RU2403251C2 - Производные 2, 4-ди(гетеро)ариламинопиримидина в качестве ингибиторов zap-70 - Google Patents

Производные 2, 4-ди(гетеро)ариламинопиримидина в качестве ингибиторов zap-70 Download PDF

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RU2403251C2
RU2403251C2 RU2006112593/04A RU2006112593A RU2403251C2 RU 2403251 C2 RU2403251 C2 RU 2403251C2 RU 2006112593/04 A RU2006112593/04 A RU 2006112593/04A RU 2006112593 A RU2006112593 A RU 2006112593A RU 2403251 C2 RU2403251 C2 RU 2403251C2
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formula
compound
pharmaceutically acceptable
acceptable salt
ylamino
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RU2006112593A (ru
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Рольф БЭНТЕЛИ (CH)
Рольф Бэнтели
Мари Клод БЕРНАР (FR)
Мари Клод БЕРНАР
Петер БЮЛЬМАЙЕР (CH)
Петер БЮЛЬМАЙЕР
Найджел Грэм КУК (CH)
Найджел Грэм Кук
Рудольф ДУТАЛЕР (CH)
Рудольф ДУТАЛЕР
Клаус ХИНТЕРДИНГ (DE)
Клаус ХИНТЕРДИНГ
Гебхард ТОМА (DE)
Гебхард Тома
Маурис ВАН-ЕЙС (FR)
Маурис ВАН-ЕЙС
Анетте ФОН-МАТТ (CH)
Анетте Фон-Матт
Луи ВАЛЛИСЕ (FR)
Луи ВАЛЛИСЕ
Герхард ЦЕНКЕ (DE)
Герхард ЦЕНКЕ
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Новартис Аг
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Abstract

Изобретение относится к новым производным 2,4-ди(гетеро)ариламинопиримидина общей формулы I или его фармацевтически приемлемой соли, обладающим свойствами ингибиторов ZAP-70. Соединения могут найти применение, например, при остром или хроническом отторжении органа или ткани, при атеросклерозе и др. заболеваниях, при которых играет роль ингибирование ZAP-70. B соединениях формулы I: ! ! Z означает =CR2; каждый из радикалов R0 и R1 представляет собой водород; R2 представляет собой (С1-С4)алкокси; R3 представляет собой -SО2NН2; или R1 и R2 образуют вместе с С-атомами, к которым они присоединены, 5-7-членный неароматический карбоциклический или гетероциклический остаток, где указанный гетероциклический остаток включает 1 или 2 гетероатома, выбранных из N и О, причем гетероциклический остаток, содержащий 1-2 атома кислорода может быть замещен атомами фтора; R4 и R6 представляют собой водород; R5 представляет собой водород, галоген, (С1-С4)алкил или СF3; один из R7, R8 и R9 обозначает NR10R11, а один или два других представляют собой водород, галоген, СООН, СF3 или (C1-С4)алкил; R10 и R11 независимо представляют собой водород или (С1-С4)алкил. Изобретение также относится к способам получения соединений. 5 н. и 4 з.п. ф-лы, 7 табл.

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Claims (9)

