TWI723148B - 作為登革熱病毒複製抑制劑的經取代的吲哚啉衍生物 - Google Patents
作為登革熱病毒複製抑制劑的經取代的吲哚啉衍生物 Download PDFInfo
- Publication number
- TWI723148B TWI723148B TW106110686A TW106110686A TWI723148B TW I723148 B TWI723148 B TW I723148B TW 106110686 A TW106110686 A TW 106110686A TW 106110686 A TW106110686 A TW 106110686A TW I723148 B TWI723148 B TW I723148B
- Authority
- TW
- Taiwan
- Prior art keywords
- compound
- mixture
- reduced pressure
- under reduced
- indolin
- Prior art date
Links
- 206010012310 Dengue fever Diseases 0.000 title claims abstract description 49
- 208000025729 dengue disease Diseases 0.000 title claims abstract description 40
- 208000001490 Dengue Diseases 0.000 title claims abstract description 37
- 125000003387 indolinyl group Chemical class N1(CCC2=CC=CC=C12)* 0.000 title abstract 2
- 229940123627 Viral replication inhibitor Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 138
- 239000003814 drug Substances 0.000 claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims description 23
- 241000725619 Dengue virus Species 0.000 claims description 10
- 229960005486 vaccine Drugs 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 239000003443 antiviral agent Substances 0.000 claims description 5
- 229940124597 therapeutic agent Drugs 0.000 claims description 5
- 239000000969 carrier Substances 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000010076 replication Effects 0.000 claims description 3
- 239000012472 biological sample Substances 0.000 claims 2
- 238000011260 co-administration Methods 0.000 claims 2
- 230000002401 inhibitory effect Effects 0.000 claims 2
- 239000000203 mixture Substances 0.000 abstract description 82
- 238000000034 method Methods 0.000 abstract description 42
- 238000002360 preparation method Methods 0.000 abstract description 10
- 208000036142 Viral infection Diseases 0.000 abstract description 7
- 230000009385 viral infection Effects 0.000 abstract description 7
- 230000002265 prevention Effects 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 131
- 235000019439 ethyl acetate Nutrition 0.000 description 65
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 60
- 239000000243 solution Substances 0.000 description 49
- 239000002904 solvent Substances 0.000 description 46
- 230000015572 biosynthetic process Effects 0.000 description 45
- 238000003786 synthesis reaction Methods 0.000 description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 41
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 41
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 41
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 39
- 239000000543 intermediate Substances 0.000 description 38
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 37
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 239000000460 chlorine Substances 0.000 description 33
- 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 30
- -1 and more preferably Substances 0.000 description 30
- 241000700605 Viruses Species 0.000 description 29
- 210000004027 cell Anatomy 0.000 description 26
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 26
- 239000000741 silica gel Substances 0.000 description 25
- 229910002027 silica gel Inorganic materials 0.000 description 25
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 22
- 230000005526 G1 to G0 transition Effects 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 21
- 239000012071 phase Substances 0.000 description 21
- 238000003818 flash chromatography Methods 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 238000000926 separation method Methods 0.000 description 19
- 239000003208 petroleum Substances 0.000 description 18
- 229910002091 carbon monoxide Inorganic materials 0.000 description 17
- 238000004808 supercritical fluid chromatography Methods 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 108091027076 Spiegelmer Proteins 0.000 description 15
- 229910052739 hydrogen Inorganic materials 0.000 description 15
