Norlobelane | 818377-18-3

• 分子结构分类: 有机化合物 - 生物碱及其衍生物
• 英文名称: Norlobelane
• 英文别名: cis-2,6-diphenethylpiperidine；Nor-Lobelane；(2S,6R)-2,6-bis(2-phenylethyl)piperidine
• CAS: 818377-18-3
• 化学式: C₂₁H₂₇N
• 分子量: 293.452
• InChiKey: FTHIJNIJEUKTEC-OYRHEFFESA-N

物化性质

• 沸点：
  422.9±14.0 °C(Predicted)
• 密度：
  0.981±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  22
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  12
• 氢给体数：
  1
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  Norlobelane 在 二异丁基氢化铝 、 potassium carbonate 作用下， 以 甲苯 、 乙腈 为溶剂， 反应 73.0h， 生成 2-[(2S,6R)-2,6-bis(2-phenylethyl)piperidin-1-yl]ethanol
  参考文献：
  名称：

  Exploring the effect of N-substitution in nor-lobelane on the interaction with VMAT2: discovery of a potential clinical candidate for treatment of methamphetamine abuse

  摘要：

  我们合成了一系列 N-取代的洛贝兰类似物，并评估了它们在囊泡单胺转运体上的[3H]二氢四苄肼结合亲和力及其对囊泡[3H]多巴胺摄取的抑制作用。化合物 19a 含有一个 N-1,2(R)-二羟基丙基，已被确定为治疗甲基苯丙胺滥用的潜在临床候选药物。

  DOI：

  10.1039/c3md20374c
• 作为产物：
  描述：

  2,6-bis (2-phenylethyl) pyridine 在 三苯基硼烷 、 二苯基硅烷 、 苯胺 作用下， 以 甲苯 为溶剂， 反应 24.0h， 以92%的产率得到Norlobelane
  参考文献：
  名称：

  B（C6F5）3-催化的吡啶级联还原

  摘要：

  已发现B（C 6 F 5）3是一种有效的催化剂，可以用氢化硅烷（或氢硼烷）和胺作为还原剂还原吡啶和其他电子不足的N-杂芳烃。该开发的成功取决于脱芳香氢化硅烷化（或硼氢化）和转移氢化的级联过程的实现。宽泛的官能团耐受性（例如酮，酯，未活化的烯烃，硝基，腈，杂环等）暗示着很高的实用性。

  DOI：

  10.1002/anie.201702304

文献信息

• Defunctionalized Lobeline Analogues:  Structure−Activity of Novel Ligands for the Vesicular Monoamine Transporter
  作者：Guangrong Zheng、Linda P. Dwoskin、Agripina G. Deaciuc、Seth D. Norrholm、Peter A. Crooks

  DOI：10.1021/jm0501228

  日期：2005.8.1

  (-)-Lobeline (2R,6S,10S; 1a), an antagonist at nicotinic acetylcholine receptors (nAChRs), inhibits the neurochemical and behavioral effects of methamphetamine and inhibits dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) function. VMAT2 is a target for the development of treatments for methamphetamine abuse. Structural modification of lobeline affords the defunctionalized analogues meso-transdiene (MTD) and lobelane, which have high potency and selectivity for VMAT2. To establish the structure-activity relationships within this novel class of VMAT2 ligands, specific stereochemical forms of MTD, lobelane, and other structurally related analogues have been synthesized. These compounds have been evaluated for inhibition of [H-3]nicotine ( [H-3]NIC) binding (alpha 4 beta 2* nAChR), [H-3]methyllycaconitine ([H-3]MLA) binding (alpha 7* nAChR), and [H-3]dihydrotetrabenazine ([H-3]DTBZ) binding (VMAT2). Generally, all of these analogues had lower affinities at alpha 4 beta 2* and alpha 7* nAChRs compared to lobeline, thereby increasing selectivity for VMAT2. The following structural modifications resulted in only modest changes in affinity for VMAT2, affording analogues that were less potent than the lead compound, lobelane: (1) altering the stereochemistry at the C-2 and C-6 positions of the piperidino ring, (2) varying unsaturation in the piperidino C-2 and C-6 substituents, (3) introducing unsaturation into the piperidine ring, (4) ring-opening or eliminating the piperidine ring, and (5) removing the piperidino N-methyl group. Furthermore, incorporating a quaternary ammonium group into defunctionalized lobeline molecules in the cis-series resulted in significant loss of affinity for VMAT2, whereas only a modest change in affinity was obtained in the trans-series. The most potent (K-i = 630 nM) and VMAT2-selective compound evaluated was the N-methyl-2,6-cis-bis(naphthaleneethyl)piperidine analogue 28b (1-NAP-lobelane), in which the phenyl groups of lobelane were replaced with 1-naphthyl moieties. Thus, initial structure-activity relationship studies reveal that the most promising structural changes to the lobeline molecule that lead to enhancement of VMAT2 affinity and selectivity are defunctionalization, affording lobelane and MTD, and replacement of the phenyl rings of lobelane with other aromatic moieties that have a pi-extended structure.

