(3S,4S)-4-(4-chlorophenyl)-1-(2-phenylethyl)piperidine-3-carboxylic acid methyl ester

• 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: (3S,4S)-4-(4-chlorophenyl)-1-(2-phenylethyl)piperidine-3-carboxylic acid methyl ester
• 英文别名: methyl (3S,4S)-4-(4-chlorophenyl)-1-(2-phenylethyl)piperidine-3-carboxylate
• 化学式: C₂₁H₂₄ClNO₂
• 分子量: 357.88
• InChiKey: BGZDNABQVVRBEL-WOJBJXKFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  (3S,4s)-4-(4-氯苯基)-1-甲基哌啶-3-羧酸甲酯 在 1-氯乙基氯甲酸酯 、 1,8-双二甲氨基萘 、 potassium carbonate 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 14.5h， 生成 (3S,4S)-4-(4-chlorophenyl)-1-(2-phenylethyl)piperidine-3-carboxylic acid methyl ester
  参考文献：
  名称：

  SAR Studies of Piperidine-Based Analogues of Cocaine. 4. Effect of N-Modification and Ester Replacement

  摘要：

  A series of novel N- and 3alpha-modified piperidine-based analogues of cocaine were synthesized and tested for their ability to inhibit reuptake of DA, 5-HT, and NE by the DA, 5-HT, and NE transporters. N-Demethylation of trans-(+)-3alpha-piperidine-based ligands leads to improved activity at the SEAT and NET and modest changes at the DAT. Replacement of the N-methyl group in trans-(+)-ester 1a with phenylalkyl groups leads to a modest 2.3-fold improvement in activity at the SERT (K-i less than or equal to 3.27 muM), insignificant changes at the NET, and a 3.5-fold loss in activity at the DAT (K-i greater than or equal to 810 nM); however, such replacement in cis-(-)-ester 4, the more potent isomer of la, leads, in general, to a significant decrease in activity at all monoamine transporters (K-i > 1 muM). Other N-modified ligands, including the ligands with polar groups incorporated in the N-alkyl substituent (3e-g) and ligands lacking the basic nitrogen (3i and 6d), show decreased activity at all monoamine transporters, though ligands 3e-g are similar in potency at the NET to la. N-Norester 2a, a possible metabolite of the lead compound la, and alcohol 1c, a compound with a 3alpha-substituent that is more stable to metabolism than la, were selected for further behavioral tests in animals. Alcohol le and ester 2a are similar in potency at the DAT to cocaine, ester 1a, and oxadiazole 1b, and both fully substitute for cocaine and have potency similar to that of cocaine in drug discrimination tests. Like cocaine, 1c increased locomotor activity (LMA) monotonically with time, whereas 2a produces biphasic effects consisting of initial locomotor depression followed by delayed locomotor stimulation. An interesting difference between cocaine, ester 1a, alcohol 1c, and N-norester 2a is that 1c and 2a are significantly longer acting in LMA tests. Although this result was anticipated for alcohol 1c, it is rather surprising for 2a which has an ester function susceptible to hydrolysis, a pathway of in vivo deactivation of cocaine and its ester analogues. The present results may have important implications for our understanding of the pharmacological mechanisms underlying the behavioral actions of cocaine and of the structural features needed for the design of the new leads in the discovery of a cocaine abuse medication.

  DOI：

  10.1021/jm0200153