PT1013661E - 2'-o,4'-c-metileno-biciclonucleósidos - Google Patents
2'-o,4'-c-metileno-biciclonucleósidos Download PDFInfo
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- PT1013661E PT1013661E PT98905804T PT98905804T PT1013661E PT 1013661 E PT1013661 E PT 1013661E PT 98905804 T PT98905804 T PT 98905804T PT 98905804 T PT98905804 T PT 98905804T PT 1013661 E PT1013661 E PT 1013661E
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- Portugal
- Prior art keywords
- group
- compound
- nucleic acid
- pyrimidine
- derivative
- Prior art date
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- -1 purine nucleic acid Chemical group 0.000 claims abstract description 48
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 31
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 31
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims abstract description 24
- 125000000714 pyrimidinyl group Chemical group 0.000 claims abstract description 9
- 229940127073 nucleoside analogue Drugs 0.000 claims description 21
- 239000002777 nucleoside Substances 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 14
- 125000002103 4,4'-dimethoxytriphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)(C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H])C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 13
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 12
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 12
- 125000002252 acyl group Chemical group 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 125000000304 alkynyl group Chemical group 0.000 claims description 10
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 10
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 8
- 229940104302 cytosine Drugs 0.000 claims description 6
- 229940035893 uracil Drugs 0.000 claims description 6
- 229930024421 Adenine Natural products 0.000 claims description 5
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 5
- 229960000643 adenine Drugs 0.000 claims description 5
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 claims description 4
- 229960003495 thiamine Drugs 0.000 claims description 4
- 235000019157 thiamine Nutrition 0.000 claims description 4
- 239000011721 thiamine Substances 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([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
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 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 2
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 claims description 2
- 125000001990 thiamine group Chemical group 0.000 claims 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical group CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims 2
- 229940113082 thymine Drugs 0.000 claims 1
- 108091034117 Oligonucleotide Proteins 0.000 abstract description 36
- 238000001727 in vivo Methods 0.000 abstract description 5
- 108091081021 Sense strand Proteins 0.000 abstract description 4
- 108091033319 polynucleotide Proteins 0.000 abstract description 4
- 102000040430 polynucleotide Human genes 0.000 abstract description 4
- 239000002157 polynucleotide Substances 0.000 abstract description 4
- 102000004190 Enzymes Human genes 0.000 abstract description 2
- 108090000790 Enzymes Proteins 0.000 abstract description 2
- 230000000692 anti-sense effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- 239000000243 solution Substances 0.000 description 57
- 150000001875 compounds Chemical class 0.000 description 49
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 39
- 230000015572 biosynthetic process Effects 0.000 description 39
- 238000003786 synthesis reaction Methods 0.000 description 36
- 238000005481 NMR spectroscopy Methods 0.000 description 34
- 239000000203 mixture Substances 0.000 description 34
- 125000003729 nucleotide group Chemical group 0.000 description 31
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 30
- 239000002904 solvent Substances 0.000 description 30
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
- 229910052757 nitrogen Inorganic materials 0.000 description 28
- 239000011541 reaction mixture Substances 0.000 description 28
- 239000012043 crude product Substances 0.000 description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- 238000010898 silica gel chromatography Methods 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 108020004414 DNA Proteins 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
- 238000004821 distillation Methods 0.000 description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- 239000000843 powder Substances 0.000 description 17
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 15
- 239000012267 brine Substances 0.000 description 15
- 229910052938 sodium sulfate Inorganic materials 0.000 description 15
- 235000011152 sodium sulphate Nutrition 0.000 description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 13
- 239000002773 nucleotide Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 150000007523 nucleic acids Chemical class 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 6
- KWQCNAXZKYMWAL-DLTWYDFYSA-N 1-[(1r,4s,6r,7s)-4-(hydroxymethyl)-7-phenylmethoxy-2,5-dioxabicyclo[2.2.1]heptan-6-yl]pyrimidine-2,4-dione Chemical compound N1([C@@H]2O[C@]3(CO[C@@]2([C@@H]3OCC=2C=CC=CC=2)[H])CO)C=CC(=O)NC1=O KWQCNAXZKYMWAL-DLTWYDFYSA-N 0.000 description 6
- KNLNWXXWKDEEFW-JIOCBJNQSA-N 1-[(1r,4s,6r,7s)-7-hydroxy-4-(hydroxymethyl)-2,5-dioxabicyclo[2.2.1]heptan-6-yl]pyrimidine-2,4-dione Chemical compound N1([C@@H]2O[C@]3(CO[C@@]2([C@@H]3O)[H])CO)C=CC(=O)NC1=O KNLNWXXWKDEEFW-JIOCBJNQSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 229940126657 Compound 17 Drugs 0.000 description 6
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 229940125782 compound 2 Drugs 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 101710163270 Nuclease Proteins 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 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 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 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 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 229940126214 compound 3 Drugs 0.000 description 5
- 229940125898 compound 5 Drugs 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 5
- 229940045145 uridine Drugs 0.000 description 5
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 4
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 4
- 108020004394 Complementary RNA Proteins 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000007832 Na2SO4 Substances 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 238000010533 azeotropic distillation Methods 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 229940126142 compound 16 Drugs 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 4
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- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
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- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
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Description
ΡΕ1013661 1
DESCRIÇÃO "2'-Ο,4'-C-METILENO-BICICLONUCLEOSIDOS"
Esta invenção diz respeito a análogos de nucleó-sidos inovadores e à sua utilização em análogos de nucleótidos e, mais especificamente, em análogos de nucleó-tidos apropriados para serem utilizados como moléculas de sentido reverso.
TÉCNICA ANTERIOR
Em 1978, relatou-se pela primeira vez que uma molécula de sentido reverso inibia infecções provocadas pelo vírus da grupe. Desde então, emitiram-se relatórios que defendiam que as moléculas de sentido reverso inibiam a expressão de oncogenes e a infecção com SIDA. Nos últimos anos, oligonucleótidos de sentido reverso têm-se tornado nuns dos produtos farmacêuticos mais promissores, uma vez que controlam especificamente a expressão de genes indesej áveis. 0 método de sentido reverso encontra-se baseado na ideia de controlar uma corrente unidireccional sendo designado por dogma central, i.e., ADN ARN -► proteína, por intermédio da utilização de um oligonucleótido de sentido reverso. 2 ΡΕ1013661
No entanto, ao aplicar-se um oligonucleótido disponível na natureza a este método, como molécula de sentido reverso, este decompôs-se com várias nucleases em vivo, ou a sua permeação através da membrana celular não foi elevada. Para se resolverem estes problemas, sintetizaram-se vários derivados e análogos de ácido nucleico, e levaram-se a cabo os seus respectivos estudos. Os exemplos de produtos sintetizados incluem um fosforotioato, tendo um átomo de enxofre em substituição de um átomo de oxigénio no átomo de fósforo, e um metilfosfonato tendo um grupo de metilo de substituição. Recentemente, sintetizaram-se produtos em que o átomo de fósforo também tem sido substituído por um átomo de carbono, ou em que a estrutura da porção se modificou, ou em que a base de ácido nucleico se modificou. No entanto, quaisquer derivados ou análogos resultantes não têm sido plenamente satisfatórios em termos da estabilidade em vivo, da facilidade de síntese, e da especificidade da sequência (a propriedade em que se controla selectivamente a expressão de um gene específico isoladamente).
Obika et al. ("Properties of Novel Oligonucleo-tide Analogues Containing an Acyclic Nucleoside and a Carbamate Linkage", Bioorganic & Medicinal Chemistry Letters, 6(12) (1996) p.1357-1360) descrevem heterodímeros contendo um nucleósido acíclico e uma ligação de carbamato na posição 3' incorporada em oligonucleótidos. Estudaram-se as temperaturas de fusão dos dímeros de ADN-ADN e ADN-ARN 3 ΡΕ1013661 bem como a resistência da nuclease dos oligonucleótidos modificados.
Nestas circunstâncias, tem surgido procura para a criação de uma molécula de sentido reverso que se decomponha minimamente com uma nuclease em vivo, se ligue ao mensageiro-alvo do ARN com afinidade elevada, tenha especificidade elevada e que, assim, possa controlar eficientemente a expressão de um gene especifico.
DESCRIÇÃO DA INVENÇÃO
Os inventores da invenção presente conceberam um análogo de ácido nucleico com configuração imobilizada da porção de açúcar presente num ácido nucleico, que teria utilidade no método de sentido reverso. Sintetizaram um análogo de nucleósido que irá, portanto, ser uma estrutura unitária, e confirmaram que um análogo de oligonucleótido preparado com a sua utilização provou ser muito útil como molécula de sentido reverso.
BREVE DESCRIÇÃO DAS FIGURAS A Fig. 1 apresenta um gráfico que representa o decurso no tempo da absorção ultravioleta (260 nm) de um oligonucleótido decomposto com uma exonuclease; e A Fig. 2 apresenta um gráfico que representa o decurso no tempo da absorção ultravioleta (260 nm) de um 4 ΡΕ1013661 oligonucleótido preparado com a utilização de um análogo de nucleósido análogo ao da invenção presente (X2) decomposto com uma exonuclease.
Em seguida descrevem-se os detalhes das invenção presente. A estrutura de um análogo de nucleósido de acordo com a invenção presente é um análogo de nucleósido com a fórmula geral (I) seguinte
X—O· d) em que B seja uma base de ácido nucleico de pirimidina ou de purina, ou um seu análogo, e X e Y sejam idênticos ou diferentes, e cada um destes representa um átomo de hidrogénio, um grupo alquilo, um grupo alcenilo, um grupo alcinilo, um grupo cicloalquilo, um grupo aralquilo, um grupo arilo, um grupo acilo, ou um grupo sililo, ou um seu derivado de amidito. 0 grupo alquilo representa um grupo alquilo, de cadeia linear ou cadeia ramificada, com 1 a 20 átomos de carbono. Os seus exemplos incluem metilo, etilo, n-propilo, 5 ΡΕ1013661 i-propilo, n-butilo, t-butilo, pentilo, hexilo, heptilo, octilo, nonilo e decilo. 0 grupo alcenilo representa um grupo alcenilo, de cadeia linear ou cadeia ramificada, com 2 a 20 átomos de carbono. Os seus exemplos incluem vinilo, alilo, butenilo, pentenilo, geranilo, e farnesilo. O grupo alcinilo representa um grupo alcinilo, de cadeia linear ou cadeia ramificada, com 2 a 20 átomos de carbono. Os seus exemplos incluem etinilo, propinilo, e butinilo. 0 grupo cicloalquilo representa um grupo cicloalquilo, com 3 a 8 átomos de carbono, e inclui, por exemplo, ciclopropilo, ciclobutilo, ciclopentilo, ciclo-hexilo, ciclo-heptilo, e ciclo-octilo. Outro exemplo é um grupo heterociclico em que um ou mais grupos metileno arbitrários no anel do grupo cicloalquilo foram substituídos por um átomo de oxigénio, um átomo de enxofre, ou um átomo de azoto alquilo-substituído. Este será, por exemplo, um grupo tetra-hidropiranilo. 0 grupo arilo diz respeito a um substituinte monovalente formado pela remoção de um átomo de hidrogénio a partir de um grupo heterociclico aromático ou um grupo hidrocarboneto aromático. De preferência, este representa um substituinte monovalente formado pela remoção de um átomo de hidrogénio a partir de um grupo heterociclico 6 ΡΕ1013661 aromático ou um grupo hidrocarboneto aromático, e inclui, por exemplo, fenilo, toluilo, xililo, bifenilo, naftilo, antrilo, e fenantrilo. 0 átomo de carbono no anel do grupo arilo pode ser substituído por um ou mais de entre um átomo de halogéneo, um grupo alquilo inferior, um grupo hidroxilo, um grupo alcoxilo, um grupo amino, um grupo nitro, e um grupo trifluorometilo. Neste caso o substituinte será, por exemplo, um átomo de halogéneo, um grupo hidroxilo, um grupo amino, um grupo alcoxilo, ou um grupo ariloxilo. 0 grupo aralquilo diz respeito a um grupo alquilo ligado a um grupo arilo, e que pode ser substituído. 0 grupo aralquilo que pode ser substituído representa um grupo alquilo ligado a um grupo arilo, com um ou mais átomos de hidrogénio arbitrários do grupo arilo e do grupo alquilo a serem substituídos opcionalmente pelos substituintes seguintes: Os exemplos de substituintes são acilo, amino, arilo, alquilo, cicloalquilo, alcoxilo, hidroxilo, nitro, e halogéneo. 0 grupo amino não necessita ser substituído, embora o grupo amino uma vez substituído inclua, por exemplo, alquilamino, arilamino, e acilamino. Os exemplos de grupos alcoxilo são metoxilo, etoxilo, n-propoxilo, i-propoxilo, n-butoxilo, i-butoxilo, s-butoxilo, t-butoxilo, pentiloxilo, hexiloxilo, e fenoxilo. Os exemplos de átomos de halogéneo são flúor, cloro, bromo, e iodo. 7 ΡΕ1013661
Os exemplos preferidos do grupo aralquilo são tritilo, benzilo, fenetilo, tritilmetilo, difenilmetilo, naftilmetilo, e 4,4'-dimetoxitritilo (DMTr). 0 grupo DMTr é especialmente preferido.
Tal como os grupos acilo, acetilo, formilo, propionilo, benzoilo, e benziloxicarbonilo se podem exemplificar. Um exemplo do grupo sililo é um grupo trial-quilsililo, de preferência trimetilsililo, trietilsililo, tri-isopropilsililo, t-butildimetilsililo ou t-butildife-nilsililo, e de preferência trimetilsililo. 0 análogo de nucleótido preparado a partir dos análogos de nucleósido da invenção presente é um análogo de oligonucleótido ou de polinucleótido tendo uma ou mais estruturas com a fórmula geral (Ia)
( la) em que B seja uma base de ácido nucleico de pirimidina ou de purina, ou um seu análogo, ou um análogo de oligonucleótido ou polinucleótido com a fórmula geral (II) ΡΕ1013661
em que B1 e B sejam idênticos ou diferentes, e cada qual representa uma base de ácido nucleico de pirimidina ou de purina, ou um seu análogo, R seja um átomo de hidrogénio, um grupo hidroxilo, um átomo de halogéneo, ou um grupo alcoxilo, W1 e W2 sejam idênticos ou diferentes, e cada qual representa um átomo de hidrogénio, um grupo alquilo, um grupo alcenilo, um grupo alcinilo, um grupo cicloalquilo, um grupo aralquilo, um grupo arilo, um grupo acilo, um grupo sililo, um resíduo de ácido fosfórico, um nucleósido que ocorre na natureza ou um nucleósido sintético ligado através de uma ligação fosfodiéster, ou um oligonucleótido ou polinucleótido contendo o nucleósido, n1 ou n2 sejam idênticos ou diferentes, e cada qual indica um número inteiro de 0 a 50, desde que os n1 ou n2 não sejam zero ao mesmo tempo, e desde que nem todos os n2 sejam zero ao mesmo tempo, n3 indica um número de 1 a 50, desde que quando n1 e/ou n2 sejam ou seja 2 ou seja 2 ou mais, B1 e B não têm que ser idênticos, e os R' não têm que ser necessariamente idênticos. A base de ácido nucleico de pirimidina ou de purina da invenção presente diz respeito a tiamina, ura-cilo, citosina, adenina, guanina, ou um seu derivado. 9 ΡΕ1013661 0 análogo de nucleósido da invenção presente pode ser sintetizado do modo abaixo descrito. (1) Síntese do análogo de nucleósido
7 B
Tratou-se o Composto 1, sintetizado a partir de uridina de acordo com a literatura [1) J.A. Secrist et al., J. Am. Chem. Soc., 101, 1554 (1979); 2) G.H. Jones et al., J. Org. Chem., 44, 1309 (1979)], com cloreto de tosilo (TsCl) para ser tosilado apenas um dos dois alcoóis primários, conduzindo ao Composto 2. 0 Composto 2 foi hidrolisado com ácido para se obter um triol, Composto 3. Condensou-se o Composto 3 com benzaldeido na presença de um catalisador ácido para se formar um benzilideno, Composto 4. Levou-se a cabo a redução do Composto 4 com cianoboro-hidreto de sódio (NaBH3CN) na presença de tetracloreto de 10 ΡΕ1013661 titânio (TiCl4) para se obter o Composto 5. Fez-se reagir este composto com hexametildisilazida de sódio (NaHMDS) em tetra-hidrofurano (THF) para se obter um biciclo, Composto 6 (Composto I: B = uracilo (U) , X = Η, Y = benzilo). Quando se efectuou cataliticamente a redução do Composto 6 na presença de um catalisador de paládio sobre carbono, obteve-se um diol, Composto 7 (Composto (I): B=U, X=Y= H) . Do tratamento posterior do Composto 7 com cloreto de 4,4'-dimetoxitritilo (DMTrCl) resultou num tritilo, Composto 8 (Composto I: B = U, X = DMTr, Y = H) . Os Compostos 6, 7 e 8 poderão ser utilizados como materiais de partida para a obtenção de vários compostos I.
Os compostos (I) tendo várias bases de ácido nucleico, tanto naturais como não naturais, que não a uridina, poderão ser sintetizados recorrendo a qualquer um dos três métodos seguintes: 0 primeiro método configura a conversão a partir do Composto 8. Isto é, acetila-se o Composto 8 para se obter o Composto 9, e em seguida faz-se reagir com 1,2,4-triazole para se formar o Composto 10. A hidrólise deste composto proporciona o Composto 11 (Composto (I): B = citosina (C) , X = DMTr, Y = H) . O Composto 12 (Composto (I) : B = benzoilcitosina (CBz) , X = DMTr, Y = Η) , que se irá tornar numa matéria de partida para a síntese de oligonucleótidos, poderá obter-se facilmente pela benzoilação do Composto 11. 11 ΡΕ1013661
0 segundo método é um método que se leva a cabo através do Composto 13 que se poderá obter facilmente a partir de D-ribose de acordo com a literatura [3 ) A.G.M. Barrett et al., J. Org. Chem., 55, 3853 (1990); 4) G.H. Jones et al., ibid. , 44, 1309 ( 1979) ] . Isto é, o Composto 13 foi conduzido ao Composto 16 em três passos, e ciclizado sob condições básicas para se obter um metilglicosilo desejado, Composto 17. 0 grupo OMe na posição 1 deste composto poderá ser substituído por diversas bases naturais de ácidos nucleicos ou bases não naturais análogas às dos ácidos nucleicos seguindo um de vários métodos que já foram desenvolvidos anteriormente. Por exemplo, pode aplicar-se um método tal como se representa por um esquema que vai do Composto 17 ao Composto 20.
HO
OH
OH OH 0-ribOSe c. HO reflux. 19 hr (SO %)
MeOH, aceona
Cr03f Py CH2CI2 rt, 20 <riin
H
1) p-dioxane rt 15 hr ( 37 %. 2 steps ) HCHO aq., NaOH aq.
2) (3 °X° 12 ΡΕ1013661 12 ΤΒθΡ3θ/80Ρ3°]^ο^ΟΟΗ3 TiCUOMAP TSOPSO-|^o-^ aaN/CH,C«z JW rsJrí 2\ rt. 13 hr ( 70 %) 14 ( 38 %) X ts
TTFA-HjO TH0P3ai NaHMOS THF rt, 20 min (77%)
Jp Ts<V OH OH THF rt, 1 hr TBOPSO.. OCHj TBDPSO· 16 (35%) 17
'0 OH (43 %) >8 OCH3
OTMS N
Me.
(7
AcgO TBOPSO·» oCH3 O MAPI Py rt, 3 hr ( 86 %) 'N- OTMS TMSOTT/ 1,1-dichloroethane CHjCN rt, 18 hr (ca. 70 %) - cy mFo 15
O terceiro método tem início em acetona-D-glucose, que se obtém a partir de D-glucose num só passo e se encontra disponível no comércio. Preparou-se o Composto 31 de acordo com a referência 5) R.D. Youssefyeh, J.P.H. Verheyden e J.G. Moffatt., J. Org. Chem., 44, 1301-1309 (1979) . Em seguida, tratou-se o Composto 31 tal como se representa pelo esquema seguinte para se protegerem os dois grupos hidroxilo primários com um grupo t-butildifenil-sililo e um grupo p-toluenossulfonilo, progressivamente. Acetilou-se o composto protegido para se obter o Composto 13 ΡΕ1013661
TBDPSOk _ HGT OSn 32
TsC)/ DM AP / Et3N TBOPSCk, CH2q2 f f L TsCT 97% iBn 33
AcOH / Ac20/ conc. H^SOí rt 86% TBDPS* Ts( iriíiAc 34
Condensou-se o Composto 34, separadamente, com tiamina, benzoiladenina, e isobutirilguanina activada por trimetilsililação (referidos como 2TMS*T, 2TMS*ABz, e 3TMS*GlBu, respectivamente) , para se obterem os Compostos 35, 40 e 44 com elevados rendimentos, tal como se representa no esquema colocado abaixo. Em seguida, sujeitaram-se estes condensados à desacetilação (Compostos 36, 41, 45), formação de anéis com cinco membros (Compostos 37, 42, 46), des-sililação (Compostos 38, 43, 47), e mais desbenzilação para se formarem os Compostos 39 pretendidos.
34 2TMS · T or 2TMS · A®* or 3TMS · G®u
TMS OTI/CIC HjCH jCI TBOPS' Ts< aq. K2C03 / MeOH "7t ~ rt. (70-97%) 35: 8=T 40: 8»Aa* 44: 8*Gi0u (64-92%) 14 ΡΕ1013661
B TBDPSl
TsOr ôsn OH
NaHMOS/THF TBOPi TBAF/THF rt. 38: B=.T +1: B=ASl 45: B»QISu (44-100%) (83-100%)
37: B=T At B=ABi 48: B=G®U
Htf 20%Pd(OH)a-C HO· MeOH rl 96% 38: B=T -Μίβ-Α31 47: BbGí6m ai iSu
39a: B=>T 39b: B=A 39c: B=G (2) Síntese do análogo de oligonucleótido
Faz-se reagir o Composto 8 com 2-cianoetil-N,N, N'N'-tetraisopropilfosforamidito para se obter um amidito, Composto 21. Combina-se este composto com amidito nucleósi-do que ocorre na natureza, e sujeita-se a um sintetizador de ADN para se sintetizarem vários análogos de oligonucleó-tidos. Purificam-se os produtos impuros sintetizados uma coluna cromatográfica de fase reversa (Oligo-Pak). Analisa-se o grau de pureza do produto purificado por HPLC, altura em que se poderá confirmar quanto à formação de um análogo de oligonucleótido. jtaidfc de nadeàskkí natai
21 15 ΡΕ1013661
Pelo menos uma unidade de monómero sob a forma de Composto 8 pode ser contida no análogo de oligonucleótido. Alternativamente, as unidades de monómero podem estar presentes em duas ou mais localizações no análogo de oligonucleótido de tal forma que se separem de cada qual através de um ou mais nucleótidos que ocorrem na natureza. A invenção presente torna possível sintetizar uma molécula de sentido reverso incorporando um número necessário de análogos de nucleótido (análogos de nucleósido) da invenção (um comprimento necessário do análogo de nucleótido ou nucleósido) numa localização necessária. 0 comprimento da totalidade do análogo de oligonucleótido é de 2 a 50, 10 a 30 de preferência, unidades de nucleósido.
Um tal análogo de nucleótido (molécula de sentido reverso) é minimamente degradável por várias nucleases, e pode existir em vivo durante um longo período de tempo após a sua administração. Esta molécula de sentido reverso opera, por exemplo, na formação de uma dupla hélice estável em conjunto com um ARN mensageiro, inibindo assim a biossíntese de uma proteína potencialmente patogénica; ou forma uma tripla hélice em combinação com ADN de cadeia dupla num genoma para se inibir a transcrição para ARN mensageiro. O análogo de oligonucleótido também poderá suprimir a proliferação de um vírus que tenha provocado a infecção. À luz destas revelações, torna-se expectável que um análogo de nucleótido (molécula de sentido reverso) 16 ΡΕ1013661 utilizando um análogo de nucleósido da invenção presente tenha utilidade sob a forma de medicamentos, incluindo os antineoplásicos e os antivirais, para tratamento de doenças por inibição das acções especificas dos genes. A molécula de sentido reverso que utiliza o análogo de nucleótido (nucleósido) da invenção presente pode ser formulada sob a forma de preparações parentéricas ou preparações de lipossomas pela incorporação auxiliares habituais tais como tampões e/ou estabilizadores. Sob a forma de preparações para aplicação tópica, esta poderá ser misturada com veículos farmacêuticos utilizados habitualmente para a preparação de unguentos, cremes, líquidos ou emplastros. A síntese dos análogos de nucleósido da invenção presente e dos análogos de nucleótido da invenção presente será descrita mais detalhadamente por intermédio dos Exemplos e Exemplos de Produção seguintes. Nestes Exemplos, o uracilo é utilizado principalmente como uma base, mas à sua semelhança também se poderão utilizar outras bases de purina de ácido nucleico.
[Exemplo 1] Síntese de um análogo de nucleósido (1) Síntese de 2',3'-O-ciclo-hexilideno-4'-(p-toluenossulfoniloximetil)uridina (Composto 2)
Adicionou-se cloreto de p-toluenossulfonilo (771 17 ΡΕ1013661 mg, 4,05 mmoles) a uma solução de piridina anidra (13,5 mL) do Composto 1 (956 mg, 2,70 mmoles) conhecida na litera tura, à temperatura ambiente numa corrente de azoto, e agitou-se a mistura durante 5 horas a 60°C.
Adicionou-se uma solução de bicarbonato de sódio à mistura reaccional, extraindo-se o sistema reaccional de seguida com benzeno por 3 vezes. Lavou-se a fase orgânica uma vez com uma solução saturada de cloreto de sódio, e secou-se por sobre MgS04 anidro. Retiraram-se os solventes por destilação sob pressão reduzida, e sujeitou-se o resíduo a uma destilação azeotrópica com benzeno, por 3 vezes. Purificou-se o produto impuro resultante por croma-tografia em coluna sobre silicagel (CHCl3:MeOH = 15:1), e em seguida precipitou-se novamente a partir de benzeno-hexano para se obter um pó branco (Composto 2) (808 mg, 1,59 mmo1e s, 59%).
Composto 2: Pó branco, p.f. 104-106°C (benzeno-hexano) . IV v (KBr) : 3326, 2929, 2850, 1628, 1577, 1544, 1437, 1311, 1244 cm1. RMN de ^ (d6-acetona) : δ 1,45-1,67 (1 OH , m) , • 2,45 ( 3H, s) , 3 ,71 (2H, ABq, J = 12 H. z) , 4 ,20 (2H, ABq, J = 11 Hz) , 4 ,92 (1H, d, J’ = 6 Hz), 5, 05, 5 , 06 (1H, dd, J = 4, 6 Hz) , 5, 60 (1H, d, J = 7 Hz ), 5,75 (1H t d, J = 4 Hz) , 7,48 ( :2h, d, J = = 8 Hz), 7,77 ( 1H , d, J = 8 H z) , \—1 co (2H, , d, J = = 8 Hz) t 10,10 (1H, s,) • RMN de 13c ( d6- acetona): δ 21,5, 24, Λ, 24, 5, 25,5, 34,8, 36 i,9, 63, 5, 69 ,7, 82,5 , 84, 7, 87,8, 92 ,9, 102,9, 115 ,4, 128 ,8 , 130,8 , 133 ,9, 142, 7, 14 5,9, 151 ,3, 163 ,5. Massa ( EI): m/z 481 (M+- -h2o) 18 ΡΕ1013661
Anál. Calculado. para C23H28N2O9S · 1/3 H20: C, 53,69; H, 5,61; N, 5,44; S, 6,22. Determinado: C, 53,99;H, 5,48; N, 5, 4 2 ; S, 6,10. (2) Síntese de 4'-(p-toluenossulfoniloximetil)-uridina (Composto 3)
Agitou-se o Composto 2 acima (107 mg, 0,21 mmole) em TFA-H20 (98:2, 1 mL) durante 10 minutos à temperatura ambiente. Retirou-se a mistura reaccional por destilação sob pressão reduzida, e adicionou-se EtOH ao resíduo, seguindo-se a realização de uma destilação azeotrópica por 3 vezes. Purificou-se o produto impuro resultante por cromatografia em coluna sobre silicagel (CHCl3:MeOH = 10:1) para se obter o Composto 3 (85.0 mg, 0.20 mmole, 94%).
Composto 3: Pó branco, p.f. 119-120°C. IV v (KBr): 3227, 3060, 2932, 2837, 1709, 1508, 1464, 1252, 978, 835, 763, 556 cm-1. RMN de 1H (d6~acetona) : δ 2,31 (3H, s) , 2,84 (3H, s) , 3, 71 (2H, s) , 4, 13, 4,20 (2H, ABq, J = 11 Hz) , 4, 28, 4,31 (1H, dd, J' = 9, 6 Hz ) , 4 ,36 ( 1H, d, J’ = = 6 Hz) , 5, 54 (1H, d, J' = 8 Hz) , 5,75 ( 1H, d, J = 7 Hz), 7, , 32 (2H, d, J = 8 Hz) 7 , 67 (2H, d, J = 8 Hz ), 7, 70 (1H, d, J’ = 8 Hz ) , 10, 14 (1H, s) . RMN de 13C (d6- -acetona) : δ 21, ,5, 63,7, 70, 8, 72,7, 74, 6, 86, 8, 88, 8, 103, 1, 128,8, 130,7, 133, 9, 141,7, 145, 8, 151,8, 163, 9. Massa (EI): m/z 256 (M+- OTs) . 19 ΡΕ1013661 (3) Síntese de 2',3'-O-benzilideno-4'-(p-tolue-nossulfoniloximetil)uridina (Composto 4)
Numa corrente de azoto, adicionaram-se benzal-deído (2.4 mL, em excesso) e cloreto de zinco (670 mg, 5,0 mmoles) ao Composto 3 acima (400 mg, 0,93 mmoles), e agitou-se a mistura durante 5 horas à temperatura ambiente. Após terminada a reacção com a adição de solução saturada de bicarbonato de sódio, extraiu-se a mistura reaccional com clorofórmio, e lavou-se com uma solução saturada de bicarbonato de sódio, água, e uma solução saturada de cloreto de sódio. Secou-se a fase orgânica sobre sulfato de sódio anidro. Retiraram-se os solventes por destilação sob pressão reduzida, e purificou-se o resíduo por cromato- grafia em coluna sobre silicagel (CHCl3:MeOH = 40:1) para se obter o Composto 4 (380 mg, 0,74 mmol, 80%).
Composto 4: Pó branco, p.f. 99-102°C (CH2CI2- hexano) . [a]D23-26, 7 ° (c = 1,0, CHC13) . IV v (KBr) : 3059, 1691, 1460, 1362, 1269, 1218, 1177 cnT1. RMN de XH (CDC13) : δ 2,41 (3H, s), 3,25 (1H, lg) , 3,79 (2H, m) , 4,19 (2H, s) ,
5, 09 (1H, cr C-l II ^1 Hz) , 5,28 (1H, dd, J = 3, 7 Hz), 5 , 60 (1H, d, J = 4 Hz), 5, 73 (1H, N CO II l~D ), 5, 94 (1H, s) , 7,24 (1H, d, J = 8 Hz) , 7,38 (2H, d, J = 9 Hz) ), 7,42 ( 5H, lg), 7, 69 (2H, d, J = 9 Hz) , 9,11 (1H, lg) . RMN de 13C (CDCL3) : δ 21, 6, 63,5, 68,3, 77,2, 82,8, 84,2, 87,7, 94, 9, 102, 6, 107,5, 126, 5, 127,9, 128,5, 129, 7, 132,2, 135, 0, 143,0, 145,0, 150,4, 163,5. 20 ΡΕ1013661
Anál. Calculado. para C24H24N2O9S· 1/3 H20: C, 55,17; H, 4,76; N, 5,36; S, 6,14. Determinado: C, 55,19; H, 4,66; N, 5,29; S, 5,98. (4) Síntese de 3'-O-benzil-4'-(p-toluenossulfo-niloximetil)uridina (Composto 5)
Adicionou-se cianoboro-hidreto de sódio (92 mg, 1,5 mmoles) a uma solução de acetonitrilo (3 mL) do Composto 4 (150 mg, 0,29 mmole) à temperatura ambiente numa corrente de azoto. Em seguida, adicionou-se tetracloreto de titânio (0,16 mL, 1,5 mmoles) gota-a-gota sob arrefecimento com gelo, e agitou-se a mistura durante 15 horas à temperatura ambiente. Diluiu-se a mistura reaccional com clorofórmio, e lavou-se com uma solução saturada de bicarbonato de sódio, água, e uma solução saturada de cloreto de sódio. Em seguida, secou-se a fase orgânica sobre sulfato de sódio anidro. Após se retirarem os solventes por destilação, purificou-se o resíduo por cromatografia em coluna sobre silicagel (CHCl3:MeOH = 25:1) para se obter o Composto 5 (112 mg, 0,22 mmole, 75%).
Composto 5: Cristais incolores. P.f. 195-197°C (AcOEt-hexano) . [a]D23-14,6° (c = 1,0, CHC13) . IV v (KBr) : 3033, 2885, 2820, 1726, 1470, 1361, 1274, 1175, 1119 cm-1. RMN de ^ (CDCI3) δ: 2,40 (3H, s), 3,59-3,77 (3H, m) , 4,10, 4,24 (2H, AB, J = 11 Hz), 4,32 (1H, d, J = 6 Hz), 4,56 (2H, m) , 4,69 (1H, d, J = 11 Hz), 5,52 (1H, d, J = 6 Hz), 5,67 (1H, d, J = 8 Hz), 7,24-7,29 (7H, m) , 7,48 (1H, d, J = 8 21 ΡΕ1013661
Hz), 7,70 (2H, d, J = 9 Hz), 9,91 (1H, s). RMN de 13C (CDC13) : δ 21, 6, 63,2, 69, 2, 73, 6, 74, 6, 78, 1, 86, 6, 92,9, 102,5, 127,9, 128,2, 128,3, 128, 6, 129, 9, 132,3, 136, 9, 142,4, 145,2, 150,7, 163,8.
Anál. Calculado, para C24H26N2O9S: C, 55, 59; H, 5,05; N, 5,40; S, 6,18, Determinado: C, 55,41;H, 5,02;N, 5,32;S, 6,15. (5) Síntese de 3'-O-benzil-2'-O,4'-C-metileno-uridina (Composto 6)
Adicionou-se uma suspensão anidra de benzeno (0,7 mL) de NaHDMS (3,2 mmoles) a uma solução anidra de THF (1,5 mL) do Composto 5 (80 mg, 0.16 mmole) , à temperatura ambi ente numa corrente de azoto, e agitou-se a mistura durante 20 horas à temperatura ambiente. Adicionou-se uma solução saturada de bicarbonato de sódio à mistura reaccional, seguindo-se a extracção da mistura com CHC13. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e em seguida secou-se sobre sulfato de sódio anidro. Após se retirarem os solventes por destilação sob pressão reduzida, purificou-se o produto impuro resultante por cromatografia de coluna sobre silicagel (CHCl3:MeOH = 10:1), and recristalizou-se em seguida a partir de MeOH para se obter o Composto 6 (41 mg, 0,10 mmole, 61%).
Composto 6: Cristais incolores. P.f. 217-219°C (MeOH). [oí]d23° +108,4° (c = 0,3, MeOH). IV v (KBr) : 3059, 22 ΡΕ1013661 2951, 1688, 1459, : 1271, 1053 cm 1. RMN de 1H (d6-DMSO) δ: 3,75, 3,85 (2H, AB, J = 8 Hz) , 3, 77 (2H, d, J = 5 Hz) , 3, 92 (1H, s), 4,44 (1H, s) , 4, 60 (2h, s; ), 5 ,39 (1H, t, J = 5 Hz) , 5,48 (1H, s) , 7,31 (5H, m) , 7, 72 ( 1H, d, J = 8 Hz ) , 11,37 (1H, s). RMN de 13C (d6 -DMSO) δ: 56,0, 71,1, 71, 6, 75,8, 76, 5, 86, 5, 8 8,3, 100,9, 127,4 , 127, 6, 128,2, 137, 9, 139, 0 , 150, 0, 163,3 . Massa (EI ) : m/z 346 (M+, 1.1) .
Anál. Calculado para C17H18N2O6: C, 58,96; H, 5,24; N, 8,09.
Determinado: C, 58,67; H, 5,23; N, 8,05. (6) Síntese de 2'-O,4'-C-metileno-uridina (Composto 7)
Adicionou-se 10% Pd-C (25 mg) a uma solução de metanol (2,5 mL) do Composto 6 (25 mg, 0, 072 mmole) , e agitou-se a mistura reaccional durante 15 horas à pressão atmosférica numa corrente de azoto. Filtrou-se a mistura reaccional, e retirou-se o solvente por destilação. Em seguida, purificou-se o resíduo por cromatografia de coluna sobre silicagel (CHCl3:MeOH = 10:1, 5:1 em seguida) para se obter o Composto 7 (18,3 mg, quant.).
Composto 7: Cristais incolores. P.f. 239-243 °C (MeOH) . [a] d23° +92.2° ( O II 0 CO MeOH). IV v (KBr) : 3331, 3091, 3059, 2961, 1689 , 1463, 1272, 1049 cm1. RMN de 1H (CD3OD) δ: 3,76, 3,96 (2H, AB, J = 8 Hz), 3,90 (2H, s), 23 ΡΕ1013661 4,04 (1Η, s), 4,28 (1H, s), 5,55 (1H, s), 5,69 (1H, d, J = 8 Hz), 7,88 (1H, d, J = 8 Hz).
Anál. Calculado para C10H12N2O6: C, 46, 88; H, 4,72; N, 10,93.
Determinado: C, 46,74; H, 4,70; N, 10,84. (7) 5'-O-(4,4'-dimetoxitritil)-2'-O,4'-C-metile- no-uridina (Composto 8)
Adicionou-se piridina anidra ao Composto 7 (140 mg, 0,53 mmole), seguindo-se uma destilação azeotrópica da mistura por 3 vezes. Em seguida, converteu-se o produto numa solução anidra de piridina (1,5 mL), e adicionaram-se cloreto de 4,4'-dimetoxitritilo (210 mg, 0,63 mmole) e DMAP (6,5 mg, 0,053 mmole) à temperatura ambiente numa corrente de azoto. Agitou-se a mistura durante 5 horas à temperatura ambiente. Adicionou-se uma solução saturada de bicarbonato de sódio à mistura reaccional, seguindo-se a extracção com CH2CI2. Lavou-se a fase orgânica com água e com uma solução saturada de cloreto de sódio, e secou-se em seguida sobre sulfato de sódio anidro. Após se retirarem os solventes por destilação sob pressão reduzida, purificou-se o produto impuro resultante por cromatografia de coluna sobre sili-cagel (CHCl3:MeOH = 40:1) para se obter o Composto 8 (230 mg, 0,34 mmole, 66%).
Composto 8: Pó branco. P.f. 117-120°C (CHC13) . 24 ΡΕ1013661 [oí] d23° +17,2° (c = 1,0, CHC13) . IV v (KBr) : 3393, 3101, 2885, 1689, 1464, 1272, 1047 cm-1. RMN de ^ (CDC13) δ: 2,59 (1H, lg) , 3,56 (2H, q, J = 7, 11 Hz), 3,87 (1H, d, J = 7
Hz), 4,26 (1H, s), 4,47 (1H, s), 5,60 (1H, d, J = 9 Hz), 5,63 (1H, s), 5,84 (4H, d, J = 9 Hz), 7,22-7,45 (9H, m) , 7,93 (1H, d, J = 9 Hz) .
[Exemplo 2] Síntese de um análogo de nucleósido (1) Síntese de metil=5-0-(t-butildifenilsilil) -4-hidroximetil-2,3-0-isopropilideno-p-D-ribofuranosida (Composto 14)
Numa corrente de azoto, adicionaram-se EtsN (2,62 mL, 18,8 mmoles) e cloreto de t-butildifenilsililo (4,88 mL, 18,8 mmoles) a uma solução anidra de CH2CI2 (40 mL) do Composto 13 (2,00 g, 8,54 mmoles) conhecido da literatura sob arrefecimento com gelo, e agitou-se a mistura durante 13 horas à temperatura ambiente. À mistura reaccional, adicionou-se uma solução saturada de bicarbonato de sódio, e extraiu-se o sistema reaccional em seguida com AcOEt por 3 vezes. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e secou-se em seguida sobre Na2S04. Retiraram-se os solventes sob pressão reduzida, e purificou-se o produto impuro resultante por cromatografia de coluna sobre silicagel (hexano:AcOEt = 5:1) para se obter um material oleoso incolor (Composto 14) (2,82 g, 5,98 mmo1e s, 7 0%). 25 ΡΕ1013661 [a] 17° D -16,2° (c — 0,52, CHCI3) • IV v ( KBr) : 3510, 3061, 2938 , 2852, 1465, 1103 cm 1. RMN de Oí (CDC1 3) δ: 1,09 (9H, s) , 1, 28 ( 3H , s) , 1,49 (3H, s) , 3,22 (3H, s: ), 3, 67, 3,76 ( 2H, AB, J = 11 Hz) , co co 00 3,93 (: 2H, AB, J = 11 Hz), 4,49 (1H, d, J = 6 Hz) , 4,57 (1H, d, J = = 6 Hz) r 4, 93 (1H, s), 7,38-7, 43 ( 6H , m) , 7, 67 (4H, d, J = 7 Hz) . RMN de 13C ( CDCI3 ) δ: 19,2, 24,4, 25, 9 t 26,9, 55, 0, 62, 9, 64, 8 , 82,2 r 85 , 9, 88,7, 108, 6, 112, 6, 127,8, 129, 9, r 133,0, 135 >,7.
