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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GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF)
Ciba-Geigy Ag
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Publication of WO1993010121A1 publication Critical patent/WO1993010121A1/en

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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

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).
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Cited By (74)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997019086A1 (en) * 1995-11-17 1997-05-29 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) Epothilone derivatives, preparation and use
WO1998008849A1 (en) * 1996-08-30 1998-03-05 Novartis Aktiengesellschaft Method for producing epothilones, and intermediate products obtained during the production process
WO1998022461A1 (en) * 1996-11-18 1998-05-28 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) Epothilone c, d, e and f, production process, and their use as cytostatic as well as phytosanitary agents
WO1998038192A1 (en) * 1997-02-25 1998-09-03 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) Epothilones with a modified side chain
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WO1999039694A2 (en) * 1998-02-05 1999-08-12 Novartis Ag Compositions containing organic compounds
WO1999042602A2 (en) * 1998-02-19 1999-08-26 Novartis Ag Fermentative preparation process for cytostatics and crystal forms thereof
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WO1999058534A2 (en) * 1998-05-08 1999-11-18 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) Epothilone derivatives, a method for the production thereof, and their use
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US6043372A (en) * 1996-08-30 2000-03-28 Novartis Ag Intermediates in the process for preparing epothilones
WO2000023452A1 (en) * 1998-10-14 2000-04-27 Schering Aktiengesellschaft Method for producing epothilone b and derivatives, and intermediate products for this method
US6121029A (en) * 1998-06-18 2000-09-19 Novartis Ag Genes for the biosynthesis of epothilones
EP1035824A1 (en) * 1997-12-04 2000-09-20 Bristol-Myers Squibb Company A process for the preparation of ring-opened epothilone intermediates which are useful for the preparation of epothilone analogs
JP2001504856A (en) * 1996-12-13 2001-04-10 ノヴァルティス アクチェンゲゼルシャフト Epothilone analogues
US6262094B1 (en) 1999-02-22 2001-07-17 Bristol-Myers Squibb Company C-21 modified epothilones
WO2001060976A1 (en) * 2000-02-17 2001-08-23 Novartis Ag Single colonies of myxobacteria cells
US6291684B1 (en) 1999-03-29 2001-09-18 Bristol-Myers Squibb Company Process for the preparation of aziridinyl epothilones from oxiranyl epothilones
US6302838B1 (en) 1998-02-25 2001-10-16 Novartis Ag Cancer treatment with epothilones
US6303342B1 (en) 1998-11-20 2001-10-16 Kason Biosciences, Inc. Recombinant methods and materials for producing epothilones C and D
US6320045B1 (en) 1997-12-04 2001-11-20 Bristol-Myers Squibb Company Process for the reduction of oxiranyl epothilones to olefinic epothilones
US6380394B1 (en) 1996-12-13 2002-04-30 The Scripps Research Institute Epothilone analogs
US6380395B1 (en) 1998-04-21 2002-04-30 Bristol-Myers Squibb Company 12, 13-cyclopropane epothilone derivatives
WO2002046196A1 (en) * 2000-12-07 2002-06-13 Novartis Ag Process for the isolation and purification of epothilones
US6410301B1 (en) 1998-11-20 2002-06-25 Kosan Biosciences, Inc. Myxococcus host cells for the production of epothilones
US6441025B2 (en) 1996-03-12 2002-08-27 Pg-Txl Company, L.P. Water soluble paclitaxel derivatives
US6498257B1 (en) 1998-04-21 2002-12-24 Bristol-Myers Squibb Company 2,3-olefinic epothilone derivatives
US6518421B1 (en) 2000-03-20 2003-02-11 Bristol-Myers Squibb Company Process for the preparation of epothilone analogs
US6576651B2 (en) 2001-01-25 2003-06-10 Bristol-Myers Squibb Company Pharmaceutical compositions, dosage forms and methods for oral administration of epothilones
US6589968B2 (en) 2001-02-13 2003-07-08 Kosan Biosciences, Inc. Epothilone compounds and methods for making and using the same
US6593115B2 (en) 2000-03-24 2003-07-15 Bristol-Myers Squibb Co. Preparation of epothilone intermediates
US6596875B2 (en) 2000-02-07 2003-07-22 James David White Method for synthesizing epothilones and epothilone analogs
US6603023B2 (en) 1996-12-03 2003-08-05 Sloan Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US6605599B1 (en) 1997-07-08 2003-08-12 Bristol-Myers Squibb Company Epothilone derivatives
WO2003078411A1 (en) 2002-03-12 2003-09-25 Bristol-Myers Squibb Company C3-cyano epothilone derivatives
US6660758B1 (en) 1996-12-13 2003-12-09 The Scripps Research Institute Epothilone analogs
US6670384B2 (en) 2001-01-25 2003-12-30 Bristol-Myers Squibb Company Methods of administering epothilone analogs for the treatment of cancer
US6683100B2 (en) 1999-01-19 2004-01-27 Novartis Ag Organic compounds
US6686380B2 (en) 2001-02-20 2004-02-03 Bristol-Myers Squibb Company Treatment of refractory tumors using epothilone derivatives
US6689802B2 (en) 2000-08-16 2004-02-10 Bristol-Myers Squibb Company Polymorphs of an epothilone analog
EP1386922A3 (en) * 1996-12-03 2004-04-07 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereof, analogues and uses thereof
