ES2610158T3 - Nuevos inhibidores pirrólicos de S-nitrosoglutatión reductasa como agentes terapéuticos - Google Patents

Nuevos inhibidores pirrólicos de S-nitrosoglutatión reductasa como agentes terapéuticos Download PDF

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ES2610158T3
ES2610158T3 ES09807378.6T ES09807378T ES2610158T3 ES 2610158 T3 ES2610158 T3 ES 2610158T3 ES 09807378 T ES09807378 T ES 09807378T ES 2610158 T3 ES2610158 T3 ES 2610158T3
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aryl
nre
phenyl
heteroaryl
unsubstituted
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Jan Wasley
Gary J. Rosenthal
Xicheng Sun
Sarah Strong
Jian Qiu
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Nivalis Therapeutics Inc
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Nivalis Therapeutics Inc
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Abstract

Un compuesto de formula I o una sal farmaceuticamente aceptable del mismo:**Fórmula** en la que Ar se selecciona entre el grupo que consiste en arilo, arilo sustituido, heteroarilo y heteroarilo sustituido, en donde el arilo es un sistema de anillo aromatico monociclico, biciclico o triciclico de 5 a 14 miembros; y el heteroarilo es un anillo heterociclo aromatico de 5 a 14 miembros que tiene al menos un heteroatomo seleccionado entre nitrogeno, oxigeno y azufre, que contiene al menos 1 atomo de carbono, incluyendo sistemas de anillo monociclicos, biciclicos y tricicicos, en donde los sustituyentes para arilo y heteroarilo se seleccionan entre el grupo que consiste en: -halo, -ORe', -OC(O)Re', -NRe'Re", -SRe', -Re', -CN, -NO2, -CO2Re', -C(O)NRe'Re" -C(O)Re', -OC(O)NRe'Re", -NRe"C(O)Re', -NRe"CO2Re', -NRe"'C(O)NRe'Re", -NRe'"SO2NRe'Re", - NHC(NH2)>=NH, -NRe'C(NH2)>=NH, -NH-C(NH2)>=NRe', -S(O)Re', -SO2Re', -SO2NRe'Re", -NRe"SO2Re', -N3, -CH(Ph)z, perfluoroalcoxi y perfluoroalquilo(C1-C4), en un numero que varia de cero al numero total de valencias abiertas en el sistema de anillo aromatico; y donde Re', Re" y Re"' se seleccionan independientemente entre hidrogeno, alquilo (C1-C8) no sustituido, heteroalquilo (C1-C8) no sustituido, arilo no sustituido, heteroarilo no sustituido, arilalquilo (C1-C4) no sustituido, ariloxialquilo (C1-C4) no sustituido, arilo monosustituido y heteroarilo monosustituido; R1 se selecciona entre el grupo que consiste en hidrogeno, alquilo C1-C6, cicloalquilo C3-C6, arilo, arilo sustituido, heteroarilo y heteroarilo sustituido, en donde arilo, heteroarilo y los sustituyentes para arilo y heteroarilo son como se han definido anteriormente; R2 se selecciona entre el grupo que consiste en halogeno, alquilo C1-C6, cicloalquilo C3-C6, ciano, nitro, CF3, carbamoilo, alquilcarbamoilo C1-C6, amino, alquilamino C1-C6, dialquilamino C1-C6, alcoxi C1-C6 y cicloalcoxilo C3-C6; R3 se selecciona entre el grupo que consiste en hidroxilo, carbamoilo, alquilcarbamoilo C1-C6, sulfamoilo, alquilsulfamoilo C1-C6, cicloalquilo C3-C6, ciano, nitro, carboxilo, amino, aminometilo, acetamido, acetamido-2-metilo, 2-metoxiacetamido, propionamido, tetrahidrofurano-2-ilmetoxi, CF3, carboxilo, ureido, sulfamoilamino, alquilsulfonamido C1-C6, 2-amino-2-oxoetilo, alquilamino C1-C6, dialquilamino C1-C6, arilamino, 30 heteroarilamino, alcoxilo