JPH023694A - Antibiotic substance 6108s, production and use thereof - Google Patents
Antibiotic substance 6108s, production and use thereofInfo
- Publication number
- JPH023694A JPH023694A JP14864888A JP14864888A JPH023694A JP H023694 A JPH023694 A JP H023694A JP 14864888 A JP14864888 A JP 14864888A JP 14864888 A JP14864888 A JP 14864888A JP H023694 A JPH023694 A JP H023694A
- Authority
- JP
- Japan
- Prior art keywords
- methanol
- strain
- micromonospora
- chloroform
- salts
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000126 substance Substances 0.000 title claims abstract description 23
- 230000003115 biocidal effect Effects 0.000 title claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 title claims description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 241000187708 Micromonospora Species 0.000 claims abstract description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract 3
- IUPCWCLVECYZRV-ZRDIBKRKSA-N rosamicin Chemical compound O=CCC1CC(C)C(=O)\C=C\C2(C)OC2C(C)C(CC)OC(=O)CC(O)C(C)C1OC1OC(C)CC(N(C)C)C1O IUPCWCLVECYZRV-ZRDIBKRKSA-N 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 7
- 241000187723 Micromonospora sp. Species 0.000 claims description 4
- OFLXLNCGODUUOT-UHFFFAOYSA-N acetohydrazide Chemical compound C\C(O)=N\N OFLXLNCGODUUOT-UHFFFAOYSA-N 0.000 claims description 4
- KAANTNXREIRLCT-UHFFFAOYSA-N 1-(triphenyl-$l^{5}-phosphanylidene)propan-2-one Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)C)C1=CC=CC=C1 KAANTNXREIRLCT-UHFFFAOYSA-N 0.000 claims description 3
- 235000018417 cysteine Nutrition 0.000 claims description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 99
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 63
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 abstract description 28
- 239000000843 powder Substances 0.000 abstract description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 abstract description 15
- 238000006243 chemical reaction Methods 0.000 abstract description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 6
- 238000001819 mass spectrum Methods 0.000 abstract description 5
- 238000002844 melting Methods 0.000 abstract description 4
- 230000008018 melting Effects 0.000 abstract description 4
- 238000004809 thin layer chromatography Methods 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract 2
- 238000004458 analytical method Methods 0.000 abstract 1
- 239000004599 antimicrobial Substances 0.000 abstract 1
- 239000002609 medium Substances 0.000 description 41
- 239000000203 mixture Substances 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 230000002829 reductive effect Effects 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 239000000741 silica gel Substances 0.000 description 17
- 229910002027 silica gel Inorganic materials 0.000 description 17
- 229920001817 Agar Polymers 0.000 description 16
- 239000008272 agar Substances 0.000 description 16
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 13
- 238000000034 method Methods 0.000 description 13
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- 239000000284 extract Substances 0.000 description 11
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- 239000007787 solid Substances 0.000 description 9
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 8
- 239000003242 anti bacterial agent Substances 0.000 description 8
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- 238000012258 culturing Methods 0.000 description 8
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 229920002472 Starch Polymers 0.000 description 7
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- 241000894006 Bacteria Species 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000000862 absorption spectrum Methods 0.000 description 6
- 230000001580 bacterial effect Effects 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 229930006000 Sucrose Natural products 0.000 description 5
- 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 5
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- WIMIROIXSHYTCN-UHFFFAOYSA-N trisodium acetonitrile borate Chemical compound [Na+].[Na+].[Na+].CC#N.[O-]B([O-])[O-] WIMIROIXSHYTCN-UHFFFAOYSA-N 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
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- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
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- 238000005194 fractionation Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000003120 macrolide antibiotic agent Substances 0.000 description 4
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- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
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- 241000187722 Micromonospora echinospora Species 0.000 description 1
- 241000218939 Micromonospora purpureochromogenes Species 0.000 description 1
- DMUAPQTXSSNEDD-QALJCMCCSA-N Midecamycin Chemical compound C1[C@](O)(C)[C@@H](OC(=O)CC)[C@H](C)O[C@H]1O[C@H]1[C@H](N(C)C)[C@@H](O)[C@H](O[C@@H]2[C@H]([C@H](OC(=O)CC)CC(=O)O[C@H](C)C/C=C/C=C/[C@H](O)[C@H](C)C[C@@H]2CC=O)OC)O[C@@H]1C DMUAPQTXSSNEDD-QALJCMCCSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 101000643905 Nostoc sp. (strain PCC 7120 / SAG 25.82 / UTEX 2576) Cytochrome b6-f complex iron-sulfur subunit 3 Proteins 0.000 description 1
- RZPAKFUAFGMUPI-UHFFFAOYSA-N Oleandomycin Natural products O1C(C)C(O)C(OC)CC1OC1C(C)C(=O)OC(C)C(C)C(O)C(C)C(=O)C2(OC2)CC(C)C(OC2C(C(CC(C)O2)N(C)C)O)C1C RZPAKFUAFGMUPI-UHFFFAOYSA-N 0.000 description 1
- 239000004104 Oleandomycin Substances 0.000 description 1
- 101000775697 Pseudopleuronectes americanus Ice-structuring protein 3 Proteins 0.000 description 1
- 101000775692 Pseudopleuronectes americanus Ice-structuring protein 4 Proteins 0.000 description 1
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 1
- 208000000260 Warts Diseases 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
- WQZQXBXIUMKNCK-UHFFFAOYSA-N [S].OB(O)O Chemical compound [S].OB(O)O WQZQXBXIUMKNCK-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 238000005377 adsorption chromatography Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 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
- 239000010775 animal oil Substances 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 235000015278 beef Nutrition 0.000 description 1
- 239000007613 bennett's agar Substances 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- DLRVVLDZNNYCBX-ZZFZYMBESA-N beta-melibiose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)O1 DLRVVLDZNNYCBX-ZZFZYMBESA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000002021 butanolic extract Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000012531 culture fluid Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- ZYBWTEQKHIADDQ-UHFFFAOYSA-N ethanol;methanol Chemical compound OC.CCO ZYBWTEQKHIADDQ-UHFFFAOYSA-N 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 239000004467 fishmeal Substances 0.000 description 1
- 210000003918 fraction a Anatomy 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000001641 gel filtration chromatography Methods 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 229960004144 josamycin Drugs 0.000 description 1
- XJSFLOJWULLJQS-NGVXBBESSA-N josamycin Chemical compound CO[C@H]1[C@H](OC(C)=O)CC(=O)O[C@H](C)C\C=C\C=C\[C@H](O)[C@H](C)C[C@H](CC=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](N(C)C)[C@H](O[C@@H]2O[C@@H](C)[C@H](OC(=O)CC(C)C)[C@](C)(O)C2)[C@@H](C)O1 XJSFLOJWULLJQS-NGVXBBESSA-N 0.000 description 1
- 238000009630 liquid culture Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000012533 medium component Substances 0.000 description 1
- 239000013028 medium composition Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000011785 micronutrient Substances 0.000 description 1
- 229960002757 midecamycin Drugs 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
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 235000013379 molasses Nutrition 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000006916 nutrient agar Substances 0.000 description 1
- 239000006877 oatmeal agar Substances 0.000 description 1
- 229960002351 oleandomycin Drugs 0.000 description 1
- RZPAKFUAFGMUPI-KGIGTXTPSA-N oleandomycin Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](C)C(=O)O[C@H](C)[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@]2(OC2)C[C@H](C)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C RZPAKFUAFGMUPI-KGIGTXTPSA-N 0.000 description 1
- 235000019367 oleandomycin Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000004810 partition chromatography Methods 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000001965 potato dextrose agar Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 201000010153 skin papilloma Diseases 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- ZPCCSZFPOXBNDL-RSMXASMKSA-N spiramycin II Chemical compound O([C@H]1/C=C/C=C/C[C@@H](C)OC(=O)C[C@H]([C@@H]([C@H]([C@@H](CC=O)C[C@H]1C)O[C@H]1[C@@H]([C@H]([C@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(O)C2)[C@@H](C)O1)N(C)C)O)OC)OC(C)=O)[C@H]1CC[C@H](N(C)C)[C@H](C)O1 ZPCCSZFPOXBNDL-RSMXASMKSA-N 0.000 description 1
- 229950006796 spiramycin ii Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 239000012137 tryptone Substances 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は医薬として有用である新規なマクロライド抗生
物質6108−A1、610B−B、6108−C16
108−D又はそれらの塩、それらの製造法及びそれら
の抗菌剤としての用途に関するものである。Detailed Description of the Invention [Industrial Application Field] The present invention provides novel macrolide antibiotics 6108-A1, 610B-B, 6108-C16 useful as medicines.
108-D or salts thereof, their production methods and their use as antibacterial agents.
マクロライド抗生物質は抗菌剤として重要な位置をしめ
ており、既に各種のものが提供されている0例えば、エ
リスロマイシン、オレアンドマイシン、アセチルスピラ
マイシン及びジョサマイシン、ミデカマイシンなどが有
る。Macrolide antibiotics play an important role as antibacterial agents, and various types are already available, including erythromycin, oleandomycin, acetylspiramycin, josamycin, and midecamycin.
〔発明が解決しようとする課題)
本発明は新規で有用なマクロライド抗生物質を提供する
ことを目的とするものである。[Problems to be Solved by the Invention] An object of the present invention is to provide a new and useful macrolide antibiotic.
本発明者らは新規な抗生物質の探索を目的として種々の
土壌から微生物を分離し、その生産する代謝産物につい
て研究を続けた結果、愛知県ej I+市の土壌から分
離した菌株B^06108株が培養液中にダラム陽性菌
およびダラム陰性菌に対して抗菌活性を示す新規マクロ
ライド抗生物質を生産することを見いだし、さらにこれ
らの抗生物質を単離した後、その理化学的及び生化学的
性質を検討し、新規な抗生物質である事を及び該BA0
6108株が新規な菌株である事を確認して本発明を完
成した。The present inventors isolated microorganisms from various soils for the purpose of searching for new antibiotics, and continued research on the metabolites produced by them. As a result, strain B^06108 was isolated from soil in Ej I+ City, Aichi Prefecture. discovered that they produced novel macrolide antibiotics that exhibited antibacterial activity against Durham-positive and Durham-negative bacteria in culture fluid, and after isolating these antibiotics, investigated their physicochemical and biochemical properties. We investigated that it is a new antibiotic and that the BA0
The present invention was completed after confirming that strain 6108 is a new strain.
本発明は一般式
又はそれらの塩、それらの生産菌、それらの製造法及び
それらの抗菌剤としての用途に関するものである。The present invention relates to general formulas or their salts, their producing bacteria, their production methods, and their use as antibacterial agents.
本発明の6108−A1、 6108−B、6108−
C及び6108−Dの理化学的性質を詳しく記載すると
次の通りである。6108-A1, 6108-B, 6108- of the present invention
The detailed physical and chemical properties of C and 6108-D are as follows.
