JPWO2011034072A1 - Rna及びその誘導体合成のための新規保護基 - Google Patents
Rna及びその誘導体合成のための新規保護基 Download PDFInfo
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- JPWO2011034072A1 JPWO2011034072A1 JP2011531939A JP2011531939A JPWO2011034072A1 JP WO2011034072 A1 JPWO2011034072 A1 JP WO2011034072A1 JP 2011531939 A JP2011531939 A JP 2011531939A JP 2011531939 A JP2011531939 A JP 2011531939A JP WO2011034072 A1 JPWO2011034072 A1 JP WO2011034072A1
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- Prior art keywords
- group
- alkyl group
- ribonucleotide
- protecting
- derivative
- Prior art date
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- 125000006239 protecting group Chemical group 0.000 title claims abstract description 88
- 238000003786 synthesis reaction Methods 0.000 title description 6
- 230000015572 biosynthetic process Effects 0.000 title description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 49
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 42
- 125000002652 ribonucleotide group Chemical group 0.000 claims abstract description 37
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 32
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 claims abstract description 27
- 108091028664 Ribonucleotide Proteins 0.000 claims abstract description 26
- 239000002342 ribonucleoside Substances 0.000 claims abstract description 26
- 239000002336 ribonucleotide Substances 0.000 claims abstract description 26
- 125000005843 halogen group Chemical group 0.000 claims abstract description 22
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 12
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 8
- -1 9-fluorenyl group Chemical group 0.000 claims description 104
- 150000001875 compounds Chemical class 0.000 claims description 59
- 239000002253 acid Substances 0.000 claims description 22
- 238000004519 manufacturing process Methods 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- 125000001153 fluoro group Chemical group F* 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 229920006395 saturated elastomer Polymers 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
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 32
- 238000001668 nucleic acid synthesis Methods 0.000 abstract description 6
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 52
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 125000001424 substituent group Chemical group 0.000 description 16
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 10
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 10
- 229940045145 uridine Drugs 0.000 description 10
- 239000010410 layer Substances 0.000 description 9
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229960005215 dichloroacetic acid Drugs 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000002808 molecular sieve Substances 0.000 description 6
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 6
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000000010 aprotic solvent Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 5
- 150000002222 fluorine compounds Chemical class 0.000 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 description 4
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- 238000001425 electrospray ionisation time-of-flight mass spectrometry Methods 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000002516 radical scavenger Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 3
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 3
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 3
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 3
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 229960005305 adenosine Drugs 0.000 description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 229940029575 guanosine Drugs 0.000 description 3
- 230000000269 nucleophilic effect Effects 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 150000003222 pyridines Chemical class 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000007790 solid phase Substances 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 3
