CN1071952A - 抗真菌剂 - Google Patents
抗真菌剂 Download PDFInfo
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- CN1071952A CN1071952A CN92111332A CN92111332A CN1071952A CN 1071952 A CN1071952 A CN 1071952A CN 92111332 A CN92111332 A CN 92111332A CN 92111332 A CN92111332 A CN 92111332A CN 1071952 A CN1071952 A CN 1071952A
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- Prior art keywords
- xanthofulvin
- salt
- tautomer
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- chs
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- 239000003429 antifungal agent Substances 0.000 title description 4
- VZJACTNXARYXEM-NHDPSOOVSA-N 5-acetyl-7-[(z)-(5-carboxy-6,7-dihydroxy-4-oxochromen-3-ylidene)-hydroxymethyl]-2,3-dihydroxy-6-methyl-9-oxoxanthene-1-carboxylic acid Chemical compound C\1OC2=CC(O)=C(O)C(C(O)=O)=C2C(=O)C/1=C(\O)C1=CC(C(C2=C(C(O)=O)C(O)=C(O)C=C2O2)=O)=C2C(C(=O)C)=C1C VZJACTNXARYXEM-NHDPSOOVSA-N 0.000 claims abstract description 40
- VZJACTNXARYXEM-UHFFFAOYSA-N xanthofulvin Natural products C1OC2=CC(O)=C(O)C(C(O)=O)=C2C(=O)C1=C(O)C1=CC(C(C2=C(C(O)=O)C(O)=C(O)C=C2O2)=O)=C2C(C(=O)C)=C1C VZJACTNXARYXEM-UHFFFAOYSA-N 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims description 17
- 241000228143 Penicillium Species 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 8
- 244000005700 microbiome Species 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 5
- 241000233866 Fungi Species 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims 5
- 239000008194 pharmaceutical composition Substances 0.000 claims 4
- 239000012752 auxiliary agent Substances 0.000 claims 2
- 206010061217 Infestation Diseases 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 241000228168 Penicillium sp. Species 0.000 abstract description 3
- 230000001857 anti-mycotic effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 101150026868 CHS1 gene Proteins 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 101150085479 CHS2 gene Proteins 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 102000005469 Chitin Synthase Human genes 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 5
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 5
- 230000001580 bacterial effect Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 229920001817 Agar Polymers 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 239000008272 agar Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 108700040089 Chitin synthases Proteins 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 3
