7-Fluoro-4-piperazin-1-yl-pyrrolo[1,2-a]quinoxaline | 195711-51-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 7-Fluoro-4-piperazin-1-yl-pyrrolo[1,2-a]quinoxaline
• 英文别名: 7-fluoro-4-piperazin-1-ylpyrrolo[1,2-a]quinoxaline
• CAS: 195711-51-4
• 化学式: C₁₅H₁₅FN₄
• mdl: MFCD16991010
• 分子量: 270.309
• InChiKey: YFOGAJAEMHMGIZ-UHFFFAOYSA-N

物化性质

• 沸点：
  436.5±45.0 °C(Predicted)
• 密度：
  1.39±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  20
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  32.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  7-Fluoro-4-piperazin-1-yl-pyrrolo[1,2-a]quinoxaline 在 sodium azide 、 哌啶盐酸盐 作用下， 以 N,N-二甲基甲酰胺 、 丁酮 为溶剂， 反应 19.0h， 生成 9-fluoro-4-[4-(1H-tetrazol-5-yl)methylpiperazin-1-yl]pyrrolo-[1,2-a]quinoxaline
  参考文献：
  名称：

  吡咯并喹喔啉衍生物作为高亲和力和选择性5-HT（3）受体激动剂：合成，进一步的结构活性关系和生物学研究。

  摘要：

  描述了一系列新型吡咯并喹喔啉和杂芳族相关衍生物的合成，药理评价和构效关系（SAR）。新的吡咯并喹喔啉相关配体在大鼠皮层，表达高密度5-HT（3）受体的组织中以及在NG108-15细胞上进行了测试，并在低纳摩尔或亚纳摩尔范围内表现出IC（50）值，方法是通过抑制[（3）H] zacopride结合。本文详述的SAR研究描述了改善亲和力所需的许多结构特征。一些配体被用作“分子尺度”，以探测5-HT（3）受体裂隙中亲脂性口袋L1，L2和L3的空间尺寸，而7-OH吡咯并喹喔啉类似物被设计用于研究与可能与5-羟色胺羟基相互作用的假定受体位点H1的氢键作用。最活跃的吡咯并喹喔啉衍生物对5-HT（3）受体显示亚纳摩尔亲和力。在功能研究中（[[14] C]胍在NG108-15杂化细胞中的体外积累试验），大多数受试化合物均显示出明确的5-HT（3）激动剂特性，而另一些则为部分激动剂。关于5-HT（3）亲和力

  DOI：

  10.1021/jm990151g
• 作为产物：
  描述：

  哌嗪 、 4-氯-7-氟吡咯并[1,2-a]喹喔啉 以 乙二醇 为溶剂， 反应 2.0h， 生成 7-Fluoro-4-piperazin-1-yl-pyrrolo[1,2-a]quinoxaline
  参考文献：
  名称：

  Novel and Highly Potent 5-HT₃ Receptor Agonists Based on a Pyrroloquinoxaline Structure

  摘要：

  The synthesis and the biological evaluation of a series of novel pyrroloquinoxaline derivatives are described. In binding studies several compounds proved to be potent and selective 5-HT3 receptor ligands. The most active pyrroloquinoxalines, 11d and 11e, showed a subnanomolar affinity for 5-HT3 receptor and were able to functionally discriminate the central and peripheral 5-HT3 receptors, being agonists and antagonists, respectively. In functional studies ([C-14]-guanidinium accumulation test in NG 108-15 cells, in vitro) most of the synthesized compounds showed clear-cut 5-HT3 agonist properties. In in vivo studies on the von Bezold-Jarisch reflex test (a peripheral interaction model) the behavior of the tested compounds ranged from agonist to antagonist, while clear agonist properties were obtained with 12a on cortical acetylcholine release in freely moving rats. Pharmacokinetic studies with 11e and 12c indicate that the compounds easily cross the blood-brain barrier (BBB) after systemic administration with a brain/plasma ratio of 17.5 and 37.5, respectively. Thus compounds 11e and 12c represent the most potent central 5-HT3 agonists identified to date that are able to cross the blood-brain barrier.

  DOI：

  10.1021/jm970376w

文献信息

• Novel, Potent, and Selective Quinoxaline-Based 5-HT₃ Receptor Ligands. 1. Further Structure−Activity Relationships and Pharmacological Characterization
  作者：Stefania Butini、Roberta Budriesi、Michel Hamon、Elena Morelli、Sandra Gemma、Margherita Brindisi、Giuseppe Borrelli、Ettore Novellino、Isabella Fiorini、Pierfranco Ioan、Alberto Chiarini、Alfredo Cagnotto、Tiziana Mennini、Claudia Fracasso、Silvio Caccia、Giuseppe Campiani

  DOI：10.1021/jm901126m

  日期：2009.11.12

  We investigated the pharmacological profile of a novel series of quinoxaline-based 5-HT3 receptor ligands bearing an extra basic moiety on the piperazine N-4. High affinity and selectivity were dependent on the electronic properties of the substituents, and at cardiac level 3a and 3c modulated chronotropy but not inotropy. In von Bezold−Jarisch reflex test 3a−c were partial agonists while 3i was a

