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WO1993010121A1 - Epothilones, process for preparing the same and their use as medicaments and as plant protecting agents - Google Patents

Epothilones, process for preparing the same and their use as medicaments and as plant protecting agents Download PDF

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Publication number
WO1993010121A1
WO1993010121A1 PCT/EP1992/002656 EP9202656W WO9310121A1 WO 1993010121 A1 WO1993010121 A1 WO 1993010121A1 EP 9202656 W EP9202656 W EP 9202656W WO 9310121 A1 WO9310121 A1 WO 9310121A1
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Prior art keywords
epothilones
methanol
merck
epothilone
hydrogen
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PCT/EP1992/002656
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German (de)
French (fr)
Inventor
Gerhard Höfle
Norbert Bedorf
Klaus Gerth
Hans Reichenbach
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Novartis AG
Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
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Ciba Geigy AG
Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
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    • 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

Definitions

  • the invention relates to epothilones of the following general formula:
  • R 1 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkanoyl, Li + , K + , Na + , 1/2 Mg 2+ or 1/2 Ca 2+ and R 2 is hydrogen or one Represents methyl group.
  • the invention further relates to an epothilone, characterized by one or more of the following parameters:
  • the invention further relates to an epothilone, characterized by one or more of the following parameters:
  • V 3400; 2958; 2931; 2875; 1735; 1689: 1629; 1609; 1463; 1378; 1250; 1149; 1049; 977 cm -1
  • Epothilones with the following structural formula are particularly preferred:
  • the invention further relates to a method for obtaining epothilones, in particular the epothilones characterized above, which is characterized in that the strain So ce90 DSM 6773 - in a carbon containing nitrogen sources and mineral salts
  • Adsorber resin is added, - the fermenter broth is separated, - the epothilones are extracted from the adsorber resin and - the eluates are removed directly or via further cleaning steps from the / the
  • Recrystallization purifies and separates the different epothilones.
  • the epothilones obtained in this way can be reacted further using common chemical processes, e.g. converted with bases into the alkali and alkaline earth salts and, if appropriate, further converted to ethers, or they can be converted into the corresponding esters with organic acids.
  • the invention further relates to an agent for crop protection in agriculture
  • Forestry and / or horticulture consisting of one or more of the above-mentioned epothilones or containing one or more of these epothilones, optionally in addition to one or more conventional carriers and / or diluents.
  • the invention relates to a therapeutic agent which can in particular develop cytotoxic activities and / or cause immunosuppression, consisting of one or more of the above-mentioned epothilones or containing one or more of these epothilones, optionally in addition to one or more conventional carriers and / or Diluent (s).
  • GEF German Collection of Microorganisms
  • the stem grows on cellulose as the only carbon and energy source with KNO 3 as the only nitrogen source, e.g. on filter paper over ST21 mineral salt agar (0.1% KNO 3 ; 0.1% MgSO 4 ⁇ 7 H 2 0; 0.1% CaCI 2 ⁇ 2 H 2 O; 0.1% K 2 HPO 4 ; 0.01% MnSO 4 ⁇ 7 H 2 O; 0.02% FeCI 3 ; 0.002% yeast extract; standard trace element solution; 1% agar). Be on this medium
  • dark red-brown to black-brown fruiting bodies formed, consisting of small sporangioles (about 15 to 30 ⁇ m in diameter) in more or less large, dense clusters and packages.
  • the strain grows very well with glucose and KNO 3 , e.g. on CA2 agar (basic medium: 1.5 g agar in 92 ml distilled water; stock solution 1: 7.5% KNO 3 , 7.5% K 2 HPO 4 in distilled water; stock solution 2: 1.5% MgSO 4 ⁇ 7 H 2 O in distilled water; stock solution 3: 0.2% CaCl 2 ⁇ 2 H 2 O, 0.15% FeCl 3 in distilled water; stock solution 4: 20% glucose in distilled water.
  • the stock solutions are autoclaved 1 ml of solutions 1 to 3 and 5 ml of solution 4 are added to the basic medium, as well as a suitable amount of a trace element solution).
  • the vegetative rods have the shape typical of Sorangium (relatively coarse, cylindrical, dark in the phase contrast microscope with broadly rounded ends, on average 3 - 6 ⁇ m long and 1 ⁇ m thick). After a longer adaptation to the growth in liquid media, the strain grows in a homogeneous cell suspension.
  • a typical fermentation proceeds as follows: A 100 l fermenter is mixed with 60 l medium (0.8% starch; 0.2% glucose; 0.2% soy flour; 0.2% yeast extract; 0.1% CaCl 2 ⁇ 2 H 2 O; 0.1% MgSO 4 ⁇ 7 H 2 O; 8 mg / l Fe-EDTA; pH 7.4) filled. Inoculation is carried out with 10 l of a preculture (160 rpm, 30 ° C.) which has been grown in the same medium but additionally with 50 mM HEPES buffer pH 7.4 in shake flasks.
  • the fermentation takes place at 32 oC with a stirring speed of 500 rpm and aeration of 0.2. NL per m 3 and hour, the pH is kept at 7.4 by adding KOH. The fermentation takes 7-10 days.
  • the active compounds formed are partly in the supernatant and partly in the cells.
  • fermentation can be carried out in the presence of adsorber resins (e.g. XAD-1180, Rohm and Haas, 2 - 5%).
  • adsorber resins e.g. XAD-1180, Rohm and Haas, 2 - 5%.
  • Sora ⁇ gium cellulosum So ce90 e.g. 70 I
  • the crude extract is taken up in 50 ml of methanol and isocratic with Lichroprep RP-18 25-40 ⁇ m (column: 400 ⁇ 100 mm; flow: 200 ml / min; Merck Prepbar)
  • Epothilon B ethyl acetate

