CN113773259A - 病毒主蛋白酶抑制剂及其制备方法和用途 - Google Patents
病毒主蛋白酶抑制剂及其制备方法和用途 Download PDFInfo
- Publication number
- CN113773259A CN113773259A CN202110795720.1A CN202110795720A CN113773259A CN 113773259 A CN113773259 A CN 113773259A CN 202110795720 A CN202110795720 A CN 202110795720A CN 113773259 A CN113773259 A CN 113773259A
- Authority
- CN
- China
- Prior art keywords
- straight
- group
- branched
- heterocyclic group
- compound
- 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.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims description 7
- 241000700605 Viruses Species 0.000 title abstract description 6
- 229940125673 3C-like protease inhibitor Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 241000711573 Coronaviridae Species 0.000 claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 241000315672 SARS coronavirus Species 0.000 claims abstract description 6
- -1 cyano, nitro, hydroxy, amino, aminomethyl Chemical group 0.000 claims description 63
- 125000001424 substituent group Chemical group 0.000 claims description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 125000003342 alkenyl group Chemical group 0.000 claims description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 239000011593 sulfur Substances 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 10
- 125000000304 alkynyl group Chemical group 0.000 claims description 10
- 125000003368 amide group Chemical group 0.000 claims description 10
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 125000000472 sulfonyl group Chemical class *S(*)(=O)=O 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 5
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical group C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 4
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical group [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- 125000003172 aldehyde group Chemical group 0.000 claims description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 3
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 claims description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 2
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 2
- 229940125890 compound Ia Drugs 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- UKNZIQFPZSCIPW-UHFFFAOYSA-N dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane methanesulfonic acid Chemical group CS(O)(=O)=O.CC(C)c1cc(C(C)C)c(c(c1)C(C)C)-c1ccccc1P(C1CCCCC1)C1CCCCC1 UKNZIQFPZSCIPW-UHFFFAOYSA-N 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 239000003596 drug target Substances 0.000 claims description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
- 125000005647 linker group Chemical group 0.000 claims description 2
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 230000008685 targeting Effects 0.000 claims description 2
- 241000711467 Human coronavirus 229E Species 0.000 claims 1
- 241001109669 Human coronavirus HKU1 Species 0.000 claims 1
- 241000482741 Human coronavirus NL63 Species 0.000 claims 1
- 241001428935 Human coronavirus OC43 Species 0.000 claims 1
- 208000025370 Middle East respiratory syndrome Diseases 0.000 claims 1
- 230000000840 anti-viral effect Effects 0.000 claims 1
- 230000000069 prophylactic effect Effects 0.000 claims 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 13
- 101800000535 3C-like proteinase Proteins 0.000 abstract description 4
- 101800002396 3C-like proteinase nsp5 Proteins 0.000 abstract description 4
- 108091005804 Peptidases Proteins 0.000 abstract description 4
- 239000004365 Protease Substances 0.000 abstract description 4
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 15
