tert-butyl N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-yl}carbamate | 1408075-33-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: tert-butyl N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-yl}carbamate
• 英文别名: 8-(2-chlorophenyl)-9-(4-chlorophenyl)-6-(4-(N-Boc-amino)piperidin-1-yl)-9H-purine；tert-butyl N-[1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)purin-6-yl]piperidin-4-yl]carbamate
• CAS: 1408075-33-1
• 化学式: C₂₇H₂₈Cl₂N₆O₂
• 分子量: 539.464
• InChiKey: MOLFFFRLZHZCTJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  37
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  85.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  tert-butyl N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-yl}carbamate 在 盐酸 作用下， 以 乙醇 、 水 为溶剂， 反应 3.0h， 生成 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-amine
  参考文献：
  名称：

  功能化的6-（哌啶-1-基）-8,9-二苯基嘌呤作为CB1受体的反向激动剂-SAR致力于选择性和外围化。

  摘要：

  1型大麻素受体（CB1）的拮抗剂可用于治疗糖尿病，肝病和纤维化。Otenabant（1）是一种有效且选择性的CB1反向激动剂，目前正在研究中作为抗肥胖药，但一旦已知与另一种市售反向激动剂rimonabant（2）相关的不良反应，其发展就会中止。CB1的非组织选择性拮抗剂具有高水平的脑部渗透性，会对一小部分患者产生不良影响，包括焦虑，抑郁和自杀意念。当前，正在努力生产大脑渗透受限的化合物。在本报告中，探索了新型的1类似物，以开发和测试外围化策略。研究了1的哌啶作为连接基，它被烷基，杂烷基，使用胺，酰胺，磺酰胺，磺酰胺，氨基甲酸酯，肟，am或胍形式的连接基形成芳基和杂芳基。我们还报告了嘌呤核9位中4-氯苯基的更多极性替代物，这改善了分子的计算物理性能。这些研究产生了诸如hCB1的有效反向激动剂之类的化合物，例如75，对hCB1的选择性比hCB2高。SAR研究揭示了调节物理特性以限制大脑暴露的方

  DOI：

  10.1016/j.bmc.2019.07.002
• 作为产物：
  描述：

  6-氯-N4-(4-氯苯基)-4,5-嘧啶二胺 在 FeCl₃/silica gel 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 N-甲基吡咯烷酮 为溶剂， 反应 37.17h， 生成 tert-butyl N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-yl}carbamate
  参考文献：
  名称：

  功能化的6-（哌啶-1-基）-8,9-二苯基嘌呤作为CB1受体的反向激动剂-SAR致力于选择性和外围化。

  摘要：

  1型大麻素受体（CB1）的拮抗剂可用于治疗糖尿病，肝病和纤维化。Otenabant（1）是一种有效且选择性的CB1反向激动剂，目前正在研究中作为抗肥胖药，但一旦已知与另一种市售反向激动剂rimonabant（2）相关的不良反应，其发展就会中止。CB1的非组织选择性拮抗剂具有高水平的脑部渗透性，会对一小部分患者产生不良影响，包括焦虑，抑郁和自杀意念。当前，正在努力生产大脑渗透受限的化合物。在本报告中，探索了新型的1类似物，以开发和测试外围化策略。研究了1的哌啶作为连接基，它被烷基，杂烷基，使用胺，酰胺，磺酰胺，磺酰胺，氨基甲酸酯，肟，am或胍形式的连接基形成芳基和杂芳基。我们还报告了嘌呤核9位中4-氯苯基的更多极性替代物，这改善了分子的计算物理性能。这些研究产生了诸如hCB1的有效反向激动剂之类的化合物，例如75，对hCB1的选择性比hCB2高。SAR研究揭示了调节物理特性以限制大脑暴露的方

  DOI：

  10.1016/j.bmc.2019.07.002

文献信息

• [EN] PERIPHERALLY RESTRICTED DIPHENYL PURINE DERIVATIVES<br/>[FR] DÉRIVÉS DE DIPHÉNYLE PURINE RESTREINTS DE MANIÈRE PÉRIPHÉRIQUE
  申请人：RES TRIANGLE INST

  公开号：WO2013123335A1

  公开（公告）日：2013-08-22

  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。
• PERIPHERALLY RESTRICTED DIPHENYL PURINE DERIVATIVES
  申请人：RESEARCH TRIANGLE INSTITUTE

  公开号：US20150031689A1

  公开（公告）日：2015-01-29

  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大麻素受体系统被涉及的疾病，如肥胖症、肝病、糖尿病、疼痛和炎症等。
• Peripherally restricted diphenyl purine derivatives
  申请人：RESEARCH TRIANGLE INSTITUTE

  公开号：US09187480B2

  公开（公告）日：2015-11-17

  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.

  该发明提供了一些化合物，其能够作为大麻素受体拮抗剂，其化学式如下：这些化合物可用于治疗大麻素受体系统被牵涉的疾病，如肥胖症、肝病、糖尿病、疼痛和炎症等疾病。
• Functionalized 6-(Piperidin-1-yl)-8,9-Diphenyl Purines as Peripherally Restricted Inverse Agonists of the CB1 Receptor
  作者：George Amato、Amruta Manke、Robert Wiethe、Vineetha Vasukuttan、Rodney Snyder、Yun Lan Yueh、Ann Decker、Scott Runyon、Rangan Maitra

  DOI：10.1021/acs.jmedchem.9b00727

  日期：2019.7.11

  Peripherally restricted CB1 receptor antagonists may be useful in treating metabolic syndrome, diabetes, liver diseases, and gastrointestinal disorders. Clinical development of the centrally acting CB1 inverse agonist otenabant (1) was halted due to its potential of producing adverse effects. SAR studies of 1 are reported herein with the objective of producing peripherally restricted analogues, Crystal structures of hCB1 and docking studies with 1 indicate that the piperidine group could be functionalized at the 4-position to access a binding pocket that can accommodate both polar and nonpolar groups. The piperidine is studied as a linker, functionalized with alkyl, heteroalkyl, aryl, and heteroaryl groups using a urea connector. Orally bioavailable and peripherally selective compounds have been produced that are potent inverse agonists of hCB1 with exceptional selectivity for hCB1 over hCB2. Compound 38 blocked alcohol-induced liver steatosis in mice and has good ADME properties for further development.
• Diphenyl Purine Derivatives as Peripherally Selective Cannabinoid Receptor 1 Antagonists
  作者：Alan Fulp、Katherine Bortoff、Yanan Zhang、Herbert Seltzman、James Mathews、Rodney Snyder、Tim Fennell、Rangan Maitra

  DOI：10.1021/jm301181r

  日期：2012.11.26

  Cannabinoid receptor 1 (CB1) antagonists are potentially useful for the treatment of several diseases. However, clinical development of several CB1 antagonists was halted due to central nervous system (CNS)-related side effects including depression and suicidal ideation in some users. Recently, studies have indicated that selective regulation of CB1 receptors in the periphery is a viable strategy for treating several important disorder. Past efforts to develop peripherally selective antagonists of CB1 have largely targeted rimonabant, an inverse agonist of CB1. Reported here are out efforts toward developing a peripherally selective CB1 antagonist based on the otenabant scaffold. Even though otenabant penetrates the CNS, it is unique among CB1 antagonists that have been clinically tested because it has properties that are normally associated with peripherally selective compounds. Our efforts have resulted in an orally absorbed compound that is a potent and selective CB1 antagonist with limited penetration into the CNS.