2-(4-bromobutyl)-1,3-dioxoperhydropyrrolo[1,2-c]imidazole | 181948-88-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 英文名称: 2-(4-bromobutyl)-1,3-dioxoperhydropyrrolo[1,2-c]imidazole
• 英文别名: 2-(4-Bromo-butyl)-tetrahydro-pyrrolo[1,2-c]imidazole-1,3-dione；2-(4-bromobutyl)-5,6,7,7a-tetrahydropyrrolo[1,2-c]imidazole-1,3-dione
• CAS: 181948-88-9
• 化学式: C₁₀H₁₅BrN₂O₂
• 分子量: 275.145
• InChiKey: KMAXFRRFMGSHNQ-UHFFFAOYSA-N

物化性质

• 沸点：
  349.9±44.0 °C(Predicted)
• 密度：
  1.54±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  15
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  40.6
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2-(4-bromobutyl)-1,3-dioxoperhydropyrrolo[1,2-c]imidazole 在 盐酸 作用下， 以 乙醚 、 乙腈 为溶剂， 生成 2-{4-[(2-thien-2-ylethyl)amino]butyl}tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione hydrochloride
  参考文献：
  名称：

  New Serotonin 5-HT_1A Receptor Agonists with Neuroprotective Effect against Ischemic Cell Damage

  摘要：

  We report the synthesis of new compounds 4 35 based on structural modifications of different moieties of previously described lead UCM-2550. The new nonpiperazine derivatives, representing second-generation agonists, were assessed for binding affinity, selectivity, and functional activity at the 5-HT1A receptor (5-HT1AR). Computational beta(2)-based homology models of the ligand receptor complexes were used to explain the observed structure affinity relationships. Selected candidates were also evaluated for their potential in vitro and in vivo neuroprotective properties. Interestingly, compound 26 (2-{6-[(3,4:-dihydro-2H-chromen-2-ylmethyl)amino]hexyl}-tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione) has been characterized as a high-affinity and potent 5-HT1AR agonist (K-i, = 5.9 nM, EC50 = 21.8 nM) and exhibits neuroprotective effect in neurotoxicity assays in primary cell cultures from rat hippocampus and in the MCAO model of focal cerebral ischemia in rats.

  DOI：

  10.1021/jm2007886
• 作为产物：
  描述：

  1,4-二溴丁烷 、 四氢-1H-吡咯并[1,2-c]咪唑-1,3(2H)-二酮 在 sodium hydride 作用下， 生成 2-(4-bromobutyl)-1,3-dioxoperhydropyrrolo[1,2-c]imidazole
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 1. 2-[[4-(o-Methoxyphenyl)piperazin-1-yl]methyl]-1,3- dioxoperhydroimidazo[1,5-a]pyridine:  A Selective 5-HT_1A Receptor Agonist

  摘要：

  A series of new bicyclohydantoin-arylpiperazines was prepared and evaluated for affinity at 5-HT1A, alpha(1), and D-2 receptors. Most of the compounds showed very low affinity for D-2 receptors, and most of them demonstrated moderate to high affinity for 5-HT1A and alpha(1) receptor binding sites. SAR observations indicated that the length of the alkyl chain between the arylpiperazine and the hydantoin moiety is of great importance for 5-HT1A/alpha(1) affinity and selectivity, n = 1 being the optimal value. Compound 1h, 2-[[4-(o-methoxyphenyl)piperazin-1-yl]methyl]-1,3-dioxoperhydroimidazo[1,5-a]pyridine, bound at 5-HT1A sites with nanomolar affinity (K-i = 31.7 nM) and high selectivity over alpha(1), D-2, and 5-HT2A receptors (K-i > 1000, > 10 000, and > 1000 nM, respectively). Preliminary studies showed that this agent is probably functioning as a partial to full 5-HT1A agonist, and it displayed anxiolytic activity on the social interaction test in mice.

