CN107011400B - 不对称辅助基团 - Google Patents
不对称辅助基团 Download PDFInfo
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- CN107011400B CN107011400B CN201610835862.5A CN201610835862A CN107011400B CN 107011400 B CN107011400 B CN 107011400B CN 201610835862 A CN201610835862 A CN 201610835862A CN 107011400 B CN107011400 B CN 107011400B
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- radical
- aryl
- alkyl
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 90
- 239000012069 chiral reagent Substances 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 150000003254 radicals Chemical class 0.000 claims description 398
- 125000000217 alkyl group Chemical group 0.000 claims description 143
- 108091034117 Oligonucleotide Proteins 0.000 claims description 112
- 150000001875 compounds Chemical class 0.000 claims description 111
- 238000000034 method Methods 0.000 claims description 99
- 239000002777 nucleoside Substances 0.000 claims description 81
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 81
- 239000000178 monomer Substances 0.000 claims description 71
- 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 64
- -1 4-monomethoxytrityl Chemical group 0.000 claims description 56
- 125000003118 aryl group Chemical group 0.000 claims description 46
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 45
- UWCWUCKPEYNDNV-LBPRGKRZSA-N 2,6-dimethyl-n-[[(2s)-pyrrolidin-2-yl]methyl]aniline Chemical compound CC1=CC=CC(C)=C1NC[C@H]1NCCC1 UWCWUCKPEYNDNV-LBPRGKRZSA-N 0.000 claims description 44
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
- 108020004707 nucleic acids Proteins 0.000 claims description 34
- 150000007523 nucleic acids Chemical class 0.000 claims description 34
- 102000039446 nucleic acids Human genes 0.000 claims description 34
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 28
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 28
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 229910052698 phosphorus Inorganic materials 0.000 claims description 20
- 238000009833 condensation Methods 0.000 claims description 18
- 230000005494 condensation Effects 0.000 claims description 18
- 239000012190 activator Substances 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 125000004437 phosphorous atom Chemical group 0.000 claims description 16
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 15
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- 229930024421 Adenine Natural products 0.000 claims description 14
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 229960000643 adenine Drugs 0.000 claims description 14
- 229940104302 cytosine Drugs 0.000 claims description 14
- 229940113082 thymine Drugs 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 11
- 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 11
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 10
- 125000006239 protecting group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 8
- 230000002194 synthesizing effect Effects 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 claims description 6
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 6
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 3
- OKHRRIGNGQFVEE-UHFFFAOYSA-N methyl(diphenyl)silicon Chemical compound C=1C=CC=CC=1[Si](C)C1=CC=CC=C1 OKHRRIGNGQFVEE-UHFFFAOYSA-N 0.000 claims 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 21
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 18
- 125000005843 halogen group Chemical group 0.000 abstract description 17
- 239000000126 substance Substances 0.000 abstract description 6
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 258
- 238000005160 1H NMR spectroscopy Methods 0.000 description 67
- 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 description 50
- 238000004679 31P NMR spectroscopy Methods 0.000 description 47
- ZIPLHLLDHUOMHV-UHFFFAOYSA-N O1C=NC=C1.P Chemical compound O1C=NC=C1.P ZIPLHLLDHUOMHV-UHFFFAOYSA-N 0.000 description 47
- 125000003342 alkenyl group Chemical group 0.000 description 28
- 239000000543 intermediate Substances 0.000 description 28
- 125000000304 alkynyl group Chemical group 0.000 description 27
- 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 25
- 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 25
- 229940029575 guanosine Drugs 0.000 description 25
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 24
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 21
- 235000000346 sugar Nutrition 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 16
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 15
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 125000000623 heterocyclic group Chemical group 0.000 description 11
- 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 10
- 238000010511 deprotection reaction Methods 0.000 description 10
- 125000001072 heteroaryl group Chemical group 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- QQCCOFYRRVMYRV-JSOSNVBQSA-N (1r)-2-(4-methylphenyl)sulfonyl-1-[(2r)-1-tritylpyrrolidin-2-yl]ethanol Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C[C@H](O)[C@@H]1N(C(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)CCC1 QQCCOFYRRVMYRV-JSOSNVBQSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 239000012039 electrophile Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 8
- 125000003710 aryl alkyl group Chemical group 0.000 description 8
- 230000008901 benefit Effects 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- VSYNDOLFWJVQNK-WMZOPIPTSA-N (1r)-2,2-diphenyl-1-[(2s)-pyrrolidin-2-yl]ethanol Chemical compound C=1C=CC=CC=1C([C@@H](O)[C@H]1NCCC1)C1=CC=CC=C1 VSYNDOLFWJVQNK-WMZOPIPTSA-N 0.000 description 7
- CBURWGINZWRUOM-NWDGAFQWSA-N (1r)-2-(4-nitrophenyl)-1-[(2s)-pyrrolidin-2-yl]ethanol Chemical compound C([C@@H](O)[C@H]1NCCC1)C1=CC=C([N+]([O-])=O)C=C1 CBURWGINZWRUOM-NWDGAFQWSA-N 0.000 description 7
- VSYNDOLFWJVQNK-SJLPKXTDSA-N (1s)-2,2-diphenyl-1-[(2r)-pyrrolidin-2-yl]ethanol Chemical compound C=1C=CC=CC=1C([C@H](O)[C@@H]1NCCC1)C1=CC=CC=C1 VSYNDOLFWJVQNK-SJLPKXTDSA-N 0.000 description 7
- CBURWGINZWRUOM-NEPJUHHUSA-N (1s)-2-(4-nitrophenyl)-1-[(2r)-pyrrolidin-2-yl]ethanol Chemical compound C([C@H](O)[C@@H]1NCCC1)C1=CC=C([N+]([O-])=O)C=C1 CBURWGINZWRUOM-NEPJUHHUSA-N 0.000 description 7
- IMSIQOPPUWTOCM-WMZOPIPTSA-N (r)-9h-fluoren-9-yl-[(2s)-pyrrolidin-2-yl]methanol Chemical compound C([C@H]1[C@H](O)C2C3=CC=CC=C3C3=CC=CC=C32)CCN1 IMSIQOPPUWTOCM-WMZOPIPTSA-N 0.000 description 7
- 125000002252 acyl group Chemical group 0.000 description 7
- 230000000903 blocking effect Effects 0.000 description 7
- 239000011669 selenium Substances 0.000 description 7
- 150000008163 sugars Chemical class 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 5
- 238000006731 degradation reaction Methods 0.000 description 5
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 125000003729 nucleotide group Chemical group 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 239000011593 sulfur Substances 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- QQCCOFYRRVMYRV-IOWSJCHKSA-N (1s)-2-(4-methylphenyl)sulfonyl-1-[(2s)-1-tritylpyrrolidin-2-yl]ethanol Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C[C@@H](O)[C@H]1N(C(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)CCC1 QQCCOFYRRVMYRV-IOWSJCHKSA-N 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 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 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 4
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 4
- 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 description 4
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 125000004104 aryloxy group Chemical group 0.000 description 4
- FSVANWBUZWHNNV-UHFFFAOYSA-N benzyl(methyl)silane Chemical compound C[SiH2]CC1=CC=CC=C1 FSVANWBUZWHNNV-UHFFFAOYSA-N 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 125000004452 carbocyclyl group Chemical group 0.000 description 4
- 125000005884 carbocyclylalkyl group Chemical group 0.000 description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 4
- 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 4
- 125000003709 fluoroalkyl group Chemical group 0.000 description 4
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 230000000069 prophylactic effect Effects 0.000 description 4
- 229910052711 selenium Inorganic materials 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 229940035893 uracil Drugs 0.000 description 4
- FJPKCRYEBMRPMW-XZWHSSHBSA-N (1R)-2-(4-nitrophenyl)-1-[(2S)-1-tritylpyrrolidin-2-yl]ethanol Chemical compound [N+](=O)([O-])C1=CC=C(C=C1)C[C@@H](O)[C@H]1N(CCC1)C(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 FJPKCRYEBMRPMW-XZWHSSHBSA-N 0.000 description 3
- CPQGQIUKYVZJQB-GIWKVKTRSA-N (1r)-2,2-diphenyl-1-[(2s)-1-tritylpyrrolidin-2-yl]ethanol Chemical compound C=1C=CC=CC=1C([C@@H](O)[C@H]1N(CCC1)C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 CPQGQIUKYVZJQB-GIWKVKTRSA-N 0.000 description 3
- BGWFJHBPHRTUOJ-HSZRJFAPSA-N (2r)-1-tritylpyrrolidine-2-carbaldehyde Chemical compound O=C[C@H]1CCCN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 BGWFJHBPHRTUOJ-HSZRJFAPSA-N 0.000 description 3
- BGWFJHBPHRTUOJ-QHCPKHFHSA-N (2s)-1-tritylpyrrolidine-2-carbaldehyde Chemical compound O=C[C@@H]1CCCN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 BGWFJHBPHRTUOJ-QHCPKHFHSA-N 0.000 description 3
- ACQLNNLTRUKJEH-GIWKVKTRSA-N (R)-9H-fluoren-9-yl-[(2S)-1-tritylpyrrolidin-2-yl]methanol Chemical compound C1=CC=CC=2C3=CC=CC=C3C(C12)[C@@H](O)[C@H]1N(CCC1)C(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 ACQLNNLTRUKJEH-GIWKVKTRSA-N 0.000 description 3
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical group OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 description 3
- LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical compound CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 description 3
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- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 125000005545 phthalimidyl group Chemical group 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- 230000009257 reactivity Effects 0.000 description 1
- TZSZZENYCISATO-WIOPSUGQSA-N rodatristat Chemical compound CCOC(=O)[C@@H]1CC2(CN1)CCN(CC2)c1cc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)nc(N)n1 TZSZZENYCISATO-WIOPSUGQSA-N 0.000 description 1
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 238000005987 sulfurization reaction Methods 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- KTQKOGBTMNDCFG-UHFFFAOYSA-N tert-butyl(diphenyl)silicon Chemical compound C=1C=CC=CC=1[Si](C(C)(C)C)C1=CC=CC=C1 KTQKOGBTMNDCFG-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- MPLHNVLQVRSVEE-UHFFFAOYSA-N texas red Chemical compound [O-]S(=O)(=O)C1=CC(S(Cl)(=O)=O)=CC=C1C(C1=CC=2CCCN3CCCC(C=23)=C1O1)=C2C1=C(CCC1)C3=[N+]1CCCC3=C2 MPLHNVLQVRSVEE-UHFFFAOYSA-N 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
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- OHSJPLSEQNCRLW-UHFFFAOYSA-N triphenylmethyl radical Chemical compound C1=CC=CC=C1[C](C=1C=CC=CC=1)C1=CC=CC=C1 OHSJPLSEQNCRLW-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明提供一种手性试剂或其盐，其中所述手性试剂具有下述化学式(I)。在式(I)中，G1和G2独立地为氢原子、硝基(‑NO2)、卤素原子、氰基(‑CN)、式(Ⅱ)或(Ⅲ)的基团，或G1和G2结合在一起形成的式(Ⅳ)的基团。
Description
本申请是于2013年7月12日申请的申请号为201380037512.9的发明专利申请“不对称辅助基团”的分案申请。
技术领域
本发明涉及用于合成立体控制的磷原子修饰的寡核苷酸衍生物的手性试剂。
背景技术
日本专利JP2005-89441A中公开了一种名为恶唑磷烷方法(oxazaphospholidinemethod)的用于生产核苷酸衍生物的方法。然而，该方法中单体的分离率低，并且需要特殊的非市售的封端剂。后期得到的单体不具有化学稳定性。此外，寡核苷酸衍生物的分离率不高。寡核苷酸衍生物的低收率被认为是由脱保护步骤下的降解反应引起的。
国际公开第WO2010/064146号小册子公开了一种生产核苷酸衍生物的方法。其中公开的方法需要特殊的非市售的封端剂。此外，寡核苷酸衍生物的分离率不高。该低产量被认为是由脱保护步骤下降解反应所引起的。当寡核苷酸衍生物的长度增长时，该趋势变得极度明显。
国际公开第WO2012/039448号小册子公开了一种用于生产立体控制的磷原子修饰的寡核苷酸衍生物的不对称辅助基团。
引用列表
专利文献
[专利文献1]JP 2005-89441 A专利文献1
[专利文献2]WO2010/064146 A专利文献2
[专利文献3]WO2012/039448 A专利文献3
发明内容
本发明的第一个方面涉及一种手性试剂或其盐。所述手性试剂有如下化学式(I)：
在(I)式中，G1和G2独立地为氢原子、硝基、卤素原子、氰基、式(II)、(III)或(V)的基团，或者G1和G2结合在一起形成式(IV)的基团。
在(II)式中，G21～G23独立地为氢原子、硝基、卤素原子、氰基或C1-3烷基。
在(III)式中，G31～G33独立地为C1-4烷基、C6-14芳基、C1-4烷氧基、C7-14芳烷基、C1-4烷基C6-14芳基、C1-4烷氧基C6-14芳基或C6-14芳基C1-4烷基。
在(IV)式中，G41～G46独立地为氢原子、硝基、卤素原子、氰基或C1-3烷基。
在(V)式中，G51～G53独立地为氢原子、硝基、卤素原子、氰基、C1-3烷基或C1-3烷氧基。
G3和G4独立地为氢原子、C1-3烷基、C6-14芳基或者G3和G4连同式(I)中的NH部分结合在一起形成包含3～16个碳原子的含杂原子的环。
作为一个优选实施例，该手性试剂有如下化学式(I')。
在式(I')中G1和G2与上文所述相同。即，G1和G2独立地为氢原子、硝基、卤素原子、氰基，式(II)或式(III)的基团，或者G1和G2结合在一起形成式(IV)的基团。
作为一个优选实施例，该手性试剂有化学式(I')并且G1和G2各为式(II)的基团，其中G21～G23独立地为氢原子、硝基、卤素原子、氰基或C1-3烷基。
作为一个优选实施例，该手性试剂有化学式(I')并且G1和G2各为式(II)的基团，G21～G23各为氢原子。
作为一个优选实施例，该手性试剂有化学式(I')并且G1为氢原子，G2为式(II)的基团，并且G21～G23独立地为氢原子、硝基、卤素原子、氰基或C1-3烷基。
作为一个优选实施例，该手性试剂有化学式(I')并且G1为氢原子，G2为式(II)的基团，G21和G22各为氢原子，G23为硝基。
作为一个优选实施例，该手性试剂有化学式(I')并且G1为氢原子，G2为式(III)的基团，并且G31～G33独立地为C1-4烷基、C6-14芳基、C7-14芳烷基、C1-4烷基C6-14芳基、C1-4烷氧基C6-14芳基或C6-14芳基C1-4烷基。
作为一个优选实施例，该手性试剂有化学式(I')并且G1为氢原子，G2为式(III)的基团，并且G31～G33独立地为C1-4烷基、C6芳基、C7-10芳烷基、C1-4烷基C6芳基、C1-4烷氧基C6-14芳基或C6芳基C1-4烷基。
作为一个优选实施例，该手性试剂有化学式(I')并且G1为氢原子，G2为式(III)的基团，并且G31～G33独立地为C1-4烷基或C6芳基。C1-4烷基的实例是甲基、乙基、正丙基、异丙基、正丁基和叔丁基。
作为一个优选实施例，该手性试剂有化学式(I')并且G1为氢原子，G2为式(III)的基团，并且G31～G33独立地为C1-4烷基。
作为一个优选实施例，该手性试剂有化学式(I')并且G1为氢原子，G2为式(III)的基团，并且G31～G33独立地为C6芳基，G32为C1-4烷基。
作为一个优选实施例，该手性试剂有化学式(I')并且G1和G2结合在一起形成式(IV)的基团，G41～G46独立地为氢原子、硝基、卤素原子、氰基或C1-4烷基。
作为一个优选实施例，该手性试剂有化学式(I')并且G1和G2结合在一起形成式(IV)的基团，其中，G41～G46各为氢原子。
作为一个优选实施例，该手性试剂有化学式(I')并且G1为氢原子，G2为式(V)的基团。进一步地，G51～G53各独立地为氢原子、硝基、甲基或甲氧基。作为更优选的实施例，G1为氢原子，G2为式(V)的基团，其中，G51和G52各为氢原子，G53为4-甲基。
作为一个优选实施例，手性试剂从III-a、III-b、V-a、VII-a、VII-b、IX-a、IX-b、XI-a、XIII-a和XIII-b中选择一个：
(S)-2-(甲基二苯基硅烷)-1-((S)-吡咯烷-2-基)乙醇(Ⅲ-a)
(R)-2-(甲基二苯基硅烷)-1-((R)-1-吡咯烷-2-基)乙醇(Ⅲ-b)
(S)-2-(三甲基硅烷)-1-((S)-1-吡咯烷-2-基)乙醇(V-a)
(R)-2,2-二苯基-1-((S)-吡咯烷-2-基)乙醇(Ⅶ-a)
(S)-2,2-二苯基-1-((R)-吡咯烷-2-基)乙醇(Ⅶ-b)
(R)-2-(4-硝基苯基)-1-((S)-吡咯烷-2-基)乙醇(Ⅸ-a)
(S)-2-(4-硝基苯基)-1-((R)-吡咯烷-2-基)乙醇(Ⅸ-b)
(R)-(9H-芴-9-基)((S)-吡咯烷-2-基)甲醇(Ⅺ-a)
(S)-2-对甲苯磺酰基-1-((S)-1-三苯甲基吡咯烷-2-基)乙醇(ⅩⅢ-a)
(R)-2-对甲苯磺酰基-1-((R)-1-三苯甲基吡咯烷-2-基)乙醇(ⅩⅢ-b)
本发明的第二个方面涉及由式(Va)或(Vb)表示的核苷3'-亚磷酰胺衍生物。
在式(Va)和(Vb)中，G1～G4与上述相同，G5是羟基的保护基团，且Bs是从由下式(Ⅵ)～(Ⅺ)表示的基团或其衍生物中选出的基团。
Bs的实例为腺嘌呤、胸腺嘧啶、胞嘧啶、鸟嘌呤、尿嘧啶、5-甲基胞嘧啶或其衍生物。
R2为氢、-OH、-SH、-NRdRd、-N3、卤素、烷基、烯基、炔基、烷基-Y1-、烯基-Y1-、炔基-Y1-、芳基-Y1-、杂芳基-Y1-、-ORb或-SRb，其中Rb是一个阻断部分。
Y1是O、NRd、S或Se。
Rd独立地为氢、烷基、烯基、炔基、芳基、酰基、被取代的甲硅烷基、氨基甲酸酯、-P(O)(Re)2或-HP(O)(Re)。
Re独立地为氢、烷基、芳基、烯基、炔基、烷基-Y2-、烯基-Y2-、炔基-Y2-、芳基-Y2-，或杂芳基-Y2-，或阳离子Na+，Li+或K+。
Y2是O、NRd或S。
R3是-CH2-、-(CH2)2-、-CH2NH-或-CH2N(CH3)-表示的基团。
G5的实例是三苯甲基、4-单甲氧基三苯甲基、4,4'-二甲氧基三苯甲基、4,4'，4”-三甲氧基三苯甲基，9-苯基黄嘌呤-9-基(Pixyl)和9-(对甲氧基苯基)黄嘌呤-9-基(MOX)。
第二方面的优选实施例是，核苷3'-亚磷酰胺衍生物由式(VA')或(Vb')表示。
在式(VA')和(Vb')中，G1、G2、G5、Bs、R2和R3与上述相同。
本发明的第三方面涉及一种用于合成立体控制的磷原子修饰的寡核苷酸衍生物的方法。
第一步是包括非手性H-膦酸酯部分的分子与第一活化剂以及手性试剂或其盐反应，以形成一个单体的步骤。所述手性试剂具有化学式(I)或(I')，所述单体可由式(Va)、(Vb)、(Va')或(Vb')表示。所述单体与第二活化剂以及核苷发生反应，以形成缩合中间体。下一步骤是将缩合中间体转化为包含手性的X膦酸酯部分的核酸的步骤。
根据本发明的方法，可使用稳定的和市售的材料作为起始原料。可使用非手性起始原料产生立体控制的磷原子修饰的寡核苷酸衍生物。
如一个实施例中所示，本发明的方法不会导致脱保护步骤下的降解。此外，该方法不要求特殊的封端剂，以产生磷原子修饰的寡核苷酸衍生物。
本发明的第四方面涉及一种用于通过使用手性单体合成立体控制的磷原子修饰的寡核苷酸的衍生物的方法。
第一步是由式(Va)、(Vb)、(Va')或(Vb')表示的核苷3'-亚磷酰胺衍生物与第二活化剂以及核苷的反应，以形成缩合中间体。第二步是将所述缩合中间体转化为包含手性的X膦酸酯部分的核酸。
[引用并入]
正如每个单独的出版物或专利申请被特定单独地说明通过引用并入本文，本说明书在此公开的所有出版物和专利申请，以相同的程度通过引用将其全文并入本文。
附图说明
图1是通过使用4b的单体来生产寡核苷酸衍生物的UPLC图谱。
图2是通过使用25的单体来生产寡核苷酸衍生物的UPLC图谱。
具体实施方式
术语“核酸”包括：多聚核糖核苷酸或寡核糖核苷酸(RNA)、以及多聚脱氧核糖核苷酸或寡脱氧核糖核苷酸(DNA)；由核碱基和/或修饰的核碱基的N-糖苷或C-糖苷衍生的RNA或DNA；由糖和/或修饰的糖衍生的核酸；由磷酸桥和/或修饰的磷原子桥衍生的核酸。该术语包括含有核碱基、修饰的核碱基、糖、修饰的糖、磷酸桥或修饰的磷原子桥的任何组合的核酸。术语“核酸”的实例包括，并且不限于，含有核糖部分的核酸、含有脱氧核糖部分的核酸、同时含有核糖和脱氧核糖部分的核酸、含有核糖和修饰核糖部分的核酸。前缀“多聚”是指含有约1～10,000个核苷酸单体单元的核酸，并且其中，前缀“寡聚”是指包含约1～200个核苷酸单体单元的核酸。
术语“核碱基”是指参与以序列特异性的方式将一条核酸链与另一条互补链结合的氢键结合的核酸的部分。最常见的天然存在的核碱基是腺嘌呤(A)、鸟嘌呤(G)、尿嘧啶(U)、胞嘧啶(C)、5-甲基胞嘧啶和胸腺嘧啶(T)。
术语“修饰的核碱基”是指可以取代核碱基的部分。所述修饰核碱基模仿该核碱基的空间排列、电子特性或其它一些物理化学性质，并保留以序列特异性的方式将一条核酸链与另一条核酸链结合的氢键结合的性质。修饰的核碱基可以与所有5个天然存在的碱基(尿嘧啶、胸腺嘧啶、腺嘌呤、胞嘧啶或鸟嘌呤)配对而基本上不影响熔解行为、被胞内酶的识别或寡核苷酸双链体的活性。
术语“核苷”是指其中核碱基或修饰的核碱基与糖或修饰的糖共价结合的部分。
术语“糖”是指处于封闭的和/或开放的形式的单糖。糖包括，但不限于，核糖、脱氧核糖、呋喃戊糖、吡喃戊糖和吡喃己糖部分。
术语“修饰的糖”是指可以替代糖的部分。所述修饰的糖模拟糖的空间排列、电子特性或其它一些物理化学性质。
术语“核苷酸”是指其中核碱基或修饰核碱基与糖或修饰的糖共价连接，且糖或修饰的糖与磷酸基团或修饰的磷原子的部分共价连接的部分。
术语“手性试剂”是指是手性的或对映异构纯(enantiopure)的，并可用于核酸合成中不对称诱导的化合物。
术语“手性配体”或“手性助剂”是指手性或对映异构纯的，并控制反应的立体化学结果的部分。
在缩合反应中，术语“活性剂”是指一种激活反应活性较小的位点并使其更容易被亲核试剂攻击的试剂。
术语“阻断部分”是指一组瞬间屏蔽官能团的反应活性的部分。该官能团可以通过除去阻断部分之后被解除屏蔽。
术语“硼化剂”、“硫亲电试剂”、“硒亲电试剂”指的是在修饰步骤中可用于分别引入BH3、S和Se的基团，来修饰磷原子的化合物。
术语“部分(moiety)”是指特定的分子的片段或官能团。化学部分通常被认为是嵌入或附加于分子的化学实体。
术语“固体支持物”是指能使合成核酸大量生产，并且可以根据需要再利用的任何支持物。如本文所用，该术语是指不溶于在进行合成核酸的反应步骤中使用的介质，并且被衍生以包括反应基团的聚合物。
术语“连接部分”是指任选位于末端核苷和固体支持物之间或在末端核苷和另一个核苷、核苷酸或核酸之间的任何部分。
如本文所用，“治疗”或“缓解”或“改善”在本文可互换使用。这些术语指的是一种用于获得有益或预期的效果，包括但不限于治疗益处和/或预防益处的方法。治疗益处意味着接受治疗的潜在疾病的根除或改善。另外，可通过一种或多种与潜在疾病相关的生理症状的根除或改善来获得治疗益处，这样尽管该患者仍然可能患有该潜在疾病，但可观察到其症状的改善。对于预防益处，所述组合物可以施用于处于患有某种特定疾病的风险的患者，或者可以施用于尽管可能并没有被诊断为某种疾病，但被报告出现一个或多个该疾病的生理症状的患者。
如本文所用，术语“治疗效果”，包括上述治疗益处和/或预防益处。所述预防益处包括延迟或消除疾病或病症的出现，延迟或消除疾病或病症的症状的发作，减缓、停止或逆转疾病或病症的发展，或上述任意组合。
“烷基”基团是指脂肪族烃基。烷基部分可以为饱和的烷基基团(指其不含有任何不饱和单元，例如碳-碳双键或碳-碳三键)，或烷基部分可以为不饱和的烷基基团(指其含有至少一个不饱和单元)。不论是饱和的或不饱和的烷基部分，其可以是支链、直链或包括环状部分。烷基的连接点是在不属于环的一部分的碳原子上。
“烷基”部分可含有1～10个碳原子(尽管本定义还涵盖了术语“烷基”在没有规定的数值范围的出现，但本文中无论何时出现如“1～10”这样的数值范围，均指在给定范围内的每个整数；例如，“1～10个碳原子”是指烷基基团可以由1个碳原子、2个碳原子、3个碳原子等，多至并包括10个碳原子组成)。烷基包括支链和直链的烷基基团。本文所述的化合物的烷基基团可以规定为“C1-C6烷基”或是类似的规定。仅仅用来举例，“C1-C6烷基”表示在烷基链中有一个、两个、三个、四个、五个或六个碳原子，也就是说，该烷基链选自于甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基。典型的烷基，包括但不应以任何方式限于，甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基、烯丙基、环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基和它们的类似物。在本发明的一个方面中，烷基是C1-C6烷基。
C1-3烷基是指具有1～3个碳原子的直链或支链烷基基团。C1-3烷基的实例是甲基、乙基、丙基和异丙基。C1-4烷基是指具有1～4个碳原子的直链或支链烷基基团。C1-4烷基的实例是甲基、乙基、丙基、异丙基、丁基、异丁基和叔丁基。
