[go: up one dir, main page]

CN1680370A - 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 - Google Patents

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 Download PDF

Info

Publication number
CN1680370A
CN1680370A CNA2005100062827A CN200510006282A CN1680370A CN 1680370 A CN1680370 A CN 1680370A CN A2005100062827 A CNA2005100062827 A CN A2005100062827A CN 200510006282 A CN200510006282 A CN 200510006282A CN 1680370 A CN1680370 A CN 1680370A
Authority
CN
China
Prior art keywords
epothilone
esperamicin
methyl alcohol
epothilones
culture
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
CNA2005100062827A
Other languages
English (en)
Other versions
CN100344627C (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=CN1680370(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 CN1680370A publication Critical patent/CN1680370A/zh
Application granted granted Critical
Publication of CN100344627C publication Critical patent/CN100344627C/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)
  • Microbiology (AREA)
  • Plant Pathology (AREA)
  • Biotechnology (AREA)
  • Environmental Sciences (AREA)
  • Dentistry (AREA)
  • Agronomy & Crop Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (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)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Silicon Polymers (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Epoxy Compounds (AREA)
  • Steroid Compounds (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

本发明涉及式(I)的埃坡霉素C(R＝氢)及其制备方法，以及其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

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
本申请是1997年11月18日提交的，发明名称为“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”的中国专利申请97199814.0的分案申请。
技术领域
本发明涉及埃坡霉素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。
发明内容
埃坡霉素C和D
根据一个实施方案，本发明涉及埃坡霉素(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：
-包含埃坡霉素A的第一部分，
-包含埃坡霉素B的第二部分，
-包含第一种其它埃坡霉素的第三部分，
-包含第二种其它埃坡霉素的第四部分；
然后分离
(h1)上述第三部分中的第一种其它埃坡霉素；和
(h2)上述第四部分中的第二种其它埃坡霉素。
本发明还涉及经验式为C26H39NO5S的埃坡霉素(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埃坡霉素C：
Figure A20051000628200061
埃坡霉素C：R＝H。
本发明还涉及经验式为C27H41NO5S的埃坡霉素(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埃坡霉素D：
埃坡霉素D：R＝CH3。
埃坡霉素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 A20051000628200071
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，但不要求保护埃坡霉素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。
埃坡霉素E和F
根据另一个实施方案，本发明涉及埃坡霉素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，用埃坡霉素A的甲醇溶液处理全部或部分经分离的培养物；
(b)用埃坡霉素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 100 C-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。
本发明还涉及该类型之埃坡霉素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埃坡霉素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(埃坡霉素E)：
埃坡霉素E：R＝H。
根据再一个实施方案，本发明涉及埃坡霉素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，用埃坡霉素B的甲醇溶液处理全部或部分经分离的培养物；
(b)用埃坡霉素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 100 C-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埃坡霉素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埃坡霉素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(埃坡霉素F)：
埃坡霉素F：R＝CH3。
制备和组合物
根据本发明的化合物或埃坡霉素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，该组合物由上述埃坡霉素C、D、E和F中的一种或多种组成或者由一种或多种上述埃坡霉素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。
附图说明
图1显示发酵结束时XAD洗脱液的HPLC分析。
图2显示在温育48小时后分析，加入埃坡霉素A和B后，发酵液中富含埃坡霉素E和F。
图3显示埃坡霉素A通过Sorangium cellulosum So ce 90向埃坡霉素E生物转化的动力学。
图4显示埃坡霉素A向埃坡霉素E的生物转化。
图5显示埃坡霉素B向埃坡霉素F的生物转化。
具体实施方式
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：埃坡霉素C和D
A、根据埃坡霉素基础专利DE-B-41 38 042制备菌株和培养条件
B、用DSM 6773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、0.1％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0.1NL/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SephadexLH-20(柱20×100cm，20ml/min的甲醇)上分步提取，得到三个部分。埃坡霉素包含在总共72g的部分中，其洗脱保留时间为240-300min。为分离埃坡霉素，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。在埃坡霉素A和B后，洗脱出Rt＝90-95min的埃坡霉素C和Rt＝100-110min的埃坡霉素D，真空蒸发后分别得到0.3g的无色油状物。
D、物理性质
埃坡霉素C：R＝H
埃坡霉素C：R＝CH3
埃坡霉素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 100 C-18 7μm，125×4mm
洗脱剂：甲醇/水＝65∶35
流速：1ml/min
检测：二极管阵列
埃坡霉素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 100 C-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：埃坡霉素C和埃坡霉素D在[D6]DMSO中于300MHz时的1H-和13C-NMR数据
                  埃坡霉素C               埃坡霉素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：
埃坡霉素A和由埃坡霉素C得到的12，13-二环氧-埃坡霉素A
将50mg埃坡霉素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的埃坡霉素A，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-埃坡霉素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 A20051000628200151
12，13-二环氧-埃坡霉素A：R＝H
实施例3：埃坡霉素E和F，埃坡霉素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Sorangium celluslosum 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DSM 6773。
产物特征和培养条件描述在：H_lfe，G.；N.Bedorf，K.Gerth & HReichenbach：埃坡霉素s，制备方法和包含该物质的组合物(埃坡霉素s，processes for their preparation and compostions containing them)。DE41 38 042 A1，于1993年5月27日公布。
在发酵期间埃坡霉素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0.2Nl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，所形成的埃坡霉素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，它们的吸收光谱与埃坡霉素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。
埃坡霉素A和B向埃坡霉素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埃坡霉素A+14mg埃坡霉素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。埃坡霉素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。埃坡霉素A的转化作用动力学见图3。
埃坡霉素E和F的分离
为分离埃坡霉素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：埃坡霉素E：50mg
              F：10mg
埃坡霉素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)，并与埃坡霉素A进行比较。
细胞株           IC50(ng/ml)
    埃坡霉素E     埃坡霉素A
HeLa.KB-3.1(人)     5     1
鼠成纤维细胞，L929     20     4
埃坡霉素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 100 C-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)
埃坡霉素F
C27H41NO7S(523)
ESI-MS(正离子)：524.5[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＝5.4min
柱：Nucleosil 100 C-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生物转化制备埃坡霉素E和F
1)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埃坡霉素A或埃坡霉素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是埃坡霉素A向埃坡霉素E转化的动力学。
图5是埃坡霉素B向埃坡霉素F转化的动力学。
2)通过生物转化1g埃坡霉素A来制备埃坡霉素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1g埃坡霉素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6l/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：
所用的埃坡霉素A：          1000mg ＝100％
21.5小时后回收的埃坡霉素A：53.7mg ＝5.4％
21.5小时后形成的埃坡霉素E：661.4mg＝66.1％
完全分解的埃坡霉素A：             ＝28.5％
实施例5
测试本发明之埃坡霉素对细胞培养物(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埃坡霉素实验
埃坡霉素     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：用埃坡霉素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
埃坡霉素A     95     60     70     70     74     39
埃坡霉素B     23     25     30     26     14
埃坡霉素C     125     76     95     80     94     49
埃坡霉素D     125     73     120     106     56
埃坡霉素E     80     60     50     45     59     31
埃坡霉素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埃坡霉素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 (5)

