CN117417334A - 含异噁唑结构的唑类衍生物及其制备方法及应用 - Google Patents
含异噁唑结构的唑类衍生物及其制备方法及应用 Download PDFInfo
- Publication number
- CN117417334A CN117417334A CN202311341317.7A CN202311341317A CN117417334A CN 117417334 A CN117417334 A CN 117417334A CN 202311341317 A CN202311341317 A CN 202311341317A CN 117417334 A CN117417334 A CN 117417334A
- Authority
- CN
- China
- Prior art keywords
- different
- group
- general formula
- same
- halogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 125000000842 isoxazolyl group Chemical group 0.000 title claims abstract description 10
- 150000007980 azole derivatives Chemical class 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 239000003429 antifungal agent Substances 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- 230000003287 optical effect Effects 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- -1 cyano, nitro, hydroxy, amino Chemical group 0.000 claims description 10
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 8
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 6
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 6
- 229940121375 antifungal agent Drugs 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 4
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 4
- 125000006642 (C1-C6) cyanoalkyl group Chemical group 0.000 claims description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 4
- 125000003320 C2-C6 alkenyloxy group Chemical group 0.000 claims description 4
- 125000005090 alkenylcarbonyl group Chemical group 0.000 claims description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 4
- 125000005087 alkynylcarbonyl group Chemical group 0.000 claims description 4
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 claims description 3
- YLRBJYMANQKEAW-UHFFFAOYSA-N 1-bromo-4-(bromomethyl)benzene Chemical compound BrCC1=CC=C(Br)C=C1 YLRBJYMANQKEAW-UHFFFAOYSA-N 0.000 claims description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 2
- 230000031709 bromination Effects 0.000 claims description 2
- 238000005893 bromination reaction Methods 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 125000001391 thioamide group Chemical group 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 16
- 229940079593 drug Drugs 0.000 abstract description 13
- 230000000843 anti-fungal effect Effects 0.000 abstract description 9
- 239000011734 sodium Substances 0.000 description 52
- 239000007787 solid Substances 0.000 description 44
- 239000002994 raw material Substances 0.000 description 35
- 238000001308 synthesis method Methods 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 241000222126 [Candida] glabrata Species 0.000 description 5
- 208000032343 candida glabrata infection Diseases 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 229960004884 fluconazole Drugs 0.000 description 5
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 241000233866 Fungi Species 0.000 description 4
- 102100021695 Lanosterol 14-alpha demethylase Human genes 0.000 description 4
- 101710146773 Lanosterol 14-alpha demethylase Proteins 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 241000222122 Candida albicans Species 0.000 description 3
- 241000222178 Candida tropicalis Species 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241000235645 Pichia kudriavzevii Species 0.000 description 3
- 229940095731 candida albicans Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 2
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 2
- GNKZMNRKLCTJAY-UHFFFAOYSA-N 4'-Methylacetophenone Chemical compound CC(=O)C1=CC=C(C)C=C1 GNKZMNRKLCTJAY-UHFFFAOYSA-N 0.000 description 2
- NTPLXRHDUXRPNE-UHFFFAOYSA-N 4-methoxyacetophenone Chemical compound COC1=CC=C(C(C)=O)C=C1 NTPLXRHDUXRPNE-UHFFFAOYSA-N 0.000 description 2
- 230000035502 ADME Effects 0.000 description 2
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical group NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 description 2
- 201000007336 Cryptococcosis Diseases 0.000 description 2
- 241001337994 Cryptococcus <scale insect> Species 0.000 description 2
- 241000221204 Cryptococcus neoformans Species 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 150000003278 haem Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- BPAFLGGUEBMWRN-UHFFFAOYSA-N (5-phenyl-1,2-oxazol-3-yl)methanol Chemical compound O1N=C(CO)C=C1C1=CC=CC=C1 BPAFLGGUEBMWRN-UHFFFAOYSA-N 0.000 description 1
