(3R-trans)-[(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)phenylamino]acetic acid, ethyl ester | 166372-04-9

• 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: (3R-trans)-[(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)phenylamino]acetic acid, ethyl ester
• 英文别名: ethyl 2-(N-[(3R,4S)-6-cyano-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]anilino)acetate
• CAS: 166372-04-9
• 化学式: C₂₂H₂₄N₂O₄
• 分子量: 380.444
• InChiKey: PPDXCJJGCZHNFV-LEWJYISDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  82.8
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (3R-trans)-[(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)phenylamino]acetic acid, ethyl ester 在 盐酸 作用下， 以 四氢呋喃 为溶剂， 反应 16.0h， 生成 2-(N-[(3R,4S)-6-cyano-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]anilino)-N-(2-oxoethyl)acetamide
  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：

  苯胺 、 alkaline earth salt of/the/ methylsulfuric acid 在 magnesium(II) perchlorate 、 三乙酰氧基硼氢化钠 、 溶剂黄146 作用下， 以 1,2-二氯乙烷 、 乙腈 为溶剂， 反应 24.0h， 生成 (3R-trans)-[(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)phenylamino]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

文献信息

• 4-arylamino-benzopyran and related compounds
  申请人：Bristol-Myers Squibb Co.

  公开号：US05837702A1

  公开（公告）日：1998-11-17

  Compounds having the formula ##STR1## and pharmaceutically acceptable salts thereof wherein X is alkyl, Y is a single bond, --CH.sub.2 --, --C(O)--, --O--, --S-- or --N(R.sup.8)-- where R.sup.8 is hydrogen, alkyl, haloalkyl, aryl, arylalkyl, cycloalkyl or (cycloalkyl)alkyl, and R.sup.1 to R.sup.7 are as defined herein. These compounds have potassium channel activating activity and are useful, therefore for example, as cardiovascular agents.

  具有以下式子##STR1##及其药物可接受的盐，其中X是烷基，Y是单键，--CH.sub.2 --，--C(O)--，--O--，--S--或--N(R.sup.8)--，其中R.sup.8是氢，烷基，卤代烷基，芳基，芳基烷基，环烷基或（环烷基）烷基，而R.sup.1到R.sup.7如本文所定义。这些化合物具有钾通道激活活性，因此例如作为心血管药物是有用的。
• 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.