methyl 6-isopropoxy-4-oxo-4H-chromene-3-carboxylate | 474431-53-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: methyl 6-isopropoxy-4-oxo-4H-chromene-3-carboxylate
• 英文别名: Methyl 4-oxo-6-propan-2-yloxychromene-3-carboxylate
• CAS: 474431-53-3
• 化学式: C₁₄H₁₄O₅
• 分子量: 262.262
• InChiKey: XOUKJQINQDWOHU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  61.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  methyl 6-isopropoxy-4-oxo-4H-chromene-3-carboxylate 在 10percent Pd/C copper(l) iodide 、 氢气 作用下， 以 四氢呋喃 、 乙酸乙酯 为溶剂， 反应 1.75h， 生成 methyl 2-(1,3-benzodioxol-5-yl)-4-hydroxy-6-propan-2-yloxy-3,4-dihydro-2H-chromene-3-carboxylate
  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
• 作为产物：
  描述：

  2,5-二羟基苯乙酮 在 sodium chlorite 、 草酰氯 、 氨基磺酸 、 potassium carbonate 、 N,N-二甲基甲酰胺 、 sodium iodide 、 三氯氧磷 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 25.75h， 生成 methyl 6-isopropoxy-4-oxo-4H-chromene-3-carboxylate
  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

• 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.