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ES2603958T3 - 4-Fenil-piridinas sustituidas para el tratamiento de enfermedades relacionadas con el receptor NK1 - Google Patents

4-Fenil-piridinas sustituidas para el tratamiento de enfermedades relacionadas con el receptor NK1 Download PDF

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Publication number
ES2603958T3
ES2603958T3 ES12798549.7T ES12798549T ES2603958T3 ES 2603958 T3 ES2603958 T3 ES 2603958T3 ES 12798549 T ES12798549 T ES 12798549T ES 2603958 T3 ES2603958 T3 ES 2603958T3
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Prior art keywords
phenyl
trifluoromethyl
dimethylpropanamide
emesis
5bis
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Luca Fadini
Peter Manini
Claudio Pietra
Claudio Giuliano
Emanuela Lovati
Roberta Cannella
Alessio Venturini
Valentino J. Stella
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Helsinn Healthcare SA
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Helsinn Healthcare SA
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

Un compuesto seleccionado entre el grupo que consiste en:**Tabla** GA1**Fórmula** 4-(5-(2-(3,5-bis(trifluorometil)fenil)-N,2-dimetilpropanamido)-4- (o-tolil)piridin-2-il)-1-metil-1-((fosfonooxi)metil)piperazin-1-io, GA2**Fórmula** 1-(acetoximetil)-4-(5-(2-(3,5-bis(trifluorometil)fenil)-N,2- dimetilpropanamido)-4-(o-tolil)piridin-2-il)-1-metilpiperazin-1-io, GA3**Fórmula** 4-(5-(2-(3,5-bis(trifluorometil)fenil)-N,2-dimetilpropanamido)-4- (o-tolil)piridin-2-il)-1-((butiriloxi)metil)-1-metilpiperazin-1-io, GA4**Fórmula** 1,4-dioxido de 1-(5-(2-(3,5-bis(trifluorometil)fenil)-N,2- dimetilpropanamido)-4-(o-tolil)piridin-2-il)-4-metilpiperazina, GA6**Fórmula** 1-oxido 4-(5-(2-(3,5-bis(trifluorometil)fenil)-N,2- dimetilpropanamido)-1-oxido-4-(o-tolil)piridin-2-il)-1- metilpiperazina, o una sal farmaceuticamente aceptable del mismo.

