(2R,3R,11bR)-9-(benzyloxy)-3-isobutyl-10-methoxy-2,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol | 1141448-87-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: (2R,3R,11bR)-9-(benzyloxy)-3-isobutyl-10-methoxy-2,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol
• 英文别名: (2R,3R,11bR)-9-(benzyloxy)-3-isobutyl-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol；(2R,3R,11bR)-10-methoxy-3-(2-methylpropyl)-9-phenylmethoxy-2,3,4,6,7,11b-hexahydro-1H-benzo[a]quinolizin-2-ol
• CAS: 1141448-87-4
• 化学式: C₂₅H₃₃NO₃
• 分子量: 395.542
• InChiKey: MZLAHVRSAKALHY-YMPZKCBVSA-N

物化性质

• 熔点：
  138-140 °C
• 沸点：
  547.8±50.0 °C(Predicted)
• 密度：
  1.15±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  41.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (2R,3R,11bR)-9-(benzyloxy)-3-isobutyl-10-methoxy-2,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol 在 palladium 10% on activated carbon 、 氢气 、 caesium carbonate 作用下， 以 四氢呋喃 、 乙醇 、 丙酮 为溶剂， 反应 2.0h， 生成 (2R,3R,11bR)-9-((allyl-d5)oxy)-3-isobutyl-10-methoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol
  参考文献：
  名称：

  VMAT2成像剂D6- [18F] FP-（+）-DTBZ：改进的放射合成，固相萃取和表征纯化。

  摘要：

  目标最近，氘化示踪剂，D6- [18F] FP-（+）-DTBZ，9-O-六氘代-3- [18F]氟丙氧基-（+）-二氢丁苯那嗪（[18F] 9），靶向囊泡单胺转运蛋白2据报道中枢神经系统中的VMAT2（VMAT2）是诊断帕金森氏病（PD）的有用成像剂。通过使用固相萃取（SPE）纯化，可以优化和简化[18F] 9的生产。方法合成并表征了三种主要的非放射性杂质。通过使用不同的标记条件优化了[18F] 9的制备，并评估了SPE纯化方法。通过体外结合测定，小鼠体内生物分布测定以及脑切片的离体和体外放射自显影，评估化学杂质对[18F] 9最终剂量的影响。结果发现[18F] 9的最佳氟化条件-在DMSO中于130°C加热10分钟，观察到高放射化学产率和三种主要化学杂质。SPE方法成功地实现了涉及带有两步洗脱过程的Sep-Pak®tC18 Plus发光柱。该过程具有良好的放射化学收率（38.7±10.5％，已校正衰变；放射化学纯度>

  DOI：

  10.1016/j.nucmedbio.2019.07.002
• 作为产物：
  描述：

  5-甲基-2-己酮 在 盐酸 、 sodium tetrahydroborate 作用下， 以 甲醇 、 乙醚 、 乙醇 、 丙酮 为溶剂， 反应 32.3h， 生成 (2R,3R,11bR)-9-(benzyloxy)-3-isobutyl-10-methoxy-2,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol
  参考文献：
  名称：

  FP-(+)DTBZ前体的合成

  摘要：

  摘要 公开了以3-羟基-4-甲氧基苯甲醛为起始原料的FP-(+)DTBZ前体的合成路线。在该方法中，由于选择性脱保护和加速反应过程的温和条件，苄基保护方案和原位Diels-Alder反应使该过程更加实用。图形概要

  DOI：

  10.1080/00397911.2019.1663539

文献信息

• [EN] NOVEL DEUTERIUM SUBSTITUTED POSITRON EMISSION TOMOGRAPHY (PET) IMAGING AGENTS AND THEIR PHARMACOLOGICAL APPLICATION<br/>[FR] NOUVEAUX AGENTS D'IMAGERIE PAR TOMOGRAPHIE PAR ÉMISSION DE POSITRONS (PET) SUBSTITUÉS PAR DU DEUTÉRIUM ET LEUR APPLICATION PHARMACOLOGIQUE
  申请人：FIVE ELEVEN PHARMA INC

