ES2929667T3 - Derivados de indolina sustituidos como inhibidores de la replicación vírica de dengue - Google Patents
Derivados de indolina sustituidos como inhibidores de la replicación vírica de dengue Download PDFInfo
- Publication number
- ES2929667T3 ES2929667T3 ES18728541T ES18728541T ES2929667T3 ES 2929667 T3 ES2929667 T3 ES 2929667T3 ES 18728541 T ES18728541 T ES 18728541T ES 18728541 T ES18728541 T ES 18728541T ES 2929667 T3 ES2929667 T3 ES 2929667T3
- Authority
- ES
- Spain
- Prior art keywords
- mmol
- compound
- mixture
- methyl
- amino
- 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.)
- Active
Links
- 125000003387 indolinyl group Chemical class N1(CCC2=CC=CC=C12)* 0.000 title abstract 2
- 241000725619 Dengue virus Species 0.000 title description 13
- 230000029812 viral genome replication Effects 0.000 title description 4
- 239000003112 inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 191
- 206010012310 Dengue fever Diseases 0.000 claims abstract description 32
- 208000001490 Dengue Diseases 0.000 claims abstract description 26
- 208000025729 dengue disease Diseases 0.000 claims abstract description 26
- 239000003814 drug Substances 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- -1 bicyclo[1.1.1]pentanyl Chemical group 0.000 claims description 93
- 239000002904 solvent Substances 0.000 claims description 46
- 241000700605 Viruses Species 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 208000015181 infectious disease Diseases 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 239000011737 fluorine Chemical group 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 4
- 239000003443 antiviral agent Substances 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- 239000000969 carrier Substances 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 163
- 238000000034 method Methods 0.000 abstract description 75
- 208000036142 Viral infection Diseases 0.000 abstract description 12
- 230000009385 viral infection Effects 0.000 abstract description 12
- 238000002360 preparation method Methods 0.000 abstract description 11
- 230000002265 prevention Effects 0.000 abstract description 8
- 230000008569 process Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 240
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 192
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 160
- 235000019439 ethyl acetate Nutrition 0.000 description 120
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 116
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 112
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 109
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 102
- 230000015572 biosynthetic process Effects 0.000 description 102
- 238000003786 synthesis reaction Methods 0.000 description 102
- 239000000243 solution Substances 0.000 description 94
- 239000000741 silica gel Substances 0.000 description 73
- 229910002027 silica gel Inorganic materials 0.000 description 73
- 239000000543 intermediate Substances 0.000 description 72
- 238000003818 flash chromatography Methods 0.000 description 59
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 58
- 235000019341 magnesium sulphate Nutrition 0.000 description 58
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 56
- 238000005160 1H NMR spectroscopy Methods 0.000 description 54
- 239000012071 phase Substances 0.000 description 51
- 239000000047 product Substances 0.000 description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 50
- 239000012044 organic layer Substances 0.000 description 49
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 44
- UHKXVRXZHGGOGP-UHFFFAOYSA-N 2-bromo-2-(4-chlorophenyl)-1-[6-(trifluoromethoxy)-2,3-dihydroindol-1-yl]ethanone Chemical compound BrC(C(=O)N1CCC2=CC=C(C=C12)OC(F)(F)F)C1=CC=C(C=C1)Cl UHKXVRXZHGGOGP-UHFFFAOYSA-N 0.000 description 43
- 230000005526 G1 to G0 transition Effects 0.000 description 43
- 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 description 40
- 238000000926 separation method Methods 0.000 description 39
- 229910002091 carbon monoxide Inorganic materials 0.000 description 34
- 239000000460 chlorine Substances 0.000 description 34
- 238000000746 purification Methods 0.000 description 34
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 33
- 239000002253 acid Substances 0.000 description 29
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 29
- 210000004027 cell Anatomy 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 24
