N-methoxy-1-azabicyclo[2.2.2]octane-3-carboxamide | 149156-47-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: N-methoxy-1-azabicyclo[2.2.2]octane-3-carboxamide
• CAS: 149156-47-8
• 化学式: C₉H₁₆N₂O₂
• 分子量: 184.238
• InChiKey: GNNVBIVIGBDZRV-UHFFFAOYSA-N

物化性质

• 密度：
  1.15±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  13
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  41.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N-methoxy-1-azabicyclo[2.2.2]octane-3-carboxamide 在 四氯化碳 、 三苯基膦 作用下， 以 乙腈 为溶剂， 反应 0.08h， 以61%的产率得到(Z)-N-methoxy-1-azabicyclo[2.2.2]octane-3-carboximidoyl chloride
  参考文献：
  名称：

  Synthesis and properties of [R-(Z)]-(+)-α-(1-azabicyclo[2.2.2]oct-3-yl)-α-(methoxyimino)acetonitrile, a novel functionally selective muscarinic partial agonist

  摘要：

  (Z)-N-甲氧基酰亚胺腈官能团是一种新型的甲酯生物异构体，将其取代到喹烯酮环系统上后，就得到了标题化合物 1，这是一种稳定、脑穿透力强且具有诱导选择性的毒蕈碱类部分激动剂；X 射线研究证实了该化合物的构型分配，并发现其酰亚胺键和氰键的长度分别与正式双键和三键的预期长度一致。

  DOI：

  10.1039/c39940002189
• 作为产物：
  描述：

  奎宁环-3-羧酸 在 吡啶 、 氯化亚砜 作用下， 以 二氯甲烷 、 氯仿 、 乙腈 为溶剂， 反应 6.0h， 生成 N-methoxy-1-azabicyclo[2.2.2]octane-3-carboxamide
  参考文献：
  名称：

  Design of [R-(Z)]-(+)-α-(Methoxyimino)-1-azabicyclo[2.2.2]octane-3-acetonitrile (SB 202026), a Functionally Selective Azabicyclic Muscarinic M1 Agonist Incorporating the N-Methoxy Imidoyl Nitrile Group as a Novel Ester Bioisostere

  摘要：

  Loss of cholinergic function is believed to be implicated in the cognitive decline associated with senile dementia of the Alzheimer type (SDAT). The disease is characterized by progressive loss of muscarinic receptors located on nerve terminals while postsynaptic muscarinic M1 receptors appear to remain largely intact. Muscarinic agonists acting directly on postsynaptic receptors offer the prospect of countering the cholinergic deficit in SDAT. This study describes a novel series of azabicyclic muscarinic agonists, which incorporate an oxime ether or modified oxime ether group as an ester bioisostere. Modification of the oxime ether function by the introduction of electron withdrawing groups led to the finding that the (Z)-N-methoxy imidoyl nitrile group serves as a stable methyl ester bioisostere. This culminated in the discovery of the quinuclidinyl N-methoxy imidoyl nitrile R-(+)-(Z)-5g which is a functionally selective muscarinic M1 partial agonist currently in phase III clinical trials for the treatment of SDAT. The selective profile of R-(+)-(Z)-5g can be rationalized in terms of the relative affinity of the compound at muscarinic receptor subtypes, the degree of agonist efficacy, and brain penetrancy.

  DOI：

  10.1021/jm9702903

文献信息

• Synthesis and properties of [R-(Z)]-(+)-α-(1-azabicyclo[2.2.2]oct-3-yl)-α-(methoxyimino)acetonitrile, a novel functionally selective muscarinic partial agonist
  作者：Steven M. Bromidge、Frederick Cassdiy、Michael S. G. Clark、Drake S. Eggeleston、Barry S. Oriek

  DOI：10.1039/c39940002189

  日期：——

  The (Z)-N-methoxy imidoyl nitrile functionality is a novel methyl ester bioisostere, which, when substituted onto the quinuclidine ring system gives the title compound 1, a stable, brain penetrant and fuctionally selective muscarinic partial agonist; X-ray studies confirm the configurational assignment and reveal that the imino and cyano bond lengths are consistent with those expected for formal double and triple bonds, respectively.

  (Z)-N-甲氧基酰亚胺腈官能团是一种新型的甲酯生物异构体，将其取代到喹烯酮环系统上后，就得到了标题化合物 1，这是一种稳定、脑穿透力强且具有诱导选择性的毒蕈碱类部分激动剂；X 射线研究证实了该化合物的构型分配，并发现其酰亚胺键和氰键的长度分别与正式双键和三键的预期长度一致。
• J. Med. Chem. 1997, 40, 4265-4280
  作者：

  DOI：——

  日期：——
• J. Chem. Soc., Chem. Commun. 1994, 18, 2189-2190
  作者：

  DOI：——

  日期：——
• Bromidge Steven M., Cassidy Frederick, Clark Michael S. G., Eggleston Dra+, J. Chem. Soc. Chem. Commun, (1994) N 18, S 2189-2190
  作者：Bromidge Steven M., Cassidy Frederick, Clark Michael S. G., Eggleston Dra+

  DOI：——

  日期：——
• Design of [<i>R</i>-(<i>Z</i>)]-(+)-α-(Methoxyimino)-1-azabicyclo[2.2.2]octane-3-acetonitrile (SB 202026), a Functionally Selective Azabicyclic Muscarinic M1 Agonist Incorporating the <i>N</i>-Methoxy Imidoyl Nitrile Group as a Novel Ester Bioisostere
  作者：Steven M. Bromidge、Frank Brown、Frederick Cassidy、Michael S. G. Clark、Steven Dabbs、Michael S. Hadley、Julie Hawkins、Julia M. Loudon、Christopher B. Naylor、Barry S. Orlek、Graham J. Riley

  DOI：10.1021/jm9702903

  日期：1997.12.1

  Loss of cholinergic function is believed to be implicated in the cognitive decline associated with senile dementia of the Alzheimer type (SDAT). The disease is characterized by progressive loss of muscarinic receptors located on nerve terminals while postsynaptic muscarinic M1 receptors appear to remain largely intact. Muscarinic agonists acting directly on postsynaptic receptors offer the prospect of countering the cholinergic deficit in SDAT. This study describes a novel series of azabicyclic muscarinic agonists, which incorporate an oxime ether or modified oxime ether group as an ester bioisostere. Modification of the oxime ether function by the introduction of electron withdrawing groups led to the finding that the (Z)-N-methoxy imidoyl nitrile group serves as a stable methyl ester bioisostere. This culminated in the discovery of the quinuclidinyl N-methoxy imidoyl nitrile R-(+)-(Z)-5g which is a functionally selective muscarinic M1 partial agonist currently in phase III clinical trials for the treatment of SDAT. The selective profile of R-(+)-(Z)-5g can be rationalized in terms of the relative affinity of the compound at muscarinic receptor subtypes, the degree of agonist efficacy, and brain penetrancy.