- 239000000203 mixture Substances 0.000 description 10
- 150000003254 radicals Chemical class 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 241000282414 Homo sapiens Species 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 239000007832 Na2SO4 Substances 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- CXMJVJJFGWCGOB-OAQYLSRUSA-N CNC([C@@H](C1CCCC1)NC(C1=CC(C(C=CC=C2)=C2C#N)=CC(C=O)=C1)=O)=O Chemical compound CNC([C@@H](C1CCCC1)NC(C1=CC(C(C=CC=C2)=C2C#N)=CC(C=O)=C1)=O)=O CXMJVJJFGWCGOB-OAQYLSRUSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 241001678559 COVID-19 virus Species 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 238000003776 cleavage reaction Methods 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
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- UPVXMNLLDMMKGF-OAHLLOKOSA-N (4R)-4-[[2-(4-bromo-2-formylphenoxy)acetyl]amino]-N,6-dimethylheptanamide Chemical compound CC(C)C[C@@H](CCC(NC)=O)NC(COC(C=C1)=C(C=O)C=C1Br)=O UPVXMNLLDMMKGF-OAHLLOKOSA-N 0.000 description 1
- IXLFSMNKDCPKLV-MRVPVSSYSA-N (4R)-4-amino-N,6-dimethylheptanamide Chemical compound CC(C)C[C@@H](CCC(NC)=O)N IXLFSMNKDCPKLV-MRVPVSSYSA-N 0.000 description 1
- QVJHCXJPZXRVPE-MRXNPFEDSA-N (4r)-4-(9h-fluoren-9-ylmethoxycarbonylamino)-6-methylheptanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@H](CCC(O)=O)CC(C)C)C3=CC=CC=C3C2=C1 QVJHCXJPZXRVPE-MRXNPFEDSA-N 0.000 description 1
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- KXRYNWDCFUKVNN-UHFFFAOYSA-N 2-(4-bromo-2-formylphenoxy)acetic acid Chemical compound OC(=O)COC1=CC=C(Br)C=C1C=O KXRYNWDCFUKVNN-UHFFFAOYSA-N 0.000 description 1
- UHDNUPHSDMOGCR-UHFFFAOYSA-N 3-Formylbenzoic acid Chemical compound OC(=O)C1=CC=CC(C=O)=C1 UHDNUPHSDMOGCR-UHFFFAOYSA-N 0.000 description 1
- YRPXZCWDXBNPBD-UHFFFAOYSA-N 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-indazole Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=CC2=C1C=NN2 YRPXZCWDXBNPBD-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- 206010003757 Atypical pneumonia Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 101100338269 Caenorhabditis elegans his-41 gene Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000001528 Coronaviridae Infections Diseases 0.000 description 1
- 108700003471 Coronavirus 3C Proteases Proteins 0.000 description 1
- 108700002673 Coronavirus M Proteins Proteins 0.000 description 1
- 108010005843 Cysteine Proteases Proteins 0.000 description 1
- 102000005927 Cysteine Proteases Human genes 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 101001091385 Homo sapiens Kallikrein-6 Proteins 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 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 1
- 102100034866 Kallikrein-6 Human genes 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- JYOAXOMPIXKMKK-YUMQZZPRSA-N Leu-Gln Chemical compound CC(C)C[C@H]([NH3+])C(=O)N[C@H](C([O-])=O)CCC(N)=O JYOAXOMPIXKMKK-YUMQZZPRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 1
- 108010076039 Polyproteins Proteins 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000002288 cocrystallisation Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 229940125808 covalent inhibitor Drugs 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 238000007824 enzymatic assay Methods 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 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
- 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
- 125000001786 isothiazolyl group Chemical group 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
