N-benzyl-2-(4-methylpiperazin-1-yl)pyrimidin-4-amine | 1236138-75-2

• 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: N-benzyl-2-(4-methylpiperazin-1-yl)pyrimidin-4-amine
• 英文别名: N-benzyl-2-(4'-N-methylpiperazin-1-yl)pyrimidin-4-amine
• CAS: 1236138-75-2
• 化学式: C₁₆H₂₁N₅
• 分子量: 283.376
• InChiKey: RIUXJXNHHCERLO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  44.3
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  苄胺 在 N,N-二异丙基乙胺 作用下， 以 乙醇 、 甲苯 为溶剂， 生成 N-benzyl-2-(4-methylpiperazin-1-yl)pyrimidin-4-amine
  参考文献：
  名称：

  新型嘧啶类胰高血糖素样肽-1受体激动剂的合成及体外生物学评价

  摘要：

  肽胰高血糖素样肽-1（GLP-1）受体激动剂在治疗2型糖尿病方面的治疗成功激发了旨在开发口服可用小分子GLP-1受体激动剂的发现努力。在这项研究中，使用有效途径设计和合成了两个新的嘧啶衍生物系列，并根据GLP-1受体激动剂活性对其进行了评估。在第一个系列中，新颖的嘧啶在2和4位被大小和电子性质变化的基团取代，合成产率高（78-90％）。在第二个系列中，设计的嘧啶模板同时包含尿素和席夫碱连接基，这些化合物均以77-84％的产率成功制备。培养细胞的体外实验表明，这些化合物3a和10a（10 -15 –10 -9  M）与不存在和存在2.8 mM葡萄糖的对照细胞相比，胰岛素分泌显着增加；化合物8b仅在不存在葡萄糖的情况下显示出重要意义。这些发现代表了设计和发现可以口服的小分子GLP-1受体激动剂的宝贵起点。

  DOI：

  10.1016/j.bmcl.2017.09.032

文献信息

• Design, synthesis and evaluation of 2,4-disubstituted pyrimidines as cholinesterase inhibitors
  作者：Tarek Mohamed、Praveen P.N. Rao

  DOI：10.1016/j.bmcl.2010.04.108

  日期：2010.6

  A group of 2,4-disubstituted pyrimidine derivatives (7a–e, 8a–e and 9a–d) that possess a variety of C-2 aliphatic five- and six-membered heterocycloalkyl ring in conjunction with a C-4 arylalkylamino substituent were designed, synthesized and evaluated as cholinesterase (ChE) inhibitors. The steric and electronic properties at C-2 and C-4 positions of the pyrimidine ring were varied to investigate

  一组具有各种C-2脂族五元和六元杂环烷基环以及一个C-4芳基烷基氨基取代基的2,4-二取代嘧啶衍生物（7a – e，8a – e和9a – d）是设计，合成并评估为胆碱酯酶（ChE）抑制剂。改变嘧啶环的C-2和C-4位的空间和电子性质，以研究其对ChE抑制能力和选择性的影响。结构-活性关系（SAR）研究确定N-苄基-2-硫代吗啉吡喃并咪唑-4-胺（7c）是最有效的胆碱酯酶抑制剂（ChEI），具有IC50  = 0.33μM（乙酰胆碱酯酶，AChE）和2.30μM（丁酰胆碱酯酶，BuChE）。分子模型研究表明，在AChE活性位点内，C-2巯基吗啉取代基朝向阳离子活性位点区域（Trp84和Phe330）取向，而在BuChE活性位点内，其C2取向朝向更靠近活性位点的疏水区域峡谷入口（Ala277）。因此，在嘧啶环的C-2位的空间和电子性质在ChE抑制中起关键作用。
• One-pot synthesis and antiproliferative activity of novel 2,4-diaminopyrimidine derivatives bearing piperidine and piperazine moieties
  作者：Wei-Feng Ma、Hai-Kui Yang、Meng-Jin Hu、Qian Li、Tian-Zhu Ma、Zhong-Zhen Zhou、Rui-Yuan Liu、Wen-Wei You、Pei-Liang Zhao

  DOI：10.1016/j.ejmech.2014.07.017

  日期：2014.9

  A series of novel 2,4-diaminopyrimidines containing piperidine and piperazine moieties were synthesized via an efficient one-pot methodology. The bioassay tests demonstrated that compounds 27 and 28 displayed much stronger antitumor activities against four human cancer cell lines (HepG2, A549, MDA-MB-231 and MCF-7) than positive control fluorouracil. Particularly, compound 28 showed a two-fold improvement compared to fluorouracil in inhibiting MDA-MB-231 and A549 cell proliferation with IC50 values of 7.46 and 12.78 μM, respectively. Further flow-activated cell sorting analysis revealed that the most promising compound 28 displayed a significant effect on G2/M cell-cycle arrest in a dose-dependent manner in MDA-MB-231 cells.
• Design, synthesis and structure–activity relationship (SAR) studies of 2,4-disubstituted pyrimidine derivatives: Dual activity as cholinesterase and Aβ-aggregation inhibitors
  作者：Tarek Mohamed、Xiaobei Zhao、Lila K. Habib、Jerry Yang、Praveen P.N. Rao

  DOI：10.1016/j.bmc.2011.02.030

  日期：2011.4

  A novel class of 2,4-disubstituted pyrimidines (7a-u, 8a-f, 9a-e) that possess substituents with varying steric and electronic properties at the C-2 and C-4 positions, were designed, synthesized and evaluated as dual cholinesterase and amyloid-beta (A beta)-aggregation inhibitors. In vitro screening identified N-(naphth-1-ylmethyl)-2-(pyrrolidin-1-yl)pyrimidin-4-amine (9a) as the most potent AChE inhibitor (IC50 = 5.5 mu M). Among this class of compounds, 2-(4-methylpiperidin-1-yl)-N-(naphth-1-ylmethyl) pyrimidin-4-amine (9e) was identified as the most potent and selective BuChE inhibitor (IC50 = 2.2 mu M, selectivity index = 11.7) and was about 5.7-fold more potent compared to the commercial, approved reference drug galanthamine (BuChE IC50 = 12.6 mu M). In addition, the selective AChE inhibitor N-benzyl-2-(4-methylpiperazin-1-yl)pyrimidin-4-amine (7d), exhibited good inhibition of hAChE-induced aggregation of A beta(1-40) fibrils (59% inhibition). Furthermore, molecular modeling studies indicate that a central pyrimidine ring serves as a suitable template to develop dual inhibitors of cholinesterase and AChE-induced A beta aggregation thereby targeting multiple pathological routes in AD. (C) 2011 Elsevier Ltd. All rights reserved.