- QEWHNJPLPZOEKU-UHFFFAOYSA-N 1-(2,4-difluorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(F)C=C1F QEWHNJPLPZOEKU-UHFFFAOYSA-N 0.000 description 1
- ZDPAWHACYDRYIW-UHFFFAOYSA-N 1-(4-fluorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(F)C=C1 ZDPAWHACYDRYIW-UHFFFAOYSA-N 0.000 description 1
- HHAISVSEJFEWBZ-UHFFFAOYSA-N 1-[4-(trifluoromethyl)phenyl]ethanone Chemical compound CC(=O)C1=CC=C(C(F)(F)F)C=C1 HHAISVSEJFEWBZ-UHFFFAOYSA-N 0.000 description 1
- 208000007288 14-alpha Demethylase Inhibitors Diseases 0.000 description 1
- 239000002615 14-alpha demethylase Inhibitor Substances 0.000 description 1
- XSKWUGLATLGSLJ-UHFFFAOYSA-M 2-(1-benzyl-1,2,4-triazol-4-ium-4-yl)-1-(2,4-dichlorophenyl)ethanone;bromide Chemical compound [Br-].ClC1=CC(Cl)=CC=C1C(=O)C[N+]1=CN(CC=2C=CC=CC=2)N=C1 XSKWUGLATLGSLJ-UHFFFAOYSA-M 0.000 description 1
- ATXGVLNFHSIBCC-UHFFFAOYSA-N 3-(bromomethyl)-5-(4-fluorophenyl)-1,2-oxazole Chemical compound C1=CC(F)=CC=C1C1=CC(CBr)=NO1 ATXGVLNFHSIBCC-UHFFFAOYSA-N 0.000 description 1
- YMIYHZCXVALGGW-UHFFFAOYSA-N 3-(bromomethyl)-5-(4-methoxyphenyl)-1,2-oxazole Chemical compound C1=CC(OC)=CC=C1C1=CC(CBr)=NO1 YMIYHZCXVALGGW-UHFFFAOYSA-N 0.000 description 1
- VKFFPZJRJWLSJW-UHFFFAOYSA-N 3-(bromomethyl)-5-[4-(trifluoromethyl)phenyl]-1,2-oxazole Chemical compound C1=CC(C(F)(F)F)=CC=C1C1=CC(CBr)=NO1 VKFFPZJRJWLSJW-UHFFFAOYSA-N 0.000 description 1
- NEBKJFRUXVPDFH-UHFFFAOYSA-N 3-(bromomethyl)-5-phenyl-1,2-oxazole Chemical compound O1N=C(CBr)C=C1C1=CC=CC=C1 NEBKJFRUXVPDFH-UHFFFAOYSA-N 0.000 description 1
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 description 1
- MTJAXRJQQMHEOA-UHFFFAOYSA-N BrC1=CC=C(COC(CN2C=NC=C2)C2=C(C=C(C=C2)Cl)Cl)C=C1 Chemical compound BrC1=CC=C(COC(CN2C=NC=C2)C2=C(C=C(C=C2)Cl)Cl)C=C1 MTJAXRJQQMHEOA-UHFFFAOYSA-N 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241000675278 Candida albicans SC5314 Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 208000037026 Invasive Fungal Infections Diseases 0.000 description 1
- BYBLEWFAAKGYCD-UHFFFAOYSA-N Miconazole Chemical compound ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- ULPAADJUUMKRRS-UHFFFAOYSA-N [5-(2,4-difluorophenyl)-1,2-oxazol-3-yl]methanol Chemical compound O1N=C(CO)C=C1C1=CC=C(F)C=C1F ULPAADJUUMKRRS-UHFFFAOYSA-N 0.000 description 1
- PALZYEIQXXRYMW-UHFFFAOYSA-N [5-(4-fluorophenyl)-1,2-oxazol-3-yl]methanol Chemical compound O1N=C(CO)C=C1C1=CC=C(F)C=C1 PALZYEIQXXRYMW-UHFFFAOYSA-N 0.000 description 1
- FZOLFKJKTKFVPO-UHFFFAOYSA-N [5-(4-methoxyphenyl)-1,2-oxazol-3-yl]methanol Chemical compound C1=CC(OC)=CC=C1C1=CC(CO)=NO1 FZOLFKJKTKFVPO-UHFFFAOYSA-N 0.000 description 1
- YPDITGIFBYDNAC-UHFFFAOYSA-N [5-(4-methylphenyl)-1,2-oxazol-3-yl]methanol Chemical compound C1=CC(C)=CC=C1C1=CC(CO)=NO1 YPDITGIFBYDNAC-UHFFFAOYSA-N 0.000 description 1
- HTDMXATWYNKLLE-UHFFFAOYSA-N [5-[4-(trifluoromethyl)phenyl]-1,2-oxazol-3-yl]methanol Chemical compound O1N=C(CO)C=C1C1=CC=C(C(F)(F)F)C=C1 HTDMXATWYNKLLE-UHFFFAOYSA-N 0.000 description 1
- 241000222295 [Candida] zeylanoides Species 0.000 description 1
- JQRLYSGCPHSLJI-UHFFFAOYSA-N [Fe].N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 Chemical compound [Fe].N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 JQRLYSGCPHSLJI-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000008406 drug-drug interaction Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008686 ergosterol biosynthesis Effects 0.000 description 1
- JHVRVXDQXHJMAK-UHFFFAOYSA-N ethyl 2,4-dioxo-4-[4-(trifluoromethyl)phenyl]butanoate Chemical compound CCOC(=O)C(=O)CC(=O)C1=CC=C(C(F)(F)F)C=C1 JHVRVXDQXHJMAK-UHFFFAOYSA-N 0.000 description 1
- UVJQQYMWMAISMQ-UHFFFAOYSA-N ethyl 2,4-dioxo-4-phenylbutanoate Chemical compound CCOC(=O)C(=O)CC(=O)C1=CC=CC=C1 UVJQQYMWMAISMQ-UHFFFAOYSA-N 0.000 description 1
- LVLZSYCLOPEBSR-UHFFFAOYSA-N ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate Chemical compound CCOC(=O)C(=O)CC(=O)C1=CC=C(F)C=C1 LVLZSYCLOPEBSR-UHFFFAOYSA-N 0.000 description 1
- JHWYUCIVJQZDEF-UHFFFAOYSA-N ethyl 4-(4-methoxyphenyl)-2,4-dioxobutanoate Chemical compound CCOC(=O)C(=O)CC(=O)C1=CC=C(OC)C=C1 JHWYUCIVJQZDEF-UHFFFAOYSA-N 0.000 description 1
- QQMYOPVSVNPECO-UHFFFAOYSA-N ethyl 4-(4-methylphenyl)-2,4-dioxobutanoate Chemical compound CCOC(=O)C(=O)CC(=O)C1=CC=C(C)C=C1 QQMYOPVSVNPECO-UHFFFAOYSA-N 0.000 description 1
