EA022875B1 - Производные 4-(индазол-5-ил-амино)-2-фенилхиназолина - Google Patents

Производные 4-(индазол-5-ил-амино)-2-фенилхиназолина Download PDF

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EA022875B1
EA022875B1 EA200702048A EA200702048A EA022875B1 EA 022875 B1 EA022875 B1 EA 022875B1 EA 200702048 A EA200702048 A EA 200702048A EA 200702048 A EA200702048 A EA 200702048A EA 022875 B1 EA022875 B1 EA 022875B1
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alkyl
ylamino
quinazolin
indazol
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EA200702048A1 (ru
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Алессандра Бартолоцци
Пол Свитнэм
Стюарт Кемпбелл
Хоуп Фоудоулакис
Брайан Кирк
Сайя Рам
Хемалатха Сешадри
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Сурфейс Логикс Инк.
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Abstract

Изобретение относится к ингибиторам ROCK1 и ROCK2 и способам модулирования фармакокинетических и/или фармакодинамических свойств таких соединений. Предложено соединение общей формулы (I)Также представлены способы ингибирования ROCK1 и/или ROCK2, применимые для лечения заболеваний.

Description

(57) Изобретение относится к ингибиторам КОСК1 и КОСК2 и способам модулирования фармакокинетических и/или фармакодинамических свойств таких соединений. Предложено соединение общей формулы (I)
022875 Β1

Claims (9)

