ES2573928T3 - Profármacos de dinucleótidos - Google Patents
Profármacos de dinucleótidos Download PDFInfo
- Publication number
- ES2573928T3 ES2573928T3 ES06848625.7T ES06848625T ES2573928T3 ES 2573928 T3 ES2573928 T3 ES 2573928T3 ES 06848625 T ES06848625 T ES 06848625T ES 2573928 T3 ES2573928 T3 ES 2573928T3
- Authority
- ES
- Spain
- Prior art keywords
- aryl
- alkyl
- absent
- ohh
- nhc
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229940002612 prodrug Drugs 0.000 title description 9
- 239000000651 prodrug Substances 0.000 title description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract 2
- 239000001257 hydrogen Substances 0.000 claims abstract 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 29
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 abstract description 6
- 125000000217 alkyl group Chemical group 0.000 abstract description 4
- 125000003118 aryl group Chemical group 0.000 abstract description 4
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 3
- 229940035893 uracil Drugs 0.000 abstract description 3
- 229930024421 Adenine Natural products 0.000 abstract description 2
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 abstract description 2
- 229960000643 adenine Drugs 0.000 abstract description 2
- 125000003710 aryl alkyl group Chemical group 0.000 abstract 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 abstract 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 abstract 2
- 125000000547 substituted alkyl group Chemical group 0.000 abstract 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 abstract 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- 229940104302 cytosine Drugs 0.000 abstract 1
- 230000003637 steroidlike Effects 0.000 abstract 1
- 125000003107 substituted aryl group Chemical group 0.000 abstract 1
- 229940113082 thymine Drugs 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- -1 hydroxy, amino Chemical group 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 125000003729 nucleotide group Chemical group 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000002777 nucleoside Substances 0.000 description 10
- 239000002773 nucleotide Substances 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 230000000840 anti-viral effect Effects 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 210000004185 liver Anatomy 0.000 description 6
- 208000004998 Abdominal Pain Diseases 0.000 description 5
- 208000002881 Colic Diseases 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 150000003833 nucleoside derivatives Chemical class 0.000 description 5
- 125000003835 nucleoside group Chemical group 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 4
- 229910052782 aluminium Inorganic materials 0.000 description 4
- JPOXNPPZZKNXOV-UHFFFAOYSA-N bromochloromethane Chemical compound ClCBr JPOXNPPZZKNXOV-UHFFFAOYSA-N 0.000 description 4
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical class [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 229940009976 deoxycholate Drugs 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 150000002497 iodine compounds Chemical class 0.000 description 4
- 230000000873 masking effect Effects 0.000 description 4
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 108091034117 Oligonucleotide Proteins 0.000 description 3
- 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 3
- 150000001408 amides Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000011888 foil Substances 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 108091033319 polynucleotide Proteins 0.000 description 3
- 239000002157 polynucleotide Substances 0.000 description 3
- 102000040430 polynucleotide Human genes 0.000 description 3
- 235000009518 sodium iodide Nutrition 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 3
- 238000004679 31P NMR spectroscopy Methods 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000371 Esterases Proteins 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical group NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 102000038379 digestive enzymes Human genes 0.000 description 2
- 108091007734 digestive enzymes Proteins 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 210000004347 intestinal mucosa Anatomy 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- DHEPIQOGGUAJGR-UHFFFAOYSA-N iodomethyl propan-2-yl carbonate Chemical compound CC(C)OC(=O)OCI DHEPIQOGGUAJGR-UHFFFAOYSA-N 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- XEYORFKUJZEQCH-UHFFFAOYSA-N n-[4-(hydroxymethyl)phenyl]acetamide Chemical compound CC(=O)NC1=CC=C(CO)C=C1 XEYORFKUJZEQCH-UHFFFAOYSA-N 0.000 description 2
- FLAQRBVNFZAMAI-UHFFFAOYSA-N n-[4-(iodomethyl)phenyl]acetamide Chemical compound CC(=O)NC1=CC=C(CI)C=C1 FLAQRBVNFZAMAI-UHFFFAOYSA-N 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000011830 transgenic mouse model Methods 0.000 description 2