- 150000003613 toluenes Chemical class 0.000 description 3
- RYVNIFSIEDRLSJ-UHFFFAOYSA-N 5-(hydroxymethyl)cytosine Chemical compound NC=1NC(=O)N=CC=1CO RYVNIFSIEDRLSJ-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
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- 125000003545 alkoxy group Chemical group 0.000 description 2
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- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
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- 125000001309 chloro group Chemical group Cl* 0.000 description 2
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- 125000001072 heteroaryl group Chemical group 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
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- 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 description 2
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- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- 125000001216 2-naphthoyl group Chemical group C1=C(C=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000005979 2-naphthyloxy group Chemical group 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- LNQVTSROQXJCDD-KQYNXXCUSA-N 3'-AMP Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](OP(O)(O)=O)[C@H]1O LNQVTSROQXJCDD-KQYNXXCUSA-N 0.000 description 1
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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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
- C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
- C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
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Abstract
Description
より具体的には、本発明の課題は、上記の保護基であって、核酸合成サイクルの反応条件下において安定であり、立体障害が小さく、かつフッ化物イオンを塩基として用いる緩和な条件下(Chem. Rev., 80, 429, 1980)や、シリル化剤などの求核種捕捉剤存在下又は強塩基性条件で脱離可能な保護基を提供することにある。
上記一般式(III)で表される化合物のうち、R21が水酸基である化合物を用いた典型的な反応工程例を以下に示すが、本発明の範囲は下記のスキームに記載された方法に限定されることはない。スキーム中、Meはメチル基を示し、Etはエチル基を示し、DIBALは水素化ジイソブチルアルミニウム、Urはウラシル塩基、TMSOTfはトリメチルシリルトリフルオロメタンスルホネート、MS4Aはモレキュラーシーブス4A、THFはテトラヒドロフラン、NISはN-ヨードスクシンイミドを示す。また、スキーム中の化合物(1)の製造方法については実施例に具体的な方法を示した。
実施例中の略号は以下のとおりである。
ac: アセチル
bz: ベンゾイル
BFEM: 2-ビス(トリフルオロメチル)エトキシメチル
CPG: コントロールポアグラス
DBU: 1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン
DCA: ジクロロ酢酸
DCM: ジクロロメタン、CH2Cl2
DMTr: 4,4'-ジメトキシトリチル
HCP: 高架橋ポリスチレン
NIS: N-ヨードスクシンイミド
pac: フェノキシアセチル
TBS: tert-ブチルジメチルシリル
TBDPS: tert-ブチルジフェニルシリル
TFA: トリフルオロ酢酸
TMSOTf: トリメチルシリルトリフルオロメタンスフホネート
Z-NT: ベンジル 3-ニトロ-1H-1,2,4-トリアゾール-1-カルボキシレート
Me: メチル
OMe: メトキシ
例1
(a)2'-O-(2-トリフルオロメチル-3,3,3-トリフルオロプロパノキシメチル)-3',5'-O-(1,1,3,3-テトライソプロピルジシロキサン-1,3-ジイル)ウリジン (1u)
13C NMR (75.5 MHz, CDCl3) δ 163.7, 150.2, 139.1, 123.1 (2C, q, J = 286.1 Hz), 101.8, 94.7, 89.0, 81.7, 78.3, 68.0, 61.3, 59.2, 48.7 (1C, quintet, J = 27.9 Hz), 17.4, 17.3, 17.3, 17.2, 16.9, 16.8, 16.8, 16.7, 13.2, 13.1, 12.8, 12.5
MALDI TOF-MS m/z Calcd for C26H42F6N2NaO8Si2 + [M+Na]+ 703.23, found 703.90.
13C NMR (75.5 MHz, CDCl3) δ 162.7, 158.8, 158.8, 150.0, 144.2, 139.8, 135.2, 135.0, 130.2, 130.1, 128.1, 128.1, 127.3, 122.9 (2C, q, J = 280.6 Hz), 113.3, 102.3, 95.3, 87.8, 87.3, 80.1, 68.8, 61.8, 61.3, 55.3, 48.9 (1C, quintet, J = 27.9 Hz)
MALDI TOF-MS m/z Calcd for C35H34F6N2NaO9 + [M+Na]+ 763.21, found 763.73.
31PNMR (121.5 MHz, CDCl3) δ 152.1 (0.5P, s, diastereomer), 150.8 (0.5P, s, diastereomer)
ESI TOF-MS m/z Calcd for C44H52F6N4O10P+ [M+H]+ 941.33, found 941.45.
(a)N6-アセチル-2'-O-(2-トリフルオロメチル-3,3,3-トリフルオロプロパノキシメチル)-3',5'-O-(1,1,3,3-テトライソプロピルジシロキサン-1,3-ジイル)アデノシン (1a)
1H NMR (300 MHz, CDCl3) δ 8.63 (1H, s), 8.55 (1H, brs), 8.32 (1H, s), 6.08 (1H, s), 5.10 (1H, d, J = 7.2 Hz), 4.96 (1H, d, J = 7.2 Hz), 4.67 (1H, dd, J = 9.6, 4.5 Hz), 4.48 (1H, d, J = 4.5 Hz), 4.34-4.14 (3H, m) 4.08-3.96 (2H, m), 3.53-3.38 (1H, m), 2.62 (3H, s), 1.16-0.92 (28H, m)
MALDI TOF-MS m/z Calcd for C29H45F6N5NaO7Si2 + [M+Na]+ 768.27, found 768.81.
