RU2012138709A - Производные арилметокси изоиндолина и композиции, включающие их, и способы их применения - Google Patents

Производные арилметокси изоиндолина и композиции, включающие их, и способы их применения Download PDF

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RU2012138709A
RU2012138709A RU2012138709/04A RU2012138709A RU2012138709A RU 2012138709 A RU2012138709 A RU 2012138709A RU 2012138709/04 A RU2012138709/04 A RU 2012138709/04A RU 2012138709 A RU2012138709 A RU 2012138709A RU 2012138709 A RU2012138709 A RU 2012138709A
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alkyl
substituted
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Хон-Вах МАН
Джордж В. Мюллер
Александер РАЧЕЛМЕН
Эхаб М. ХАЛИЛ
Роджер Шэнь-Чу Чэнь
Вэйхун ЧЖАН
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Селджин Корпорейшн
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Abstract

1. Соединение формулы (I):или его фармацевтически приемлемая соль, сольват или стереоизомер, в которой:X обозначает C=O илиCH;Rобозначает -Y-R;Rобозначает H или(C-C)алкил;Y обозначает 6-10-членный арил, гетероарил или гетероцикл, каждый из которых может быть замещен одним или более галогенами; или связь;Rобозначает -(CH)-арил, -O-(CH)-арил или -(CH)-O-арил, в которых арил может быть замещен одним или более из следующих заместителей:(C-C)алкил, который сам может быть замещен одним или более галогенами; (C-C)алкокси, который сам замещен одним или более галогенами; оксо; амино; карбоксил; циано; гидроксил; галоген; дейтерий; 6-10-членный арил или гетероарил, в случае необходимости замещенный одним или более (C-C)алкилами, (C-C)алкокси или галогенами; -CONH; или -COO-(C-C)алкил, причем алкил может быть замещен одним или более галогенами;-(CH)-гетероцикл, -O-(CH)-гетероцикл или -(CH)-O-гетероцикл, причем гетероцикл может быть замещен одним или более из следующих заместителей: (C-C)алкил, сам в случае необходимости замещенный одним или более галогенами; (C-C)алкокси, сам замещенный одним или более галогенами; оксо; амино; карбоксил; циано; гидроксил; галоген; дейтерий; 6-10-членный арил или гетероарил, в случае необходимости замещенный одним или более (C-C)алкилами, (C-C)алкокси или галогенами; -CONH; или -COO-(C-C)алкил, причем алкил может быть замещен одним или более галогенами; или-(CH)-гетероарил, -O-(CH)-гетероарил или -(CH)-O-гетероарил, причем гетероарил может быть замещен одним или более из следующих заместителей: (C-C)алкил, сам в случае необходимости замещенный одним или более галогенами;(C-C)алкокси, сам замещенный одним или более галогенами; оксо; амино; карбоксил; циано; гидроксил; галоген; д

Claims (20)