1. Соединение формулы I
Figure 00000064

в которой Z означает =CR2-;
каждый из радикалов R0 и R1 представляет собой водород;
R2 представляет собой (С1-С4)алкокси;
R3 представляет собой -SO2NH2;
или R1 и R2 образуют вместе с С-атомами, к которым они присоединены, 5-7-членный неароматический карбоциклический или гетероциклический остаток, где указанный гетероциклический остаток включает 1 или 2 гетероатома, выбранных из N и О, причем, гетероциклический остаток, содержащий 1-2 атома кислорода, может быть замещен атомами фтора;
R4 и R6 представляют собой водород;
R5 представляет собой водород, галоген, (С1-С4)алкил или СF3;
один из R7, R8 и R9 обозначает NR10R11, а один или два других представляют собой водород, галоген, СООН, СF3 или (С1-С4)алкил;
R10 и R11 независимо представляет собой водород или (С1-С4)алкил
или его фармацевтически приемлемая соль.
2. Соединение по п.1, в котором R1 и R2 вместе образуют остаток формулы -O-(СН2)n-O-, где n означает 2, 3, 4 или 5; в частности, формулы -O-(СН2)3-O-,
-O-(СН2)2-O-, -O-СН2-O-, или -O-CF2-O-, или -O-(CF2)2-O-, или его фармацевтически приемлемая соль.
3. Соединение по п.1, где Z представляет собой =CR2-, каждый из радикалов R0, R4,
R5, R6 и R9 означает водород;
R3 представляет собой -SO2NH2;
R1 и R2 вместе образуют остаток формулы -O-CH2-CH2-O-;
R7 представляет собой NHCH3;
R8 представляет собой СН3,
или его фармацевтически приемлемая соль.
4. Соединение по п.1, которое представляет собой
амид 6-{2-[3-(2-метокси-этиламино)-4-метил-фениламино]пиримидин-4-иламино}-2,3-дигидробензо[1,4]диоксин-5-сульфоновой кислоты;
2-метокси-6-[2-(4-амино-3-метил-фениламино)пиримидин-4-иламино] бензолсульфонамид;
2-метокси-6-[2-(4-этил-3-метил-амино-фениламино)пиримидин-4-иламино]бензолсульфонамид;
2-метокси-6-[2-(4-метиламино-3-трифторметил-фениламино)пиримидин-4-иламино] бензолсульфонамид;
2-метокси-6-[2-(4-метил-3-метил-амино-фениламино)пиримидин-4-иламино]бензолсульфонамид;
амид 6-[2-(4-метил-3-метиламино-фениламино)пиримидин-4-иламино]-2,3-дигидробензо[1,4]диоксин-5-сульфоновой кислоты;
амид 6-[2-(4-метил-3-метиламино-фениламино)пиримидин-4-иламино]-2,3-дигидробензофуран-7-сульфоновой кислоты;
амид 7-[2-(4-метил-3-метиламино-фениламино]пиримидин-4-иламино]-хроман-8-сульфоновой кислоты,
или его фармацевтически приемлемая соль.
5. Соединение формулы I по п.1 или его фармацевтически приемлемая соль, предназначенные для получения лекарственного средства, обладающего активностью ингибитора ZAP-70.
6. Фармацевтическая композиция, обладающая активностью ингибитора ZAP-70, содержащая соединение формулы I по п.1 или его фармацевтически приемлемую соль вместе с одним или несколькими фармацевтически приемлемыми носителями или разбавителями.
7. Применение соединения формулы I по п.1 при приготовлении фармацевтической композиции для использования при нарушениях или заболеваниях, при которых играет роль ингибирование ZAP-70.
8. Способ получения соединения формулы I, определенной в п.1, включающий а) взаимодействие соединения формулы II
Figure 00000065

в которой R5, R6, R7, R8 и R9 являются такими, как определено в п.1, и Х означает отщепляемую группу, предпочтительно галоген, например, такой, как хлорид, бромид, или иодид, или метилсульфанил;
с соединением формулы III
Figure 00000066

в которой R0, R1, R3, R4, и Z являются такими, как определено в п.1, и выделение полученного соединения формулы I в свободном состоянии или в виде фармацевтически приемлемой соли, и в том случае, когда это необходимо, превращение соединения формулы I, полученного в свободном состоянии, в необходимую солевую форму, или наоборот.
9. Способ получения соединения формулы I, определенной в п.1, включающий
б) взаимодействие соединения формулы IV
Figure 00000067

в которой R0, R1, R3, R4, R5, R6 и Z являются такими, как определено в п.1, и Y означает отщепляемую группу, предпочтительно галоген, например, такой, как хлорид, бромид, или иодид, или метилсульфанил,
с соединением формулы V
Figure 00000068

в которой R7, R8 и R9 являются такими, как определено в п.1,
и выделение полученного соединения формулы I в свободном состоянии или в виде фармацевтически приемлемой соли, и в том случае, когда это необходимо, превращение соединения формулы I, полученного в свободном состоянии, в необходимую солевую форму, или наоборот.
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