DK2970968T3 - Forbundne bicykliske nukleosider - Google Patents

Forbundne bicykliske nukleosider Download PDF

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DK2970968T3
DK2970968T3 DK14765516.1T DK14765516T DK2970968T3 DK 2970968 T3 DK2970968 T3 DK 2970968T3 DK 14765516 T DK14765516 T DK 14765516T DK 2970968 T3 DK2970968 T3 DK 2970968T3
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oligonucleotide
nucleotides
nucleotide
protecting group
solution
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Kurt Vagle
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Miragen Therapeutics Inc
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Claims (21)

1. Oligonukleotid omfattende mindst et 2'-C-forbundet bicyklisk nukleotid, hvor det 2'-C-forbundne bicykliske nukleotid har strukturen med formel I:
hvor Xer N; Wi og W2 hver uafhængigt er udvalgt blandt H, en alkoholbeskyttelsesgruppe, phosphatester, phosphorothioatester, di- eller tri-phosphat, phosphorami-dit eller en eller flere nukleotid(er) på 5'- eller 3'-siden; W3 uafhængigt er udvalgt blandt nul, H, O, en amin-beskyttelsesgruppe, phosphoramidit, phosphoramidatester, phosphordiamidatester, methyl, alkyl, cycloalkyl, carboxamid, et sukker, en fedtsyre, et andet molekylært konjugat, -Ci-4(0)R eller -COOR, hvor R er aryl, lineær eller cyklisk alkyl eller alkenyl, sukker, fedtsyre eller et andet molekylært konjugat, såsom et lægemiddel-konjugat; og B er en nukleobase.
2. 2'-C-forbundet bicyklisk nukleosid eller nukleotid med strukturen med formel I:
hvor XerN; Wi og W2 hver uafhængigt er udvalgt blandt H, en alkoholbeskyttelsesgruppe, phosphatester, phosphorothioatester, di- eller tri-phosphat eller phospho-ramidit; W3 uafhængigt er udvalgt blandt H, en amin-beskyttelsesgruppe, phospho-ramidit, phosphoramidatester, phosphordiamidatester, methyl, alkyl, cycloal-kyl, carboxamid, et sukker, en fedtsyre, et andet molekylært konjugat, -C-i-4(0)R eller -COOR, hvor R er aryl, lineær eller cyklisk alkyl eller alkenyl, sukker, fedtsyre eller et andet molekylært konjugat, såsom et lægemiddelkonju-gat; og B er en nukleobase.
3. Oligonukleotid ifølge krav 1, hvor alkoholbeskyttelsesgruppen er udvalgt blandt 4,4'-dimethoxytrityl, acetyl, silyl eller syrelabil ether.
4. Oligonukleotid ifølge krav 1 eller 3, hvor amin-beskyttelsesgruppen er udvalgt blandt carbobenzyloxy (Cbz), p-methoxybenzyl-carbonyl (Moz eller MeOZ), tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn) eller trifluoracetyl (tfa).
5. Oligonukleotid ifølge et hvilket som helst af kravene 1 eller 3-4, hvor nu-kleobasen er en purinbase.
6. Oligonukleotid ifølge et hvilket som helst af kravene 1 eller 3-5, hvor nu-kleobasen er en pyrimidinbase.
7. Oligonukleotid ifølge et hvilket som helst af kravene 1 eller 3-6, som har fra 5 til 9 2'-C-forbundne bicykliske nukleotider.
8. Oligonukleotid ifølge et hvilket som helst af kravene 1 eller 3-7, hvor mindst 25 % af nukleotiderne er 2'-C-forbundne bicykliske nukleotider.
9. Oligonukleotid ifølge et hvilket som helst af kravene 1 eller 3-8, hvor oligo-nukleotidet er fra ca. 5 til 50 nukleotider langt.
10. Oligonukleotid ifølge et hvilket som helst af kravene 1 eller 3-9, hvor nu-kleotidet omfatter mindst et nukleotid udvalgt blandt 2'-deoxy, 2'-0-methyl, 2'- fluor eller en 2'- til 4'-methoxy-brostruktur.
11. Oligonukleotid ifølge et hvilket som helst af kravene 1 eller 3-10 omfattende en eller flere phosphorothioat-bindinger.
12. Oligonukleotid ifølge krav 11, hvor oligonukleotidet er fuldstændig phosphorothioat-bundet.
13. Oligonukleotid ifølge krav 11, omfattende en til tre phosphat-bindinger.
14. Oligonukleotid ifølge et hvilket som helst af kravene 11-13, hvor de 2'-C-forbundne bicykliske nukleotider er phosphorothioat-bundne.
15. Oligonukleotid ifølge et hvilket som helst af kravene 1 eller 3-10, hvor de 2'-C-forbundne bicykliske nukleotider er phosphorodiamidat-bundne.
16. Oligonukleotid ifølge krav 15, hvor phosphorodiamidat-bindingen er vist som
hvor Ri, R2 og R3 hver uafhængigt er udvalgt blandt H, alkyl, alkenyl, oxo, aryl, benzyl, halogen, -OH, -NH2, alkoxy, en alkoholbeskyttelsesgruppe eller en amino-beskyttelsesgruppe; og B er en nukleobase.
17. Oligonukleotid ifølge et hvilket som helst af kravene 1 eller 3-16, omfattende mindst en purin- og/eller pyrimidinbase-modifikation.
18. Oligonukleotid ifølge krav 17, hvor base-modifikationen er en car-boxamido.
19. Oligonukleotid ifølge krav 17, hvor base-modifikationen er en car-boxamido-del ved C-8-positionen for purin eller C-5-positionen for pyrimidin.
20. Oligonukleotid ifølge et hvilket som helst af kravene 1 eller 3-19 omfattende en eller flere morpholino-nukleotider.
21. Oligonukleotid ifølge et hvilket som helst af kravene 1 eller 3-20, omfattende en nukleotidsekvens, der er i det væsentlige komplementær til en nu-kleotidsekvens af human mikroRNA.
DK14765516.1T 2013-03-15 2014-03-16 Forbundne bicykliske nukleosider DK2970968T3 (da)

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US201361791704P 2013-03-15 2013-03-15
PCT/US2014/030100 WO2014145356A1 (en) 2013-03-15 2014-03-16 Bridged bicyclic nucleosides

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US (1) US10011833B2 (da)
EP (1) EP2970968B1 (da)
JP (1) JP6446026B2 (da)
KR (1) KR20150131365A (da)
CN (1) CN105189751B (da)
AU (1) AU2014233115B2 (da)
CA (1) CA2902571A1 (da)
DK (1) DK2970968T3 (da)
HK (1) HK1213018A1 (da)
MX (1) MX364814B (da)
WO (1) WO2014145356A1 (da)

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