1-(4-aminophenyl)-5-methyl-7,8-methylenedioxy-3,5-dihydro-2,3-benzodiazepin-4(4H)-one | 197368-83-5

• 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: 1-(4-aminophenyl)-5-methyl-7,8-methylenedioxy-3,5-dihydro-2,3-benzodiazepin-4(4H)-one
• 英文别名: 5-(4-Aminophenyl)-9-methyl-7,9-dihydro-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-8-one
• CAS: 197368-83-5
• 化学式: C₁₇H₁₅N₃O₃
• 分子量: 309.324
• InChiKey: LFRNFUXNACAKBP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  23
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  85.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-(4-aminophenyl)-5-methyl-7,8-methylenedioxy-3,5-dihydro-2,3-benzodiazepin-4(4H)-one 在 N-氯代丁二酰亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 20.0h， 以80%的产率得到5-(4-Amino-3-chlorophenyl)-9-methyl-7,9-dihydro-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-8-one
  参考文献：
  名称：

  Structure–activity study of 2,3-benzodiazepin-4-ones noncompetitive AMPAR antagonists: Identification of the 1-(4-amino-3-methylphenyl)-3,5-dihydro-7,8-ethylenedioxy-4H-2,3-benzodiazepin-4-one as neuroprotective agent

  摘要：

  In the search for AMPA receptor (AMPAR) antagonists, 2,3-benzodiazepines represent a family of specific noncompetitive antaaonists with anticonvulsant and neuroprotective properties. We have previously shown that 2,3-benzodiazepin-4-ones possess marked anticonvulsant properties and high affinity for the noncompetitive binding site of the AMPAR complex. In this paper, we report the synthesis and pharmacological characterization of a full set of 2,3-benzodiazepin-4-ones in order to better define the structure-activity relationship (SAR) of this class of compounds. Binding assays and functional tests were performed to evaluate the antagonistic activity at the AMPARs. Through these results we have identified a potent AMPAR antagonist, 1-(4-amino-3-methylphenyl)-3,5-dihydro-7,8-ethylenedioxy-4H-2,3-benzodiazepin-4-one (5c). This compound noncompetitively inhibited AMPAR-mediated toxicity in primary mouse hippocampal cultures with an IC50 of 1.6 mu M and blocked kainate-induced calcium influx in rat cerebellar granule cells with an IC50 of 6.4 mu M. Thus, 5c has the in vitro potential as therapeutic drug in the treatment of various neurological disorders. (C) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.11.080
• 作为产物：
  描述：

  3,5-dihydro-5-methyl-7,8-methylenedioxy-1-(4-nitrophenyl)-4H-2,3-benzodiazepin-4-one 在 ammonium formate 、 镍 作用下， 以 乙醇 为溶剂， 反应 2.0h， 以25%的产率得到1-(4-aminophenyl)-5-methyl-7,8-methylenedioxy-3,5-dihydro-2,3-benzodiazepin-4(4H)-one
  参考文献：
  名称：

  有效的2,3-苯并二氮杂pine衍生物作为非竞争性AMPA受体拮抗剂的合成，手性拆分和对映药理学。

  摘要：

  本文描述了外消旋的3,5-二氢-5-甲基-7,8-亚甲基二氧基-4H-2,3-苯并二氮杂-4--4-（+/-）-5的合成，其对映异构体手性的立体选择性合成尝试外消旋体的HPLC分辨率，以及绝对构型的分配。对映异构体（5S）-（-）-5具有比其对映异构体（5R）-（+）-5高8倍的体内抗惊厥活性。该结果在体外测试中得到了证实，即在表达α-氨基-3-羟基-的大鼠小脑颗粒细胞的原代培养物中，抑制海藻酸盐诱导的[Ca（2 +）]（i）增加的能力得到了证实。 5-甲基-4-异恶唑丙酸（AMPA）受体。还评估了化合物（+/-）-5在AMPA和N-甲基-d-天冬氨酸（NMDA）受体上的结合亲和力。

  DOI：

  10.1021/jm050552y

文献信息

• SUBSTITUTED 2,3-BENZODIAZEPIN-4-ONES AND THE USE THEREOF
  申请人：Euro-Celtique S.A.