US6727276B2 (en) 2001-02-20 2004-04-27 Bristol-Myers Squibb Company Epothilone derivatives for the treatment of refractory tumors
US6780620B1 (en) 1998-12-23 2004-08-24 Bristol-Myers Squibb Company Microbial transformation method for the preparation of an epothilone
US6800653B2 (en) 2001-06-01 2004-10-05 Bristol-Myers Squibb Compnay Epothilone derivatives
WO2005030767A1 (en) * 2003-09-26 2005-04-07 Wolfgang Richter Novel macrocycles for treating tumor diseases
US6884608B2 (en) 2001-12-26 2005-04-26 Bristol-Myers Squibb Company Compositions and methods for hydroxylating epothilones
US6893859B2 (en) 2001-02-13 2005-05-17 Kosan Biosciences, Inc. Epothilone derivatives and methods for making and using the same
EP1542998A2 (en) * 2002-09-23 2005-06-22 Bristol-Myers Squibb Company Methods for the preparation, isolation and purification of epothilone b, and x-ray crystal structures of epothilone b
US6936628B2 (en) 2002-04-04 2005-08-30 Bristol-Myers Squibb Company Oral administration of epothilones
US7008936B2 (en) 2002-06-14 2006-03-07 Bristol-Myers Squibb Company Combination of epothilone analogs and chemotherapeutic agents for the treatment of proliferative diseases
US7022330B2 (en) 2001-01-25 2006-04-04 Bristol-Myers Squibb Company Parenteral formulation for epothilone analogs
US7053069B2 (en) 2002-05-15 2006-05-30 Bristol-Myers Squibb Company Pharmaceutical compositions and methods of using C-21 modified epothilone derivatives
US7153864B2 (en) 2000-03-17 2006-12-26 Cell Therapeutics Inc. Polyglutamic acid-camptothecin conjugates and methods of preparation
CN1312286C (en) * 2005-10-19 2007-04-25 华南理工大学 Method for highly-effective producing epothilone using myxobacteria sorangium cellulosum
US7211593B2 (en) 2002-03-12 2007-05-01 Bristol-Myers Squibb Co. C12-cyano epothilone derivatives
EP1800664A1 (en) * 1998-02-05 2007-06-27 Novartis AG Pharmaceutical formulations for parenteral administration comprising epothilone
WO2007117439A2 (en) 2006-03-31 2007-10-18 Bristol-Myers Squibb Company Biomarkers and methods for determining sensitivity to microtubule-stabilizing agents
US7312237B2 (en) 2001-03-14 2007-12-25 Bristol-Myers Squibb Co. Combination of epothilone analogs and chemotherapeutic agents for the treatment of prolilferative diseases
EP2030618A2 (en) 2002-01-14 2009-03-04 Novartis AG Combinations comprising epothilones and anti-metabolites
EP2065054A1 (en) 2007-11-29 2009-06-03 Bayer Schering Pharma Aktiengesellschaft Combinations comprising a prostaglandin and uses thereof
EP2070521A1 (en) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft Surface-modified nanoparticles
DE102007059752A1 (en) 2007-12-10 2009-06-18 Bayer Schering Pharma Aktiengesellschaft Functionalized solid polymer nanoparticles containing epothilones
US7649006B2 (en) 2002-08-23 2010-01-19 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
WO2010040252A1 (en) * 2008-10-06 2010-04-15 山东大学 Epothilone glycoside compounds, compositions containing epothilone glycoside compounds as active components and uses thereof
US7723339B2 (en) 2001-02-27 2010-05-25 Novartis Ag Combination comprising a signal transduction inhibitor and an epothilone derivative
EP2210584A1 (en) 2009-01-27 2010-07-28 Bayer Schering Pharma Aktiengesellschaft Stable polymeric composition comprising an epothilone and an amphiphilic block copolymer
EP2210643A2 (en) 2001-07-19 2010-07-28 Novartis AG Combinations comprising epothilones and pharmaceutical uses thereof
EP2241566A1 (en) * 2008-02-01 2010-10-20 Zhejiang Hisun Pharmaceutical Co. Ltd. A method for the separation and purification of epothilones
US7932031B2 (en) 2004-11-30 2011-04-26 Bristol-Myers Squibb Company Methods for determining sensitivity to microtubule-stabilizing agents comprising ixabepilone by measuring the level of estrogen receptor 1
US8143415B2 (en) 2007-05-25 2012-03-27 Bristol-Myers Squibb Company Processes for making epothilone compounds and analogs
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
US8618146B2 (en) 2011-01-03 2013-12-31 Dr. Reddy's Laboratories Limited Epothilone compound formulations
WO2015024884A1 (en) * 2013-08-19 2015-02-26 Sandoz Ag Method for the purifiction of epothilones via crystallization
EP3566719A1 (en) 2010-05-18 2019-11-13 Cerulean Pharma Inc. Compositions and methods for treatment of autoimmune and other diseases

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19636343C1 (en) * 1996-08-30 1997-10-23 Schering Ag New (di:methyl)-dioxanyl-methyl-pentanone and related compounds
EP1847540A1 (en) 1997-08-09 2007-10-24 Bayer Schering Pharma Aktiengesellschaft Nouveaux dérivés d'épothilone, leur procédé de production et leur utilisation pharmaceutique
US7001916B1 (en) 1999-02-11 2006-02-21 Schering, Ag Epothilon derivatives, method for the production and the use thereof as pharmaceuticals
ID30460A (en) 1999-04-15 2001-12-06 Bristol Myers Squibb Co INHIBITORS, INHIBITORS, THYROCIN CINASE PROTEIN
US7125875B2 (en) 1999-04-15 2006-10-24 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US7125893B1 (en) 1999-04-30 2006-10-24 Schering Ag 6-alkenyl-, 6-alkinyl- and 6-epoxy-epothilone derivatives, process for their production, and their use in pharmaceutical preparations
MXPA03002521A (en) 2000-09-22 2004-02-12 Biotechnolog Forschung Gmbh Triazolo-epothilones.
