DE4138042C2 - Epothilones, their production processes and agents containing these compounds - Google Patents
Epothilones, their production processes and agents containing these compoundsInfo
- Publication number
- DE4138042C2 DE4138042C2 DE19914138042 DE4138042A DE4138042C2 DE 4138042 C2 DE4138042 C2 DE 4138042C2 DE 19914138042 DE19914138042 DE 19914138042 DE 4138042 A DE4138042 A DE 4138042A DE 4138042 C2 DE4138042 C2 DE 4138042C2
- Authority
- DE
- Germany
- Prior art keywords
- epothilones
- methanol
- strain
- epothilone
- irtran
- 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.)
- Expired - Lifetime
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
-
- 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
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
- C12P17/181—Heterocyclic compounds containing oxygen atoms as the only ring heteroatoms in the condensed system, e.g. Salinomycin, Septamycin
Description
Die Erfindung betrifft Epothilone der folgenden allgemeinen Formel:The invention relates to epothilones of the following general formula:
worin R¹ Wasserstoff, C₁- bis C₄-Alkyl, C₁- bis C₄-Acyl, Li⁺, K⁺, Na⁺, 1/2 Mg2+ oder 1/2 Ca2+ bedeutet und R² Wasserstoff oder eine Methylgruppe darstellt.wherein R¹ is hydrogen, C₁ to C₄ alkyl, C₁ to C₄ acyl, Li⁺, K⁺, Na⁺, 1/2 Mg 2+ or 1/2 Ca 2+ and R² represents hydrogen or a methyl group.
Ferner betrifft die Erfindung ein Epothilon, gekennzeichnet durch einen oder mehrere der folgenden Parameter: The invention further relates to an epothilone, characterized by one or more of the following parameters:
C₂₆H₃₉NO₆S[493]
FAB-MS (neg. Ionen): 429.25 für (M-H)-
UV (MeOH) λmax (log ε) = 210 (4.17); 249 (3.97)C₂₆H₃₉NO₆S [493]
FAB-MS (neg. Ions): 429.25 for (MH) -
UV (MeOH) λ max (log ε) = 210 (4.17); 249 (3.97)
IR Film auf Irtran:
ν: 3429; 2966; 2937; 1737; 1691; 1463; 1374; 1295; 1257; 1185; 1150; 1087; 1029; 1014; 979 cm-1 IR film on Irtran:
ν: 3429; 2966; 2937; 1737; 1691; 1463; 1374; 1295; 1257; 1185; 1150; 1087; 1029; 1014; 979 cm -1
DC: RF = 0,75
DC-Alufolie 60 F₂₅₄, Merck; Laufmittel:
Dichlormethan/Methanol = 90 : 10
Detektion:
1. UV-Löschung bei 254 nm
2. Ansprühen mit Vanillin/Schwefelsäure-Reagenz und erhitzen auf 120°C, braune
AnfärbungDC: R F = 0.75
TLC aluminum foil 60 F₂₅₄, Merck; Eluent:
Dichloromethane / methanol = 90:10
Detection:
1. UV quenching at 254 nm
2. Spray on with vanillin / sulfuric acid reagent and heat to 120 ° C, brown color
HPLC: Rt = 5,4 min
Säule: 4 × 250 mm Lichrosorb® RP-18 7 µm;
Fluß: 1,5 ml/min; Laufmittel: Methanol/Wasser = 65 : 35
Detektor: UV 254 nmHPLC: R t = 5.4 min
Column: 4 × 250 mm Lichrosorb® RP-18 7 µm;
Flow: 1.5 ml / min; Mobile solvent: methanol / water = 65:35
Detector: UV 254 nm
Des weiteren betrifft die Erfindung ein Epothilon, gekennzeichnet durch einen oder mehrere der folgenden Parameter: The invention further relates to an epothilone, characterized by one or more of the following parameters:
C₂₇H₄₁NO₆S[507]
FAB-MS (neg. Ionen): 506.25 für (M-H)- C₂₇H₄₁NO₆S [507]
FAB-MS (neg. Ions): 506.25 for (MH) -
UV (MeOH)λmax (log ε) = 210 (4.17); 249 (3.97)UV (MeOH) λ max (log ε) = 210 (4.17); 249 (3.97)
IR Film auf Irtran:
ν = 3400; 2958; 2931; 2875; 1735; 1689; 1629; 1609; 1463; 1378; 1250; 1149; 1049; 977 cm-1 IR film on Irtran:
ν = 3400; 2958; 2931; 2875; 1735; 1689; 1629; 1609; 1463; 1378; 1250; 1149; 1049; 977 cm -1
DC: RF = 0,75
DC-Alufolie 60 F₂₅₄, Merck; Laufmittel:
Dichlormethan/Methanol = 90 : 10
Detektion:
1. UV-Löschung bei 254 nm
