RU2015129065A - Производные хлор-пиразинкарбоксамида, обладающие активностью блокирования эпителиальных натриевых каналов - Google Patents
Производные хлор-пиразинкарбоксамида, обладающие активностью блокирования эпителиальных натриевых каналов Download PDFInfo
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Claims (83)
1. Соединение формулы
где Ar выбран из:
n обозначает целое число, выбранное из 0, 1, 2, 3, 4, 5 или 6;
R1 выбран из водорода, С1-С8 алкила и полигидроксилированной алкильной группы, содержащей от 3 до 8 атомов углерода;
R2 представляет собой водород или полигидроксилированную алкильную группу, содержащую от 3 до 8 атомов углерода;
R3 и R4, каждый, независимо представляют собой водород или С1-С3 алкил;
или его фармацевтически приемлемая соль.
2. Соединение по п. 1 формулы
или его фармацевтически приемлемая соль.
3. Соединение по п. 1 формулы
или его фармацевтически приемлемая соль.
4. Соединение по п. 1 формулы (II)
где n обозначает целое число, выбранное из 1, 2, 3, 4, 5 или 6;
R1 выбран из водорода, С1-С8 алкила и полигидроксилированной алкильной группы, содержащей от 3 до 8 атомов углерода;
R2 представляет собой водород или полигидроксилированную алкильную группу, содержащую от 3 до 8 атомов углерода;
R3 и R4, каждый, независимо представляют собой водород или C1-С3 алкил;
или его фармацевтически приемлемая соль.
5. Соединение по п. 4, выбранное из группы, состоящей из
и его фармацевтически приемлемых солей.
6. Соединение по п. 1 формулы (III)
где n обозначает целое число, выбранное из 1, 2, 3, 4, 5 или 6;
R1 выбран из водорода, С1-С8 алкила и полигидроксилированной алкильной группы, содержащей от 3 до 8 атомов углерода;
R2 представляет собой водород или полигидроксилированную алкильную группу, содержащую от 3 до 8 атомов углерода;
R3 и R4, каждый, независимо представляют собой водород или C1-С3 алкил;
или его фармацевтически приемлемая соль.
7. Соединение по п. 6, выбранное из группы, состоящей из
и его фармацевтически приемлемых солей.
8. Соединение по п. 1 формулы (IV)
где n обозначает целое число, выбранное из 1, 2, 3, 4, 5 или 6;
R1 выбран из водорода, С1-С8 алкила и полигидроксилированной алкильной группы, содержащей от 3 до 8 атомов углерода;
R2 представляет собой водород или полигидроксилированную алкильную группу, содержащую от 3 до 8 атомов углерода;
R3 и R4, каждый, независимо представляют собой водород или С1-С3 алкил;
или его фармацевтически приемлемая соль.
9. Соединение по п. 8, выбранное из группы, состоящей из
и его фармацевтически приемлемых солей.
10. Фармацевтическая композиция, содержащая фармацевтически эффективное количество соединения по пп. 1-8 или 9 или его фармацевтически приемлемой соли и фармацевтически приемлемый носитель или инертный наполнитель.
11. Фармацевтическая композиция по п. 10, где соединением является 3,5-диамино-N-(N-(4-(4-((S)-2-амино-3-(4-(3-(бис((2S,3R,4R,5R)-2,3,4,5,6-пентагидроксигексил)амино)пропил)фениламино)-3-оксопропил)нафталин-1-ил)бутил)карбамимидоил)-6-хлорпиразин-2-карбоксамид или его фармацевтически приемлемая соль.
12. Композиция по п. 10, где указанная композиция является подходящей для ингаляции.
13. Композиция по п. 10, где указанная композиция представляет собой раствор для аэрозолизации и введения с помощью небулайзера.
14. Композиция по п. 10, где указанная композиция является
подходящей для введения с помощью дозирующего ингалятора.
15. Композиция по п. 10, где указанная композиция представляет собой сухой порошок, подходящий для ингаляции с помощью ингалятора для сухого порошка.
16. Композиция по п. 10, дополнительно содержащая фармацевтически эффективное количество терапевтически активного агента, выбранного из противовоспалительных агентов, антихолинергических агентов, β-агонистов, агонистов рецептора P2Y2, агонистов рецепторов, активирующих пролиферацию пероксисом, ингибиторов киназ, антиинфекционных агентов и антигистаминов.