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical class OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 2
- QYIXCDOBOSTCEI-QCYZZNICSA-N (5alpha)-cholestan-3beta-ol Chemical compound C([C@@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CCCC(C)C)[C@@]2(C)CC1 QYIXCDOBOSTCEI-QCYZZNICSA-N 0.000 description 1
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 description 1
- SXUXMRMBWZCMEN-UHFFFAOYSA-N 2'-O-methyl uridine Natural products COC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 SXUXMRMBWZCMEN-UHFFFAOYSA-N 0.000 description 1
- QOJSGTNPCSBPFK-UHFFFAOYSA-N 2-methylpropanoyloxymethylsulfanylphosphonic acid Chemical compound CC(C)C(=O)OCSP(O)(O)=O QOJSGTNPCSBPFK-UHFFFAOYSA-N 0.000 description 1
- YEYCQJVCAMFWCO-UHFFFAOYSA-N 3beta-cholesteryl formate Natural products C1C=C2CC(OC=O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 YEYCQJVCAMFWCO-UHFFFAOYSA-N 0.000 description 1
- SKLUWKYNZNXSLX-UHFFFAOYSA-N 4-Acetamidobenzaldehyde Chemical compound CC(=O)NC1=CC=C(C=O)C=C1 SKLUWKYNZNXSLX-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 108090000317 Chymotrypsin Proteins 0.000 description 1
- 241000208011 Digitalis Species 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical class C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 101710163270 Nuclease Proteins 0.000 description 1
- CTNWJLSMPVPRKT-UHFFFAOYSA-N OP(O)(O)=S.Cl.Cl.Cl Chemical compound OP(O)(O)=S.Cl.Cl.Cl CTNWJLSMPVPRKT-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
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- 241000555745 Sciuridae Species 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical group OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 description 1
- YEYCQJVCAMFWCO-PXBBAZSNSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] formate Chemical compound C1C=C2C[C@@H](OC=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 YEYCQJVCAMFWCO-PXBBAZSNSA-N 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- QYIXCDOBOSTCEI-UHFFFAOYSA-N alpha-cholestanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 QYIXCDOBOSTCEI-UHFFFAOYSA-N 0.000 description 1
- 239000002215 arabinonucleoside Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- JPUUAYFQHNNDBM-UHFFFAOYSA-N bicyclo[4.1.0]hepta-1(6),3-diene-2,5-dione Chemical compound O=C1C=CC(=O)C2=C1C2 JPUUAYFQHNNDBM-UHFFFAOYSA-N 0.000 description 1
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- 238000011097 chromatography purification Methods 0.000 description 1
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- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
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Classifications
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- 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
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
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- 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
- 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
- C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
Landscapes
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- Chemical & Material Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
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- Public Health (AREA)
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- Biotechnology (AREA)
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- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Virology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Steroid Compounds (AREA)
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| US8076303B2 (en) * | 2005-12-13 | 2011-12-13 | Spring Bank Pharmaceuticals, Inc. | Nucleotide and oligonucleotide prodrugs |
| EP2271351A4 (en) | 2008-04-03 | 2016-08-31 | Spring Bank Pharmaceuticals Inc | COMPOSITIONS AND METHODS FOR TREATING VIRAL INFECTIONS |
| EP2346883B1 (en) * | 2008-09-23 | 2016-03-23 | Scott G. Petersen | Self delivering bio-labile phosphate protected pro-oligos for oligonucleotide based therapeutics and mediating rna interference |
| RU2015151857A (ru) | 2008-12-02 | 2019-01-15 | Уэйв Лайф Сайенсес Джапан, Инк. | Способ синтеза модифицированных по атому фосфора нуклеиновых кислот |
| EP2382227A1 (en) * | 2008-12-23 | 2011-11-02 | Girindus America, Inc. | Sulfurizing reagents and their use for oligonucleotides synthesis |
| AU2015255202B2 (en) * | 2009-07-06 | 2017-07-27 | Wave Life Sciences Ltd. | Novel nucleic acid prodrugs and methods of use thereof |
| MX342945B (es) | 2009-07-06 | 2016-10-18 | Ontorii Inc * | Profármacos de ácido nucleico novedosos y métodos de uso de los mismos. |
