ES2556460T3 - Derivados novedosos de metilciclohexano y usos de los mismos - Google Patents

Derivados novedosos de metilciclohexano y usos de los mismos Download PDF

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ES2556460T3
ES2556460T3 ES11829552.6T ES11829552T ES2556460T3 ES 2556460 T3 ES2556460 T3 ES 2556460T3 ES 11829552 T ES11829552 T ES 11829552T ES 2556460 T3 ES2556460 T3 ES 2556460T3
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pyridin
carboxylic acid
methylcyclohexane
synthesis
nmr
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Sung Jin Bae
Han Ju Yi
Sun Gwan Hwang
Mo Ses Jeong
Yeo Jin Yoon
Sang Mi Chae
Joo Young Park
Eun Ju Ryu
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SK Biopharmaceuticals Co Ltd
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Abstract

Un compuesto seleccionado del grupo que consiste en un derivado de metilciclohexano representado por la Fórmula I siguiente y una sal, un solvato y un hidrato del derivado de metilciclohexano farmacéuticamente aceptables y una combinación de los mismos.**Fórmula** en la que Ar se selecciona entre el grupo que consiste en fenilo, piridina y piridin-N-óxido, cada uno de los cuales está sustituido con uno o más sustituyentes idénticos o diferentes seleccionados del grupo que consiste en un átomo de hidrógeno, un alquilo C1 a C6 lineal o ramificado, halógeno, un alcoxi C1 a C6 lineal o ramificado y trifluorometilo; X es O, (C>=O)O, NR1(C>=O)O, NH, (C>=O)NH o O(C>=O)NH y R1 es H o CH3; Y es CH2, O o N-R2; R2 es H o CH3; A es O o NH; B es CH o N; y m es un número entero entre 0 y 2 y n es 0 o 1.

