KR101617472B1 - 모르폴리노 올리고머의 합성 방법 - Google Patents
모르폴리노 올리고머의 합성 방법 Download PDFInfo
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- KR101617472B1 KR101617472B1 KR1020107009620A KR20107009620A KR101617472B1 KR 101617472 B1 KR101617472 B1 KR 101617472B1 KR 1020107009620 A KR1020107009620 A KR 1020107009620A KR 20107009620 A KR20107009620 A KR 20107009620A KR 101617472 B1 KR101617472 B1 KR 101617472B1
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- South Korea
- Prior art keywords
- morpholino
- group
- protected
- ring nitrogen
- compound
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- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 title claims abstract description 102
- 238000000034 method Methods 0.000 title claims abstract description 48
- 230000015572 biosynthetic process Effects 0.000 title abstract description 48
- 238000003786 synthesis reaction Methods 0.000 title abstract description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 112
- -1 morpholino compound Chemical class 0.000 claims abstract description 77
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 57
- 239000000178 monomer Substances 0.000 claims abstract description 43
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 35
- UYTPUPDQBNUYGX-UHFFFAOYSA-N Guanine Natural products O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 13
- 230000008569 process Effects 0.000 claims abstract description 13
- 125000005039 triarylmethyl group Chemical group 0.000 claims abstract description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 9
- MCKANBCWFDYIJO-UHFFFAOYSA-N chloro-dihydroxy-imino-$l^{5}-phosphane Chemical group NP(O)(Cl)=O MCKANBCWFDYIJO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 8
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 7
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 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 189
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 25
- 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 22
- 239000003153 chemical reaction reagent Substances 0.000 claims description 21
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 20
- ANCLJVISBRWUTR-UHFFFAOYSA-N diaminophosphinic acid Chemical compound NP(N)(O)=O ANCLJVISBRWUTR-UHFFFAOYSA-N 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- UALLSUGEWWKKKQ-UHFFFAOYSA-N chlorooxyphosphonamidic acid Chemical group NP(=O)(O)OCl UALLSUGEWWKKKQ-UHFFFAOYSA-N 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical group CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 claims description 7
- 150000003222 pyridines Chemical class 0.000 claims description 7
- 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 6
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 6
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical group NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- LMWFKCYJTRUATP-UHFFFAOYSA-N pyridin-1-ium-4-carbonitrile;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.N#CC1=CC=[NH+]C=C1 LMWFKCYJTRUATP-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
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 150000003217 pyrazoles Chemical class 0.000 claims description 3
- 150000003557 thiazoles Chemical class 0.000 claims description 3
- 150000003852 triazoles Chemical class 0.000 claims description 3
- 229930194542 Keto Natural products 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 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
- 150000004892 pyridazines Chemical class 0.000 claims description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 2