1、下式的埃坡霉素C：
埃坡霉素C：R＝H。
2、经验式为C26H39NO5S的权利要求1的埃坡霉素，其特征在于具有如表1所示的1H-和13C-NMR谱：
表1：埃坡霉素C在[D6]DMSO中于300MHz的1H-和13C-NMR数据                      埃坡霉素C     H原子     δ(ppm)     C原子     δ(ppm)     1     170.3     2-Ha     2.38     2     38.4     2-Hb     2.50     3     71.2     3-H     3.97     4     53.1     3-OH     5.12     5     217.1     6-H     3.07     6     45.4     7-H     3.49     7     75.9     7-OH     4.46     8     35.4     8-H     1.34     9     27.6     9-Ha     1.15     10     30.0     9-Hb     1.40     11     27.6     10-Ha     1.15*     12     124.6     10-Hb     1.35*     13     133.1     11-Ha     1.90     14     31.1     11-Hb     2.18     15     76.3     12-H     5.38**     16     137.3     13-H     5.44**     17     119.1     14-Ha     2.35     18     152.1     14-Hb     2.70     19     117.7     15-H     5.27     20     164.2     17-H     6.50     21     18.8     19-H     7.35     22     20.8     21-H3     2.65     23     22.6     22-H3     0.94     24     16.7     23-H3     1.21     25     18.4     24-H3     1.06     27     14.2     25-H3     0.90     26-H3     27-H3     2.10
*、**可互换的归属。
3、埃坡霉素C的制备方法，其中
(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，并浓缩洗脱液，得到粗提物，
(d)用乙酸乙酯提取所得浓缩物，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，并将该浓缩物在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部分，
(g)在C18反相柱上用甲醇/水混合物对所得部分进行色谱分离，并顺序得到：
—包含埃坡霉素A的第一部分，
—包含埃坡霉素B的第二部分，
—包含埃坡霉素C作为第一种其它埃坡霉素的第三部分，和
—包含埃坡霉素D作为第二种其它埃坡霉素的第四部分；
(h)分离第一其他部分的埃坡霉素C。
4、用于在农业、林业和/或园艺中保护植物的组合物，其由如前述权利要求之一所述的化合物中的一种或多种组成，或者由一种或多种这些化合物以及一种或多种常规载体和/或稀释剂组成。
5、治疗性组合物，其特别地用作细胞抑制剂，其由如前述权利要求之一项或多项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权利要求之一项或多项所述的化合物以及一种或多种常规载体和/或稀释剂组成。
CNB2005100062827A 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 Expired - Lifetime CN100344627C (zh)

