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RU2018107695A - Заряженные блокаторы ионных каналов и способы их применения - Google Patents

Заряженные блокаторы ионных каналов и способы их применения Download PDF

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RU2018107695A
RU2018107695A RU2018107695A RU2018107695A RU2018107695A RU 2018107695 A RU2018107695 A RU 2018107695A RU 2018107695 A RU2018107695 A RU 2018107695A RU 2018107695 A RU2018107695 A RU 2018107695A RU 2018107695 A RU2018107695 A RU 2018107695A
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Брюс П. БИН
Клиффорд Дж. ВУЛФ
Дзинбо ЛИ
Сооиеон ДЗО
Дэвид РОБЕРСОН
Себастьен ТАЛЬБО
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Президент Энд Феллоуз Оф Гарвард Колледж
Чилдрен'З Медикал Сентер Корпорейшн
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Claims (54)

1. Четвертичное аминное соединение, имеющее формулу (I)
Figure 00000001
где
R1F и R1G вместе образуют гетероциклическое кольцо, имеющее по меньшей мере один атом азота; и где
каждый из R1A, R1B, и R1C независимо выбран из H, галогена, C1-4 алкила, C2-4 алкенила, C2-4 алкинила, OR1I, NR1JR1K, NR1LC(O)R1M, S(O)R1N, SO2R1OR1P, SO2NR1QR1R, SO3R1S, CO2R1T, C(O)R1U и C(O)NR1VR1W; и каждый из R1I, R1J, R1K, R1L, R1M, R1N, R1O, R1P, R1Q, R1R, R1S, R1T, R1U, R1V и R1W независимо выбран из H, C1-4 алкила, C2-4 алкенила, C2-4 алкинила и C2-4 гетероалкила; где
X1 выбран из -CR1XR1Y-, -NR1ZC(O)-, -OC(O)-, -SC(O)-, -C(O)NR1AA-, -CO2- и -OC(S)-; и каждый из R1X, R1Y, R1Z и R1AA независимо выбран из H, C1-4 алкила, C2-4 алкенила, C2-4 алкинила, и C2-4 гетероалкила; где
каждый из R1D и R1E независимо выбран из H, C1-4 алкила, C2-4 алкенила, C2-4 алкинила, C2-4 гетероалкила, необязательно замещенного галогеном, C3-8 циклическим алкилом, арилом или гетероарилом, и C3-6 циклоалкила или R1D и R1E вместе образуют 3-6-членное гетероциклическое или гетероалкильное кольцо; и где
R1H выбран из C1-4 алкила, C2-4 алкенила, C2-4 алкинила, C2-4 гетероалкила, необязательно замещенного галогеном, C3-8 циклическим алкилом, арилом или гетероарилом, и C3-6 циклоалкила.
2. Соединение по п.1, где X1 представляет собой -NHC(O)-.
3. Соединение по п.1 или 2, где каждый из R1A и R1B независимо выбран из H, галогена, C1-4 алкила, C2-4 алкенила, C2-4 алкинила и NR1JR1K; и каждый из R1J и R1K независимо выбран из H, C1-4 алкила, C2-4 алкенила, C2-4 алкинила и C2-4 гетероалкила; или где по меньшей мере один R1C присутствует.
4. Соединение по любому из пп. 1-3, где R1D представляет собой C1-4 алкил, необязательно замещенный галогеном, C3-8 циклическим алкилом, арилом или гетероарилом.
5. Соединение по любому из пп. 1-4, где R1E представляет собой H или C1-4 алкил, необязательно замещенный галогеном, C3-8 циклическим алкилом, арилом или гетероарилом.
6. Соединение по любому из пп. 1-5, где R1H представляет собой C1-4 алкил, необязательно замещенный галогеном, C3-8 циклическим алкилом, арилом или гетероарилом.
7. Соединение по любому из пп. 1-6, где указанное соединение представляет собой соединение в таблице 1.
