1-(chloromethyl)-5-methylamino-<(5,6,7-trimethoxyindol-2-yl)carbonyl>-1,2-dihydro-3H-benzindole | 193225-67-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 1-(chloromethyl)-5-methylamino-<(5,6,7-trimethoxyindol-2-yl)carbonyl>-1,2-dihydro-3H-benzindole
• 英文别名: 1-(chloromethyl)-5-methylamino-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-benz[e]indole；1H-Benz[e]indol-5-amine,3-dihydro-N-methyl-3-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-；[1-(chloromethyl)-5-(methylamino)-1,2-dihydrobenzo[e]indol-3-yl]-(5,6,7-trimethoxy-1H-indol-2-yl)methanone
• CAS: 193225-67-1
• 化学式: C₂₆H₂₆ClN₃O₄
• 分子量: 479.963
• InChiKey: DRTNXALIYSNZIV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  34
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  75.8
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-(chloromethyl)-5-methylamino-<(5,6,7-trimethoxyindol-2-yl)carbonyl>-1,2-dihydro-3H-benzindole 、 氯甲酸对硝基苄酯 以 吡啶 、 二氯甲烷 为溶剂， 反应 0.75h， 以79%的产率得到(4-nitrophenyl)methyl N-[1-(chloromethyl)-3-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-1,2-dihydrobenzo[e]indol-5-yl]-N-methylcarbamate
  参考文献：
  名称：

  Structure−Activity Relationships for 4-Nitrobenzyl Carbamates of 5-Aminobenz[e]indoline Minor Groove Alkylating Agents as Prodrugs for GDEPT in Conjunction with E. coli Nitroreductase

  摘要：

  Twelve substituted 4-nitrobenzyl carbamate prodrugs of the 5-aminobenz[e]indoline class of DNA minor groove alkylating agents were prepared and tested as prodrugs for gene-directed enzyme prodrug therapy (GDEPT) using a two-electron nitroreductase (NTR) from E. coli B. The prodrugs and effectors were tested in a cell line panel comprising parental and transfected human (SKOV/Skov-NTRneo, WiDr/WiDr-NTRneo), Chinese hamster (V79(puro)/VN79-NTRpuro), and murine (EMT6/EMT6-NTRpuro) cell line pairs. In the human cell line pairs, several analogues bearing neutral methoxyethoxy-, 2-hydroxyethoxy-, or 3-hydroxypropoxy-substituted side chains were good substrates for NTR as measured by cytotoxicity ratios, with NTR-ve/NTR+ve ratios similar to the established NTR substrates CB1954 (an aziridinyl dinitrobenzamide) and the analogous bromomustard. Selectivity for NTR decreased with increasing side-chain size or the presence of a basic amine group. Low to modest selectivity was observed in the Chinese hamster-derived cell line pair; however, in the murine EMT6/EMT6-NTRpuro cell line pair, the above hydroxyalkoxy analogues again showed significant selectivity for NTR. The activity of the 2-hydroxyethoxy analogue was evaluated against NTR-expressing EMT6 tumors comprising ca. 10% NTR+ve cells at the time of tumor treatment. A small decrease in NTR+ve cells was observed after treatment, with a lesser effect against NTR-ve target cells, but these effects were not statistically significant and were much less than for the dinitrobenzamides. These results suggest that useful GDEPT prodrugs based on the 4-nitrobenzyl carbamate and 5-aminobenz[e]indoline motifs may be developed if optimization of pharmacokinetics can be addressed.

  DOI：

  10.1021/jm0205191
• 作为产物：
  描述：

  3-(tert-butoxycarbonyl)-1,1-di(methoxycarbonyl)-5-nitro-1,2-dihydro-3H-benzindole 在 platinum(IV) oxide 盐酸 、 dimethyl sulfide borane 、 氢气 、 sodium methylate 、 二异丁基氢化铝 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 lithium chloride 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 吡啶 、 甲醇 、 正己烷 、 N,N-二甲基乙酰胺 、 N,N-二甲基甲酰胺 为溶剂， 80.0 ℃ 、344.74 kPa 条件下， 反应 13.75h， 生成 1-(chloromethyl)-5-methylamino-<(5,6,7-trimethoxyindol-2-yl)carbonyl>-1,2-dihydro-3H-benzindole
  参考文献：
  名称：

  Synthesis and Cytotoxicity of 5-Amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2- dihydro-3H-benz[e]indole (Amino-seco-CBI-TMI) and Related 5-Alkylamino Analogues:  New DNA Minor Groove Alkylating Agents