如本文所用，术语“芳基”是指其中每个形成环的原子均为碳原子的芳香环。芳基环由五个、六个、七个、八个、九个或九个以上碳原子形成。芳基可为取代或未取代的。在本发明的一个方面中，芳基为苯基或萘基。根据其结构，芳基基团可以是单自由基(monoradical)或双自由基(diradical)(即亚芳基)。在本发明的一个方面中，芳基是C6-C10芳基。
C6-14芳基是指具有6～14个碳原子的芳基。C6-14芳基的实例是苯基、联苯基、萘基、蒽基、茚满基、邻苯二甲酰亚胺、萘酰亚胺基(naphthimidyl)、菲啶基和四氢萘基。
术语“芳烷基”是指被芳基取代的烷基。合适的芳烷基包括均可任选被取代的苄基、吡啶甲基以及它们的类似物。
“酰基部分”是指烷基-(C＝O)、芳基-(C＝O)或芳烷基-(C＝O)基团。酰基部分可以有一个插入羰基和烃基基团之间的中间部分(Y)，其为氧基、氨基、硫基或硒基。例如，酰基基团可以是烷基-Y-(C＝O)、芳基-Y-(C＝O)或芳烷基-Y-(C＝O)。
“烯基”基团是含有至少一个碳-碳双键的直链、支链以及环状的烃基。烯基可以被取代。
“炔基”基团是含有至少一个碳-碳三键的直链、支链以及环状的烃基。炔基可以被取代。
“烷氧基”基团指连接氧的烷基，即(烷基)-O-基团，其中烷基如本文所定义。实例包括甲氧基(-OCH3)或乙氧基(-OCH2CH3)基团。
“烯氧基”基团是指连接氧的烯基，即(烯基)-O-基团，其中烯基如本文所定义。
“炔氧基”基团指连接氧的炔基，即(炔基)-O-基团，其中炔基如本文所定义。
“芳氧基”基团指连接氧的芳基，即(芳基)-O-基团，其中该芳基如本文所定义。实例包括苯氧基(-OC6H5)基团。
术语“烷硒基”是指具有与其相连的取代的硒基的烷基，即(烷基)-Se-基团，其中烷基如本文所定义。
术语“烯硒基”是指具有与其相连的取代的硒基的烯基，即(烯基)-Se-基团，其中烯基如本文所定义。
术语“炔硒基”是指具有与其相连的取代的硒基的炔基，即(炔基)-Se-基团，其中炔基如本文所定义。
术语“烷硫基”是指连接到一个桥联硫原子的烷基，即(烷基)-S-基团，其中烷基如本文所定义。例如，烷硫基是甲硫基及其类似物。
术语“烯硫基”指的是连接到一个桥联硫原子的烯基，即(烯基)-S-基团，其中烯基如本文所定义。
术语“炔硫基”指的是连接到一个桥联硫原子的炔基，即(炔基)-S-基团，其中炔基如本文所定义。
术语“烷氨基”指的是被至少一个烷基替代的氨基，即-NH(烷基)或-N(烷基)2，其中烷基如本文所定义。
术语“烯氨基”指的是被至少一个烯基替代的氨基，如-NH(烯基)或-N(烯基)2，其中烯基如本文所定义。
术语“炔氨基”指的是被至少一个炔基替代的氨基，如-NH(炔基)或-N(炔基)2，其中炔基如本文所定义。
术语“卤素”是指包括氟、氯、溴和碘。
“荧光基团”是指一种当被具有所选波长的光激发时，发射不同波长的光的分子。荧光基团包括，但不限于，吲哚基、荧光素、四甲基罗丹明、德克萨斯红、氟化硼二吡咯(BODIPY)、5-(2-氨基乙氨基)-1-萘磺酸(EDANS)、香豆素和荧光黄。
“铵离子”指化学式NH4 +的带正电荷的多原子阳离子。
“烷基铵离子”指至少有一个氢原子被烷基取代的铵离子，其中烷基如本文所定义。实例包括三乙基铵离子，N，N-二异丙基乙基铵离子。
“亚铵离子”具有通式结构R2C＝NR2 +。所述R基团是指如本文所定义的烷基、烯基、炔基、芳基。“杂芳族亚铵离子”指的是其中氮及其连接的R基团形成杂芳环的亚铵离子。“杂环亚铵离子”是指其中氮及其连接的R基团形成杂环的亚铵离子。
除非本说明书内另有具体所指，术语“氨基”或“胺”指的是-N(Rh)2自由基基团，其中每个Rh独立地为氢、烷基、氟烷基、碳环基、碳环基烷基、芳基、芳烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基。当-N(Rh)2基团具有两个非氢的Rh时，它们可以与氮原子组合形成四、五、六或七元环。例如，-N(Rh)2是指包括，但不限于，1-吡咯烷基和4-吗啉基。任何一个或多个的氢、烷基、氟烷基、碳环基、碳环基烷基、芳基、芳烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基可任选地被一个或多个取代基取代，该取代基独立地为烷基、杂烷基、烯基、炔基、环烷基、杂环烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、羟基、卤素、氰基、三氟甲基、三氟甲氧基、硝基、三甲基硅烷、-ORi、-SRi、-OC(O)Ri、-N(Ri)2、-C(O)Ri、-C(O)ORi、-OC(O)N(Ri)2、-C(O)N(Ri)2、-N(Ri)C(O)OR、-N(Ri)C(O)Ri、-N(Ri)C(O)N(Ri)2、N(Ri)C(NRi)N(Ri)2、-N(Ri)S(O)tRi(其中t为1或2)、-S(O)或-S(O)tN(Ri)2(其中t为1或2)，其中每个Ri独立地为氢、烷基、氟烷基、碳环基、碳环基烷基、芳基、芳烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基。
本文使用的“氨基甲酸酯”是指连接到含有式-C(O)OR的氨基的部分，其中R是烷基、氟烷基、碳环基、碳环基烷基、芳基、芳烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基。实例包括但不限于Boc(叔丁基-OC(O)-)、CBz(苯甲基-OC(O)-)、Teoc((CH3)3SiCH2CH2OC(O)-)，alloc(烯丙基-OC(O)-)或Fmoc(9-芴甲基-OC(O)-)基团。
如本文所用的“取代的甲硅烷基”是指具有式R3Si-的部分。实例包括，但不限于，TBDMS(叔丁基二甲基硅烷基)、TBDPS(叔丁基二苯基硅烷基)或TMS(三甲基硅烷基)。
术语“巯基”指-SH基团，并包括被取代的巯基，即-SRJ基团，其中RJ各独立地为如本文所定义的被取代或未被取代的烷基、环烷基、烯基、炔基、芳基、芳烷基、杂环基或杂环基。
本发明的第一方面涉及一种手性试剂或其盐。所述手性试剂具有下述化学式(I)。术语“手性试剂”是指用于产生立体控制的磷原子修饰的核苷酸或寡核苷酸衍生物的化学组合物。手性试剂与核苷酸反应以形成手性中间体。
在(I)式中，G1和G2独立地为氢原子、硝基、卤素原子、氰基、式(II)、(III)或(V)的基团，或者G1和G2结合在一起形成式(IV)的基团。
在(II)式中，G21～G23独立地为氢原子、硝基、卤素原子、氰基或C1-3烷基。G21～G23的优选实例为氢原子。
在(III)式中，G31～G33独立地为C1-4烷基、C6-14芳基、C1-4烷氧基、C7-14芳烷基、C1-4烷基C6-14芳基、C1-4烷氧基C6-14芳基或C6-14芳基C1-4烷基。
C1-4烷基C6-14芳基的实例是甲基苯基和乙基苯基。C1-4烷氧基C6-14芳基的实例是甲氧基苯基和乙氧基苯基。C6-14芳基C1-4烷基的实例是苄基和苯乙基。G31～G33的优选实例独立地为甲基和苯基。
在(IV)式中，G41～G46独立地为氢原子、硝基、卤素原子、氰基或C1-3烷基。G41～G46的优选实例为氢原子。
在式(V)中，G51～G53独立地为氢原子、硝基、卤素原子、氰基、C1-3烷基或C1-3烷氧基。
G3和G4独立地为氢原子、C1-3烷基、C6-14芳基或者G3和G4结合在一起形成含有3～16个碳原子的含杂原子的环。G3和G4的优选实例是G3和G4结合在一起与式(I)中的NH部分形成含有3～16个碳原子的含杂原子的环。
作为一个优选的实施例，所述手性试剂具有下述化学式(I')。
在式(Ⅰ')中，G1和G2与上述相同，且G1和G2独立地为氢原子、硝基、卤素原子、氰基、式(Ⅱ)或(Ⅲ)的基团，或G1和G2结合在一起形成式(Ⅳ)的基团。
作为一个优选的实施例，所述手性试剂具有化学式(I')，且G1和G2各为式(II)的基团，其中G21～G23独立地为氢原子、硝基、卤素原子、氰基或C1-3烷基。
作为一个优选的实施例，所述手性试剂具有化学式(I')，且G1和G2各为式(II)的基团，G21～G23各为氢原子。
作为一个优选的实施例，所述手性试剂具有化学式(I')，且G1是氢原子，G2为式(II)的基团，G21～G23独立地为氢原子、硝基、卤素原子、氰基或C1-3烷基。
作为一个优选的实施例，所述手性试剂具有化学式(I')，且G1是氢原子，G2为式(II)的基团，G21和G22各为氢原子，G23是硝基(-NO2)。
作为一个优选的实施例，所述手性试剂具有化学式(I')，且G1是氢原子，G2为式(Ⅲ)的基团，G31～G33独立地为C1-4烷基、C6-14芳基、C7-14芳烷基、C1-4烷基C6-14芳基、C1-4烷氧基C6-14芳基或C6-14芳基C1-4烷基。
作为一个优选的实施例，所述手性试剂具有化学式(I')，且G1是氢原子，G2为式(Ⅲ)的基团，G31～G33独立地为C1-4烷基、C6芳基、C7-10芳烷基、C1-4烷基C6芳基、C1-4烷氧基C6芳基或C6芳基C1-4烷基。
作为一个优选的实施例，所述手性试剂具有化学式(I')且G1是氢原子，G2为式(Ⅲ)的基团，G31～G33独立地为C1-4烷基或C6芳基(苯基)。C1-4烷基的实例是甲基、乙基、正丙基、异丙基、正丁基和叔丁基。
作为一个优选的实施例，所述手性试剂具有化学式(I')，且G1是氢原子，G2为式(Ⅲ)的基团，G31～G33独立地为C1-4烷基。
作为一个优选的实施例，所述手性试剂具有化学式(I')，且G1是氢原子，G2为式(Ⅲ)的基团，G31和G33为C6芳基(苯基)，G32为C1-2烷基。
作为一个优选的实施例，所述手性试剂具有化学式(I')，且G1和G22一起形成式(Ⅳ)的基团，G41～G46独立地为氢原子、硝基、卤素原子、氰基或C1-3烷基。
作为一个优选的实施例，所述手性试剂具有化学式(I')，且G1和G2一起形成式(Ⅳ)的基团，其中G41～G46各为氢原子。
作为一个优选的实施例，所述手性试剂具有化学式(I')，且G1是氢原子，G2为式(V)的基团。进一步地，G51～G53各独立地为氢原子、硝基、甲基或甲氧基。作为更优选的实施例，G1是氢原子，G2为式(V)的基团，其中，G51和G52各为氢原子，G53是4-甲基。
作为一个优选的实施例，所述手性试剂从III-a、III-b、V-a、VII-a、VII-b、IX-a、IX-b、XI-a、XIII-a和XIII-b中选择的一个：
(S)-2-(甲基二苯基硅烷)-1-((S)-吡咯烷-2-基)乙醇(Ⅲ-a)
(R)-2-(甲基二苯基硅烷)-1-((R)-1-吡咯烷-2-基)乙醇(Ⅲ-b)
(S)-2-(三甲基硅烷)-1-((S)-1-吡咯烷-2-基)乙醇(Va)
(R)-2,2-二苯基-1-((S)-吡咯烷-2-基)乙醇(Ⅶ-a)
(S)-2,2-二苯基-1-((R)-吡咯烷-2-基)乙醇(Ⅶ-b)
(R)-2-(4-硝基苯基)-1-((S)-吡咯烷-2-基)乙醇(Ⅸ-a)
(S)-2-(4-硝基苯基)-1-((R)-吡咯烷-2-基)乙醇(Ⅸ-b)
(R)-(9H-芴-9-基)((S)-吡咯烷-2-基)甲醇(Ⅺ-a)
(S)-2-对甲苯磺酰基-1-((S)-1-三苯甲基吡咯烷-2-基)乙醇(ⅩⅢ-a)
(R)-2-对甲苯磺酰基-1-((R)-1-三苯甲基吡咯烷-2-基)乙醇(ⅩⅢ-b)
手性试剂与核酸或修饰核酸反应，生成不对称辅助基团。通过手性试剂与核酸或修饰核酸反应，得到核苷3'-亚磷酰胺衍生物，其为生产立体控制的磷原子修饰的寡核苷酸衍生物的中间体。
本发明的第二个方面涉及由式(Va)或(Vb)表示的核苷3'-亚磷酰胺衍生物。式(Va)和(Vb)的化合物被称为用于合成寡核苷酸衍生物的单体。这些化合物也被称为恶唑磷烷(oxazaphospholidine)单体。由式(Vb)代表的化合物的糖部分被称为BNA和LNA(当R3是亚甲基时)。
在式(Va)和(Vb)，G1～G4与上述相同，G5是羟基的保护基，且Bs从由式(VI)～(Ⅺ)或它们的衍生物表示的基团中选取。
Bs的实例为腺嘌呤、胸腺嘧啶、胞嘧啶、鸟嘌呤、尿嘧啶、5-甲基胞嘧啶、或它们的衍生物。
R2为氢、-OH、-SH、-NRdRd、-N3、卤素、烷基、烯基、炔基、烷基-Y1-、烯基-Y1-、炔基-Y1-、芳基-Y1-、杂芳基-Y1-、-ORb,或-SRb，其中Rb为阻断部分。
Y1为O、NRd、S或Se。
Rd独立地为氢、烷基、烯基、炔基、芳基、酰基、取代的甲硅烷基、氨基甲酸酯、-P(O)(Re)2或-HP(O)(Re)。
Re独立地为氢、烷基、芳基、烯基、炔基、烷基-Y2-、烯基-Y2-、炔基-Y2-、芳基-Y2-或杂芳基-Y2-，或阳离子Na+、Li+或K+。
Y2为O、NRd或S。
烷基的优选实例是C1-10烷基，烯基的优选实例是C2-10烯基，炔基的优选实例是C2-10炔基，芳基的优选实例为C6-14芳基，杂芳基的优选实例是C6-14杂芳基。
R3是-CH2-、-(CH2)2-、-CH2NH-或-CH2N(CH3)-表示的基团。
G5的实例为三苯甲基、4-单甲氧基三苯甲基、4,4'-二甲氧基三苯甲基、4，4'，4”-三甲氧基三苯甲基、9-苯基黄嘌呤-9-基(Pixyl)和9-(对-甲氧基苯基)黄嘌呤-9-基(MOX)。
Bs是腺嘌呤、胸腺嘧啶、胞嘧啶、鸟嘌呤或它们的衍生物。Bs是核碱基或修饰的核碱基。衍生物的实例被JP2005-89441A公开，并以下式表示。
在上述式中，R8～R10各独立地是C1-10烷基、C6-C10芳基、C6-C10芳烷基或C6-C1芳氧基。R8的优选实例是甲基、异丙基、苯基、苄基和苯氧基甲基。R9和R10的优选实例是C1-4烷基。
作为第二个方面的优选实施例，核苷3'-亚磷酰胺衍生物由式(VA')或(Vb')表示。
在式(Va')和(Vb')中，G1、G2、G5、Bs、R2和R3与上述相同。核苷3'-亚磷酰胺衍生物是用来产生立体控制的磷原子修饰的核苷酸和寡核苷酸的衍生物的手性单体。
核苷3'-亚磷酰胺衍生物的优选实施例是由式1a、1b、2a、2b、3a、3b、4a、4b、5a、5b、6a、6b、7a、7b、8a、8b、9a、9b、10a、10b、11a、11b、12a、12b、13a、13b、14a、14b、15a、15b、16a、16b、17a、17b、18a、18b、19a、19b、20a、20b、21a、21b、22a、22b、23a、23b或24a表示。实施例部分描述了这些公式。
DMTr表示4,4'-二甲氧基三苯甲基，TOM表示三异丙基硅氧基甲基。
例如，日本专利JP2005-89441A公开于使用核苷3'-亚磷酰胺衍生物的实例。如其所公开的，通过重复缩合反应和脱保护反应的步骤，可延长寡核苷酸衍生物的链。
所述寡核苷酸衍生物的式子如式(X)所示。
在式(X)中，X表示硫(＝S)、C1-3烷基、C1-3烷氧基、C1-3烷硫基、C6-C10芳基、C6-C10芳烷基或C6-C10芳氧烷基(aryloxialkyl)。优选地，X表示硫(＝S)。“n”是一个整数，表示
或
“n”可以是优选为
优选
优选
并且更优选为
本发明的第三方面涉及一种用于合成立体控制的磷原子修饰的寡核苷酸衍生物的方法。第一步是包含非手性H-膦酸酯部分的分子与第一活化剂和手性试剂或其盐反应，形成单体的步骤。手性试剂具有化学式(I)或(I')，单体可由式(Va)、(Vb)、(Va')或(Vb')。单体与第二活化剂和核苷反应，形成缩合中间体。下一步是将缩合中间体转化为包含手性的X-膦酸酯部分的核酸的步骤。所述方法主要基于国际公开第WO2010/064146号小册子的公开内容。即，基本步骤被公开为其中的途径A和途径B。在所述方法中使用了本发明的手性试剂。
第一个图示涉及合成手性寡核苷酸。
活化步骤
非手性H-膦酸酯部分经过第一活化剂处理，形成第一中间体。在一个实施例中，第一活化剂在缩合步骤中添加到反应混合物中。第一活化剂的使用取决于反应条件，如用于该反应的溶剂。第一活化剂的实例是碳酰氯、氯甲酸三氯甲酯、双(三氯甲基)碳酸酯(BTC)、乙二酰氯、Ph3PCl2、(PhO)3PCl2、N，N'-双(2-氧代-3-恶唑烷基)次膦酰氯(BopCl)，1,3-二甲基-2-(3-硝基-1,2,4-三唑-1-基)-2-吡咯烷-1-基-1,3,2-二氮杂磷杂环戊烷六氟磷酸盐(MNTP)，或3硝基-1,2,4-三唑-1-基-三(吡咯烷-1-基)磷鐺六氟磷酸盐(PyNTP)。
非手性H-膦酸酯部分的实例是在上述图示中示出的化合物。DBU表示1,8-二氮杂双环[5.4.0]十一碳-7-烯。H+DBU可以是，例如，铵离子、烷基铵离子、杂亚铵离子或杂环亚胺离子，其中任何一个是一级、二级、三级或四级，或一价金属离子。
手性试剂反应
第一活化步骤后，活化的非手性H-膦酸酯部分与由式(I)或(I')表示的手性试剂反应，形成式(Va)、(Vb)、(Va')或(Vb')的手性中间体。
立体定向缩合步骤
式Va((Vb)、(Va')或(Vb'))的手性中间体经过第二活化剂处理和核苷处理，形成缩合中间体。所述核苷可以被固体化。第二活化剂的实例是4,5-二氰基咪唑(DCI)、4,5-二氯咪唑、1-苯基咪唑鐺三氟甲磺酸盐(PhIMT)、苯并咪唑三氟甲磺酸盐(BIT)、苯并三唑、3-硝基-1,2,4-三唑(NT)、四唑、5-乙硫基四唑(ETT)、5-苄巯基四唑(BTT)、5-(4-硝基苯基)四唑、N-氰基甲基吡咯烷鐺三氟甲磺酸盐(CMPT)、N-氰基甲基哌啶鐺三氟甲磺酸盐、N-氰基甲基二甲基铵三氟甲磺酸盐。式Va((Vb)、(Va')或(Vb'))的手性中间体可作为单体被分离。通常，式Va((Vb)、(Va')或(Vb'))的手性中间体不被分离，并在同一锅(pot)内与核苷或修饰的核苷反应，提供手性磷酸酯化合物，即缩合中间体。在其它实施例中，当通过固相合成实施该方法时，所述包含该化合物的固体支持物可从副产物、杂质和/或试剂中过滤出来。
封端步骤
如果最终得到的核酸比二聚体大，则用阻断部分将未反应的-OH基团封端，且该化合物的手性助剂，也可以用阻断部分封端，以形成封端的缩合中间体。如果最终得到的核酸是二聚体，则无需封端步骤。
修饰步骤
该化合物通过与亲电试剂发生反应而被修饰。该封端的缩合中间体可发生(实施)修饰步骤。在本方法的一些实施例中，通过使用硫亲电试剂、硒亲电试剂或硼化剂进行修饰步骤。修饰步骤的优选实例是氧化步骤和硫化步骤。
在本方法的一些实施例中，硫亲电试剂是具有下式之一的化合物：
S8(式B)，Z1-S-S-Z2或Z1-S-V-Z2。
Z1和Z2独立地为烷基、氨基烷基、环烷基、杂环基、环烷基烷基、杂环烷基、芳基、杂芳基、烷氧基、芳氧基、杂芳氧基、酰基、酰胺、酰亚胺或硫代羰基，或Z1和Z2结合在一起形成可被取代或未被取代的三元至八元脂环或杂环环；V是SO2、O或NRf；Rf是氢、烷基、烯基、炔基或芳基。
在本方法的一些实施例中，硫亲电试剂是具有下式A、B、C、D、E或F的化合物：
在本方法的一些实施例中，硒亲电试剂是具有下式之一的化合物：
Se(式G)、Z3-Se-Se-Z4或Z3-Se-V-Z4
Z3和Z4独立地为烷基、氨基烷基、环烷基、杂环基、环烷基烷基、杂环烷基、芳基、杂芳基、烷氧基、芳氧基、杂芳氧基、酰基、酰胺、酰亚胺或硫代羰基，或Z3和Z4结合在一起形成可被取代或未被取代的三元至八元脂环或杂环环；V是SO2、O或NRf；Rf是氢、烷基、烯基、炔基或芳基。
在本方法的一些实施例中，硒亲电试剂是具有下式G、H、I、J、K或L的化合物：
在本方法的一些实施例中，所述硼化剂是硼烷-N，N-二异丙基乙胺(BH3 DIPEA)、硼烷-吡啶(BH3 Py)、硼烷-2-氯吡啶(BH3 CPy)、硼烷-苯胺(BH3 An)、硼烷-四氢呋喃(BH3THF)或硼烷-二甲基硫醚(BH3 Me2S)。
在本方法的一些实施例中，修饰步骤是氧化步骤。例如，日本专利JP2010-265304A和国际公开第WO2010/064146号公开了该氧化步骤。
链延伸循环和脱保护步骤
该封端的缩合中间体通过除去生长中的核酸链5'端的阻断部分而被解阻断，从而提供化合物。所述化合物可任选地重新进入链延伸循环，以形成缩合中间体、封端的缩合中间体、修饰的封端的缩合中间体和5'端脱保护的修饰封端的中间体。经过至少一轮链延伸循环后，5'端脱保护的修饰的封端中间体进一步通过除去手性辅助配体和其它保护基团，如核碱基、修饰的核碱基、糖和修饰的糖的保护基团来解阻断，从而提供核酸。在其他实施例中，该包含5'-OH部分的核苷是如本文所述从之前的链延伸循环而来的中间体。而在另一些其他实施例中，该包含5'-OH部分的核苷是由其它已知的核酸合成方法得到的中间体。在使用固体支持物的实施例中，磷原子修饰的核酸，随后被从固体支持物上切除。在某些实施例中，核酸被留下附着在用于纯化目的的固体支持物上，并在随后的纯化过程中从固体支持物上切除。
根据本发明的方法，能够使用稳定的和市售的材料作为起始原料。有可能通过使用非手性原料，生产立体控制的磷原子修饰的寡核苷酸衍生物。
如一个实施例所示，本发明的方法不会导致脱保护步骤下的降解。此外，该方法不要求特殊的封端剂，来产生磷原子修饰的寡核苷酸衍生物。
本发明的第四方面涉及一种通过使用手性单体合成立体控制的磷原子修饰的寡核苷酸衍生物的方法。第一步是由式(Va)、(Vb)、(Va')或(Vb')表示的核苷3'-亚磷酰胺衍生物与第二活化剂和核苷反应，形成缩合中间体。第二步是将所述缩合中间体转化为包含手性X-膦酸酯部分的核酸。
第二个图示涉及通过使用由式Va((Vb)、(Va')或(Vb'))表示的单体合成手性寡核苷酸的反应。第二个图示基于公开在日本专利JP2005-89441A中的方法。
上述图示的具体条件类似于第一个图示。式Ⅴa(Vb)的原料，尤其是式Va'(或Vb')的原料，是化学稳定的。如一个实施例所示，本发明的方法不会导致脱保护步骤下的降解。此外，该方法不要求特殊的封端剂，以产生磷原子修饰的寡核苷酸衍生物。
用于去除助剂的机制如下图所示：
在上述图示中，Nu代表亲核试剂。上述机制被认为不同于之前用于去除助剂的机制。
实施例
缩写
ac：乙酰
bz：苯甲酰
CSO：(1S)-(+)-10-樟脑磺哑嗪
DBU：1,8-二氮杂双环[5.4.0]十一碳-7-烯
DCA：二氯乙酸
DCM：二氯甲烷，CH2Cl2
DMTr：4,4'-二甲氧基三苯甲基
Tr：三苯甲基
MeIm：N-甲基咪唑
NIS：N-碘代丁二酰亚胺
pac：苯氧基乙酰
Ph：苯基
PhIMT：N-苯基咪唑三氟甲磺酸
POS：3-苯基-1,2,4-二噻唑啉-5-酮
TBS：叔丁基二甲基硅基
TBDPS：叔丁基二苯基硅基
TOM：三异丙基硅氧基甲基
TFA：三氟乙酸
实施例1
(S)-1-三苯甲基吡咯烷-2-甲醛(I-a)
根据在文献(Guga,P.Curr.Top.Med.Chem.2007,7,695-713.)中描述的步骤由L-脯氨酸合成化合物I-a。
实施例2
(R)-1-三苯甲基吡咯烷-2-甲醛(I-b)
以类似合成化合物I-a的方式由D-脯氨酸合成化合物I-b。
实施例3
(S)-2-(甲基二苯基甲硅烷)-1-((S)-1-三苯甲基吡咯烷-1-基)乙醇(II-a)
由氯甲基二苯基甲基硅烷(4.02g,16.3mmol)和镁(402mg,16.3mmol)在四氢呋喃(14mL)中制备甲基二苯基硅基甲基氯化镁的四氢呋喃溶液。将I-a(2.79g,8.14mmol)的四氢呋喃(30mL)溶液，在冰冷却条件下添加到该甲基二苯基硅基甲基氯化镁的四氢呋喃溶液中。在冰冷却条件下搅拌1.5小时后，将混合物加热至室温并继续搅拌30分钟。将饱和NH4Cl水溶液(100mL)混合物在0℃加入到该反应混合物，并用乙醚(100mL)萃取三次。将合并的萃取液用Na2SO4干燥，过滤，并减压浓缩。将残余物通过硅胶色谱分离，得到无色泡沫状物的II-a(3.91g,87％)。
1H NMR(300MHz,CDCl3)δ7.48-7.08(25H,m),4.33-4.23(1H,m),3.16-2.89(3H,m),2.84(1H,brs),1.70-1.54(1H,m),1.35(1H,dd,J＝14.7,6.3Hz),1.10(1H,dd,J＝14.7,8.1Hz),1.18-1.05(1H,m),1.04-0.90(1H,m),0.34(3H,s),-0.17--0.36(1H,m).
实施例4
(S)-2-(甲基二苯基硅烷)-1-((S)-吡咯烷-2-基)乙醇(III-a)
将II-a(3.91g,7.06mmol)溶解在3％DCA的DCM溶液(70mL)中，在室温下搅拌10分钟。将1M NaOH(200mL)加入该混合物，并用DCM(100mL)萃取三次。将合并的萃取液用Na2SO4干燥，过滤，并减压浓缩。将残余物通过硅胶色谱分离，得到淡黄色油状物的III-a(1.99g,90％)。
1H NMR(300MHz,CDCl3)δ7.57-7.52(5H,m),7.38-7.33(5H,m),3.77(1H,ddd,J＝8.9,5.4,3.5Hz),3.01(1H,dt,J＝7.4,3.6Hz),2.97-2.79(2H,m),2.27(2H,brs),1.76-1.53(4H,m),1.38(1H,dd,J＝15.0,9.0Hz),1.24(1H,dd,J＝15.0,5.4Hz),0.65(3H,s)；13CNMR(100.4MHz,CDCl3)δ137.4,137.1,134.6,134.5,129.1,127.8,69.5,64.1,47.0,25.8,24.0,19.6,-3.4。MALDI TOF-MS m/z:C19H26NOSi[M+H]+计算值312.18,实测值312.06。
实施例5
(R)-2-(甲基二苯基硅烷)-1-(R)-1-三苯甲基吡咯烷-2-基)乙醇(II-b)
以与得到化合物II-a类似的方式，使用I-b代替I-a，得到化合物II-b。
1H NMR(300MHz,CDCl3)δ7.48-7.12(25H,m),4.33-4.24(1H,m),3.16-2.89(3H,m),2.86(1H,brs),1.69-1.52(1H,m),1.35(1H,dd,J＝14.4,6.0Hz),1.10(1H,dd,J＝14.4,8.4Hz),1.18-1.05(1H,m),1.03-0.89(1H,m),0.33(3H,s),-0.19--0.39(1H,m)；13C NMR(75.5MHz,CDCl3)δ144.5,137.5,136.8,134.6,134.3,129.8,129.0,127.8,127.7,127.4,126.1,77.9,71.7,65.1,53.5,25.0,24.8,19.6,-4.0。MALDI TOF-MS m/z:C38H40NOSi[M+H]+计算值554.29,实测值554.09.
实施例6
(R)-2-(甲基二苯基硅烷)-1-(R)-1-吡咯烷-2-基)乙醇(III-b)
以与得到化合物III-a类似的方式，使用II-b代替II-a，得到化合物III-b。
1H NMR(300MHz,CDCl3)δ7.58-7.52(5H,m),7.38-7.33(5H,m),3.78(1H,ddd,J＝9.0,5.1,3.6Hz),3.00(1H,dt,J＝7.4,3.3Hz),2.97-2.78(2H,m),2.19(2H,brs),1.76-1.53(4H,m),1.38(1H,dd,J＝14.6,9.0Hz),1.24(1H,dd,J＝14.6,5.1Hz),0.66(3H,s)；13CNMR(75.5MHz,CDCl3)δ137.5,137.1,134.5,134.4,129.0,127.7,69.2,64.2,46.9,25.8,24.0,19.7,-3.4。MALDI TOF-MS m/z:C19H26NOSi[M+H]+计算值312.18,实测值312.09。
实施例7
(S)-2-(三甲基硅烷)-1-(S)-1-三苯甲基吡咯烷-2-基)乙醇(IV-a)
以与得到化合物II-a类似的方式，使用“氯甲基三甲基硅烷”代替“氯甲基二苯基甲基硅烷”，得到化合物IV-a。
1H NMR(300MHz,CDCl3)δ7.58-7.51(5H,m),7.31-7.14(10H,m),4.13(1H,dt,J＝7.5,3.0Hz),3.39-3.31(1H,m),3.20-2.99(2H,m),2.84(1H,s),1.74-1.57(1H,m),1.29-1.10(2H,m),0.74(1H,dd,J＝14.4,7.2Hz),0.46(1H,dd,J＝14.4,7.2Hz),-0.15(9H,s)。MALDI TOF-MS m/z：C28H36NOSi[M+H]+计算值430.26,实测值430.09。
实施例8
(S)-2-(三甲基硅烷)-1-((S)-1-吡咯烷-2-基)乙醇(V-a)
以与得到化合物III-a类似的方式，使用IV-a代替II-a，得到化合物V-a。
1H NMR(300MHz,CDCl3)δ3.76(1H,ddd,J＝8.8,5.7,3.3Hz),3.08(1H,dt,J＝7.8,3.3Hz),3.02-2.87(2H,m),2.48(2H,brs),1.81-1.58(4H,m),0.83(1H,dd,J＝14.7,8.7Hz),0.68(1H,dd,J＝14.7,6.0Hz),0.05(9H,s)；13C NMR(75.5MHz,CDCl3)δ69.6,64.3,46.9,25.8,23.9,22.0,-0.8。MALDI TOF-MS m/z：C9H22NOSi[M+H]+计算值188.15,实测值188.00.
实施例9
(R)-2，2-二苯基-1-((S)-1-三苯甲基吡咯烷-2-基)乙醇(VI-a)
在室温下将正丁基锂n-BuLi(1.67M己烷溶液,24mL,40mmol)逐滴加入二苯基甲烷(6.7mL,40mmol)的四氢呋喃(36mL)溶液并搅拌1小时。用甲苯反复共同蒸发的I-a(3.41g,10mmol)的无水四氢呋喃(40mL)溶液在0℃缓慢加入到上述混合物中，并继续搅拌45分钟。然后加入饱和NH4Cl水溶液(100mL)和乙醚(100mL)，将有机层分离开，用乙醚(2x 100mL)萃取水层。合并有机层，并用硫酸钠干燥，过滤并减压浓缩。将残余物通过硅胶色谱柱纯化，得到白色泡沫状物的VI-a(1.41g,28％)。
1H NMR(300MHz,CDCl3)δ7.45-7.01(23H,m),6.67-6.61(2H,m),4.80(1H,d,J＝10.8Hz),3.63(1H,d,J＝10.8Hz),3.36-3.27(1H,m),3.23-3.09(1H,m),3.02-2.89(1H,m),2.66(1H,s),1.90-1.75(1H,m),1.32-1.04(2H,m),0--0.18(1H,m)。
实施例10
(R)-2，2-二苯基-1-((S)-吡咯烷-2-基)乙醇(VII-a)
以与得到化合物III-a类似的方式，使用VI-a代替II-a，得到化合物VII-a。
1H NMR(300MHz,CDCl3)δ7.44-7.38(2H,m),7.33-7.14(8H,m),4.46(1H,dd,J＝9.9,3.3Hz),3.91(1H,d,J＝9.9Hz),3.02-2.88(2H,m),2.81-2.69(1H,m),2.52(2H,brs),1.88-1.56(4H,m)；13C NMR(75.5MHz,CDCl3)d 142.3,142.0,128.6,128.5,128.4,128.2,126.5,126.4,73.5,60.1,55.8,46.6,25.8,23.4。MALDI TOF-MS m/z：C18H22NO[M+H]+计算值268.17,实测值268.06.
实施例11
(S)-2，2-二苯基-1-((R)-1-三苯甲基吡咯烷-2-基)乙醇(VI-b)
以与得到化合物VI-a类似的方式，使用I-b代替I-a。，得到化合物VI-b。
1H NMR(300MHz,CDCl3)δ7.44-7.37(6H,m),7.30-7.01(17H,m),6.66-6.61(2H,m),4.80(1H,d,J＝10.8Hz),3.63(1H,d,J＝10.8Hz),3.36-3.28(1H,m),3.22-3.09(1H,m),3.01-2.89(1H,m),2.66(1H,s),1.90-1.75(1H,m),1.29-1.04(2H,m),0.00--0.19(1H,m)；13C NMR(75.5MHz,CDCl3)d 144.2,142.9,141.6,130.0,128.5,128.4,127.9,127.8,127.4,126.4,126.2,77.9,75.9,61.9,55.4,53.4,24.7,24.5。MALDI TOF-MS m/z：C37H36NO[M+H]+计算值510.28,实测值510.11.
实施例12
(S)-2，2-二苯基-1-((R)-吡咯烷-2-基)乙醇(VII-b)
以与得到化合物VII-a类似的方式，使用VI-b代替VI-a,得到化合物VII-b。
1H NMR(300MHz,CDCl3)δ7.45-7.14(10H,m),4.45(1H,dd,J＝9.9,3.3Hz),3.91(1H,d,J＝9.9Hz),3.00-2.89(2H,m),2.82-2.71(1H,m),2.40(2H,brs),1.87-1.55(4H,m)；13C NMR(75.5MHz,CDCl3)δ142.3,142.0,128.5,128.3,128.1,126.3,126.2,73.4,60.1,55.9,46.5,25.8,23.5。MALDI TOF-MS m/z：C18H22NO[M+H]+计算值268.17,实测值268.03。
实施例13
(R)-2-(4-硝基苯基)-1-((S)-1-三苯甲基吡咯烷-2-基)乙醇(VIII-a)
以与得到化合物VI-a类似的方式，使用“4-硝基氯化苄”代替“二苯基甲烷”,得到化合物VIII-a。
1H NMR(300MHz,CDCl3)δ8.09-8.03(2H,m),7.49-7.43(6H,m),7.28-7.09(11H,m),4.23(1H,ddd,J＝8.3,5.6,3.0Hz),3.43-3.33(1H,m),3.23-3.11(1H,m),3.07-2.96(1H,m),2.83(1H,brs),2.74(1H,dd,J＝13.8,8.4Hz),2.49(1H,dd,J＝13.8,5.1Hz),1.83-1.67(1H,m),1.41-1.17(2H,m),0.27-0.08(1H,m)；13C NMR(75.5MHz,CDCl3)δ147.3,146.3,144.3,129.8,129.6,127.5,126.3,123.4,77.9,74.8,63.5,53.2,39.5,25.0,24.9。MALDITOF-MS m/z：C31H31N2O3[M+H]+计算值479.23,实测值479.08。
实施例14
(R)-2-(4-硝基苯基)-1-((S)-吡咯烷-2-基)乙醇(IX-a)
以与得到化合物VII-a类似的方式，使用VIII-a代替VI-a,得到化合物IX-a。
1H NMR(300MHz,CDCl3)δ8.15(2H,d,J＝8.7Hz),7.42(2H,d,J＝8.7Hz),3.86-3.79(1H,m),3.16-3.07(1H,m),2.99-2.68(6H,m),1.84-1.68(4H,m)；13C NMR(75.5MHz,CDCl3)δ147.4,146.2,129.9,123.2,72.4,62.0,46.6,40.4,25.7,24.4。MALDI TOF-MS m/z：C12H17N2O3[M+H]+计算值237.12,实测值237.01。
实施例15
(S)-2-(4-硝基苯基)-1-((R)-1-三苯甲基吡咯烷-2-基)乙醇(VIII-b)
以与得到化合物VIII-a类似的方式，使用I-b代替I-a,得到化合物VIII-b。
1H NMR(300MHz,CDCl3)δ8.09-8.04(2H,m),7.49-7.43(6H,m),7.28-7.09(11H,m),4.22(1H,ddd,J＝8.4,5.6,3.0Hz),3.43-3.33(1H,m),3.24-3.10(1H,m),3.08-2.94(1H,m),2.81(1H,brs),2.75(1H,dd,J＝14.0,8.1Hz),2.49(1H,dd,J＝14.0,5.1Hz),1.81-1.67(1H,m),1.40-1.16(2H,m),0.26-0.09(1H,m)；13C NMR(75.5MHz,CDCl3)δ147.3,144.3,129.8,129.6,129.4,126.3,123.5,77.9,74.8,63.5,53.2,39.5,25.0,24.9。MALDITOF-MSm/z：C31H31N2O3[M+H]+计算值479.23,实测值479.08。
实施例16
(S)-2-(4-硝基苯基)-1-((R)-吡咯烷-2-基)乙醇(IX-b)
以与得到化合物IX-a类似的方式，使用VIII-b代替VIII-a,得到化合物IX-b。
1H NMR(300MHz,CDCl3)d 8.19-8.13(2H,m),7.45-7.39(2H,m),3.83(1H,ddd,J＝7.7,5.4,3.9Hz),3.14(1H,dt,J＝7.7,3.9Hz),3.01-2.87(2H,m),2.83(1H,d,J＝3.3Hz),2.81(1H,s),2.62(2H,brs),1.79-1.72(4H,m)；13C NMR(75.5MHz,CDCl3)δ147.3,146.5,130.0,123.5,72.7,61.7,46.7,40.1,25.8,24.2.MALDI TOF-MS m/z：C12H17N2O3[M+H]+计算值237.12,实测值237.02。
实施例17
(R)-(9H-芴-9-基)((S)-1-三苯甲基吡咯烷-2-基)甲醇(X-a)
以与得到化合物VI-a类似的方式，使用芴代替二苯基甲烷,得到化合物X-a。
1H NMR(300MHz,CDCl3)δ7.70(1H,d,J＝7.5Hz),7.66(1H,d,J＝7.8Hz),7.55(2H,d,J＝7.5Hz),7.44-7.09(18H,m),6.87-6.62(1H,m),4.55-4.48(1H,m),4.06(1H,d,J＝7.5Hz),3.43-3.34(1H,m),3.18-3.06(1H,m),2.98-2.88(1H,m),2.85(1H,brs),1.42-1.24(1H,m),1.18-1.04(1H,m),0.53-0.39(1H,m),-0.02--0.20(1H,m)；MALDI TOF-MS m/z：C37H34NO[M+H]+计算值508.26,实测值508.12。
实施例18
(R)-(9H-芴-9-基)((S)-吡咯烷-2-基)甲醇(XI-a)
以与得到化合物III-a类似的方式，使用X-a代替II-a,得到化合物XI-a。
1H NMR(300MHz,CDCl3)δ7.76(2H,d,J＝7.5Hz),7.68(2H,t,J＝8.0Hz),7.43-7.35(2H,m),7.34-7.25(2H,m),4.28(1H,d,J＝6.3Hz),4.03(1H,dd,J＝6.5,4.2Hz),3.19-3.11(1H,m),2.97-2.88(1H,m),2.86-2.76(1H,m),2.02(2H,brs),1.77-1.53(3H,m),1.38-1.23(1H,m)；MALDI TOF-MS m/z：C18H20NO[M+H]+计算值266.15,实测值266.04。
实施例19
(S)-2-对甲苯磺酰基-1-(S)-1-三苯甲基吡咯烷-2-基)乙醇(XII-a)
以与得到化合物II-a类似的方式，使用氯甲基对甲苯砜代替氯甲基二苯甲基硅烷,得到化合物XII-a。
1H NMR(600MHz,CDCl3)d 7.66(2H,d,J＝8.4Hz),7.48-7.44(6H,m),7.35(2H,d,J＝7.2Hz),7.21-7.13(9H,m),4.39-4.36(1H,m),3.33(1H,s),3.24-3.20(1H,m),3.19-3.10(2H,m),2.98-2.92(2H,m),2.49(3H,s),1.55-1.49(1H,m),1.33-1.26(1H,m),1.12-1.04(1H,m),0.22-0.14(1H,m)；13C NMR(150.9MHz,CDCl3)δ144.6,144.5,136.3,129.9,129.5,128.1,127.5,126.2,78.0,69.1,63.9,60.2,52.6,25.5,24.7,21.7.