Description

imagen1
imagen2
imagen3
imagen4
imagen5
imagen6
imagen7
imagen8
imagen9
imagen10
imagen11
imagen12
(m, 3H), 3,91 (s, 2H), 3,40~3,23 (m, 4H), 3,01~2,91 (m, 3H), 2,11~1,51 (m, 9H), 1,42~1,05 (m, 4H)
Ejemplo 11: Síntesis del éster 4-(1-oxi-piridin-4-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin-1carboxílico
imagen13
Un compuesto objetivo (393 mg, 52 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(1-oxi-piridin-4-il)metilamina.
10 RMN de 1H (500 MHz, CDCl3), ppm (δ): 8,14-8,13 (d, 2H, J = 6,3 Hz), 7,29-7,21 (d, 2H, J = 6,3 Hz), 5,95 (s, 1H), 4,58-4,52 (m, 1H) , 3,91-3,85 (m, 2H), 3,36-3,30 (m, 5H), 3,00-2,50 (m, 1H), 2,0 (m, 2H), 1,83-1,82 (m, 7H), 1,591,53 (m, 2H), 1,31-1,21 (m, 4H), 1,14-1,3 (m, 2H)
15 Ejemplo 12: Síntesis del éster 4-(1-oxi-piridin-3-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin-1carboxílico
imagen14
20 Un compuesto objetivo (325 mg, 43 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(1-oxi-piridin-3-il)-metilamina.
RMN de 1H (500 MHz, CDCl3), ppm (δ): 8,21-8,13 (m, 1H), 7,26-7,24 (m, 3H), 5,16-4,59 (m, 1H), 4,35 (m, 1H), 3,923,91 (m, 1H), 3,41-3,33 (m, 2H), 2,8-2,4 (m, 1H), 1,87-1,84 (m, 4H), 1,63 (m, 4H), 1,35-1,11 (m, 2H)
25 Ejemplo 13: Síntesis del éster 4-(1-oxi-piridin-2-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin-1carboxílico
imagen15
Un compuesto objetivo (264 mg, 35 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(1-oxi-piridin-2-il)metilamina.
14
RMN de 1H (500 MHz, CDCl3), ppm (δ): 8,29-8,19 (d, 1H, J = 6,3 Hz), 7,38-7,37 (m, 1H), 7,25-7,18 (m, 2H), 6,236,21 (m, 1H), 4,48-4,45 (m, 3H), 3,85-3,82 (m, 2H), 3,32-3,25 (m, 4H), 1,97-1,93 (m, 2H), 1,81-1,74 (m, 6H), 1,581,82 (m , 2H), 1,27-1,20 (m, 4H)
Ejemplo 14: Síntesis del éster 4-(6-cloro-piridin-2-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin1-carboxílico
imagen16
10 Un compuesto objetivo (491 mg, 62 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(6-cloro-piridin-2-il)metilamina.
RMN de 1H (300 MHz, CDCl3), ppm (δ): 7,67~7,60 (m, 1H), 7,26~7,21 (m, 2H), 5,61~5,55 (m, 1H), 4,64~4,53 (m, 1H), 4,44 (d, 2H, J = 5,7 Hz), 3,90 (d, 2H, J = 6,0 Hz), 3,42~3,28 (m, 4H), 2,10~1,99 (m, 2H), 1,92~1,84 (m, 5H), 15 1,67~1,55 (m, 2H), 1,40~1,03 (m, 4H)
Ejemplo 15: Síntesis del éster 4-(6-metil-piridin-2-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin-1ácido carboxílico
imagen17
Un compuesto objetivo (451 mg, 60 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(6-metil-piridin-2-il)metilamina.
25 RMN de 1H (300 MHz, CDCl3), ppm (δ): 7,58~7,50 (m, 1H), 7,10~7,01 (m, 2H), 5,84~5,79 (m, 1H), 4,65~4,55 (m, 1H), 4,44 (d, 2H, J = 5,1 Hz), 3,90 (d, 2H, J = 6,3 Hz), 3,42~3,10 (m, 4H), 2,53 (s, 3H), 2,15~1,99 (m, 2H), 1,95~1,75 (m, 5H), 1,73~1,52 (m, 2H), 1,44~1,03 (m, 4H)
Ejemplo 16: Síntesis del éster 4-(2-cloro-piridin-4-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin30 1-carboxílico
imagen18
Un compuesto objetivo (523 mg, 66 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(2-cloro-piridin-4-il)metilamina.
15
RMN de 1H (300 MHz, CDCl3), ppm (δ): 8,33 (d, 1H, J = 5,1 Hz), 7,25 (s, 1H), 7,14 (d, 1H, J = 4,8 Hz), 5,33~5,26 (m, 1H), 4,65~4,54 (m, 1H), 4,36 (d, 2H, J = 6,3 Hz), 3,90 (d, 2H, J = 6,3 Hz), 3,41~3,29 (m, 4H), 2,18~1,99 (m, 2H), 1,95~1,77 (m, 6H), 1,70~1,52 (m, 1H), 1,43~1,03 (m, 4H)
Ejemplo 17: Síntesis del éster 4-(6-cloro-piridin-3-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin1-carboxílico
imagen19
10 Un compuesto objetivo (435 mg, 55 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(6-cloro-piridin-3-il)-metilamina.
RMN de 1H (300 MHz, CDCl3), ppm (~): 8,31 (s, 1H), 7,63 (d, 1H, J = 7,2 Hz), 7,30 (d, 1H, J = 8,4 Hz), 5,20~5,12 (m, 1H), 4,63~4,52 (m, 1H), 4,34 (d, 2H, J = 6,0 Hz), 3,90 (d, 2H, J = 6,6 Hz), 3,41~3,28 (m, 4H), 2,13~1,99 (m, 2H), 15 1,97~1,72 (m, 6H), 1,69~1,53 (m, 1H), 1,42~1,04 (m, 4H)
Ejemplo 18: Síntesis del éster 4-(2-cloro-piridin-3-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido pirrolidin1-carboxílico
imagen20