Description

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7
o una sal o un aducto farmacéuticamente aceptables del mismo. En una realización adicional, la invención es un compuesto de fórmula GA1,
o una sal o un aducto farmacéuticamente aceptables del mismo.
imagen7
Breve descripción de los dibujos
La FIGURA 1 reproduce los datos de estabilidad para diversas sales de 4(5(2(3,5bis(trifluorometil)fenil)N,2
8
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la emesis. La emesis retardada se refiere al segundo, tercer, cuarto y quinto período de veinticuatro horas siguientes a un acontecimiento inductor de la emesis. Cuando se dice que un tratamiento es eficaz durante la fase tardía, se entenderá en el sentido de que la eficacia del tratamiento es estadísticamente significativa durante toda la fase retardada, independientemente de si el tratamiento es eficaz durante cualquier período en particular de veinticuatro 5 horas la fase retardada. También se entenderá que el uso médico puede definirse basándose en su eficacia durante cualquiera de los períodos de veinticuatro horas de la fase retardada. Por tanto, a menos que se especifique lo contrario, cualquiera de los usos médicos para el tratamiento de las náuseas y/o vómitos durante las fases retardadas, como se describen en el presente documento, también podrían practicarse para tratar las náuseas y/o vómitos durante el segundo, tercer, cuarto y quinto período de veinticuatro horas siguientes a un acontecimiento
10 inductor de la emesis o una combinación de los mismos.
En algunas otras formas, se desvelan usos médicos para la prevención y/o el tratamiento de enfermedades que están fisiopatológicamente moduladas por el receptor NK1, en los que dichas fases agudas y/o retardadas de las NVIQ son inducidas la quimioterapia moderada o altamente emetógena. "Quimioterapia altamente emetógena" se
15 refiere a la quimioterapia que tiene un alto grado de potencial emético, e incluye la quimioterapia a base de carmustina, cisplatino, ciclofosfamida ≥ 1500 mg/m2, dacarbazina, dactinomicina, mecloretamina y estreptozotocina. "Quimioterapia moderadamente emetógena" se refiere a la quimioterapia que tiene un grado moderado de potencial emético, e incluye la quimioterapia a base de carboplatino, ciclofosfamida < 1500 mg/m2, citarabina > 1 mg/m2, daunorubicina, doxorubicina, epirubicina, idarubicina, ifosfamida, irinotecán y oxaliplatino.
20 En una realización preferida, los usos médicos de la presente invención son eficaces para tratar la emesis aguda y retardada resultante de la quimioterapia moderadamente y altamente emetógena, a partir de una sola dosis del derivado de netupitant administrado antes de la quimioterapia, opcionalmente en combinación con otros principios activos.
25 Una posología particularmente preferida para el tratamiento de la emesis, especialmente la emesis inducida por la quimioterapia, implica un derivado de netupitant de la presente invención, un antagonista de 5HT3 tal como palonosetrón o una sal farmacéuticamente aceptable del mismo y un corticoesteroide tal como dexametasona. Una posología fija adecuada para el tratamiento de las NVIQ agudas y retardadas incluye una única administración del
30 derivado de netupitant el día uno (preferentemente antes de la quimioterapia), una única administración del antagonista de 5HT3 el día 1 (preferentemente antes de la quimioterapia). Se añade un corticoesteroide opcionalmente a la combinación en un día y, cuando se administra la quimioterapia altamente emetógena, en días 2, 3 y 4 también. Una dosis intravenosa preferida de HCl de palonosetrón es de 0,25 mg sobre la base del peso de la base libre. Las dosis preferidas de dexametasona son 12 mg por vía oral el día 1, seguidos de 8 mg por vía oral los
35 días 2, 3 y 4 para la quimioterapia altamente emetógena.
En algunas otras formas, se desvelan usos médicos para la prevención y/o el tratamiento de enfermedades que están fisiopatológicamente moduladas por el receptor NK1, en los que dicha disfunción de la vejiga se selecciona entre urgencia, frecuencia, poliaquiuria, nicturia, bajo tiempo el aplazamiento, umbral de volumen subóptimo y vejiga
40 neurógena o una combinación de los mismos.
En algunas otras formas, se desvelan usos médicos para la prevención y/o el tratamiento de enfermedades que están fisiopatológicamente moduladas por el receptor NK1, en los que dicho compuesto o una sal o un aducto farmacéuticamente aceptables del mismo, se administra por una o más vías seleccionadas entre el grupo que
45 consiste en la administración rectal, bucal, sublingual, intravenosa, subcutánea, intradérmica, transdérmica, intraperitoneal, oral, colirio, parenteral y tópica.
En algunas otras formas, se desvelan usos médicos para la prevención y/o el tratamiento de enfermedades que están fisiopatológicamente moduladas por el receptor NK1, en los que dicha administración se realiza mediante la
50 administración por vía intravenosa de una forma líquida de dicho compuesto o una sal o un aducto farmacéuticamente aceptables del mismo.
En algunas otras formas, se desvelan usos médicos para la prevención y/o el tratamiento de enfermedades que están fisiopatológicamente moduladas por el receptor NK1, en particular por los derivados de netupitant, en los que
55 dicha administración se consigue mediante la administración por vía oral de dicho compuesto o una sal o un aducto farmacéuticamente aceptables del mismo. En algunas otras formas, se desvelan usos médicos para la prevención y/o el tratamiento de enfermedades que están fisiopatológicamente moduladas por el receptor NK1, en los que dicho derivado de netupitant se administra por vía oral a una dosis de aproximadamente 50 mg a aproximadamente 500 mg, de aproximadamente 100 mg a aproximadamente 400 mg, de aproximadamente 150 mg a
60 aproximadamente 350 mg o aproximadamente 300 mg, sobre la base del peso del componente netupitant de la molécula.
En algunas otras formas, se desvelan usos médicos para la prevención y/o el tratamiento de enfermedades que
23
imagen22
imagen23
imagen24
imagen25
imagen26
imagen27
imagen28
imagen29
imagen30
imagen31
imagen32
Cuando la especie de ácido parental no se almacenó en estado seco se descubrió que experimentó una degradación de más del 8 % en la primera semana y una degradación de más del 65 % en los primeros seis meses. Cuando la especie de ácido parental seca se mantuvo a 30 ºC al aire experimentó una degradación del 0,05 % en los primeros 7 días y una degradación total del 7,03 % en seis meses. Cuando la especie de ácido parental seca se mantuvo en atmósfera de argón a temperatura ambiente experimentó una degradación de hasta el 0,13 % en los primeros 7 días, pero después fue esencialmente estable durante seis meses. Se muestran resultados para diversas sales derivadas en la Tabla 1 a continuación.
Tabla 1: Resultados de degradación representativos para sales
Disolventes
Aditivos % de Rendimiento Pureza % de A por HPLC Comentarios
MeOH
LHistidina, 2 eq. 26,6 % 95,94 % Degradación: +0,70 % en 6 días (en aire) +0,46 % en 6 días (en atmósfera de argón)
MeOH
Mg(OH)2, 2 eq. 48,6 % 94,11 % Degradación: +0,81 % en 6 días (en aire) +0,29 % en 6 días (en atmósfera de argón)
MeOH + DCM, 1:1
Ácido cítrico, 2 eq. N.A. 94,40 % A partir de especie protegida.
MeOH
1. HCl de dioxano, 4 eq. 2. Ca(OH)2 > 90 % 94,50 % A partir de especie protegida.
MeOH
H3PO4, 85 %, 2 eq. > 90 % 98,81 % A partir de especie protegida y conserva el 0,39 % de esa especie.
MeOH
HBr, 48 %, 4 eq. 84,6 % 96,11 % A partir de especie protegida. El producto se degrada rápidamente.
MeOH + DCM, 1:4
CH3SO3H N.A. 61,54 % A partir de especie protegida. Producto NO estable: contiene el 32,45 % de especie de descomposición.
MeOH
NaH2PO4, 4 eq. N.A. n.d. Solo se formó 1,27 de especie parental. Reacción pobre.
MeOH
NmetilDglucamina N.A. 96,88 % Degradación: +0,87 % en 6 días (en aire)
(Meglumina), 2 eq.
+1,52 % en 11 días (en atmósfera de argón)
MeOH
NmetilDglucamina (Meglumina), 1 eq. > 99 % 97,42 % Degradación: +0,77 % en 6 días (en aire) +0,83 % en 7 días (en atmósfera de argón)
MeOH + DCM, 5:2
1. NaOH, 3 eq 2. Ácido cítrico, 1 eq. 96,5 % 97,49 % Degradación: +0,09 % en 2 días (en atmósfera de argón) +0,59 % en 89 días (en atmósfera de argón)
MeOH + DCM, 5:2
1. NaOH, 3 eq. 2. Ácido fumárico, 1 eq. 93,8 % 97,46 % Degradación: +1,95 % en 14 días (en aire) +1,80 % en 12 días (en atmósfera de argón)
MeOH
Llisina, 1 eq. > 99 % 97,62 % Degradación: +0,69 % en 14 días (en aire) +0,48 % en 12 días (en atmósfera de argón)
Una muestra más completa de los resultados de estabilidad se proporciona en la Fig. 1, donde el eje horizontal representa el número de días del ensayo y el eje vertical representa el porcentaje en masa de degradación. Se usan
35

