IE43592B1 - Improvements in or relating to organic compounds - Google Patents
Improvements in or relating to organic compoundsInfo
- Publication number
- IE43592B1 IE43592B1 IE2187/75A IE218775A IE43592B1 IE 43592 B1 IE43592 B1 IE 43592B1 IE 2187/75 A IE2187/75 A IE 2187/75A IE 218775 A IE218775 A IE 218775A IE 43592 B1 IE43592 B1 IE 43592B1
- Authority
- IE
- Ireland
- Prior art keywords
- iii
- formula
- tetrahydro
- methanol
- production
- Prior art date
Links
- 150000002894 organic compounds Chemical class 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 33
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 235000015097 nutrients Nutrition 0.000 claims abstract description 12
- 241000133685 Aspergillus rugulosus Species 0.000 claims abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 239000003085 diluting agent Substances 0.000 claims abstract 2
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 239000002609 medium Substances 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 5
- 238000000855 fermentation Methods 0.000 claims description 5
- 230000004151 fermentation Effects 0.000 claims description 5
- 239000008024 pharmaceutical diluent Substances 0.000 claims description 5
- 239000001963 growth medium Substances 0.000 claims 1
- 239000003242 anti bacterial agent Substances 0.000 abstract description 25
- 229940088710 antibiotic agent Drugs 0.000 abstract description 23
- FAUOJMHVEYMQQG-HVYQDZECSA-N echinocandin B Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCC\C=C/C\C=C/CCCCC)[C@@H](C)O)=CC=C(O)C=C1 FAUOJMHVEYMQQG-HVYQDZECSA-N 0.000 abstract description 8
- 230000003115 biocidal effect Effects 0.000 abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 138
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 48
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 241001465754 Metazoa Species 0.000 description 17
- 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
- 208000015181 infectious disease Diseases 0.000 description 16
- 238000012360 testing method Methods 0.000 description 16
- 239000000243 solution Substances 0.000 description 15
- 241000222122 Candida albicans Species 0.000 description 14
- 229940095731 candida albicans Drugs 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000010828 elution Methods 0.000 description 12
- 238000011534 incubation Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 244000052616 bacterial pathogen Species 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 10
- 229920001817 Agar Polymers 0.000 description 9
- 239000008272 agar Substances 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000005984 hydrogenation reaction Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 8
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 210000003608 fece Anatomy 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000002329 infrared spectrum Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 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 6
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 6
- 239000002674 ointment Substances 0.000 description 6
- 238000002211 ultraviolet spectrum Methods 0.000 description 6
- 230000037396 body weight Effects 0.000 description 5
- 238000012505 colouration Methods 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 241000894007 species Species 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 241000233866 Fungi Species 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 229960000988 nystatin Drugs 0.000 description 4
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 4
- 238000009806 oophorectomy Methods 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 229960005322 streptomycin Drugs 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- 241000228212 Aspergillus Species 0.000 description 3
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 3
- 206010064899 Vulvovaginal mycotic infection Diseases 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 230000012173 estrus Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000002523 gelfiltration Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000011081 inoculation Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- NAHBVNMACPIHAH-HLICZWCASA-N p-ii Chemical compound C([C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H]2CSSC[C@H](NC(=O)[C@H](CC=3C=CC=CC=3)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC2=O)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(N)=O)=O)C(C)C)C1=CC=CC=C1 NAHBVNMACPIHAH-HLICZWCASA-N 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000011877 solvent mixture Substances 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010022678 Intestinal infections Diseases 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 239000006159 Sabouraud's agar Substances 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
- 239000006787 czapek-dox agar Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000002054 inoculum Substances 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003883 ointment base Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000012449 sabouraud dextrose agar Substances 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- RBTBFTRPCNLSDE-UHFFFAOYSA-N 3,7-bis(dimethylamino)phenothiazin-5-ium Chemical compound C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 RBTBFTRPCNLSDE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000134991 Aspergillus flavipes Species 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- 241000223211 Curvularia lunata Species 0.000 description 1
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 description 1
- 241000588722 Escherichia Species 0.000 description 1
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 description 1
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- 238000011785 NMRI mouse Methods 0.000 description 1
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 description 1
- 241000364057 Peoria Species 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- 229910019020 PtO2 Inorganic materials 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 208000010513 Stupor Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 201000007096 Vulvovaginal Candidiasis Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- HFACYLZERDEVSX-UHFFFAOYSA-N benzidine Chemical compound C1=CC(N)=CC=C1C1=CC=C(N)C=C1 HFACYLZERDEVSX-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 1
- 229960004022 clotrimazole Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 239000000287 crude extract Substances 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
- 238000001514 detection method Methods 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- AIUDWMLXCFRVDR-UHFFFAOYSA-N dimethyl 2-(3-ethyl-3-methylpentyl)propanedioate Chemical compound CCC(C)(CC)CCC(C(=O)OC)C(=O)OC AIUDWMLXCFRVDR-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 229960002867 griseofulvin Drugs 0.000 description 1
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 210000004276 hyalin Anatomy 0.000 description 1
- 238000005470 impregnation Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 1
- 235000020778 linoleic acid Nutrition 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 231100000219 mutagenic Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- 229940105631 nembutal Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 230000019612 pigmentation Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229940093430 polyethylene glycol 1500 Drugs 0.000 description 1
- 229940068886 polyethylene glycol 300 Drugs 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229960001005 tuberculin Drugs 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/06—Fungi, e.g. yeasts
- A61K36/062—Ascomycota
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07G—COMPOUNDS OF UNKNOWN CONSTITUTION
- C07G11/00—Antibiotics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Mycology (AREA)
- General Health & Medical Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Animal Behavior & Ethology (AREA)
- Alternative & Traditional Medicine (AREA)
- Medicinal Chemistry (AREA)
- Microbiology (AREA)
- Botany (AREA)
- Epidemiology (AREA)
- Biotechnology (AREA)
- Medical Informatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Compounds Of Unknown Constitution (AREA)
Abstract
1527494 Antibiotic SANDOZ Ltd 2 Oct 1975 [7 Oct 1974 12 Dec 1974 12 Feb 1975 7 April 1975 24 July 1975] 40301/75 Heading C2C A process for producing a compound selected from antibiotics SL 7810/F, SL 7810/F-II and SL 7810/F-III and their tetrahydro derivatives comprises (a) cultivating a SL 7810/F and/or SL 7810/F-II and/or SL 7810/F-III producing strain of Aspergillus rugulosus Thorn and Raper in the presence of a nutrient medium to produce one or more of the above antibodies or (b) hydrogenating an antibiotic chosen from SL 7810/F, SL 7810/F-II and SL 7810/F-III to produce the corresponding tetrahydro derivative. The strain used is suitably NRRL 8039. The compound may be mixed with a suitable diluent or carrier to form a pharmaceutical composition. Antibiotic SL 7810/F has the formula wherein R is Antibiotic SL 7810/FII has the formula wherein R is as above. Antibiotic SL 7810/F-III has the formula wherein R is as above.
