ES2549979T3 - El uso de estimuladores de la sGC, activadores de la sGC, solos y en combinaciones con inhibidores de la PDE5 para el tratamiento de esclerosis sistémica (EcS) - Google Patents

El uso de estimuladores de la sGC, activadores de la sGC, solos y en combinaciones con inhibidores de la PDE5 para el tratamiento de esclerosis sistémica (EcS) Download PDF

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ES2549979T3
ES2549979T3 ES11722786.8T ES11722786T ES2549979T3 ES 2549979 T3 ES2549979 T3 ES 2549979T3 ES 11722786 T ES11722786 T ES 11722786T ES 2549979 T3 ES2549979 T3 ES 2549979T3
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sgc
treatment
ecs
alone
combinations
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Claudia Hirth-Dietrich
Peter Sandner
Johannes-Peter Stasch
Andreas Knorr
Georges Von Degenfeld
Michael Hahn
Markus Follmann
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Adverio Pharma GmbH
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Abstract

Compuestos de acuerdo con las fórmulas (1) a (27)**Fórmula** para su uso en la prevención y/o el tratamiento de la esclerosis sistémica (EcS).

Description

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E11722786
16-10-2015
Se introdujo una suspensión de 16,03 g (43,19 mmol) de 5-fluoro-1-(2-fluorobencil)-3-yodo-1H-pirazol[3,4-b]piridina (ejemplo 6A) y 4,25 g (47,51 mmol) de cianuro de cobre en DMSO (120 ml) y se agitó a 150 ºC durante 2 horas. Después de enfriar, se enfriaron los contenidos del matraz hasta aproximadamente 40 ºC, se vertieron en una solución de amoníaco acuoso concentrado (90 ml) y agua (500 ml), se mezclaron con acetato de etilo (200 ml) y se
5 sometieron a agitación extractiva corta. La fase acuosa se separó y se extrajo dos veces más con acetato de etilo (200 ml cada vez). Las fases orgánicas combinadas se lavaron dos veces con solución de cloruro sódico acuoso a concentración del 10 % (100 ml cada vez), se secaron y se concentraron a presión reducida. El producto en bruto se hizo reaccionar sin purificación adicional.
Rendimiento: 11,1 g (91 % de teoría)
10 RMN de 1H (400 MHz, DMSO-d6):  = 5,87 (s, 2H), 7,17-7,42 (m, 4H), 8,52 (dd, 1H), 8,87 (dd, 1H).
Ejemplo 9A
Acetato de 5-fluoro-1-(2-fluorobencil)-1H-pirazolo[3,4-b]piridin-3-carboximidamida
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HN
A 2,22 g (41,07 mmol) de metóxido sódico en metanol (270 ml) se añadieron 11,1 g (41,07 mmol) de 5-fluoro-1-(2
15 fluorobencil)-1H-pirazolo[3,4-b]piridin-3-carbonitrilo (ejemplo 8A) y la mezcla se agitó a TA durante 2 horas. Después se añadieron 2,64 g (49,29 mmol) de cloruro amónico y ácido acético (9,17 ml) y la mezcla se calentó a reflujo durante la noche. Después se concentró hasta sequedad y el residuo se suspendió en agua (100 ml) y acetato de etilo (100 ml) y se ajustó hasta un pH de 10 usando una solución de hidróxido sódico acuoso 2N. Se agitó intensamente a TA durante 1 hora. La suspensión resultante se filtró con succión y el producto del filtro se lavó con
20 acetato de etilo (100 ml), con agua (100 ml) y de nuevo con acetato de etilo (100 ml). El residuo se secó en alto vacío sobre pentóxido de fósforo.
Rendimiento: 9,6 g (78 % de teoría)
EM (ESIpos): m/z = 288 (M+H)+
RMN de 1H (400 MHz, DMSO-d6):  = 1,85 (s, 3H), 5,80 (s, 2H), 7,14-7,25 (m, 3H), 7,36 (m, 1H), 8,42 (dd, 1H), 8,72 25 (dd, 1H).
Ejemplo 10A
2-[5-fluoro-1-(2-fluorobencil)-1H-pirazolo[3,4-b]piridin-3-il]-5-[(E)-fenildiacenil]pirimidin-4,6-diamina
20
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E11722786
16-10-2015
Una cantidad de 3,470 g (8,138 mmol) del compuesto del ejemplo 1 se suspendió en 35 ml de THF, se mezcló a 0 ºC con 358 mg (8,952 mmol) de hidruro sódico (suspensión al 60 % en aceite mineral) y se agitó a 0 ºC durante 90 minutos, en el curso de los que se formó una solución. Se añadió una cantidad de 2,519 g (8,952 mmol) de 2,2,2trifluoroetil-triclorometanosulfonato y la mezcla se agitó a TA durante 48 horas. Después se agitó con agua y se
