(R)-(+)-N-甲氧基甲基-N-(三甲基甲硅基)甲基-1-苯乙胺 | 133407-38-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: (R)-(+)-N-甲氧基甲基-N-(三甲基甲硅基)甲基-1-苯乙胺
• 中文别名: (R)-(+)-n-甲氧基甲基-n-(三甲基甲硅烷基)甲基-1-苯乙胺；N-甲氧基甲基-N-(三甲基甲硅基)甲基-1-苯乙胺；(R)-(+)-N-甲氧基-N-(三甲基甲硅烷基)甲基-1-苯乙胺
• 英文名称: (R)-(+)-N-methoxymethyl-N-(trimethylsilyl)methyl-1-phenylethylamine
• 英文别名: (R)-N-(methoxymethyl)-1-phenyl-N-((trimethylsilyl)methyl)ethanamine；(1R)-N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl)ethanamine
• CAS: 133407-38-2
• 化学式: C₁₄H₂₅NOSi
• 分子量: 251.444
• InChiKey: FRQGYHCIEIDEAD-CYBMUJFWSA-N

物化性质

• 沸点：
  82-84°C 0,2mm
• 密度：
  0,926 g/cm3
• 闪点：
  82-84°C/0.2mm

计算性质

• 辛醇/水分配系数(LogP)：
  3.53
• 重原子数：
  17
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  12.5
• 氢给体数：
  0
• 氢受体数：
  2

安全信息

• 危险类别码：
  R36/37/38
• 安全说明：
  S26,S36
• 危险性防范说明：
  P305+P351+P338
• 危险性描述：
  H227,H315,H319,H335

反应信息

• 作为反应物：
  描述：

  (R)-(+)-N-甲氧基甲基-N-(三甲基甲硅基)甲基-1-苯乙胺 在 氢溴酸 、 碳酸氢钠 、 三氟乙酸 作用下， 以 乙酸乙酯 为溶剂， 反应 3.5h， 生成 (3S,4R)-3-butoxycarbonyl-1-<(R)-1-phenylethyl>-1-azoniabicyclo<2.2.1>heptane bromide
  参考文献：
  名称：

  Cottrell, Ian F.; Hands, David; Kennedy, Derek J., Journal of the Chemical Society. Perkin transactions I, 1991, # 5, p. 1091 - 1097

  摘要：

  DOI：
• 作为产物：
  描述：

  R(+)-alpha-甲基苄胺 、 alkaline earth salt of/the/ methylsulfuric acid 在 potassium carbonate 作用下， 以 水 、 乙腈 为溶剂， 反应 6.5h， 生成 (R)-(+)-N-甲氧基甲基-N-(三甲基甲硅基)甲基-1-苯乙胺
  参考文献：
  名称：

  Non-stabilized azomethine ylides in [3 + 2] cycloadditions. Pyrrolidinylfuranones from (5S )-5-menthyloxy-4-vinylfuran-2(5H )-one

  摘要：

  用氟化锂在乙腈中超声 N-苄基-N-甲氧基甲基（三甲基硅甲基）胺 9a-c 与 4-乙烯基呋喃酮 2 和 6 发生化学选择性 1,3-二极环加成反应，得到吡咯烷基呋喃酮 10、11a-c 和 12a-c。通过 X 射线分析和与相关的环氧丙烷基呋喃酮 13 的质子核磁共振数据比较，确定了其立体化学性质。

  DOI：

  10.1039/a803693d

文献信息

• (Indazol-4-YL) Hexahydropyrrolopyrrolones and Methods of Use
  申请人：AbbVie Inc.

  公开号：US20160264582A1

  公开（公告）日：2016-09-15

  Compounds of formula (I) and pharmaceutically acceptable salts, esters, amides, or radiolabelled forms thereof, wherein G Ar , L 1 , Z 1 and Z 2 are as defined in the specification, are useful in treating conditions or disorders prevented by or ameliorated by voltage-gated sodium channels, e.g., Na v 1.7 and/or Na v 1.8. Methods for making the compounds are disclosed. Also disclosed are pharmaceutical compositions of compounds of formula (I), and methods for using such compounds and compositions.

