DK2951191T3 - Fremgangsmåde til fremstilling af oligomeriske forbindelser under anvendelse af modificerede koblingsprotokoller - Google Patents
Fremgangsmåde til fremstilling af oligomeriske forbindelser under anvendelse af modificerede koblingsprotokoller Download PDFInfo
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- DK2951191T3 DK2951191T3 DK14746224.6T DK14746224T DK2951191T3 DK 2951191 T3 DK2951191 T3 DK 2951191T3 DK 14746224 T DK14746224 T DK 14746224T DK 2951191 T3 DK2951191 T3 DK 2951191T3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- 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
- C07H21/02—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/02—Phosphorylation
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/02—Phosphorylation
- C07H1/04—Introducing polyphosphoric acid radicals
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Claims (15)
1. Fremgangsmåde til kobling af fast bærer-bundne frie hydroxylgrupper til bicykliske nukleosider med formel I:
hvor for hvert bicyklisk nukleosid med formel I: Bx er en eventuelt beskyttet heterocyklisk baseenhed; Ti er en hydroxylbeskyttelsesgruppe; T2 er en reaktiv phosphorgruppe der er i stand til at danne en internukleosid binding; en af Qi og Q2 er H, Ci-Ce alkyl, substitueret Ci-Ce alkyl, C2-C6 alkenyl, substitueret C2-C6 alkenyl, C2-C6 alkynyl eller substitueret C2-C6 alkynyl og den anden af Qi og Q2 er Ci-Ce alkyl, substitueret Ci-Ce alkyl, C2-C6 alkenyl, substitueret C2-C6 alkenyl, C2-C6 alkynyl eller substitueret C2-C6 alkynyl; hver substitueret gruppe er, uafhængigt, mono- eller polysubstitueret med substituentgrupper uafhængigt valgt fra halogen, OJi, SJi, NJ1J2, N3, CN, C( = O)OJi, C(=O)NJiJ2, C( = O)Ji, O-C( = O)NJiJ2, N(H)C( = O)NJiJ2 og N(H)C( = S)NJiJ2; hver Ji og J2 er, uafhængigt, H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 aminoalkyl eller en beskyttelsesgruppe; omfattende behandling af de frie hydroxylgrupper med et koblingsmiddel som er 70 volumenprocent aktivatoropløsning og 30 volumenprocent afen opløsning med en 0,2 molær koncentration af bicykliske nukleosider med formel I og hvor volumenet af det tilsatte koblingsmiddel tilvejebringer fra
1,4 til 1,75 ækvivalenter bicykliske nukleosider med formel I; hvor de fra 1,4 til 1,75 ækvivalenter bicykliske nukleosider med formel I er baseret på den indledende belastning af den faste bærer med frie hydroxylgrupper.
2. Fremgangsmåden ifølge krav 1, hvor volumenet af det tilsatte koblingsmiddel tilvejebringer 1,75 ækvivalenter bicykliske nukleosider med formel I og de 1,75 ækvivalenter af bicykliske nukleosider med formel I er baseret på den indledende belastning af den faste bærer med frie hydroxylgrupper.
3. Fremgangsmåden ifølge krav 1 eller krav 2, hvor aktivatoropløsningen omfatter 1,0 molær 4,5-dicyanoimidazol og 0,1 molær N-methylimidazol i acetonitril.
4. Fremgangsmåden ifølge et hvilket som helst af kravene 1 til 3, hvor opløsningen af de bicykliske nukleosider med formel I er fremstillet ved opløsning af det bicykliske nukleosid i enten acetonitril eller en blanding af acetonitril og toluen ved 50/50 (v/v) for at tilvejebringe en 0,2 molær opløsning.
5. Fremgangsmåden ifølge et hvilket som helst af kravene 1 til 4, hvor den indledende belastning af de frie hydroxylgrupper på den faste bærer er større end 100 mmol; eller større end 200 mmol; eller fra 220 mmol til 900 mmol; eller fra 220 mmol til 600 mmol.
6. Fremgangsmåden ifølge et hvilket som helst af kravene 1 til 4, hvor volumenet af det tilsatte koblingsmiddel tilvejebringer 1,75 ækvivalenter af bicykliske nukleosider med formel I; og den indledende belastning af de frie hydroxylgrupper på den faste bærer er større end 200 mmol og leveringen af koblingsmidlet til den faste bærer sker ved en strømningshastighed der kræver fra 4 til 5 minutter til at levere de 1,75 ækvivalenter.
7. Fremgangsmåden ifølge krav 6 yderligere omfattende recirkulation af koblingsmiddelreagenset i en tid på fra 4,5 til 5,5 minutter.
