7-溴吡啶并[2,3-B]吡嗪-2,3(1H,4H)-二酮 | 168123-82-8

• 物质功能分类: 医药中间体 - 吡啶类化合物
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶吡嗪类
• 中文名称: 7-溴吡啶并[2,3-B]吡嗪-2,3(1H,4H)-二酮
• 英文名称: 7-bromopyrido[2,3-b]pyrazin-2,3-diol
• 英文别名: 2,3-dihydroxy-7-bromopyrido[2,3-b]pyrazine；7-Bromopyrido[2,3-b]pyrazine-2,3(1H,4H)-dione；7-bromo-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
• CAS: 168123-82-8
• 化学式: C₇H₄BrN₃O₂
• 分子量: 242.032
• InChiKey: SMQUNTGAPNGDHP-UHFFFAOYSA-N

物化性质

• 密度：
  1.851±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  13
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  71.1
• 氢给体数：
  2
• 氢受体数：
  3

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

反应信息

• 作为反应物：
  描述：

  7-溴吡啶并[2,3-B]吡嗪-2,3(1H,4H)-二酮 在 palladium diacetate 、 potassium carbonate 、 三乙胺 、 三(邻甲基苯基)磷 、 lithium hydroxide 、 三氯氧磷 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 32.0h， 生成
  参考文献：
  名称：

  一系列的吡啶并[2,3 - b ]吡嗪-3（4 H）-一衍生物作为具有抗氧化活性的醛糖还原酶抑制剂

  摘要：

  设计了一系列基于吡啶并[2,3 - b ]吡嗪-3（4 H）-one的衍生物作为醛糖还原酶（ALR2）的抑制剂，该酶在糖尿病并发症的发生和发展中起着关键作用。与糖尿病和其他病理相关的氧化应激过程。发现大多数衍生物在核心结构上具有取代的C2芳族基团和N4乙酸基团，是具有亚微摩尔IC 50值的强效选择性醛糖还原酶抑制剂，而9c对IC 50活性最高。值0.009μM。特别是，设计的许多带有酚羟基取代的C2-苯乙烯基侧链的化合物不仅在ALR2抑制方面表现出优异的性能，而且在抗氧化剂方面也表现出优异的性能，并且在这些11i中被证明是具有最高抗氧化能力的化合物，甚至与之相比。著名的抗氧化剂Trolox。结构-活性关系和分子对接研究强调了在支架的C2侧链中酚羟基取代基和乙烯基间隔基对于构建高效和多功能ALR2抑制剂的重要性。

  DOI：

  10.1016/j.ejmech.2016.05.036
• 作为产物：
  描述：

  2-氨基-5-溴-3-硝基吡啶 在 盐酸 、 tin(ll) chloride 作用下， 以 乙醇 为溶剂， 反应 31.0h， 生成 7-溴吡啶并[2,3-B]吡嗪-2,3(1H,4H)-二酮
  参考文献：
  名称：

  5-(N-Oxyaza)-7-substituted-1,4-dihydroquinoxaline-2,3-diones:  Novel, Systemically Active and Broad Spectrum Antagonists for NMDA/glycine, AMPA, and Kainate Receptors

