9-bromo-(20S)-camptothecin | 91421-50-0

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 喜树碱
• 英文名称: 9-bromo-(20S)-camptothecin
• 英文别名: 9-bromocamptothecin；10-bromo-camptothecin；9-Bromo camptothecin；(19S)-8-bromo-19-ethyl-19-hydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaene-14,18-dione
• CAS: 91421-50-0
• 化学式: C₂₀H₁₅BrN₂O₄
• 分子量: 427.254
• InChiKey: IKVRTIMRPCOPOQ-FQEVSTJZSA-N

物化性质

• 沸点：
  791.2±60.0 °C(Predicted)
• 密度：
  1.75±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  27
• 可旋转键数：
  1
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  79.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  9-bromo-(20S)-camptothecin 在 palladium on activated charcoal 1,1'-双(二苯基膦)二茂铁 、 palladium diacetate 、 氢气 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 methyl 3-[(19S)-19-ethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4,6,8,10,15(20)-heptaen-8-yl]propanoate
  参考文献：
  名称：

  Synthesis and cytotoxic activity of alkylidene- and alkyl-substituted camptothecins

  摘要：

  A new family of camptothecin derivatives is described. Their synthesis, in vitro cytotoxicity, and topoisomerase I inhibition is reported. (C) 1997 Elsevier Science Ltd.

  DOI：

  10.1016/s0960-894x(97)00105-4
• 作为产物：
  描述：

  鲁比替康 在 platinum(IV) oxide 氢溴酸 、 氢气 、 copper(I) bromide 、 sodium nitrite 作用下， 以 1,4-二氧六环 、 乙醇 为溶剂， 70.0 ℃ 、101.33 kPa 条件下， 反应 3.0h， 生成 9-bromo-(20S)-camptothecin
  参考文献：
  名称：

  Synthesis and Antitumor Activity of 20(S)-Camptothecin Derivatives: A-Ring Modified and 7,10-Disubstituted Camptothecins.

  摘要：

  在A环上具有硝基、氨基、氯、溴、羟基和甲氧基的20(S)-喜树碱衍生物被合成出来。通过在三氟乙酸中用四乙酸铅处理，B环氢化的喜树碱（2a）被转化为10-羟基喜树碱（6e）。通过N-氧化物（9）的光反应得到了10-取代的衍生物（6）。对A环修饰的喜树碱的细胞毒性进行了体外KB细胞和小鼠中的白血病L1210的评估。鉴定出7-乙基-10-羟基喜树碱（6i）作为一个有潜力的衍生物，可进一步进行修饰。

  DOI：

  10.1248/cpb.39.3183

文献信息

• [EN] BIOLOGICAL MATERIALS AND USES THEREOF<br/>[FR] MATÉRIELS BIOLOGIQUES ET LEURS UTILISATIONS
  申请人：ANTIKOR BIOPHARMA LTD

  公开号：WO2016046574A1

  公开（公告）日：2016-03-31

  The invention provides compounds comprising a therapeutic agent coupled to a carrier molecule, with a minimum coupling ratio of 5: 1; wherein the carrier molecule is (i) an antibody fragment or derivative thereof or (ii) an antibody mimetic or derivative thereof; and wherein the therapeutic agents are coupled onto a lysine amino acid residue; and further wherein the therapeutic agent is not a photosensitising agent. There is also provided uses, methods relating to such compounds, as well as processes for their manufacture.

  该发明提供了包含治疗剂与载体分子偶联的化合物，最低偶联比为5:1；其中，载体分子是(i)抗体片段或其衍生物，或(ii)抗体模拟物或其衍生物；治疗剂偶联到赖氨酸氨基酸残基上；进一步，治疗剂不是光敏剂。还提供了关于这些化合物的用途、方法以及其制造过程。
• Plant antitumor agents. 30. Synthesis and structure activity of novel camptothecin analogs
  作者：Monroe E. Wall、Mansukh C. Wani、Allan W. Nicholas、Govindarajan Manikumar、Chhagan Tele、Linda Moore、Anne Truesdale、Peter Leitner、Jeffrey M. Besterman