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 3
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 229940041514 candida albicans extract Drugs 0.000 description 3
- 238000000855 fermentation Methods 0.000 description 3
- 230000004151 fermentation Effects 0.000 description 3
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229950006780 n-acetylglucosamine Drugs 0.000 description 3
- 239000000049 pigment Substances 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000012138 yeast extract Substances 0.000 description 3
- 229920002101 Chitin Polymers 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 241001480581 Marasmius Species 0.000 description 2
- 239000001888 Peptone Substances 0.000 description 2
- 108010080698 Peptones Proteins 0.000 description 2
- JPFWJDMDPLEUBD-UHFFFAOYSA-N Polyoxin D Natural products OC1C(O)C(C(NC(=O)C(C(O)C(O)COC(N)=O)N)C(O)=O)OC1N1C(=O)NC(=O)C(C(O)=O)=C1 JPFWJDMDPLEUBD-UHFFFAOYSA-N 0.000 description 2
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 2
- 108700006921 chitin synthase 2 Proteins 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 210000000416 exudates and transudate Anatomy 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 235000012204 lemonade/lime carbonate Nutrition 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000000877 morphologic effect Effects 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 235000019319 peptone Nutrition 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- JPFWJDMDPLEUBD-ITJAGOAWSA-N polyoxorim Polymers O[C@@H]1[C@H](O)[C@@H]([C@H](NC(=O)[C@H]([C@H](O)[C@@H](O)COC(N)=O)N)C(O)=O)O[C@H]1N1C(=O)NC(=O)C(C(O)=O)=C1 JPFWJDMDPLEUBD-ITJAGOAWSA-N 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 101710164537 Chitin synthase 1 Proteins 0.000 description 1
- 229940123277 Chitin synthase inhibitor Drugs 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- QRLVDLBMBULFAL-UHFFFAOYSA-N Digitonin Natural products CC1CCC2(OC1)OC3C(O)C4C5CCC6CC(OC7OC(CO)C(OC8OC(CO)C(O)C(OC9OCC(O)C(O)C9OC%10OC(CO)C(O)C(OC%11OC(CO)C(O)C(O)C%11O)C%10O)C8O)C(O)C7O)C(O)CC6(C)C5CCC4(C)C3C2C QRLVDLBMBULFAL-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 101001018064 Homo sapiens Lysosomal-trafficking regulator Proteins 0.000 description 1
