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RU2018138195A - Соединения 3,5-диамино-6-хлор-n-(n-(4- фенилбутил)карбамимидоил)пиразин-2-карбоксамида - Google Patents

Соединения 3,5-диамино-6-хлор-n-(n-(4- фенилбутил)карбамимидоил)пиразин-2-карбоксамида Download PDF

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RU2018138195A
RU2018138195A RU2018138195A RU2018138195A RU2018138195A RU 2018138195 A RU2018138195 A RU 2018138195A RU 2018138195 A RU2018138195 A RU 2018138195A RU 2018138195 A RU2018138195 A RU 2018138195A RU 2018138195 A RU2018138195 A RU 2018138195A
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pharmaceutically acceptable
acceptable salt
compound according
treatment
dry
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RU2018138195A
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Майкл Р. Джонсон
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Пэрион Сайенсиз, Инк.
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Claims (53)

1. Соединение формулы:
Figure 00000001
,
где Ar представляет собой фрагмент молекулы, выбранный из группы:
Figure 00000002
X выбран из -CH2-, -O- или -S-;
R1 и R2 независимо выбраны из H и C1-C6 алкила;
или R1 и R2 вместе с атомом азота, с которым они соединены связью, формируют 5-членное или 6-членное гетероциклическое кольцо, необязательно содержащее один дополнительный гетероатом в цикле, выбранный из N или O;
R3 представляет собой алкильную группу, содержащую от 3 до 8 атомов углерода, или полигидроксилированную алкильную группу, содержащую от 3 до 8 атомов углерода;
R4 представляет собой полигидроксилированную алкильную группу, содержащую от 3 до 8 атомов углерода;
R5 выбран из H или C1-C3 алкила;
или его фармацевтически приемлемая соль.
2. Соединение по п.1 формулы:
Figure 00000003
Figure 00000004
Figure 00000005
Figure 00000006
Figure 00000007
Figure 00000008
Figure 00000009
,
где R1 и R2 независимо выбраны из H и C1-C6 алкила;
или R1 и R2 вместе с атомом азота, с которым они соединены связью, формируют 5-членное или 6-членное гетероциклическое кольцо, необязательно содержащее один дополнительный гетероатом в цикле, выбранный из N или O;
R3 представляет собой алкильную группу, содержащую от 3 до 8 атомов углерода, или полигидроксилированную алкильную группу, содержащую от 3 до 8 атомов углерода;
R4 представляет собой полигидроксилированную алкильную группу, содержащую от 3 до 8 атомов углерода; и
R5 выбран из H или C1-C3 алкила;
или его фармацевтически приемлемая соль.
3. Соединение по п.1 или 2, в котором R3 полигидроксилированная алкильная группа имеет формулу -CH2-(CHR5)n, где n представляет собой целое число, выбранное из 2, 3, 4, 5, 6 или 7, и R5, независимо, в каждом случае, представляет собой H или OH при условии, что, по меньшей мере, две из R5 групп представляют собой OH, или его фармацевтически приемлемая соль.
4. Соединение по п.1, 2 или 3, в котором полигидроксилированная алкильная группа имеет формулу -CH2-CHOH-(CHR6)m, где m представляет собой целое число, выбранное из 1, 2, 3, 4, 5 или 6, и R6, независимо, в каждом случае, представляет собой H или OH при условии, что, по меньшей мере, одна из R6 групп представляют собой OH, или его фармацевтически приемлемая соль.
5. Соединение по п.1, 2, 3 или 4, в котором полигидроксилированная алкильная группа имеет формулу -CH2-(CHOH)n-CH2OH, где n представляет собой целое число, выбранное из 1, 2, 3, 4, 5 или 6, или его фармацевтически приемлемая соль.
6. Соединение по п.1, 2, 3, 4 или 5, в котором полигидроксилированная алкильная группа имеет формулу:
Figure 00000010
или его фармацевтически приемлемая соль.
7. Соединение по п.1, 2, 3, 4, 5 или 6, в котором полигидроксилированная алкильная группа имеет формулу:
Figure 00000011
или его фармацевтически приемлемая соль.
8. Соединение по п.1, 2, 3, 4, 5, 6 или 7, имеющее формулу, выбранную из группы:
Figure 00000012
;
Figure 00000013
;
Figure 00000014
;
Figure 00000015
;
Figure 00000016
Figure 00000017
Figure 00000018
Figure 00000019
Figure 00000020
или его фармацевтически приемлемая соль.
