JPH09509663A - 新規ホスホルアミデートおよびホスホロチオアミデートオリゴマー化合物 - Google Patents
新規ホスホルアミデートおよびホスホロチオアミデートオリゴマー化合物Info
- Publication number
- JPH09509663A JPH09509663A JP7522463A JP52246395A JPH09509663A JP H09509663 A JPH09509663 A JP H09509663A JP 7522463 A JP7522463 A JP 7522463A JP 52246395 A JP52246395 A JP 52246395A JP H09509663 A JPH09509663 A JP H09509663A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- group
- alkyl
- carbon atoms
- independently
- Prior art date
- 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.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 177
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 title description 58
- RJBIAAZJODIFHR-UHFFFAOYSA-N dihydroxy-imino-sulfanyl-$l^{5}-phosphane Chemical compound NP(O)(O)=S RJBIAAZJODIFHR-UHFFFAOYSA-N 0.000 title description 40
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 19
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000001301 oxygen Substances 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 168
- -1 methoxytrityl Chemical group 0.000 claims description 94
- 239000007787 solid Substances 0.000 claims description 69
- 150000001412 amines Chemical group 0.000 claims description 53
- 125000004432 carbon atom Chemical group C* 0.000 claims description 39
- 108091034117 Oligonucleotide Proteins 0.000 claims description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 31
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 25
- 125000006239 protecting group Chemical group 0.000 claims description 24
- 239000002253 acid Chemical group 0.000 claims description 21
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 18
- 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 17
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 15
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 15
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 13
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims description 13
- 239000002202 Polyethylene glycol Substances 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 229920001223 polyethylene glycol Polymers 0.000 claims description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 150000004713 phosphodiesters Chemical class 0.000 claims description 11
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 10
- 229910052751 metal Inorganic materials 0.000 claims description 9
- 239000002184 metal Substances 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 8
- 229960000643 adenine Drugs 0.000 claims description 8
- 229940104302 cytosine Drugs 0.000 claims description 8
- 229930024421 Adenine Natural products 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 239000002773 nucleotide Substances 0.000 claims description 7
- 229920000570 polyether Chemical group 0.000 claims description 7
- 125000006853 reporter group Chemical group 0.000 claims description 7
- 229940113082 thymine Drugs 0.000 claims description 7
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 6
- 239000004721 Polyphenylene oxide Chemical group 0.000 claims description 6
- 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 claims description 6
- 125000000304 alkynyl group Chemical group 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
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 150000003573 thiols Chemical group 0.000 claims description 6
- 125000003729 nucleotide group Chemical group 0.000 claims description 5
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims description 5
