8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepin-5-amine | 136772-01-5

• 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: 8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepin-5-amine
• 英文别名: 3-Chloro-6-(4-methylpiperazin-1-yl)benzo[b][1,4]benzodiazepin-11-amine
• CAS: 136772-01-5
• 化学式: C₁₈H₂₀ClN₅
• 分子量: 341.843
• InChiKey: KAGSOBJQFAROBR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  24
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  48.1
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepin-5-amine 、 己二酰氯 在 吡啶 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 以0.209 g的产率得到N1,N6-bis[8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepin-5-yl]hexanediamide
  参考文献：
  名称：

  Homobivalent Ligands of the Atypical Antipsychotic Clozapine: Design, Synthesis, and Pharmacological Evaluation

  摘要：

  To date all typical and atypical antipsychotics target the dopamine D-2 receptor. Clozapine represents the best-characterized atypical antipsychotic, although it displays only moderate (submicromolar) affinity for the dopamine D-2 receptor. Herein, we present the design, synthesis, and pharmacological evaluation of three series of homobivalent ligands of clozapine, differing in the length and nature of the spacer and the point of attachment to the pharmacophore. Attachment of the spacer at the N4' position of clozapine yielded a series of homobivalent ligands that displayed spacer-length-dependent gains in affinity and activity for the dopamine D-2 receptor. The 16 and 18 atom spacer bivalent ligands were the highlight compounds, displaying marked low nanomolar receptor binding affinity (1.41 and 1.35 nM, respectively) and functional activity (23 and 44 nM), which correspond to significant gains in affinity (75- and 79-fold) and activity (9- and 5-fold) relative to the original pharmacophore, clozapine. As such these ligands represent useful tools with which to investigate dopamine receptor dimerization and the atypical nature of clozapine.

  DOI：

  10.1021/jm201420s
• 作为产物：
  描述：

  氯氮平 在 溶剂黄146 、 锌 、 亚硝酸异戊酯 作用下， 以 二氯甲烷 为溶剂， 生成 8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepin-5-amine
  参考文献：
  名称：

  Hydrazides of clozapine: A new class of D1 dopamine receptor subtype selective antagonists

  摘要：

  Acylated and aroylated hydrazinoclozapines are highly potent dopamine D, antagonists that show remarkable selectivity over other dopamine receptors. The most potent compound in this series is the 2,6-dimethoxybenzhydrazide 33 with a D-1 K-i of 1.6 nM and 212-fold selectivity over D-2 receptor. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2006.06.022

文献信息

• Modification of the clozapine structure by parallel synthesis
  作者：Jing Su、Haiqun Tang、Brian A. McKittrick、Duane A. Burnett、Hongtao Zhang、April Smith-Torhan、Ahmad Fawzi、Jean Lachowicz

  DOI：10.1016/j.bmcl.2006.06.034

  日期：2006.9

  A structure-activity study based on the core structure of clozapine 1b was accomplished by utilizing high-throughput synthesis. Several focused libraries were designed and synthesized to quickly develop SAR. The results indicate that by varying different regions of clozapine, both D-1-selective and D-2-selective compounds can be obtained. (c) 2006 Elsevier Ltd. All rights reserved.
• An imprinted dopamine receptor for discovery of highly potent and selective D 3 analogues with neuroprotective effects
  作者：Wanpen Naklua、Krishna Mahesh、Phern Aundorn、Niwan Tanmanee、Kannatha Aenukulpong、Salilla Sutto、Yu Zong Chen、Shangying Chen、Roongnapa Suedee

  DOI：10.1016/j.procbio.2015.06.018

  日期：2015.10

  In this study, we have developed a novel molecular imprinting method for the cloning of a drug with multiple templates to achieve a broad selectivity, and then produce reactive dopamine analogs. The products were produced within selective recognition sites of the artificial system prepared against dopamine (D) and serotonin (S) as a single and a mixed template. As a consequence of the functionality of the anchoring sites being was able to make proximity changes that could promote changes in the nanosized space for surface access for the reactants but avoided the non-active center of the formed nanosized assembly. The most effective analogues had a B-max of the DS-MIP (1.0 M per g polymer) that was about twice that of the D-MIP. The receptor-ligand interaction studies revealed differences in the absorbance by the rat hypothalamus, and indicated that an additional potent hit was obvious. The dopamine analogs had a smaller space for receptor subtypes as determined by molecular docking and the implication of the selective D-3 receptor agonists as well as the 5HT(1b) receptors, for the treatment of Parkinson's disease. The proposed model indicated a possible role from the desired fragments that had been inserted into a specific binding pocket of the protein near to the gorge rim as being the significant pharmacophore of this class. They showed good binding affinity for the 5-HT1b receptors. The screening test with a natural D-1 receptor yielded a B-max of 0.44 mu M and the corresponding K-d values were 100-500 nM. Thus, this process that occurred in an artificial dopamine-imprinted receptor allowed for preclinical testing to identify possible neuroleptic agents and their neuroprotective effects hopefully with reduced side effects. (C) 2015 Elsevier Ltd. All rights reserved.
• Homobivalent Ligands of the Atypical Antipsychotic Clozapine: Design, Synthesis, and Pharmacological Evaluation
  作者：Fiona M. McRobb、Ian T. Crosby、Elizabeth Yuriev、J. Robert Lane、Ben Capuano

  DOI：10.1021/jm201420s

  日期：2012.2.23

  To date all typical and atypical antipsychotics target the dopamine D-2 receptor. Clozapine represents the best-characterized atypical antipsychotic, although it displays only moderate (submicromolar) affinity for the dopamine D-2 receptor. Herein, we present the design, synthesis, and pharmacological evaluation of three series of homobivalent ligands of clozapine, differing in the length and nature of the spacer and the point of attachment to the pharmacophore. Attachment of the spacer at the N4' position of clozapine yielded a series of homobivalent ligands that displayed spacer-length-dependent gains in affinity and activity for the dopamine D-2 receptor. The 16 and 18 atom spacer bivalent ligands were the highlight compounds, displaying marked low nanomolar receptor binding affinity (1.41 and 1.35 nM, respectively) and functional activity (23 and 44 nM), which correspond to significant gains in affinity (75- and 79-fold) and activity (9- and 5-fold) relative to the original pharmacophore, clozapine. As such these ligands represent useful tools with which to investigate dopamine receptor dimerization and the atypical nature of clozapine.
• Hydrazides of clozapine: A new class of D1 dopamine receptor subtype selective antagonists
  作者：T.K. Sasikumar、D.A. Burnett、H. Zhang、A. Smith-Torhan、A. Fawzi、J.E. Lachowicz

  DOI：10.1016/j.bmcl.2006.06.022

  日期：2006.9

  Acylated and aroylated hydrazinoclozapines are highly potent dopamine D, antagonists that show remarkable selectivity over other dopamine receptors. The most potent compound in this series is the 2,6-dimethoxybenzhydrazide 33 with a D-1 K-i of 1.6 nM and 212-fold selectivity over D-2 receptor. (c) 2006 Elsevier Ltd. All rights reserved.