1-[9-(2-cyclopropylethoxy)-2-(2,6-dibromo-4-fluorophenyl)-1H-phenanthro[9,10-d]imidazol-9-yl]-2-methylpropan-2-ol | 1057384-97-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 1-[9-(2-cyclopropylethoxy)-2-(2,6-dibromo-4-fluorophenyl)-1H-phenanthro[9,10-d]imidazol-9-yl]-2-methylpropan-2-ol
• 英文别名: 1-[9-(2-cyclopropylethoxy)-2-(2,6-dibromo-4-fluorophenyl)-1H-phenanthro[9,10-d]imidazol-6-yl]-2-methylpropan-2-ol；1-[6-(2-cyclopropylethoxy)-2-(2,6-dibromo-4-fluorophenyl)-1H-phenanthro[9,10-d]imidazol-9-yl]-2-methylpropan-2-ol
• CAS: 1057384-97-0
• 化学式: C₃₀H₂₇Br₂FN₂O₂
• 分子量: 626.363
• InChiKey: OVPXIDULZDSJCK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.8
• 重原子数：
  37
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  58.1
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-[9-(2-cyclopropylethoxy)-2-(2,6-dibromo-4-fluorophenyl)-1H-phenanthro[9,10-d]imidazol-9-yl]-2-methylpropan-2-ol 、 copper(II) cyanide 在 N,N-二甲基乙酰胺 、 水 作用下， 以10%的产率得到2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1H-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarboxamide
  参考文献：
  名称：

  A Practical Synthesis of m-Prostaglandin E Synthase-1 Inhibitor MK-7285

  摘要：

  A practical, kilogram-scale chromatography-free synthesis of mPGE synthase I inhibitor MK-7285 is described. The route features a convergent assembly of the core phenanthrene unit via amide-directed ortho-metalation and proximity-induced anionic cyclization, followed by imidazole synthesis and late-stage cyanation.

  DOI：

  10.1021/jo901798d
• 作为产物：
  描述：

  2,6-二溴-4-氟苯甲醛 、 3-(2-cyclopropylethoxy)-6-(2-hydroxy-2-methylpropyl)phenanthrene-9,10-dione 在 ammonium acetate 、 溶剂黄146 作用下， 反应 1.0h， 以85.3%的产率得到1-[9-(2-cyclopropylethoxy)-2-(2,6-dibromo-4-fluorophenyl)-1H-phenanthro[9,10-d]imidazol-9-yl]-2-methylpropan-2-ol
  参考文献：
  名称：

  A Practical Synthesis of m-Prostaglandin E Synthase-1 Inhibitor MK-7285

  摘要：

  A practical, kilogram-scale chromatography-free synthesis of mPGE synthase I inhibitor MK-7285 is described. The route features a convergent assembly of the core phenanthrene unit via amide-directed ortho-metalation and proximity-induced anionic cyclization, followed by imidazole synthesis and late-stage cyanation.

  DOI：

  10.1021/jo901798d

文献信息

• Targeted delivery of mPGES-1 inhibitors to macrophages via the folate receptor-β for inflammatory pain
  作者：Liudmila L. Mazaleuskaya、Seokwoo Lee、Hu Meng、Jeffrey D. Winkler、Garret A. FitzGerald

  DOI：10.1016/j.bmcl.2021.128313

  日期：2021.10

  Activated macrophages overexpress the folate receptor β (FR-β) that can be used for targeted delivery of drugs conjugated to folic acid. FR-expressing macrophages contribute to arthritis progression by secreting prostaglandin E2 (PGE2). Non-steroidal anti-inflammatory drugs (NSAIDs) block PGs and thromboxane by inhibiting the cyclooxygenase (COX) enzymes and are used for chronic pain and inflammation

  活化的巨噬细胞过表达叶酸受体 β (FR-β)，可用于靶向递送与叶酸结合的药物。表达 FR 的巨噬细胞通过分泌前列腺素 E 2 (PGE 2）。非甾体抗炎药 (NSAID) 通过抑制环氧合酶 (COX) 来阻断 PG 和血栓素，尽管它们具有众所周知的毒性，但仍用于治疗慢性疼痛和炎症。新的 NSAIDs 靶向 COXs 下游的一种酶，微粒体前列腺素 E 合酶 1 (mPGES-1)。抑制炎性巨噬细胞中的 mPGES-1 有望保留 NSAID 功效，同时限制毒性。我们将一种有效的 mPGES-1 抑制剂 MK-7285 与叶酸结合，但该构建体无法有效地释放药物。叶酸与 MK-7285 的伯醇结合提高了构建体的稳定性和游离药物的释放。令人惊讶的是，药物-叶酸偶联物增强了 FR 阳性 KB 细胞中的 PGE 2 并降低了PGE 2在独立于 FR 的巨噬细胞中。非甾体抗炎药的叶酸结合不是靶向巨噬细胞的最佳策略。
• 2-(phenyl or heterocyclic)-1H-phenantrho[9,10-d]imidazoles as mPGES-1 inhibitors
  申请人：Chau Anh