2. Ansprühen mit Vanillin/Schwefelsäure-Reagenz und erhitzt auf 120°C, braune AnfärbungDC: R F = 0.75
TLC aluminum foil 60 F₂₅₄, Merck; Eluent:
Dichloromethane / methanol = 90:10
Detection:
1. UV quenching at 254 nm
2. Spray on with vanillin / sulfuric acid reagent and heat to 120 ° C, brown color
HPLC: Rt = 6,3 min
Säule: 4 × 250 mm Lichrosorb® RP-18 7 µm;
Fluß: 1,5 ml/min; Laufmittel: Methanol/Wasser = 65 : 35
Detektor: UV 254 nmHPLC: R t = 6.3 min
Column: 4 × 250 mm Lichrosorb® RP-18 7 µm;
Flow: 1.5 ml / min; Mobile solvent: methanol / water = 65:35
Detector: UV 254 nm
Besonders bevorzugt sind Epothilone mit der folgenden StrukturformelEpothilones with the following structural formula are particularly preferred
worin R² Wasserstoff oder Methyl bedeutet. (Das Kohlenstoffatom der Methylgruppe wird als C27 bezeichnet). Ferner betrifft die Erfindung ein Verfahren zum Gewinnen von Epothilonen, insbesondere der vorstehend charakterisierten Epothilone, das dadurch gekennzeichnet ist, daß man den Stamm So ce90 DSM 6773wherein R² is hydrogen or methyl. (The carbon atom the methyl group is referred to as C27). Furthermore, the Invention a method for obtaining epothilones, in particular of the epothilones characterized above, which thereby is characterized in that the strain So ce90 DSM 6773
- - in einem Kohlenstoffquellen, Stickstoffquellen und Mineralsalze enthaltenden Medium kultiviert,- in a carbon sources, nitrogen sources and mineral salts cultivated medium,
- - entweder während der Kultivierung des Stammes oder anschließend ein Adsorberharz zusetzt,- either during the cultivation of the strain or afterwards adds an adsorber resin,
- - die Fermenterbrühe abtrennt,- separates the fermenter broth,
- - die Epothilone aus dem Adsorberharz eluiert und- the epothilones eluted from the adsorber resin and
- - die Eluate direkt oder über weitere Reinigungsschritte von dem/den Lösungsmittel(n) befreit,- the eluate directly or via further cleaning steps from freed from the solvent (s),
- - und gegebenenfalls über Hochdruck/Niederdruckchromatographie und/oder Umkristallisation die verschiedenen Epothilone aufreinigt und voneinander trennt.- And if necessary via high pressure / low pressure chromatography and / or recrystallization of the different epothilones purified and separated from each other.
Gegebenenfalls können die so gewonnenen Epothilone mit gängigen chemischen Verfahren weiter umgesetzt werden, z. B. mit Basen in die Alkali- und Erdalkalisalze überführt und gegebenenfalls weiter zu Ethern umgesetzt werden, oder sie können mit organischen Säuren in die entsprechenden Ester überführt werden.If necessary, the epothilones obtained in this way can be used with common chemical processes are further implemented, e.g. B. with bases in the alkali and alkaline earth metal salts are transferred and, if appropriate be further converted to ethers, or they can be organic Acids are converted into the corresponding esters.
Ferner betrifft die Erfindung Mittel für den Pflanzenschutz in Landwirtschaft, Forstwirtschaft und/oder Gartenbau, bestehend aus einem oder mehreren der vorstehend aufgeführten Epothilone oder eines oder mehrere dieser Epothilone enthaltend, neben einem oder mehreren üblichen Träger(n) und/oder Verdünnungsmittel(n). The invention further relates to agents for crop protection in agriculture, forestry and / or horticulture from one or more of the epothilones listed above or containing one or more of these epothilones, in addition to one or more conventional carriers and / or diluents.
