US20080293784A1 - Epothilones c, d, e and f, preparation and compositions - Google Patents

Epothilones c, d, e and f, preparation and compositions Download PDF

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US20080293784A1
US20080293784A1 US12/110,781 US11078108A US2008293784A1 US 20080293784 A1 US20080293784 A1 US 20080293784A1 US 11078108 A US11078108 A US 11078108A US 2008293784 A1 US2008293784 A1 US 2008293784A1
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epothilone
methanol
epothilones
culture
compound
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Gerhard Hoefle
Heinrich Steinmetz
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Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
    • 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
    • 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
    • A01N63/00—Biocides, pest repellants or attractants, or plant growth regulators containing microorganisms, viruses, microbial fungi, animals or substances produced by, or obtained from, microorganisms, viruses, microbial fungi or animals, e.g. enzymes or fermentates
    • A01N63/20—Bacteria; Substances produced thereby or obtained therefrom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
    • C12P17/167—Heterorings having sulfur atoms as ring heteroatoms, e.g. vitamin B1, thiamine nucleus and open chain analogs
    • 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 present invention relates to epothilones C, D, E and F, their preparation and their use for the production of therapeutic compositions and compositions for plant protection.
  • the invention relates to epothilones [C and D] which are obtainable in that
  • the invention further relates to an epothilone [C] of the empirical formula C 26 H 39 NO 5 S, characterized by the 1 H- and 13 C-NMR spectrum as in Table 1.
  • the invention furthermore relates to epothilone C of the formula:
  • the invention furthermore relates to epothilone [D] of the empirical formula C 27 H 41 NO 5 S, characterized by the 1 H- and 13 C-NMR spectrum as in Table 1.
  • the invention furthermore relates to epothilone D of the formula:
  • Epothilones C and D can be used for the preparation of the compounds of the following formula 1, where for their derivatization reference can be made to the derivatization methods described in WO-A-97/19 086.
  • the invention relates to a biotransformant of epothilone A, which is obtainable in that
  • Sorangium cellulosum DSM 6773 is cultured in a manner known per se in the presence of an adsorber resin, removed from the adsorber resin and, if appropriate, the total amount or a part of the separated culture is treated with a methanolic solution of epothilone A,
  • the invention furthermore relates to a biotransformant of epothilone A of this type, which is obtainable in that in stage (a) a culture is separated off which is three or four or more days old.
  • the invention furthermore relates to a biotransformant of epothilone A of this type, which is obtainable in that in stage (b) incubation is carried out for one or two or more days.
  • the invention furthermore relates to a compound (epothilone E) of the formula:
  • the invention relates to a biotransformant of epothilone B, which is obtainable in that
  • Sorangium cellulosum DSM 6773 is cultured in a manner known per se in the presence of an adsorber resin, separated from the adsorber resin and, if appropriate, the total amount or a part of the separated culture is treated with a methanolic solution of epothilone B,
  • the invention furthermore relates to a biotransformant of epothilone B of this type, which is obtainable in that in stage (a) a culture is separated off which is three or four or more days old.
  • the invention furthermore relates to a biotransformant of epothilone B of this type, which is obtainable in that in stage (b) incubation is carried out for one or two or more days.
  • the invention furthermore relates to a compound (epothilone F) of the formula:
  • FIG. 1 shows a HPLC analysis of an XAD eluate at the end of a fermentation.
  • FIG. 2 shows an enrichment of epothilone E and F in a fermentation broth after feeding of a mixture of epothilone A and B, analysed after incubation for 48 hours.
  • FIG. 3 shows kinetics of the biotransformation of epothilone A to epothilone E by Sorangium cellulosum So ce90.
  • FIG. 4 shows biotransformation of epothilone A to epothilone E.
  • FIG. 5 shows biotransformation of epothilone B to epothilone F.
  • the compounds or epothilones according to the invention are obtainable by the abovementioned measures.
  • the invention furthermore relates to compositions for plant protection in agriculture, forestry and/or horticulture, consisting of one or more of the abovementioned epothilones C, D, E and F or consisting of one or more of the abovementioned epothilones in addition to one or more customary carrier(s) and/or diluent(s).
  • the invention finally relates to therapeutic compositions, consisting of one or more of the abovementioned compounds or one or more of the above-mentioned compounds in addition to one or more customary carrier(s) and/or diluent(s).
  • these compositions can show cytotoxic activities and/or bring about immunosuppression and/or be employed for the control of malignant tumours, it being particularly preferably possible for them to be used as cytostatics.
  • the fermentation lasts 7-10 days at 30 C, aeration with 2 m 3 /hr. By controlling the speed of rotation, the PO 2 is kept at 30%.
  • the adsorber resin is separated from the culture using a 0.7 m 2 , 100 mesh process filter and freed from polar concomitants by washing with 3 bed volumes of water/methanol 2:1. By elution with 4 bed volumes of methanol, a crude extract is obtained which is evaporated in vacuo until the water phase appears. This is extracted three times with the same volume of ethyl acetate. Evaporation of the organic phase affords 240 g of crude extract, which is partitioned between methanol and heptane in order to separate off lipophilic concomitants.
  • epothilone A 50 mg are dissolved in 1.5 ml of acetone and treated with 1.5 ml of a 0.07 molar solution of dimethyldioxirane in acetone. After standing at room temperature for 6 hours, the mixture is evaporated in vacuo and the residue is separated by preparative HPLC on silica gel (eluent: methyl tert-butyl ether/petroleum ether/methanol 33:66:1).
  • Epothilone E and F Novel Biotransformation Products of Epothilones A and B Production Strain:
  • a typical fermentation proceeds in the following manner: A 100 l bioreactor is filled with 60 l of medium (0.8% starch; 0.2% glucose; 0.2% soya flour; 0.2% yeast extract; 0.1% CaCl 2 ⁇ 2H 2 O; 0.1% MgSO 4 ⁇ 7H 2 O; 8 mg/l of Fe-EDTA; pH 7.4). 2% of adsorber resin (XAD-16, Rohm & Haas) are additionally added. The medium is sterilized by autoclaving (2 hours, 120° C.). Inoculation is carried out with 10 l of a preculture grown in the same medium (additionally 50 mM HEPES buffer pH 7.4) in a shaker flask (160 rpm, 30° C.).
  • Fermentation is carried out at 32° C. with a stirrer speed of 500 rpm and an introduction of 0.2 Ni per m 3 per hour of air, the pH is kept at 7.4 by addition of KOH.
  • the fermentation lasts 7 to 10 days.
  • the epothilones formed are continuously bound to the adsorber resin during the fermentation.
  • the resin is washed with 3 bed volumes of water and eluted with 4 bed volumes of methanol.
  • the eluate is concentrated to dryness and taken up in 700 ml of methanol.
  • the eluate is concentrated 100:1.
  • the analysis is carried out using a 1090 HPLC unit from Hewlett Packard.
  • a microbore column 125/2 Nucleosil 120-5 C 18 ) from Machery-Nagel (Düren) is used.
  • Elution is carried out using a gradient of water/acetonitrile from initially 75:25 up to 50:50 after 5.5 minutes. This ratio is maintained up to the 7th minute, in order to then increase it up to the 10th minute to 100% acetonitrile.
  • Measurement is carried out at a wavelength of 250 nm and a bandwidth of 4 nm.
  • the diode array spectra are measured in the wavelength range from 200 to 400 nm.
  • two novel substances with R t 5.29 and R t 5.91 stand out, whose adsorption spectra are identical with those of epothilones A and B (FIG. 1 ; E corresponds to A, F corresponds to B). These substances are only formed in traces under the given fermentation conditions.
  • the concentration was determined which reduces the growth by 50% (IC 50 ) and compared with the values for epothilone A.
  • a culture of Sorangium cellulosum So ce90 is used which has been shaken for four days in the presence of 2% XAD 16 adsorber resin (Rohm and Haas, Frankfurt/M.) at 30° C. and 160 rpm.
  • the culture medium has the following composition in g/litre of distilled water: potato starch (Maizena), 8; glucose (Maizena), 8; defatted soya flour, 2; yeast extract (Marcor), 2; ethylenediaminetetraacetic acid, iron(III) sodium salt, 0.008; MgSO 4 ⁇ 7H 2 O, 1; CaCl 2 ⁇ 2H 2 O, 1; HEPES 11.5.
  • the pH is adjusted to 7.4 before autoclaving with KOH.
  • the XAD is separated from the culture by sieving through a stainless steel sieve (200 ⁇ m mesh width).
  • the bacteria are sedimented by centrifugation for 10 min at 10,000 rpm and the pellet is resuspended in 1 ⁇ 5 of the culture supernatant.
  • Epothilone A or epothilone B in methanolic solution is then added to the concentrated bacterial suspension in a concentration of 0.5 ⁇ l litre.
  • the culture is cultured further as described above.
  • To analyse the biotransformation a 1 ml sample is taken at the desired times, 0.1 ml of XAD is added and the sample is shaken at 30° C. for 30 min.
  • the XAD is eluted with methanol.
  • the eluate is concentrated to dryness and taken up again in 0.2 ml of methanol. This sample is analysed by means of HPLC.
  • FIG. 4 Kinetics of the biotransformation of epothilone A to epothilone E
  • FIG. 5 Kinetics of the biotransformation of epothilone B to epothilone F.
  • strain Sorangium cellulosum So ce90 is grown for four days in 8.5 l of the above medium (but without XAD addition) in a 10 litre bioreactor at 30° C., a speed of rotation of 150 rpm and an introduction of 1 l/min of air.
  • the culture is then concentrated to 3 l by crossflow filtration.
  • 0.6 m 2 of a membrane having a pore size of 0.3 ⁇ m are used.
  • the concentrated culture is transferred to a 4 litre bioreactor and a methanolic solution of 1 g of epothilone A in 10 ml of methanol is added.
  • the culture is then cultured further for a period of time of 21.5 h.
  • the temperature is 32° C.
  • the stirrer speed is 455 rpm and the introduction of air takes place at 6 l/min.
  • 100 ml of XAD is added and the mixture is incubated further for 1 h.
  • the XAD is separated from the cells by screening and exhaustively eluted with methanol.
  • the concentrated eluate is analysed by means of HPLC.
  • Epothilone E formed after 21.5 h: 661.4 mg 66.1%
  • Epothilone A completely decomposed: 28.5%
  • Epothilone tests with cell cultures Epothilone B C A 507 477 D E F 493 IC-50 [ng/ml] 491 509 523 Mouse fibroblasts L 929 4 1 100 20 20 1.5 human tumor cell lines: HL-60 (leukaemia) 0.2 0.2 10 3 1 0.3 K-562 (leukaemia) 0.3 0.3 20 10 2 0.5 U-937 (lymphoma) 0.2 0.2 10 3 1 0.2 KB-3.1 (carcinoma of the 1 0.6 20 12 5 0.5 cervix) KB-V1 (carcinoma of the 0.3 0.3 15 3 5 0.6 cervix multires A-498 (carcinoma of the — 1.5 150 20 20 3 kidney) A-549 (carcinoma of the 0.7 0.1 30 10 3 0.1 lung)
  • the polymerization test is an in vitro test using purified tubulin from pigs' brain. Evaluation is carried out photometrically. Polymerization-promoting substances such as the epothilones reduce the time up to which half-maximal polymerization has taken place, i.e. the shorter the time, the more active the compound. w, x, y and z are four independent experiments, the relative activity is expressed in the last column in % of the control; again the lowest values indicate the best activity. The ranking list corresponds reasonably accurately to that found in cell cultures.

