CN113773275B - Antiviral compound and preparation method thereof - Google Patents
Antiviral compound and preparation method thereof Download PDFInfo
- Publication number
- CN113773275B CN113773275B CN202110895286.4A CN202110895286A CN113773275B CN 113773275 B CN113773275 B CN 113773275B CN 202110895286 A CN202110895286 A CN 202110895286A CN 113773275 B CN113773275 B CN 113773275B
- Authority
- CN
- China
- Prior art keywords
- formula
- reaction
- virus
- compound
- influenza
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 79
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 230000000840 anti-viral effect Effects 0.000 title abstract description 15
- 241000700605 Viruses Species 0.000 claims abstract description 48
- 241000711573 Coronaviridae Species 0.000 claims abstract description 23
- 230000000694 effects Effects 0.000 claims abstract description 20
- 241000712431 Influenza A virus Species 0.000 claims abstract description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 10
- 150000001335 aliphatic alkanes Chemical class 0.000 claims abstract description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 33
- 239000003814 drug Substances 0.000 claims description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 241000712461 unidentified influenza virus Species 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- 241000711467 Human coronavirus 229E Species 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 13
- 230000009385 viral infection Effects 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 9
- 238000006482 condensation reaction Methods 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 208000036142 Viral infection Diseases 0.000 claims description 5
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 4
- 239000003443 antiviral agent Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 229940035676 analgesics Drugs 0.000 claims description 3
- 239000000730 antalgic agent Substances 0.000 claims description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 3
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- VGTPCRGMBIAPIM-UHFFFAOYSA-M sodium thiocyanate Chemical compound [Na+].[S-]C#N VGTPCRGMBIAPIM-UHFFFAOYSA-M 0.000 claims description 3
- 230000005764 inhibitory process Effects 0.000 abstract description 13
- 238000002474 experimental method Methods 0.000 abstract description 11
- 206010069767 H1N1 influenza Diseases 0.000 abstract description 6
- 201000010740 swine influenza Diseases 0.000 abstract description 6
- 206010061218 Inflammation Diseases 0.000 abstract description 3
- 230000004054 inflammatory process Effects 0.000 abstract description 3
- 231100000956 nontoxicity Toxicity 0.000 abstract description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 abstract description 2
- 210000005260 human cell Anatomy 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 52
- -1 thiazole compound Chemical class 0.000 description 33
- 238000012360 testing method Methods 0.000 description 27
- 241000699670 Mus sp. Species 0.000 description 17
- 229940079593 drug Drugs 0.000 description 15
- 239000001963 growth medium Substances 0.000 description 14
- 208000015181 infectious disease Diseases 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 13
- 241000700159 Rattus Species 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 238000012258 culturing Methods 0.000 description 10
- 230000000120 cytopathologic effect Effects 0.000 description 10
- 241001397616 Influenza A virus (H1N1) Species 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 210000004072 lung Anatomy 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 241000282414 Homo sapiens Species 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- 230000037396 body weight Effects 0.000 description 8
- 238000010790 dilution Methods 0.000 description 8
- 239000012895 dilution Substances 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- 239000013641 positive control Substances 0.000 description 8
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 7
- 241000197306 H1N1 subtype Species 0.000 description 7
- 206010022000 influenza Diseases 0.000 description 7
- 230000003902 lesion Effects 0.000 description 7
- VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 description 7
- 239000012453 solvate Substances 0.000 description 7
- MWIQPUXVXAVFRM-KEBDBYFISA-N 2-[(E)-[[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-methylhydrazinylidene]methyl]benzoic acid Chemical compound ClC1=C(C=CC=C1)C=1N=C(SC=1)N(/N=C/C1=C(C=CC=C1)C(=O)O)C MWIQPUXVXAVFRM-KEBDBYFISA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 241000282898 Sus scrofa Species 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 230000002354 daily effect Effects 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 229960002194 oseltamivir phosphate Drugs 0.000 description 5
- IIGQLQZSWDUOBI-UHFFFAOYSA-N 1-amino-1-methylthiourea Chemical compound CN(N)C(N)=S IIGQLQZSWDUOBI-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 102100040018 Interferon alpha-2 Human genes 0.000 description 4
- 108010079944 Interferon-alpha2b Proteins 0.000 description 4
- 206010035664 Pneumonia Diseases 0.000 description 4
- 206010057190 Respiratory tract infections Diseases 0.000 description 4
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 241000004176 Alphacoronavirus Species 0.000 description 3
- 208000001528 Coronaviridae Infections Diseases 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 241000282887 Suidae Species 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000006285 cell suspension Substances 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 230000029087 digestion Effects 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000002458 infectious effect Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 230000000241 respiratory effect Effects 0.000 description 3
- 208000023504 respiratory system disease Diseases 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 241000282465 Canis Species 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 108010052167 Dihydroorotate Dehydrogenase Proteins 0.000 description 2
- 102100032823 Dihydroorotate dehydrogenase (quinone), mitochondrial Human genes 0.000 description 2
- 238000012313 Kruskal-Wallis test Methods 0.000 description 2
- 208000025370 Middle East respiratory syndrome Diseases 0.000 description 2
- 208000009620 Orthomyxoviridae Infections Diseases 0.000 description 2
- 108010019160 Pancreatin Proteins 0.000 description 2
- 206010035737 Pneumonia viral Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 230000003044 adaptive effect Effects 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 239000012737 fresh medium Substances 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 210000003292 kidney cell Anatomy 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 210000005265 lung cell Anatomy 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 210000003928 nasal cavity Anatomy 0.000 description 2
- 201000009240 nasopharyngitis Diseases 0.000 description 2
- 229940055695 pancreatin Drugs 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 238000010257 thawing Methods 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 208000009421 viral pneumonia Diseases 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- JVKUCNQGESRUCL-UHFFFAOYSA-N 2-Hydroxyethyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCCO JVKUCNQGESRUCL-UHFFFAOYSA-N 0.000 description 1
- WZWWEVCLPKAQTA-UHFFFAOYSA-N 2-bromo-1-(2-chlorophenyl)ethanone Chemical compound ClC1=CC=CC=C1C(=O)CBr WZWWEVCLPKAQTA-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- CDUACMUYDHRMBX-UHFFFAOYSA-N 6-(oxomethylidene)cyclohexa-2,4-diene-1-carboxylic acid Chemical compound OC(=O)C1C=CC=CC1=C=O CDUACMUYDHRMBX-UHFFFAOYSA-N 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 241000008904 Betacoronavirus Species 0.000 description 1
- 241000288673 Chiroptera Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 241001506042 Duck influenza virus Species 0.000 description 1
- 238000001061 Dunnett's test Methods 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 244000309467 Human Coronavirus Species 0.000 description 1
- 206010020843 Hyperthermia Diseases 0.000 description 1
- 241000713196 Influenza B virus Species 0.000 description 1
- 208000002979 Influenza in Birds Diseases 0.000 description 1
- 208000032376 Lung infection Diseases 0.000 description 1
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 1
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 241000233805 Phoenix Species 0.000 description 1
- 229920001304 Solutol HS 15 Polymers 0.000 description 1
- 241000725681 Swine influenza virus Species 0.000 description 1
- 206010044302 Tracheitis Diseases 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N aminomethyl benzene Natural products NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- SOIFLUNRINLCBN-UHFFFAOYSA-N ammonium thiocyanate Chemical compound [NH4+].[S-]C#N SOIFLUNRINLCBN-UHFFFAOYSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000027645 antigenic variation Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 206010064097 avian influenza Diseases 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- 150000003936 benzamides Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000037058 blood plasma level Effects 0.000 description 1
- PHEZJEYUWHETKO-UHFFFAOYSA-N brequinar Chemical compound N1=C2C=CC(F)=CC2=C(C(O)=O)C(C)=C1C(C=C1)=CC=C1C1=CC=CC=C1F PHEZJEYUWHETKO-UHFFFAOYSA-N 0.000 description 1
- 229950010231 brequinar Drugs 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000003837 chick embryo Anatomy 0.000 description 1
- 238000010835 comparative analysis Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- ZCRZCMUDOWDGOB-UHFFFAOYSA-N ethanesulfonimidic acid Chemical compound CCS(N)(=O)=O ZCRZCMUDOWDGOB-UHFFFAOYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000003777 experimental drug Substances 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 244000144980 herd Species 0.000 description 1
- 230000036031 hyperthermia Effects 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000001524 infective effect Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 229960003752 oseltamivir Drugs 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- DROIHSMGGKKIJT-UHFFFAOYSA-N propane-1-sulfonamide Chemical compound CCCS(N)(=O)=O DROIHSMGGKKIJT-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 210000001243 pseudopodia Anatomy 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
- C07D277/38—Nitrogen atoms
- C07D277/50—Nitrogen atoms bound to hetero atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/04—Drugs for disorders of the respiratory system for throat disorders
-
- 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
-
- 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
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
- C07F9/6539—Five-membered rings
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pulmonology (AREA)
- Virology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Otolaryngology (AREA)
- Biochemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an antiviral compound and a preparation method thereof. The structural formula of the compound is shown as formula I, wherein R in formula I 1 Selected from: mono-or polysubstituted H, F, methyl, trifluoromethyl, preferably H; r is R 2 Selected from: H. linear or substituted alkanes (C1-C6), preferably methyl, isopropyl; r is R 3 Selected from: monosubstituted or polysubstituted H, cl, br, F, preferably Cl; r is R 4 Selected from: linear or substituted alkanes (C1-C6), preferably methyl, ethyl or propyl. Experiments prove that the compound has a good inhibition effect on H1N1 influenza A virus and also has a good inhibition effect on coronavirus, has no toxicity to normal human cells, and can inhibit the degree of inflammatory reaction while resisting viruses.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to an antiviral compound and a preparation method thereof.
