JP2022530537A - レニウムキレート化mag3オリゴヌクレオチドを調製するための新規の方法 - Google Patents
レニウムキレート化mag3オリゴヌクレオチドを調製するための新規の方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 63
- 108091034117 Oligonucleotide Proteins 0.000 title claims abstract description 50
- 229910052702 rhenium Inorganic materials 0.000 title claims abstract description 29
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 title claims abstract description 25
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 title claims description 19
- RXACEEPNTRHYBQ-UHFFFAOYSA-N 2-[[2-[[2-[(2-sulfanylacetyl)amino]acetyl]amino]acetyl]amino]acetic acid Chemical compound OC(=O)CNC(=O)CNC(=O)CNC(=O)CS RXACEEPNTRHYBQ-UHFFFAOYSA-N 0.000 title abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- -1 dimethoxytrityl Chemical group 0.000 claims description 68
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 239000002777 nucleoside Substances 0.000 claims description 35
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 33
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 24
- 239000003153 chemical reaction reagent Substances 0.000 claims description 17
- 238000005859 coupling reaction Methods 0.000 claims description 17
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 16
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 16
- 230000008878 coupling Effects 0.000 claims description 16
- 238000010168 coupling process Methods 0.000 claims description 16
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 13
- 238000005580 one pot reaction Methods 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 claims description 12
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 239000000074 antisense oligonucleotide Substances 0.000 claims description 11
- 238000012230 antisense oligonucleotides Methods 0.000 claims description 11
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 11
- 239000002243 precursor Substances 0.000 claims description 11
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 10
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 9
- SDTORDSXCYSNTD-UHFFFAOYSA-N 1-methoxy-4-[(4-methoxyphenyl)methoxymethyl]benzene Chemical compound C1=CC(OC)=CC=C1COCC1=CC=C(OC)C=C1 SDTORDSXCYSNTD-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 claims description 8
- 150000003573 thiols Chemical group 0.000 claims description 8
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 8
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 7
- 239000003880 polar aprotic solvent Substances 0.000 claims description 7
- 239000003586 protic polar solvent Substances 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- BMTZEAOGFDXDAD-UHFFFAOYSA-M 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium;chloride Chemical compound [Cl-].COC1=NC(OC)=NC([N+]2(C)CCOCC2)=N1 BMTZEAOGFDXDAD-UHFFFAOYSA-M 0.000 claims description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 4
