ES2634653T3 - Derivado de fenilo - Google Patents

Derivado de fenilo Download PDF

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ES2634653T3
ES2634653T3 ES12837524.3T ES12837524T ES2634653T3 ES 2634653 T3 ES2634653 T3 ES 2634653T3 ES 12837524 T ES12837524 T ES 12837524T ES 2634653 T3 ES2634653 T3 ES 2634653T3
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solution
added
hexane
ethyl acetate
room temperature
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Atsushi Naganawa
Kensuke Kusumi
Kazuhiro Otsuki
Tetsuya Sekiguchi
Akito KAKUUCHI
Koji Shinozaki
Hiroshi Yamamoto
Shigeyuki Nonaka
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Ono Pharmaceutical Co Ltd
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Ono Pharmaceutical Co Ltd
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Abstract

Un compuesto seleccionado entre el ácido 2-{4-[3-(4-fluorofenoxi)-5-{[(4-hidroxi-4-isobutil-1- piperidinil)carbonil]amino}fenoxi]fenil}-2-metilpropanoico, una de sus sales o uno de sus solvatos.

Description

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sodio y a continuación se secó con sulfato de magnesio anhidro. El disolvente se eliminó mediante destilación a presión reducida para dar el compuesto del título (245 g) que tiene las siguientes propiedades físicas. TLC: Rf 0,68 (hexano:acetato de etilo = 3:1); RMN 1H (CDCl3) δ 3,56 (3H), 3,68 (3H), 5,05 (2H), 6,93 (3H), 7,19 (2H), 7,26-7,50 (5H).
5 Ejemplo 2 (Referencia): 2-[4-(benciloxi)fenil]-2-metilpropanoato de metilo
En una atmósfera de argón, a un matraz de cuatro bocas de 1 l se añadió el compuesto preparado en el Ejemplo 1 (66,5 g) que se disolvió en tetrahidrofurano (THF) (260 ml). La solución se enfrió a -10 ºC y se añadió a yoduro de metilo (8,1 ml) y una solución de terc-butóxido de potasio 1,53 M (85 ml) en THF, a la vez que la temperatura interna de la solución de reacción se mantuvo de -10°C a -7.5°C. Este procedimiento se repitió ocho veces. A continuación se agitó la solución a -10 ºC durante 10 minutos y se añadió ácido acético (50,5 ml) lentamente gota a gota. La solución se neutralizó con una solución acuosa de hidróxido de sodio 2 N y una solución saturada acuosa de bicarbonato de sodio y se extrajo con acetato de etilo y hexano. El extracto se lavó con agua y solución saturada de
15 cloruro de sodio y a continuación se secó con sulfato de magnesio anhidro. A continuación el disolvente se eliminó mediante destilación a presión reducida. A continuación se añadió al anterior carbón activo (4 g), la mezcla se agitó a temperatura ambiente durante 30 minutos, el carbón activo se eliminó mediante filtración, y el disolvente se eliminó mediante filtración a presión reducida para dar el compuesto del título (73,0 g) que tiene las siguientes propiedades físicas. TLC: Rf 0,54 (hexano:acetato de etilo = 5:1); RMN 1H (CDCl3) δ 1,55 (6H), 3,64 (3H), 5,05 (2H), 6,93 (2H), 7,26 (2H), 7,30-7,48 (5H).
Ejemplo 3 (Referencia): 2-(4-hidroxifenil)-2-metilpropanoato de metilo