C1-C6, cicloalcoxilo C3-C6, 1H-imidazol-2-ilo, oxazol-2-ilo, tiazol-2-ilo, metilcarbamoilo, dimetilcarbamoilo, metoxietilcarbamoilo, hidroxietilcarbamoilo, (dimetilamino)etilcarbamoilo, piridin-3-ilcarbamoilo, piridin-4-il-carbamoilo, 6-metoxipiridin-3-ilcarbamoilo, piridazin-4-ilcarbamoilo y pirimidin-5-il- carbamoilo; R4 se selecciona entre el grupo que consiste en hidrogeno, hidroxilo, halogeno, alquilo C1-C6, cicloalquilo C3-C6, ciano, nitro, carbamoilo, alquilcarbamoilo C1-C6, sulfamoilo, alquil C1-C6 sulfamoilo, amino, alquilamino C1-C6, dialquilamino C1-C6, alcoxilo C1-C6 y cicloalcoxilo C3-C6; n es 0-3; en donde Ar excluye indazol-3-ilo sustituido o no sustituido y 1H-pirazolo[3,4-b]piridilo sustituido o no sustituido; con las siguientes condiciones: condicion Ia: cuando R3 es carboxilo, metilsulfonamido o sulfamoilo, entonces Ar no puede ser fenilo, fenilalquilo (C1-C3) sustituido o no sustituido o fenil-alquenilo (C2-C6); y condicion Ib: cuando R2 y R3 son ambos metoxi, entonces Ar no puede ser fenilo, 4-metil-fenilo, 4-metoxi-fenilo, 4-halo-fenilo o tiofenilo.

Description

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de acuerdo con la reivindicación 1.
En realizaciones de la invención de fórmula I, Ar se selecciona entre el grupo que consiste en fenilo, fenilo sustituido,
5 tiofenilo, tiofenilo sustituido, piridinilo, piridinilo sustituido, tiazolilo, tiazolilo sustituido, pirimidinilo, pirimidinilo sustituido, furanilo, furanilo sustituido, arilo bicíclico, arilo bicíclico sustituido, heteroarilo bicíclico y heteroarilo bicíclico sustituido; R1 se selecciona entre el grupo que consiste en hidrógeno y alquilo C1-C6; R2 se selecciona entre el grupo que consiste en halógeno, alquilo C1-C6 y CF3; R3 se selecciona entre el grupo que consiste en hidroxilo, carbamoílo, sulfamoílo, sulfamoilamino, alcoxi C1-C6, amino,
10 aminometilo, acetamido, acetamido-2-metilo, 2-metoxiacetamido, propionamido, tetrahidrofurano-2-ilmetoxi, metilsulfamido, carboxilo, alquilamino C1-C6, 1H-imidazol-2-ilo, oxazol-2-ilo, tiazol-2-ilo, metilcarbamoílo, dimetilcarbamoílo, metoxietilcarbamoílo, hidroxietilcarbamoílo, (dimetilamino)etilcarbamoílo, piridin-3-ilcarbamoílo, piridin-4-il-carbamoílo, 6-metoxipiridin-3-ilcarbamoílo, piridazin-4-ilcarbamoílo y pirimidin-5-ilcarbamoílo; R4 se selecciona entre el grupo que consiste en hidrógeno y alquilo C1-C6;y
15 nes1.
En realizaciones de la invención de fórmula I, Ar se selecciona entre el grupo que consiste en fenilo, fenilo sustituido, aril-fenilo, aril-fenilo sustituido, heteroaril-fenilo, heteroaril-fenilo sustituido, tiofenilo, tiofenilo sustituido, aril-tiofenilo, aril-tiofenilo sustituido, heteroaril-tiofenilo, heteroaril-tiofenilo sustituido, piridinilo, piridinilo sustituido, aril-piridinilo,
20 aril-piridinilo sustituido, heteroaril-piridinilo, heteroaril-piridinilo sustituido, tiazolilo, tiazolilo sustituido, aril-tiazolilo; aril-tiozolilo sustituido; heteroaril-tiazolilo; heteroaril-tiazolilo sustituido, pirimidinilo, pirimidinilo sustituido, aril-pirimidinilo, aril-pirimidinilo sustituido, heteroaril-pirimidinilo, heteroaril-pirimidinilo sustituido, furanilo, furanilo sustituido, aril-furanilo, aril-furanilo sustituido, heteroaril-furanilo y heteroaril-furanilo sustituido.
