methyl 4-amino-2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-7-carboxylate | 1374298-18-6

• 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: methyl 4-amino-2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-7-carboxylate
• 英文别名: methyl 4-amino-2,3-dihydro-2,2-dimethyl-5-nitrobenzofuran-7-carboxylate；methyl 4-amino-2,2-dimethyl-5-nitro-2,3-dihydro-1-benzofuran-7-carboxylate；methyl 4-amino-2,2-dimethyl-5-nitro-3H-1-benzofuran-7-carboxylate
• CAS: 1374298-18-6
• 化学式: C₁₂H₁₄N₂O₅
• 分子量: 266.254
• InChiKey: NBWKLTFKYSXGCG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  19
• 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：
  107
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl 4-amino-2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-7-carboxylate 在 N-甲基吗啉 、 盐酸 、 水 、 铁粉 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 25.5h， 生成 N-cyclohexyl-2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxamide
  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
• 作为产物：
  描述：

  4-氨基水杨酸 在 aluminum (III) chloride 、 sodium nitrate 、 硫酸 、 potassium carbonate 、 三氟乙酸 作用下， 以 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 59.0h， 生成 methyl 4-amino-2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-7-carboxylate
  参考文献：
  名称：

  氟化唑类抗结核药物的设计、合成和药理学评价

  摘要：

  描述了作为抗结核药物的 2,2-二甲基-2,3-二氢苯并呋喃系留 1,3,4-恶二唑衍生物的设计、合成和生物筛选。目标化合物的合成通过一系列反应方案进行。所有合成的化合物均通过IR、1H NMR、13C NMR和质谱进行表征。分子对接研究证实了合成化合物的治疗潜力。在合成的化合物中，发现 12a、12c、12d、12e、12g 和 12j 在体外和体外对非复制性结核分枝杆菌 H37Ra 的复制培养物比对复制培养物更有活性。这些化合物的最低抑菌浓度 (MIC) 值在 2.31–23.91 μg/mL 范围内。针对细胞系 THP-1、A549 和 PANC-1 进行细胞毒性研究，并且观察到这些化合物对宿主细胞无毒。用 InhA (FabI/ENR) 进行分子对接，并表明合成化合物的抗分枝杆菌潜力。发现这里提出的调查对于开发针对分枝杆菌感染的新治疗剂是偶然的。

  DOI：

  10.1002/ardp.201700294

文献信息

• 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
  作者：Nagarajan Muthukaman、Macchindra Tambe、Sanjay Deshmukh、Dnyandeo Pisal、Shital Tondlekar、Mahamadhanif Shaikh、Neelam Sarode、Vidya G. Kattige、Monali Pisat、Pooja Sawant、Srinivasa Honnegowda、Vikas Karande、Abhay Kulkarni、Dayanidhi Behera、Satyawan B. Jadhav、Ramchandra R. Sangana、Girish S. Gudi、Neelima Khairatkar-Joshi、Laxmikant A. Gharat

  DOI：10.1016/j.bmcl.2017.10.062

  日期：2017.12

  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.
• 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.