RU2015151204A - Композиции и способы - Google Patents

Композиции и способы

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RU2015151204A
RU2015151204A RU2015151204A RU2015151204A RU2015151204A RU 2015151204 A RU2015151204 A RU 2015151204A RU 2015151204 A RU2015151204 A RU 2015151204A RU 2015151204 A RU2015151204 A RU 2015151204A RU 2015151204 A RU2015151204 A RU 2015151204A
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compound according
modified
compound
modified oligonucleotide
characterized
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RU2015151204A
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RU2015151204A3 (ru )
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Тхажа П. Пракаш
Пунит П. Сет
Эрик Е. Свейз
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Ионис Фармасьютикалз, Инк.
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Claims (60)

1. Соединение, содержащее модифицированный олигонуклеотид и конъгирующую группу, причем модифицированный олигонуклеотид состоит из последовательности азотистых оснований SEQ ID NO: 81, 55 или 59, при этом конъгирующая группа содержит
Figure 00000001
,
и при этом конъгирующая группа связана с модифицированным олигонуклеотидом на 5'-конце модифицированного олигонуклеотида.
2. Соединение по п. 1, отличающееся тем, что модифицированный олигонуклеотид содержит по меньшей мере один модифицированный сахар.
3. Соединение по п. 2, отличающееся тем, что модифицированный сахар представляет собой бициклический сахар.
4. Соединение по п. 3, отличающееся тем, что бициклический сахар выбран из группы, состоящей из: 4'-(СН2)-O-2' (LNA); 4'-(СН2)2-O-2' (ENA) и 4'-СН(СН3)-O-2' (cEt).
5. Соединение по п. 3, отличающееся тем, что модифицированный сахар представляет собой 2'-O-метоксиэтиловый сахар.
6. Соединение по п. 1, отличающееся тем, что модифицированный олигонуклеотид содержит по меньшей мере одно модифицированное азотистое основание.
7. Соединение по п. 6, отличающееся тем, что модифицированное азотистое основание представляет собой 5-метилцитозин.
8. Соединение по п. 1, отличающееся тем, что соединение является одноцепочечным.
9. Соединение по п. 1, отличающееся тем, что соединение является двухцепочечным.
10. Соединение по п. 1, отличающееся тем, что модифицированный олигонуклеотид содержит по меньшей мере одну модифицированную межнуклеозидную связь.
11. Соединение по п. 10, отличающееся тем, что модифицированная межнуклеозидная связь представляет собой тиофосфатную межнуклеозидную связь.
12. Соединение по п. 10, отличающееся тем, что модифицированный олигонуклеотид содержит по меньшей мере одну фосфодиэфирную межнуклеозидную связь.
13. Соединение по п. 1, отличающееся тем, что конъюгирующая группа содержит
Figure 00000002
где Q13 представляет собой Н или O(СН2)2-ОСН3;
А представляет собой модифицированный олигонуклеотид; и
Вх представляет собой фрагмент гетероциклического основания.
14. Композиция, содержащая соединение по любому из пп. 1-13 или его соль и по меньшей мере один фармацевтически приемлемый носитель или растворитель.
15. Пролекарство, содержащее соединение по любому из пп. 1-13.
16. Применение соединения по любому из пп. 1-13 или композиции по п. 14 в способе, включающем введение животному.
17. Применение по п. 16, отличающееся тем, что животное представляет собой человека.
18. Применение по п. 16, включающее совместное введение указанного соединения или композиции и второго агента.
19. Соединение, содержащее модифицированный олигонуклеотид и конъюгирующую группу, при этом конъюгирующая группа содержит
Figure 00000003
,
и при этом модифицированный олигонуклеотид имеет формулу Ges Ges Tes Tds mCds mCds mCds Gds Ads Gds Gds Tds Gds mCes mCes mCes Ae (SEQ ID NO: 81), где
A - аденин,
mC - 5'-метилцитозин,
G - гуанин,
T - тимин,
e - 2'-O-метоксиэтиловый модифицированный нуклеозид,
d - 2'-дезоксинуклеозид и
s - тиофосфатная межнуклеозидная связь.
20. Композиция, содержащая соединение по п. 19 или его соль и по меньшей мере один фармацевтически приемлемый носитель или растворитель.
21. Применение соединения по п. 19 или комозиции по п. 20 для лечения метаболических заболеваний, при этом метаболическое заболевание необязательно представляет собой метаболический синдром, сахарный диабет, инсулинорезистентность, диабетическую дислипидемию, гипертриглицеридемию, ожирение или рост массы тела.
22. Соединение, содержащее модифицированный олигонуклеотид и конъюгирующую группу, при этом конъюгирующая группа содержит
Figure 00000004
,
и при этом модифицированный олигонуклеотид имеет формулу Aes Aes Tes Ges Ges Tds Tds Tds Ads Tds Tds mCds mCds Ads Tds Ges Ges mCes mCes Ae (SEQ ID NO: 55), где
A - аденин,
mC - 5'-метилцитозин,
G - гуанин,
T - тимин,
e - 2'-O-метоксиэтиловый модифицированный нуклеозид,
d - 2'-дезоксинуклеозид, и
s - тиофосфатная межнуклеозидная связь.
23. Композиция, содержащая соединение по п. 22 или его соль и по меньшей мере один фармацевтически приемлемый носитель или растворитель.
24. Применение соединение по п. 22 или комозиции по п. 23 для лечения метаболических заболеваний, при этом метаболическое заболевание необязательно представляет собой метаболический синдром, сахарный диабет, инсулинорезистентность, диабетическую дислипидемию, гипертриглицеридемию, ожирение или рост массы тела.
25. Соединение, содержащее модифицированный олигонуклеотид и конъюгирующую группу, при этом конъюгирующая группа содержит
Figure 00000005
,
и при этом модифицированный олигонуклеотид имеет формулу Ges mCes Aes mCes Aes mCds Tds mCds Ads Gds mCds Ads Gds Gds Ads mCes mCes mCes mCes mCe (SEQ ID NO: 59), при этом
A - аденин,
mC - 5'-метилцитозин,
G - гуанин,
T - тимин,
е - 2'-O-метоксиэтиловый модифицированный нуклеозид,
d - 2'-дезоксинуклеозид, и
s - тиофосфатная межнуклеозидная связь.
26. Композиция, содержащая соединение по п. 25 или его соль и по меньшей мере один фармацевтически приемлемый носитель или растворитель.
27. Применение соединения по п. 25 или комозиции по п. 26 для лечения метаболических заболеваний, при этом метаболическое заболевание необязательно представляет собой метаболический синдром, сахарный диабет, инсулинорезистентность, диабетическую дислипидемию, гипертриглицеридемию, ожирение или рост массы тела.
RU2015151204A 2013-05-01 2014-05-01 RU2015151204A3 (ru)

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US201361818442 true 2013-05-01 2013-05-01
US61/818,442 2013-05-01
US201361823826 true 2013-05-15 2013-05-15
US61/823,826 2013-05-15
US201361843887 true 2013-07-08 2013-07-08
US61/843,887 2013-07-08
US201361871673 true 2013-08-29 2013-08-29
US61/871,673 2013-08-29
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