1H NMR (300 MHz, CDCl3) δ 9.15 (1H, brs), 8.59 (1H, s), 8.24 (1H, s), 7.47-7.15 (9H, m), 6.79 (4H, d, J = 8.7 Hz), 6.23 (1H, d, J = 4.5 Hz), 4.93 (1H, t, J = 4.5 Hz), 4.86 (2H, s), 4.62-4.54 (1H, m), 4.30-4.24 (1H, m), 3.94 (1H, dd, J = 11.0, 5.1 Hz), 3.83 (1H, dd, J =11.0, 4.5 Hz), 3.76 (6H, s), 3.55 (1H, dd, J = 10.8, 3.0 Hz), 3.45 (1H, dd, J = 10.8, 3.9 Hz), 3.26-3.10 (1H, m), 3.08 (1H, d, J = 5.4 Hz), 2.59 (3H, s)
MALDI TOF-MS m/z Calcd for C38H37F6N5NaO8 + [M+Na]+ 828.24, found 828.83.
1H NMR (300 MHz, CDCl3) δ 8.83 (1H, brs), 8.59 (1H, s), 8.23 (0.5H, s, diastereomer), 8.23 (0.5H, s, diastereomer), 7.48-7.10 (9H, m), 6.86-6.72 (4H, m), 6.21 (0.5H, d, J = 4.8 Hz, diastereomer), 6.17 (0.5H, d, J = 5.1 Hz, diastereomer), 5.06-4.62 (4H, m), 4.44-4.30 (1H, m), 3.86-3.50 (5H, m), 3.78 (3H. s, diastereomer), 3.77 (3H, s, diastereomer), 3.44-3.32 (1H, m), 3.30-3.08 (1H, m), 2.64-2.56 (1H, m, diastereomer), 2.60 (1.5H, s, diastereomer), 2.42-2.32 (1H, m, diastereomer), 2.35 (1.5H, s, diastereomer), 1.14-1.00 (14H, m)
31P NMR (121.5 MHz, CDCl3) δ 151.7 (0.5P, s, diastereomer), 151.6 (0.5P, s, diastereomer)
ESI TOF-MS m/z Calcd for C47H55F6N7O9P+ [M+H]+ 1006.37, found 1006.39.
(a)N4-アセチル-2'-O-(2-トリフルオロメチル-3,3,3-トリフルオロプロパノキシメチル)-3',5'-O-(1,1,3,3-テトライソプロピルジシロキサン-1,3-ジイル)シチジン (1c)
13C NMR (75.5 MHz, CDCl3) δ 171.2, 163.4, 154.8, 144.0, 123.1 (2C, q, J = 281.5 Hz), 96.6, 94.7, 89.9, 81.9, 78.3, 67.6, 61.3, 59.3, 48.8 (1C, quintet, J = 27.6 Hz), 24.7, 17.5, 17.4, 17.3, 17.2, 16.9, 16.9, 16.8, 13.2, 13.1, 12.8, 12.5
MALDI TOF-MS m/z Calcd for C28H45F6N3NaO8Si2 + [M+Na]+ 744.25, found 744.97.
1H NMR (300 MHz, CDCl3) δ 9.34 (1H, brs), 8.49 (1H, d, J = 7.5 Hz), 7.46-7.22 (9H, m), 7.13 (1H, d, J = 7.5 Hz), 6.87 (4H, d, J = 9.3 Hz), 5.94 (1H, s), 5.26 (1H, d, J = 6.9 Hz), 4.93 (1H, d, J = 6.9 Hz), 4.50-4.38 (1H, m), 4.24 (1H, d, J = 5.1 Hz), 4.12-3.92 (3H, m), 3.81 (6H, s), 3.66 (1H, dd, J = 11.3, 3.0 Hz), 3.54 (1H, dd, J = 11.3, 2.4 Hz), 3.40-3.22 (1H, m), 2.45 (1H, d, J = 9.6 Hz), 2.21 (3H, s)
13C NMR (75.5 MHz, CDCl3) δ 170.7, 162.9, 158.7, 158.7, 155.0, 144.6, 144.2, 135.4, 135.2, 130.1, 128.1, 128.1, 127.2, 122.9 (2C, q, J = 285.2 Hz), 113.3, 96.9, 94.9, 89.5, 87.1, 82.9, 79.8, 67.8, 61.5, 60.7, 55.2, 48.8 (1C, quintet, J = 27.9 Hz), 24.7
MALDI TOF-MS m/z Calcd for C37H37F6N3NaO9 + [M+Na]+ 804.23, found 804.85.