  摘要：

  A group of 5-aza-7-substituted-1,4-dihydroquinoxaline-2,3-diones (QXs) and the corresponding 5-(N-oxyaza)-7-substituted QXs were prepared and evaluated as antagonists of ionotropic glutamate receptors. The in vitro potency of these QXs was determined by inhibition of [H-3]- 5,7-dichlorokynurenic acid ([H-3]DCKA) binding to N-methyl-D-aspartate (NMDA)/glycine receptors, [H-3]-(S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([H-3]AMPA) binding to AMPA receptors, and [H-3]kainate ([H-3]KA) binding to KA receptors in rat brain membranes. 5-(N-Oxyaza)-QXs 12a-e all have low micromolar or submicromolar potency for NMDA/glycine receptors and low micromolar potencies for AMPA and KA receptors. QXs 12a-e display 2-12-fold selectivity for NMDA/glycine receptors compared to AMPA receptors, and similar to 2-fold difference between AMPA and KA potency. In contrast to other QXs that either show high selectivity for NMDA (such as ACEA 1021) or AMPA (such as NBQX) receptors, these molecules are broad spectrum antagonists of ionotropic glutamate receptors. 7-Nitro-5-(N-oxyaza)-QX (12e) is the most potent inhibitor among 12a-e, having IC50 values of 0.69, 1.3, and 2.4 mu M at NMDA, AMPA, and KA receptors, respectively. In functional assays on glutamate receptors expressed in oocytes by rat cerebral cortex poly(A(+)) RNA, 7-chloro-5-(N-oxyaza)-QX (12a) and 7-nitro-5-(N-oxyaza)-QX (12e) have K-b values of 0.63 and 0.31 mu M for NMDA/glycine receptors, and are 6- and 4-fold selective for NMDA over AMPA receptors, respectively. 5-(N-Oxyaza)-7-substituted-QXs 12a-e all have surprisingly high in vivo potency as anticonvulsants in a mouse maximal electroshock-induced seizure (MES) model. 7-Chloro-5-(N-oxyaza)-QX (12a), 7-bromo-5-(N-oxyaza)-QX (12b), and 7-methyl-5-(N-oxyaza)-QX (12c) have ED50 values of 0.82, 0.87, and 0.97 mg/kg iv, respectively. The high in vivo potency of QXs 12a-e is particularly surprising given their low log P values (similar to-2.7). Separate studies indicate that QXs 12a and 12e are also active in vivo as neuroprotectants and also have antinociceptive activity in animal pain models. In terms of in vivo activity, these 5-(N-oxyaza)-7-substituted-QXs are among the most potent broad spectrum ionotropic glutamate antagonists reported.

  DOI：

  10.1021/jm970396y

文献信息

• Large-Scale Solvent-Free Chlorination of Hydroxy-Pyrimidines, -Pyridines, -Pyrazines and -Amides Using Equimolar POCl3
  作者：Han Wang、Kun Wen、Le Wang、Ye Xiang、Xiaocheng Xu、Yongjia Shen、Zhihua Sun

  DOI：10.3390/molecules17044533

  日期：——

  Chlorination with equimolar POCl3 can be efficiently achieved not only for hydroxypyrimidines, but also for many other substrates such as 2-hydroxy-pyridines, -quinoxalines, or even -amides. The procedure is solvent-free and involves heating in a sealed reactor at high temperatures using one equivalent of pyridine as base. It is suitable for large scale (multigram) batch preparations.

  使用等摩尔量的POCl3对羟基嘧啶进行氯化不仅是有效的，而且对许多其他底物，如2-羟基吡啶、喹唑啉或甚至酰胺也是如此。该过程是无溶剂的，涉及在密封反应器中高温加热，使用一当量的吡啶作为碱。它适用于大规模（多克级）批次制备。
• NOVEL HETEROCYCLIC DERIVATIVES AND THEIR USES
  申请人：Ho Pil Su

  公开号：US20140315888A1

  公开（公告）日：2014-10-23

  The present invention relates to novel heterocyclic compounds useful in preparing drugs for treatment of diseases associated with various functions of the histamine 4 receptor. Especially, the said drugs are useful for treatment of inflammatory diseases, allergy, pain, nasal polyps, rhinitis, chronic sinusitis, nasal congestion, nasal itch, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, atopic dermatitis, psoriasis, eczema, pruritus, itchy skin, urticaria, idiopathic chronic urticaria, scleroderma, conjunctivitis, keratoconjunctivitis, ocular inflammation, dry eye, cardiac dysfunction, arrhythmia, atherosclerosis, multiple sclerosis, inflammatory bowel disease (including colitis, Crohn's disease, ulcerative colitis), inflammatory pain, neuropathic pain, osteoarthritic pain, autoimmune thyroid disease, immune-mediated (also known as type I) diabetes, lupus, post-operative adhesions, vestibular disorders and cancer.

