-, -N(alquilo)-, S-, -SO-, -SO2-, -OC(=O), -C(=O)O-, -NHC(=O)-, -N(alquilo)C(=O)-, -C(=O)NH-, -C(=O)N(alquilo)-, -OC(=O)O-, -NHC(=O)O-, -OC(=O)NH-, -N(alquilo)C(=O)O-, -OC(=O)N(alquilo)-, -NHC(=O)NH-, -NHC(=O)N(alquilo)-, -N(alquilo)C(=O)NH-, -N(alquilo)C(=O)N(alquilo)-, -NHSO2-, -SO2NH-, -N(alquilo)SO2- y -SO2N(alquilo)-; A1 está ausente o está seleccionado entre alquilo o alquenilo; A2 está seleccionado entre alquilo, alquenilo, o H; donde, cuando A1 o A2 es alquilo o alquenilo, el grupo alquilo o alquenilo puede estar opcionalmente sustituido con uno o más grupos independientemente seleccionados de halógeno, ciano, hidroxi, alcoxi, tio, alcoxi halogenado, -OC(=O)alquilo, -OC(=O)Oalquilo, amino, alquilamino, -NHC(=O)alquilo, -N(alquilo)C(=O)alquilo, diaquilamino, -NHC(=O)NH2, -NHC(=O)NHalquilo, -N(alquilo)C(=O)NHalquilo, -N(alquilo)C(=O)NH2, -OC(=O)NHalquilo, -NHC(=O)Oalquilo, -N(alquilo)C(=O)Oalquilo, -NHSO2alquilo, -N(alquilo)SO2alquilo, tioalquilo, tioalquilo halogenado, -SO2alquilo, -SO2alquilo, -SO2alquilo halogenado, -NHC(=O)N(alquilo)2, -N(alquilo)C(=O)N(alquilo)2 o -OC(=O)N(alquilo)2; el anillo D está seleccionado del grupo que consiste en un arilo, un cicloalquilo, un carbociclo parcialmente insaturado, un heteroarilo, un heterocicloalquilo, un cicloalquilo benzo-fusionado de nueve a diez miembros, y un heterocicloalquilo benzo-fusionado de nueve a diez miembros; donde el arilo, cicloalquilo, carbociclo parcialmente insaturado, heteroarilo, heterocicloalquilo, cicloalquilo benzo-fusionado o heterocicloalquilo benzo-fusionado, está opcionalmente sustituido con uno o más sustituyentes independientemente seleccionados de halógeno, hidroxi, amino, tio, nitro, ciano, alquilo, alquilo halogenado, alcoxi, alcoxi halogenado, alquilamino, -NHC(=O)alquilo, -N(alquilo)C(=O)alquilo, o dialquilamino, -NHC(=O)NH2, -NHC(=O)NHalquilo, -N(alquilo)C(=O)NHalquilo, -OC(=O)NHalquilo, -NHC(=O)Oalquilo, -N(alquilo)C(=O)Oalquilo, -NHSO2alquilo, -N(alquilo)SO2alquilo, tioalquilo, tioalquilo halogenado, -SO2alquilo, -SO2alquilo halogenado, -NHC(=O)N(alquilo)2, -N(alquilo)C(=O)N(alquilo)2 o OC(=O)N(alquilo)2; q es un número entero de 0 a 4; R3 está seleccionado del grupo que consiste en halógeno, hidroxi, amino, tio, nitro, ciano, alquilo, alquilo halogenado, alcoxi, alquiloxi halogenado, alquilamino, -NHC(=O)alquilo, -N(alquilo)C(=O)alquilo, o dialquilamino, -NHC(=O)NH2, -NHC(=O)NHalquilo, -N(alquilo)C(=O)NHalquilo, -OC(=O)NHalquilo, -NHC(=O)Oalquilo, -N(alquilo)C(=O)Oalquilo, -NHSO2alquilo, -N(alquilo)SO2alquilo, tioalquilo, tioalquilo halogenado, -SO2alquilo, -SO2alquilo halogenado, -NHC(=O)N(alquilo)2, -N(alquilo)C(=O)N(alquilo)2 y -OC(=O)N(alquilo)2; con la condición de que la suma p y q es un número entero de 0 a 4; L1 esta ausente o está seleccionado del grupo que consiste en alquilo; el anillo B está seleccionado del grupo que consiste en un arilo, un cicloalquilo, un carbociclo parcialmente insaturado, un heteroarilo, un heterocicloalquilo, un cicloalquilo benzo-fusionado de nueve a diez miembros, y un heterocicloalquilo benzo-fusionado de nueve a diez miembros; o un isómero óptico, un enantiómero, un diastereómero, un racemato o una sal farmacéuticamente aceptable del mismo; que comprende un resto de fórmula (4), hacer reaccionar un compuesto de fórmula (4) con hidrazina, para proporcionar el correspondiente compuesto de la fórmula (1).
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US7196110B2 (en) 2007-03-27
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CN100396670C (zh) 2008-06-25
EP1506175A1 (en) 2005-02-16
US7795440B2 (en) 2010-09-14
UY27811A1 (es) 2003-10-31
DE60326950D1 (de) 2009-05-14
EA200401378A1 (ru) 2005-06-30
ES2323952T3 (es) 2009-07-28
US20040082639A1 (en) 2004-04-29
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JP2006502097A (ja) 2006-01-19
US20070142305A1 (en) 2007-06-21
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CN1668601A (zh) 2005-09-14
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MY138268A (en) 2009-05-29
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