17. Способ, включающий введение человеку эффективного количества соединения по любому из пп. 1-9 или его фармацевтически приемлемой соли.
18. Способ блокирования натриевых каналов у человека, включающий введение указанному человеку эффективного количества соединения по любому из пп. 1-9 или его фармацевтически приемлемой соли.
19. Способ стимуляции гидратации поверхности слизистой оболочки или восстановления защиты слизистой оболочки у человека, включающий введение указанному человеку эффективного количества соединения по любому из п.п. 1-9 или его фармацевтически приемлемой соли.
20. Способ лечения заболевания, выбранного из группы, включающей обратимую или необратимую обструкцию дыхательных путей, хроническое обструктивное заболевание легких (ХОЗЛ), астму, бронхоэктаз (включая бронхоэктаз, вызванный состояниями, отличными от кистозного фиброза), острый бронхит, хронический бронхит, поствирусный кашель, кистозный фиброз, эмфизему, воспаление легких, панбронхеолит, бронхиолит, связанный с трансплантацией, и вентилятор-ассоциированный трахеобронхит или предотвращение вентилятор-ассоциированной пневмонии у человека, нуждающегося в этом, где указанный способ включает введение указанному человеку эффективного количества соединения по любому из пп. 1-9 или его фармацевтически приемлемой соли.
21. Способ лечения хронического обструктивного заболевания легких (ХОЗЛ) у человека, нуждающегося в этом, где указанный способ включает введение указанному человеку эффективного количества соединения по любому из п.п. 1-9 или его фармацевтически приемлемой соли.
22. Способ лечения кистозного фиброза у человека, нуждающегося в этом, где указанный способ включает введение указанному человеку эффективного количества соединения по любому из пп. 1-9 или его фармацевтически приемлемой соли.
23. Способ лечения сухости во рту (ксеростомии), сухости кожи, вагинальной сухости, синусита, риносинусита или обезвоживания носовых мембран, в том числе обезвоживания носовых мембран, вызванного введением сухого кислорода, сухости глаз или болезни Шегрена, стимуляции гидратации глаз или роговицы, лечения дистального интестинального обструктивного синдрома, лечения отита среднего уха, первичной цилиарной дискинезии, дистального интестинального обструктивного синдрома, эзофагита, констипации или хронического дивертикулита у человека, нуждающегося в этом, где указанный способ включает введение указанному человеку эффективного количества соединения по любому из пп. 1-9 или его фармацевтически приемлемой соли.
24. Соединение по любому из пп. 1-9 или его фармацевтически приемлемая соль для применения в качестве лекарственного средства.
25. Соединение по любому из пп. 1-9 или его фармацевтически приемлемая соль для применения при лечении заболевания, связанного с обратимой или необратимой обструкцией дыхательных путей, хронического обструктивного заболевания легких (ХОЗЛ), астмы, бронхоэктаза (включая бронхоэктаз, вызванный состояниями, отличными от кистозного фиброза), острого бронхита, хронического бронхита, поствирусного кашля, кистозного фиброза, эмфиземы, пневмонии, панбронхеолита, бронхиолита, связанного с трансплантацией, и вентилятор-ассоциированного трахеобронхита или предотвращения вентилятор-ассоциированной пневмонии у человека, нуждающегося в этом.
26. Соединение по любому из пп. 1-9 или его
фармацевтически приемлемая соль для применения при лечении сухости во рту (ксеростомии), сухости кожи, вагинальной сухости, синусита, риносинусита или обезвоживания носовых мембран, в том числе обезвоживания носовых мембран, вызванного введением сухого кислорода, сухости глаз или болезни Шегрена, стимуляции гидратации глаз или роговицы, при лечении дистального интестинального обструктивного синдрома, лечении отита среднего уха, первичной цилиарной дискинезии, дистального интестинального обструктивного синдрома, эзофагита, констипации или хронического дивертикулита у человека, нуждающегося в этом.