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Environmental Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Plant Pathology (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (AREA)
  • Biotechnology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dentistry (AREA)
  • Microbiology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Epothilones having general formula (I), a process for preparing the same and epothilone-containing agents are disclosed.

Description

EPOTHILONE, DEREN HERSTELLUNGSVERFAHREN UND IHRE VERWENDUNG ALS ARZNEIMITTEL UND PFLANZENSCHUTZENDE MITTEL EPOTHILONES, THEIR PRODUCTION PROCESS AND THEIR USE AS MEDICINAL PRODUCTS AND PLANT PROTECTIVE AGENTS

Die Erfindung betrifft Epothilone der folgenden allgemeinen Formel: The invention relates to epothilones of the following general formula:

Figure imgf000003_0001
Figure imgf000003_0001

worin R1 Wasserstoff, C1-C4-Alkyl, C1-C4-Alkanoyl, Li+, K+, Na+, 1/2 Mg2+ oder 1/2 Ca2+ bedeutet und R2 Wasserstoff oder eine Methylgruppe darstellt. wherein R 1 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkanoyl, Li + , K + , Na + , 1/2 Mg 2+ or 1/2 Ca 2+ and R 2 is hydrogen or one Represents 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:

Figure imgf000004_0001
C26H39NO6S [493]
Figure imgf000004_0001
C 26 H 39 NO 6 S [493]

FAB-MS (neg. Ionen): 492.25 für (M - H)- FAB-MS (neg. Ions): 492.25 for (M - H) -

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: IR film on Irtran:

v: 3429:2966; 2937; 1737; 1691; 1463; 1374; 1295; 1257; 1185; 1150; 1087; 1029; 1014; 979 cm-1 v: 3429: 2966; 2937; 1737; 1691; 1463; 1374; 1295; 1257; 1185; 1150; 1087; 1029; 1014; 979 cm -1

DC: RF = 0,75 DC: R F = 0.75

DC-Alufolie 60 F254, Merck; Laufmittel: TLC aluminum foil 60 F 254 , Merck; Solvent:

Dichlormethan/Methanol = 90 : 10 Dichloromethane / methanol = 90:10

Detektion: 1. UV-Löschung bei 254 nm Detection: 1. UV quenching at 254 nm

2. Ansprühen mit Vanillin/Schwefelsäure-Reagenz und erhitzen auf 120 °C, braune Anfärbung  2. Spray on with vanillin / sulfuric acid reagent and heat to 120 ° C, brown color

HPLC: Rt = 5,4 min HPLC: R t = 5.4 min

Säule: 4 × 250 mm Lichrosorb RP-187 μm, Merck;  Column: 4 × 250 mm Lichrosorb RP-187 μm, Merck;

Fluß: 1 ,5 ml/min; Laufmittel: Methanol/Wasser = 65 : 35 Flow: 1.5 ml / min; Mobile solvent: methanol / water = 65: 35