- 101000667110 Homo sapiens Vacuolar protein sorting-associated protein 13B Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 102100033472 Lysosomal-trafficking regulator Human genes 0.000 description 1
- 241000046866 Metula Species 0.000 description 1
- 229930182764 Polyoxin Natural products 0.000 description 1
- 108010076039 Polyproteins Proteins 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 241001558929 Sclerotium <basidiomycota> Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 101710162629 Trypsin inhibitor Proteins 0.000 description 1
- 229940122618 Trypsin inhibitor Drugs 0.000 description 1
- LFTYTUAZOPRMMI-CFRASDGPSA-N UDP-N-acetyl-alpha-D-glucosamine Chemical compound O1[C@H](CO)[C@@H](O)[C@H](O)[C@@H](NC(=O)C)[C@H]1OP(O)(=O)OP(O)(=O)OC[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C(NC(=O)C=C2)=O)O1 LFTYTUAZOPRMMI-CFRASDGPSA-N 0.000 description 1
- LFTYTUAZOPRMMI-UHFFFAOYSA-N UNPD164450 Natural products O1C(CO)C(O)C(O)C(NC(=O)C)C1OP(O)(=O)OP(O)(=O)OCC1C(O)C(O)C(N2C(NC(=O)C=C2)=O)O1 LFTYTUAZOPRMMI-UHFFFAOYSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- BOXNENYOGRMVAM-UHFFFAOYSA-L [Na+].[Na+].[O-]P([O-])(Cl)=O Chemical compound [Na+].[Na+].[O-]P([O-])(Cl)=O BOXNENYOGRMVAM-UHFFFAOYSA-L 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229940043232 butyl acetate Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- UVYVLBIGDKGWPX-KUAJCENISA-N digitonin Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)C[C@@H](O)[C@H](O[C@H]5[C@@H]([C@@H](O)[C@@H](O[C@H]6[C@@H]([C@@H](O[C@H]7[C@@H]([C@@H](O)[C@H](O)CO7)O)[C@H](O)[C@@H](CO)O6)O[C@H]6[C@@H]([C@@H](O[C@H]7[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O7)O)[C@@H](O)[C@@H](CO)O6)O)[C@@H](CO)O5)O)C[C@@H]4CC[C@H]3[C@@H]2[C@@H]1O)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 UVYVLBIGDKGWPX-KUAJCENISA-N 0.000 description 1
- UVYVLBIGDKGWPX-UHFFFAOYSA-N digitonine Natural products CC1C(C2(CCC3C4(C)CC(O)C(OC5C(C(O)C(OC6C(C(OC7C(C(O)C(O)CO7)O)C(O)C(CO)O6)OC6C(C(OC7C(C(O)C(O)C(CO)O7)O)C(O)C(CO)O6)O)C(CO)O5)O)CC4CCC3C2C2O)C)C2OC11CCC(C)CO1 UVYVLBIGDKGWPX-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002085 enols Chemical group 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000013882 gravy Nutrition 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000002000 high resolution fast-atom bombardment mass spectrometry Methods 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 150000004715 keto acids Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013379 molasses Nutrition 0.000 description 1
