4,4,7'-trifluoro-5'-vinylspiro[cyclohexane-1,3'-indolin]-2'-one | 1367877-31-3

• 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: 4,4,7'-trifluoro-5'-vinylspiro[cyclohexane-1,3'-indolin]-2'-one
• CAS: 1367877-31-3
• 化学式: C₁₅H₁₄F₃NO
• 分子量: 281.277
• InChiKey: ZJQLFPRYMLTAMY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.87
• 重原子数：
  20.0
• 可旋转键数：
  1.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  29.1
• 氢给体数：
  1.0
• 氢受体数：
  1.0

反应信息

• 作为反应物：
  描述：

  4,4,7'-trifluoro-5'-vinylspiro[cyclohexane-1,3'-indolin]-2'-one 在 吗啉 、 盐酸 、 sodium tetrahydroborate 、 lithium aluminium tetrahydride 、 四(三苯基膦)钯 、 potassium peroxymonosulfate 、 偶氮二甲酸二异丙酯 、 sodium acetate 、 碳酸氢钠 、 臭氧 、 三苯基膦 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 16.75h， 生成 (3RS₄SR,5SR)-3-((3-(tertbutyl)benzyl)amino)-5-((4,4,7'-trifluoro-2'-oxospiro[cyclohexane-1,3'-indolin]-5'-yl)methyl)-4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide
  参考文献：
  名称：

  Discovery of Cyclic Sulfone Hydroxyethylamines as Potent and Selective β-Site APP-Cleaving Enzyme 1 (BACE1) Inhibitors: Structure-Based Design and in Vivo Reduction of Amyloid β-Peptides

  摘要：

  Structure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the structure activity relationship development were supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed the enhancement of potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with central nervous system drugs led to inhibitors with improved blood brain barrier permeability. Guided by structure-based optimization, we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC50 values of 2 and 50 nM, respectively, and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APPS1/16 transgenic mice at oral doses of 180 mu mol/kg demonstrated significant reduction of brain A beta levels.

  DOI：

  10.1021/jm300069y
• 作为产物：
  描述：

  7-氟吲哚满二酮 在 N-溴代丁二酰亚胺(NBS) 、 亚硝酸特丁酯 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 盐酸羟胺 、 potassium tert-butylate 、 sodium acetate 、 氟化氢吡啶 、 一水合肼 、 三乙胺 作用下， 以 丙醇 、 乙醇 、 二氯甲烷 、 水 、 乙二醇 、 二甲基亚砜 、 乙腈 为溶剂， 反应 31.0h， 生成 4,4,7'-trifluoro-5'-vinylspiro[cyclohexane-1,3'-indolin]-2'-one
  参考文献：
  名称：

  Discovery of Cyclic Sulfone Hydroxyethylamines as Potent and Selective β-Site APP-Cleaving Enzyme 1 (BACE1) Inhibitors: Structure-Based Design and in Vivo Reduction of Amyloid β-Peptides

  摘要：

  Structure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the structure activity relationship development were supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed the enhancement of potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with central nervous system drugs led to inhibitors with improved blood brain barrier permeability. Guided by structure-based optimization, we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC50 values of 2 and 50 nM, respectively, and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APPS1/16 transgenic mice at oral doses of 180 mu mol/kg demonstrated significant reduction of brain A beta levels.

  DOI：

  10.1021/jm300069y