ES2479393T3 - Método de síntesis de oligómeros de morfolino - Google Patents
Método de síntesis de oligómeros de morfolino Download PDFInfo
- Publication number
- ES2479393T3 ES2479393T3 ES08850132.5T ES08850132T ES2479393T3 ES 2479393 T3 ES2479393 T3 ES 2479393T3 ES 08850132 T ES08850132 T ES 08850132T ES 2479393 T3 ES2479393 T3 ES 2479393T3
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- morpholino
- group
- compound
- protected
- nitrogen
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- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 title claims abstract description 112
- 238000001308 synthesis method Methods 0.000 title description 2
- -1 morpholino compound Chemical class 0.000 claims abstract description 101
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 39
- 125000005039 triarylmethyl group Chemical group 0.000 claims abstract description 25
- MCKANBCWFDYIJO-UHFFFAOYSA-N chloro-dihydroxy-imino-$l^{5}-phosphane Chemical group NP(O)(Cl)=O MCKANBCWFDYIJO-UHFFFAOYSA-N 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 239000007787 solid Substances 0.000 claims abstract description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 11
- 229910052739 hydrogen Chemical group 0.000 claims abstract description 11
- 239000001257 hydrogen Chemical group 0.000 claims abstract description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 7
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 7
- 125000003277 amino group Chemical group 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 186
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 107
- 229910052757 nitrogen Inorganic materials 0.000 claims description 57
- 230000015572 biosynthetic process Effects 0.000 claims description 50
- 238000000034 method Methods 0.000 claims description 42
- 238000003786 synthesis reaction Methods 0.000 claims description 39
- 239000000178 monomer Substances 0.000 claims description 38
- UYTPUPDQBNUYGX-UHFFFAOYSA-N Guanine Natural products O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 33
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 25
- 239000003153 chemical reaction reagent Substances 0.000 claims description 23
- 238000010511 deprotection reaction Methods 0.000 claims description 23
- 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 23
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 15
- 239000007790 solid phase Substances 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 9
- POEJZKASYFKLKY-UHFFFAOYSA-N 3-chloropyridin-1-ium;methanesulfonate Chemical group CS([O-])(=O)=O.ClC1=CC=C[NH+]=C1 POEJZKASYFKLKY-UHFFFAOYSA-N 0.000 claims description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical group NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 3
- 150000003852 triazoles Chemical class 0.000 claims description 3
- 229930194542 Keto Natural products 0.000 claims description 2
- 150000008052 alkyl sulfonates Chemical class 0.000 claims description 2
- 150000003857 carboxamides Chemical class 0.000 claims description 2
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 2
- 125000000468 ketone group Chemical group 0.000 claims description 2
- 150000008298 phosphoramidates Chemical class 0.000 claims description 2
- LMWFKCYJTRUATP-UHFFFAOYSA-N pyridin-1-ium-4-carbonitrile;2,2,2-trifluoroacetate Chemical group [O-]C(=O)C(F)(F)F.N#CC1=CC=[NH+]C=C1 LMWFKCYJTRUATP-UHFFFAOYSA-N 0.000 claims description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 claims 3
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical class C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 239000000243 solution Substances 0.000 description 90
- 239000011347 resin Substances 0.000 description 56