EP1767535B1 (en) 2002-08-23 2009-12-02 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
EP1567487A4 (en) 2002-11-15 2005-11-16 Bristol Myers Squibb Co Open chain prolyl urea-related modulators of androgen receptor function
US20050171167A1 (en) 2003-11-04 2005-08-04 Haby Thomas A. Process and formulation containing epothilones and analogs thereof
DE10355223A1 (en) 2003-11-26 2005-06-30 Institut für Pflanzenbiochemie (IPB) New macrocycles for the treatment of cancer
US7378426B2 (en) 2004-03-01 2008-05-27 Bristol-Myers Squibb Company Fused heterotricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3
AU2007329375A1 (en) 2006-12-04 2008-06-12 The Board Of Trustees Of The University Of Illinois Compositions and methods to treat cancer with cupredoxins and CpG rich DNA
CN102863474A (en) 2011-07-09 2013-01-09 陈小平 Platinum compounds for treating cell proliferative diseases and preparation method and application thereof
CN102993239A (en) 2011-09-19 2013-03-27 陈小平 Platinum compound of succinic acid derivative with leaving group containing amino or alkylamino
CN104768962B (en) 2012-11-17 2017-04-05 北京市丰硕维康技术开发有限责任公司 Leaving group is the platinum-like compounds of the malonate derivative containing amino or alkylamino

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 93, no. 7, 18. August 1980, Columbus, Ohio, US; abstract no. 72218v, Y. SHIMAUCHI ET AL. 'Deltamycin antibiotics' Seite 1025 ; *

Cited By (192)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1440973A3 (en) * 1995-11-17 2004-10-20 Gesellschaft für biotechnologische Forschung mbH (GBF) Epothilone derivatives, preparation and use
EP1186606A1 (en) * 1995-11-17 2002-03-13 Gesellschaft für biotechnologische Forschung mbH (GBF) Epothilone derivatives, their preparation and utilization
WO1997019086A1 (en) * 1995-11-17 1997-05-29 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) Epothilone derivatives, preparation and use
US6288237B1 (en) 1995-11-17 2001-09-11 Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) Epothilons C and D, preparation and compositions
EP0903348A1 (en) * 1995-11-17 1999-03-24 Gesellschaft für Biotechnologische Forschung mbH (GBF) Epothilone derivatives, preparation and utilization
US6831076B2 (en) 1995-11-17 2004-12-14 Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) Epothilons C and D, preparation and compositions
US6613912B2 (en) 1995-11-17 2003-09-02 Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) Epothilons C and D, preparation and compositions
EP1440973A2 (en) * 1995-11-17 2004-07-28 Gesellschaft für biotechnologische Forschung mbH (GBF) Epothilone derivatives, preparation and use
US6884817B2 (en) 1996-03-12 2005-04-26 Pg-Txl Company, L.P. Water soluble paclitaxel derivatives
US7384977B2 (en) 1996-03-12 2008-06-10 Pg-Txl Company, L.P. Water soluble paclitaxel prodrugs
US7135496B2 (en) 1996-03-12 2006-11-14 Pg-Txl Company, L.P. Water soluble paclitaxel derivatives
US7060724B2 (en) 1996-03-12 2006-06-13 Pg-Txl Company, L.P. Water soluble paclitaxel derivatives
US6441025B2 (en) 1996-03-12 2002-08-27 Pg-Txl Company, L.P. Water soluble paclitaxel derivatives
US6043372A (en) * 1996-08-30 2000-03-28 Novartis Ag Intermediates in the process for preparing epothilones
US6156905A (en) * 1996-08-30 2000-12-05 Novartis Ag Deoxy epothilones and intermediates utilized in the process for preparing epothilones
WO1998008849A1 (en) * 1996-08-30 1998-03-05 Novartis Aktiengesellschaft Method for producing epothilones, and intermediate products obtained during the production process
CZ303422B6 (en) * 1996-11-18 2012-09-05 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) Epothilone C, process for its preparation and its use as cytostatic and plant protection composition
WO1998022461A1 (en) * 1996-11-18 1998-05-28 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) Epothilone c, d, e and f, production process, and their use as cytostatic as well as phytosanitary agents
KR100538095B1 (en) * 1996-11-18 2005-12-21 게젤샤프트 퓌어 비오테크놀로기쉐 포르슝 엠베하(게베에프) Epothilone c, d, e and f, production process, and their use as cytostatic as well as phytosanitary agents
US7846952B2 (en) 1996-11-18 2010-12-07 Helmholtz-Zentrum Fuer Infektionsforschung Gmbh Epothilones C, D, E, and F, preparation and compositions
CN100344627C (en) * 1996-11-18 2007-10-24 生物技术研究有限公司(Gbf) Epothilones C, and its preparation and use as cell inhibitor
