Ethyl 3-(4-benzyloxyphenyl)but-2-enoate | 951124-53-1

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 肉桂酸及其衍生物
• 英文名称: Ethyl 3-(4-benzyloxyphenyl)but-2-enoate
• 英文别名: ethyl 3-(4-phenylmethoxyphenyl)but-2-enoate
• CAS: 951124-53-1
• 化学式: C₁₉H₂₀O₃
• 分子量: 296.366
• InChiKey: BGZLGAKOWILIFW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  22
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  35.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  Ethyl 3-(4-benzyloxyphenyl)but-2-enoate 在 钯 silica gel 、 正己烷 、 乙酸乙酯 作用下， 以 乙酸乙酯 为溶剂， 25.0 ℃ 、13.51 MPa 条件下， 以to give ethyl 3-(4-hydroxyphenyl)butanoate (1.51 g) as a pale yellow oil的产率得到ethyl 3-(4-hydroxyphenyl)butanoate
  参考文献：
  名称：

  Heterocyclic derivatives

  摘要：

  式(I)的化合物，其中R.sup.1是氢或羟基；R.sup.2是氢；或R.sup.1和R.sup.2结合在一起，使得CR.sup.1 14 CR.sup.2是双键；X选自--Ch.sub.2 CH.sub.2 --、--C.dbd.CH--、--C.tbd.C--、--CH.sub.2 O--、--OCH.sub.2 CH.sub.2 NH--、--NHCH.sub.2 --、--CH.sub.2 CO--、--COCH.sub.2 --、--CH.sub.2 S(O).sub.n --和--S(O).sub.n CH.sub.2 --（其中n为0、1或2）；Ar是苯基，其承载一个或多个取自（1-6C）烷基、（2-6C）烯基、（2-6C）炔基、（1-6C）氧烷基、（1-6C）氧烷基羰基、（1-6C）氧烷基羰基（1-6C）烷基、（1-6C）氧烷基（1-6C）烷基、（1-6C）烷基氨基、二-(1-6C)烷基!氨基、氨基甲酰基、（1-6C）烷基甲酰基、二-(1-6C)烷基!甲酰基、（1-6C）烯基和其氧化物衍生物及其O-（1-6C）烷基醚化物（1-6C）硫醚基、（1-6C）磺醇基和（1-6C）磺酰基，当被一个或多个取自（1-6C）氧烷基羰基、（1-6C）酰基和其氧化物衍生物和O-（1-6C）烷基醚化物的羟肟衍生物所取代时，以及（1-6C）酰胺基、（1-6C）酰氧基、（1-6C）酰氧基（1-6）烷基、氨基甲酰基、N-（1-6C）烷基甲酰基、N，N-二（1-6C）烷基!甲酰基、氨基、（1-6C）烷基氨基、二-(1-6C)烷基!氨基、（1-6C）氧烷基、（2-6C）烯基氧基、（1-6C）烷基硫基、（1-6C）磺醇基、（1-6C）磺酰基、卤代（1-6C）烷基、（2-6C）烯基、（2-6C）炔基、苯基、苯氧基、氰基、硝基、羟基和羧基；其中Ar可能承载进一步的取代基；它们的药学上可接受的盐抑制角鲨烷合成，因此在降低血浆胆固醇水平方面有用。本发明还涉及制备式(I)化合物的方法，以及含有它们的制药组合物和它们在医学上的用途。

  公开号：

  US05919793A1
• 作为产物：
  描述：

  磷酰基乙酸三乙酯 、 4-苯甲氧基苯乙酮 在 sodium hydride 作用下， 以 四氢呋喃 、 mineral oil 为溶剂， 反应 2.25h， 生成 Ethyl 3-(4-benzyloxyphenyl)but-2-enoate
  参考文献：
  名称：

  Design, Synthesis, and Biological Activity of Potent and Orally Available G Protein-Coupled Receptor 40 Agonists

  摘要：

  G protein-coupled receptor 40 (GPR40) is being recently considered to be a new potential drug target for the treatment of type 2 diabetes because of its role in the enhancement of free fatty acid-regulated glucose-stimulated insulin secretion in pancreatic beta-cells. We initially identified benzyloxyphenylproparoic acid (1b) (EC50 = 510 nM), which was designed based on the structure of free fatty acids, as a promising lead compound with GPR40 agonist activity. Chemical modification of compound 1b led to the discovery of 3-{4-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid (4p) as a potent GPR40 agonist (EC50 = 5,7 nM). Compound 4p exhibited acceptable pharmacokinetic profiles and significant glucose-lowering effects during an oral glucose tolerance test in diabetic rat;. Moreover, no hypoglycemic event was observed even after administration of a high dose of compound 4p to normal fasted rats. These pharmacological results suggest that GPR40 agonists might be novel glucose-dependent insulin secretagogues with little or no risk of hypoglycemia.