108−A (1) 色および性状:無色粉末 (2)分子式: C,,B、,0,N。108-A (1) Color and properties: colorless powder (2) Molecular formula: C,,B,,0,N.
(3)元素分析:実測値C・61.84.l+=B、9
5.N=5.86理論値C=62.05,11=B、8
9.N=6゜58(4) 分子Ji : 637 (
マススペクトルより)(5)融 点: 108〜112
℃
(6)比旋光度: [a ] o −39,0’ (C
=f 、メタノール)λ nm(t ) : 23
4.5(21,500)ax
(8)赤外1)11吸収スペクトル:第5図(Kllr
法)(9)核磁気具鳴スペトクル
第9図 ’I+核磁核磁気共鳴スペルクルMS[準、
CDC1,中、300MIlz)第13図 “′C
核磁気共鳴人ベトクル(TMSJI:AI!!、CDC
l、中、75Ml1z)(10)シリカゲル(メルク社
製1&5715)薄層クロマトグラム:
クロロホルム−メタノール−5%アンモニア水(40:
12:10)(7)下層 Rr=0.25クロ
ロホルム−メタノール(1:I) Rr=0.30ア
セトニトリル−酢酸−水(4:l:1) Rr・0.3
4(11)呈色反応二20%硫酸水による薄層クロマト
グラフィーの発色は黒色
(12)溶解性:メタノール、クロロホルム及び酢酸エ
チルに可溶、エーテ
ル及びヘキサンに不溶。(3) Elemental analysis: Actual value C・61.84. l+=B, 9
5. N=5.86 theoretical value C=62.05, 11=B, 8
9. N=6゜58(4) Molecule Ji: 637 (
(from mass spectrum) (5) Melting point: 108-112
°C (6) Specific rotation: [a] o -39,0' (C
=f, methanol) λ nm(t): 23
4.5(21,500)ax (8) Infrared 1) 11 Absorption spectrum: Figure 5 (Kllr
(9) Nuclear magnetic resonance speckle Figure 9 'I+Nuclear magnetic resonance spectrometer MS [quasi,
CDC1, Medium, 300 MIlz) Figure 13 “'C
Nuclear Magnetic Resonance (TMSJI:AI!!, CDC)
(10) Silica gel (Merck & Co., Ltd. 1 & 5715) Thin layer chromatogram: Chloroform-methanol-5% aqueous ammonia (40:
12:10) (7) Lower layer Rr=0.25 chloroform-methanol (1:I) Rr=0.30 acetonitrile-acetic acid-water (4:l:1) Rr・0.3
4 (11) Color reaction (2) The color developed by thin layer chromatography using 20% sulfuric acid water is black (12) Solubility: Soluble in methanol, chloroform and ethyl acetate, insoluble in ether and hexane.
108−B
(1) 色、性状:無色粉末
分子式: (1,1、+1..0.、N元素分析:実測
値C:64.15.l1=B、70.N=2.07理論
値C”62.29.l1=B、60.N=2.34分子
、ltk : 597 (マススペクトルより)融
点:138〜141℃
比旋光度:〔α)ニー11.9°(C=1.メタノール
)
λ nta(t ) : 239.5(9,980
)aX
(8)赤外部吸収スペクトル:第6図(KBr法)(9
)核磁気共鳴スペクトル
第1O図 ’+1核磁気共鳴スベトクル(TMS、l
[Qa、CD、 OD中、300MIIz)第14図
10核磁気共鳴スペクトル(TMS標べへ、CD、
OD中、75M1lz)(10)シリカゲル(メルク社
製に5715)6’X層クロマトグラム:
クロロホルム−メタノール−5%アンモニア水(40:
12:10)(7)下層 i?r=o、o。108-B (1) Color, properties: Colorless powder Molecular formula: (1, 1, +1..0., N Elemental analysis: Actual value C: 64.15.l1=B, 70.N=2.07 Theoretical value C”62.29.l1=B, 60.N=2.34 molecules, ltk: 597 (from mass spectrum)
Point: 138-141°C Specific optical rotation: [α) knee 11.9° (C = 1. methanol) λ nta (t): 239.5 (9,980
) aX (8) Infrared absorption spectrum: Figure 6 (KBr method) (9
) Nuclear Magnetic Resonance Spectrum Figure 1O'+1 Nuclear Magnetic Resonance Spectrum (TMS, l
[Qa, CD, OD, 300 MIIz) Figure 14
10 Nuclear magnetic resonance spectra (TMS label, CD,
OD, 75M1lz) (10) Silica gel (Merck 5715) 6'X layer chromatogram: Chloroform-methanol-5% aqueous ammonia (40:
12:10) (7) Lower layer i? r=o, o.
クロロホルム−メタノール(1:l) ’Rr=0.0
8アセトニトリルー酢酸−水(4:1:1) Rf=0
.34(11)呈色反応:20%硫酸水による薄層クロ
マトグラフィーの発色は黒色
(12)溶解性:ブタノール、メタノール及び水に可溶
、クロロホルム及び
酢酸エチルに難溶、ヘキサン
に不溶。Chloroform-methanol (1:l) 'Rr=0.0
8 Acetonitrile-acetic acid-water (4:1:1) Rf=0
.. 34 (11) Color reaction: Color developed by thin layer chromatography with 20% sulfuric acid water is black (12) Solubility: Soluble in butanol, methanol and water, sparingly soluble in chloroform and ethyl acetate, insoluble in hexane.
6108−C
(+) 色、性状:無色結晶
(2)分子式: C,4B、,0,、N5(3) 元
素分析:実測イll1(C=5B、10,11=B、2
1 、N=3.!10理論値C=5B、10.I+=B
、32.N=コ3.99(4)分子j、I、 : 70
2 (マススペクトルより)(5)融 点:168〜1
69℃
(6)比旋光度:〔α] : −97,4’ (C=1
.メタノール)ax
(8)赤外部吸収スペクトル:第7図(KBr法)核磁
気共鳴スペクトル
第1I図 “11核磁気共鳴スペトクル(7MS標準
、 CD、OD中、300MI+7.)第15図 ″
3C核磁気共鳴スベトクル(TMS標iQ、 CD、0
0中、75MI+7.)シリカゲル(メルク社製Na5
715)薄層クロマトグラム:
クロロホルム−メタノール−5%アンモニア水(40:
12:10)(7)下層 Rr=0.00クロ
ロホ)Lム−メタ/ −ル(1:D Rr=0.11
アセトニトリル−酢酸−水(4:1;1) Rr=O,
+8呈色反応:20%硫酸水による薄層クロマトグラフ
ィーの発色は黒色
ニンヒドリンによる薄層クロ
マトグラフィーの発色は赤紫
色
溶解性:ブタノール、メタノール及び
水に可溶、クロロホルム及び
酢酸エチルに難溶、ヘキサン
に不溶。6108-C (+) Color, properties: Colorless crystal (2) Molecular formula: C, 4B, 0,, N5 (3) Elemental analysis: Actual measurement Ill1 (C=5B, 10,11=B, 2
1, N=3. ! 10 Theoretical value C=5B, 10. I+=B
, 32. N=co3.99(4) Molecule j, I, : 70
2 (from mass spectrum) (5) Melting point: 168-1
69℃ (6) Specific optical rotation: [α]: -97,4' (C=1
.. Methanol) ax (8) Infrared absorption spectrum: Figure 7 (KBr method) Nuclear magnetic resonance spectrum Figure 1I "11 Nuclear magnetic resonance spectrum (7MS standard, CD, in OD, 300 MI + 7.) Figure 15"
3C nuclear magnetic resonance spectrum (TMS mark iQ, CD, 0
0 out of 75MI+7. ) Silica gel (Merck Na5
715) Thin layer chromatogram: Chloroform-methanol-5% aqueous ammonia (40:
12:10) (7) Lower layer Rr=0.00 chloroform)
Acetonitrile-acetic acid-water (4:1;1) Rr=O,
+8 Color reaction: The color developed in thin layer chromatography with 20% sulfuric acid water is black, the color developed in thin layer chromatography with ninhydrin is reddish-purple Solubility: Soluble in butanol, methanol and water, sparingly soluble in chloroform and ethyl acetate, hexane Insoluble in
(1)色、性状:無色粉末
(2)分子式: C,4+1..0.N(3)元素分析
:実測値C=64.54,11=B、80.N=2.I
O理論値C=65.68,1l=B、92.N=2.2
5(4) 分子Q:621(マススペクトルより)(
5)融 点:95〜98℃
([;)比旋光度:〔α]ニー37.5°(C=1.メ
タノール)λ nl11(ε) : 232(21
,550)ax
光外部吸収スペクトル:第8図(KBr法)核磁気共鳴
スペクトル
第12図 ゛11核磁気共鳴スペクトル(1’ M
S標べQ、 CDCl、中、300MI+7.)第16
図 ″5C核磁気共鳴スペクトル(7MS標準、 C
DCl5中、75MIIy、)シリカゲル(メルク社!
!1JNa5715)薄層クロマトグラム:
クロロホルム−メタノール−5%アンモニア水(40:
12:10)ノ下R’r RC=0.78
クロロホルム−メタノール(1:I) 旧’=(+、
38アセトニj・リルー耐酸−水(4コI :I )
R1’0.fiO(11)呈色反応:20%硫酸水によ
る薄層クロマトグラフィーの発色は黒色
(12)溶解性;メタノール、クロロホルム及び酢酸エ
チルに可溶、エーテ
ル及び水に難溶。ヘキサンに
不溶。(1) Color, properties: colorless powder (2) Molecular formula: C, 4+1. .. 0. N(3) Elemental analysis: Actual value C=64.54, 11=B, 80. N=2. I
O theoretical value C=65.68, 1l=B, 92. N=2.2
5(4) Molecule Q: 621 (from mass spectrum) (
5) Melting point: 95-98°C ([;) Specific rotation: [α] knee 37.5° (C = 1. methanol) λ nl11 (ε): 232 (21
, 550) ax Optical external absorption spectrum: Figure 8 (KBr method) Nuclear magnetic resonance spectrum Figure 12 ゛11 Nuclear magnetic resonance spectrum (1' M
S mark Q, CDCl, medium, 300MI+7. ) No. 16
Figure ``5C nuclear magnetic resonance spectrum (7MS standard, C
75 MIIy in DCl5) silica gel (Merck!
! 1JNa5715) Thin layer chromatogram: Chloroform-methanol-5% ammonia water (40:
12:10) Noshita R'r RC=0.78
Chloroform-methanol (1:I) old'=(+,
38 Acetonij/Lilu Acid Resistance-Water (4 pieces I:I)
R1'0. fiO(11) Color reaction: The color developed by thin layer chromatography with 20% sulfuric acid water is black (12) Solubility; Soluble in methanol, chloroform and ethyl acetate, sparingly soluble in ether and water. Insoluble in hexane.
