5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-4-yl)-1H-pyrazole-3-carboxamide | 1365037-86-0

• 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-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-4-yl)-1H-pyrazole-3-carboxamide
• 英文别名: 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-piperidin-4-ylpyrazole-3-carboxamide
• CAS: 1365037-86-0
• 化学式: C₂₂H₂₁Cl₃N₄O
• 分子量: 463.794
• InChiKey: HMFNDBOCIYTQSQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  59
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-4-yl)-1H-pyrazole-3-carboxamide 在 sulfonamide 作用下， 以 1,4-二氧六环 为溶剂， 反应 16.0h， 以67%的产率得到5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(1-sulfamoylpiperidin-4-yl)-1H-pyrazole-3-carboxamide
  参考文献：
  名称：

  Design and Synthesis of Cannabinoid Receptor 1 Antagonists for Peripheral Selectivity

  摘要：

  Antagonists of cannabinoid receptor 1 (CB1) have potential for the treatment of several diseases such as obesity, liver disease, and diabetes. Recently, development of several CB1 antagonists was halted because of adverse central nervous system (CNS) related side effects observed with rimonabant, the first clinically approved CB1 inverse agonist. However, recent studies indicate that regulation of peripherally expressed CB1 with CNS-sparing compounds is a viable strategy to treat several important disorders. Our efforts aimed at rationally designing peripherally restricted CB1 antagonists have resulted in compounds that have limited blood-brain barrier (BBB) permeability and CNS exposure in preclinical in vitro and in vivo models. Typically, compounds with high topological polar surface areas (TPSAs) do not cross the BBB passively. Compounds with TPSAs higher than that for rimonabant (rimonabant TPSA = 50) and excellent functional activity with limited CNS penetration were identified. These compounds will serve as templates for further optimization.

  DOI：

  10.1021/jm201731z
• 作为产物：
  描述：

  1-(2,4-二氯苯基)-5-对氯苯基-4-甲基-吡唑-3-甲酸 在 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 32.0h， 生成 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-4-yl)-1H-pyrazole-3-carboxamide
  参考文献：
  名称：

  [EN] PYRAZOLE DERIVATIVES AS CANNABINOID RECEPTOR 1 ANTAGONISTS
  [FR] DÉRIVÉS DE PYRAZOLE UTILISÉS EN TANT QU'ANTAGONISTES DU RÉCEPTEUR DE TYPE 1 DES CANNABINOÏDES

  摘要：

  该发明提供了一种能够作为大麻素受体拮抗剂的化合物，其化学式如下：这些化合物可用于治疗与大麻素受体系统有关的疾病，如肥胖、肝病、糖尿病、疼痛和炎症。

  公开号：

  WO2012174362A1

文献信息

• Pyrazole antagonists of the CB1 receptor with reduced brain penetration
  作者：Alan Fulp、Yanan Zhang、Katherine Bortoff、Herbert Seltzman、Rodney Snyder、Robert Wiethe、George Amato、Rangan Maitra

  DOI：10.1016/j.bmc.2016.01.033

  日期：2016.3

  peripherally selective CB1 antagonists to circumvent CNS-associated adverse effects. In this study, novel analogs of rimonabant (1) were explored in which the 1-aminopiperidine group was switched to a 4-aminopiperidine, attached at the 4-amino position (5). The piperidine nitrogen was functionalized with carbamates, amides, and sulfonamides, providing compounds that are potent inverse agonists of hCB1

  1型大麻素受体（CB1）拮抗剂可能对治疗肥胖，肝脏疾病，代谢综合征和血脂异常有用。不幸的是，在中枢神经系统（CNS）中抑制CB1会产生不利影响，包括对某些患者的抑郁，焦虑和自杀意念，从而导致吡唑反向激动剂利莫那班（SR141716A）从欧洲市场撤出。正在努力生产外周选择性的CB1拮抗剂来规避CNS相关的不良反应。在这项研究中，探索了利莫那班（1）的新类似物，其中将1-氨基哌啶基团切换为附着在4-氨基位置的4-氨基哌啶（5）。哌啶氮被氨基甲酸酯，酰胺和磺酰胺官能化，提供了与hCB1相比对hCB1具有良好选择性的hCB1高效反向激动剂化合物。使用脑渗透，口服吸收和代谢稳定性的体外模型进一步研究了选择的化合物。鉴定出几种化合物，这些化合物可预测出最低的脑渗透和良好的代谢稳定性。体内药代动力学测试表明，与利莫那班相比，反向激动剂8c具有口服生物利用度，并且大大降低了脑部渗透性。
• PYRAZOLE DERIVATIVES AS CANNABINOID RECEPTOR 1 ANTAGONISTS
  申请人：Fulp Alan Bradley

  公开号：US20140107157A1

  公开（公告）日：2014-04-17

  The invention provides compounds capable of acting as antagonists at cannabanoid receptors according to the following formula: Such compounds may be used to treat conditions for which the cannabinoid receptor system has been implicated, such as obesity, liver disease, diabetes, pain, and inflammation.

  本发明提供了一种能够作为大麻素受体拮抗剂的化合物，其化学式如下：这些化合物可用于治疗与大麻素受体系统有关的疾病，如肥胖症、肝脏疾病、糖尿病、疼痛和炎症等。
• Pyrazole derivatives as cannabinoid receptor 1 antagonists
  申请人：Fulp Alan Bradley

  公开号：US09133128B2

  公开（公告）日：2015-09-15

  The invention provides compounds capable of acting as antagonists at cannabanoid receptors according to the following formula: Such compounds may be used to treat conditions for which the cannabinoid receptor system has been implicated, such as obesity, liver disease, diabetes, pain, and inflammation.

  该发明提供了一些化合物，其能够作为大麻素受体的拮抗剂，化合物的化学式如下：这些化合物可以用于治疗与大麻素受体系统有关的疾病，例如肥胖症、肝病、糖尿病、疼痛和炎症。
• Bivalent Ligands That Target μ Opioid (MOP) and Cannabinoid1 (CB₁) Receptors Are Potent Analgesics Devoid of Tolerance
  作者：Morgan Le Naour、Eyup Akgün、Ajay Yekkirala、Mary M. Lunzer、Mike D. Powers、Alexander E. Kalyuzhny、Philip S. Portoghese

  DOI：10.1021/jm4005219

  日期：2013.7.11

  Given that mu opioid (MOP) and canabinoid (CB1) receptors are colocalized in various regions of the central nervous system and have been reported to associate as heteromer (MOP-CB1) in cultured cells, the possibility of functional, endogenous MOP CB1 in nociception and other pharmacologic effects has been raised. As a first step in investigating this possibility, we have synthesized a series of bivalent ligands 1-5 that contain both mu agonist and CB1 antagonist pharmacophores for use as tools to study the functional interaction between MOP and CB1 receptors in vivo. Immunofluorescent studies on HEK293 cells coexpressing both receptors suggested 5 (20-atom spacer) to be the only member of the series that bridges the protomers of the heteromer. Antinociceptive testing in mice revealed 5 to be the most potent member of the series. As neither a mixture of monovalent ligands 9 + 10 nor bivalents 2-5 produced tolerance in mice, MOR-CB1 apparently is not an important target for reducing tolerance.
• US9133128B2
  申请人：——

  公开号：US9133128B2

  公开（公告）日：2015-09-15