实施例20
(S)-2-甲苯磺酰基-1-(S)-1-三苯甲基吡咯烷-2-基)乙醇(XIII-a)
以与得到化合物III-a类似的方式，使用XII-a代替II-a,得到化合物XIII-a。
1H NMR(600MHz,CDCl3)δ7.82(2H,d,J＝8.4Hz),7.37(2H,d,J＝8.4Hz),4.01(1H,ddd,J＝12.0,5.1,3.0Hz),3.32(1H,dd,J＝14.4,3.0Hz),3.25(1H,dd,J＝14.4,9.0Hz),3.16(1H,dt,J＝7.8,5.1Hz),2.90-2.82(2H,m),2.46(3H,s),2.04(2H,brs),1.78-1.63(3H,m),1.62-1.55(1H,m)；13C NMR(150.9MHz,CDCl3)δ144.5,136.7,129.7,127.7,67.4,61.8,60.1,46.7,25.7,21.4.MALDI TOF-MS m/z：C13H20NO3S[M+H]+计算值270.12,实测值270.04。
实施例21
(R)-2-对甲苯磺酰基-1-((R)-1-三苯甲基吡咯烷-2-基)乙醇(XII-b)
以与得到化合物XII-a类似的方式，使用I-b代替I-a,得到化合物XII-b。
1H NMR(600MHz,CDCl3)δ7.66(2H,d,J＝8.4Hz),7.47-7.44(6H,m),7.35(2H,d,J＝7.8Hz),7.21-7.13(9H,m),4.37(1H,dt,J＝8.6,2.4Hz),3.33(1H,s),3.23-3.20(1H,m),3.19-3.12(2H,m),2.98-2.92(2H,m),2.49(3H,s),1.56-1.49(1H,m),1.32-1.26(1H,m),1.11-1.03(1H,m),0.23-0.15(1H,m)；13C NMR(150.9MHz,CDCl3)δ144.6,144.5,136.3,129.9,129.6,128.1,127.6,126.2,78.0,69.1,63.9,60.2,52.6,25.5,24.7,21.7.
实施例22
(R)-2-对甲苯磺酰基-1-((R)-1-三苯甲基吡咯烷-2-基)乙醇(XIII-b)
以与得到化合物XIII-a.类似的方式，使用XII-b代替XII-a,得到化合物XIII-b。
1H NMR(600MHz,CDCl3)δ7.82(2H,d,J＝8.4Hz),7.37(2H,d,J＝8.4Hz),4.01(1H,ddd,J＝9.0,5.1,3.0Hz),3.32(1H,dd,J＝14.4,3.0Hz),3.25(1H,dd,J＝14.4,9.0Hz),3.17(1H,dt,J＝7.2,5.1Hz),2.89-2.83(2H,m),2.46(3H,s),2.04(2H,brs),1.79-1.64(3H,m),1.62-1.55(1H,m)；13CNMR(150.9MHz,CDCl3)δ144.8,136.6,129.8,127.9,67.7,61.8,60.1,46.8,25.9,25.8,21.6.MALDI TOF-MS m/z：C13H20NO3S[M+H]+计算值270.12,实测值270.05。
实施例23
恶唑磷烷单体3a
III-a(560mg,1.80mmol)通过反复多次与干燥甲苯共同蒸发干燥，并在氩气中溶解于干燥乙醚(0.90mL)。将N-甲基吗啉(400L,3.60mmol)加入到该溶液中，并在0℃下在氩气中将所得溶液逐滴加入到PCl3(160L,1.80mmol)的无水乙醚溶液(0.90mL)中并搅拌。然后，将混合物温热至室温并搅拌30分钟。将在氮气下过滤除去所得的N-甲基吗啉盐酸盐，并将滤液在减压下浓缩至干燥，得到粗2-氯-1,3,2-恶唑磷烷衍生物。将粗物质溶解在新鲜蒸馏的四氢呋喃(3.6mL)中，以制备0.5M的溶液，无需进一步纯化，其被用于合成核苷3'-O-恶唑磷烷。
5'-O-(DMTr)-2-N-(苯氧基乙酰基)-6-O-(氰基乙基)鸟苷((636mg,0.84mmol)通过用干燥甲苯反复共同蒸发干燥，并在氩气下溶解在新鲜蒸馏的四氢呋喃(2.5mL)。加入三乙胺(0.58mL,4.2mmol)，并将该混合物冷却至-78℃。通过注射器逐滴加入0.5M相应粗制的2-氯-1,3,2-恶唑磷烷衍生物的新鲜蒸馏的四氢呋喃(3.6mL,1.80mmol)溶液，并将混合物在室温下搅拌15分钟。然后加入饱和的NaHCO3水溶液((70mL)和三氯甲烷(70mL)，并且分离有机层并用饱和的NaHCO3水溶液(2x 70mL)清洗。用CHCl3(70mL)反萃取合并的水层。将有机层合并，经Na2SO4干燥，过滤，并减压浓缩。将残余物通过色谱法在硅胶柱上纯化，得到白色泡沫状物的3a(829mg,90％)，。
1H NMR(300MHz,CDCl3)d 8.77(1H,brs),7.99(1H,s),7.54-6.98(24H,m),6.81-6.73(4H,m),6.35(1H,dd,J＝8.0,6.3Hz),4.89-4.73(4H,m),4.68(2H,brs),4.05-3.98(1H,m),3.75(6H,s),3.62-3.46(1H,m),3.41-3.20(3H,m),3.18-3.04(1H,m),3.08(2H,t,J＝6.6Hz),2.58-2.36(2H,m),1.94-1.59(2H,m),1.56(1H,dd,J＝15.0,8.7Hz),1.43(1H,dd,J＝15.0,5.7Hz),1.33-1.16(2H,m),0.62(3H,s)；31P NMR(121.5MHz,CDCl3)δ153.5(1P,s).
实施例24
恶唑磷烷单体3b
以与得到化合物3a类似的方式，使用III-b代替III-a,得到化合物3b。
1H NMR(300MHz,CDCl3)δ8.80(1H,brs),7.96(1H,s),7.54-6.96(24H,m),6.79-6.71(4H,m),6.19(1H,t,J＝6.6Hz),4.90-4.73(4H,m),4.66(2H,brs),4.16-4.08(1H,m),3.76(6H,s),3.60-3.36(2H,m),3.29(1H,d,J＝3.9Hz),3.27-3.12(2H,m),3.09(2H,t,J＝6.6Hz),2.59-2.46(1H,m),2.07-1.97(1H,m),1.94-1.41(5H,m),1.36-1.18(1H,m),0.65(3H,s)；31P NMR(121.5MHz,CDCl3)δ157.1(1P,s).
实施例25
恶唑磷烷单体1a
以与得到化合物3a类似的方式，使用5'-O-(DMTr)-6-N-(苯甲酰基)腺苷代替5'-O-(DMTr)-2-N-(苯氧基乙酰基)-6-O-(氰基乙基)鸟苷,得到化合物1a。
1H NMR(600MHz,CDCl3)δ8.71(1H,s),8.12(1H,s),8.04(2H,d,J＝7.8Hz),7.62-7.15(23H,m),6.80-6.75(4H,m),6.37(1H,dd,J＝7.8,6.0Hz),4.94-4.88(1H,m),4.80(1H,ddd,J＝12.0,6.0,5.4Hz),4.07-4.04(1H,m),3.76(6H,s),3.58-3.49(1H,m),3.41-3.34(1H,m),3.33(1H,dd,J＝10.8,4.8Hz),3.25(1H,dd,J＝10.8,4.8Hz),3.13-3.06(1H,m),2.66-2.58(1H,m),2.40-2.35(1H,m),1.91-1.84(1H,m),1.73-1.66(1H,m),1.56(1H,dd,J＝15.0,9.0Hz),1.44(1H,dd,J＝15.0,5.4Hz),1.47-1.41(1H,m),1.30-1.23(1H,m),0.63(3H,s)；31P NMR(243.0MHz,CDCl3)δ151.8(1P,s).
实施例26
恶唑磷烷单体1b
以与得到化合物1a类似的方式，使用III-b代替III-a,得到化合物1b。
1H NMR(300MHz,CDCl3)δ9.06(1H,brs),8.76(1H,s),8.12(1H,s),8.07-7.99(2H,m),7.64-7.14(22H,m),6.83-6.75(4H,m),6.25(1H,t,J＝6.6Hz),4.86-4.75(2H,m),4.20-4.15(1H,m),3.77(6H,s),3.61-3.38(2H,m),3.36(1H,dd,J＝10.2,4.2Hz),3.27(1H,dd,J＝10.2,4.2Hz),3.27-3.13(1H,m),2.71-2.59(1H,m),2.12-2.01(1H,m),1.94-1.42(5H,m),1.36-1.20(1H,m),0.67(3H,s)；31P NMR(121.5MHz,CDCl3)δ157.3(1P,s).
实施例27
恶唑磷烷单体2a
以与得到化合物3a类似的方式，使用5'-O-(DMTr)-4-N-(异丁酰基)胞苷代替5'-O-(DMTr)-2-N-(苯氧基乙酰基)-6-O-(氰基乙基)鸟苷,得到化合物2a。
1H NMR(300MHz,CDCl3)δ8.33(1H,brs),8.17(1H,d,J＝7.5Hz),7.52-7.22(19H,m),7.07(1H,d,J＝7.5Hz),6.88-6.81(4H,m),6.20(1H,t,J＝6.2Hz),4.81-4.64(2H,m),3.93-3.87(1H,m),3.79(6H,s),3.59-3.43(1H,m),3.39-3.29(3H,m),3.16-3.02(1H,m),2.69-2.52(2H,m),2.12-2.00(1H,m),1.91-1.50(3H,m),1.47-1.32(2H,m),1.27-1.16(7H,m),0.60(3H,s)；31P NMR(121.5MHz,CDCl3)δ154.8(1P,s).
实施例28
恶唑磷烷单体2b
以与得到化合物2a类似的方式，使用III-代替III-a,得到化合物2b。
1H NMR(300MHz,CDCl3)δ8.33(1H,d,J＝7.5Hz),8.23(1H,brs),7.57-7.22(19H,m),7.12(1H,d,J＝7.5Hz),6.88-6.81(4H,m),6.15(1H,dd,J＝6.6,4.2Hz),4.82-4.63(2H,m),4.03-3.97(1H,m),3.80(6H,s),3.55-3.26(4H,m),3.19-3.05(1H,m),2.59(1H,quintet,J＝6.9Hz),2.39-2.27(1H,m),2.21-2.10(1H,m),1.90-1.56(3H,m),1.50-1.32(2H,m),1.26-1.17(7H,m),0.66(3H,s)；31P NMR(121.5MHz,CDCl3)δ157.2(1P,s).
实施例29
恶唑磷烷单体4a
以与得到化合物3a类似的方式，使用5'-O-(DMTr)胸苷代替5'-O-(DMTr)-2-N-(苯氧基乙酰基)-6-O-(氰基乙基)鸟苷，得到化合物4a。
1H NMR(300MHz,CDCl3)δ7.58-7.23(21H,m),6.86-6.79(4H,m),6.35(1H,dd,J＝8.1,5.7Hz),4.79-4.67(2H,m),3.83-3.78(1H,m),3.78(6H,s),3.59-3.43(1H,m),3.34(1H,dd,J＝10.5,2.4Hz),3.35-3.24(1H,m),3.20(1H,dd,J＝10.5,2.4Hz),3.16-3.02(1H,m),2.36-2.26(1H,m),2.15-2.02(1H,m),1.92-1.77(1H,m),1.74-1.59(1H,m),1.52(1H,dd,J＝14.7,9.0Hz),1.40(3H,s),1.45-1.15(3H,m),0.60(3H,s)；31P NMR(121.5MHz,CDCl3)δ153.7(1P,s).
实施例30
恶唑磷烷单体4b
以与得到化合物4a类似的方式，使用III-b代替III-a,得到化合物4b。
1H NMR(300MHz,CDCl3)δ8.46(1H,brs),7.59-7.20(20H,m),6.86-6.79(4H,m),6.26(1H,t,J＝6.8Hz),4.78-4.65(2H,m),4.01-3.95(1H,m),3.78(6H,s),3.55-3.40(1H,m),3.42(1H,dd,J＝10.5,2.7Hz),3.40-3.28(1H,m),3.22(1H,dd,J＝10.5,3.0Hz),3.19-3.06(1H,m),2.16-1.95(2H,m),1.90-1.54(3H,m),1.49-1.35(1H,m),1.43(3H,s),1.34-1.17(2H,m),0.67(3H,s)；31P NMR(121.5MHz,CDCl3)δ156.2(1P,s).
实施例31
恶唑磷烷单体5a
以与得到化合物3a.类似的方式，使用5'-O-(DMTr)-2'-O-甲基-6-N-(苯甲酰基)腺苷代替5'-O-(DMTr)-2-N-(苯氧基乙酰基)-6-O-(氰乙基)鸟苷,得到化合物5a。
1H NMR(300MHz,CDCl3)δ8.66(1H,s),8.13(1H,s),8.03(2H,d,J＝7.2Hz),7.64-7.16(23H,m),6.79(4H,d,J＝8.7Hz),6.08(1H,d,J＝6.3Hz),4.91-4.81(1H,m),4.77-4.69(1H,m),4.64-4.57(1H,m),4.15-4.10(1H,m),3.76(6H,s),3.60-3.23(4H,m),3.35(3H,s),3.14-3.00(1H,m),1.90-1.19(6H,m),0.62(3H,s)；31P NMR(121.5MHz,CDCl3)δ155.8(1P,s).
实施例32
恶唑磷烷单体5b
以与得到化合物5a类似的方式，使用III-b代替III-a,得到化合物5b。
1H NMR(300MHz,CDCl3)δ9.12(1H,brs),8.73(1H,s),8.24(1H,s),8.07-8.01(2H,m),7.62-7.17(22H,m),6.83-6.77(4H,m),6.12(1H,d,J＝4.8Hz),4.84-4.73(2H,m),4.43(1H,t,J＝4.8Hz),4.25-4.19(1H,m),3.77(6H,s),3.55-3.20(4H,m),3.28(3H,s),3.16-3.03(1H,m),1.90-1.17(6H,m),0.65(3H,s)；31P NMR(121.5MHz,CDCl3)δ155.0(1P,s).
实施例33
恶唑磷烷单体6a
以与得到化合物3a类似的方式，使用5'-O-(DMTr)-2'-O-甲基-4-N-(异丁酰基)胞苷代替5'-O-(DMTr)-2-N-(苯氧基乙酰基)-6-O-(氰乙基)鸟苷,得到化合物6a。
1H NMR(300MHz,CDCl3)δ8.49(1H,d,J＝7.2Hz),7.58-7.20(19H,m),6.96(1H,d,J＝7.2Hz),6.90-6.82(4H,m),5.98(1H,s),4.84(1H,dd,J＝13.1,7.5Hz),4.59(1H,dt,J＝8.3,4.5Hz),4.19-4.13(1H,m),3.79(6H,s),3.78-3.72(1H,m),3.63-3.40(3H,m),3.55(3H,s),3.36-3.24(1H,m),3.09-2.95(1H,m),2.59(1H,septet,J＝6.9Hz),1.85-1.53(5H,m),1.48-1.37(1H,m),1.24-1.17(6H,m),0.59(3H,s)；31P NMR(121.5MHz,CDCl3)δ155.2(1P,s).
实施例34
恶唑磷烷单体6b
以与得到化合物6a类似的方式，使用III-b代替III-a,得到化合物6b。
1H NMR(300MHz,CDCl3)δ8.62(1H,d,J＝7.5Hz),7.57-7.23(19H,m),7.02(1H,d,J＝7.5Hz),6.89-6.81(4H,m),5.92(1H,s),4.90(1H,dt,J＝9.0,5.7Hz),4.61(1H,dt,J＝8.7,4.8Hz),4.25-4.17(1H,m),3.81(6H,s),3.67(1H,d,J＝4.5Hz),3.62-3.25(4H,m),3.38(3H,s),3.16-3.02(1H,m),2.58(1H,septet,J＝6.9Hz),1.87-1.40(6H,m),1.26-1.14(6H,m),0.64(3H,s)；31P NMR(121.5MHz,CDCl3)δ158.2(1P,s).
实施例35
恶唑磷烷单体7a
以与得到化合物3a类似的方式，使用5'-O-(DMTr)-2'-O-甲基-2-N-(苯氧基乙酰基)-6-O-(氰基乙基)鸟苷代替5'-O-(DMTr)-2-N-(苯氧基乙酰基)-6-O-(氰基乙基)鸟苷,得到化合物7a。
1H NMR(300MHz,CDCl3)δ8.67(1H,brs),8.01(1H,s),7.56-7.16(24H,m),6.83-6.74(4H,m),6.08(1H,d,J＝6.9Hz),4.85-4.76(1H,m),4.84(2H,t,J＝6.6Hz),4.65-4.56(1H,m),4.59(2H,brs),4.48(1H,dd,J＝6.6,5.1Hz),4.09-4.05(1H,m),3.75(6H,s),3.60-3.42(2H,m),3.40-3.26(2H,m),3.35(3H,s),3.18-3.05(1H,m),3.08(2H,t,J＝6.6Hz),1.89-1.49(3H,m),1.48-1.16(3H,m),0.59(3H,s)；31P NMR(121.5MHz,CDCl3)δ156.9(1P,s).
实施例36
恶唑磷烷单体7b
以与得到化合物7a类似的方式，使用III-b代替III-a,得到化合物7b。
1H NMR(300MHz,CDCl3)δ8.74(1H,brs),8.09(1H,s),7.56-6.94(24H,m),6.84-6.71(4H,m),6.09(1H,d,J＝4.8Hz),4.83-4.70(2H,m),4.83(2H,t,J＝6.6Hz),4.63(2H,brs),4.35(1H,t,J＝5.0Hz),4.23-4.16(1H,m),3.75(6H,s),3.58-3.19(4H,m),3.32(3H,s),3.16-3.04(1H,m),3.07(2H,t,J＝6.6Hz),1.90-1.55(3H,m),1.48-1.15(3H,m),0.64(3H,s)；31PNMR(121.5MHz,CDCl3)δ154.6(1P,s).
实施例37
恶唑磷烷单体8a
以与得到化合物3a类似的方式，使用5'-O-(DMTr)-2'-O-(甲基)尿苷代替5'-O-(DMTr)-2-N-(苯氧基乙酰基)-6-O-(氰基乙基)鸟苷,得到化合物8a。
1H NMR(300MHz,CDCl3)δ7.91(1H,d,J＝7.8Hz),7.58-7.20(19H,m),6.88-6.80(4H,m),5.96(1H,d,J＝3.3Hz),5.19(1H,d,J＝7.8Hz),4.88-4.78(1H,m),4.66-4.57(1H,m),4.03-3.95(1H,m),3.90-3.74(1H,m),3.78(6H,s),3.77-3.71(1H,m),3.58-3.29(2H,m),3.45(3H,s),3.13-2.82(2H,m),1.88-1.53(3H,m),1.49-1.16(3H,m),0.60(3H,s)；31PNMR(121.5MHz,CDCl3)δ155.3(1P,s).
实施例38
恶唑磷烷单体8b
以与得到化合物8a类似的方式，使用III-b代替III-a,得到化合物8b。
1H NMR(300MHz,CDCl3)δ8.10(1H,d,J＝8.4Hz),7.58-7.20(19H,m),6.87-6.79(4H,m),5.89(1H,d,J＝1.5Hz),5.21(1H,d,J＝8.4Hz),4.92-4.82(1H,m),4.73-4.63(1H,m),4.15-4.08(1H,m),3.89-3.73(1H,m),3.78(6H,s),3.66-3.62(1H,m),3.57-3.27(2H,m),3.30(3H,s),3.17-2.82(2H,m),1.89-1.55(3H,m),1.55-1.40(1H,m),1.35-1.15(2H,m),0.66(3H,s)；31P NMR(121.5MHz,CDCl3)δ157.5(1P,s).
实施例39
恶唑磷烷单体9a
以与得到化合物3a类似的方式，使用5'-O-(DMTr)-2'-脱氧-2'-氟-6-N-(苯甲酰基)腺苷代替5'-O-(DMTr)-2-N-(苯氧基乙酰基)-6O-(氰基乙基)鸟苷,得到化合物9a。
1H NMR(300MHz,CDCl3)δ8.64(1H,s),8.14(1H,s),8.06-8.01(2H,m),7.63-7.07(23H,m),6.78-6.70(4H,m),6.12(1H,dd,J＝18.0,2.4Hz),5.24-5.01(2H,m),4.94-4.84(1H,m),4.17-4.06(1H,m),3.73(6H,s),3.55-3.40(3H,m),3.30-3.22(1H,m),3.03-2.88(1H,m),1.92-1.19(6H,m),0.62(3H,s)；31P NMR(121.5MHz,CDCl3)δ150.5(1P,d,J＝7.7Hz).
实施例40
恶唑磷烷单体9b
以与得到化合物9a类似的方式，使用III-b代替III-a,得到化合物9b。
1H NMR(300MHz,CDCl3)δ9.07(1H,brs),8.80(1H,s),8.24(1H,s),8.08-8.01(2H,m),7.66-7.15(22H,m),6.81-6.75(4H,m),6.14(1H,dd,J＝18.0,1.8Hz),5.16-4.91(3H,m),4.28-4.21(1H,m),3.76(6H,s),3.57-3.11(5H,m),1.82-1.16(6H,m),0.65(3H,s)；31PNMR(121.5MHz,CDCl3)δ157.8(1P,d,J＝5.6Hz).
实施例41
恶唑磷烷单体10a
以与得到化合物3a类似的方式，使用“5'-O-(DMTr)-2'-脱氧-2'-氟-4-N-(异丁)胞苷代替5'-0-(DMTr)-2-N-(苯氧基乙酰基)-6-O-(氰基乙基)鸟苷,得到化合物10a。
1H NMR(300MHz,CDCl3)δ8.66(1H,brs),8.41(1H,d,J＝7.5Hz),7.55-7.20(19H,m),7.01(1H,d,J＝7.5Hz),6.89-6.81(4H,m),6.06(1H,d,J＝15.9Hz),4.85(1H,dd,J＝51.4,3.9Hz),4.84(1H,dd,J＝12.9,7.5Hz),4.77-4.59(1H,m),4.15-4.08(1H,m),3.79(6H,s),3.63-3.29(4H,m),3.10-2.96(1H,m),2.65(1H,septet,J＝6.9Hz),1.85-1.53(3H,m),1.48-1.17(3H,m),1.21(3H,d,J＝4.8Hz),1.19(3H,d,J＝4.8Hz),0.59(3H,s)；31P NMR(121.5MHz,CDCl3)δ155.5(1P,d,J＝6.6Hz).
实施例42
恶唑磷烷单体10b
以与得到化合物10a类似的方式，使用III-b代替III-a,得到化合物10b。
1H NMR(300MHz,CDCl3)δ8.53(1H,d,J＝7.5Hz),7.57-7.23(20H,m),7.10(1H,d,J＝7.5Hz),6.89-6.81(4H,m),6.10(1H,d,J＝15.9Hz),5.00-4.92(1H,m),4.84(1H,dd,J＝51.5,3.3Hz),4.75-4.58(1H,m),4.24(1H,d,J＝9.3Hz),3.81(6H,s),3.65-3.39(3H,m),3.32-3.06(2H,m),2.59(1H,septet,J＝6.9Hz),1.88-1.53(4H,m),1.49-1.34(2H,m),1.27-1.18(6H,m),0.65(3H,s)；31P NMR(121.5MHz,CDCl3)δ159.0(1P,d,J＝4.4).
实施例43
恶唑磷烷单体11a
以与得到化合物3a类似的方式，使用5'-O-(DMTr)-2'-脱氧-2'-氟-2-N-(苯氧基乙酰基)-6-O-(氰基乙基)鸟苷代替5'-O-(DMTr)-2-N-(苯氧基乙酰基)-6-O-(氰基乙基)鸟苷,得到化合物11a。
1H NMR(300MHz,CDCl3)δ8.74(1H,brs),8.03(1H,s),7.55-6.94(24H,m),6.80-6.69(4H,m),6.21(1H,dd,J＝14.9,3.6Hz),5.34(1H,dt,J＝52.3,3.6Hz),5.01-4.75(2H,m),4.84(1H,t,J＝6.6Hz),4.62(2H,brs),4.15-4.07(1H,m),3.73(6H,s),3.59-3.29(4H,m),3.15-3.00(1H,m),3.07(2H,t,J＝6.6Hz),1.90-1.49(3H,m),1.47-1.12(3H,m),0.58(3H,s)；31P NMR(121.5MHz,CDCl3)δ155.6(1P,d,J＝10.9Hz).
实施例44
恶唑磷烷单体11b
以与得到化合物11a类似的方式，使用III-b代替III-a,得到化合物11b。
1H NMR(300MHz,CDCl3)δ8.81(1H,brs),8.06(1H,s),7.55-6.95(24H,m),6.77-6.69(4H,m),6.06(1H,d,J＝17.1Hz),5.24-5.08(1H,m),5.04-4.80(2H,m),4.87(1H,t,J＝6.6Hz),4.62(2H,brs),4.25-4.19(1H,m),3.73(6H,s),3.58-3.02(5H,m),3.10(2H,t,J＝6.6Hz),1.90-1.56(3H,m),1.50-1.15(3H,m),0.63(3H,s)；31P NMR(121.5MHz,CDCl3)δ158.0(1P,d,J＝4.4Hz).
实施例45
恶唑磷烷单体12a
以与得到化合物3a类似的方式，使用5'-O-(DMTr)-2'-脱氧-2'-氟尿苷代替5'-O-(DMTr)-2-N-(苯氧基乙酰基)-6-O-(氰基乙基)鸟苷,得到化合物12a。
1H NMR(300MHz,CDCl3)δ7.85(1H,d,J＝8.1Hz),7.58-7.20(19H,m),6.87-6.79(4H,m),5.98(1H,d,J＝16.5Hz),5.23(1H,d,J＝8.1Hz),4.86-4.61(3H,m),3.99(1H,d,J＝6.9Hz),3.76(6H,d,J＝3.0Hz),3.56-3.34(4H,m),3.10-2.96(1H,m),1.88-1.74(1H,m),1.72-1.52(2H,m),1.48-1.16(3H,m),0.61(3H,s)；31P NMR(121.5MHz,CDCl3)δ154.3(1P,d,J＝8.9Hz).
实施例46
恶唑磷烷单体12b
以与得到化合物12a类似的方式，使用III-b代替III-a,得到化合物12b。
1H NMR(300MHz,CDCl3)δ8.01(1H,d,J＝8.4Hz),7.58-7.20(19H,m),6.87-6.79(4H,m),6.03(1H,d,J＝16.2Hz),5.29(1H,d,J＝8.4Hz),4.96(1H,dd,J＝13.1,7.5Hz),4.80-4.54(2H,m),4.15(1H,d,J＝9.0Hz),3.78(6H,s),3.61-3.39(3H,m),3.37-3.25(1H,m),3.23-3.09(1H,m),1.91-1.56(3H,m),1.51-1.13(3H,m),0.66(3H,s)；31P NMR(121.5MHz,CDCl3)δ158.9(1P,d,J＝4.4Hz).
实施例47
恶唑磷烷单体13a
以与得到化合物3a类似的方式，使用5'-O-(DMTr)-2'-O-TOM-6-N-(乙酰基)腺苷代替5'-O-(DMTr)-2-N-(苯氧基乙酰基)-6-O-(氰乙基)鸟苷,得到化合物13a。
1H NMR(300MHz,CDCl3)δ8.82(1H,brs),8.49(1H,s),8.10(1H,s),7.58-7.17(19H,m),6.83-6.73(4H,m),6.11(1H,d,J＝6.6Hz),5.15(1H,dd,J＝6.6,5.4Hz),4.98-4.77(4H,m),4.18-4.11(1H,m),3.76(6H,s),3.59-3.25(4H,m),3.16-3.02(1H,m),2.62(3H,s),1.91-1.53(3H,m),1.49-1.18(3H,m),0.96-0.80(3H,m),0.90(18H,s),0.62(3H,s)；31P NMR(121.5MHz,CDCl3)δ156.7(1P,s).
实施例48
恶唑磷烷单体13b
以与得到化合物13a类似的方式，使用III-b代替III-a,得到化合物13b。
1H NMR(300MHz,CDCl3)δ8.56(1H,brs),8.55(1H,s),8.13(1H,s),7.57-7.17(19H,m),6.82-6.73(4H,m),6.16(1H,d,J＝5.7Hz),5.06(1H,t,J＝5.6Hz),4.93(1H,d,J＝5.1Hz),4.83(1H,d,J＝5.1Hz),4.81-4.69(2H,m),4.27-4.19(1H,m),3.76(6H,s),3.55-3.40(2H,m),3.33-3.16(2H,m),3.12-2.97(1H,m),2.63(3H,s),1.88-1.52(3H,m),1.45-1.16(3H,m),0.91-0.79(3H,m),0.86(18H,s),0.64(3H,s)；31P NMR(121.5MHz,CDCl3)δ154.8(1P,s)。
实施例49
恶唑磷烷单体14a
以与得到化合物3a类似的方式，使用5'-O-(DMTr)-2'-O-TOM-4-N-(乙酰基)胞苷代替5'-O-(DMTr)-2-N-(苯氧基乙酰基)-6-O-(氰基乙基)鸟苷,得到化合物14a。
1H NMR(300MHz,CDCl3)δ10.04(1H,brs),8.30(1H,d,J＝7.5Hz),7.51-7.21(19H,m),6.99(1H,d,J＝7.5Hz),6.89-6.81(4H,m),6.12(1H,d,J＝3.3Hz),5.07(1H,d,J＝4.8Hz),5.05(1H,d,J＝4.8Hz),4.84-4.75(1H,m),4.62-4.52(1H,m),4.31-4.25(1H,m),4.08-4.01(1H,m),3.78(6H,d,J＝3.0Hz),3.55-3.23(4H,m),3.10-2.96(1H,m),2.24(3H,s),1.84-1.49(3H,m),1.46-0.96(24H,m),0.58(3H,s)；31P NMR(121.5MHz,CDCl3)δ156.5(1P,s).
实施例50
恶唑磷烷单体14b
以与得到化合物14a类似的方式，使用III-b代替III-a,得到化合物14b。
1H NMR(300MHz,CDCl3)δ10.19(1H,brs),8.46(1H,d,J＝7.5Hz),7.54-7.23(19H,m),7.01(1H,d,J＝7.5Hz),6.88-6.79(4H,m),6.19(1H,d,J＝1.8Hz),5.11(1H,d,J＝4.8Hz),5.07(1H,d,J＝4.8Hz),4.81-4.71(1H,m),4.60-4.51(1H,m),4.26-4.18(2H,m),3.79(6H,s),3.63-3.55(1H,m),3.48-3.28(2H,m),3.21-2.94(2H,m),2.26(3H,s),1.81-1.49(3H,m),1.43-0.96(24H,m),0.62(3H,s)；31P NMR(121.5MHz,CDCl3)δ156.4(1P,s).
实施例51
恶唑磷烷单体15a
以与得到化合物3a类似的方式，使用5'-O-(DMTr)-2'--O-TOM-2-N-(乙酰基)鸟苷代替5'-0-(DMTr)-2-N-(苯氧基乙酰基)-6-O-(氰基乙基)鸟苷,得到化合物15a。
1H NMR(300MHz,CDCl3)δ7.70(1H,s),7.63-7.13(21H,m),6.84-6.76(4H,m),5.77(1H,d,J＝8.4Hz),5.41-5.33(1H,m),4.90(2H,s),4.78-4.68(2H,m),3.86(1H,brs),3.75(3H,s),3.74(3H,s),3.56-3.41(2H,m),3.32-2.90(3H,m),1.92-1.10(9H,m),0.97-0.87(21H,m),0.52(3H,s)；31P NMR(121.5MHz,CDCl3)δ158.1(1P,s).
实施例52
恶唑磷烷单体15b
以与得到化合物15a类似的方式，使用III-b代替III-a,得到化合物15b。
1H NMR(300MHz,CDCl3)δ7.77(1H,s),7.56-7.15(21H,m),6.82-6.75(4H,m),5.86(1H,d,J＝7.5Hz),5.26-5.17(1H,m),4.95(1H,d,J＝5.4Hz),4.85(1H,d,J＝5.4Hz),4.78-4.71(1H,m),4.59-4.49(1H,m),4.10-4.05(1H,m),3.74(6H,s),3.52-3.37(2H,m),3.30-3.18(1H,m),3.11-2.85(2H,m),1.85-1.15(9H,m),0.93-0.84(21H,m),0.62(3H,s)；31P NMR(121.5MHz,CDCl3)δ152.3(1P,s).
实施例53
恶唑磷烷单体16a
以与得到化合物3a类似的方式，使用5'-O-(DMTr)-2'-O-TOM-尿苷代替5'-O-(DMTr)-2-N-(苯氧基乙酰基)-6-O-(氰基乙基)鸟苷,得到化合物16a。
1H NMR(300MHz,CDCl3)δ7.76(1H,d,J＝8.1Hz),7.55-7.18(20H,m),6.88-6.80(4H,m),6.11(1H,d,J＝6.0Hz),5.32(1H,d,J＝8.1Hz),4.99(1H,d,J＝5.1Hz),4.93(1H,d,J＝5.1Hz),4.84-4.75(1H,m),4.54-4.46(1H,m),4.38(1H,t,J＝5.7Hz),3.87-3.83(1H,m),3.78(3H,s),3.77(3H,s),3.56-3.42(1H,m),3.39-3.28(1H,m),3.36(1H,dd,J＝11.0,2.7Hz),3.25(1H,dd,J＝11.0,2.7Hz),3.16-3.03(1H,m),1.88-1.12(6H,m),1.08-0.97(21H,m),0.59(3H,s)；31P NMR(121.5MHz,CDCl3)δ156.6(1P,s).
实施例54
恶唑磷烷单体16b
以与得到化合物16a类似的方式，使用III-b代替III-a,得到化合物16b。
1H NMR(600MHz,CDCl3)δ7.87(1H,d,J＝7.8Hz),7.52-7.48(4H,m),7.38-7.21(16H,m),6.83-6.79(4H,m),6.14(1H,d,J＝4.8Hz),5.33(1H,d,J＝7.8Hz),4.99(1H,d,J＝5.4Hz),4.89(1H,d,J＝5.4Hz),4.67(1H,dd,J＝13.8,7.2Hz),4.52(1H,dt,J＝10.4,4.8Hz),4.31(1H,t,J＝4.8Hz),4.06-4.03(1H,m),3.78(3H,s),3.77(3H,s),3.47(1H,dd,J＝10.4,2.4Hz),3.47-3.39(1H,m),3.22-3.17(2H,m),3.00(1H,ddd,J＝19.5,10.4,4.8Hz),1.82-1.74(1H,m),1.68-1.58(1H,m),1.56(1H,dd,J＝14.4,8.4Hz),1.38(1H,dd,J＝14.4,7.2Hz),1.31-1.25(1H,m),1.26-1.17(1H,m),1.08-0.98(21H,m),0.63(3H,s)；31PNMR(243.0MHz,CDCl3)δ154.3(1P,s).
实施例55
恶唑磷烷单体17a
以与得到化合物3a.类似的方式，使用5'-O-(DMTr)-2'-O，4'-C-亚甲基-6-N-(苯甲酰基)腺苷代替5'-O-(DMTr)-2-N-(苯氧基乙酰基)-6-O-(氰基乙基)鸟苷,得到化合物17a。
1H NMR(300MHz,CDCl3)δ9.10(1H,brs),8.76(1H,s),8.32(1H,s),8.04(2H,d,J＝7.2Hz),7.64-7.18(22H,m),6.84(4H,d,J＝8.7Hz),6.10(1H,s),4.76(1H,d J＝6.9Hz),4.58(1H,s),4.61-4.51(1H,m),3.91(1H,d,J＝7.8Hz),3.77(1H,d,J＝7.8Hz),3.75(6H,s),3.50(1H,s),3.47-3.33(1H,m),3.31-3.19(1H,m),3.03-2.88(1H,m),1.84-1.09(6H,m),0.51(3H,s)；31P NMR(121.5MHz,CDCl3)δ152.9(1P,s).