8. Fremgangsmåden ifølge et hvilket som helst af kravene 1 til 7, hvor de frie hydroxylgrupper er bundet til den faste bærer gennem bindings-enheder; eventuelt hvor bindings-enhederne er U nylin ker™ grupper.
9. Fremgangsmåden ifølge et hvilket som helst af kravene 1 til 7, hvor de frie hydroxylgrupper er lokaliseret på monomerunderenheder der er bundet direkte eller gennem en flerhed af monomerunderenheder til den faste bærer.
10. Fremgangsmåden ifølge et hvilket som helst af kravene 1 til 9, hvor hver reaktiv phosphorgruppe er en diisopropyl-cyanoethoxyphosphoramidit, og hver Ti er 4,4'-dimethoxytrityl.
11. Fremgangsmåden ifølge et hvilket som helst af kravene 1 til 10, hvor (a) Qi og Q2 er hver, uafhængigt, Ci-Ce alkyl eller substitueret Ci-Ce alkyl hvor hver substituentgruppe er OJi, SJi, NJ1J2, N3 eller CN og hver Ji og J2 er, uafhængigt, H eller C1-C6 alkyl; eventuelt hvor Qi og Q2 hver er CH3; eller (b) en af Qi og Q2 er H og den anden af Qi og Q2 er Ci-Ce alkyl eller substitueret C1-C6 alkyl hvor hver substitueret gruppe er OJi, SJi, NJ1J2, N3 eller CN hvor hver Ji og J2 er, uafhængigt, H eller C1-C6 alkyl; eventuelt hvor den anden af Qi og Q2 er CH3.
12. Fremgangsmåden ifølge et hvilket som helst af kravene 1 til 11, hvor hver heterocyclisk baseenhed er, uafhængigt, uracil, thymine, cytosine, 4-N-benzoylcytosine, 4-N-benzoyl-5-methylcytosine, adenin, 6-N-benzoyladenin, guanin eller 2-N-isobutyrylguanin.
13. Fremgangsmåden ifølge krav 1, hvor fremgangsmåden er en fremgangsmide af stor skala fast bærersyntese af en oligomerisk forbindelse omfattende en flerhed af monomer-underenheder hvor mindst én af monomer-underenhederne er et bicyklisk nukleosid med formel I: hvor uafhængigt for hvert bicyklisk nukleosid med formel I: Bx er en eventuelt beskyttet heterocyklisk baseenhed; Ti er en hydroxylbeskyttelsesgruppe; T2 er en reaktiv phosphorgruppe der er i stand til at danne en internukleosid binding; en af Qi og Q2 er H, Ci-Ce alkyl, substitueret Ci-Ce alkyl, C2-C6 alkenyl, substitueret C2-C6 alkenyl, C2-C6 alkynyl eller substitueret C2-C6 alkynyl og den anden af Qi og Q2 er Ci-Ce alkyl, substitueret Ci-Ce alkyl, C2-C6 alkenyl, substitueret C2-C6 alkenyl, C2-C6 alkynyl eller substitueret C2-C6 alkynyl; hver substitueret gruppe er, uafhængigt, mono- eller polysubstitueret med substituentgrupper uafhængigt valgt fra halogen, OJi, SJi, NJ1J2, N3, CN, C( = O)OJi, C(=O)NJiJ2, C( = O)Ji, O-C( = O)NJiJ2, N(H)C( = O)NJiJ2 og N(H)C( = S)NJiJ2; hver Ji og J2 er, uafhængigt, H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 aminoalkyl eller en beskyttelsesgruppe; omfattende trinnene at: a) tilvejebringe en fast bærer med en flerhed af blokerede hydroxylgrupper bundet dertil, hvor den indledende belastning af den faste bærer er større end 100 mmol; b) de-blokere de blokerede hydroxylgrupper for at tilvejebringe frie hydroxylgrupper;
c) koble monomerunderenheder til de frie hydroxylgrupper, hvor hver monomer underenhed omfatter en phosphoramiditgruppe og en blokeret hydroxylgruppe til at tilvejebringe phosphortriesterbundne monomerunderenheder; d) oxidere eller sulforisere de phosphit-triester-bundne monomerunderenheder for at tilvejebringe triester eller thiophosphat-triester-bundne monomerunderenheder; e) eventuelt behandle phosphattriester- eller thiophosphattriesterbundne monomerunderenheder med en blanding af kapping-reagenser for at blokere hvilke som helst ikke-omsatte frie hydroxylgrupper; f) iterativt gentage trinnene b) til e) et forudbestemt antal gange for at tilvejebringe den oligomeriske forbindelse; og hvor standardprotokoller følges for hver af de iterative trin med undtagelse af at koblingstrinnet (trin c) er modificeret for bicykliske nukleosider med formel I således at kobling udføres under anvendelse af et koblingsmiddel omfattende 70 volumenprocent aktivatoropløsning og 30 volumenprocent afen opløsning med en 0,2 molær koncentration af bicykliske nukleosider med formel I og hvor volumenet af det tilsatte koblingsmiddel tilvejebringer fra 1,4 til 1,75 ækvivalenter bicykliske nukleosider med formel I baseret på den indledende belastning af den faste bærer og hvor standardleveringsstrømningshastigheden af koblingsmidlet til den faste bærer er reduceret og recirkulationstiden af koblingsmidlet til den faste bærer er øget.
