CN117562890A - 一种色酮类化合物在制备抗冠状病毒药物中的用途 - Google Patents
一种色酮类化合物在制备抗冠状病毒药物中的用途 Download PDFInfo
- Publication number
- CN117562890A CN117562890A CN202310970496.4A CN202310970496A CN117562890A CN 117562890 A CN117562890 A CN 117562890A CN 202310970496 A CN202310970496 A CN 202310970496A CN 117562890 A CN117562890 A CN 117562890A
- Authority
- CN
- China
- Prior art keywords
- coronavirus
- formula
- hcov
- pharmaceutically acceptable
- application
- 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
- 239000003814 drug Substances 0.000 title claims abstract description 40
- 229940079593 drug Drugs 0.000 title claims abstract description 19
- -1 chromone compound Chemical class 0.000 title description 12
- 238000002360 preparation method Methods 0.000 title description 12
- 241000711573 Coronaviridae Species 0.000 claims abstract description 44
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 230000000694 effects Effects 0.000 claims abstract description 9
- 241000711467 Human coronavirus 229E Species 0.000 claims abstract description 6
- 230000010076 replication Effects 0.000 claims abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 14
- 208000001528 Coronaviridae Infections Diseases 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- 238000002347 injection Methods 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- 239000003826 tablet Substances 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 6
- 239000002552 dosage form Substances 0.000 claims description 6
- 239000003112 inhibitor Substances 0.000 claims description 6
- 241001678559 COVID-19 virus Species 0.000 claims description 4
- 241001428935 Human coronavirus OC43 Species 0.000 claims description 4
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 claims description 4
- 241000315672 SARS coronavirus Species 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 2
- 238000000338 in vitro Methods 0.000 abstract description 5
- 208000015181 infectious disease Diseases 0.000 abstract description 4
- 150000004777 chromones Chemical class 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 19
- 235000002639 sodium chloride Nutrition 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 description 9
- 102100037401 Putative uncharacterized protein encoded by MIR7-3HG Human genes 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- 241000700605 Viruses Species 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- 230000000120 cytopathologic effect Effects 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 241000282412 Homo Species 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- 239000012876 carrier material Substances 0.000 description 5
- 230000030833 cell death Effects 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 239000001856 Ethyl cellulose Substances 0.000 description 4
