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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- Prior art keywords
- substituted
- alkyl
- groups
- solid support
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- 150000001875 compounds Chemical class 0.000 title claims description 87
- 238000000034 method Methods 0.000 title claims description 51
- 238000004519 manufacturing process Methods 0.000 title 1
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- 238000010168 coupling process Methods 0.000 claims description 115
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 87
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- 125000001424 substituent group Chemical group 0.000 claims description 62
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 60
- 239000000178 monomer Substances 0.000 claims description 58
- 125000000623 heterocyclic group Chemical group 0.000 claims description 44
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- 238000011068 loading method Methods 0.000 claims description 27
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 229910052698 phosphorus Inorganic materials 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 125000002743 phosphorus functional group Chemical group 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims description 16
- 239000011574 phosphorus Substances 0.000 claims description 16
- 229910019142 PO4 Inorganic materials 0.000 claims description 14
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 13
- 239000010452 phosphate Substances 0.000 claims description 11
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical group [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims description 11
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 10
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 10
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 10
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 9
- 229960005215 dichloroacetic acid Drugs 0.000 claims description 8
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- 230000008569 process Effects 0.000 claims description 8
- XGDRLCRGKUCBQL-UHFFFAOYSA-N 1h-imidazole-4,5-dicarbonitrile Chemical compound N#CC=1N=CNC=1C#N XGDRLCRGKUCBQL-UHFFFAOYSA-N 0.000 claims description 6
- SXADIBFZNXBEGI-UHFFFAOYSA-N phosphoramidous acid Chemical group NP(O)O SXADIBFZNXBEGI-UHFFFAOYSA-N 0.000 claims description 6
- CFIBTBBTJWHPQV-UHFFFAOYSA-N 2-methyl-n-(6-oxo-3,7-dihydropurin-2-yl)propanamide Chemical compound N1C(NC(=O)C(C)C)=NC(=O)C2=C1N=CN2 CFIBTBBTJWHPQV-UHFFFAOYSA-N 0.000 claims description 5
- 125000002103 4,4'-dimethoxytriphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)(C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H])C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 5
- QQJXZVKXNSFHRI-UHFFFAOYSA-N 6-Benzamidopurine Chemical compound N=1C=NC=2N=CNC=2C=1NC(=O)C1=CC=CC=C1 QQJXZVKXNSFHRI-UHFFFAOYSA-N 0.000 claims description 5
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- 229960000643 adenine Drugs 0.000 claims description 5
- 229940104302 cytosine Drugs 0.000 claims description 5
- XBDUZBHKKUFFRH-UHFFFAOYSA-N n-(2-oxo-1h-pyrimidin-6-yl)benzamide Chemical compound OC1=NC=CC(NC(=O)C=2C=CC=CC=2)=N1 XBDUZBHKKUFFRH-UHFFFAOYSA-N 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
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- 229940113082 thymine Drugs 0.000 claims description 5
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- FMKLITBCOZWOEX-UHFFFAOYSA-N n-(5-methyl-2-oxo-1h-pyrimidin-6-yl)benzamide Chemical compound CC1=CNC(=O)N=C1NC(=O)C1=CC=CC=C1 FMKLITBCOZWOEX-UHFFFAOYSA-N 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- 239000000908 ammonium hydroxide Substances 0.000 claims description 3
- 230000003134 recirculating effect Effects 0.000 claims description 2
- 239000007822 coupling agent Substances 0.000 claims 10
