methyl 3-{4-[(4'-hydroxy-2',6'-dimethylbiphenyl-3-yl)methoxy]phenyl}propanoate | 858096-99-8

• 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: methyl 3-{4-[(4'-hydroxy-2',6'-dimethylbiphenyl-3-yl)methoxy]phenyl}propanoate
• 英文别名: methyl 3-[4-[(4'-hydroxy-2',6'-dimethylbiphenyl-3-yl)methoxy]phenyl]propanoate；methyl 3-[4-[[3-(4-hydroxy-2,6-dimethylphenyl)phenyl]methoxy]phenyl]propanoate
• CAS: 858096-99-8
• 化学式: C₂₅H₂₆O₄
• 分子量: 390.479
• InChiKey: YUBYMEWWKAUDBN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  29
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  55.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 3-{4-[(4'-hydroxy-2',6'-dimethylbiphenyl-3-yl)methoxy]phenyl}propanoate 在 水 、 三苯基膦 、 sodium hydroxide 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 甲醇 、 甲苯 为溶剂， 反应 16.0h， 生成 3-(4-{[4'-(cyclopropylmethoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}phenyl)propanoic acid
  参考文献：
  名称：

  Discovery of Phenylpropanoic Acid Derivatives Containing Polar Functionalities as Potent and Orally Bioavailable G Protein-Coupled Receptor 40 Agonists for the Treatment of Type 2 Diabetes

  摘要：

  As part of a program to identify potent GPR40 agonists with drug-like properties suitable for clinical development, the incorporation of polar substituents was explored with the intention of decreasing the lipophilicity of our recently disclosed phenylpropanoic acid derivative 1. This incorporation would allow us to mitigate the cytotoxicity issues observed with compound 1 and enable us to move away from the multifunctional free fatty acid-like structure. Substitutions on the 2',6'-dimethylbiphenyl ring were initially undertaken, which revealed the feasibility of introducing polar functionalities at the biphenyl 4'-position. Further optimization of this position and the linker led to the discovery of several 4'-alkoxybiphenyl derivatives, which showed potent GPR40 agonist activities with the best balance in terms of improved cytotoxicity profiles and favorable pharmacokinetic properties. Among them, 3-{2-fluoro-4[({4'-[(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2',6'-dimethylbiphenyl-3-yl}methyl)amino]phenyl}propanoic acid (35) exhibited a robust plasma glucose-lowering effect and insulinotropic action during an oral glucose tolerance test in rats with impaired glucose tolerance.

  DOI：

  10.1021/jm2016123
• 作为产物：
  描述：

  methyl 3-(4-{[2',6'-dimethyl-4'-(tetrahydro-2H-pyran-2-yloxy)biphenyl-3-yl]methoxy}phenyl)propanoate 在 对甲苯磺酸 甲醇 作用下， 反应 2.0h， 以88%的产率得到methyl 3-{4-[(4'-hydroxy-2',6'-dimethylbiphenyl-3-yl)methoxy]phenyl}propanoate
  参考文献：
  名称：

  [EN] 3-(4-BENZYLOXYPHENYL)PROPANOIC ACID DERIVATIVES
  [FR] DERIVES D'ACIDE 3-(4-BENZYLOXYPHENYL) PROPANOIQUE

  摘要：

  本发明提供了一种由公式(I)表示的新的化合物，其中每个符号如说明书中所定义，以及其盐和前药，具有优越的GPR40受体功能调节作用，可用作胰岛素分泌剂，用于预防或治疗糖尿病等的药剂。它们出人意料地显示出优越的GPR40受体激动剂活性，并且还显示出作为药物产品的优越性质，如稳定性等。因此，它们可以成为预防或治疗哺乳动物中与GPR40受体相关疾病的既安全又有用的药物。

  公开号：

  WO2005063729A1

文献信息

• 3-(4-Benzyloxyphenyl) propanoic acid derivatives
  申请人：Yasuma Tsuneo

  公开号：US20070149608A1

  公开（公告）日：2007-06-28

  The present invention provides a novel compound represented by the formula (I) wherein each symbol is as defined in the specification, a salt thereof and a prodrug thereof having a superior GPR40 receptor function modulating action, which can be used as an insulin secretagogue, an agent for the prophylaxis or treatment of diabetes and the like. They unexpectedly show superior GPR40 receptor agonist activity, and also show superior properties as a pharmaceutical product, such as stability and the like. Thus, they can be safe and useful pharmaceutical agents for the prophylaxis or treatment of GPR40 receptor related diseases in mammals.

