CN1237970A - Epothilone C、D、E和F,其制备方法,以及作为细胞抑制剂和植物保护剂的应用 - Google Patents

Epothilone C、D、E和F,其制备方法,以及作为细胞抑制剂和植物保护剂的应用 Download PDF

Info

Publication number
CN1237970A
CN1237970A CN97199814A CN97199814A CN1237970A CN 1237970 A CN1237970 A CN 1237970A CN 97199814 A CN97199814 A CN 97199814A CN 97199814 A CN97199814 A CN 97199814A CN 1237970 A CN1237970 A CN 1237970A
Authority
CN
China
Prior art keywords
epothilone
culture
bio
polymeric adsorbent
mentioned
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN97199814A
Other languages
English (en)
Other versions
CN1196698C (zh
Inventor
汉斯·赖兴巴赫
格哈德·赫夫勒
克劳斯·格特
海因里希·施泰因梅茨
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
Original Assignee
Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26031383&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CN1237970(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Helmholtz Zentrum fuer Infektionsforschung HZI GmbH filed Critical Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
Publication of CN1237970A publication Critical patent/CN1237970A/zh
Application granted granted Critical
Publication of CN1196698C publication Critical patent/CN1196698C/zh
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • 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

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biotechnology (AREA)
  • Environmental Sciences (AREA)
  • Plant Pathology (AREA)
  • Dentistry (AREA)
  • Microbiology (AREA)
  • Agronomy & Crop Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Silicon Polymers (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Steroid Compounds (AREA)
  • Epoxy Compounds (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

本发明涉及epothilone，特别是涉及式(Ⅰ)之epothilone C(R＝氢)和epothilone D(R＝甲基)以及式(Ⅱ)之epothilone E(R＝氢)和epothiloneF(R＝甲基)。本发明还涉及它们的制备方法，以及在制备治疗剂和植物保护剂中的应用，所述治疗剂特别是细胞抑制剂。

