WO1993013094A1 - Archazolides, leur procede de fabrication et agents les renfermant - Google Patents
Archazolides, leur procede de fabrication et agents les renfermant Download PDFInfo
- Publication number
- WO1993013094A1 WO1993013094A1 PCT/EP1992/002980 EP9202980W WO9313094A1 WO 1993013094 A1 WO1993013094 A1 WO 1993013094A1 EP 9202980 W EP9202980 W EP 9202980W WO 9313094 A1 WO9313094 A1 WO 9313094A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- archazolide
- methanol
- archazolides
- nych
- nhch
- Prior art date
Links
- 229930193499 archazolide Natural products 0.000 title claims abstract description 33
- 238000000034 method Methods 0.000 title claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 63
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 229930195634 archazolid Natural products 0.000 claims description 9
- 229920005989 resin Polymers 0.000 claims description 9
- 239000011347 resin Substances 0.000 claims description 9
- 239000002609 medium Substances 0.000 claims description 7
- 239000003480 eluent Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000004809 thin layer chromatography Methods 0.000 claims description 5
- 241000863009 Archangium gephyra Species 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 229920001429 chelating resin Polymers 0.000 claims description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052782 aluminium Inorganic materials 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000004587 chromatography analysis Methods 0.000 claims description 3
- 239000002024 ethyl acetate extract Substances 0.000 claims description 3
- 239000011888 foil Substances 0.000 claims description 3
- 239000001963 growth medium Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 101100241859 Mus musculus Oacyl gene Proteins 0.000 claims description 2
- 229920005654 Sephadex Polymers 0.000 claims description 2
- 239000012507 Sephadex™ Substances 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 238000004811 liquid chromatography Methods 0.000 claims description 2
- 238000001819 mass spectrum Methods 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 230000005855 radiation Effects 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 210000004027 cell Anatomy 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 6
- 229920001817 Agar Polymers 0.000 description 5
- 239000008272 agar Substances 0.000 description 5
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 4
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000000855 fermentation Methods 0.000 description 4
- 230000004151 fermentation Effects 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 241000233866 Fungi Species 0.000 description 2
- 210000004102 animal cell Anatomy 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- FDJOLVPMNUYSCM-UVKKECPRSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2,7, Chemical compound [Co+3].N#[C-].C1([C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)[N-]\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O FDJOLVPMNUYSCM-UVKKECPRSA-L 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000007179 vy/2 agar Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 102100027324 2-hydroxyacyl-CoA lyase 1 Human genes 0.000 description 1
- 235000001674 Agaricus brunnescens Nutrition 0.000 description 1
- 241000272525 Anas platyrhynchos Species 0.000 description 1
- 241000863426 Archangiaceae Species 0.000 description 1
- 241000228245 Aspergillus niger Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000123650 Botrytis cinerea Species 0.000 description 1
- 0 CC(*)C[C@@](C1=I(C)C(C([C@](C(*)=CC)N)OC(C(N=C)=CCC(*)=CC(*)[C@@](*)C=C(*)C=C(*)C=CC(*)C(C(*(*)=C)O)I)=O)=CN1)O Chemical compound CC(*)C[C@@](C1=I(C)C(C([C@](C(*)=CC)N)OC(C(N=C)=CCC(*)=CC(*)[C@@](*)C=C(*)C=C(*)C=CC(*)C(C(*(*)=C)O)I)=O)=CN1)O 0.000 description 1
- 241001600177 Cystobacterineae Species 0.000 description 1
- 241001465310 Eremothecium coryli Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 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 1
- 244000286779 Hansenula anomala Species 0.000 description 1
- 235000014683 Hansenula anomala Nutrition 0.000 description 1
