α-(azidomethyl)-4-[2-(1-methylethoxy)phenyl]-1-piperazineethanol | 239807-62-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: α-(azidomethyl)-4-[2-(1-methylethoxy)phenyl]-1-piperazineethanol
• 英文别名: 1-Azido-3-[4-(2-propan-2-yloxyphenyl)piperazin-1-yl]propan-2-ol
• CAS: 239807-62-6
• 化学式: C₁₆H₂₅N₅O₂
• 分子量: 319.407
• InChiKey: CBCNMUGWPMJBFC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  23
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  50.3
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  α-(azidomethyl)-4-[2-(1-methylethoxy)phenyl]-1-piperazineethanol 在 4-二甲氨基吡啶 、 palladium on activated charcoal 盐酸 、 氢气 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 二氯甲烷 、 水 为溶剂， 20.0 ℃ 、344.74 kPa 条件下， 反应 36.0h， 生成 2-chloro-N-[2-hydroxy-3-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]propyl]-3-pyridinecarboxamide
  参考文献：
  名称：

  Design, synthesis and biological evaluation of pyridine-phenylpiperazines: A novel series of potent and selective α1a-adrenergic receptor antagonist

  摘要：

  Beginning from the screening hit and literature alpha(1)-adrenergic compounds, a hybridized basic skeleton A was proposed as the pharmacophore for potent and selective alpha(1a)-AR antagonists. Introduction of a hydroxy group to increase the flexibility afforded B which served as the screening model and resulted in the identification of the second-generation lead 1. Using the Topliss approach, a number of potent and selective alpha(1a)-AR antagonists were discovered. In all cases, binding affinity and selectivity at the alpha(1a)-AR of S-hydroxy enantiomers were higher than the R-hydroxy enantiomers. As compared to the des-hydroxy analogues, the S-hydroxy enantiomers displayed comparable potency and better selectivity at alpha(1a)-AR. The S-hydroxy enantiomer 17 (K-i = 0.79 nM; alpha(1b)/alpha(1a) = 800; alpha(1d)/alpha(1a) = 104) was slightly less potent but much more selective at alpha(1a)-AR than tamsulosin (K-i = 0.13 nM, alpha(1b)/alpha(1a) = 15, alpha(1d)/alpha(1a) = 1.4). Compound 17 displayed higher selectivity in inhibiting rat prostate contraction over rat aorta contraction and also exhibited a higher degree of uroselectivity than tamsulosin in the anesthetized dog model. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00151-6
• 作为产物：
  描述：

  1-叠氮基-2-羟基-3-甲苯磺酰氧基丙烷 、 2-(1-methylethoxy)phenyl-1-piperazine 以 N-甲基吡咯烷酮 为溶剂， 反应 36.0h， 以76%的产率得到α-(azidomethyl)-4-[2-(1-methylethoxy)phenyl]-1-piperazineethanol
  参考文献：
  名称：

  Design, synthesis and biological evaluation of pyridine-phenylpiperazines: A novel series of potent and selective α1a-adrenergic receptor antagonist

  摘要：

  Beginning from the screening hit and literature alpha(1)-adrenergic compounds, a hybridized basic skeleton A was proposed as the pharmacophore for potent and selective alpha(1a)-AR antagonists. Introduction of a hydroxy group to increase the flexibility afforded B which served as the screening model and resulted in the identification of the second-generation lead 1. Using the Topliss approach, a number of potent and selective alpha(1a)-AR antagonists were discovered. In all cases, binding affinity and selectivity at the alpha(1a)-AR of S-hydroxy enantiomers were higher than the R-hydroxy enantiomers. As compared to the des-hydroxy analogues, the S-hydroxy enantiomers displayed comparable potency and better selectivity at alpha(1a)-AR. The S-hydroxy enantiomer 17 (K-i = 0.79 nM; alpha(1b)/alpha(1a) = 800; alpha(1d)/alpha(1a) = 104) was slightly less potent but much more selective at alpha(1a)-AR than tamsulosin (K-i = 0.13 nM, alpha(1b)/alpha(1a) = 15, alpha(1d)/alpha(1a) = 1.4). Compound 17 displayed higher selectivity in inhibiting rat prostate contraction over rat aorta contraction and also exhibited a higher degree of uroselectivity than tamsulosin in the anesthetized dog model. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00151-6

文献信息

• Phthalimido arylpiperazines useful in the treatment of benign prostatic hyperplasia
  申请人：Ortho-McNeil Pharmaceutical, Inc.

  公开号：US06362338B1

  公开（公告）日：2002-03-26

  This invention relates to a series of substituted piperazines of Formula II, as well as enantiomers thereof These compounds are useful in the manufacture of pharmaceutical compositions.

  这项发明涉及到一系列Formula II的替代哌嗪，以及其对映体。这些化合物在制药组合物的制造中是有用的。
• Design, Synthesis, and Structure−Activity Relationships of Phthalimide-Phenylpiperazines:  A Novel Series of Potent and Selective α₁_a-Adrenergic Receptor Antagonists
  作者：Gee-Hong Kuo、Catherine Prouty、William V. Murray、Virginia Pulito、Linda Jolliffe、Peter Cheung、Sally Varga、Mary Evangelisto、Jian Wang

  DOI：10.1021/jm9905918

  日期：2000.6.1

  Beginning from the screening hit and literature alpha(1)-adrenergic compounds, a hybridized basic skeleton A was proposed as the pharmacophore for potent and selective alpha(1a)-AR antagonists. Introduction of a hydroxy group to increase the flexibility afforded B which served as the screening model and resulted in the identification of the second-generation lead 1. Using the Topliss approach, a number of potent and selective alpha(1a)-AR antagonists were discovered. In all cases, binding affinity and selectivity at the alpha(1a)-AR of S-hydroxy enantiomers were higher than those of the R-hydroxy enantiomers. As compared to the des-hydroxy analogues, the S-hydroxy enantiomers had slightly lower binding affinity at alpha(1a)-AR but gained more than 2-fold selectivity for alpha(1a)-AR over alpha(1b)-AR, and 2- to 6-fold selectivity for alpha(1a)-AR over alpha(1d)-AR. They also had less cross activities against a panel of 25-35 peripheral and CNS receptors. The S-hydroxy enantiomers 23 and 24 (K-i = 0.29 nM, 0.33 nM; alpha(1b)/alpha(1a) >5690, >6060; alpha(1d)/alpha(1a) = 186, 158, respectively) were slightly less potent but much more selective at alpha(1a)-AR than tamsulosin (K-i = 0.13 nM, alpha(1d)/alpha(1a)= 14.8, alpha(1d)/alpha(1a) = 1.4). In the functional assay, the S-hydroxy enantiomers 20, 23, and 24 were less potent than tamsulosin in inhibiting contractions of rat prostate tissue but more selective in the inhibition of tissue contractions of rat prostate versus rat aorta. Compound 24 was selected as the development candidate for the treatment of BPH.