4-(1-苄基哌啶-4-基)丁-1-醇 | 318508-02-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: 4-(1-苄基哌啶-4-基)丁-1-醇
• 中文别名: 4-(1-苄基哌啶-4-基)-1-丁醇
• 英文名称: 4-(N-benzyl-4'-piperidinyl)-1-butanol
• 英文别名: 4-(1-benzyl-4-piperidinyl)butanol；4-(1-benzylpiperidin-4-yl)butan-1-ol；1-benzyl-4-(4-hydroxybutyl)piperidine；MBA384
• CAS: 318508-02-0
• 化学式: C₁₆H₂₅NO
• 分子量: 247.381
• InChiKey: SXNYWACHEZSLBF-UHFFFAOYSA-N

物化性质

• 沸点：
  358.5±15.0 °C(Predicted)
• 密度：
  1.014±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  18
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  23.5
• 氢给体数：
  1
• 氢受体数：
  2

安全信息

• 海关编码：
  2933399090

反应信息

• 作为反应物：
  描述：

  4-(1-苄基哌啶-4-基)丁-1-醇 在 氢溴酸 、 一水合肼 作用下， 以 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 10.0h， 生成 3-(1-benzylpiperidin-4-yl)propan-1-amine
  参考文献：
  名称：

  M2 Subtype preferring dibenzodiazepinone-type muscarinic receptor ligands: Effect of chemical homo-dimerization on orthosteric (and allosteric?) binding

  摘要：

  A series of new dibenzodiazepinone-type muscarinic receptor ligands, including two homo-dimeric compounds, was prepared. Sixteen representative compounds were characterized in equilibrium binding studies with [H-3]N-methylscopolamine ([H-3]NMS) at the muscarinic receptor subtype M-2, and seven selected compounds were additionally investigated at M-1, M-3, M-4 and M-5 with respect to receptor subtype selectivity. The side chain of the known M-2 preferring muscarinic receptor antagonist DIBA was widely varied with respect to chain length and type of the basic group (amine, imidazole, guanidine and piperazine). Most of the structural changes were well tolerated with respect to muscarinic receptor binding, determined by displacement of [H-3]NMS. Compounds investigated at all subtypes shared a similar selectivity profile, which can be summarized as M-2 > M-1 approximate to M-4 > M-3 approximate to M-5 (46, 50, 57, 62-64) and M-2 > M-1 approximate to M-4 > M-3 > M-5 (1, 58). The homo-dimeric dibenzodiazepinone derivatives UNSW-MK250 (63) and UNSW-MK262 (64) exhibited the highest M-2 receptor affinities (pIC(50) = 9.0 and 9.2, respectively). At the M-2 receptor a steep curve slope of -2 was found for the dimeric ligand 63, which cannot be described according to the law of mass action, suggesting a more complex mechanism of binding. In addition to equilibrium binding studies, for selected ligands, we determined pEC(50,diss), an estimate of affinity to the allosteric site of M-2 receptors occupied with [H-3]NMS. Compounds 58 and 62-64 were capable of retarding [H-3]NMS dissociation by a factor > 10 (E-max,E-diss >92%), with highest potency (pEC(50,diss) = 5.56) residing in the dimeric compound 64. As the monomeric counterpart of 64 was 100 times less potent (62: pEC(50),(diss) = 3.59), these data suggest that chemical dimerization of dibenzodiazepinone-type M receptor ligands can enhance allosteric binding. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.01.015
• 作为产物：
  描述：

  N-benzyl-2-p-toluenesulfonylacetamide 在 palladium on activated charcoal 氨 、 氢气 、 sodium 、 sodium hydride 作用下， 以 四氢呋喃 、 乙酸乙酯 为溶剂， 反应 7.75h， 生成 4-(1-苄基哌啶-4-基)丁-1-醇
  参考文献：
  名称：

  Elarofiban、RWJ-50042、替罗非班和帕罗西汀中4-取代哌啶环的合成研究

  摘要：

  一种合成 4-取代哌啶环的新策略使用正式的 [3+3] 环加成反应作为关键方案。该方法提供了一种方便的正式合成 elarofiban、RWJ-50042、tirofiban 和帕罗西汀的方法。

  DOI：

  10.1002/jccs.200200156

文献信息

• Synthesis of New Cardioselective M2 Muscarinic Receptor Antagonists.
  作者：Giacomina R. MANDELLI、Stefano MAIORANA、Patrizia TERNI、Giuseppina LAMPERTI、Maria Luisa COLIBRETTI、Bruno P. IMBIMBO

  DOI：10.1248/cpb.48.1611

  日期：——

  A series of 5H-dibenz[b, f]azepine derivatives was prepared and evaluated for binding affinities to muscarinic receptors in vitro. Among them, compound 8 showed a high affinity for human recombinant M2 receptors (Ki=2.6 nM), a low affinity for M4 receptors (39-fold less than for M2 receptors) and a very low affinity for M1 and M3 receptors (119- and 112-fold less than for M2 receptors, respectively). The high M2 selectivity of 8 may be attributed to the olefinic bond of the azepine ring. Functional experiments showed 8 to be a competitive antagonist with high affinity to the cardiac (pA2=7.1) and low affinity to the intestinal muscarinic receptors (IC50=0.54 μM). In vivo experiments confirmed the in vitro M2 selectivity of 8. Acetylcholine-induced bradycardia was dose-dependently antagonized in rats after both intravenous and intraduodenal administration of 8. In rats, cholinergic functions mediated by M1 or M3 receptors (salivary secretion, pupil diameter, gastric emptying, intestinal transit time) were not affected by the oral administration of 8 even at doses as high as 30 times the antibradycardic effective dose. Furthermore, 8 had no analgesic activity in mice, indicating poor central nervous system penetration. In dogs, nocturnal bradycardia was dose-dependently inhibited by the oral route with a duration of action of about 24 h. Compound 8 appears to be a promising cardioselective antimuscarinic agent for the treatment of dysfunctions of the cardiac conduction system such as sinus or nodal bradycardia ("sick-sinus syndrome") and atrioventricular block.