AU753546B2 (en) * 1996-11-18 2002-10-24 Helmholtz-Zentrum Fuer Infektionsforschung Gmbh Epothilone C, D, E and F, production process, and their use as cytostatic as well as phytosanitary agents
EP1367057A1 (en) * 1996-11-18 2003-12-03 Gesellschaft für biotechnologische Forschung mbH (GBF) Epothilones C, E and F
US8076490B2 (en) 1996-11-18 2011-12-13 Helmholtz-Zentrum Fuer Infektionsforschung Gmbh Epothilones C, D, E, and F, preparation and compositions
USRE41990E1 (en) 1996-12-03 2010-12-07 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
EP1386922A3 (en) * 1996-12-03 2004-04-07 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereof, analogues and uses thereof
US6603023B2 (en) 1996-12-03 2003-08-05 Sloan Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US6828340B2 (en) 1996-12-03 2004-12-07 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US6723854B2 (en) 1996-12-03 2004-04-20 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
JP2001504856A (en) * 1996-12-13 2001-04-10 ノヴァルティス アクチェンゲゼルシャフト Epothilone analogues
US7173137B2 (en) * 1996-12-13 2007-02-06 The Scripps Research Institute Epothilone analogs
US6380394B1 (en) 1996-12-13 2002-04-30 The Scripps Research Institute Epothilone analogs
US6441186B1 (en) 1996-12-13 2002-08-27 The Scripps Research Institute Epothilone analogs
US6660758B1 (en) 1996-12-13 2003-12-09 The Scripps Research Institute Epothilone analogs
US6359140B1 (en) 1997-02-25 2002-03-19 Gesellschaft Fuer Biotechnologische Forschung Mbh (Gbf) Epothilones with modified side chain
WO1998038192A1 (en) * 1997-02-25 1998-09-03 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) Epothilones with a modified side chain
CZ298027B6 (en) * 1997-02-25 2007-05-30 Gesellschaft Fuer Biotechnologische Forschung Mbh(Gbf) Process for preparing epothilone-N-oxides and N-oxides of epothilones per se
EP1201666A2 (en) * 1997-02-25 2002-05-02 Gesellschaft für biotechnologische Forschung mbH (GBF) Epothilones with a modified side chain
US8536327B2 (en) 1997-07-08 2013-09-17 Bristol-Myers Squibb Company Epothilone derivatives
USRE43003E1 (en) 1997-07-08 2011-12-06 Bristol-Myers Squibb Company Epothilone derivatives
USRE41893E1 (en) 1997-07-08 2010-10-26 Bristol-Myers Squibb Company Epothilone derivatives
CN100384834C (en) * 1997-07-08 2008-04-30 布里斯托尔-迈尔斯斯奎布公司 Epothilone derivatives
US6605599B1 (en) 1997-07-08 2003-08-12 Bristol-Myers Squibb Company Epothilone derivatives
USRE41911E1 (en) 1997-07-08 2010-11-02 Bristol-Myers Squibb Company Epothilone derivatives
USRE41895E1 (en) 1997-07-08 2010-10-26 Bristol-Myers Squibb Company Epothilone derivatives
US8921542B2 (en) 1997-07-08 2014-12-30 Bristol-Myers Squibb Company Epothilone derivatives
US7125899B2 (en) 1997-07-08 2006-10-24 Bristol-Myers Squibb Company Epothilone derivatives
US7241755B2 (en) 1997-07-08 2007-07-10 Bristol-Myers Squibb Company Epothilone derivatives
US6320045B1 (en) 1997-12-04 2001-11-20 Bristol-Myers Squibb Company Process for the reduction of oxiranyl epothilones to olefinic epothilones
US6365749B1 (en) 1997-12-04 2002-04-02 Bristol-Myers Squibb Company Process for the preparation of ring-opened epothilone intermediates which are useful for the preparation of epothilone analogs
WO1999028324A1 (en) * 1997-12-04 1999-06-10 Bristol-Myers Squibb Company A process for the reduction of oxiranyl epothilones to olefinic epothilones
EP1035824A1 (en) * 1997-12-04 2000-09-20 Bristol-Myers Squibb Company A process for the preparation of ring-opened epothilone intermediates which are useful for the preparation of epothilone analogs
EP1035824A4 (en) * 1997-12-04 2001-10-24 Bristol Myers Squibb Co A process for the preparation of ring-opened epothilone intermediates which are useful for the preparation of epothilone analogs
JP4644364B2 (en) * 1998-02-05 2011-03-02 ノバルティス アーゲー Epothilone composition
CZ303168B6 (en) * 1998-02-05 2012-05-09 Novartis Ag Pharmaceutical composition
AU753519B2 (en) * 1998-02-05 2002-10-17 Novartis Ag Compositions containing organic compounds
WO1999039694A3 (en) * 1998-02-05 1999-09-23 Novartis Ag Compositions containing organic compounds
JP2002502810A (en) * 1998-02-05 2002-01-29 ノバルティス アクチエンゲゼルシャフト Epothilone composition
CN100396276C (en) * 1998-02-05 2008-06-25 诺瓦提斯公司 Compositions containing organic compounds
EP1800664A1 (en) * 1998-02-05 2007-06-27 Novartis AG Pharmaceutical formulations for parenteral administration comprising epothilone
BE1012140A3 (en) * 1998-02-05 2000-05-02 Novartis Ag Organic compounds.
