ES2552990T3 - Derivados de piridilo como moduladores del CFTR - Google Patents

Derivados de piridilo como moduladores del CFTR Download PDF

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ES2552990T3
ES2552990T3 ES12188920.8T ES12188920T ES2552990T3 ES 2552990 T3 ES2552990 T3 ES 2552990T3 ES 12188920 T ES12188920 T ES 12188920T ES 2552990 T3 ES2552990 T3 ES 2552990T3
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heteroaryl
aryl
cyclopropanecarboxamide
independently
alkylidene
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Sara Hadida-Ruah
Mark Miller
Jinglan Zhou
Brian Bear
Peter Grootenhuis
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Vertex Pharmaceuticals Inc
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Abstract

Un compuesto de fórmula I:**Fórmula** o una sal farmacéuticamente aceptable del mismo, en el que: RN es H, alquilo, arilo, heteroarilo, aralquilo, cicloalquilo o heterocicloalquilo; A es un anillo monocíclico de 3 miembros; B está opcionalmente condensado a un anillo de 5-7 miembros seleccionado del grupo que consiste en cicloalifático, arilo, heterocíclico y heteroarilo; R1 es halo, alquilo, OH, alcoxi, tioalquilo, trifluorometoxi; o dos R1 en átomos adyacentes que, tomados conjuntamente, forman:**Fórmula** en el que J se selecciona del grupo que consiste en CH2, CF2 o C(CH3)2; W es, de manera independiente, un enlace o una cadena alquilideno (C1-C6) opcionalmente sustituida, en la que hasta dos unidades de metileno de W están reemplazadas, de manera independiente, por -O-, -S-, -SO2- o -NR'-; R' es, de manera independiente, H, alquilo, arilo, heteroarilo, aralquilo, cicloalquilo o heterocicloalquilo; Rw es, de manera independiente, H, CN, NO2, N(R)2, CF3, OCF3, OH, OR, C(O)N(R)2, C(O)R, CO2R, -O(alquiliden(C1-C6))-OR, O(alquiliden(C1-C6))-N(R)2, -O(alquiliden(C1-C6))-heterociclo o un alifático, cicloalifático, arilo, ariloxi, heterocíclico o heteroarilo, en el que, cuando está sustituido, Rw está sustituido con hasta dos R2; R2 es halo, CN, NO2, CF3, OCF3, OR, OC(O)R, OC(O)N(R)2, SR, S(O)R, SO2R, SO2N(R)2, SO3R, C(O)R, CO2R, C(O)N(R)2, N(R)2, NRC(O)R, NRCO2R, NRC(O)N(R)2, NRSO2R, B(OH)2 o NRSO2N(R)2; R es, de manera independiente, H, alquilo, cicloalquilo, heterocíclico, arilo o heteroarilo; n es 1 o 2; w es un número entero de 0 a 4 ambos inclusive; y x es un número entero de 0 a 5 ambos inclusive; siempre que cuando W sea un enlace y Rw sea cicloalifático, heterocicloalifático, arilo o heteroarilo, -W-Rw estará unido a la posición 3 o 4 del anillo piridilo.

