JPH03501128A - ヌクレオシドおよびポリヌクレオチドチオホスホラミダイトおよびホスホロジチオエイト化合物並びに方法 - Google Patents

ヌクレオシドおよびポリヌクレオチドチオホスホラミダイトおよびホスホロジチオエイト化合物並びに方法

Info

Publication number: JPH03501128A
Authority: JP; Japan
Prior art keywords: nucleoside; substituted; oligonucleotide; group; unsubstituted
Prior art date: 1988-05-26
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Pending

Application number

JP1506397A

Other languages

English (en)

Japanese (ja)

Inventor

カルザース，マービン

ブリル，ウォルフギャング

ニールセン，ジョン

Original Assignee

ユニバーシティ　パテンツ，インコーポレイティド

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1988-05-26

Filing date

1989-05-25

Publication date

1991-03-14

1989-05-25 Application filed by ユニバーシティ　パテンツ，インコーポレイティド filed Critical ユニバーシティ　パテンツ，インコーポレイティド

1991-03-14 Publication of JPH03501128A publication Critical patent/JPH03501128A/ja

Status Pending legal-status Critical Current

Links

239000002777 nucleoside Substances 0.000 title claims description 83
238000000034 method Methods 0.000 title claims description 82
150000003833 nucleoside derivatives Chemical class 0.000 title claims description 66
NAGJZTKCGNOGPW-UHFFFAOYSA-N dithiophosphoric acid Chemical class OP(O)(S)=S NAGJZTKCGNOGPW-UHFFFAOYSA-N 0.000 title claims description 17
239000002157 polynucleotide Substances 0.000 title description 36
102000040430 polynucleotide Human genes 0.000 title description 35
108091033319 polynucleotide Proteins 0.000 title description 35
-1 aralkenyl Chemical group 0.000 claims description 138
150000001875 compounds Chemical class 0.000 claims description 107
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 69
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 65
108091034117 Oligonucleotide Proteins 0.000 claims description 60
229910052717 sulfur Inorganic materials 0.000 claims description 60
238000006243 chemical reaction Methods 0.000 claims description 59
230000000903 blocking effect Effects 0.000 claims description 58
239000011593 sulfur Substances 0.000 claims description 58
230000015572 biosynthetic process Effects 0.000 claims description 54
238000003786 synthesis reaction Methods 0.000 claims description 52
OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 49
NAGJZTKCGNOGPW-UHFFFAOYSA-K dioxido-sulfanylidene-sulfido-$l^{5}-phosphane Chemical compound [O-]P([O-])([S-])=S NAGJZTKCGNOGPW-UHFFFAOYSA-K 0.000 claims description 49
229910052698 phosphorus Inorganic materials 0.000 claims description 44
239000011574 phosphorus Substances 0.000 claims description 44
229910052757 nitrogen Inorganic materials 0.000 claims description 43
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 34
229910052760 oxygen Inorganic materials 0.000 claims description 34
239000001301 oxygen Substances 0.000 claims description 34
125000003118 aryl group Chemical group 0.000 claims description 31
125000000217 alkyl group Chemical group 0.000 claims description 29
125000005842 heteroatom Chemical group 0.000 claims description 25
239000000126 substance Substances 0.000 claims description 23
150000003536 tetrazoles Chemical group 0.000 claims description 23
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 claims description 22
229910052736 halogen Inorganic materials 0.000 claims description 21
150000002367 halogens Chemical class 0.000 claims description 21
125000001424 substituent group Chemical group 0.000 claims description 21
229910019142 PO4 Inorganic materials 0.000 claims description 18
125000004429 atom Chemical group 0.000 claims description 18
125000004432 carbon atom Chemical group C* 0.000 claims description 18
125000000753 cycloalkyl group Chemical group 0.000 claims description 18
235000021317 phosphate Nutrition 0.000 claims description 18
125000003710 aryl alkyl group Chemical group 0.000 claims description 17
230000003647 oxidation Effects 0.000 claims description 17
238000007254 oxidation reaction Methods 0.000 claims description 17
OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical group NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 16
150000001540 azides Chemical class 0.000 claims description 15
UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 15
125000003342 alkenyl group Chemical group 0.000 claims description 14
RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims description 14
229910052740 iodine Inorganic materials 0.000 claims description 13
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 12