- 229920005989 resin Polymers 0.000 description 56
- 238000006243 chemical reaction Methods 0.000 description 38
- 239000000203 mixture Substances 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- 239000002585 base Substances 0.000 description 30
- 238000002360 preparation method Methods 0.000 description 29
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 21
- 125000006239 protecting group Chemical group 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 239000000047 product Substances 0.000 description 20
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- LAZQWLMVJAIYFE-UHFFFAOYSA-N 1-tritylpiperazine Chemical compound C1CNCCN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 LAZQWLMVJAIYFE-UHFFFAOYSA-N 0.000 description 14
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 14
- 239000010410 layer Substances 0.000 description 14
- 241000894007 species Species 0.000 description 14
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 13
- 238000005859 coupling reaction Methods 0.000 description 13
- 239000006227 byproduct Substances 0.000 description 11
- 230000008878 coupling Effects 0.000 description 11
- 238000010168 coupling process Methods 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 238000006386 neutralization reaction Methods 0.000 description 9
- MHCMWGPPLOSCJY-UHFFFAOYSA-N 4-$l^{1}-azanylmorpholine Chemical compound [N]N1CCOCC1 MHCMWGPPLOSCJY-UHFFFAOYSA-N 0.000 description 8
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 238000003776 cleavage reaction Methods 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 230000007017 scission Effects 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 7
- PFKFTWBEEFSNDU-UHFFFAOYSA-N 1,1'-Carbonyldiimidazole Substances C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 7
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 7
- 108091034117 Oligonucleotide Proteins 0.000 description 7
- 230000000295 complement effect Effects 0.000 description 7
- 230000007062 hydrolysis Effects 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 description 7
- 150000003222 pyridines Chemical class 0.000 description 7
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000007836 KH2PO4 Substances 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 239000004793 Polystyrene Substances 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 6
- ANCLJVISBRWUTR-UHFFFAOYSA-N diaminophosphinic acid Chemical compound NP(N)(O)=O ANCLJVISBRWUTR-UHFFFAOYSA-N 0.000 description 6
- 238000003379 elimination reaction Methods 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 6
- 235000019796 monopotassium phosphate Nutrition 0.000 description 6
- 229920002223 polystyrene Polymers 0.000 description 6
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 6
- 230000002194 synthesizing effect Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- RODBEKUWCLMBSW-FGZHOGPDSA-M (3r,5r)-7-[1-cyclohexyl-4-(4-fluorophenyl)-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC(C)C1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=CN1C1CCCCC1 RODBEKUWCLMBSW-FGZHOGPDSA-M 0.000 description 5
- VKKXEIQIGGPMHT-UHFFFAOYSA-N 7h-purine-2,8-diamine Chemical class NC1=NC=C2NC(N)=NC2=N1 VKKXEIQIGGPMHT-UHFFFAOYSA-N 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
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- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 238000010532 solid phase synthesis reaction Methods 0.000 description 5
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- 108020004414 DNA Proteins 0.000 description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 4
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- 229940059260 amidate Drugs 0.000 description 4