- 239000001257 hydrogen Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- 238000002844 melting Methods 0.000 description 13
- 230000008018 melting Effects 0.000 description 13
- 239000002244 precipitate Substances 0.000 description 13
- 108020004414 DNA Proteins 0.000 description 12
- 208000009714 Severe Dengue Diseases 0.000 description 12
- 150000003840 hydrochlorides Chemical class 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 239000012267 brine Substances 0.000 description 11
- 229910052801 chlorine Inorganic materials 0.000 description 11
- 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 11
- 239000002609 medium Substances 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- PNPLYTNOEFFKNA-UHFFFAOYSA-N tert-butyl 4-(3-amino-5-methoxyphenoxy)butanoate Chemical compound COc1cc(N)cc(OCCCC(=O)OC(C)(C)C)c1 PNPLYTNOEFFKNA-UHFFFAOYSA-N 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 10
- 239000002552 dosage form Substances 0.000 description 10
- 239000012047 saturated solution Substances 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 208000015181 infectious disease Diseases 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 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 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 229940125782 compound 2 Drugs 0.000 description 6
- 229940126214 compound 3 Drugs 0.000 description 6
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 6
- VHQPEHBWUWLJFQ-UHFFFAOYSA-N 2-(4-chlorophenyl)-1-[6-(trifluoromethyl)-2,3-dihydroindol-1-yl]ethanone Chemical compound ClC1=CC=C(C=C1)CC(=O)N1CCC2=CC=C(C=C12)C(F)(F)F VHQPEHBWUWLJFQ-UHFFFAOYSA-N 0.000 description 5
- PFJAAZZTRRUMTE-UHFFFAOYSA-N 2-(4-fluorophenyl)-2-[3-methoxy-5-[4-[(2-methylpropan-2-yl)oxy]-4-oxobutoxy]anilino]acetic acid Chemical compound COc1cc(NC(C(O)=O)c2ccc(F)cc2)cc(OCCCC(=O)OC(C)(C)C)c1 PFJAAZZTRRUMTE-UHFFFAOYSA-N 0.000 description 5
- CTLOPAORVXJWOV-UHFFFAOYSA-N 2-bromo-2-(4-chloro-2-fluorophenyl)-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)F CTLOPAORVXJWOV-UHFFFAOYSA-N 0.000 description 5
- JILKWBDIRAQERV-UHFFFAOYSA-N 2-bromo-2-(4-chloro-2-fluorophenyl)-1-[6-(trifluoromethyl)-2,3-dihydroindol-1-yl]ethanone Chemical compound BrC(C(=O)N1CCC2=CC=C(C=C12)C(F)(F)F)C1=C(C=C(C=C1)Cl)F JILKWBDIRAQERV-UHFFFAOYSA-N 0.000 description 5
- 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 5
- FOJLMEWOZYCPJI-UHFFFAOYSA-N 2-bromo-2-(4-chloro-2-methoxyphenyl)-1-[6-(trifluoromethyl)-2,3-dihydroindol-1-yl]ethanone Chemical compound BrC(C(=O)N1CCC2=CC=C(C=C12)C(F)(F)F)C1=C(C=C(C=C1)Cl)OC FOJLMEWOZYCPJI-UHFFFAOYSA-N 0.000 description 5
- JMPVPWIAZHUIGD-UHFFFAOYSA-N 2-bromo-2-(4-chlorophenyl)-1-[5-methoxy-6-(trifluoromethoxy)-2,3-dihydroindol-1-yl]ethanone Chemical compound BrC(C(=O)N1CCC2=CC(=C(C=C12)OC(F)(F)F)OC)C1=CC=C(C=C1)Cl JMPVPWIAZHUIGD-UHFFFAOYSA-N 0.000 description 5
- AYHLFSWSYYENTK-UHFFFAOYSA-N 2-bromo-2-(4-chlorophenyl)-1-[5-methoxy-6-(trifluoromethyl)-2,3-dihydroindol-1-yl]ethanone Chemical compound BrC(C(=O)N1CCC2=CC(=C(C=C12)C(F)(F)F)OC)C1=CC=C(C=C1)Cl AYHLFSWSYYENTK-UHFFFAOYSA-N 0.000 description 5
- 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 5
- RRTXSYYNUIEUJC-UHFFFAOYSA-N 2-bromo-2-(4-chlorophenyl)-1-[6-(trifluoromethyl)-2,3-dihydroindol-1-yl]ethanone Chemical compound BrC(C(=O)N1CCC2=CC=C(C=C12)C(F)(F)F)C1=CC=C(C=C1)Cl RRTXSYYNUIEUJC-UHFFFAOYSA-N 0.000 description 5
- FERVQOJSXHQSBS-UHFFFAOYSA-N 2-bromo-4-methoxy-5-(trifluoromethoxy)aniline Chemical compound BrC1=C(N)C=C(C(=C1)OC)OC(F)(F)F FERVQOJSXHQSBS-UHFFFAOYSA-N 0.000 description 5
- BLRRJWAWRFPKLT-UHFFFAOYSA-N 4-methoxy-5-(trifluoromethoxy)-2-(2-trimethylsilylethynyl)aniline Chemical compound COC1=CC(=C(N)C=C1OC(F)(F)F)C#C[Si](C)(C)C BLRRJWAWRFPKLT-UHFFFAOYSA-N 0.000 description 5
- LJPJLAKIEGLOPZ-UHFFFAOYSA-N 5-methoxy-6-(trifluoromethoxy)-1H-indole Chemical compound COC=1C=C2C=CNC2=CC=1OC(F)(F)F LJPJLAKIEGLOPZ-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
