RU2015129062A - 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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RU2015129062A
RU2015129062A RU2015129062A RU2015129062A RU2015129062A RU 2015129062 A RU2015129062 A RU 2015129062A RU 2015129062 A RU2015129062 A RU 2015129062A RU 2015129062 A RU2015129062 A RU 2015129062A RU 2015129062 A RU2015129062 A RU 2015129062A
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pharmaceutically acceptable
acceptable salt
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Майкл Р. Джонсон
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Пэрион Сайенсиз, Инк.
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Claims (68)

1. Соединение формулы
Figure 00000001
где Ar представляет собой фрагмент молекулы, выбранный из группы
Figure 00000002
Figure 00000003
Figure 00000004
и
Figure 00000005
X выбран из -СН2-, -О- или -S-;
R1 и R2 независимо выбраны из Н и С1-С6 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 О;
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 Н или С1-С3 алкила;
или его фармацевтически приемлемая соль.
2. Соединение по п. 1 формулы, выбранной из группы
Figure 00000006
Figure 00000007
Figure 00000008
Figure 00000009
или
Figure 00000010
где R1 и R2 независимо выбраны из Н и C1-C6 алкила;
или R1 и R2 вместе с атомом азота, с которым они соединены связью, формируют 5- или 6-членное гетероциклическое кольцо, необязательно содержащее один дополнительный гетероатом в цикле, выбранный из N или О;
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 Н или С1-С3 алкила;
или его фармацевтически приемлемая соль.
3. Соединение по п. 1, в котором R3 - полигидроксилированная алкильная группа имеет формулу -СН2-(CHR5)n, где n представляет собой целое число 2, 3, 4, 5, 6 или 7 и R5 независимо в каждом случае представляет собой Н или ОН при условии, что, по меньшей мере, две из R5 групп представляют собой ОН, или его фармацевтически приемлемая соль.
4. Соединение по п. 1, в котором полигидроксилированная алкильная группа имеет формулу -СН2-СНОН-(CHR6)m, где m представляет собой целое число 1, 2, 3, 4, 5 или 6 и R6 независимо в каждом случае представляет собой Н или ОН при условии, что, по меньшей мере, одна из R6 групп представляют собой ОН, или его фармацевтически приемлемая соль.
5. Соединение по п. 1, в котором полигидроксилированная алкильная группа имеет формулу -СН2-(СНОН)n-СН2ОН, где n представляет собой целое число 1, 2, 3, 4, 5 или 6, или его фармацевтически приемлемая соль.
6. Соединение по п. 1, в котором полигидроксилированная алкильная группа имеет формулу
Figure 00000011
или его фармацевтически приемлемая соль.
7. Соединение по п. 1, в котором полигидроксилированная алкильная группа имеет формулу
Figure 00000012
или его фармацевтически приемлемая соль.
8. Соединение по п. 1, имеющее формулу, выбранную из группы
Figure 00000013
Figure 00000014
Figure 00000015
Figure 00000016
Figure 00000017
Figure 00000018
Figure 00000019
Figure 00000020
Figure 00000021
Figure 00000022
Figure 00000023
Figure 00000024
Figure 00000025
Figure 00000026
Figure 00000027
Figure 00000028
или его фармацевтически приемлемая соль.
9. Фармацевтическая композиция, включающая фармацевтически эффективное количество соединения по пп. 1-7 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, 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, 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 пп. 1-7 или 8 или его фармацевтически приемлемой соли.
14. Способ блокирования натриевых каналов у человека, включающий введение указанному человеку эффективного количества соединения по пп. 1-7 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 пп. 1-7 или 8 или его фармацевтически приемлемой соли.
16. Способ лечения заболевания, выбранного из группы, состоящей 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 и профилактики вентиляторно-ассоциированной пневмонии у нуждающегося в этом человека, причем указанный способ включает введение указанному человеку эффективного количества соединения по пп. 1-7 или 8 или его фармацевтически приемлемой соли.
17. Способ лечения сухости во рту (ксеростомии), сухой кожи, вагинальной сухости, синусита, риносинусита, обезвоживания слизистой оболочки носа, включая обезвоживание слизистой оболочки носа, вызванное применением сухого кислорода, сухого кератита, болезни Шегрена, лечения синдрома дистальной кишечной непроходимости, среднего отита, первичной цилиарной дискинезии, синдрома дистальной кишечной непроходимости, эзофагита, запора или хронического дивертикулита, или для стимуляции глазного яблока и гидратации роговицы, у нуждающегося в этом человека, причем указанный способ включает введение указанному человеку эффективного количества соединения по пп. 1-7 или 8 или его фармацевтически приемлемой соли.
18. Соединение по пп. 1-7 или 8 или его фармацевтически приемлемая соль, предназначенное для применения в качестве лекарственного средства.
19. Соединение по пп. 1-7 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 нуждающегося в этом человека.
20. Соединение по пп. 1-7 или 8 или его фармацевтически приемлемая соль, предназначенное для лечения сухости во рту (ксеростомии), сухой кожи, вагинальной сухости, синусита, риносинусита, обезвоживания слизистой оболочки носа, включая обезвоживание слизистой оболочки носа, вызванное применением сухого кислорода, сухого кератита, болезни Шегрена, синдрома дистальной кишечной непроходимости, среднего отита, первичной цилиарной дискинезии, синдрома дистальной кишечной непроходимости, эзофагита, запора или хронического дивертикулита, или для стимуляции глазного яблока и гидратации роговицы у нуждающегося в этом человека.
21. Применение соединения по пп. 1-7 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 пп. 1-7 или 8 или его фармацевтически приемлемой соли, для изготовления лекарственного средства для лечения сухости во рту (ксеростомии), сухой кожи, вагинальной сухости, синусита, риносинусита, обезвоживания слизистой оболочки носа, включая обезвоживание слизистой оболочки носа, вызванное применением сухого кислорода, сухого кератита, болезни Шегрена, синдрома дистальной кишечной непроходимости, среднего отита, первичной цилиарной дискинезии, синдрома дистальной кишечной непроходимости, эзофагита, запора или хронического дивертикулита, или для стимуляции глазного яблока и гидратации роговицы.
23. Композиция, включающая соединение по пп. 1-7 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 пп. 1-7 или 8 или его фармацевтически приемлемую соль, предназначенная для получения лекарственного средства для лечения сухости во рту (ксеростомии), сухой кожи, вагинальной сухости, синусита, риносинусита, обезвоживания слизистой оболочки носа, включая обезвоживание слизистой оболочки носа, вызванное применением сухого кислорода, сухого кератита, болезни Шегрена, синдрома дистальной кишечной непроходимости, среднего отита, первичной цилиарной дискинезии, синдрома дистальной кишечной непроходимости, эзофагита, запора или хронического дивертикулита, или для стимуляции глазного яблока и гидратации роговицы.
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. 1-7 или 8 или его фармацевтически приемлемой соли.
26. Фармацевтическая композиция, включающая фармацевтически эффективное количество соединения по пп. 1-7 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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