CN1170412A - 糖修饰的核苷和它们用于合成低聚核苷酸的应用 - Google Patents
糖修饰的核苷和它们用于合成低聚核苷酸的应用 Download PDFInfo
- Publication number
- CN1170412A CN1170412A CN95196962A CN95196962A CN1170412A CN 1170412 A CN1170412 A CN 1170412A CN 95196962 A CN95196962 A CN 95196962A CN 95196962 A CN95196962 A CN 95196962A CN 1170412 A CN1170412 A CN 1170412A
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- China
- Prior art keywords
- alkyl
- compound
- aralkyl
- aryl
- thymidine
- Prior art date
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- Granted
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- 108091034117 Oligonucleotide Proteins 0.000 title claims abstract description 96
- 125000003835 nucleoside group Chemical group 0.000 title abstract description 86
- 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 title abstract description 4
- 230000015572 biosynthetic process Effects 0.000 title description 3
- 238000003786 synthesis reaction Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 94
- -1 aralkoxy Chemical group 0.000 claims description 89
- 125000000217 alkyl group Chemical group 0.000 claims description 79
- 125000003118 aryl group Chemical group 0.000 claims description 56
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 52
- 108091033319 polynucleotide Proteins 0.000 claims description 28
- 102000040430 polynucleotide Human genes 0.000 claims description 28
- 239000002157 polynucleotide Substances 0.000 claims description 28
- 239000002773 nucleotide Substances 0.000 claims description 23
- 125000003729 nucleotide group Chemical group 0.000 claims description 21
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 229910052801 chlorine Inorganic materials 0.000 claims description 15
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 15
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 125000004104 aryloxy group Chemical group 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 229910052740 iodine Inorganic materials 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 238000004690 coupled electron pair approximation Methods 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- UDPGUMQDCGORJQ-UHFFFAOYSA-N (2-chloroethyl)phosphonic acid Chemical compound OP(O)(=O)CCCl UDPGUMQDCGORJQ-UHFFFAOYSA-N 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims 8
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 8
- 150000001408 amides Chemical class 0.000 claims 4
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims 4
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims 4
- 125000002944 cyanoaryl group Chemical group 0.000 claims 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims 4
- 125000005027 hydroxyaryl group Chemical group 0.000 claims 4
- 125000004999 nitroaryl group Chemical group 0.000 claims 4
- 125000002769 thiazolinyl group Chemical group 0.000 claims 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 2
- 125000003700 epoxy group Chemical group 0.000 claims 2
- 239000002777 nucleoside Substances 0.000 abstract description 62
- 150000007523 nucleic acids Chemical class 0.000 abstract description 11
- 102000039446 nucleic acids Human genes 0.000 abstract description 10
- 108020004707 nucleic acids Proteins 0.000 abstract description 10
- 235000000346 sugar Nutrition 0.000 abstract description 10
- 125000001424 substituent group Chemical group 0.000 abstract description 9
- 230000000692 anti-sense effect Effects 0.000 abstract description 8
- 101710163270 Nuclease Proteins 0.000 abstract description 7
- 230000004700 cellular uptake Effects 0.000 abstract description 3
- 150000008300 phosphoramidites Chemical class 0.000 abstract description 3
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical group OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 abstract description 2
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Chemical group OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 abstract description 2
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Chemical group OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 abstract description 2
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical group OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 abstract 1
- 238000000338 in vitro Methods 0.000 abstract 1
- 238000001727 in vivo Methods 0.000 abstract 1
- 150000003833 nucleoside derivatives Chemical class 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 297
- 229940104230 thymidine Drugs 0.000 description 177
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 176
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 176
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 94
- 238000002360 preparation method Methods 0.000 description 78
- 239000000243 solution Substances 0.000 description 71
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 56
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- 238000006243 chemical reaction Methods 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
- 238000010898 silica gel chromatography Methods 0.000 description 36
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 34
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 34
- 238000000034 method Methods 0.000 description 33
- 239000000203 mixture Substances 0.000 description 31
- 238000003756 stirring Methods 0.000 description 29
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 28
- 238000005406 washing Methods 0.000 description 28
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 25
- 229910052938 sodium sulfate Inorganic materials 0.000 description 25
- 235000011152 sodium sulphate Nutrition 0.000 description 25
- 239000002585 base Substances 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 24
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 20
- 239000003513 alkali Substances 0.000 description 20
- 235000019439 ethyl acetate Nutrition 0.000 description 20
- 238000001704 evaporation Methods 0.000 description 17
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 17
- 235000017557 sodium bicarbonate Nutrition 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
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- JCVDICFLPGDHAT-DJLDLDEBSA-N 1-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3,5-dimethylpyrimidine-2,4-dione Chemical compound O=C1N(C)C(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 JCVDICFLPGDHAT-DJLDLDEBSA-N 0.000 description 15
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 14
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- 239000000460 chlorine Substances 0.000 description 14
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 14
- 239000012141 concentrate Substances 0.000 description 13
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 13
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 11
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- 150000003839 salts Chemical class 0.000 description 8
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
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- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 7
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- PGKUAPBTNAPDFG-UHFFFAOYSA-N dimethoxy(trityl)-$l^{3}-chlorane Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl(OC)OC)C1=CC=CC=C1 PGKUAPBTNAPDFG-UHFFFAOYSA-N 0.000 description 7
- DQAZPZIYEOGZAF-UHFFFAOYSA-N 4-ethyl-n-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]piperazine-1-carboxamide Chemical compound C1CN(CC)CCN1C(=O)NC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(C#C)=C1 DQAZPZIYEOGZAF-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
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- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 6
