NO316902B1 - Oligonukleotider og modifiserte nukleotiddimerer, samt fremgangsmate for a fremstille dimeren og anvendelse av denne for fremstilling av oligonukleotidene, og et farmasoytisk preparat omfattende oligonukleotidene - Google Patents
Oligonukleotider og modifiserte nukleotiddimerer, samt fremgangsmate for a fremstille dimeren og anvendelse av denne for fremstilling av oligonukleotidene, og et farmasoytisk preparat omfattende oligonukleotidene Download PDFInfo
- Publication number
- NO316902B1 NO316902B1 NO19963092A NO963092A NO316902B1 NO 316902 B1 NO316902 B1 NO 316902B1 NO 19963092 A NO19963092 A NO 19963092A NO 963092 A NO963092 A NO 963092A NO 316902 B1 NO316902 B1 NO 316902B1
- Authority
- NO
- Norway
- Prior art keywords
- alkyl
- phenyl
- formula
- compound
- amino
- Prior art date
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- 125000003729 nucleotide group Chemical group 0.000 title claims abstract description 20
- 108091034117 Oligonucleotide Proteins 0.000 title claims description 80
- 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 claims description 44
- 239000000539 dimer Substances 0.000 title claims description 19
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 7
- 238000000034 method Methods 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title description 12
- 239000002777 nucleoside Substances 0.000 claims abstract description 19
- 125000003835 nucleoside group Chemical group 0.000 claims abstract description 16
- 239000002773 nucleotide Substances 0.000 claims abstract description 9
- 150000003833 nucleoside derivatives Chemical class 0.000 claims abstract description 3
- -1 pyrimidine radical Chemical group 0.000 claims description 200
- 150000001875 compounds Chemical class 0.000 claims description 179
- 125000000217 alkyl group Chemical group 0.000 claims description 130
- 229910052739 hydrogen Inorganic materials 0.000 claims description 92
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 59
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 45
- 229910052799 carbon Inorganic materials 0.000 claims description 43
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 36
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 28
- 125000004432 carbon atom Chemical group C* 0.000 claims description 28
- 125000006239 protecting group Chemical group 0.000 claims description 27
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 24
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 23
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 150000003254 radicals Chemical class 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 229910052801 chlorine Inorganic materials 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 229910052794 bromium Inorganic materials 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 13
- 125000004414 alkyl thio group Chemical group 0.000 claims description 13
- 239000000138 intercalating agent Substances 0.000 claims description 12
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims description 12
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 9
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000005210 alkyl ammonium group Chemical group 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 6
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 6
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Natural products NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 6
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910052698 phosphorus Inorganic materials 0.000 claims description 6
- 239000011574 phosphorus Substances 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 5
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 239000000178 monomer Substances 0.000 claims description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000006678 phenoxycarbonyl group Chemical group 0.000 claims description 5
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 5
- 229940113082 thymine Drugs 0.000 claims description 5
- OIVLITBTBDPEFK-UHFFFAOYSA-N 5,6-dihydrouracil Chemical compound O=C1CCNC(=O)N1 OIVLITBTBDPEFK-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 229940104302 cytosine Drugs 0.000 claims description 4
- 125000006182 dimethyl benzyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- 125000005059 halophenyl group Chemical group 0.000 claims description 4