Detektor: UV 254 nm 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:

Figure imgf000006_0001
C27H41NO6S [507]
Figure imgf000006_0001
C 27 H 41 NO 6 S [507]

FAB-MS (neg. Ionen): 506.25 für (M - H)-  FAB-MS (neg. Ions): 506.25 for (M - H) -

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: IR film on Irtran:

V = 3400; 2958; 2931; 2875; 1735; 1689: 1629; 1609; 1463; 1378; 1250; 1149; 1049; 977 cm-1 V = 3400; 2958; 2931; 2875; 1735; 1689: 1629; 1609; 1463; 1378; 1250; 1149; 1049; 977 cm -1

DC: RF = 0,75 DC: R F = 0.75

DC-Alufolie 60 F254, Merck; Laufmittel: TLC aluminum foil 60 F 254 , Merck; Solvent:

Dichlormethan/Methanol = 90 : 10 Dichloromethane / methanol = 90:10

Detektion: 1. UV-Löschung bei 254 nm Detection: 1. UV quenching at 254 nm

2. Ansprühen mit Vanillin/Schwefelsäure-Reagenz und erhitzt auf 120 ºC, braune Anfärbung  2. Spray on with vanillin / sulfuric acid reagent and heat to 120 ºC, brown color

HPLC: Rt = 6,3 min HPLC: R t = 6.3 min

Säule: 4 × 250 mm Lichrosorb RP-187 μm, Merck;  Column: 4 × 250 mm Lichrosorb RP-187 μm, Merck;

Fluß: 1 ,5 ml/min; Laufmittel: Methanol/Wasser = 65 : 35 Flow: 1.5 ml / min; Mobile solvent: methanol / water = 65: 35

Detektor: UV 254 nm Detector: UV 254 nm

Besonders bevorzugt sind Epothilone mit der folgenden Strukturformel: Epothilones with the following structural formula are particularly preferred:

Figure imgf000007_0001
worin R2 Wasserstoff oder Methyl bedeutet. (Das Kohlenstoffatom der Methyigruppe 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 6773 - in einem Kohlenstoffquellen, Stickstoffquellen und Mineralsalze enthaltenden
Figure imgf000007_0001
wherein R 2 is hydrogen or methyl. (The carbon atom of the methyl group is called C27). The invention further relates to a method for obtaining epothilones, in particular the epothilones characterized above, which is characterized in that the strain So ce90 DSM 6773 - in a carbon containing nitrogen sources and mineral salts

Medium kultiviert, - entweder während der Kultivierung des Stammes oder anschließend ein  Medium cultivated, - either during the cultivation of the strain or afterwards

Adsorberharz zusetzt, - die Fermenterbrühe abtrennt, - die Epothilone aus dem Adsorberharz efuiert und - die Eluate direkt oder über weitere Reinigungsschritte von dem/den  Adsorber resin is added, - the fermenter broth is separated, - the epothilones are extracted from the adsorber resin and - the eluates are removed directly or via further cleaning steps from the / the

Lösungsmittel (n) befreit, - und gegebenenfalls über Hochdruck/Niederdruckchromatographie und/oder  Solvent (s) freed - and if necessary via high pressure / low pressure chromatography and / or

Umkristallisation die verschiedenen Epothilone aufreinigt und voneinander trennt.  Recrystallization purifies and separates the different epothilones.

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 Ethem umgesetzt werden, oder sie können mit organischen Säuren in die entsprechenden Ester überführt werden. If necessary, the epothilones obtained in this way can be reacted further using common chemical processes, e.g. converted with bases into the alkali and alkaline earth salts and, if appropriate, further converted to ethers, or they can be converted into the corresponding esters with organic acids.