Applications Claiming Priority (4)

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

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CNB971998140A Division 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

Publications (2)

Publication Number Publication Date
CN1680370A true CN1680370A (zh) 2005-10-12
CN100344627C CN100344627C (zh) 2007-10-24

Family

ID=26031383

Family Applications (2)

Application Number Title Priority Date Filing Date
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
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

Family Applications Before (1)

Application Number Title Priority Date Filing Date
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

Country Status (23)

Country Link
US (6) US7067544B2 (zh)
EP (2) EP0941227B2 (zh)
JP (1) JP4274583B2 (zh)
KR (1) KR100538095B1 (zh)
CN (2) CN1196698C (zh)
AT (2) ATE408612T1 (zh)
AU (1) AU753546B2 (zh)
BR (1) BR9713363B1 (zh)
CA (1) CA2269118C (zh)
CY (1) CY2542B1 (zh)
CZ (2) CZ296164B6 (zh)
DE (2) DE59712968D1 (zh)
DK (2) DK1367057T3 (zh)
ES (2) ES2221692T5 (zh)
HU (1) HU229833B1 (zh)
IL (1) IL129558A (zh)
NO (1) NO319984B1 (zh)
NZ (1) NZ335383A (zh)
PL (1) PL193229B1 (zh)
PT (2) PT941227E (zh)
RU (1) RU2198173C2 (zh)
TW (1) TW408119B (zh)
WO (1) WO1998022461A1 (zh)