  本发明提供一种新型化合物，其表示为式（I），其中每个符号如规范中所定义，其盐和前药具有优越的GPR40受体功能调节作用，可用作胰岛素分泌促进剂、糖尿病预防或治疗剂等。它们意外地表现出优越的GPR40受体激动剂活性，并且还表现出优越的药物产品特性，如稳定性等。因此，它们可以作为安全和有用的药物剂量，用于哺乳动物的GPR40受体相关疾病的预防或治疗。
• 3-(4-benzyloxyphenyl) propanoic acid derivatives
  申请人：Takeda Pharmaceutical Company Limited

  公开号：US07456218B2

  公开（公告）日：2008-11-25

  The present invention provides a novel compound represented by the formula (I) wherein each symbol is as defined in the specification, a salt thereof and a prodrug thereof having a superior GPR40 receptor function modulating action, which can be used as an insulin secretagogue, an agent for the prophylaxis or treatment of diabetes and the like. They unexpectedly show superior GPR40 receptor agonist activity, and also show superior properties as a pharmaceutical product, such as stability and the like. Thus, they can be safe and useful pharmaceutical agents for the prophylaxis or treatment of GPR40 receptor related diseases in mammals.

  本发明提供了一种新型化合物，其由公式（I）所表示，其中每个符号如规范中所定义，其盐和前药具有优越的GPR40受体功能调节作用，可用作胰岛素分泌剂、糖尿病预防或治疗剂等。它们意外地表现出优越的GPR40受体激动剂活性，并且还表现出优越的药物产品性质，如稳定性等。因此，它们可以是哺乳动物GPR40受体相关疾病预防或治疗的安全和有用的药物剂。
• 3-(4-BENZYLOXYPHENYL)PROPANOIC ACID DERIVATIVES
  申请人：Takeda Pharmaceutical Company Limited

  公开号：EP1697339A1

  公开（公告）日：2006-09-06
• US7456218B2
  申请人：——

  公开号：US7456218B2

  公开（公告）日：2008-11-25
• [EN] 3-(4-BENZYLOXYPHENYL)PROPANOIC ACID DERIVATIVES<br/>[FR] DERIVES D'ACIDE 3-(4-BENZYLOXYPHENYL) PROPANOIQUE
  申请人：TAKEDA PHARMACEUTICAL

  公开号：WO2005063729A1

  公开（公告）日：2005-07-14

  The present invention provides a novel compound represented by the formula (I) wherein each symbol is as defined in the specification, a salt thereof and a prodrug thereof having a superior GPR40 receptor function modulating action, which can be used as an insulin secretagogue, an agent for the prophylaxis or treatment of diabetes and the like. They unexpectedly show superior GPR40 receptor agonist activity, and also show superior properties as a pharmaceutical product, such as stability and the like. Thus, they can be safe and useful pharmaceutical agents for the prophylaxis or treatment of GPR40 receptor related diseases in mammals.

  本发明提供了一种由公式(I)表示的新的化合物，其中每个符号如说明书中所定义，以及其盐和前药，具有优越的GPR40受体功能调节作用，可用作胰岛素分泌剂，用于预防或治疗糖尿病等的药剂。它们出人意料地显示出优越的GPR40受体激动剂活性，并且还显示出作为药物产品的优越性质，如稳定性等。因此，它们可以成为预防或治疗哺乳动物中与GPR40受体相关疾病的既安全又有用的药物。