- 241000710831 Flavivirus Species 0.000 description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 5
- 230000000840 anti-viral effect Effects 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 5
- 201000002950 dengue hemorrhagic fever Diseases 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 150000002476 indolines Chemical class 0.000 description 5
- 239000000377 silicon dioxide Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 5
- JXQOTIDFVFDRRW-UHFFFAOYSA-N 1-[6-(trifluoromethoxy)-2,3-dihydroindol-1-yl]ethanone Chemical compound FC(OC1=CC=C2CCN(C2=C1)C(C)=O)(F)F JXQOTIDFVFDRRW-UHFFFAOYSA-N 0.000 description 4
- MGFDOOGLLSEOAQ-UHFFFAOYSA-N 2-bromo-2-(4-chloro-2-fluorophenyl)-1-[5-methoxy-6-(trifluoromethyl)-2,3-dihydroindol-1-yl]ethanone Chemical compound BrC(C(=O)N1CCC2=CC(=C(C=C12)C(F)(F)F)OC)C1=C(C=C(C=C1)Cl)F MGFDOOGLLSEOAQ-UHFFFAOYSA-N 0.000 description 4
- KKMCPRBVFGVTIV-UHFFFAOYSA-N 2-bromo-2-(4-chloro-2-methoxyphenyl)-1-[5-methoxy-6-(trifluoromethyl)-2,3-dihydroindol-1-yl]ethanone Chemical compound BrC(C(=O)N1CCC2=CC(=C(C=C12)C(F)(F)F)OC)C1=C(C=C(C=C1)Cl)OC KKMCPRBVFGVTIV-UHFFFAOYSA-N 0.000 description 4
- 108020005345 3' Untranslated Regions Proteins 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 4
- CDPKJZJVTHSESZ-UHFFFAOYSA-N 4-chlorophenylacetic acid Chemical compound OC(=O)CC1=CC=C(Cl)C=C1 CDPKJZJVTHSESZ-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 210000003501 vero cell Anatomy 0.000 description 4
- 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
- QLRKBYZLPCDISY-UHFFFAOYSA-N 4-[3-[[1-(4-chloro-2-methoxyphenyl)-2-oxo-2-[6-(trifluoromethyl)-2,3-dihydroindol-1-yl]ethyl]amino]-5-methoxyphenoxy]butanoic acid Chemical compound ClC1=CC(=C(C=C1)C(C(N1CCC2=CC=C(C=C12)C(F)(F)F)=O)NC=1C=C(OCCCC(=O)O)C=C(C=1)OC)OC QLRKBYZLPCDISY-UHFFFAOYSA-N 0.000 description 3
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 3
- 102000007469 Actins Human genes 0.000 description 3
- 108010085238 Actins Proteins 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 239000013592 cell lysate Substances 0.000 description 3
- 239000002299 complementary DNA Substances 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 201000009892 dengue shock syndrome Diseases 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 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 3
- 238000005259 measurement Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000010839 reverse transcription Methods 0.000 description 3
- 230000029812 viral genome replication Effects 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- IDZHGNMTEPOUAZ-UHFFFAOYSA-N 4-[3-[[1-(4-chloro-2-fluorophenyl)-2-[5-methoxy-6-(trifluoromethyl)-2,3-dihydroindol-1-yl]-2-oxoethyl]amino]-5-methoxyphenoxy]butanoic acid Chemical compound ClC1=CC(=C(C=C1)C(C(=O)N1CCC2=CC(=C(C=C12)C(F)(F)F)OC)NC=1C=C(OCCCC(=O)O)C=C(C=1)OC)F IDZHGNMTEPOUAZ-UHFFFAOYSA-N 0.000 description 2
- CSJFHVMGOOLJKB-UHFFFAOYSA-N 4-[3-[[1-(4-chloro-2-methoxyphenyl)-2-[5-methoxy-6-(trifluoromethyl)-2,3-dihydroindol-1-yl]-2-oxoethyl]amino]-5-methoxyphenoxy]butanoic acid Chemical compound ClC1=CC(=C(C=C1)C(C(=O)N1CCC2=CC(=C(C=C12)C(F)(F)F)OC)NC=1C=C(OCCCC(=O)O)C=C(C=1)OC)OC CSJFHVMGOOLJKB-UHFFFAOYSA-N 0.000 description 2
- JXHWTBYDKCXMBE-UHFFFAOYSA-N 4-[3-[[1-(4-chloro-2-methoxyphenyl)-2-oxo-2-[6-(trifluoromethoxy)-2,3-dihydroindol-1-yl]ethyl]amino]-5-methoxyphenoxy]butanoic acid Chemical compound ClC1=CC(=C(C=C1)C(C(N1CCC2=CC=C(C=C12)OC(F)(F)F)=O)NC=1C=C(OCCCC(=O)O)C=C(C=1)OC)OC JXHWTBYDKCXMBE-UHFFFAOYSA-N 0.000 description 2
- WUBVXTOLZKVNEG-UHFFFAOYSA-N 4-[3-[[1-(4-chlorophenyl)-2-oxo-2-[6-(trifluoromethoxy)-2,3-dihydroindol-1-yl]ethyl]amino]-5-methoxyphenoxy]butanoic acid Chemical compound ClC1=CC=C(C=C1)C(C(N1CCC2=CC=C(C=C12)OC(F)(F)F)=O)NC=1C=C(OCCCC(=O)O)C=C(C=1)OC WUBVXTOLZKVNEG-UHFFFAOYSA-N 0.000 description 2
- GRURNZDSWAIYNK-UHFFFAOYSA-N 4-[3-[[1-(4-fluorophenyl)-2-oxo-2-[6-(trifluoromethyl)-2,3-dihydroindol-1-yl]ethyl]amino]-5-methoxyphenoxy]butanoic acid Chemical compound FC1=CC=C(C=C1)C(C(N1CCC2=CC=C(C=C12)C(F)(F)F)=O)NC=1C=C(OCCCC(=O)O)C=C(C=1)OC GRURNZDSWAIYNK-UHFFFAOYSA-N 0.000 description 2