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- DAZLLISJDYLHQH-WUNLWTINSA-N 1-[(2r,4s,5r)-5-[[bis(4-methoxyphenyl)-phenylmethoxy]methyl]-4-hydroxy-4-methyloxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound C1=CC(OC)=CC=C1C(C=1C=CC(OC)=CC=1)(C=1C=CC=CC=1)OC[C@@H]1[C@](O)(C)C[C@H](N2C(NC(=O)C(C)=C2)=O)O1 DAZLLISJDYLHQH-WUNLWTINSA-N 0.000 description 4
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
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Abstract
本发明公开了许多含有修饰的糖部分组成的被修饰的核苷,所述糖部分在脱氧核糖或核糖的C1和C4位含有取代基,或在脱氧核糖或核糖的C3和C5上含有支链取代基,各核苷可被转化或合适地保护然后转化为相应的氨基亚磷酸酯,这些氨基亚磷酸酯可用于组配低聚核苷酸,其中至少有一个上述的核苷。这些糖修饰的低聚核苷酸有可能用作反义治疗剂,因为它们预期能提高核酸酶抵抗性和细胞的摄取,同时在体外或体内保持序列特异性和对核酸靶的亲和力。
Description
发明领域
本发明属于含有被修饰的糖的多核苷酸类似物的领域。
发明背景
低聚核苷酸的治疗应用是一个非常重要的领域,并且已被描述在(1)Zamecinik,P.C.和Stephson,M.L.Proc.Natl.Acad.Sci.U.S.A.1978,75,280,285.;(2)Uhlmann,E.和Peyman,A.Chemical Reviews,1990,90,543-584;(3)Goodchild,J.Bioconjugate chemistry,1990,1,165-187;和(4)Crooke,S.T.和Lebleu,B.“Antisense Research and Applications”,CRC Press(1993))。反义多核苷酸与重要的DNA或RNA靶的特异结合可以灭活与DNA或RNA有关的功能如复制、转录或转译,从而提供了一种控制疾病如癌症和病毒传染的机理。因此,在各种情况下反义多核苷酸与靶的结合可用于改变基因表达,例如,干扰与病毒生命周期或癌细胞的生长(Stein,C.A.,Cheng,Y.C.Science,1993,261,1004-1012)。另外,一些低聚核苷酸也可与蛋白质靶紧密结合,从而用作酶抑制剂。Bock等人描述了在体外抑制人凝血酶催化的纤维蛋白凝块形成的低聚核苷酸(Bock,L.C.,Griffin,L.C.,Latham,J.A,,Vermaas,E.H.,Toole,J.J.Nature,1992,355,564-566)。Ecker等人描述了在低于1.0μmol下抑制人单纯疱疹病毒的几种低聚核苷酸。通过使用组合技术容易发现具有酶抑制性质的多核苷酸(Ecker,D.J.,Vickers,T.A.,Hanecak,R.,Driver,V.,Anderson,K.Nucleic Acids Res.1993,21,1853-1856)。
已有报道含有5′-C-甲基支链的核苷的低聚核苷酸表现出增强的核酸酶抵抗性(Saha,A.K.等人,第206次ACS会议的墙报,Chicago,1993)。也已有报道含有2′-O-甲基核苷的低聚核苷酸表现出对核酸酶的稳定性得到改善,对RNA的结合亲和力得到增强(a.Inoue,H.,Hayase,Y.,Imura,A.,Iwai,S.,Miura,K.,Ohtsuka,E.,Nucleic Acids Res。1987,15,6131;b.Shibahara,S.,Mukai,S.,Morisawa,H.,Nakashima,H.,Cobayashi,S.,Yamamoto,N.Nucleic AcidsRes.1989,17,239)。已有报道含有1′-取代的核苷的低聚核苷酸表现出一些核酸酶抵抗性(Ono,A.,Dan,A.,Matsuda,A.BioconjugateChemistry,1993,4,499-508)。
除了具有对互补靶多核苷酸序列的特异结合亲和力外,反义低聚核苷酸可望满足治疗目的的需要,例如,药效,生物利用度、低毒性和低花费。因为具有天然磷酸二酯主链的低聚核苷酸对核酸酶不稳定,并且不容易渗透过细胞膜,研究人员试图对多核苷酸主链进行修饰,以改善核苷酶抵抗性和细胞摄取。用于反义的低聚核苷酸类似物的主要缺点在于被修饰的核苷酸间的键消除了反义低聚核苷酸的核糖核酸酶H的活性,从而降解了与低聚核苷酸类似物结合的RNA链。因此,希望提供具有能提高核苷酶抵抗性和细胞摄取的多核苷酸类似物,而同时保持核糖核酸酶H的活性。
发明概述
本发明提供了各种新的糖修饰的核苷以及相应的糖修饰的低聚核苷酸,当它们用于反义、诊断或其它目的时,所具有的性质优越于天然的RNA和DNA低聚核苷酸。
本发明的化合物包括各种已被修饰的核苷,从而在核苷的糖部分的C1′,C3′,C4′或C5′位置上有取代基。
本发明的另一方面提供了低聚核苷酸,它包括一种或多种本发明的糖修饰的核苷。
本发明的另一方面提供了低聚核苷酸的共轭物,它包括一种或多种本发明的糖修饰的核苷。
附图简述
图1表示本发明的低聚核苷酸的实例,其中的核苷取代基被正电荷基团取代。
图2表示用于合成3′-C-支链的胸苷的反应路线1。
图3表示用于合成3′-C-支链的胸苷的反应路线2。
图4表示用于合成4′-C-支链的胸苷的反应路线3。
图5表示用于合成4′-C-支链的胸苷的反应路线3的另一部分。
图6表示用于合成4′-C-支链的胸苷的反应路线4。
图7表示用于合成5′-C-支链的胸苷的反应路线5。
图8表示用于合成5′-C-支链的胸苷的反应路线6。
图9表示用于合成5′-C-支链的胸苷的反应路线6的另一部分。
图10表示用于合成5′-C-支链的胸苷的反应路线7。
图11表示用于合成5′-C-支链的胸苷的反应路线8。
图12为表示化合物44和其它化合物的立体化学构型图。
图13表示用于合成1′-C-支链的胸苷的反应路线9。
图14表示用于合成1′-C-支链的胸苷的反应路线10。
缩写和定义
DMTr=4,4′-二甲氧基三苯甲基
CEPA=2-氰基乙基-(N,N′-二异丙基)磷酰氨基
TBDMS=叔丁基二甲基甲硅烷基
Ac=乙酰基
TBDMSM=叔丁基二甲基甲硅烷氧基甲基
N3=偶氮基
CF3CO=三氟乙酰基
Tf=三氟甲磺酰基
THP=四氢吡喃基
OTs=甲苯磺酰基
本文所用的术语“核苷”是指含有与5个碳原子的环状糖(呋喃糖)例如核糖,2′-脱氧核糖和2′,3′-二脱氧核糖共价连接的嘌呤或嘧啶碱(或其衍生物)的化合物。广义上使用的术语“核苷”以包括本发明的糖修饰的核苷。
本文所用的术语“多核苷酸”是指含有2个或多个核苷部分的聚合物,其中各个核苷部分与一个(末端)或二个(内部)其它核苷部分通过核苷间的键如磷酸二酯键,肽键,磷酸酯键,硫代磷酸酯键等连接。RNA和DNA为多核苷酸的实例。除非另有说明,本文广义上所用的术语“多核苷酸”包括本发明的糖修饰的多核苷酸。
本文所用的术语“低聚核苷酸”是指相对较小的多核苷酸,例如长度为2至大约50个碱基对的多核苷酸;然而低聚核苷酸也可以是较长的。
本文所用的术语“羟基保护基”可被有机化学的本领域普通技术人员容易理解。羟基保护基和其它保护基的实例可在Greene&Wuts,“Protective Groups in Organic Synthesis”John Wiley&Sons,NY,NY(1991)中找到(其它地方)。
本文所用的术语“碱和核苷碱”是指在天然存在的核酸如腺嘌呤,胞嘧啶,次黄嘌呤,尿嘧啶,胸腺嘧啶,鸟嘌呤及其类似物中存在的杂环核苷酸碱,包括能够与天然存在的核苷酸碱形成碱对关系的非天然存在的碱。这些非天然存在的杂环碱包括(但不局限于)氮杂和去氮杂嘧啶类似物,氮杂和去氮杂嘌呤类似物以及其它杂环碱类似物,其中嘌呤和嘧啶环的一个或多个碳和氮原子已经被杂原子例如氧、硫、硒、磷等取代。具体实施方案的描述
本发明提供了用于反义、诊断和使用低聚核苷酸的其它方法中具有所需性质的新的核苷和低聚核苷酸。本发明的化合物包括已经被修饰从而在核苷的糖部分的C1′,C3′,C4′或C5′位有取代基的各种核苷。本发明的核苷可含有一个或多个取代基,从而使核苷适合于固相合成或有关的合成技术,例如,本发明的核苷可以为具有5′-二甲氧基三苯甲基或其它保护基的氨基亚磷酸酯(Phosphoramidite)衍生物,本发明还提供了低聚核苷酸,它在核酸链中含有一个或多个本发明的糖修饰的核苷。
在核苷的C3′或C5′位上加入合适的取代基改变了含有所述糖修饰的核苷的低聚核苷酸的磷酸二酯主链周围的环境。优选地,在C3′或C5′位的大取代基用于抑制与酶或其活性部位的不需要的相互作用。这些C3′或C5′取代基预计可使低聚核苷酸的磷酸二酯主链不接近各种酶。由于取代基的存在,与DNA或RNA比较,含有这些C3′或C5′支链核苷的低聚核苷酸具有更大的核酸酶抵抗性。在核苷的C1′和C4′位的取代基具有与核苷的C3′和C5′位的取代基的同样的所需作用。在本发明的实施方案中,本发明的低聚核苷酸包括带正电荷的氨基烷基修饰的糖,在生理条件下本发明的低聚核苷酸上的净负电荷被还原,从而使得至少由这些低聚核苷酸的一条链形成的双螺旋比相应的未修饰的低聚核苷酸(参见图1)更为稳定。因此,在含有氨基烷基修饰的糖或类似的正电荷取代基的本发明实施方案中,在本发明的低聚核苷酸与多核苷酸杂交靶之间的结合亲和力可通过正电荷而改善,本领域普通技术人员应理解到上述理论只是提供了使用指南和其它本发明的实施方案的设计,而不必准确到实施或使用本文提供的发明的程度。
本发明的一个实施方案为具有下式的糖修饰的核苷:其中R1可为烷基,芳烷基,芳基,取代的烷基,取代的芳烷基,取代的烷基,取代的芳基,其中取代基可以是NO2,CN,N3,COOEt,OH,SH,CONH2,CONHR,CONR2,COOH,OAC,NH2,NHAc,NMe2,CF3CONH,OR,SR,SO2CH3,CF3,F,Cl,Br,I,OTs,+NMe3,CH=CHR,C=CR,其中R为烷基;R2可为H,OH,烷氧基,芳氧基;R3可为OH,O-CEPA;R4可为OH或羟基保护基;B为杂环核苷碱;X可为O,S,NH或CH2。
用式45,46,47,48,49和50表示的本发明的糖修饰的核苷的杂环核苷碱B可以是天然存在的或非天然存在的任何杂环核苷碱,因此,可作为本发明的糖修饰的核苷中的碱部分的杂环核苷碱,可以是嘌呤类(例如腺嘌呤,鸟嘌呤或黄嘌呤),嘧啶类(例如胸腺嘧啶,尿嘧啶,胞嘧啶)及其杂环类似物和互变异构体。可作为本发明核苷化合物的碱部分的合适的杂环碱为可以掺入到双链多核苷酸的一条链中从而保持在多核苷酸的互补链上与天然存在的碱保持碱对结构关系。另外,正如上面所讨论的那样,本发明的核苷化合物的碱部分在允许碱进入碱对关系的碱位上与糖部分连接。
本发明的另一个实施方案是提供了具有下式的核苷酸:其中R1可为烷基,芳烷基,芳基,取代的烷基,取代的芳烷基,取代的烷基,取代的芳基,其中取代基可以是NO2,CN,N3,COOEt,OH,SH,CONH2,CONHR,CONR2,COOH,OAC,NH2,NHAc,NMe2,CF3CONH,OR,SR,SO2Me,CF3,F,Cl,Br,I,OTs,+NMe3,CH=CHR,C=CR,其中R为烷基;R2可为H,OH,烷氧基,芳氧基;R3可为OH,O-TBDMS,O-CEPA;R4可为OH,CHO或羟基保护基;B为杂环核苷碱;X可为O,S,NH或CH2;其中与R1和R4连接的碳可以是R或S构型。
本发明的另一实施方案是具有下式的核苷:其中R1可为烷基,芳烷基,芳基,取代的烷基,取代的芳烷基,取代的烷基,取代的芳基,其中取代基可以是NO2,CN,N3,COOEt,OH,SH,CONH2,CONHR,CONR2,COOH,OAC,NH2,NHAc,NMe2,CF3CONH,OR,SR,SO2Me,CF3,F,Cl,Br,I,OTs,+NMe3,CH=CHR,C=CR,其中R为烷基;R2可为H,OH,烷氧基,芳氧基;R3可为OH,OTBDMS,O-CEPA;R4可为OH或羟基保护基;B为杂环核苷碱;X可为O,S,NH或CH2。
本发明的另一方面是提供了具有下式的核苷酸:其中R1可为烷基,芳烷基,芳基,取代的烷基,取代的芳烷基,取代的烷基,取代的芳基,其中取代基可以是NO2,CN,N3,COOEt,OH,SH,CONH2,CONHR,CONR2,COOH,OAC,NH2,NHAc,NMe2,CF3CONH,OR,SR,SO2Me,CF3,F,Cl,Br,I,OTs,+NMe3,CH=CHR,C=CR,其中R为烷基;R2可为H,OH,烷氧基,芳氧基;R3可为OH,O-MBn,O-CEPA;R4可为OH或羟基保护基;B为杂环核苷碱;X可为O,S,NH或CH2。
本发明的另一方面是提供了各种具有下式的本发明的糖修饰的核苷的环氧衍生物:其中R选自CH2OH,CH2ODMTr,CHO,COOH和COOEt;和X选自O和CH2。环氧化物可以两种可能的立体化学取向存在。
通过参考本申请的实施例部分提供的实例可合成本发明的糖修饰的核苷。用本文所提供的实例,有机化学领域普通技术人员可以合成出大量本发明化合物,而这些化合物的详细合成在本文中没有给出。含有糖修饰的核苷的低聚核苷酸
本发明的多核苷酸含有一个或多个本发明的糖修饰的核苷,其中本发明的糖修饰的核苷与第二个糖修饰的核苷或未修饰的核苷相连接,在其中核苷是通过核苷间的键连接。掺入到本发明的低聚核苷酸的糖修饰的核苷包括式45,46,47和48的化合物。本发明的多核苷酸类似物不应受到在单个多核苷酸类似物中可能的核苷亚单位数目的限制;然而,合成短的多核苷酸类似物一般更为方便,例如,含有少于50个碱的多核苷酸类似物。
本发明的各个核苷可通过核苷间的键彼此连接从而得到具有所需核苷碱序列的新的低聚核苷酸。核苷间的键可以是C3′与C5′键或C2′与C5′键。本文所用的术语“核苷间键”不仅指在DNA(二脱氧核糖核酸)或RNA(核糖核酸)中形成核苷间键的磷酸二酯主链类型,而且也指与DNA和RNA中的磷酸二酯键具有同样结构功能的各种其它部分。合适于本发明的低聚核苷酸的其它核苷间键的实例包括硫代磷酸酯,甲基磷酸酯,二硫代磷酸酯,硼磷酸酯,硒代磷酸酯,氨基磷酸酯,乙酰氨酸酯等。各种核苷间键的合成和使用的描述在下列其它文献找到:美国专利5,256,775,PCT公开号WO93/24507,PCT公开号WO/92/05186,美国专利5,264,562,PCT公开号WO92/02534,PCT公开号WO92/06811,PCT公开号WO/93/17717,美国专利5,212,295,美国专利5,292,875,美国专利5,218,103,美国专利5,166,387,美国专利5,151,516,美国专利4,814,448,美国专利4,814,451,美国专利4,096,210,美国专利4,094,873,美国专利4,092,312,美国专利4,016,225,美国专利4,007,197等。
使用有机化学领域的普通技术人员公知的核酸聚合物合成技术很容易制备具有所需碱序列的本发明的多核苷酸。优选使用氨基亚磷酸酯化学合成本发明的多核苷酸,从而将一个或多个本发明的新的核苷掺入多核苷酸类似物中。根据取代基的大小,本发明的核苷的C3′或C5′上的支链取代基可能降低偶合速度,因此,对于一些大取代基的支链核苷,偶合时间可能需要延长至多达10倍或10倍以上。当必要时,用新鲜的试剂的重复偶合和使用较浓的偶合剂也可用于提高偶合反应的速度,合成后,可用与常规未修饰的低聚核苷酸的同样方法对低聚核苷酸进行后处理,即用30%氨水从固体载体上裂解,在55℃下脱保护8小时,用反相HPLC纯化。
为了确证低聚核苷酸的纯度和所需糖修饰的核苷的掺入,可通过使用一些酶如蛇毒磷酸二酯酶和细菌碱性磷酸酶来降解低聚核苷酸并通过分析酶消化产物鉴定纯化的低聚核苷酸。然后将降解产物进行HPLC分析(或其它分离技术) 并且与标准核苷样品比较。纯化的低聚核苷酸的结构也可通过质谱如电喷射技术确证。
本发明的另一方面为本发明的糖修饰的低聚核苷酸的缀合物。氨基-,羟基,硫基-或羧基烷基接头可与本发明的核苷的C1′,C3′,C4′和C5′位连接,从而提供了缀合低聚核苷酸有重要意义的部分的部位。与C1′和C3′位连接的接头可用于将缀合部分定向于双链核酸的小沟,而与C4′位连接的接头可用于将缀合部分定向于大沟。根据在C5′上的接头的立体化学,与C5′位连接的接头可用于将缀合部分定向于双链核酸的大沟或小沟。通过接头,各种功能部分如人工的核酸酶、交联剂、嵌入剂和报导分子可以键连并且位于所需的位置。用途和施用
由于本发明的低聚核苷酸具有重要的单链或双链靶核酸结合活性,此活性能够与天然存在的多核苷酸及其结构类似物形成二股螺旋、三股螺旋或其它的稳定缔合形式,因此本发明的低聚核苷酸可用于使用常规低聚核苷酸的许多方法中。例如,本发明的低聚核苷酸可用于多核苷酸杂交探针,聚合酶链反应的引物(类似环放大反应),序列分析引物等。本发明的低聚核苷酸也可用于疾病的诊断和治疗。本发明的低聚核苷酸的治疗应用包括基因表达的特异抑制(或抑制这些基因编码的RNA序列的转译),而这些基因的表达与通过使用反义低聚核苷酸确定或保持病理状态有关。本发明的低聚核苷酸可用于介导各种遗传靶的反义抑制。典型的基因或通过本发明的反义低聚核苷酸作为靶的基因编码的RNAs包括编码酶的低聚核苷酸激素,血清蛋白,跨膜蛋白质,粘连分子(LFA-1,GPIIb/IIIa,ELAM-1,VACM-1,ICAM-1,E-选择蛋白等),受体分子包括细胞因子受体,细胞因子(IL-1,IL-2,IL-3,IL-4,IL-6等),癌基因,生长因子和白介素。靶基因或RNA可能与任何病理疾病有关例如与下列疾病有关:炎症、心血管疾病、免疫反应,癌,病毒传染病,细菌传染病,酵母传染病,寄生虫传染病等。