Claims (4)

  1. REIVINDICACIONES
    1. Un compuesto seleccionado entre el grupo que consiste en:
    GA1
    imagen1 4(5(2(3,5bis(trifluorometil)fenil)N,2dimetilpropanamido)4(otolil)piridin2il)1metil1((fosfonooxi)metil)piperazin1io,
    GA2
    imagen2 1(acetoximetil)4(5(2(3,5bis(trifluorometil)fenil)N,2dimetilpropanamido)4(otolil)piridin2il)1metilpiperazin1io,
    GA3
    imagen3 4(5(2(3,5bis(trifluorometil)fenil)N,2dimetilpropanamido)4(otolil)piridin2il)1((butiriloxi)metil)1metilpiperazin1io,
    GA4
    imagen4 1,4dióxido de 1(5(2(3,5bis(trifluorometil)fenil)N,2dimetilpropanamido)4(otolil)piridin2il)4metilpiperazina,
    GA6
    imagen5 1óxido 4(5(2(3,5bis(trifluorometil)fenil)N,2dimetilpropanamido)1oxido4(otolil)piridin2il)1metilpiperazina,
    5
    o una sal farmacéuticamente aceptable del mismo.
  2. 2. Un compuesto de acuerdo con la reivindicación 1 para su uso en un método de tratamiento de la emesis, la
    disfunción de la vejiga, la depresión o la ansiedad, en un paciente que lo necesite. 10
  3. 3. El compuesto para el uso de acuerdo con la reivindicación 2, en el que dicha emesis comprende las náuseas y vómitos inducidos por quimioterapia (NVIQ), las náuseas y vómitos inducidos por radioterapia (NVIR) o las nausea y vómitos postoperatorios (NVPO).
    15 4. El compuesto para el uso de acuerdo con cualquiera de las reivindicaciones 23, en el que dicha emesis es inducida por la quimioterapia moderadamente o altamente emetógena.
  4. 5. El compuesto para el uso de acuerdo con cualquiera de las reivindicaciones 24, en el que la emesis es la emesis
    aguda y retardada inducida por la quimioterapia moderadamente o altamente emetógena. 20
    42
    imagen6
    imagen7
    imagen8
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