4'-hydroxy-2'-methyl-[1,1'-biphenyl]-3-carbaldehyde | 955930-70-8

• 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: 4'-hydroxy-2'-methyl-[1,1'-biphenyl]-3-carbaldehyde
• 英文别名: 3-(4-hydroxy-2-methylphenyl)benzaldehyde
• CAS: 955930-70-8
• 化学式: C₁₄H₁₂O₂
• 分子量: 212.248
• InChiKey: ZQVJIOYKPWWZJX-UHFFFAOYSA-N

物化性质

• 沸点：
  370.8±30.0 °C(Predicted)
• 密度：
  1.172±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  37.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4'-hydroxy-2'-methyl-[1,1'-biphenyl]-3-carbaldehyde 在 甲醇 、 sodium tetrahydroborate 作用下， 以96%的产率得到3'-(hydroxymethyl)-2-methyl-[1,1'-biphenyl]-4-ol
  参考文献：
  名称：

  [EN] PHENYL ALKANOIC ACID DERIVATIVES AS GPR AGONISTS
  [FR] DÉRIVÉS D'ACIDE PHÉNYLALCANOÏQUE EN TANT QU'AGONISTES DU RPG

  摘要：

  本发明涉及苯基烷酸衍生物（公式(I)的化合物）；及其同位素形式、立体异构体、互变异构体和所有比例的混合物，或其药物可接受的盐、药物可接受的溶剂化物、前药、多态性、N-氧化物、S-氧化物或羧酸的等排体。本发明还涉及制备公式(I)化合物的方法和包含一个或多个公式(I)化合物的药物组合物。所述化合物和药物组合物作为GPR（G蛋白偶联受体）激动剂，特别是作为GPR40激动剂，并且可用于治疗由GPR40介导的疾病或状况。本发明进一步涉及一种治疗由GPR40介导的疾病或状况的方法，包括向需要治疗的受试者施用治疗有效量的公式(I)化合物。

  公开号：

  WO2013128378A1
• 作为产物：
  描述：

  4-溴-3-甲基苯酚 、 3-甲酰基苯硼酸 在 四(三苯基膦)钯 、 sodium carbonate 作用下， 以 乙醇 、 水 、 甲苯 为溶剂， 反应 8.0h， 以64.5%的产率得到4'-hydroxy-2'-methyl-[1,1'-biphenyl]-3-carbaldehyde
  参考文献：
  名称：

  设计，合成和评估FFA1的一系列新型苯丙酸衍生物激动剂。

  摘要：

  游离脂肪酸1（FFA1 / GPR40）作为治疗2型糖尿病的新靶标已受到广泛关注，因为它在增强葡萄糖依赖性胰岛素分泌方面发挥了作用。为了开发新型有效的FFA1激动剂，在对TAK-875，AMG-837和LY2881835化学水泥进行改性的基础上，设计并合成了一系列新的苯丙酸衍生物。其中，获得最有前途的化合物7、14和15，其EC50值为82、79和88 nM，与TAK-875（95.1 nM）相比，显示出强大的激动活性。在正常小鼠的口服葡萄糖耐量试验期间，化合物7、14和15在50 mg / kg的剂量下具有显着的降糖作用。此外，化合物15（50 mg / kg）在2型糖尿病小鼠中的葡萄糖耐量也显着提高。在此处，我们报道了一系列有效的FFA1激动剂的发现和优化。这一发现支持了对该支架的进一步探索。

  DOI：

  10.1111/cbdd.13480

文献信息

• Design, synthesis and biological evaluation of novel FFA1/GPR40 agonists: New breakthrough in an old scaffold
  作者：Zheng Li、Chunxia Liu、Jianyong Yang、Jiaqi Zhou、Zhiwen Ye、Dazhi Feng、Na Yue、Jiayi Tong、Wenlong Huang、Hai Qian

  DOI：10.1016/j.ejmech.2019.06.087

  日期：2019.10

  on an old phenoxyacetic acid scaffold, CPU014 (compound 14) has been identified as a superior agonist by comprehensive exploration of structure-activity relationship. In vitro toxicity study suggested that CPU014 has lower risk of hepatotoxicity than TAK-875. During acute toxicity study (5–500 mg/kg), a favorable therapeutic window of CPU014 was observed by evaluation of plasma profiles and liver slices

  基于旧的苯氧乙酸支架，通过全面探索结构-活性关系，CPU014（化合物14）被确定为优良的激动剂。体外毒性研究表明，CPU014的肝毒性风险低于TAK-875。在急性毒性研究（5-500 mg / kg）中，通过评估血浆谱和肝切片观察到了CPU014的有利治疗窗口。此外，CPU014以葡萄糖依赖的方式促进胰岛素分泌，而GLP-1的分泌却没有增加。除了良好的药代动力学特性，CPU014在正常和糖尿病模型中均显着提高了葡萄糖耐量，没有低血糖的风险。这些颠覆性发现提供了更安全的候选CPU014，目前正在临床前研究中评估其在糖尿病治疗中的潜力。
• OXADIAZOLIDINEDIONE COMPOUND
  申请人：Negoro Kenji

  公开号：US20100267775A1

  公开（公告）日：2010-10-21

  A pharmaceutical agent having GPR40 receptor agonistic action, particularly a compound which is useful as an insulin secretagogue or an agent for preventing and/or treating diabetes mellitus. The present inventors have examined a compound having GPR40 receptor agonistic action, confirmed that an oxadiazolidinedione compound which has a substituent such as a benzyl group, etc. linked with a substituent such as a phenyl group, etc. through a linker at the 2-position of an oxadiazolidinedione ring, or a pharmaceutically acceptable salt thereof has an excellent GPR40 agonistic activity, and thus completed the invention. The oxadiazolidinedione compound has excellent insulin secretagogue action and anti-hyperglycemic action, and therefore can be used as an insulin secretagogue or an agent for preventing and/or treating diabetes mellitus.

