ES2694375T3 - Composiciones para el tratamiento de la hipertensión y/o de la fibrosis - Google Patents

Composiciones para el tratamiento de la hipertensión y/o de la fibrosis Download PDF

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ES2694375T3
ES2694375T3 ES14845828.4T ES14845828T ES2694375T3 ES 2694375 T3 ES2694375 T3 ES 2694375T3 ES 14845828 T ES14845828 T ES 14845828T ES 2694375 T3 ES2694375 T3 ES 2694375T3
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stereoisomer
pharmaceutically acceptable
acceptable salt
fibrosis
compound according
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Karen Annette Duggan
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Vectus Biosystems Ltd
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Vectus Biosystems Ltd
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    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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 in position 2
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    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
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Abstract

Un compuesto de fórmula**Fórmula** en la que A se selecciona del grupo que consiste en:**Fórmula** Q se selecciona independientemente de halo, alquilo, hidroxi, amino y amino sustituido; n es 0, 1, 2, 3, 4 o 5; R1, R3 y R4 son independientemente, C, CH, CH2, O, N, NH o S, y R2 es C, CH, CH2, N, NH, C-CF3, CH-CF3 o C>=O, o un esteroisómero o una sal farmacéuticamente aceptable de los mismos, en los que, cuando n es 1, Q no puede ser hidroxi, y en los que el amino sustituido es de fórmula -NHW y en los que: W se selecciona de -CN, -SO2(X)aY y -CO(X)aY, a es 0 o 1, X se selecciona de -NH- y -O-, e Y se selecciona de -H, -CH3, -CH2CH3, -CH2OH y -CH2CH2OH.

Description

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DESCRIPCION
Composiciones para el tratamiento de la hipertensión y/o de la fibrosis Campo de la invención
La presente invención versa sobre compuestos novedosos y su uso en el tratamiento profiláctico y/o terapéutico de enfermedades cardiovasculares y, en particular, para el tratamiento de la prehipertensión, la hipertensión y/o de afecciones fibróticas.
La invención ha sido desarrollada fundamentalmente para el tratamiento profiláctico y/o terapéutico de enfermedades cardiovasculares y será descrita en lo que sigue con referencia a esta solicitud. Sin embargo, se apreciará que la invención no está limitada a este campo particular de uso.
Antecedentes de la invención
No debería considerarse en modo alguno que cualquier exposición de la técnica anterior en toda la memoria sea una admisión de que tal técnica sea conocida de forma generalizada o que forma parte del conocimiento general común en la técnica.
La hipertensión (presión arterial elevada) afecta al 26% de la población adulta del mundo entero, con una incidencia del 30-33% en los países occidentales. Se espera que la incidencia mundial de la hipertensión alcance el 29% antes de 2025 como consecuencia de la occidentalización de la India y de China. Los estudios actuales indican que menos del 20% de los pacientes con hipertensión logra su objetivo recomendado de presión arterial (PA) y que para lograr estos objetivos >75% de los pacientes requiere terapia con múltiples antihipertensivos. La prehipertensión (presión arterial ligeramente elevada) afecta a un 31% de los adultos en los EE. UU., y puede convertirse en hipertensión si no es tratada.
Todas las terapias actualmente disponibles tienen efectos secundarios:
• Inhibidores de la enzima convertidora de la angiotensina (IECA): tos, edema angioneurótico, hiperkalemia;
• Antagonistas de los receptores de angiotensina (ARA): edema angioneurótico, hiperkalemia;
• Bloqueadores de los canales de calcio (BCC): sofocos, edema de la pierna o el tobillo, estreñimiento;
• Diuréticos tiazídicos: diabetes de aparición reciente, gota, hiponatremia;
• Beta (p) bloqueadores: diabetes de aparición reciente, incapacidad de hacer ejercicio, bradicardia, ocultación de la hipoglucemia en diabéticos; y
• Antagonistas de la aldosterona - ginecomastia, menorragia, hiperkalemia.
La necesidad de usar terapia de combinación aumenta la probabilidad de que los pacientes experimenten efectos secundarios y, en consecuencia, de que no logren su objetivo de PA.