- 239000000706 filtrate Substances 0.000 description 23
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 23
- 239000012074 organic phase Substances 0.000 description 23
- 239000012267 brine Substances 0.000 description 21
- 239000003054 catalyst Substances 0.000 description 21
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
- 238000001914 filtration Methods 0.000 description 16
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 238000007711 solidification Methods 0.000 description 15
- 230000008023 solidification Effects 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 13
- YETHUNXROLCEGJ-UHFFFAOYSA-N 3-methoxy-5-nitrophenol Chemical compound COC1=CC(O)=CC([N+]([O-])=O)=C1 YETHUNXROLCEGJ-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 12
- TXWOGHSRPAYOML-UHFFFAOYSA-M cyclobutanecarboxylate Chemical compound [O-]C(=O)C1CCC1 TXWOGHSRPAYOML-UHFFFAOYSA-M 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 11
- 238000011529 RT qPCR Methods 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- 208000009714 Severe Dengue Diseases 0.000 description 10
- 239000012065 filter cake Substances 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 230000003197 catalytic effect Effects 0.000 description 9
- 239000012046 mixed solvent Substances 0.000 description 9
- UUXWIOLRYXMDJP-UHFFFAOYSA-N 2-bromo-2-(4-chloro-2-methoxyphenyl)-1-[6-(trifluoromethoxy)-2,3-dihydroindol-1-yl]ethanone Chemical compound BrC(C(=O)N1CCC2=CC=C(C=C12)OC(F)(F)F)C1=C(C=C(C=C1)Cl)OC UUXWIOLRYXMDJP-UHFFFAOYSA-N 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 8
- OCABOAQENCPTSP-UHFFFAOYSA-N 5-fluoro-6-(trifluoromethoxy)-1H-indole Chemical compound FC=1C=C2C=CNC2=CC=1OC(F)(F)F OCABOAQENCPTSP-UHFFFAOYSA-N 0.000 description 7
- 229910004373 HOAc Inorganic materials 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 238000007792 addition Methods 0.000 description 7
- 239000001963 growth medium Substances 0.000 description 7
- 239000005457 ice water Substances 0.000 description 7
- 238000003762 quantitative reverse transcription PCR Methods 0.000 description 7
- 239000000377 silicon dioxide Substances 0.000 description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 6
- GZLKNDMDIICBFQ-UHFFFAOYSA-N 2-(4-chloro-2-methoxyphenyl)-1-[6-(trifluoromethoxy)-2,3-dihydroindol-1-yl]ethanone Chemical compound ClC1=CC(=C(C=C1)CC(=O)N1CCC2=CC=C(C=C12)OC(F)(F)F)OC GZLKNDMDIICBFQ-UHFFFAOYSA-N 0.000 description 5
- SVIBMMGTHZMHTR-UHFFFAOYSA-N 2-(4-chlorophenyl)-1-[6-(trifluoromethoxy)-2,3-dihydroindol-1-yl]ethanone Chemical compound ClC1=CC=C(C=C1)CC(=O)N1CCC2=CC=C(C=C12)OC(F)(F)F SVIBMMGTHZMHTR-UHFFFAOYSA-N 0.000 description 5
- NNYYXTHPUFLAOQ-UHFFFAOYSA-N 2-bromo-4-fluoro-5-(trifluoromethoxy)aniline Chemical compound BrC1=C(N)C=C(C(=C1)F)OC(F)(F)F NNYYXTHPUFLAOQ-UHFFFAOYSA-N 0.000 description 5
- QBEUDXAREIDECL-UHFFFAOYSA-N 4-fluoro-5-(trifluoromethoxy)-2-(2-trimethylsilylethynyl)aniline Chemical compound FC1=CC(=C(N)C=C1OC(F)(F)F)C#C[Si](C)(C)C QBEUDXAREIDECL-UHFFFAOYSA-N 0.000 description 5
- GWDCINSZLONNLV-UHFFFAOYSA-N 5-fluoro-6-(trifluoromethoxy)-2,3-dihydro-1H-indole Chemical compound FC=1C=C2CCNC2=CC=1OC(F)(F)F GWDCINSZLONNLV-UHFFFAOYSA-N 0.000 description 5
- KNMAZUXTEPXPOM-UHFFFAOYSA-N 5-methoxy-6-(trifluoromethyl)-1h-indole Chemical compound C1=C(C(F)(F)F)C(OC)=CC2=C1NC=C2 KNMAZUXTEPXPOM-UHFFFAOYSA-N 0.000 description 5
- 241000255925 Diptera Species 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 230000000840 anti-viral effect Effects 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 5
- 201000002950 dengue hemorrhagic fever Diseases 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 5
- DBRMDPWHXKAPCD-UHFFFAOYSA-N ethyl 3-(3-amino-5-methoxyphenoxy)propanoate Chemical compound NC=1C=C(OCCC(=O)OCC)C=C(C=1)OC DBRMDPWHXKAPCD-UHFFFAOYSA-N 0.000 description 5
- SWIAMQXNLZLKSS-UHFFFAOYSA-N ethyl 3-[[3-(dibenzylamino)-5-methoxyphenyl]methoxy]propanoate Chemical compound C(C1=CC=CC=C1)N(C=1C=C(COCCC(=O)OCC)C=C(C=1)OC)CC1=CC=CC=C1 SWIAMQXNLZLKSS-UHFFFAOYSA-N 0.000 description 5
- 150000002476 indolines Chemical class 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- AHBGIAOHPLEUDF-UHFFFAOYSA-N methyl 1-(2-bromoethyl)cyclopropane-1-carboxylate Chemical compound COC(=O)C1(CC1)CCBr AHBGIAOHPLEUDF-UHFFFAOYSA-N 0.000 description 5
