(S)-9-((3-amino-5-((((S)-8-methoxy-6-oxo-11,12,12a,13-tetrahydro-6H-benzo[5,6][1,4]diazepino[1,2-a]indol-9-yl)oxy)methyl)benzyl)oxy)-8-methoxy-12a,13-dihydro-6H-benzo[5,6] [1,4]diazepino[1,2-a]indol-6-one | 2069250-01-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 英文名称: (S)-9-((3-amino-5-((((S)-8-methoxy-6-oxo-11,12,12a,13-tetrahydro-6H-benzo[5,6][1,4]diazepino[1,2-a]indol-9-yl)oxy)methyl)benzyl)oxy)-8-methoxy-12a,13-dihydro-6H-benzo[5,6] [1,4]diazepino[1,2-a]indol-6-one
• 英文别名: DGN549；Rfz57U5fje；(12aS)-9-[[3-[[(12aS)-8-methoxy-6-oxo-11,12,12a,13-tetrahydroindolo[2,1-c][1,4]benzodiazepin-9-yl]oxymethyl]-5-aminophenyl]methoxy]-8-methoxy-12a,13-dihydroindolo[2,1-c][1,4]benzodiazepin-6-one
• CAS: 2069250-01-5
• 化学式: C₄₂H₃₇N₅O₆
• 分子量: 707.786
• InChiKey: MPZZBNVMDYKZRF-KYJUHHDHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  53
• 可旋转键数：
  8
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  128
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (S)-9-((3-amino-5-((((S)-8-methoxy-6-oxo-11,12,12a,13-tetrahydro-6H-benzo[5,6][1,4]diazepino[1,2-a]indol-9-yl)oxy)methyl)benzyl)oxy)-8-methoxy-12a,13-dihydro-6H-benzo[5,6] [1,4]diazepino[1,2-a]indol-6-one 、 (S)-2-((S)-2-(6-((2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)amino)-6-oxohexanamido)propanamido)propanoic acid 在 N-羟基-7-氮杂苯并三氮唑 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 甲醇 为溶剂， 反应 0.58h， 以51.9%的产率得到N1-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)-N6-((S)-1-(((S)-1-((3-((((S)-8-methoxy-6-oxo-11,12,12a,13-tetrahydro-6H-benzo[5,6][1,4]diazepino[1,2-a]indol-9-yl)oxy)methyl)-5-((((S)-8-methoxy-6-oxo-12a,13-dihydro-6H-benzo[5,6][1,4]diazepino[1,2-a]indol-9-yl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)adipamide
  参考文献：
  名称：

  WO2020102053A5

  摘要：

  公开号：

  WO2020102053A5
• 作为产物：
  描述：

  (S)-9-hydroxy-8-methoxy-12a,13-dihydro-6H-benzo[5,6][1,4]diazepino[1,2-a]indol-6-one 在 偶氮二甲酸二异丙酯 、 铁粉 、 potassium carbonate 、 氯化铵 、 三苯基膦 、 potassium iodide 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基乙酰胺 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 19.0h， 生成 (S)-9-((3-amino-5-((((S)-8-methoxy-6-oxo-11,12,12a,13-tetrahydro-6H-benzo[5,6][1,4]diazepino[1,2-a]indol-9-yl)oxy)methyl)benzyl)oxy)-8-methoxy-12a,13-dihydro-6H-benzo[5,6] [1,4]diazepino[1,2-a]indol-6-one
  参考文献：
  名称：

  [EN] METHODS OF PREPARING CYTOTOXIC BENZODIAZEPINE DERIVATIVES
  [FR] PROCÉDÉS DE PRÉPARATION DE DÉRIVÉS DE BENZODIAZÉPINE CYTOTOXIQUES

  摘要：

  本发明涉及一种制备吲哚啉苯二氮平二聚物化合物及其合成前体的新方法。

  公开号：

  WO2017015495A1

文献信息

• Effect of Linker Stereochemistry on the Activity of Indolinobenzodiazepine Containing Antibody–Drug Conjugates (ADCs)
  作者：Emily E. Reid、Katie E. Archer、Manami Shizuka、Alan Wilhelm、Nicholas C. Yoder、Chen Bai、Nathan E. Fishkin、Luke Harris、Erin K. Maloney、Paulin Salomon、Erica Hong、Rui Wu、Olga Ab、Shan Jin、Katharine C. Lai、Surina Sikka、Ravi V. J. Chari、Michael L. Miller

  DOI：10.1021/acsmedchemlett.9b00240

  日期：2019.8.8

  determine the role of amino acid stereochemistry on antitumor activity and tolerability, we incorporated l- and d-alanyl groups in the dipeptide, synthesized all four diastereomers, and prepared and tested the corresponding ADCs. Results of our preclinical evaluation showed that the l-Ala-l-Ala configuration provided the ADC with the highest therapeutic index (antitumor activity vs toxicity).