  一系列5H-二苯[b, f]氮杂环戊烯衍生物被合成并评估其对体外毒蕈碱受体的结合亲和力。在这些化合物中，化合物8对人重组M2受体表现出高亲和力（Ki=2.6 nM），对M4受体的亲和力较低（比M2受体低39倍），对M1和M3受体的亲和力非常低（分别比M2受体低119倍和112倍）。化合物8的高M2选择性可能归因于氮杂环上的烯键。功能实验表明，8是一个竞争性拮抗剂，对心脏的亲和力较高（pA2=7.1），而对肠道毒蕈碱受体的亲和力较低（IC50=0.54 μM）。体内实验确认了8的体外M2选择性。经过静脉注射和十二指肠内给药后，乙酰胆碱诱导的心动过缓在大鼠中呈剂量依赖性被拮抗。在大鼠中，介导M1或M3受体的胆碱能功能（唾液分泌、瞳孔直径、胃排空、肠道转运时间）在口服给药8的情况下未受到影响，即使在高达抗心动过缓有效剂量30倍的剂量下。此外，8在小鼠中没有镇痛活性，表明其对中枢神经系统的穿透性差。在犬中，口服给药后夜间心动过缓呈剂量依赖性抑制，作用持续约24小时。化合物8似乎是一种有前途的心脏选择性抗毒蕈碱药物，可用于治疗心脏传导系统的功能障碍，如窦性或结性心动过缓（“病态窦综合征”）和房室传导阻滞。
• Synthesis, Biological Evaluation, and Molecular Modeling of Donepezil and <i>N</i>-[(5-(Benzyloxy)-1-methyl-1<i>H</i>-indol-2-yl)methyl]-<i>N</i>-methylprop-2-yn-1-amine Hybrids as New Multipotent Cholinesterase/Monoamine Oxidase Inhibitors for the Treatment of Alzheimer’s Disease
  作者：Irene Bolea、Jordi Juárez-Jiménez、Cristóbal de los Rı́os、Mourad Chioua、Ramón Pouplana、F. Javier Luque、Mercedes Unzeta、José Marco-Contelles、Abdelouahid Samadi

  DOI：10.1021/jm200853t

  日期：2011.12.22

  A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel compounds (3-9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC50 = 5.2 +/- 1.1 nM) and MAO-B (IC50 = 43 +/- 8.0 nM) and is a moderately potent inhibitor of AChE (IC50 = 0.35 +/- 0.01 mu M) and BuChE (IC50 = 0.46 +/- 0.06 mu M). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on A beta aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer's disease therapy.
• Pyridonepezils, new dual AChE inhibitors as potential drugs for the treatment of Alzheimer's disease: Synthesis, biological assessment, and molecular modeling
  作者：Abdelouahid Samadi、Martín Estrada、Concepción Pérez、María Isabel Rodríguez-Franco、Isabel Iriepa、Ignacio Moraleda、Mourad Chioua、José Marco-Contelles

  DOI：10.1016/j.ejmech.2012.09.030

  日期：2012.11

  The synthesis, biological assessment and molecular modeling of new pyridonepezils 1-8, able to inhibit human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBuChE), are described. The new compounds have been designed as hybrids resulting from a conjunctive approach that combines the N-benzylpiperidine moiety, present in donepezil, and the 2-amino-6-chloropyridine heterocyclic ring system, connected by an appropriate polymethylene linker. Compounds 1-8 were prepared by reaction of 2-amino-6-chloro-4-phenylpyridine-3,5-dicarbonitrile (13) [or 2-amino-6-chloropyridine-3,5-dicarbonitrile (14)] with 2-(1-benzylpiperidin-4-yl)alkylamines (9-12). The biological evaluation of molecules 1-8 showed that compounds 1-6 are potent AChE inhibitors, in the submicromolar, while compounds 7 and 8 are on the nanomolar range, the most potent, 2-amino-6-((3-(1-benzylpiperidin-4-yl)propyl)amino)pyridine-3,5-dicarbonitrile (7), showing a IC50 (hAChE) = 9.4 +/- 0.4 nM. Inhibitors 2-8 are permeable as determined in the PAMPA assay. Compared to donepezil, compound 7 is in the same range of inhibitory activity for hAChE, and 703-fold more selective for hAChE than for hBuChE. Molecular modeling investigation on pyridonepezil 7 supports its dual AChE inhibitory profile, binding simultaneously at the catalytic active and at peripheral anionic sites of the enzyme. The theoretical ADME analysis of pyridonepezils 1-8 has been carried out. Overall, compound 7, a potent and selective dual AChEI, can be considered as a candidate with potential impact for further pharmacological development in Alzheimer's therapy. (C) 2012 Elsevier Masson SAS. All rights reserved.