- GSNFVCINDLFWDP-UHFFFAOYSA-N methyl 2-[(3-methoxy-5-nitrophenoxy)methyl]cyclopropane-1-carboxylate Chemical compound COC=1C=C(OCC2C(C2)C(=O)OC)C=C(C=1)[N+](=O)[O-] GSNFVCINDLFWDP-UHFFFAOYSA-N 0.000 description 5
- RUTOXMJIOZUHCR-UHFFFAOYSA-N methyl 4-(3-amino-5-methoxyphenoxy)-2,2-dimethylbutanoate Chemical compound NC=1C=C(OCCC(C(=O)OC)(C)C)C=C(C=1)OC RUTOXMJIOZUHCR-UHFFFAOYSA-N 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 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 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
- QAKGVPAQOZSDOZ-UHFFFAOYSA-N 2-(hydroxymethyl)cyclopropane-1-carboxylic acid Chemical compound OCC1CC1C(O)=O QAKGVPAQOZSDOZ-UHFFFAOYSA-N 0.000 description 4
- ILTCFIIXWWUIPC-UHFFFAOYSA-N 3-amino-5-methoxyphenol Chemical compound COC1=CC(N)=CC(O)=C1 ILTCFIIXWWUIPC-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- MCSWKSCZARDPJX-UHFFFAOYSA-N 5-methoxy-6-(trifluoromethyl)-2,3-dihydro-1h-indole Chemical compound C1=C(C(F)(F)F)C(OC)=CC2=C1NCC2 MCSWKSCZARDPJX-UHFFFAOYSA-N 0.000 description 4
- CZFUAUSGMISVFX-UHFFFAOYSA-N 6-(trifluoromethoxy)-2,3-dihydro-1h-indole Chemical compound FC(F)(F)OC1=CC=C2CCNC2=C1 CZFUAUSGMISVFX-UHFFFAOYSA-N 0.000 description 4
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 4
- PJHUUSIPDVULCT-UHFFFAOYSA-N BrC1=C(C=C(C(=C1)F)OC(F)(F)F)[N+](=O)[O-] Chemical compound BrC1=C(C=C(C(=C1)F)OC(F)(F)F)[N+](=O)[O-] PJHUUSIPDVULCT-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 229940126657 Compound 17 Drugs 0.000 description 4
- 241000710831 Flavivirus Species 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 4
- 239000002299 complementary DNA Substances 0.000 description 4
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 4
- MIBSJZIXDXHQTL-UHFFFAOYSA-N ethyl 3-(3-methoxy-5-nitroanilino)cyclobutane-1-carboxylate Chemical compound COC=1C=C(C=C(C=1)[N+](=O)[O-])NC1CC(C1)C(=O)OCC MIBSJZIXDXHQTL-UHFFFAOYSA-N 0.000 description 4
- NETFSWBEMWQYFS-UHFFFAOYSA-N ethyl 3-(3-methoxy-5-nitrophenoxy)prop-2-enoate Chemical compound COC=1C=C(OC=CC(=O)OCC)C=C(C=1)[N+](=O)[O-] NETFSWBEMWQYFS-UHFFFAOYSA-N 0.000 description 4
- UUBYKQPQLBLTKH-UHFFFAOYSA-N ethyl 3-(4-methylphenyl)sulfonyloxycyclobutane-1-carboxylate Chemical compound C1C(C(=O)OCC)CC1OS(=O)(=O)C1=CC=C(C)C=C1 UUBYKQPQLBLTKH-UHFFFAOYSA-N 0.000 description 4
- JGDVUJFJIFRNAX-UHFFFAOYSA-N ethyl 4-(3-amino-5-methoxyphenyl)butanoate Chemical compound NC=1C=C(C=C(C=1)OC)CCCC(=O)OCC JGDVUJFJIFRNAX-UHFFFAOYSA-N 0.000 description 4
- FZQYPZHBHLEJGH-UHFFFAOYSA-N ethyl 4-(3-methoxy-5-nitrophenyl)butanoate Chemical compound COC=1C=C(C=C(C=1)[N+](=O)[O-])CCCC(=O)OCC FZQYPZHBHLEJGH-UHFFFAOYSA-N 0.000 description 4
- INKYXXACWOULNY-UHFFFAOYSA-N ethyl 5-(3-amino-5-methoxyphenyl)pentanoate Chemical compound NC=1C=C(C=C(C=1)OC)CCCCC(=O)OCC INKYXXACWOULNY-UHFFFAOYSA-N 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 150000002431 hydrogen Chemical group 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- APNITNSHOZKCGV-UHFFFAOYSA-N methyl 1-[2-(3-amino-5-methoxyphenoxy)ethyl]cyclopropane-1-carboxylate Chemical compound NC=1C=C(OCCC2(CC2)C(=O)OC)C=C(C=1)OC APNITNSHOZKCGV-UHFFFAOYSA-N 0.000 description 4
- OPZFSKWZAHETLR-UHFFFAOYSA-N methyl 3-[(3-amino-5-methoxyphenoxy)methyl]bicyclo[1.1.1]pentane-1-carboxylate Chemical compound NC=1C=C(OCC23CC(C2)(C3)C(=O)OC)C=C(C=1)OC OPZFSKWZAHETLR-UHFFFAOYSA-N 0.000 description 4
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 235000019260 propionic acid Nutrition 0.000 description 4
- 230000006340 racemization Effects 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 229960005486 vaccine Drugs 0.000 description 4
- 210000003501 vero cell Anatomy 0.000 description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- 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 3
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 3
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 3
- 108020005345 3' Untranslated Regions Proteins 0.000 description 3
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 3
- NOZCSQJFRSSGBP-UHFFFAOYSA-N [3-(dibenzylamino)-5-methoxyphenyl]methanol Chemical compound C(C1=CC=CC=C1)N(C=1C=C(C=C(C=1)OC)CO)CC1=CC=CC=C1 NOZCSQJFRSSGBP-UHFFFAOYSA-N 0.000 description 3
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000013592 cell lysate Substances 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
- 229940126543 compound 14 Drugs 0.000 description 3
- 229940125758 compound 15 Drugs 0.000 description 3