  式（I）的化合物及其药用可接受的盐、酯、酰胺或放射标记形式，其中G、Ar、L1、Z1和Z2如规范中所定义，可用于治疗由电压门控钠通道如Na v 1.7和/或Na v 1.8预防或改善的病症或紊乱。公开了制备这些化合物的方法。还公开了式（I）化合物的药物组合物，以及使用这些化合物和组合物的方法。
• [EN] IMIDAZOPYRIDINE DERIVATIVES AS MODULATORS OF TNF ACTIVITY<br/>[FR] DÉRIVÉS D'IMIDAZOPYRIDINE UTILISABLES EN TANT QUE MODULATEURS DE L'ACTIVITÉ TNF
  申请人：UCB PHARMA SA

  公开号：WO2014009295A1

  公开（公告）日：2014-01-16

  A series of imidazo[l,2-a]pyridine derivatives of formula (I), being potent modulators of human TNFa activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.

  一系列式(I)的咪唑并[1,2-a]吡啶衍生物，作为人类TNFa活性的有效调节剂，因此在治疗和/或预防各种人类疾病方面具有益处，包括自身免疫和炎症性疾病；神经学和神经退行性疾病；疼痛和伤害感知性疾病；心血管疾病；代谢性疾病；眼科疾病；以及肿瘤学疾病。
• Substituted Indazoles as Na_v1.7 Blockers for the Treatment of Pain
  作者：Jennifer M. Frost、David A. DeGoey、Lei Shi、Rebecca J. Gum、Meagan M. Fricano、Greta L. Lundgaard、Odile F. El-Kouhen、Gin C. Hsieh、Torben Neelands、Mark A. Matulenko、Jerome F. Daanen、Madhavi Pai、Nayereh Ghoreishi-Haack、Cenchen Zhan、Xu-Feng Zhang、Michael E. Kort

  DOI：10.1021/acs.jmedchem.6b00063

  日期：2016.4.14

  makes it an appealing target for the potential development of new pain drugs. The utility of nonselective Nav blockers is often limited due to adverse cardiovascular and CNS side effects. We sought more selective Nav1.7 blockers with oral activity, improved selectivity, and good druglike properties. The work described herein focused on a series of 3- and 4-substituted indazoles. SAR studies of 3-substituted

  Na v 1.7电压门控离子通道在疼痛信号传导途径中的作用的遗传验证使其成为潜在的新型止痛药开发目标。由于心血管和中枢神经系统的不良反应，非选择性Na v阻滞剂的应用常常受到限制。我们寻求具有口服活性，更高的选择性和良好的药物性质的更具选择性的Na v 1.7阻滞剂。本文所述的工作集中于一系列3-和4-取代的吲唑。3取代的吲唑的SAR研究得到了类似物7，其在体外和体内的活性良好，但在大鼠体内的药代动力学却很差。对4-取代的吲唑的优化产生了两种化合物27和48，具有良好的体外和体内活性，并具有改善的大鼠药代动力学特征。27和48在急性大鼠单碘乙酸盐诱发的骨关节炎模型的疼痛中均显示出强劲的活性，而48的亚慢性给药则显示在7天内向较低的EC 50转移。
• Synthesis of 6-Azaspiro[4.3]alkanes: Innovative Scaffolds for Drug Discovery
  作者：Bohdan A. Chalyk、Andrei A. Isakov、Maryna V. Butko、Kateryna V. Hrebeniuk、Olena V. Savych、Olexandr V. Kucher、Konstantin S. Gavrilenko、Tetiana V. Druzhenko、Vladimir S. Yarmolchuk、Sergey Zozulya、Pavel K. Mykhailiuk

  DOI：10.1002/ejoc.201700536

  日期：2017.8.24

  New scaffolds for drug discovery, 6-azaspiro[4.3]alkanes, have been synthesized in two steps from four-membered-ring ketones: cyclobutanone, thienone, N-Boc-azetidinone (Boc = tert-butoxycarbonyl), etc. The key transformation was the reaction between electron-deficient exocyclic alkenes and an in-situ generated N-benzylazomethine ylide.

