CN107118204A - 一种3－氮杂环硫色酮类化合物及其合成方法和在抗真菌药物中的应用 - Google Patents
一种3－氮杂环硫色酮类化合物及其合成方法和在抗真菌药物中的应用 Download PDFInfo
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- CN107118204A CN107118204A CN201710462711.4A CN201710462711A CN107118204A CN 107118204 A CN107118204 A CN 107118204A CN 201710462711 A CN201710462711 A CN 201710462711A CN 107118204 A CN107118204 A CN 107118204A
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- Prior art keywords
- compound
- hydrogen
- thiochromone
- azacyclo
- formula
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- -1 Thiochromone compound Chemical class 0.000 title claims abstract description 33
- 238000010189 synthetic method Methods 0.000 title claims description 11
- 239000003429 antifungal agent Substances 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 239000000460 chlorine Substances 0.000 claims abstract description 9
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 9
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 8
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000011737 fluorine Substances 0.000 claims abstract description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000004215 Carbon black (E152) Substances 0.000 claims abstract description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 3
- 239000011630 iodine Substances 0.000 claims abstract description 3
- 238000006467 substitution reaction Methods 0.000 claims abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 9
- 230000000844 anti-bacterial effect Effects 0.000 claims description 8
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical group O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 239000003899 bactericide agent Substances 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 239000012752 auxiliary agent Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical class CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 2
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 claims description 2
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical class CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 claims description 2
- MOFINMJRLYEONQ-UHFFFAOYSA-N [N].C=1C=CNC=1 Chemical group [N].C=1C=CNC=1 MOFINMJRLYEONQ-UHFFFAOYSA-N 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 229940040526 anhydrous sodium acetate Drugs 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- USSBDBZGEDUBHE-UHFFFAOYSA-L magnesium;2-oxidooxycarbonylbenzoate Chemical compound [Mg+2].[O-]OC(=O)C1=CC=CC=C1C([O-])=O USSBDBZGEDUBHE-UHFFFAOYSA-L 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims 1