- 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 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 206010057190 Respiratory tract infections Diseases 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 235000019325 ethyl cellulose Nutrition 0.000 description 4
- 229920001249 ethyl cellulose Polymers 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 3
- 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 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- 206010035737 Pneumonia viral Diseases 0.000 description 3
- 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 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical compound C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 235000019868 cocoa butter Nutrition 0.000 description 3
- 229940110456 cocoa butter Drugs 0.000 description 3
- 230000001079 digestive effect Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 235000010981 methylcellulose Nutrition 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 208000009421 viral pneumonia Diseases 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 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 2
- 239000005995 Aluminium silicate Substances 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 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
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 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 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 231100000645 Reed–Muench method Toxicity 0.000 description 2
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 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
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000002250 absorbent Substances 0.000 description 2
- 230000002745 absorbent Effects 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 235000012211 aluminium silicate Nutrition 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 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
- 230000005754 cellular signaling Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 208000019836 digestive system infectious disease Diseases 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 235000012907 honey Nutrition 0.000 description 2
- 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 2
- 239000008101 lactose Substances 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 201000009240 nasopharyngitis Diseases 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 230000000241 respiratory effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 208000024891 symptom Diseases 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
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- 229940035437 1,3-propanediol Drugs 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical class CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000004176 Alphacoronavirus Species 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 241000008904 Betacoronavirus Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 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 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 244000309467 Human Coronavirus Species 0.000 description 1
- 241001109669 Human coronavirus HKU1 Species 0.000 description 1
- 241000482741 Human coronavirus NL63 Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- 241000218963 Lachnum virgineum Species 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 208000032376 Lung infection Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 241000199919 Phaeophyceae Species 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000004495 STAT3 Transcription Factor Human genes 0.000 description 1
- 108010017324 STAT3 Transcription Factor Proteins 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 206010044302 Tracheitis Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- 229940124532 absorption promoter Drugs 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
- 239000000443 aerosol Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- XHRPOTDGOASDJS-UHFFFAOYSA-N cholesterol n-octadecanoate Natural products C12CCC3(C)C(C(C)CCCC(C)C)CCC3C2CC=C2C1(C)CCC(OC(=O)CCCCCCCCCCCCCCCCC)C2 XHRPOTDGOASDJS-UHFFFAOYSA-N 0.000 description 1
- XHRPOTDGOASDJS-XNTGVSEISA-N cholesteryl stearate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)CCCCCCCCCCCCCCCCC)C1 XHRPOTDGOASDJS-XNTGVSEISA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 231100001134 median toxic concentration Toxicity 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 235000003715 nutritional status Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000002188 osteogenic effect Effects 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- DAJSVUQLFFJUSX-UHFFFAOYSA-M sodium;dodecane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCCCS([O-])(=O)=O DAJSVUQLFFJUSX-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种色酮类化合物在制备抗冠状病毒药物中的应用。具体地，本发明涉及式I所示的化合物，或其药学上可接受的盐。本发明发现该化合物能在体外有效抑制α冠状病毒HCoV‑229E的复制，对HCoV‑229E的IC50为0.24μg/ml，显示该化合物具有抗冠状病毒活性，可用于治疗冠状病毒引起的感染。
Description
技术领域
本发明属于生物医药技术领域，具体涉及一种色酮类化合物在制备抗冠状病毒药物中的用途。
背景技术
冠状病毒(Coronavirus，CoV)广泛存在于自然界，是一类具有囊膜、基因组为线性单股正链的RNA病毒，冠状病毒仅感染脊椎动物，与人类和动物的多种疾病有关，可引起人和动物呼吸道、消化道和神经系统疾病。
既往已知感染人的冠状病毒有6种，分别是人冠状病毒HCoV-229E、HCoV-OC43、HCoV-NL63和HCoV-HKU1，以及严重急性呼吸系统综合征冠状病毒SARS-CoV和中东呼吸综合症冠状病毒MERS-CoV，SARS-CoV-2是目前已知的第7种可以感染人的冠状病毒。以上冠状病毒中，前4种冠状病毒会引发较轻微症状的普通感冒，而后3种则会导致严重症状且传染性强，甚至引发致死的病毒性肺炎。寻找能够有效抗冠状病毒的药物依然十分重要。