  公开号：EP1021418B1

  公开（公告）日：2004-05-19
• US5891871A
  申请人：——

  公开号：US5891871A

  公开（公告）日：1999-04-06
• Synthesis, Chiral Resolution, and Enantiopharmacology of a Potent 2,3-Benzodiazepine Derivative as Noncompetitive AMPA Receptor Antagonist
  作者：Maria Zappalà、Giovanna Postorino、Nicola Micale、Salvatore Caccamese、Nunziatina Parrinello、Giovanni Grazioso、Gabriella Roda、Frank S. Menniti、Giovambattista De Sarro、Silvana Grasso

  DOI：10.1021/jm050552y

  日期：2006.1.1

  This paper describes the synthesis of racemic 3,5-dihydro-5-methyl-7,8-methylenedioxy-4H-2,3-benzodiazepin-4-one (+/-)-5, attempted stereoselective synthesis of its enantiomers, chiral HPLC resolution of the racemate, and assignment of the absolute configuration. Enantiomer (5S)-(-)-5 is provided with an in vivo anticonvulsant activity 8 times higher than its enantiomer (5R)-(+)-5. This result is confirmed

  本文描述了外消旋的3,5-二氢-5-甲基-7,8-亚甲基二氧基-4H-2,3-苯并二氮杂-4--4-（+/-）-5的合成，其对映异构体手性的立体选择性合成尝试外消旋体的HPLC分辨率，以及绝对构型的分配。对映异构体（5S）-（-）-5具有比其对映异构体（5R）-（+）-5高8倍的体内抗惊厥活性。该结果在体外测试中得到了证实，即在表达α-氨基-3-羟基-的大鼠小脑颗粒细胞的原代培养物中，抑制海藻酸盐诱导的[Ca（2 +）]（i）增加的能力得到了证实。 5-甲基-4-异恶唑丙酸（AMPA）受体。还评估了化合物（+/-）-5在AMPA和N-甲基-d-天冬氨酸（NMDA）受体上的结合亲和力。
• Structure–activity study of 2,3-benzodiazepin-4-ones noncompetitive AMPAR antagonists: Identification of the 1-(4-amino-3-methylphenyl)-3,5-dihydro-7,8-ethylenedioxy-4H-2,3-benzodiazepin-4-one as neuroprotective agent
  作者：Nicola Micale、Simona Colleoni、Giovanna Postorino、Alessia Pellicanò、Maria Zappalà、John Lazzaro、Valentina Diana、Alfredo Cagnotto、Tiziana Mennini、Silvana Grasso

  DOI：10.1016/j.bmc.2007.11.080

  日期：2008.3

  In the search for AMPA receptor (AMPAR) antagonists, 2,3-benzodiazepines represent a family of specific noncompetitive antaaonists with anticonvulsant and neuroprotective properties. We have previously shown that 2,3-benzodiazepin-4-ones possess marked anticonvulsant properties and high affinity for the noncompetitive binding site of the AMPAR complex. In this paper, we report the synthesis and pharmacological characterization of a full set of 2,3-benzodiazepin-4-ones in order to better define the structure-activity relationship (SAR) of this class of compounds. Binding assays and functional tests were performed to evaluate the antagonistic activity at the AMPARs. Through these results we have identified a potent AMPAR antagonist, 1-(4-amino-3-methylphenyl)-3,5-dihydro-7,8-ethylenedioxy-4H-2,3-benzodiazepin-4-one (5c). This compound noncompetitively inhibited AMPAR-mediated toxicity in primary mouse hippocampal cultures with an IC50 of 1.6 mu M and blocked kainate-induced calcium influx in rat cerebellar granule cells with an IC50 of 6.4 mu M. Thus, 5c has the in vitro potential as therapeutic drug in the treatment of various neurological disorders. (C) 2007 Elsevier Ltd. All rights reserved.