7-t-butyl-2-thioxo-2,3-dihydro-1H-pyrazolo[1,5-a][1,3,5]triazin-4-one | 1448466-56-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡唑并三嗪类
• 英文名称: 7-t-butyl-2-thioxo-2,3-dihydro-1H-pyrazolo[1,5-a][1,3,5]triazin-4-one
• 英文别名: 1,3-dihydro-7-tert-butylpyrazolo[1,5-a][1,3,5]triazin-2-thioxo-4-one；7-(tert-butyl)-2-thioxo-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H)-one
• CAS: 1448466-56-5
• 化学式: C₉H₁₂N₄OS
• 分子量: 224.286
• InChiKey: DCWAJKBRVZWXPQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.38
• 重原子数：
  15.0
• 可旋转键数：
  0.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  65.95
• 氢给体数：
  2.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  7-t-butyl-2-thioxo-2,3-dihydro-1H-pyrazolo[1,5-a][1,3,5]triazin-4-one 在 ammonium hydroxide 作用下， 以 甲醇 、 水 为溶剂， 反应 4.0h， 以50%的产率得到7-(叔丁基)吡唑并[1,5-a][1,3,5]三嗪-4(3H)-酮
  参考文献：
  名称：

  BMS-813160: A Potent CCR2 and CCR5 Dual Antagonist Selected as a Clinical Candidate

  摘要：

  DOI：

  10.1021/acsmedchemlett.1c00373
• 作为产物：
  描述：

  新戊酰基乙腈 在 hydrazine hydrate 、 sodium hydroxide 作用下， 以 甲醇 、 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.33h， 生成 7-t-butyl-2-thioxo-2,3-dihydro-1H-pyrazolo[1,5-a][1,3,5]triazin-4-one
  参考文献：
  名称：

  Discovery of mixed type thymidine phosphorylase inhibitors endowed with antiangiogenic properties: Synthesis, pharmacological evaluation and molecular docking study of 2-thioxo-pyrazolo[1,5-a][1,3,5]triazin-4-ones. Part II

  摘要：

  In our drug discovery program, a series of 2-thioxo-pyrazolo[1,5-a][1,3,5]triazin-4-ones were designed, synthesized and evaluated for their TP inhibitory potential. All the synthesized analogues conferred a varying degree of TP inhibitory activity, comparable or better than positive control, 7-deazaxanthine (7-DX, 2) (IC50 value = 42.63 mu M). A systematic approach to the lead optimization identified compounds 3c and 4a as the most promising TP inhibitors, exhibiting mixed mode of enzyme inhibition. Moreover, selected compounds demonstrated the ability to attenuate the expression of the angiogenic markers (viz. MMP-9 and VEGF) in MDA-MB-231 cells at sublethal concentrations. In addition, molecular docking studies revealed the plausible binding orientation of these inhibitors towards TP, which was in accordance with the experimental results. Taken as a whole, these compounds would constitute a new direction for the design of novel TP inhibitors with promising antiangiogenic properties. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.03.063

文献信息

• Synthesis of pyrazolo[1,5-a][1,3,5]triazine derivatives as inhibitors of thymidine phosphorylase
  作者：Lingyi Sun、Hriday Bera、Wai Keung Chui

  DOI：10.1016/j.ejmech.2013.03.063

  日期：2013.7

  evaluate whether pyrazolo[1,5-a][1,3,5]triazin-2,4-diones and pyrazolo[1,5-a][1,3,5]triazin-2-thioxo-4-ones would exhibit TP inhibitory activity. The pyrazolo[1,5-a][1,3,5]triazine nucleus was constructed using a reaction that annulated the 1,3,5-triazine ring onto a pyrazole scaffold. Among the 52 compounds synthesized and tested, it was found that 1,3-dihydro-pyrazolo[1,5-a][1,3,5]triazin-2-thioxo-4-ones

