N-(4-(6-chloropyrimidin-4-yl)phenyl)acetamide | 954219-22-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: N-(4-(6-chloropyrimidin-4-yl)phenyl)acetamide
• 英文别名: 6-chloro-4-(4'-acetamidophenyl)pyrimidine；N-[4-(6-chloropyrimidin-4-yl)phenyl]acetamide
• CAS: 954219-22-8
• 化学式: C₁₂H₁₀ClN₃O
• 分子量: 247.684
• InChiKey: XGMSHHVGZGWWMO-UHFFFAOYSA-N

物化性质

• 沸点：
  489.6±35.0 °C(Predicted)
• 密度：
  1.330±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  54.9
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N-(4-(6-chloropyrimidin-4-yl)phenyl)acetamide 在 盐酸 、 ammonium hydroxide 、 锌 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 6.0h， 生成 4-(4-氨基苯基)嘧啶
  参考文献：
  名称：

  Synthesis and methemoglobinemia-inducing properties of benzocaine isosteres designed as humane rodenticides

  摘要：

  A number of isosteres (oxadiazoles, thiadiazoles, tetrazoles and diazines) of benzocaine were prepared and evaluated for their capacity to induce methemoglobinemia-with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed within each series, with 1,2,4-oxadiazole 3 (metHb% = 61.0 +/- 3.6) and 1,3,4-oxadiazole 10 (metHb% = 52.4 +/- 0.9) demonstrating the greatest activity. Of the 5 candidates (compounds 3, 10, 11, 13 and 23) evaluated in vivo, failure to induce a lethal end-point at doses of 120 mg/kg was observed in all cases. Inadequate metabolic stability, particularly towards hepatic enzymes such as the CYPs, was postulated as one reason for their failure. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.02.013
• 作为产物：
  描述：

  4,6-二氯嘧啶 、 4-乙酰胺基苯硼酸 在 palladium diacetate 、 potassium carbonate 、 三苯基膦 作用下， 以 水 、 异丙醇 为溶剂， 反应 20.0h， 以64%的产率得到N-(4-(6-chloropyrimidin-4-yl)phenyl)acetamide
  参考文献：
  名称：

  [EN] SUBSTITUTED PYRIMIDINE COMPOUNDS AND USES THEREOF
  [FR] COMPOSÉS DE PYRIMIDINE SUBSTITUÉE ET LEURS UTILISATIONS

  摘要：

  本发明涉及嘧啶化合物（式1的化合物），其所有立体异构体和互变异构体形式及其在所有比例上的混合物；以及它们的药学上可接受的盐、溶剂合物、前药和多型体以及其N-氧化物。本发明还涉及制备嘧啶化合物的方法以及含有它们的药物组合物。本发明还涉及式1化合物在治疗由一个或多个激酶介导的疾病或紊乱中的用途，特别是增殖性疾病或紊乱，如癌症。这些化合物还可用于治疗由一个或多个促炎细胞因子（如肿瘤坏死因子-α（TNF-α）或白细胞介素（IL-1β、IL-2、IL-6和/或IL-8））介导的紊乱。

  公开号：

  WO2013175415A1

文献信息

• [EN] SUBSTITUTED PYRIMIDINE COMPOUNDS AND USES THEREOF<br/>[FR] COMPOSÉS DE PYRIMIDINE SUBSTITUÉE ET LEURS UTILISATIONS
  申请人：PIRAMAL ENTPR LTD

  公开号：WO2013175415A1

  公开（公告）日：2013-11-28

  The present invention relates to pyrimidine compounds, (the compounds of formula 1), in all its stereoisomeric and tautomeric forms and mixtures thereof in all ratios; and their pharmaceutically acceptable salts, solvates, prodrugs and polymorphs and N-oxides thereof. The invention also relates to processes for the manufacture of the pyrimidine compounds and to pharmaceutical compositions containing them. The invention also relates to use of the compounds of formula 1 in the treatment of diseases or disorders mediated by one or more kinases, particularly proliferative diseases or disorders such as cancer. These compounds can also be used in the treatment of disorders mediated by one or more pro-inflammatory cytokines selected from Tumor Necrosis Factor-alpha (TNF-α) or interleukins (IL-1β, IL-2, IL-6, and/or IL- 8).

