α-(2-Propenyl)-[2-(2-amino-6-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester | 111605-01-7

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: α-(2-Propenyl)-[2-(2-amino-6-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester
• 英文别名: alpha-(2-Propenyl)-[2-(2-amino-6-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester；dimethyl 2-[2-[2-amino-6-(trifluoromethyl)phenyl]-1-(4-methoxyphenyl)ethyl]-2-prop-2-enylpropanedioate
• CAS: 111605-01-7
• 化学式: C₂₄H₂₆F₃NO₅
• 分子量: 465.469
• InChiKey: RUBZYVWMWSDRNL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  33
• 可旋转键数：
  11
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  87.8
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  α-(2-Propenyl)-[2-(2-amino-6-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester 在 吡啶 、 sodium methylate 、 sodium hydride 、 lithium iodide 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 12.83h， 生成 (3R,4S)-3-Allyl-1-(2-dimethylamino-ethyl)-4-(4-methoxy-phenyl)-6-trifluoromethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one
  参考文献：
  名称：

  Benzazepinone calcium channel blockers. 3. Synthesis and structure-activity studies of 3-alkylbenzazepinones

  摘要：

  As part of a program aimed at identifying novel analogues of diltiazem, we developed several synthetic routes for 3-alkylbenzazepinones, both in racemic and nonracemic form. Structure-activity relationship studies in this series have led to identification of several analogues as potent calcium channel blocking agents, both in vitro and in vivo. Analogues containing a 6-trifluoromethyl substituent (17a and 17b) are the most potent vasorelaxants in vitro. The oral antihypertensive activity of these compounds is comparable to its 3-acetoxy derivative 1 (X = 6-CF3) and 8-chlorodiltiazem (2b). The 3-allyl analogue 17c is a more potent antihypertensive agent than 17a, 17b, or 8-chlorodiltiazem (2b), and has a longer duration of action in vivo.

  DOI：

  10.1021/jm00082a019
• 作为产物：
  描述：

  4-甲氧基苯亚甲基丙二酸二甲酯 在 palladium on activated charcoal 氢气 、 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 25.0 ℃ 、275.79 kPa 条件下， 反应 8.33h， 生成 α-(2-Propenyl)-[2-(2-amino-6-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester
  参考文献：
  名称：

  Benzazepinone calcium channel blockers. 4. Structure-activity overview and intracellular binding site

  摘要：

  We have synthesized a series of benzazepinones (2) in order to determine the structure-activity relationships (SAR) for calcium channel blockers related to diltiazem. A prerequisite for calcium channel blocking activity in vitro and in vivo is the presence of two pharmacophores: a 4'-aryl methyl ether and a basic substituent appended to N1 with a pK(a) in the physiological range. When these constraints are satisfied, a wide variety of substitution is tolerated at C6, C7, and C3. The presence of an electron-withdrawing group at C6 appears to enhance potency in vitro and in vivo. For such benzazepinones, activity is primarily dependent upon lipophilicity, as measured by log P. We believe these compounds must partition into the cell membrane in order to access their receptor. The quaternary methiodide 15k was used to demonstrate that the binding site for benzazepinones is on the intracellular face of the membrane. This work represents the first comprehensive SAR of diltiazem-like calcium channel blockers.

  DOI：

  10.1021/jm00082a020

文献信息

• Benzazepine derivatives
  申请人：E. R. Squibb & Sons, Inc.

  公开号：US04752645A1

  公开（公告）日：1988-06-21

  Vasodilating activity is exhibited by compounds having the formula ##STR1## and pharmaceutically acceptable salts thereof.

  具有如下式子##STR1##和其药学上可接受的盐，表现出扩张血管的活性。
• Benzazepinone calcium channel blockers. 4. Structure-activity overview and intracellular binding site
  作者：S. David Kimball、David M. Floyd、Jagabandhu Das、John T. Hunt、John Krapcho、George Rovnyak、Keith J. Duff、Ving G. Lee、Robert V. Moquin

  DOI：10.1021/jm00082a020

  日期：1992.2

  We have synthesized a series of benzazepinones (2) in order to determine the structure-activity relationships (SAR) for calcium channel blockers related to diltiazem. A prerequisite for calcium channel blocking activity in vitro and in vivo is the presence of two pharmacophores: a 4'-aryl methyl ether and a basic substituent appended to N1 with a pK(a) in the physiological range. When these constraints are satisfied, a wide variety of substitution is tolerated at C6, C7, and C3. The presence of an electron-withdrawing group at C6 appears to enhance potency in vitro and in vivo. For such benzazepinones, activity is primarily dependent upon lipophilicity, as measured by log P. We believe these compounds must partition into the cell membrane in order to access their receptor. The quaternary methiodide 15k was used to demonstrate that the binding site for benzazepinones is on the intracellular face of the membrane. This work represents the first comprehensive SAR of diltiazem-like calcium channel blockers.
• Benzazepinone calcium channel blockers. 3. Synthesis and structure-activity studies of 3-alkylbenzazepinones
  作者：Jagabandhu Das、David M. Floyd、S. David Kimball、Keith J. Duff、Michael W. Lago、Robert V. Moquin、Ving G. Lee、Jack Z. Gougoutas、Vu Chi Truc

  DOI：10.1021/jm00082a019

  日期：1992.2

  As part of a program aimed at identifying novel analogues of diltiazem, we developed several synthetic routes for 3-alkylbenzazepinones, both in racemic and nonracemic form. Structure-activity relationship studies in this series have led to identification of several analogues as potent calcium channel blocking agents, both in vitro and in vivo. Analogues containing a 6-trifluoromethyl substituent (17a and 17b) are the most potent vasorelaxants in vitro. The oral antihypertensive activity of these compounds is comparable to its 3-acetoxy derivative 1 (X = 6-CF3) and 8-chlorodiltiazem (2b). The 3-allyl analogue 17c is a more potent antihypertensive agent than 17a, 17b, or 8-chlorodiltiazem (2b), and has a longer duration of action in vivo.