125000000392 cycloalkenyl group Chemical group 0.000 claims description 12
UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical group O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 12
239000011630 iodine Substances 0.000 claims description 12
150000003839 salts Chemical class 0.000 claims description 12
RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical group CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 12
150000005691 triesters Chemical class 0.000 claims description 12
238000004519 manufacturing process Methods 0.000 claims description 11
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
125000000304 alkynyl group Chemical group 0.000 claims description 10
230000001590 oxidative effect Effects 0.000 claims description 10
IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical group O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 claims description 9
125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 9
239000010452 phosphate Substances 0.000 claims description 9
229940104302 cytosine Drugs 0.000 claims description 8
125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 8
150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 8
229920000642 polymer Polymers 0.000 claims description 8
150000002148 esters Chemical class 0.000 claims description 7
229910052700 potassium Inorganic materials 0.000 claims description 7
125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims description 7
229930024421 Adenine Natural products 0.000 claims description 6
229960000643 adenine Drugs 0.000 claims description 6
GFFGJBXGBJISGV-UHFFFAOYSA-N adenyl group Chemical group N1=CN=C2N=CNC2=C1N GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 6
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
125000003835 nucleoside group Chemical group 0.000 claims description 6
NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
229940113082 thymine Drugs 0.000 claims description 6
RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical class OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 claims description 5
229940043279 diisopropylamine Drugs 0.000 claims description 5
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Chemical group O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 claims description 4
ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical group O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 4
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Chemical group O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 claims description 4
229940104230 thymidine Drugs 0.000 claims description 4
VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical group CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 claims description 3
125000002947 alkylene group Chemical group 0.000 claims description 3
230000008569 process Effects 0.000 claims description 3
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 2
229940035893 uracil Drugs 0.000 claims description 2
239000007822 coupling agent Substances 0.000 claims 9
241000021375 Xenogenes Species 0.000 claims 3
239000007800 oxidant agent Substances 0.000 claims 3
WPPONCHFOIIFIJ-UHFFFAOYSA-N N1N=NN=[C-]1 Chemical class N1N=NN=[C-]1 WPPONCHFOIIFIJ-UHFFFAOYSA-N 0.000 claims 2
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
AKUNSTOMHUXJOZ-UHFFFAOYSA-N 1-hydroperoxybutane Chemical compound CCCCOO AKUNSTOMHUXJOZ-UHFFFAOYSA-N 0.000 claims 1
102000004190 Enzymes Human genes 0.000 claims 1
108090000790 Enzymes Proteins 0.000 claims 1
125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims 1
125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
239000002184 metal Substances 0.000 claims 1
229910052751 metal Inorganic materials 0.000 claims 1
SXADIBFZNXBEGI-UHFFFAOYSA-N phosphoramidous acid Chemical group NP(O)O SXADIBFZNXBEGI-UHFFFAOYSA-N 0.000 claims 1
241000894007 species Species 0.000 claims 1
CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims 1
125000002480 thymidyl group Chemical group 0.000 claims 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 93
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 66
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 58
239000000243 solution Substances 0.000 description 36
239000000047 product Substances 0.000 description 35
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
239000011541 reaction mixture Substances 0.000 description 27
238000005481 NMR spectroscopy Methods 0.000 description 25
OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 24
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 19
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
229910052799 carbon Inorganic materials 0.000 description 15
238000001819 mass spectrum Methods 0.000 description 14
239000002773 nucleotide Substances 0.000 description 14
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
239000000377 silicon dioxide Substances 0.000 description 13
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
108020004414 DNA Proteins 0.000 description 12
102000053602 DNA Human genes 0.000 description 12
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
USJRLGNYCQWLPF-UHFFFAOYSA-N chlorophosphane Chemical compound ClP USJRLGNYCQWLPF-UHFFFAOYSA-N 0.000 description 12
150000008300 phosphoramidites Chemical class 0.000 description 12
CKTSBUTUHBMZGZ-UHFFFAOYSA-N Deoxycytidine Natural products O=C1N=C(N)C=CN1C1OC(CO)C(O)C1 CKTSBUTUHBMZGZ-UHFFFAOYSA-N 0.000 description 11
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
239000000203 mixture Substances 0.000 description 11
125000003729 nucleotide group Chemical group 0.000 description 11
OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 10
XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 10
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
238000001914 filtration Methods 0.000 description 10
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
239000012190 activator Substances 0.000 description 9
150000001412 amines Chemical class 0.000 description 9
238000002360 preparation method Methods 0.000 description 9
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
239000007787 solid Substances 0.000 description 9
238000003756 stirring Methods 0.000 description 9
RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 9
CKTSBUTUHBMZGZ-SHYZEUOFSA-N 2'‐deoxycytidine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 CKTSBUTUHBMZGZ-SHYZEUOFSA-N 0.000 description 8
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 8
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
239000000543 intermediate Substances 0.000 description 8
229910052938 sodium sulfate Inorganic materials 0.000 description 8
235000011152 sodium sulphate Nutrition 0.000 description 8
239000002904 solvent Substances 0.000 description 8
BIIUNHCUZONUSM-UHFFFAOYSA-N sulfanylphosphonamidous acid Chemical compound NP(O)S BIIUNHCUZONUSM-UHFFFAOYSA-N 0.000 description 8
239000007864 aqueous solution Substances 0.000 description 7
150000001721 carbon Chemical group 0.000 description 7
239000003153 chemical reaction reagent Substances 0.000 description 7
230000008878 coupling Effects 0.000 description 7
238000010168 coupling process Methods 0.000 description 7
238000005859 coupling reaction Methods 0.000 description 7
238000005516 engineering process Methods 0.000 description 7
229910052739 hydrogen Inorganic materials 0.000 description 7
239000002244 precipitate Substances 0.000 description 7
125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 6
RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 6
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
239000002253 acid Chemical group 0.000 description 6
239000008346 aqueous phase Substances 0.000 description 6
229910052786 argon Inorganic materials 0.000 description 6
238000009833 condensation Methods 0.000 description 6
230000005494 condensation Effects 0.000 description 6
229910052720 vanadium Inorganic materials 0.000 description 6
GKQXPTHQTXCXEV-UHFFFAOYSA-N (4-chlorophenyl)methanethiol Chemical compound SCC1=CC=C(Cl)C=C1 GKQXPTHQTXCXEV-UHFFFAOYSA-N 0.000 description 5
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
150000007513 acids Chemical group 0.000 description 5
230000004913 activation Effects 0.000 description 5
OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 5
QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
238000004440 column chromatography Methods 0.000 description 5
238000004821 distillation Methods 0.000 description 5
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
239000012074 organic phase Substances 0.000 description 5
239000003960 organic solvent Substances 0.000 description 5
229910000073 phosphorus hydride Inorganic materials 0.000 description 5
150000003335 secondary amines Chemical class 0.000 description 5
239000000741 silica gel Substances 0.000 description 5
229910002027 silica gel Inorganic materials 0.000 description 5
