bis-o-tolylmethylamine bromoacetamide | 246853-45-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: bis-o-tolylmethylamine bromoacetamide
• 英文别名: n-(Bis-(o-tolyl)methyl) bromoacetamide；N-[bis(2-methylphenyl)methyl]-2-bromoacetamide
• CAS: 246853-45-2
• 化学式: C₁₇H₁₈BrNO
• 分子量: 332.24
• InChiKey: BPRUXZJINIQAKJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  29.1
• 氢给体数：
  1
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  bis-o-tolylmethylamine bromoacetamide 在 sodium hydroxide 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 乙腈 为溶剂， 生成 trans,trans-2-[4-(2-isopropoxyethoxy)phenyl]-4-(1,3-benzodioxol-5-yl)-1-(bis-o-tolylaminocarbonylmethyl)pyrrolidine-3-carboxylic acid
  参考文献：
  名称：

  Design, Synthesis, and Activity of a Series of Pyrrolidine-3-carboxylic Acid-Based, Highly Specific, Orally Active ET_B Antagonists Containing a Diphenylmethylamine Acetamide Side Chain

  摘要：

  The endothelin (ET)-B receptor subtype is expressed on vascular endothelial and smooth muscle cells and mediates both vasodilation and vasoconstriction. On the basis of the pharmacophore of the previously reported ETA-specific antagonist 1, (ABT-627), we are reporting the discovery of a novel series of highly specific, orally active ETB receptor antagonists. Replacing the dibutylaminoacetamide group of 1 with a diphenylmethylaminoacetamide group resulted in antagonist 2 with a complete reversal of receptor specificity. Structure-activity relationship studies revealed that ortho-alkylation of the phenyl rings could further increase ETB affinity and also boost the ETA/ETB activity ratio of the resulting antagonists. A similar antagonism selectivity profile could also be achieved when one of the phenyl rings of the acetamide side chain was replaced with an alkyl group, preferably a tert-butyl group,(10h). Combining these features with modification of the a-aryl group of the pyrrolidine core, we have identified a potent antagonist (9k, A-308165) with over 27 000-fold selectivity favoring the ETB receptor and an acceptable pharmacokinetic profile (F = 24%) in rats.

  DOI：

  10.1021/jm990171i
• 作为产物：
  描述：

  bis-o-tolyl N-hydroxyoxime 在 氨 、 sodium 、 三乙胺 作用下， 以 四氢呋喃 、 1,2-二氯乙烷 为溶剂， 反应 3.17h， 生成 bis-o-tolylmethylamine bromoacetamide
  参考文献：
  名称：

  Design, Synthesis, and Activity of a Series of Pyrrolidine-3-carboxylic Acid-Based, Highly Specific, Orally Active ET_B Antagonists Containing a Diphenylmethylamine Acetamide Side Chain

  摘要：

  The endothelin (ET)-B receptor subtype is expressed on vascular endothelial and smooth muscle cells and mediates both vasodilation and vasoconstriction. On the basis of the pharmacophore of the previously reported ETA-specific antagonist 1, (ABT-627), we are reporting the discovery of a novel series of highly specific, orally active ETB receptor antagonists. Replacing the dibutylaminoacetamide group of 1 with a diphenylmethylaminoacetamide group resulted in antagonist 2 with a complete reversal of receptor specificity. Structure-activity relationship studies revealed that ortho-alkylation of the phenyl rings could further increase ETB affinity and also boost the ETA/ETB activity ratio of the resulting antagonists. A similar antagonism selectivity profile could also be achieved when one of the phenyl rings of the acetamide side chain was replaced with an alkyl group, preferably a tert-butyl group,(10h). Combining these features with modification of the a-aryl group of the pyrrolidine core, we have identified a potent antagonist (9k, A-308165) with over 27 000-fold selectivity favoring the ETB receptor and an acceptable pharmacokinetic profile (F = 24%) in rats.

  DOI：

  10.1021/jm990171i

文献信息

• Endothelin antagonists
  申请人：Abbott Labortories

  公开号：US07208517B1

  公开（公告）日：2007-04-24

  A compound of the formula (I): or a pharmaceutically acceptable salt thereof is disclosed, as well as processes for and intermediates in the preparation thereof, a method of antagonizing endothelin, methods for the inhibition of bone metastases, methods for the prevention of growth of new metastases, methods for the inhibition of bone turnover, and methods for the prevention of bone loss in patients, including cancer patients, using an endothelin ET-A receptor antagonist.

  本发明公开了一种化合物的公式（I）或其药学上可接受的盐，以及其制备过程和中间体，一种拮抗内皮素的方法，用于抑制骨转移的方法，用于预防新的转移生长的方法，用于抑制骨转换的方法，以及使用内皮素ET-A受体拮抗剂预防患者，包括癌症患者的骨质丢失的方法。
• US7208517B1
  申请人：——

  公开号：US7208517B1

  公开（公告）日：2007-04-24
• Design, Synthesis, and Activity of a Series of Pyrrolidine-3-carboxylic Acid-Based, Highly Specific, Orally Active ET_B Antagonists Containing a Diphenylmethylamine Acetamide Side Chain
  作者：Gang Liu、Natasha S. Kozmina、Martin Winn、Thomas W. von Geldern、William J. Chiou、Douglas B. Dixon、Bach Nguyen、Kennan C. Marsh、Terry J. Opgenorth

  DOI：10.1021/jm990171i

  日期：1999.9.1

  The endothelin (ET)-B receptor subtype is expressed on vascular endothelial and smooth muscle cells and mediates both vasodilation and vasoconstriction. On the basis of the pharmacophore of the previously reported ETA-specific antagonist 1, (ABT-627), we are reporting the discovery of a novel series of highly specific, orally active ETB receptor antagonists. Replacing the dibutylaminoacetamide group of 1 with a diphenylmethylaminoacetamide group resulted in antagonist 2 with a complete reversal of receptor specificity. Structure-activity relationship studies revealed that ortho-alkylation of the phenyl rings could further increase ETB affinity and also boost the ETA/ETB activity ratio of the resulting antagonists. A similar antagonism selectivity profile could also be achieved when one of the phenyl rings of the acetamide side chain was replaced with an alkyl group, preferably a tert-butyl group,(10h). Combining these features with modification of the a-aryl group of the pyrrolidine core, we have identified a potent antagonist (9k, A-308165) with over 27 000-fold selectivity favoring the ETB receptor and an acceptable pharmacokinetic profile (F = 24%) in rats.