5 concentró en un evaporador rotatorio. El residuo se aceptó en acetato de etilo y la fase orgánica se lavó dos veces con agua y se secó sobre sulfato sódico. Esto dio 5,005 g del compuesto objetivo (79 % de teoría, pureza por HPLC del 65 %). Una cantidad de 250 mg del residuo se purificó por HPLC preparativa (Eluyente: gradiente de metanol/agua de 30:70  90:10).
CL-EM (Procedimiento 2): Tr = 0,97 min; EM (ESIpos): m/z = 509 [M+H]+.
10 RMN de 1H (400 MHz, DMSO-d6):  [ppm] = 3,63 (s, 3H), 4,06-4,15 (m, 2H), 5,80 (s, 2H), 6,46 (s a, 4H) 7,11-7,15 (m, 2H), 7,20-7,25 (m, 1H), 7,33-7,38 (m, 1H), 8,66 (dd, 1H), 8,91 (dd, 1H).
Ejemplo A
Fibrosis cutánea inducida por bleomicina
Se indujo fibrosis cutánea local en ratones DBA/2 sin patógenos, hembras, de 6 semanas de edad (Charles River,
15 Sulzfeld, Alemania) por inyecciones subcutáneas repetidas (en días alternos) de bleomicina (0,5 mg/ml en solución salina) en un área definida de la parte superior del dorso. Los ratones control se inyectaron del mismo modo solo con solución salina y sirvieron como referencia. Para todos los grupos el volumen de inyección fue 100 µl. Al mismo tiempo que con el tratamiento con bleomicina, los ratones se trataron oralmente con el fármaco de ensayo o con vehículo. Se trató a los ratones a) con vehículo b) con 1 mg/kg del ejemplo 27 y c) con 3 mg/kg del ejemplo 27, dos
20 veces al día por sonda durante 21 días. Después de este periodo de tratamiento de 3 semanas los animales se sacrificaron y se obtuvieron muestras de piel para análisis.
Análisis histológico
Las áreas de piel inyectadas se fijaron en formalina al 4 % y se incrustaron en parafina. Las secciones histológicas se tiñeron con hematoxilina y eosina para la determinación del espesor dérmico. El espesor dérmico se determinó
25 midiendo la distancia más grande entre la unión epidérmica-dérmica y la unión de grasa dérmica-subcutánea. Las mediciones las realizó un investigador ciego respecto al tratamiento de los ratones.
Ensayo de hidroxiprolina
Analizando el contenido en colágeno en muestras de piel se realizó un ensayo con hidroxiprolina. Tras la digestión con biopsias por punción (Ø 3mm) en HCl 6M durante tres horas a 120 ºC, se añadió cloramina T (0,06 M) y las
30 muestras se mezclaron y se incubaron durante 20 minutos a temperatura ambiente. Se añadió ácido perclórico 3,15 M y p-dimetilaminobenzaldehído al 20 % y las muestras se incubaron durante 20 minutos adicionales a 60 ºC. La absorbancia se determinó a 557 nm.
Inmunohistoquímica para la α-actina de músculo liso
La expresión de la actina α de músculo liso (αSMA) se analizó en secciones incrustadas en parafina. Después de la
35 desparafinización, las muestras se incubaron con seroalbúmina bovina al 3 % seguido de incubación con H2O2 al 3 %. Las células positivas a αSMA en secciones de ratón se detectaron por incubación con anticuerpos anti-αSMA monoclonales (clon 1A4, Sigma-Aldrich, Steinheim, Alemania). Como control se usaron anticuerpos de isotipo irrelevante a la misma concentración (Santa Cruz Biotechnology, Santa Cruz, CA, EE.UU.). Como anticuerpos secundarios se usaron anticuerpos marcados con peroxidasa de rábano picante (Dako, Hamburgo, Alemania). La
40 expresión de NICD y αSMA se visualizó con una solución de sustrato de DAB peroxidasa (Sigma-Aldrich). El número de miofibroblastos se contó a partir de 4 secciones diferentes de piel dañada para cada ratón por un investigador ciego con respecto al tratamiento de los ratones.
Tabla 1: Efectos del ejemplo 27 sobre el desarrollo de fibrosis cutánea inducida por bleomicina.
a) Bleomicina + vehículo
b) Bleomicina + 1 mg/kg del ejemplo 27 c) Bleomicina + 3 mg/kg del ejemplo 27
Espesor dérmico
1,70 1,37 1,19
Contenido en colágeno
1,31 1,19 1,11
Recuento de miofibroblastos
3,72 3,23 1,90
24
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