Background
Influenza virus is abbreviated as influenza virus. It is classified into three types of A (A), B (B) and C (C), and influenza viruses which have been found only in recent years are classified into the type D. Influenza virus can cause infection and morbidity of various animals such as human beings, birds, pigs, horses, bats and the like, and is a pathogen of epidemic diseases of human beings, avian influenza, swine influenza, horse influenza and the like.
Typical clinical symptoms of these epidemic diseases are acute hyperthermia, general pain, significant debilitation and respiratory symptoms. Influenza viruses are transmitted mainly by droplets in the air, contact between susceptible and infected persons, or contact with contaminated objects. The autumn and winter season is the high-rise period. Human influenza is mainly caused by influenza a virus and influenza b virus. Influenza a viruses often undergo antigenic variation and can be further divided into subtypes H1N1, H3N2, H5N1, H7N9, etc. (where H and N represent two surface glycoproteins of influenza virus, respectively). Influenza virus is not strong against the outside world. Animal influenza viruses are not typically infectious to humans, human influenza viruses are not typically infectious to animals, but swine is a comparison exception. Pigs can be infected with either human influenza virus or avian influenza virus, but they are mainly infected with swine influenza virus. Few animal influenza viruses, when adapted to humans, can cause human influenza pandemics.
Human coronaviruses can produce common cold, severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) with certain differences in epidemiological characteristics.
Influenza a H1N1 is a highly infectious acute respiratory disease in pigs caused by one or more swine influenza type a viruses. Morbidity is often higher but mortality is lower (1-4%). Viruses are transmitted in swine herds by aerosols, direct and indirect contact, but asymptomatic swine. Swinery epidemic situation can occur throughout the year. The incidence rate increases in autumn and winter of the temperate zone. Human influenza a H1N1 is usually from an infected pig, but some human cases have no history of exposure to the pig or the environment in which the pig is located. Interpersonal transmission occurs in some cases, but is limited to people in close contact and in a closed environment.
Coronavirus (HCoV-229E) is one type of coronavirus. Coronaviruses belong to the order of the family of the viruses, the family of the coronaviridae, the genus coronavirus, a large family of viruses, which are widely available in nature. Coronaviruses infect only vertebrates, are associated with a variety of diseases in humans and animals, and can cause respiratory, digestive and nervous system diseases in humans and animals.
Therefore, research on an effective antiviral drug has important practical significance.
Disclosure of Invention
The invention aims to provide a compound shown in a formula I and pharmaceutically acceptable salts and solvates thereof.
The structural general formula of the compound provided by the invention is shown as formula I:
in the formula (I) of the formula,
R 1 selected from: mono-or polysubstituted H, F, methyl, trifluoromethyl, preferably H;
R 2 selected from: H. linear or substituted alkanes (C1-C6), preferably methyl, isopropyl;
R 3 selected from: monosubstituted or polysubstituted H, cl, br, F, preferably Cl;
R 4 selected from: linear or substituted alkanes (C1-C6), preferably methyl, ethyl or propyl.
In some embodiments of the present invention, the compounds of formula I according to the present invention may be exemplified by, but are not limited to, the structures shown below:
the invention also provides a preparation method of the compound shown in the formula I.
According to the document med. Chem. Commun.,2016,7,1441-1448, the alkylhydrazine of compound 1 (formula a) is reacted with sodium thiocyanate to give thiourea compound 2 (formula b), which is then condensed with R1-substituted benzaldehyde o-formate to give compound 3 (formula c), which is finally reacted with R 3 The thiazole compound 4 (formula d) can be obtained easily by substituting bromoacetophenone for ring closure; under the action of condensing agent, the benzamide derivative shown in the formula I is obtained. The method comprises the following specific steps:
1) Reacting a compound shown in a formula a with sodium thiocyanate to obtain a compound shown in a formula b;
wherein R in formula a 2 Is defined as formula I; r in formula b 2 Is defined as formula a;
2) Combining a compound represented by formula b with R represented by formula e 1 Carrying out condensation reaction on the substituted o-formoxyl benzaldehyde to obtain a compound shown in a formula c;
wherein R in formula e 1 Is defined as formula I; r in c 1 Is defined as formula e, R 2 Is defined as formula b;
3) Combining a compound represented by formula c with R represented by formula f 3 The bromoacetophenone is substituted for ring closure reaction to obtain a compound shown in a formula d;
wherein R in formula f 3 Is defined as formula I, R in formula d 1 、R 2 Is defined as formula c, R 3 Is defined as formula f;
4) Under the action of a condensing agent, carrying out condensation reaction on a compound shown in a formula d and a compound shown in a formula g to obtain a compound shown in a formula I;
wherein X, R in g 4 Is defined as in formula I.
In the step 1), the reaction conditions of the reaction are as follows: the reaction temperature is 50-100 ℃ and the reaction time is 24-72 hours; the reaction is carried out in a solvent which may be methanol, ethanol, tetrahydrofuran, acetonitrile, etc., preferably ethanol.
In the step 2), the reaction conditions of the condensation reaction are as follows: the reaction temperature is 50-100 ℃ and the reaction time is 1-3 hours; the reaction is carried out in a solvent which may be methanol, ethanol, tetrahydrofuran, acetonitrile, etc., preferably ethanol.
In the step 3), the reaction conditions of the ring-closing reaction are as follows: the reaction temperature is 50-100 ℃ and the reaction time is 3-6 hours; the reaction is carried out in a solvent which may be methanol, ethanol, tetrahydrofuran, acetonitrile, etc., preferably ethanol.
In the step 4), the reaction conditions of the condensation reaction are as follows: the reaction temperature is 0-25 ℃, and the reaction time is 2-8 hours; the reaction is carried out in a solvent which may be methylene chloride, tetrahydrofuran, acetonitrile, etc., preferably dichloromethane.
Other compounds as claimed in the claims of the present invention may be obtained by reference to the preparation methods of the examples of the present invention.
It is another object of the present invention to provide the use of the compounds of formula I as described above.