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Abstract

The present invention relates to epothilones C, D, E and F, their preparation and their use for the production of therapeutic compositions and compositions for plant protection.

Description

  • This application is a continuation of application Ser. No. 11/412,536 filed Apr. 27, 2006, which is a division of application Ser. No. 10/988,328 filed on Nov. 12, 2004 (now U.S. Pat. No. 7,067,544), which is a division of application Ser. No. 09/313,524, filed on May 17, 1999, which is a continuation of Application No. PCT/EP97/06442 filed on Nov. 18, 1997, which claims priority to DE 197 07 506.1 filed Feb. 25, 1997 and DE 196 47 580.5 filed Nov. 18, 1996.
    • BACKGROUND OF THE INVENTION
  • The present invention relates to epothilones C, D, E and F, their preparation and their use for the production of therapeutic compositions and compositions for plant protection.
    • Epothilones C and D
  • According to one embodiment, the invention relates to epothilones [C and D] which are obtainable in that
  • (a) Sorangium cellulosum DSM 6773 is cultured in a manner known per se in the presence of an adsorber resin,
  • (b) the adsorber resin is removed from the culture and washed with a water/methanol mixture,
  • (c) the washed adsorber resin is eluted with methanol and the eluate is concentrated to give a crude extract,
  • (d) the concentrate obtained is extracted with ethyl acetate, the extract is concentrated and partitioned between methanol and hexane,
  • (e) the methanolic phase is concentrated to give a raffinate and the concentrate is fractionated on a Sephadex column,
  • (f) a fraction containing metabolic products of the microorganism employed is obtained,
  • (g) the fraction obtained is chromatographed on a C18 reverse phase to a methanol/water mixture and, sequentially
      • after a first fraction containing epothilone A and
      • a second fraction containing epothilone B
      • a third fraction containing a first further epothilone and
      • a fourth fraction containing a second further epothilone are obtained and
  • (h1) and the epothilone of the first further fraction and/or
  • (h2) the epothilone of the second further fraction are isolated.
  • The invention further relates to an epothilone [C] of the empirical formula C26H39NO5S, characterized by the 1H- and 13C-NMR spectrum as in Table 1.
  • The invention furthermore relates to epothilone C of the formula:
  • Figure US20080293784A1-20081127-C00001
  • The invention furthermore relates to epothilone [D] of the empirical formula C27H41NO5S, characterized by the 1H- and 13C-NMR spectrum as in Table 1.
  • The invention furthermore relates to epothilone D of the formula:
  • Figure US20080293784A1-20081127-C00002
  • Epothilones C and D can be used for the preparation of the compounds of the following formula 1, where for their derivatization reference can be made to the derivatization methods described in WO-A-97/19 086.
  • Figure US20080293784A1-20081127-C00003
  • In the above formula 1:
    R═H, C1-4-alkyl;
    R1, R2, R3, R4, R═H, C1-6-alkyl,
      • C1-6-acylbenzoyl,
      • C1-4-trialkylsilyl,
      • benzyl,
      • phenyl,
      • C1-6-alkoxy-,
      • C6-alkyl-, hydroxy- and halogen-substituted benzyl or phenyl;
        where two of the radicals R1 to R5 can also combine to form the group —(CH2)n— with n=1 to 6 and the alkyl or acyl groups contained in the radicals are straight-chain or branched radicals;
        Y and Z are either identical or different and are each hydrogen, halogen, such as F, Cl, Br or I, pseudohalogen, such as —NCO, —NCS or —N3, OH, O—(C1-6)-acyl, O—(C1-6)-alkyl, O-benzoyl. Y and Z can also be the O atom of an epoxide, epothilone A and B not being claimed, or form one of the C—C bonds of a C═C double bond.
  • Thus the 12,13-double bond can be selectively
      • hydrogenated, for example catalytically or with diimine, a compound of the formula I being obtained with Y=Z=H; or
      • epoxidized, for example with dimethyldioxirane or a peracid, a compound of the formula I being obtained with Y and Z=-O—; or
      • converted into the dihalides, dipseudohalides or diazides, a compound of the formula I being obtained with Y and Z=Hal, pseudo-hal or N3.
    Epothilones E and F
  • According to a further embodiment the invention relates to a biotransformant of epothilone A, which is obtainable in that
  • (a) Sorangium cellulosum DSM 6773 is cultured in a manner known per se in the presence of an adsorber resin, removed from the adsorber resin and, if appropriate, the total amount or a part of the separated culture is treated with a methanolic solution of epothilone A,
  • (b) the culture treated with epothilone A is incubated and then treated with adsorber resin,
  • (c) the adsorber resin is separated from the culture, eluted with methanol and the eluate is concentrated to give a crude extract,
  • (d) the crude extract is partitioned between ethyl acetate and water, the ethyl acetate phase is separated off and concentrated to give an oil,
  • (e) the oil is chromatographed on a reverse phase under the following conditions:
  •
    column material: Nucleosil 100 C-18 7 μm
    column dimensions: 250 × 16 mm
    eluent: methanol/water = 60:40
    flow rate: 10 ml/min

    and fractions having a content of biotransformant and which can be detected by UV extinction at 254 nm and have an Rt value of 20 min are separated off and the biotransformants are isolated.
  • The invention furthermore relates to a biotransformant of epothilone A of this type, which is obtainable in that in stage (a) a culture is separated off which is three or four or more days old.
  • The invention furthermore relates to a biotransformant of epothilone A of this type, which is obtainable in that in stage (b) incubation is carried out for one or two or more days.
  • The invention furthermore relates to a compound of the empirical formula C26H39NO7S, characterized by the following 1H-NMR spectrum (300 MHz, CDCl3): delta=2.38 (2-Ha), 2.51 (2-Hb), 4.17 (3-H), 3.19 (6-H), 3.74 (7-H), 1.30-1.70 (8-H, 9-H2, 10-H2, 11-H2), 2.89 (12-H), 3.00 (13-H), 1.88 (14-Ha), 2.07 (14-Hb), 5.40 (15-H), 6.57 (17-H), 7.08 (19-H), 4.85 (21-H2), 1.05 (22-H3), 1.32 (23-H3), 1.17 (24-H3), 0.97 (25-H3), 2.04 (27-H3)
  • The invention furthermore relates to a compound (epothilone E) of the formula:
  • Figure US20080293784A1-20081127-C00004
  • According to a further embodiment, the invention relates to a biotransformant of epothilone B, which is obtainable in that
  • (a) Sorangium cellulosum DSM 6773 is cultured in a manner known per se in the presence of an adsorber resin, separated from the adsorber resin and, if appropriate, the total amount or a part of the separated culture is treated with a methanolic solution of epothilone B,
  • (b) the culture treated with epothilone B is incubated and then treated with adsorber resin,
  • (c) the adsorber resin is separated from the culture, eluted with methanol and the eluate is concentrated to give a crude extract,
  • (d) the crude extract is partitioned between ethyl acetate and water, the ethyl acetate phase is separated off and concentrated to give an oil,
  • (e) the oil is chromatographed on a reverse phase under the following conditions:
  •
    column material: Nucleosil 100 C-18 7 μm
    column dimensions: 250 × 16 mm
    eluent: methanol/water = 60:40
    flow rate: 10 ml/min