また本発明によると、ミクロモノスポラ属に属する61
08−A、類生産菌を培j曜rし、tl)られた培養液
から6108−A1、6108−B、6108−C及び
/又は6108−Dまたはそれらの塩を採取することを
特徴とする6108−^い6108−I3.6108−
(’;及び/又は6108−Dまたはそれらの塩の製造
法が提供される。Further, according to the present invention, 61 belonging to the genus Micromonospora
08-A, 6108-A1, 6108-B, 6108-C and/or 6108-D or their salts are collected from the culture solution obtained by culturing the type-producing bacteria. 6108-^i6108-I3.6108-
('; and/or a method for producing 6108-D or a salt thereof is provided.
本発明に使用される6108−A1、6108−13.
−6108−C1及びは6108−Dの生産菌としては
培養物中に6108−^1.6108−B、6108−
C及び/又は6108−Dを生産するものであれば、い
かなるものであってもよいが、その−例として、本発明
者らによす愛知系層1u市の土壌より新たに分離された
BAO6108株が挙げられる。6108-A1, 6108-13 used in the present invention.
-6108-C1 and 6108-D producing bacteria include 6108-^1.6108-B and 6108-
Any material may be used as long as it produces C and/or 6108-D, but as an example, BAO6108 newly isolated from the soil of Aichi-type layer 1u city by the present inventors is used. Stocks are one example.
+JAO6108株の蘭学的性質は下記の通りである。The orchidological properties of +JAO6108 strain are as follows.
形 態
よく発達した基土菌糸から単純分枝した、短い胞子柄上
に1個の胞子を着生する。胞子は0.8〜1.2μの大
きさの球形または卵型でその表面はイボ状である。天然
培地上で豊富な胞子層を形成する。気菌糸または5.偽
気菌糸の形成は観察されず、菌糸の分断も認められない
。A single spore is attached to a short sporophyte that is simply branched from a well-developed substrate hyphae. The spores are spherical or egg-shaped with a size of 0.8 to 1.2 μ, and the surface is wart-like. Forms an abundant spore layer on natural media. Aerial mycelium or 5. No formation of pseudoaerial hyphae was observed, and no hyphal fragmentation was observed.
2、 各種寒天平板培地における生育状態下記に28℃
、180間培養し、!5!察した結果を記す6色名は「
色の標III!」(日本色彩QF究所)にべC!じた。2. Growth conditions on various agar plate media are shown below at 28°C.
, cultured for 180 hours,! 5! The names of the six colors that describe the results are:
Color mark III! ” (Japan Color QF Institute) Nibe C! It was.
(1)イースト・麦芽寒天培地(IsP−2培地)淡橙
色の基土菌糸の生育は良好で黒色の胞子を豊富に着生し
、黒褐色を帯びた可溶性色素の生成が五gぬられる。(1) Yeast/malt agar medium (IsP-2 medium) The growth of pale orange substratum mycelium is good, with abundant black spores, and 5 g of dark brown soluble pigment is produced.
(2)オートミール寒天培地(ISP−3培地)淡橙色
の基土菌糸の生育は良好で黒色の胞子を豊富に着生し、
赤紫色を帯びた可溶性色素の生成が認められる。(2) Oatmeal agar medium (ISP-3 medium) The pale orange substratum hyphae grow well, with abundant black spores attached.
The formation of a reddish-purple soluble pigment is observed.
(3)スターチ・無機塩寒天培地(ISP−4培地)淡
橙色の基土菌糸の生育は良好で黒色の胞子を豊富に着生
し、赤紫色を帯びた可溶性色素の生成が認められる。(3) Starch/inorganic salt agar medium (ISP-4 medium) The pale orange substratum hyphae grow well, with abundant black spores attached, and the production of a reddish-purple soluble pigment is observed.
(4)グリセリン・アスパラギン寒天培地生育は極めて
悪い。(4) Growth on glycerin/asparagine agar medium is extremely poor.
(5)ペプトン・イースト・鉄寒天培地(ISI’−6
培地)
淡橙色の基土菌糸の生育は良好で黒色の胞子なt’′i
富に着生し、黒褐色を帯びた可溶性色素の生成が認めら
れる。(5) Peptone yeast iron agar medium (ISI'-6
Medium) Pale orange substratum hyphae grow well and black spores t''i.
The formation of a dark brown soluble pigment is observed.
(6)チロシン寒天培地(ISP−7培地)生育は極め
て悪い。(6) Growth on tyrosine agar medium (ISP-7 medium) is extremely poor.
(7)栄養寒天培地
淡橙色の基土菌糸の生育は良好で黒色の胞子を豊富に着
生するが、可溶性色素の生成は認められない。(7) Nutrient agar medium The pale orange substratum hyphae grow well, with abundant black spores attached, but no production of soluble pigments is observed.
(8)シュークロース・硝酸塩寒天培地生Yrは極めて
悪い。(8) Sucrose/nitrate agar medium Raw Yr is extremely poor.
(9)グルコース・アスパラギン寒天培地生育は極めて
悪い。(9) Growth on glucose-asparagine agar medium is extremely poor.
(10)ポテト・デキストローズ寒天培地淡橙色の基土
菌糸の生育は良好で黒色の胞f・を豊富に着生し、赤紫
色を帯びた可溶性色素の生成が認められる。(10) Potato dextrose agar medium The pale orange substratum hyphae grow well, with abundant black spores f., and the production of a reddish-purple soluble pigment is observed.
3、 生理的性質
(1)グルコース・ペプトン・ゼラチン培地(28℃培
養)でゼラチンの液化が認められない。3. Physiological properties (1) No liquefaction of gelatin was observed in glucose-peptone-gelatin medium (cultured at 28°C).
(2)スターチの加水分解
スターチ・無機塩寒天培地(28℃培養)でスターチの
加水分解が認められる。(2) Hydrolysis of starch Hydrolysis of starch is observed on starch/inorganic salt agar medium (cultured at 28°C).
(3) IBtllH牛乳の凝固、ペプトン化スキムミ
ルク培地(28℃培養)でスキムミルクの凝固・ペプト
ン化は認められない。(3) Coagulation and peptonization of IBtllH milk No coagulation or peptonization of skim milk was observed in skim milk medium (cultured at 28°C).
(4)メラニン様色素の生成
ペプトン・イースト・軟寒天培地でメラニン様色素の生
成が、わずかに認められるか、チロシン寒天培地および
トリプトン・イースト液体培地では認められない。(4) Production of melanin-like pigment The production of melanin-like pigment is slightly observed in peptone yeast soft agar medium, or not observed in tyrosine agar medium and tryptone yeast liquid medium.
(5)炭素源の利用性(ブリドハム・ゴドリーブ寒天培
地、28℃培養)
D−グルコースは比較的よく利用されるが、1、−アラ
ビノース、D−キシロース、D−フラクトース、シュク
ロース、イノシトール、!4−ラムノース、ラフィノー
ス、D−マンニット、サリシン及びグリセリンは利用さ
れない。(5) Utilization of carbon sources (Bridham-Godelive agar medium, cultured at 28°C) D-glucose is relatively commonly used, but 1, -arabinose, D-xylose, D-fructose, sucrose, inositol,! 4-rhamnose, raffinose, D-mannitol, salicin and glycerin are not utilized.
(6)生育温度
改変ベネット寒天培地(マルトース1.0%、イースト
・エキス0.1’%)、牛肉エキス0.1ヅ、。(6) Bennett agar medium with modified growth temperature (1.0% maltose, 0.1'% yeast extract), 0.1% beef extract.
N−Zアミン・タイプ八〇、2%、寒天1.6ヅ、。N-Z amine type 80, 2%, agar 1.6㎡.
pH7,3)を用い、12℃、20℃、28℃、37℃
及び45℃の各温度で培養した結果、 12℃及び45
℃を除いて何れの温度でも生育するが、最適温度は20
〜28℃付近である。pH 7.3) at 12°C, 20°C, 28°C, 37°C
As a result of culturing at each temperature of 12°C and 45°C,
It grows at any temperature except ℃, but the optimum temperature is 20℃.
It is around ~28°C.
(7)食塩耐性
イースト・麦芽寒天培地(lsI)−2培地)をJ、1
7本培地として培t(28℃)した結果、食塩含有4%
以下で生育する。(7) Salt-tolerant yeast malt agar medium (lsI)-2 medium) J, 1
As a result of culturing (at 28°C) as a 7-tube medium, the salt content was 4%.
Grows below.
4、細胞壁のアミノ酸、および全菌体の糖組成細胞壁の
加水分解物からはヒドロキシ!<172.6−ジアミツ
ビメリン酸及びグリシンが検出された。全菌体の糖成分
としてアラビノース及びキシロースが検出された。4. Amino acids in the cell wall and sugar composition of the whole bacterial cell Hydroxy! from the cell wall hydrolyzate! <172.6-diamitubimelic acid and glycine were detected. Arabinose and xylose were detected as sugar components in all bacterial cells.
以」二のごとき BAO6108閑の菌学的性質をバー
シーズ・マニュアル・オブディ ターミナテイブ・バク
テリオロジ−(第8版、1974年)およびその他の文
献などの記載な参11(1すると、本菌株はミクロモノ
スポラ属に属するものと同定され、比較的類似している
と思われるものにミクロモノスポラ・エキノスポラ、ミ
クロモノスポラ・プルプレオクロモゲネスなどがあげら
れる。前者はl、−ラムノース、D−キシロース、L−
アラビノース、L−フラクトースおよびシュクロースを
利用し、可溶性色素を生成せず、胞子の形成が非常に悪
い点で本菌株とはy4なり、後者はラフィノース、D−
キシロースおよびD−フラクトースを利用し、明らかな
菌糸の分断がみられる点で本菌株と異なる。Since the mycological properties of BAO 6108 are described in Terminal Bacteriology (8th edition, 1974) and other literature, the present strain is a microorganism. Examples of species that have been identified as belonging to the genus Spora and are thought to be relatively similar include Micromonospora echinospora and Micromonospora purpureochromogenes.The former contains l,-rhamnose, D-xylose, L-
This strain is different from y4 in that it utilizes arabinose, L-fructose and sucrose, does not produce soluble pigments, and has very poor spore formation, while the latter uses raffinose, D-
This strain differs from this strain in that it utilizes xylose and D-fructose and has clear hyphal division.
(以下余白)
また既知ミクロモノスポラ属菌種には抗生物質ロザマイ
シン生産菌として、ミクロモノスポラ・ロザリア、抗生
物質シュベニマイシン生産菌としてミクロモノスポラ・
チャルセア・バー・イズメンシス及び抗生物質M−43
65生産菌としてミクロモノスポラ・カビラータがそれ
ぞれ知られている。(Margins below) Also, known Micromonospora species include Micromonospora rosaria, which produces the antibiotic rosamycin, and Micromonospora rosaria, which produces the antibiotic shubenimycin.
Charcea bar ismensis and antibiotic M-43
Micromonospora cavirata is known as a 65-producing bacterium.
しかし、ミクロモノスポラ・ロザリアはL−アラビノー
ス、シュクロース及びD−マンニットを利用し。However, Micromonospora rosaria utilizes L-arabinose, sucrose and D-mannitol.
