8-aza-8-methylbicyclo [3.2.1]oct-3-yl 2-phenylcyclohex-2-enecarboxylate | 24259-15-2

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 托烷生物碱
• 英文名称: 8-aza-8-methylbicyclo [3.2.1]oct-3-yl 2-phenylcyclohex-2-enecarboxylate
• CAS: 24259-15-2
• 化学式: C₂₁H₂₇NO₂
• 分子量: 325.451
• InChiKey: AFGVIXCJKFSDIV-GKUGNITKSA-N

物化性质

• 沸点：
  436.3±45.0 °C(Predicted)
• 密度：
  1.14±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.04
• 重原子数：
  24.0
• 可旋转键数：
  3.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  29.54
• 氢给体数：
  0.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  8-aza-8-methylbicyclo [3.2.1]oct-3-yl 2-phenylcyclohex-2-enecarboxylate 以 甲醇 、 1,2-二氯乙烷 为溶剂， 反应 1.75h， 生成 8-azabicyclo[3.2.1]oct-3-yl 2-phenylcyclohex-2-enecarboxylate
  参考文献：
  名称：

  摘要：

  Purpose. To design and evaluate a new class of soft anticholinergics with subtype selectivity.Methods. A new class of soft anticholinergics was designed based on the "inactive metabolite" approach. Four compounds were synthesized. The potency and soft nature of the compounds were evaluated by receptor binding, cardiac, and mydriatic studies. Stability and pharmacokinetic studies were also performed on these newly synthesized soft anticholinergics.Results. Receptor binding studies of the soft anticholinergics on cloned muscarinic receptors indicated pKi values in the range of 7.5 to 8.9. Two compounds, 9a and 13a, of the series showed muscarinic subtype receptor selectivity (M-3/M-2). In mydriatic studies, 13a and 13b showed shorter duration of action in the treated eyes than tropicamide. In the control eyes, significant dilation of pupils was found only in rabbits treated with atropine and tropicamide, indicating that the soft anticholinergics lack systemic effects because of their facile hydrolytic deactivation. Consistent with their soft nature, this new class of soft anticholinergics displayed much shorter cardiovascular effects in the carbachol-induced bradycardia (10 to 15 min) in rats than atropine (>60 min). Stability and pharmacokinetic studies suggested that the new soft anticholinergics were rapidly eliminated from plasma (systemic circulation) after i.v. administration.Conclusions. A new class of anticholinergics was designed and synthesized, and the PK/PD evaluation confirmed they were potent "soft" anticholinergics; two of them showed muscarinic receptor subtype selectivity (M-3/M-2).

  DOI：

  10.1023/a:1026160023030
• 作为产物：
  描述：

  1,4-二氧杂螺[4.5]癸-6-基-甲醇 在 potassium permanganate 、 氯化亚砜 、 硫酸 、 草酸 、 silica gel 、 溶剂黄146 作用下， 以 二氯甲烷 为溶剂， 反应 0.25h， 生成 8-aza-8-methylbicyclo [3.2.1]oct-3-yl 2-phenylcyclohex-2-enecarboxylate
  参考文献：
  名称：

  摘要：

  Purpose. To design and evaluate a new class of soft anticholinergics with subtype selectivity.Methods. A new class of soft anticholinergics was designed based on the "inactive metabolite" approach. Four compounds were synthesized. The potency and soft nature of the compounds were evaluated by receptor binding, cardiac, and mydriatic studies. Stability and pharmacokinetic studies were also performed on these newly synthesized soft anticholinergics.Results. Receptor binding studies of the soft anticholinergics on cloned muscarinic receptors indicated pKi values in the range of 7.5 to 8.9. Two compounds, 9a and 13a, of the series showed muscarinic subtype receptor selectivity (M-3/M-2). In mydriatic studies, 13a and 13b showed shorter duration of action in the treated eyes than tropicamide. In the control eyes, significant dilation of pupils was found only in rabbits treated with atropine and tropicamide, indicating that the soft anticholinergics lack systemic effects because of their facile hydrolytic deactivation. Consistent with their soft nature, this new class of soft anticholinergics displayed much shorter cardiovascular effects in the carbachol-induced bradycardia (10 to 15 min) in rats than atropine (>60 min). Stability and pharmacokinetic studies suggested that the new soft anticholinergics were rapidly eliminated from plasma (systemic circulation) after i.v. administration.Conclusions. A new class of anticholinergics was designed and synthesized, and the PK/PD evaluation confirmed they were potent "soft" anticholinergics; two of them showed muscarinic receptor subtype selectivity (M-3/M-2).

  DOI：

  10.1023/a:1026160023030

文献信息

• N-alkyl-nor-tropine esters of 2-phenyl-cyclohexenic acids as new bronchodilator agents. Effect of structural and conformational modifications on affinity for muscarinic receptors
  作者：L Turbanti、G Cerbai、G Garzelli、AR Renzetti、M Criscuoli、A Subissi、G Bramanti、A Martinelli

  DOI：10.1016/0223-5234(92)90179-5

  日期：1992.8

  A series of N-alkyl-nor-tropine esters of 2-phenyl-2-cyclohexene-1-carboxylic, 2-phenyl-cyclohexanecarboxylic, and 2-phenyl-1-cyclohexene-1-acetic acids and their quaternary ammonium salts were synthesized and evaluated for bronchodilator activity by binding assays and pharmacological tests. The in vitro and in vivo functional activity results showed that some quaternary derivatives are potent anticholinergic bronchodilator agents, and 4 compounds (14-A, 16-A, 25-A and 28-A) were selected for pharmacotoxicological evaluation. The binding data also indicated that the affinity of these compounds for the tracheal membrane muscarinic receptors is markedly affected by structural modifications of both the cationic head and the acyl moiety of the molecule. In the series of N-alkyl-nor-tropine 2-phenyl-2-cyclohexene-1-carboxylate derivatives, a rather strict limitation of the bulk of the equatorial substituent of tropine nitrogen is required for very high affinity. Conformational analysis and molecular graphics techniques evidenced an influence of the acyl moiety conformation on the affinity of the different tropinic esters, suggesting that the carbonyl oxygen may participate in interaction with the binding site, eliciting a marked increase of potency when it is oriented in a proper conformation with respect to the tropinic nitrogen and the phenyl ring.