- DUVZZCODYYUDAN-UHFFFAOYSA-N 5-methoxy-6-(trifluoromethoxy)-2,3-dihydro-1H-indole Chemical compound COC=1C=C2CCNC2=CC=1OC(F)(F)F DUVZZCODYYUDAN-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 108700039887 Essential Genes Proteins 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
- 229910004373 HOAc Inorganic materials 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
- 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
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- XUPYJHCZDLZNFP-UHFFFAOYSA-N butyl butanoate Chemical group CCCCOC(=O)CCC XUPYJHCZDLZNFP-UHFFFAOYSA-N 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 238000013480 data collection Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 229960002518 gentamicin Drugs 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000004989 laser desorption mass spectroscopy Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- ZDQQNZRQRARBNB-UHFFFAOYSA-N methyl 2-bromo-2-(4-fluorophenyl)acetate Chemical compound COC(=O)C(Br)C1=CC=C(F)C=C1 ZDQQNZRQRARBNB-UHFFFAOYSA-N 0.000 description 2
- 239000007758 minimum essential medium Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 238000001556 precipitation Methods 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
- 238000003753 real-time PCR Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- HJEZRYIJNHAIGY-UHFFFAOYSA-N tert-butyl 4-bromobutanoate Chemical compound CC(C)(C)OC(=O)CCCBr HJEZRYIJNHAIGY-UHFFFAOYSA-N 0.000 description 2
- TWBUVVYSQBFVGZ-UHFFFAOYSA-N tert-butyl butanoate Chemical compound CCCC(=O)OC(C)(C)C TWBUVVYSQBFVGZ-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
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- CSJCEQXZVMIHRX-UHFFFAOYSA-N 2,3-dibenzyl-2,3-dihydroxybutanedioic acid Chemical compound C=1C=CC=CC=1CC(O)(C(O)=O)C(O)(C(=O)O)CC1=CC=CC=C1 CSJCEQXZVMIHRX-UHFFFAOYSA-N 0.000 description 1
- SUDDXMSROFLAQH-UHFFFAOYSA-N 2,3-dihydroxy-2-methylbutanedioic acid Chemical compound OC(=O)C(O)(C)C(O)C(O)=O SUDDXMSROFLAQH-UHFFFAOYSA-N 0.000 description 1
- GVXYUPXSNSXAJR-UHFFFAOYSA-N 2-(4-chloro-2-fluorophenyl)-1-[5-methoxy-6-(trifluoromethyl)-2,3-dihydroindol-1-yl]ethanone Chemical compound ClC1=CC(=C(C=C1)CC(=O)N1CCC2=CC(=C(C=C12)C(F)(F)F)OC)F GVXYUPXSNSXAJR-UHFFFAOYSA-N 0.000 description 1
- ZIMFCYSPYGTOTG-UHFFFAOYSA-N 2-(4-chloro-2-fluorophenyl)-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)F ZIMFCYSPYGTOTG-UHFFFAOYSA-N 0.000 description 1
- SVGCGBBTQQCSTB-UHFFFAOYSA-N 2-(4-chloro-2-fluorophenyl)-1-[6-(trifluoromethyl)-2,3-dihydroindol-1-yl]ethanone Chemical compound ClC1=CC(=C(C=C1)CC(=O)N1CCC2=CC=C(C=C12)C(F)(F)F)F SVGCGBBTQQCSTB-UHFFFAOYSA-N 0.000 description 1
- KNSKQEBRBDTLOY-UHFFFAOYSA-N 2-(4-chloro-2-methoxyphenyl)-1-[5-methoxy-6-(trifluoromethyl)-2,3-dihydroindol-1-yl]ethanone Chemical compound ClC1=CC(=C(C=C1)CC(=O)N1CCC2=CC(=C(C=C12)C(F)(F)F)OC)OC KNSKQEBRBDTLOY-UHFFFAOYSA-N 0.000 description 1
- 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 1
- QCUAKQLTEQWKJC-UHFFFAOYSA-N 2-(4-chloro-2-methoxyphenyl)-1-[6-(trifluoromethyl)-2,3-dihydroindol-1-yl]ethanone Chemical compound ClC1=CC(=C(C=C1)CC(=O)N1CCC2=CC=C(C=C12)C(F)(F)F)OC QCUAKQLTEQWKJC-UHFFFAOYSA-N 0.000 description 1
- OMHNSGDZKOCPGD-UHFFFAOYSA-N 2-(4-chlorophenyl)-1-[5-methoxy-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 OMHNSGDZKOCPGD-UHFFFAOYSA-N 0.000 description 1
- 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 1
- JJYGLVJBOIUCCE-UHFFFAOYSA-N 2-(4-fluorophenyl)-1-[6-(trifluoromethoxy)-2,3-dihydroindol-1-yl]ethanone Chemical compound FC1=CC=C(C=C1)CC(=O)N1CCC2=CC=C(C=C12)OC(F)(F)F JJYGLVJBOIUCCE-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
- CECFBCCDJBWCSO-UHFFFAOYSA-N 2-bromo-2-(4-fluorophenyl)-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)F CECFBCCDJBWCSO-UHFFFAOYSA-N 0.000 description 1