- UYDKOSYWGWXDRQ-UHFFFAOYSA-N 3-morpholin-4-ylpyrrolidine-2,5-dione Chemical compound O=C1NC(=O)CC1N1CCOCC1 UYDKOSYWGWXDRQ-UHFFFAOYSA-N 0.000 claims 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 150000004857 phospholes Chemical class 0.000 claims 1
- 150000003017 phosphorus Chemical class 0.000 claims 1
- 238000001308 synthesis method Methods 0.000 claims 1
- 238000005859 coupling reaction Methods 0.000 abstract description 13
- 230000008878 coupling Effects 0.000 abstract description 11
- 238000010168 coupling process Methods 0.000 abstract description 11
- 150000008299 phosphorodiamidates Chemical group 0.000 abstract description 9
- 239000000243 solution Substances 0.000 description 86
- 239000011347 resin Substances 0.000 description 55
- 229920005989 resin Polymers 0.000 description 55
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 29
- 239000000203 mixture Substances 0.000 description 28
- 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
- 238000002360 preparation method Methods 0.000 description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 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
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 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
- 239000012044 organic layer Substances 0.000 description 16
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000002585 base Substances 0.000 description 15
- 239000010410 layer Substances 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 13
- 238000011068 loading method Methods 0.000 description 13
- NWXYXESOGVYUNX-UHFFFAOYSA-N butanedioic acid;1-tritylpiperazine Chemical compound OC(=O)CCC(O)=O.C1CNCCN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 NWXYXESOGVYUNX-UHFFFAOYSA-N 0.000 description 11
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 11
- 238000001914 filtration 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
- QRDAPCMJAOQZSU-KQQUZDAGSA-N (e)-3-[4-[(e)-3-(3-fluorophenyl)-3-oxoprop-1-enyl]-1-methylpyrrol-2-yl]-n-hydroxyprop-2-enamide Chemical compound C1=C(\C=C\C(=O)NO)N(C)C=C1\C=C\C(=O)C1=CC=CC(F)=C1 QRDAPCMJAOQZSU-KQQUZDAGSA-N 0.000 description 9
- 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
- 238000000746 purification Methods 0.000 description 9
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-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
- 239000006227 byproduct 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
- MHCMWGPPLOSCJY-UHFFFAOYSA-N 4-$l^{1}-azanylmorpholine Chemical compound [N]N1CCOCC1 MHCMWGPPLOSCJY-UHFFFAOYSA-N 0.000 description 7
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 7
- 230000007062 hydrolysis Effects 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- PFKFTWBEEFSNDU-UHFFFAOYSA-N 1,1'-Carbonyldiimidazole Substances C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 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
- 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
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000002002 slurry Substances 0.000 description 6
- 239000007790 solid phase Substances 0.000 description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 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
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 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
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 125000006575 electron-withdrawing group Chemical group 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000008363 phosphate buffer Substances 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
- 125000001424 substituent group Chemical group 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- 150000003573 thiols Chemical class 0.000 description 5
