DK2751270T3 - Oligomer-konjugatkomplekser og deres anvendelse - Google Patents
Oligomer-konjugatkomplekser og deres anvendelse Download PDFInfo
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- DK2751270T3 DK2751270T3 DK12828351.2T DK12828351T DK2751270T3 DK 2751270 T3 DK2751270 T3 DK 2751270T3 DK 12828351 T DK12828351 T DK 12828351T DK 2751270 T3 DK2751270 T3 DK 2751270T3
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- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
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- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
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- C12N2310/00—Structure or type of the nucleic acid
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- C12N2310/32—Chemical structure of the sugar
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- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/34—Spatial arrangement of the modifications
- C12N2310/341—Gapmers, i.e. of the type ===---===
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- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/35—Nature of the modification
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- C12N2310/3515—Lipophilic moiety, e.g. cholesterol
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Claims (13)
1. Forbindelse omfattende et oligonukleotid bestående af 10-30 bundne nukleosider og mindst én konjugatgruppe, hvor forbindelsen omfatter en konjugatgruppe bundet til det 6., 7., 8., og/eller 9. nukleosid fra den 5'-terminale ende af oligonukleotidet; hvor oligomerforbindelsen omfatter en stabiliseret phosphatgruppe kovalent bundet til det 5'-terminale nukleosid, hvor den stabiliserede phosphatgruppe omfatter en phosphor-carbonbinding, hvor den stabiliserede phosphatgruppe er bundet til det 5'-terminale nukleosid via en phosphor-carbonbinding, hvor den stabiliserede phosphatgruppe omfatter følgende formel:
hvor: Ra og Rc er hver, uafhængigt, OH, SH, Ci-Ce alkyl, substitueret Ci-Ce alkyl, Ci-Ce alkoxy, substitueret C1-C6 alkoxy, amino eller substitueret amino; og Rb er O eller S; og hvor det 5'-terminale nukleosid har en struktur vist med formel I nedenfor:
hvor: Ti er en phosphorgruppe; T2 er en internukleosid-forbindelsesgruppe der forbinder forbindelsen med formel I til den resterende af oligomerforbindelsen;
A har én af formlerne:
or
Qi og Q2 er hver, uafhængigt, H, halogen, Ci-Ce alkyl, substitueret Ci-Ce alkyl, C2-C6 alkenyl, substitueret C2-C6 alkenyl, C2-C6 alkynyl, substitueret C2-C6 alkynyl, Ci-Ce alkoxy, substitueret Ci-Ce alkoxy eller N(R3)(FU); hver R3 og R4 er, uafhængigt, H, C1-C6 alkyl, substitueret C1-C6 alkyl eller C1-C6 alkoxy; M3 er O, S, NRm, C(Ris)(Ri6), C(Ris)(Ri6)C(Ri7)(Ri8), C(Ri5)=C(Ri7), OC(Ri5)(Ri6) eller OC(Ri5)(Bx2); Rm er H, Ci-Ce alkyl, substitueret Ci-Ce alkyl, Ci-Ce alkoxy, substitueret Ci-Ce alkoxy, C2-C6 alkenyl, substitueret C2-C6 alkenyl, C2-C6 alkynyl eller substitueret C2-C6 alkynyl; Ris, Rie, R17 og Ris er hver, uafhængigt, H, halogen, Ci-Ce alkyl, substitueret C1-C6 alkyl, C1-C6 alkoxy, substitueret C1-C6 alkoxy, C2-C6 alkenyl, substitueret C2-C6 alkenyl, C2-C6 alkynyl eller substitueret C2-C6 alkynyl; én af Bxi og Bx2 er er en heterocyklisk basisgruppe og den anden af Bxi og Bx2, hvis til stede, er H, halogen, Ci-Ce alkyl, substitueret Ci-Ce alkyl, Ci-Ce alkoxy, substitueret Ci-Ce alkoxy, C2-C6 alkenyl, substitueret C2-C6 alkenyl, C2-C6 alkynyl eller substitueret C2-C6 alkynyl; J4, Js, Je og J7 er hver, uafhængigt, H, halogen, Ci-Ce alkyl, substitueret Ci-Ce alkyl, Ci-Ce alkoxy, substitueret Ci-Ce alkoxy, C2-C6 alkenyl, substitueret C2-C6 alkenyl, C2-C6 alkynyl eller substitueret C2-C6 alkynyl; eller J4 danner en bro med enten Js eller J7 hvor broen omfatter fra 1 til 3 bundne biradikale grupper valgt fra O, S, NR19, C(R2o)(R2i), C(R2o)=C(R2i), C[=C(R2o)(R2i)] og C(=O) og de andre to af Js, Je og J7 er hver, uafhængigt, H, halogen, Ci-Ce alkyl, substitueret Ci-Ce alkyl, Ci-Ce alkoxy, substitueret Ci-Ce alkoxy, C2-C6 alkenyl, substitueret C2-C6 alkenyl, C2-C6 alkynyl eller substitueret C2-C6 alkynyl;