- WYJPRVBFXLXFRG-UHFFFAOYSA-N ethyl 5-(2,4-difluorophenyl)-1,2-oxazole-3-carboxylate Chemical compound O1N=C(C(=O)OCC)C=C1C1=CC=C(F)C=C1F WYJPRVBFXLXFRG-UHFFFAOYSA-N 0.000 description 1
- IYDBYHCVVNAFSM-UHFFFAOYSA-N ethyl 5-(4-fluorophenyl)-1,2-oxazole-3-carboxylate Chemical compound O1N=C(C(=O)OCC)C=C1C1=CC=C(F)C=C1 IYDBYHCVVNAFSM-UHFFFAOYSA-N 0.000 description 1
- OHKWTCCYUHOKLC-UHFFFAOYSA-N ethyl 5-(4-methoxyphenyl)-1,2-oxazole-3-carboxylate Chemical compound O1N=C(C(=O)OCC)C=C1C1=CC=C(OC)C=C1 OHKWTCCYUHOKLC-UHFFFAOYSA-N 0.000 description 1
- XPIUEGYFYXHZBH-UHFFFAOYSA-N ethyl 5-(4-methylphenyl)-1,2-oxazole-3-carboxylate Chemical compound O1N=C(C(=O)OCC)C=C1C1=CC=C(C)C=C1 XPIUEGYFYXHZBH-UHFFFAOYSA-N 0.000 description 1
- MKMLEMDGZCVWJB-UHFFFAOYSA-N ethyl 5-[4-(trifluoromethyl)phenyl]-1,2-oxazole-3-carboxylate Chemical compound O1N=C(C(=O)OCC)C=C1C1=CC=C(C(F)(F)F)C=C1 MKMLEMDGZCVWJB-UHFFFAOYSA-N 0.000 description 1
- DSUXKYCDKKYGKX-UHFFFAOYSA-N ethyl 5-phenyl-1,2-oxazole-3-carboxylate Chemical compound O1N=C(C(=O)OCC)C=C1C1=CC=CC=C1 DSUXKYCDKKYGKX-UHFFFAOYSA-N 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 102000056262 human PPIG Human genes 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229960002509 miconazole Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229960004740 voriconazole Drugs 0.000 description 1
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
本发明属于医药技术领域，涉及含异噁唑结构的唑类衍生物及其制备方法及医药用途。化合物如通式(1)所示，该类化合物实现了强效广谱的抗真菌活性，在作为抗真菌药物方面具有潜在应用。本发明涉及的通式(1)中的R的定义见说明书
Description
技术领域
本发明属于医药技术领域，涉及含异噁唑结构的唑类衍生物及其制备方法及医药用途。
背景技术
在全球范围内，侵袭性真菌感染(IFIs)正成为主要的传染性疾病。在现有的抗真菌药物中，CYP51抑制剂因其显著的抗真菌效果而被最广泛地应用于临床。唑类药物是细胞色素P450-14α-demethylase(CYP51)抑制剂，可阻止真菌中麦角甾醇的生物合成，导致细胞膜通透性发生变化，从而抑制真菌生长。
据报道，CYP51活性位点有三个不同的部分：(a)唑环(与CYP51的血红素铁配位)；(b)疏水通道Ⅰ；(c)另一个狭窄的疏水通道Ⅱ(底物进入通道)；目前临床应用的唑类抗真菌药物主要有：氟康唑、咪康唑、伏立康唑和艾氟康唑等，唑类药物的肝毒性表现为普遍的药物-药物相互作用，主要是由于它们与人类CYP酶的相互作用，限制了临床上氮唑药物的应用。另一方面，大部分唑类药物疏水性过强，导致ADME性质较差，目前对唑类药物ADME性质的优化也是开发新型唑类药物的一个方向。，
发明内容
本发明的目的在于设计与合成含异噁唑结构的唑类衍生物及其制备方法及医药用途。
为实现上述目的，本发明采用技术方案为：
一种含异噁唑结构的唑类衍生物，化合物如通式(1)所示
通式中：
X，Y，Z可相同或不同的选自N或CH；
R1，R2，R3，R4可相同或不同的选自氢原子、卤素、氰基、硝基、羟基、氨基，未取代或被至少一个下述基团取代的C1-6烷基、C3-8环烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C2-6烯氧基、C2-6炔氧基，下述基团可相同或不同的选自卤素、羟基、氰基、硝基和氨基；未取代或如下述基团取代的氨基，如下述基团选自C1-6烷基、C1-6氨基烷基、C1-6羟基烷基、C1-6烷氧基烷基、C1-6氰基烷基、C2-6烯基、C2-6炔基、C1-6烷基磺酰基、C1-6烷基羰基、C2-6烯基羰基或C2-6炔基羰基；未取代或下述基团取代的硫酰胺基或酰胺基，其中硫酰胺基或酰胺基的取代位为氨基，取代基团选自C1-6烷基、C1-6氨基烷基、C1-6羟基烷基、C1-6烷氧基烷基、C1-6氰基烷基、C2-6烯基、C2-6炔基、C1-6烷基磺酰基、C1-6烷基羰基、C2-6烯基羰基或C2-6炔基羰基；
或，通式(1)所示化合物的光学异构体，非对映异构体。
优选，所述通式中：
X，Y，Z可相同或不同的选自N或CH；
R1，R2，R3，R4可相同或不同的选自氢原子、卤素、氰基、硝基、羟基、氨基，未取代或被至少一个下述基团取代的C1-6烷基、C3-8环烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C2-6烯氧基、C2-6炔氧基，下述基团可相同或不同的选自卤素、羟基、氰基、硝基和氨基；
或，通式(1)所示化合物的光学异构体，非对映异构体。
进一步优选，所述通式中：
X，Y，Z可相同或不同的选自N或CH；
R1，R2，R3，R4可相同或不同的选自氢原子、卤素、氰基、硝基、羟基、氨基、未取代或被至少一个下述基团取代的C1-4烷基、C1-4烷氧基，下述基团可相同或不同的选自卤素、羟基、氰基、硝基和氨基；
或，通式(1)所示化合物的光学异构体，非对映异构体。
再进一步优选，所述通式中：
X，Y，Z可相同或不同的选自N或CH；
R1，R2，R3，R4可相同或不同的选自氢原子、卤素、氰基、硝基、羟基、氨基、未取代或被至少一个下述基团取代的C1-4烷基、C1-4烷氧基，下述基团可相同或不同的选自卤素或羟基；
或，通式(1)所示化合物的光学异构体，非对映异构体。
再更进一步优选，所述通式中：
X，Y，Z可相同或不同的选自N或CH；
R1，R2，R3，R4可相同或不同的选自氢原子、卤素、氰基、硝基、羟基、氨基、未取代或被至少一个下述基团取代的C1-4烷基、C1-4烷氧基，下述基团可相同或不同的选自卤素；
或，通式(1)所示化合物的光学异构体，非对映异构体。
最优选所述通式(1)所示化合物为下述E01-E14化合物及其光学异构体，非对映异构体；
一种所述化合物的制备方法，反应式如下：首先苯环上含有不同取代基的苯乙酮与草酸二乙酯反应生成中间体Z-1a-f，再与盐酸羟胺反应生成异噁唑环中间体Z-2a-f，再经还原、溴代得到中间体Z-4a-f。化合物a和b分别与对溴溴苄发生取代反应生成中间体Z-5a-b，再硼酯化后与中间体Z-4a-f发生Suzuki反应得到通式(1)的化合物；
一种药物组合物，组合物包含所述的化合物及其光学活性体，非对映异构体和药学上可接受的载体。
一种化合物和组合物的应用，所述的化合物及其光学活性体，非对映异构体或所述组合物在制备抗真菌药物中的应用。进一步的说是，在制备抑制CYP51药物中的应用。
所述的化合物及其光学活性体，非对映异构体或权利要求7所述组合物在制备抗真菌药物中的应用。
本发明所具有的优点：
本发明化合物根据CYP51的活性空腔设计获得通式(1)所述的化合物，该类化合物在结构上具有与血红素铁卟啉配位结合的氮唑官能团、芳环区域以及能够伸入狭长蛋白空腔的长链片段，实现了CYP51的抑制活性，提高了抗真菌活性，在作为抗真菌药物方面具有潜在应用。
具体实施方式
如下实施例，将更好地理解本发明的化合物和他们的制备，这些实施例旨在阐述而不是限制本发明的范围。
实施例1：2,4-二氧代-4-苯基丁酸乙酯(Z-1a)
500mL茄形瓶中，加入苯乙酮(10g,83mmol),草酸二乙酯(18.24g,120mmol,1.4eq),氢化钠(6.66g,208mmol,2.5eq),加入四氢呋喃40mL。搅拌下，0℃加热反应6h。将100mL水加入反应液中，乙酸乙酯萃取(3×100mL)，合并有机相，依次水洗(3×50mL)、饱和食盐水洗涤(50mL)有机相，无水硫酸钠干燥，过滤干燥剂后减压浓缩得到粗品,得Z-1a为黄色固体，得量13.2g。粗品未经纯化，直接进行下一步反应。HRMS(ESI):Calcd.for C12H12O4[M+Na]+:243.0628,Found 243.0638[M+Na]+.
4-(4-氟苯基)-2,4-二氧代丁酸乙酯(Z-1b)
以4-氟苯乙酮为原料，参照中间体Z-1a的合成方法，得白色固体。HRMS(ESI):Calcd.for C12H11FO4[M+Na]+:261.0534,Found 261.0540[M+Na]+.