235000017557 sodium bicarbonate Nutrition 0.000 description 5
229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
239000011780 sodium chloride Substances 0.000 description 5
230000001225 therapeutic effect Effects 0.000 description 5
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 4
230000002378 acidificating effect Effects 0.000 description 4
239000012267 brine Substances 0.000 description 4
238000004587 chromatography analysis Methods 0.000 description 4
239000012141 concentrate Substances 0.000 description 4
239000000706 filtrate Substances 0.000 description 4
239000011521 glass Substances 0.000 description 4
239000001257 hydrogen Substances 0.000 description 4
125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
229910000037 hydrogen sulfide Inorganic materials 0.000 description 4
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FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
229940106681 chloroacetic acid Drugs 0.000 description 1
MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
229940125904 compound 1 Drugs 0.000 description 1
238000007796 conventional method Methods 0.000 description 1
229930189851 creoside Natural products 0.000 description 1
239000013078 crystal Substances 0.000 description 1
238000002425 crystallisation Methods 0.000 description 1
230000008025 crystallization Effects 0.000 description 1
RCHVMFNYFYQEMB-UHFFFAOYSA-N ctk0h8384 Chemical group NPCl RCHVMFNYFYQEMB-UHFFFAOYSA-N 0.000 description 1
125000005112 cycloalkylalkoxy group Chemical group 0.000 description 1
FCXGCSBZKOHCLB-KPRKPIBOSA-N dT2 Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)CO)[C@@H](O)C1 FCXGCSBZKOHCLB-KPRKPIBOSA-N 0.000 description 1
230000020176 deacylation Effects 0.000 description 1
238000005947 deacylation reaction Methods 0.000 description 1
230000007547 defect Effects 0.000 description 1
238000011161 development Methods 0.000 description 1
230000018109 developmental process Effects 0.000 description 1
PBGGNZZGJIKBMJ-UHFFFAOYSA-N di(propan-2-yl)azanide Chemical compound CC(C)[N-]C(C)C PBGGNZZGJIKBMJ-UHFFFAOYSA-N 0.000 description 1
URAZVWXGWMBUGJ-UHFFFAOYSA-N di(propan-2-yl)azanium;chloride Chemical compound [Cl-].CC(C)[NH2+]C(C)C URAZVWXGWMBUGJ-UHFFFAOYSA-N 0.000 description 1
125000003963 dichloro group Chemical group Cl* 0.000 description 1
DAKIDYQCFJQMDF-UHFFFAOYSA-N dichloromethane;pyridine Chemical compound ClCCl.C1=CC=NC=C1 DAKIDYQCFJQMDF-UHFFFAOYSA-N 0.000 description 1
150000005690 diesters Chemical class 0.000 description 1
HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
238000010790 dilution Methods 0.000 description 1
239000012895 dilution Substances 0.000 description 1
201000010099 disease Diseases 0.000 description 1
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
238000001035 drying Methods 0.000 description 1
238000001493 electron microscopy Methods 0.000 description 1
238000010828 elution Methods 0.000 description 1
238000006911 enzymatic reaction Methods 0.000 description 1
230000002349 favourable effect Effects 0.000 description 1
239000012467 final product Substances 0.000 description 1
239000010436 fluorite Substances 0.000 description 1
HKIOYBQGHSTUDB-UHFFFAOYSA-N folpet Chemical group C1=CC=C2C(=O)N(SC(Cl)(Cl)Cl)C(=O)C2=C1 HKIOYBQGHSTUDB-UHFFFAOYSA-N 0.000 description 1
238000005194 fractionation Methods 0.000 description 1
239000012634 fragment Substances 0.000 description 1
238000004108 freeze drying Methods 0.000 description 1
239000007789 gas Substances 0.000 description 1
238000002523 gelfiltration Methods 0.000 description 1
239000001307 helium Substances 0.000 description 1
229910052734 helium Inorganic materials 0.000 description 1
SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
238000004128 high performance liquid chromatography Methods 0.000 description 1
229920001519 homopolymer Polymers 0.000 description 1
229930195733 hydrocarbon Natural products 0.000 description 1
239000012535 impurity Substances 0.000 description 1
238000009830 intercalation Methods 0.000 description 1
230000002687 intercalation Effects 0.000 description 1
PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
238000006317 isomerization reaction Methods 0.000 description 1
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
239000010410 layer Substances 0.000 description 1
TWXDDNPPQUTEOV-FVGYRXGTSA-N methamphetamine hydrochloride Chemical compound Cl.CN[C@@H](C)CC1=CC=CC=C1 TWXDDNPPQUTEOV-FVGYRXGTSA-N 0.000 description 1