  一种具有GPR40受体激动作用的药物，特别是一种可用作胰岛素分泌剂或预防和/或治疗糖尿病的药物。本发明人研究了一种具有GPR40受体激动作用的化合物，确认了一种氧杂二唑烷环的2位上有一个连接着苯基等取代基的连接基的苯甲基等取代基的氧杂二唑烷酮化合物，或其药学上可接受的盐具有优异的GPR40激动活性，从而完成了本发明。氧杂二唑烷酮化合物具有优异的胰岛素分泌剂作用和抗高血糖作用，因此可用作胰岛素分泌剂或预防和/或治疗糖尿病的药物。
• PHENYL ALKANOIC ACID DERIVATIVES AS GPR AGONISTS
  申请人：PIRAMAL ENTERPRISES LIMITED

  公开号：US20150072969A1

  公开（公告）日：2015-03-12

  The present invention relates to phenyl alkanoic acid derivatives (the compounds of Formula (I)); and their isotopic forms, stereoisomeric and tautomeric forms and mixtures thereof in all ratios, or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, prodrugs, polymorphs, N-oxides, S-oxides or carboxylic acid isosteres thereof. The invention also relates to processes for the preparation of compounds of Formula (I) and pharmaceutical compositions comprising one or more of the compounds of Formula (I). The said compounds and the pharmaceutical composition function as GPR (G-protein coupled receptor) agonists, particularly as GPR40 agonists, and are useful in the treatment of diseases or conditions mediated by GPR40. The present invention further relates to a method of treatment of diseases or conditions mediated by GPR40 comprising administering to a subject in need thereof a therapeutically effective amount of the compounds of Formula (I).

  本发明涉及苯基脂肪酸衍生物（式（I）化合物）及其同位素形式、立体异构体和互变异构体，以及所有比例的混合物或药学上可接受的盐、药学上可接受的溶剂化物、前药、多晶型、N-氧化物、S-氧化物或其羧酸异构体。该发明还涉及制备式（I）化合物的过程和包含一种或多种式（I）化合物的制药组合物。所述化合物和制药组合物作为GPR（G蛋白偶联受体）激动剂，特别是作为GPR40激动剂，并且在治疗由GPR40介导的疾病或病况中有用。本发明还涉及一种治疗由GPR40介导的疾病或病况的方法，包括向需要治疗的受体中注射式（I）化合物的治疗有效量。
• Oxadiazolidinedione Compound
  申请人：Negoro Kenji

  公开号：US20090186909A1

  公开（公告）日：2009-07-23

  [Problem] A compound which can be used as a pharmaceutical, particularly a insulin secretion promoter or a agent for preventing/treating disease in which GPR40 is concerned such as diabetes or the like, is provided. [Means for resolution] It was found that an oxadiazolidinedione compound which is characterized by the possession of a benzyl or the like substituent binding to the cyclic group via a linker at the 2-position of the oxadiazolidinedione ring, or a pharmaceutically acceptable salt thereof, has excellent GPR40 agonist action. In addition, since the oxadiazolidinedione compound of the present invention showed excellent insulin secretion promoting action and blood glucose level-lowering action, it is useful as an insulin secretion promoter or an agent for preventing/treating diabetes.

  【问题】提供一种可用作药物的化合物，特别是胰岛素分泌促进剂或用于预防/治疗涉及GPR40的疾病，如糖尿病等。 【解决方法】发现一种氧代唑烷二酮化合物，其特征在于在氧代唑烷二酮环的2位通过连接基与环上的苯甲基或类似取代基结合，或其药学上可接受的盐具有优异的GPR40激动剂作用。此外，由于本发明的氧代唑烷二酮化合物表现出良好的胰岛素分泌促进作用和降低血糖水平的作用，因此它可用作胰岛素分泌促进剂或预防/治疗糖尿病的药物。
• Discovery of HWL-088: A highly potent FFA1/GPR40 agonist bearing a phenoxyacetic acid scaffold
  作者：Zheng Li、Qiang Ren、Xuekun Wang、Zongtao Zhou、Lijun Hu、Liming Deng、Li Guan、Qianqian Qiu

  DOI：10.1016/j.bioorg.2019.103209

  日期：2019.11

  Based on a previously reported phenoxyacetic acid scaffold, compound 7 (HWL-088) has been identified as a superior free fatty acid receptor 1 (FFA1) agonist by comprehensive structure-activity relationship study. Our results indicated that the introduction of ortho-fluoro greatly increased the activity of phenoxyacetic acid series, and the unique structure-activity relationship in biphenyl moiety is different from previously reported FFA1 agonists. Moreover, the modeling study was also performed to better understand the binding mode of present series. Compound 7 significantly improved glucose tolerance both in normal and diabetic models, and even exerted greater potential on glucose control than that of TAK-875. These findings provided a novel candidate HWL-088, which is currently in preclinical study to evaluate its potential for the treatment of diabetes.