Ferner betrifft die Erfindung ein Mittel für den Pflanzenschutz in Landwirtschaft, The invention further relates to an agent for crop protection in agriculture,

Forstwirtschaft und/oder Gartenbau, bestehend aus einem oder mehreren der vorstehend aufgeführten Epothilone oder eines oder mehrere dieser Epothilone enthaltend, gegebenenfalls neben einem oder mehreren üblichen Träger(n) und/oder Verdünnungsmittel(n). Schließlich betrifft die Erfindung ein therapeutisches Mittel, das insbesondere cytotoxische Aktivitäten entwickeln und/oder Immunsuppression bewirken kann, bestehend aus einem oder mehreren der vorstehend aufgeführten Epothilone oder eines oder mehrere dieser Epothilone enthaltend, gegebenenfalls neben einem oder mehreren üblichen Träger(n) und/oder Verdünnungsmittel(n). Forestry and / or horticulture consisting of one or more of the above-mentioned epothilones or containing one or more of these epothilones, optionally in addition to one or more conventional carriers and / or diluents. Finally, the invention relates to a therapeutic agent which can in particular develop cytotoxic activities and / or cause immunosuppression, consisting of one or more of the above-mentioned epothilones or containing one or more of these epothilones, optionally in addition to one or more conventional carriers and / or Diluent (s).

- Administrationsform: oral - Administration form: oral

- Dosis 0.5 bis 200 mg für einen Menschen mit 70 kg Normalgewicht  - Dose 0.5 to 200 mg for a person with a normal weight of 70 kg

- Verwendungszweck: Antitumor  - Intended use: anti-tumor

Im folgenden wird die Erfindung anhand von Beispielen und experimentellen Daten näher erläutert. The invention is explained in more detail below with the aid of examples and experimental data.

Produktionsstamm Production master

Stamm So ce90 wurde im Juli 1985 an der Gesellschaft für Biotechnologische Strain So ce90 was born in July 1985 at the Society for Biotechnological

Forschung (GBF) aus einer Bodenprobe von den Ufern des Zambesi, im südlichen Afrika, isoliert. Der Stamm ist bei der Deutschen Sammlung von Mikroorganismen (DSM) unter Nr. 6773 hinterlegt. Research (GBF) isolated from a soil sample from the banks of the Zambesi, in southern Africa. The strain is deposited with the German Collection of Microorganisms (DSM) 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 H20; 0.1 % CaCI2 × 2 H2O; 0.1% K2HPO4; 0.01 % MnSO4 × 7 H2O; 0.02% FeCI3; 0.002% Hefeextrakt; Standard-Spurenelementlösung; 1% Agar). Auf diesem Medium werden Strain culture and morphological description: The stem grows on cellulose as the only carbon and energy source with KNO 3 as the only nitrogen source, e.g. on filter paper over ST21 mineral salt agar (0.1% KNO 3 ; 0.1% MgSO 4 × 7 H 2 0; 0.1% CaCI 2 × 2 H 2 O; 0.1% K 2 HPO 4 ; 0.01% MnSO 4 × 7 H 2 O; 0.02% FeCI 3 ; 0.002% yeast extract; standard trace element solution; 1% agar). Be on this medium

dunkelrotbraune bis schwarzbraune Fruchtkörper gebildet, bestehend aus kleinen Sporangiolen (etwa 15 bis 30 μm Durchmesser) in mehr oder weniger großen dichten Haufen und Paketen. dark red-brown to black-brown fruiting bodies formed, consisting of small sporangioles (about 15 to 30 μm in diameter) in more or less large, dense clusters 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; Stammiösung 2: 1.5% MgSO4 × 7 H2O in Aqua dest; Stammlösung 3: 0.2% CaCI2 × 2 H2O, 0.15% FeCl3 in Aqua dest.; Stammlösung 4: 20% Glucose in Aqua dest. Die Stammiösungen 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). 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 Zeilsuspension. The strain grows very well with glucose and KNO 3 , e.g. on CA2 agar (basic medium: 1.5 g agar in 92 ml distilled water; stock solution 1: 7.5% KNO 3 , 7.5% K 2 HPO 4 in distilled water; stock solution 2: 1.5% MgSO 4 × 7 H 2 O in distilled water; stock solution 3: 0.2% CaCl 2 × 2 H 2 O, 0.15% FeCl 3 in distilled water; stock solution 4: 20% glucose in distilled water. The stock solutions are autoclaved 1 ml of solutions 1 to 3 and 5 ml of solution 4 are added to the basic medium, as well as a suitable amount of a trace element solution). The vegetative rods have the shape typical of Sorangium (relatively coarse, cylindrical, dark in the phase contrast microscope with broadly rounded ends, on average 3 - 6 μm long and 1 μm thick). After a longer adaptation to the growth in liquid media, the strain grows in a homogeneous cell suspension.