Anál. Calculado para C26H36O6S1 · 1/4 H20: C, 65,45; H, 7,71.
Determinado: C, 65,43; H, 7,59. (2) Síntese de metil=5-0-(t-butildifenilsilil)-2,3-0-isopropylideno-4-(p-toluenossulfoniloximetil)-β-ribofuranósido (Composto 15)
Numa corrente de azoto, adicionaram-se EtsN (3,92 g, 28,0 mmoles), cloreto de p-toluenossulfonilo (1.34 g, 7,22 mmoles), e 4-dimetilaminopiridina (90 mg, 0,72 mmole) a uma solução anidra de CH2CI2 (15 mL) do Composto 14 (2,13 g, 4,51 mmoles), e agitou-se a mistura durante 17 horas à 26 ΡΕ1013661 temperatura ambiente. Adicionou-se uma solução saturada de bicarbonato de sódio à mistura reaccional, e em seguida extraiu-se o sistema reaccional com AcOEt por 3 vezes. Lavou-se uma vez a fase orgânica com solução saturada de cloreto de sódio, e secou-se sobre Na2S04 anidro. Retiraram-se os solventes por destilação sob pressão reduzida, e purificou-se o produto impuro resultante por cromato-grafia de coluna sobre silicagel (hexano:AcOEt = 10:1) para se obter um material oleoso incolor, Composto 15 (2,76 g, 4,42 mmo1e s, 98%).
[a] d17° -3.82o (c = 0,56, CHC13) . IV v (KBr) : 2934, 2852, 1369, 1104 cm'1. RMN de 3H (CDCls) δ: 1,02 (9H, s) , 1, 20 (3H, s) , 1,32 (3H, s) , 2,41 ( :3h, s), 3, 09 (3H, s) , 3 ,51 , 3 ,77 (2H, AB, J = 1 0 Hz ), 4,34 (1H, d, J = 6 Hz) , 4 ,25, 4, 39 (2H, AB, J = 9 Hz) , 4, 47 (1H, d, J = 6 H z) , 4,77 (: 1H, s) , 7, 28, 7, 81 (4H, AB, J = 9 Hz) , 7,39 - 7,4 4 ( 6H, m) , 7, 62 - 7 , 65 (4H, m) , 7 ,81 (2H, d, J = 9 Hz) . 13c- NMR (CDCI3) δ: 19 ,2, 21, 6, 24,. 5, 25, 8, 2 6,8, 54,9 f 62, 7, 68,8, 8: 1,9, 85 , 6, 87 ,5, 108 ,7, 112,8 , 12 7,7, 127, 8 , 12 8,2, 129, 6, 129,9, 132 ,9, 135 , 6, 144 f 4 .
Anál. Calculado para C33H42O8SSÍ: C, 63,23; H, 6,75; S, 5,11.
Determinado: C, 62,99; H, 6,53; S, 5,13. 27 ΡΕ1013661 (3) Síntese de metil=5-0-(t-butildifenylsilil)-4-(p-toluenossulfoniloximetil)-β-D-ribofuranósido (Composto 16)
Adicionou-se ácido trifluoroacético (14 mL) a uma solução de THF-H20 [11 mL, 8:3 em volume] do Composto 15 (645 mg, 1,03 mmoles) à temperatura ambiente, e agitou-se a mistura durante 20 minutos à temperatura ambiente. Retiraram-se os solventes por destilação sob pressão reduzida e purificou-se o produto impuro resultante por cromatografia de coluna sobre silicagel (hexano: AcOEt = 5: 1) para se obter um material oleoso incolor, Composto 16 (464 mg, 0,79 mmole, 77%).
[a] d17° -35.8° (c=l, 90, CHC13) IV v (KBr): 3499, 3051, 2931, 2840, 1594, 1468, 1362, 1109 crrf1. RMN de ^ (CDCI3) δ: 1,02 (9H,s), 2,42 (3H,s), 3,16 (3H,s), 3,54, 3,70 (2H,AB,J=10Hz ) , 3,97 (1H,d,J=5Hz), 4,18 (1H,d,J=5Hz) , 4,26, 4,39 (2H,AB,J=10Hz) , 4,73 (lH,s), 7,30 (2H,d,J=8Hz), 7,36-7,44 (6H,m), 7,59-7,66 (4H,m), 7,78 (2H,d,J=8Hz). RMN de 13C-NMR (CDCI3) δ: 19, 2, 21, 6, 26, 7, 55, 2, 66, 5, 69, 6, 74, 0, 75, 2, 76, 5, 84, 8, 107,5, 127,7, 128,0, 129, 8, 132, 6, 132,7, 132,8, 135, 5, 135, 6, 144,9. 28 ΡΕ1013661
Anál. Calculado para C3oH38SSi08· 1/4 H20: C, 60, 94; H, 6,56.
Determinado: C, 60,94; H, 6,43. (4) Síntese de metil=5-0-(t-butildifenilsilil)-2-O,4-C-metileno-p-D-ribofuranósido (Composto 17) e metil=5-0-(t-butildifenilsilil)-3-0,4-C-metileno-p-D-ribofuranósido (Composto 18)
Numa corrente de azoto, adicionou-se uma suspensão de benzeno (1,6 mL) de NaHMDS (3,30 mmoles) a uma solução anidra de THF (4 mL) do Composto 16 (194 mg, 0,33 mmol) à temperatura ambiente, e agitou-se a mistura durante 1 hora à temperatura ambiente. Após a adição de uma solução saturada de bicarbonato de sódio à mistura reaccional, retiraram-se os solventes por destilação, e extraiu-se o resíduo com AcOEt por 3 vezes. Lavou-se a fase orgânica uma vez com uma solução saturada de cloreto de sódio, e secou-se em seguida sobre Na2S04 anidro. Retirou-se o solvente por destilação sob pressão reduzida, e purificou-se o produto impuro resultante por cromatografia de coluna sobre silicagel (hexano:AcOEt = 5:1) para se obter um material oleoso incolor, Composto 17 (48 mg, 0,116 mmole, 35%) e um material oleoso incolor, Composto 18 (59 mg, 0,142 mmole, 43%) . ΡΕ1013661 29
Composto 17: IV v (KBr) : 3438, 3064, 1103, 1036 cm 1. RMN de 1H (CDC13) δ: 1,08 (9H,s), 2,04 (1H, s lg) , 3,39 (3H,s), 3, 65, 3, 98 (2 Η, AB, J= 8 H z ) , 3,95, 4,02 (2 Η, AB, J= 12 H z ) , 4,02 (lH,s), 4,30 (lH,s), 4,79 (lH,s), 7,38-7,46 (6H,m), 7,65-7,69(4H,m). RMN de 13C (CDC13) δ: 19, 2, 26, 7, 55, 0, 60,7, 71,2, 73, 1, 79, 9, 85, 5, 104,3, 127,8, 129, 9, 130, 0, 132,9, 135, 6, 135, 7.
Anál. Calculado para C23H30O5SÍ · 1/4 H20: C, 65, 68; H, 7,34.
Determinado: C, 65,98; H, 7,23.
Composto 18: IV v (KBr): 3456, 3058, 2938, 2852, 1467, 1108crrf1. RMN de 3Η (CDC13)õ: 1,10 (9H,s), 3,26 (3H,s), 3,71 (2H,s), 4,02 (1H, d, J=6Hz ) , 4,35, 4,95 (2H, d, J=7Hz ) , 5,01 (1H,s) , 5,11 (1H, d,J=6Hz) , 7,38-7,44 (6H,m), 7,66 (4H, d, J=7Hz) . RMN de 13C (CDC13) δ: 19, 3, 26, 8, 55, 4, 63,7, 75, 1, 77,9, 84,5, 86, 3, 111,9, 127,8, 128,0, 129, 9, 132,9, 133, 0, 135, 6, 135, 8, 135, 9. 30 ΡΕ1013661
Anál. Calculado para C23H30O5S1 · 1/4 H20: C, 65,91; H, 7,34.
Determinado: C, 66,07; H, 7,14. (5) Sintese de metil=3-0-acetil-5-0-(t-butildi-fenilsilil)-2-0,4-C-metileno-p-D-ribofuranósido (Composto 19)
Numa corrente de azoto, adicionaram-se anidrido acético (0,38 mL, 4,08 mmoles) e 4-dimetilaminopiridina (21 mg, 0,170 mmoles) a uma solução em piridina anidra (10 mL) do Composto 17 (704 mg, 1,70 mmoles) à temperatura ambi ente, e agitou-se a mistura durante 3 horas à temperatura ambiente. Após a adição de uma solução saturada de bicarbonato de sódio à mistura reaccional, extraiu-se o sistema com AcOEt por 3 vezes. Lavou-se uma vez a fase orgânica com uma solução saturada de cloreto de sódio, and secou-se em seguida sobre Na2S04 anidro. Retiraram-se os solventes por destilação sob pressão reduzida, e purificou-se o produto impuro resultante por cromatografia de coluna sobre sili-cagel (hexano:AcOEt = 7:1) para se obter um material oleoso incolor, Composto 19 (665 mg, 1,46 mmoles, 86%).
[a]D17° -34.3° (c=0, 93, CHC13) IV v (KBr) : 3438, 3064, 2934, 1749, 1468, 1103, 103 6 cm-1. 31 ΡΕ1013661 RMN de 1H (CDC13) δ: 0,99 (9H,s), 1,97 (3H,s), 3,34 (3H,s), 3, 69, 3, 86 (2H, AB, J=8Hz) , 3,86 (2H,s), 4,17 (1H,s) , 4,77 (1H,s), 5,06 (lH,s), 7,28-7,39 (6H,m), 7,58- 7,63 (4H, m) . RMN de 13C (CDC13) õc: 19, 3, 20, 9, 26, 7, 55, 0, 60, 3, 72,0, 73, 6, 78,3, 85, 3, 104,4, 127,7, 129, 8, 133, 0, 135, 6, 169, 8.
Anál. Calculado para C25H3206Si· 1/4 H20: C, 65,12/ H, 7,10.
Determinado: C, 65,27; H, 7,00. (6) Síntese de 5'-O-(t-butildifenilsilil)-2'-O,4'-C-metileno-5-metiluridina (Composto 20)
Numa corrente de azoto, adicionou-se Ο,Ο'-bis-trimetilsililtimina (154 mg, 0,598 mmoles) a uma solução anidra de CH3CN (2 mL) do Composto 19 (109,2 g, 0,239 mmole) à temperatura ambiente. Em seguida, adicionou-se sob arrefecimento com gelo uma solução de 1,1-dicloroetano (0,31 mL) de trifluorometanossulfonato de trimetilsililo (0,82 mL, 8,74 mmoles), e agitou-se a mistura durante 18 horas à temperatura ambiente. Diluiu-se a mistura reacci-onal com CH2C12, e adicionou-se uma solução saturada de bicarbonato de sódio, seguindo-se a extracção do sistema com AcOEt por 3 vezes. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e secou-se em seguida 32 ΡΕ1013661 sobre Na2S04 anidro. Retiraram-se os solventes sob pressão reduzida, e purificou-se o produto impuro resultante por cromatografia de coluna sobre silicagel (hexano:AcOEt = 3:1) para se obter um material oleoso incolor, Composto 20 (87,7 mg, 0,173 mmole, 70%). IV v (KBr): 3048, 2935, 2852, 1749, 1466, 1369, 1234, 1108, 1040 cm1. RMN de ^ (CDC13) δ: 1,06 (9H,s), 1.94 (3H,s), 2,98 (1H,br s), 3, 63, 4, 00 (2H,AB,J=10Hz), 3,72 (1H,d,J=7Hz), 3,82-3,84 (2H,m), 4,30 (lH,s), 5,25 (lH,s), 7,40-7,46 (6H,m), 7,60 (4H, d, J=6Hz) , 7,66 (lH,s), 9,68 (1H,s lg).
[Exemplo 3] Síntese de análogo de nucleósido (método diferente) (1) Síntese de 3-0-benzil-5-0-t-butildifenilsi-lil-4-(hidroximetil)-1,2-O-isopropilideno-a-D-eritropento-furanose (Composto 32)
Sob uma corrente de azoto, adicionaram-se tri-etilamina (3,71 mL, 26,6 mmol) e cloreto de t-butildife-nilsililo (6,94 mL, 26,7 mmol), sob arrefecimento com gelo, a uma solução em cloreto de metileno (50 mL) do Composto 31 (2,50 g, 8,08 mmol) preparada consoante a referência 5) mencionada acima. Agitou-se a mistura durante 10,5 horas à temperatura ambiente. Em seguida adicionou-se uma solução 33 ΡΕ1013661 saturada de bicarbonato de sódio à mistura reaccional, extraiu-se o sistema com acetato de etilo. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e depois secou-se sobre sulfato de sódio. Separaram-se os solventes por destilação sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (AcOEt-hexano: = 1:4 — 1:3) para se obter um sólido branco, Composto 32 (2,97 g, 5,41 mmol, 67%) . P.f. 98-99°C (hexano) . [oí]d20 +54,8°(c = 1,12, acetona). IV vmax (KBr) : 3553, 2936, 1463 , 137 9, 1107 cm 1. RMN de 2H (CDC13) δ: 1, 13 (9H, s) , 1,50 (: 3H, s ) , 1,78 (3H, s), 2,56 (1H, t, J = = 7 Hz) , 3, 82, 3 ,92 (2H , AB, J = 11 Hz) , 3, 94 (2H, t, J = 6 Hz) , 4 ,57 (1H, d, J = 5 Hz ) , 4, 64, 4,95 (2H, AB, J = 12 Hz) , 4, 83 (1H, dd, , J = 4, 5 Hz) , 5, 95 (1H, d, J = 4 Hz) , 7,44-7, , 55 (11H, m) , 7, 72-7, 78 (4H, m) . RMN de 13C (CDC13) 5C: 19 72, 26, 2 , 26,5, 26, 8, 63,2, 65, 4, 72,5, 77,9, 79,1 , 87,4, , 104,4, 113,7, 127, 6, 127,7 , 12 :8, 0, 128,5, 129, 5, 129,7, 132,9, 133,1, 134, 7, 135,5, 137,2.
Anál, Calculado para C32H4o06Si : C, 70, 04; H, 7,38. Determinado: C, 70,19; H, 7,35. 34 ΡΕ1013661 (2) Síntese de 3-0-benzil-5-0-(t-butildifenilsi-lil)-4-(p-toluenossulfoniloximetil)-1,2-a-D-eritropentofu-ranose (Composto 33)
Sob uma corrente de azoto, adicionaram-se tri-etilamina (395 pL, 2,83 mmol) , cloreto de p-toluenossul-fonilo (139,2 mg, 0,730 mmol), e 4-dimetilaminopiridina (8,92 mg, 0, 0730 mmol), sob arrefecimento com gelo, a uma solução em cloreto de metileno do Composto 32 (250 mg, 0,456 mmol). Agitou-se a mistura durante 15,5 horas à temperatura ambiente. Depois de se adicionar um solução saturada de bicarbonato de sódio à mistura reaccional, extraiu-se o sistema com acetato de etilo. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e depois secou-se sobre sulfato de sódio. Separaram-se os solventes por destilação sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (AcOEt-hexano: = 1:6) para se obter um material oleoso amarelo claro, Composto 33 (310,6 mg, 0,442 mmol, 97%).
[a]D20 +16,0° (c = 0,44, acetona). IV vmax (KBr) : 2935, 1595, 1462, 1363, 1174, 1106 cm-1. RMN de XH (CDC13) δ co 0 \—1 (9H , s) O \—1 (3H, s ) , 1/ 46 (3H, S) , 2, 48 (3H, s) , 3 , 68, 3 , 83 (2H, AB, J = 11 Hz ) , 4, 45 (2H, dd, J = 4 , 5 Hz), 4 ,64, 4 ,81 (2H, AB, J = 12 Hz ) , 4, 68 (1H, dd, J = 4, 5 Hz) f 5, 81 (1H, d, J = 4 Hz) , 7, 32 (2H, d, J = 8 Hz) , 7,42 -7,72 (15H, m) , 7,82, (2H, d, J 8 Hz ) , 7, 66 (4H, m) , 7,72 (2H, f d, J = 8 Hz) . 35 ΡΕ1013661 RMN de 13C (CDC13) õc: 19, 1, 21,5, 26,1, 26, 4, 26,7, 64,4,70 , 0, 72,5, 78, 1, 78,9, 85,4, 104,2, 113, 6, 127,3, 127,7, 127,9, 128,0, 128,4, 129, 6, 129, 7, 129, 8, 132,7, 132,8, 135,5, 137,2, 144,4. MS (EI) m/z : 646 (M+-t-Bu) . HRMS(EI): Calculado para C35H37O8SS1 (M+-t-Bu) : 645, 1978, Determinado: 645, 1969. (3) Síntese de 1,2-di-0-acetil-3-0-benzil-5-0-t-butildifenilsilil-4-(p-toluenossulfoniloximetil)-a- e -β-D-ribofuranose (Composto 34)
Sob uma corrente de azoto, adicionou-se anidrido acético (6,0 mL, 63,6 mmol) e ácido sulfúrico concentrado (56 pL, 1,10 μπιοί) a uma solução em ácido acético (56 mL) do Composto 34 (3, 70 g, 5,27 mmol) . Agitou-se a mistura durante 2 horas à temperatura ambiente. Verteu-se a mistura reaccional sobre água gelada (300 mL), e agitou-se durante 30 minutos. Depois de se lhe adicionar uma solução saturada de cloreto de sódio, extraiu-se a mistura com acetato de etilo. Em seguida secou-se a fase orgânica sobre sulfato de magnésio. Separaram-se os solventes por destilação, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (AcOEt-hexano, a 2:1) para se obter um material oleoso amarelo, Composto 34 (3,36 g, 4,53 mmol, 86%), sob a forma de uma mistura α-β (a 1:4). ΡΕ1013661 36 IV vmax (KBr) : 2934, 2863, 1751, 1365, 1217, 1106 cm RMN de 1H (CDCI3) [configuração β] δ: 1,02 (9H, s) , 1,77 (3H, s ) , CO \—1 (3H, s), 2, 39 (3H, s ) , 3 , 61, 3,76 (2H, AB, J = 11 Hz) , 4, 21-4,58 (5H, m) , 5,26 (1H, d, J = 5 Hz) , 5, 94 (1H, s) , 7,15-7,59 (13H, m) , 7,58- 7, 66 (4H, m) , 7,72 (2H, d, J = 8 Hz) [configuração cí] δ: 1,02 (9H, s) , co \—1 (3H, s) , 2, 36 (3H, s), 3,48, 3, 58 (2H, AB, J = 11 Hz) , 4,21 -4,58 (5H , m) , 5, 12 (1H, dd, J = : 5, 6 Hz), . 6,33 (1H , d, j = 5 Hz) , 7, 15- 7,59 (13H, m) , 7,58- 7,66 (4H, m) , 7,72 (2H, d, J = 8 Hz). RMN de 13C (CDCI3) 5C: 14,2, 19,3, 20,5, 20, 8, 21, 6, 26,7, 26 ,8, 60,3, 64,8 , 69,1 , 73, 6, 74, 1, 78, 6, 85, 3, 97,4, 127,4, 127, ,6, 127,7, 127, 8, 127,9, 128, 0, 128, 2, 128,3, 128,4, 129 ,5, 129,6, 1289 , 8, 129, 9, 132,4, 132, 8, 132,9, 135,4, 135, 5, 135,6, 136, 9, 144,5, 168,7, 169, 4 . HRMS (FAB) : Calculado para C^H^OioSSiNa (M++Na) : 769,2479, Determinado: 769,2484. (4) Síntese de 2'-O-acetil-3'-O-benzil-5'-O-t-butildifenilsilil-4'-p-toluenossulfoniloximetil-5-metiluri-dina (Composto 35)
Sob uma corrente de azoto, adicionaram-se 2TMS»T (1,04 g, 4,03 mmol) e trifluorometanossulfonato de trime-tilsililo (730 pL, 4,03 mmol), sob arrefecimento com gelo, 37 ΡΕ1013661 a uma solução em 1,2-dicloroetano (26 mL) do Composto 34 (1,88 g, 2,52 mmol), e agitou-se a mistura durante 17 horas à temperatura ambiente. Adicionou-se uma solução saturada de bicarbonato de sódio à mistura reaccional, e filtrou-se o sistema através de Celite, extraindo-se as águas-mães em seguida com clorofórmio. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e depois secou-se sobre sulfato de sódio. Removeram-se os solventes por destilação sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (AcOEt-hexano, a 2:3) para se obter um pó branco, Composto 35 (2,00 g, 2,44 mmol, 97%). P.f. 70-71,5°C. [a] D24 +4,58° (c = 1,25, acetona). IV vmax (KBr) : 3059, 2934, 1694, 1465, 1368, 704 cnf1. RMN de ^ (CDC13) δ: 1,11 3 (9H, s) , 1,63 (3H, d, = 1H z) , 2, 10 (3H, s ) , 2,42 (3H , s) , 3,73 , 3,8 6 (2H, AB , J : 11 H z) , 4, 12, 4,20 (2H , ab, J = 11 Hz) , 4,44, 4,57 i !2H , AB J = 11 Hz) , 4 ,45 (1H, d, J = 6 Hz) , 5, 38 (1H, t, J = = 6 Hz) 6, 02 ( 1H, d, J = 6 Hz) ', 7, 21-' 7, 60 (13H, m) , 7,62-7, 69 (7H m) , 8, 91 ( 1H, s lg) • RMN de 13 !C (CDC1 3 ) õc: 11,9, 19, 3 , 20, 6 f 21, 6 27,0 f 65, 3, 68, 6, 74 :,1, 74, 8, 1 77,2, 77,3, , 86,0, f 86, 4 111, 6, 12 7,9, 128, 0, 128, 2, 128, 5, 12 9,7, 130,1, 1 30,2 131, 8, 132,3, 132, 5, 135, 3, 135, 5, 135,6, 136,8, 1 44,9 150, 2, 163 !,4, 170,2 * 38 ΡΕ1013661 MS (FAB) m/z : 813 (M++H).
Anál, Calculado para C43H48N2O10SS1 ·2H20: C, 60,83; H, 6,17; N, 3,30. Determinado: C, 60,55; H, 5,78; N, 3,22. (5) Síntese de 3'-O-benzil-5'-O-t-butildifenil-silil-4'-p-toluenossulfoniloximetil-5-metiluridina (Composto 36)
Adicionaram-se carbonato de potássio (12,75 mg, 0,0923 mmol) e água (0,5 mL), sob arrefecimento com gelo, a uma solução em metanol (4 mL) do Composto 35 (250 mg, 0,308 mmol), e agitou-se a mistura durante 22 horas à temperatura ambiente. Sob arrefecimento com gelo, adicionou-se ácido acético à mistura reaccional para a neutralizar, e depois separou-se o solvente por destilação sob pressão reduzida. Depois de se adicionar água ao resíduo, extraiu-se a mistura com acetato de etilo. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e depois secou-se sobre sulfato de sódio. Separou-se o solvente por destilação sob pressão reduzida, e purificou-se o produto em bruto resultante por cromatografia em coluna sobre gel (AcOEt-hexano, a 3:2) para se obter um pó branco, Composto 36 (216,7 mg, 0,283 mmol, 92%). p. f. . 74 - 77 °C. [a] d23 + 5,15° (c = 1,23, CHC13) . IV vmax (KBr) : 3048, 2934, 1695, 1363, 1181, 1108, 977, 819, 704 cm-1. 39 ΡΕ1013661 RMN de XH (CDCI3) δ: 1,05 (9H, s), 1, 65 (3H, d, J = 1 Hz) , 2,39 (3H, s), 3,04 (1H, d lg, J = 9 Hz) , 3, 72 (2H, s) t 4, 17 (2H, s) , 4,18 (1H, d, J = 5 Hz), 4,24 -4,32 (1H, m) f 4,54, 4, 62 (2H, AB, J = 11 Hz), 5,62 (1H , d, J = 6 Hz) , 7, 19 -7, 69 (2 0H , m) , 8,46 (1H, s lg) φ RMN 13C (CDC13) õc: 12,1, 19, 4, 26, 9, 58,8, 72,0, 72.2, 75,8, 76,7, 87,4, 88,8, 110,4, 127,7, 12,79, 128,1, 128.2, 128,5, 128,7, 129,8, 130,0, 130,1, 132,2, 134,3, 135.3, 135,5, 136,8, 149,8, 163,9. MS(FAB) m/z : 771 (N++H) .
Anál. Calculado para C41H46N2O9SSÍ: C, 63,41; H, 6,16; N, 3,51; S, 3,95.
Determinado: C, 63,87; H, 6,01; N, 3,63; S, 4,16. (6) Síntese de 3'-O-benzil-5'-O-t-butildifenil-silil-2'-O,4'-C-metileno-5-metiluridina (Composto 37)
Numa corrente de azoto, adicionou-se bis(trime-tilsilil) amideto de sódio (1,0 M em THF, 8,47 mL, 8,47 mmol), sob arrefecimento com gelo, a uma solução em tetra-hidrofurano (30 mL) do Composto 36 (1,86 g, 2,42 mmol), e agitou-se a mistura durante 1 hora à temperatura ambiente. Adicionou-se uma solução saturada de bicarbonato de sódio (14 mL) à mistura reaccional, e depois destilou-se o solvente sob pressão reduzida. Adicionou-se água ao resí- 40 ΡΕ1013661 duo, extraiu-se a mistura com clorofórmio. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e depois secou-se sobre sulfato de sódio. Separaram-se os solventes por destilação sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (AcOEt-hexano, 2:3) para se obter um pó branco, Composto 37 (1,42 g, 2,37 mmol, 98%). P.f. 7 0,5-72 °C. [a]D22+52.47 (c= 1,025, acetona). IV vmax (KBr) : 2936, 1694, 1465, 1275, 1106, 1055, 809, 7040101. RMN de 1H (CDC13 ) δ: 1,21 (9H, s) , 1,76 (3H 3, 88, 4,07(2H, AB, J = 8 Hz) , 4,07, 4,15 (2H, AB, J Hz) , 4,16 (1H, s), 4, 66, 4, 80 (2H, AB, J = 11 Hz), (1H, s), 7,34-7,79 (16H, m) , 10,0 (1H, s lg) . MS (FAB) m/z : 599 (M++H) .
Anál. Calculado para C34H38N206Si · 2H20: C, 64,33; H, 6,03; N, 4,41, Determinado: C, 64,58; H, 6,15; N, 4,28. (7) Sintese de 3'-O-benzil-2'-O,4'-C-metileno-5-metiluridina (Composto 38)
Em corrente de azoto, adicionou-se fluoreto de tetrabutilamónio (1,0 M em THF, 379 pL, 0,379 pmol) a uma solução em tetra-hidrofurano (1 mL) do Composto 37 (188,7 mg, 0,316 mmol), e agitou-se a mistura durante 2,5 horas à 41 ΡΕ1013661 temperatura ambiente. Destilou-se a mistura reaccional sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (AcOEt-hexano, 1:1-+1:0) para se obter um pó branco, Composto 38 (94,6 mg, 0, 262 itimol, 83%). IV vmax (KBr) : 3424, 3183, 3063, 2950, 1691, 1463, 1273, 1057, 7340101. RMN de XH (CDC13) δ: 1,90 ( 3H, d, J = 1 Hz) , 3, 83, . 4,05 (2H, AB, J = 8 Hz) , 3,93, 4 , 02 (2H, AB, J = 12 Hz) , 3,94 (1H, s), 4 ,53 (1H, s), 4,56, 4,58 (2H, AB, J = 12 Hz) , 5, 65 (1H, s) , 7,32 (5H, s) 1, 7,44 (1H, d, J = 1 Hz) . HRMS (EI): Calculado para Ci8H2oN06 (M+) : 360, 1321,
Determinado: 360,1312. (8) Síntese de 2'-O,4'-C-metileno-5-metiluridina (Composto 39a)
Adicionou-se a uma solução em álcool metílico (4 mL) do Composto 38 (86, 5 mg, 0,240 mmol) , Pd(0H)2 a 20 % sobre C (86,5 mg), e agitou-se a mistura durante 14,5 horas à pressão atmosférica em corrente de hidrogénio. Filtrou-se a mistura reaccional, e depois separou-se o solvente por destilação sob pressão reduzida para se obterem cristais incolores, Composto 39 (62,5 mg, 0,230 mmol, 96%).
p.f. 194-195°C. [a] D20 + 53, 7° (c =1,02, EtOH) . IV vmax (KBr) : 3323, 3163, 3027, 2889, 2826, 1689, 1471, 1276, 1057 cm1. 42 ΡΕ1013661 RMN de (CD3OD) δ: 1,89 (3H, q, J = 1 3,74, 3,95 (2H, AB, J = 8 Hz ), 3,90 (1H, s) , 4,07 (1H 4,26 (1H, s), 5,53 ( 1H, s) , 7,74 (1H, d, J = 1 Hz) RMN de 13C (CD3OD) õc: 12, 6, 57, 6, 70, 3, 72, 4, 80,8, 88,3, 90,4, 110,7, 136,8, 151,8, 166,5.
[Exemplo 4] (1) Síntese de 2'-O-acetil-3'-O-benzil-5'-O-t-butildifenilsilil-4'-p-toluenossulfoniloximetil-N6-benzoíladenosina (Composto 40)
Numa corrente de azoto, adicionaram-se uma solução em 1,2-dicloroetano (5,0 mL) do Composto 34 (250 mg, 0,336 mmol) e trifluorometanossulfonato de trimetilsililo (6,7 pL, 0,0336 mmol), à temperatura ambiente, a 2TMS*ABz (128,7 mg, 0,336 mmol) preparado de acordo com a referência 6) (H. Vorbrggen, K. Krolikiewicz e B. Bennua, Chem., Ber., 114, 1234-1255 (1981)). Aqueceu-se a mistura ao refluxo durante 26 horas. Depois de se adicionar uma solução saturada de bicarbonato de sódio à mistura reaccional, extraiu-se 3 vezes o sistema com cloreto de metileno. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e depois secou-se sobre sulfato de sódio. Separaram-se os solventes por destilação sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (CHCl3-MeOH, a 1:3) para se obter um pó branco, Composto 40 (234,5 mg, 0,253 mmol, 75%). 43 ΡΕ1013661 P.f. 77-7 8°C (AcOEt/hexano) . [oí]d24 - 13,2° (c = 1,00, CHC13) . IV vmax (KBr) : 3058, 2934, 1749, 1703, 1606, 1105 cm-1. RMN de 3H (CDCI3) δ: 0,99 ( 9H, s ), 2 ,04 (3H, s) , 2,38 (3H, s) , 3, 7 4, 3, 85 (2H, AB, J = 11 Hz) , 4,31, 4,43 (2H, AB, J = 11 Hz) , 4, 52, 4,58 (2H, AB, J = 11 Hz), 4,81 (1H, d, J = 6 Hz ) , 5, 94 (1H , d, J = 6 Hz) , 6, 04 (1H, d, J = 5 Hz' >, 7, 18 - 7, 61 ( 2 0H, m ), 7,69 (2H, d, J = 8 Hz) , 7,99 (1H, s), 8,01 (2H, d, J = 7 Hz), 8,56 (1H, s), 8,99 (1H, s ig) · RMN de 13C (CDCI3 ) δ: 19, 1, 2 0,5 , 21 ,5, 26 ,7, 64, 1 f 00 4,0, 74 ,6, 77, «·. to 00 σΤ 57, to co 64, 123, 4, 127 ,7, 127, 8, 127,9, 128 /1/ 128,5 , 128, 8, 129, 6, 129, 9, 132 ,0, 132, 3, 132,6, 132 ,7, 133, 5 , 135, 4, 135, 5, 136, 8, 142 ,0, 144, 7, 149, 6, 151, 2, 152,6, 164,5, 169,8. MS ( FAB) m/z : 926 (M++H) . (2) Síntese de 3'-O-benzil-5'-O-t-butildifenil-silil-4 ' -p-toluenossulfoniloximetil-N6-benzoíladenosina (Composto 41)
Adicionou-se a uma solução em metanol (3,0 mL) do Composto 40 (167,9 mg, 0,182 mmol), carbonato de potássio (15,0 mg, 0,109 mmol) à temperatura ambiente, e agitou-se a mistura durante 15 minutos à temperatura ambiente. Adicionou-se ácido clorídrico concentrado à mistura reaccional para a neutralizar, em seguida extraiu-se o sistema 3 vezes 44 ΡΕ1013661 com cloreto de metileno. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e depois secou-se sobre sulfato de sódio. Removeram-se os solventes sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (CHC13-MeOH, a 30:1) para se obter um pó branco, Composto 41 (140,5 mg, 0,160 mmo1, 88%). P.f. 82-83°C (AcOEt-hexano) . [a]D25 - 6, 02° (c = 0,96, CHCI3) . IV vmax (KBr) : 3306, 3066, 2935, 2859, 1701, 1611 cm-1. RMN de XH (CDCI3) δ: 0,98 ( :9H, ; S) , 2,37 (3H, s ) , 3,76 (2H, s), 4, 39, 4,45 (1H, AB, J = 11 Hz) , 4,54 ( 1H, d, II 1~D Hz), 4,67, 4, 76 (2H, AB / J = 1 1 Hz) , 4 , 85 (1H, dd, J = 5, 6 Hz), 5 ,79 (1H, d, J = 5 Hz) , 7,20 - 7,58 (21H, m ) , 7,73 (2H, d, J = 8 Hz), 7,80 (1H, s ), 7, 96 (2H, d, J = 8 NI 8,49 (1H, s) , 9,18 (1H, s ig) . RMN de 13C (CDCI3) δ: 19, 1, 2 1, 6 , 26 ,8, 64, 4, 68,9, 74,1, 7 4, 6 , 7 9, 2, 86, 8, 89,8, 123, 127, 7, 127, 8, 128,0 , 128,2, 12 CO C\J \—1 00 128,8, 129, 7, 130, 0, 132, 1, 132,5 , 132,6, 132,8, 133,4, 135,4, 135, 5, 136, 8, 142, 1, 144,8 , 149,4, 152 ,3, 164,5. (3) Síntese de 3'-O-benzil-5'-O-t-butildifenil-silil-2 ' -0,4 ' -C-metileno-N6-benziladenosina (Composto 42)
Sob uma corrente de azoto, adicionou-se bis(tri- 45 ΡΕ1013661 metilsilil) amideto de sódio (1,0 M em THF, 0,58 mL, 0,572 mmol) a uma solução em tetra-hidrofurano (8,0 mL) do Composto 41 (210,5 mg, 0,238 mmol) à temperatura ambiente, e agitou-se a mistura durante 3 horas à temperatura ambiente. Adicionou-se uma solução saturada de bicarbonato de sódio à mistura reaccional, e depois extraiu-se o sistema 3 vezes com cloreto de metileno. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e depois secou-se sobre sulfato de sódio. Destilaram-se os solventes sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (CHCI3-MeOH, a 30:1) para se obter um pó branco, Composto 42 (169,5 mg, 0,238 mmol, quant.). P .f . 80-81° C. IV ^max (KBr): 3259, 3064, 2932, 2858 , 1703, 1 607 cnf1. RMN de 1H (CDC13) δ: 1,07 (9H, s), 3,95, 4, 10 (2H, AB, J = 8 Hz) , 4, 02 (2H, d, J = 8 Hz), 4,56, 4, 64 (2H, AB, J = 12 Hz), 4,26 ( 1H, s ), 4,86 (1H, s ), 6,14 (1H, S) , 7,26 - 7, ,70 (18H , m) , 8,04 (2 H, d, J = 7 Hz) , 8,22 (1H, s) , 8, 78 (1H, s) , 9,18 (1H, s lg) . RMN de 13C (CDCI3) δ: 19,2, 26,5 , 26,8, 29, 7 59,2, 72,4, 72 , 6, 7 6, 5, 76, 8, 86,7, 88,6, 123,4, 127,7 127,8, 127,9, 128,1, 128,4, 128,8, 129, 5, 130,0, 132,4 132,5, 132,8, 133,5, 134,8, 135,2, 135,5, 135,6, 136, 8 140,4, 152,7. 46 ΡΕ1013661 (4) Síntese de 3'-O-benzil-2'-O,4'-C-metileno-N6-benzoíladenosina (Composto 43)
Adicionou-se fluoreto de tetrabutilamónio (1,0 M em THF, 1,0 mL, 1,0 mmol) , à temperatura ambiente, a uma solução em tetra-hidrofurano (7,0 mL) do Composto 42 (173,6 mg, 0,244 mmol), e agitou-se a mistura durante 25 minutos à temperatura ambiente. Destilou-se a mistura reaccional sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (CHC13-MeOH, 15:1) para se obter um pó branco, Composto 43 (115,4 mg, 0,244 mmol, quant.). p.f. 154 - 155°C (Et20) . IV vmax (KBr) : 3339, 2944, 1701, 1611 cm-1. RMN de 1H (CDC13) δ: 3, 91, 4,13 ( 2H, AB, J = 8 Hz) , 3, 93 , 4, 01 (2H, , AB, J = 12 Hz) , 4,38 (1H , s) r 4, 64 (1H, s) t 4,85 (1H, s) , 6,08 l :ih, s) , 7,29 (1H, , s) r 7,51 (2H, d, J = 8 Hz), 7, ,58 (1H, d, j = 7 Hz), 8, , 05 (2H, d, J = 7 Hz), 8,14 (1H, s), 8,75 (1H, s), 9,50 (1H, s lg). RMN de 13C (CDC13) δ: 57,1, 72,4, 77, 0, 77, 1, 86, 9, 88, 6, 122,9, 127, 6, 128,0, 128,1, 128,4, 128,7, 132,8, 133, 5, 136, 9, 140, 5, 149, 8, 150, 5, 152, 8, 165, 0. 47 ΡΕ1013661 [Exemplo 5] (1) Síntese de 2'-0-acetil-3'-0-benzil-5'-0-t-butildifenilsilil-4'-p-toluenossulfoniloximetil-N2-isobutirilguanosina (Composto 44)
Sob uma corrente de azoto, adicionou-se uma solução em 1,2-dicloroetileno (5,0 mL) do Composto 4 (250 mg, 0,336 mmol) e trifluorometanossulfonato de trimetilsililo (6,7 pL, 0, 0336 mmol), à temperatura ambiente, a 3TMS*GlBu (146,8 mg, 0,336 mmol) preparado de acordo com a referência 6 mencionada acima). Aqueceu-se a mistura ao refluxo durante 15 horas. Em seguida adicionou uma solução saturada de bicarbonato de sódio à mistura reaccional, extraiu-se o sistema 3 vezes com cloreto de metileno. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e depois secou-se sobre sulfato de sódio. Separaram-se os solventes por destilação sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (CHCl3-MeOH, a 30:1) para se obter um pó branco, Composto 44 (213,6 mg, 0,235 mmol, 70 %). P. f. 96-97°C (AcOEt-hexano). [«]d24° -11,09° (c = 0, 97, CHC13) . IV vmax (KBr) : 3152, 3065 , 2934 , 1746, 1681, 160 6 cm 1. RMN de XH (CDCI3) δ: 0,96 (9H, s), 1 .,10 (3H, d, J = 9 Hz), 1, 13 (3H, d, J = 9 Hz), 1,98 (3H, s), 2,36 (3H, s), 2,48 (1H, m), 3,65, 3, 72 (2H, AB, J = 11 Hz), 4,23, 4,43 (2H, AB, J = 11 Hz), 4 ,47 (2H, s), 4, 63 (1H, d, J = 6 48 ΡΕ1013661
Hz) , 5 ,74 (1H , t, J = 6 Hz) , 5,96 (1H, d, J = 6 Hz), 7, 14 - 7,68 ( 20H, m) , 9,15 (1H, s) , 12, 2 :o (1H, s) . RMN de 13C (CDCI3) δ: 19 ,1, 19, 3, 19,4, 20, 8, 21,9, 27,0, 27,2, 36, 5, 64,5, 68 ,9, 74, 4, 74,9, 76, 7, 86,1, 86,7, 122,0, 127,6, 12 7, 7, 127 ,9, 128,1, 128, 3, 128,4, 128,8, 130, 1, 130, 4, 132, -3, 132 ,7, 132,9, 135, 7, 135,8, 137,3, 137, 8, 145, 2, 147, -8, 148 ,5, 156,2, 170, 2, 178,8. (2) Síntese de 3'-O-benzil-5'-O-t-butildifenilsi-lil-4 ' -p-toluenossulfoniloximetil-N2-isobutirilguanosina (Composto 45)
Adicionou-se a uma solução em álcool metilico (3,0 mL) do Composto 44 (137,0 mg, 0,151 mmol), carbonato de potássio (15,8 mg, 0,113 mmol), à temperatura ambiente, e agitou-se a mistura durante 45 minutos à temperatura ambiente. Adicionou-se ácido clorídrico concentrado à mistura reaccional para a neutralizar, e em seguida extraiu-se o sistema por 3 vezes com cloreto de metileno. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e depois secou-se sobre sulfato de sódio. Separaram-se os solventes por destilação sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (CHCl3-MeOH, 30:1) para se obter um pó branco, Composto 45 (83,4 mg, 0,097 mmol, 64%). p.f. 102-103°C (AcOEt-hexano) [a]D25 -2,00° (c = 0,40, CHC13) . IV vmax( KBr) : 3166, 2932, 1684, 1607 cm-1. 49 ΡΕ1013661 RMN de 1H (CDCI3) δ: 0, 90 ( 9H, s) , 1, 09 (3H, d , J = 7 Hz) , 1,13 (3H, d, J = 7 Hz), 2, , 30 (1H, , m ), 2,37 ( 3H, s) , 3, 71, 3,76 (2H, AB, J = = 11 Hz) , L 1,32, 4, 48 (2H, AB , J = 11 Hz) , 4 ,35 (1H, d , J = 6 Hz) , 4,63 , 4, 90 (2H , AB, J = 12 Hz) , 4 , 96 (1H, t, J = 6 H z) , 5,67 ( 1H, d, J = 7 Hz) , 7 ,17 - 7, 71 (21 OH, m) , 8, í 32 (1H, s) , 12,05 (1H, s Ig) • RMN de 13C (CDCI3) δ: 18,7, 19,0, , 21,6, 26, 5, 36 ,2, 63, 5 f 69, 1, 73,7, 74,3, 78,8 , 86,2 , 89,5, 127,7, 127 ,8, 128, 0, 12 : 8, 1, 128,. 5, 129, 7, 130,0, 132 '! 0, 132,6, 132 ,7, 135, 3, 135,4, 137,4, 138,2, 144 ,8, 146 5,9, 155 ,5, 178,5. (3) Síntese de 3'-O-benzil-5'-O-t-butildifenilsi-lil-2 ' -0,4 ' -C-metileno-N2-isobutirilguanosina (Composto 46)
Sob uma corrente de azoto, adicionou-se bis (tri-metilsilil) amideto de sódio (1,0 M em THF, 0,31 mL, 0,315 mmol) a uma solução em tetra-hidrofurano (3,0 mL) do Composto 45 (92,1 mg, 0,102 mmol), à temperatura ambiente, e agitou-se a mistura durante 3 horas à temperatura ambiente. Adicionou-se uma solução saturada de bicarbonato de sódio à mistura reaccional, e depois extraiu-se o sistema por 3 vezes com cloreto de metileno. Lavou-se a fase orgânica com uma solução saturada de cloreto de sódio, e depois secou-se sobre sulfato de sódio. Removeram-se os solventes por destilação sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (CHCI3, MeOH, a 25:1) para se obter um pó branco, Composto 46 (31,4 mg, 0,160 mmol, 44%). 50 ΡΕ1013661 p.f. 99-100 °C. IV vmax (KBr) : 3162, 3068, 2932, 1683, 1610 cnf1. RMN de 3H (CDC13) δ: 1,0 6 (9H, s), 1,25 (3H , d , J = 7 Hz :) , 1,27 (3H, d, J = 7 Hz) , 2,64 (1H, m) , 3 , 83 , 4 ,01 (2H, AB, J = 8 Hz) , 3, 97 ( 2H, d, J = 7 Hz), 4,18 (1H, s) , 4,51 ( 1H, s) , 4,54 (2H , d, J = 2 Hz), 5,77 (1H, s) , 7, 17- 7,42 ( 5H, m) , 7, 64 - ' 7, 72 ( 10H , m) , 7,84 (1H, s) , 9,03 ( 1H, s) , 12 , 08 (1H, s lg) • RMN de 13( C ( :cdci 3) δ: 18,9, 19,0 , 19, a, 26 ,5, 26, 7 t 36, , 4, 59,1, 72, 4, 72, 5, 76, 8, 77,5 , 86, ,3, 88 ,3, 121, 7, 12 !7, 6, 127,7 , 127, 8, 127 ,9, 128,1, 128, 4, 129 ,6, 130, o, 132,36, 132,42, 134, 8, 135, 45, 135, 54, 135, 8, 136 ,8, 146, 8, 14 7,7, 155,4, 17 8, 6. (4) Síntese de 3'-O-benzil-2'-O,4'-C-metileno-N2-isobutirilguanosina (Composto 47)
Adicionou-se fluoreto de tetrabutilamónio (1,0 M em THF, 0,90 mL, 0,90 mmol), à temperatura ambiente, a uma solução em tetra-hidrofurano (3,0 mL) do Composto 46 (41,3 mg, 0,060 mmol), e agitou-se a mistura durante 1 hora à temperatura ambiente. Destilou-se a mistura reaccional sob pressão reduzida, e purificou-se o produto resultante em bruto por cromatografia em coluna sobre silicagel (AcOH-EtOH, a 20:1) para se obter um pó branco, Composto 47 (27,1 mg, 0,060 mmol, quant.). 51 ΡΕ1013661 P. f. 228 - 229°C (Et20) . [a] d25 +32,90° (c = 0, 875 , CHCls) . IR v max (KBr) : 3162 , 2934, 1683, 1608 cnT1. RMN de 1H (CDC13) δ: 1,24 (3H, d, J = 7 Hz), 1,26 (3H, d, J = 7 Hz), 2, 76 (1H, m) , 3, 83, 4,03 1 I2H, AB, J = 8 Hz) , 3,92, 4, 02 (2H, AB, J = 13 Hz), 4,33 (1H, s), 4,55 (1H, s), 4,62 (2H, s ), 5,80 (1H, s), 7,25 (5H, s), 7,91 (1H, s) , 9,85 (1H, s), . 12,05 (1H, s) . RMN de 13C (CDCI3) δ: 19,19, 19,25 , 36,4, 57,4, 72,5, 77, 0, 77,5, 86, 5, 88,8 , 121,0, 127,8, 128,1, 128,2, 128,3 , 128,4, 128,6, 137,1, 137,5, 147,5, 148,2, 155,7, 179,9.
