ES2657900T3 - Compuestos de biaril-amida como inhibidores de quinasa - Google Patents

Compuestos de biaril-amida como inhibidores de quinasa Download PDF

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ES2657900T3
ES2657900T3 ES14714134.5T ES14714134T ES2657900T3 ES 2657900 T3 ES2657900 T3 ES 2657900T3 ES 14714134 T ES14714134 T ES 14714134T ES 2657900 T3 ES2657900 T3 ES 2657900T3
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raf
cancer
kinase inhibitors
amide compounds
compound
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Robert AVERSA
Paul A. Barsanti
Matthew Burger
Michael Patrick Dillon
Alan Dipesa
Cheng Hu
Yan Lou
Gisele Nishiguchi
Yue Pan
Valery Polyakov
Savithri Ramurthy
Alice Rico
Lina Setti
Aaron Smith
Sharadha Subramanian
Benjamin TAFT
Huw Tanner
Lifeng Wan
Naeem Yusuff
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Novartis AG
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Novartis AG
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • 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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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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Abstract

Un compuesto seleccionado de:**Fórmula** o**Fórmula** o una sal farmacéuticamente aceptable del mismo.

Description

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tieno-[2,3-b]-furanilo, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, u 11-7H-pirazino-[2,3-c]-carbazolilo, 2-, 3-, 5-, 6-, o 7-2Hfuro-[3,2-b]-piranilo, 2-, 3-, 4-, 5-, 7-, u 8-5H-pirido-[2,3-d]-o-oxazinilo, 1-, 3-, o 5-1H-pirazolo-[4,3-d]-oxazolilo, 2-, 4-, o 5-4H-imidazo-[4,5-d]-tiazolilo, 3-, 5-, u 8-pirazino-[2,3-d]-piridazinilo, 2-, 3-, 5-, o 6-imidazo-[2,1-b]tiazolilo, 1-, 3-, 6-, 7-, 8-, o 9-furo-[3,4-c]-cinolinilo, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10, u 11-4H-pirido-[2,3-c]5 carbazolilo, 2-, 3-, 6-, o 7-imidazo-[1,2-b][1,2,4]-triazinilo, 7-benzo-[b]-tienilo, 2-, 4-, 5-, 6-, o 7-benzoxazolilo, 2, 4-, 5-, 6-, o 7-bencimidazolilo, 2-, 4-, 4-, 5-, 6-, o 7-benzo-tiazolilo, 1-, 2-, 4-, 5-, 6-, 7-, 8-, o 9-benzoxapinilo, 2-, 4-, 5-, 6-, 7-, u 8-benzoxazinilo, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, u 11-1H-pirrolo-[1,2-b][2]-benzazapinilo. Los grupos heteroarilo fusionados típicos incluyen, pero no se limitan a, 2-, 3-, 4-, 5-, 6-, 7-, u 8-quinolinilo, 1-, 3-, 4-, 5-, 6-, 7-, u 8-isoquinolinilo, 2-, 3-, 4-, 5-, 6-, o 7-indolilo, 2-, 3-, 4-, 5-, 6-, o 7-benzo-[b]-tienilo, 2-, 4-, 5-, 6-,
10 o 7-benzoxazolilo, 2-, 4-, 5-, 6-, o 7-bencimidazolilo, y 2-, 4-, 5-, 6-, o 7-benzo-tiazolilo.
Un heteroarilo sustituido es un grupo heteroarilo que contiene uno o más sustituyentes, típicamente 1, 2 o 3 sustituyentes seleccionados a partir de los sustituyentes descritos anteriormente como adecuados o preferidos para un grupo arilo.
De una manera similar, cada parte de heteroarilo de otros grupos como “heteroariloxilo", “heteroariloxi
15 alquilo”, “heteroariloxi-carbonilo" tendrán el mismo significado que se describe en la definición anteriormente mencionada de “heteroarilo".