    and fractions having a content of biotransformant and which can be detected by UV extinction at 254 nm and have an Rt value of 24.5 min are separated off and the biotransformants are isolated.
  • The invention furthermore relates to a biotransformant of epothilone B of this type, which is obtainable in that in stage (a) a culture is separated off which is three or four or more days old.
  • The invention furthermore relates to a biotransformant of epothilone B of this type, which is obtainable in that in stage (b) incubation is carried out for one or two or more days.
  • The invention furthermore relates to a compound of the empirical formula C27H41NO7S, characterized by the following 1H-NMR spectrum (300 MHz, CDCl3): delta=2.37 (2-Ha), 2.52 (2-Hb), 4.20 (3-H), 3.27 (6-H), 3.74 (7-H), 1.30-1.70 (8-H, 9-H2, 10-H2, 11-H2), 2.78 (13-H), 1.91 (14-H), 2.06 (14-Hb), 5.42 (15-H), 6.58 (17-H), 7.10 (19-H), 4.89 (21-H2), 1.05 (22-H3), 1.26 (23-H3), 1.14 (24-H3), 0.98 (25-H3), 1.35 (26-H3), 2.06 (27-H3).
  • The invention furthermore relates to a compound (epothilone F) of the formula:
  • Figure US20080293784A1-20081127-C00005
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 shows a HPLC analysis of an XAD eluate at the end of a fermentation.
  • FIG. 2 shows an enrichment of epothilone E and F in a fermentation broth after feeding of a mixture of epothilone A and B, analysed after incubation for 48 hours.
  • FIG. 3 shows kinetics of the biotransformation of epothilone A to epothilone E by Sorangium cellulosum So ce90.
  • FIG. 4 shows biotransformation of epothilone A to epothilone E.
  • FIG. 5 shows biotransformation of epothilone B to epothilone F.
    •  PREPARATION AND COMPOSITIONS
  • The compounds or epothilones according to the invention are obtainable by the abovementioned measures.
  • The invention furthermore relates to compositions for plant protection in agriculture, forestry and/or horticulture, consisting of one or more of the abovementioned epothilones C, D, E and F or consisting of one or more of the abovementioned epothilones in addition to one or more customary carrier(s) and/or diluent(s).
  • The invention finally relates to therapeutic compositions, consisting of one or more of the abovementioned compounds or one or more of the above-mentioned compounds in addition to one or more customary carrier(s) and/or diluent(s). In particular, these compositions can show cytotoxic activities and/or bring about immunosuppression and/or be employed for the control of malignant tumours, it being particularly preferably possible for them to be used as cytostatics.
  • In the following, the invention is illustrated and described in greater detail by the description of some selected working examples.
    • EXAMPLES Example 1 Epothilones C and D A. Production Strain and Culture Conditions According to the Epothilone Basic Patent DE-B-41 38 042.
  • B. Production with DSM 6773
  • 75 l of culture are grown as described in the basic patent and used for the inoculation of a production fermenter with 700 l of production medium consisting of 0.8% starch, 0.2% glucose, 0.2% soya flour, 0.2% yeast extract, 0.1% CaCl2×2H2O, 0.1% MgSO4×7H2O, 8 mg/l of Fe-EDTA, pH=7.4 and optionally 15 l of Amberlite XAD-16 adsorber resin. The fermentation lasts 7-10 days at 30 C, aeration with 2 m3/hr. By controlling the speed of rotation, the PO2 is kept at 30%.
    • C. Isolation
  • The adsorber resin is separated from the culture using a 0.7 m2, 100 mesh process filter and freed from polar concomitants by washing with 3 bed volumes of water/methanol 2:1. By elution with 4 bed volumes of methanol, a crude extract is obtained which is evaporated in vacuo until the water phase appears. This is extracted three times with the same volume of ethyl acetate. Evaporation of the organic phase affords 240 g of crude extract, which is partitioned between methanol and heptane in order to separate off lipophilic concomitants. By evaporation in vacuo, 180 g of raffinate are obtained from the methanol phase and are fractionated into three portions on Sephadex LH-20 (column 20×100 cm, 20 ml/min of methanol). The epothilones are contained in the fraction of a total of 72 g eluted with a 240-300 min retention time. To separate the epothilones, the fraction is chromatographed in three portions on Lichrosorb RP-18 (15 μm, column 10×40 cm, eluent 180 ml/min methanol/water 65:35). After epothilone A and B, epothilone C, with Rt=90-95 min, and epothilone D, 100-110 min, are eluted and after evaporation in vacuo obtained in a yield of 0.3 g each as colourless oils.
    • D. Physical Properties
  • Figure US20080293784A1-20081127-C00006
  • Epothilone C R═H
  • Epothilone D R═CH3
  • Epothilone C
  • C26H39NO5S [477]
  • ESI-MS: (positive ions): 478.5 for [M+H]+
  • 1H and 13C see NMR table
  • TLC: Rf=0.82
  • TLC aluminum foil 60 F 254 Merck, eluent: dichloromethane/methanol=9:1
  • Detection: UV extinction at 254 nm. Spraying with vanillin-sulphuric acid reagent, blue-grey coloration on heating to 120° C.
  • HPLC: Rt=11.5 min
  • Column: Nucleosil 100 C-18 7 μm, 125×4 mm
  • Eluent: methanol/water=65:35
  • Flow rate: 1 ml/min
  • Detection: diode array
  • Epothilone D
  • C27H41NO5S [491]
  • ESI-MS: (positive ions): 492.5 for [M+H]+
  • 1H and 13C see NMR table
  • TLC: Rt=0.82
  • TLC aluminum foil 60 F 254 Merck, eluent: dichloromethane/methanol=9:1
  • Detection: UV extinction at 254 nm. Spraying with vanillin-sulphuric acid reagent, blue-grey coloration on heating to 120° C.
  • HPLC: Rt=15.3 min
  • Column: Nucleosil 100 C-18 7 μm, 125×4 mm
  • Eluent: methanol/water=65:35
  • Flow rate: 1 ml/min
  • Detection: diode array
  • TABLE 1
    1H- and 13C-NMR data of epothilone C and epothilone
    D in [D6] DMSO at 300 MHz
    Epothilone C Epothilone D
    δ δ δ δ
    H atom (ppm) C atom (ppm) (ppm) C atom (ppm)
    1 170.3 1 170.1
     2-Ha 2.38 2 38.4 2.35 2 39.0
     2-Hb 2.50 3 71.2 2.38 3 70.8
     3-H 3.97 4 53.1 4.10 4 53.2
     3-OH 5.12 5 217.1 5.08 5 217.4
     6-H 3.07 6 45.4 3.11 6 44.4
     7-H 3.49 7 75.9 3.48 7 75.5
     7-OH 4.46 8 35.4 4.46 8 36.3
     8-H 1.34 9 27.6 1.29 9 29.9
     9-Ha 1.15 10 30.0 1.14 10 25.9
     9-Hb 1.40 11 27.6 1.38 11 31.8*
    10-Ha 1.15* 12 124.6 1.14* 12 138.3
    10-Hb 1.35* 13 133.1 1.35* 13 120.3
    11-Ha 1.90 14 31.1 1.75 14 31.6*
    11-Hb 2.18 15 76.3 2.10 15 76.6
    12-H 5.38** 16 137.3 16 137.2
    13-H 5.44** 17 119.1 5.08 17 119.2
    14-Ha 2.35 18 152.1 2.30 18 152.1
    14-Hb 2.70 19 117.7 2.65 19 117.7
    15-H 5.27 20 164.2 5.29 20 164.3
    17-H 6.50 21 18.8 6.51 21 18.9
    19-H 7.35 22 20.8 7.35 22 19.7
    21-H3 2.65 23 22.6 2.65 23 22.5
    22-H3 0.94 24 16.7 0.90 24 16.4
    23-H3 1.21 25 18.4 1.19 25 18.4
    24-H3 1.06 27 14.2 1.07 26 22.9
    25-H3 0.90 0.91 27 14.1
    26-H3 1.63
    27-H3 2.10 2.11
    *, **assignment interchangeable
    • Example 2
  • Epothilone A and 12,13-bisepi-epothilone A from Epothilone C
  • 50 mg of epothilone A are dissolved in 1.5 ml of acetone and treated with 1.5 ml of a 0.07 molar solution of dimethyldioxirane in acetone. After standing at room temperature for 6 hours, the mixture is evaporated in vacuo and the residue is separated by preparative HPLC on silica gel (eluent: methyl tert-butyl ether/petroleum ether/methanol 33:66:1).
    • Yield:
    • 25 mg of epothilone A, Rt=3.5 min (analyt. HPLC, 7 μm, column 4×250 mm, eluent see above, flow rate 1.5 ml/min)
      and
    • 20 mg of 12,13-bisepi-epothilone A, Rt=3.7 min, ESI-MS (pos. ions) m/e=494 [M+H]+
  • 1H-NMR in [D4] methanol, selected signals:
  • delta=4.32 (3-H), 3.79 (7-H), 3.06 (12-H), 3.16 (13-H), 5.54 (15-H), 6.69 (17-H), 1.20 (22-H), 1.45 (23-H)
  • Figure US20080293784A1-20081127-C00007
  • 12,13-bisepi-epothilone A R═H
    • Example 3 Epothilone E and F, Novel Biotransformation Products of Epothilones A and B Production Strain:
  • The production strain Sorangium cellulosum So ce90 was isolated in July 1985 in GBF from a soil sample from the banks of the Zambesi and deposited on 28.10.91 in the German Collection for Microorganisms under No. DSM 6773.
  • The characterization of the producer and the culture conditions are described in: Höfle, G.; N. Bedorf, K. Gerth & H. Reichenbach: Epothilones, processes for their preparation and compositions containing them. DE 41 38 042 A1, laid open on 27 May 1993.
    • Formation of Epothilones E and F During Fermentation:
