5-(4-chlorophenyl)-1-(3,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid | 1016557-93-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 5-(4-chlorophenyl)-1-(3,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid
• 英文别名: 5-(4-Chlorophenyl)-1-(3,4-dichlorophenyl)-4-methylpyrazole-3-carboxylic acid
• CAS: 1016557-93-9
• 化学式: C₁₇H₁₁Cl₃N₂O₂
• 分子量: 381.646
• InChiKey: JRGLJWOKJQWYKE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  55.1
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  5-(4-chlorophenyl)-1-(3,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid 在 氯化亚砜 、 N,N-二异丙基乙胺 作用下， 以 氯仿 、 甲苯 为溶剂， 反应 6.5h， 生成 5-(4-chlorophenyl)-1-(3,4-dichlorophenyl)-4-methyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide
  参考文献：
  名称：

  Synthesis, hypoglycemic activity and molecular modeling studies of pyrazole-3-carbohydrazides designed by a CoMFA model

  摘要：

  Diabetes and obesity are two universal health problems that constitute a research objective of several groups due to the lack of efficient and safe drug treatment. In this sense, cannabinoid receptor 1 (CBI) has attracted interest because of its role in food intake and metabolic balance, two targets in the control of metabolic syndrome. In this work, novel 1,5-diaryl pyrazole derivatives were synthesized in accordance with the pKi prediction of a previously reported CoMFA model by our group. To further investigate the biological activity of these compounds in metabolic disorders, their hypoglycemic activity in an in vivo model was tested. Interestingly, a high degree of correlation was observed between the predicted pK(i) and hypoglycemic effect 7 h after administration. Compounds 4, 9 and 13 showed the most significant plasma glucose reduction with decreases of 60%, 64% and 60% respectively. This result not only surpasses the activity of the lead rimonabant, but also that of the reference drug glibenclamide. Moreover, PASS prediction and molecular docking in an excellent validated homology model of CBI suggest that these compounds would probably act as CBI antagonists/inverse agonists and therefore, antiobesity agents. The ligand receptor complexes demonstrate that 1,5-diaryl pyrazole derivatives bind to the proposed binding site where a hydrophobic moiety interacts with the phenyl rings in the pyrazole nucleus and Lys192 forms a hydrogen bond with the oxygen of the carbonyl group. Dynamics simulations were also carried out to study the stability of the ligand receptor complexes where the most active compounds showed smaller Delta G values and more hydrogen bonds throughout the simulation. These compounds are considered useful leads for further optimization in the treatment of such metabolic illnesses. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.07.054
• 作为产物：
  描述：

  (3,4-二氯苯基)肼 在 potassium hydroxide 、 lithium hexamethyldisilazane 作用下， 以 乙醇 、 甲基环己烷 为溶剂， 反应 39.0h， 生成 5-(4-chlorophenyl)-1-(3,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid
  参考文献：
  名称：

  N'-亚芳基-5-（4-氯苯基）-1-（3,4-二氯苯基）-4-甲基-1H-吡唑-3-碳酰肼的合成和分子对接，作为新型降血糖和抗氧化剂双重试剂。

  摘要：

  在此，描述了10种新颖的N'-亚芳基吡唑-3-碳酰肼的设计和合成。化合物被认为是对抗糖尿病和氧化应激的双重药物，氧化应激是代谢综合征发展和进程的两个相关病理。抗氧化剂能力通过DPPH和FRAP体外测定来评估。发现在at部分的4-位带有羟基的化合物是有效的抗氧化剂实体，是活性最高的化合物3g（丁醛醛衍生物）。另外，确定了类似物的体内降血糖作用。关于上述，肉桂醛衍生物显示出稀缺的生物学活性，而4-羟基类似物在给药后7小时显示出较高的血糖降低。有趣的是，在降低血浆葡萄糖方面，最有效的抗氧化剂3b和3g也是活性最高的化合物，在3g的情况下，可达到减少量的80％。提出了分子对接结合姿势以对生物学结果进行合理解释，并提出羟基与CB1R的Asn287之间可能的相互作用是增强观察到的活性的重要特征。

  DOI：

  10.1016/j.bmc.2016.04.007

文献信息

• 1,5-Diarylpyrazole and vanillin hybrids: Synthesis, biological activity and DFT studies
  作者：Eduardo Hernández-Vázquez、Romina Castañeda-Arriaga、Juan José Ramírez-Espinosa、Omar Noel Medina-Campos、Francisco Hernández-Luis、José Pedraza Chaverri、Samuel Estrada-Soto

  DOI：10.1016/j.ejmech.2015.06.010

  日期：2015.7

  Herein, we report the design and synthesis of 13 diarylpyrazole hybrids with vanillin constructed as dual compounds against oxidative stress and diabetes. Compounds were tested in two different antioxidant assays. It was found that all compounds showed an important antioxidant activity in both DPPH and ORAC models and the activity was even more remarkable than vanillin. In addition, the hypoglycemic effect of compounds 1, 2, 4 and 12 was evaluated. Interestingly, compound 1 had the most potent hypoglycemic effect with a glycemia reduction of 71%, which was higher than rimonabant. Finally, a DFT study to propose a reasonable antioxidant mechanism is detailed. Both thermodynamic and kinetic studies indicated that the most feasible mechanism consists in the HAT abstraction of the phenolic hydrogen due to the formation of an stable transition state through the most rapid and exergonic path, while the SPLET mechanism is the most significant at higher pH values. (C) 2015 Elsevier Masson SAS. All rights reserved.
• [EN] AN IMPROVED PROCESS FOR THE PREPARATION OF RIMONABANT<br/>[FR] PROCÉDÉ AMÉLIORÉ DE PRÉPARATION DU RIMONABANT
  申请人：IND SWIFT LAB LTD