  用于药物发现的新支架，6-氮杂螺[4.3]烷烃，由四元环酮分两步合成：环丁酮、噻吩酮、N-Boc-氮杂环丁酮（Boc = 叔丁氧基羰基）等。 关键转化是缺电子环外烯烃与原位生成的 N-苄基偶氮甲碱叶立德之间的反应。
• Novel Antimuscarinic Antidepressant-like Compounds with Reduced Effects on Cognition
  作者：Chad R. Johnson、Brian D. Kangas、Emily M. Jutkiewicz、Gail Winger、Jack Bergman、Andrew Coop、James H. Woods

  DOI：10.1124/jpet.120.000337

  日期：2021.6

  The cholinergic nervous system has been implicated in mood disorders, evident in the fast-onset antidepressant effects of scopolamine, a potent muscarinic antagonist, in clinical studies. One prominent disadvantage of the use of scopolamine in the treatment of depression is its detrimental effects on cognition, especially as such effects might aggravate cognitive deficits that occur with depression itself. Thus, the identification of antimuscarinic drugs that are free of such detrimental effects may provide an important avenue for the development of novel therapeutics for the management of depression. The present data in rats indicate that a historical muscarinic antagonist, L-687,306, and a muscarinic antagonist of our own design, CJ2100, were as or more effective than scopolamine in antagonizing both the bradycardic effects of the muscarinic agonist arecoline in cardiovascular studies and its discriminative stimulus and rate-decreasing effects in behavioral studies. Additionally, both novel muscarinic antagonists were as effective as scopolamine in decreasing immobility in the forced swim test, a preclinical indicator of potential antidepressant activity. However, at equieffective or even larger doses, they were considerably less disruptive than scopolamine in assays of cognition-related behavior. All three drugs displayed high specificity for the mAChRs with few off-target binding sites, and CJ2100 showed modest affinity across the mAChRs when compared with L-687,306 and scopolamine. These data emphasize the dissimilar pharmacological profiles that are evident across antimuscarinic compounds and the potential utility of novel antagonists for the improved treatment of depression. SIGNIFICANCE STATEMENT Some clinical studies with the muscarinic antagonist scopolamine document its ability to produce antidepressant effects in patients with mood disorders; however, scopolamine also has well known adverse effects on both autonomic and centrally mediated physiological functions that limit its therapeutic use. This study characterizes the cardiovascular and discriminative stimulus effects of two novel muscarinic antagonists, L-687,306 and CJ2100, that produce antidepressant-like effects in a rodent model (forced swim test) without affecting touchscreen-based cognitive performance (titrating psychomotor vigilance and delayed matching-to-position).

  胆碱能神经系统与情绪障碍密切相关，这在临床研究中表现为阿托品（一种强效的毒蕈碱拮抗剂）快速起效的抗抑郁作用。使用阿托品治疗抑郁症的一个显著缺点是对认知的负面影响，尤其是这些影响可能加剧抑郁症本身所导致的认知缺陷。因此，识别不具有这些有害影响的抗毒蕈碱药物可能为开发新型治疗抑郁症的药物提供重要途径。目前在大鼠中的数据表明，历史上已知的毒蕈碱拮抗剂L-687,306，以及我们自行设计的毒蕈碱拮抗剂CJ2100，在抵消心血管研究中毒蕈碱受体激动剂阿瑞可林的心动过缓效应以及在行为研究中的分辨刺激和降低速率效果方面，效果与阿托品相当或更为显著。此外，这两种新型毒蕈碱拮抗剂在强迫游泳试验中减少无动性的效果与阿托品相当，该试验是潜在抗抑郁活性的前临床指示。然而，在等效或更高剂量下，它们在认知相关行为的测量中对行为的干扰程度明显低于阿托品。这三种药物对mAChRs显示出高度特异性，几乎没有偏离靶点的结合位点，并且与L-687,306和阿托品相比，CJ2100在mAChRs上显示出适度的亲和力。这些数据强调了不同的抗毒蕈碱化合物之间明显不同的药理特征，以及新型拮抗剂在改善抑郁症治疗中的潜在用途。 重要声明：一些与毒蕈碱拮抗剂阿托品相关的临床研究记录了其在情绪障碍患者中产生抗抑郁效果的能力；然而，阿托品对自主神经及中枢介导的生理功能的负面影响是众所周知的，这限制了其治疗用途。本研究描述了两种新型毒蕈碱拮抗剂L-687,306和CJ2100的心血管和分辨刺激效果，这两者在啮齿动物模型（强迫游泳试验）中产生类似抗抑郁的效果，同时没有影响基于触摸屏的认知表现（逐级心理运动警觉性和延迟匹配位置）。