CN115636817B - 含三唑环的靛红类衍生物及其制备方法与应用 - Google Patents
含三唑环的靛红类衍生物及其制备方法与应用 Download PDFInfo
- Publication number
- CN115636817B CN115636817B CN202210694873.1A CN202210694873A CN115636817B CN 115636817 B CN115636817 B CN 115636817B CN 202210694873 A CN202210694873 A CN 202210694873A CN 115636817 B CN115636817 B CN 115636817B
- Authority
- CN
- China
- Prior art keywords
- azide
- derivative containing
- reaction
- triazole ring
- fragments
- 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
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical class C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 125000001425 triazolyl group Chemical group 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- 239000003814 drug Substances 0.000 claims abstract description 10
- 229940079593 drug Drugs 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 150000003852 triazoles Chemical group 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- -1 1- (azidomethyl) -2-fluoro-4- (trifluoromethyl) benzene Chemical compound 0.000 claims description 10
- 238000010791 quenching Methods 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 150000001345 alkine derivatives Chemical group 0.000 claims description 7
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 claims description 7
- 230000000171 quenching effect Effects 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 239000000741 silica gel Substances 0.000 claims description 6
- 229910002027 silica gel Inorganic materials 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- XXFUZSHTIOFGNV-UHFFFAOYSA-N 1-bromoprop-1-yne Chemical compound CC#CBr XXFUZSHTIOFGNV-UHFFFAOYSA-N 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 238000012544 monitoring process Methods 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- WYFWUPTWYUKGQM-UHFFFAOYSA-N 1-(azidomethyl)-3-chlorobenzene Chemical compound ClC1=CC=CC(CN=[N+]=[N-])=C1 WYFWUPTWYUKGQM-UHFFFAOYSA-N 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 238000006352 cycloaddition reaction Methods 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- AARFXJVACBOQII-UHFFFAOYSA-N 2,3-dioxo-1h-indole-5-carboxamide Chemical compound NC(=O)C1=CC=C2NC(=O)C(=O)C2=C1 AARFXJVACBOQII-UHFFFAOYSA-N 0.000 claims 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims 1
- 235000010378 sodium ascorbate Nutrition 0.000 claims 1
- 229960005055 sodium ascorbate Drugs 0.000 claims 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims 1
- 229940124530 sulfonamide Drugs 0.000 claims 1
- 230000000694 effects Effects 0.000 description 21
- 102000004190 Enzymes Human genes 0.000 description 12
- 108090000790 Enzymes Proteins 0.000 description 12
- 230000005764 inhibitory process Effects 0.000 description 11
