CN111601788A - 衣壳蛋白装配抑制剂、其药物组合物和用途 - Google Patents
衣壳蛋白装配抑制剂、其药物组合物和用途 Download PDFInfo
- Publication number
- CN111601788A CN111601788A CN201980007896.7A CN201980007896A CN111601788A CN 111601788 A CN111601788 A CN 111601788A CN 201980007896 A CN201980007896 A CN 201980007896A CN 111601788 A CN111601788 A CN 111601788A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutically acceptable
- hydrogen
- compound
- prodrug
- tautomer
- 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.)
- Granted
Links
- 108090000565 Capsid Proteins Proteins 0.000 title claims abstract description 38
- 102100023321 Ceruloplasmin Human genes 0.000 title claims abstract description 38
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 33
- 239000003112 inhibitor Substances 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 111
- 239000000651 prodrug Substances 0.000 claims abstract description 62
- 229940002612 prodrug Drugs 0.000 claims abstract description 62
- 150000003839 salts Chemical class 0.000 claims abstract description 61
- 239000012453 solvate Substances 0.000 claims abstract description 57
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 48
- 201000010099 disease Diseases 0.000 claims abstract description 44
- 230000005764 inhibitory process Effects 0.000 claims abstract description 27
- 239000000203 mixture Substances 0.000 claims abstract description 23
- 208000002672 hepatitis B Diseases 0.000 claims abstract description 13
- -1 hydrate Substances 0.000 claims description 64
- 229910052739 hydrogen Inorganic materials 0.000 claims description 62
- 239000001257 hydrogen Substances 0.000 claims description 62
- 150000002431 hydrogen Chemical class 0.000 claims description 47
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 46
- 229910052805 deuterium Inorganic materials 0.000 claims description 45
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 36
- 229910052801 chlorine Inorganic materials 0.000 claims description 36
- 239000000460 chlorine Substances 0.000 claims description 36
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 34
- 229910052731 fluorine Inorganic materials 0.000 claims description 34
- 239000011737 fluorine Substances 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 125000001153 fluoro group Chemical group F* 0.000 claims description 14
- 230000008901 benefit Effects 0.000 claims description 12
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 11
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 11
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 150000003254 radicals Chemical class 0.000 claims description 8
- 239000012634 fragment Substances 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 208000019423 liver disease Diseases 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 150000004677 hydrates Chemical class 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 230000009286 beneficial effect Effects 0.000 claims 4