Description

Epothilone C、D、E和F，其制备方法， 以及作为细胞抑制剂和植物保护剂的应用
本发明涉及epothilone C、D、E和F，其制备方法，以及在制备治疗性组合物和用于植物保护之组合物中的应用。Epothilone C和D
根据一个实施方案，本发明涉及Epothilone(C和D)，它们是如下得到的：
(a)在吸附树脂存在下以本领域已知的方式培养Sorangiumcellulosum DSM 6773，
(b)从培养物中取出吸附树脂，并用水/甲醇混合物洗涤，
(c)用甲醇淋洗经洗涤的吸附树脂，然后浓缩洗脱液，得到粗提物，
(d)用乙酸乙酯提取上述得到的浓缩物，浓缩提取物，并在甲醇和己烷之间分配，
(e)浓缩甲醇相，得到残液，该浓缩物在Sephadex柱上进行分步提取，
(f)得到包含所用微生物之代谢产物的提取部分，
(g)在C18反相柱上用甲醇/水混合物对上述得到的部分进行色谱分离，并顺序得到：
-包含Epothilone A的第一部分，
-包含Epothilone B的第二部分，
-包含第一种其它Epothilone的第三部分，
-包含第二种其它Epothilone的第四部分；
然后分离
(h1)上述第三部分中的第一种其它Epothilone；和
(h2)上述第四部分中的第二种其它Epothilone。
本发明还涉及经验式为C26H39NO5S的Epothilone(C)，其特征在于具有如表1所示的1H-和13C-NMR光谱。
本发明还涉及以下式的Epothilone C：
Figure A9719981400091
Epothilone C:R=H。
本发明还涉及经验式为C27H41NO5S的Epothilone(D)，其特征在于具有如表1所示的1H-和13C-NMR光谱。
本发明还涉及以下式的Epothilone D：
Figure A9719981400101
Epothilone D:R=CH3。
Epothilone C和D可用于制备下式1的化合物，其衍生化过程可参考WO-A-97/19086中描述的衍生法。
Figure A9719981400102
在上式1中：
R=H,C1-4-烷基；
R1、R2、R3、R4、R5=H,C1-6-烷基，C1-6-酰基苄氧基，C1-4-三烷基甲硅烷基，苄基，苯基，C1-6-烷氧基，C6-烷基-、羟基-和卤素-取代的苄基或苯基；
R1-R5基团中的两个也可合并形成基团-(CH2)n-(其中n=1-6)，基团中包含的烷基或酰基是直链或支链基团；
Y和Z可相同或不同，分别是氢，卤素，如F、Cl、Br或I，假卤素，如-NCO、-NCS、或-N3,OH,O-(C1-6)-酰基，O-(C1-6)-烷基，O-苄氧基；Y和Z也可是环氧化物中的O原子，但不要求保护epothilone A和B，或者形成C=C双键中的一个C-C键。
因此，12,13-双键可选择性地进行
-氢化，例如经催化或用二亚胺，所得到的式1化合物中Y=Z=H；或者
-环氧化，例如用二甲基二环氧乙烷或过酸，得到的式1化合物中Y与Z=-O-，或者
-转化为二卤化物、二假卤化物或二叠氮化物，得到的式1化合物中Y和Z=卤素、假卤素或N3。EpothiloneE和F
根据另一个实施方案，本发明涉及Epothilone A的生物转化体，该生物转化体是如下得到的：
(a)在吸附树脂存在下按本领域已知的方式培养Sorangiumcellulosum DSM 6773，取出吸附树脂，如果需要，用Epothilone A的甲醇溶液处理全部或部分经分离的培养物；
(b)用Epothilone A处理的培养物进行温育，然后用吸附树脂处理；
(c)从培养物中分离吸附树脂，用甲醇淋洗，浓缩洗脱液，得到粗提物；
(d)在乙酸乙酯和水之间分配上述粗提物，分离出乙酸乙酯相，并浓缩至油状；
(e)在以下条件对上述油状物进行反相色谱分离：
柱材料：Nucleosil 100C-18 7μm
柱尺寸：250×16mm
洗脱剂：甲醇/水=60∶40
流速：10 ml/min
并分离出含有生物转化体的部分，该部分可在254nm处通过UV消光来检测，其Rt值为20min，然后分离所述生物转化体。
本发明还涉及该类型之Epothilone A的生物转化体，其是在步骤(a)中培养物培养3或4或更多天时分离该培养物而得到的。
本发明还涉及该类型之Epothilone A的生物转化体，其是在步骤(b)中进行温育1或2或更多天而得到的。
本发明还涉及经验式为C26N39NO7S的化合物，其特征在于具有以下1H-NMR光谱(300MHz,CDCl3):δ=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)。
本发明还涉及下式的化合物(Epothilone E)：Epothilone E:R=H。
根据再一个实施方案，本发明涉及Epothilone B的生物转化体，该生物转化体是如下得到的：
(a)在吸附树脂存在下按本领域已知的方式培养Sorangiumcellulosum DSM 6773，与吸附树脂分离，如果需要，用Epothilone B的甲醇溶液处理全部或部分经分离的培养物；
(b)用Epothilone B处理的培养物进行温育，然后用吸附树脂处理；
(c)从培养物中分离吸附树脂，用甲醇淋洗，浓缩洗脱液，得到粗提物；
(d)在乙酸乙酯和水之间分配上述粗提物，分出乙酸乙酯相，并浓缩至油状；
(e)在以下条件对上述油状物进行反相色谱分离：
柱材料：Nucleosil 100C-18 7μm
柱尺寸：250×16mm
洗脱剂：甲醇/水=60∶40
流速：10ml/min
并分离出含有生物转化体的部分，该部分可在254nm处通过UV消光来检测，其Rt值为24.5min，然后分离所述生物转化体。
本发明还涉及该类型之Epothilone B的生物转化体，其是在步骤(a)中培养物培养3或4或更多天时分离该培养物而得到的。
本发明还涉及该类型之Epothilone B的生物转化体，其是在步骤(b)中进行温育1或2或更多天而得到的。
本发明还涉及经验式为C27N41NO7S的化合物，其特征在于具有以下1H-NMR光谱(300MHz,CDCl3):δ=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)。
本发明还涉及下式的化合物(Epothilone F)：Epothilone F:R=CH3。制备和组合物
根据本发明的化合物或epothilone可通过上述方法得到。
本发明还涉及用于在农业、林业和/或园艺中保护植物的组合物，该组合物由上述epothilone C、D、E和F中的一种或多种组成或者由一种或多种上述epothilone以及一种或多种常规载体和/或稀释剂组成。
本发明最后涉及治疗性组合物，该组合物由一种或多种上述化合物或者一种或多种上述化合物与一种或多种常规载体和/或稀释剂组成。具体而言，这些组合物具有细胞毒性活性和/或产生免疫抑制作用和/或用于控制恶性肿瘤，它们特别优选用作细胞抑制剂。
以下将通过一些具体实施例的描述来更为详细地阐明和描述本发明。
                       实施例实施例1：Epothilone C和DA、根据epothilone基础专利DE-B-4138042制备菌株和培养条件B、用DSM6773进行制备
如基础专利所述进行75升培养物的培养，并用于制备发酵罐的接种，该发酵罐中有700升制备培养基，其由0.8％淀粉、0.2％葡萄糖、0.2％大豆粉、0.2％酵母浸膏、0.1％CaCl2·2H2O、O.1％MgSO4·7H2O、8mg/l的Fe-EDTA组成，其pH=7.4，以及任选的15升Amberlite XAD-16吸附树脂。发酵在30℃下持续7-10天，通气量为0.1 NL/m3。控制旋转速度，使pO2保持在30％。C、分离
使用0.7m2、100目工艺过滤器从培养物中分离吸附树脂，用3倍床体积的水/甲醇2∶1洗涤，由此除去极性的伴随物质。用4倍床体积的甲醇淋洗，得到粗提物，真空蒸发该粗提物，直至出现水相。用相同体积的乙酸乙酯提取该物质三次。蒸发有机相，得到240g的粗提物，在甲醇和己烷之间分配该粗提物，以分离除去亲脂性伴随物质。真空蒸发，从甲醇相中得到180g残液。该残液在Sephadex LH-20(柱20×100cm,20ml/min的甲醇)上分步提取，得到三个部分。Epothilone包含在总共72g的部分中，其洗脱保留时间为240-300min。为分离epothilone，在Lichrosorb RP-18(15μm，柱10×40cm，洗脱剂180ml/min甲醇/水65∶35)上将所述部分色谱分离为三个部分。在epothilone A和B后，洗脱出Rt=90-95min的epothilone C和Rt=100-110min的epothilone D，真空蒸发后分别得到0.3g的无色油状物。D、物理性质
Figure A9719981400161
Epothilone C:R=HEpothilone C:R=CH3Epothilone C
C26H39NO5S(477)
ESI-MS(正离子)：478.5[M+H]+
1H和13C见NMR表
TLC:Rf=0.82
TLC铝箔60 F 254 Merck，洗脱剂：二氯甲烷/甲醇=9∶1
检测：254nm处的UV消光。用香草醛-硫酸试剂喷雾，加热至120℃时为兰灰色。
HPLC:Rt=11.5min
柱：Nucleosil 100C-18 7μm,125×4mm
洗脱剂：甲醇/水=65∶35
流速：1ml/min
检测：二极管阵列Epothilone D
C27H41NO5S(491)
ESI-MS(正离子)：492.5[M+H]+
1H和13C见NMR表
TLC:Rf=0.82
TLC铝箔60 F 254 Merck，洗脱剂：二氯甲烷/甲醇=9∶1
检测：254nm处的UV消光。用香草醛-硫酸试剂喷雾，加热至120℃时为兰灰色。
HPLC:Rt=15.3min
柱：Nucleosil 100C-18 7μm,125×4mm
洗脱剂：甲醇/水=65∶35
流速：1ml/min
检测：二极管阵列表1:epothilone C和epothilone D在[D6]DMSO中于300MHz时的1H-和13C-NMR数据
                     Epothilone C            Epothilone D
  H原子    δ(ppm)  C原子   δ(ppm)   δ(ppm) C 原子   δ(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
*、**可以互换实施例2：Epothilone A和由epothilone C得到的12,13-二环氧-epothilone A
将50mg epothilone A溶解在1.5ml丙酮中，用1.5ml之0.07mol二甲基二环氧乙烷丙酮溶液处理。在室温下静置6小时后，真空蒸发混合物，用制备性HPLC在硅胶上(洗脱剂：叔丁基甲醚/石油醚/甲醇33∶66∶1)分离残留物。产量：