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 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 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 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
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000000079 pharmacotherapeutic effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 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
- 238000012360 testing method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (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
本发明公开了一种对病毒主蛋白酶(3CL蛋白酶，Mpro)有抑制作用的化合物，同时对SARS冠状病毒(SARS‑CoV)和新型冠状病毒(SARS‑Cov‑2)的Mpro有显著抑制活性。本发明还涉及含此类化合物的药用组合物或其药学上可接受的盐在制备、预防和/或治疗病毒Mpro相关疾病的应用，例如用于治疗对新型冠状病毒(SARS‑Cov‑2)的疾病。
Description
技术领域
本发明涉及药物化学和药物治疗学领域。具体涉及一种对病毒主蛋白酶(3CL蛋白酶，Mpro)有抑制作用的通式(I)化合物、其制备方法、含此类化合物的药用组合物及用途。
背景技术
由新型冠状病毒(SARS-Cov-2)引起的二型非典型性肺炎迅速席卷全球，给人类健康和社会发展带来前所未有的的挑战。SARS-CoV-2是继SARS冠状病毒(SARS- CoV)、MERS冠状病毒(MERS-CoV)之后发现的一种新型冠状病毒。
在病毒感染宿主的过程中，冠状病毒中的3CL蛋白酶(又称为Mpro)是一类半胱氨酸水解酶，能够在病毒中11个不同的位点裂解多蛋白，生成多个有活性的功能蛋白，研究结果表明SARS-CoV-2与SARS-CoV的Mpro结构基本一致，同源性>96％。而且 SARS-Cov2 Mpro具有独特的识别序列和切割位点[Leu-Gln(Ser，Ala，Gly)]，在人类蛋白酶中类似结构不存在。Mpro中的催化残基Cys145和His41埋在位于蛋白质表面的活性位点腔中，以上结构和活性位点特征为其作为成药靶点奠定了理论基础。因此，Mpro目前已经成为抗冠状病毒的关键靶标之一，可通过开发其抑制剂，阻断冠状病毒复制过程，对于冠状病毒感染的防治具有重要价值与意义。
发明内容
本发明的目的是提供一种结构新颖且有效的病毒主蛋白酶Mpro的抑制剂。
本发明的另一个目的在于，提供一种有效的抗病毒药物。
本发明的第一方面，提供一种如式(I)所示的化合物或其在药学上可接受的盐、溶剂合物、水合物、对映异构体、非对应异构体或外消旋体：
式(Ⅰ)中：
环A为苯环或者芳杂环基，W1,W2,W3,W4和W5独立自为CH或者N；
环Ar为未被取代或被1-2个取代基取代的以下基团：苯基、5～6元芳杂环基、苯并5～6元芳杂环基、苯并5～6元杂环基，1～3个氮杂苯基并5～6元芳杂环基、1～3个氮杂苯基并5～6元杂环基，所述杂环基和芳杂环基各自含有1～3个选自氧、硫和氮的杂原子；所述取代基各自独立地选自下组：卤素、C1～C4直链或支链烷基、C2～C4直链或支链烯基、C2～C4直链或支链炔基、C1～C4直链或支链烷氧基、C1～C4直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、氨甲基、二甲基氨基、羟甲基、三氟甲基、羧基、巯基、C1～C4酰基、酰胺基、氨基磺酰基、C1～C4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5～7元环；
X为空,或为-ORa-连接基团；
Ra为空，或C1～C4直链或支链烷基；
R1为氢、未被取代或被1-2个取代基取代的以下基团：C3～C7环烷基、C1～C6烷基、C5～C7芳环基、C5～C7芳杂环基、苯并5～6元芳杂环基、5～6元杂环基、苯并5～6 元杂环基、C2～C7炔基、C2～C7烯基，所述杂环基和芳杂环基各自含有1～3个选自氧、硫和氮的杂原子；所述取代基各自独立地选自下组：卤素、C1～C4直链或支链烷基、C2～C4直链或支链烯基、C2～C4直链或支链炔基、C1～C4直链或支链烷氧基、C1～ C4直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、氨甲基、二甲基氨基、羟甲基、三氟甲基、羧基、巯基、C1～C4酰基、酰胺基、氨基磺酰基、C1～C4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5～7元环；
R2为氢，未被取代或被1-3个取代基取代的以下基团：C3～C7环烷基、C1～C6烷基、C5～C7芳环基、C5～C7芳杂环基、苯并5～6元芳杂环基、5～6元杂环基、苯并5～6 元杂环基、C2～C7炔基、C2～C7烯基，所述杂环基和芳杂环基各自含有1～3个选自氧、硫和氮的杂原子；所述取代基各自独立地选自下组：卤素、C1～C4直链或支链烷基、C2～C4直链或支链烯基、C2～C4直链或支链炔基、C1～C4直链或支链烷氧基、C1～ C4直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、甲巯基、C1～C4酰基、酰胺基、氨基磺酰基、C1～C4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5～7元环；
R3为氢、未被取代或被1-2个取代基取代的以下基团：C3～C7环烷基、C1～C6烷基、C5～C7芳环基、C5～C7元芳杂环基、5～6元杂环基、C2～C7炔基、C2～C7烯基，所述杂环基和芳杂环基各自含有1～3个选自氧、硫和氮的杂原子；所述取代基各自独立地选自下组：卤素、C1～C4直链或支链烷基、C2～C4直链或支链烯基、C2～C4直链或支链炔基、C1～C4直链或支链烷氧基、C1～C4直链或支链烷基羰氧基、C1～C4直链或支链烷硫基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、C1～C4酰基、酰胺基、氨基磺酰基、C1～C4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5～7元环；
R4为共价反应或可逆共价反应基团，包括未取代或1-2个取代基取代的醛基、氰基、硼酸、羧酸基、α-羰基醇、α-羰基醛、α-羰基酰胺、α-羰基三氟甲基、丙烯酰基、α-卤代乙酰基、1-(环氧乙烷-2-基)乙酰基、2-丁炔酰基，所述取代基各自独立地选自下组：卤素、C1～C4直链或支链烷基、C2～C4直链或支链烯基、C2～C4直链或支链炔基、C1～C4直链或支链烷氧基、C1～C4直链或支链烷基羰氧基、C1～C4直链或支链烷硫基、C3～C7环烷基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、 C1～C4酰基、酰胺基、氨基磺酰基、C1～C4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5～7元环；
m是0，1，2或3；
n是0，1，2，3，4或5。
优选例中，所述的(I)式化合物选自表1所示的化合物。
在本发明第二方面中，提供了一种如本发明第一方面所述通式(I)所示的化合物的制备方法，包括步骤：
通式(Ib)化合物的合成方法：
在惰性溶剂中，在缩合剂和碱存在下，用化合物II和化合物Ia反应，得到化合物Ib；优选地，所述的缩合剂为1-羟基苯并***(HOBT)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)，碱为N,N-二异丙基乙胺(DIEA)；
通式(I)化合物的合成方法：
在惰性溶剂中，在催化剂和碱存在下，用化合物Ib和化合物III反应，得到式I化合物；优选地，所述的催化剂为甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(XPhos Pd G3)，碱为磷酸钾(K3PO4)。
