methyl 2,2-dimethyl-4-(methylamino)-5-nitro-2,3-dihydrobenzofuran-7-carboxylate | 1374299-96-3

• 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 2,2-dimethyl-4-(methylamino)-5-nitro-2,3-dihydrobenzofuran-7-carboxylate
• 英文别名: methyl 2,2-dimethyl-4-(methylamino)-5-nitro-3H-1-benzofuran-7-carboxylate
• CAS: 1374299-96-3
• 化学式: C₁₃H₁₆N₂O₅
• 分子量: 280.28
• InChiKey: WNKBNWOLMMPDBS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  93.4
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl 2,2-dimethyl-4-(methylamino)-5-nitro-2,3-dihydrobenzofuran-7-carboxylate 在 铁粉 作用下， 以 甲醇 、 乙腈 为溶剂， 反应 26.0h， 生成 methyl 2-((2-chloro-6-fluorophenyl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate
  参考文献：
  名称：

  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

  摘要：

  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.

  DOI：

  10.1016/j.bmcl.2018.02.048
• 作为产物：
  描述：

  methyl 4-amino-2-((2-methylallyl)oxy)-5-nitrobenzoate 在 sodium hydride 、 N,N-二甲基苯胺 作用下， 以 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 4.5h， 生成 methyl 2,2-dimethyl-4-(methylamino)-5-nitro-2,3-dihydrobenzofuran-7-carboxylate
  参考文献：
  名称：

  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

  摘要：

  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.

  DOI：

  10.1016/j.bmcl.2018.02.048

文献信息

• Tricyclic Compounds As mPGES-1 Inhibitors
  申请人：Gharat Laxmikant A.

  公开号：US20120108583A1

  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 asthma, osteoarthritis, rheumatoid arthritis, acute or chronic pain and neurodegenerative diseases.

  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。
• 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。
• 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.