  DOI：

  10.1021/jm960416g

文献信息

• Design, Synthesis and Pharmacological Evaluation of 5-Hydroxytryptamine_1aReceptor Ligands to Explore the Three-Dimensional Structure of the Receptor
  作者：Marı́a L. López-Rodrı́guez、Bruno Vicente、Xavier Deupi、Sergio Barrondo、Mireia Olivella、M. José Morcillo、Bellinda Behamú、Juan A. Ballesteros、Joan Sallés、Leonardo Pardo

  DOI：10.1124/mol.62.1.15

  日期：2002.7.1

  In this work, we evaluate the structural differences of transmembrane helix 3 in rhodopsin and the 5-hydroxytryptamine 1A (5-HT1A) receptor caused by their different amino acid sequence. Molecular dynamics simulations of helix 3 in the 5-HT1A receptor tends to bend toward helix 5, in sharp contrast to helix 3 in rhodopsin, which is properly located within the position observed in the crystal structure. The relocation of the central helix 3 in the helical bundle facilitates the experimentally derived interactions between the neurotransmitters and the Asp residue in helix 3 and the Ser/Thr residues in helix 5. The different amino acid sequence that forms helix 3 in rhodopsin (basically the conserved Gly3.36Glu3.37 motif in the opsin family) and the 5-HT1A receptor (the conserved Cys3.36Thr3.37 motif in the neurotransmitter family) produces these structural divergences. These structural differences were experimentally checked by designing and testing ligands that contain comparable functional groups but at different interatomic distance. We have estimated the position of helix 3 relative to the other helices by systematically changing the distance between the functional groups of the ligands ( 1 and 2 ) that interact with the residues in the receptor. Thus, ligand 1 optimally interacts with a model of the 5-HT1A receptor that matches rhodopsin template, whereas ligand 2 optimally interacts with a model that possesses the proposed conformation of helix 3. The lack of affinity of 1 ( K i > 10,000 nM) and the high affinity of 2 ( K i = 24 nM) for the 5-HT1A receptor binding sites, provide experimental support to the proposed structural divergences of helix 3 between the 5-HT1A receptor and rhodopsin.

  在这项研究中，我们评估了因氨基酸序列不同而导致的犀牛蛋白和5-羟色胺1A（5-HT1A）受体跨膜螺旋3的结构差异。分子动力学模拟显示，5-HT1A 受体中的螺旋 3 趋向于向螺旋 5 弯曲，这与斜视素中的螺旋 3 形成鲜明对比，后者正确地位于晶体结构中观察到的位置。螺旋 3 在螺旋束中的中心位置有利于神经递质与螺旋 3 中的 Asp 残基和螺旋 5 中的 Ser/Thr 残基之间的相互作用。形成螺旋 3 的氨基酸序列在犀牛蛋白（基本上是视蛋白家族中的 Gly3.36Glu3.37 保守基团）和 5-HT1A 受体（神经递质家族中的 Cys3.36Thr3.37 保守基团）中不同，从而产生了这些结构差异。通过设计和测试含有相似功能基团但原子间距离不同的配体，我们在实验中检验了这些结构差异。我们通过系统地改变与受体残基相互作用的配体（1 和 2）的功能基团之间的距离，估算出了螺旋 3 相对于其他螺旋的位置。因此，配体 1 与符合犀牛蛋白模板的 5-HT1A 受体模型的相互作用最佳，而配体 2 与具有拟议的螺旋 3 构象的模型的相互作用最佳。配体 1 与 5-HT1A 受体结合位点的亲和力不足（K i > 10,000 nM），而配体 2 与 5-HT1A 受体结合位点的亲和力较高（K i = 24 nM），这为 5-HT1A 受体和视网膜视蛋白之间的螺旋 3 结构差异提供了实验支持。
• ARYLPIPERAZINE DERIVATIVE AND USE THEREOF AS 5-HT1A RECEPTOR LIGANDS
  申请人：Lopez-Rodriguez Maria Luz

  公开号：US20090036455A1

  公开（公告）日：2009-02-05

  Novel substituted arylpiperazine derivatives with activity as 5-hydroxytryptamine 1A (5-HT 1A ) receptor subtype ligands, to their stereochemical isomers, methods of their preparation, and to their use and to pharmaceutical compositions containing them for the treatment of Parkinson disease, cerebral damage by thromboembolic ictus, craneoencephalic traumatisms, depression, migraine, pain, psychosis, anxiety disorders, aggressive disorders or urinary tract disorders.