本发明的低聚核苷酸适用于体内和离体治疗应用。所指的离体使用包括处理细胞如在疾病如白血病(慢性骨髓性白血病,急性淋巴细胞白血病)或病毒传染病中的骨髓或外周血。可以作为癌症治疗靶的靶基因或这些基因编码的RNA包括癌基因如ras,k-ras,bcl-2,c-myb,bcr,c-myc,c-abl或过分表达的序列如mdm2,制癌蛋白M,IL-6(Kaposi肉瘤),HER-2和转运如bcr-abl。病毒基因序列或这些基因编码的RNA如聚合酶或疱疹病毒的逆转录酶基因如CMV,HSV-1,HSV-2,逆转录病毒如HTLV-1,HIV-1,HIV-2或其它DNA或RNA病毒如HBV,HPV,VZV,流感病毒,腺病毒,黄热病病毒,鼻病毒等也是合适的靶。特定结合的低聚核苷酸的应用可与其它治疗结合。本发明的低聚核苷酸的其它治疗应用包括(1)通过调节在介导炎症中产生重要作用的基因如IL-1受体,IL-1,ICAM-1或E-选择蛋白的表达来调节炎症应答,(2)调节疾病中的细胞增生,所述疾病如血管成形术后的动脉闭塞,它是通过调节下列情况的表达进行的:(a)生长因子或有丝分裂因子如非肌肉肌浆球蛋白,myc,fox,PCNA,PDGF或FGF或其受体,或(b)细胞增殖因子如c-myb。其它合适的增殖因子或信号转导因子如TGFa,IL-6,gINF,蛋白激酶C,酪氨酸激酶(如p210,p190)可作为治疗牛皮癣或其它疾病的目标。另外,EGF受体,TGFa或MHC等位基因也可作为自身免疫疾病的目标。
本发明的低聚核苷酸也可有利的替代在许多非治疗技术中的常规低聚核苷酸,例如杂交测定核酸序列,聚合酶链反应等。这些非治疗技术对于分子生物学领域的普通技术人员是公知的,例如可在Sambrook等人,MoLecular C1oning Techniques第二版,Clod Spring Harbor(1989)中找到。
通过任何合适的方法可提高本发明的低聚核苷酸输送至细胞,所述方法包括磷酸钙,DMSO,甘油或葡聚糖转染,电穿孔或按国际公开号WO90/14074,WO/91/16024,WO91/17424,美国专利4,897,355所述方法使用阳离子,阴离子和/或中性脂质组合物或脂质体。可以通过将低聚核苷酸与阳离子脂质如DOTMA(它可形成或不形成脂质体)络合引入到细胞中,然后将该络合物与细胞接触。合适的阳离子脂质包括(但不局限于)N-2,3-二(9-(Z)-十八碳烯基氧基))-丙-1-基-N,N,N-三甲基铵(DOTMA)及其盐,1-O-油基-2-O-油基-3-二甲基氨基丙基-β-羟基乙基铵及其盐和2,2-二(油氧基)-3-(三甲基铵基)丙烷及其盐。
提高本发明的低聚核苷酸的输送也可通过使用下列方法来介导:(1)病毒如Sendai病毒(Bartzatt,R.,Biotechnol Appl Biochem.,1989,11,133-135)或腺病毒(Wagner,E.等人,Proc Natl AcadSci.USA,1992,89.,6099-6013);(ii)使用化合物的多胺或多阳离子缀合物如聚赖氨酸,鱼精蛋白或Na,N12-双(乙基)精胺(Wagner,E.等人,Proc Natl Acad Sci.USA,1991,88,4255-4259;Zenke,M.等人,Proc Natl Acad Sci.USA,1990,87,3655-3659;Chank,B.K.等人,Biochem Biophys Res Commun.,1988,157,264-270;美国专利5,138,045);(iii)使用化合物的脂多胺络合物如脂精胺(Behr,J.-P.等人,Proc Natl Acad Sci,USA,1989,86,6982-6986;Loeffler,J.P.等人,J。Neurochem.,1990,54,1812-1815);(iv)使用化合物的阴离子、中性或pH敏感的脂质包括阴离子磷脂如磷脂酰甘油,心磷脂,磷脂酸或磷脂酰乙醇胺(Lee,K.-D.等人,Biochem Biophys ACTA,1992,1103,185-192;Cheddar,G.等人,Arch Biochem Biophys,1992,294,188-192;Yoshimura,T.等人,Biochem Int.,1990,20,697-706);(v)与化合物的共轭物如运铁蛋白或生物素或(vi)与能够提高在个体中本发明的低聚核苷酸的药物动力学性质的蛋白质(包括白蛋白或抗体)、糖蛋白或聚合物(包括聚乙二醇)的共轭物。本文所用的转染是指合适于将低聚核苷酸输送至细胞的任何方法。任何试剂如脂质或任何介质如可用于转染过程的病毒在本文中都称为“渗透增强剂”。将低聚核苷酸输送至细胞内可通过与其它核酸共转染进行例如(i)编码蛋白质或蛋白质片段的可表达的DNA片段或(ii)编码蛋白质或蛋白质片段的可翻译的RNA。
因此,本发明的低聚核苷酸可加入到提高低聚核苷酸输送至细胞的任何合适的制剂中,合适的药物制剂还包括常用于将化合物通过局部给药输送至细胞或组织的药物制剂。化合物如聚乙二醇,丙二醇,吖酮(Azone),nonoxony1-9,油酸,DMSO,多胺或脂多胺可用于含有低聚核苷酸的局部制剂。3′-C-支链核苷的合成
在其它文献如De Clercq,E.,Antiviral Res.1989,12,1-20中描述了保存C3′位上的氢用其它官能团取代核苷的C3′的羟基。在Fedorov,I.I.,Kazmina,E.M.,Novicov,N.A.,Gurskaya,G.V.,Bochkarev,A.V.,Jasko,M.V.,Victorova,L.S.,Kuhkanova,M.K.,Balzarini,J.,De Clercq,E.J.Med.Chem.1992,35,4567-4575中报道了核苷的C3′上的氢被其它官能团取代。本发明提供了制备大量不同的3′-C-支链的核苷的方法。制备3′-C-支链的胸苷的方法的实例如反应路线1和2(分别为图2和3)所示。这些方法容易适合于合成本发明的其它核苷,包括其中核苷含有非胸苷的碱的本发明的实施方案。如Jorgensen,P.N.,Thrane,H.,Wengel,J.J.Am.Chem.Soc.1994,116,2231所述,由胸苷经过三步可制备化合物4。用甲苯磺酰基氯在吡啶中处理化合物4得到甲苯磺酸酯(化合物5)。化合物5与氰化钾在DMF中反应得到3′-C-氰基甲基胸苷衍生物(化合物6)。化合物5与叠氮化钠在DMF中反应得到3′-C-叠氮基甲基胸苷衍生物(化合物7)。同样,化合物5与各种亲核试剂反应得到各种3′-C-支链胸苷衍生物,其中3′-C-羟基保持在胸苷中的同样取向。用2-氰基乙基-N,N-二异丙基氯代氨基亚磷酸酯和二异丙基乙胺在二氯甲烷中处理化合物6得到氨基亚磷酸酯(化合物8),它为一个用于低聚核苷酸合成的结构单元。将化合物7进行同样处理得到化合物9。同样,通过常规方法(F.Eckstein,“Oligonucleotide Synthesis”,OxfordUniversity Press(1991))可将其它的3′-C-支链胸苷衍生物转化为相应的氨基亚磷酸酯。用氢化钠在THF中处理化合物5得到环氧化物衍生物(化合物10),化合物10与氢化铝锂在THF中反应得到3′-C-甲基胸苷衍生物(化合物11),它可转化为氨基亚磷酸酯(化合物12)。化合物10与氨在甲醇中反应得到3′-C-氨基甲基胸苷衍生物(化合物13),用硫代三氟乙酸乙酯在THF中处理得到被保护的氨基衍生物(化合物14),化合物14可转化为氨基亚磷酸酯(化合物15)。同样,化合物10与各种亲核试剂反应得到各种3′-C-支链胸苷衍生物,其中因为亲核试剂攻击环氧化物环的较少位阻的碳,所以3′-C-羟基保持在胸苷中的同样取向。化合物10与醇在碱存在下反应得到烷氧基甲基胸苷。取代的醇也可用于制备3′-C-取代的烷氧基甲基胸苷。取代基包括(但不局限于)NO2,CN,COOEt和被保护的氨基。化合物10与二醇反应得到3′-C-羟基烷氧基甲基胸苷,它很容易转化为3′-C-卤代烷氧基甲基胸苷,化合物10与硝基甲烷反应得到3′-C-硝基乙基胸苷,将3′-C-硝基烷基胸苷10还原得到3′-C-氨基烷基胸苷,化合物10与氰基取代的有机镉试剂反应得到3′-C-氰基烷基胸苷,化合物10与乙氧基羰基烷基锌试剂反应得到3′-C-乙氧基羰基烷基胸苷,它很容易在碱性条件下水解为3′-C-羧基烷基胸苷。
对于一些涉及有机铜酸锂试剂的反应,胸苷的酰氨基可能需要保护。优选使用叔丁基二甲基甲硅烷氧基甲基(TBDMSM)作为保护基,因为在接着的转化后,它很容易通过氟化四丁基铵(TBAF)除去。通过使3,5-二酰基化的胸苷与叔丁基二甲基甲硅烷氧基甲基氯在吡啶中反应引入N-TBDMSM基团,按上述对胸苷的同样方法处理N-TBDMSM胸苷分别得到甲苯磺酸盐(化合物5的衍生物)和环氧化物(化合物10的衍生物),这两种化合物均可与锂试剂反应用于制备3′-C-烷基胸苷和3′-C-链烯基胸苷。所得的3′-C-(ω-链烯基)胸苷进行硼氢化反应或氧化裂解得到羟基烷基胸苷,其羟基可转化为各种官能团如NH2,OR,SR,SH和X,其中R为H或烷基,X为F,Cl,Br,I,OTs。4′-C-支链核苷的合成。
在O-Yang C.,Wu,H.Y.,Fraser-Smith,E.B.Walker,K.A.M.Tetrahedron Lett.s,1992,33,37-40中报道了许多4′-C-支链核苷。本发明提供了制备许多新的4′-C-支链的核苷的方法。4′-C-支链的胸苷的制备如反应路线3,4和5(分别为图4,5,6和7)所示。这些方法容易适合于合成本发明的其它核苷,包括其中核苷含有非胸苷的碱的本发明的实施方案。用二甲氧基三苯甲基氯处理由胸苷制备的化合物16得到化合物17,用TBAF处理除去化合物17的叔丁基二甲基甲硅烷基(TBDMS)得到化合物18,将其用二甲亚砜,DCC,三氟乙酸和吡啶处理,氧化为醛,化合物19。用文献(a:O-Yang C.,Wu,H.Y.,Fraser-Smith,E.B.Walker,K.A.M.TetrahedronLetts,1992,33,37-40;b.Jones,G.H.,Taniguchi,M.,Tegg,D.,Moffatt,J.G.J.Org.Chem.1979,44,1309-17)所描述的相似方法,可将化合物19转化为化合物20(4′-C-羟基甲基胸苷衍生物)。用80%乙酸除去化合物20的二甲氧基三苯甲基得到化合物21(4′-C-羟基甲基胸苷)。用苯甲酸酐选择性地苯甲酰化化合物21得到化合物22,其3′-和5′-羟基通过将化合物22与二氢吡喃在甲苯磺酸存在下在二氯甲烷中反应用四氢吡喃基(THP)保护。所得的化合物23用氢氧化钠水溶液处理得到化合物24,接着在0℃下在氢氧化钠存在下与甲基碘反应得到4′-C-甲氧基甲基胸苷衍生物(化合物25)。除去化合物25的THP保护基得到化合物26(4′-C-甲氧基甲基胸苷)。对于一些反应,由于THP引起生成非对映体,TBDMS保护基优于THP。因此,用叔丁基二甲基氯硅烷处理化合物22得到3′,5′-O-(双TBDMS)胸苷衍生物(化合物27),在50℃下用乙二胺除去苯甲酰基得到化合物28,与三氟甲基磺酸酐和吡啶在二氯甲烷中反应得到三氟甲磺酸酯(化合物29),化合物29与氨在二噁烷中反应得到4′-C-氨基甲基胸苷衍生物(化合物30),化合物29与叠氮化钠在DMF中反应得到4′-C-叠氮基甲基胸苷衍生物(化合物31)。除去化合物30和31的TBDMS保护基分别得到化合物32和33(4′-C-氨基甲基胸苷和4′-C-叠氮基甲基胸苷)。用三氟乙酰基保护化合物33的氨基得到化合物34,化合物32和34与二甲氧基三苯甲基氯在吡啶中反应分别得到化合物35和36。用2-氰基乙基-N,N-二异丙基氯代氨基亚磷酸酯处理化合物35和36分别转化为相应的氨基亚磷酸酯。
化合物29与格利雅试剂反应得到4′-C-烷基胸苷和4′-C-链烯基胸苷。所得的4′-C-(ω-链烯基)胸苷进行硼氢化反应或氧化裂解得到羟基烷基胸苷,其羟基可转化为各种官能团如NH2,OR,SR,SH和X,其中R为H或烷基,X为F,Cl,Br,I,OTs。化合物29与氰基烷基镉反应得到4′-C-氰基烷基胸苷,化合物29与乙氧基羰基烷基锌试剂反应得到4′-C-乙氧基羰基烷基胸苷,它可水解为4′-C-羧基烷基胸苷。化合物29与链烷醇钠反应得到4′-C-烷氧基甲基胸苷,取代的醇和酚可用于制备4′-C-取代的烷氧基甲基胸苷。取代基可为NO2,CN,COOEt,OAc或被保护的氨基。合成4′-C-支链胸苷后,用二甲氧基三苯甲基保护5′-羟基,用常规方法(F.Eckstein,“Oligonucleotide Synthesis“,OxfordUniversity Press(1991))可将3′-羟基转化为用于低聚核苷酸合成的氨基亚磷酸酯。5′-C-支链核苷的合成
本发明提供了制备许多数目的5′-C-支链核苷的方法,制备5′-C-支链的胸苷的方法的实例如反应路线6,7和8(分别为图8,9和10)所示。这些方法容易适合于合成本发明的其它核苷,包括其中核苷含有非胸苷的碱的本发明的实施方案。由已知方法(O-Yang C.,Wu,H.Y.,Fraser-Smith,E.B.Walker,K.A.M.Tetrahedron Letts,1992,33,37-40)经过三步制备化合物42。或者,化合物42可通过使80%乙酸与化合物41反应制备,化合物41是由胸苷与过量的叔丁基二甲基氯甲硅烷和咪唑在吡啶中反应制备3′,5′-O-(双-叔丁基二甲基甲硅烷基)胸苷。化合物42和磷内鎓盐(由溴化甲基三苯基鎓和氢化钠在DMSO反应制备)进行Wittig反应得到烯烃衍生物(化合物43)。化合物43与间氯过苯甲酸在二氯甲烷中进行环氧化反应得到5′-(S)-环氧化物衍生物,化合物44为主要产物,5′-(R)-环氧衍生物为少的产物。化合物44和其它化合物的立体化学排列如图表1(图12)所示。在碳酸钠存在下化合物44与甲醇反应得到5′-(S)-C-甲氧基甲基胸苷(化合物45)。化合物44与氨在甲醇中反应得到5′-(S)-C-氨基甲基胸苷,用三氟乙酰基保护得到化合物46。化合物44与氰化钾在DMF中反应得到5′-(S)-C-氰基甲基胸苷(化合物47),通过与二甲氧基三苯甲基氯和三氟甲基磺酸银在吡啶中反应用二甲氧基三苯甲基保护化合物45-47的5′-羟基分别得到化合物48-50。用TBAF在THF中除去化合物48-50的TBDMS基团分别得到化合物51-53。化合物51-53分别转化为相应的氨基亚磷酸酯(化合物54-56)。化合物42与烯丙基溴化镁进行格利雅反应得到异构体5′-(R)-C-烯丙基胸苷和5′-(S)-C-烯丙基胸苷衍生物(化合物57和58)的混合物,它们可用硅胶色谱法进行分离。用TBAF在THF中除去化合物57和58的TBDMS基团分别得到5′-(R)-和5′-(S)-C-烯丙基胸苷(化合物59和60)。化合物59和60分别转化为相应的氨基亚磷酸酯(化合物61和62)。
同样,化合物42与各种格利雅试剂反应得到各种5′-(S或R)-C-烷基胸苷和5′-(S或R)-C-链烯基胸苷。所得的5′-C-(ω-链烯基)胸苷进行硼氢化反应或氧化裂解得到羟基烷基胸苷,其羟基可转化为各种官能团如NH2,OR,SR,SH和X,其中R为H或烷基,X为F,Cl,Br,I,OTs。
化合物44与各种亲核试剂反应得到各种5′-C-支链胸苷衍生物,因此,化合物44与醇在碱存在下反应得到5′-C-烷氧基甲基胸苷。取代的醇也可用于制备5′-C-取代的烷氧基甲基胸苷。取代基可包括(但不局限于)NO2,CN,COOEt和保护的氨基。化合物44与二醇反应得到5′-C-羟基烷氧基甲基胸苷,它容易转化为5′-C-卤代烷基胸苷。化合物44与硝基甲烷反应得到5′-C-硝基乙基胸苷,将5′-C-硝基烷基胸苷还原得到5′-C-氨基烷基胸苷,化合物44与氰基烷基镉试剂反应得到5′-C-氰基烷基胸苷,化合物44与乙氧基羰基烷基锌试剂反应得到5′-C-乙氧基羰基烷基胸苷,在碱性条件下很容易水解得到5′-C-羧基烷基胸苷。5′-(S)-异构体的所有转化均可用于5′-(R)-异构体。最后,用常规方法(F.Eckstein,“Oligonucleotide Synthesis”,Oxford University Press(1991))可分别将5′-C-支链胸苷与二甲氧基三苯甲基氯和三氟甲磺酸银在吡啶中反应得到5′-O-DMTr-5′-C-支链胸苷,它可转化为相应的氨基亚磷酸酯。
为了测定5′-C-支链的胸苷的C5′位的构型,利用了空间相接近的质子的NOE增强效应。因为在C5′上的取代基的刚性取向对于NOE试验是必须的,在胸苷衍生物的3′-O-和5′-O-之间引入TIPDS环(路线8,图11),其中5′-质子取向朝向3′位或向离开3′-位的方向。当3′-质子被饱和时,可容易观察到有或没有5′-质子的NOE增强(图表1,图12)。对于5′-C-烯丙基胸苷,具有4.8%NOE增强的异构体很明显为5′-(R)-异构体,其它没有NOE增强的异构体为5′-(S)-异构体。不用X射线晶体学,直接测定5′-环氧基团的立体化学是困难的。然而,将环氧化物转化为开环产物不会改变C5′的手性,如果测定一对这些开环产物的立体化学,环氧化物对的立体化学也可确定。因此,与5′-C-烯丙基胸苷相似,一对开环产物(由环氧化物制备的5′-C-氰基甲基胸苷)可转化为TIPDS环产物。当3′-质子被饱和时,一种异构体得到6.3%NOE增强。显然,这种异构体为5′-(R)-异构体,另一种为5′-(S)-异构体。1′-C-支链核苷的合成
