HRP20221378T1 - Spojevi i postupci za modulaciju smn2 - Google Patents

Spojevi i postupci za modulaciju smn2 Download PDF

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HRP20221378T1
HRP20221378T1 HRP20221378TT HRP20221378T HRP20221378T1 HR P20221378 T1 HRP20221378 T1 HR P20221378T1 HR P20221378T T HRP20221378T T HR P20221378TT HR P20221378 T HRP20221378 T HR P20221378T HR P20221378 T1 HRP20221378 T1 HR P20221378T1
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modified oligonucleotide
modified
group
nucleosides
sugar residue
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Frank Rigo
Thazha P. Prakash
Punit P. Seth
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Ionis Pharmaceuticals, Inc.
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Publication of HRP20221378T1 publication Critical patent/HRP20221378T1/hr

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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
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    • C12N2310/00—Structure or type of the nucleic acid
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    • C12N2320/30—Special therapeutic applications
    • C12N2320/33—Alteration of splicing

Claims (18)

1. Oligomerni spoj, naznačen time, što sadrži modificirani oligonukleotid koji se sastoji od 14-25 povezanih nukleozida, pri čemu je modificirani oligonukleotid komplementaran s pre-mRNA SMN2; i pri čemu najmanje jedan nukleozid od modificiranog oligonukleotida sadrži ostatak šećera modificiran 2'-O-(N-alkil acetamid) skupinom.
2. Oligomerni spoj prema patentnom zahtjevu 1, naznačen time, što: a. svaki od 7 nukleozida od modificiranog oligonukleotida sadrži ostatak šećera modificiran skupinom 2'-O-(N-alkil acetamid); b. svaki od 8 nukleozida od modificiranog oligonukleotida sadrži ostatak šećera modificiran skupinom 2'-O-(N-alkil acetamid); c. svaki od 9 nukleozida od modificiranog oligonukleotida sadrži ostatak šećera modificiran skupinom 2'-O-(N-alkil acetamid); d. svaki od 10 nukleozida od modificiranog oligonukleotida sadrži ostatak šećera modificiran skupinom 2'-O-(N-alkil acetamid); e. svaki od 11 nukleozida od modificiranog oligonukleotida sadrži ostatak šećera modificiran skupinom 2'-O-(N-alkil acetamid); f. svaki od 12 nukleozida od modificiranog oligonukleotida sadrži ostatak šećera modificiran skupinom 2'-O-(N-alkil acetamid); g. svaki od 13 nukleozida od modificiranog oligonukleotida sadrži ostatak šećera modificiran skupinom 2'-O-(N-alkil acetamid); h. svaki od 14 nukleozida od modificiranog oligonukleotida sadrži ostatak šećera modificiran skupinom 2'-O-(N-alkil acetamid); i. svaki od 15 nukleozida od modificiranog oligonukleotida sadrži ostatak šećera modificiran skupinom 2'-O-(N-alkil acetamid); j. svaki od 16 nukleozida od modificiranog oligonukleotida sadrži ostatak šećera modificiran skupinom 2'-O-(N-alkil acetamid); k. svaki od 17 nukleozida od modificiranog oligonukleotida sadrži ostatak šećera modificiran skupinom 2'-O-(N-alkil acetamid); l. svaki od 18 nukleozida od modificiranog oligonukleotida sadrži ostatak šećera modificiran skupinom 2'-O-(N-alkil acetamid); m. svaki od 19 nukleozida od modificiranog oligonukleotida sadrži ostatak šećera modificiran skupinom 2'-O-(N-alkil acetamid); n. svaki od 20 nukleozida od modificiranog oligonukleotida sadrži ostatak šećera modificiran skupinom 2'-O-(N-alkil acetamid).
3. Oligomerni spoj prema patentnom zahtjevu 1 ili zahtjevu 2, naznačen time, što: a. svaki od ostataka šećera modificiranog skupinom 2'-O-(N-alkil acetamid) jest ostatak šećera modificiran skupinom 2'-O-(N-metil acetamid); ili b. svaki ostatak šećera od svakog nukleozida od modificiranog oligonukleotida jest ostatak šećera modificiran skupinom 2'-O-(N-alkil acetamid); ili c. svaki ostatak šećera od svakog nukleozida od modificiranog oligonukleotida jest ostatak šećera modificiran skupinom 2'-O-(N-metil acetamid).
4. Oligomerni spoj prema bilo kojem od patentnih zahtjeva 1 do 3, naznačen time, što: a. modificirani oligonukleotid se sastoji od 16-23 povezanih nukleozida; ili b. modificirani oligonukleotid se sastoji od 18-20 povezanih nukleozida.
5. Oligomerni spoj prema bilo kojem od patentnih zahtjeva 1 do 4, naznačen time, što: a. modificirani oligonukleotid se sastoji od 16 nukleozida; b. modificirani oligonukleotid se sastoji od 17 nukleozida; c. modificirani oligonukleotid se sastoji od 18 nukleozida; d. modificirani oligonukleotid se sastoji od 19 nukleozida; ili e. modificirani oligonukleotid se sastoji od 20 nukleozida.
6. Oligomerni spoj prema bilo kojem od patentnih zahtjeva 1 do 5, naznačen time, što se svaki međunukleozidni veznik od modificiranog oligonukleotida bira između fosforotioatnog međunukleozidnog veznika i fosfodiesterskog međunukleozidnog veznika, pri čemu opcionalno: a. modificirani oligonukleotid sadrži 5 fosfodiesterskih međunukleozidnih veznika; b. modificirani oligonukleotid sadrži 6 fosfodiesterskih međunukleozidnih veznika; ili c. modificirani oligonukleotid sadrži najmanje 6 fosfodiesterskih međunukleozidnih veznika.