La hipertensión y la prehipertensión son un factor fundamental en el desarrollo de lesiones en el corazón, los riñones y los vasos sanguíneos que dan lugar a la sustitución del tejido funcional normal por tejido cicatricial o fibrosis. Aunque algunos de los antihipertensivos actuales —inhibidores ECA, inhibidores de renina de ARA y antagonistas de la aldosterona— son capaces de ralentizar el avance de la sustitución del tejido funcional por fibrosis, ninguno ha demostrado revertir la fibrosis existente ni restaurar la arquitectura tisular normal. Existe, así, la necesidad de agentes que tengan eficacia en reducir significativamente la PA y, así, en lograr que una mayor proporción de pacientes logre el objetivo de PA con la terapia de un único agente y/o en revertir la fibrosis existente y/o en restaurar la arquitectura tisular normal.
El documento US 2011/0082109 A1 tiene como objetivo proporcionar un fármaco que posee un efecto inhibidor sobre el NHE3 (intercambiador de Na+/H+ de tipo 3). El documento WO 2004/000814 A1 está dirigido a compuestos que son8-(biaril)quinolinas sustituidas. El documento WO 2010/091876 A2 versa sobre antagonistas selectivos del receptor B1 de la bradiquinina (B1R) y sus usos para el tratamiento de afecciones y enfermedades.
Es un objeto de la presente invención superar o paliar al menos una de las desventajas de la técnica anterior, o proporcionar una alternativa útil.
Compendio de la invención
Los presentes inventores han descubierto, con sorpresa, que ciertos compuestos novedosos de terfenilo tienen efectos de disminución de la presión arterial y/o antifibróticos. Estos efectos pueden verse en estudios de dosificación intravenosa y/u oral.
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Según un aspecto, la presente invención proporciona el compuesto según la reivindicación 1.
Según otro aspecto, la presente invención proporciona el compuesto, o un esteroisómero o una sal farmacéuticamente aceptable del mismo, según las reivindicaciones 2-6.
Según otro aspecto, la presente invención versa sobre la composición farmacéutica según la reivindicación 7.
Según otro aspecto, la presente invención versa sobre el uso según las reivindicaciones 8-14.
A no ser que el contexto requiera claramente algo distinto, en toda la descripción y las reivindicaciones, las palabras “comprende”, “que comprende” y similares han de ser interpretadas en un sentido incluyente, no excluyente o exhaustivo; es decir, en el sentido de “incluye, sin limitación”.
Breve descripción de las figuras
Figura 1: Síntesis de 3-formilbifenil-4-il trifluorometanosulfonato.
Figura 2: Síntesis de T1, T2, T10 y T18.
Figura 3: Síntesis de dietil(carbamoilmetil)fosfonato.
Figura 4: Síntesis de T20.
Figura 5: Síntesis de T70.
Figura 6: Síntesis de T48.
Figura 7: Síntesis de 3-(3-amino-3-oxopropil)bifenil-4-il-trifluorometanosulfonato.
Figura 8: Síntesis de T25.
Figura 9: Síntesis de éster pinacol borónico de indolona.
Figura 10: Síntesis de T31.
Figura 11: Índice celular normalizado de referencia para diversos compuestos a tres concentraciones —62,5 pM (barras abiertas), 125 pM (barras rayadas) y 250 pM (barras sólidas)—, en células de músculo liso vascular A10 de rata determinado usando el instrumento xCELLigence RTCA.
Figura 12: Índice celular normalizado de referencia para diversos compuestos a tres concentraciones—62,5pM (barras abiertas), 125pM (barras rayadas) y 250pM (barras sólidas)—, en células endoteliales aórticas bovinas determinado usando el instrumento xCELLigence RTCA.
Figura 13: Presiones arteriales sistólica (barras rayadas) y diastólica (barras abiertas) en controles y ratas hipertensivas espontáneas (RHE) tratadas con una dieta de sal al 2,2% después de 4 semanas de terapia. Se administraron T1, T2, T20, T31 y T48 a razón de 500pmol/kg/min en la solución de bebida (etanol al 5%) durante 4 semanas, se administró T70 a razón de 100 pmol/kg/min en la solución de bebida. * p<0,05, ** p<0,01, *** p<0,005 y **** p<0,0005 sistólica tratada con respecto a sistólica de control; # p<0,05, ## p<0,025 y ### p<0,005 diastólica tratada con respecto a diastólica de control.
