N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-{4-[(2-oxotetrahydro furan-3-yl)amino]butoxy}benzamide | 1422361-47-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-{4-[(2-oxotetrahydro furan-3-yl)amino]butoxy}benzamide
• 英文别名: N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-{4-[(2-oxotetrahydrofuran-3-yl)amino]butoxy}benzamide；N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-[4-[(2-oxooxolan-3-yl)amino]butoxy]benzamide
• CAS: 1422361-47-4
• 化学式: C₂₁H₂₁Cl₂F₂N₃O₅
• 分子量: 504.318
• InChiKey: DXCZVUGSWTZEKE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  33
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  98.8
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-{4-[(2-oxotetrahydro furan-3-yl)amino]butoxy}benzamide 在 lithium hydroxide 作用下， 生成 2-[4-[5-[(3,5-Dichloropyridin-4-yl)carbamoyl]-2-(difluoromethoxy)phenoxy]butylamino]-4-hydroxybutanoic acid
  参考文献：
  名称：

  Novel Roflumilast analogs as soft PDE4 inhibitors

  摘要：

  PDE4 inhibitors are of high interest for treatment of a wide range of inflammatory or autoimmune diseases. Their potential however has not yet been realized due to target-associated side effects, resulting in a low therapeutic window. We herein report the design, synthesis and evaluation of novel PDE4 inhibitors containing a gamma-lactone structure. Such molecules are designed to undergo metabolic inactivation when entering circulation, thereby limiting systemic exposure and reducing the risk for side effects. The resulting inhibitors were highly active on both PDE4B1 and PDE4D2 and underwent rapid degradation in human plasma by paraoxonase 1. In contrast, their metabolites displayed markedly reduced permeability and/or on-target activity. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.07.016
• 作为产物：
  描述：

  4-二氟甲氧基-3-羟基苯甲醛 在 ammonium hydroxide 、 sodium chlorite 、 氯化亚砜 、 氨基磺酸 、 sodium hydride 、 potassium carbonate 、 溶剂黄146 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 、 mineral oil 为溶剂， 反应 8.0h， 生成 N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-{4-[(2-oxotetrahydro furan-3-yl)amino]butoxy}benzamide
  参考文献：
  名称：

  [EN] NOVEL SOFT PDE4 INHIBITORS
  [FR] NOUVEAUX INHIBITEURS DOUX DE PDE4

  摘要：

  本发明涉及新的磷酸二酯酶抑制剂，更具体地说是软PDE4抑制剂，包括这些抑制剂的组合物，特别是制药品，以及这些抑制剂在疾病的治疗和预防中的用途。具体来说，本发明涉及新的软PDE4抑制剂组合物，特别是包括这些抑制剂的制药品，以及这些抑制剂在疾病的治疗和预防中的用途。此外，本发明涉及治疗方法和使用上述化合物制造药物的方法，适用于多种治疗适应症，包括炎症性疾病。

  公开号：

  WO2013021021A1

文献信息

• [EN] NOVEL SOFT PDE4 INHIBITORS<br/>[FR] NOUVEAUX INHIBITEURS DOUX DE PDE4
  申请人：AMAKEM NV

  公开号：WO2013021021A1

  公开（公告）日：2013-02-14

  The present invention relates to new phosphodiesterase inhibitors, more specifically soft PDE4 inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In particular, the present invention relates to new soft PDE4 inhibitors compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In addition, the invention relates to methods of treatment and use of said compounds in the manufacture of a medicament for the application to a number of therapeutic indications including inflammatory diseases.

  本发明涉及新的磷酸二酯酶抑制剂，更具体地说是软PDE4抑制剂，包括这些抑制剂的组合物，特别是制药品，以及这些抑制剂在疾病的治疗和预防中的用途。具体来说，本发明涉及新的软PDE4抑制剂组合物，特别是包括这些抑制剂的制药品，以及这些抑制剂在疾病的治疗和预防中的用途。此外，本发明涉及治疗方法和使用上述化合物制造药物的方法，适用于多种治疗适应症，包括炎症性疾病。
• NOVEL SOFT PDE4 INHIBITORS
  申请人：Leysen Dirk

  公开号：US20140187555A1

  公开（公告）日：2014-07-03

  The present invention relates to new phosphodiesterase inhibitors, more specifically soft PDE4 inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In particular, the present invention relates to new soft PDE4 inhibitors compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In addition, the invention relates to methods of treatment and use of said compounds in the manufacture of a medicament for the application to a number of therapeutic indications including inflammatory diseases.

  本发明涉及新的磷酸二酯酶抑制剂，更具体地是软性PDE4抑制剂，包括这种抑制剂的组合物，特别是制药用途的组合物，并且涉及使用这种抑制剂来治疗和预防疾病的用途。特别地，本发明涉及新的软性PDE4抑制剂组合物，特别是制药用途的组合物，并且涉及使用这种抑制剂来治疗和预防疾病的用途。此外，本发明还涉及治疗方法和使用所述化合物制造药物，用于多种治疗适应症，包括炎症性疾病。
• US9126933B2
  申请人：——

  公开号：US9126933B2

  公开（公告）日：2015-09-08
• Novel Roflumilast analogs as soft PDE4 inhibitors
  作者：Sandro Boland、Jo Alen、Arnaud Bourin、Karolien Castermans、Nicki Boumans、Laura Panitti、Jessica Vanormelingen、Dirk Leysen、Olivier Defert

  DOI：10.1016/j.bmcl.2014.07.016

  日期：2014.9

  PDE4 inhibitors are of high interest for treatment of a wide range of inflammatory or autoimmune diseases. Their potential however has not yet been realized due to target-associated side effects, resulting in a low therapeutic window. We herein report the design, synthesis and evaluation of novel PDE4 inhibitors containing a gamma-lactone structure. Such molecules are designed to undergo metabolic inactivation when entering circulation, thereby limiting systemic exposure and reducing the risk for side effects. The resulting inhibitors were highly active on both PDE4B1 and PDE4D2 and underwent rapid degradation in human plasma by paraoxonase 1. In contrast, their metabolites displayed markedly reduced permeability and/or on-target activity. (C) 2014 Elsevier Ltd. All rights reserved.