WO1999039694A2 (en) * 1998-02-05 1999-08-12 Novartis Ag Compositions containing organic compounds
FR2774909A1 (en) * 1998-02-05 1999-08-20 Novartis Ag PHARMACEUTICAL FORMULATION, INFUSION SOLUTION AND LYOPHILIZED COMPOSITION COMPRISING EPOTHILONE.
KR100873526B1 (en) * 1998-02-19 2008-12-11 노파르티스 아게 Fermentative preparation Process for Cytostatics and Crystal Forms Thereof
WO1999042602A3 (en) * 1998-02-19 1999-11-25 Novartis Ag Fermentative preparation process for cytostatics and crystal forms thereof
AU746294B2 (en) * 1998-02-19 2002-04-18 Novartis Ag Fermentative preparation process for cytostatics and crystal forms thereof
WO1999042602A2 (en) * 1998-02-19 1999-08-26 Novartis Ag Fermentative preparation process for cytostatics and crystal forms thereof
US6380227B1 (en) 1998-02-19 2002-04-30 Novartis Ag Fermentative preparation process for and crystal forms of cytostatics
EP1428826A2 (en) * 1998-02-19 2004-06-16 Novartis AG Crystal forms of cytostatics
US6656711B2 (en) 1998-02-19 2003-12-02 Novartis Ag Fermentative preparation process for and crystal forms of cytostatics
EP1428826A3 (en) * 1998-02-19 2004-10-27 Novartis AG Crystal forms of cytostatics
CZ301517B6 (en) * 1998-02-19 2010-03-31 Novartis Ag Process for concentrating epothilones, culture medium therefor and process for preparing epothilones
US7101702B2 (en) 1998-02-19 2006-09-05 Novartis Ag Fermentative preparation process for and crystal forms of cytostatics
JP2005068156A (en) * 1998-02-19 2005-03-17 Novartis Ag Fermentative preparation process and crystal form of cytostatic
US6194181B1 (en) 1998-02-19 2001-02-27 Novartis Ag Fermentative preparation process for and crystal forms of cytostatics
US7875601B2 (en) 1998-02-25 2011-01-25 Novartis Ag Cancer treatment with epothilones
FR2775187A1 (en) * 1998-02-25 1999-08-27 Novartis Ag Treatment of proliferative diseases, especially drug-resistant cancers - with epothilone B
WO1999043320A1 (en) * 1998-02-25 1999-09-02 Novartis Ag Use of epothilones for the treatment of cancer
BE1011980A5 (en) * 1998-02-25 2000-03-07 Novartis Ag Cancer treatment with epothilones.
US6302838B1 (en) 1998-02-25 2001-10-16 Novartis Ag Cancer treatment with epothilones
US7091226B2 (en) 1998-02-25 2006-08-15 Novartis Ag Cancer treatment with epothilones
US6399638B1 (en) 1998-04-21 2002-06-04 Bristol-Myers Squibb Company 12,13-modified epothilone derivatives
US6498257B1 (en) 1998-04-21 2002-12-24 Bristol-Myers Squibb Company 2,3-olefinic epothilone derivatives
US6831090B2 (en) 1998-04-21 2004-12-14 Bristol-Myers Squibb Company 2,3-olefinic epothilone derivatives
US6380395B1 (en) 1998-04-21 2002-04-30 Bristol-Myers Squibb Company 12, 13-cyclopropane epothilone derivatives
WO1999058534A2 (en) * 1998-05-08 1999-11-18 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) Epothilone derivatives, a method for the production thereof, and their use
US6982280B1 (en) 1998-05-08 2006-01-03 Gerhard Hoefle Epothilone derivatives, a method for the production thereof, and their use
AU754212B2 (en) * 1998-05-08 2002-11-07 Gesellschaft Fur Biotechnologische Forschung Mbh Epothilone derivatives, a method for the production thereof, and their use
WO1999058534A3 (en) * 1998-05-08 2000-01-13 Biotechnolog Forschung Gmbh Epothilone derivatives, a method for the production thereof, and their use
US6355459B1 (en) 1998-06-18 2002-03-12 Novartis Ag Genes for the biosynthesis of epothilones
US6358719B1 (en) 1998-06-18 2002-03-19 Novartis Ag Genes for the biosynthesis of epothilones
US6121029A (en) * 1998-06-18 2000-09-19 Novartis Ag Genes for the biosynthesis of epothilones
US6858404B2 (en) 1998-06-18 2005-02-22 Novartis Ag Genes for the biosynthesis of epothilones
US6346404B1 (en) 1998-06-18 2002-02-12 Novartis Ag Genes for the biosynthesis of epothilones
US6355457B1 (en) 1998-06-18 2002-03-12 Novartis Ag Genes for the biosynthesis of epothilones
US6355458B1 (en) 1998-06-18 2002-03-12 Novartis Ag Genes for the biosynthesis of epothilones
US6383787B1 (en) 1998-06-18 2002-05-07 Novartis Ag Genes for the biosynthesis of epothilones
US7579366B2 (en) 1998-06-22 2009-08-25 The Scripps Research Institute Epothilone derivatives and their synthesis and use
US6531497B1 (en) 1998-06-22 2003-03-11 The Scripps Research Institute Epothilone derivatives and their synthesis and use