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- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 8
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- 238000011172 small scale experimental method Methods 0.000 description 1
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- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
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- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical group NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
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- 229940124530 sulfonamide Drugs 0.000 description 1
- 125000005864 sulfonamidyl group Chemical group 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 125000004962 sulfoxyl group Chemical group 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
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- ZAMCTDDIJFNXOH-UHFFFAOYSA-N tributylazanium;acetate Chemical compound CC(O)=O.CCCCN(CCCC)CCCC ZAMCTDDIJFNXOH-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
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Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- 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
-
- C—CHEMISTRY; METALLURGY
- 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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- C—CHEMISTRY; METALLURGY
- 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
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
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- Genetics & Genomics (AREA)
- Saccharide Compounds (AREA)
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 |
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| DK2951191T3 true DK2951191T3 (da) | 2019-01-14 |
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Family Applications (1)
| 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 |
Country Status (5)
| 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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| EP2595663A4 (en) | 2010-07-19 | 2014-03-05 | Isis Pharmaceuticals Inc | MODULATION OF DYSTROPHIA MYOTONICA PROTEIN KINASE (DMPK) EXPRESSION |
| 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 |
| CA3043768A1 (en) | 2016-11-29 | 2018-06-07 | PureTech Health LLC | Exosomes for delivery of therapeutic agents |
| US11542294B2 (en) | 2017-03-29 | 2023-01-03 | Roche Innovation Center Copenhagen A/S | Rapid unylinker cleavage |
| JP2020528910A (ja) * | 2017-07-28 | 2020-10-01 | セルジーン コーポレイション | オリゴヌクレオチド化合物の調製方法 |
| SG11202006528XA (en) | 2018-01-12 | 2020-08-28 | Bristol Myers Squibb Co | Antisense oligonucleotides targeting alpha-synuclein and uses thereof |
| CN120310791A (zh) | 2018-01-12 | 2025-07-15 | 百时美施贵宝公司 | 靶向α-突触核蛋白的反义寡核苷酸及其用途 |
| KR20230145318A (ko) * | 2021-02-17 | 2023-10-17 | 에프. 호프만-라 로슈 아게 | 올리고뉴클레오타이드의 탈트리틸화 방법 |
| WO2023034870A2 (en) | 2021-09-01 | 2023-03-09 | Ionis Pharmaceuticals, Inc. | Compounds and methods for reducing dmpk expression |
| EP4559925A1 (en) * | 2022-07-22 | 2025-05-28 | Sumitomo Chemical Company, Limited | Production method of oligonucleotide |
Family Cites Families (113)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3687808A (en) | 1969-08-14 | 1972-08-29 | Univ Leland Stanford Junior | Synthetic polynucleotides |
| US4458066A (en) | 1980-02-29 | 1984-07-03 | University Patents, Inc. | Process for preparing polynucleotides |
| US4500707A (en) | 1980-02-29 | 1985-02-19 | University Patents, Inc. | Nucleosides useful in the preparation of polynucleotides |
| US5132418A (en) | 1980-02-29 | 1992-07-21 | University Patents, Inc. | Process for preparing polynucleotides |
| US4469863A (en) | 1980-11-12 | 1984-09-04 | Ts O Paul O P | Nonionic nucleic acid alkyl and aryl phosphonates and processes for manufacture and use thereof |
| US4668777A (en) | 1981-03-27 | 1987-05-26 | University Patents, Inc. | Phosphoramidite nucleoside compounds |