  (-)-Lobeline（2R,6S,10S；1a）是一种烟碱型乙酰胆碱受体（nAChRs）拮抗剂，能够抑制甲基苯丙胺的神经化学和行为效应，并抑制多巴胺转运体（DAT）和囊泡单胺转运体（VMAT2）的功能。VMAT2是开发甲基苯丙胺滥用治疗药物的目标。通过对lobeline进行结构修饰，得到了功能丧失的类似物meso-transdiene（MTD）和lobeLAne，它们对VMAT2具有高活性和选择性。为了建立这一新型VMAT2配体类别的结构-活性关系，研究人员合成了MTD、lobeLAne以及其它结构相关类似物的特定立体化学形式。这些化合物已被评估用于抑制[H-3]尼古丁（[H-3]NIC）结合（α4β2* nAChR）、[H-3]甲基鲁康宁（[H-3]MLA）结合（α7* nAChR）以及[H-3]二氢四苯肼（[H-3]DTBZ）结合（VMAT2）的能力。总体而言，与lobeline相比，所有这些类似物在α4β2*和α7* nAChRs上的结合亲和力较低，从而提高了对VMAT2的选择性。以下是导致VMAT2亲和力变化不大，且活性低于先导化合物lobeLAne的结构修饰： 1. 改变哌啶环C-2和C-6位的立体化学； 2. 在哌啶C-2和C-6取代基中改变不饱和度； 3. 将不饱和引入哌啶环； 4. 开环或消除哌啶环； 5. 去除哌啶环上的N-甲基基团。 此外，在顺式系列失去功能的lobeLAne分子中引入季铵基团，导致对VMAT2的亲和力显著降低，而在反式系列中仅获得亲和力的小变化。评估中发现，最活跃（K-i = 630 nM）且对VMAT2选择性最高的化合物是N-甲基-2,6-顺式-双（萘乙基）哌啶类似物28b（1-NAP-lobeLAne），其中lobeLAne的苯基被1-萘基基团取代。因此，初步的结构-活性关系研究表明，对lobeLAne分子结构进行修饰以增强VMAT2亲和力和选择性的最有前途的变化是去功能化（得到lobeLAne和MTD）以及将lobeLAne的苯环替换为具有π扩展结构的其他芳香基团。
• Expedient Synthesis of 1,5-Diketones by Rhodium-Catalyzed Hydroacylation Enabled by C–C Bond Cleavage
  作者：Rui Guo、Guozhu Zhang

  DOI：10.1021/jacs.7b05427

  日期：2017.9.20

  A rhodium-catalyzed intermolecular hydroacylation reaction of vinyl cyclobutanols with non-chelating aldehydes has been developed. This reaction offers a new and atom-economical approach for the selective preparation of 1,5-diketones in high yields. Experimental data suggest a sequential ring-opening, transfer hydrogenation, and hydroacylation mechanism. We propose that aldehyde decarbonylation is

  已经开发了一种铑催化的乙烯基环丁醇与非螯合醛的分子间加氢酰化反应。该反应为高产率选择性制备 1,5-二酮提供了一种新的、原子经济的方法。实验数据表明顺序开环、转移氢化和加氢酰化机制。我们建议通过形成新的铑烯醇化物物种来避免醛脱羰，这也解释了广泛的醛的相容性及其抗马尔科夫尼科夫选择性。
• Vesicular Monoamine Transporter-2 Ligands and Their Use in the Treatment of Psychostimulant Abuse
  申请人：University of Kentucky Research Foundation

  公开号：US20170304227A1

  公开（公告）日：2017-10-26

  The present invention relates to methods of treatment of a disease or pathology of the central nervous system, an eating disorder, or substance use disorder, drug dependence/abuse and withdrawal therefrom comprising administering at least one N-phenylalkyl amphetamine derivative and pharmaceutical compositions comprising at least one N-phenylalkyl amphetamine derivative to an individual in need thereof.

  本发明涉及治疗中枢神经系统疾病或病理、进食障碍、物质使用障碍、药物依赖/滥用及其戒断的方法，包括给予至少一种N-苯基烷基苯丙胺衍生物和包含至少一种N-苯基烷基苯丙胺衍生物的药物组合物给需要的个体。
• Iterative direct C_(sp3)–H functionalization of amines: diastereoselective divergent syntheses of α,α′-disubstituted alicyclic amines
  作者：Sujit Mahato、Chandan K. Jana

  DOI：10.1039/c6ob02257j

  日期：——

  A novel iterative C(sp3)–H oxygenation/C–C bond formation strategy, which avoids repetitive N-protection/-deprotection steps, was developed for direct α,α′-difunctionalization of alicyclic amines. The method is highly efficient and stereoselective in producing syn-α,α′-disubstituted aliphatic N-heterocycles. Synthetic potential and practicability of the method was demonstrated by an easy and straightforward

  针对脂环族胺的直接α，α′-双官能化，开发了一种新颖的迭代C （sp 3） -H氧合/ CC键形成策略，该方法避免了重复的N-保护/去保护步骤。该方法在产生顺-α，α′-二取代的脂族N-杂环上是高效且立体选择性的。合成电位和方法的实用性是由一个容易和简单的合成神经活性生物碱证明也不-lobelane及其衍生物。
• 2,6-disubstituted piperidines and piperazine compounds
  申请人：——

  公开号：US20040266824A1

  公开（公告）日：2004-12-30

  The present invention is directed to 2,6-disubstituted piperidine and piperazine analogs having the following general formula: 1 which are used to treat diseases of the central nervous system, drug abuse, and withdrawal therefrom as well as treating eating disorders.

  本发明涉及具有以下一般式的2,6-二取代哌啶和哌嗪类似物：1，用于治疗中枢神经系统疾病、药物滥用及其戒断，以及治疗进食障碍。