Description
The present invention relates to the antibiotics SL 7810/F, SL 7810/F-II and SL 7810/F-III and their tetrahydro derivatives.
The structures of SL 7810/F and tetrahydro-SL. 7810/F as follows:- R = cis.cis.CO. JcHzJ7.CH = CH.CHg.CH = CHjcH^CHg (in the case of SL 7810/F) R = . CO JCKgJi 6‘CH3 0" the case of tetrahydro-SL 7810/F) 3592 The structures of SL 7810/F-II as follows:and tetrahydro-SL 7810/F-II are OH / R = cis,cis - CO. (in the case of SL «·"· Wl6 7 . CH = CH . CH2 . CH = CH . JCH^ . CH3 7810/F-II . CHg (in the case of tetrahydro - SL 7810/F-II) The structures of SL 7810/F-III and its tetrahydro derivative are as follows:- wherein R is cis,cis . CO . |cH^j y . CH = CH . CHg.CH = CH jCH^| 4 . CH, (in the case of SL 7810/F - III) ' . or R is .CO . ^CHgj . CHg (in the case of tetrahydro SL 7810/F - III) In accordance with this invention the new antibiotics SL 7810/F, SL 7810/F-II, SL 7810/F-III and the tetrahydro derivatives thereof may be obtained by a process comprising: a) cultivating a SL 7810/F and/or SL 7810/F-II and/or SL 7810/F-III producing strain of Aspergillus rugulosus Thom and Raper in the presence of a nutrient medium to produce ,5 SL 7810/F and/or SL 7810/F-II and/or SL 7810/F-III, b) hydrogenating an antibiotic chosen from SL 7810/F, SL 7810/F-II and SL 7810/F-III to produce the corresponding tetrahydro derivative.
The new antibiotics and the tetrahydro derivatives thereof have the following characteristics: SL 7810/F Colourless amorphous powder having an M.P. of 16O-163°C 5 (decomp.)f [α)θ°= "48.3° (c = 0.806 in methanol).
Analysis: Found C57.3 H 7.9 N9.2 025.2% Malecular weight (determined by osncmetry in ethanol): 1190.
UV spectrum in methanol: ^max= 194 nm, log £ ' =1.98 (see Fig. 1) 276 nm, log,£ ' = 0.14 IR spectrum in Nujol (see Fig. 2).
NMR spectrum in DMSO (100 megacycles per second, tetramethylsilane a3 internal standard) [see Fig. 3].
Hydrolysis of SL 7810/F with 6N hydrochloric acid (4 hours at 11O°C under an Nj atmosphere) yields a IS hydrolysis product, inter alia linoleic aoid.
Colour reactions: ninhydrin negative Cl2-benzidine blue (Solubility, stability, thin layer chromatogram and MIC values, see below) 435S& SL 7610/F-II Colourless amorphous powder having an M.P. of 158-160°C (decomp.); [0]^°= -47.9° (c = 0.81 in methanol). Analysis: Found C 58.5 H 8.0 89.3 0 23.8 % Molecular weight (determined by osnaretry in methanol): 1018.
UV spectrum in methanol: Lmax 193 nm, log 6' =3 1.95 (see Fig. 4) 278 nm, log £' = 0.18 IR spectrum in Nujol (see Fig. 5).
NMR spectrum in DMSO (100 megacycles per second, tetramethylsilane as internal standard) [see Fig. 6).
Colour reactions: ninhydrin negative Cl2~benzidine blue (Solubility, stability, thin layer chromatogram and MIC values, see below) SL 7810/F-III Colourless amorphous powder having an M.P. of 164-168°C (decomp.); [a]*0- -53.0° (c = 1.00 in methanol). Analysis: Found C 61.1 H 8.0 N 9.0 0 22,0 % UV spectrum in methanol: λΜΒν193 max nm, log £' = 1.98 (see Fig. 7) 278 nm, log 2' 0.24 IR spectrum in Nujol (see Fig. 8).
J ΰ 3 2 ^11 NMR spectrum in DMSO (100 megacycles per second, tetramethylsilane as internal standard) [see Pig, 9], Colour reactions: ninhydrin negative Clg-benzidine blue (Solubility, stability, thin layer chromatogram and MIC values, see below) Tetrahydro-SL 7810/F Colourless amorphous powder having an M.P. of 173-178°C (decomp.); after crystallization from ethanoJ/water (95:3) M.P. 190-205/210-212° (decomp.); [α]ρΟ" -47.8° (c = 0.984 in methanol). % Analysis: Found C 56.8 H 8.0 N 9.0 0 25.5 UV spectrum in methanol:λ max 194 nm' log £ 1 = 1.85 (see Fig. 10) 277 nm, log £ 1 = 0.09 227 (shoulder) log£‘ = 1.00 IR spectrum in Nujol (see Pig. 11).
^H. NMR spectrum in DMSO (100 megacycles per second, tetramethylsilane as internal standard) [see Pig. 12). 13 C NMR spectrum in CDgOD with tetramethylsilane as internal standard (see Table 1).
Colour reactions: ninhydrin negative Clg-benzidine blue (Solubility, stability, thin layer chromatogram and MIC values, see below) Hydrolysis of tetrahydro-SL 7810/F with 6N hydrochloric acid (4 hours at 110° under an Ng atmosphere) yields a hydrolysis product, Inter alia stearic acid.
Tetrahydro-SL 7810/F-II Colourless amorphous powder having an M.P. of 160-163uc (decomp.); [a]p°= -41.4° (c « 0.823 in methanol).
Analysis: Found C 58.7 H 8.1 N UV spectrum in methanol: λ majj, 194 (see Fig. 13) 278 227 9.6 0 23.7 % nm, log £' = 1.90 nm, log £' =»0.25 (shoulder) log £' = 1.07 IR spectrum in Nujol (see Fig. 14). 3’H NMR spectrum in DMSO (90 megacycles per second, tetramethylsilane as internal standard) [see Fig. 15]. 13 C NMR spectrum in CDjOD with tetramethylsilane as internal standard (see Table 2).
Colour reactions: ninhydrin negative Clj-benzidine blue (Solubility, stability, thin layer chromatogram and MIC values, see below) Tetrahydro-SL 7810/F-III Colourless amorphous powder having an M.P. of 175-180°C 5 (decomp.); [α]θ = -41.5° (c = 1,094 in methanol).
Analysis: Found C 60.5 H 8.5 N 9.2 0 21.9 % UV spectrum in methanol: \__193 c max nm, log δ' = 1.93 (see Fig. 16) 278 nm, log S' = 0.19 224 nm, log £' = 1.01 (shoulder) IR spectrum in Nujol (see Pig. 17).
Si NMR spectrum in DMSO (100 megacycles per second, tetramethylsilane as internal standard) [see Fig. 18).
