N-(1,2,3,4-tetrahydro-5-methoxy-1-naphthalenyl)bromoacetamide | 178452-26-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 四氢化萘
• 英文名称: N-(1,2,3,4-tetrahydro-5-methoxy-1-naphthalenyl)bromoacetamide
• 英文别名: N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)bromoacetamide；2-bromo-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide；2-Bromo-N-(1,2,3,4-tetrahydro-5-methoxy-1-naphthalenyl)acetamide
• CAS: 178452-26-1
• 化学式: C₁₃H₁₆BrNO₂
• 分子量: 298.18
• InChiKey: BFNCTAREGZHAFQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  38.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  N-(1,2,3,4-tetrahydro-5-methoxy-1-naphthalenyl)bromoacetamide 在 lithium aluminium tetrahydride 、 三乙胺 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 2.0h， 生成 4-(1-naphthalenyl)-N-(1,2,3,4-tetrahydro-5-methoxy-1-naphthalenyl)-1-piperazineethanamine
  参考文献：
  名称：

  1-取代的4- [3-（1,2,3,4-四氢-5-或7-甲氧基萘-1-基）丙基]哌嗪：N-1哌嗪取代基对5-HT1A受体亲和力的影响对D2和alpha1受体的选择性。第六部分

  摘要：

  在本论文中，我们报告了1取代的4- [3-（5-或7-甲氧基-1,2,3,4-四氢萘）在5-HT1A，D2和alpha1受体上的合成和结合情况-1-基）丙基]哌嗪衍生物19-32和一些相关的杂烷基衍生物33-35。将获得的结果与先前报道的1-苯基，1-（2-甲氧基苯基），1-（2-吡啶基）类似物2-9的结果进行比较。结果指出，就5-HT1A结合亲和力而言，连接在哌嗪N-1位的基团的关键作用。实际上，1-环己基，1-（3-苯并恶唑基），1-（苯并噻唑-2-羰基），1-（2-苯并噻唑基），1-（2-喹啉基）取代的哌嗪21-30显示中等或低5 -HT1A受体亲和力；相反，1-（3-苯并噻唑基）和1-（1-萘基）取代的哌嗪19，20和32显示出高的5-HT1A受体亲和力，Ki值在亚纳摩尔范围内。此外，与参考化合物2-9相比，化合物19、20和32表现出比alpha1受体更好的选择性。

  DOI：

  10.1016/s0968-0896(00)00028-6
• 作为产物：
  描述：

  5-甲氧基-3,4-二氢-2H-1-萘酮 在 palladium on activated charcoal sodium hydroxide 、 盐酸羟胺 、 氢气 、 sodium acetate 作用下， 以 二氯甲烷 为溶剂， 生成 N-(1,2,3,4-tetrahydro-5-methoxy-1-naphthalenyl)bromoacetamide
  参考文献：
  名称：

  1-芳基-4-[（1-四林基）烷基]哌嗪：烷基酰胺基和烷基氨基衍生物。合成，5-HT1A受体亲和力和选择性。3。

  摘要：

  报告了N-4长链芳基哌嗪22-40的5-HT1A，5-HT2，D-1，D-2，α1和α2受体的合成和结合情况，其中氨基或酰胺基功能将“α”插入与四氢化萘核的α位连接的中间链中。与丁螺环酮类似物不同，对于本文研究的酰胺衍生物，长链哌嗪的末端酰胺功能对于5-HT1A受体亲和力结合并不重要，并且其去除会产生高亲和力的5-HT1A受体剂。

  DOI：

  10.1021/jm960087s

文献信息

• <i>N</i>-[2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide:  A Potent and Selective Dopamine D₄ Ligand
  作者：Roberto Perrone、Francesco Berardi、Nicola A. Colabufo、Marcello Leopoldo、Vincenzo Tortorella

  DOI：10.1021/jm981041x

  日期：1998.11.1

  binding at cloned human dopamine D4 and D2 receptor subtypes. A SAFIR (structure-affinity relationship) study on this series is herein discussed. The most relevant D4 receptor affinities were displayed by N-[omega-[4-arylpiperazin-1-yl]alkyl]-methoxybenzamides (compounds 5, 16-20), their IC50 values ranging between 0.057 and 7.8 nM. Among these, N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide

  合成了一系列新的在烷基链上包含末端苯甲酰胺片段或四氢-1-基核的1-芳基-4-烷基哌嗪，并测试了在克隆的人多巴胺D4和D2受体亚型上的结合。本文讨论了对该系列的SAFIR（结构亲和关系）研究。N-ω-[4-芳基哌嗪-1-基]烷基]-甲氧基苯甲酰胺（化合物5、16-20）显示出最相关的D4受体亲和力，其IC50值在0.057至7.8 nM之间。其中，N- [2- [4-（4-氯苯基）哌嗪-1-基]乙基] -3-甲氧基苯甲酰胺（17）出现了，因为它对多巴胺D4受体表现出很高的亲和力（IC50 = 0.057 nM）。 D4相对于D2受体> 10000; 化合物17对5-羟色胺5-HT1A和肾上腺素α1受体也具有选择性。
• Exploring the Importance of Piperazine N-Atoms for σ₂ Receptor Affinity and Activity in a Series of Analogs of 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28)
  作者：Francesco Berardi、Carmen Abate、Savina Ferorelli、Vincenzo Uricchio、Nicola A. Colabufo、Mauro Niso、Roberto Perrone