- NRGGMCIBEHEAIL-UHFFFAOYSA-N 2-ethylpyridine Chemical compound CCC1=CC=CC=N1 NRGGMCIBEHEAIL-UHFFFAOYSA-N 0.000 description 1
- JUTDHSGANMHVIC-UHFFFAOYSA-N 2-phenylpyrrolidine Chemical compound C1CCNC1C1=CC=CC=C1 JUTDHSGANMHVIC-UHFFFAOYSA-N 0.000 description 1
- MAKLWNLHSDQZDV-UHFFFAOYSA-N 4-[3-[[1-(4-chloro-2-fluorophenyl)-2-oxo-2-[6-(trifluoromethoxy)-2,3-dihydroindol-1-yl]ethyl]amino]-5-methoxyphenoxy]butanoic acid Chemical compound ClC1=CC(=C(C=C1)C(C(N1CCC2=CC=C(C=C12)OC(F)(F)F)=O)NC=1C=C(OCCCC(=O)O)C=C(C=1)OC)F MAKLWNLHSDQZDV-UHFFFAOYSA-N 0.000 description 1
- OOOZVXBDNJBTSS-UHFFFAOYSA-N 4-[3-[[1-(4-chloro-2-fluorophenyl)-2-oxo-2-[6-(trifluoromethyl)-2,3-dihydroindol-1-yl]ethyl]amino]-5-methoxyphenoxy]butanoic acid Chemical compound ClC1=CC(=C(C=C1)C(C(N1CCC2=CC=C(C=C12)C(F)(F)F)=O)NC=1C=C(OCCCC(=O)O)C=C(C=1)OC)F OOOZVXBDNJBTSS-UHFFFAOYSA-N 0.000 description 1
- QRUHUNZPVYZIMH-UHFFFAOYSA-N 4-[3-[[1-(4-chlorophenyl)-2-[5-methoxy-6-(trifluoromethyl)-2,3-dihydroindol-1-yl]-2-oxoethyl]amino]-5-methoxyphenoxy]butanoic acid Chemical compound ClC1=CC=C(C=C1)C(C(=O)N1CCC2=CC(=C(C=C12)C(F)(F)F)OC)NC=1C=C(OCCCC(=O)O)C=C(C=1)OC QRUHUNZPVYZIMH-UHFFFAOYSA-N 0.000 description 1
- DQDKOANVADPVQR-UHFFFAOYSA-N 5-imino-3,4-dihydropyrrol-2-amine Chemical compound NC1=NC(=N)CC1 DQDKOANVADPVQR-UHFFFAOYSA-N 0.000 description 1
- WWBVZCBWSHFMLP-UHFFFAOYSA-N 6-(trifluoromethyl)-2,3-dihydro-1h-indole Chemical compound FC(F)(F)C1=CC=C2CCNC2=C1 WWBVZCBWSHFMLP-UHFFFAOYSA-N 0.000 description 1
- 241000238876 Acari Species 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
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- YXKXFNWPLRLIQQ-UHFFFAOYSA-N CCCCOC(=O)CCCOC1=CC(=CC(=C1)OC)N Chemical group CCCCOC(=O)CCCOC1=CC(=CC(=C1)OC)N YXKXFNWPLRLIQQ-UHFFFAOYSA-N 0.000 description 1
- AGNQZUXPHCHKMG-UHFFFAOYSA-N COc1cc(NC(C(N2c3cc(C(F)(F)F)ccc3CC2)=O)c(cc2)ccc2Cl)cc(OCCCC(O)=O)c1 Chemical compound COc1cc(NC(C(N2c3cc(C(F)(F)F)ccc3CC2)=O)c(cc2)ccc2Cl)cc(OCCCC(O)=O)c1 AGNQZUXPHCHKMG-UHFFFAOYSA-N 0.000 description 1
- 0 COc1cc(OCCCC(O)=O)cc(NC(C(N2c3cc(*)c(*)cc3CC2)=O)c2c(*)cc(*)cc2)c1 Chemical compound COc1cc(OCCCC(O)=O)cc(NC(C(N2c3cc(*)c(*)cc3CC2)=O)c2c(*)cc(*)cc2)c1 0.000 description 1
- GISXLKCJMHWQTE-UHFFFAOYSA-N COc1cc(OCCCC(O)=O)cc(NC(C(N2c3cc(OC(F)(F)F)ccc3CC2)=O)c(cc2)ccc2F)c1 Chemical compound COc1cc(OCCCC(O)=O)cc(NC(C(N2c3cc(OC(F)(F)F)ccc3CC2)=O)c(cc2)ccc2F)c1 GISXLKCJMHWQTE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000003322 Coinfection Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 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
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 231100000491 EC50 Toxicity 0.000 description 1
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 1
- 206010061192 Haemorrhagic fever Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 241000282376 Panthera tigris Species 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 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
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000002832 anti-viral assay Methods 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 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
- XWRLQRLQUKZEEU-UHFFFAOYSA-N ethyl(hydroxy)silicon Chemical class CC[Si]O XWRLQRLQUKZEEU-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000006872 improvement Effects 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
- 239000011872 intimate mixture Substances 0.000 description 1
- 230000000155 isotopic effect 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
- 239000010410 layer Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000014759 maintenance of location Effects 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
- 239000003607 modifier Substances 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 238000004305 normal phase HPLC Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000008520 organization Effects 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