Figura 14: Relación entre el índice celular normalizado de referencia para células musculares lisas vasculares A10 y la presión arterial sistólica para diversos compuestos.
Figura 15: Relación entre el índice celular normalizado de referencia para células endoteliales aórticas bovinas y la presión arterial sistólica para diversos compuestos.
Figura 16: Fibrosis miocárdica cuantificada por histomorfometría computarizada en secciones histológicas tincionadas con tinción tricrómica de Masson en RHE con una dieta de sal al 2,2% a las 14 semanas y después de 4 semanas de tratamiento con el fármaco en la solución de bebida o el control de vehículo. * p<0,005, ** p<0,001 y *** p<0,0005 con respecto al control de 18 semanas de tratamiento con vehículo. # p<0,05, ## p<0,01, ### p<0,005 y //////// p<0,0005 en relación con el control de 14 semanas. Esta comparación indica la capacidad de revertir la patología existente.
Figura 17: Fibrosis intersticial del riñón cuantificada por histomorfometría computarizada en secciones histológicas tincionadas con tinción tricrómica de Masson en RHE con una dieta de sal al 2,2% a las 14 semanas y después de 4 semanas de tratamiento con el fármaco en la solución de bebida o el control de vehículo. * p<0,005, ** p<0,001 y *** p<0,0005 en relación con el control de 18 semanas de tratamiento con vehículo. # p<0,05 con respecto al control de 14 semanas. Esta comparación indica la capacidad de revertir la patología existente.
Figura 18: Relación entre el índice celular normalizado de referencia para células endoteliales aórticas bovinas y la fibrosis miocárdica para diversos compuestos.
Figura 19: Relación entre el índice celular normalizado de referencia para células endoteliales aórticas bovinas y la fibrosis intersticial renal para diversos compuestos.
Figura 20: Micrografías del corazón para ratas de control (A) y ratas tratadas durante cuatro semanas con 500pmol/kg/min de T1 (B), T2 (C), T20 (D) o T31 (E).
5 Figura 21: Micrografías del riñón para ratas de control (A) y ratas tratadas durante cuatro semanas con 500pmol/kg/min de T1 (B), T2 (C), T20 (D) o T31 (E).
Descripción detallada de la invención
La presente invención versa sobre ciertos compuestos novedosos de terfenilo que presentan disminución de la presión y efectos antifibróticos en estudios de dosificación oral en un modelo animal experimental. Con respecto a la actividad 10 antifibrótica, los compuestos de la presente invención son eficaces en la prevención de la fibrosis, ralentizando el avance de la fibrosis establecida y/o disminuyendo el grado de la fibrosis establecida (reversión). Estos son hallazgos importantes con respecto a la gama y a la gravedad de las afecciones que pueden ser tratadas con los compuestos de la presente invención.
Los compuestos de la presente invención están definidos por la reivindicación 1.
15 Los siguientes compuestos son ejemplos específicos, pero no limitantes, de los compuestos de la presente invención:
imagen1

Claims (12)

  1. 5
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    REIVINDICACIONES
    1. Un compuesto de fórmula
    imagen1
    en la que
    A se selecciona del grupo que consiste en:
    imagen2
    imagen3
    Q se selecciona independientemente de halo, alquilo, hidroxi, amino y amino sustituido; n es 0, 1,2, 3, 4 o 5;
    Ri, R3 y R4 son independientemente, C, CH, CH2, O, N, NH o S, y
    R2 es C, CH, CH2, N, NH, C-CF3, CH-CF3 o C=O,
    o un esteroisómero o una sal farmacéuticamente aceptable de los mismos,
    en los que, cuando n es 1, Q no puede ser hidroxi, y
    en los que el amino sustituido es de fórmula -NHW y en los que:
    W se selecciona de -CN, -SO2(X)aY y -CO(X)aY, a es 0 o 1,
    X se selecciona de -NH- y -O-, e
    Y se selecciona de -H, -CH3, -CH2CH3, -CH2OH y -CH2CH2OH.