色酮(Chromone)是一类次级代谢产物，广泛存在于植物和真菌中，其结构特征为分子中具有含苯并吡喃酮母核。该类化合物生物活性广泛，如抗炎、抗菌、抗氧化、抗肿瘤等广泛的药理活性，连接在母核上的取代基的类型、数量和位置的结构多样性对天然和合成衍生物的物理、化学和生物特性尤其重要。Lachnochromonin为本课题组从Lachnumvirgineum菌株的发酵产物中发现的色酮类化合物，结构式如式I所示。公开号为CN102442985 A的专利公开了lachnochromonin具有抑制肿瘤细胞生殖生长的活性，公开号为US 9221811 B2的专利公开了包含lachnochromonin等一系列色酮衍生物具有促进成骨作用，Chu等也报道了lachnochromonin通过JAK/STAT3信号抑制肿瘤细胞生长并促进细胞凋亡[参见，Cellular Signalling(细胞信号).2023,106,110592]。目前尚未见该化合物作为制备抗冠状病毒的药物报道。
发明内容
本发明的目的是提供一种色酮类化合物在制备抗冠状病毒药物中的新用途。药效学试验证实了该化合物在体外细胞模型中能有效抑制α群冠状病毒HCoV-229E的复制，具有用于制备抗冠状病毒药物的潜力。
所述色酮类化合物的结构式如式I所示。
本发明所提供的式I所示化合物或其药学上可接受的盐的应用为下述(a)和/或(b)和/或(c)：
(a)式I所示化合物或其药学上可接受的盐在制备治疗冠状病毒所致疾病或冠状病毒感染的产品中的应用；
(b)式I所示化合物或其药学上可接受的盐在制备预防冠状病毒所致疾病或冠状病毒感染的产品中的应用；
(c)式I所示化合物或其药学上可接受的盐在制备冠状病毒抑制剂中的应用。
所述产品可为药物或药物制剂。
所述冠状病毒抑制剂能够抑制冠状病毒的复制。
所述冠状病毒可为α属冠状病毒和/或β属冠状病毒，具体的选自人冠状病毒2019-nCoV、HCoV-229E、HCoV-OC43、SARS-CoV和MERS-CoV中的至少一种。
上述应用中，“式I所示化合物药学上可接受的盐”指在可靠的医学判断范围内，适合用于与人类和低等动物的组织接触而不出现过度的毒性、刺激、过敏反应等，且与合理的效果/风险比相称的盐。式I所示化合物药学上可接受的盐是本领域公知的，包括但不限于钠盐、钾盐、钙盐、盐酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、乙酸盐、草酸盐、乳酸盐、柠檬酸盐、酒石酸盐和马来酸盐等。
上述应用中，制备药物或药物制剂时，式I所示化合物或其药学上可接受的盐可作为有效成分之一，也可作为唯一有效成分。
上述应用中，制备药物或药物制剂时，式I所示化合物或其药学上可接受的盐可作为活性成分之一，也可作为唯一活性成分。
上述应用中，制备药物时，还可加入载体材料。
载体材料包括但不限于水溶性载体材料(如聚乙二醇、聚乙烯吡咯烷酮、有机酸等)、难溶性载体材料(如乙基纤维素、胆固醇硬脂酸酯等)、肠溶性载体材料(如醋酸纤维素酞酸酯和羧甲乙纤维素等)。使用这些材料可以制成多种剂型，包括但不限于片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、脂质体、透皮剂、口含片、栓剂、冻干粉针剂等。可以是普通制剂、缓释制剂、控释制剂及各种微粒给药系统。为了将单位给药剂型制成片剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如稀释剂与吸收剂，如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等；湿润剂与粘合剂，如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等；崩解剂，例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯、山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等；崩解抑制剂，例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等；吸收促进剂，例如季铵盐、十二烷基硫酸钠等；润滑剂，例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。为了将单位给药剂型制成丸剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如稀释剂与吸收剂，如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、高岭土、滑石粉等；粘合剂如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等；崩解剂，如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。为了将单位给药剂型制成栓剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如聚乙二醇、卵磷脂、可可脂、高级醇、高级醇的酯、明胶、半合成甘油酯等。为了将单位给药剂型制成注射用制剂，如溶液剂、乳剂、冻干粉针剂和混悬剂，可以使用本领域常用的所有稀释剂，例如，水、乙醇、聚乙二醇、1,3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酯等。另外，为了制备等渗注射液，可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油，此外，还可以添加常规的助溶剂、缓冲剂、pH调节剂等。此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。使用上述剂型可以经注射给药，包括皮下注射、静脉注射、肌肉注射和腔内注射等；腔道给药，如经直肠和阴道；呼吸道给药，如经鼻腔；粘膜给药。
本发明还提供了一种药物或药物组合物，其活性成分为式I所示化合物或其药学上可接受的盐。
所述药物或药物组合物具有下述至少一种功效：
1)治疗冠状病毒所致疾病或冠状病毒感染；
2)预防冠状病毒所致疾病或冠状病毒感染；
3)抑制冠状病毒。
上述药物或药物组合物可以按照本领域技术人员已知的常规方法制成溶液剂、片剂、胶囊或注射剂等剂型。
利用本发明提供的式I所示化合物或其药学上可接受的盐预防和/或治疗冠状病毒引起的感染时，给予受试者生物体有效量的式I化合物或其药学上可接受的盐。
