CA2692579A1 - Analogues d'acides nucleiques bicycliques disubstitues en position 6 - Google Patents

Analogues d'acides nucleiques bicycliques disubstitues en position 6 Download PDF

Info

Publication number: CA2692579A1
Authority: CA; Canada
Prior art keywords: alkyl; substituted; oligomeric compound; nj1j2; independently
Prior art date: 2007-07-05
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Granted

Application number

CA 2692579

Other languages

English (en)

Other versions

CA2692579C (fr

Inventor

Eric E. Swayze

Punit P. Seth

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Ionis Pharmaceuticals Inc

Original Assignee

Individual

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

2007-07-05

Filing date

2008-07-01

Publication date

2009-01-08

Family has litigation

First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=40087523&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CA2692579(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

2008-07-01 Application filed by Individual filed Critical Individual

2009-01-08 Publication of CA2692579A1 publication Critical patent/CA2692579A1/fr

2016-05-03 Application granted granted Critical

2016-05-03 Publication of CA2692579C publication Critical patent/CA2692579C/fr

Status Expired - Fee Related legal-status Critical Current

2028-07-01 Anticipated expiration legal-status Critical

Links

-1 6-disubstituted bicyclic nucleic acid Chemical class 0.000 title claims description 187
102000039446 nucleic acids Human genes 0.000 title description 37
108020004707 nucleic acids Proteins 0.000 title description 37
150000001875 compounds Chemical class 0.000 claims abstract description 274
239000002777 nucleoside Substances 0.000 claims abstract description 206
238000000034 method Methods 0.000 claims abstract description 64
125000001424 substituent group Chemical group 0.000 claims abstract description 42
125000003835 nucleoside group Chemical group 0.000 claims description 74
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 63
125000005647 linker group Chemical group 0.000 claims description 45
229910052736 halogen Inorganic materials 0.000 claims description 40
150000002367 halogens Chemical class 0.000 claims description 35
108090000623 proteins and genes Proteins 0.000 claims description 34
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 33
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
125000006239 protecting group Chemical group 0.000 claims description 31
125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 30
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 29
230000014509 gene expression Effects 0.000 claims description 28
125000000623 heterocyclic group Chemical group 0.000 claims description 28
229910052799 carbon Inorganic materials 0.000 claims description 26
239000005549 deoxyribonucleoside Substances 0.000 claims description 25
230000000692 anti-sense effect Effects 0.000 claims description 23
125000004103 aminoalkyl group Chemical group 0.000 claims description 22
108020004999 messenger RNA Proteins 0.000 claims description 21
125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 20
ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical group O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 19
125000006710 (C2-C12) alkenyl group Chemical group 0.000 claims description 18
230000000295 complement effect Effects 0.000 claims description 18
239000000178 monomer Substances 0.000 claims description 18
125000006711 (C2-C12) alkynyl group Chemical group 0.000 claims description 17
230000000694 effects Effects 0.000 claims description 17
150000004713 phosphodiesters Chemical group 0.000 claims description 17
102000004169 proteins and genes Human genes 0.000 claims description 16
RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical group CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 16
RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical group [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims description 15
229940035893 uracil Drugs 0.000 claims description 14
UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 13
125000002743 phosphorus functional group Chemical group 0.000 claims description 13
KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical class N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 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
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
125000004642 (C1-C12) alkoxy group Chemical group 0.000 claims description 10
108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 10
229940104302 cytosine Drugs 0.000 claims description 10
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 9
238000001514 detection method Methods 0.000 claims description 9
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 9
LVUCQZQLDPFLBJ-UHFFFAOYSA-N (2-cyano-3-methyl-2-propan-2-ylbutyl)peroxyphosphonamidous acid Chemical group CC(C)C(C(C)C)(C#N)COOP(N)O LVUCQZQLDPFLBJ-UHFFFAOYSA-N 0.000 claims description 8
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 8
229960000643 adenine Drugs 0.000 claims description 8
ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 8
229930024421 Adenine Natural products 0.000 claims description 7
241001465754 Metazoa Species 0.000 claims description 7
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 6
230000002401 inhibitory effect Effects 0.000 claims description 6
LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical compound CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 claims description 5
MSSXOMSJDRHRMC-UHFFFAOYSA-N 9H-purine-2,6-diamine Chemical compound NC1=NC(N)=C2NC=NC2=N1 MSSXOMSJDRHRMC-UHFFFAOYSA-N 0.000 claims description 5
GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 5
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
150000003212 purines Chemical class 0.000 claims description 5
150000003230 pyrimidines Chemical class 0.000 claims description 5
229940113082 thymine Drugs 0.000 claims description 5
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 5
125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 5
UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 claims description 4
YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 4