- 125000006178 methyl benzyl group Chemical group 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 4
- 229940035893 uracil Drugs 0.000 claims description 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 3
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 3
- MSSXOMSJDRHRMC-UHFFFAOYSA-N 9H-purine-2,6-diamine Chemical compound NC1=NC(N)=C2NC=NC2=N1 MSSXOMSJDRHRMC-UHFFFAOYSA-N 0.000 claims description 3
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 3
- 229930024421 Adenine Natural products 0.000 claims description 3
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 229960000643 adenine Drugs 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 3
- 125000006177 alkyl benzyl group Chemical group 0.000 claims description 3
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000006278 bromobenzyl group Chemical group 0.000 claims description 3
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 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 description 3
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims description 3
- 125000005647 linker group Chemical group 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 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
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- CFIBTBBTJWHPQV-UHFFFAOYSA-N 2-methyl-n-(6-oxo-3,7-dihydropurin-2-yl)propanamide Chemical compound N1C(NC(=O)C(C)C)=NC(=O)C2=C1N=CN2 CFIBTBBTJWHPQV-UHFFFAOYSA-N 0.000 claims description 2
- FXGXEFXCWDTSQK-UHFFFAOYSA-N 2-methylsulfanyl-7h-purin-6-amine Chemical compound CSC1=NC(N)=C2NC=NC2=N1 FXGXEFXCWDTSQK-UHFFFAOYSA-N 0.000 claims description 2
- LQLQRFGHAALLLE-UHFFFAOYSA-N 5-bromouracil Chemical compound BrC1=CNC(=O)NC1=O LQLQRFGHAALLLE-UHFFFAOYSA-N 0.000 claims description 2
- ZFTBZKVVGZNMJR-UHFFFAOYSA-N 5-chlorouracil Chemical compound ClC1=CNC(=O)NC1=O ZFTBZKVVGZNMJR-UHFFFAOYSA-N 0.000 claims description 2
- LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical compound CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 claims description 2
- QQJXZVKXNSFHRI-UHFFFAOYSA-N 6-Benzamidopurine Chemical compound N=1C=NC=2N=CNC=2C=1NC(=O)C1=CC=CC=C1 QQJXZVKXNSFHRI-UHFFFAOYSA-N 0.000 claims description 2
- RYYIULNRIVUMTQ-UHFFFAOYSA-N 6-chloroguanine Chemical compound NC1=NC(Cl)=C2N=CNC2=N1 RYYIULNRIVUMTQ-UHFFFAOYSA-N 0.000 claims description 2
- CKOMXBHMKXXTNW-UHFFFAOYSA-N 6-methyladenine Chemical compound CNC1=NC=NC2=C1N=CN2 CKOMXBHMKXXTNW-UHFFFAOYSA-N 0.000 claims description 2
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 claims description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 2
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 claims description 2
- 150000004056 anthraquinones Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 229960002949 fluorouracil Drugs 0.000 claims description 2
- 230000003993 interaction Effects 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 229910003204 NH2 Inorganic materials 0.000 claims 3
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- CRIZPXKICGBNKG-UHFFFAOYSA-N 3,7-dihydropurin-2-one Chemical compound OC1=NC=C2NC=NC2=N1 CRIZPXKICGBNKG-UHFFFAOYSA-N 0.000 claims 1
- YEGKYFQLKYGHAR-UHFFFAOYSA-N 6-methylthioguanine Chemical compound CSC1=NC(N)=NC2=C1NC=N2 YEGKYFQLKYGHAR-UHFFFAOYSA-N 0.000 claims 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 123
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 112
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 100
- 239000000243 solution Substances 0.000 description 96
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 89
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 72
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 69
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 62
- 239000011541 reaction mixture Substances 0.000 description 61
- 238000005160 1H NMR spectroscopy Methods 0.000 description 60
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
- 239000000203 mixture Substances 0.000 description 54
- 238000003818 flash chromatography Methods 0.000 description 42
- 239000000741 silica gel Substances 0.000 description 42
- 229910002027 silica gel Inorganic materials 0.000 description 42
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 38
- 239000002904 solvent Substances 0.000 description 32
- 239000012047 saturated solution Substances 0.000 description 30