- 239000003112 inhibitor Substances 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 150000001540 azides Chemical class 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 241001678559 COVID-19 virus Species 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 102220024935 rs199473369 Human genes 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 241000711573 Coronaviridae Species 0.000 description 4
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 229940125673 3C-like protease inhibitor Drugs 0.000 description 3
- 101800000535 3C-like proteinase Proteins 0.000 description 3
- 101800002396 3C-like proteinase nsp5 Proteins 0.000 description 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 108091005532 SARS-CoV-2 main proteases Proteins 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 150000002611 lead compounds Chemical class 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 239000010413 mother solution Substances 0.000 description 2
- LIENCHBZNNMNKG-OJFNHCPVSA-N nirmatrelvir Chemical compound CC1([C@@H]2[C@H]1[C@H](N(C2)C(=O)[C@H](C(C)(C)C)NC(=O)C(F)(F)F)C(=O)N[C@@H](C[C@@H]3CCNC3=O)C#N)C LIENCHBZNNMNKG-OJFNHCPVSA-N 0.000 description 2
- 229940125675 paxlovid Drugs 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- FVFRGKBIKRFGNG-UHFFFAOYSA-N 1-(azidomethyl)-2,4-difluorobenzene Chemical compound FC1=CC=C(CN=[N+]=[N-])C(F)=C1 FVFRGKBIKRFGNG-UHFFFAOYSA-N 0.000 description 1
- UQTIJSCAOJIGQZ-UHFFFAOYSA-N 1-(azidomethyl)-2-bromobenzene Chemical compound BrC1=CC=CC=C1CN=[N+]=[N-] UQTIJSCAOJIGQZ-UHFFFAOYSA-N 0.000 description 1
- BOSNISRGGXSMHE-UHFFFAOYSA-N 1-(azidomethyl)-2-chlorobenzene Chemical compound ClC1=CC=CC=C1CN=[N+]=[N-] BOSNISRGGXSMHE-UHFFFAOYSA-N 0.000 description 1
- WJSUIHLKOGPGRY-UHFFFAOYSA-N 1-(azidomethyl)-2-fluorobenzene Chemical compound FC1=CC=CC=C1CN=[N+]=[N-] WJSUIHLKOGPGRY-UHFFFAOYSA-N 0.000 description 1
- TWZXVFYNRLIXRY-UHFFFAOYSA-N 1-(azidomethyl)-2-methylbenzene Chemical compound CC1=CC=CC=C1CN=[N+]=[N-] TWZXVFYNRLIXRY-UHFFFAOYSA-N 0.000 description 1
- NCARQSCDRIWXMR-UHFFFAOYSA-N 1-(azidomethyl)-2-methylsulfonylbenzene Chemical compound CS(=O)(=O)c1ccccc1CN=[N+]=[N-] NCARQSCDRIWXMR-UHFFFAOYSA-N 0.000 description 1
- RWJRBVYNMRKGAG-UHFFFAOYSA-N 1-(azidomethyl)-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1CN=[N+]=[N-] RWJRBVYNMRKGAG-UHFFFAOYSA-N 0.000 description 1
- GXOCMECOGWAHFX-UHFFFAOYSA-N 1-(azidomethyl)-3-bromobenzene Chemical compound BrC1=CC=CC(CN=[N+]=[N-])=C1 GXOCMECOGWAHFX-UHFFFAOYSA-N 0.000 description 1
- BMKYIDKVBAKRAK-UHFFFAOYSA-N 1-(azidomethyl)-3-fluorobenzene Chemical compound FC1=CC=CC(CN=[N+]=[N-])=C1 BMKYIDKVBAKRAK-UHFFFAOYSA-N 0.000 description 1
- NGSNSSXJWWLJAX-UHFFFAOYSA-N 1-(azidomethyl)-3-methoxybenzene Chemical compound COC1=CC=CC(CN=[N+]=[N-])=C1 NGSNSSXJWWLJAX-UHFFFAOYSA-N 0.000 description 1
- FCVHHYNXTVRWJE-UHFFFAOYSA-N 1-(azidomethyl)-3-methylbenzene Chemical compound CC1=CC=CC(CN=[N+]=[N-])=C1 FCVHHYNXTVRWJE-UHFFFAOYSA-N 0.000 description 1
