4-bromo-N-[4-(6-chloropyrimidin-4-yl)-1,3-thiazol-2-yl]-N-methylbenzamide | 1414953-57-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-bromo-N-[4-(6-chloropyrimidin-4-yl)-1,3-thiazol-2-yl]-N-methylbenzamide
• CAS: 1414953-57-3
• 化学式: C₁₅H₁₀BrClN₄OS
• 分子量: 409.694
• InChiKey: OJFGQVBVHVGCME-UHFFFAOYSA-N

物化性质

• 沸点：
  565.6±60.0 °C(Predicted)
• 密度：
  1.642±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  87.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-bromo-N-[4-(6-chloropyrimidin-4-yl)-1,3-thiazol-2-yl]-N-methylbenzamide 在 4-二甲氨基吡啶 、 四(三苯基膦)钯 、 potassium carbonate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 二氯甲烷 为溶剂， 反应 108.0h， 生成 (4-(N-(4-(6-(tert-butoxycarbonyl(methyl)amino)pyrimidin-4-yl)thiazol-2-yl)-N-(methyl)carbamoyl)phenyl)(phenyl)iodonium tosylate
  参考文献：
  名称：

  Synthesis and Evaluation in Monkey of [¹⁸F]4-Fluoro-N-methyl-N-(4-(6-(methylamino)pyrimidin-4-yl)thiazol-2-yl)benzamide ([¹⁸F]FIMX): A Promising Radioligand for PET Imaging of Brain Metabotropic Glutamate Receptor 1 (mGluR1)

  摘要：

  We sought to develop a PET radioligand that would be useful for imaging human brain metabotropic subtype 1 receptors (mGluR1) in neuropsychiatric disorders and in drug development. 4-Fluoro-N-methyl-N-(4-(6(methylamino)pyrimidin-4-yOthiazol-2-ylbenzamide (FIMX, 11) was identified as having favorable properties for development as a PET radioligand. We developed a method for preparing [F-18]11 in useful radiochemical yield and in high specific activity from [18F]fluoride ion and an N-Boc-protected (phenyl)aryliodonium salt precursor (15). In baseline experiments in rhesus monkey, [F-18 ]11 gave high brain radioactivity uptake, reflecting the expected distribution of mGluR1 with notably high uptake in cerebellum, which became 47% lower by 120 min after radioligand injection. Pharmacological challenges demonstrated that a very high proportion of the radioactivity in monkey brain was bound specifically and reversibly to mGluRl. [F-18]11 is concluded to be an effective PET radioligand for imaging mGluR1 in monkey brain and therefore merits further evaluation in human subjects.

  DOI：

  10.1021/jm4012017
• 作为产物：
  描述：

  2-Bromo-1-(6-chloropyrimidin-4-yl)ethanone 在 三乙胺 作用下， 以 甲苯 为溶剂， 反应 9.0h， 生成 4-bromo-N-[4-(6-chloropyrimidin-4-yl)-1,3-thiazol-2-yl]-N-methylbenzamide
  参考文献：
  名称：

  4-卤代-N- [4- [6-（异丙基氨基）嘧啶-4-基] -1,3-噻唑-2-基] -N- [ 11 C]甲基苯甲酰胺的合成和评价用于代谢型谷氨酸1的成像黑色素瘤受体