1H NMR (300 MHz, CDCl3) δ 10.35 (1H, brs), 8.56 (0.7H, d, J = 7.8 Hz, diastereomer), 8.49 (0.3H, d, J = 7.8 Hz, diastereomer), 7.48-7.24 (9H, m), 7.05 (0.7H, d, J = 7.8 Hz, diastereomer), 6.95 (0.3H, d, J = 7.8 Hz, diastereomer), 6.90-6.81 (4H, m), 5.98 (1H, s), 5.08-4.96 (2H, m), 4.60-4.42 (1H, m), 4.32-3.98 (4H, m), 3.81 (4.2H, s, diastereomer), 3.80 (1.8H, s, diastereomer), 3.76-3.40 (5H, m), 2.64-2.54 (0.6H, m, diastereomere), 2.42 (1.4H, t, J = 6.3 Hz, diastereomer), 2.23 (2.1H, s, diastereomer), 2.22 (0.9H, s, diastereomer), 1.21-0.96 (14H, m)
31P NMR (121.5 MHz, CDCl3) δ 152.4 (0.3P, s, diastereomer), 150.5 (0.7P, s, diastereomer); ESI TOF-MS m/z Calcd for C46H55F6N5O10P+ [M+H]+ 982.36, found 982.43.
(a)N2-フェノキシアセチル-2'-O-(2-トリフルオロメチル-3,3,3-トリフルオロプロパノキシメチル)-3',5'-O-(1,1,3,3-テトライソプロピルジシロキサン-1,3-ジイル)グアノシン (1g)
13C NMR (75.5 MHz, CDCl3) δ 169.6, 156.4, 155.2, 146.7, 146.3, 136.7, 130.0, 123.1, 122.9 (2C, q, J = 281.5 Hz), 114.8, 94.8, 87.5, 81.4, 78.8, 68.8, 67.1, 61.4, 59.5, 48.8 (1C, quintet, J = 27.9 Hz), 17.4, 17.3, 17.2, 17.0, 16.9, 16.9, 16.8, 13.3, 13.0, 12.9, 12.6
MALDI TOF-MS m/z Calcd for C35H49F6N5NaO9Si2 + [M+Na]+ 876.29, found 876.94.
1H NMR (300 MHz, CDCl3) δ 11.82 (1H, brs), 9.07 (1H, brs), 7.84 (1H,s), 7.46-7.14 (11H, m), 7.08 (1H, t, J = 7.5 Hz), 6.91 (2H, d, J = 7.5 Hz), 6.79 (4H, d, J = 8.7 Hz), 6.05 (1H, d, J = 5.4 Hz), 4.83 (2H, dd, J = 10.8, 7.2 Hz), 4.74 (1H, t, J = 5.1 Hz), 4.62 (2H, s), 4.54-4.46 (1H, m), 4.28-4.21 (1H, m), 3.98 (1H, dd, J = 11.1, 5.4 Hz), 3.82 (1H, dd, J = 11.1, 4.8 Hz), 3.76 (6H, s), 3.46 (1H, dd, J = 10.8, 3.0 Hz), 3.40 (1H, dd, J = 10.8, 4.2 Hz), 3.20-3.02 (1H, m), 2.90 (1H, brs)
13C NMR (75.5 MHz, CDCl3) δ 169.5, 158.6, 156.3, 155.2, 147.9, 146.4, 144.3, 137.3, 135.4, 135.3, 130.0, 123.0, 129.1, 128.1, 128.0, 127.1, 123.0, 122.8 (2C, q, J = 282.3 Hz), 114.8, 113.2, 113.1, 95.8, 86.8, 85.7, 84.1, 80.4, 70.7, 66.8, 63.3, 61.7, 55.2, 48.7(1C, quintet, 27.9 Hz)
MALDI TOF-MS m/z Calcd for C44H41F6N5NaO10 + [M+Na]+ 936.26, found 937.01.
