(S)-2-[3-(benzyl(methyl)amino)propyl]-10,10a-dihydro-5H-imidazo[1,5-b]isoquinoline-1,3-dione

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 英文名称: (S)-2-[3-(benzyl(methyl)amino)propyl]-10,10a-dihydro-5H-imidazo[1,5-b]isoquinoline-1,3-dione
• 英文别名: (10aS)-2-[3-[benzyl(methyl)amino]propyl]-10,10a-dihydro-5H-imidazo[1,5-b]isoquinoline-1,3-dione
• 化学式: C₂₂H₂₅N₃O₂
• 分子量: 363.459
• InChiKey: AFFCTPXDLCCREL-FQEVSTJZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  43.9
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (S)-2-[3-(benzyl(methyl)amino)propyl]-10,10a-dihydro-5H-imidazo[1,5-b]isoquinoline-1,3-dione 在 溶剂黄146 作用下， 以 乙醇 为溶剂， 生成 2-[3-[benzyl(methyl)amino]propyl]-10,10a-dihydro-5H-imidazo[1,5-b]isoquinoline-1,3-dione
  参考文献：
  名称：

  Kinetics and mechanism of racemization of Tic-hydantoins, potent sigma-1 agonists

  摘要：

  The configurational stability of seven Tic-hydantoin sigma-1 agonists 1-7 was studied in organic and aqueous media to mimic conditions encountered during either their synthesis or their evaluation as a drug candidate (physico chemical property determination and pharmacological study). This study was performed from the enantiomers directly obtained by asymmetric synthesis (hydantoins 1,3-7) or after semi-preparative separation of the racemic obtained according to the same asymmetric procedure (thiohydantoin 2), by chiral HPLC. The racemization phenomenon was followed using recently validated chiral HPLC and capillary electrophoresis separation methods using derivatized cellulose and amylose chiral stationary phases (Chiralcel OD-H and Chiralpak AD) and highly sulphated cyclodextrins [highly S-beta-CD in the background electrolyte (BGE)], respectively. The kinetic parameters (rate constant, half-life and apparent free energy barriers) of racemization were calculated using a first-order reaction model. The influence of the acid-base content, pH in aqueous medium, concentration of the buffer, and temperature were investigated. The fastest racemization rates were observed under basic conditions. All hydantoins were shown to present the same magnitude of configurational stability, whereas thiohydantoin 2 was characterized by a high chiral instability, especially in ethanolic and aqueous media: its high instability in ethanol explains that a racemic mixture was obtained after asymmetric synthesis; its instantaneous racemization observed from the neutral pH makes the preparation of the enantiomers of 2 not relevant. Finally, the mechanism of racemization was elucidated using nuclear magnetic resonance (NMR): the comparison of the kinetics of the deuteration to the kinetics of the racemization suggests the involvement of a common reaction mechanism of S(E)1 type for hydantoin 1, while an S(E)2 type reaction seems to be involved for thiohydantoin 2. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetasy.2011.01.015
• 作为产物：
  描述：

  N-叔丁氧羰基-(S)-1,2,3,4-四氢异喹啉-3-羧酸 在 potassium carbonate 、 caesium carbonate 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 24.92h， 生成 (S)-2-[3-(benzyl(methyl)amino)propyl]-10,10a-dihydro-5H-imidazo[1,5-b]isoquinoline-1,3-dione
  参考文献：
  名称：

  Tic-乙内酰脲衍生物作为选择性sigma1配体的合成和药理评价。第2部分。

  摘要：

  本文描述了由四氢异喹啉-乙内酰脲（Tic-乙内酰脲）衍生物组成的一类新的选择性sigma1配体。化合物1a对sigma1受体具有高亲和力（IC50 = 16 nM），并且在许多治疗靶标中具有选择性。这项研究提出了tic乙内酰脲核心的侧链上的结构变化。可以鉴定出具有更高亲和力的类似物（IC50约为2-3 nM）。