实施例56
恶唑磷烷单体17b
以与得到化合物17a类似的方式，使用III-b代替III-a,得到化合物17b。
1H NMR(300MHz,CDCl3)δ8.81(1H,s),8.30(1H,s),8.07-8.00(2H,m),7.64-7.17(22H,m),6.86-6.79(4H,m),6.12(1H,s),4.81-4.72(1H,m),4.62(1H,d J＝7.2Hz),4.57(1H,s),3.94(1H,d,J＝7.8Hz),3.89(1H,d,J＝7.8Hz),3.77(6H,s),3.48(2H,s),3.46-3.32(1H,m),3.24-3.13(1H,m),3.10-2.97(1H,m),1.84-1.49(3H,m),1.42-1.09(3H,m),0.58(3H,s)；31P NMR(121.5MHz,CDCl3)δ157.3(1P,s).
实施例57
恶唑磷烷单体18a
以与得到化合物3a类似的方式，使用5'-O-(DMTr)-2'-O，4'-C-亚甲基-4-N-(异丁基)-5-甲基胞苷代替5'-O-(DMTr)-2-N-(苯氧基乙酰基)-6-O-(氰基乙基)鸟苷,得到化合物18a。
1H NMR(300MHz,CDCl3)δ7.88(1H,brs),7.58-7.18(20H,m),6.88-6.80(4H,m),5.65(1H,s),4.69-4.60(1H,m),4.52(1H,d,J＝6.6Hz),4.49(1H,s),3.81-3.74(1H,m),3.75(3H,s),3.73(3H,s),3.64(1H,d,J＝8.1Hz),3.56(1H,d,J＝11.1Hz),3.53(1H,d,J＝8.1Hz),3.46(1H,d,J＝11.1Hz),3.56-3.40(1H,m),3.32-3.20(1H,m),3.14-3.00(1H,m),1.85-1.12(6H,m),1.60(3H,s),1.19(6H,d,J＝6.9Hz),0.55(3H,s)；31P NMR(121.5MHz,CDCl3)δ155.9(1P,s).
实施例58
恶唑磷烷单体18b
以与得到化合物18a类似的方式，使用III-b代替III-a,得到化合物18b。
1H NMR(300MHz,CDCl3)δ7.86(1H,brs),7.56-7.19(20H,m),6.88-6.79(4H,m),5.69(1H,s),4.86-4.76(1H,m),4.46(1H,s),4.45(1H,d,J＝7.5Hz),3.80-3.75(1H,m),3.79(6H,s),3.74(1H,d,J＝8.1Hz),3.69(1H,d,J＝8.1Hz),3.51(1H,d,J＝11.1Hz),3.44-3.30(1H,m),3.39(1H,d,J＝11.1Hz),3.29-3.17(1H,m),3.11-2.97(1H,m),1.86-1.52(3H,m),1.64(3H,s),1.45-1.10(3H,m),1.21(6H,d,J＝6.6Hz),0.62(3H,s)；31P NMR(121.5MHz,CDCl3)δ158.2(1P,s).
实施例59
恶唑磷烷单体19a
以与得到化合物3a.类似的方式，使用5'-O-(DMTr)-2'-O，4'-C-亚甲基-2-N-(苯氧基乙酰基)-6-O-(氰基乙基)鸟苷代替5'-O-(DMTr)-2-N-(苯氧基乙酰基)-6-O-(氰基乙基)鸟苷,得到化合物19a。
1H NMR(300MHz,CDCl3)δ8.71(1H,brs),8.16(1H,s),7.50-7.17(21H,m),7.09-7.01(3H,m),6.86-6.79(4H,m),6.03(1H,s),4.84(2H,t,J＝6.6Hz),4.72(2H,s),4.68(1H,d,J＝7.2Hz),4.55-4.46(1H,m),4.50(1H,s),3.90(1H,d,J＝7.8Hz),3.77(1H,d,J＝7.8Hz),3.75(6H,s),3.51(1H,d,J＝10.8Hz),3.47(1H,d,J＝10.8Hz),3.45-3.21(2H,m),3.08(2H,t,J＝6.6Hz),3.03-2.89(1H,m),1.80-1.08(6H,m),0.47(3H,s)；31P NMR(121.5MHz,CDCl3)δ153.2(1P,s).
实施例60
恶唑磷烷单体19b
以与得到化合物19a类似的方式，使用III-b代替III-a,得到化合物19b。
1H NMR(300MHz,CDCl3)δ8.86(1H,brs),8.13(1H,s),7.55-7.17(21H,m),7.08-6.98(3H,m),6.95-6.78(4H,m),6.01(1H,s),4.86(2H,t,J＝6.6Hz),4.82-4.73(1H,m),4.70(2H,s),4.64(1H,d,J＝7.5Hz),4.49(1H,s),3.94(1H,d,J＝7.8Hz),3.89(1H,d,J＝7.8Hz),3.77(6H,s),3.46(2H,s),3.45-3.30(1H,m),3.24-3.12(1H,m),3.09(2H,t,J＝6.6Hz),3.09-2.96(1H,m),1.81-1.50(3H,m),1.41-1.06(3H,m),0.58(3H,s)；31P NMR(121.5MHz,CDCl3)δ157.4(1P,s).
实施例61
恶唑磷烷单体20a
以与得到化合物3a类似的方式，使用5'-O-(DMTr)-2'-O，4'-C-亚甲基-5-甲基尿苷代替5'-O-(DMTr)-2-N-(苯氧基乙酰基)-6-O-(氰乙基)鸟苷,得到化合物20a。
1H NMR(300MHz,CDCl3)δ7.71(1H,d,J＝0.9Hz),7.50-7.17(20H,m),6.87-6.80(4H,m),5.61(1H,s),4.69-4.60(1H,m),4.55(1H,d,J＝6.9Hz),4.41(1H,s),3.74(3H,s),3.73(3H,s),3.64(1H,d,J＝7.8Hz),3.55(1H,d,J＝7.8Hz),3.53(1H,d,J＝10.8Hz),3.46(1H,d,J＝10.8Hz),3.56-3.42(1H,m),3.35-3.24(1H,m),3.13-3.00(1H,m),1.85-1.45(3H,m),1.55(3H,d,J＝0.9Hz),1.41-1.12(3H,m),0.56(3H,s)；31P NMR(121.5MHz,CDCl3)δ155.1(1P,s).
实施例62
恶唑磷烷单体20b
以与得到化合物20a类似的方式，使用III-b代替III-a,得到化合物20b。
1H NMR(300MHz,CDCl3)δ7.69(1H,s),7.56-7.19(20H,m),6.88-6.79(4H,m),5.66(1H,s),4.87-4.77(1H,m),4.47(1H,d,J＝7.8Hz),4.40(1H,s),3.78(6H,s),3.74(1H,d,J＝7.8Hz),3.68(1H,d,J＝7.8Hz),3.50(1H,d,J＝10.8Hz),3.46-3.32(1H,m),3.39(1H,d,J＝10.8Hz),3.30-3.19(1H,m),3.12-2.98(1H,m),1.85-1.56(3H,m),1.59(3H,s),1.46-1.12(3H,m),0.63(3H,s)；31P NMR(121.5MHz,CDCl3)d 158.1(1P,s).
实施例63
恶唑磷烷单体21a
以与得到化合物3a类似的方式，使用5'-O-(DMTr)-2'-O-甲氧基乙基-5-甲基尿苷代替5'-O-(DMTr)-2-N-(苯氧基乙酰基)-6-O-(氰基乙基)鸟苷,得到化合物21a。
1H NMR(300MHz,CDCl3)δ7.62-7.18(21H,m),6.84(4H,d,J＝8.7Hz),6.07(1H,d,J＝5.7Hz),4.86-4.76(1H,m),4.63-4.54(1H,m),4.20(1H,t,J＝5.4Hz),3.95-3.89(1H,m),3.78(6H,s),3.78-3.71(2H,m),3.60-3.48(2H,m),3.44-3.02(5H,m),3.31(3H,s),1.88-1.15(6H,m),1.35(3H,s),0.58(3H,s)；31P NMR(121.5MHz,CDCl3)d 156.3(1P,s).
实施例64
恶唑磷烷单体21b
以与得到化合物21a类似的方式，使用III-b代替III-a,得到化合物21b。
1H NMR(300MHz,CDCl3)δ7.71(1H,d,J＝1.2Hz),7.55-7.22(20H,m),6.86-6.78(4H,m),5.99(1H,d,J＝3.9Hz),4.78-4.62(2H,m),4.13-4.08(1H,m),4.07-4.02(1H,m),3.77(6H,s),3.77-3.70(1H,m),3.65-3.56(1H,m),3.52-3.36(4H,m),3.33-3.14(2H,m),3.29(3H,s),3.08-2.94(1H,m),1.86-1.72(1H,m),1.71-1.55(2H,m),1.30(3H,d,J＝1.2Hz),1.47-1.16(3H,m)0.64(3H,s)；31P NMR(121.5MHz,CDCl3)δ155.6(1P,s).
实施例65
恶唑磷烷单体22a
以与得到化合物4a类似的方式，使用VII-a代替III-a,得到化合物22a。
1H NMR(300MHz,CDCl3)δ7.57(1H,d,J＝0.9Hz),7.37-6.94(20H,m),6.87-6.78(4H,m),6.48(1H,dd,J＝8.6,5.7Hz),5.42(1H,dd,J＝11.0,5.1Hz),4.81-4.71(1H,m),4.02(1H,d,J＝11.0Hz),3.83(1H,d,J＝2.1Hz),3.79(6H,s),3.61-3.41(2H,m),3.24-3.09(1H,m),3.16(1H,dd,J＝10.8,2.4Hz),3.02(1H,dd,J＝10.8,2.4Hz),2.54-2.44(1H,m),2.34-2.22(1H,m),1.94-1.79(1H,m),1.74-1.56(1H,m),1.38(3H,s),1.38-1.28(2H,m)；31PNMR(121.5MHz,CDCl3)δ160.9(1P,s).
实施例66
恶唑磷烷单体22b
以与得到化合物22a类似的方式，使用VII-b代替VII-a,得到化合物22b。
1H NMR(300MHz,CDCl3)δ7.57(1H,d,J＝1.5Hz),7.43-7.11(20H,m),6.85-6.78(4H,m),6.48(1H,dd,J＝7.5,5.7Hz),5.58(1H,dd,J＝11.4,5.1Hz),4.82-4.73(1H,m),4.17-4.02(2H,m),3.78(6H,s),3.56-3.40(3H,m),3.32(1H,dd,J＝10.7,2.4Hz),3.22-3.07(1H,m),2.26-2.04(2H,m),1.95-1.81(1H,m),1.74-1.56(1H,m),1.40(3H,d,J＝1.5Hz),1.44-1.34(2H,m)；31P NMR(121.5MHz,CDCl3)δ162.2(1P,s).
实施例67
恶唑磷烷单体23a
以与得到化合物4a类似的方式，使用IX-a代替III-a,得到化合物23a。
1H NMR(300MHz,CDCl3)δ9.22(1H,brs),8.05-7.99(2H,m),7.52(1H,d,J＝1.2Hz),7.41-7.19(11H,m),6.87-6.79(4H,m),6.37(1H,dd,J＝8.4,5.7Hz),4.88-4.75(2H,m),3.86-3.80(1H,m),3.79(6H,s),3.64-3.49(2H,m),3.27-3.12(3H,m),2.97(2H,d,J＝6.6Hz),2.51-2.41(1H,m),2.33-2.20(1H,m),2.03-1.75(2H,m),1.72-1.59(1H,m),1.46-1.36(1H,m),1.40(3H,s)；31P NMR(121.5MHz,CDCl3)δ157.5(1P,s).
实施例68
恶唑磷烷单体23b
以与得到化合物23a类似的方式，使用IX-b代替IX-a,得到化合物23b。
1H NMR(300MHz,CDCl3)δ8.67(1H,brs),8.18-8.11(2H,m),7.57(1H,d,J＝1.2Hz),7.47-7.22(11H,m),6.86-6.79(4H,m),6.29(1H,t,J＝6.6Hz),4.87(1H,dt,J＝7.5,5.7Hz),4.80-4.72(1H,m),4.11-4.05(1H,m),3.79(6H,s),3.67-3.47(2H,m),3.43(1H,dd,J＝10.8,2.7Hz),3.27(1H,dd,J＝10.8,2.4Hz),3.25-3.13(1H,m),3.07-2.99(2H,m),2.19-2.12(2H,m),2.03-1.62(3H,m),1.46-1.30(1H,m),1.41(3H,s)；31P NMR(121.5MHz,CDCl3)δ158.1(1P,s).
实施例69
恶唑磷烷单体24a
以与得到化合物4a类似的方式，使用XIII-a代替III-a,得到化合物24a。
1H NMR(600MHz,CDCl3)δ7.76(2H,d,J＝9.0Hz),7.62(1H,d,J＝1.2Hz),7.40(2H,d,J＝7.2Hz),7.32-7.23(10H,m),6.85(4H,d,J＝8.4Hz),6.41(1H,dd,J＝8.4,5.4Hz),4.94(1H,dd,J＝12.3,5.4Hz),4.84-4.79(1H,m),4.03-4.01(1H,m),3.79(6H,s),3.59-3.53(1H,m),3.52-3.44(2H,m),3.41(1H,dd,J＝14.7,7.2Hz),3.37-3.30(2H,m),3.13(1H,ddd,J＝19.3,10.3,4.1Hz),2.50-2.44(1H,m),2.39(3H,s),2.35-2.29(1H,m),1.91-1.72(2H,m),1.64-1.59(1H,m),1.40(3H,s),1.12-1.05(1H,m)；31P NMR(243.0MHz,CDCl3)δ154.2(1P,s).
合成手性寡核苷酸的一般步骤：
根据表1中所示循环进行手性寡核苷酸的自动化固相合成。合成后，树脂经过25％NH3水溶液(1mL)在55℃下处理12个小时。将混合物冷却至室温，用膜过滤的方法除去树脂。滤液通过减压浓缩至干燥。将残留物溶解于H2O(3mL)，用RP-UPLC-MS进行分析，采用0.1M三乙基乙酸铵缓冲液(pH＝7.0)中的乙腈进行线性梯度洗脱(0-50％/30分钟)，柱温为50℃，流速为0.3mL/min。
表1
比较实施例1
使用上述代表常规的单体的化合物25，生产寡聚核苷酸。图2示出通过比较实施例1得到的产物的图表。
分析
实施例中的单体是化学稳定的。单体的分离率均超过80％，高于常规方法的分离率。
我们使用基于第二个一般步骤的上述实施例中的手性试剂以及基于第一个一般步骤的上述实施例中的单体合成寡核苷酸衍生物。如图2所示，常规的单体会造成不完全的脱保护产物、副产物和失败的序列。而另一方面，如图1所示，即使造成了失败的序列，本发明的方法几乎不造成不完全的脱保护产物和副产物。可以看出，本发明的方法能够减少不完全的脱保护产物和副产物。因为本发明可以减少非期望的产物，所以易于分离目标寡核苷酸衍生物。
Claims (216)
1.一种手性试剂或其盐，其中，所述手性试剂有如下化学式(I')：
其中，所述G1和G2独立地为氢原子或者式(III)的基团，前提是G1和G2中的至少一者为(III)的基团，
其中，所述G31～G33独立地为C1-4烷基、C1-4烷氧基、C6-14芳基、C7-14芳烷基、C1-4烷基C6-14芳基、C1-4烷氧基C6-14芳基或C6-14芳基C1-4烷基。
2.根据权利要求1所述的手性试剂或其盐，其中G1是氢原子。
3.根据权利要求1-2任一项所述的手性试剂或其盐，其中，所述G2为式(III)的基团，其中，所述G31～G33独立地为C1-4烷基、C6-14芳基、C7-14芳烷基、C1-4烷基C6-14芳基、C1-4烷氧基C6-14芳基或C6-14芳基C1-4烷基。
4.根据权利要求1-2任一项所述的手性试剂或其盐，其中，G2为式(III)的基团，其中，所述G31～G33独立地为C1-4烷基、C6芳基、C7-10芳烷基、C1-4烷基C6芳基、C1-4烷氧基C6芳基或C6芳基C1-4烷基。
5.根据权利要求1-2任一项所述的手性试剂或其盐，其中，G2为式(III)的基团，其中，所述G31～G33独立地为C1-4烷基或C6芳基。
6.根据权利要求1-2任一项所述的手性试剂或其盐，其中，所述G2为式(III)的基团，其中，所述G31～G33独立地为C1-4烷基。
7.根据权利要求1-2任一项所述的手性试剂或其盐，其中，所述G2为式(III)的基团，其中，所述G31和G33独立地为C6芳基，所述G32为C1-4烷基。
8.根据权利要求7所述的手性试剂或其盐，其中，G2是式(III)的基团，其中C1-4烷基是甲基。
9.根据权利要求1所述的手性试剂或其盐，其中，所述手性试剂为(S)-2-(甲基二苯基硅烷)-1-((S)-吡咯烷-2-基)乙醇。
10.根据权利要求1所述的手性试剂或其盐，其中，所述手性试剂为(R)-2-(甲基二苯基硅烷)-1-((R)-1-吡咯烷-2-基)乙醇。
11.根据权利要求1所述的手性试剂或其盐，其中，所述手性试剂为(S)-2-(三甲基硅烷)-1-((S)-1-吡咯烷-2-基)乙醇。
12.一种核苷3'-亚磷酰胺衍生物，其中所述核苷3'-亚磷酰胺衍生物由式(Va')或(Vb')表示，
其中所述G1和G2独立地为氢原子或者式(III)的基团，前提是G1和G2中的至少一者为式(III)的基团，
其中所述G31～G33独立地为C1-4烷基、C1-4烷氧基、C6-14芳基、C7-14芳烷基、C1-4烷基C6-14芳基、C1-4烷氧基C6-14芳基或C6-14芳基C1-4烷基，
所述G5是羟基的保护基团，
R2为氢、-OH、-SH、-NRdRd、-N3、卤素、C1-10烷基、C1-10烷基-Y1-、或C6-14芳基-Y1-，
Y1是O，
Rd为氢，
所述R3是-CH2-、-(CH2)2-、-CH2NH-或-CH2N(CH3)-表示的基团，以及
所述Bs是从由下式(Ⅵ)～(Ⅺ)表示的基团或它们的衍生物中选出的基团：
13.根据权利要求12所述的核苷3'-亚磷酰胺衍生物，其中所述核苷3'-亚磷酰胺衍生物由式(Va')表示：
14.根据权利要求13所述的核苷3'-亚磷酰胺衍生物，其中G1是氢原子。
15.根据权利要求14所述的核苷3'-亚磷酰胺衍生物，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基、C6-14芳基、C7-14芳烷基、C1-4烷基C6-14芳基、C1-4烷氧基C6-14芳基或C6-14芳基C1-4烷基。
16.根据权利要求14所述的核苷3'-亚磷酰胺衍生物，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基、C6芳基、C7-10芳烷基、C1-4烷基C6芳基、C1-4烷氧基C6芳基或C6芳基C1-4烷基。
17.根据权利要求14所述的核苷3'-亚磷酰胺衍生物，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基或C6芳基。
18.根据权利要求14所述的核苷3'-亚磷酰胺衍生物，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基。
19.根据权利要求14所述的核苷3'-亚磷酰胺衍生物，其中G2为式(III)的基团，其中G31和G33为C6芳基且G28为C1-4烷基。
20.权利要求19的核苷3'-亚磷酰胺衍生物，其中G2是式(III)的基团，其中C1-4烷基是甲基。
21.根据权利要求14所述的核苷3'-亚磷酰胺衍生物，其中R2是氢。
22.根据权利要求14所述的核苷3'-亚磷酰胺衍生物，其中R2为卤素。
23.根据权利要求14所述的核苷3'-亚磷酰胺衍生物，其中R2为C6-14芳基-Y1-。
24.根据权利要求14所述的核苷3'-亚磷酰胺衍生物，其中R2为C1-10烷基-Y1-。
25.根据权利要求12-24中任一项所述的核苷3'-亚磷酰胺衍生物，其中G5是三苯甲基、4-单甲氧基三苯甲基、4,4'-二甲氧基三苯甲基、4,4',4”-三甲氧基三苯甲基、9-苯基黄嘌呤-9-基或9-(对甲氧基苯基)黄嘌呤-9-基。
26.根据权利要求25所述的核苷3'-亚磷酰胺衍生物，其中G5是4,4'-二甲氧基三苯甲基。
27.根据权利要求12-24和26中任一项所述的核苷3'-亚磷酰胺衍生物，其中Bs是腺嘌呤、胸腺嘧啶、胞嘧啶、鸟嘌呤或其衍生物。
28.根据权利要求27所述的核苷3'-亚磷酰胺衍生物，其中Bs选自：
其中R8至R10中的每一个独立地为C1-10烷基、C6-C10芳基、C6-C10芳烷基或C6-C10芳氧基烷基。
29.根据权利要求28所述的核苷3'-亚磷酰胺衍生物，其中R8是甲基、异丙基、苯基、苄基和苯氧基甲基。
30.根据权利要求28或29所述的核苷3'-亚磷酰胺衍生物，其中R9和R10是C1-4烷基。
31.根据权利要求12所述的核苷3'-亚磷酰胺衍生物，其中所述核苷3'-亚磷酰胺衍生物由式(Vb')表示：
32.根据权利要求31所述的核苷3'-亚磷酰胺衍生物，其中G1是氢原子。
33.根据权利要求32所述的核苷3'-亚磷酰胺衍生物，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基、C6-14芳基、C7-14芳烷基、C1-4烷基C6-14芳基、C1-4烷氧基C6-14芳基或C6-14芳基C1-4烷基。
34.根据权利要求32所述的核苷3'-亚磷酰胺衍生物，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基、C6芳基、C7-10芳烷基、C1-4烷基C6芳基、C1-4烷氧基C6芳基或C6芳基C1-4烷基。
35.根据权利要求32所述的核苷3'-亚磷酰胺衍生物，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基或C6芳基。
36.根据权利要求32所述的核苷3'-亚磷酰胺衍生物，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基。
37.根据权利要求32所述的核苷3'-亚磷酰胺衍生物，其中G2为式(III)的基团，其中G31和G33为C6芳基且G32为C1-4烷基。
38.根据权利要求37的核苷3'-亚磷酰胺衍生物，其中G2是式(III)的基团，其中C1-4烷基是甲基。
39.根据权利要求31-38中任一项所述的核苷3'-亚磷酰胺衍生物，其中R3是-CH2-。
40.根据权利要求31-38中任一项所述的核苷3'-亚磷酰胺衍生物，其中R3是-(CH2)2-。
41.根据权利要求31-38中任一项所述的核苷3'-亚磷酰胺衍生物，其中R3是-CH2NH-。
42.根据权利要求31-38中任一项所述的核苷3'-亚磷酰胺衍生物，其中R3是-CH2N(CH3)-。
43.根据权利要求31-38中任一项所述的核苷3'-亚磷酰胺衍生物，其中G5是三苯甲基、4-单甲氧基三苯甲基、4,4'-二甲氧基三苯甲基、4,4',4”-三甲氧基三苯甲基、9-苯基黄嘌呤-9-基或9-(对甲氧基苯基)黄嘌呤-9-基。
44.根据权利要求43所述的核苷3'-亚磷酰胺衍生物，其中G5是4,4'-二甲氧基三苯甲基。
45.根据权利要求31-38和44中任一项所述的核苷3'-亚磷酰胺衍生物，其中Bs是腺嘌呤、胸腺嘧啶、胞嘧啶、鸟嘌呤或其衍生物。
46.根据权利要求45所述的核苷3'-亚磷酰胺衍生物，其中Bs选自：
其中R8至R10中的每一个独立地为C1-10烷基、C6-C10芳基、C6-C10芳烷基或C6-C10芳氧基烷基。
47.根据权利要求46所述的核苷3'-亚磷酰胺衍生物，其中R8是甲基、异丙基、苯基、苄基和苯氧基甲基。
48.根据权利要求46或47所述的核苷3'-亚磷酰胺衍生物，其中R9和R10是C1-4烷基。
49.一种核苷3'-亚磷酰胺衍生物，其为选自以下的化合物：
其中DMTr表示4,4'-二甲氧基三苯甲基。
50.一种用于合成立体控制的磷原子修饰的寡核苷酸衍生物的方法，其包括提供手性试剂或其盐，所述手性试剂具有以下化学式(I’)：
其中G1和G2独立地为氢原子或者式(III)的基团，前提是G1和G2中的至少一者为式(III)的基团，
其中G31至G33独立地为C1-4烷基、C1-4烷氧基、C6-14芳基、C7-14芳烷基、C1-4烷基C6-14芳基、C1-4烷氧基C6-14芳基、或C6-14芳基C1-4烷基。
51.一种用于合成立体控制的磷原子修饰的寡核苷酸衍生物的方法，其中所述方法包括以下步骤：
包含非手性H-膦酸酯部分的分子与手性试剂或其盐反应，生成核苷3'-亚磷酰胺衍生物的单体；
单体与核苷反应，生成缩合中间体；以及
将缩合中间体转化为包含手性的X-膦酸酯部分的核酸，
其中，所述G1和G2独立地为氢原子或者式(III)的基团，前提是G1和G2中的至少一者为式(III)的基团，
其中，所述G31～G33独立地为C1-4烷基、C1-4烷氧基、C6-14芳基、C7-14芳烷基、C1-4烷基C6-14芳基、C1-4烷氧基C6-14芳基或C6-14芳基C1-4烷基。
52.根据权利要求50-51中任一项所述的方法，其中G1是氢原子。
53.根据权利要求52所述的方法，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基，C6-14芳基，C7-14芳烷基，C1-4烷基C6-14芳基，C1-4烷氧基C6-14芳基或C6-14芳基C1-4烷基。
54.根据权利要求52所述的方法，其中G2是式(III)的基团，其中G31至G33独立地为C1-4烷基，C6芳基，C7-10芳烷基，C1-4烷基C6芳基，C1-4烷氧基C6芳基或C6芳基C1-4烷基。
55.根据权利要求52所述的方法，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基或C6芳基。
56.根据权利要求52所述的方法，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基。
57.根据权利要求52所述的方法，其中G2是式(III)的基团，其中G31和G33是C6芳基并且G32是C1-4烷基。
58.根据权利要求57所述的方法，其中G2是式(III)的基团，其中所述C1-4烷基是甲基。
59.根据权利要求50或51所述的方法，其中所述手性试剂为(S)-2-(甲基二苯基硅烷)-1-((S)-吡咯烷-2-基)乙醇。
60.根据权利要求50或51所述的方法，其中所述手性试剂为(R)-2-(甲基二苯基硅烷)-1-((R)-1-吡咯烷-2-基)乙醇。
61.根据权利要求50或51所述的方法，其中所述手性试剂为(S)-2-(三甲基硅烷)-1-((S)-1-吡咯烷-2-基)乙醇。
62.一种用于合成立体控制的磷原子修饰的寡核苷酸衍生物的方法，其中所述方法包括以下步骤：
由式(Va')或(Vb')表示的核苷3'-亚磷酰胺衍生物与活化剂和核苷反应，生成缩合中间体；以及将缩合中间体转化为包含手性的X-膦酸酯部分的核酸，
其中G1和G2独立地为氢原子或者式(III)的基团，前提是G1和G2中的至少一者为式(III)的基团，
其中G31至G33独立地为C1-4烷基，C1-4烷氧基，C6-14芳基，C7-14芳烷基，C1-4烷基C6-14芳基，C1-4烷氧基C6-14芳基，或C6-14芳基C1-4烷基，
G5是羟基的保护基团，
R2为氢、-OH、-SH、-NRdRd、-N3、卤素、C1-10烷基、C1-10烷基-Y1-、或C6-14芳基-Y1-，
Y1是O，
Rd为氢原子，
R3是由-CH2-，-(CH2)2-，-CH2NH-或-CH2N(CH3)-表示的基团，以及
Bs为选自由下式(VI)至(XI)表示的基团或其衍生物的基团：
63.根据权利要求62所述的方法，其中所述核苷3'-亚磷酰胺衍生物由式(Va')表示：
64.根据权利要求63所述的用于合成的方法，其中G1是氢原子。
65.根据权利要求64所述的方法，其中G2是式(III)的基团，其中G31至G33独立地为C1-4烷基，C6-14芳基，C7-14芳烷基，C1-4烷基C6-14芳基，C1-4烷氧基C6-14芳基或C6-14芳基C1-4烷基。
66.根据权利要求64所述的方法，其中G2是式(III)的基团，其中G31至G33独立地为C1-4烷基，C6芳基，C7-10芳烷基，C1-4烷基C6芳基，C1-4烷氧基C6芳基或C6芳基C1-4烷基。
67.根据权利要求64所述的方法，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基或C6芳基。
68.根据权利要求64所述的方法，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基。
69.根据权利要求64所述的方法，其中G2为式(III)的基团，其中G31和G33为C6芳基且G32为C1-4烷基。
70.根据权利要求69所述的方法，其中G2是式(III)的基团，其中C1-4烷基是甲基。
71.根据权利要求64所述的方法，其中R2是氢。
72.根据权利要求64所述的方法，其中R2是卤素。
73.根据权利要求64所述的方法，其中R2为C6-14芳基-Y1-。
74.根据权利要求64所述的方法，其中R2是C1-10烷基-Y1-。
75.根据权利要求62-74中任一项所述的方法，其中G5是三苯甲基，4-单甲氧基三苯甲基，4,4'-二甲氧基三苯甲基，4,4',4”-三甲氧基三苯甲基，9-苯基黄嘌呤-9-基或9-(对甲氧基苯基)黄嘌呤-9-基。
76.根据权利要求75所述的方法，其中G5是4,4'-二甲氧基三苯甲基。
77.根据权利要求62-74和76中任一项所述的方法，其中Bs是腺嘌呤，胸腺嘧啶，胞嘧啶，鸟嘌呤，或其衍生物。
78.根据权利要求77所述的方法，其中Bs选自：
其中R8至R10中的每一个独立地为C1-10烷基，C6-C10芳基，C6-C10芳烷基或C6-C10芳氧基烷基。
79.根据权利要求78的方法，其中R8是甲基，异丙基，苯基，苄基和苯氧基甲基。
80.根据权利要求78或79的方法，其中R9和R10是C1-4烷基。
81.根据权利要求62所述的方法，其中所述核苷3'-亚磷酰胺衍生物由式(Vb')表示：
82.根据权利要求81所述的方法，其中G1是氢原子。
83.根据权利要求82所述的方法，其中G2是式(III)的基团，其中G31至G33独立地为C1-4烷基，C6-14芳基，C7-14芳烷基，C1-4烷基C6-14芳基，C1-4烷氧基C6-14芳基或C6-14芳基C1-4烷基。
84.根据权利要求82所述的方法，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基，C6芳基，C7-10芳烷基，C1-4烷基C6芳基，C1-4烷氧基C6芳基或C6芳基C1-4烷基。
85.根据权利要求82所述的方法，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基或C6芳基。
86.根据权利要求82所述的方法，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基。
87.根据权利要求82所述的方法，其中G2是式(III)的基团，其中G31和G33是C6芳基，G32是C1-4烷基。
88.根据权利要求87的方法，其中G2是式(III)的基团，其中C1-4烷基是甲基。
89.根据权利要求81-88中任一项所述的方法，其中R3是-CH2-。
90.根据权利要求81-88中任一项所述的方法，其中R3是-(CH2)2-。
91.根据权利要求81-88中任一项所述的方法，其中R3是-CH2NH-。
92.根据权利要求81-88中任一项所述的方法，其中R3是-CH2N(CH3)-。
93.根据权利要求81-88中任一项所述的方法，其中G5是三苯甲基，4-单甲氧基三苯甲基，4,4'-二甲氧基三苯甲基，4,4',4”-三甲氧基三苯甲基，9-苯基黄嘌呤-9-基或9-(对甲氧基苯基)黄嘌呤-9-基。
94.根据权利要求93所述的方法，其中G5是4,4'-二甲氧基三苯甲基。
95.根据权利要求81-88和94中任一项所述的方法，其中Bs是腺嘌呤，胸腺嘧啶，胞嘧啶，鸟嘌呤，或其衍生物。
96.根据权利要求95所述的方法，其中Bs选自：
其中R8至R10中的每一个独立地为C1-10烷基，C6-C10芳基，C6-C10芳烷基或C6-C10芳氧基烷基。
97.根据权利要求96的方法，其中R8是甲基，异丙基，苯基，苄基和苯氧基甲基。
98.根据权利要求96或97的方法，其中R9和R10是C1-4烷基。
99.一种用于合成立体控制的磷原子修饰的寡核苷酸衍生物的方法，其中所述方法包括以下步骤：
使核苷3'-亚磷酰胺衍生物与活化剂和核苷反应，生成缩合中间体；以及将缩合中间体转化为包含手性的X-膦酸酯部分的核酸，其中所述核苷3'-亚磷酰胺衍生物为选自以下的化合物：
其中DMTr表示4,4'-二甲氧基三苯甲基。
100.通过核苷3'-亚磷酰胺衍生物与活化剂和核苷反应形成的化合物，其中所述核苷3'-亚磷酰胺衍生物具有式(Va')或(Vb')的结构：
其中G1和G2独立地为氢原子或者式(III)的基团，前提是G1和G2中的至少一者为式(III)的基团，
其中G31至G33独立地为C1-4烷基，C1-4烷氧基，C6-14芳基，C7-14芳烷基，C1-4烷基C6-14芳基，C1-4烷氧基C6-14芳基，或C6-14芳基C1-4烷基，
G5是羟基的保护基团，
R2为氢、-OH、-SH、-NRdRd、-N3、卤素、C1-10烷基、C1-10烷基-Y1-、或C6-14芳基-Y1-，
Y1是O，
Rd为氢原子，
R3是由-CH2-，-(CH2)2-，-CH2NH-或-CH2N(CH3)-表示的基团，和
Bs为选自由下式(VI)至(XI)表示的基团或其衍生物的基团：
101.根据权利要求100所述的化合物，其中核苷3'-亚磷酰胺衍生物由式(Va')表示：
102.根据权利要求101所述的化合物，其中G1是氢原子。
103.根据权利要求102所述的化合物，其中G2是式(III)的基团，其中G31至G33独立地为C1-4烷基，C6-14芳基，C7-14芳烷基，C1-4烷基C6-14芳基，C1-4烷氧基C6-14芳基或C6-14芳基C1-4烷基。
104.根据权利要求102所述的化合物，其中G2是式(III)的基团，其中G31至G33独立地为C1-4烷基，C6芳基，C7-10芳烷基，C1-4烷基C6芳基，C1-4烷氧基C6芳基或C6芳基C1-4烷基。
105.根据权利要求102所述的化合物，其中G2是式(III)的基团，其中G31至G33独立地为C1-4烷基或C6芳基。
106.根据权利要求102所述的化合物，其中G2是式(III)的基团，其中G31至G33独立地为C1-4烷基。
107.根据权利要求102所述的化合物，其中G2是式(III)的基团，其中G31和G33是C6芳基，G32是C1-4烷基。
108.根据权利要求107的化合物，其中G2是式(III)的基团，其中C1-4烷基是甲基。
109.根据权利要求108的化合物，其中G31和G33是苯基。
110.根据权利要求102所述的化合物，其中R2是氢。
111.根据权利要求102所述的化合物，其中R2是卤素。
112.根据权利要求102所述的化合物，其中R2是C6-14芳基-Y1-。
113.根据权利要求102所述的化合物，其中R2是C1-10烷基-Y1-。
114.根据权利要求100-113中任一项所述的化合物，其中G5是三苯甲基，4-单甲氧基三苯甲基，4,4'-二甲氧基三苯甲基，4,4',4”-三甲氧基三苯甲基，9-苯基黄嘌呤-9-基或9-(对甲氧基苯基)黄嘌呤-9-基。
115.根据权利要求114所述的化合物，其中G5是4,4'-二甲氧基三苯甲基。
116.根据权利要求100-113和115中任一项所述的化合物，其中Bs是腺嘌呤，胸腺嘧啶，胞嘧啶，鸟嘌呤，或其衍生物。
117.根据权利要求116所述的化合物，其中Bs选自：
其中R8至R10中的每一个独立地为C1-10烷基，C6-C10芳基，C6-C10芳烷基或C6-C10芳氧基烷基。
118.根据权利要求117的化合物，其中R8是甲基，异丙基，苯基，苄基和苯氧基甲基。
119.根据权利要求117或118所述的化合物，其中R9和R10是C1-4烷基。
120.根据权利要求100所述的化合物，其中所述核苷3'-亚磷酰胺衍生物由式(Vb')表示：
121.根据权利要求120所述的化合物，其中G1为氢原子。
122.根据权利要求121所述的化合物，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基，C6-14芳基，C7-14芳烷基，C1-4烷基C6-14芳基，C1-4烷氧基C6-14芳基或C6-14芳基C1-4烷基。
123.根据权利要求121所述的化合物，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基，C6芳基，C7-10芳烷基，C1-4烷基C6芳基，C1-4烷氧基C6芳基或C6芳基C1-4烷基。
124.根据权利要求121所述的化合物，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基或C6芳基。
125.根据权利要求121所述的化合物，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基。
126.根据权利要求121所述的化合物，其中G2是式(III)的基团，其中G31和G33是C6芳基并且G32是C1-4烷基。
127.根据权利要求126的化合物，其中G2是式(III)的基团，其中C1-4烷基是甲基。
128.根据权利要求127的化合物，其中G31和G33是苯基。
129.根据权利要求120-128中任一项所述的化合物，其中R3是-CH2-。
130.根据权利要求120-128中任一项所述的化合物，其中R3是-(CH2)2-。
131.根据权利要求120-128中任一项所述的化合物，其中R3是-CH2NH-。
132.根据权利要求120-128中任一项所述的化合物，其中R3是-CH2N(CH3)-。
133.根据权利要求120-128中任一项所述的化合物，其中G5是三苯甲基，4-单甲氧基三苯甲基，4,4'-二甲氧基三苯甲基，4,4',4”-三甲氧基三苯甲基，9-苯基黄嘌呤-9-基或9-(对甲氧基苯基)黄嘌呤-9-基。
134.根据权利要求133所述的化合物，其中G5是4,4'-二甲氧基三苯甲基。
135.根据权利要求120-128中任一项所述的化合物，其中Bs是腺嘌呤，胸腺嘧啶，胞嘧啶，鸟嘌呤，或其衍生物。
136.根据权利要求135所述的化合物，其中Bs选自：
其中R8至R10中的每一个独立地为C1-10烷基，C6-C10芳基，C6-C10芳烷基或C6-C10芳氧基烷基。
137.根据权利要求136的化合物，其中R8是甲基，异丙基，苯基，苄基和苯氧基甲基。
138.根据权利要求136或137的化合物，其中R9和R10是C1-4烷基。
139.根据权利要求135所述的化合物，其中所述核苷3'-亚磷酰胺衍生物与活化剂和位于固体支持物上的核苷反应。
140.一种在固体支持物上的具有以下结构的寡核苷酸：
其中：
其中G1和G2独立地为氢原子或者式(III)的基团，前提是G1和G2中的至少一者为式(III)的基团，
其中G31至G33独立地为C1-4烷基，C1-4烷氧基，C6-14芳基，C7-14芳烷基，C1-4烷基C6-14芳基，C1-4烷氧基C6-14芳基，或C6-14芳基C1-4烷基，
G3和G4与他们的间隔原子一起形成吡咯烷基环，
G5是羟基的保护基团，
R2为氢、-OH、-SH、-NRdRd、-N3、卤素、C1-10烷基、C1-10烷基-Y1-、或C6-14芳基-Y1-，
Y1是O，
Rd为氢原子，
每个Bs独立地为选自由下式(VI)至(XI)表示的基团或其衍生物的基团：
141.根据权利要求140所述的寡核苷酸，其中G1是氢原子。
142.根据权利要求141所述的寡核苷酸，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基，C6-14芳基，C7-14芳烷基，C1-4烷基C6-14芳基，C1-4烷氧基C6-14芳基或C6-14芳基C1-4烷基。
143.根据权利要求141所述的寡核苷酸，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基，C6芳基，C7-10芳烷基，C1-4烷基C6芳基，C1-4烷氧基C6芳基或C6芳基C1-4烷基。
144.根据权利要求141所述的寡核苷酸，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基或C6芳基。
145.根据权利要求141所述的寡核苷酸，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基。
146.根据权利要求141所述的寡核苷酸，其中G2是式(III)的基团，其中G31和G33是C6芳基并且G32是C1-4烷基。
147.根据权利要求146所述的寡核苷酸，其中G2是式(III)的基团，其中所述C1-4烷基是甲基。
148.根据权利要求147的寡核苷酸，其中G2是式(III)的基团，其中G31和G33是苯基。
149.根据权利要求141所述的寡核苷酸，其中R2是氢。
150.根据权利要求141所述的寡核苷酸，其中R2是卤素。
151.根据权利要求141所述的寡核苷酸，其中R2是C6-14芳基-Y1-。
152.根据权利要求141所述的寡核苷酸，其中R2是C1-10烷基-Y1-。
153.根据权利要求140-152中任一项所述的寡核苷酸，其中G5是三苯甲基，4-单甲氧基三苯甲基，4,4'-二甲氧基三苯甲基，4,4',4”-三甲氧基三苯甲基，9-苯基黄嘌呤-9-基或9-(对甲氧基苯基)黄嘌呤-9-基。
154.根据权利要求153所述的寡核苷酸，其中G5是4,4'-二甲氧基三苯甲基。
155.根据权利要求140-152和154中任一项所述的寡核苷酸，其中Bs独立地为腺嘌呤，胸腺嘧啶，胞嘧啶，鸟嘌呤，或其衍生物。
156.根据权利要求155所述的寡核苷酸，其中每个Bs独立地选自：
其中R8至R10中的每一个独立地为C1-10烷基，C6-C10芳基，C6-C10芳烷基或C6-C10芳氧基烷基。
157.根据权利要求156的寡核苷酸，其中R8是甲基，异丙基，苯基，苄基和苯氧基甲基。
158.根据权利要求156或157所述的寡核苷酸，其中R9和R10是C1-4烷基。
159.一种在固体支持物上的具有以下结构的寡核苷酸：
其中：
其中G1和G2独立地为氢原子或者式(III)的基团，前提是G1和G2中的至少一者为式(III)的基团，
其中G31至G33独立地为C1-4烷基，C1-4烷氧基，C6-14芳基，C7-14芳烷基，C1-4烷基C6-14芳基，C1-4烷氧基C6-14芳基，或C6-14芳基C1-4烷基，
G3和G4与他们的间隔原子一起形成吡咯烷基环，
G5是羟基的保护基团，
X是O或S，
R2为氢、-OH、-SH、-NRdRd、-N3、卤素、C1-10烷基、C1-10烷基-Y1-、或C6-14芳基-Y1-，
Y1是O，
Rd为氢原子，
每个Bs独立地为选自由下式(VI)至(XI)表示的基团或其衍生物的基团：
160.根据权利要求159的寡核苷酸，其中X是S。
161.根据权利要求159的寡核苷酸，其中X是O。
162.根据权利要求160所述的寡核苷酸，其中G1是氢原子。
163.根据权利要求160所述的寡核苷酸，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基，C6-14芳基，C7-14芳烷基，C1-4烷基C6-14芳基，C1-4烷氧基C6-14芳基或C6-14芳基C1-4烷基。
164.根据权利要求160所述的寡核苷酸，其中G2是式(III)的基团，其中G31至G33独立地为C1-4烷基，C6芳基，C7-10芳烷基，C1-4烷基C6芳基，C1-4烷氧基C6芳基或C6芳基C1-4烷基。
165.根据权利要求160所述的寡核苷酸，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基或C6芳基。
166.根据权利要求160所述的寡核苷酸，其中G2是式(III)的基团，其中G31至G33独立地为C1-4烷基。
167.根据权利要求160所述的寡核苷酸，其中G2是式(III)的基团，其中G31和G33是C6芳基，G32是C1-4烷基。
168.根据权利要求167的寡核苷酸，其中G2是式(III)的基团，其中C1-4烷基是甲基。
169.根据权利要求168的寡核苷酸，其中G2是式(III)的基团，其中G31和G33是苯基。
170.根据权利要求160所述的寡核苷酸，其中R2是氢。
171.根据权利要求160所述的寡核苷酸，其中R2是卤素。
172.根据权利要求160所述的寡核苷酸，其中R2是C6-14芳基-Y1-。
173.根据权利要求160所述的寡核苷酸，其中R2是C1-10烷基-Y1-。
174.根据权利要求159-173中任一项所述的寡核苷酸，其中G5是三苯甲基，4-单甲氧基三苯甲基，4,4'-二甲氧基三苯甲基，4,4',4”-三甲氧基三苯甲基，9-苯基黄嘌呤-9-基或9-(对甲氧基苯基)黄嘌呤-9-基。
175.根据权利要求174所述的寡核苷酸，其中G5是4,4'-二甲氧基三苯甲基。
176.根据权利要求159-173和175中任一项所述的寡核苷酸，其中Bs独立地为腺嘌呤，胸腺嘧啶，胞嘧啶，鸟嘌呤，或其衍生物。
177.根据权利要求176所述的寡核苷酸，其中每个Bs独立地选自：
其中R8至R10中的每一个独立地为C1-10烷基，C6-C10芳基，C6-C10芳烷基或C6-C10芳氧基烷基。
178.根据权利要求177的寡核苷酸，其中R8是甲基，异丙基，苯基，苄基和苯氧基甲基。
179.根据权利要求177或178的寡核苷酸，其中R9和R10是C1-4烷基。
180.一种在固体支持物上的具有以下结构的寡核苷酸：
其中：
其中G1和G2独立地为氢原子或者式(III)的基团，前提是G1和G2中的至少一者为式(III)的基团，
其中G31至G33独立地为C1-4烷基，C1-4烷氧基，C6-14芳基，C7-14芳烷基，C1-4烷基C6-14芳基，C1-4烷氧基C6-14芳基，或C6-14芳基C1-4烷基，
G3和G4与他们的间隔原子一起形成吡咯烷基环，
G5是羟基的保护基团，
X是O或S，
n是1-150，
R2为氢、-OH、-SH、-NRdRd、-N3、卤素、C1-10烷基、C1-10烷基-Y1-、或C6-14芳基-Y1-，
Y1是O，
Rd为氢原子，
每个Bs独立地为选自由下式(VI)至(XI)表示的基团或其衍生物的基团：
181.根据权利要求180所述的寡核苷酸，其中X是S。
182.根据权利要求180所述的寡核苷酸，其中X是O。
183.根据权利要求181所述的寡核苷酸，其中n是2-100。
184.根据权利要求181所述的寡核苷酸，其中n是10-100。
185.根据权利要求181所述的寡核苷酸，其中n是10-50。
186.根据权利要求181所述的寡核苷酸，其中n是15-30。
187.根据权利要求181所述的寡核苷酸，其中G1是氢原子。
188.根据权利要求181所述的寡核苷酸，其中G2是式(III)的基团，其中G31至G33独立地为C1-4烷基，C6-14芳基，C7-14芳烷基，C1-4烷基C6-14芳基，C1-4烷氧基C6-14芳基或C6-14芳基C1-4烷基。
189.根据权利要求181所述的寡核苷酸，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基，C6芳基，C7-10芳烷基，C1-4烷基C6芳基，C1-4烷氧基C6芳基或C6芳基C1-4烷基。
190.根据权利要求181所述的寡核苷酸，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基或C6芳基。
191.根据权利要求181所述的寡核苷酸，其中G2为式(III)的基团，其中G31至G33独立地为C1-4烷基。
192.根据权利要求181所述的寡核苷酸，其中G2是式(III)的基团，其中G31和G33是C6芳基并且G32是C1-4烷基。
193.根据权利要求192的寡核苷酸，其中G2是式(III)的基团，其中C1-4烷基是甲基。
194.根据权利要求193的寡核苷酸，其中G2是式(III)的基团，其中G31和G33是苯基。
195.根据权利要求181所述的寡核苷酸，其中R2是氢。
196.根据权利要求181所述的寡核苷酸，其中R2是卤素。
197.根据权利要求181所述的寡核苷酸，其中R2为C6-14芳基-Y1-。
198.根据权利要求181所述的寡核苷酸，其中R2是C1-10烷基-Y1-。
199.根据权利要求180-198中任一项所述的寡核苷酸，其中G5是三苯甲基，4-单甲氧基三苯甲基，4,4'-二甲氧基三苯甲基，4,4',4”-三甲氧基三苯甲基，9-苯基黄嘌呤-9-基或9-(对甲氧基苯基)黄嘌呤-9-基。
200.根据权利要求199所述的寡核苷酸，其中G5是4,4'-二甲氧基三苯甲基。
201.根据权利要求180-198和200中任一项所述的寡核苷酸，其中Bs独立地为腺嘌呤，胸腺嘧啶，胞嘧啶，鸟嘌呤，或其衍生物。
202.根据权利要求201所述的寡核苷酸，其中每个Bs独立地选自：
其中R8至R10中的每一个独立地为C1-10烷基，C6-C10芳基，C6-C10芳烷基或C6-C10芳氧基烷基。
203.根据权利要求202的寡核苷酸，其中R8是甲基，异丙基，苯基，苄基和苯氧基甲基。
204.根据权利要求202或203所述的寡核苷酸，其中R9和R10是C1-4烷基。
205.根据权利要求50-51和53-58中任一项所述的方法，其中产物是权利要求140-152、154、156和157中任一项所述的寡核苷酸。
206.根据权利要求50-51和53-58中任一项所述的方法，其中产物是权利要求159-173、175、177和178中任一项所述的寡核苷酸。
207.根据权利要求50-51和53-58中任一项所述的方法，其中产物是权利要求180-198、200、202和203中任一项所述的寡核苷酸。
208.根据权利要求62-74、76、78和79中任一项所述的方法，其中产物是权利要求140-152、154、156和157中任一项所述的寡核苷酸。
209.根据权利要求62-74、76、78和79中任一项所述的方法，其中产物是权利要求159-173、175、177和178中任一项所述的寡核苷酸。
210.根据权利要求62-74、76、78和79中任一项所述的方法，其中产物是权利要求180-198、200、202和203中任一项所述的寡核苷酸。
211.根据权利要求140-152、154、156和157中任一项所述的寡核苷酸，其通过权利要求50-51和53-58中任一项所述的方法制备。
212.权利要求159-173、175、177和178中任一项所述的寡核苷酸，其通过权利要求50-51和53-58中任一项所述的方法制备。
213.根据权利要求180-198、200、202和203中任一项所述的寡核苷酸，其通过权利要求50-51和53-58中任一项所述的方法制备。
214.根据权利要求140-152、154、156和157中任一项所述的寡核苷酸，其通过权利要求62-74、76、78和79中任一项所述的方法制备。
215.根据权利要求159-173、175、177和178中任一项所述的寡核苷酸，其通过权利要求62-74、76、78和79中任一项所述的方法制备。
216.根据权利要求180-198、200、202和203中任一项所述的寡核苷酸，其通过权利要求62-74、76、78和79中任一项所述的方法制备。
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Families Citing this family (73)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2012039448A1 (ja) * | 2010-09-24 | 2012-03-29 | 株式会社キラルジェン | 不斉補助基 |
| US9605019B2 (en) | 2011-07-19 | 2017-03-28 | Wave Life Sciences Ltd. | Methods for the synthesis of functionalized nucleic acids |
| KR20220139425A (ko) | 2012-07-13 | 2022-10-14 | 웨이브 라이프 사이언시스 리미티드 | 키랄 제어 |
| AU2013288048A1 (en) | 2012-07-13 | 2015-01-22 | Wave Life Sciences Ltd. | Asymmetric auxiliary group |
| KR101835401B1 (ko) | 2012-07-13 | 2018-03-08 | 신 니뽄 바이오메디칼 라보라토리즈, 엘티디. | 키랄 핵산 어쥬번트 |
| 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 |
| 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 |
| 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 |
| PT3094728T (pt) | 2014-01-16 | 2022-05-19 | Wave Life Sciences Ltd | Desenho quiral |
| RU2708237C2 (ru) | 2014-08-22 | 2019-12-05 | Общество с ограниченной ответственностью "НооГен" | Модифицированные олигонуклеотиды и способ их получения |
| JP6689279B2 (ja) | 2014-12-16 | 2020-05-20 | ロシュ イノベーション センター コペンハーゲン エーエス | キラル毒性のスクリーニング方法 |
| EP3712269A1 (en) | 2014-12-17 | 2020-09-23 | ProQR Therapeutics II B.V. | Targeted rna editing |
| 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 |
| AU2017235278C1 (en) | 2016-03-14 | 2022-03-10 | F. Hoffmann-La Roche Ag | Oligonucleotides for reduction of PD-L1 expression |
| US11267843B2 (en) | 2016-03-18 | 2022-03-08 | Roche Innovation Center Copenhagen A/S | Stereodefining L-monomers |
