2-(4-Bromo-butyl)-4-(2-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine-1,3-dione | 532427-84-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 2-(4-Bromo-butyl)-4-(2-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine-1,3-dione
• CAS: 532427-84-2
• 化学式: C₁₉H₂₃BrN₂O₃
• 分子量: 407.307
• InChiKey: NVFNFKPBPXFOKB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  25.0
• 可旋转键数：
  6.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  53.23
• 氢给体数：
  0.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  1-(2-甲基苯基)哌嗪 、 2-(4-Bromo-butyl)-4-(2-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine-1,3-dione 在 potassium iodate 、 盐酸 作用下， 以 乙腈 、 甲醇 为溶剂， 反应 30.0h， 以33.8%的产率得到4-(2-Methoxy-phenyl)-2-[4-(4-o-tolyl-piperazin-1-yl)-butyl]-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine-1,3-dione; compound with GENERIC INORGANIC NEUTRAL COMPONENT
  参考文献：
  名称：

  Herold, Fraciszek; Krol, Marek; Kleps, Jerzy, Acta poloniae pharmaceutica, 2004, vol. 61, # 2, p. 139 - 150

  摘要：

  DOI：
• 作为产物：
  描述：

  邻甲氧基苯乙腈 在 硫酸 、 palladium 10% on activated carbon 、 氢气 、 sodium ethanolate 、 potassium carbonate 、 溶剂黄146 、 potassium hydroxide 作用下， 以 甲醇 、 乙醇 、 二甲基亚砜 、 丙酮 为溶剂， 生成 2-(4-Bromo-butyl)-4-(2-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine-1,3-dione
  参考文献：
  名称：

  合成新的5,6,7,8-四氢吡啶并[1,2-c]嘧啶衍生物，其具有潜在的SSRI和5-HT1A受体配体，具有刚性化的色胺部分。

  摘要：

  在4-芳基-吡啶并[1,2-c]嘧啶基团中进行的深入研究产生了27种新化合物（10.1-10.27），5,6,7,8-四氢吡啶并[1,2-c]嘧啶衍生物。为了确定它们与5-HT1A受体和SERT蛋白的亲和力，对10.1-10.27化合物进行了体外测试（RBA）。10.1-10.3、10.6、10.7、10.16和10.27化合物对两个分子靶标都有很高的结合能力（5-HT1A Ki = 8-87 nM； SERT Ki = 8-52 nM）。对于这些化合物（10.1-10.3、10.6、10.7、10.16、10.27），还进行了体外，体内和代谢稳定性测试。在扩展的受体谱（D2、5-HT2A，5-HT6和5-HT7）中的体外研究表明，它们对5-HT1A受体和SERT蛋白具有选择性。体内试验表明，化合物10.7和10.16具有5-HT1A受体突触前拮抗剂的特性。

  DOI：

  10.1016/j.ejmech.2019.07.027

文献信息

• Synthesis of new hexahydro- and octahydropyrido[1,2-c]pyrimidine derivatives with an arylpiperazine moiety as ligands for 5-HT1A and 5-HT2A receptors
  作者：Franciszek Herold、Jerzy Kleps、Irena Wolska、Gabriel Nowak

  DOI：10.1016/s0014-827x(02)01274-0

  日期：2002.12

  Synthesis applied to prepare compounds 5-15 and 17-22 discussed in this paper has been presented in Scheme 1. Multi-stage preparation techniques were used to obtain 4-aryl-hexahydro 1-4 and (R,R) and (S,S) 4-aryl-octahydropyrido[1,2-c]pyrimidine-1,3-dione (16) derivatives, being the starting compounds for further modification. N-Alkylation of the imide group in compounds 1-4 and 16 followed, using

  方案1中介绍了用于制备本文讨论的化合物5-15和17-22的合成方法。采用多步制备技术获得了4-芳基-六氢1-4和（R，R）和（S， S）4-芳基-八氢吡啶并[1,2-c]嘧啶-1,3-二酮（16）衍生物，是进一步修饰的起始化合物。随后使用1,4-二溴丁烷将化合物1-4和16中的酰亚胺基团进行N-烷基化反应，生成单溴丁基衍生物5-8和17。随后将这些化合物与合适的1-芳基或1-杂芳基哌嗪缩合，得到最终的六氢-9-15和八氢-18-22吡啶并[1,2-c]嘧啶-1,3-二酮衍生物。对最终产物进行筛选测试，以阐明对5-HT1A和5-HT2A受体的亲和力。
• Synthesis of Novel Pyrido[1,2-c]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT1A Receptor Ligands
  作者：Marek Król、Grzegorz Ślifirski、Jerzy Kleps、Szymon Ulenberg、Mariusz Belka、Tomasz Bączek、Agata Siwek、Katarzyna Stachowicz、Bernadeta Szewczyk、Gabriel Nowak、Beata Duszyńska、Franciszek Herold

  DOI：10.3390/ijms22052329

  日期：——

  radioligand binding assays. The test compounds demonstrated very high binding affinities for the 5-HT1A receptor of all derivatives in the series (6a–i and 7a–i) and generally low binding affinities for the SERT protein, with the exception of compounds 6a and 7g. Extended affinity tests for the receptors D2, 5-HT2A, 5-HT6 and 5-HT7 were conducted with regard to selected compounds (6a, 7g, 6d and 7i). All