25mg的epothiloneA,Rt=3.5min(分析HPLC,7μm，柱4×250mm，洗脱剂如上，流速1.5ml/min)，和
20mg的12,13-二环氧-epothilone A,Rt=3.7min,ESI-MS(正离子)：m/e=494[M+H]+,1H-NMR([D4]甲醇)选择信号：δ=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 A9719981400201
12,13-二环氧-epothilone A:R=H实施例3：Epothilone E和F,epothilone A和B的新型生物转化产物制备菌株
GBF在1985年7月从Zambesi河岸的土壤样品中分离出Sorangiumcelluslosum So ce90菌株，并于1991年10月28日保藏在德国微生物保藏中心(German Collection for Microorganisms)中，保藏号为DSM6773。
产物特征和培养条件描述在：Hlfe,G.；N.Bedorf,K.Gerth & HReichenbach:Epothilones，制备方法和包含该物质的组合物(Epothilones,processes for their preparation and compostions containing them)。DE4138042 A1，于1993年5月27日公布。在发酵期间epothilone E和F的形成
如下进行典型的发酵反应：100升生物反应器中装入60升培养基(0.8％淀粉、0.2％葡萄糖、0.2％大豆粉、0.2％酵母浸膏、0.1％CaCl2·2H2O、0.1％MgSO4·7H2O、8mg/l的Fe-EDTA,pH7.4)。另外加入2％的吸附树脂(XAD-16,Rohm & Haas)。对培养基进行高压灭菌(2小时，120℃)。用在相同培养基(另外加入50mM HEPES缓冲液，pH7.4)中于摇瓶(160rpm,30℃)中培养的预培养物10升进行接种。在32℃下进行发酵，搅拌器速度为500rpm，每小时每立方米引入0.2 Nl的空气，通过添加氢氧化钾使pH保持在7.4。发酵持续7-10天。在发酵期间，所形成的epothilone连续地结合在吸附树脂上。在除去培养液(例如用工艺过滤器进行过筛)后，用3倍床体积的水洗涤树脂，然后用4倍床体积的甲醇淋洗。洗脱液浓缩至干，并放入700ml甲醇中。XAD洗脱液的HPLC分析
相对于反应器的起始体积(70升)，将洗脱液浓缩为100∶1。用Hewlett Packard的1090 HPLC装置进行分析。为分离组分，使用Machery-Nagel(Düren)的微孔柱(125/2 Nucleosil 120-5 C18)。使用水/乙腈由开始75∶25至5.5分钟后50∶50的梯度进行洗脱。该比例保持至第7分钟，然后在第10分钟时增加至100％乙腈。
在250nm的波长、4nm的带宽下进行测量。在200-400nm的波长范围中测量二极管阵列光谱。在XAD洗脱液中，发现两种新型物质，Rt分别为5.29和5.91，它们的吸收光谱与epothilone A和B的相同(图1,E相应于A,F相应于B)。这些物质在给定的条件下仅形成非常少的量。Epothilone A和B向epothilone E和F的生物转化
500ml的So ce90培养物，已培养4天，与吸附树脂在一起，用该培养物进行具体的生物转化。250ml该培养物转移至无菌的1升Erlenmeyer烧瓶中，而留下XAD。然后加入总共36mg epothilone A+14mg epothilone B的混合物的甲醇溶液，该烧瓶在振荡架上于30℃、200rpm下温育2天。Epothilone E和F的形成直接由10μl培养物的离心上清液来分析(图2)。仅在有细胞时才发生转化，而且取决于所用细胞的密度和时间。Epothilone A的转化作用动力学见图3。EpothiloneE和F的分离
为分离Epothilone E和F，合并三个生物转化用摇瓶中的物料(见上)，然后与20ml XAD-16振摇1小时。过滤得到XAD，用200ml甲醇淋洗。真空蒸发洗脱液，得到1.7g的粗提物。该粗提物在30ml乙酸乙酯和100ml水之间分配。真空蒸发，从乙酸乙酯相中得到330mg的油状残留物，该残留物在250×20mm的RP-18柱(洗脱剂甲醇/水58∶42,254nm检测)进行5轮色谱分离。产量：epothilone E:50mg
             F:10mgEpothilone E的生物作用
在细胞培养物中，测定生长降低50％时的浓度(IC50)，并与epothilone A进行比较。
细胞株              IC50(ng/ml)
    Epothilone E     Epothilone A
 HeLa.KB-3.1(人)          5          1
鼠成纤维细胞，L929          20          4
Epothilone E
C26H39NO7S(509)
ESI-MS(正离子)：510.3[M+H]+
TLC:Rf=0.58
TLC铝箔60 F 254 Merck，洗脱剂：二氯甲烷/甲醇=9∶1
检测：254nm处的UV消光。用香草醛-硫酸试剂喷雾，加热至120℃时为兰灰色。
HPLC:Rt=5.0min
柱：Nucleosil 100C-18 7μm,250×4mm
洗脱剂：甲醇/水=60∶40
流速：1.2ml/min
检测：二极管阵列
1H-NMR(300MHz,CDCl3):δ=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(正离子)：524.5[M+H]+
TLC:Rf=0.58
TLC铝箔60F 254 Merck，洗脱剂：二氯甲烷/甲醇=9∶1
检测：254nm处的UV消光。用香草醛-硫酸试剂喷雾，加热至120℃时为兰灰色。
HPLC:Rt=5.4min
柱：Nucleosil 100C-18 7μm,250×4mm
洗脱剂：甲醇/水=60∶40
流速：1.2ml/min
检测：二极管阵列
1H-NMR光谱(300MHz,CDCl3):δ=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)。实施例4通过用Sorangium cellulosum So ce90生物转化制备epothilone E和F1)进行生物转化
为进行生物转化，使用Sorangium cellulosum So ce90的培养物，该培养物已在2％XAD 16吸附树脂(Rohm & Haas,Frankfurt/M.)存在下于30℃、160rpm下振摇了4天。培养基具有以下组成(g/升蒸馏水)：马铃薯淀粉(Maizena),8；葡萄糖(Maizena),8；脱脂大豆粉，2；酵母浸膏(Marcor),2；乙二胺四乙酸，铁(Ⅲ)钠盐，0.008；MgSO4·7H2O,1；CaCl2·2H2O,1；HEPES,11.5。在高压灭菌之前，用氢氧化钾将pH调节为7.4。用不锈钢筛网(筛孔宽200μm)过筛，由此从培养物中分离XAD。在10000rpm下离心10分钟，使细菌沉积，将沉淀物重新悬浮在1/5的培养物上清液中。然后以0.5g/升的浓度将甲醇溶液中的epothilone A或epothilone B添加至浓缩细菌悬浮液中。如上所述进一步培养培养物。为分析生物转化作用，在所希望的时间取1ml样品，加入0.1ml的XAD，然后在30下振摇样品30分钟。用甲醇淋洗XAD。浓缩洗脱液至干，然后再溶于0.2ml甲醇中。通过HPLC分析该样品。
图4是epothilone A向epothilone E转化的动力学。
图5是epothilone B向epothilone F转化的动力学。2)通过生物转化1g epothilone A来制备epothilone E
在10升生物反应器中，Sorangium cellulosum So Ce90菌株于30℃在8.5升上述培养基(但没有XAD)中培养4天，旋转速度为150rpm，并引入0.1vvm的空气。
通过交叉流过滤将该培养物浓缩至3升。为此，使用0.6m2的膜，其孔径为0.3μm。
将经浓缩的培养物转移至一个4升的生物反应器中，然后加入1gepothilone A在10ml甲醇中的溶液。进一步培养该培养物21.5小时。温度为32℃，搅拌器速度为455rpm，空气引入速率为61/min。在收集时，加入100ml的XAD，再将该混合物温育1小时。过筛从细胞中分离XAD，并用甲醇完全洗脱。用HPLC分析经浓缩的洗脱液。
生物转化的平衡：所用的epothilone A:       1000mg=100％21.5小时后回收的epothilone A:53.7mg=5.4％21.5小时后形成的epothilone E:661.4mg=66.1％完全分解的epothilone A:             =28.5％实施例5
测试本发明之epothilone对细胞培养物(表2)和促进聚合反应(表3)的作用。
        表2：用细胞培养物进行的epothilone实验
Epothilone     A493     B507    C477    D491    E509     F523
                                IC-50(ng/ml)
鼠成纤维细胞L929     4     1   100    20    20    1.5
人肿瘤细胞
HL-60(白血病)    0.2    0.2    10     3     1    0.3
K-562(白血病)    0.3    0.3    20    10     2    0.5
U-937(淋巴瘤)    0.2    0.2    10     3     1    0.2
KB-3.1(子宫颈癌)     1    0.6    20    12     5    0.5
KB-V1(子宫颈癌)    0.3    0.3    15     3     5    0.6
A-498(肾癌)     -    1.5   150    20    20     3
A-549(肺癌)    0.7    0.1    30    10     3    0.1
表3：用epothilone进行的聚合反应实验
参数：至与对照相比为半最大聚合反应时的时间
测量     w     x     y     z  试剂[s]  试剂[％]
对照     20     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
标准实验用0.9mg的微管蛋白/ml和1μm样品浓度
聚合反应实验是体外实验，其使用从猪脑中纯制的微管蛋白。用分光光度计进行评估。促进聚合反应的物质如epothilone降低达到半最大聚合反应所需要的时间，即、时间越短，化合物的活性越高。w、x、y和z是四个独立的实验，相对活性以最后一栏中对照的百分数来表示；该值最低表明活性最佳。排名表与细胞培养物中发现的值非常一致。

