10-(4-nitrophenyl)acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯氮卓类
• 英文名称: 10-(4-nitrophenyl)acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide
• 英文别名: (11-Carbamoyl-5,6-dihydrobenzo[b][1]benzazepin-5-yl) 2-(4-nitrophenyl)acetate
• 化学式: C₂₃H₁₉N₃O₅
• 分子量: 417.421
• InChiKey: CRAGGPZREJQBNS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  118
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  奥卡西平 在 4-二甲氨基吡啶 、 sodium tetrahydroborate 、 N,N'-二环己基碳二亚胺 作用下， 以 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 1.0h， 生成 10-(4-nitrophenyl)acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide
  参考文献：
  名称：

  Anticonvulsant and Sodium Channel-Blocking Properties of Novel 10,11-Dihydro-5H-dibenz[b,f]azepine-5-carboxamide Derivatives

  摘要：

  A. series of esters of the major metabolite of oxcarbazepine (2), 10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide, were synthesized and evaluated for their anticonvulsant and brain sodium channel-blocking properties. The compounds were assayed intraperitoneally and per os in rats against seizures induced by maximal electroshock (MES). Neurologic deficit was evaluated by the rotarod test. The enantiomeric acetates (R)-11 and (S)-12 were the most active of the series against MES-induced seizures with oral ED50 values at t(max) of 10.9 +/- 2.3 and 4.7 +/- 9 mg/kg, respectively. After intraperitoneal administration, carbamazepine (1) behaved more potently than 2 and all other new dibenz[b,f]azepine-5-carboxamide derivatives in the MES test; compounds 2 and 12 were equally potent. In the rotarod test, low doses of 1. produced considerable motor impairment, which did not occur with 2, enantiomeric alcohols (S)-6;, (R)-7, and racemic alcohol, or racemic acetate 10 or (R)-11. The potencies of the racemic and enantiomerically pure alcohols 8, (S)-6, and (R)-7 derived from 2 in the MES and rotarod test were found to be similar between them, and consequently they exhibit similar protective index values. All three forms of the alcohol and their corresponding acetates (pairs 8 & 10, 6 & 12, and 7 & 11) were found to differ in the MES or rotarod tests; the ED50 value for (S)-6 against MES-induced seizures was nearly 3-fold that for (S)-12. The protective index also differed markedly between all stereoisomers of the alcohol and their corresponding acetates, most pronouncedly for compound (S)-12 which attained the highest value (12.5) among all compounds tested. Blockade of voltage-sensitive sodium channels was studied by investigating [H-3]-batrachotoxinin A 20-alpha-benzoate ([H-3]BTX) binding. Acetates (R)-11 and (S)-12 were more potent than the standards 1 and-2 at inhibiting the binding of [H-3]BTX to sodium channels and the influx: of Na-22(+) into rat brain synaptosomes. It is concluded that acetates (R)-11 and (5)-12 are not simple metabolic precursors of alcohols (R)-7 and (S)-6 in rodents but that they possess anticonvulsant and sodium channel-blocking properties in their own right.

  DOI：

  10.1021/jm980627g

文献信息

• [EN] 10-ACYLOXY-10,11-DIHYDRODIBENZ/b,f/AZEPINE-5-CARBOXAMIDES USEFUL FOR TREATING NERVOUS SYSTEM DISORDERS<br/>[FR] 10-ACYLOXY-10,11-DIHYDRODIBENZ-/b,f/AZEPINE-5-CARBOXAMIDES UTILES DANS LE TRAITEMENT DE TROUBLES DU SYSTEME NERVEUX
  申请人：PORTELA & CA., S.A.

  公开号：WO1997002250A1

  公开（公告）日：1997-01-23

  (EN) Compounds of general formula (I), including all possible stereoisomers, wherein: R is hydrogen, alkyl, aminoalkyl, halogenalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, alkoxy, phenyl or substituted phenyl or pyridyl group, are useful in pharmaceutical compositions for treating some central nervous system disorders. The compounds are made by reaction of compound (II) with an acylating agent.(FR) On décrit des composés de la formule générale (I), et notamment tous les stéréo-isomères possibles de ceux-ci, dans laquelle R représente hydrogène, alkyle, aminoalkyle, halogénalkyle, aralkyle, cycloalkyle, cycloalkylalkyle, alcoxy, phényle ou un groupe phényle ou pyridyle substitué. Ces composés sont utiles dans des compositions pharmaceutiques destinées au traitement de certains troubles du système nerveux central. On prépare ces composés en faisant réagir un composé de la formule (II) avec un agent d'acylation.