Families Citing this family (183)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1186606B2 (de) 1995-11-17 2011-09-07 Gesellschaft für Biotechnologische Forschung mbH (GBF) Epothilon-Derivate, ihre Herstellung und Verwendung
US5969145A (en) * 1996-08-30 1999-10-19 Novartis Ag Process for the production of epothilones and intermediate products within the process
CN1196698C (zh) 1996-11-18 2005-04-13 生物技术研究有限公司(Gbf) 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
DE69734362T2 (de) 1996-12-03 2006-07-20 Sloan-Kettering Institute For Cancer Research Synthese von epothilonen, zwischenprodukte dazu, analoga und verwendungen davon
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
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
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
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 (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
WO2000031247A2 (en) * 1998-11-20 2000-06-02 Kosan Biosciences, Inc. 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
ATE254615T1 (de) * 1999-02-22 2003-12-15 Biotechnolog Forschung Gmbh C-21 modifizierte epothilone
US6291684B1 (en) 1999-03-29 2001-09-18 Bristol-Myers Squibb Company Process for the preparation of aziridinyl epothilones from oxiranyl epothilones
HUP0202708A3 (en) 1999-04-15 2004-12-28 Bristol Myers Squibb Co Cyclic protein tyrosine kinase inhibitors, pharmaceutical compositions containing them and their use
US7125875B2 (en) 1999-04-15 2006-10-24 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
EP2289549A3 (en) 1999-10-01 2011-06-15 Immunogen, Inc. Immunoconjugates for treating cancer
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
KR20070092334A (ko) * 2000-04-28 2007-09-12 코산 바이오사이언시즈, 인코포레이티드 폴리케타이드의 제조방법
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
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
WO2002062338A1 (en) 2001-01-25 2002-08-15 Bristol-Myers Squibb Company Parenteral formulation containing epothilone analogs
ES2304240T3 (es) 2001-01-25 2008-10-01 Bristol-Myers Squibb Company Procedimientos para la preparacion de preparaciones farmaceuticas que contienen analogos de epotilona para el tratamiento de cancer.
US6893859B2 (en) 2001-02-13 2005-05-17 Kosan Biosciences, Inc. Epothilone derivatives and methods for making and using the same
MXPA03007423A (es) 2001-02-20 2003-11-18 Bristol Myers Squibb Co Derivados de epotilona para tratamiento de tumores refractarios.
KR20040025895A (ko) 2001-02-20 2004-03-26 브리스톨-마이어스스퀴브컴파니 에포틸론 유도체를 사용하는 치료불응성 종양의 치료
CA2437707A1 (en) 2001-02-27 2002-09-19 Gesellschaft Fuer Biotechnologische Forschung Mbh (Gbf) Degradation of epothilones and ethynyl substituted epothilones
CA2439268C (en) 2001-02-27 2010-01-19 Novartis Ag Combination comprising a signal transduction inhibitor and an epothilone derivative
BRPI0207961B8 (pt) 2001-03-14 2021-05-25 Bristol Myers Squibb Co uso de análogos de epotilona e capecitabina para fabricar medicamento para tratar tumores cancerosos sólidos e kit compreendendo os referidos compostos.
EP1392664A4 (en) 2001-06-01 2005-01-26 Bristol Myers Squibb Co EPOTHILONE DERIVATIVES
TWI315982B (en) 2001-07-19 2009-10-21 Novartis Ag Combinations comprising epothilones and pharmaceutical uses thereof
DE10138347A1 (de) * 2001-08-03 2003-02-27 Schering Ag Geschützte 3,5-Dihydroxy-2,2-dimethyl-valeronitrile für die Synthese von Epothilonen- und Derivaten und Verfahren zur Herstellung
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
WO2003057217A1 (en) 2002-01-14 2003-07-17 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
AU2003218110A1 (en) 2002-03-12 2003-09-29 Bristol-Myers Squibb Company C3-cyano epothilone derivatives
WO2003077903A1 (en) 2002-03-12 2003-09-25 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
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
AU2003251902B2 (en) * 2002-07-29 2008-03-06 Merck Sharp & Dohme Llc Tiacumicin production
ES2281692T3 (es) * 2002-08-23 2007-10-01 Sloan-Kettering Institute For Cancer Research Sintesis de epotilones, sus intermediarios, sus analogos y sus usos.
US6921769B2 (en) 2002-08-23 2005-07-26 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
HRP20050278A2 (en) * 2002-09-23 2005-10-31 Bristol-Myers Squibb Company Methods for the preparation, isolation and purification of epothilone b, and x-ray crystal structures of epothilone b
EP1553938B1 (en) * 2002-10-15 2007-01-03 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Use of epothilone derivatives for the treatment of hyperparathyroidism
EP1567487A4 (en) 2002-11-15 2005-11-16 Bristol Myers Squibb Co OPEN-CHAINED, PROLYL-FROSTED MODULATORS OF ANDROGEN RECEPTOR FUNCTION
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
