CN103819464A - Thiochromane type compound as well as synthesis method and application thereof to preparation of antifungal drugs - Google Patents
Thiochromane type compound as well as synthesis method and application thereof to preparation of antifungal drugs Download PDFInfo
- Publication number
- CN103819464A CN103819464A CN201410087557.3A CN201410087557A CN103819464A CN 103819464 A CN103819464 A CN 103819464A CN 201410087557 A CN201410087557 A CN 201410087557A CN 103819464 A CN103819464 A CN 103819464A
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- Prior art keywords
- formula
- compound
- hydrogen
- sulphur chroman
- sulphur
- Prior art date
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Links
- 239000003814 drug Substances 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims description 15
- 230000000843 anti-fungal effect Effects 0.000 title abstract description 10
- 229940121375 antifungal agent Drugs 0.000 title abstract description 7
- 229940079593 drug Drugs 0.000 title abstract description 6
- WPWNEKFMGCWNPR-UHFFFAOYSA-N 3,4-dihydro-2h-thiochromene Chemical class C1=CC=C2CCCSC2=C1 WPWNEKFMGCWNPR-UHFFFAOYSA-N 0.000 title abstract 2
- 238000001308 synthesis method Methods 0.000 title 1
- 239000001257 hydrogen Substances 0.000 claims abstract description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 17
- 239000011737 fluorine Substances 0.000 claims abstract description 17
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000000460 chlorine Substances 0.000 claims abstract description 15
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 14
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 14
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 14
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000011630 iodine Substances 0.000 claims abstract description 5
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 5
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims abstract description 5
- -1 sulphur chroman compound Chemical class 0.000 claims description 69
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 16
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
- 239000005864 Sulphur Substances 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 8
- 241000233866 Fungi Species 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 206010061217 Infestation Diseases 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- 238000010189 synthetic method Methods 0.000 claims description 6
- 230000000844 anti-bacterial effect Effects 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000002798 polar solvent Substances 0.000 claims description 5
- 230000002829 reductive effect Effects 0.000 claims description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 4
- 241001465754 Metazoa Species 0.000 claims description 4
- 239000012752 auxiliary agent Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 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 4
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims description 4
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 239000003899 bactericide agent Substances 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- 239000002674 ointment Substances 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 239000000829 suppository Substances 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- 239000012448 Lithium borohydride Substances 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 3
- 238000010413 gardening Methods 0.000 abstract description 2
- 239000011593 sulfur Substances 0.000 abstract description 2
- 229910052717 sulfur Inorganic materials 0.000 abstract description 2
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 abstract 1
- 239000000417 fungicide Substances 0.000 abstract 1
- 125000000623 heterocyclic group Chemical group 0.000 abstract 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 abstract 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract 1
- 230000001766 physiological effect Effects 0.000 abstract 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 238000012360 testing method Methods 0.000 description 8
- 239000003429 antifungal agent Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 230000001857 anti-mycotic effect Effects 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 241000222122 Candida albicans Species 0.000 description 4
- MHBLQZYBQMZPCT-UHFFFAOYSA-N O1CCCC2=CC=CC=C12.[S] Chemical class O1CCCC2=CC=CC=C12.[S] MHBLQZYBQMZPCT-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
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- 238000000605 extraction Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
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- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical class [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
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- 230000001580 bacterial effect Effects 0.000 description 2
- 229940095731 candida albicans Drugs 0.000 description 2
- 208000032343 candida glabrata infection Diseases 0.000 description 2
- 229940055022 candida parapsilosis Drugs 0.000 description 2
- 201000003984 candidiasis Diseases 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- TXKMVPPZCYKFAC-UHFFFAOYSA-N disulfur monoxide Inorganic materials O=S=S TXKMVPPZCYKFAC-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
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- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- BBBBLWVTCPHENO-UHFFFAOYSA-N 3-benzyl-3,4-dihydrothiochromen-2-one Chemical compound O=C1SC2=CC=CC=C2CC1CC1=CC=CC=C1 BBBBLWVTCPHENO-UHFFFAOYSA-N 0.000 description 1
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 1