9. Фармацевтическая композиция, включающая фармацевтически эффективное количество соединения по п.1, 2, 3, 4, 5, 6, 7 или 8, или его фармацевтически приемлемой соли, и фармацевтически приемлемый носитель или наполнитель.
10. Композиция по п.9, где указанная композиция подходит для ингаляции.
11. Композиция по п.9 или 10, где указанная композиция представляет собой раствор для распыления в виде аэрозоля и введения с помощью распылителя, дозирующего ингалятора или ингалятора сухого порошка.
12. Композиция по п.9, 10 или 11, дополнительно включающая фармацевтически эффективное количество терапевтически активного агента, выбранного из противовоспалительных средств, антихолинергических средств, бета-агонистов, модуляторов муковисцидозного трансмембранного регулятора проводимости (CFTR), агонистов P2Y2-рецепторов, агонистов гамма-рецептора, активируемого пролифератором пероксисом, ингибиторов киназы, противоинфекционных средств и антигистаминных средств.
13. Способ, включающий введение человеку эффективного количества соединения по п.1, 2, 3, 4, 5, 6, 7 или 8, или его фармацевтически приемлемой соли.
14. Способ блокирования натриевых каналов у человека, включающий введение указанному человеку эффективного количества соединения по п.1, 2, 3, 4, 5, 6, 7 или 8, или его фармацевтически приемлемой соли.
15. Способ стимулирования гидратации поверхности слизистой оболочки или восстановления защиты слизистой оболочки у человека, включающий введение указанному человеку эффективного количества соединения по п.1, 2, 3, 4, 5, 6, 7 или 8, или его фармацевтически приемлемой соли.
16. Способ лечения заболевания, выбранного из обратимой или необратимой обструкции верхних дыхательных путей, хронической обструктивной болезни легких (ХОБЛ), астмы, бронхоэктаза (включая бронхоэктаз вследствие состояний, отличных от кистозного фиброза), острого бронхита, хронического бронхита, поствирусного кашля, кистозного фиброза, эмфиземы, пневмонии, панбронхиолита, бронхиолита после трансплантации и вентиляторно-ассоциированного трахеобронхита или профилактики вентиляторно-ассоциированной пневмонии у нуждающегося в этом человека, причем указанный способ включает введение указанному человеку эффективного количества соединения по п.1, 2, 3, 4, 5, 6, 7 или 8, или его фармацевтически приемлемой соли.
17. Способ лечения сухости во рту (ксеростомии), сухой кожи, вагинальной сухости, синусита, риносинусита или обезвоживания слизистой оболочки носа, включая обезвоживание слизистой оболочки носа, вызванное применением сухого кислорода, сухого кератита или болезни Шегрена, стимуляции гидратация глазного яблока и роговицы, лечения синдрома дистальной кишечной непроходимости, лечения среднего отита, первичной цилиарной дискинезии, синдрома дистальной кишечной непроходимости, эзофагита, запора или хронического дивертикулита у нуждающегося в этом человека, причем указанный способ включает введение указанному человеку эффективного количества соединения по п.1, 2, 3, 4, 5, 6, 7 или 8, или его фармацевтически приемлемой соли.
18. Соединение по п.1, 2, 3, 4, 5, 6, 7 или 8, или его фармацевтически приемлемая соль, предназначенное для применения в качестве лекарственного средства.
19. Соединение по п.1, 2, 3, 4, 5, 6, 7 или 8, или его фармацевтически приемлемая соль, предназначенное для применения при терапии заболевания, связанного с обратимой или необратимой обструкцией верхних дыхательных путей, хронической обструктивной болезнью легких (ХОБЛ), астмой, бронхоэктазом (включая бронхоэктаз вследствие состояний, отличных от кистозного фиброза), острым бронхитом, хроническим бронхитом, поствирусным кашлем, кистозным фиброзом, эмфиземой, пневмонией, панбронхиолитом, бронхиолитом после трансплантации и вентиляторно-ассоциированным трахеобронхитом, или при профилактике вентиляторно-ассоциированной пневмонии у человека, при необходимости этого.