En la presente, se describen diferentes realizaciones de la invención. Se reconocerá que las características especificadas en cada realización se pueden combinar con otras características especificadas para proporcionar otras realizaciones de la presente invención. Las siguientes realizaciones enumeradas son
20 representativas de la invención:
1. En ciertas realizaciones, la invención proporciona un compuesto que es:
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huésped. Por ejemplo, los dispositivos transdérmicos están en la forma de un parche que comprende un miembro de respaldo, un depósito que contiene al compuesto opcionalmente con vehículos, opcionalmente una barrera de control de velocidad para suministrar el compuesto de la piel del huésped a una velocidad controlada y previamente determinada durante un período de tiempo prolongado, y elementos para asegurar el dispositivo a la piel.
Las composiciones adecuadas para su aplicación tópica, por ejemplo, a la piel y a los ojos, incluyen soluciones acuosas, suspensiones, ungüentos, cremas, geles o formulaciones rociables, por ejemplo, para su suministro mediante aerosol o similares. Estos sistemas de suministro tópico serán particularmente apropiados para la aplicación dérmica, por ejemplo, para el tratamiento de cáncer de piel, por ejemplo, para su uso profiláctico en cremas solares, lociones, aspersiones y similares. Por consiguiente, éstas son particularmente adecuadas para utilizarse en formulaciones tópicas, incluyendo cosméticas bien conocidas en este campo. Pueden contener solubilizantes, estabilizantes, agentes mejoradores de la tonicidad, reguladores, y conservantes.
Como se utiliza en la presente, una aplicación tópica también puede pertenecer a una inhalación o a una aplicación intranasal. Se pueden suministrar de una manera conveniente en la forma de un polvo seco (ya sea solo, como una mezcla, por ejemplo, una mezcla seca con lactosa, o una partícula componente mixta, por ejemplo, con fosfolípidos) a partir de un inhalador de polvo seco o de una presentación de aspersión en aerosol a partir de un recipiente presurizado, una bomba, aspersor, atomizador o nebulizador, con o sin el uso de un propelente adecuado.
La presente invención proporciona además las composiciones farmacéuticas y formas de dosificación anhidras, las cuales comprenden los compuestos de la presente invención como ingredientes activos, debido a que el agua puede facilitar la degradación de ciertos compuestos.
Las composiciones farmacéuticas y formas de dosificación anhidras de la invención se pueden preparar utilizando ingredientes anhidros o con un bajo contenido de humedad y condiciones de baja humedad. Una composición farmacéutica anhidra se puede preparar y almacenar de tal manera que se mantenga su naturaleza anhidra. De conformidad con lo anterior, las composiciones anhidras se empacan utilizando materiales conocidos para prevenir su exposición al agua, de tal manera que se puedan incluir en kits de formulación adecuados. Los ejemplos de los empaques adecuados incluyen, pero no se limitan a, láminas herméticamente selladas, plásticos, recipientes de dosis unitarias (por ejemplo, frascos), paquetes de burbujas, y paquetes de tiras.
La invención proporciona además composiciones farmacéuticas y formas de dosificación que comprenden uno o más agentes que reducen la velocidad a la cual se descompondrá el compuesto de la presente invención como un ingrediente activo. Estos agentes, los cuales son referidos en la presente como "estabilizantes", incluyen, pero no se limitan a, antioxidantes, tales como ácido ascórbico, reguladores del pH,
o reguladores de sales, etc.
