ethyl 2-[[(3R,4S)-3-(1,3-benzoxazol-2-yloxy)-6-cyano-2,2-dimethyl-3,4-dihydrochromen-4-yl]amino]acetate | 185690-28-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: ethyl 2-[[(3R,4S)-3-(1,3-benzoxazol-2-yloxy)-6-cyano-2,2-dimethyl-3,4-dihydrochromen-4-yl]amino]acetate
• CAS: 185690-28-2
• 化学式: C₂₃H₂₃N₃O₅
• 分子量: 421.453
• InChiKey: XMGHRKVIYMAAHH-LEWJYISDSA-N

物化性质

• 沸点：
  554.5±60.0 °C(Predicted)
• 密度：
  1.31±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  107
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  ethyl 2-[[(3R,4S)-3-(1,3-benzoxazol-2-yloxy)-6-cyano-2,2-dimethyl-3,4-dihydrochromen-4-yl]amino]acetate 在 溶剂黄146 作用下， 以 乙酸乙酯 为溶剂， 反应 16.0h， 生成 (3R-trans)-[(2-benzoxazolyl)(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4yl)amino]acetic acid, ethyl ester
  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
• 作为产物：
  描述：

  (3R-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile 在 sodium hydride 、 sodium cyanoborohydride 、 溶剂黄146 作用下， 以 甲醇 为溶剂， 反应 1.25h， 生成 ethyl 2-[[(3R,4S)-3-(1,3-benzoxazol-2-yloxy)-6-cyano-2,2-dimethyl-3,4-dihydrochromen-4-yl]amino]acetate
  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