1-(2,4-二氯苯基)-5-(2,5-二甲基-1H-吡咯-1-基)-4-甲基-1H-吡唑-3-羧酸 | 1015765-71-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 中文名称: 1-(2,4-二氯苯基)-5-(2,5-二甲基-1H-吡咯-1-基)-4-甲基-1H-吡唑-3-羧酸
• 英文名称: 1-(2,4-dichlorophenyl)-5-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methyl-1H-pyrazole-3-carboxylic acid
• 英文别名: 1-(2,4-Dichlorophenyl)-5-(2,5-dimethylpyrrol-1-yl)-4-methylpyrazole-3-carboxylic acid
• CAS: 1015765-71-5
• 化学式: C₁₇H₁₅Cl₂N₃O₂
• 分子量: 364.231
• InChiKey: FWUUYEJKYFMNDH-UHFFFAOYSA-N

物化性质

• 熔点：
  205-208 °C(Solvent: Ethanol)
• 沸点：
  558.8±50.0 °C(predicted)
• 密度：
  1.41±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  60
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-(2,4-二氯苯基)-5-(2,5-二甲基-1H-吡咯-1-基)-4-甲基-1H-吡唑-3-羧酸 、 1-氨基戊烷 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 25.0h， 以71%的产率得到1-(2,4-dichlorophenyl)-5-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methyl-N-pentyl-1H-pyrazole-3-carboxamide
  参考文献：
  名称：

  Synthesis and biological evaluation of new N-alkyl 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides as cannabinoid receptor ligands

  摘要：

  A series of N-alkyl 1-ary1-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized as new ligands of the human recombinant receptor hCB(1). n-Alkyl carboxamides brought out different SARs from the branched subgroup. Unsubstituted pyrrole derivatives bearing a tert-alkyl chain at the 3-carboxamide nitrogen showed greater hCB1 receptor affinity than the corresponding unbranched compounds. In particular, the tert-butyl group as a chain terminal moiety strongly improved hCB(1) receptor affinity (compound 24: K-i; = 45.6 nM; 29: K-i = 37.5 nM). Acute administration of either compound 12 or 29 resulted in a specific, dose-dependent reduction in food intake in rats. Such results provide an useful basis for the design of new CB1 ligands. (C) 2010 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2010.09.053
• 作为产物：
  描述：

  ethyl 1-(2,4-dichlorophenyl)-5-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methyl-1H-pyrazole-3-carboxylate 在 lithium hydroxide 作用下， 以 四氢呋喃 、 水 为溶剂， 以90%的产率得到1-(2,4-二氯苯基)-5-(2,5-二甲基-1H-吡咯-1-基)-4-甲基-1H-吡唑-3-羧酸
  参考文献：
  名称：

  Synthesis, Cannabinoid Receptor Affinity, and Molecular Modeling Studies of Substituted 1-Aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides

  摘要：

  The new 1-phenyl-5-(1H-pyrrol-1-yl)pyrazole-3-carboxamides were compared with the reference compounds AM251 and SR144528 for cannabinoid hCB(1) and hCB(2) receptor affinity. Compounds bearing 2,4-dichlorophenyl or 2,4-difluorophenyl groups at position 1 and 2,5-dimethylpyrrole moiety at position 5 of the pyrazole nucleus were generally more selective for hCB(1). On the other hand, the N-cyclohexyl group at the 3-carboxamide was the determinant for the hCB2 selectivity, in particular when a 3,4-dichlorophenyl group was also present at position 1. Compound 26 was the most selective ligand for the hCB(1) receptor (K-i (CB2)/K-i (CB1) = 140.7). Derivative 30, the most potent hCB(1) ligand (Ki = 5.6 nM), was equipotent to AM251 and behaved as an inverse agonist in the cAMP assay (EC50 similar to 1 nM). The carbonyl oxygen of both 26 and 30 formed a H-bond with K3.28(192), while the substituents at the nitrogen fitted in a pocket formed by lipophilic residues. This H-bonding interaction was proposed to account for the high affinity for receptors' inactive state and the inverse agonist activity.