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
XBDUZBHKKUFFRH-UHFFFAOYSA-N n-(2-oxo-1h-pyrimidin-6-yl)benzamide Chemical compound OC1=NC=CC(NC(=O)C=2C=CC=CC=2)=N1 XBDUZBHKKUFFRH-UHFFFAOYSA-N 0.000 description 1
GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
XVDBWWRIXBMVJV-UHFFFAOYSA-N n-[bis(dimethylamino)phosphanyl]-n-methylmethanamine Chemical compound CN(C)P(N(C)C)N(C)C XVDBWWRIXBMVJV-UHFFFAOYSA-N 0.000 description 1
MAJFLEHNBOUSIY-UHFFFAOYSA-N n-[chloro(dimethylamino)phosphanyl]-n-methylmethanamine Chemical compound CN(C)P(Cl)N(C)C MAJFLEHNBOUSIY-UHFFFAOYSA-N 0.000 description 1
VXXLEXCQCSPKFI-UHFFFAOYSA-N n-butylcyclohexanamine Chemical compound CCCCNC1CCCCC1 VXXLEXCQCSPKFI-UHFFFAOYSA-N 0.000 description 1
AGVKXDPPPSLISR-UHFFFAOYSA-N n-ethylcyclohexanamine Chemical compound CCNC1CCCCC1 AGVKXDPPPSLISR-UHFFFAOYSA-N 0.000 description 1
RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
VEBLEROFGPOMPB-UHFFFAOYSA-N n-methylcyclopropanamine Chemical compound CNC1CC1 VEBLEROFGPOMPB-UHFFFAOYSA-N 0.000 description 1
XJINZNWPEQMMBV-UHFFFAOYSA-N n-methylhexan-1-amine Chemical compound CCCCCCNC XJINZNWPEQMMBV-UHFFFAOYSA-N 0.000 description 1
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
230000000269 nucleophilic effect Effects 0.000 description 1
238000002515 oligonucleotide synthesis Methods 0.000 description 1
AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
239000012071 phase Substances 0.000 description 1
150000003017 phosphorus Chemical class 0.000 description 1
150000003018 phosphorus compounds Chemical class 0.000 description 1
125000002743 phosphorus functional group Chemical group 0.000 description 1
102000020233 phosphotransferase Human genes 0.000 description 1
AXIPBRXJGSXLHF-UHFFFAOYSA-N piperidine;pyrrolidine Chemical compound C1CCNC1.C1CCNCC1 AXIPBRXJGSXLHF-UHFFFAOYSA-N 0.000 description 1
238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
239000011148 porous material Substances 0.000 description 1
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
239000000843 powder Substances 0.000 description 1
150000003141 primary amines Chemical class 0.000 description 1
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
230000005588 protonation Effects 0.000 description 1
229940070891 pyridium Drugs 0.000 description 1
125000004076 pyridyl group Chemical group 0.000 description 1
230000035484 reaction time Effects 0.000 description 1
239000012070 reactive reagent Substances 0.000 description 1
230000009257 reactivity Effects 0.000 description 1
238000007363 ring formation reaction Methods 0.000 description 1
229920002477 rna polymer Polymers 0.000 description 1
239000012047 saturated solution Substances 0.000 description 1
239000003352 sequestering agent Substances 0.000 description 1
230000020509 sex determination Effects 0.000 description 1
238000007086 side reaction Methods 0.000 description 1
239000003998 snake venom Substances 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
238000001228 spectrum Methods 0.000 description 1
239000007858 starting material Substances 0.000 description 1
238000003860 storage Methods 0.000 description 1
238000001308 synthesis method Methods 0.000 description 1
YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
238000012360 testing method Methods 0.000 description 1
HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 description 1
125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
150000003573 thiols Chemical class 0.000 description 1
BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
239000003053 toxin Substances 0.000 description 1
231100000765 toxin Toxicity 0.000 description 1
108700012359 toxins Proteins 0.000 description 1
125000005208 trialkylammonium group Chemical group 0.000 description 1
125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
210000002700 urine Anatomy 0.000 description 1
238000005292 vacuum distillation Methods 0.000 description 1
238000001291 vacuum drying Methods 0.000 description 1
230000009385 viral infection Effects 0.000 description 1
238000005406 washing Methods 0.000 description 1
238000010626 work up procedure Methods 0.000 description 1
238000002424 x-ray crystallography Methods 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- 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
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H21/04—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 deoxyribosyl as saccharide radical