在本发明第三方面中，提供了一种药物组合物，所述的药物组合物包括：治疗有效量的一种或多种本发明第一方面所述通式(I)所示化合物，或其药学上可接受的盐，以及任选的药学上可接受的载体。
在本发明第四方面中，提供了一种本发明第一方面所述通式(I)的药物组合物在用于制备抑制病毒复制的药物的用途，优选地，所述的药物组合物用于抑制冠状病毒主蛋白酶Mpro。
药物施用方法
由于本发明化合物对冠状病毒主蛋白酶Mpro具有优异的抑制活性，因此本发明化合物及其药学上可接受的盐，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由冠状病毒介导的疾病的产品均包含在本专利中。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-200mg本发明化合物/剂。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、肠胃外(静脉内、肌肉内)和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺盐化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的优点主要包括：本发明提供一种式I所示结构的化合物，该化合物对冠状病毒Mpro具有优异的抑制活性。
本发明化合物制备工艺简单、生产成本低，在和病毒发生、发展密切相关的实验中均显示出良好的阳性结果，因此有望开发成靶向Mpro抗病毒药物。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
附图说明
图1为SARS-CoV-2 Mpro/化合物I-1复合物的晶体结构，其中图1A示出化合物I- 1复合物结合到Mpro的催化口袋，从而竞争性地抑制了Mpro底物的结合，图1B示出化合物I-1与Mpro底物的主要结合相互作用。
具体实施方式
下面将对本发明的技术方案进行清楚、完整的描述，显然，所描述的实施例是本发明的一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。
术语
术语“芳环基”是指具有芳香性的基团，优选为具有5元至12元的芳环基，例如选自下组(但不限于)：苯基、萘基。
术语“5～6元芳杂环基”是指具有一个或多个选自氮、氧或硫的杂原子5元或6元的芳香基，可选自下组(但不限于)：吡啶基、嘧啶基、噻唑基、异噻唑基、呋喃基、噻吩基、吡咯基。
术语“苯并5～6元芳杂环基”是指具有一个或多个选自氮、氧或硫的杂原子5元或6元的芳香基与苯环稠合的基团，可选自下组(但不限于)：苯并吡啶基、苯并嘧啶基、苯并噻唑基、苯并异噻唑基、苯并吡咯基、苯并呋喃基、苯并噻吩基、苯并咪唑基、吲哚基、吲唑基。
术语“5～6元杂环基”是指具有一个或多个选自氮、氧或硫的杂原子5元或6元的环状基团，可选自下组(但不限于)：吗啉基、四氢呋喃基、四氢噻唑基、二氧六环基、二氧五环基。
述语“苯并5～6元杂环基”是指具有一个或多个选自氮、氧或硫的杂原子5元或6元的环状基团与苯环稠合的基团，可选自下组(但不限于)：苯并二氧六环、苯并二氧五环。
述语“C1～C6烷基”是指具有1个至6个碳原子的直连或支链的烷基，可选自下组(但不限于)：甲基、乙基、正丙基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基。
述语“C3～C6环烷基”是指具有3个至6个碳原子的环状基团，可选自下组(但不限于)：环丙基、环丁基、环戊基、环己基。
述语“C5～C7环烷基”是指具有5个至7个碳原子的环状基团，可选自下组(但不限于)：环戊基、环己基、环庚基。
术语“C1～C3烷氧基”是指具有1个至3个碳原子的直连或支链的烷氧基，可选自下组(但不限于)：甲氧基、乙氧基、正丙氧基、异丙氧基。
术语“卤素”是指氟、氯、溴、碘。术语“卤代的”是指氟代的、氯代的、溴代的、碘代的。
本发明的各个基团可以未取代或取代的，所述取代的是指被选自下组的取代基所取代：羟基、卤素、C1～C6烷基、卤代C1～C6烷基、C1～C3烷氧基、卤代的C1～C3烷氧基、氰基、叔丁氨基、-O-(CH2)n-O-；其中，n为1～3之间的整数。所述取代基可取代在各基团的各个位置上。
实施案例1
(R)-4-(2-(2-甲酰基-4-(1H-吲唑-4-基)苯酚)乙酰胺-N,6-二甲基庚酰胺(I-1)的合成路线
步骤1.(6-甲基-1-(甲基氨基)-1-氧代庚-4-基)氨基甲酸叔丁酯(1.1)的合成
称取甲胺盐酸盐(21.2mg,315umol)和(4R)-4-(9H-芴-9-基甲氧基羰基氨基)-6-甲基 -庚酸(100mg,262umol)于2mL CH2CL2溶液中，然后依次加入HOBT(53.1mg,393 umol)和DIEA(102mg,786umol,137uL)，室温下反应1小时，TLC检测反应完全，结束反应。加入6mLCH2Cl2于反应液中萃取，用柠檬酸(5mL x 2)洗，收集有机相溶液再用碳酸氢钠饱和溶液洗(5mL x 2)和饱和食盐水(5mL x 2)洗，并用无水 Na2SO4干燥，过滤，旋除溶剂，经柱层析(CH2Cl2/MeOH＝80/1到20/1)分离，得白色固体物1.1(82.0mg，产率为79.29％)。
步骤2.(R)-4-氨基-N,6-二甲基庚酰胺(1.2)合成
将化合物1.1(82.0mg,208umol)溶于10mL乙腈溶剂中，称取N,N-二乙基苯胺(DEA,78.1mg,208umol)加入反应瓶中，在室温下反应30分钟，TLC检测反应是否完全，结束反应，浓缩反应液得黄色胶状粗品1.2(70mg)，直接用于下一步反应。
步骤3.(4R)-4-[[2-(4-溴-2-甲酰苯氧基)乙酰基]氨基]-N,6-二甲基-庚酰胺(1.3)合成
称取化合物1.2(85.0mg,493umol)和2-(4-溴-2-甲酰苯氧基)乙酸(89.5mg,345umol)溶于3mL CH2Cl2中，然后在氮气保护下加入HOBT(100mg,740umol),EDCI (142mg,740umol)和DIEA(191mg,1.48mmol)，混合体系室温反应2小时。LCMS 监测显示反应完全，结束反应。加入6mL CH2Cl2于反应液中萃取，用柠檬酸(5mL x 2)洗，收集有机相溶液再用碳酸氢钠饱和溶液洗(5mL x 2)和饱和食盐水(5mL x 2) 洗，并用无水Na2SO4干燥，过滤，旋除溶剂，经柱层析(CH2Cl2/MeOH＝80/1到20/ 1)分离，得无色胶状物1.3(82.0mg，产率为40.21％)。
步骤4.(R)-4-(2-(4-bromo-2-formylphenoxy)acetamido)-N,6-二甲基庚酰胺(I-1)合成
称取化合物1.3(82.0mg,198umol)溶于3mL二氧六环和1mL水中，然后在氮气保护下加入4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(48.4mg,198 umol),K3PO4(126mg,595umol)和Xphos Pd G3(16.8mg,19.8umol)，混合体系95℃反应10小时。LCMS监测显示反应完全，结束反应。加入5mL水，用EtOAc(5mL x 2)萃取，有机相溶液再用饱和食盐水(5mL x 2)洗，并用无水Na2SO4干燥，过滤，旋除溶剂，经HPLC([water(0.05％HCl)-ACN]；B％:35％-65％,8min)分离，得黄色固体产物I-1(20.0mg，纯度为99.8％，产率为22.3％)。
1HNMR:EB3098-19-P1M2(400MHz,DMSO-d6)
δ10.47-10.51(m,1H),8.11(s,1H),8.00-8.07(m,2H),7.93(d,J＝9.2Hz,1H),7.71 (brs,1H),7.56(d,J＝8.4Hz,1H),7.41-7.47(m,1H),7.20-7.29(m,2H),4.75(s,2H),3.85- 3.90(m,1H),2.51-2.54(m,3H),2.05(t,J＝7.8Hz,2H),1.62-1.73(m,1H),1.56-1.60(m, 1H),1.45-1.54(m,1H),1.23-1.26(m,1H),1.20-1.22(m,1H),0.82(d,J＝6.8Hz,6H)
LCMS:m/z＝451.4(M+H)+,Rt＝1.420min
实施案例2.
