RU2011108969A - Соединения, модулирующие внутриклеточный кальций - Google Patents

Соединения, модулирующие внутриклеточный кальций Download PDF

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RU2011108969A
RU2011108969A RU2011108969/04A RU2011108969A RU2011108969A RU 2011108969 A RU2011108969 A RU 2011108969A RU 2011108969/04 A RU2011108969/04 A RU 2011108969/04A RU 2011108969 A RU2011108969 A RU 2011108969A RU 2011108969 A RU2011108969 A RU 2011108969A
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phenyl
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Гонул ВЕЛИСЕЛЕБИ (US)
Гонул ВЕЛИСЕЛЕБИ
Кеннет А. СТОДЕРМАН (US)
Кеннет А. СТОДЕРМАН
Джеффри П. УИТТЕН (US)
Джеффри П. УИТТЕН
Яжонг ПЕЙ (US)
Яжонг ПЕЙ
Цзяньгуо ЦАО (US)
Цзяньгуо ЦАО
Чжицзунь ВАНГ (US)
Чжицзунь ВАНГ
Эван РОДЖЕРС (US)
Эван РОДЖЕРС
Брайан ДИК (US)
Брайан Дик
Джонатан ГРЕЙ (US)
Джонатан ГРЕЙ
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КалсиМедика Инк. (US)
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Abstract

1. Соединение формулы (I): ! ! где А представляет собой фенил или бензофуран, каждый из которых возможно замещен по меньшей мере одним R; или А представляет собой фенил, замещенный двумя группами R на соседних атомах углерода, причем эти две группы R и атомы углерода, к которым они присоединены, образуют C4-С8циклоалкил или С3-С8гетероциклоалкил; ! R выбран из F, Cl, Br, I, -CN, -NO2, -CF3, -ОН, -OR3, -OCF3, -С≡СН, -С≡CF3, C1-С6алкиленалкина, C1-С6алкила, С3-С6циклоалкила, C1-С6гетероалкила, C1-С6галогеноалкила, тетразолила, С2-С6гетероциклоалкила, фенила, NHS(=O)2R3, S(=O)2N(R4)2, -С(=O)CF3, -C(=O)NHS(=O)2R3, -S(=O)2NHC(=O)R4, N(R4)2, -N(R4)C(=O)R3, -CO2R4, -С(=O)R3, -ОС(=O)R3, -C(=O)N(R4)2, -SR3, -S(=O)R3 и -S(=O)2R3; ! J представляет собой связь; ! R1 представляет собой CO2R2 или биоизостер карбоновой кислоты, где R2 представляет собой водород, C1-С6алкил, C1-С6циклоалкил, C1-С6галогеноалкил, фенил или бензил; ! Z представляет собой О, S или NH; ! Х представляет собой W-L-B, В, W-L-D или D, где В и D каждый возможно замещен по меньшей мере одним R; ! W представляет собой NR2, О или связь; ! L представляет собой метилен, этилен, замещенный по меньшей мере одним R, С3-С6алкилен, С2-С6алкенилен, С2-С6алкинилен, C1-С6гетероалкилен, С3-С6циклоалкилен или С2-С6гетероциклоалкилен, где метилен, С3-С6алкилен, С2-С6алкенилен, С2-С6алкинилен, C1-С6гетероалкилен, С3-С6циклоалкилен и C2-С6гетероциклоалкилен возможно замещены по меньшей мере одним R; ! В выбран из фурана, тиофена, пиррола, пиридина, оксазола, тиазола, имидазола, тиадиазола, изоксазола, изотиазола, пиразола, пиридазина, пиримидина, пиразина, оксадиазола, тиадиазола, триазола, индола, бензоксазола, бензотиазола, бензимидазола, бензоксадиазола, бензотиадиазола, бензотриазола, пиразолопиридина, имидазопиридина, пиррол�

Claims (19)