- OTKCDFNVBPBSNB-UHFFFAOYSA-N nitric acid;propane-1,2,3-triol Chemical compound O[N+]([O-])=O.OCC(O)CO OTKCDFNVBPBSNB-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000006916 nutrient agar Substances 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- YEBIHIICWDDQOL-YBHNRIQQSA-N polyoxin Polymers O[C@@H]1[C@H](O)[C@@H](C(C=O)N)O[C@H]1N1C(=O)NC(=O)C(C(O)=O)=C1 YEBIHIICWDDQOL-YBHNRIQQSA-N 0.000 description 1
- 238000000247 postprecipitation Methods 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000012716 precipitator Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 229940001516 sodium nitrate Drugs 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
- C07D311/82—Xanthenes
- C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
- C07D311/86—Oxygen atoms, e.g. xanthones
-
- 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
- A61P31/04—Antibacterial agents
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/8215—Microorganisms
- Y10S435/911—Microorganisms using fungi
- Y10S435/933—Penicillium
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Pharmacology & Pharmacy (AREA)
- Communicable Diseases (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Pyrane Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
具有上式的黄褐霉素得自正青霉属的培养物。
该化合物具有抗真菌活性。
Description
本发明涉及式Ⅰ的新化合物(以下称作黄褐霉素(Xanthofulvin))或其盐。
黄褐霉素也以式Ⅰa的互变形式存在。
外观:黄色结晶
熔点:249~251℃(分解)
分子式:C28H18O14
*HRFAB-MS(m/z)(M+H)+:
计算值:579.0775
实测值:579.0786
UV λmaxnm(ε):
在甲醇中 239 (33,600), 317 (20,400),
400 (17,800)
在甲醇H/1N HCl(100:1)中 240 (30,900), 313 (25,000),
365 (17,900)
在甲醇 /1N NaOH(100:1)中 233 (35,400), 383 (31,000)
IR Vmax(KBr) cm-1: 3430, 1700, 1600, 1480, 1360,
1280
溶解性: 溶于二甲亚砜、甲醇
微溶于水
不溶于正己烷
1H NMR (400 MHz, 2.37 (3H,s), 2.72 (3H,s),
CD3OD/CDCl3/DMSO-d64.67 (2H,br s), 6.43 (1H,s),
(2:1:1) 6.97 (1H,s), 8.03 (1H,s)
用TMS作内标)δ:
13C NMR (100 MHz, 16.8, 32.4, 66.6, 102.9, 103.5,
CD3OD/CDCl3/DMSO-d6104.9, 110.3, 110.8, 119.2, 120.2,
(2:1:1) 121.1, 126.6, 130.0, 132.6, 139.1,
用TMS作内标)δ: 139.3, 141.6, 151.0, 152.4, 154.1,
154.7, 156.5, 168.6, 168.8, 171.1,
173.6, 184.4, 202.5
*HRFAB-MS:高分辨快原子轰击质谱
按照本发明所提供的方法,黄褐霉素是如下生产的:在需氧条件下,于含水培养基中,培养一种属于正青霉属(Eupenicillium)的能产生黄褐霉素的微生物,并从培养物中分离出黄褐霉素。
用于上述方法中的微生物可以是属于能产生黄褐霉素的正青霉属的任何菌株(包括变种)。特别优选的菌株是正青霉 NR 7125及其变种。正青霉 NR 7125直接分离自采自日本东京八丈岛的小皮伞属(Marasmius)的子实体,且被鉴定为属于正青霉属。
定名为正青霉NR 7125的菌株已于1991年9月30日按照《布达佩斯条约》保藏在日本工业科技局发酵研究所,保藏号为FERM-BP3588。正青霉 NR 7125(FERM-BP3588)的培养特征和形态特征如下:
