2-((2-chloro-6-fluorophenyl)amino)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1H-[1,4]dioxino[2',3':3,4]benzo[1,2-d]imidazole-5-carboxamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-((2-chloro-6-fluorophenyl)amino)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1H-[1,4]dioxino[2',3':3,4]benzo[1,2-d]imidazole-5-carboxamide
• 英文别名: 2-(2-chloro-6-fluoroanilino)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-7,8-dihydro-[1,4]dioxino[2,3-e]benzimidazole-5-carboxamide
• 化学式: C₂₄H₁₆ClF₅N₄O₃
• 分子量: 538.861
• InChiKey: MRUCMCCYXQYKGZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  37
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  77.4
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  methyl 8-(methylamino)-7-nitro-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylate 在 盐酸 、 三甲基铝 、 铁粉 作用下， 以 甲醇 、 水 、 甲苯 、 乙腈 为溶剂， 反应 38.0h， 生成 2-((2-chloro-6-fluorophenyl)amino)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1H-[1,4]dioxino[2',3':3,4]benzo[1,2-d]imidazole-5-carboxamide
  参考文献：
  名称：

  Discovery of 2-((2-chloro-6-fluorophenyl)amino)- N -(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1 H -[1,4]dioxino[2′,3′:3,4]benzo[1,2- d ]imidazole-5-carboxamide as potent, selective and efficacious microsomal prostaglandin E 2 synthase-1 (mPGES-1) inhibitor

  摘要：

  The discovery and SAR of potent, selective dioxane-fused tricyclic benz[d]imidazole derivatives as mPGES-1 inhibitor are herein described. Various amide modifications in this series afforded many potent mPGES-1 inhibitors, of which 17d proved to be suitable for further profiling in vivo. Compound 17d (24(2-chloro-6-fluorophenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)pheny1)-1-methy1-7,8-dihydro-1H- [1,4]dioxino[2',3':3,4]benzo[1,2-dlimidazole-5-carboxamide) exhibited excellent mPGES-1 enzyme (IC50: 8 nM), cell (A549 IC50: 16.24 nM) and human whole blood potency (IC50: 249.9 nM). In rodent species, 17d strongly inhibited guinea pig mPGES-1 (IC50: 10.79 nM), but not the rat and mouse enzyme. Furthermore 17d displayed excellent in vitro selectivity over mPGES-2, cPGES, COX-enzymes (COX-1, 2), selectivity against other prostanoid synthases, favorable hERG and CEREP panel profile. Likewise, our lead 17d demonstrated good oral pharmacokinetic profiles and good CNS B/P ratio in rat and guinea pig. Lead 17d also unveiled good efficacy in LPS-induced thermal hyperalgesia pain model with ED50 of 36.7 mg/kg, respectively. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2016.10.079

文献信息

• [EN] TRICYCLIC COMPOUNDS AS mPGES-1 INHIBITORS<br/>[FR] COMPOSÉS TRICYCLIQUES À TITRE D'INHIBITEURS DE LA MPGES-1
  申请人：GLENMARK PHARMACEUTICALS SA

  公开号：WO2013153535A1

  公开（公告）日：2013-10-17

  The present disclosure is directed to compounds of formula (I), and pharmaceutically acceptable salts thereof, as m PGES-1 inhibitors. These compounds are inhibitors of the microsomal prostaglandin E synthase-1 (m PGES-1) enzyme and are therefore useful in the treatment of pain and/or inflammation from a variety of diseases or conditions, such as asthma, osteoarthritis, rheumatoid arthritis, acute or chronic pain and neurodegenerative diseases.

  本公开涉及式(I)的化合物及其药学上可接受的盐，作为m PGES-1抑制剂。这些化合物是微粒体前列腺素E合成酶-1（m PGES-1）酶的抑制剂，因此在治疗来自多种疾病或状况的疼痛和/或炎症方面非常有用，如哮喘、骨关节炎、风湿性关节炎、急性或慢性疼痛和神经退行性疾病。
• Discovery of 2-((2-chloro-6-fluorophenyl)amino)- N -(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1 H -[1,4]dioxino[2′,3′:3,4]benzo[1,2- d ]imidazole-5-carboxamide as potent, selective and efficacious microsomal prostaglandin E 2 synthase-1 (mPGES-1) inhibitor
  作者：Nagarajan Muthukaman、Sanjay Deshmukh、Neelam Sarode、Shital Tondlekar、Macchindra Tambe、Dnyandeo Pisal、Mahamadhanif Shaikh、Vidya G. Kattige、Srinivasa Honnegowda、Vikas Karande、Abhay Kulkarni、Satyawan B. Jadhav、Mahamad Yunnus A. Mahat、Girish S. Gudi、Neelima Khairatkar-Joshi、Laxmikant A. Gharat

  DOI：10.1016/j.bmcl.2016.10.079

  日期：2016.12

  The discovery and SAR of potent, selective dioxane-fused tricyclic benz[d]imidazole derivatives as mPGES-1 inhibitor are herein described. Various amide modifications in this series afforded many potent mPGES-1 inhibitors, of which 17d proved to be suitable for further profiling in vivo. Compound 17d (24(2-chloro-6-fluorophenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)pheny1)-1-methy1-7,8-dihydro-1H- [1,4]dioxino[2',3':3,4]benzo[1,2-dlimidazole-5-carboxamide) exhibited excellent mPGES-1 enzyme (IC50: 8 nM), cell (A549 IC50: 16.24 nM) and human whole blood potency (IC50: 249.9 nM). In rodent species, 17d strongly inhibited guinea pig mPGES-1 (IC50: 10.79 nM), but not the rat and mouse enzyme. Furthermore 17d displayed excellent in vitro selectivity over mPGES-2, cPGES, COX-enzymes (COX-1, 2), selectivity against other prostanoid synthases, favorable hERG and CEREP panel profile. Likewise, our lead 17d demonstrated good oral pharmacokinetic profiles and good CNS B/P ratio in rat and guinea pig. Lead 17d also unveiled good efficacy in LPS-induced thermal hyperalgesia pain model with ED50 of 36.7 mg/kg, respectively. (C) 2016 Elsevier Ltd. All rights reserved.