Description

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En otra realización, la presente invención se refiere a un compuesto de fórmula I y las definiciones que conlleva, en el que n es 1. En una realización adicional, n es 2.
En otra realización, la presente invención se refiere a un compuesto de fórmula I y las definiciones que
5 conlleva, en el que W es un enlace. En una realización adicional, W es una cadena alquilideno (C1-C6). En una realización adicional, W es -CH2-. En una realización adicional, W es -NH-. En una realización adicional, W es -O-. En una realización adicional, W es -OCH2-.
En otra realización, la presente invención se refiere a un compuesto de fórmula I y las definiciones que
10 conlleva, en el que Rw es H. En una realización adicional, Rw es OH. En una realización adicional, Rw es heterocíclico. En una realización adicional, Rw es arilo. En una realización adicional, Rw es fenilo. En una realización adicional, Rw es heteroarilo. En una realización adicional, Rw es piridilo. En una realización adicional, Rw es alcoxi. En una realización adicional, Rw es cicloalquilo. En una realización adicional, Rw es ciclohexilo.
15 En otra realización, la presente invención se refiere a un compuesto de fórmula I y las definiciones que conlleva, en el que –W-Rw es acíclico. En otra realización, -W-Rw es un anillo arilo, heteroarilo, cicloalifático o heterocicloalifático. En una realización adicional, -W(Rw)n se selecciona entre los siguientes:
-F, -CH3, -CH2CH3, -CN, -CF3, -CONH2, -CH2CH(CH3)2, 20
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R es, de manera independiente, H, alquilo, cicloalquilo, heterocíclico, arilo o heteroarilo; n es 1 o2; y
5
x es un número entero de 0 a 4, ambos inclusive, y x es un número entero de 0 a 5, ambos inclusive. 10 En otra realización, la presente invención se refiere a un compuesto de fórmula Ib y las definiciones que conlleva, en el que dos R1 de átomos adyacentes, tomados conjuntamente, forman:
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y J es CH2. En otra realización, J es CF2. En otra realización, la presente invención se refiere a un compuesto de fórmula Ib y las definiciones que conlleva, en el que –W(Rw)n se selecciona de entre los siguientes: -CH3, -CH2CH3, -CH2CH(CH3)2,
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con éter (100 ml) y se acidificó la capa acuosa a pH 2 con ácido clorhídrico 2 M. Se filtró el sólido precipitado, dando ácido 1-(2,2-difluoro-benzo[1,3]dioxol-5-il)-ciclopropanocarboxílico en forma de un sólido de color blanco (0,15 g, al 2 % durante cuatro etapas). IEN-EM m/z calc. 242,2; encontrado 243,3; RMN de 1H (CDCl3) δ 7,14-7,04 (m, 2H), 6,98-6,96 (m, 1H), 1,74-1,64 (m, 2H), 1,26-1,08 (m, 2H).
La siguiente Tabla 2 contiene una lista de componentes básicos de ácido carboxílico que se encontraban disponibles en el mercado o que se prepararon mediante los métodos descritos anteriormente.
Tabla 2: Componentes básicos de ácido carboxílico
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Nombre
Estructura
Ácido 1-(2-metoxifenil)ciclopropan-1-carboxílico
Ácido 1-(3-metoxifenil)ciclopropan-1-carboxílico
Ácido 1-(4-metoxifenil)ciclopropan-1-carboxílico
