2-(5-amino-3-(4-iodophenyl)-1H-pyrazol-4-yl)-N,N-diethylacetamide | 1580494-14-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-(5-amino-3-(4-iodophenyl)-1H-pyrazol-4-yl)-N,N-diethylacetamide
• CAS: 1580494-14-9
• 化学式: C₁₅H₁₉IN₄O
• 分子量: 398.247
• InChiKey: ROQPFVYMRAGJJX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.67
• 重原子数：
  21.0
• 可旋转键数：
  5.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  75.01
• 氢给体数：
  2.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  2-(5-amino-3-(4-iodophenyl)-1H-pyrazol-4-yl)-N,N-diethylacetamide 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 二乙胺 作用下， 以 乙醇 为溶剂， 反应 29.0h， 生成 N,N-diethyl-2-(2-(4-(4-hydroxybut-1-yn-1-yl)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide
  参考文献：
  名称：

  Preparation and evaluation of novel pyrazolo[1,5-a]pyrimidine acetamides, closely related to DPA-714, as potent ligands for imaging the TSPO 18kDa with PET

  摘要：

  A series of four novel analogues of DPA-714, bearing a fluoroalkynyl side chain (with a length ranging from three to six carbon atoms) in replacement of the fluoroethoxy motif, have been synthetized in six steps from commercially available methyl 4-iodobenzoate. The synthetic strategy for the preparation of these N,N-diethyl-2-(2-(4-(omega-fluoroalk-1-ynyl) phenyl)-5,7-dimethylpyrazolo[1,5-a] pyrimidin-3-yl) acetamides (7a-d) consisted in derivatizing a key iodinated building block featuring the pyrazolopyrimidine acetamide backbone of DPA-714, by Sonogashira couplings with various alkynyl reagents. The resulting alkynols were subsequently fluorinated, yielding the expected target derivatives. All four analogues exhibited slightly higher affinity and selectivity towards the TSPO 18 kDa (K-i vs [H-3]PK11195: 0.35-0.79 nM; Ki vs [H-3] flunitrazepam: > 1000 nM) when compared to DPA-714 (Ki vs [H-3] PK11195: 0.91 nM; Ki vs [H-3] flunitrazepam: > 1000 nM). Lipophilicities (HPLC, logD(7.4)) increased with the chain length (from 3.6 to 4.3) and were significantly higher than the one determined for DPA-714 (2.9). Preliminary in vitro metabolism evaluation using rat microsomal incubations and LC-MS analyses showed, for all four novel analogues, the absence of defluorinated metabolites. Among them, the fluoropentynyl compound, DPA-C5yne (7c), was selected, labelled in one single step with fluorine-18 from the corresponding tosylate and in vivo evaluated with PET on our in-house-developed rat model of acute local neuroinflammation. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.01.080
• 作为产物：
  描述：

  4-碘苯甲酰乙腈 在 一水合肼 、 溶剂黄146 、 sodium hydroxide 作用下， 以 乙醇 为溶剂， 反应 96.25h， 生成 2-(5-amino-3-(4-iodophenyl)-1H-pyrazol-4-yl)-N,N-diethylacetamide
  参考文献：
  名称：

  Preparation and evaluation of novel pyrazolo[1,5-a]pyrimidine acetamides, closely related to DPA-714, as potent ligands for imaging the TSPO 18kDa with PET

  摘要：

  A series of four novel analogues of DPA-714, bearing a fluoroalkynyl side chain (with a length ranging from three to six carbon atoms) in replacement of the fluoroethoxy motif, have been synthetized in six steps from commercially available methyl 4-iodobenzoate. The synthetic strategy for the preparation of these N,N-diethyl-2-(2-(4-(omega-fluoroalk-1-ynyl) phenyl)-5,7-dimethylpyrazolo[1,5-a] pyrimidin-3-yl) acetamides (7a-d) consisted in derivatizing a key iodinated building block featuring the pyrazolopyrimidine acetamide backbone of DPA-714, by Sonogashira couplings with various alkynyl reagents. The resulting alkynols were subsequently fluorinated, yielding the expected target derivatives. All four analogues exhibited slightly higher affinity and selectivity towards the TSPO 18 kDa (K-i vs [H-3]PK11195: 0.35-0.79 nM; Ki vs [H-3] flunitrazepam: > 1000 nM) when compared to DPA-714 (Ki vs [H-3] PK11195: 0.91 nM; Ki vs [H-3] flunitrazepam: > 1000 nM). Lipophilicities (HPLC, logD(7.4)) increased with the chain length (from 3.6 to 4.3) and were significantly higher than the one determined for DPA-714 (2.9). Preliminary in vitro metabolism evaluation using rat microsomal incubations and LC-MS analyses showed, for all four novel analogues, the absence of defluorinated metabolites. Among them, the fluoropentynyl compound, DPA-C5yne (7c), was selected, labelled in one single step with fluorine-18 from the corresponding tosylate and in vivo evaluated with PET on our in-house-developed rat model of acute local neuroinflammation. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.01.080

文献信息

• Novel Pyrazolo[1,5-<i>a</i>]pyrimidines as Translocator Protein 18 kDa (TSPO) Ligands: Synthesis, <i>in Vitro</i> Biological Evaluation, [¹⁸F]-Labeling, and <i>in Vivo</i> Neuroinflammation PET Images
  作者：Annelaure Damont、Vincent Médran-Navarrete、Fanny Cacheux、Bertrand Kuhnast、Géraldine Pottier、Nicholas Bernards、Frank Marguet、Frédéric Puech、Raphaël Boisgard、Frédéric Dollé

  DOI：10.1021/acs.jmedchem.5b00932

  日期：2015.9.24

  A series of novel pyrazolo[1,5-a]pyrimidines, closely related to N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide (2, DPA-714), were synthesized and biologically in vitro evaluated for their potential to bind the translocator protein 18 kDa (TSPO), a protein today recognized as an early biomarker of neuroinflammatory processes. This series is composed

  一系列新的吡唑的[1,5-一个]嘧啶，密切相关的Ñ，ñ -二乙基- 2-（2-（4-（2-氟乙氧基）苯基）-5,7-二甲基[1,5-一个合成]嘧啶-3-基）乙酰胺（2，DPA-714），并在生物学上体外评估其结合转运蛋白18 kDa（TSPO）的潜力，该蛋白今天被认为是神经炎症过程的早期生物标记。该系列由氟烷基-和氟炔基-类似物组成，它们是通过Sonogashira偶联反应从常见的碘化中间体制得的。所有衍生物均表现出对TSPO的亚纳摩尔亲和力（0.37至0.86 nM），与2的亲和力相当（0.91 nM）。其中两个被氟18放射性标记，并通过体外放射自显影和正电子发射断层扫描（PET）成像在啮齿类神经炎模型上研究了它们的生物分布。两种化合物在AMPA介导的病变中的大脑摄取和局部蓄积证实了它们作为体内PET放射治疗者的潜力。特别地，[ 18 F] 23在体内显示出比母体分子[ 18 F] 2在60分钟时显着更高的ipsi-对侧比。
• A Facile Radiolabeling of [¹⁸F]FDPA via Spirocyclic Iodonium Ylides: Preliminary PET Imaging Studies in Preclinical Models of Neuroinflammation
  作者：Lu Wang、Ran Cheng、Masayuki Fujinaga、Jian Yang、Yiding Zhang、Akiko Hatori、Katsushi Kumata、Jing Yang、Neil Vasdev、Yunfei Du、Chongzhao Ran、Ming-Rong Zhang、Steven H. Liang

  DOI：10.1021/acs.jmedchem.7b00432

  日期：2017.6.22

  A suitable TSPO PET ligand may visualize and quantify neuroinflammation in a living brain. Herein we report a F-18-ligand, [F-18]2 ([F-18]FDPA), is radiolabeled in high yield and high specific activity based on our spirocyclic iodonium ylide (SCIDY) strategy. [F-18]2. demonstrated saturable specific binding to TSPO, substantially elevated brain uptake, and slow washout of bound PET signal in the preclinical models of brain neuroinflammation (cerebral ischemia and Alzheimer's disease).