ES2587014T3 - Derivados de N-(metil)-piridin-2-amina para el tratamiento de enfermedades asociadas a proteínas amiloides o de tipo amiloide - Google Patents

Derivados de N-(metil)-piridin-2-amina para el tratamiento de enfermedades asociadas a proteínas amiloides o de tipo amiloide Download PDF

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ES2587014T3
ES2587014T3 ES09164401.3T ES09164401T ES2587014T3 ES 2587014 T3 ES2587014 T3 ES 2587014T3 ES 09164401 T ES09164401 T ES 09164401T ES 2587014 T3 ES2587014 T3 ES 2587014T3
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4alkyl
aryl
amyloid
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heteroaryl
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Wolfgang Froestl
Nampally Sreenivasachary
Sophie Lohmann
Maria Pilar Lopez Deber
Andreas Muhs
Maria Pihlgren Bosch
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AC Immune SA
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Abstract

Un compuesto que tiene la fórmula general (IIa) o (IIb)**Fórmula** en la que p es 2 o 3; cada enlazador K es independientemente alquileno C1-3 que está opcionalmente sustituido con uno o más grupos alquilo C1-4; el anillo heterocíclico B está opcionalmente sustituido con uno o más sustituyentes seleccionados entre alquilo C1-4, alcoxi C1-4, mono- y di-alquilamino C1-4, cicloalquilamino C3-7 y heterociclilo saturado de 5 o 6 miembros, o dos sustituyentes pueden unirse para formar un anillo saturado, insaturado o aromático de 5 a 7 miembros que se condensa con el anillo heterocíclico B; R1 se selecciona entre -H, -halógeno, -alquilo C1-4, NH2, -NH-alquilo C1-4, -alquilen C1-4-NH2, -alquilen C1-4-NH-alquilo C1-4, -arilo, -aril-R3, -alquilenarilo C1-4, -alquilenaril C1-4-R3, -heteroarilo, heteroaril-R3, -NH-alquilenarilo C1-4, -NH-alquilenaril C1-4-R3, -OH y -O-alquilo C1-4; y R3 es alquilo C1-4, halógeno, OH u O-alquilo C1-4; R2 es -H, -alquilo C1-4, -arilo o un grupo de las fórmulas (IIIa) o (IIIb)**Fórmula** en donde en las fórmulas (IIIa) y (IIIb): el anillo heterocíclico B está opcionalmente sustituido con uno o más sustituyentes seleccionados entre alquilo C1-4, alcoxi C1-4, mono- y di-alquilamino C1-4, cicloalquilamino C3-7 y heterociclilo saturado de 5 o 6 miembros, o dos sustituyentes pueden unirse para formar un anillo saturado, insaturado o aromático de 5 a 7 miembros que se condensa con el anillo heterocíclico B; cada enlazador K es independientemente alquileno C1-3 que está opcionalmente sustituido con uno o más grupos alquilo C1-4; R1 se selecciona entre -H, -halógeno, -alquilo C1-4, -NH2, -NH-alquilo C1-4, -alquilen C1-4-NH2, -alquilen C1-4-NHalquilo C1-4, -arilo, -aril-R3, -alquilenarilo C1-4, -alquilenaril C1-4-R3, -heteroarilo, -heteroaril-R3, -NH-alquilenarilo C1-4, -NH-alquilenaril C1-4-R3, -OH y -O-alquilo C1-4; q es 0 o 1; y r es 0 o 1.