4-(2,4-二氟苯基)-2,4-二氧代丁酸乙酯(Z-1c)
以2,4-二氟苯乙酮为原料，参照中间体Z-1a的合成方法，得白色固体。4-(4-三氟甲基苯基)-2,4-二氧代丁酸乙酯(Z-1d)
以4-三氟甲基苯乙酮为原料，参照中间体Z-1a的合成方法，得白色固体。
4-(4-甲基苯基)-2,4-二氧代丁酸乙酯(Z-1e)
以4-甲基苯乙酮为原料，参照中间体Z-1a的合成方法，得白色固体。4-(4-甲氧基苯基)-2,4-二氧代丁酸乙酯(Z-1f)
以4-甲氧基苯乙酮为原料，参照中间体Z-1a的合成方法，得白色固体。HRMS(ESI):Calcd.for C13H14O5[M+Na]+:273.0733,Found 273.0739[M+Na]+.
实施例2：5-苯基异噁唑-3-甲酸乙酯(Z-2a)
250mL茄形瓶中，加入中间体Z-1a(13.2g,60mmol),盐酸羟胺(8.34g,120mmol)，乙醇60mL。搅拌下，85℃反应4h。减压蒸除部分溶剂，加水40mL，抽滤得到固体，干燥，经柱层析纯化(石油醚：乙酸乙酯＝10:1)得Z-2a为白色固体，得量7.5g，收率57.65％。
5-(4-氟苯基)异噁唑-3-甲酸乙酯(Z-2b)
以中间体Z-1b为原料，参照中间体Z-2a的合成方法，得白色固体。HRMS(ESI):Calcd.for C12H10FNO3[M+Na]+:258.0537,Found 258.0537[M+Na]+.
5-(2,4-二氟苯基)异噁唑-3-甲酸乙酯(Z-2c)
以中间体Z-1c为原料，参照中间体Z-2a的合成方法，得白色固体。
5-(4-三氟甲基苯基)异噁唑-3-甲酸乙酯(Z-2d)
以中间体Z-1c为原料，参照中间体Z-2a的合成方法，得白色固体。HRMS(ESI):Calcd.for C13H10F3NO3[M+Na]+:308.0505,Found 308.0521[M+Na]+.
5-(4-甲基苯基)异噁唑-3-甲酸乙酯(Z-2e)
以中间体Z-1e为原料，参照中间体Z-2a的合成方法，得白色固体。HRMS(ESI):Calcd.for C13H13NO3[M+Na]+:254.0788,Found 254.0792[M+Na]+.
5-(4-甲氧基苯基)异噁唑-3-甲酸乙酯(Z-2f)
以中间体Z-1f为原料，参照中间体Z-2a的合成方法，得白色固体。HRMS(ESI):Calcd.for C13H13NO4[M+Na]+:270.0737,Found 270.0748[M+Na]+.
实施例3：(5-苯基异噁唑-3-基)甲醇(Z-3a)
250mL茄形瓶中，加入中间体Z-2a(7.5g,35mmol),甲醇60mL，分批加入硼氢化钠(5.12g,138mmol)。搅拌下，25℃反应2h。减压蒸除部分溶剂，加水40mL，抽滤得到固体，干燥，得Z-3a为白色固体，得量5.93g，收率98.02％。HRMS(ESI):Calcd.for C10H9NO2[M+Na]+:198.0525,Found198.0528[M+Na]+.
(5-(4-氟苯基)异噁唑-3-基)甲醇(Z-3b)
以中间体Z-2b为原料，参照中间体Z-3a的合成方法，得白色固体。(5-(2,4-二氟苯基)异噁唑-3-基)甲醇(Z-3c)
以中间体Z-2c为原料，参照中间体Z-3a的合成方法，得白色固体。
(5-(4-三氟甲基苯基)异噁唑-3-基)甲醇(Z-3d)
以中间体Z-2d为原料，参照中间体Z-3a的合成方法，得白色固体。(5-(4-甲基苯基)异噁唑-3-基)甲醇(Z-3e)
以中间体Z-2e为原料，参照中间体Z-3a的合成方法，得白色固体。HRMS(ESI):Calcd.for C11H11NO2[M+Na]+:212.0682,Found 212.0697[M+Na]+.
(5-(4-甲氧基苯基)异噁唑-3-基)甲醇(Z-3f)
以中间体Z-2f为原料，参照中间体Z-3a的合成方法，得白色固体。HRMS(ESI):Calcd.for C11H11NO3[M+Na]+:228.0631,Found 228.0635[M+Na]+.
实施例4：3-(溴甲基)-5-苯基异噁唑(Z-4a)
100mL茄形瓶中，加入中间体Z-3a(1.58g,9mmol)，四溴化碳(4.48g,13.5mmol)，二氯甲烷15mL。搅拌下，25℃反应6h。减压蒸除部分溶剂，加水40mL，二氯甲烷萃取(3×30mL)，合并有机相，依次水洗(3×20mL)、饱和食盐水洗涤(20mL)有机相，无水硫酸钠干燥，过滤干燥剂后减压浓缩得到粗品，经柱层析纯化(石油醚：乙酸乙酯15:1)，得Z-4a为白色固体，得量1.45g，收率67.75％。
3-(溴甲基)-5-(4-氟苯基)异噁唑(Z-4b)
以中间体Z-3b为原料，参照中间体Z-4a的合成方法，得白色固体。
3-(溴甲基)-5-(2,4-二氟苯基)异噁唑(Z-4c)
以中间体Z-3c为原料，参照中间体Z-4a的合成方法，得白色固体。
3-(溴甲基)-5-(4-三氟甲基苯基)异噁唑(Z-4d)
以中间体Z-3d为原料，参照中间体Z-4a的合成方法，得白色固体。
3-(溴甲基)-5-(4-甲基苯基)异噁唑(Z-4e)
以中间体Z-3e为原料，参照中间体Z-4a的合成方法，得白色固体。
3-(溴甲基)-5-(4-甲氧基苯基)异噁唑(Z-4f)
以中间体Z-3f为原料，参照中间体Z-4a的合成方法，得白色固体。HRMS(ESI):Calcd.for C11H11NO3[M+H]+:267.9968,Found 267.9974[M+H]+.
实施例5：1-(2-((4-溴苄基)氧基)-2-(2,4-二氟苯基)乙基)-1H-1,2,4-三唑(Z-5a)
50mL茄形瓶中，加入1-(2,4-二氟苯基)-2-(1H-1,2,4-三唑)乙醇(0.50g,2.22mmol),对溴溴苄(1.11g,4.44mmol,2eq),氢化钠(0.12g,5mmol,2.5eq),加入四氢呋喃5mL。搅拌下，70℃加热反应3h。将10mL水加入反应液中，乙酸乙酯萃取(3×10mL)，合并有机相，依次水洗(3×10mL)、饱和食盐水洗涤(10mL)有机相，无水硫酸钠干燥，过滤干燥剂后减压浓缩得到粗品，经柱层析纯化(二氯甲烷:甲醇＝20:1),得Z-5为黄色固体，得量0.76g,收率86.40％。HRMS(ESI):Calcd.for C17H14BrF2N3O[M+H]+:394.0361,Found 394.0374[M+H]+.