  本发明涉及嘧啶化合物（式1的化合物），其所有立体异构体和互变异构体形式及其在所有比例上的混合物；以及它们的药学上可接受的盐、溶剂合物、前药和多型体以及其N-氧化物。本发明还涉及制备嘧啶化合物的方法以及含有它们的药物组合物。本发明还涉及式1化合物在治疗由一个或多个激酶介导的疾病或紊乱中的用途，特别是增殖性疾病或紊乱，如癌症。这些化合物还可用于治疗由一个或多个促炎细胞因子（如肿瘤坏死因子-α（TNF-α）或白细胞介素（IL-1β、IL-2、IL-6和/或IL-8））介导的紊乱。
• Discovery of amide replacements that improve activity and metabolic stability of a bis-amide smoothened antagonist hit
  作者：Matthew L. Brown、Wade Aaron、Richard J. Austin、Angela Chong、Tom Huang、Ben Jiang、Jacob A. Kaizerman、Gary Lee、Brian S. Lucas、Dustin L. McMinn、Jessica Orf、Minqing Rong、Maria M. Toteva、Guifen Xu、Qiuping Ye、Wendy Zhong、Michael R. DeGraffenreid、Dineli Wickramasinghe、Jay P. Powers、Randall Hungate、Michael G. Johnson

  DOI：10.1016/j.bmcl.2011.07.052

  日期：2011.9

  A bis-amide antagonist of Smoothened, a seven-transmembrane receptor in the Hedgehog signaling pathway, was discovered via high throughput screening. In vitro and in vivo experiments demonstrated that the bis-amide was susceptible to N-acyl transferase mediated amide scission. Several bioisosteric replacements of the labile amide that maintained in vitro potency were identified and shown to be metabolically stable in vitro and in vivo. (C) 2011 Elsevier Ltd. All rights reserved.
• Synthesis and methemoglobinemia-inducing properties of benzocaine isosteres designed as humane rodenticides
  作者：Daniel Conole、Thorsten M. Beck、Morgan Jay-Smith、Malcolm D. Tingle、Charles T. Eason、Margaret A. Brimble、David Rennison

  DOI：10.1016/j.bmc.2014.02.013

  日期：2014.4

  A number of isosteres (oxadiazoles, thiadiazoles, tetrazoles and diazines) of benzocaine were prepared and evaluated for their capacity to induce methemoglobinemia-with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed within each series, with 1,2,4-oxadiazole 3 (metHb% = 61.0 +/- 3.6) and 1,3,4-oxadiazole 10 (metHb% = 52.4 +/- 0.9) demonstrating the greatest activity. Of the 5 candidates (compounds 3, 10, 11, 13 and 23) evaluated in vivo, failure to induce a lethal end-point at doses of 120 mg/kg was observed in all cases. Inadequate metabolic stability, particularly towards hepatic enzymes such as the CYPs, was postulated as one reason for their failure. (C) 2014 Elsevier Ltd. All rights reserved.
• SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors
  作者：Timothy Forsyth、Patrick C. Kearney、Byung Gyu Kim、Henry W.B. Johnson、Naing Aay、Arlyn Arcalas、David S. Brown、Vicky Chan、Jeff Chen、Hongwang Du、Sergey Epshteyn、Adam A. Galan、Tai P. Huynh、Mohamed A. Ibrahim、Brian Kane、Elena S. Koltun、Grace Mann、Lisa E. Meyr、Matthew S. Lee、Gary L. Lewis、Robin T. Noguchi、Michael Pack、Brian H. Ridgway、Xian Shi、Craig S. Takeuchi、Peiwen Zu、James W. Leahy、John M. Nuss、Ron Aoyama、Stefan Engst、Steven B. Gendreau、Robert Kassees、Jia Li、Shwu-Hwa Lin、Jean-Francois Martini、Thomas Stout、Philip Tong、John Woolfrey、Wentao Zhang、Peiwen Yu

  DOI：10.1016/j.bmcl.2012.10.007

  日期：2012.12

  We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model. Based upon the desirable profile of 10d (XL019) it was advanced into clinical trials. (C) 2012 Elsevier Ltd. All rights reserved.