- 238000002360 preparation method Methods 0.000 abstract description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 66
- 238000006243 chemical reaction Methods 0.000 description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 20
- 241000700721 Hepatitis B virus Species 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 108020004414 DNA Proteins 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 230000003013 cytotoxicity Effects 0.000 description 8
- 231100000135 cytotoxicity Toxicity 0.000 description 8
- LYEKPFNLQCTNCD-UHFFFAOYSA-N ethyl 1,3-dimethylpyrrole-2-carboxylate Chemical compound CCOC(=O)C1=C(C)C=CN1C LYEKPFNLQCTNCD-UHFFFAOYSA-N 0.000 description 8
- 238000002156 mixing Methods 0.000 description 8
- 210000002966 serum Anatomy 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 241000124008 Mammalia Species 0.000 description 7
- 125000000217 alkyl group Chemical group 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 230000002265 prevention Effects 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 241000282414 Homo sapiens Species 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000002671 adjuvant Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- GVLLVABLNQEYEJ-UHFFFAOYSA-N ethyl 4-chlorosulfonyl-1,3-dimethylpyrrole-2-carboxylate Chemical compound CCOC(=O)c1c(C)c(cn1C)S(Cl)(=O)=O GVLLVABLNQEYEJ-UHFFFAOYSA-N 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- UBJNUMBVUAVDIC-UHFFFAOYSA-N CCOC(=O)C(=O)c1cn(C)c(C(=O)OCC)c1C Chemical compound CCOC(=O)C(=O)c1cn(C)c(C(=O)OCC)c1C UBJNUMBVUAVDIC-UHFFFAOYSA-N 0.000 description 4
- 101710142246 External core antigen Proteins 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 108010019160 Pancreatin Proteins 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- IIKHONWHFIKUQV-UHFFFAOYSA-N ethyl 1-methylpyrrole-2-carboxylate Chemical compound CCOC(=O)C1=CC=CN1C IIKHONWHFIKUQV-UHFFFAOYSA-N 0.000 description 4
- FGILMAYWLMWCQA-UHFFFAOYSA-N ethyl 3-methyl-1h-pyrrole-2-carboxylate Chemical compound CCOC(=O)C=1NC=CC=1C FGILMAYWLMWCQA-UHFFFAOYSA-N 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 229940055695 pancreatin Drugs 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- HHTRAISBAAXRKZ-UHFFFAOYSA-N 5-amino-2-fluorobenzonitrile Chemical compound NC1=CC=C(F)C(C#N)=C1 HHTRAISBAAXRKZ-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000011740 C57BL/6 mouse Methods 0.000 description 3
- 108091036055 CccDNA Proteins 0.000 description 3
- PAEYAKGINDQUCT-UHFFFAOYSA-N Ethyl 2-pyrrolecarboxylate Chemical group CCOC(=O)C1=CC=CN1 PAEYAKGINDQUCT-UHFFFAOYSA-N 0.000 description 3
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- NBSXNLNHQRYDTC-UHFFFAOYSA-N ethyl 1,3,5-trimethylpyrrole-2-carboxylate Chemical compound CCOC(=O)C1=C(C)C=C(C)N1C NBSXNLNHQRYDTC-UHFFFAOYSA-N 0.000 description 3