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 229940059260 amidate Drugs 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000007979 citrate buffer Substances 0.000 description 4
- 239000013058 crude material Substances 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 238000007086 side reaction Methods 0.000 description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 3
- 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 3
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 3
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 238000003109 Karl Fischer titration Methods 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- 239000004793 Polystyrene Substances 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 238000005571 anion exchange chromatography Methods 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 238000005277 cation exchange chromatography Methods 0.000 description 3
- 125000002091 cationic group Chemical group 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000011097 chromatography purification Methods 0.000 description 3
- 229960004106 citric acid Drugs 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 238000012217 deletion Methods 0.000 description 3
- 230000037430 deletion Effects 0.000 description 3
- 238000000605 extraction Methods 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
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 229920002223 polystyrene Polymers 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- GPHQHTOMRSGBNZ-UHFFFAOYSA-N pyridine-4-carbonitrile Chemical class N#CC1=CC=NC=C1 GPHQHTOMRSGBNZ-UHFFFAOYSA-N 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
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- C07—ORGANIC CHEMISTRY
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- 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
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
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- 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)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Saccharide Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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| AU2006213686A1 (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 |
| WO2011060320A1 (en) | 2009-11-13 | 2011-05-19 | Avi Biopharma, Inc. | Antisense antiviral compound and method for treating influenza viral infection |
| EP2576574A2 (en) | 2010-05-28 | 2013-04-10 | Sarepta Therapeutics, Inc. | Oligonucleotide analogues having modified intersubunit linkages and/or terminal groups |
| 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 |
| HUE030292T2 (en) | 2010-09-30 | 2017-04-28 | Nippon Shinyaku Co Ltd | Morpholino-nucleic acid derivatives |
| US20120122769A1 (en) | 2010-11-12 | 2012-05-17 | Avi Biopharma, Inc. | Antisense antibacterial compounds and methods |
| KR102183273B1 (ko) | 2011-05-05 | 2020-11-27 | 사렙타 쎄러퓨틱스, 인코퍼레이티드 | 펩타이드 올리고뉴클레오타이드 접합체 |
| US10100305B2 (en) | 2011-07-15 | 2018-10-16 | Sarepta Therapeutics, Inc. | Methods and compositions for manipulating translation of protein isoforms from alternative initiation of start sites |
| US20130085139A1 (en) | 2011-10-04 | 2013-04-04 | Royal Holloway And Bedford New College | Oligomers |
| CN108864192A (zh) * | 2011-11-18 | 2018-11-23 | 萨勒普塔医疗公司 | 功能改性的寡核苷酸及其亚单元 |
| US10066228B2 (en) | 2011-11-30 | 2018-09-04 | 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 |
| WO2013086441A2 (en) | 2011-12-08 | 2013-06-13 | Sarepta Therapeutics, Inc. | Oligonucleotide analogues targeting human lmna |
