N-methoxy-1-azabicyclo[2.2.1]heptane-4-carboxamide | 133643-00-2

• 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[2.2.1]heptane-4-carboxamide
• 英文别名: 1-Azabicyclo[2.2.1]hept-4-yl-N-methoxycarboxamide
• CAS: 133643-00-2
• 化学式: C₈H₁₄N₂O₂
• 分子量: 170.211
• InChiKey: DREPEXJDUSCRST-UHFFFAOYSA-N

物化性质

• 密度：
  1.20±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.3
• 重原子数：
  12
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.88
• 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[2.2.1]heptane-4-carboxamide 在 四氯化碳 、 三苯基膦 作用下， 以 乙腈 为溶剂， 反应 0.33h， 以77%的产率得到(Z)-1-azabicyclo[2.2.1]heptane-4-N-methoxycarboximidoyl chloride
  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
• 作为产物：
  描述：

  1-氮杂双环[2.2.1]庚烷-4-羧酸 在 氯化亚砜 、 三乙胺 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[2.2.1]heptane-4-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

• Azabicylo oxime compounds
  申请人：Beecham Group p.l.c.

  公开号：USRE035593E1

  公开（公告）日：1997-08-19

  A compound of formula (I) or a pharmaceutically acceptable salt thereof: ##STR1## wherein R.sup.1 represents ##STR2## in which each of p and q independently represents an integer of 2 to 4, r represents an integer of 2 to 4, s represents 1 or 2 and t represents 0 or 1; R.sub.2 is a group OR.sub.4, where R.sub.4 is C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, a group OCOR.sub.5 where R.sub.5 is hydrogen or R.sub.4, or a group NHR.sub.6 or NR.sub.7 R.sub.8 where R.sub.6, R.sub.7 and R.sub.8 are independently C.sub.1-2 alkyl; and R.sub.3 is chloro, fluoro, bromo, cyclopropyl, C.sub.1-3 alkyl substituted by one, two or three halogen atoms, or R.sub.3 is a group (CH.sub.2).sub.n R.sub.9 where R.sub.9 is --CN, --OH, --OCH.sub.3, --SH, --SCH.sub.3, --C.tbd.CH or --CH.dbd.CH.sub.2 and n is O or 1, with the proviso that when n is 0, R.sub.9 is not --OH or --SH.

  化合物的式子(I)或其药学上可接受的盐：##STR1## 其中R.sup.1代表##STR2## 其中p和q各自表示2到4的整数，r表示2到4的整数，s表示1或2，t表示0或1; R.sub.2是一个OR.sub.4基团，其中R.sub.4是C.sub.1-4烷基，C.sub.2-4烯基，C.sub.2-4炔基，OCOR.sub.5基团，其中R.sub.5是氢或R.sub.4，或NHR.sub.6或NR.sub.7R.sub.8基团，其中R.sub.6，R.sub.7和R.sub.8分别是C.sub.1-2烷基; R.sub.3是氯，氟，溴，环丙基，C.sub.1-3烷基，被一个，两个或三个卤原子取代的，或R.sub.3是(CH.sub.2).sub.nR.sub.9基团，其中R.sub.9是--CN，--OH，--OCH.sub.3，--SH，--SCH.sub.3，--C.tbd.CH或--CH.dbd.CH.sub.2，n为0或1，但当n为0时，R.sub.9不是--OH或--SH。
• 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.