[Exemplo de Referência 1] Síntese de um análogo de um oligonucleótido
CMTQ
J&, 'RÍ
1 Sinfetizader de AON
Diversos Anâiops Olqomdã駱s de P · "rM 21
$'-&asxrmT9CTx3' pera s^csrrxmscT^· rrsxrsj y^csrmsTFscT-y rrssní r-acGTTTmfQCT,3< ítss} s^csxxrmàcr^ ^ecsrnocrrscT-y h&aim s'-<jCsmTxxQCT-a’ í?mi «‘-scaxxtxxxscT-y im sN^TmTTTradc^ 'pes 52 ΡΕ1013661 (1) 3'-O-[2-cianoetoxi(di-isopropilamino)fosfi- no]-5'-O-(4,4'-dimetoxitritil)-2'-0,4'-metano-uridina (Composto 21)
Submeteram-se a uma destilação azeotrópica o Composto 8 (200 mg, 0,31 mmol) tetrazolido de di- isopropilamónio (39,6 mg, 0,23 mmol) com CH3CN anidro, três vezes, e depois transformou-se o sistema numa solução em CH3CN anidro-THF anidro (a 3:1, 4 mL) . Numa corrente de azoto, adicionou-se 2-cianoetil-N,N,Ν',Ν'-tetraisopropil-fosforodiamidito (0,12 mL, 0,37 mmol), e agitou-se a mistura durante 90 minutos à temperatura ambiente. Separaram-se os solventes por destilação sob pressão reduzida, e purificou-se o produto resultante em bruto por croma-tografia em coluna sobre silicagel (AcOEt:hexano:Et3N = 75:25:1). Em seguida, voltou a precipitar-se o produto purificado a partir de AcOEt-hexano para se obter um composto amidito, 21 (181 mg, 0,25 mmol, 81%). P.f. 71-74°C (AcOEt-hexano). RMN de 31P (CDC13) : δ 149, 6, 149, 5, 149, 4, 149, 3, 149,2. (2) Síntese geral de análogos de oligonucleótidos A síntese de um oligómero foi conduzida recorrendo ao sintetizador de ADN da Pharmacia, Gene Assembler 53 ΡΕ1013661
Plus, a uma escala de 0,2 pmol. As concentrações de solventes, reagentes, e fosforamidito eram as mesmas que se utilizaram para a síntese de ADN natural. Desprotegeu-se um grupo DMTr da 5'-O-DMTr-timidina (0,2 pmol) contendo um grupo 3'-hidroxilo ligado a um suporte CPG, com ácido tricloroacético. No seu grupo 5'-hidroxilo, repetiu-se a reacção de condensação utilizando um amidito que incluía quatro bases para síntese de ácido nucleico de ADN natural e Composto 21, para se sintetizarem análogos oligonucleo-tídicos das sequências respectivas. O ciclo sintético era como se segue:
Ciclo sintético (escala de 0,2 ymole) 1) Destritilação 2) Acoplamento 3) Terminação 4) Oxidação 1% de CCI3COOH em CH2C1CH2C1, 6 s fosforamidito 0,1 M (25 equiv.), lH-tetrazole 0,5 M (500 equiv.) em MeCN, 2 minutos 3% de 4-(dimetilamino)piridina, 10 % de Ac2Oi em MeCN, 18 s I2 0,01 M em 2,4,6-colidina/H20/ MeCN (1:5:11), 6 s
Clivou-se o oligómero sintetizado do suporte por tratamento com solução aquosa concentrada de amoníaco, do modo habitual. Ao mesmo tempo, clivou-se o grupo protector cianoetilo do átomo de fósforo, e também se removeram os grupos protectores das adenina, guanina e citosina. 54 ΡΕ1013661
Retirou-se ao análogo de oligonucleótido 5'-0-dimetoxitritilado o grupo DMTr usando 5 mL de ácido trifluoroacético numa coluna cromatográfica de fase reversa (Millipore, 01igo-Pak™SP) , e purificou-se mais para se obter o análogo de oligonucleótido pretendido.
De acordo com o método geral de síntese acima, sintetizaram-se os seguintes oligonucleótidos: (2) 5'-GCGXTTTTTGCT-3' (XT5)
Rendimento 0,06 pmole (rendimento de 30%) (3) 5'-GCGTTXTTTGCT-3' (T2XT3)
Rendimento 0,05 pmole (rendimento de 25%) (4) 5'-GCGTTTXTTGCT-3' (T3XT2)
Rendimento 0,03 pmole (rendimento de 15%) (5) 5'-GCGTTTTTXGCT-3' (T5X)
Rendimento 0,06 pmole (rendimento de 30%) (6) 5'-GCGXXTTTTGCT-3' (X2T4)
Rendimento 0,06 pmole (rendimento de 30%) (7) 5'-GCGTTXXTTGCT-3' (T2X2T2)
Rendimento 0,05 pmole (rendimento de 25%) (8) 5'-GCGTTTTXXGCT-3' (T4X2)
Rendimento 0,06 pmole (rendimento de 30%) (9) 5'-GCGXXXXXXGCT-3' (X6)
Rendimento 0,06 pmole (rendimento de 30%) (10) -5'-GTTTTTTTTXXC-3' (X2)
Rendimento 0,07 pmole (rendimento de 35%) 55 ΡΕ1013661 [Exemplo de Referência 2] Medição da temperatura de fusão (Tm)
Mediram-se as temperaturas de fusão (Tm) dos produtos de recozimento entre as estirpes de sentido reverso, que eram os diversos análogos de oligonucleótidos sintetizados no Exemplo 2, e cadeias baseadas em ADN ou ARN naturais de sentido directo, para se investigar a capacidade hibridizante doa análogos a oligonucleótidos da invenção presente para ADN e ARN complementares.
Cada solução de amostra (500 pL) com concentrações finais de 100 mM em NaCl, 10 mM em tampão de fosfato de sódio (pH 7,2), 4 μΜ em cadeia de sentido reverso, e 4 μΜ em cadeia de sentido directo, respectivamente, foi banhada em água a ferver, e lentamente arrefecida até à temperatura ambiente ao longo de 10 horas. Arrefeceu-se a solução de amostra gradualmente até 5°C, manteve-se a 5°C durante mais um período de 20 minutos, e depois começou a medir-se, passando-se uma corrente de azoto através da câmara com a célula de um espectrofotómetro (UV-2100PC, Shimadzu) para evitar a condensação de humidade. Aumentou-se a temperatura a uma taxa de 0,2°C/minuto até aos 90°C, e mediu-se a absorção no ultravioleta a 260 nm a intervalos de 0,1°C. Para evitar alterações da concentração das amostras com os aumentos de temperatura, a célula tinha uma tampa, e aplicou-se uma gota de óleo mineral sobre a superfície da solução de cada amostra durante a medição. ΡΕ1013661 56
Os resultados estão listados na tabela seguinte.
Tabela 1 Temperaturas de fusão (Tm) de Análogos de Oligonu-cleótidos de sentido reverso para ADN e ARN Complementares
Molécula de sentido reverso Tm para o ADNa> complementar (ATm/mod.) Tm para o ARNb) complementar (ATm/mod.) 5'-GCGTTTTTTGCT-3’ (natural) O O 45°C 5'-GCGXTTTTTGCT-3' (XT5) 50°C (+3°C) 49°C ( + 4 °C) 5'-GCGTTXTTTGCT-3' (T2XT3) 49°C ( + 2 °C) 49°C ( + 4 °C) 5’-GCGTTTXTTGCT-3' (T3XT2) 49°C ( + 2 °C) 50°C (+5°C) 5'-GCGTTTTTXGCT-3’ (T5X) 52 °C ( + 4 °C) 51°C (+6°C) 5'-GCGXXTTTTGCT-3' (X2T4) 51°C (+2 °C) 53°C (+4°C) 5'-GCGTTXXTTGCT-3’ (T2X2T2) 49°C (+1°C) 53°C ( + 4 °C) 5'-GCGTTTTXXGCT-3' (T4X2) 54 °C (+3,5°C) 55°C (+5°C) 5'-GCGXXXXXXGCT-3' (X6) 58 °C ( + 1,8 °C) 71.°C (+4,3°C) a): 3'-CGCAAAAAACGA-5' . b) : 3 ' -r(CGCAAAAAAC
Tal como se ilustra na tabela, no caso do oligómero contendo uma ou duas unidades (X) do análogo de nucleósido da invenção presente (fórmula geral (Ia)) introduzidas numa cadeia de ADN natural, a capacidade de se hibridizarem com o oligómero de ADN complementar, avaliada através da Tm, aumentou 2 a 7 graus (cerca de 2 graus por resíduo modificado) em comparação com a cadeia natural. Com o oligómero com todos os T substituídos por X (X6), o 57 ΡΕ1013661 aumento da capacidade foi tão elevado como 11 graus. Quando a capacidade de se hibridizar com o ARN complementar foi avaliada, o oligómero que incorporava um ou dois X apresentava um aumento em Tm de 4 - 10 graus (4 a 6 graus por resíduo modificado) ao longo da cadeia modificada. No caso de X6, a capacidade de se hibridizar com o ARN complementar era mais aumentada, mostrando um aumento de Tm de mais do que 25 graus (4 graus por resíduo modificado) . Não houve nenhum exemplo de análogos sofrendo estes aumentos em Tm em comparação com estirpes naturais, e a afinidade do oligómero era maior para o ARN do que para o ADN. Estes factos significam que o análogo de oligonucleótido constituído pelo análogo de biciclo-oligonucleósido da invenção presente tem um desempenho extremamente elevado a título de molécula de sentido reverso, e é útil como material para produtos farmacêuticos.
[Exemplo de Referência 3] Medição da resistência à nuclease
Misturou-se uma solução tampão (0,003 U/mL, 400 pL) de uma fosfodiesterase de um veneno de cobra com uma solução tampão (10 μΜ, 400 pL) do oligonucleótido mantendo-se a 37 °C durante 15 minutos. Colocou-se a mistura de soluções numa células em quartzo (800 pL) mantida a 37°C, e mediram-se os aumentos na absorção no ultravioleta (a 260 nm) devidos á decomposição do oligonucleótido ao longo do tempo usando um SHIMADZU UV-2100PC. O tampão utilizando incluía Tris-HCl 0,1 M (pH 8,6), NaClO,1 M, e MgCl2 14 mM, e foi suficientemente desgaseifiçado antes da medição. ΡΕ1013661 58
Medição da vida média (11/2) :
Calculou-se a média dos valores da absorção no UV medidos no inicio da medição (t=0) e a média medida na altura em que não se notou qualquer aumento deste parâmetro. 0 período correspondente a esta média foi designado como vida média (11/2) ·
Sequência de Oligonucleótido_ti/2 (segundos) 5’-GTTTTTTTTTTTC-3' (de tipo natural) 260 5’-GTTTTTTTTT-XX-C-3' (X2) 850
Apresentam-se a título de Fig. 1 gráficos mostrando o decurso temporal da absorção no ultravioleta (cadeia natural) e também na Fig. 2 (X2) . A absorção no ultravioleta atingiu um patamar em cerca de 30 minutos para a estirpe natural, e em cerca de 90 minutos para X2, após iniciação da reacção enzimática.
APLICABILIDADE INDUSTRIAL A utilização deste análogo proporciona um análogo de um oligonucleótido, molécula de sentido reverso, que é minimamente hidrolisável com um enzima em vivo, tem uma elevada capacidade para se ligar a uma cadeia de sentido directo, e se sintetiza facilmente. 59 ΡΕ1013661
Listagem de Sequências
Nome do requerente: Takeshi Imanishi
Titulo da invenção: Biciclonucleósido novo e análogo de oligonucleótido Referência N.°:
Pedido N.°:
Data do pedido: Março, 1998 Prioridade N.°: JPA 53409/97 Data de prioridade: 7 de Março, 1997 Número de sequências: 11 N.° ID Seq.: 1
Comprimento da sequência: 12 Tipo de sequência: Nucleótido Número de cadeias: Cadeia simples Topologia: Linear Sequência: 5'-GCGTTTTTTGCT-3' N.0 ID Seq.: 2
Comprimento da sequência: 12
Tipo de sequência: Nucleótido, análogo de nucleótido Número de cadeias: Cadeia simples Topologia: Linear Sequência: 5'-GCGXTTTTTGCT-3' N.° ID Seq.: 3
Comprimento da sequência: 12
Tipo de sequência: Nucleótido, análogo de nucleótido Número de cadeias: Cadeia simples 60 ΡΕ1013661
Topologia: Linear Sequência: 5'-GCGTTXTTTGCT-3' N.° ID Seq.: 4
Comprimento da sequência: 12
Tipo de sequência: Nucleótido, análogo de nucleótido Número de cadeias: Cadeia simples Topologia: Linear Sequência: 5'-GCGTTTXTTGCT-3' N.° ID Seq.: 5
Comprimento da sequência: 12
Tipo de sequência: Nucleótido, análogo de nucleótido Número de cadeias: Cadeia simples Topologia: Linear Sequência: 5'-GCGTTTTTXGCT-3' N.° ID Seq.: 6 Comprimento da sequência: 12
Tipo de sequência: Nucleótido, análogo de nucleótido Número de cadeias: Cadeia simples Topologia: Linear Sequência: 5'-GCGXXTTTTGCT-3' N.° ID Seq.: 7
Comprimento da sequência: 12
Tipo de sequência: Nucleótido, análogo de nucleótido Número de cadeias: Cadeia simples Topologia: Linear 61 ΡΕ1013661
Sequência: 5' 1-GCGTTXXTTGCT-3' N.0 ID Seq.: 8
Comprimento da sequência: 12
Tipo de sequência: Nucleótido, análogo de nucleótido Número de cadeias: Cadeia simples Topologia: Linear
Sequência: 5' 1-GCGTTTTXXGCT-3’ N.° ID Seq.: 9
Comprimento da sequência: 12
Tipo de sequência: Nucleótido, análogo de nucleótido Número de cadeias: Cadeia simples Topologia: Linear
Sequência: 5' 1-GCGXXXXXXGCT-3' N.° ID Seq.: 10
Comprimento da sequência: 13
Tipo de sequência: Nucleótido, análogo de nucleótido Número de cadeias: Cadeia simples Topologia: Linear
Sequência: 5' ,-gtttttttttttc-3' N.0 ID Seq.: 11
Comprimento da sequência: 13
Tipo de sequência: Nucleótido, análogo de nucleótido Número de cadeias: Cadeia simples Topologia: Linear Sequência: 5' -GTTTTTTTTXXTC-3' 62 ΡΕ1013661
Listagem de Sequências <110> <12 0> <130> Imanishi, Takeshi Biciclonucleósido inovador e análogo de oligonucleótido <14 0> <141> <150> <151> <160> 98905804.5 1998-03-09 JPA 53409/97 1997-03-07 11 <210> <211> 1 12
<212> ADN <213> <22 0> <221> <222> <223> Sequência Artificial Λ o o V gcgttttttgct <210> 2 <211> 12
<212> ADN <213> <22 0> Sequência Artificial <221> <222> <223> base modificada <400> gcgntttttgct <210> <211> 3 12
<212> ADN
<213> <22 0> Sequência Artificial <221> <222> <223> base modificada <400> gcgttntttgct <210> <211> 4 12 <212> <213> <22 0> <221> ADN Sequência Artificial <222> <223> base modificada <400> gcgtttnttgct <210> <211> 5 12 <212> ADN 63 ΡΕ1013661 <213> Sequência Artificial <22 0> <221> base modificada <222> <223> <400> gcgtttttngct
<210> 6 <211> 12 <212> ADN <213> Sequência Artificial <22 0> <221> <222> base modificada <223> <400> gcgnnttttgct
<210> 7 <211> 12 <212> ADN <213> Sequência Artificial <22 0> <221> <222> base modificada <223> <400> gcgttnnttgct
<210> 8 <211> 12 <212> ADN <213> Sequência Artificial <22 0> <221> <222> base modificada <223> <400> gcgttttnngct
<210> 9 <211> 12 <212> ADN <213> Sequência Artificial <22 0> <221> <222> base modificada <223> <400> gcgnnnnnngct
<210> 10 <211> 13 <212> ADN <213> Sequência Artificial <22 0> <221> <222> <223> 64 ΡΕ1013661 Λ o o V gtttttttttttc <210> 11 <211> 13 <212> ADN <213> Sequência Artificial <22 0> <221> <222> base modificada <223> Λ o o V gttttttttnntc
Lisboa, 15 de Março de 2012
Claims (16)
- ΡΕ1013661 1 REIVINDICAÇÕES 1. Um análogo do nucleósido com a fórmula geral (I) seguinte(D em que B seja uma base de ácido nucleico de pirimidina ou de purina, ou um seu análogo, e X e Y sejam idênticos ou diferentes, e cada um destes representa um átomo de hidrogénio, um grupo alquilo, um grupo alcenilo, um grupo alcinilo, um grupo cicloalquilo, um grupo aral-quilo, um grupo arilo, um grupo acilo, ou um grupo sililo, ou um seu derivado de amidito.
- 2. Um análogo de nucleósido de acordo com a reivindicação 1, em que a base de ácido nucleico de pirimidina ou de purina seja seleccionada de entre tiamina, uracilo, citosina, adenina, guanina, ou um seu derivado.
- 3. Um análogo de nucleósido de acordo com a reivindicação 1, em que a base de ácido nucleico de pirimidina ou de purina seja tiamina, ou um seu derivado.
- 4. Um análogo de nucleósido de acordo com a 2 ΡΕ1013661 reivindicação 1, em que a base de ácido nucleico de pirimidina ou de purina seja uracilo, ou um seu derivado.
- 5. Um análogo de nucleósido de acordo com a reivindicação 1, em que a base de ácido nucleico de pirimidina ou de purina seja citosina, ou um seu derivado.
- 6. Um análogo de nucleósido de acordo com a reivindicação 1, em que a base de ácido nucleico de pirimidina ou de purina seja adenina, ou um seu derivado.
- 7. Um análogo de nucleósido de acordo com a reivindicação 1, em que a base de ácido nucleico de pirimidina ou de purina seja guanina, ou um seu derivado.
- 8. Um análogo de nucleósido de acordo com qualquer uma das reivindicações 1-3 com a fórmula geral (li) seguinteem que B seja uma base de ácido nucleico de pirimidina ou de purina, ou um seu análogo, e X e Y sejam idênticos ou diferentes, e cada um destes representa um átomo de hidrogénio, um grupo alquilo, 3 ΡΕ1013661 um grupo alcenilo, um grupo alcinilo, um grupo cicloal-quilo, um grupo aralquilo, um grupo arilo, um grupo acilo, ou um grupo sililo, ou um seu derivado; em que a referida base de ácido nucleico de pirimidina ou de purina seja timina.
- 9. Um análogo de nucleósido de acordo com qualquer uma das reivindicações 1, 2 e 4 com a fórmula geral (Iii) seguinteem que B seja uma base de ácido nucleico de pirimidina ou de purina, ou um seu análogo, e X e Y sejam idênticos ou diferentes, e cada um destes representa um átomo de hidrogénio, um grupo alquilo, um grupo alcenilo, um grupo alcinilo, um grupo cicloalquilo, um grupo aralquilo, um grupo arilo, um grupo acilo, ou um grupo sililo, ou um seu derivado de amidito; em que a referida base de ácido nucleico de pirimidina ou de purina seja uracilo.
- 10. Um análogo de nucleósido de acordo com qualquer uma das reivindicações 1, 2 e 5 com a fórmula geral (Iiii) seguinte 4 ΡΕ1013661em que B seja uma base de ácido nucleico de pirimidina ou de purina, ou um seu derivado, e X e Y sejam idênticos ou diferentes, e cada um destes representa um átomo de hidrogénio, um grupo alquilo, um grupo alcenilo, um grupo alcinilo, um grupo ciclo-alquilo, um grupo aralquilo, um grupo arilo, um grupo acilo, ou um grupo sililo, ou um seu derivado de amidito; em que a referida base de ácido nucleico de pirimidina ou de purina seja citosina.
- 11. Um análogo de nucleósido de acordo com qualquer uma das reivindicações 1, 2 e 6 com a fórmula geral (Iiv) seguinteem que B seja uma base de ácido nucleico de pirimidina ou de purina, ou um seu derivado, e 5 ΡΕ1013661 X e Y sejam idênticos ou diferentes, e cada um destes representa um átomo de hidrogénio, um grupo alquilo, um grupo alcenilo, um grupo alcinilo, um grupo cicloal-quilo, um grupo aralquilo, um grupo arilo, um grupo acilo, ou um grupo sililo, ou um seu derivado de amidito; em que a referida base de ácido nucleico de pirimidina ou de purina seja adenina.
- 12. Um análogo de nucleósido de acordo com qualquer uma das reivindicações 1, 2 e 7 com a fórmula geral (Iv) seguinteem que B seja uma base de ácido nucleico de pirimidina ou de purina, ou um seu derivado, e X e Y sejam idênticos ou diferentes, e cada um destes representa um átomo de hidrogénio, um grupo alquilo, um grupo alcenilo, um grupo alcinilo, um grupo cicloal-quilo, um grupo aralquilo, um grupo arilo, um grupo acilo, ou um grupo sililo, ou um seu derivado de amidito; em que a referida base de ácido nucleico de pirimidina ou de purina seja guanina. 6 ΡΕ1013661
- 13. Um análogo de nucleósido tal como se reivindica em qualquer uma das reivindicações 1 a 12, em que X e Y representem cada qual um átomo de hidrogénio.
- 14. Um análogo de nucleósido tal como se reivindica em qualquer uma das reivindicações 1 a 12 que seja um derivado de amidito de mononucleósido, em que X seja 4,4-dimetoxitritilo (DMTr), e Y seja um grupo 2-cianoetoxi(di-isopropilamino)fosfino (grupo amidito).
- 15. Um análogo de nucleósido tal como se reivindica na reivindicação 1, em que o grupo aralquilo seja seleccionado de entre tritilo, benzilo, fenetilo, tritil-metilo, difenilmetilo, naftilmetilo e 4,4'-dimetoxitritilo (DMTr).
- 16. Um análogo de nucleósido de acordo com a reivindicação 1 que seja seleccionado de entre os seguintes :ΡΕ1013661 7 οTBDPSOv. . »Βη 37:Β-Τ 42:3mABx 4β: 8=G®U 38: Β=Τ 43: ΒβΑ®* 47: B-G10" 39a: Β«=Τ 39b: BaA02 39c: BaGíaj Lisboa, 15 de Março de 2012
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|---|---|---|---|
| JP5340997 | 1997-03-07 |
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| PT1013661E true PT1013661E (pt) | 2012-03-28 |
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| PT101729713T PT2295441E (pt) | 1997-03-07 | 1998-03-09 | Novo biciclonucleosido e análogo de oligonucleotido |
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| PT101729713T PT2295441E (pt) | 1997-03-07 | 1998-03-09 | Novo biciclonucleosido e análogo de oligonucleotido |
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| US (1) | US6268490B1 (pt) |
| EP (3) | EP2295441B1 (pt) |
| JP (1) | JP3756313B2 (pt) |
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| AU (1) | AU720472B2 (pt) |
| CA (1) | CA2283509C (pt) |
| DE (1) | DE98905804T1 (pt) |
| DK (3) | DK2361921T3 (pt) |
| ES (3) | ES2380354T5 (pt) |
| PT (2) | PT1013661E (pt) |
| WO (1) | WO1998039352A1 (pt) |
Families Citing this family (1207)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7119184B2 (en) * | 1991-08-12 | 2006-10-10 | Isis Pharmaceuticals, Inc. | Oligonucleotides having A-DNA form and B-DNA form conformational geometry |
| US5898031A (en) | 1996-06-06 | 1999-04-27 | Isis Pharmaceuticals, Inc. | Oligoribonucleotides for cleaving RNA |
| US9096636B2 (en) | 1996-06-06 | 2015-08-04 | Isis Pharmaceuticals, Inc. | Chimeric oligomeric compounds and their use in gene modulation |
| US7812149B2 (en) | 1996-06-06 | 2010-10-12 | Isis Pharmaceuticals, Inc. | 2′-Fluoro substituted oligomeric compounds and compositions for use in gene modulations |
| USRE44779E1 (en) | 1997-03-07 | 2014-02-25 | Santaris Pharma A/S | Bicyclonucleoside and oligonucleotide analogues |
| JP3756313B2 (ja) † | 1997-03-07 | 2006-03-15 | 武 今西 | 新規ビシクロヌクレオシド及びオリゴヌクレオチド類縁体 |
| US6770748B2 (en) | 1997-03-07 | 2004-08-03 | Takeshi Imanishi | Bicyclonucleoside and oligonucleotide analogue |
| RU2243231C2 (ru) * | 1997-09-12 | 2004-12-27 | Эксикон А/С | Бициклические аналоги нуклеозидов, нуклеотидов и олигонуклеотидов |
| US7572582B2 (en) | 1997-09-12 | 2009-08-11 | Exiqon A/S | Oligonucleotide analogues |
| US6794499B2 (en) | 1997-09-12 | 2004-09-21 | Exiqon A/S | Oligonucleotide analogues |
| JP4236812B2 (ja) * | 1997-09-12 | 2009-03-11 | エクシコン エ／エス | オリゴヌクレオチド類似体 |
| US6583168B1 (en) | 1997-11-25 | 2003-06-24 | Applera Corporation | Sulfonated diarylrhodamine dyes |
| JP2002516256A (ja) * | 1998-05-26 | 2002-06-04 | アイ・シー・エヌ・フアーマシユーテイカルズ・インコーポレイテツド | 二環式糖成分を有する新規ヌクレオシド |
| JP4148662B2 (ja) * | 2000-08-10 | 2008-09-10 | 第一三共株式会社 | ヌクレオシド及びオリゴヌクレオチド類縁体を含有する核酸試薬及び医薬 |
| ES2234563T5 (es) | 1999-02-12 | 2018-01-17 | Daiichi Sankyo Company, Limited | Nuevos análogos de nucleósidos y oligonucleótidos |
| DE60025172T2 (de) | 1999-03-18 | 2006-09-21 | Exiqon A/S | Einstufige probezubereitung und bestimmung von nukleinsäure in biologischen proben |
| KR20020013513A (ko) * | 1999-03-18 | 2002-02-20 | 추후제출 | Ｘｙｌｏ-ｌｎａ 유사체 |
| HK1048339A1 (zh) | 1999-03-18 | 2003-03-28 | 埃克西库恩公司 | 利用特异性lna引物检测基因突变 |
| US6436640B1 (en) * | 1999-03-18 | 2002-08-20 | Exiqon A/S | Use of LNA in mass spectrometry |
| US7084125B2 (en) | 1999-03-18 | 2006-08-01 | Exiqon A/S | Xylo-LNA analogues |
| DE60029314T2 (de) * | 1999-03-24 | 2007-07-12 | Exiqon A/S | Verbesserte Synthese für -2.2.1. I Bicyclo-Nukleoside |
| US6734291B2 (en) * | 1999-03-24 | 2004-05-11 | Exiqon A/S | Synthesis of [2.2.1]bicyclo nucleosides |
| US7098192B2 (en) | 1999-04-08 | 2006-08-29 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotide modulation of STAT3 expression |
| US7053207B2 (en) | 1999-05-04 | 2006-05-30 | Exiqon A/S | L-ribo-LNA analogues |
| JP4151751B2 (ja) * | 1999-07-22 | 2008-09-17 | 第一三共株式会社 | 新規ビシクロヌクレオシド類縁体 |
| IL149694A0 (en) * | 1999-12-23 | 2002-11-10 | Exiqon As | Therapeutic uses of lna-modified oligonucleotides |
| US6887664B2 (en) | 2000-06-06 | 2005-05-03 | Applera Corporation | Asynchronous primed PCR |
| AU2001271042A1 (en) * | 2000-07-19 | 2002-01-30 | Chugai Seiyaku Kabushiki Kaisha | Novel antisense oligonucleotide derivatives against wilms's tumor gene |
| JP2002322192A (ja) * | 2000-08-10 | 2002-11-08 | Sankyo Co Ltd | ２’−ｏ，４’−ｃ−架橋ヌクレオシドトリリン酸体 |
| US7053199B2 (en) * | 2000-08-29 | 2006-05-30 | Takeshi Imanishi | Nucleoside analogs and oligonucleotide derivatives containing these analogs |
| JP4413493B2 (ja) * | 2000-10-04 | 2010-02-10 | サンタリス ファーマ アー／エス | プリンｌｎａ類似体の改善された合成方法 |
| EP1414840A4 (en) * | 2001-03-27 | 2005-04-13 | Univ Delaware | GENOMICS APPLICATIONS FOR MODIFIED OLIGONUCLEOTIDES |
| EP1251183A3 (en) * | 2001-04-18 | 2003-12-10 | Exiqon A/S | Improved helper probes for detection of a target sequence by a capture oligonucleotide |
| PT2000545E (pt) | 2001-06-20 | 2011-12-21 | Genentech Inc | Composições e métodos para o diagnóstico e tratamento do tumor pulmonar |
| EP2221376B1 (en) | 2001-06-21 | 2012-11-21 | Isis Pharmaceuticals, Inc. | Antisense modulation of superoxide dismutase 1, soluble expression |
| US6822088B2 (en) | 2001-07-17 | 2004-11-23 | Isis Pharmaceuticals, Inc. | Synthesis of oligonucleotides on solid support |
| AU2002365115A1 (en) | 2001-07-20 | 2003-09-02 | North Carolina State University | Light addressable electrochemical detection of duplex structures |
| US6964950B2 (en) | 2001-07-25 | 2005-11-15 | Isis Pharmaceuticals, Inc. | Antisense modulation of C-reactive protein expression |
| US7425545B2 (en) | 2001-07-25 | 2008-09-16 | Isis Pharmaceuticals, Inc. | Modulation of C-reactive protein expression |
| US20030096772A1 (en) | 2001-07-30 | 2003-05-22 | Crooke Rosanne M. | Antisense modulation of acyl CoA cholesterol acyltransferase-2 expression |
| US7407943B2 (en) | 2001-08-01 | 2008-08-05 | Isis Pharmaceuticals, Inc. | Antisense modulation of apolipoprotein B expression |
| US20040096880A1 (en) * | 2001-08-07 | 2004-05-20 | Kmiec Eric B. | Compositions and methods for the treatment of diseases exhibiting protein misassembly and aggregation |
| US7227014B2 (en) | 2001-08-07 | 2007-06-05 | Isis Pharmaceuticals, Inc. | Antisense modulation of apolipoprotein (a) expression |
| EP1437408A4 (en) * | 2001-09-17 | 2006-08-23 | Takeshi Imanishi | NOVEL ANTISENSE OLIGONUCLEOTIDE DERIVATIVES AGAINST HEPATITIS C VIRUS |
| DE60238143D1 (de) | 2001-09-18 | 2010-12-09 | Genentech Inc | Zusammensetzungen und verfahren für die diagnose von tumoren |
| US7468244B2 (en) * | 2001-09-27 | 2008-12-23 | University Of Delaware | Polymorphism detection and separation |
| EP1448766A2 (en) * | 2001-09-27 | 2004-08-25 | University Of Delaware | Coisogenic eukaryotic cell collections |
| NZ585001A (en) | 2001-10-09 | 2011-08-26 | Isis Pharmaceuticals Inc | Antisense modulation of insulin-like growth factor binding protein 5 expression |
| US6750019B2 (en) | 2001-10-09 | 2004-06-15 | Isis Pharmaceuticals, Inc. | Antisense modulation of insulin-like growth factor binding protein 5 expression |
| WO2003033696A1 (en) * | 2001-10-18 | 2003-04-24 | Sankyo Company, Limited | Vegf antisense compound |
| WO2003040395A2 (en) * | 2001-11-07 | 2003-05-15 | Applera Corporation | Universal nucleotides for nucleic acid analysis |
| US20030165935A1 (en) | 2001-11-21 | 2003-09-04 | Vann Charles S. | Digital assay |
| US6965025B2 (en) | 2001-12-10 | 2005-11-15 | Isis Pharmaceuticals, Inc. | Antisense modulation of connective tissue growth factor expression |
| CA2471218A1 (en) * | 2001-12-21 | 2003-07-24 | Applera Corporation | Heteroconfigurational polynucleotide and methods of use |
| AU2002367318B2 (en) | 2002-01-02 | 2007-07-12 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
| EP1572902B1 (en) | 2002-02-01 | 2014-06-11 | Life Technologies Corporation | HIGH POTENCY siRNAS FOR REDUCING THE EXPRESSION OF TARGET GENES |
| ATE556714T1 (de) | 2002-02-01 | 2012-05-15 | Life Technologies Corp | Doppelsträngige oligonukleotide |
| US20060009409A1 (en) | 2002-02-01 | 2006-01-12 | Woolf Tod M | Double-stranded oligonucleotides |
| EP1481983A4 (en) * | 2002-02-13 | 2008-04-02 | Takeshi Imanishi | NUCLEOSIDE ANALOGUE AND OLIGONUCLEOTIDE DERIVATIVES CONTAINING A NUCLEOTIDE ANALOGON THEREOF |
| WO2003075856A2 (en) | 2002-03-07 | 2003-09-18 | University Of Delaware | Methods, compositions, and kits for enhancing oligonucleotide-mediated nucleic acid sequence alteration using compositions comprising a histone deacetylase inhibitor, lambda phage beta protein, or hydroxyurea |
| US20030198960A1 (en) * | 2002-04-01 | 2003-10-23 | Wenhong Fan | Signal amplifying targeted reporters for biological and chemical sensor applications |
| US7211382B2 (en) * | 2002-04-09 | 2007-05-01 | Orchid Cellmark Inc. | Primer extension using modified nucleotides |
| JP2005536190A (ja) | 2002-04-16 | 2005-12-02 | ジェネンテック・インコーポレーテッド | 腫瘍の診断と治療のための組成物と方法 |
| US7569575B2 (en) | 2002-05-08 | 2009-08-04 | Santaris Pharma A/S | Synthesis of locked nucleic acid derivatives |
| US7199107B2 (en) | 2002-05-23 | 2007-04-03 | Isis Pharmaceuticals, Inc. | Antisense modulation of kinesin-like 1 expression |
| US20100075423A1 (en) * | 2002-06-12 | 2010-03-25 | Life Technologies Corporation | Methods and compositions relating to polypeptides with rnase iii domains that mediate rna interference |
| GB2406169B (en) * | 2002-06-12 | 2006-11-01 | Ambion Inc | Methods and compositions relating to labeled rna molecules that reduce gene expression |
| US20040248094A1 (en) * | 2002-06-12 | 2004-12-09 | Ford Lance P. | Methods and compositions relating to labeled RNA molecules that reduce gene expression |
| US7005265B1 (en) | 2002-06-20 | 2006-02-28 | Wenhong Fan | Nonenzymatic catalytic signal amplification for nucleic acid hybridization assays |
| BR0314236A (pt) | 2002-09-13 | 2005-08-09 | Replicor Inc | Formulação de oligonucleotìdeo, composição farmacêutica, kit, composto antiviral, preparação de oligonucleotìdeo e métodos para seleção de um oligonucleotìdeo antiviral para uso como um agente antiviral, para profilaxia ou tratamento de uma infecção viral em um paciente, para tratamento profilático de câncer causado por oncovìrus, para identificação de um composto que altera a ligação de um oligonucleotìdeo a pelo menos um componente viral, para purificação da ligação de oligonucleotìdeos a pelo menos um componente viral e para enriquecimento de oligonucleotìdeos a partir de um agrupamento de oligonucleotìdeos |
| US7229976B2 (en) | 2002-09-26 | 2007-06-12 | Isis Pharmaceuticals, Inc. | Modulation of forkhead box O1A expression |
| AU2003282477A1 (en) * | 2002-10-07 | 2004-05-04 | Napro Bio Therapeutics, Inc. | Methods and compositions for reducing screening in oligonucleotide-directed nucleic acid sequence alteration |
| US20040219565A1 (en) | 2002-10-21 | 2004-11-04 | Sakari Kauppinen | Oligonucleotides useful for detecting and analyzing nucleic acids of interest |
| WO2004041889A2 (en) | 2002-11-05 | 2004-05-21 | Isis Pharmaceuticals, Inc. | Polycyclic sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation |
| AU2003291755A1 (en) * | 2002-11-05 | 2004-06-07 | Isis Pharmaceuticals, Inc. | Oligomers comprising modified bases for binding cytosine and uracil or thymine and their use |
| SI1569695T1 (sl) | 2002-11-13 | 2013-08-30 | Genzyme Corporation | Protismiselna modulacija ekspresije apolipoproteina B |
| EP2336318B1 (en) | 2002-11-13 | 2013-04-24 | Genzyme Corporation | Antisense modulation of apolipoprotein b expression |
| WO2004046160A2 (en) | 2002-11-18 | 2004-06-03 | Santaris Pharma A/S | Amino-lna, thio-lna and alpha-l-oxy-ln |
| TWI347948B (en) | 2002-11-19 | 2011-09-01 | Sankyo Co | Novel 2',5'-oligoadenylic acid compositions |
| JP5132025B2 (ja) * | 2002-11-19 | 2013-01-30 | 第一三共株式会社 | 新規２’，５’−オリゴアデニル酸類縁体 |
| US7144999B2 (en) | 2002-11-23 | 2006-12-05 | Isis Pharmaceuticals, Inc. | Modulation of hypoxia-inducible factor 1 alpha expression |
| NZ541637A (en) | 2003-02-11 | 2008-07-31 | Antisense Therapeutics Pty Ltd | Modulation of insulin like growth factor I receptor |
| US7803781B2 (en) | 2003-02-28 | 2010-09-28 | Isis Pharmaceuticals, Inc. | Modulation of growth hormone receptor expression and insulin-like growth factor expression |
| US20040185559A1 (en) | 2003-03-21 | 2004-09-23 | Isis Pharmaceuticals Inc. | Modulation of diacylglycerol acyltransferase 1 expression |
| AU2003237792A1 (en) | 2003-04-01 | 2004-11-23 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
| US7598227B2 (en) | 2003-04-16 | 2009-10-06 | Isis Pharmaceuticals Inc. | Modulation of apolipoprotein C-III expression |
| US7399853B2 (en) | 2003-04-28 | 2008-07-15 | Isis Pharmaceuticals | Modulation of glucagon receptor expression |
| EP1633893B1 (en) | 2003-05-19 | 2012-01-25 | Gen-Probe Incorporated | Compositions, methods and kits for determining the presence of trichomonas vaginalis in a test sample |
| JP4579911B2 (ja) | 2003-06-03 | 2010-11-10 | アイシス・ファーマシューティカルズ・インコーポレイテッド | スルビビン発現の調節 |
| CN1833034B (zh) * | 2003-06-20 | 2014-04-16 | 埃克斯魁恩公司 | 用于分析核酸混合物的探针、文库和试剂盒及其构建方法 |
| US7683036B2 (en) | 2003-07-31 | 2010-03-23 | Regulus Therapeutics Inc. | Oligomeric compounds and compositions for use in modulation of small non-coding RNAs |