  小说替代了具有5-羟色胺1A（5-HT1A）受体亚型配体活性的芳基哌嗪衍生物，包括它们的立体化异构体、制备方法以及它们在治疗帕金森病、血栓栓塞性卒中引起的脑损伤、颅脑外伤、抑郁症、偏头痛、疼痛、精神病、焦虑症、攻击性障碍或泌尿道障碍的药物组成物中的使用。
• New Serotonin 5-HT_1A Receptor Agonists Endowed with Antinociceptive Activity <i>in Vivo</i>
  作者：Margarita Valhondo、Isabel Marco、Mar Martín-Fontecha、Henar Vázquez-Villa、José A. Ramos、Reinhard Berkels、Thomas Lauterbach、Bellinda Benhamú、María L. López-Rodríguez

  DOI：10.1021/jm400766k

  日期：2013.10.24

  We report the synthesis of new compounds 4-35 based on two different openings (A and B) of the chromane ring present in the previously identified 5-HT1A receptor (5-HT1AR) ligand 3. The synthesized compounds were assessed for binding affinity, selectivity, and functional activity at the 5-HT1AR Selected candidates resulting from B opening were also evaluated for their potential antinociceptive effect in vivo and pharmacokinetic properties in vitro. Analogue 19 [2-(4-[2-(2-ethoxyphenoxy)ethyl]amino}butyl)tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione] has been characterized as a high-affinity and potent 5-HT1AR agonist (K-i = 2.3 nM; EC50 = 19 nM). Pharmacokinetic studies indicated that compound 19 displays a good metabolic stability in human liver microsomes (t(1/2) similar to 3 h and CLint = 3.5 mL/min/kg, at 5 mu M), and a low level of protein binding (25%, at 5 mu M). Interestingly, 19 (3 mg/kg, ip, and 30 mg/kg, po) caused significant attenuation of formalin-induced behavior in early and late phases of the mouse intradermal formalin test of pain, and this in vivo effect was reversed by the selective 5-HT1AR antagonist WAY-100635. Thus, the new 5-HT1AR agonist identified in this work, 19, exhibits oral analgesic activity, and the results herein represent a step toward identifying new therapeutics for the control of pain.
• Synthesis of new (benzimidazolyl)piperazines with affinity for the 5-HT1A receptor via Pd(0) amination of bromobenzimidazoles
  作者：María L López-Rodríguez、Alma Viso、Bellinda Benhamú、J.Luis Rominguera、Marta Murcia

  DOI：10.1016/s0960-894x(99)00384-4

  日期：1999.8

  The synthesis of a new family of (benzimidazolyl)piperazines has been developed through Pd(0) mediated amination of 4- and 6-bromobenzimidazole derivatives. Preliminary studies showed that some of these compounds are potent 5-HT1A receptor ligands. (C) 1999 Elsevier Science Ltd. All rights reserved.
• Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 8. Computational Simulation of Ligand−Receptor Interaction of 5-HT_1AR Agonists with Selectivity over α₁-Adrenoceptors
  作者：María L. López-Rodríguez、Maria José Morcillo、Esther Fernández、Bellinda Benhamú、Ignacio Tejada、David Ayala、Alma Viso、Mercedes Campillo、Leonardo Pardo、Mercedes Delgado、Jorge Manzanares、José A. Fuentes

  DOI：10.1021/jm048999e

  日期：2005.4.1

  We have designed and synthesized a new series of arylpiperazines V exhibiting high 5-HT1AR affinity and selectivity over alpha(1)-adrenoceptors. The new selective 5-HT1AR ligands contain a hydantoin (m = 0) or diketopiperazine (m = 1) moiety and an arylpiperazine moiety separated by one methylene unit (n = 1). The aryl substituent of the piperazine moiety (Ar) consists of different benzofused rings mimicking the favorable voluminous substituents at ortho and meta positions predicted by 3D-QSAR analysis in the previously reported series I. In particular, (S)-2-[[4-(naphth-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-a]pyrazine [(S)-9, CSP-2503] (5-HT1A, K-i = 4.1 nM; alpha(1), Ki > 1000 nM) has been pharmacologically characterized as a 5-HT1AR agonist at somatodendritic and postsynaptic sites, endowed with anxiolytic properties. Ligand (S)-9 is predicted, in computer simulations, to bind Asp(3.32) in TMH 3, Thr(5.39) and Ser(5.42) in TMH 5, and Trp(6.48) in TMH 6. We propose that agonists modify, by means of an explicit hydrogen bond, the conformation of Trp(6.48) from pointing toward TMH 7, in the inactive gauche+ conformation, to pointing toward the ligand binding site, in the active trans conformation.