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
SG152225A1 (en) 2004-04-07 2009-05-29 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
KR20070084325A (ko) * 2004-11-18 2007-08-24 브리스톨-마이어스 스큅 컴퍼니 익사베필론을 포함하는 장용성 코팅된 비드 및 그의 제조방법
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
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
JP2009510073A (ja) 2005-09-27 2009-03-12 ノバルティス アクチエンゲゼルシャフト カルボキシアミン化合物およびその使用方法
US9006224B2 (en) 2005-11-21 2015-04-14 Novartis Ag Neuroendocrine tumor treatment
GB0605120D0 (en) 2006-03-14 2006-04-26 Novartis Ag Organic Compounds
WO2007117439A2 (en) 2006-03-31 2007-10-18 Bristol-Myers Squibb Company Biomarkers and methods for determining sensitivity to microtubule-stabilizing agents
WO2007115289A2 (en) 2006-04-05 2007-10-11 Novartis Ag Combinations comprising bcr-abl/c-kit/pdgf-r tk inhibitors for treating cancer
RU2447891C2 (ru) 2006-04-05 2012-04-20 Новартис Аг Комбинации терапевтических средств, предназначенные для лечения рака
EP2026800A1 (en) 2006-05-09 2009-02-25 Novartis AG Combination comprising an iron chelator and an anti-neoplastic agent and use thereof
JP2010504933A (ja) 2006-09-29 2010-02-18 ノバルティス アーゲー Ｐｉ３ｋ脂質キナーゼ阻害剤としてのピラゾロピリミジン
KR20090095626A (ko) 2006-12-04 2009-09-09 더 보드 오브 트러스티즈 오브 더 유니버시티 오브 일리노이 쿠프레독신과 ＣｐＧ 리치 ＤＮＡ를 이용한 조성물 및 암 치료 방법
AU2008212788A1 (en) 2007-02-08 2008-08-14 The Board Of Trustees Of The University Of Illinois Compositions and methods to prevent cancer with cupredoxins
EP2120900A2 (en) 2007-02-15 2009-11-25 Novartis AG Combination of lbh589 with other therapeutic agents for treating cancer
PT2268612E (pt) 2008-03-24 2014-11-13 Novartis Ag Inibidores de metaloprotease de matriz à base de arilsulfonamidas
PT2260020E (pt) 2008-03-26 2014-10-28 Novartis Ag Inibidores das desacetilases b baseados no hidroxamato
CN101362784A (zh) * 2008-10-06 2009-02-11 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
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
NZ596488A (en) 2009-06-26 2012-11-30 Novartis Ag 1, 3-disubstituted imidazolidin-2-one derivatives as inhibitors of cyp 17
US8389526B2 (en) 2009-08-07 2013-03-05 Novartis Ag 3-heteroarylmethyl-imidazo[1,2-b]pyridazin-6-yl derivatives
KR20120089643A (ko) 2009-08-12 2012-08-13 노파르티스 아게 헤테로시클릭 히드라존 화합물, 및 암 및 염증을 치료하기 위한 그의 용도
IN2012DN01453A (zh) 2009-08-20 2015-06-05 Novartis Ag
KR20120050492A (ko) 2009-08-26 2012-05-18 노파르티스 아게 테트라-치환된 헤테로아릴 화합물 및 ｍｄｍ2 및/또는 ｍｄｍ4 조절제로서의 그의 용도
JP5466767B2 (ja) 2009-11-04 2014-04-09 ノバルティス アーゲー Ｍｅｋ阻害剤として有用なヘテロ環式スルホンアミド誘導体
PE20121384A1 (es) 2009-12-08 2012-10-13 Novartis Ag Derivados de sulfonamida heterociclicos
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
US20110300150A1 (en) 2010-05-18 2011-12-08 Scott Eliasof Compositions and methods for treatment of autoimmune and other disease
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
EP2702052B1 (en) 2011-04-28 2017-10-18 Novartis AG 17alpha-hydroxylase/c17,20-lyase inhibitors
IN2014DN00123A (zh) 2011-06-09 2015-05-22 Novartis Ag
KR102087854B1 (ko) 2011-06-10 2020-03-12 메르사나 테라퓨틱스, 인코포레이티드 단백질-중합체-약물 접합체
WO2012175487A1 (en) 2011-06-20 2012-12-27 Novartis Ag Cyclohexyl isoquinolinone compounds
WO2012175520A1 (en) 2011-06-20 2012-12-27 Novartis Ag Hydroxy substituted isoquinolinone derivatives
CA2840315A1 (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
UY34329A (es) 2011-09-15 2013-04-30 Novartis Ag Compuestos de triazolopiridina
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
US20150148377A1 (en) 2011-12-22 2015-05-28 Novartis Ag Quinoline Derivatives
JO3398B1 (ar) 2011-12-22 2019-10-20 Novartis Ag مشتقات 2،3- ثانى هيدرو- بنزو[1,4] أوكسازين والمركبات المتعلقة بها كمثبطات كيناز فسفواينوسيتيد-3 (pi3k) لمعالجة على سبيل المثال التهاب المفاصل الروماتيدي
JP2015503519A (ja) 2011-12-23 2015-02-02 ノバルティス アーゲー Ｂｃｌ２と結合相手の相互作用を阻害するための化合物
EP2794588A1 (en) 2011-12-23 2014-10-29 Novartis AG Compounds for inhibiting the interaction of bcl2 with binding partners
KR20140104047A (ko) 2011-12-23 2014-08-27 노파르티스 아게 Bcl2와 결합 파트너의 상호작용을 억제하기 위한 화합물
CA2859873A1 (en) 2011-12-23 2013-06-27 Novartis Ag Compounds for inhibiting the interaction of bcl2 with binding partners
KR20140107575A (ko) 2011-12-23 2014-09-04 노파르티스 아게 Bcl2와 결합 파트너의 상호작용을 억제하기 위한 화합물
KR101372563B1 (ko) * 2011-12-26 2014-03-14 주식회사 삼양바이오팜 에포틸론 함유물질로부터 에포틸론 ａ와 ｂ의 추출 및 정제 방법
US8815926B2 (en) 2012-01-26 2014-08-26 Novartis Ag Substituted pyrrolo[3,4-D]imidazoles for the treatment of MDM2/4 mediated diseases
EP2861576B1 (en) 2012-05-15 2018-01-10 Novartis AG Benzamide derivatives for inhibiting the activity of abl1, abl2 and bcr-abl1
EP2858988B1 (en) 2012-05-15 2018-02-28 Novartis AG Benzamide derivatives for inhibiting the activity of abl1, abl2 and bcr-abl1
