LE 404 | 882673-48-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - Dibenzazecins
• 英文名称: LE 404
• 英文别名: 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecine-3-ol；7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-ol；LE404；11-methyl-11-azatricyclo[12.4.0.03,8]octadeca-1(18),3(8),4,6,14,16-hexaen-6-ol
• CAS: 882673-48-5
• 化学式: C₁₈H₂₁NO
• 分子量: 267.371
• InChiKey: ODBZJKXOIQSFOA-UHFFFAOYSA-N

物化性质

• 沸点：
  433.0±45.0 °C(Predicted)
• 密度：
  1.084±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  20
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  23.5
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  LE 404 在 盐酸 、 4-二甲氨基吡啶 、 magnesium sulfate 、 N,N'-二环己基碳二亚胺 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 26.0h， 生成 3-((2-ammonio-3-methylbutanoyl)oxy)-7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-7-ium chloride
  参考文献：
  名称：

  Optimized synthesis of new LE404-derived azecine-prodrugs

  摘要：

  Dibenzoazecines represent a class of high-affinity dopamine and serotonin receptor antagonists. The former synthesis of the lead structure 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-ol (LE404) has been 5 steps with a total yield of 13%. The present work enabled the synthesis of LE404 with a much higher yield. Based on this research, further azecin derivatives were synthesized with the aim to improve pharmacokinetic parameters. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetlet.2017.08.007
• 作为产物：
  描述：

  3-methoxy-7-methyl-5,6,8,9-tetrahydro-13bH-dibenzo[a,h]quinolizinium iodide 在 氨 、 氢溴酸 、 sodium 作用下， 以 乙醇 为溶剂， 反应 4.0h， 生成 LE 404
  参考文献：
  名称：

  Dopamine/Serotonin Receptor Ligands. 10: SAR Studies on Azecine-type Dopamine Receptor Ligands by Functional Screening at Human Cloned D₁, D_2L, and D₅ Receptors with a Microplate Reader Based Calcium Assay Lead to a Novel Potent D₁/D₅ Selective Antagonist

  摘要：

  On the basis of the benz[d]indolo[2,3-g]azecine derivative I (LE300), structure-activity relations were investigated in order to identify the pharmacophore in this new class of ligands. Various structural modifications were performed and the inhibitory activities at human cloned D-1, D-2L, and D-5 receptors were measured by using a simple fluorescence microplate reader based calcium assay. Subsequently, the affinities of active compounds were estimated by radioligand binding experiments. Deleting one of the aromatic rings as well as replacing it by a phenyl moiety abolishes the inhibitory activities almost completely. Contraction of the 10-membered central ring decreases them significantly. The replacement of indole by thiophene or N-methylpyrrole reduces the inhibitory activity, whereas replacing the indole by benzene increases it. Finally, the hydroxylated dibenz[d,g]azecine derivative 11d (LE404) was found to be more active than the lead I in the functional calcium assay as well as in radioligand displacement experiments.

  DOI：

  10.1021/jm050846j

文献信息

• A Novel Non-phenolic Dibenzazecine Derivative with Nanomolar Affinities for Dopamine Receptors
  作者：Dina Robaa、Shams ElDin AbulAzm、Jochen Lehmann、Christoph Enzensperger

  DOI：10.1002/cbdv.201000317

  日期：2011.3

  phenolic group. A novel dibenzazecine derivative was prepared, with methylenedioxy moiety, connecting C(2) amd C(3), instead of the 3-OH group. The newly synthesized derivative 3 showed high affinities similar to the lead LE404, displaying nanomolar affinities for all dopamine receptor subtypes. Its dibrominated derivative 4, though exhibiting almost a fivefold decrease in affinities, still displayed

  Dibenzazecines是一类新的多巴胺受体拮抗剂，其特征是其高亲和力以及对D（1）选择性的倾向。迄今为止，最活跃的二苯甲ze嗪本质上是酚类的。发现3-OH取代基产生最高的亲和力。然而，由于酚基团赋予的不良的药代动力学特性，这些化合物的酚性质主要使其不适用于体内应用。制备了一种新的二苯并was庚因衍生物，其具有亚甲基二氧基部分，而不是3-OH基连接C（2）和C（3）。新合成的衍生物3显示出与LE404相似的高亲和力，对所有多巴胺受体亚型均表现出纳摩尔亲和力。它的二溴代衍生物4虽然亲和力下降了将近五倍，除D（4）外，所有多巴胺受体仍显示纳摩尔浓度。在功能性Ca（2+）分析中，发现化合物3和4都具有对多巴胺受体的拮抗特性。
• Synthesis and Characterization of new Azecine-Derivatives as Potential Neuroleptics
  作者：Stephanie Zergiebel、Christian Fleck、Hans-Dieter Arndt、Christoph Enzensperger、Andreas Seeling

  DOI：10.1055/s-0043-108651

  日期：2017.8

  Dibenzo- and benzindolo-azecines represent a class of potential neuroleptics. To characterize the effectiveness at the dopamine and 5-HT2A-receptor representative structures were synthesized and tested by radio ligand binding studies, in vivo and in vitro studies.