  我们研究了新的基于喹喔啉的5-HT 3受体配体系列的药理学特征，该配体在哌嗪N-4上具有一个额外的碱性部分。高亲和力和选择性取决于取代基的电子性质，并且在心脏水平3a和3c上具有调制变时性，但不具有变质性。在von Bezold-Jarisch反射测试中，3a - c是部分激动剂，而3i是完全激动剂。初步的药代动力学研究表明3a是一种脑渗透剂。
• Specific Targeting of Peripheral Serotonin 5-HT₃ Receptors. Synthesis, Biological Investigation, and Structure−Activity Relationships
  作者：Elena Morelli、Sandra Gemma、Roberta Budriesi、Giuseppe Campiani、Ettore Novellino、Caterina Fattorusso、Bruno Catalanotti、Salvatore Sanna Coccone、Sindu Ros、Giuseppe Borrelli、Marco Persico、Isabella Fiorini、Vito Nacci、Pierfranco Ioan、Alberto Chiarini、Michel Hamon、Alfredo Cagnotto、Tiziana Mennini、Claudia Fracasso、Milena Colovic、Silvio Caccia、Stefania Butini

  DOI：10.1021/jm900018b

  日期：2009.6.11

  The synthesis and the biological characterization of novel highly selective pyrroloquinoxaline 5-HT3 receptor (5-HT3R) ligands are described. In functional and in vivo biological studies the novel quinoxalines modulated cardiac parameters by direct interaction with myocardial 5-HT(3)Rs. The potent 5-HT3R ligands 4h and 4n modulate chronotropy (right atrium) but not inotropy (left atrium) at the cardiac level, being antagonist and partial agonist, respectively. Preliminary pharmacokinetic studies indicate that (S)-4n and 4a, representatives of the novel 5-HT3R ligands, possess poor blood-brain barrier permeability, being the prototypes of peripherally acting 5-HT3R modulators endowed with a clear-cut pharmacological activity at the cardiac level. The unique properties of 4h and 4n, compared to their previously described centrally active N-methyl analogue 5a, are mainly due to the hydrophilic groups at the distal piperazine nitrogen. These analogues represent novel pharmacological tools for investigating the role of peripheral 5-HT3R in the modulation of cardiac parameters.
• Pyrroloquinoxaline Derivatives as High-Affinity and Selective 5-HT₃ Receptor Agonists:  Synthesis, Further Structure−Activity Relationships, and Biological Studies
  作者：Giuseppe Campiani、Elena Morelli、Sandra Gemma、Vito Nacci、Stefania Butini、Michel Hamon、Ettore Novellino、Giovanni Greco、Alfredo Cagnotto、Mara Goegan、Luigi Cervo、Fabio Dalla Valle、Claudia Fracasso、Silvio Caccia、Tiziana Mennini

  DOI：10.1021/jm990151g

  日期：1999.10.1

  [(3)H]zacopride binding. The SAR studies detailed herein delineated a number of structural features required for improving affinity. Some of the ligands were employed as "molecular yardsticks" to probe the spatial dimensions of the lipophilic pockets L1, L2, and L3 in the 5-HT(3) receptor cleft, while the 7-OH pyrroloquinoxaline analogue was designed to investigate hydrogen bonding with a putative receptor site

  描述了一系列新型吡咯并喹喔啉和杂芳族相关衍生物的合成，药理评价和构效关系（SAR）。新的吡咯并喹喔啉相关配体在大鼠皮层，表达高密度5-HT（3）受体的组织中以及在NG108-15细胞上进行了测试，并在低纳摩尔或亚纳摩尔范围内表现出IC（50）值，方法是通过抑制[（3）H] zacopride结合。本文详述的SAR研究描述了改善亲和力所需的许多结构特征。一些配体被用作“分子尺度”，以探测5-HT（3）受体裂隙中亲脂性口袋L1，L2和L3的空间尺寸，而7-OH吡咯并喹喔啉类似物被设计用于研究与可能与5-羟色胺羟基相互作用的假定受体位点H1的氢键作用。最活跃的吡咯并喹喔啉衍生物对5-HT（3）受体显示亚纳摩尔亲和力。在功能研究中（[[14] C]胍在NG108-15杂化细胞中的体外积累试验），大多数受试化合物均显示出明确的5-HT（3）激动剂特性，而另一些则为部分激动剂。关于5-HT（3）亲和力
• Novel and Highly Potent 5-HT₃ Receptor Agonists Based on a Pyrroloquinoxaline Structure
  作者：Giuseppe Campiani、Andrea Cappelli、Vito Nacci、Maurizio Anzini、Salvatore Vomero、Michel Hamon、Alfredo Cagnotto、Claudia Fracasso、Chiara Uboldi、Silvio Caccia、Silvana Consolo、Tiziana Mennini

  DOI：10.1021/jm970376w

  日期：1997.10.1

  The synthesis and the biological evaluation of a series of novel pyrroloquinoxaline derivatives are described. In binding studies several compounds proved to be potent and selective 5-HT3 receptor ligands. The most active pyrroloquinoxalines, 11d and 11e, showed a subnanomolar affinity for 5-HT3 receptor and were able to functionally discriminate the central and peripheral 5-HT3 receptors, being agonists and antagonists, respectively. In functional studies ([C-14]-guanidinium accumulation test in NG 108-15 cells, in vitro) most of the synthesized compounds showed clear-cut 5-HT3 agonist properties. In in vivo studies on the von Bezold-Jarisch reflex test (a peripheral interaction model) the behavior of the tested compounds ranged from agonist to antagonist, while clear agonist properties were obtained with 12a on cortical acetylcholine release in freely moving rats. Pharmacokinetic studies with 11e and 12c indicate that the compounds easily cross the blood-brain barrier (BBB) after systemic administration with a brain/plasma ratio of 17.5 and 37.5, respectively. Thus compounds 11e and 12c represent the most potent central 5-HT3 agonists identified to date that are able to cross the blood-brain barrier.