- 229940126142 compound 16 Drugs 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940126086 compound 21 Drugs 0.000 description 3
- 229940125851 compound 27 Drugs 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- TXWOGHSRPAYOML-UHFFFAOYSA-N cyclobutanecarboxylic acid Chemical compound OC(=O)C1CCC1 TXWOGHSRPAYOML-UHFFFAOYSA-N 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- MCTSVNGBDYPRPR-UHFFFAOYSA-N ethyl 4-(3-amino-5-methoxyphenoxy)-3-methylbutanoate Chemical compound NC=1C=C(OCC(CC(=O)OCC)C)C=C(C=1)OC MCTSVNGBDYPRPR-UHFFFAOYSA-N 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 3
- HSTKVNUJKSLSTR-UHFFFAOYSA-N methyl 2-[(3-amino-5-methoxyphenoxy)methyl]cyclopropane-1-carboxylate Chemical compound NC=1C=C(OCC2C(C2)C(=O)OC)C=C(C=1)OC HSTKVNUJKSLSTR-UHFFFAOYSA-N 0.000 description 3
- VKNCKYSJZTVFSU-UHFFFAOYSA-N methyl 3-[(4-methylphenyl)sulfonyloxymethyl]cyclobutane-1-carboxylate Chemical compound S(=O)(=O)(C1=CC=C(C)C=C1)OCC1CC(C1)C(=O)OC VKNCKYSJZTVFSU-UHFFFAOYSA-N 0.000 description 3
- NVFROOBLMCOHAB-UHFFFAOYSA-N methyl 5-(3-amino-5-methoxyphenoxy)pentanoate Chemical compound NC=1C=C(OCCCCC(=O)OC)C=C(C=1)OC NVFROOBLMCOHAB-UHFFFAOYSA-N 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000002953 preparative HPLC Methods 0.000 description 3
- 238000010839 reverse transcription Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- 239000003039 volatile agent Substances 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- UXJIWCMQVOEXTG-UHFFFAOYSA-N 2-(4-chloro-2-methoxyphenyl)acetic acid Chemical compound COC1=CC(Cl)=CC=C1CC(O)=O UXJIWCMQVOEXTG-UHFFFAOYSA-N 0.000 description 2
- KKOAAWLOOHBFQP-UHFFFAOYSA-N 2-bromo-2-(4-chlorophenyl)acetic acid Chemical compound OC(=O)C(Br)C1=CC=C(Cl)C=C1 KKOAAWLOOHBFQP-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 208000003322 Coinfection Diseases 0.000 description 2
- 229940126639 Compound 33 Drugs 0.000 description 2
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 2
- 229930182566 Gentamicin Natural products 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- 229930182816 L-glutamine Natural products 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 2
- RXIDABFEUOURPA-UHFFFAOYSA-N OCC(C1)(C1C(O)=O)F Chemical compound OCC(C1)(C1C(O)=O)F RXIDABFEUOURPA-UHFFFAOYSA-N 0.000 description 2
- 229910020175 SiOH Inorganic materials 0.000 description 2
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- YMGUBTXCNDTFJI-UHFFFAOYSA-M cyclopropanecarboxylate Chemical compound [O-]C(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-M 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 238000004925 denaturation Methods 0.000 description 2
- 230000036425 denaturation Effects 0.000 description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- VUAMJAQNWQKOTC-UHFFFAOYSA-N ethyl 4-bromo-3-methylbutanoate Chemical compound CCOC(=O)CC(C)CBr VUAMJAQNWQKOTC-UHFFFAOYSA-N 0.000 description 2
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 2
- PPXUHEORWJQRHJ-UHFFFAOYSA-N ethyl isovalerate Chemical compound CCOC(=O)CC(C)C PPXUHEORWJQRHJ-UHFFFAOYSA-N 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 238000005227 gel permeation chromatography Methods 0.000 description 2
- 229960002518 gentamicin Drugs 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- 230000000155 isotopic effect Effects 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 238000004989 laser desorption mass spectroscopy Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- VIZZXGCLXWDKCT-UHFFFAOYSA-N methyl 2-[1-[(3-methoxy-5-nitrophenoxy)methyl]cyclopropyl]acetate Chemical compound COC=1C=C(OCC2(CC2)CC(=O)OC)C=C(C=1)[N+](=O)[O-] VIZZXGCLXWDKCT-UHFFFAOYSA-N 0.000 description 2
- HNBDRPTVWVGKBR-UHFFFAOYSA-N methyl pentanoate Chemical compound CCCCC(=O)OC HNBDRPTVWVGKBR-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- JHOKFKZRRFUAIC-RLWLMLJZSA-N (3S)-3-[3-[[(1S)-1-(4-chlorophenyl)-2-[5-fluoro-6-(trifluoromethoxy)-2,3-dihydroindol-1-yl]-2-oxoethyl]amino]-5-methoxyphenoxy]cyclobutene-1-carboxylic acid Chemical compound ClC1=CC=C(C=C1)[C@@H](C(=O)N1CCC2=CC(=C(C=C12)OC(F)(F)F)F)NC=1C=C(O[C@@H]2C=C(C2)C(=O)O)C=C(C=1)OC JHOKFKZRRFUAIC-RLWLMLJZSA-N 0.000 description 1
- FEFNPBVAOCHKMP-CRYYWNKWSA-N (3S)-3-[[3-[[(1S)-1-(4-chlorophenyl)-2-oxo-2-[6-(trifluoromethoxy)-2,3-dihydroindol-1-yl]ethyl]amino]-5-methoxyphenoxy]methyl]cyclobutene-1-carboxylic acid Chemical compound ClC1=CC=C(C=C1)[C@@H](C(N1CCC2=CC=C(C=C12)OC(F)(F)F)=O)NC=1C=C(OC[C@@H]2C=C(C2)C(=O)O)C=C(C=1)OC FEFNPBVAOCHKMP-CRYYWNKWSA-N 0.000 description 1
