ethyl (3,4-dihydro-2,2-dimethyl-6-nitro-3-oxo-2H1,4-benzoxazin-4-yl)acetate | 136544-97-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: ethyl (3,4-dihydro-2,2-dimethyl-6-nitro-3-oxo-2H1,4-benzoxazin-4-yl)acetate
• 英文别名: ethyl 2-(2,2-dimethyl-6-nitro-3-oxo-1,4-benzoxazin-4-yl)acetate
• CAS: 136544-97-3
• 化学式: C₁₄H₁₆N₂O₆
• 分子量: 308.291
• InChiKey: ONHHHMCFMGEPPJ-UHFFFAOYSA-N

物化性质

• 熔点：
  132-134 °C(Solv: isopropyl ether (108-20-3); hexane (110-54-3))
• 沸点：
  516.4±50.0 °C(Predicted)
• 密度：
  1.288±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  102
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  甲胺 、 ethyl (3,4-dihydro-2,2-dimethyl-6-nitro-3-oxo-2H1,4-benzoxazin-4-yl)acetate 以 甲醇 为溶剂， 反应 1.0h， 以28%的产率得到2-(2,2-dimethyl-6-nitro-3-oxo-1,4-benzoxazin-4-yl)-N-methylacetamide
  参考文献：
  名称：

  Novel Potassium Channel Activators: Synthesis and Structure-Activity Relationship Studies of 3,4-Dihydro-2H-1,4-benzoxazine Derivatives.

  摘要：

  在一系列新型的4-取代3,4-二氢-2H-1,4-苯并氧氮杂䓬衍生物中，发现了强烈的钾通道激活效应。制备的关键步骤是用3,4-二氢-2H-1,4-苯并氧氮杂䓬（3）与活性卤代吡啶进行亲核取代反应，例如卤代吡啶N-氧化物（15a-c）和4-溴吡啶的硼烷加合物（15d）。构效关系研究表明，2-（3,4-二氢-2,2-二甲基-6-硝基-2H-1,4-苯并氧氮杂䓬-4-基）吡啶-1-氧化物（16a：YM934）为最佳化合物。该化合物（16a）在清醒的自发性高血压大鼠中显示出比克罗卡林更强的口服降压效果。

  DOI：

  10.1248/cpb.44.103
• 作为产物：
  描述：

  2-氨基-4-硝基苯酚 在 potassium carbonate 、 三乙胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 生成 ethyl (3,4-dihydro-2,2-dimethyl-6-nitro-3-oxo-2H1,4-benzoxazin-4-yl)acetate
  参考文献：
  名称：

  Novel Potassium Channel Activators: Synthesis and Structure-Activity Relationship Studies of 3,4-Dihydro-2H-1,4-benzoxazine Derivatives.

  摘要：

  在一系列新型的4-取代3,4-二氢-2H-1,4-苯并氧氮杂䓬衍生物中，发现了强烈的钾通道激活效应。制备的关键步骤是用3,4-二氢-2H-1,4-苯并氧氮杂䓬（3）与活性卤代吡啶进行亲核取代反应，例如卤代吡啶N-氧化物（15a-c）和4-溴吡啶的硼烷加合物（15d）。构效关系研究表明，2-（3,4-二氢-2,2-二甲基-6-硝基-2H-1,4-苯并氧氮杂䓬-4-基）吡啶-1-氧化物（16a：YM934）为最佳化合物。该化合物（16a）在清醒的自发性高血压大鼠中显示出比克罗卡林更强的口服降压效果。

  DOI：

  10.1248/cpb.44.103

文献信息

• 3,4-dihydro-2H-1,4-benzoxazine derivatives and pharmaceutical
  申请人：Yamanouchi Pharmaceutical Co., Ltd.

  公开号：US05420126A1

  公开（公告）日：1995-05-30

  Novel benzoxazine derivatives of the formula (I): ##STR1## are provided as well as their pharmaceutically acceptable salts and a method for their use as potassium channel activating agents 2-(3,4-Dihydro-2, 2-dimethyl-6-phenylsulfonyl-2H-1,4-benzoxazin-4-yl)pyridine N-oxide is illustrative of a benzoxazine derivative of formula (I). Also provided are intermediate compounds such as those of formula (II): ##STR2##