- HGNVEXMJZVUWJO-UHFFFAOYSA-N 3-methylhexan-3-amine Chemical compound CCCC(C)(N)CC HGNVEXMJZVUWJO-UHFFFAOYSA-N 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000003086 colorant Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 229910052738 indium Inorganic materials 0.000 claims 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 229910001950 potassium oxide Inorganic materials 0.000 claims 1
- 208000031888 Mycoses Diseases 0.000 abstract description 7
- 206010017533 Fungal infection Diseases 0.000 abstract description 6
- 238000001228 spectrum Methods 0.000 abstract description 4
- 241000233866 Fungi Species 0.000 abstract description 3
- 230000003385 bacteriostatic effect Effects 0.000 abstract description 2
- 150000002431 hydrogen Chemical class 0.000 abstract 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- 125000004093 cyano group Chemical group *C#N 0.000 abstract 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract 1
- 230000001988 toxicity Effects 0.000 abstract 1
- 231100000419 toxicity Toxicity 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 12
- 230000000843 anti-fungal effect Effects 0.000 description 10
- 241000894006 Bacteria Species 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 0 C[n](c(*)c1I)nc1I Chemical compound C[n](c(*)c1I)nc1I 0.000 description 6
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 230000001857 anti-mycotic effect Effects 0.000 description 4
- 239000002543 antimycotic Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 150000004777 chromones Chemical class 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 241000222122 Candida albicans Species 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- 229940095731 candida albicans Drugs 0.000 description 3
- FLGZHHJNRZUPIL-UHFFFAOYSA-N chromene-4-thione Chemical compound C1=CC=C2C(=S)C=COC2=C1 FLGZHHJNRZUPIL-UHFFFAOYSA-N 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 2
- 241000222173 Candida parapsilosis Species 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 241000209140 Triticum Species 0.000 description 2
- 235000021307 Triticum Nutrition 0.000 description 2
- 241000222126 [Candida] glabrata Species 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 208000032343 candida glabrata infection Diseases 0.000 description 2
- 229940055022 candida parapsilosis Drugs 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- JATPDXYCHIJZQN-UHFFFAOYSA-N C[n](nc1I)nc1[IH]C Chemical compound C[n](nc1I)nc1[IH]C JATPDXYCHIJZQN-UHFFFAOYSA-N 0.000 description 1
- 241000222178 Candida tropicalis Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- IBHJATUAVSGNAE-UHFFFAOYSA-N Cc([n](C)nn1)c1I Chemical compound Cc([n](C)nn1)c1I IBHJATUAVSGNAE-UHFFFAOYSA-N 0.000 description 1
- 241001337994 Cryptococcus <scale insect> Species 0.000 description 1
- 240000008067 Cucumis sativus Species 0.000 description 1
- 235000010799 Cucumis sativus var sativus Nutrition 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 240000005979 Hordeum vulgare Species 0.000 description 1