- MZAJKOBLQCTSKA-UHFFFAOYSA-N 1-(azidomethyl)-3-methylsulfonylbenzene Chemical compound CS(=O)(=O)C1=CC=CC(CN=[N+]=[N-])=C1 MZAJKOBLQCTSKA-UHFFFAOYSA-N 0.000 description 1
- JMTPIENQTKMREN-UHFFFAOYSA-N 1-(azidomethyl)-4-chlorobenzene Chemical compound ClC1=CC=C(CN=[N+]=[N-])C=C1 JMTPIENQTKMREN-UHFFFAOYSA-N 0.000 description 1
- UEQMFQIPTDUPPJ-UHFFFAOYSA-N 1-(azidomethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CN=[N+]=[N-])C=C1 UEQMFQIPTDUPPJ-UHFFFAOYSA-N 0.000 description 1
- IAKGGJYLHBHSQD-UHFFFAOYSA-N 1-(azidomethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CN=[N+]=[N-])C=C1 IAKGGJYLHBHSQD-UHFFFAOYSA-N 0.000 description 1
- NBXGSUCKCKGTCH-UHFFFAOYSA-N 1-(azidomethyl)-4-methylbenzene Chemical compound CC1=CC=C(CN=[N+]=[N-])C=C1 NBXGSUCKCKGTCH-UHFFFAOYSA-N 0.000 description 1
- GQMYQEAXTITUAE-UHFFFAOYSA-N 1H-indole-5-carboxamide Chemical compound NC(=O)C1=CC=C2NC=CC2=C1 GQMYQEAXTITUAE-UHFFFAOYSA-N 0.000 description 1
- DTRXXTVEVDAOME-UHFFFAOYSA-N 2-(azidomethyl)benzonitrile Chemical compound [N-]=[N+]=NCC1=CC=CC=C1C#N DTRXXTVEVDAOME-UHFFFAOYSA-N 0.000 description 1
- UOGZFMFIYPOEQS-UHFFFAOYSA-N 3-(azidomethyl)benzonitrile Chemical compound [N-]=[N+]=NCC1=CC=CC(C#N)=C1 UOGZFMFIYPOEQS-UHFFFAOYSA-N 0.000 description 1
- WULHNUGSMDNQSA-UHFFFAOYSA-N 4-(azidomethyl)-1,2-difluorobenzene Chemical compound FC1=CC=C(CN=[N+]=[N-])C=C1F WULHNUGSMDNQSA-UHFFFAOYSA-N 0.000 description 1
- GWVIVHINAVAKKV-UHFFFAOYSA-N 4-(azidomethyl)benzonitrile Chemical compound [N-]=[N+]=NCC1=CC=C(C#N)C=C1 GWVIVHINAVAKKV-UHFFFAOYSA-N 0.000 description 1
- BNMFQWUHWYJTRI-BQFCYCMXSA-N 7-chloro-N-[(2S)-1-[[(1S)-1-cyano-2-[(3S)-2-oxopiperidin-3-yl]ethyl]amino]-3-cyclopropyl-1-oxopropan-2-yl]-1H-indole-2-carboxamide Chemical compound ClC=1C=CC=C2C=C(NC=12)C(=O)N[C@H](C(=O)N[C@@H](C[C@H]1C(NCCC1)=O)C#N)CC1CC1 BNMFQWUHWYJTRI-BQFCYCMXSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 102000005927 Cysteine Proteases Human genes 0.000 description 1
- 108010005843 Cysteine Proteases Proteins 0.000 description 1
- DYEFUKCXAQOFHX-UHFFFAOYSA-N Ebselen Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=CC=CC=C1 DYEFUKCXAQOFHX-UHFFFAOYSA-N 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical compound CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 description 1
- 102000006833 Multifunctional Enzymes Human genes 0.000 description 1
- 108010047290 Multifunctional Enzymes Proteins 0.000 description 1
- FQKALOFOWPDTED-WBAXXEDZSA-N PF-07304814 Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C[C@@H]1CCNC1=O)C(=O)COP(=O)(O)O)NC(=O)C2=CC3=C(N2)C=CC=C3OC FQKALOFOWPDTED-WBAXXEDZSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- 241000315672 SARS coronavirus Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 150000001555 benzenes Chemical group 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 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