125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 claims description 4
125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 claims description 4
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 4
FGIVSGPRGVABAB-UHFFFAOYSA-N fluoren-9-ylmethyl hydrogen carbonate Chemical group C1=CC=C2C(COC(=O)O)C3=CC=CC=C3C2=C1 FGIVSGPRGVABAB-UHFFFAOYSA-N 0.000 claims description 4
125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 4
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 4
FAQJJMHZNSSFSM-UHFFFAOYSA-N phenylglyoxylic acid Chemical group OC(=O)C(=O)C1=CC=CC=C1 FAQJJMHZNSSFSM-UHFFFAOYSA-N 0.000 claims description 4
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 4
125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
UJBCLAXPPIDQEE-UHFFFAOYSA-N 5-prop-1-ynyl-1h-pyrimidine-2,4-dione Chemical group CC#CC1=CNC(=O)NC1=O UJBCLAXPPIDQEE-UHFFFAOYSA-N 0.000 claims description 3
QNNARSZPGNJZIX-UHFFFAOYSA-N 6-amino-5-prop-1-ynyl-1h-pyrimidin-2-one Chemical compound CC#CC1=CNC(=O)N=C1N QNNARSZPGNJZIX-UHFFFAOYSA-N 0.000 claims description 3
108091070501 miRNA Proteins 0.000 claims description 3
239000002679 microRNA Substances 0.000 claims description 3
125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical group [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 3
101710163270 Nuclease Proteins 0.000 abstract description 4
230000002708 enhancing effect Effects 0.000 abstract description 4
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
238000006243 chemical reaction Methods 0.000 description 69
108091034117 Oligonucleotide Proteins 0.000 description 66
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 58
210000004027 cell Anatomy 0.000 description 48
235000019439 ethyl acetate Nutrition 0.000 description 48
239000000243 solution Substances 0.000 description 47
238000003756 stirring Methods 0.000 description 40
150000003833 nucleoside derivatives Chemical class 0.000 description 38
229920002477 rna polymer Polymers 0.000 description 36
150000007523 nucleic acids Chemical class 0.000 description 35
239000012267 brine Substances 0.000 description 34
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 34
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 34
235000000346 sugar Nutrition 0.000 description 31
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 29
125000000217 alkyl group Chemical group 0.000 description 29
238000000746 purification Methods 0.000 description 28
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
239000012044 organic layer Substances 0.000 description 25
239000000523 sample Substances 0.000 description 24
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
125000004432 carbon atom Chemical group C* 0.000 description 21
238000004440 column chromatography Methods 0.000 description 20
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
230000015572 biosynthetic process Effects 0.000 description 16
238000004458 analytical method Methods 0.000 description 15
125000003118 aryl group Chemical group 0.000 description 15
238000003752 polymerase chain reaction Methods 0.000 description 15
238000003786 synthesis reaction Methods 0.000 description 15
HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 14
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 14
108020004414 DNA Proteins 0.000 description 14
102000053602 DNA Human genes 0.000 description 14
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
125000001072 heteroaryl group Chemical group 0.000 description 14
239000000203 mixture Substances 0.000 description 14
238000011282 treatment Methods 0.000 description 14
238000005516 engineering process Methods 0.000 description 13
238000002514 liquid chromatography mass spectrum Methods 0.000 description 13
125000001931 aliphatic group Chemical group 0.000 description 12
125000003342 alkenyl group Chemical group 0.000 description 12
125000005842 heteroatom Chemical group 0.000 description 12
229910052698 phosphorus Inorganic materials 0.000 description 12
239000007787 solid Substances 0.000 description 12
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
125000000304 alkynyl group Chemical group 0.000 description 11
238000003556 assay Methods 0.000 description 11
230000006870 function Effects 0.000 description 11
239000002773 nucleotide Substances 0.000 description 11
238000002360 preparation method Methods 0.000 description 11
125000004122 cyclic group Chemical group 0.000 description 10
239000000975 dye Substances 0.000 description 10
125000000524 functional group Chemical group 0.000 description 10
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 10
125000003729 nucleotide group Chemical group 0.000 description 10
150000003254 radicals Chemical class 0.000 description 10
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
125000005843 halogen group Chemical group 0.000 description 9
125000003545 alkoxy group Chemical group 0.000 description 8
125000003710 aryl alkyl group Chemical group 0.000 description 8
150000008300 phosphoramidites Chemical class 0.000 description 8
238000011160 research Methods 0.000 description 8
210000001519 tissue Anatomy 0.000 description 8
OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 7
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
125000002723 alicyclic group Chemical group 0.000 description 7
108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 7
238000009396 hybridization Methods 0.000 description 7
229910052739 hydrogen Inorganic materials 0.000 description 7
239000001257 hydrogen Substances 0.000 description 7
229910052757 nitrogen Inorganic materials 0.000 description 7
125000004437 phosphorous atom Chemical group 0.000 description 7
239000011574 phosphorus Substances 0.000 description 7
125000003367 polycyclic group Polymers 0.000 description 7
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
229920006395 saturated elastomer Polymers 0.000 description 7
150000008163 sugars Chemical class 0.000 description 7
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 6
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
230000001588 bifunctional effect Effects 0.000 description 6
230000027455 binding Effects 0.000 description 6
239000003153 chemical reaction reagent Substances 0.000 description 6