| US8969314B2 (en) | 2003-07-31 | 2015-03-03 | Regulus Therapeutics, Inc. | Methods for use in modulating miR-122a |
| US7825235B2 (en) | 2003-08-18 | 2010-11-02 | Isis Pharmaceuticals, Inc. | Modulation of diacylglycerol acyltransferase 2 expression |
| US20050053981A1 (en) * | 2003-09-09 | 2005-03-10 | Swayze Eric E. | Gapped oligomeric compounds having linked bicyclic sugar moieties at the termini |
| EP2256201A3 (en) | 2003-09-18 | 2012-07-04 | Isis Pharmaceuticals, Inc. | Modulation of eIF4E expression |
| US20050191653A1 (en) | 2003-11-03 | 2005-09-01 | Freier Susan M. | Modulation of SGLT2 expression |
| WO2005045033A1 (ja) | 2003-11-07 | 2005-05-19 | Sankyo Company, Limited | 遺伝子多型の検出方法 |
| DK2295073T3 (da) | 2003-11-17 | 2014-07-28 | Genentech Inc | Antistof mod cd22 til behandling af tumor af hæmatopoietisk oprindelse |
| PT1538154E (pt) | 2003-11-20 | 2009-03-23 | Exiqon As | Composições de agentes de extinção com porções de antraquinona |
| US7972783B2 (en) * | 2003-11-24 | 2011-07-05 | Branhaven LLC | Method and markers for determining the genotype of horned/polled cattle |
| EP1711606A2 (en) | 2004-01-20 | 2006-10-18 | Isis Pharmaceuticals, Inc. | Modulation of glucocorticoid receptor expression |
| US7468431B2 (en) | 2004-01-22 | 2008-12-23 | Isis Pharmaceuticals, Inc. | Modulation of eIF4E-BP2 expression |
| US8569474B2 (en) | 2004-03-09 | 2013-10-29 | Isis Pharmaceuticals, Inc. | Double stranded constructs comprising one or more short strands hybridized to a longer strand |
| US8790919B2 (en) | 2004-03-15 | 2014-07-29 | Isis Pharmaceuticals, Inc. | Compositions and methods for optimizing cleavage of RNA by RNase H |
| US8192937B2 (en) * | 2004-04-07 | 2012-06-05 | Exiqon A/S | Methods for quantification of microRNAs and small interfering RNAs |
| US8394947B2 (en) | 2004-06-03 | 2013-03-12 | Isis Pharmaceuticals, Inc. | Positionally modified siRNA constructs |
| CA2957197C (en) | 2004-08-27 | 2017-12-12 | Gen-Probe Incorporated | Single-primer nucleic acid amplification methods |
| US7713697B2 (en) * | 2004-08-27 | 2010-05-11 | Gen-Probe Incorporated | Methods and kits for amplifying DNA |
| US7884086B2 (en) | 2004-09-08 | 2011-02-08 | Isis Pharmaceuticals, Inc. | Conjugates for use in hepatocyte free uptake assays |
| US20060073506A1 (en) | 2004-09-17 | 2006-04-06 | Affymetrix, Inc. | Methods for identifying biological samples |
| US20060073511A1 (en) | 2004-10-05 | 2006-04-06 | Affymetrix, Inc. | Methods for amplifying and analyzing nucleic acids |
| US7682782B2 (en) | 2004-10-29 | 2010-03-23 | Affymetrix, Inc. | System, method, and product for multiple wavelength detection using single source excitation |
| WO2006059507A1 (ja) * | 2004-11-30 | 2006-06-08 | Sankyo Company, Limited | 11β-HSD1アンチセンス化合物 |
| US20060166238A1 (en) * | 2004-12-22 | 2006-07-27 | Ramsing Niels B | Probes, libraries and kits for analysis of mixtures of nucleic acids and methods for constructing the same |
| US20060142228A1 (en) * | 2004-12-23 | 2006-06-29 | Ambion, Inc. | Methods and compositions concerning siRNA's as mediators of RNA interference |
| EP1838870A2 (en) * | 2004-12-29 | 2007-10-03 | Exiqon A/S | NOVEL OLIGONUCLEOTIDE COMPOSITIONS AND PROBE SEQUENCES USEFUL FOR DETECTION AND ANALYSIS OF MICRORNAS AND THEIR TARGET MRNAs |
| US20060228726A1 (en) | 2005-01-06 | 2006-10-12 | Martin Patrick K | Polypeptides having nucleic acid binding activity and compositions and methods for nucleic acid amplification |
| EP2230316A1 (en) | 2005-02-01 | 2010-09-22 | AB Advanced Genetic Analysis Corporation | Nucleic acid sequencing by performing successive cycles of duplex extension |
| EP2241637A1 (en) | 2005-02-01 | 2010-10-20 | AB Advanced Genetic Analysis Corporation | Nucleic acid sequencing by performing successive cycles of duplex extension |
| ZA200707490B (en) | 2005-03-10 | 2008-12-31 | Genentech Inc | Methods and compositions for modulatiing vascular integrity |
| US20070065840A1 (en) * | 2005-03-23 | 2007-03-22 | Irena Naguibneva | Novel oligonucleotide compositions and probe sequences useful for detection and analysis of microRNAS and their target mRNAS |
| WO2006138145A1 (en) | 2005-06-14 | 2006-12-28 | Northwestern University | Nucleic acid functionalized nanoparticles for therapeutic applications |
| EP2308990B1 (en) | 2005-07-15 | 2012-09-26 | Life Technologies Corporation | Analyzing messenger RNA and micro RNA in the same reaction mixture |
| US20070128620A1 (en) | 2005-07-15 | 2007-06-07 | Applera Corporation | Hot start reverse transcription by primer design |
| EP1915461B1 (en) | 2005-08-17 | 2018-08-01 | Dx4U GmbH | Composition and method for determination of ck19 expression |
| EP1931780B1 (en) | 2005-08-29 | 2016-01-06 | Regulus Therapeutics Inc. | Antisense compounds having enhanced anti-microrna activity |
| JP4741328B2 (ja) * | 2005-09-08 | 2011-08-03 | クラリオン株式会社 | ナビゲーション装置 |
| US20070059713A1 (en) | 2005-09-09 | 2007-03-15 | Lee Jun E | SSB-DNA polymerase fusion proteins |
| US20070212704A1 (en) | 2005-10-03 | 2007-09-13 | Applera Corporation | Compositions, methods, and kits for amplifying nucleic acids |
| WO2007062442A2 (en) | 2005-11-30 | 2007-06-07 | St. Anna Kinderkrebsforschung | Detection of fungi |
| ES2548240T3 (es) | 2005-12-01 | 2015-10-15 | Pronai Therapeutics, Inc. | Terapias para el cáncer y composiciones farmacéuticas usadas en las mismas |
| WO2007073149A1 (en) | 2005-12-22 | 2007-06-28 | Keygene N.V. | Alternative nucleotides for improved targeted nucleotide exchange |
| JP5713377B2 (ja) | 2005-12-28 | 2015-05-07 | ザ スクリプス リサーチ インスティテュート | 薬物標的としての天然アンチセンスおよび非コードｒｎａ転写物 |
| WO2007073737A1 (en) * | 2005-12-29 | 2007-07-05 | Exiqon A/S | Detection of tissue origin of cancer |
| EP1991677A2 (en) | 2006-01-26 | 2008-11-19 | Isis Pharmaceuticals, Inc. | Compositions and their uses directed to huntingtin |
| AU2007211082B2 (en) | 2006-01-27 | 2012-09-27 | Isis Pharmaceuticals, Inc. | Oligomeric compounds and compositions for the use in modulation of microRNAs |
| US7569686B1 (en) | 2006-01-27 | 2009-08-04 | Isis Pharmaceuticals, Inc. | Compounds and methods for synthesis of bicyclic nucleic acid analogs |
| WO2007090071A2 (en) | 2006-01-27 | 2007-08-09 | Isis Pharmaceuticals, Inc. | 6-modified bicyclic nucleic acid analogs |
| US9677123B2 (en) | 2006-03-15 | 2017-06-13 | Siemens Healthcare Diagnostics Inc. | Degenerate nucleobase analogs |
| CN101495654A (zh) * | 2006-04-19 | 2009-07-29 | 阿普里拉股份有限公司 | 无凝胶珠基测序的试剂、方法和文库 |
| EP2021511A4 (en) | 2006-05-03 | 2010-02-10 | Geisinger Clinic | METHODS OF DIAGNOSIS AND PREDICTION OF NON ALCOHOLIC STHEATHYPATITIS (NASH) |
| EP2505648A1 (en) | 2006-05-05 | 2012-10-03 | Isis Pharmaceuticals, Inc. | Compounds and methods for modulating expression of PTP1B |
| JP2009536222A (ja) | 2006-05-05 | 2009-10-08 | アイシス ファーマシューティカルズ， インコーポレーテッド | Ｐｃｓｋ９の発現を調節するための化合物および方法 |
| AU2007249349B2 (en) * | 2006-05-11 | 2012-03-08 | Isis Pharmaceuticals, Inc. | 5'-Modified bicyclic nucleic acid analogs |
| US7666854B2 (en) * | 2006-05-11 | 2010-02-23 | Isis Pharmaceuticals, Inc. | Bis-modified bicyclic nucleic acid analogs |
| US20090023221A1 (en) * | 2006-05-19 | 2009-01-22 | Exigon A/S | Oligonucleotide probes useful for detection and analysis of microrna precursors |
| DE602007012045D1 (de) | 2006-06-06 | 2011-03-03 | Gen Probe Inc | Markierte oligonukleotide und ihre verwendung in nukleinsäureverstärkungsverfahren |
| US20080076674A1 (en) * | 2006-07-06 | 2008-03-27 | Thomas Litman | Novel oligonucleotide compositions and probe sequences useful for detection and analysis of non coding RNAs associated with cancer |
| US8198253B2 (en) | 2006-07-19 | 2012-06-12 | Isis Pharmaceuticals, Inc. | Compositions and their uses directed to HBXIP |
| AU2007281535A1 (en) | 2006-08-01 | 2008-02-07 | Applied Biosystems, Llc. | Detection of analytes and nucleic acids |
| AU2007284651B2 (en) | 2006-08-09 | 2014-03-20 | Institute For Systems Biology | Organ-specific proteins and methods of their use |
| KR101556798B1 (ko) | 2006-10-05 | 2015-10-01 | 메사츄세츠 인스티튜트 어브 테크놀로지 | 고성능 분석을 위한 다중기능성 인코딩된 입자 |
| ES2526295T5 (es) | 2006-10-18 | 2021-05-04 | Ionis Pharmaceuticals Inc | Compuestos antisentido |
| CA2666657A1 (en) * | 2006-10-18 | 2008-04-24 | Nastech Pharmaceutical Company Inc. | Nicked or gapped nucleic acid molecules and uses thereof |
| US8188255B2 (en) * | 2006-10-20 | 2012-05-29 | Exiqon A/S | Human microRNAs associated with cancer |
| EP2090665A2 (en) | 2006-10-20 | 2009-08-19 | Exiqon A/S | Novel human microRNAs associated with cancer |
| US8093222B2 (en) | 2006-11-27 | 2012-01-10 | Isis Pharmaceuticals, Inc. | Methods for treating hypercholesterolemia |
| CA2670563A1 (en) * | 2006-11-27 | 2008-06-05 | Isis Pharmaceuticals, Inc. | Methods for treating hypercholesterolemia |
| US8293684B2 (en) * | 2006-11-29 | 2012-10-23 | Exiqon | Locked nucleic acid reagents for labelling nucleic acids |
| EP3536788A1 (en) | 2006-12-21 | 2019-09-11 | QIAGEN GmbH | Microrna target site blocking oligos and uses thereof |
| WO2008086807A2 (en) | 2007-01-19 | 2008-07-24 | Exiqon A/S | Mediated cellular delivery of lna oligonucleotides |
| WO2009045469A2 (en) | 2007-10-02 | 2009-04-09 | Amgen Inc. | Increasing erythropoietin using nucleic acids hybridizable to micro-rna and precursors thereof |
| EP2121987B1 (en) | 2007-02-09 | 2012-06-13 | Northwestern University | Particles for detecting intracellular targets |
| US20100292301A1 (en) * | 2007-02-28 | 2010-11-18 | Elena Feinstein | Novel sirna structures |
| US8183359B2 (en) * | 2007-03-01 | 2012-05-22 | Gen-Probe Incorporated | Kits for amplifying DNA |
| US20100105134A1 (en) * | 2007-03-02 | 2010-04-29 | Mdrna, Inc. | Nucleic acid compounds for inhibiting gene expression and uses thereof |
| EP2126080A2 (en) * | 2007-03-02 | 2009-12-02 | MDRNA, Inc. | Nucleic acid compounds for inhibiting akt gene expression and uses thereof |
| US20100015706A1 (en) * | 2007-03-02 | 2010-01-21 | Mdrna, Inc. | Nucleic acid compounds for inhibiting hif1a gene expression and uses thereof |
| WO2008109362A1 (en) * | 2007-03-02 | 2008-09-12 | Mdrna, Inc. | Nucleic acid compounds for inhibiting vegf gene expression and uses thereof |
| JP2010519913A (ja) * | 2007-03-02 | 2010-06-10 | エムディーアールエヌエー，インコーポレイテッド | Ｗｎｔ遺伝子の発現を抑制するための核酸化合物およびその使用 |
| US20100055782A1 (en) * | 2007-03-02 | 2010-03-04 | Mdrna, Inc. | Nucleic acid compounds for inhibiting myc gene expression and uses thereof |
| US20080299659A1 (en) * | 2007-03-02 | 2008-12-04 | Nastech Pharmaceutical Company Inc. | Nucleic acid compounds for inhibiting apob gene expression and uses thereof |
| CA2679347A1 (en) * | 2007-03-02 | 2008-09-12 | Mdrna Inc. | Nucleic acid compounds for inhibiting bcl2 gene expression and uses thereof |
| EP2121924A1 (en) * | 2007-03-02 | 2009-11-25 | MDRNA, Inc. | Nucleic acid compounds for inhibiting vegf family gene expression and uses thereof |
| CA2679757A1 (en) * | 2007-03-02 | 2008-09-12 | Mdrna, Inc. | Nucleic acid compounds for inhibiting erbb family gene expression and uses thereof |
| CA2680060A1 (en) * | 2007-03-07 | 2008-09-12 | Nventa Biopharmaceuticals Corporation | Double-stranded locked nucleic acid compositions |
| WO2008111908A1 (en) * | 2007-03-15 | 2008-09-18 | Jyoti Chattopadhyaya | Five- and six-membered conformationally locked 2',4'- carbocyclic ribo-thymidines for the treatment of infections and cancer |
| EP1978111B1 (en) | 2007-04-02 | 2013-03-27 | Gen-Probe Incorporated | Compositions, kits and related methods for the detection and/or monitoring of Pseudomonas aeruginosa |
| FR2915208A1 (fr) | 2007-04-20 | 2008-10-24 | Millipore Corp | Composition comprenant l'association d'edta et de pei pour augmenter la permeabilite des parois des microorganismes et utilisations de ladite composition |
| US8999634B2 (en) | 2007-04-27 | 2015-04-07 | Quest Diagnostics Investments Incorporated | Nucleic acid detection combining amplification with fragmentation |
| EP2160464B1 (en) | 2007-05-30 | 2014-05-21 | Northwestern University | Nucleic acid functionalized nanoparticles for therapeutic applications |
| CA2688321A1 (en) | 2007-05-30 | 2008-12-11 | Isis Pharmaceuticals, Inc. | N-substituted-aminomethylene bridged bicyclic nucleic acid analogs |
| WO2008151023A2 (en) | 2007-06-01 | 2008-12-11 | Ibis Biosciences, Inc. | Methods and compositions for multiple displacement amplification of nucleic acids |
| US7807372B2 (en) | 2007-06-04 | 2010-10-05 | Northwestern University | Screening sequence selectivity of oligonucleotide-binding molecules using nanoparticle based colorimetric assay |
| DK2173760T4 (en) | 2007-06-08 | 2016-02-08 | Isis Pharmaceuticals Inc | Carbocyclic bicyclic nukleinsyreanaloge |
| WO2008151631A2 (en) * | 2007-06-15 | 2008-12-18 | Exiqon A/S | Use of short oligonucleotides for reagent redundancy experiments in rna functional analysis |
| AU2008272918B2 (en) * | 2007-07-05 | 2012-09-13 | Isis Pharmaceuticals, Inc. | 6-disubstituted bicyclic nucleic acid analogs |
| EP2195428B1 (en) | 2007-09-19 | 2013-12-11 | Applied Biosystems, LLC | SiRNA SEQUENCE-INDEPENDENT MODIFICATION FORMATS FOR REDUCING OFF-TARGET PHENOTYPIC EFFECTS IN RNAi, AND STABILIZED FORMS THEREOF |
| RU2487716C2 (ru) | 2007-10-03 | 2013-07-20 | Кварк Фармасьютикалс, Инк. | Новые структуры малых интерферирующих рнк (sirna) |
| US9211537B2 (en) * | 2007-11-07 | 2015-12-15 | The University Of British Columbia | Microfluidic device and method of using same |
| WO2009067632A1 (en) * | 2007-11-20 | 2009-05-28 | Applied Biosystems Inc. | Method of sequencing nucleic acids using elaborated nucleotide phosphorothiolate compounds |
| US8017338B2 (en) | 2007-11-20 | 2011-09-13 | Life Technologies Corporation | Reversible di-nucleotide terminator sequencing |
| WO2009067647A1 (en) * | 2007-11-21 | 2009-05-28 | Isis Pharmaceuticals, Inc. | Carbocyclic alpha-l-bicyclic nucleic acid analogs |
| EP4053546A1 (en) | 2007-12-06 | 2022-09-07 | Genalyte, Inc. | Device and method for performing label-free monitoring of processes. |
| US8614311B2 (en) | 2007-12-12 | 2013-12-24 | Quark Pharmaceuticals, Inc. | RTP801L siRNA compounds and methods of use thereof |
| US20110105584A1 (en) * | 2007-12-12 | 2011-05-05 | Elena Feinstein | Rtp80il sirna compounds and methods of use thereof |
| JP5498954B2 (ja) | 2007-12-21 | 2014-05-21 | ジェン−プロウブ インコーポレイテッド | 抗生剤耐性微生物の検出 |
| EP2242854A4 (en) * | 2008-01-15 | 2012-08-15 | Quark Pharmaceuticals Inc | COMPOUNDS AND USES THEREOF |
| WO2009093384A1 (ja) | 2008-01-24 | 2009-07-30 | National Institute Of Advanced Industrial Science And Technology | ポリヌクレオチド及びポリヌクレオチド類似体並びにこれらを用いた遺伝子発現制御方法 |
| WO2009100320A2 (en) * | 2008-02-07 | 2009-08-13 | Isis Pharmaceuticals, Inc. | Bicyclic cyclohexitol nucleic acid analogs |
| US20090215050A1 (en) * | 2008-02-22 | 2009-08-27 | Robert Delmar Jenison | Systems and methods for point-of-care amplification and detection of polynucleotides |
| CA2718765A1 (en) * | 2008-03-20 | 2009-09-24 | Quark Pharmaceuticals, Inc. | Novel sirna compounds for inhibiting rtp801 |
| US20090326049A1 (en) * | 2008-04-04 | 2009-12-31 | Alexander Aristarkhov | Blocking oligos for inhibition of microrna and sirna activity and uses thereof |
| US9290534B2 (en) * | 2008-04-04 | 2016-03-22 | Ionis Pharmaceuticals, Inc. | Oligomeric compounds having at least one neutrally linked terminal bicyclic nucleoside |
| EP2274423A2 (en) * | 2008-04-04 | 2011-01-19 | Isis Pharmaceuticals, Inc. | Oligomeric compounds comprising bicyclic nucleosides and having reduced toxicity |
| US20100113284A1 (en) * | 2008-04-04 | 2010-05-06 | Alexander Aristarkhov | Small interfering rna (sirna) target site blocking oligos and uses thereof |
| EP2285385A4 (en) * | 2008-04-15 | 2013-01-16 | Quark Pharmaceuticals Inc | COMPOUNDS BASED ON RNSI TO INHIBIT NRF2 |
| ES2686708T3 (es) | 2008-04-18 | 2018-10-19 | Baxter International Inc. | Composición basada en microesferas para prevenir y/o revertir la diabetes autoinmune de nueva aparición |
| US10316352B2 (en) | 2008-05-13 | 2019-06-11 | Gen-Probe Incorporated | Methods of capturing a target nucleic acid for amplification and detection using an inactivatable target capture oligomer |
| AU2009262870B2 (en) | 2008-05-30 | 2014-03-20 | Gen-Probe Incorporated | Compositions, kits and related methods for the detection and/or monitoring of Salmonella |
| US8222221B2 (en) | 2008-06-04 | 2012-07-17 | The Board Of Regents Of The University Of Texas System | Modulation of gene expression through endogenous small RNA targeting of gene promoters |
| WO2009147684A2 (en) | 2008-06-06 | 2009-12-10 | Quark Pharmaceuticals, Inc. | Compositions and methods for treatment of ear disorders |
| CA2732343C (en) | 2008-07-29 | 2017-05-09 | The Board Of Regents Of The University Of Texas System | Selective inhibition of polyglutamine protein expression |
| NZ601660A (en) | 2008-08-25 | 2014-05-30 | Excaliard Pharmaceuticals Inc | Antisense oligonucleotides directed against connective tissue growth factor and uses thereof |
| WO2010027831A1 (en) | 2008-08-25 | 2010-03-11 | Excaliard Pharmaceuticals, Inc. | Method for reducing scarring during wound healing using antisense compounds directed to ctgf |
| JP5221248B2 (ja) * | 2008-08-26 | 2013-06-26 | 株式会社日立ハイテクノロジーズ | 高発現遺伝子由来のｃＤＮＡクローンの含有率を低減させたｃＤＮＡライブラリーの作製方法 |
| US8962247B2 (en) | 2008-09-16 | 2015-02-24 | Sequenom, Inc. | Processes and compositions for methylation-based enrichment of fetal nucleic acid from a maternal sample useful for non invasive prenatal diagnoses |
| US8476013B2 (en) | 2008-09-16 | 2013-07-02 | Sequenom, Inc. | Processes and compositions for methylation-based acid enrichment of fetal nucleic acid from a maternal sample useful for non-invasive prenatal diagnoses |
| DK2356129T3 (da) * | 2008-09-24 | 2013-05-13 | Isis Pharmaceuticals Inc | Substituerede alpha-L-bicykliske nukleosider |
| CN102239260B (zh) | 2008-10-03 | 2017-04-12 | 库尔纳公司 | 通过抑制针对载脂蛋白‑a1的天然反义转录物治疗载脂蛋白‑a1相关疾病 |
| EP2447274B1 (en) | 2008-10-24 | 2017-10-04 | Ionis Pharmaceuticals, Inc. | Oligomeric compounds and methods |
| EP3572796B8 (en) | 2008-10-27 | 2023-01-18 | Genalyte, Inc. | Biosensors based on optical probing and sensing |
| EP2365803B1 (en) | 2008-11-24 | 2017-11-01 | Northwestern University | Polyvalent rna-nanoparticle compositions |
| ES2600781T3 (es) | 2008-12-04 | 2017-02-10 | Curna, Inc. | Tratamiento para enfermedades relacionadas con el factor de crecimiento del endotelio vascular (vegf) mediante la inhibición de transcritos antisentido naturales de vegf |
| ES2629630T3 (es) | 2008-12-04 | 2017-08-11 | Curna, Inc. | Tratamiento de enfermedades relacionadas con eritropoyetina (EPO) mediante inhibición del transcrito antisentido natural a EPO |
| US20110294870A1 (en) | 2008-12-04 | 2011-12-01 | Opko Curna, Llc | Treatment of tumor suppressor gene related diseases by inhibition of natural antisense transcript to the gene |
| WO2010080452A2 (en) | 2008-12-18 | 2010-07-15 | Quark Pharmaceuticals, Inc. | siRNA COMPOUNDS AND METHODS OF USE THEREOF |
| US20110312094A1 (en) | 2008-12-22 | 2011-12-22 | Keygene N.V. | Use of double stranded rna to increase the efficiency of targeted gene alteration in plant protoplasts |
| EP2910647A1 (en) | 2008-12-30 | 2015-08-26 | Gen-Probe Incorporated | Compositions, kits and related methods for the detection and/or monitoring of listeria |
| US20100233270A1 (en) | 2009-01-08 | 2010-09-16 | Northwestern University | Delivery of Oligonucleotide-Functionalized Nanoparticles |
| CA2750379A1 (en) | 2009-01-14 | 2010-07-22 | Gordon J. Lutz | Modulation of pre-mrna using splice modulating oligonucleotides as therapeutic agents in the treatment of disease |
| DK2391736T3 (en) | 2009-02-02 | 2015-05-11 | Exiqon As | A method for the quantitation of small RNA species |
| US20120021515A1 (en) | 2009-02-06 | 2012-01-26 | Swayze Eric E | Oligomeric compounds and methods |
| ES2762610T3 (es) | 2009-02-12 | 2020-05-25 | Curna Inc | Tratamiento de enfermedades relacionadas con el factor neurotrófico derivado de cerebro (BDNF) por inhibición de transcrito antisentido natural para BDNF |
| EP3257859B1 (en) | 2009-02-26 | 2020-09-23 | Gen-Probe Incorporated | Assay for detection of human parvovirus nucleic acid |
| CN102482677B (zh) | 2009-03-16 | 2017-10-17 | 库尔纳公司 | 通过抑制nrf2的天然反义转录物治疗核因子(红细胞衍生2)‑样2(nrf2)相关疾病 |
| WO2010107740A2 (en) | 2009-03-17 | 2010-09-23 | Curna, Inc. | Treatment of delta-like 1 homolog (dlk1) related diseases by inhibition of natural antisense transcript to dlk1 |
| US8481698B2 (en) * | 2009-03-19 | 2013-07-09 | The President And Fellows Of Harvard College | Parallel proximity ligation event analysis |
| CN102449170A (zh) | 2009-04-15 | 2012-05-09 | 西北大学 | 寡核苷酸功能化的纳米颗粒的递送 |
| EP3248618A1 (en) | 2009-04-22 | 2017-11-29 | Massachusetts Institute Of Technology | Innate immune suppression enables repeated delivery of long rna molecules |
| WO2010124231A2 (en) | 2009-04-24 | 2010-10-28 | The Board Of Regents Of The University Of Texas System | Modulation of gene expression using oligomers that target gene regions downstream of 3' untranslated regions |
| WO2010126913A1 (en) | 2009-04-27 | 2010-11-04 | Gen-Probe Incorporated | Methods and kits for use in the selective amplification of target sequences |
| CN103223177B (zh) | 2009-05-06 | 2016-08-10 | 库尔纳公司 | 通过针对脂质转运和代谢基因的天然反义转录物的抑制治疗脂质转运和代谢基因相关疾病 |
| ES2609655T3 (es) | 2009-05-06 | 2017-04-21 | Curna, Inc. | Tratamiento de enfermedades relacionadas con tristetraprolina (TTP) mediante inhibición de transcrito antisentido natural para TTP |
| JP5931720B2 (ja) | 2009-05-08 | 2016-06-08 | クルナ・インコーポレーテッド | Ｄｍｄファミリーに対する天然アンチセンス転写物の抑制によるジストロフィンファミリー関連疾患の治療 |
| DK2432881T3 (en) | 2009-05-18 | 2018-02-26 | Curna Inc | TREATMENT OF REPROGRAMMING FACTOR-RELATED DISEASES BY INHIBITING NATURAL ANTISENSE TRANSCRIPTS TO A REPROGRAMMING FACTOR |
| EP2432796B1 (en) | 2009-05-21 | 2016-08-17 | Siemens Healthcare Diagnostics Inc. | Universal tags with non-natural nucleobases |
| CA2762987A1 (en) | 2009-05-22 | 2010-11-25 | Joseph Collard | Treatment of transcription factor e3 (tfe3) and insulin receptor substrate 2 (irs2) related diseases by inhibition of natural antisense transcript to tfe3 |
| KR101704988B1 (ko) | 2009-05-28 | 2017-02-08 | 큐알엔에이, 인크. | 항바이러스 유전자에 대한 천연 안티센스 전사체의 억제에 의한 항바이러스 유전자 관련된 질환의 치료 |
| CN102458418B (zh) | 2009-06-08 | 2015-09-16 | 夸克制药公司 | 一种寡核苷酸化合物的制药用途 |
| US8951981B2 (en) | 2009-06-16 | 2015-02-10 | Curna, Inc. | Treatment of paraoxonase 1 (PON1) related diseases by inhibition of natural antisense transcript to PON1 |
| WO2010148050A2 (en) | 2009-06-16 | 2010-12-23 | Curna, Inc. | Treatment of collagen gene related diseases by inhibition of natural antisense transcript to a collagen gene |
| WO2010151671A2 (en) | 2009-06-24 | 2010-12-29 | Curna, Inc. | Treatment of tumor necrosis factor receptor 2 (tnfr2) related diseases by inhibition of natural antisense transcript to tnfr2 |
| EP2446037B1 (en) | 2009-06-26 | 2016-04-20 | CuRNA, Inc. | Treatment of down syndrome gene related diseases by inhibition of natural antisense transcript to a down syndrome gene |
| JP2011024434A (ja) | 2009-07-22 | 2011-02-10 | Galaxy Pharma Inc | オリゴヌクレオチドのスクリーニング方法及びオリゴヌクレオチドライブラリー |
| CN102712925B (zh) | 2009-07-24 | 2017-10-27 | 库尔纳公司 | 通过抑制sirtuin(sirt)的天然反义转录物来治疗sirtuin(sirt)相关性疾病 |
| WO2011012136A1 (en) | 2009-07-28 | 2011-02-03 | Exiqon A/S | A method for classifying a human cell sample as cancerous |
| CN102762731B (zh) | 2009-08-05 | 2018-06-22 | 库尔纳公司 | 通过抑制针对胰岛素基因(ins)的天然反义转录物来治疗胰岛素基因(ins)相关的疾病 |
| US9012421B2 (en) | 2009-08-06 | 2015-04-21 | Isis Pharmaceuticals, Inc. | Bicyclic cyclohexose nucleic acid analogs |
| CN104313027B (zh) | 2009-08-11 | 2018-11-20 | 库尔纳公司 | 通过抑制脂连蛋白(adipoq)的天然反义转录物治疗脂连蛋白(adipoq)相关疾病 |
| KR101805213B1 (ko) | 2009-08-21 | 2017-12-06 | 큐알엔에이, 인크. | Ｃｈｉｐ에 대한 천연 안티센스 전사체의 억제에 의한 “ｈｓｐ70-상호작용 단백질(ｃｈｉｐ)의 ｃ-말단” 관련된 질환의 치료 |
| CA2771172C (en) | 2009-08-25 | 2021-11-30 | Opko Curna, Llc | Treatment of 'iq motif containing gtpase activating protein' (iqgap) related diseases by inhibition of natural antisense transcript to iqgap |
| CA2772715C (en) | 2009-09-02 | 2019-03-26 | Genentech, Inc. | Mutant smoothened and methods of using the same |
| US20110196141A1 (en) * | 2009-09-07 | 2011-08-11 | Council Of Scientific & Industrial Research | Locked and unlocked 2'-o phosphoramidite nucleosides, process of preparation thereof and oligomers comprising the nucleosides |
| US20120295952A1 (en) | 2009-09-25 | 2012-11-22 | Curna, Inc. | Treatment of filaggrin (flg) related diseases by modulation of flg expression and activity |
| US20150025122A1 (en) | 2009-10-12 | 2015-01-22 | Larry J. Smith | Methods and Compositions for Modulating Gene Expression Using Oligonucleotide Based Drugs Administered in vivo or in vitro |
| EP2488656B1 (en) | 2009-10-15 | 2015-06-03 | Ibis Biosciences, Inc. | Multiple displacement amplification |
| JP5819308B2 (ja) | 2009-10-22 | 2015-11-24 | ジェネンテック， インコーポレイテッド | マクロファージ刺激タンパク質のヘプシン活性化を調節するための方法及び組成物 |
| WO2011056687A2 (en) | 2009-10-27 | 2011-05-12 | Swift Biosciences, Inc. | Polynucleotide primers and probes |
| CA2778171C (en) | 2009-10-29 | 2017-07-25 | Osaka University | Bridged artificial nucleoside and nucleotide |
| CA2779099C (en) | 2009-10-30 | 2021-08-10 | Northwestern University | Templated nanoconjugates |
| US20110110860A1 (en) | 2009-11-02 | 2011-05-12 | The Board Of Regents Of The University Of Texas System | Modulation of ldl receptor gene expression with double-stranded rnas targeting the ldl receptor gene promoter |
| EP2496716A1 (en) | 2009-11-03 | 2012-09-12 | University Of Virginia Patent Foundation | Versatile, visible method for detecting polymeric analytes |
| WO2011063403A1 (en) | 2009-11-23 | 2011-05-26 | Swift Biosciences, Inc. | Devices to extend single stranded target molecules |
| PH12012500982A1 (en) | 2009-11-30 | 2019-07-10 | Genentech Inc | Antibodies for treating and diagnosing tumors expressing slc34a2 (tat211=seqid2) |
| WO2011072082A2 (en) | 2009-12-09 | 2011-06-16 | Nitto Denko Corporation | Modulation of hsp47 expression |
| EP2862929B1 (en) | 2009-12-09 | 2017-09-06 | Quark Pharmaceuticals, Inc. | Compositions and methods for treating diseases, disorders or injury of the CNS |
| JP6025567B2 (ja) | 2009-12-16 | 2016-11-16 | カッパーアールエヌエー，インコーポレイテッド | 膜結合転写因子ペプチダーゼ、部位１（ｍｂｔｐｓ１）に対する天然アンチセンス転写物の阻害によるｍｂｔｐｓ１関連性疾患の治療 |
| ES2577017T3 (es) | 2009-12-22 | 2016-07-12 | Sequenom, Inc. | Procedimientos y kits para identificar la aneuploidia |
| US9404160B2 (en) | 2009-12-22 | 2016-08-02 | Becton, Dickinson And Company | Methods for the detection of microorganisms |
| RU2619185C2 (ru) | 2009-12-23 | 2017-05-12 | Курна, Инк. | Лечение заболеваний, связанных с разобщающим белком 2 (ucp2), путем ингибирования природного антисмыслового транскрипта к ucp2 |
| CN102869776B (zh) | 2009-12-23 | 2017-06-23 | 库尔纳公司 | 通过抑制肝细胞生长因子(hgf)的天然反义转录物而治疗hgf相关疾病 |
| JP2011130725A (ja) * | 2009-12-25 | 2011-07-07 | Contig I:Kk | Ｌｎａオリゴヌクレオチドとそれを含有する化粧品 |
| ES2585829T3 (es) | 2009-12-29 | 2016-10-10 | Curna, Inc. | Tratamiento de las enfermedades relacionadas con la proteína tumoral 63 (p63) por inhibición de transcripción antisentido natural a p63 |
| EP2519633B1 (en) | 2009-12-29 | 2017-10-25 | CuRNA, Inc. | Treatment of nuclear respiratory factor 1 (nrf1) related diseases by inhibition of natural antisense transcript to nrf1 |
| CA2785727C (en) | 2009-12-31 | 2020-01-07 | Curna, Inc. | Treatment of insulin receptor substrate 2 (irs2) related diseases by inhibition of natural antisense transcript to irs2 and transcription factor e3 (tfe3) |
| CA2785832A1 (en) | 2010-01-04 | 2011-07-07 | Curna, Inc. | Treatment of interferon regulatory factor 8 (irf8) related diseases by inhibition of natural antisense transcript to irf8 |
| KR101853509B1 (ko) | 2010-01-06 | 2018-04-30 | 큐알엔에이, 인크. | 췌장 발달 유전자에 대한 천연 안티센스 전사체의 억제에 의한 췌장 발달 유전자와 관련된 질환의 치료 |
| WO2011084193A1 (en) | 2010-01-07 | 2011-07-14 | Quark Pharmaceuticals, Inc. | Oligonucleotide compounds comprising non-nucleotide overhangs |
| CN102753186B (zh) | 2010-01-08 | 2016-09-14 | Isis制药公司 | 血管生成素样3表达的调节 |
| JP6027893B2 (ja) | 2010-01-11 | 2016-11-16 | カッパーアールエヌエー，インコーポレイテッド | 性ホルモン結合グロブリン（ｓｈｂｇ）に対する天然アンチセンス転写物の阻害による性ホルモン結合グロブリン（ｓｈｂｇ）関連疾患の治療 |
| WO2011085102A1 (en) | 2010-01-11 | 2011-07-14 | Isis Pharmaceuticals, Inc. | Base modified bicyclic nucleosides and oligomeric compounds prepared therefrom |
| WO2011088148A1 (en) * | 2010-01-12 | 2011-07-21 | Isis Pharmaceuticals, Inc. | Modulation of transforming growth factor-beta 1 expression |
| EP2529015B1 (en) | 2010-01-25 | 2017-11-15 | CuRNA, Inc. | Treatment of rnase h1 related diseases by inhibition of natural antisense transcript to rnase h1 |
| WO2011097388A1 (en) | 2010-02-03 | 2011-08-11 | Alnylam Pharmaceuticals, Inc. | Selective inhibition of polyglutamine protein expression |
| US8957040B2 (en) | 2010-02-08 | 2015-02-17 | Isis Pharmaceuticals, Inc. | Selective reduction of allelic variants |
| CA2789038A1 (en) | 2010-02-08 | 2011-08-11 | Isis Pharmaceuticals, Inc. | Selective reduction of allelic variants |
| CN102844435B (zh) | 2010-02-22 | 2017-05-10 | 库尔纳公司 | 通过抑制吡咯啉‑5‑羧酸还原酶1(pycr1)的天然反义转录物而治疗pycr1相关疾病 |
| WO2011105901A2 (en) | 2010-02-23 | 2011-09-01 | Academisch Ziekenhuis Bij De Universiteit Van Amsterdam | Antagonists of complement component 9 (c9) and uses thereof |
| WO2011105902A2 (en) | 2010-02-23 | 2011-09-01 | Academisch Ziekenhuis Bij De Universiteit Van Amsterdam | Antagonists of complement component 8-beta (c8-beta) and uses thereof |
| MA34057B1 (fr) | 2010-02-23 | 2013-03-05 | Genentech Inc | Compositions et methodes pour le diagnostic et le traitement d'une tumeur |
| WO2011105900A2 (en) | 2010-02-23 | 2011-09-01 | Academisch Ziekenhuis Bij De Universiteit Van Amsterdam | Antagonists of complement component 8-alpha (c8-alpha) and uses thereof |
| US20110213011A1 (en) * | 2010-02-26 | 2011-09-01 | Dean Nicholas M | Modulation of smad3 expression |
| EP2542678B1 (en) | 2010-03-04 | 2017-04-12 | InteRNA Technologies B.V. | A MiRNA MOLECULE DEFINED BY ITS SOURCE AND ITS THERAPEUTIC USES IN CANCER ASSOCIATED WITH EMT |
| US20130101512A1 (en) | 2010-03-12 | 2013-04-25 | Chad A. Mirkin | Crosslinked polynucleotide structure |
| EP3210611B1 (en) | 2010-03-12 | 2019-08-21 | The Brigham and Women's Hospital, Inc. | Methods of treating vascular inflammatory disorders |
| US9193752B2 (en) | 2010-03-17 | 2015-11-24 | Isis Pharmaceuticals, Inc. | 5′-substituted bicyclic nucleosides and oligomeric compounds prepared therefrom |
| WO2011120023A1 (en) | 2010-03-26 | 2011-09-29 | Marina Biotech, Inc. | Nucleic acid compounds for inhibiting survivin gene expression uses thereof |
| US8889350B2 (en) | 2010-03-26 | 2014-11-18 | Swift Biosciences, Inc. | Methods and compositions for isolating polynucleotides |
| RU2612884C2 (ru) | 2010-04-02 | 2017-03-13 | Курна, Инк. | Лечение заболеваний, связанных с колониестимулирующим фактором 3 (csf3), путем ингибирования природного антисмыслового транскрипта k csf3 |