培养特征
在查氏酵母提取物琼脂培养基(CYA)上,菌落快速生长,在25℃下7天内达到直径为42-45毫米,显示出絮状外观并起辐射状皱纹。菌丝体是白色的。分生孢子发生和子囊果形成不显著,以致不能影响菌落的颜色。不产生渗出物或可溶性色素。反面呈淡黄色(乳黄,芒塞尔颜色体系,2.5Y 9/4)。
在麦芽汁琼脂培养基(MEA)上,菌落快速生长,7天后达到直径为37-40毫米,显示絮状外观,菌丝体是白色的。分生孢子发生显著,特别是在菌落的中心区域,显示柔和的蓝绿色(芒塞尔颜色体系,2.5BG7/4)。在琼脂的表面,有丰富的子囊果形成。没有渗出物或可溶性色素。反面呈浅黄色(乳黄,芒塞尔颜色体系,5Y 9/2)。
在25%甘油-硝酸盐琼脂(G-25N)上。菌落生长缓慢,呈致密绒状,在25℃下7天内达到直径为16-17.5毫米。分生孢子的生成不显著。菌丝体是白色的。反面呈乳黄色。琼脂内不存在色素。
在37℃于CYA上,菌落快速生长,达到直径为29-33毫米。
形态特征
分生孢子梗自表面菌丝或气生菌丝长出,平滑且薄壁,一般为细长形,长度为100-250微米。通常它们终止于有3-5个瓶梗的一轮孢子上(单轮生的),但有时带一或两个,少数为3个梗基(双轮生的),梗基大部分是长形和分叉的,10-20×2-3微米。瓶梗呈安瓿状,8-12×2-3.5微米,到带顶端分生孢子的部分陡然尖削。分生孢子最常见的是近球形,2.9-3.6×2.7-3.3微米,带有粗糙的疣状壁,且长成短链。子囊果是假薄壁组织的闭囊壳,直径为100-250微米,变成白色至乳色的,具有菌核状但柔软的质地,在三周内成熟。子囊单个生长,椭圆形,直径8.4-11.7×6.8-7.2微米。子囊孢子是透明的,近球形至宽椭圆形,直径2.9-3.5×2.6-3.1微米,带有具小刺但无翼的壁。
子囊果是菌核状的,被假薄壁组织的壁所包围。在CYA和MEA上容易观察到青霉变形。这些特征清楚地表明,该菌株NR 7125(FERM-BP 3588)包括在正青霉属之内。因此,该菌株被鉴定为正青霉NR7125。
按照本发明提供的方法,培养可以在培养基内进行,该培养基含有可被所培养的微生物利用的常见营养物。可以提到的碳源有,例如葡萄糖、蔗糖、淀粉、甘油、糖蜜、糊精及其混合物。氮源有,例如大豆粉、棉子粉、肉汁、蛋白胨、干酵母、酵母提取物、玉米浸液、硫酸铵、硝酸钠及其混合物。此外,可以向培养基内加进其他有机或无机物质,以促进微生物的生长,并增加黄褐霉素的产量,
此处所用的术语黄褐霉素指的是烯醇式及二酮式互变体。
本发明也涉及生产黄褐霉素的方法、能生产黄褐霉素的微生物以及几丁质合酶2的抑制组合物。
几丁质系一线性的N-乙酰葡萄糖胺均聚物,通常在真菌细胞内发现,且广泛分布于几乎所有的真菌属中。几丁质是真菌细胞壁的次要但必需的成分,它并不存在于哺乳动物细胞内,所以它已被认为是抗真菌剂的最具有吸引力的靶子之一,尽管迄今没有发现几种抑制剂。多氧霉素和烟雾素作为几丁质合酶抑制剂是公知的,但尚未发现其临床应用。然而,这些化合物仍引起很大关注,因为它对几丁质合酶的抑制活性特异而强烈。最近鉴定出三种酿酒酵母的几丁质合酶(几丁质合酶1、2和3),其中几丁质合酶2(Chs 2)被证明是三者中间最关键的(N.H.Valdivieso,P.C.Mol,J.A.Shaw,E.Cabib and A.Duran.J.Cell Biol.,114,101-109(1991);J.W.Shaw,P.C.Mol,B.Bowers,S.J.Silverman,M.H.Valdivieso,A.Duran and E.Cabib.J.Cell Biol.,114,111-123(1991))。发现多氧霉素D和烟霉素X能抑制几丁质合酶1(Chs 1),而不抑制Chs 2(E.Cabib.Antimicrob.Agents Chemother.,35,170-173(1991))。
按照本发明,发现某些特定微生物能产生具有高度Chs-2抑制活性的新化合物(此处称之为黄褐霉素)。按下文所给出的实例所述得到的黄褐霉素的物化性质如下:
这类物质的实例是无机盐,例如碳酸钙、氯化钠、磷酸盐等等。
培养在需氧条件下于含水培养基中进行,优选深层发酵。培养适宜在20°-35℃的温度进行,最佳温度为27℃。最好在pH为3-9时进行培养。培养时间随培养进行时的条件而定。通常进行50-200小时培养就足够了。
可以按照本来已知的方法,将黄褐霉素从发酵液内分离出来。例如,通过离心或过滤,可将菌丝体从发酵液内分离出来,可用与水不相混溶的有机溶剂,例如链烷醇(如正丁醇)及酯类(如乙酸乙酯、乙酸丁酯等),从滤液中提取黄褐霉素。另一方面,可以获得在分离出的菌丝体内所含有的黄褐霉素,例如,用含水丙酮或含水甲醇之类的溶剂提取菌丝体,然后除去溶剂,进一步用与水不相混溶的有机溶剂提取残渣。如此得到的溶剂相用诸如硫酸钠等干燥剂干燥,而后减压浓缩。生成的黄褐霉素粗品可用提取法、分配法、沉淀法、柱层析法(用硅胶、氧化铝等作吸附剂)或用分子筛法纯化。
黄褐霉素是作为游离酸被分离出来的,但如有需要,能通过常规方法将其转变为可药用的盐类,例如钠盐、钾盐和钙盐。
分别测定黄褐霉素对酿酒酵母Chs 1和Chs 2的抑制活性。
(1)对Chs 1的抑制活性