| US4415732A (en) | 1981-03-27 | 1983-11-15 | University Patents, Inc. | Phosphoramidite compounds and processes |
| US4973679A (en) | 1981-03-27 | 1990-11-27 | University Patents, Inc. | Process for oligonucleo tide synthesis using phosphormidite intermediates |
| US5023243A (en) | 1981-10-23 | 1991-06-11 | Molecular Biosystems, Inc. | Oligonucleotide therapeutic agent and method of making same |
| US4476301A (en) | 1982-04-29 | 1984-10-09 | Centre National De La Recherche Scientifique | Oligonucleotides, a process for preparing the same and their application as mediators of the action of interferon |
| USRE34069E (en) | 1983-08-18 | 1992-09-15 | Biosyntech Gmbh | Process for the preparation of oligonucleotides |
| DE3329892A1 (de) | 1983-08-18 | 1985-03-07 | Köster, Hubert, Prof. Dr., 2000 Hamburg | Verfahren zur herstellung von oligonucleotiden |
| US5118800A (en) | 1983-12-20 | 1992-06-02 | California Institute Of Technology | Oligonucleotides possessing a primary amino group in the terminal nucleotide |
| US5550111A (en) | 1984-07-11 | 1996-08-27 | Temple University-Of The Commonwealth System Of Higher Education | Dual action 2',5'-oligoadenylate antiviral derivatives and uses thereof |
| FR2567892B1 (fr) | 1984-07-19 | 1989-02-17 | Centre Nat Rech Scient | Nouveaux oligonucleotides, leur procede de preparation et leurs applications comme mediateurs dans le developpement des effets des interferons |
| US5235033A (en) | 1985-03-15 | 1993-08-10 | Anti-Gene Development Group | Alpha-morpholino ribonucleoside derivatives and polymers thereof |
| US5185444A (en) | 1985-03-15 | 1993-02-09 | Anti-Gene Deveopment Group | Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages |
| US5034506A (en) | 1985-03-15 | 1991-07-23 | Anti-Gene Development Group | Uncharged morpholino-based polymers having achiral intersubunit linkages |
| US5405938A (en) | 1989-12-20 | 1995-04-11 | Anti-Gene Development Group | Sequence-specific binding polymers for duplex nucleic acids |
| US5166315A (en) | 1989-12-20 | 1992-11-24 | Anti-Gene Development Group | Sequence-specific binding polymers for duplex nucleic acids |
| US5264423A (en) | 1987-03-25 | 1993-11-23 | The United States Of America As Represented By The Department Of Health And Human Services | Inhibitors for replication of retroviruses and for the expression of oncogene products |
| US5276019A (en) | 1987-03-25 | 1994-01-04 | The United States Of America As Represented By The Department Of Health And Human Services | Inhibitors for replication of retroviruses and for the expression of oncogene products |
| US5188897A (en) | 1987-10-22 | 1993-02-23 | Temple University Of The Commonwealth System Of Higher Education | Encapsulated 2',5'-phosphorothioate oligoadenylates |
| US4924624A (en) | 1987-10-22 | 1990-05-15 | Temple University-Of The Commonwealth System Of Higher Education | 2,',5'-phosphorothioate oligoadenylates and plant antiviral uses thereof |
| JPH03503894A (ja) | 1988-03-25 | 1991-08-29 | ユニバーシィティ オブ バージニア アランミ パテンツ ファウンデイション | オリゴヌクレオチド ｎ‐アルキルホスホラミデート |
| US5278302A (en) | 1988-05-26 | 1994-01-11 | University Patents, Inc. | Polynucleotide phosphorodithioates |
| US5216141A (en) | 1988-06-06 | 1993-06-01 | Benner Steven A | Oligonucleotide analogs containing sulfur linkages |
| US5194599A (en) | 1988-09-23 | 1993-03-16 | Gilead Sciences, Inc. | Hydrogen phosphonodithioate compositions |
| US5591722A (en) | 1989-09-15 | 1997-01-07 | Southern Research Institute | 2'-deoxy-4'-thioribonucleosides and their antiviral activity |
| US5399676A (en) | 1989-10-23 | 1995-03-21 | Gilead Sciences | Oligonucleotides with inverted polarity |
| US5721218A (en) | 1989-10-23 | 1998-02-24 | Gilead Sciences, Inc. | Oligonucleotides with inverted polarity |
| US5264564A (en) | 1989-10-24 | 1993-11-23 | Gilead Sciences | Oligonucleotide analogs with novel linkages |