Claims (17)

1、Epothilone，它们是如下得到的：
(a)在吸附树脂存在下以本领域已知的方式培养Sorangiumcellulosum DSM6773，
(b)从培养物中取出吸附树脂，并用水/甲醇混合物洗涤，
(c)用甲醇淋洗经洗涤的吸附树脂，然后浓缩洗脱液，得到粗提物，
(d)用乙酸乙酯提取上述得到的浓缩物，浓缩提取物，并在甲醇和己烷之间分配，
(e)浓缩甲醇相，得到残液，该浓缩物在Sephadex柱上进行分步提取，
(f)得到包含所用微生物之代谢产物的提取部分，
(g)在C18反相柱上用甲醇/水混合物对上述得到的部分进行色谱分离，并顺序得到：
-包含Epothilone A的第一部分，
-包含Epothilone B的第二部分，
-包含第一种其它Epothilone的第三部分，
-包含第二种其它Epothilone的第四部分；
然后分离
(h1)上述第三部分中的第一种其它Epothilone；和
(h2)上述第四部分中的第二种其它Epothilone。
2、经验式为C26H39NO5S的Epothilone，其特征在于具有如表1所示的1H-和13C-NMR光谱。
3、以下式的Epothilone C：Epothilone C:R=H。
4、经验式为C27H41NO5S的Epothilone，其特征在于具有如表1所示的1H-和13C-NMR光谱。
5、以下式的Epothilone D：Epothilone D:R=CH3。
6、Epothilone A的生物转化体，其是如下得到的：
(a)在吸附树脂存在下按本领域已知的方式培养Sorangiumcellulosum DSM 6773，取出吸附树脂，如果需要，用Epothilone A的甲醇溶液处理全部或部分经分离的培养物；
(b)温育用Epothilone A处理的培养物，然后用吸附树脂处理；
(c)从培养物中分离吸附树脂，用甲醇淋洗，浓缩洗脱液，得到粗提物；
(d)在乙酸乙酯和水之间分配上述粗提物，分出乙酸乙酯相，并浓缩至油状；
(e)在以下条件对上述油状物进行反相色谱分离：
柱材料：Nucleosil 100C-18 7μm
柱尺寸：250×16mm
洗脱剂：甲醇/水=60∶40
流速：10ml/min
并分离出含有生物转化体的部分，该部分可在254nm处通过UV消光来检测，其Rt值为20min，然后分离所述生物转化体。
7、如权利要求6所述的Epothilone A生物转化体，其是在步骤(a)中培养物培养3或4或更多天时分离该培养物而得到的。
8、如权利要求6或7所述的Epothilone A生物转化体，其是在步骤(b)中进行温育1或2或更多天而得到的。
9、经验式为C26N39NO7S的化合物，其特征在于具有以下1H-NMR光谱(300MHz,CDCl3):δ=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)。
10、下式的化合物(Epothilone E)：Epothilone E:R=H。
11、Epothilone B的生物转化体，其是如下得到的：
(a)在吸附树脂存在下按本领域已知的方式培养Sorangiumcellulosum DSM 6773，与吸附树脂分离，如果需要，用Epothilone B的甲醇溶液处理全部或部分经分离的培养物；
(b)温育用Epothilone B处理的培养物，然后用吸附树脂处理；
(c)从培养物中分离吸附树脂，用甲醇淋洗，浓缩洗脱液，得到粗提物；
(d)在乙酸乙酯和水之间分配上述粗提物，分出乙酸乙酯相，并浓缩至油状；
(e)在以下条件对上述油状物进行反相色谱分离：
柱材料：Nucleosil 100C-18 7μm
柱尺寸：250×16mm
洗脱剂：甲醇/水=60∶40
流速：10ml/min
并分离出含有生物转化体的部分，该部分可在254nm处通过UV消光来检测，其Rt值为24.5min，然后分离所述生物转化体。
12、如权利要求11所述的Epothilone B生物转化体，其是在步骤(a)中培养物培养3或4或更多天时分离该培养物而得到的。
13、如权利要求11或12所述的Epothilone B生物转化体，其是在步骤(b)中进行1或2或更多天而得到的。
14、经验式为C27N41NO7S的化合物，其特征在于具有以下1H-NMR光谱(300MHz,CDCl3):δ=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)。
15、下式的化合物(Epothilone F)：
Figure A9719981400071
Epothilone F:R=CH3。
16、用于在农业、林业和/或园艺中保护植物的组合物，该组合物由如前述任一权利要求所述的化合物中的一种或多种组成或者由一种或多种所述化合物以及一种或多种常规载体和/或稀释剂组成。
17、治疗性组合物，其用作细胞抑制剂，由如前述任一权利要求所述的化合物中的一种或多种组成或者由一种或多种如前述任一权利要求所述的化合物以及一种或多种常规载体和/或稀释剂组成。
CNB971998140A 1996-11-18 1997-11-18 Epothilone D、E和F,其制备方法,以及作为细胞抑制剂和植物保护剂的应用 Expired - Lifetime CN1196698C (zh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE19647580.5 1996-11-18
DE19647580 1996-11-18
DE19707506.1 1997-02-25
DE19707506 1997-02-25

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CNB2005100062827A Division CN100344627C (zh) 1996-11-18 1997-11-18 埃坡霉素c、其制备方法以及作为细胞抑制剂和植物保护剂的应用

Publications (2)

Publication Number Publication Date
CN1237970A true CN1237970A (zh) 1999-12-08
CN1196698C CN1196698C (zh) 2005-04-13

Family

ID=26031383

Family Applications (2)

Application Number Title Priority Date Filing Date
CNB2005100062827A Expired - Lifetime CN100344627C (zh) 1996-11-18 1997-11-18 埃坡霉素c、其制备方法以及作为细胞抑制剂和植物保护剂的应用
CNB971998140A Expired - Lifetime CN1196698C (zh) 1996-11-18 1997-11-18 Epothilone D、E和F,其制备方法,以及作为细胞抑制剂和植物保护剂的应用

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CNB2005100062827A Expired - Lifetime CN100344627C (zh) 1996-11-18 1997-11-18 埃坡霉素c、其制备方法以及作为细胞抑制剂和植物保护剂的应用

Country Status (24)

Country Link
US (6) US7067544B2 (zh)
EP (2) EP0941227B2 (zh)
JP (1) JP4274583B2 (zh)
KR (1) KR100538095B1 (zh)
CN (2) CN100344627C (zh)
AT (2) ATE267197T1 (zh)
AU (1) AU753546B2 (zh)
BR (1) BR9713363B1 (zh)
CA (1) CA2269118C (zh)
CY (1) CY2542B1 (zh)
CZ (2) CZ303422B6 (zh)
DE (2) DE59712968D1 (zh)
DK (2) DK1367057T3 (zh)
ES (2) ES2221692T5 (zh)
HK (2) HK1022314A1 (zh)
HU (1) HU229833B1 (zh)
IL (1) IL129558A (zh)
NO (1) NO319984B1 (zh)
NZ (1) NZ335383A (zh)
PL (1) PL193229B1 (zh)
PT (2) PT1367057E (zh)
RU (1) RU2198173C2 (zh)
TW (1) TW408119B (zh)
WO (1) WO1998022461A1 (zh)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010040252A1 (zh) * 2008-10-06 2010-04-15 山东大学 埃博霉素苷类化合物和以其为活性成分的组合物及其应用
CN1705662B (zh) * 2002-09-23 2011-07-06 布里斯托尔-迈尔斯斯奎布公司 埃坡霉素b的制备、分离和纯化的方法,及埃坡霉素b的x-射线晶体结构
CN102532120A (zh) * 2002-08-23 2012-07-04 索隆-基特林癌症研究协会 埃坡霉素(epothilone)，合成埃坡霉素的中间体，其类似物及其用途
CN101177425B (zh) * 2003-01-28 2012-07-18 北京华昊中天生物技术有限公司 一类新型埃坡霉素化合物及其制备方法和用途