已经报道了一些1′-C-支链核苷(a.Uteza,V.,Chen,G-R.,Tuoi,J.L.Q.,Descotes,G.,Fenet,B.,Grouiller,A.Tetrahedron,1993,49,8579-8588;B.Azhayev,A.,Gouzaev,A.,Hovinen,J.,Azhayeva,E.,Lonnberg,H.Tetrahedron Letts,1993,34,6435-6438)。本发明提供了制备大量1′-C-支链核苷的方法,1′-C-支链胸苷的制备如反应路线9和10(分别为图13和14)所示。按照已知方法(Uteza,V.,Chen,G-R.,Tuoi,J.L.Q.,Descotes,G.,Fenet,B.,Grouiller,A.Tetrahedron,1993,49,8579-8588)制备化合物63。用二甲氧基三苯甲基保护化合物63的5′-羟基得到化合物64,用叔丁基二甲基氯甲硅烷处理得到化合物65。用叔丁基二甲基甲硅烷氧基甲基氯处理化合物65得到化合物66,化合物66用三乙氧基氢化铝锂在乙醚中处理得到醛(化合物67),化合物67用硼氢化钠还原,接着用三氟甲基磺酸酐处理,得到三氟甲基磺酸盐衍生物(化合物68)。用各种亲核试剂处理化合物68得到许多新的1′-C-支链胸苷(化合物69),因此用氰化钠、亚硝酸钠、叠氮化钠处理化合物68分别得到相应的1′-C-氰基甲基,1′-C-硝基甲基和1′-C-叠氮基甲基胸苷。用硝基甲烷处理化合物68得到1′-C-硝基乙基胸苷。用烷基硫化钠处理化合物68得到1′-C-烷基硫甲基胸苷,用链烷醇钠处理化合物68得到1′-C-烷氧基甲基胸苷,用有机铜锂试剂处理化合物68得到1′-C-烷基-和1′-C-链烯基胸苷。取代的烷基或链烯基锌或镉试剂可用于制备1′-C-取代的烷基或1′-C-取代的链烯基胸苷。取代基包括COOEt,CN,NO2。所得的3′-C-(ω-链烯基)胸苷的硼氢化或氧化裂解得到羟基烷基胸苷,羟基可转化为各种官能团如NH2,OR,SR,SH和X,其中R为H或烷基,X为F,Cl,Br,I,OTs。取代的醇和酚可用于制备1′-C-烷氧基甲基-和1′-C-苯氧基甲基胸苷。取代基可以是NO2,CN,COOEt或OAc。1′-C-硝基烷基胸苷可被还原为相应的氨基烷基胸苷,用TBAF处理化合物69得到脱保护的化合物70,它可被转化为相应的氨基亚磷酸酯(化合物71)。
用对甲氧基苄基(MPM)完全保护化合物63得到化合物72,在过氧化氢和碱存在下水解化合物72得到化合物73,将其进行Hofmann重排得到胺,用甲基溴可转化为季铵衍生物(化合物74)。各种亲核试剂可用于取代三甲胺,用链烷醇钠处理化合物74得到1′-C-烷氧基胸苷,用烷基硫化钠处理化合物74得到1′-C-烷基硫基胸苷。当与溴化钠加热时,化合物74可转化为1′-C-溴胸苷,它用氰化钠、亚硝酸钠或硝基甲烷处理分别得到相应的1′-C-取代的胸苷。用硝酸铈铵处理化合物75得到脱保护的化合物76,用二甲氧基三苯甲基保护5′-羟基,并将所得的产物(化合物77)转化为相应的氨基亚磷酸酯(化合物78)。含有糖修饰的核苷的低聚核苷酸
最近已经报道了含有糖修饰的核苷的低聚核苷酸(A.Jorgensen,P.N.,Stein,P.C.,Wengel,J.J.Am.Chem.Soc.1994,116,2231;B.Fensholdt,J.,Thrane,H.,Wengel,J.Tetrahedron Letts.1995,36,2535;C.Thrane,H.,Fensholdt,J.,Regner,M.,Wengel,J.Tetrahedron,1995,51,10389;D.Saha,A.K.,Caulfield,T.J.,Hobbs,C.,Upson,D.A.,Waychunas,C.,Yawman,A.M.J.Org.Chem.1995,60,788;E.Azhayev,A.,Gouzaev,A.,Hovinen,J.,Azhayeva,E.,Lonnberg,H.Tetrahedron Lett.1993,34,6435-6438;F.Ono,A.,Dan,A.,Matsuda,A.BioconjugateChemistry,1993,4,499-508;G.Inoue,H.,Hayase,Y.,Imura,A.,Iwai,S.,Miuta,K.,Ohtsuka,E.,Nucleic Acids Res.1987,15,6131;H.Lesnik,E.A.,Guinosso,C.J.,Kawasaki,A.M.,Sasmor,H.,Zounes,M.,Cummins,L.L.,Ecker D.J.,Cook,P.D.,and Freier,S.M.Biochemistry,1993,32,7832).本发明提供了大量新的糖修饰的核苷,它们可用氨基亚磷酸酯化学方法容易掺入到低聚核苷酸中,糖修饰的低聚核苷酸含有至少一种本发明的糖修饰的核苷,它们在序列中可含有多个糖修饰的核苷或它们仅含有本发明的糖修饰的核苷。糖修饰的低聚核苷酸也可含有其它修饰如主链修饰,碱修饰和任何其它糖修饰。很明显依赖于取代基的大小,在核苷的C3′或C5′上的支链取代基可降低偶合速度。因此,对于一些大取代基支链核苷来说,偶合时间增加。例如,对于5′-C-支链低聚核苷酸和4′-C-支链低聚核苷酸的合成来说,使用的偶合时间为2-5分钟,对于3′-C-支链低聚核苷酸的合成来说,使用的偶合时间多达45(3×15分)分钟。因为3′-羟基是叔型的,用新鲜试剂重复偶合仅对于3′-C-支链低聚核苷酸的合成是必须的。纯化的糖修饰的低聚核苷酸的组成可通过酶消化产物分析确证。
实施例
可通过参考下列实施例更好地理解上面已经描述了的本发明。下列实施例是用于说明而不是限制本发明。
实施例15′-O-(4,4′-二甲氧基三苯甲基)-3′-对甲苯磺酰氧基
甲基胸苷的制备
将按照已知方法(Jorgensen,P.N.,Thrane,H.,Wengel,J.J.Am.Chem.Soc.1994,116,2231)制备的5′-O-(4,4′-二甲氧基三苯甲基)-3′-羟基甲基胸苷(2.12g,3.69mmol),对甲苯磺酰基氯(1.76g,9.23mmol),DMAP(0.180g,1.48mmol)的无水吡啶(13ml)溶液在室温下搅拌过夜,反应混合物冷却至0℃,用EtOAc(500ml)稀释,用10%NaHCO3洗涤,用硫酸钠干燥并且浓缩。粗产物通过硅胶色谱纯化(5%CH3OH/CH2Cl2)得到2.39g(89%)5′-O-(4,4′-二甲氧基三苯甲基)-3′-对甲苯磺酰氧基甲基胸苷,为无色粉末。
实施例25′-O-(4,4′-二甲氧基三苯甲基)-3′-C-氰基甲基胸
苷的制备
将5′-O-(4,4′-二甲氧基三苯甲基)-3′-对甲苯磺酰氧基甲基胸苷(0.50g,0.686mmol)和氰化钾(0.134g,2.06mmol)的无水DMF(7ml)浆状液在室温下搅拌过夜,反应混合物用EtOAc(60ml)稀释,用水洗涤(3×75ml),然后用10%碳酸氢钠(3×75ml)洗涤。有机层用硫酸钠干燥,浓缩并且通过硅胶色谱纯化(EtOAc-己烷,1∶1)得到0.386g(97%)5′-O-(4,4′-二甲氧基三苯甲基)-3′-C-氰基甲基胸苷,为无色粉末。
实施例35′-O-(4,4′-二甲氧基三苯甲基)-3′-C-叠氮基甲基
胸苷的制备
将5′-O-(4,4′-二甲氧基三苯甲基)-3′-对甲苯磺酰氧基甲基胸苷(0.40g,0.55mmol)和NaN3(0.11g,1.65mmol)在无水DMF中的(3ml)浆状液在50℃下加热3天,反应混合物冷却至室温,用EtOAc(30ml)稀释,用水(3×40ml)洗涤,然后用10%碳酸氢钠(3×40ml)洗涤。有机层用硫酸钠干燥,浓缩并且通过硅胶色谱纯化(EtOAc-己烷,1∶1)得到0.30g(92%)5′-O-(4,4′-二甲氧基三苯甲基)-3′-C-叠氮基甲基胸苷,为无色粉末。
实施例45′-O-(4,4′-二甲氧基三苯甲基)-3′-C-氰基甲基胸苷3′-(2-氰基乙基-N,N-二异丙基氨基亚磷酸酯)的制备
在0℃氩气氛下向搅拌着的5′-O-(4,4′-二甲氧基三苯甲基)-3′-C-氰基甲基胸苷(0.20g,0.344mmol)和二异丙基乙基胺(0.24ml;1.38mmol)的无水二氯甲烷(3ml)溶液中滴加入2′-氰基乙基-N,N-二异丙基氯代氨基亚磷酸酯(170mg;0.715mmol)的二氯甲烷溶液,所得到的反应混合物在室温下搅拌2小时,冷却至0℃,用冷的二氯甲烷(20ml)稀释,用冷的碳酸氢钠(3×15ml)洗涤,有机层用硫酸钠干燥并且浓缩,残余物通过硅胶色谱纯化(Et3N-EtOAc-CH2Cl2,5∶50∶45)得到177mg(66%)泡沫状的5′-O-(4,4′-二甲氧基三苯甲基)-3′-C-氰基甲基胸苷3′-(2-氰基乙基-N,N-二异丙基氨基亚磷酸酯)。
实施例55′-O-(4,4′-二甲氧基三苯甲基)-3′-C-叠氮基甲基胸苷3′-(2-氰基乙基-N,N-二异丙基氨基亚磷酸酯)的制备
在0℃氩气氛下向搅拌着的5′-O-(4,4′-二甲氧基三苯甲基)-3′-C-叠氮基甲基胸苷(252mg,0.344mmol)和二异丙基乙基胺(0.44ml;2.51mmol)的无水二氯甲烷(3ml)溶液中滴加入2′-氰基乙基-N,N-二异丙基氯代氨基亚磷酸酯(296mg;1.25mmol)的二氯甲烷溶液,所得的反应混合物在室温下搅拌2小时,冷却至0℃,用冷的二氯甲烷(20ml)稀释,用冷的碳酸氢钠(3×15ml)洗涤,有机层用硫酸钠干燥并且浓缩,残余物通过硅胶色谱纯化(Et3N-EtOAc-CH2Cl2,5∶50∶45)得到128mg(38%)泡沫状的5′-O-(4,4′-二甲氧基三苯甲基)-3′-C-叠氮基甲基胸苷3′-(2-叠氮基甲基-N,N-二异丙基氨基亚磷酸酯)。
实施例65′-O-(4,4′-二甲氧基三苯甲基)-3′-C,O-亚甲基
胸苷的制备
在0℃氩气氛下向NaH(60%矿物油液,0.18g,7.5mmol)的无水THF(18ml)悬浮液中滴加入5′-O-(4,4′-二甲氧基三苯甲基)-3′-对甲苯磺酰氧基甲基胸苷(1.5g,2.06mmol)的THF(10ml)溶液,所得的反应混合物在室温下搅拌2小时,冷却至0℃,加入水中止反应。混合物用EtOAc(250ml)稀释,用水洗涤(2×200ml),然后用10%碳酸氢钠(2×200ml)洗涤,用硫酸钠干燥和浓缩,残余物通过硅胶色谱纯化(5%甲醇/二氯甲烷)得到0.97g(85%)泡沫状的5′-O-(4,4′-二甲氧基三苯甲基)-3′-C,O-亚甲基胸苷。
实施例75′-O-(4,4′-二甲氧基三苯甲基)-3′-C-甲基胸苷的
制备
在0℃氩气氛下向搅拌着的氢化铝锂(58mg;1.53mmol)的无水THF(10ml)悬浮液中滴加入5′-O-(4,4′-二甲氧基三苯甲基)-3′-C,O-亚甲基胸苷(385mg,0.692mmol)的THF(10ml)溶液,反应混合物在0℃下搅拌1小时,通过缓慢加入10%碳酸氢钠中止反应,所得的混合物用EtOAc(30ml)稀释,用碳酸氢钠(3×20ml)洗涤,用硫酸钠干燥和浓缩,残余物通过硅胶色谱纯化(5%甲醇/三氯甲烷)得到306mg(79%)泡沫状的5′-O-(4,4′-二甲氧基三苯甲基)-3′-C-甲基胸苷。
实施例85′-O-(4,4′-二甲氧基三苯甲基)-3′-C-甲基胸苷3′-(2-氰基乙基-N,N-二异丙基氨基亚磷酸酯)的制备
在0℃氩气氛下向搅拌着的5′-O-(4,4′-二甲氧基三苯甲基)-3′-C-甲基胸苷(98mg,0.17mmol)和二异丙基乙基胺(0.13ml;0.742mmol)的无水二氯甲烷(2ml)溶液中滴加入2′-氰基乙基-N,N-二异丙基氯代氨基亚磷酸酯(85mg;0.36mmol)的二氯甲烷溶液。所得的反应混合物在室温下搅拌1小时,冷却至0℃,用冷的二氯甲烷(20ml)稀释,用冷的碳酸氢钠(3×15ml)洗涤,有机层用硫酸钠干燥并且浓缩,残余物通过硅胶色谱纯化(Et3N-EtOAc-己烷,5∶50∶45)得到117mg(88%)泡沫状的5′-O-(4,4′-二甲氧基三苯甲基)-3′-C-甲基胸苷3′-(2-氰基乙基-N,N-二异丙基氨基亚磷酸酯)。
实施例95′-O-(4,4′-二甲氧基三苯甲基)-3′-C-氨基甲基胸
苷的制备
将氨的甲醇(9ml)饱和溶液加入到5′-O-(4,4′-二甲氧基三苯甲基)-3′-C,O-亚甲基胸苷(901mg,1.62mmol)的甲醇(3ml)溶液中,所得的溶液在室温下放置3天,蒸发过量的氨和甲醇,残余物通过色谱纯化(甲醇-己烷-三氯甲烷,1∶1∶8)得到414mg(45%)5′-O-(4,4′-二甲氧基三苯甲基)-3′-C-氨基甲基胸苷,为无色固体。
实施例105′-O-(4,4′-二甲氧基三苯甲基)-3′-C-三氟乙酰氨
基甲基胸苷的制备
将5′-O-(4,4′-二甲氧基三苯甲基)-3′-C-氨基甲基胸苷(361mg,0.628mmol)和硫代三氟乙酸乙酯(490mg,3.12mmol)的无水THF(6ml)的溶液在室温下搅拌6小时,蒸发溶剂,残余物通过硅胶色谱纯化(5%甲醇/二氯甲烷)得到411mg(98%)5′-O-(4,4′-二甲氧基三苯甲基)-3′-C-三氟乙酰氨基甲基胸苷,为无色粉末。
实施例115′-O-(4,4′-二甲氧基三苯甲基)-3′-C-三氟乙酰氨基甲基胸苷3′-(2-氰基乙基-N,N-二异丙基氨基亚磷酸酯)
在0℃氩气氛下向搅拌着的5′-O-(4,4′-二甲氧基三苯甲基)-3′-C-甲基胸苷(411mg,0.614mmol)和二异丙基乙基胺(0.64ml;3.65mmol)的无水二氯甲烷(6ml)溶液中滴加入2′-氰基乙基-N,N-二异丙基氯代氨基亚磷酸酯(410mg;1.83mmol)的无水二氯甲烷溶液,所得的反应混合物在室温下搅拌2小时,冷却至0℃,用冷的二氯甲烷(30ml)稀释,用冷的碳酸氢钠(3×20ml)洗涤,有机层用硫酸钠干燥并且浓缩,残余物通过硅胶色谱纯化(Et3N-EtOAc-CHCl3,5∶30∶65)得到386mg(72%)粉末状的5′-O-(4,4′-二甲氧基三苯甲基)-3′-C-三氟乙酰氨基甲基胸苷3′-(2-氰基乙基-N,N-二异丙基氨基亚磷酸酯酸酯)。
实施例123′-O-(4,4′-二甲氧基三苯甲基)-5′-甲酰基胸苷的制
备
向搅拌着的冷的3′-O-(4,4′-二甲氧基三苯甲基)胸苷(通过常规方法由胸苷制备,40.4g,0.072mol)的无水DMSO溶液中加DCC(45.86g,0.224mol)的DMSO(180ml)溶液。所得的溶液在5℃下搅拌5分钟,加入吡啶(2.94g,3.0ml,0.0371mol),再搅拌5分钟后,滴加入三氟乙酸(2.11g,1.43ml,0.0185mol)的DMSO(2ml)溶液,所得的反应混合物在5℃下搅拌10分钟,在室温下搅拌6小时,在冷却下滴加入水(20ml),混合物在室温下搅拌1小时,过滤出沉淀,用DMSO洗涤,搅拌下将合并的DMSO溶液倒入粉碎的冰(4L)中,放置1小时后,过滤出沉淀,用水充分洗涤,将滤饼溶于二氯甲烷(500ml)中,分离有机层,干燥(硫酸钠)并且浓缩。粗产物通过硅胶色谱纯化(3%甲醇/二氯甲烷)得到32.6g(81%)3′-O-(4,4′-二甲氧基三苯甲基)-5′-甲酰基胸苷,为无色粉末。
实施例133′-O-(4,4′-二甲氧基三苯甲基)-4′-C-羟基甲基胸苷的制备
在0℃下向搅拌着的3′-O-(4,4′-二甲氧基三苯甲基)-5′-甲酰基胸苷(16.3g,30.07mmol)的二噁烷(120ml)溶液中依次滴加入36%甲醛(24ml)和2N氢氧化钠(60ml)。所得的溶液在室温下搅拌6小时,将反应混合物冷却至0℃,滴加入10%乙酸水溶液直至pH达到7.5,混合物用乙酸乙酯(1L)稀释,用10%盐水洗涤(500ml,然后2×300ml),干燥(硫酸钠)并且浓缩。粗产物通过硅胶色谱纯化(EtOAc-己烷,3∶1)得到11.45g(66.3%)3′-O-(4,4′-二甲氧基三苯甲基)-4′-C-羟基甲基胸苷,为无色粉末。
实施例14
4′-C-羟基甲基胸苷的制备
将3′-O-(4,4′-二甲氧基三苯甲基)-4′-C-羟基甲基胸苷(6.32g,11.0mmol)的80%乙酸水(50ml)溶液在室温下放置4小时,在减压下除去溶剂,加入水(200ml),所得的混浊混合物用乙醚(3×80ml)洗涤,蒸发水。残余物溶于甲醇和甲苯中,浓缩所得的溶液,重复所述方法两次,得到泡沫状的4′-C-羟基甲基胸苷(2.72g,91%)。
实施例15
4′-C-苯甲酰氧基甲基胸苷的制备
在0℃下向搅拌着的4′-羟基甲基胸苷(3.72g,13.67mmol)的无水吡啶(10ml)溶液中加入苯甲酸酐(4.64g,51mmol)的吡啶(10ml)溶液,所得的溶液在0℃下放置1小时,然后在室温下放置20小时,在0℃下加入水(5ml),蒸发吡啶,残余物进行硅胶色谱纯化(7%乙醇/氯仿)得到2.27g(44%)4′-C-苯甲酰基甲基胸苷,为无色固体。
实施例163′,5′-O-(双四氢吡喃基)-4′-C-羟基甲基胸苷的制备
在0℃下向搅拌着的4′-C-苯甲酰基甲基胸苷(1.65g,4.39mmol)和对甲苯磺酸(50mg)的无水二氯甲烷(70ml)溶液中滴加入二氢吡喃(1.84g,1.89ml,21.80mmol),所得的溶液在室温下搅拌2小时,在冷却下加入2N氢氧化钠(20ml),所得的混合物浓缩除去二氯甲烷,加入二噁烷(10ml)。混合物在室温下搅拌3小时,用二氯甲烷(3×30ml)萃取。有机层用水(3×50ml)洗涤,干燥(硫酸钠)并且浓缩。残余物通过硅胶柱纯化得到1.50g(77.7%)泡沫状的3′,5′-O-(双四氢吡喃基)-4′-C-羟基甲基胸苷。
实施例17
4′-C-甲氧基甲基胸苷的制备
在0℃下向搅拌着的3′,5′-O-(双四氢吡喃基)-4′-C-羟基甲基胸苷(660mg,1.5mmol)和氢化钠(60%矿物油,180mg,4.5mmol)在无水THF(15ml)中的混合物中滴加入甲基碘(1.06g,0.46ml)。所得的混合物在0℃下搅拌1.5小时,在0℃下滴加入水(1ml),加入乙酸调节PH至7,混合物用乙酸乙酯(50ml)稀释,用水(3×30ml)洗涤,干燥(硫酸钠)并且浓缩。残余物溶于酸性混合物(5ml THF,10ml CH3COOH和5ml水)中,溶液在50℃下放置3小时,蒸发溶剂,残余物溶于甲醇-甲苯混合物中,浓缩,然后重复一次,通过硅胶色谱纯化(10%乙醇/氯仿)得到271mg(63%)4′-C-甲氧基甲基胸苷,为无色固体。
实施例185′-O-(4,4′-二甲氧基三苯甲基)-4′-C-甲氧基甲基
胸苷的制备