25 En realizaciones de la invención de fórmula I, Ar es fenilo, tiofenilo, tiazolilo, piridinilo, pirimidinilo o furanilo que tiene 0, 1, 2 o 3 sustituciones, en el que tales sustituciones se seleccionan independientemente entre el grupo que consiste en hidrógeno, hidroxilo, halógeno, alcoxi C1-C6, amino, ciano, alquilo C1-C6, imidazolilo, metil imidazolilo, etil imidazolilo, furanilo, metiltio, nitro, triazolilo, tetrazolilo, carbamoílo, pirazolilo, trifluorometoxi, trifluorometilo, 2-amino-2oxoetoxi, ureido, morfolino, piridinilo, pirrolilo, metil sulfonamido, carbamoil fenilo, 6-oxo-1,6-dihidropiridinilo,
30 3,5-dimetilisoxazolilo, carboximatoxi, hidroxiacetamido, metoxiacetamido, sulfamoílo, piperazinilo, oxoimidazolidinilo, metilsulfinilo, metilsulfonilo, pirrolidinilo, piperidinilo, metilpirazolilo, fenilo, tiazolilo, hidroxicarbamoílo, ciclopropilimidazolilo, carboxi, metilamino, metoximetilo, dimetilamino, hidroximetilimidazolilo, oxooxazolidinilo, formamido, hidroxifenilo y tiofenilo.
35 En realizaciones de la invención de fórmula I, Ar se selecciona entre el grupo que consiste en 4-(1H-imidazol-1-il)fenilo, 5-(1H-imidazol-1-il)tiofen-2-ilo, 4-(2-metil-1H-imidazol-1-il)fenilo, tiazol-5-ilo, 4-hidroxifenilo, 5-bro-motiofen-2-ilo, 4-metoxifenilo, 4-aminofenilo, 4-bromofenilo, 4-(furan-3-il)fenilo, fenilo, 3-cloro-4-metoxifenilo, 3-fluoro-4-metoxifenilo, 4-cianofenilo, 3-cloro-4-hidroxifenilo, 4-metoxi-3-metilfenilo, 4-yodofenilo, 3-metoxifenilo, 6-metoxipiridin-3-ilo, benzo[d]tiazol-6-ilo, 4-(metiltio)fenilo, 4-nitrofenilo, 4-(4H-1,2,4-triazol-4-il)fenilo, 4-(2H-tetrazol-5-il)fenilo,
40 benzo[d][1,3]dioxol-5-ilo, 6-(1H-imidazol-1-il)piridin-3-ilo, 5-carbamoiltiofen-2-ilo, 4-(1H-pirazol-4-il)fenilo, 4-(trifluorometoxi)fenilo, 4-carbamoilfenilo, 4-(trifluorometil)fenilo, 4-(1H-1,2,4- triazol-1-il)fenilo, 4-(1H-pirazol-1-il)fenilo, 4-(2-amino-2-oxoetoxi)fenilo, 4-(1-metil-1H-pirazol-4-il)fenilo, 4-(1H-tetrazol-1-il)fenilo, 4-(4-metil-1H-imidazol-1-il)fenilo, 4-ureidofenilo, 4-morfolinofenilo, 4-(2H-tetrazol-5-il)fenilo, 4-(piridin-4-il)fenilo, 4-(1H-pirrol-1-il)fenilo, 4-(metilsulfonamido)fenilo, 1H-1,2,3-triazol-1-il)fenilo, naftalen-2-ilo, 3’-carbamoilbifenil-4-ilo,
45 4-(6-oxo-1,6-dihidropiridin-3-il)fenilo, 4-(3,5-dimetilisoxazol-4-il)fenilo, 4-(piridin-3-il)fenilo, 4-(carboximatoxi)fenilo, 4-(2-hidroxiacetamido)fenilo, 4-(2-metoxiacetamido)fenilo, 4-sulfamoilfenilo, 4-(piperazin-1-il)fenilo, 4-(2-oxoimidazolidin-1-il)fenilo, 4-etoxifenilo, 4-(metilsulfinil)fenilo, 4-(2-etil-1H-imidazol-1-il)fenilo, 4-(furan-2-il)fenilo, 4-(metilsulfonil)fenilo, 4-(pirrolidin-1-il)fenilo, 4-(piperidin-1-il)fenilo, 4-(1-metil-1H-pirazol-5-il)fenilo, 5-(2-metil-1H-imidazol-1-il)tiofen-2-ilo, 4-(furan-3-il)fenilo, 2-metoxipirimidin-5-ilo, 2-metil-4-(metilsulfonamido)fenilo,