  该发明涉及新型杂环化合物，用于制备治疗与组织胺4受体的各种功能相关的疾病的药物。特别是，所述药物适用于治疗炎症性疾病、过敏、疼痛、鼻息肉、鼻炎、慢性鼻窦炎、鼻塞、鼻痒、哮喘、慢性阻塞性肺病、类风湿性关节炎、特应性皮炎、牛皮癣、湿疹、瘙痒、瘙痒皮肤、荨麻疹、特发性慢性荨麻疹、硬皮病、结膜炎、角膜结膜炎、眼部炎症、干眼症、心脏功能障碍、心律失常、动脉粥样硬化、多发性硬化、炎症性肠病（包括结肠炎、克罗恩病、溃疡性结肠炎）、炎症性疼痛、神经痛、骨关节炎疼痛、自身免疫性甲状腺疾病、免疫介导（也称为I型）糖尿病、红斑狼疮、术后粘连、前庭障碍和癌症的药物治疗。
• Discovery of a Novel Highly Selective Histamine H4 Receptor Antagonist for the Treatment of Atopic Dermatitis
  作者：Kwangseok Ko、Hye-Jung Kim、Pil-Su Ho、Soon Ok Lee、Ji-Eun Lee、Cho-Rong Min、Yu Chul Kim、Ju-Han Yoon、Eun-Jung Park、Young-Jin Kwon、Jee-Hun Yun、Dong-Oh Yoon、Jung-Sook Kim、Woul-Seong Park、Seung-Su Oh、Yu-Mi Song、Woon-Ki Cho、Kazumi Morikawa、Kyoung-June Lee、Chan-Hee Park

  DOI：10.1021/acs.jmedchem.7b01855

  日期：2018.4.12

  activity as well as excellent selectivity against off-targets. A pharmacophore-based virtual screening system constructed in-house successfully identified initial hit compound 9, and the subsequent homology model-guided optimization efficiently led us to discover pyrido[2,3-e]tetrazolo[1,5-a]pyrazine analogue 48 as a novel chemotype of a potent and highly selective H4R antagonist. Importantly, orally administered

  组胺H4受体（H4R）是G蛋白偶联受体家族的成员，被认为是治疗特应性皮炎（AD）的潜在治疗靶标。已经公开了许多H4R拮抗剂，但是尚未开发出控制AD中瘙痒和炎症的有效药物。在这里，我们发现了一类新型的口服H4R拮抗剂，显示出强大的止痒和消炎活性以及对脱靶的极好的选择性。在内部构建的基于药效团的虚拟筛选系统成功鉴定了初始命中化合物9，随后的同源性模型指导的优化有效地引导我们发现了吡啶并[2,3- e ] tetrazolo [1,5- a ] pyrazine类似物48是一种有效且高度选择性的H4R拮抗剂的新型化学型。重要的是，在几种AD小鼠模型中，口服给药的化合物48在止痒和抗炎方面显示出显着的功效，并具有良好的药代动力学（PK）特征。因此，这些数据强烈表明我们的化合物48是用于治疗AD的有前途的临床候选药物。
• Discovery and analgesic evaluation of 8-chloro-1,4-dihydropyrido[2,3- b ]pyrazine-2,3-dione as a novel potent d -amino acid oxidase inhibitor
  作者：Dongsheng Xie、Jun Lu、Jin Xie、Junjun Cui、Teng-Fei Li、Yan-Chao Wang、Yuan Chen、Nian Gong、Xin-Yan Li、Lei Fu、Yong-Xiang Wang

  DOI：10.1016/j.ejmech.2016.04.017

  日期：2016.7

  A series of 5-azaquinoxaline-2,3-dione derivatives were synthesized and evaluated on d-amino acid oxidase (DAAO) inhibition as potential α-hydroxylactam-based inhibitors. The potent inhibitory activities in vitro suggested that 5-nitrogen could significantly enhance the binding affinity by strengthening relevant hydrogen bond interactions. The analgesic effects of intrathecal and systemic injection

  合成了一系列5-氮杂喹喔啉-2,3-二酮衍生物，并评估了其作为潜在的基于α-羟基内酰胺的抑制剂对d-氨基酸氧化酶（DAAO）的抑制作用。体外的强抑制活性表明5-氮可以通过增强相关的氢键相互作用来显着增强结合亲和力。研究了鞘内和全身注射8-氯-1,4-二氢吡啶并[2,3- b ]吡嗪-2,3-二酮（5-氮杂喹喔啉-2,3-二酮的代表分子）的镇痛作用。啮齿动物。这项研究不仅证实了DAAO抑制剂的镇痛作用，而且还提供了一类具有口服应用潜力的新型化学实体，可用于治疗慢性疼痛和吗啡镇痛耐受性。
• 8-AZA, 6-AZA AND 6,8-DIAZA-1,4-DIHYDROQUINOXALINE-2,3-DIONES AND THE USE THEREOF AS ANTAGONISTS FOR THE GLYCINE/NMDA RECEPTOR
  申请人：ACEA PHARMACEUTICALS, INC.

  公开号：EP0743855A1

  公开（公告）日：1996-11-27