- 150000001735 carboxylic acids Chemical class 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000007979 citrate buffer Substances 0.000 description 4
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- 229910021641 deionized water Inorganic materials 0.000 description 4
- 230000008030 elimination Effects 0.000 description 4
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 4
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- 108020004707 nucleic acids Proteins 0.000 description 4
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
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- 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 3
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- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 3
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- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
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- 238000005571 anion exchange chromatography Methods 0.000 description 3
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- 238000006731 degradation reaction Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
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- 108091033319 polynucleotide Proteins 0.000 description 3
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- GPHQHTOMRSGBNZ-UHFFFAOYSA-N pyridine-4-carbonitrile Chemical compound N#CC1=CC=NC=C1 GPHQHTOMRSGBNZ-UHFFFAOYSA-N 0.000 description 3
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- 238000003756 stirring Methods 0.000 description 3
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- 239000001384 succinic acid Substances 0.000 description 3
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- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- CSPHPKQCLCBONW-UHFFFAOYSA-N pyridin-1-ium-1-carbonitrile Chemical class N#C[N+]1=CC=CC=C1 CSPHPKQCLCBONW-UHFFFAOYSA-N 0.000 description 1
- ILAILUUAUWUQNG-UHFFFAOYSA-N pyridin-1-ium-3-carbonitrile;2,2,2-trifluoroacetate Chemical compound OC(=O)C(F)(F)F.N#CC1=CC=CN=C1 ILAILUUAUWUQNG-UHFFFAOYSA-N 0.000 description 1
- ODNFVADIRXKBCY-UHFFFAOYSA-N pyrrolidin-1-yl carbamate Chemical class NC(=O)ON1CCCC1 ODNFVADIRXKBCY-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000002342 ribonucleoside Substances 0.000 description 1
- 238000010517 secondary reaction Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000002305 strong-anion-exchange chromatography Methods 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229920003002 synthetic resin Polymers 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
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 238000013519 translation Methods 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
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 239000001043 yellow dye Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Saccharide Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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| US98819207P | 2007-11-15 | 2007-11-15 | |
| US98820007P | 2007-11-15 | 2007-11-15 | |
| US988192P | 2007-11-15 | ||
| US988200P | 2007-11-15 | ||
| PCT/US2008/012804 WO2009064471A1 (en) | 2007-11-15 | 2008-11-14 | Method of synthesis of morpholino oligomers |
Publications (1)
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| ES2479393T3 true ES2479393T3 (es) | 2014-07-24 |
Family
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| ES08850132.5T Active ES2479393T3 (es) | 2007-11-15 | 2008-11-14 | Método de síntesis de oligómeros de morfolino |
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Families Citing this family (92)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006086667A2 (en) | 2005-02-09 | 2006-08-17 | Avi Bio Pharma, Inc. | Antisense composition and method for treating muscle atrophy |