TR201807023T4 (tr) 2012-05-15 2018-06-21 Novartis Ag Abl1, abl2 ve bcr- abl1 aktivitesinin inhibe edilmesi için benzamid türevleri.
KR102190848B1 (ko) 2012-05-15 2020-12-15 노파르티스 아게 Abl1, abl2 및 bcr-abl1의 활성을 억제하기 위한 화합물 및 조성물
WO2013175417A1 (en) 2012-05-24 2013-11-28 Novartis Ag Pyrrolopyrrolidinone compounds
BR112014031421A2 (pt) 2012-06-15 2017-06-27 Brigham & Womens Hospital Inc composições para tratamento de câncer e métodos para produção das mesmas
KR102160320B1 (ko) 2012-10-02 2020-09-28 에피테라퓨틱스 에이피에스 히스톤 탈메틸효소의 저해제
EP2924044B1 (en) 2012-11-17 2018-10-31 Beijing Shuobai Pharmaceutical Co., LTD Platinum compound 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
AU2013359506B2 (en) 2012-12-10 2018-05-24 Mersana Therapeutics, Inc. Protein-polymer-drug conjugates
US9872918B2 (en) 2012-12-12 2018-01-23 Mersana Therapeutics, Inc. Hydroxyl-polymer-drug-protein conjugates
JO3464B1 (ar) 2013-01-15 2020-07-05 Astellas Pharma Europe Ltd التركيبات الخاصة بمركبات التياكوميسين
WO2014115080A1 (en) 2013-01-22 2014-07-31 Novartis Ag Pyrazolo[3,4-d]pyrimidinone compounds as inhibitors of the p53/mdm2 interaction
WO2014115077A1 (en) 2013-01-22 2014-07-31 Novartis Ag Substituted purinone compounds
WO2014128612A1 (en) 2013-02-20 2014-08-28 Novartis Ag Quinazolin-4-one derivatives
ES2670864T3 (es) 2013-02-27 2018-06-01 Gilead Sciences, Inc. Inhibidores de histonas desmetilasas
US20150018376A1 (en) 2013-05-17 2015-01-15 Novartis Ag Pyrimidin-4-yl)oxy)-1h-indole-1-carboxamide derivatives and use thereof
SG11201509350RA (en) 2013-06-11 2015-12-30 Bayer Pharma AG Combinations for the treatment of cancer comprising a mps-1 kinase inhibitor and a mitotic inhibitor
UY35675A (es) 2013-07-24 2015-02-27 Novartis Ag Derivados sustituidos de quinazolin-4-ona
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
US9227969B2 (en) 2013-08-14 2016-01-05 Novartis Ag Compounds and compositions as inhibitors of MEK
AU2014321420B2 (en) 2013-09-22 2017-06-15 Sunshine Lake Pharma Co., Ltd. Substituted aminopyrimidine compounds and methods of use
EP3054992B1 (en) 2013-10-11 2019-08-14 Asana BioSciences, LLC Protein-polymer-drug conjugates
DK3054991T3 (da) 2013-10-11 2019-05-06 Mersana Therapeutics Inc Protein-polymer-lægemiddelkonjugater
US9403801B2 (en) 2014-03-28 2016-08-02 Calitor Sciences, Llc Substituted heteroaryl compounds and methods of use
TW201625535A (en) 2014-03-31 2016-07-16 Epitherapeutics Aps Inhibitors of histone demethylases
KR20160132496A (ko) 2014-04-03 2016-11-18 인빅터스 온콜로지 피비티. 엘티디. 초분자 조합 치료제
TW201625536A (zh) 2014-08-27 2016-07-16 艾比療法公司 抑制組蛋白去甲基酶之化合物及方法
US9938257B2 (en) 2015-09-11 2018-04-10 Calitor Sciences, Llc Substituted heteroaryl compounds and methods of use
EP3474901B1 (en) 2016-06-27 2025-08-06 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
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
KR102737185B1 (ko) 2018-01-20 2024-12-05 선샤인 레이크 파르마 컴퍼니 리미티드 치환된 아미노피리미딘 화합물 및 이의 사용 방법
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
KR20210084546A (ko) 2018-10-29 2021-07-07 메르사나 테라퓨틱스, 인코포레이티드 펩티드 함유 링커를 갖는 시스테인 조작된 항체-약물 접합체
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
EP4382129A3 (en) 2019-06-17 2024-07-03 Tagworks Pharmaceuticals B.V. Compounds for fast and efficient click release
EP4399283A2 (en) 2021-09-06 2024-07-17 Veraxa Biotech GmbH Novel aminoacyl-trna synthetase variants for genetic code expansion in eukaryotes
EP4437005A1 (en) 2021-11-25 2024-10-02 Veraxa Biotech GmbH Improved antibody-payload conjugates (apcs) prepared by site-specific conjugation utilizing genetic code expansion
EP4186529B1 (en) 2021-11-25 2025-07-09 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
IL314951B2 (en) 2022-02-15 2025-07-01 Tagworks Pharmaceuticals B V Masked il12 protein
KR20250049568A (ko) 2022-07-15 2025-04-11 페온 테라퓨틱스 리미티드 Cdcp1에 결합하는 항체 약물 접합체 및 이의 용도
WO2024080872A1 (en) 2022-10-12 2024-04-18 Tagworks Pharmaceuticals B.V. Strained bicyclononenes
CN120569216A (zh) 2023-01-20 2025-08-29 巴斯夫欧洲公司 稳定型生物聚合物组合物、其制造和用途
KR20250169530A (ko) 2023-03-10 2025-12-03 태그웍스 파마슈티컬스 비.브이. 개선된 t-링커를 갖는 트랜스-사이클로옥텐
AU2024300552A1 (en) 2023-07-27 2026-01-29 Veraxa Biotech Gmbh Hydrophilic trans-cyclooctene (hytco) compounds, constructs and conjugates containing the same
EP4512395A1 (en) 2023-08-21 2025-02-26 Bio Even Composition comprising flavin adenine dinucleotide (fad), l-gsh, atp and myristic acid, alone or with a drug
WO2025056807A1 (en) 2023-09-15 2025-03-20 Basf Se Stabilized biopolymer composition, their manufacture and use
WO2025149667A1 (en) 2024-01-12 2025-07-17 Pheon Therapeutics Ltd Antibody drug conjugates and uses thereof
WO2025174248A1 (en) 2024-02-16 2025-08-21 Tagworks Pharmaceuticals B.V. Trans-cyclooctenes with "or gate" release