本发明化合物的使用剂量和使用方法取决于诸多因素，包括患者的年龄、体重、性别、自然健康状况、营养状况、化合物的活性强度、服用时间、代谢速率、病症的严重程度以及诊治医生的主观判断。优选的使用剂量介于0.01～100mg/kg体重/天，其中最优剂量在0.1～10mg/kg体重/天。
本发明中，术语“有效量”是指可在受试者中实现治疗、预防、减轻和/或缓解本发明所述疾病或病症的剂量。
本发明中，术语“受试者”可以指患者或者其它接受本发明组合物以治疗、预防、减轻和/或缓解本发明所述疾病或病症的动物，特别是哺乳动物，例如人、狗、猴、牛、马等。
本发明中，所述冠状病毒所致疾病可为呼吸系统感染和/或消化系统感染。
所述呼吸系统感染为呼吸道感染和/或肺部感染；所述呼吸道感染可为鼻咽炎、鼻炎、咽喉炎、气管炎和/或支气管炎；所述肺部感染可为肺炎；所述消化系统感染可为腹泻。
本发明中，所述冠状病毒所致疾病通常包括病毒性肺炎、严重急性呼吸综合征等。
本发明中，所述冠状病毒感染通常引起病毒性肺炎、严重急性呼吸综合征等疾病。
本发明选择α群冠状病毒HCoV-229E，探讨上述式I所示的色酮类化合物在制备抗冠状病毒药物中应用的可能性，通过实验研究，发现该化合物能在体外显著抑制α群冠状病毒HCoV-229E的复制，具有用于制备抗冠状病毒药物的潜力。
附图说明
图1为式I所示化合物的核磁共振1H-NMR谱图。
图2为式I所示化合物的核磁共振13C-NMR谱图。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例中所用的冠状病毒HCoV-229E为人冠状病毒229E株(Humancoronavirus229E(VR-740TM))；文献：Hamre D,Procknow JJ.A new virusisolated from the human respiratory tract.Proc.Soc.Exp.Biol.Med.121:190-193,1966.PubMed:4285768。
实施例1、式I化合物体外抗HCoV-229E活性效果检测
1.实验目的
为研究式I化合物在体外抗冠状病毒的药效，拟用细胞病变效应(CPE)实验测定化合物在Huh7细胞中对冠状病毒(HCoV-229E)的半数抑制浓度(IC50)及SI。采用利巴韦林(RBV)作为阳性对照药物。
实验在中国医学科学院医药生物技术研究所病毒室BSL-2生物安全实验室(实验楼329房间)进行。
2.材料
供试品：
式I化合物，为本实验室制备分离(分离方法公开号为CN 102442985 A的专利)，为无定型粉末，纯度大于98％；结构确证数据见表1。
表1.式I所示化合物的氢谱(1H NMR)和碳谱(13C NMR)数据
a在400MHz以DMS0-d6为溶剂测试。
b在100MHz以DMS0-d6为溶剂测试。
阳性对照药利巴韦林注射液(RBV)，购自天津金耀集团湖北天药药业股份有限公司，规格为100mg/ml，用时稀释至所需浓度，4℃冰箱保存。
细胞：传代人肝癌细胞Huh7细胞为中国医学科学院医药生物技术研究所传代保存，在含10％胎牛血清(inactivated fetal bovine serum)和1％双抗(青霉素和链霉素)的DMEM或1640培养基中，37℃，5％ CO2培养箱中培养，2-3天传代一次。
毒株：HCoV-229E于Huh7细胞中传代，保存于-80℃冰箱。
3.实验方法
细胞培养
以Huh7细胞为例：在长满Huh7细胞的培养瓶内加0.25％ Trypsin-EDTA(胰酶细胞消化液)3ml，37℃消化1～2分钟，弃消化液，加培养液吹打，1:4传代，2-3天传代一次，种板时配制成每毫升20万个细胞，接种96孔细胞培养板，每孔0.1ml，37℃，5％ CO2培养过夜，细胞长成单层后进行实验。
抗HCoV-229E的活性测定(CPE法)
实验在传代Huh7细胞中进行，Huh7细胞1×104个/孔接种于96孔板中，过夜培养后将100μl HCoV-229E病毒液(100TCID50)感染96孔板内Huh7细胞，待测药物用维持液稀释，分别于感染同时给药和感染后2h给药两种给药方案进行测定，待测药物以三倍稀释8个剂量的样品进行实验，每个剂量设2个平行孔，同时设物无药物的病毒对照组。以观察细胞病变为指标，显微镜下观察细胞病变，以细胞死亡比例分别标记为4+(细胞死亡比例75％～100％)、3+(细胞死亡比例50％～75％)、2+(细胞死亡比例25％～50％)、1+(细胞死亡比例0～25％)、0+(细胞全部存活)。待病毒对照组病变达4+号时观察结果，记录并用Reed-Muench法计算药物对病毒的半数抑制浓度(公式如下)及选择指数(SI＝TC50/IC50)。
其中：A＝累积抑制率<50％的药物浓度，B＝累积抑制率>50％的抑制率，C＝累积抑制率<50％的抑制率，D＝log稀释倍数
细胞毒性测定方法(CPE法)
细胞按1.5×104个/孔接种于96孔板中，过夜培养后加入含待测药物的维持液，待测药物以三倍稀释8个剂量的样品进行实验，继续培养。给药2天后倒置显微镜下药物对细胞的毒性，并用Reed-Muench法计算半数有毒浓度TC50，计算公式如下：
其中：A＝累积抑制率<50％的药物浓度，B＝累积抑制率>50％的抑制率，C＝累积抑制率<50％的抑制率，D＝log稀释倍数
4.实验结果
药物在Huh7细胞内对HCoV-229E的抑制作用
如表1所示，CPE法测定式I化合物对HCoV-229E毒株的IC50为0.24μg/ml，选择指数SI为27；RBV对HCoV-229E的IC50为4.81μg/ml，选择指数SI为19.23。
表1.化合物在Huh7细胞内对HCoV-229E的抑制作用(IC50)(CPE法)
5.结论
本实验条件下，式I化合物对HCoV-229E毒株具有抑制作用；RBV对HCoV-229E毒株具有抑制作用，并且RBV的抗冠状病毒HCoV-229E活性与文献和本实验之前的结果相当，说明实验系统成立。
尽管本发明的具体实施方式已经得到详细的描述，本领域技术人员将会理解：根据已经公开的所有教导，可以对那些细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。下面结合具体实施例对本发明作进一步阐述，但本发明并不限于以下实施例。所述方法如无特别说明均为常规方法。所述原材料如无特别说明均能从公开商业途径获得。
Claims (8)
1.结构式如式I所示化合物或其药学上可接受的盐的应用，所述应用为下述(a)和/或(b)和/或(c)：