- JWZPNELADMADRY-UHFFFAOYSA-N ethyl 4-(1-bicyclo[1.1.1]pentanylsulfamoyl)-1,3,5-trimethylpyrrole-2-carboxylate Chemical compound CCOC(=O)c1c(C)c(c(C)n1C)S(=O)(=O)NC12CC(C1)C2 JWZPNELADMADRY-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- BMFZEADLZBHSHT-UHFFFAOYSA-N methyl 3-chloro-1-methylpyrrole-2-carboxylate Chemical compound COC(=O)C1=C(Cl)C=CN1C BMFZEADLZBHSHT-UHFFFAOYSA-N 0.000 description 3
- 238000010172 mouse model Methods 0.000 description 3
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Substances ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000003753 real-time PCR Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 229910021642 ultra pure water Inorganic materials 0.000 description 3
- 239000012498 ultrapure water Substances 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- IWHKVYYEFYCGMJ-UHFFFAOYSA-N 4-(1-bicyclo[1.1.1]pentanylsulfamoyl)-1,3-dimethylpyrrole-2-carboxylic acid Chemical compound C12(CC(C1)C2)NS(=O)(=O)C=2C(=C(N(C2)C)C(=O)O)C IWHKVYYEFYCGMJ-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 102000012422 Collagen Type I Human genes 0.000 description 2
- 108010022452 Collagen Type I Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- KUBMOOQSRPDDCY-UHFFFAOYSA-N N-(3-cyano-4-fluorophenyl)-1,3,5-trimethylpyrrole-2-carboxamide Chemical compound Cc1cc(C)n(C)c1C(=O)Nc1ccc(F)c(c1)C#N KUBMOOQSRPDDCY-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 210000000234 capsid Anatomy 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 2
- 229960003529 diazepam Drugs 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- IZSBSZYFPYIJDI-UHFFFAOYSA-N ethyl 3,5-dimethyl-1h-pyrrole-2-carboxylate Chemical compound CCOC(=O)C=1NC(C)=CC=1C IZSBSZYFPYIJDI-UHFFFAOYSA-N 0.000 description 2
- CJSCIYLEFXEDLN-UHFFFAOYSA-N ethyl 4-(1-bicyclo[1.1.1]pentanylsulfamoyl)-1,3-dimethylpyrrole-2-carboxylate Chemical compound CCOC(=O)c1c(C)c(cn1C)S(=O)(=O)NC12CC(C1)C2 CJSCIYLEFXEDLN-UHFFFAOYSA-N 0.000 description 2
- UGTRHGGZIGRIRV-UHFFFAOYSA-N ethyl 4-(2-ethoxy-2-oxoacetyl)-1-methylpyrrole-2-carboxylate Chemical compound CCOC(=O)C(=O)c1cc(C(=O)OCC)n(C)c1 UGTRHGGZIGRIRV-UHFFFAOYSA-N 0.000 description 2
- QXEITASMDAQCCA-UHFFFAOYSA-N ethyl 4-chlorosulfonyl-1,3,5-trimethylpyrrole-2-carboxylate Chemical compound CCOC(=O)c1c(C)c(c(C)n1C)S(Cl)(=O)=O QXEITASMDAQCCA-UHFFFAOYSA-N 0.000 description 2
- PIIKOURGUCCBAO-UHFFFAOYSA-N ethyl 4-chlorosulfonyl-1-methylpyrrole-2-carboxylate Chemical compound CCOC(=O)C1=CC(S(Cl)(=O)=O)=CN1C PIIKOURGUCCBAO-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 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
- 210000001853 liver microsome Anatomy 0.000 description 2
- WNZYRBKSHXQQHS-UHFFFAOYSA-N methyl 3-chloro-4-(2-ethoxy-2-oxoacetyl)-1-methylpyrrole-2-carboxylate Chemical compound CCOC(=O)C(=O)c1cn(C)c(C(=O)OC)c1Cl WNZYRBKSHXQQHS-UHFFFAOYSA-N 0.000 description 2
- PNSIPDUJIQVUCE-UHFFFAOYSA-N methyl 3-chloro-4-chlorosulfonyl-1-methylpyrrole-2-carboxylate Chemical compound COC(=O)c1c(Cl)c(cn1C)S(Cl)(=O)=O PNSIPDUJIQVUCE-UHFFFAOYSA-N 0.000 description 2