| DE69034150T2 (de) | 1989-10-24 | 2005-08-25 | Isis Pharmaceuticals, Inc., Carlsbad | 2'-Modifizierte Oligonukleotide |
| US5264562A (en) | 1989-10-24 | 1993-11-23 | Gilead Sciences, Inc. | Oligonucleotide analogs with novel linkages |
| US5177198A (en) | 1989-11-30 | 1993-01-05 | University Of N.C. At Chapel Hill | Process for preparing oligoribonucleoside and oligodeoxyribonucleoside boranophosphates |
| US5587361A (en) | 1991-10-15 | 1996-12-24 | Isis Pharmaceuticals, Inc. | Oligonucleotides having phosphorothioate linkages of high chiral purity |
| US5646265A (en) | 1990-01-11 | 1997-07-08 | Isis Pharmceuticals, Inc. | Process for the preparation of 2'-O-alkyl purine phosphoramidites |
| US5670633A (en) | 1990-01-11 | 1997-09-23 | Isis Pharmaceuticals, Inc. | Sugar modified oligonucleotides that detect and modulate gene expression |
| US5321131A (en) | 1990-03-08 | 1994-06-14 | Hybridon, Inc. | Site-specific functionalization of oligodeoxynucleotides for non-radioactive labelling |
| US5470967A (en) | 1990-04-10 | 1995-11-28 | The Dupont Merck Pharmaceutical Company | Oligonucleotide analogs with sulfamate linkages |
| GB9009980D0 (en) | 1990-05-03 | 1990-06-27 | Amersham Int Plc | Phosphoramidite derivatives,their preparation and the use thereof in the incorporation of reporter groups on synthetic oligonucleotides |
| ES2116977T3 (es) | 1990-05-11 | 1998-08-01 | Microprobe Corp | Soportes solidos para ensayos de hibridacion de acidos nucleicos y metodos para inmovilizar oligonucleotidos de modo covalente. |
| US5677437A (en) | 1990-07-27 | 1997-10-14 | Isis Pharmaceuticals, Inc. | Heteroatomic oligonucleoside linkages |
| US5608046A (en) | 1990-07-27 | 1997-03-04 | Isis Pharmaceuticals, Inc. | Conjugated 4'-desmethyl nucleoside analog compounds |
| US5602240A (en) | 1990-07-27 | 1997-02-11 | Ciba Geigy Ag. | Backbone modified oligonucleotide analogs |
| US5489677A (en) | 1990-07-27 | 1996-02-06 | Isis Pharmaceuticals, Inc. | Oligonucleoside linkages containing adjacent oxygen and nitrogen atoms |
| US5541307A (en) | 1990-07-27 | 1996-07-30 | Isis Pharmaceuticals, Inc. | Backbone modified oligonucleotide analogs and solid phase synthesis thereof |
| US5618704A (en) | 1990-07-27 | 1997-04-08 | Isis Pharmacueticals, Inc. | Backbone-modified oligonucleotide analogs and preparation thereof through radical coupling |
| US5623070A (en) | 1990-07-27 | 1997-04-22 | Isis Pharmaceuticals, Inc. | Heteroatomic oligonucleoside linkages |
| US5610289A (en) | 1990-07-27 | 1997-03-11 | Isis Pharmaceuticals, Inc. | Backbone modified oligonucleotide analogues |
| MY107332A (en) | 1990-08-03 | 1995-11-30 | Sterling Drug Inc | Compounds and methods for inhibiting gene expression. |
| US5177196A (en) | 1990-08-16 | 1993-01-05 | Microprobe Corporation | Oligo (α-arabinofuranosyl nucleotides) and α-arabinofuranosyl precursors thereof |
| US5214134A (en) | 1990-09-12 | 1993-05-25 | Sterling Winthrop Inc. | Process of linking nucleosides with a siloxane bridge |
| US5561225A (en) | 1990-09-19 | 1996-10-01 | Southern Research Institute | Polynucleotide analogs containing sulfonate and sulfonamide internucleoside linkages |
| JPH06505704A (ja) | 1990-09-20 | 1994-06-30 | ギリアド サイエンシズ，インコーポレイテッド | 改変ヌクレオシド間結合 |
| US5672697A (en) | 1991-02-08 | 1997-09-30 | Gilead Sciences, Inc. | Nucleoside 5'-methylene phosphonates |
| US5571799A (en) | 1991-08-12 | 1996-11-05 | Basco, Ltd. | (2'-5') oligoadenylate analogues useful as inhibitors of host-v5.-graft response |
| EP0538194B1 (de) | 1991-10-17 | 1997-06-04 | Novartis AG | Bicyclische Nukleoside, Oligonukleotide, Verfahren zu deren Herstellung und Zwischenprodukte |
| US5792608A (en) | 1991-12-12 | 1998-08-11 | Gilead Sciences, Inc. | Nuclease stable and binding competent oligomers and methods for their use |
| US5359044A (en) | 1991-12-13 | 1994-10-25 | Isis Pharmaceuticals | Cyclobutyl oligonucleotide surrogates |