The application provided by the invention is the application of the compound shown in the formula I or pharmaceutically acceptable salt, ester and solvate thereof, namely (a) and/or (b) and/or (c) as follows:
(a) The application of a compound shown in a formula I or pharmaceutically acceptable salts, esters and solvates thereof in preparing a product for treating diseases caused by viruses or virus infection;
(b) The application of a compound shown in a formula I or pharmaceutically acceptable salts, esters and solvates thereof in preparing a product for preventing diseases caused by viruses or virus infection;
(c) The application of a compound shown in a formula I or pharmaceutically acceptable salts, esters and solvates thereof in preparing a virus inhibitor;
(d) The application of a compound shown in a formula I or pharmaceutically acceptable salts, esters and solvates thereof in preparing analgesic drugs.
The product may be a medicament or a pharmaceutical formulation.
The virus inhibitor is capable of inhibiting replication of a virus.
The virus includes influenza virus and coronavirus.
The influenza virus may specifically be influenza a virus (H1N 1);
the coronavirus may be an alpha and/or beta coronavirus, in particular selected from HCoV-229E.
In the present invention, the virus-caused disease may be a respiratory infectious disease.
The respiratory infection is a respiratory tract infection and/or a lung infection; the respiratory tract infection can be nasopharyngitis, rhinitis, pharyngolaryngitis, tracheitis and/or bronchitis; the pulmonary infection may be pneumonia.
In the present invention, the diseases caused by influenza virus generally include acute respiratory tract infection diseases caused by influenza virus, and the like.
In the present invention, the diseases caused by coronaviruses generally include viral pneumonia, severe acute respiratory syndrome, and the like.
In the present invention, the coronavirus infection usually causes viral pneumonia, severe acute respiratory syndrome and other diseases.
The compound has the inhibition effect on coronavirus and H1N1 influenza A virus, has no toxicity on normal cells of human, can inhibit the occurrence degree of inflammatory reaction, reduces the harm of pneumonia to organisms and promotes organism recovery.
An antiviral drug or an analgesic drug prepared by taking the compound shown in the formula I as an active ingredient also belongs to the protection scope of the invention.
The antiviral drug can be introduced into body such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue by injection, nasal drip, eye drip, permeation, absorption, physical or chemical mediated method; or mixed or wrapped with other substances and introduced into the body.
If necessary, one or more pharmaceutically acceptable carriers can be added into the medicine. The carrier includes diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers, lubricants, etc. which are conventional in the pharmaceutical field.
The medicine can be prepared into various forms such as tablets, powder, granules, capsules, oral liquid, ointment, cream, injection and the like; the medicaments of the various formulations can be prepared according to the conventional method in the pharmaceutical field.
The invention also provides a medicine or a medicine composition, and the active ingredient of the medicine or the medicine composition is a compound shown in a formula I or pharmaceutically acceptable salt, ester and solvate thereof.
The medicament or pharmaceutical composition has at least one of the following effects:
1) Treating a disease caused by a virus or a viral infection;
2) Preventing diseases caused by viruses or virus infection;
3) Inhibiting the virus;
4) Pain relief.
The above-mentioned drugs or pharmaceutical compositions may be formulated into solutions, tablets, capsules or injections according to conventional methods known to those skilled in the art.
When the compound shown as the formula I or the pharmaceutically acceptable salt thereof provided by the invention is used for preventing and/or treating infection caused by viruses, an effective amount of the compound shown as the formula I or the pharmaceutically acceptable salt thereof is given to a subject organism.
Experiments prove that the compound has a good inhibition effect on H1N1 influenza A virus and also has a good inhibition effect on coronavirus, has no toxicity to normal cells of human, and can inhibit the degree of inflammatory reaction while resisting viruses; in addition, the compound has obvious analgesic effect.
Drawings
FIG. 1 is a synthetic scheme for compounds of formula I of the present invention.
Detailed Description
The invention will be further illustrated with reference to the following specific examples, but the invention is not limited to the following examples. The methods are conventional methods unless otherwise specified. The starting materials are available from published commercial sources unless otherwise specified.
Examples 1 to 13
1. Synthesis of (E) -2- ((2- (4- (2-chlorophenyl) thiazol-2-yl) -2-methylhydrazono) methyl) benzamide (ZONK 2003-1)
1) 2-Methylthiosemicarbazide (1-2)
Methyl hydrazine (23.0 g,0.5 mol), ammonium thiocyanate (38.0 g,0.5 mol) and ethanol (200 mL) were added to each of the single neck round bottom flasks and heated to reflux for 72h. The reaction solution was cooled and concentrated, and purified by column chromatography to give 2-methylthiosemicarbazide (44.1 g, 84.0%) as an off-white solid. 1 H NMR(DMSO-d6 400MHz)δ7.24(s,2 H),6.85(s,2H),3.14(s,3H).ESI-MS m/z:106.1[M+H]+.
2) (E) -2- ((2-aminomethyl-2-methylhydrazono) methyl) benzoic acid (1-3)
2-Methylthiosemicarbazide (40.0 g,0.38 mol), 2-carbonylbenzoic acid (57.0 g,0.38 mol) and ethanol (300 mL) were added to the single-neck round-bottom flask, respectively, and the mixture was heated under reflux for 2 hours. The reaction solution was cooled and concentrated, and purified by column chromatography to give (E) -2- ((2-aminomethyl-2-methylhydrazono) methyl) benzoic acid (85.6 g, 95.0%) as a pale yellow solid. 1 H NMR(DMSO-d6 400MHz)δ13.0(s,1H),8.12-7.23(m,7H),2.47(s,3 H).ESI-MS m/z:238.1[M+H]+.
3) (E) -2- ((2- (4- (2-chlorophenyl) thiazol-2-yl) -2-methylhydrazono) methyl) benzoic acid (1-4) (abbreviated as ZONK 2003-0)
(E) -2- ((2-aminomethyl-2-methylhydrazono) methyl) benzoic acid (80.0 g,0.34 mol), 2-bromo-1- (2-chlorophenyl) ethanone (79.2 g,0.34 mol) and ethanol (400 mL) were each added to a single-necked round-bottomed flask, and heated for reflux reaction for 3 hours. The reaction solution was cooled and concentrated, and purified by column chromatography to give (E) -2- ((2- (4- (2-chlorophenyl) thiazol-2-yl) -2-methylhydrazono) methyl) benzoic acid (124 g, 98.5%) as a pale yellow solid. 1 H NMR(DMSO-d6 400MHz)δ13.23 (s,1H),8.60(s,1H),8.01-7.34(m,9H),3.66(s,3H).ESI-MS m/z:372.1[M+H]+.
4) Synthesis of (E) -2- ((2- (4- (2-chlorophenyl) thiazol-2-yl) -2-methylhydrazono) methyl) -N- (methylsulfonyl) benzamide (ZONK 2003-2)
(E) -2- ((2- (4- (2-chlorophenyl) thiazol-2-yl) -2-methylhydrazono) methyl) benzoic acid (3.71 g,10 mmol), 4-dimethylaminopyridine (1.22 g,10 mmol), sulfamic acid (1.11 g,10 mmol) were dissolved in dichloromethane (30 mL) respectively, dicyclohexylcarbodiimide (2.27 g,11 mmol) was then added and stirred at room temperature for 5h. The reaction solution was concentrated and purified by column chromatography to give (E) -2- ((2- (4- (2-chlorophenyl) thiazol-2-yl) -2-methylhydrazono) methyl) -N- (methylsulfonyl) benzamide (3.41 g, 76.2%) as a pale yellow solid. 1 H NMR(DMSO-d6 400MHz)δ8.10 (s,1H),8.00-7.43(m,9H),3.67(s,3H),3.42(s,3H).ESI-MS m/z:449.1[M+H]+.