  DOI：10.1021/jm00070a013

  日期：1993.9

  A large number of camptothecin (CPT) analogs have been prepared in the 20S, 20RS, and 20R configurations with a number of ring A substituents. Topoisomerase I (T-I) inhibition data (IC50) have been obtained by standard procedures. In general, substitution at the 9 or 10 positions with amino, halogeno, or hydroxyl groups in compounds with 20S configuration results in compounds with enhanced T-I inhibition

  已经制备了具有许多环A取代基的20S，20RS和20R构型的大量喜树碱（CPT）类似物。拓扑异构酶I（TI）抑制数据（IC50）已通过标准程序获得。通常，具有20S构型的化合物在9或10位上被氨基，卤代或羟基取代会导致TI抑制作用增强。20RS构型的化合物在体外和体内活性较低，而20R构型的化合物则无活性。在TI抑制试验中，在A环上具有10,11-亚甲二氧基取代的化合物显示出显着的效能增强。在包括L-1210小鼠白血病测定法在内的各种体内测定法中确定的某些类似物的活性通常与TI抑制作用一致。制备了许多水溶性类似物，例如20-甘氨酸酯，9-甘氨酰胺或水解的内酯盐，并在体外和体内试验中进行了测试。通常，就L-1210分析中的TI抑制作用和寿命延长而言，这些化合物的活性均不如CPT。然而，某些20-甘氨酸酯在静脉内给药后显示出良好的体内活性。
• Alkynyl-substituted camptothecins and process for their preparation
  申请人：Pharmacia & Upjohn S.p.A.

  公开号：US06420379B1

  公开（公告）日：2002-07-16

  The present invention relates to alkynyl-substituted camptothecins of formula (I) wherein X, R1, R2 are as defined herein, and the pharmaceutically salts thereof. These compounds are useful in therapy as antitumor agents.

  本发明涉及公式（I）中X，R1，R2如定义的炔基取代喜树碱及其药物盐。这些化合物在治疗抗肿瘤剂方面有用。
• Substituted camptothecin derivatives and process for their preparation
  申请人：Pharmacia & Upjohn S.p.A.

  公开号：US05856333A1

  公开（公告）日：1999-01-05

  The present invention relates to substituted camptothecin derivatives of formula (I) wherein the symbol - - - - represents a single or double bond; R.sub.1, R.sub.2 and R.sub.3 are as defined under (a) or (b) below: (a) R.sub.1 and R.sub.2 are, each independently, hydrogen; C.sub.1 -C.sub.4 alkyl; C.sub.3 -C.sub.7 cycloalkyl; phenyl C.sub.1 -C.sub.6 alkyl; an optionally substituted phenyl ring; --NR.sub.5 R.sub.6 wherein one of R.sub.5 and R.sub.6 is hydrogen, C.sub.1 -C.sub.6 alkyl or benzyl and the other is hydrogen, C.sub.1 -C.sub.6 alkanoyl, an optionally substituted C.sub.1 -C.sub.6 alkoxycarbonyl, an optionally substituted benzoyl, phenyl C.sub.1 -C.sub.6 alkanoyl, an optionally substituted C.sub.1 -C.sub.6 alkoxycarbonyl, an optionally substituted phenoxycarbonyl or phenyl C.sub.1 -C.sub.6 alkoxycarbonyl, or R.sub.5 and R.sub.6, combined together with the nitrogen atom to which they are linked, form a 4-7 membered saturated, optionally substituted, heteromonocyclic ring residue; COOR.sub.8 wherein R.sub.8 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl or phenyl C.sub.1 -C.sub.6 alkyl; or COR.sub.9 wherein Rg is C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl C.sub.1 -C.sub.6 alkyl, an optionally substituted phenyl ring or NR.sub.10 R.sub.11 wherein R.sub.10 and R.sub.11 are, each independently, hydrogen or C.sub.1 -C.sub.6 alkyl; and R.sub.3 is hydrogen, C.sub.1 -C.sub.6 alkyl or an optionally substituted phenyl ring; or (b) R.sub.1 and R.sub.3, combined together, form a 5-8 membered, optionally substituted, carbomonocyclic ring, and R.sub.2 is hydrogen, C.sub.1 -C.sub.4 alkyl or C.sub.3 -C.sub.7 cycloalkyl; R.sub.4 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl or phenyl C.sub.1 -C.sub.6 alkyl; X is hydrogen,C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.3 -C.sub.7 cycloalkoxy, C.sub.1 -C.sub.6 alkanoyloxy, benzoyloxy, amino, hydroxy, nitro, halogen or it is a methylenedioxy group linked to the positions 10 and 11 of the molecule, and the pharmaceutically acceptable salts thereof. The compounds according to the invention are useful in therapy as antitumor agents. ##STR1##