7. Oligomerni spoj prema bilo kojem od patentnih zahtjeva 1 do 6, naznačen time, što modificirani oligonukleotid sadrži najmanje jednu modificiranu nukleobazu, opcionalno pritom modificirani oligonukleotid sadrži najmanje jedan 5-metil citozin.
8. Oligomerni spoj prema bilo kojem od patentnih zahtjeva 1 do 7, naznačen time, što: a. modificirani oligonukleotid je najmanje 70% komplementaran s pre-mRNA SMN2; b. modificirani oligonukleotid je najmanje 75% komplementaran s pre-mRNA SMN2; c. modificirani oligonukleotid je najmanje 80% komplementaran s pre-mRNA SMN2; d. modificirani oligonukleotid je najmanje 85% komplementaran s pre-mRNA SMN2; e. modificirani oligonukleotid je najmanje 90% komplementaran s pre-mRNA SMN2; f. modificirani oligonukleotid je najmanje 95% komplementaran s pre-mRNA SMN2; ili g. modificirani oligonukleotid je najmanje 100% komplementaran s pre-mRNA SMN2.
9. Oligomerni spoj prema bilo kojem od patentnih zahtjeva 1 do 8, naznačen time, što oligomerni spoj sadrži skupinu konjugata, pri čemu opcionalno skupina konjugata sadrži lipidnu ili lipofilnu skupinu, opcionalno pritom: a. lipidna ili lipofilna skupina se bira između kolesterola, C10-C26 zasićene masne kiseline, C10-C26 nezasićene masne kiseline, C10-C26 alkila, triglicerida, tokoferola, ili holne kiseline; b. lipidna ili lipofilna skupina je zasićeni ugljikovodični lanac ili nezasićeni ugljikovodični lanac; c. lipidna ili lipofilna skupina jest C16 alkil; ili d. lipidna ili lipofilna skupina jest zasićeni C16.
10. Oligomerni spoj prema bilo kojem od patentnih zahtjeva 1 do 9, naznačen time, što je modificirani oligonukleotid komplementaran s ISS-N1 od pre-mRNA SMN2.
11. Oligomerni spoj prema bilo kojem od patentnih zahtjeva 1 do 10, naznačen time, što nukleobazni slijed od modificiranog oligonukleotida sadrži slijed odabran od SEQ ID NO: 1, 2 ili 3, tako da se pritom nukleobazni slijed od modificiranog oligonukleotida sastoji od SEQ ID NO: 3.
12. Oligomerni spoj prema bilo kojem od patentnih zahtjeva 1 do 11, naznačen time, što oligomerni spoj je jednolančani.
13. Modificirani oligonukleotid, naznačen time, što se sastoji od 18 povezanih nukleozida i ima nukleobazni slijed SEQ ID NO: 3, pri čemu svaki nukleozid od modificiranog oligonukleotida sadrži ostatak šećera modificiran skupinom 2'-O-(N-metil acetamid), i time, što se svaki međunukleozidni veznik od modificiranog oligonukleotida bira između fosforotioatnog međunukleozidnog veznika i fosfodiesterskog međunukleozidnog veznika.
14. Modificirani oligonukleotid, naznačen time, što se sastoji od 18 do 20 povezanih nukleozida koji sadrže nukleobazni slijed SEQ ID NO: 1, pri čemu svaki od 18 nukleozida od modificiranog oligonukleotida sadrži ostatak šećera modificiran skupinom 2'-O-(N-metil acetamid), i time, što se svaki međunukleozidni veznik od modificiranog oligonukleotida bira između fosforotioatnog međunukleozidnog veznika i fosfodiesterskog međunukleozidnog veznika.
15. Oligomerni spoj prema bilo kojem od patentnih zahtjeva 1 do 12, ili modificirani oligonukleotid prema patentnom zahtjevu 13 ili zahtjevu 14, naznačen time, što modificirani oligonukleotid je natrijeva sol ili kalijeva sol.
16. Farmaceutski pripravak, naznačen time, što sadrži oligomerni spoj prema bilo kojem od patentnih zahtjeva 1 do 12 ili 15, ili modificirani oligonukleotid prema bilo kojem od patentnih zahtjeva 13 do 15, te najmanje jedan farmaceutski prihvatljiv nosač ili razrjeđivač.
17. Farmaceutski pripravak prema patentnom zahtjevu 16, naznačen time, što pripravak sadrži farmaceutski prihvatljiv razrjeđivač, i farmaceutski prihvatljiv razrjeđivač je fosfatna puferirana slana otopina (PBS), opcionalno pritom se farmaceutski pripravak sastoji od spoja i PBS.
18. Oligomerni spoj prema bilo kojem od patentnih zahtjeva 1 do 12 ili 15, modificirani oligonukleotid prema bilo kojem od patentnih zahtjeva 13 do 15, ili farmaceutski pripravak prema patentnom zahtjevu 16 ili 17, naznačen time, što je za uporabu u postupku liječenja pacijenta od spinalne muskularne atrofije.
HRP20221378TT 2016-07-15 2017-07-17 Spojevi i postupci za modulaciju smn2 HRP20221378T1 (hr)

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US201662363195P 2016-07-15 2016-07-15
PCT/US2017/042463 WO2018014041A2 (en) 2016-07-15 2017-07-17 Compounds and methods for modulation of smn2
EP17828625.8A EP3484524B1 (en) 2016-07-15 2017-07-17 Compounds and methods for modulation of smn2

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AU (1) AU2017297622A1 (hr)
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