- DJCKHSJWILZDJR-UHFFFAOYSA-N methyl 4-(1-bicyclo[1.1.1]pentanylsulfamoyl)-3-chloro-1-methylpyrrole-2-carboxylate Chemical compound COC(=O)C=1N(C=C(C1Cl)S(NC12CC(C1)C2)(=O)=O)C DJCKHSJWILZDJR-UHFFFAOYSA-N 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 210000004279 orbit Anatomy 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- SHLOCUXXGIHZLV-UHFFFAOYSA-N 2-(3-cyano-4-fluorophenyl)-1,3,5-trimethyl-3H-pyrrole-2,4-dicarboxamide Chemical compound C(#N)C=1C=C(C=CC1F)C1(N(C(=C(C1C)C(=O)N)C)C)C(=O)N SHLOCUXXGIHZLV-UHFFFAOYSA-N 0.000 description 1
- UCCQBZOVNDRONW-UHFFFAOYSA-N 2-(5-ethoxycarbonyl-1-methylpyrrol-3-yl)-2-oxoacetic acid Chemical compound C(C)OC(=O)C1=CC(=CN1C)C(C(=O)O)=O UCCQBZOVNDRONW-UHFFFAOYSA-N 0.000 description 1
- SGNUGXVYOUTDSB-UHFFFAOYSA-N 2-[5-[(3-cyano-4-fluorophenyl)carbamoyl]-1,2,4-trimethylpyrrol-3-yl]-2-oxoacetic acid Chemical compound Cc1c(C(=O)C(O)=O)c(C)n(C)c1C(=O)Nc1ccc(F)c(c1)C#N SGNUGXVYOUTDSB-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- LQKLVOWNBKJRJE-UHFFFAOYSA-N 3-bicyclo[1.1.1]pentanylazanium;chloride Chemical compound Cl.C1C2CC1(N)C2 LQKLVOWNBKJRJE-UHFFFAOYSA-N 0.000 description 1
- YSEMCVGMNUUNRK-UHFFFAOYSA-N 3-chloro-4-fluoroaniline Chemical group NC1=CC=C(F)C(Cl)=C1 YSEMCVGMNUUNRK-UHFFFAOYSA-N 0.000 description 1
- TVNNIPLRVKGPQG-UHFFFAOYSA-N 4-(1-bicyclo[1.1.1]pentanylsulfamoyl)-1,3,5-trimethylpyrrole-2-carboxylic acid Chemical compound C12(CC(C1)C2)NS(=O)(=O)C=2C(=C(N(C2C)C)C(=O)O)C TVNNIPLRVKGPQG-UHFFFAOYSA-N 0.000 description 1
- OJXYKPNJZLPWJZ-UHFFFAOYSA-N 4-(1-bicyclo[1.1.1]pentanylsulfamoyl)-3-chloro-1-methylpyrrole-2-carboxylic acid Chemical compound C12(CC(C1)C2)NS(=O)(=O)C=2C(=C(N(C2)C)C(=O)O)Cl OJXYKPNJZLPWJZ-UHFFFAOYSA-N 0.000 description 1
- MHBKUZPJHSAFBK-UHFFFAOYSA-N 4-(1-bicyclo[1.1.1]pentanylsulfamoyl)-N-(3-chloro-4-fluorophenyl)-1,3,5-trimethylpyrrole-2-carboxamide Chemical compound Cc1c(C(=O)Nc2ccc(F)c(Cl)c2)n(C)c(C)c1S(=O)(=O)NC12CC(C1)C2 MHBKUZPJHSAFBK-UHFFFAOYSA-N 0.000 description 1
- HOMPRWZQMWEHIP-UHFFFAOYSA-N 4-(1-bicyclo[1.1.1]pentanylsulfamoyl)-N-(3-cyano-4-fluorophenyl)-1,3-dimethylpyrrole-2-carboxamide Chemical compound Cc1c(cn(C)c1C(=O)Nc1ccc(F)c(c1)C#N)S(=O)(=O)NC12CC(C1)C2 HOMPRWZQMWEHIP-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 241000271566 Aves Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- XVZYDKGXMGWSJT-UHFFFAOYSA-N C(C)OC(=O)C=1N(C=C(C1Cl)S(NC12CC(C1)C2)(=O)=O)C Chemical compound C(C)OC(=O)C=1N(C=C(C1Cl)S(NC12CC(C1)C2)(=O)=O)C XVZYDKGXMGWSJT-UHFFFAOYSA-N 0.000 description 1
- WYAFYBCDSIDHBY-UHFFFAOYSA-N CCOC(=O)c1c(C)c(cn1C)C(=O)C(O)=O Chemical compound CCOC(=O)c1c(C)c(cn1C)C(=O)C(O)=O WYAFYBCDSIDHBY-UHFFFAOYSA-N 0.000 description 1
- ZGLIANGVWQYZNS-UHFFFAOYSA-N COC(=O)c1c(Cl)c(cn1C)C(=O)C(O)=O Chemical compound COC(=O)c1c(Cl)c(cn1C)C(=O)C(O)=O ZGLIANGVWQYZNS-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 101710132601 Capsid protein Proteins 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- 108020004638 Circular DNA Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- QQIRAVWVGBTHMJ-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;lithium Chemical compound [Li].C[Si](C)(C)N[Si](C)(C)C QQIRAVWVGBTHMJ-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- QWAVYHVJMVVDAT-UHFFFAOYSA-N ethyl 2-[5-[(3-cyano-4-fluorophenyl)carbamoyl]-1,2,4-trimethylpyrrol-3-yl]-2-oxoacetate Chemical compound CCOC(=O)C(=O)c1c(C)c(C(=O)Nc2ccc(F)c(c2)C#N)n(C)c1C QWAVYHVJMVVDAT-UHFFFAOYSA-N 0.000 description 1