2. Synthesis of (E) -2- ((2- (4- (2-chlorophenyl) thiazol-2-yl) -2-methylhydrazono) methyl) -N- (ethylsulfonyl) benzyl amine (ZONK 2003-4)
(E) -2- ((2- (4- (2-chlorophenyl) thiazol-2-yl) -2-methylhydrazono) methyl) benzoic acid (5.0 g,13.4 mmol), ethyl sulfonamide (1.46 g,13.4 mol), 4-dimethylaminopyridine (1.63 g,13.4 mol) were dissolved in dichloromethane (100 mL), dicyclohexylcarbodiimide (2.90 g,14.1 mol) was added to the solution in an ice-water bath, and the mixture was reacted at room temperature for 5 hours. The reaction solution was concentrated and purified by column chromatography to give (E) -2- ((2- (4- (2-chlorophenyl) thiazol-2-yl) -2-methylhydrazono) methyl) -N- (ethanesulfonyl) benzamide (5.27 g, 85.1%) as a white solid. 1 H NMR(DMSO-d 6 400MHz)δ8.60(s,1 H),8.01-7.34(m,9H),3.66(s,3H),3.43(m,2H),1.23(m,3H).ESI-MS m/z:463.5[M+H]+.
3. Synthesis of (E) -2- ((2- (4- (2-chlorophenyl) thiazol-2-yl) -2-methylhydrazono) methyl) -N- (propylsulfonyl) benzamide (abbreviated as ZONK 2003-14)
(E) -2- ((2- (4- (2-chlorophenyl) thiazol-2-yl) -2-methylhydrazono) methyl) benzoic acid (5.0 g,13.4 mmol), propylsulfonamide (1.65 g,13.4 mol), 4-dimethylaminopyridine (1.63 g,13.4 mol) were dissolved in methylene chloride (100 mL), and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.70 g,14.1 mol) was added to the solution in an ice-water bath to react for 5 hours at room temperature. The reaction solution was concentrated and purified by column chromatography to give (E) -2- ((2- (4- (2-chlorophenyl) thiadiazol-2-yl) -2-methylhydrazono) methyl) -N- (propanesulfonyl) benzamide (5.50 g, 86.2%) as a white solid. 1 H NMR(DMSO-d 6 400MHz)δ8.60(s,1H),8.01-7.34(m,9H),3.66(s,3H),3.43(m,2H),1.69(m,2H),1.23(m,3 H).ESI-MS m/z:477.5[M+H] + .
4. Synthesis of (E) -2- ((2- (4- (2-chlorophenyl) thiazol-2-yl) -2-isopropylhydrazono) methyl) -N- (methylsulfonyl) benzamide (abbreviated as ZONK 2003-15)
The preparation of examples 1-3 was followed to synthesize (E) -2- ((2- (4- (2-chlorophenyl) thiazol-2-yl) -2-isopropylhydrazono) methyl) -N- (methylsulfonyl) benzamide. 1 H NMR(DMSO-d 6 400MHz)δ8.60(s,1H),8.01-7.34 (m,9H),3.34(s,3H),3.13(m,1H),1.09(d,6H).ESI-MS m/z:477.1[M+H] + .
5. Synthesis of (E) -2- ((2- (4- (2-chlorophenyl) thiazol-2-yl) -2-isopropylhydrazono) methyl) -4-fluoro-N- (methylsulfonyl) benzamide (abbreviated as ZONK 2003-16)
The preparation of examples 1-3 was followed to synthesize (E) -2- ((2- (4- (2-chlorophenyl) thiazol-2-yl) -2-isopropylhydrazono) methyl) -4-fluoro-N- (methylsulfonyl) benzamide. 1 H NMR(DMSO-d 6 400MHz)δ8.60(s,1 H),8.01-7.34(m,8H),3.34(s,3H),3.13(m,1H),1.09(d,6H).ESI-MS m/z:495.5[M+H] + .
6. Synthesis of (E) -2- ((2- (4- (2-chlorophenyl) thiazol-2-yl) -2-isopropylhydrazono) methyl) -N- (ethylsulfonyl) -5-fluorobenzamide (abbreviated as ZONK 2003-17)
The preparation of examples 1-3 was followed to synthesize (E) -2- ((2- (4- (2-chlorophenyl) thiazol-2-yl) -2-isopropylhydrazono) methyl) -N- (ethylsulfonyl) -5-fluorobenzamide. 1 H NMR(DMSO-d 6 400MHz)δ8.60(s,1 H),8.01-7.34(m,8H),346(m,2H),3.25(m,1H),1.,23(m,3H)，1.09(d,6H).ESI-MS m/z:509.5[M+H] + .
7. Synthesis of (E) -2- ((2- (4- (2-chlorophenyl) thiazol-2-yl) -2-methylhydrazono) methyl) -4-fluoro-N- (methylsulfonyl) benzamide (abbreviated as ZONK 2003-18)
The preparation of examples 1-3 was followed to synthesize (E) -2- ((2- (4- (2-chlorophenyl) thiazol-2-yl) -2-methylhydrazono) methyl) -4-fluoro-N- (methylsulfonyl) benzamide. 1 H NMR(DMSO-d 6 400MHz)δ8.60(s,1 H),8.01-7.34(m,8H),3.66(s,3H),3.42(s,3H).ESI-MS m/z:467.1[M+H] + .
8. Synthesis of (E) -2- ((2- (4- (2-chlorophenyl) thiazol-2-yl) -2-methylhydrazono) methyl) -N- (ethylsulfonyl) -4-fluorobenzamide (abbreviated as ZONK 2003-19)
The preparation of examples 1-3 was followed to synthesize (E) -2- ((2- (4- (2-chlorophenyl) thiazol-2-yl) -2-methylhydrazono) methyl) -N- (ethylsulfonyl) -4-fluorobenzamide. 1 H NMR(DMSO-d 6 400MHz)δ8.60(s,1 H),8.01-7.34(m,8H),3.66(s,3H),3.12(m,2H),1.29(m,3H).ESI-MS m/z:481.5[M+H] + .
9. Synthesis of (E) -2- ((2- (4- (2-chlorophenyl) thiazol-2-yl) hydrazono) methyl) -5-methyl-N- (methylsulfonyl) benzamide (abbreviated as ZONK 2003-20)
The preparation of examples 1-3 was followed to synthesize (E) -2- ((2- (4- (2-chlorophenyl) thiazol-2-yl) hydrazono) methyl) -5-methyl-N- (methylsulfonyl) benzamide. 1 H NMR(DMSO-d 6 400MHz)δ8.60(s,1H),8.01-7.34 (m,8H),3.42(s,3H),2.54(s,3H).ESI-MS m/z:449.5[M+H] + .
10. Synthesis of (E) -2- ((2- (4- (3, 5-dichlorophenyl) thiazol-2-yl) hydrazono) methyl) -5-methyl-N- (methylsulfonyl) benzamide (abbreviated as ZONK 2003-21)
The preparation of examples 1-3 was followed to synthesize (E) -2- ((2- (4- (3, 5-dichlorophenyl) thiazol-2-yl) hydrazono) methyl) -5-methyl-N- (methylsulfonyl) benzamide. 1 H NMR(DMSO-d 6 400MHz)δ8.60(s,1H),8.01-7.34 (m,7H),3.42(s,3H),2.54(s,3H).ESI-MS m/z:483.5[M+H] + .
Example 11 in vitro antiviral test of series of Compounds
And determining the toxic effect of ZONK2003 series compounds (compounds shown in a formula I) on MRC-5 and MDCK cells of the cultured viruses by adopting an MTT method, and designing a proper concentration for carrying out an antiviral test. In vitro antiviral pharmacodynamic tests were performed using cytopathic method (cytopathic effect, CPE method) to evaluate the effect of ZONK2003 series compounds on viruses causing respiratory diseases.
Test results: the ZONK2003 series compounds have no obvious toxicity to MRC-5 and MDCK cells; the antiviral effect was evaluated with half the effective rate (EC 50) for both strains of virus with varying degrees of antiviral effect. The EC50 against coronavirus (HCoV-229E) was 12.83. Mu. Mol/L, 15.00. Mu. Mol/L; the EC50 against influenza A virus (H1N 1) was 11.75. Mu. Mol/L, 18.19. Mu. Mol/L.