| 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 |
| CN109311925B (zh) * | 2016-05-12 | 2022-06-03 | 罗氏创新中心哥本哈根有限公司 | 立体限定的氧杂氮杂磷杂环戊烷亚磷酰胺单体与核苷或寡核苷酸的增强的偶联 |
| US10882884B2 (en) | 2016-05-18 | 2021-01-05 | Eth Zurich | Stereoselective synthesis of phosphorothioate oligoribonucleotides |
| 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 |
| AU2017281497B2 (en) | 2016-06-22 | 2023-04-06 | Proqr Therapeutics Ii B.V. | Single-stranded RNA-editing oligonucleotides |
| KR20190024977A (ko) | 2016-06-30 | 2019-03-08 | 사렙타 쎄러퓨틱스 인코퍼레이티드 | 근육 이상증에 대한 엑손 스킵핑 올리고머 |
| KR20190027373A (ko) | 2016-07-05 | 2019-03-14 | 바이오마린 테크놀로지스 비.브이. | 유전적 장애 치료를 위한, 특징이 개선된, 비사이클릭 스캐폴드 모이어티를 포함하는 프리-mrna 스플라이스 스위칭 또는 조정 올리고뉴클레오티드 |
| EP3500581A4 (en) | 2016-08-17 | 2021-10-06 | Solstice Biologics, Ltd. | POLYNUCLEOTIDE CONSTRUCTS |
| KR102501980B1 (ko) | 2016-09-01 | 2023-02-20 | 프로큐알 테라퓨틱스 Ⅱ 비.브이. | 화학적으로 변형된 단일 가닥 rna-편집 올리고뉴클레오타이드 |
| 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 |
| BR112019012651A2 (pt) | 2016-12-19 | 2020-01-28 | Sarepta Therapeutics Inc | conjugados de oligômero de salto de éxon para distrofia muscular |
| MX2019006882A (es) | 2016-12-19 | 2019-08-16 | Sarepta Therapeutics Inc | Conjugados de oligomeros de omision de exon para distrofia muscular. |
| HUE059905T2 (hu) | 2016-12-19 | 2023-01-28 | Sarepta Therapeutics Inc | Exonátugró oligomerkonjugátumok izomdisztrófiára |
| KR20180076661A (ko) * | 2016-12-28 | 2018-07-06 | 엘지디스플레이 주식회사 | 표시 장치용 기판과 그를 포함하는 표시 장치 |
| WO2018189382A1 (en) | 2017-04-14 | 2018-10-18 | Solstice Biologics, Ltd. | Immunomodulating polynucleotides, antibody conjugates thereof, and methods of their use |
| US11597927B2 (en) | 2017-06-02 | 2023-03-07 | Wave Life Sciences Ltd. | Oligonucleotide compositions and methods of use thereof |
| WO2018223056A1 (en) | 2017-06-02 | 2018-12-06 | 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 |
| JP7492829B2 (ja) | 2017-06-28 | 2024-05-30 | ロシュ イノベーション センター コペンハーゲン エーエス | 多重カップリングおよび酸化の方法 |
| US11597744B2 (en) | 2017-06-30 | 2023-03-07 | Sirius Therapeutics, Inc. | Chiral phosphoramidite auxiliaries and methods of their use |
| 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 |
| WO2019187691A1 (ja) | 2018-03-26 | 2019-10-03 | 株式会社カネカ | コラゲナーゼ活性を有するポリペプチド及びその製造方法 |
| 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 |
| EP3874044A1 (en) | 2018-11-02 | 2021-09-08 | BioMarin Technologies B.V. | Bispecific antisense oligonucleotides for dystrophin exon skipping |
| KR20210104759A (ko) | 2018-12-13 | 2021-08-25 | 사렙타 쎄러퓨틱스 인코퍼레이티드 | 근 이영양증을 위한 엑손 스키핑 올리고머 접합체 |
| CA3134036A1 (en) * | 2019-03-20 | 2020-09-24 | Wave Life Sciences Ltd. | Technologies useful for oligonucleotide preparation |
| JPWO2020196890A1 (zh) | 2019-03-28 | 2020-10-01 | ||
| CN113661168A (zh) * | 2019-04-16 | 2021-11-16 | 罗氏创新中心哥本哈根有限公司 | 用于制备核苷酸p(v)单体的新方法 |
| EP3955966A1 (en) | 2019-04-18 | 2022-02-23 | Sarepta Therapeutics, Inc. | Compositions for treating muscular dystrophy |
| IL298406A (en) | 2020-05-22 | 2023-01-01 | Wave Life Sciences Ltd | Double-stranded oligonucleotide assemblies and related methods |
| CA3226001A1 (en) | 2021-07-16 | 2023-01-19 | Anton Jan Van Zonneveld | Oligonucleotide for inhibiting quaking activity |
| WO2023055774A1 (en) | 2021-09-30 | 2023-04-06 | Sarepta Therapeutics, Inc. | Antisense oligonucleotides having one or more abasic units |
| WO2023154528A1 (en) * | 2022-02-11 | 2023-08-17 | Wave Life Sciences Ltd. | Stereoselective technologies for chiral compounds |
| WO2023152371A1 (en) | 2022-02-14 | 2023-08-17 | Proqr Therapeutics Ii B.V. | Guide oligonucleotides for nucleic acid editing in the treatment of hypercholesterolemia |
| WO2023214373A2 (en) | 2022-05-06 | 2023-11-09 | Academisch Ziekenhuis Leiden H.O.D.N. Lumc | Oligonucleotide |
| WO2024013360A1 (en) | 2022-07-15 | 2024-01-18 | Proqr Therapeutics Ii B.V. | Chemically modified oligonucleotides for adar-mediated rna editing |
| WO2024013361A1 (en) | 2022-07-15 | 2024-01-18 | Proqr Therapeutics Ii B.V. | Oligonucleotides for adar-mediated rna editing and use thereof |
| WO2024022911A1 (en) | 2022-07-25 | 2024-02-01 | Vico Therapeutics B.V. | Antisense oligonucleotides for treating a disease or condition associated with an abnormal processing of app |
| WO2024064237A2 (en) | 2022-09-21 | 2024-03-28 | Sarepta Therapeutics, Inc. | Dmd antisense oligonucleotide-mediated exon skipping efficiency |
| GB202215614D0 (en) | 2022-10-21 | 2022-12-07 | Proqr Therapeutics Ii Bv | Heteroduplex rna editing oligonucleotide complexes |
| WO2024110565A1 (en) | 2022-11-24 | 2024-05-30 | Proqr Therapeutics Ii B.V. | Antisense oligonucleotides for the treatment of hereditary hfe-hemochromatosis |
| GB202218090D0 (en) | 2022-12-01 | 2023-01-18 | Proqr Therapeutics Ii Bv | Antisense oligonucleotides for the treatment of aldehyde dehydrogenase 2 deficiency |
| WO2024121373A1 (en) | 2022-12-09 | 2024-06-13 | Proqr Therapeutics Ii B.V. | Antisense oligonucleotides for the treatment of cardiovascular disease |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102143746A (zh) * | 2008-07-03 | 2011-08-03 | 埃克塞利希斯股份有限公司 | Cdk 调节剂 |
Family Cites Families (702)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2878264A (en) | 1959-03-17 | Substituted amino alcohols | ||
| DE1144279B (de) | 1957-09-26 | 1963-02-28 | Robins Co Inc A H | Verfahren zur Herstellung von 3-Aryl-3-hydroxypyrrolidinen und deren Salzen |
| US3135766A (en) | 1961-10-03 | 1964-06-02 | Mead Johnson & Co | 3-substituted-3-pyrrolidinols |
| US3484473A (en) | 1967-05-12 | 1969-12-16 | Buckman Labor Inc | Methylene bisesters of thiolsulfonic acids |
| DE1934150A1 (de) | 1968-07-10 | 1970-01-15 | Pennwalt Corp | Neue 1-Alkanoyloxy-1,2,4,5-tetrahydro-3H,3-benzazepine |
| US3687808A (en) | 1969-08-14 | 1972-08-29 | Univ Leland Stanford Junior | Synthetic polynucleotides |
| US3745162A (en) | 1970-08-31 | 1973-07-10 | Robins Co Inc A H | 1,2,3,4-tetrahydroisoquinoline-2-(thio)-carboxamides |
| GB1448437A (en) | 1973-02-24 | 1976-09-08 | Beecham Group Ltd | Diphenylpropylamines |
| US4022791A (en) | 1975-06-03 | 1977-05-10 | Pfizer Inc. | 2-Aminomethyl-3,4-dihydronaphthalenes |
| GB1504424A (en) | 1975-08-09 | 1978-03-22 | Beecham Group Ltd | Isoquinoline-derived aminoethers |
| BR7807288A (pt) | 1977-11-08 | 1979-06-12 | Genentech Inc | Processo para sintese de polinucleotidos |
| DD133885B1 (de) | 1978-01-04 | 1981-02-25 | Hans Lehmann | Mittel zur bekaempfung von phytopathogenen bakterien und pilzen |
| US5132418A (en) | 1980-02-29 | 1992-07-21 | University Patents, Inc. | Process for preparing 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 |
| 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 |
| US4542142A (en) | 1982-11-22 | 1985-09-17 | Roussel Uclaf | Insecticidal cyclopropane carboxylic acid derivatives with 3-unsaturated-side chain |
| 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 |
| US5643889A (en) | 1984-07-11 | 1997-07-01 | Temple University-Of The Commonwealth System Of Pennsylvania | Cholesterol conjugates of 2'5'-oligoadenylate derivatives and antiviral 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 |
| US5367066A (en) | 1984-10-16 | 1994-11-22 | Chiron Corporation | Oligonucleotides with selectably cleavable and/or abasic sites |
| FR2575751B1 (fr) | 1985-01-08 | 1987-04-03 | Pasteur Institut | Nouveaux nucleosides de derives de l'adenosine, leur preparation et leurs applications biologiques |
| FR2576898B1 (fr) | 1985-02-01 | 1988-01-08 | Lafon Labor | Derives de 3-phenyl-tetrahydropyridine, procede de preparation et utilisation en therapeutique |
| US4659774A (en) | 1985-11-01 | 1987-04-21 | American Hoechst Corporation | Support for solid-phase oligonucleotide synthesis |
| US4666777A (en) | 1985-12-23 | 1987-05-19 | The Dow Chemical Company | Structured latex core-shell polymer particles suitable for use in the preparation of composite sheets |
| US4735949A (en) | 1986-02-18 | 1988-04-05 | Warner-Lambert Company | Disubstituted-7-pyrrolidinonaphthyridine antibacterial agents |
| US4840956A (en) | 1986-02-18 | 1989-06-20 | Warner-Lambert Company | Novel disubstituted-7-pyrrolidinoquinoline antibacterial agents |
| IL83663A0 (en) | 1986-10-27 | 1988-01-31 | Robins Co Inc A H | Preparation of 3-pyrrolidinols |
| AU598946B2 (en) | 1987-06-24 | 1990-07-05 | Howard Florey Institute Of Experimental Physiology And Medicine | Nucleoside derivatives |
| EP0302349B1 (en) | 1987-07-30 | 1993-09-29 | Bar Ilan University | Biologically active carboxylic acid esters |
| US4923901A (en) | 1987-09-04 | 1990-05-08 | Millipore Corporation | Membranes with bound oligonucleotides and peptides |
| US5175273A (en) | 1988-07-01 | 1992-12-29 | Genentech, Inc. | Nucleic acid intercalating agents |
| US4945158A (en) | 1988-08-12 | 1990-07-31 | American Cyanamid Company | Antidiabetic phosphonates |
| US4943629A (en) | 1988-08-12 | 1990-07-24 | American Cyanamid Company | Antidiabetic alpha-substituted phosphonates |
| US5047524A (en) | 1988-12-21 | 1991-09-10 | Applied Biosystems, Inc. | Automated system for polynucleotide synthesis and purification |
| US5262530A (en) | 1988-12-21 | 1993-11-16 | Applied Biosystems, Inc. | Automated system for polynucleotide synthesis and purification |
| US5141813A (en) | 1989-08-28 | 1992-08-25 | Clontech Laboratories, Inc. | Multifunctional controlled pore glass reagent for solid phase oligonucleotide synthesis |
| US5134066A (en) | 1989-08-29 | 1992-07-28 | Monsanto Company | Improved probes using nucleosides containing 3-dezauracil analogs |
| CA2029273A1 (en) | 1989-12-04 | 1991-06-05 | Christine L. Brakel | Modified nucleotide compounds |
| US5130302A (en) | 1989-12-20 | 1992-07-14 | Boron Bilogicals, Inc. | Boronated nucleoside, nucleotide and oligonucleotide compounds, compositions and methods for using same |
| CA2071897A1 (en) | 1989-12-28 | 1991-06-29 | Richard A. Glennon | Sigma receptor ligands and the use thereof |
| US5620963A (en) | 1991-10-15 | 1997-04-15 | Isis Pharmaceuticals, Inc. | Oligonucleotides for modulating protein kinase C having phosphorothioate linkages of high chiral purity |
| US5587470A (en) | 1990-01-11 | 1996-12-24 | Isis Pharmaceuticals, Inc. | 3-deazapurines |
| US5852188A (en) | 1990-01-11 | 1998-12-22 | Isis Pharmaceuticals, Inc. | Oligonucleotides having chiral phosphorus linkages |
| AU651569B2 (en) | 1990-01-11 | 1994-07-28 | Isis Pharmaceuticals, Inc. | Compositions and methods for detecting and modulating RNA activity and gene expression |
| US5914396A (en) | 1990-01-11 | 1999-06-22 | Isis Pharmaceuticals, Inc. | 2'-O-modified nucleosides and phosphoramidites |
| US5457191A (en) | 1990-01-11 | 1995-10-10 | Isis Pharmaceuticals, Inc. | 3-deazapurines |
| US7101993B1 (en) | 1990-01-11 | 2006-09-05 | Isis Pharmaceuticals, Inc. | Oligonucleotides containing 2′-O-modified purines |
| US5506212A (en) | 1990-01-11 | 1996-04-09 | Isis Pharmaceuticals, Inc. | Oligonucleotides with substantially chirally pure phosphorothioate linkages |
| US5587361A (en) | 1991-10-15 | 1996-12-24 | Isis Pharmaceuticals, Inc. | Oligonucleotides having phosphorothioate linkages of high chiral purity |
| US6339066B1 (en) | 1990-01-11 | 2002-01-15 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotides which have phosphorothioate linkages of high chiral purity and which modulate βI, βII, γ, δ, Ε, ζ and η isoforms of human protein kinase C |
| US5459255A (en) | 1990-01-11 | 1995-10-17 | Isis Pharmaceuticals, Inc. | N-2 substituted purines |
| US5646265A (en) | 1990-01-11 | 1997-07-08 | Isis Pharmceuticals, Inc. | Process for the preparation of 2'-O-alkyl purine phosphoramidites |
| US5635488A (en) | 1991-10-15 | 1997-06-03 | Isis Pharmaceuticals, Inc. | Compounds having phosphorodithioate linkages of high chiral purity |
| US5212295A (en) | 1990-01-11 | 1993-05-18 | Isis Pharmaceuticals | Monomers for preparation of oligonucleotides having chiral phosphorus linkages |
| US5681941A (en) | 1990-01-11 | 1997-10-28 | Isis Pharmaceuticals, Inc. | Substituted purines and oligonucleotide cross-linking |
| US5292875A (en) | 1990-04-20 | 1994-03-08 | Lynx Therapeutics, Inc. | Method of synthesizing sulfurized oligonucleotide analogs |
| US5151510A (en) | 1990-04-20 | 1992-09-29 | Applied Biosystems, Inc. | Method of synethesizing sulfurized oligonucleotide analogs |
| AU649458B2 (en) | 1990-05-23 | 1994-05-26 | Isis Pharmaceuticals, Inc. | Compositions and methods for modulating RNA activity through modification of the 5' cap structure of RNA |
| US5223618A (en) | 1990-08-13 | 1993-06-29 | Isis Pharmaceuticals, Inc. | 4'-desmethyl nucleoside analog compounds |
| US6087482A (en) | 1990-07-27 | 2000-07-11 | Isis Pharmaceuticals, Inc. | Heteroatomic oligonucleoside linkages |
| US5378825A (en) | 1990-07-27 | 1995-01-03 | Isis Pharmaceuticals, Inc. | Backbone modified oligonucleotide analogs |
| US5834607A (en) | 1990-07-27 | 1998-11-10 | Isis Pharmaceuticals, Inc. | Amines and methods of making and using the same |
| US5386023A (en) | 1990-07-27 | 1995-01-31 | Isis Pharmaceuticals | Backbone modified oligonucleotide analogs and preparation thereof through reductive coupling |
| ATE154246T1 (de) | 1990-07-27 | 1997-06-15 | Isis Pharmaceuticals Inc | Nuklease resistente, pyrimidin modifizierte oligonukleotide, die die gen-expression detektieren und modulieren |
| US5618704A (en) | 1990-07-27 | 1997-04-08 | Isis Pharmacueticals, Inc. | Backbone-modified oligonucleotide analogs and preparation thereof through radical coupling |
| WO1994022886A1 (en) | 1993-03-30 | 1994-10-13 | Isis Pharmaceuticals, Inc. | Heteroatomic oligonucleoside linkages |
| US5610289A (en) | 1990-07-27 | 1997-03-11 | Isis Pharmaceuticals, Inc. | Backbone modified oligonucleotide analogues |
| US5792844A (en) | 1990-07-27 | 1998-08-11 | Isis Pharmaceuticals, Inc. | Oligonucleoside linkages containing adjacent nitrogen atoms |
| US5138045A (en) | 1990-07-27 | 1992-08-11 | Isis Pharmaceuticals | Polyamine conjugated oligonucleotides |
| 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 |
| US5623070A (en) | 1990-07-27 | 1997-04-22 | Isis Pharmaceuticals, Inc. | Heteroatomic oligonucleoside linkages |
| US5541307A (en) | 1990-07-27 | 1996-07-30 | Isis Pharmaceuticals, Inc. | Backbone modified oligonucleotide analogs and solid phase synthesis thereof |
| US6121433A (en) | 1990-07-27 | 2000-09-19 | Isis Pharmaceuticals, Inc. | Oligomeric compounds having nitrogen-containing linkages |
| US5489677A (en) | 1990-07-27 | 1996-02-06 | Isis Pharmaceuticals, Inc. | Oligonucleoside linkages containing adjacent oxygen and nitrogen atoms |
| US5783682A (en) | 1990-07-27 | 1998-07-21 | Isis Pharmaceuticals, Inc. | Oligonucleotide mimics having nitrogen-containing linkages |
| US5688941A (en) | 1990-07-27 | 1997-11-18 | Isis Pharmaceuticals, Inc. | Methods of making conjugated 4' desmethyl nucleoside analog compounds |
| US5677437A (en) | 1990-07-27 | 1997-10-14 | Isis Pharmaceuticals, Inc. | Heteroatomic oligonucleoside linkages |
| US5998603A (en) | 1994-09-29 | 1999-12-07 | Isis Pharmaceuticals, Inc. | 4'-desmethyl nucleoside analogs, and oligomers thereof |
| US5432272A (en) | 1990-10-09 | 1995-07-11 | Benner; Steven A. | Method for incorporating into a DNA or RNA oligonucleotide using nucleotides bearing heterocyclic bases |
| US5512668A (en) | 1991-03-06 | 1996-04-30 | Polish Academy Of Sciences | Solid phase oligonucleotide synthesis using phospholane intermediates |
| US20020183502A1 (en) | 1991-05-21 | 2002-12-05 | Mesmaeker Alain De | Backbone-modified oligonucleotide analogs and methods for using same |
| US7015315B1 (en) | 1991-12-24 | 2006-03-21 | Isis Pharmaceuticals, Inc. | Gapped oligonucleotides |
| US6414112B1 (en) | 1991-05-24 | 2002-07-02 | Ole Buchardt | Peptide nucleic acids having 2,6-diaminopurine nucleobases |
| JPH04348077A (ja) | 1991-05-24 | 1992-12-03 | Nec Corp | 薄膜トランジスタ |
| GB2272443B (en) | 1991-06-10 | 1995-10-25 | Lucky Ltd | Nucleotide and amino acid sequences of Korean hepatitis C virus |
| US5359052A (en) | 1991-08-05 | 1994-10-25 | Polish Academy Of Sciences | Chalcophospholanes useful in the synthesis of oligonucleoside phosphorothioates, phosphorodithioates and related selenates |
| US5646267A (en) | 1991-08-05 | 1997-07-08 | Polish Academy Of Sciences | Method of making oligonucleotides and oligonucleotide analogs using phospholanes and enantiomerically resolved phospholane analogues |
| US6369209B1 (en) | 1999-05-03 | 2002-04-09 | Isis Pharmaceuticals, Inc. | Oligonucleotides having A-DNA form and B-DNA form conformational geometry |
| US7119184B2 (en) | 1991-08-12 | 2006-10-10 | Isis Pharmaceuticals, Inc. | Oligonucleotides having A-DNA form and B-DNA form conformational geometry |
| ATE221127T1 (de) | 1991-10-15 | 2002-08-15 | Isis Pharmaceuticals Inc | Über chirale phosphoratome gebundene oligonukleotide |
| US5599797A (en) | 1991-10-15 | 1997-02-04 | Isis Pharmaceuticals, Inc. | Oligonucleotides having phosphorothioate linkages of high chiral purity |
| US5607923A (en) | 1991-10-15 | 1997-03-04 | Isis Pharmaceuticals, Inc. | Oligonucleotides for modulating cytomegalovirus having phosphorothioate linkages of high chiral purity |
| US5576302A (en) | 1991-10-15 | 1996-11-19 | Isis Pharmaceuticals, Inc. | Oligonucleotides for modulating hepatitis C virus having phosphorothioate linkages of high chiral purity |
| US5654284A (en) | 1991-10-15 | 1997-08-05 | Isis Pharmaceuticals, Inc. | Oligonucleotides for modulating RAF kinase having phosphorothioate linkages of high chiral purity |
| US5661134A (en) | 1991-10-15 | 1997-08-26 | Isis Pharmaceuticals, Inc. | Oligonucleotides for modulating Ha-ras or Ki-ras having phosphorothioate linkages of high chiral purity |
| ES2103918T3 (es) | 1991-10-17 | 1997-10-01 | Ciba Geigy Ag | Nucleosidos biciclicos, oligonucleotidos, procedimiento para su obtencion y productos intermedios. |
| US5594121A (en) | 1991-11-07 | 1997-01-14 | Gilead Sciences, Inc. | Enhanced triple-helix and double-helix formation with oligomers containing modified purines |
| US5484908A (en) | 1991-11-26 | 1996-01-16 | Gilead Sciences, Inc. | Oligonucleotides containing 5-propynyl pyrimidines |
| US6235887B1 (en) | 1991-11-26 | 2001-05-22 | Isis Pharmaceuticals, Inc. | Enhanced triple-helix and double-helix formation directed by oligonucleotides containing modified pyrimidines |
| US5359044A (en) | 1991-12-13 | 1994-10-25 | Isis Pharmaceuticals | Cyclobutyl oligonucleotide surrogates |
| EP0618925B2 (en) | 1991-12-24 | 2012-04-18 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotides |
| GB9213601D0 (en) | 1992-06-26 | 1992-08-12 | Mastico Robert A | Protein based delivery system |
| US7067497B2 (en) | 1992-09-29 | 2006-06-27 | Isis Pharmaceuticals, Inc. | Modulation of telomere length by oligonucleotides having a G-core sequence |
| US6005107A (en) | 1992-12-23 | 1999-12-21 | Biochem Pharma, Inc. | Antiviral compounds |
| US6444656B1 (en) | 1992-12-23 | 2002-09-03 | Biochem Pharma, Inc. | Antiviral phosphonate nucleotides |
| CA2154578A1 (en) | 1993-01-25 | 1994-08-04 | Ekambar R. Kandimalla | Oligonucleotide alkylphosphonates and alkylphosphonothioates |
| HU9501978D0 (en) | 1993-03-31 | 1995-09-28 | Sterling Winthorp Inc | Bifunctional nucleosides, oligomers thereof, and methods of making and using the same |
| CA2159632A1 (en) | 1993-03-31 | 1994-10-13 | Ashis Kumar Saha | Novel 5'-substituted nucleosides and oligomers produced therefrom |
| US5955591A (en) | 1993-05-12 | 1999-09-21 | Imbach; Jean-Louis | Phosphotriester oligonucleotides, amidites and method of preparation |
| US6015886A (en) | 1993-05-24 | 2000-01-18 | Chemgenes Corporation | Oligonucleotide phosphate esters |
| EP0628394B1 (en) | 1993-06-10 | 1998-08-26 | Idemitsu Petrochemical Co. Ltd. | Injection molding die |
| US5502177A (en) | 1993-09-17 | 1996-03-26 | Gilead Sciences, Inc. | Pyrimidine derivatives for labeled binding partners |
| US5643989A (en) | 1993-10-29 | 1997-07-01 | Azdel, Inc. | Fiber reinforced functionalized polyolefin composites |
| US5457187A (en) | 1993-12-08 | 1995-10-10 | Board Of Regents University Of Nebraska | Oligonucleotides containing 5-fluorouracil |
| DE4435728A1 (de) | 1994-01-19 | 1995-07-20 | Boehringer Mannheim Gmbh | Biotinsilan-Verbindungen und diese Verbindungen enthaltende Bindematrix |
| US6117679A (en) | 1994-02-17 | 2000-09-12 | Maxygen, Inc. | Methods for generating polynucleotides having desired characteristics by iterative selection and recombination |
| AU1806795A (en) | 1994-02-22 | 1995-09-04 | Novo Nordisk A/S | A method of preparing a variant of a lipolytic enzyme |
| US5596091A (en) | 1994-03-18 | 1997-01-21 | The Regents Of The University Of California | Antisense oligonucleotides comprising 5-aminoalkyl pyrimidine nucleotides |
| BR9507678A (pt) | 1994-05-11 | 1997-09-23 | Novo Nordisk As | Construção de dna vetor de expressão recombinante célula proceso para produzir uma enzima enzima preparação de enzima uso da enzima e cultura |
| US5525711A (en) | 1994-05-18 | 1996-06-11 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Pteridine nucleotide analogs as fluorescent DNA probes |
| EP0685475B1 (en) | 1994-05-31 | 1999-01-13 | Bayer Ag | Amino-benzofuryl-and thienyl-derivatives |
| HRP950288A2 (en) | 1994-05-31 | 1997-08-31 | Bayer Ag | Oxalylamino-benzofuran- and benzothienyl-derivatives |
| ATE420171T1 (de) | 1994-07-15 | 2009-01-15 | Univ Iowa Res Found | Immunomodulatorische oligonukleotide |
| US6207646B1 (en) | 1994-07-15 | 2001-03-27 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
| US6239116B1 (en) | 1994-07-15 | 2001-05-29 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
| ATE202569T1 (de) | 1994-09-07 | 2001-07-15 | Hybridon Inc | Prodrug-oligonukleotide |
| US5681940A (en) | 1994-11-02 | 1997-10-28 | Icn Pharmaceuticals | Sugar modified nucleosides and oligonucleotides |
| CA2208528A1 (en) | 1994-12-22 | 1996-06-27 | Hybridon, Inc. | Synthesis of stereospecific oligonucleotide phosphorothioates |
| GB9501465D0 (en) | 1995-01-25 | 1995-03-15 | King S College London | Nucleoside phosphorothioate derivatives,synthesis and use thereof |
| US6166197A (en) | 1995-03-06 | 2000-12-26 | Isis Pharmaceuticals, Inc. | Oligomeric compounds having pyrimidine nucleotide (S) with 2'and 5 substitutions |
| WO1996027606A1 (en) | 1995-03-06 | 1996-09-12 | Isis Pharmaceuticals, Inc. | Improved process for the synthesis of 2'-o-substituted pyrimidines and oligomeric compounds therefrom |
| EP0739983B1 (en) | 1995-04-27 | 2009-12-30 | Takara Bio Inc. | Gene encoding lacto-n-biosidase |
| DE69533264T2 (de) | 1995-05-11 | 2004-11-25 | Applied Research Systems Ars Holding N.V. | Inhibitoren der il-6 aktivitaet |
| WO1996036627A1 (en) | 1995-05-19 | 1996-11-21 | Glycomed Incorporated | Collection of activated glycoside compounds and their biological use |
| AU5871196A (en) | 1995-05-23 | 1996-12-24 | Hybridon, Inc. | Methods and compounds for the synthesis of oligonucleotides and the oligonucleotides thereby produced |
| DE69609511T2 (de) | 1995-05-23 | 2001-03-29 | Hybridon Inc | Neue Synthons für die stereoselektive Oligonuklodsynthese |
| WO1996039154A1 (en) | 1995-06-06 | 1996-12-12 | Isis Pharmaceuticals, Inc. | Oligonucleotides having phosphorothioate linkages of high chiral purity |
| US5932450A (en) | 1995-06-07 | 1999-08-03 | Gen-Probe Incorporated | Enzymatic synthesis of oligonucleotides using digestible templates |
| US5795765A (en) | 1995-06-29 | 1998-08-18 | Takara Shuzo Co., Ltd. | Gene encoding endoglycoceramidase |
| EP0759470B1 (en) | 1995-06-29 | 2006-10-25 | Takara Bio Inc. | Gene encoding endoglycoceramidase activator |
| US6017700A (en) | 1995-08-04 | 2000-01-25 | Bayer Corporation | Cationic oligonucleotides, and related methods of synthesis and use |
| US5936080A (en) | 1996-05-24 | 1999-08-10 | Genta Incorporated | Compositions and methods for the synthesis of organophosphorus derivatives |
| WO1997009443A1 (en) | 1995-09-05 | 1997-03-13 | Michigan State University | PROCESS FOR THE ISOLATION AND PURIFICATION OF TAXOL AND TAXANES FROM TAXUS spp |