1. Соединение формулы (I):
Figure 00000001
или его фармацевтически приемлемая соль, сольват или стереоизомер, в которой:
X обозначает C=O или CH2;
R1 обозначает -Y-R3;
R2 обозначает H или (C1-C6)алкил;
Y обозначает 6-10-членный арил, гетероарил или гетероцикл, каждый из которых может быть замещен одним или более галогенами; или связь;
R3 обозначает -(CH2)n-арил, -O-(CH2)n-арил или -(CH2)n-O-арил, в которых арил может быть замещен одним или более из следующих заместителей: (C1-C6)алкил, который сам может быть замещен одним или более галогенами; (C1-C6)алкокси, который сам замещен одним или более галогенами; оксо; амино; карбоксил; циано; гидроксил; галоген; дейтерий; 6-10-членный арил или гетероарил, в случае необходимости замещенный одним или более (C1-C6)алкилами, (C1-C6)алкокси или галогенами; -CONH2; или -COO-(C1-C6)алкил, причем алкил может быть замещен одним или более галогенами;
-(CH2)n-гетероцикл, -O-(CH2)n-гетероцикл или -(CH2)n-O-гетероцикл, причем гетероцикл может быть замещен одним или более из следующих заместителей: (C1-C6)алкил, сам в случае необходимости замещенный одним или более галогенами; (C1-C6)алкокси, сам замещенный одним или более галогенами; оксо; амино; карбоксил; циано; гидроксил; галоген; дейтерий; 6-10-членный арил или гетероарил, в случае необходимости замещенный одним или более (C1-C6)алкилами, (C1-C6)алкокси или галогенами; -CONH2; или -COO-(C1-C6)алкил, причем алкил может быть замещен одним или более галогенами; или
-(CH2)n-гетероарил, -O-(CH2)n-гетероарил или -(CH2)n-O-гетероарил, причем гетероарил может быть замещен одним или более из следующих заместителей: (C1-C6)алкил, сам в случае необходимости замещенный одним или более галогенами; (C1-C6)алкокси, сам замещенный одним или более галогенами; оксо; амино; карбоксил; циано; гидроксил; галоген; дейтерий; 6-10-членный арил или гетероарил, в случае необходимости замещенный одним или более (C1-C6)алкилами, (C1-C6)алкокси или галогенами; -CONH2; или -COO-(C1-C6)алкил, причем алкил может быть замещен одним или более галогенами; и
n=0, 1, 2 или 3.
2. Соединение по п.1, в котором X обозначает CH2.
3. Соединение по п.1, в котором Y обозначает фенил и R3 обозначает (CH2)n-гетероцикл.
4. Соединение по п.1, в котором Y обозначает гетероарил и R3 обозначает (CH2)n-гетероцикл.
5. Соединение по п.1, в котором Y обозначает связь.
6. Соединение по п.1, в котором Y обозначает связь и R3 обозначает (CH2)n-гетероцикл или -(CH2)n-гетероарил.
7. Соединение по п.1, которое представляет собой:
Figure 00000002
Figure 00000003
Figure 00000004
Figure 00000005
Figure 00000006
Figure 00000007
Figure 00000008
Figure 00000009
Figure 00000010
Figure 00000011
Figure 00000012
Figure 00000013
Figure 00000014
,
или его фармацевтически приемлемая соль, сольват или стереоизомер.
8. Соединение формулы (II):
Figure 00000015
или его фармацевтически приемлемая соль, сольват или стереоизомер, в которой:
R4 обозначает незамещенное 9-10-членное бициклическое кольцо, представляющее собой бензотиазол, хинолин, изохинолин, нафталин, 2,3-дигидро-1H-инден, бензо[d][1,2,3]триазол, имидазо[1,2-а]пиридин, бензофуран, 2,3-дигидробензофуран, бензотиофен, бензо[d]оксазол изоиндолин или хроман;
при условии, что, если бициклическое кольцо представляет собой бензофуран или бензотиофен, то кольцо не связано с изоиндольным кольцом через положение 2.
9. Соединение по п.8, которое представляет собой:
Figure 00000016
Figure 00000017
,
или его фармацевтически приемлемая соль, сольват или стереоизомер.
10. Соединение формулы (III):
Figure 00000018
или его фармацевтически приемлемая соль, сольват или стереоизомер, в которой:
X обозначает CH2 или C=O;
R5, R6 и R7 обозначают каждый независимо водород, галоген, нитро, карбамоил, амино, -SO2R8, -CONR9R10, -(C1-C6)алкил или -(C1-C6)алкокси, причем указанный алкил или алкокси может быть замещен одним или более галогенами, амино, гидроксилами или NR9R10;
