((3aR,6aS)-5-(4,6-dimethylpyrimidin-2- yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone | 1293281-49-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2- yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone
• 英文别名: Seltorexant；[(3aS,6aR)-2-(4,6-dimethylpyrimidin-2-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-[2-fluoro-6-(triazol-2-yl)phenyl]methanone
• CAS: 1293281-49-8；1452539-75-1
• 化学式: C₂₁H₂₂FN₇O
• 分子量: 407.45
• InChiKey: SQOCEMCKYDVLMM-IYBDPMFKSA-N

物化性质

• 沸点：
  667.7±65.0 °C(Predicted)
• 密度：
  1.46±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  80
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2-氟-6-碘苯甲酸 在 copper(l) iodide 、 氯化亚砜 、 sodium carbonate 、 caesium carbonate 、 (1R,2R)-(-)-N,N'-二甲基-1,2-环己二胺 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 水 、 甲苯 为溶剂， 反应 7.5h， 生成 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2- yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone
  参考文献：
  名称：

  Novel Octahydropyrrolo[3,4-c]pyrroles Are Selective Orexin-2 Antagonists: SAR Leading to a Clinical Candidate

  摘要：

  The preclinical characterization of novel octahydropyrrolo[3,4-c]pyrroles that are potent land selective orexin-2 antagonists is described-Optimization of physicochemical and DMPK properties led to the discovery of Compounds with tissue distribution and duration of action suitable for evaluation in the treatment of primary insomnia. These selective orexin-2 antagonists are proven to promote sleep in rats, and this work ultimately led to the identification of a compound that progressed into human clinical trials for the treatment Of primary insomnia. The synthesis, SAR, and optimization, of the pharmacokinetic properties of this series of compounds as well as the identification of the clinical candidate, JNJ-42847922 (34), are described herein.

  DOI：

  10.1021/acs.jmedchem.5b00742

文献信息

• [EN] IMPROVED SYNTHETIC METHODS OF MAKING (2H-1,2,3-TRIAZOL-2-YL)PHENYL COMPOUNDS AS OREXIN RECEPTOR MODULATORS<br/>[FR] PROCÉDÉS SYNTHÉTIQUES AMÉLIORÉS POUR LA FABRICATION DE COMPOSÉS DE (2H-1,2,3-TRIAZOL-2-YL)PHÉNYLE UTILISÉS COMME MODULATEURS DES RÉCEPTEURS DE L'OREXINE
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2021023843A1

  公开（公告）日：2021-02-11

  Processes for preparing (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-l,2,3-triazol-2- yl)phenyl)methanone are described, which are useful for commercial manufacturing. Said compound is an orexin receptor modulator and may be useful in pharmaceutical compositions and methods for the treatment of diseased states, disorders, and conditions mediated by orexin activity, such as insomnia and depression.

  描述了制备(((3aR,6aS)-5-(4,6-二甲基嘧啶-2-基)己氢吡咯[3,4-c]吡咯-2(1H)-基)(2-氟-6-(2H-1,2,3-三唑-2-基)苯基)甲酮的过程，这对于商业生产是有用的。所述化合物是一种促进睡眠素受体的调节剂，可能在制药组合物和治疗由促进睡眠素活性介导的疾病状态、紊乱和症状，如失眠和抑郁症的方法中是有用的。
• [EN] IMPROVED SYNTHETIC METHODS OF MAKING FUSED HETEROCYCLIC COMPOUNDS AS OREXIN RECEPTOR MODULATORS<br/>[FR] PROCÉDÉS SYNTHÉTIQUES AMÉLIORÉS DE PRODUCTION DE COMPOSÉS HÉTÉROCYCLIQUES FUSIONNÉS UTILISÉS EN TANT QUE MODULATEURS DU RÉCEPTEUR DE L'OREXINE
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2020100011A1

  公开（公告）日：2020-05-22

  Processes for preparing (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone are described, which are useful for commercial manufacturing. Said compound is an orexin receptor modulator and may be useful in pharmaceutical compositions and methods for the treatment of diseased states, disorders, and conditions mediated by orexin activity, such as insomnia and depression.

  描述了制备(((3aR,6aS)-5-(4,6-二甲基嘧啶-2-基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-氟-6-(1,2,3-三氮唑-2-基)苯基)甲酮的工艺，该工艺适用于商业生产。所述化合物是一种促进睡眠素受体的调节剂，可用于制备药物组合物和治疗由促进睡眠素活动介导的疾病状态、障碍和症状，如失眠和抑郁症。
• IMPROVED SYNTHETIC METHODS OF MAKING FUSED HETEROCYCLIC COMPOUNDS AS OREXIN RECEPTOR MODULATORS
  申请人：GALA Dinesh

  公开号：US20220009932A1

  公开（公告）日：2022-01-13

  Processes for preparing (((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl) methanone are described, which are useful for commercial manufacturing. Said compound is an orexin receptor modulator and may be useful in pharmaceutical compositions and methods for the treatment of diseased states, disorders, and conditions mediated by orexin activity, such as insomnia and depression.
• Novel Octahydropyrrolo[3,4-<i>c</i>]pyrroles Are Selective Orexin-2 Antagonists: SAR Leading to a Clinical Candidate
  作者：Michael A. Letavic、Pascal Bonaventure、Nicholas I. Carruthers、Christine Dugovic、Tatiana Koudriakova、Brian Lord、Timothy W. Lovenberg、Kiev S. Ly、Neelakandha S. Mani、Diane Nepomuceno、Daniel J. Pippel、Michele Rizzolio、Jonathan E. Shelton、Chandra R. Shah、Brock T. Shireman、Lana K. Young、Sujin Yun

  DOI：10.1021/acs.jmedchem.5b00742

  日期：2015.7.23

  The preclinical characterization of novel octahydropyrrolo[3,4-c]pyrroles that are potent land selective orexin-2 antagonists is described-Optimization of physicochemical and DMPK properties led to the discovery of Compounds with tissue distribution and duration of action suitable for evaluation in the treatment of primary insomnia. These selective orexin-2 antagonists are proven to promote sleep in rats, and this work ultimately led to the identification of a compound that progressed into human clinical trials for the treatment Of primary insomnia. The synthesis, SAR, and optimization, of the pharmacokinetic properties of this series of compounds as well as the identification of the clinical candidate, JNJ-42847922 (34), are described herein.