| EP2555778A4 (en) | 2010-04-06 | 2014-05-21 | Alnylam Pharmaceuticals Inc | COMPOSITIONS AND METHODS FOR INHIBITING CD274 / PD-L1 GENE EXPRESSION |
| WO2011127337A2 (en) | 2010-04-09 | 2011-10-13 | Opko Curna Llc | Treatment of fibroblast growth factor 21 (fgf21) related diseases by inhibition of natural antisense transcript to fgf21 |
| WO2011133584A2 (en) | 2010-04-19 | 2011-10-27 | Marina Biotech, Inc. | Nucleic acid compounds for inhibiting hras gene expression and uses thereof |
| US20110269194A1 (en) | 2010-04-20 | 2011-11-03 | Swift Biosciences, Inc. | Materials and methods for nucleic acid fractionation by solid phase entrapment and enzyme-mediated detachment |
| US8278049B2 (en) | 2010-04-26 | 2012-10-02 | Ann & Robert H. Lurie Children's Hospital of Chicago | Selective enrichment of CpG islands |
| EP2563922A1 (en) | 2010-04-26 | 2013-03-06 | Marina Biotech, Inc. | Nucleic acid compounds with conformationally restricted monomers and uses thereof |
| EP2601204B1 (en) | 2010-04-28 | 2016-09-07 | Ionis Pharmaceuticals, Inc. | Modified nucleosides and oligomeric compounds prepared therefrom |
| WO2011139843A2 (en) | 2010-04-28 | 2011-11-10 | Marina Biotech, Inc. | Multi-sirna compositions for reducing gene expression |
| US9156873B2 (en) | 2010-04-28 | 2015-10-13 | Isis Pharmaceuticals, Inc. | Modified 5′ diphosphate nucleosides and oligomeric compounds prepared therefrom |
| WO2011139699A2 (en) | 2010-04-28 | 2011-11-10 | Isis Pharmaceuticals, Inc. | 5' modified nucleosides and oligomeric compounds prepared therefrom |
| US20130156845A1 (en) | 2010-04-29 | 2013-06-20 | Alnylam Pharmaceuticals, Inc. | Lipid formulated single stranded rna |
| PL2563920T3 (pl) | 2010-04-29 | 2017-08-31 | Ionis Pharmaceuticals, Inc. | Modulacja ekspresji transtyretyny |
| ES2465948T3 (es) | 2010-04-30 | 2014-06-09 | Exiqon A/S | Procedimiento de hibridación in situ y tampón |
| SG185027A1 (en) | 2010-05-03 | 2012-11-29 | Genentech Inc | Compositions and methods for the diagnosis and treatment of tumor |
| WO2011139387A1 (en) | 2010-05-03 | 2011-11-10 | Opko Curna, Llc | Treatment of sirtuin (sirt) related diseases by inhibition of natural antisense transcript to a sirtuin (sirt) |
| TWI531370B (zh) | 2010-05-14 | 2016-05-01 | 可娜公司 | 藉由抑制ｐａｒ４天然反股轉錄本治療ｐａｒ４相關疾病 |
| WO2011150226A1 (en) | 2010-05-26 | 2011-12-01 | Landers James P | Method for detecting nucleic acids based on aggregate formation |
| US8895528B2 (en) | 2010-05-26 | 2014-11-25 | Curna, Inc. | Treatment of atonal homolog 1 (ATOH1) related diseases by inhibition of natural antisense transcript to ATOH1 |
| ES2664585T3 (es) | 2010-05-26 | 2018-04-20 | Curna, Inc. | Tratamiento de enfermedades relacionadas con metionina sulfóxido reductasa (MSRA) mediante inhibición del transcrito antisentido natural a MSRA |
| CA3102008A1 (en) | 2010-06-02 | 2011-12-08 | Alnylam Pharmaceuticals, Inc. | Compositions and methods directed to treating liver fibrosis |
| KR101932628B1 (ko) | 2010-06-07 | 2018-12-27 | 파이어플라이 바이오웍스, 인코포레이티드 | 후혼성 표지화 및 범용 코드화에 의한 핵산 검출 및 정량화 |
| US8957200B2 (en) | 2010-06-07 | 2015-02-17 | Isis Pharmaceuticals, Inc. | Bicyclic nucleosides and oligomeric compounds prepared therefrom |
| EP2580228B1 (en) | 2010-06-08 | 2016-03-23 | Ionis Pharmaceuticals, Inc. | Substituted 2'-amino and 2'-thio-bicyclic nucleosides and oligomeric compounds prepared therefrom |
| US9518259B2 (en) | 2010-06-15 | 2016-12-13 | Ionis Pharmaceuticals, Inc. | Compounds and methods for modulating interaction between proteins and target nucleic acids |
| CN109112126B (zh) | 2010-06-23 | 2024-06-14 | 库尔纳公司 | 通过抑制电压门控钠通道α亚基(SCNA)的天然反义转录物而治疗SCNA相关疾病 |
| WO2012003289A1 (en) | 2010-06-30 | 2012-01-05 | Gen-Probe Incorporated | Method and apparatus for identifying analyte-containing samples using single-read determination of analyte and process control signals |
| EP2591106A1 (en) | 2010-07-06 | 2013-05-15 | InteRNA Technologies B.V. | Mirna and its diagnostic and therapeutic uses in diseases or conditions associated with melanoma, or in diseases or conditions associated with activated braf pathway |
| WO2012006551A2 (en) | 2010-07-08 | 2012-01-12 | The Brigham And Women's Hospital, Inc. | Neuroprotective molecules and methods of treating neurological disorders and inducing stress granules |
| JP5998131B2 (ja) | 2010-07-14 | 2016-09-28 | カッパーアールエヌエー，インコーポレイテッド | Ｄｉｓｃｓｌａｒｇｅｈｏｍｏｌｏｇ（ｄｌｇ）ｄｌｇ１への天然アンチセンス転写物の阻害によるｄｌｇ関連疾患の治療 |
| EP2913402B1 (en) | 2010-07-16 | 2017-10-18 | Tocagen Inc. | Retrovirus detection |
| EP2595663A4 (en) | 2010-07-19 | 2014-03-05 | Isis Pharmaceuticals Inc | MODULATION OF DYSTROPHIA MYOTONICA PROTEIN KINASE (DMPK) EXPRESSION |
| EP2412724A1 (en) | 2010-07-29 | 2012-02-01 | Centre National de la Recherche Scientifique (C.N.R.S) | Regulation of Glypican 4 activity to modulate the fate of stem cells and uses thereof |
| DK2601611T3 (da) | 2010-08-02 | 2021-02-01 | Integrated Dna Tech Inc | Fremgangsmåder til forudsigelse af stabilitet og smeltetemperaturer for nukleinsyreduplekser |
| DK2625197T3 (en) | 2010-10-05 | 2016-10-03 | Genentech Inc | Smoothened MUTANT AND METHODS OF USING THE SAME |
| CN103210086B (zh) | 2010-10-06 | 2017-06-09 | 库尔纳公司 | 通过抑制唾液酸酶4(neu4)的天然反义转录物而治疗neu4相关疾病 |
| EP2625292B1 (en) | 2010-10-07 | 2018-12-05 | The General Hospital Corporation | Biomarkers of cancer |
| US8648053B2 (en) | 2010-10-20 | 2014-02-11 | Rosalind Franklin University Of Medicine And Science | Antisense oligonucleotides that target a cryptic splice site in Ush1c as a therapeutic for Usher syndrome |
| KR101865433B1 (ko) | 2010-10-22 | 2018-07-13 | 큐알엔에이, 인크. | 알파-l 이두로니다아제 (idua)에 대한 자연 안티센스 전사체의 저해에 의한 idua 관련된 질환의 치료 |
| WO2012061810A1 (en) | 2010-11-05 | 2012-05-10 | Miragen Therapeutics | Base modified oligonucleotides |
| EP2635710B1 (en) | 2010-11-05 | 2017-08-09 | Genalyte, Inc. | Optical analyte detection systems and methods of use |
| US9150864B2 (en) | 2010-11-08 | 2015-10-06 | Isis Pharmaceuticals, Inc. | Methods for modulating factor 12 expression |
| CA2817256A1 (en) | 2010-11-12 | 2012-05-18 | The General Hospital Corporation | Polycomb-associated non-coding rnas |
| CA2817960C (en) | 2010-11-17 | 2020-06-09 | Ionis Pharmaceuticals, Inc. | Modulation of alpha synuclein expression |
| US10000752B2 (en) | 2010-11-18 | 2018-06-19 | Curna, Inc. | Antagonat compositions and methods of use |
| WO2012068519A2 (en) | 2010-11-19 | 2012-05-24 | Sirius Genomics Inc. | Markers associated with response to activated protein c administration, and uses thereof |
| WO2012071238A2 (en) | 2010-11-23 | 2012-05-31 | Opko Curna Llc | Treatment of nanog related diseases by inhibition of natural antisense transcript to nanog |
| DK2646550T3 (en) | 2010-12-02 | 2015-05-26 | Keygene Nv | Targeted DNA modification with oligonucleotides |
| EP2857512B1 (en) | 2010-12-02 | 2016-06-29 | Keygene N.V. | Targeted alteration of DNA |
| EP2648763A4 (en) | 2010-12-10 | 2014-05-14 | Alnylam Pharmaceuticals Inc | COMPOSITIONS AND METHODS FOR EXPRESSION INHIBITION OF GENES KLF-1 AND BCL11A |
| EP2649182A4 (en) | 2010-12-10 | 2015-05-06 | Alnylam Pharmaceuticals Inc | Compositions and methods for increasing erythropoietin (epo) production |
| KR20140004646A (ko) | 2010-12-15 | 2014-01-13 | 미라젠 세러퓨틱스 | 잠금 뉴클레오티드를 포함하는 마이크로rna 억제제 |
| EP2474617A1 (en) | 2011-01-11 | 2012-07-11 | InteRNA Technologies BV | Mir for treating neo-angiogenesis |
| MX352460B (es) | 2011-01-11 | 2017-11-24 | Seegene Inc | Detección de secuencias de ácido nucleico objetivo mediante ensayo de escisión y extensión del pto. |
| EP2663323B1 (en) | 2011-01-14 | 2017-08-16 | The General Hospital Corporation | Methods targeting mir-128 for regulating cholesterol/lipid metabolism |
| DK2670404T3 (en) | 2011-02-02 | 2018-11-19 | Univ Princeton | CIRCUIT MODULATORS AS VIRUS PRODUCTION MODULATORS |
| PT2670411T (pt) | 2011-02-02 | 2019-06-18 | Excaliard Pharmaceuticals Inc | Compostos anti sentido visando um fator de crescimento do tecido conetivo (ctfg) para utilização num método de tratamento de queloides ou cicatrizes hipertróficas |
| EP2673361B1 (en) | 2011-02-08 | 2016-04-13 | Ionis Pharmaceuticals, Inc. | Oligomeric compounds comprising bicyclic nucleotides and uses thereof |
| WO2012109495A1 (en) | 2011-02-09 | 2012-08-16 | Metabolic Solutions Development Company, Llc | Cellular targets of thiazolidinediones |
| CA2828544A1 (en) | 2011-03-03 | 2012-09-07 | Quark Pharmaceuticals, Inc. | Oligonucleotide modulators of the toll-like receptor pathway |
| US9796979B2 (en) | 2011-03-03 | 2017-10-24 | Quark Pharmaceuticals Inc. | Oligonucleotide modulators of the toll-like receptor pathway |
| EP2681314B1 (en) | 2011-03-03 | 2017-11-01 | Quark Pharmaceuticals, Inc. | Compositions and methods for treating lung disease and injury |
| PH12013501969B1 (en) | 2011-03-29 | 2018-08-31 | Alnylam Pharmaceuticals Inc | Compositions and methods for inhibiting expression of tmprss6 gene |
| JP5852222B2 (ja) | 2011-03-29 | 2016-02-03 | シージーン アイエヌシー | Ｐｔｏ切断及び延長−依存的切断によるターゲット核酸配列の検出 |
| CN103562215B (zh) | 2011-04-01 | 2017-04-26 | 埃西斯药品公司 | 信号转导及转录激活蛋白3(stat3)表达的调节 |
| EP2508607A1 (en) | 2011-04-07 | 2012-10-10 | Helmholtz-Zentrum für Infektionsforschung GmbH | Medicament for liver regeneration and for treatment of liver failure |
| CN103547588B (zh) | 2011-04-13 | 2016-06-29 | Isis制药公司 | Ptp1b表达的反义调节 |
| RS61447B1 (sr) | 2011-04-21 | 2021-03-31 | Glaxo Group Ltd | Modulacija ekspresije virusa hepatitisa b (hbv) |
| WO2012149154A1 (en) | 2011-04-26 | 2012-11-01 | Swift Biosciences, Inc. | Polynucleotide primers and probes |
| SG194671A1 (en) | 2011-04-27 | 2013-12-30 | Isis Pharmaceuticals Inc | Modulation of apolipoprotein ciii (apociii) expression |
| AU2012249531B2 (en) | 2011-04-29 | 2017-06-29 | Sequenom, Inc. | Quantification of a minority nucleic acid species |
| US9353371B2 (en) | 2011-05-02 | 2016-05-31 | Ionis Pharmaceuticals, Inc. | Antisense compounds targeting genes associated with usher syndrome |
| WO2012151289A2 (en) | 2011-05-02 | 2012-11-08 | University Of Virginia Patent Foundation | Method and system to detect aggregate formation on a substrate |
| WO2012151268A1 (en) | 2011-05-02 | 2012-11-08 | University Of Virginia Patent Foundation | Method and system for high throughput optical and label free detection of analytes |
| MX342067B (es) | 2011-05-04 | 2016-09-09 | Seegene Inc | Detección de secuencias de ácido nucleico objetivo por desdoblamiento e hibridización de oligonucleótido de sonda. |
| TWI658830B (zh) | 2011-06-08 | 2019-05-11 | 日東電工股份有限公司 | Ｈｓｐ47表現調控強化用類視色素脂質體 |
| US10196637B2 (en) | 2011-06-08 | 2019-02-05 | Nitto Denko Corporation | Retinoid-lipid drug carrier |
| KR102043422B1 (ko) | 2011-06-09 | 2019-11-11 | 큐알엔에이, 인크. | 프라탁신 (fxn)에 대한 자연 안티센스 전사체의 저해에 의한 프라탁신 (fxn) 관련된 질환의 치료 |
| WO2012170347A1 (en) | 2011-06-09 | 2012-12-13 | Isis Pharmaceuticals, Inc. | Bicyclic nucleosides and oligomeric compounds prepared therefrom |
| EP3320922A1 (en) | 2011-06-10 | 2018-05-16 | Ionis Pharmaceuticals, Inc. | Methods for modulating kallikrein (klkb1) expression |
| WO2012170947A2 (en) | 2011-06-10 | 2012-12-13 | Isis Pharmaceuticals, Inc. | Methods for modulating factor 12 expression |
| JP6043347B2 (ja) | 2011-06-16 | 2016-12-14 | アイオーニス ファーマシューティカルズ， インコーポレーテッドＩｏｎｉｓ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． | 線維芽細胞増殖因子受容体４の発現のアンチセンス調節 |
| EP2723758B1 (en) | 2011-06-21 | 2018-06-20 | Alnylam Pharmaceuticals, Inc. | Angiopoietin-like 3 (angptl3) irna compostions and methods of use thereof |
| WO2012178033A2 (en) | 2011-06-23 | 2012-12-27 | Alnylam Pharmaceuticals, Inc. | Serpina1 sirnas: compositions of matter and methods of treatment |
| WO2013003112A1 (en) | 2011-06-27 | 2013-01-03 | The Jackson Laboratory | Methods and compositions for treatment of cancer and autoimmune disease |
| US9322021B2 (en) | 2011-06-29 | 2016-04-26 | Ionis Pharmaceuticals, Inc. | Methods for modulating kallikrein (KLKB1) expression |
| EP2739735A2 (en) | 2011-08-01 | 2014-06-11 | Alnylam Pharmaceuticals, Inc. | Method for improving the success rate of hematopoietic stem cell transplants |
| US10202599B2 (en) | 2011-08-11 | 2019-02-12 | Ionis Pharmaceuticals, Inc. | Selective antisense compounds and uses thereof |
| WO2013033223A1 (en) | 2011-08-29 | 2013-03-07 | Isis Pharmaceuticals, Inc. | Methods and compounds useful in conditions related to repeat expansion |
| WO2013033230A1 (en) | 2011-08-29 | 2013-03-07 | Isis Pharmaceuticals, Inc. | Oligomer-conjugate complexes and their use |
| US9650421B2 (en) | 2011-09-02 | 2017-05-16 | Northwestern University | Self-assembled nanostructures |
| MX365525B (es) | 2011-09-06 | 2019-06-06 | Curna Inc | Compuestos que regulan la expresión de subunidades alfa de canales de sodio regulados por voltaje en enfermedades relacionadas con epilepsia mioclónica severa de la infancia. |
| AU2012308302A1 (en) | 2011-09-14 | 2014-03-20 | Northwestern University | Nanoconjugates able to cross the blood-brain barrier |
| AU2012308320C1 (en) | 2011-09-14 | 2018-08-23 | Translate Bio Ma, Inc. | Multimeric oligonucleotide compounds |
| WO2013043817A1 (en) | 2011-09-20 | 2013-03-28 | Isis Phamaceuticals, Inc. | Antisense modulation of gcgr expression |
| US9175337B2 (en) | 2011-09-21 | 2015-11-03 | Gen-Probe Incorporated | Methods for amplifying nucleic acid using tag-mediated displacement |
| US10184151B2 (en) | 2011-10-11 | 2019-01-22 | The Brigham And Women's Hospital, Inc. | Micrornas in neurodegenerative disorders |
| WO2013059740A1 (en) | 2011-10-21 | 2013-04-25 | Foundation Medicine, Inc. | Novel alk and ntrk1 fusion molecules and uses thereof |
| AU2012328680A1 (en) | 2011-10-25 | 2014-05-01 | Ionis Pharmaceuticals, Inc. | Antisense modulation of GCCR expression |
| WO2013067050A1 (en) | 2011-10-31 | 2013-05-10 | University Of Utah Research Foundation | Genetic alterations in glioblastoma |
| AU2012332517B9 (en) | 2011-11-03 | 2017-08-10 | Quark Pharmaceuticals, Inc. | Methods and compositions for neuroprotection |
| HRP20191883T1 (hr) | 2011-11-07 | 2019-12-27 | Ionis Pharmaceuticals, Inc. | Modulacija ekspresije tmprss6 |
| US9243291B1 (en) | 2011-12-01 | 2016-01-26 | Isis Pharmaceuticals, Inc. | Methods of predicting toxicity |
| JP2015502365A (ja) | 2011-12-12 | 2015-01-22 | オンコイミューニン，インコーポレイティド | オリゴヌクレオチドのイン−ビボ送達 |
| JP6112569B2 (ja) | 2011-12-16 | 2017-04-12 | 国立大学法人 東京医科歯科大学 | キメラ２重鎖核酸 |
| CA3018046A1 (en) | 2011-12-16 | 2013-06-20 | Moderna Therapeutics, Inc. | Modified nucleoside, nucleotide, and nucleic acid compositions |
| EP3369818B1 (en) | 2011-12-22 | 2021-06-09 | InteRNA Technologies B.V. | Mirna for treating head and neck cancer |
| AU2012358238B2 (en) | 2011-12-22 | 2017-12-07 | C. Frank Bennett | Methods for modulating Metastasis-Associated-in-Lung-Adenocarcinoma-Transcript-1(MALAT-1) expression |
| EP2802674B1 (en) | 2012-01-11 | 2020-12-16 | Ionis Pharmaceuticals, Inc. | Compositions and methods for modulation of ikbkap splicing |
| WO2013120003A1 (en) | 2012-02-08 | 2013-08-15 | Isis Pharmaceuticals, Inc. | Modulation of rna by repeat targeting |
| EP2820129A1 (en) | 2012-03-02 | 2015-01-07 | Sequenom, Inc. | Methods and processes for non-invasive assessment of genetic variations |
| EP2823061B1 (en) | 2012-03-05 | 2018-02-14 | Seegene, Inc. | Detection of nucleotide variation on target nucleic acid sequence by pto cleavage and extension assay |
| EP3907506A1 (en) | 2012-03-12 | 2021-11-10 | The Board of Trustees of the University of Illinois | Optical analyte detection systems with magnetic enhancement and methods of their use |
| LT2825672T (lt) | 2012-03-13 | 2019-06-10 | Swift Biosciences, Inc. | Būdai ir kompozicijos, skirti valdomam pagal dydį substrato polinukleotidų homopolimeriniam uodegų formavimui su nukleorūgščių polimeraze |
| HK1210211A1 (en) | 2012-03-15 | 2016-04-15 | 科纳公司 | Treatment of brain derived neurotrophic factor (bdnf) related diseases by inhibition of natural antisense transcript to bdnf |
| CA2907072A1 (en) | 2012-03-16 | 2013-09-19 | Valerion Therapeutics, Llc | Antisense conjugates for decreasing expression of dmpk |
| EP2828289B1 (en) | 2012-03-19 | 2020-02-26 | The Brigham and Women's Hospital, Inc. | Growth differentiation factor (gdf) 11 for treatment of age-related cardiovascular condition |
| US9340784B2 (en) | 2012-03-19 | 2016-05-17 | Ionis Pharmaceuticals, Inc. | Methods and compositions for modulating alpha-1-antitrypsin expression |
| EP2831232A4 (en) | 2012-03-30 | 2015-11-04 | Univ Washington | METHOD FOR MODULATING TAU EXPRESSION TO REDUCE PROBLEMS AND MODIFY A NEURODEGENERATIVE SYNDROME |
| WO2013151665A2 (en) | 2012-04-02 | 2013-10-10 | modeRNA Therapeutics | Modified polynucleotides for the production of proteins associated with human disease |
| CN104411338A (zh) | 2012-04-02 | 2015-03-11 | 现代治疗公司 | 用于产生与人类疾病相关的生物制剂和蛋白质的修饰多核苷酸 |
| WO2013154799A1 (en) | 2012-04-09 | 2013-10-17 | Isis Pharmaceuticals, Inc. | Tricyclic nucleosides and oligomeric compounds prepared therefrom |
| EP2850092B1 (en) | 2012-04-09 | 2017-03-01 | Ionis Pharmaceuticals, Inc. | Tricyclic nucleic acid analogs |
| US9133461B2 (en) | 2012-04-10 | 2015-09-15 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of the ALAS1 gene |
| WO2013159108A2 (en) | 2012-04-20 | 2013-10-24 | Isis Pharmaceuticals, Inc. | Oligomeric compounds comprising bicyclic nucleotides and uses thereof |
| US9127274B2 (en) | 2012-04-26 | 2015-09-08 | Alnylam Pharmaceuticals, Inc. | Serpinc1 iRNA compositions and methods of use thereof |
| WO2013163628A2 (en) | 2012-04-27 | 2013-10-31 | Duke University | Genetic correction of mutated genes |
| US20160002624A1 (en) | 2012-05-17 | 2016-01-07 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotide compositions |
| US9574193B2 (en) | 2012-05-17 | 2017-02-21 | Ionis Pharmaceuticals, Inc. | Methods and compositions for modulating apolipoprotein (a) expression |
| US10504613B2 (en) | 2012-12-20 | 2019-12-10 | Sequenom, Inc. | Methods and processes for non-invasive assessment of genetic variations |
| US9920361B2 (en) | 2012-05-21 | 2018-03-20 | Sequenom, Inc. | Methods and compositions for analyzing nucleic acid |
| WO2013177248A2 (en) | 2012-05-22 | 2013-11-28 | Isis Pharmaceuticals, Inc. | Modulation of enhancer rna mediated gene expression |
| EP3822352A3 (en) | 2012-05-24 | 2021-11-03 | Ionis Pharmaceuticals, Inc. | Methods and compositions for modulating apolipoprotein(a) expression |
| AU2013266968B2 (en) | 2012-05-25 | 2017-06-29 | Emmanuelle CHARPENTIER | Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription |
| US9828602B2 (en) | 2012-06-01 | 2017-11-28 | Ionis Pharmaceuticals, Inc. | Antisense compounds targeting genes associated with fibronectin |
| WO2013181666A2 (en) | 2012-06-01 | 2013-12-05 | Isis Pharmaceuticals, Inc. | Antisense compounds targeting genes associated with fibronectin |
| WO2013184209A1 (en) | 2012-06-04 | 2013-12-12 | Ludwig Institute For Cancer Research Ltd. | Mif for use in methods of treating subjects with a neurodegenerative disorder |
| CN107236735B (zh) | 2012-06-21 | 2019-11-08 | 米拉根医疗股份有限公司 | 包含锁核酸基序的基于寡核苷酸的抑制剂 |
| WO2014004572A2 (en) | 2012-06-25 | 2014-01-03 | Isis Pharmaceuticals, Inc. | Modulation of ube3a-ats expression |
| US20140093873A1 (en) | 2012-07-13 | 2014-04-03 | Sequenom, Inc. | Processes and compositions for methylation-based enrichment of fetal nucleic acid from a maternal sample useful for non-invasive prenatal diagnoses |
| WO2014015098A1 (en) | 2012-07-18 | 2014-01-23 | Siemens Healthcare Diagnostics Inc. | A method of normalizing biological samples |
| WO2014018930A1 (en) | 2012-07-27 | 2014-01-30 | Isis Pharmaceuticals. Inc. | Modulation of renin-angiotensin system (ras) related diseases by angiotensinogen |
| AU2013202793B2 (en) | 2012-07-31 | 2014-09-18 | Gen-Probe Incorporated | System, method and apparatus for automated incubation |
| CN104736551B (zh) | 2012-08-15 | 2017-07-28 | Ionis制药公司 | 使用改进的封端方案制备寡聚化合物的方法 |
| HUE054260T2 (hu) | 2012-09-06 | 2021-08-30 | Univ Chicago | Antiszensz polinukleotidok exon-ugrás indukálására és eljárások disztrófiák kezelésére |
| WO2014045126A2 (en) | 2012-09-18 | 2014-03-27 | Uti Limited Partnership | Treatment of pain by inhibition of usp5 de-ubiquitinase |
| KR101707437B1 (ko) | 2012-09-21 | 2017-02-16 | 고꾸리쯔 다이가꾸 호우징 오사까 다이가꾸 | 구아니딘 가교를 갖는 인공 뉴클레오시드 및 올리고뉴클레오티드 |
| WO2014051076A1 (ja) | 2012-09-28 | 2014-04-03 | 株式会社Ｂｎａ | Ｂｎａクランプ法 |
| US9695418B2 (en) | 2012-10-11 | 2017-07-04 | Ionis Pharmaceuticals, Inc. | Oligomeric compounds comprising bicyclic nucleosides and uses thereof |
| EP4052709A1 (en) | 2012-10-11 | 2022-09-07 | Ionis Pharmaceuticals, Inc. | Methods of treating kennedy's disease |
| AR092982A1 (es) | 2012-10-11 | 2015-05-13 | Isis Pharmaceuticals Inc | Modulacion de la expresion de receptores androgenicos |
| EP2906255B1 (en) | 2012-10-12 | 2023-02-22 | Ionis Pharmaceuticals, Inc. | Antisense compounds and uses thereof |
| EP3459549B1 (en) | 2012-10-12 | 2022-04-06 | Ionis Pharmaceuticals, Inc. | Selective antisense compounds and uses thereof |
| ES2762326T5 (es) | 2012-10-15 | 2023-04-27 | Ionis Pharmaceuticals Inc | Métodos para modular la expresión de C9ORF72 |
| CN104968783B (zh) | 2012-10-15 | 2019-12-10 | Ionis制药公司 | 用于调节c9orf72表达的组合物 |
| EP2906697A4 (en) | 2012-10-15 | 2016-06-22 | Ionis Pharmaceuticals Inc | METHOD FOR MONITORING THE C9ORF72 EXPRESSION |
| US9029335B2 (en) | 2012-10-16 | 2015-05-12 | Isis Pharmaceuticals, Inc. | Substituted 2′-thio-bicyclic nucleosides and oligomeric compounds prepared therefrom |
| US10723754B2 (en) | 2012-10-22 | 2020-07-28 | Idenix Pharmaceuticals Llc | 2′,4′-bridged nucleosides for HCV infection |
| HRP20190303T1 (hr) | 2012-10-31 | 2019-05-17 | Ionis Pharmaceuticals, Inc. | Liječenje raka |
| CA2890725A1 (en) | 2012-11-05 | 2014-05-08 | Pronai Therapeutics, Inc. | Methods of using biomarkers for the treatment of cancer by modulation of bcl2|expression |
| US11230589B2 (en) | 2012-11-05 | 2022-01-25 | Foundation Medicine, Inc. | Fusion molecules and uses thereof |
| EP2914621B1 (en) | 2012-11-05 | 2023-06-07 | Foundation Medicine, Inc. | Novel ntrk1 fusion molecules and uses thereof |
| EP2917348A1 (en) | 2012-11-06 | 2015-09-16 | InteRNA Technologies B.V. | Combination for use in treating diseases or conditions associated with melanoma, or treating diseases or conditions associated with activated b-raf pathway |
| CN104837996A (zh) | 2012-11-15 | 2015-08-12 | 罗氏创新中心哥本哈根有限公司 | 抗apob反义缀合物化合物 |
| PL2922554T3 (pl) | 2012-11-26 | 2022-06-20 | Modernatx, Inc. | Na zmodyfikowany na końcach |
| WO2014080004A1 (en) | 2012-11-26 | 2014-05-30 | Santaris Pharma A/S | Compositions and methods for modulation of fgfr3 expression |
| US9695475B2 (en) | 2012-12-11 | 2017-07-04 | Ionis Pharmaceuticals, Inc. | Competitive modulation of microRNAs |
| WO2014113540A1 (en) | 2013-01-16 | 2014-07-24 | Iowa State University Research Foundation, Inc. | A deep intronic target for splicing correction on spinal muscular atrophy gene |
| AU2013374345A1 (en) | 2013-01-17 | 2015-08-06 | Moderna Therapeutics, Inc. | Signal-sensor polynucleotides for the alteration of cellular phenotypes |
| CA3150658A1 (en) | 2013-01-18 | 2014-07-24 | Foundation Medicine, Inc. | Methods of treating cholangiocarcinoma |
| AU2014211406B2 (en) | 2013-01-30 | 2019-07-18 | Roche Innovation Center Copenhagen A/S | LNA oligonucleotide carbohydrate conjugates |
| WO2014118272A1 (en) | 2013-01-30 | 2014-08-07 | Santaris Pharma A/S | Antimir-122 oligonucleotide carbohydrate conjugates |
| DK2951191T3 (en) | 2013-01-31 | 2019-01-14 | Ionis Pharmaceuticals Inc | PROCEDURE FOR MANUFACTURING OLIGOMERIC COMPOUNDS USING MODIFIED CLUTCH PROTOCOLS |
| WO2014121287A2 (en) | 2013-02-04 | 2014-08-07 | Isis Pharmaceuticals, Inc. | Selective antisense compounds and uses thereof |
| DK2956176T3 (en) | 2013-02-14 | 2018-08-27 | Ionis Pharmaceuticals Inc | MODULATION OF APOLIPOPROTEIN C-III (APOCIII) EXPRESSION IN LIPOPROTEIN LIPASE DEFICIENT (LPLD) POPULATIONS |
| WO2014126229A1 (ja) | 2013-02-18 | 2014-08-21 | 塩野義製薬株式会社 | 含窒素複素環構造を有するヌクレオシド及びヌクレオチド |
| WO2014130922A1 (en) | 2013-02-25 | 2014-08-28 | Trustees Of Boston University | Compositions and methods for treating fungal infections |
| AU2014200958B2 (en) | 2013-02-25 | 2016-01-14 | Seegene, Inc. | Detection of nucleotide variation on target nucleic acid sequence |
| WO2014134179A1 (en) | 2013-02-28 | 2014-09-04 | The Board Of Regents Of The University Of Texas System | Methods for classifying a cancer as susceptible to tmepai-directed therapies and treating such cancers |
| WO2014134144A1 (en) | 2013-02-28 | 2014-09-04 | The General Hospital Corporation | Mirna profiling compositions and methods of use |
| WO2014132671A1 (en) | 2013-03-01 | 2014-09-04 | National University Corporation Tokyo Medical And Dental University | Chimeric single-stranded antisense polynucleotides and double-stranded antisense agent |
| US11060145B2 (en) | 2013-03-13 | 2021-07-13 | Sequenom, Inc. | Methods and compositions for identifying presence or absence of hypermethylation or hypomethylation locus |
| EP2968391A1 (en) | 2013-03-13 | 2016-01-20 | Moderna Therapeutics, Inc. | Long-lived polynucleotide molecules |
| WO2014142575A1 (en) | 2013-03-13 | 2014-09-18 | Seegene, Inc. | Quantification of target nucleic acid using melting peak analysis |
| WO2014152211A1 (en) | 2013-03-14 | 2014-09-25 | Moderna Therapeutics, Inc. | Formulation and delivery of modified nucleoside, nucleotide, and nucleic acid compositions |
| US9273349B2 (en) | 2013-03-14 | 2016-03-01 | Affymetrix, Inc. | Detection of nucleic acids |
| ES2708562T3 (es) | 2013-03-14 | 2019-04-10 | Translate Bio Inc | Evaluación cuantitativa de la eficacidad de tapa de ARN mensajero |
| BR112015022505A2 (pt) | 2013-03-14 | 2017-10-24 | Shire Human Genetic Therapies | avaliação quantitativa para eficiência do cap de rna mensageiro |
| CN105264091B (zh) | 2013-03-14 | 2020-02-28 | Ionis制药公司 | 用于调节tau表达的组合物和方法 |
| IL288931B2 (en) | 2013-03-14 | 2025-05-01 | Alnylam Pharmaceuticals Inc | Compositions comprising a complementary portion of C5 IRNA and methods of using them |
| US8980864B2 (en) | 2013-03-15 | 2015-03-17 | Moderna Therapeutics, Inc. | Compositions and methods of altering cholesterol levels |
| DK2970968T3 (en) | 2013-03-15 | 2018-03-05 | Miragen Therapeutics Inc | CONNECTED BICYCLIC Nucleosides |
| WO2014143637A1 (en) | 2013-03-15 | 2014-09-18 | The Board Of Trustees Of The University Of Illinois | Methods and compositions for enhancing immunoassays |
| WO2014151835A1 (en) | 2013-03-15 | 2014-09-25 | Miragen Therapeutics, Inc | Locked nucleic acid inhibitor of mir-145 and uses thereof |
| US9347095B2 (en) | 2013-03-15 | 2016-05-24 | Bio-Rad Laboratories, Inc. | Digital assays for mutation detection |
| US9828582B2 (en) | 2013-03-19 | 2017-11-28 | Duke University | Compositions and methods for the induction and tuning of gene expression |
| ES2924479T3 (es) | 2013-04-08 | 2022-10-07 | Harvard College | Composiciones para rejuvenecer las células madre del músculo esquelético |
| US10590412B2 (en) | 2013-04-19 | 2020-03-17 | Ionis Pharmaceuticals, Inc. | Compositions and methods for modulation nucleic acids through nonsense mediated decay |
| EP2992112B1 (en) | 2013-04-22 | 2020-06-03 | Icahn School of Medicine at Mount Sinai | Mutations in pdgfrb and notch3 as causes of autosomal dominant infantile myofibromatosis |
| US9840533B2 (en) | 2013-04-29 | 2017-12-12 | Memorial Sloan Kettering Cancer Center | Compositions and methods for altering second messenger signaling |
| DK2992098T3 (da) | 2013-05-01 | 2019-06-17 | Ionis Pharmaceuticals Inc | Sammensætninger og fremgangsmåder til modulering af hbv- og ttr-ekspression |
| EA038792B1 (ru) | 2013-05-22 | 2021-10-20 | Элнилэм Фармасьютикалз, Инк. | КОМПОЗИЦИИ НА ОСНОВЕ RNAi Serpina1 И СПОСОБЫ ИХ ПРИМЕНЕНИЯ |
| KR102234623B1 (ko) | 2013-05-22 | 2021-04-02 | 알닐람 파마슈티칼스 인코포레이티드 | Ｔｍｐｒｓｓ6 조성물 및 이의 사용 방법 |
| EP3004347B1 (en) | 2013-05-30 | 2018-09-26 | National University Corporation Tokyo Medical and Dental University | Double-stranded agents for delivering therapeutic oligonucleotides |
| EP3004396B1 (en) | 2013-06-06 | 2019-10-16 | The General Hospital Corporation | Compositions for the treatment of cancer |
| US20160220640A1 (en) | 2013-06-11 | 2016-08-04 | The Brigham And Women's Hospital, Inc. | Methods and compositions for increasing neurogenesis and angiogenesis |
| JP6869720B2 (ja) | 2013-06-13 | 2021-05-12 | アンチセンス セラピューティクス リミテッド | 併用療法 |
| AU2014282666A1 (en) | 2013-06-16 | 2016-01-07 | National University Corporation Tokyo Medical And Dental University | Double-stranded antisense nucleic acid with exon-skipping effect |
| EP3011026B1 (en) | 2013-06-21 | 2019-12-18 | Ionis Pharmaceuticals, Inc. | Compounds and methods for modulating apolipoprotein c-iii expression for improving a diabetic profile |
| EP3564374A1 (en) | 2013-06-21 | 2019-11-06 | Ionis Pharmaceuticals, Inc. | Compositions and methods for modulation of target nucleic acids |
| HUE048738T2 (hu) | 2013-06-27 | 2020-08-28 | Roche Innovation Ct Copenhagen As | Antiszensz oligomerek és konjugátumok, amelyek a PCK9-t célozzák meg |
| CA2917229A1 (en) | 2013-07-02 | 2015-01-08 | Isis Pharmaceuticals, Inc. | Modulators of growth hormone receptor |
| CA2917348A1 (en) | 2013-07-11 | 2015-01-15 | Moderna Therapeutics, Inc. | Compositions comprising synthetic polynucleotides encoding crispr related proteins and synthetic sgrnas and methods of use |
| JP6050555B2 (ja) | 2013-07-15 | 2016-12-21 | シージーン アイエヌシー | Ｐｔｏの切断及び延長−依存的固定化オリゴヌクレオチドハイブリダイゼーションを用いたターゲット核酸配列の検出 |
| EP3022176B8 (en) | 2013-07-15 | 2019-12-25 | The Regents of the University of California | Azacyclic constrained analogs of fty720 |
| TW202246503A (zh) | 2013-07-19 | 2022-12-01 | 美商百健Ｍａ公司 | 用於調節τ蛋白表現之組合物 |
| US10435430B2 (en) | 2013-07-31 | 2019-10-08 | Ionis Pharmaceuticals, Inc. | Methods and compounds useful in conditions related to repeat expansion |
| HRP20200250T1 (hr) | 2013-08-08 | 2020-05-29 | The Scripps Research Institute | Metoda site-specifično enzimsko obilježavanje nukleinskih kiselina in vitro ugradnjom neprirodnih nukleotida |
| TW201536329A (zh) | 2013-08-09 | 2015-10-01 | Isis Pharmaceuticals Inc | 用於調節失養性肌強直蛋白質激酶(dmpk)表現之化合物及方法 |
| CN105745335A (zh) | 2013-08-14 | 2016-07-06 | 佳根曼斯菲尔德有限公司 | 用于对cMET核酸进行多模态分析的组合物及方法 |
| US20160108479A1 (en) | 2013-08-14 | 2016-04-21 | Qiagen Mansfield, Inc. | Compositions and methods for multiplex analysis of nras and braf nucleic acids |
| KR102365486B1 (ko) | 2013-08-28 | 2022-02-18 | 아이오니스 파마수티컬즈, 인코포레이티드 | 프리칼리크레인 (pkk) 발현의 조절 |
| WO2015034925A1 (en) | 2013-09-03 | 2015-03-12 | Moderna Therapeutics, Inc. | Circular polynucleotides |
| EP3041934A1 (en) | 2013-09-03 | 2016-07-13 | Moderna Therapeutics, Inc. | Chimeric polynucleotides |
| MY181251A (en) | 2013-09-13 | 2020-12-21 | Ionis Pharmaceuticals Inc | Modulators of complement factor b |
| WO2015042447A1 (en) | 2013-09-20 | 2015-03-26 | Isis Pharmaceuticals, Inc. | Targeted therapeutic nucleosides and their use |