| US8067571B2 (en) | 2005-07-13 | 2011-11-29 | Avi Biopharma, Inc. | Antibacterial antisense oligonucleotide and method |
| WO2010141511A2 (en) | 2009-06-01 | 2010-12-09 | Halo-Bio Rnai Therapeutics, Inc. | Polynucleotides for multivalent rna interference, compositions and methods of use thereof |
| AU2010319314C1 (en) | 2009-11-13 | 2016-09-01 | Sarepta Therapeutics, Inc. | Antisense antiviral compound and method for treating influenza viral infection |
| KR101981705B1 (ko) | 2010-05-28 | 2019-05-24 | 사렙타 쎄러퓨틱스, 인코퍼레이티드 | 변형된 서브유니트간 결합 및/또는 말단 그룹을 갖는 올리고뉴클레오타이드 유사체 |
| TWI541024B (zh) | 2010-09-01 | 2016-07-11 | 日本新藥股份有限公司 | 反義核酸 |
| WO2012031243A2 (en) | 2010-09-03 | 2012-03-08 | Avi Biopharma, Inc. | dsRNA MOLECULES COMPRISING OLIGONUCLEOTIDE ANALOGS HAVING MODIFIED INTERSUBUNIT LINKAGES AND/OR TERMINAL GROUPS |
| CN103154009B (zh) | 2010-09-30 | 2015-06-10 | 日本新药株式会社 | 吗啉基核酸衍生物 |
| AU2011326364B2 (en) | 2010-11-12 | 2016-08-11 | Sarepta Therapeutics, Inc. | Antisense antibacterial compounds and methods |
| AU2011367230B2 (en) | 2011-05-05 | 2017-08-10 | Sarepta Therapeutics, Inc. | Peptide oligonucleotide conjugates |
| CA2839593A1 (en) | 2011-07-15 | 2013-01-24 | Sarepta Therapeutics, Inc. | Methods and compositions for manipulating translation of protein isoforms from alternative initiation start sites |
| US20130085139A1 (en) | 2011-10-04 | 2013-04-04 | Royal Holloway And Bedford New College | Oligomers |
| KR20140097398A (ko) | 2011-11-18 | 2014-08-06 | 사렙타 쎄러퓨틱스, 인코퍼레이티드 | 기능적으로-변형된 올리고뉴클레오티드 및 이의 서브유니트 |
| WO2013082548A1 (en) | 2011-11-30 | 2013-06-06 | Sarepta Therapeutics, Inc. | Oligonucleotides for treating expanded repeat diseases |
| ES2727481T3 (es) | 2011-11-30 | 2019-10-16 | Sarepta Therapeutics Inc | Inclusión inducida de exón en atrofia muscular espinal |
| WO2013086444A2 (en) | 2011-12-08 | 2013-06-13 | Sarepta Therapeutics, Inc. | Methods for treating progeroid laminopathies using oligonucleotide analogues targeting human lmna |
| CN108588073A (zh) | 2011-12-28 | 2018-09-28 | 日本新药株式会社 | 反义核酸 |
| US9920085B2 (en) | 2012-03-20 | 2018-03-20 | Sarepta Therapeutics, Inc. | Boronic acid conjugates of oligonucleotide analogues |
| CN102702265A (zh) * | 2012-05-14 | 2012-10-03 | 天津特安化学科技有限公司 | 一种固相合成磷酰二胺吗啉代寡核苷酸及方法 |
| WO2014113540A1 (en) | 2013-01-16 | 2014-07-24 | Iowa State University Research Foundation, Inc. | A deep intronic target for splicing correction on spinal muscular atrophy gene |
| JP6477464B2 (ja) * | 2013-05-24 | 2019-03-06 | 味の素株式会社 | モルフォリノオリゴヌクレオチドの製造方法 |
| AU2014317961B2 (en) | 2013-09-05 | 2020-07-30 | Murdoch University | Antisense-induced exon2 inclusion in acid alpha-glucosidase |
| EP3052512A4 (en) | 2013-09-30 | 2017-02-22 | Geron Corporation | Phosphorodiamidate backbone linkage for oligonucleotides |
| BR112016020618B1 (pt) | 2014-03-12 | 2023-04-04 | Nippon Shinyaku Co., Ltd. | Oligômero antissentido, composição farmacêutica, e, uso de um oligômero antissentido |
| US9790495B2 (en) | 2014-05-16 | 2017-10-17 | Oregon State University | Antisense antibacterial compounds and methods |
| CA2948568A1 (en) | 2014-05-19 | 2015-11-26 | David Greenberg | Antisense antibacterial compounds and methods |
| PT3159409T (pt) | 2014-06-17 | 2020-01-21 | Nippon Shinyaku Co Ltd | Ácido nucleico anti-sentido para utilização no tratamento da distrofia muscular de duchenne |
| JP6673211B2 (ja) | 2014-10-14 | 2020-03-25 | 味の素株式会社 | モルフォリノオリゴヌクレオチドの製造方法 |
| WO2016108930A2 (en) | 2014-12-31 | 2016-07-07 | Geller Bruce L | Antisense antibacterial compounds and methods |