EP0987268A1 (en) * 1998-08-05 2000-03-22 Gesellschaft für biotechnologische Forschung mbH (GBF) Epothilone A-N-oxide, epothilone B-N-oxide, process for their preparation and agent containing same
US6605726B1 (en) 1998-10-14 2003-08-12 Schering Ag Method for producing epothilone B and derivatives, and intermediate products for this method
WO2000023452A1 (en) * 1998-10-14 2000-04-27 Schering Aktiengesellschaft Method for producing epothilone b and derivatives, and intermediate products for this method
US6303342B1 (en) 1998-11-20 2001-10-16 Kason Biosciences, Inc. Recombinant methods and materials for producing epothilones C and D
US7732186B2 (en) 1998-11-20 2010-06-08 Kosan Biosciences, Inc. Recombinant methods and materials for producing epothilone and epothilone derivatives
US7402421B2 (en) 1998-11-20 2008-07-22 Kosan Biosciences, Inc. Recombinant methods and materials for producing epothilone and epothilone derivatives
US6921650B1 (en) 1998-11-20 2005-07-26 Kosan Biosciences, Inc. Recombinant methods and materials for producing epothilone and epothilone derivatives
US7129071B1 (en) 1998-11-20 2006-10-31 Kosan Biosciences, Inc. Recombinant methods and materials for producing epothilone and epothilone derivatives
US6583290B1 (en) 1998-11-20 2003-06-24 Kosam Biosciences, Inc. 14-methyl epothilone derivatives
US6858411B1 (en) 1998-11-20 2005-02-22 Kosan Biosciences, Inc. Recombinant methods and materials for producing epothilone and epothilone derivatives
US7067286B2 (en) 1998-11-20 2006-06-27 Kosan Biosciences, Inc. Cystobacterineae host cells containing heterologous PKS genes for the synthesis of polykedtides
US6410301B1 (en) 1998-11-20 2002-06-25 Kosan Biosciences, Inc. Myxococcus host cells for the production of epothilones
US7244594B2 (en) 1998-12-23 2007-07-17 Bristol-Myers Squibb Company Microbial transformation method for the preparation of an epothilone
US6780620B1 (en) 1998-12-23 2004-08-24 Bristol-Myers Squibb Company Microbial transformation method for the preparation of an epothilone
US6683100B2 (en) 1999-01-19 2004-01-27 Novartis Ag Organic compounds
US6958401B2 (en) 1999-02-05 2005-10-25 The State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of Oregon State University Method for synthesizing epothilones and epothilone analogs
US7145018B2 (en) 1999-02-05 2006-12-05 State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of The Oregon State University Method for synthesizing epothilones and epothilone analogs
US6262094B1 (en) 1999-02-22 2001-07-17 Bristol-Myers Squibb Company C-21 modified epothilones
US6291684B1 (en) 1999-03-29 2001-09-18 Bristol-Myers Squibb Company Process for the preparation of aziridinyl epothilones from oxiranyl epothilones
US6596875B2 (en) 2000-02-07 2003-07-22 James David White Method for synthesizing epothilones and epothilone analogs
WO2001060976A1 (en) * 2000-02-17 2001-08-23 Novartis Ag Single colonies of myxobacteria cells
US7153864B2 (en) 2000-03-17 2006-12-26 Cell Therapeutics Inc. Polyglutamic acid-camptothecin conjugates and methods of preparation
US7173041B2 (en) 2000-03-17 2007-02-06 Cell Therapeutics Inc. Polyglutamic acid-camptothecin conjugates and methods of preparation
USRE39356E1 (en) * 2000-03-20 2006-10-17 Bristol-Myers Squibb Co. Process for the preparation of epothilone analogs
US6518421B1 (en) 2000-03-20 2003-02-11 Bristol-Myers Squibb Company Process for the preparation of epothilone analogs
US6593115B2 (en) 2000-03-24 2003-07-15 Bristol-Myers Squibb Co. Preparation of epothilone intermediates
USRE39251E1 (en) * 2000-08-16 2006-08-29 Bristol-Myers Squibb Co. Polymorphs of an epothilone analog
US6982276B2 (en) 2000-08-16 2006-01-03 Bristol-Myers Squibb Company Polymorphs of an epothilone analog
BG66132B1 (en) * 2000-08-16 2011-06-30 Bristol-Myers Squibb Company Polymorphs of an epothilone analog
LT5138B (en) 2000-08-16 2004-06-25 Bristol-Myers Squibb Company Polymorphs of an epothilone analog
US7153879B2 (en) 2000-08-16 2006-12-26 Bristol-Myers Squibb Company Polymorphs of an epothilone analog
US6689802B2 (en) 2000-08-16 2004-02-10 Bristol-Myers Squibb Company Polymorphs of an epothilone analog