| FR2687679B1 (fr) | 1992-02-05 | 1994-10-28 | Centre Nat Rech Scient | Oligothionucleotides. |
| US5633360A (en) | 1992-04-14 | 1997-05-27 | Gilead Sciences, Inc. | Oligonucleotide analogs capable of passive cell membrane permeation |
| US5434257A (en) | 1992-06-01 | 1995-07-18 | Gilead Sciences, Inc. | Binding compentent oligomers containing unsaturated 3',5' and 2',5' linkages |
| EP0577558A2 (de) | 1992-07-01 | 1994-01-05 | Ciba-Geigy Ag | Carbocyclische Nukleoside mit bicyclischen Ringen, Oligonukleotide daraus, Verfahren zu deren Herstellung, deren Verwendung und Zwischenproduckte |
| US5476925A (en) | 1993-02-01 | 1995-12-19 | Northwestern University | Oligodeoxyribonucleotides including 3'-aminonucleoside-phosphoramidate linkages and terminal 3'-amino groups |
| GB9304618D0 (en) | 1993-03-06 | 1993-04-21 | Ciba Geigy Ag | Chemical compounds |
| CA2159631A1 (en) | 1993-03-30 | 1994-10-13 | Sanofi | Acyclic nucleoside analogs and oligonucleotide sequences containing them |
| HU9501974D0 (en) | 1993-03-31 | 1995-09-28 | Sterling Winthrop Inc | Oligonucleotides with amide linkages replacing phosphodiester linkages |
| US5446137B1 (en) | 1993-12-09 | 1998-10-06 | Behringwerke Ag | Oligonucleotides containing 4'-substituted nucleotides |
| FR2714061B1 (fr) | 1993-12-16 | 1996-03-08 | Genset Sa | Procédé de préparation de polynucléotides sur support solide et appareil permettant sa mise en Óoeuvre. |
| US5519134A (en) | 1994-01-11 | 1996-05-21 | Isis Pharmaceuticals, Inc. | Pyrrolidine-containing monomers and oligomers |
| US5627053A (en) | 1994-03-29 | 1997-05-06 | Ribozyme Pharmaceuticals, Inc. | 2'deoxy-2'-alkylnucleotide containing nucleic acid |
| US5625050A (en) | 1994-03-31 | 1997-04-29 | Amgen Inc. | Modified oligonucleotides and intermediates useful in nucleic acid therapeutics |
| US5646269A (en) | 1994-04-28 | 1997-07-08 | Gilead Sciences, Inc. | Method for oligonucleotide analog synthesis |
| US5597909A (en) | 1994-08-25 | 1997-01-28 | Chiron Corporation | Polynucleotide reagents containing modified deoxyribose moieties, and associated methods of synthesis and use |
| US20080119427A1 (en) | 1996-06-06 | 2008-05-22 | Isis Pharmaceuticals, Inc. | Double Strand Compositions Comprising Differentially Modified Strands for Use in Gene Modulation |
| US6770748B2 (en) | 1997-03-07 | 2004-08-03 | Takeshi Imanishi | Bicyclonucleoside and oligonucleotide analogue |
| JP3756313B2 (ja) | 1997-03-07 | 2006-03-15 | 武 今西 | 新規ビシクロヌクレオシド及びオリゴヌクレオチド類縁体 |
| US6794499B2 (en) | 1997-09-12 | 2004-09-21 | Exiqon A/S | Oligonucleotide analogues |
| JP4236812B2 (ja) | 1997-09-12 | 2009-03-11 | エクシコン エ／エス | オリゴヌクレオチド類似体 |
| US7572582B2 (en) | 1997-09-12 | 2009-08-11 | Exiqon A/S | Oligonucleotide analogues |
| US6867294B1 (en) | 1998-07-14 | 2005-03-15 | Isis Pharmaceuticals, Inc. | Gapped oligomers having site specific chiral phosphorothioate internucleoside linkages |
| US6043352A (en) | 1998-08-07 | 2000-03-28 | Isis Pharmaceuticals, Inc. | 2'-O-Dimethylaminoethyloxyethyl-modified oligonucleotides |
| US6069243A (en) * | 1998-10-06 | 2000-05-30 | Isis Pharmaceuticals, Inc. | Process for oligonucleotide synthesis |
| US7053207B2 (en) | 1999-05-04 | 2006-05-30 | Exiqon A/S | L-ribo-LNA analogues |
| US6525191B1 (en) | 1999-05-11 | 2003-02-25 | Kanda S. Ramasamy | Conformationally constrained L-nucleosides |
| EP1244667B1 (en) | 1999-12-30 | 2006-04-05 | K.U. Leuven Research & Development | Cyclohexene nucleic acids |
| US7524950B2 (en) | 2001-10-31 | 2009-04-28 | Agilent Technologies, Inc. | Uses of cationic salts for polynucleotide synthesis |
| AU2003291755A1 (en) | 2002-11-05 | 2004-06-07 | Isis Pharmaceuticals, Inc. | Oligomers comprising modified bases for binding cytosine and uracil or thymine and their use |
| WO2004041889A2 (en) | 2002-11-05 | 2004-05-21 | Isis Pharmaceuticals, Inc. | Polycyclic sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation |
