4-tert-butyl-N-[5-(3-methoxyphenoxy)-6-{2-(pyrimidin-2-yloxy)ethylthio}pyrimidin-4-yl]benzenesulfonamide

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-tert-butyl-N-[5-(3-methoxyphenoxy)-6-{2-(pyrimidin-2-yloxy)ethylthio}pyrimidin-4-yl]benzenesulfonamide
• 英文别名: 4-tert-Butyl-N-{5-(3-methoxy-phenoxy)-6-[2-(pyrimidin-2-yloxy)-ethylsulfanyl]-pyrimidin-4-yl}-benzenesulfonamide；4-tert-butyl-N-[5-(3-methoxyphenoxy)-6-(2-pyrimidin-2-yloxyethylsulfanyl)pyrimidin-4-yl]benzenesulfonamide
• 化学式: C₂₇H₂₉N₅O₅S₂
• 分子量: 567.69
• InChiKey: QGRASIBHNIRVJH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  39
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  159
• 氢给体数：
  1
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  4-叔丁基-N-{6-氯-5-(3-甲氧基苯氧基)嘧啶-4-基}苯磺酰胺 在 sodium hydride 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 反应 50.0h， 生成 4-tert-butyl-N-[5-(3-methoxyphenoxy)-6-{2-(pyrimidin-2-yloxy)ethylthio}pyrimidin-4-yl]benzenesulfonamide
  参考文献：
  名称：

  Potent and Selective ET-A Antagonists. 1. Syntheses and Structure−Activity Relationships of N-(6-(2-(Aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide Derivatives

  摘要：

  Modifications to the ETA/B mixed type compounds 1 (Ro. 46-2005) and 2 (bosentan) were performed. Introduction of a pyrimidine group into 1 resulted in a dramatic increase in affinity for the ETA receptor, and the subsequent optimization of substituents on the pyrimidine ring led us to the discovery of N-(6-(2-((5-bromo-2-pyrimidinyl)oxy)ethoxy)-5-(4-methylphenyl)-4pyrimidinyl)-4-tert-butylbenzenesulfonamide (7k), which showed an extremely high affinity for the human cloned ETA receptor (K-i = 0.0042 +/-0.0038 nM) and an ETA/B receptor selectivity up to 29 000 (K-i = 130 +/- 50 nM for the human cloned ETB receptor). The compound was designed on the hypothesis that the hydrogen atom of the hydroxyl group in 1 and 2 played a role not as a proton donor but as an acceptor in the possible hydrogen bonding with Tyr129. Since the incorporation of a pyrimidinyl group into the hydroxyethoxy side chain of the nonselective antagonist (1) dramatically enhanced both the ETA receptor affinity and selectivity, and since similar results were obtained from the benzene analogues, we put forward the hypothesis that a "pyrimidine binding pocket" might exist in the ETA receptor.

  DOI：

  10.1021/jm0102304

文献信息

• Benzenesulfonamide derivative and process for preparing thereof
  申请人：TANABE SEIYAKU CO., LTD.

  公开号：EP0658548A1

  公开（公告）日：1995-06-21

  A benzenesulfonamide derivative of the formula [I]: wherein Ring A and Ring B are the same or different and each substituted or unsubstituted benzene ring, Q is a single bond or a group of the formula: -O-, -S-, -SO-, -SO₂- or -CH₂-, Y is a group of the formula: -O-, -S- or -NH-, Alk is lower alkylene group or lower alkenylene group, Z is a single bond or a group of the formula: -O- or -NH-, R is a substituted or unsubstituted aromatic heterocyclic or aryl group, R¹ is hydrogen atom, trifluoromethyl group, substituted or unsubstituted lower alkyl group, substituted or unsubstituted lower alkenyl group, mono- or di-lower alkylamino group, substituted or unsubstituted lower alkylthio group, substituted or unsubstituted lower alkoxy group, substituted or unsubstituted lower alkynyl group, aromatic heterocyclic group, substituted or unsubstituted aliphatic heterocyclic group or aryl group, provided that when Z is a single bond, R is a substituted or unsubstituted aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof, and processes for preparing the same, these compounds having endothelin antagonistic activity and being useful in the prophylaxis or treatment of various diseases caused by endothelin.

  式 [I] 的苯磺酰胺衍生物： 其中环 A 和环 B 相同或不同，且各自为取代或未取代的苯环，Q 为单键或式中的基团：-O-、-S-、-SO-、-SO₂- 或 -CH₂-， Y 是式中的基团：-Alk 是低级亚烷基或低级亚烯基，Z 是单键或式中的一个基团：-R¹是氢原子、三氟甲基、取代或未取代的低级烷基、取代或未取代的低级烯基、单-或双-低级烷基氨基、取代或未取代的低级烷硫基、取代或未取代的低级烷氧基、取代或未取代的低级炔基、芳香杂环基团、取代或未取代的脂肪杂环基团或芳基，条件是当 Z 为单键时，R 为取代或未取代的芳香杂环基团，或其药学上可接受的盐，以及制备这些化合物的工艺，这些化合物具有内皮素拮抗活性，可用于预防或治疗由内皮素引起的各种疾病。
• US5589478A
  申请人：——

  公开号：US5589478A

  公开（公告）日：1996-12-31
• US5728706A
  申请人：——

  公开号：US5728706A

  公开（公告）日：1998-03-17
• Potent and Selective ET-A Antagonists. 1. Syntheses and Structure−Activity Relationships of <i>N</i>-(6-(2-(Aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide Derivatives
  作者：Hiroshi Morimoto、Hideshi Shimadzu、Emi Kushiyama、Hiroyuki Kawanishi、Toshihiro Hosaka、Yasushi Kawase、Kosuke Yasuda、Kohei Kikkawa、Rikako Yamauchi-Kohno、Koichiro Yamada

  DOI：10.1021/jm0102304

  日期：2001.10.1

  Modifications to the ETA/B mixed type compounds 1 (Ro. 46-2005) and 2 (bosentan) were performed. Introduction of a pyrimidine group into 1 resulted in a dramatic increase in affinity for the ETA receptor, and the subsequent optimization of substituents on the pyrimidine ring led us to the discovery of N-(6-(2-((5-bromo-2-pyrimidinyl)oxy)ethoxy)-5-(4-methylphenyl)-4pyrimidinyl)-4-tert-butylbenzenesulfonamide (7k), which showed an extremely high affinity for the human cloned ETA receptor (K-i = 0.0042 +/-0.0038 nM) and an ETA/B receptor selectivity up to 29 000 (K-i = 130 +/- 50 nM for the human cloned ETB receptor). The compound was designed on the hypothesis that the hydrogen atom of the hydroxyl group in 1 and 2 played a role not as a proton donor but as an acceptor in the possible hydrogen bonding with Tyr129. Since the incorporation of a pyrimidinyl group into the hydroxyethoxy side chain of the nonselective antagonist (1) dramatically enhanced both the ETA receptor affinity and selectivity, and since similar results were obtained from the benzene analogues, we put forward the hypothesis that a "pyrimidine binding pocket" might exist in the ETA receptor.