Epothilone H₂ | 198571-09-4

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酯类和类似物
• 英文名称: Epothilone H₂
• 英文别名: 19-oxazole-EpoD；(4S,7R,8S,9S,13Z,16S(E))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione；epothilone H2；(4S,7R,8S,9S,13Z,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-(2-methyl-1,3-oxazol-4-yl)prop-1-en-2-yl]-1-oxacyclohexadec-13-ene-2,6-dione
• CAS: 198571-09-4
• 化学式: C₂₇H₄₁NO₆
• 分子量: 475.626
• InChiKey: QJBTYCVYJKZKMC-GIQCAXHBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  34
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  110
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  Epothilone H₂ 在 间氯过氧苯甲酸 作用下， 以 氯仿 为溶剂， 反应 3.0h， 以6%的产率得到(1R,3S,7S,10R,11S,12S,16S)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[(E)-1-methyl-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione
  参考文献：
  名称：

  Total Synthesis of Oxazole- and Cyclopropane-Containing Epothilone B Analogues by the Macrolactonization Approach

  摘要：

  AbstractIn order to probe structure‐activity relationships in the epothilone area, two series of epothilone B analogues have been designed and synthesized. The first series containing an oxazole moiety in place of a thiazole on the side chain was constructed by utilizing key intermediates 7–9 or 10, 12, and 13 (Scheme 1), whereas the second series containing an ethano group instead of the gem‐dimethyl group at position 4 was synthesized from fragments 42 and 43. A Yamaguchi‐type macrolactonization reaction was used to construct the macrocycle from a secoacid, which was assembled, in both cases, by means of a) an aldol reaction, b) an Enders alkylation, and c) a Wittig‐type reaction. This convergent strategy provided access to oxazole analogues 2,4,29–32 and 4,4‐ethano derivatives 3,40,60–63 for biological studies.

  DOI：

  10.1002/chem.19970031212
• 作为产物：
  描述：

  (2E,6E)-(S)-2-Allyl-5-(tert-butyl-dimethyl-silanyloxy)-6-methyl-7-(2-methyl-oxazol-4-yl)-hepta-2,6-dienoic acid methyl ester 在 咪唑 、 2,6-二甲基吡啶 、 四氯化碳 、 4-二甲氨基吡啶 、 sodium hydroxide 、 sodium chlorite 、 sodium dihydrogenphosphate 、 9-borabicyclo[3.3.1]nonane dimer 、 phosphate buffer 、 2-甲基-2-丁烯 、 草酰氯 、 MMPP 、 2,4,6-三氯苯甲酰氯 、 camphor-10-sulfonic acid 、 四丁基氟化铵 、 双氧水 、 碘 、 二异丁基氢化铝 、 三乙基硼氢化锂 、 氟化氢吡啶 、 二甲基亚砜 、 三乙胺 、 三苯基膦 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 正己烷 、 二氯甲烷 、 甲苯 、 乙腈 、 叔丁醇 为溶剂， 反应 117.25h， 生成 Epothilone H₂
  参考文献：
  名称：

  Total Synthesis of Oxazole- and Cyclopropane-Containing Epothilone B Analogues by the Macrolactonization Approach

  摘要：

  AbstractIn order to probe structure‐activity relationships in the epothilone area, two series of epothilone B analogues have been designed and synthesized. The first series containing an oxazole moiety in place of a thiazole on the side chain was constructed by utilizing key intermediates 7–9 or 10, 12, and 13 (Scheme 1), whereas the second series containing an ethano group instead of the gem‐dimethyl group at position 4 was synthesized from fragments 42 and 43. A Yamaguchi‐type macrolactonization reaction was used to construct the macrocycle from a secoacid, which was assembled, in both cases, by means of a) an aldol reaction, b) an Enders alkylation, and c) a Wittig‐type reaction. This convergent strategy provided access to oxazole analogues 2,4,29–32 and 4,4‐ethano derivatives 3,40,60–63 for biological studies.

  DOI：

  10.1002/chem.19970031212

文献信息

• [DE] VERFAHREN FÜR DIE HERSTELLUNG VON C1-C15-FRAGMENTEN VON EPOTHILONEN UND DEREN DERIVATEN<br/>[EN] METHOD FOR PRODUCING C1-C15 FRAGMENTS OF EPOTHILONES AND THE DERIVATIVES THEREOF<br/>[FR] PROCEDE DE FABRICATION DE FRAGMENTS C1-C15 D'EPOTHILONES ET DE LEURS DERIVES
  申请人：SCHERING AG

  公开号：WO2005003071A1

  公开（公告）日：2005-01-13

  Die vorliegende Erfindung beschreibt ein Verfahren für die Herstellung von C1-C15-Fragmenten von Epothilonen und deren Derivaten, bei dem ein C1 - C6-Fragment mit einem C7 -C12-Fragment zu einem C1 - C12-Fragment verknüpft, und dieses dann mit einem C13 - C15-Fragment zu dem herzustellenden C1 - C15-Epothilon-Vorprodukt umgesetzt wird. Die so erhaltenen C1 - C15-Epothilon-Vorprodukte lassen sich nach bekannten Methoden zu den eigentlichen Wirkstoffen umsetzen. Die Erfindung betrifft außerdem die entsprechenden C1 - C12-Fragmente.

