1-Azabicyclo[2.2.1]hept-4-ylcarboxaldehyde | 126344-05-6

• 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: 1-Azabicyclo[2.2.1]hept-4-ylcarboxaldehyde
• 英文别名: 1-Azabicyclo[2.2.1]heptane-4-carbaldehyde
• CAS: 126344-05-6
• 化学式: C₇H₁₁NO
• mdl: MFCD18806522
• 分子量: 125.17
• InChiKey: KRXFNXMCMSUEOM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  9
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.857
• 拓扑面积：
  20.3
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  甲氧基胺盐酸盐 、 1-Azabicyclo[2.2.1]hept-4-ylcarboxaldehyde 以 甲醇 为溶剂， 生成 1-Aza-bicyclo[2.2.1]heptane-4-carbaldehyde O-methyl-oxime
  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：

  N-methoxy-N-methyl-1-azabicyclo[2.2.1]heptane-4-carboxamide 在 盐酸 、 二异丁基氢化铝 作用下， 生成 1-Azabicyclo[2.2.1]hept-4-ylcarboxaldehyde
  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

• Novel compounds
  申请人：BEECHAM GROUP PLC

  公开号：EP0338723A1

  公开（公告）日：1989-10-25

  Novel compounds of formula (I), a process for their preparation, and their use as pharmaceutical agents are described: wherein R₁ represents 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; R₂ is a group OR₄, where R₄ is C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, a group OCOR₅ where R₅ is hydrogen or R₄, or a group NHR₆ or NR₇R₈ where R₆, R₇ and R₈ are independently C₁₋₂ alkyl; and R₃ is hydrogen or C₁₋₄ alkyl, subject to the proviso that when R₂ is a group OCOR₅ or a group NHR₆, R₃ is C₁₋₄ alkyl.

  本研究描述了式 (I) 的新型化合物、其制备方法及其作为药剂的用途： 其中 R₁ 代表 其中 p 和 q 各自独立地代表 2 至 4 的整数，r 代表 2 至 4 的整数，s 代表 1 或 2，t 代表 0 或 1； R₂ 是基团 OR₄，其中 R₄ 是 C₁₋₄ 烷基、C₂₋₄ 烯基、C₂₋₄ 烷炔基、基团 OCOR₅（其中 R₅ 是氢或 R₄）或基团 NHR₆ 或 NR₇（其中 R₆、R₇ 和 R₈ 独立地是 C₁₋₂ 烷基）；以及 R₃ 是氢或 C₁₋₄ 烷基，但当 R₂ 是基团 OCOR₅ 或基团 NHR₆ 时，R₃ 是 C₁₋₄ 烷基。
• US5091397A
  申请人：——

  公开号：US5091397A

  公开（公告）日：1992-02-25
• US5110828A
  申请人：——

  公开号：US5110828A

  公开（公告）日：1992-05-05
• 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.