Los compuestos de la fórmula I en forma libre o en forma de sal, exhiben valiosas actividades farmacológicas, por ejemplo, modulan o inhiben la actividad de A-Raf, B-Raf y/o C-Raf, como se indica por los datos de prueba proporcionados en las siguientes secciones y, por consiguiente, se indican para terapia o para utilizarse como productos químicos de investigación, por ejemplo, como compuestos de herramienta. Estos compuestos son en especial útiles para el tratamiento de cánceres activados por las mutaciones en la senda de Raf/Raf/MEK/ERK, incluyendo cánceres caracterizados por una mutación activadora de Raf, tal como Raf V600E, incluyendo, pero no limitándose a, melanoma (por ejemplo, melanoma maligno), cáncer de mama, cáncer de pulmón (por ejemplo, cáncer pulmonar no microcelular), sarcoma, tumores gastrointestinales (GI), tales como tumores estromales gastro-intestinales, cáncer de ovario, cáncer colo-rectal, cáncer de tiroides, y cáncer pancreático.
Por consiguiente, como una realización adicional, la presente invención proporciona el compuesto de la invención como se describe en la presente, para uso en en terapia. En una realización adicional, la terapia es para una enfermedad que se pueda tratar mediante la inhibición de A-Raf, B-Raf o C-Raf. En otra realización, los compuestos de la invención son útiles para tratar cánceres, incluyendo, pero no limitándose a, melanoma, cáncer de mama, cáncer de pulmón, sarcoma, tumores gastrointestinales (GI), tales como tumores estromales gastrointestinales, cáncer de ovario, cáncer colo-rectal, cáncer de tiroides, y cáncer pancreático.
En otra realización, la invención divulga un método para el tratamiento de una enfermedad que se pueda tratar mediante la inhibición de A-Raf, B-Raf o C-Raf, o una combinación de las mismas, el cual comprende la administración de una cantidad terapéuticamente efectiva de un compuesto de la invención como se describe en la presente. En una realización adicional, la enfermedad se selecciona a partir de la lista anteriormente mencionada, de una manera adecuada melanoma, cáncer de mama, cáncer de pulmón, sarcoma, tumores gastrointestinales (GI), tales como tumores estromales gastrointestinales, cáncer de ovario, cáncer colo-rectal, cáncer de tiroides, y cáncer pancreático. El método típicamente comprende administrar una cantidad efectiva de un compuesto como se describe en la presente o una composición farmacéutica que comprenda este
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DIAD
azodicarboxilato de di-isopropilo
DIEA
di-isopropil-etil-amina
DMA
dimetil-acetamida
DMAP
4-dimetil-amino-piridina
DME
1,2-dimetoxi-etano
DMF
N,N-dimetil-formamida
DPPF
1,1'-bis-(difenil-fosfino)-ferroceno
EDC
clorhidrato de 1-(3-dimetil-amino-propil)-3-etil-carbodi-imida
EtOAc
acetato de etilo
EtOH
etanol
HOAT
hidroxi-aza-benzotriazol
HOBt
hidroxi-benzotriazol
K2CO3
carbonato de potasio
MeCN
acetonitrilo
MgSO4
sulfato de magnesio
MeOH
metanol
Na2CO3
carbonato de sodio
NaCl
cloruro de sodio
NaHCO3
bicarbonato de sodio
NBS
N-bromo-succinimida
NMP
N-metil-2-pirrolidona
Pd2(dba)3
tris-(dibenciliden-acetona)-dipaladio(0)
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piridin-4-il)-4-metil-fenil)-2-(trifluoro-metil)-isonicotinamida en un 81 % de rendimiento. ¹H RMN (400 MHz, metanol-d4) δ 8.93 – 8.86 (m, 1H), 8.31 – 8.26 (m, 1H), 8.14 – 8.07 (m, 1H), 7.68 – 7.56 (m, 2H), 7.33 – 7.25 (m, 1H), 6.32 – 6.24 (m, 1H), 6.13 (dd, J = 28.4, 0.9 Hz, 1H), 4.76 – 4.59 (m, 2H), 4.41 – 4.33 (m, 1H), 3.91 –
3.84 (m, 1H), 3.79 (ddd, J = 6.7, 4.0, 1.8 Hz, 4H), 3.51 (q, J = 4.8 Hz, 4H), 2.26 (d, J = 4.9 Hz, 3H). LC/MS (m/z): 503.2 (MH+), Rt = 0.88 minutos.