Schließlich betrifft die Erfindung therapeutische Mittel, die insbesondere cytotoxische Aktivitäten entwickeln und/oder Immunsupression bewirken können, bestehend aus einem oder mehreren der vorstehend aufgeführten Epothilone oder eines oder mehrere dieser Epothilone enthaltend, neben einem oder mehreren üblichen Träger(n) und/oder Verdünnungsmittel(n).Finally, the invention relates to therapeutic agents who develop cytotoxic activities in particular and / or Can cause immunosuppression consisting of one or more the epothilones listed above or one or more containing these epothilones, next to one or several common carriers (s) and / or diluent (s).
Im folgenden wird die Erfindung anhand von Beispielen und experimentellen Daten näher erläutert.In the following the invention is illustrated by examples and experimental Data explained in more detail.
Stamm So ce90 wurde im Juli 1985 an der Gesellschaft für Biotechnologische Forschung (GBF) aus einer Bodenprobe von den Ufern des Zambesi, Südafrika, isoliert. Der Stamm ist bei der Deutschen Sammlung von Mikroorganismen (DSM) unter Nr. 6773 hinterlegt.Strain So ce90 was born in July 1985 at the Society for Biotechnological Research (GBF) a soil sample isolated from the banks of the Zambesi, South Africa. The tribe is with the German Collection of microorganisms (DSM) deposited under No. 6773.
Stammkultur und morphologische Beschreibung: Der Stamm wächst auf Cellulose als einziger Kohlenstoff- und Energiequelle mit KNO₃ als einzige Stickstoffquelle, z. B. auf Filterpapier über ST21 Mineralsalzagar (0.1% KNO₃; 0.1% MgSO₄ × 7 H₂O; 0.1% CaCl₂ × 2 H₂O; 0.1% K₂HPO₄; 0.01% MnSO₄ × 7 H₂O; 0.02% FeCl₃; 0.002% Hefeextrakt; Standard-Spurenelementlösung; 1% Agar). Auf diesem Medium werden dunkelrotbraune bis schwarzbraune Fruchtkörper gebildet, bestehend aus kleinen Sporangiolen (etwa 15 bis 30 µm Durchmesser) in mehr oder weniger großen dichten Haufen und Paketen.Strain culture and morphological description: The stem grows on cellulose as the only carbon and energy source with KNO₃ as the only nitrogen source, for. B. on filter paper over ST21 mineral salt agar (0.1% KNO₃; 0.1% MgSO₄ × 7 H₂O; 0.1% CaCl₂ × 2 H₂O; 0.1% K₂HPO₄; 0.01% MnSO₄ × 7 H₂O; 0.02% FeCl₃; 0.002% yeast extract; standard trace element solution; 1% agar). On this Medium dark red-brown to black-brown fruiting bodies are formed, consisting of small ones Sporangioles (about 15 to 30 µm in diameter) in more or less large dense piles and Packages.
Der Stamm wächst sehr gut mit Glucose und KNO₃, z. B. auf CA2-Agar (Grundmedium: 1.5 g Agar in 92 ml Aqua dest.; Stammlösung 1: 7.5% KNO₃, 7.5% K₂HPO₄ in Aqua dest,; Stammlösung 2: 1.5% MgSO₄ × 7 H₂O in Aqua dest.; Stammlösung 3: 0.2% CaCl₂ × 2 H₂O, 0.15% FeCl₃ in Aqua dest.; Stammlösung 4: 20% Glucose in Aqua dest. Die Stammlösungen werden durch Autoklavieren sterilisiert. Je 1 ml der Lösungen 1 bis 3, sowie 5 ml der Lösung 4 werden dem Grundmedium zugegeben, ebenso eine geeignete Menge einer Spurenelementlösung).The strain grows very well with glucose and KNO₃, e.g. B. on CA2 agar (basic medium: 1.5 g agar in 92 ml aqua dest .; Stock solution 1: 7.5% KNO₃, 7.5% K₂HPO₄ in distilled water ,; Stock solution 2: 1.5% MgSO₄ × 7 H₂O in aqua dest .; Stock solution 3: 0.2% CaCl₂ × 2 H₂O, 0.15% FeCl₃ in distilled water; Stock solution 4: 20% glucose in aqua dest. The stock solutions are made by autoclaving sterilized. 1 ml each of solutions 1 to 3 and 5 ml of solution 4 become the basic medium added, as well as a suitable amount of a trace element solution).