| CN101659612B (zh) * | 2009-09-24 | 2013-01-09 | 华润赛科药业有限责任公司 | 一种选择性酯化的方法 |
| CN103298475A (zh) * | 2010-08-30 | 2013-09-11 | 斯普林银行医药公司 | 作为治疗剂的寡核苷酸类似物的设计 |
| US10428019B2 (en) | 2010-09-24 | 2019-10-01 | Wave Life Sciences Ltd. | Chiral auxiliaries |
| EP3248982A1 (en) | 2011-07-19 | 2017-11-29 | Wave Life Sciences Ltd. | Thiosulfonate reagents for the synthesis of functionalized nucleic acids |
| KR101327026B1 (ko) | 2011-11-29 | 2013-11-13 | 현대자동차주식회사 | 운전자 보호장치 |
| CN104661664B (zh) | 2012-07-13 | 2020-07-03 | 波涛生命科学有限公司 | 手性控制 |
| CA2879066C (en) | 2012-07-13 | 2019-08-13 | Shin Nippon Biomedical Laboratories, Ltd. | Chiral nucleic acid adjuvant |
| CA2879023C (en) | 2012-07-13 | 2017-03-28 | Wave Life Sciences Japan | Asymmetric auxiliary group |
| CN105992587A (zh) * | 2013-02-18 | 2016-10-05 | 春堤制药公司 | 作为疫苗佐剂和治疗试剂的短寡核苷酸的设计 |
| US10322173B2 (en) | 2014-01-15 | 2019-06-18 | Shin Nippon Biomedical Laboratories, Ltd. | Chiral nucleic acid adjuvant having anti-allergic activity, and anti-allergic agent |
| JPWO2015108048A1 (ja) | 2014-01-15 | 2017-03-23 | 株式会社新日本科学 | 抗腫瘍作用を有するキラル核酸アジュバンド及び抗腫瘍剤 |
| US10144933B2 (en) | 2014-01-15 | 2018-12-04 | Shin Nippon Biomedical Laboratories, Ltd. | Chiral nucleic acid adjuvant having immunity induction activity, and immunity induction activator |
| MX2016009290A (es) | 2014-01-16 | 2017-02-28 | Wave Life Sciences Ltd | Diseño quiral. |
| GB201403697D0 (en) * | 2014-03-03 | 2014-04-16 | Link Technologies Ltd | Compounds and methods of use |
| EP3197459B1 (en) * | 2014-09-28 | 2025-02-12 | Huahui Health Ltd. | Polymeric bile acid derivatives inhibit hepatitis b and d virus and ntcp transport |
| WO2016164625A1 (en) * | 2015-04-07 | 2016-10-13 | Spring Bank Pharmaceuticals, Inc. | Compositions and methods for the treatment of hcv infection |
| CN107922455A (zh) * | 2015-07-02 | 2018-04-17 | 春季银行制药股份有限公司 | 用于治疗病毒感染的组合物和方法 |
| EP3426671A4 (en) * | 2016-03-11 | 2019-11-20 | Spring Bank Pharmaceuticals, Inc. | COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF INFECTIONS |
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| JOP20170192A1 (ar) * | 2016-12-01 | 2019-01-30 | Takeda Pharmaceuticals Co | داي نوكليوتيد حلقي |
| US20200055883A1 (en) | 2017-02-17 | 2020-02-20 | Eisai R&D Management Co., Ltd. | Cyclic di-nucleotides derivative for the treatment of cancer |
| AR113224A1 (es) | 2017-04-28 | 2020-02-19 | Novartis Ag | Conjugados de anticuerpo que comprenden un agonista de sting |
| WO2019051488A1 (en) | 2017-09-11 | 2019-03-14 | Sperovie Biosciences, Inc. | COMPOUNDS, COMPOSITIONS AND METHODS OF TREATING DISEASE |
| US11707531B2 (en) | 2017-09-11 | 2023-07-25 | F-star Therapeutics, Inc. | Compounds, compositions, and methods for the treatment of disease |
| CN110467647B (zh) * | 2018-05-09 | 2022-08-30 | 博瑞生物医药（苏州）股份有限公司 | 双核苷酸前体药物的制备方法 |
| CN110467646A (zh) * | 2018-05-09 | 2019-11-19 | 博瑞生物医药（苏州）股份有限公司 | 双核苷酸前体药物 |
| WO2019219070A1 (zh) * | 2018-05-18 | 2019-11-21 | 正大天晴药业集团股份有限公司 | 氘代的低聚核苷酸及前体药物 |
| CN112512531B (zh) | 2018-06-01 | 2024-04-09 | 卫材R&D管理有限公司 | 用于膀胱癌的治疗的方法 |
| FR3082434B1 (fr) | 2018-06-14 | 2021-04-30 | Cairdac | Implant cardiaque autonome de type "capsule leadless", comprenant un recuperateur d'energie a lame piezoelectrique |
| MX2020013322A (es) | 2018-08-16 | 2021-02-22 | Eisai R&D Man Co Ltd | Sales de compuestos y cristales de los mismos. |
| WO2020089815A1 (en) | 2018-10-31 | 2020-05-07 | Novartis Ag | Antibody conjugates comprising sting agonist |
| JP2022509929A (ja) | 2018-10-31 | 2022-01-25 | ノバルティス アーゲー | Ｓｔｉｎｇアゴニストを含むｄｃ－ｓｉｇｎ抗体コンジュゲート |
| WO2020114495A1 (zh) * | 2018-12-06 | 2020-06-11 | 正大天晴药业集团股份有限公司 | 二核苷酸化合物及其前体药物 |
| CN111484540B (zh) * | 2019-01-25 | 2023-09-08 | 博瑞生物医药（苏州）股份有限公司 | 含双核苷酸结构的化合物 |
| CN111484541B (zh) * | 2019-01-25 | 2023-06-02 | 博瑞生物医药（苏州）股份有限公司 | 双核苷酸前体药物及其制备方法 |
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| US688183A (en) | 1900-12-17 | 1901-12-03 | Carl C Lantz | Adjusting-clip for garment-supporters. |
| DE2817041C2 (de) | 1978-04-19 | 1987-02-19 | Reich Spezialmaschinen GmbH, 7440 Nürtingen | Vorrichtung zum Aufteilen von Platten |
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| US5914331A (en) | 1990-02-01 | 1999-06-22 | Emory University | Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane |
| US5204466A (en) | 1990-02-01 | 1993-04-20 | Emory University | Method and compositions for the synthesis of bch-189 and related compounds |
| JPH05506033A (ja) | 1990-04-18 | 1993-09-02 | ノーウィッチ、イートン、ファーマスーティカルズ、インコーポレーテッド | 抗微生物性キノロニルラクタム類 |
| US5444063A (en) | 1990-12-05 | 1995-08-22 | Emory University | Enantiomerically pure β-D-dioxolane nucleosides with selective anti-Hepatitis B virus activity |
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