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 108091093037 Peptide nucleic acid Proteins 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- 229920001515 polyalkylene glycol Polymers 0.000 claims description 4
- 150000003212 purines Chemical group 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 claims description 3
- 125000006242 amine protecting group Chemical group 0.000 claims description 3
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 claims description 3
- 230000001268 conjugating effect Effects 0.000 claims description 3
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 3
- 150000003235 pyrrolidines Chemical class 0.000 claims description 3
- 150000003254 radicals Chemical class 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 3
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 claims description 3
- 229940045145 uridine Drugs 0.000 claims description 3
- 150000002334 glycols Chemical class 0.000 claims description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims 4
- 125000003386 piperidinyl group Chemical group 0.000 claims 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 claims 1
- 125000000524 functional group Chemical group 0.000 abstract description 61
- 238000003786 synthesis reaction Methods 0.000 abstract description 47
- 230000015572 biosynthetic process Effects 0.000 abstract description 45
- 238000007254 oxidation reaction Methods 0.000 abstract description 29
- 230000003647 oxidation Effects 0.000 abstract description 27
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 abstract description 14
- 238000010168 coupling process Methods 0.000 abstract description 12
- 230000008878 coupling Effects 0.000 abstract description 10
- 238000005859 coupling reaction Methods 0.000 abstract description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract description 2
- 239000005864 Sulphur Chemical group 0.000 abstract 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 89
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 84
- 239000000243 solution Substances 0.000 description 76
- 239000011347 resin Substances 0.000 description 58
- 229920005989 resin Polymers 0.000 description 58
- 239000000203 mixture Substances 0.000 description 53
- 239000005289 controlled pore glass Substances 0.000 description 51
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- 239000000178 monomer Substances 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 102000004190 Enzymes Human genes 0.000 description 29
- 108090000790 Enzymes Proteins 0.000 description 29
- 230000000694 effects Effects 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 25
- 238000009739 binding Methods 0.000 description 24
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 24
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 23
- 150000002148 esters Chemical class 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 238000003556 assay Methods 0.000 description 21
- 239000000047 product Substances 0.000 description 20
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- 230000008569 process Effects 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 16
- 150000008298 phosphoramidates Chemical class 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 15
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- 239000006228 supernatant Substances 0.000 description 14
- 125000003277 amino group Chemical group 0.000 description 13
- 239000003153 chemical reaction reagent Substances 0.000 description 13