- LXDAXMNPKXIGMB-UHFFFAOYSA-N ethyl 4-(1-bicyclo[1.1.1]pentanylsulfamoyl)-1-methylpyrrole-2-carboxylate Chemical compound C(C)OC(=O)C=1N(C=C(C1)S(NC12CC(C1)C2)(=O)=O)C LXDAXMNPKXIGMB-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- INQOMBQAUSQDDS-BJUDXGSMSA-N iodomethane Chemical class I[11CH3] INQOMBQAUSQDDS-BJUDXGSMSA-N 0.000 description 1
- 230000000622 irritating effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- YFKTWBUEAJFGRQ-UHFFFAOYSA-N methyl 3-chloro-1h-pyrrole-2-carboxylate Chemical compound COC(=O)C=1NC=CC=1Cl YFKTWBUEAJFGRQ-UHFFFAOYSA-N 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- WRHZVMBBRYBTKZ-UHFFFAOYSA-M pyrrole-2-carboxylate Chemical compound [O-]C(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-M 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000000405 serological effect Effects 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 238000005533 tritiation Methods 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于药物化学领域,涉及一种衣壳蛋白装配抑制剂,具体而言,涉及式I所示的化合物、其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐,其制备方法、药物组合物及医药用途,包括用于治疗受益于衣壳蛋白装配抑制的疾病的用途,尤其是乙型肝炎病毒感染引起的疾病。
Description
PCT国内申请,说明书已公开。
Claims (21)
- PCT国内申请,权利要求书已公开。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810132621 | 2018-02-09 | ||
CN2018101326213 | 2018-02-09 | ||
PCT/CN2019/074527 WO2019154343A1 (zh) | 2018-02-09 | 2019-02-02 | 衣壳蛋白装配抑制剂、其药物组合物和用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111601788A true CN111601788A (zh) | 2020-08-28 |
CN111601788B CN111601788B (zh) | 2022-06-14 |
Family
ID=67549287
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980007896.7A Active CN111601788B (zh) | 2018-02-09 | 2019-02-02 | 衣壳蛋白装配抑制剂、其药物组合物和用途 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN111601788B (zh) |
WO (1) | WO2019154343A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022156758A1 (zh) * | 2021-01-22 | 2022-07-28 | 广东东阳光药业有限公司 | 新型酰胺吡咯类化合物及其在药物中的用途 |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP7434166B2 (ja) | 2018-03-30 | 2024-02-20 | チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッド | N-複素環式5員環含有カプシドタンパク質のアセンブリの阻害剤、その医薬組成物および使用 |
WO2021093172A1 (zh) | 2019-11-13 | 2021-05-20 | 西安新通药物研究有限公司 | Hbv抑制剂及其用途 |
WO2021197486A1 (zh) * | 2020-04-03 | 2021-10-07 | 东莞市东阳光新药研发有限公司 | 新型螺环类化合物及其在药物中的应用 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014161888A1 (en) * | 2013-04-03 | 2014-10-09 | Janssen R&D Ireland | N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis b |
CN104902885A (zh) * | 2012-08-28 | 2015-09-09 | 爱尔兰詹森科学公司 | 氨磺酰基-芳基酰胺和其作为药物用于治疗乙型肝炎的用途 |
CN105452220A (zh) * | 2013-05-17 | 2016-03-30 | 爱尔兰詹森科学公司 | 氨磺酰基吡咯酰胺衍生物及其作为药物用于治疗乙型肝炎的用途 |
