(2S)-2-[(2-fluorophenyl)methyl]-3-(2-fluorospiro[4,5-dihydrothieno-[2,3-c]pyran-7,4'-piperidine]-1'-yl)-N-methylpropanamide | 1283095-70-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (2S)-2-[(2-fluorophenyl)methyl]-3-(2-fluorospiro[4,5-dihydrothieno-[2,3-c]pyran-7,4'-piperidine]-1'-yl)-N-methylpropanamide
• 英文别名: Spiro(piperidine-4,7'-(7H)thieno(2,3-C)pyran)-1-propanamide, 2'-fluoro-alpha-((2-fluorophenyl)methyl)-4',5'-dihydro-N-methyl-, (alphaS)-；(2S)-2-[(2-fluorophenyl)methyl]-3-(2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)-N-methylpropanamide
• CAS: 1283095-70-4
• 化学式: C₂₂H₂₆F₂N₂O₂S
• 分子量: 420.523
• InChiKey: MZBCQWLYUQJXKA-KRWDZBQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  69.8
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  4',5'-二氢-螺[哌啶-4,7'-[7H]噻吩并[2,3-c]吡喃]-1-羧酸叔丁酯 在 盐酸 、 正丁基锂 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸 、 N,N-二乙基苯胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 正己烷 、 二氯甲烷 为溶剂， 反应 43.5h， 生成 (2R)-2-[(2-fluorophenyl)methyl]-3-(2-fluorospiro[4,5-dihydrothieno-[2,3-c]pyran-7,4'-piperidine]-1'-yl)-N-methylpropanamide 、 (2S)-2-[(2-fluorophenyl)methyl]-3-(2-fluorospiro[4,5-dihydrothieno-[2,3-c]pyran-7,4'-piperidine]-1'-yl)-N-methylpropanamide
  参考文献：
  名称：

  Synthesis and Evaluation of Radioligands for Imaging Brain Nociceptin/Orphanin FQ Peptide (NOP) Receptors with Positron Emission Tomography

  摘要：

  Positron emission tomography (PET) coupled to an effective radioligand could provide an important tool for understanding possible links between neuropsychiatric disorders and brain NOP (nociceptin/orphanin FQ peptide) receptors. We sought to develop such a PET radioligand. High-affinity NOP ligands were synthesized based on a 3-(2'-fluoro-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-1-yl)-2(2-halobenzyl)-N-alkylpropanamide scaffold and from experimental screens in rats, with ex vivo LC-MS/MS measures, three ligands were identified for labeling with carbon-11 and evaluation with PET in monkey. Each ligand was labeled by C-11-methylation of an N-desmethyl precursor and studied in monkey under baseline and NOP receptor-preblock conditions. The three radioligands, [C-11] (S) 10a-c, gave similar results. Baseline scans showed high entry of radioactivity into the brain to give a distribution reflecting that expected for NOP receptors. Preblock experiments showed high early peak levels of brain radioactivity, which rapidly declined to a Much lower level than seen in baseline scans, thereby indicating a high level of receptor-specific binding in baseline experiments. Overall, [C-11](S)-10c showed the most favorable receptor-specific signal and kinetics and is now selected for evaluation in human subjects.

  DOI：

  10.1021/jm101487v

文献信息

• Development of LC-MS/MS-Based Receptor Occupancy Tracers and Positron Emission Tomography Radioligands for the Nociceptin/Orphanin FQ (NOP) Receptor
  作者：Concepción Pedregal、Elizabeth M. Joshi、Miguel A. Toledo、Celia Lafuente、Nuria Diaz、Maria A. Martinez-Grau、Alma Jiménez、Ana Benito、Antonio Navarro、Zhaogen Chen、Daniel R. Mudra、Steven D. Kahl、Karen S. Rash、Michael A. Statnick、Vanessa N. Barth

  DOI：10.1021/jm201629q

  日期：2012.6.14

  understanding of the relationship between neuropsychiatric disorders and the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor. Herein, we describe the discovery and development of an antagonist NOP receptor occupancy (RO) tracer and a novel positron emission tomography (PET) radioligand suitable to probe the NOP receptor in human clinical studies. A thorough structure–activity relationship (SAR) around

  当前，缺乏足够的工具限制了对神经精神疾病与伤害感受素/孤儿啡FQ（N / OFQ）肽（NOP）受体之间关系的理解。在本文中，我们描述了拮抗剂NOP受体占有率（RO）示踪剂和适合在人类临床研究中探测NOP受体的新型正电子发射断层扫描（PET）放射性配体的发现和发展。高亲和力3-（2'-氟-4'，5'-二氢螺[哌啶-4,7'-噻吩并[2,3- c ]吡喃] -1-周围的结构-活性关系（SAR）yl）-2-（2-卤代苄基）-N-烷基丙酰胺支架鉴定了一系列亚纳摩尔的高选择性NOP拮抗剂。随后，在大鼠体内通过液相色谱-串联质谱法（LC-MS / MS）对这些未标记的NOP配体进行了体内评估，以确定脑摄取，动力学和特异性结合。（S）-27被确定为合适的未标记临床前RO示踪剂，可准确定量大鼠脑中NOP受体的参与。选择了三种化合物在非人类灵长类动物中作为PET示踪剂进行评估：（-）- 26，（-）- 30和（-）-