- 101001009252 Homo sapiens 2-hydroxyacyl-CoA lyase 1 Proteins 0.000 description 1
- 238000002768 Kirby-Bauer method Methods 0.000 description 1
- 241001489207 Lipomyces lipofer Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000589344 Methylomonas Species 0.000 description 1
- 241001123676 Metschnikowia pulcherrima Species 0.000 description 1
- 241000907556 Mucor hiemalis Species 0.000 description 1
- 241000863434 Myxococcales Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241000235062 Pichia membranifaciens Species 0.000 description 1
- 241000599030 Pythium debaryanum Species 0.000 description 1
- 241000221696 Sclerotinia sclerotiorum Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 244000301083 Ustilago maydis Species 0.000 description 1
- 235000015919 Ustilago maydis Nutrition 0.000 description 1
- CUYVVUGLFUIZAZ-YYRKZZGWSA-N [(1s)-1-[4-[(2s,3s,4e,6e,8s,9s,10r,11e,13z,15z,17s,18s,19e,22e)-10,18-dihydroxy-8-methoxy-3,7,9,13,15,17,20,23-octamethyl-24-oxo-1-oxacyclotetracosa-4,6,11,13,15,19,22-heptaen-2-yl]-1,3-thiazol-2-yl]-3-methylbutyl] n-methylcarbamate Chemical compound S1C([C@H](CC(C)C)OC(=O)NC)=NC([C@@H]2[C@H](/C=C/C=C(C)/[C@@H](OC)[C@@H](C)[C@H](O)/C=C/C(/C)=C\C(\C)=C/[C@H](C)[C@H](O)/C=C(C)/C/C=C(C)/C(=O)O2)C)=C1 CUYVVUGLFUIZAZ-YYRKZZGWSA-N 0.000 description 1
- 241000222126 [Candida] glabrata Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- CUYVVUGLFUIZAZ-CYWJEVBMSA-N archazolide A Natural products CNC(=O)OC(CC(C)C)c1nc(cs1)C2OC(=O)C(=CCC(=CC(O)C(C)C=C(C)/C=C(C)/C=C/C(O)C(C)C(OC)C(=CC=CC2C)C)C)C CUYVVUGLFUIZAZ-CYWJEVBMSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000000287 crude extract Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 238000001228 spectrum Methods 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
- 238000003756 stirring Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
Definitions
- the invention relates to archazolides of the following general formula:
- NYCH 3 is NHCH 3 or
- NYCH 3 is N (CH 3 ) 2
- the invention relates to an archazolid of the empirical formula C 42 H 62 N 2 SO 7 with the following parameters:
- the invention relates to archazolides which can be prepared by isomerizing the above-described archazolide by UV radiation and, if appropriate, separating the isomer mixture by chromatography in a manner known per se.
- the invention relates to a process for the preparation of the archazolide of the empirical formula C 42 H 62 N 2 SO 7 with the parameters specified above, this process being characterized in that
- This method according to the invention can be characterized in that - adsorbed on Amberlite XAD16,
- Variant (b) receives, or
- the invention further relates to an agent that consists of one or more archazolides according to the invention or comprises these in addition to customary auxiliaries, for example carriers and diluents.
- the bacterium Archangium gephyra belongs to the order of the
- the Ar 3548 production strain was isolated in January 198 at the Deutschen für Biotechnologische Anlagen mbh (GBF) from a soil sample from the Karawanken in Austria. The strain was deposited on November 13, 1991 at the German Collection of Microorganisms (DSM) under number DSM 6806. The characteristics of the production strain are consistent with the description of Archangium gephyra in Bergey's Manual of Systematic
- the stock culture is carried out on agar plates, preferably on yeast agar (VY / 2 agar).
- This medium contains 0.5% baker's yeast, 0.1% CaCl 2 x 2 H 2 O, 0.1 ⁇ g / l vitamin B 12 and 1.2% agar.
- the pH is adjusted to 7.4.
- the plates are incubated at 30 ° C. A.3. Morphological description
- the vegetative cells are long, slender rods with tapered ends, approximately 0.8 x 6 - 10 ⁇ m. Due to the
- the myxospores are short, clumsy, very thick and well rounded rods, often somewhat irregular in outline, and always strongly refractive. They measure approximately 1.4-1.8 x 1.8-2.2 ⁇ m.
- the Ar 3548 strain produces a substance, namely archazolide, that inhibits the growth of human cancer cell lines and other animal cell cultures and the growth of fungi.
