(3R-trans)-4-[[2-(acetylamino)ethyl]phenylamino]-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile | 166095-22-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: (3R-trans)-4-[[2-(acetylamino)ethyl]phenylamino]-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile
• 英文别名: N-[2-[[(3R,4S)-6-Cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl]phenylamino]ethyl]acetamide；N-[2-(N-[(3R,4S)-6-cyano-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]anilino)ethyl]acetamide
• CAS: 166095-22-3
• 化学式: C₂₂H₂₅N₃O₃
• 分子量: 379.459
• InChiKey: YLSGCDRMEJVTJV-LEWJYISDSA-N

物化性质

• 沸点：
  606.3±55.0 °C(Predicted)
• 密度：
  1.25±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  85.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  N-(2-(苯基氨基)乙基)邻苯二甲酰亚胺 在 吡啶 、 magnesium(II) perchlorate 、 甲基肼 作用下， 以 乙醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 3.5h， 生成 (3R-trans)-4-[[2-(acetylamino)ethyl]phenylamino]-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile
  参考文献：
  名称：

  Cardioselective Antiischemic ATP-Sensitive Potassium Channel (K_ATP) Openers. 5. Identification of 4-(N-Aryl)-Substituted Benzopyran Derivatives with High Selectivity

  摘要：

  This paper describes our studies aimed at the discovery of structurally distinct analogs of the cardioprotective K-ATP Opener BMS-180448 (2) with improved selectivity for the ischemic myocardium. The starting compound 6, derived from the indole analog 4, showed good cardioprotective potency and excellent selectivity compared to 2 and the first-generation K-ATP opener cromakalim (1). The structure-activity studies indicate that increasing the size of the alkyl ester leads to diminished potency as does its replacement with a variety of other groups (nitrile, methyl sulfone). Replacement of the ethyl ester of 6 with an imidazole gave the best compound 3 (BMS-191095) of this series which maintains the potency and selectivity of its predecessor 6. The results described in this publication further support that there is no correlation between vasorelaxant and cardioprotective potencies of K-ATP openers. Compound 3 is over 20- and 4000-fold more selective far the ischemic myocardium than 2 and cromakalim (1), respectively. The selectivity for the ischemic myocardium is achieved by reduction of vasorelaxant potency rather than enhancement in antiischemic potency. As for cromakalim (1) and 2, the cardioprotective effects of compound 3 are inhibited by cotreatment with the K-ATP blocker glyburide, indicating that the K-ATP Opening is involved in its mechanism of cardioprotection With its good oral bioavailability (47%) and plasma elimination half life (3 h) in rats, compound 3 offers an excellent candidate to investigate the role of residual vasorelaxant potency of 2 toward its cardioprotective activity in vivo.

  DOI：

  10.1021/jm9605905

文献信息

• 4-Arylamino-benzopyran and related compounds
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：EP0648758A1

  公开（公告）日：1995-04-19

  Compounds having the formula and pharmaceutically acceptable salts thereof wherein X is alkyl, Y is a single bond, -CH₂-, -C(O)-, -O-, -S- or -N(R⁸)- where R⁸ is hydrogen, alkyl, haloalkyl, aryl, arylalkyl, cycloalkyl or (cycloalkyl)alkyl, and R¹ to R⁷ are as defined herein. These compounds have potassium channel activating activity and are useful, therefore for example, as cardiovascular agents.

  具有以下化学式和药学上可接受的盐的化合物，其中X为烷基，Y为单键，-CH₂-，-C（O）-，-O-，-S-或-N（R⁸）-，其中R⁸为氢，烷基，卤代烷基，芳基，芳基烷基，环烷基或（环烷基）烷基，而R¹到R⁷如本文所定义。这些化合物具有钾通道激活活性，因此可用作心血管药物等用途。
• Cardioselective Antiischemic ATP-Sensitive Potassium Channel (K_ATP) Openers. 5. Identification of 4-(<i>N</i>-Aryl)-Substituted Benzopyran Derivatives with High Selectivity
  作者：George C. Rovnyak、Syed Z. Ahmed、Charles Z. Ding、Steven Dzwonczyk、Francis N. Ferrara、W. Griffith Humphreys、Gary J. Grover、Dinos Santafianos、Karnail S. Atwal、Anne J. Baird、Lee G. McLaughlin、Diane E. Normandin、Paul G. Sleph、Sarah C. Traeger

  DOI：10.1021/jm9605905

  日期：1997.1.1

  This paper describes our studies aimed at the discovery of structurally distinct analogs of the cardioprotective K-ATP Opener BMS-180448 (2) with improved selectivity for the ischemic myocardium. The starting compound 6, derived from the indole analog 4, showed good cardioprotective potency and excellent selectivity compared to 2 and the first-generation K-ATP opener cromakalim (1). The structure-activity studies indicate that increasing the size of the alkyl ester leads to diminished potency as does its replacement with a variety of other groups (nitrile, methyl sulfone). Replacement of the ethyl ester of 6 with an imidazole gave the best compound 3 (BMS-191095) of this series which maintains the potency and selectivity of its predecessor 6. The results described in this publication further support that there is no correlation between vasorelaxant and cardioprotective potencies of K-ATP openers. Compound 3 is over 20- and 4000-fold more selective far the ischemic myocardium than 2 and cromakalim (1), respectively. The selectivity for the ischemic myocardium is achieved by reduction of vasorelaxant potency rather than enhancement in antiischemic potency. As for cromakalim (1) and 2, the cardioprotective effects of compound 3 are inhibited by cotreatment with the K-ATP blocker glyburide, indicating that the K-ATP Opening is involved in its mechanism of cardioprotection With its good oral bioavailability (47%) and plasma elimination half life (3 h) in rats, compound 3 offers an excellent candidate to investigate the role of residual vasorelaxant potency of 2 toward its cardioprotective activity in vivo.