- 210000004508 polar body Anatomy 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- JMMIEJNIXKVNOG-UHFFFAOYSA-N tert-butyl 4-[3-[[1-(4-chloro-2-fluorophenyl)-2-oxo-2-[6-(trifluoromethoxy)-2,3-dihydroindol-1-yl]ethyl]amino]-5-methoxyphenoxy]butanoate Chemical compound COc1cc(NC(C(=O)N2CCc3ccc(OC(F)(F)F)cc23)c2ccc(Cl)cc2F)cc(OCCCC(=O)OC(C)(C)C)c1 JMMIEJNIXKVNOG-UHFFFAOYSA-N 0.000 description 1
- IILJOLDKUMXNTR-UHFFFAOYSA-N tert-butyl 4-[3-[[1-(4-chloro-2-fluorophenyl)-2-oxo-2-[6-(trifluoromethyl)-2,3-dihydroindol-1-yl]ethyl]amino]-5-methoxyphenoxy]butanoate Chemical compound COc1cc(NC(C(=O)N2CCc3ccc(cc23)C(F)(F)F)c2ccc(Cl)cc2F)cc(OCCCC(=O)OC(C)(C)C)c1 IILJOLDKUMXNTR-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 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
- 230000001052 transient effect Effects 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000008096 xylene Substances 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
- 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
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- 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)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ??16163488.6 | 2016-04-01 | ||
| EP16163488 | 2016-04-01 | ||
| EP16163488.6 | 2016-04-01 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW201808898A TW201808898A (zh) | 2018-03-16 |
| TWI723148B true TWI723148B (zh) | 2021-04-01 |
Family
ID=55650311
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW106110686A TWI723148B (zh) | 2016-04-01 | 2017-03-30 | 作為登革熱病毒複製抑制劑的經取代的吲哚啉衍生物 |
Country Status (31)
| Country | Link |
|---|---|
| US (2) | US10689340B2 (enExample) |
| EP (1) | EP3436437B1 (enExample) |
| JP (1) | JP6970115B2 (enExample) |
| KR (1) | KR102359776B1 (enExample) |
| CN (1) | CN108884037B (enExample) |
| AR (1) | AR108046A1 (enExample) |
| AU (1) | AU2017242894B2 (enExample) |
| CA (1) | CA3013406C (enExample) |
| CL (1) | CL2018002758A1 (enExample) |
| CO (1) | CO2018009563A2 (enExample) |
| CR (1) | CR20180493A (enExample) |
| DK (1) | DK3436437T3 (enExample) |
| EA (1) | EA037988B1 (enExample) |
| EC (1) | ECSP18073293A (enExample) |
| ES (1) | ES2884067T3 (enExample) |
| HR (1) | HRP20211278T1 (enExample) |
| HU (1) | HUE055577T2 (enExample) |
| IL (1) | IL261948B (enExample) |
| JO (1) | JOP20170069B1 (enExample) |
| LT (1) | LT3436437T (enExample) |
| MX (1) | MX381634B (enExample) |
| MY (1) | MY195194A (enExample) |
| PE (1) | PE20181778A1 (enExample) |
| PH (1) | PH12018502077A1 (enExample) |
| SG (1) | SG11201808409XA (enExample) |
| SI (1) | SI3436437T1 (enExample) |
| TW (1) | TWI723148B (enExample) |
| UA (1) | UA125296C2 (enExample) |
| UY (1) | UY37182A (enExample) |
| WO (1) | WO2017167951A1 (enExample) |
| ZA (1) | ZA201806482B (enExample) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB201116559D0 (en) | 2011-09-26 | 2011-11-09 | Univ Leuven Kath | Novel viral replication inhibitors |
| GB201305376D0 (en) | 2013-03-25 | 2013-05-08 | 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 |
| SG11201808138YA (en) | 2016-03-31 | 2018-10-30 | Janssen Pharmaceuticals Inc | Substituted indole derivatives as dengue viral replication inhibitors |
| US10913716B2 (en) | 2016-03-31 | 2021-02-09 | Janssen Pharmaceuticals, Inc. | Substituted indoline derivatives as dengue viral replication inhibitors |
| CR20180494A (es) | 2016-04-01 | 2019-01-29 | Janssen Pharmaceuticals Inc | Derivados de compuestos de indol sustituidos como inhibidores de la replicación vírica del dengue |
| JOP20170069B1 (ar) | 2016-04-01 | 2021-08-17 | 1 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 |
| JOP20180025B1 (ar) | 2017-03-31 | 2021-08-17 | Janssen Pharmaceuticals Inc | مشتقات اندولين مستبدلة بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| KR102625988B1 (ko) | 2017-05-22 | 2024-01-16 | 얀센 파마슈티칼즈, 인코포레이티드 | 뎅기 바이러스 복제 억제제로서의 치환 인돌린 유도체 |
| EA039702B1 (ru) | 2017-05-22 | 2022-03-01 | Янссен Фармасьютикалз, Инк. | Замещенные производные индолина в качестве ингибиторов репликации вирусов денге |