  • A typical fermentation proceeds in the following manner: A 100 l bioreactor is filled with 60 l of medium (0.8% starch; 0.2% glucose; 0.2% soya flour; 0.2% yeast extract; 0.1% CaCl2×2H2O; 0.1% MgSO4×7H2O; 8 mg/l of Fe-EDTA; pH 7.4). 2% of adsorber resin (XAD-16, Rohm & Haas) are additionally added. The medium is sterilized by autoclaving (2 hours, 120° C.). Inoculation is carried out with 10 l of a preculture grown in the same medium (additionally 50 mM HEPES buffer pH 7.4) in a shaker flask (160 rpm, 30° C.). Fermentation is carried out at 32° C. with a stirrer speed of 500 rpm and an introduction of 0.2 Ni per m3 per hour of air, the pH is kept at 7.4 by addition of KOH. The fermentation lasts 7 to 10 days. The epothilones formed are continuously bound to the adsorber resin during the fermentation. After separating off the culture broth (e.g. by screening in a process filter), the resin is washed with 3 bed volumes of water and eluted with 4 bed volumes of methanol. The eluate is concentrated to dryness and taken up in 700 ml of methanol.
    • HPLC Analysis of the XAD Eluate:
  • In relation to the starting volume of the reactor (70 l), the eluate is concentrated 100:1. The analysis is carried out using a 1090 HPLC unit from Hewlett Packard. To separate the constituents, a microbore column (125/2 Nucleosil 120-5 C18) from Machery-Nagel (Düren) is used. Elution is carried out using a gradient of water/acetonitrile from initially 75:25 up to 50:50 after 5.5 minutes. This ratio is maintained up to the 7th minute, in order to then increase it up to the 10th minute to 100% acetonitrile.
  • Measurement is carried out at a wavelength of 250 nm and a bandwidth of 4 nm. The diode array spectra are measured in the wavelength range from 200 to 400 nm. In the XAD eluate, two novel substances with Rt 5.29 and Rt 5.91 stand out, whose adsorption spectra are identical with those of epothilones A and B (FIG. 1; E corresponds to A, F corresponds to B). These substances are only formed in traces under the given fermentation conditions.
    • Biotransformation of Epothilone A and B to Epothilone E and F:
  • A 500 ml culture of So ce90, 4 days old and maintained with adsorber resin, is used for the specific biotransformation. 250 ml of this are transferred to a sterile 111 Erlenmeyer flask leaving behind the XAD. A methanolic solution of a mixture of a total of 36 mg of epothilone A+14 mg of B is then added and the flask is incubated on a shaking rack for two days at 30° C. and 200 rpm. The formation of the epothilones E and F is analysed directly from 10 μl of the centrifuged culture supernatant (FIG. 2). The conversion takes place only in the presence of the cells and is dependent on the cell densities employed and the time. Kinetics of the conversion are shown for epothilone A in FIG. 3.
  • Isolation of Epothilone E and F
  • To isolate epothilone E and F, three shaker flask batches from the biotransformation (see above) are combined and shaken with 20 ml of XAD-16 for 1 h. The XAD is obtained by screening and eluted with 200 ml of methanol. The eluate is evaporated in vacuo to give 1.7 g of crude extract. This is partitioned between 30 ml of ethyl acetate and 100 ml of water. On evaporation in vacuo, 330 mg of an oily residue are obtained from the ethyl acetate phase, which are chromatographed in five runs on a 250×20 mm RP=18 column (eluent: methanol/water 58:42, detection 254 nm).
  •
    Yield: epothilone E 50 mg
    F
    10 mg
    • Biological Action of Epothilone E:
  • In cell cultures, the concentration was determined which reduces the growth by 50% (IC50) and compared with the values for epothilone A.
  • IC50 (ng/ml)
    Cell line Epothilone E Epothilone A
    HeLa.KB-3.1 (human) 5 1
    Mouse fibroblasts, L929 20 4
  • Epothilone E
  • C26H39HO7S [509]
  • ESI-MS: (positive ions): 510.3 for [M+H]+
  • TLC: Rf=0.58
  • TLC aluminum foil 60 F 254 Merck, eluent: dichloromethane/methanol=9:1
  • Detection: UV extinction at 254 nm. Spraying with vanillin-sulphuric acid reagent, blue-grey colouration on heating to 120° C.
  • HPLC: Rt=5.0 min
  • Column: Nucleosil 100 C-18 7 μm, 250×4 mm
  • Eluent: methanol/water=60:40
  • Flow rate: 1.2 ml/min
  • Detection: diode array
  • 1H-NMR (300 MHz, CDCl3): delta=2.38 (2-Ha), 2.51 (2-Hb), 4.17 (3-H), 3.19 (6-H), 3.74 (7-H), 1.30-1.70 (8-H, 9-H2, 10-H2, 11-H2), 2.89 (12-H), 3.00 (13-H), 1.88 (14-Ha), 2.07 (14-Hb), 5.40 (15-H), 6.57 (17-H), 7.08 (19-H), 4.85 (21-H2), 1.05 (22-H3), 1.32 (23-H3), 1.17 (24-H3), 0.97 (25-H3), 2.04 (27-H3)
  • Epothilone F
  • C27H41NO7S [523]
  • ESI-MS: (positive ions): 524.5 for [M+H]+
  • TLC: Rf=0.58
  • TLC aluminum foil 60 F 254 Merck, eluent: dichloromethane/methanol=9:1
  • Detection: UV extinction at 254 nm. Spraying with vanillin-sulphuric acid reagent, blue-grey colouration on heating to 120° C.
  • HPLC: Rt=5.4 min
  • Column: Nucleosil 100 C-18 7 μm, 250×4 mm
  • Eluent: methanol/water=60:40
  • Flow rate: 1.2 ml/min
  • Detection: diode array
  • 1H-NMR (300 MHz, CDCl3): delta=2.37 (2-Ha), 2.52 (2-Hb), 4.20 (3-H), 3.27 (6-H), 3.74 (7-H), 1.30-1.70 (8-H, 9-H2, 10-H2, 11-H2), 2.78 (13-H), 1.91 (14-H), 2.06 (14-Hb), 5.42 (15-H), 6.58 (17-H), 7.10 (19-H), 4.89 (21-H2), 1.05 (22-H3), 1.26 (23-H3), 1.14 (24-H3), 0.98 (25-H3), 1.35 (26-H3), 2.06 (27-H3).
    • Example 4 Preparation of Epothilone E and F by Biotransformation with Sorangium Cellulosum So ce90 1) Carrying out the Biotransformation:
  • For the biotransformation, a culture of Sorangium cellulosum So ce90 is used which has been shaken for four days in the presence of 2% XAD 16 adsorber resin (Rohm and Haas, Frankfurt/M.) at 30° C. and 160 rpm. The culture medium has the following composition in g/litre of distilled water: potato starch (Maizena), 8; glucose (Maizena), 8; defatted soya flour, 2; yeast extract (Marcor), 2; ethylenediaminetetraacetic acid, iron(III) sodium salt, 0.008; MgSO4×7H2O, 1; CaCl2×2H2O, 1; HEPES 11.5. The pH is adjusted to 7.4 before autoclaving with KOH. The XAD is separated from the culture by sieving through a stainless steel sieve (200 μm mesh width). The bacteria are sedimented by centrifugation for 10 min at 10,000 rpm and the pellet is resuspended in ⅕ of the culture supernatant. Epothilone A or epothilone B in methanolic solution is then added to the concentrated bacterial suspension in a concentration of 0.5 μl litre. The culture is cultured further as described above. To analyse the biotransformation, a 1 ml sample is taken at the desired times, 0.1 ml of XAD is added and the sample is shaken at 30° C. for 30 min. The XAD is eluted with methanol. The eluate is concentrated to dryness and taken up again in 0.2 ml of methanol. This sample is analysed by means of HPLC.
  • FIG. 4) Kinetics of the biotransformation of epothilone A to epothilone E
    FIG. 5) Kinetics of the biotransformation of epothilone B to epothilone F.
    • 2) Preparation of Epothilone E by Biotransformation of 1 g of Epothilone A.
  • The strain Sorangium cellulosum So ce90 is grown for four days in 8.5 l of the above medium (but without XAD addition) in a 10 litre bioreactor at 30° C., a speed of rotation of 150 rpm and an introduction of 1 l/min of air.
  • The culture is then concentrated to 3 l by crossflow filtration. For this purpose, 0.6 m2 of a membrane having a pore size of 0.3 μm are used.
  • The concentrated culture is transferred to a 4 litre bioreactor and a methanolic solution of 1 g of epothilone A in 10 ml of methanol is added. The culture is then cultured further for a period of time of 21.5 h. The temperature is 32° C., the stirrer speed is 455 rpm and the introduction of air takes place at 6 l/min. At the time of harvesting, 100 ml of XAD is added and the mixture is incubated further for 1 h. The XAD is separated from the cells by screening and exhaustively eluted with methanol. The concentrated eluate is analysed by means of HPLC.
  • Balancing of the Biotransformation:
  • Epothilone A employed: 1000 mg=100%
  • Epothilone A recovered after 21.5 h: 53.7 mg=5.4%
  • Epothilone E formed after 21.5 h: 661.4 mg=66.1%
  • Epothilone A completely decomposed:=28.5%
    • Experiment 5
  • The epothilones according to the invention were tested with cell cultures (Table 2) and for promotion of polymerization (Table 3).
  • TABLE 2
    Epothilone tests with cell cultures
    Epothilone
    B C
    A 507 477 D E F
    493 IC-50 [ng/ml] 491 509 523
    Mouse fibroblasts L 929 4 1 100 20 20 1.5
    human tumor cell lines:
    HL-60 (leukaemia) 0.2 0.2 10 3 1 0.3
    K-562 (leukaemia) 0.3 0.3 20 10 2 0.5
    U-937 (lymphoma) 0.2 0.2 10 3 1 0.2
    KB-3.1 (carcinoma of the 1 0.6 20 12 5 0.5
    cervix)
    KB-V1 (carcinoma of the 0.3 0.3 15 3 5 0.6
    cervix multires
    A-498 (carcinoma of the — 1.5 150 20 20 3
    kidney)
    A-549 (carcinoma of the 0.7 0.1 30 10 3 0.1
    lung)
  • TABLE 3
    Polymerization test with epothilones
    Parameter: Time up to the half-maximal polymerization of the control
    Measurement: Agent Agent
    w x y z [s] [%]
    Control 200 170 180 210 190 100
    Epothilone A 95 60 70 70 74 39
    Epothilone B 23 25 30 26 14
    Epothilone C 125 76 95 80 94 49
    Epothilone D 125 73 120 106 56
    Epothilone E 80 60 50 45 59 31
    Epothilone F 80 40 30 50 50 26