Die vegetativen Stäbchen haben die für Sorangium typische Form (relativ derbe, im Phasenkontrastmikroskop dunkle, zylindrische Stäbchen mit breit abgerundeten Enden, im Mittel 3-6 µm lang und 1 µm dick). Nach längerer Adaptation an das Wachstum in Flüssigmedien wächst der Stamm in homogener Zellsuspension. The vegetative rods have the shape typical of Sorangium (relatively coarse, in the phase contrast microscope dark, cylindrical rods with broadly rounded ends, on average 3-6 µm long and 1 µm thick). After a long adaptation to the growth in liquid media, the strain grows in homogeneous cell suspension.
Der Stamm So ce90 produziert chemisch nahe verwandte Verbindungen, die antibiotische Aktivität besitzen. Insbesondere sind diese Verbindungen cytotoxisch sowie antifungal wirksam. Hervorzuheben ist z. B. die Hemmung von Mucor hiemalis.The So ce90 strain produces chemically closely related compounds, which have antibiotic activity. In particular are these compounds are cytotoxic and antifungal. To emphasize is z. B. the inhibition of Mucor hiemalis.
Die Verbindungen werden während der logarithmischen bis hin zur stationären Wachstumsphase produziert.The connections are made during the logarithmic to the stationary growth phase produced.
Eine typische Fermentation verläuft folgendermaßen: Ein 100 l-Fermenter wird mit 60 l Medium (0.8% Stärke; 0.2% Glucose; 0.2% Sojamehl; 0.2% Hefeextrakt; 0.1% CaCl₂×2H₂O; 0.1% MgSO₄ × 7 H₂O; 8 mg/l Fe-EDTA; pH 7.4) gefüllt. Beimpft wird mit 10 l einer im gleichen Medium jedoch zusätzlich mit 50 mM HEPES-Puffer pH 7.4 in Schüttelkolben angezogenen Vorkultur (160 upm, 30°C). Fermentiert wird bei 32°C mit einer Rührgeschwindigkeit von 500 upm und einer Belüftung von 0.2 NL pro m³ Reaktorvolumen und Std., der pH-Wert wird durch Zugabe von KOH bei 7.4 gehalten. Die Fermentation dauert 7-10 Tage . Die gebildeten aktiven Verbindungen befinden sich teils im Überstand und teils in den Zellen.A typical fermentation proceeds as follows: A 100 l fermenter is mixed with 60 l medium (0.8% Strength; 0.2% glucose; 0.2% soy flour; 0.2% yeast extract; 0.1% CaCl₂ × 2H₂O; 0.1% MgSO₄ × 7 H₂O; 8 mg / l Fe-EDTA; pH 7.4) filled. Inoculated with 10 l one in the same medium but also with 50 mM HEPES buffer pH 7.4 in pre-culture (160 rpm, 30 ° C) grown in shake flasks. It is fermented at 32 ° C with a stirring speed of 500 rpm and aeration of 0.2 NL per m³ of reactor volume and hour, the pH is kept at 7.4 by adding KOH. The fermentation lasts 7-10 days. The active compounds formed are partly in the supernatant and partly in the cells.
Alternativ dazu kann in Gegenwart von Adsorberharzen (z. B. XAD-1180, Rohm und Haas, 2-5%) fermentiert werden.Alternatively, in the presence of adsorber resins (e.g. XAD-1180, Rohm and Haas, 2-5%) be fermented.
Während der Fermentation von Sorangium cellulosum So ce90 (z. B. 70 l Fermentationsvolumen) in Gegenwart eines Adsorberharzes (z. B.: XAD-1180, Röhm und Haas, 2% v/v) werden die gebildeten Antibiotika Epothilon A und B vollständig an das Harz gebunden. Nach Abtrennung der Kulturbrühe (z. B. durch Absieben in einem Prozeßfilter) wird das Harz mit 3 Bettvolumen Wasser gewaschen und mit 4 Bettvolumen Methanol eluiert. Die vereinigten Eluate werden im Vakuum bis auf den Wassergehalt eingeengt und dreimal mit je 0,2 l Ethylacetat extrahiert. Die vereinigten Ethylacetatextrakte werden zur Trockne eingeengt (ca. 40 g Trockengewicht).During the fermentation of Sorangium cellulosum So ce90 (e.g. 70 l fermentation volume) in In the presence of an adsorber resin (e.g. XAD-1180, Röhm and Haas, 2% v / v) the formed Antibiotics Epothilon A and B fully bound to the resin. After separation the culture broth (e.g. by sieving in a process filter) the resin with 3 bed volumes of water washed and eluted with 4 bed volumes of methanol. The combined eluates are vacuumed up to the water content was concentrated and extracted three times with 0.2 l of ethyl acetate. The United Ethyl acetate extracts are evaporated to dryness (approx. 40 g dry weight).