1H NMR (300 MHz, CDCl3) δ 7.88 (0.5H, s, diastereomer), 7.87 (0.5H, s, diastereomer), 7.45-7.16 (11H, m), 7.07 (1H, t, J = 7.5 Hz), 6.93 (1H, d, J = 8.7 Hz, diastereomer), 6.88 (1H, d, J = 8.7 Hz, diastereomer), 6.81 (2H, d, J = 2.3 Hz, diastereomer), 6.78 (2H, d, J = 2.3 Hz, diastereomer), 6.07 (0.5H, d, J = 6.0 Hz, diastereomer), 6.01 (0.5H, d, J = 6.3 Hz, diastereomer), 4.92-4.78 (2H, m), 4.75-4.68 (1H, m), 4.63-4.54 (2H, m), 4.41-4.35 (0.5H, m, diastereomer), 4.32-4.35 (0.5H, m, diastereomer), 4.04-3.28 (7H, m), 3.77 (6H, s), 3.18-3.00 (1H, m), 2.65 (1H, t, J = 6.3 Hz, diastereomer), 2.35 (1H, t, J = 6.3 Hz, diastereomer), 1.44-1.00 (14H, m)
31P NMR (121.5 MHz, CDCl3) δ 151.7 (0.5P, s, diastereomer), 151.6 (0.5P, s, diastereomer); ESI TOF-MS m/z Calcd for C53H59F6N7O11P+ [M+H]+ 1114.39, found 1114.50.
31P NMR (121.5 MHz, CDCl3) δ -1.5 (0.5P, s, diastereomer), -1.7 (0.5P, s, diastereomer).
31P NMR (121.5 MHz, CDCl3) δ -0.9 (0.5P, s, diastereomer), -2.5 (0.5P, s, diastereomer).
MALDI TOF-MS m/z Calcd for C26H30F6N5NaO15P+ [M+Na]+ 820.13, found 820.30.
N6-アセチル-2'-O-(2-トリフルオロメチル-3,3,3-トリフルオロプロパノキシメチル)-5'-O-(4,4'-ジメトキシトリチル)アデノシン 3'-O-((3S,3aR)-3-フェニルヘキサヒドロピローロ [1,2-c][1,3,2]オキサザホスホール-1-イル) ((Sp)-9a)
31P NMR (121.5 MHz, CDCl3) δ 157.2.