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- 0 CCS(/C1=*/C(*)/C(/C)=C(\[*+])/C(*)/*=C1\C(C[n]1*(C)cnc1)OCC(C)O)=O Chemical compound CCS(/C1=*/C(*)/C(/C)=C(\[*+])/C(*)/*=C1\C(C[n]1*(C)cnc1)OCC(C)O)=O 0.000 description 1
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- VVTDHOIRNPCGTH-UHFFFAOYSA-N Mycosporin 1 Natural products COC1=C(NC(CO)CO)CC(O)(CO)CC1=O VVTDHOIRNPCGTH-UHFFFAOYSA-N 0.000 description 1
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- ZYPGADGCNXOUJP-CXVPHVKISA-N Variotin Chemical compound CCCC[C@@H](O)\C=C(/C)\C=C\C=C\C(=O)N1CCCC1=O ZYPGADGCNXOUJP-CXVPHVKISA-N 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
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- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- MOFINMJRLYEONQ-UHFFFAOYSA-N [N].C=1C=CNC=1 Chemical compound [N].C=1C=CNC=1 MOFINMJRLYEONQ-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
- 229960003942 amphotericin b Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
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- 239000011324 bead Substances 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
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- FLGZHHJNRZUPIL-UHFFFAOYSA-N chromene-4-thione Chemical class C1=CC=C2C(=S)C=COC2=C1 FLGZHHJNRZUPIL-UHFFFAOYSA-N 0.000 description 1
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 1
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- ZYPGADGCNXOUJP-UHFFFAOYSA-N dl-Variotin Natural products CCCCC(O)C=C(C)C=CC=CC(=O)N1CCCC1=O ZYPGADGCNXOUJP-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
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- 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
- 230000002538 fungal effect Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
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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
- A01N43/60—1,4-Diazines; Hydrogenated 1,4-diazines
-
- 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
- A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
- A01N43/647—Triazoles; Hydrogenated triazoles
- A01N43/653—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- 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
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/84—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4
Abstract
The invention relates to a thiochromane type compound. The compound can be used for preparing antifungal drugs and is represented by a structural formula in the specification, wherein Z represents sulfur, sulfinyl or sulfonyl; Y represents carbon or nitrogen; R5 and R8 are selected from hydrogen, fluorine, chlorine, bromine or iodine respectively or simultaneously; R6 is selected from the fluorine, the chlorine, the bromine, the iodine, the hydrogen, alcoholate of C1-C3, alkyl of C1-C4, amidogen or a five-membered or six-membered nitrogenous heterocyclic ring; preferably, R7 is selected from the fluorine or the alcoholate of C1-C3, and the R5, the R6 and the R8 are the hydrogen. The compound has the broad antifungal physiological activity and can be used for preparing the broad-spectrum, low-toxicity and efficient antifungal drugs and plant fungicides for agriculture and gardening.
Description
Technical field
The present invention relates to the synthetic method of a kind of antimycotic sulphur chroman compound, this compound and in the application of preparing in antifungal drug.
Background technology
The diseases such as the ringworm of the foot, ringworm, candidiasis and crypotococcal result from fungi infestation more.In recent years, due to being widely used of Broad spectrum antibiotics, immunosuppressor and all kinds of hormone medicines, in addition the many reasons such as application and infected by HIV of the methods for the treatment of such as chemicotherapy, organ transplantation, cause human immune system's function reduction, the chance of fungal infection increases, and causes the M & M of Mycophyta disease constantly to rise.In addition, the problem such as resistance and narrow antimicrobial spectrum existing in clinical treatment, has also aggravated the treatment difficulty of fungi infestation disease.Therefore in the urgent need to the novel antifungal drugs of developing wide spectrum, efficient, low toxicity for clinical treatment.
Antifungal drug is divided into the classifications such as polyenoid class, nitrogen azole, allylamine and Thiourea conventionally, thiochromanone is the sulfur-bearing antifungal drug developing rapidly in recent years, research shows, it has stronger inhibition activity to several important pathogeny bacterium such as Cryptococcus neoformans, yeast, sporule silk bacterium, mould and trichophytons.The chemical structural formula of thiochromanone is:
For the antifungal drug of research and development high-efficiency low-toxicity, at present the structural modification of sulphur look (expiring) ketone is mainly concentrated to 1,3,4.Wherein, modify for 1 and generate sulphur look (expire) ketone 1,1-dioxide, 3 modifiers comprise beta-amino ketones compound, 3-benzyl-6-chlorine thiochromanone and 3-benzyl-thiochromanone, 4 modify current more be the modification of heteroatoms and amido-containing group.Through the above thiochromone derivative obtaining of modifying, its anti-mycotic activity has raising in various degree, or certain class fungi is had to higher activity.But sulphur look (expiring) ketone antifungal drug is far above in this, the present invention is according to the structure effect relation of sulphur look (expiring) ketone compounds, and further research acquisition anti-mycotic activity is more excellent, the more sulphur look of kind (expiring) ketone compounds.