Colour reactions: ninhydrin negative 15 Clj-benzidine green (Solubility, stability, thin layer chromatogram and MIC values, see below) 3 3 5 2 Solubility At room temperature, the antibiotics SL 7810/F, SL 7810/F-II and SL 7810/F-III and the tetrahydro derivatives thereof are readily soluble in methanol and ethanol, difficultly soluble in chloroform, ether, petroleum ether and hexane, and practically insoluble in water.
Stability In the presence of light and especially in the air the new antibiotics SL 7810/F, SL 7810/F-II and SL 7810/F-III show little stability and decompose. The decomposition is also observed when heating to over 5O'£ By hydrogenation to the tetrahydro derivatives the instability is eliminated to a great extent.
A characteristic of the three antibiotics and the tetrahydro derivatives thereof is the instability under basic conditions. At a pH over 8 conversion to decomposition products occurs, the latter being biologically only slightly active or no longer active.
Thin layer chromatogram Analysis is effected on silica gel Merck 60 plates (thickness of layer 0.25 mm). With the eluant indicated hereinafter the following Rf values may be ascertained : Λ 'J Ιί :· 3 Eluant Rj, values SL 7810/1' SL 7Β10/Ε-Π SL 7810/E-lll chloroform/methanol/water (70 : 25 : 5) 0.28 0.47 0.59 chloroform/methanol (10 : 3) 0.15 0,27 0,44 chloroform/methanol (2 : 1) 0.41 (ethyl acetate/n-butanol) water-saturated (3 i 1) 0,22 0,33 0,34 In this determination, the antibiotics SL 7810/F, SL 7810/F-II and SL 7810/F-III show the same R^ values as their tetrahydro derivatives.
Upon development with a 0.2!(w/v) solution of ' CetSO^)^ in 50i£.(w/v) sulphuric acid as spray reagent the following spots may be detected (after heating to 130°c): SL 7810/F SL 7810/F-II SL 7810/F-III tetrahydro-SL 7810/F tetrahydro-SL 7810/F-II tetrahydro-SL 7810/F-III brown spots brown spots brown spots yellowish colouration faint colouration light brown colouration ' 43^32 Iodine vapour may alternatively be used for the detection of the antibiotics SL 7810/F, SL 7810/F-II and SL 7810/F-III.
The three antibiotics SL 7810/F, SL 7810/F-II and SL 7810/F-III may Le differentiated from their tetrahydro derivatives by thin layer chromatography on silica gel GF 254 plates (thickness of layer 0.3 mm), whereby the silica gel is mixed with a 3% (w/v) of AgNOg. Using chloroform/methanol/water (70:25:5 - parts by volume) as eluant, the following values may be ascertained with 40 of the compound: Antibiotic Rf value SL 7810/F 0.33 SL 7810/F-II 0.42 SL 7810/F-III 0.64 £- hydroxybenzaldehyde 0.80 Tetrahydro derivative R£ value tetrahydro-SL 7810/F 0.40 tetrahydro-SL 7810/F-II 0.45 tetrahydro-SL 7810/F-III 0.66 griseofulvin 0.92 The compounds are detected by spraying with vanillin-sulphuric acid. Upon heating to 120-130° yellow-brown colour spots appear in the case of the tetrahydro compounds. The non-hydrogenated compounds show a reddish colouration.
Process variant a) of the invention may be carried out in accordance with known methods for the fermentative obtention of antibiotics. A culture of the new strain of Aspergillus rugulosus Thom and Raper, usable in the process of the invention, has been deposited with the United States Department of Agriculture (Northern Utilization Research and Development Division), Peoria, Ill., USA, under the reference NRRL 8039, where it is freely available for examination.
It is preferred to use the strain NRRL 8039, but other strains which may be obtained from the initial strain Aspergillus rugulosus Thom αηή*Raper by treatment with mutagenic substances or rays or by selection, may alternatively be used.
Characteristics of the strain NRRL 8039 The new strain NRRL 8039 of Aspergillus rugulosus Thom and Raper was isolated from a soil sample found at the Jaun pass (Switzerland), and owing to its morphologic characteristics corresponds to the description of the species Aspergillus rugulosus Thom and Raper in the Aspergillus monograph of K.B.Raper and D.I.Fennell (THE GENUS ASPERGILLUS, The Williams and Wilkins Company, Baltimore 1965).
The strain NRRL 8039 grows on an agar nutrient medium at a temperature between 15 and 50eCi the growth optimum is between 35 and 42eC. On CzapekDox-agar the strain NRRL 8039 grows rather slowly, the cultures approximately correspond to the description cf the speciee (Raper and Fennell, 1965): days old colonies are strongly wrinkled, and the short, velvet-like aerial mycelium has a gray, light brown or brown-violet pigmentation. The margin of the colony remains white at lower incubation temperatures (e.g. 18-27°C), and has a yellow-brown appearance at higher temperatures (e.g. 33-45*0. The under side of the colony remains yellowish at lower incubation temperatures; at higher temperatures a violet pigment is formed and is given off into the agar. Even after a 20 day incubation on Czapek-Dox-agar no cleistothecia are formed, and only at higher incubation temperatures sporadic, stunted conidiophores are formed.
The strain NRRL 8039 develops much better and more rapidly on 2% (w/w) malt-dextrose-agar, where a considerable number of the cleistothecia and the eonidial heads are formed and are mature after 20 days incubation at 27°C. The colonies are at best slightly plicated, but usually not plicated at all, and the velvet-like aerial mycelium is uniformly yellowish coloured. The under side of the colony is yellow at lower incubation temperatures, and light brown at higher temperatures.
The strain NRRL 8039 grown on 2% (w/w) hialt5 dextrose-agar shows dark green oonidial heads which usually appear in small groups in the colony and at the margin of the same.
The morphology and dimension of all the structures of the asexual state conform well with the description of the species of Aspergillus rugulosus mentioned above.
However, the ascigerous state differs somewhat from the description of the^species. Thus, the spherical cleistothecia which develop in large numbers at several layers of the velvet-like aerial mycelium, remain considerably smaller than indicated for the species (50-80 p. in diameter as compared with 225-350 jl). The Httlle cells are also hyaline, whereas they should be dark brown in this species. However, there is a good conformity with the description of the species as regards the characteristic feature of the species of the violet-orange-red, lenticular 4.1-5.0 x 3.4-3.8 Jx measuring ascospores, the surface of which is more or less clearly wrinkled and sulcated, and the two parallel equatorial crests pf which have a width of 0.4-0.7 Ji. 359 a.
The new strain NRRL 8039 may be cultivated on various nutrient media containing the usual nutrients, e.g. as described in the following example.
The new antibiotics SL 7810/F, SL 7810/F-II and SL 7810/F-III may be produced in such a manner that a liquid nutrient medium is inoculated with a suspension of spores or mycelium of the strain NRRL 8039, and the culture is incubated for 2 to 4 days, preferably 3 days, at 27°C. The culture is effected under aerobic conditions, either by surface culture fermentation or submerged culture fermentation. As soon as the maximum amount of antibiotics has been produced (ascertainable by determining the activity against Candida albicans), the antibiotics are obtained from the culture solution in accordance with known methods, e.g. as described in the following example, whereby other organic solvents, e.g. butyl acetate or butanol, may alternatively be used as solvent in place of ethyl acetate.