Ácido 1-[4-(trifluorometoxi)fenil]ciclopropan-1-carboxílico
Ácido 1-fenilciclopropan-1-carboxílico
Ácido 1-(4-clorofenil)ciclopropan-1-carboxílico
Ácido 1-(3,4-dimetoxifenil)ciclopropano-carboxílico
Ácido 1-(4-(metiltio)fenil)ciclopropano-carboxílico
Ácido 1-p-tolilciclopropano-carboxílico
Preparación de (6-aminopiridin-3-il)(2-metoxifenil)metanona
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65
37
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Tabla 3
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60
Nombre
Estructura
1-(benzo[d][1,3]dioxol-5-il)-N-(6-metilpiridin-2-il) ciclopropanocarboxamida
1-(benzo[d][1,3]dioxol-5-il)-N-(5-metilpiridin-2-il) ciclopropanocarboxamida
1-(benzo[d][1,3]dioxol-5-il)-N-(5-cianopiridin-2-il) ciclopropanocarboxamida
1-(benzo[d][1,3]dioxol-5-il)-N-(4-etilpiridin-2-il)ciclopropanocarboxamida
1-(benzo[d][1,3]dioxol-5-il)-N-(4-metilpiridin-2-il) ciclopropanocarboxamida
6-(1-(benzo[d][1,3]dioxol-5-il)ciclopropanocarboxamido)nicotinamida
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1-(benzo[d][1,3]dioxol-5-il)-N-(5-(trifluorometil)piridin-2-il) ciclopropanocarboxamida
imagen40
1-(benzo[d][1,3]dioxol-5-il)-N-(3-etil-6-metilpiridin-2-il) ciclopropanocarboxamida
1-(benzo[d][1,3]dioxol-5-il)-N-(6-etilpiridin-2-il)ciclopropanocarboxamida
1-(benzo[d][1,3]dioxol-5-il)-N-(5-fluoropiridin-2-il) ciclopropanocarboxamida
40
5
10
15
20
25
30
35
40
45
50
55
60
N-(5-(2-metoxibencil)piridin-2-il)-1-(2-metoxifenil) ciclopropanocarboxamida
imagen41
N-(5-(3-metoxibencil)piridin-2-il)-1-(2-metoxifenil) ciclopropanocarboxamida
imagen42
N-(3-(benciloxi)piridin-2-il)-1-fenilciclopropanocarboxamida
1-(4-metoxifenil)-N-(5-metilpiridin-2-il)ciclopropanocarboxamida
N-(6-etilpiridin-2-il)-1-fenilciclopropanocarboxamida
imagen43
1-(benzo[d][1,3]dioxol-5-il)-N-(3-(benciloxi)piridin-2-il) ciclopropanocarboxamida
N-(4-etilpiridin-2-il)-1-(4-metoxifenil)ciclopropanocarboxamida
1-(4-metoxifenil)-N-(6-metilpiridin-2-il)ciclopropanocarboxamida
N-(6-etilpiridin-2-il)-1-(4-metoxifenil)ciclopropanocarboxamida
imagen44
41
imagen45
5
10
15
20
25
30
35
40
45
50
55
60
N-(5-(2-metoxibezoil)piridin-2-il)-1-(4-metoxifenil) ciclopropanocarboxamida (Comparativo)
N-(5-(2-metoxibencil)piridin-2-il)-1-ptolilciclopropanocarboxamida
1-(4-clorofenil)-N-(5-(2-metoxibencil)piridin-2-il) ciclopropanocarboxamida
1-(3,4-dimetoxifenil)-N-(5-(2-metoxibencil)piridin-2-il) ciclopropanocarboxamida
1-(3-metoxifenil)-N-(5-(2-metoxibencil)piridin-2-il) ciclopropanocarboxamida
N-(5-(2-metoxibencil)piridin-2-il)-1-(4-(trifluorometoxi) fenil)ciclopropanocarboxamida
N-(5-(2-metoxibezoil)piridin-2-il)-1-fenilciclopropanocarboxamida (Comparativo)
N-(5-(2-metoxibezoil)piridin-2-il)-1-ptolilciclopropanocarboxamida (Comparativo)
1-(4-clorofenil)-N-(5-(2-metoxibezoil)piridin-2-il) ciclopropanocarboxamida (Comparativo)
43
5
10
15
20
25
30
35
1-(2,2-difluorobenzo[d][1,3]dioxol-5-il)-N-(5-(2-metoxibezoil) piridin-2-il)ciclopropanocarboxamida (Comparativo)
1-(3,4-dimetoxifenil)-N-(5-(2-metoxibezoil)piridin-2-il) ciclopropanocarboxamida (Comparativo)
N-(5-(2-metoxibezoil)piridin-2-il)-1-(2-metoxifenil) ciclopropanocarboxamida (Comparativo)
N-(5-(2-metoxibezoil)piridin-2-il)-1-(4-(metiltio)fenil) ciclopropanocarboxamida (Comparativo)
