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 PDF

Info

Publication number: NO316902B1
Authority: NO; Norway
Prior art keywords: alkyl; phenyl; formula; compound; amino
Prior art date: 1994-01-26

Application number

NO19963092A

Other languages

English (en)

Norwegian (no)

Other versions

NO963092D0 (no

NO963092L (no

Inventor

Alain De Mesmaeker

Adrian Waldner

Jacques Lebreton

Marc-Olivier Bevierre

Catherine Lesueur

Original Assignee

Novartis Ag

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.)

1994-01-26

Filing date

1996-07-24

Publication date

2004-06-21

1994-01-26 Priority claimed from GB9401446A external-priority patent/GB9401446D0/en

1994-06-22 Priority claimed from GB9412526A external-priority patent/GB9412526D0/en

1996-07-24 Application filed by Novartis Ag filed Critical Novartis Ag

1996-07-24 Publication of NO963092D0 publication Critical patent/NO963092D0/no

1996-09-16 Publication of NO963092L publication Critical patent/NO963092L/no

2004-06-21 Publication of NO316902B1 publication Critical patent/NO316902B1/no

Links

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
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SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
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HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 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
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229910052905 tridymite Inorganic materials 0.000 description 1
ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
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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

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Health & Medical Sciences (AREA)
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Organic Chemistry (AREA)
Biochemistry (AREA)
Molecular Biology (AREA)
General Health & Medical Sciences (AREA)
Engineering & Computer Science (AREA)
Animal Behavior & Ethology (AREA)
Pharmacology & Pharmacy (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Genetics & Genomics (AREA)
Biotechnology (AREA)
Medicinal Chemistry (AREA)
Bioinformatics & Cheminformatics (AREA)
Oncology (AREA)
Communicable Diseases (AREA)
Virology (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)

NO19963092A 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 NO316902B1 (no)

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

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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 (de)
EP (1)	EP0741741B1 (de)
JP (1)	JPH09508134A (de)
AT (1)	ATE222921T1 (de)
AU (1)	AU697134B2 (de)
CA (1)	CA2180727A1 (de)
DE (1)	DE69527942T2 (de)
DK (1)	DK0741741T3 (de)
FI (1)	FI116677B (de)
HU (1)	HU220423B (de)
IL (1)	IL112424A0 (de)
NO (1)	NO316902B1 (de)
WO (1)	WO1995020597A1 (de)

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BR9408310A (pt) *	1993-12-13	1997-08-26	Procter & Gamble	Composição de amaciamento de tecido concentrada líquida de viscosidade estável
US6166197A (en) *	1995-03-06	2000-12-26	Isis Pharmaceuticals, Inc.	Oligomeric compounds having pyrimidine nucleotide (S) with 2'and 5 substitutions
WO1996027606A1 (en)	1995-03-06	1996-09-12	Isis Pharmaceuticals, Inc.	Improved process for the synthesis of 2'-o-substituted pyrimidines and oligomeric compounds therefrom
AU7286696A (en) *	1995-10-13	1997-05-07	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
US6686366B1 (en)	1998-06-02	2004-02-03	Osi Pharmaceuticals, Inc.	Compounds specific to adenosine A3 receptor and uses thereof
US6878716B1 (en)	1998-06-02	2005-04-12	Osi Pharmaceuticals, Inc.	Compounds specific to adenosine A1 receptor and uses thereof
JP4611524B2 (ja)	1998-06-02	2011-01-12	オーエスアイ・ファーマスーティカルズ・インコーポレーテッド	ピロロ［２，３ｄ］ピリミジン組成物およびその使用
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1995
- 1995-01-17 HU HU9602040A patent/HU220423B/hu not_active IP Right Cessation
- 1995-01-17 WO PCT/EP1995/000156 patent/WO1995020597A1/en not_active Ceased
- 1995-01-17 DE DE69527942T patent/DE69527942T2/de not_active Expired - Fee Related
- 1995-01-17 EP EP95906958A patent/EP0741741B1/de not_active Expired - Lifetime
- 1995-01-17 JP JP7519861A patent/JPH09508134A/ja active Pending
- 1995-01-17 AT AT95906958T patent/ATE222921T1/de not_active IP Right Cessation
- 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 DK DK95906958T patent/DK0741741T3/da active
- 1995-01-17 AU AU15347/95A patent/AU697134B2/en not_active Ceased
- 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
CA2180727A1 (en)	1995-08-03
US6066447A (en)	2000-05-23
JPH09508134A (ja)	1997-08-19
NO963092D0 (no)	1996-07-24
EP0741741A1 (de)	1996-11-13
EP0741741B1 (de)	2002-08-28
DE69527942D1 (de)	2002-10-02
FI962980A0 (fi)	1996-07-26
ATE222921T1 (de)	2002-09-15
DE69527942T2 (de)	2003-03-27
NO963092L (no)	1996-09-16
WO1995020597A1 (en)	1995-08-03
FI116677B (fi)	2006-01-31
FI962980L (fi)	1996-07-26
HUT75704A (en)	1997-05-28
DK0741741T3 (da)	2002-12-23
AU1534795A (en)	1995-08-15
HU9602040D0 (en)	1996-09-30
HU220423B (hu)	2002-01-28
AU697134B2 (en)	1998-09-24
IL112424A0 (en)	1995-03-30

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JP3911703B2 (ja)	2007-05-09	アンチセンス核酸同族体
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JPH08119945A (ja)	1996-05-14	新規ヌクレオチド類縁体
WO1996018640A9 (de)	1998-07-16