| CA2925107A1 (en) | 2013-10-02 | 2015-04-09 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of the lect2 gene |
| EP3052521A1 (en) | 2013-10-03 | 2016-08-10 | Moderna Therapeutics, Inc. | Polynucleotides encoding low density lipoprotein receptor |
| LT3052628T (lt) | 2013-10-04 | 2020-09-10 | Alnylam Pharmaceuticals, Inc. | Kompozicijos ir būdai alas1 geno raiškai nuslopinti |
| US10221414B2 (en) | 2013-10-11 | 2019-03-05 | Ionis Pharmaceuticals, Inc. | Compositions for modulating C9ORF72 expression |
| US11162096B2 (en) | 2013-10-14 | 2021-11-02 | Ionis Pharmaceuticals, Inc | Methods for modulating expression of C9ORF72 antisense transcript |
| JP6640079B2 (ja) | 2013-10-16 | 2020-02-05 | ザ・ユニバーシティ・オブ・ブリティッシュ・コロンビア | 小容積の粒子を調製するためのデバイス及び方法 |
| KR101757473B1 (ko) | 2013-10-18 | 2017-07-13 | 주식회사 씨젠 | ｈＣＴＯ를 이용하는 ＰＴＯ 절단 및 연장 분석에 의한 고상에서의 타겟 핵산 서열 검출 |
| WO2015061246A1 (en) | 2013-10-21 | 2015-04-30 | Isis Pharmaceuticals, Inc. | Method for solution phase detritylation of oligomeric compounds |
| EP3683321B1 (en) | 2013-10-21 | 2021-12-08 | The General Hospital Corporation | Methods relating to circulating tumor cell clusters and the treatment of cancer |
| US10301622B2 (en) | 2013-11-04 | 2019-05-28 | Northwestern University | Quantification and spatio-temporal tracking of a target using a spherical nucleic acid (SNA) |
| CA2930877A1 (en) | 2013-11-18 | 2015-05-21 | Crispr Therapeutics Ag | Crispr-cas system materials and methods |
| WO2015075166A1 (en) | 2013-11-22 | 2015-05-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for treatment of a bacterial infection |
| DK3077510T3 (da) | 2013-12-02 | 2020-06-08 | Ionis Pharmaceuticals Inc | Antisense-forbindelser og anvendelser deraf |
| US10182988B2 (en) | 2013-12-03 | 2019-01-22 | Northwestern University | Liposomal particles, methods of making same and uses thereof |
| CA2844640A1 (en) | 2013-12-06 | 2015-06-06 | The University Of British Columbia | Method for treatment of castration-resistant prostate cancer |
| US10385388B2 (en) | 2013-12-06 | 2019-08-20 | Swift Biosciences, Inc. | Cleavable competitor polynucleotides |
| SG10201804960RA (en) | 2013-12-12 | 2018-07-30 | Alnylam Pharmaceuticals Inc | Complement component irna compositions and methods of use thereof |
| EP3835419A1 (en) | 2013-12-12 | 2021-06-16 | The Regents of The University of California | Methods and compositions for modifying a single stranded target nucleic acid |
| CN111729090A (zh) | 2013-12-20 | 2020-10-02 | 通用医疗公司 | 与循环肿瘤细胞相关的方法和测定法 |
| PT3087183T (pt) | 2013-12-24 | 2020-10-08 | Ionis Pharmaceuticals Inc | Modulação da expressão da proteína relacionada com angiopoietina 3 |
| EP3099798B1 (en) | 2014-01-29 | 2018-06-27 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Oligonucleotides and methods for inhibiting or reducing bacterial biofilms |
| ES2694857T3 (es) | 2014-02-04 | 2018-12-27 | Genentech, Inc. | Smoothened mutante y métodos de uso de la misma |
| CN113057959B (zh) | 2014-02-11 | 2024-07-16 | 阿尔尼拉姆医药品有限公司 | 己酮糖激酶（KHK）iRNA组合物及其使用方法 |
| CN106103463B (zh) * | 2014-02-18 | 2018-11-30 | 国立大学法人大阪大学 | 桥连型核苷和核苷酸 |
| EP3736344A1 (en) | 2014-03-13 | 2020-11-11 | Sequenom, Inc. | Methods and processes for non-invasive assessment of genetic variations |
| EP3119789B1 (en) | 2014-03-17 | 2020-04-22 | Ionis Pharmaceuticals, Inc. | Bicyclic carbocyclic nucleosides and oligomeric compounds prepared therefrom |
| EP3119888B1 (en) | 2014-03-19 | 2021-07-28 | Ionis Pharmaceuticals, Inc. | Compositions for modulating ataxin 2 expression |
| HUE050704T2 (hu) | 2014-04-01 | 2020-12-28 | Biogen Ma Inc | Összetételek a SOD-1 expressziójának modulálására |
| TWI638047B (zh) | 2014-04-09 | 2018-10-11 | 史基普研究協會 | 藉由核酸三磷酸酯轉運子將非天然或經修飾的核苷三磷酸酯輸入至細胞中 |
| WO2015164693A1 (en) | 2014-04-24 | 2015-10-29 | Isis Pharmaceuticals, Inc. | Oligomeric compounds comprising alpha-beta-constrained nucleic acid |
| WO2015168172A1 (en) | 2014-04-28 | 2015-11-05 | Isis Pharmaceuticals, Inc. | Linkage modified oligomeric compounds |
| US10098959B2 (en) | 2014-05-01 | 2018-10-16 | Ionis Pharmaceuticals, Inc. | Method for synthesis of reactive conjugate clusters |
| HUE052709T2 (hu) | 2014-05-01 | 2021-05-28 | Ionis Pharmaceuticals Inc | Módosított antiszensz oligonukleotidok konjugátumai és azok alkalmazása PKK expressziójának módosítására |
| US9382540B2 (en) | 2014-05-01 | 2016-07-05 | Isis Pharmaceuticals, Inc | Compositions and methods for modulating angiopoietin-like 3 expression |
| EA036496B1 (ru) | 2014-05-01 | 2020-11-17 | Ионис Фармасьютикалз, Инк. | Конъюгированные олигонуклеотиды для модулирования экспрессии фактора комплемента b |
| BR112016022742B1 (pt) | 2014-05-01 | 2022-06-14 | Ionis Pharmaceuticals, Inc | Composto químico, composição compreendendo o composto e uso dos mesmos |
| TW201607559A (zh) | 2014-05-12 | 2016-03-01 | 阿尼拉製藥公司 | 治療ｓｅｒｐｉｎｃ１相關疾患之方法和組成物 |
| AU2015264038B2 (en) | 2014-05-22 | 2021-02-11 | Alnylam Pharmaceuticals, Inc. | Angiotensinogen (AGT) iRNA compositions and methods of use thereof |
| WO2015179693A1 (en) | 2014-05-22 | 2015-11-26 | Isis Pharmaceuticals, Inc. | Conjugated antisense compounds and their use |
| EP3148564B1 (en) | 2014-06-02 | 2020-01-08 | Children's Medical Center Corporation | Methods and compositions for immunomodulation |
| TR201908550T4 (tr) | 2014-06-04 | 2019-07-22 | Exicure Inc | Profilaktik veya terapötik uygulamalar için lipozomal sferik nükleik asitler tarafından immün modülatörlerin çok değerlikli teslimi. |
| KR102524543B1 (ko) | 2014-06-10 | 2023-04-20 | 에라스무스 유니버시티 메디컬 센터 로테르담 | 폼페병의 치료에 유용한 안티센스 올리고뉴클레오티드 |
| GB201410693D0 (en) | 2014-06-16 | 2014-07-30 | Univ Southampton | Splicing modulation |
| TW201620526A (zh) | 2014-06-17 | 2016-06-16 | 愛羅海德研究公司 | 用於抑制α－１抗胰蛋白酶基因表現之組合物及方法 |
| EP3161159B1 (en) | 2014-06-25 | 2020-08-05 | The General Hospital Corporation | Targeting human satellite ii (hsatii) |
| JP6722586B2 (ja) * | 2014-07-10 | 2020-07-15 | 賢二 中野 | アンチセンス抗悪性腫瘍剤 |
| US20170204152A1 (en) | 2014-07-16 | 2017-07-20 | Moderna Therapeutics, Inc. | Chimeric polynucleotides |
| EP3171895A1 (en) | 2014-07-23 | 2017-05-31 | Modernatx, Inc. | Modified polynucleotides for the production of intrabodies |
| WO2016017422A1 (ja) * | 2014-07-31 | 2016-02-04 | 国立大学法人大阪大学 | 架橋型ヌクレオシドおよびヌクレオチド |
| WO2016028940A1 (en) | 2014-08-19 | 2016-02-25 | Northwestern University | Protein/oligonucleotide core-shell nanoparticle therapeutics |
| WO2016027168A2 (en) | 2014-08-20 | 2016-02-25 | Lifesplice Pharma Llc | Splice modulating oligonucleotides and methods of use thereof |
| IL234246A0 (en) | 2014-08-21 | 2014-11-30 | Omrix Biopharmaceuticals Ltd | Stabilized thrombin |
| WO2016033424A1 (en) | 2014-08-29 | 2016-03-03 | Genzyme Corporation | Methods for the prevention and treatment of major adverse cardiovascular events using compounds that modulate apolipoprotein b |
| CN107106704A (zh) | 2014-08-29 | 2017-08-29 | 儿童医疗中心有限公司 | 用于治疗癌症的方法和组合物 |
| EP3189141B1 (en) | 2014-09-02 | 2020-06-24 | Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft | Antisense oligonucleotides targeting 3'utr region of a20 |
| US10436802B2 (en) | 2014-09-12 | 2019-10-08 | Biogen Ma Inc. | Methods for treating spinal muscular atrophy |
| WO2016040589A1 (en) | 2014-09-12 | 2016-03-17 | Alnylam Pharmaceuticals, Inc. | Polynucleotide agents targeting complement component c5 and methods of use thereof |
| US10533172B2 (en) | 2014-09-18 | 2020-01-14 | The University Of British Columbia | Allele-specific therapy for huntington disease haplotypes |
| JP2017534295A (ja) | 2014-09-29 | 2017-11-24 | ザ ジャクソン ラボラトリー | エレクトロポレーションによる遺伝子改変哺乳動物の高効率ハイスループット生成 |
| AU2015327836B2 (en) | 2014-10-03 | 2021-07-01 | Cold Spring Harbor Laboratory | Targeted augmentation of nuclear gene output |
| TW202503057A (zh) | 2014-10-10 | 2025-01-16 | 美商艾爾妮蘭製藥公司 | 用於抑制hao1(羥酸氧化酶1(乙醇酸鹽氧化酶))基因表現的組合物及方法 |
| WO2016061131A1 (en) | 2014-10-14 | 2016-04-21 | The J. David Gladstone Institutes | Compositions and methods for reactivating latent immunodeficiency virus |
| WO2016061487A1 (en) | 2014-10-17 | 2016-04-21 | Alnylam Pharmaceuticals, Inc. | Polynucleotide agents targeting aminolevulinic acid synthase-1 (alas1) and uses thereof |
| EP3212794B1 (en) | 2014-10-30 | 2021-04-07 | Genzyme Corporation | Polynucleotide agents targeting serpinc1 (at3) and methods of use thereof |
| KR102545316B1 (ko) | 2014-11-10 | 2023-06-22 | 알닐람 파마슈티칼스 인코포레이티드 | Ｂ형 간염 바이러스(ｈｂｖ) ｉｒｎａ 조성물 및 그의 이용 방법 |
| SG11201703645XA (en) | 2014-11-10 | 2017-06-29 | Glaxosmithkline Intellectual Property (No 2) Ltd | Long acting pharmaceutical compositions for hepatitis c |
| KR20170081257A (ko) | 2014-11-10 | 2017-07-11 | 글락소스미스클라인 인털렉츄얼 프로퍼티 (넘버 2) 리미티드 | C형 간염에 대한 조합 장기 작용 조성물 및 방법 |
| WO2016077704A1 (en) | 2014-11-14 | 2016-05-19 | The Regents Of The University Of California | Modulation of agpat5 expression |
| CA2964979A1 (en) | 2014-11-14 | 2016-05-19 | Ionis Pharmaceuticals, Inc. | Compounds and methods for the modulation of proteins |
| JP2017535552A (ja) | 2014-11-17 | 2017-11-30 | アルナイラム ファーマシューティカルズ， インコーポレイテッドＡｌｎｙｌａｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． | アポリポタンパク質Ｃ３（ＡＰＯＣ３）ｉＲＮＡ組成物およびその使用方法 |
| US11213593B2 (en) | 2014-11-21 | 2022-01-04 | Northwestern University | Sequence-specific cellular uptake of spherical nucleic acid nanoparticle conjugates |
| US10400243B2 (en) | 2014-11-25 | 2019-09-03 | Ionis Pharmaceuticals, Inc. | Modulation of UBE3A-ATS expression |
| WO2016094342A1 (en) | 2014-12-08 | 2016-06-16 | The Board Of Regents Of The University Of Texas System | Lipocationic polymers and uses thereof |
| JP2018504380A (ja) | 2014-12-18 | 2018-02-15 | アルナイラム ファーマシューティカルズ， インコーポレイテッドＡｌｎｙｌａｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． | Ｒｅｖｅｒｓｉｒ（商標）化合物 |
| US9688707B2 (en) | 2014-12-30 | 2017-06-27 | Ionis Pharmaceuticals, Inc. | Bicyclic morpholino compounds and oligomeric compounds prepared therefrom |
| US10793855B2 (en) | 2015-01-06 | 2020-10-06 | Ionis Pharmaceuticals, Inc. | Compositions for modulating expression of C9ORF72 antisense transcript |
| WO2016118476A1 (en) | 2015-01-20 | 2016-07-28 | The Children's Medical Center Corporation | Anti-net compounds for treating and preventing fibrosis and for facilitating wound healing |
| EP3247716A4 (en) | 2015-01-20 | 2018-10-17 | Miragen Therapeutics, Inc. | Mir-92 inhibitors and uses thereof |
| EP3253784B1 (en) | 2015-02-04 | 2020-05-06 | Genentech, Inc. | Mutant smoothened and methods of using the same |
| WO2016130600A2 (en) | 2015-02-09 | 2016-08-18 | Duke University | Compositions and methods for epigenome editing |
| CA2976445A1 (en) | 2015-02-13 | 2016-08-18 | Alnylam Pharmaceuticals, Inc. | Patatin-like phospholipase domain containing 3 (pnpla3) irna compositions and methods of use thereof |
| WO2016138175A1 (en) | 2015-02-24 | 2016-09-01 | The University Of British Columbia | Continuous flow microfluidic system |
| AU2016222546B2 (en) | 2015-02-26 | 2020-01-23 | Ionis Pharmaceuticals, Inc. | Allele specific modulators of P23H rhodopsin |
| WO2016141236A1 (en) | 2015-03-03 | 2016-09-09 | Ionis Pharmaceuticals, Inc. | Compositions for modulating mecp2 expression |
| US20180044673A1 (en) | 2015-03-03 | 2018-02-15 | Ionis Pharmaceuticals, Inc. | Methods for modulating mecp2 expression |
| MX2017012426A (es) | 2015-04-03 | 2018-01-26 | Ionis Pharmaceuticals Inc | Composiciones y metodos para modular la expresion de tmprss6. |
| US10961532B2 (en) | 2015-04-07 | 2021-03-30 | The General Hospital Corporation | Methods for reactivating genes on the inactive X chromosome |
| US10745702B2 (en) | 2015-04-08 | 2020-08-18 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of the LECT2 gene |
| PT3283500T (pt) | 2015-04-08 | 2021-01-28 | Univ Chicago | Composições e métodos para corrigir distrofia muscular das cinturas tipo 2c com utilização de salto do exão |
| US10407678B2 (en) | 2015-04-16 | 2019-09-10 | Ionis Pharmaceuticals, Inc. | Compositions for modulating expression of C9ORF72 antisense transcript |
| RS60230B1 (sr) | 2015-04-16 | 2020-06-30 | Ionis Pharmaceuticals Inc | Kompozicije za moduliranje ekspresije c9orf72 |
| CA2983819A1 (en) | 2015-04-24 | 2016-10-27 | Atila Biosystems Incorporated | Amplification with primers of limited nucleotide composition |
| WO2016196655A1 (en) | 2015-06-03 | 2016-12-08 | The Regents Of The University Of California | Cas9 variants and methods of use thereof |
| WO2016201301A1 (en) | 2015-06-12 | 2016-12-15 | Alnylam Pharmaceuticals, Inc. | Complement component c5 irna compositions and methods of use thereof |
| EP3310918B1 (en) | 2015-06-18 | 2020-08-05 | Alnylam Pharmaceuticals, Inc. | Polynucleotide agents targeting hydroxyacid oxidase (glycolate oxidase, hao1) and methods of use thereof |
| WO2016209862A1 (en) | 2015-06-23 | 2016-12-29 | Alnylam Pharmaceuticals, Inc. | Glucokinase (gck) irna compositions and methods of use thereof |
| CN108139375A (zh) | 2015-06-26 | 2018-06-08 | 贝斯以色列女执事医疗中心股份有限公司 | 靶向髓样衍生的抑制细胞中的四跨膜蛋白33(tspan33)的癌症疗法 |
| WO2017004261A1 (en) | 2015-06-29 | 2017-01-05 | Ionis Pharmaceuticals, Inc. | Modified crispr rna and modified single crispr rna and uses thereof |
| MX2018000412A (es) | 2015-07-10 | 2018-03-14 | Ionis Pharmaceuticals Inc | Moduladores de diaciglicerol aciltransferasa 2 (dgat2). |
| WO2017011286A1 (en) | 2015-07-10 | 2017-01-19 | Alnylam Pharmaceuticals, Inc. | Insulin-like growth factor binding protein, acid labile subunit (igfals) and insulin-like growth factor 1 (igf-1) irna compositions and methods of use thereof |
| CA3205381A1 (en) | 2015-07-17 | 2017-01-26 | Alnylam Pharmaceuticals, Inc. | Multi-targeted single entity conjugates |
| JP2018140938A (ja) * | 2015-07-24 | 2018-09-13 | 日産化学株式会社 | 人工ヌクレオシド及び人工ヌクレオチド並びに人工オリゴヌクレオチド |
| EP3331536A4 (en) | 2015-08-03 | 2019-03-27 | The Regents of The University of California | COMPOSITIONS AND METHODS OF MODULATING THE ABHD2 ACTIVITY |
| JP6835826B2 (ja) | 2015-08-24 | 2021-02-24 | ロシュ イノベーション センター コペンハーゲン エーエス | Ｌｎａ−ｇプロセス |
| CA2996873A1 (en) | 2015-09-02 | 2017-03-09 | Alnylam Pharmaceuticals, Inc. | Programmed cell death 1 ligand 1 (pd-l1) irna compositions and methods of use thereof |
| WO2017048789A1 (en) | 2015-09-14 | 2017-03-23 | The Board Of Regents Of The University Of Texas System | Lipocationic dendrimers and uses thereof |
| TW201718618A (zh) * | 2015-09-18 | 2017-06-01 | 田邊三菱製藥股份有限公司 | 架橋型核酸ＧｕＮＡ，其製造方法，及中間體化合物 |
| CA2999177A1 (en) | 2015-09-24 | 2017-03-30 | The Regents Of The University Of California | Synthetic sphingolipid-like molecules, drugs, methods of their synthesis and methods of treatment |
| CN108513588A (zh) | 2015-09-24 | 2018-09-07 | Ionis制药公司 | Kras表达的调节剂 |
| US20190048340A1 (en) | 2015-09-24 | 2019-02-14 | Crispr Therapeutics Ag | Novel family of rna-programmable endonucleases and their uses in genome editing and other applications |
| EP4285912A3 (en) | 2015-09-25 | 2024-07-10 | Ionis Pharmaceuticals, Inc. | Compositions and methods for modulating ataxin 3 expression |
| CN113817735A (zh) | 2015-10-08 | 2021-12-21 | Ionis制药公司 | 用于调节血管紧张素原表达的化合物和方法 |
| CN108603230A (zh) | 2015-10-09 | 2018-09-28 | 南安普敦大学 | 基因表达的调节与蛋白质表达失调的筛选 |
| EP4089175A1 (en) | 2015-10-13 | 2022-11-16 | Duke University | Genome engineering with type i crispr systems in eukaryotic cells |
| WO2017068087A1 (en) | 2015-10-22 | 2017-04-27 | Roche Innovation Center Copenhagen A/S | Oligonucleotide detection method |
| EP3368692B1 (en) | 2015-10-29 | 2021-07-21 | Temple University Of The Commonwealth System Of Higher Education | Modification of 3' terminal ends of nucleic acids by dna polymerase theta |
| WO2017079291A1 (en) | 2015-11-02 | 2017-05-11 | Ionis Pharmaceuticals, Inc. | Compounds and methods for modulating c90rf72 |
| EP3371211B1 (en) | 2015-11-04 | 2025-01-01 | Icahn School of Medicine at Mount Sinai | Rho-associated protein kinase ("rock") inhibitor for treating tumors and cancer, and identifying candidate subjects for such treatment |
| KR20250078597A (ko) | 2015-11-06 | 2025-06-02 | 아이오니스 파마수티컬즈, 인코포레이티드 | 아포리포프로테인 (a) 발현 조정 |
| PL4119569T3 (pl) | 2015-11-06 | 2024-11-18 | Ionis Pharmaceuticals, Inc. | Sprzężone związki antysensowne do zastosowania w terapii |
| LT3374509T (lt) | 2015-11-12 | 2021-03-10 | F. Hoffmann-La Roche Ag | Oligonukleotidai, skirti sukelti iš tėvo paveldėto ube3a raišką |
| CA3005968A1 (en) | 2015-11-23 | 2017-06-01 | The Regents Of The University Of California | Tracking and manipulating cellular rna via nuclear delivery of crispr/cas9 |
| KR102787119B1 (ko) | 2015-11-30 | 2025-03-27 | 듀크 유니버시티 | 유전자 편집에 의한 인간 디스트로핀 유전자의 교정을 위한 치료용 표적 및 사용 방법 |
| EP3389670A4 (en) | 2015-12-04 | 2020-01-08 | Ionis Pharmaceuticals, Inc. | METHODS OF TREATING BREAST CANCER |
| WO2017099579A1 (en) | 2015-12-07 | 2017-06-15 | Erasmus University Medical Center Rotterdam | Enzymatic replacement therapy and antisense therapy for pompe disease |
| KR20180095843A (ko) | 2015-12-07 | 2018-08-28 | 젠자임 코포레이션 | Serpinc1-연관 장애의 치료를 위한 방법 및 조성물 |
| ES2763822T3 (es) | 2015-12-09 | 2020-06-01 | Novartis Ag | Análisis exento de marcas de la eficacia de la adición de caperuzas al arn utilizando rnasa h, sondas y cromatografía líquida/espectrometría de masas |
| US11096956B2 (en) | 2015-12-14 | 2021-08-24 | Stoke Therapeutics, Inc. | Antisense oligomers and uses thereof |
| WO2017106377A1 (en) | 2015-12-14 | 2017-06-22 | Cold Spring Harbor Laboratory | Antisense oligomers for treatment of autosomal dominant mental retardation-5 and dravet syndrome |
| WO2017106767A1 (en) | 2015-12-18 | 2017-06-22 | The Scripps Research Institute | Production of unnatural nucleotides using a crispr/cas9 system |
| PH12018501207B1 (en) | 2015-12-21 | 2024-02-23 | Novartis Ag | Compositions and methods for decreasing tau expression |
| CA3006599A1 (en) | 2016-01-05 | 2017-07-13 | Ionis Pharmaceuticals, Inc. | Methods for reducing lrrk2 expression |
| EP3400097B1 (en) | 2016-01-06 | 2021-01-27 | The University Of British Columbia | Bifurcating mixers and methods of their use and manufacture |
| CN109414001A (zh) | 2016-01-15 | 2019-03-01 | 杰克逊实验室 | 通过cas9蛋白的多循环电穿孔产生的遗传修饰的非人哺乳动物 |
| WO2017131124A1 (ja) | 2016-01-26 | 2017-08-03 | 日産化学工業株式会社 | 一本鎖オリゴヌクレオチド |
| EP3411396A1 (en) | 2016-02-04 | 2018-12-12 | Curis, Inc. | Mutant smoothened and methods of using the same |
| EP3418289B1 (en) | 2016-02-17 | 2026-04-08 | Institute Of Science Tokyo | Artificial nucleoside and artificial nucleotide, and artificial oligonucleotide |
| JP7033072B2 (ja) | 2016-02-25 | 2022-03-09 | ザ ブリガム アンド ウィメンズ ホスピタル インコーポレイテッド | Ｓｍｏｃ２を標的化する線維症のための治療方法 |
| EP4354140A3 (en) | 2016-02-26 | 2024-07-24 | The Board of Trustees of the Leland Stanford Junior University | Multiplexed single molecule rna visualization with a two-probe proximity ligation system |
| WO2017156242A1 (en) | 2016-03-09 | 2017-09-14 | Ionis Pharmaceuticals, Inc. | Methods and compositions for inhibiting pmp22 expression |
| WO2023150553A1 (en) | 2022-02-01 | 2023-08-10 | University Of Rochester | Gpr17 promoter-based targeting and transduction of glial progenitor cells |
| RU2747822C2 (ru) | 2016-03-14 | 2021-05-14 | Ф. Хоффманн-Ля Рош Аг | Олигонуклеотиды для понижения экспрессии pd-l1 |
| WO2017161168A1 (en) | 2016-03-16 | 2017-09-21 | Ionis Pharmaceuticals, Inc. | Modulation of dyrk1b expression |
| EP3429690A4 (en) | 2016-03-16 | 2019-10-23 | Ionis Pharmaceuticals, Inc. | METHOD FOR MODULATING KEAP1 |
| US20190127713A1 (en) | 2016-04-13 | 2019-05-02 | Duke University | Crispr/cas9-based repressors for silencing gene targets in vivo and methods of use |
| US20190142856A1 (en) | 2016-04-13 | 2019-05-16 | Ionis Pharmaceuticals, Inc. | Methods for reducing c9orf72 expression |
| WO2017178656A1 (en) | 2016-04-14 | 2017-10-19 | Roche Innovation Center Copenhagen A/S | TRITYL-MONO-GalNAc COMPOUNDS AND THEIR USE |
| WO2017184689A1 (en) | 2016-04-19 | 2017-10-26 | Alnylam Pharmaceuticals, Inc. | High density lipoprotein binding protein (hdlbp/vigilin) irna compositions and methods of use thereof |
| WO2017189730A1 (en) | 2016-04-26 | 2017-11-02 | Icahn School Of Medicine At Mount Sinai | Treatment of hippo pathway mutant tumors and methods of identifying subjects as candidates for treatment |
| WO2017192820A1 (en) | 2016-05-06 | 2017-11-09 | Ionis Pharmaceuticals, Inc. | Glp-1 receptor ligand moiety conjugated oligonucleotides and uses thereof |
| CN109414408B (zh) | 2016-05-16 | 2022-03-29 | 得克萨斯州大学系统董事会 | 阳离子磺酰胺氨基脂质和两亲性两性离子氨基脂质 |
| EP3469083A1 (en) | 2016-06-10 | 2019-04-17 | Alnylam Pharmaceuticals, Inc. | COMPLEMENT COMPONENT C5 iRNA COMPOSITIONS AND METHODS OF USE THEREOF FOR TREATING PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) |
| US11708614B2 (en) | 2016-06-15 | 2023-07-25 | Streck Llc | Assays and methods for determining microbial resistance |
| US10337051B2 (en) | 2016-06-16 | 2019-07-02 | The Regents Of The University Of California | Methods and compositions for detecting a target RNA |
| EP4219767A1 (en) | 2016-06-17 | 2023-08-02 | F. Hoffmann-La Roche AG | Papd5 and papd7 inhibitors for treating a hepatitis b infection |
| AU2017286811A1 (en) | 2016-06-17 | 2018-11-22 | Ionis Pharmaceuticals, Inc. | Modulation of gys1 expression |
| US20190218257A1 (en) | 2016-06-24 | 2019-07-18 | The Scripps Research Institute | Novel nucleoside triphosphate transporter and uses thereof |
| MX2018015722A (es) | 2016-07-01 | 2019-05-27 | Hoffmann La Roche | Oligonucleotidos antisentido para modular expresion del requisito de alta temperatura a 1 (htra1). |
| EP3484524B1 (en) | 2016-07-15 | 2022-11-09 | Ionis Pharmaceuticals, Inc. | Compounds and methods for modulation of smn2 |
| JP7490211B2 (ja) | 2016-07-19 | 2024-05-27 | デューク ユニバーシティ | Ｃｐｆ１に基づくゲノム編集の治療適用 |
| NL2017294B1 (en) | 2016-08-05 | 2018-02-14 | Univ Erasmus Med Ct Rotterdam | Natural cryptic exon removal by pairs of antisense oligonucleotides. |
| NL2017295B1 (en) | 2016-08-05 | 2018-02-14 | Univ Erasmus Med Ct Rotterdam | Antisense oligomeric compound for Pompe disease |
| WO2018039629A2 (en) | 2016-08-25 | 2018-03-01 | Northwestern University | Micellar spherical nucleic acids from thermoresponsive, traceless templates |
| SG10201607303YA (en) | 2016-09-01 | 2018-04-27 | Agency Science Tech & Res | Antisense oligonucleotides to induce exon skipping |
| KR102533038B1 (ko) | 2016-09-14 | 2023-05-17 | 얀센 바이오파마, 인크. | 변형된 올리고뉴클레오티드 및 사용 방법 |
| ES2893411T3 (es) | 2016-09-15 | 2022-02-09 | Hoffmann La Roche | Procedimientos para realizar PCR multiplexada |
| HUE065170T2 (hu) | 2016-09-29 | 2024-05-28 | Biogen Ma Inc | Vegyületek és módszerek a TAU expresszió csökkentésére |
| US11400161B2 (en) | 2016-10-06 | 2022-08-02 | Ionis Pharmaceuticals, Inc. | Method of conjugating oligomeric compounds |
| SG10201609048RA (en) | 2016-10-28 | 2018-05-30 | Agency Science Tech & Res | Antisense oligonucleotides |
| US11459568B2 (en) | 2016-10-31 | 2022-10-04 | University Of Massachusetts | Targeting microRNA-101-3p in cancer therapy |
| JOP20190104A1 (ar) | 2016-11-10 | 2019-05-07 | Ionis Pharmaceuticals Inc | مركبات وطرق لتقليل التعبير عن atxn3 |
| US20190284621A1 (en) | 2016-11-11 | 2019-09-19 | Roche Innovation Center Copenhagen A/S | Therapeutic oligonucleotides capture and detection |
| TWI788312B (zh) | 2016-11-23 | 2023-01-01 | 美商阿尼拉製藥公司 | 絲胺酸蛋白酶抑制因子Ａ１ ｉＲＮＡ組成物及其使用方法 |
| WO2018102745A1 (en) | 2016-12-02 | 2018-06-07 | Cold Spring Harbor Laboratory | Modulation of lnc05 expression |
| WO2018112320A1 (en) | 2016-12-16 | 2018-06-21 | Alnylam Pharmaceuticals, Inc. | Methods for treating or preventing ttr-associated diseases using transthyretin (ttr) irna compositions |
| CN110268060B (zh) | 2017-01-10 | 2024-07-26 | 箭头药业股份有限公司 | α-1抗胰蛋白酶(AAT)RNAi物质、包含AAT RNAi物质的组合物和使用方法 |
| EP3568479A1 (en) | 2017-01-13 | 2019-11-20 | Roche Innovation Center Copenhagen A/S | Antisense oligonucleotides for modulating nfkb1 expression |
| EP3568478A1 (en) | 2017-01-13 | 2019-11-20 | Roche Innovation Center Copenhagen A/S | Antisense oligonucleotides for modulating rel expression |
| EP3568477A1 (en) | 2017-01-13 | 2019-11-20 | Roche Innovation Center Copenhagen A/S | Antisense oligonucleotides for modulating rela expression |
| WO2018130584A1 (en) | 2017-01-13 | 2018-07-19 | Roche Innovation Center Copenhagen A/S | Antisense oligonucleotides for modulating nfkb2 expression |
| US20190345496A1 (en) | 2017-01-13 | 2019-11-14 | Roche Innovation Center Copenhagen A/S | Antisense oligonucleotides for modulating relb expression |
| AU2018215440B2 (en) | 2017-02-06 | 2024-10-24 | Nissan Chemical Corporation | Single-stranded oligonucleotide |
| US11180756B2 (en) | 2017-03-09 | 2021-11-23 | Ionis Pharmaceuticals | Morpholino modified oligomeric compounds |
| EP3597197A4 (en) | 2017-03-17 | 2021-01-06 | National University Corporation Chiba University | Novel technique for treating cancer using structurally-reinforced s-tud |
| JOP20190215A1 (ar) | 2017-03-24 | 2019-09-19 | Ionis Pharmaceuticals Inc | مُعدّلات التعبير الوراثي عن pcsk9 |
| EP3603648B1 (en) | 2017-03-29 | 2025-09-17 | Shionogi & Co., Ltd | Complex of nucleic acid medicine and multibranched lipid |
| EP3609521A4 (en) | 2017-04-14 | 2021-06-16 | University of Massachusetts | TARGETING OF CELL TROPISM RECEPTORS TO INHIBIT INFECTION BY THE CYTOMEGALOVIRUS |
| CA3059446A1 (en) | 2017-04-18 | 2018-10-25 | Alnylam Pharmaceuticals, Inc. | Methods for the treatment of subjects having a hepatitis b virus (hbv) infection |
| WO2018208998A1 (en) | 2017-05-10 | 2018-11-15 | The Regents Of The University Of California | Directed editing of cellular rna via nuclear delivery of crispr/cas9 |
| US20190055564A1 (en) | 2017-06-01 | 2019-02-21 | F. Hoffmann-La Roche Ag | Antisense oligonucleotides for modulating htra1 expression |
| TW202434265A (zh) | 2017-07-10 | 2024-09-01 | 美商健贊公司 | 於患有血友病之個體中治療出血事件之方法及組成物 |
| JP7325341B2 (ja) | 2017-07-11 | 2023-08-14 | シンソークス，インク． | 非天然ヌクレオチドの組み込み及びその方法 |
| WO2019014262A1 (en) | 2017-07-11 | 2019-01-17 | The Scripps Research Institute | INCORPORATION OF NON-NATURAL NUCLEOTIDES AND METHODS OF IN VIVO USE THEREOF |
| MX2020000387A (es) | 2017-07-13 | 2020-08-17 | Univ Northwestern | Método general y directo para preparar nanopartículas de estructura organometálica funcionalizadas con oligonucleotidos. |
| BR112020001430A2 (pt) | 2017-07-26 | 2020-07-28 | Nissan Chemical Corporation | oligonucleotídeo de fita simples |
| KR20240141853A (ko) | 2017-08-03 | 2024-09-27 | 신톡스, 인크. | 자가면역 질환의 치료를 위한 사이토카인 접합체 |
| WO2019030313A2 (en) | 2017-08-11 | 2019-02-14 | Roche Innovation Center Copenhagen A/S | OLIGONUCLEOTIDES FOR MODULATION OF UBE3C EXPRESSION |
| WO2019036613A1 (en) | 2017-08-18 | 2019-02-21 | Ionis Pharmaceuticals, Inc. | MODULATION OF THE NOTCH SIGNALING PATHWAY FOR THE TREATMENT OF RESPIRATORY DISORDERS |
| WO2019038228A1 (en) | 2017-08-22 | 2019-02-28 | Roche Innovation Center Copenhagen A/S | OLIGONUCLEOTIDES FOR MODULATION OF TOM1 EXPRESSION |
| KR102318434B1 (ko) | 2017-08-25 | 2021-11-01 | 스톡 테라퓨틱스, 인크. | 병태 및 질환 치료용 안티센스 올리고머 |
| IL272864B2 (en) | 2017-08-31 | 2024-03-01 | Mitsubishi Tanabe Pharma Corp | Il-33 antagonist-containing therapeutic agent for endometriosis |
| WO2019045532A2 (en) | 2017-08-31 | 2019-03-07 | Seegene, Inc. | EVALUATION OF COMPONENT PERFORMANCE USING A PAIR OF DIMER FORMER PRIMERS |
| US10517889B2 (en) | 2017-09-08 | 2019-12-31 | Ionis Pharmaceuticals, Inc. | Modulators of SMAD7 expression |
| EA202090720A1 (ru) | 2017-09-14 | 2020-07-07 | Янссен Байофарма, Инк. | ПРОИЗВОДНЫЕ GalNAc |
| KR102345601B1 (ko) | 2017-09-29 | 2021-12-30 | 주식회사 씨젠 | Pto 절단 및 연장-의존적 연장 분석에 의한 타겟 핵산 서열의 검출 |
| EP3694995A1 (en) | 2017-10-13 | 2020-08-19 | Roche Innovation Center Copenhagen A/S | Methods for identifying improved stereodefined phosphorothioate oligonucleotide variants of antisense oligonucleotides utilising sub-libraries of partially stereodefined oligonucleotides |
| CN111511914B (zh) | 2017-10-16 | 2023-11-17 | 豪夫迈·罗氏有限公司 | 减少PAPD5和PAPD7 mRNA的核酸分子用于治疗乙型肝炎感染 |
| WO2019076919A1 (en) | 2017-10-17 | 2019-04-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | COMBINED TREATMENT OF CYSTIC FIBROSIS |
| SG11202002940QA (en) | 2017-11-01 | 2020-04-29 | Alnylam Pharmaceuticals Inc | Complement component c3 irna compositions and methods of use thereof |
| CN111566212A (zh) | 2017-11-03 | 2020-08-21 | 因特尔纳技术有限公司 | miRNA分子，等同物，安塔够妙或其来源用于治疗和/或诊断与神经元缺陷相关的病症和/或疾病或用于神经元生成和/或再生 |
| TWI809004B (zh) | 2017-11-09 | 2023-07-21 | 美商Ionis製藥公司 | 用於降低snca表現之化合物及方法 |
| US20200385719A1 (en) | 2017-11-16 | 2020-12-10 | Alnylam Pharmaceuticals, Inc. | Kisspeptin 1 (kiss1) irna compositions and methods of use thereof |
| WO2019100039A1 (en) | 2017-11-20 | 2019-05-23 | Alnylam Pharmaceuticals, Inc. | Serum amyloid p component (apcs) irna compositions and methods of use thereof |
| WO2019115416A2 (en) | 2017-12-11 | 2019-06-20 | Roche Innovation Center Copenhagen A/S | Oligonucleotides for modulating fndc3b expression |
| WO2019115417A2 (en) | 2017-12-12 | 2019-06-20 | Roche Innovation Center Copenhagen A/S | Oligonucleotides for modulating rb1 expression |
| JP2021506251A (ja) | 2017-12-14 | 2021-02-22 | クリスパー セラピューティクス アーゲー | 新規ｒｎａプログラム可能エンドヌクレアーゼ系、ならびにゲノム編集および他の適用におけるその使用 |
| US11725208B2 (en) | 2017-12-14 | 2023-08-15 | Ionis Pharmaceuticals, Inc. | Conjugated antisense compounds and their use |
| WO2019116346A1 (en) | 2017-12-15 | 2019-06-20 | Novartis Ag | Polya tail length analysis of rna by mass spectrometry |
| EP3728593A1 (en) | 2017-12-18 | 2020-10-28 | Alnylam Pharmaceuticals, Inc. | High mobility group box-1 (hmgb1) irna compositions and methods of use thereof |
| WO2019121838A1 (en) | 2017-12-21 | 2019-06-27 | F. Hoffmann-La Roche Ag | Companion diagnostic for htra1 rna antagonists |
| CA3084170A1 (en) | 2017-12-22 | 2019-06-27 | Roche Innovation Center Copenhagen A/S | Gapmer oligonucleotides comprising a phosphorodithioate internucleoside linkage |
| US11597926B2 (en) | 2017-12-22 | 2023-03-07 | Roche Innovation Center Copenhagen A/S | Thiophosphoramidites |
| WO2019122279A1 (en) | 2017-12-22 | 2019-06-27 | Roche Innovation Center Copenhagen A/S | Oligonucleotides comprising a phosphorodithioate internucleoside linkage |
| SG11202006101WA (en) | 2017-12-29 | 2020-07-29 | Scripps Research Inst | Unnatural base pair compositions and methods of use |
| US20210095274A1 (en) | 2018-01-10 | 2021-04-01 | Roche Innovation Center Copenhagen A/S | Oligonucleotides for modulating pias4 expression |
| CN120310791A (zh) | 2018-01-12 | 2025-07-15 | 百时美施贵宝公司 | 靶向α-突触核蛋白的反义寡核苷酸及其用途 |
| WO2019137974A1 (en) | 2018-01-12 | 2019-07-18 | Roche Innovation Center Copenhagen A/S | Oligonucleotides for modulating gsk3b expression |
| SG11202006142PA (en) | 2018-01-12 | 2020-07-29 | Roche Innovation Ct Copenhagen As | Alpha-synuclein antisense oligonucleotides and uses thereof |
| SG11202006528XA (en) | 2018-01-12 | 2020-08-28 | Bristol Myers Squibb Co | Antisense oligonucleotides targeting alpha-synuclein and uses thereof |