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 claims description 4
- GPAAEZIXSQCCES-UHFFFAOYSA-N 1-methoxy-2-(2-methoxyethoxymethoxymethoxy)ethane Chemical compound COCCOCOCOCCOC GPAAEZIXSQCCES-UHFFFAOYSA-N 0.000 claims description 4
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 4
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 4
- 239000007821 HATU Substances 0.000 claims description 4
- 239000012317 TBTU Substances 0.000 claims description 4
- 241000289690 Xenarthra Species 0.000 claims description 4
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- CPZBTYRIGVOOMI-UHFFFAOYSA-N methylsulfanyl(methylsulfanylmethoxy)methane Chemical compound CSCOCSC CPZBTYRIGVOOMI-UHFFFAOYSA-N 0.000 claims description 4
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 4
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000005500 uronium group Chemical group 0.000 claims description 4
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 2
- 125000003835 nucleoside group Chemical group 0.000 description 17
- 125000006239 protecting group Chemical group 0.000 description 17
- 239000002585 base Substances 0.000 description 11
- 235000000346 sugar Nutrition 0.000 description 11
- 108020004707 nucleic acids Proteins 0.000 description 10
- 102000039446 nucleic acids Human genes 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 239000002738 chelating agent Substances 0.000 description 7
- 230000004048 modification Effects 0.000 description 7
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- 150000007523 nucleic acids Chemical class 0.000 description 7
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
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- 238000009206 nuclear medicine Methods 0.000 description 5
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 4
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 239000013522 chelant Substances 0.000 description 4
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 4
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- 108020004414 DNA Proteins 0.000 description 3
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- 125000003118 aryl group Chemical group 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- 150000008431 aliphatic amides Chemical class 0.000 description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic System
- C07F13/005—Compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0491—Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/32—Chemical structure of the sugar
- C12N2310/323—Chemical structure of the sugar modified ring structure
- C12N2310/3231—Chemical structure of the sugar modified ring structure having an additional ring, e.g. LNA, ENA
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/35—Nature of the modification
- C12N2310/351—Conjugate