  DOI：

  10.1021/jm070566z

文献信息

• Synthesis, cannabinoid receptor affinity, molecular modeling studies and in vivo pharmacological evaluation of new substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides. 2. Effect of the 3-carboxamide substituent on the affinity and selectivity profile
  作者：Romano Silvestri、Alessia Ligresti、Giuseppe La Regina、Francesco Piscitelli、Valerio Gatti、Antonella Brizzi、Serena Pasquini、Antonio Lavecchia、Marco Allarà、Noemi Fantini、Mauro Antonio Maria Carai、Ettore Novellino、Giancarlo Colombo、Vincenzo Di Marzo、Federico Corelli

  DOI：10.1016/j.bmc.2009.06.027

  日期：2009.8

  New substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized by replacing the 2,4-dichlorobenzyl and cyclohexyl moieties at the 3-carboxamide nitrogen of the previously reported CB1 receptor antagonists/inverse agonists 4 and 5. Several ligands showed potent affinity for the hCB1 receptor, with Ki concentrations comparable to the reference compounds 1, 4 and 5, and exhibited

  通过取代先前报道的3-羧酰胺氮上的2,4-二氯苄基和环己基部分，合成了新的取代的1-芳基-5-（1 H-吡咯-1-基）-1 H-吡唑-3-羧酰胺CB 1受体拮抗剂/反向激动剂4和5。几个配体显示了强的亲合性为HCB 1受体，具有ķ我浓度下媲美的参考化合物1，4和5，并显示出CB 1选择性比得上1和2。对接实验和分子动力学（MD）模拟解释了化合物31和37与hCB 1的强结合亲和力。根据我们以前的研究，31和37与K3.28（192）形成H键，这说明对受体无活性状态和反向激动剂活性具有高亲和力。在对大鼠急性给药后发现食物摄入受到抑制，这支持了CB 1选择性化合物4和52充当拮抗剂/反向激动剂的概念。
• Synthesis, Cannabinoid Receptor Affinity, and Molecular Modeling Studies of Substituted 1-Aryl-5-(1<i>H</i>-pyrrol-1-yl)-1<i>H</i>-pyrazole-3-carboxamides
  作者：Romano Silvestri、Maria Grazia Cascio、Giuseppe La Regina、Francesco Piscitelli、Antonio Lavecchia、Antonella Brizzi、Serena Pasquini、Maurizio Botta、Ettore Novellino、Vincenzo Di Marzo、Federico Corelli

  DOI：10.1021/jm070566z

  日期：2008.3.1

  The new 1-phenyl-5-(1H-pyrrol-1-yl)pyrazole-3-carboxamides were compared with the reference compounds AM251 and SR144528 for cannabinoid hCB(1) and hCB(2) receptor affinity. Compounds bearing 2,4-dichlorophenyl or 2,4-difluorophenyl groups at position 1 and 2,5-dimethylpyrrole moiety at position 5 of the pyrazole nucleus were generally more selective for hCB(1). On the other hand, the N-cyclohexyl group at the 3-carboxamide was the determinant for the hCB2 selectivity, in particular when a 3,4-dichlorophenyl group was also present at position 1. Compound 26 was the most selective ligand for the hCB(1) receptor (K-i (CB2)/K-i (CB1) = 140.7). Derivative 30, the most potent hCB(1) ligand (Ki = 5.6 nM), was equipotent to AM251 and behaved as an inverse agonist in the cAMP assay (EC50 similar to 1 nM). The carbonyl oxygen of both 26 and 30 formed a H-bond with K3.28(192), while the substituents at the nitrogen fitted in a pocket formed by lipophilic residues. This H-bonding interaction was proposed to account for the high affinity for receptors' inactive state and the inverse agonist activity.
• Synthesis and biological evaluation of new N-alkyl 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides as cannabinoid receptor ligands
  作者：Romano Silvestri、Alessia Ligresti、Giuseppe La Regina、Francesco Piscitelli、Valerio Gatti、Antonio Lavecchia、Antonella Brizzi、Serena Pasquini、Marco Allarà、Noemi Fantini、Mauro Antonio Maria Carai、Chiara Bigogno、Marco Giulio Rozio、Roberta Sinisi、Ettore Novellino、Giancarlo Colombo、Vincenzo Di Marzo、Giulio Dondio、Federico Corelli

  DOI：10.1016/j.ejmech.2010.09.053

  日期：2010.12

  A series of N-alkyl 1-ary1-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized as new ligands of the human recombinant receptor hCB(1). n-Alkyl carboxamides brought out different SARs from the branched subgroup. Unsubstituted pyrrole derivatives bearing a tert-alkyl chain at the 3-carboxamide nitrogen showed greater hCB1 receptor affinity than the corresponding unbranched compounds. In particular, the tert-butyl group as a chain terminal moiety strongly improved hCB(1) receptor affinity (compound 24: K-i; = 45.6 nM; 29: K-i = 37.5 nM). Acute administration of either compound 12 or 29 resulted in a specific, dose-dependent reduction in food intake in rats. Such results provide an useful basis for the design of new CB1 ligands. (C) 2010 Elsevier Masson SAS. All rights reserved.