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Biochemistry (AREA)
Molecular Biology (AREA)
Engineering & Computer Science (AREA)
Biotechnology (AREA)
General Health & Medical Sciences (AREA)
Genetics & Genomics (AREA)
Saccharide Compounds (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

JP1506397A 1988-05-26 1989-05-25 ヌクレオシドおよびポリヌクレオチドチオホスホラミダイトおよびホスホロジチオエイト化合物並びに方法 Pending JPH03501128A (ja)

Applications Claiming Priority (4)

Application Number	Priority Date	Filing Date
US19888688A	1988-05-26	1988-05-26
US198,886		1988-05-26
US31401189A	1989-02-22	1989-02-22
US314,011		1989-02-22

Publications (1)

Publication Number	Publication Date
JPH03501128A true JPH03501128A (ja)	1991-03-14

Family

ID=26894243

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
JP1506397A Pending JPH03501128A (ja)	1988-05-26	1989-05-25	ヌクレオシドおよびポリヌクレオチドチオホスホラミダイトおよびホスホロジチオエイト化合物並びに方法

Country Status (7)

Country	Link
EP (1)	EP0378615A4 (es)
JP (1)	JPH03501128A (es)
KR (1)	KR900701813A (es)
AU (1)	AU626305B2 (es)
ES (1)	ES2015665A6 (es)
IL (1)	IL90359A0 (es)
WO (1)	WO1989011486A1 (es)

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JP2021508690A (ja) *	2017-12-22	2021-03-11	ロシュイノベーションセンターコペンハーゲンエーエス	ホスホロジチオアートヌクレオシド間結合を含むオリゴヌクレオチド
JP2021508689A (ja) *	2017-12-22	2021-03-11	ロシュイノベーションセンターコペンハーゲンエーエス	ホスホロジチオアートヌクレオシド間結合を含むギャップマーオリゴヌクレオチド

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US5194599A (en) *	1988-09-23	1993-03-16	Gilead Sciences, Inc.	Hydrogen phosphonodithioate compositions
US5470967A (en) *	1990-04-10	1995-11-28	The Dupont Merck Pharmaceutical Company	Oligonucleotide analogs with sulfamate linkages
US5151510A (en) *	1990-04-20	1992-09-29	Applied Biosystems, Inc.	Method of synethesizing sulfurized oligonucleotide analogs
EP0463712A3 (en)	1990-06-27	1992-04-08	University Patents, Inc.	Polynucleotide phosphorodithioates as therapeutic agents for retroviral infections
US5623070A (en) *	1990-07-27	1997-04-22	Isis Pharmaceuticals, Inc.	Heteroatomic oligonucleoside linkages
US5602240A (en) *	1990-07-27	1997-02-11	Ciba Geigy Ag.	Backbone modified oligonucleotide analogs
US5378825A (en) *	1990-07-27	1995-01-03	Isis Pharmaceuticals, Inc.	Backbone modified oligonucleotide analogs
US5610289A (en) *	1990-07-27	1997-03-11	Isis Pharmaceuticals, Inc.	Backbone modified oligonucleotide analogues
EP0549686A4 (en) *	1990-09-20	1995-01-18	Gilead Sciences Inc	Modified internucleoside linkages
US5965722A (en) *	1991-05-21	1999-10-12	Isis Pharmaceuticals, Inc.	Antisense inhibition of ras gene with chimeric and alternating oligonucleotides
EP0549107B1 (en)	1991-10-11	1997-12-29	BEHRINGWERKE Aktiengesellschaft	Method for producing a polynucleotide for use in single primer amplification and phosphorothioate-containing oligonucleotides as primers in nucleic acid amplification
AU3920293A (en) *	1993-03-16	1994-10-11	Board Of Regents Of The University Of Nebraska, The	Novel metal binding agents, and methods and compositions for their use to treat metal toxicity
US6001982A (en)	1993-07-29	1999-12-14	Isis Pharmaceuticals, Inc.	Synthesis of oligonucleotides
US5571902A (en) *	1993-07-29	1996-11-05	Isis Pharmaceuticals, Inc.	Synthesis of oligonucleotides
EP0932698A1 (en) *	1996-03-26	1999-08-04	Lynx Therapeutics, Inc.	Oligonucleotide treatments and compositions for human melanoma
US7255874B1 (en)	2001-12-21	2007-08-14	Closure Medical Corporation	Biocompatible polymers and adhesives: compositions, methods of making and uses related thereto
EP2915815B1 (en)	2012-10-31	2018-01-17	Takeda Pharmaceutical Company Limited	New modified nucleic acid
PT3512861T (pt)	2016-12-01	2021-04-29	Takeda Pharmaceuticals Co	Dinucleotídeos cíclicos
EP3643706B1 (en)	2017-06-16	2023-11-15	Eisai R&D Management Co., Ltd.	Modified nucleic acid monomers and oligonucleic acid analogues, with high biological stability and target gene silencing activity, for use in therapy and diagnosis of cancer and viral diseases
CN111039977B (zh) *	2019-12-31	2022-11-08	广州同隽医药科技有限公司	一种亚磷酰化试剂及其在寡核苷酸合成中的应用
JP2023553069A (ja) *	2020-12-08	2023-12-20	エフ．ホフマン－ラロシュアーゲー	ホスホロジチオエートオリゴヌクレオチドの新規合成