hver Rig, R20 og R21 er, uafhængigt, H, Ci-Ce alkyl, substitueret Ci-Ce alkyl, C1-C6 alkoxy, substitueret Οι-Οβ alkoxy, C2-C6 alkenyl, substitueret C2-C6 alkenyl, C2-C6 alkynyl eller substitueret C2-C6 alkynyl; G er H, OH, halogen, en konjugatgruppe, eller O-[C(R8)(R9)]n,-[(C=O)m-Xi]j-Z; hver Rs og R9 er, uafhængigt, H, halogen, Οι-Οβ alkyl eller substitueret Ci-Ce alkyl; Xi er O, S eller N(Ei); Z er H, halogen, Ci-Ce alkyl, substitueret Ci-Ce alkyl, C2-C6 alkenyl, substitueret C2-C6 alkenyl, C2-C6 alkynyl, substitueret C2-C6 alkynyl eller N(E2)(E3); Ei, E2 og E3 er hver, uafhængigt, H, Ci-Ce alkyl eller substitueret Ci-Ce alkyl; n er fra 1 til ca. 6; m er 0 eller 1; j er 0 eller 1; hver substitueret gruppe omfatter én eller flere eventuelt beskyttede substituentgrupper uafhængigt valgt fra halogen, OJi, N(Ji)(J2), =NJi, SJi, Ns, CN, OC(=X2)J1, OC(=X2)N(J1)(J2) og C(=X2)N(Ji)(J2); X2 er O, S eller NJ3; hver Ji, J2 og J3 er, uafhængigt, H eller Ci-Ce alkyl; og når j er 1 så er Z anden end halogen eller N(E2)(E3); og hvor forbindelsen er i stand til at hybridisere til en del af et mål-RNA der resulterer i tab af normal funktion af mål-RNA'et.
2. Forbindelsen ifølge krav 1, hvor A har formlen:
3. Forbindelsen ifølge et hvilket som helst af de foregående krav, hvor det 5'-terminale nukleosid har formel IV:
IV
4. Forbindelsen ifølge et hvilket som helst af de foregående krav, omfattende en konjugatgruppe bundet til det 6. nukleosid fra den 5'- terminal ende af oligonukleotidet.
5. Forbindelsen ifølge et hvilket som helst af de foregående krav, omfattende en konjugatgruppe bundet til det 8. nukleosid fra den 5'- terminal ende af oligonukleotidet.
6. Forbindelsen ifølge et hvilket som helst af de foregående krav, hvor hvert nukleosid er et modificeret nukleosid.
7. Forbindelsen ifølge et hvilket som helst af de foregående krav, omfattende mindst ét 2'-modificeret nukleosid.
8. Forbindelsen ifølge et hvilket som helst af de foregående krav, hvor hver af de 6 til 9 3'-ende-internukleosidbindinger er en phosphorthioatbinding og hver af de andre internukleosidbindinger er en phosphodiesterbinding.
9. Forbindelsen ifølge et hvilket som helst af de foregående krav, hvor hver af de 6 til 9 3'-ende internukleosidbindinger er en phosphorthioatbinding og hver af de
andre internukleosidbindinger er en phosphodiester- eller en phosphorthioatbinding.
10. Forbindelsen ifølge et hvilket som helst af de foregående krav, hvor konjugatgruppen omfatter cholesterol, eller carbohydrat, eller N-Acetylgalactosamin, eller et steroid, eller C20 alkyl, eller Ci6 alkyl, eller C10 alkyl.
11. Forbindelsen ifølge et hvilket som helst af de foregående krav, hvor forbindelsen er enkeltstrenget.
12. Forbindelsen ifølge et hvilket som helst af de foregående krav, hvor oligonukleotidet består af 17-24 bundne nukleosider.
13. Oligomerforbindelsen ifølge et hvilket som helst af de foregående krav til anvendelse i en fremgangsmåde til behandling eller lindring afen sygdom eller tilstand, hvilken fremgangsmåde omfatter administration af en effektiv mængde af oligomeren.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161528740P | 2011-08-29 | 2011-08-29 | |
US201161532529P | 2011-09-08 | 2011-09-08 | |
US201161535323P | 2011-09-15 | 2011-09-15 | |
US201261583963P | 2012-01-06 | 2012-01-06 | |
PCT/US2012/052884 WO2013033230A1 (en) | 2011-08-29 | 2012-08-29 | Oligomer-conjugate complexes and their use |
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DK2751270T3 true DK2751270T3 (da) | 2018-10-29 |
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DK12828351.2T DK2751270T3 (da) | 2011-08-29 | 2012-08-29 | Oligomer-konjugatkomplekser og deres anvendelse |
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US (3) | US10023861B2 (da) |
EP (3) | EP2751270B1 (da) |
DK (1) | DK2751270T3 (da) |
WO (1) | WO2013033230A1 (da) |
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US20150018540A1 (en) | 2015-01-15 |
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US20190136234A1 (en) | 2019-05-09 |
EP2751270A1 (en) | 2014-07-09 |
EP3453761A1 (en) | 2019-03-13 |
WO2013033230A1 (en) | 2013-03-07 |
US11104899B2 (en) | 2021-08-31 |
EP3640332A1 (en) | 2020-04-22 |
EP2751270B1 (en) | 2018-08-22 |
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