  本发明涉及式（I）的取代喜树碱衍生物，其中符号——表示单键或双键；R.sub.1，R.sub.2和R.sub.3如下定义的（a）或（b）：（a）R.sub.1和R.sub.2分别是氢；C.sub.1-C.sub.4烷基；C.sub.3-C.sub.7环烷基；苯基C.sub.1-C.sub.6烷基；可选择取代的苯环；-NR.sub.5 R.sub.6，其中R.sub.5和R.sub.6中的一个是氢，C.sub.1-C.sub.6烷基或苄基，另一个是氢，C.sub.1-C.sub.6烷酰基，可选择取代的C.sub.1-C.sub.6烷氧羰基，可选择取代的苯甲酰基，苯基C.sub.1-C.sub.6烷酰基，可选择取代的C.sub.1-C.sub.6烷氧羰基，可选择取代的苯氧羰基或苯基C.sub.1-C.sub.6烷氧羰基，或R.sub.5和R.sub.6与它们连接的氮原子结合在一起形成4-7成员饱和的、可选择取代的、杂单环环残基；COOR.sub.8，其中R.sub.8是氢，C.sub.1-C.sub.6烷基，C.sub.3-C.sub.7环烷基或苯基C.sub.1-C.sub.6烷基；或COR.sub.9，其中Rg是C.sub.1-C.sub.6烷基，C.sub.3-C.sub.7环烷基，苯基C.sub.1-C.sub.6烷基，可选择取代的苯环或NR.sub.10 R.sub.11，其中R.sub.10和R.sub.11分别是氢或C.sub.1-C.sub.6烷基；以及R.sub.3是氢，C.sub.1-C.sub.6烷基或可选择取代的苯环；或（b）R.sub.1和R.sub.3结合在一起形成5-8成员的、可选择取代的、碳单环环，R.sub.2是氢，C.sub.1-C.sub.4烷基或C.sub.3-C.sub.7环烷基；R.sub.4是氢，C.sub.1-C.sub.6烷基，C.sub.3-C.sub.7环烷基或苯基C.sub.1-C.sub.6烷基；X是氢，C.sub.1-C.sub.6烷基，C.sub.3-C.sub.7环烷基，C.sub.1-C.sub.6烷氧基，C.sub.3-C.sub.7环烷氧基，C.sub.1-C.sub.6烷酰氧基，苯甲酰氧基，氨基，羟基，硝基，卤素或它是与分子的10和11位置相连的亚甲二氧基基团，以及其药学上可接受的盐。本发明的化合物在治疗中作为抗肿瘤剂是有用的。
• FUNCTIONALIZED 9-BROMO-CAMPTOTHECIN DERIVATIVES
  申请人：NERVIANO MEDICAL SCIENCES S.R.L.

  公开号：US20150291613A1

  公开（公告）日：2015-10-15

  The present invention relates to new functionalized 9-bromo-camptothecin derivatives (I) which have cytotoxic activity and are useful in treating diseases such as cancer, cellular proliferation disorders and viral infections. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising them and methods of treating diseases utilizing such compounds or the pharmaceutical composition containing them. The invention also relates to the use of these functionalized 9-bromo-camptothecin derivatives in the preparation of conjugates.

  本发明涉及新的功能化9-溴喜树碱衍生物(I)，具有细胞毒性活性，可用于治疗癌症、细胞增殖紊乱和病毒感染等疾病。本发明还提供制备这些化合物的方法、包含它们的药物组合物以及利用这些化合物或包含它们的药物组合物治疗疾病的方法。本发明还涉及在制备共轭物时使用这些功能化9-溴喜树碱衍生物的用途。