S 1255

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 黄酮类化合物
• 英文名称: S 1255
• 英文别名: (R)-2-(benzo[1,3]dioxol-5-yl)-6-isopropoxy-4-(4-methoxyphenyl)-2H-chromene-3-carboxylic acid；S-1255；2-Benzo[1,3]dioxol-5-yl-6-isopropoxy-4-(4-methoxy-phenyl)-2H-chromene-3-carboxylic acid；(2R)-2-(1,3-benzodioxol-5-yl)-4-(4-methoxyphenyl)-6-propan-2-yloxy-2H-chromene-3-carboxylic acid
• 化学式: C₂₇H₂₄O₇
• 分子量: 460.483
• InChiKey: BATSJXIVNKJCKQ-AREMUKBSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  34
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  83.4
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2,5-二羟基苯乙酮 在 sodium hydroxide 、 sodium chlorite 、 copper(l) iodide 、 四(三苯基膦)钯 、 草酰氯 、 氨基磺酸 、 sodium hydride 、 sodium carbonate 、 potassium carbonate 、 N,N-二甲基甲酰胺 、 sodium iodide 、 lithium chloride 、 三氯氧磷 作用下， 以 四氢呋喃 、 甲醇 、 乙二醇二甲醚 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 37.0h， 生成 S 1255
  参考文献：
  名称：

  Structure−Activity Relationships of a Novel Class of Endothelin-A Receptor Antagonists and Discovery of Potent and Selective Receptor Antagonist, 2-(Benzo[1,3]dioxol-5-yl)-6-isopropyloxy-4-(4-methoxyphenyl)-2H-chromene-3- carboxylic Acid (S-1255). 1. Study on Structure−Activity Relationships and Basic Structure Crucial for ET_A Antagonism

  摘要：

  A novel series of endothelin-A (ETA) selective receptor antagonists having a 2H-chromene skeleton are described. A lead compound, 2-(benzo[1,3]dioxol-5-yl)-2H-chromene-3-carboxylic acid (3), was found by modifications of our own angiotensin II antagonist. A structure-activity relationship (SAR) study of 3 reveals that the structural requirements essential for potent and selective ETA receptor binding affinity are the m,p-methylenedioxyphenyl, carboxyl, and isopropoxy groups at the 2-, 3-, and 6-positions, respectively, on the (R)-2H-chromene skeleton. The substituent at the 4-position is also important for improving the activity, and various hydrophobic functional groups of 6-9 Angstrom such as liner, branched, and cyclic aliphatic groups, unsubstituted and substituted aryl groups, and even halogen atoms were acceptable. These results suggest that (R)-2-(benzo[1,3]dioxol-5-yl)-6-isopropoxy-2H-chromene-3-carboxylic acid, formula 108, is the crucial basic structure to be recognized by the ETA receptor. The most potent compound is (R)-48 (S-1255), which binds to the ETA receptor with an IC50 value of 0.19 nM and is 630-fold selective for the ETA receptor than for the ETB receptor. This compound has 55% oral bioavailability in rats. On the basis of the SAR, the roles of each substituent in the receptor binding are discussed.

  DOI：

  10.1021/jm010382z

文献信息

• Practical Enantioselective Synthesis of Endothelin Antagonist S-1255 by Dynamic Resolution of 4-Methoxychromene-3-carboxylic Acid Intermediate
  作者：Toshiro Konoike、Ken-ichi Matsumura、Tadahiko Yorifuji、Shoji Shinomoto、Yutaka Ide、Takashi Ohya

  DOI：10.1021/jo0261092

  日期：2002.11.1

  carbon-carbon bond formation between the C4 carbon and the p-anisyl group was accomplished by a conjugate addition-elimination reaction of Grignard reagent 3 to (R)-16 to give 1 having 98% ee. Owing to high efficiencies of functional group transformations, carbon-carbon bond formations, and the dynamic resolution, the synthesis required no chromatographic purification and was amenable to a multikilogram-scale preparation

  描述了对映体纯的S-1255（1）（一种有效的口服活性ET（A）受体拮抗剂）的实用多千克级合成方法。利用容易获得的原料和试剂，从2,5-二羟基苯乙酮8开始的整个反应序列在温和的条件下进行，以优异的化学收率（8步，总收率41％）和高对映体纯度（98％）得到1 ee）。合成的关键步骤是关键中间体16的动态拆分。从外消旋体16以结晶形式（1S，2R）获得具有97-99％ee的（R）-甲氧基酸（R）-16，产率为83-84％。 ）-（+）-去氧麻黄碱或（+）-辛可宁盐的动态拆分包括同时结晶和原位外消旋。讨论了通过开环的两性离子中间体进行动态拆分的机理。在最后的合成步骤中，通过格氏试剂3与（R）-16的共轭加成-消除反应，在C4碳和对-茴香基之间有效地形成碳-碳键，得到具有98％ee的1。由于高效的官能团转化，碳-碳键形成和动态拆分，该合成方法无需进行色谱纯化，可进行多千克级的制备。通过此过程成功制
• Structure−Activity Relationships of a Novel Class of Endothelin-A Receptor Antagonists and Discovery of Potent and Selective Receptor Antagonist, 2-(Benzo[1,3]dioxol-5-yl)-6-isopropyloxy-4-(4-methoxyphenyl)-2<i>H</i>-chromene-3- carboxylic Acid (S-1255). 1. Study on Structure−Activity Relationships and Basic Structure Crucial for ET_A Antagonism
  作者：Natsuki Ishizuka、Ken-ichi Matsumura、Katsunori Sakai、Masafumi Fujimoto、Shin-ichi Mihara、Teruo Yamamori

  DOI：10.1021/jm010382z

  日期：2002.5.1

  A novel series of endothelin-A (ETA) selective receptor antagonists having a 2H-chromene skeleton are described. A lead compound, 2-(benzo[1,3]dioxol-5-yl)-2H-chromene-3-carboxylic acid (3), was found by modifications of our own angiotensin II antagonist. A structure-activity relationship (SAR) study of 3 reveals that the structural requirements essential for potent and selective ETA receptor binding affinity are the m,p-methylenedioxyphenyl, carboxyl, and isopropoxy groups at the 2-, 3-, and 6-positions, respectively, on the (R)-2H-chromene skeleton. The substituent at the 4-position is also important for improving the activity, and various hydrophobic functional groups of 6-9 Angstrom such as liner, branched, and cyclic aliphatic groups, unsubstituted and substituted aryl groups, and even halogen atoms were acceptable. These results suggest that (R)-2-(benzo[1,3]dioxol-5-yl)-6-isopropoxy-2H-chromene-3-carboxylic acid, formula 108, is the crucial basic structure to be recognized by the ETA receptor. The most potent compound is (R)-48 (S-1255), which binds to the ETA receptor with an IC50 value of 0.19 nM and is 630-fold selective for the ETA receptor than for the ETB receptor. This compound has 55% oral bioavailability in rats. On the basis of the SAR, the roles of each substituent in the receptor binding are discussed.