The separation of fatty impurities from the crude extract may be effected by filtering over a silica gel column, whereby about a 4- to 5-fold quantity by weight of silica gel, calculated on the amount of extract, is used. Elution is effected with mixtures of chloroform/methanol (see following example). Λ further process may, for example, be carried out as follows: The fatty impurities and other by-products are separated by suitable precipitation reactions.
This is effected, for example, by triturating the ethyl acetate extract with petroleum ether, whereby the antibiotics which are active against Candida albicans, remain in the insoluble portion. This residue is suspended in methanol, and after filtering off the insoluble, inactive portions, the filtrate is concentrated by evaporation in a vacuum. This material is dissolved in methanol, ahd the clear solution is added dropwise to a 10-fold amount of ethyl acetate. The precipitated material contains SL 7810/F, SL 7810/F-II and SL 7810/F-III, aside from inactive accompanying substances.
The further purification and separation of the components from the precipitate is effected by known chromatographic methods, very suitable methods being gel chromatography on Sephadex LH 20 and chromatography on silica gel. These methods are used combined, and repeatedly for the purification of the individual components. Thus, for example, one of the crude products decribed above is first chromatographed on Sephadex LH 20 with methanol, whereby the three 0592 antibiotics appear in the same fractions upon elution. The combined active fractions are subsequently chromatographed on silica gel, grain size 0.06-0.2 mm. Elution may be effected either by using chloroform to which increasing amounts of methanol have been added, or by continuously using a mixture of chloroform/methanol/water (80:17.5:2 - parts by volume). In accordance with the R^. values in the thin layer chromatogram, elution from the silica gel columns first yields SL 7810/P-III, then SL 7810/P-II, and finally SL 7810/P. Separation of the mixed fractions, particularly SL 7810/P-II and SL 7810/P-III, is effected by repeated chromatography on a 250- to 400-fold amount of silica gel. The fractions which are active against Candida albicans and which are pure in accordancewith the thin layer chromatogram, correspond to the required antibiotics in accordance with the Rf values.
Process variant b) of the invention may be carried out in accordance with known methods, e.g. by catalytic hydrogenation.
Solvents which are preferably used are methanol and ethanol.
Hydrogenation is conveniently effected in a neutral or weakly acid medium, e.g. in the presence of weak 43ϊ>38 organic acids such as acetic acid. Hydrogenation is effected at temperatures between 10 and 40°C, preferably between 20 and 25°C. Hydrogenation is conveniently effected under atmospheric pressure or under a slightly elevated pressure, in the presence of a platinum containing catalyst, e.g. PtO2, which is prehydrogenated to Pt, or preferably a palladium catalyst, e.g. palladium on carbon or barium sulphate. Hydrogenation is effected until the hydrogen t This is effected considering that the hydrogen take-up of two mols for every mol of antibiotic SL 7810/F, SL 7810/F-II and SL 7810/F-III corresponds to a molecular weight of about 1000 to 1200. In the case of the hydrogenated derivatives of the indicated anti15 biotics, no protons indicating linoleic acid can be detected in the NMR spectrum.
The resulting hydrogenated derivatives of the antibiotics SL 7810/F, SL 7810/F-II and SL 7810/F-III are purified in known manner if necessary. This is preferably effected by chromatography • on Sephadex LH 20 (elution with methanol) and/or chromatography on finely grained silica gel, whereby elution is conveniently effected with mixtures of chloroform/methanol (9:1 - parts by volume) to (3:1 - parts by volume or with mixtures of chloroform/methanol with the addition of a small amount of water. 3 5 5 3 The present invention also includes fermentation liquors obtained from the cultivation of an antibiotic SL 7810/F-, SL 7810/F-II- and/or SL 7810/F-III-produclng strain of the species Aspergillus rugulosus 'horn and Raper.
The new antibiotics and their tetrahydro derivatives exhibit interesting pharmacological properties.
The antibiotics SL 7810/F, SL 7810/F-II, SL 7810/F-III and their tetrahydro derivatives may be characterized biologically by their activity spectrum. Whereas all of the compounds are Ineffective against Staphylococcus aureus and Escherichia ooll, under the usual test conditions, they exhibit pronounced effects against yeasts and fungi.
The following Table indicates the minimum inhibiting concentrations against different yeasts and fungi. The series dilution test used was conducted in known manner with the indicated test strains. The incubation in the series dilution test was effected in a malt extract medium (2% w/v) having a pH of 4.4-4,7, at 27-37,’c, depending on the optimum temperature for the test strain concerned. Evaluation was effected after an incubation time of 72 hours. The test strains have been deposited in the fungi collection of the firm Sandoz, where they are available for examination. 43S33 Strain ϊ Tetrahydro- Tetrahydro- TetrahydroSL 7810/F SL 7810/F-II j SL 7810/F-III SL 7810/F SL 7810/F-II SL 7810/F-III «η ο r Ο rM Ο ο CO ο μ Ο ο co ο ο μ Ο co ο ο tn r Ο Ο Ο Η ο ο μ Ν Ν μ »μ (Ο Ο 10 10 cs Ο C μ Α * Α Α ». Ο «μ μ CO W Ο ο Ο Ο ο ο Ο co co ο μ μ ο co o Ο O © o o co en fn μ » f ♦ A Μ Ο μ Ο Ο Ο O μ io Ο O !-< r-l CO CO co co μ 10 CO μ to Ο ο ο to ο 10 μ Α ο ο ο Ο Ο ο ο Ο ο ο μ CO to μ co co (0 μ <0 CO CO co ο <0 ο ο r A » ϊ ♦ Ο ο ο ο Ο ο ο μ ο μ ο © © r-l <3 Μ d μ rrt 0 « 0 0 co 04 rt •μ S CS b* •H W O rt 0 rt .μ Oi Ol W rt u μ QJ •μ Ρ CO co rt •rl Wi AS rt μ W tn M Ό 0 0 rt y d μ ο •μ •μ •μ μ rt μ rt (It 1U ω Μ w (4 0 y μ μ rt •rl d rt μ μ ο <5 0 rt c a •μ rt rt d rt y μ ,Q rt d rt rt rt rt « μ y y •μ β o* rt rt y rt ο υ o u y • rl •μ y 0 Fi μ •μ •rl •Η H •μ •μ rt & 0· 0 rt rt d g 04 0 Α Α .0 23 A μ 0 0 s 0 0 y rt « rt rt μ r-l μ μ μ 23 μ μ μ μ μ b rt μ y « rt rt rt rt μ μ as b k» 0 rt « y 23 0 rt μ μ o rt rt rt « rt 0 rt rt rt 04 α μ r-i ο d y •ο *e *0 Π3 *0 T3 Ό *0 0 0 « d μ Μ 0 •Η •Η •μ •μ •μ μ >μ •rl •μ tfi r· »rt rt 0 y μ Ό »0 *0 *0 *0 rt Ό *0 *0 y 'y y 0 Ό ο 04 α rt rt rt rt ·> rt rt c •μ •μ y rt ο 0 α rt rt rt 0 rt rt w μ μ rt rt 23 μ μ ο ο o u u w o u ϋ Η Η w W &ί Μ υ Aspergillus flavipes 3,2 Giberella fujikuroi 3,2 Aspergillus aiger 100 Curvularia lunata ·ρ· 100 As may bo seen from tho above tost results (MIC values), the indicated compounds exhibit tin effect against certain fungi, especially against Candida albicans. The effect against Candida albioans may be ascertained in vivo by the following tests: 1. Experimental intestinal infection with Candida albicans A 124 in the female mouse In this method the balance of the normal intestinal flora is broken in favour of perorally administered Candida albicans A 124 by treatment with antibiotics. The wide spectrum anbitiotic treatment leads to a suppression of bacterial flora and, hence, to a selective reproduction of Candida fungi in the intestine of the female mouse. The Candida organisms which settle in the intestine are regularly eliminated with the faeces (number of germs lo4/g of faeces) over a period of at least 3 weeks.
