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WO1993010121A1 - Epothilones, leur procede de preparation et leur utilisation comme medicaments et comme agents phytosanitaires - Google Patents

Epothilones, leur procede de preparation et leur utilisation comme medicaments et comme agents phytosanitaires 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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WO
WIPO (PCT)
Prior art keywords
epothilones
methanol
merck
epothilone
hydrogen
Prior art date
Application number
PCT/EP1992/002656
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German (de)
English (en)
Inventor
Gerhard Höfle
Norbert Bedorf
Klaus Gerth
Hans Reichenbach
Original Assignee
GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF)
Ciba-Geigy Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF), Ciba-Geigy Ag filed Critical GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF)
Publication of WO1993010121A1 publication Critical patent/WO1993010121A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
    • C12P17/181—Heterocyclic compounds containing oxygen atoms as the only ring heteroatoms in the condensed system, e.g. Salinomycin, Septamycin

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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

L'invention concerne des épothilones qui répondent à la formule générale (I), leur procédé de préparation et des produits contenant des épothilones.
PCT/EP1992/002656 1991-11-19 1992-11-19 Epothilones, leur procede de preparation et leur utilisation comme medicaments et comme agents phytosanitaires WO1993010121A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4138042.8 1991-11-19
DE19914138042 DE4138042C2 (de) 1991-11-19 1991-11-19 Epothilone, deren Herstellungsverfahren sowie diese Verbindungen enthaltende Mittel

Publications (1)

Publication Number Publication Date
WO1993010121A1 true WO1993010121A1 (fr) 1993-05-27

Family

ID=6445140

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1992/002656 WO1993010121A1 (fr) 1991-11-19 1992-11-19 Epothilones, leur procede de preparation et leur utilisation comme medicaments et comme agents phytosanitaires

Country Status (3)

Country Link
AU (1) AU2943792A (fr)
DE (1) DE4138042C2 (fr)
WO (1) WO1993010121A1 (fr)

Cited By (75)

* Cited by examiner, † Cited by third party
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WO1997019086A1 (fr) * 1995-11-17 1997-05-29 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) Derives d'epothilone, leur preparation et leur utilisation
WO1998008849A1 (fr) * 1996-08-30 1998-03-05 Novartis Aktiengesellschaft Procede de fabrication d'epothilones, et composes intermediaires obtenus au cours de ce procede
WO1998022461A1 (fr) * 1996-11-18 1998-05-28 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) Epothilone c, d, e et f, mode de preparation et application comme agents cytostatiques et phytosanitaires
WO1998038192A1 (fr) * 1997-02-25 1998-09-03 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) Epothilones a chaine laterale modifiee
WO1999028324A1 (fr) * 1997-12-04 1999-06-10 Bristol-Myers Squibb Company Procede de reduction d'epothilones d'oxiranyle en epothilones olefiniques
FR2774909A1 (fr) * 1998-02-05 1999-08-20 Novartis Ag Formulation pharmaceutique, solution de perfusion et composition lyophilisee comprenant une epothilone.
FR2775187A1 (fr) * 1998-02-25 1999-08-27 Novartis Ag Utilisation de l'epothilone b pour la fabrication d'une preparation pharmaceutique antiproliferative et d'une composition comprenant l'epothilone b comme agent antiproliferatif in vivo
WO1999042602A3 (fr) * 1998-02-19 1999-11-25 Novartis Ag Procede de preparation par fermentation de cytostatiques et de formes cristallines
WO1999058534A3 (fr) * 1998-05-08 2000-01-13 Biotechnolog Forschung Gmbh Derives d'epothilone, leur procede de preparation et leur utilisation
EP0987268A1 (fr) * 1998-08-05 2000-03-22 Gesellschaft für biotechnologische Forschung mbH (GBF) Epothilone A N-oxyde, épothilone B N-oxyde, procédé de leur préparation et agents les contenant
US6043372A (en) * 1996-08-30 2000-03-28 Novartis Ag Intermediates in the process for preparing epothilones
WO2000023452A1 (fr) * 1998-10-14 2000-04-27 Schering Aktiengesellschaft Procede de preparation d'epothilone b et de derives, et produits intermediaires pour ledit procede
US6121029A (en) * 1998-06-18 2000-09-19 Novartis Ag Genes for the biosynthesis of epothilones
EP1035824A1 (fr) * 1997-12-04 2000-09-20 Bristol-Myers Squibb Company Procede de preparation de produits intermediaires d'epothilone a noyau ouvert s'utilisant dans la preparation d'analogues d'epothilone
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US6262094B1 (en) 1999-02-22 2001-07-17 Bristol-Myers Squibb Company C-21 modified epothilones
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US6288237B1 (en) 1995-11-17 2001-09-11 Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) Epothilons C and D, preparation and compositions
EP1186606A1 (fr) * 1995-11-17 2002-03-13 Gesellschaft für biotechnologische Forschung mbH (GBF) Derivés d'épothilone, leur procédé de production et utilisation
EP1440973A3 (fr) * 1995-11-17 2004-10-20 Gesellschaft für biotechnologische Forschung mbH (GBF) Dérivés d'épothilone, procédé de production et utilisation
EP0903348A1 (fr) * 1995-11-17 1999-03-24 Gesellschaft für Biotechnologische Forschung mbH (GBF) Dérivés d'epothilone, préparation et utilisation
US6831076B2 (en) 1995-11-17 2004-12-14 Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) Epothilons C and D, preparation and compositions
WO1997019086A1 (fr) * 1995-11-17 1997-05-29 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) Derives d'epothilone, leur preparation et leur utilisation
US6613912B2 (en) 1995-11-17 2003-09-02 Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) Epothilons C and D, preparation and compositions
US6884817B2 (en) 1996-03-12 2005-04-26 Pg-Txl Company, L.P. Water soluble paclitaxel derivatives
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EP2070521A1 (fr) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft Nanoparticules à surface modifiée
EP2241566A1 (fr) * 2008-02-01 2010-10-20 Zhejiang Hisun Pharmaceutical Co. Ltd. Procédé de séparation et de purification d'épothilones
EP2241566A4 (fr) * 2008-02-01 2011-06-15 Zhejiang Hisun Pharm Co Ltd Procédé de séparation et de purification d'épothilones
WO2010040252A1 (fr) * 2008-10-06 2010-04-15 山东大学 Composés de glycoside d’épothilone, composition les utilisant comme principe actif et leur utilisation
EP2210584A1 (fr) 2009-01-27 2010-07-28 Bayer Schering Pharma Aktiengesellschaft Composition polymère stable comprenant un copolymère séquencé d'épothilone et amphiphile
EP3566719A1 (fr) 2010-05-18 2019-11-13 Cerulean Pharma Inc. Compositions et procédés pour le traitement de maladies auto-immunes et d'autres maladies
US8618146B2 (en) 2011-01-03 2013-12-31 Dr. Reddy's Laboratories Limited Epothilone compound formulations
CN103145722A (zh) * 2013-03-05 2013-06-12 福建省微生物研究所 一种高速逆流色谱分离提纯埃博霉素的方法
WO2015024884A1 (fr) * 2013-08-19 2015-02-26 Sandoz Ag Procédé de purification d'épothilones par cristallisation

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DE4138042A1 (de) 1993-05-27
AU2943792A (en) 1993-06-15

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