- 102000039446 nucleic acids Human genes 0.000 description 13
- 108020004707 nucleic acids Proteins 0.000 description 13
- 150000007523 nucleic acids Chemical class 0.000 description 13
- LOSXTWDYAWERDB-UHFFFAOYSA-N 1-[chloro(diphenyl)methyl]-2,3-dimethoxybenzene Chemical compound COC1=CC=CC(C(Cl)(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1OC LOSXTWDYAWERDB-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 238000010348 incorporation Methods 0.000 description 12
- 239000003112 inhibitor Substances 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 12
- 150000002632 lipids Chemical class 0.000 description 12
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 12
- 238000012216 screening Methods 0.000 description 12
- 239000000758 substrate Substances 0.000 description 12
- 238000001212 derivatisation Methods 0.000 description 11
- 239000001257 hydrogen Substances 0.000 description 11
- 229910052739 hydrogen Inorganic materials 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 10
- BVVCDLLKIBUISQ-UHFFFAOYSA-N acetonitrile;pyridine Chemical compound CC#N.C1=CC=NC=C1 BVVCDLLKIBUISQ-UHFFFAOYSA-N 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical group OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 150000008300 phosphoramidites Chemical class 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 9
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 9
- 239000012267 brine Substances 0.000 description 9
- 239000000539 dimer Substances 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- 108020004999 messenger RNA Proteins 0.000 description 9
- 230000001590 oxidative effect Effects 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 238000003818 flash chromatography Methods 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- FUWGSUOSJRCEIV-UHFFFAOYSA-N phosphonothioic O,O-acid Chemical compound OP(O)=S FUWGSUOSJRCEIV-UHFFFAOYSA-N 0.000 description 8
- 229910052698 phosphorus Inorganic materials 0.000 description 8
- 238000011160 research Methods 0.000 description 8
- WERYXYBDKMZEQL-UHFFFAOYSA-N 1,4-butanediol Substances OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 7
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 7
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 239000000908 ammonium hydroxide Substances 0.000 description 7
- 230000008901 benefit Effects 0.000 description 7
- 239000012472 biological sample Substances 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 229960005215 dichloroacetic acid Drugs 0.000 description 7
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000002777 nucleoside Substances 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 150000003335 secondary amines Chemical class 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 238000006467 substitution reaction Methods 0.000 description 7
- 229940014800 succinic anhydride Drugs 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229940059260 amidate Drugs 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 6
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 125000003835 nucleoside group Chemical group 0.000 description 6
- 239000011574 phosphorus Substances 0.000 description 6
- 239000002243 precursor Substances 0.000 description 6
- 230000009257 reactivity Effects 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 229940086735 succinate Drugs 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 5