  DOI：

  10.1021/jm101405t

文献信息

• Heterocyclic derivatives
  申请人：Zeneca Limited

  公开号：US05919793A1

  公开（公告）日：1999-07-06

  Compounds of formula (I) wherein R.sup.1 is hydrogen or hydroxy; R.sup.2 is hydrogen; or R.sup.1 and R.sup.2 are joined together so that CR.sup.1 14 CR.sup.2 is a double bond; X is selected from --Ch.sub.2 CH.sub.2 --, --C.dbd.CH--, --C.tbd.C--, --CH.sub.2 O--, --OCH.sub.2, CH.sub.2 NH--, --NHCH.sub.2 --, --CH.sub.2 CO--, --COCH.sub.2 --, --CH.sub.2 S(O).sub.n -- and --S(O).sub.n CH.sub.2 -- (wherein n is 0, 1 or 2); Ar is phenyl which bears one or more substituents independently selected from the groups (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, (1-6C)alkylamino, di-\x9b(1-6C)alkyl!amino, carbamoyl, (1-6C) alkylcarbamoyl, di-\x9b(1-6C)alkyl!carbamoyl, (1-6C)alkenyl and oxime derivatives thereof and O--(1-6C)alkyl ethers of said oximes (1-6C)alkylthio, (1-6C)alkylsulphinyl and (1-6C)alkylsulphonyl when substituted by one or more groups selected from (1-6C)alkoxycarbonyl, (1-6C)alkanoyl and oxime derivatives thereof and O-(1-6C)alkyl ethers of said oxime derivatives, (1-6C)alkanoylamimo, (1-6C)alkanoyloxy, (1-6C)alkanoyloxy(1-6)alkyl, carbamoyl, N-(1-6C)alkylcarbamoyl, N,N-di\x9b(1-6C)alkyl!carbamoyl, amino, (1-6C)alkylamino, di-\x9b(1-6C)alkyl!amino, (1-6C)alkoxy, (2-6C)alkenyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl (2-6C)alkenyl, (2-6C)alkynyl, phenyl, phenoxy, cyano, nitro, hydroxy and carboxy; and wherein Ar may bear further substituents; and their pharmaceutically acceptable salts inhibit squalene synthese and are hence useful in lowering cholesterol levels in blood plasma Processes for preparing compounds of formula (I) are also referred to as well as pharmaceutical compositions containing them and their use in medicine.

  式(I)的化合物，其中R.sup.1是氢或羟基；R.sup.2是氢；或R.sup.1和R.sup.2结合在一起，使得CR.sup.1 14 CR.sup.2是双键；X选自--Ch.sub.2 CH.sub.2 --、--C.dbd.CH--、--C.tbd.C--、--CH.sub.2 O--、--OCH.sub.2 CH.sub.2 NH--、--NHCH.sub.2 --、--CH.sub.2 CO--、--COCH.sub.2 --、--CH.sub.2 S(O).sub.n --和--S(O).sub.n CH.sub.2 --（其中n为0、1或2）；Ar是苯基，其承载一个或多个取自（1-6C）烷基、（2-6C）烯基、（2-6C）炔基、（1-6C）氧烷基、（1-6C）氧烷基羰基、（1-6C）氧烷基羰基（1-6C）烷基、（1-6C）氧烷基（1-6C）烷基、（1-6C）烷基氨基、二-(1-6C)烷基!氨基、氨基甲酰基、（1-6C）烷基甲酰基、二-(1-6C)烷基!甲酰基、（1-6C）烯基和其氧化物衍生物及其O-（1-6C）烷基醚化物（1-6C）硫醚基、（1-6C）磺醇基和（1-6C）磺酰基，当被一个或多个取自（1-6C）氧烷基羰基、（1-6C）酰基和其氧化物衍生物和O-（1-6C）烷基醚化物的羟肟衍生物所取代时，以及（1-6C）酰胺基、（1-6C）酰氧基、（1-6C）酰氧基（1-6）烷基、氨基甲酰基、N-（1-6C）烷基甲酰基、N，N-二（1-6C）烷基!甲酰基、氨基、（1-6C）烷基氨基、二-(1-6C)烷基!氨基、（1-6C）氧烷基、（2-6C）烯基氧基、（1-6C）烷基硫基、（1-6C）磺醇基、（1-6C）磺酰基、卤代（1-6C）烷基、（2-6C）烯基、（2-6C）炔基、苯基、苯氧基、氰基、硝基、羟基和羧基；其中Ar可能承载进一步的取代基；它们的药学上可接受的盐抑制角鲨烷合成，因此在降低血浆胆固醇水平方面有用。本发明还涉及制备式(I)化合物的方法，以及含有它们的制药组合物和它们在医学上的用途。
• Design, Synthesis, and Biological Activity of Potent and Orally Available G Protein-Coupled Receptor 40 Agonists
  作者：Shinobu Sasaki、Shuji Kitamura、Nobuyuki Negoro、Masami Suzuki、Yoshiyuki Tsujihata、Nobuhiro Suzuki、Takashi Santou、Naoyuki Kanzaki、Masataka Harada、Yasuhiro Tanaka、Makoto Kobayashi、Norio Tada、Miyuki Funami、Toshimasa Tanaka、Yoshio Yamamoto、Kohji Fukatsu、Tsuneo Yasuma、Yu Momose

  DOI：10.1021/jm101405t

  日期：2011.3.10

  G protein-coupled receptor 40 (GPR40) is being recently considered to be a new potential drug target for the treatment of type 2 diabetes because of its role in the enhancement of free fatty acid-regulated glucose-stimulated insulin secretion in pancreatic beta-cells. We initially identified benzyloxyphenylproparoic acid (1b) (EC50 = 510 nM), which was designed based on the structure of free fatty acids, as a promising lead compound with GPR40 agonist activity. Chemical modification of compound 1b led to the discovery of 3-4-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid (4p) as a potent GPR40 agonist (EC50 = 5,7 nM). Compound 4p exhibited acceptable pharmacokinetic profiles and significant glucose-lowering effects during an oral glucose tolerance test in diabetic rat;. Moreover, no hypoglycemic event was observed even after administration of a high dose of compound 4p to normal fasted rats. These pharmacological results suggest that GPR40 agonists might be novel glucose-dependent insulin secretagogues with little or no risk of hypoglycemia.