  2. 2. El compuesto según la reivindicación 1, o un esteroisómero o una sal farmacéuticamente aceptable del mismo, en el que Q es halo seleccionado del grupo que consiste en F, Cl, Br e I.
  3. 3. El compuesto según la reivindicación 1, o un esteroisómero o una sal farmacéuticamente aceptable del mismo, en el que Q es amino sustituido seleccionado del grupo que consiste en -NHSO2CH3, -NHCOH, -NHCONHCH3,
    5 -NHCONHCH2CH3, -NHSO2NHCH3, -NHSO2NHCH2CH3, -NHCOCH3, -NHCOOCH3, -NHCOOCH2CH2OH, -
    NHCONH2 y -NHCN.
  4. 4. El compuesto según la reivindicación 1, o un esteroisómero o una sal farmacéuticamente aceptable del mismo, en el que Q es alquilo seleccionado del grupo que consiste en metilo, etilo, propilo, butilo y pentilo.
  5. 5. El compuesto según la reivindicación 1, o un esteroisómero o una sal farmacéuticamente aceptable del 10 mismo, en el que A se selecciona entre:
    imagen4
    imagen5
    15
    imagen6
  6. 6. El compuesto según la reivindicación 1, o un esteroisómero o una sal farmacéuticamente aceptable del mismo, en el que el compuesto es seleccionado del grupo que consiste en:
    imagen7
    imagen8
    imagen9
    imagen10
    imagen11
    (T23),
    imagen12
    (T26),
    imagen13
    imagen14
    imagen15
    imagen16
    (T29),
    imagen17
    imagen18
    imagen19
    kk
    kk
    íT^i
    kk
    imagen20
    imagen21
    imagen22
  7. 7. Una composición farmacéutica que comprende un compuesto según una cualquiera de las reivindicaciones
    5 1 a 6, o un esteroisómero o una sal farmacéuticamente aceptable del mismo, y un excipiente farmacéuticamente
    aceptable.
  8. 8. Un compuesto según una cualquiera de las reivindicaciones 1 a 6, o un esteroisómero o una sal farmacéuticamente aceptable del mismo, para ser usado en el tratamiento terapéutico de la hipertensión o la prehipertensión.
    10 9. Un compuesto según una cualquiera de las reivindicaciones 1 a 6, o un esteroisómero o una sal
    farmacéuticamente aceptable del mismo, para ser usado en el tratamiento profiláctico de la fibrosis.
  9. 10. Un compuesto según una cualquiera de las reivindicaciones 1 a 6, o un esteroisómero o una sal farmacéuticamente aceptable del mismo, para ser usado en el tratamiento terapéuticode la fibrosis.
  10. 11. Un compuesto según una cualquiera de las reivindicaciones 1 a 6, o un esteroisómero o una sal 15 farmacéuticamente aceptable del mismo, para ser usado en el tratamiento terapéuticode la hipertensión y la fibrosis.
  11. 12. Un compuesto según una cualquiera de las reivindicaciones 1 a 6, o un esteroisómero o una sal farmacéuticamente aceptable del mismo, para ser usado en el tratamiento de la prehipertensión y la fibrosis.
  12. 13. El compuesto, o un esteroisómero o una sal farmacéuticamente aceptable del mismo, para ser usado según una cualquiera de las reivindicaciones 9 a 12 en el que la fibrosis es fibrosis miocárdica o fibrosis renal.
    5 14. El compuesto, o un esteroisómero o una sal farmacéuticamente aceptable del mismo, para ser usado según
    una cualquiera de las reivindicaciones 9 a 12 en el que la fibrosis es fibrosis miocárdica y fibrosis renal.
    imagen23
    CONH
    'NCONB
    Br As A "\N.