8. Соединение по п.7, где указанное соединение представляет собой
Figure 00000002
(Соединение 6).
9. Соединение по п.7, где указанное соединение представляет собой
Figure 00000003
(Соединение 3).
10. Четвертичное аминное соединение, имеющее формулу (II)
Figure 00000004
где m равен 0 или 1; где
каждый из R2A, R2B, и R2C, независимо выбран из H, галогена, C1-4 алкила, C2-4 алкенила, C2-4 алкинила, CF3, OR2H, NR2IR2J, NR2KC(O)R2L, S(O)R2M, SO2R2NR2O, SO2NR2PR2Q, SO3R2R, CO2R2S, C(O)R2T, и C(O)NR2UR2V; и каждый из R2H, R2I, R2J, R2K, R2L, R2M, R2N, R2O, R2P, R2Q, R2R, R2S, R2T, R2U и R2V независимо выбран из H, C1-4 алкила, C2-4 алкенила, C2-4 алкинила и C2-4 гетероалкила; где
n равен 0, 1, 2, 3, 4, 5, 6, 7, 8 или 9 и каждый R2F независимо выбран из галогена, C1-4 алкила, C2-4 алкенила, C2-4 алкинила, CF3, OR2H, NR2IR2J, NR2KC(O)R2L, S(O)R2M, SO2R2NR2O, SO2NR2PR2Q, SO3R2R, CO2R2S, C(O)R2T и C(O)NR2UR2V; и каждый из R2H, R2I, R2J, R2K, R2L, R2M, R2N, R2O, R2P, R2Q, R2R, R2S, R2T, R2U и R2V независимо выбран из H, C1-4 алкила, C2-4 алкенила, C2-4 алкинила и C2-4 гетероалкила; и где
каждый из R2D и R2E независимо выбран из C1-4 алкила, C2-4 алкенила, C2-4 алкинила, C2-4 гетероалкила, необязательно замещенного галогеном, циклическим алкилом, арилом или гетероарилом, и C3-6 циклоалкила.
11. Соединение по п.10, где каждый из R2D и R2E представляет собой C1-4 алкил, необязательно замещенный галогеном, циклическим алкилом, арилом или гетероарилом.
12. Соединение по п.10 или 11, где каждый из R2A, R2B и R2C независимо выбран из H, галогена, C1-4 алкила и CF3; или где по меньшей мере один R2C присутствует; или где по меньшей мере один R2F присутствует.
13. Соединение по любому из пп. 10-12, где указанное соединение представляет собой соединение в таблице 2.
14. Соединение по п.13, где указанное соединение представляет собой
Figure 00000005
(Соединение 14).
15. Четвертичное аминное соединение, имеющее общую формулу (III)
Figure 00000006
где n равен 0, 1, 2, или 3; где
каждый из R3A, R3B, и R3C независимо выбран из H, галогена, C1-4 алкила, C2-4 алкенила, C2-4 алкинила, OR3I, NR3JR3K, NR3LC(O)R3M, S(O)R3N, SO2R3OR3P, SO2NR3QR3R, SO3R3S, CO2R3T, C(O)R3U и C(O)NR3VR3W; и каждый из R3I, R3J, R3K, R3L, R3M, R3N, R3O, R3P, R3Q, R3R, R3S, R3T, R3U, R3V и R3W независимо выбран из H, C1-4 алкила, C2-4 алкенила, C2-4 алкинила и C2-4 гетероалкила; где
X3 выбран из -NHC(O)- и -C(O)NH; где
каждый из R3D и R3E могут быть независимо выбраны из H, C1-4 алкила, C2-4 алкенила, C2-4 алкинила, C2-4 гетероалкила, необязательно замещенного галогеном, циклическим алкилом, арилом или гетероарилом, и C3-6 циклоалкила, или R1D и R1E вместе могут образовывать 3-6-членное гетероциклическое или гетероалкильное кольцо; и где
каждый из R3F, R3G, и R3H независимо выбран из C1-4 алкила, C2-4 алкенила, C2-4 алкинила, C2-4 гетероалкила, необязательно замещенного галогеном, циклическим алкилом, арилом или гетероарилом, и C3-6 циклоалкила
16. Соединение по п.15, где X3 представляет собой -NHC(O)-.