例7
例1で得られた化合物(1u)又は化合物(2u)を用いて、保護基の脱離条件を検討した。基質濃度は0.1 Mとし、反応番号4、5、7、及び8については基質濃度を10 mMとした。反応は室温で行い、反応の進行は薄層クロマトグラフィーで確認した。反応条件及び結果を表1に示す(表中、Meはメトキシ基、TBAFはテトラブチルアンモニウムフルオリド、THFはテトラヒドロフラン、DBUは1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン、TMSClはトリメチルシリルクロリド、EtOHはエタノール、Et3Nはトリエチルアミン、DCAはジクロロ酢酸、DCMはジクロロメタン、及びTFAはトリフルオロ酢酸を示す)。表1に示された結果から、本発明の保護基はテトラブチルアンモニウムフルオリドなどのフッ素化合物を作用させることにより、緩和な条件下で極めて速やかに除去できること、及び酸性条件化において安定であることが示された。
Claims (16)
- リボヌクレオシド、リボヌクレオチド、又はそれらの誘導体の2'-位水酸基の保護基であって、下記の一般式(I):
- R1及びR2が共に水素原子である請求項1に記載の保護基。
- R3及びR4が共に水素原子である請求項1又は2に記載の保護基。
- R5及びR6がそれぞれ独立にハロゲン原子又はフルオロ置換C1-6アルキル基である請求項1ないし3のいずれか1項に記載の保護基。
- R5及びR6が同一のフルオロ置換C1-6アルキル基である請求項1ないし3のいずれか1項に記載の保護基。
- R5及びR6が同一のパーフルオロC1-6アルキル基である請求項1ないし3のいずれか1項に記載の保護基。
- R5及びR6が共にトリフルオロメチル基である請求項1ないし3のいずれか1項に記載の保護基。
- リボヌクレオチドの誘導体がホスホロアミダイト化合物である請求項1ないし7のいずれか1項に記載の保護基。
- 2'-位水酸基の酸素原子が請求項1ないし7のいずれか1項に記載の保護基で保護されたリボヌクレオシド、リボヌクレオチド、又はそれらの誘導体。
- ホスホロアミダイト化合物である請求項9に記載のリボヌクレオチドの誘導体。
- ホスホロアミダイト化合物が下記の一般式(II):
- 請求項11又は12に記載のホスホロアミダイト化合物を用いるオリゴリボ核酸の製造方法。
- 請求項1ないし8のいずれか1項に記載の保護基の導入方法であって、R21が水酸基である請求項13に記載の試薬と2'-位水酸基がC1-6アルキルチオメチル基で保護されたリボヌクレオシド、リボヌクレオチド、又はそれらの誘導体とを反応させる工程を含む方法。
- 請求項1ないし8のいずれか1項に記載の保護基の導入方法であって、R21が水酸基以外である請求項13に記載の試薬と2'-位水酸基が保護されていないリボヌクレオシド、リボヌクレオチド、又はそれらの誘導体とを反応させる工程を含む方法。
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CA2744987C (en) | 2008-12-02 | 2018-01-16 | Chiralgen, Ltd. | Method for the synthesis of phosphorus atom modified nucleic acids |
BR112012000828A8 (pt) | 2009-07-06 | 2017-10-10 | Ontorii Inc | Novas pró-drogas de ácido nucleico e métodos de uso das mesmas |
JP5878758B2 (ja) * | 2009-09-16 | 2016-03-08 | 株式会社Wave Life Sciences Japan | Rna及びその誘導体合成のための新規保護基 |
WO2012039448A1 (ja) | 2010-09-24 | 2012-03-29 | 株式会社キラルジェン | 不斉補助基 |
EP2647644B1 (en) * | 2010-11-30 | 2020-09-09 | Wave Life Sciences Japan, Inc. | 2'-o-modified rna |
US9605019B2 (en) | 2011-07-19 | 2017-03-28 | Wave Life Sciences Ltd. | Methods for the synthesis of functionalized nucleic acids |
KR101835401B1 (ko) | 2012-07-13 | 2018-03-08 | 신 니뽄 바이오메디칼 라보라토리즈, 엘티디. | 키랄 핵산 어쥬번트 |
AU2013288048A1 (en) | 2012-07-13 | 2015-01-22 | Wave Life Sciences Ltd. | Asymmetric auxiliary group |
KR20220139425A (ko) | 2012-07-13 | 2022-10-14 | 웨이브 라이프 사이언시스 리미티드 | 키랄 제어 |
US8859754B2 (en) * | 2012-07-31 | 2014-10-14 | Ased, Llc | Synthesis of deuterated ribo nucleosides, N-protected phosphoramidites, and oligonucleotides |
WO2015108048A1 (ja) | 2014-01-15 | 2015-07-23 | 株式会社新日本科学 | 抗腫瘍作用を有するキラル核酸アジュバンド及び抗腫瘍剤 |
US10322173B2 (en) | 2014-01-15 | 2019-06-18 | Shin Nippon Biomedical Laboratories, Ltd. | Chiral nucleic acid adjuvant having anti-allergic activity, and anti-allergic agent |