胞子の形成が悪い点で本菌株と異なり、ミクロモノスポ
ラ・チャルセア・バー・イズメンシスはD−キシロース
、D−ガラクトース、メリビオース、シュクロース、ラ
フィノース及びサリシンを利用し。Unlike this strain in that it has poor spore formation, Micromonospora chalcea var. ismensis utilizes D-xylose, D-galactose, melibiose, sucrose, raffinose, and salicin.
赤紫系のIi)溶性色素を生成せず、胞子の表面が平滑
である点で本菌株とは異なり、ミクロモノスポラ・カビ
ラータはL−アラビノース、D−キシロース、シュクロ
ース及びI、−ラムノースを利用し、気菌糸を形成する
点で本菌株と異なる。Micromonospora cabirata differs from this strain in that it does not produce reddish-purple soluble pigments and the surface of its spores is smooth. This strain differs from this strain in that it utilizes hyphae and forms aerial mycelia.
したがって、上記のごとく、すでに報告されたミクロモ
ノスポラ属菌株中には B^06108菌と性質が一致
する菌株はみあたらず、新菌種と認め。Therefore, as mentioned above, among the Micromonospora strains that have already been reported, there were no strains with the same characteristics as B^06108, and it was recognized as a new bacterial species.
本菌株をミクロモノスポラ・エスピー(Micro−n
+onospora sp、) Il^06108株と
命名した1本aI株は微工研に昭和63年2ノ129日
に受託されており、その機工IσF受託番号は微工研菌
第9897号(FEI?MT’−9897号)である。This bacterial strain was Micromonospora sp.
+onospora sp,) One aI strain, named strain Il^06108, was entrusted to FEI on February 129, 1988, and its IσF accession number was FEI?MT. '-9897).
以上6108−Aい6108−13,6108−Cおよ
び6108−Dの生産菌について説明したが、放線菌の
諸性質は一定したものではなく、自然的1人コニ的に容
易に変化することは周知の通りである0本発明で使用し
つる菌株はミクロモノスポラ属に属する6108−A1
、6108−13.6108−C及び6108−Dを生
産する。すべての菌株を包含するものである。The bacteria producing 6108-A, 6108-13, 6108-C, and 6108-D have been explained above, but it is well known that the properties of actinomycetes are not constant and can easily change in a natural, monogenic manner. The vine strain used in the present invention is 6108-A1, which belongs to the genus Micromonospora.
, 6108-13.6108-C and 6108-D. It includes all strains.
本発明における培養は一般放線菌における培使方法に申
じて行われ、液体培地中での振どう培養あるいは通気攪
拌培養によるのが好ましい。培地成分としては、例えば
、炭素源としてブドウ糖、マルトース、デキストリン、
i!!粉又は糖蜜などが。Cultivation in the present invention is carried out in a manner similar to that used for general actinomycetes, and is preferably carried out by shaking culture in a liquid medium or aerated agitation culture. Examples of medium components include glucose, maltose, dextrin, and carbon sources.
i! ! powder or molasses, etc.
窒素源としては大豆粉、落花生粉、綿実粉、魚粉、コー
ンスチープリカー、ペプトン、肉エキス、イースト、硝
酸ソーダ又は硫酸アンモニウムなどが。Nitrogen sources include soybean flour, peanut flour, cottonseed flour, fish meal, corn steep liquor, peptone, meat extract, yeast, sodium nitrate, or ammonium sulfate.
また無機塩として例えばナトリウム塩、カリウム塩、燐
酸塩、カルシウム塩、マグネシウム塩又は微M llL
屈塩などが必要に応じて添加される。さらに、6108
−A1、 6108−B、 6108−C及び6108
−Dの生産を促進する微量栄養素、発育促進物質を添加
してもよい。液体培養に際しては例えばシリコン油、動
植物油又は界面活性剤等が消泡剤として適宜使用される
。培地の1)IIは中性付近がよく、培養温度は20℃
から37℃、好ましくは25℃〜30℃である。Inorganic salts such as sodium salts, potassium salts, phosphates, calcium salts, magnesium salts,
Salt and the like are added as necessary. Furthermore, 6108
-A1, 6108-B, 6108-C and 6108
-Micronutrients and growth-promoting substances that promote the production of D may be added. For liquid culture, silicone oil, animal and vegetable oils, surfactants, and the like are appropriately used as antifoaming agents. 1) II of the medium should be near neutrality, and the culture temperature should be 20°C.
to 37°C, preferably 25°C to 30°C.
通常72時間から96時間の培養で6108−^1.6
108−B。Usually 6108-^1.6 after culturing for 72 to 96 hours.
108-B.
+3108−Cおよび6108−nの生産量は最高41
(に達する。+3108-C and 6108-n production up to 41
(reaches.
これらの培地組成、培養温度、攪拌速度および通気XU
tなどの培養条件は使用する菌株や外部の条件に応じて
好ましい結果が得られるように適宜選択されることは言
うまでもない。These medium composition, culture temperature, stirring speed and ventilation XU
It goes without saying that culture conditions such as t are appropriately selected depending on the strain used and external conditions so as to obtain preferable results.
本発明において、+3108−A1、 6108−B、
6108−C。In the present invention, +3108-A1, 6108-B,
6108-C.
6108−Dおよびそれらの塩を培養物より採取するに
当たっては、合目的な任意の方法が利用可能である。そ
の一つの方法は抽出の原理にもとづくものであって、具
体的には水不混和性の有機溶媒、例えば酢酸エチル、酢
酸ブチル、クロロホルム又はブタノールなどで抽出する
方法があり、また菌体を分離せずに培養液そのままを上
記の抽出操作に付することもできる。Any suitable method can be used to collect 6108-D and salts thereof from the culture. One method is based on the principle of extraction, and specifically, there is a method of extraction with water-immiscible organic solvents such as ethyl acetate, butyl acetate, chloroform, or butanol, and there is also a method of separating bacterial cells. It is also possible to subject the culture solution as it is to the above extraction operation without separating it.
培養物から6108−^い6108−n、6108−C
1GI08−Dおよび/又はそれらの塩を採取する他の
方法の一つは、吸着の原理にもとづくものであって、培
養ろ故あるいは上記のようにして抽出操作を行うことに
よって得られる抽出液を対象として、適当な吸着剤1例
えば活性炭、アンバーライトXAD−7(ロームアンド
ハース社製)又はダイヤイオン11P−20(三菱化成
製)等を用いて吸着させ、その後溶離させることによっ
て得ることが出来る。このようにして得られた溶液を減
圧濃縮乾固すれば、6108−A1、 6tos−a、
6tos−c;6108−D物質及び/又はこれらの物
質を二種類以」二含む粗製物が得られる。6108-n, 6108-C from culture
Another method for collecting 1GI08-D and/or its salts is based on the principle of adsorption, using the extract obtained through a culture filter or by performing the extraction operation as described above. The target can be obtained by adsorption using a suitable adsorbent 1 such as activated carbon, Amberlite XAD-7 (manufactured by Rohm and Haas) or Diaion 11P-20 (manufactured by Mitsubishi Kasei), followed by elution. . If the solution obtained in this way is concentrated to dryness under reduced pressure, 6108-A1, 6tos-a,
A crude product containing the 6tos-c; 6108-D substance and/or two or more of these substances is obtained.
このようにして得られる粗製物をさらに精製するために
は、混合物との溶解度の差、混じり合わない二液層間の
分配率の差又は各種吸着担体に対する吸着ノJの差を利
用したクロマトグラフィーなど多くの手段が可能である
が、特にクロマトグラフィーは有効な方法である。 6
108−^1、6108−B、G108−C及び/又は
6108−Dの精製に有効なりロマトグラフィーとして
は1例えばシリカゲル、アルミナ、活性炭、セルローズ
、ヒドロキシルアパタイト+IP−20もしくはXAD
−7などの吸着剤による吸着クロマトグラフィー、例え
ばオクタデシルシラン化シリカゲル等シラン化シリカゲ
ルを用いる逆用分配クロマトグラフィー1例えばセファ
デックスLll−20もしくはトヨバール等を用いる分
子篩にもとづくゲルろ過クロマトグラフィー、例えばD
lミ^Eセルロース、DEAEセファデックスもしくは
DEAIEトヨパール等を用いるイオン交換クロマトグ
ラフィー等があげられる。これらのクロマトグラフィー
向流分配、限外ろ過又は蒸留などの手段を単独あるいは
任意の順序に組み合わせるか、また反復して用いること
に依り行うこともできる。In order to further purify the crude product obtained in this way, chromatography, etc. that utilizes the difference in solubility with the mixture, the difference in the distribution ratio between two immiscible liquid layers, or the difference in the adsorption capacity for various adsorption carriers, etc. Although many means are possible, chromatography is a particularly effective method. 6
Effective for purification of 108-^1, 6108-B, G108-C and/or 6108-D, chromatographic methods such as silica gel, alumina, activated carbon, cellulose, hydroxylapatite + IP-20 or XAD
Adsorption chromatography using adsorbents such as -7, for example, reverse partition chromatography using silanized silica gel such as octadecylsilanized silica gel 1 Gel filtration chromatography based on molecular sieves using Sephadex Lll-20 or Toyovar, etc., e.g. D
Examples include ion exchange chromatography using cellulose, DEAE Sephadex, or DEAIE Toyopearl. These methods such as chromatography countercurrent distribution, ultrafiltration, and distillation can be used alone or in combination in any order, or can be carried out by using them repeatedly.
例えば前記粗製物を小量のクロロホルム又はメタノール
などに溶かし、これを予め充填されたシリカゲルのカラ
ムに吸着させ、クロロホルム−メタノール系混合溶媒を
用いてカラムクロマトグラフィーを行い、その品性両分
を分取し減圧部オ、宿後。For example, dissolve the crude product in a small amount of chloroform or methanol, adsorb it on a pre-packed silica gel column, perform column chromatography using a chloroform-methanol mixed solvent, and separate the quality of the product. Take the decompression section, and then leave.
小量のメタノールに溶かし、これを逆相シリカゲルカラ
ムに吸着させメタノール−水系あるいはアセトニトリル
−水系混合溶媒でカラムクロマトグラフィーを行うこと
により 6108−A1、 6108−8゜6108−
C及び/又はG108−Dを分子li精製することがで
きる。 このようにして得られた61013−A、及び
6108−Dは塩基性物質であり、6108−Bと61
08−Cは両性物質であるから公知の方法により塩に変
換し得る。6108-A1, 6108-8゜6108-
C and/or G108-D can be molecularly purified. 61013-A and 6108-D thus obtained are basic substances, and 6108-B and 6108-D are basic substances.
Since 08-C is an amphoteric substance, it can be converted into a salt by a known method.