  提供了式(I)的新型苯并噁嗪衍生物：##STR1##以及它们的药学上可接受的盐和用作钾通道激活剂的方法。2-(3,4-二氢-2,2-二甲基-6-苯基磺酰基-2H-1,4-苯并噁嗪-4-基)吡啶N-氧化物是式(I)的苯并噁嗪衍生物的实例。还提供了中间化合物，例如式(II)的化合物：##STR2##
• Synthesis, biological activity and conformational study of 1,4-benzoxazine derivatives as potassium channel modulators
  作者：Giuseppe Caliendo、Paolo Grieco、Elisa Perissutti、Vincenzo Santagada、Antonello Santini、Stefania Albrizio、Caterina Fattorusso、Aldo Pinto、Raffaella Sorrentino

  DOI：10.1016/s0223-5234(99)80020-8

  日期：1998.12

  With the aim of discovering new molecules with K+-channel activating properties, we have synthesized derivatives of cromakalim (CRK), an important molecule which shows specific affinity towards K+ channels, by replacing the benzopyrane ring of this reference compound with a 1,4-benzoxazine moiety. A different number of substituents showing a good discrimination between hydrophobic and electronic properties have been inserted at the 6-position of the 1,4-benzoxazine ring. We describe here the synthesis and discuss the solid state conformation of these new molecules. When tested on rat aorta ring precontracted with phenylephrine, two compounds (2c and 2d) showed a concentration-dependent relaxation similar to that measured for cromakalim but less potent than this reference drug. (C) Elsevier, Paris.
• Synthesis by microwave irradiation of a substituted benzoxazine parallel library with preferential relaxant activity for guinea pig trachealis
  作者：Giuseppe Caliendo、Elisa Perissutti、Vincenzo Santagada、Ferdinando Fiorino、Beatrice Severino、Donatella Cirillo、Roberta d’Emmanuele di Villa Bianca、Laura Lippolis、Aldo Pinto、Raffaella Sorrentino

  DOI：10.1016/j.ejmech.2004.05.003

  日期：2004.10

  An efficient, facile, and practical parallel combinatorial synthesis of substituted-benzoxazines under microwave irradiation was described. The procedure involved the use of a microwave oven especially designed for organic synthesis suitable for parallel synthesis of solution libraries. A demonstration 19-membered library of substituted N,N-dimethyl- and N-methyl-benzoxazine amide derivatives, structurally related to the potassium channel opener cromakalim, was generated by both conventional and microwave procedures, achieving a reduction from 7 h to 30-36 min in library generation time for the microwave approach. All the synthesized compounds were tested using the in vitro models of rat aorta and guinea pig trachea rings pre-contracted with phenylephrine and carbachol, respectively. All N,N-dimethyl amide derivatives showed a relaxant activity higher on guinea pig trachea rings than on rat aorta rings. (C) 2004 Elsevier SAS. All rights reserved.
• Novel Potassium Channel Activators: Synthesis and Structure-Activity Relationship Studies of 3,4-Dihydro-2H-1,4-benzoxazine Derivatives.
  作者：Yuzo MATSUMOTO、Ryuji TSUZUKI、Akira MATSUHISA、Kazuhisa TAKAYAMA、Toru YODEN、Wataru UCHIDA、Masaharu ASANO、Shigeo FUJITA、Isao YANAGISAWA、Takashi FUJIKURA

  DOI：10.1248/cpb.44.103

  日期：——

  Strong potassium channel-activating effects were found among a series of novel 4-substituted 3, 4-dihydro-2H-1, 4-benzoxazine derivatives. The key step in preparation was the nucleophilic substitution of 3, 4-dihydro-2H-1, 4-benzoxazine (3) with activated halogenopyridines, such as halogenopyridine N-oxides (15a-c) and the borane adduct (15d) of 4-bromopyridine. Structure-activity relationship studies identified 2-(3, 4-dihydro-2, 2-dimethyl-6-nitro-2H-1, 4-benzoxazin-4-yl)pyridine-1-oxide (16a : YM934) as the optimal compound. This compound (16a) showed a more potent oral antihypertensive effect than cromakalim in conscious spontaneously hypertensive rats.

  在一系列新型的4-取代3,4-二氢-2H-1,4-苯并氧氮杂䓬衍生物中，发现了强烈的钾通道激活效应。制备的关键步骤是用3,4-二氢-2H-1,4-苯并氧氮杂䓬（3）与活性卤代吡啶进行亲核取代反应，例如卤代吡啶N-氧化物（15a-c）和4-溴吡啶的硼烷加合物（15d）。构效关系研究表明，2-（3,4-二氢-2,2-二甲基-6-硝基-2H-1,4-苯并氧氮杂䓬-4-基）吡啶-1-氧化物（16a：YM934）为最佳化合物。该化合物（16a）在清醒的自发性高血压大鼠中显示出比克罗卡林更强的口服降压效果。