1-(2,4-dichlorophenyl)-5-(4-(trifluoromethyl)phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester | 1170701-04-8

• 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-(2,4-dichlorophenyl)-5-(4-(trifluoromethyl)phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester
• 英文别名: 1-(2,4-dichloro-phenyl)-5-(4-trifluoromethyl-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester；Ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-[4-(trifluoromethyl)phenyl]pyrazole-3-carboxylate
• CAS: 1170701-04-8
• 化学式: C₂₀H₁₅Cl₂F₃N₂O₂
• 分子量: 443.253
• InChiKey: ABYUICGFLCOPFC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.6
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  44.1
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-(2,4-dichlorophenyl)-5-(4-(trifluoromethyl)phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester 在 氯化亚砜 、 potassium hydroxide 作用下， 以 乙醇 、 甲苯 为溶剂， 反应 14.5h， 生成
  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：

  4-三氟甲基苯丙酮 在 硫酸 、 lithium hexamethyldisilazane 作用下， 以 乙醇 、 甲基环己烷 为溶剂， 反应 25.0h， 生成 1-(2,4-dichlorophenyl)-5-(4-(trifluoromethyl)phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester
  参考文献：
  名称：

  Pyrazole Derivatives And Their Use As LPAR5 Antagonists

  摘要：

  本发明涉及式(I)化合物，其中残基R1至R5、V、G和M具有所述权利要求中指示的含义。式(I)化合物是有价值的药理活性化合物，可用于治疗多种疾病，例如心血管疾病，如血栓栓塞疾病或再狭窄。本发明的化合物是血小板LPA受体LPAR5（GPR92）的有效拮抗剂，通常可应用于存在血小板LPA受体LPAR5、肥大细胞LPA受体LPAR5或微胶质细胞LPA受体LPAR5的不良激活情况或治疗或预防需要抑制血小板、肥大细胞或微胶质细胞LPA受体LPAR5的情况。本发明还涉及制备式(I)化合物的方法，它们的用途，特别是作为药物中的活性成分，以及包含它们的制药组合物。

  公开号：

  US20150141477A1

文献信息

• Imidazol-4-one and Imidazole-4-thione Compounds
  申请人：Shia Kak-Shan

  公开号：US20100113546A1

  公开（公告）日：2010-05-06

  Imidazol-4-one or imidazole-4-thione compounds of formula (I): wherein X, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are defined herein. Also disclosed is a method for treating a cannabinoid receptor-mediated disorder with these compounds.

  咪唑-4-酮或咪唑-4-硫酮化合物的化学式（I）：其中X，R1，R2，R3，R4，R5和R6在此定义。还揭示了使用这些化合物治疗大麻素受体介导的疾病的方法。
• Pyrazole Derivatives And Their Use As LPAR5 Antagonists
  申请人：SANOFI

  公开号：US20150141477A1

  公开（公告）日：2015-05-21

  The present invention relates to compounds of the formula (I), wherein the residues R 1 to R 5 , V, G and M have the meanings indicated in the claims. The compounds of the formula (I) are valuable pharmacologically active compounds for use in the treatment of diverse disorders, for example cardiovascular disorders like thromboembolic diseases or restenoses. The compounds of the invention are effective antagonists of the platelet LPA receptor LPAR5 (GPR92) and can in general be applied in conditions in which an undesired activation of the platelet LPA receptor LPAR5, the mast cell LPA receptor LPAR5 or the microglia cell LPA receptor LPAR5 is present or for the cure or prevention of which an inhibition of the platelet, mast cell or microglia cell LPA receptor LPAR5 is intended. The invention furthermore relates to processes for the preparation of compounds of the formula (I), their use, in particular as active ingredients in medicaments, and pharmaceutical compositions comprising them.

  本发明涉及式(I)化合物，其中残基R1至R5、V、G和M具有所述权利要求中指示的含义。式(I)化合物是有价值的药理活性化合物，可用于治疗多种疾病，例如心血管疾病，如血栓栓塞疾病或再狭窄。本发明的化合物是血小板LPA受体LPAR5（GPR92）的有效拮抗剂，通常可应用于存在血小板LPA受体LPAR5、肥大细胞LPA受体LPAR5或微胶质细胞LPA受体LPAR5的不良激活情况或治疗或预防需要抑制血小板、肥大细胞或微胶质细胞LPA受体LPAR5的情况。本发明还涉及制备式(I)化合物的方法，它们的用途，特别是作为药物中的活性成分，以及包含它们的制药组合物。
• 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.
• Discovery of 2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-ethyl-1<i>H</i>-pyrazol-3-yl]-1,5,5-trimethyl-1,5-dihydro-imidazol-4-thione (BPR-890) via an Active Metabolite. A Novel, Potent and Selective Cannabinoid-1 Receptor Inverse Agonist with High Antiobesity Efficacy in DIO Mice
  作者：Chien-Huang Wu、Ming-Shiu Hung、Jen-Shin Song、Teng-Kuang Yeh、Ming-Chen Chou、Cheng-Ming Chu、Jiing-Jyh Jan、Min-Tsang Hsieh、Shi-Liang Tseng、Chun-Ping Chang、Wan-Ping Hsieh、Yinchiu Lin、Yen-Nan Yeh、Wan-Ling Chung、Chun-Wei Kuo、Chin-Yu Lin、Horng-Shing Shy、Yu-Sheng Chao、Kak-Shan Shia

  DOI：10.1021/jm900471u

  日期：2009.7.23

  By using the active metabolite 5 as an initial template, further structural modifications led to the identification of the titled compound 24 (BPR-890) as a highly potent CB I inverse agonist possessing an excellent CB2/1 selectivity and remarkable in vivo efficacy in diet-induced obese mice with a minimum effective dose as low as 0.03 mg/kg (po qd) at the end of the 30-day chronic study. Current SAR studies along with those of many existing rimonabant-mimicking molecules imply that around the pyrazole C3-position, a rigid and deep binding pocket should exist for CB1 receptor. In addition, relative to the conventional carboxamide carbonyl, serving as a key hydrogen-bond acceptor during ligand-CB1 receptor interaction, the corresponding polarizable thione carbonyl might play a more critical role in stabilizing the Asp366-Lys192 salt bridge in the proposed CB1-receptor homology model and inducing significant selectivity for CB1R over CB2R.
• US8354442B2
  申请人：——

  公开号：US8354442B2

  公开（公告）日：2013-01-15