- C12N2310/3517—Marker; Tag
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2320/00—Applications; Uses
- C12N2320/30—Special therapeutic applications
Abstract
Description
「カップリング試薬」という用語は、カルボン酸と、アミン、アルコール、又はチオールなどとの2つの有機分子の共有結合を可能にする化合物を意味する。さらに本発明の文脈において、カップリング試薬は、カルボン酸がアミンにカップリングするカップリング反応を補助することができる化合物を意味する。カップリング試薬は、水溶性HCl塩として使用することができる。EDCは、他のカルボジイミドの例である。EDCの副産物は水溶性であり、水性ワークアップによって簡単に除去することができる。他のカップリング試薬の例は、DCC(N,N’-ジシクロヘキシルカルボジイミド)、DIC(N,N’-ジイソプロピルカルボジイミド)、EDC(1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド)、EDC-HCl(1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド-HCl)、BOP、PyBOP((ベンゾトリアゾール-1-イル-オキシトリピロリジノホスホニウムヘキサフルオロホスファート)、PyBrOP(ブロモトリピロリジノホスホニウムヘキサフルオロホスファート)、TBTU(2-(1H-ベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルアミニウムテトラフルオロボレート)、TSTU(N,N,N’,N’-テトラメチル-O-(N-スクシンイミジル)ウロニウムテトラフルオロボレート)、TNTU(O-(ビシクロ[2.2.1]ヘプタ-5-エン-2,3-ジカルボキシイミド)-N,N,N’,N’-テトラメチルウロニウムテトラフルオロボレート)、T3P(2,4,6-トリプロピル-1,3,5,2,4,6-トリオキサトリホスホリナン-2,4,6-トリオキシド)、HCTU(O-(6-クロロベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウムヘキサフルオロホスファート)、TATU、HATU(N-[(ジメチルアミノ)-1H-1,2,3-トリアゾロ-[4,5-b]ピリジン-1-イルメチレン]-N-メチルメタンアミニウムヘキサフルオロホスファートN-オキシド)、DMTMM(4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド)、CDI(1,1’-カルボニルジイミダゾール)などである。
本明細書で用いられる「オリゴヌクレオチド」という用語は、2つ以上の共有結合したヌクレオシドを含む分子として当業者に一般に理解されるように定義される。このような共有結合したヌクレオシドはまた、核酸分子又はオリゴマーとも称されうる。オリゴヌクレオチドは、通常、固相化学合成と、その後の精製によって研究室内で作製される。オリゴヌクレオチドの配列に言及する場合には、共有結合したヌクレオチド又はヌクレオシドの核酸塩基部分の配列又は順序、若しくはその修飾が言及される。本発明のオリゴヌクレオチドは、人工のものであり、化学的に合成され、通常は精製又は単離される。本発明のオリゴヌクレオチドは、1つ以上の修飾ヌクレオシド又はヌクレオチドを含みうる。
本明細書で用いられる「アンチセンスオリゴヌクレオチド」という用語は、標的核酸、特に標的核酸上の連続配列にハイブリダイズすることによって標的遺伝子の発現を調節することができるオリゴヌクレオチドとして定義される。アンチセンスオリゴヌクレオチドは、本質的に二本鎖ではなく、したがってsiRNA又はshRNAではない。好ましくは、本発明のアンチセンスオリゴヌクレオチドは一本鎖である。本発明の単鎖オリゴヌクレオチドは、自己内又は自己間の相補性の程度がオリゴヌクレオチドの全長にわたって50%未満である限り、ヘアピン又は分子間二重構造(同じオリゴヌクレオチドの2つの分子間の二重鎖)を形成することができるものと理解される。
本発明のオリゴマーは、修飾された糖部分、すなわち、DNA及びRNAに見られるリボース糖部分と比較して、糖部分が修飾された1つ以上のヌクレオシドを含みうる。
2’糖修飾ヌクレオシドは、2’位にH又は-OH以外の置換基を有するか(2’置換ヌクレオシド)、又は2’炭素とリボース環上の第2の炭素との間に架橋を形成することができる2’結合ビラジカルを含むヌクレオシド、例えばLNA(2’-4’ビラジカル架橋)ヌクレオシドである。
「LNAヌクレオシド」は、前記ヌクレオシドのリボース糖環のC2’及びC4’を結合するビラジカル結合(「2’-4’架橋」とも呼ばれる)を含む、2’-修飾ヌクレオシドであり、これはリボース環の立体配座を制限又は固定する。これらのヌクレオシドはまた、文献において、架橋核酸又は二環式核酸(BNA)とも称されている。リボースの立体配座の固定は、LNAが相補的RNA又はDNA分子のオリゴヌクレオチドに組み込まれる場合、ハイブリダイゼーションの親和性の向上(二重鎖の安定化)に関連している。これは、オリゴヌクレオチド/相補二重鎖の融解温度を測定することによって、日常的に決定することができる。
一態様では、本発明は、式(III)の化合物の調製方法に関し、該方法は、
a)式(I)の化合物:
[式中、RはH又はチオール保護基である]
を、溶媒中でレニウム錯体の前駆体と反応させて、式(II)の化合物:
を得るステップ、
b)N-ヒドロキシスクシンイミドをカップリング試薬とともに加えて、式(III)の化合物:
を得るステップ
を含み、
ここで、ステップa)及びb)は、ワンポット反応で行われる。
c)式(I)の化合物:
[式中、Rは、Hであるか、又はアセチル(Ac)及びベンゾイル(Bz),からなる群より選択されるチオール保護基である]
を、ReOCl3(PPh3)2と、
体積比約1:1のDMF:MeOH中で反応させて、式(II)の化合物:
を得るステップ、
d)N-ヒドロキシスクシンイミドをEDC-HClとともに加えて、式(III)の化合物を得るステップ:
c)アミノオリゴヌクレオチドを塩基とともに加えて、式(IV)の化合物:
を得るステップ
を含み、
ここで、オリゴヌクレオチドは、少なくとも1つの2’糖修飾ヌクレオシド又はLNAヌクレオシドを含む。
[式中、RはH又はチオール保護基である]