    Standard Test with 0.9 mg of Tubulin/ml and 1 μM Sample Concentration
  • The polymerization test is an in vitro test using purified tubulin from pigs' brain. Evaluation is carried out photometrically. Polymerization-promoting substances such as the epothilones reduce the time up to which half-maximal polymerization has taken place, i.e. the shorter the time, the more active the compound. w, x, y and z are four independent experiments, the relative activity is expressed in the last column in % of the control; again the lowest values indicate the best activity. The ranking list corresponds reasonably accurately to that found in cell cultures.

Claims (4)

1-16. (canceled)
17. A compound of the formula:
Figure US20080293784A1-20081127-C00008
said compound having a state of purity such as to be substantially free of other major metabolic products produced by Sorangium cellulosum.
18. A composition comprising at least one compound according to claim 17, and at least one carrier or diluent.
19. A method of treating tumor comprising administering to a recipient in need thereof a therapeutic amount of a compound of the formula:
Figure US20080293784A1-20081127-C00009
wherein said tumor is selected from the group consisting of leukemia, lymphoma, carcinoma of the cervix, carcinoma of the kidney and carcinoma of the lung.
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PT1186606E (en) 1995-11-17 2004-08-31 Biotechnolog Forschung Mbh Gbf DERIVATIVES OF THE EPOTILONE ITS PREPARATION AND UTILIZATION
US5969145A (en) * 1996-08-30 1999-10-19 Novartis Ag Process for the production of epothilones and intermediate products within the process
US6204388B1 (en) 1996-12-03 2001-03-20 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US6867305B2 (en) 1996-12-03 2005-03-15 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
CA2273083C (en) 1996-12-03 2012-09-18 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
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
US6605599B1 (en) 1997-07-08 2003-08-12 Bristol-Myers Squibb Company Epothilone derivatives
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
US6320045B1 (en) 1997-12-04 2001-11-20 Bristol-Myers Squibb Company Process for the reduction of oxiranyl epothilones to olefinic epothilones
US6683100B2 (en) 1999-01-19 2004-01-27 Novartis Ag Organic compounds
US6194181B1 (en) 1998-02-19 2001-02-27 Novartis Ag Fermentative preparation process for and crystal forms of cytostatics
FR2775187B1 (en) 1998-02-25 2003-02-21 Novartis Ag USE OF EPOTHILONE B FOR THE MANUFACTURE OF AN ANTIPROLIFERATIVE PHARMACEUTICAL PREPARATION AND A COMPOSITION COMPRISING EPOTHILONE B AS AN IN VIVO ANTIPROLIFERATIVE AGENT
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
DE19820599A1 (en) 1998-05-08 1999-11-11 Biotechnolog Forschung Gmbh New epothilone derivatives useful as pharmaceuticals and in plant protection
DE19826988A1 (en) 1998-06-18 1999-12-23 Biotechnolog Forschung Gmbh Epothilone minor components
NZ508326A (en) * 1998-06-18 2003-10-31 Novartis Ag A polyketide synthase and non ribosomal peptide synthase genes, isolated from a myxobacterium, necessary for synthesis of epothiones A and B
DE19846493A1 (en) * 1998-10-09 2000-04-13 Biotechnolog Forschung Gmbh DNA sequence coding for products involved in the biosynthesis of polyketide or heteropolyketide compounds, especially epothilone
KR100716272B1 (en) 1998-11-20 2007-05-09 코산 바이오사이언시즈, 인코포레이티드 Recombinant methods and materials for producing epothilone and epothilone derivatives
US6410301B1 (en) 1998-11-20 2002-06-25 Kosan Biosciences, Inc. Myxococcus host cells for the production of epothilones
IL142938A0 (en) * 1998-12-23 2002-04-21 Bristol Myers Squibb Co Microbiological 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
US6596875B2 (en) 2000-02-07 2003-07-22 James David White Method for synthesizing epothilones and epothilone analogs
CZ301498B6 (en) 1999-02-22 2010-03-24 Gesellschaft Fuer Biotechnologische Forschung Mbh (Gbf) 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
US7125875B2 (en) 1999-04-15 2006-10-24 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
BR0009721A (en) 1999-04-15 2002-02-13 Bristol Myers Squibb Co Cyclic protein tyrosine kinase inhibitors
CA2385528C (en) 1999-10-01 2013-12-10 Immunogen, Inc. Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents
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
US6589968B2 (en) 2001-02-13 2003-07-08 Kosan Biosciences, Inc. Epothilone compounds and methods for making and using the same
US6998256B2 (en) 2000-04-28 2006-02-14 Kosan Biosciences, Inc. Methods of obtaining epothilone D using crystallization and /or by the culture of cells in the presence of methyl oleate
PT1652926E (en) * 2000-04-28 2009-12-03 Kosan Biosciences Inc Crystalline epothilone d
UA75365C2 (en) * 2000-08-16 2006-04-17 Bristol Myers Squibb Co Epothilone analog polymorph modifications, a method for obtaining thereof (variants), a pharmaceutical composition based thereon
GB0029895D0 (en) * 2000-12-07 2001-01-24 Novartis Ag Organic compounds
NZ526871A (en) * 2001-01-25 2006-01-27 Bristol Myers Squibb Co Pharmaceutical dosage forms of epothilones for oral administration
NZ526870A (en) 2001-01-25 2005-11-25 Bristol Myers Squibb Co Methods of administering epothilone analogs for the treatment of cancer
BR0206511A (en) 2001-01-25 2003-10-21 Bristol Myeres Squibb Company Parenteral formulation for epothilone analogs
US6893859B2 (en) 2001-02-13 2005-05-17 Kosan Biosciences, Inc. Epothilone derivatives and methods for making and using the same
WO2002066038A1 (en) 2001-02-20 2002-08-29 Bristol-Myers Squibb Company Treatment of refractory tumors using epothilone derivatives
IL157128A0 (en) 2001-02-20 2004-02-08 Bristol Myers Squibb Co Pharmaceutical compositions containing epothilone derivatives
EP1385522B1 (en) 2001-02-27 2009-06-24 Novartis AG Combination comprising a signal transduction inhibitor and an epothilone derivative
DE60211124T2 (en) 2001-02-27 2006-11-30 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) Degradation of epothilones
CN1496256A (en) 2001-03-14 2004-05-12 ����˹�ж�-����˹˹������˾ Combination of EPOTHILONE analogs and chemotherapeutic agents for treatment of proliferative diseases
CA2449077A1 (en) 2001-06-01 2002-12-12 Gregory D. Vite Epothilone derivatives
TWI315982B (en) 2001-07-19 2009-10-21 Novartis Ag Combinations comprising epothilones and pharmaceutical uses thereof
TWI287986B (en) * 2001-12-13 2007-10-11 Novartis Ag Use of Epothilones for the treatment of the carcinoid syndrome
US6884608B2 (en) 2001-12-26 2005-04-26 Bristol-Myers Squibb Company Compositions and methods for hydroxylating epothilones
TWI341728B (en) 2002-01-14 2011-05-11 Novartis Ag Combinations comprising epothilones and anti-metabolites
TW200303202A (en) 2002-02-15 2003-09-01 Bristol Myers Squibb Co Method of preparation of 21-amino epothilone derivatives
US6719540B2 (en) 2002-03-12 2004-04-13 Bristol-Myers Squibb Company C3-cyano epothilone derivatives
US7211593B2 (en) 2002-03-12 2007-05-01 Bristol-Myers Squibb Co. C12-cyano epothilone derivatives
TW200403994A (en) 2002-04-04 2004-03-16 Bristol Myers Squibb Co Oral administration of EPOTHILONES
TW200400191A (en) 2002-05-15 2004-01-01 Bristol Myers Squibb Co Pharmaceutical compositions and methods of using C-21 modified epothilone derivatives
US7405234B2 (en) 2002-05-17 2008-07-29 Bristol-Myers Squibb Company Bicyclic modulators of androgen receptor function
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
CA2494742C (en) * 2002-07-29 2015-05-12 Optimer Pharmaceuticals, Inc. Tiacumicin production
PT1506203E (en) * 2002-08-23 2007-04-30 Sloan Kettering Inst Cancer Synthesis of epothilones, intermediates thereto, analogues and uses thereof
AU2003275068B2 (en) 2002-09-23 2009-09-17 Bristol-Myers Squibb Company Methods for the preparation, isolation and purification of epothilone B, and X-Ray crystal structures of epothilone B
SI1553938T1 (en) * 2002-10-15 2007-06-30 Univ Louisiana State Use of epothilone derivatives for the treatment of hyperparathyroidism
AU2003302084A1 (en) 2002-11-15 2004-06-15 Bristol-Myers Squibb Company Open chain prolyl urea-related modulators of androgen receptor function
CN100359014C (en) * 2003-01-28 2008-01-02 北京华昊中天生物技术有限公司 Novel epothilones compound and its preparation method and application
US20050171167A1 (en) 2003-11-04 2005-08-04 Haby Thomas A. Process and formulation containing epothilones and analogs thereof
EP1559447A1 (en) 2004-01-30 2005-08-03 Institut National De La Sante Et De La Recherche Medicale (Inserm) Use of epothilones in the treatment of neuronal connectivity defects such as schizophrenia and autism
US7820702B2 (en) 2004-02-04 2010-10-26 Bristol-Myers Squibb Company Sulfonylpyrrolidine modulators of androgen receptor function and method
US7378426B2 (en) 2004-03-01 2008-05-27 Bristol-Myers Squibb Company Fused heterotricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3
US7625923B2 (en) 2004-03-04 2009-12-01 Bristol-Myers Squibb Company Bicyclic modulators of androgen receptor function
US7696241B2 (en) 2004-03-04 2010-04-13 Bristol-Myers Squibb Company Bicyclic compounds as modulators of androgen receptor function and method
SI2253614T1 (en) 2004-04-07 2013-01-31 Novartis Ag Inhibitors of IAP
US10675326B2 (en) 2004-10-07 2020-06-09 The Board Of Trustees Of The University Of Illinois Compositions comprising cupredoxins for treating cancer
EP1817013B1 (en) * 2004-11-18 2008-06-04 Brystol-Myers Squibb Company Enteric coated bead comprising ixabepilone
EP1824458A1 (en) * 2004-11-18 2007-08-29 Bristol-Myers Squibb Company Enteric coated bead comprising epothilone or an epothilone analog, and preparation and administration thereof
US20060121511A1 (en) 2004-11-30 2006-06-08 Hyerim Lee Biomarkers and methods for determining sensitivity to microtubule-stabilizing agents
GB0510390D0 (en) 2005-05-20 2005-06-29 Novartis Ag Organic compounds
KR20080054417A (en) 2005-09-27 2008-06-17 노파르티스 아게 Carboxyamine compounds and their use in the treatment of hdac dependent diseases
EP2275103B1 (en) 2005-11-21 2014-04-23 Novartis AG mTOR inhibitors in the treatment of endocrine tumors
GB0605120D0 (en) 2006-03-14 2006-04-26 Novartis Ag Organic Compounds
EP1994412A2 (en) 2006-03-31 2008-11-26 Brystol-Myers Squibb Company Biomarkers and methods for determining sensitivity to microtubule-stabilizing agents
CN102671196B (en) 2006-04-05 2014-12-03 诺华股份有限公司 Combinations of therapeutic agents for treating cancer
EP2606890A1 (en) 2006-04-05 2013-06-26 Novartis AG Combinations comprising BCR-ABL/C-KIT/PDGF-R TK inhibitors for treating cancer
AU2007247112B2 (en) 2006-05-09 2010-08-26 Novartis Ag Combination comprising an iron chelator and an anti-neoplastic agent and use thereof