| CN107881175B (zh) * | 2011-12-28 | 2022-05-13 | 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 |
| US9856474B2 (en) | 2013-01-16 | 2018-01-02 | Iowa State University Research Foundation, Inc. | Deep intronic target for splicing correction on spinal muscular atrophy gene |
| CN105228999B (zh) | 2013-05-24 | 2021-03-02 | 味之素株式会社 | 吗啉代寡核苷酸的制备方法 |
| CN105793422B (zh) | 2013-09-05 | 2020-03-03 | 萨罗塔治疗公司(美国) | 酸性α-葡糖苷酶中反义诱导的外显子2纳入 |
| CA2925500C (en) | 2013-09-30 | 2023-03-14 | Geron Corporation | Phosphorodiamidate backbone linkage for oligonucleotides |
| TR201901939T4 (tr) | 2014-03-12 | 2019-03-21 | Nat Center Neurology & Psychiatry | Antisens nükleik asit. |
| JP6901966B2 (ja) | 2014-05-16 | 2021-07-14 | オレゴン ステート ユニバーシティ | アンチセンス抗菌化合物および方法 |
| JP6687542B2 (ja) | 2014-05-19 | 2020-04-22 | オレゴン ステート ユニバーシティ | アンチセンス抗菌化合物および方法 |
| EP3159409B1 (en) | 2014-06-17 | 2019-12-04 | Nippon Shinyaku Co., Ltd. | Antisense nucleic acid for use in the treatment of duchenne's muscular dystrophy |
| CN106795186B (zh) | 2014-10-14 | 2021-03-02 | 味之素株式会社 | 吗啉代寡核苷酸的制备方法 |
| AU2015372560B2 (en) | 2014-12-31 | 2021-12-02 | Board Of Regents, The University Of Texas System | 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 |
| NZ737757A (en) | 2015-05-19 | 2023-07-28 | Sarepta Therapeutics Inc | Peptide oligonucleotide conjugates |
| WO2016196670A1 (en) | 2015-06-01 | 2016-12-08 | 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 |
| PE20231843A1 (es) * | 2015-08-05 | 2023-11-21 | Eisai Randd Man Co Ltd | Reactivos quirales para la preparacion de oligomeros homogeneos |
| WO2017035278A1 (en) | 2015-08-24 | 2017-03-02 | Halo-Bio Rnai Therapeutics, Inc. | Polynucleotide nanoparticles for the modulation of gene expression and uses thereof |
| SMT202000379T1 (it) | 2015-09-15 | 2020-09-10 | Nippon Shinyaku Co Ltd | Acido nucleico antisenso |
| EP3351634A4 (en) | 2015-09-16 | 2019-05-08 | Nippon Shinyaku Co., Ltd. | ANTISENSE NUCLEIC ACID FOR THE TREATMENT OF AMYOTROPHY |
| MA45819A (fr) | 2015-10-09 | 2018-08-15 | Sarepta Therapeutics Inc | Compositions et méthodes pour traiter la dystrophie musculaire de duchenne et troubles associés |
| US20190030176A1 (en) | 2015-12-15 | 2019-01-31 | Sarepta Therapeutics, Inc. | Peptide oligonucleotide conjugates |
| US11142764B2 (en) | 2015-12-23 | 2021-10-12 | Board Of Regents, The University Of Texas System | Antisense antibacterial compounds and methods |
| WO2017112885A1 (en) | 2015-12-23 | 2017-06-29 | David Greenberg | Antisense antibacterial compounds and methods |
| EP3445405A4 (en) | 2016-04-18 | 2019-12-18 | Sarepta Therapeutics, Inc. | ANTISENSE OLIGOMERS AND METHOD FOR USE THEREOF TO TREAT DISEASES RELATING TO THE ACID ALPHA GLUCOSIDASE GENE |
| CN109477109B (zh) | 2016-04-29 | 2022-09-23 | 萨勒普塔医疗公司 | 靶向人lmna的寡核苷酸类似物 |
| EP3464305B1 (en) * | 2016-05-24 | 2024-08-21 | Sarepta Therapeutics, Inc. | Processes for preparing oligomers |
| BR112018074299A2 (pt) | 2016-05-24 | 2019-03-12 | Sarepta Therapeutics, Inc. | composições farmacêuticas compreendendo eteplirsen |
| HRP20240583T1 (hr) | 2016-05-24 | 2024-07-19 | Sarepta Therapeutics, Inc. | Postupci za pripremu fosforodiamidat morfolino oligomera |
| IL263044B2 (en) | 2016-05-24 | 2024-06-01 | Sarepta Therapeutics Inc | Processes for preparing phosphorodiamidate morpholino oligomers |
| MA45362A (fr) | 2016-05-24 | 2019-04-10 | Sarepta Therapeutics Inc | Procédés de préparation d'oligomères morpholino de phosphorodiamidate |
| US11472824B2 (en) | 2016-05-24 | 2022-10-18 | Sarepta Therapeutics, Inc. | Processes for preparing phosphorodiamidate morpholino oligomers |