将4′-C-甲氧基甲基胸苷(173mg,0.6mmol)和二甲氧基三苯甲基氯(287mg,0.84mmol)的吡啶溶液在室温下放置5小时,蒸发吡啶,残余物通过硅胶色谱纯化(EtOAc-己烷,2∶1)得到264mg(74%)泡沫状的5′-O-(4,4′-二甲氧基三苯甲基)-4′-C-甲氧基甲基胸苷。
实施例195′-O-(4,4′-二甲氧基三苯甲基)-4′-C-甲氧基甲基胸苷3′-(2-氰基乙基-N,N-二异丙基氨基亚磷酸酯)的制备
在0℃氮气氛下向搅拌着的5′-O-(4,4′-二甲氧基三苯甲基)-4′-C-甲氧基甲基胸苷(200mg,0.34mmol)和二异丙基乙基胺(176mg,236μl,1.36mmol)的无水二氯甲烷(3ml)溶液中滴加入2-氰基乙基-N,N-二异丙基氯代氨基亚磷酸酯(161mg;152μl,0.68mmol)的二氯甲烷(1ml)溶液,所得的溶液在室温下搅拌30分钟,冷却至0℃,用乙酸乙酯(30ml)稀释,混合物用10%碳酸氢钠(3×20ml)洗涤,干燥(硫酸钠)并且浓缩,残余物通过硅胶色谱纯化(Et3N-EtOAc-己烷,5∶45∶50)得到190mg(71%)泡沫状的5′-O-(4,4′-二甲氧基三苯甲基)-4′-C-甲氧基甲基胸苷3′-(2-氰基乙基-N,N-二异丙基氨基亚磷酸酯)。
实施例203′,5′-(双叔丁基二甲基甲硅烷基)-4′-C-羟基甲基胸苷
的制备
向冷的搅拌着的4′-C-苯甲酰基甲基胸苷(1.14g,3.03mmol)和咪唑(985mg,15.15mmol)的吡啶溶液中加入叔丁基二甲基氯甲硅烷(1.37g,9.09mmol)的吡啶溶液,反应混合物在50℃下放置过夜,用乙酸乙酯(100ml)稀释,用水(3×50ml)洗涤,浓缩。残余物溶于乙醇(10ml)中,加入乙二胺和乙醇(1∶1,20ml)的混合物,溶液在50℃下加热2天,在减压下蒸发乙醇和乙二胺,残余物溶于氯仿(60ml)中,溶液用水(3×40ml)洗涤,干燥(硫酸钠)并且浓缩。残余物通过硅胶色谱纯化(EtOAc-己烷,1∶1)得到780mmg(52%)3′,5′-(双叔丁基二甲基甲硅烷基)-4′-C-羟基甲基胸苷,为白色固体。
实施例213′,5′-(双叔丁基二甲基甲硅烷基)-4′-C-氨基甲基胸苷
的制备
在0℃下向搅拌着的3′,5′-(双叔丁基二甲基甲硅烷基)-4′-C-羟基甲基胸苷(500mg,1.0mmol)和吡啶(0.4ml)的无水二氯甲烷(5ml)溶液中滴加入三氟甲磺酸酐(564mg,332μl,2.0mmol)和吡啶(0.4ml)在二氯甲烷(5ml)中的混合物,反应混合物在0℃下搅拌30分钟,在-10℃下加入0.5ml 10%碳酸氢钠,混合物用二氯甲烷(20ml)稀释,用冷的10%碳酸氢钠(2×30ml)洗涤,干燥(硫酸钠),浓缩,在真空下干燥1小时,将粗产物溶于二噁烷(30ml)和用氨气饱和。溶液在室温下放置过夜,然后在50℃下加热2天,蒸发过量的氨和二噁烷,残余物通过硅胶色谱纯化(1%MeOH和5%Et3N/CHCl3)得到266mg(53%)3′,5′-(双叔丁基二甲基甲硅烷基)-4′-C-氨基甲基胸苷,为白色固体。
实施例223′,5′-(双叔丁基二甲基甲硅烷基)-4′-C-三氟乙酰氨基
甲基胸苷的制备
将3′,5′-(双叔丁基二甲基甲硅烷基)-4′-C-氨基甲基胸苷(260mg,0.52mmol)和硫代三氟乙酸乙酯(635mg,0.52ml,4.0mmol)的二噁烷溶液在室温下搅拌5小时。蒸发溶剂,残余物通过硅胶色谱纯化(5%甲醇/氯仿)得到220mg(71%)3′,5′-(双叔丁基二甲基甲硅烷基)-4′-C-三氟乙酰基甲基胸苷,为白色固体。
实施例23
4′-C-三氟乙酰氨基甲基胸苷的制备
将3′,5′-(双叔丁基二甲基甲硅烷基)-4′-C-三氟乙酰氨基甲基胸苷(215mg,0.36mmol)和TBAF(1.0M的THF溶液,用乙酸中和至pH=7.5,0.72ml)的THF(3ml)液在室温下放置20小时。蒸发溶剂,残余物用硅胶色谱纯化(10%甲醇/氯仿)得到118mg(89%)4′-C-三氟乙酰氨基甲基胸苷,为无色固体。
实施例245′-O-(4,4′-二甲氧基三苯甲基)-4′-C-三氟乙酰氨
基甲基胸苷的制备
将4′-C-三氟乙酰氨基甲基胸苷(110mg,0.3mmol)和二甲氧基三苯甲基氯(152mg,0.45mmol)的无水吡啶(2ml)溶液在室温下放置过夜,蒸发吡啶,残余物通过硅胶色谱纯化(EtOAc-己烷,2∶1)得到122mg(61%)泡沫状的5′-O-(4,4′-二甲氧基三苯甲基)-4′-C-三氟乙酰氨基甲基胸苷。
实施例255′-O-(4,4′-二甲氧基三苯甲基)-4′-C-三氟乙酰氨基甲基胸苷3′-(2-氰基乙基-N,N-二异丙基氨基亚磷酸酯)
在0℃氮气氛下向搅拌着的5′-O-(4,4′-二甲氧基三苯甲基)-4′-C-三氟乙酰氨基甲基胸苷(110mg,0.165mmol)和二异丙基乙基胺(129mg,174μl,1.0mmol)的无水二氯甲烷(3ml)溶液中滴加入2-氰基乙基-N,N-二异丙基氯代氨基亚磷酸酯(78mg;74μl,0.33mmol)的二氯甲烷(1ml)溶液。所得的溶液在室温下搅拌30分钟,冷却至0℃,用乙酸乙酯(20ml)稀释,混合物用10%碳酸氢钠(3×15ml)洗涤,干燥(硫酸钠)并且浓缩,残余物通过硅胶色谱纯化(Et3N-EtOAc-己烷,5∶45∶50)得到137mg(86%)泡沫状的5′-O-(4,4′-二甲氧基三苯甲基)-4′-C-甲氧基甲基胸苷3′-(2-氰基乙基-N,N-二异丙基氨基亚磷酸酯)。
实施例263′,5′-O-(双叔丁基二甲基甲硅烷基)-4′-C-叠氮基甲
基胸苷的制备
在0℃下向搅拌着的3′,5′-(双叔丁基二甲基甲硅烷基)-4′-C-羟基甲基胸苷(0.95g,0.19mmol)和吡啶(0.1ml)的无水二氯甲烷(1ml)溶液中滴加入三氟甲磺酸酐(107mg,0.38mmol,63μl)和吡啶(0.2ml)在二氯甲烷(2.5ml)中的混合物。反应混合物在0℃下搅拌30分钟,冷却至-10℃,加入0.5ml 10%碳酸氢钠,混合物用冷的二氯甲烷(10ml)稀释,用冷的10%碳酸氢钠(2×10ml)洗涤,干燥(硫酸钠),浓缩,在真空下干燥10分钟。将粗产物溶于无水DMF(1ml)中,加入叠氮化钠(50mg)。混合物在50℃下加热14小时,用乙酸乙酯(20mml)稀释,用水(5×10ml)洗涤,干燥(硫酸钠)并且浓缩。残余物通过硅胶色谱纯化(10%乙酸乙酯/二氯甲烷)得到42mg泡沫状的3′,5′-O-(双叔丁基二甲基甲硅烷基)-4′-C-叠氮基甲基胸苷。
实施例27
4′-C-叠氮基甲基胸苷的制备
将3′,5′-O-(双叔丁基二甲基甲硅烷基)-4′-C-叠氮基甲基胸苷(25ml)和TBAF(1.0M的THF溶液,0.5ml)的THF(1ml)溶液在室温下放置30分钟,蒸发溶剂,残余物通过硅胶色谱纯化(6%甲醇/二氯甲烷)得到11mg 4′-C-叠氮基甲基胸苷,为无色固体。
实施例283′-O-叔丁基二甲基甲硅烷基-5′-脱氧-5′-亚甲基胸苷的
制备
在65℃氮气氛下搅拌1.5小时后,氢化钠(60%矿物油液,2.88g,72mmol)的无水DMSO(100ml)悬浮液变成澄清溶液,冷却至室温,在氮气氛下转移到冷的搅拌着的溴化甲基三苯基鏻(27.0g,75.6mmol)的DMSO(20ml)悬浮液中。反应混合物在室温下搅拌45分钟,在冷却下加入3′-O-叔丁基二甲基甲硅烷基-5′-甲酰基胸苷(8.50g,24mmol)的DMSO(40ml)溶液,反应混合物在室温下搅拌2小时,用乙酸乙酯(2L)稀释,用盐水洗涤(5×800ml),干燥(硫酸钠),浓缩。粗产物通过硅胶色谱纯化(EtOAc-己烷,30∶70)得到6.79g(80.2%)无色固体的3′-O-叔丁基二甲基甲硅烷基-5′-脱氧-5′-亚甲基胸苷,m.p.122℃(用乙酸乙酯和己烷重结晶)。
实施例293′-O-叔丁基二甲基甲硅烷基-5′-C,O-亚甲基胸苷的制备
将3′-O-叔丁基二甲基甲硅烷基-5′-脱氧-5′-亚甲基胸苷(6.26g,17.78mmol)和间氯过苯甲酸(4.61g,26.68mmol)的二氯甲烷(160ml)溶液在室温下搅拌过夜,用二氯甲烷(200ml)稀释,用10%碳酸氢钠(2×240ml)和盐水(160ml)依次洗涤,干燥(硫酸钠)并且浓缩。残余物通过硅胶色谱纯化(EtOAc-己烷,1∶2)得到完整的起始原料(2.25g,35.9%),3′-O-叔丁基二甲基甲硅烷基-5′-(S)-C,O-亚甲基胸苷(3.2g,76%)和3′-O-叔丁基二甲基甲硅烷基-5′-(R)-C,O-亚甲基胸苷(0.365g,8%)。
实施例303′-O-叔丁基二甲基甲硅烷基-5′-C-甲氧基甲基胸苷的制备
将3′-O-叔丁基二甲基甲硅烷基-5′-(R)-C,O-亚甲基胸苷(1.84g,5mmol)和无水碳酸钾(1.38g,10mmol)的甲醇溶液在室温下搅拌90小时,加入乙酸乙酯(70ml),用乙酸中和混合物至pH=7,蒸发溶剂,残余物溶于二氯甲烷(30ml)中,过滤沉淀,浓缩溶液,残余物通过硅胶色谱纯化(EtOAc-己烷,1∶1)得到310mg完整的起始原料和578mg 3′-O-叔丁基二甲基甲硅烷基-5′-C-甲氧基甲基胸苷,为无色固体。
实施例313′-O-叔丁基二甲基甲硅烷基-5′-C-三氟乙酰氨基甲基胸苷
的制备
将3′-O-叔丁基二甲基甲硅烷基-5′-(R)-C,O-亚甲基胸苷(0.84g,2.28mmol)的甲醇液与氨饱和的甲醇溶液(10ml)混合,所得的溶液在室温下放置15小时,然后蒸发过量的氨和甲醇。将干燥的残余物溶于二噁烷(10ml)中,加入硫代三氟乙酸乙酯(1.80g,11.4mmol,1.46ml)。反应混合物在室温下搅拌6小时,然后蒸发溶剂,残余物通过硅胶色谱纯化(EtOAc-己烷,1∶1)得到895mg(81.8%)3′-O-叔丁基二甲基甲硅烷基-5′-C-三氟乙酰氨基甲基胸苷,为无色固体。
实施例323′-O-叔丁基二甲基甲硅烷基-5′-(S)-C-氰基甲基胸苷
的制备
将3′-O-叔丁基二甲基甲硅烷基-5′-(R)-C,O-亚甲基胸苷(0.77g,2.09mmol)和氰化钾(520mg,8.0mmol)在DMF(10ml)的混合物在室温下搅拌40小时,用乙酸乙酯(100ml)稀释,用盐水(5×60ml)洗涤,干燥(硫酸钠)并且浓缩。粗品通过硅胶色谱纯化(EtOAc-己烷,1∶1)得到3′-O-叔丁基二甲基甲硅烷基-5′-(S)-C-氰基甲基胸苷(580mg,70%),为白色固体。
实施例333′-O-叔丁基二甲基甲硅烷基-5′-(S)-C-叠氮基甲基胸
苷的制备
将3′-O-叔丁基二甲基甲硅烷基-5′-(R)-C,O-亚甲基胸苷(368mg,1.0mmol)和氰化钾(325mg,5.0mmol)在DMF(3ml)的混合物在50℃下加热16小时,用乙酸乙酯(60ml)稀释,用盐水(5×40ml)洗涤,干燥(硫酸钠)并且浓缩。粗品通过硅胶色谱纯化(EtOAc-己烷,1∶1)得到3′-O-叔丁基二甲基甲硅烷基-5′-(S)-C-氰基甲基胸苷(173mg,42%),为白色固体。
实施例343′-O-叔丁基二甲基甲硅烷基-5′-C-烯丙基胸苷的制备
在-5℃氩气氛下向无水氰化亚铜(7.57g,84.7mmol)的无水THF悬浮液中滴加入溴化烯丙基镁(2.0M的THF溶液,46.6ml,93.2mmol)。浆状液在-5℃下搅拌15分钟,滴加入冷的3′-O-叔丁基二甲基甲硅烷基-5′-甲酰基胸苷(5.0g,14.12mmol)的THF(200ml)溶液,反应混合物在室温下搅拌6小时,在0℃下加入10%碳酸氢钠(150ml)中止反应,用乙酸乙酯(200ml)稀释,有机层用10%碳酸氢钠(2×150ml)洗涤,干燥(硫酸钠)并且浓缩得到5.18g粗产物3′-O-叔丁基二甲基甲硅烷基-5′-C-烯丙基胸苷(含有两种5′-(R)和5′-(S)-异构体)。用15%EtOAc的CHCl3通过硅胶色谱分离两种异构体(比例:大约1∶1)。
实施例353′-O-叔丁基二甲基甲硅烷基-5′-O-(4,4′-二甲氧基
三苯甲基)-5′-(S)-C-甲氧基甲基胸苷的制备
将3′-O-叔丁基二甲基甲硅烷基-5′-C-甲氧基甲基胸苷(258mg,0.645mmol),二甲氧基三苯甲基氯(1.09g,3.22mmol)和三氟甲磺酸酐(835mg,3.22mmol)在无水吡啶(3ml)中的混合物在50℃下加热18小时,蒸发吡啶,残余物通过硅胶色谱纯化(EtOAc-己烷,1∶1)得到372mg(82%)3′-O-叔丁基二甲基甲硅烷基-5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-甲氧基甲基胸苷,为白色固体。
相似地,制备下列化合物:
由3′-O-叔丁基二甲基甲硅烷基-5′-(S)-C-氰基甲基胸苷制备3-O-叔丁基二甲基甲硅烷基-5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-氰基甲基胸苷;
由3′-O-叔丁基二甲基甲硅烷基-5′-(S)-C-叠氮基甲基胸苷制备3′-O-叔丁基二甲基甲硅烷基-5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-叠氮基甲基胸苷;
由3′-O-叔丁基二甲基甲硅烷基-5′-(S)-C-烯丙基胸苷制备3′-O-叔丁基二甲基甲硅烷基-5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-烯丙基胸苷;
由3′-O-叔丁基二甲基甲硅烷基-5′-(R)-C-烯丙基胸苷制备3′-O-叔丁基二甲基甲硅烷基-5′-O-(4,4′-二甲氧基三苯甲基)-5′-(R)-C-烯丙基胸苷;
由3′-O-叔丁基二甲基甲硅烷基-5′-(S)-C-三氟乙酰氨基甲基胸苷制备3′-O-叔丁基二甲基甲硅烷基-5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-三氟乙酰氨基甲基胸苷。
实施例365′-O-(4、4′-二甲氧基三苯甲基)-5′-(S)-C-甲
氧基甲基胸苷的制备
将3′-O-叔丁基二甲基甲硅烷基-5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-甲氧基甲基胸苷(825mg,1.17mmol)和TBAF(1.0M的THF溶液,3.6ml,3.6mmol)的THF(15ml)溶液在室温下搅拌2小时,蒸发THF,残余物通过硅胶色谱纯化(EtOAc-己烷,3∶2)得到551mg(80%)5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-甲氧基甲基胸苷。
相似地,制备下列化合物:
由3′-O-叔丁基二甲基甲硅烷基-5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-氰基甲基胸苷制备5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-氰基甲基胸苷。
由3′-O-叔丁基二甲基甲硅烷基-5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-叠氮基甲基胸苷制备5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-叠氮基甲基胸苷。
由3′-O-叔丁基二甲基甲硅烷基-5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-烯丙基胸苷制备5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-烯丙基胸苷。
由3′-O-叔丁基二甲基甲硅烷基-5′-O-(4,4′-二甲氧基三苯甲基)-5′-(R)-C-烯丙基甲基胸苷制备5′-O-(4,4′-二甲氧基三苯甲基)-5′-(R)-C-烯丙基胸苷。
由3′-O-叔丁基二甲基甲硅烷基-5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-三氟乙酰氨基甲基胸苷制备5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-三氟乙酰氨基甲基胸苷。
实施例375′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-甲氧基甲基胸苷3′-(2-氰基乙基-N,N-二异丙基氨基亚磷酸酯)
的制备
在0℃氮气氛下向3′-O-叔丁基二甲基甲硅烷基-5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-甲氧基甲基胸苷(490mg,0.83mmol)、二异丙基乙基胺(646mg,0.87ml,5.0mmol)的无水二氯甲烷(5ml)溶液中滴加入2-氰基乙基-N,N-二异丙基氯代氨基亚磷酸酯(592mg;2.5mmol,558μl)的二氯甲烷(1ml)溶液,溶液在室温下搅拌40分钟,冷却至0℃,用二氯甲烷(60ml)稀释,用冷的5%碳酸氢钠洗涤(3×40ml),干燥(硫酸钠)并且浓缩,残余物通过硅胶色谱纯化(Et3N-EtOAc-己烷,5∶45∶50)得到584mg(89%)泡沫状的5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-甲氧基甲基胸苷3′-(2-氰基乙基-N,N-二异丙基氨基亚磷酸酯)。
相似地,制备下列化合物:
由5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-氰基甲基胸苷制备5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-氰基甲基胸苷3′-(2-氰基乙基-N,N-二异丙基氨基亚磷酸酯)。
由5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-叠氮基甲基胸苷制备5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-叠氮基甲基胸苷3′-(2-氰基乙基-N,N-二异丙基氨基亚磷酸酯)。