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1989
- 1989-05-19 IL IL90359A patent/IL90359A0/xx unknown
- 1989-05-25 EP EP19890906571 patent/EP0378615A4/en not_active Withdrawn
- 1989-05-25 WO PCT/US1989/002293 patent/WO1989011486A1/en not_active Ceased
- 1989-05-25 JP JP1506397A patent/JPH03501128A/ja active Pending
- 1989-05-25 KR KR1019900700156A patent/KR900701813A/ko not_active Ceased
- 1989-05-25 AU AU37392/89A patent/AU626305B2/en not_active Ceased
- 1989-05-26 ES ES8901786A patent/ES2015665A6/es not_active Expired - Fee Related

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Publication number	Priority date	Publication date	Assignee	Title
JP2021508690A (ja) *	2017-12-22	2021-03-11	ロシュイノベーションセンターコペンハーゲンエーエス	ホスホロジチオアートヌクレオシド間結合を含むオリゴヌクレオチド
JP2021508689A (ja) *	2017-12-22	2021-03-11	ロシュイノベーションセンターコペンハーゲンエーエス	ホスホロジチオアートヌクレオシド間結合を含むギャップマーオリゴヌクレオチド
JP2024041886A (ja) *	2017-12-22	2024-03-27	ロシュイノベーションセンターコペンハーゲンエーエス	ホスホロジチオアートヌクレオシド間結合を含むオリゴヌクレオチド
JP2024041845A (ja) *	2017-12-22	2024-03-27	ロシュイノベーションセンターコペンハーゲンエーエス	ホスホロジチオアートヌクレオシド間結合を含むギャップマーオリゴヌクレオチド

Also Published As

Publication number	Publication date
ES2015665A6 (es)	1990-09-01
AU626305B2 (en)	1992-07-30
AU3739289A (en)	1989-12-12
EP0378615A1 (en)	1990-07-25
EP0378615A4 (en)	1992-04-08
IL90359A0 (en)	1989-12-15
KR900701813A (ko)	1990-12-04
WO1989011486A1 (en)	1989-11-30

Publication	Publication Date	Title
US5750666A (en)	1998-05-12	Polynucleotide phosphorodithioate compounds
US5684148A (en)	1997-11-04	Nucleoside thiophosphoramidites
US5218103A (en)	1993-06-08	Nucleoside thiophosphoramidites
JP2511005B2 (ja)	1996-06-26	インビトロにおけるオリゴヌクレオチド合成法並びにそれに用いる試薬
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