- 235000007340 Hordeum vulgare Nutrition 0.000 description 1
- 241000220225 Malus Species 0.000 description 1
- 235000011430 Malus pumila Nutrition 0.000 description 1
- 235000015103 Malus silvestris Nutrition 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 241000893976 Nannizzia gypsea Species 0.000 description 1
- XCHRPVARHBCFMJ-UHFFFAOYSA-N O=C(C[n]1ncnc1)c(ccc(F)c1)c1F Chemical compound O=C(C[n]1ncnc1)c(ccc(F)c1)c1F XCHRPVARHBCFMJ-UHFFFAOYSA-N 0.000 description 1
- YYFYRDFSXSZRJI-UHFFFAOYSA-N O=C1C([n]2ncnc2)=CSc2cc(F)ccc12 Chemical compound O=C1C([n]2ncnc2)=CSc2cc(F)ccc12 YYFYRDFSXSZRJI-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 241000228150 Penicillium chrysogenum Species 0.000 description 1
- 241000233622 Phytophthora infestans Species 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241001149962 Sporothrix Species 0.000 description 1
- 208000002474 Tinea Diseases 0.000 description 1
- 241000130764 Tinea Species 0.000 description 1
- 241000223229 Trichophyton rubrum Species 0.000 description 1
- 241000893966 Trichophyton verrucosum Species 0.000 description 1
- 241001480050 Trichophyton violaceum Species 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical compound C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 description 1
- 230000001332 colony forming effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
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- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
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- 239000000706 filtrate Substances 0.000 description 1
- 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 1
- 229960004884 fluconazole Drugs 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000010413 gardening Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- RIVIDPPYRINTTH-UHFFFAOYSA-N n-ethylpropan-2-amine Chemical compound CCNC(C)C RIVIDPPYRINTTH-UHFFFAOYSA-N 0.000 description 1
- 230000009707 neogenesis Effects 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
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- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
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- 229940055035 trichophyton verrucosum Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/50—1,3-Diazoles; Hydrogenated 1,3-diazoles
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
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Abstract
本发明涉及一种3‑氮杂环硫色酮类化合物具有如右结构：其中R3是被氢、甲基、硝基或氰基取代的五元含氮芳杂环；R4、R5、R7分别独立的选自氢、氟、氯、溴或碘；R6选自氢、氟、氯、溴、碘、C1‑C6的烃氧基、C1‑C6的烃氨基、苯氧基、被1个或多个C1‑C6烃基或C1‑C6烃氧基取代的苯氧基。本发明的化合物具有制备抗真菌药物用途，对常见致病真菌以及深部真菌感染都具有较强的抑菌活性，并且毒性低、稳定性好、抗真菌谱广。
Description
技术领域
本发明涉及一种抗真菌的3-氮杂环硫色酮类化合物及其合成方法和其在制备抗真菌药物中的应用。
背景技术