由5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-烯丙基胸苷制备5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-烯丙基胸苷3′-(2-氰基乙基-N,N-二异丙基氨基亚磷酸酯)。
由5′-O-(4,4′-二甲氧基三苯甲基)-5′-(R)-C-烯丙基胸苷制备5′-O-(4,4′-二甲氧基三苯甲基)-5′-(R)-C-烯丙基胸苷3′-(2-氰基乙基-N,N-二异丙基氨基亚磷酸酯)。
由5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-三氟乙酰氨基甲基胸苷制备5′-O-(4,4′-二甲氧基三苯甲基)-5′-(S)-C-三氟乙酰氨基甲基胸苷3′-(2-氰基乙基-N,N-二异丙基氨基亚磷酸酯)。
实施例381′-氰基-3′-叔丁基二甲基甲硅烷基-5′-(4,4′-二甲氧
基三苯甲基)胸苷的制备
在0℃下将1′-氰基-5′-(4,4′-二甲氧基三苯甲基)胸苷的无水吡啶液加入到搅拌着的叔丁基二甲基氯甲硅烷(1.5当量)和咪唑(3.0当量)的无水吡啶溶液中,所得的反应混合物在室温下搅拌过夜,蒸发吡啶,残余物溶于乙酸乙酯中,用盐水洗涤,粗产物直接用于下一步反应。
实施例393′-叔丁基二甲基甲硅烷基-5′-二甲氧基三苯甲基-1′-甲酰基
-5-甲氧基苄基胸苷的制备
在-20℃氮气氛下将3′-叔丁基二甲基甲硅烷基-1′-氰基-5′-二甲氧基三苯甲基-5-(对甲氧基苄基)胸苷(1.0mmol)的THF溶液加入到搅拌着的三乙氧基氢化铝锂(2.0mmol)在THF溶液中,反应混合物在5-10℃下搅拌1小时,用氯化铵水溶液中止反应,混合物用乙酸乙酯萃取,粗产物用硅胶色谱纯化。
实施例40
1′-酰氨基-3′,5′,5-三(甲氧基苄基)胸苷的制备
在0℃下将1′-酰氨基-3′,5′,5-三(甲氧基苄基)胸苷加入到搅拌着的30%过氧化氢和碳酸钠的水溶液中,反应混合物在室温下搅拌2小时,用水洗涤,用稀盐酸中和,用二氯甲烷萃取,粗产物通过色谱纯化。
实施例41
1′-氨基-3′,5′,5-三(甲氧基苄基)胸苷的制备
制备方法与在文献(Radhakrishna,A.S.,Parham,M.E.,Riggs,R.M.,和Loudon,G.M.J.Org.Chem.1979,44,1746)中描述的相似。在0℃下将1′-氰基-3′,5′,5-三(甲氧基苄基)胸苷(1.0mmol)的无水THF溶液加入到搅拌着的I,I-双(三氟乙酰氧基碘苯)(2.0mmol)的THF溶液中,反应混合物在室温下搅拌5小时,用二氯甲烷稀释,用5%碳酸钠和盐水洗涤,粗产物通过色谱纯化。
实施例42三甲基-3′,5′,5-三(甲氧基苄基)胸苷-1′-基溴化铵的
制备
在0℃下将1′-氨基-3′,5′,5-三(甲氧基苄基)胸苷加入到搅拌着的甲基溴(10当量)的THF溶液中,反应混合物在50℃下搅拌过夜,蒸发溶剂,粗产物通过重结晶纯化。
实施例43
1′-溴-3′,5′,5-三(甲氧基苄基)胸苷的制备
制备方法类似于文献(Deady,L.W.,Korytsky,O.L.TetrahedronLett.1979,451)所描述的方法。将三甲基-3′,5′,5-三(甲氧基苄基)胸苷-1-基溴化铵在150℃真空下加热过夜,所得的产物直接用于下一步反应。
实施例44
1′-乙氧基-3′,5′,5-三(甲氧基苄基)胸苷的制备
在-10℃下将1′-溴-3′,5′,5-三(甲氧基苄基)胸苷的乙醇溶液加入到搅拌着的乙醇钠的乙醇溶液中,所得的反应混合物在室温下搅拌1小时,用稀盐酸中和,蒸发乙醇,剩余的混合物用乙酸乙酯萃取,粗产物通过色谱纯化得到α和β非对映异构体的混合物。
类似地,制备下列化合物:
由1′-溴-3′,5′,5-三(甲氧基苄基)胸苷和4-硝基丁醇-1制备1′-(4-硝基丁氧基)-3′,5′,5-三(甲氧基苄基)胸苷。
由1′-溴-3′,5′,5-三(甲氧基苄基)胸苷和硫代乙醇钠制备1′-乙硫基-3′,5′,5-三(甲氧基苄基)胸苷。
实施例45
1′-氨基胸苷的制备
将1′-氨基-3′,5′,5-三(甲氧基苄基)胸苷和10%钯/炭在乙醇中的悬浮液在氢化装置中在氢气压50psi下振荡24小时,过滤出固体,滤液浓缩,粗产物通过重结晶纯化。
实施例46
糖修饰的低聚核苷酸的制备
本实施例说明化合物55(图8)用于合成具有如下序列的无规低聚核苷酸的合成:
5′-d(ATC TCT CCG CTT CCT*TT*C)-3′在此序列中A,C,G和T表示未修饰的脱氧核糖核酸和T*表示5′-C-氨基甲基胸苷。在本实施例中低聚核苷酸通过ABI394DNA合成器合成。通过使用氨基亚磷酸酯化学引入所有核苷酸。通过使用常规DNA合成试剂和常规方法引入dA,dC,dG和T。由于在胸苷的C5′位上的支链取代基的空间位阻,T*的引入需要较长的偶合时间(5分钟)。合成后,按常规方法对合成的低聚核苷酸进行后处理。通过反相C18柱在Beckman HPLC上使用TEAA缓冲剂(pH7.0)和乙腈作为流动相纯化粗的低聚核苷酸,得到62.4ODs的纯化的低聚核苷酸。
类似地,合成了下列无规糖修饰的低聚核苷酸:5′-C-支链的糖修饰的低聚核苷酸:
1. 5′-TTCCTGTCTGATGGCTTC-3′
2. 5′-XXCCTGTCTGATGGCTTC-3′
3. 5′-TTCCTGTCXGATGGCTTC-3′
4. 5′-ATCTCTCCGCTTCCTTTC-3′
5. 5′-ATCTCTCCGCTTCCTTXC-3′
6. 5′-ATCTCTCCGCTTCCTXXC-3′
7. 5′-ATCTCXCCGCTXCCTTTC-3′
8. 5′-ATCTCTCCGCTTCCTTYC-3′
9. 5′-ATCTCTCCGCTTCCTYYC-3′
10. 5′-ATCTCTCCGCTTCCYTYC-3′
11. 5′-AYCTCYCCGCTYCCTTYC-3′
12. 5′-ATCTCTCCGCTTCCTTZC-3′
13. 5′-ATCTCTCCGCTTCCTZZC-3
14. 5′-ATCTCTCCGCTTCCZTZC-3′
15. 5′-ATCTCTCCGCTTCCTTVC-3′
16. 5′-ATCTCTCCGCTTCCTVVC-3′
17. 5′-ATCTCTCCGCTTCCVTVC-3′
18. 5′-ATCTCVCCGCVTCCTTTC-3′
19. 5′-AVCTCTCCGCTTCCTTTC-3′
20. 5′-ATCTCTCCGCTTCCTTWC-3′
21. 5′-ATCTCTCCGCTTCCTWWC-3′
22. 5′-ATCTCTCCGCTTCCWTWC-3′
23. 5′-ATCTCWCCGCWTCCTTTC-3′
24. 5′-AWCTCTCCGCTTCCTTTC-3′X=5′-(S)-C-甲氧基甲基胸苷,Y=5′-(S)-C-氨基甲基胸苷,Z=5′-(S)-C-氰基甲基胸苷,V=5′-(S)-C-烯丙基胸苷和W=5-(R)-C-烯丙基胸苷。4′-C-支链的糖修饰的低聚核苷酸:
25. 5′-ATCTCTCCGCTTCCTTTC-3′
26. 5′-ATCTCTCCGCTTCCTTXC-3′
27. 5′-ATCTCTCCGCTTCCTXXC-3′
28. 5′-ATCTCTCCGCTTCCXTXC-3′
29. 5′-AXCTCTCCGCTTCCTTTC-3′
30. 5′-ATCTCXCCGCTXCCTTTC-3′
31. 5′-ATCTCTCCGCTTCCTTYC-3′
32. 5′-ATCTCTCCGCTTCCTYXC-3′
33. 5′-ATCTCTCCGCTTCCYTXC-3′
34. 5′-AYCTCTCCGCTTCCXTXC-3′
35. 5′-ATCTCYCCGCTYCCTTTC-3′X=4′-C-甲氧基甲基胸苷,Y=4′-C-氨基甲基胸苷。3′-C-支链的糖修饰的低聚核苷酸:
36. 5′-ATCTCTCCGCTTCCTTTC-3′
37. 5′-ATCTCTCCGCTTCCTTXC-3′
38. 5′-ATCTCTCCGCTTCCTXXC-3′
39. 5′-ATCTCTCCGCTTCCXTXC-3′
40. 5′-ATCTCTCCGCXTCCTTTC-3′
41. 5′-AXCTCTCCGCTTCCTTTC-3′
42. 5′-ATCTCTCCGCTTCCTTYC-3′
43. 5′-ATCTCTCCGCTTCCTYYC-3′
44. 5′-ATCTCTCCGCYTCCTTTC-3′
45. 5′-AYCTCTCCGCTTCCXTXC-3′
46. 5′-ATCTCYCCGCTYCCTTTC-3′
47. 5′-ATCTCTCCGCTTCCTTZC-3′
48. 5′-ATCTCTCCGCTTCCTZZC-3′
49. 5′-ATCTCTCCGCTTCCZTZC-3′X=3-C-氨基甲基胸苷,Y=3′-C-甲基胸苷,Z=3′-C-氰基甲基胸苷。
所引用的参考文献
本文所列出的所有的专利,专利申请和出版物在此引入作为参考。
等同物
上面所写的说明书被认为足以使本领域技术人员实施本发明。实际上,对于有机化学领域和相关领域的技术人员来说显而易见的上述本发明的各种改进都将要包括在下列权利要求书的范围内。
Claims (54)
2.权利要求1的化合物,其中R1选自氰基烷基,氰基芳基和氰基芳烷基。
3.权利要求1的化合物,其中R1选自硝基烷基,硝基芳基和硝基芳烷基。
4.权利要求1的化合物,其中R1为式X1X2NR的氨基衍生基团,其中X1选自H,甲基,乙基,Ac和CF3CO;X2选自H,甲基,乙基,Ac和CF3CO;和R为接头,它可为烷基,芳烷基或芳基。
5.权利要求1的化合物,其中R1选自羟基烷基,羟基芳基和羟基芳烷基,其中任一烷基部分为C2-C8。
6.权利要求1的化合物,其中R1选自烷氧基烷基,烷氧基芳烷基,芳氧基烷基,芳氧基芳烷基,芳烷氧基烷基,芳烷氧基芳烷基和芳氧基。
7.权利要求1的化合物,其中R1为XSR,这里的X选自H,Ac,CF3CO,烷基,芳基和芳烷基;R为接头,它可为烷基,芳烷基或芳基。
8.权利要求1的化合物,其中R1为式X1X2NCOR的酰胺衍生基团,这里的X1为H或烷基;X2为H或烷基;R为接头,它可为烷基,芳烷基或芳基。
9.权利要求1的化合物,其中R1为XOOCR,这里的X选自H,烷基,芳烷基和芳基;R为接头,它可为烷基,芳烷基或芳基。
10.权利要求1的化合物,其中R1为XR,这里的X选自F,Cl,Br,I,OTs,N3;R为接头,它可为烷基,芳烷基或芳基。
11.权利要求1的化合物,其中R1选自烷基,芳烷基,芳基,链烯基,芳链烯基,其中的任一烷基部分为C2-C10直链或支链烷基,任一链烯基部分为C2-C10直链或支链烯基,并且,任一芳基部分为苯基或杂环基。
12.权利要求1的化合物,其中R1选自CN,NO2,N3和CF3。
14.权利要求13的化合物,其中R1选自氰基烷基,氰基芳基和氰基芳烷基。
15.权利要求13的化合物,其中R1选自硝基烷基,硝基芳基和硝基芳烷基。
16.权利要求13的化合物,其中R1为式X1X2NR的氨基衍生基团,其中X1选自H,甲基,乙基,Ac和CF3CO;X2选自H,甲基,乙基,Ac和CF3CO;和R为接头,它可为烷基,芳烷基或芳基。
17.权利要求13的化合物,其中R1选自羟基烷基,羟基芳基和羟基芳烷基,其中任一烷基部分为C1-C8。
18.权利要求13的化合物,其中R1选自烷氧基烷基,烷氧基芳烷基,芳氧基烷基,芳氧基芳烷基,芳烷氧基烷基,芳烷氧基芳烷基和芳氧基。
19.权利要求13的化合物,其中R1为XSR,这里的X选自H,Ac,CF3CO,烷基,芳基和芳烷基;R为接头,它可为烷基,芳烷基或芳基。
20.权利要求13的化合物,其中R1为式X1X2NCOR的酰胺衍生基团,这里的X1为H或烷基;X2为H或烷基;R为接头,它可为烷基,芳烷基或芳基。
21.权利要求13的化合物,其中R1为XOOCR,这里的X选自H,烷基,芳烷基和芳基;R为接头,它可为烷基,芳烷基或芳基。
22.权利要求13的化合物,其中R1为XR,这里的X选自F,Cl,Br,I,OTs,N3;R为接头,它可为烷基,芳烷基或芳基。
23.权利要求13的化合物,其中R1选自烷基,芳烷基,芳基,链烯基,芳链烯基,其中的任一烷基部分为C2-C10直链或支链烷基,任一链烯基部分为C2-C10直链或支链烯基,任一芳基部分为苯基或杂环基。
24.权利要求13的化合物,其中R1选自CN,NO2,N3和CF3。
26.权利要求25的化合物,其中R1选自氰基烷基,氰基芳基和氰基芳烷基。
27.权利要求25的化合物,其中R1选自硝基烷基,硝基芳基和硝基芳烷基。
28.权利要求25的化合物,其中R1为式X1X2NR的氨基衍生基团,其中X1选自H,甲基,乙基,Ac和CF3CO;X2选自H,甲基,乙基,Ac和CF3CO;和R为接头,它可为烷基,芳烷基或芳基。
29.权利要求25的化合物,其中R1选自羟基烷基,羟基芳基和羟基芳烷基,其中任一烷基部分为C2-C8。
30.权利要求25的化合物,其中R1选自烷氧基烷基,烷氧基芳烷基,芳氧基烷基,芳氧基芳烷基,芳烷氧基烷基,芳烷氧基芳烷基和芳氧基。
31.权利要求25的化合物,其中R1为XSR,这里的X选自H,Ac,CF3CO,烷基,芳基和芳烷基;R为接头,它可为烷基,芳烷基或芳基。
32.权利要求25的化合物,其中R1为式X1X2NCOR的酰胺衍生基团,这里的X1为H或烷基;X2为H或烷基;R为接头,它可为烷基,芳烷基或芳基。
33.权利要求25的化合物,其中R1为XOOCR,这里的X选自H,烷基,芳烷基和芳基;R为接头,它可为烷基,芳烷基或芳基。
34.权利要求25的化合物,其中R1为XR,这里的X选自F,Cl,Br,I,OTs,N3;R为接头,它可为烷基,芳烷基或芳基。
35.权利要求25的化合物,其中R1选自烷基,芳烷基,芳基,链烯基,芳链烯基,其中的任一烷基部分为C1-C10直链或支链烷基,任一链烯基部分为C2-C10直链或支链烯基,任一芳基部分为苯基或杂环基。
36.权利要求25的化合物,其中R1选自NO2和CF3。
38.权利要求37的化合物,其中R1选自氰基烷基,氰基芳基和氰基芳烷基。
39.权利要求37的化合物,其中R1选自硝基烷基,硝基芳基和硝基芳烷基。
40.权利要求37的化合物,其中R1为式X1X2NR的氨基衍生基团,其中X1选自H,甲基,乙基,Ac和CF3CO;X2选自H,甲基,乙基,Ac和CF3CO;和R为接头,它可为烷基,芳烷基或芳基。
41.权利要求37的化合物,其中R1选自羟基烷基,羟基芳基和羟基芳烷基,其中任一烷基部分为C2-C8。
42.权利要求37的化合物,其中R1选自烷氧基烷基,烷氧基芳烷基,芳氧基烷基,芳氧基芳烷基,芳烷氧基烷基,芳烷氧基芳烷基和芳氧基。
43.权利要求37的化合物,其中R1为XSR,这里的X选自H,Ac,CF3CO,烷基,芳基和芳烷基;R为接头,它可为烷基,芳烷基或芳基。
44.权利要求37的化合物,其中R1为式X1X2NCOR的酰胺衍生基团,这里的X1为H或烷基;X2为H或烷基;R为接头,它可为烷基,芳烷基或芳基。
45.权利要求37的化合物,其中R1为XOOCR,这里的X选自H,烷基,芳烷基和芳基;R为接头,它可为烷基,芳烷基或芳基。
46.权利要求37的化合物,其中R1为XR,这里的X选自F,Cl,Br,I,OTs,N3;R为接头,它可为烷基,芳烷基或芳基。
47.权利要求37的化合物,其中R1选自烷基,芳烷基,芳基,链烯基,芳链烯基,其中的任一烷基部分为C1-C10直链或支链烷基,任一链烯基部分为C2-C10直链或支链烯基,任一芳基部分为苯基或杂环基。
48.权利要求37的化合物,其中R1选自NO2、N3和CF3。
51.包含至少2个核苷酸亚单位的多核苷酸,其中至少一个核苷酸亚单位为权利要求1的化合物。
52.包含至少2个核苷酸亚单位的多核苷酸,其中至少一个核苷酸亚单位为权利要求13的化合物。
53.包含至少2个核苷酸亚单位的多核苷酸,其中至少一个核苷酸亚单位为权利要求25的化合物。
54.包含至少2个核苷酸亚单位的多核苷酸,其中至少一个核苷酸亚单位为权利要求37的化合物。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102421293A (zh) * | 2009-03-20 | 2012-04-18 | 艾丽奥斯生物制药有限公司 | 取代的核苷和核苷酸类似物 |
CN101460619B (zh) * | 2006-06-06 | 2012-07-25 | 松下电器产业株式会社 | 核苷酸链的修饰方法 |
Families Citing this family (110)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6743902B1 (en) * | 1994-11-02 | 2004-06-01 | Valeant Pharmaceuticals International | Sugar modified nucleosides |
KR0177372B1 (ko) * | 1994-12-13 | 1999-04-01 | 아키라 마츠다 | 3'-치환 뉴클레오시드 유도체 |
US20040161844A1 (en) * | 1996-06-06 | 2004-08-19 | Baker Brenda F. | Sugar and backbone-surrogate-containing oligomeric compounds and compositions for use in gene modulation |
US5898031A (en) * | 1996-06-06 | 1999-04-27 | Isis Pharmaceuticals, Inc. | Oligoribonucleotides for cleaving RNA |