  摘要：

  代谢型谷氨酸1（mGlu1）受体不仅存在于大脑中，而且还存在于黑色素瘤和乳腺癌中。mGlu1是基于分子影像学的黑色素瘤诊断和治疗的有希望的靶标，因为它的过度表达会诱导黑色素细胞癌变。在这里，我们开发了三种PET示踪剂：4-卤代-N- [4- [6-（异丙基氨基）嘧啶-4-基] -1,3-噻唑-2-基] -N- [ 11 C]甲基苯甲酰胺（[ 11 C] 4 – 6），在目标肿瘤中表现出较高的摄取，在非目标脑组织中表现出减少的摄取。体外结合试验表明结合亲和力为4 – 6（K i（22–143 nM）用于mGlu1受体。在植入了B16F10黑色素瘤细胞的小鼠中进行的体内生物分布研究证实，肿瘤中放射性的摄取较高，而血液，皮肤和肌肉的摄取较低。使用mGlu1选择性配体抑制mGlu1受体导致肿瘤中放射性吸收的减少。[ 11 C] 6在肿瘤和非靶组织之间显示出最高的摄取率，可能被证明可作为黑色素瘤中mGlu1成像的PET示踪剂。

  DOI：

  10.1021/jm501845n

文献信息

• Derisking the Cu-Mediated ¹⁸F-Fluorination of Heterocyclic Positron Emission Tomography Radioligands
  作者：Nicholas J. Taylor、Enrico Emer、Sean Preshlock、Michael Schedler、Matthew Tredwell、Stefan Verhoog、Joel Mercier、Christophe Genicot、Véronique Gouverneur

  DOI：10.1021/jacs.7b03131

  日期：2017.6.21

  Molecules labeled with fluorine-18 (18F) are used in positron emission tomography to visualize, characterize and measure biological processes in the body. Despite recent advances in the incorporation of 18F onto arenes, the development of general and efficient approaches to label radioligands necessary for drug discovery programs remains a significant task. This full account describes a derisking approach

  用氟 18 (18F) 标记的分子用于正电子发射断层扫描，以可视化、表征和测量体内的生物过程。尽管最近在将 18F 掺入芳烃方面取得了进展，但开发通用且有效的方法来标记药物发现计划所需的放射性配体仍然是一项重大任务。这个完整的描述描述了杂环正电子发射断层扫描 (PET) 放射性配体的放射合成方法，使用铜介导的 18F 氟化芳基硼试剂与 18F 氟化物作为模型反应。该方法基于一项研究，该研究检查了药物开发中常用的杂环的存在如何影响代表性芳基硼试剂的 18F-氟化效率，以及超过 50 种（杂）芳基硼酸酯的标记。这组数据允许将这种去风险策略应用于七种结构复杂的药物相关含杂环分子的成功放射合成。
• Development of <i>N</i>-[4-[6-(Isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-<i>N</i>-methyl-4-[¹¹C]methylbenzamide for Positron Emission Tomography Imaging of Metabotropic Glutamate 1 Receptor in Monkey Brain
  作者：Masayuki Fujinaga、Tomoteru Yamasaki、Jun Maeda、Joji Yui、Lin Xie、Yuji Nagai、Nobuki Nengaki、Akiko Hatori、Katsushi Kumata、Kazunori Kawamura、Ming-Rong Zhang

  DOI：10.1021/jm301597s

  日期：2012.12.27

  Three novel 4-substituted benzamides have been synthesized as potential ligands for the positron emission tomography (PET) imaging of metabotropic glutamate 1 (mGlu1) receptor in the brain. Of these compounds, N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-N,4-dimethylbenzamide (4) exhibited the highest binding affinity (K-i = 13.6 nM) for mGlu1 and was subsequently labeled with carbon-11. In vitro autoradiography using rat brain sections showed that [C-11]4 binding was consistent with the distribution of mGlu1, with high specific binding in the cerebellum and thalamus. PET studies with [C-11]4 in monkey showed a high brain uptake and a kinetic profile suitable for quantitative analysis. Pretreatment with a mGlu1-selective ligand 16 largely decreased the brain uptake, indicating high in vivo specific binding of [C-11]4 to mGlu1. In metabolite analysis, only unchanged [C-11]4 was found in the brain. [C-11]4 is a useful PET ligand for the imaging and quantitative analysis of mGlu1 in monkey brain and merits further evaluation in humans.
• J. Med. Chem. 2013, 56, 9146-9155
  作者：