Conclusion of the test: within the concentration range of 10-20 mu mol/L, ZONK2003 series compounds have different degrees of inhibition effects on two strains of viruses, and can promote recovery of cells after infection by the viruses.
1. Test materials
1.1 test article
Test article: ZONK2003-4, lot number: 20200521, purity 98.70%; ZONK2003-2, lot number: 20200513, 99.01% pure, supplied by Guangdong middle-branch of medicine research Co. The culture medium DMEM is used for preparing 50.0, 25.0, 12.5, 6.25, 3.13 and 1.56 mu mol/L, and the culture medium DMEM is stored at the temperature of 2-8 ℃ for standby.
1.2 Positive control
Oseltamivir phosphate granules, 15mg×10 bags, suitable for Changdong sunshine Changjiang pharmaceutical industry Co., ltd., lot number: 0371912115 the effective period is 2021.12.11, usingPositive control against influenza a virus; recombinant human interferon alpha 2b gel, specification 1.0X10 5 IU/g, 10 g/g, md.Co., ltd., for positive control against coronavirus.
1.3 viral strains
Coronavirus (HCoV-229E), numbered: ATCC-VR-740, available from ATCC in the United states; influenza A virus (H1N 1), accession number ATCC-VR-95, available from ATCC in the United states. Are cultivated and stored in a class II biosafety laboratory.
1.4 cell lines
Human embryonic lung cells (MRC-5), canine kidney cells (MDCK), were all derived from the limited-technology company of Withanbozier life sciences.
1.5 major reagents
1.6 Main instruments
BSCIIB2-1101 biosafety cabinet, manufactured by Shanghai Ruiyan clean-up equipment Co., ltd., center number: 019, YXQ-50A type vertical pressure steam sterilizer, manufactured by Shanghai Boqun medical biological instruments Co., ltd., center number: 584;3111 CO 2 Incubator, manufactured by thermo fisher company, usa, center number: 147.
1.7 test facility
Pathogenic microorganisms laboratory, laboratory grade in Changsha: biosafety class II (BSL-II), record No.: long Wei Jishi spare (2019) No. B001. The test was performed in a center biosafety class II laboratory (BSL-II-1), and was performed in strict compliance with regulations and with the present center SOPs.
2. Test method
2.1 cell culture
Human embryonic lung cells (MRC-5) are adherent growth cells. The culture medium is DMEM culture medium containing 10% FBS, and when the growth state is good, the culture medium can be passaged every 2-3 d. Discarding culture medium in a purification workbench, washing with 1 XPBS for 2-3 times, adding proper amount of 0.25% Trypsin-EDTA for digestion, and taking off cells after about 1-3 minAppropriate amount of DMEM medium containing 10% fbs was added to terminate the digestion of pancreatin, blown into single cell suspension, transferred into EP tubes and centrifuged at 1000rpm for 5min. The medium was discarded, resuspended in fresh medium, and the medium was added at a ratio (cell density of about 10 5 /mL) was inoculated into a new flask, and placed at 37℃with 5% CO 2 Culturing in an incubator.
Canine kidney cells (MDCK) are adherent growing cells. The culture medium is DMEM culture medium containing 10% FBS, and when the growth state is good, the culture medium can be passaged every 2-3 d. The medium was discarded in a clean bench, washed 2-3 times with 1 XPBS, then digested with an appropriate amount of 0.25% Trypsin-EDTA, after about 2-5 min, after cell shedding, with an appropriate amount of DMEM medium containing 10% FBS to terminate the digestion of pancreatin, blown into single cell suspension, transferred into an EP tube, and centrifuged at 1000rpm for 5min. The medium was discarded, resuspended in fresh medium, and the cells were concentrated at a ratio (cell density of about 10 5 /mL) was inoculated into a new flask, and placed at 37℃with 5% CO 2 Culturing in an incubator.
2.2 amplification of viruses
2.2.1 coronavirus (HCoV-229E): MRC-5 cell expansion
MRC-5 cells were seeded at 75cm 2 Removing part of culture medium when cell density reaches 80-90%, covering the rest cells, adding appropriate amount of HCoV-229E virus, adsorbing virus on cell surface (about 3 hr, slightly shaking culture plate every 30min to make virus adsorption uniform), changing fresh culture medium without FBS, placing at 35deg.C, 5% CO 2 Culturing in a humidified constant temperature incubator. When observing that the cells start to generate lesions until no more lesions are generated (generally 5-7 days), adopting a repeated freeze thawing method, separating for 10min at 3000rpm to remove cell residues, collecting supernatant, packaging into a freezing tube, labeling, and storing in-80 ℃ for a short period or liquid nitrogen for a long period for later use.
2.2.2 influenza a virus (H1N 1): MDCK cell expansion
MDCK cells were seeded at 75cm 2 In the flask, when the cell density reaches 70-80%, part is removedAdding proper amount of H1N1 virus into the culture medium which is just covered with the rest cells, slightly shaking the culture plate at intervals of 30min after the virus is adsorbed on the cell surface (about 3H to make the virus adsorbed uniformly), replacing fresh culture medium without FBS, and placing at 33deg.C and 5% CO 2 Culturing in a humidified constant temperature incubator. Observing when the cells begin to generate lesions until no more lesions are generated (generally for 2-3 days), adopting a repeated freeze thawing method, separating for 10min at 3000rpm to remove cell residues, collecting supernatant, subpackaging in a freezing tube, labeling, and storing in a medium-80 ℃ for a short period or liquid nitrogen for a long period for later use.
2.3 half tissue culture infection concentration of virus (Tissue culture infective dose, TCID) 50 ) Is (are) determined by
Subjecting 2.2.1 and 2.2.2 collected virus solutions to TCID 50 Is determined by: inoculating 100 μl of corresponding cell suspension with appropriate density into 96-well cell culture plate, culturing for 24 hr, sucking off culture solution in the culture plate, adding 100 μl of virus solution diluted with cell maintenance solution (virus 10) -1 、10 -2 、10 -3 、10 -4 、10 -5 、10 -6 Gradient dilution) of 10 duplicate wells per dilution, 33 ℃,5% co 2 The incubator is used for carrying out adsorption culture for 3 hours, unadsorbed virus liquid is sucked, 100 mu L of cell maintenance growth maintaining liquid is added into each hole, and the culture is continued. Cytopathic effects (cytopathic effect, CPE, characteristics of CPE caused by viruses in cultured cells: rounded cells, strong in refraction, fused cell processes, partial wall release, filamentous processes or pseudopodia of the cytoplasm, and irregular maps of the whole shape, forming large and round fused multinucleated megacytes) were observed daily under an inverted microscope. And the number of wells in which CPE occurred was recorded, with the highest dilution at which no more lesions occurred as the endpoint, for the degree of cytopathic effect "- + - ++" shows: no cytopathy "-", less than or equal to 25 percent of cytopathy "+",25% -50% of cytopathy "+",50% -75% of cells lesions "+++",>75% of cell lesions "+ ++ + plus" ". Calculation of TCID according to Reed-Muench formula 50 ：
TCID 50 Log (CPE less than 50% virus dilution) +distance ratio x dilution spacing
Wherein the distance ratio = (above 50% percent-50)/(above 50% percent-below 50% percent)
2.4 concentration design of the test substance
2.4.1 cytotoxicity assays
ZONK2003 series of compounds (concentration gradients 50.0, 25.0, 12.5, 6.25, 3.13, 1.56. Mu. Mol/L) and oseltamivir phosphate (concentration gradients 20.0, 10.0, 5.0, 2.5, 1.25, 0.625. Mu.g/mL), interferon alpha 2b (concentration gradients 1X 10) were formulated in DMEM medium 3 、5×10 2 、2.5×10 2 、 1.25×10 2 、6.25×10 1 、3.1×10 1 IU/mL), and adding into cultured MRC-5 and MDCK cells, respectively, at 37deg.C, 5% CO 2 Culturing in humidified constant temperature incubator for 72 hr, adding MTT, culturing for 4 hr, measuring OD value of each well at 492nm wavelength, and calculating EC of ZONK2003 series compound on each cell 50 。
2.4.2 when the compound is cytotoxic, 1/2IC is used 50 3 test concentrations were set at 2-fold spacing dilution down for the highest concentration; when the compound was not toxic to cells, 3 test concentrations were set at 2-fold interval dilution down with 20. Mu. Mol/L at the highest concentration.