201000010099 disease Diseases 0.000 description 6
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
239000003814 drug Substances 0.000 description 6
150000002243 furanoses Chemical class 0.000 description 6
125000004446 heteroarylalkyl group Chemical group 0.000 description 6
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
230000001965 increasing effect Effects 0.000 description 6
125000002950 monocyclic group Chemical group 0.000 description 6
IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 6
230000007935 neutral effect Effects 0.000 description 6
238000012247 phenotypical assay Methods 0.000 description 6
229920000642 polymer Polymers 0.000 description 6
238000003753 real-time PCR Methods 0.000 description 6
239000000126 substance Substances 0.000 description 6
150000003536 tetrazoles Chemical class 0.000 description 6
UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 5
XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 5
UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 5
102000004190 Enzymes Human genes 0.000 description 5
108090000790 Enzymes Proteins 0.000 description 5
229910019142 PO4 Inorganic materials 0.000 description 5
108010011536 PTEN Phosphohydrolase Proteins 0.000 description 5
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230000003321 amplification Effects 0.000 description 5
239000000074 antisense oligonucleotide Substances 0.000 description 5
238000012230 antisense oligonucleotides Methods 0.000 description 5
239000012230 colorless oil Substances 0.000 description 5
UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 5
238000010828 elution Methods 0.000 description 5
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IGFXRKMLLMBKSA-UHFFFAOYSA-N purine Chemical compound N1=C[N]C2=NC=NC2=C1 IGFXRKMLLMBKSA-UHFFFAOYSA-N 0.000 description 1
125000003373 pyrazinyl group Chemical group 0.000 description 1
125000003072 pyrazolidinyl group Chemical group 0.000 description 1
125000002755 pyrazolinyl group Chemical group 0.000 description 1
125000003226 pyrazolyl group Chemical group 0.000 description 1
UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
125000006513 pyridinyl methyl group Chemical group 0.000 description 1
125000004076 pyridyl group Chemical group 0.000 description 1
RXTQGIIIYVEHBN-UHFFFAOYSA-N pyrimido[4,5-b]indol-2-one Chemical compound C1=CC=CC2=NC3=NC(=O)N=CC3=C21 RXTQGIIIYVEHBN-UHFFFAOYSA-N 0.000 description 1
125000000719 pyrrolidinyl group Chemical group 0.000 description 1
SRBUGYKMBLUTIS-UHFFFAOYSA-N pyrrolo[2,3-d]pyrimidin-2-one Chemical compound O=C1N=CC2=CC=NC2=N1 SRBUGYKMBLUTIS-UHFFFAOYSA-N 0.000 description 1
125000000168 pyrrolyl group Chemical group 0.000 description 1
125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
238000000163 radioactive labelling Methods 0.000 description 1
239000011541 reaction mixture Substances 0.000 description 1
230000009467 reduction Effects 0.000 description 1
230000003252 repetitive effect Effects 0.000 description 1
108091008146 restriction endonucleases Proteins 0.000 description 1
238000003757 reverse transcription PCR Methods 0.000 description 1
239000003161 ribonuclease inhibitor Substances 0.000 description 1
125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
108091092562 ribozyme Proteins 0.000 description 1
IXGZXXBJSZISOO-UHFFFAOYSA-N s-(2-phenylacetyl)sulfanyl 2-phenylethanethioate Chemical compound C=1C=CC=CC=1CC(=O)SSC(=O)CC1=CC=CC=C1 IXGZXXBJSZISOO-UHFFFAOYSA-N 0.000 description 1
239000012047 saturated solution Substances 0.000 description 1
238000012216 screening Methods 0.000 description 1
238000000926 separation method Methods 0.000 description 1
238000012163 sequencing technique Methods 0.000 description 1
238000013207 serial dilution Methods 0.000 description 1
PXIPVTKHYLBLMZ-UHFFFAOYSA-N sodium azide Substances [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 1
238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
238000011895 specific detection Methods 0.000 description 1
238000010561 standard procedure Methods 0.000 description 1
239000008223 sterile water Substances 0.000 description 1
238000007920 subcutaneous administration Methods 0.000 description 1
239000000758 substrate Substances 0.000 description 1
IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical group NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
229940124530 sulfonamide Drugs 0.000 description 1
125000005864 sulfonamidyl group Chemical group 0.000 description 1
BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
238000005987 sulfurization reaction Methods 0.000 description 1
230000004083 survival effect Effects 0.000 description 1
230000008685 targeting Effects 0.000 description 1
KJTULOVPMGUBJS-UHFFFAOYSA-N tert-butyl-[tert-butyl(diphenyl)silyl]oxy-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](C=1C=CC=CC=1)(C(C)(C)C)O[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 KJTULOVPMGUBJS-UHFFFAOYSA-N 0.000 description 1
210000001550 testis Anatomy 0.000 description 1
125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
231100001274 therapeutic index Toxicity 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
125000001113 thiadiazolyl group Chemical group 0.000 description 1
125000001984 thiazolidinyl group Chemical group 0.000 description 1
125000000335 thiazolyl group Chemical group 0.000 description 1
125000001544 thienyl group Chemical group 0.000 description 1
125000005309 thioalkoxy group Chemical group 0.000 description 1
150000003568 thioethers Chemical class 0.000 description 1
125000003396 thiol group Chemical group [H]S* 0.000 description 1
231100000331 toxic Toxicity 0.000 description 1
230000002588 toxic effect Effects 0.000 description 1
231100000440 toxicity profile Toxicity 0.000 description 1
239000012096 transfection reagent Substances 0.000 description 1
238000013519 translation Methods 0.000 description 1
125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 description 1
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
230000003612 virological effect Effects 0.000 description 1
239000002699 waste material Substances 0.000 description 1
229940075420 xanthine Drugs 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof

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Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Biochemistry (AREA)
Molecular Biology (AREA)
Engineering & Computer Science (AREA)
General Health & Medical Sciences (AREA)
Biotechnology (AREA)
Genetics & Genomics (AREA)
Bioinformatics & Cheminformatics (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Pharmacology & Pharmacy (AREA)
Animal Behavior & Ethology (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Saccharide Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)

CA2692579A 2007-07-05 2008-07-01 Analogues d'acides nucleiques bicycliques disubstitues en position 6 Expired - Fee Related CA2692579C (fr)

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US94813407P	2007-07-05	2007-07-05
US60/948,134		2007-07-05
PCT/US2008/068922 WO2009006478A2 (fr)	2007-07-05	2008-07-01	Analogues d'acides nucléiques bicycliques disubstitués en position 6

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US (1)	US8278283B2 (fr)
EP (1)	EP2176280B2 (fr)
CN (1)	CN101796062B (fr)
AT (1)	ATE538127T1 (fr)
AU (1)	AU2008272918B2 (fr)
CA (1)	CA2692579C (fr)
DK (1)	DK2176280T4 (fr)
ES (1)	ES2376507T5 (fr)
WO (1)	WO2009006478A2 (fr)

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2008
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- 2008-07-01 DK DK08781239.2T patent/DK2176280T4/en active
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ATE538127T1 (de)	2012-01-15
US8278283B2 (en)	2012-10-02
CN101796062B (zh)	2014-07-30
ES2376507T3 (es)	2012-03-14
DK2176280T3 (da)	2012-03-05
ES2376507T5 (es)	2015-08-31
EP2176280B1 (fr)	2011-12-21
US20110053881A1 (en)	2011-03-03
EP2176280B2 (fr)	2015-06-24
AU2008272918A1 (en)	2009-01-08
DK2176280T4 (en)	2015-07-20
AU2008272918B2 (en)	2012-09-13
WO2009006478A3 (fr)	2009-02-19
CA2692579C (fr)	2016-05-03
CN101796062A (zh)	2010-08-04
EP2176280A2 (fr)	2010-04-21

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