ethyl (3R,4S)-1-azabicyclo<2.2.1>heptane-3-carboxylate | 134234-17-6

• 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: ethyl (3R,4S)-1-azabicyclo<2.2.1>heptane-3-carboxylate
• 英文别名: ethyl (3R,4S)-1-azabicyclo[2.2.1]heptane-3-carboxylate
• CAS: 134234-17-6
• 化学式: C₉H₁₅NO₂
• 分子量: 169.224
• InChiKey: BQNAHLRWSVMSEA-SFYZADRCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  12
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  ethyl (3R,4S)-1-azabicyclo<2.2.1>heptane-3-carboxylate 在 盐酸 作用下， 反应 5.0h， 生成 (3S,4R)-1-azoniabicyclo[2.2.1]heptane-3-carboxylate
  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：

  cis-2-benzylhexahydropyrano<3,4-c>pyrrol-4(3aH)-one 在 palladium on activated charcoal 氢溴酸 、 氢气 、 potassium carbonate 作用下， 以 乙醇 、 水 为溶剂， 生成 ethyl (3R,4S)-1-azabicyclo<2.2.1>heptane-3-carboxylate
  参考文献：
  名称：

  非对映选择性路线和乙基1-氮杂双环[2.2.1]庚-3-基羧酸酯

  摘要：

  非对映选择性路线和乙基1-氮杂双环[2.2.1]庚-3-基羧酸酯（1）和（2）基于同分异构的的溴化氢裂解[4.3.0]双环稠内酯（3）和（4）被描述。

  DOI：

  10.1016/s0040-4039(00)92055-0

文献信息

• Diastereoselective routes to and ethyl 1-azabicyclo[2.2.1] hept-3-YL carboxylates
  作者：Barry S. Orlek、Harry Wadsworth、Paul Wyman、Michael S. Hadley

  DOI：10.1016/s0040-4039(00)92055-0

  日期：1991.2

  Diastereoselective routes to and ethyl 1-azabicyclo[2.2.1]hept-3-yl carboxylates (1) and (2) based on the hydrogen bromide cleavage of the isomeric [4.3.0] bicyclic fused lactones (3) and (4) are described.

  非对映选择性路线和乙基1-氮杂双环[2.2.1]庚-3-基羧酸酯（1）和（2）基于同分异构的的溴化氢裂解[4.3.0]双环稠内酯（3）和（4）被描述。
• Azabicyclic carbamoyloxy mutilin derivatives for antibacterial use
  申请人：SmithKline Beecham p.l.c.

  公开号：US06121281A1

  公开（公告）日：2000-09-19

  Compounds of formula (3), and pharmaceutically acceptable salts and derivatives thereof, in which R.sup.1 is vinyl or ethyl; and R.sup.2 is a group R.sup.3, R.sup.4 CH.sub.2 --, or R.sup.5 R.sup.6 C.dbd.CH--; wherein each of R.sup.3 and R.sup.4 is an azabicyclic ring system or R.sup.5 and R.sup.6 together with the carbon atom to which they are attached form an azabicyclic ring system, are useful in the prevention and treatment of microbial infections. ##STR1##

  式子（3）的化合物，以及其药学上可接受的盐和衍生物，其中R.sup.1为乙烯基或乙基基团；R.sup.2为R.sup.3基团、R.sup.4 CH.sub.2 --基团或R.sup.5 R.sup.6 C.dbd.CH--基团；其中R.sup.3和R.sup.4中的每一个是一个氮杂双环环系，或R.sup.5和R.sup.6与它们所连接的碳原子一起形成一个氮杂双环环系，对于预防和治疗微生物感染很有用。 ##STR1##
• Substituent variation in azabicyclic triazole- and tetrazole-based muscarinic receptor ligands
  作者：Sarah M. Jenkins、Harry J. Wadsworth、Steven Bromidge、Barry S. Orlek、Paul A. Wyman、Graham J. Riley、Julie Hawkins

  DOI：10.1021/jm00091a007

  日期：1992.6

  The effect of variation of the 1-azabicyclic substituent on the novel 1,2,3-triazol-4-yl-, 1,2,4-triazol-1-yl-, tetrazol-5-yl-, and tetrazol-2-yl-based muscarinic receptor ligands ha, been studied, and the exo-azabicyclic[2.2.1]hept-3-yl substituent was found to give the most potent and efficacious compounds. In addition, variation of the second substituent on 1,2,4-triazol-1-yl- and tetrazol-2-yl-based muscarinic receptor ligands has yielded a series of novel compounds with high potencies and efficacies, ranging from full agonists to antagonists. Small lipophilic electron withdrawing substituents give potent but low efficacy compounds, while small polar electron donating substituents give potent and efficacious compounds. The activity of these compounds is described in terms of a model of the receptor involving lipophilic and hydrogen bonding interactions. These compounds provide muscarinic ligands with high potency and a range of efficacies suitable for testing as candidate drugs in the treatment of Alzheimer's disease.
• 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.