Summary of the invention
The object of this invention is to provide a kind of sulphur chroman class antifungal compound, this compound all has stronger inhibition activity to common pathomycete and deep fungal, and has the features such as toxicity is low, good stability, anti-fungus spectra is wide, security is good.The present invention also provides the preparation method of this sulphur chroman class antifungal compound and the application in the medicine of preparing transplantation in treating systemic fungi infestation thereof.
A kind of sulphur chroman compound, chemical structure is suc as formula (I):
In formula (I):
Z is selected from sulphur (S), sulfinyl
or alkylsulfonyl
Y is selected from carbon or nitrogen;
R
6be selected from fluorine, chlorine, bromine, iodine, hydrogen, C
1-C
3-oxyl or C
1-C
4alkyl;
R
5, R
8respectively independently selected from hydrogen, fluorine, chlorine, bromine or iodine;
R
7be selected from fluorine, chlorine, bromine, iodine, hydrogen, C
1-C
3-oxyl, amino or be selected from following five yuan or hexa-atomic nitrogen heterocyclic ring:
Wherein:
W, V, M, G are respectively independently selected from hydrogen, C
1-C
4alkyl, hydroxyl, C
1-C
4-oxyl or amino, the one or more hydrogen in described amino can be by C
1-C
4alkyl replaces;
L is selected from hydrogen, C
1-C
4alkyl, hydroxyl or C
1-C
4-oxyl.
In described formula (I) sulphur chroman compound, preferred scheme is: Z is alkylsulfonyl; Y is selected from carbon or nitrogen; R7 is selected from fluorine or C
1-C
3-oxyl; R5, R6, R8 are hydrogen.
Sulphur chroman compound synthetic method of the present invention, press step:
Take formula II compound as raw material, in polar solvent, under the effect of hydride ion reductive agent, reaction acquisition formula (Ia) solid chemical compound, Z is selected from formula (I) the sulphur chroman compound product of sulphur; Described polar solvent is selected from least one in methyl-sulphoxide, ethanol, methyl alcohol, Virahol, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, water; Described hydride ion reductive agent is selected from sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, lithium aluminum hydride, aluminum isopropylate or diborane or their derivative, and its reaction formula is as follows:
Wherein Y is selected from carbon or nitrogen;
R
6be selected from fluorine, chlorine, bromine, iodine, hydrogen, C
1-C
3-oxyl or C
1-C
4alkyl;
R
5, R
8respectively independently selected from hydrogen, fluorine, chlorine, bromine or iodine;
R
7be selected from fluorine, chlorine, bromine, iodine, hydrogen, C
1-C
3-oxyl, amino or be selected from following five yuan or hexa-atomic nitrogen heterocyclic ring:
W, V, M, G are respectively independently selected from hydrogen, C
1-C
4alkyl, hydroxyl, C
1-C
4-oxyl or amino, the one or more hydrogen in described amino can be by C
1-C
4alkyl replaces.
By the formula of gained (Ia) compound elder generation and acetic anhydride, protection hydroxyl, then add the oxygenant of 0.9-1.1 equivalent, under the effect of oxygenant, there is oxidizing reaction, obtain oxo sulphur chroman compound, finally in sodium hydroxide solution, be hydrolyzed suc as formula the oxo sulphur chroman compound of (Ib), it is formula (I) the sulphur chroman compound product that Z is selected from sulfinyl; Described oxygenant is selected from Manganse Dioxide, hydrogen peroxide, benzoyl hydroperoxide, metachloroperbenzoic acid, magnesium monoperoxyphthalate or Peracetic Acid; Reaction formula is as follows:
By the formula of step 1 gained (Ia) compound elder generation and acetic anhydride, protection hydroxyl, then add oxygenants more than 2 equivalents, oxidizing reaction obtains oxo sulphur chroman compound, finally in sodium hydroxide solution, be hydrolyzed suc as formula (Ic) compound, be formula (I) the sulphur chroman compound product that Z is selected from alkylsulfonyl; Described oxygenant is selected from Manganse Dioxide, hydrogen peroxide, benzoyl hydroperoxide, metachloroperbenzoic acid, magnesium monoperoxyphthalate or Peracetic Acid; Reaction formula is as follows:
The invention provides described sulphur chroman compound the people of preparation treatment fungi infestation disease with the application in medicine or medicine for animal.