  DOI：10.1021/jm9007505

  日期：2009.12.10

  sigma(2)-Agonist 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (7, PB 28), which proved to revert doxorubicin resistance in breast cancer cells, was taken as a template to prepare new analogs. One of the two basic N-atoms wits alternatively replaced by it methine or converted into an amide or ammonium function, with the aim of finding out which of them was essential For sigma(2) receptor affinity and activity. Some simply 4-substituted 1-cyclohexylpiperazines were also investigated. None of the compounds was as high-affinity as 7 (sigma K-2(i) = 0.68, sigma K-1(i) = 0.38 nM), proving that both basic N-atoms ensure better sigma(2) receptor binding. Amide 36 emerged as high-affinity (K-i = 0.11 nM) and noteworthy selective (1627-fold) or, ligand. Small N-cyclohexylpiperazine 59 displayed the highest sigma(2) affinity (K-i = 4.70 nM). The sigma(2)/sigma(1) selectivities were generally low. Antiproliferative assay in SK-N-SH cells revealed piperidines 24 and 15 as putative sigma(2), agonists (EC(50)s 1.40 and 3.64 mu M respectively) more potent than 7.
• Analogues of σ Receptor Ligand 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28) with Added Polar Functionality and Reduced Lipophilicity for Potential Use as Positron Emission Tomography Radiotracers
  作者：Carmen Abate、Mauro Niso、Enza Lacivita、Philip D. Mosier、Annamaria Toscano、Roberto Perrone

  DOI：10.1021/jm1013133

  日期：2011.2.24

  1-Cyclohexyl-4[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine 1 (PB28) represents an excellent lead candidate for therapeutic and/or diagnostic applications in oncology. However, because its utility is limited by its relatively high degree of lipophilicity, novel analogues of 1 with reduced lipophilic character were designed by substituting methylene groups with more polar functional groups in the propylene linker and at the tetralin C4 position. For the chiral analogues, separate enantiomers exhibited substantial and roughly equal affinities within a given receptor subtype, with the greatest difference observed for compound 9 at sigma(1) (7.5-fold; (-)-(S)-9 K(i) = 94.6 nM, (+)-(R)-9 K(i) = 12.6 nM). Compound (-)-(S)-9 was also found to be the most sigma(2)-selective agent (sigma(2) K(i) = 5.92 nM), to possess a lipophilicity consistent with entry into tumor cells (log D(7.4) = 2.38), and to show minimal antiproliferative activity. However, (-)-(S)-9 exhibited moderate activity (EC(50) = 8.1 mu M) at the P-gp efflux pump.
• Potential applications for sigma receptor ligands in cancer diagnosis and therapy
  作者：Aren van Waarde、Anna A. Rybczynska、Nisha K. Ramakrishnan、Kiichi Ishiwata、Philip H. Elsinga、Rudi A.J.O. Dierckx

  DOI：10.1016/j.bbamem.2014.08.022

  日期：2015.10

  Sigma receptors (sigma-1 and sigma-2) represent two independent classes of proteins. Their endogenous ligands may include the hallucinogen N,N-dimethyltryptamine (DMT) and sphingolipid-derived amines which interact with sigma-1 receptors, besides steroid hormones (e.g., progesterone) which bind to both sigma receptor sub-populations. The sigma-1 receptor is a ligand-regulated molecular chaperone with various ion channels and G-protein-coupled membrane receptors as clients. The sigma-2 receptor was identified as the progesterone receptor membrane component 1 (PGRMC1). Although sigma receptors are over-expressed in tumors and up-regulated in rapidly dividing normal tissue, their ligands induce significant cell death only in tumor tissue. Sigma ligands may therefore be used to selectively eradicate tumors. Multiple mechanisms appear to underlie cell killing after administration of sigma ligands, and the signaling pathways are dependent both on the type of ligand and the type of tumor cell. Recent evidence suggests that the sigma-2 receptor is a potential tumor and serum biomarker for humaniung cancer and an important target for inhibiting tumor invasion and cancer progression. Current radiochemical efforts are focused on the development of subtype-selective radioligands for positron emission tomography (PET) imaging. Right now, the mostpromising tracers are [F-18]fluspidine and [F-18]FTC-146 for sigma-1 receptors and [C-11]RHM-1 and [F-18]ISO-1 for the sigma-2 subtype. Nanoparticles coupled to sigma ligands have shown considerable potential for targeted delivery of antitumor drugs in animal models of cancer, but clinical studies exploring this strategy in cancer patients have not yet been reported. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. (C) 2014 Elsevier B.V. All rights reserved.
• From mixed sigma-2 receptor/P-glycoprotein targeting agents to selective P-glycoprotein modulators: Small structural changes address the mechanism of interaction at the efflux pump
  作者：Carmen Abate、Maria Laura Pati、Marialessandra Contino、Nicola Antonio Colabufo、Roberto Perrone、Mauro Niso、Francesco Berardi

  DOI：10.1016/j.ejmech.2014.10.082

  日期：2015.1

  Generations of modulators of the efflux pump P-glycoprotein (P-gp) have been produced as tools to counteract the Multidrug Resistance (MDR) phenomenon in tumor therapy, but clinical trials were not successful so far. With the aim of contributing to the development of novel P-gp modulators, we started from recently studied high-affinity sigma-2 (sigma(2)) receptor ligands that showed also potent interaction with P-gp. For sigma(2) receptors high-affinity binding, a basic N-atom is a strict requirement. Therefore, we reduced the basic character of the N-atom present in these ligands, and we obtained potent P-gp modulators with poor or null sigma(2) receptor affinity. We also evaluated whether modulation of P-gp by these novel compounds involved consumption of ATP (as P-gp substrates do), as a source of energy to support the efflux. Surprisingly, even small structural changes resulted in opposite behavior, with amide 13 depleting ATP, in contrast to its isomer 18. Two compounds, 15 and 25, emerged for their potent activity at P-gp, and deserve further investigations as tools for P-gp modulation. (C) 2014 Elsevier Masson SAS. All rights reserved.