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RU2018127537A - Соединения и способы лечения phk-опосредованных заболеваний - Google Patents

Соединения и способы лечения phk-опосредованных заболеваний Download PDF

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RU2018127537A
RU2018127537A RU2018127537A RU2018127537A RU2018127537A RU 2018127537 A RU2018127537 A RU 2018127537A RU 2018127537 A RU2018127537 A RU 2018127537A RU 2018127537 A RU2018127537 A RU 2018127537A RU 2018127537 A RU2018127537 A RU 2018127537A
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Дженнифер Колин ПЕТТЕР
Джеймс Грегори БАРСУМ
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Арракис Терапьютикс, Инк.
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Claims (36)

1. Соединение Формулы I:
Figure 00000001
или его фармацевтически приемлемая соль; где:
Лиганд представляет собой маломолекулярный РНК-связывающий элемент;
Т1 представляет собой двухвалентную соединяющую группу; и
Rmod представляет собой РНК-модифицирующий фрагмент.
2. Соединение Формулы II:
Figure 00000002
или его фармацевтически приемлемая соль; где:
Лиганд представляет собой маломолекулярный РНК-связывающий элемент;
каждый из Т1 и Т2 независимо представляет собой двухвалентную соединяющую группу;
Rmod представляет собой РНК-модифицирующий фрагмент; и
RCG представляет собой реакционную клик-группу.
2. Соединение Формулы III:
Figure 00000003
или его фармацевтически приемлемая соль; где:
Лиганд представляет собой маломолекулярный РНК-связывающий элемент;
Т1 представляет собой трехвалентную соединяющую группу;
Т2 представляет собой двухвалентную соединяющую группу;
Rmod представляет собой РНК-модифицирующий фрагмент; и
RCG представляет собой реакционную клик-группу.
4. Соединение по любому из пп. 1-3, отличающееся тем, что Лиганд выбран из группы, состоящей из макролида, алкалоида, аминогликозида, тетрациклина, SMN2-лиганда, выбранного из показанных на Фиг. 34, плевромутилина, теофиллина или его аналога, рибоцила или его аналога, замещенного антрацена, замещенного триптицена, оксазолидинона и CPNQ или его аналога; где Лиганд может быть необязательно замещен одним или более заместителями.
5. Соединение по любому из пп. 1-4, отличающееся тем, что Лиганд выбран из группы, состоящей из эритромицина, азитромицина, берберина, пальматина, паромомицина, неомицина, канамицина, доксициклина, окситетрациклина, плевромутилина, теофиллина или его аналога, рибоцила или его аналога, NVS-SM1, замещенного антрацена, замещенного триптицена, линезолида, тедизолида и CPNQ или его аналога; где Лиганд может быть необязательно замещен 1, 2, 3 или 4 заместителями.
6. Соединение по любому из пп. 1-5, отличающееся тем, что Т1 выбран из показанных на Фиг. 46-53.
7. Соединение по любому из пп. 1-6, отличающееся тем, что Т1 выбран из группы полиэтиленгликоля (ПЭГ), необязательно замещенной С1-12 алифатической группы или пептида, содержащего 1-8 аминокислот.
8. Соединение по любому из пп. 2 или 3, отличающееся тем, что Т2 выбран из показанных на Фиг. 46-53.
9. Соединение по любому из пп. 1-8, отличающееся тем, что Rmod выбран из сульфонилгалогенидов, аренкарбонилимидазолов, активных сложных эфиров, эпоксидов, оксиранов, окислителей, альдегидов, алкилгалогенидов, бензилгалогенидов или изоцианатов; где Rmod реагирует со свободной 2'-гидроксильной группой целевой РНК, к которой присоединяется Лиганд с образованием 2'-ковалентно модифицированной РНК.
10. Соединение по любому из пп. 1-9, в котором RCG выбран из реакционноспособной клик-группы или группы, способной вступать в реакцию нитрона с циклооктином, образования оксимов/гидразонов, тетразинового лигирования, клик-реакции на основе изоцианида или квадрицикланового лигирования.
11. Соединение по п. 11, в котором RCG является реакционной клик-группой.
12. Соединение по любому из пп. 1-11, отличающееся тем, что Лиганд связывается со структурой типа "мультипетля", "петля-на-стебле" или "выпетливание" в целевой РНК.
13. Соединение по любому из пп. 1-12, отличающееся тем, что Лиганд связывается со структурой типа "трехсторонняя мультипетля" (3WJ) нуклеиновой кислоты.
14. Соединение по п. 13, отличающееся тем, что 3WJ представляет собой транс-3WJ между двумя молекулами РНК.
15. Соединение по п. 14, отличающееся тем, что 3WJ представляет собой транс-3WJ между микроРНК и мРНК.
16. РНК-конъюгат, содержащий целевую РНК и соединение по любому из пп. 1-15, где Rmod образует ковалентную связь с указанной целевой РНК.
17. Способ идентификации малой молекулы, которая связывается с целевой РНК и модулирует ее функцию, включающий следующие стадии:
скрининг одного или более соединений по любому из пп. 1-15 в отношении связывания с указанной целевой РНК; и анализ результатов путем анализа связывания РНК.
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