(R)-1-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide | 1268713-31-0

• 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: (R)-1-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
• 英文别名: 1-(5,6-dichloro-1H-benzimidazol-2-yl)-N-[(3R)-oxolan-3-yl]piperidine-4-carboxamide
• CAS: 1268713-31-0
• 化学式: C₁₇H₂₀Cl₂N₄O₂
• 分子量: 383.277
• InChiKey: KERAHQPIDBAXAI-LLVKDONJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  70.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-溴异喹啉 、 (R)-1-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide 在 copper(I) oxide 、 8-羟基喹啉 caesium carbonate 作用下， 以 二甲基亚砜 为溶剂， 反应 3.0h， 以8%的产率得到(R)-1-(5,6-dichloro-1-(isoquinolin-3-yl)-1H-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
  参考文献：
  名称：

  [EN] PIPERIDINYL BENZOIMIDAZOLE DERIVATIVES AS MPGES-1 INIHIBITORS
  [FR] DÉRIVÉS DE PIPÉRIDINYL BENZOIMIDAZOLE COMME INHIBITEURS DE MPGES-1

  摘要：

  式（I）的化合物及其药用盐，以及包含该化合物的药物组合物。该化合物可用于治疗选择自炎症性疾病、疼痛、自身免疫疾病、呼吸系统疾病、发热、癌症、与炎症相关的厌食症、膀胱过度活跃、家族性腺瘤性息肉病（FAP）病情、神经退行性疾病、骨病和心血管疾病的混合物。

  公开号：

  WO2012117062A1
• 作为产物：
  描述：

  2,5,6-三氯苯并咪唑 在 水 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.67h， 生成 (R)-1-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
  参考文献：
  名称：

  [EN] MICROSOMAL PROSTAGLANDIN E SYNTHASE-1 (MPGES1) INHIBITORS
  [FR] INHIBITEURS DE PROSTAGLANDINE E SYNTHASE-1 (MPGES1) MICROSOMALE

  摘要：

  公式（I）的化合物，以及其药用盐，以及包括该化合物的药物组合物。该化合物用于治疗选择自炎性疾病、伤害性疼痛、自身免疫疾病、呼吸系统疾病、发热、癌症、与炎症相关的厌食症、阿尔茨海默病和心血管疾病的紊乱。

  公开号：

  WO2011023812A1

文献信息

• [EN] MICROSOMAL PROSTAGLANDIN E SYNTHASE-1 (MPGES1) INHIBITORS<br/>[FR] INHIBITEURS DE PROSTAGLANDINE E SYNTHASE-1 (MPGES1) MICROSOMALE
  申请人：NOVASAID AB

  公开号：WO2011023812A1

  公开（公告）日：2011-03-03

  A compound of formula (I): as well as pharmaceutically acceptable salts thereof, and a pharmaceutical composition comprising the compound. The compound is useful for the treatment of disorder selected from inflammatory diseases, nociceptive pain, auto-immune disease, breathing disorders, fever, cancer, inflammation related anorexia, Alzheimer's disease and cardiovascular diseases.

  公式（I）的化合物，以及其药用盐，以及包括该化合物的药物组合物。该化合物用于治疗选择自炎性疾病、伤害性疼痛、自身免疫疾病、呼吸系统疾病、发热、癌症、与炎症相关的厌食症、阿尔茨海默病和心血管疾病的紊乱。
• Piperidinyl benzoimidazole derivatives as mPGEs-1 inhibitors
  申请人：NovaSaid AB

  公开号：EP2495244A1

  公开（公告）日：2012-09-05

  A compound of formula (I): as well as pharmaceutically acceptable salts thereof, and a pharmaceutical composition comprising the compound. The compound is useful for the treatment of disorder selected from inflammatory diseases, pain, auto-immune disease, breathing disorders, fever, cancer, inflammation related anorexia, overactive bladder, familial adenomatous polyposis (FAP) condition, neurodegenerative diseases, bone diseases and cardiovascular diseases.

  式 (I) 的化合物： 及其药学上可接受的盐类，以及包含该化合物的药物组合物。该化合物可用于治疗选自炎症性疾病、疼痛、自身免疫性疾病、呼吸障碍、发热、癌症、与炎症相关的厌食症、膀胱过度活动症、家族性腺瘤性息肉病（FAP）、神经退行性疾病、骨病和心血管疾病的疾病。
• [EN] PIPERIDINYL BENZOIMIDAZOLE DERIVATIVES AS MPGES-1 INIHIBITORS<br/>[FR] DÉRIVÉS DE PIPÉRIDINYL BENZOIMIDAZOLE COMME INHIBITEURS DE MPGES-1
  申请人：NOVASAID AB

  公开号：WO2012117062A1

  公开（公告）日：2012-09-07

  A compound of formula (I) as well as pharmaceutically acceptable salts thereof, and a pharmaceutical composition comprising the compound. The compound is useful for the treatment of disorder selected from inflammatory diseases, pain, auto-immune disease, breathing disorders, fever, cancer, inflammation related anorexia, overactive bladder, familial adenomatous polyposis (FAP) condition, neurodegenerative diseases, bone diseases and cardiovascular diseases.

  式（I）的化合物及其药用盐，以及包含该化合物的药物组合物。该化合物可用于治疗选择自炎症性疾病、疼痛、自身免疫疾病、呼吸系统疾病、发热、癌症、与炎症相关的厌食症、膀胱过度活跃、家族性腺瘤性息肉病（FAP）病情、神经退行性疾病、骨病和心血管疾病的混合物。
• Biological characterization of new inhibitors of microsomal PGE synthase‐1 in preclinical models of inflammation and vascular tone
  作者：Karin Larsson、Julia Steinmetz、Filip Bergqvist、Samsul Arefin、Linda Spahiu、Johan Wannberg、Sven‐Christian Pawelzik、Ralf Morgenstern、Patric Stenberg、Karolina Kublickiene、Marina Korotkova、Per‐Johan Jakobsson

  DOI：10.1111/bph.14827

  日期：2019.12

  Background and PurposeMicrosomal PGE synthase‐1 (mPGES‐1), the inducible synthase that catalyses the terminal step in PGE2 biosynthesis, is of high interest as therapeutic target to treat inflammation. Inhibition of mPGES‐1 is suggested to be safer than traditional NSAIDs, and recent data demonstrate anti‐constrictive effects on vascular tone, indicating new therapeutic opportunities. However, there is a lack of potent mPGES‐1 inhibitors lacking interspecies differences for conducting in vivo studies in relevant preclinical disease models.Experimental ApproachPotency was determined based on the reduction of PGE2 formation in recombinant enzyme assays, cellular assay, human whole blood assay, and air pouch mouse model. Anti‐inflammatory properties were assessed by acute paw swelling in a paw oedema rat model. Effect on vascular tone was determined with human ex vivo wire myography.Key ResultsWe report five new mPGES‐1 inhibitors (named 934, 117, 118, 322, and 323) that selectively inhibit recombinant human and rat mPGES‐1 with IC50 values of 10–29 and 67–250 nM respectively. The compounds inhibited PGE2 production in a cellular assay (IC50 values 0.15–0.82 μM) and in a human whole blood assay (IC50 values 3.3–8.7 μM). Moreover, the compounds blocked PGE2 formation in an air pouch mouse model and reduced acute paw swelling in a paw oedema rat model. Human ex vivo wire myography analysis showed reduced adrenergic vasoconstriction after incubation with the compounds.Conclusion and ImplicationsThese mPGES‐1 inhibitors can be used as refined tools in further investigations of the role of mPGES‐1 in inflammation and microvascular disease.