Families Citing this family (170)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE218556T1 (de) 1995-11-17 2002-06-15 Biotechnolog Forschung Gmbh Epothilon-derivate und deren herstellung
US5969145A (en) * 1996-08-30 1999-10-19 Novartis Ag Process for the production of epothilones and intermediate products within the process
AU753546B2 (en) 1996-11-18 2002-10-24 Helmholtz-Zentrum Fuer Infektionsforschung Gmbh Epothilone C, D, E and F, production process, and their use as cytostatic as well as phytosanitary agents
WO1999001124A1 (en) 1996-12-03 1999-01-14 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US6867305B2 (en) 1996-12-03 2005-03-15 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US6204388B1 (en) 1996-12-03 2001-03-20 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues 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 (fr) 1998-02-25 2003-02-21 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
US6380395B1 (en) 1998-04-21 2002-04-30 Bristol-Myers Squibb Company 12, 13-cyclopropane epothilone derivatives
US6498257B1 (en) 1998-04-21 2002-12-24 Bristol-Myers Squibb Company 2,3-olefinic epothilone derivatives
DE19820599A1 (de) 1998-05-08 1999-11-11 Biotechnolog Forschung Gmbh Epothilonderivate, Verfahren zu deren Herstellung und deren Verwendung
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
DE19826988A1 (de) * 1998-06-18 1999-12-23 Biotechnolog Forschung Gmbh Epothilon-Nebenkomponenten
DE19846493A1 (de) * 1998-10-09 2000-04-13 Biotechnolog Forschung Gmbh DNA-Sequenzen für die enzymatische Synthese von Polyketid- oder Heteropolyketidverbindungen
JP4662635B2 (ja) 1998-11-20 2011-03-30 コーサン バイオサイエンシーズ， インコーポレイテッド エポチロンおよびエポチロン誘導体を生成するための組換え方法および材料
US6410301B1 (en) 1998-11-20 2002-06-25 Kosan Biosciences, Inc. Myxococcus host cells for the production of epothilones
WO2000039276A2 (en) * 1998-12-23 2000-07-06 Bristol-Myers Squibb Company Microbial transformation method for the preparation of an epothilone
US6780620B1 (en) 1998-12-23 2004-08-24 Bristol-Myers Squibb Company Microbial transformation method for the preparation of an epothilone
US6596875B2 (en) 2000-02-07 2003-07-22 James David White Method for synthesizing epothilones and epothilone analogs
CZ301498B6 (cs) * 1999-02-22 2010-03-24 Gesellschaft Fuer Biotechnologische Forschung Mbh (Gbf) C-21 modifikované epothilony
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
EP3222619A1 (en) 1999-04-15 2017-09-27 Bristol-Myers Squibb Holdings Ireland Cyclic protein tyrosine kinase inhibitors
AU775373B2 (en) 1999-10-01 2004-07-29 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
ATE309369T1 (de) * 2000-04-28 2005-11-15 Kosan Biosciences Inc Heterologe herstellung von polyketiden
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
US6589968B2 (en) 2001-02-13 2003-07-08 Kosan Biosciences, Inc. Epothilone compounds and methods for making and using the same
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
CZ20032021A3 (cs) 2001-01-25 2004-05-12 Bristol@Myersásquibbácompany Způsoby podávání analogů epothilonu při léčbě rakoviny
CN1489466A (zh) 2001-01-25 2004-04-14 ����˹�ж�-����˹˹������˾ 包含埃博霉素类似物的非肠道制剂
WO2002058699A1 (en) 2001-01-25 2002-08-01 Bristol-Myers Squibb Company Pharmaceutical forms of epothilones for oral administration
US6893859B2 (en) 2001-02-13 2005-05-17 Kosan Biosciences, Inc. Epothilone derivatives and methods for making and using the same
IL156988A0 (en) 2001-02-20 2004-02-08 Bristol Myers Squibb Co Pharmaceutical compositions containing epothilone derivatives
KR20040028720A (ko) 2001-02-20 2004-04-03 브리스톨-마이어스스퀴브컴파니 치료불응성 종양 치료용 에포틸론 유도체
CN1511036B (zh) 2001-02-27 2010-05-05 诺瓦提斯公司 包含信号转导抑制剂和埃坡霉素衍生物的联合形式
IL157312A0 (en) 2001-02-27 2004-02-19 Biotechnolog Forschung Gmbh Processes for the preparation of epothilone derivatives and compounds produced thereby
US7312237B2 (en) 2001-03-14 2007-12-25 Bristol-Myers Squibb Co. Combination of epothilone analogs and chemotherapeutic agents for the treatment of prolilferative diseases
WO2002098868A1 (en) 2001-06-01 2002-12-12 Bristol-Myers Squibb Company 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
EP1469847A1 (en) 2002-01-14 2004-10-27 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
SI1483251T1 (sl) 2002-03-12 2010-03-31 Bristol Myers Squibb Co C cian epotilonski derivati
AU2003218107A1 (en) 2002-03-12 2003-09-29 Bristol-Myers Squibb Company 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
AU2003243561A1 (en) 2002-06-14 2003-12-31 Bristol-Myers Squibb Company Combination of epothilone analogs and chemotherapeutic agents for the treatment of proliferative diseases
US7507564B2 (en) * 2002-07-29 2009-03-24 Optimer Pharmaceuticals, Inc. Tiacumicin production
WO2004035050A1 (en) * 2002-10-15 2004-04-29 Board Of Supervisors Of Louisiana State Universityand Agricultural And Mechanical College 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
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
US7696241B2 (en) 2004-03-04 2010-04-13 Bristol-Myers Squibb Company Bicyclic compounds as modulators of androgen receptor function and method
US7625923B2 (en) 2004-03-04 2009-12-01 Bristol-Myers Squibb Company Bicyclic modulators of androgen receptor function
KR20080083220A (ko) 2004-04-07 2008-09-16 노파르티스 아게 Ｉａｐ 억제제
US10675326B2 (en) 2004-10-07 2020-06-09 The Board Of Trustees Of The University Of Illinois Compositions comprising cupredoxins for treating cancer
WO2006055742A1 (en) * 2004-11-18 2006-05-26 Bristol-Myers Squibb Company Enteric coated bead comprising epothilone or epothilone analog, and preparation and administration thereof
AR052142A1 (es) * 2004-11-18 2007-03-07 Bristol Myers Squibb Co Perla recubierta enterica que comprende ixabepilona, y preparacion y administracion de la misma
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
AU2006294850A1 (en) 2005-09-27 2007-04-05 Novartis Ag Carboxyamine compounds and their use in the treatment of HDAC dependent diseases
ES2481671T3 (es) 2005-11-21 2014-07-31 Novartis Ag Inhibidores de mTOR en el tratamiento de tumores endocrinos
GB0605120D0 (en) 2006-03-14 2006-04-26 Novartis Ag Organic Compounds
CA2647565A1 (en) 2006-03-31 2007-10-18 Bristol-Myers Squibb Company Biomarkers and methods for determining sensitivity to microtubule-stabilizing agents
EP2591775A1 (en) 2006-04-05 2013-05-15 Novartis AG Combinations comprising mtor inhibitors for treating cancer
MX2008012728A (es) 2006-04-05 2008-10-14 Novartis Ag Combinaciones de agentes terapeuticos para el tratamiento de cancer.
JP2009536180A (ja) 2006-05-09 2009-10-08 ノバルティス アクチエンゲゼルシャフト 鉄キレート剤と抗新生物剤を含む組合せ剤およびそれらの使用
CA2664378A1 (en) 2006-09-29 2008-04-03 Novartis Ag Pyrazolopyrimidines as pi3k lipid kinase inhibitors
BRPI0718360A2 (pt) 2006-12-04 2013-11-12 Univ Illinois "composições e métodos para o tratamento do câncer com cupredoxinas e dna rico em cpg"
EP2114429A4 (en) 2007-02-08 2010-05-19 Univ Illinois COMPOSITIONS AND METHODS FOR PREVENTING CANCER WITH CUPREDOXINS
RU2009134223A (ru) 2007-02-15 2011-03-20 Новартис АГ (CH) Комбинация lbh589 с другими терапевтическими средствами, предназначенная для лечения рака
EA020114B1 (ru) 2008-03-24 2014-08-29 Новартис Аг Производные арилсульфонамида в качестве ингибиторов матриксной металлопротеазы
EP2628726A1 (en) 2008-03-26 2013-08-21 Novartis AG Hydroxamate-based inhibitors of deacetylases b
WO2010083617A1 (en) 2009-01-21 2010-07-29 Oncalis Ag Pyrazolopyrimidines as protein kinase inhibitors
TW201031406A (en) 2009-01-29 2010-09-01 Novartis Ag Substituted benzimidazoles for the treatment of astrocytomas
KR101360725B1 (ko) 2009-06-26 2014-02-07 노파르티스 아게 Ｃｙｐ17의 억제제로서의 1,3-이치환된 이미다졸리딘-2-온 유도체
US8389526B2 (en) 2009-08-07 2013-03-05 Novartis Ag 3-heteroarylmethyl-imidazo[1,2-b]pyridazin-6-yl derivatives
CA2770873A1 (en) 2009-08-12 2011-02-17 Novartis Ag Heterocyclic hydrazone compounds and their uses to treat cancer and inflammation
EP2467383A1 (en) 2009-08-20 2012-06-27 Novartis AG Heterocyclic oxime compounds