このような6108−^、と6+08−Dの塩としては
、医学的に許容し得る非毒性塩があげられ、例えばナト
リウム塩もしくはカリウム塩等のアルカリ金属塩、又は
例えばトリエチルアミン等の公知の有機アミン塩等があ
げられる、また6108−Bと6108−Cの塩として
は、医学的に許容し得る非毒性塩があげられ、例えばナ
トリウム塩もしくはカリウム塩などのアルカリ金属塩、
例えばトリエチルアミン等の公知の有機アミン、例えば
硫酸塩、塩酸塩もしくは燐酸塩などの鉱酸塩又は例えば
酒石酸塩等の公知の有機酸塩等があげられる。Such salts of 6108-^ and 6+08-D include medically acceptable non-toxic salts, such as alkali metal salts such as sodium salts or potassium salts, or known organic amine salts such as triethylamine. Salts of 6108-B and 6108-C include medically acceptable non-toxic salts, such as alkali metal salts such as sodium salts or potassium salts;
Examples include known organic amines such as triethylamine, mineral acid salts such as sulfates, hydrochlorides or phosphates, or known organic acid salts such as tartrates.
さらに、第三の本発明によると、抗生物質ロザマイシン
とアセトヒドラジンから6108−^を、抗生物質ロザ
マイシンとシスティンから6108−Cを、抗生物質ロ
ザマイシンと1−トリフェニル ホスフォラニリデンー
2−プロパノンから6108−D合成することができる
。Furthermore, according to the third invention, 6108-^ is obtained from the antibiotic rosamycin and acetohydrazine, 6108-C is obtained from the antibiotic rosamycin and cysteine, and 6108-C is obtained from the antibiotic rosamycin and 1-triphenyl phosphoranylidene-2-propanone. 6108-D can be synthesized.
本発明に使用される溶剤は原料宅ある日ザマイシンとア
セトヒドラジン、システィン、トリフェニル又はホスフ
ァラニジンー2−プロパノンとを溶解するものであれば
よく1例としてはメタノール又はエタノール等がある。The solvent used in the present invention may be any solvent that can dissolve the raw material zamycin and acetohydrazine, cysteine, triphenyl or phosfaranidine-2-propanone, and examples include methanol or ethanol.
望ましくは塩酸等の添加により酸性条件下で反応させた
後、シリカゲル等によるクロマトグラフィー等によって
採取及び精製純化することができる。Desirably, after reacting under acidic conditions by adding hydrochloric acid or the like, it can be collected and purified by chromatography using silica gel or the like.
6108−A1、 6108−B、6108−Cおよび
6108−Dは種々の微生物に対して抗菌活性を示す物
質であり、最小増ta<+阻止濃度(旧C)を寒天平板
希釈法により求めた。結果は第1表に示すとおりである
。6108-A1, 6108-B, 6108-C and 6108-D are substances that exhibit antibacterial activity against various microorganisms, and the minimum increase ta<+inhibitory concentration (formerly C) was determined by the agar plate dilution method. The results are shown in Table 1.
測定条件二
ミュラー・ヒントン(Mueller−11in’Lo
n)寒天培地/り117.4/37℃/16時間旧Cは
10“個/lIQに検定間の菌体懸濁液を調整し、ミク
ロプランタ−で接種して、培養後の生育の有無で判定し
た。Measurement conditions Two Mueller-Hinton (Mueller-11in'Lo)
n) Agar medium / 117.4 / 37℃ / 16 hours Old C: Adjust the bacterial suspension between assays to 10'' cells / lIQ, inoculate in a microplanter, and check whether there is growth after culturing. It was judged.
(以下余白)
第1表に示すように6108−Aい6108−Cおよび
6108−Dはグラ1、陽ff、 +“/1だけではな
く、ダラム陰性閑に対しても高い活性を示すことから抗
菌剤として用いることができる。(Left below) As shown in Table 1, 6108-A, 6108-C, and 6108-D show high activity not only against Gura 1, positive ff, and +“/1, but also against Durham negative. It can be used as an antibacterial agent.
急性毒性試験
ICRマウス(雌、4週令)を用いて、試M薬物を5%
DMSO及び、0.5%tween80を含む生理食塩
水に溶解して、腹腔内に投与して急性毒性(1,D、1
mg / kg >を測定した。その結果を第2表に示
す。Acute toxicity test Using ICR mice (female, 4 weeks old), test M drug was administered at 5%.
Acute toxicity (1, D, 1
mg/kg> was measured. The results are shown in Table 2.
第2表
試験薬剤 LD1. (mg/kg)610
8−^、 3506108
−C490
るロザマイシンに比較して明らかに低11に性である。Table 2 Test drugs LD1. (mg/kg)610
8-^, 3506108
-C490 is clearly less sensitive than rosamycin.
本発明の抗菌性化合物またはその塩をli乳類に使用す
るとき、化合物単独で投与することが出来、或いは他の
抗生物質及び/又は公知の医薬用N1体又は希釈剤と混
合した形で投与することもできる。When the antibacterial compound of the present invention or a salt thereof is used in mammals, the compound can be administered alone or in a mixed form with other antibiotics and/or known pharmaceutical N1 forms or diluents. You can also.
該担体又は希釈剤は投4方法により適時選択する+11
ができる6例えばシロップ、エリキシル、水溶液又は水
性懸濁剤等の剤形で使用する11(ができる。The carrier or diluent is appropriately selected according to the administration method.+11
It can be used in dosage forms such as syrups, elixirs, aqueous solutions or suspensions.
詠剤形において活性成分対1■体の比率は剤形によって
異なるが、通常l:6〜6:l (重量比)であり、好
ましくはl:l〜1・4である6本発明の抗菌性化合物
は非経口的に投与する事もでき。In the elixir form, the ratio of active ingredient to 1.5% varies depending on the dosage form, but is usually 1:6 to 6:1 (weight ratio), preferably 1:1 to 1.4. Compounds can also be administered parenterally.
例えば筋肉内、腹腔内または静脈内投与できる。For example, it can be administered intramuscularly, intraperitoneally or intravenously.
この投与方法では、活性成分の滅菌溶液が通常、潤製さ
れるが、この滅菌溶液のpHを調節するために緩衝剤を
添加してもよい。静脈内設+7.のために。In this method of administration, a sterile solution of the active ingredient is usually prepared, and a buffering agent may be added to adjust the pH of the sterile solution. Intravenous installation +7. for.
溶質の濃度を調節して等張にしてもよい。The concentration of solute may be adjusted to make it isotonic.
本発明の化合物は通常経1コ的には1日当たりおよそ2
0〜1100II/kg(体重)を、非経口的には11
1当たりおよそlO〜50 mg / kgを、通常・
1回ないし数回に分けて投q、する事ができるが、患者
の症状によっては医者の指示により、この投与量の範囲
外での使用も可能である。The compounds of the present invention will normally be administered orally at approximately 2 doses per day.
0 to 1100 II/kg (body weight), parenterally 11
Approximately lO to 50 mg/kg per 1
It can be administered once or in divided doses, but depending on the patient's symptoms, it may be possible to use doses outside this range according to the doctor's instructions.
以下に本発明の実施例を示すが、この実施例は単なる一
例を示すものであり1本発明は下記の諸例に限定される
ものではない。Examples of the present invention are shown below, but these examples are merely examples, and the present invention is not limited to the following examples.
実施例 l
水U目、0%、肉エキス0.2%、綿実粉0.5%、小
麦胚芽0.5%、硫酸マグネシウム0.2%、炭酸カル
シウム0.2%、塩化ナトリウム0.2%、第一燐酸カ
リ0.1%(pH7、o)を含有する前培養培地1OO
rd、を含む500mf、容三角フラスコにミクロモノ
スポラhエスピー11AO(3108株を一白金耳接種
し、220rpmの回転振どう培養機により28℃で7
2時間培養して種母を調製した。Example 1 Water grains 0%, meat extract 0.2%, cottonseed flour 0.5%, wheat germ 0.5%, magnesium sulfate 0.2%, calcium carbonate 0.2%, sodium chloride 0. 1 OO of preculture medium containing 2%, potassium monophosphate 0.1% (pH 7, o)
A loopful of Micromonospora h sp. 11AO (strain 3108) was inoculated into a 500mf Erlenmeyer flask containing RD, and incubated at 28°C in a rotary shaking incubator at 220rpm.
A seed mother was prepared by culturing for 2 hours.
1];1培養培地と同じ組成の培地120 Qを含む2
00Q容ファーメンタ−に種母を1.2Q接種し、27
℃、回転数20Orpm、通気量120Q/分で72時
間通気攪拌した。1]; 2 containing medium 120 Q with the same composition as 1 culture medium
00Q fermenter was inoculated with 1.2Q seed mother, 27
The mixture was aerated and stirred for 72 hours at a temperature of 20 rpm and an air flow rate of 120 Q/min.
実施例 2
実施例1で得られた培養液110Qにろ過補助剤3kg
を加えろ過し、ろl100Qを得た。このろ故を6Q容
のアンバーライトXAD−7(ローム・アンド・ハース
社製)カラムに通過させ活性成分を吸着させた。水18
9、次いで25%メタノール水で洗浄した後、80%メ
タノール水で溶出させた。溶出液を濃縮し、淵オ、宿液
に5%水酸化ナトリウム水溶液を加えpl+9.0に調
整し、等量の酢酸エチルで2回反復抽出した。この抽出
液を無水硫酸ナトリウムで脱水後、減圧濃縮し6108
−A、を含む油状物57gを得た。Example 2 3 kg of filter aid was added to the culture solution 110Q obtained in Example 1.
was added and filtered to obtain Filter 1100Q. This filtrate was passed through a 6Q volume Amberlite XAD-7 (manufactured by Rohm and Haas) column to adsorb the active ingredients. water 18
9. Then, after washing with 25% methanol water, it was eluted with 80% methanol water. The eluate was concentrated, and the retained solution was adjusted to PL+9.0 by adding 5% aqueous sodium hydroxide solution, and extracted twice with an equal volume of ethyl acetate. This extract was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure.
57 g of an oil containing -A was obtained.
前記の如くして得られた6108−A、を含む油状物を
予めクロロホルムで充填されたシリカゲルC−300(
和光純12 ”A )カラム(4x75an)に吸着せ
しめクロロホルムとクロロホルム−メタノール(3:2
) ihs t&によるグラジェント溶出クロマトグ
ラフィーを行った。得られた6108−A、両分2.5
Qを減圧濃縮し6108−^、の精製固形物0.7 g
を得た。The oil containing 6108-A obtained as described above was poured into silica gel C-300 (pre-filled with chloroform).
Adsorbed onto a Wako Pure 12” A) column (4x75an) and mixed chloroform and chloroform-methanol (3:2).
) Gradient elution chromatography was performed using ihs t&. Obtained 6108-A, both parts 2.5
Q was concentrated under reduced pressure to obtain 0.7 g of purified solid matter of 6108-^.
I got it.