を、溶媒中でレニウム錯体の前駆体と反応させて、式(II)の化合物:
を得るステップ、
b)N-ヒドロキシスクシンイミドをカップリング試薬とともに加えて、式(III)の化合物:
を得るステップ
を含み、
ここで、ステップa)及びb)はワンポット反応で行われる、
式(III)の化合物の調製方法。
[式中、Rは、アセチル(Ac)及びベンゾイル(Bz)からなる群より選択されるチオール保護基である]
を、ReOCl3(PPh3)2と、
体積比約1:1のDMF:MeOH中で反応させて、式(II)の化合物:
を得るステップ、
b)N-ヒドロキシスクシンイミドをEDC-HClとともに加えて、式(III)の化合物:
を得るステップ、
c)アミノオリゴヌクレオチドを塩基とともに加えて、式(IV)の化合物:
を得るステップ
を含み、
ここで、オリゴヌクレオチドが、少なくとも1つの2’糖修飾ヌクレオシド又はLNAヌクレオシドを含み、かつ、ステップa)、b)、及びc)がワンポット反応で行われる、
実施態様1から12のいずれかに記載の方法。
Claims (17)
- ステップa)、b)、及びc)がワンポット反応で行われる、請求項2に記載の方法。
- レニウム錯体の前駆体が、ReOCl3(PPh3)2、Re(NPh)Cl3(PPh3)2、ReO2(PPh3)2I、及びRe(NPh)Cl3(PPh3)2からなる群より選択される、請求項1から3のいずれか一項に記載の方法。
- レニウム錯体の前駆体がReOCl3(PPh3)2である、請求項4に記載の方法。
- Rが、アセチル(Ac)、ベンゾイル(Bz)、ベンジル(Bn)、β-メトキシエトキシメチルエーテル(MEM)、ジメトキシトリチル(又はビス-(4-メトキシフェニル)フェニルメチル)(DMT)、トリメトキシトリチル(又はトリス-(4-メトキシフェニル)フェニルメチル)(TMT)、メトキシメチルエーテル(MOM)、メトキシトリチル[(4-メトキシフェニル)ジフェニルメチル(MMT)、p-メトキシベンジルエーテル(PMB)、メチルチオメチルエーテル、ピバロイル(Piv)、テトラヒドロピラニル(THP)、テトラヒドロフラン(THF)、トリチル又はトリフェニルメチル(Tr)、シリルエーテル(例えば、トリメチルシリル(TMS)、tert-ブチルジメチルシリル(TBDMS)、トリ-イソ-プロピルシリルオキシメチル(TOM)及びトリイソプロピルシリル(TIPS)エーテル)、並びにメチルエーテル及びエトキシエチルエーテル(EE)からなる群より選択されるチオール保護基である、請求項1から5のいずれか一項に記載の方法。
- Rが、アセチル(Ac)及びベンゾイル(Bz)からなる群より選択されるチオール保護基である、請求項6に記載の方法。
- ステップa)の溶媒が、極性非プロトン性溶媒と極性プロトン性溶媒との混合物である、請求項1から7のいずれか一項に記載の方法。
- DMF:MeOHが約1:1の体積比である、請求項8に記載の方法。
- 塩基がステップa)でさらに用いられる、請求項1から9のいずれか一項に記載の方法。
- 塩基がNaOMeである、請求項10に記載の方法。
- a)式(I)の化合物:
[式中、Rは、Hであるか、アセチル(Ac)及びベンゾイル(Bz)からなる群より選択されるチオール保護基である]
を、ReOCl3(PPh3)2と、
体積比約1:1のDMF:MeOH中で反応させて、式(II)の化合物:
を得るステップ、
b)N-ヒドロキシスクシンイミドをEDC-HClとともに加えて、式(III)の化合物:
を得るステップ、
c)アミノオリゴヌクレオチドを塩基とともに加えて、式(IV)の化合物:
を得るステップ
を含み、
ここで、オリゴヌクレオチドが、少なくとも1つの2’糖修飾ヌクレオシド又はLNAヌクレオシドを含み、かつ、ステップa)、b)、及びc)がワンポット反応で行われる、
請求項1から11のいずれか一項に記載の方法。 - オリゴヌクレオチドがアンチセンスオリゴヌクレオチドである、請求項1から12のいずれか一項に記載の方法。
- アンチセンスオリゴヌクレオチドが、少なくとも1つの2’糖修飾ヌクレオシド又はLNAヌクレオシドを含む、請求項13に記載の方法。
- カップリング試薬が、DCC(N,N’-ジシクロヘキシルカルボジイミド)、DIC(N,N’-ジイソプロピルカルボジイミド)、EDC(1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド)、EDC-HCl(1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド-HCl)、BOP、PyBOP((ベンゾトリアゾール-1-イル-オキシトリピロリジノホスホニウムヘキサフルオロホスファート)、PyBrOP(ブロモトリピロリジノホスホニウムヘキサフルオロホスファート)、TBTU(2-(1H-ベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルアミニウムテトラフルオロボレート)、TSTU(N,N,N’,N’-テトラメチル-O-(N-スクシンイミジル)ウロニウムテトラフルオロボレート)、TNTU(O-(ビシクロ[2.2.1]ヘプタ-5-エン-2,3-ジカルボキシイミド)-N,N,N’,N’-テトラメチルウロニウムテトラフルオロボレート)、T3P(2,4,6-トリプロピル-1,3,5,2,4,6-トリオキサトリホスホリナン-2,4,6-トリオキシド)、HCTU(O-(6-クロロベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウムヘキサフルオロホスファート)、TATU、HATU(N-[(ジメチルアミノ)-1H-1,2,3-トリアゾロ-[4,5-b]ピリジン-1-イルメチレン]-N-メチルメタンアミニウムヘキサフルオロホスファートN-オキシド)及びDMTMM(4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド)、CDI(1,1’-カルボニルジイミダゾール)であるカップリング試薬からなる群より選択される、請求項1から14のいずれか一項に記載の方法。
- カップリング試薬が、EDC-HCl(1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド-HCl)である、請求項15に記載の方法。
- 前述の発明。
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