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 238000002835 absorbance Methods 0.000 description 5
- 239000000370 acceptor Substances 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 238000009826 distribution Methods 0.000 description 5
- 230000002209 hydrophobic effect Effects 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 5
- 238000006384 oligomerization reaction Methods 0.000 description 5
- 150000003904 phospholipids Chemical class 0.000 description 5
- 150000003141 primary amines Chemical class 0.000 description 5
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- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- XSOKHXFFCGXDJZ-UHFFFAOYSA-N telluride(2-) Chemical compound [Te-2] XSOKHXFFCGXDJZ-UHFFFAOYSA-N 0.000 description 1
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- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
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- 125000005310 triazolidinyl group Chemical group N1(NNCC1)* 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Classifications
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Luminescent Compositions (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
Description
Claims (1)
- 【特許請求の範囲】 1. 下記の構造の化合物: [式中 各々のXは独立してOまたはSであり; 各々のYは[Q2]j−Z2であり; 各々のTは独立して[Q1]k−Z1であるか、またはYおよびTが一緒に窒素 へテロ環に組み込まれ; Q1、Q2および各々のLは独立してC2−C10アルキル、C2−C10アルケニル 、C2−C10アルキニル、C4−C7炭素環−アルキルまたは−アルケニル、ヘテ ロ環、2から10の炭素原子を有しおよび1から4の酸素または硫黄原子を有す るエーテル、ポリアルキレングリコール、またはC7−C14アラルキルであり、 Lがヘテロ環である場合は少なくとも一つのLは置換ピロリジンまたは天然の核 塩基ではなく、およびLがアルキルの場合は少なくとも一つのLは置換グリコー ルではない; E1およびE2は独立してH、ヒドロキシル保護基、活性化固体支持体、コンジ ュゲート基、レポーター基、ポリエチレングリコール、アルキル、オリゴヌクレ オチド、ペプチド核酸、ホスフェート、ホスファイト、活性化ホスフェートまた は活性化ホスファイトであり; jおよびkは独立して0または1であり; mは2から約50であり; Z1およびZ2は独立して、H、C1−C2アルキル、C2−C20アルケニル、C2 −C20アルキニル、C6−C14アリール、C7−C15アラルキル、ハロゲン、CH =O、OR1、SR2、NR3R4、C(=NH)NR3R4、CH(NR3R4)、N HC(=NH)NR3R4、CH(NH2)C(=O)OH、C(=O)NR3R4 、C(=O)OR5、金属配位基、レポーター基、窒素含有ヘテロ環、プリン、 ピリミジン、ホスフェート基、ポリエーテル基、またはポリエチレングリコール 基であり; AはL1、L1−G1、L2、L2−G2、NR3R4、H、窒素含有ヘテロ環、プリ ン、ピリミジン、ホスフェート基、ポリエーテル基、またはポリエチレングリコ ール基であり; JはL1、G3、L1−G3、またはG3−L1−G3であり; L1は1から約20の炭素原子を有するアルキル、2から約20の炭素原子を 有するアルケニル、または2から約20の炭素原子を有するアルキニルであり; L2は6から約14の炭素原子を有するアリールまたは7から15の炭素原子 を有するアラルキルであり; G1はハロゲン、OR1、SR2、NR3R4、C(=NH)NR3R4、NHC( =NH)NR3R4、CH=O、C(=O)OR5、CH(NR3R4)(C(=O )OR5)、C(=O)NR3R4、金属配位基、またはホスフェート基であり; G2はハロゲン、OH、SH、SCH3、またはNR3R4であり; G3はC(=O)、C(=S)、C(O)−O、C(O)−NH、C(S)− O、C(S)−NHまたはS(O)2であり; 各々のd1は独立して0または1であり; 各々のd2は独立して0から6であり; 各々のd3は独立して1から6であり; R1はH、1から約6の炭素原子を有するアルキル、またはヒドロキシル保護 基であり; R2はH、1から約6の炭素原子を有するアルキル、またはチオール保護基で あ り; R3およびR4は独立してH、1から約6の炭素原子を有するアルキル、または アミン保護基であり;および R5はH、1から約6の炭素原子を有するアルキル、または酸保護基である] 。 2. Lが約2から約10の炭素を有するアルキルである請求項1に記載の化 合物。 3. YおよびTが一緒に窒素ヘテロ環に組み込まれている請求項1に記載の 化合物。 4. 前記ヘテロ環がピペリジンまたはビロリジンである請求項3に記載の化 合物。 5. E1がH、ヒドロキシル保護基、または活性化固体支持体である請求項 1に記載の化合物。 6. E2がトリチル、メトキシトリチル、ジメトキシトリチルまたはトリメ トキシトリチルである請求項1に記載の化合物。 7. E2がHまたはヒドロキシル保護基である請求項1に記載の化合物。 8. Z2がHである請求項1に記載の化合物。 9. Z1がプリンまたはピリミジンである請求項1に記載の化合物。 10. Z1がアデニン、グアニン、シトシン、ウリジンまたはチミンである請 求項9に記載の化合物。 11. Z1が1から約20の炭素原子を有するアルキルである請求項1に記載 の化合物。 12. Z1が6から約14の炭素原子を有するアリールまたは7から約15の 炭素原子を有するアラルキルである請求項1に記載の化合物。 13. Z1がフルオレニルメチル、フェニル、またはベンジルである請求項1 に記載の化合物。 14. Z1がポリエチレングリコールまたはグルタミルである請求項1に記載 の化合物。 15. mが約2から約25である請求項1に記載の化合物。 16. XがOである請求項1に記載の化合物。 17. XがSである請求項1に記載の化合物。 の化合物。 20. 少なくとも一つの前記L基が他の前記L基と異なっている請求項1に記 載の化合物。 