KR101707437B1 - 구아니딘 가교를 갖는 인공 뉴클레오시드 및 올리고뉴클레오티드 - Google Patents
구아니딘 가교를 갖는 인공 뉴클레오시드 및 올리고뉴클레오티드 Download PDFInfo
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- KR101707437B1 KR101707437B1 KR1020157010144A KR20157010144A KR101707437B1 KR 101707437 B1 KR101707437 B1 KR 101707437B1 KR 1020157010144 A KR1020157010144 A KR 1020157010144A KR 20157010144 A KR20157010144 A KR 20157010144A KR 101707437 B1 KR101707437 B1 KR 101707437B1
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- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 title description 89
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 title description 46
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 title description 46
- 239000002777 nucleoside Substances 0.000 title description 33
- 150000003833 nucleoside derivatives Chemical class 0.000 title description 26
- 108091034117 Oligonucleotide Proteins 0.000 claims abstract description 196
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 88
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- 125000003835 nucleoside group Chemical group 0.000 claims abstract description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 155
- -1 2-oxo-1,2-dihydropyrimidin-1-yl group Chemical group 0.000 claims description 131
- 125000006239 protecting group Chemical group 0.000 claims description 61
- 125000000217 alkyl group Chemical group 0.000 claims description 49
- 125000003277 amino group Chemical group 0.000 claims description 39
- 125000003118 aryl group Chemical group 0.000 claims description 39
- 125000003545 alkoxy group Chemical group 0.000 claims description 37
- 238000001668 nucleic acid synthesis Methods 0.000 claims description 36
- 125000001424 substituent group Chemical group 0.000 claims description 30
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 29
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 25
- 125000002252 acyl group Chemical group 0.000 claims description 19
- 125000005843 halogen group Chemical group 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 125000004414 alkyl thio group Chemical group 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 14
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 13
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 10
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
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- 101710163270 Nuclease Proteins 0.000 abstract description 21
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 23
- 239000002904 solvent Substances 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 230000015572 biosynthetic process Effects 0.000 description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 20
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 19
- 238000000034 method Methods 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- 239000002585 base Substances 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- 238000003786 synthesis reaction Methods 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 230000000704 physical effect Effects 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 239000012141 concentrate Substances 0.000 description 12
- 239000012071 phase Substances 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 11
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- 230000001965 increasing effect Effects 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000003550 marker Substances 0.000 description 9
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- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 8
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- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 7
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 7
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- 108010068698 spleen exonuclease Proteins 0.000 description 7
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- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 6
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- C07H21/02—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical
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| US11261440B2 (en) | 2017-02-21 | 2022-03-01 | Osaka University | Antisense oligonucleic acid |
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| WO2020050307A1 (ja) | 2018-09-05 | 2020-03-12 | 国立大学法人大阪大学 | Ａｒｌ４ｃを標的分子とするアンチセンスオリゴヌクレオチド、及び当該アンチセンスオリゴヌクレオチドを使用した核酸医薬 |
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| EP2899197B1 (en) | 2017-03-22 |
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| JP6048982B2 (ja) | 2016-12-21 |
| CA2885719A1 (en) | 2014-03-27 |
| CN104768964B (zh) | 2017-03-29 |
| CN104768964A (zh) | 2015-07-08 |
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| US10377789B2 (en) | 2019-08-13 |
| ES2622716T3 (es) | 2017-07-07 |
| EP2899197A4 (en) | 2016-03-09 |
| KR20150056647A (ko) | 2015-05-26 |
| IN2015DN02238A (enExample) | 2015-08-21 |
| CA2885719C (en) | 2017-07-11 |
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