27. Применение соединения по любому из пп. 1-9 или его фармацевтически приемлемой соли для производства лекарственного средства для лечения заболевания, связанного с обратимой или необратимой обструкцией дыхательных путей, хронического обструктивного заболевания легких (ХОЗЛ), астмы, бронхоэктаза (включая бронхоэктаз, вызванный состояниями, отличными от кистозного фиброза), острого бронхита, хронического бронхита, поствирусного кашля, кистозного фиброза, эмфиземы, пневмонии, панбронхеолита, бронхиолита, связанного с трансплантацией, и вентилятор-ассоциированного трахеобронхита или предотвращения вентилятор-ассоциированной пневмонии.
28. Применение соединения по любому из пп. 1-9 или его фармацевтически приемлемой соли для производства лекарственного средства для лечения сухости во рту (ксеростомии), сухости кожи, вагинальной сухости, синусита, риносинусита или обезвоживания носовых мембран, в том числе обезвоживания носовых мембран, вызванного введением сухого кислорода, сухости глаз или болезни Шегрена, стимуляции гидратации глаз или роговицы, для лечения дистального интестинального обструктивного синдрома, лечения отита среднего уха, первичной цилиарной дискинезии, дистального интестинального обструктивного синдрома, эзофагита, констипации или хронического дивертикулита.
29. Композиция, содержащая соединение по любому из пп. 1-9 или его фармацевтически приемлемую соль для применения при получении лекарственного средства для лечения заболевания, связанного с обратимой или необратимой обструкцией дыхательных путей, хронического обструктивного заболевания легких (ХОЗЛ), астмы, бронхоэктаза (включая бронхоэктаз, вызванный состояниями, отличными от кистозного фиброза), острого бронхита, хронического бронхита, поствирусного кашля, кистозного фиброза, эмфиземы, пневмонии, панбронхеолита, бронхиолита, связанного с трансплантацией и вентилятор-ассоциированного трахеобронхита или предотвращения вентилятор-ассоциированной пневмонии.
30. Композиция, содержащая соединение по любому из пп. 1-9 или его фармацевтически приемлемую соль для применения при получении лекарственного средства для лечения сухости во рту (ксеростомии), сухости кожи, вагинальной сухости, синусита, риносинусита или обезвоживания носовых мембран, в том числе обезвоживания носовых мембран, вызванного введением сухого кислорода, сухости глаз или болезни Шегрена, стимуляции гидратации глаз или роговицы, для лечения дистального интестинального обструктивного синдрома, лечения отита среднего уха, первичной цилиарной дискинезии, дистального интестинального обструктивного синдрома, эзофагита, констипации или хронического дивертикулита.
31. Способ профилактики, смягчения и/или лечения детерминированных эффектов для здоровья дыхательных путей и/или других органов тела, вызванных вдыханием аэрозолей, содержащих радионуклиды, у человека, нуждающегося в этом, где указанный способ включает введение указанному человеку эффективного количества соединения по любому из пп. 1-9 или его фармацевтически приемлемой соли.
32. Фармацевтическая композиция, содержащая фармацевтически эффективное количество соединения по пп. 1-8 или 9 или его фармацевтически приемлемой соли и осмолит.
33. Фармацевтическая композиция по п. 32 где осмолит представляет собой гипертонический солевой раствор.
34. Фармацевтическая композиция по п. 32, где осмолит представляет собой маннит.
35. Композиция по п. 11, где указанная композиция является подходящей для ингаляции.
36. Композиция по п. 11, где указанная композиция
представляет собой раствор для аэрозолизации и введения с помощью небулайзера.
37. Композиция по п. 11, где указанная композиция является подходящей для введения с помощью дозирующего ингалятора.
38. Композиция по п. 11, где указанная композиция представляет собой сухой порошок, подходящий для ингаляции с помощью ингалятора для сухого порошка.
39. Композиция по п. 11, дополнительно содержащая фармацевтически эффективное количество терапевтически активного агента, выбранного из противовоспалительных агентов, антихолинергических агентов, β-агонистов, агонистов рецептора P2Y2, агонистов рецепторов, активирующих пролиферацию пероксисом, ингибиторов киназ, антиинфекционных агентов и антигистаминов.
40. Способ лечения бронхоэктаза (включая бронхоэктаз, вызванный состояниями, отличными от кистозного фиброза) у человека, нуждающегося в этом, где указанный способ включает введение указанному человеку эффективного количества соединения по любому из пп. 1-9 или его фармацевтически приемлемой соли.
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