1);j記の如くして得られた6108−^、の精製固
形物を精製して、その純品を得るために高速液体クロマ
トグラフィー(日本分光TRIROTAR−V、UVI
DIミC−100V)をおこなった。その際、使用した
カラムはステンレス製バツクドカラムDevelosi
l 0DS−1020/250 (立村化学製)2本を
用いた。6108−Aの組成固形物0.7 gをメタノ
ール14+a Qに溶解した試料を7回に分けて注入し
た。展開溶媒として0.0IMホウ酸すトリウム−アセ
トニトリル(55: 45)を用いて分画な行った,
240nmの紫外部吸収で6108−A,に該当するピ
ークを集め、これを減圧下アセトニトリルを留去した.
残渣に酢酸エチルを加え5%水酸化ナトリウム水でpH
9.oに調整し、酢酸エチル層に転溶させた.酢酸エチ
ル層を精製水で洗浄し無水硫酸ナトリウムで1151水
した後。1); To purify the purified solid substance of 6108-^ obtained as described in j, high performance liquid chromatography (JASCO TRIROTAR-V, UVI
DI MiC-100V) was performed. At that time, the column used was a stainless steel back column Developosi.
Two l0DS-1020/250 (manufactured by Tatemura Chemical) were used. Composition of 6108-A A sample prepared by dissolving 0.7 g of solid matter in methanol 14+aQ was injected in seven portions. Fractionation was performed using 0.0 IM sodium borate-acetonitrile (55:45) as a developing solvent.
A peak corresponding to 6108-A was collected by ultraviolet absorption at 240 nm, and acetonitrile was distilled off from this peak under reduced pressure.
Add ethyl acetate to the residue and adjust the pH with 5% sodium hydroxide.
9. o and transferred to the ethyl acetate layer. The ethyl acetate layer was washed with purified water and diluted with anhydrous sodium sulfate.
濃縮乾固し6108−^,無色の粉末21 8 tng
を得た。Concentrated to dryness 6108-^, colorless powder 218 tng
I got it.
実施例 3
水飴1.0%、肉エキス0.2%、綿実粉0.5%,小
麦胚芽0.5%、硫酸マグネシウム0.2%、炭酸カル
シウム0.2%、塩化ナトリウム0 、 2 %、第一
燐酸カリ0.1%(pH7、0)を含有する前培養培地
100mgを含む50〇−容三角フラスコにミクロモノ
スポラ属エスピー!3^06108株を一白金耳接粍し
. 220rpmの回転振どう培養機により28℃で7
2時間培養して種母を調製した。Example 3 Starch syrup 1.0%, meat extract 0.2%, cottonseed flour 0.5%, wheat germ 0.5%, magnesium sulfate 0.2%, calcium carbonate 0.2%, sodium chloride 0,2 %, Micromonospora sp. in a 500-mL Erlenmeyer flask containing 100 mg of preculture medium containing 0.1% potassium monophosphate (pH 7.0). 3^06108 stocks were installed with one platinum ear. 7 at 28°C in a rotary shaker at 220 rpm.
A seed mother was prepared by culturing for 2 hours.
前培養培地と同じ組成の培地120Qを含む200 Q
容ファーメンタ−に種母を1.2Q接托し、27℃、回
転数200rpm、通気量12012 7分で96時間
通気攪拌した。200Q containing medium 120Q with the same composition as the preculture medium
1.2 Q of seedlings were inoculated into a capacity fermenter, and the mixture was aerated and stirred for 96 hours at 27° C., at a rotation speed of 200 rpm, and at an aeration rate of 12,012 7 minutes.
実施例 4
実施例3で得られた培養液110Qにろ過補助剤5、!
’ikgを加えろ過し、ろ液95Qを得た.、このろ肢
を4Q容のダイヤイオンIIP−20 (三菱化成!!
A)カラムに通過させ活性成分を吸着させた.水8Q、
次いで50%メタノール水Illで洗浄した後80%ア
セトン水で溶出させた.溶出液12Qをc4縮し,i*
kf液に5%,水酸化ナトリウム水溶液を加えpH9.
0に調整し、等量の酢酸エチルで2回反復洗浄した後、
等量のブタノールで抽出した.この抽出液を減圧′f:
4縮し6108−8を含む油状物19gを得た。Example 4 Filter aid 5 was added to the culture solution 110Q obtained in Example 3!
'ikg was added and filtered to obtain filtrate 95Q. , this limb is 4Q capacity Diaion IIP-20 (Mitsubishi Kasei!!
A) Passed through a column to adsorb active ingredients. Water 8Q,
The column was then washed with 50% methanol water and eluted with 80% acetone water. Eluate 12Q was condensed with c4 and i*
Add 5% aqueous sodium hydroxide solution to the kf solution and adjust the pH to 9.
After adjusting to 0 and washing twice with an equal volume of ethyl acetate,
Extracted with an equal volume of butanol. This extract is depressurized′f:
19 g of an oil containing 6108-8 was obtained by condensation.
前記の如くして得られた6108−8を含む油状物を予
めクロロホルム−メタノール
充填されたシリカゲルC−300 (和光純桑製)カラ
ム(4x50cm)に吸着せしとクロロホルム−メタノ
ール(10:I)混液とメタノールによるグラジェント
溶出クロマトグラフィーを行った.得られた6108−
Biilii分0.9αを減圧′f:4縮り,6108
−I3(7)精1 11111 形物1.1gを得た。The oily substance containing 6108-8 obtained as above was adsorbed on a silica gel C-300 (manufactured by Wako Junkuwa) column (4 x 50 cm) filled with chloroform-methanol and chloroform-methanol (10:I). Gradient elution chromatography was performed using the mixture and methanol. Obtained 6108-
Depressurize Biillii minute 0.9α'f: 4 compression, 6108
1.1 g of -I3(7) Sei 1 11111 shaped product was obtained.
前記の如くして得られた6108−Bの111製固形物
1.05gをメタノール6mQl、溶解した試料を、予
めメタノールで充填したトヨバールIIW−40(東洋
曹達工業製)カラム(3x30an)に負荷し、メタノ
ールで展開した。得られた6108−13画分ヲ1圧c
4縮シロ108−B(7)8I製粒粉末138+を得た
。A sample obtained by dissolving 1.05 g of the 111 solid of 6108-B obtained as described above in 6 mQl of methanol was loaded onto a Toyovar IIW-40 (manufactured by Toyo Soda Kogyo Co., Ltd.) column (3 x 30 ann) filled with methanol in advance. , developed with methanol. 1 pressure c of the obtained 6108-13 fraction
A 4-condensed Shiro 108-B(7)8I granulated powder 138+ was obtained.
前記の如くして得られた6108−8の精製固形物を精
製して、その純品を得るために高速液体クロマトグラフ
ィー(日本分光TRIROTAR−V、 UVIDEC
−100V)を行った。その際、使用したカラムはステ
ンレス製バツクドカラムDevclosil 005−
10207250(立村化学製)2本を用いた。 61
08−Bの和製固形物135mgをメタノール5+iに
溶解した試料を3回に分けて注入した。 ff4開溶媒
として0.01Mホウ酸ナトリウムーアセトニトリル混
液(75: 25)を用いて分画を行った。 240m
mの紫外部吸収で6108−8に該当するピークを集め
、これを減圧下アセトニトリルを留去した。残渣をダイ
ヤイオン11P−20SS (三菱化成製)カラム(l
x20an)に通液し精製水25IIQで洗浄後、エタ
ノールで溶出した。The purified solid substance of 6108-8 obtained as described above was purified by high performance liquid chromatography (JASCO TRIROTAR-V, UVIDEC) to obtain a pure product.
-100V). At that time, the column used was a stainless steel back column Devclosil 005-
Two bottles of 10207250 (manufactured by Tachimura Chemical) were used. 61
A sample prepared by dissolving 135 mg of Japanese solid 08-B in methanol 5+i was injected in three parts. Fractionation was performed using a 0.01M sodium borate-acetonitrile mixture (75:25) as an ff4 opening solvent. 240m
A peak corresponding to 6108-8 was collected by ultraviolet absorption at m, and acetonitrile was distilled off from this peak under reduced pressure. The residue was transferred to a Diaion 11P-20SS (manufactured by Mitsubishi Kasei) column (l
After washing with purified water 25IIQ, the solution was eluted with ethanol.
溶出液を濃j宿乾固し6108−13の無色の粉末44
n1τを/Jjた。The eluate was concentrated and dried to give 6108-13 colorless powder 44
n1τ/Jj.
実施例 5
グルコース0.1%、可溶性澱粉1.0%、スキムミル
ク2.0%、乾燥酵母0.4%、イーストエキス0.1
%、Mail 0.1%、K、111”040.05%
、Mg5O,−7B、00,05%、CaC1,・2B
、00.05%(1,117,Q)を含有する前培養培
地100m Qを含む500m(1,容三角フラスコに
ミクロモノスポラ属エスピーBAO6108株を一白金
耳接種し、220rpmの回転振どう培養機により28
℃で72時間”r’f養して種母を調製した。Example 5 Glucose 0.1%, soluble starch 1.0%, skim milk 2.0%, dried yeast 0.4%, yeast extract 0.1
%, Mail 0.1%, K, 111”040.05%
, Mg5O,-7B, 00,05%, CaC1,・2B
, 100 m of preculture medium containing 00.05% (1,117, Q) and 500 m of preculture medium containing Q (1) A loopful of Micromonospora sp. 28 depending on the machine
Seed seeds were prepared by incubation at ℃ for 72 hours.
前培J’j ”ff地と同シ#Jl成)r72sB+z
o rb 3 含ムzoo o。Previous culture J'j "FF ground and same #Jl composition) r72sB+z
o rb 3 containing zoo o.
容ファーメンタ−に種はを1.2g接種し、27℃。1.2 g of seeds were inoculated into a fermenter at 27°C.
回転vi200rpm、通気量120Q/分で96時間
通気攪拌した。The mixture was aerated and stirred for 96 hours at a rotation speed of 200 rpm and an aeration rate of 120 Q/min.
実施例 6
実施例5で得られた培養液115Qにろ過補助剤3.5
kgを加えろ過し、ろ液107111を得た。このろ液
を8Q容のダイヤイオンIIP−20(三菱化成製)カ
ラムに通過させ活性成分を吸着させた。水20Q、次y
いで30’%、メタノール水16Qで洗浄した後、30
’%、メタノール水−メタノールのグラジェント溶出を
行った。6108−Cを含む溶出液15Qf!:濃縮し
、濃縮故に5%水酸化ナトリウム水溶液を加えpo9.
oに調整し、等量の酢酸エチルで2回反復洗浄した後、
等i^のブタノールで抽出した。この抽出液を減圧濃縮
し6108−Cを含む油状物32gを得た。Example 6 3.5% of the filter aid was added to the culture solution 115Q obtained in Example 5.
kg was added and filtered to obtain filtrate 107111. This filtrate was passed through an 8Q volume Diaion IIP-20 (manufactured by Mitsubishi Kasei) column to adsorb the active ingredient. Wed 20Q, next y
After washing with methanol water 16Q,
'%, methanol, water-methanol gradient elution was performed. Eluate 15Qf containing 6108-C! : Concentrate and add 5% sodium hydroxide aqueous solution for concentration, po9.
