2,3-Dimethyl-5-phenyl-2,5-dihydro-1H-benzo[e][1,3]diazepine | 142149-85-7

• 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: 2,3-Dimethyl-5-phenyl-2,5-dihydro-1H-benzo[e][1,3]diazepine
• 英文别名: 2,3-Dimethyl-5-phenyl-1,5-dihydro-2,4-benzodiazepine
• CAS: 142149-85-7
• 化学式: C₁₇H₁₈N₂
• 分子量: 250.343
• InChiKey: YGUJOCJQMZPTLX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  15.6
• 氢给体数：
  0
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  2,3-Dimethyl-5-phenyl-2,5-dihydro-1H-benzo[e][1,3]diazepine 在 乙二胺 作用下， 以 甲苯 为溶剂， 反应 24.0h， 生成 (R)-N-methyl-α'-phenyl-1,2-phenylenedimethanamine
  参考文献：
  名称：

  4,5-Dihydro-3-(methanesulfonamidophenyl)-1-phenyl-1H-2,4-benzodiazepines: A Novel Class III Antiarrhythmic Agents

  摘要：

  A series of 4,5-dihydro-3-[2-(methanesulfonamidophenyl)ethyl]-1H-2,4-benzodiazepines has been identified as potential antiarrhythmic agents that interact at the delayed rectifier myocardial potassium channels (I-Kr) and prolong the ventricular effective refractory period (ERP) in rabbit isolated Langendorff heart preparations. Structure-activity relationship (SAR) studies based upon prolongation of ERP indicate that placement of the sulfonamido group is important for potent activity in this model. Furthermore, methanesulfonamido has enhanced activity over its ethyl or trifluoromethyl analogs. Slightly greater activity was observed in compounds that had a heteroatom in the ethyl bridge that connects the methanesulfonamidophenyl to the benzodiazepine. Further incremental improvements in activity were noted when the 1-phenyl ring was substituted with a variety of substituents. Chirality of the compounds of interest in this series does not appear to influence activity in this model. Several of these compounds were chosen for advanced evaluation, and all possess high selectivity for blockade of potassium current in hearts relative to other ion channels. In addition, these compounds prolong cardiac refractoriness in dogs following oral dosing. Thus, these agents may represent potential new class III agents, but with the potential liability of myocardial I-Kr blockers.

  DOI：

  10.1021/jm00014a008
• 作为产物：
  描述：

  原乙酸三甲酯 、 N-methyl-α'-phenyl-1,2-phenylenedimethanamine dihydrochloride 在 sodium acetate 作用下， 以 甲醇 为溶剂， 生成 2,3-Dimethyl-5-phenyl-2,5-dihydro-1H-benzo[e][1,3]diazepine
  参考文献：
  名称：

  4,5-Dihydro-3-(methanesulfonamidophenyl)-1-phenyl-1H-2,4-benzodiazepines: A Novel Class III Antiarrhythmic Agents

  摘要：

  A series of 4,5-dihydro-3-[2-(methanesulfonamidophenyl)ethyl]-1H-2,4-benzodiazepines has been identified as potential antiarrhythmic agents that interact at the delayed rectifier myocardial potassium channels (I-Kr) and prolong the ventricular effective refractory period (ERP) in rabbit isolated Langendorff heart preparations. Structure-activity relationship (SAR) studies based upon prolongation of ERP indicate that placement of the sulfonamido group is important for potent activity in this model. Furthermore, methanesulfonamido has enhanced activity over its ethyl or trifluoromethyl analogs. Slightly greater activity was observed in compounds that had a heteroatom in the ethyl bridge that connects the methanesulfonamidophenyl to the benzodiazepine. Further incremental improvements in activity were noted when the 1-phenyl ring was substituted with a variety of substituents. Chirality of the compounds of interest in this series does not appear to influence activity in this model. Several of these compounds were chosen for advanced evaluation, and all possess high selectivity for blockade of potassium current in hearts relative to other ion channels. In addition, these compounds prolong cardiac refractoriness in dogs following oral dosing. Thus, these agents may represent potential new class III agents, but with the potential liability of myocardial I-Kr blockers.

