N-甲基-3-吩噻嗪-10-基丙-1-胺 | 2095-20-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻嗪类
• 中文名称: N-甲基-3-吩噻嗪-10-基丙-1-胺
• 英文名称: Norpromazine
• 英文别名: N-methyl-10H-phenothiazine-10-propanamine；N-(3-methylaminopropyl)phenothiazine；N-methyl-3-phenothiazin-10-yl-propan-1-amine；N-methyl-3-(10H-phenothiazin-10-yl)propan-1-amine；methyl-(3-phenothiazin-10-yl-propyl)-amine；Methyl[3-(10H-phenothiazin-10-YL)propyl]amine；N-methyl-3-phenothiazin-10-ylpropan-1-amine
• CAS: 2095-20-7
• 化学式: C₁₆H₁₈N₂S
• mdl: MFCD08059214
• 分子量: 270.398
• InChiKey: WOCOVPRTRIBGFZ-UHFFFAOYSA-N

物化性质

• 沸点：
  188-190 °C(Press: 2 Torr)
• 密度：
  1.145±0.06 g/cm3(Predicted)
• 保留指数：
  2348.5

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  40.6
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

代谢

N-去甲基氯丙嗪是氯丙嗪在人體內的已知代谢物。

N-Desmethyl promazine is a known human metabolite of promazine.

来源:NORMAN Suspect List Exchange

安全信息

• 海关编码：
  2934300000

反应信息

• 作为反应物：
  描述：

  甲醛-13C 、 N-甲基-3-吩噻嗪-10-基丙-1-胺 在 sodium tetrahydroborate 作用下， 以 甲醇 、 水 为溶剂， 反应 2.0h， 以69%的产率得到N-([13C]methyl)-N-methyl-10H-phenothiazine-10-propanamine
  参考文献：
  名称：

  Synthesis of [N-13CH3] drugs (chlorpromazine, triflupromazine and promazine)

  摘要：

  These [N-(CH3)-C-13] containing drugs (chlorpromazine, triflupromazine and promazine) have been synthesized by means of a two-step demethylation/methylation procedure.

  DOI：

  10.1002/1099-1344(200008)43:9<865::aid-jlcr370>3.0.co;2-e
• 作为产物：
  描述：

  丙嗪 在 三乙胺 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 4.5h， 生成 N-甲基-3-吩噻嗪-10-基丙-1-胺
  参考文献：
  名称：

  NB 06: From a simple lysosomotropic aSMase inhibitor to tools for elucidating the role of lysosomes in signaling apoptosis and LPS-induced inflammation

  摘要：

  Ceramide generation is involved in signal transduction of cellular stress response, in particular during stress-induced apoptosis in response to stimuli such as minimally modified Low-density lipoproteins, TNFalpha and exogenous C-6-ceramide. In this paper we describe 48 diverse synthetic products and evaluate their lysosomotropic and acid sphingomyelinase inhibiting activities in macrophages. A stimuli induced increase of C-16-ceramide in macrophages can be almost completely suppressed by representative compound NB 06 providing an effective protection of macrophages against apoptosis. Compounds like NB 06 thus offer highly interesting fields of application besides prevention of apoptosis of macrophages in atherosclerotic plaques in vessel walls. Most importantly, they can be used for blocking pH dependent lysosomal processes and enzymes in general as well as for analyzing lysosomal dependent cellular signaling. Modulation of gene expression of several prominent inflammatory messengers IL1B, IL6, IL23A, CCL4 and CCL20 further indicate potentially beneficial effects in the field of (systemic) infections involving bacterial endotoxins like LPS or infections with influenza A virus. (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2017.09.021

文献信息

• The Singlet Oxygen Oxidation of Chlorpromazine and Some Phenothiazine Derivatives. Products and Reaction Mechanisms
  作者：Enrico Baciocchi、Tiziana Del Giacco、Osvaldo Lanzalunga、Andrea Lapi、Daniele Raponi

  DOI：10.1021/jo0706980

  日期：2007.7.1

  and product study of the reactions of chlorpromazine 1, N-methylphenothiazine 2, and N-ethylphenothiazine 3 with singlet oxygen was carried out in MeOH and MeCN. 1 undergoes exclusive side-chain cleavage, whereas the reactions of 2 and 3, in MeOH, afforded only the corresponding sulfoxides. A mechanism for the reaction of 1 is proposed where the first step involves an interaction between singlet oxygen