US20040161777A1 (en) * | 1996-06-06 | 2004-08-19 | Baker Brenda F. | Modified oligonucleotides for use in RNA interference |
US9096636B2 (en) * | 1996-06-06 | 2015-08-04 | Isis Pharmaceuticals, Inc. | Chimeric oligomeric compounds and their use in gene modulation |
US20040171032A1 (en) * | 1996-06-06 | 2004-09-02 | Baker Brenda F. | Non-phosphorous-linked oligomeric compounds and their use in gene modulation |
US20050118605A9 (en) * | 1996-06-06 | 2005-06-02 | Baker Brenda F. | Oligomeric compounds having modified bases for binding to adenine and guanine and their use in gene modulation |
US7812149B2 (en) | 1996-06-06 | 2010-10-12 | Isis Pharmaceuticals, Inc. | 2′-Fluoro substituted oligomeric compounds and compositions for use in gene modulations |
US20040171030A1 (en) * | 1996-06-06 | 2004-09-02 | Baker Brenda F. | Oligomeric compounds having modified bases for binding to cytosine and uracil or thymine and their use in gene modulation |
US6210707B1 (en) * | 1996-11-12 | 2001-04-03 | The Regents Of The University Of California | Methods of forming protein-linked lipidic microparticles, and compositions thereof |
US6127533A (en) * | 1997-02-14 | 2000-10-03 | Isis Pharmaceuticals, Inc. | 2'-O-aminooxy-modified oligonucleotides |
US6576752B1 (en) | 1997-02-14 | 2003-06-10 | Isis Pharmaceuticals, Inc. | Aminooxy functionalized oligomers |
US6172209B1 (en) | 1997-02-14 | 2001-01-09 | Isis Pharmaceuticals Inc. | Aminooxy-modified oligonucleotides and methods for making same |
GB9711040D0 (en) * | 1997-05-29 | 1997-07-23 | Duff Gordon W | Prediction of inflammatory disease |
US20050282198A1 (en) * | 1997-05-29 | 2005-12-22 | Interleukin Genetics, Inc. | Diagnostics and therapeutics for diseases associated with an IL-1 inflammatory haplotype |
CN1273476C (zh) | 1997-09-12 | 2006-09-06 | 埃克西康有限公司 | 寡核苷酸类似物 |
US6965041B1 (en) | 1999-03-24 | 2005-11-15 | The United States Of America As Represented By The Department Of Health And Human Services | N-acylphosphoramidites and their use in oligonucleotide synthesis |
US6900186B1 (en) * | 1999-06-21 | 2005-05-31 | Murdock Children's Research Institute | Method for the prophylaxis and/or treatment of medical disorders |
US20020142982A1 (en) * | 1999-09-02 | 2002-10-03 | Timothy Hla | Method for regulating angiogenesis |
CN1446258B (zh) * | 2000-05-26 | 2013-01-09 | 艾文蒂斯药品公司 | 用固定化的寡核苷酸纯化三股螺旋体结构 |
GB0013276D0 (en) * | 2000-06-01 | 2000-07-26 | Amersham Pharm Biotech Uk Ltd | Nucleotide analogues |
US6936702B2 (en) * | 2000-06-07 | 2005-08-30 | Li-Cor, Inc. | Charge-switch nucleotides |
EP1287154A4 (en) | 2000-06-07 | 2010-12-15 | Pacific Biosciences California | NUCLEOTIDES WITH CHARGE SWITCHING |
US6869764B2 (en) | 2000-06-07 | 2005-03-22 | L--Cor, Inc. | Nucleic acid sequencing using charge-switch nucleotides |
AU2002226687B9 (en) | 2001-01-26 | 2005-10-20 | Btg International Limited | Benzylamine analogue |
WO2002086088A2 (en) * | 2001-04-24 | 2002-10-31 | Li-Cor, Inc. | Polymerases with charge-switch activity and methods of generating such polymerases |
US7118907B2 (en) * | 2001-06-06 | 2006-10-10 | Li-Cor, Inc. | Single molecule detection systems and methods |
GB0114286D0 (en) * | 2001-06-12 | 2001-08-01 | Hoffmann La Roche | Nucleoside Derivatives |
JP2005536440A (ja) * | 2001-09-28 | 2005-12-02 | イデニクス(ケイマン)リミテツド | 4’位が修飾されたヌクレオシドを使用するフラビウイルスおよびペスチウイルスの治療のための方法および組成物 |
US7138376B2 (en) * | 2001-09-28 | 2006-11-21 | Idenix Pharmaceuticals, Inc. | Methods and compositions for treating hepatitis C virus using 4'-modified nucleosides |
US20080311581A1 (en) * | 2001-11-19 | 2008-12-18 | David Wyllie | Functional polymorphisms of the interleukin-1 locus affecting transcription and susceptibility to inflammatory and infectious diseases |
WO2003048179A2 (en) * | 2001-12-03 | 2003-06-12 | The Government Of The United States Of America, Represented By The Secretary Of The Department Of Health And Human Services | Thermolabile hydroxyl protecting groups and methods of use |
GB0129012D0 (en) | 2001-12-04 | 2002-01-23 | Solexa Ltd | Labelled nucleotides |
US11008359B2 (en) | 2002-08-23 | 2021-05-18 | Illumina Cambridge Limited | Labelled nucleotides |
US7414116B2 (en) | 2002-08-23 | 2008-08-19 | Illumina Cambridge Limited | Labelled nucleotides |
EP2607369B1 (en) | 2002-08-23 | 2015-09-23 | Illumina Cambridge Limited | Modified nucleotides for polynucleotide sequencing |
AU2003291755A1 (en) | 2002-11-05 | 2004-06-07 | Isis Pharmaceuticals, Inc. | Oligomers comprising modified bases for binding cytosine and uracil or thymine and their use |
US9150605B2 (en) * | 2002-11-05 | 2015-10-06 | Isis Pharmaceuticals, Inc. | Compositions comprising alternating 2′-modified nucleosides for use in gene modulation |
US9150606B2 (en) | 2002-11-05 | 2015-10-06 | Isis Pharmaceuticals, Inc. | Compositions comprising alternating 2'-modified nucleosides for use in gene modulation |
CA2504694C (en) * | 2002-11-05 | 2013-10-01 | Isis Pharmaceuticals, Inc. | Polycyclic sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation |
EP1625140A4 (en) * | 2002-12-23 | 2008-06-18 | Dynavax Tech Corp | BRANCHED IMMUNOMODULAR COMPOUNDS AND METHOD OF USE THEREOF |
US8569474B2 (en) | 2004-03-09 | 2013-10-29 | Isis Pharmaceuticals, Inc. | Double stranded constructs comprising one or more short strands hybridized to a longer strand |
US8394947B2 (en) | 2004-06-03 | 2013-03-12 | Isis Pharmaceuticals, Inc. | Positionally modified siRNA constructs |
US7884086B2 (en) | 2004-09-08 | 2011-02-08 | Isis Pharmaceuticals, Inc. | Conjugates for use in hepatocyte free uptake assays |
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 |
DK1888748T3 (da) * | 2005-05-25 | 2013-11-18 | Tina Holding Aps | STABIL OG SELEKTIV DANNELSE AF HOOGSTEEN-TYPE TRIPLEX'er OG DUPLEX'er UNDER ANVENDELSE AF TWISTEDE INTERKALERENDE NUKLEINSYRER (TINA) OG FREMGANGSMÅDE TIL FREMSTILLINGEN AF TINA |
JP2009535383A (ja) | 2006-05-03 | 2009-10-01 | バルティック テクロノジー デヴェロプメント,リミテッド | 強く結合した塩基で修飾されたオリゴヌクレオチドと人工ヌクレアーゼを組み合わせたアンチセンス作用物質 |
SI2494993T1 (sl) | 2007-05-04 | 2019-01-31 | Marina Biotech, Inc. | Aminokislinski lipidi in njihove uporabe |
JP5697993B2 (ja) | 2008-02-11 | 2015-04-08 | アールエックスアイ ファーマシューティカルズ コーポレーション | 修飾RNAiポリヌクレオチドおよびその使用 |
US20100015708A1 (en) * | 2008-06-18 | 2010-01-21 | Mdrna, Inc. | Ribonucleic acids with non-standard bases and uses thereof |
US8815818B2 (en) | 2008-07-18 | 2014-08-26 | Rxi Pharmaceuticals Corporation | Phagocytic cell delivery of RNAI |
CA2753338A1 (en) | 2008-09-22 | 2010-03-25 | Rxi Pharmaceuticals Corporation | Neutral nanotransporters |
WO2010045512A2 (en) | 2008-10-16 | 2010-04-22 | Mdrna , Inc. | Processes and compositions for liposomal and efficient delivery of gene silencing therapeutics |
JP5763539B2 (ja) | 2008-10-24 | 2015-08-12 | 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 | 5’及び2’ビス置換ヌクレオシド及びそれから製造されるオリゴマー化合物 |
US8987435B2 (en) | 2008-10-24 | 2015-03-24 | Isis Pharmaceuticals, Inc. | Oligomeric compounds and methods |
WO2010059226A2 (en) | 2008-11-19 | 2010-05-27 | Rxi Pharmaceuticals Corporation | Inhibition of map4k4 through rnai |
AU2009323766B2 (en) | 2008-12-02 | 2016-10-06 | Wave Life Sciences Ltd. | Method for the synthesis of phosphorus atom modified nucleic acids |
WO2010078536A1 (en) | 2009-01-05 | 2010-07-08 | Rxi Pharmaceuticals Corporation | Inhibition of pcsk9 through rnai |
WO2010090762A1 (en) | 2009-02-04 | 2010-08-12 | Rxi Pharmaceuticals Corporation | Rna duplexes with single stranded phosphorothioate nucleotide regions for additional functionality |
SG177564A1 (en) | 2009-07-06 | 2012-02-28 | Ontorii Inc | Novel nucleic acid prodrugs and methods of use thereof |
EP2550001B1 (en) | 2010-03-24 | 2019-05-22 | Phio Pharmaceuticals Corp. | Rna interference in ocular indications |
