4-<2-<6,7-dihydro-6-oxo-5H-pyrrolo<3,2-f>-1,2-benzisoxazol-3-yl>ethyl>-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester | 145509-12-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并异恶唑
• 英文名称: 4-<2-<6,7-dihydro-6-oxo-5H-pyrrolo<3,2-f>-1,2-benzisoxazol-3-yl>ethyl>-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester
• 英文别名: 4-[2-[5,7-Dihydro-6H-pyrrolo[3,2-f]-1,2-benzisoxazol-6-one-3-yl ]ethyl]-1-piperidinecarboxylic acid, 1-(1,1-dimethylethyl)ester；4-[2-[5,7-Dihydro-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one-3-yl]ethyl]-1-piperidinecarboxylic acid, 1-(1,1-dimethylethyl) ester；tert-butyl 4-[2-(6-oxo-5,7-dihydropyrrolo[3,2-f][1,2]benzoxazol-3-yl)ethyl]piperidine-1-carboxylate
• CAS: 145509-12-2
• 化学式: C₂₁H₂₇N₃O₄
• 分子量: 385.463
• InChiKey: BJKAMOUIKVAKNV-UHFFFAOYSA-N

物化性质

• 沸点：
  576.2±50.0 °C(Predicted)
• 密度：
  1.224±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  84.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-<2-<6,7-dihydro-6-oxo-5H-pyrrolo<3,2-f>-1,2-benzisoxazol-3-yl>ethyl>-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 生成 CP-144,885
  参考文献：
  名称：

  5,7-Dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[3,2-f]-1,2-benzisoxazol-6-one: A Potent and Centrally-Selective Inhibitor of Acetylcholinesterase

  摘要：

  A series of N-benzylpiperidines (2a-d, 10) with novel isoxazole-containing tricycles has been prepared. This series has shown potent in vitro inhibition of the enzyme acetylcholinesterase (AChE), with IC(50)s = 0.33-3.6 nM. Compound 2a was the most potent inhibitor with an IC50 = 0.33 +/- 0.09 nM. Derivatives 2a-d and 10 displayed weak in vitro inhibition of butyrylcholinesterase (BuChE) with IC(50)s = 600-23 000 nM. The most selective compound was 2a with a BuChE/AChE ratio in excess of 4 orders of magnitude (>10 000). Pyrrolobenzisoxazole 2a also displayed a favorable profile in vivo. In microdialysis experiments, 2a produced a 200% increase in extracellular levels of acetylcholine (ACh) at a dose of 0.4 mg/kg in freely moving, conscious rats. Peripheral side effects (salivation ED(50) = 26 +/- 1.5 mg/kg) and acute lethality (LD(50)[1 h] = 42 mg/kg) were observed at >60-fold higher doses. These data indicate that 2a is an AChE inhibitor with good central selectivity and a favorable margin of safety. Compound 2a, designated as CP-118,954, is currently in clinical development for the treatment of cognitive disorders.

  DOI：

  10.1021/jm00015a002
• 作为产物：
  描述：

  5-乙酰基-1,3-二氢-6-羟基-2H-吲哚-2-酮,5-肟乙酸酯 在 吡啶 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 8.0h， 生成 4-<2-<6,7-dihydro-6-oxo-5H-pyrrolo<3,2-f>-1,2-benzisoxazol-3-yl>ethyl>-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester
  参考文献：
  名称：

  5,7-Dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[3,2-f]-1,2-benzisoxazol-6-one: A Potent and Centrally-Selective Inhibitor of Acetylcholinesterase

  摘要：

  A series of N-benzylpiperidines (2a-d, 10) with novel isoxazole-containing tricycles has been prepared. This series has shown potent in vitro inhibition of the enzyme acetylcholinesterase (AChE), with IC(50)s = 0.33-3.6 nM. Compound 2a was the most potent inhibitor with an IC50 = 0.33 +/- 0.09 nM. Derivatives 2a-d and 10 displayed weak in vitro inhibition of butyrylcholinesterase (BuChE) with IC(50)s = 600-23 000 nM. The most selective compound was 2a with a BuChE/AChE ratio in excess of 4 orders of magnitude (>10 000). Pyrrolobenzisoxazole 2a also displayed a favorable profile in vivo. In microdialysis experiments, 2a produced a 200% increase in extracellular levels of acetylcholine (ACh) at a dose of 0.4 mg/kg in freely moving, conscious rats. Peripheral side effects (salivation ED(50) = 26 +/- 1.5 mg/kg) and acute lethality (LD(50)[1 h] = 42 mg/kg) were observed at >60-fold higher doses. These data indicate that 2a is an AChE inhibitor with good central selectivity and a favorable margin of safety. Compound 2a, designated as CP-118,954, is currently in clinical development for the treatment of cognitive disorders.

  DOI：

  10.1021/jm00015a002

文献信息

• Methods of using piperidyl-benzisoxazole and benisothiazole derivatives
  申请人：Pfizer Inc.

  公开号：US05538984A1

  公开（公告）日：1996-07-23

  Disclosed herein are compounds of the formula ##STR1## wherein R.sup.1 R.sup.2, R.sup.7, R.sup.8, X, Y, M and L are defined as below The compounds of formula I are cholinesterase inhibitors and are useful in enhancing memory in patients suffering from dementia and Alzheimer's disease.

  本文披露了以下式的化合物##STR1##其中R.sup.1、R.sup.2、R.sup.7、R.sup.8、X、Y、M和L的定义如下。式I的化合物是胆碱酯酶抑制剂，对于增强患有痴呆症和阿尔茨海默病的患者的记忆有用。
• Heterocyclic-cyclic amine derivatives
  申请人：Eisai Co., LTD

  公开号：US06326382B1

  公开（公告）日：2001-12-04

  Compounds of the formula wherein R1 R2, R7, R8, X, Y, M and L are defined as below. The compounds of formula I are cholinesterase inhibitors and are useful in enhancing memory in patients suffering from dementia and Alzheimer's disease.

  公式为I的化合物，其中R1 R2，R7，R8，X，Y，M和L的定义如下。公式I的化合物是胆碱酯酶抑制剂，并且在增强患有痴呆和阿尔茨海默病的患者的记忆方面非常有用。
• Radiotracers for in vivo study of acetylcholinesterase and Alzheimer's disease
  申请人：Pfizer Products Inc.

  公开号：EP1048302A2

  公开（公告）日：2000-11-02

  Radio-labeled compounds of the formula are useful as in vivo imaging agents for diagnosis of Alzheimer's disease.

  放射性标记的式 可用作诊断阿尔茨海默病的体内成像剂。
• J. Med. Chem. 1995, 38, 2802-2808
  作者：

  DOI：——

  日期：——
• HETEROCYCLIC-CYCLIC AMINE DERIVATIVES
  申请人：Eisai Co., Ltd.

  公开号：EP0646115B1

  公开（公告）日：2003-01-22