In described medicine, except containing activeconstituents sulphur chroman compound, also contain and pharmaceutically acceptable carrier, auxiliary agent and/or thinner composition composition.
The formulation of described medicine is solution, creme, suppository, ointment or solution.
The present invention also provides the application of described sulphur chroman compound as agricultural and horticultural bactericides.
In described sterilant, except containing activeconstituents sulphur chroman compound, also contain and pharmaceutically acceptable carrier, auxiliary agent and/or thinner composition composition.
By measuring minimum inhibitory concentration MIC (being the concentration of compound energy inhibition test microorganism growth), the anti-mycotic activity of sulphur chroman compound of the present invention is carried out to in-vitro evaluation.Test confirms, sulphur chroman compound of the present invention has broad-spectrum antifungal activity, in human body and animal (particularly Mammals) body, there is pharmacological activity, can mix mutually with the acceptable diluent or carrier of common chemotherapy, or with other vehicle, make the formulations such as solution, creme, suppository, ointment, solution, carry out partial smearing use with the form of medicine.Also can be simultaneously and other antiseptic-germicide, as mixing, amphotericin B, fungistatin, trichomycin, variotin or Mycosporin etc. use, there is obvious curative effect for fungi infestation disease.Except using or animal antifungal drug beyond the region of objective existence for the preparation of antimycotic people, sulphur chroman compound of the present invention also can be used for the bactericide of agricultural and gardening, to various phytopathogen diseases, as the hat rust of the rust of the powder mildew of the powder mildew of rice blast, barley and wheat and other various host plants (as cucumber, apple, grape), wheat, oat and other various hosts' rust, the control that the late blight of tomato and the pathogenicity bo of other host plants are rotted etc. is very effective.
Embodiment
Below by embodiment, foregoing of the present invention is further elaborated.It should be noted that, scope of the present invention is not limited by embodiment, and is as the criterion with claim.
Embodiment 1:3-(1H-1,2,4-triazol-1-yl) the synthetic preparation feedback formula of-4-hydroxyl sulphur chroman (formula I a1) is as follows:
Press step preparation:
Get 2-ethylmercapto group-3-(1H-1,2,4-triazol-1-yl) thiochromone compound 22.4mmol, be dissolved in 50% 50mL ethanol; 89.6mmol sodium borohydride is added in above-mentioned solution in batches, under room temperature, stir and spend the night, underpressure distillation is except desolventizing, and 50mL ethyl acetate and the extraction of 50mL water for solid, get ethyl acetate layer, wash with water twice (50mL × 2), reclaim organic layer evaporate to dryness, obtain formula (I a1) product 3-(1H-1,2,4-triazol-1-yl)-4-hydroxyl sulphur chroman 19.3mmol, yield 86%.
1H NMR(CDCl
3):8.77(s,1H),8.06(s,1H),7.26-7.32(m,3H),7.14(t,1H),5.17(d,1H),4.50(d,1H),4.42-4.44(m,1H),3.30-3.34(m,1H),3.06-3.08(m,1H).
Embodiment 2-embodiment 19: (I is the preparation of sulphur chroman compound a) for formula
Take formula II compound as raw material, prepare product formula (I is compound (target product is the each compound of formula (I a2)～formula (I a19) in table 1) a), and reaction formula is as follows:
Preparation process is as follows:
Get 22.4mmol formula II compound and be dissolved in polar solvent, 89.6mmol reductive agent is added in solution in batches, under room temperature, stir and spend the night, by embodiment 1 method processing, obtain the each sulphur chroman compound of formula (I a2)～formula (I a19).
In embodiment 2～embodiment 19, product formula (select and prepare with reagent and detect data and all list in table 1 by I a) the each group of sulphur chroman compound.