Material and method Female NMRI mice, having a weight of 18 to 24 g and fed ad libitum with mouse pellets, are used. The drinking water contains 1 mg/oc of 3 5 9 3 streptomycin. ϊ22£2ϊ:2ΐ5_225_ΐ2ί222ΐ2Ξΐ The intestinal infection of the female mouse with Candida albicans is effected as follows: A dilution, containing 5 x 10 germs in 0.25 cc is prepared from an ampoule kept in liquid nitrogen 7 and thawed. 5 x 10 germs are then administered perorally to each mouse. After infection, the animals are placed separately in cages (6 or 10 animals which are kept separately form a group). 22221151125252(1-2^-29.5(5-5)1(5^25-55-^.112 faeces (GN/g_of faeces) : On the 6th day or at the time the germ number in the faeces is to be determined, the test animals are placed in sterile Makralon cages, and the faeces of 4 hours' are collected and weighed.
A suspension of 10-1 units 1s subsequently prepared in . -7 a NaCl solution and is diluted to 10 . units. The perms are then counted out by the plate process with Sabouraud agar, whereby 50 |ig of streptomycin are added for every cc of SAB agar. The addition of streptomycin to the agar eliminates the growth of the remaining intestinal germs, so that a pure culture of the fungus Candida albicans is obtained on the agar plate. << a sq a ?222_22^_i5252_2i_ti22l:!!f2S£2_ The highest dose of a test compound which is administered generally depends on the maximum tolerable dose. It usually amounts to 300 mgAg of body weight of the mouse; a further dose amounts to 100 mgAg of body weight. These daily doses are administered perorally for five days starting on the day of infection. The daily doses are divided into 3 unit doses and are administered perorally at a volume of 0.25 cc (in the case of water-insoluble compounds 0.2 % of CMC + 0.2 % of *Cween 80 are used as suspension agent) for 20 g of mouse.
Each infection test is supplemented with 10 control animals, to which a standard compound is administered. Xn this infection test, nystatin at daily doses of 300 and 100 mgAg of body weight, administered perorally, is used as standard compound. These doses are administered as for the test compound. When a dose of 300 mgAg of body weight of nystatin is administered perorally, no germs of Candida albicans can be detected in the faeces one day after conclusion of treatment, whereas 100 mgAg of body weight of nystatin cause a germ reduction of at least 2 powers of ten, in certain cases even *Tween is a trade mark 3 S 9 3 a complete elimination of those germs.
A group of 6 animals, kept separately in cages, is used for each dosage. Six further animals are given, as all the others, streptomycin in the drinking water and the solvent without compound as control. The animals are also kept separately.
Por the evaluation of such a test, germ 10 number reductions or germ eliminations are ascertained and compared with the untreated control animals or the control animals with the standard compounds, and calculated in percentages. 2. Vaginal Candida albicans infection of the rat (strain Δ.124) The vaginal mycosis of the female rat is a mucous membrane infection. Through an ovariectomy and a subsequent continuous estrus induced by administration of hormones in the pubescent rat, it is possible to induce an experimental vaginal mycosis, This local infection usually only involves the most superficial layer of the vaginal mucous membrane.
The .development of the infection can ba readily controlled by smears. The good reproducibility and regular development of the infection fulfil all the necessary requirements in the search for a new active agent.
Female Wistar rats having a weight of about 200 g are used. The animals are given feed and water ad libitum. 10 animals are used for each test group.
EE2E2£§£i22_52SL52S£2!£li£h5}i:GiL2£..l;tl§ An ovariectomy is performed in the animals under Nembutal narcosis. One day after ovariectomy, 100 pg of oestradiol in 0.5 cc of sesame oil are administered subcutaneously to each rat. One week after administration of the hormone, the animals are in the estrus, this being readily detectable by means of smears and methylene blue colouration under a microscope.
In this condition of continuous estrus, hardly any leucocytes can be found in the vaginal content, this being of advantage for the development of an infection, since foreign germs which penetrate the vagina are not phagooyted immediately by the leucocytes.
*Nembuta1 Is a trade mark Seven days after the ovariectomy the animals are infected. Candida albicans germs in 5 quantities of 0.05 cc or 10 germs are applied intravaginally to each rat by means of a tuberculin syringe and an esophageal sound.
The production of the inoculum is effected in accordance with the usual processes and the inoculum is kept in liquid nitrogen. The germs are used for the infection directly from the after rapid thawing.
The development of the local vaginal mycosis is checked on the 3rd, 7th, 10th, ISth and 20th day after infection. Vaginal content is smeared with a platinum-wire loop on a streptomycincontaining Sabouraud agar plate (20 μg/cc).
Parallel smears are prepared with vaginal content, are stained with Gram's colouring matter and ι examined under a microscope for the presence of pseudomycelium. After incubation of the SAB plates (tubes) at 30° C for 2 days, these are evaluated semiquantitatively. The infection may be considered serious (growth as furry coating), moderate (countable colonies) or insignificant (sporadic colony growth), depending on the growth of the Candida albicans colonies.
Tr ea tmen t _and_dos ag e: Local treatment o£ the experimental vaginal candidasis commence^ 24 hours after infection. Intravaginal treatment is effected twice daily (in the mornings and afternoons) on 5 successive days. 0.1 cc of a 1.5 % and 5 % ointment are administered to each rat ae unit dose of the test compound. The compounds are worked up with a mixture of 2 parts of polyethylene glycol 300 and 1 part of polyethylene glycol 1500 ointment base and are administered intravaginally.
Each infection test is supplemented by conducting a group of 10 animals as controls, to which a known standard compound is administered. Nystatin as 1.5 % ointment or clotrimazole as 1.5 % ointment may alternatively be used as standard compound. Ointment base without compound is administered to 10 further animals, and a group of 10 animals is used as infection control.