Der Stamm So ce90 produziert chemisch nahe verwandte Verbindungen, die The So ce90 strain produces chemically closely related compounds that

antibiotische Aktivität besitzen. Insbesondere sind diese Verbindungen cytotoxisch sowie antifungal wirksam. Hervorzuheben ist z.B. die Hemmung von Mucor hiemalis. have antibiotic activity. In particular, these compounds are cytotoxic and antifungal. It should be emphasized e.g. the inhibition of Mucor hiemalis.

Produktion der biologisch aktiven Verbindungen: Production of the biologically active compounds:

Die Verbindungen werden während der iogarithmischen bis hin zur stationären  The connections are made during the logarithmic to the stationary

Wachstumsphase produziert. Eine typische Fermentation verläuft folgendermaßen: Ein 100 l-Fermenter wird mit 60 I Medium (0.8% Stärke; 0.2% Glucose; 0.2% Soyamehl; 0.2% Hefeextrakt; 0.1% CaCI2 × 2 H2O; 0.1% MgSO4 × 7 H2O; 8 mg/l Fe-EDTA; pH 7.4) gefüllt. Beimpft wird mit 10 I einer im gleichen Medium jedoch zusätzlich mit 50 mM HEPES-Puffer pH 7.4 in Schüttelkolben angezogenen Vorkultur (160 upm, 30 ºC). Growth phase produced. A typical fermentation proceeds as follows: A 100 l fermenter is mixed with 60 l medium (0.8% starch; 0.2% glucose; 0.2% soy flour; 0.2% yeast extract; 0.1% CaCl 2 × 2 H 2 O; 0.1% MgSO 4 × 7 H 2 O; 8 mg / l Fe-EDTA; pH 7.4) filled. Inoculation is carried out with 10 l of a preculture (160 rpm, 30 ° C.) which has been grown in the same medium but additionally with 50 mM HEPES buffer pH 7.4 in shake flasks.

Fermentiert wird bei 32 ºC mit einer Rührgeschwindigkeit von 500 upm und einer Belüftung von 0.2. NL pro m3 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. The fermentation takes place at 32 ºC with a stirring speed of 500 rpm and aeration of 0.2. NL per m 3 and hour, the pH is kept at 7.4 by adding KOH. The fermentation takes 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, fermentation can be carried out in the presence of adsorber resins (e.g. XAD-1180, Rohm and Haas, 2 - 5%).

Isolierung von Epothilon A und B Isolation of epothilones A and B

Während der Fermentation von Soraπgium cellulosum So ce90 (z.B. 70 I  During the fermentation of Soraπgium cellulosum So ce90 (e.g. 70 I

Fermentationsvolumen) in Gegenwart eines Adsorberharzes (z.B.: XAD-1180, Röhm und Haas, 2 % v/v) werden die gebildeten Antibiotika Epothilon A (Abb. 1 ) und B (Abb. 2) 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 1 Ethylacetat extrahiert. Die vereinigten Ethylacetatextrakte werden zur Trockne eingeengt (ca. 40 g Fermentation volume) in the presence of an adsorber resin (e.g. XAD-1180, Röhm and Haas, 2% v / v), the antibiotics Epothilon A (Fig. 1) and B (Fig. 2) are completely bound to the resin. After the culture broth has been separated off (e.g. by sieving in a process filter), the resin is washed with 3 bed volumes of water and eluted with 4 bed volumes of methanol. The combined eluates are concentrated in vacuo to the water content and extracted three times with 0.2 l of ethyl acetate each time. The combined ethyl acetate extracts are evaporated to dryness (approx. 40 g

Trockengewicht). Der Rohextrakt wird in 50 ml Methanol aufgenommen und an Lichroprep RP-18 25-40 μm (Säule: 400 × 100 mm; Fluß: 200 ml/min; Merck Prepbar) isokratisch mit Dry weight). The crude extract is taken up in 50 ml of methanol and isocratic with Lichroprep RP-18 25-40 μm (column: 400 × 100 mm; flow: 200 ml / min; Merck Prepbar)

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). Chromatographed methanol / water 6/4. The fractions containing epothilones (R t approx. 95-125 min) are purified by RP-18 low pressure chromatography. (Column 400 × 60; 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 aus The epothilones are cleaned out by crystallization