    B(OH% v 1 Pd(OA)s .A>x. íj 1 v PhNTí'j M .-—WWW - --W. - ----- --J—. V
    f; 7>^i5 i J í
    Y .....................•.}»■ 1
    ¡j A "A' VCHO + OH
    I J aq K;?COs ' 80% 13 V Ax A" CHO OH THF B5% í OTf
    Figura 1
    KjPO^
    dioxano
    67%
    Mesóla A
    " A ..-•'41%
    KGH
    THF
    63%
    Q
    A
    I | |
    I
    f | 19
    ^A.NC[2
    .A
    ..A'' ¡% Pd/C ^.AfVSeOH/EtOAC 59%
    I 2
    X.^A...-'XG0Nh.;
    jjjjPÍV
    CXk,u ACjO. DMAP
    HOQjH A. 47%
    * o
    A. \'*A
    rx
    A o
    TIO ! I) u
    A>Asnh,a
    Figura 2
    imagen24
    CONH
    FfQBüa
    PiOSO
    reflujo
    33%
    Figura 3
    OH)
    EtO
    PüfFFli
    Na
    CO-
    KOH
    dioxano,'HjO/
    HF
    BOH
    96%
    Ptí/G
    tú
    28%
    T20
    Figura 4
    imagen25
    CGNH
    HHSOjMe
    N' 'NHBoc
    CC«H.
    o _ b
    D¿N >4?" f40j
    KOAc, DMSO osN' ^'vNOs PHfPH^
    3(3 N«-.,CO
    Ph%e;BOB ' NQ2
    iBO'J a
    i í¿ vV -KiH
    MsC!
    MIC
    Bídv
    CONH, Dc^
    NaoH
    "S'CÜNH> 98%
    IMF. 72%
    25%
    T7G
    Figura 5
    m)A. A».
    *ppn?}4
    NH.
    Na-jCO-,
    dioxano/H,0/
    NSOH
    BOH
    THF; 83%
    H*, Pd/C
    TFA
    sm
    Figura 6
    imagen26
    ETAPA 1
    ETAPA 2
    ETAPA 3
    ETAPA 4
    ví*fs
    ETAPA 5
    ETAPA 6
    ...... ÍS ,.N
    Figura 7
    mA x
    m
    NaOH. THF
    Pd(PFh.^
    13$
    Sq Naxo
    PhmmoH
    15%
    H,, PcS/C
    NH T2í!
    Figura 8
    imagen27
    CO-¿Ue,
    CONH.
    ) DfvISO. US!
    CHfCO.
    100 X
    8 r ii) Fe. ACOH
    904X87%
    100 X, 20%
    FdC^oppf}
    KOAC, DMSO, 55%
    Figura 9
    PdiPPh
    NBs
    st
    KOH
    dioxano/H,0/
    iHF, 50%
    4 58%
    H,, Pd/C
    73%
    ¥31
    Figura 10
    2
    TC
    imagen28
    CTQ
    C
    as
    imagen29
    imagen30
    Control T1/500 12/500 T2G/5GG
    imagen31
    T31/500
    imagen32
    T48/500
    imagen33
    T70/100
    200 205 210 215 220 225 230 235
    Presión arterial sistólica (mmHg)
    í o
    < » O * O
    O p O
    í
    ís N> m «í o
    ................................ nr*"
    imagen34
    Qioz-n-zo
    838Sfr8H3
    Presión arterial sistólica (mmHg)
    imagen35
    4^
    CO
    <ü
    3
    +■»
    C
    <1>
    O
    i-
    O
    Q.
    <D
    O
    í
    O
    Q.
    3
    (¿l
    (ü
    O
    o
    o
    E
    </)
    '</)
    o
    imagen36
    *
    imagen37
    T48/500
    imagen38
    T7D/100 Control
    de 18 semanas
    imagen39
    imagen40
    Fibrosis miocárdica (superficie porcentual)
    índice celular normalizado de referencia
    imagen41
    Figura 19
    imagen42
    Figura 20
    imagen43
    Figura 21
ES14845828.4T 2013-09-17 2014-09-17 Composiciones para el tratamiento de la hipertensión y/o de la fibrosis Active ES2694375T3 (es)

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AU2014324075A1 (en) 2016-04-07
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US9630935B2 (en) 2017-04-25
CN105683153A (zh) 2016-06-15
AP2016009080A0 (en) 2016-03-31
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