  结合有效的吲哚基二氮杂卓DNA烷基化剂作为有效载荷成分的抗体-药物偶联物（ADC）目前正在临床评估中。在一个ADC设计中，有效负载分子通过肽酶不稳定的连接到抗体升-Ala-升-Ala接头。为了确定氨基酸立体化学对抗肿瘤活性和耐受性的作用，我们在二肽中掺入了l和d-丙氨酰基，合成了所有四种非对映异构体，并制备并测试了相应的ADC。我们的临床前评估结果表明，l- Ala- 1 -Ala构型为ADC提供了最高的治疗指数（抗肿瘤活性与毒性）。
• [EN] G-A CROSSLINKING CYTOTOXIC AGENTS<br/>[FR] AGENTS CYTOTOXIQUES DE RÉTICULATION G-A
  申请人：FEMTOGENIX LTD

  公开号：WO2020157491A1

  公开（公告）日：2020-08-06

  The invention relates to a compound of formula (I): or salts, solvates, isomers or tautomers thereof, wherein; A is a group selected from: R1 is selected from H and halogen; either R2 is selected from -CH2-halogen, C1-6 alkyl and H, and R3 is H or is absent; or R2 and R3 together with the carbon atoms to which they are attached form a cyclopropyl ring; SP is a spacer group; B is a polycyclic group: R11, R12, R13 and R14 are selected such that either: (aa) one of R11, R12, R13 and R14 is E and another of R11, R12, R13 and R14 is an optionally substituted Ar1 group; or (ab) one of R11, R12, R13 and R14 is Rx, wherein Rx is Ar1-Z1-E or -E1-Z1-Ar1; and Ar1 is an optionally substituted C5-20 aryl or C5-10 heteroaryl groupeach E is independently selected from (CH2)j-S(0)2-NR25R26, (CH2)j-S(0)2-0H, CH2CH2[0CH2CH2]WR25 and E1; and Z1 is NR26, C(=0)-0, O or is absent and these compounds are useful as medicaments, in particular as anti-proliferative agents.

  该发明涉及一种化合物，其化学式为(I)：或其盐、溶剂合物、异构体或互变异构体，其中；A是从中选择的一个基团：R1从H和卤素中选择；R2从-CH2-卤素、C1-6烷基和H中选择，R3是H或不存在；或者R2和R3与它们连接的碳原子一起形成环丙基环；SP是一个间隔基团；B是一个多环基团：R11、R12、R13和R14被选择为：(aa) R11、R12、R13和R14中的一个是E，另一个是可选择取代的Ar1基团；或者(ab) R11、R12、R13和R14中的一个是Rx，其中Rx是Ar1-Z1-E或-E1-Z1-Ar1；Ar1是可选择取代的C5-20芳基或C5-10杂环芳基，每个E独立选择自( )j-S(0)2-NR25R26、( )j-S(0)2-0H、 [0 ]WR25和E1；Z1是NR26、C(=0)-0、O或不存在，这些化合物可用作药物，特别是作为抗增殖剂。
• Cytotoxic benzodiazepine derivatives
  申请人：ImmunoGen, Inc.

  公开号：US10238751B2

  公开（公告）日：2019-03-26

  The invention relates to novel benzodiazepine derivatives with antiproliferative activity and more specifically to novel benzodiazepine compounds of formula (I)-(VI). The invention also provides conjugates of the benzodiazepine compounds linked to a cell-binding agent. The invention further provides compositions and methods useful for inhibiting abnormal cell growth or treating a proliferative disorder in a mammal using the compounds or conjugates of the invention.

  本发明涉及具有抗增殖活性的新型苯并二氮杂卓衍生物，更具体地说，涉及式（I）-（VI）的新型苯并二氮杂卓化合物。本发明还提供了与细胞结合剂连接的苯二氮杂卓化合物共轭物。本发明进一步提供了使用本发明化合物或共轭物抑制哺乳动物异常细胞生长或治疗增殖性疾病的组合物和方法。
• Methods of preparing cytotoxic benzodiazepine derivatives
  申请人：IMMUNOGEN, INC.

  公开号：US10392407B2

  公开（公告）日：2019-08-27

  The invention relates to novel methods for preparing indolinobenzodiazepine dimer compounds and their synthetic precursors.

  本发明涉及制备吲哚啉并二氮杂卓二聚化合物及其合成前体的新方法。
• Synthesis of Highly Potent N-10 Amino-Linked DNA-Alkylating Indolinobenzodiazepine Antibody–Drug Conjugates (ADCs)
  作者：Katie E. Archer、Emily E. Reid、Manami Shizuka、James Woods、Luke Harris、Erin K. Maloney、Laura M. Bartle、Olga Ab、Alan Wilhelm、Yulius Setiady、Jose F. Ponte、Rajeeva Singh、Thomas A. Keating、Ravi V. J. Chari、Michael L. Miller

  DOI：10.1021/acsmedchemlett.9b00254

  日期：2019.8.8

  Indolinobenzodiazepine DNA alkylators (IGNs) are the cytotoxic payloads in antibody-drug conjugates (ADCs) currently undergoing Phase I clinical evaluation (IMGN779, IMGN632, and TAK164). These ADCs possess linkers that have been incorporated into a central substituted phenyl spacer. Here, we present an alternative strategy for the IGNs, linking through a carbamate at the readily available N-10 amine present in the monoimine containing dimer. As a result, we have designed a series of N-10 linked IGN ADCs with a wide range of in vitro potency and tolerability, which may allow us to better match an IGN with a particular target based on the potential dosing needs.