14. Fremgangsmåden ifølge krav 13, hvor dichloreddikesyre i toluen anvendes til de-blokering af blokerede hydroxylgrupper.
15. Fremgangsmåden ifølge krav 14 yderligere omfattende behandling af de oligomeriske forbindelser med triethylamin i acetonitril for at fjerne phosphorbeskyttelsesgrupper derved tilvejebringe bindinger mellem monomerunderenheder der er uafhængigt valgt fra phosphodiester og phosphorthioat og yderligere omfatter behandling af de oligomeriske forbindelser med ammoniumhydroxid for at fjerne yderligere beskyttelsesgrupper og spalte de oligomeriske forbindelser fra den faste bærer.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201361758913P | 2013-01-31 | 2013-01-31 | |
| PCT/US2014/013732 WO2014120861A2 (en) | 2013-01-31 | 2014-01-30 | Method of preparing oligomeric compounds using modified coupling protocols |
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| Publication Number | Publication Date |
|---|---|
| DK2951191T3 true DK2951191T3 (da) | 2019-01-14 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK14746224.6T DK2951191T3 (da) | 2013-01-31 | 2014-01-30 | Fremgangsmåde til fremstilling af oligomeriske forbindelser under anvendelse af modificerede koblingsprotokoller |
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| Country | Link |
|---|---|
| US (1) | US9701708B2 (da) |
| EP (1) | EP2951191B1 (da) |
| KR (1) | KR102190852B1 (da) |
| DK (1) | DK2951191T3 (da) |
| WO (1) | WO2014120861A2 (da) |
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| TW201536329A (zh) | 2013-08-09 | 2015-10-01 | Isis Pharmaceuticals Inc | 用於調節失養性肌強直蛋白質激酶(dmpk)表現之化合物及方法 |
| US11400161B2 (en) | 2016-10-06 | 2022-08-02 | Ionis Pharmaceuticals, Inc. | Method of conjugating oligomeric compounds |
| EP3548005A4 (en) | 2016-11-29 | 2020-06-17 | Puretech Health LLC | EXOSOMES FOR THE ADMINISTRATION OF THERAPEUTIC AGENTS |
| US11542294B2 (en) | 2017-03-29 | 2023-01-03 | Roche Innovation Center Copenhagen A/S | Rapid unylinker cleavage |
| WO2019023439A1 (en) * | 2017-07-28 | 2019-01-31 | Celgene Corporation | PROCESS FOR THE PREPARATION OF OLIGONUCLEOTIDE COMPOUNDS |
| CA3088112A1 (en) | 2018-01-12 | 2019-07-18 | Bristol-Myers Squibb Company | Antisense oligonucleotides targeting alpha-synuclein and uses thereof |
| AU2022224306A1 (en) * | 2021-02-17 | 2023-06-01 | F. Hoffmann-La Roche Ag | Process for the de-tritylation of oligonucleotides |
| EP4396352A2 (en) | 2021-09-01 | 2024-07-10 | Ionis Pharmaceuticals, Inc. | Compounds and methods for reducing dmpk expression |
| WO2024019137A1 (ja) * | 2022-07-22 | 2024-01-25 | 住友化学株式会社 | オリゴヌクレオチドの製造方法 |
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-
2014
- 2014-01-30 WO PCT/US2014/013732 patent/WO2014120861A2/en active Application Filing
- 2014-01-30 KR KR1020157023079A patent/KR102190852B1/ko active IP Right Grant
- 2014-01-30 US US14/764,655 patent/US9701708B2/en active Active
- 2014-01-30 DK DK14746224.6T patent/DK2951191T3/da active
- 2014-01-30 EP EP14746224.6A patent/EP2951191B1/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| KR102190852B1 (ko) | 2020-12-14 |
| EP2951191B1 (en) | 2018-10-17 |
| EP2951191A2 (en) | 2015-12-09 |
| EP2951191A4 (en) | 2016-08-17 |
| KR20150111989A (ko) | 2015-10-06 |
| US9701708B2 (en) | 2017-07-11 |
| WO2014120861A2 (en) | 2014-08-07 |
| WO2014120861A3 (en) | 2015-10-29 |
| US20150368288A1 (en) | 2015-12-24 |
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