3-(1-acetyl-4-piperidinyl)-1-(1-acetyl-2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone | 142853-11-0

• 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: 3-(1-acetyl-4-piperidinyl)-1-(1-acetyl-2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone
• 英文别名: 3-(1-Acetylpiperidin-4-yl)-1-(1-acetyl-2,3,4,5-tetrahydro-1-benzazepin-8-yl)propan-1-one
• CAS: 142853-11-0
• 化学式: C₂₂H₃₀N₂O₃
• 分子量: 370.492
• InChiKey: JRUYPWHMNAJIFV-UHFFFAOYSA-N

物化性质

• 沸点：
  644.2±50.0 °C(Predicted)
• 密度：
  1.125±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  57.7
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-(1-acetyl-4-piperidinyl)-1-(1-acetyl-2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone 在 盐酸 、 potassium carbonate 作用下， 以 乙醇 为溶剂， 反应 19.0h， 生成 扎那哌齐
  参考文献：
  名称：

  Central Cholinergic Agents. 6. Synthesis and Evaluation of 3-[1-(Phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)- 1-propanones and Their Analogs as Central Selective Acetylcholinesterase Inhibitors

  摘要：

  In an attempt to find central selective acetylcholinesterase (AChE) inhibitors, 3-[1-(phenyl-methyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanones 9 and their analogs were designed on the basis of our working hypothesis of the enzyme's active site. These compounds were prepared by regioselective Friedel-Crafts acylation of 2,3,4,5-tetrahydro-1H-benzazepines and related nitrogen heterocycles as a key step. Most compounds showed potent inhibitory activities with IC(50)s in the 10-300 nM range. In order to estimate their central selectivities, we examined their effects on the apomorphine-induced circling behavior in rats with unilateral striatal lesions. Among compounds with potent AChE inhibition, 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone fumarate (9a, TAK-147) (IC50 of AChE inhibition = 97.7 nM) inhibited the circling behavior at 3 mg/kg po, in which it had no significant effect on peripheral cholinergic effects. This demonstrates that 9a has favorable central selectivity. Furthermore, 9a significantly ameliorated diazepam-induced passive avoidance deficit at 1 mg/kg po. The benzazepine derivative 9a was selected as a candidate for clinical evaluation.

  DOI：

  10.1021/jm00041a007
• 作为产物：
  描述：

  3-(1-acetyl-4-piperidinyl)propionyl chloride 、 1-acetyl-2,3,4,5-tetrahydro-1H-1-benzazepine 以38的产率得到3-(1-acetyl-4-piperidinyl)-1-(1-acetyl-2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone
  参考文献：
  名称：

  Condensed heterocyclic compounds, their production and use

  摘要：

  一种公式（I）的缩合杂环衍生物：##STR1## 其中X是氧原子、硫原子或R.sup.1 -N<，其中R.sup.1是氢原子、可取代的碳氢基团或可取代的酰基基团；R.sup.2是氢原子或可取代的碳氢基团；环A是苯环，可取代；k是0至3的整数；m是1至8的整数；n是1至6的整数；或其药学上可接受的盐，具有高胆碱酯酶抑制活性，以及其制备方法。

  公开号：

  US05273974A1

文献信息

• Drugs Fut. 1995, 20, 248
  作者：

  DOI：——

  日期：——
• J. Med. Chem. 1994, 37, 2292-2299
  作者：

  DOI：——

  日期：——
• US5273974A
  申请人：——

  公开号：US5273974A

  公开（公告）日：1993-12-28
• Central Cholinergic Agents. 6. Synthesis and Evaluation of 3-[1-(Phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)- 1-propanones and Their Analogs as Central Selective Acetylcholinesterase Inhibitors
  作者：Yuji Ishihara、Keisuke Hirai、Masaomi Miyamoto、Giichi Goto

  DOI：10.1021/jm00041a007

  日期：1994.7

  In an attempt to find central selective acetylcholinesterase (AChE) inhibitors, 3-[1-(phenyl-methyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanones 9 and their analogs were designed on the basis of our working hypothesis of the enzyme's active site. These compounds were prepared by regioselective Friedel-Crafts acylation of 2,3,4,5-tetrahydro-1H-benzazepines and related nitrogen heterocycles as a key step. Most compounds showed potent inhibitory activities with IC(50)s in the 10-300 nM range. In order to estimate their central selectivities, we examined their effects on the apomorphine-induced circling behavior in rats with unilateral striatal lesions. Among compounds with potent AChE inhibition, 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone fumarate (9a, TAK-147) (IC50 of AChE inhibition = 97.7 nM) inhibited the circling behavior at 3 mg/kg po, in which it had no significant effect on peripheral cholinergic effects. This demonstrates that 9a has favorable central selectivity. Furthermore, 9a significantly ameliorated diazepam-induced passive avoidance deficit at 1 mg/kg po. The benzazepine derivative 9a was selected as a candidate for clinical evaluation.
• Condensed heterocyclic compounds, their production and use
  申请人：Takeda Chemical Industries, Ltd.

  公开号：US05273974A1

  公开（公告）日：1993-12-28

  A condensed heterocyclic derivative of the formula (I): ##STR1## wherein X is an oxygen atom, a sulfur atom or R.sup.1 --N< wherein R.sup.1 is a hydrogen atom, a hydrocarbon group which may be substituted or an acyl group which may be substituted; R.sup.2 is a hydrogen atom or a hydrocarbon group which may be substituted; ring A is a benzene ring which may be substituted, k is a whole number of 0 to 3; m is a whole number of 1 to 8; and n is a whole number of 1 to 6, or a pharmaceutically acceptable salt thereof exhibiting high colinesterase inhibitory activity, and a method for producing the same.

  一种公式（I）的缩合杂环衍生物：##STR1## 其中X是氧原子、硫原子或R.sup.1 -N<，其中R.sup.1是氢原子、可取代的碳氢基团或可取代的酰基基团；R.sup.2是氢原子或可取代的碳氢基团；环A是苯环，可取代；k是0至3的整数；m是1至8的整数；n是1至6的整数；或其药学上可接受的盐，具有高胆碱酯酶抑制活性，以及其制备方法。