R8 обозначает (C1-C6)алкил, в случае необходимости замещенный (C1-C6)алкилом или (C6-C10)арилом; амино, в случае необходимости замещенный (C1-C6)алкилом или (C6-C10)арилом; или 6-10-членный гетероцикл, в случае необходимости замещенный (C1-C6)алкилом или (C6-C10)арилом;
R9 и R10 обозначают каждый независимо водород, 6-10-членный арил, -COO-(C1-C6)алкил, -(C0-C6)алкил-CHO, -(C0-C6)алкил-COOH, -(C0-C6)алкил-NR9'R10', -(C0-C6)алкил-(5-10-членный гетероцикл), -(C1-C6)алкил-ОН, -(C1-C6)алкил-О-(C1-C6)алкил, (C1-C6)алкил или (C3-C6)циклоалкил; или
R9 и R10 вместе могут образовывать в случае необходимости замещенное 5-6-членное кольцо, содержащее один или более гетероатомов; и
R9' и R10' обозначают каждым независимо водород или (C1-C6)алкил;
при условии, что все R5-R7 не могут быть водородом; и
при условии, что, если один из R5-R7 обозначает водород и остальные два из R5-R7 оба являются хлором, тогда два атома хлора не могут быть в положениях 3 и 4 фенильного кольца.
11. Соединение по п.10, в котором один из R5-R7 обозначает водород и остальные два из R5-R7 обозначают каждый независимо галоген, (C1-C6)алкокси или (C1-C6)алкил.
12. Соединение по п.10, в котором два из R5-R7 обозначают водород и оставшийся из R5-R7 обозначает галоген, (C1-C6)алкокси или (C1-C6)алкил.
13. Соединение по п.10, которое представляет собой:
Figure 00000019
Figure 00000020
Figure 00000021
Figure 00000022
Figure 00000023
,
или его фармацевтически приемлемая соль, сольват или стереоизомер.
14. Соединение формулы (IV):
Figure 00000024
или его фармацевтически приемлемая соль, сольват или стереоизомер, в которой:
X обозначает N или C;
Y обозначает CH2 или C=O;
R11 и R12 обозначают каждый независимо водород, -(C1-C6)алкил, -(C1-C6)алкил-(C3-C6)циклоалкил, -(C1-C6)алкокси, -(C6-C10)арил, -CO(C1-C6)алкил, -CO(C3-C6)циклоалкил, -CO(C6-C10)арил, -COO(C1-C6)алкил, галоген, гидроксил, оксо, 3-10-членный гетероцикл, 6-10-членный гетероарил, -NHCO(C1-C6)алкил, -(CH2)n-фенил, -SO2(C1-C6)алкил, -SO2(C3-C6)циклоалкил, -SO2(C6-C10)арил или -NR14R15, причем алкильная, арильная или гетероарильная часть каждой из групп может быть замещенной одним или более галогенами, гидроксилами или -(C1-C6)алкокси;
R13 обозначает водород или -(C1-C6)алкил;
R14 и R15 обозначают каждый независимо водород или -(C1-C6)алкил; и
n=0, 1, 2 или 3.
15. Соединение по п.14, в котором X обозначает N.
16. Соединение по п.14, в котором Y обозначает CH2.
17. Соединение по п.14, которое представляет собой:
Figure 00000025
Figure 00000026
Figure 00000027
Figure 00000028
Figure 00000029
Figure 00000030
Figure 00000031
Figure 00000032
Figure 00000033
Figure 00000034
Figure 00000035
,
или его фармацевтически приемлемая соль, сольват или стереоизомер.
18. Соединение, которое представляет собой:
Figure 00000036
Figure 00000037
,
или его фармацевтически приемлемая соль, сольват или стереоизомер.
19. Фармацевтическая композиция, включающая соединение по любому из пп.1-18 или его фармацевтически приемлемую соль, сольват или стереоизомер.
20. Способ лечения, контроля или профилактики заболевания или нарушения, включающий введение пациенту соединения по любому из пп.1-18 или его фармацевтически приемлемой соли, сольвата или стереоизомера, причем заболевание или нарушение представляет собой рак, нарушения, связанные с ангиогенезом, боль, дегенерацию желтого пятна или связанный синдром, кожное заболевание, легочное нарушение, связанное с асбестом нарушение, паразитарное заболевание, иммунодефицит, нарушение ЦНС, повреждение ЦНС, атеросклероз или связанное нарушение, дисфункциональный сон или связанное нарушение, инфекционное заболевание, гемоглобинопатию или связанное нарушение или связанное с TNFα нарушение.
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