  化合物的一般式（I），包括所有可能的立体异构体，其中：R是氢，烷基，氨基烷基，卤代烷基，芳基烷基，环烷基，环烷基烷基，烷氧基，苯基或取代苯基或吡啶基，可用于治疗某些中枢神经系统疾病的药物组合物中。这些化合物是通过化合物（II）与酰化试剂的反应制备的。
• [EN] METHOD FOR RACEMISATION OF (S)-(+)- AND (R)-(-)-10,11-DIHYDRO-10-HYDROXY-5H­DIBENZ/B,F/AZEPINE-5-CARBOXAMIDE AND OPTICALLY ENRICHED MIXTURES THEREOF<br/>[FR] PROCEDE DE RACEMISATION DE (S)-(+)- ET (R)-(-)-10,11-DIHYDRO-10-HYDROXY-5H-DIBENZ/B,F/AZEPINE-5-CARBOXAMIDE, ET LEURS MELANGES ENRICHIS OPTIQUEMENT
  申请人：PORTELA & CA SA

  公开号：WO2004099153A1

  公开（公告）日：2004-11-18

  A high-yielding method for racemisation of (S)-(+)- and (R)-(-)-10, 11- dihydro-l0-­hydroxy-5H-dibenz/b,f/azepine-5-carboxamide and a useful intermediate, 10-chloro-10, 11 dihydro-5H-dibenz/b,f/azepine-5-carboxamide (VII) are disclosed. Also disclosed are methods for the racemisation of optically pure or optically enriched mixtures of (S)-(+)-10,11-dihydro-l0-­hydroxy-5H-dibenz/b,f/azepine-5-carboxamide (I) and (R)-(-)-10,11-dihydro-l0-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide (II) to racemic (±)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide (III).

  本文揭示了一种高产的(S)-(+)-和(R)-(-)-10,11-二氢-10-羟基-5H-二苯并[b,f]氮杂-5-羧酰胺的消旋方法，以及一个有用的中间体，10-氯-10,11-二氢-5H-二苯并[b,f]氮杂-5-羧酰胺(VII)。还揭示了将光学纯或光学富集的(S)-(+)-10,11-二氢-10-羟基-5H-二苯并[b,f]氮杂-5-羧酰胺(I)和(R)-(-)-10,11-二氢-10-羟基-5H-二苯并[b,f]氮杂-5-羧酰胺(II)消旋为(±)-10,11-二氢-10-羟基-5H-二苯并[b,f]氮杂-5-羧酰胺(III)的方法。
• Substituted dihydrodibenzo(b,f)azepines, method for their preparation, their use in the treatment of some central nervous system disorders, and pharmaceutical compositions containing them
  申请人：Portela & Ca., S.A.

  公开号：EP0751129B1

  公开（公告）日：1998-11-18
• Anticonvulsant and Sodium Channel-Blocking Properties of Novel 10,11-Dihydro-5<i>H</i>-dibenz[<i>b</i>,<i>f</i>]azepine-5-carboxamide Derivatives
  作者：Jan Benes、António Parada、Anabela A. Figueiredo、Paula C. Alves、Ana P. Freitas、David A. Learmonth、Rodrigo A. Cunha、José Garrett、Patrício Soares-da-Silva

  DOI：10.1021/jm980627g

  日期：1999.7.1

  A. series of esters of the major metabolite of oxcarbazepine (2), 10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide, were synthesized and evaluated for their anticonvulsant and brain sodium channel-blocking properties. The compounds were assayed intraperitoneally and per os in rats against seizures induced by maximal electroshock (MES). Neurologic deficit was evaluated by the rotarod test. The enantiomeric acetates (R)-11 and (S)-12 were the most active of the series against MES-induced seizures with oral ED50 values at t(max) of 10.9 +/- 2.3 and 4.7 +/- 9 mg/kg, respectively. After intraperitoneal administration, carbamazepine (1) behaved more potently than 2 and all other new dibenz[b,f]azepine-5-carboxamide derivatives in the MES test; compounds 2 and 12 were equally potent. In the rotarod test, low doses of 1. produced considerable motor impairment, which did not occur with 2, enantiomeric alcohols (S)-6;, (R)-7, and racemic alcohol, or racemic acetate 10 or (R)-11. The potencies of the racemic and enantiomerically pure alcohols 8, (S)-6, and (R)-7 derived from 2 in the MES and rotarod test were found to be similar between them, and consequently they exhibit similar protective index values. All three forms of the alcohol and their corresponding acetates (pairs 8 & 10, 6 & 12, and 7 & 11) were found to differ in the MES or rotarod tests; the ED50 value for (S)-6 against MES-induced seizures was nearly 3-fold that for (S)-12. The protective index also differed markedly between all stereoisomers of the alcohol and their corresponding acetates, most pronouncedly for compound (S)-12 which attained the highest value (12.5) among all compounds tested. Blockade of voltage-sensitive sodium channels was studied by investigating [H-3]-batrachotoxinin A 20-alpha-benzoate ([H-3]BTX) binding. Acetates (R)-11 and (S)-12 were more potent than the standards 1 and-2 at inhibiting the binding of [H-3]BTX to sodium channels and the influx: of Na-22(+) into rat brain synaptosomes. It is concluded that acetates (R)-11 and (5)-12 are not simple metabolic precursors of alcohols (R)-7 and (S)-6 in rodents but that they possess anticonvulsant and sodium channel-blocking properties in their own right.