1-(2-((4-溴苄基)氧基)-2-(2,4-二氯苯基)乙基)-1H-咪唑(Z-5b)
以1-(2,4-二氯苯基)-2-(1H-咪唑)乙醇为原料，参照中间体Z-5a的合成方法，得白色固体。HRMS(ESI):Calcd.for C17H14BrCl2N3O[M+H]+:425.9770,Found 425.9766[M+H]+.
实施例6：1-(2-(2,4-二氟苯基)-2-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苄氧基)乙基)-1H-1,2,4-三唑(Z-6a)
50mL三颈瓶中，加入中间体Z-5(3.7g,9.39mmol,1eq),联硼酸频哪醇酯(3.58g,14.08mmol,1.5eq),醋酸钾(3.38g,28.17mmol,3eq),1,1'-双(二苯膦基)二茂铁合氯化钯(0.2g,0.28mmol,0.03eq),二氧六环10mL。氮气保护下，80℃加热反应4h。将10mL水加入反应液中，乙酸乙酯萃取(3×10mL)，合并有机相，依次水洗(3×10mL)、饱和食盐水洗涤(10mL)有机相，无水硫酸钠干燥，过滤干燥剂后减压浓缩得到粗品，经柱层析纯化(二氯甲烷:甲醇＝20:1),得Z-6a为黄色固体，得量1.75g,收率42.27％。HRMS(ESI):Calcd.forC23H26BF2N3O3[M+Na]+:464.1927,Found 464.1948[M+Na]+.
1-(2-(2,4-二氯苯基)-2-((4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苄氧基)乙基)-1H-咪唑(Z-6b)
以中间体Z-5b为原料，参照中间体Z-6a的合成方法，得黄色固体。HRMS(ESI):Calcd.for C23H26BF2N3O3[M+Na]+:497.1782,Found 497.1763[M+Na]+.
实施例7：3-(4-((1-(2,4-二氟苯基)-2-(1H-1,2,4-三唑-1-基)乙氧基)甲基)苄基)-5-苯基异噁唑(E01)
50mL三颈瓶中，加入中间体Z-4a(0.5g,2.1mmol,1eq),中间体Z-6(0.92g,2.1mmol,1eq),碳酸铯(2.05g,6.3mmol,3eq),1,1'-双(二苯膦基)二茂铁合氯化钯(0.043g,0.06mmol,0.03eq),二氧六环10mL。氮气保护下，110℃加热反应4h。将10mL水加入反应液中，乙酸乙酯萃取(3×10mL)，合并有机相，依次水洗(3×10mL)、饱和食盐水洗涤(10mL)有机相，无水硫酸钠干燥，过滤干燥剂后减压浓缩得到粗品，经柱层析纯化(二氯甲烷:甲醇＝20:1),得E01为黄色固体，得量0.3g,收率30.6％。HRMS(ESI):Calcd.forC27H22F2N4O2[M+Na]+:495.1603,Found 495.1603[M+Na]+.1H NMR(400MHz,DMSO-d6)δ8.45(s,1H),7.94(s,1H),7.83(dd,J＝8.0,1.7Hz,2H),7.52-7.47(m,4H),7.31-7.26(m,1H),7.23(d,J＝8.2Hz,2H),7.16-7.13(m,1H),7.05(d,J＝8.1Hz,2H),6.85(s,1H),5.06(dd,J＝8.4,4.2Hz,1H),4.58(dd,J＝14.1,8.3Hz,1H),4.44-4.35(m,2H),4.22(d,J＝12.0Hz,1H),4.01(s,2H).
实施例8：3-(4-((1-(2,4-二氟苯基)-2-(1H-1,2,4-三唑-1-基)乙氧基)甲基)苄基)-5-(4-氟苯基)异噁唑(E02)
以中间体Z-4b和中间体Z-6a为原料，参照中间体E01的合成方法，得黄色固体E02。HRMS(ESI):Calcd.for C27H21F3N4O2[M+Na]+:513.1509,Found 513.1516[M+Na]+.1H NMR(400MHz,DMSO-d6)δ8.45(s,1H),8.00-7.86(m,3H),7.52-7.45(m,1H),7.36-7.03(m,8H),6.85(s,1H),5.05(dd,J＝8.4,4.2Hz,1H),4.61-4.54(m,1H),4.44-4.35(m,2H),4.22(d,J＝12.0Hz,1H),4.00(s,2H).
实施例9：3-(4-((1-(2,4-二氟苯基)-2-(1H-1,2,4-三唑-1-基)乙氧基)甲基)苄基)-5-(2,4-二氟苯基)异噁唑(E03)
以中间体Z-4c和中间体Z-6a为原料，参照中间体E01的合成方法，得黄色固体E03。HRMS(ESI):Calcd.for C27H20F4N4O2[M+Na]+:531.1415,Found 531.1422[M+Na]+.1H NMR(400MHz,DMSO-d6)δ8.45(s,1H),7.98-7.92(m,2H),7.52-7.46(m,2H),7.29-7.22(m,4H),7.16-7.12(m,1H),7.06-7.02(m,2H),6.70(d,J＝3.4Hz,1H),5.06-5.03(m,1H),4.58(dd,J＝14.0,8.3Hz,1H),4.43-4.34(m,2H),4.22(d,J＝12.0Hz,1H),4.03(s,2H).
实施例10：3-(4-((1-(2,4-二氟苯基)-2-(1H-1,2,4-三唑-1-基)乙氧基)甲基)苄基)-5-(4-三氟甲基苯基)异噁唑(E04)
以中间体Z-4d和中间体Z-6a为原料，参照中间体E01的合成方法，得黄色固体E04。HRMS(ESI):Calcd.for C28H21F5N4O2[M+Na]+:563.1477,Found 563.1492[M+Na]+.1H NMR(400MHz,DMSO-d6)δ8.45(s,1H),8.05(d,J＝8.1Hz,2H),7.94(s,1H),7.86(d,J＝8.3Hz,2H),7.52-7.46(m,1H),7.29-7.22(m,3H),7.17-7.12(m,1H),7.08-7.04(m,3H),5.06(dd,J＝8.3,4.1Hz,1H),4.58(dd,J＝14.1,8.3Hz,1H),4.44-4.35(m,2H),4.22(d,J＝12.0Hz,1H),4.04(s,2H).