  Neuroleptic potency and the risk of side effects of the prodrug 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-yl isobutyrate, an ester derivative of the most promising azecine 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-ol (LE404), was tested in vivo concerning conditioned avoidance response inhibition, locomotor activity and triggering of catalepsy vs. haloperidol as a reference. Also ester hydrolysis was examined using porcine liver esterase to thereby obtain an indication of the stability of the prodrug in vivo. An HPLC method was developed for purity control and determination of octanol/water-distribution coefficients.

  It has been shown that the tested substances in their efficacy are comparable to haloperidol and risperidone, but the therapeutic index in most cases is larger. Esterification as a prodrug principle leads to significantly prolonged effectiveness.

  二苯并[b]氮杂环和苯并[b]氮杂环是一类潜在的神经类药物。为了表征它们在多巴胺和5-HT2A受体上的效力，代表性结构被合成并通过放射性配体结合研究，体内和体外研究进行了测试。

  通过对比参考药物氟哌啶，采用体内条件性避免反应抑制、运动活动和触发白鼠强直的方法，测试了前药7-甲基-5,6,7,8,9,14-六氢二苯并[d,g]氮杂环-3-酸异丁酯的神经类药效和副作用风险。同时，使用猪肝酯酶检测酯水解，从而获得前药在体内的稳定性指示。还开发了高效液相色谱法进行纯度控制和辛醇/水分配系数的测定。

  研究表明，测试的物质在其功效上与氟哌啶和利培酮相当，但在大多数情况下，治疗指数更大。酯化作为一种前药原理，可以显著延长其有效性。

• Dopamine/Serotonin Receptor Ligands. 12:  SAR Studies on Hexahydro-dibenz[<i>d</i>,<i>g</i>]azecines Lead to 4-Chloro-7-methyl-5,6,7,8,9,14-hexahydrodibenz[<i>d,g</i>]azecin-3-ol, the First Picomolar D₅-Selective Dopamine-Receptor Antagonist
  作者：Patrick Mohr、Michael Decker、Christoph Enzensperger、Jochen Lehmann

  DOI：10.1021/jm051237e

  日期：2006.3.1

  Hydroxylated, methoxylated, and/or chlorinated 7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecines were generally synthesized out of substituted 2-phenylethylamines and isochromanones by Bischler-Napieralski cyclization of the resulting benzamides to dibenzoquinolizines and the quaternization and cleavage of the central C-N bond under Birch conditions. Chlorination of 2-phenylethylamines was useful for the site direction of cyclization, but chlorine atoms were removed under Birch conditions so that chlorination had to be repeated to get the respective chlorinated dibenz[dg]azecines. The target compounds were tested for their affinity at the different human-cloned dopamine-receptor subtypes (D-1 family, D-2 family). Generally, hydroxylation and chlorination of the dibenz-azecines increased affinities significantly. 1-Chloro-2-hydroxyhexahydro-dibenz[d,g]azecine was a subnanomolar antagonist at both subtype families. 4-Chloro-3-hydroxy7-methyl-5,6,7,8,9,14-hexahydro-dibenz[d,g]azecine was identified as the most potent and selective dopamine D-5 receptor ligand described to date with K-i(D-1) = 0.83, K-i(D-2L) = 4.0, K-i(D-3) = 24.6, K-i(D-4) = 5.2 nM, and K-i(D-5) = 57 pM (radioligand binding experiments), respectively.
• Dopamine/Serotonin Receptor Ligands. 10: SAR Studies on Azecine-type Dopamine Receptor Ligands by Functional Screening at Human Cloned D₁, D_2L, and D₅ Receptors with a Microplate Reader Based Calcium Assay Lead to a Novel Potent D₁/D₅ Selective Antagonist
  作者：Barbara Hoefgen、Michael Decker、Patrick Mohr、Astrid M. Schramm、Sherif A. F. Rostom、Hussein El-Subbagh、Peter M. Schweikert、Dirk R. Rudolf、Matthias U. Kassack、Jochen Lehmann

  DOI：10.1021/jm050846j

  日期：2006.1.1

  On the basis of the benz[d]indolo[2,3-g]azecine derivative I (LE300), structure-activity relations were investigated in order to identify the pharmacophore in this new class of ligands. Various structural modifications were performed and the inhibitory activities at human cloned D-1, D-2L, and D-5 receptors were measured by using a simple fluorescence microplate reader based calcium assay. Subsequently, the affinities of active compounds were estimated by radioligand binding experiments. Deleting one of the aromatic rings as well as replacing it by a phenyl moiety abolishes the inhibitory activities almost completely. Contraction of the 10-membered central ring decreases them significantly. The replacement of indole by thiophene or N-methylpyrrole reduces the inhibitory activity, whereas replacing the indole by benzene increases it. Finally, the hydroxylated dibenz[d,g]azecine derivative 11d (LE404) was found to be more active than the lead I in the functional calcium assay as well as in radioligand displacement experiments.
• Optimized synthesis of new LE404-derived azecine-prodrugs
  作者：Stephanie Zergiebel、Hans-Dieter Arndt、Andreas Seeling

  DOI：10.1016/j.tetlet.2017.08.007

  日期：2017.9

  Dibenzoazecines represent a class of high-affinity dopamine and serotonin receptor antagonists. The former synthesis of the lead structure 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-ol (LE404) has been 5 steps with a total yield of 13%. The present work enabled the synthesis of LE404 with a much higher yield. Based on this research, further azecin derivatives were synthesized with the aim to improve pharmacokinetic parameters. (C) 2017 Elsevier Ltd. All rights reserved.