2-[5-Methoxy-2-(4-{[2-(4-methoxy-phenoxy)-ethyl]-methyl-amino}-butoxy)-phenyl]-4-methyl-4H-benzo[1,4]thiazin-3-one | 127732-37-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻嗪类
• 英文名称: 2-[5-Methoxy-2-(4-{[2-(4-methoxy-phenoxy)-ethyl]-methyl-amino}-butoxy)-phenyl]-4-methyl-4H-benzo[1,4]thiazin-3-one
• 英文别名: 2-[5-Methoxy-2-[4-[2-(4-methoxyphenoxy)ethyl-methylamino]butoxy]phenyl]-4-methyl-1,4-benzothiazin-3-one
• CAS: 127732-37-0
• 化学式: C₃₀H₃₆N₂O₅S
• 分子量: 536.692
• InChiKey: OUOAHKBNSMBARV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  38
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  85.8
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-[5-Methoxy-2-(4-{[2-(4-methoxy-phenoxy)-ethyl]-methyl-amino}-butoxy)-phenyl]-4-methyl-4H-benzo[1,4]thiazin-3-one 在 一水合肼 作用下， 以 乙醇 为溶剂， 反应 4.5h， 生成 tert-butyl 2-[4-[2-[[9-[(3aR,4R,6S,6aS)-6-(ethylcarbamoyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-6-aminopurin-2-yl]amino]ethyl]phenyl]acetate
  参考文献：
  名称：

  2-(Arylalkylamino)adenosin-5'-uronamides: a new class of highly selective adenosine A2 receptor ligands

  摘要：

  The synthesis and receptor-binding profiles at adenosine receptor subtypes for a series of 2-(arylalkylamino)-adenosin-5'-uronamides is described. Halogenated 2-phenethylamino analogues such as 3e show greater than 200-fold selectivity for the A2 receptor subtype on the basis of rat brain receptor binding. The general structure-activity relationship of this series of compounds is discussed both in terms of potency at A2 receptors as well as receptor subtype selectivity. It is possible to introduce a hydrophilic carboxyalkyl substituent to this series such as in CGS 21680A (3h) and still retain good potency and selectivity for A2 receptors. In addition, functional data in a perfused working rat heart model shows that these compounds possess full agonist properties at A2 receptors with 3h having a greater than 1500-fold separation between A2 (coronary vasodilatory) and A1 (negative chronotropic) receptor mediated events.

  DOI：

  10.1021/jm00169a015
• 作为产物：
  描述：

  3,4-Dihydro-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine 在 sodium hydride 、 碳酸氢钠 、 sodium iodide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 5.5h， 生成 2-[5-Methoxy-2-(4-{[2-(4-methoxy-phenoxy)-ethyl]-methyl-amino}-butoxy)-phenyl]-4-methyl-4H-benzo[1,4]thiazin-3-one
  参考文献：
  名称：

  Synthesis and calcium ion antagonistic activity of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazines

  摘要：

  As an extension of the previous investigation (J. Med. Chem. 1988, 31, 919), we synthesized a series of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H- 1,4-benzothiazines (3) and evaluated their Ca2+ antagonistic activities. Ca2+ antagonistic activity was measured with isolated depolarized guinea pig taenia cecum. On the basis of their potent Ca2+ antagonistic activity, six benzothiazines were selected and further evaluated for their vasocardioselectivity. Among these six compounds, the key compound 15 [3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[3,4- (methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo- 2H-1,4-benzothiazine hydrogen fumarate] was recognized as having the lowest cardioselectivity. Following optical resolution, the absolute configuration of the compound's optically active enantiomer was determined by means of X-ray crystallography of a synthetic precursor (+)-4a. The Ca2+ antagonistic activity of 15 was found to reside primarily in (+)-15 (which was about 7 times more potent than (-)-15). The in vitro study showed that (+)-15 had a low cardioselectivity compared to verapamil and diltiazem. This result suggests that (+)-15 would exhibit less adverse effects due to cardiac inhibition than diltiazem and verapamil in therapeutic use.

  DOI：

  10.1021/jm00169a011

文献信息

• Synthesis and calcium ion antagonistic activity of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazines
  作者：Masanobu Fujita、Susumu Ito、Atsutoshi Ota、Nobuharu Kato、Koji Yamamoto、Yoichi Kawashima、Hideyasu Yamauchi、Junichi Iwao

  DOI：10.1021/jm00169a011

  日期：1990.7

  As an extension of the previous investigation (J. Med. Chem. 1988, 31, 919), we synthesized a series of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H- 1,4-benzothiazines (3) and evaluated their Ca2+ antagonistic activities. Ca2+ antagonistic activity was measured with isolated depolarized guinea pig taenia cecum. On the basis of their potent Ca2+ antagonistic activity, six benzothiazines were selected and further evaluated for their vasocardioselectivity. Among these six compounds, the key compound 15 [3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[3,4- (methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo- 2H-1,4-benzothiazine hydrogen fumarate] was recognized as having the lowest cardioselectivity. Following optical resolution, the absolute configuration of the compound's optically active enantiomer was determined by means of X-ray crystallography of a synthetic precursor (+)-4a. The Ca2+ antagonistic activity of 15 was found to reside primarily in (+)-15 (which was about 7 times more potent than (-)-15). The in vitro study showed that (+)-15 had a low cardioselectivity compared to verapamil and diltiazem. This result suggests that (+)-15 would exhibit less adverse effects due to cardiac inhibition than diltiazem and verapamil in therapeutic use.
• 2-(Arylalkylamino)adenosin-5'-uronamides: a new class of highly selective adenosine A2 receptor ligands
  作者：Alan J. Hutchison、Michael Williams、Reynalda De Jesus、Rina Yokoyama、Howard H. Oei、Geetha R. Ghai、Randy L. Webb、Harry C. Zoganas、George A. Stone、Michael F. Jarvis

  DOI：10.1021/jm00169a015

  日期：1990.7

  The synthesis and receptor-binding profiles at adenosine receptor subtypes for a series of 2-(arylalkylamino)-adenosin-5'-uronamides is described. Halogenated 2-phenethylamino analogues such as 3e show greater than 200-fold selectivity for the A2 receptor subtype on the basis of rat brain receptor binding. The general structure-activity relationship of this series of compounds is discussed both in terms of potency at A2 receptors as well as receptor subtype selectivity. It is possible to introduce a hydrophilic carboxyalkyl substituent to this series such as in CGS 21680A (3h) and still retain good potency and selectivity for A2 receptors. In addition, functional data in a perfused working rat heart model shows that these compounds possess full agonist properties at A2 receptors with 3h having a greater than 1500-fold separation between A2 (coronary vasodilatory) and A1 (negative chronotropic) receptor mediated events.