5,7-dihydro-3-methyl-6H-pyrrolo<3,2-f>-1,2-benzisoxazol-6-one | 145509-11-1

• 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: 5,7-dihydro-3-methyl-6H-pyrrolo<3,2-f>-1,2-benzisoxazol-6-one
• 英文别名: 5,7-dihydro-3-methyl-6H-pyrrolo[3,2-f]-1,2-benzisoxazol-6-one；5,7-dihydro-3-methyl-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one；3-Methyl-5,7-dihydro-6H-isoxazolo[4,5-f]indol-6-one；3-methyl-5,7-dihydropyrrolo[3,2-f][1,2]benzoxazol-6-one
• CAS: 145509-11-1
• 化学式: C₁₀H₈N₂O₂
• 分子量: 188.186
• InChiKey: YZOYWHBJOJTCQQ-UHFFFAOYSA-N

物化性质

• 沸点：
  436.4±45.0 °C(Predicted)
• 密度：
  1.368±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  14
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  55.1
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  5,7-dihydro-3-methyl-6H-pyrrolo<3,2-f>-1,2-benzisoxazol-6-one 在 sodium hydride 、 sodium carbonate 、 三氟乙酸 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 11.5h， 生成 5,7-dihydro-7-methyl-3-<2-<1-(phenylmethyl)-4-piperidinyl>ethyl>-6H-pyrrolo<3,2-f>-1,2-benzisoxazole-6-one
  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 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 以65%的产率得到5,7-dihydro-3-methyl-6H-pyrrolo<3,2-f>-1,2-benzisoxazol-6-one
  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
• 作为试剂：
  描述：

  1-叔丁氧羰基-4-碘甲基哌啶 在 二异丙胺 作用下， 以 四氢呋喃 、 5,7-dihydro-3-methyl-6H-pyrrolo<3,2-f>-1,2-benzisoxazol-6-one 为溶剂， 以9%的产率得到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：

  Methods of using piperidyl-benzisoxazole and benisothiazole derivatives

  摘要：

  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。

  公开号：

  US05538984A1

文献信息

• Radiotracers for in vivo study of acetylcholinesterase and alzheimer's disease
  申请人：——

  公开号：US20020064500A1

  公开（公告）日：2002-05-30

  Methods for detecting acetylcholinesterase in a brain of a patient, comprising administering to the patient a detectable amount of a radiolabeled compound of a class of benzisoxazoles or a pharmaceutically acceptable salt thereof, are disclosed herein. The methods are useful for diagnosing, estimating the severity of, or monitoring the progression of a dementia, such as Alzheimer's disease, in a patient. In a preferred embodiment, the benzisoxazole is: 1

  本文公开了检测患者脑部乙酰胆碱酯酶的方法，包括向患者注射一种可检测量的类苯并异噁唑化合物的放射性标记或其药学上可接受的盐。该方法可用于诊断、评估或监测患者的痴呆症，如阿尔茨海默病的严重程度或进展。在一个优选实施例中，苯并异噁唑是：1。
• [EN] HETEROCYCLIC-CYCLIC AMINE DERIVATIVES
  申请人：PFIZER INC.

  公开号：WO1992017475A1

  公开（公告）日：1992-10-15

  (EN) Compounds of formula (I) 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.(FR) Composés de la formule (I) dans laquelle R1, R2, R7, R8, X, Y, M et L sont définis ci-dessous. Les composés de la formule (I) sont des inhibiteurs de la cholinestérase et ils sont utiles pour améliorer la mémoire chez des patients souffrant de démence ou de la maladie d'Alzheimer.

  (中) 公式（I）中的化合物，其中R1、R2、R7、R8、X、Y、M和L的定义如下。公式（I）中的化合物是胆碱酯酶抑制剂，对于患有痴呆症和阿尔茨海默病的患者增强记忆有用。
• Radiotracers for in vivo study of acetylcholinesterase and Alzheimer's disease
  申请人：Frost James J.

  公开号：US20050100509A1

  公开（公告）日：2005-05-12

  Methods for detecting acetylcholinesterase in a brain of a patent, comprising administering to the patient a detectable amount of a radiolabeled compound of a class of benzisoxazoles or a pharmaceutically acceptable salt thereof, are disclosed herein. The methods are useful for diagnosing, estimating the severity of, or monitoring the progression of a dementia, such as Alzheimer's disease, in a patient. In a preferred embodiment, the benzisoxazole is:

  本发明公开了一种检测病人脑部乙酰胆碱酯酶的方法，包括向病人施用一种可检测量的放射性标记的苯并异噁唑类化合物或其药学上可接受的盐。该方法对于诊断、评估或监测病人的认知障碍，如阿尔茨海默病的严重程度或进展情况非常有用。在一种优选实施例中，苯并异噁唑类化合物为：
• Heterocyclic-cyclic amine derivatives
  申请人：——

  公开号：US20020028834A1

  公开（公告）日：2002-03-07

  Compounds of the formula 1 wherein R 1 R 2 , R 7 , R 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.

  化合物的式子为1，其中R1、R2、R7、R8、X、Y、M和L的定义如下。式I的化合物是胆碱酯酶抑制剂，并可用于增强患有痴呆和阿尔茨海默病的患者的记忆力。
• Benzisoxazole and benzisothizole derivatives as cholinesterase inhibitors
  申请人：Pfizer

  公开号：US05750542A1

  公开（公告）日：1998-05-12

  Described 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.

  本文描述的是式子 ##STR1## 中的化合物，其中R.sup.1、R.sup.2、R.sup.7、R.sup.8、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，对于患有痴呆症和阿尔茨海默病的患者增强记忆力很有用。