  DOI：——

  日期：——
• Synthesis and Evaluation of 4-Halogeno-<i>N</i>-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-<i>N</i>-[¹¹C]methylbenzamide for Imaging of Metabotropic Glutamate 1 Receptor in Melanoma
  作者：Masayuki Fujinaga、Lin Xie、Tomoteru Yamasaki、Joji Yui、Yoko Shimoda、Akiko Hatori、Katsushi Kumata、Yiding Zhang、Nobuki Nengaki、Kazunori Kawamura、Ming-Rong Zhang

  DOI：10.1021/jm501845n

  日期：2015.2.12

  Metabotropic glutamate 1 (mGlu1) receptor is found not only in the brain but also in melanomas and breast cancers. mGlu1 is a promising target for molecular imaging-based diagnosis and treatment of melanoma because its overexpression induces melanocyte carcinogenesis. Here we developed three PET tracers: 4-halogeno-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol- 2-yl]-N-[11C]methylbenzamide ([11C]4–6)

  代谢型谷氨酸1（mGlu1）受体不仅存在于大脑中，而且还存在于黑色素瘤和乳腺癌中。mGlu1是基于分子影像学的黑色素瘤诊断和治疗的有希望的靶标，因为它的过度表达会诱导黑色素细胞癌变。在这里，我们开发了三种PET示踪剂：4-卤代-N- [4- [6-（异丙基氨基）嘧啶-4-基] -1,3-噻唑-2-基] -N- [ 11 C]甲基苯甲酰胺（[ 11 C] 4 – 6），在目标肿瘤中表现出较高的摄取，在非目标脑组织中表现出减少的摄取。体外结合试验表明结合亲和力为4 – 6（K i（22–143 nM）用于mGlu1受体。在植入了B16F10黑色素瘤细胞的小鼠中进行的体内生物分布研究证实，肿瘤中放射性的摄取较高，而血液，皮肤和肌肉的摄取较低。使用mGlu1选择性配体抑制mGlu1受体导致肿瘤中放射性吸收的减少。[ 11 C] 6在肿瘤和非靶组织之间显示出最高的摄取率，可能被证明可作为黑色素瘤中mGlu1成像的PET示踪剂。
• Synthesis and Evaluation in Monkey of [¹⁸F]4-Fluoro-<i>N</i>-methyl-<i>N</i>-(4-(6-(methylamino)pyrimidin-4-yl)thiazol-2-yl)benzamide ([¹⁸F]FIMX): A Promising Radioligand for PET Imaging of Brain Metabotropic Glutamate Receptor 1 (mGluR1)
  作者：Rong Xu、Paolo Zanotti-Fregonara、Sami S. Zoghbi、Robert L. Gladding、Alicia E. Woock、Robert B. Innis、Victor W Pike

  DOI：10.1021/jm4012017

  日期：2013.11.27

  We sought to develop a PET radioligand that would be useful for imaging human brain metabotropic subtype 1 receptors (mGluR1) in neuropsychiatric disorders and in drug development. 4-Fluoro-N-methyl-N-(4-(6(methylamino)pyrimidin-4-yOthiazol-2-ylbenzamide (FIMX, 11) was identified as having favorable properties for development as a PET radioligand. We developed a method for preparing [F-18]11 in useful radiochemical yield and in high specific activity from [18F]fluoride ion and an N-Boc-protected (phenyl)aryliodonium salt precursor (15). In baseline experiments in rhesus monkey, [F-18 ]11 gave high brain radioactivity uptake, reflecting the expected distribution of mGluR1 with notably high uptake in cerebellum, which became 47% lower by 120 min after radioligand injection. Pharmacological challenges demonstrated that a very high proportion of the radioactivity in monkey brain was bound specifically and reversibly to mGluRl. [F-18]11 is concluded to be an effective PET radioligand for imaging mGluR1 in monkey brain and therefore merits further evaluation in human subjects.