| US5734041A (en) | 1995-10-20 | 1998-03-31 | Mcgill University | Preparation of chiral phosphorothioate oligomers |
| US6476216B1 (en) | 1995-10-20 | 2002-11-05 | Mcgill University | Preparation of phosphorothioate oligomers |
| US6160109A (en) | 1995-10-20 | 2000-12-12 | Isis Pharmaceuticals, Inc. | Preparation of phosphorothioate and boranophosphate oligomers |
| US7018793B1 (en) | 1995-12-07 | 2006-03-28 | Diversa Corporation | Combinatorial screening of mixed populations of organisms |
| US5998602A (en) | 1996-02-15 | 1999-12-07 | The Cleveland Clinic Fouindation And Government | RNase L activators and antisense oligonucleotides effective to treat RSV infections |
| US6214805B1 (en) | 1996-02-15 | 2001-04-10 | The United States Of America As Represented By The Department Of Health And Human Services | RNase L activators and antisense oligonucleotides effective to treat RSV infections |
| GB9604669D0 (en) | 1996-03-05 | 1996-05-01 | Ciba Geigy Ag | Chemical compounds |
| US5824669A (en) | 1996-03-22 | 1998-10-20 | Nitromed, Inc. | Nitrosated and nitrosylated compounds and compositions and their use for treating respiratory disorders |
| DE69738254T2 (de) | 1996-05-10 | 2008-08-14 | Novozymes A/S | Methode zur bereitstellung von dna sequenzen |
| US5856465A (en) | 1996-05-24 | 1999-01-05 | Polska Akademia Nauk Centrum Badan Molekularnych I Makromolekularnych | Compositions and methods for the synthesis of chirally pure organophosphorus nucleoside derivatives |
| US5898031A (en) | 1996-06-06 | 1999-04-27 | Isis Pharmaceuticals, Inc. | Oligoribonucleotides for cleaving RNA |
| DE19622783A1 (de) | 1996-06-07 | 1997-12-11 | Hoechst Ag | Isolierung der Biosynthesegene für Pseudo-Oligosaccharide aus Streptomyces glaucescens GLA.O und ihre Verwendung |
| JP2000514307A (ja) | 1996-07-16 | 2000-10-31 | ジェン―プローブ・インコーポレーテッド | 増加した標的特異的ｔ▲下ｍ▼を持つ修飾オリゴヌクレオチドを用いた核酸配列の検出および増幅のための方法 |
| DE69734783T2 (de) | 1996-07-24 | 2006-08-17 | Buchardt, Dorte | Peptidnukleinsäuren mit erhöhter bindungsaffinität, sequenzspezifität und löslichkeit |
| AU4156197A (en) | 1996-08-21 | 1998-03-06 | Hybridon, Inc. | Oligonucleotide prodrugs |
| US6056973A (en) | 1996-10-11 | 2000-05-02 | Sequus Pharmaceuticals, Inc. | Therapeutic liposome composition and method of preparation |
| GB9621522D0 (en) | 1996-10-16 | 1996-12-04 | Biocompatibles Ltd | Synthesis of phosphorus compounds |
| US6172209B1 (en) | 1997-02-14 | 2001-01-09 | Isis Pharmaceuticals Inc. | Aminooxy-modified oligonucleotides and methods for making same |
| US6639062B2 (en) | 1997-02-14 | 2003-10-28 | Isis Pharmaceuticals, Inc. | Aminooxy-modified nucleosidic compounds and oligomeric compounds prepared therefrom |
| US6369237B1 (en) | 1997-03-07 | 2002-04-09 | President And Fellows Of Harvard College | DNA glycosylase inhibitors, and uses related thereto |
| US6015887A (en) | 1997-04-11 | 2000-01-18 | Isis Pharmaceuticals, Inc. | Chiral peptide nucleic acids and methods for preparing same |
| US6468983B2 (en) | 1997-04-21 | 2002-10-22 | The Cleveland Clinic Foundation | RNase L activators and antisense oligonucleotides effective to treat telomerase-expressing malignancies |
| PL184612B1 (pl) | 1997-04-25 | 2002-11-29 | Pan | Sposób wytwarzania modyfikowanych P chiralnych analogów nukleotydów |
| IL133087A0 (en) | 1997-05-28 | 2001-03-19 | Nielsen Peter E | Conjugated peptide nucleic acids having enhanced cellular uptake |
| JP2002507212A (ja) | 1997-06-27 | 2002-03-05 | ザ、プロクター、エンド、ギャンブル、カンパニー | プロ芳香性環状アセタール |
| AU8512598A (en) | 1997-07-25 | 1999-02-16 | Hybridon, Inc. | Oligonuclotides having 3' terminal stereospecific phosphorothioates |
| US6767739B2 (en) | 2001-07-30 | 2004-07-27 | Isis Pharmaceuticals Inc. | Antisense modulation of microsomal triglyceride transfer protein expression |
| US6383808B1 (en) | 2000-09-11 | 2002-05-07 | Isis Pharmaceuticals, Inc. | Antisense inhibition of clusterin expression |
| GB9717158D0 (en) | 1997-08-13 | 1997-10-22 | King S College London | Solution synthesis of oligonucleotides and their phosphorothioate analogues |
| US6750344B1 (en) | 1997-09-05 | 2004-06-15 | Isis Pharmaceuticals, Inc. | Amine compounds and combinatorial libraries comprising same |
| US6794499B2 (en) | 1997-09-12 | 2004-09-21 | Exiqon A/S | Oligonucleotide analogues |
| DE19741715A1 (de) | 1997-09-22 | 1999-03-25 | Hoechst Ag | Pentopyranosyl-Nucleosid, seine Herstellung und Verwendung |
| US6232463B1 (en) | 1997-10-09 | 2001-05-15 | Isis Pharmaceuticals, Inc. | Substituted purines and oligonucleotide cross-linking |
| US6528640B1 (en) | 1997-11-05 | 2003-03-04 | Ribozyme Pharmaceuticals, Incorporated | Synthetic ribonucleic acids with RNAse activity |
| US6617438B1 (en) | 1997-11-05 | 2003-09-09 | Sirna Therapeutics, Inc. | Oligoribonucleotides with enzymatic activity |
| US6080543A (en) | 1997-12-08 | 2000-06-27 | E. & J. Gallo Winery | Detection of fungal pathogens |
| US6582936B1 (en) | 1997-12-12 | 2003-06-24 | The Regents Of The University Of California | Methods for making nucleic acids |
| US6248519B1 (en) | 1998-03-11 | 2001-06-19 | E & J Gallo Winery | Detection of fermentation-related microorganisms |
| US7045610B2 (en) | 1998-04-03 | 2006-05-16 | Epoch Biosciences, Inc. | Modified oligonucleotides for mismatch discrimination |
| CA2328602A1 (en) | 1998-05-06 | 1999-11-11 | University Of Iowa Research Foundation | Methods for the prevention and treatment of parasitic infections and related diseases using cpg oligonucleotides |
| CA2328406A1 (en) | 1998-05-14 | 1999-11-18 | Hermann Wagner | Methods for regulating hematopoiesis using cpg-oligonucleotides |
| US6867294B1 (en) | 1998-07-14 | 2005-03-15 | Isis Pharmaceuticals, Inc. | Gapped oligomers having site specific chiral phosphorothioate internucleoside linkages |
| US6242589B1 (en) | 1998-07-14 | 2001-06-05 | Isis Pharmaceuticals, Inc. | Phosphorothioate oligonucleotides having modified internucleoside linkages |
| WO2000006588A1 (en) | 1998-07-27 | 2000-02-10 | University Of Iowa Research Foundation | STEREOISOMERS OF CpG OLIGONUCLEOTIDES AND RELATED METHODS |
| DE69929444T2 (de) | 1998-08-10 | 2006-09-28 | Antigenics Inc., Woburn | Cpg-zusammensetzungen, saponin-adjuvantien und verfahren zu deren verwendung |
| WO2000023444A1 (en) | 1998-10-21 | 2000-04-27 | Abbott Laboratories | 5,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds |
| US6995259B1 (en) | 1998-10-23 | 2006-02-07 | Sirna Therapeutics, Inc. | Method for the chemical synthesis of oligonucleotides |
| AU1742600A (en) | 1998-11-25 | 2000-06-13 | Isis Pharmaceuticals, Inc. | Identification of disease predictive nucleic acids |
| US6451524B1 (en) | 1998-11-25 | 2002-09-17 | Isis Pharmaceuticals, Inc. | Identification of disease predictive nucleic acids |
| DK1141335T3 (da) | 1998-12-21 | 2009-11-09 | Genencor Int | Kemisk modificerede enzymer med multipelt ladede varianter |
| CA2359816C (en) | 1999-01-06 | 2010-08-03 | Genenews Inc. | Method for the detection of gene transcripts in blood and uses thereof |
| US6265172B1 (en) | 1999-02-08 | 2001-07-24 | University Of Kentucky | Diagnostic test and therapy for manganese superoxide dismutate (mNsod) associated diseases |
| US6121437A (en) | 1999-03-16 | 2000-09-19 | Isis Pharmaceuticals, Inc. | Phosphate and thiophosphate protecting groups |
| US6506594B1 (en) | 1999-03-19 | 2003-01-14 | Cornell Res Foundation Inc | Detection of nucleic acid sequence differences using the ligase detection reaction with addressable arrays |
| GB9907245D0 (en) | 1999-03-29 | 1999-05-26 | Goldsborough Andrew | Cleavage of nucleic acids from solid supports |
| JP3072345B1 (ja) | 1999-03-31 | 2000-07-31 | 農林水産省家畜衛生試験場長 | 豚丹毒菌の組換えサブユニットワクチン |
| US5998148A (en) | 1999-04-08 | 1999-12-07 | Isis Pharmaceuticals Inc. | Antisense modulation of microtubule-associated protein 4 expression |
| US6977245B2 (en) | 1999-04-12 | 2005-12-20 | The United States Of America As Represented By The Department Of Health And Human Services | Oligodeoxynucleotide and its use to induce an immune response |
| US6300069B1 (en) | 1999-05-03 | 2001-10-09 | Qiagen Gmbh | Generation and amplification of nucleic acids from ribonucleic acids |
| US6656730B1 (en) | 1999-06-15 | 2003-12-02 | Isis Pharmaceuticals, Inc. | Oligonucleotides conjugated to protein-binding drugs |
| US6066500A (en) | 1999-06-25 | 2000-05-23 | Isis Pharmaceuticals Inc. | Antisense modulation of Beta catenin expression |
| US6271004B1 (en) | 1999-06-25 | 2001-08-07 | Display Systems Biotech A/S | Method for improved reverse transcription at high temperatures |
| US6414135B1 (en) | 1999-07-07 | 2002-07-02 | Isis Pharmaceuticals, Inc. | C3′-methylene hydrogen phosphonate monomers and related compounds |
| US20030092647A1 (en) | 2001-08-08 | 2003-05-15 | Crooke Rosanne M. | Antisense modulation of cholesteryl ester transfer protein expression |
| US6147200A (en) | 1999-08-19 | 2000-11-14 | Isis Pharmaceuticals, Inc. | 2'-O-acetamido modified monomers and oligomers |
| US7264932B2 (en) | 1999-09-24 | 2007-09-04 | Applera Corporation | Nuclease inhibitor cocktail |
| DE60022665T2 (de) | 1999-09-25 | 2006-06-22 | Coley Pharmaceutical Gmbh | Immunstimulierende nukeinsäuren |
| US6949520B1 (en) | 1999-09-27 | 2005-09-27 | Coley Pharmaceutical Group, Inc. | Methods related to immunostimulatory nucleic acid-induced interferon |
| AU783118B2 (en) | 1999-09-27 | 2005-09-29 | Coley Pharmaceutical Gmbh | Methods related to immunostimulatory nucleic acid-induced interferon |
| US20020082227A1 (en) | 1999-09-30 | 2002-06-27 | Scott Henry | Use of oligonucleotides for inhibition of complement activation |
| WO2001025488A2 (en) | 1999-10-06 | 2001-04-12 | Quark Biotech, Inc. | Method for enrichment of natural antisense messenger rna |
| GB9924285D0 (en) | 1999-10-14 | 1999-12-15 | Avecia Ltd | Process |
| US20010055761A1 (en) | 1999-10-29 | 2001-12-27 | Agilent Technologies | Small scale dna synthesis using polymeric solid support with functionalized regions |
| FR2800750B1 (fr) | 1999-11-05 | 2003-01-31 | Centre Nat Rech Scient | Proteines membranaires ctl (choline transporter like) impliquees dans le transport de la choline |
| AU1656601A (en) | 1999-11-12 | 2001-06-12 | Isis Pharmaceuticals, Inc. | Gapped oligomers having site specific chiral phosphorothioate internucleoside linkages |
| US6322985B1 (en) | 1999-12-27 | 2001-11-27 | Technion Research And Development Foundation Ltd. | Abundant, well distributed and hyperpolymorphic simple sequence repeats in prokaryote genomes and use of same for prokaryote classification and typing |
| WO2001050117A1 (en) | 1999-12-30 | 2001-07-12 | Cabot Corporation | Sensors with improved properties |
| WO2001050349A1 (en) | 1999-12-30 | 2001-07-12 | Rutgers, The State University Of New Jersey | Electronic document customization and transformation utilizing user feedback |
| US6649750B1 (en) | 2000-01-05 | 2003-11-18 | Isis Pharmaceuticals, Inc. | Process for the preparation of oligonucleotide compounds |
| US6159697A (en) | 2000-01-19 | 2000-12-12 | Isis Pharmaceuticals, Inc. | Antisense modulation of Smad7 expression |
| US7585847B2 (en) | 2000-02-03 | 2009-09-08 | Coley Pharmaceutical Group, Inc. | Immunostimulatory nucleic acids for the treatment of asthma and allergy |
| US6495677B1 (en) | 2000-02-15 | 2002-12-17 | Kanda S. Ramasamy | Nucleoside compounds |
| US6936432B2 (en) | 2000-03-01 | 2005-08-30 | Message Pharmaceuticals | Bacterial RNase P proteins and their use in identifying antibacterial compounds |
| GB0004889D0 (en) | 2000-03-01 | 2000-04-19 | Avecia Ltd | Synthesis of oligonucleotides |
| JP2003528068A (ja) | 2000-03-17 | 2003-09-24 | コリクサ コーポレイション | 新規両親媒性アルデヒドならびにアジュバントおよび免疫エフェクターとしてのそれらの使用 |
| DE10019756A1 (de) | 2000-04-20 | 2001-10-25 | Bayer Ag | Verfahren zur Herstellung von superabsorbierenden Polymeren aus Polyacrylnitrilen |
| KR100501606B1 (ko) | 2000-04-20 | 2005-07-18 | 에프. 호프만-라 로슈 아게 | 피롤리딘 및 피페리딘 유도체, 및 신경퇴화성 질환의치료를 위한 그의 용도 |
| US20020013287A1 (en) | 2000-05-09 | 2002-01-31 | Reliable Biopharmaceuticals, Inc. St Louis Missouri | Polymeric compounds useful as prodrugs |
| US6492171B2 (en) | 2000-05-16 | 2002-12-10 | Isis Pharmaceuticals, Inc. | Antisense modulation of TERT expression |
| US6815542B2 (en) | 2000-06-16 | 2004-11-09 | Ribapharm, Inc. | Nucleoside compounds and uses thereof |
| JP3074398U (ja) | 2000-06-27 | 2001-01-12 | ドンウー キヨン ジュシクヘサ | 自動車内装形オゾン発生装置 |
| AU2001278517A1 (en) | 2000-08-03 | 2002-02-18 | F. Hoffman-La Roche Ag | Nucleic acid binding compounds containing pyrazolo(3,4-d)pyrimidine analogues of purin-2,6-diamine and their uses |
| US6725412B1 (en) | 2000-08-15 | 2004-04-20 | Dolby Laboratories Licensing Corporation | Low latency data encoder |
| US6809195B1 (en) | 2000-08-16 | 2004-10-26 | Isis Pharmaceuticals, Inc. | Process for the preparation of oligonucleotides |
| US6559279B1 (en) | 2000-09-08 | 2003-05-06 | Isis Pharmaceuticals, Inc. | Process for preparing peptide derivatized oligomeric compounds |
| WO2002022809A2 (en) | 2000-09-15 | 2002-03-21 | Coley Pharmaceutical Gmbh | PROCESS FOR HIGH THROUGHPUT SCREENING OF CpG-BASED IMMUNO-AGONIST/ANTAGONIST |
| EP1191097A1 (en) | 2000-09-21 | 2002-03-27 | Leids Universitair Medisch Centrum | Induction of exon skipping in eukaryotic cells |
| GB0024752D0 (en) | 2000-10-10 | 2000-11-22 | Univ Belfast | Oxidative halogenation of aromatic compounds |
| ES2295229T3 (es) | 2000-10-18 | 2008-04-16 | Glaxosmithkline Biologicals S.A. | Vacunas contra canceres. |
| US6372492B1 (en) | 2000-10-30 | 2002-04-16 | Isis Pharmaceuticals, Inc. | Antisense modulation of talin expression |
| US6682889B1 (en) | 2000-11-08 | 2004-01-27 | Becton, Dickinson And Company | Amplification and detection of organisms of the Chlamydiaceae family |
| NL1016978C2 (nl) | 2000-12-22 | 2002-06-25 | Robert Jan Colenbrander | Inrichting en werkwijze voor het verpakken en bereiden van voedsel en werkwijze voor het vervaardigen van een dergelijke inrichting. |
| MXPA03006514A (es) | 2001-01-22 | 2004-12-02 | Merck & Co Inc | Derivados de nucleosidos como inhibidores de polimerasa de acido ribonucleico viral dependiente de acido ribonucleico. |
| US8008459B2 (en) | 2001-01-25 | 2011-08-30 | Evolva Sa | Concatemers of differentially expressed multiple genes |
| US7838287B2 (en) | 2001-01-25 | 2010-11-23 | Evolva Sa | Library of a collection of cells |
| AU2002224668B2 (en) | 2001-01-26 | 2007-09-20 | Commonwealth Scientific And Industrial Research Organisation | Methods and means for producing efficient silencing construct using recombinational cloning |
| US20050277133A1 (en) | 2001-05-18 | 2005-12-15 | Sirna Therapeutics, Inc. | RNA interference mediated treatment of polyglutamine (polyQ) repeat expansion diseases using short interfering nucleic acid (siNA) |
| US20030207804A1 (en) | 2001-05-25 | 2003-11-06 | Muthiah Manoharan | Modified peptide nucleic acids |
| GB0113523D0 (en) | 2001-06-04 | 2001-07-25 | Torotrak Dev Ltd | An Hydraulic control circuit for a continuosly variable transmission |
| US20030069410A1 (en) | 2001-06-14 | 2003-04-10 | Isis Pharmaceuticals, Inc. | Methods for preparing oligonucleotides having chiral phosphorothioate linkages |
| US20050019915A1 (en) | 2001-06-21 | 2005-01-27 | Bennett C. Frank | Antisense modulation of superoxide dismutase 1, soluble expression |
| CA2451739A1 (en) | 2001-06-29 | 2003-01-09 | Chiron Corporation | Hcv e1e2 vaccine compositions |
| JP2005504020A (ja) | 2001-07-03 | 2005-02-10 | アイシス・ファーマシューティカルス・インコーポレーテッド | ヌクレアーゼ耐性キメラオリゴヌクレオチド |
| US7205399B1 (en) | 2001-07-06 | 2007-04-17 | Sirna Therapeutics, Inc. | Methods and reagents for oligonucleotide synthesis |
| US6440739B1 (en) | 2001-07-17 | 2002-08-27 | Isis Pharmaceuticals, Inc. | Antisense modulation of glioma-associated oncogene-2 expression |
| US7425545B2 (en) | 2001-07-25 | 2008-09-16 | Isis Pharmaceuticals, Inc. | Modulation of C-reactive protein expression |
| US7888324B2 (en) | 2001-08-01 | 2011-02-15 | Genzyme Corporation | Antisense modulation of apolipoprotein B expression |
| US7407943B2 (en) | 2001-08-01 | 2008-08-05 | Isis Pharmaceuticals, Inc. | Antisense modulation of apolipoprotein B expression |
| US6455308B1 (en) | 2001-08-01 | 2002-09-24 | Isis Pharmaceuticals, Inc. | Antisense modulation of serum amyloid A4 expression |
| US7227014B2 (en) | 2001-08-07 | 2007-06-05 | Isis Pharmaceuticals, Inc. | Antisense modulation of apolipoprotein (a) expression |
| US7259150B2 (en) | 2001-08-07 | 2007-08-21 | Isis Pharmaceuticals, Inc. | Modulation of apolipoprotein (a) expression |
| US7354909B2 (en) | 2001-08-14 | 2008-04-08 | The United States Of America As Represented By Secretary Of The Department Of Health And Human Services | Method for rapid generation of mature dendritic cells |
| WO2003017930A2 (en) | 2001-08-24 | 2003-03-06 | Massachusetts Institute Of Technology | Reagents that facilitate the purification of compounds synthesized on a solid support |
| US7049122B2 (en) | 2001-09-21 | 2006-05-23 | Academia Sinica | Mutant-type lipases and applications thereof |
| US6933288B2 (en) | 2002-02-04 | 2005-08-23 | Isis Pharmaceuticals, Inc. | Pyranosyl cytosines: pharmaceutical formulations and methods |
| JP4348044B2 (ja) | 2002-02-12 | 2009-10-21 | 株式会社キラルジェン | 立体規則性の高いジヌクレオシドホスホロチオエートの製造法 |
| US20030159938A1 (en) | 2002-02-15 | 2003-08-28 | George Hradil | Electroplating solution containing organic acid complexing agent |
| US20040149587A1 (en) | 2002-02-15 | 2004-08-05 | George Hradil | Electroplating solution containing organic acid complexing agent |
| US8232383B2 (en) | 2002-02-20 | 2012-07-31 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
| US20050096284A1 (en) | 2002-02-20 | 2005-05-05 | Sirna Therapeutics, Inc. | RNA interference mediated treatment of polyglutamine (polyQ) repeat expansion diseases using short interfering nucleic acid (siNA) |
| AU2003217863B9 (en) | 2002-02-28 | 2009-10-29 | Biota Scientific Management Pty Ltd | Nucleotide mimics and their prodrugs |
| CA2477795A1 (en) | 2002-02-28 | 2003-09-12 | Kandasamy Sakthivel | Nucleoside 5'-monophosphate mimics and their prodrugs |
| US7288376B2 (en) | 2002-03-22 | 2007-10-30 | Council Of Scientific And Industrial Research | Method of detection of SP-A2 gene variants useful for prediction of predisposition to aspergillosis |
| US20040102394A1 (en) | 2002-11-23 | 2004-05-27 | Isis Pharmaceuticals Inc. | Modulation of huntingtin interacting protein 2 expression |
| US7247621B2 (en) | 2002-04-30 | 2007-07-24 | Valeant Research & Development | Antiviral phosphonate compounds and methods therefor |
| AU2003237875A1 (en) | 2002-05-15 | 2003-12-02 | Isis Pharmaceuticals, Inc. | Antisense modulation of apolipoprotein b expression |
| WO2003099840A1 (en) | 2002-05-24 | 2003-12-04 | Isis Pharmaceuticals, Inc. | Oligonucleotides having modified nucleoside units |
| WO2003100017A2 (en) | 2002-05-24 | 2003-12-04 | Isis Pharmaceuticals, Inc. | Oligonucleotides having modified nucleoside units |
| US7507808B2 (en) | 2002-12-12 | 2009-03-24 | Isis Pharmaceuticals, Inc. | Modulation of endothelial lipase expression |
| WO2003106477A1 (en) | 2002-06-01 | 2003-12-24 | Isis Pharmaceuticals, Inc. | Oligomeric compounds that include carbocyclic nucleosides and their use in gene modulation |
| AU2003242742B2 (en) | 2002-06-20 | 2009-04-30 | Cytos Biotechnology Ag | Packaged virus-like particles for use as adjuvants: method of preparation and use |
| WO2004003228A1 (en) | 2002-07-01 | 2004-01-08 | Unisearch Limited | Genotyping method |
| AU2003254334A1 (en) | 2002-07-10 | 2004-02-02 | Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. | Rna-interference by single-stranded rna molecules |
| US20040023905A1 (en) | 2002-07-31 | 2004-02-05 | Isis Pharmaceuticals Inc. | Antisense modulation of LAR expression |
| US20050042646A1 (en) | 2002-08-05 | 2005-02-24 | Davidson Beverly L. | RNA interference suppresion of neurodegenerative diseases and methods of use thereof |
| US20080274989A1 (en) | 2002-08-05 | 2008-11-06 | University Of Iowa Research Foundation | Rna Interference Suppression of Neurodegenerative Diseases and Methods of Use Thereof |
| US20050255086A1 (en) | 2002-08-05 | 2005-11-17 | Davidson Beverly L | Nucleic acid silencing of Huntington's Disease gene |
| WO2004014933A1 (en) | 2002-08-07 | 2004-02-19 | University Of Massachusetts | Compositions for rna interference and methods of use thereof |
| AU2003259735A1 (en) | 2002-08-08 | 2004-02-25 | Sirna Therapeutics, Inc. | Small-mer compositions and methods of use |
| AR040996A1 (es) | 2002-08-19 | 2005-04-27 | Coley Pharm Group Inc | Acidos nucleicos inmunoestimuladores |
| US7414116B2 (en) | 2002-08-23 | 2008-08-19 | Illumina Cambridge Limited | Labelled nucleotides |
| EP1537208A1 (en) | 2002-09-13 | 2005-06-08 | Replicor, Inc. | Non-sequence complementary antiviral oligonucleotides |
| US7030230B2 (en) | 2002-10-25 | 2006-04-18 | Isis Pharmaceuticals, Inc. | Process of purifying phosphoramidites |
| EP1556077A2 (en) | 2002-10-29 | 2005-07-27 | Coley Pharmaceutical Group, Ltd | Use of cpg oligonucleotides in the treatment of hepatitis c virus infection |
| WO2004044141A2 (en) | 2002-11-05 | 2004-05-27 | Isis Pharmaceuticals, Inc. | Conjugated oligomeric compounds and their use in gene modulation |
| WO2004041889A2 (en) | 2002-11-05 | 2004-05-21 | Isis Pharmaceuticals, Inc. | Polycyclic sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation |
| WO2004044136A2 (en) | 2002-11-05 | 2004-05-27 | Isis Pharmaceuticals, Inc. | Compositions comprising alternating 2’-modified nucleosides for use in gene modulation |
| AU2003291721A1 (en) | 2002-11-05 | 2004-06-03 | Isis Pharmaceuticals, Inc. | Phosphorous-linked oligomeric compounds and their use in gene modulation |
| US7381527B2 (en) | 2002-11-06 | 2008-06-03 | Council Of Scientific And Industrial Research | Method of detection of SP-A2 gene variants |
| US7511131B2 (en) | 2002-11-13 | 2009-03-31 | Genzyme Corporation | Antisense modulation of apolipoprotein B expression |
| JP4986109B2 (ja) | 2002-11-13 | 2012-07-25 | ジェンザイム・コーポレーション | アポリポタンパク質ｂ発現のアンチセンス調節 |
| JP2006507841A (ja) | 2002-11-14 | 2006-03-09 | ダーマコン， インコーポレイテッド | 機能的ｓｉＲＮＡおよび超機能的ｓｉＲＮＡ |
| DK2216407T3 (en) | 2003-03-07 | 2016-03-29 | Alnylam Pharmaceuticals Inc | therapeutic compositions |
| WO2004080466A1 (en) | 2003-03-07 | 2004-09-23 | Ribapharm Inc. | Cytidine analogs and methods of use |
| AU2003225410A1 (en) | 2003-03-21 | 2004-10-11 | Academisch Ziekenhuis Leiden | Modulation of exon recognition in pre-mrna by interfering with the secondary rna structure |
| GB0306657D0 (en) | 2003-03-24 | 2003-04-30 | Avecia Ltd | Process and compounds |
| US7537767B2 (en) | 2003-03-26 | 2009-05-26 | Cytis Biotechnology Ag | Melan-A- carrier conjugates |
| KR20050115913A (ko) | 2003-03-26 | 2005-12-08 | 사이토스 바이오테크놀로지 아게 | Ｍｅｌａｎ―ａ 펩티드 유사체-바이러스-양-입자컨쥬게이트 |
| ITRM20030149A1 (it) | 2003-04-02 | 2004-10-03 | Giuliani Spa | Oligonucleotidi (odn) antisenso per smad7 e loro usi in campo medico |
| US7598227B2 (en) | 2003-04-16 | 2009-10-06 | Isis Pharmaceuticals Inc. | Modulation of apolipoprotein C-III expression |
| US20090247488A1 (en) | 2003-04-25 | 2009-10-01 | Carina Cannizzaro | Anti-inflammatory phosphonate compounds |
| CN101410120A (zh) | 2003-04-25 | 2009-04-15 | 吉里德科学公司 | 抗炎的膦酸酯化合物 |
| US20050261237A1 (en) | 2003-04-25 | 2005-11-24 | Boojamra Constantine G | Nucleoside phosphonate analogs |
| WO2005002626A2 (en) | 2003-04-25 | 2005-01-13 | Gilead Sciences, Inc. | Therapeutic phosphonate compounds |
| US7470724B2 (en) | 2003-04-25 | 2008-12-30 | Gilead Sciences, Inc. | Phosphonate compounds having immuno-modulatory activity |
| US7432261B2 (en) | 2003-04-25 | 2008-10-07 | Gilead Sciences, Inc. | Anti-inflammatory phosphonate compounds |
| ATE490788T1 (de) | 2003-04-25 | 2010-12-15 | Gilead Sciences Inc | Antivirale phosphonate analoge |
| US7452901B2 (en) | 2003-04-25 | 2008-11-18 | Gilead Sciences, Inc. | Anti-cancer phosphonate analogs |
| EP1617848A2 (en) | 2003-04-25 | 2006-01-25 | Gilead Sciences, Inc. | Anti-cancer phosphonate conjugates |
| WO2004096233A2 (en) | 2003-04-25 | 2004-11-11 | Gilead Sciences, Inc. | Nucleoside phosphonate conjugates |