CN101516885A (en) 2006-09-29 2009-08-26 诺瓦提斯公司 Pyrazolopyrimidines as PI3K lipid kinase inhibitors
JP2010511408A (en) 2006-12-04 2010-04-15 ザ・ボード・オブ・トラスティーズ・オブ・ザ・ユニバーシティ・オブ・イリノイ Compositions and methods for treating cancer with CpG rich DNA and cupredoxins
CA2677803A1 (en) 2007-02-08 2008-08-14 The Board Of Trustees Of The University Of Illinois Compositions and methods to prevent cancer with cupredoxins
BRPI0807812A2 (en) 2007-02-15 2020-06-23 Novartis Ag COMBINATIONS OF LBH589 WITH OTHER THERAPEUTIC AGENTS TO TREAT CANCER
US8222424B2 (en) 2008-03-24 2012-07-17 Novartis Ag Arylsulfonamide-based matrix metalloprotease inhibitors
CA2719477C (en) 2008-03-26 2016-11-08 Novartis Ag Hydroxamate-based inhibitors of deacetylases b
CN101362784A (en) * 2008-10-06 2009-02-11 山东大学 Ebomycin glycosides compounds, composition using the same as activity component and use thereof
WO2010083617A1 (en) 2009-01-21 2010-07-29 Oncalis Ag Pyrazolopyrimidines as protein kinase inhibitors
WO2010088335A1 (en) 2009-01-29 2010-08-05 Novartis Ag Substituted benzimidazoles for the treatment of astrocytomas
JO2892B1 (en) 2009-06-26 2015-09-15 نوفارتيس ايه جي Inhibitors of cyp 17
US8389526B2 (en) 2009-08-07 2013-03-05 Novartis Ag 3-heteroarylmethyl-imidazo[1,2-b]pyridazin-6-yl derivatives
WO2011018454A1 (en) 2009-08-12 2011-02-17 Novartis Ag Heterocyclic hydrazone compounds and their uses to treat cancer and inflammation
BR112012008061A2 (en) 2009-08-20 2016-03-01 Novartis Ag heterocyclic oxime compounds
WO2011023677A1 (en) 2009-08-26 2011-03-03 Novartis Ag Tetra-substituted heteroaryl compounds and their use as mdm2 and/or mdm4 modulators
ES2487628T3 (en) 2009-11-04 2014-08-22 Novartis Ag Heterocyclic sulfonamide derivatives useful as MEK inhibitors
CN102648188A (en) 2009-12-08 2012-08-22 诺瓦提斯公司 Heterocyclic sulfonamide derivatives
US8440693B2 (en) 2009-12-22 2013-05-14 Novartis Ag Substituted isoquinolinones and quinazolinones
CU24130B1 (en) 2009-12-22 2015-09-29 Novartis Ag ISOQUINOLINONES AND REPLACED QUINAZOLINONES
EP3566719A1 (en) 2010-05-18 2019-11-13 Cerulean Pharma Inc. Compositions and methods for treatment of autoimmune and other diseases
UA112517C2 (en) 2010-07-06 2016-09-26 Новартіс Аг TETRAHYDROPYRIDOPYRIMIDINE DERIVATIVES
JP2013537210A (en) 2010-09-16 2013-09-30 ノバルティス アーゲー 17α-hydroxylase / C17,20-lyase inhibitor
BR112013018534B1 (en) 2011-01-20 2021-04-06 Board Of Regents, The University Of Texas System CONTRAST AGENT, ITS PREPARATION METHODS, AND COMBINATION PRODUCT
US20130324526A1 (en) 2011-02-10 2013-12-05 Novartis Ag [1,2,4] triazolo [4,3-b] pyridazine compounds as inhibitors of the c-met tyrosine kinase
JP6002210B2 (en) 2011-04-28 2016-10-05 ノバルティス アーゲー 17α-hydroxylase / C17,20-lyase inhibitor
CA2838029A1 (en) 2011-06-09 2012-12-13 Novartis Ag Heterocyclic sulfonamide derivatives
KR102087854B1 (en) 2011-06-10 2020-03-12 메르사나 테라퓨틱스, 인코포레이티드 Protein-Polymer-Drug Conjugates
WO2012175487A1 (en) 2011-06-20 2012-12-27 Novartis Ag Cyclohexyl isoquinolinone compounds
EP2721008B1 (en) 2011-06-20 2015-04-29 Novartis AG Hydroxy substituted isoquinolinone derivatives as p53 (mdm2 or mdm4) inhibitors
CA2840315A1 (en) 2011-06-27 2013-01-03 Novartis Ag Solid forms and salts of tetrahydro-pyrido-pyrimidine derivatives
CN102863474A (en) 2011-07-09 2013-01-09 陈小平 Platinum compounds for treating cell proliferative diseases and preparation method and application thereof
US9062045B2 (en) 2011-09-15 2015-06-23 Novartis Ag Triazolopyridine compounds
CN102993239A (en) 2011-09-19 2013-03-27 陈小平 Platinum compound of succinic acid derivative with leaving group containing amino or alkylamino
WO2013080141A1 (en) 2011-11-29 2013-06-06 Novartis Ag Pyrazolopyrrolidine compounds
SI2794600T1 (en) 2011-12-22 2018-03-30 Novartis Ag 2,3-Dihydro-benzo(1,4)oxazine derivatives and related compounds as phosphoinositide-3 kinase (PI3K) inhibitors for the treatment of e.g. rheumatoid arthritis
US20150148377A1 (en) 2011-12-22 2015-05-28 Novartis Ag Quinoline Derivatives
EA201491264A1 (en) 2011-12-23 2014-11-28 Новартис Аг COMPOUNDS FOR INHIBITING THE INTERACTION OF BCL-2 WITH PARTNERS ON BINDING
CA2859876A1 (en) 2011-12-23 2013-06-27 Novartis Ag Compounds for inhibiting the interaction of bcl2 with binding partners
CN104136429A (en) 2011-12-23 2014-11-05 诺华股份有限公司 Compounds for inhibiting the interaction of bcl2 with binding partners
WO2013096049A1 (en) 2011-12-23 2013-06-27 Novartis Ag Compounds for inhibiting the interaction of bcl2 with binding partners
BR112014015442A8 (en) 2011-12-23 2017-07-04 Novartis Ag compounds and compositions for inhibiting bcl2 interaction with binding partners
KR101372563B1 (en) 2011-12-26 2014-03-14 주식회사 삼양바이오팜 Method of isolating and purifying epothilone A and B from epothilone containing material
US8815926B2 (en) 2012-01-26 2014-08-26 Novartis Ag Substituted pyrrolo[3,4-D]imidazoles for the treatment of MDM2/4 mediated diseases
MX2014013376A (en) 2012-05-15 2015-08-14 Novartis Ag Benzamide derivatives for inhibiting the activity of abl1, abl2 and bcr-abl1.
MX2014013373A (en) 2012-05-15 2015-08-14 Novartis Ag Benzamide derivatives for inhibiting the activity of abl1, abl2 and bcr-abl1.
MX357305B (en) 2012-05-15 2018-07-04 Novartis Ag Compounds and compositions for inhibiting the activity of abl1, abl2 and bcr-abl1.
PT2861579T (en) 2012-05-15 2018-04-27 Novartis Ag Benzamide derivatives for inhibiting the activity of abl1, abl2 and bcr-abl1
JP6171003B2 (en) 2012-05-24 2017-07-26 ノバルティス アーゲー Pyrrolopyrrolidinone compounds
WO2013188763A1 (en) 2012-06-15 2013-12-19 The Brigham And Women's Hospital, Inc. Compositions for treating cancer and methods for making the same
MD20150043A2 (en) 2012-10-02 2015-08-31 Epitherapeutics Aps Inhibitors of histone demethylases
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
TW201422625A (en) 2012-11-26 2014-06-16 Novartis Ag Solid form of dihydro-pyrido-oxazine derivative
AU2013359506B2 (en) 2012-12-10 2018-05-24 Mersana Therapeutics, Inc. Protein-polymer-drug conjugates
WO2014093640A1 (en) 2012-12-12 2014-06-19 Mersana Therapeutics,Inc. Hydroxy-polmer-drug-protein conjugates
JO3464B1 (en) 2013-01-15 2020-07-05 Astellas Pharma Europe Ltd Compositions of Tiacumicin Compounds
EP2948453B1 (en) 2013-01-22 2017-08-02 Novartis AG Pyrazolo[3,4-d]pyrimidinone compounds as inhibitors of the p53/mdm2 interaction
EP2948451B1 (en) 2013-01-22 2017-07-12 Novartis AG Substituted purinone compounds
WO2014128612A1 (en) 2013-02-20 2014-08-28 Novartis Ag Quinazolin-4-one derivatives
KR102229992B1 (en) 2013-02-27 2021-03-19 에피테라퓨틱스 에이피에스 Inhibitors of histone demethylases
US20150018376A1 (en) 2013-05-17 2015-01-15 Novartis Ag Pyrimidin-4-yl)oxy)-1h-indole-1-carboxamide derivatives and use thereof
EP3007692A1 (en) 2013-06-11 2016-04-20 Bayer Pharma Aktiengesellschaft Combinations for the treatment of cancer comprising a mps-1 kinase inhibitor and a mitotic inhibitor
UY35675A (en) 2013-07-24 2015-02-27 Novartis Ag SUBSTITUTED DERIVATIVES OF QUINAZOLIN-4-ONA
US9227969B2 (en) 2013-08-14 2016-01-05 Novartis Ag Compounds and compositions as inhibitors of MEK
WO2015022664A1 (en) 2013-08-14 2015-02-19 Novartis Ag Compounds and compositions as inhibitors of mek
WO2015022663A1 (en) 2013-08-14 2015-02-19 Novartis Ag Compounds and compositions as inhibitors of mek
KR20160058889A (en) 2013-09-22 2016-05-25 칼리토르 사이언시즈, 엘엘씨 Substituted aminopyrimidine compounds and methods of use
PL3054992T3 (en) 2013-10-11 2020-01-31 Asana Biosciences, Llc Protein-polymer-drug conjugates
CA2926586C (en) 2013-10-11 2020-04-07 Mersana Therapeutics, Inc. Polymeric scaffold based on phf for targeted drug delivery
JP6517319B2 (en) 2014-03-28 2019-05-22 キャリター・サイエンシーズ・リミテッド・ライアビリティ・カンパニーＣａｌｉｔｏｒ Ｓｃｉｅｎｃｅｓ， Ｌｌｃ Substituted heteroaryl compounds and methods of use
TW201625535A (en) 2014-03-31 2016-07-16 Epitherapeutics Aps Inhibitors of histone demethylases
AU2015241198A1 (en) 2014-04-03 2016-11-17 Invictus Oncology Pvt. Ltd. Supramolecular combinatorial therapeutics
CA2957947A1 (en) 2014-08-27 2016-03-03 Gilead Sciences, Inc. Compounds and methods for inhibiting histone demethylases
JP2018527362A (en) 2015-09-11 2018-09-20 サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． Substituted heteroaryl compounds and methods of use
EP3474901A1 (en) 2016-06-27 2019-05-01 Tagworks Pharmaceuticals B.V. Cleavable tetrazine used in bio-orthogonal drug activation
US11135307B2 (en) 2016-11-23 2021-10-05 Mersana Therapeutics, Inc. Peptide-containing linkers for antibody-drug conjugates
WO2018237262A1 (en) 2017-06-22 2018-12-27 Mersana Therapeutics, Inc. Methods of producing drug-carrying polymer scaffolds and protein-polymer-drug conjugates
US10683297B2 (en) 2017-11-19 2020-06-16 Calitor Sciences, Llc Substituted heteroaryl compounds and methods of use
AU2019209960B2 (en) 2018-01-20 2023-11-23 Sunshine Lake Pharma Co., Ltd. Substituted aminopyrimidine compounds and methods of use
EP4382167A3 (en) 2018-05-04 2024-08-28 Tagworks Pharmaceuticals B.V. Compounds comprising a linker for increasing transcyclooctene stability
US20210299286A1 (en) 2018-05-04 2021-09-30 Tagworks Pharmaceuticals B.V. Tetrazines for high click conjugation yield in vivo and high click release yield
KR20210084546A (en) 2018-10-29 2021-07-07 메르사나 테라퓨틱스, 인코포레이티드 Cysteine Engineered Antibody-Drug Conjugates with Peptide-Containing Linkers
FR3087650B1 (en) 2018-10-31 2021-01-29 Bio Even FLAVINE ADENINE DINUCLEOTIDE (FAD) FOR USE FOR THE PREVENTION AND / OR TREATMENT OF CANCER
IL289094A (en) 2019-06-17 2022-02-01 Tagworks Pharmaceuticals B V Tetrazines for high click release speed and yield
AU2020297253B2 (en) 2019-06-17 2024-05-23 Tagworks Pharmaceuticals B.V. Compounds for fast and efficient click release
CA3230774A1 (en) 2021-09-06 2023-03-09 Veraxa Biotech Gmbh Novel aminoacyl-trna synthetase variants for genetic code expansion in eukaryotes
CA3238627A1 (en) 2021-11-25 2023-06-01 Christine Kohler Improved antibody-payload conjugates (apcs) prepared by site-specific conjugation utilizing genetic code expansion
EP4186529A1 (en) 2021-11-25 2023-05-31 Veraxa Biotech GmbH Improved antibody-payload conjugates (apcs) prepared by site-specific conjugation utilizing genetic code expansion
CN118574641A (en) 2021-12-08 2024-08-30 欧洲分子生物学实验室 Hydrophilic tetrazine functionalized supports for preparing targeted conjugates
EP4372000A3 (en) 2022-02-15 2024-07-17 Tagworks Pharmaceuticals B.V. Masked il12 protein
WO2024013723A1 (en) 2022-07-15 2024-01-18 Pheon Therapeutics Ltd Antibody drug conjugates that bind cdcp1 and uses thereof
WO2024080872A1 (en) 2022-10-12 2024-04-18 Tagworks Pharmaceuticals B.V. Strained bicyclononenes
WO2024153789A1 (en) 2023-01-20 2024-07-25 Basf Se Stabilized biopolymer composition, their manufacture and use
WO2024191293A1 (en) 2023-03-10 2024-09-19 Tagworks Pharmaceuticals B.V. Trans-cyclooctene with improved t-linker