- 239000011780 sodium chloride Substances 0.000 description 29
- 239000011734 sodium Substances 0.000 description 28
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 27
- 239000000377 silicon dioxide Substances 0.000 description 27
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 27
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 19
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 17
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 17
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- 238000001704 evaporation Methods 0.000 description 15
- 230000008020 evaporation Effects 0.000 description 15
- 229920006395 saturated elastomer Polymers 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
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- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
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- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(I) nitrate Inorganic materials [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
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- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- FCFMKFHUNDYKEG-UHFFFAOYSA-N thietane 1,1-dioxide Chemical compound O=S1(=O)CCC1 FCFMKFHUNDYKEG-UHFFFAOYSA-N 0.000 description 1
- 239000001585 thymus vulgaris Substances 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- YLGRTLMDMVAFNI-UHFFFAOYSA-N tributyl(prop-2-enyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)CC=C YLGRTLMDMVAFNI-UHFFFAOYSA-N 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
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- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Biotechnology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Genetics & Genomics (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Compositions Of Macromolecular Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9401446A GB9401446D0 (en) | 1994-01-26 | 1994-01-26 | Modified oligonucleotides |
| GB9412526A GB9412526D0 (en) | 1994-06-22 | 1994-06-22 | Modified oligonucleotides |
| PCT/EP1995/000156 WO1995020597A1 (en) | 1994-01-26 | 1995-01-17 | Modified oligonucleotides |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO963092D0 NO963092D0 (no) | 1996-07-24 |
| NO963092L NO963092L (no) | 1996-09-16 |
| NO316902B1 true NO316902B1 (no) | 2004-06-21 |
Family
ID=26304218
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO19963092A NO316902B1 (no) | 1994-01-26 | 1996-07-24 | Oligonukleotider og modifiserte nukleotiddimerer, samt fremgangsmate for a fremstille dimeren og anvendelse av denne for fremstilling av oligonukleotidene, og et farmasoytisk preparat omfattende oligonukleotidene |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US6066447A (da) |
| EP (1) | EP0741741B1 (da) |
| JP (1) | JPH09508134A (da) |
| AT (1) | ATE222921T1 (da) |
| AU (1) | AU697134B2 (da) |
| CA (1) | CA2180727A1 (da) |
| DE (1) | DE69527942T2 (da) |
| DK (1) | DK0741741T3 (da) |
| FI (1) | FI116677B (da) |
| HU (1) | HU220423B (da) |
| IL (1) | IL112424A0 (da) |
| NO (1) | NO316902B1 (da) |
| WO (1) | WO1995020597A1 (da) |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2144603T5 (es) * | 1993-12-13 | 2004-11-16 | THE PROCTER & GAMBLE COMPANY | Composiciones liquidas concentradas, de viscosidad estable, de suavizante para materiales textiles. |
| US6166197A (en) * | 1995-03-06 | 2000-12-26 | Isis Pharmaceuticals, Inc. | Oligomeric compounds having pyrimidine nucleotide (S) with 2'and 5 substitutions |
| US6222025B1 (en) | 1995-03-06 | 2001-04-24 | Isis Pharmaceuticals, Inc. | Process for the synthesis of 2′-O-substituted pyrimidines and oligomeric compounds therefrom |
| WO1997014709A1 (en) * | 1995-10-13 | 1997-04-24 | F. Hoffmann-La Roche Ag | Antisense oligomers |
| US5808035A (en) * | 1995-12-08 | 1998-09-15 | Usher; David A. | Protected nucleoside and method for its synthesis |
| WO1998000434A1 (en) * | 1996-06-28 | 1998-01-08 | Novartis Ag | Modified oligonucleotides |
| PL337888A1 (en) | 1997-07-03 | 2000-09-11 | Du Pont Pharm Co | Imidazoprimidines and imidazopyridines for use in treating neurological disorders |
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| HUP0103836A3 (en) | 1998-06-02 | 2003-05-28 | Osi Pharmaceuticals Inc Uniond | Pyrrolo[2,3d]pyrimidine compositions and their use |