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- VHDRROCOAMDAAU-UHFFFAOYSA-N 1-(2-bromoethyl)cyclopropane-1-carboxylic acid Chemical compound BrCCC1(C(=O)O)CC1 VHDRROCOAMDAAU-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- UQMMZXMHJYJWCO-UHFFFAOYSA-N 2-[1-[[3-[[1-(4-chlorophenyl)-2-oxo-2-[6-(trifluoromethoxy)-2,3-dihydroindol-1-yl]ethyl]amino]-5-methoxyphenoxy]methyl]cyclopropyl]acetic acid Chemical compound ClC1=CC=C(C=C1)C(C(N1CCC2=CC=C(C=C12)OC(F)(F)F)=O)NC=1C=C(OCC2(CC2)CC(=O)O)C=C(C=1)OC UQMMZXMHJYJWCO-UHFFFAOYSA-N 0.000 description 1
- IANAREFPKLOIAF-UHFFFAOYSA-N 2-[5-methoxy-2-nitro-4-(trifluoromethyl)phenyl]acetonitrile Chemical compound COC1=CC(CC#N)=C([N+]([O-])=O)C=C1C(F)(F)F IANAREFPKLOIAF-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- JUTDHSGANMHVIC-UHFFFAOYSA-N 2-phenylpyrrolidine Chemical compound C1CCNC1C1=CC=CC=C1 JUTDHSGANMHVIC-UHFFFAOYSA-N 0.000 description 1
- GWKPZCSHFMNLNY-UHFFFAOYSA-N 3-(3-methoxy-5-nitrophenyl)prop-2-enoic acid Chemical compound COC1=CC(C=CC(O)=O)=CC([N+]([O-])=O)=C1 GWKPZCSHFMNLNY-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- KASHQCGWTCLVGR-UHFFFAOYSA-N 3-[(4-methylphenyl)sulfonyloxymethyl]cyclobutane-1-carboxylic acid Chemical compound CC1=CC=C(C=C1)S(=O)(=O)OCC1CC(C1)C(=O)O KASHQCGWTCLVGR-UHFFFAOYSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- GIFMCRXPVKYTKM-UHFFFAOYSA-N 4-[3-[[1-(4-chlorophenyl)-2-oxo-2-[6-(trifluoromethoxy)-2,3-dihydroindol-1-yl]ethyl]amino]-5-methoxyphenoxy]-3-methylbutanoic acid Chemical compound ClC1=CC=C(C=C1)C(C(N1CCC2=CC=C(C=C12)OC(F)(F)F)=O)NC=1C=C(OCC(CC(=O)O)C)C=C(C=1)OC GIFMCRXPVKYTKM-UHFFFAOYSA-N 0.000 description 1
- FPBAJDLCOXBRNU-UHFFFAOYSA-N 4-[3-[[1-(4-chlorophenyl)-2-oxo-2-[6-(trifluoromethoxy)-2,3-dihydroindol-1-yl]ethyl]amino]-5-methoxyphenyl]butanoic acid Chemical compound ClC1=CC=C(C=C1)C(C(N1CCC2=CC=C(C=C12)OC(F)(F)F)=O)NC=1C=C(C=C(C=1)OC)CCCC(=O)O FPBAJDLCOXBRNU-UHFFFAOYSA-N 0.000 description 1
- CDPKJZJVTHSESZ-UHFFFAOYSA-N 4-chlorophenylacetic acid Chemical compound OC(=O)CC1=CC=C(Cl)C=C1 CDPKJZJVTHSESZ-UHFFFAOYSA-N 0.000 description 1
- 241000238876 Acari Species 0.000 description 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 241000256118 Aedes aegypti Species 0.000 description 1
- 241000256173 Aedes albopictus Species 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- KYGRHHWECKOEAE-UHFFFAOYSA-N COC1=CC=C(COCC(C2)(C2C(O)=O)F)C=C1 Chemical compound COC1=CC=C(COCC(C2)(C2C(O)=O)F)C=C1 KYGRHHWECKOEAE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- ICMAFTSLXCXHRK-UHFFFAOYSA-N Ethyl pentanoate Chemical compound CCCCC(=O)OCC ICMAFTSLXCXHRK-UHFFFAOYSA-N 0.000 description 1
- 206010061192 Haemorrhagic fever Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 241000282376 Panthera tigris Species 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000012435 analytical chromatography Methods 0.000 description 1
- 238000002832 anti-viral assay Methods 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- ORCXPYPDHLVQFP-UHFFFAOYSA-N bicyclo[1.1.1]pentane-3-carboxylic acid Chemical compound C1C2CC1(C(=O)O)C2 ORCXPYPDHLVQFP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000001343 butyl (2R)-2-methylbutanoate Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 201000009892 dengue shock syndrome Diseases 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- VVYZCBNOQLSBGE-YDFGWWAZSA-N ethyl (2E,4E)-5-(3-methoxy-5-nitrophenyl)penta-2,4-dienoate Chemical compound COC=1C=C(C=C(C=1)[N+](=O)[O-])/C=C/C=C/C(=O)OCC VVYZCBNOQLSBGE-YDFGWWAZSA-N 0.000 description 1
- MRASEHLNSDXSDL-UHFFFAOYSA-N ethyl 3-(3-amino-5-methoxyanilino)cyclobutane-1-carboxylate Chemical compound NC=1C=C(C=C(C=1)OC)NC1CC(C1)C(=O)OCC MRASEHLNSDXSDL-UHFFFAOYSA-N 0.000 description 1
- JDPRQLJJXIQEHN-UHFFFAOYSA-N ethyl 3-[(3-amino-5-methoxyphenyl)methoxy]propanoate Chemical compound NC=1C=C(COCCC(=O)OCC)C=C(C=1)OC JDPRQLJJXIQEHN-UHFFFAOYSA-N 0.000 description 1
- FQTIYMRSUOADDK-UHFFFAOYSA-N ethyl 3-bromopropanoate Chemical compound CCOC(=O)CCBr FQTIYMRSUOADDK-UHFFFAOYSA-N 0.000 description 1
- XWRLQRLQUKZEEU-UHFFFAOYSA-N ethyl(hydroxy)silicon Chemical group CC[Si]O XWRLQRLQUKZEEU-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000008774 maternal effect Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- IGHXQNDUQCTKSH-UHFFFAOYSA-N methyl 2,2-dimethylbutanoate Chemical compound CCC(C)(C)C(=O)OC IGHXQNDUQCTKSH-UHFFFAOYSA-N 0.000 description 1