Der Rohextrakt wird in 50 ml Methanol aufgenommen und an Lichroprep® RP-18 25-40 µm (Säule: 400 × 100 mm; Fluß: 200 ml/min;) isokratisch mit Methanol/Wasser 6/4 chromatographiert. Die Epothilone enthaltenden Fraktionen (Rt ca. 95-125 min) werden durch RP-18 Niederdruckchromatographie aufgereinigt. (Säule 400 × 60; HD-Sil-18-20-60, Labomatic; Laufmittel: Methanol/Wasser 65/35; Fluß 25 ml/min; Rt Epothilon A: 140-165 min; Rt Epothilon B: 170-195 min).The crude extract is taken up in 50 ml of methanol and chromatographed on Lichroprep® RP-18 25-40 µm (column: 400 × 100 mm; flow: 200 ml / min;) with methanol / water 6/4. The fractions containing epothilones (R t approx. 95-125 min) are purified by RP-18 low pressure chromatography. (400 × 60 column; HD-Sil-18-20-60, Labomatic; mobile solvent: methanol / water 65/35; flow 25 ml / min; R t epothilone A: 140-165 min; R t epothilone B: 170- 195 min).
Die Feinreinigung der Epothilone erfolgt durch Kristallisation ausThe epothilones are purified by crystallization
- 1. Epothilon A: Toluol/Ethylacetat = 3 : 21. Epothilon A: toluene / ethyl acetate = 3: 2
- 2. Epothilon B: Ethylacetat2. Epothilon B: ethyl acetate
Epothilon AEpothilone A
C₂₆H₃₉NO₆S[493]
FAB-MS (neg. Ionen): 429.25 für (M-H)-
¹H-NMR-Daten s. Tab. 1
¹³C-NMR-Daten s. Tab. 2
UV (MeOH) λmax (log ε) = 210 (4.17); 249 (3.97)
IR Film auf Irtran:
ν: 3429; 2966; 2937; 1737; 1691; 1463; 1374; 1295; 1257; 1185; 1150; 1087; 1029; 1014; 979 cm-1
DC: RF = 0,75
DC-Alufolie 60 F₂₅₄, Merck; Laufmittel:
Dichlormethan/Methanol = 90 : 10
Detektion:
1. UV-Löschung bei 254 nm
2. Ansprühen mit Vanillin/Schwefelsäure-Reagenz und erhitzen auf 120°C, braune
Anfärbung
HPLC: Rt = 5,4 min
Säule: 4 × 250 mm Lichrosorb® RP-18 7 µm;
Fluß: 1,5 ml/min; Laufmittel: Methanol/Wasser = 65 : 35
Detektor: UV 254 nmC₂₆H₃₉NO₆S [493]
FAB-MS (neg. Ions): 429.25 for (MH) -
1 H-NMR data s. Tab. 1
13 C NMR data see. Tab. 2
UV (MeOH) λ max (log ε) = 210 (4.17); 249 (3.97)
IR film on Irtran:
ν: 3429; 2966; 2937; 1737; 1691; 1463; 1374; 1295; 1257; 1185; 1150; 1087; 1029; 1014; 979 cm -1
DC: R F = 0.75
TLC aluminum foil 60 F₂₅₄, Merck; Eluent:
Dichloromethane / methanol = 90:10
Detection:
1. UV quenching at 254 nm
2. Spray on with vanillin / sulfuric acid reagent and heat to 120 ° C, brown color
HPLC: R t = 5.4 min
Column: 4 × 250 mm Lichrosorb® RP-18 7 µm;
Flow: 1.5 ml / min; Mobile solvent: methanol / water = 65:35
Detector: UV 254 nm
Epothilon BEpothilon B
C₂₇H₄₁NO₆S[507]
FAB-MS (neg. Ionen): 506.25 für (M-H)-
¹H-NMR-Daten s. Tab. 1
¹³C-NMR-Daten s. Tab. 2
UV (MeOH) λmax (log ε) = 210 (4.17); 249 (3.97)
IR Film auf Irtran:
ν = 3400; 2958; 2931; 2875; 1735; 1689; 1629; 1609; 1463; 1378; 1250; 1149; 1049; 977 cm-1
DC: RF = 0,75
DC-Alufolie 60 F₂₅₄, Merck; Laufmittel:
Dichlormethan/Methanol = 90 : 10
Detektion:
1. UV-Löschung bei 254 nm
2. Ansprühen mit Vanillin/Schwefelsäure-Reagenz und erhitzt auf 120°C, braune Anfärbung
HPLC: Rt = 6,3 min
Säule: 4 × 250 mm Lichrosorb® RP-18 7 µm;
Fluß: 1,5 ml/min; Laufmittel: Methanol/Wasser = 65 : 35
Detektor: UV 254 nm
C₂₇H₄₁NO₆S [507]
FAB-MS (neg. Ions): 506.25 for (MH) -
1 H-NMR data s. Tab. 1
