(+)-4(R)-(3-benzyloxyphenyl)-3(R),4-dimethylpiperidine | 205999-81-1

• 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: (+)-4(R)-(3-benzyloxyphenyl)-3(R),4-dimethylpiperidine
• 英文别名: (+)-(3R,4R)-4-(3-(benzyloxy)phenyl)-3,4-dimethylpiperidine；(3R,4R)-3,4-dimethyl-4-(3-phenylmethoxyphenyl)piperidine
• CAS: 205999-81-1
• 化学式: C₂₀H₂₅NO
• 分子量: 295.425
• InChiKey: AZOKLNXJETYBQG-OXJNMPFZSA-N

物化性质

• 沸点：
  428.1±45.0 °C(Predicted)
• 密度：
  1.019±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  21.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (+)-4(R)-(3-benzyloxyphenyl)-3(R),4-dimethylpiperidine 在 sodium tungstate 、 双氧水 、 溶剂黄146 、 锌 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 生成 (2R,4R,5R)-2-allyl-4-(3-(benzyloxy)phenyl)-4,5-dimethyl-piperidine
  参考文献：
  名称：

  一系列新的2α-取代的反式-4,5-二甲基-4-（3-羟苯基）哌啶作为mu选择性阿片类拮抗剂的合成与构效关系。

  摘要：

  研究了反式-4,5-二甲基-4-（3-羟苯基）哌啶mu-阿片样物质拮抗剂系列的哌啶环的2α-位的构效关系。这项研究表明，在该系列哌啶环的2α-位仅能容忍小的直链烷基（甲基，丙基）。

  DOI：

  10.1016/j.bmcl.2005.11.010
• 作为产物：
  描述：

  (3R,4R)-3,4-二甲基-4-(3-羟基苯基)哌啶 在 potassium carbonate 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 生成 (+)-4(R)-(3-benzyloxyphenyl)-3(R),4-dimethylpiperidine
  参考文献：
  名称：

  Investigation of the N-Substituent Conformation Governing Potency and μ Receptor Subtype-Selectivity in (+)-(3R,4R)-Dimethyl-4-(3-hydroxyphenyl)- piperidine Opioid Antagonists

  摘要：

  A study of the binding site requirements associated with the N-substituent of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) derivatives was undertaken using a set of rigid vs flexible N-substituents. The study showed that compounds 7-9 bearing the trans-cinnamyl N-substituent most closely reproduced the potency at the opioid receptor of the flexible N-propylphenyl or N-propylcyclohexyl analogues previously reported. Neither the N-substituted cis-cinnamyl nor the cis-phenylcyclopropylmethyl compounds 10 and 11, respectively, showed high affinity for the opioid receptor. However, the N-trans-phenylcyclopropylmethyl compound 12 closely approximated the affinity of compounds 7-9. Additionally, we found that free rotation of the phenyl ring is necessary for high affinity binding and mu receptor subtype selectivity as the planar N-substituted thianaphthylmethyl and benzofuranylmethyl compounds 13 and 14 had significantly lower binding affinities. Altogether, these findings suggest that the high binding affinity, selectivity, and antagonist potency of N-propylphenyl or N-propylcyclohexyl analogues of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl) (4) are achieved via a conformation wherein the connecting chain of the N-substituents is extended away from piperidine nitrogen with the appended ring system rotated out-of-plane relative to the connecting chain atoms. This conformation is quite similar to that observed in the solid state for 5, as determined by single crystal X-ray analysis. Additionally, it was found that, unlike naltrexone, N-substituents bearing secondary carbons attached directly to the piperidine nitrogen of 4 suffer dramatic losses of potency vs analogues not substituted in this manner. Using a functional assay which measured stimulation or inhibition of [S-35]GTP-gamma-S binding, we show that the trans-cinnamyl analogues of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) retain opioid pure antagonist activity and possess picomolar antagonist potency at the mu receptor.

  DOI：

  10.1021/jm980063g

文献信息

• NOVEL OPIOID ANTAGONISTS
  申请人：Dolle E. Roland

  公开号：US20070105863A1

  公开（公告）日：2007-05-10

  Certain quinolizidine and octahydropyridopyrazine compounds, pharmaceutical compositions, and methods of their use, inter alia, as opioid receptor antagonists are disclosed.

  某些喹诺里西啶和八氢吡啶吡嗪化合物、药物组合物及其使用方法被披露，例如作为阿片受体拮抗剂。
• Elucidation of the Bioactive Conformation of the <i>N</i>-Substituted <i>trans</i>-3,4-Dimethyl-4-(3-hydroxyphenyl)piperidine Class of μ-Opioid Receptor Antagonists
  作者：Bertrand Le Bourdonnec、Allan J. Goodman、Mathieu Michaut、Hai-Fen Ye、Thomas M. Graczyk、Serge Belanger、Torsten Herbertz、Glenn P. A. Yap、Robert N. DeHaven、Roland E. Dolle

  DOI：10.1021/jm060486f

  日期：2006.12.1

  The series of trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidines have been widely investigated as opioid receptor antagonists. One of our research goals was to explore the bioactive conformation of the N-phenethyl trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine derivative 3, prototypical A-opioid antagonist in this series. In this effort, the rotational degrees of freedom of the N-substituent of 3 were limited by incorporation of an ethylene bridge between the piperidine 2- or 6-position of 3 and the benzylic position of the N-phenethyl moiety. The overall modification led to a novel series of fused bicyclic derivatives of the octahydroquinolizine chemical class, conformationally restricted analogue of 3. The constrained analogues 6 and 9 showed high affinity toward the mu-opioid receptor. Compound 6 was found to be a mu-opioid antagonist, whereas the constrained analogue 9 displayed potent mu-agonist activity in vitro. This study provides additional information about the molecular determinants for mu recognition, the structural features affecting ligand binding, and the structure function relationships.
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