2.5 detection of antiviral Effect
2.5.1 cell seeding: the corresponding well-grown cell lines were grown at the appropriate density 24h before virus infection (about 10 5 Individual/well) was inoculated in 96-well plates at 100. Mu.L/well at 37℃with 5% CO 2 Culturing in an incubator;
2.5.2 after the cells reach about 70% -80%, part of the culture medium is sucked off, the rest just covers the cells (the viruses and the cells are better adsorbed), and 100TCID is inoculated 50 After culturing in an incubator for 3 hours, the medium in the 96-well plate was aspirated, and 200. Mu.L/well of a sample solution (according to cytotoxicity setting) of different concentrations prepared with a serum-free cell-retaining solution was added, and the mixture was incubated at 33℃with 5% CO 2 Culturing in an incubator.
2.5.3 grouping
Normal control group: the group was infected with the virus;
model control group: a virus infection group;
positive control group: a commercially available control;
test group: infected groups + different concentrations of the test substance.
2.5.4 evaluation of antiviral Activity (CPE method)
Cytopathic effect was observed daily, and cytopathic effect was observed continuously until no more increase in cytopathic effect was observed, and the number of cytopathic and non-diseased holes at each concentration was recorded.
2.6 evaluation of results
The cytopathic rate (%) = (1-each group of cells was not diseased in the well/8) ×100% was set to 100% for the normal control group.
The significant digital modification of the test data was performed by rounding off, and the software used for statistics was SPSS 16.0. The measurement data is expressed as mean ± standard deviation
The normalization and variance alignment were checked using the level's test method. If there is no statistical significance (P>0.05 Statistical analysis was performed using one-way analysis of variance (ANOVA). If ANOVA is statistically significant (P.ltoreq.0.05), a comparison analysis is performed by the LSD method. If the variance is not uniform (P.ltoreq.0.05), then the Kruskal-Wallis test is used. If the Kruskal-Wallis Test is statistically significant (P.ltoreq.0.05), a comparative analysis is performed using Dunnett's Test (nonparametric method). The statistical result takes alpha=0.05 as a test limit, wherein P is less than or equal to 0.05 and has statistical significance, and P is less than or equal to 0.01 and has very significant significance for the tested difference.
3. Test results
3.1 Effect of series of Compounds on proliferation of Individual cells
As shown in tables 1-1 and 1-2, the two compounds have no obvious cytotoxicity to MRC-5 and MDCK in the range of the tested concentration (1.56-50.0 mu mol/L), so that the highest concentration is set to be 20.0 mu mol/L in the antiviral study. As shown in Table 2, the positive drug was interferon alpha 2b (6.25X10 1 ～1×10 3 IU/mL) on MRC-5 cells, phosphoric acidOseltamivir (0.625-20.0 mu mol/L) has no obvious cytotoxicity to MDCK cells, so the highest concentration in antiviral research is respectively set to 1 multiplied by 10 3 IU/mL、20.0μmol/L。
TABLE 1-1 Effect of two Compounds on MRC-5 cell proliferation
Table 1-2 effect of two compounds on MDCK cell proliferation
TABLE 2 influence of Positive drugs on proliferation of cells
3.2 detection of viral titre results
As shown in tables 3 and 4, the half viral infection amount TCID of coronavirus (HCoV-229E) and influenza A virus (H1N 1) 50 Respectively 10 -3.5 /0.1mL、10 -3.85 0.1mL, 3.16X10 virus respectively 4 Multiple of 7.08X10 4 0.1mL of inoculated cells were used for dilution, and 50% of the cells were diseased. Take 100 TCIDs 50 The virus amount, i.e. diluted 316-fold and 708-fold respectively, was tested for antiviral in vitro.
TABLE 3 half of the viral infection of MRC-5 cells by HCoV-229E
TABLE 4 half viral infection of MDCK cells by H1N1
3.3 Effect of series concentration of ZONK2003 series Compounds on cell viability after infection with Virus
EC of compounds ZONK2003-4, ZONK2003-2 against coronavirus (HCoV-229E) 50 12.83 mu mol/L and 15.00 mu mol/L respectively; EC of compounds ZONK2003-4, ZONK2003-2 against influenza A virus (H1N 1) 50 11.75. Mu. Mol/L and 18.19. Mu. Mol/L, respectively.
EC of interferon alpha 2b on coronavirus (HCoV-229E) 50 Is 2.42 multiplied by 10 2 IU/mL; oseltamivir phosphate EC against influenza A virus (H1N 1) 50 5.06. Mu. Mol/L.
TABLE 5 Effect of test/control on HCoV-229E infection of MRC-5 cells
TABLE 6 Effect of two Compounds on H1N1 infection of MDCK cells
4. Conclusion and evaluation
Under the test conditions:
the compounds ZONK2003-4 and ZONK2003-2 have no obvious cytotoxicity to MRC-5 and MDCK cells within the range of the test concentration (1.56-50.0 mu mol/L). The positive control medicine has no obvious toxicity to MRC-5 and MDCK cells within the range of the test concentration (0.625-20 mmol/L).
Compounds ZONK2003-4 and ZONK2003-2 have different degrees of inhibition on both viruses in the test and EC on coronavirus (HCoV-229E) 50 12.83 mu mol/L and 15.00 mu mol/L respectively; EC against influenza a virus (H1N 1) 50 11.75. Mu. Mol/L and 18.19. Mu. Mol/L, respectively.
The positive control agent has different degrees of inhibition on both viruses in the experiment, and has an EC on coronavirus (HCoV-229E) 50 Is 2.42 multiplied by 10 2 IU/mL; oseltamivir phosphate EC against influenza A virus (H1N 1) 50 5.06. Mu. Mol/L.
EXAMPLE 15 protection of Compounds against influenza A virus A/FM/1/47 (H1N 1) infected mice
Test article: ZONK2003-0, ZONK2003-2, ZONK2003-4; supplied by guangdong middling pharmaceutical research limited.
Oseltamivir phosphate granules, 15mg×10 bags, suitable for Changdong sunshine Changjiang pharmaceutical industry Co., ltd., lot number: 0371912115, expiration date to 2021.12.11, for positive control against influenza a virus;
experimental materials: influenza A virus mouse lung adapted strain A/FM/1/47 (H1N 1), chick embryos are inoculated, and allantoic fluid is collected for preservation. ICR mice, body weight 18-22 g. The administration period is free of feeding and drinking water, 12 hours of illumination every day, 12 hours of darkness, 22+ -2deg.C and 55-70% humidity. The experimental method comprises the following steps: after 3 days of adaptive feeding, experiments were started. The mice of each group, except the uninfected control group, were lightly anesthetized with diethyl ether, and inoculated in nasal cavity with saline diluted to 8 XLD 50 The positive control oseltamivir group and mice of the example compound group were administered by first gavage 2H after infection, each compound was orally administered at a dose of 10. Mu. Mol/kg, 20. Mu. Mol/kg, 30. Mu. Mol/kg, twice daily, and continuouslyThe medicine is taken for 5 days. Survival of mice was observed over 14 days and mortality protection of the mice by the drug was calculated (mortality protection = model group mortality—experimental group mortality).
