(7R)-7-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane | 1030377-29-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: (7R)-7-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane
• 英文别名: [(7R)-7-methyl-1,4-diazepan-1-yl]-[2-(triazol-2-yl)phenyl]methanone
• CAS: 1030377-29-7
• 化学式: C₁₅H₁₉N₅O
• 分子量: 285.349
• InChiKey: NQECYSIGFGSQJX-GFCCVEGCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  63
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (7R)-7-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane 、 2,4,5-三氯嘧啶 在 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 以73%的产率得到[(7R)-4-(2,5-dichloropyrimidin-4-yl)-7-methyl-1,4-diazepan-1-yl]-[2-(triazol-2-yl)phenyl]methanone
  参考文献：
  名称：

  通过探索等位性喹唑啉替代物，发现二氮杂烷酰胺DORA和2-SORA

  摘要：

  双重orexin受体拮抗剂（DORAs）或orexin 1（OX 1）和orexin 2（OX 2）受体拮抗剂已证明可用于治疗失眠症。药物化学工作的重点是降低二氮杂庚烷酰胺1的生物活化潜能通过西方杂环的修饰导致发现了suvorexant，这是FDA最近批准的用于治疗失眠症的DORA。通过探索单环喹唑啉等排体，即取代的嘧啶，在本文中提出了降低生物活化风险的第二种策略。这些研究提供了有效的DORA，在啮齿动物睡眠模型中具有显着降低的生物激活风险和功效。令人惊讶地，用于生产这些DORA的化学副产物产生具有异构的含嘧啶的二氮杂环庚烷酰胺，其具有选择性的OX 2 R拮抗剂（2-SORA）谱。在小鼠脑电图研究中，对这些异构的嘧啶类化合物的进一步探索发现了有效的2-SORA二氮杂环庚烷酰胺具有睡眠功效。

  DOI：

  10.1016/j.bmcl.2014.12.081
• 作为产物：
  描述：

  benzyl (5R)-5-methyl-4-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane-1-carboxylate 在 palladium(II) hydroxide/carbon 氢气 作用下， 以 乙酸乙酯 为溶剂， 生成 (7R)-7-methyl-1-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane
  参考文献：
  名称：

  Substituted diazepan orexin receptor antagonists

  摘要：

  本发明涉及替代二氮杂环丙烷化合物，其为促进睡眠蛋白受体的拮抗剂，可用于治疗或预防神经和精神疾病，以及涉及促进睡眠蛋白受体的疾病。该发明还涉及包含这些化合物的药物组合物，以及利用这些化合物和组合物在预防或治疗涉及促进睡眠蛋白受体的疾病中的用途。

  公开号：

  US20080132490A1

文献信息

• [EN] METHYL DIAZEPANE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] ANTAGONISTES DE RÉCEPTEUR D'OREXINE DE TYPE MÉTHYL-DIAZÉPANE
  申请人：MERCK SHARP & DOHME

  公开号：WO2016085784A1

  公开（公告）日：2016-06-02

  The present invention is directed to methyl diazepane compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

  本发明涉及甲基二氮杂环己烷化合物，其为促进睡眠的受体拮抗剂。本发明还涉及所述化合物在潜在的治疗或预防涉及促进睡眠的神经和精神障碍和疾病中的用途。本发明还涉及包含这些化合物的组合物。本发明还涉及这些组合物在潜在的预防或治疗涉及促进睡眠的疾病中的用途。
• Substituted diazepan compounds as orexin receptor antagonists
  申请人：Merck Sharp & Dohme Corp.

  公开号：EP2392572A1

  公开（公告）日：2011-12-07

  The present invention is directed to substituted diazepan compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

  本发明涉及取代的二氮杂环庚烷化合物，它们是奥曲肽受体的拮抗剂，可用于治疗或预防涉及奥曲肽受体的神经和精神紊乱及疾病。本发明还涉及包含这些化合物的药物组合物，以及这些化合物和组合物在预防或治疗涉及奥曲肽受体的此类疾病中的用途。
• Methyl diazepane orexin receptor antagonists
  申请人：MERCK SHARP & DOHME CORP.

  公开号：US10000499B2

  公开（公告）日：2018-06-19

  The present invention is directed to methyl diazepane compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

  本发明涉及甲基二氮杂环庚烷化合物，它是奥曲肽受体的拮抗剂。本发明还涉及本文所述化合物在潜在治疗或预防涉及奥曲肽受体的神经和精神疾病中的用途。本发明还涉及包含这些化合物的组合物。本发明还涉及这些组合物在潜在预防或治疗涉及奥曲肽受体的此类疾病中的用途。
• Discovery of dual orexin receptor antagonists with rat sleep efficacy enabled by expansion of the acetonitrile-assisted/diphosgene-mediated 2,4-dichloropyrimidine synthesis
  作者：Anthony J. Roecker、Swati P. Mercer、C. Meacham Harrell、Susan L. Garson、Steven V. Fox、Anthony L. Gotter、Thomayant Prueksaritanont、Tamara D. Cabalu、Donghui Cui、Wei Lemaire、Christopher J. Winrow、John J. Renger、Paul J. Coleman

  DOI：10.1016/j.bmcl.2014.03.052

  日期：2014.5

  Recent clinical studies have demonstrated that dual orexin receptor antagonists (OX1R and OX2R antagonists or DORAs) represent a novel treatment option for insomnia patients. Previously we have disclosed several compounds in the diazepane amide DORA series with excellent potency and both preclinical and clinical sleep efficacy. Additional SAR studies in this series were enabled by the expansion of the acetonitrile-assisted, diphosgene-mediated 2,4-dichloropyrimidine synthesis to novel substrates providing an array of Western heterocycles. These heterocycles were utilized to synthesize analogs in short order with high levels of potency on orexin 1 and orexin 2 receptors as well as in vivo sleep efficacy in the rat. (C) 2014 Elsevier Ltd. All rights reserved.
• Discovery of the Dual Orexin Receptor Antagonist [(7<i>R</i>)-4-(5-Chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2<i>H</i>-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the Treatment of Insomnia
  作者：Christopher D. Cox、Michael J. Breslin、David B. Whitman、John D. Schreier、Georgia B. McGaughey、Michael J. Bogusky、Anthony J. Roecker、Swati P. Mercer、Rodney A. Bednar、Wei Lemaire、Joseph G. Bruno、Duane R. Reiss、C. Meacham Harrell、Kathy L. Murphy、Susan L. Garson、Scott M. Doran、Thomayant Prueksaritanont、Wayne B. Anderson、Cuyue Tang、Shane Roller、Tamara D. Cabalu、Donghui Cui、George D. Hartman、Steven D. Young、Ken S. Koblan、Christopher J. Winrow、John J. Renger、Paul J. Coleman

  DOI：10.1021/jm100541c

  日期：2010.7.22

  Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years. One notable exception is inhibition of the excitatory neuropeptides orexins A and B by design of orexin receptor antagonists. Herein, we describe how efforts to understand the origin of poor oral pharmacokinetics in a leading HTS-derived diazepane orexin receptor antagonist led to the identification of compound 10 with a 7-methyl substitution on the diazepane core. Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations. A mechanistic hypothesis coupled with an in vitro assay to assess bioactivation led to replacement of the fluoroquina-zoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.