{5-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-1H-indole-1-yl}acetic acid | 805249-15-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: {5-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-1H-indole-1-yl}acetic acid
• 英文别名: {5-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-1H-indol-1-yl}acetic acid；2-[5-[[3-(2,6-dimethylphenyl)phenyl]methoxy]indol-1-yl]acetic acid
• CAS: 805249-15-4
• 化学式: C₂₅H₂₃NO₃
• 分子量: 385.463
• InChiKey: OYBMHHFUOSHEIX-UHFFFAOYSA-N

物化性质

• 沸点：
  582.9±50.0 °C(Predicted)
• 密度：
  1.16±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  51.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  2',6'-二甲基-3-联苯甲醛 在 sodium tetrahydroborate 、 三丁基膦 、 sodium hydride 、 potassium hydroxide 、 1,1'-azodicarbonyl-dipiperidine 作用下， 以 四氢呋喃 、 甲醇 、 乙二醇二甲醚 、 水 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 66.33h， 生成 {5-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-1H-indole-1-yl}acetic acid
  参考文献：
  名称：

  Identification of Fused-Ring Alkanoic Acids with Improved Pharmacokinetic Profiles that Act as G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1 Agonists

  摘要：

  The G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. We previously identified phenylpropanoic acid derivative 1 (3-{4-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid) as a potent and orally available GPR40/FFA1 agonist; however, 1 exhibited high clearance and low oral bioavailability, which was likely due to its susceptibility to beta-oxidation at the phenylpropanoic acid moiety. To identify long-acting compounds, we attempted to block the metabolically labile sites at the phenylpropanoic acid moiety by introducing a fused-ring structure. Various fused-ring alkanoic acids with potent GPR40/FFA1 activities and good PK profiles were produced. Further optimizations of the lipophilic portion and the acidic moiety led to the discovery of dihydrobenzofuran derivative 53 ((6-{[4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}-2,3-dihydro-1-benzofuran-3-yl)acetic acid), which acted as a GPR40/FFA1 agonist with in vivo efficacy during an oral glucose tolerance test (OGTT) in rats with impaired glucose tolerance.

  DOI：

  10.1021/jm2012968

文献信息

• Condensed ring compound
  申请人：Yasuma Tsuneo

  公开号：US20060258722A1

  公开（公告）日：2006-11-16

  The present invention aims at providing a novel fused ring compound having a GPR40 receptor function modulating action and being useful as an insulin secretagogue or a pharmaceutical agent for the prophylaxis or treatment of diabetes, more particularly, a compound represented by the formula: wherein Ar is an optionally substituted cyclic group, ring A is a ring optionally further substituted (provided that the ring is not thiazole, oxazole, imidazole and pyrazole), Xa and Xb are each independently a bond or a spacer having a main chain of 1 to 5 atom(s), Xc is O, S, SO or SO 2 , ring B is a 5- to 7-membered ring, Xd is a bond, CH or CH 2 , is a single bond when Xd is a bond or CH 2 , or a double bond when Xd is CH, and R 1 is an optionally substituted hydroxy group, and a salt thereof.

  本发明旨在提供一种新的融合环化合物，具有GPR40受体功能调节作用，并可用作胰岛素分泌剂或用于预防或治疗糖尿病的药物，更具体地说，是一种由以下公式表示的化合物：其中Ar是一个可选取代的环状基团，环A是一个环状基团，可选地进一步取代（前提是该环不是噻唑、噁唑、咪唑和吡唑），Xa和Xb分别是1到5个原子的主链具有键或间隔物，Xc是O、S、SO或SO2，环B是一个5-至7-成员环，Xd是键、CH或CH2，当Xd是键或CH2时为单键，当Xd为CH时为双键，R1为可选取代的羟基，以及其盐。
• CONDENSED RING COMPOUND
  申请人：Takeda Pharmaceutical Company Limited

  公开号：EP1630152A1

  公开（公告）日：2006-03-01

  The present invention aims at providing a novel fused ring compound having a GPR40 receptor function modulating action and being useful as an insulin secretagogue or a pharmaceutical agent for the prophylaxis or treatment of diabetes, more particularly, a compound represented by the formula: wherein Ar is an optionally substituted cyclic group, ring A is a ring optionally further substituted (provided that the ring is not thiazole, oxazole, imidazole and pyrazole), Xa and Xb are each independently a bond or a spacer having a main chain of 1 to 5 atom(s), Xc is O, S, SO or SO2, is ring B is a 5- to 7-membered ring, Xd is a bond, CH or CH2, •••••• is a single bond when Xd is a bond or CH2, or a double bond when Xd is CH, and R1 is an optionally substituted hydroxy group, and a salt thereof.

  本发明旨在提供一种新型融合环化合物，该化合物具有调节 GPR40 受体功能的作用，可用作预防或治疗糖尿病的胰岛素分泌剂或药物制剂，特别是由式表示的化合物： 其中 Ar 是任选取代的环状基团，环 A 是任选进一步取代的环（条件是该环不是噻唑、噁唑、咪唑和吡唑），Xa 和 Xb 各自独立地是键或主链为 1 至 5 个原子的间隔物，Xc 是 O、S、SO 或 SO2、 是 环 B 是 5 至 7 元环、 Xd 是键、CH 或 CH2、 ------ 是单键（当 Xd 是键或 CH2 时）或双键（当 Xd 是 CH 时），以及 R1 是任选取代的羟基及其盐。
• US7820837B2
  申请人：——

  公开号：US7820837B2

  公开（公告）日：2010-10-26
• Identification of Fused-Ring Alkanoic Acids with Improved Pharmacokinetic Profiles that Act as G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1 Agonists
  作者：Nobuyuki Negoro、Shinobu Sasaki、Masahiro Ito、Shuji Kitamura、Yoshiyuki Tsujihata、Ryo Ito、Masami Suzuki、Koji Takeuchi、Nobuhiro Suzuki、Junichi Miyazaki、Takashi Santou、Tomoyuki Odani、Naoyuki Kanzaki、Miyuki Funami、Toshimasa Tanaka、Tsuneo Yasuma、Yu Momose

  DOI：10.1021/jm2012968

  日期：2012.2.23

  The G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. We previously identified phenylpropanoic acid derivative 1 (3-4-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid) as a potent and orally available GPR40/FFA1 agonist; however, 1 exhibited high clearance and low oral bioavailability, which was likely due to its susceptibility to beta-oxidation at the phenylpropanoic acid moiety. To identify long-acting compounds, we attempted to block the metabolically labile sites at the phenylpropanoic acid moiety by introducing a fused-ring structure. Various fused-ring alkanoic acids with potent GPR40/FFA1 activities and good PK profiles were produced. Further optimizations of the lipophilic portion and the acidic moiety led to the discovery of dihydrobenzofuran derivative 53 ((6-[4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}-2,3-dihydro-1-benzofuran-3-yl)acetic acid), which acted as a GPR40/FFA1 agonist with in vivo efficacy during an oral glucose tolerance test (OGTT) in rats with impaired glucose tolerance.