TABLE 7 protection of compounds against influenza A virus (H1N 1 influenza A virus) infected mice
Example 16: alleviation of pulmonary inflammation in mice caused by infection with influenza virus H1N1 by drug
The experimental method comprises the following steps: after 3 days of adaptive feeding, experiments were started. The mice of each group, except the uninfected control group, were lightly anesthetized with diethyl ether, and inoculated in nasal cavity with saline diluted to 8 XLD 50 The positive control oseltamium Wei Zuxiao mice and the test administration group were administered by first gastric lavage at 80mg/kg 24H after virus infection, and then physiological saline was orally administered 1 time daily in the same way as the virus control group and the uninfected control group 1 time daily, with a dose volume of 0.1mL/10g body weight. For a total of 5 days. On day 6, 3 mice were weighed for each group, eyeballs were removed for bleeding and mortality, whole lungs were removed, weighed, and lung index inhibition were calculated.
Percent weight loss%o =pre-dose body weight-post-dose body weight/pre-dose body weight x 100%
Lung index = mouse lung weight/mouse body weight x 100
Lung index inhibition (%) = mean lung index of virus control group-mean lung index of administration group/mean lung index of virus control group x 100%
TABLE 8
Experimental results: therefore, the compound of the embodiment has obvious protective and inhibitory effects on lung inflammation caused by influenza virus, and the effect is superior to that of oseltamivir control group and ZONK2003-0 group.
Example 17: ZONK2003 drug rat pharmacokinetics experiments
Male rats were divided into 4 groups, ZONK2003-0 injection and oral administration, ZONK2003-2 injection and oral administration, respectively, wherein 3 ZONK2003-0 injection and oral administration, and 3 ZONK2003-2 injection groups, 6 ZONK2003-2 oral administration groups, respectively, were each collected for 10 discrete time points.
An LC-MS/MS analysis method for measuring ZONK2003-0 and ZONK2003-2 concentration in whole blood of the ICR mouse was established. The obtained blood concentration data adopts pharmacokinetic processing software Pharsight Phoenix WinNonlin 8.0.0 non-atrioventricular model to calculate related pharmacokinetic parameters.
The rat is perfused with ZONK2003-2, the oral dosage is 25mg/kg, and the injection of ZONK2003-2 is 1.21mg/kg;
the oral dosage of the rat lavage ZONK2003-0 is 2.51mg/kg, the injection ZONK2003-0 is 1.00mg/kg,
detecting the blood concentration and calculating pharmacokinetic parameters:
solvent: 20% Solutol HS-15/saline
The detailed results are shown in the following table.
TABLE 9 detection of blood concentration of proto-drug in rat (ng/mL) after rat tail vein administration of 1.00mg/kg ZONK2003-0
TABLE 10 essential pharmacokinetic parameters of prototype drug after rat tail vein administration of 1.00mg/kg ZONK2003-0
TABLE 11 detection of proto-drug blood concentration in rats (ng/mL) after 2.51mg/kg of ZONK2003-0 administered by gavage
TABLE 12 Primary pharmacokinetic parameters of prototype drug after 2.51mg/kg ZONK2003-0 intragastric administration in rats
TABLE 13 essential pharmacokinetic parameters of prototype drug after rat tail vein administration of 1.21mg/kg ZONK2003-2
TABLE 14 detection results of blood plasma levels of ZONK2003-2 intragastric administration of 25mg/kg group rat prototype drug (ng/mL)
ND: not detected, i.e. the measured value after the peak of the blood concentration is lower than the quantitative lower limit point
TABLE 15 Primary pharmacokinetic parameters of prototype drug after gastric lavage of 25mg/kg ZONK2003-2 in rats
From the above table, the absolute bioavailability F value of ZONK2003-0 was 62.5% and the absolute bioavailability F value of ZONK2003-2 group was 106.0%.
Example 18: analgesic experiment of ZONK2003 series Compounds
Effect of example Compounds on glacial acetic acid induced NIH mice torsion
NIH mice: SPF grade, male and female halves, 15-17g,110, provided by the medical laboratory animal center of Guangdong province, ZONK2003-0, ZONK2003-2, ZONK2003-4, ZONK2003-14, ZONK2003-18; supplied by guangdong middling pharmaceutical research limited.
2. Experimental methods and results
NIH mice 110, male, body weight 15-17g. After quarantine is finished, the animals are randomly divided into groups according to the weight for 3 days, and 10 animals in each group are: model group, experimental drug group. The mice were given the corresponding drugs intravenously at the time of the experiment, dosing volumes: 0.1ml/10g body weight, and an equal volume of physiological saline was administered to the model group. The inhibition was calculated by intraperitoneal injection of 0.7% (0.7 g/100 mL) HAc at 10mL/kg body weight at 0.5 hours after administration, immediately observing the torsion response of each mouse within 15min, and recording the number of torsion times.
The test results are shown in Table 17, and compared with the model group, each dose group can obviously inhibit the twisting times (p <0.05 or p < 0.01) of the glacial acetic acid induced NIH mice, and the action intensity is better than that of the ZONK2003-0 group.
Effects of the compounds of Table 17 on glacial acetic acid induced NIH mice torsion
Example 19DHODH enzyme inhibition Activity assay
The results of the DHODH enzyme activity tests for ZONK2003-0 and ZONK2003-2, brequinar, were as follows:
TABLE 18
Unlike ZONK2003-0, ZONK2003-2 does not exert an antiviral effect through inhibition of the DHODH enzyme.
Claims (6)
1. A compound having the structural formula (I) or a pharmaceutically acceptable salt thereof:
formula (I)
In the formula (I) of the formula,
R 1 selected from: mono-or polysubstituted H, F, methyl, trifluoromethyl;
R 2 selected from: h or a linear C1-C6 alkane;
R 3 selected from: monosubstituted or polysubstituted H, cl, br, F;
R 4 selected from: methyl or ethyl.
2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
the R is 1 Selected from H;
or, the R 2 Selected from methyl or isopropyl;
or, the R 3 Selected from Cl;
or, the R 4 Selected from methyl or ethyl.
3. A process for the preparation of a compound of formula I according to claim 1 or 2, comprising the steps of:
1) Reacting a compound shown in a formula a with sodium thiocyanate to obtain a compound shown in a formula b;
a and b
Wherein R in formula a 2 Is defined as formula I; r in formula b 2 Is defined as formula a;
2) Combining a compound represented by formula b with R represented by formula e 1 Carrying out condensation reaction on the substituted o-formoxyl benzaldehyde to obtain a compound shown in a formula c;
e type c
Wherein R in formula e 1 Is defined as formula I; r in c 1 Is defined as formula e, R 2 Is defined as formula b;
3) Combining a compound represented by formula c with R represented by formula f 3 The bromoacetophenone is substituted for ring closure reaction to obtain a compound shown in a formula d;
f-d
Wherein R in formula f 3 Is defined as formula I, R in formula d 1 、R 2 Is defined as formula c, R 3 Is defined as formula f;
4) Under the action of a condensing agent, carrying out condensation reaction on a compound shown in a formula d and a compound shown in a formula g to obtain a compound shown in a formula I;
g (g)
Wherein R in formula g 4 Is defined as in formula I.
4. A method according to claim 3, characterized in that:
in the step 1), the reaction conditions of the reaction are as follows: the reaction temperature is 50-100 ℃ and the reaction time is 24-72 hours; the reaction is carried out in a solvent selected from any one of the following: methanol, ethanol, tetrahydrofuran, acetonitrile;
in the step 2), the reaction conditions of the condensation reaction are as follows: the reaction temperature is 50-100 ℃ and the reaction time is 1-3 hours; the reaction is carried out in a solvent selected from any one of the following: methanol, ethanol, tetrahydrofuran, acetonitrile;
in the step 3), the reaction conditions of the ring closing reaction are as follows: the reaction temperature is 50-100 ℃ and the reaction time is 3-6 hours; the reaction is carried out in a solvent selected from any one of the following: methanol, ethanol, tetrahydrofuran, acetonitrile;
in the step 4), the reaction conditions of the condensation reaction are as follows: the reaction temperature is 0-25 ℃, and the reaction time is 2-8 hours; the reaction is carried out in a solvent selected from any one of the following: dichloromethane, tetrahydrofuran, acetonitrile.
5. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 is (a) and/or (c) and/or (d) as follows:
(a) The application of a compound shown in a formula (I) or pharmaceutically acceptable salt thereof in preparing a medicament for treating diseases caused by viruses or virus infection;
(c) The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a viral inhibitor;
(d) The application of a compound shown in a formula (I) or pharmaceutically acceptable salt thereof in preparing analgesic drugs;
the virus is influenza virus or coronavirus;
the influenza virus is influenza A virus; the coronavirus is HCoV-229E.
6. A medicament or pharmaceutical composition comprising as active ingredient a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof;
the medicament or pharmaceutical composition has at least one of the following effects:
1) Treating a disease caused by a virus or a viral infection;
2) Inhibiting the virus;
3) Pain relief;
the virus is influenza virus or coronavirus;
the influenza virus is influenza A virus; the coronavirus is HCoV-229E.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2021/128879 WO2022142727A1 (en) | 2020-12-29 | 2021-11-05 | Antiviral compound and method for preparation thereof |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011590753.4A CN112707874A (en) | 2020-12-29 | 2020-12-29 | Antiviral compound and preparation method thereof |
| CN2020115907534 | 2020-12-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113773275A CN113773275A (en) | 2021-12-10 |
| CN113773275B true CN113773275B (en) | 2023-04-25 |
Family
ID=75546128
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011590753.4A Pending CN112707874A (en) | 2020-12-29 | 2020-12-29 | Antiviral compound and preparation method thereof |
| CN202110895286.4A Active CN113773275B (en) | 2020-12-29 | 2021-08-05 | Antiviral compound and preparation method thereof |
| CN202110895352.8A Active CN113416172B (en) | 2020-12-29 | 2021-08-05 | Antiviral compound and preparation method thereof |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011590753.4A Pending CN112707874A (en) | 2020-12-29 | 2020-12-29 | Antiviral compound and preparation method thereof |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110895352.8A Active CN113416172B (en) | 2020-12-29 | 2021-08-05 | Antiviral compound and preparation method thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (3) | CN112707874A (en) |
| WO (2) | WO2022142731A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112707874A (en) * | 2020-12-29 | 2021-04-27 | 广东中科药物研究有限公司 | Antiviral compound and preparation method thereof |
| CN115701427A (en) * | 2021-08-02 | 2023-02-10 | 上海汇伦医药股份有限公司 | Polysubstituted thiazole derivatives and their use in the treatment of diseases |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9208492D0 (en) * | 1992-04-16 | 1992-06-03 | Glaxo Spa | Heterocyclic compounds |
| CA2195847A1 (en) * | 1994-07-27 | 1996-02-08 | John J. Talley | Substituted thiazoles for the treatment of inflammation |
| DE10111877A1 (en) * | 2001-03-10 | 2002-09-12 | Aventis Pharma Gmbh | Novel imidazolidine derivatives, their preparation, their use and pharmaceutical compositions containing them |
| WO2014136059A2 (en) * | 2013-03-05 | 2014-09-12 | Radikal Therapeutics Inc. | Prodrugs of multifunctional nitroxide derivatives and uses thereof |
| CN106892878B (en) * | 2015-12-18 | 2020-01-10 | 华东理工大学 | Thiazole derivative and application thereof in inhibiting dihydroorotate dehydrogenase |
| CN107375279B (en) * | 2016-05-17 | 2022-11-01 | 华东理工大学 | Use of novel thiazole derivatives for the treatment of inflammatory bowel disease |
| CN107382902B (en) * | 2016-05-17 | 2022-08-12 | 华东理工大学 | Thiazole derivative and application thereof |
| CN107459496B (en) * | 2016-06-03 | 2022-07-19 | 华东理工大学 | Use of thiazole derivatives for treating viral infections |
| CN108721283A (en) * | 2017-04-20 | 2018-11-02 | 华东理工大学 | Application of the thiazole in treating non-lymphocytic leukemia |
| CN108503604B (en) * | 2018-04-24 | 2020-04-24 | 湖南大学 | (4-alkyl-5-acyl-2-thiazole) hydrazone derivatives and medical application thereof |
| CA3134824A1 (en) * | 2019-03-28 | 2020-10-01 | Escient Pharmaceuticals, Inc. | Modulators of mas-related g-protein receptor x4 and related products and methods |
| CN112707874A (en) * | 2020-12-29 | 2021-04-27 | 广东中科药物研究有限公司 | Antiviral compound and preparation method thereof |
-
2020
- 2020-12-29 CN CN202011590753.4A patent/CN112707874A/en active Pending
-
2021
- 2021-08-05 CN CN202110895286.4A patent/CN113773275B/en active Active
- 2021-08-05 CN CN202110895352.8A patent/CN113416172B/en active Active
- 2021-11-05 WO PCT/CN2021/128948 patent/WO2022142731A1/en active Application Filing
- 2021-11-05 WO PCT/CN2021/128879 patent/WO2022142727A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| WO2022142727A1 (en) | 2022-07-07 |
| WO2022142731A1 (en) | 2022-07-07 |
| CN113416172A (en) | 2021-09-21 |
| CN113416172B (en) | 2022-06-21 |
| CN113773275A (en) | 2021-12-10 |
| CN112707874A (en) | 2021-04-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113773275B (en) | Antiviral compound and preparation method thereof | |
| CN111557939B (en) | Use of favipiravir for the treatment of coronavirus infections | |
| CN116236580B (en) | Application of old medicines such as auranofin and the like and compositions thereof in resisting single positive strand RNA viruses | |
| CN111743899B (en) | Application of nitazoxanide and its active form tizoxanide in preparing medicine for treating SARS-CoV-2 infection | |
| EP4116296A1 (en) | Anti-rna virus drug and application thereof | |
| CN113491700B (en) | Application of taurolidine in antivirus | |
| CN112641789A (en) | Application of compound in medicine for treating and preventing novel coronavirus and influenza virus | |
| US11655268B2 (en) | Nucleoside or nucleotide derivatives, and uses thereof | |
| CN115381816A (en) | Application of VER50589 in preparing medicine for resisting enterovirus 71 | |
| US20220298149A1 (en) | Isoxazole-3-carboxamide derivatives and their use for treatment of diseases caused by virus infection | |
| CN115141206B (en) | Alpha-lipoic acid lycorine conjugate and preparation method and application thereof | |
| CN110721312B (en) | Pharmaceutical composition for treating infantile respiratory tract infection and related preparation thereof | |
| US20230226027A1 (en) | Thienopyridine derivatives for use in the treatment of coronavirus infection | |
| CN116763902B (en) | Use of anti-coronavirus lipopeptides for the treatment and prevention of influenza | |
| EP4108241A1 (en) | Anti-rna virus drug and application thereof | |
| TWI811724B (en) | Inhibitors of positive strand rna viruses | |
| CN113546066B (en) | Pharmaceutical composition for preventing and treating viral pneumonia | |
| CN113924093A (en) | Enterovirus inhibitor | |
| CN117510409A (en) | Broad-spectrum antiviral traditional Chinese medicine monomer bat Ge Sulin alkali, and pharmaceutical composition and application thereof | |
| CN118307542A (en) | Heterocyclic derivative containing quinazolinone pyrrolidone unit, and preparation method and application thereof | |
| RU2552422C2 (en) | Indole-3-carboxylic acid derivatives having antiviral activity | |
| JPH03236366A (en) | Guanidinobenzene derivative | |
| CN113398120A (en) | Application of Abidol in preparing medicine for preventing or treating SARS-CoV-2 virus disease | |
| CN112891329A (en) | Application of terpenoid in preparation of anti-influenza virus medicine | |
| KR800001505B1 (en) | Process for preparing of thiazolyl phenyl guanidines |
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 |