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
CA2157190A1 (en) 1993-03-05 1994-09-15 Wilfried Fischer Crystalline cyclodextrin inclusion complexes of ranitidine hydrochloride and process for their preparation
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
EP1186606B2 (de) 1995-11-17 2011-09-07 Gesellschaft für Biotechnologische Forschung mbH (GBF) Epothilon-Derivate, ihre Herstellung und Verwendung
DE19639456A1 (de) 1996-09-25 1998-03-26 Biotechnolog Forschung Gmbh Epothilon-Derivate, Herstellung und Mittel
DE19542986A1 (de) * 1995-11-17 1997-05-22 Biotechnolog Forschung Gmbh Epothilon-Derivate und deren Verwendung
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
DE19636343C1 (de) 1996-08-30 1997-10-23 Schering Ag Zwischenprodukte innerhalb der Totalsynthese von Epothilon A und B
DE19645361A1 (de) 1996-08-30 1998-04-30 Ciba Geigy Ag Zwischenprodukte innerhalb der Totalsynthese von Epothilon A und B, Teil II
AU716610B2 (en) 1996-08-30 2000-03-02 Novartis Ag Method for producing epothilones, and intermediate products obtained during the production process
CN1196698C (zh) 1996-11-18 2005-04-13 生物技术研究有限公司(Gbf) 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
US6515016B2 (en) 1996-12-02 2003-02-04 Angiotech Pharmaceuticals, Inc. Composition and methods of paclitaxel for treating psoriasis
US6204388B1 (en) * 1996-12-03 2001-03-20 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
DE69734362T2 (de) * 1996-12-03 2006-07-20 Sloan-Kettering Institute For Cancer Research Synthese von epothilonen, zwischenprodukte dazu, analoga und verwendungen davon
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
DE19701758A1 (de) 1997-01-20 1998-07-23 Wessjohann Ludgar A Dr Epothilone-Synthesebausteine
HU228851B1 (en) 1997-02-25 2013-06-28 Biotechnolog Forschung Gmbh Process for preparing epothilones with a modified side chain and compounds prepared by this process
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
WO1998047891A1 (de) 1997-04-18 1998-10-29 Studiengesellschaft Kohle Mbh Selektive olefinmetathese von bi- oder polyfunktionellen substraten in komprimiertem kohlendioxid als reaktionsmedium
DE19821954A1 (de) 1997-05-15 1998-11-19 Biotechnolog Forschung Gmbh Verfahren zur Herstellung eines Epothilon-Derivats
DE19720312A1 (de) 1997-05-15 1998-11-19 Hoechst Ag Zubereitung mit erhöhter in vivo Verträglichkeit
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
DE19833750A1 (de) 1997-07-16 1999-02-25 Schering Ag Thiazolderivate, Verfahren zur Herstellung und Verwendung
AU9340998A (en) 1997-08-09 1999-03-01 Schering Aktiengesellschaft New epothilone derivatives, method for producing same and their pharmaceutical use
ES2324378T3 (es) 1998-02-05 2009-08-05 Novartis Ag Composicion farmaceutica que contiene epotilona.
US6194181B1 (en) * 1998-02-19 2001-02-27 Novartis Ag Fermentative preparation process for and crystal forms of cytostatics
EP1058679B1 (en) 1998-02-25 2005-10-19 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues therof
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
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
WO2000031247A2 (en) 1998-11-20 2000-06-02 Kosan Biosciences, Inc. Recombinant methods and materials for producing epothilone and epothilone derivatives
PT1140944E (pt) 1998-12-22 2004-01-30 Novartis Pharma Gmbh Derivados de epotilona e sua utilizacao como agentes antitumorais
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
MXPA01008328A (es) 1999-02-18 2002-06-04 Schering Ag Derivados de 18 -haluro epotilona, metodo para su produccion y su uso farmaceutico.
ATE254615T1 (de) * 1999-02-22 2003-12-15 Biotechnolog Forschung Gmbh C-21 modifizierte epothilone
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 (en) * 2001-09-28 2003-04-10 Sumika Fine Chemicals Co., Ltd. Intermediates for epothilone derivative and process for producing these
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
HRP20050278A2 (en) 2002-09-23 2005-10-31 Bristol-Myers Squibb Company Methods for the preparation, isolation and purification of epothilone b, and x-ray crystal structures of epothilone b