  公开号：WO2008062480A2

  公开（公告）日：2008-05-29

  [EN] The present invention relates to an industrially advantageous, eco-friendly process for the re aration of rimonabant of formula-(I), staring from l-(4-chlorophenyl)-propan-l-one in high yields and high purity by using mild reaction conditions and avoiding use of toxic and expensive reagents, as well as stringent reaction conditions. The present invention relates to an isolated impurity of rimonabant, referred to as "Bis impurity" and removal thereof.1 The present invention also relates to novel crystalline form-Ill of rimonabant and processes for its preparation and conversion to form-I of rimonabant.
  [FR] L'invention porte sur un procédé industriellement avantageux, écologique et à fort rendement, de préparation de rimonabant de formule (I) de grande pureté, à partir de l-(4-chlorophényle)-propane-l-one en utilisant des conditions de réaction douces et en évitant l'utilisation de réactifs toxiques et chers, aussi bien que des conditions de réaction contraignantes. L'invention porte également sur l'isolement et l'élimination d'une impureté du rimonabant, dite "impureté Bis ". L'invention porte en outre sur une nouvelle forme cristalline de formule (III) du rimonabant et sur son procédé de préparation et de conversion pour obtenir le rimonabant de formule (I)
• Synthesis and molecular docking of N′-arylidene-5-(4-chlorophenyl)-1-(3,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbohydrazides as novel hypoglycemic and antioxidant dual agents
  作者：Eduardo Hernández-Vázquez、Sandybel Salgado-Barrera、Juan José Ramírez-Espinosa、Samuel Estrada-Soto、Francisco Hernández-Luis

  DOI：10.1016/j.bmc.2016.04.007

  日期：2016.5

  design and synthesis of 10 novel N'-arylidene pyrazole-3-carbohydrazides are described. Compounds were pretended to act as dual agents against diabetes and oxidative stress, two correlated pathologies involved in metabolic syndrome development and progression. The antioxidant capacity was evaluated by means of DPPH and FRAP in vitro assays. It was found that compounds bearing a hydroxyl group at 4-position

  在此，描述了10种新颖的N'-亚芳基吡唑-3-碳酰肼的设计和合成。化合物被认为是对抗糖尿病和氧化应激的双重药物，氧化应激是代谢综合征发展和进程的两个相关病理。抗氧化剂能力通过DPPH和FRAP体外测定来评估。发现在at部分的4-位带有羟基的化合物是有效的抗氧化剂实体，是活性最高的化合物3g（丁醛醛衍生物）。另外，确定了类似物的体内降血糖作用。关于上述，肉桂醛衍生物显示出稀缺的生物学活性，而4-羟基类似物在给药后7小时显示出较高的血糖降低。有趣的是，在降低血浆葡萄糖方面，最有效的抗氧化剂3b和3g也是活性最高的化合物，在3g的情况下，可达到减少量的80％。提出了分子对接结合姿势以对生物学结果进行合理解释，并提出羟基与CB1R的Asn287之间可能的相互作用是增强观察到的活性的重要特征。
• Synthesis, hypoglycemic activity and molecular modeling studies of pyrazole-3-carbohydrazides designed by a CoMFA model
  作者：Eduardo Hernández-Vázquez、Rodrigo Aguayo-Ortiz、Juan José Ramírez-Espinosa、Samuel Estrada-Soto、Francisco Hernández-Luis

  DOI：10.1016/j.ejmech.2013.07.054

  日期：2013.11

  Diabetes and obesity are two universal health problems that constitute a research objective of several groups due to the lack of efficient and safe drug treatment. In this sense, cannabinoid receptor 1 (CBI) has attracted interest because of its role in food intake and metabolic balance, two targets in the control of metabolic syndrome. In this work, novel 1,5-diaryl pyrazole derivatives were synthesized in accordance with the pKi prediction of a previously reported CoMFA model by our group. To further investigate the biological activity of these compounds in metabolic disorders, their hypoglycemic activity in an in vivo model was tested. Interestingly, a high degree of correlation was observed between the predicted pK(i) and hypoglycemic effect 7 h after administration. Compounds 4, 9 and 13 showed the most significant plasma glucose reduction with decreases of 60%, 64% and 60% respectively. This result not only surpasses the activity of the lead rimonabant, but also that of the reference drug glibenclamide. Moreover, PASS prediction and molecular docking in an excellent validated homology model of CBI suggest that these compounds would probably act as CBI antagonists/inverse agonists and therefore, antiobesity agents. The ligand receptor complexes demonstrate that 1,5-diaryl pyrazole derivatives bind to the proposed binding site where a hydrophobic moiety interacts with the phenyl rings in the pyrazole nucleus and Lys192 forms a hydrogen bond with the oxygen of the carbonyl group. Dynamics simulations were also carried out to study the stability of the ligand receptor complexes where the most active compounds showed smaller Delta G values and more hydrogen bonds throughout the simulation. These compounds are considered useful leads for further optimization in the treatment of such metabolic illnesses. (C) 2013 Elsevier Masson SAS. All rights reserved.