Citations (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5969145A (en) * 1996-08-30 1999-10-19 Novartis Ag Process for the production of epothilones and intermediate products within the process
US6194181B1 (en) * 1998-02-19 2001-02-27 Novartis Ag Fermentative preparation process for and crystal forms of cytostatics
US6204388B1 (en) * 1996-12-03 2001-03-20 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US6211412B1 (en) * 1999-03-29 2001-04-03 The University Of Kansas Synthesis of epothilones
US6252094B1 (en) * 1994-01-11 2001-06-26 The Scripps Research Institute Chemical switching of taxo-diterpenoids between low solubility active forms and high solubility inactive forms
US6262094B1 (en) * 1999-02-22 2001-07-17 Bristol-Myers Squibb Company C-21 modified epothilones
US6288237B1 (en) * 1995-11-17 2001-09-11 Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) Epothilons C and D, preparation and compositions
US6359140B1 (en) * 1997-02-25 2002-03-19 Gesellschaft Fuer Biotechnologische Forschung Mbh (Gbf) Epothilones with modified side chain
US6380394B1 (en) * 1996-12-13 2002-04-30 The Scripps Research Institute Epothilone analogs
US6410301B1 (en) * 1998-11-20 2002-06-25 Kosan Biosciences, Inc. Myxococcus host cells for the production of epothilones
US6441186B1 (en) * 1996-12-13 2002-08-27 The Scripps Research Institute Epothilone analogs
US6489314B1 (en) * 2001-04-03 2002-12-03 Kosan Biosciences, Inc. Epothilone derivatives and methods for making and using the same
US6537988B2 (en) * 2000-03-27 2003-03-25 Bristol-Myers Squibb Company Synergistic methods and compositions for treating cancer
US6589968B2 (en) * 2001-02-13 2003-07-08 Kosan Biosciences, Inc. Epothilone compounds and methods for making and using the same
US6596875B2 (en) * 2000-02-07 2003-07-22 James David White Method for synthesizing epothilones and epothilone analogs
US6605599B1 (en) * 1997-07-08 2003-08-12 Bristol-Myers Squibb Company Epothilone derivatives
US6624310B1 (en) * 1998-06-18 2003-09-23 Gesellschaft Fuer Biotechnologische Forschung, Mbh (Gbf) Epothilone minor constituents
US20030187039A1 (en) * 2002-02-15 2003-10-02 Denis Favreau Method of preparation of 21-amino epothilone derivatives
US6656961B2 (en) * 1996-12-03 2003-12-02 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US6660758B1 (en) * 1996-12-13 2003-12-09 The Scripps Research Institute Epothilone analogs
US6730803B2 (en) * 2001-09-28 2004-05-04 Sumika Fine Chemicals Co., Ltd. Synthetic intermediate for epothilone derivative and production method thereof
US20040132146A1 (en) * 2002-09-23 2004-07-08 Daniel Benigni Methods for the preparation, isolation and purification of epothilone B, and x-ray crystal structures of epothilone B
US6780620B1 (en) * 1998-12-23 2004-08-24 Bristol-Myers Squibb Company Microbial transformation method for the preparation of an epothilone
US6884608B2 (en) * 2001-12-26 2005-04-26 Bristol-Myers Squibb Company Compositions and methods for hydroxylating epothilones
US6906188B2 (en) * 2001-04-30 2005-06-14 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
US6921769B2 (en) * 2002-08-23 2005-07-26 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US7067544B2 (en) * 1996-11-18 2006-06-27 Geselllschaft Fuer Biotechnologishce Forschung Mbh (Gbf) Epothilones C, D, E and F, preparation and compositions