| AU2019206731A1 (en) | 2018-01-15 | 2020-07-30 | Ionis Pharmaceuticals, Inc. | Modulators of DNM2 expression |
| CN111615558A (zh) | 2018-01-17 | 2020-09-01 | 罗氏创新中心哥本哈根有限公司 | 用于调节erc1表达的寡核苷酸 |
| CN111655851A (zh) | 2018-01-18 | 2020-09-11 | 哥本哈根罗氏创新中心 | 靶向srebp1的反义寡核苷酸 |
| EP3740580A4 (en) | 2018-01-19 | 2021-10-20 | Duke University | GENOME ENGINEERING WITH CRISPR-CAS SYSTEMS IN EUKARYONTS |
| WO2019145386A1 (en) | 2018-01-26 | 2019-08-01 | Roche Innovation Center Copenhagen A/S | Oligonucleotides for modulating csnk1d expression |
| BR112020016170A2 (pt) | 2018-02-09 | 2020-12-15 | Genentech, Inc. | Oligonucleotídeos terapêutico e antissenso, conjugado, sal farmaceuticamente aceitável, composição farmacêutica, método in vitro ou in vivo para modular a expressão de tmem106b, método para tratar ou prevenir uma doença, uso do oligonucleotídeo e uso ou método |
| JP2021513508A (ja) | 2018-02-12 | 2021-05-27 | インテアールエヌエー テクノロジーズ ビー．ヴイ．ＩｎｔｅＲＮＡ Ｔｅｃｈｎｏｌｏｇｉｅｓ Ｂ．Ｖ． | 抗がんマイクロｒｎａ及びその脂質製剤 |
| WO2019157531A1 (en) | 2018-02-12 | 2019-08-15 | Ionis Pharmaceuticals, Inc. | Modified compounds and uses thereof |
| MX2020008581A (es) | 2018-02-21 | 2020-09-21 | Bristol Myers Squibb Co | Oligonucleotidos antisentido de la proteina cinasa del tipo ii delta dependiente del calcio/calmodulina (camk2d) y sus usos. |
| CN112004547A (zh) | 2018-02-26 | 2020-11-27 | 新索思股份有限公司 | Il-15缀合物及其用途 |
| MX2020009532A (es) | 2018-03-13 | 2020-10-05 | Janssen Pharmaceutica Nv | Oligonucleotidos modificados para uso en el tratamiento de tauopatias. |
| MA52074A (fr) | 2018-03-19 | 2021-01-27 | Bayer Healthcare Llc | Nouveaux systèmes d'endonucléase à arn programmable et leurs utilisations |
| BR112020018902A2 (pt) | 2018-03-20 | 2021-01-26 | Tokyo Institute Of Technology | oligonucleotídeo antissenso com toxicidade reduzida |
| SG11202009680XA (en) | 2018-04-05 | 2020-10-29 | Hoffmann La Roche | Use of fubp1 inhibitors for treating hepatitis b virus infection |
| WO2019213016A1 (en) | 2018-04-30 | 2019-11-07 | The Children's Hospital Of Philadelphia | Methods of improving anemias by combining agents |
| CA3099280A1 (en) | 2018-05-04 | 2019-11-07 | Stoke Therapeutics, Inc. | Methods and compositions for treatment of cholesteryl ester storage disease |
| MX2020011570A (es) | 2018-05-07 | 2020-11-24 | Alnylam Pharmaceuticals Inc | Administracion extrahepatica. |
| CN112105745A (zh) | 2018-05-07 | 2020-12-18 | 罗氏创新中心哥本哈根有限公司 | 用于寡核苷酸治疗剂的大规模平行发现方法 |
| US20210371860A1 (en) | 2018-05-08 | 2021-12-02 | Roche Innovation Center Copenhagen A/S | Oligonucleotides for modulating myh7 expression |
| EP4663758A3 (en) | 2018-05-09 | 2026-04-29 | Ionis Pharmaceuticals, Inc. | Compounds and methods for reducing atxn3 expression |
| CU20200082A7 (es) | 2018-05-09 | 2021-06-08 | Ionis Pharmaceuticals Inc | Compuestos y métodos para la reducción de la expresión de fxi |
| US12582702B2 (en) | 2018-05-11 | 2026-03-24 | University Of Massachusetts | Methods for improving leptin sensitivity for the treatment of obesity and diabetes |
| TWI851574B (zh) | 2018-05-14 | 2024-08-11 | 美商阿尼拉製藥公司 | 血管收縮素原（ＡＧＴ）ｉＲＮＡ組成物及其使用方法 |
| JP2021524450A (ja) | 2018-05-18 | 2021-09-13 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | マイクロｒｎａ関連疾患の処置のための薬学的組成物 |
| US11578325B2 (en) | 2018-05-24 | 2023-02-14 | David Berz | Methods and formulations for the treatment of obesity and obesity-related metabolic diseases |
| WO2019224172A1 (en) | 2018-05-25 | 2019-11-28 | Roche Innovation Center Copenhagen A/S | Novel process for making allofuranose from glucofuranose |
| JP7379387B2 (ja) | 2018-06-05 | 2023-11-14 | エフ． ホフマン－ラ ロシュ アーゲー | Ａｔｘｎ２発現を制御するためのオリゴヌクレオチド |
| JP7555542B2 (ja) | 2018-06-18 | 2024-09-25 | ユニバーシティー オブ ロチェスター | 統合失調症及び他の神経精神障害の治療方法 |
| EP3810151B1 (en) | 2018-06-20 | 2025-08-06 | Yale University | Rig-i agonists and treatments using same |
| JP7595464B2 (ja) | 2018-06-21 | 2024-12-06 | エフ． ホフマン－ラ ロシュ アーゲー | 全ｌｎａオリゴヌクレオチドのハイブリダイズ |
| CA3103675A1 (en) | 2018-06-21 | 2019-12-26 | University Of Rochester | Methods of treating or inhibiting onset of huntington's disease |
| WO2020007772A1 (en) | 2018-07-02 | 2020-01-09 | Roche Innovation Center Copenhagen A/S | Antisense oligonucleotides targeting gbp-1 |
| WO2020007702A1 (en) | 2018-07-02 | 2020-01-09 | Roche Innovation Center Copenhagen A/S | Antisense oligonucleotides targeting bcl2l11 |
| WO2020007700A1 (en) | 2018-07-02 | 2020-01-09 | Roche Innovation Center Copenhagen A/S | Antisense oligonucleotides targeting spi1 |
| PE20210346A1 (es) | 2018-07-03 | 2021-02-25 | Hoffmann La Roche | Oligonucleotidos para modular la expresion de tau |
| WO2020007826A1 (en) | 2018-07-05 | 2020-01-09 | Roche Innovation Center Copenhagen A/S | Antisense oligonucleotides targeting mbtps1 |
| WO2020007889A1 (en) | 2018-07-05 | 2020-01-09 | Roche Innovation Center Copenhagen A/S | Antisense oligonucleotides targeting stat1 |
| WO2020011653A1 (en) | 2018-07-09 | 2020-01-16 | Roche Innovation Center Copenhagen A/S | Antisense oligonucleotides targeting kynu |
| WO2020011743A1 (en) | 2018-07-09 | 2020-01-16 | Roche Innovation Center Copenhagen A/S | Antisense oligonucleotides targeting mafb |
| WO2020011744A2 (en) | 2018-07-11 | 2020-01-16 | Roche Innovation Center Copenhagen A/S | Antisense oligonucleotides targeting cers5 |
| WO2020011745A2 (en) | 2018-07-11 | 2020-01-16 | Roche Innovation Center Copenhagen A/S | Antisense oligonucleotides targeting cers6 |
| WO2020011869A2 (en) | 2018-07-11 | 2020-01-16 | Roche Innovation Center Copenhagen A/S | Antisense oligonucleotides targeting tlr2 |
| CN112534055A (zh) | 2018-07-13 | 2021-03-19 | 豪夫迈·罗氏有限公司 | 用于调节rtel1表达的寡核苷酸 |
| US12496311B2 (en) | 2018-07-17 | 2025-12-16 | Aronora, Inc. | Methods for safely reducing thrombopoietin |
| AR115847A1 (es) | 2018-07-25 | 2021-03-03 | Ionis Pharmaceuticals Inc | Compuestos y métodos para reducir la expresión de la atxn2 |
| WO2020022499A1 (ja) | 2018-07-27 | 2020-01-30 | 国立大学法人大阪大学 | 老化の抑制、加齢性の疾患もしくは症状の予防、改善、もしくは治療、または寿命の延長のための組成物 |
| EP4122943B1 (en) | 2018-07-31 | 2024-05-29 | Roche Innovation Center Copenhagen A/S | Oligonucleotides comprising a phosphorotrithioate internucleoside linkage |
| BR112020025272A2 (pt) | 2018-07-31 | 2021-03-09 | Roche Innovation Center Copenhagen A/S | Oligonucleotídeos, oligonucleotídeo gapmer, sal farmaceuticamente aceitável, conjugado, composição farmacêutica, usos de um oligonucleotídeo, método para o tratamento ou profilaxia de uma doença, processo para a fabricação de um oligonucleotídeo e invenção |
| EP3830301B1 (en) | 2018-08-01 | 2024-05-22 | Mammoth Biosciences, Inc. | Programmable nuclease compositions and methods of use thereof |
| EP3833762A4 (en) | 2018-08-09 | 2022-09-28 | Verseau Therapeutics, Inc. | Oligonucleotide compositions for targeting ccr2 and csf1r and uses thereof |
| JP7625512B2 (ja) | 2018-08-13 | 2025-02-03 | アルナイラム ファーマシューティカルズ， インコーポレイテッド | Ｂ型肝炎ウイルス（ＨＢＶ）ｄｓＲＮＡ物質組成物およびその使用方法 |
| TW202020157A (zh) | 2018-08-16 | 2020-06-01 | 美商艾爾妮蘭製藥公司 | 用於抑制lect2基因表現之組合物及方法 |
| BR112021003224A2 (pt) | 2018-08-20 | 2021-07-20 | Rogcon, Inc. | oligonucleotídeos antissentido direcionados a scn2a para o tratamento de encefalopatias por scn1a |
| US12275964B2 (en) | 2018-08-22 | 2025-04-15 | The Regents Of The University Of California | Variant type V CRISPR/Cas effector polypeptides and methods of use thereof |
| WO2020038971A1 (en) | 2018-08-23 | 2020-02-27 | Roche Innovation Center Copenhagen A/S | Antisense oligonucleotides targeting vcan |
| WO2020038976A1 (en) | 2018-08-23 | 2020-02-27 | Roche Innovation Center Copenhagen A/S | Antisense oligonucleotides targeting usp8 |
| CN112585280A (zh) | 2018-08-23 | 2021-03-30 | 罗氏创新中心哥本哈根有限公司 | 微小rna-134生物标志物 |
| WO2020038973A1 (en) | 2018-08-23 | 2020-02-27 | Roche Innovation Center Copenhagen A/S | Antisense oligonucleotides targeting sptlc1 |
| US20210317527A1 (en) | 2018-08-27 | 2021-10-14 | The Regents Of The University Of California | Reporter nucleic acids for type v crispr-mediated detection |
| WO2020043750A1 (en) | 2018-08-28 | 2020-03-05 | Roche Innovation Center Copenhagen A/S | Neoantigen engineering using splice modulating compounds |
| CA3110661A1 (en) | 2018-08-29 | 2020-03-05 | University Of Massachusetts | Inhibition of protein kinases to treat friedreich ataxia |
| EP3620519A1 (en) | 2018-09-04 | 2020-03-11 | F. Hoffmann-La Roche AG | Use of isolated milk extracellular vesicles for delivering oligonucleotides orally |
| CA3111562A1 (en) | 2018-09-07 | 2020-04-02 | The General Hospital Corporation | Compositions and methods for immune checkpoint inhibition |
| EP3620520A1 (en) | 2018-09-10 | 2020-03-11 | Universidad del Pais Vasco | Novel target to treat a metabolic disease in an individual |
| JP7535310B2 (ja) | 2018-09-14 | 2024-08-16 | ノースウェスタン ユニバーシティ | Ｄｎａとのタンパク質重合のプログラミング |
| US20210332367A1 (en) | 2018-09-18 | 2021-10-28 | Alnylam Pharmaceuticals, Inc. | KETOHEXOKINASE (KHK) iRNA COMPOSITIONS AND METHODS OF USE THEREOF |
| TW202542311A (zh) | 2018-09-19 | 2025-11-01 | 美商Ionis製藥公司 | Pnpla3表現之調節劑 |
| EP3856931B1 (en) | 2018-09-25 | 2023-10-11 | Co-Diagnostics, Inc. | Allele-specific design of cooperative primers for improved nucleic acid variant genotyping |
| WO2020069055A1 (en) | 2018-09-28 | 2020-04-02 | Alnylam Pharmaceuticals, Inc. | Transthyretin (ttr) irna compositions and methods of use thereof for treating or preventing ttr-associated ocular diseases |
| EP3870700A1 (en) | 2018-10-24 | 2021-09-01 | Codiak BioSciences, Inc. | Methods to improve potency of electroporation |
| US10913951B2 (en) | 2018-10-31 | 2021-02-09 | University of Pittsburgh—of the Commonwealth System of Higher Education | Silencing of HNF4A-P2 isoforms with siRNA to improve hepatocyte function in liver failure |
| JP2022512877A (ja) | 2018-11-01 | 2022-02-07 | エフ．ホフマン－ラ ロシュ アーゲー | Ｔｉａ１を標的とするアンチセンスオリゴヌクレオチド |
| SG11202102930YA (en) | 2018-11-08 | 2021-04-29 | Synthorx Inc | Interleukin 10 conjugates and uses thereof |
| WO2020097445A1 (en) | 2018-11-09 | 2020-05-14 | Inari Agriculture, Inc. | Rna-guided nucleases and dna binding proteins |
| TW202028222A (zh) | 2018-11-14 | 2020-08-01 | 美商Ionis製藥公司 | Foxp3表現之調節劑 |
| CR20210311A (es) | 2018-11-15 | 2021-07-22 | Ionis Pharmaceuticals Inc | Moduladores de la expresión de irf5 |
| JP7307793B2 (ja) | 2018-11-16 | 2023-07-12 | エフ． ホフマン－ラ ロシュ アーゲー | 結合対のメンバーを有するストレプトアビジン被覆固相 |
| US12281305B2 (en) | 2018-11-21 | 2025-04-22 | Ionis Pharmaceuticals, Inc. | Compounds and methods for reducing prion expression |
| WO2020104492A1 (en) | 2018-11-22 | 2020-05-28 | Roche Innovation Center Copenhagen A/S | Pyridinium salts as activators in the synthesis of stereodefined oligonucleotides |
| CN113710799B (zh) | 2018-11-28 | 2024-11-12 | 克里斯珀医疗股份公司 | 用于在LNP中使用的编码CAS9的优化mRNA |
| WO2020109344A1 (en) | 2018-11-29 | 2020-06-04 | F. Hoffmann-La Roche Ag | Occular administration device for antisense oligonucleotides |
| WO2020109343A1 (en) | 2018-11-29 | 2020-06-04 | F. Hoffmann-La Roche Ag | Combination therapy for treatment of macular degeneration |
| WO2020117706A1 (en) | 2018-12-03 | 2020-06-11 | Triplet Therapeutics, Inc. | Methods for the treatment of trinucleotide repeat expansion disorders associated with mlh3 activity |
| US20210332495A1 (en) | 2018-12-06 | 2021-10-28 | Northwestern University | Protein Crystal Engineering Through DNA Hybridization Interactions |
| CA3122289A1 (en) | 2018-12-11 | 2020-06-18 | University Of Rochester | Methods of treating schizophrenia and other neuropsychiatric disorders |
| CN112654714B (zh) | 2018-12-17 | 2024-10-11 | 伊卢米纳剑桥有限公司 | 用于测序的引物寡核苷酸 |
| US20220298555A1 (en) | 2018-12-20 | 2022-09-22 | Roche Molecular Systems, Inc. | Detection of target nucleic acid by solid-phase molography |
| RS67553B1 (sr) | 2018-12-20 | 2026-01-30 | Humabs Biomed Sa | Kombinovana hbv terapija |
| AU2019406186A1 (en) | 2018-12-20 | 2021-07-15 | Praxis Precision Medicines, Inc. | Compositions and methods for the treatment of KCNT1 related disorders |
| CR20210395A (es) | 2018-12-21 | 2021-11-05 | Ionis Pharmaceuticals Inc | Moduladores de la expresión de hsd17b13 |
| WO2020136125A2 (en) | 2018-12-21 | 2020-07-02 | Boehringer Ingelheim International Gmbh | Antisense oligonucleotides targeting card9 |
| EP3931313A2 (en) | 2019-01-04 | 2022-01-05 | Mammoth Biosciences, Inc. | Programmable nuclease improvements and compositions and methods for nucleic acid amplification and detection |
| MX2021008628A (es) | 2019-01-16 | 2021-11-17 | Genzyme Corp | Composiciones de arni para serpinc1 y metodos de uso de las mismas. |
| EP3914232A1 (en) | 2019-01-25 | 2021-12-01 | F. Hoffmann-La Roche AG | Lipid vesicle for oral drug delivery |
| BR112021013369A2 (pt) | 2019-01-31 | 2021-09-21 | Ionis Pharmaceuticals, Inc. | Moduladores de expressão de yap1 |
| EP3923974A4 (en) | 2019-02-06 | 2023-02-08 | Synthorx, Inc. | IL-2 CONJUGATES AND METHODS OF USE THEREOF |
| US20230057355A1 (en) | 2019-02-13 | 2023-02-23 | University Of Rochester | Gene networks that mediate remyelination of the human brain |
| TW202102516A (zh) | 2019-02-20 | 2021-01-16 | 丹麥商羅氏創新中心哥本哈根有限公司 | 膦醯基乙酸酯間隙子寡核苷酸 |
| TW202045521A (zh) | 2019-02-20 | 2020-12-16 | 丹麥商羅氏創新中心哥本哈根有限公司 | 新穎亞磷醯胺化物 |
| JP7503072B2 (ja) | 2019-02-26 | 2024-06-19 | ロシュ イノベーション センター コペンハーゲン エーエス | オリゴヌクレオチドの製剤化方法 |
| AU2020227825B2 (en) | 2019-02-27 | 2026-03-26 | Stoke Therapeutics, Inc. | Antisense oligomers for treatment of conditions and diseases |
| AU2020227824B2 (en) | 2019-02-27 | 2025-07-10 | Ionis Pharmaceuticals, Inc. | Modulators of MALAT1 expression |
| US12215382B2 (en) | 2019-03-01 | 2025-02-04 | The General Hospital Corporation | Liver protective MARC variants and uses thereof |
| CN113507942A (zh) | 2019-03-05 | 2021-10-15 | 豪夫迈·罗氏有限公司 | 分子的细胞内靶向 |
| MX2021010559A (es) | 2019-03-07 | 2021-12-15 | Univ California | Polipéptidos efectores de crispr-cas y métodos de uso de estos. |
| SG11202109741VA (en) | 2019-03-12 | 2021-10-28 | Crispr Therapeutics Ag | Novel high fidelity rna-programmable endonuclease systems and uses thereof |
| US12492399B2 (en) | 2019-03-14 | 2025-12-09 | Rena Therapeutics Inc. | Nucleic acid complex for regulating IHH expression |
| US20240108747A1 (en) | 2019-03-21 | 2024-04-04 | Lonza Sales Ag | Extracellular vesicle conjugates and uses thereof |
| WO2020191177A1 (en) | 2019-03-21 | 2020-09-24 | Sudhir Agrawal | Antisense oligonucleotides for allele specificity |
| PT3947684T (pt) | 2019-03-29 | 2025-05-19 | Ionis Pharmaceuticals Inc | Compostos e métodos para modular ube3a‑ats |
| WO2020203880A1 (ja) | 2019-03-29 | 2020-10-08 | 田辺三菱製薬株式会社 | Ｄｕｘ４の発現を調節するための化合物、方法及び医薬組成物 |
| EP3947680A2 (en) | 2019-04-03 | 2022-02-09 | Bristol-Myers Squibb Company | Angptl2 antisense oligonucleotides and uses thereof |
| EP3947677A1 (en) | 2019-04-04 | 2022-02-09 | F. Hoffmann-La Roche AG | Oligonucleotides for modulating atxn2 expression |
| US11286485B2 (en) | 2019-04-04 | 2022-03-29 | Hoffmann-La Roche Inc. | Oligonucleotides for modulating ATXN2 expression |
| US12421268B2 (en) | 2019-04-16 | 2025-09-23 | Roche Innovation Center Copenhagen A/S | Process for preparing nucleotide P(V) monomers |
| CN113767108A (zh) | 2019-04-30 | 2021-12-07 | 罗氏创新中心哥本哈根有限公司 | 制备铼螯合mag3寡核苷酸的新方法 |
| AU2020268798A1 (en) | 2019-05-03 | 2021-11-04 | Dicerna Pharmaceuticals, Inc. | Double-stranded nucleic acid inhibitor molecules with shortened sense strands |
| PH12021552870A1 (en) | 2019-05-13 | 2022-03-21 | Vir Biotechnology Inc | Compositions and methods for treating hepatitis b virus (hbv) infection |
| AU2020279101B2 (en) | 2019-05-17 | 2025-07-24 | Alnylam Pharmaceuticals, Inc. | Oral delivery of oligonucleotides |
| HRP20250468T1 (hr) | 2019-05-28 | 2025-07-18 | Ionis Pharmaceuticals. Inc. | SPOJEVI I METODE ZA SMANJENJE POKAZATELJA FUS-a |
| US20250270657A1 (en) | 2019-05-31 | 2025-08-28 | Streck, Inc. | Detection of Antibiotic Resistance Genes |
| MX2021015003A (es) | 2019-06-06 | 2022-01-24 | Arrowhead Pharmaceuticals Inc | Metodos para el tratamiento de la deficiencia de alfa-1 antitripsina (aatd). |
| CN113950529A (zh) | 2019-06-06 | 2022-01-18 | 豪夫迈·罗氏有限公司 | 靶向atxn3的反义寡核苷酸 |
| CN120665985A (zh) | 2019-06-07 | 2025-09-19 | 豪夫迈·罗氏有限公司 | 杂交全lna寡核苷酸 |
| AU2020291535A1 (en) | 2019-06-14 | 2022-01-20 | The Scripps Research Institute | Reagents and methods for replication, transcription, and translation in semi-synthetic organisms |
| KR102899410B1 (ko) | 2019-06-19 | 2025-12-12 | 야마사 쇼유 가부시키가이샤 | 가교형 뉴클레오시드 중간체의 결정 및 그의 제조 방법, 그리고 가교형 뉴클레오시드 아미다이트의 제조 방법 |
| EP3997225A1 (en) | 2019-07-10 | 2022-05-18 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for the treatment of epilepsy |
| WO2021011936A2 (en) | 2019-07-18 | 2021-01-21 | University Of Rochester | Cell-type selective immunoprotection of cells |
| WO2021021673A1 (en) | 2019-07-26 | 2021-02-04 | Ionis Pharmaceuticals, Inc. | Compounds and methods for modulating gfap |
| JP7692829B2 (ja) | 2019-07-30 | 2025-06-16 | 塩野義製薬株式会社 | Ｍｕｒｆ１を標的とする核酸医薬 |
| EP4007812A1 (en) | 2019-08-01 | 2022-06-08 | Alnylam Pharmaceuticals, Inc. | Serpin family f member 2 (serpinf2) irna compositions and methods of use thereof |
| EP4007811A2 (en) | 2019-08-01 | 2022-06-08 | Alnylam Pharmaceuticals, Inc. | Carboxypeptidase b2 (cpb2) irna compositions and methods of use thereof |
| EP4013870A1 (en) | 2019-08-13 | 2022-06-22 | Alnylam Pharmaceuticals, Inc. | Small ribosomal protein subunit 25 (rps25) irna agent compositions and methods of use thereof |
| CA3147701A1 (en) | 2019-08-14 | 2021-02-18 | Codiak Biosciences, Inc. | Extracellular vesicles with antisense oligonucleotides targeting kras |
| AU2020330133A1 (en) | 2019-08-14 | 2022-03-17 | Lonza Sales Ag | Extracellular vesicle-ASO constructs targeting CEBP/beta |
| CA3147365A1 (en) | 2019-08-14 | 2021-02-18 | Joanne LIM | Extracellular vesicle-nlrp3 antagonist |
| KR20220070433A (ko) | 2019-08-14 | 2022-05-31 | 코디악 바이오사이언시즈, 인크. | Stat6을 표적으로 하는 세포외 소포-aso 작제물 |
| US20220354963A1 (en) | 2019-08-14 | 2022-11-10 | Codiak Biosciences, Inc. | Extracellular vesicle linked to molecules and uses thereof |
| CA3147366A1 (en) | 2019-08-14 | 2021-02-18 | Adam T. BOUTIN | Extracellular vesicles with stat3-antisense oligonucleotides |
| KR20220062517A (ko) | 2019-08-15 | 2022-05-17 | 아이오니스 파마수티컬즈, 인코포레이티드 | 결합 변형된 올리고머 화합물 및 이의 용도 |
| CN114555128A (zh) | 2019-08-15 | 2022-05-27 | 新索思股份有限公司 | 采用il-2缀合物的免疫肿瘤学组合疗法 |
| EP4017540A1 (en) | 2019-08-23 | 2022-06-29 | Synthorx, Inc. | Il-15 conjugates and uses thereof |
| BR112022003860A2 (pt) | 2019-09-03 | 2022-08-16 | Alnylam Pharmaceuticals Inc | Composições e métodos para inibir a expressão do gene lect2 |
| US12234271B2 (en) | 2019-09-10 | 2025-02-25 | Synthorx, Inc. | Il-2 conjugates and methods of use to treat autoimmune diseases |
| US12319711B2 (en) | 2019-09-20 | 2025-06-03 | Northwestern University | Spherical nucleic acids with tailored and active protein coronae |
| WO2021062058A1 (en) | 2019-09-25 | 2021-04-01 | Codiak Biosciences, Inc. | Sting agonist comprising exosomes for treating neuroimmunological disorders |
| US12503699B2 (en) | 2019-10-04 | 2025-12-23 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for silencing UGT1a1 gene expression |
| WO2021074772A1 (en) | 2019-10-14 | 2021-04-22 | Astrazeneca Ab | Modulators of pnpla3 expression |
| WO2021074657A1 (en) | 2019-10-17 | 2021-04-22 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Combination treatment for cystic fibrosis |
| IL292286A (en) | 2019-10-18 | 2022-06-01 | Daiichi Sankyo Co Ltd | Production method for bicyclic phosphoramidite |
| EP4045652A1 (en) | 2019-10-18 | 2022-08-24 | Alnylam Pharmaceuticals, Inc. | Solute carrier family member irna compositions and methods of use thereof |
| WO2021081026A1 (en) | 2019-10-22 | 2021-04-29 | Alnylam Pharmaceuticals, Inc. | Complement component c3 irna compositions and methods of use thereof |
| US12378560B2 (en) | 2019-10-29 | 2025-08-05 | Northwestern University | Sequence multiplicity within spherical nucleic acids |
| US20230040920A1 (en) | 2019-11-01 | 2023-02-09 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for silencing dnajb1-prkaca fusion gene expression |
| EP4051795A1 (en) | 2019-11-01 | 2022-09-07 | Alnylam Pharmaceuticals, Inc. | Huntingtin (htt) irna agent compositions and methods of use thereof |
| WO2021091986A1 (en) | 2019-11-04 | 2021-05-14 | Synthorx, Inc. | Interleukin 10 conjugates and uses thereof |
| WO2021092145A1 (en) | 2019-11-06 | 2021-05-14 | Alnylam Pharmaceuticals, Inc. | Transthyretin (ttr) irna composition and methods of use thereof for treating or preventing ttr-associated ocular diseases |
| BR112022007795A2 (pt) | 2019-11-06 | 2022-07-05 | Alnylam Pharmaceuticals Inc | Administração extra-hepática |
| BR112022009216A2 (pt) | 2019-11-13 | 2022-08-02 | Alnylam Pharmaceuticals Inc | Métodos e composições para tratar um distúrbio associado a angiotensinogênio (agt) |
| US20230016983A1 (en) | 2019-11-19 | 2023-01-19 | lNSERM (INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE) | Antisense oligonucleotides and thier use for the treatment of cancer |
| US12565653B2 (en) | 2019-11-22 | 2026-03-03 | Alnylam Pharmaceuticals, Inc. | ATAXIN3 (ATXN3) RNAi agent compositions and methods of use thereof |
| CN115335521B (zh) | 2019-11-27 | 2026-04-28 | 克里斯珀医疗股份公司 | 合成rna分子的方法 |
| EP3831843A1 (en) | 2019-12-08 | 2021-06-09 | Royal College Of Surgeons In Ireland | A hemostatic agent and uses thereof |
| EP4073249A1 (en) | 2019-12-11 | 2022-10-19 | Intellia Therapeutics, Inc. | Modified guide rnas for gene editing |
| KR20220115995A (ko) | 2019-12-13 | 2022-08-19 | 알닐람 파마슈티칼스 인코포레이티드 | 인간 염색체 ９ 개방 판독 프레임 72 (C9orf72) iRNA 제제 조성물 및 이의 사용 방법 |
| WO2021126734A1 (en) | 2019-12-16 | 2021-06-24 | Alnylam Pharmaceuticals, Inc. | Patatin-like phospholipase domain containing 3 (pnpla3) irna compositions and methods of use thereof |
| AU2020407267A1 (en) | 2019-12-18 | 2022-06-16 | F. Hoffmann-La Roche Ag | Methods of sequencing by synthesis using a consecutive labeling scheme |
| WO2021122735A1 (en) | 2019-12-19 | 2021-06-24 | F. Hoffmann-La Roche Ag | Use of sept9 inhibitors for treating hepatitis b virus infection |
| WO2021122869A1 (en) | 2019-12-19 | 2021-06-24 | F. Hoffmann-La Roche Ag | Use of scamp3 inhibitors for treating hepatitis b virus infection |
| EP4058032A4 (en) | 2019-12-19 | 2024-01-10 | Entrada Therapeutics, Inc. | Compositions for delivery of antisense compounds |
| EP4077669A1 (en) | 2019-12-19 | 2022-10-26 | F. Hoffmann-La Roche AG | Use of sbds inhibitors for treating hepatitis b virus infection |
| WO2021122921A1 (en) | 2019-12-19 | 2021-06-24 | F. Hoffmann-La Roche Ag | Use of cops3 inhibitors for treating hepatitis b virus infection |
| JP2023506954A (ja) | 2019-12-19 | 2023-02-20 | エフ． ホフマン－ラ ロシュ エージー． | Ｂ型肝炎ウイルス感染を処置するためのｓａｒａｆ阻害剤の使用 |
| EP4077672A1 (en) | 2019-12-20 | 2022-10-26 | F. Hoffmann-La Roche AG | Enhanced oligonucleotides for inhibiting scn9a expression |
| EP4081217A1 (en) | 2019-12-24 | 2022-11-02 | F. Hoffmann-La Roche AG | Pharmaceutical combination of antiviral agents targeting hbv and/or an immune modulator for treatment of hbv |
| MX2022007908A (es) | 2019-12-24 | 2022-07-21 | Hoffmann La Roche | Combinacion farmaceutica de un oligonucleotido terapeutico que actua sobre hbv y un agonista de tlr7 para el tratamiento de hbv. |
| WO2021154941A1 (en) | 2020-01-31 | 2021-08-05 | Alnylam Pharmaceuticals, Inc. | Complement component c5 irna compositions for use in the treatment of amyotrophic lateral sclerosis (als) |
| KR20220133925A (ko) | 2020-01-31 | 2022-10-05 | 가부시키가이샤산와카가쿠켄큐쇼 | Atn1의 안티센스 올리고뉴클레오티드 |
| WO2021158810A1 (en) | 2020-02-05 | 2021-08-12 | Bristol-Myers Squibb Company | Oligonucleotides for splice modulation of camk2d |
| IL295445A (en) | 2020-02-10 | 2022-10-01 | Alnylam Pharmaceuticals Inc | Preparations and methods for silencing vegf-a expression |
| JP7735288B2 (ja) | 2020-02-18 | 2025-09-08 | アルナイラム ファーマシューティカルズ， インコーポレイテッド | アポリポタンパク質Ｃ３（ＡＰＯＣ３）ｉＲＮＡ組成物およびその使用法 |
| CN120505310A (zh) | 2020-02-28 | 2025-08-19 | Ionis制药公司 | 用于调节smn2的化合物和方法 |
| EP4110916A1 (en) | 2020-02-28 | 2023-01-04 | F. Hoffmann-La Roche AG | Oligonucleotides for modulating cd73 exon 7 splicing |
| EP4116419A1 (en) | 2020-03-04 | 2023-01-11 | Nissan Chemical Corporation | Antisense oligonucleotide of calm2 |
| EP4114947A1 (en) | 2020-03-05 | 2023-01-11 | Alnylam Pharmaceuticals, Inc. | Complement component c3 irna compositions and methods of use thereof for treating or preventing complement component c3-associated diseases |
| CN115461460A (zh) | 2020-03-06 | 2022-12-09 | 阿尔尼拉姆医药品有限公司 | 用于抑制转甲状腺素蛋白(ttr)的表达的组合物和方法 |
| BR112022017822A2 (pt) | 2020-03-06 | 2022-11-08 | Alnylam Pharmaceuticals Inc | Composições de irna de cetoexocinase (khk) e métodos de uso das mesmas |
| WO2021184021A1 (en) | 2020-03-13 | 2021-09-16 | Codiak Biosciences, Inc. | Extracellular vesicle-aso constructs targeting pmp22 |
| WO2021184020A1 (en) | 2020-03-13 | 2021-09-16 | Codiak Biosciences, Inc. | Methods of treating neuroinflammation |
| EP4121534A1 (en) | 2020-03-18 | 2023-01-25 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for treating subjects having a heterozygous alanine-glyoxylate aminotransferase gene (agxt) variant |
| TW202204615A (zh) | 2020-03-26 | 2022-02-01 | 美商阿尼拉製藥公司 | 冠狀病毒ｉＲＮＡ組成物及其使用方法 |
| US20230190785A1 (en) | 2020-03-30 | 2023-06-22 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for silencing dnajc15 gene expression |
| US20240092821A1 (en) | 2020-03-31 | 2024-03-21 | Janssen Biopharma, Inc. | Synthesis of oligonucleotides and related compounds |
| US12534731B2 (en) | 2020-04-01 | 2026-01-27 | Alnylam Pharmaceuticals, Inc. | Alpha-2A adrenergic receptor (ADRA2A) iRNA agent compositions and methods of use thereof |
| KR20230008729A (ko) | 2020-04-06 | 2023-01-16 | 알닐람 파마슈티칼스 인코포레이티드 | Myoc 발현을 사일런싱하기 위한 조성물 및 방법 |
| EP4133077A1 (en) | 2020-04-07 | 2023-02-15 | Alnylam Pharmaceuticals, Inc. | Transmembrane serine protease 2 (tmprss2) irna compositions and methods of use thereof |
| JP2023521094A (ja) | 2020-04-07 | 2023-05-23 | アルナイラム ファーマシューティカルズ， インコーポレイテッド | Ｓｃｎ９ａ発現をサイレンシングするための組成物および方法 |
| EP4133076A1 (en) | 2020-04-07 | 2023-02-15 | Alnylam Pharmaceuticals, Inc. | Angiotensin-converting enzyme 2 (ace2) irna compositions and methods of use thereof |
| CN115916262A (zh) | 2020-04-21 | 2023-04-04 | 旗舰创业股份有限公司 | 双官能分子及其使用方法 |
| IL297702A (en) | 2020-04-27 | 2022-12-01 | Alnylam Pharmaceuticals Inc | Apolipoprotein e (apoe) irna agent compositions and methods of use thereof |
| JP2023523790A (ja) | 2020-04-30 | 2023-06-07 | アルナイラム ファーマシューティカルズ， インコーポレイテッド | 補体因子Ｂ（ＣＦＢ）ｉＲＮＡ組成物およびその使用方法 |
| CN115867657A (zh) | 2020-05-11 | 2023-03-28 | 斯托克制药公司 | 用于治疗疾患和疾病的opa1反义寡聚物 |
| JP2023525770A (ja) | 2020-05-11 | 2023-06-19 | ジェネンテック， インコーポレイテッド | 神経学的疾患を処置するための補体ｃ４阻害剤および関連する組成物、ならびにそれを使用するシステムおよび方法 |
| WO2021231210A1 (en) | 2020-05-11 | 2021-11-18 | Genentech, Inc. | Complement component c1r inhibitors for treating a neurological disease, and related compositions, systems and methods of using same |
| EP4149486A1 (en) | 2020-05-11 | 2023-03-22 | Genentech, Inc. | Complement component c1s inhibitors for treating a neurological disease, and related compositions, systems and methods of using same |
| JP7776420B2 (ja) | 2020-05-12 | 2025-11-26 | 田辺三菱製薬株式会社 | Ａｔａｘｉｎ ３発現を調節するための化合物、方法及び医薬組成物 |
| WO2021229036A1 (en) | 2020-05-13 | 2021-11-18 | F. Hoffmann-La Roche Ag | Oligonucleotide agonists targeting progranulin |
| WO2021231698A1 (en) | 2020-05-15 | 2021-11-18 | Korro Bio, Inc. | Methods and compositions for the adar-mediated editing of argininosuccinate lyase (asl) |
| WO2021231673A1 (en) | 2020-05-15 | 2021-11-18 | Korro Bio, Inc. | Methods and compositions for the adar-mediated editing of leucine rich repeat kinase 2 (lrrk2) |
| WO2021231691A1 (en) | 2020-05-15 | 2021-11-18 | Korro Bio, Inc. | Methods and compositions for the adar-mediated editing of retinoschisin 1 (rsi) |
| WO2021231680A1 (en) | 2020-05-15 | 2021-11-18 | Korro Bio, Inc. | Methods and compositions for the adar-mediated editing of methyl-cpg binding protein 2 (mecp2) |
| WO2021231675A1 (en) | 2020-05-15 | 2021-11-18 | Korro Bio, Inc. | Methods and compositions for the adar-mediated editing of argininosuccinate synthetase (ass1) |
| WO2021231685A1 (en) | 2020-05-15 | 2021-11-18 | Korro Bio, Inc. | Methods and compositions for the adar-mediated editing of transmembrane channel-like protein 1 (tmc1) |
| EP4150090A1 (en) | 2020-05-15 | 2023-03-22 | Korro Bio, Inc. | Methods and compositions for the adar-mediated editing of otoferlin (otof) |
| EP4150087A1 (en) | 2020-05-15 | 2023-03-22 | Korro Bio, Inc. | Methods and compositions for the adar-mediated editing of gap junction protein beta 2 (gjb2) |
| US20230183707A1 (en) | 2020-05-21 | 2023-06-15 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting marc1 gene expression |
| CN115884777A (zh) | 2020-05-22 | 2023-03-31 | 豪夫迈·罗氏有限公司 | 用于card9的剪接调节的寡核苷酸 |
| AR122534A1 (es) | 2020-06-03 | 2022-09-21 | Triplet Therapeutics Inc | Métodos para el tratamiento de los trastornos de expansión por repetición de nucleótidos asociados con la actividad de msh3 |
| US20230212572A1 (en) | 2020-06-09 | 2023-07-06 | Roche Innovation Center Copenhagen A/S | Guanosine Analogues for Use in Therapeutics Polynucleotides |
| EP4162050A1 (en) | 2020-06-09 | 2023-04-12 | Alnylam Pharmaceuticals, Inc. | Rnai compositions and methods of use thereof for delivery by inhalation |
| WO2021252649A2 (en) | 2020-06-09 | 2021-12-16 | Alnylam Pharmaceuticals, Inc. | Sirna compositions and methods for silencing gpam (glycerol-3-phosphate acyltransferase 1, mitochondrial) expression |
| WO2021257782A1 (en) | 2020-06-18 | 2021-12-23 | Alnylam Pharmaceuticals, Inc. | XANTHINE DEHYDROGENASE (XDH) iRNA COMPOSITIONS AND METHODS OF USE THEREOF |
| PH12022553569A1 (en) | 2020-06-24 | 2023-04-12 | Humabs Biomed Sa | Engineered hepatitis b virus neutralizing antibodies and uses thereof |
| IL299074A (en) | 2020-06-25 | 2023-02-01 | Synthorx Inc | Immuno-oncology therapeutic combination with IL-2 and anti-AGFR antibody conjugates |
| AR122731A1 (es) | 2020-06-26 | 2022-10-05 | Hoffmann La Roche | Oligonucleótidos mejorados para modular la expresión de fubp1 |
| WO2022011214A1 (en) | 2020-07-10 | 2022-01-13 | Alnylam Pharmaceuticals, Inc. | Circular sirnas |
| WO2022008935A1 (en) | 2020-07-10 | 2022-01-13 | Horizon Discovery Limited | Method for producing genetically modified cells |
| KR20230050336A (ko) | 2020-07-10 | 2023-04-14 | 인스티튜트 내셔널 드 라 싼테 에 드 라 리셰르셰 메디칼르 (인 썸) | 뇌전증을 치료하기 위한 방법과 조성물 |
| JP2023534557A (ja) | 2020-07-23 | 2023-08-09 | エフ． ホフマン－ラ ロシュ アーゲー | Ｒｎａ結合タンパク質部位を標的とするオリゴヌクレオチド |
| WO2022018155A1 (en) | 2020-07-23 | 2022-01-27 | F. Hoffmann-La Roche Ag | Lna oligonucleotides for splice modulation of stmn2 |
| CN116157522A (zh) | 2020-08-21 | 2023-05-23 | 豪夫迈·罗氏有限公司 | A1cf抑制剂用于治疗乙型肝炎病毒感染的用途 |
| TW202227102A (zh) | 2020-09-22 | 2022-07-16 | 瑞典商阿斯特捷利康公司 | 治療脂肪肝病之方法 |