3-(2-氰基苯基)-N-[(1R)-1-环戊基-2-(甲氨基)-2-氧代-乙基]-5-甲酰基-苯甲酰胺(I- 2)的合成路线
步骤1.3-溴-5-甲酰基-苯甲酸(2.3)的合成
称取3-甲酰基苯甲酸(400mg,2.66mmol)于室温下加入4mL浓硫酸中，而后升温至60℃，向反应液中分三次加入NBS(500mg,2.81mmol)，每次间隔反应15分钟，加毕继续在该温度下反应2小时。TLC检测反应完全，结束反应。加入5g冰于反应液中，过滤其中的固体，滤液用10mL水洗，无水Na2SO4干燥，过滤，旋除溶剂，经柱层析(CH2Cl2/MeOH＝80/1到20/1)分离，得黄色固体物2.3(660mg，产率为 98.33％)。
合成路线中剩余步骤，化合物2.1，化合物2.2,化合物2.4和化合物I-2分别替换实施案例1中的化合物1.1，化合物1.2，化合物1.3和化合物I-1的合成方法。最终得到5.01mg白色固体产物I-2，纯度为98.74％。
1HNMR:EB3098-23-P1N1(400MHz,CDCl3)
δ10.47-10.51(m,1H),8.36(s,1H),8.25(s,1H),8.21(s,1H),7.82(d,J＝7.6Hz,1H), 7.71-7.74(m,1H),7.53-7.59(m,2H),6.95-6.97(m,1H),5.99-6.01(m,1H),4.41-4.52(m, 1H),2.86(s,3H),2.41-2.45(m,1H),1.86-1.89(m,2H),1.83-1.85(m,2H),1.25-1.49(m, 4H)
LCMS:m/z＝390.0(M+H)+,Rt＝1.819min
实施案例3.
(S)-3-(2-((2'-氰基-3-甲酰基-[1,1'-联苯]-4-基)氧基)乙酰氨基)-N,5-二甲基己酰胺(I-4)的合成路线
化合物4.2合成步骤：
称取化合物4.1(100mg,387umol)溶于1.5mL CH2Cl2溶剂中，室温下逐滴加入盐酸/二氧六环溶液(4M,0.5mL)，室温下反应2小时，TLC检测反应是否完全，结束反应，浓缩反应液得白色固体粗品4.2，110mg，直接用于下一步反应。
合成路线中剩余步骤，化合物4.1，化合物4.3和化合物I-4分别替换实施案例1 中的化合物1.1，化合物1.3和化合物I-1的合成方法。最终得到10.78mg白色固体产物I-4，纯度为99.4％。
1HNMR:EB3098-13-P1N1(400MHz,CDCl3)
δ10.41(s,1H),8.02-8.13(m,1H),8.01(s,1H),7.80-7.81(m,2H),7.69(s,1H),7.46- 7.56(m,2H),7.04-7.13(m,1H),6.04(br s,1H),4.67(br s,2H),4.35-4.47(m,1H),2.80(br s,3H),2.38-2.57(m,2H),1.65-1.73(m,2H),1.37-1.48(m,1H),0.95(t,J＝6.0Hz,6H)
LCMS:m/z＝422.4(M+H)+,Rt＝1.465min
实施案例4.
按照实施案例1-3的化合物I-1,I-2和I-4的合成方法，进一步制备得到化合物I-3，I-5，I-6，I-7，I-8，I-9，I-10，I-11，I-12，I-13，I-14，I-15，I-16，I-17，I-18， I-19，I-20，I-21，I-22，I-23，I-24，I-25。
实施案例5.