Family Cites Families (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0358606A3 (en) 1988-09-09 1990-10-31 Gesellschaft für Biotechnologische Forschung mbH (GBF) Microbiological method for the preparation of agrochemically useful macrocyclic lactone derivatives with a microbicidal activity
GB8909737D0 (en) 1989-04-27 1989-06-14 Shell Int Research Thiazole derivatives
DE4138042C2 (en) * 1991-11-19 1993-10-14 Biotechnolog Forschung Gmbh Epothilones, their production processes and agents containing these compounds
US5665767A (en) 1993-03-05 1997-09-09 Hexal Pharma Gmbh Crystalline cyclodextrin complexes of ranitidine hydrochloride, process for their preparation and pharmaceutical compositions containing the same
DE19639456A1 (en) 1996-09-25 1998-03-26 Biotechnolog Forschung Gmbh New epothilone derivatives
DE19542986A1 (en) * 1995-11-17 1997-05-22 Biotechnolog Forschung Gmbh New epothilone derivatives useful as cytostatics
NZ334821A (en) 1996-08-30 2000-12-22 Novartis Ag Method for producing epothilones
DE19645361A1 (en) 1996-08-30 1998-04-30 Ciba Geigy Ag Production of epothilone compounds with taxol-like activity
DE19645362A1 (en) 1996-10-28 1998-04-30 Ciba Geigy Ag Production of epothilone compounds with taxol-like activity
DE19636343C1 (en) 1996-08-30 1997-10-23 Schering Ag New (di:methyl)-dioxanyl-methyl-pentanone and related compounds
US6515016B2 (en) 1996-12-02 2003-02-04 Angiotech Pharmaceuticals, Inc. Composition and methods of paclitaxel for treating psoriasis
DE19701758A1 (en) 1997-01-20 1998-07-23 Wessjohann Ludgar A Dr New beta-keto-alcohol derivatives
US5828449A (en) 1997-02-26 1998-10-27 Acuity Imaging, Llc Ring illumination reflective elements on a generally planar surface
DE19713970B4 (en) 1997-04-04 2006-08-31 R&D-Biopharmaceuticals Gmbh Epothilone Synthesis Building Blocks II - Prenyl Derivatives
CA2286610C (en) 1997-04-18 2007-03-13 Studiengesellschaft Kohle Mbh Selective olefin metathesis of bifunctional or polyfunctional substrates in compressed carbon dioxide as reaction medium
DE19821954A1 (en) 1997-05-15 1998-11-19 Biotechnolog Forschung Gmbh Preparation of epothilone derivatives
DE19720312A1 (en) 1997-05-15 1998-11-19 Hoechst Ag Preparation with increased in vivo tolerance
DE19726627A1 (en) 1997-06-17 1998-12-24 Schering Ag New intermediates for epothilone
DE19833750A1 (en) 1997-07-16 1999-02-25 Schering Ag New thiazolyl-alkadienol and -epoxide derivatives
ES2290993T3 (en) 1997-08-09 2008-02-16 Bayer Schering Pharma Aktiengesellschaft NEW DERIVATIVES OF EPOTILONE, PROCESS FOR ITS PRODUCTION AND ITS PHARMACEUTICAL USE.
HUP0101564A3 (en) 1998-02-05 2002-06-28 Novartis Ag Compositions containing epothilone
FR2775187B1 (en) 1998-02-25 2003-02-21 Novartis Ag USE OF EPOTHILONE B FOR THE MANUFACTURE OF AN ANTIPROLIFERATIVE PHARMACEUTICAL PREPARATION AND A COMPOSITION COMPRISING EPOTHILONE B AS AN IN VIVO ANTIPROLIFERATIVE AGENT
JP2002504540A (en) 1998-02-25 2002-02-12 スローン−ケッタリング インスティトゥート フォア キャンサー リサーチ Synthesis of epothilone, its intermediates and analogs
AU5036999A (en) 1998-06-30 2000-01-17 Schering Aktiengesellschaft Epothilon derivatives, their preparation process, intermediate products and their pharmaceutical use
KR100716272B1 (en) 1998-11-20 2007-05-09 코산 바이오사이언시즈, 인코포레이티드 Recombinant methods and materials for producing epothilone and epothilone derivatives
ATE248175T1 (en) 1998-12-22 2003-09-15 Novartis Pharma Gmbh EPOTHILONE DERIVATIVES AND THEIR USE AS ANTI-TUMOR AGENTS
CZ20012951A3 (en) 1999-02-18 2001-11-14 Schering Aktiengesellschaft Epothilone 16-halosubstituted derivatives, process of their preparation and pharmaceutical use thereof
AR023792A1 (en) 1999-04-30 2002-09-04 Bayer Schering Pharma Ag DERIVATIVES 6-ALQUENILO- AND 6-ALQUINILO-EPOTILONA, THE PROCEDURES TO PREPARE THEM AND THEIR USE IN PHARMACEUTICAL PRODUCTS

Patent Citations (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6252094B1 (en) * 1994-01-11 2001-06-26 The Scripps Research Institute Chemical switching of taxo-diterpenoids between low solubility active forms and high solubility inactive forms
US6613912B2 (en) * 1995-11-17 2003-09-02 Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) Epothilons C and D, preparation and compositions
US20040087634A1 (en) * 1995-11-17 2004-05-06 Gerhard Hoefle Epothilons C and D, preparation and compositions
US6288237B1 (en) * 1995-11-17 2001-09-11 Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) Epothilons C and D, preparation and compositions
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
US5969145A (en) * 1996-08-30 1999-10-19 Novartis Ag Process for the production of epothilones and intermediate products within the process
US7067544B2 (en) * 1996-11-18 2006-06-27 Geselllschaft Fuer Biotechnologishce Forschung Mbh (Gbf) Epothilones C, D, E and F, preparation and compositions
US6204388B1 (en) * 1996-12-03 2001-03-20 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US6316630B1 (en) * 1996-12-03 2001-11-13 Sloan Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US6656961B2 (en) * 1996-12-03 2003-12-02 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US20040127432A1 (en) * 1996-12-13 2004-07-01 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
US6380394B1 (en) * 1996-12-13 2002-04-30 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
US6605599B1 (en) * 1997-07-08 2003-08-12 Bristol-Myers Squibb Company Epothilone derivatives
US6194181B1 (en) * 1998-02-19 2001-02-27 Novartis Ag Fermentative preparation process for and crystal forms of cytostatics
US7235669B2 (en) * 1998-06-18 2007-06-26 Helmholtz-Zentrum Fur Infektionsforschung, Gmbh Epothilone side components
US6624310B1 (en) * 1998-06-18 2003-09-23 Gesellschaft Fuer Biotechnologische Forschung, Mbh (Gbf) Epothilone minor constituents
US6531497B1 (en) * 1998-06-22 2003-03-11 The Scripps Research Institute Epothilone derivatives and their synthesis and use
US6410301B1 (en) * 1998-11-20 2002-06-25 Kosan Biosciences, Inc. Myxococcus host cells for the production of epothilones
US20040176429A1 (en) * 1998-12-23 2004-09-09 Wenying Li 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
US6262094B1 (en) * 1999-02-22 2001-07-17 Bristol-Myers Squibb Company C-21 modified epothilones
US6211412B1 (en) * 1999-03-29 2001-04-03 The University Of Kansas Synthesis of epothilones
US6596875B2 (en) * 2000-02-07 2003-07-22 James David White Method for synthesizing epothilones and epothilone analogs
US6537988B2 (en) * 2000-03-27 2003-03-25 Bristol-Myers Squibb Company Synergistic methods and compositions for treating cancer
US6589968B2 (en) * 2001-02-13 2003-07-08 Kosan Biosciences, Inc. Epothilone compounds and methods for making and using the same
US6489314B1 (en) * 2001-04-03 2002-12-03 Kosan Biosciences, Inc. Epothilone derivatives and methods for making and using the same
US6906188B2 (en) * 2001-04-30 2005-06-14 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
US6730803B2 (en) * 2001-09-28 2004-05-04 Sumika Fine Chemicals Co., Ltd. Synthetic intermediate for epothilone derivative and production method thereof
US6884608B2 (en) * 2001-12-26 2005-04-26 Bristol-Myers Squibb Company Compositions and methods for hydroxylating epothilones
US20030187039A1 (en) * 2002-02-15 2003-10-02 Denis Favreau Method of preparation of 21-amino epothilone derivatives
US6921769B2 (en) * 2002-08-23 2005-07-26 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US20040132146A1 (en) * 2002-09-23 2004-07-08 Daniel Benigni Methods for the preparation, isolation and purification of epothilone B, and x-ray crystal structures of epothilone B

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110136185A1 (en) * 1996-11-18 2011-06-09 Helmholtz Center for Infection Research Epothilones c, d, e, and f, preparation and compositions
US8076490B2 (en) 1996-11-18 2011-12-13 Helmholtz-Zentrum Fuer Infektionsforschung Gmbh Epothilones C, D, E, and F, preparation and compositions

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