US6946561B2 (en) 2000-12-07 2005-09-20 Novartis Ag Process for the isolation and purification of epothilones
US7569698B2 (en) 2000-12-07 2009-08-04 Novartis Ag Process for the isolation and purification of epothilones
WO2002046196A1 (en) * 2000-12-07 2002-06-13 Novartis Ag Process for the isolation and purification of epothilones
KR100894990B1 (en) * 2000-12-07 2009-04-24 노파르티스 아게 Process for the isolation and purification of epothilones
CZ301664B6 (en) * 2000-12-07 2010-05-19 Novartis Ag Method of desorption and obtaining epothilones A, B, D, E and/or F and use of weakly polar or apolar solvent for desorption of epothilones A, B, D, E and/or F from a resin
US7022330B2 (en) 2001-01-25 2006-04-04 Bristol-Myers Squibb Company Parenteral formulation for epothilone analogs
US8632788B2 (en) 2001-01-25 2014-01-21 Bristol-Myers Squibb Company Parenteral formulation for epothilone analogs
US6670384B2 (en) 2001-01-25 2003-12-30 Bristol-Myers Squibb Company Methods of administering epothilone analogs for the treatment of cancer
USRE40387E1 (en) * 2001-01-25 2008-06-17 Bristol-Myers Squibb Company Pharmaceutical compositions, dosage forms and methods for oral administration of epothilones
EP1938821A2 (en) 2001-01-25 2008-07-02 Bristol-Myers Squibb Company Methods of administering epothilone analogs for the treatment of cancer
US6576651B2 (en) 2001-01-25 2003-06-10 Bristol-Myers Squibb Company Pharmaceutical compositions, dosage forms and methods for oral administration of epothilones
US6893859B2 (en) 2001-02-13 2005-05-17 Kosan Biosciences, Inc. Epothilone derivatives and methods for making and using the same
US6589968B2 (en) 2001-02-13 2003-07-08 Kosan Biosciences, Inc. Epothilone compounds and methods for making and using the same
US7176235B2 (en) 2001-02-13 2007-02-13 Kosan Biosciences, Inc. Epothilone derivatives and methods for making and using the same
US6727276B2 (en) 2001-02-20 2004-04-27 Bristol-Myers Squibb Company Epothilone derivatives for the treatment of refractory tumors
USRE41393E1 (en) 2001-02-20 2010-06-22 Bristol-Myers Squibb Company Treatment of refractory tumors using epothilone derivatives
US6686380B2 (en) 2001-02-20 2004-02-03 Bristol-Myers Squibb Company Treatment of refractory tumors using epothilone derivatives
US7723339B2 (en) 2001-02-27 2010-05-25 Novartis Ag Combination comprising a signal transduction inhibitor and an epothilone derivative
US7312237B2 (en) 2001-03-14 2007-12-25 Bristol-Myers Squibb Co. Combination of epothilone analogs and chemotherapeutic agents for the treatment of prolilferative diseases
US8598215B2 (en) 2001-03-14 2013-12-03 Bristol-Myers Squibb Company Combination of epothilone analogs and chemotherapeutic agents for the treatment of proliferative diseases
US8569347B2 (en) 2001-03-14 2013-10-29 Bristol-Myers Squibb Company Combination of epothilone analogs and chemotherapeutic agents for the treatment of proliferative diseases
US6800653B2 (en) 2001-06-01 2004-10-05 Bristol-Myers Squibb Compnay Epothilone derivatives
EP2210643A2 (en) 2001-07-19 2010-07-28 Novartis AG Combinations comprising epothilones and pharmaceutical uses thereof
US7214527B2 (en) 2001-12-26 2007-05-08 Bristol-Myers Squibb Company Compositions and methods for hydroxylating epothilones
US6884608B2 (en) 2001-12-26 2005-04-26 Bristol-Myers Squibb Company Compositions and methods for hydroxylating epothilones
EP2030618A2 (en) 2002-01-14 2009-03-04 Novartis AG Combinations comprising epothilones and anti-metabolites
US7211593B2 (en) 2002-03-12 2007-05-01 Bristol-Myers Squibb Co. C12-cyano epothilone derivatives
WO2003078411A1 (en) 2002-03-12 2003-09-25 Bristol-Myers Squibb Company C3-cyano epothilone derivatives
US6936628B2 (en) 2002-04-04 2005-08-30 Bristol-Myers Squibb Company Oral administration of epothilones
US7053069B2 (en) 2002-05-15 2006-05-30 Bristol-Myers Squibb Company Pharmaceutical compositions and methods of using C-21 modified epothilone derivatives
US7008936B2 (en) 2002-06-14 2006-03-07 Bristol-Myers Squibb Company Combination of epothilone analogs and chemotherapeutic agents for the treatment of proliferative diseases
US7649006B2 (en) 2002-08-23 2010-01-19 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US7767432B2 (en) 2002-09-23 2010-08-03 Bristol-Myers Squibb Company Methods for the preparation, isolation and purification of epothilone B, and x-ray crystal structures of epothilone B
