2-(4-bromobutyl)-1,3-dioxoperhydroimidazo[1,5-a]pyridine | 176219-01-5

• 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-dioxoperhydroimidazo[1,5-a]pyridine
• 英文别名: 2-(4-bromobutyl)-6,7,8,8a-tetrahydro-5H-imidazo[1,5-a]pyridine-1,3(2H,5H)-dione；2-(4-bromobutyl)-6,7,8,8a-tetrahydro-5H-imidazo[1,5-a]pyridine-1,3-dione
• CAS: 176219-01-5
• 化学式: C₁₁H₁₇BrN₂O₂
• 分子量: 289.172
• InChiKey: NGVCOLYVIMZFMP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  16
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.82
• 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-dioxoperhydroimidazo[1,5-a]pyridine 在 palladium on activated charcoal 氢气 、 三乙胺 作用下， 以 甲醇 、 乙腈 为溶剂， 20.0~60.0 ℃ 、241.32 kPa 条件下， 生成 2-{4-[4-(3-Amino-phenyl)-piperazin-1-yl]-butyl}-tetrahydro-imidazo[1,5-a]pyridine-1,3-dione
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 5. Study of the Physicochemical Influence of the Pharmacophore on 5-HT_1A/α₁-Adrenergic Receptor Affinity:  Synthesis of a New Derivative with Mixed 5-HT_1A/D₂ Antagonist Properties

  摘要：

  In this paper we have designed and synthesized a test series of 32 amide arylpiperazine derivatives VI in order to gain insight into the physicochemical influence of the pharmacophores of 5-HT1A and alpha (1)-adrenergic receptors. The training set was designed applying a fractional factorial design using six physicochemical descriptors. The amide moiety is a bicyclohydantoin or a diketopiperazine (X = -(CH2)(3)-, -(CH2)(4)-; m = 0, 1), the spacer length is 3 or 4 methylene units, which are the optimum values for both receptors, and the aromatic substituent R occupies the ortho- or meta-position and has been selected from a database of 387 substituents using the EDISFAR program. The 5-HT1A and alpha (1)-adrenergic receptor binding affinities of synthesized compounds VI (1-32) have been determined. This data set has been used to derive classical quantitative structure-activity relationships (QSAR) and neural-networks models for both receptors (following paper). A comparison of these models gives information for the design of the new ligand EF-7412 (46) (5-HT1A: K-i = 27 nM; alpha (1): K-i > 1000 nM). This derivative displays affinity for the dopamine D-2 receptor (K-i = 22 nM) and is selective versus all other receptors examined (5-HT2A, 5-HT3, 5-HT4 and Bz; K-i > 1000 nM). EF-7412 (46) acts as an antagonist in vivo in pre- and postsynaptic 5-HT1A receptor sites and; as an antagonist in the dopamine D-2 receptor. Thus, EF-7412 (46) is a derivative with mixed 5-HT1A/D-2 antagonist properties and this derivative could be useful as a pharmacological tool.

  DOI：

  10.1021/jm000929u
• 作为产物：
  描述：

  1,4-二溴丁烷 、 四氢咪唑并[1,5-a]吡啶-1,3(2H,5H)-二酮 在 sodium hydride 作用下， 生成 2-(4-bromobutyl)-1,3-dioxoperhydroimidazo[1,5-a]pyridine
  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

• Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 6. Study of the 5-HT_1A/α₁-Adrenergic Receptor Affinity by Classical Hansch Analysis, Artificial Neural Networks, and Computational Simulation of Ligand Recognition
  作者：María L. López-Rodríguez、M. José Morcillo、Esther Fernández、M. Luisa Rosado、Leonardo Pardo、Klaus-Jürgen Schaper

  DOI：10.1021/jm000930t

  日期：2001.1.1

  the alpha(1)-adrenergic receptor; (c) the meta-position seems to be implicated in the 5-HT(1A)/alpha(1) selectivity. While the 5-HT(1A) receptor is able to accommodate bulky substituents in the region of its active site, the steric requirements of the alpha(1)-adrenergic receptor at this position are more restricted. This information was used for the design of the new ligand EF-7412 (33) (5-HT(1A): K(i

  经典的定量结构-活性关系（Hansch）研究和人工神经网络（ANN）已应用于32种对5-HT（1A）和α（1）-肾上腺素受体具有亲和力的取代苯基哌嗪的训练集，以评估负责5-HT（1A）/ alpha（1）选择性的结构要求。所得模型提供了电子，空间和疏水参数与生物亲和力的显着相关性。尽管派生的线性Hansch相关性提供了良好的统计量和可接受的预测，但是在分析中引入非线性关系可提供更可靠的模型和更准确的预测。在基于获得的3D图的ANN模型中，5-HT（1A）亲和力与F，V（o），V（m）和pi（o）呈非线性关系，尽管非线性关系离平面关系不远。alpha（1）-肾上腺素受体亲和力对F，V（o），V（m），pi（o）和pi（m）具有明显的非线性依赖性。两种分析方法的比较为5-HT（1A）/ alpha（1）选择性提供了额外的理解：（a）高F值会增加对5-HT（1A）受体的结合亲和力，并降低对alp
• New Serotonin 5-HT_1A Receptor Agonists with Neuroprotective Effect against Ischemic Cell Damage
  作者：Isabel Marco、Margarita Valhondo、Mar Martı́n-Fontecha、Henar Vázquez-Villa、Joaquı́n Del Rı́o、Anna Planas、Onintza Sagredo、José A. Ramos、Iván R. Torrecillas、Leonardo Pardo、Diana Frechilla、Bellinda Benhamú、Marı́a L. López-Rodrı́guez

  DOI：10.1021/jm2007886

  日期：2011.12.8

  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.
• 2-[4-(o-methoxyphenyl)piperazin-1-ylmethyl]-1,3-dioxoperhydroimidazo[1,5-a]pyridine as a new selective 5-HT1A receptor ligand
  作者：María L. López-Rodríguez、MaJosé Morcillo、MaLuisa Rosado、Bellinda Benhamu、Antonio M. Sanz

  DOI：10.1016/0960-894x(96)00081-9

  日期：1996.3

  A series of 2-[omega-(4-arylpiperazin-1-yl)alkyl]-1,3-dioxoperhydroimidazo[1,5-a]pyridine derivatives was prepared and evaluated for affinity at 5-HT1A and alpha(1) receptors. The most promising analogue Im bound at 5-HT1A sites with nanomolar affinity (K-i=31.7) and high selectivity over alpha(1), D-2 and 5-HT2A receptors (K-i>1000, K-i>10 000, K-i>1000 nM, respectively). Preliminary studies showed that this agent is a presynaptic 5-HT1A agonist, and it displayed activity in the face to face behavioural model.