近年来，由于广谱抗生素、免疫抑制剂和各类激素类药物的广泛使用，以及放化疗、器官移植及感染HIV等原因导致人体免疫系统功能下降，造成了机体真菌感染的机率增加，从而致使真菌类疾病的发病率和死亡率不断上升。另外临床治疗中存在的耐药性及抗菌谱窄等问题，也增加了真菌感染类疾病的治疗难度。因此开发出广谱、高效、低毒的新型抗真菌药物，已是急需解决的科学难题。
活性研究表明，硫色酮类化合物具有明显的抗真菌活性，目前文献报道的硫色酮类化合物，多以合成得到为主。早在1976年，Hiroyuki NakazuMi等人就报道了其合成的硫色酮类化合物；1998年方林等人在其文献中，报道了6位、7位卤代和1位硫醚键氧化成砜的硫色(满)酮的合成及其抗真菌活性；1998年，于新蕊等人在其文献中，介绍了3-苄基-6-氯硫色满酮的合成及抗真菌活性；2007年，黄伟等人设计合成了一系列2位含硫的硫色酮类化合物，介绍了体外抗尖孢镰刀菌等七种真菌试验显示抑菌活性，2009年，肖涛等人在硫色酮类化合物2位引入烃硫基，介绍了该类化合物对常见致病真菌及深部真菌感染具有较强的抑菌和抗真菌活性等。
色酮及硫色酮类化合物，因其具有的特殊的化学结构和生物活性，已经引起国际上药物研究者的广泛关注。无论是天然提取物还是合成产物，抑菌新的靶点和作用机制已经成为目前重要的研究方向。近几十年，随着计算机辅助分子设计技术、生物活性筛选技术、分子生物学、基因组学等新技术的应用和日臻成熟，大大加快了抗真菌药物的研发进度。可以预见，随着研究的不断深入，会有更多高效、低毒、广谱的抗真菌药物被研发出并造福于人类。
发明内容
本发明目的是提供一种3-氮杂环硫色酮类化合物及其合成方法和在抗真菌和抑菌药物中的应用。
本发明所涉及的3-氮杂环硫色酮类化合物，其化学结构如下：
R3选自如式(II)五元氮唑环中的一种：
其中：J、K、L分别独立地选自氢、C1-C3的烃基；
R4、R5、R7分别独立地选自氢、氟、氯、溴或碘；
R6选自氢、氟、氯、溴、碘、C1-C6的烃氧基、C1-C6的烃氨基、C1-C6的烃基、苯氧基、被1个或多个C1-C6烃氧基取代的苯氧基；
式(I)化合物的合成方法，是采用一步法，将化合物(III)、碱、二硫化碳溶于有机溶剂中，经缩合、关环后生成化合物(IV)，化合物(IV)不需分离经氧化剂直接氧化生成3-氮杂环硫色酮类化合物
所述化合物(III)的结构式如下：
所述化合物(IV)的结构式如下：
其中，X表示F或Cl；
R3、R4、R5、R6、R7的定义同式(I)；
所述有机溶剂选自N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、二甲亚砜、二氧六环、乙腈、四氢呋喃、甲醇、乙醇、异丙醇、叔丁醇中的至少一种。优选N，N-二甲基甲酰胺、二甲亚砜。
所述氧化剂选自二氧化锰、高锰酸钾、重铬酸钾、过氧化氢、过氧苯甲酸、间氯过氧苯甲酸、单过氧邻苯二甲酸镁或过氧乙酸中的至少一种。优选过氧化氢、二氧化锰。
所述碱性化合物选自碱金属碳酸盐、碱金属氢氧化物、碱金属醋酸盐或三乙胺、二乙基异丙胺、N-甲基哌啶、N-乙基哌啶、N-甲基吗啉、N-乙基吗啉、吡啶、4-甲基吡啶中的至少一种。优选氢氧化钠、氢氧化钾、碳酸钾、碳酸铯、无水乙酸钠。
该反应采用一步合成法，将所有反应试剂和溶剂在同一反应器中进行，每一步反应的生成物依次进行下一步反应的多组份串联反应。
本发明的合成方法是一种通用方法，适合于合成硫色酮化合物及其衍生物，对芳环上的多种官能团具有高的容忍度，因此事实上对硫色酮类化合物及其衍生物中的取代基个数和种类并无特别限制。
本发明式(I)化合物还包括其在药物制剂学上所容许的盐。
本发明提供所述3-氮杂环硫色酮类化合物在制备治疗真菌感染疾病的人用药物或动物用药物中的应用。
所述药物中除含有活性成分3-氮杂环硫色酮类化合物外，还含有与药物上可接受的载体、助剂和/或稀释剂，组成组合物。
所述药物的剂型是溶液、霜剂、栓剂、膏剂或溶液剂。
本发明还提供所述3-氮杂环硫色酮类化合物作为农业和园艺杀菌剂的应用。
所述杀菌剂中除含有活性成分3-氮杂环硫色酮类化合物外，还含有与药物上可接受的载体、助剂和/或稀释剂，组成组合物。
通过测定最低抑菌浓度MIC(即化合物能抑制试验微生物生长的浓度)，对本发明3-氮杂环硫色酮类化合物的抗真菌活性进行了体外评价。试验证实，本发明3-氮杂环硫色酮类化合物具有广谱抗真菌活性，在人体及动物(特别是哺乳动物)体内具有药理学活性，可与普通化疗可接受的稀释剂或载体相混合，或用其他的赋形剂，制成溶液、霜剂、栓剂、软膏、溶液等剂型，以药物的形式进行局部涂抹使用，对于真菌感染病具有明显的疗效。除了用于制备抗真菌的人用或动物用抗真菌药物外，本发明3-氮杂环硫色酮类化合物还可以用于农业和园艺的植物杀菌剂，对各种植物病原体疾病如稻瘟病、大麦和小麦的粉霉病及其他各种寄主植物(如黄瓜、苹果、葡萄)的粉霉病、小麦的锈病、燕麦的冠锈和其他各种寄主的锈病，西红柿的晚疫病及其他寄主植物的病原性腐烂等的防治非常有效。
具体实施方式
下面通过具体实施例对本发明的合成方法进行说明。应当注意到，这里给出的描述和实施例仅仅是为了描述本发明的具体实施方式，使技术人员更容易理解本发明，它们并非意欲限定本发明的范围。
实施例1，式(I)3-氮唑环硫色酮的合成制备反应式如下：
制备步骤如下：
单口烧瓶中加入1-(2，4-二氟苯基)-2-(1，2，4-三氮唑-1-基)乙酮18.4mmol，DMSO30mL、NaOAc 43mmol、MnO2 92mmol，20℃下搅拌，在此温度下滴加CS2 22.8mmol的5mL DMSO的溶液。滴毕，控温20℃搅拌反应。反应毕，将反应抽滤，滤液用乙酸乙酯(50mL×3)和水(50mL)萃取。合并有机相，减压旋蒸得类白色固体，无水甲醇重结晶得式(I1)产物3-(1，2，4-三氮唑-1-基)-7氟硫色酮--16.2mmol，收率88％。
1H NMR(300MHz，DMSO)δ9.16(s，1H)，9.00(s，1H)，8.62-8.44(m，1H)，8.23(s，1H)，8.03(d，J＝8.9Hz，1H)，7.56(t，J＝8.4Hz，1H).
实施例2，式(I)3-氮唑环硫色酮的合成制备反应式如下
制备步骤如下：
单口烧瓶中加入1-(2，4-二氯-5-氟苯基)-2-(咪唑-1-基)乙酮18.4mmol，DMSO30mL、KOH 43mmol，40℃下搅拌，在此温度下滴加CS2 22.8mmol的5mLDMSO的溶液。滴毕，控温40℃搅拌反应3h，滴加100mmol H2O2，继续保温反应10h。反应毕，将反应液用乙酸乙酯(50mL×3)和水(50mL)萃取。合并有机相，减压旋蒸得类白色固体，无水甲醇重结晶得式(I2)产物3-(咪唑-1-基)-6-氟-7-氯硫色酮--17.1mmol，收率93％。