  两个系列的新型4-芳基-2H-吡啶[1,2-c]嘧啶（6a–i）和4-芳基-5,6,7,8-四氢吡啶基[1,2-c]嘧啶（7a–i）衍生物被合成。通过1 H和13 C NMR光谱法和ESI-HRMS光谱法确认了新化合物的化学结构。通过体外放射性配体结合测定法确定所有化合物对5-HT 1A受体和5-羟色胺转运蛋白（SERT）的亲和力。除化合物6a外，测试化合物对系列（6a–i和7a–i）中所有衍生物的5-HT 1A受体具有很高的结合亲和力，对SERT蛋白的结合亲和力通常很低。和7克。对于受体亲和性扩展测试ð 2，5-HT 2A，5-HT 6和5-HT 7相对于选择的化合物（进行了图6a，7克，6D和7I）。所有四种化合物均表现出对D 2和5-HT 2A受体的极高亲和力。化合物6a和7g也对5-HT 7具有高亲和力，而化合物6d和7i对该受体具有中等亲和力。化合物6a和7g还在体内进行了测试，以鉴定它们关于5-HT
• Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity: Part 2☆
  作者：Franciszek Herold、Łukasz Izbicki、Andrzej Chodkowski、Maciej Dawidowski、Marek Król、Jerzy Kleps、Jadwiga Turło、Irena Wolska、Gabriel Nowak、Katarzyna Stachowicz

  DOI：10.1016/j.ejmech.2009.07.007

  日期：2009.11

  showed that the presence of the 3-(4-piperidyl)-1H-indole group or its 5-methoxy derivative, as well as a para substitution with –OCH3 or –F in the aryl ring of 4-aryl-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine, results in an increased affinity for both the 5-HT1A receptors and SERT. In contrast, the presence of the 2-methyl-3-(4-piperidyl)-1H-indole group resulted in a considerable decrease in binding

  合成了4-芳基-5,6,7,8-四氢吡啶并[1,2- c ]嘧啶的衍生物。这些化合物含有3-（4-哌啶基）-1H-吲哚残基或其5-甲氧基或2-甲基衍生物。进行了体外结合试验，以确定化合物对大鼠大脑皮层中5-HT 1A受体和血清素转运蛋白（SERT）的亲和力。进行了体内研究，特别是诱导性低温测试和强迫游泳测试，以确定突触前和突触后5-HT 1A受体的激动/拮抗活性。使用分子建模技术确定所选化合物在5-HT 1A的结合模式受体和SERT。特区分析表明，3-（4-哌啶基）的存在-1 ħ -吲哚基或它的5-甲氧基衍生物，以及一对位取代有-OCH 3或-F 4 -芳基的芳基环-5,6,7,8-四氢-吡啶并[1,2- c ]嘧啶对5-HT 1A受体和SERT的亲和力均增加。相反，2-甲基-3-（4-哌啶基）-1 H-吲哚基的存在导致结合亲和力显着降低。
• Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity. part 3
  作者：Franciszek Herold、Andrzej Chodkowski、Łukasz Izbicki、Jadwiga Turło、Maciej Dawidowski、Jerzy Kleps、Gabriel Nowak、Katarzyna Stachowicz、Małgorzata Dybała、Agata Siwek、Aleksander P. Mazurek、Andrzej Mazurek、Franciszek Pluciński

  DOI：10.1016/j.ejmech.2010.10.026

  日期：2011.1

  A number of 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine with 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole or 2-methyl-3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole residues were synthesized for further investigation of SAR in a group of pyrido[1,2-c]pyrimidine derivatives with dual 5-HT1A/SERT activity. Compounds 8a-8p were found to be potent ligands for both 5-HT1A and SERI with K-i ranging from 28,3 to 642 nM and 42,4 nM-1,8 mu M, respectively. Moreover compounds 8a, 8b, 8c, 8d, 8e and 8g were found to be selective agonists, while 81 as an antagonist of 5-HT1A presynaptic receptors in the inducible hypothermia test in mice. (C) 2010 Elsevier Masson SAS. All rights reserved.
• Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity. Part 5
  作者：Anna Gomółka、Agnieszka Ciesielska、Martyna Z. Wróbel、Andrzej Chodkowski、Jerzy Kleps、Maciej Dawidowski、Agata Siwek、Małgorzata Wolak、Katarzyna Stachowicz、Anna Sławińska、Gabriel Nowak、Grzegorz Satała、Andrzej J. Bojarski、Mariusz Belka、Szymon Ulenberg、Tomasz Bączek、Paweł Skowronek、Jadwiga Turło、Franciszek Herold

  DOI：10.1016/j.ejmech.2015.05.003

  日期：2015.6

  A series of novel 4-aryl-pyrido[1,2-c]pyrimidine derivatives containing a 1-(2-quinoline)piperazine moiety was synthesized. The chemical structure of new compounds was confirmed by FT-IR, H-1 NMR,C-13 NMR and HRMS spectra as well as elemental analysis. Affinity of the novel pyrido[1,2-c]pyrimidine derivatives for 5-HT1A, 5-HT2A receptors and serotonin transporter (SERT) was evaluated in an in vitro radioligand binding assay. Tested compounds showed moderate to high affinity for 5-HT1AR and SERT and low affinity for 5-HT2AR. Selected ligands were subjected to in vivo tests, such as induced hypothermia and the forced swimming test in mice, which determined presynaptic agonistic activity of the ligands 8d, 8e, 9d and 9e and presynaptic antagonistic activity of the ligands 8a, 8b, 9a, 9b. Additionally, metabolic stability evaluation was performed for selected ligands, proving that a para-substitution in the 4-aryl-pyrido[1,2-c]pyrimidine moiety leads to an increase in stability, whereas a substitution in the ortho-position lowers the stability. (C) 2015 Elsevier Masson SAS. All rights reserved.