Table 1
Embodiment 20:3-(1H-1,2,4-triazol-1-yl)-4-hydroxyl-1-sulfur oxide chroman synthetic
With 3-(1H-1,2,4-triazol-1-yl)-4-hydroxyl sulphur chroman is raw material, prepares target product (I b1) sulphur chroman compound.
Preparation feedback formula is as follows:
Preparation process is as follows:
Get raw material 3-(1H-1,2,4-triazol-1-yl)-4-hydroxyl sulphur chroman 19.3mmol, add in 35mL diacetyl oxide solvent, there is acetylization reaction protection hydroxyl, reaction finishes rear underpressure distillation and removes diacetyl oxide solvent.Add 30mL saturated sodium bicarbonate solution and 30mL ethyl acetate, isolate ethyl acetate layer; Water layer is with merging organic layer after the extraction of 20mL ethyl acetate, at room temperature drip wherein again the hydrogen peroxide 3.4g(20mmol of 30% concentration) generation oxidizing reaction, reaction finishes rear use respectively 10mL saturated sodium bisulfite solution and 30mL water washing, separates organic layer evaporate to dryness.Finally add the sodium hydroxide solution of 20mL20% concentration and the mixed solution of 20mL ethanol, heating hydrolysis at 50 ℃, solvent evaporated after complete reaction, with getting organic layer after 20mL water and the washing of 20mL ethyl acetate, after evaporate to dryness, obtain product sulfoxide compound 3-(1H-1,2,4-triazol-1-yl)-4-hydroxyl-1-sulfur oxide chroman (13.8mmol), yield 72%.
1H NMR(CDCl
3):8.71(s,1H),8.03(s,1H),7.51-7.55(m,3H),7.38(t,1H),5.19(s,1H),4.55(d,1H),4.18-4.22(m,1H),3.30-3.34(m,1H),3.09-3.13(m,1H).
Embodiment 21-embodiment 38: sulfoxide type sulphur chroman (b) synthetic of I
Take formula (I a) sulphur chroman compound as raw material, prepare general formula (I b) sulphur chroman compound product (target product is the formula I b2～formula I b19 in table 2, and preparation process is with embodiment 20.Reaction formula is as follows:
The formula of embodiment 21～embodiment 38 (select and prepare with reagent and detect data and all list in table 2 by I b) the each group of sulphur chroman compound.
Table 2
Embodiment 39:3-(1H-1,2,4-triazol-1-yl)-4-hydroxyl-1,1-sulfurous gas chroman (formula I c1) synthetic
With 3-(1H-1,2,4-triazol-1-yl)-4-hydroxyl sulphur chroman is raw material, prepares target product (I c1) compound, reaction formula is as follows:
By 3-(1H-1,2,4-triazol-1-yl)-4-hydroxyl sulphur chroman (19.3mmol) adds in 35mL diacetyl oxide solvent, and acetylization reaction protection hydroxyl occurs, and reaction finishes rear underpressure distillation and removes diacetyl oxide solvent.Add saturated sodium bicarbonate 30mL solution and ethyl acetate 30mL, separate ethyl acetate layer, water layer is with merging organic layer after the extraction of 20mL ethyl acetate, at room temperature drip wherein again 30% excessive hydrogen peroxide 13.6g(80mmol) generation oxidizing reaction, reaction finishes rear use respectively 10mL saturated sodium bisulfite solution and 30mL water washing, separates organic layer evaporate to dryness.Finally add the sodium hydroxide solution of 20mL20% and the mixed solution of 20mL ethanol, heating hydrolysis at 50 ℃, solvent evaporated after complete reaction, with getting organic layer after 20mL water and the washing of 20mL ethyl acetate, after evaporate to dryness, obtain sulfone compound 3-(1H-1,2,4-triazol-1-yl)-4-hydroxyl-1,1-sulfurous gas chroman (14.1mmol), yield 73%.
1H NMR(CDCl
3):8.73(s,1H),8.09(s,1H),7.81(d,1H),7.68(d,1H),7.51(t,1H),7.35(t,1H),5.19(s,1H),4.45(d,1H),4.19-4.24(m,1H),3.96-4.01(m,1H),3.79-3.84(m,1H).
