3,4-二甲基-6H-异噁唑并[3,4-d]哒嗪-7-酮 | 15911-16-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 中文名称: 3,4-二甲基-6H-异噁唑并[3,4-d]哒嗪-7-酮
• 中文别名: 3,4-二甲基-6H-异噁唑并[3,4-D]哒嗪-7-酮
• 英文名称: 3,4-Dimethyl-isoxazolo<3,4-d>pyridazin-7-on
• 英文别名: ISOXAZOLO(3,4-d)PYRIDAZIN-7(6H)-ONE, 3,4-DIMETHYL-；3,4-dimethyl-6H-[1,2]oxazolo[3,4-d]pyridazin-7-one
• CAS: 15911-16-7
• 化学式: C₇H₇N₃O₂
• mdl: MFCD00126308
• 分子量: 165.151
• InChiKey: DINKYECDKUZHJM-UHFFFAOYSA-N

物化性质

• 密度：
  1.58±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  12
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.285
• 拓扑面积：
  67.5
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3,4-二甲基-6H-异噁唑并[3,4-d]哒嗪-7-酮 在 sodium methylate 、 potassium carbonate 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 生成 6-isopropyl-4-methyl-3-styrylisoxazolo[3,4-d]pyridazin-7(6H)-one
  参考文献：
  名称：

  Novel Pyrazolopyrimidopyridazinones with Potent and Selective Phosphodiesterase 5 (PDE5) Inhibitory Activity as Potential Agents for Treatment of Erectile Dysfunction

  摘要：

  Pyrazolo[1', 5': 1,6] pyrimido[4,5-d] pyridazin-4(3H)-ones and their analogues, potentially useful for the treatment of erectile dysfunction, were synthesized and evaluated as inhibitors of phosphodiesterase 5 (PDE5). Several compounds showed IC50 values in the low nanomolar range, and in particular, compound 5r, displaying high potency toward PDE5 (IC50 = 8.3 nM) and high selectivity versus PDE6 (240-fold) appeared to be a very promising new lead both in comparison with the potent but not selective sildenafil and in comparison with some analogues previously reported by us. SAR studies in this triheterocyclic scaffold led us to conclude that the best arranged groups are a methyl in position 1, a benzyl in position 3, a phenyl in position 9, and a linear four-carbon chain in position 6.

  DOI：

  10.1021/jm060265+
• 作为产物：
  描述：

  4-乙酰基-5-甲基异恶唑-3-甲酸乙酯 在 一水合肼 作用下， 以 乙醇 为溶剂， 反应 0.03h， 生成 3,4-二甲基-6H-异噁唑并[3,4-d]哒嗪-7-酮
  参考文献：
  名称：

  Renzi,G.; Dal Piaz,V., Gazzetta Chimica Italiana, 1965, vol. 95, p. 1478 - 1491

  摘要：

  DOI：

文献信息

• Isoxazolo-[3,4-<i>d</i>]-pyridazin-7-(6<i>H</i>)-one as a Potential Substrate for New Aldose Reductase Inhibitors
  作者：Luca Costantino、Giulio Rastelli、M. Cristina Gamberini、M. Paola Giovannoni、Vittorio Dal Piaz、Paola Vianello、Daniela Barlocco

  DOI：10.1021/jm981107o

  日期：1999.6.1

  5-acetyl-4-amino-(4-nitro)-6-substituted-3(2H)pyridazinones (3, 4) were used as simplified substrates for the synthesis of new aldose reductase inhibitors with respect to the previously reported 5, 6-dihydrobenzo[h]cinnolin-3(2H)one-2 acetic acids (1). Moreover, a few derivatives lacking the 5-acetyl group were prepared. Several compounds derived from 2 displayed inhibitory properties comparable to those

  异恶唑-[3,4-d]-哒嗪-7-（6H）-一（2）及其相应的开放衍生物5-乙酰基-4-氨基-（4-硝基）-6-取代的3（2H）相对于先前报道的5，6-二氢苯并[h] cinnolin-3（2H）one-2乙酸（1），哒嗪酮（3，4）被用作合成新的醛糖还原酶抑制剂的简化底物。此外，制备了一些缺少5-乙酰基的衍生物。衍生自2的几种化合物具有与索比尼尔相当的抑制特性。在这一类中，带有吸电子取代基的苯基在6位上的存在被证明是有益的，而与它在环上的位置（5g，jl）无关。乙酸衍生物比丙酸和丁酸类似物更有效。相反，所有的单环化合物（6-8）都是无活性的或仅是弱活性的。还研究了3-甲基-4-（对氯苯基）异唑并-[3,4-d]-哒嗪-7-（6H）-一乙酸（5g），它是最有效的衍生物。分子建模研究，以评估与模型1在与酶的相互作用中可能存在的相似性。
• Synthesis of five and six-membered heterocycles bearing an arylpiperazinylalkyl side chain as orally active antinociceptive agents
  作者：Claudia Vergelli、Giovanna Ciciani、Agostino Cilibrizzi、Letizia Crocetti、Lorenzo Di Cesare Mannelli、Carla Ghelardini、Gabriella Guerrini、Antonella Iacovone、Maria Paola Giovannoni