EP3095461A4 (en) | 2014-01-15 | 2017-08-23 | Shin Nippon Biomedical Laboratories, Ltd. | Chiral nucleic acid adjuvant having immunity induction activity, and immunity induction activator |
PT3094728T (pt) | 2014-01-16 | 2022-05-19 | Wave Life Sciences Ltd | Desenho quiral |
MA43072A (fr) | 2015-07-22 | 2018-05-30 | Wave Life Sciences Ltd | Compositions d'oligonucléotides et procédés associés |
EP3359523A4 (en) | 2015-10-09 | 2019-07-24 | Wave Life Sciences Ltd. | OLIGONUCLEOTIDE COMPOSITIONS AND RELATED METHODS |
AU2017234150B2 (en) | 2016-03-13 | 2021-09-16 | Wave Life Sciences Ltd. | Compositions and methods for phosphoramidite and oligonucleotide synthesis |
EA201892366A1 (ru) | 2016-04-18 | 2019-03-29 | Сарепта Терапьютикс, Инк. | Антисмысловые олигомеры и способы их применения для лечения заболеваний, связанных с геном кислой альфа-глюкозидазы |
EA201892467A1 (ru) | 2016-04-29 | 2019-05-31 | Сарепта Терапьютикс, Инк. | Олигонуклеотидные аналоги, нацеленные на lmna человека |
MA45270A (fr) | 2016-05-04 | 2017-11-09 | Wave Life Sciences Ltd | Compositions d'oligonucléotides et procédés associés |
JP2019520339A (ja) | 2016-06-03 | 2019-07-18 | ウェイブ ライフ サイエンシズ リミテッドWave Life Sciences Ltd. | オリゴヌクレオチド、その組成物および方法 |
KR20190024977A (ko) | 2016-06-30 | 2019-03-08 | 사렙타 쎄러퓨틱스 인코퍼레이티드 | 근육 이상증에 대한 엑손 스킵핑 올리고머 |
WO2018088491A1 (ja) * | 2016-11-14 | 2018-05-17 | 学校法人東京理科大学 | 重合性化合物、化合物、及び、ボラノホスフェートオリゴマーの製造方法 |
JP7296882B2 (ja) | 2016-11-23 | 2023-06-23 | ウェイブ ライフ サイエンシズ リミテッド | ホスホラミダイト及びオリゴヌクレオチド合成のための組成物及び方法 |
MX2019006882A (es) | 2016-12-19 | 2019-08-16 | Sarepta Therapeutics Inc | Conjugados de oligomeros de omision de exon para distrofia muscular. |
BR112019012651A2 (pt) | 2016-12-19 | 2020-01-28 | Sarepta Therapeutics Inc | conjugados de oligômero de salto de éxon para distrofia muscular |
HUE059905T2 (hu) | 2016-12-19 | 2023-01-28 | Sarepta Therapeutics Inc | Exonátugró oligomerkonjugátumok izomdisztrófiára |
WO2018223056A1 (en) | 2017-06-02 | 2018-12-06 | Wave Life Sciences Ltd. | Oligonucleotide compositions and methods of use thereof |
US11597927B2 (en) | 2017-06-02 | 2023-03-07 | Wave Life Sciences Ltd. | Oligonucleotide compositions and methods of use thereof |
US11718638B2 (en) | 2017-06-21 | 2023-08-08 | Wave Life Sciences Ltd. | Compounds, compositions and methods for synthesis |
WO2019032607A1 (en) | 2017-08-08 | 2019-02-14 | Wave Life Sciences Ltd. | OLIGONUCLEOTIDE COMPOSITIONS AND RELATED METHODS |
CN111108096A (zh) | 2017-09-18 | 2020-05-05 | 波涛生命科学有限公司 | 寡核苷酸制备技术 |
EA201991450A1 (ru) | 2017-09-22 | 2019-12-30 | Сарепта Терапьютикс, Инк. | Конъюгаты олигомеров для пропуска экзона при мышечной дистрофии |
