1-(2-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester | 891866-07-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-(2-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester
• 英文别名: ethyl 1-(2-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxylate；Ethyl 1-(2-chlorophenyl)-4-methyl-5-phenylpyrazole-3-carboxylate
• CAS: 891866-07-2
• 化学式: C₁₉H₁₇ClN₂O₂
• 分子量: 340.809
• InChiKey: CNXDHEVFVHPUPM-UHFFFAOYSA-N

物化性质

• 熔点：
  116-118 °C
• 沸点：
  482.1±45.0 °C(Predicted)
• 密度：
  1.21±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  44.1
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-(2-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester 在 草酰氯 、 sodium hydride 、 N,N-二异丙基乙胺 、 N,N-二甲基甲酰胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 1.0h， 生成 1-(2-chlorophenyl)-N-(4-cyanotetrahydro-2H-pyran-4-yl)-N,4-dimethyl-5-phenyl-1H-pyrazole-3-carboxamide
  参考文献：
  名称：

  N-(4-Cyanotetrahydro-2H-pyran-4-yl) and N-(1-Cyanocyclohexyl) Derivatives of 1,5-Diarylpyrazole-3-carboxamides Showing High Affinity for 18 kDa Translocator Protein and/or Cannabinoid Receptors

  摘要：

  In order to develop improved radioligands for imaging brain CB(1) receptors with positron emission tomography (PET) based on rimonabant (5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide, 1), we synthesized compounds 9a-s in which the N-piperidinyl ring was replaced with a 4-(4-cyanotetrahydro-2H-pyranyl) or 1-cyanocyclohexyl ring. Such changes were expected to be almost isosteric with 1, confer greater metabolic resistance, and in the case of the 4-(4-cyanotetrahydro-2H-pyranyl) compounds, substantially reduce lipophilicity. One derivative, 1-(2-bromophenyl)-N-(1-cyanocyclohexyl)-5-(4-methoxyphenyl)-4-methylpyrazole-3-carboxamide (9n), showed high affinity (K(i) = 15.7 nM) and selectivity for binding to CB(1) receptors. The corresponding 4-(4-cyanotetrahydro-2H-pyranyl) derivative (9m) also showed quite high affinity for CB(1) receptors (K(i) = 62 nM) but was found to have even higher affinity (K(i) = 29 nM) for the structurally unrelated 18 kDa translocator protein (TSPO). Some other minor structural changes among 9a-s were also found to switch binding selectivity from CB(1) receptors to TSPO or vice versa. These unexpected findings and their implications for the development of selective ligands or PET radioligands for CB(1) receptors or TSPO are discussed in relation to current pharmacophore models of CB(1) receptor and TSPO binding sites.

  DOI：

  10.1021/jm2000536
• 作为产物：
  描述：

  2-氯苯肼盐酸盐 在 溶剂黄146 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 乙醚 为溶剂， 反应 35.75h， 生成 1-(2-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester
  参考文献：
  名称：

  1,5-二芳基吡唑大麻素1型（CB（1））受体配体的合成和构效关系（SAR），可用于分子成像。

  摘要：

  大麻素1型（CB（1））受体配体衍生自利莫那班（Acomplia）的1,5-二芳基吡唑核心模板，已成为旨在研究结构与活性关系（SAR）的多项研究的重点。这项研究的目的是设计和合成一组基于1,5-二芳基吡唑模板的化合物，同时侧重于发现可能用作体内分子成像探针的CB（1）受体放射性配体的潜力。使用GTPgamma（35）S结合测定法评估了每种合成的配体在体外作为CB（1）和2型大麻素（CB（2））受体拮抗剂的效能。clog P值是使用Pallas 3.0计算的。CB（1）受体的拮抗剂结合亲和力（K（B））范围从11到> 16,000 nM，CB（1）对CB（2）的选择性从0.6到773，堵塞Ps从3.61到6.25。

  DOI：

  10.1016/j.bmc.2006.01.047

文献信息

• Development of Yin-Yang ligand for cannabinoid receptors
  作者：Yanli Qiu、Yitian Zhao、Tao Hu、Meifang Yang、Fei Li、Cuixia Li、Weiliang Gu、Xiaodi Yang、Suwen Zhao、Houchao Tao

  DOI：10.1016/j.bioorg.2023.106377

  日期：2023.4
• <i>N</i>-(4-Cyanotetrahydro-2<i>H</i>-pyran-4-yl) and <i>N</i>-(1-Cyanocyclohexyl) Derivatives of 1,5-Diarylpyrazole-3-carboxamides Showing High Affinity for 18 kDa Translocator Protein and/or Cannabinoid Receptors
  作者：Sean R. Donohue、Robert F. Dannals、Christer Halldin、Victor W. Pike

  DOI：10.1021/jm2000536

  日期：2011.4.28

  In order to develop improved radioligands for imaging brain CB(1) receptors with positron emission tomography (PET) based on rimonabant (5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide, 1), we synthesized compounds 9a-s in which the N-piperidinyl ring was replaced with a 4-(4-cyanotetrahydro-2H-pyranyl) or 1-cyanocyclohexyl ring. Such changes were expected to be almost isosteric with 1, confer greater metabolic resistance, and in the case of the 4-(4-cyanotetrahydro-2H-pyranyl) compounds, substantially reduce lipophilicity. One derivative, 1-(2-bromophenyl)-N-(1-cyanocyclohexyl)-5-(4-methoxyphenyl)-4-methylpyrazole-3-carboxamide (9n), showed high affinity (K(i) = 15.7 nM) and selectivity for binding to CB(1) receptors. The corresponding 4-(4-cyanotetrahydro-2H-pyranyl) derivative (9m) also showed quite high affinity for CB(1) receptors (K(i) = 62 nM) but was found to have even higher affinity (K(i) = 29 nM) for the structurally unrelated 18 kDa translocator protein (TSPO). Some other minor structural changes among 9a-s were also found to switch binding selectivity from CB(1) receptors to TSPO or vice versa. These unexpected findings and their implications for the development of selective ligands or PET radioligands for CB(1) receptors or TSPO are discussed in relation to current pharmacophore models of CB(1) receptor and TSPO binding sites.
• Synthesis and structure–activity relationships (SARs) of 1,5-diarylpyrazole cannabinoid type-1 (CB1) receptor ligands for potential use in molecular imaging
  作者：Sean R. Donohue、Christer Halldin、Victor W. Pike

  DOI：10.1016/j.bmc.2006.01.047

  日期：2006.6

  An interesting new ligand, namely N-(piperidin-1-yl)-1-(2-bromophenyl)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-c arboxamide (9j), emerged from the synthesized set with appealing properties (K(B)=11 nM; CB(1) selectivity>773; clog P=5.85), for labeling with carbon-11 and development as a radioligand for imaging brain CB(1) receptors in vivo with positron emission tomography (PET).

  大麻素1型（CB（1））受体配体衍生自利莫那班（Acomplia）的1,5-二芳基吡唑核心模板，已成为旨在研究结构与活性关系（SAR）的多项研究的重点。这项研究的目的是设计和合成一组基于1,5-二芳基吡唑模板的化合物，同时侧重于发现可能用作体内分子成像探针的CB（1）受体放射性配体的潜力。使用GTPgamma（35）S结合测定法评估了每种合成的配体在体外作为CB（1）和2型大麻素（CB（2））受体拮抗剂的效能。clog P值是使用Pallas 3.0计算的。CB（1）受体的拮抗剂结合亲和力（K（B））范围从11到> 16,000 nM，CB（1）对CB（2）的选择性从0.6到773，堵塞Ps从3.61到6.25。