| US7407965B2 (en) | 2003-04-25 | 2008-08-05 | Gilead Sciences, Inc. | Phosphonate analogs for treating metabolic diseases |
| US7045306B2 (en) | 2003-04-28 | 2006-05-16 | The General Hospital Corporation | Method for identifying compounds in vitro that modulate the dysregulation of transcription of transcription mediated by mutant huntingtin protein |
| US7214491B2 (en) | 2003-05-07 | 2007-05-08 | E. I. Du Pont De Nemours And Company | Δ-12 desaturase gene suitable for altering levels of polyunsaturated fatty acids in oleaginous yeasts |
| US7589189B2 (en) | 2003-05-14 | 2009-09-15 | Japan Science And Technology Agency | Inhibition of the expression of huntingtin gene |
| BRPI0410886A (pt) | 2003-06-03 | 2006-07-04 | Isis Pharmaceuticals Inc | composto de filamento duplo, composição farmacêutica, sal farmaceuticamente aceitável, métodos de modificação do ácido nucleico que codifica a survivina humana, de inibição da expressão da suvivina em células ou tecidos, e de tratamento de uma condição associada com a expressão ou superexpressão da suvivina, e, oligonucleotìdeo de rnai de filamento único |
| BRPI0411514A (pt) | 2003-06-20 | 2006-08-01 | Coley Pharm Gmbh | antagonistas de receptor toll-like de molécula pequena |
| US7683036B2 (en) | 2003-07-31 | 2010-03-23 | Regulus Therapeutics Inc. | Oligomeric compounds and compositions for use in modulation of small non-coding RNAs |
| JP2011088935A (ja) | 2003-08-08 | 2011-05-06 | Chiralgen Ltd | リン原子修飾ヌクレオチド類縁体の製造のための光学活性ヌクレオシド３’−ホスホロアミダイト |
| JP2005089441A (ja) * | 2003-08-08 | 2005-04-07 | Toudai Tlo Ltd | 立体規則性の高いリン原子修飾ヌクレオチド類縁体の製造法 |
| US7825235B2 (en) | 2003-08-18 | 2010-11-02 | Isis Pharmaceuticals, Inc. | Modulation of diacylglycerol acyltransferase 2 expression |
| JP2007502778A (ja) | 2003-08-21 | 2007-02-15 | グリフィス ユニバーシティ | 新規スルフェンアミドオキシド |
| MXPA06001976A (es) | 2003-08-21 | 2006-05-31 | Univ Griffith | Nuevas sulfenamidas. |
| MXPA06002198A (es) | 2003-08-27 | 2007-08-14 | Biota Scient Management | Nucleosidos o nucleotidos triciclicos novedosos como agentes terapeuticos. |
| ATE555118T1 (de) | 2003-08-28 | 2012-05-15 | Takeshi Imanishi | Neue synthetische nukleidsäuren vom typ mit quervernetzter n-o-bindung |
| WO2005028494A1 (ja) | 2003-09-02 | 2005-03-31 | Takeshi Wada | ５'-ホスフィチル化モノマーおよびh-ホスホネートオリゴヌクレオチド誘導体の製造方法 |
| 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 |
| US20050053981A1 (en) | 2003-09-09 | 2005-03-10 | Swayze Eric E. | Gapped oligomeric compounds having linked bicyclic sugar moieties at the termini |
| US20050074801A1 (en) | 2003-09-09 | 2005-04-07 | Monia Brett P. | Chimeric oligomeric compounds comprising alternating regions of northern and southern conformational geometry |
| EP1667522B1 (en) | 2003-09-09 | 2018-01-17 | Geron Corporation | Modified oligonucleotides for telomerase inhibition |
| DK2821085T3 (da) | 2003-09-12 | 2020-08-03 | Univ Massachusetts | Rna-interferens til behandling af "gain-of-function"-forstyrrelser |
| US8680063B2 (en) | 2003-09-12 | 2014-03-25 | University Of Massachusetts | RNA interference for the treatment of gain-of-function disorders |
| GB0323968D0 (en) | 2003-10-13 | 2003-11-19 | Glaxosmithkline Biolog Sa | Immunogenic compositions |
| SG122973A1 (en) | 2003-10-30 | 2006-06-29 | Coley Pharm Gmbh | C-class oligonucleotide analogs with enhanced immunostimulatory potency |
| US20050239102A1 (en) | 2003-10-31 | 2005-10-27 | Verdine Gregory L | Nucleic acid binding oligonucleotides |
| US7846436B2 (en) | 2003-11-28 | 2010-12-07 | Chemgenes Corporation | Oligonucleotides and related compounds |
| WO2005063983A1 (en) | 2003-12-29 | 2005-07-14 | Galapagos Genomics N.V. | Modulators of bone homeostasis identified in a high-throughput screen |
| JP4945129B2 (ja) | 2004-01-27 | 2012-06-06 | 株式会社キラルジェン | フルオラス担体およびそれを用いたオリゴヌクレオチド誘導体の製造方法 |
| US20050176045A1 (en) | 2004-02-06 | 2005-08-11 | Dharmacon, Inc. | SNP discriminatory siRNA |
| EP1725250A2 (en) | 2004-02-18 | 2006-11-29 | Frutarom Ltd. | Method for the preparation of peptide-oligonucleotide conjugates |
| JP3976742B2 (ja) | 2004-02-27 | 2007-09-19 | 江守商事株式会社 | インターフェロンアルファを誘導する免疫刺激オリゴヌクレオチド |
| WO2005085272A1 (ja) | 2004-03-05 | 2005-09-15 | Takeshi Wada | ボラノホスフェートモノマーおよびそれを用いたオリゴ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 |
| US20050244869A1 (en) | 2004-04-05 | 2005-11-03 | Brown-Driver Vickie L | Modulation of transthyretin expression |
| WO2005097817A2 (en) | 2004-04-05 | 2005-10-20 | Alnylam Pharmaceuticals, Inc. | Process and reagents for oligonucleotide synthesis and purification |
| TWI350168B (en) | 2004-05-07 | 2011-10-11 | Incyte Corp | Amido compounds and their use as pharmaceuticals |
| WO2005116268A2 (en) | 2004-05-27 | 2005-12-08 | The Government Of The United States Of America As Represented By The Secretary, Department Of Health | Differential expression of molecules associated with acute stroke |
| US7759318B1 (en) | 2004-05-28 | 2010-07-20 | Isis Pharmaceuticals, Inc. | Identification of novel pathways, genes and promoter motifs regulating adipogenesis |
| EP1765415A4 (en) | 2004-06-03 | 2010-03-24 | Isis Pharmaceuticals Inc | OLIGOMERIC COMPOUNDS FACILITATING THE "RISC" LOAD |
| SI1766010T1 (sl) | 2004-06-28 | 2011-06-30 | Univ Western Australia | Protismiselni oligonukleotidi za induciranje preskakovanja eksonov in postopki za njihovo uporabo |
| PT1786472E (pt) | 2004-08-10 | 2013-03-06 | Genzyme Corp | Modulação anti-sentido de expressão de apolipoproteína |
| EP1795536B1 (en) | 2004-08-26 | 2012-05-02 | Nippon Shinyaku Co., Ltd. | Phosphoramidite compound and method for producing oligo-rna |
| CA2578046A1 (en) | 2004-09-07 | 2006-03-16 | Archemix Corp. | Aptamer medicinal chemistry |
| US7884086B2 (en) | 2004-09-08 | 2011-02-08 | Isis Pharmaceuticals, Inc. | Conjugates for use in hepatocyte free uptake assays |
| WO2006031461A2 (en) | 2004-09-09 | 2006-03-23 | Isis Pharmaceuticals, Inc. | Pyrrolidinyl groups for attaching conjugates to oligomeric compounds |
| US7919472B2 (en) | 2004-09-17 | 2011-04-05 | Isis Pharmaceuticals, Inc. | Enhanced antisense oligonucleotides |
| CA2582464A1 (en) | 2004-10-13 | 2006-04-27 | Sanjay Bhanot | Antisense modulation of ptp1b expression |
| US9120774B2 (en) | 2004-11-03 | 2015-09-01 | University Of Kansas | Novobiocin analogues having modified sugar moieties |
| US8212012B2 (en) | 2004-11-03 | 2012-07-03 | University Of Kansas | Novobiocin analogues having modified sugar moieties |
| AU2005301957B2 (en) | 2004-11-03 | 2012-02-23 | Department Of Health And Human Services | Novobiocin analogues as anticancer agents |
| US7622451B2 (en) | 2004-11-03 | 2009-11-24 | University Of Kansas | Novobiocin analogues as neuroprotective agents and in the treatment of autoimmune disorders |
| US8212011B2 (en) | 2004-11-03 | 2012-07-03 | University Of Kansas | Novobiocin analogues |
| KR100721928B1 (ko) | 2004-11-05 | 2007-05-28 | 주식회사 바이오씨에스 | ＣｐＧ 올리고데옥시뉴클레오티드를 함유하는 피부질환의치료 또는 예방용 약학적 조성물 |
| EP1657307A1 (en) | 2004-11-16 | 2006-05-17 | Immunotech S.A. | Oligonucleotides that induce the secretion of GM-CSF |
| AU2005313883B2 (en) | 2004-12-09 | 2011-03-31 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inducing an immune response in a mammal and methods of avoiding an immune response to oligonucleotide agents such as short interfering RNAs |
| WO2006065751A2 (en) | 2004-12-13 | 2006-06-22 | Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Cpg oligonucleotide prodrugs, compositions thereof and associated therapeutic methods |
| WO2006066260A2 (en) | 2004-12-17 | 2006-06-22 | Thiosense, Inc. | Compositions of and methods for producing phosphorus-chiral monomers and oligomers |
| US20070099851A1 (en) | 2004-12-30 | 2007-05-03 | Linn Gregory S | Stable analogues of ribose-1-phosphate and methods for treating diabetes and other metabolic disorders |
| US20060183763A1 (en) | 2004-12-31 | 2006-08-17 | Pfizer Inc | Novel pyrrolidyl derivatives of heteroaromatic compounds |
| KR100980898B1 (ko) | 2005-01-28 | 2010-09-07 | 권형주 | 마이코박테리아 유래 면역기능 증진, 면역질환 치료, 아토피성 피부질환 및/또는 면역세포 생존용 올리고뉴크레오타이드 |
| AU2006216493A1 (en) | 2005-02-24 | 2006-08-31 | Coley Pharmaceutical Gmbh | Immunostimulatory oligonucleotides |
| ATE534652T1 (de) | 2005-04-01 | 2011-12-15 | Univ California | Phosphono-pent-2-en-1-yl-nukleoside und analoga |
| ZA200709237B (en) | 2005-05-05 | 2009-04-29 | Antisense Pharma Gmbh | Dosage of oligonucleotides |
| US7902352B2 (en) | 2005-05-06 | 2011-03-08 | Medtronic, Inc. | Isolated nucleic acid duplex for reducing huntington gene expression |
| EP1885854B1 (en) | 2005-05-06 | 2012-10-17 | Medtronic, Inc. | Methods and sequences to suppress primate huntington gene expression |
| WO2007002390A2 (en) | 2005-06-23 | 2007-01-04 | Isis Pharmaceuticals, Inc. | Compositions and methods for modulation of smn2 splicing |
| ATE522626T1 (de) | 2005-06-28 | 2011-09-15 | Medtronic Inc | Verfahren und nukleotid-sequenzen, die bevorzugt die expression eines mutierten huntingtin-genes unterdrücken |
| US9133517B2 (en) | 2005-06-28 | 2015-09-15 | Medtronics, Inc. | Methods and sequences to preferentially suppress expression of mutated huntingtin |
| EP1948600B1 (en) | 2005-07-05 | 2014-04-16 | The President & Fellows Of Harvard College | Liver targeted conjugates |
| JP4984634B2 (ja) | 2005-07-21 | 2012-07-25 | ソニー株式会社 | 物理情報取得方法および物理情報取得装置 |
| CA2641599C (en) | 2005-07-28 | 2012-07-10 | Id-Fish Technology, Inc. | Method for improving cell permeability to foreign particles |
| WO2007027775A2 (en) | 2005-08-29 | 2007-03-08 | Isis Pharmaceuticals, Inc. | Methods for use in modulating mir-122a |
| EP1937312B1 (en) | 2005-08-30 | 2016-06-29 | Ionis Pharmaceuticals, Inc. | Chimeric oligomeric compounds for modulation of splicing |
| US7700567B2 (en) | 2005-09-29 | 2010-04-20 | Supergen, Inc. | Oligonucleotide analogues incorporating 5-aza-cytosine therein |
| US20070077993A1 (en) | 2005-09-30 | 2007-04-05 | Midgley Timothy M | Method and apparatus for collecting user game play data and crediting users in a gaming environment |
| ES2542989T3 (es) | 2005-10-12 | 2015-08-13 | Idera Pharmaceuticals, Inc. | Compuestos oligonucleótidos inmuno reguladores (IRO) para modular la respuesta inmune basada en receptor semejante a Toll |
| US9308252B2 (en) | 2005-10-27 | 2016-04-12 | Cook Biotech, Inc. | Extracellular matrix materials as vaccine adjuvants for diseases associated with infectious pathogens or toxins |
| CN101466834B (zh) | 2005-10-28 | 2013-09-25 | 东曹株式会社 | 制备类胡萝卜素合成性微生物的方法和生产类胡萝卜素的方法 |
| US7320965B2 (en) | 2005-10-28 | 2008-01-22 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of Huntingtin gene |
| RU2008118144A (ru) | 2005-11-11 | 2009-11-20 | Пфайзер Инк. (US) | Комбинации иммуномодулирующих олигоодезоксинуклеотидов и способы их применения |
| WO2007064291A1 (en) | 2005-11-30 | 2007-06-07 | Jyoti Chattopadhyaya | Method and compounds for rna synthesis |
| CA2632968A1 (en) | 2005-12-02 | 2007-06-07 | Isis Pharmaceuticals, Inc. | Antibacterial 4,5-substituted aminoglycoside analogs having multiple substituents |
| US8076303B2 (en) | 2005-12-13 | 2011-12-13 | Spring Bank Pharmaceuticals, Inc. | Nucleotide and oligonucleotide prodrugs |
| ES2435405T3 (es) | 2005-12-21 | 2013-12-19 | Pfizer Products Inc. | Carbonilamino pirrolopirazoles, potentes inhibidores de quinasa |
| WO2007089584A2 (en) | 2006-01-26 | 2007-08-09 | Isis Pharmaceuticals, Inc. | Compositions and their uses directed to huntingtin |
| JP5342881B2 (ja) | 2006-01-27 | 2013-11-13 | 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 | ６−修飾された二環式核酸類似体 |
| JP5473336B2 (ja) | 2006-02-15 | 2014-04-16 | アディウタイド・ファーマスーティカルズ・ゲーエムベーハー | オリゴヌクレオチドの処方に関する組成物および方法 |
| JP4713514B2 (ja) | 2006-02-20 | 2011-06-29 | エフ．ホフマン−ラ ロシュ アーゲー | 改善された標識試薬 |
| US8383660B2 (en) | 2006-03-10 | 2013-02-26 | Pfizer Inc. | Dibenzyl amine compounds and derivatives |
| EP2001871B1 (en) | 2006-03-31 | 2014-07-16 | Applied Biosystems, LLC | Rhodamine-labeled oligonucleotides |
| EP2010679A2 (en) | 2006-04-06 | 2009-01-07 | Ibis Biosciences, Inc. | Compositions for the use in identification of fungi |
| DE602007008222D1 (de) | 2006-04-20 | 2010-09-16 | Hoffmann La Roche | Diazepanderivate als modulatoren von chemokinrezeptoren |
| BRPI0710889A2 (pt) | 2006-04-24 | 2011-08-16 | Sigma Alimentos Sa De Cv | método para a detecção e quantificação múltipla e simultánea de patogênicos mediante a reação em cadeia da polimerasa em tempo real |
| WO2007127221A2 (en) | 2006-04-25 | 2007-11-08 | Immune Disease Institute Inc. | Targeted delivery to leukocytes using non-protein carriers |
| GB0608838D0 (en) | 2006-05-04 | 2006-06-14 | Novartis Ag | Organic compounds |
| CN103554205A (zh) | 2006-05-05 | 2014-02-05 | Isis制药公司 | 调节gccr的表达的化合物和方法 |
| US8158598B2 (en) | 2006-05-05 | 2012-04-17 | Isis Pharmaceuticals, Inc. | Compositions and their uses directed to PTPR alpha |
| US20090012120A1 (en) | 2006-05-10 | 2009-01-08 | Board Of Trustees Of Michigan State University | Synthesis of N-heterocycles, beta-amino acids, and allyl amines via aza-payne mediated reaction of ylides and hydroxy aziridines |
| US7666854B2 (en) | 2006-05-11 | 2010-02-23 | Isis Pharmaceuticals, Inc. | Bis-modified bicyclic nucleic acid analogs |
| AU2007249349B2 (en) | 2006-05-11 | 2012-03-08 | Isis Pharmaceuticals, Inc. | 5'-Modified bicyclic nucleic acid analogs |
| ES2389112T3 (es) | 2006-05-31 | 2012-10-23 | Toray Industries, Inc. | Oligonucleótido inmunoestimulador y aplicación farmacéutica del mismo |
| US8097596B2 (en) | 2006-06-30 | 2012-01-17 | Lakewood-Amedex, Inc. | Compositions and methods for the treatment of muscle wasting |
| EP2046993A4 (en) | 2006-07-07 | 2010-11-17 | Univ Massachusetts | RNA INTERFERENCE COMPOSITIONS AND METHOD FOR TREATING MORBUS HUNTINGTON |
| CN101506368B (zh) | 2006-07-12 | 2017-02-08 | 加利福尼亚大学董事会 | 通过可逆的磷酸三酯电荷中和保护基转导运输核酸 |
| AU2007275301A1 (en) | 2006-07-20 | 2008-01-24 | Amgen Inc. | Substituted azole aromatic heterocycles as inhibitors of 11-beta-HSD-1 |
| GB0614947D0 (en) | 2006-07-27 | 2006-09-06 | Isis Innovation | Epitope reduction therapy |
| CA2660052A1 (en) | 2006-08-04 | 2008-02-07 | Isis Pharmaceuticals, Inc. | Compositions and methods for the modulation of jnk proteins |
| AT504194B1 (de) | 2006-09-07 | 2008-07-15 | Oesterr Rotes Kreuz | Bakteriennachweis |
| US8138330B2 (en) | 2006-09-11 | 2012-03-20 | Sigma-Aldrich Co. Llc | Process for the synthesis of oligonucleotides |
| NZ575437A (en) | 2006-09-27 | 2012-02-24 | Coley Pharm Gmbh | Cpg oligonucleotide analogs containing hydrophobic t analogs with enhanced immunostimulatory activity |
| DK2410054T4 (da) | 2006-10-18 | 2020-02-10 | Ionis Pharmaceuticals Inc | Antisenseforbindelser |
| AU2007309195A1 (en) | 2006-10-23 | 2008-05-02 | Irm Llc | Cathepsin proteases inhibitors |
| BRPI0718182A2 (pt) | 2006-10-26 | 2014-02-25 | Coley Pharm Gmbh | Oligorribonucleotídeos e seus usos. |
| FR2908414B1 (fr) | 2006-11-13 | 2012-01-20 | Centre Nat Rech Scient | Immobilisation de proteines membranaires sur un support par l'intermediaire d'une molecule amphiphile |
| JP2010510224A (ja) | 2006-11-17 | 2010-04-02 | アボット・ラボラトリーズ | ケモカイン受容体拮抗薬としてのアミノピロリジン類 |
| US8093222B2 (en) | 2006-11-27 | 2012-01-10 | Isis Pharmaceuticals, Inc. | Methods for treating hypercholesterolemia |
| MX2009005527A (es) | 2006-11-27 | 2009-06-08 | Isis Pharmaceuticals Inc | Metodos para el tratamiento de hipercolesterolemia. |
| CN101610671A (zh) | 2006-12-12 | 2009-12-23 | 艾德拉药物股份有限公司 | 合成的tlr9激动剂 |
| UY30892A1 (es) | 2007-02-07 | 2008-09-02 | Smithkline Beckman Corp | Inhibidores de la actividad akt |
| US20100190837A1 (en) | 2007-02-15 | 2010-07-29 | Isis Pharmaceuticals, Inc. | 5'-Substituted-2-F' Modified Nucleosides and Oligomeric Compounds Prepared Therefrom |
| JP2010522245A (ja) | 2007-03-24 | 2010-07-01 | ゲンザイム コーポレイション | ヒトアポリポタンパク質ｂと相補的なアンチセンスオリゴヌクレオチドの投与 |
| US7960353B2 (en) | 2007-05-10 | 2011-06-14 | University Of Kansas | Novobiocin analogues as neuroprotective agents and in the treatment of autoimmune disorders |
| EP2818550B1 (en) | 2007-05-11 | 2016-12-28 | Adynxx, Inc. | Gene expression and pain |
| WO2008143343A1 (ja) | 2007-05-24 | 2008-11-27 | Kyorin Pharmaceutical Co., Ltd. | １４位置換基に複素芳香環カルボン酸構造を有するムチリン誘導体 |
| GB0710186D0 (en) | 2007-05-29 | 2007-07-04 | Texas Instr Denmark | PWM loop with minimum allasing error property |
| US8278425B2 (en) | 2007-05-30 | 2012-10-02 | Isis Pharmaceuticals, Inc. | N-substituted-aminomethylene bridged bicyclic nucleic acid analogs |
| KR20100038295A (ko) | 2007-06-05 | 2010-04-14 | 엔에스아베 필리알 아프 뉴로서치 스웨덴 아베 스베리게 | 피질 카테콜아민성 신경 전달의 조정자로서의 이치환된 페닐피롤리딘 |
| EP2173760B2 (en) | 2007-06-08 | 2015-11-04 | Isis Pharmaceuticals, Inc. | Carbocyclic bicyclic nucleic acid analogs |
| WO2008151833A2 (en) | 2007-06-13 | 2008-12-18 | Hochschule Mannheim | Compounds for the modulation of huntingtin aggregation, methods and means for identifying such compounds |
| EP2014769B1 (en) | 2007-06-18 | 2010-03-31 | Commissariat à l'Energie Atomique | Reversible siRNAa-based silencing of mutated and endogenous wild-type huntingtin gene and its application for the treatment of Huntington's disease |
| GB0712494D0 (en) | 2007-06-27 | 2007-08-08 | Isis Innovation | Substrate reduction therapy |
| CN101796062B (zh) | 2007-07-05 | 2014-07-30 | Isis制药公司 | 6-双取代双环核酸类似物 |
| AU2008279509B2 (en) | 2007-07-09 | 2011-07-21 | Idera Pharmaceuticals, Inc. | Stabilized immune modulatory RNA (SIMRA) compounds |
| TWI413530B (zh) | 2007-07-20 | 2013-11-01 | Kao Corp | 有機聚矽氧 |
| CA2694718A1 (en) | 2007-07-31 | 2009-02-05 | University Of Saskatchewan | Genetic variation in pro-melanin-concentrating hormone gene affects carcass traits in cattle |
| WO2009017803A2 (en) | 2007-08-02 | 2009-02-05 | The Texas A & M University System | Antisense microrna and uses therefor |
| WO2009023819A2 (en) | 2007-08-15 | 2009-02-19 | Idera Pharmaceuticals, Inc. | Toll like receptor modulators |
| CA2701128A1 (en) | 2007-10-01 | 2009-04-09 | Isis Pharmaceuticals, Inc. | Antisense modulation of fibroblast growth factor receptor 4 expression |
| KR100886139B1 (ko) | 2007-11-13 | 2009-02-27 | 주식회사 삼천리제약 | 올리고뉴클레오타이드의 제조방법 |
| TW200930375A (en) | 2007-12-21 | 2009-07-16 | Exelixis Inc | Benzofuropyrimidinones |
| TWI340765B (en) | 2007-12-26 | 2011-04-21 | Ind Tech Res Inst | Oligonucleotide sequences and dna chip for identifying filamentous microorganisms and the identification method thereof |
| WO2009089689A1 (en) | 2008-01-15 | 2009-07-23 | Mediatek Inc. | Multimedia presenting system, multimedia processing apparatus thereof, and method for presenting video and audio signals |
| WO2009089659A1 (en) | 2008-01-18 | 2009-07-23 | Shanghai Targetdrug Co., Ltd. | Pyrollidine-based compounds |
| JP2011515653A (ja) | 2008-02-04 | 2011-05-19 | ガラパゴス・ナムローゼ・フェンノートシャップ | 神経変性疾患の治療に有用な標的配列及びそれらの同定方法 |
| JP2009190983A (ja) | 2008-02-12 | 2009-08-27 | Tokyo Institute Of Technology | オリゴヌクレオチド誘導体 |
| US8426378B2 (en) | 2008-03-21 | 2013-04-23 | Isis Pharmaceuticals, Inc. | Oligomeric compounds comprising tricyclic nucelosides and methods for their use |
| WO2009142822A2 (en) | 2008-03-26 | 2009-11-26 | Alnylam Pharmaceuticals, Inc. | 2-f modified rna interference agents |
| GB2471806B (en) | 2008-04-03 | 2012-12-19 | Spring Bank Pharmaceuticals Inc | Compositions and methods for treating viral infections |
| EP2262820B1 (de) | 2008-04-04 | 2013-06-19 | Universität Hamburg | Verfahren zur stereoselektiven synthese von phosphorverbindungen |
| EP2285819B1 (en) | 2008-04-04 | 2013-10-16 | Isis Pharmaceuticals, Inc. | Oligomeric compounds comprising neutrally linked terminal bicyclic nucleosides |
| AU2009244013B2 (en) | 2008-05-09 | 2015-06-25 | The University Of British Columbia | Methods and compositions for the treatment of Huntington's disease |
| US8679750B2 (en) | 2008-05-09 | 2014-03-25 | The University Of British Columbia | Methods and compositions for the treatment of Huntington'S disease |
| JP5727367B2 (ja) | 2008-05-15 | 2015-06-03 | ダイナバックス テクノロジーズ コーポレイション | 免疫賦活オリゴヌクレオチドを使用する長期疾患改良 |
| WO2009143391A2 (en) | 2008-05-22 | 2009-11-26 | Isis Pharmaceuticals, Inc | Methods for modulation expression of creb |
| WO2009143390A2 (en) | 2008-05-22 | 2009-11-26 | Isis Pharmaceuticals, Inc. | Methods for modulating expression of rbp4 |
| US8541387B2 (en) | 2008-05-22 | 2013-09-24 | Isis Pharmaceuticals, Inc. | Modulation of SMRT expression |
| WO2009148605A2 (en) | 2008-06-04 | 2009-12-10 | Isis Pharmaceuticals, Inc. | Methods for treating hypercholesterolemia |
| US8410070B2 (en) | 2008-09-12 | 2013-04-02 | University Of Louisville Research Foundation, Inc. | Compositions and methods for treating cancer, inhibiting proliferation, and inducing cell death |
| WO2010030858A1 (en) | 2008-09-15 | 2010-03-18 | Enanta Pharmaceuticals, Inc. | 4'-allene-substituted nucleoside derivatives |
| EP2341793A4 (en) * | 2008-09-22 | 2012-06-20 | Daymen Canada Acquisition Ulc | CASE WITH INTEGRATED EXTRACTS |
| EP3067359A1 (en) | 2008-09-23 | 2016-09-14 | Scott G. Petersen | Self delivering bio-labile phosphate protected pro-oligos for oligonucleotide based therapeutics and mediating rna interference |
| US8604192B2 (en) | 2008-09-24 | 2013-12-10 | Isis Pharmaceuticals, Inc. | Cyclohexenyl nucleic acids analogs |
| DK2356129T3 (da) | 2008-09-24 | 2013-05-13 | Isis Pharmaceuticals Inc | Substituerede alpha-L-bicykliske nukleosider |
| CA2739788A1 (en) | 2008-10-07 | 2010-04-15 | President And Fellows Of Harvard College | Telomerase inhibitors that bind to the cr4-cr5 domain of the rna component of human telomerase and methods of use thereof |
| NZ591391A (en) | 2008-10-22 | 2012-10-26 | Quark Pharmaceuticals Inc | Non-invasive methods for treating eye disorders using a topical oligonucleotide composition |
| WO2010048585A2 (en) | 2008-10-24 | 2010-04-29 | Isis Pharmaceuticals, Inc. | Oligomeric compounds and methods |
| WO2010048549A2 (en) | 2008-10-24 | 2010-04-29 | Isis Pharmaceuticals, Inc. | 5' and 2' bis-substituted nucleosides and oligomeric compounds prepared therefrom |
| CA2744987C (en) | 2008-12-02 | 2018-01-16 | Chiralgen, Ltd. | Method for the synthesis of phosphorus atom modified nucleic acids |
| JP2012513450A (ja) | 2008-12-23 | 2012-06-14 | ギリンダス・アメリカ・インコーポレイテッド | 硫化剤およびオリゴヌクレオチドを合成するためのその使用 |
| WO2010080953A1 (en) | 2009-01-08 | 2010-07-15 | Isis Pharmaceuticals, Inc. | Transgenic murine model of human lipoprotein metabolism, hypercholesterolemia and cardiovascular disease |
| KR20100087540A (ko) | 2009-01-28 | 2010-08-05 | 삼성전자주식회사 | 잉크젯 기록용 잉크 조성물 |
| WO2010091301A1 (en) | 2009-02-06 | 2010-08-12 | Isis Pharmaceuticals, Inc. | Oligomeric compounds and excipients |
| CA2752694A1 (en) | 2009-02-10 | 2010-08-19 | Idera Pharmaceuticals, Inc. | Synthetic rna-based agonists of tlr7 |
| JP5766617B2 (ja) | 2009-02-20 | 2015-08-19 | ユニバーシティ・オブ・カンザス | 修飾された糖部分を有するノボビオシン類似体 |
| US8975389B2 (en) | 2009-03-02 | 2015-03-10 | Alnylam Pharmaceuticals, Inc. | Nucleic acid chemical modifications |
| US9107933B2 (en) | 2009-03-16 | 2015-08-18 | Isis Pharmaceuticals, Inc. | Compositions and methods of targeting apolipoprotein B for the reduction of apolipoprotein C-III |
| DK2415777T3 (en) | 2009-03-31 | 2015-08-24 | Takeda Pharmaceutical | A process for the preparation of nucleoside |
| US8987222B2 (en) | 2009-04-08 | 2015-03-24 | University Of Massachusetts | Single nucleotide polymorphism (SNP) targeting therapies for the treatment of huntington'S disease |
| US20120156138A1 (en) | 2009-04-14 | 2012-06-21 | Smith Larry J | Methods and Compositions for the Treatment of Medical Conditions Involving Cellular Reprogramming |
| US9260493B2 (en) | 2009-05-07 | 2016-02-16 | The Regents Of The University Of California | Transducible delivery of nucleic acids using modified dsRNA binding domains |
| KR20120052909A (ko) | 2009-06-01 | 2012-05-24 | 더 리전트 오브 더 유니버시티 오브 캘리포니아 | 핵산 수송용 조성물 및 이의 사용 방법 |
| CN102481312B (zh) | 2009-06-05 | 2015-07-15 | 传染性疾病研究院 | 合成的吡喃葡萄糖脂佐剂 |
| CN106983768B (zh) | 2009-06-17 | 2023-04-07 | 冷泉港实验室 | 用于在对象中调节smn2剪接的组合物和方法 |
| JP5670097B2 (ja) | 2009-06-19 | 2015-02-18 | 花王株式会社 | 二層分離型毛髪化粧料 |