1. Соединение формулы (I):
Figure 00000001
где А представляет собой фенил или бензофуран, каждый из которых возможно замещен по меньшей мере одним R; или А представляет собой фенил, замещенный двумя группами R на соседних атомах углерода, причем эти две группы R и атомы углерода, к которым они присоединены, образуют C4-С8циклоалкил или С3-С8гетероциклоалкил;
R выбран из F, Cl, Br, I, -CN, -NO2, -CF3, -ОН, -OR3, -OCF3, -С≡СН, -С≡CF3, C1-С6алкиленалкина, C1-С6алкила, С3-С6циклоалкила, C1-С6гетероалкила, C1-С6галогеноалкила, тетразолила, С2-С6гетероциклоалкила, фенила, NHS(=O)2R3, S(=O)2N(R4)2, -С(=O)CF3, -C(=O)NHS(=O)2R3, -S(=O)2NHC(=O)R4, N(R4)2, -N(R4)C(=O)R3, -CO2R4, -С(=O)R3, -ОС(=O)R3, -C(=O)N(R4)2, -SR3, -S(=O)R3 и -S(=O)2R3;
J представляет собой связь;
R1 представляет собой CO2R2 или биоизостер карбоновой кислоты, где R2 представляет собой водород, C1-С6алкил, C1-С6циклоалкил, C1-С6галогеноалкил, фенил или бензил;
Z представляет собой О, S или NH;
Х представляет собой W-L-B, В, W-L-D или D, где В и D каждый возможно замещен по меньшей мере одним R;
W представляет собой NR2, О или связь;
L представляет собой метилен, этилен, замещенный по меньшей мере одним R, С3-С6алкилен, С2-С6алкенилен, С2-С6алкинилен, C1-С6гетероалкилен, С3-С6циклоалкилен или С2-С6гетероциклоалкилен, где метилен, С3-С6алкилен, С2-С6алкенилен, С2-С6алкинилен, C1-С6гетероалкилен, С3-С6циклоалкилен и C2-С6гетероциклоалкилен возможно замещены по меньшей мере одним R;
В выбран из фурана, тиофена, пиррола, пиридина, оксазола, тиазола, имидазола, тиадиазола, изоксазола, изотиазола, пиразола, пиридазина, пиримидина, пиразина, оксадиазола, тиадиазола, триазола, индола, бензоксазола, бензотиазола, бензимидазола, бензоксадиазола, бензотиадиазола, бензотриазола, пиразолопиридина, имидазопиридина, пирролопиридина, пирролопиримидина, индолизина, пурина, фуропиридина, тиенопиридина, фуропиррола, фурофурана, тиенофурана, 1,4-дигидропирролопиррола, тиенопиррола, тиенотиофена, хинолина, изохинолина, фуропиразола, тиенопиразола и 1,6-дигидропирролопиразола;
D представляет собой С3-С10циклоалкил или С2-С9гетероциклоалкил;
каждый R3 независимо выбран из C1-С6алкила, C1-С6галогеноалкила, С3-С8циклоалкила, фенила и бензила;
каждый R4 независимо выбран из водорода, C1-С6алкила, C1-С6галогеноалкила, С3-С8циклоалкила, фенила и бензила; или его фармацевтически приемлемые соль, сольват, N-оксид или пролекарство.
2. Соединение по п.1, где R1 представляет собой СО2Н.
3. Соединение по п.2, где R4 представляет собой водород.
4. Соединение по п.3, где Z представляет собой О.
5. Соединение по п.4, где А представляет собой фенил.
6. Соединение по п.5, где фенил замещен по меньшей мере одним R.
7. Соединение по п.6, где фенил замещен тремя R.
8. Соединение по п.7, где R выбран из F, Cl, Br, I или C1-С6алкила.
9. Соединение по п.8, где C1-С6алкил представляет собой метил, этил, н-пропил, изопропил, н-бутил, изобутил или третбутил.
10. Соединение по п.9, где Х представляет собой В.
11. Соединение по п.10, где В выбран из бензоксазола, бензотиазола, бензимидазола, пиразолопиридина, имидазопиридина, бензоксадиазола, бензотиадиазола и бензотриазола.
12. Соединение по п.1, где Х представляет собой D.
13. Соединение, выбранное из:
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
,
Figure 00000015
,
Figure 00000016
,
Figure 00000017
,
Figure 00000018
,
Figure 00000019
,
Figure 00000016
,
Figure 00000020
,
Figure 00000021
,
Figure 00000017
,
Figure 00000022
,
Figure 00000023
,
Figure 00000024
,
Figure 00000025
,
Figure 00000026
,
Figure 00000027
,
Figure 00000028
,
Figure 00000029
,
Figure 00000030
,
Figure 00000031
,
Figure 00000032
,
Figure 00000033
,
Figure 00000034
,
Figure 00000035
,
Figure 00000036
,
Figure 00000037
,
Figure 00000038
,
Figure 00000039
,
Figure 00000040
,