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 230000008406 drug-drug interaction Effects 0.000 description 1
- 229950010033 ebselen Drugs 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229940125674 nirmatrelvir Drugs 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000006490 viral transcription Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种含有三唑环的靛红类衍生物及其制备方法和应用。所述化合物具有式I所示的结构。本发明还涉及含有式I结构化合物的制备方法,药物组合物以及提供上述化合物在制备抗SARS‑CoV‑2Mpro药物中的应用。
Description
技术领域
本发明属于有机化合物合成与医药应用技术领域,具体涉及一种含三唑环的靛红类衍生物及其制备方法与应用。
背景技术
SARS-CoV-2主蛋白酶(Mpro)是一种半胱氨酸蛋白酶,在病毒复制和转录中起关键作用。此外,Mpro在冠状病毒中是保守的,并且在不同冠状病毒中主蛋白酶的底物之间具有一些共同特征。因此,Mpro是广谱抗冠状病毒药物研发的重要靶点。Paxlovid是世界上第一个针对 SARS-CoV-2Mpro上市的口服治疗药物,其包含两种现有的“蛋白酶抑制剂”-Nirmatrelvir和 Ritonavir。其中,Ritonavir有助于减缓Nirmatrelvir的分解,使Nirmatrelvir在体内保持更强和更长时间的活性,但这种复方制剂增加了药物-药物相互作用风险,不利于具有慢性病和需要服用其它药物的人群。目前靶向SARS-CoV-2Mpro的候选药物有处于临床Ⅰ期的S-217622、 PF-07304814、PBI-0451和处于临床II期的Ebselen,但这些候选药物大部分都需要注射使用,患者的依从性差,并且其治疗效果尚需进一步确证。因此,研发新型的SARS-CoV-2Mpro抑制剂仍具有十分重要的意义。
靛红类衍生物D-75对SARS-CoV和SARS-CoV-2的主蛋白酶均具有较好的抑制活性,是一类潜在的广谱抗冠状病毒化合物。对D-75的构效关系和机制研究表明,这类化合物可较好地占据主蛋白酶的底物结合位点从而抑制病毒的复制。但该类化合物的细胞毒性较大,且抗病毒细胞活性仍有待改善。因此,靛红类SARS-CoV-2Mpro抑制剂仍具有继续开发的价值。
发明内容
针对现有技术的不足,本发明提供了一类含三唑环的靛红类衍生物及其制备方法,本发明还提供上述化合物作为SARS-CoV-2Mpro抑制剂的活性筛选结果及其应用。
本发明的技术方案如下:
1.含有三唑环的靛红类衍生物
含有三唑环的靛红类衍生物,或其药学上可接受的盐,具有通式I所示的结构:
其中,
n=1,2,3;
m=0,1,2,3;
R1为:酰胺;
R2为:C1-C6烷基、OC1-C6烷基、C2-C6烯基、C3-C6环烷基、OC3-C6环烷基、取代苯环、取代萘环、取代芳砜、取代芳硫醚、取代芳亚砜、取代的六元杂环、各种取代的五元杂环、各种取代的六元并五元杂环、各种取代的六元并六元杂环、各种取代的五元并五元杂环、各种取代的苯并五元杂环或各种取代的苯并六元杂环;所述的取代基选自硝基、氰基、甲基、甲氧基、酰胺、卤素、硼酸、羧酸、三氟甲基、酯基、叔丁基。
根据本发明优选的,所述的五元杂环、六元杂环为含氮五元杂环或者含氮六元杂环;
根据本发明进一步优选的,含三唑环的靛红类衍生物是下列化合物之一:
本发明中所述的“药学上可接受的盐”是指在可靠的医药评价范围内,化合物的盐类适于与人或较低等动物的组织相接触而无不适当的毒性、刺激及过敏反应等,具有相当合理的收益与风险比例,通常是水或油可溶的或可分散的,并可有效地用于其预期的用途。包括药学上可接受的酸加成盐和药学上可接受的碱加成盐,在这里是可做预期的用途并与式I、II化合物的化学性质相容的。适宜的盐的列表参见S.M.Birge等,J.Pharm.Sci.,1977,66,1-19页。
2.含有三唑环的靛红类衍生物的制备方法
含有三唑环的靛红类衍生物的制备方法,步骤如下:以取代的吲哚-2,3-二酮I-1为起始原料,在碳酸铯的作用下,通过亲核取代反应与溴丙炔I-2反应,得相应炔片段;随后,取代的吲哚2,3-二酮炔片段与不同的叠氮片段通过Cu(I)催化的叠氮-Husigen-Click环加成反应生成目标产物通式I;
反应路线如下:
试剂及条件:(i)碳酸铯,N,N-二甲基甲酰胺,室温,0.5h;(ii)五水硫酸铜,醋酸钠,四氢呋喃/水,8-12h。
其中,n、m、R1、R2同上述通式I所示;
所述的叠氮片段为:邻甲基苄基叠氮、间甲基苄基叠氮、对甲基苄基叠氮、邻氯苄基叠氮、间氯苄基叠氮、对氯苄基叠氮、邻溴苄基叠氮、间溴苄基叠氮、对溴苄基叠氮、邻氟苄基叠氮、间氟苄基叠氮、对氟苄基叠氮、2,4-二氟苄基叠氮、3,4-二氟苄基叠氮、邻氰基苄基叠氮、间氰基苄基叠氮、对氰基苄基叠氮、邻硝基苄基叠氮、间硝基苄基叠氮、对硝基苄基叠氮、邻甲氧基苄基叠氮、间甲氧基苄基叠氮、对甲氧基苄基叠氮、对甲磺酰基苄基叠氮、间甲磺酰基苄基叠氮、邻甲磺酰基苄基叠氮、对磺酰胺基苄基叠氮、间磺酰胺基苄基叠氮、邻磺酰胺基苄基叠氮、对甲酰胺基苄基叠氮、间甲酰胺基苄基叠氮、邻甲酰胺基苄基叠氮苄、2-叠氮基-1-(吡咯烷-1-基)乙-1-酮、2-叠氮基-N-环丙基乙酰胺、2-叠氮基-1-吗啉-1-酮。
本发明所述的室温为20-30℃。
根据本发明优选的,含有三唑环的靛红类衍生物的制备方法,具体步骤如下:
(1)将取代的吲哚-2,3-二酮溶于5.0mL的DMF中,随后加入Cs2CO3和溴丙炔,室温条件下搅拌0.5h;TLC监测反应完毕,加水淬灭反应,加入乙酸乙酯萃取,饱和氯化钠溶液洗涤,硅胶拌样,乙酸乙酯:石油醚=1:2v/v柱层析得相应炔片段的纯品;
(2)把炔片段和不同的叠氮片段溶于2.0mL、体积比为1:1的四氢呋喃:水混合溶液中,然后加入VcNa和CuSO4·5H2O,室温搅拌8-12小时,经TLC监测反应完毕后,淬灭反应,乙酸乙酯萃取;然后有机相用饱和氯化钠溶液洗涤3次,无水硫酸钠干燥;过滤,硅胶拌样,甲醇:二氯甲烷=1:30v/v柱层析洗脱,浓缩,干燥,得目标化合物的纯品。