| EP2447273A4 (en) | 2009-06-23 | 2013-06-19 | Takeda Pharmaceutical | METHOD OF SYNTHESIZING A NUCLEIC ACID |
| BR112012000828A8 (pt) | 2009-07-06 | 2017-10-10 | Ontorii Inc | Novas pró-drogas de ácido nucleico e métodos de uso das mesmas |
| WO2011005764A1 (en) | 2009-07-06 | 2011-01-13 | Ada Technologies, Inc. | Electrochemical device and method for long-term measurement of hypohalites |
| WO2011005860A2 (en) | 2009-07-07 | 2011-01-13 | Alnylam Pharmaceuticals, Inc. | 5' phosphate mimics |
| EP2451974A2 (en) | 2009-07-08 | 2012-05-16 | Idera Pharmaceuticals, Inc. | Oligonucleotide-based compounds as inhibitors of toll-like receptors |
| WO2011010706A1 (ja) | 2009-07-23 | 2011-01-27 | 武田薬品工業株式会社 | Fgf21シスエレメント結合物質 |
| WO2011015572A1 (en) | 2009-08-03 | 2011-02-10 | Galapagos Nv | Molecular targets and compounds, and methods to identify the same, useful in the treatment of neurodegenerative diseases |
| WO2011015573A1 (en) | 2009-08-03 | 2011-02-10 | Galapagos Nv | Molecular targets and compounds, and methods to identify the same, useful in the treatment of neurodegenerative diseases |
| UA107360C2 (en) | 2009-08-05 | 2014-12-25 | Biogen Idec Inc | Bicyclic aryl sphingosine 1-phosphate analogs |
| EP2462153B1 (en) | 2009-08-06 | 2015-07-29 | Isis Pharmaceuticals, Inc. | Bicyclic cyclohexose nucleic acid analogs |
| US8927553B2 (en) | 2009-08-10 | 2015-01-06 | Daljit Singh Dhanoa | Deuterium-enriched alkyl sulfonamides and uses thereof |
| KR101774526B1 (ko) | 2009-09-11 | 2017-09-04 | 아이오니스 파마수티컬즈, 인코포레이티드 | 헌팅틴 발현의 조절 |
| 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 |
| US20120270929A1 (en) | 2009-09-25 | 2012-10-25 | Isis Pharmaceuticals, Inc. | Modulation of ttc39 expression to increase hdl |
| KR20120083452A (ko) | 2009-10-15 | 2012-07-25 | 화이자 인코포레이티드 | 피롤로［2,3-ｄ］피리미딘 화합물 |
| TWI475051B (zh) | 2009-11-18 | 2015-03-01 | Kao Corp | Organic polysiloxane |
| JP5809408B2 (ja) | 2009-11-25 | 2015-11-10 | 花王株式会社 | 毛髪化粧料 |
| EP2512246B1 (en) | 2009-12-17 | 2015-09-30 | Merck Sharp & Dohme Corp. | Aminopyrimidines as syk inhibitors |
| BR112012016912A2 (pt) | 2009-12-28 | 2016-04-05 | Achira Labs Pvt Ltd | composição de gel de diagnóstico, método para preparar uma composição de gel de diagnóstico |
| AU2011203986C1 (en) | 2010-01-08 | 2015-03-05 | Ionis Pharmaceuticals, Inc. | Modulation of angiopoietin-like 3 expression |
| US8750507B2 (en) | 2010-01-25 | 2014-06-10 | Cisco Technology, Inc. | Dynamic group creation for managed key servers |
| CA2789005A1 (en) | 2010-02-08 | 2011-08-11 | Isis Pharmaceuticals, Inc. | Selective reduction of allelic variants |
| EP3208347B1 (en) | 2010-02-08 | 2019-08-14 | Ionis Pharmaceuticals, Inc. | Selective reduction of allelic variants |
| MX2012009316A (es) | 2010-02-10 | 2012-09-12 | Glaxosmithkline Llc | Maleato de 6-amino-2-{ [ (1s) -1-metil-butil] -oxi} -9-[ 5-(1-piperidinil) -7, 9-dihidro-8h-purin-8-ona. |
| US8859755B2 (en) | 2010-03-05 | 2014-10-14 | Chiralgen, Ltd. | Method for preparing ribonucleoside phosphorothioate |
| WO2011127175A1 (en) | 2010-04-06 | 2011-10-13 | Isis Pharmaceuticals, Inc. | Modulation of cd130 (gp130) expression |
| EP2556159A1 (en) | 2010-04-07 | 2013-02-13 | Isis Pharmaceuticals, Inc. | Modulation of cetp expression |
| US9725479B2 (en) | 2010-04-22 | 2017-08-08 | Ionis Pharmaceuticals, Inc. | 5′-end derivatives |
| EP2601204B1 (en) | 2010-04-28 | 2016-09-07 | Ionis Pharmaceuticals, Inc. | Modified nucleosides and oligomeric compounds prepared therefrom |
| WO2011139699A2 (en) | 2010-04-28 | 2011-11-10 | Isis Pharmaceuticals, Inc. | 5' modified nucleosides and oligomeric compounds prepared therefrom |
| US20130156845A1 (en) | 2010-04-29 | 2013-06-20 | Alnylam Pharmaceuticals, Inc. | Lipid formulated single stranded rna |
| EP2563921B1 (en) | 2010-04-30 | 2016-11-23 | Cellectis | Method for modulating double-strand break-induced homologous recombination |
| GB201008902D0 (en) | 2010-05-27 | 2010-07-14 | Imp Innovations Ltd | Membrane enhanced polymer sythesis |
| US20130253168A1 (en) | 2010-08-31 | 2013-09-26 | Steven L. Colletti | Novel single chemical entities and methods for delivery of oligonucleotides |
| WO2012039448A1 (ja) | 2010-09-24 | 2012-03-29 | 株式会社キラルジェン | 不斉補助基 |
| EP2623600A4 (en) | 2010-09-30 | 2014-11-26 | Lsip Llc | EXPRESSION INHIBITOR OF A DOMINANTLY MUTANT GENE |
| KR101381048B1 (ko) | 2010-10-20 | 2014-04-14 | 씨제이제일제당 (주) | Ｏ-포스포세린 생산 균주 및 이로부터 생산된 ｏ-포스포세린으로부터 ｌ-시스테인 또는 이의 유도체의 생산방법 |
| US9260471B2 (en) | 2010-10-29 | 2016-02-16 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using short interfering nucleic acids (siNA) |
| JP6336755B2 (ja) | 2010-11-12 | 2018-06-06 | ザ ジェネラル ホスピタル コーポレイション | ポリコームに関連する非コードｒｎａ |
| EP2647644B1 (en) | 2010-11-30 | 2020-09-09 | Wave Life Sciences Japan, Inc. | 2'-o-modified rna |
| US20140050778A1 (en) | 2010-12-28 | 2014-02-20 | University Of Rochester | Nucleic acid binding compounds, methods of making, and use thereof |
| US10017764B2 (en) | 2011-02-08 | 2018-07-10 | Ionis Pharmaceuticals, Inc. | Oligomeric compounds comprising bicyclic nucleotides and uses thereof |
| ES2739804T3 (es) | 2011-02-12 | 2020-02-04 | Univ Iowa Res Found | Compuestos terapéuticos |
| US9353371B2 (en) | 2011-05-02 | 2016-05-31 | Ionis Pharmaceuticals, Inc. | Antisense compounds targeting genes associated with usher syndrome |
| FR2975600B1 (fr) | 2011-05-24 | 2013-07-05 | Assist Publ Hopitaux De Paris | Agents pour le traitement de tumeurs |
| RU2014106024A (ru) | 2011-07-19 | 2015-08-27 | Юниверсити Оф Айдахо | Варианты осуществления зонда и способы направленного действия на нуклеиновые кислоты |
| US9605019B2 (en) | 2011-07-19 | 2017-03-28 | Wave Life Sciences Ltd. | Methods for the synthesis of functionalized nucleic acids |
| EP2742136B1 (en) | 2011-08-11 | 2017-09-27 | Ionis Pharmaceuticals, Inc. | Gapped oligomeric compounds comprising 5'-modified deoxyribonucleosides in the gap and uses thereof |
| WO2013033223A1 (en) | 2011-08-29 | 2013-03-07 | Isis Pharmaceuticals, Inc. | Methods and compounds useful in conditions related to repeat expansion |
| US20140080896A1 (en) | 2011-08-30 | 2014-03-20 | The Regents Of The University Of California | Identification of small molecules that facilitate therapeutic exon skipping |
| US9896729B2 (en) | 2011-08-31 | 2018-02-20 | The University Of Manchester | Method for diagnosing a neurodegenerative disease |
| US20140255936A1 (en) | 2011-09-09 | 2014-09-11 | Mayo Foundation For Medical Education And Research | Detecting frontotemporal dementia and amyotrophic lateral sclerosis |
| US10066228B2 (en) | 2011-11-30 | 2018-09-04 | Sarepta Therapeutics, Inc. | Oligonucleotides for treating expanded repeat diseases |
| US10557136B2 (en) | 2011-12-12 | 2020-02-11 | Oncolmmunin Inc. | In vivo delivery of oligonucleotides |
| JP6112569B2 (ja) | 2011-12-16 | 2017-04-12 | 国立大学法人 東京医科歯科大学 | キメラ２重鎖核酸 |
| CN104114605B (zh) | 2011-12-20 | 2018-06-22 | 沙特阿美技术公司 | 聚合物合成的方法 |
| CN102675386B (zh) | 2011-12-24 | 2014-07-02 | 河南科技大学 | 一种龙胆苦苷分离提纯方法 |
| WO2013134558A1 (en) | 2012-03-07 | 2013-09-12 | The Texas A & M University System | Cancer treatment targeting non-coding rna overexpression |
| PT2834258T (pt) | 2012-03-13 | 2017-04-07 | Gilead Sciences Inc | Análogos de carba-nucleósido 2¿- substituído para tratamento antiviral |
| US9809616B2 (en) | 2012-10-29 | 2017-11-07 | Emory University | Pyrimidine nucleosides and their monophosphate prodrugs for the treatment of viral infections and cancer |
| KR20130114435A (ko) | 2012-04-09 | 2013-10-17 | 삼성전자주식회사 | 다수의 전극을 갖는 생분자 검출 장치 |
| SI2841578T1 (sl) | 2012-04-23 | 2017-12-29 | Biomarin Technologies B.V. | Rna modulirajoči oligonukleotidi z izboljšanimi karakteristikami za zdravljenje nevromuskularnih motenj |
| AP3913A (en) | 2012-05-22 | 2016-11-26 | Idenix Pharamaceuticals Inc | D-amino acid compounds for liver disease |
| DK2857412T3 (en) | 2012-05-30 | 2017-04-03 | Hokkaido System Science Co Ltd | Method for Oligonucleotide Synthesis Using High-Resolution Liquid Phase Carrier |
| AU2013288048A1 (en) | 2012-07-13 | 2015-01-22 | Wave Life Sciences Ltd. | Asymmetric auxiliary group |
| KR101835401B1 (ko) | 2012-07-13 | 2018-03-08 | 신 니뽄 바이오메디칼 라보라토리즈, 엘티디. | 키랄 핵산 어쥬번트 |
| KR20220139425A (ko) | 2012-07-13 | 2022-10-14 | 웨이브 라이프 사이언시스 리미티드 | 키랄 제어 |
| CN104717982B (zh) | 2012-08-06 | 2018-08-28 | 阿尔尼拉姆医药品有限公司 | 碳水化合物共轭物及其制备改进工艺 |
| EP2885312A4 (en) | 2012-08-15 | 2016-01-20 | Isis Pharmaceuticals Inc | PROCESS FOR THE PREPARATION OF OLIGOMERIC COMPOUNDS USING MODIFIED STREAMING PROTOCOLS |
| CA2887884A1 (en) | 2012-10-12 | 2014-04-17 | Isis Pharmaceuticals, Inc. | Selective antisense compounds and uses thereof |
| RU2730677C2 (ru) | 2012-10-15 | 2020-08-24 | Ионис Фармасьютикалз, Инк. | Соединение для модуляции экспрессии гена c9orf72 и его применение |
| DK2906696T4 (da) | 2012-10-15 | 2023-02-27 | Ionis Pharmaceuticals Inc | Fremgangsmåder til modulering af c9orf72-ekspression |
| WO2014062736A1 (en) | 2012-10-15 | 2014-04-24 | Isis Pharmaceuticals, Inc. | Methods for monitoring c9orf72 expression |
| EP2725029A1 (en) | 2012-10-29 | 2014-04-30 | Laboratoire Biodim | New antibacterial compounds and biological applications thereof |
| EP2915815B1 (en) | 2012-10-31 | 2018-01-17 | Takeda Pharmaceutical Company Limited | New modified nucleic acid |
| JP2016503300A (ja) | 2012-11-15 | 2016-02-04 | ロシュ・イノベーション・センター・コペンハーゲン・アクティーゼルスカブＲｏｃｈｅ Ｉｎｎｏｖａｔｉｏｎ Ｃｅｎｔｅｒ Ｃｏｐｅｎｈａｇｅｎ Ａ／Ｓ | 抗ＡｐｏＢアンチセンス複合体化合物 |
| RU2015120645A (ru) | 2012-11-26 | 2017-01-10 | Рош Инновейшен Сентер Копенгаген А/С | Композиции и способы модуляции экспрессии рецептора фактора роста фибробластов 3 типа (fgfr3) |
| EP2935304A1 (en) | 2012-12-19 | 2015-10-28 | IDENIX Pharmaceuticals, Inc. | 4'-fluoro nucleosides for the treatment of hcv |
| CN104955952A (zh) | 2013-01-30 | 2015-09-30 | 弗·哈夫曼-拉罗切有限公司 | Lna寡核苷酸碳水化合物缀合物 |
| WO2014118272A1 (en) | 2013-01-30 | 2014-08-07 | Santaris Pharma A/S | Antimir-122 oligonucleotide carbohydrate conjugates |
| EP3778618A1 (en) | 2013-02-04 | 2021-02-17 | Ionis Pharmaceuticals, Inc. | Selective antisense compounds and uses thereof |
| CA2900238A1 (en) | 2013-02-22 | 2014-08-28 | Sirna Therapeutics, Inc. | Short interfering nucleic acid (sina) molecules containing a 2' internucleoside linkage |
| US20160108395A1 (en) | 2013-03-01 | 2016-04-21 | National University Corporation Tokyo Medical And Dental University | Chimeric single-stranded antisense polynucleotides and double-stranded antisense agent |
| WO2014154488A1 (en) | 2013-03-28 | 2014-10-02 | Syngenta Participations Ag | Methods of controlling neonicotinoid resistant pests |
| CN105120667A (zh) | 2013-03-28 | 2015-12-02 | 先正达参股股份有限公司 | 控制新烟碱抗性有害生物的方法 |
| EP2992009B1 (en) | 2013-05-01 | 2020-06-24 | Ionis Pharmaceuticals, Inc. | Compositions and methods for modulating apolipoprotein (a) expression |
| EP3015467A4 (en) | 2013-05-24 | 2016-11-02 | Ajinomoto Kk | PROCESS FOR THE PRODUCTION OF MORPHOLINO-OLIGONUCLEOTIDE |
| BR112015029327A2 (pt) | 2013-05-24 | 2017-09-19 | Roche Innovation Ct Copenhagen As | Moduladores de oligonucleotídeo de linfoma 11a/cll de célula b (bcl11a) e usos dos mesmos |
| AU2014272526A1 (en) | 2013-05-30 | 2015-12-10 | National University Corporation Tokyo Medical And Dental University | Double-stranded agents for delivering therapeutic oligonucleotides |
| CA2915443A1 (en) | 2013-06-16 | 2014-12-24 | National University Corporation Tokyo Medical And Dental University | Double-stranded antisense nucleic acid with exon-skipping effect |
| AU2014284152B2 (en) | 2013-06-21 | 2020-01-23 | Ionis Pharmaceuticals, Inc. | Compositions and methods for modulation of target nucleic acids |
| DK3013959T3 (da) | 2013-06-27 | 2020-02-17 | Roche Innovation Ct Copenhagen As | Antisense-oligomerer og konjugater målrettet pcsk9 |
| TWI657819B (zh) | 2013-07-19 | 2019-05-01 | 美商Ionis製藥公司 | 用於調節τ蛋白表現之組合物 |
| CN105579582A (zh) | 2013-07-25 | 2016-05-11 | 埃克西奎雷股份有限公司 | 用于预防和治疗用途的作为免疫刺激剂的基于球形核酸的构建体 |
| US10435430B2 (en) | 2013-07-31 | 2019-10-08 | Ionis Pharmaceuticals, Inc. | Methods and compounds useful in conditions related to repeat expansion |
| CN105579442A (zh) | 2013-09-06 | 2016-05-11 | 先正达参股股份有限公司 | 杀虫化合物 |
| WO2015051169A2 (en) | 2013-10-02 | 2015-04-09 | Moderna Therapeutics, Inc. | Polynucleotide molecules and uses thereof |
| US10323076B2 (en) | 2013-10-03 | 2019-06-18 | Modernatx, Inc. | Polynucleotides encoding low density lipoprotein receptor |
| US9988627B2 (en) | 2013-10-04 | 2018-06-05 | Novartis Ag | Formats for organic compounds for use in RNA interference |
| SG11201602597YA (en) | 2013-10-11 | 2016-05-30 | Ionis Pharmaceuticals Inc | Compositions for modulating c9orf72 expression |
| ES2747260T3 (es) | 2013-10-14 | 2020-03-10 | Ionis Pharmaceuticals Inc | Métodos para modular la expresión de transcrito antisentido C9ORF72 |
| WO2015057727A1 (en) | 2013-10-14 | 2015-04-23 | Isis Pharmaceuticals, Inc. | Compositions for modulating expression of c9orf72 antisense transcript |
| CA2929179A1 (en) | 2013-11-11 | 2015-05-14 | Sangamo Biosciences, Inc. | Htt genetic repressor, viral vector, and uses thereof |
| WO2015071388A1 (en) | 2013-11-14 | 2015-05-21 | Roche Innovation Center Copenhagen A/S | Apob antisense conjugate compounds |
| EP3053585A1 (en) | 2013-12-13 | 2016-08-10 | Moderna Therapeutics, Inc. | Alternative nucleic acid molecules and uses thereof |
| 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 |
| 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 |
| 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 |
| PT3094728T (pt) | 2014-01-16 | 2022-05-19 | Wave Life Sciences Ltd | Desenho quiral |
| WO2015143078A1 (en) | 2014-03-18 | 2015-09-24 | University Of Massachusetts | Raav-based compositions and methods for treating amyotrophic lateral sclerosis |
| WO2015168172A1 (en) | 2014-04-28 | 2015-11-05 | Isis Pharmaceuticals, Inc. | Linkage modified oligomeric compounds |
| WO2015168589A2 (en) | 2014-05-01 | 2015-11-05 | Isis Pharmaceuticals, Inc. | Compositions and methods for modulating angiopoietin-like 3 expression |
| US11110154B2 (en) | 2014-05-08 | 2021-09-07 | Sangamo Therapeutics, Inc. | Methods and compositions for treating Huntington's Disease |
| AU2015264263B2 (en) | 2014-05-20 | 2021-08-05 | University Of Iowa Research Foundation | Huntington's disease therapeutic compounds |
| US20160017327A1 (en) | 2014-07-11 | 2016-01-21 | The Johns Hopkins University | Phosphorodiamidate morpholino oligomers (pmos) and their use in suppression of mutant huntingtin expression and attenuation of neurotoxicity |
| CA2955250A1 (en) | 2014-07-16 | 2016-01-21 | Moderna Therapeutics, Inc. | Chimeric polynucleotides |
| EP2982758A1 (en) | 2014-08-04 | 2016-02-10 | Centre Hospitalier Universitaire Vaudois (CHUV) | Genome editing for the treatment of huntington's disease |
| CA2956554C (en) | 2014-08-07 | 2022-03-01 | Takeda Pharmaceutical Company Limited | Preparation of cationic lipid compounds and their salts as nucleic acid carriers |
| WO2016024205A1 (en) | 2014-08-15 | 2016-02-18 | Pfizer Inc. | Oligomers targeting hexanucleotide repeat expansion in human c9orf72 gene |
| WO2016037191A1 (en) | 2014-09-05 | 2016-03-10 | Health Research, Inc. | Use of huntingtin-derived plasmids and peptides for active immunization as a huntington's disease (hd) therapeutic |
| JP2017536366A (ja) | 2014-11-19 | 2017-12-07 | ロシュ イノベーション センター コペンハーゲン エーエス | Ｌｎａキラルホスホロチオエート |
| JP6689279B2 (ja) | 2014-12-16 | 2020-05-20 | ロシュ イノベーション センター コペンハーゲン エーエス | キラル毒性のスクリーニング方法 |
| CA2971920C (en) | 2014-12-24 | 2024-05-07 | Uniqure Ip B.V. | Rnai induced huntingtin gene suppression |
| US9688707B2 (en) | 2014-12-30 | 2017-06-27 | Ionis Pharmaceuticals, Inc. | Bicyclic morpholino compounds and oligomeric compounds prepared therefrom |
| US10793855B2 (en) | 2015-01-06 | 2020-10-06 | Ionis Pharmaceuticals, Inc. | Compositions for modulating expression of C9ORF72 antisense transcript |
| CN115181778A (zh) | 2015-02-04 | 2022-10-14 | 百时美施贵宝公司 | 选择治疗性分子的方法 |
| MX2017010066A (es) | 2015-02-04 | 2017-11-01 | Hoffmann La Roche | Oligomeros antisentido de tau y usos de los mismos. |
| WO2016127002A1 (en) | 2015-02-04 | 2016-08-11 | Bristol-Myers Squibb Company | Lna oligonucleotides with alternating flanks |
| US10450563B2 (en) | 2015-02-10 | 2019-10-22 | Genzyme Corporation | Variant RNAi |
| EP3256587A2 (en) | 2015-02-13 | 2017-12-20 | Alnylam Pharmaceuticals, Inc. | Patatin-like phospholipase domain containing 3 (pnpla3) irna compositions and methods of use thereof |
| EP3262174A4 (en) | 2015-02-23 | 2018-10-17 | Ionis Pharmaceuticals, Inc. | Compounds and methods for increasing antisense activity |
| US20180036335A1 (en) | 2015-03-03 | 2018-02-08 | Ionis Pharmaceuticals, Inc. | Compositions for modulating mecp2 expression |
| WO2016145142A1 (en) | 2015-03-10 | 2016-09-15 | Emory University | Nucleotide and nucleoside therapeutics compositions and uses related thereto |
| WO2016154096A1 (en) | 2015-03-20 | 2016-09-29 | Ionis Pharmaceuticals, Inc. | Modulation of smggds expression |
| LT3277814T (lt) | 2015-04-03 | 2020-10-26 | University Of Massachusetts | Oligonukleotidų junginiai, skirti nukreipimui į hantingtino mrnr |
| US10851371B2 (en) | 2015-04-10 | 2020-12-01 | Ionis Pharmaceuticals, Inc. | Modulation of SMN expression |
| SG11201708468YA (en) | 2015-04-16 | 2017-11-29 | Ionis Pharmaceuticals Inc | Compositions for modulating c9orf72 expression |
| US10407678B2 (en) | 2015-04-16 | 2019-09-10 | Ionis Pharmaceuticals, Inc. | Compositions for modulating expression of C9ORF72 antisense transcript |
| WO2016209862A1 (en) | 2015-06-23 | 2016-12-29 | Alnylam Pharmaceuticals, Inc. | Glucokinase (gck) irna compositions and methods of use thereof |
| WO2017004261A1 (en) | 2015-06-29 | 2017-01-05 | Ionis Pharmaceuticals, Inc. | Modified crispr rna and modified single crispr rna and uses thereof |
| WO2017011286A1 (en) | 2015-07-10 | 2017-01-19 | Alnylam Pharmaceuticals, Inc. | Insulin-like growth factor binding protein, acid labile subunit (igfals) and insulin-like growth factor 1 (igf-1) irna compositions and methods of use thereof |
| AU2016294347B2 (en) | 2015-07-10 | 2022-07-28 | Ionis Pharmaceuticals, Inc. | Modulators of diacyglycerol acyltransferase 2 (DGAT2) |
| US11053495B2 (en) | 2015-07-17 | 2021-07-06 | Alnylam Pharmaceuticals, Inc. | Multi-targeted single entity conjugates |
| MA43072A (fr) | 2015-07-22 | 2018-05-30 | Wave Life Sciences Ltd | Compositions d'oligonucléotides et procédés associés |
| US20180216114A1 (en) | 2015-07-27 | 2018-08-02 | Alnylam Pharmaceuticals, Inc. | Xanthine dehydrogenase (xdh) irna compositions and methods of use thereof |
| SG10201912341SA (en) | 2015-07-31 | 2020-02-27 | Alnylam Pharmaceuticals Inc | TRANSTHYRETIN (TTR) iRNA COMPOSITIONS AND METHODS OF USE THEREOF FOR TREATING OR PREVENTING TTR-ASSOCIATED DISEASES |
| CN107922945A (zh) | 2015-08-24 | 2018-04-17 | 罗氏创新中心哥本哈根有限公司 | Lna‑g 方法 |
| CN114939124A (zh) | 2015-08-25 | 2022-08-26 | 阿尔尼拉姆医药品有限公司 | 治疗前蛋白转化酶枯草杆菌蛋白酶kexin(pcsk9)基因相关障碍的方法和组合物 |
| JP7028764B2 (ja) | 2015-09-02 | 2022-03-02 | アルナイラム ファーマシューティカルズ， インコーポレイテッド | プログラム細胞死１リガンド１（ＰＤ－Ｌ１）ｉＲＮＡ組成物およびその使用方法 |
| CA3000709A1 (en) | 2015-10-01 | 2017-04-06 | Memorial Sloan-Kettering Cancer Center | Inhibitors of menaquinone biosynthesis |
| WO2017059446A1 (en) | 2015-10-01 | 2017-04-06 | Memorial Sloan-Kettering Cancer Center | Anthranilyl-adenosinemonosulfamate analogs and uses thereof |
| EP3355932B1 (en) | 2015-10-02 | 2023-04-12 | Roche Innovation Center Copenhagen A/S | Oligonucleotide conjugation process |
| EP3359523A4 (en) | 2015-10-09 | 2019-07-24 | Wave Life Sciences Ltd. | OLIGONUCLEOTIDE COMPOSITIONS AND RELATED METHODS |
| EP3183347A4 (en) | 2015-10-17 | 2018-04-18 | Lifesplice Pharma LLC | Splice modulating oligonucleotides and methods of use thereof |
| WO2017068087A1 (en) | 2015-10-22 | 2017-04-27 | Roche Innovation Center Copenhagen A/S | Oligonucleotide detection method |
| US10955407B2 (en) | 2015-10-22 | 2021-03-23 | Roche Innovation Center Copenhagen A/S | In vitro toxicity screening assay |
| WO2017079291A1 (en) | 2015-11-02 | 2017-05-11 | Ionis Pharmaceuticals, Inc. | Compounds and methods for modulating c90rf72 |
| CA3004799C (en) | 2015-11-12 | 2024-05-14 | F. Hoffmann-La Roche Ag | Oligonucleotides for inducing paternal ube3a expression |
| AU2017234150B2 (en) | 2016-03-13 | 2021-09-16 | Wave Life Sciences Ltd. | Compositions and methods for phosphoramidite and oligonucleotide synthesis |
| AU2017235278C1 (en) | 2016-03-14 | 2022-03-10 | F. Hoffmann-La Roche Ag | Oligonucleotides for reduction of PD-L1 expression |
| US11267843B2 (en) | 2016-03-18 | 2022-03-08 | Roche Innovation Center Copenhagen A/S | Stereodefining L-monomers |
| US11963972B2 (en) | 2016-03-23 | 2024-04-23 | Emory University | Antiviral agents and nucleoside analogs for treatment of Zika virus |
| US20190142856A1 (en) | 2016-04-13 | 2019-05-16 | Ionis Pharmaceuticals, Inc. | Methods for reducing c9orf72 expression |
| WO2017178656A1 (en) | 2016-04-14 | 2017-10-19 | Roche Innovation Center Copenhagen A/S | TRITYL-MONO-GalNAc COMPOUNDS AND THEIR USE |
| MA45270A (fr) | 2016-05-04 | 2017-11-09 | Wave Life Sciences Ltd | Compositions d'oligonucléotides et procédés associés |
| MA45290A (fr) | 2016-05-04 | 2019-03-13 | Wave Life Sciences Ltd | Procédés et compositions d'agents biologiquement actifs |
| CN109311925B (zh) | 2016-05-12 | 2022-06-03 | 罗氏创新中心哥本哈根有限公司 | 立体限定的氧杂氮杂磷杂环戊烷亚磷酰胺单体与核苷或寡核苷酸的增强的偶联 |
| JP7083756B2 (ja) | 2016-05-13 | 2022-06-13 | エフ．ホフマン－ラ ロシュ アーゲー | タンパク質系試料回収マトリックス及び装置 |
| US10882884B2 (en) | 2016-05-18 | 2021-01-05 | Eth Zurich | Stereoselective synthesis of phosphorothioate oligoribonucleotides |
| 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 |
| EP4212176A1 (en) | 2016-06-20 | 2023-07-19 | Genahead Bio, Inc. | Antibody-drug conjugate |
| WO2018022473A1 (en) | 2016-07-25 | 2018-02-01 | Wave Life Sciences Ltd. | Phasing |
| 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 |
| 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 |
| JP2020522265A (ja) | 2017-06-02 | 2020-07-30 | 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組成物及びその使用方法 |
| 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 |
| EP3694530A4 (en) | 2017-10-12 | 2021-06-30 | Wave Life Sciences Ltd. | OLIGONUCLEOTIDE COMPOSITIONS AND METHOD FOR THEREFORE |
| CA3096667A1 (en) | 2018-04-12 | 2019-10-17 | Wave Life Sciences Ltd. | Oligonucleotide compositions and methods of use thereof |
| CN112218664A (zh) | 2018-05-11 | 2021-01-12 | 波涛生命科学有限公司 | 寡核苷酸组合物及其使用方法 |
| CA3122271A1 (en) | 2018-12-06 | 2020-06-11 | Wave Life Sciences Ltd. | Oligonucleotide compositions and methods thereof |
| JP2022519019A (ja) | 2019-02-01 | 2022-03-18 | ウェイブ ライフ サイエンシズ リミテッド | オリゴヌクレオチド組成物及びその方法 |
| CA3134036A1 (en) | 2019-03-20 | 2020-09-24 | Wave Life Sciences Ltd. | Technologies useful for oligonucleotide preparation |
| US20220307019A1 (en) | 2019-03-25 | 2022-09-29 | National University Corporation Tokyo Medical And Dental University | Double-stranded nucleic acid complex and use thereof |
| CA3137741A1 (en) | 2019-04-25 | 2020-10-29 | Wave Life Sciences Ltd. | Oligonucleotide compositions and methods of use thereof |
| AU2020261434A1 (en) | 2019-04-25 | 2021-11-11 | Wave Life Sciences Ltd. | Oligonucleotide compositions and methods of use thereof |
| JP2022532169A (ja) | 2019-05-09 | 2022-07-13 | ウェイブ ライフ サイエンシズ リミテッド | オリゴヌクレオチド組成物及びその使用方法 |
| AU2020363344A1 (en) | 2019-10-06 | 2022-05-26 | Wave Life Sciences Ltd. | Oligonucleotide compositions and methods of use thereof |
| EP4022059A4 (en) | 2019-10-06 | 2023-11-01 | Wave Life Sciences Ltd. | OLIGONUCLEOTIDE COMPOSITIONS AND METHODS OF USE THEREOF |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102143746A (zh) * | 2008-07-03 | 2011-08-03 | 埃克塞利希斯股份有限公司 | Cdk 调节剂 |
Non-Patent Citations (1)
| Title |
|---|
| A One-Pot Formal [4 + 2] Cycloaddition Approach to Substituted Piperidines, Indolizidines, and Quinolizidines. Total Synthesis of Indolizidine (-)-209I;Shanghai Yu等;《J. Org. Chem.》;20050805;第7364-7370页 * |
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