4H-8-溴-1,2,4-噁二唑(3,4-d)苯并(b)(1,4)噁嗪-1-酮 | 204326-43-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 4H-8-溴-1,2,4-噁二唑(3,4-d)苯并(b)(1,4)噁嗪-1-酮
• 英文名称: 4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one
• 英文别名: 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]-benzoxazin-1-one；8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one；NS-2028；NS2028；4H-8-bromo-1,2,4-oxadiazolo[3,4]-dibenz[b][1,4]oxazin-1-one；4H-8-bromo-1,2,4-oxadiazolo[3,4-d]benz[b][1,4]oxazin-1-one
• CAS: 204326-43-2
• 化学式: C₉H₅BrN₂O₃
• 分子量: 269.054
• InChiKey: MUDRLQRJCGJJTB-UHFFFAOYSA-N

物化性质

• 熔点：
  160～170℃
• 沸点：
  353.8±52.0 °C(Predicted)
• 密度：
  2.06±0.1 g/cm3(Predicted)
• 溶解度：
  在DMSO中的溶解度为13 毫克/毫升

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  15
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  51.1
• 氢给体数：
  0
• 氢受体数：
  4

安全信息

• 储存条件：
  存储条件：2-8℃，干燥且密封。

制备方法与用途

生物活性

NS-2028 是一种高选择性可溶性鸟苷酸环化酶 (sGC) 抑制剂，其对 basal 和 NO 刺激的酶活性的 IC50 值分别为 30 nM 和 200 nM。它还抑制小鼠小脑匀浆和神经元中 NO 合酶中的可溶性鸟苷酸环化酶活性，IC50值分别为17 nM和20 nM。在人培养的脐静脉内皮细胞中，NS-2028 抑制 3-吗啉代-sydnonimine (SIN-1) 形成环状GMP 的 IC50 值为30 nM。NS-2028 常用于一氧化氮信号通路的研究，并能完全抑制非血管平滑肌中 NO 依赖性松弛反应（浓度为 1 μM）。此外，它还能够降低血管内皮生长因子诱导的血管生成和通透性。

靶点

• IC50: 30 nM (可溶性鸟苷酸环化酶 sGC)

体外研究

• NS-2028（浓度为 10 μM，孵育时间为 24 小时）抑制细胞增殖，与对照组相比减少了约 25% 的细胞数量。

• NS-2028（浓度为 10 μM，孵育时间为 30 分钟）通过抑制 p38 MAPK 活性，减弱血管内皮生长因子 (VEGF) 引起的内皮细胞迁移。

细胞增殖试验

细胞系	HUVEC 细胞
浓度	10 μM
孵育时间	24 小时
结果	增殖减少

Western Blot 分析

细胞系	HUVEC 细胞
浓度	10 μM
孵育时间	30 分钟
结果	抑制 VEGF 增强的 p38 磷酸化

体内研究

NS-2028（口服给药，浓度为 1 g/L，连续给药 8 天）在兔角膜中明显抑制了由 VEGF 颗粒植入引起的血管生成。

动物模型

动物类型	兔
剂量	1 g/L
给药方式	口服；1g/L，连续给药 8 天
结果	抑制 VEGF 引起的体内血管生成

反应信息

• 作为反应物：
  描述：

  4H-8-溴-1,2,4-噁二唑(3,4-d)苯并(b)(1,4)噁嗪-1-酮 在 tetraphosphorus decasulfide 作用下， 以 5,5-dimethyl-1,3-cyclohexadiene 为溶剂， 反应 48.0h， 以80%的产率得到8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazine-1-thione
  参考文献：
  名称：

  Synthesis of sulfur containing analogues of the soluble guanylate cyclase inhibitor 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one NS2028

  摘要：

  Sulfur analogues of the soluble guanylate cyclase (sGC) inhibitor NS2028 la are synthesized. Treating 8-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one oxime (6) with 1,1'-thiocarbonyldiimidazole (1.1 equiv) gave the carbamothioate 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazine-1-thione (3a) in 83% yield. Alternatively reacting NS2028 1a with P2S5 (0.5 equiv) affords the carbamothioate 3a in 80% yield. Similar treatment of 8-aryl substituted NS2028 analogues 1b-d with P2S5 gave the carbamothioates 3b-d in 64-91% yields. Although quite stable, the carbamothioates 3a-d could be thermally isomerized in the presence of Cu (10 mol X) to afford the thiocarbamates 4a-d in high yields. Interestingly, in the case of carbamothioate 3a Pd and In metals also facilitated the isomerization. Furthermore, treatment of the thiocarbamates 4a-d with P2S5 (0.5 equiv) affords the carbamodithioates 5a-d in 72-89% yields. All new compounds are fully characterized including single crystal X-ray data for carbamothioate 3a and thiocarbamate 4a. Finally, a mechanism is proposed for the carbamothioate to thiocarbamate isomerization. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tet.2011.05.071
• 作为产物：
  描述：

  6-bromo-2H-1,4-benzoxazin-3(4H)-one oxime 、 N,N'-羰基二咪唑 以 四氢呋喃 为溶剂， 反应 24.0h， 以95%的产率得到4H-8-溴-1,2,4-噁二唑(3,4-d)苯并(b)(1,4)噁嗪-1-酮
  参考文献：
  名称：