1H NMR(300MHz，DMSO)δ8.77(s，1H)，8.51(d，J＝6.7Hz，1H)，8.25(d，J＝10.0Hz，1H)，7.99(s，1H)，7.48(s，1H)，7.10(s，1H).
实施例3～实施例9：式(I)3-氮唑环硫色酮类化合物的制备
以(III)化合物为原料，制备产物式(I)化合物(目标产物为表1中的式(I3)～(I9)各化合物)，制备步骤同实施例1，反应式如下
实施例3～实施例9中，产物式(I)3-氮唑环硫色酮类化合物各基团选择及制备用试剂和检测数据均列于表1。
表1
实施例10：体外抗真菌活性实验
1、实验用菌株
近平滑念珠菌、孢子丝菌、啤酒酵母菌曲霉菌、白色念珠菌、光滑念珠菌、热带念珠菌、红色毛癣菌、青霉菌、疣状毛癣菌、紫色毛癣菌、新生隐球菌、克柔氏念珠菌、絮状表皮癣菌、石膏样毛癣菌。
2、试药及材料
试验用材料：
改良马丁培养基、96孔培养板、DMSO
对照药物：氟康唑
3、实验方法
(1)抗菌药液的制备
将受试药物分别用DMSO溶解，配成25.6g/L的溶液，于-20℃以下保存备用。试验前将低温冷藏的受试药液取出，在35℃恒温箱中融化，用RPMI1640稀释10倍，备用。
(2)接种液的制备
哥受试念珠菌株(近平滑念珠菌，白色念珠菌，光滑念珠菌，热带念珠菌)在改良马丁培养基上转种，将其用质量分数为0.85％的无菌盐水制成悬液。用血细胞计数板计数孢子，调整含菌量，使集落形成单位为1×106～5×106CFU/mL。接种时用RPMI-1640培养液将其稀释200倍后，再稀释10倍，CFU值调至0.5×103～6.0×103CFU/mL，备用。
(3)MIC板制备
无菌操作下，在灭菌的96孔聚乙烯板的第1号孔加RPMI-1640培养液100μL，作为空白对照。第2号孔加菌液190μL，第3-12号孔加配置好的菌液100μL。然后在2号孔中加入10μL受试药液，按10级倍比稀释2-11号孔的浓度，使各孔的最终浓度为128，64，32，16，8，4，2，1，0.5，0.25mg/L，第12号孔不加受试药液作为生长对照。各MIC板密闭后置于35℃普通空气孵箱中，孵育满24h判断结果。
(4)结果判断
用酶标分析仪于620nm测各孔的OD值，以OD值下降80％以上的最低浓度作为MIC值。当MIC值高于128mg/L时计为＞128mg/L；当MIC值低于0.25mg/L时计为≤0.25mg/L。
(5)重复观察与统计
上述试验需要至少重复三次，当出现MIC值单一跳孔时，则记录为最大的抑制细菌浓度，当MIC值出现两个或两个以上跳孔时，则重新进行试验。
4、抗真菌敏感性试验结果
通过初步的MIC测定发现，受试化合物具有广谱抗真菌活性，其中实施例(1)～实施例(2)的硫色酮类化合物抑制真菌活性更为显著，对以上受试菌株的MIC值均小于10mg/L。
Claims (8)
1.一种如式(I)的3-氮杂环硫色酮类化合物，其化学结构如下：
R3选自如式(II)五元氮唑环中的一种：
其中：J、K、L分别独立地选自氢、C1-C3的烃基；
R4、R5、R7分别独立地选自氢、氟、氯、溴或碘；
R6选自氢、氟、氯、溴、碘、C1-C6的烃氧基、C1-C6的烃氨基、C1-C6的烃基、苯氧基、被1个或多个C1-C6烃氧基取代的苯氧基。
2.根据权利要求1所述的化合物，其特征该化合物包含其在制剂学上所容许的盐。
3.一种权利要求1的式(I)化合物的合成方法，其特征是采用一步法，将化合物(III)、碱、二硫化碳溶于有机溶剂中，经缩合、关环后生成化合物(IV)，化合物(IV)不需分离经氧化剂直接氧化生成3-氮杂环硫色酮类化合物；
所述化合物(III)的结构式如下：
所述化合物(IV)的结构式如下：
其中，X表示F、Cl或Br；
R3、R4、R5、R6、R7的定义同式(I)。
4.根据权利要求3所述的合成方法，其特征是所述有机溶剂选自N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、二甲亚砜、二氧六环、乙腈、四氢呋喃、甲醇、乙醇、异丙醇、叔丁醇中的至少一种；所述氧化剂选自二氧化锰、高锰酸钾、重铬酸钾、过氧化氢、过氧苯甲酸、间氯过氧苯甲酸、单过氧邻苯二甲酸镁或过氧乙酸中的至少一种；所述碱性化合物选自碱金属碳酸盐、碱金属氢氧化物、碱金属醋酸盐或三乙胺、二乙基异丙胺、N-甲基哌啶、N-乙基哌啶、N-甲基吗啉、N-乙基吗啉、吡啶、4-甲基吡啶中的至少一种。
5.根据权利要求3、4所述的合成方法，其特征是所述有机溶剂选自N，N-二甲基甲酰胺、二甲亚砜；所述氧化剂选自过氧化氢、间氯过氧苯甲酸；所述碱性化合物选自氢氧化钠、氢氧化钾、碳酸钾、碳酸铯、无水乙酸钠。
6.根据权利要求3-5所述的合成方法，其特征是化合物(I)采用一步合成法，所有反应试剂和溶剂在同一反应器中进行，每一步反应的生成物依次进行下一步反应的多组份串联反应。
7.一种权利要求1所述3-氮杂环硫色酮类化合物作为农业和园艺杀菌剂的应用。
8.根据权利要求7所述的应用，其特征是所述杀菌剂中除含有活性成分3-氮杂环硫色酮类化合物外，还含有药物上可接受的载体、助剂和/或稀释剂，组成组合物。
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| CN101519402A (zh) * | 2009-04-13 | 2009-09-02 | 南京工业大学 | 一种硫色酮类化合物及其合成方法和在制备抗真菌药物中的应用 |
| CN103819464A (zh) * | 2014-03-11 | 2014-05-28 | 南京工业大学 | 硫色满类化合物及其合成方法和制备抗真菌药物的应用 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107556296A (zh) * | 2017-09-06 | 2018-01-09 | 南京工业大学 | 一种2－羟基－3－氮杂环色酮类化合物及其合成方法和在抗真菌药物中的应用 |
| CN107556296B (zh) * | 2017-09-06 | 2020-10-02 | 南京工业大学 | 一种2-羟基-3-氮杂环色酮类化合物及其合成方法和在抗真菌药物中的应用 |
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