Description

imagen1
imagen2
imagen3
imagen4
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amiloidogénicas en un tejido y/o un fluido corporal, que comprende:
(a) proporcionar una muestra representativa del tejido y/o fluido corporal bajo investigación;
(b) probar la muestra para la presencia de proteína amiloide con un compuesto de acuerdo con la presente 5 invención;
(c)
determinar la cantidad de compuesto unido a la proteína amiloide; y
(d)
calcular la carga de placas en el tejido y/o fluido corporal.
Un aspecto adicional se refiere a un método de recolección de datos para determinar una predisposición a una
10 enfermedad o afección asociada a amiloide en un paciente que comprende detectar la unión específica de un compuesto de acuerdo con la presente invención a una proteína amiloide en una muestra o in situ que comprende las etapas de:
(a) poner la muestra o una parte corporal o área corporal específica sospechosa de contener la proteína amiloide
15 en contacto con un compuesto de acuerdo con la presente invención, compuesto que se une específicamente a la proteína amiloide;
(b)
permitir que el compuesto se una a la proteína amiloide para formar un complejo compuesto/proteína;
(c)
detectar la formación del complejo compuesto/proteína;
(d) correlacionar opcionalmente la presencia o ausencia del complejo compuesto/proteína con la presencia o 20 ausencia de proteína amiloide en la muestra o parte o área corporal específica; y
(e) comparar opcionalmente la cantidad del complejo compuesto/proteína a un valor de control normal.
Aún otro aspecto de la presente invención es un método de recolección de datos para controlar la enfermedad residual mínima en un paciente después del tratamiento con un anticuerpo i una composición vacuna, en la que el método
25 comprende:
(a) poner la muestra o una parte corporal o área corporal específica sospechosa de contener una proteína amiloide en contacto con un compuesto de acuerdo con la presente invención, compuesto que se une específicamente a la proteína amiloide;
30 (b) permitir que el compuesto se una a la proteína amiloide para formar un complejo compuesto/proteína;
(c)
detectar la formación del complejo compuesto/proteína;
(d)
correlacionar opcionalmente la presencia o ausencia del complejo compuesto/proteína con la presencia o ausencia de proteína amiloide en la muestra o parte o área corporal específica; y
(e)
comparar opcionalmente la cantidad del complejo compuesto/proteína a un valor de control normal.
35 También se describe un método de recolección de datos para predecir la capacidad de respuesta de un paciente que se trata con un anticuerpo o una composición vacuna, que comprende:
(a) poner la muestra o una parte corporal o área corporal específica sospechosa de contener una proteína amiloide
40 en contacto con un compuesto de acuerdo con la presente invención, compuesto que se une específicamente a la proteína amiloide;
(b)
permitir que el compuesto se una a la proteína amiloide para formar un complejo compuesto/proteína;
(c)
detectar la formación del complejo compuesto/proteína;
(d) correlacionar opcionalmente la presencia o ausencia del complejo compuesto/proteína con la presencia o 45 ausencia de proteína amiloide en la muestra o parte o área corporal específica; y
(e) comparar opcionalmente la cantidad del complejo compuesto/proteína a un valor de control normal.
Un aspecto adicional de la presente invención es un kit de prueba para la detección y/o diagnóstico de una enfermedad
o afección asociada a amiloide que comprende un compuesto de acuerdo con la presente invención.
50 En una primera realización la presente invención se refiere a un compuesto de la fórmula general (IIa) o (IIb)
imagen9
55 pes2o3. Cada enlazador K es independientemente alquileno C1-3 que está opcionalmente sustituido con uno o más grupos
10
alquilo C1-4. Preferentemente, cada enlazador K es -CH2-, -CH2CH2-o -CH2CH2CH2-.
El anillo heterocíclico B está opcionalmente sustituido con uno o más, preferentemente uno o dos, sustituyentes seleccionados entre alquilo C1-4, alcoxi C1-4, mono-y di-alquilamino C1-4, cicloalquilamino C3-7 y heterociclo saturado de 5 5 o 6 miembros, o dos sustituyentes pueden unirse para formar un anillo de 5 a 7 miembros saturado, insaturado o aromático que se condensa con el anillo heterocíclico B.
R1 se selecciona entre -H, -halógeno, -alquilo C1-4, -NH2, -NH-alquilo C1-4, -alquilen C1-4-NH2, -alquilen C1-4-NH-alquilo C1-4, -arilo, -aril-R3, -alquilenarilo C1-4, -alquilenaril C1-4-R3, -Heteroarilo, -heteroaril-R3, -NH-alquilenarilo C1-4, 10 -NH-alquilenaril C1-4-R3, -OH y -O-alquilo C1-4. R1 es preferentemente -H, -CH3, -NH-alquilo C1-4 o -CH2-NH-CH3.
R3 es alquilo C1-4, halógeno, OH u O-alquilo C1-4.
R2 es -H, -arilo, -alquilo C1-4 o un grupo de la fórmula (IIIa) o (IIIb) 15
imagen10
en la que en la fórmula (IIIa) y (IIIb):