  摘要：

  The first synthesis of seco-CBI-TMI alkylating agents with 5-nitrogen substituents is reported. The parent 5-amino compound was prepared in a 15-step synthesis from 1-hydroxynaphthalene-2-carboxylic acid. Reductive alkylation of the 5-amino compound gave the corresponding 5-methylamino and 5-dimethylamino analogues, while resolution of an intermediate by chiral HPLC allowed preparation of the R and S enantiomers of the 5-amino analogue. Absolute configuration was assigned by X-ray crystallography. The S enantiomer was about 65-fold more cytotoxic than the R enantiomer in cell line assays. The 5-amino and 5-methylamino compounds had in vitro cytotoxicities comparable to that of the known 5-hydroxy analogue (0.2-0.5 nM), while the 5-dimethylamino derivative was about 10-fold less potent. The high potencies of the 5-amino and 5-methylamino analogues make them of interest for the formation of relatively stable amine-based prodrugs.

  DOI：

  10.1021/jo981395w

文献信息

• Processes for preparing 3-substituted 1-(chloromethyl)-1,2-dihydro-3h-[ring fused indol-5-yl-(amine- derived)] compounds and analogues thereof, and to products obtained therefrom
  申请人：Denny Alexander William

  公开号：US20050148651A1

  公开（公告）日：2005-07-07

  The invention provides processes of preparing 3-substituted 1-(chloromethyl)-1,2-dihydro-3H-[ring fused indol-5-yl(amine-derived)] compounds of formula (I) and its analogues, or a physiologically functional derivative thereof, (I), wherein A and B together may represent a fused optionally substituted benezene, naphthalene, pyridine, furan or a pyrrole ring, where the optional substituents are represented by Y; X is halogen or OSO 2 R, and W is selected from NO 2 , NHOH, N(R 3 ) 2 NHR 3 , NHCO 2 R 3 , N(phthaloyl) or NH 2 , or W is further selected from the group (a), wherein J is selected from OH or R, and P is a group which is a substrate suitable for a nitroreductase or carboxypeptidase enzyme. The invention is also directed to the use of compounds of formula (I) prepared by the processes of the invention as cytotoxins for cancer therapy and as prodrugs for gene-directed enzyme-prodrug therapy (GDEPT) and antibody-directed enzyme-prodrug therapy (ADEPT).

  本发明提供了制备式(I)及其类似物或其生理功能衍生物的3-取代-1-(氯甲基)-1,2-二氢-3H-[环融合吲哚-5-基(氨基衍生)]化合物的过程，其中A和B在一起可以表示为融合的可选取代苯、萘、吡啶、呋喃或吡咯环，其中可选的取代基由Y表示；X是卤素或OSO2R，W从NO2、NHOH、N(R3)2NHR3、NHCO2R3、N(phthaloyl)或NH2中选择，或者W进一步从(a)组中选择，其中J从OH或R中选择，P是适用于硝基还原酶或羧肽酶酶的底物基团。本发明还涉及使用通过本发明的方法制备的式(I)化合物作为癌症治疗的细胞毒素以及基因导向酶前药治疗(GDEPT)和抗体导向酶前药治疗(ADEPT)的前药。
• Synthesis and cytotoxicity of amino analogues of the potent DNA alkylating agent seco-CBI-TMI
  作者：G.J. Atwell、W.R. Wilson、W.A. Denny

  DOI：10.1016/s0960-894x(97)00259-x

  日期：1997.6

  The synthesis of racemic seco-CBI-TMI analogues containing nitrogen-based groups in place of the 5-OH is reported, employing a synthetic strategy where the incipient C-5 amino substituent is generated in the last step from a nitro precursor. The resulting amino seco-CBI analogues are up to 1000-fold more potent cytotoxins than the corresponding known amino seco-CI compounds, making them attractive candidates as effecters in prodrug strategies. (C) 1997 Elsevier Science Ltd.
• CYCLOPROPYLINDOLE COMPOUNDS AND THEIR USE AS PRODRUGS
  申请人：AUCKLAND UNISERVICES LIMITED

  公开号：EP0938474B1

  公开（公告）日：2005-11-23
• US6130237A
  申请人：——

  公开号：US6130237A

  公开（公告）日：2000-10-10
• US7235578B2
  申请人：——

  公开号：US7235578B2

  公开（公告）日：2007-06-26