USRE42191E1 (en) 2002-09-23 2011-03-01 Bristol-Myers Squibb Company Methods for the preparation, isolation and purification of epothilone B, and X-ray crystal structures of epothilone B
US7172884B2 (en) 2002-09-23 2007-02-06 Bristol-Myers Squibb Company Methods for the preparation, isolation and purification of epothilone B, and x-ray crystal structures of epothilone B
EP2280014A3 (en) * 2002-09-23 2011-08-03 Bristol-Myers Squibb Company Methods for the preparation, isolation and purification of epothilone B, and X-ray crystal structures of epothilone B
JP2006500031A (en) * 2002-09-23 2006-01-05 ブリストル−マイヤーズ　スクイブ　カンパニー Method for producing, isolating and purifying epothilone B and X-ray crystal structure of epothilone B
EP2280014A2 (en) 2002-09-23 2011-02-02 Bristol-Myers Squibb Company Methods for the preparation, isolation and purification of epothilone B, and X-ray crystal structures of epothilone B
EP2287168A2 (en) 2002-09-23 2011-02-23 Bristol-Myers Squibb Company Methods for the preparation, isolation and purification of epothilone B, and X-ray crystal structures of epothilone B
EP1542998A4 (en) * 2002-09-23 2007-01-31 Bristol Myers Squibb Co Methods for the preparation, isolation and purification of epothilone b, and x-ray crystal structures of epothilone b
US7241899B2 (en) 2002-09-23 2007-07-10 Bristol-Myers Squibb Company Methods for the preparation, isolation and purification of epothilone B, and X-ray crystal structures of epothilone B
EP2287168A3 (en) * 2002-09-23 2011-03-16 Bristol-Myers Squibb Company Methods for the preparation, isolation and purification of epothilone B, and X-ray crystal structures of epothilone B
EP1542998A2 (en) * 2002-09-23 2005-06-22 Bristol-Myers Squibb Company Methods for the preparation, isolation and purification of epothilone b, and x-ray crystal structures of epothilone b
WO2005030767A1 (en) * 2003-09-26 2005-04-07 Wolfgang Richter Novel macrocycles for treating tumor diseases
US7807710B2 (en) 2003-09-26 2010-10-05 R&D-Biopharmaceuticals Gmbh Macrocycles for the treatment of cancer
US7932031B2 (en) 2004-11-30 2011-04-26 Bristol-Myers Squibb Company Methods for determining sensitivity to microtubule-stabilizing agents comprising ixabepilone by measuring the level of estrogen receptor 1
CN1312286C (en) * 2005-10-19 2007-04-25 华南理工大学 Method for highly-effective producing epothilone using myxobacteria sorangium cellulosum
WO2007117439A2 (en) 2006-03-31 2007-10-18 Bristol-Myers Squibb Company Biomarkers and methods for determining sensitivity to microtubule-stabilizing agents
US8143415B2 (en) 2007-05-25 2012-03-27 Bristol-Myers Squibb Company Processes for making epothilone compounds and analogs
US8299266B2 (en) 2007-05-25 2012-10-30 Bristol-Myers Squibb Company Processes for making epothilone compounds and analogs
EP2065054A1 (en) 2007-11-29 2009-06-03 Bayer Schering Pharma Aktiengesellschaft Combinations comprising a prostaglandin and uses thereof
EP2070521A1 (en) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft Surface-modified nanoparticles
DE102007059752A1 (en) 2007-12-10 2009-06-18 Bayer Schering Pharma Aktiengesellschaft Functionalized solid polymer nanoparticles containing epothilones
EP2241566A1 (en) * 2008-02-01 2010-10-20 Zhejiang Hisun Pharmaceutical Co. Ltd. A method for the separation and purification of epothilones
EP2241566A4 (en) * 2008-02-01 2011-06-15 Zhejiang Hisun Pharm Co Ltd A method for the separation and purification of epothilones
WO2010040252A1 (en) * 2008-10-06 2010-04-15 山东大学 Epothilone glycoside compounds, compositions containing epothilone glycoside compounds as active components and uses thereof
EP2210584A1 (en) 2009-01-27 2010-07-28 Bayer Schering Pharma Aktiengesellschaft Stable polymeric composition comprising an epothilone and an amphiphilic block copolymer
EP3566719A1 (en) 2010-05-18 2019-11-13 Cerulean Pharma Inc. Compositions and methods for treatment of autoimmune and other diseases
US8618146B2 (en) 2011-01-03 2013-12-31 Dr. Reddy's Laboratories Limited Epothilone compound formulations
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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