EP3560503B1 (en) | 2010-03-24 | 2021-11-17 | Phio Pharmaceuticals Corp. | Rna interference in dermal and fibrotic indications |
US9080171B2 (en) | 2010-03-24 | 2015-07-14 | RXi Parmaceuticals Corporation | Reduced size self-delivering RNAi compounds |
US9127033B2 (en) | 2010-04-28 | 2015-09-08 | Isis Pharmaceuticals, Inc. | 5′ modified nucleosides and oligomeric compounds prepared therefrom |
EP3173419A1 (en) | 2010-04-28 | 2017-05-31 | Ionis Pharmaceuticals, Inc. | Modified nucleosides, analogs thereof and oligomeric compounds prepared therefrom |
US8871737B2 (en) | 2010-09-22 | 2014-10-28 | Alios Biopharma, Inc. | Substituted nucleotide analogs |
ES2701020T3 (es) | 2010-09-22 | 2019-02-20 | Alios Biopharma Inc | Nucleósidos azido y análogos nucleotídicos |
DK2620428T3 (da) | 2010-09-24 | 2019-07-01 | Wave Life Sciences Ltd | Asymmetrisk hjælpegruppe |
BR112014001244A2 (pt) | 2011-07-19 | 2017-02-21 | Wave Life Sciences Pte Ltd | métodos para a síntese de ácidos nucléicos funcionalizados |
EP2794627B1 (en) | 2011-12-22 | 2018-09-26 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
EP2794630A4 (en) | 2011-12-22 | 2015-04-01 | Alios Biopharma Inc | SUBSTITUTED PHOSPHORTHIOAT NUCLEOTIDE ANALOGUE |
US9441007B2 (en) | 2012-03-21 | 2016-09-13 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
WO2013142124A1 (en) | 2012-03-21 | 2013-09-26 | Vertex Pharmaceuticals Incorporated | Solid forms of a thiophosphoramidate nucleotide prodrug |
USRE48171E1 (en) | 2012-03-21 | 2020-08-25 | Janssen Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
US9012427B2 (en) | 2012-03-22 | 2015-04-21 | Alios Biopharma, Inc. | Pharmaceutical combinations comprising a thionucleotide analog |
EP3812370A1 (en) | 2012-07-13 | 2021-04-28 | Wave Life Sciences Ltd. | Asymmetric auxiliary group |
SG11201500243WA (en) | 2012-07-13 | 2015-04-29 | Shin Nippon Biomedical Lab Ltd | Chiral nucleic acid adjuvant |
KR102450907B1 (ko) | 2012-07-13 | 2022-10-04 | 웨이브 라이프 사이언시스 리미티드 | 키랄 제어 |
RU2730677C2 (ru) | 2012-10-15 | 2020-08-24 | Ионис Фармасьютикалз, Инк. | Соединение для модуляции экспрессии гена c9orf72 и его применение |
WO2014062736A1 (en) | 2012-10-15 | 2014-04-24 | Isis Pharmaceuticals, Inc. | Methods for monitoring c9orf72 expression |
WO2014069520A1 (ja) * | 2012-10-31 | 2014-05-08 | 武田薬品工業株式会社 | 新規修飾核酸 |
WO2014139596A1 (en) | 2013-03-15 | 2014-09-18 | Illumina Cambridge Limited | Modified nucleosides or nucleotides |
BR112015027321A8 (pt) | 2013-05-01 | 2018-01-02 | Isis Pharmaceuticals Inc | Compostos e composições para modular a expressão de apolipoproteína(a) e seus usos |
EP3715457A3 (en) | 2013-08-28 | 2020-12-16 | Ionis Pharmaceuticals, Inc. | Modulation of prekallikrein (pkk) expression |
AU2014331652B2 (en) | 2013-10-11 | 2020-05-21 | Ionis Pharmaceuticals, Inc. | Compositions for modulating C9ORF72 expression |
JP6772062B2 (ja) | 2013-12-02 | 2020-10-21 | フィオ ファーマシューティカルズ コーポレーションPhio Pharmaceuticals Corp. | 癌の免疫療法 |
WO2015106128A2 (en) * | 2014-01-09 | 2015-07-16 | Alnylam Pharmaceuticals, Inc. | MODIFIED RNAi AGENTS |
EP3095459A4 (en) | 2014-01-15 | 2017-08-23 | Shin Nippon Biomedical Laboratories, Ltd. | Chiral nucleic acid adjuvant having antitumor effect and antitumor agent |
JPWO2015108047A1 (ja) | 2014-01-15 | 2017-03-23 | 株式会社新日本科学 | 免疫誘導活性を有するキラル核酸アジュバンド及び免疫誘導活性剤 |
JPWO2015108046A1 (ja) | 2014-01-15 | 2017-03-23 | 株式会社新日本科学 | 抗アレルギー作用を有するキラル核酸アジュバンド及び抗アレルギー剤 |
EP4137572A1 (en) | 2014-01-16 | 2023-02-22 | Wave Life Sciences Ltd. | Chiral design |
EP3137119B1 (en) | 2014-04-28 | 2020-07-01 | Phio Pharmaceuticals Corp. | Methods for treating cancer using a nucleic acid targeting mdm2 |
MX2016014140A (es) | 2014-05-01 | 2017-09-15 | Ionis Pharmaceuticals Inc | Composiciones y metodos para modular la expresion de pkk. |
DK3137596T3 (da) * | 2014-05-01 | 2019-09-02 | Ionis Pharmaceuticals Inc | Sammensætninger og fremgangsmåder til modulation af komplement faktor b-ekspression |
CN104211741B (zh) * | 2014-09-05 | 2017-05-31 | 河南师范大学 | 一种氘代核苷亚磷酰胺单体的合成方法 |
WO2016037071A2 (en) | 2014-09-05 | 2016-03-10 | Rxi Pharmaceuticals Corporation | Methods for treating aging and skin disorders using nucleic acids targeting tyr or mmp1 |
PL3283080T3 (pl) | 2015-04-16 | 2020-07-27 | Ionis Pharmaceuticals, Inc. | Kompozycja do modulowania ekspresji c9orf72 |
US10808247B2 (en) | 2015-07-06 | 2020-10-20 | Phio Pharmaceuticals Corp. | Methods for treating neurological disorders using a synergistic small molecule and nucleic acids therapeutic approach |
US11001845B2 (en) | 2015-07-06 | 2021-05-11 | Phio Pharmaceuticals Corp. | Nucleic acid molecules targeting superoxide dismutase 1 (SOD1) |
US11021707B2 (en) | 2015-10-19 | 2021-06-01 | Phio Pharmaceuticals Corp. | Reduced size self-delivering nucleic acid compounds targeting long non-coding RNA |
WO2017079291A1 (en) | 2015-11-02 | 2017-05-11 | Ionis Pharmaceuticals, Inc. | Compounds and methods for modulating c90rf72 |
JP7016170B2 (ja) | 2016-12-16 | 2022-02-04 | 国立大学法人東海国立大学機構 | ヌクレオシド誘導体及びその利用 |
JP7231147B2 (ja) * | 2017-06-29 | 2023-03-01 | 国立大学法人東海国立大学機構 | Rna導入試薬及びその利用 |
JP7173467B2 (ja) * | 2017-10-31 | 2022-11-16 | ヤマサ醤油株式会社 | ヌクレオシド誘導体及びその利用 |
EP3770256A4 (en) * | 2018-03-20 | 2021-12-22 | Tokyo Institute of Technology | ANTISENSE OLIGONUCLEOTIDE WITH REDUCED TOXICITY |
AU2020256166A1 (en) | 2019-04-02 | 2021-10-14 | Aligos Therapeutics, Inc. | Compounds targeting PRMT5 |
TWI794742B (zh) | 2020-02-18 | 2023-03-01 | 美商基利科學股份有限公司 | 抗病毒化合物 |
EP4106876A1 (en) | 2020-02-18 | 2022-12-28 | Gilead Sciences, Inc. | Antiviral compounds |
CN117120444A (zh) | 2021-04-16 | 2023-11-24 | 吉利德科学公司 | 使用酰胺制备卡巴核苷的方法 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5190969A (en) * | 1988-12-20 | 1993-03-02 | The United States Of America As Represented By The Secretary Of The Department Of Health & Human Services | 2,3-epoxy derivatives as anti retrovital chemotherapeutic agents |
US5378825A (en) * | 1990-07-27 | 1995-01-03 | Isis Pharmaceuticals, Inc. | Backbone modified oligonucleotide analogs |
FR2687679B1 (fr) * | 1992-02-05 | 1994-10-28 | Centre Nat Rech Scient | Oligothionucleotides. |
HU9501994D0 (en) * | 1993-03-31 | 1995-09-28 | Sterling Winthrop Inc | Novel 5'-substituted nucleosides and oligomers produced therefrom |
US5446137B1 (en) * | 1993-12-09 | 1998-10-06 | Behringwerke Ag | Oligonucleotides containing 4'-substituted nucleotides |
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- 1994-11-02 US US08/333,545 patent/US5681940A/en not_active Expired - Lifetime
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- 1995-11-02 KR KR1019970702924A patent/KR100274331B1/ko not_active IP Right Cessation
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101460619B (zh) * | 2006-06-06 | 2012-07-25 | 松下电器产业株式会社 | 核苷酸链的修饰方法 |
CN102421293A (zh) * | 2009-03-20 | 2012-04-18 | 艾丽奥斯生物制药有限公司 | 取代的核苷和核苷酸类似物 |
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CA2307311A1 (en) | 1996-05-17 |
CN1122040C (zh) | 2003-09-24 |
AU690394B2 (en) | 1998-04-23 |
US5681940A (en) | 1997-10-28 |
CZ293731B6 (cs) | 2004-07-14 |
CA2202280C (en) | 2000-08-15 |
EP0789706A4 (en) | 1999-08-11 |
US5712378A (en) | 1998-01-27 |
KR100274331B1 (ko) | 2000-12-15 |
JP3633626B2 (ja) | 2005-03-30 |
WO1996014329A1 (en) | 1996-05-17 |
HK1007881A1 (en) | 1999-04-30 |
HUT77516A (hu) | 1998-05-28 |
CZ129197A3 (en) | 1997-10-15 |
PL184378B1 (pl) | 2002-10-31 |
CA2202280A1 (en) | 1996-05-17 |
UA45362C2 (uk) | 2002-04-15 |
SI9520113A (sl) | 1998-06-30 |
JPH10506915A (ja) | 1998-07-07 |
MX9703192A (es) | 1997-12-31 |
SK54897A3 (en) | 1997-09-10 |
AU4152596A (en) | 1996-05-31 |
US6191266B1 (en) | 2001-02-20 |
RU2145964C1 (ru) | 2000-02-27 |
PL319944A1 (en) | 1997-09-01 |
EP0789706A1 (en) | 1997-08-20 |
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