After washing twice with an equal volume of ethyl acetate,
Extracted with equal amount of butanol. This extract was concentrated under reduced pressure to obtain 32 g of an oil containing 6108-C.
1);I記の如くしてfi)られた610B−Cを含む
油状物を予めクロロホルム−メタノール(9:1)混液
で充填されたシリナゲルC−300(和光純薬製)カラ
ム(4x50an)に吸着せしめクロロホルム−メタノ
ール(9: l)混液とメタノールによるグラジェント
溶出クロマトグラフィーを行った。得られた6108−
8画分0.9111を減圧I:4縮し6108−Cの粗
製固形物7.3gを得た。1); The oily substance containing 610B-C prepared as described in I) was transferred to a Silina Gel C-300 (manufactured by Wako Pure Chemical Industries, Ltd.) column (4x50an) filled in advance with a chloroform-methanol (9:1) mixture. After adsorption, gradient elution chromatography was performed using a chloroform-methanol (9:1) mixture and methanol. Obtained 6108-
8 fractions, 0.9111, were condensed under reduced pressure I:4 to obtain 7.3 g of crude solid 6108-C.
前記の如くして得られた6108−Cの粗製固形物を少
量のメタノールに溶解し、オクタデシルシリル化シリカ
ゲル(粒子径80μ、ウォータース社製)カラム(3x
30an)に吸着し0.01Mホウ酸ナトリウムーアセ
トニトリル混液(75: 25)を用いて溶出した。6
108−Cを含む両分を集め、減圧蒸留によりアセトニ
トリルを留去した後、等量のブタノールで抽出した。ブ
タノール抽出液を減圧濃縮乾固して6108−C粗製粉
末1.3gを得た。The crude solid of 6108-C obtained as described above was dissolved in a small amount of methanol and applied to an octadecylsilylated silica gel (particle size 80μ, manufactured by Waters) column (3x
30an) and eluted using a 0.01M sodium borate-acetonitrile mixture (75:25). 6
Both fractions containing 108-C were collected, acetonitrile was distilled off under reduced pressure, and then extracted with an equal amount of butanol. The butanol extract was concentrated to dryness under reduced pressure to obtain 1.3 g of 6108-C crude powder.
6108−C相製粉末を少量のメタノールに溶解し、予
めクロロホルム−メタノール(9:l)混液で充填され
たシリカゲルC−300(和光純薬製)カラム(2x3
0+xn)に吸着せしめクロロホルム−メタノール(9
:I)混液とメタノールによるグラジェント溶出クロマ
トグラフィーを行った。得られた6108−13画分3
3軸αを減圧濃縮し6108−Cの粗粉末360II1
gを11)だ。6108-C phase powder was dissolved in a small amount of methanol, and a silica gel C-300 (Wako Pure Chemical Industries, Ltd.) column (2x3) filled with a chloroform-methanol (9:l) mixture was prepared.
0+xn) and chloroform-methanol (9
:I) Gradient elution chromatography using the mixture and methanol was performed. Obtained 6108-13 fraction 3
Concentrate 3-axis α under reduced pressure to obtain 6108-C crude powder 360II1
g is 11).
610B−Cの粗粉末20011tgをエタノール−メ
タノール(1: l)混液な用いて再結晶を行い610
8−C結晶33mgを得た。20011 tg of coarse powder of 610B-C was recrystallized using ethanol-methanol (1: l) mixture.
33 mg of 8-C crystals were obtained.
実施例 7
グルコース0.1%、可溶性澱粉1.0%、スキムミル
ク2.0%、乾燥酵母0.4%、イーストエキス0.1
%、 NaC1O,1%、K、IIPo、 0.05%
、Mg5O,・711.00.05%、CaC1,・2
B、00.05%(pH7,0)を含有する前培養培地
loom Qを含む500m Q容三角フラスコにミク
ロモノスポラか:エスビーロAO6108株を−・白金
「接種し、220rpmの回転振どう培養機により28
℃で72時間培養して種母を調製した8
前培養培地と同じ組成の培地+20Qを含む2000゜
容ファーメンタ−に種母を1.20接種し、27℃、回
転数200rpI11.通気量120Q/分で66時間
通気攪11゛シた。Example 7 Glucose 0.1%, soluble starch 1.0%, skim milk 2.0%, dried yeast 0.4%, yeast extract 0.1
%, NaC1O, 1%, K, IIPo, 0.05%
, Mg5O, 711.00.05%, CaC1, 2
A preculture medium containing B, 0.05% (pH 7,0) was inoculated with Micromonospora: Esviro AO6108 strain in a 500 m Erlenmeyer flask containing Q, and placed in a rotary shaking culture machine at 220 rpm. by 28
A seed mother was prepared by culturing at 72 hours at 8. 1.20 seeds were inoculated into a 2000° fermenter containing medium + 20Q with the same composition as the preculture medium, and the seed mother was incubated at 27°C with a rotational speed of 200 rpm. Aeration and stirring were carried out for 66 hours at an aeration rate of 120 Q/min for 11 degrees.
実施例 8
実施例7で得られた培養液120Qにろ過補助剤3 、
5 kgを加えろ過し、ろ液105Qを得た。このろ故
を7Q容のダイヤイオンIIP−20(三菱化成製)カ
ラムに通過させ活性成分を吸着させた。水20Q、次い
で50%メタノール水20Qで洗浄した後80’%、ア
セトン水で溶出させた。溶出液13QをV:4縮し、’
(L’4 h管1液に5%水酸化ナトリウム水溶液を加
えpH9,0に調整し、等量の酢酸エチルで2回反復抽
出した。酢酸エチル抽出液を合わせ1等量の水を加え6
N−塩酸を用いて9113.0に調整し6108−Dを
水層に転溶した7本層を分取し5%水酸化ナトリウム水
溶液を加えpH9,0に調整し1等量の酢酸エチルで抽
出した。抽出液を無水硫酸ナトリウムで脱水したのち減
圧濃縮し6108−Dを含む油状物5.5gを得た。Example 8 Filter aid 3 was added to the culture solution 120Q obtained in Example 7.
5 kg was added and filtered to obtain filtrate 105Q. This filtrate was passed through a 7Q volume Diaion IIP-20 (manufactured by Mitsubishi Kasei) column to adsorb the active ingredients. After washing with 20Q of water and then 20Q of 50% methanol water, it was eluted with 80'% acetone water. Eluate 13Q was condensed by V:4 and '
(Add 5% aqueous sodium hydroxide solution to the L'4 h tube 1 solution to adjust the pH to 9.0, and extract twice with an equal amount of ethyl acetate. Combine the ethyl acetate extracts, add 1 equivalent of water, and add 6.
The pH was adjusted to 9113.0 using N-hydrochloric acid, 6108-D was transferred to the aqueous layer, the seven layers were separated, 5% sodium hydroxide aqueous solution was added, the pH was adjusted to 9.0, and 1 equivalent of ethyl acetate was added. Extracted. The extract was dehydrated over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 5.5 g of an oil containing 6108-D.
前記の如くして得られた6108−Dを含む油状物を少
量のメタノールに溶解し、オクタデシルシリル化シリカ
ゲル(粒子径80μ、ウォータース社製)カラム(3x
30an)に吸着し0.0回Mホウ酸ナトリウムーアセ
トニトリル混液(45: 55)を用いて溶出した。
610B−Dを含む両分を集め、減圧蒸留によりアセト
ニトリルを留去した後、5%水酸化ナトリウム水溶液を
加えpH9,0に調整し、等11(の酢酸エチルで2回
反復抽出した抽出液を無水硫酸すI・リウムで脱水した
のち減圧c4縮乾固して6108−1)111粉末1.
3gを得た。The oily substance containing 6108-D obtained as described above was dissolved in a small amount of methanol and applied to an octadecylsilylated silica gel (particle size 80μ, manufactured by Waters) column (3x
30 ann) and eluted using a 0.0 M sodium borate-acetonitrile mixture (45:55).
Both parts containing 610B-D were collected, and the acetonitrile was distilled off under reduced pressure. A 5% aqueous sodium hydroxide solution was added to adjust the pH to 9.0, and the extract was extracted twice with ethyl acetate. After dehydrating with anhydrous sodium sulfate and lithium, it was concentrated to dryness under reduced pressure C4 to obtain 6108-1) 111 powder 1.
3g was obtained.
6108−D粗粉末を少量のメタノールに溶解し、予め
クロロホルムで充填されたシリカゲルC−300(和光
純@製)カラム(2x30cm)に吸着せしめ、クロロ
ホルムとクロロホルム−メタノール(9:1)混液によ
るグラジェント溶出クロマトグラフィーを行った。得ら
れた6108−D画分を減圧濃縮し、6108−Dの粗
粉末500mgを得た。6108-D crude powder was dissolved in a small amount of methanol and adsorbed onto a silica gel C-300 (manufactured by Wako Jun@) column (2 x 30 cm) that had been filled with chloroform in advance. Gent elution chromatography was performed. The obtained 6108-D fraction was concentrated under reduced pressure to obtain 500 mg of crude powder of 6108-D.
111j記の如くして得られた6108−Dの粗粉末を
111製して、その純品を得るために高速液体クロマト
グラフィー(日本分光TRIROTAR−V、 UVI
DEC−100V)を行った。その際、使用したカラム
はステンレス製バツクドカラムDevelosil 0
DS−10207250(立村化学製)2本を用いた。The crude powder of 6108-D obtained as described in Section 111j was purified by high performance liquid chromatography (JASCO TRIROTAR-V, UVI) to obtain a pure product.
DEC-100V) was performed. At that time, the column used was a stainless steel backed column Developosil 0.
Two DS-10207250 (manufactured by Tachimura Chemical) were used.
6108−Dの粗粉末45On+gをメタノール9I
IQに溶解した試料を3回に分けて注入した。展開溶媒
として0.0回Mホウ酸ナトリウムーアセトニトリル混
液(45: 55)を用いて分画な行った。240n+
eの望外部吸収で6108−I)に該当するピークを集
め、これを減圧下アセトニトリルを留去した。残渣に酢
酸エチルを加え5%水酸化ナトリウム水でpH9,0に
調整し、酢酸エテル層に転溶させた。酢酸エチル層を精
製水で洗浄し無水硫酸ナトリウムで11;ト水した後、
′e4縮乾固し6108−Dの無色の粉末51mgを得
た。6108-D coarse powder 45On+g methanol 9I
The sample dissolved in IQ was injected in three doses. Fractionation was carried out using a 0.0 M sodium borate-acetonitrile mixture (45:55) as a developing solvent. 240n+
A peak corresponding to 6108-I) was collected by the undesired absorption of e, and acetonitrile was distilled off from this peak under reduced pressure. Ethyl acetate was added to the residue, the pH was adjusted to 9.0 with 5% aqueous sodium hydroxide, and the mixture was transferred to the ethyl acetate layer. The ethyl acetate layer was washed with purified water and diluted with anhydrous sodium sulfate for 11 minutes.