The new antibiotics and their tetrahydro derivatives are therefore indicated for use in the treatment of diseases caused by Candida albicans.
For this use an indicated daily dose is from about 100 to about 1500 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from 30 to 750 mg, or in sustained release form. The present invention also provides a pharmaceutical composition comprising a compound chosen from antibiotic SL 7810/F, SL 7810/F-II, SL 7810/F-III and their tetrahydro derivatives in association with a pharmaceutical carrier or diluent, such compositions may be formulated in conventional manner so as to be in forms suitable for enteral, parenteral or topical administration. For example they may be in the form of tablets, capsules and solutions. For example they may be used as component of an ointment, whereby the concentration in the ointment may amount to 5 to 130 mg of active agent for every gram of ointment.
In the following non-limitative Examples all temperatures are indicated in degrees Centigrade.
All the indicated ratios are volume/volume.
Merck, Sephadex and Dispax are trade names.
EXAMPLE li A spore suspension for the inoculation of the nutrient solution is produced from a culture of the strain NRRL 8039. This is effected by inoculating 200 cc of an agar nutrient solution having the following composition: * g of cerelose (glucose) g Of peptone g of malt extract g of yeast extract g of potassium phosphate g of lfeS04. 7 H20 g of agar ' liter of de-ionized water After incubation at 27° for 10 days, the resulting spores are suspended in 200 cc of sterile water, and this is used for Inoculation in a steel fermenter containing 50 liters of the following nutrient solution: *Cerelose .1s a trade mark g of cerelose (glucose) g of starch g of soy peptone g of calcium carbonate g of sodium nitrate g of primary potassium phosphate 0.5 g of potassium chloride 0.5 g of MgSO^ . 7 HjO cc of a mixture of 90 % of*Rhcdorsil silicone emulsion • Antimousse B and 10 3 of polypropylene glycol 2020 (Chem.Werke Hiils, Marl, German Federal Republic) liter of de-ionized water t . This fermenter is incubated at 27° for 42 hours while aerating (1 liter of air/minute/liter of medium) and stirring (250 revolutions/minute).
This culture is used as preculture for inoculation bf a 500 liter fermenter of the same nutrient solution, and incubation is effected at 27° for 66 hours., while aerating (1 liter of air/minute/liter of medium) and stirring (150 revolutions/minute).
After an incubation time of 66 hours, the culture liquid is harvested and worked up as follows: The pH of 450 liters of culture liquid is adjusted to 7.0 with 2N hydrochloric acid, 500 liters *Rhodorsi1 Is a trade mark Λ 9598 of ethyl acetate are added, and homogenelzation is effected with a Dispax reactor. The organic phase is subsequently separated from the liquid with a separator and washed with 50 liters of water. This extraction step is repeated twice. The resulting three extracts are combined and evaporated to dryness under a vacuum (water ring pump) at 20-40°.
This material is fractionated on a 4-fold quantity of silica gel Merck 60 (grain size ' 0.063-0.20 mm). The eluates with chloroform + 10 % of methanol and chloroform + 20 % of methanol contain inactive impurities. The chromatography column is subsequently eluted with chloroform/methanol (lsl), and the fractions showing an activity against Candida albicans are combined and evaporated to dryness.
Chromatography of 16.4 g of the active material on 1 kg of silica gel Merck 60 (grain size 0.063-0.20 mm) and elution with chloroform + 20 % of methanol first yield mixed fractions of SL 7810/F-II and SL 7810/F-III. Subsequent elution with chloroform + 30 % of methanol yields fractions with SL 7810/F as main component. After gel filtration of the SB 7810/F fraction (8.1 g) on 1.2 kg of Sephadex LH 20 with methanol, SL 7810/F is obtained in approximately pure form. This preparation is dissolved in acetone with heating, and the clear solution is concentrated to 1/4 of its volume. After standing at -15° for 3 hours, the resulting precipitate is filtered off, and after washing with acetone and ether is dried in a high vacuum over PjOj. at room temperature for 24 hours.
SL 7810/F is obtained as a colourless powder having an M.P. of 160-163’ (decomp.).
The two antibiotics may be isolated by further chromatography of the active mixed fractions of SL 7810/F-II and SL 7810/F-III from the above silica gel chromatography. This is effected by dissolving the material (2.5 g) in chloroform + 20 % of methanol and adsorbing the solution on a column of 1 kg of silica gel which has been prepared with the same solvent mixture. Elution is continually effected with chloroform + 20 % of methanol, whereby SL 7810/F-III is first mainly eluted, and then mainly SL 7810/F-II. Pure SL 7810/F-III is obtained by dissolving the concentrated mixed fractions (0.75 g) containing this antibiotic, in chloroform + 10 % of methanol, and. adsorbing-the solution on 1 kg of silica gel Merck, as described above. Elution with chloroform + 10 % of methanol to 15 % of methanol yields the strongly enriched material of SL 7810/F-III. After gel filtration (0.55 g) on 500 g of Sephadex LH 20 43332 with methanol, pure SL 7810/P-III is obtained: a colourless amorphous powder having an M.P. of 164-168° (decomp.).
SL 7810/F-II is isolated by dissolving the mixed fractions (1.7 g) -:ontaining SL ’810/F-!, in chloroform + 20 % of methanol, and adsorbing this solution on a column of 1 kg of silica gel prepared with the same solvent mixture. Elution with chloroform + 20 % of methanol yields strongly enriched fractions of SL 7810/F-II. Subsequent gel filtration (1.2 g) on 1.2 kg of Sephadex LH 20 with methanol yields pure SL 7810/P-II, an amorphous powder having an M.P. of 158-160’ (decomp.).
EXAMPLE 2: Tetrahydro-SL 7810/P A suspension of 1 g of palladium/charcoal (10 % of Pd) in 250 cc of alcohol or 250 cc of alcohol/glacial acetic acid (1:1) is prehydrogenated for 30 minutes. Subsequently a solution of 5 g of SL 7810/F in 50 cc of alcohol/glacial acetic acid (1:1) is added. After hydrogenation for 3 hours at 20° under atmospheric pressure, the catalyst is separated on a talc suction filter, and the clear· filtrate is concentrated by evaporation in a vacuum.
The evaporation residue is dissolved in chloroform/ methanol (1:1), this solution is used for the impregnation of 10 g of silica gel 60 Merck, (grain size 0.063-0.20 mm), and this is placed on a column of 500 g of silica gel. Subsequent elution with chloroform/ methanol (4:1) yields the amorphous hydrogenation product as colourless powder having an M.P. of 173-178° (decomp.). The preparation crystallizes from ethanol/ water (95:5). M.P. after drying in a high vacuum for 3 hours at 50°: 19O-2O5°/21O-212° (decomp.).
EXAMPLE 3: Tetrahydro-SL 7810/F-II Production is effected in a manner analogous to that described in Example 2, whereby the antibiotic SL 7810/F-II is used as starting material.