- ZCFDKHQXEZFZMQ-UHFFFAOYSA-N methyl 2-[1-[(3-amino-5-methoxyphenoxy)methyl]cyclopropyl]acetate Chemical compound NC=1C=C(OCC2(CC2)CC(=O)OC)C=C(C=1)OC ZCFDKHQXEZFZMQ-UHFFFAOYSA-N 0.000 description 1
- DQOQAPSWZIIAOL-UHFFFAOYSA-N methyl 3-[(3-methoxy-5-nitrophenoxy)methyl]bicyclo[1.1.1]pentane-1-carboxylate Chemical compound COC=1C=C(OCC23CC(C2)(C3)C(=O)OC)C=C(C=1)[N+](=O)[O-] DQOQAPSWZIIAOL-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical compound C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- IIHPVYJPDKJYOU-UHFFFAOYSA-N triphenylcarbethoxymethylenephosphorane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OCC)C1=CC=CC=C1 IIHPVYJPDKJYOU-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP17172237 | 2017-05-22 | ||
| PCT/EP2018/063028 WO2018215315A1 (en) | 2017-05-22 | 2018-05-18 | Substituted indoline derivatives as dengue viral replication inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2929667T3 true ES2929667T3 (es) | 2022-11-30 |
Family
ID=58745157
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES18728541T Active ES2929667T3 (es) | 2017-05-22 | 2018-05-18 | Derivados de indolina sustituidos como inhibidores de la replicación vírica de dengue |
Country Status (25)
| Country | Link |
|---|---|
| US (2) | US11407715B2 (enExample) |
| EP (1) | EP3630723B1 (enExample) |
| JP (1) | JP7203764B2 (enExample) |
| KR (1) | KR102625988B1 (enExample) |
| CN (1) | CN110691773B (enExample) |
| AR (1) | AR111878A1 (enExample) |
| AU (1) | AU2018274100B2 (enExample) |
| BR (1) | BR112019024195A2 (enExample) |
| CA (1) | CA3060583C (enExample) |
| CL (1) | CL2019003294A1 (enExample) |
| CO (1) | CO2019012035A2 (enExample) |
| CR (1) | CR20190530A (enExample) |
| EA (1) | EA201992782A1 (enExample) |
| EC (1) | ECSP19083640A (enExample) |
| ES (1) | ES2929667T3 (enExample) |
| IL (1) | IL270726B2 (enExample) |
| MA (1) | MA48943A (enExample) |
| MX (1) | MX393586B (enExample) |
| NI (1) | NI201900119A (enExample) |
| PE (1) | PE20200604A1 (enExample) |
| PH (1) | PH12019502559A1 (enExample) |
| TW (1) | TWI758480B (enExample) |
| UA (1) | UA125407C2 (enExample) |
| UY (1) | UY37742A (enExample) |
| WO (1) | WO2018215315A1 (enExample) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB201116559D0 (en) | 2011-09-26 | 2011-11-09 | Univ Leuven Kath | Novel viral replication inhibitors |
| JOP20160086B1 (ar) | 2015-05-08 | 2021-08-17 | 2 Katholieke Univ Leuven Ku Leuven Research And Development | مشتقات اندول مستبدلة احاديا او ثنائيا بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| JOP20160198B1 (ar) | 2015-09-16 | 2022-03-14 | Janssen Pharmaceuticals Inc | مشتقات اندول مستبدلة احاديا او ثنائيا بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| JO3633B1 (ar) | 2015-09-16 | 2020-08-27 | Katholieke Univ Leuven Ku Leuven Research & Development | مشتقات اندول مستبدلة احاديا او ثنائيا بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| HUE054936T2 (hu) | 2016-03-31 | 2021-10-28 | Janssen Pharmaceuticals Inc | Helyettesített indol-származékok mint a dengue-vírus replikációjának inhibitorai |
| CA3013407A1 (en) | 2016-03-31 | 2017-10-05 | Janssen Pharmaceuticals, Inc. | Substituted indoline derivatives as dengue viral replication inhibitors |
| JOP20170069B1 (ar) | 2016-04-01 | 2021-08-17 | 1 Janssen Pharmaceuticals Inc | مشتقات اندولين مستبدلة بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| EP3436004B1 (en) | 2016-04-01 | 2024-12-11 | Janssen Pharmaceuticals, Inc. | Substituted indole compound derivatives as dengue viral replication inhibitors |
| JOP20180025B1 (ar) | 2017-03-31 | 2021-08-17 | Janssen Pharmaceuticals Inc | مشتقات اندولين مستبدلة بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| JOP20180026A1 (ar) | 2017-03-31 | 2019-01-30 | Univ Leuven Kath | مشتقات اندولين مستبدلة بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| EA039702B1 (ru) | 2017-05-22 | 2022-03-01 | Янссен Фармасьютикалз, Инк. | Замещенные производные индолина в качестве ингибиторов репликации вирусов денге |
| WO2024252254A1 (en) * | 2023-06-05 | 2024-12-12 | Zydus Lifesciences Limited | Novel compounds to treat viral infections |
Family Cites Families (43)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU1200899A (en) | 1997-10-27 | 1999-05-17 | Eli Lilly And Company | Morpholino-n-ethyl ester prodrugs of indole spla2 inhibitors |
| GB0110832D0 (en) | 2001-05-03 | 2001-06-27 | Virogen Ltd | Antiviral compounds |