JP2020536060A (ja) | 2017-09-28 | 2020-12-10 | サレプタ セラピューティクス, インコーポレイテッド | 筋ジストロフィーを処置するための併用療法 |
EP3687577A1 (en) | 2017-09-28 | 2020-08-05 | Sarepta Therapeutics, Inc. | Combination therapies for treating muscular dystrophy |
WO2019067979A1 (en) | 2017-09-28 | 2019-04-04 | Sarepta Therapeutics, Inc. | POLYTHERAPIES FOR TREATING MUSCLE DYSTROPHY |
EP3694530A4 (en) | 2017-10-12 | 2021-06-30 | Wave Life Sciences Ltd. | OLIGONUCLEOTIDE COMPOSITIONS AND METHOD FOR THEREFORE |
EP3697910A4 (en) | 2017-10-18 | 2021-07-14 | Sarepta Therapeutics, Inc. | ANTISENSE OLIGOMERIC COMPOUNDS |
WO2019208571A1 (ja) * | 2018-04-24 | 2019-10-31 | 住友化学株式会社 | アミダイト化合物及び該化合物を用いたポリヌクレオチドの製造方法 |
US10758629B2 (en) | 2018-05-29 | 2020-09-01 | Sarepta Therapeutics, Inc. | Exon skipping oligomer conjugates for muscular dystrophy |
EP4219717A3 (en) | 2018-06-13 | 2023-12-20 | Sarepta Therapeutics, Inc. | Exon skipping oligomers for muscular dystrophy |
TW202020153A (zh) | 2018-07-27 | 2020-06-01 | 美商薩羅塔治療公司 | 用於肌肉萎縮症之外顯子跳躍寡聚物 |
KR20210104759A (ko) | 2018-12-13 | 2021-08-25 | 사렙타 쎄러퓨틱스 인코퍼레이티드 | 근 이영양증을 위한 엑손 스키핑 올리고머 접합체 |
EP3955966A1 (en) | 2019-04-18 | 2022-02-23 | Sarepta Therapeutics, Inc. | Compositions for treating muscular dystrophy |
JPWO2021070494A1 (ja) * | 2019-10-11 | 2021-04-15 | ||
WO2022147223A2 (en) * | 2020-12-31 | 2022-07-07 | Alnylam Pharmaceuticals, Inc. | 2'-modified nucleoside based oligonucleotide prodrugs |
WO2023055774A1 (en) | 2021-09-30 | 2023-04-06 | Sarepta Therapeutics, Inc. | Antisense oligonucleotides having one or more abasic units |
WO2024064237A2 (en) | 2022-09-21 | 2024-03-28 | Sarepta Therapeutics, Inc. | Dmd antisense oligonucleotide-mediated exon skipping efficiency |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DD133885B1 (de) | 1978-01-04 | 1981-02-25 | Hans Lehmann | Mittel zur bekaempfung von phytopathogenen bakterien und pilzen |
US4542142A (en) | 1982-11-22 | 1985-09-17 | Roussel Uclaf | Insecticidal cyclopropane carboxylic acid derivatives with 3-unsaturated-side chain |
GB0306820D0 (en) * | 2003-03-25 | 2003-04-30 | Ici Plc | Polymerisation of ethylenically unsaturated monomers |
JP4580870B2 (ja) * | 2003-09-02 | 2010-11-17 | 株式会社キラルジェン | リボヌクレオチド又はリボヌクレオチド誘導体の製造方法 |
JP4865544B2 (ja) | 2004-03-25 | 2012-02-01 | 株式会社キラルジェン | 立体規則性の高いリボヌクレオチド類縁体及びデオキシリボヌクレオチド類縁体の製造法 |
EP1795536B1 (en) * | 2004-08-26 | 2012-05-02 | Nippon Shinyaku Co., Ltd. | Phosphoramidite compound and method for producing oligo-rna |
WO2007064291A1 (en) * | 2005-11-30 | 2007-06-07 | Jyoti Chattopadhyaya | Method and compounds for rna synthesis |
JP5878758B2 (ja) * | 2009-09-16 | 2016-03-08 | 株式会社Wave Life Sciences Japan | Rna及びその誘導体合成のための新規保護基 |
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