EXAMPLE 4: Tetrahydro-SL 7810/F-III Production is effected in a manner analogous to that described in Example 2, whereby the antibiotic SL 7810/F-III is used as starting material, hydrogenation has a duration of 4 hours, and chloroform/methanol/water (80:17.5:2) is used as solvent mixture for the chromatography on silica gel. 3 5 3 2 Table 1: 13C NMR spectrum of tetrahydro-SL 7810/F. Instrument: Bruker HX-90 E Taken at 22.63 magacycles p'r second Sweep width : 6000 megacycles per second Concentration: 250 mg in 1.2 cc of CDgOD fi (ppm) 6 (ppm) (cont'd) 173,3 49,8* 173,5 48,8* 172,7 47,8* 171,9 46,9* 171,7 45,9* 169,1 38,8 157,7 36,7 132,2 35,0 129,1 33,8 115,8 32,9 76,6 31,5 75,2 30,6 74,1 30,2 70,6 28,9* 69,3 26,9 68,0 23,6 62,1 20,1 58,4 19,5 56,4 19,2* 55,9 14,4 52,6 11,3 51,3 0,00** 50,7* * Signals of CD?OD and higher sound peaks ** Signals of tetramethylsilane - 0 ppm. 4388 3 Table 2; ^3C NMR spectrum of tetrahydro-SL 7810/F-ll Instrument: Bruker HX-90 E Taken at 22.63 megacycles per second Sweep width:. 6000 megacycles per second Concentration: 250 mg in 1.2 cc of CDgOD 6'(ppm) 6(ppm) (cont'd) 175,3 51,6* 173,4 51,3* 173,2 50,6* 172,0 49,7* 171,8 48,7* 171,7 47,8* 169,3 46,9* 156,3 40,7 130,9 38,8 129,1 36,6 115,7 35,0 75,2 32,8 74,0 30,5 70,9 30,2 70,5 26,8 69,1 23,5 68,0 20,1 62,1 19,3 58,5 14,4 57,2 . 11,2 56,3 0,00** 52,6 Signals of CDgOD and higher sound peaks ** Signal of tetramethylsilane = 0 ppm.
Claims (29)
1. SL 7810/F which has the formula wherein R is 5 cis,cis . CojcH^yCH » CH .-CHg . CH - CH . |0hJ 4 , CH 3<
2. A process for the production of SL 7810/F of the formula defined in claim 1 which comprises cultivating a SL 7810/F producing strain of Aspergillus rugulosus Thom and Raper in the presence of a nutrient medium.
3. A process as defined in claim 2 wherein the strain is NRRL 8039. >
4. A process for the production of a SL 7810/F of the formula as defined in claim 1 substantially as hereinbefore described 5. With reference to Example 1.
5. SL 7810/F whenever prepared by a process as claimed in claim 2, 3 or 4.
6. A pharmaceutical composition comprising a compound as defined in claim 1 or 5 in association with a pharmaceutical 0 carrier or diluent.
7. Tetrahydro-SL 7810/F which has the formula wherein R is .CO . JcH^g . CH 3 .
8. A process for the production of tetrahydro-SL 7810/F of the formula defined in claim 7 which comprises hydrogenating S! 7810/F as defined in claim 1. 5
9. A process for the production of tetrahydro-SL 7810/F of the formula as defined in claim 7 substantially as hereinbefore described with reference to Example 2.
10. Tetrahydro-SL 7810/F whenever prepared by a process as claimed in claim 8 or 9. 10
11. A pharmaceutical composition comprising a compound as defined in claim 7 or 10 in association with a pharmaceutical carrier or diluent.
12. SL 7810/F-Il which has the formula or SL 7810/F-III of formula HO wherein cis,cis
13. A process for the production of SL 7810/F-II or SL 7810/F - II’' of the formula defined in claim 12 which comprises cultivating a SL 7810/F-II or SL 7810/F-III producing strain of 5 Aspergillus rugulosus Thom and Raper in the presence of a nutrient medium.
14. A process as defined in claim 13 wherein the strain is NRRL 8039.
15. A process for the production of a 10 SL 7810/F-II or SL 7810/F-III of the formula as defined in claim 12 substantially as hereinbefore described with reference fo Example 1.
16. SL 7810/F-II or SL 7810/F-III whenever prepared by a process as claimed in claim 13, 14 or 15 15.
17. A pharmaceutical composition comprising a compound as defined in claim 12 or 16, in association with a pharmaceutical carrier or diluent.
18. Tetrahydro-SL 7810/F-II which has the formula 9. J u w m
19. A process for the production of tetrahydroSL 7810/F-II of the formula defined in claim 18 which comprises hydrogenating SL 7810/F-II as defined in claim 12. 5
20. A process for the production of tetrahydroSL 7810/F-II of the formula as defined in claim 18 substantially as hereinbefore described with reference to Example 3.
21. Tetrahydro-SL 7810/F-II whenever prepared by 10. A process as claimed in claim 19 or 20.
22. A pharmaceutical composition comprising a compound as defined in claim 18 or 21 1n association with a pharmaceutical carrier or diluent.
23. 15 23. Tetrahydro-SL 7810/F-III which has the formula ajaaz wherein R is . CO . [cH^g . CH. 43392
24. A process for the production of tetrahydro-SL 7810/F-III of the formula defined in claim 23 which comprises hydrogenating SL 7810/F-III as defined in claim 12.
25. A process for the production of a tetrahydro-SL 7810/F-III of the formula as defined in claim 23 substantially as hereinbefore described with reference to Example 4.
26. Tetrahydro-SL 7810/F-III whenever prepared by a process as claimed in claim 24 or 25.
27. A pharmaceutical composition comprising a compound as defined in claim 23 or 26 in association with a pharmaceutical carrier or diluent.