US20160264522A1 (en) * | 2013-10-23 | 2016-09-15 | Janssen Sciences Ireland Uc | Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis b |
WO2017156255A1 (en) * | 2016-03-09 | 2017-09-14 | Emory University | Elimination of hepatitis b virus with antiviral agents |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SI3024819T1 (en) * | 2013-07-25 | 2018-06-29 | Janssen Sciences Ireland Uc | Glyoxamide-substituted pyrrolamide derivatives and their use as medicines for the treatment of hepatitis B |
-
2019
- 2019-02-02 CN CN201980007896.7A patent/CN111601788B/zh active Active
- 2019-02-02 WO PCT/CN2019/074527 patent/WO2019154343A1/zh active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104902885A (zh) * | 2012-08-28 | 2015-09-09 | 爱尔兰詹森科学公司 | 氨磺酰基-芳基酰胺和其作为药物用于治疗乙型肝炎的用途 |
WO2014161888A1 (en) * | 2013-04-03 | 2014-10-09 | Janssen R&D Ireland | N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis b |
CN105452220A (zh) * | 2013-05-17 | 2016-03-30 | 爱尔兰詹森科学公司 | 氨磺酰基吡咯酰胺衍生物及其作为药物用于治疗乙型肝炎的用途 |
US20160115125A1 (en) * | 2013-05-17 | 2016-04-28 | Janssen Sciences Ireland Uc | Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b |
US20160264522A1 (en) * | 2013-10-23 | 2016-09-15 | Janssen Sciences Ireland Uc | Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis b |
WO2017156255A1 (en) * | 2016-03-09 | 2017-09-14 | Emory University | Elimination of hepatitis b virus with antiviral agents |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022156758A1 (zh) * | 2021-01-22 | 2022-07-28 | 广东东阳光药业有限公司 | 新型酰胺吡咯类化合物及其在药物中的用途 |
Also Published As
Publication number | Publication date |
---|---|
WO2019154343A1 (zh) | 2019-08-15 |
CN111601788B (zh) | 2022-06-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111601788B (zh) | 衣壳蛋白装配抑制剂、其药物组合物和用途 | |
US12116356B2 (en) | N-heterocyclic five-membered ring-containing capsid protein assembly inhibitor, pharmaceutical composition thereof, and use thereof | |
EP3180319B1 (en) | Novel pyridazones and triazinones for the treatment and prophylaxis of hepatitis b virus infection | |
ES2442907T3 (es) | Tiazolil dihidropirimidinas sustituidas con bromo-fenilo | |
JP7479384B2 (ja) | N-複素環式5員環含有カプシドタンパク質のアセンブリの阻害剤、その医薬組成物および使用 | |
CN113365999B (zh) | 含有吡咯并杂环的衣壳蛋白装配抑制剂 | |
TW201141488A (en) | Antiviral nucleosides | |
WO2020088442A1 (zh) | 三氟甲基取代的磺酰胺类选择性bcl-2抑制剂 | |
JP2022549923A (ja) | Nヘテロ五員環含有カプシドタンパク質集合阻害剤の結晶形及びその使用 | |
CN116547276A (zh) | 含酰胺基和杂环烷基的tyk2抑制剂化合物 | |
CN109180649B (zh) | 一种含吲哚环的ido抑制剂及其制备方法 | |
WO2022143995A1 (zh) | 四环类化合物及其医药用途 | |
CN113666877A (zh) | 含烷氧基及酰胺基的tyk2抑制剂化合物 | |
CN114805438A (zh) | 含磷酰基的tyk2抑制剂化合物 | |
RU2802259C2 (ru) | Ингибитор сборки капсидного белка, содержащий n-гетероциклическое пятичленное кольцо, его фармацевтическая композиция и применение | |
WO2024146631A1 (zh) | 一种parp7抑制剂的制备方法 | |
WO2024149314A1 (zh) | 氨基噻吩类化合物、其制备方法及用途 | |
WO2021204252A1 (zh) | 作为乙肝表面抗原抑制剂的四环化合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |