4-(6-氯嘧啶-4-基)-n-甲基噻唑-2-胺 | 932738-80-2

• 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: 4-(6-氯嘧啶-4-基)-n-甲基噻唑-2-胺
• 英文名称: 4-(6-chloropyrimidin-4-yl)-N-methylthiazol-2-amine
• 英文别名: 4-(6-Chloropyrimidin-4-yl)-N-methylthiazol-2-amine；4-(6-chloropyrimidin-4-yl)-N-methyl-1,3-thiazol-2-amine
• CAS: 932738-80-2
• 化学式: C₈H₇ClN₄S
• 分子量: 226.689
• InChiKey: WVOKVBIEELFKFB-UHFFFAOYSA-N

物化性质

• 沸点：
  405.8±53.0 °C(Predicted)
• 密度：
  1.459±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  14
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  78.9
• 氢给体数：
  1
• 氢受体数：
  5

安全信息

• 海关编码：
  2934100090
• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302

反应信息

• 作为反应物：
  描述：

  4-(6-氯嘧啶-4-基)-n-甲基噻唑-2-胺 在 potassium carbonate 、 三乙胺 作用下， 以 1,4-二氧六环 、 甲苯 为溶剂， 反应 2.0h， 生成 4-nitro-N-[4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl]-N-methylbenzamide
  参考文献：
  名称：

  Radiosynthesis and preliminary evaluation of 4-[18F]fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide as a new positron emission tomography ligand for metabotropic glutamate receptor subtype 1

  摘要：

  The purpose of this study was to develop 4-[F-18]fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide ([F-18]FITM, [F-18]4) as a new PET ligand for imaging metabotropic glutamate receptor subtype 1 (mGluR1). [F-18]4 was synthesized by [F-18]fluorination of a novel nitro precursor 3 with [F-18]KF in the presence of Kryptofix 222. At the end of synthesis, 429-936 MBq (n = 8) of [F-18]4 was obtained with > 99% radiochemical purity and 204-559 GBq/mu mol specific activity starting from 6.7 to 13.0 GBq of [F-18]F. The brain distribution of [F-18]4 was determined by the in vitro and ex vivo autoradiography using rat brain sections. The in vitro and in vivo specific binding of [F-18]4 to mGluR1 was detected in the cerebellum, thalamus, hippocampus, and striatum. These results suggest that [F-18]4 is a promising PET ligand for the in vivo evaluation of mGluR1. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.03.046
• 作为产物：
  描述：

  4-chloro-6-(1-ethoxyvinyl)pyrimidine 在 N-溴代丁二酰亚胺(NBS) 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 5.0h， 生成 4-(6-氯嘧啶-4-基)-n-甲基噻唑-2-胺
  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。
• Synthesis and Evaluation of Novel Radioligands for Positron Emission Tomography Imaging of Metabotropic Glutamate Receptor Subtype 1 (mGluR1) in Rodent Brain
  作者：Masayuki Fujinaga、Tomoteru Yamasaki、Joji Yui、Akiko Hatori、Lin Xie、Kazunori Kawamura、Chiharu Asagawa、Katsushi Kumata、Yuichiro Yoshida、Masanao Ogawa、Nobuki Nengaki、Toshimitsu Fukumura、Ming-Rong Zhang

  DOI：10.1021/jm201590g

  日期：2012.3.8

  designed three novel positron emission tomography ligands, N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-4-[11C]methoxy-N-methylbenzamide ([11C]6), 4-[18F]fluoroethoxy-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide ([18F]7), and 4-[18F]fluoropropoxy-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide ([18F]8), for imaging metabotropic glutamate

  我们设计了三个新颖的正电子发射断层成像配体，N-（4-（6-（异丙基氨基）嘧啶-4-基）-1,3-噻唑-2-基）-4- [ 11 C]甲氧基-N-甲基苯甲酰胺（ [ 11 C] 6），4- [ 18 F]氟乙氧基-N- [4- [6-（异丙基氨基）嘧啶-4-基] -1,3-噻唑-2-基] -N-甲基苯甲酰胺（[ 18 F] 7）和4- [ 18 F]氟丙氧基-N- [4- [6-（异丙基氨基）嘧啶-4-基] -1,3-噻唑-2-基] -N-甲基苯甲酰胺（[ 18 F ] 8），用于对啮齿动物脑中的1型代谢型谷氨酸受体（mGluR1）进行成像。通过4-嘧啶基-2-甲基氨基噻唑10的苯甲酰化，然后与异丙胺反应，合成未标记的化合物6。除去6中的甲基得到用于放射合成的苯酚前体12。通过使12与甲苯磺酸酯13和14反应制备了两个氟代烷氧基类似物7和8。放射性配体[ 11 C] 6，[ 18 F] 7和[
• 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.
• 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.
• Discovery and in vitro and in vivo profiles of 4-fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide as novel class of an orally active metabotropic glutamate receptor 1 (mGluR1) antagonist
  作者：Atsushi Satoh、Yasushi Nagatomi、Yukari Hirata、Satoru Ito、Gentaroh Suzuki、Toshifumi Kimura、Shunsuke Maehara、Hirohiko Hikichi、Akio Satow、Mikiko Hata、Hisashi Ohta、Hiroshi Kawamoto

  DOI：10.1016/j.bmcl.2009.07.097

  日期：2009.9

  We identified 4-fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide 27 as a potent mGluR1 antagonist. The compound possessed excellent subtype selectivity and good PK profile in rats. It also demonstrated relatively potent antipsychotic-like effects in several animal models. Suitable for development as a PET tracer, compound 27 would have great potential for elucidation of mGluR1 functions in human. (C) 2009 Elsevier Ltd. All rights reserved.