Embodiment 40～embodiment 57: sulfone class sulphur chroman (c) synthetic of formula I
Take formula, (a) sulphur chroman compound is as raw material for I, and by embodiment 39 same procedure, (I is sulphur chroman compound product (object product is the formula I c2～formula I c19 in table 3) c) to prepare general formula.Reaction formula is as follows:
The formula of embodiment 40～embodiment 57 (select and prepare with reagent and detect data and all list in table 3 by I c) the each group of sulphur chroman compound.
Table 3
Embodiment 58: extracorporeal antifungal activity experiment
1, test bacterial strain
Candida parapsilosis, sporothrix, saccharomyces cerevisiae aspergillus tubigensis,, Candida albicans, Candida glabrata, Oidium tropicale, trichophyton, Penicillium notatum, Trichophyton verrucosum, Trichophyton violaceum, cryptococcus neoformans, gram Rou Shi candidiasis, acrothesium floccosum, trichophyton gypseum.
2, reagent and material
Test material:
Improvement Martin substratum, 96 well culture plates, DMSO
Control drug: fluconazole
3, test method
(1) preparation of antibacterial liquid
Tested medicine is dissolved with DMSO respectively, be made into the solution of 25.6g/L, save backup below in one 20 ℃.Before test, the tested liquid of deepfreeze is taken out, in 35 ℃ of thermostat containers, melt, with 10 times of RPMI1640 dilutions, for subsequent use.
(2) preparation of inoculation liquid
Each tested beads bacterial strain (Candida albicans, Candida glabrata, Oidium tropicale, Candida parapsilosis) is transferred species on improvement Martin substratum, and being used massfraction is that 0.85% Sterile Saline is made suspension.Count spore with blood cell counting plate, adjust bacteria containing amount, making colony forming unit is 1 × 10
6～5 × 10
6cFU/mL.When inoculation, diluted after 200 times with RPMI-1640 nutrient solution, 10 times of redilution, CFU value is adjusted to 0.5 × 10
3～6.0 × 10
3cFU/mL, for subsequent use.
(3) preparation of MIC plate
Under aseptic technique, add RPMI-1640 nutrient solution 100 μ L in No. 1 hole of 96 hole polystyrene plates of sterilizing, as blank.No. 2 hole adds bacterium liquid 190 μ L, and 3-12 hole adds the bacterium liquid 100 μ L that configure.Then in No. 2 holes, add the tested liquid of 10 μ L, by the concentration in 10 grades of doubling dilution 2-11 holes, the ultimate density that makes each hole is 128,64,32,16,8,4,2,1,0.5,0.25mg/L, and No. 12 hole does not add tested liquid as growth control.Each MIC plate is airtight to be placed in 35 ℃ of normal air incubators, hatches full 24h judged result.
(4) result judgement
The OD value of surveying each hole with enzyme micro-plate reader in 620nm, the minimum concentration declining more than 80% using OD value is as MIC value.When MIC value is counted ﹥ 128mg/L during higher than 128mg/L; As MIC value count≤0.25mg/L during lower than 0.25mg/L.
(5) repeated observation and statistics
Above-mentioned test needs at least in triplicate, in the time there is the single jumping of MIC value hole, is recorded as maximum anti-bacteria concentration, in the time that MIC value occurs that two or more jump hole, re-starts test.
4, antimycotic sensitivity test result
Measure and find by preliminary MIC, test-compound has broad-spectrum antifungal activity, wherein the sulphur chroman compound Antifungi activity of embodiment 1, embodiment 4, embodiment 5, example 9, embodiment 10, embodiment 11, embodiment 13, embodiment 14, embodiment 15, embodiment 20～embodiment 57 is more remarkable, and the MIC value of above strain subject is all less than to 2mg/L.
Claims (10)
1. a sulphur chroman compound, it is characterized in that chemical structure suc as formula (
):
Formula (
) in:
Z be selected from sulphur (S), sulfinyl (
) or alkylsulfonyl (
);
Y is selected from carbon or nitrogen;
R
6be selected from fluorine, chlorine, bromine, iodine, hydrogen, C
1-C
3-oxyl or C
1-C
4alkyl;
R
5, R
8respectively independently selected from hydrogen, fluorine, chlorine, bromine or iodine;
R
7be selected from fluorine, chlorine, bromine, iodine, hydrogen, C
1-C
3-oxyl, amino or be selected from following five yuan or hexa-atomic nitrogen heterocyclic ring:
；
Wherein:
W, V, M, G are respectively independently selected from hydrogen, C
1-C
4alkyl, hydroxyl, C
1-C
4-oxyl or amino, the one or more hydrogen in described amino can be by C
1-C
4alkyl replace;
L is selected from hydrogen, C
1-C
4alkyl, hydroxyl or C
1-C
4-oxyl.