实施例11：3-(4-((1-(2,4-二氟苯基)-2-(1H-1,2,4-三唑-1-基)乙氧基)甲基)苄基)-5-(4-甲基苯基)异噁唑(E05)
以中间体Z-4e和中间体Z-6a为原料，参照中间体E01的合成方法，得黄色固体E05。HRMS(ESI):Calcd.for C28H24F2N4O2[M+Na]+:509.1760,Found 509.1759[M+Na]+.1H NMR(400MHz,DMSO-d6)δ8.45(s,1H),7.94(s,1H),7.71(d,J＝8.2Hz,2H),7.49(td,J＝8.5,6.6Hz,1H),7.33-7.20(m,5H),7.18-7.12(m,1H),7.05(d,J＝8.0Hz,2H),6.77(s,1H),5.05(dd,J＝8.3,4.1Hz,1H),4.58(dd,J＝14.3,8.3Hz,1H),4.45-4.35(m,2H),4.22(d,J＝11.9Hz,1H),3.99(s,2H),2.34(s,3H).
实施例12：3-(4-((1-(2,4-二氟苯基)-2-(1H-1,2,4-三唑-1-基)乙氧基)甲基)苄基)-5-(4-甲氧基苯基)异噁唑(E06)
以中间体Z-4f和中间体Z-6a为原料，参照中间体E01的合成方法，得黄色固体E06。HRMS(ESI):Calcd.for C28H24F2N4O3[M+Na]+:525.1709,Found 525.1715[M+Na]+.1H NMR(400MHz,DMSO-d6)δ8.45(s,1H),7.94(s,1H),7.79-7.73(m,2H),7.49(td,J＝8.5,6.6Hz,1H),7.30-7.21(m,3H),7.17-7.12(m,1H),7.05(d,J＝8.8Hz,4H),6.69(s,1H),5.05(dd,J＝8.3,4.2Hz,1H),4.58(dd,J＝14.1,8.3Hz,1H),4.45-4.35(m,2H),4.22(d,J＝11.9Hz,1H),3.98(s,2H),3.81(s,3H).
实施例13：3-(3-(4-(1-(2，4-二氟苯基)-2-(1H-1，2，4-三唑-1-基)乙氧基)甲基)苄基)异噁唑-5-基)吡啶-2-胺(E07)
以3-(3-溴甲基)异噁唑-5-基)吡啶-2-胺和中间体Z-6a为原料，参照中间体E01的合成方法，得黄色固体E07。HRMS(ESI):Calcd.for C26H22F2N6O2[M+Na]+:511.1665,Found511.1647[M+Na]+.1H NMR(500MHz,Chloroform-d)δ8.31(dd,J＝4.2,2.2Hz,1H),8.25(d,J＝1.6Hz,1H),8.00(dd,J＝9.2,2.2Hz,1H),7.75(d,J＝1.6Hz,1H),7.50(dtd,J＝7.9,5.0,1.0Hz,1H),7.28-7.20(m,4H),7.09(dd,J＝9.1,4.1Hz,1H),6.98(dtd,J＝19.6,8.0,1.9Hz,2H),6.68(d,J＝8.2Hz,1H),6.50(d,J＝8.2Hz,1H),6.23(s,1H),5.19(td,J＝4.4,0.9Hz,1H),4.70(q,J＝0.9Hz,2H),4.45(dd,J＝14.5,4.4Hz,1H),4.39(dd,J＝14.5,4.4Hz,1H),4.16-4.08(m,2H).
实施例14：3-(4-((1-(2,4-二氯苯基)-2-(1H-咪唑-1-基)乙氧基)甲基)苄基)-5-苯基异噁唑(E08)
以中间体Z-4a和中间体Z-7b为原料，参照中间体E01的合成方法，得黄色固体E08。HRMS(ESI):Calcd.for C28H23Cl2N3O2[M+Na]+:526.1060,Found 526.1044[M+Na]+.1H NMR(500MHz,Chloroform-d)δ7.83-7.75(m,2H),7.70(t,J＝1.7Hz,1H),7.54-7.36(m,6H),7.27-7.22(m,2H),7.25-7.19(m,3H),7.07(dd,J＝4.1,1.7Hz,1H),6.74(s,1H),5.13(td,J＝5.0,0.9Hz,1H),4.74-4.64(m,2H),4.45-4.34(m,2H),4.16-4.08(m,2H).
实施例15：3-(4-((1-(2,4-二氯苯基)-2-(1H-咪基)乙氧基)甲基)苄基)-5-(4-氟苯基)异噁唑(E09)
以中间体Z-4b和中间体Z-7b为原料，参照中间体E01的合成方法，得黄色固体E09。
HRMS(ESI):Calcd.for C28H22Cl2FN3O2[M+Na]+:544.0965,Found544.0945[M+Na]+.1H NMR(500MHz,Chloroform-d)δ7.87-7.80(m,2H),7.70(t,J＝1.7Hz,1H),7.52(d,J＝2.0Hz,1H),7.41(qd,J＝8.6,1.4Hz,2H),7.24(t,J＝0.9Hz,2H),7.25-7.13(m,5H),7.07(dd,J＝4.1,1.7Hz,1H),6.74(s,1H),5.13(td,J＝5.0,0.9Hz,1H),4.74-4.64(m,2H),4.45-4.34(m,2H),4.16-4.08(m,2H).
实施例16：3-(4-((1-(2,4-二氯苯基)-2-(1H-咪基)乙氧基)甲基)苄基)-5-(2，4-二氟苯基)异噁唑(E10)
以中间体Z-4c和中间体Z-7b为原料，参照中间体E01的合成方法，得黄色固体E10。HRMS(ESI):Calcd.for C28H21Cl2F2N3O2[M+Na]+:562.0871,Found 562.0864[M+Na]+.1H NMR(500MHz,Chloroform-d)δ7.78(dt,J＝7.8,4.9Hz,1H),7.70(t,J＝1.7Hz,1H),7.52(d,J＝2.1Hz,1H),7.41(qd,J＝8.6,1.4Hz,2H),7.28-7.22(m,2H),7.25-7.19(m,3H),7.12-7.02(m,3H),6.79(d,J＝2.0Hz,1H),5.13(td,J＝5.0,0.9Hz,1H),4.74-4.64(m,2H),4.45-4.34(m,2H),4.16-4.08(m,2H).
实施例17：3-(4-((1-(2,4-二氯苯基)-2-(1H-咪基)乙氧基)甲基)苄基)-5-(4-三氟甲基苯基)异噁唑(E11)
以中间体Z-4d和中间体Z-7b为原料，参照中间体E01的合成方法，得黄色固体E11。HRMS(ESI):Calcd.for C29H22Cl2F3N3O2[M+Na]+:594.0933,Found 594.0920[M+Na]+.1H NMR(500MHz,Chloroform-d)δ7.91-7.84(m,2H),7.72-7.63(m,3H),7.52(d,J＝2.0Hz,1H),7.41(qd,J＝8.6,1.4Hz,2H),7.28-7.19(m,5H),7.07(dd,J＝4.1,1.7Hz,1H),6.78(s,1H),5.13(td,J＝5.0,0.9Hz,1H),4.74-4.64(m,2H),4.45-4.34(m,2H),4.16-4.08(m,2H).