'e4 was condensed to dryness to obtain 51 mg of colorless powder of 6108-D.
実施例 9
0ザマイシン53I1gを2a+Qのクロロホルムに溶
解し、6N−塩酸で約pH4に調整し、これにIn+g
/a+Qのアセトヒドラジン溶液6.5+IIQを加え
、6N−塩酸で約pH4に調整し、反応を行った。これ
をシリカゲルC−300(和光純:2!l!J )カラ
ム(lx5an)に吸着せしめ、クロロホルムとクロロ
ホルム−メタノール(3: 2)混液によるグラジェン
ト溶出クロマトグラフィーを行った。得られた6108
−A、画分20m Qを減圧濃縮し、6108−A、の
精製固形物22mgを得た。Example 9 1 g of 0zamycin 53I was dissolved in 2a+Q chloroform, the pH was adjusted to about 4 with 6N-hydrochloric acid, and In+g
/a+Q acetohydrazine solution 6.5+IIQ was added, the pH was adjusted to about 4 with 6N-hydrochloric acid, and the reaction was carried out. This was adsorbed on a silica gel C-300 (Wako Pure: 2!l!J) column (lx5an), and gradient elution chromatography using chloroform and a chloroform-methanol (3:2) mixture was performed. Obtained 6108
-A, fraction 20m Q was concentrated under reduced pressure to obtain 22 mg of purified solid 6108-A.
実施例 10
ロザマイシン2.3gとL−システィン塩酸塩620m
gをメタノール15m Qに溶解し、lN−Na0Il
メタノール溶液3.3ta Qを加え室温で2.5時間
攪拌した。反応液を減圧上濃縮乾固した後、クロロホル
ム−メタノール(9:1)混液1OIIQに溶解し、予
めクロロホルムで充填したシリカゲルC−300(和光
紬薬製)カラム(3x50an)に吸着せしめ、クロロ
ホルム−メタノール(9:1)混液で溶出した。 61
08−Cを含む両分を集め、減圧上濃縮乾固し6108
−Cを含む油状物を得た。6108−Cを含む油状物を
エタノール−メタノール混液(1: l)を用いて再結
晶を行い、6108−C結晶520■を得た。Example 10 2.3 g of rosamycin and 620 m of L-cystine hydrochloride
Dissolve g in methanol 15mQ, IN-Na0Il
3.3 taQ of methanol solution was added and stirred at room temperature for 2.5 hours. After the reaction solution was concentrated to dryness under reduced pressure, it was dissolved in a chloroform-methanol (9:1) mixture 1OIIQ and adsorbed on a silica gel C-300 (Wako Tsumugi Co., Ltd.) column (3x50an) filled with chloroform in advance. Elution was performed with a mixture of methanol (9:1). 61
Both fractions containing 08-C were collected and concentrated to dryness under reduced pressure to give 6108
An oil containing -C was obtained. The oil containing 6108-C was recrystallized using a mixture of ethanol and methanol (1:1) to obtain 520 cm of 6108-C crystals.
実施例 11
0ザマイシン2.3gとトリフェニルホスフォラニリデ
ン−2−プロパノン6、ogをメタノール15meに溶
解し、3規定塩酸水溶液1.4o+Qを加えて、60℃
に加温し4時間反応を行った0反応酸を減圧下濃糸宿乾
固し、6108−Dを含む油状物1.35gを得た。Example 11 2.3 g of 0zamycin and 6.0 g of triphenylphosphoranylidene-2-propanone were dissolved in 15 me of methanol, 1.4 o + Q of 3N hydrochloric acid aqueous solution was added, and the mixture was heated at 60°C.
The zero-reacted acid, which had been reacted for 4 hours, was dried under reduced pressure to obtain 1.35 g of an oil containing 6108-D.
6108−Dを含む油状物を精製して、その純品を得る
ために高速液体クロマトグラフィー(11本分光TI?
ll1OTAR−V、UVIDEC−100V)を行ツ
タ。ソノ際、使用したカラムはステンレス製バツクドカ
ラムDcvelosil 0DS−1020/250
(立村化学gJ)2木を用いた。6108−Dの油状物
をメタノールl0IIQに溶解した試料を8回に分けて
注入した。展開溶媒としてO,01Mホウ酸すl・リウ
ムーアセトニトリル(昆改(/15 + 55)を用い
て分画を行った。 240nmの望外部吸収で6108
−Dに該当するピークを集め、これを減圧下アセトニト
リルを留去した。残渣に酢酸エチルを加え5%水酸化ナ
トリウム水でpH9,0に調整し。In order to purify the oil containing 6108-D and obtain a pure product, high performance liquid chromatography (11 spectroscopy TI?
ll1OTAR-V, UVIDEC-100V). The column used was a stainless steel backed column Dcvelosil 0DS-1020/250.
(Tachimura Kagaku gJ) 2 wood was used. A sample of 6108-D oil dissolved in methanol 10IIQ was injected in 8 portions. Fractionation was carried out using O, 01M sulfur boric acid, lium-acetonitrile (Kunkai (/15 + 55)) as a developing solvent. 6108 at 240 nm extraneous absorption.
A peak corresponding to -D was collected, and acetonitrile was distilled off from this peak under reduced pressure. Ethyl acetate was added to the residue, and the pH was adjusted to 9.0 with 5% aqueous sodium hydroxide.
酢酸エチル層に転溶させた。酢酸エチル層を精製水で洗
浄し無水硫酸ナトリウムでIJ52水した後、′t:4
縮乾固し6108−Dの無色粉末1.06mgを得た。The mixture was transferred to the ethyl acetate layer. After washing the ethyl acetate layer with purified water and diluting with anhydrous sodium sulfate,
The mixture was condensed to dryness to obtain 1.06 mg of colorless powder of 6108-D.
本発明の6108−^1.6108−II、6108−
C及び6108−Dは、すぐれた抗174活性を示しか
つ低毒性であることから、抗菌剤として有用である。6108-^1.6108-II, 6108- of the present invention
Since C and 6108-D exhibit excellent anti-174 activity and have low toxicity, they are useful as antibacterial agents.
第1図、第2図、第3袋、及び第4図はそれぞれメタノ
ール中で測定した6108−A1、6108−B、61
08−C及び6108−Dの紫外線吸収スペクトルを示
す。
第5図、第6図、第7図、及び第8図はそれぞれ610
1(−A1、 6108−11.6108−C及び61
08−Dの赤外ね吸収スペクトル(KBr法)を示す。
第9図、第1O図、第11図、及び第12図はそれぞれ
fi108−A1、6108−11.6108−C及び
6108−Dの重クロロホルム中300旧1zで測定し
た゛1ト核磁気共鳴スペクトルを示す。
第13図、第14図、第15図、及び第16図はそれぞ
れ6108−A、 、 6108−11.610B−C
及び6108−Dの重クロロホルム中75MIIzで測
定した1′C−核磁気共鳴スペクi・ルを示す。
特許出願人 、’?3’(、有製薬株式会社第
1 図
第
2 図
a長
(nm)
/i長
(nm)
第
図
5G
波長
(nm)
第
図
波長
(nm)Figures 1, 2, 3, and 4 are 6108-A1, 6108-B, and 61, respectively, measured in methanol.
The ultraviolet absorption spectra of 08-C and 6108-D are shown. Figures 5, 6, 7, and 8 are each 610
1 (-A1, 6108-11.6108-C and 61
The infrared absorption spectrum (KBr method) of 08-D is shown. Figure 9, Figure 1O, Figure 11, and Figure 12 are the nuclear magnetic resonance spectra of fi108-A1, 6108-11. shows. Figures 13, 14, 15, and 16 are 6108-A, , 6108-11.610B-C, respectively.
and 1'C-nuclear magnetic resonance spectra of 6108-D measured at 75 MIIz in deuterated chloroform. Patent applicant,'? 3' (Yu Pharmaceutical Co., Ltd. Figure 1 Figure 2 Figure a length (nm) /i length (nm) Figure 5G Wavelength (nm) Figure 5 Wavelength (nm)
Claims (8)
、−CH(OH)−SCH_2−CH(NH_2)−C
OOH又は−CH=CHCOCH_3を示す〕で表され
る6108−A_1、6108−B、6108−C、6
108−D又はそれらの塩。(1) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] [In the formula, R is -CH=NNHCOCH_3, -COOH
, -CH(OH)-SCH_2-CH(NH_2)-C
OOH or -CH=CHCOCH_3] 6108-A_1, 6108-B, 6108-C, 6
108-D or salts thereof.
る菌株を培養し、得られた培養液中より 6108−A_1、6108−B、6108−C及び/
又は6108−Dを採取することを特徴とする6108
−A_1、6108−B、6108−C及び/又は61
08−Dの製造法。(2) Cultivate a strain that belongs to the genus Micromonospora and produces 6108, and select 6108-A_1, 6108-B, 6108-C and/or
or 6108 characterized by collecting 6108-D
-A_1, 6108-B, 6108-C and/or 61
08-D manufacturing method.
6108−B、6108−C及び/又は6108−Dを
生産する菌株。(3) Belongs to the genus Micromonospora, 6108-A_1,
Strains producing 6108-B, 6108-C and/or 6108-D.
6108−B、6108−C及び/又は6108−Dを
生産する菌株がミクロモノスポラ・エスピーBA610
8株(FERM−P)であることを特徴とする第三請求
項記載の菌株。(4) Belongs to the genus Micromonospora, 6108-A_1,
The strain producing 6108-B, 6108-C and/or 6108-D is Micromonospora sp. BA610.
8 strain (FERM-P) according to claim 3.
させ6108−A_1を採取する事を特徴とする610
8−A_1の製造法。(5) 610 characterized by reacting the antibiotic rosamycin with acetohydrazine and collecting 6108-A_1
8-Production method of A_1.
108−Cを採取する事を特徴とする6108−Cの製
造法。(6) Reacting cysteine with the antibiotic rosamycin6
A method for producing 6108-C, characterized by collecting 108-C.
オラニリデン−2−プロパノンを反応させ6108−D
を採取する事を特徴とする6108−Dの製造法。(7) Reacting the antibiotic rosamycin with 1-triphenylphosphoranylidene-2-propanone 6108-D
A method for producing 6108-D, which is characterized by collecting 6108-D.
、6108−D又はそれらの塩を有効成分とする抗菌剤
。(8) 6108-A_1, 6108-B, 6108-C
, 6108-D or a salt thereof as an active ingredient.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP14864888A JPH023694A (en) | 1988-06-16 | 1988-06-16 | Antibiotic substance 6108s, production and use thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP14864888A JPH023694A (en) | 1988-06-16 | 1988-06-16 | Antibiotic substance 6108s, production and use thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH023694A true JPH023694A (en) | 1990-01-09 |
Family
ID=15457502
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP14864888A Pending JPH023694A (en) | 1988-06-16 | 1988-06-16 | Antibiotic substance 6108s, production and use thereof |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH023694A (en) |
-
1988
- 1988-06-16 JP JP14864888A patent/JPH023694A/en active Pending
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