2. sulphur chroman compound according to claim 1, it is characterized in that described formula (
) in sulphur chroman compound, Z is alkylsulfonyl; Y is selected from carbon or nitrogen; R7 is selected from fluorine or C
1-C
3-oxyl; R5, R6, R8 are hydrogen.
3. a sulphur chroman compound synthetic method for claim 1, is characterized in that according to the following steps:
Take formula II compound as raw material, in polar solvent, under the effect of hydride ion reductive agent, reaction acquisition formula (
a) solid chemical compound, Z be selected from sulphur formula (
) sulphur chroman compound product; Described polar solvent is selected from least one in methyl-sulphoxide, ethanol, methyl alcohol, Virahol, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, water; Described hydride ion reductive agent is selected from sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, lithium aluminum hydride, aluminum isopropylate or diborane or their derivative, and its reaction formula is as follows:
Wherein, Y is selected from carbon or nitrogen;
R
6be selected from fluorine, chlorine, bromine, iodine, hydrogen, C
1-C
3-oxyl or C
1-C
4alkyl;
R
5, R
8respectively independently selected from hydrogen, fluorine, chlorine, bromine or iodine;
R
7be selected from fluorine, chlorine, bromine, iodine, hydrogen, C
1-C
3-oxyl, amino or be selected from following five yuan or hexa-atomic nitrogen heterocyclic ring:
W, V, M, G are respectively independently selected from hydrogen, C
1-C
4alkyl, hydroxyl, C
1-C
4-oxyl or amino, the one or more hydrogen in described amino can be by C
1-C
4alkyl replaces.
4. sulphur chroman compound synthetic method according to claim 3, it is characterized in that by the formula of gained (
a) compound elder generation and acetic anhydride, protection hydroxyl, then adds the oxygenant of 0.9-1.1 equivalent, under the effect of oxygenant, oxidizing reaction occurs, and obtains oxo sulphur chroman compound, finally in sodium hydroxide solution, be hydrolyzed suc as formula (
b) oxo sulphur chroman compound, its be the formula that Z is selected from sulfinyl (
) sulphur chroman compound product; Described oxygenant is selected from Manganse Dioxide, hydrogen peroxide, benzoyl hydroperoxide, metachloroperbenzoic acid, magnesium monoperoxyphthalate or Peracetic Acid; Reaction formula is as follows:
。
5. sulphur chroman compound synthetic method according to claim 3, it is characterized in that by the formula of step 1 gained (
a) compound elder generation and acetic anhydride, protection hydroxyl, then add oxygenants more than 2 equivalents, oxidizing reaction obtains oxo sulphur chroman compound, finally in sodium hydroxide solution, be hydrolyzed suc as formula (
c) compound, be the formula that Z is selected from alkylsulfonyl (
) sulphur chroman compound product; Described oxygenant is selected from Manganse Dioxide, hydrogen peroxide, benzoyl hydroperoxide, metachloroperbenzoic acid, magnesium monoperoxyphthalate or Peracetic Acid; Reaction formula is as follows:
。
Described in a claim 1 or 2 sulphur chroman compound the people of preparation treatment fungi infestation disease with the application in medicine or medicine for animal.
7. application according to claim 6, is characterized in that in described medicine, except containing activeconstituents sulphur chroman compound, also containing pharmaceutically acceptable carrier, auxiliary agent and/or thinner, composition composition.
8. application according to claim 7, the formulation that it is characterized in that described medicine is solution, creme, suppository, ointment or solution.
Described in a claim 1 or 2 sulphur chroman compound as agricultural and the application of horticultural bactericides.