Figure 00000041
,
Figure 00000042
,
Figure 00000043
,
Figure 00000044
,
Figure 00000045
,
Figure 00000046
,
Figure 00000047
,
Figure 00000048
,
Figure 00000049
,
Figure 00000050
,
Figure 00000051
,
Figure 00000052
,
Figure 00000053
,
Figure 00000054
,
Figure 00000055
,
Figure 00000056
,
Figure 00000057
,
Figure 00000058
,
Figure 00000059
,
Figure 00000060
,
Figure 00000061
,
Figure 00000062
,
Figure 00000063
,
Figure 00000064
,
Figure 00000065
,
Figure 00000066
,
Figure 00000067
,
Figure 00000068
,
Figure 00000069
,
Figure 00000070
,
Figure 00000071
,
Figure 00000072
,
Figure 00000073
,
Figure 00000074
,
Figure 00000075
,
Figure 00000076
,
Figure 00000077
,
Figure 00000078
и
Figure 00000079
,
Figure 00000080
,
Figure 00000081
,
Figure 00000082
,
Figure 00000083
,
Figure 00000084
,
Figure 00000085
,
Figure 00000086
,
Figure 00000087
,
Figure 00000088
,
Figure 00000089
,
Figure 00000090
,
Figure 00000091
,
Figure 00000092
,
Figure 00000093
,
Figure 00000094
Figure 00000095
,
Figure 00000096
,
Figure 00000097
и
Figure 00000098
,
Figure 00000099
,
Figure 00000100
,
Figure 00000101
,
Figure 00000102
,
Figure 00000103
,
Figure 00000104
,
Figure 00000105
и
Figure 00000106
,
Figure 00000107
,
Figure 00000108
,
Figure 00000109
,
Figure 00000110
,
Figure 00000111
,
Figure 00000112
,
Figure 00000113
,
Figure 00000114
,
Figure 00000115
,
Figure 00000116
,
Figure 00000117
,
Figure 00000118
и
Figure 00000119
,
Figure 00000120
,
Figure 00000121
,
Figure 00000122
,
Figure 00000123
,
Figure 00000124
,
Figure 00000125
,
Figure 00000126
,
Figure 00000127
,
Figure 00000128
,
Figure 00000129
,
Figure 00000130
,
Figure 00000131
,
Figure 00000132
,
Figure 00000133
,
Figure 00000134
,
Figure 00000135
,
Figure 00000136
,
Figure 00000137
,
Figure 00000138
,
Figure 00000139
,
Figure 00000140
,
Figure 00000141
,
Figure 00000142
,
Figure 00000143
,
Figure 00000144
,
Figure 00000145
,
Figure 00000146
,
Figure 00000147
,
Figure 00000148
,
Figure 00000149
,
Figure 00000150
,
Figure 00000151
,
Figure 00000152
,
Figure 00000153
,
Figure 00000154
,
Figure 00000155
,
Figure 00000156
,
Figure 00000157
,
Figure 00000158
,
Figure 00000159
,
Figure 00000160
,
Figure 00000161
,
Figure 00000162
,
Figure 00000163
,
Figure 00000164
,
Figure 00000165
,
Figure 00000166
,
Figure 00000167
,
Figure 00000168
и
Figure 00000169
;
или его фармацевтически приемлемые соль, сольват или пролекарство.
14. Фармацевтическая композиция, содержащая соединение по п.1 и фармацевтически приемлемый разбавитель, эксципиент, носитель или связующее вещество для них.
15. Применение соединения по п.1 или его фармацевтически приемлемых соли или пролекарства в изготовлении лекарственного средства для лечения аутоиммунного заболевания, гетероиммунного заболевания или состояния либо воспалительного заболевания.
16. Применение по п.15, где аутоиммунное заболевание представляет собой воспалительное заболевание кишечника, ревматоидный артрит, тяжелую псевдопаралитическую миастению, рассеянный склероз, синдром Шегрена, диабет I типа, красную волчанку, псориаз, остеоартрит, склеродермию и аутоиммунную гемолитическую анемию.
17. Применение по п.16, где аутоиммунное заболевание представляет собой псориаз.
18. Применение по п.15, где гетероиммунное заболевание или состояние представляет собой реакцию «трансплантат против хозяина», отторжение трансплантата, атопический дерматит, аллергический конъюнктивит, отторжение органного трансплантата, аллогенную или ксеногенную трансплантацию и аллергический ринит.
19. Применение по п.15, где воспалительное заболевание представляет собой увеит, васкулит, вагинит, астму, воспалительное заболевание мышц, дерматит, интерстициальный цистит, дерматомиозит, колит, болезнь Крона, гепатит и хронический рецидивирующий гепатит.
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