用于生产Chs 1的过量生产细胞是携有质粒(CHS1,URA3)的酿酒酵母(ura 3)。用0.5%洋地黄皂苷在30℃下处理15分钟使细胞具有渗透性,接着用终浓度为100微克/毫升的胰蛋白酶于30℃下处理15分钟。加入大豆胰蛋白酶抑制剂后,取50微升2.5×107个细胞/毫升,与40微升测定溶液和10微升样品溶液一起于30℃下保温1小时,测定溶液中含有50mM MES(pH 6.5)、5mM Mg(OAc)2、32mM N-乙酰基葡糖胺和0.1mM[14C]-UDP-N-乙酰基葡糖胺。加入TCA使反应终止,在滤器上收集细胞,用含有0.3M乙酸的70%乙醇水溶液洗涤。用液体闪烁计数器对细胞的放射性计数。根据结合到细胞上的放射性,测定所形成的几丁质的量(S.J.Silverman,A.Sburlati,M.J.Slater和E.Cabib.Proc.Natl.Acad.Sci.USA,85,4735-4739(1988))。黄褐霉素对Chs 1的抑制活性示于表1。
(2)黄褐霉素对Chs 2 的抑制活性
用于生产Chs 2的过量生产细胞是带有质粒(CHS 1,LEU 2)的破裂Chs 1基因(chs 1∶∶URA 3,ura 3,Leu 2)的酿酒酵母菌株。除测定溶液外,测定方法与上述用于Chs 1的方法相同。用于Chs 2的测定溶液含有30mM Tris(pH7.5)、2.5mM Co(OAc)2、32mM N-乙酰基葡糖胺和0.1mM[14C]-UDP-N-乙酰基葡糖胺(见Silverman等人,同上)。黄褐霉素的抑制活性示于表1。
表 1IC50(μM)
Chs1 Chs2
黄褐霉素 >200 2.2
多氧霉素D 0.26 10.3
如以上表1所示,黄褐霉素具有高度的Chs 2抑制活性。这样,黄褐霉素能用作抗真菌剂,例如,用来治疗念珠菌感染(念珠菌病)。
未观察到黄褐霉素的急性毒性。
本发明所提供的新的黄褐霉素及其盐能用作药物,例如制成含有这类化合物及其盐类的药物制剂的形式,药物制剂中混合有适于经肠给药的有机或无机惰性载体物质,例如水、明胶、阿拉伯树胶、乳糖、淀粉、硬脂酸镁、滑石、植物油、聚亚烷基二醇等。药物制剂可以固态形式存在,例如片剂、糖衣丸或胶囊;或以液态形式存在,例如溶液或悬浮液。
每一剂量单位可以含10-200毫克活性成分。成人日剂量可在10-400毫克范围内,并且可按个体要求加以改变。
以下实例进一步阐明本发明。
实例
瓶发酵
从生长良好的正青霉NR 7125(FERM-BP 3588)斜面上取孢子悬浮液,接种到500毫升锥形瓶内,该锥形瓶内装有100毫升由2%葡萄糖、3%甘油、0.5%聚蛋白胨(日本制药)、0.2%酵母提取物(日本制药)、0.3%氯化钠和1%碳酸钙组成的培养基。将此锥形瓶在27℃下以200rpm振摇3天。将每份2毫升的所得培养物分别转移到50个装有上述同样培养基的500毫升锥形瓶内。在220rpm的旋转摇床上在27℃下进行发酵。培养5天后,将培养液按下述步骤进行分离。
分离步骤
用离心法将5升培养液分离成滤液和菌丝体。培养滤液(3.2升)用2升正丁醇在pH9.0条件下提取,并将有机层弃去。而后将水层(3.1升)用5升正丁醇在pH2.0条件下提取,并将有机层减压浓缩。将浓缩物(24.1克)溶于1升甲醇中,用2升正己烷分配。然后将甲醇层减压浓缩至干,残渣(24克)用50毫升甲醇研制。过滤除去沉淀后,将滤液在10.5升Sephadex LH-20(Pharmacia)上进行柱色谱,用甲醇作洗脱剂。合并活性部分,减压浓缩,得到淡黄色粉末,用甲醇结晶,得到32毫克黄褐霉素黄色结晶。
下列实例阐明含有本发明提供的黄褐霉素的药物制剂:
实例
用常规方法生产每片含有如下成分的片剂:
黄褐霉素 100毫克
淀粉 26毫克
羧甲基纤维素钙 15毫克
结晶纤维素 20毫克
硬脂酸镁 4毫克
165毫克
Claims (7)
1、制备式Ⅰ化合物黄褐霉素、其互变体或其盐的方法,
该方法包括,在需氧条件下,在培养基中培养能产生黄褐霉素的属于正青霉属的微生物,并从培养物中分离出黄褐霉素。
2、按照权利要求1的方法,其中微生物是正青霉NR 7125(FERM-BP 3588)。
3、制备含有如权利要求1所定义的黄褐霉素的药物组合物的方法,该方法包括,用通常的药用助剂与黄褐霉素、其互变体或其盐配合。
4、药物组合物,该组合物含有如权利要求1所定义的黄褐霉素、其互变体或其盐,以及通常的药用助剂。
5、如权利要求1所定义的黄褐霉素、其互变体或其盐在制备治疗真菌感染的药物组合物中的应用。
6、用权利要求1或2的方法制备的如权利要求1所定义的黄褐霉素、其互变体或其盐。
7、基本上如上所述的黄褐霉素、其制备方法、以及含有黄褐霉素的药物组合物。
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US5635493A (en) * | 1993-12-01 | 1997-06-03 | Marine Polymer Technologies, Inc. | Methods and compositions for poly-β-1-4-N-acetylglucosamine chemotherapeutics |
US5846952A (en) * | 1993-12-01 | 1998-12-08 | Marine Polymer Technologies, Inc. | Methods and compositions for poly-β-1-4-N-acetylglucosamine drug delivery |
US6743783B1 (en) * | 1993-12-01 | 2004-06-01 | Marine Polymer Technologies, Inc. | Pharmaceutical compositions comprising poly-β-1→4-N-acetylglucosamine |