21. ホスホジエステルまたはホスホロチオエートオリゴヌクレオチドを含む 第一の領域および下記の構造を有する第二の領域を有するキメラオリゴマー化合 物: [式中 各々のXは独立してOまたはSであり; 各々のYは[Q2]j−Z2であり; 各々のTは独立して[Q1]k−Z1であるか、またはYおよびTが一緒に窒素 へテロ環に組み込まれ; Q1、Q2および各々のLは独立してC2−C10アルキル、C2−C10アルケニル 、 C2−C10アルキニル、C4−C7炭素環−アルキルまたは−アルケニル、ヘテロ 環、2から10の炭素原子を有しおよび1から4の酸素または硫黄原子を有する エーテル、ポリアルキレングリコール、またはC7−C14アラルキルであり、L がヘテロ環である場合は少なくとも一つのLは置換ピロリジンまたは天然の核塩 基ではなく、およびLがアルキルの場合は少なくとも一つのLは置換グリコール ではない; E1およびE2の一つがホスホジエステルまたはホスホロチオエートオリゴヌク レオチドを含む前記第一の領域であり、および前記E1およびE2の他方がH、ヒ ドロキシル保護基、活性化固体支持体、コンジュゲート基、レポーター基、ポリ エチレングリコール、アルキル、オリゴヌクレオチド、ペプチド核酸、ホスフェ ート、ホスファイト、活性化ホスフェートまたは活性化ホスファイトであり; jおよびkは独立して0または1であり; mは2から約50であり; Z1およびZ2は独立して、H、C1−C2アルキル、C2−C20アルケニル、C2 −C20アルキニル、C6−C14アリール、C7−C15アラルキル、ハロゲン、CH =O、OR1、SR2、NR3R4、C(=NH)NR3R4、CH(NR3R4)、N HC(=NH)NR3R4、CH(NH2)C(=O)OH、C(=O)NR3R4 、C(=O)OR5、金属配位基、レポーター基、窒素含有ヘテロ環、プリン、 ピリミジン、ホスフェート基、ポリエーテル基、またはポリエチレングリコール 基であり; AはL1、L1−G1、L2、L2−G2、NR3R4、H、窒素含有ヘテロ環、プリ ン、ピリミジン、ホスフェート基、ポリエーテル基、またはポリエチレングリコ ール基であり: JはL1、G3、L1−G3、またはG3−L1−G3であり; L1は1から約20の炭素原子を有するアルキル、2から約20の炭素原子を 有するアルケニル、または2から約20の炭素原子を有するアルキニルであり; L2は6から約14の炭素原子を有するアリールまたは7から15の炭素原子 を有するアラルキルであり; G1はハロゲン、OR1、SR2、NR3R4、C(=NH)NR3R4、NHC( = NH)NR3R4、CH=O、C(=O)OR5、CH(NR3R4)(C(=O) OR5)、C(=O)NR3R4、金属配位基、またはホスフェート基であり; G2はハロゲン、OH、SH、SCH3、またはNR3R4であり; G3はC(=O)、C(=S)、C(O)−O、C(O)−NH、C(S)− O、C(S)−NHまたはS(O)2であり; 各々のd1は独立して0または1であり; 各々のd2は独立して0から6であり; 各々のd3は独立して1から6であり; R1はH、1から約6の炭素原子を有するアルキル、またはヒドロキシル保護 基であり; R2はH、1から約6の炭素原子を有するアルキル、またはチオール保護基で あり; R3およびR4は独立してH、1から約6の炭素原子を有するアルキル、または アミン保護基であり; R5はH、1から約6の炭素原子を有するアルキル、または酸保護基であり; および E1およびE2の一つは前記ホスホジエステルまたはホスホロチオエートオリゴ ヌクレオチドを含み、および前記E1およびE2の他方がH、ヒドロキシル保護基 またはコンジュゲート基である]。 22. Lが約2から約10の炭素を有するアルキルである請求項21に記載の 化合物。 23. YおよびTが一緒に窒素ヘテロ環に組み込まれている請求項21に記載 の化合物。 24. 前記ヘテロ環がピペリジンまたはピロリジンである請求項23に記載の 化合物。 25. E1がH、ヒドロキシル保護基、または活性化固体支持体である請求項 21に記載の化合物。 26. E2がトリチル、メトキシトリチル、ジメトキシトリチルまたはトリメ トキシトリチルである請求項21に記載の化合物。 27. E2がHまたはヒドロキシル保護基である請求項21に記載の化合物。 28. Z2がHである請求項21に記載の化合物。 29. Z1がプリンまたはピリミジンである請求項21に記載の化合物。 30. Z1がアデニン、グアニン、シトシン、ウリジンまたはチミンである請 求項29に記載の化合物。 31. Z1が1から約20の炭素原子を有するアルキルである請求項1に記載 の化合物。 32. Z1が6から約14の炭素原子を有するアリールまたは7から約15の 炭素原子を有するアラルキルである請求項21に記載の化合物。 33. Z1がフルオレニルメチル、フェニル、またはベンジルである請求項2 1に記載の化合物。 34. Z1がポリエチレングリコールまたはグルタミルである請求項21に記 載の化合物。 35. mが約2から約25である請求項21に記載の化合物。 36. XがOである請求項21に記載の化合物。 37. XがSである請求項21に記載の化合物。 記載の化合物。 40. 少なくとも一つの前記L基が他の前記L基と異なっている請求項21に 記載の化合物。
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US08/200,638 US5637684A (en) | 1994-02-23 | 1994-02-23 | Phosphoramidate and phosphorothioamidate oligomeric compounds |
US08/200,638 | 1994-02-23 | ||
US200,638 | 1994-02-23 | ||
PCT/US1995/002267 WO1995023160A1 (en) | 1994-02-23 | 1995-02-23 | Novel phosphoramidate and phophorothioamidate oligomeric compounds |
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JPH09509663A true JPH09509663A (ja) | 1997-09-30 |
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AT (1) | ATE224908T1 (ja) |
AU (1) | AU677150B2 (ja) |
CA (1) | CA2184005C (ja) |
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JPWO2018230624A1 (ja) * | 2017-06-16 | 2020-06-11 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 修飾核酸モノマー化合物及びオリゴ核酸類縁体 |
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EP0751948B1 (en) | 2002-09-25 |
WO1995023160A1 (en) | 1995-08-31 |
AU1969195A (en) | 1995-09-11 |
EP0751948A1 (en) | 1997-01-08 |
DE69528362D1 (de) | 2002-10-31 |
US5717083A (en) | 1998-02-10 |
EP0751948A4 (en) | 1997-03-19 |
JP2972344B2 (ja) | 1999-11-08 |
CA2184005C (en) | 2000-01-25 |
ATE224908T1 (de) | 2002-10-15 |
AU677150B2 (en) | 1997-04-10 |
US5637684A (en) | 1997-06-10 |
CA2184005A1 (en) | 1995-08-31 |
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