N-(5-(2-metoxibezoil)piridin-2-il)-1-(-(trifluorometoxi) fenil)ciclopropanocarboxamida (Comparativo)
Preparación de ácido 3-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-il)ciclopropanocarboxamido)-5-metil-piridin-440 il)benzoico)
45
50
55
44
imagen46
imagen47
imagen48
imagen49
imagen50
imagen51
imagen52
imagen53
imagen54
imagen55
imagen56
imagen57
imagen58
imagen59
15
25
35
45
55
6
326,3 2,33
7
474,3 2,94
8
389,3 3,2
9
472,3 2,88
10
419,3 2,91
11
532,3 2,39
12
433,3 3,3
13
389,1 2,89
14
387,1 3,45
15
390,3 2,93
16
379,3 8,16
17
351,1 3,5
18
546,5 2,59
19
297,1 2,67
20
446,3 2,8
21
297,3 2,09
22
545,5 2,74
23
516,3 2,96
24
441,3 8,81
25
269,1 2,82
26
311,3 2,4
27 (Comparativo)
417,3 3,5
28
403,5 3,57
29
339,3 6,6
30
457,5 3,79
31
373,3 3,33
32
486,3 2,94
33
461,5 3,6
34
389,1 2,97
35
403,3 3,15
36
516,3 2,97
37
419,3 3,69
38
283,1 2,68
39
531,5 2,61
40
333,1 1,48
41
345,1 3,07
42
297,3 2,18
43
325,3 2,13
59
5
15
25
35
45
55
44
419,3 2,57
45
515,5 2,75
46
393,1 3,3
47
301,3 3,05
48
389,1 2,55
49
488,3 2,8
50
453 1,63
51
516,3 3,01
52
404,5 2,73
53
432,3 2,74
54
283,1 2,61
55
488,3 2,76
56
339,2 3,19
57
463,5 2,66
58
502,3 2,75
59
407,5 3,39
60
403,5 3,11
61
267,1 1,6
62
460,3 2,86
63
373,1 7,14
64
404,5 3,01
65
308,1 3,07
66
477,3 2,71
67
379,1 3,56
68
453,1 3,69
69
283,1 2,13
70
387,3 3,7
71
530,5 2,53
72
297,3 2,19
73
438,3 1,83
74
418,3 2,87
75
297,1 2,48
76
407,5 3,69
77
373,1 3,5
78
407 3,6
Ensayos para la detección y medición de las propiedades de corrección del ΔF508-CFTR de los compuestos 65 Métodos ópticos de potencial de membrana para ensayar las propiedades de modulación del ΔF508-CFTR de los
60
imagen60
imagen61
imagen62
Tabla 6
Agrupaciones de CI50/CE50:+++ ≤ 2,0 < ++ ≤ 5,0 < +
Agrupaciones del porcentaje de actividad:+ ≤ 25,0 < ++ ≤ 100,0 < +++
Comp. Nº
EC50 agrupada Eficacia máxima agrupada
1
+ ++
2
+ +++
3
+++ +++
4
+ +++
+++
+++
6
+ ++
7
+++ +++
8
++ ++
9
++ +++
++
++
11
++ +++
12
+ ++
13
++ ++
14
++ +++
++
++
16
+++ +++
17
++ ++
18
+++ ++
19
+ ++
++
+++
21
+ +++
22
+++ ++
23
+++ +++
24
+++ +++
+
++
26
++ +++
27 (Comparativo)
++ +++
28
+ +++
29
++ +++
+
++
31
++ ++
32
+++ +++
33
++ +++
34
++ ++
64 65
35
+++ +++
36
+++ +++
37
++ +++
38
+ ++
39
+++ ++
40
++ +++
41
+ ++
42
+ +++
43
+ ++
44
+ +++
45
++ +++
46
++ +++
47
+ +++
48
+ ++
49
+++ +++
50
++ ++
51
+++ +++
52
+++ +++
53
++ +++
54
+ ++
55
++ +++
56
+ +++
57
++ +++
58
++ +++
59
+++ +++
60
+++ +++
61
+ ++
62
++ +++
63
+++ +++
64
+++ ++
65
+ ++
66
++ +++
67
++ +++
68
++ +++
69
+ +++
70
++ +++
71
+++ ++
72
+ +++
imagen63

Claims (1)

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ES2442945T3 (es) 2014-02-14
US8524910B2 (en) 2013-09-03
CY1116953T1 (el) 2017-04-05
CN101981011B (zh) 2014-05-07
AU2009231993A1 (en) 2009-10-08
EP2615085B1 (en) 2015-08-26
CN103951614A (zh) 2014-07-30
DK2615085T3 (en) 2015-10-05
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CA2718310C (en) 2018-08-07
JP2011516420A (ja) 2011-05-26
PL2615085T3 (pl) 2016-02-29
JP5622285B2 (ja) 2014-11-12
JP5930487B2 (ja) 2016-06-08
US8889875B2 (en) 2014-11-18
US20120270869A1 (en) 2012-10-25
NZ616097A (en) 2015-04-24
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