| MA41795A (fr) | 2015-03-18 | 2018-01-23 | Sarepta Therapeutics Inc | Exclusion d'un exon induite par des composés antisens dans la myostatine |
| KR102644053B1 (ko) | 2015-05-19 | 2024-03-06 | 사렙타 쎄러퓨틱스 인코퍼레이티드 | 펩티드 올리고뉴클레오티드 콘주게이트 |
| US10849917B2 (en) | 2015-06-01 | 2020-12-01 | Sarepta Therapeutics, Inc. | Antisense-induced exon exclusion in type VII collagen |
| US11020417B2 (en) | 2015-06-04 | 2021-06-01 | Sarepta Therapeutics, Inc | Methods and compounds for treatment of lymphocyte-related diseases and conditions |
| RS62930B1 (sr) * | 2015-08-05 | 2022-03-31 | Eisai R&D Man Co Ltd | Postupak za pripremu suštinski dijastereomerno čistog fosforodiamidatnog oligomera, fosforodiamidatni oligomer proizveden takvim postupkom i farmaceutska kompozicija koja sadrži fosforodiamidatni oligomer |
| MX2018002090A (es) | 2015-08-24 | 2018-09-12 | Halo Bio Rnai Therapeutics Inc | Nanoparticulas de polinucleótido para modulación de expresión génica y sus usos. |
| HUE050061T2 (hu) | 2015-09-15 | 2020-12-28 | Nippon Shinyaku Co Ltd | Antiszensz nukleinsav |
| WO2017047741A1 (ja) | 2015-09-16 | 2017-03-23 | 日本新薬株式会社 | 筋萎縮症治療用アンチセンス核酸 |
| JP2018530560A (ja) | 2015-10-09 | 2018-10-18 | サレプタ セラピューティクス， インコーポレイテッド | デュシェンヌ型筋ジストロフィーおよび関連障害の処置のための組成物および方法 |
| EA201891419A1 (ru) | 2015-12-15 | 2019-01-31 | Сарепта Терапьютикс, Инк. | Пептид-олигонуклеотидные конъюгаты |
| US11142764B2 (en) | 2015-12-23 | 2021-10-12 | Board Of Regents, The University Of Texas System | Antisense antibacterial compounds and methods |
| AU2016379399B2 (en) | 2015-12-23 | 2022-12-08 | Board Of Regents, The University Of Texas System | Antisense antibacterial compounds and methods |
| US11060089B2 (en) | 2016-04-18 | 2021-07-13 | Sarepta Therapeutics, Inc. | Antisense oligomers and methods of using the same for treating diseases associated with the acid alpha-glucosidase gene |
| JP7042255B2 (ja) | 2016-04-29 | 2022-03-25 | サレプタ セラピューティクス， インコーポレイテッド | ヒトｌｍｎａを標的にするオリゴヌクレオチド類縁体 |
| US11472824B2 (en) | 2016-05-24 | 2022-10-18 | Sarepta Therapeutics, Inc. | Processes for preparing phosphorodiamidate morpholino oligomers |
| MX384727B (es) | 2016-05-24 | 2025-03-14 | Sarepta Therapeutics Inc | Procesos para preparar oligómeros |
| TWI737736B (zh) | 2016-05-24 | 2021-09-01 | 美商薩羅塔治療公司 | 製備磷醯二胺嗎啉代寡聚物之方法 |
| MX390906B (es) | 2016-05-24 | 2025-03-21 | Sarepta Therapeutics Inc | Procesos para preparar oligómeros de morfolino fosforodiamidato. |
| US10947533B2 (en) | 2016-05-24 | 2021-03-16 | Sarepta Therapeutics, Inc. | Processes for preparing phosphorodiamidate morpholino oligomers |
| MA45158A (fr) | 2016-05-24 | 2019-04-10 | Sarepta Therapeutics Inc | Composition pharmaceutique comprenant de l'éteplirsen |
| CA3024153A1 (en) * | 2016-06-30 | 2017-11-30 | Sarepta Therapeutics, Inc. | Processes for preparing phosphorodiamidate morpholino oligomers |
| AU2017330276B2 (en) * | 2016-09-20 | 2022-01-20 | The Regents Of The University Of Colorado, A Body Corporate | Synthesis of backbone modified morpholino oligonucleotides and chimeras using phosphoramidite chemistry |
| ES3051834T3 (en) | 2016-12-19 | 2025-12-30 | Sarepta Therapeutics Inc | Exon skipping oligomer conjugates for muscular dystrophy |
| NZ755416A (en) | 2016-12-19 | 2023-05-26 | Sarepta Therapeutics Inc | Exon skipping oligomer conjugates for muscular dystrophy |
| PT4122497T (pt) | 2016-12-19 | 2024-06-12 | Sarepta Therapeutics Inc | Conjugados oligoméricos de salto de exão para a distrofia muscular |
| ES2994451T3 (en) | 2017-04-20 | 2025-01-24 | Atyr Pharma Inc | Compositions for treating lung inflammation |
| EA201991450A1 (ru) | 2017-09-22 | 2019-12-30 | Сарепта Терапьютикс, Инк. | Конъюгаты олигомеров для пропуска экзона при мышечной дистрофии |