| US7202264B2 (en) | 2003-01-31 | 2007-04-10 | Isis Pharmaceuticals, Inc. | Supports for oligomer synthesis |
| WO2004106356A1 (en) | 2003-05-27 | 2004-12-09 | Syddansk Universitet | Functionalized nucleotide derivatives |
| EP1661905B9 (en) | 2003-08-28 | 2012-12-19 | IMANISHI, Takeshi | Novel artificial nucleic acids of n-o bond crosslinkage type |
| CA2538252C (en) | 2003-09-18 | 2014-02-25 | Isis Pharmaceuticals, Inc. | 4'-thionucleosides and oligomeric compounds |
| WO2006047842A2 (en) | 2004-11-08 | 2006-05-11 | K.U. Leuven Research And Development | Modified nucleosides for rna interference |
| WO2007090071A2 (en) | 2006-01-27 | 2007-08-09 | Isis Pharmaceuticals, Inc. | 6-modified bicyclic nucleic acid analogs |
| JP2009536222A (ja) * | 2006-05-05 | 2009-10-08 | アイシス ファーマシューティカルズ， インコーポレーテッド | Ｐｃｓｋ９の発現を調節するための化合物および方法 |
| AU2007249349B2 (en) | 2006-05-11 | 2012-03-08 | Isis Pharmaceuticals, Inc. | 5'-Modified bicyclic nucleic acid analogs |
| WO2008101157A1 (en) | 2007-02-15 | 2008-08-21 | Isis Pharmaceuticals, Inc. | 5'-substituted-2'-f modified nucleosides and oligomeric compounds prepared therefrom |
| CA2688321A1 (en) | 2007-05-30 | 2008-12-11 | Isis Pharmaceuticals, Inc. | N-substituted-aminomethylene bridged bicyclic nucleic acid analogs |
| DK2173760T4 (da) | 2007-06-08 | 2016-02-08 | Isis Pharmaceuticals Inc | Carbocycliske bicycliske nukleinsyreanaloge |
| AU2008272918B2 (en) | 2007-07-05 | 2012-09-13 | Isis Pharmaceuticals, Inc. | 6-disubstituted bicyclic nucleic acid analogs |
| WO2009067647A1 (en) | 2007-11-21 | 2009-05-28 | Isis Pharmaceuticals, Inc. | Carbocyclic alpha-l-bicyclic nucleic acid analogs |
| WO2009100320A2 (en) | 2008-02-07 | 2009-08-13 | Isis Pharmaceuticals, Inc. | Bicyclic cyclohexitol nucleic acid analogs |
| FR2927901B1 (fr) | 2008-02-21 | 2010-09-03 | Centre Nat Rech Scient | Procede de preparation de nucleotides et analogues a facon par synthese sur support soluble et outils biologiques prepares |
| US9290534B2 (en) | 2008-04-04 | 2016-03-22 | Ionis Pharmaceuticals, Inc. | Oligomeric compounds having at least one neutrally linked terminal bicyclic nucleoside |
| DK2356129T3 (da) | 2008-09-24 | 2013-05-13 | Isis Pharmaceuticals Inc | Substituerede alpha-L-bicykliske nukleosider |
| DK2361256T3 (da) | 2008-09-24 | 2013-07-01 | Isis Pharmaceuticals Inc | Cyclohexenyl-nukleinsyreanaloger |
| US9012421B2 (en) | 2009-08-06 | 2015-04-21 | Isis Pharmaceuticals, Inc. | Bicyclic cyclohexose nucleic acid analogs |
| US9193752B2 (en) * | 2010-03-17 | 2015-11-24 | Isis Pharmaceuticals, Inc. | 5′-substituted bicyclic nucleosides and oligomeric compounds prepared therefrom |
| US9156873B2 (en) | 2010-04-28 | 2015-10-13 | Isis Pharmaceuticals, Inc. | Modified 5′ diphosphate nucleosides and oligomeric compounds prepared therefrom |
| EP2601204B1 (en) | 2010-04-28 | 2016-09-07 | Ionis Pharmaceuticals, Inc. | Modified nucleosides and oligomeric compounds prepared therefrom |
| EP2580228B1 (en) | 2010-06-08 | 2016-03-23 | Ionis Pharmaceuticals, Inc. | Substituted 2'-amino and 2'-thio-bicyclic nucleosides and oligomeric compounds prepared therefrom |
-
2014
- 2014-01-30 DK DK14746224.6T patent/DK2951191T3/da active
- 2014-01-30 WO PCT/US2014/013732 patent/WO2014120861A2/en not_active Ceased
- 2014-01-30 EP EP14746224.6A patent/EP2951191B1/en active Active
- 2014-01-30 KR KR1020157023079A patent/KR102190852B1/ko not_active Expired - Fee Related
- 2014-01-30 US US14/764,655 patent/US9701708B2/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| EP2951191A2 (en) | 2015-12-09 |
| KR102190852B1 (ko) | 2020-12-14 |
| US9701708B2 (en) | 2017-07-11 |
| WO2014120861A2 (en) | 2014-08-07 |
| EP2951191A4 (en) | 2016-08-17 |
| KR20150111989A (ko) | 2015-10-06 |
| EP2951191B1 (en) | 2018-10-17 |
| US20150368288A1 (en) | 2015-12-24 |
| WO2014120861A3 (en) | 2015-10-29 |
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