  Synthesis and biological evaluation of oxadiazole derivatives as inhibitors of soluble guanylyl cyclase

  摘要：

  Soluble guanylyl cyclase (sGC) is an ubiquitously expressed enzyme that generates the second messenger cGMP and hence, leads to a number of physiological responses including vasodilation, inhibition of platelet aggregation and neurotransmission. Whilst many activating and stimulating modulators of sGC were identified and studied in recent years, only two selective inhibitors are known: ODQ and NS 2028. Furthermore, a synthetic approach to these inhibitors has not been reported yet. Herein, we describe a novel and efficient synthesis of these inhibitors, as well as the preparation of three different classes of NS 2028 analogues. Biological evaluation of this library using rat aortic smooth muscle cells revealed four new compounds with good to moderate sGC inhibitory activity. Our experiments underline the major importance of the oxadiazole ring in ODQ and NS 2028 for the efficiency of this class of inhibitors. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.12.027

文献信息

• Suzuki–Miyaura reactions of the soluble guanylate cyclase inhibitor NS2028: a non-product specific route to C-8 substituted analogues
  作者：Andrey A. Berezin、Panayiotis A. Koutentis

  DOI：10.1016/j.tet.2011.04.003

  日期：2011.6

  Both soluble guanylate cyclase (sGC) inhibitors ODQ 1 and NS2028 2 are synthesized via improved protocols. In the former case treating 3,4-dihydroquinoxalin-2(1H)-one oxime 8, which can be prepared in two steps from 1,2-benzenediamine, with 1,1'-carbonyldiimidazole (CDI) gives the dihydro-ODQ 10 that in the presence of KMnO4 oxidises to give ODQ 1 in an overall yield of 46% starting from 1,2-benzenediamine. In the latter case, the synthesis affords NS2028 2 from 2-amino-4-bromophenol 3 in three steps with an overall yield of 85% and avoids the need for chromatography. Furthermore, Suzuki-Miyaura reaction conditions are described that enable the preparation of 8-aryl and 8-heteroaryl derivatives of NS2028 directly from NS2028 2. Finally, demethylation of the 8-(methoxyphenyl) substituted analogues afforded the 8-(hydroxyphenyl) derivatives 40-42. All new products are fully characterised. (C) 2011 Elsevier Ltd. All rights reserved.
• Synthesis and biological evaluation of oxadiazole derivatives as inhibitors of soluble guanylyl cyclase
  作者：Margarete von Wantoch Rekowski、Anastasia Pyriochou、Nektarios Papapetropoulos、Anne Stößel、Andreas Papapetropoulos、Athanassios Giannis

  DOI：10.1016/j.bmc.2009.12.027

  日期：2010.2

  Soluble guanylyl cyclase (sGC) is an ubiquitously expressed enzyme that generates the second messenger cGMP and hence, leads to a number of physiological responses including vasodilation, inhibition of platelet aggregation and neurotransmission. Whilst many activating and stimulating modulators of sGC were identified and studied in recent years, only two selective inhibitors are known: ODQ and NS 2028. Furthermore, a synthetic approach to these inhibitors has not been reported yet. Herein, we describe a novel and efficient synthesis of these inhibitors, as well as the preparation of three different classes of NS 2028 analogues. Biological evaluation of this library using rat aortic smooth muscle cells revealed four new compounds with good to moderate sGC inhibitory activity. Our experiments underline the major importance of the oxadiazole ring in ODQ and NS 2028 for the efficiency of this class of inhibitors. (C) 2009 Elsevier Ltd. All rights reserved.
• Synthesis of sulfur containing analogues of the soluble guanylate cyclase inhibitor 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one NS2028
  作者：Andrey A. Berezin、Panayiotis A. Koutentis、Manolis J. Manos

  DOI：10.1016/j.tet.2011.05.071

  日期：2011.7

  Sulfur analogues of the soluble guanylate cyclase (sGC) inhibitor NS2028 la are synthesized. Treating 8-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one oxime (6) with 1,1'-thiocarbonyldiimidazole (1.1 equiv) gave the carbamothioate 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazine-1-thione (3a) in 83% yield. Alternatively reacting NS2028 1a with P2S5 (0.5 equiv) affords the carbamothioate 3a in 80% yield. Similar treatment of 8-aryl substituted NS2028 analogues 1b-d with P2S5 gave the carbamothioates 3b-d in 64-91% yields. Although quite stable, the carbamothioates 3a-d could be thermally isomerized in the presence of Cu (10 mol X) to afford the thiocarbamates 4a-d in high yields. Interestingly, in the case of carbamothioate 3a Pd and In metals also facilitated the isomerization. Furthermore, treatment of the thiocarbamates 4a-d with P2S5 (0.5 equiv) affords the carbamodithioates 5a-d in 72-89% yields. All new compounds are fully characterized including single crystal X-ray data for carbamothioate 3a and thiocarbamate 4a. Finally, a mechanism is proposed for the carbamothioate to thiocarbamate isomerization. (C) 2011 Elsevier Ltd. All rights reserved.