US5686115A (en) * | 1993-12-01 | 1997-11-11 | Marine Polymer Technologies, Inc. | Poly-β-1→4-N-acetylucosamine copolymer composition with collagen |
US5622834A (en) * | 1993-12-01 | 1997-04-22 | Marine Polymer Technologies, Inc. | Method of isolating poly-β-1-4-N-acetylglucosamine from microalgal culture |
US6063911A (en) * | 1993-12-01 | 2000-05-16 | Marine Polymer Technologies, Inc. | Methods and compositions for treatment of cell proliferative disorders |
US5858350A (en) | 1993-12-01 | 1999-01-12 | Marine Polymer Technologies | Methods and compositions for poly-β-1→4-N-acetylglucosamine cell therapy system |
US5789387A (en) * | 1995-08-28 | 1998-08-04 | Shaman Pharmaceitucals, Inc. | Methods and compositions for treating fungal infections in mammals |
US5824545A (en) * | 1995-11-01 | 1998-10-20 | Millennium Pharaceuticals, Inc. | Identification of eukaryotic growth-related genes and promoter isolation vector and method of use |
US5888757A (en) * | 1996-05-03 | 1999-03-30 | Millennium Pharmaceuticals, Inc. | Cell wall assay |
AU2001276694A1 (en) * | 2000-07-28 | 2002-02-13 | Sumitomo Pharmaceuticals Company, Limited | Nerve regeneration promoters containing semaphorin inhibitor as the active ingredient |
DE60325172D1 (de) * | 2002-01-24 | 2009-01-22 | Dainippon Sumitomo Pharma Co | Verbindungen als semaphorininhibitoren |
US6917256B2 (en) * | 2002-08-20 | 2005-07-12 | Motorola, Inc. | Low loss waveguide launch |
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AU2011239466B2 (en) | 2010-04-15 | 2015-01-22 | Marine Polymer Technologies, Inc. | Anti-bacterial applications of poly -N-acetylglucosamine nanofibers |
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CN107827805A (zh) * | 2017-06-05 | 2018-03-23 | 海南师范大学 | 一种红树植物木果楝真菌来源的吲哚二萜类化合物及其制备方法与应用 |
Also Published As
Publication number | Publication date |
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ATE156126T1 (de) | 1997-08-15 |
AU656028B2 (en) | 1995-01-19 |
EP0537622B1 (en) | 1997-07-30 |
NZ244604A (en) | 1995-07-26 |
DE69221251T2 (de) | 1998-03-19 |
AU2623192A (en) | 1993-04-22 |
CA2079309A1 (en) | 1993-04-10 |
ES2106809T3 (es) | 1997-11-16 |
JPH0791284B2 (ja) | 1995-10-04 |
US5229123A (en) | 1993-07-20 |
JPH05239050A (ja) | 1993-09-17 |
GR3024925T3 (en) | 1998-01-30 |
DE69221251D1 (de) | 1997-09-04 |
ZA927606B (en) | 1993-04-13 |
DK0537622T3 (da) | 1998-03-09 |
US5292648A (en) | 1994-03-08 |
EP0537622A1 (en) | 1993-04-21 |
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