20 el anillo heterocíclico B está opcionalmente sustituido con uno o más sustituyentes seleccionados entre alquilo C1-4, alcoxi C1-4, mono-y di-alquilamino C1-4, cicloalquilamino C3-7 y heterociclilo saturado de 5 o 6 miembros, o dos sustituyentes pueden unirse formar un anillo saturado, insaturado o aromático de 5 a 7 miembros que se condensa con el anillo heterocíclico B; cada enlazador K es independientemente alquileno C1-3 que está opcionalmente sustituido con uno o más alquilo grupos C1-4;
25 R1 se selecciona entre -H, halógeno, -alquilo C1-4, -NH2, -NH-alquilo C1-4, -C1-4 alquileno-NH2, -alquilen C1-4-NH-alquilo C1-4, -arilo, -aril-R3, -alquilenarilo C1-4, -alquilenaril C1-4-R3, -heteroarilo, heteroaril-R3, -NH-alquilenarilo C1-4, -NH-alquilenaril C1-4-R3, -OH y -O-alquilo C1-4; q es 0 o1;y r es 0o 1.
30 Arilo es preferentemente un arilo de 5 a 7 miembros, tal como fenilo.
Heteroarilo es preferentemente un heteroarilo de 5 a 7 miembros (preferentemente un heteroarilo de 5 miembros), que incluye al menos un heteroátomo seleccionado entre O, S o N. Son ejemplos
35
imagen11
Halógeno es preferentemente F o Cl. 40 En una realización los compuestos de la fórmula (II) tiene la fórmula (II'a) o (II'b)
imagen12
p es 2 o3.
11
imagen13
imagen14
imagen15
imagen16
2a
2c
2h
2j
2k
2n
imagen17
16
2o
2p
2q
2s
2t
2u
imagen18
17
2w
2y
2z
2aa
imagen19
2ab
2ac
2ad
imagen20
18
2ae
2af
imagen21
2ag
2ah
2ai
2ak
2al
2am
imagen22
En los compuestos de la presente invención los donante de enlace H y los aceptores de enlace se disponen preferentemente en un patrón que es esencialmente complementario al patrón de los donantes de enlace H y aceptores de enlace H presentes en las hebras de aminoácidos de las estructuras de β-hoja como se muestra en la
5 parte introductoria. En particular, las distancias entre los donantes de enlace H y los aceptores de enlace H vecinos en los compuestos de la presente invención están preferentemente dentro del intervalo de 2,6 a 2,9 Å o de 3,5 a 4,0 Å.
Las distancias entre los donantes de enlace H y los aceptores de enlace H vecinos en los compuestos de la presente invención pueden, por ejemplo, medirse directamente a partir de los modelos de Dreiding de los compuestos. Como 10 alternativa, pueden usarse programas de computadora de modelado molecular, tal como MacroModel 7.2, para la determinación de la distancia.
19
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imagen25
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Inhibición de agregación de Aβ1-42
Para valorar la inhibición mediada por moléculas pequeñas de la agregación de Aβ1-42, las moléculas pequeñas se disolvieron antes de cada experimento en dimetilsulfóxido anhidro (DMSO, Sigma-Aldrich) hasta alcanzar una 5 concentración de 7,4 mM. La película de péptido Aβ-42 se disolvió en DMSO para alcanzar 400 µM. Se preparó una solución de ensayo en tampón PBS en tubos de incubación no tratados con silicón para alcanzar las siguientes concentraciones: molécula pequeña 330 µM, Aβ1-42 33 µM, tioflavina T 10 µM (ThT) y DMSO al 12,8 %. Por lo tanto, la relación molar final de molécula pequeña a Aβ1-42 fue 10:1. Se preparó un control positivo sin una molécula pequeña para medir la RFU máxima. Se preparó un control negativo sin Aβ1-42 para cada molécula pequeña. Se
10 probó trímero de 3-aminopirazol (trímero) en todos los ensayos para determinar la reproductibilidad entre experimentos independientes. Las soluciones se incubaron durante 24 h a 37 ºC, y se leyó la espectrofluorescencia (unidades de fluorescencia relativa; RFU) en seis réplicas en 384 pocillos de ensayo (Perkin-Elmer) o en un espectrofluorómetro FluoroCount de Perkin-Elmer. La inhibición de la agregación se expresa como el % medio de la inhibición o ± 1 desviación estándar (SD) de acuerdo con la siguiente ecuación:
15
imagen59
El criterio de corte para la selección de moléculas funcionales se definió a una capacidad de inhibición del 50 %.
20 Resultados
Las moléculas pequeñas se probaron para su capacidad para inhibir la agregación de Aβ1-42 en el ensayo ThT. Los resultados para las moléculas se resumen en la siguiente tabla. Todas las moléculas pequeñas sintetizadas inhibieron las agregación de Aβ1-42 en el ensayo ThT a algún grado y una serie de las moléculas probadas demostraron una
25 capacidad de inhibición de más del 50 %.
Tabla: Inhibición de la agregación de y desagregación de Aβ1-42 de fibras preformadas de Aβ1-42 por pequeñas moléculas
Compuesto
% de inhibición
2a*
65,3 ± 2,6
2c
77,0 ± 5,3
2 h
31,9 ± 10,1
2j
70,7 ± 6,8
2k
81,2 ± 7,3
2n
27,8 ± 9,9
2o
39,6 ± 2,8
2p
43,6 ± 2,1
2q
45,0 ± 8,3
2s*
55,1 ± 6,4
2t
86,8 ± 2,9
2u
55,3 ± 1,0
2w
13,9 ± 12,9
2y
57,0 ± 15,9
2z
58,7 ± 3,0
2aa
41,5 ± 9,6
2ab
1,7 ± 11
2ac
78,5 ± 1,3
2ad
82,1 ± 2,2
2ae
51,2 ± 1,5
2af
41,3 ± 9,2
2ag
34,2 ± 1,6
2ah
35,7 ±5,6
2ai
84,8 ± 0,0
2ak
37,2 ± 14,8
2al
66,1 ± 15,4
2am
68..2 ± 9,7
* Compuesto fluorescente en ausencia de Amiloide β1-42
56
imagen60

Claims (1)

  1. imagen1
    imagen2
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