1. Epothilon A: Toluol/Ethyiacetat = 3 : 2  1. Epothilone A: toluene / ethyl acetate = 3: 2

2. Epothilon B: Ethylacetat  2. Epothilon B: ethyl acetate

Epothilon A Epothilone A

C26H39NO6S [493] C 26 H 39 NO 6 S [493]

FAB-MS (neg. Ionen): 492.25 für (M - H)- FAB-MS (neg. Ions): 492.25 for (M - H) -

1H-NMR-Daten s. Tab. 1 1 H-NMR data see. Tab. 1

13C-NMR-Daten s. Tab. 2 13 C-NMR data see. Tab. 2

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: IR film on Irtran:

ν: 3429:2966:2937; 1737; 1691; 1463: 1374; 1295; 1257; 1185; 1150; 1087; 1029: 1014:979 CITT1 ν: 3429: 2966: 2937; 1737; 1691; 1463: 1374; 1295; 1257; 1185; 1150; 1087; 1029: 1014: 979 CITT 1

DC: RF = 0,75 DC: R F = 0.75

DC-Alufolie 60 F254, Merck; Laufmittel: TLC aluminum foil 60 F 254 , Merck; Solvent:

Dichlormethan/Methanol = 90 : 10 Dichloromethane / methanol = 90:10

Detektion: 1. UV-Löschung bei 254 nm Detection: 1. UV quenching at 254 nm

2. Ansprühen mit Vanillin/Schwefelsäure-Reagenz und erhitzen auf 120 ºC, braune Anfärbung  2. Spray on with vanillin / sulfuric acid reagent and heat to 120 ºC, brown color

HPLC: Rt = 5,4 min HPLC: R t = 5.4 min

Säule: 4 × 250 mm Lichrosorb RP-18 7 μm, Merck;  Column: 4 × 250 mm Lichrosorb RP-18 7 μm, Merck;

Fluß: 1 ,5 ml/min; Laufmittel: Methanol/Wasser = 65 : 35  Flow: 1.5 ml / min; Mobile solvent: methanol / water = 65: 35

Detektor: UV 254 nm Epothilon B Detector: UV 254 nm Epothilon B

C27H41NO6S [507] C 27 H 41 NO 6 S [507]

FAB-MS (neg. Ionen): 506.25 für (M - H)- 1H-NMR-Daten s. Tab. 1 FAB-MS (neg. Ions): 506.25 for (M - H) - 1 H NMR data see. Tab. 1

13C-NMR-Daten s. Tab. 2 1 3 C-NMR data see. Tab. 2

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 lrtran: IR film on lrtran:

ν = 3400:2958: 2931: 2875: 1735: 1689: 1629: 1609: 1463: 1378: 1250; 1149: 1049; 977 cm-1 ν = 3400: 2958: 2931: 2875: 1735: 1689: 1629: 1609: 1463: 1378: 1250; 1149: 1049; 977 cm -1

DC: RF = 0,75 DC: R F = 0.75

DC-Alufolie 60 F254, Merck; Laufmittel: TLC aluminum foil 60 F 254 , Merck; Solvent:

Dichiormethan/Methanol = 90 : 10 Dichloromethane / methanol = 90:10

Detektion: 1. UV-Löschung bei 254 nm Detection: 1. UV quenching at 254 nm

2. Ansprühen mit Vanillin/Schwefelsäure-Reagenz und erhitzt auf 120 ºC, braune Anfärbung  2. Spray on with vanillin / sulfuric acid reagent and heat to 120 ºC, brown color

HPLC: Rt = 6,3 min HPLC: R t = 6.3 min

Säule: 4 × 250 mm Lichrosorb RP-187 μm, Merck;  Column: 4 × 250 mm Lichrosorb RP-187 μm, Merck;

Fluß: 1,5 mi/min; Laufmittel: Methanol/Wasser = 65 : 35 Flow: 1.5 mi / min; Mobile solvent: methanol / water = 65: 35

Detektor: UV 254 nm Detector: UV 254 nm

Figure imgf000013_0001
Figure imgf000014_0001
Anwendungsbeispiel
Figure imgf000013_0001
Figure imgf000014_0001
Application example