| AU2002364566B2 (en) | 2001-12-12 | 2009-03-26 | Conforma Therapeutics Corporation | Assays and implements for determining and modulating HSP90 binding activity |
| GB0215293D0 (en) | 2002-07-03 | 2002-08-14 | Rega Foundation | Viral inhibitors |
| CA2593450A1 (en) | 2005-01-14 | 2006-07-20 | Genelabs Technologies, Inc. | Indole derivatives for treating viral infections |
| US20060194835A1 (en) | 2005-02-09 | 2006-08-31 | Migenix Inc. | Compositions and methods for treating or preventing flaviviridae infections |
| US9029376B2 (en) | 2008-06-03 | 2015-05-12 | Siga Technologies, Inc. | Small molecule inhibitors for the treatment or prevention of dengue virus infection |
| JP5559174B2 (ja) | 2008-08-19 | 2014-07-23 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 冷感−メントール受容体拮抗剤 |
| TWI453207B (zh) | 2008-09-08 | 2014-09-21 | Signal Pharm Llc | 胺基三唑并吡啶，其組合物及使用其之治療方法 |
| EP2393359A4 (en) | 2009-02-09 | 2012-10-03 | Enanta Pharm Inc | COMPOUND DIBENZIMIDAZOLE DERIVATIVES |
| GB0910003D0 (en) | 2009-06-11 | 2009-07-22 | Univ Leuven Kath | Novel compounds for the treatment of neurodegenerative diseases |
| US8993604B2 (en) | 2009-06-30 | 2015-03-31 | Siga Technologies, Inc. | Treatment and prevention of dengue virus infections |
| US7948798B1 (en) | 2009-07-22 | 2011-05-24 | Marvell International Ltd. | Mixed multi-level cell and single level cell storage device |
| WO2011088303A1 (en) | 2010-01-15 | 2011-07-21 | Gilead Sciences , Inc. | Inhibitors of flaviviridae viruses |
| EP2552211A4 (en) | 2010-03-26 | 2013-10-23 | Glaxo Group Ltd | INDAZOLYL-PYRIMIDINE AS KINASEHEMMER |
| JP5716205B2 (ja) | 2011-03-29 | 2015-05-13 | 学校法人日本大学 | グルコシダーゼ活性阻害用組成物及びそのスクリーニング方法 |
| GB201116559D0 (en) * | 2011-09-26 | 2011-11-09 | Univ Leuven Kath | Novel viral replication inhibitors |
| KR20140054425A (ko) * | 2011-09-30 | 2014-05-08 | 후아웨이 테크놀러지 컴퍼니 리미티드 | 네트워크 발호 방법 및 장치 |
| GB201305376D0 (en) | 2013-03-25 | 2013-05-08 | Univ Leuven Kath | Novel viral replication inhibitors |
| DK3060547T3 (en) | 2013-10-23 | 2018-01-15 | Janssen Sciences Ireland Uc | CARBOXAMIDE DERIVATIVES AND USE THEREOF AS MEDICINES FOR TREATMENT OF HEPATITS B |
| UY35971A (es) | 2014-01-31 | 2015-07-31 | Bristol Myers Squibb Company Una Corporación Del Estado De Delaware | Macrociclos con grupos p2? aromáticos como inhibidores del factor xia |
| BR112017006299A2 (pt) * | 2014-10-01 | 2018-01-16 | Janssen Pharmaceuticals, Inc. | derivados indol mono- ou dissubstituídos como inibidores da replicação viral da dengue |
| ME03344B (me) | 2014-10-01 | 2019-10-20 | Janssen Pharmaceuticals Inc | Mono- ili di-supstituisani indoli kao inнibitori replikacije denga virusa |
| NO2721243T3 (enExample) | 2014-10-01 | 2018-10-20 | ||
| PH12017501272B1 (en) | 2015-01-16 | 2023-01-11 | Janssen Pharmaceuticals Inc | Indole derivatives as dengue viral replication inhibitors |
| AR103680A1 (es) | 2015-02-23 | 2017-05-24 | Lilly Co Eli | Inhibidores selectivos de bace1 |
| JOP20160086B1 (ar) | 2015-05-08 | 2021-08-17 | 2 Katholieke Univ Leuven Ku Leuven Research And Development | مشتقات اندول مستبدلة احاديا او ثنائيا بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| JO3633B1 (ar) | 2015-09-16 | 2020-08-27 | Katholieke Univ Leuven Ku Leuven Research & Development | مشتقات اندول مستبدلة احاديا او ثنائيا بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| JOP20160198B1 (ar) | 2015-09-16 | 2022-03-14 | Janssen Pharmaceuticals Inc | مشتقات اندول مستبدلة احاديا او ثنائيا بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| CN108601723B (zh) | 2015-11-03 | 2022-05-17 | 硕腾服务有限责任公司 | 溶胶-凝胶聚合物复合材料及其用途 |
| CA3013407A1 (en) | 2016-03-31 | 2017-10-05 | Janssen Pharmaceuticals, Inc. | Substituted indoline derivatives as dengue viral replication inhibitors |
| HUE054936T2 (hu) | 2016-03-31 | 2021-10-28 | Janssen Pharmaceuticals Inc | Helyettesített indol-származékok mint a dengue-vírus replikációjának inhibitorai |
| SG11201807539UA (en) | 2016-03-31 | 2018-09-27 | Takeda Pharmaceuticals Co | Heterocyclic compound |
| JOP20170069B1 (ar) | 2016-04-01 | 2021-08-17 | 1 Janssen Pharmaceuticals Inc | مشتقات اندولين مستبدلة بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| SG11201808411RA (en) | 2016-04-01 | 2018-10-30 | Kite Pharma Inc | Chimeric antigen and t cell receptors and methods of use |
| KR102411744B1 (ko) | 2016-04-01 | 2022-06-21 | 바스프 에스이 | 바이시클릭 화합물 |