25 En una atmósfera de argón, a un matraz evaporativo piriforme de 2 l se añadió una solución del compuesto preparada en el Ejemplo 2 (72,0 g) en metanol (420 ml) mezclada con acetato de etilo (150 ml). Tras purgar con argón, se añadió paladio carbón al 20 % (7,60 g). El matraz se desgasificó y se cargó con hidrógeno gas. El matraz se agitó vigorosamente a temperatura ambiente durante 4 horas. El sistema de reacción se purgó con argón, se filtró a través de celite y se lavó con acetato de etilo. El filtrado se sometió a destilación a presión reducida seguido por dilución con acetato de etilo (150 ml) y hexano (50 ml). La solución diluida se secó con sulfato de magnesio anhidro y el disolvente se eliminó mediante destilación para obtener un sólido gris-blanco (50 g). El sólido se disolvió en acetato de etilo (70 ml) calentando a la vez que se añadía hexano (700 ml) y se agitó a temperatura ambiente. El sólido precipitado se recogió por filtración, se lavó con hexano/acetato de etilo (10:1) y se secó para dar el compuesto del título (41,1 g) que tiene las siguientes propiedades físicas.
35 TLC: Rf 0,27 (hexano:acetato de etilo = 5:1); RMN 1H (CDCl3) δ 1,55 (6H), 3,65 (3H), 6,77 (2H), 7,19 (2H).
Ejemplo 4 (Referencia): 2-[4-(3-Fluoro-5-nitrofenoxi)fenil]-2-metilpropanoato de metilo
En atmósfera de argón y a temperatura ambiente, a un matraz evaporativo piriforme de 500 ml se añadieron el compuesto preparado en el Ejemplo 3 (41,1 g) y fosfato potásico (81,5 g). Al sistema de reacción se añadió 1,3difluoro-5-nitrobenceno (30,6 g) disuelto en DMA (128 ml) y se agitó. El sistema de reacción se calentó a continuación a 70 ºC y se agitó durante 6,5 horas. La solución de reacción se enfrió a temperatura ambiente, se diluyó con MTBE (150 ml) y se añadió agua helada (150 ml) antes de la agitación. Se extrajo una capa orgánica
45 añadiendo MTBE y agua. Se añadió a la capa acuosa MTBE y agua para extraer una capa orgánica. La capa orgánica se combinó, se lavó dos veces con una solución acuosa de hidróxido de sodio 1 N y a continuación con una solución saturada de cloruro de sodio y se secó con sulfato de magnesio anhidro, y el disolvente se eliminó mediante destilación a presión reducida. Se obtuvo el compuesto del título (66,0 g) que tenía las siguientes propiedades físicas. TLC: Rf 0,68 (hexano:acetato de etilo = 3:1); RMN 1H (CDCl3) δ 1,62 (6H), 3,69 (3H), 6,91 (2H), 6,96-7,08 (4H), 7,40 (2H), 7,65 (1H).
Ejemplo 5 (Referencia): 2-{4-[3-(4-fluorofenoxi)-5-nitrofenoxi]fenil}-2-metilpropanoato de metilo
55 En atmósfera de argón y a temperatura ambiente, a un matraz evaporativo piriforme de 500 ml se añadieron el compuesto preparado en el Ejemplo 4 (64 g), 4-fluorofenol (40 g) y fosfato de potasio (102 g) que se disolvieron en DMA (130 ml) antes de agitación. A continuación se calentó la solución a 100 ºC y se agitó durante 10 horas. La solución de reacción se enfrió a temperatura ambiente, se diluyó con MTBE (200 ml) y se añadió agua helada (400 ml) antes de la agitación. La solución de reacción se lavó adicionalmente con MTBE, una solución acuosa de hidróxido de sodio 1 N y agua. Se extrajo la capa acuosa dos veces con MTBE. La capa orgánica se combinó, se lavó dos veces con una solución acuosa de hidróxido de sodio 1 N y a continuación con agua y una solución saturada de cloruro de sodio y se secó con sulfato de magnesio anhidro, y el disolvente se eliminó mediante destilación a presión reducida. Al residuo obtenido se añadió etanol (104 ml), se calentó y disolvió. A la solución se añadió gradualmente hexano (520 ml) y se agitó a temperatura ambiente para permitir la precipitación de sólidos. El
65 precipitado se recogió mediante filtración con un embudo Kiriyama (nº 5B-Φ95) y se lavó con hexano/etanol (10:1) y el residuo obtenido se secó a presión reducida a 50 ºC. Se obtuvo el compuesto del título (54,8 g) que tenía las