  公开号：WO2018222549A1

  公开（公告）日：2018-12-06

  The present invention relates to deuterated compounds according to Formula I-A, Formula II-A, Formula II-D, and Formula III-A. These compounds can be used as PET imaging agents for evaluating Parkinson's Disease, Alzheimer Disease, and for determining specific serotonin reuptake inhibitor (SSRIi) activity for treatment of depression. The present invention also relates to pharmaceutical compositions comprising a pharmaceutical acceptable carrier and a compound of Formula I-A, Formulae II-A, Formula II-D, or Formula III-A, or a pharmaceutically acceptable salt thereof.

  本发明涉及根据式I-A、式II-A、式II-D和式III-A的氘代化合物。这些化合物可用作PET成像剂，用于评估帕金森病、阿尔茨海默病，并确定特定的选择性5-羟色胺再摄取抑制剂（SSRIi）活性，用于治疗抑郁症。本发明还涉及包括药用可接受载体和式I-A、式II-A、式II-D或式III-A的化合物，或其药用可接受盐的药物组合物。
• (+)-9-Benzyloxy-α-Dihydrotetrabenazine as an Important Intermediate for the VMAT2 Imaging Agents: Absolute Configuration and Chiral Recognition
  作者：Chunyi liu、Zhengping Chen、Xiaomin Li、Jie Tang、Xiaofeng Qin

  DOI：10.1002/chir.22126

  日期：2013.4

  carbonyl‐assisted salt bridges and the OH…O hydrogen bonds formed polar columns in the crystal structure of the diastereomeric salt of compound 8, resembling butterflies with open wings as viewed along the c‐axis. These polar columns were extended to three‐dimensional network by intermolecular CH…O hydrogen bonds and intermolecular CH…π interactions. Chirality, 2013. © 2013 Wiley Periodicals, Inc.

  本文首次报道了从X射线晶体学角度确定的（+）-9-苄氧基-α-二氢丁苯那嗪的绝对构型（8）。使用3-苄氧基-4-甲氧基苯甲醛（1）作为起始原料，通过六步反应制备化合物8。本文还首次描述了外消旋的9-苄氧基丁苯那嗪（5）和化合物8的非对映体盐的两种化合物的X射线晶体衍射结构。X射线结果和手性HPLC有助于阐明化合物8的绝对构型为2 R，3 R，11b R。外消旋化合物5的晶体结构在晶胞中包含两个独立于对称性的分子。有趣的是，尽管它们是结构异构体，但它们也就是对映体，即在溶液中，因为它们在晶格中不是彼此的镜像。为了阐明化合物8的非对映异构体盐的分子间相互作用机理，研究了其盐键，OH…O和CH…O氢键以及分子间CH…π相互作用等弱相互作用的晶体堆积。结果表明，羰基辅助盐桥和OH…O氢键在化合物8的非对映体盐的晶体结构中形成了极性柱，沿c轴看似带有张开翅膀的蝴蝶。这些极柱通过分子间CH…O氢键和分
• Deuterium substituted positron emission tomography (PET) imaging agents and their pharmacological application
  申请人：Five Eleven Pharma Inc.

  公开号：US10912849B2

  公开（公告）日：2021-02-09

  The present invention relates to deuterated compounds according to Formula I-A, Formula II-A, Formula II-D, and Formula III-A. These compounds can be used as PET imaging agents for evaluating Parkinson's Disease, Alzheimer Disease, and for determining specific serotonin reuptake inhibitor (SSRIi) activity for treatment of depression. The present invention also relates to pharmaceutical compositions comprising a pharmaceutical acceptable carrier and a compound of Formula I-A, Formulae II-A, Formula II-D, or Formula III-A, or a pharmaceutically acceptable salt thereof.