US20120149661A1 (en) 2009-08-26 2012-06-14 Novartis Ag Tetra-substituted heteroaryl compounds and their use as mdm2 and/or mdm4 modulators
MY156209A (en) 2009-11-04 2016-01-29 Novartis Ag Heterocyclic sulfonamide derivatives useful mek inhibitors
EP2509964B1 (en) 2009-12-08 2014-04-30 Novartis AG Heterocyclic sulfonamide derivatives
US8440693B2 (en) 2009-12-22 2013-05-14 Novartis Ag Substituted isoquinolinones and quinazolinones
CU24130B1 (es) 2009-12-22 2015-09-29 Novartis Ag Isoquinolinonas y quinazolinonas sustituidas
CA2799202C (en) 2010-05-18 2016-07-05 Cerulean Pharma Inc. Compositions and methods for treatment of autoimmune and other diseases
UA112517C2 (uk) 2010-07-06 2016-09-26 Новартіс Аг Тетрагідропіридопіримідинові похідні
US8946260B2 (en) 2010-09-16 2015-02-03 Novartis Ag 17α-hydroxylase/C17,20-lyase inhibitors
MX356514B (es) 2011-01-20 2018-05-30 Univ Texas Marcadores de formación de imagen por resonancia magnética, sistemas de suministro y extracción, y métodos de fabricación y uso de los mismos.
EP2673277A1 (en) 2011-02-10 2013-12-18 Novartis AG [1, 2, 4]triazolo [4, 3 -b]pyridazine compounds as inhibitors of the c-met tyrosine kinase
MX359399B (es) 2011-04-28 2018-09-27 Novartis Ag Inhibidores de 17alfa-hidroxilasa/c17-20-liasa.
MX2013014398A (es) 2011-06-09 2014-03-21 Novartis Ag Derivados de sulfonamida heterociclicos.
EP3228325A1 (en) 2011-06-10 2017-10-11 Mersana Therapeutics, Inc. Protein-polymer-drug conjugates
EP2721008B1 (en) 2011-06-20 2015-04-29 Novartis AG Hydroxy substituted isoquinolinone derivatives as p53 (mdm2 or mdm4) inhibitors
EP2721007B1 (en) 2011-06-20 2015-04-29 Novartis AG Cyclohexyl isoquinolinone compounds
WO2013001445A1 (en) 2011-06-27 2013-01-03 Novartis Ag Solid forms and salts of tetrahydro-pyrido-pyrimidine derivatives
CN102863474A (zh) 2011-07-09 2013-01-09 陈小平 一类治疗细胞增殖性疾病的铂化合物、其制备方法和应用
ES2691650T3 (es) 2011-09-15 2018-11-28 Novartis Ag 3-(quinolin-6-il-tio)-[1,2,4]-triazolo-[4,3-a]-piridinas 6-sustituidas como inhibidores de tirosina quinasa c-Met
CN102993239A (zh) 2011-09-19 2013-03-27 陈小平 离去基团含氨基或烷胺基的丁二酸衍生物的铂类化合物
WO2013080141A1 (en) 2011-11-29 2013-06-06 Novartis Ag Pyrazolopyrrolidine compounds
PL2794600T3 (pl) 2011-12-22 2018-06-29 Novartis Ag Pochodne 2,3-dihydro-benzo[1,4]oksazyny i powiązane związki jako inhibitory kinazy fosfoinozytydu-3 (PI3K) do leczenia np. reumatoidalnego zapalenia stawów
EP2794594A1 (en) 2011-12-22 2014-10-29 Novartis AG Quinoline derivatives
US9126980B2 (en) 2011-12-23 2015-09-08 Novartis Ag Compounds for inhibiting the interaction of BCL2 with binding partners
BR112014015308A2 (pt) 2011-12-23 2017-06-13 Novartis Ag compostos para inibição da interação de bcl2 com contrapartes de ligação
EA201491259A1 (ru) 2011-12-23 2014-11-28 Новартис Аг Соединения и композиции для ингибирования взаимодействия bcl2 с партнерами связывания
CA2859869A1 (en) 2011-12-23 2013-06-27 Novartis Ag Compounds for inhibiting the interaction of bcl2 with binding partners
MX2014007731A (es) 2011-12-23 2015-01-12 Novartis Ag Compuestos para inhibir la interaccion de bcl2 con los componentes de enlace.
KR101372563B1 (ko) 2011-12-26 2014-03-14 주식회사 삼양바이오팜 에포틸론 함유물질로부터 에포틸론 ａ와 ｂ의 추출 및 정제 방법
JO3357B1 (ar) 2012-01-26 2019-03-13 Novartis Ag مركبات إيميدازوبيروليدينون
WO2013171642A1 (en) 2012-05-15 2013-11-21 Novartis Ag Benzamide derivatives for inhibiting the activity of abl1, abl2 and bcr-abl1
SI2861579T1 (en) 2012-05-15 2018-05-31 Novartis Ag Benzamide derivatives for inhibiting the activity of ABL1, ABL2 and BCR-ABL1
BR112014027584B1 (pt) 2012-05-15 2023-01-24 Novartis Ag Uso de inibidores da atividade de abl1, abl2 e bcr-abl1, e composição farmacêutica
AU2013261128B2 (en) 2012-05-15 2015-11-12 Novartis Ag Benzamide derivatives for inhibiting the activity of ABL1, ABL2 and BCR-ABL1
JP6171003B2 (ja) 2012-05-24 2017-07-26 ノバルティス アーゲー ピロロピロリジノン化合物
JP6427097B2 (ja) 2012-06-15 2018-11-21 ザ ブリガム アンド ウィメンズ ホスピタル インコーポレイテッドＴｈｅ Ｂｒｉｇｈａｍ ａｎｄ Ｗｏｍｅｎ’ｓ Ｈｏｓｐｉｔａｌ， Ｉｎｃ． 癌を処置するための組成物および該組成物を製造するための方法
NZ706635A (en) 2012-10-02 2018-08-31 Gilead Sciences Inc Inhibitors of histone demethylases
US9725477B2 (en) 2012-11-17 2017-08-08 Beijing Fswelcome Technology Development Co., Ltd Platinum compounds of malonic acid derivative having leaving group containing amino or alkylamino
TW201422625A (zh) 2012-11-26 2014-06-16 Novartis Ag 二氫－吡啶并－□衍生物之固體形式
CA2892863C (en) 2012-12-10 2022-03-15 Mersana Therapeutics, Inc. Polymeric scaffold based on phf for targeted drug delivery
WO2014093640A1 (en) 2012-12-12 2014-06-19 Mersana Therapeutics,Inc. Hydroxy-polmer-drug-protein conjugates
JO3464B1 (ar) 2013-01-15 2020-07-05 Astellas Pharma Europe Ltd التركيبات الخاصة بمركبات التياكوميسين
US9403827B2 (en) 2013-01-22 2016-08-02 Novartis Ag Substituted purinone compounds
EP2948453B1 (en) 2013-01-22 2017-08-02 Novartis AG Pyrazolo[3,4-d]pyrimidinone compounds as inhibitors of the p53/mdm2 interaction
WO2014128612A1 (en) 2013-02-20 2014-08-28 Novartis Ag Quinazolin-4-one derivatives
SG11201506717UA (en) 2013-02-27 2015-09-29 Epitherapeutics Aps 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
CA2914742A1 (en) 2013-06-11 2014-12-18 Bayer Pharma Aktiengesellschaft Handovers with co-operating cells configured to provide coordinated multi-point transmission/reception
UY35675A (es) 2013-07-24 2015-02-27 Novartis Ag Derivados sustituidos de quinazolin-4-ona
WO2015022663A1 (en) 2013-08-14 2015-02-19 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
US9227969B2 (en) 2013-08-14 2016-01-05 Novartis Ag Compounds and compositions as inhibitors of MEK
BR112016003229A8 (pt) 2013-09-22 2020-02-04 Calitor Sciences Llc composto, composição farmacêutica, e, uso de um composto ou de uma composição farmacêutica
JP6427564B2 (ja) 2013-10-11 2018-11-21 アサナ・バイオサイエンシズ，リミテッド・ライアビリティ・カンパニー タンパク質−ポリマー−薬物共役体
EP3054991B1 (en) 2013-10-11 2019-04-03 Mersana Therapeutics, Inc. Protein-polymer-drug conjugates
WO2015148867A1 (en) 2014-03-28 2015-10-01 Calitor Sciences, Llc Substituted heteroaryl compounds and methods of use
EP3126345A1 (en) 2014-03-31 2017-02-08 Gilead Sciences, Inc. Inhibitors of histone demethylases
WO2015153345A1 (en) 2014-04-03 2015-10-08 Invictus Oncology Pvt. Ltd. Supramolecular combinatorial therapeutics
WO2016033169A1 (en) 2014-08-27 2016-03-03 Epitherapeutics Aps Compounds and methods for inhibiting histone demethylases
WO2017044434A1 (en) 2015-09-11 2017-03-16 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
CN111315414A (zh) 2017-06-22 2020-06-19 梅尔莎纳医疗公司 产生载药聚合物支架和蛋白-聚合物-药物缀合物的方法
JP7254076B2 (ja) 2017-11-19 2023-04-07 サンシャイン・レイク・ファーマ・カンパニー・リミテッド 置換ヘテロアリール化合物及び使用方法
WO2019143874A1 (en) 2018-01-20 2019-07-25 Sunshine Lake Pharma Co., Ltd. Substituted aminopyrimidine compounds and methods of use
WO2019212357A1 (en) 2018-05-04 2019-11-07 Tagworks Pharmaceuticals B.V. Compounds comprising a linker for increasing transcyclooctene stability
EP3787691A1 (en) 2018-05-04 2021-03-10 Tagworks Pharmaceuticals B.V. Tetrazines for high click conjugation yield in vivo and high click release yield
JP2022513400A (ja) 2018-10-29 2022-02-07 メルサナ セラピューティクス インコーポレイテッド ペプチド含有リンカーを有するシステイン操作抗体－薬物コンジュゲート
FR3087650B1 (fr) 2018-10-31 2021-01-29 Bio Even Flavine adenine dinucleotide (fad) pour son utilisation pour la prevention et/ou le traitement de cancer
IL289094A (en) 2019-06-17 2022-02-01 Tagworks Pharmaceuticals B V Tetrazines for increasing the speed and yield of the "click release" reaction
JP2022537543A (ja) 2019-06-17 2022-08-26 タグワークス ファーマシューティカルス ビー．ブイ． 高速で且つ効率的なクリック放出の為の化合物
CN118339280A (zh) 2021-09-06 2024-07-12 维拉克萨生物技术有限责任公司 用于真核生物中遗传密码子扩展的新型氨酰tRNA合成酶变体
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
WO2023094525A1 (en) 2021-11-25 2023-06-01 Veraxa Biotech Gmbh Improved antibody-payload conjugates (apcs) prepared by site-specific conjugation utilizing genetic code expansion
CA3239713A1 (en) 2021-12-08 2023-06-15 Edward A. LEMKE Hydrophilic tetrazine-functionalized payloads for preparation of targeting conjugates
EP4314031B1 (en) 2022-02-15 2024-03-13 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

