RU2019124314A - Сопряженные антисмысловые соединения и их применение - Google Patents
Сопряженные антисмысловые соединения и их применение Download PDFInfo
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Claims (33)
1. Соединение, содержащее группу конъюгата, отличающееся тем, что группа конъюгата содержит фрагмент, направляющий на клетку; причем фрагмент, направляющий на клетку, содержит группу ветвления, имеющую структуру:
2. Соединение по п. 1, отличающееся тем, что фрагмент, направляющий на клетку, имеет следующую структуру:
где X представляет собой замещенную или незамещенную связку из четырех-тринадцати последовательно связанных атомов, и при этом X не содержит эфирную группу.
3. Соединение по п. 2, отличающееся тем, что фрагмент, направляющий на клетку, имеет следующую структуру:
где Y выбран из C1-C12 замещенной или незамещенной алкильной, алкенильной или алкинильной группы или группы, содержащей эфир, кетон, амид, сложный эфир, карбамат, амин, пиперидин, фосфат, фосфодиэфир, тиофосфат, триазол, пирролидин, дисульфид или тиоэфир.
4. Соединение по п. 3, отличающееся тем, что фрагмент, направляющий на клетку, имеет следующую структуру:
5. Соединение по п. 4, отличающееся тем, что соединение содержит олигонуклеотид;
где олигонуклеотид содержит по меньшей мере один модифицированный нуклеозид;
где остальная часть олигонуклеотида содержит по меньшей мере один нуклеозид, содержащий модифицированный сахар, при этом по меньшей мере один модифицированный нуклеозид, содержащий модифицированный сахар, выбран из бициклического нуклеозида и 2’-модифицированного нуклеозида;
например, где по меньшей мере один модифицированный нуклеозид представляет собой бициклический нуклеозид; при этом бициклический нуклеозид выбран из: (4’-CH2-O-2’) BNA нуклеозида, (4’-(CH2)2-O-2’) BNA нуклеозида и (4’-C(СН3)НО-2’) BNA нуклеозида;
например, где по меньшей мере один модифицированный нуклеозид представляет собой 2’-модифицированный нуклеозид; при этом по меньшей мере один 2’-модифицированный нуклеозид выбран из 2’-F нуклеозида, 2’-OCH3 нуклеозида и 2’-O(CH2)2OCH3 нуклеозида.
6. Соединение по п. 5, отличающееся тем, что олигонуклеотид имеет сахарный мотив, содержащий:
5’-область, состоящую из 2-8 связанных нуклеозидов 5’-области, при этом по меньшей мере два нуклеозида 5’-области представляют собой модифицированные нуклеозиды, и при этом 3’-ближайший нуклеозид 5’-области представляет собой модифицированный нуклеозид;
3’-область, состоящую из 2-8 связанных нуклеозидов 3’-области, при этом по меньшей мере два нуклеозида 3’-области представляют собой модифицированные нуклеозиды, и при этом 5’-ближайший нуклеозид 3’-области представляет собой модифицированный нуклеозид; и
центральную область между 5’-областью и 3’-областью, состоящую из 5-10 связанных нуклеозидов центральной области, каждый независимо выбран из: модифицированного нуклеозида и немодифицированного дезоксинуклеозида, при этом 5’-ближайший нуклеозид центральной области представляет собой немодифицированный дезоксинуклеозид, и 3’-ближайший нуклеозид центральной области представляет собой немодифицированный дезоксинуклеотид.
7. Соединение по п. 6, отличающееся тем, что 5’-область состоит из 2-5 связанных нуклеозидов 5’-области; 3’-область состоит из 2-5 связанных нуклеозидов 3’-области; а центральная область состоит из 8-10 нуклеозидов центральной области.
8. Соединение по п. 5, отличающееся тем, что олигонуклеотид содержит по меньшей мере одну модифицированную межнуклеозидную связь;
и/или где олигонуклеотид содержит по меньшей мере одну модифицированную связь и по меньшей мере одну немодифицированную фосфодиэфирную межнуклеозидную связь;
и/или где олигонуклеотид содержит по меньшей мере одну тиофосфатную межнуклеозидную связь.
9. Соединение по п. 5, отличающееся тем, что группа конъюгата присоединена к 5’-концевому нуклеозиду олигонуклеотида; или в котором группа конъюгата присоединена к 3’-концевому нуклеозиду антисмыслового олигонуклеотида.
10. Соединение по п. 5, отличающееся тем, что олигонуклеотид является одноцепочечным или в котором олигонуклеотид является двухцепочечным.
11. Соединение по п. 5, отличающееся тем, что олигонуклеотид представляет собой антисмысловой олигонуклеотид.
12. Соединение по п. 11, отличающееся тем, что олигонуклеотид активирует путь RISC; или в котором олигонуклеотид представляет собой антисмысловое соединение на основе РНКазы H.
13. Соединение по любому из пп. 11 или 12, отличающееся тем, что олигонуклеотид комплементарен целевой нуклеиновой кислоте; например, целевая нуклеиновая кислота выбрана из пре-мРНК, мРНК или микроРНК.
14. Соединение по любому из пп. 11 или 12, отличающееся тем, что олигонуклеотид состоит из 10-30 связанных нуклеозидов;
например, в котором олигонуклеотид состоит из 18-22 связанных нуклеозидов;
например, в котором олигонуклеотид состоит из 16-20 связанных нуклеозидов.
15. Соединение по любому из пп. 11-14 для применения в способе лечения метаболического расстройства.
16. Соединение по любому из пп. 11-14 для применения в способе лечения сердечно-сосудистого расстройства.
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