(a)式I所示化合物或其药学上可接受的盐在制备治疗冠状病毒所致疾病或冠状病毒感染的产品中的应用；
(b)式I所示化合物或其药学上可接受的盐在制备预防冠状病毒所致疾病或冠状病毒感染的产品中的应用；
(c)式I所示化合物或其药学上可接受的盐在制备冠状病毒抑制剂中的应用；
2.根据权利要求1所述的应用，其特征在于：所述产品为药物或药物制剂。
3.根据权利要求1或2所述的应用，其特征在于：所述冠状病毒为α属冠状病毒和/或β属冠状病毒；所述冠状病毒抑制剂能够抑制冠状病毒的复制。
4.根据权利要求3所述的应用，其特征在于：所述冠状病毒选自人冠状病毒2019-nCoV、HCoV-229E、HCoV-OC43、SARS-CoV和MERS-CoV中的至少一种。
5.一种药物或药物组合物，其活性成分为式I所示化合物或其药学上可接受的盐；
所述药物或药物组合物具有下述至少一种功效：
1)治疗冠状病毒所致疾病或冠状病毒感染；
2)预防冠状病毒所致疾病或冠状病毒感染；
3)抑制冠状病毒。
6.根据权利要求5所述的药物或药物组合物，其特征在于：所述冠状病毒为α属冠状病毒和/或β属冠状病毒；
所述冠状病毒抑制剂能够抑制冠状病毒的复制。
7.根据权利要求6所述的药物或药物组合物，其特征在于：所述冠状病毒选自人冠状病毒2019-nCoV、HCoV-229E、HCoV-OC43、SARS-CoV和MERS-CoV中的至少一种。
8.根据权利要求5-7中任一项所述的药物或药物组合物，其特征在于：所述药物或药物组合物为药学上可接受的任意剂型，包括片剂、胶囊剂、注射剂、颗粒剂、混悬剂和溶液剂中的至少一种。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310970496.4A CN117562890A (zh) | 2023-08-03 | 2023-08-03 | 一种色酮类化合物在制备抗冠状病毒药物中的用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310970496.4A CN117562890A (zh) | 2023-08-03 | 2023-08-03 | 一种色酮类化合物在制备抗冠状病毒药物中的用途 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117562890A true CN117562890A (zh) | 2024-02-20 |
Family
ID=89890543
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310970496.4A Pending CN117562890A (zh) | 2023-08-03 | 2023-08-03 | 一种色酮类化合物在制备抗冠状病毒药物中的用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117562890A (zh) |
-
2023
- 2023-08-03 CN CN202310970496.4A patent/CN117562890A/zh active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112587536A (zh) | 白藜芦醇-4′-o-(6″-没食子酰基)吡喃葡糖苷在制备抗冠状病毒药物中的应用 | |
| CN112694463B (zh) | 一种异戊烯基色原酮类化合物在制备抗冠状病毒药物中的用途 | |
| CN113456657B (zh) | 糖基聚醚化合物在制备抗rna病毒药物中的用途 | |
| CN112245424B (zh) | 一种没药烷倍半萜结构类似物在制备抗冠状病毒药物中的用途 | |
| CN112675172B (zh) | 一种二酮哌嗪类化合物在制备抗冠状病毒药物中的用途 | |
| CN111374985B (zh) | 盐酸非那吡啶的医药用途 | |
| CN111904959A (zh) | α-L-岩藻糖苷酶抑制剂在制备治疗小儿肺炎的药物中的用途 | |
| CN115006383B (zh) | 一种二苯醚类化合物在制备抗冠状病毒药物中的用途 | |
| CN115634227B (zh) | 一种n-羟基吡啶酮类化合物在制备抗冠状病毒药物中的用途 | |
| CN117562890A (zh) | 一种色酮类化合物在制备抗冠状病毒药物中的用途 | |
| WO2022143710A1 (zh) | 吡咯喹啉醌、其衍生物和/或盐作为抗病毒新药的用途及其药物组合物 | |
| CN116036071A (zh) | 一种聚酮类化合物在制备抗冠状病毒药物中的用途 | |
| CN116832018A (zh) | 一种萘醌类化合物在制备抗冠状病毒药物中的用途 | |
| CN111202732B (zh) | Caulilexin C在制备预防或治疗甲型流感的药物中的应用 | |
| CN110327317B (zh) | 紫草素在制备抗轮状病毒感染的药物中的应用 | |
| CN113332286A (zh) | Onalespib化合物在制备抗EV71病毒药物中的应用 | |
| CN110974826B (zh) | 欧乌碱或12-表-欧乌碱在制备治疗白血病的药物中的应用 | |
| EP3960173A1 (en) | Enterovirus inhibitor | |
| CN117379432B (zh) | 化合物或其药用盐在制备治疗和预防猪伪狂犬病毒所致疾病药物中的应用 | |
| CN116350643A (zh) | 2’岩藻糖基乳糖在制备柯萨奇病毒抑制剂中的应用 | |
| CN115105491B (zh) | 丝氨酸在制备抑制猪链球菌药物中的用途 | |
| CN117510408A (zh) | 抗病毒中药单体蝙蝠葛碱、及其药物组合物和应用 | |
| CN116617226A (zh) | 新型吲哚喹啉衍生物作为肠道病毒71型抑制剂的应用 | |
| JP2023072634A (ja) | 抗ウイルス剤 | |
| CN117582448A (zh) | 地高辛在制备用于预防或治疗肾上腺皮质癌的药物中的用途 |
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 |