  DOI：

  10.1021/jm00014a008

文献信息

• 4,5-Dihydro-1-phenyl-1H-2,4-benzodiazepines: Novel antiarrhythmic agents
  作者：Robert E. Johnson、Eugene R. Baizman、Carolyn Becker、Eric A. Bohnet、Rebecca H. Bell、Nancy C. Birsner、Carl A. Busacca、Philip M. Carabateas、Christopher C. Chadwick

  DOI：10.1021/jm00074a017

  日期：1993.10

  A series of 4,5-dihydro-1-phenyl-1H-2,4-benzodiazepines has been identified as potential antiarrhythmic agents that interact with sodium and potassium channels and prolong the ventricular effective refractory period (ERP) in anesthetized guinea pigs. Concomitant displacement of radiolabeled bactrachotoxin from site II in Na+ channels and of radiolabeled dofetilide from delayed rectifier K+ channels was evident with all members of this chemical series at a concentration of 10 muM. Structure-activity relationship (SAR) studies using a paced guinea pig model to assess prolongation of the ERP indicated that methyl or ethyl at the 1-position had little effect on activity, while larger groups caused a diminution of activity. Compounds with substituents at either the 3- or 4-position that increased lipophilicity generally were more potent; however, too many lipophilic substituents simultaneously at positions 1, 3, and 4 resulted in less active compounds. Substituents on either aromatic ring had little influence on activity, and phenyl at the 5-position resulted in a significant reduction in antiarrhythmic activity. When two sets of enantiomerically pure compounds were tested in the guinea pig, chirality was shown to be important for activity of 8, where the (R)-enantiomer was the more active, but not in the case of 15, where the enantiomers were equiactive. Several compounds in this series increased the threshold for vertricular fibrillation and refractoriness in myocardially-infarcted anesthetized cata and delayed the onset of aconitine-induced arrhythmias in anesthetized guinea pigs following intravenous dosing. Moreover, these compounds possessed oral antiarrhythmic activity in conscious myocardially-infarcted dogs. Compound R-15 has been advanced for further biological and toxicological evaluations.
• 4,5-Dihydro-3-(methanesulfonamidophenyl)-1-phenyl-1H-2,4-benzodiazepines: A Novel Class III Antiarrhythmic Agents
  作者：Robert E. Johnson、Paul J. Silver、Russell Becker、Nancy C. Birsner、Eric A. Bohnet、G. Maurice Briggs、Carl A. Busacca、Paul Canniff、Philip M. Carabateas、Thomas D'Ambra、Ronald L. Dundore、Jen-Sen Dung、Christopher C. Chadwick、Alan M. Ezrin、William Gorczyca、Peter G. Habeeb、Patrick Horan、Douglas S. Krafte、Gary Pelling、Bernard O'Connor、Manohar T. Saindane、Donald C. Schlegel、Gerald P. Stankus、John Swestock、Walter A. Volberg

  DOI：10.1021/jm00014a008

  日期：1995.7

  A series of 4,5-dihydro-3-[2-(methanesulfonamidophenyl)ethyl]-1H-2,4-benzodiazepines has been identified as potential antiarrhythmic agents that interact at the delayed rectifier myocardial potassium channels (I-Kr) and prolong the ventricular effective refractory period (ERP) in rabbit isolated Langendorff heart preparations. Structure-activity relationship (SAR) studies based upon prolongation of ERP indicate that placement of the sulfonamido group is important for potent activity in this model. Furthermore, methanesulfonamido has enhanced activity over its ethyl or trifluoromethyl analogs. Slightly greater activity was observed in compounds that had a heteroatom in the ethyl bridge that connects the methanesulfonamidophenyl to the benzodiazepine. Further incremental improvements in activity were noted when the 1-phenyl ring was substituted with a variety of substituents. Chirality of the compounds of interest in this series does not appear to influence activity in this model. Several of these compounds were chosen for advanced evaluation, and all possess high selectivity for blockade of potassium current in hearts relative to other ion channels. In addition, these compounds prolong cardiac refractoriness in dogs following oral dosing. Thus, these agents may represent potential new class III agents, but with the potential liability of myocardial I-Kr blockers.