methyl 4, 5-diamino-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate | 1374298-19-7

• 分子结构分类: 有机化合物 - 苯类化合物
• 英文名称: methyl 4, 5-diamino-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate
• 英文别名: methyl 4,5-diamino-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylate；methyl 4,5-diamino-2,2-dimethyl-3H-1-benzofuran-7-carboxylate
• CAS: 1374298-19-7
• 化学式: C₁₂H₁₆N₂O₃
• 分子量: 236.271
• InChiKey: XLKHLOHMZQLVPM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  87.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  methyl 4, 5-diamino-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate 在 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 甲醇 、 水 、 乙腈 为溶剂， 反应 24.0h， 生成 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid
  参考文献：
  名称：

  Discovery of furan and dihydrofuran-fused tricyclic benzo[ d ]imidazole derivatives as potent and orally efficacious microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors: Part-1

  摘要：

  This letter describes the synthesis and biological evaluation of furan and dihydrofuran-fused tricyclic benzo[d]imidazole derivatives as novel mPGES-1 inhibitors, capable of inhibiting an increased PGE(2) production in the disease state. Structure-activity optimization afforded many potent mPGES-1 inhibitors having <50 nM potencies in the A549 cellular assay and adequate metabolic stability in liver microsomes. Lead compounds 8l and 8m demonstrated reasonable in vitro pharmacology and pharmacokinetic properties over other compounds. In particular, 8m revealed satisfactory oral pharmacokinetics and bioavailability in multiple species like rat, guinea pig, dog and cynomolgus monkey. In addition, the representative compound 8m showed in vivo efficacy by inhibiting LPS-induced thermal hyperalgesia with an ED50 of 14.3 mg/kg in guinea pig. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2017.10.062
• 作为产物：
  描述：

  ethyl 4-(benzylamino)-2-fluoro-5-nitrobenzoate 在 盐酸 、 aluminum (III) chloride 、 甲酸 、 sodium methylate 、 铁粉 、 potassium carbonate 、 N,N-二乙基苯胺 作用下， 以 甲醇 、 水 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.8h， 生成 methyl 4, 5-diamino-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate
  参考文献：
  名称：

  Tricyclic Compounds As mPGES-1 Inhibitors

  摘要：

  本发明涉及式(I)的三环化合物或其药用可接受的盐作为mPGES-1抑制剂。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，因此在治疗各种疾病或病况引起的疼痛和/或炎症方面具有用处，如哮喘、骨关节炎、类风湿性关节炎、急性或慢性疼痛和神经退行性疾病。

  公开号：

  US20120108583A1

文献信息

• Tricyclic compounds as mPGES-1 inhibitors
  申请人：Gharat Laxmikant A.

  公开号：US08519149B2

  公开（公告）日：2013-08-27

  The present invention relates to tricyclic compounds of formula (I) or pharmaceutically acceptable salt thereof as mPGES-1 inhibitors. These compounds are inhibitors of the microsomal prostaglandin E synthase-1 (mPGES-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.

  本发明涉及公式(I)的三环化合物或其药学上可接受的盐，作为mPGES-1抑制剂。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，因此在治疗多种疾病或病况引起的疼痛和/或炎症方面非常有用，例如哮喘、骨关节炎、类风湿性关节炎、急性或慢性疼痛和神经退行性疾病。
• Alleviating CYP and hERG liabilities by structure optimization of dihydrofuran-fused tricyclic benzo[ d ]imidazole series – Potent, selective and orally efficacious microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors: Part-2
  作者：Nagarajan Muthukaman、Sanjay Deshmukh、Macchindra Tambe、Dnyandeo Pisal、Shital Tondlekar、Mahamadhanif Shaikh、Neelam Sarode、Vidya G. Kattige、Pooja Sawant、Monali Pisat、Vikas Karande、Srinivasa Honnegowda、Abhay Kulkarni、Dayanidhi Behera、Satyawan B. Jadhav、Ramchandra R. Sangana、Girish S. Gudi、Neelima Khairatkar-Joshi、Laxmikant A. Gharat

  DOI：10.1016/j.bmcl.2018.02.048

  日期：2018.4

  In an effort to identify CYP and hERG clean mPGES-1 inhibitors from the dihydrofuran-fused tricyclic benzo[d] imidazole series lead 7, an extensive structure-activity relationship (SAR) studies were performed. Optimization of A, D and E-rings in 7 afforded many potent compounds with human whole blood potency in the range of 160-950 nM. Selected inhibitors 21d, 21j, 21m, 21n, 21p and 22b provided selectivity against COX-enzymes and mPGES-1 isoforms (mPGES-2 and cPGES) along with sufficient selectivity against prostanoid synthases. Most of the tested analogs demonstrated required metabolic stability in liver microsomes, low hERG and CYP liability. Oral pharmacokinetics and bioavailability of lead compounds 21j, 21m and 21p are discussed in multiple species like rat, guinea pig, dog, and cynomolgus monkey. Besides, these compounds revealed low to moderate activity against human pregnane X receptor (hPXR). The selected lead 21j further demonstrated in vivo efficacy in acute hyperalgesia (ED50: 39.6 mg/kg) and MIA-induced osteoarthritic pain models (ED50: 106 mg/kg). (C) 2018 Elsevier Ltd. All rights reserved.
• US8519149B2
  申请人：——

  公开号：US8519149B2

  公开（公告）日：2013-08-27
• [EN] TRICYCLIC COMPOUNDS AS MPGES-1 INHIBITORS<br/>[FR] COMPOSÉS TRICYCLIQUES EN TANT QU'INHIBITEURS DE MPGES-1
  申请人：GLENMARK PHARMACEUTICALS SA

  公开号：WO2012055995A1

  公开（公告）日：2012-05-03

  The present invention relates to tricyclic compounds of formula (I) or pharmaceutically acceptable salt thereof as mPGES-1 inhibitors. These compounds are inhibitors of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme and are therefore useful in the treatment of pain and/or inflammation from a variety of diseases or conditions, such as asthama, osteoarthritis, rheumatoid arthritis, acute or chronic pain and neurodegenerative diseases.