La actividad de un compuesto de acuerdo con la presente invención se puede evaluar mediante los métodos in vitro e in vivo bien conocidos. Los datos de inhibición de Raf proporcionados en la presente, se obtuvieron utilizando los siguientes procedimientos.
Ejemplo 1236. Actividad in vitro de determinación de Raf
Las enzimas Raf y el sustrato de proteína de MEK1 catalíticamente inactivo, se hicieron todos en la empresa empleando los métodos convencionales. El ADNc de CRAF se subclonó como la proteína de longitud completa, con las mutaciones activadoras Y340E e Y341E, en un vector de expresión de baculovirus para la expresión en células de insecto Sf9. El ADNc de h14-3-3 zeta se subclonó en un vector de expresión de baculovirus para la expresión en células de insecto Sf9. Las células Sf9 que co-expresaron ambas proteínas, se lisaron y se sometieron a cromatografía en níquel inmovilizado, y se eluyeron con Imidazol. Se utilizó una segunda columna (columna de enlace de StrepII), y se eluyó con destiobiotina. Las marcas de proteína se removieron utilizando la enzima Prescission, y la proteína se purificó adicionalmente utilizando un paso de flujo atravesado para remover las marcas.
C-Raf TR se refiere a una proteína C-Raf truncada, un mutante de supresión ∆1-324.
C-Raf FL se refiere a la proteína C-Raf de longitud completa.
Se utiliza la MEK1 de longitud completa con una mutación del sitio de enlace de ATP K97R inactivadora como un sustrato de RAF. El ADNc de MEK1 se subclonó con una marca N-terminal (his)6 en un vector para la expresión en E. Coli. El sustrato de MEK1 se purificó a partir del lisado de E. Coli mediante cromatografía de afinidad en níquel, seguida por intercambio de aniones. La preparación final de MEK1 se biotiniló (Pierce EZ-Link Sulfo-NHS-LC-Biotin), y se concentró.
Materiales de Ensayo
Regulador de ensayo: Tris 50 mM, pH de 7.5, MgCl2 15 mM, Albúmina de suero bovino (BSA) al 0.01 %, ditioeritritol 1 mM (DTT).
Regulador de detención: Ácido etilen-diamina-tetra-acético (EDTA) 60 mM, Tween® 20 al 0.01 %. bRaf(V600E), activa.
Mek biotinilada, quinasa muerta.
Kit de detección Alpha Screen (disponible en PerkinElmerMR, #6760617R).
Anti fosfo-MEK1/2 (disponible en Cell Signaling Technology, Inc. #9121).
Placas de ensayo de bajo volumen de 384 pozos (placas blancas Greiner®).
Condiciones de Ensayo
b-Raf(V600E) aproximadamente 4 pM.
c-Raf aproximadamente 4 nM.
Mek biotinilada, Cinasa muerta aproximadamente 10 nM.
ATP 10 µM para BRAF(V600E), y 1 µM para CRAF.
Tiempo de pre-incubación con los compuestos durante 60 minutos a temperatura ambiente.
Tiempo de reacción durante 1 o 3 horas a temperatura ambiente.
Protocolo de ensayo
Se combinaron Raf y Mek biotinilada, quinasa muerta, en concentraciones finales 2X en regulador de ensayo (Tris 50 mM, pH de 7.5, MgCl2 15 mM, albúmina de suero bovino (BSA) al 0.01 %, y DTT 1 mM), y se dosificaron 5 mililitros por pozo en las placas de ensayo (placas de ensayo blancas Greiner de 384 pozos #781207) que contenían 0.25 mililitros de 40X de un compuesto de prueba inhibidor de quinasa Raf diluido en un 100 % de sulfóxido de dimetilo (DMSO). La placa se incubó durante 60 minutos a temperatura ambiente.
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