  本发明涉及符合式 I-A、式 II-A、式 II-D 和式 III-A 的氚代化合物。这些化合物可用作 PET 成像剂，用于评估帕金森病、阿尔茨海默病，以及确定治疗抑郁症的特异性血清素再摄取抑制剂 (SSRIi) 的活性。本发明还涉及药物组合物，其包含药物可接受载体和式 I-A、式 II-A、式 II-D 或式 III-A 的化合物或其药物可接受盐。
• Deuterated 18 F-9-O-hexadeutero-3-fluoropropoxyl-(+)-dihydrotetrabenazine (D6-FP-(+)-DTBZ): A vesicular monoamine transporter 2 (VMAT2) imaging agent
  作者：Futao Liu、Seok Rye Choi、Zhihao Zha、Karl Ploessl、Lin Zhu、Hank F. Kung

  DOI：10.1016/j.nucmedbio.2017.11.009

  日期：2018.2

  Introduction: Vesicular monoamine transporters 2 (VMAT2) in the brain serve as transporter for packaging monoamine in vesicles for normal CNS neurotransmission. Several VMAT2 imaging agents, [C-11]-(+)-DTBZ, dihydrotetrabenazine and [F-18]FP-(+)-DTBZ (9-0-fluoropropyl-(+)-dihydro tetrabenazine, a.k.a. [F-18]AV133), are useful for studying the changes in brain function related to monoamine transmission by in vivo imaging. Deuterated analogs have been reported targeting VMAT2 binding sites.Methods: A novel deuterated [F-18]9-0-hexaduterofluoropropyl-(+)-dihydrotetrabenazine,[18F]D6-FP-(+)DTBZ, [18F]1, was prepared as a VMAT2 imaging agent. This F-18 agent which targeted VMAT2 was evaluated by in vitro binding, in vivo biodistribution and microPET imaging studies in rodents.Results: The one step radiolabeling reaction led to the desired [F-18]D6-FP-(+)-DTBZ, [F-18]1, which showed excellent binding affinity to VMAT2 (Ki = 0.32 +/- 0.07 nM) comparable to that of FP-(+)-DTBZ (Ki = 033 +/- 0.02 nM) using [F-18]FP-(+)-DTBZ and rat striatum membrane homogenates. In vivo biodistribution in normal rats showed that 1, exhibited excellent brain uptake and comparable high ratio of striatum to cerebellum (target/background) ratio at 1 h after injection (ratio of 6.05 +/- 0.43 vs 5.66 +/- 0.72 for [18F]FP-(+)-DTBZ vs [F-18]1, respectively). MicroPET imaging studies in rats further confirm that the striatum with high VMAT2 concentration was clearly delineated in normal rat brain after iv injection of [F-18]1. We observed minor changes of metabolism in rat plasma between these two agents; however, the changes showed little effect on regional brain uptake and retention.Conclusions: The results reported here lend support for using [F-18]D6-FP-(+)-DTBZ, [F-18]1, as in vivo PET imaging agent for VMAT2 binding in the brain. (C) 2017 Elsevier Inc. All rights reserved.
• NOVEL DEUTERIUM SUBSTITUTED POSITRON EMISSION TOMOGRAPHY (PET) IMAGING AGENTS AND THEIR PHARMACOLOGICAL APPLICATION
  申请人：Five Eleven Pharma Inc.

  公开号：US20200230263A1

  公开（公告）日：2020-07-23

  The present invention relates to deuterated compounds according to Formula I-A, Formula II-A, Formula II-D, and Formula III-A. These compounds can be used as PET imaging agents for evaluating Parkinson's Disease, Alzheimer Disease, and for determining specific serotonin reuptake inhibitor (SSRIi) activity for treatment of depression. The present invention also relates to pharmaceutical compositions comprising a pharmaceutical acceptable carrier and a compound of Formula I-A, Formulae II-A, Formula II-D, or Formula III-A, or a pharmaceutically acceptable salt thereof.