体外化合物对靶点蛋白Mpro的抑制活性测试研究
测试方法：已知的广谱冠状病毒Mpro半胱氨酸蛋白酶共价抑制剂GC376被用作酶活性测定的阳性对照。对化合物进行对于酶促测定，具体测试步骤为：首先将待测试化合物与SARS-CoV-2 Mpro在室温下预孵育60分钟；温育后，将底物加入混合物中，并在37℃下开始底物的裂解；以时间依赖性方式记录荧光信号以评估化合物的抑制作用。分析得到其中三个化合物抑制冠状病毒Mpro的能力如表2所示
表2:化合物抑制冠状病毒Mpro的IC50
IC50:(++++)≤0.2μM；0.2μM<(+++)≤1μM；1μM<(++)≤10μM；
10μM<(+)≤100μM；100μM<(-)。
实验结论：从以上实验结果可以看出，本发明的化合物对冠状病毒Mpro有一定的选择性抑制，对SARS和SARS-2冠状病毒抑制活性最高。其中I-1的活性对SARS和 SARS-2冠状病毒的抑制活性均小于200nM,潜在治疗指数高。
实施案例6.
结构生物学研究
为了探索本文公开的化合物与冠状病毒Mpro结合并抑制其酶活性的机理，将某些抑制剂与SARS-CoV-2 Mpro共同结晶。培养共结晶的最优条件是0.1M MES pH 6.0,11％PEG4000，形成晶体后，以SARS-CoV-2 Mpro的晶体结构被作为初始模型，通过分子置换确定了SARS-CoV-2 Mpro/化合物I-1复合物的晶体结构，并将其细化到
化合物I-1与SARS-CoV-2 Mpro形成1:1的复合物。在晶体结构中，化合物I-1结合到Mpro的催化口袋，从而竞争性地抑制了Mpro底物的结合(图1A)。化合物I-1与Mpro底物的主要结合相互作用如附图(图1B)所示：化合物I-1苯环上醛基靶向SARS- CoV-2 Mpro活性口袋中的Cys145，和Cys145形成共价键，同时共价连接后形成的羟基和这周围的Gly143在水分子的介导下形成氢键；化合物I-1吡唑环上的氮原子和 His163和Glu166的侧链形成两个氢键，化合物I-1酰胺键的羰基和氨基基团分别与 Glu166的氨基和羧基基团形成两个氢键。化合物与SARS-CoV-2 Mpro的可逆共价作用和多个氢键相互作用增加了二者的结合作用力。
综上所述，上述各实施例仅为本发明的较佳实施例而已，并不用以限定本发明的保护范围，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，皆应包含在本发明的保护范围内。
Claims (6)
1.一种通式(I)所示的化合物，或其药学上可接受的盐、对映异构体、非对应异构体或外消旋体：
式(Ⅰ)中：
环A为苯环或者芳杂环基，W1,W2,W3,W4和W5独立自为CH或者N；
环Ar为未被取代或被1-2个取代基取代的以下基团：苯基、5～6元芳杂环基、苯并5～6元芳杂环基、苯并5～6元杂环基，1～3个氮杂苯基并5～6元芳杂环基、1～3个氮杂苯基并5～6元杂环基，所述杂环基和芳杂环基各自含有1～3个选自氧、硫和氮的杂原子；所述取代基各自独立地选自下组：卤素、C1～C4直链或支链烷基、C2～C4直链或支链烯基、C2～C4直链或支链炔基、C1～C4直链或支链烷氧基、C1～C4直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、氨甲基、二甲基氨基、羟甲基、三氟甲基、羧基、巯基、C1～C4酰基、酰胺基、氨基磺酰基、C1～C4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5～7元环；
X为空,或为-ORa-连接基团；
Ra为空，或C1～C4直链或支链烷基；
R1为氢、未被取代或被1-2个取代基取代的以下基团：C3～C7环烷基、C1～C6烷基、C5～C7芳环基、C5～C7芳杂环基、苯并5～6元芳杂环基、5～6元杂环基、苯并5～6元杂环基、C2～C7炔基、C2～C7烯基，所述杂环基和芳杂环基各自含有1～3个选自氧、硫和氮的杂原子；所述取代基各自独立地选自下组：卤素、C1～C4直链或支链烷基、C2～C4直链或支链烯基、C2～C4直链或支链炔基、C1～C4直链或支链烷氧基、C1～C4直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、氨甲基、二甲基氨基、羟甲基、三氟甲基、羧基、巯基、C1～C4酰基、酰胺基、氨基磺酰基、C1～C4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5～7元环；
R2为氢，未被取代或被1-3个取代基取代的以下基团：C3～C7环烷基、C1～C6烷基、C5～C7芳环基、C5～C7芳杂环基、苯并5～6元芳杂环基、5～6元杂环基、苯并5～6元杂环基、C2～C7炔基、C2～C7烯基，所述杂环基和芳杂环基各自含有1～3个选自氧、硫和氮的杂原子；所述取代基各自独立地选自下组：卤素、C1～C4直链或支链烷基、C2～C4直链或支链烯基、C2～C4直链或支链炔基、C1～C4直链或支链烷氧基、C1～C4直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、甲巯基、C1～C4酰基、酰胺基、氨基磺酰基、C1～C4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5～7元环；
R3为氢、未被取代或被1-2个取代基取代的以下基团：C3～C7环烷基、C1～C6烷基、C5～C7芳环基、C5～C7元芳杂环基、5～6元杂环基、C2～C7炔基、C2～C7烯基，所述杂环基和芳杂环基各自含有1～3个选自氧、硫和氮的杂原子；所述取代基各自独立地选自下组：卤素、C1～C4直链或支链烷基、C2～C4直链或支链烯基、C2～C4直链或支链炔基、C1～C4直链或支链烷氧基、C1～C4直链或支链烷基羰氧基、C1～C4直链或支链烷硫基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、C1～C4酰基、酰胺基、氨基磺酰基、C1～C4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5～7元环；
R4为共价反应或可逆共价反应基团，包括未取代或1-2个取代基取代的醛基、氰基、硼酸、羧酸基、α-羰基醇、α-羰基醛、α-羰基酰胺、α-羰基三氟甲基、丙烯酰基、α-卤代乙酰基、1-(环氧乙烷-2-基)乙酰基、2-丁炔酰基，所述取代基各自独立地选自下组：卤素、C1～C4直链或支链烷基、C2～C4直链或支链烯基、C2～C4直链或支链炔基、C1～C4直链或支链烷氧基、C1～C4直链或支链烷基羰氧基、C1～C4直链或支链烷硫基、C3～C7环烷基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、羧基、巯基、C1～C4酰基、酰胺基、氨基磺酰基、C1～C4烷基取代的磺酰基，或者两个相邻的取代基连同与其连接的碳原子构成5～7元环；