本发明所述的室温为20-30℃。
3.含有三唑环的靛红类SARS-CoV-2Mpro抑制剂的抗SARS-CoV-2活性及应用
本发明对按照上述方法合成的部分含三唑环的靛红类衍生物进行了抑酶活性及细胞水平的抗SARS-CoV-2活性测试,以文献报道的D-75作为阳性对照。
目标化合物D71N8、D71N18、D71N52对SARS-CoV-2Mpro的抑制活性如表1所示,化合物D71N8(IC50=0.44±0.12μM)和D71N52(IC50=0.53±0.21μM)的抑酶活性与D-75 (IC50=0.30±0.14μM)相当,化合物D71N18(IC50=1.12±0.54μM)的抑酶活性略弱于 D-75(IC50=0.30±0.14μM)。
目标化合物D71N8、D71N18、D71N52的抗SARS-CoV-2细胞活性结果如表2所示,整体来看,与阳性对照D-75相比,化合物D71N8、D71N18、D71N52在Vero E6细胞中对SARS- CoV-2的抑制活性无显著提高,但细胞毒性大幅降低,可作为先导化合物供进一步开发。
本发明公开了含三唑环的靛红类衍生物抗SARS-CoV-2Mpro的筛选结果及其作为主蛋白酶抑制剂的应用。通过实验证明本发明的含三唑环的靛红类衍生物可作为主蛋白酶抑制剂用于制备抗冠状病毒药物。本发明还提供上述化合物在制备抗冠状病毒药物中的应用。
本发明的一类含有含三唑环的靛红类衍生物可作为冠状病毒主蛋白酶抑制剂用于制备抗冠状病毒药物。
一种抗冠状病毒药物组合物,包括本发明的一类含三唑环的靛红类衍生物和一种或多种药学上可接受载体或赋形剂。
本发明提供了一类含三唑环的靛红类衍生物及其制备方法,并通过抑酶活性测试和细胞活性测试得出该系列化合物的抑酶活性和细胞活性。具体地说,本发明发现了抑酶活性较好且细胞毒性大幅降低的靛红类主蛋白酶抑制剂。
说明书附图
图1是以SARS-CoV-2Mpro为靶点的药物筛选原理图。
具体实施方式
通过下述实施例有助于理解本发明,但是不能限制本发明的内容,所述百分比数均为质量百分比。
实施例中所涉及的合成路线如下:
试剂及条件:(i)碳酸铯,N,N-二甲基甲酰胺,室温,0.5h;(ii)五水硫酸铜,醋酸钠,四氢呋喃/水,8- 12h。
实施例1:2,3-二氧代-1-丙炔-1-丙基吲哚啉-5-甲酰胺(I-4)
将I-3(0.1g,0.53mmol,1.0eq.)溶于5.0mL的DMF中,随后加入Cs2CO3(0.43g,1.33mmol,2.5eq.)和溴丙炔(0.08g,0.64mmol,1.2eq.),室温条件下搅拌0.5h。TLC 监测反应完毕,加水5.0mL淬灭反应,乙酸乙酯(3×8mL)萃取,饱和氯化钠溶液洗涤(3 ×15mL),经无水硫酸钠干燥,硅胶拌样柱层析(乙酸乙酯:石油醚=1:2)得2,3-二氧代 -1-丙炔-1-丙基吲哚啉-5-甲酰胺(I-4)的纯品0.09g,淡黄色固体,产率82%。1H NMR(400 MHz,DMSO-d6)δ8.25(dd,J=8.3,1.9Hz,1H),8.11(d,J=1.8Hz,1H),8.08(s,1H),7.44(s,1H), 7.32(d,J=8.3Hz,1H),4.59(d,J=2.5Hz,2H),3.37(t,J=2.5Hz,1H).13C NMR(100MHz, DMSO-d6)δ167.66,167.27,166.77,162.37,161.86,158.09,148.21,146.61,137.94,134.47,133.46,129.95,124.17,123.88,122.41,120.41,111.30,110.62,109.99,77.97,77.75,75.63,75.51,75.25,29.79,29.70,29.59.
实施例2:目标化合物(D71N8、D71N18、D71N52)的制备
首先把炔片段I-4(1.0eq)和不同的叠氮片段(1.2eq)溶于2.0mL、体积比为1:1的四氢呋喃:水混合溶液中,然后加入VcNa(0.6eq)和CuSO4·5H2O(0.3eq),室温搅拌8-12 小时,经TLC监测反应完毕后,淬灭反应,乙酸乙酯(3×10.0mL)萃取;然后有机相用饱和氯化钠溶液洗涤3次,无水硫酸钠干燥;过滤,硅胶拌样,柱层析(甲醇:二氯甲烷=1: 30)洗脱,浓缩,干燥,得目标化合物D71N8、D71N18、D71N52。
1-((1-(3-氯苄基)-1H-1,2,3-三唑-4-基)甲基)-2,3-二氧吲哚-5-甲酰胺(D71N8)
所用叠氮化物为间氯苯甲基。产物为黄色固体,收率:75%,熔点208-210℃。
1H NMR(600MHz,DMSO-d6)δ8.24(s,1H),8.15(dd,J=8.3,1.9Hz,1H),8.08(d,J=1.8Hz, 1H),8.04(s,1H),7.43–7.36(m,3H),7.34(q,J=1.4Hz,1H),7.25–7.20(m,2H),5.59(s,2H),5.00(s,2H).13C NMR(100MHz,DMSO-d6)δ183.01,166.72,158.71,152.61,142.22,138.75, 137.84,133.76,131.15,129.63,128.62,128.25,127.09,124.45,123.75,117.92,111.27,52.55,35.74.ESI-MS:m/z 396.20[M+1]+,C19H14ClN5O3[395.80].
2,3-二氧基-1-((1-(4-氨磺酰苄基)-1H-1,2,3-三唑-4-基)甲基)吲哚-5-甲酰胺(D71N18)
所用叠氮化物为对磺酰胺基苯甲基。产物为淡黄色固体,收率:75%,熔点218-220℃。
1H NMR(600MHz,DMSO-d6)δ8.25(s,1H),8.16(d,J=8.4Hz,1H),8.08(s,1H),8.05(s,1H), 7.80(d,J=8.0Hz,2H),7.44(d,J=8.7Hz,3H),7.36(s,2H),7.25(d,J=8.4Hz,1H),5.66(s,2H),5.00(s,2H).13C NMR(100MHz,DMSO-d6)δ183.01,166.73,158.72,152.61,144.33,142.25, 140.09,137.84,129.63,128.89,126.58,124.43,123.74,117.94,111.27,52.73,35.74.ESI-MS:m/z441.40[M+1]+,463.30[M+Na]+,C19H16N6O5S[440.43].
