N-(1-naphthyl)methyl-2-chloropyrimidin-4-amine | 1236138-67-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: N-(1-naphthyl)methyl-2-chloropyrimidin-4-amine
• 英文别名: 2-chloro-N-(naphth-1-ylmethyl)pyrimidin-4-amine；N-(naphth-1-ylmethyl)-2-chloropyrimidin-4-amine；2-chloro-N-(naphthalen-1-ylmethyl)pyrimidin-4-amine
• CAS: 1236138-67-2
• 化学式: C₁₅H₁₂ClN₃
• mdl: MFCD17966170
• 分子量: 269.733
• InChiKey: ZDTVPYZWTLZISK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.066
• 拓扑面积：
  37.8
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N-(1-naphthyl)methyl-2-chloropyrimidin-4-amine 在 三氟乙酸 作用下， 以 二氯甲烷 、 正丁醇 为溶剂， 反应 2.08h， 生成 N-(naphth-1-ylmethyl)-2-(piperazin-1-yl)pyrimidin-4-amine
  参考文献：
  名称：

  Development of 2-substituted-N-(naphth-1-ylmethyl) and N-benzhydrylpyrimidin-4-amines as dual cholinesterase and Aβ-aggregation inhibitors: Synthesis and biological evaluation

  摘要：

  A group of 2-substituted N-(naphth-1-ylmethyl)pyrimidin-4-amines (6a-k) and N-benzhydrylpyrimidin4-amines (7a-k) in conjunction with varying steric and electronic properties at the C-2 position were designed, synthesized and evaluated as dual cholinesterase and amyloid-beta (A beta)-aggregation inhibitors. The naphth-1-ylmethyl compound 6f (2-(4-cyclohexylpiperazin-1-yl)-N-(naphth-1-ylmethyl)pyrimidin-4-amine) exhibited optimum dual ChE (AChE IC50 = 8.0 mu M, BuChE IC50 = 3.9 mu M) and hAChE-promoted A beta-aggregation inhibition (30.8% at 100 mu M), whereas in the N-benzhydryl series, compound 7f (N-benzhydryl-2-(4-cyclohexylpiperazin-1-yl)pyrimidin-4-amine) exhibited optimum combination of dual ChE (AChE IC50 = 10.0 mu M, BuChE IC50 = 7.6 mu M) and hAChE-promoted A beta-aggregation inhibition (32% at 100 mu M). These results demonstrate that a 2,4-disubstituted pyrimidine ring serves as a suitable template to target multiple pathological routes in AD, with a C-2 cyclohexylpiperazine substituent providing dual ChE inhibition and potency whereas a C-4 diphenylmethane substituent provides A beta-aggregation inhibition. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.07.091
• 作为产物：
  描述：

  2,4-二氯嘧啶 、 1-萘甲基胺 在 N,N-二异丙基乙胺 作用下， 以 乙醇 为溶剂， 反应 3.08h， 以75%的产率得到N-(1-naphthyl)methyl-2-chloropyrimidin-4-amine
  参考文献：
  名称：

  2,4-二取代嘧啶类胆碱酯酶抑制剂的设计，合成和评价

  摘要：

  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。

  DOI：

  10.1016/j.bmcl.2010.04.108

文献信息

• 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.
• 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。
• Development of 2-substituted-N-(naphth-1-ylmethyl) and N-benzhydrylpyrimidin-4-amines as dual cholinesterase and Aβ-aggregation inhibitors: Synthesis and biological evaluation
  作者：Tarek Mohamed、Jacky C.K. Yeung、Praveen P.N. Rao

  DOI：10.1016/j.bmcl.2011.07.091

  日期：2011.10

  A group of 2-substituted N-(naphth-1-ylmethyl)pyrimidin-4-amines (6a-k) and N-benzhydrylpyrimidin4-amines (7a-k) in conjunction with varying steric and electronic properties at the C-2 position were designed, synthesized and evaluated as dual cholinesterase and amyloid-beta (A beta)-aggregation inhibitors. The naphth-1-ylmethyl compound 6f (2-(4-cyclohexylpiperazin-1-yl)-N-(naphth-1-ylmethyl)pyrimidin-4-amine) exhibited optimum dual ChE (AChE IC50 = 8.0 mu M, BuChE IC50 = 3.9 mu M) and hAChE-promoted A beta-aggregation inhibition (30.8% at 100 mu M), whereas in the N-benzhydryl series, compound 7f (N-benzhydryl-2-(4-cyclohexylpiperazin-1-yl)pyrimidin-4-amine) exhibited optimum combination of dual ChE (AChE IC50 = 10.0 mu M, BuChE IC50 = 7.6 mu M) and hAChE-promoted A beta-aggregation inhibition (32% at 100 mu M). These results demonstrate that a 2,4-disubstituted pyrimidine ring serves as a suitable template to target multiple pathological routes in AD, with a C-2 cyclohexylpiperazine substituent providing dual ChE inhibition and potency whereas a C-4 diphenylmethane substituent provides A beta-aggregation inhibition. (C) 2011 Elsevier Ltd. All rights reserved.