13 C NMR data see. Tab. 2
UV (MeOH) λ max (log ε) = 210 (4.17); 249 (3.97)
IR film on Irtran:
ν = 3400; 2958; 2931; 2875; 1735; 1689; 1629; 1609; 1463; 1378; 1250; 1149; 1049; 977 cm -1
DC: R F = 0.75
TLC aluminum foil 60 F₂₅₄, Merck; Eluent:
Dichloromethane / methanol = 90:10
Detection:
1. UV quenching at 254 nm
2. Spray on with vanillin / sulfuric acid reagent and heat to 120 ° C, brown color
HPLC: R t = 6.3 min
Column: 4 × 250 mm Lichrosorb® RP-18 7 µm;
Flow: 1.5 ml / min; Mobile solvent: methanol / water = 65:35
Detector: UV 254 nm
Claims (7)
FAB-MS (neg. Ionen): 492.25 für (M-H)-
UV (MeOH) λmax (log ε) = 210 (4.17); 249 (3.97)IR Film auf Irtran:
ν: 3429; 2966; 2937; 1737; 1691; 1463; 1374; 1295; 1257; 1185; 1150; 1087; 1029; 1014; 979 cm-1DC: RF = 0,75
DC-Alufolie 60 F₂₅₄, Merck; Laufmittel:
Dichlormethan/Methanol = 90 : 10
Detektion:
1. UV-Löschung bei 254 nm
2. Ansprühen mit Vanillin/Schwefelsäure-Reagenz und erhitzen auf 120°C, braune AnfärbungHPLC: Rt = 5,4 min
Säule: 4 × 250 mm Lichrosorb® RP-18 7 µm;
Fluß: 1,5 ml/min; Laufmittel: Methanol/Wasser = 65 : 35
Detektor: UV 254 nm2. epothilone, characterized by one or more of the following parameters: C₂₆H₃₉NO₆S [493]
FAB-MS (neg. Ions): 492.25 for (MH) -
UV (MeOH) λ max (log ε) = 210 (4.17); 249 (3.97) IR film on Irtran:
ν: 3429; 2966; 2937; 1737; 1691; 1463; 1374; 1295; 1257; 1185; 1150; 1087; 1029; 1014; 979 cm -1 DC: R F = 0.75
TLC aluminum foil 60 F₂₅₄, Merck; Eluent:
Dichloromethane / methanol = 90:10
Detection:
1. UV quenching at 254 nm
2. Spray on with vanillin / sulfuric acid reagent and heat to 120 ° C, brown staining HPLC: R t = 5.4 min
Column: 4 × 250 mm Lichrosorb® RP-18 7 µm;
Flow: 1.5 ml / min; Mobile solvent: methanol / water = 65:35
Detector: UV 254 nm
FAB-MS (neg. Ionen): 506.25 für (M-H)-
UV (MeOH)λmax (log ε) = 210 (4.17); 249 (3.97)IR Film auf Irtran:
ν = 3400; 2958; 2931; 2875; 1735; 1689; 1629; 1609; 1463; 1378; 1250; 1149; 1049; 977 cm-1DC: RF = 0,75
DC-Alufolie 60 F₂₅₄, Merck; Laufmittel:
Dichlormethan/Methanol = 90 : 10
Detektion:
1. UV-Löschung bei 254 nm
2. Ansprühen mit Vanillin/Schwefelsäure-Reagenz und erhitzt auf 120°C, braune AnfärbungHPLC: Rt = 6,3 min
Säule: 4 × 250 mm Lichrosorb® RP-18 7 µm;
Fluß: 1,5 ml/min; Laufmittel: Methanol/Wasser = 65 : 35
Detektor: UV 254 nm3. epothilone, characterized by one or more of the following parameters: C₂₇H₄₁NO₆S [507]
FAB-MS (neg. Ions): 506.25 for (MH) -
UV (MeOH) λ max (log ε) = 210 (4.17); 249 (3.97) IR film on Irtran:
ν = 3400; 2958; 2931; 2875; 1735; 1689; 1629; 1609; 1463; 1378; 1250; 1149; 1049; 977 cm -1 DC: R F = 0.75
TLC aluminum foil 60 F₂₅₄, Merck; Eluent:
Dichloromethane / methanol = 90:10
Detection:
1. UV quenching at 254 nm
2. Spray on with vanillin / sulfuric acid reagent and heat to 120 ° C, brown staining HPLC: R t = 6.3 min
Column: 4 × 250 mm Lichrosorb® RP-18 7 µm;
Flow: 1.5 ml / min; Mobile solvent: methanol / water = 65:35
Detector: UV 254 nm
- - in einem Kohlenstoffquellen, Stickstoffquellen und Mineralsalze enthaltenden Medium kultiviert,
- - entweder während der Kultivierung des Stammes oder anschließend ein Adsorberharz zusetzt,