| TWI812647B (zh) | 2017-09-25 | 2023-08-21 | 美商薩羅塔治療公司 | 經由速流合成以製備磷醯二胺嗎啉代寡聚物之製程 |
| US11555189B2 (en) | 2017-10-18 | 2023-01-17 | Sarepta Therapeutics, Inc. | Antisense oligomer compounds |
| US11560401B2 (en) | 2018-05-10 | 2023-01-24 | Nippon Shinyaku Co., Ltd. | Method for preparing oligonucleic acid compound |
| US10765760B2 (en) | 2018-05-29 | 2020-09-08 | 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 |
| JP7345466B2 (ja) | 2018-06-26 | 2023-09-15 | 日本新薬株式会社 | アンチセンスオリゴヌクレオチドを含有する組成物およびデュシェンヌ型筋ジストロフィーの治療へのその使用 |
| TW202449155A (zh) | 2018-07-27 | 2024-12-16 | 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 |
| BR112021011018A2 (pt) | 2018-12-13 | 2021-08-31 | Sarepta Therapeutics, Inc. | Conjugados de oligômero para exon skipping para distrofia muscular |
| GB201821269D0 (en) | 2018-12-28 | 2019-02-13 | Nippon Shinyaku Co Ltd | Myostatin signal inhibitor |
| WO2021025899A1 (en) | 2019-08-02 | 2021-02-11 | Sarepta Therapeutics, Inc. | Phosphorodiamidate morpholino oligomer pharmaceutical compositions |
| EP4059943A4 (en) | 2019-11-13 | 2024-01-31 | Nippon Shinyaku Co., Ltd. | METHOD FOR PRODUCING OLIGONUCLEIC ACID COMPOUND |
| EP4059944A4 (en) | 2019-11-13 | 2024-04-10 | Nippon Shinyaku Co., Ltd. | METHOD FOR PREPARING AN OLIGONUCLICE ACID COMPOUND |
| EP4079329A4 (en) | 2019-12-19 | 2024-04-17 | Nippon Shinyaku Co., Ltd. | ANTISENSE NUCLEIC ACID ENABLING EXON SKIPPING |
| IL294271A (en) | 2019-12-26 | 2022-08-01 | Nippon Shinyaku Co Ltd | Antisense nucleic acid that induces skipping of exon 50 |
| PE20230237A1 (es) | 2020-02-28 | 2023-02-07 | Nippon Shinyaku Co Ltd | Acidos nucleicos antisentido que inducen la omision del exon 51 |
| EP4182315A4 (en) * | 2020-07-10 | 2024-07-03 | Changzhou Syntheall Pharmaceuticals Co., Ltd. | Processes for preparing oligonucleotides |
| EP4276104A3 (en) * | 2021-03-19 | 2024-05-22 | Bachem Holding AG | Improved oligonucleotide synthesis suppressing depurination |
| CN117279926A (zh) | 2021-04-28 | 2023-12-22 | 日本新药株式会社 | 低聚核酸化合物的制造方法 |
| WO2022239863A1 (ja) | 2021-05-13 | 2022-11-17 | 国立大学法人千葉大学 | アンチセンスオリゴマー |
| AU2022279820A1 (en) | 2021-05-28 | 2023-12-14 | Sumitomo Pharma Co., Ltd. | Antisense nucleic acid |
| JPWO2022270585A1 (enExample) | 2021-06-23 | 2022-12-29 | ||
| TW202308664A (zh) | 2021-07-08 | 2023-03-01 | 日商日本新藥股份有限公司 | 腎毒性減輕劑 |
| US20240316093A1 (en) | 2021-07-08 | 2024-09-26 | Nippon Shinyaku Co., Ltd. | Nephrotoxicity reducing agent |
| TW202317147A (zh) | 2021-07-08 | 2023-05-01 | 日商日本新藥股份有限公司 | 析出抑制劑 |
| WO2023026994A1 (ja) | 2021-08-21 | 2023-03-02 | 武田薬品工業株式会社 | ヒトトランスフェリンレセプター結合ペプチド－薬物コンジュゲート |
| WO2023034515A2 (en) | 2021-09-03 | 2023-03-09 | Sarepta Therapeutics, Inc. | Delivery of anitsense oligomers by mirror image peptides |
| US20240425864A1 (en) | 2021-09-30 | 2024-12-26 | Sarepta Therapeutics, Inc. | Antisense oligonucleotides having one or more abasic units |
| WO2023070086A1 (en) | 2021-10-22 | 2023-04-27 | Sarepta Therapeutics, Inc. | Morpholino oligomers for treatment of peripheral myelin protein 22 related diseases |
| KR20240129006A (ko) | 2021-12-27 | 2024-08-27 | 니뽄 신야쿠 가부시키가이샤 | 올리고 핵산 화합물의 제조 방법 |
| KR20240155905A (ko) * | 2022-03-01 | 2024-10-29 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 비스-보호된 활성화된 구아닌 단량체 |
| EP4590311A2 (en) | 2022-09-21 | 2025-07-30 | Sarepta Therapeutics, Inc. | Dmd antisense oligonucleotide-mediated exon skipping efficiency |
| EP4702144A1 (en) | 2023-04-27 | 2026-03-04 | Sarepta Therapeutics, Inc. | Antisense oligomers for treatment of chronic kidney disease |
| JP2026526969A (ja) | 2023-08-02 | 2026-08-10 | サレプタ セラピューティクス， インコーポレイテッド | アンチセンスオリゴマー送達のための非標準細胞透過性ペプチド |
