1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid methyl ester | 1586791-31-2

• 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-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid methyl ester
• 英文别名: methyl 1-(pentan-3-yl)-2-(thiophen-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxylate；methyl 1-pentan-3-yl-2-(thiophen-2-ylmethyl)benzimidazole-5-carboxylate
• CAS: 1586791-31-2
• 化学式: C₁₉H₂₂N₂O₂S
• 分子量: 342.462
• InChiKey: VTIOEAVXSVYJNU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  24
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  72.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid methyl ester 在 N-羟基-7-氮杂苯并三氮唑 、 水 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 20.33h， 生成 1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid ((S)-3-methyl-1-methylsulfamoylmethyl-butyl)-amide
  参考文献：
  名称：

  BENZOIMIDAZOLE-CARBOXYLIC ACID AMIDE DERIVATIVES AS APJ RECEPTOR MODULATORS

  摘要：

  本发明涉及公式I的苯并咪唑羧酰胺化合物，其中R′、R″、R′″、R1、R2、R3、R4、R5、R6和Z的定义如下所示。公式I的化合物是APJ受体调节剂，对治疗与增高血压相关的疾病有用。此外，本发明还涉及将公式I的化合物用作药物中的活性成分，以及包含它们的药物组合物。

  公开号：

  US20140094450A1
• 作为产物：
  描述：

  2-噻吩乙腈 在 乙酰氯 作用下， 以 甲醇 、 乙醚 为溶剂， 反应 9.0h， 生成 1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid methyl ester
  参考文献：
  名称：

  CMF-019的简便合成方法：（S）-5-甲基-3- {1-（戊-3-基）-2-（噻吩-2-基甲基）-1H-苯并[d]咪唑-5-甲酰胺基}己酸，有效的Apelin受体（APJ）激动剂。

  摘要：

  背景技术Apelin受体（APJ）是由内源性肽Apelin激活的G蛋白偶联受体（GPCR）。apelin-APJ系统已成为心血管稳态的重要调节剂。最近，一种强效的苯并咪唑衍生的阿珀林肽模拟物CMF-019获得了专利，但没有对其合成方法和中间体的完整光谱表征进行全面描述。目的本文描述了通过改良和改进的合成途径制备CMF-019的详细方法。方法特别是7-中的苯并咪唑环是通过3-氨基-4-（戊-3-基氨基）苯甲酸甲酯（4）与（噻吩-2-基）乙酰基亚氨酸盐6的缩合反应制得的。将7皂化，然后将游离酸8与相应的对映纯β-氨基酸甲酯缩合，生成甲基（S）-5-甲基-3- {1-（戊-3-基）-2-（噻吩- （2-基甲基）-1H苯并[d]咪唑-5-甲酰胺基}己酸酯（9）。后者用KOH在THF /水中水解，然后进行HPLC纯化，得到所需的产物CMF-019（钾盐）10。结果与结论本文报道的方法能够以10％的总

  DOI：

  10.2174/1573406414666180412154952

文献信息

• BENZOIMIDAZOLE-CARBOXYLIC ACID AMIDE DERIVATIVES AS APJ RECEPTOR MODULATORS
  申请人：HACHTEL Stephanie

  公开号：US20140094450A1

  公开（公告）日：2014-04-03

  The present invention relates to benzoimidazole-carboxylic acid amide compounds of the formula I, in which R′, R″, R′″, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Z are defined as indicated below. The compounds of the formula I are APJ receptor modulators, and are useful for the treatment of diseases associated with increased blood pressure for example. The invention furthermore relates to the use of compounds of the formula I, in particular as active ingredients in pharmaceuticals, and pharmaceutical compositions comprising them.

