RU2016151411A - Производные о-алкил-бензилиденгуанидина и их терапевтическое использование для лечения заболеваний, связанных с накоплением неправильно свернутых белков - Google Patents

Производные о-алкил-бензилиденгуанидина и их терапевтическое использование для лечения заболеваний, связанных с накоплением неправильно свернутых белков Download PDF

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RU2016151411A
RU2016151411A RU2016151411A RU2016151411A RU2016151411A RU 2016151411 A RU2016151411 A RU 2016151411A RU 2016151411 A RU2016151411 A RU 2016151411A RU 2016151411 A RU2016151411 A RU 2016151411A RU 2016151411 A RU2016151411 A RU 2016151411A
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aryl
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Филипп ГЕДА
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Инфлектис Байосайенс
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Claims (52)

1. Соединение формулы (I) или его фармацевтически приемлемая соль:
Figure 00000001
в которой:
Hal=F, Cl, Br, I
X представляет собой или -CR1= или -N=,
Y представляет собой или -CR2= или -N=,
Z представляет собой или -CR3= или -N=,
W представляет собой или -CR4= или -N=,
R1 выбирают из Н, Hal, алкила и О-алкила;
R2 выбирают из Н, Hal, алкила, О-алкила и C(O)R6;
R3 выбирают из Н, Hal, алкила и О-алкила;
R4 представляет собой Н, Cl, F, I или Br;
R5 представляет собой алкил, циклоалкил, аралкил, алкенил, циклоалкенил, гетероциклил, арил, С(O)-алкил, и С(O)-арил, каждый из которых необязательно является замещенным одной или более R7 группами;
R6 выбирают из ОН, О-алкила, О-арила, аралкила, NH2, NH-алкила, N(алкил)2, NH-арила, CF3, алкила и алкоксигруппы;
каждый R7 независимо выбирают из галогена, ОН, CN, СОО-алкила, аралкила, гетероциклила, S-алкила, SO-алкила, SO2-алкила, SO2-арила, СООН, СО-алкила, СО-арила, NH2, NH-алкила, N(алкил)2, CF3, алкила и алкоксигруппы.
2. Соединение по п. 1, в котором Hal представляет собой Cl.
3. Соединение по п. 1, в котором X представляет собой -CR1=, и R1 представляет собой Н или F.
4. Соединение по п. 1, в котором Y представляет собой -CR2=, и R2 представляет собой Н или F.
5. Соединение по п. 1, в котором Z=-CR3= и R3 представляет собой Н или F.
6. Соединение по п. 1, в котором W=-CR4= и R4 представляет собой Н, Cl или F.
7. Соединение по п. 1, в котором R5 выбирают из алкенила или алкила, каждый из которых необязательно является замещенным одной или более R7 группами, выбранными из галогена, ОН, гетероциклила, S-алкила, SO-алкила, SO2-алкила, О-алкила.
8. Соединение по п. 1, которое выбирают из следующих:
Figure 00000002
Figure 00000003
Figure 00000004
или его приемлемая соль.
9. Способ получения соединения формулы (I) или его фармацевтически приемлемых солей по любому из пп. 1-8, включающий стадию взаимодействия соединения формулы (А):
Figure 00000005
в которой R5 определяется как в любом из пп. 1-8, с соединением формулы (В):
Figure 00000006
,
в которой X, Y, Z, W и Hal определяются как в любом из пп. 1-8.
10. Способ по п. 9, который включает дополнительную стадию очистки.
11. Фармацевтическая композиция, содержащая соединение формулы (II):
Figure 00000007
в которой:
Hal=F, Cl, Br, I
X представляет собой или -CR1= или -N=,
Y представляет собой или -CR2= или -N=,
Z представляет собой или -CR3= или -N=,
W представляет собой или -CR4= или -N=,
R1 выбирают из Н, Hal, алкила и О-алкила;
R2 выбирают из Н, Hal, алкила, О-алкила и C(O)R6;
R3 выбирают из Н, Hal, алкила и О-алкила;
R4 представляет собой Н, Cl, F, I или Br;
R5 представляет собой алкил, циклоалкил, аралкил, алкенил, циклоалкенил, гетероциклил, арил, С(O)-алкил, и С(O)-арил, каждый из которых необязательно является замещенным одной или более R7 группами;
R6 выбирают из ОН, О-алкила, О-арила, аралкила, NH2, NH-алкила, N(алкил)2, NH-арила, CF3, алкила и алкоксигруппы;
каждый R7 независимо выбирают из галогена, ОН, CN, СОО-алкила, аралкила, гетероциклила, SO-алкила, SO2-алкила, SO2-арила, СООН, СО-алкила, СО-арила, NH2, NH-алкила, N(алкил)2, CF3, алкила и алкоксигруппы;
вместе с подходящим фармацевтически приемлемым разбавителем, эксципиентом или носителем.
12. Композиция по п. 11, в которой соединение (II) является соединением формулы (I) по любому из пп. 1-8.
13. Соединение формулы (II) для применения при лечении заболевания, связанного со стрессом, вызванным мисфолдингом белков, и в частности, с накоплением неправильно свернутых белков, где соединение (II) определяется по любому из пп. 11 или 12.
14. Соединение по п. 13, отличающееся тем, что болезнь связана с путем PPP1R15A.
15. Соединение по п. 13, отличающееся тем, что болезнь выбирают из группы таупатий, включающих болезнь Альцгеймера, прогрессирующий надъядерный паралич, кортико-базальную дегенерацию, лобновисочную лобарную дегенерацию или лобно-височную деменцию (FTD) (болезнь Пика); синуклеопатий, выбранных из болезни Паркинсона, деменции с тельцами Леви, первичной вегетативной недостаточности и множественной системной атрофии; полиглутаминных и полиаланиновых заболеваний, выбранных из болезни Хантингтона, спинобульбарной мышечной атрофии (или болезни Кеннеди), дентато-рубро-паллидо-льюисовой атрофии, спинально-церебеллярной атаксии 1 типа, спинально-церебеллярной атаксии 2 типа, спинально-церебеллярной атаксии 3 типа (или болезни Мачадо-Джозефа), спинально-церебеллярной атаксии 6 типа, спинально-церебеллярной атаксии 7 типа и спинально-церебеллярной атаксии 17 типа и окулофарингеальнаой мышечной дистрофии; демиелинизирующих заболеваний, таких как лейкодистрофия, болезнь Шарко-Мари-Тута и рассеянный склероз, муковисцидоза, выбранного из системной красной волчанки, панкреатита и сепсиса, сейпинопатий, лизосомных болезней накопления, амилоидоза, воспаления, метаболических нарушений и сердечнососудистых заболеваний, выбранных из ожирения, гиперлипидемии, семейной гиперхолестеринемии, атеросклероза, гипертензии, болезней сердца, ишемии сердца, инсульта, инфаркта миокарда, трансаортального стеноза, сосудистого инсульта; остеопороза, травмы нервной системы, ишемии, ретильных болезней, выбранных из пигментной дегенерации сетчатки, ретинальной цилиопатии, глаукомы, макулярной дегенерации и старения.
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