| CN109069512B (zh) | 2016-04-01 | 2022-06-14 | 西格诺药品有限公司 | 取代的氨基嘌呤化合物、其组合物以及相关治疗方法 |
| KR20210089262A (ko) | 2016-04-01 | 2021-07-15 | 카이트 파마 인코포레이티드 | 키메라 수용체 및 그의 사용 방법 |
| EP3436004B1 (en) | 2016-04-01 | 2024-12-11 | Janssen Pharmaceuticals, Inc. | Substituted indole compound derivatives as dengue viral replication inhibitors |
| UA128326C2 (uk) | 2016-04-01 | 2024-06-12 | Амджен Інк. | Химерний рецептор до flt3 та спосіб його застосування |
| JOP20180025B1 (ar) | 2017-03-31 | 2021-08-17 | Janssen Pharmaceuticals Inc | مشتقات اندولين مستبدلة بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| JOP20180026A1 (ar) | 2017-03-31 | 2019-01-30 | Univ Leuven Kath | مشتقات اندولين مستبدلة بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| EA039702B1 (ru) | 2017-05-22 | 2022-03-01 | Янссен Фармасьютикалз, Инк. | Замещенные производные индолина в качестве ингибиторов репликации вирусов денге |
-
2018
- 2018-05-18 EA EA201992782A patent/EA201992782A1/ru unknown
- 2018-05-18 JP JP2019564166A patent/JP7203764B2/ja active Active
- 2018-05-18 MX MX2019013893A patent/MX393586B/es unknown
- 2018-05-18 CA CA3060583A patent/CA3060583C/en active Active
- 2018-05-18 TW TW107116924A patent/TWI758480B/zh not_active IP Right Cessation
- 2018-05-18 EP EP18728541.6A patent/EP3630723B1/en active Active
- 2018-05-18 PE PE2019002404A patent/PE20200604A1/es unknown
- 2018-05-18 AU AU2018274100A patent/AU2018274100B2/en active Active
- 2018-05-18 KR KR1020197036401A patent/KR102625988B1/ko active Active
- 2018-05-18 ES ES18728541T patent/ES2929667T3/es active Active
- 2018-05-18 WO PCT/EP2018/063028 patent/WO2018215315A1/en not_active Ceased
- 2018-05-18 US US16/612,670 patent/US11407715B2/en active Active
- 2018-05-18 MA MA048943A patent/MA48943A/fr unknown
- 2018-05-18 UA UAA201912024A patent/UA125407C2/uk unknown
- 2018-05-18 CN CN201880033697.9A patent/CN110691773B/zh active Active
- 2018-05-18 BR BR112019024195-7A patent/BR112019024195A2/pt active Search and Examination
- 2018-05-18 CR CR20190530A patent/CR20190530A/es unknown
- 2018-05-21 AR ARP180101342A patent/AR111878A1/es not_active Application Discontinuation
- 2018-05-22 UY UY0001037742A patent/UY37742A/es unknown
-
2019
- 2019-10-28 CO CONC2019/0012035A patent/CO2019012035A2/es unknown
- 2019-11-15 CL CL2019003294A patent/CL2019003294A1/es unknown
- 2019-11-15 PH PH12019502559A patent/PH12019502559A1/en unknown
- 2019-11-18 IL IL270726A patent/IL270726B2/en unknown
- 2019-11-21 NI NI201900119A patent/NI201900119A/es unknown
- 2019-11-22 EC ECSENADI201983640A patent/ECSP19083640A/es unknown
-
2022
- 2022-06-16 US US17/842,367 patent/US11795149B2/en active Active
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2929667T3 (es) | Derivados de indolina sustituidos como inhibidores de la replicación vírica de dengue | |
| ES2884067T3 (es) | Derivados de indolina sustituidos como inhibidores de la replicación viral del dengue | |
| ES2882488T3 (es) | Derivados de indol sustituidos como inhibidores de la replicación vírica del dengue | |
| ES2877404T3 (es) | Derivados de indol mono o disustituidos como inhibidores de la replicación viral del dengue | |
| ES2778431T3 (es) | Derivados de indol mono- o disustituidos como inhibidores de la replicación viral del dengue | |
| ES2887673T3 (es) | Derivados de indolina sustituidos como inhibidores de la replicación vírica de dengue | |
| ES2923771T3 (es) | Derivados de indolina sustituidos como inhibidores de la replicación vírica de dengue | |
| ES2714074T3 (es) | Derivados de indol mono- o disustituidos como inhibidores de la replicación del virus del dengue | |
| AU2016254700A1 (en) | RSV antiviral pyrazolo- and triazolo-pyrimidine compounds | |
| AU2012206555A1 (en) | Oxazine derivatives and their use in the treatment of neurological disorders | |
| BR112019024311A2 (pt) | derivados de indolina substituídos como inibidores da replicação viral do dengue | |
| KR20170103820A (ko) | 뎅기 바이러스 복제 억제제로서의 인돌 유도체 | |
| HK40023943B (en) | Substituted indoline derivatives as dengue viral replication inhibitors | |
| HK40023943A (en) | Substituted indoline derivatives as dengue viral replication inhibitors | |
| EA041349B1 (ru) | Замещенные производные индолина в качестве ингибиторов репликации вирусов денге | |
| OA19488A (en) | Substituted indoline derivatives as dengue viral replication inhibitors. | |
| HK1260967B (en) | Substituted indoline derivatives as dengue viral replication inhibitors |