(9CI)-1,4-二氢-7-甲基吡啶并[2,3-b]吡嗪-2,3-二酮 | 144435-02-9

• 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: (9CI)-1,4-二氢-7-甲基吡啶并[2,3-b]吡嗪-2,3-二酮
• 英文名称: 7-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione
• 英文别名: 8-aza-6-methyl-1,4-dihydroquinoxaline-2,3-dione
• CAS: 144435-02-9
• 化学式: C₈H₇N₃O₂
• 分子量: 177.162
• InChiKey: CRNKRWHGMHPFKN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  13
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  71.1
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (9CI)-1,4-二氢-7-甲基吡啶并[2,3-b]吡嗪-2,3-二酮 在 间氯过氧苯甲酸 、 三氟乙酸 作用下， 反应 15.0h， 以74%的产率得到
  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
• 作为产物：
  描述：

  2-氨基-5-甲基吡啶 在 Pd-C aq. NaOH 、 草酸 作用下， 以 盐酸 、 甲醇 为溶剂， 生成 (9CI)-1,4-二氢-7-甲基吡啶并[2,3-b]吡嗪-2,3-二酮
  参考文献：
  名称：

  8-aza, 6-aza and 6,8-diaza-1,4-dihydroquinoxaline-2,3-diones and the use

  摘要：

  揭示了一种用于治疗或预防与中风、缺血、中枢神经系统创伤或低血糖相关的神经元丧失的方法。该方法包括向动物施用以下化合物的步骤：##STR1## 或其药学上可接受的盐；其中n为零或1；R.sup.4、R.sup.5、R.sup.6分别独立地是氢、硝基、氨基、卤素、卤代烷基、氰基、烷基、环烷基、烯基、炔基、叠氮基、酰胺基、烷基磺酰基、芳基、取代芳基、杂芳基、烷氧基、三烷基硅基取代的烷氧基、芳氧基、取代芳氧基、杂芳氧基、杂环基团、杂环氧基团、芳基烷氧基或卤代烷氧基；且R.sup.c和R.sup.d在规范中有定义。这些化合物具有高结合NMDA受体的甘氨酸位点的能力。

  公开号：

  US05620978A1

文献信息

• 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。
• Novel α-Amino-3-hydroxy-5-methylisoxazole-4-propionate Receptor Antagonists:  Synthesis and Structure−Activity Relationships of 6-(1<i>H</i>-Imidazol-1-yl)- 7-nitro-2,3(1<i>H</i>,4<i>H</i>)-pyrido[2,3-<i>b</i>]pyrazinedione and Related Compounds
  作者：Junya Ohmori、Hirokazu Kubota、Masao Shimizu-Sasamata、Masamichi Okada、Shuichi Sakamoto

  DOI：10.1021/jm950304+

  日期：1996.3.15

  for quinoxalinedione in AMPA receptor binding. The detailed structure-activity relationships of 6- and/or 7-substituted 2,3(1H,4H)-pyrido[2,3-b]pyrazinedione derivatives 4, 7-1-, 13, 15 and 16 showed some differences in comparison with those of the corresponding substituted quinoxalinediones, including 6-(1H-imidazol-1-yl)-7-nitro-2,3-(1H,4H)-quinoxalinedione (1) (YM90K). The X-ray study exhibited that

  我们已经合成并评估了氮杂喹喔啉酮3a-c在抑制大鼠全脑[3H] AMPA结合中的活性。发现氮杂喹喔啉二酮核在AMPA受体结合中起喹喔啉二酮的生物同工异构体的作用。6-和/或7-取代的2,3（1H，4H）-吡啶并[2,3-b]吡嗪二酮衍生物4、7-1、13、15和16的详细结构-活性关系显示出一些差异与包括6-（1H-咪唑-1-基）-7-硝基-2,3-（1H，4H）-喹喔啉二酮（1）（YM90K）的相应取代喹喔啉二酮的比较。X射线研究表明1.HCl的7-硝基基团与喹喔啉环几乎共面，而6-咪唑-1-基相对于芳环旋转。从NMDA受体结合研究中的甘氨酸位点开始，表明在吡啶并吡嗪二酮上6-取代基的庞大可能是针对甘氨酸位点的选择性的原因。在一系列的氮杂喹喔啉二酮中，6-（1H-咪唑-1-基）-7-硝基-2,3（1H，4H）-吡啶并[2,3-b]吡嗪二酮（8c）表现出最佳亲和力的组合对AMPA受体具有Ki值为0
• 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

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