m是0，1，2或3；
n是0，1，2，3，4或5。
2.根据权利要求1要求所述的化合物或其药学上可接受的盐、对映异构体、非对应异构体或外消旋体，其中，所述化合物选自以下表1所示的化合物：
表1：代表化合物I-1～I-25
3.一种如权利要求1所述通式(I)所示的化合物的制备方法，包括步骤：
(1)在惰性溶剂中，在缩合剂和碱存在下，用化合物II和化合物Ia反应，得到式化合物Ib；优选地，所述的缩合剂为1-羟基苯并***(HOBT)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)，碱为N,N-二异丙基乙胺(DIEA)；
(2)在惰性溶剂中，在催化剂和碱存在下，用化合物Ib和化合物III反应，得到化合物I；优选地，所述的催化剂为甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(XPhos Pd G3)，碱为磷酸钾(K3PO4)；
上述各反应通式中，各基团的定义如权利要求1所述。
4.一种药物组合物，所述的药物组合物包括：治疗有效量的一种或多种权利要求1所述通式(I)所示化合物，其药学上可接受的盐，以及任选的药学上可接受的载体。
5.如权利要求1要求的通式(I)的药物组合物在以病毒关键药物靶点Mpro为作用靶点中的应用。
6.如权利要求1要求的通式(I)的药物组合物在预防或抗病毒的药物中的应用，其特征在于，所述冠状病毒包括人冠状病毒OC43、人冠状病毒229E、人冠状病毒NL63、人冠状病毒HKU1、重症急性呼吸综合征冠状病毒(SARS-Cov-1)、中东呼吸综合征冠状病毒(MERS)和新型冠状病毒(SARS-Cov-2)。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110795720.1A CN113773259A (zh) | 2021-07-14 | 2021-07-14 | 病毒主蛋白酶抑制剂及其制备方法和用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110795720.1A CN113773259A (zh) | 2021-07-14 | 2021-07-14 | 病毒主蛋白酶抑制剂及其制备方法和用途 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113773259A true CN113773259A (zh) | 2021-12-10 |
Family
ID=78835887
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110795720.1A Pending CN113773259A (zh) | 2021-07-14 | 2021-07-14 | 病毒主蛋白酶抑制剂及其制备方法和用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113773259A (zh) |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004093860A1 (en) * | 2003-04-21 | 2004-11-04 | Pfizer Inc. | Inhibitors of sars related coronavirus proteinase |
| CN1569841A (zh) * | 2003-07-15 | 2005-01-26 | 北京大学 | Sars冠状病毒3cl蛋白酶抑制剂及其用途 |
| US20050267071A1 (en) * | 2003-10-31 | 2005-12-01 | Fulcrum Pharmaceuticals, Inc. | Inhibitors of coronavirus protease and methods of use thereof |
| CN103159665A (zh) * | 2011-12-09 | 2013-06-19 | 天津市国际生物医药联合研究院 | 对sars冠状病毒主蛋白酶具有抑制作用的靛红-5-酰胺类抑制剂 |
| US20150133368A1 (en) * | 2012-05-02 | 2015-05-14 | Kansa State University Research Foundation | Macrocyclic and peptidomimetic compounds as broad-spectrum antivirals against 3c or 3c-like proteases of picornaviruses, caliciviruses and coronaviruses |
| CN105837487A (zh) * | 2016-03-17 | 2016-08-10 | 天津国际生物医药联合研究院 | MERS-CoV主蛋白酶小分子抑制剂及其制备方法和用途 |
| CN106928206A (zh) * | 2015-12-31 | 2017-07-07 | 中国科学院上海药物研究所 | 醛基类化合物及其制法和用途 |
| WO2018042343A2 (en) * | 2016-08-30 | 2018-03-08 | Glaxosmithkline Intellectual Property (No.2) Limited | Compounds that inhibit 3c and 3cl proteases and methods of use thereof |
| US20210008150A1 (en) * | 2019-06-05 | 2021-01-14 | Emory University | Peptidomimetics for the treatment of coronavirus and picornavirus infections |
-
2021
- 2021-07-14 CN CN202110795720.1A patent/CN113773259A/zh active Pending