  本发明涉及公式I的苯并咪唑羧酰胺化合物，其中R′、R″、R′″、R1、R2、R3、R4、R5、R6和Z的定义如下所示。公式I的化合物是APJ受体调节剂，对治疗与增高血压相关的疾病有用。此外，本发明还涉及将公式I的化合物用作药物中的活性成分，以及包含它们的药物组合物。
• Benzoimidazole-carboxylic acid amide derivatives as APJ receptor modulators
  申请人：SANOFI

  公开号：US09156796B2

  公开（公告）日：2015-10-13

  The present invention relates to benzoimidazole-carboxylic acid amide compounds of the formula I, in which R′, R″, R′″, R1, R2, R3, R4, R5, R6 and Z are defined as indicated below. The compounds of the formula I are APJ receptor modulators, and are useful for the treatment of diseases associated with increased blood pressure for example. The invention furthermore relates to the use of compounds of the formula I, in particular as active ingredients in pharmaceuticals, and pharmaceutical compositions comprising them.

  本发明涉及式I的苯并咪唑羧酸酰胺化合物，其中R'、R"、R'"、R1、R2、R3、R4、R5、R6和Z如下所示。式I的化合物是APJ受体调节剂，可用于治疗与血压升高相关的疾病。此外，本发明还涉及使用式I的化合物，特别是作为药物的活性成分，以及包含它们的制药组合物。
• Cardiac action of the first G protein biased small molecule apelin agonist
  作者：Cai Read、Christopher M. Fitzpatrick、Peiran Yang、Rhoda E. Kuc、Janet J. Maguire、Robert C. Glen、Richard E. Foster、Anthony P. Davenport

  DOI：10.1016/j.bcp.2016.07.018

  日期：2016.9

  Apelin peptide analogues displaying bias towards G protein signalling pathways have beneficial cardiovascular actions compared with the native peptide in humans in vivo. Our aim was to determine whether small molecule agonists could retain G protein bias. We have identified a biased small molecule, CMF-019, and characterised it in vitro and in vivo.In competition radioligand binding experiments in heart homogenates, CMF-019 bound to the human, rat and mouse apelin receptor with high affinity (pK(i) = 8.58 +/- 0.04, 8.49 +/- 0.04 and 8.71 +/- 0.06 respectively). In cell-based functional assays, whereas, CMF-019 showed similar potency for the G(alpha i) pathway to the endogenous agonist [Pyr(1)]apelin-13 (pD(2) = 10.00 +/- 0.13 vs 9.34 +/- 0.15), in beta-arrestin and internalisation assays it was less potent (pD(2) = 6.65 +/- 0.15 vs 8.65 +/- 0.10 and pD(2) = 6.16 +/- 0.21 vs 9.28 +/- 0.10 respectively). Analysis of these data demonstrated a bias of similar to 400 for the G(alpha i) over the beta-arrestin pathway and similar to 6000 over receptor internalisation. CMF-019 was tested for in vivo activity using intravenous injections into anaesthetised male Sprague-Dawley rats fitted with a pressure-volume catheter in the left ventricle. CMF-019 caused a significant increase in cardiac contractility of 606 +/- 112 mmHg/s (p < 0.001) at 500 nmol. CMF-019 is the first biased small molecule identified at the apelin receptor and increases cardiac contractility in vivo. We have demonstrated that G(alpha i) over beta-arrestin/internalisation bias can be retained in a non-peptide analogue and predict that such bias will have the therapeutic benefit following chronic use. CMF-019 is suitable as a tool compound and provides the basis for design of biased agonists with improved pharmacokinetics for treatment of cardiovascular conditions such as pulmonary arterial hypertension. (C) 2016 The Author(s). Published by Elsevier Inc.
• BENZOIMIDAZOLE-CARBOXYLIC ACID AMIDE DERIVATIVES FOR TREATING METABOLIC OR CARDIOVASCULAR DISEASES
  申请人：SANOFI

  公开号：EP2897939B1

  公开（公告）日：2017-02-01
• US9156796B2
  申请人：——

  公开号：US9156796B2

  公开（公告）日：2015-10-13