Also Published As

Publication number Publication date
ES2221692T3 (es) 2005-01-01
KR20000053308A (ko) 2000-08-25
CA2269118A1 (en) 1998-05-28
DK0941227T3 (da) 2004-06-28
US8076490B2 (en) 2011-12-13
US20050090535A1 (en) 2005-04-28
WO1998022461A1 (de) 1998-05-28
HK1083832A1 (zh) 2006-07-14
ES2221692T5 (es) 2009-12-14
PT1367057E (pt) 2008-12-04
CN1237970A (zh) 1999-12-08
HUP0000497A2 (hu) 2000-06-28
US20090247592A1 (en) 2009-10-01
PT941227E (pt) 2004-08-31
CY2542B1 (en) 2006-06-28
EP0941227B9 (de) 2005-05-04
DK0941227T5 (da) 2009-10-05
HUP0000497A3 (en) 2001-10-29
BR9713363B1 (pt) 2011-02-08
CZ296164B6 (cs) 2006-01-11
ES2221692T4 (es) 2005-10-01
HK1022314A1 (zh) 2000-08-04
NO992338L (no) 1999-05-14
US7759375B2 (en) 2010-07-20
DE59712968D1 (de) 2008-10-30
EP0941227B2 (de) 2009-10-14
US7067544B2 (en) 2006-06-27
ES2312695T3 (es) 2009-03-01
EP1367057A1 (de) 2003-12-03
CA2269118C (en) 2012-05-29
HU229833B1 (en) 2014-09-29
CZ303422B6 (cs) 2012-09-05
PL333435A1 (en) 1999-12-06
US20090270466A1 (en) 2009-10-29
IL129558A (en) 2001-10-31
US7846952B2 (en) 2010-12-07
DK1367057T3 (da) 2009-01-19
JP2001504474A (ja) 2001-04-03
US20110136185A1 (en) 2011-06-09
EP0941227B1 (de) 2004-05-19
AU5483798A (en) 1998-06-10
RU2198173C2 (ru) 2003-02-10
JP4274583B2 (ja) 2009-06-10
EP0941227A1 (de) 1999-09-15
NO319984B1 (no) 2005-10-10
CN1196698C (zh) 2005-04-13
BR9713363A (pt) 2000-01-25
ATE408612T1 (de) 2008-10-15
CZ175099A3 (cs) 1999-09-15
CN100344627C (zh) 2007-10-24
TW408119B (en) 2000-10-11
KR100538095B1 (ko) 2005-12-21
US20080293784A1 (en) 2008-11-27
US20060264482A1 (en) 2006-11-23
IL129558A0 (en) 2000-02-29
NZ335383A (en) 2000-10-27
NO992338D0 (no) 1999-05-14
DE59711647D1 (de) 2004-06-24
EP1367057B1 (de) 2008-09-17
PL193229B1 (pl) 2007-01-31
ATE267197T1 (de) 2004-06-15
AU753546B2 (en) 2002-10-24
DK0941227T4 (da) 2008-05-19

Similar Documents

Publication Publication Date Title
CN1680370A (zh) 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
CN1218947C (zh) 杀菌剂三氟甲基烷氨基三唑并嘧啶及其制备方法和应用
CN1286839C (zh) 细胞抑制剂及其晶形的发酵制备方法
CN101050445A (zh) 产埃坡霉素的微生物
CN1028712C (zh) 新型除莠剂组合物
CN85101191A (zh) L-肉毒碱的微生物学制备方法
CN101037658A (zh) 枯草芽孢杆菌zjb－063及其应用
CN1030470C (zh) 新抗生素金核霉素的制备方法
CN1053446C (zh) 新的thiomarinol衍生物及其制备方法
CN1800273A (zh) 海洋微生物发酵产生的化合物在抗生物污损中的应用
CN1849313A (zh) 抗生素化合物
CN1194006A (zh) 利用双加氧酶生物转化与化学步骤相结合的茚向无任何立体异构体的(is)－氨基－(2r)－茚满醇的转化
CN1067921A (zh) 新抗菌化合物
HK1022314B (zh) 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
CN1066772C (zh) 通过卤过氧化物酶生物转化与化学步骤结合将茚定量转化为(1s,2r)-茚氧化物和(1s,2r)-二氢茚二醇的方法
HK1083832B (zh) 埃坡霉素 c、其制备方法以及作爲细胞抑制剂和植物保护剂的应用
CN1011245B (zh) 抗生素do-248-a和do-248-b的生产方法
CN87106657A (zh) 新抗生素b-3543的生产方法和应用
CN85109322A (zh) 新的乙烯酮s，s-乙缩醛衍生物的制造方法以及治疗真菌病的方法
CN1102434A (zh) 真菌除草剂的生产方法
KR20050019892A (ko) 에포틸론 씨, 디, 이 및 에프, 그 제조방법 및 세포증식억제제와 식물 위생제로서의 이들의 용도
HK1042927A1 (zh) 生產赤蘚糖醇的酵母菌株
CN104313078A (zh) 一种生物催化生产手性噻唑乙醇的方法

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1083832

Country of ref document: HK

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: 1083832

Country of ref document: HK

CX01 Expiry of patent term

Granted publication date: 20071024