  公开号：US20090075998A1

  公开（公告）日：2009-03-19

  The invention encompasses novel compounds of Formula I or pharmaceutically acceptable salts thereof. These compounds are inhibitors of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme and are therefore useful to treat pain and/or inflammation from a variety of diseases or conditions, such as osteoarthritis, rheumatoid arthritis and acute or chronic pain. Methods of treating diseases or conditions mediated by the mPGES-1 enzyme and pharmaceutical compositions are also encompassed.

  该发明涵盖了式I的新化合物或其药学上可接受的盐。这些化合物是微粒体前列腺素E合酶-1（mPGES-1）酶的抑制剂，因此可用于治疗多种疾病或情况引起的疼痛和/或炎症，如骨关节炎，类风湿性关节炎和急性或慢性疼痛。还包括治疗由mPGES-1酶介导的疾病或情况的方法和制药组合物。
• 2-(Phenyl or heterocyclic)-1H-phenantrho[9,10-d]imidazoles as mPGES-1 inhibitors
  申请人：Chau Anh

  公开号：US20070208017A1

  公开（公告）日：2007-09-06

  The invention encompasses novel compounds of Formula I or pharmaceutically acceptable salts thereof. These compounds are inhibitors of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme and are therefore useful to treat pain and/or inflammation from a variety of diseases or conditions, such as osteoarthritis, rheumatoid arthritis and acute or chronic pain. Methods of treating diseases or conditions mediated by the mPGES-1 enzyme and pharmaceutical compositions are also encompassed.

  本发明涵盖了公式I的新化合物或其药学上可接受的盐。这些化合物是微粒体前列腺素E合成酶-1（mPGES-1）酶的抑制剂，因此可用于治疗各种疾病或病况引起的疼痛和/或炎症，如骨关节炎、类风湿性关节炎和急性或慢性疼痛。还包括治疗由mPGES-1酶介导的疾病或病况的方法和制药组合物。
• Methods for Treating or Preventing Neoplasias
  申请人：Kargman Stacia

  公开号：US20090192158A1

  公开（公告）日：2009-07-30

  The present invention is directed to a method for treating or preventing a neoplasia in a human patient in need of such treatment comprising administering to the patient a compound that inhibits microsomal prostaglandin E synthase-1 in an amount that is effective for treating or preventing the neoplasia.

  本发明涉及一种治疗或预防人类患者肿瘤的方法，包括向患者施用一种抑制微粒体前列腺素E合酶-1的化合物，其剂量足以治疗或预防该肿瘤。
• Discovery of disubstituted phenanthrene imidazoles as potent, selective and orally active mPGES-1 inhibitors
  作者：André Giroux、Louise Boulet、Christine Brideau、Anh Chau、David Claveau、Bernard Côté、Diane Ethier、Richard Frenette、Marc Gagnon、Jocelyne Guay、Sébastien Guiral、Joseph Mancini、Evelyn Martins、Frédéric Massé、Nathalie Méthot、Denis Riendeau、Joel Rubin、Daigen Xu、Hongping Yu、Yves Ducharme、Richard W. Friesen

  DOI：10.1016/j.bmcl.2009.08.085

  日期：2009.10

  Phenanthrene imidazoles 26 and 44 have been identified as novel potent, selective and orally active mPGES-1 inhibitors. These inhibitors are significantly more potent than the previously reported chlorophenanthrene imidazole 1 (MF63) with a human whole blood IC50 of 0.20 and 0.14 mu M, respectively. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model at oral doses as low as 14 mg/kg. Both active and selective mPGES-1 inhibitors (26 and 44) have a relatively distinct pharmacokinetic profile and are suitable for clinical development. Crown Copyright (C) 2009 Published by Elsevier Ltd. All rights reserved.