trans-6-[2-[2-(1,1-dimethylethyl)-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: trans-6-[2-[2-(1,1-dimethylethyl)-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one
• 英文别名: 6-{2-[2-tert-Butyl-5-(4-fluoro-phenyl)-pyrrol-1-yl]-ethyl}-4-hydroxy-tetrahydro-pyran-2-one；(4R,6R)-6-[2-[2-tert-butyl-5-(4-fluorophenyl)pyrrol-1-yl]ethyl]-4-hydroxyoxan-2-one
• 化学式: C₂₁H₂₆FNO₃
• 分子量: 359.441
• InChiKey: PMSBINLIZBHCDF-IAGOWNOFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  51.5
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-<2-(4-fluorophenyl)-5-(1,1-dimethylethyl)-1H-pyrrol-1-yl>-2-ethyl methanesulfonate 在 盐酸 、 二异丁基氢化铝 、 potassium iodide 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 trans-6-[2-[2-(1,1-dimethylethyl)-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one
  参考文献：
  名称：

  Inhibitors of cholesterol biosynthesis. 1. trans-6-(2-Pyrrol-1-ylethyl)-4-hydroxypyran-2-ones, a novel series of HMG-CoA reductase inhibitors. 1. Effects of structural modifications at the 2- and 5-positions of the pyrrole nucleus

  摘要：

  A novel series of trans-6-(2-pyrrol-1-ylethyl)-4-hydroxypyran-2-ones and their dihydroxy acid derivatives were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase in vitro. A systematic study of substitution at the 2- and 5-positions of the pyrrole ring revealed that optimum potency was realized with the 2-(4-fluorophenyl)-5-isopropyl derivative 8x, which possessed 30% of the in vitro activity of the potent fungal metabolite compactin (I). A molecular modeling analysis led to the description of a pharmacophore model characterized by (A) length limits of 5.9 and 3.3 A for the 2- and 5-substituents, respectively, as well as an overall width limit of 10.6 A across the pyrrole ring from the 2- to the 5-substituent and (B) an orientation of the ethyl(ene) bridge to the 4-hydroxypyran-2-one ring nearly perpendicular to the planes of the parent pyrrole, hexahydronaphthalene, and phenyl rings of the structures examined (Figure 3, theta = 80-110 degrees). Attempts to more closely mimic compactin's polar isobutyric ester side chain with the synthesis of 2-phenylpyrroles containing polar phenyl substituents resulted in analogues with equal or slightly reduced potencies when compared to the 2-[(unsubstituted or 4-fluoro)phenyl]pyrroles, supporting the hypothesis that inhibitory potency is relatively insensitive to side-chain polarity or charge distribution in this area.

  DOI：

  10.1021/jm00163a005

文献信息

• Trans-6-[2-(substitutedpyrrol-1-yl)alkyl]-pyran-2-one inhibitors of cholesterol synthesis
  申请人：WARNER-LAMBERT COMPANY

  公开号：EP0179559A2

  公开（公告）日：1986-04-30

  6-[2-lSubstituted-pyrrol-1-yl)alkyl]pyran-2-ones of formula I and the corresponding ring-opened hydroxy-acids derived therefrom are potent inhibitors of the enzyme 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMG-CoA reductase), and are thus useful hypolipidemic and hypocholesterolemic agents. Pharmaceutical compositions containing such compounds. and a method of preparing the compounds are also disclosed.

  式 I 的 6-[2-取代-吡咯-1-基)烷基]吡喃-2-酮 及其衍生的相应开环羟基酸是 3-羟基-3-甲基戊二酰辅酶 A 还原酶（HMG-CoA 还原酶）的强效抑制剂，因此是有用的降血脂和降胆固醇药物。此外，还公开了含有此类化合物的药物组合物以及制备这些化合物的方法。
• Improved process for trans-6-[2-(substituted-pyrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
  申请人：WARNER-LAMBERT COMPANY

  公开号：EP0330172B1

  公开（公告）日：1994-08-10
• IMPROVED PROCESS FOR $i(TRANS)-6- 2-(SUBSTITUTED-PYRROL-1-YL)ALKYL]PYRAN-2-ONE INHIBITORS OF CHOLESTEROL SYNTHESIS
  申请人：Warner-Lambert Company

  公开号：EP0448552A1

  公开（公告）日：1991-10-02
• NOVEL PROCESS FOR $i(TRANS)-6- 2-(SUBSTITUTED-PYRROL-1-YL)ALKYL]PYRAN-2-ONE INHIBITORS OF CHOLESTEROL SYNTHESIS
  申请人：WARNER-LAMBERT COMPANY

  公开号：EP0687263A1

  公开（公告）日：1995-12-20
• PROCESS FOR PREPARING (TRANS)-6- [2-(SUBSTITUTED-PYRROL-1-YL)ALKYL]PYRAN-2-ONE INHIBITORS OF CHOLESTEROL SYNTHESIS
  申请人：WARNER-LAMBERT COMPANY

  公开号：EP0687263B1

  公开（公告）日：1997-07-30