| WO2022066847A1 (en) | 2020-09-24 | 2022-03-31 | Alnylam Pharmaceuticals, Inc. | Dipeptidyl peptidase 4 (dpp4) irna compositions and methods of use thereof |
| EP4225917A1 (en) | 2020-10-05 | 2023-08-16 | Alnylam Pharmaceuticals, Inc. | G protein-coupled receptor 75 (gpr75) irna compositions and methods of use thereof |
| US20230364127A1 (en) | 2020-10-06 | 2023-11-16 | Codiak Biosciences, Inc. | Extracellular vesicle-aso constructs targeting stat6 |
| JP2023546010A (ja) | 2020-10-09 | 2023-11-01 | シンソークス， インコーポレイテッド | Ｉｌ－２コンジュゲートを用いた免疫腫瘍療法 |
| IL301611A (en) | 2020-10-09 | 2023-05-01 | Synthorx Inc | Immuno oncology combination therapy with il-2 conjugates and pembrolizumab |
| CA3198823A1 (en) | 2020-10-21 | 2022-04-28 | Alnylam Pharmaceuticals, Inc. | Methods and compositions for treating primary hyperoxaluria |
| CN116761885A (zh) | 2020-10-23 | 2023-09-15 | 斯克利普斯研究所 | 包含非天然核苷酸的多核苷酸的逆转录 |
| EP4232582A1 (en) | 2020-10-23 | 2023-08-30 | Alnylam Pharmaceuticals, Inc. | Mucin 5b (muc5b) irna compositions and methods of use thereof |
| KR20230107625A (ko) | 2020-11-13 | 2023-07-17 | 알닐람 파마슈티칼스 인코포레이티드 | 응고 인자 V(F5) iRNA 조성물 및 이의 사용 방법 |
| LT4136092T (lt) | 2020-11-18 | 2024-09-25 | Ionis Pharmaceuticals, Inc. | Junginiai ir būdai, skirti angiotenzinogeno raiškos moduliavimui |
| JP2023550935A (ja) | 2020-11-18 | 2023-12-06 | レンバ・ベーフェー | Ｕｍｌｉｌｏアンチセンス転写阻害剤 |
| EP4247949A1 (en) | 2020-11-23 | 2023-09-27 | Alpha Anomeric SAS | Nucleic acid duplexes |
| TW202237150A (zh) | 2020-12-01 | 2022-10-01 | 美商艾拉倫製藥股份有限公司 | 用於抑制ｈａｏ１（羥基酸氧化酶１（乙醇酸氧化酶））基因表現的方法及組成物 |
| AR124229A1 (es) | 2020-12-03 | 2023-03-01 | Hoffmann La Roche | Oligonucleótidos antisentido que actúan sobre atxn3 |
| US20230060373A1 (en) | 2020-12-03 | 2023-03-02 | Hoffmann-La Roche Inc. | Antisense Oligonucleotides Targeting ATXN3 |
| WO2022125490A1 (en) | 2020-12-08 | 2022-06-16 | Alnylam Pharmaceuticals, Inc. | Coagulation factor x (f10) irna compositions and methods of use thereof |
| WO2022122613A1 (en) | 2020-12-08 | 2022-06-16 | F. Hoffmann-La Roche Ag | Novel synthesis of phosphorodithioate oligonucleotides |
| GB2603454A (en) | 2020-12-09 | 2022-08-10 | Ucl Business Ltd | Novel therapeutics for the treatment of neurodegenerative disorders |
| CR20230308A (es) | 2020-12-11 | 2023-09-08 | Civi Biopharma Inc | Entrega oral de conjugados antisentido que tienen por blanco a pcsk9 |
| CN116472276A (zh) | 2020-12-11 | 2023-07-21 | 雅玛山酱油株式会社 | 胞嘧啶型交联型核苷亚磷酰胺晶体及其制造方法 |
| AR124378A1 (es) | 2020-12-18 | 2023-03-22 | Hoffmann La Roche | Oligonucleótidos antisentido dirigida a progranulina |
| WO2022133278A2 (en) | 2020-12-18 | 2022-06-23 | Ionis Pharmaceuticals, Inc. | Compounds and methods for modulating factor xii |
| CN116601308A (zh) | 2020-12-22 | 2023-08-15 | 豪夫迈·罗氏有限公司 | 使用大斯托克斯位移荧光染料进行多重实时pcr的方法 |
| WO2022136140A1 (en) | 2020-12-22 | 2022-06-30 | F. Hoffmann-La Roche Ag | Oligonucleotides targeting xbp1 |
| EP4271696A2 (en) | 2020-12-31 | 2023-11-08 | Alnylam Pharmaceuticals, Inc. | Cyclic-disulfide modified phosphate based oligonucleotide prodrugs |
| EP4271695A2 (en) | 2020-12-31 | 2023-11-08 | Alnylam Pharmaceuticals, Inc. | 2'-modified nucleoside based oligonucleotide prodrugs |
| EP4274896A1 (en) | 2021-01-05 | 2023-11-15 | Alnylam Pharmaceuticals, Inc. | Complement component 9 (c9) irna compositions and methods of use thereof |
| EP4277933A4 (en) | 2021-01-14 | 2024-12-11 | Senti Biosciences, Inc. | SECRETABLE PAYLOAD REGULATION |
| TW202246500A (zh) | 2021-02-02 | 2022-12-01 | 瑞士商赫孚孟拉羅股份公司 | 用於抑制 ｒｔｅｌ１ 表現之增強型寡核苷酸 |
| WO2022174102A1 (en) | 2021-02-12 | 2022-08-18 | Synthorx, Inc. | Lung cancer combination therapy with il-2 conjugates and an anti-pd-1 antibody or antigen-binding fragment thereof |
| EP4291654A2 (en) | 2021-02-12 | 2023-12-20 | Alnylam Pharmaceuticals, Inc. | Superoxide dismutase 1 (sod1) irna compositions and methods of use thereof for treating or preventing superoxide dismutase 1- (sod1-) associated neurodegenerative diseases |
| TW202245843A (zh) | 2021-02-12 | 2022-12-01 | 美商欣爍克斯公司 | Ｉｌ－２接合物及西米普利單抗（ｃｅｍｉｐｌｉｍａｂ）之皮膚癌組合療法 |
| EP4294456A1 (en) | 2021-02-17 | 2023-12-27 | Lonza Sales AG | Extracellular vesicle linked to a biologically active molecule via an optimized linker and an anchoring moiety |
| CA3207944A1 (en) | 2021-02-17 | 2022-08-25 | Ajay Verma | Extracellular vesicle-nlrp3 antagonist |
| EP4298220A1 (en) | 2021-02-25 | 2024-01-03 | Alnylam Pharmaceuticals, Inc. | Prion protein (prnp) irna compositions and methods of use thereof |
| AU2022226098A1 (en) | 2021-02-26 | 2023-08-24 | Alnylam Pharmaceuticals, Inc. | KETOHEXOKINASE (KHK) iRNA COMPOSITIONS AND METHODS OF USE THEREOF |
| JP2024508896A (ja) | 2021-03-04 | 2024-02-28 | アルナイラム ファーマシューティカルズ， インコーポレイテッド | アンジオポエチン様３（ＡＮＧＰＴＬ３）ｉＲＮＡ組成物およびその使用方法 |
| WO2022192038A1 (en) | 2021-03-12 | 2022-09-15 | Northwestern University | Antiviral vaccines using spherical nucleic acids |
| WO2022192519A1 (en) | 2021-03-12 | 2022-09-15 | Alnylam Pharmaceuticals, Inc. | Glycogen synthase kinase 3 alpha (gsk3a) irna compositions and methods of use thereof |
| US20220290221A1 (en) | 2021-03-15 | 2022-09-15 | Roche Molecular Systems, Inc. | Compositions and methods for detecting severe acute respiratory syndrome coronavirus 2 (sars-cov-2) variants having spike protein mutations |
| EP4314296A2 (en) | 2021-03-29 | 2024-02-07 | Alnylam Pharmaceuticals, Inc. | Huntingtin (htt) irna agent compositions and methods of use thereof |
| EP4314016A1 (en) | 2021-03-31 | 2024-02-07 | Entrada Therapeutics, Inc. | Cyclic cell penetrating peptides |
| EP4314293A1 (en) | 2021-04-01 | 2024-02-07 | Alnylam Pharmaceuticals, Inc. | Proline dehydrogenase 2 (prodh2) irna compositions and methods of use thereof |
| KR20230166101A (ko) | 2021-04-01 | 2023-12-06 | 론자 세일즈 아게 | 세포외 소포 조성물 |
| EP4330392A1 (en) | 2021-04-26 | 2024-03-06 | Alnylam Pharmaceuticals, Inc. | Transmembrane protease, serine 6 (tmprss6) irna compositions and methods of use thereof |
| WO2022232343A1 (en) | 2021-04-29 | 2022-11-03 | Alnylam Pharmaceuticals, Inc. | Signal transducer and activator of transcription factor 6 (stat6) irna compositions and methods of use thereof |
| WO2022240760A2 (en) | 2021-05-10 | 2022-11-17 | Entrada Therapeutics, Inc. | COMPOSITIONS AND METHODS FOR MODULATING mRNA SPLICING |
| AU2022271873A1 (en) | 2021-05-10 | 2024-01-04 | Entrada Therapeutics, Inc. | Compositions and methods for intracellular therapeutics |
| EP4337263A1 (en) | 2021-05-10 | 2024-03-20 | Entrada Therapeutics, Inc. | Compositions and methods for modulating interferon regulatory factor-5 (irf-5) activity |
| EP4341401A1 (en) | 2021-05-18 | 2024-03-27 | Alnylam Pharmaceuticals, Inc. | Sodium-glucose cotransporter-2 (sglt2) irna compositions and methods of use thereof |
| EP4341405A1 (en) | 2021-05-20 | 2024-03-27 | Korro Bio, Inc. | Methods and compositions for adar-mediated editing |
| AU2022285344A1 (en) | 2021-05-31 | 2023-12-14 | Rena Therapeutics Inc. | Ligand-bound nucleic acid complex |
| WO2022256283A2 (en) | 2021-06-01 | 2022-12-08 | Korro Bio, Inc. | Methods for restoring protein function using adar |
| EP4347823A1 (en) | 2021-06-02 | 2024-04-10 | Alnylam Pharmaceuticals, Inc. | Patatin-like phospholipase domain containing 3 (pnpla3) irna compositions and methods of use thereof |
| EP4346904A1 (en) | 2021-06-03 | 2024-04-10 | Synthorx, Inc. | Head and neck cancer combination therapy comprising an il-2 conjugate and cetuximab |
| KR20240017865A (ko) | 2021-06-04 | 2024-02-08 | 트랜슬레이트 바이오 인코포레이티드 | Mrna 캡핑 효율의 정량적 평가를 위한 분석 |
| EP4347822A2 (en) | 2021-06-04 | 2024-04-10 | Alnylam Pharmaceuticals, Inc. | Human chromosome 9 open reading frame 72 (c9orf72) irna agent compositions and methods of use thereof |
| AR126070A1 (es) | 2021-06-08 | 2023-09-06 | Alnylam Pharmaceuticals Inc | Composiciones y métodos para tratar o prevenir la enfermedad de stargardt y/o trastornos asociados con la proteína transportadora de retinol 4 (rbp4) |
| CA3222546A1 (en) | 2021-06-08 | 2022-12-15 | F. Hoffmann-La Roche Ag | Oligonucleotide progranulin agonists |
| WO2022261292A1 (en) | 2021-06-10 | 2022-12-15 | Intellia Therapeutics, Inc. | Modified guide rnas comprising an internal linker for gene editing |
| AU2022290382A1 (en) | 2021-06-11 | 2023-11-23 | Bayer Aktiengesellschaft | Type v rna programmable endonuclease systems |
| EP4101928A1 (en) | 2021-06-11 | 2022-12-14 | Bayer AG | Type v rna programmable endonuclease systems |
| US12104159B2 (en) | 2021-06-22 | 2024-10-01 | AcuraStem Incorporated | PIKFYVE antisense oligonucleotides |
| AU2022298774A1 (en) | 2021-06-23 | 2023-12-14 | Entrada Therapeutics, Inc. | Antisense compounds and methods for targeting cug repeats |
| US20230194709A9 (en) | 2021-06-29 | 2023-06-22 | Seagate Technology Llc | Range information detection using coherent pulse sets with selected waveform characteristics |
| EP4363574A1 (en) | 2021-06-29 | 2024-05-08 | Korro Bio, Inc. | Methods and compositions for adar-mediated editing |
| AU2022303164A1 (en) | 2021-06-30 | 2024-01-18 | Alnylam Pharmaceuticals, Inc. | Methods and compositions for treating an angiotensinogen- (agt-) associated disorder |
| WO2023283403A2 (en) | 2021-07-09 | 2023-01-12 | Alnylam Pharmaceuticals, Inc. | Bis-rnai compounds for cns delivery |
| WO2023003805A1 (en) | 2021-07-19 | 2023-01-26 | Alnylam Pharmaceuticals, Inc. | Methods and compositions for treating subjects having or at risk of developing a non-primary hyperoxaluria disease or disorder |
| MX2024000981A (es) | 2021-07-21 | 2024-02-12 | Alnylam Pharmaceuticals Inc | Composiciones de acido ribonucleico de interferencia (arni) de gen diana asociado con trastorno metabolico y sus metodos de uso. |
| WO2023004049A1 (en) | 2021-07-21 | 2023-01-26 | AcuraStem, Inc. | Unc13a antisense oligonucleotides |
| AU2022316139A1 (en) | 2021-07-23 | 2024-01-18 | Alnylam Pharmaceuticals, Inc. | Beta-catenin (ctnnb1) irna compositions and methods of use thereof |
| WO2023009687A1 (en) | 2021-07-29 | 2023-02-02 | Alnylam Pharmaceuticals, Inc. | 3-hydroxy-3-methylglutaryl-coa reductase (hmgcr) irna compositions and methods of use thereof |
| CA3227852A1 (en) | 2021-08-03 | 2023-02-09 | Alnylam Pharmaceuticals, Inc. | Transthyretin (ttr) irna compositions and methods of use thereof |
| EP4381071A1 (en) | 2021-08-04 | 2024-06-12 | Alnylam Pharmaceuticals, Inc. | Irna compositions and methods for silencing angiotensinogen (agt) |
| CN118076737A (zh) | 2021-08-13 | 2024-05-24 | 阿尔尼拉姆医药品有限公司 | 因子XII（F12）iRNA组合物及其使用方法 |
| WO2023021046A1 (en) | 2021-08-16 | 2023-02-23 | Vib Vzw | Oligonucleotides for modulating synaptogyrin-3 expression |
| JP2024538859A (ja) | 2021-08-31 | 2024-10-24 | アルナイラム ファーマシューティカルズ， インコーポレイテッド | 細胞死誘導ＤＦＦＡ様エフェクターＢ（ＣＩＤＥＢ）ｉＲＮＡ組成物およびその使用方法 |
| WO2023034870A2 (en) | 2021-09-01 | 2023-03-09 | Ionis Pharmaceuticals, Inc. | Compounds and methods for reducing dmpk expression |
| MX2024002640A (es) | 2021-09-01 | 2024-07-19 | Entrada Therapeutics Inc | Compuestos y metodos para salto de exon 44 en la distrofia muscular de duchenne. |
| EP4144841A1 (en) | 2021-09-07 | 2023-03-08 | Bayer AG | Novel small rna programmable endonuclease systems with impoved pam specificity and uses thereof |
| KR20240058112A (ko) | 2021-09-17 | 2024-05-03 | 주식회사 씨젠 | 합성 비자연 염기를 포함하는 태그 올리고뉴클레오타이드를 이용한 타겟 핵산 서열의 검출 |
| JP2024535850A (ja) | 2021-09-17 | 2024-10-02 | アルナイラム ファーマシューティカルズ， インコーポレイテッド | 補体成分（Ｃ３）をサイレンシングするためのｉＲＮＡ組成物および方法 |
| AU2022345881A1 (en) | 2021-09-20 | 2024-03-21 | Alnylam Pharmaceuticals, Inc. | Inhibin subunit beta e (inhbe) modulator compositions and methods of use thereof |
| TW202328449A (zh) | 2021-09-24 | 2023-07-16 | 美商艾拉倫製藥公司 | 微管相關蛋白ＴＡＵ（ＭＡＰＴ）ｉＲＮＡ試劑組合物及其使用方法 |
| JP2024536132A (ja) | 2021-09-29 | 2024-10-04 | エフ． ホフマン－ラ ロシュ アーゲー | Ｒｎａ編集方法 |
| US12042509B2 (en) | 2021-10-01 | 2024-07-23 | Adarx Pharmaceuticals, Inc. | Prekallikrein-modulating compositions and methods of use thereof |
| CN118369427A (zh) | 2021-10-15 | 2024-07-19 | 阿尔尼拉姆医药品有限公司 | 肝外递送irna组合物及其使用方法 |
| WO2023069603A1 (en) | 2021-10-22 | 2023-04-27 | Korro Bio, Inc. | Methods and compositions for disrupting nrf2-keap1 protein interaction by adar mediated rna editing |
| CN118302525A (zh) | 2021-10-29 | 2024-07-05 | 阿尔尼拉姆医药品有限公司 | 补体因子B（CFB）iRNA组合物及其使用方法 |
| EP4423272A2 (en) | 2021-10-29 | 2024-09-04 | Alnylam Pharmaceuticals, Inc. | Huntingtin (htt) irna agent compositions and methods of use thereof |
| CN118318042A (zh) | 2021-11-03 | 2024-07-09 | 豪夫迈·罗氏有限公司 | 用于调节载脂蛋白e4表达的寡核苷酸 |
| CA3237770A1 (en) | 2021-11-10 | 2023-05-19 | University Of Rochester | Antisense oligonucleotides for modifying protein expression |
| US20250019702A1 (en) | 2021-11-10 | 2025-01-16 | University Of Rochester | Gata4-targeted therapeutics for treatment of cardiac hypertrophy |
| KR20240101580A9 (ko) | 2021-11-11 | 2025-12-10 | 에프. 호프만-라 로슈 아게 | Hbv 치료를 위한 약학 조합물 |
| EP4441224A4 (en) | 2021-12-03 | 2026-03-11 | Quralis Corp | Antisense oligonucleotides with modified skeletal chemicals |
| WO2023104693A1 (en) | 2021-12-07 | 2023-06-15 | F. Hoffmann-La Roche Ag | Antisense oligonucleotides targeting actl6b |
| GB202117758D0 (en) | 2021-12-09 | 2022-01-26 | Ucl Business Ltd | Therapeutics for the treatment of neurodegenerative disorders |
| CN118369437B (zh) | 2021-12-10 | 2025-03-25 | 日东纺绩株式会社 | 用于检测核酸的对象碱基序列中的变异的方法、选择性地抑制核酸的扩增的方法、及用于实施这些的试剂盒 |
| KR102731759B1 (ko) | 2021-12-10 | 2024-11-21 | 니토 보세키 가부시기가이샤 | 핵산의 대상 염기 서열 중에 있어서의 변이를 검출하기 위한 방법, 핵산의 증폭을 선택적으로 저해하는 방법, 및 이것들을 실시하기 위한 키트 |
| JP2024546887A (ja) | 2021-12-17 | 2024-12-26 | ジェネンテック， インコーポレイテッド | オリゴヌクレオチドｇｂａアゴニスト |
| WO2023111210A1 (en) | 2021-12-17 | 2023-06-22 | F. Hoffmann-La Roche Ag | Combination of oligonucleotides for modulating rtel1 and fubp1 |
| WO2023117738A1 (en) | 2021-12-20 | 2023-06-29 | F. Hoffmann-La Roche Ag | Threose nucleic acid antisense oligonucleotides and methods thereof |
| EP4452327A1 (en) | 2021-12-20 | 2024-10-30 | Synthorx, Inc. | Head and neck cancer combination therapy comprising an il-2 conjugate and pembrolizumab |
| KR20240126870A (ko) | 2021-12-22 | 2024-08-21 | 캠프4 테라퓨틱스 코포레이션 | 조절 rna들을 표적으로 하는 안티센스 올리고뉴클레오티드를 사용한 유전자 전사의 조절 |
| US20250066436A1 (en) | 2021-12-22 | 2025-02-27 | Royal College Of Surgeons In Ireland | A conjugate for use in localising a molecule to the vascular endothelium |
| EP4453191A1 (en) | 2021-12-23 | 2024-10-30 | Bayer Aktiengesellschaft | Novel small type v rna programmable endonuclease systems |
| WO2023122750A1 (en) | 2021-12-23 | 2023-06-29 | Synthorx, Inc. | Cancer combination therapy with il-2 conjugates and cetuximab |
| TW202340468A (zh) | 2022-01-10 | 2023-10-16 | 中國大陸商杭州浩博醫藥有限公司 | B型肝炎病毒(hbv)表現之調節 |
| WO2023141507A1 (en) | 2022-01-20 | 2023-07-27 | Genentech, Inc. | Antisense oligonucleotides for modulating tmem106b expression |
| WO2023141314A2 (en) | 2022-01-24 | 2023-07-27 | Alnylam Pharmaceuticals, Inc. | Heparin sulfate biosynthesis pathway enzyme irna agent compositions and methods of use thereof |
| WO2023152369A1 (en) | 2022-02-14 | 2023-08-17 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Nucleic acid mir-9 inhibitor for the treatment of cystic fibrosis |
| AR128558A1 (es) | 2022-02-21 | 2024-05-22 | Hoffmann La Roche | Oligonucleótido antisentido |
| WO2023212625A1 (en) | 2022-04-28 | 2023-11-02 | AcuraStem Incorporated | Syf2 antisense oligonucleotides |
| CN119173632A (zh) | 2022-05-10 | 2024-12-20 | 豪夫迈·罗氏有限公司 | 靶向cfp-elk1基因间区域的反义寡核苷酸 |
| EP4522742A2 (en) | 2022-05-13 | 2025-03-19 | Alnylam Pharmaceuticals, Inc. | Single-stranded loop oligonucleotides |
| WO2023222858A1 (en) | 2022-05-18 | 2023-11-23 | F. Hoffmann-La Roche Ag | Improved oligonucleotides targeting rna binding protein sites |
| IL317425A (en) | 2022-06-10 | 2025-02-01 | Camp4 Therapeutics Corp | Methods of modulating progranulin expression using antisense oligonucleotides targeting regulatory RNAs |
| CN119403922A (zh) | 2022-06-10 | 2025-02-07 | 拜耳公司 | 新的小型v型rna可编程内切核酸酶系统 |
| CN119365600A (zh) | 2022-06-17 | 2025-01-24 | 豪夫迈·罗氏有限公司 | 靶向颗粒蛋白前体的反义寡核苷酸 |
| JP2025522880A (ja) | 2022-06-30 | 2025-07-17 | アルナイラム ファーマシューティカルズ， インコーポレイテッド | 環状ジスルフィド修飾リン酸ベースのオリゴヌクレオチドプロドラッグ |
| CN119855910A (zh) | 2022-07-06 | 2025-04-18 | 美国微哲默理有限责任公司 | 用于治疗胰腺癌的组合物和方法 |
| WO2024017990A1 (en) | 2022-07-21 | 2024-01-25 | Institut National de la Santé et de la Recherche Médicale | Methods and compositions for treating chronic pain disorders |
| WO2024040041A1 (en) | 2022-08-15 | 2024-02-22 | Dicerna Pharmaceuticals, Inc. | Regulation of activity of rnai molecules |
| WO2024039776A2 (en) | 2022-08-18 | 2024-02-22 | Alnylam Pharmaceuticals, Inc. | Universal non-targeting sirna compositions and methods of use thereof |
| EP4332221A1 (en) | 2022-08-29 | 2024-03-06 | Roche Innovation Center Copenhagen A/S | Threose nucleic acid antisense oligonucleotides and methods thereof |
| WO2024050261A1 (en) | 2022-08-29 | 2024-03-07 | University Of Rochester | Antisense oligonucleotide-based anti-fibrotic therapeutics |
| KR20250059413A (ko) | 2022-09-06 | 2025-05-02 | 에프. 호프만-라 로슈 아게 | 눈에 투여하기 위한 이중 가닥 rna 분자 |
| EP4569113A1 (en) | 2022-09-15 | 2025-06-18 | Regeneron Pharmaceuticals, Inc. | 17b-hydroxysteroid dehydrogenase type 13 (hsd17b13) irna compositions and methods of use thereof |
| WO2024073732A1 (en) | 2022-09-30 | 2024-04-04 | Alnylam Pharmaceuticals, Inc. | Modified double-stranded rna agents |
| WO2024073042A1 (en) | 2022-09-30 | 2024-04-04 | Entrada Therapeutics, Inc. | Ocular delivery of therapeutic agents |
| WO2024098061A2 (en) | 2022-11-04 | 2024-05-10 | Genkardia Inc. | Oligonucleotide-based therapeutics targeting cyclin d2 for the treatment of heart failure |
| WO2024101446A1 (ja) | 2022-11-10 | 2024-05-16 | ルクサナバイオテク株式会社 | 架橋部にグアニジノ構造を有する修飾ヌクレオシドおよびそれを用いたオリゴヌクレオチドの製造方法 |
| JP2025539043A (ja) | 2022-11-14 | 2025-12-03 | バイオンテック・エスイー | Ｒｎａキャッピング効率アッセイ |
| EP4627084A1 (en) | 2022-12-01 | 2025-10-08 | Camp4 Therapeutics Corporation | Modulation of syngap1 gene transcription using antisense oligonucleotides targeting regulatory rnas |
| WO2024126654A1 (en) | 2022-12-14 | 2024-06-20 | F. Hoffmann-La Roche Ag | Antisense oligonucleotides targeting actl6b |
| WO2024136899A1 (en) | 2022-12-21 | 2024-06-27 | Synthorx, Inc. | Cancer therapy with il-2 conjugates and chimeric antigen receptor therapies |
| EP4646478A1 (en) | 2023-01-06 | 2025-11-12 | Institut National de la Santé et de la Recherche Médicale | Intravenous administration of antisense oligonucleotides for the treatment of pain |
| EP4652276A2 (en) | 2023-01-20 | 2025-11-26 | AcuraStem Incorporated | Unc13a antisense oligonucleotides |
| WO2024160756A1 (en) | 2023-01-30 | 2024-08-08 | Vib Vzw | Suppressors of tauopathies |
| AU2024215901A1 (en) | 2023-01-31 | 2025-07-24 | AcuraStem Incorporated | Syf2 antisense oligonucleotides |
| JP2026505178A (ja) | 2023-01-31 | 2026-02-12 | セキラス インコーポレイテッド | キャップ形成アッセイ |
| WO2024167945A1 (en) | 2023-02-06 | 2024-08-15 | AcuraStem Incorporated | Pikfyve antisense oligonucleotides |
| TW202449152A (zh) | 2023-02-09 | 2024-12-16 | 美商艾拉倫製藥股份有限公司 | Ｒｅｖｅｒｓｉｒ分子及其使用方法 |
| EP4669750A2 (en) | 2023-02-21 | 2025-12-31 | Vib Vzw | SYNAPTOGYRIN-3 EXPRESSION INHIBITORS |
| WO2024175588A1 (en) | 2023-02-21 | 2024-08-29 | Vib Vzw | Oligonucleotides for modulating synaptogyrin-3 expression |
| WO2024175707A1 (en) | 2023-02-22 | 2024-08-29 | Helmholtz-Zentrum für Infektionsforschung GmbH | A synthetic oligonucleotide for treating nidovirales infections |
| CN121263208A (zh) | 2023-03-20 | 2026-01-02 | 新索思股份有限公司 | 使用il-2 peg缀合物的癌症疗法 |
| KR20260009305A (ko) | 2023-04-12 | 2026-01-19 | 알닐람 파마슈티칼스 인코포레이티드 | 이중 가닥 rna 제제의 간외 전달 |
| TW202448484A (zh) | 2023-04-20 | 2024-12-16 | 美商雅迪克斯製藥公司 | Ｍａｐｔ調節組合物及其使用方法 |
| WO2024220746A2 (en) | 2023-04-21 | 2024-10-24 | Flagship Pioneering Innovations Vii, Llc | Rnai agents targeting fatty acid synthase and related methods |
| CN121079412A (zh) | 2023-04-28 | 2025-12-05 | 比姆医疗股份有限公司 | 经修饰的指导rna |
| EP4705457A2 (en) | 2023-05-04 | 2026-03-11 | F. Hoffmann-La Roche AG | Oligonucleotides capable of upregulating glucocerebrosidase expression |
| WO2024231285A1 (en) | 2023-05-05 | 2024-11-14 | BioNTech SE | Method of analysing contaminants in rna products by ion-pair chromatography |
| GB202306715D0 (en) | 2023-05-05 | 2023-06-21 | Univ Dublin | Microfluidic nucleic acid extraction |
| WO2024233864A2 (en) | 2023-05-10 | 2024-11-14 | Dicerna Pharmaceuticals, Inc. | Galnac-conjugated rnai oligonucleotides |
| WO2024238396A1 (en) | 2023-05-12 | 2024-11-21 | Adarx Pharmaceuticals, Inc. | Nmda ligand conjugated compounds and uses thereof |
| EP4709855A2 (en) | 2023-05-12 | 2026-03-18 | Alnylam Pharmaceuticals, Inc. | Single-stranded loop oligonucleotides |
| WO2024243062A1 (en) | 2023-05-19 | 2024-11-28 | Streck Llc | Detection of antibiotic resistance genes |
| CN121335980A (zh) | 2023-05-26 | 2026-01-13 | 阿达尔克斯制药有限公司 | Sod1调节组合物及其使用方法 |
| AU2024304484A1 (en) | 2023-06-14 | 2026-02-05 | Sanofi Pasteur Inc. | Methods of simultaneously identifying or quantifying capping and tailing modifications of messenger rna |
| TW202516004A (zh) | 2023-06-16 | 2025-04-16 | 瑞士商赫孚孟拉羅股份公司 | 調節ｊａｋ１表現之雙股寡核苷酸 |
| EP4731763A1 (en) | 2023-06-20 | 2026-04-29 | Adarx Pharmaceuticals, Inc. | Lrrk2-modulating compositions and methods of use thereof |
| JPWO2025005265A1 (pt) * | 2023-06-30 | 2025-01-02 | ||
| WO2025008406A1 (en) | 2023-07-04 | 2025-01-09 | Institut National de la Santé et de la Recherche Médicale | Antisense oligonucleotides and their use for the treatment of cancer |
| WO2025015335A1 (en) | 2023-07-13 | 2025-01-16 | Korro Bio, Inc. | Rna-editing oligonucleotides and uses thereof |
| AU2024299328A1 (en) | 2023-07-21 | 2026-01-22 | Marrow Therapeutics, Inc. | Hematopoietic cell targeting conjugates and related methods |
| KR20260044217A (ko) | 2023-07-25 | 2026-04-01 | 플래그쉽 파이어니어링 이노베이션스 Vii, 엘엘씨 | Cas 엔도뉴클레아제 및 관련 방법 |
| WO2025024493A1 (en) | 2023-07-25 | 2025-01-30 | Flagship Pioneering Innovations Vii, Llc | Cas endonucleases and related methods |
| KR20260049597A (ko) | 2023-08-04 | 2026-04-14 | 알닐람 파마슈티칼스 인코포레이티드 | Ctnnb1-관련 질환을 치료하기 위한 방법 및 조성물 |
| WO2025038901A1 (en) | 2023-08-17 | 2025-02-20 | Entrada Therapeutics, Inc. | Cyclic peptides for delivering therapeutics |
| AU2024325879A1 (en) | 2023-08-17 | 2026-03-12 | Entrada Therapeutics, Inc. | Intracellular targeting of oligonucleotides |
| WO2025047953A1 (ja) | 2023-08-30 | 2025-03-06 | 株式会社Stratoimmune | ＲａｓＧＲＰ４のアンチセンスオリゴヌクレオチド |
| WO2025054459A1 (en) | 2023-09-08 | 2025-03-13 | Dicerna Pharmaceuticals, Inc. | Rnai oligonucleotide conjugates |
| WO2025061842A1 (en) | 2023-09-19 | 2025-03-27 | Charité - Universitätsmedizin Berlin | Gene editing tgm1 mutations for treating autosomal recessive congenital ichthyosis (arci) |
| WO2025064660A2 (en) | 2023-09-21 | 2025-03-27 | Alnylam Pharmaceuticals, Inc. | Activin a receptor type 1c (acvr1c) irna compositions and methods of use thereof |
| WO2025072331A1 (en) | 2023-09-26 | 2025-04-03 | Flagship Pioneering Innovations Vii, Llc | Cas nucleases and related methods |
| WO2025072246A1 (en) | 2023-09-26 | 2025-04-03 | Entrada Therapeutics, Inc. | Compounds and methods for skipping exon 50 in duchenne muscular dystrophy |
| WO2025076031A2 (en) | 2023-10-03 | 2025-04-10 | Alnylam Pharmaceuticals, Inc. | Peritoneal macrophages comprising a nanoparticle encapsulating a nucleic acid molecule and methods of use thereof |
| AU2024354241A1 (en) | 2023-10-04 | 2026-04-23 | Lemba Bv | Compounds for inhibition of il-1beta expression |
| US20250115909A1 (en) | 2023-10-04 | 2025-04-10 | Lemba Bv | Compounds for inhibiting amanzi |
| WO2025080939A1 (en) | 2023-10-13 | 2025-04-17 | Ultragenyx Pharmaceutical, Inc. | Compositions and methods for treating conditions associated with cartilage oligomeric matrix protein (comp) mutations |
| WO2025096809A1 (en) | 2023-10-31 | 2025-05-08 | Korro Bio, Inc. | Oligonucleotides comprising phosphoramidate internucleotide linkages |
| WO2025101994A2 (en) | 2023-11-10 | 2025-05-15 | Intellia Therapeutics, Inc. | Compositions, methods, and systems for genomic editing |
| WO2025117877A2 (en) | 2023-12-01 | 2025-06-05 | Flagship Pioneering Innovations Vii, Llc | Cas nucleases and related methods |
| WO2025128799A1 (en) | 2023-12-12 | 2025-06-19 | Korro Bio, Inc. | Double-stranded rna-editing oligonucleotides and uses thereof |
| WO2025128853A2 (en) | 2023-12-13 | 2025-06-19 | Ultragenyx Pharmaceutical Inc. | Compositions and methods for treating conditions associated with ube3a overexpression |
| WO2025132962A2 (en) | 2023-12-21 | 2025-06-26 | F. Hoffmann-La Roche Ag | Antisense oligonucleotide |
| GB202400711D0 (en) | 2024-01-18 | 2024-03-06 | Univ Dublin | A method for determining the risk of, or prognosis of, lung, pancreatic, and ovarian cancer, and cutaneous and uveal melanoma. |
| WO2025158385A1 (en) | 2024-01-25 | 2025-07-31 | Genzyme Corporation | Pegylated il-2 for suppressing adaptive immune response to gene therapy |
| WO2025178854A2 (en) | 2024-02-19 | 2025-08-28 | Flagship Pioneering Innovations Vii, Llc | Rnai agents targeting cideb and related methods |
| WO2025199231A2 (en) | 2024-03-20 | 2025-09-25 | Vertex Pharmaceuticals Incorporated | Mucin-5b (muc5b) targeted sirna and antisense oligonucleotides and methods of use thereof |
| WO2025207517A2 (en) | 2024-03-25 | 2025-10-02 | Synthorx, Inc. | Synthetic trna synthetases and cells comprising synthetic molecules for production of polypeptides |
| GB202404290D0 (en) | 2024-03-26 | 2024-05-08 | Senisca Ltd | Novel oligoncleotides |
| WO2025217275A2 (en) | 2024-04-10 | 2025-10-16 | Flagship Pioneering Innovations Vii, Llc | Immune cell targeted compositions and related methods |
| WO2025237990A1 (en) | 2024-05-14 | 2025-11-20 | Institut National de la Santé et de la Recherche Médicale | Antisense oligonucleotides and their use for the treatment of pulmonary fibrosis |
| WO2025252669A1 (en) | 2024-06-03 | 2025-12-11 | Evotec International Gmbh | Modified oligonucleotides for reducing atxn3 expression |
| WO2025255388A1 (en) | 2024-06-05 | 2025-12-11 | Camp4 Therapeutics Corporation | Modulation of syngap1 gene transcription using antisense oligonucleotides targeting regulatory rnas |
| WO2025259747A2 (en) | 2024-06-12 | 2025-12-18 | Alnylam Pharmaceuticals, Inc. | Dystrophy myotonic protein kinase (dmpk) irna compositions and methods of use thereof |
| WO2025259743A1 (en) | 2024-06-12 | 2025-12-18 | Alnylam Pharmaceuticals, Inc. | Dual conjugate compounds for extrahepatic delivery |
| WO2026006436A1 (en) | 2024-06-25 | 2026-01-02 | Korro Bio, Inc. | Methods and compositions for the adar-mediated editing of tar dna binding protein 43 kda (tdp43) |
| WO2026006390A2 (en) | 2024-06-26 | 2026-01-02 | Intellia Therapeutics, Inc. | Modified guide rnas for genome editing |
| WO2026041784A1 (en) | 2024-08-23 | 2026-02-26 | Vib Vzw | Oligonucleotides for modulating synaptogyrin-3 expression |
| WO2026050243A1 (en) | 2024-08-26 | 2026-03-05 | Korro Bio, Inc. | Galnac conjugated oligonucleotides for rna editing |
| WO2026055461A1 (en) | 2024-09-05 | 2026-03-12 | Aperture Therapeutics, Inc. | Antibody oligonucleotide conjugates comprising an antisense polynucleotide agent conjugated to a cd33 antibody and methods of use thereof |
| WO2026052826A1 (en) | 2024-09-09 | 2026-03-12 | Roche Diagnostics Gmbh | Methods for producing fluorescent dyes |
| WO2026057749A1 (en) | 2024-09-11 | 2026-03-19 | Sixfold Bioscience Ltd. | Method and product |
| EP4711455A1 (en) | 2024-09-11 | 2026-03-18 | Aarhus Universitet | Small artificial rna (smartrna) oligonucleotide for modulating protein expression |
| WO2026061986A1 (en) | 2024-09-17 | 2026-03-26 | Institut National de la Santé et de la Recherche Médicale | Antisense oligonucleotide (aso)-mediated down-regulation of cd33 to safely enrich for genetically modified cells |
| WO2026062247A1 (en) | 2024-09-20 | 2026-03-26 | Astrazeneca Ab | Liquid-phase oligonucleotide synthesis using 2-(2-nitrophenyl)propyloxycarbonyl (nppoc) as a protecting group |
| WO2026080323A1 (en) | 2024-10-09 | 2026-04-16 | Quralis Corporation | Treatment of neurological diseases using modulators of unc13a gene transcripts |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5859221A (en) * | 1990-01-11 | 1999-01-12 | Isis Pharmaceuticals, Inc. | 2'-modified oligonucleotides |
| JPH0953409A (ja) † | 1995-08-15 | 1997-02-25 | Mitsubishi Heavy Ind Ltd | ガスタービン用セラミック静翼 |
| GB9612600D0 (en) * | 1996-06-13 | 1996-08-21 | Ciba Geigy Ag | Chemical compounds |
| JP3756313B2 (ja) † | 1997-03-07 | 2006-03-15 | 武 今西 | 新規ビシクロヌクレオシド及びオリゴヌクレオチド類縁体 |
| JP4236812B2 (ja) | 1997-09-12 | 2009-03-11 | エクシコン エ／エス | オリゴヌクレオチド類似体 |
-
1998
- 1998-03-06 JP JP05511498A patent/JP3756313B2/ja not_active Expired - Lifetime
- 1998-03-09 CA CA002283509A patent/CA2283509C/en not_active Expired - Lifetime
- 1998-03-09 DK DK10011863.7T patent/DK2361921T3/en active
- 1998-03-09 PT PT98905804T patent/PT1013661E/pt unknown
- 1998-03-09 ES ES98905804T patent/ES2380354T5/es not_active Expired - Lifetime
- 1998-03-09 DK DK98905804.5T patent/DK1013661T4/en active
- 1998-03-09 DK DK10172971.3T patent/DK2295441T3/da active
- 1998-03-09 EP EP10172971.3A patent/EP2295441B1/en not_active Expired - Lifetime
- 1998-03-09 EP EP98905804.5A patent/EP1013661B2/en not_active Expired - Lifetime
- 1998-03-09 ES ES10011863.7T patent/ES2545211T3/es not_active Expired - Lifetime
- 1998-03-09 US US09/380,638 patent/US6268490B1/en not_active Ceased
- 1998-03-09 EP EP10011863.7A patent/EP2361921B1/en not_active Expired - Lifetime
- 1998-03-09 PT PT101729713T patent/PT2295441E/pt unknown
- 1998-03-09 DE DE98905804T patent/DE98905804T1/de active Pending
- 1998-03-09 WO PCT/JP1998/000945 patent/WO1998039352A1/ja not_active Ceased
- 1998-03-09 AT AT98905804T patent/ATE541576T2/de active
- 1998-03-09 AU AU61209/98A patent/AU720472B2/en not_active Expired
- 1998-03-09 ES ES10172971.3T patent/ES2485716T3/es not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| DK1013661T4 (en) | 2019-01-21 |
| ES2380354T3 (es) | 2012-05-10 |
| US6268490B1 (en) | 2001-07-31 |
| EP2361921A2 (en) | 2011-08-31 |
| DK2295441T3 (da) | 2014-07-21 |
| EP2361921B1 (en) | 2015-06-03 |
| AU720472B2 (en) | 2000-06-01 |
| ES2485716T3 (es) | 2014-08-14 |
| PT2295441E (pt) | 2014-07-25 |
| CA2283509C (en) | 2005-01-04 |
| EP1013661B2 (en) | 2018-10-24 |
| CA2283509A1 (en) | 1998-09-11 |
| JPH10304889A (ja) | 1998-11-17 |
| EP2361921A3 (en) | 2012-06-27 |
| DK2361921T3 (en) | 2015-09-14 |
| ATE541576T2 (de) | 2012-02-15 |
| JP3756313B2 (ja) | 2006-03-15 |
| DE98905804T1 (de) | 2010-08-26 |
| EP1013661A1 (en) | 2000-06-28 |
| HK1154590A1 (en) | 2012-04-27 |
| WO1998039352A1 (en) | 1998-09-11 |
| AU6120998A (en) | 1998-09-22 |
| EP2295441A2 (en) | 2011-03-16 |
| EP2295441A3 (en) | 2011-10-26 |
| DK1013661T3 (da) | 2012-03-19 |
| ES2380354T5 (es) | 2019-04-02 |
| EP1013661A4 (en) | 2000-11-22 |
| ES2545211T3 (es) | 2015-09-09 |
| EP2295441B1 (en) | 2014-05-07 |
| EP1013661B1 (en) | 2012-01-18 |
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