Family Cites Families (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0358606A3 (de) 1988-09-09 1990-10-31 Gesellschaft für Biotechnologische Forschung mbH (GBF) Mikrobiologisches Verfahren zur Herstellung agrarchemisch verwendbarer mikrobizider makrozyklischer Lactonderivate
GB8909737D0 (en) * 1989-04-27 1989-06-14 Shell Int Research Thiazole derivatives
DE4138042C2 (de) * 1991-11-19 1993-10-14 Biotechnolog Forschung Gmbh Epothilone, deren Herstellungsverfahren sowie diese Verbindungen enthaltende Mittel
JPH09502698A (ja) * 1993-03-05 1997-03-18 ヘクサル・アクチエンゲゼルシャフト 塩酸ラニチジンの結晶シクロデキストリン複合体、その製造方法およびその複合体を含有する薬剤組成物
WO1995018798A1 (en) * 1994-01-11 1995-07-13 The Scripps Research Institute Chemical switching of taxo-diterpenoids between low solubility active forms and high solubility inactive forms
DE19542986A1 (de) * 1995-11-17 1997-05-22 Biotechnolog Forschung Gmbh Epothilon-Derivate und deren Verwendung
ATE218556T1 (de) * 1995-11-17 2002-06-15 Biotechnolog Forschung Gmbh Epothilon-derivate und deren herstellung
DE19639456A1 (de) 1996-09-25 1998-03-26 Biotechnolog Forschung Gmbh Epothilon-Derivate, Herstellung und Mittel
US5969145A (en) * 1996-08-30 1999-10-19 Novartis Ag Process for the production of epothilones and intermediate products within the process
DE19645362A1 (de) 1996-10-28 1998-04-30 Ciba Geigy Ag Verfahren zur Herstellung von Epothilon A und B und Derivaten
DE19645361A1 (de) 1996-08-30 1998-04-30 Ciba Geigy Ag Zwischenprodukte innerhalb der Totalsynthese von Epothilon A und B, Teil II
DE19636343C1 (de) 1996-08-30 1997-10-23 Schering Ag Zwischenprodukte innerhalb der Totalsynthese von Epothilon A und B
JP2001500851A (ja) 1996-08-30 2001-01-23 ノバルティス アクチエンゲゼルシャフト エポシロンの製造法および製造過程中に得られる中間生産物
AU753546B2 (en) 1996-11-18 2002-10-24 Helmholtz-Zentrum Fuer Infektionsforschung Gmbh Epothilone C, D, E and F, production process, and their use as cytostatic as well as phytosanitary agents
US6515016B2 (en) 1996-12-02 2003-02-04 Angiotech Pharmaceuticals, Inc. Composition and methods of paclitaxel for treating psoriasis
WO1999001124A1 (en) 1996-12-03 1999-01-14 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US6204388B1 (en) * 1996-12-03 2001-03-20 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US6380394B1 (en) 1996-12-13 2002-04-30 The Scripps Research Institute Epothilone analogs
US6660758B1 (en) 1996-12-13 2003-12-09 The Scripps Research Institute Epothilone analogs
US6441186B1 (en) 1996-12-13 2002-08-27 The Scripps Research Institute Epothilone analogs
DE19701758A1 (de) 1997-01-20 1998-07-23 Wessjohann Ludgar A Dr Epothilone-Synthesebausteine
CN1544436A (zh) * 1997-02-25 2004-11-10 ���＼���о����޹�˾��GBF�� 3，7-保护的环氧噻嗪酮-n-氧化物及其制备方法
US5828449A (en) 1997-02-26 1998-10-27 Acuity Imaging, Llc Ring illumination reflective elements on a generally planar surface
DE19713970B4 (de) 1997-04-04 2006-08-31 R&D-Biopharmaceuticals Gmbh Epothilone-Synthesebausteine II - Prenylderivate
JP4065573B2 (ja) 1997-04-18 2008-03-26 ベーリンガー・インゲルハイム・インテルナツィオナール・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 反応媒体として圧縮二酸化炭素中における二官能性または多官能性基質の選択的オレフィンメタセシス
DE19720312A1 (de) 1997-05-15 1998-11-19 Hoechst Ag Zubereitung mit erhöhter in vivo Verträglichkeit
DE19821954A1 (de) 1997-05-15 1998-11-19 Biotechnolog Forschung Gmbh Verfahren zur Herstellung eines Epothilon-Derivats
DE19726627A1 (de) 1997-06-17 1998-12-24 Schering Ag Zwischenprodukte, Verfahren zu ihrer Herstellung und ihre Verwendung zur Herstellung von Epothilon
US6605599B1 (en) * 1997-07-08 2003-08-12 Bristol-Myers Squibb Company Epothilone derivatives
ES2184307T3 (es) 1997-07-16 2003-04-01 Schering Ag Derivados de tiazol, procedimiento para su preparacion y su utilizacion.
IL134419A0 (en) 1997-08-09 2001-04-30 Schering Ag Epothilone derivatives, process for the preparation thereof and pharmaceutical compositions containing the same
SI1052974T1 (sl) 1998-02-05 2009-10-31 Novartis Ag Farmacevtska formulacija, ki vsebuje epotilon
US6194181B1 (en) * 1998-02-19 2001-02-27 Novartis Ag Fermentative preparation process for and crystal forms of cytostatics
FR2775187B1 (fr) 1998-02-25 2003-02-21 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
DE69927790T2 (de) 1998-02-25 2006-07-20 Sloan-Kettering Institute For Cancer Research Synthese von epothilonen, ihren zwischenprodukten und analogen verbindungen
DE19826988A1 (de) * 1998-06-18 1999-12-23 Biotechnolog Forschung Gmbh Epothilon-Nebenkomponenten
AU5036999A (en) 1998-06-30 2000-01-17 Schering Aktiengesellschaft Epothilon derivatives, their preparation process, intermediate products and their pharmaceutical use
US6410301B1 (en) * 1998-11-20 2002-06-25 Kosan Biosciences, Inc. Myxococcus host cells for the production of epothilones
JP4662635B2 (ja) 1998-11-20 2011-03-30 コーサン バイオサイエンシーズ， インコーポレイテッド エポチロンおよびエポチロン誘導体を生成するための組換え方法および材料
AU2795000A (en) 1998-12-22 2000-07-12 Novartis Ag Epothilone derivatives and their use as antitumor agents
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
US6610736B1 (en) 1999-02-18 2003-08-26 Schering Ag 16-Halogen-epothilone derivatives, method for producing them and their pharmaceutical use
CZ301498B6 (cs) * 1999-02-22 2010-03-24 Gesellschaft Fuer Biotechnologische Forschung Mbh (Gbf) C-21 modifikované epothilony
US6211412B1 (en) * 1999-03-29 2001-04-03 The University Of Kansas Synthesis of epothilones
PE20010116A1 (es) 1999-04-30 2001-02-15 Schering Ag Derivados de 6-alquenil-, 6-alquinil- y 6-epoxi-epotilona, procedimientos para su preparacion
TWI310684B (en) * 2000-03-27 2009-06-11 Bristol Myers Squibb Co Synergistic pharmaceutical kits 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
WO2003029195A1 (fr) * 2001-09-28 2003-04-10 Sumika Fine Chemicals Co., Ltd. Intermediaires pour l'elaboration d'un derive de l'epothilone, et leur procede de production
US6884608B2 (en) * 2001-12-26 2005-04-26 Bristol-Myers Squibb Company Compositions and methods for hydroxylating epothilones
TW200303202A (en) 2002-02-15 2003-09-01 Bristol Myers Squibb Co 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
KR101406635B1 (ko) 2002-09-23 2014-06-11 브리스톨-마이어스 스큅 컴퍼니 에포틸론 ｂ의 제조, 분리 및 정제 방법, 및 에포틸론 ｂ의 ｘ-선 결정 구조