11
imagen10
imagen11
13,0
46
13,4
42,9
14,0
24,2
15,3
18,5
16,6
39,5
17,3
44,6
18,3
49,5
19,0
47,8
19,6
50,1
20,0
31,3
21,1
18
22,8
23,6
23,5
23
23,8
23,8
24,4
14
El presente cristal mostró el inicio del pico endotérmico a aproximadamente 143 ºC.
[Ejemplos experimentales]
5 Se verificaron los efectos de los presentes compuestos basándose en los métodos experimentales que se muestran a partir de ahora en el presente documento como los ejemplos biológicos experimentales y los ejemplos físicos experimentales.
10 Ejemplo biológico experimental 1: Evaluación de la actividad antagonista de S1P2 mediante el control en el cambio en la concentración intracelular de iones calcio.
Se cultivaron células de ovario de hámster chino (CHO) que expresaban en exceso el gen S1P2 humano en un medio F12 de Ham que contenía suero de feto bovino (FBS) al 10 %, un agente antibiótico/antifúngico y G418. Se 15 cultivaron células CHO que expresaban en exceso el gen S1P2 de rata en un medio F12 de Ham que contenía FBS al 10 %, penicilina/estreptomicina y blasticidina S. Las células cultivadas se incubaron en una solución Fura2-AM (5 µM) [un medio F12 de Ham que contenía FBS (10 %), tampón HEPES (20 mM, pH 7,2 a 7,5) y probenecid (2,5 mM)] a 37°C durante 60 minutos. Las células se lavaron dos veces con solución salina equilibrada de Hanks que contenía tampón HEPES (20 mM, pH 7,2 a 7,5) y probenecid (2,5 mM) y se sumergió en la misma solución. Se montó una 20 placa sobre un sistema de cribado de fármacos basado en fluorescencia y se midió la concentración intracelular del ion calcio durante 30 segundos sin estimulación. Se añadió una sustancia de prueba (la concentración final de S1P2 humano: 0,25 nm a 25 µM y la concentración final de un S1P2 de rata: 0,25 nm a 2,5 µM) o una solución de dimetil sulfóxido (DMSO) y después de 3 minutos se añadió S1P (concentración final: 300 nM) y se midió el aumento en la concentración intracelular del ion calcio antes y después de la adición de S1P con un intervalo de 3 segundos
25 (longitud de onda de excitación: 340 nm y 380 nm, longitud de onda de fluorescencia: 540 nm).
Se calculó la actividad antagónica de S1P2 utilizando la supresión obtenida de la siguiente fórmula, en la que A es un valor control que tenía un valor máximo tras la adición de S1P (concentración final: 300 nM) en los pocillos a los que se había añadido DMSO sin una sustancia de prueba y B está en una cantidad creciente tras la adición de S1P en
30 las células tratadas con una sustancia de prueba:
Supresión (%) = [(A-B)/A] X 100
Se calculó el valor de CI50 como la concentración del presente compuesto que mostró el 50 % de supresión.
35 Los compuestos comparativos utilizados fueron los compuestos divulgados en el Ejemplo 1(64) (denominados a partir de ahora en el presente documento como compuesto comparativo A) y Ejemplo 1(85) (denominado a partir de ahora en el presente documento como compuesto comparativo B) en el documento de patente 3 (documento WO 2004/002531). Se muestran a continuación de forma respectiva las fórmulas estructurales de los compuestos
40 comparativos.
14
imagen12
Aplicabilidad industrial
El presente compuesto tiene una elevada actividad antagonista de S1P2 humano y por tanto es útil para el tratamiento de enfermedades mediadas por S1P2 tales como enfermedades resultantes de la constricción y la fibrosis vascular.
16

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