p-tert-butyl-N-[6-(2-hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl]benzenesulfonamide | 146532-04-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: p-tert-butyl-N-[6-(2-hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl]benzenesulfonamide
• 英文别名: 4-tert-Butyl-N-[6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-benzenesulfonamide；4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(4-methylphenyl)pyrimidin-4-yl]benzenesulfonamide
• CAS: 146532-04-9
• 化学式: C₂₃H₂₇N₃O₄S
• 分子量: 441.551
• InChiKey: ALQRUULAVXAWSN-UHFFFAOYSA-N

物化性质

• 沸点：
  600.0±65.0 °C(predicted)
• 密度：
  1.257±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  31
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  110
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  p-tert-butyl-N-[6-(2-hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl]benzenesulfonamide 在 bis-triphenylphosphine-palladium(II) chloride 、 sodium hydride 作用下， 以 1,4-二氧六环 、 N,N-二甲基乙酰胺 为溶剂， 反应 25.33h， 生成 4-tert-Butyl-N-{6-[2-(5-thiophen-2-yl-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-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
• 作为产物：
  描述：

  4-tert-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide 以 乙二醇 为溶剂， 生成 p-tert-butyl-N-[6-(2-hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl]benzenesulfonamide
  参考文献：
  名称：

  Sulfonamides and uses

  摘要：

  公式I中的磺胺类化合物，其中符号R.sup.1 -R.sup.6、X、Y和n具有描述中给定的含义，并且其中部分化合物是新颖的，以及其盐，可用作制造用于治疗循环障碍的药物的活性成分，特别是高血压、缺血、血管痉挛和心绞痛。

  公开号：

  US05270313A1

文献信息

• Potent and Selective ET-A Antagonists. 2. Discovery and Evaluation of Potent and Water Soluble <i>N</i>-(6-(2-(Aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide Derivatives
  作者：Hiroshi Morimoto、Noriko Ohashi、Hideshi Shimadzu、Emi Kushiyama、Hiroyuki Kawanishi、Toshihiro Hosaka、Yasushi Kawase、Kosuke Yasuda、Kohei Kikkawa、Rikako Yamauchi-Kohno、Koichiro Yamada

  DOI：10.1021/jm000538f

  日期：2001.10.1

  activity were identified. This study suggested the metabolic pathways of 1 were considerably affected by species. Consequently, structural modification of 1 intended to improve the complexity of the metabolic pathway, and water solubility was performed. The subsequent introduction of a hydroxyl group into the tert-butyl moiety of 1 led to the discovery of our new clinical candidate, 6b, which showed

  在上一篇文章中，（1）我们概述了有效的选择性ET（A）受体拮抗剂1及其相关化合物的发现及其与构效关系。鉴定出具有有效的选择性ET（A）受体拮抗剂活性的1的代谢物。这项研究表明1的代谢途径受物种的影响很大。因此，进行了结构修饰1以改善代谢途径的复杂性和水溶性。随后在1的叔丁基部分引入羟基导致了我们新的临床候选物6b的发现，该候选物显示出更高的水溶性，物种间统一的代谢途径以及对人类的极高亲和力和选择性ET（A）受体（ET（A）受体的K（i）：0.015 +/- 0.004 nM; ET（B）受体的K（i）：41 +/- 21 nM）。
• Verwendung von Sulfonamiden als Heilmittel und neue Sulfonamide
  申请人：F.HOFFMANN-LA ROCHE & CO. AKTIENGESELLSCHAFT

  公开号：EP0510526A1

  公开（公告）日：1992-10-28

  Sulfonamide der Formel I, in der die Symbole R¹-R⁶, X, Y und n die in der Beschreibung angegebene Bedeutung haben und die zum Teil neue Verbindungen sind, und Salze davon können als Wirkstoff bei der Herstellung von Heilmitteln zur Behandlung von Kreislauferkrankungen, insbesondere Hypertonie, Ischämie, Vasopasmen und Angina pectoris Anwendung finden.

  式 I 的磺酰胺类化合物（其中符号 R¹-R⁶、X、Y 和 n 具有说明中给出的含义）及其盐类可用作制备治疗循环系统疾病，特别是高血压、缺血、血管痉挛和心绞痛药物的活性成分。
• US5270313A
  申请人：——

  公开号：US5270313A

  公开（公告）日：1993-12-14
• 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.
• Sulfonamides and uses
  申请人：Hoffmann-La Roche Inc.

  公开号：US05270313A1

  公开（公告）日：1993-12-14

  Sulfonamides of formula I, in which the symbols R.sup.1 -R.sup.6, X, Y and n have the significance given in the description and which are in part novel compounds, and salts thereof, which can be used as active ingredients for the manufacture of medicaments for the treatment of circulatory disorders, especially hypertension, ischemia, vasospasms and angina pectoris, are described.

  公式I中的磺胺类化合物，其中符号R.sup.1 -R.sup.6、X、Y和n具有描述中给定的含义，并且其中部分化合物是新颖的，以及其盐，可用作制造用于治疗循环障碍的药物的活性成分，特别是高血压、缺血、血管痉挛和心绞痛。