4-(4-methylpiperazin-1-yl)-5,6-dihydrobenzo[h]quinazolin-2-ylamine | 1027331-46-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 4-(4-methylpiperazin-1-yl)-5,6-dihydrobenzo[h]quinazolin-2-ylamine
• 英文别名: 4-(4-methylpiperazin-1-yl)-5,6-dihydrobenzo[h]quinazolin-2-amine；4-(4-methyl-piperazin-1-yl)-5,6-dihydro-benzo[h]quinazolin-2-ylamine；6-(4-Methylpiperazin-1-yl)-3,5-diazatricyclo[8.4.0.0^{2,7}]tetradeca-1(14),2,4,6,10,12-hexaen-4-amine
• CAS: 1027331-46-9
• 化学式: C₁₇H₂₁N₅
• 分子量: 295.387
• InChiKey: CEUMRIVIGREJGB-UHFFFAOYSA-N

物化性质

• 沸点：
  546.2±60.0 °C(Predicted)
• 密度：
  1.240±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  58.3
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  N-甲基哌嗪 、 4-chloro-5,6-dihydrobenzo[h]quinazolin-2-ylamine 在 N,N-二异丙基乙胺 作用下， 以 甲乙醚 为溶剂， 反应 24.0h， 以67%的产率得到4-(4-methylpiperazin-1-yl)-5,6-dihydrobenzo[h]quinazolin-2-ylamine
  参考文献：
  名称：

  Rotationally Constrained 2,4-Diamino-5,6-disubstituted Pyrimidines: A New Class of Histamine H₄ Receptor Antagonists with Improved Druglikeness and in Vivo Efficacy in Pain and Inflammation Models

  摘要：

  A new structural class of histamine H-4 receptor antagonists (6-14) was designed based on rotationally restricted 2,4-diaminopyrimidines. Series compounds showed potent and selective in vitro H-4 antagonism across multiple species, good CNS penetration, improved PK properties compared to reference H-4 antagonists, functional H-4 antagonism in cellular and in vivo pharmacological assays, and in vivo anti-inflammatory and antinociceptive efficacy. One compound, 10 (A-943931), combined the best features of the series in a single molecule and is an excellent tool compound to probe H-4 pharmacology. It is a potent H-4 antagonist in functional assays across species (FLIPR Ca2+ flux, K-b < 5.7 nM), has high (> 190x) selectivity for H-4, and combines good PK in rats and mice (t(1/2) of 2.6 and 1.6 h, oral bioavailability of 37% and 90%) with anti-inflammatory activity (ED50 = 37 mu mol/kg, mouse) and efficacy in pain models (thermal hyperalgesia, ED50 = 72 mu mol/kg, rat).

  DOI：

  10.1021/jm800670r

文献信息

• 2,4-Diaminopyrimidines as dual ligands at the histamine H 1 and H 4 receptor—H 1 /H 4 -receptor selectivity
  作者：Sebastian G. Hammer、Susanne Gobleder、Franziska Naporra、Hans-Joachim Wittmann、Sigurd Elz、Markus R. Heinrich、Andrea Strasser

  DOI：10.1016/j.bmcl.2015.12.035

  日期：2016.1

  Distinct diaminopyrimidines, for example, 4-(4-methylpiperazin-1-yl)-5,6-dihydrobenzo[h]quinazolin-2-amine are histamine H4 receptor (H4R) antagonists and show high affinity to the H4R, but only a moderate affinity to the histamine H1 receptor (H1R). Within previous studies it was shown that an aromatic side chain with a distinct distance to the basic amine and aromatic core is necessary for affinity

  不同的二氨基嘧啶，例如4-（4-甲基哌嗪-1-基）-5,6-二氢苯并[h]喹唑啉-2-胺是组胺H4受体（H4R）拮抗剂，对H4R具有高亲和力，但仅对组胺H1受体（H1R）具有中等亲和力。在以前的研究中，表明与人的H1R（hH1R）亲和力必须与碱性胺和芳族核有明显距离的芳族侧链。因此，具有三环核的刚性氨基嘧啶用作前导结构。在那里，（1）引入了柔性芳族侧链，（2）交换了嘧啶核的取代方式，（3）通过打开三环核降低了刚性。在本研究中，鉴定出了两种与人类H1R和H4R具有相似亲和力的化合物，其亲合力均在一个μM范围内。与亲本二氨基嘧啶相比，hH1R的亲和力提高了约4至8倍，而hH4R的亲和力降低了约5至8倍。除母体二氨基嘧啶外，还将两个选定的化合物对接至H1R和H4R中，并进行了分子动力学研究，以预测结合模式并在分子水平上解释实验结果。这两种新化合物可能是具有相同亲和力的双H1 / H4受体配体开发
• Macrocyclic Benzofused Pyrimidine Derivatives
  申请人：Altenbach Robert J.

  公开号：US20080188452A1

  公开（公告）日：2008-08-07

  Macrocyclic benzofused pyrimidine compounds, compositions comprising such compounds, methods for making the compounds, and methods of treating and preventing the progression of diseases, conditions and disorders using such compounds and compositions are described herein.

  本文描述了大环苯并嘧啶化合物、包含这种化合物的组合物、制备这种化合物的方法，以及使用这种化合物和组合物治疗和预防疾病、病症和障碍的方法。
• US8735411B2
  申请人：——

  公开号：US8735411B2

  公开（公告）日：2014-05-27
• Rotationally Constrained 2,4-Diamino-5,6-disubstituted Pyrimidines: A New Class of Histamine H₄ Receptor Antagonists with Improved Druglikeness and in Vivo Efficacy in Pain and Inflammation Models
  作者：Marlon D. Cowart、Robert J. Altenbach、Huaqing Liu、Gin C. Hsieh、Irene Drizin、Ivan Milicic、Thomas R. Miller、David G. Witte、Neil Wishart、Shannon R. Fix-Stenzel、Michael J. McPherson、Ronald M. Adair、Jill M. Wetter、Brian M. Bettencourt、Kennan C. Marsh、James P. Sullivan、Prisca Honore、Timothy A. Esbenshade、Jorge D. Brioni

  DOI：10.1021/jm800670r

  日期：2008.10.23

  A new structural class of histamine H-4 receptor antagonists (6-14) was designed based on rotationally restricted 2,4-diaminopyrimidines. Series compounds showed potent and selective in vitro H-4 antagonism across multiple species, good CNS penetration, improved PK properties compared to reference H-4 antagonists, functional H-4 antagonism in cellular and in vivo pharmacological assays, and in vivo anti-inflammatory and antinociceptive efficacy. One compound, 10 (A-943931), combined the best features of the series in a single molecule and is an excellent tool compound to probe H-4 pharmacology. It is a potent H-4 antagonist in functional assays across species (FLIPR Ca2+ flux, K-b < 5.7 nM), has high (> 190x) selectivity for H-4, and combines good PK in rats and mice (t(1/2) of 2.6 and 1.6 h, oral bioavailability of 37% and 90%) with anti-inflammatory activity (ED50 = 37 mu mol/kg, mouse) and efficacy in pain models (thermal hyperalgesia, ED50 = 72 mu mol/kg, rat).