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RU2019143106A - Двойные модуляторы фарнезоидного x-рецептора и растворимой эпоксидгидролазы - Google Patents

Двойные модуляторы фарнезоидного x-рецептора и растворимой эпоксидгидролазы Download PDF

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RU2019143106A
RU2019143106A RU2019143106A RU2019143106A RU2019143106A RU 2019143106 A RU2019143106 A RU 2019143106A RU 2019143106 A RU2019143106 A RU 2019143106A RU 2019143106 A RU2019143106 A RU 2019143106A RU 2019143106 A RU2019143106 A RU 2019143106A
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Даниель МЕРК
Журема ШМИДТ
Евгений ПРОШАК
Манфред ШУБЕРТ- ЖИЛАВЕЦ
Моритц ХЕЛЬМШТЕДЛЕР
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Йоханн Вольфганг Гете-Универзитет Франкфурт Ам Майн
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Claims (32)

1. Соединение формулы I:
Figure 00000001
где R1, R2, R3 и R4 независимо выбраны из Н, незамещенного, монозамещенного или полизамещенного C1-C18 алкила или гетероалкила, где указанный алкил является прямым, разветвленным или циклическим, незамещенным, монозамещенным или полизамещенным C1-C18 алкенилом или гетероалкенилом, при этом указанный алкенил является прямым, разветвленным или циклическим, незамещенным, монозамещенным или полизамещенным арилом или гетероарилом, незамещенной, монозамещенной или полизамещенной бензильной группой, ацильной группой, такой как формильная, ацетильная, трихлорацетильная, фумарильная, малеильная, сукцинильная, бензоильная или ацильная группы, гетероатом-замещенная или арил-замещенная, сахар или другая ацеталь и сульфонильная группа, и/или R2, R3 и/или R4 образуют вместе незамещенное, монозамещенное или полизамещенное кольцо, предпочтительно ароматическое кольцо;
Z является С с или без какого-либо замещения;
или изомер, пролекарство или его производное, или фармацевтически приемлемая соль, или сольват этих соединений.
2. Соединение по п. 1, отличающееся тем, что R2 является C1-C10-алкилом, предпочтительно, разветвленным алкилом, более предпочтительно -C(CH3)3, предпочтительно, R3 является H, -OH или -OMe и, предпочтительно, R4 является H, -ОН или -ОМе.
3. Соединение по п. 1 или 2, отличающееся тем, что R1 является моно- или полизамещенным арилом.
4. Соединение по п. 3, отличающееся тем, что R1 выбран из любой из следующих групп:
Figure 00000002
5. Соединение по любому из пп. 1-3, отличающееся тем, что R1 выбран из группы, состоящей из:
Figure 00000003
Z является С, R2 является - C(CH3)3 и R3 является H.
6. Соединение по любому из пп. 1-3, отличающееся тем, что R1 выбран из группы, состоящей из:
Figure 00000003
где Z является С, R3 является H или ОН и R4 является H или ОН, в частности, R3 и R4 не одновременно являются ОН; и отличающееся тем, что R2 выбран из - C(CH3)3, -N(CH3)2 или R2 является любой из следующих структур:
Figure 00000003
7. Соединение по любому из пп. 1-6, которое является агонистом фарнезоидного X-рецептора (FXR) и ингибитором растворимой эпоксидгидролазы (sEH).
8. Соединение по любому из пп. 1-7 для применения при лечении заболевания.
9. Соединение по п. 8, отличающееся тем, что заболевание является нарушением, связанным с FXR и sEH.
10. Соединение по п. 8, отличающееся тем, что заболевание является нарушением обмена веществ, предпочтительно нарушением обмена веществ, вызванным или связанным с диетой с высоким содержанием жиров.
11. Соединение по любому из пп. 8-10, отличающееся тем, что заболевание является заболеванием печени, таким как неалкогольная жировая болезнь печени или неалкогольный стеатогепатит (НАСГ).
12. Способ получения соединения по любому из пп.1-7.
13. Фармацевтическая композиция, содержащая соединение по любому из пп. 1-6, вместе с фармацевтически приемлемым носителем и/или наполнителем.
14. Способ сопутствующей модуляции FXR и sEH, содержащий стадию введения субъекту соединения по любому из пп.1-7, или фармацевтической композиции по п. 13.
15. Способ по п. 14, отличающийся тем, что субъект страдает заболеванием, предпочтительно метаболическим заболеванием.
16. Способ по п. 15, отличающийся тем, что является способом лечения заболевания субъекта путем введения указанного соединения субъекту.
17. Способ по п. 14, отличающийся тем, что модуляция является активацией FXR и ингибированием sEH.
18. Способ по любому из пп. 14-17, отличающийся тем, что введение содержит введение субъекту терапевтически эффективного количества.
19. Способ лечения заболевания у субъекта, содержащий стадию введения субъекту терапевтически эффективного количества соединения по любому из пп. 1-7, или фармацевтической композиции по п.13.
20. Способ по любому из пп. 14-19, отличающийся тем, что субъектом является млекопитающее, предпочтительно мышь, крыса, осел, лошадь, кошка, собака, морская свинка, обезьяна, человекоподобная обезьяна или предпочтительно пациент является человеком.
21. Способ по любому из пп. 16-20, отличающийся тем, что заболевание является нарушением обмена веществ, предпочтительно нарушением обмена веществ, вызванным или связанным с диетой с высоким содержанием жиров.
22. Способ по любому из пп. 16-21, отличающийся тем, что заболевание является заболеванием печени, таким как неалкогольная жировая болезнь печени или неалкогольный стеатогепатит (НАСГ).
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