| WO2025085810A2 (en) | 2023-10-18 | 2025-04-24 | Sarepta Therapeutics, Inc. | Antisense oligomers for treatment of centronuclear myopathies |
| CN117586307B (zh) * | 2024-01-19 | 2024-04-16 | 凯莱英生命科学技术(天津)有限公司 | Pmo鸟苷单体的合成方法 |
| CN122145519A (zh) * | 2026-05-09 | 2026-06-05 | 中肽生化有限公司 | 磷酰二胺吗啉代寡核苷酸的合成方法 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH577464A5 (enExample) * | 1972-09-22 | 1976-07-15 | Ciba Geigy Ag | |
| US5185444A (en) | 1985-03-15 | 1993-02-09 | Anti-Gene Deveopment Group | Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages |
| ATE312834T1 (de) * | 1989-12-20 | 2005-12-15 | Avi Biopharma Inc | Ungeladene, auf morpholin basierende polymere mit chiralen, phosphor enthaltenden brücken zwischen den untereinheiten |
| WO1991018898A1 (en) * | 1990-06-01 | 1991-12-12 | Nippon Shinyaku Co., Ltd. | Nucleic acid homolog |
| US5510476A (en) | 1994-07-07 | 1996-04-23 | Isis Pharmaceuticals, Inc. | Carbocation scavenging during oligonucleotide synthesis |
| UA48150C2 (uk) * | 1994-11-02 | 2002-08-15 | Ай-Сі-Ен Фармасьютикалз | Похідні амінокислот або аміноспиртів, олігонуклеотид |
| US7790694B2 (en) * | 2005-07-13 | 2010-09-07 | Avi Biopharma Inc. | Antisense antibacterial method and compound |
| LT2735568T (lt) * | 2006-05-10 | 2017-11-27 | Sarepta Therapeutics, Inc. | Oligonukleotido analogai, turintys katijonines jungtis tarp subvienetų |
-
2008
- 2008-11-14 MX MX2010004955A patent/MX2010004955A/es active IP Right Grant
- 2008-11-14 KR KR1020107009620A patent/KR101617472B1/ko active Active
- 2008-11-14 CA CA2704261A patent/CA2704261C/en active Active
- 2008-11-14 JP JP2010534042A patent/JP5512533B2/ja active Active
- 2008-11-14 EP EP08850132.5A patent/EP2207779B1/en active Active
- 2008-11-14 CA CA2884340A patent/CA2884340C/en active Active
- 2008-11-14 DK DK08850132.5T patent/DK2207779T3/da active
- 2008-11-14 CN CN200880116219A patent/CN101861318A/zh active Pending
- 2008-11-14 ES ES08850132.5T patent/ES2479393T3/es active Active
- 2008-11-14 WO PCT/US2008/012804 patent/WO2009064471A1/en not_active Ceased
- 2008-11-14 HR HRP20140646AT patent/HRP20140646T1/hr unknown
- 2008-11-14 RU RU2010123958A patent/RU2606627C2/ru not_active Application Discontinuation
- 2008-11-14 BR BR122019021332A patent/BR122019021332A8/pt not_active Application Discontinuation
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2010
- 2010-05-13 IL IL205776A patent/IL205776A0/en unknown
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2014
- 2014-03-26 JP JP2014063314A patent/JP6178744B2/ja active Active
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2016
- 2016-06-30 JP JP2016129716A patent/JP2016196494A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| BRPI0819828A8 (pt) | 2022-12-27 |
| CN101861318A (zh) | 2010-10-13 |
| RU2010123958A (ru) | 2011-12-20 |
| JP2016196494A (ja) | 2016-11-24 |
| JP2011503184A (ja) | 2011-01-27 |
| WO2009064471A1 (en) | 2009-05-22 |
| CA2704261C (en) | 2015-05-26 |
| BRPI0819828A2 (pt) | 2015-05-26 |
| MX2010004955A (es) | 2010-06-30 |
| BR122019021332A2 (enExample) | 2015-05-26 |
| HK1144424A1 (en) | 2011-02-18 |
| KR101617472B1 (ko) | 2016-05-02 |
| EP2207779A1 (en) | 2010-07-21 |
| KR20100090681A (ko) | 2010-08-16 |
| CA2704261A1 (en) | 2009-05-22 |
| AU2008321409B2 (en) | 2014-08-14 |
| RU2606627C2 (ru) | 2017-01-10 |
| CA2884340C (en) | 2017-07-25 |
| BR122019021332A8 (pt) | 2022-12-06 |
| CA2884340A1 (en) | 2009-05-22 |
| DK2207779T3 (da) | 2014-07-14 |
| AU2008321409A1 (en) | 2009-05-22 |
| IL205776A0 (en) | 2010-11-30 |
| HRP20140646T1 (hr) | 2014-09-26 |
| EP2207779B1 (en) | 2014-04-09 |
| JP5512533B2 (ja) | 2014-06-04 |
| JP2014159432A (ja) | 2014-09-04 |
| JP6178744B2 (ja) | 2017-08-09 |
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