methyl 2-(benzo[1,3]dioxol-5-yl)-6-isopropoxy-4-(trifluoromethanesulfonyloxy)-2H-chromene-3-carboxylate | 203919-37-3

• 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: methyl 2-(benzo[1,3]dioxol-5-yl)-6-isopropoxy-4-(trifluoromethanesulfonyloxy)-2H-chromene-3-carboxylate
• 英文别名: methyl 2-(1,3-benzodioxol-5-yl)-6-propan-2-yloxy-4-(trifluoromethylsulfonyloxy)-2H-chromene-3-carboxylate
• CAS: 203919-37-3
• 化学式: C₂₂H₁₉F₃O₉S
• 分子量: 516.449
• InChiKey: SSSHORCGGJETKL-UHFFFAOYSA-N

物化性质

• 熔点：
  88-90 °C
• 沸点：
  588.697±50.00 °C(Press: 760.00 Torr)(predicted)
• 密度：
  1.538±0.10 g/cm3(Temp: 25 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  35
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  115
• 氢给体数：
  0
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  methyl 2-(benzo[1,3]dioxol-5-yl)-6-isopropoxy-4-(trifluoromethanesulfonyloxy)-2H-chromene-3-carboxylate 在 sodium hydroxide 、 四(三苯基膦)钯 、 sodium carbonate 、 lithium chloride 作用下， 以 四氢呋喃 、 甲醇 、 乙二醇二甲醚 为溶剂， 反应 6.0h， 生成 2-Benzo[1,3]dioxol-5-yl-6-isopropoxy-4-phenyl-2H-chromene-3-carboxylic acid
  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 、 copper(l) iodide 、 草酰氯 、 氨基磺酸 、 sodium hydride 、 potassium carbonate 、 N,N-二甲基甲酰胺 、 sodium iodide 、 三氯氧磷 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 31.0h， 生成 methyl 2-(benzo[1,3]dioxol-5-yl)-6-isopropoxy-4-(trifluoromethanesulfonyloxy)-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

文献信息

• Chromene-3-carboxylate derivatives
  申请人：Shionogi & Co., Ltd.

  公开号：US06218427B1

  公开（公告）日：2001-04-17

  The present invention provides a compound of the formula (I): wherein R1, R2, R3 and R4 are each independently hydrogen, optionally substituted alkyl, hydroxy, optionally substituted alkoxy or the like, R5 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocyclic or the like, R6 is hydrogen, optionally substituted alkyl or the like, R7 is hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heterocyclic or the like, A is S or O and a broken line represents presence or absence of a bond, pharmaceutically acceptable salt or hydrate thereof and a pharmaceutical composition or a pharmaceutical composition for use as an endothelin receptor antagonist, a peripheral circulation insufficiency-improving agent or a macrophage foam cell formation inhibitor comprising the compound.

  本发明提供了一种化合物，其化学式为（I）： 其中R1、R2、R3和R4分别独立地为氢、可选择取代的烷基、羟基、可选择取代的烷氧基或类似物，R5为可选择取代的烷基、可选择取代的芳基、可选择取代的杂环基或类似物，R6为氢、可选择取代的烷基或类似物，R7为氢、可选择取代的烷基、可选择取代的烷氧基、可选择取代的芳基、可选择取代的杂环基或类似物，A为S或O，虚线表示键的存在或缺失，以及其药学上可接受的盐或水合物，以及包含该化合物的用作内皮素受体拮抗剂、外周循环不足改善剂或巨噬细胞泡沫细胞形成抑制剂的药物组合物或药物组合物。
• CHROMENE-3-CARBOXYLATE DERIVATIVES
  申请人：SHIONOGI & CO., LTD.

  公开号：EP0924207A1

  公开（公告）日：1999-06-23

  The present invention provides a compound of the formula (I): wherein R1, R2, R3 and R4 are each independently hydrogen, optionally substituted alkyl, hydroxy, optionally substituted alkoxy or the like, R5 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocyclic or the like, R6 is hydrogen, optionally substituted alkyl or the like, R7 is hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heterocyclic or the like, A is S or O and a broken line represents presence or absence of a bond, pharmaceutically acceptable salt or hydrate thereof and a pharmaceutical composition or a pharmaceutical composition for use as an endothelin receptor antagonist, a peripheral circulation insufficiency-improving agent or a macrophage foam cell formation inhibitor comprising the compound.

  本发明提供了式 (I) 的化合物： 其中 R1、R2、R3 和 R4 各自独立地是氢、任选取代的烷基、羟基、任选取代的烷氧基或类似物，R5 是任选取代的烷基、任选取代的芳基、任选取代的杂环或类似物，R6 是氢、任选取代的烷基或类似物，R7 是氢、任选取代的烷基、任选取代的烷氧基、任选取代的芳基、任选取代的杂环或类似物，A 是 S 或 O，断线表示存在或不存在键、 其药学上可接受的盐或水合物，以及包含该化合物的用作内皮素受体拮抗剂、外周循环不全改善剂或巨噬细胞泡沫形成抑制剂的药物组合物或药物组合物。
• US6218427B1
  申请人：——

  公开号：US6218427B1

  公开（公告）日：2001-04-17
• 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.