实施例18：3-(4-((1-(2,4-二氯苯基)-2-(1H-咪基)乙氧基)甲基)苄基)-5-(4-甲基苯基)异噁唑(E12)
以中间体Z-4e和中间体Z-7b为原料，参照中间体E01的合成方法，得黄色固体E12。HRMS(ESI):Calcd.for C29H25Cl2N3O2[M+Na]+:540.1216,Found 540.1210[M+Na]+.1H NMR(500MHz,Chloroform-d)δ7.73-7.67(m,3H),7.52(d,J＝2.0Hz,1H),7.45-7.36(m,2H),7.28-7.19(m,7H),7.07(dd,J＝4.1,1.7Hz,1H),6.73(s,1H),5.13(td,J＝5.0,0.9Hz,1H),4.74-4.64(m,2H),4.45-4.34(m,2H),4.16-4.08(m,2H),2.40(d,J＝1.5Hz,1H).
实施例19：3-(4-((1-(2,4-二氯苯基)-2-(1H-咪基)乙氧基)甲基)苄基)-5-(4-甲氧基苯基)异噁唑(E13)
以中间体Z-4f和中间体Z-7b为原料，参照中间体E01的合成方法，得黄色固体E13。HRMS(ESI):Calcd.for C29H25Cl2N3O3[M+Na]+:556.1165,Found 556.1147[M+Na]+.1H NMR(500MHz,Chloroform-d)δ7.80-7.75(m,2H),7.70(t,J＝1.7Hz,1H),7.52(d,J＝2.0Hz,1H),7.41(qd,J＝8.6,1.4Hz,2H),7.28-7.19(m,4H),7.07(dd,J＝4.1,1.7Hz,1H),7.05-7.00(m,2H),6.72(s,1H),5.13(td,J＝5.0,0.9Hz,1H),4.74-4.64(m,2H),4.45-4.34(m,2H),4.16-4.08(m,2H),3.83(s,2H).
实施例20：3-(3-(4-(1-(2，4-二氯苯基)-2-(1H-咪唑-1-基)乙氧基)甲基)苄基)异噁唑-5-基)吡啶-2-胺(E14)
以3-(3-溴甲基)异噁唑-5-基)吡啶-2-胺和中间体Z-6b为原料，参照中间体E01的合成方法，得黄色固体E14。HRMS(ESI):Calcd.for C27H23Cl2N5O2[M+Na]+:542.1121,Found542.1105[M+Na]+.1H NMR(500MHz,Chloroform-d)δ8.31(dd,J＝4.2,2.2Hz,1H),8.00(dd,J＝9.2,2.2Hz,1H),7.70(t,J＝1.7Hz,1H),7.52(d,J＝2.0Hz,1H),7.41(qd,J＝8.6,1.4Hz,2H),7.28-7.21(m,4H),7.24-7.19(m,1H),7.12-7.05(m,2H),6.68(d,J＝8.2Hz,1H),6.50(d,J＝8.2Hz,1H),6.23(s,1H),5.13(td,J＝5.0,0.9Hz,1H),4.74-4.64(m,2H),4.45-4.34(m,2H),4.16-4.08(m,2H).
本发明的药理研究
采用二倍浓度稀释法测定化合物E01-E18的体外抗真菌活性。
实验参照美国国家临床实验室标准化委员会(NCCLS)公布的2003年版产孢丝状真菌药敏试验方案,培养及稀释用培养基均用RPMI-1640。
阳性对照药：氟康唑(Fluconazole)。
供试菌种：7种供试真菌均市购获得，并由沈阳药科大学微生物教研室保存并提供,分别为白色念珠菌(CPCC400616和ATCCSC5314)，新型隐球菌(Cryptococcusneoformans，CGMCC2.3161)和热带假丝酵母菌(Candida zeylanoides CGMCC2.3739)，克鲁斯念珠菌(AS2.1045)，平滑念珠菌(ATCC 22019)和光滑念珠菌(Candida glabrata)。
目标化合物和对照药样储备液的配置：分别称取目标化合物(E01-E18)和阳性对照药4mg，溶于5mL DMSO中，加入5mL吐温80和4.0mL蒸馏水，配制成储配液，4℃下保存备用。
体外最小抑菌浓度的测定：将RPM1640培养基加入到96板中，第1孔加入180μL，生长对照孔与实验孔加入100μL，空白对照孔加入200μL。然后向第1孔内加入20μL药样储备液，混匀后吸取100μL，转移至第2孔内。第2孔混匀后再吸取100μL，转移至第3孔内，依次类推加至所有试验孔中。生长对照孔与空白对照孔不加入任何药样储备液。然后在试验孔与生长对照孔中加入100μL制备好且经稀释至1×103～103cuf/mL的菌悬液。96板于35℃培养箱内培养，白色念珠菌、热带假丝酵母菌、克鲁斯念珠菌、平滑念珠菌和光滑念珠在培养24h后进行MIC值的读数，新型隐球菌和在培养72h后进行MIC值的读数。所有实验至少进行三次独立实验，实验误差不超过10％。
注：MIC：最小抑菌浓度，Fluconazole：氟康唑，C.alb：白色念珠菌，C.alb(5314):白色念珠菌SC5314，C.par：平滑念珠菌，C.gla：光滑念珠菌，C.kru：克鲁斯念珠菌，C.tro：热带假丝酵母菌，C.neo：新型隐球菌。
由上述可见本发明E01-E14体外抗真菌活性较优，部分化合物的抗真菌活性远优于阳性药，且抗菌谱也更广。本发明设计与合成的含异噁唑结构的唑类衍生物具有较强的抗真菌活性，相较于阳性药显著提高其抗菌效果。
Claims (9)
1.一种含异噁唑结构的唑类衍生物，其特征在于：化合物如通式(1)所示
通式中：
X，Y，Z可相同或不同的选自N或CH；
R1，R2，R3，R4可相同或不同的选自氢原子、卤素、氰基、硝基、羟基、氨基，未取代或被至少一个下述基团取代的C1-6烷基、C3-8环烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C2-6烯氧基、C2-6炔氧基，下述基团可相同或不同的选自卤素、羟基、氰基、硝基和氨基；未取代或如下述基团取代的氨基，如下述基团选自C1-6烷基、C1-6氨基烷基、C1-6羟基烷基、C1-6烷氧基烷基、C1-6氰基烷基、C2-6烯基、C2-6炔基、C1-6烷基磺酰基、C1-6烷基羰基、C2-6烯基羰基或C2-6炔基羰基；未取代或下述基团取代的硫酰胺基或酰胺基，其中硫酰胺基或酰胺基的取代位为氨基，取代基团选自C1-6烷基、C1-6氨基烷基、C1-6羟基烷基、C1-6烷氧基烷基、C1-6氰基烷基、C2-6烯基、C2-6炔基、C1-6烷基磺酰基、C1-6烷基羰基、C2-6烯基羰基或C2-6炔基羰基；
或，通式(1)所示化合物的光学异构体，非对映异构体。
2.根据权利要求1所述的化合物，其特征在于：
所述通式中：
X，Y，Z可相同或不同的选自N或CH；
R1，R2，R3，R4可相同或不同的选自氢原子、卤素、氰基、硝基、羟基、氨基，未取代或被至少一个下述基团取代的C1-6烷基、C3-8环烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C2-6烯氧基、C2-6炔氧基，下述基团可相同或不同的选自卤素、羟基、氰基、硝基和氨基；
或，通式(1)所示化合物的光学异构体，非对映异构体。
3.根据权利要求2所述的化合物，其特征在于：
所述通式中：
X，Y，Z可相同或不同的选自N或CH；
R1，R2，R3，R4可相同或不同的选自氢原子、卤素、氰基、硝基、羟基、氨基、未取代或被至少一个下述基团取代的C1-4烷基、C1-4烷氧基，下述基团可相同或不同的选自卤素、羟基、氰基、硝基和氨基；
或，通式(1)所示化合物的光学异构体，非对映异构体。
4.根据权利要求3所述的化合物，其特征在于：
所述通式中：
X，Y，Z可相同或不同的选自N或CH；