  1. или его фармацевтически приемлемая соль, где К1 выбран из группы, состоящей из -О-(СН2)У-С(=О)-NΗ-(С1 -С6-алкил)-О-(С1 -С6алкил)группы,
    -Θ-(СН2)у-С(=Θ)-NΗ-(С1-С8алкил)группы,
    -Θ-(СН2)у-С(=Θ)-NΗ-(С1-С8алкил)-(С3-С7Циклоалкил)группы,
    -Θ-(СΗ2)у-С(=Θ)-NΗ-(С1-С6алкил)фенилгруппы,
    -Θ-(СН2)у-С(=Θ)-NΗ-пиридинилгруппы,
    -Θ-(СΗ2)у-С(=Θ)-NΗ2-группы,
    -NΗ-С(=О)фуранилгруппы,
    -N4 -С(=О) пиридинилгруппы,
    -NΗ-С(=О)пиперидинилгруппы,
    -NΗ-С(=Θ)-(СΗ2)у-морфолинилгруппы,
    -NΗ-С(=О)-(С1-С6алкил)-О-(С1-С6алкил)группы,
    -NΗ-С(=О)-(СН2)у-пирролидинилгруппы,
    -NΗ-С(=Θ) -(^^-N4-^1 -С8алкил)группы,
    -NΗ-С(=Θ)-(СН2)у-N-(С1 -С8алкил)(С1 -С6алкил)-О-(С -С6алкил)группы и -NΗ-С(=Θ)-(СН2)у-N(С1-С8алкил)2-группы, у имеет значение от 0 до 6;
    К2 является атомом водорода;
    К3 выбран из группы, состоящей из атома водорода, гидроксилгруппы и метоксигруппы;
    К4 выбран из группы, состоящей из атома водорода,
    -О-(СН2)с-^С1 -С8алкил)2-группы,
    -О-(С1 -С6алкил)-О-(С1 -С6алкил)группы,
    -О-(СН2)а-(С3-С7циклоалкил)группы,
    -О-(СН2)с-морфолинилгруппы,
    -О-(СН2)с-пирролидонилгруппы,
    -О-(СН2)с-пирролидинилгруппы, где пирролидинилгруппа, возможно, может замещаться -ОНгруппой и -ИК2-группой, К является С1-С6алкилгруппой,
    -О-(СН2)с-пиперидинилгруппы и
    -О-(СН2)с-пиперазинилгруппы, где пиперазинилгруппа, возможно, может замещаться С1С6алкилгруппой;
    а имеет значение от 0 до 6; с имеет значение от 2 до 6;
    К5 выбран из группы, состоящей из атома водорода,
    -(СН2)<^-С(=Θ)-NΗ-(С1-С8алкил)-(С3-С7циклоалкил)группы,
    -(СΗ2)<^-С(=Θ)-NΗ-(С1 -С8алкил)фенилгруппы и -(СН2)<^-С(=О)-NΗ-(С1 -С6алкил)-О-(С1 -С6алкил)группы, б имеет значение от 0 до 6;
    К6 выбран из группы, состоящей из атома водорода и С1 -С6алкилгруппы, η равен 0;
    т выбран из 0 и 1 и р выбран из 0 и 1.
  2. 2. Соединение, выбранное из группы, состоящей из
    2-(3-(4-(1Н-индазол-5-иламино)хиназолин-2-ил)фенокси)-^изопропилацетамида,
    2-(3-(4-(1Н-индазол-5-иламино)хиназолин-2-ил)фенокси)-^(2-метоксиэтил)ацетамида,
    2-(3-(4-(1Н-индазол-5-иламино)хиназолин-2-ил)фенокси)-^(пиридин-3-ил)ацетамида,
    - 106 022875
    2-(3-(4-(1Н-индазол-5-иламино)хиназолин-2-ил)фенокси)-^метилацетамида,
    2-(3-(4-(1Н-индазол-5-иламино)хиназолин-2-ил)фенокси)-^трет-бутилацетамида,
    2-(3-(4-(1Н-индазол-5-иламино)хиназолин-2-ил)фенокси)-^этилацетамида,
    2-(3-(4-(1Н-индазол-5-иламино)хиназолин-2-ил)фенокси)-^неопентилацетамида,
  3. 3 -(3 -(
  4. 4-(1Н-индазол-5-иламино)хиназолин-2-ил)фенил)-1,1 -диметилмочевины,
    N-(3 -(4-(1Н-индазол-5 -иламино)хиназолин-2-ил)фенил)-2-метоксиацетамида,
    N-(3 -(4-(1Н-индазол-5 -иламино)хиназолин-2-ил)фенил)-2-морфолинацетамида,
    N-(3 -(4-(1Н-индазол-5 -иламино)хиназолин-2-ил)фенил)пиперидин-4-карбоксамида, ^(3-(4-(1Н-индазол-5-иламино)-6-(2-метоксиэтокси)хиназолин-2-ил)фенил)бутирамида и 2-(3-(4-(1Н-индазол-5-иламино)хиназолин-2-ил)фенокси)ацетамида.
    3. Соединение, отвечающее структуре
  5. 5. Фармацевтическая композиция для ингибирования активности КЬо-киназы, включающая соединение по любому из пп. 1 -4 вместе с фармацевтически приемлемым носителем.
  6. 6. Применение соединения по любому из пп.1-4 в производстве медикамента для лечения рака, нейродегенерации, повреждения спинного мозга, эректильной дисфункции, атеросклероза, гипертонии, спазма мозговых сосудов, церебральной ишемии, рестеноза, астмы, глаукомы, остеопороза, фиброзного
    - 107 022875 заболевания или воспаления или для диализа почек.
  7. 7. Применение соединения по любому из пп.1-4 в производстве медикамента для лечения периферической нейродегенерации, центральной нейродегенерации, фиброзного заболевания печени или фиброзного заболевания почек.
  8. 8. Применение соединения по любому из пп.1-4 для ингибирования активности КЬо-киназы.
  9. 9. Применение по п.8, в котором КЬо-киназой является КОСК2.
    Фиг. 1
    - 108 022875
    Фиг. 2
    - 109 022875
    Фиг. 3
    - 110 022875
    - 111 022875
    Фиг. 6
EA200702048A 2005-03-25 2006-03-27 Производные 4-(индазол-5-ил-амино)-2-фенилхиназолина EA022875B1 (ru)

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