| US6878716B1 (en) | 1998-06-02 | 2005-04-12 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A1 receptor and uses thereof |
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| US6664252B2 (en) | 1999-12-02 | 2003-12-16 | Osi Pharmaceuticals, Inc. | 4-aminopyrrolo[2,3-d]pyrimidine compounds specific to adenosine A2a receptor and uses thereof |
| US6673802B2 (en) | 2000-12-01 | 2004-01-06 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A3 receptor and uses thereof |
| US6680324B2 (en) | 2000-12-01 | 2004-01-20 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A1 receptors and uses thereof |
| DE60234118D1 (de) | 2001-11-30 | 2009-12-03 | Osi Pharm Inc | Verbindungen, die für Adenosin A1 und A3 Rezeptoren spezifisch sind, und deren Anwendungen |
| US20030229067A1 (en) | 2001-12-20 | 2003-12-11 | Arlindo Castelhano | Pyrrolopyrimidine A2b selective antagonist compounds, their synthesis and use |
| ATE458483T1 (de) | 2001-12-20 | 2010-03-15 | Osi Pharm Inc | Selektive pyrimidin-a2b-antagonistenverbindungen, ihre synthese und verwendung |
| KR100649352B1 (ko) * | 2005-04-30 | 2006-11-27 | 주식회사 하이닉스반도체 | 반도체소자의 제조 방법 |
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| MX2011010050A (es) | 2009-03-25 | 2011-12-14 | Univ Texas | Composiciones para estimulación de resistencia inmune innata de mamiferos a patógenos. |
| WO2016044839A2 (en) | 2014-09-19 | 2016-03-24 | The Board Of Regents Of The University Of Texas System | Compositions and methods for treating viral infections through stimulated innate immunity in combination with antiviral compounds |
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|---|---|---|---|---|
| US4806463A (en) * | 1986-05-23 | 1989-02-21 | Worcester Foundation For Experimental Biology | Inhibition of HTLV-III by exogenous oligonucleotides |
| EP0266099A3 (en) * | 1986-10-28 | 1990-09-19 | The Johns Hopkins University | Oligonucleoside alkyl or arylphosphonate derivatives capable of crosslinking with or cleaving nucleic acids |
| WO1989008146A1 (en) * | 1988-02-26 | 1989-09-08 | Worcester Foundation For Experimental Biology | Inhibition of htlv-iii by exogenous oligonucleotides |
| DK0942000T3 (da) * | 1989-10-24 | 2004-11-01 | Isis Pharmaceuticals Inc | 2'-modificerede oligonukleotider |
| US5378825A (en) * | 1990-07-27 | 1995-01-03 | Isis Pharmaceuticals, Inc. | Backbone modified oligonucleotide analogs |
| ATE131827T1 (de) * | 1990-08-03 | 1996-01-15 | Sterling Winthrop Inc | Verbindungen und verfahren zur unterdrückung der genexpression |
| EP0549686A4 (en) * | 1990-09-20 | 1995-01-18 | Gilead Sciences Inc | Modified internucleoside linkages |
-
1995
- 1995-01-17 JP JP7519861A patent/JPH09508134A/ja active Pending
- 1995-01-17 AU AU15347/95A patent/AU697134B2/en not_active Ceased
- 1995-01-17 EP EP95906958A patent/EP0741741B1/en not_active Expired - Lifetime
- 1995-01-17 WO PCT/EP1995/000156 patent/WO1995020597A1/en not_active Ceased
- 1995-01-17 AT AT95906958T patent/ATE222921T1/de not_active IP Right Cessation
- 1995-01-17 DK DK95906958T patent/DK0741741T3/da active
- 1995-01-17 US US08/687,456 patent/US6066447A/en not_active Expired - Fee Related
- 1995-01-17 CA CA002180727A patent/CA2180727A1/en not_active Abandoned
- 1995-01-17 HU HU9602040A patent/HU220423B/hu not_active IP Right Cessation
- 1995-01-17 DE DE69527942T patent/DE69527942T2/de not_active Expired - Fee Related
- 1995-01-24 IL IL11242495A patent/IL112424A0/xx unknown
-
1996
- 1996-07-24 NO NO19963092A patent/NO316902B1/no unknown
- 1996-07-26 FI FI962980A patent/FI116677B/fi active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| HUT75704A (en) | 1997-05-28 |
| HU220423B (hu) | 2002-01-28 |
| WO1995020597A1 (en) | 1995-08-03 |
| NO963092D0 (no) | 1996-07-24 |
| EP0741741A1 (en) | 1996-11-13 |
| EP0741741B1 (en) | 2002-08-28 |
| AU1534795A (en) | 1995-08-15 |
| IL112424A0 (en) | 1995-03-30 |
| NO963092L (no) | 1996-09-16 |
| DE69527942T2 (de) | 2003-03-27 |
| FI962980A0 (fi) | 1996-07-26 |
| CA2180727A1 (en) | 1995-08-03 |
| HU9602040D0 (en) | 1996-09-30 |
| FI962980L (fi) | 1996-07-26 |
| FI116677B (fi) | 2006-01-31 |
| US6066447A (en) | 2000-05-23 |
| DK0741741T3 (da) | 2002-12-23 |
| JPH09508134A (ja) | 1997-08-19 |
| AU697134B2 (en) | 1998-09-24 |
| ATE222921T1 (de) | 2002-09-15 |
| DE69527942D1 (de) | 2002-10-02 |
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