(1S)-4,7,7-trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid (S,S)-4-(2-benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidin-3-yl ester | 514805-93-7

• 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: (1S)-4,7,7-trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid (S,S)-4-(2-benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidin-3-yl ester
• 英文别名: [(3S,4S)-4-(2-benzhydryloxyethyl)-1-[(4-fluorophenyl)methyl]piperidin-3-yl] (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylate
• CAS: 514805-93-7
• 化学式: C₃₇H₄₂FNO₅
• 分子量: 599.743
• InChiKey: RGOWOBXPIYXVCF-PFMNXFHYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.2
• 重原子数：
  44
• 可旋转键数：
  11
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  65.1
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (1S)-4,7,7-trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid (S,S)-4-(2-benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidin-3-yl ester 在 potassium carbonate 作用下， 以 甲醇 为溶剂， 反应 12.0h， 以0.3 g的产率得到(-)-S,S-D-83
  参考文献：
  名称：

  High Affinity Hydroxypiperidine Analogues of 4-(2-Benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidine for the Dopamine Transporter:  Stereospecific Interactions in Vitro and in Vivo

  摘要：

  In our effort to develop high-affinity ligands for the dopamine transporter which might find potential use as cocaine medication, a polar hydroxy substituent was introduced into the piperidine ring of one of our disubstituted lead analogues derived from 1-[2-(diphenylmethoxy)ethyl] -4-(3-phenylpropyl)piperazine (GBR 12935). Both cis- and trans-3-hydroxy derivatives were synthesized and the racemic trans isomer, (+/-)-5, was further resolved into two enantiomers. Newly synthesized compounds were characterized for their binding affinity at the dopamine, serotonin, and norepinephrine transporter systems in rat brain. The two enantiomers (+)-5 and (-)-5 exhibited marked differential affinities at the dopamine transporter with (+)-5 being 122-fold more potent than (-)-5 in inhibiting radiolabeled cocaine analogue binding (IC50; 0.46 vs 56.7 nM) and 9-fold more active for inhibiting dopamine uptake (IC50; 4.05 vs 38.0 nM). Furthermore, the most active (+)-5 was 22-fold more potent at the dopamine transporter compared to the standard GBR 12909. Absolute configuration of one of the enantiomers was determined unambiguously by X-ray structural analysis. In in vivo locomotor activity studies, the enantiomer (+)-5 and the racemic ()-5, but not (-)-5, exhibited stimulant activity with a long duration of effect. All three compounds, (+)-5, (-)-5, and ()-5, within the dose range tested, partially (50%) but incompletely (80%) produced cocaine-like responses in mice trained to discriminate 10 mg/kg ip cocaine from vehicle. Compound (-)-5 was distinctive in this regard in that, unlike (+)-5 and (+/-)-5, it did not affect locomotor activity yet, but similar to them, was able to engender (albeit incompletely) cocaine-like responses.

  DOI：

  10.1021/jm020275k
• 作为产物：
  描述：

  4-(2-Benzhydryloxy-ethyl)-1-(4-fluoro-benzyl)-1,2,3,6-tetrahydro-pyridine 在 4-二甲氨基吡啶 、 sodium tetrahydroborate 、 三氟化硼乙醚 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 5.0h， 生成 (1S)-4,7,7-trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid (S,S)-4-(2-benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidin-3-yl ester
  参考文献：
  名称：

  High Affinity Hydroxypiperidine Analogues of 4-(2-Benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidine for the Dopamine Transporter:  Stereospecific Interactions in Vitro and in Vivo

  摘要：

  In our effort to develop high-affinity ligands for the dopamine transporter which might find potential use as cocaine medication, a polar hydroxy substituent was introduced into the piperidine ring of one of our disubstituted lead analogues derived from 1-[2-(diphenylmethoxy)ethyl] -4-(3-phenylpropyl)piperazine (GBR 12935). Both cis- and trans-3-hydroxy derivatives were synthesized and the racemic trans isomer, (+/-)-5, was further resolved into two enantiomers. Newly synthesized compounds were characterized for their binding affinity at the dopamine, serotonin, and norepinephrine transporter systems in rat brain. The two enantiomers (+)-5 and (-)-5 exhibited marked differential affinities at the dopamine transporter with (+)-5 being 122-fold more potent than (-)-5 in inhibiting radiolabeled cocaine analogue binding (IC50; 0.46 vs 56.7 nM) and 9-fold more active for inhibiting dopamine uptake (IC50; 4.05 vs 38.0 nM). Furthermore, the most active (+)-5 was 22-fold more potent at the dopamine transporter compared to the standard GBR 12909. Absolute configuration of one of the enantiomers was determined unambiguously by X-ray structural analysis. In in vivo locomotor activity studies, the enantiomer (+)-5 and the racemic ()-5, but not (-)-5, exhibited stimulant activity with a long duration of effect. All three compounds, (+)-5, (-)-5, and ()-5, within the dose range tested, partially (50%) but incompletely (80%) produced cocaine-like responses in mice trained to discriminate 10 mg/kg ip cocaine from vehicle. Compound (-)-5 was distinctive in this regard in that, unlike (+)-5 and (+/-)-5, it did not affect locomotor activity yet, but similar to them, was able to engender (albeit incompletely) cocaine-like responses.

  DOI：

  10.1021/jm020275k