1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-amine | 1408075-34-2

• 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-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-amine
• 英文别名: 1-(8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl)piperidin-4-amine；1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)purin-6-yl]piperidin-4-amine
• CAS: 1408075-34-2
• 化学式: C₂₂H₂₀Cl₂N₆
• 分子量: 439.347
• InChiKey: FHOSDLKAQUCLRP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  72.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-amine 在 三乙胺 作用下， 以 1,4-二氧六环 、 1,2-二氯乙烷 为溶剂， 反应 22.0h， 生成 3-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-piperidin-4-yl}-1-cyclohexylurea
  参考文献：
  名称：

  Functionalized 6-(Piperidin-1-yl)-8,9-Diphenyl Purines as Peripherally Restricted Inverse Agonists of the CB1 Receptor

  摘要：

  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.

  DOI：

  10.1021/acs.jmedchem.9b00727
• 作为产物：
  描述：

  4-叔丁氧羰基氨基哌啶 在 三氟乙酸 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 32.0h， 生成 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-amine
  参考文献：
  名称：

  [EN] PERIPHERALLY RESTRICTED DIPHENYL PURINE DERIVATIVES
  [FR] DÉRIVÉS DE DIPHÉNYLE PURINE RESTREINTS DE MANIÈRE PÉRIPHÉRIQUE

  摘要：

  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。

  公开号：

  WO2013123335A1

文献信息

• Functionalized 6-(piperidin-1-yl)-8,9-diphenyl purines as inverse agonists of the CB1 receptor – SAR efforts towards selectivity and peripheralization
  作者：George Amato、Robert Wiethe、Amruta Manke、Vineetha Vasukuttan、Rodney Snyder、Scott Runyon、Rangan Maitra

  DOI：10.1016/j.bmc.2019.07.002

  日期：2019.8

  is functionalized with alkyl, heteroalkyl, aryl and heteroaryl groups using a connector in the form of an amine, amide, sulfonamide, sulfamide, carbamate, oxime, amidine, or guanidine. We also report more polar replacements for the 4-chlorophenyl group in the 9-position of the purine core, which improve calculated physical properties of the molecules. These studies resulted in compounds such as 75 that

  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
• [EN] DIARYL PURINE DERIVATIVES WITH IMPROVED BIOAVAILABILITY<br/>[FR] DÉRIVÉS DE DIARYLPURINE PRÉSENTANT UNE BIODISPONIBILITÉ AMÉLIORÉE
  申请人：RES TRIANGLE INST

  公开号：WO2018119076A1

  公开（公告）日：2018-06-28

  This disclosure is directed to various compounds and methods of preparation of improved compounds that are capable of functioning as cannabinoid receptor 1 (CB1) antagonists with reduced central nervous system (CNS) side effects. The application is also directed to pharmaceutical compositions containing one or more of these compounds, which may also contain one or more additional therapeutic agents. It is also directed to methods of treatment of various conditions that may be responsive to antagonism of the CB1 receptors, including, but not limited to, metabolic syndromes (including liver disease, obesity, and diabetes).

  本公开涉及各种化合物及改进化合物的制备方法，这些改进化合物能够作为大麻素受体1（CB1）拮抗剂，并具有减少中枢神经系统（CNS）副作用的能力。该申请还涉及含有这些化合物中的一个或多个的药物组合物，该组合物还可以含有一个或多个额外的治疗剂。此外，还涉及治疗各种可能对CB1受体拮抗产生反应的疾病的方法，包括但不限于代谢综合征（包括肝病、肥胖和糖尿病）。
• 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。
• Peripherally Selective Diphenyl Purine Antagonist of the CB1 Receptor
  作者：Alan Fulp、Katherine Bortoff、Yanan Zhang、Rodney Snyder、Tim Fennell、Julie A. Marusich、Jenny L. Wiley、Herbert Seltzman、Rangan Maitra

  DOI：10.1021/jm401129n

  日期：2013.10.24

  Antagonists of the CB1 receptor can be useful in the treatment of several important disorders. However, to NN date, the only clinically approved CB1 receptor antagonist, rimonabant, was withdrawn because of adverse central nervous system (CNS)-related side effects. Since rimonabant's withdrawal, several groups are pursuing peripherally selective CB1 antagonists. These compounds are expected to be devoid of undesirable CNS-related effects but maintain efficacy through antagonism of peripherally expressed CB1 receptors. Reported here are our latest results toward the development of a peripherally selective analog of the diphenyl purine CB1 antagonist otenabant 1. Compound 9 (N-148-(2-chlorophenyl)-9-(4chloropheny1)-9H-purin-6-yl]piperidin-4-y1}pentanamide) is a potent, orally absorbed antagonist of the CB1 receptor that is >50-fold selective for CBI over CB2, highly selective for the periphery in a rodent model, and without efficacy in a series of in vivo assays designed to evaluate its ability to mitigate the central effects of Delta(9)-tetrahydrocannabinol through the CB1 receptor.