  DOI：10.1016/j.bmc.2015.08.043

  日期：2015.10

  A number of heterocycles bearing an arylpiperazinylalkyl side chain and structurally related to the previously described lead ET1 (4-amino-6-methyl-2-[3-(4-p-tolylpiperazin-1-yl) propyl]-5-vinylpyridazin-3 (2H)-one) was synthesized and tested for their antinociceptive activity in Writhing Test. Many compounds, tested at doses of 20-40 mg/kg po were able to reduce the number of abdominal constrictions by more than 47% and, in same cases, the potency is comparable to lead ET1 as for 5e, 24a, 27b and 27c. The analgesia induced by the active compounds was completely prevented by pretreatment with alpha(2)-antagonist yohimbine, confirming the involvement of the adrenergic system in the mechanism of action for these new compounds. (C) 2015 Elsevier Ltd. All rights reserved.
• 4-Amino-3(2H)-pyridazinones bearing arylpiperazinylalkyl groups and related compounds: synthesis and antinociceptive activity
  作者：Vittorio Dal Piaz、Claudia Vergelli、Maria Paola Giovannoni、Mark A Scheideler、Giuseppe Petrone、Paola Zaratin

  DOI：10.1016/s0014-827x(03)00162-9

  日期：2003.11

  A series of 4-amino-3(2H)-pyridazinones substituted at position 2 with arylpiperazinylalkyl groups and analogues were synthesized and their antinociceptive effect was evaluated in the mouse abdominal constriction model. Preliminary SARs studies were performed. Several of the novel compounds dosed at 100 mg/kg s.c. significantly reduced the number of writhes induced by the noxious stimulus. Compound 12e showed 100% inhibition of writhes and was able to protect all the treated animals from the effect of the chemical stimulus. Subsequent dose-response studies revealed 12e to be almost 40-fold more potent than the structurally related Emorfazone.
• [(3-Chlorophenyl)piperazinylpropyl]pyridazinones and Analogues as Potent Antinociceptive Agents
  作者：Maria Paola Giovannoni、Claudia Vergelli、Carla Ghelardini、Nicoletta Galeotti、Alessandro Bartolini、Vittorio Dal Piaz

  DOI：10.1021/jm021057u

  日期：2003.3.1

  A number of [(3-chlorophenyl)piperazinylpropyl]pyridazinones and the corresponding isoxazolo-pyridazinones, showing the arylpiperazinyl substructure present in very potent antinociceptive agents reported in the literature, were synthesized and tested for their analgesic activity. The investigated compounds showed antinociceptive properties in the mouse hot-plate test (thermal nociceptive stimulus) after systemic administration with an efficacy similar to that exerted by morphine. The increase of the pain threshold induced by the compounds labeled 5a, 7, 8, and 11 was prevented by reserpine, suggesting the involvement of the noradrenergic and/or serotoninergic system in their mechanism of action. Among them, 7 and 11 showed the highest analgesic potency and efficacy together with a good ratio (133 and 200, respectively) of the minimal nontoxic dose (MNTD) to the minimal analgesic dose (MAD). Furthermore, they were also active after icv administration and in the presence of a chemical, painful stimulus (abdominal constriction test).
• 2-Arylacetamido-4-phenylamino-5-substituted pyridazinones as formyl peptide receptors agonists
  作者：Claudia Vergelli、Igor A. Schepetkin、Giovanna Ciciani、Agostino Cilibrizzi、Letizia Crocetti、Maria Paola Giovannoni、Gabriella Guerrini、Antonella Iacovone、Liliya N. Kirpotina、Andrei I. Khlebnikov、Richard D. Ye、Mark T. Quinn

  DOI：10.1016/j.bmc.2016.04.019

  日期：2016.6

  N-Formyl peptide receptors (FPRs: FPR1, FPR2, and FPR3) are G protein-coupled receptors that play key roles in modulating immune cells. FPRs represent potentially important therapeutic targets for the development of drugs that could enhance endogenous anti-inflammation systems associated with various pathologies, thereby reducing the progression of inflammatory conditions. Previously, we identified 2-arylacetamide pyridazin-3(2H)-ones as FPR1- or FPR2-selective agonists, as well as a large number of FPR1/FPR2-dual agonists and several mixed-agonists for the three FPR isoforms. Here, we report a new series of 2-arylacetamido-4-aniline pyridazin-3(2H)-ones substituted in position 5 as a further development of these FPR agonists. Chemical manipulation presented in this work resulted in mixed FPR agonists 8a, 13a and 27b, which had EC50 values in nanomolar range. In particular, compound 8a showed a preference for FPR1 (EC50 = 45 nM), while 13a and 27b showed a moderate preference for FPR2 (EC50 = 35 and 61 nM, respectively). Thus, these compounds may represent valuable tools for studying FPR activation and signaling. (C) 2016 Published by Elsevier Ltd.