- the inhibitor can be isolated both from the cells and from the culture supernatant.
- a typical fermentation proceeds as follows: A fermentor with 350 1 working volume is filled with 300 1 culture medium (composition: 0.5%
- Adsorber resin (Amberlite XAD-16) added. Inoculation is carried out with 10 l of a 2-day-old preculture which was produced in the same medium in a correspondingly smaller fermenter. It is fermented at 30 ° C. with a stirring speed of 150 rpm and aeration of 10% by volume per min. Initial foam formation is prevented by adding 50 ml of silicone anti-foam (e.g. Tegosipon). The pH increases during the fermentation. The increase is limited to 7.8 by adding 5% sulfuric acid. The fermentation is ended after 6 days.
- silicone anti-foam e.g. Tegosipon
- Archazolid very effectively inhibits the growth of human cancer cell lines and other animal cell cultures without immediately killing the cells. Under the influence of archazolide, adherently growing cells round off and become freely mobile. Archazolid inhibits the growth of certain fungi (see table).
- HeLa (ATCC CCL 2) 1ng / ml
- the resin is sieved from a 100 l fermentation batch of the Ar 3548 strain in the presence of 1 l adsorber resin (Amberlite XAD 16) and eluted with 5 l methanol over a period of 2.5 hours.
- the eluate is concentrated to the water phase and extracted 3 times with ethyl acetate in order to separate polar constituents.
- the ethyl acetate extract is concentrated.
- the remaining crude extract (12 g) is dissolved in 200 ml of methanol and fractionated in 2 portions over a Sephadex-LH20 column (62 mm x 63 mm) at a flow of 3.5 ml / min.
- Eluent methanol Detection at 227 nm and by TLC chromatography.
- the fractions containing archazolide (4.1 g) are in 10 0.41 g portions over a preparative Nucleosil C-18, 7 ⁇ m column (250 x 16 mm) with the mobile solvent methanol / water 85/15 and a flow of 15 ml / min (detection at 227 nm) chromatographed. After evaporation of the fractions containing Archazolid until
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Wood Science & Technology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
L'invention concerne des archazolides de formule générale (I) ainsi que leur procédé de fabrication et des agents renfermant des archazolides.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4142951.6 | 1991-12-24 | ||
| DE19914142951 DE4142951C1 (fr) | 1991-12-24 | 1991-12-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1993013094A1 true WO1993013094A1 (fr) | 1993-07-08 |
Family
ID=6448119
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1992/002980 WO1993013094A1 (fr) | 1991-12-24 | 1992-12-22 | Archazolides, leur procede de fabrication et agents les renfermant |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU3257793A (fr) |
| DE (1) | DE4142951C1 (fr) |
| WO (1) | WO1993013094A1 (fr) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998013375A1 (fr) * | 1996-09-23 | 1998-04-02 | GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) | Composes a effet antimycotique et cytostatique, leur procede de production, agents contenant ces composes et dsm 11 092 |
-
1991
- 1991-12-24 DE DE19914142951 patent/DE4142951C1/de not_active Expired - Lifetime
-
1992
- 1992-12-22 AU AU32577/93A patent/AU3257793A/en not_active Abandoned
- 1992-12-22 WO PCT/EP1992/002980 patent/WO1993013094A1/fr active Application Filing
Non-Patent Citations (1)
| Title |
|---|
| Keine einschl{gigen Dokumente gefunden * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998013375A1 (fr) * | 1996-09-23 | 1998-04-02 | GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) | Composes a effet antimycotique et cytostatique, leur procede de production, agents contenant ces composes et dsm 11 092 |
| DE19638870B4 (de) * | 1996-09-23 | 2009-05-14 | Helmholtz-Zentrum für Infektionsforschung GmbH | Tubulysine, Verfahren zu ihrer Gewinnung und sie enthaltende Mittel |
Also Published As
| Publication number | Publication date |
|---|---|
| DE4142951C1 (fr) | 1993-05-13 |
| AU3257793A (en) | 1993-07-28 |
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