Nach bekannten Methoden (T. Meyer, U. Renegass, D. Fabbro, E. Alten, J. Rösel, M. Müller, G. Caravatti & A. Matter: A derivative of staurosporine (CGP 41 251 ) shows selectivity for protein kinase C inhibition and in vitro anti-prol iterative as well as in vivo anti-tumor activity. Int. J. Cancer 1989, 43, 851-6) wird Epothilon A auf die Hemmung der T-24 Zellinie untersucht. Es wird ein IC50 Wert von < 0.05 μM ermittelt. According to known methods (T. Meyer, U. Renegass, D. Fabbro, E. Alten, J. Rösel, M. Müller, G. Caravatti & A. Matter: A derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and in vitro anti-prol iterative as well as in vivo anti-tumor activity. Int. J. Cancer 1989, 43, 851-6), epothilone A is examined for the inhibition of the T-24 cell line. An IC 50 value of <0.05 μM is determined.

Claims

Patentansprüche Patent claims 1. Epothilone der allgemeinen Formel: 1. Epothilone of general formula:
Figure imgf000016_0001
Figure imgf000016_0001
 worin R1 Wasserstoff, C1-C4-Alkyl, C1-C4-Acyl, Li+, K+, Na+, 1/2 Mg2+ oder 1/2 Ca2+ bedeutet und R2 Wasserstoff oder eine Methylgruppe darstellt. where R 1 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 acyl, Li + , K + , Na +, 1/2 Mg 2+ or 1/2 Ca 2+ and R 2 is hydrogen or a methyl group represents. 2. Epothilone der allgemeinen Formel: 2. Epothilones of general formula:
Figure imgf000016_0002
S
Figure imgf000016_0002
S worin R2 Wasserstoff oder Methyl ist where R 2 is hydrogen or methyl 3. Epothilon, gekennzeichnet durch einen oder mehrere der folgenden Parameter:
Figure imgf000017_0001
C26H39NO6S [493] 3. Epothilone, characterized by one or more of the following parameters:
Figure imgf000017_0001
C26H39NO6S [ 493 ] FAB-MS (neg. Ionen): 492.25 für (M - H)- FAB-MS (neg. ions): 492.25 for (M - H)- 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: IR film on Irtran: v: 3429; 2966; 2937; 1737; 1691 ; 1463; 1374; 1295; 1257; 1185; 1150; 1087; 1029; 1014; 979 cm-1 v: 3429; 2966; 2937; 1737; 1691 ; 1463; 1374; 1295; 1257; 1185; 1150; 1087; 1029; 1014; 979 cm -1 DC: RF = 0,75 TLC: R F = 0.75 DC-Alufolie 60 F254, Merck; Laufmittel: DC aluminum foil 60 F 254 , Merck; Mobile solvent: Dϊchiormethan/Methanol = 90 : 10 Dichloromethane/methanol = 90:10 Detektion: 1. UV-Löschung bei 254 nm Detection: 1. UV quenching at 254 nm 2. Ansprühen mit Vanillin/Schwefelsäure-Reagenz und erhitzen auf 120 *C, braune Anfärbung 2. Spray with vanillin/sulfuric acid reagent and heat to 120 * C, brown color HPLC: Rt = 5,4 min HPLC: R t = 5.4 min Säule: 4 × 250 mm Lichrosorb RP-187 μm, Merck: Column: 4 × 250 mm Lichrosorb RP-187 μm, Merck: Fluß: 1,5 ml/min: Laufmittel: Methanol/Wasser = 65 : 35 Flow: 1.5 ml/min: mobile phase: methanol/water = 65:35 Detektor: UV 254 nm Detector: UV 254 nm 4. Epothilon, gekennzeichnet durch einen oder mehrere der folgenden Parameter: 4. Epothilone, characterized by one or more of the following parameters:
Figure imgf000019_0001
C27H41NO6S [507]
Figure imgf000019_0001
C 27 H 41 NO 6 S [507] FAB-MS (neg. Ionen): 506.25 für (M - H)- FAB-MS (neg. ions): 506.25 for (M - H)- 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: IR film on Irtran: v = 3400; 2958:2931, 2875; 1735; 1689; 1629; 1609; 1463; 1378; 1250; 1149; 1049; 977 cm-1 v = 3400; 2958:2931, 2875; 1735; 1689; 1629; 1609; 1463; 1378; 1250; 1149; 1049; 977 cm -1 DC: RF = 0,75 TLC: R F = 0.75 DC-Alufolie 60 F254, Merck; Laufmittel: DC aluminum foil 60 F254, Merck; Mobile solvent: Dichlormethan/Methanol = 90 : 10 Dichloromethane/methanol = 90:10 Detektion: 1. UV-Löschung bei 254 nm Detection: 1. UV quenching at 254 nm 2. Ansprühen mit Vanillin/Schwefelsäure-Reagenz