| AU2017270598B2 (en) * | 2016-05-24 | 2022-12-01 | Sarepta Therapeutics, Inc. | Processes for preparing phosphorodiamidate morpholino oligomers |
| EP3515445A4 (en) * | 2016-09-20 | 2020-05-27 | The Regents of The University of Colorado, A Body Corporate | SYNTHESIS OF BACKBONE-MODIFIED MORPHOLINO-OLIGONUCLEOTIDES AND CHIMERES WITH THE AID OF PHOSPHORAMIDITE CHEMISTRY |
| MD3554553T2 (ro) | 2016-12-19 | 2022-10-31 | Sarepta Therapeutics Inc | Conjugați de oligomeri de omitere a exonului, pentru distrofie musculară |
| WO2018118627A1 (en) | 2016-12-19 | 2018-06-28 | Sarepta Therapeutics, Inc. | Exon skipping oligomer conjugates for muscular dystrophy |
| KR20240006057A (ko) | 2016-12-19 | 2024-01-12 | 사렙타 쎄러퓨틱스 인코퍼레이티드 | 근육 이상증에 대한 엑손 스킵핑 올리고머 결합체 |
| EP3612215B1 (en) | 2017-04-20 | 2024-08-28 | 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 |
| US20200362339A1 (en) * | 2017-09-25 | 2020-11-19 | Sarepta Therapeutics, Inc. | Processes for preparing phosphorodiamidate morpholino oligomers via fast-flow synthesis |
| 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 |
| EP3806868A4 (en) | 2018-06-13 | 2022-06-22 | Sarepta Therapeutics, Inc. | EXON SKIPPING OLIGOMERS FOR MUSCULAR DYSTROPHY |
| MX2020013880A (es) | 2018-06-26 | 2021-03-09 | Nippon Shinyaku Co Ltd | Composición que comprende el oligonucleótido antisentido y su uso para el tratamiento de la distrofia muscular de duchenne. |
| 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 |
| IL318474A (en) | 2018-12-13 | 2025-03-01 | Sarepta Therapeutics Inc | Axon-skipping oligomer complexes for muscular dystrophy |
| 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 |
| CN114981280A (zh) | 2019-11-13 | 2022-08-30 | 日本新药株式会社 | 寡核苷酸化合物的制造方法 |
| US20230018780A1 (en) | 2019-11-13 | 2023-01-19 | Nippon Shinyaku Co., Ltd. | Method for producing oligonucleic acid compound |
| EP4079329A4 (en) | 2019-12-19 | 2024-04-17 | Nippon Shinyaku Co., Ltd. | Antisense nucleic acid enabling exon skipping |
| CN118109468A (zh) | 2019-12-26 | 2024-05-31 | 日本新药株式会社 | 诱导外显子50的跳读的反义核酸 |
| KR20220145865A (ko) | 2020-02-28 | 2022-10-31 | 니뽄 신야쿠 가부시키가이샤 | 엑손 51의 스키핑을 유도하는 안티센스 핵산 |
| JP7703579B2 (ja) * | 2020-07-10 | 2025-07-07 | チャンヂョウ シンザオール ファーマシューティカルズ カンパニー リミテッド | オリゴヌクレオチドを調製するための方法 |
| CA3218264A1 (en) | 2021-04-28 | 2022-11-03 | Nippon Shinyaku Co., Ltd. | Method for producing oligonucleic acid compound |
| EP4342498A4 (en) | 2021-05-13 | 2025-01-08 | National University Corporation Chiba University | ANTISENSE OLIGOMER |
| CA3221758A1 (en) | 2021-05-28 | 2022-12-01 | Sumitomo Pharma Co., Ltd. | Antisense nucleic acid |
| AU2022298028A1 (en) | 2021-06-23 | 2023-12-21 | National Center Of Neurology And Psychiatry | Combination of antisense oligomers |
| IL310001A (en) | 2021-07-08 | 2024-03-01 | Nippon Shinyaku Co Ltd | Precipitation suppressing agent |
| EP4368186A4 (en) | 2021-07-08 | 2025-06-25 | Nippon Shinyaku Co., Ltd. | NEPHROTOXICITY REDUCING AGENT |
| JPWO2023282344A1 (enExample) | 2021-07-08 | 2023-01-12 | ||
| JPWO2023026994A1 (enExample) | 2021-08-21 | 2023-03-02 | ||
| US20250011777A1 (en) | 2021-09-03 | 2025-01-09 | Sarepta Therapeutics, Inc. | Delivery of anitsense oligomers by mirror image peptides |
| KR20240070615A (ko) | 2021-09-30 | 2024-05-21 | 사렙타 쎄러퓨틱스 인코퍼레이티드 | 하나 이상의 비염기성 유닛을 갖는 안티센스 올리고뉴클레오티드 |
| JP2024539223A (ja) | 2021-10-22 | 2024-10-28 | サレプタ セラピューティクス， インコーポレイテッド | 末梢ミエリンタンパク質２２関連疾患の処置のためのモルフォリノオリゴマー |
| JPWO2023127918A1 (enExample) | 2021-12-27 | 2023-07-06 | ||
| IL315344A (en) * | 2022-03-01 | 2024-10-01 | Eisai R&D Man Co Ltd | Bis-protected, activated guanine monomers |