  本发明描述了一种制备Epothilone及其衍生物的C1-C15片段的方法，其中将一个C1-C6片段与一个C7-C12片段连接成一个C1-C12片段，然后将其与一个C13-C15片段反应以制备C1-C15 Epothilon前体。通过已知方法，可以将得到的C1-C15 Epothilon前体转化为实际的药物。该发明还涉及相应的C1-C12片段。
• Method for producing c1-c15 fragments of epothilones and the derivatives thereof
  申请人：Klar Ulrich

  公开号：US20070142675A1

  公开（公告）日：2007-06-21

  This invention describes a process for the production of C 1 -C 15 -fragments of epothilones and derivatives thereof, in which a C1-C6-fragment is linked with a C7-C12-fragment to a C1-C12-fragment, and the latter then is reacted with a C13-15-fragment to form the C1-C15 initial epothilone product that is to be produced. The thus obtained C1-C15 initial epothilone products can be reacted according to known methods to form the actual active ingredients. In addition, the invention relates to the corresponding C1-C12-fragments.

  该发明描述了一种生产依托利酮及其衍生物的C1-C15片段的过程，其中将一个C1-C6片段与一个C7-C12片段连接成一个C1-C12片段，然后将后者与一个C13-15片段反应以形成要生产的C1-C15初始依托利酮产物。所得的C1-C15初始依托利酮产物可以按照已知方法反应以形成实际的活性成分。此外，该发明还涉及相应的C1-C12片段。
• Epothilone derivatives and methods for making and using the same
  申请人：——

  公开号：US20030023082A1

  公开（公告）日：2003-01-30

  The present invention relates to bicyclic compounds wherein one of the cyclic moieties is a 16-membered macrocycle and to methods for making and using these compounds. The present invention provides compounds of the formula 1 wherein: R 1 , R 2 , and R 3 are each independently hydrogen, methyl or ethyl; R 4 is hydrogen, hydroxyl, fluoro, oxo, oximino, or NRR′ where R and R′ are independently hydrogen, C 1 -C 10 aliphatic, aryl or alkylaryl; R 5 is hydrogen, oxo, or C 1 -C 10 aliphatic; R 6 is hydrogen, hydroxyl, oxo, C 1 -C 10 aliphatic, C 1 -C 10 alkylester, or halide, or optionally R 5 and R 6 together form a carbon-carbon bond; R 7 is hydrogen, methyl, ethyl, methoxy, or OH; X is fused substituted or unsubstituted heterocyclo; Y is substituted or unsubstituted heterocyclo; R 9 is aryl or —CH═C(Me)-Aryl; and, W is O or NR 8 where R 8 is hydrogen, C 1 -C 10 aliphatic, aryl or alkylaryl.

  本发明涉及双环化合物，其中一个环状基团为16元大环，并涉及制备和使用这些化合物的方法。本发明提供了化合物1的公式，其中：R1、R2和R3各自独立地为氢、甲基或乙基；R4为氢、羟基、氟、氧、氧肟或NRR′，其中R和R′各自独立地为氢、C1-C10脂肪基、芳基或烷基芳基；R5为氢、氧或C1-C10脂肪基；R6为氢、羟基、氧、C1-C10脂肪基、C1-C10烷基酯或卤素，或者可选地，R5和R6共同形成碳-碳键；R7为氢、甲基、乙基、甲氧基或羟基；X为融合的取代或未取代的杂环；Y为取代或未取代的杂环；R9为芳基或-CH═C(Me)-芳基；W为O或NR8，其中R8为氢、C1-C10脂肪基、芳基或烷基芳基。
• New effector conjugates, process for their production and their pharmaceutical use
  申请人：Klar Ulrich

  公开号：US20050234247A1

  公开（公告）日：2005-10-20

  Conjugates of epothilones and epothilone derivatives (as effectors) with suitable biomolecules (as recognition units) are described. Their production is carried out by the effectors being reacted with suitable linkers, and the compounds that are produced are conjugated to the recognition units. The pharmaceutical use of conjugates for treating proliferative or angiogenesis-associated processes is described.

  描述了与适当的生物分子（作为识别单元）的环丙沙星和环丙沙星衍生物（作为效应物）的共轭体。它们的生产是通过将效应物与适当的连接剂反应，然后将产生的化合物与识别单元结合。描述了共轭体在治疗增殖或血管生成相关过程的药物用途。
• METHODS, KITS, AND COMPOUNDS FOR DETERMINING RESPONSIVENESS TO TREATMENT OF A PATHOLOGICAL DISORDER BY EPOTHILONES
  申请人：Hoffmann Jens

  公开号：US20090076098A1

  公开（公告）日：2009-03-19

  The invention provides methods, kits and compounds for determining the potential responsiveness of a subject suffering from a pathological disorder, including non-small cell lung cancer (NSCLC), to treatment with an epothilone by analyzing the gene expression profile and/or certain molecular markers in a sample obtained from said subject. The invention further relates to methods, compounds and uses of said compounds for treating subjects suffering from said pathologic disorder, optionally in combination with other therapeutic agents. Also provided are genes and/or proteins encoded by them whose expression level have been determined to differ between epothilone responders and epothilone non-responders.

  该发明提供了用于确定患有病理性疾病（包括非小细胞肺癌（NSCLC））的受试者对依托泊苷治疗的潜在反应性的方法、试剂盒和化合物，包括通过分析从该受试者获得的样本中的基因表达谱和/或某些分子标记来进行。该发明还涉及用于治疗患有该病理性疾病的受试者的方法、化合物和使用该化合物，可选择与其他治疗剂联合使用。还提供了由它们编码的基因和/或蛋白质，其表达水平已确定在依托泊苷反应者和依托泊苷非反应者之间存在差异。