R1，R2，R3，R4可相同或不同的选自氢原子、卤素、氰基、硝基、羟基、氨基、未取代或被至少一个下述基团取代的C1-4烷基、C1-4烷氧基，下述基团可相同或不同的选自卤素或羟基；
或，通式(1)所示化合物的光学异构体，非对映异构体。
5.根据权利要求4所述的化合物，其特征在于：
所述通式中：
X，Y，Z可相同或不同的选自N或CH；
R1，R2，R3，R4可相同或不同的选自氢原子、卤素、氰基、硝基、羟基、氨基、未取代或被至少一个下述基团取代的C1-4烷基、C1-4烷氧基，下述基团可相同或不同的选自卤素；
或，通式(1)所示化合物的光学异构体，非对映异构体。
6.一种权利要求1所述化合物的制备方法，反应式如下：首先苯环上含有不同取代基的苯乙酮与草酸二乙酯反应生成中间体Z-1a-f，再与盐酸羟胺反应生成异噁唑环中间体Z-2a-f，再经还原、溴代得到中间体Z-4a-f；化合物a和b分别与对溴溴苄发生取代反应生成中间体Z-5a-b，再硼酯化后与中间体Z-4a-f发生Suzuki反应得到通式(1)的化合物；
7.一种药物组合物，其特征在于：组合物包含权利要求1-5任何一项所述的化合物及其光学活性体，非对映异构体和药学上可接受的载体。
8.一种化合物和组合物的应用，其特征在于：权利要求1-5任意一项所述的化合物及其光学活性体，非对映异构体或权利要求7所述组合物在制备抗真菌药物中的应用。
9.按权利要求8所述的应用，其特征在于：权利要求1-6任意一项所述的化合物及其光学活性体，非对映异构体或权利要求7所述组合物在制备抗真菌药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311341317.7A CN117417334A (zh) | 2023-10-17 | 2023-10-17 | 含异噁唑结构的唑类衍生物及其制备方法及应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311341317.7A CN117417334A (zh) | 2023-10-17 | 2023-10-17 | 含异噁唑结构的唑类衍生物及其制备方法及应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117417334A true CN117417334A (zh) | 2024-01-19 |
Family
ID=89529376
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311341317.7A Pending CN117417334A (zh) | 2023-10-17 | 2023-10-17 | 含异噁唑结构的唑类衍生物及其制备方法及应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117417334A (zh) |
-
2023
- 2023-10-17 CN CN202311341317.7A patent/CN117417334A/zh active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2625584B2 (ja) | トリアゾール系抗真菌薬 | |
| JP2997947B2 (ja) | トリアゾール化合物およびその用途 | |
| CN101657424A (zh) | 双重作用的抗高血压药剂 | |
| HU187564B (en) | Process for producing substituted imidazol derivatives | |
| KR100347639B1 (ko) | 디페닐 트리아졸 유도체 화합물, 이의 제조방법 및 이를 포함하는 약제학적 조성물 | |
| JPH1045750A (ja) | アゾール化合物、その製造方法及び用途 | |
| WO2022022616A1 (zh) | 2,4,4-三取代二氢噁唑衍生物及其制备方法和用途 | |
| KR20050017962A (ko) | 불소화 비닐 에테르 측쇄기를 갖는 아졸계 살균제 화합물및 그의 제조방법 | |
| JPS6052147B2 (ja) | イミダゾリルビニルエ−テル、それの酸附加塩及びそれの製造方法 | |
| TW438784B (en) | Triazole derivative or salt thereof and pharmaceutical composition for treating mycosis containing the same | |
| FI85701B (fi) | Foerfarande foer framstaellning av nya terapeutiskt anvaendbara triazolderivat. | |
| CA1325212C (en) | (benzofuran-2-yl) imidazoles having pharmaceutical activity, their salts and relevant production processes | |
| EP2721014B1 (en) | Hybrid molecules containing pharmacophores of fluconazole as antifungal agents and their preparation | |
| AU2003205733B2 (en) | R-(-)-1-[2-(7-chlorobenzo [b] thiophen-3 - yl - methoxy) -2-(2,4-dichlorophenyl)-ethyl] -1H-imidazole | |
| CN117417334A (zh) | 含异噁唑结构的唑类衍生物及其制备方法及应用 | |
| US4560696A (en) | Analgesic, antipyretic or anti-inflammatory imidazole compounds | |
| JP2004359646A (ja) | 抗真菌活性を有する新規アゾール誘導体 | |
| JPS62149666A (ja) | Ｎ−ビニルアゾ−ル類 | |
| CZ282969B6 (cs) | Imidazolové sloučeniny, farmaceutické prostředky na jejich bázi a meziprodukty pro jejich výrobu | |
| EP2638017B1 (en) | Crystalline forms of an alkoxyimidazol-1-ylmethyl biphenyl carboxylic acid | |
| CN115894461B (zh) | 新型含香豆素唑类衍生物及其制备方法及应用 | |
| CN117417335A (zh) | 含哌嗪结构的唑类衍生物及其制备方法及应用 | |
| AU713049B2 (en) | Azole compounds endowed with antimycotic activity for human and veterinary use | |
| CN108440506B (zh) | 抗真菌剂-含1,2,3-三氮唑结构的烯醇醚类化合物 | |
| AP875A (en) | Azole compounds with antimycotic activity for human and veterinary use. |
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 |