20. Соединение по п.1, 2, 3, 4, 5, 6, 7 или 8, или его фармацевтически приемлемая соль, предназначенное для лечения сухости во рту (ксеростомии), сухой кожи, вагинальной сухости, синусита, риносинусита или обезвоживания слизистой оболочки носа, включая обезвоживание слизистой оболочки носа, вызванное применением сухого кислорода, сухого кератита или болезни Шегрена, стимуляции гидратация глазного яблока и роговицы, лечения синдрома дистальной кишечной непроходимости, лечения среднего отита, первичной цилиарной дискинезии, синдрома дистальной кишечной непроходимости, эзофагита, запора или хронического дивертикулита у человека, при необходимости этого.
21. Применение соединения по п.1, 2, 3, 4, 5, 6, 7 или 8, или его фармацевтически приемлемой соли, для изготовления лекарственного средства для лечения заболевания, связанного с обратимой или необратимой обструкцией верхних дыхательных путей, хронической обструктивной болезнью легких (ХОБЛ), астмой, бронхоэктазом (включая бронхоэктаз вследствие состояний, отличных от кистозного фиброза), острым бронхитом, хроническим бронхитом, поствирусным кашлем, кистозным фиброзом, эмфиземой, пневмонией, панбронхиолитом, бронхиолитом после трансплантации и вентиляторно-ассоциированным трахеобронхитом, или для профилактики вентиляторно-ассоциированной пневмонии у человека.
22. Применение соединения по п.1, 2, 3, 4, 5, 6, 7 или 8, или его фармацевтически приемлемой соли, для изготовления лекарственного средства для лечения сухости во рту (ксеростомии), сухой кожи, вагинальной сухости, синусита, риносинусита или обезвоживания слизистой оболочки носа, включая обезвоживание слизистой оболочки носа, вызванное применением сухого кислорода, сухого кератита или болезни Шегрена, стимуляции гидратация глазного яблока и роговицы, лечения синдрома дистальной кишечной непроходимости, лечения среднего отита, первичной цилиарной дискинезии, синдрома дистальной кишечной непроходимости, эзофагита, запора или хронического дивертикулита.
23. Композиция, включающая соединение по п.1, 2, 3, 4, 5, 6, 7 или 8, или его фармацевтически приемлемую соль, предназначенная для получения лекарственного средства для лечения заболевания, связанного с обратимой или необратимой обструкцией верхних дыхательных путей, хронической обструктивной болезнью легких (ХОБЛ), астмой, бронхоэктазом (включая бронхоэктаз вследствие состояний, отличных от кистозного фиброза), острым бронхитом, хроническим бронхитом, поствирусным кашлем, кистозным фиброзом, эмфиземой, пневмонией, панбронхиолитом, бронхиолитом после трансплантации и вентиляторно-ассоциированным трахеобронхитом, или для профилактики вентиляторно-ассоциированной пневмонии у человека.
24. Композиция, включающая соединение по п.1, 2, 3, 4, 5, 6, 7 или 8, или его фармацевтически приемлемую соль, предназначенная для получения лекарственного средства для лечения сухости во рту (ксеростомии), сухой кожи, вагинальной сухости, синусита, риносинусита или обезвоживания слизистой оболочки носа, включая обезвоживание слизистой оболочки носа, вызванное применением сухого кислорода, сухого кератита или болезни Шегрена, стимуляции гидратация глазного яблока и роговицы, лечения синдрома дистальной кишечной непроходимости, лечения среднего отита, первичной цилиарной дискинезии, синдрома дистальной кишечной непроходимости, эзофагита, запора или хронического дивертикулита.
25. Способ профилактики, облегчения и/или лечения детерминированных воздействий на состояние дыхательных путей и/или других органов, вызванных вдыхаемыми аэрозолями, содержащими радионуклиды, у нуждающегося в этом человека, причем указанный способ включает введение указанному человеку эффективного количества соединения по п.1, 2, 3, 4, 5, 6, 7 или 8, или его фармацевтически приемлемой соли.
26. Фармацевтическая композиция, включающая фармацевтически эффективное количество соединения по п.1, 2, 3, 4, 5, 6, 7 или 8, или его фармацевтически приемлемой соли, и осмолит.
27. Фармацевтическая композиция по п.26, в которой осмолит представляет собой гипертонический раствор соли.
28. Фармацевтическая композиция по п.26, в которой осмолит представляет собой маннитол.
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