  DOI：

  10.1016/j.bmcl.2005.07.039

文献信息

• Optimized synthesis of tetrahydroisoquinoline-hydantoins
  作者：Julie Charton、Amaury Cazenave Gassiot、Patricia Melnyk、Sophie Girault-Mizzi、Christian Sergheraert

  DOI：10.1016/j.tetlet.2004.07.112

  日期：2004.9

  Several methods have been developed and compared for the solution synthesis of tetrahydroisoquinoline-hydantoin (Tichydantoin) derivatives. Starting materials were Tic-OH and amines readily available from commercial sources. The best yields were observed when the imidazolidine-2,4-dione ring was synthesized in two steps: (1) reaction of Tic-OH with the appropriate amine and (2) cyclization with 1,1'-carbonyldiimidazole. (C) 2004 Elsevier Ltd. All rights reserved.
• Synthesis and pharmacological evaluation of Tic-hydantoin derivatives as selective σ1 ligands. Part 2
  作者：Amaury Cazenave Gassiot、Julie Charton、Sophie Girault-Mizzi、Pauline Gilleron、Marie-Ange Debreu-Fontaine、Christian Sergheraert、Patricia Melnyk

  DOI：10.1016/j.bmcl.2005.07.039

  日期：2005.11

  Herein is described a new class of selective sigma1 ligands consisting of tetrahydroisoquinoline-hydantoin (Tic-hydantoin) derivatives. Compound 1a has high affinity (IC50 = 16 nM) for sigma1 receptor and is selective in a large panel of therapeutic targets. This study presents structural changes on the side chain of the Tic-hydantoin core. Analogs of higher affinity could be identified (IC50 approximately

  本文描述了由四氢异喹啉-乙内酰脲（Tic-乙内酰脲）衍生物组成的一类新的选择性sigma1配体。化合物1a对sigma1受体具有高亲和力（IC50 = 16 nM），并且在许多治疗靶标中具有选择性。这项研究提出了tic乙内酰脲核心的侧链上的结构变化。可以鉴定出具有更高亲和力的类似物（IC50约为2-3 nM）。
• Kinetics and mechanism of racemization of Tic-hydantoins, potent sigma-1 agonists
  作者：Anne-Claire Cabordery、Marion Toussaint、Nathalie Azaroual、Jean-Paul Bonte、Patricia Melnyk、Claud Vaccher、Catherine Foulon

  DOI：10.1016/j.tetasy.2011.01.015

  日期：2011.1

  The configurational stability of seven Tic-hydantoin sigma-1 agonists 1-7 was studied in organic and aqueous media to mimic conditions encountered during either their synthesis or their evaluation as a drug candidate (physico chemical property determination and pharmacological study). This study was performed from the enantiomers directly obtained by asymmetric synthesis (hydantoins 1,3-7) or after semi-preparative separation of the racemic obtained according to the same asymmetric procedure (thiohydantoin 2), by chiral HPLC. The racemization phenomenon was followed using recently validated chiral HPLC and capillary electrophoresis separation methods using derivatized cellulose and amylose chiral stationary phases (Chiralcel OD-H and Chiralpak AD) and highly sulphated cyclodextrins [highly S-beta-CD in the background electrolyte (BGE)], respectively. The kinetic parameters (rate constant, half-life and apparent free energy barriers) of racemization were calculated using a first-order reaction model. The influence of the acid-base content, pH in aqueous medium, concentration of the buffer, and temperature were investigated. The fastest racemization rates were observed under basic conditions. All hydantoins were shown to present the same magnitude of configurational stability, whereas thiohydantoin 2 was characterized by a high chiral instability, especially in ethanolic and aqueous media: its high instability in ethanol explains that a racemic mixture was obtained after asymmetric synthesis; its instantaneous racemization observed from the neutral pH makes the preparation of the enantiomers of 2 not relevant. Finally, the mechanism of racemization was elucidated using nuclear magnetic resonance (NMR): the comparison of the kinetics of the deuteration to the kinetics of the racemization suggests the involvement of a common reaction mechanism of S(E)1 type for hydantoin 1, while an S(E)2 type reaction seems to be involved for thiohydantoin 2. (C) 2011 Elsevier Ltd. All rights reserved.