28. Fermentation liquor when produced by carrying out a process as claimed in any one of claims 2 to 4, and 13 to 15.
29. Fermentation liquor comprising SL 7810/F, SL 7810/F-II or SL 7810/F-III whenever produced by cultivating the strain NRRL 8039 on a synthetic culture medium.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH1342574 | 1974-10-07 | ||
CH1655674A CH606069A5 (en) | 1974-12-12 | 1974-12-12 | Antibiotic SL 7810 F and their tetrahydro derivs |
CH171375A CH616705A5 (en) | 1975-02-12 | 1975-02-12 | Process for the preparation of the metabolites SL 7810/F-II and SL 7810/F-III. |
CH436475 | 1975-04-07 | ||
CH967975 | 1975-07-24 |
Publications (2)
Publication Number | Publication Date |
---|---|
IE43592L IE43592L (en) | 1976-04-07 |
IE43592B1 true IE43592B1 (en) | 1981-04-08 |
Family
ID=27508997
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE2187/75A IE43592B1 (en) | 1974-10-07 | 1975-10-06 | Improvements in or relating to organic compounds |
Country Status (12)
Country | Link |
---|---|
JP (1) | JPS5195189A (en) |
AU (1) | AU508075B2 (en) |
BE (1) | BE834289A (en) |
DK (1) | DK438475A (en) |
FI (1) | FI752696A (en) |
FR (1) | FR2287235A1 (en) |
GB (1) | GB1527494A (en) |
IE (1) | IE43592B1 (en) |
IL (1) | IL48248A0 (en) |
NL (1) | NL7511649A (en) |
NO (1) | NO753291L (en) |
SE (1) | SE7510899L (en) |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4293482A (en) * | 1979-12-13 | 1981-10-06 | Eli Lilly And Company | A-30912A Nucleus |
US4293484A (en) * | 1979-12-13 | 1981-10-06 | Eli Lilly And Company | Derivatives of A-30912H nucleus |
US4320054A (en) * | 1979-12-13 | 1982-03-16 | Eli Lilly And Company | Derivatives of A-30912H nucleus |
US4293487A (en) * | 1979-12-13 | 1981-10-06 | Eli Lilly And Company | Derivatives of A-30912D nucleus |
US4293488A (en) * | 1979-12-13 | 1981-10-06 | Eli Lilly And Company | Derivatives of A-30912B nucleus |
US4322338A (en) * | 1979-12-13 | 1982-03-30 | Eli Lilly And Company | Derivatives of A-30912B nucleus |
US4293491A (en) * | 1979-12-13 | 1981-10-06 | Eli Lilly And Company | Derivatives of A-30912H nucleus |
US4293489A (en) * | 1979-12-13 | 1981-10-06 | Eli Lilly And Company | Derivatives of A-30912A nucleus |
US4289692A (en) * | 1979-12-13 | 1981-09-15 | Eli Lilly And Company | Derivatives of A-30912D nucleus |
US4299763A (en) * | 1979-12-13 | 1981-11-10 | Eli Lilly And Company | A-30912B Nucleus |
US4320052A (en) * | 1979-12-13 | 1982-03-16 | Eli Lilly And Company | Derivatives of A-30912A nucleus |
US4320053A (en) * | 1979-12-13 | 1982-03-16 | Eli Lilly And Company | Derivatives of A-30912D nucleus |
US4293485A (en) * | 1979-12-13 | 1981-10-06 | Eli Lilly And Company | Derivatives of S31794/F-1 nucleus |
US4293490A (en) * | 1979-12-13 | 1981-10-06 | Eli Lilly And Company | A-30912H Nuclei |
US4297277A (en) * | 1979-12-13 | 1981-10-27 | Eli Lilly And Company | Derivatives of A-30912B nucleus |
US4293483A (en) * | 1979-12-13 | 1981-10-06 | Eli Lilly And Company | Derivatives of A-30912A nucleus |
US4287120A (en) * | 1979-12-13 | 1981-09-01 | Eli Lilly And Company | Derivatives of S31794/F-1 nucleus |
US4293486A (en) * | 1979-12-13 | 1981-10-06 | Eli Lilly And Company | Derivatives of S31794/F-1 nucleus |
US4304716A (en) * | 1979-12-13 | 1981-12-08 | Eli Lilly And Company | S 31794/F-1 Nucleus |
US4299762A (en) * | 1979-12-13 | 1981-11-10 | Eli Lilly And Company | A-30912D Nucleus |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH79A (en) * | 1889-01-09 | Adam Sautter Johann | Movement for pocket watches with an open barrel, new gear pusher system and simplified movement fastening | |
JPS5134916B2 (en) * | 1974-03-06 | 1976-09-29 |
-
1975
- 1975-09-26 FI FI752696A patent/FI752696A/fi not_active Application Discontinuation
- 1975-09-29 NO NO753291A patent/NO753291L/no unknown
- 1975-09-29 SE SE7510899A patent/SE7510899L/en unknown
- 1975-09-29 DK DK438475A patent/DK438475A/en unknown
- 1975-10-02 GB GB40301/75A patent/GB1527494A/en not_active Expired
- 1975-10-03 NL NL7511649A patent/NL7511649A/en unknown
- 1975-10-06 IE IE2187/75A patent/IE43592B1/en unknown
- 1975-10-06 JP JP50119866A patent/JPS5195189A/ja active Pending
- 1975-10-06 IL IL48248A patent/IL48248A0/en unknown
- 1975-10-07 FR FR7530625A patent/FR2287235A1/en active Granted
- 1975-10-07 AU AU85523/75A patent/AU508075B2/en not_active Expired
- 1975-10-07 BE BE160769A patent/BE834289A/en unknown
Also Published As
Publication number | Publication date |
---|---|
DK438475A (en) | 1976-04-08 |
IL48248A0 (en) | 1975-12-31 |
AU8552375A (en) | 1977-04-21 |
FR2287235A1 (en) | 1976-05-07 |
FI752696A (en) | 1976-04-08 |
GB1527494A (en) | 1978-10-04 |
NO753291L (en) | 1976-04-08 |
BE834289A (en) | 1976-04-07 |
IE43592L (en) | 1976-04-07 |
FR2287235B1 (en) | 1979-03-16 |
SE7510899L (en) | 1976-04-08 |
AU508075B2 (en) | 1980-03-06 |
NL7511649A (en) | 1976-04-09 |
JPS5195189A (en) | 1976-08-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
IE43592B1 (en) | Improvements in or relating to organic compounds | |
US4173629A (en) | Antibiotic S 31794/F-1 | |
IE49743B1 (en) | Antihypercholesteraemic agent,monacolin k,and its preparation | |
HU221276B1 (en) | Polycyclic antiparasitic agents, process and strain for their preparation and their use | |
US5756472A (en) | Antifungal agent obtained from hormonema | |
CH641452A5 (en) | SESQUITER PEN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. | |
US3773925A (en) | Partricin | |
CH668974A5 (en) | ANTITUMOR-ANTIBIOTIC. | |
EP0478061A1 (en) | Antiviral agent | |
US3824305A (en) | Antibiotic a-287 and process for production thereof | |
JPH0368570A (en) | Fungicide | |
IE50661B1 (en) | New antibiotics,processes for their production and pharmaceutical compositions containing them | |
US5276055A (en) | Antibiotic agents | |
US5801172A (en) | Antifungal agent from sporomiella minimoides | |
US3991052A (en) | Antibiotic A-30641 | |
US3465079A (en) | Antibiotic sl 1846 | |
CA2244142C (en) | Antifungal compound from hormonema sp. | |
WO1982000587A1 (en) | New metabolites,processes for their production and their use | |
CA1146885A (en) | Antibiotically active compounds and their fermentative preparation | |
AU760975B2 (en) | Microbial transformation product | |
KR850001939B1 (en) | Process for preparing a-32724 antibiotics | |
US3105794A (en) | Spiramycin d | |
US5712109A (en) | Antifungal agent produced by arthrinium arundinis ATCC 74359 | |
US5597806A (en) | Antifungal agents | |
US5770587A (en) | Antifungal agents |