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004093860A1 (en) * | 2003-04-21 | 2004-11-04 | Pfizer Inc. | Inhibitors of sars related coronavirus proteinase |
| CN1569841A (zh) * | 2003-07-15 | 2005-01-26 | 北京大学 | Sars冠状病毒3cl蛋白酶抑制剂及其用途 |
| US20050267071A1 (en) * | 2003-10-31 | 2005-12-01 | Fulcrum Pharmaceuticals, Inc. | Inhibitors of coronavirus protease and methods of use thereof |
| CN103159665A (zh) * | 2011-12-09 | 2013-06-19 | 天津市国际生物医药联合研究院 | 对sars冠状病毒主蛋白酶具有抑制作用的靛红-5-酰胺类抑制剂 |
| US20150133368A1 (en) * | 2012-05-02 | 2015-05-14 | Kansa State University Research Foundation | Macrocyclic and peptidomimetic compounds as broad-spectrum antivirals against 3c or 3c-like proteases of picornaviruses, caliciviruses and coronaviruses |
| CN106928206A (zh) * | 2015-12-31 | 2017-07-07 | 中国科学院上海药物研究所 | 醛基类化合物及其制法和用途 |
| CN105837487A (zh) * | 2016-03-17 | 2016-08-10 | 天津国际生物医药联合研究院 | MERS-CoV主蛋白酶小分子抑制剂及其制备方法和用途 |
| WO2018042343A2 (en) * | 2016-08-30 | 2018-03-08 | Glaxosmithkline Intellectual Property (No.2) Limited | Compounds that inhibit 3c and 3cl proteases and methods of use thereof |
| US20210008150A1 (en) * | 2019-06-05 | 2021-01-14 | Emory University | Peptidomimetics for the treatment of coronavirus and picornavirus infections |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106928206B (zh) | 醛基类化合物及其制法和用途 | |
| KR20210043617A (ko) | 케토아미드계 화합물 및 이의 제조 방법, 약학 조성물과 용도 | |
| CA2691442C (en) | Antiviral compounds | |
| CN114057702B (zh) | 一种新型冠状病毒主蛋白酶的抑制剂及其制备方法和用途 | |
| JP5372751B2 (ja) | Ａｚａ−ペプチドプロテアーゼ阻害剤 | |
| JP5599611B2 (ja) | 抗ウイルスプロテアーゼインヒビター | |
| KR20010101675A (ko) | 2ｈ-프탈라진-1-온 유도체 및 그 유도체를 유효 성분으로하는 약제 | |
| CA3210873A1 (en) | Compounds, compositions, and methods of using the same | |
| KR20220134772A (ko) | 케토아미드계 화합물의 약물 용도 | |
| CN107459511B (zh) | 抗肠病毒71(ev71)4-亚氨基恶唑烷-2-酮类化合物及其制备方法和用途 | |
| WO2023283831A1 (zh) | 病毒主蛋白酶抑制剂及其制备方法和用途 | |
| WO2004052879A1 (en) | Thiophenederivatives for the treatment of flavivirus infections | |
| CN113773259A (zh) | 病毒主蛋白酶抑制剂及其制备方法和用途 | |
| CN117836272A (zh) | 用于治疗或预防冠状病毒感染的3cl蛋白酶小分子抑制剂及其用途 | |
| CA3178647A1 (en) | Substituted tricyclic amides, analogues thereof, and methods using same | |
| EP1844775B1 (en) | Therapeutic agent for the treatment of herpes progenitalis after development of lesions | |
| CN113698383B (zh) | 一种哌嗪类化合物及其应用 | |
| CN112010774A (zh) | FXIa凝血因子抑制剂、其药物组合物和用途 | |
| CN115141206B (zh) | 一种ɑ-硫辛酸石蒜碱偶联物及其制备方法和应用 | |
| CN112961081B (zh) | 一种联苯甲酰胺脲类化合物及其制备方法和应用 | |
| CN114920663B (zh) | 一种联苯类奥司他韦衍生物及其制备方法与应用 | |
| WO2023185763A1 (zh) | 一种拟肽类化合物及其制备方法、药物组合物和用途 | |
| TW202200565A (zh) | 抗病毒性1,3-二氧代茚化合物 | |
| CN113620936A (zh) | 一种吡咯烷类化合物及其应用 | |
| TW202214574A (zh) | 經取代之(呔-1-基甲基)脲類、經取代之n-(呔-1-基甲基)醯胺類及其類似物 |
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 | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20211210 |
|
| WD01 | Invention patent application deemed withdrawn after publication |