1-((1-(2-氟-4-(三氟甲基)苄基)-1H-1,2,3-三唑-4-基)甲基)-2,3-二氧吲哚-5-甲酰胺(D71N52)
所用叠氮化物为4-三氟甲基-2-氟苯甲基。产物为淡黄色固体,收率:72%,熔点320-322℃。
1H NMR(600MHz,DMSO-d6)δ8.25(s,1H),8.15(dd,J=8.3,1.9Hz,1H),8.08(d,J=1.9Hz, 1H),8.03(s,1H),7.77–7.72(m,1H),7.61(dd,J=7.6,1.5Hz,1H),7.49(t,J=7.6Hz,1H),7.41(s,1H),7.23(d,J=8.3Hz,1H),5.73(s,2H),5.00(s,2H).13C NMR(100MHz,DMSO-d6)δ183.01, 166.70,161.52,159.04,158.71,152.59,142.18,137.82,132.25,132.21,129.64,128.10,127.95,124.67,123.74,122.26,117.93,113.60,111.28,47.13,47.10,35.70ESI-MS:m/z 448.40[M+H]+, C20H13F4N5O3[447.35].
制备实施例3:目标化合物的抗主蛋白酶(Mpro)的实验
实验原理:
采用的荧光共振能量转移(Fluorescence resonance energy transfer,FRET)法,使用的底物结构为:MCA-AVLQSGFR-Lys(Dnp)-Lys-NH2,其中MCA是荧光供体,Dnp是荧光受体(Acceptor)或称为荧光淬灭基团(Quencher),完整的序列既含有荧光基团,又含有荧光淬灭基团,由于两个基团空间距离较近,淬灭基团的抑制作用使得荧光基团不会产生荧光。当加入SARS-CoV-2主蛋白酶后,由于主蛋白酶能够在氨基酸Q和S之间进行切割,使得荧光基团远离淬灭基团,在激发光为320nm,发射波长为405nm下产生荧光,通过测定荧光来检测Mpro的活性,进而间接反应化合物的抑制活性(见附图1)(Dai Wenhao,et al.,Science.368(6497):1331-1335,2020;Qiao Jingxin,et al.,Science.371(6536):1374-1378,2021.)。
实验方法:
基于FRET原理,利用酶标仪,采用96孔全黑板进行测试。首先用适量的DMSO溶液溶解先导化合物D-75和待测化合物,将其配制成一定浓度的母液,再用缓冲溶液稀释为所需浓度。在避光条件下,将1.5μM的SARS-CoV-2Mpro和1.0μM的待测化合物加入96孔板中,37℃下孵育振荡10分钟。然后在冰上快速加入10μL浓度为500μM的底物。使用多功能酶标仪在激发波长为320nm,发射波长为405nm下,每隔10秒测一次,测10分钟,获取荧光强度。
结果计算:
用反应初速率的变化来表示抑制剂对酶活力的抑制程度,取用相应数据来计算初速率,空白对照的反应初速率为Vo,添加抑制剂后为Vi,则酶活力的抑制程度可用如下方程式:i%=1-Vi/Vo×100%。
按照上述实验方法对合成的含三唑环的靛红类SARS-CoV-2Mpro抑制剂进行了酶活水平的测试,结果如表1所示。
表1目标化合物对SARS-CoV-2Mpro的抑制作用
注:所有实验结果均经过至少三次重复实验。
实验结论分析:
新合成的含三唑环的靛红类衍生物呈现出显著的抗SARS-CoV-2Mpro活性。目标化合物 D71N8、D71N18、D71N52对SARS-CoV-2Mpro的抑酶活性如表1所示,化合物D71N8(IC50=0.44±0.12μM)和D71N52(IC50=0.53±0.21μM)的抑酶活性与D-75(IC50=0.30±0.14 μM)相当,化合物D71N18(IC50=1.12±0.54μM)的抑酶活性略弱于D-75(IC50=0.30± 0.14μM)。
实施例4:目标化合物的抗SARS-CoV-2细胞活性实验
实验原理:酶联免疫吸附测定(Enzyme linked immunosorbent assay,ELISA):将特定的抗原或抗体固定在聚乙烯等固相载体上,其中抗原抗体可发生特异性结合,根据免疫反应的特征进行定性和定量的检测(Yi Y,et al.,J Adv Res.36:201-210,2021.)。
实验方法:将待测化合物用DMSO溶液稀释为10mM的母液,用5%胎牛血清的Dulbecco’s MEM稀释为所需浓度。取出50μL不同浓度的化合物加入到接种Vero E6细胞(1.7×104) 的培养基中,然后将96孔板转移到BSL-3实验室中感染SARS-CoV-2,待接种SARS-CoV-2 后,将96孔板置于37℃,5%CO2条件下孵育1小时,然后向每个孔中添加含有甲基纤维素的培养基(约125μL),继续孵育25-26小时。孵育完成后,去除甲基纤维素覆盖层,并用 PBS清洗2遍,向每孔加入5%的多聚甲醛,然后将96孔板置于5%福尔马林中,取出后,向每孔加入新鲜的PBS,并将96孔板移出BSL-3实验室。取出后使用缓冲液冲洗板子,然后与豚鼠抗SARS-CoV抗体(针对病毒产生)共孵育,其二抗(能与抗体结合)为山羊抗豚鼠lgG(辣根过氧化物酶结合物)。死细胞会被染色而呈现蓝色,将96孔板在EliSpot阅读器上进行读取。以染色细胞复盖的相对表面积作为药物活性的衡量指标。用染色后的相对表面积来计算EC50值。
按照上述实验方法对合成的含三唑环的靛红类SARS-CoV-2Mpro抑制剂进行了细胞水平的测试,结果如表2所示。
表2目标化合物D71N8、D71N18和D71N52对SARS-CoV-2的抑制作用(Vero E6细胞)
aND:无法确定
bNA:无活性