- - die Fermenterbrühe abtrennt,
- - die Epothilone aus dem Adsorberharz eluiert und
- - die Eluate direkt oder über weitere Reinigungsschritte von dem/den Lösungsmittel(n) befreit,
- - und gegebenenfalls über Hochdruck/Niederdruckchromatographie und/oder Umkristallisation die verschiedenen Epothilone aufreinigt und voneinander trennt.
- - cultivated in a medium containing carbon sources, nitrogen sources and mineral salts,
- - either during the cultivation of the strain or subsequently adding an adsorber resin,
- - separates the fermenter broth,
- - the epothilones eluted from the adsorber resin and
- - the eluates are freed from the solvent (s) directly or through further cleaning steps,
- - and, if necessary, the various epothilones are purified and separated from one another by means of high pressure / low pressure chromatography and / or recrystallization.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19914138042 DE4138042C2 (en) | 1991-11-19 | 1991-11-19 | Epothilones, their production processes and agents containing these compounds |
| AU29437/92A AU2943792A (en) | 1991-11-19 | 1992-11-19 | Epothilones, process for preparing the same and their use as medicaments and as plant protecting agents |
| PCT/EP1992/002656 WO1993010121A1 (en) | 1991-11-19 | 1992-11-19 | Epothilones, process for preparing the same and their use as medicaments and as plant protecting agents |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19914138042 DE4138042C2 (en) | 1991-11-19 | 1991-11-19 | Epothilones, their production processes and agents containing these compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE4138042A1 DE4138042A1 (en) | 1993-05-27 |
| DE4138042C2 true DE4138042C2 (en) | 1993-10-14 |
Family
ID=6445140
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19914138042 Expired - Lifetime DE4138042C2 (en) | 1991-11-19 | 1991-11-19 | Epothilones, their production processes and agents containing these compounds |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU2943792A (en) |
| DE (1) | DE4138042C2 (en) |
| WO (1) | WO1993010121A1 (en) |
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| US7750164B2 (en) | 1996-12-03 | 2010-07-06 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
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-
1991
- 1991-11-19 DE DE19914138042 patent/DE4138042C2/en not_active Expired - Lifetime
-
1992
- 1992-11-19 AU AU29437/92A patent/AU2943792A/en not_active Abandoned
- 1992-11-19 WO PCT/EP1992/002656 patent/WO1993010121A1/en active Application Filing
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7750164B2 (en) | 1996-12-03 | 2010-07-06 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
| USRE41990E1 (en) | 1996-12-03 | 2010-12-07 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
| US8481575B2 (en) | 1996-12-03 | 2013-07-09 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
| US7649006B2 (en) | 2002-08-23 | 2010-01-19 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1993010121A1 (en) | 1993-05-27 |
| DE4138042A1 (en) | 1993-05-27 |
| AU2943792A (en) | 1993-06-15 |
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