2-(5-bromo-pentyl)-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-(5-bromo-pentyl)-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one
• 英文别名: (4aR,8aS)-2-(5-bromopentyl)-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1-one
• 化学式: C₂₁H₂₇BrN₂O₃
• 分子量: 435.361
• InChiKey: BKWWNLJWEVOUOL-SJORKVTESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  27
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  51.1
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  cis-2-aminoethyl-5-(2'-methoxy-5'-fluorophenethyl)tetrahydrofuran 、 2-(5-bromo-pentyl)-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one 在 caesium hydroxide monohydrate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.5h， 以31%的产率得到4-(3,4-dimethoxyphenyl)-2-[5-(2-{5-[2-(5-fluoro-2-methoxyphenyl)-ethyl]-tetrahydrofuran-2-yl}-ethylamino)-pentyl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one
  参考文献：
  名称：

  Dual Inhibitors of Phosphodiesterase-4 and Serotonin Reuptake

  摘要：

  A new class of multitarget compounds was synthesized by linking a novel selective serotonin reuptake inhibitor (SSRI) to a PDE4 inhibitor. The new dual PDE4 inhibitor/SSRI showed antidepressant-like activity in the forced swim test in mice The SSRIs 2-{5-[3-(5-fluoro-2-methoxy-phenyl)-ethyl]-tetrahydro-furan-2-yl}-ethylamine (14) and 2-{5-[3-(5-fluoro-2-methoxy-phenyl)-propyl]-tetrahydro-furan-2-yl}-ethylamine (15) were both individually linked to the PDE4 inhibitor 4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one (19), via a five-carbon chain. The dual PDE4 inhibitor/SSRI 2-{5-[3-(5-fluoro-2-methoxyphenyl)-ethyl]-tetrahydro-furan-2-yl}-ethylamine)-pentyl]-4,5,8,8a-tetrahydro-2H-phthalazin-1-one (21) showed potent and selective serotonin reuptake inhibition (IC50 value of 127 nM). The dual PDE4 inhibitor/SSRI 21 also inhibited PDE4D3 with a K-i value of 2.0 nM. The dual PDE4 inhibitor/SSRI was significantly more effective than the individual SSRI alone or fluoxetine in the forced swim test at standard doses. On a molar basis, the antidepressant-like effect of the dual PDE4 inhibitor/SSRI 21 showed a 129-fold increase in in vivo efficacy compared to fluoxetine.

  DOI：

  10.1021/jm8010993
• 作为产物：
  描述：

  1,5-二溴戊烷 、 (cis)-4-(3,4-Dimethoxyphenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one 在 sodium hydride 作用下， 反应 0.5h， 生成 2-(5-bromo-pentyl)-4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one
  参考文献：
  名称：

  [EN] MODULATORS OF CENTRAL NERVOUS SYSTEM NEUROTRANSMITTERS
  [FR] MODULATEURS DE NEUROTRANSMETTEURS DU SYSTEME NERVEUX CENTRAL

  摘要：

  公开号：

  WO2006025920A3

文献信息

• MODULATORS OF CENTRAL NERVOUS SYSTEM NEUROTRANSMITTERS
  申请人：CASHMAN John

  公开号：US20130123253A1

  公开（公告）日：2013-05-16

  Disclosed are agents having pharmacological activity against cellular receptors and intracellular signaling, particularly receptors and signaling pathways of central nervous system (CNS) neurotransmitters. Also disclosed are related methods and compositions for the treatment or prevention of diseases or disorders using the agents.

  本发明涉及一种对细胞受体和细胞内信号传导具有药理活性的药剂，特别是针对中枢神经系统（CNS）神经递质的受体和信号通路。本发明还涉及使用这些药剂的相关方法和组合物，用于治疗或预防疾病或障碍。
• Inhibition of serotonin and norepinephrine reuptake and inhibition of phosphodiesterase by multi-target inhibitors as potential agents for depression
  作者：John R. Cashman、Senait Ghirmai

  DOI：10.1016/j.bmc.2009.08.025

  日期：2009.10

  Compounds possessing more than one functional activity incorporated into the same molecule may have advantages in treating complex disease states. Balanced serotonin/norepinephrine reuptake inhibitors (SNRIs) (i.e., (R)- and (S)-norduloxetine) were chemically linked to a PDE4 inhibitor via a five carbon bridge. The new dual SNRI/PDE4 inhibitors (i.e., (R)-15 and (S)-15) showed moderately potent serotonin reuptake inhibition (IC(50) values of 442 and 404 nM, respectively) but low reuptake inhibition of norepinephrine (IC(50) values of 2097 and 2190 nM, respectively) in vitro. The dual SNRI/PDE4 inhibitors (i.e., (R)-15 and (S)-15) also inhibited PDE4D2 (i.e., K(i) values of 23 and 45 nM, respectively). Due to their synergistic functional activity, SNRI/PDE4 inhibitors may be effective in treating diseases such as depression. (C) 2009 Elsevier Ltd. All rights reserved.
• [EN] MODULATORS OF CENTRAL NERVOUS SYSTEM NEUROTRANSMITTERS<br/>[FR] MODULATEURS DE NEUROTRANSMETTEURS DU SYSTEME NERVEUX CENTRAL
  申请人：HUMAN BIOMOLECULAR RES INST

  公开号：WO2006025920A3

  公开（公告）日：2006-08-17
• Dual Inhibitors of Phosphodiesterase-4 and Serotonin Reuptake
  作者：John R. Cashman、Troy Voelker、Han-Ting Zhang、James M. O’Donnell

  DOI：10.1021/jm8010993

  日期：2009.3.26

  A new class of multitarget compounds was synthesized by linking a novel selective serotonin reuptake inhibitor (SSRI) to a PDE4 inhibitor. The new dual PDE4 inhibitor/SSRI showed antidepressant-like activity in the forced swim test in mice The SSRIs 2-5-[3-(5-fluoro-2-methoxy-phenyl)-ethyl]-tetrahydro-furan-2-yl}-ethylamine (14) and 2-5-[3-(5-fluoro-2-methoxy-phenyl)-propyl]-tetrahydro-furan-2-yl}-ethylamine (15) were both individually linked to the PDE4 inhibitor 4-(3,4-dimethoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one (19), via a five-carbon chain. The dual PDE4 inhibitor/SSRI 2-5-[3-(5-fluoro-2-methoxyphenyl)-ethyl]-tetrahydro-furan-2-yl}-ethylamine)-pentyl]-4,5,8,8a-tetrahydro-2H-phthalazin-1-one (21) showed potent and selective serotonin reuptake inhibition (IC50 value of 127 nM). The dual PDE4 inhibitor/SSRI 21 also inhibited PDE4D3 with a K-i value of 2.0 nM. The dual PDE4 inhibitor/SSRI was significantly more effective than the individual SSRI alone or fluoxetine in the forced swim test at standard doses. On a molar basis, the antidepressant-like effect of the dual PDE4 inhibitor/SSRI 21 showed a 129-fold increase in in vivo efficacy compared to fluoxetine.