  胸苷磷酸化酶（TP）是一种促进肿瘤生长和转移的酶，因此是有吸引力的可药物治疗靶标。使用已报道的TP抑制剂7-脱氮黄嘌呤（7DX）作为先导化合物；进行这项研究是为了评估吡唑并[1,5- a ] [1,3,5]三嗪-2,4-二酮和吡唑并[1,5- a ] [1,3,5]三嗪-2- thioxo-4-ones将表现出TP抑制活性。吡唑并[1,5- a ] [1,3,5]三嗪核是通过将1,3,5-三嗪环环化到吡唑支架上的反应构建的。在合成和测试的52种化合物中，发现1,3-二氢-吡唑并[1,5- a ] [1,3,5] triazin-2-thioxo-4-ones对TP表现出不同程度的抑制活性。 。最好的化合物17p带有对位取代的五氟硫基的，其IC 50值为0.04μM， 在相同的生物测定条件下，其效价是7DX（IC 50 = 32μM）的800倍左右。研究结果表明，在吡唑并[1,5- a ] [1
• Fragment-based approach to the design of 5-chlorouracil-linked-pyrazolo[1,5-a][1,3,5]triazines as thymidine phosphorylase inhibitors
  作者：Lingyi Sun、Jiarong Li、Hriday Bera、Anton V. Dolzhenko、Gigi N.C. Chiu、Wai Keung Chui

  DOI：10.1016/j.ejmech.2013.10.022

  日期：2013.12

  were devised to generate the target compounds. The intermediate 5-chloro-6-chloromethyluracil was synthesized by a 4-step reaction. A series of the second bicyclic intermediates, namely pyrazolo[1,5-a][1,3,5]triazin-2-thioxo-4-one, was obtained from various substituted 3-aminopyrazoles. These two intermediates were coupled finally in the presence of sodium ethoxide and methanol to yield the desirable target

  基于基于片段的药物设计方法，将5-氯尿嘧啶连接的吡唑并[1,5- a ] [1,3,5]三嗪设计为新型胸苷磷酸化酶抑制剂。设计了多步收敛合成方案以生成目标化合物。中间体5-氯-6-氯甲基尿嘧啶通过4步反应合成。一系列第二双环中间体，即吡唑并[1,5- a从各种取代的3-氨基吡唑获得] [1,3,5]三嗪-2-硫代-4-酮。最后将这两种中间体在乙醇钠和甲醇的存在下偶联，得到所需的目标化合物。发现甲硫基偶联间隔基适合于使两个片段在酶的活性位点和变构位点相互作用。最佳偶联化合物（9q）抑制了胸苷磷酸化酶，IC 50值低至0.36±0.1μM。另外，9q表现出混合型的酶抑制动力学，因此表明它可能确实可能在酶的两个不同位点结合。
• Discovery of mixed type thymidine phosphorylase inhibitors endowed with antiangiogenic properties: Synthesis, pharmacological evaluation and molecular docking study of 2-thioxo-pyrazolo[1,5-a][1,3,5]triazin-4-ones. Part II
  作者：Hriday Bera、Probir kumar Ojha、Bee Jen Tan、Lingyi Sun、Anton V. Dolzhenko、Wai-Keung Chui、Gigi Ngar Chee Chiu

  DOI：10.1016/j.ejmech.2014.03.063

  日期：2014.5

  In our drug discovery program, a series of 2-thioxo-pyrazolo[1,5-a][1,3,5]triazin-4-ones were designed, synthesized and evaluated for their TP inhibitory potential. All the synthesized analogues conferred a varying degree of TP inhibitory activity, comparable or better than positive control, 7-deazaxanthine (7-DX, 2) (IC50 value = 42.63 mu M). A systematic approach to the lead optimization identified compounds 3c and 4a as the most promising TP inhibitors, exhibiting mixed mode of enzyme inhibition. Moreover, selected compounds demonstrated the ability to attenuate the expression of the angiogenic markers (viz. MMP-9 and VEGF) in MDA-MB-231 cells at sublethal concentrations. In addition, molecular docking studies revealed the plausible binding orientation of these inhibitors towards TP, which was in accordance with the experimental results. Taken as a whole, these compounds would constitute a new direction for the design of novel TP inhibitors with promising antiangiogenic properties. (C) 2014 Elsevier Masson SAS. All rights reserved.
• BMS-813160: A Potent CCR2 and CCR5 Dual Antagonist Selected as a Clinical Candidate
  作者：Robert J. Cherney、Prakash Anjanappa、Kumaravel Selvakumar、Douglas G. Batt、Gregory D. Brown、Anne V. Rose、Ragini Vuppugalla、Jing Chen、Jian Pang、Songmei Xu、Melissa Yarde、Andrew J. Tebben、Venkatram Reddy Paidi、Mary Ellen Cvijic、Arvind Mathur、Joel C. Barrish、Sandhya Mandlekar、Qihong Zhao、Percy H. Carter

  DOI：10.1021/acsmedchemlett.1c00373

  日期：2021.11.11