10. application according to claim 9, is characterized in that in described sterilant, except containing activeconstituents sulphur chroman compound, also containing pharmaceutically acceptable carrier, auxiliary agent and/or thinner, composition composition.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107118204A (en) * | 2017-06-13 | 2017-09-01 | 南京工业大学 | A kind of 3- azacyclo-s Thiochromone compound and its synthetic method and the application in antifungal drug |
| CN107556296A (en) * | 2017-09-06 | 2018-01-09 | 南京工业大学 | A kind of 2- hydroxyls -3- azacyclo-s chromone compounds and its synthetic method and the application in antifungal drug |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3682899A (en) * | 1969-06-20 | 1972-08-08 | Meiji Seika Kaisha | 1-oxo - 3-benzal-thiochromanone derivatives and a process for the production of these compounds |
| US4007203A (en) * | 1973-12-04 | 1977-02-08 | Warner-Lambert Company | 4-(1-Pyrolidenyl)-2H-1-benzothiopyran-3-carboxanilide |
| US4703057A (en) * | 1985-10-04 | 1987-10-27 | Adir Et Compagnie | Beta-blocking thiochroman derivatives, compositions and method of use therefor |
| US5403842A (en) * | 1992-02-25 | 1995-04-04 | Recordati S.A., Chemical And Pharmaceutical Company | Benzopyran and benzothiopyran derivatives |
| US6716834B2 (en) * | 2000-05-16 | 2004-04-06 | Astrazeneca Ab | Thiochromane derivatives and their use as thrombin inhibitors |
| CN101519402A (en) * | 2009-04-13 | 2009-09-02 | 南京工业大学 | Thiochromone compound, synthetic method and application thereof in preparing antifungal medicaments |
-
2014
- 2014-03-11 CN CN201410087557.3A patent/CN103819464B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3682899A (en) * | 1969-06-20 | 1972-08-08 | Meiji Seika Kaisha | 1-oxo - 3-benzal-thiochromanone derivatives and a process for the production of these compounds |
| US4007203A (en) * | 1973-12-04 | 1977-02-08 | Warner-Lambert Company | 4-(1-Pyrolidenyl)-2H-1-benzothiopyran-3-carboxanilide |
| US4703057A (en) * | 1985-10-04 | 1987-10-27 | Adir Et Compagnie | Beta-blocking thiochroman derivatives, compositions and method of use therefor |
| US5403842A (en) * | 1992-02-25 | 1995-04-04 | Recordati S.A., Chemical And Pharmaceutical Company | Benzopyran and benzothiopyran derivatives |
| US6716834B2 (en) * | 2000-05-16 | 2004-04-06 | Astrazeneca Ab | Thiochromane derivatives and their use as thrombin inhibitors |
| CN101519402A (en) * | 2009-04-13 | 2009-09-02 | 南京工业大学 | Thiochromone compound, synthetic method and application thereof in preparing antifungal medicaments |
Non-Patent Citations (3)
| Title |
|---|
| SAEED EMAMI, ET AL.,: "Stereoselective Synthesis and in Vitro Antifungal Evaluation of (E)- and (Z)-Imidazolylchromanone Oxime Ethers.", 《ARCH. PHARM. PHARM. MED. CHEM.》, 31 December 2002 (2002-12-31), pages 318 - 324 * |
| 田欣，肖涛.: "色酮及硫色酮类化合物的合成进展.", 《化学试剂》, vol. 36, no. 2, 15 February 2014 (2014-02-15), pages 125 - 130 * |
| 马正月: "硫色满酮衍生物的合成及其生物活性研究.", 《中国博士学位论文全文数据库 工程科技I辑》, no. 1, 15 January 2012 (2012-01-15), pages 8 - 10 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107118204A (en) * | 2017-06-13 | 2017-09-01 | 南京工业大学 | A kind of 3- azacyclo-s Thiochromone compound and its synthetic method and the application in antifungal drug |
| CN107118204B (en) * | 2017-06-13 | 2020-07-10 | 南京工业大学 | 3-azacyclo-thiochromanone compound, synthesis method thereof and application thereof in antifungal drugs |
| CN107556296A (en) * | 2017-09-06 | 2018-01-09 | 南京工业大学 | A kind of 2- hydroxyls -3- azacyclo-s chromone compounds and its synthetic method and the application in antifungal drug |
| CN107556296B (en) * | 2017-09-06 | 2020-10-02 | 南京工业大学 | 2-hydroxy-3-azacyclo chromone compound, synthetic method thereof and application thereof in antifungal drugs |
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| CN103819464B (en) | 2015-10-07 |
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