| BR112022009199A2 (pt) | 2019-11-15 | 2022-07-26 | Janssen Pharmaceuticals Inc | Tratamento e prevenção da dengue |
| WO2025248536A1 (en) * | 2024-05-29 | 2025-12-04 | Zydus Lifesciences Limited | Novel oxime derivatives to treat viral infections |
| WO2025253267A1 (en) | 2024-06-06 | 2025-12-11 | Janssen Pharmaceuticals, Inc. | Combination of mosnodenvir and close analogs with nitd-688 for use in the treatment and prevention of dengue disease |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010021878A1 (en) * | 2008-08-19 | 2010-02-25 | Janssen Pharmaceutica Nv | Cold menthol receptor antagonists |
| WO2013045516A1 (en) * | 2011-09-26 | 2013-04-04 | Katholieke Universiteit Leuven | Viral replication inhibitors |
Family Cites Families (40)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2308443A1 (en) | 1997-10-27 | 1999-05-06 | Michael Lyle Denney | Morpholino-n-ethyl ester prodrugs of indole spla2 inhibitors |
| GB0110832D0 (en) | 2001-05-03 | 2001-06-27 | Virogen Ltd | Antiviral compounds |
| US20050074457A1 (en) | 2001-12-12 | 2005-04-07 | Adeela Kamal | Assays and implements for determining and modulating hsp90 binding activity |
| GB0215293D0 (en) | 2002-07-03 | 2002-08-14 | Rega Foundation | Viral inhibitors |
| RU2007130896A (ru) | 2005-01-14 | 2009-02-20 | Дженелэбс Текнолоджиз, Инк. (Us) | Индольные производные для лечения вирусных инфекций |
| EA200701669A1 (ru) | 2005-02-09 | 2008-02-28 | Мидженикс Инк. | Композиции и способы лечения или предотвращения инфекций, вызванных вирусами семейства flaviviridae |
| AU2009256390A1 (en) | 2008-06-03 | 2009-12-10 | Siga Technologies, Inc. | Small molecule inhibitors for the treatment or prevention of dengue virus infection |
| 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 |
| UA108221C2 (uk) | 2010-01-15 | 2015-04-10 | Похідні тіофен-2-карбонової кислоти як інгібітори вірусів flaviviridae | |
| 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 |
| GB201305376D0 (en) * | 2013-03-25 | 2013-05-08 | Univ Leuven Kath | Novel viral replication inhibitors |
| MX368158B (es) | 2013-10-23 | 2019-09-20 | Janssen Sciences Ireland Uc | Derivados de carboxamida y su uso como medicamentos para el tratamiento de la hepatitis b. |
| ES2784841T3 (es) | 2014-01-31 | 2020-10-01 | Bristol Myers Squibb Co | Macrociclos con grupos aromáticos P2' como inhibidores del factor XIa |
| CA2958022A1 (en) | 2014-10-01 | 2016-04-07 | Janssen Pharmaceuticals, Inc | Mono- or di-substituted indoles as dengue viral replication inhibitors |
| LT3201176T (lt) | 2014-10-01 | 2019-03-25 | Janssen Pharmaceuticals, Inc. | Mono- arba dipakeistieji indolo dariniai kaip dengės viruso replikacijos slopikliai |
| 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 |
| ES2907686T3 (es) | 2015-11-03 | 2022-04-26 | Zoetis Services Llc | Compuestos poliméricos sol-gel y sus usos |
| JP6788683B2 (ja) | 2016-03-31 | 2020-11-25 | 武田薬品工業株式会社 | 複素環化合物 |
| US10913716B2 (en) | 2016-03-31 | 2021-02-09 | Janssen Pharmaceuticals, Inc. | Substituted indoline derivatives as dengue viral replication inhibitors |
| SG11201808138YA (en) | 2016-03-31 | 2018-10-30 | Janssen Pharmaceuticals Inc | Substituted indole 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 |
| WO2017173410A1 (en) | 2016-04-01 | 2017-10-05 | Amgen Inc. | Chimeric receptors to flt3 and methods of use thereof |
| CR20180494A (es) | 2016-04-01 | 2019-01-29 | Janssen Pharmaceuticals Inc | Derivados de compuestos de indol sustituidos como inhibidores de la replicación vírica del dengue |
| BR112018070163A2 (pt) | 2016-04-01 | 2019-01-29 | Signal Pharm Llc | compostos de aminopurina substituída, composições e métodos de tratamento |
| BR112018068851B1 (pt) | 2016-04-01 | 2022-11-22 | Basf Se | Composto de fórmula i, composição, métodos de combate ou controle de pragas invertebradas e de proteção de plantas, semente revestida e uso de pelo menos um composto |
| UA128781C2 (uk) | 2016-04-01 | 2024-10-23 | Кайт Фарма, Інк. | Т-клітина, спосіб її отримання та застосування |