| WO2024064237A2 (en) | 2022-09-21 | 2024-03-28 | Sarepta Therapeutics, Inc. | Dmd antisense oligonucleotide-mediated exon skipping efficiency |
| US20250066776A1 (en) | 2023-04-27 | 2025-02-27 | Sarepta Therapeutics, Inc. | Antisense oligomers for treatment of chronic kidney disease |
| US20250171776A1 (en) | 2023-08-02 | 2025-05-29 | Sarepta Therapeutics, Inc. | Non-canonical cell-penetrating peptides for antisense oligomer delivery |
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5185444A (en) | 1985-03-15 | 1993-02-09 | Anti-Gene Deveopment Group | Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages |
| US20070135333A1 (en) | 2005-07-13 | 2007-06-14 | Geller Bruce L | Antisense antibacterial method and compound |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH577464A5 (enExample) * | 1972-09-22 | 1976-07-15 | Ciba Geigy Ag | |
| 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 |
| ES2645410T3 (es) * | 2006-05-10 | 2017-12-05 | Sarepta Therapeutics, Inc. | Análogos de oligonucleótidos que tienen enlaces intersubunitarios catiónicos |
-
2008
- 2008-11-14 WO PCT/US2008/012804 patent/WO2009064471A1/en not_active Ceased
- 2008-11-14 MX MX2010004955A patent/MX2010004955A/es active IP Right Grant
- 2008-11-14 JP JP2010534042A patent/JP5512533B2/ja active Active
- 2008-11-14 KR KR1020107009620A patent/KR101617472B1/ko active Active
- 2008-11-14 CA CA2704261A patent/CA2704261C/en active Active
- 2008-11-14 HR HRP20140646AT patent/HRP20140646T1/hr unknown
- 2008-11-14 DK DK08850132.5T patent/DK2207779T3/da active
- 2008-11-14 CN CN200880116219A patent/CN101861318A/zh active Pending
- 2008-11-14 CA CA2884340A patent/CA2884340C/en active Active
- 2008-11-14 EP EP08850132.5A patent/EP2207779B1/en active Active
- 2008-11-14 BR BR122019021332A patent/BR122019021332A8/pt not_active Application Discontinuation
- 2008-11-14 RU RU2010123958A patent/RU2606627C2/ru not_active Application Discontinuation
- 2008-11-14 ES ES08850132.5T patent/ES2479393T3/es active Active
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2010
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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
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5185444A (en) | 1985-03-15 | 1993-02-09 | Anti-Gene Deveopment Group | Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages |
| US20070135333A1 (en) | 2005-07-13 | 2007-06-14 | Geller Bruce L | Antisense antibacterial method and compound |
Non-Patent Citations (1)
| Title |
|---|
| ANTISENSE & NUCLEIC ACID DRUG DEVELOPMENT, 1997, 7권, 페이지 187-195 |
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| AU2008321409B2 (en) | 2014-08-14 |
| ES2479393T3 (es) | 2014-07-24 |
| BR122019021332A8 (pt) | 2022-12-06 |
| JP2011503184A (ja) | 2011-01-27 |
| BRPI0819828A8 (pt) | 2022-12-27 |
| EP2207779A1 (en) | 2010-07-21 |
| CN101861318A (zh) | 2010-10-13 |
| BRPI0819828A2 (pt) | 2015-05-26 |
| DK2207779T3 (da) | 2014-07-14 |
| CA2704261A1 (en) | 2009-05-22 |
| IL205776A0 (en) | 2010-11-30 |
| JP5512533B2 (ja) | 2014-06-04 |
| EP2207779B1 (en) | 2014-04-09 |
| JP6178744B2 (ja) | 2017-08-09 |
| CA2884340A1 (en) | 2009-05-22 |
| MX2010004955A (es) | 2010-06-30 |
| RU2606627C2 (ru) | 2017-01-10 |
| AU2008321409A1 (en) | 2009-05-22 |
| HK1144424A1 (en) | 2011-02-18 |
| JP2014159432A (ja) | 2014-09-04 |
| WO2009064471A1 (en) | 2009-05-22 |
| HRP20140646T1 (hr) | 2014-09-26 |
| CA2884340C (en) | 2017-07-25 |
| JP2016196494A (ja) | 2016-11-24 |
| CA2704261C (en) | 2015-05-26 |
| BR122019021332A2 (enExample) | 2015-05-26 |
| RU2010123958A (ru) | 2011-12-20 |
| KR20100090681A (ko) | 2010-08-16 |
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