und erhitzt auf 120 ºC, braune Anfärbung 2. Spraying with vanillin/sulfuric acid reagent and heated to 120 ºC, brown color HPLC: Rt = 6,3 min HPLC: R t = 6.3 min Säule: 4 × 250 mm Lichrosorb RP-187 μm, Merck; Column: 4 × 250 mm Lichrosorb RP-187 μm, Merck; Ruß: 1 ,5 ml/min; Laufmittel: Methanol/Wasser= 65 : 35 Carbon black: 1.5 ml/min; Mobile phase: methanol/water = 65:35 Detektor: UV 254 nm Detector: UV 254 nm 5. Verfahren zum Herstellen von Epothilonen nach einem der vor anstehenden 5. Process for producing epothilones according to one of the above Ansprüche, dadurch gekennzeichnet, daß man den Stamm So ce90 - in einem Kohlenstoffquellen, Stickstoffquellen und Mineralsalze enthaltenden Medium kultiviert, - entweder während der Kultivierung des Stammes oder anschließend ein Claims, characterized in that the So ce90 strain is cultivated in a medium containing carbon sources, nitrogen sources and mineral salts, either during the cultivation of the strain or subsequently Adsorberharz zusetzt, - die Fermenterbrühe abtrennt, - die Epothilone aus dem Adsorberharz eluiert und - die Eluate direkt oder über weitere Reinigungsschritte von dem/den Adsorber resin is added, - the fermenter broth is separated, - the epothilones are eluted from the adsorber resin and - the eluates are removed directly or via further purification steps Lösungsmittel(n) befreit, - und gegebenenfalls über Hochdruck/Niederdruckchromatographie und/oder Solvent(s) freed, - and if necessary via high pressure/low pressure chromatography and/or Umkristailisation die verschiedenen Epothilone aufreinigt und voneinander trennt. Recrystallization purifies the different epothilones and separates them from each other. 6. Mittel für den Pflanzenschutz in der Landwirtschaft und Forstwirtschaft und/oder im Gartenbau, bestehend aus einem oder mehreren Epothilonen gemäß einem der voranstehenden Ansprüche oder eines oder mehrerer dieser Epothilone enthaltend, gegebenenfalls neben einem oder mehreren üblichen Träger(n) und/oder 6. Agents for plant protection in agriculture and forestry and/or in horticulture, consisting of one or more epothilones according to one of the preceding claims or containing one or more of these epothilones, optionally in addition to one or more usual carriers and/or Verdünnungsmittel(n). Diluent(s). 7. Mittel nach Anspruch 6, dadurch gekennzeichnet, daß es ein Fungizid oder Fungistatikum ist. 7. Agent according to claim 6, characterized in that it is a fungicide or fungistatic. 8. Therapeutisches Mittel, das insbesondere cytotoxische Aktivitäten entwickeln und/oder Immunsuppresion bewirken kann, bestehend aus einem oder mehreren Epothilonen nach einem der Ansprüche 1 bis 4 oder diese Epothilone enthaltend, gegebenenfalls neben einem oder mehreren üblichen Träger(n) und/oder 8. Therapeutic agent which can in particular develop cytotoxic activities and/or cause immunosuppression, consisting of one or more epothilones according to one of claims 1 to 4 or containing these epothilones, optionally in addition to one or more usual carriers and/or Verdünnungsmittel(n). Diluent(s).
PCT/EP1992/002656 1991-11-19 1992-11-19 Epothilones, process for preparing the same and their use as medicaments and as plant protecting agents Ceased WO1993010121A1 (en)

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CN103145722A (en) * 2013-03-05 2013-06-12 福建省微生物研究所 Method for separating and purifying epothilone by high-speed counter-current chromatography
WO2015024884A1 (en) * 2013-08-19 2015-02-26 Sandoz Ag Method for the purifiction of epothilones via crystallization

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