50 4-amino-3-clorofenilo, 3,4-difluorofenilo, 2,4-difluorofenilo, 4-clorofenilo, 4-bromotiofen-2-ilo, bifenil-4-ilo, 2-(1H-imidazol-1-il)pirimidin-5-ilo, 4-fluoro-3-metoxifenilo, 3-ciano-4-fluorofenilo, 4-carbamoil-2-metilfenilo, 4-metoxi-2-metilfenilo, 4-cloro-2-fluorofenilo, 4-fluorofenilo, 4-fluoro-2-metilfenilo, 4-cloro-2-(trifluorometil)fenilo, 4-cloro-2-metoxifenilo, 4-ciano-3-fluorofenilo, 2-cloro-4-metoxifenilo, 4-(1H-imidazol-1-il)tiofen-2-ilo, 3,5-dimetil-4-nitrofenilo, 4-amino-3,5-dimetilfenilo, 2-(1H-imidazol-1-il)tiazol-4-ilo, 2-etoxi-4-fluorofenilo,
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Se debe observar que algunos isómeros que surgen a partir de tal asimetría (por ejemplo, todos los enantiómeros y diastereómeros) están incluidos dentro del alcance de la invención, a menos que se indique de otro modo. tales isómero se pueden obtener en forma sustancialmente pura mediante técnicas clásicas de separación y mediante síntesis controlada de forma estereoquímica. Además, las estructuras y otros compuestos y restos que se analizan en
5 la presente solicitud también incluyen todos los tautómeros de los mismos. Algunos alquenos pueden incluir, cuando sea apropiado, cualquiera de las geometrías E o Z.
2. Inhibidores de GSNOR representativos
10 La Tabla 1 que sigue a continuación enumera nuevos análogos de pirrol representativos de Fórmula I útiles como inhibidores de GSNOR de la invención. Los métodos sintéticos que pueden usarse para preparar cada uno de los compuestos, identificados en la Tabla 1 (es decir Esquema 1, Esquema 2, etc.) se detallan más adelante. En algunos casos, si el material de partida o intermedio de un esquema no está disponible en el mercado, entonces un método correspondiente (llamado Método 1, Método 2, etc.) describe la síntesis de ese material de partida o intermedio. La
15 Tabla 1 proporciona el número de Esquema, define los materiales de partida mostrados en los Esquemas y donde es necesario proporciona el número de método que se corresponde a la síntesis de un intermedio o material de partida. En la Tabla 1 también se incluyen datos de espectrometría de masas de apoyo para cada compuesto. La actividad del inhibidor de GSNOR se determinó mediante el ensayo que se describe en el Ejemplo 2 y se obtuvieron valores de CI50 se obtuvieron. Los compuestos inhibidores de GSNOR 1-198 de la Tabla 1 tuvieron un CI50 de aproximadamente
20 <100 µM. Los compuestos inhibidores de GSNOR 1-42, 69-71, 73-77, 79-81, 84-86, 92-103, 105-108, 110, 112-118, 120, 123-142, 144-164, 166-168, 170-172, 175-181, 183, 185-198 de la Tabla 1 tuvieron un CI50 de aproximadamente inferior a 5,0 µM. Los compuestos inhibidores de GSNOR 1-25, 69, 75-76, 80, 84-86, 92-94, 96-99, 101-103, 105-106, 110, 112-116, 118, 120, 124-126, 128-131, 133-137, 139-141, 144, 146, 149-150, 152, 154-157, 162-163, 166-168, 170-172, 175-180, 186-192, 194 y 196-197 de la Tabla 1 tuvieron un valor de CI50 de aproximadamente inferior a
25 1,0 µM.
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