Claims (5)
1.含有三唑环的靛红类衍生物,或其药学上可接受的盐,其特征在于,是下列结构的化合物之一:
2.如权利要求1所述的含三唑环的靛红类衍生物的制备方法,步骤如下:
以2,3-二氧吲哚啉-5-甲酰胺为起始原料,在碳酸铯的作用下,通过亲核取代反应与溴丙炔I-2反应,得相应炔片段;随后,取代的吲哚2,3-二酮炔片段与不同的叠氮片段通过Cu(I)催化的叠氮-Husigen-Click环加成反应生成目标产物D71N8、D71N18、D71N52;
反应路线如下:
试剂及条件:(i)碳酸铯,N,N-二甲基甲酰胺,室温,0.5h;(ii)五水硫酸铜,抗坏血酸钠,四氢呋喃/水,8-12h;
所述的叠氮片段为:间氯苄基叠氮、对磺酰胺基苄基叠氮、1-(叠氮甲基)-2-氟-4-(三氟甲基)苯。
3.如权利要求2所述的含三氮唑的靛红类衍生物的制备方法,步骤如下:
(1)将起始原料I-1溶于5.0mL的DMF中,随后加入Cs2CO3和溴丙炔,室温条件下搅拌0.5h;TLC监测反应完毕,加水淬灭反应,加入乙酸乙酯萃取,饱和氯化钠溶液洗涤,硅胶拌样,乙酸乙酯:石油醚=1:2v/v柱层析得相应炔片段的纯品;
(2)把炔片段和不同的叠氮片段溶于2.0mL、体积比为1:1的四氢呋喃:水混合溶液中,然后加入VcNa和CuSO4·5H2O,室温搅拌8-12小时,经TLC监测反应完毕后,淬灭反应,乙酸乙酯萃取;然后有机相用饱和氯化钠溶液洗涤三次,无水硫酸钠干燥;过滤,硅胶拌样,甲醇:二氯甲烷=1:30v/v柱层析洗脱,浓缩,干燥,得目标化合物的纯品。
4.如权利要求1所述含三氮唑的靛红类衍生物在制备抗冠状病毒药物中的应用。
5.一种药物组合物,包含权利要求1所述含三氮唑的靛红类衍生物和一种或多种药学上可接受的载体或赋形剂。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210694873.1A CN115636817B (zh) | 2022-06-20 | 2022-06-20 | 含三唑环的靛红类衍生物及其制备方法与应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210694873.1A CN115636817B (zh) | 2022-06-20 | 2022-06-20 | 含三唑环的靛红类衍生物及其制备方法与应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115636817A CN115636817A (zh) | 2023-01-24 |
CN115636817B true CN115636817B (zh) | 2023-11-24 |
Family
ID=84940344
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210694873.1A Active CN115636817B (zh) | 2022-06-20 | 2022-06-20 | 含三唑环的靛红类衍生物及其制备方法与应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115636817B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI811812B (zh) | 2020-10-16 | 2023-08-11 | 美商基利科學股份有限公司 | 磷脂化合物及其用途 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103159666A (zh) * | 2011-12-09 | 2013-06-19 | 天津市国际生物医药联合研究院 | 靛红衍生物及其用途 |
CN103230393A (zh) * | 2011-12-09 | 2013-08-07 | 天津市国际生物医药联合研究院 | 靛红衍生物在制备抗sars的药物中的应用 |
CN109705095A (zh) * | 2019-02-25 | 2019-05-03 | 山东大学 | 一种含三氮唑环的稠环对苯醌类cdc25蛋白磷酸酶抑制剂及其制备方法和应用 |
CN110066273A (zh) * | 2019-06-05 | 2019-07-30 | 山东大学 | 一种含三氮唑环的单芳基嘧啶类hiv-1逆转录酶抑制剂及其制备方法与应用 |
-
2022
- 2022-06-20 CN CN202210694873.1A patent/CN115636817B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103159666A (zh) * | 2011-12-09 | 2013-06-19 | 天津市国际生物医药联合研究院 | 靛红衍生物及其用途 |
CN103230393A (zh) * | 2011-12-09 | 2013-08-07 | 天津市国际生物医药联合研究院 | 靛红衍生物在制备抗sars的药物中的应用 |
CN109705095A (zh) * | 2019-02-25 | 2019-05-03 | 山东大学 | 一种含三氮唑环的稠环对苯醌类cdc25蛋白磷酸酶抑制剂及其制备方法和应用 |
CN110066273A (zh) * | 2019-06-05 | 2019-07-30 | 山东大学 | 一种含三氮唑环的单芳基嘧啶类hiv-1逆转录酶抑制剂及其制备方法与应用 |
Non-Patent Citations (3)
Title |
---|