Un compuesto objetivo (404 mg, 51 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que se utilizó como material de partida C-(2-cloro-piridin-3-il)-metilamina.
25 RMN de 1H (300 MHz, CDCl3), ppm (δ): 8,34~8,28 (m, 1H), 7,75 (d, 1H, J = 6,6 Hz), 7,27~7,21 (m, 1H), 5,35~5,27 (m, 1H), 4,62~4,50 ( m, 1H), 4,42 (d, 2H, J = 6,6 Hz), 3,90 (d, 2H, J = 6,3 Hz), 3,42~3,28 (m, 4H), 2,15~1,77 (m, 8H), 1,74~1,50 (m, 1H), 1,46~1,02 (m, 4H)
Ejemplo 19: Síntesis del éster del 4-(6-trifluorometil-piridin-3-ilmetilcarbamoiloxi)-ciclohexilmetílico del ácido 30 pirrolidin-1-carboxílico
imagen21
16
imagen22
imagen23
imagen24
Ejemplo 29: Síntesis del éster 4-bencilcarbamoiloxi-ciclohexilmetílico del ácido 4-metil-piperazin-1carboxílico
imagen25
5 Un compuesto objetivo (101 mg, 13 % de rendimiento) se obtuvo de la misma manera que en el Ejemplo 1, excepto que fueron utilizados como materiales de partida bencilamina y 1-metil-piperazina y el yoduro de metilo no se utilizó en el segundo paso.
10 RMN de 1H (500 MHz, CDCl3), ppm (δ): 7,38~7,24 (m, 5H), 4,96 (sa, 1H), 4,65~4,54 (m, 1H), 3,92 (d, 2H, J = 6,4 Hz), 3,51~3,47 (m, 4H), 2,41~2,34 (m, 4H), 2,30 (s, 3H), 2,12~2,02 (m, 1H), 1,94~1,79 (m, 2H), 1,68~1,52 (m, 2H), 1,38~1,29 ( m, 2H), 1,20~1,09 (m, 2H)
Ejemplo 30: Síntesis del éster 4-(pirrolidin-1-carboniloximetil)-ciclohexílico del ácido piridin-2-carboxílico
15
imagen26
A una solución de éster 4-hidroxi-ciclohexilmetílico del ácido pirrolidin-1-carboxílico (1 mmol) en cloruro de metileno (5 ml) se añadieron cloruro de picolinoílo (1,1 mmol) y trietilamina (1,5 mmol) y la mezcla resultante se agitó durante
20 16 horas a temperatura ambiente. La mezcla de reacción se diluyó con agua, seguido de par de veces de extracción con cloruro de metileno. La capa orgánica combinada se secó sobre sulfato de magnesio anhidro, se filtró y se concentró a presión reducida. El residuo se purificó por cromatografía en columna (gel de sílice, acetato de etilo), completando de este modo la preparación de un compuesto objetivo (233 mg, rendimiento del 70 %).
25 RMN del 1H (300 MHz, CDCl3), ppm (δ): 8,80~8,76 (m, 1H), 8,15~8,11 (m, 1H), 7,90~7,80 (m, 1H), 7,50~7,45 (m, 1H), 5,08~4,98 (m, 1H ), 3,98 (d, 2H, J = 6,6 Hz), 3,43~3,33 (m, 4H), 2,17~2,08 (m, 2H), 1,99~1,83 (m, 5H), 1,81~1,53 (m, 3H), 1,20~1,08 (m, 3H)
Los Ejemplos 31 a 33 siguientes se llevan a cabo cada uno de la misma manera que en el Ejemplo 30, excepto que 30 el material de partida utilizado era diferente del material de partida utilizado en el Ejemplo 30.
20
imagen27
imagen28
imagen29
imagen30
imagen31
imagen32
imagen33
imagen34
imagen35
imagen36
Ejemplo 13
27,9 >50
Ejemplo 14
21,7 22,3
Ejemplo 15
19,9 19,4
Ejemplo 16
27,9 10,8
Ejemplo 17
29,5 12,5
Ejemplo 18
5,7 18,3
Ejemplo 19
11,1 13,8
Ejemplo 20
50 37,9
Ejemplo 21
15,9 44,8
Ejemplo 22
35,8 21,7
Ejemplo 23
28,6 >50
Ejemplo 24
>50 >50
Ejemplo 25
24,9 15,5
Ejemplo 26
46,1 36,8
Ejemplo 27
50,0 >50
Ejemplo 28
>50 44,8
Ejemplo 29
46,1 >50
Ejemplo 30
>50 >50
Ejemplo 31
>50 21,1
Ejemplo 32
21,1 34,8
Ejemplo 33
>50 >50
Ejemplo 34
24,9 27,1
Ejemplo 35
>50 50,0
Ejemplo 36
>50 >50
Ejemplo 37
46,1 >50
Ejemplo 38
35,8 >50
Ejemplo 39
>50 >50
Ejemplo 40
>50 >50
Ejemplo 41
50 >50
Ejemplo 42
50 >50
Ejemplo 43
10,5 12,0
Ejemplo 44
21,7 16,8
Ejemplo 45
9,9 7,5
Ejemplo 46
32,0 26,3
Ejemplo 47
13,1 21,1
Ejemplo 48
13,5 10,2
Ejemplo 49
12,0 10,2
Ejemplo 50
5,7 14,2
Ejemplo 51
50 >50
Ejemplo 52
22,3 >50
Ejemplo 53
33,9 >50
Ejemplo 54
48,7 >50
Ejemplo 55
25,6 >50

Ejemplo 57: Prueba de alivio del dolor utilizando un modelo animal
1) Modelo animal 5 Se adquirieron as ratas macho (Sprague-Dawley, 150-200 g, de 6 semanas de edad, Orient Bio Co., Ltd) y se aclimataron en una cámara de animales durante una semana. La cámara de animales se encendía y apagaba alternativamente a intervalos de 12 horas, con una temperatura de 22 a 25 ºC y una humedad relativa de 40-60 % y se suministró agua y alimento ad libitum a las ratas. 10
31
imagen37

Claims (1)

  1. imagen1
    imagen2
    imagen3
    imagen4
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