| SG11201808411RA (en) | 2016-04-01 | 2018-10-30 | Kite Pharma Inc | Chimeric antigen and t cell receptors and methods of use |
| 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 |
| KR102625988B1 (ko) | 2017-05-22 | 2024-01-16 | 얀센 파마슈티칼즈, 인코포레이티드 | 뎅기 바이러스 복제 억제제로서의 치환 인돌린 유도체 |
| EA039702B1 (ru) | 2017-05-22 | 2022-03-01 | Янссен Фармасьютикалз, Инк. | Замещенные производные индолина в качестве ингибиторов репликации вирусов денге |
-
2017
- 2017-03-22 JO JOP/2017/0069A patent/JOP20170069B1/ar active
- 2017-03-30 TW TW106110686A patent/TWI723148B/zh not_active IP Right Cessation
- 2017-03-30 AR ARP170100795A patent/AR108046A1/es unknown
- 2017-03-31 DK DK17714751.9T patent/DK3436437T3/da active
- 2017-03-31 CN CN201780021323.0A patent/CN108884037B/zh active Active
- 2017-03-31 HR HRP20211278TT patent/HRP20211278T1/hr unknown
- 2017-03-31 EA EA201892219A patent/EA037988B1/ru unknown
- 2017-03-31 CA CA3013406A patent/CA3013406C/en active Active
- 2017-03-31 MY MYPI2018001596A patent/MY195194A/en unknown
- 2017-03-31 CR CR20180493A patent/CR20180493A/es unknown
- 2017-03-31 CO CONC2018/0009563A patent/CO2018009563A2/es unknown
- 2017-03-31 PE PE2018001870A patent/PE20181778A1/es unknown
- 2017-03-31 LT LTEP17714751.9T patent/LT3436437T/lt unknown
- 2017-03-31 HU HUE17714751A patent/HUE055577T2/hu unknown
- 2017-03-31 AU AU2017242894A patent/AU2017242894B2/en active Active
- 2017-03-31 EP EP17714751.9A patent/EP3436437B1/en active Active
- 2017-03-31 JP JP2018550545A patent/JP6970115B2/ja active Active
- 2017-03-31 UY UY0001037182A patent/UY37182A/es unknown
- 2017-03-31 US US16/088,090 patent/US10689340B2/en active Active
- 2017-03-31 KR KR1020187028180A patent/KR102359776B1/ko active Active
- 2017-03-31 WO PCT/EP2017/057661 patent/WO2017167951A1/en not_active Ceased
- 2017-03-31 SG SG11201808409XA patent/SG11201808409XA/en unknown
- 2017-03-31 SI SI201730871T patent/SI3436437T1/sl unknown
- 2017-03-31 ES ES17714751T patent/ES2884067T3/es active Active
- 2017-03-31 MX MX2018011785A patent/MX381634B/es unknown
- 2017-03-31 UA UAA201810728A patent/UA125296C2/uk unknown
-
2018
- 2018-09-26 IL IL261948A patent/IL261948B/en unknown
- 2018-09-27 PH PH12018502077A patent/PH12018502077A1/en unknown
- 2018-09-27 CL CL2018002758A patent/CL2018002758A1/es unknown
- 2018-09-28 ZA ZA2018/06482A patent/ZA201806482B/en unknown
- 2018-09-28 EC ECSENADI201873293A patent/ECSP18073293A/es unknown
-
2020
- 2020-06-05 US US16/893,685 patent/US11180450B2/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010021878A1 (en) * | 2008-08-19 | 2010-02-25 | Janssen Pharmaceutica Nv | Cold menthol receptor antagonists |
| WO2013045516A1 (en) * | 2011-09-26 | 2013-04-04 | Katholieke Universiteit Leuven | Viral replication inhibitors |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI723148B (zh) | 作為登革熱病毒複製抑制劑的經取代的吲哚啉衍生物 | |
| CN109195949B (zh) | 作为登革热病毒复制抑制剂的经取代的吲哚啉衍生物 | |
| TWI795393B (zh) | 作為登革熱病毒複製抑制劑之經取代之吲哚啉衍生物 | |
| TWI758255B (zh) | 作為登革熱病毒複製抑制劑之單-或二-取代之吲哚衍生物 | |
| TWI771420B (zh) | 作為登革熱病毒複製抑制劑之經取代之吲哚啉衍生物（一） | |
| CN109069482B (zh) | 作为登革热病毒复制抑制剂的经取代的吲哚化合物衍生物 | |
| TWI758256B (zh) | 作為登革熱病毒複製抑制劑之單取代或二取代吲哚衍生物 | |
| TW201900610A (zh) | 作為登革熱病毒複製抑制劑之經取代的吲哚啉衍生物 | |
| JP6888021B2 (ja) | デングウイルス複製阻害剤としての置換インドール誘導体 | |
| TWI681951B (zh) | 作為登革熱病毒複製抑制劑之單-或二-取代的吲哚衍生物 | |
| KR20180002644A (ko) | 뎅기 바이러스 복제 억제제로서의 １치환 또는 ２치환 인돌 유도체 | |
| KR20170103820A (ko) | 뎅기 바이러스 복제 억제제로서의 인돌 유도체 | |
| HK1260482B (zh) | 作为登革热病毒复制抑制剂的经取代的吲哚啉衍生物 | |
| HK1260482A1 (en) | Substituted indoline derivatives as dengue viral replication inhibitors | |
| HK1260478A1 (en) | Substituted indole compound derivatives as dengue viral replication inhibitors | |
| BR112018068640B1 (pt) | Derivados de indolina substituídos, seu uso como inibidores da replicação viral da dengue e composições farmacêuticas que os compreendem |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Annulment or lapse of patent due to non-payment of fees |