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102532120A (zh) * 2002-08-23 2012-07-04 索隆-基特林癌症研究协会 埃坡霉素(epothilone)，合成埃坡霉素的中间体，其类似物及其用途
CN1705662B (zh) * 2002-09-23 2011-07-06 布里斯托尔-迈尔斯斯奎布公司 埃坡霉素b的制备、分离和纯化的方法,及埃坡霉素b的x-射线晶体结构
CN101177425B (zh) * 2003-01-28 2012-07-18 北京华昊中天生物技术有限公司 一类新型埃坡霉素化合物及其制备方法和用途
WO2010040252A1 (zh) * 2008-10-06 2010-04-15 山东大学 埃博霉素苷类化合物和以其为活性成分的组合物及其应用

Also Published As

Publication number Publication date
RU2198173C2 (ru) 2003-02-10
NZ335383A (en) 2000-10-27
EP1367057A1 (de) 2003-12-03
US20080293784A1 (en) 2008-11-27
US7846952B2 (en) 2010-12-07
PT1367057E (pt) 2008-12-04
HK1083832A1 (en) 2006-07-14
EP1367057B1 (de) 2008-09-17
HUP0000497A3 (en) 2001-10-29
JP4274583B2 (ja) 2009-06-10
CN1680370A (zh) 2005-10-12
US8076490B2 (en) 2011-12-13
DK1367057T3 (da) 2009-01-19
NO992338L (no) 1999-05-14
US7759375B2 (en) 2010-07-20
US20090247592A1 (en) 2009-10-01
NO992338D0 (no) 1999-05-14
ES2221692T4 (es) 2005-10-01
IL129558A0 (en) 2000-02-29
WO1998022461A1 (de) 1998-05-28
CZ175099A3 (cs) 1999-09-15
AU753546B2 (en) 2002-10-24
PL193229B1 (pl) 2007-01-31
ES2221692T3 (es) 2005-01-01
US20110136185A1 (en) 2011-06-09
ES2312695T3 (es) 2009-03-01
NO319984B1 (no) 2005-10-10
HUP0000497A2 (hu) 2000-06-28
US20050090535A1 (en) 2005-04-28
HK1022314A1 (en) 2000-08-04
ES2221692T5 (es) 2009-12-14
US20090270466A1 (en) 2009-10-29
CA2269118C (en) 2012-05-29
PL333435A1 (en) 1999-12-06
EP0941227B2 (de) 2009-10-14
IL129558A (en) 2001-10-31
KR100538095B1 (ko) 2005-12-21
DK0941227T3 (da) 2004-06-28
DK0941227T5 (da) 2009-10-05
EP0941227B1 (de) 2004-05-19
EP0941227A1 (de) 1999-09-15
KR20000053308A (ko) 2000-08-25
EP0941227B9 (de) 2005-05-04
BR9713363B1 (pt) 2011-02-08
CZ296164B6 (cs) 2006-01-11
ATE408612T1 (de) 2008-10-15
TW408119B (en) 2000-10-11
AU5483798A (en) 1998-06-10
CZ303422B6 (cs) 2012-09-05
CY2542B1 (en) 2006-06-28
US20060264482A1 (en) 2006-11-23
HU229833B1 (en) 2014-09-29
PT941227E (pt) 2004-08-31
JP2001504474A (ja) 2001-04-03
CN1196698C (zh) 2005-04-13
BR9713363A (pt) 2000-01-25
DE59712968D1 (de) 2008-10-30
CN100344627C (zh) 2007-10-24
DK0941227T4 (da) 2008-05-19
CA2269118A1 (en) 1998-05-28
ATE267197T1 (de) 2004-06-15
DE59711647D1 (de) 2004-06-24
US7067544B2 (en) 2006-06-27

Similar Documents

Publication Publication Date Title
CN1237970A (zh) Epothilone C、D、E和F,其制备方法,以及作为细胞抑制剂和植物保护剂的应用
CN101037658A (zh) 枯草芽孢杆菌zjb－063及其应用
CN1082052C (zh) 制备环状缩肽化合物的方法和新的环状缩肽
CN1724643A (zh) 一种新的菌株及应用该菌株生产紫杉醇的方法
CN1043786C (zh) 一种新抗菌化合物的制备方法
CN1200608C (zh) 吴茱萸吲哚类生物碱在制备防治或抗稻瘟病的药物中的应用
JP5694708B2 (ja) Ａ−８７７７４化合物又はその塩、それらの製法及びそれらを有効成分として含有する農薬
CN115521877B (zh) 青霉菌株及其在制备布雷菲德菌素a中的应用
CN112646854B (zh) 一种棘白菌素b合成培养基及应用
KR20050019892A (ko) 에포틸론 씨, 디, 이 및 에프, 그 제조방법 및 세포증식억제제와 식물 위생제로서의 이들의 용도
CN104328147A (zh) 一种含氯(2r,3s)甲基丙酸甲酯的生产方法
Elkhateeb et al. Daba (2022). Botryotrichum and Scopulariopsis Secondary Metabolites and Biological Activities
CN87106657A (zh) 新抗生素b-3543的生产方法和应用
CN104313066A (zh) 一种生产(2r,3s)含碘甲基丙酸甲酯的生物还原法
CN104263767A (zh) 一种产朊酵母还原生产碘苯基丙酸甲酯的方法
CN104313073A (zh) 一种 (2r,3r) 庚烯醇的生产方法
CN104313064A (zh) 一种细胞法生产手性溴苯基丙酸甲酯的方法
MXPA99004471A (en) Epothilone c, d, e and f, production process, and their use as cytostatic as well as phytosanitary agents

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1060569

Country of ref document: HK

CX01 Expiry of patent term

Granted publication date: 20050413