Design, Synthesis, and Evaluation of Nonpeptidic Inhibitors of Human Rhinovirus 3C Protease;Webber, Stephen E等;《Journal of Medicinal Chemistry》;5072-5082 * |
Isatin Compounds as Noncovalent SARS Coronavirus 3C-like Protease Inhibitors;Zhou, Lu等;《Journal of Medicinal Chemistry》;3440-3443 * |
非肽类SARS 冠状病毒3CL 蛋白酶抑制剂的设计与活性表征;刘莹 等;《化学学报》;1707-1712 * |
Also Published As
Publication number | Publication date |
---|---|
CN115636817A (zh) | 2023-01-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI437992B (zh) | 人類免疫缺乏病毒複製之抑制劑 | |
WO2022021841A1 (zh) | 一种新型冠状病毒主蛋白酶的抑制剂及其制备方法和用途 | |
He et al. | Design, synthesis and biological evaluation of 3-substituted 2, 5-dimethyl-N-(3-(1H-tetrazol-5-yl) phenyl) pyrroles as novel potential HIV-1 gp41 inhibitors | |
JP2020512399A (ja) | Idoを抑制する化合物、その調製方法及びその使用 | |
CN107540608A (zh) | 4‑取代萘酰亚胺类化合物及其应用 | |
KR20200051646A (ko) | Ahr 억제제 및 이의 용도 | |
JP2007518720A (ja) | イミダゾ[4,5−c]ピリジン化合物および抗ウイルス治療の方法 | |
BRPI0707689A2 (pt) | inibidores de polimerase viral | |
EP3774743B1 (en) | Prodrug compounds activated by akr1c3 and their use for treating hyperproliferative disorders | |
CN115636817B (zh) | 含三唑环的靛红类衍生物及其制备方法与应用 | |
JP2012520246A (ja) | Kcnq2/3モジュレータとしての置換された3−アミノイソオキサゾロピリジン | |
Zishiri et al. | A series of structurally simple chloroquine chemosensitizing dibemethin derivatives that inhibit chloroquine transport by PfCRT | |
WO2011140817A1 (zh) | 1-[(4-羟基哌啶-4-基)甲基]吡啶-2(1h)-酮衍生物及其制备方法和用途 | |
Manzano et al. | Arylthiosemicarbazones as antileishmanial agents | |
Gao et al. | Discovery and anti-inflammatory evaluation of benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of glycogen synthase kinase-3β (GSK-3β) | |
Xu et al. | Design, synthesis, and evaluation of potent Wnt signaling inhibitors featuring a fused 3-ring system | |
CN109810108A (zh) | 2,8-二氮杂-螺-[4,5]-癸烷类嘧啶-异羟肟酸化合物及其用途 | |
CN116283978B (zh) | 一类抗冠状病毒的化合物及其制备方法和应用 | |
Deng et al. | Design, synthesis, and evaluation of dihydrobenzo [cd] indole-6-sulfonamide as TNF-α inhibitors | |
Puerstinger et al. | Substituted 5-benzyl-2-phenyl-5H-imidazo [4, 5-c] pyridines: a new class of pestivirus inhibitors | |
CN105968095B (zh) | 吲哚芳砜类衍生物及其制备方法与应用 | |
US8653102B2 (en) | Substituted 2-oxo- and 2-thioxo-dihydroquinoline-3-carboxamides as KCNQ2/3 modulators | |
CN104876860B (zh) | 一种二芳基吡啶衍生物及其制备方法与应用 | |
CN111233851A (zh) | 东莨菪素苯磺酰基呋咱氮氧化物类衍生物及其制备方法与用途 | |
CN113956233B (zh) | 一种酰胺类化合物或其药学上可接受的盐及其制备方法和应用 |
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 |