17. Соединение по п.15 или 16, где n равно 0 или 1.
18. Соединение по любому из пп. 15-17, где каждый из R3A, R3B и R3C независимо выбран из H, C1-4 алкила и NR3JR3K; и каждый из R3J и R3K независимо выбран из H, C1-4 алкила, C2-4 алкенила, C2-4 алкинила и C2-4 гетероалкила.
19. Соединение по любому из пп. 15-18, где каждый из R3E, R3F и R3G независимо выбран из C1-4 алкила, необязательно замещенного галогеном, циклическим алкилом, арилом или гетероарилом, и C3-6 циклоалкила.
20. Соединение по любому из пп. 15-19, где указанное соединение представляет собой любое из соединений No 21-24 в таблице 3.
21. Соединение по любому из пп.15-20, где указанное соединение представляет собой
Figure 00000007
(Соединение 21).
22. Композиция, содержащая четвертичное аминное соединение по любому из пп.1-21 и фармацевтически приемлемый эксципиент.
23. Соединение по п.21, где указанная композиция составлена для перорального, внутривенного, внутримышечного, ректального, кожного, подкожного, местного, трансдермального, подъязычного, назального, ингаляционного, вагинального, интратекального, эпидурального или глазного введения.
24. Способ лечения боли, зуда или нейрогенного воспалительного заболевания у пациента, указанный способ включает введение указанному пациенту композиции, содержащей четвертичное аминное соединение по любому из пп.1-21, где указанное соединение ингибирует один или несколько потенциалзависимых ионных каналов, присутствующих в ноцицепторах и/или прурицепторах при нанесении на внутреннюю поверхность указанных каналов, но по существу не ингибируют указанные каналы при нанесении на внешнюю поверхность указанных каналов, и где указанное соединение способно проникать в ноцицепторы или прурицепторы через каналообразующий рецептор, когда указанный рецептор активирован и ингибирует упомянутый один или несколько потенциалзависимых ионных каналов, присутствующих в указанных ноцицепторах.
25. Способ по п.24, где указанный каналообразующий рецептор представляет собой ионный канал, действующий по механизму транзиторного рецепторного потенциала (TRP-каналообразующий рецептор)
26. Способ по п.24 или 25, где указанный TRP-каналообразующий рецептор активируется экзогенным или эндогенным агонистом.
27. Способ по п.25 или 26, где указанным TRP-каналообразующим рецептором является TRPA1 или TRPV1.
28. Способ по п.27, где указанное соединение способно проникать в ноцицепторы или прурицепторы через указанный рецептор TRPA1 или TRPV1, когда указанный рецептор активирован.
29. Способ по п.24, где указанное соединение ингибирует потенциалзависимые натриевые каналы.
30. Способ по п. 24, где указанная боль выбрана из группы, состоящей из нейропатической боли, воспалительной боли, ноцицептивной боли, боли, вызванной инфекцией и боли во время процедуры.
31. Способ по п.24, где указанное нейрогенное воспалительное заболевание выбрано из группы, состоящей из аллергического воспаления, астмы, хронического кашля, конъюнктивита, ринита, псориаза, воспалительного заболевания кишечника и интерстициального цистита, атопического дерматита.
32. Способ по п.24, где указанная композиция содержит четвертичное аминное соединение, выбранное из группы, состоящей из:
(Соединение 6)
Figure 00000008
, (Соединение 3)
Figure 00000009
, (Соединение 14)
Figure 00000010
и (Соединение21)
Figure 00000011
.
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