  在MeOH和MeCN中进行了氯丙嗪1，N-甲基吩噻嗪2和N-乙基吩噻嗪3与单线态氧反应的动力学和产物研究。1在甲醇中仅进行侧链裂解，而2和3的反应仅提供相应的亚砜。提出了1的反应机理，其中第一步涉及单线态氧与侧链二甲基氨基氮之间的相互作用。这就解释了为什么2和3都没有观察到侧链断裂的原因。
• Contribution of human cytochrome<i>P</i>-450 isoforms to the metabolism of the simplest phenothiazine neuroleptic promazine
  作者：Jacek Wójcikowski、Lydiane Pichard-Garcia、Patrick Maurel、Władysława A Daniel

  DOI：10.1038/sj.bjp.0705195

  日期：2003.4

  The aim of the present study was to identify human cytochrome P‐450 isoforms (CYPs) involved in 5‐sulphoxidation and N‐demethylation of the simplest phenothiazine neuroleptic promazine in human liver. The experiments were performed in the following in vitro models: (A) a study of promazine metabolism in liver microsomes—(a) correlations between the rate of promazine metabolism and the level and activity of CYPs; (b) the effect of specific inhibitors on the rate of promazine metabolism (inhibitors: CYP1A2—furafylline, CYP2D6—quinidine, CYP2A6+CYP2E1—diethyldithiocarbamic acid, CYP2C9—sulfaphenazole, CYP2C19—ticlopidine, CYP3A4—ketoconazole); (B) promazine biotransformation by cDNA‐expressed human CYPs (Supersomes 1A1, 1A2, 2A6, 2B6, 2C9, 2C19, 2E1, 3A4); (C) promazine metabolism in a primary culture of human hepatocytes treated with specific inducers (rifampicin—CYP3A4, CYP2B6 and CYP2C inducer, 2,3,7,8‐tetrachlordibenzeno‐p‐dioxin (TCDD)—CYP1A1/1A2 inducer). In human liver microsomes, the formation of promazine 5‐sulphoxide and N‐desmethylpromazine was significantly correlated with the level of CYP1A2 and ethoxyresorufin O‐deethylase and acetanilide 4‐hydroxylase activities, as well as with the level of CYP3A4 and cyclosporin A oxidase activity. Moreover, the formation of N‐desmethylpromazine was correlated well with S‐mephenytoin 4′‐hydroxylation. Furafylline (a CYP1A2 inhibitor) and ketoconazole (a CYP3A4 inhibitor) significantly decreased the rate of promazine 5‐sulphoxidation, while furafylline and ticlopidine (a CYP2C19 inhibitor) significantly decreased the rate of promazine N‐demethylation in human liver microsomes. The cDNA‐expressed human CYPs generated different amounts of promazine metabolites, but the rates of CYP isoforms to catalyse promazine metabolism at therapeutic concentration (10 μM) was as follows: 1A1>2B6>1A2>2C9>3A4>2E1>2A6>2D6>2C19 for 5‐sulphoxidation and 2C19>2B6>1A1>1A2>2D6>3A4>2C9>2E1>2A6 for N‐demethylation. The highest intrinsic clearance (Vmax/Km) was found for CYP1A subfamily, CYP3A4 and CYP2B6 in the case of 5– sulphoxidation, and for CYP2C19, CYP1A subfamily and CYP2B6 in the case of N‐demethylation. In a primary culture of human hepatocytes, TCDD (a CYP1A subfamily inducer), as well as rifampicin (mainly a CYP3A4 inducer) induced the formation of promazine 5‐sulphoxide and N‐desmethylpromazine. Regarding the relative expression of various CYPs in human liver, the obtained results indicate that CYP1A2 and CYP3A4 are the main isoforms responsible for 5‐sulphoxidation, while CYP1A2 and CYP2C19 are the basic isoforms that catalyse N‐demethylation of promazine in human liver. Of the other isoforms studied, CYP2C9 and CYP3A4 contribute to a lesser degree to promazine 5‐sulphoxidation and N‐demethylation, respectively. The role of CYP2A6, CYP2B6, CYP2D6 and CYP2E1 in the investigated metabolic pathways of promazine seems negligible. British Journal of Pharmacology (2003) 138, 1465–1474. doi:10.1038/sj.bjp.0705195

  本研究的目的是在人类肝脏中确定参与简单吩噻嗪抗精神病药物普罗迷嗪（promazine）5-硫氧化和N-脱甲基作用的人类细胞色素P-450异构体（CYPs）。 实验是在以下体外模型中进行的：(A) 研究普罗迷嗪在肝微粒体中的代谢——(a) 普罗迷嗪代谢速率与CYPs的水平和活性的相关性；(b) 特异性抑制剂对普罗迷嗪代谢速率的影响（抑制剂：CYP1A2—呋拉西林，CYP2D6—金鸡纳碱，CYP2A6 + CYP2E1—二乙基二硫代碳酸盐，CYP2C9—磺胺苯唑，CYP2C19—噻氯匹啶，CYP3A4—酮康唑）；(B) cDNA表达的重组人CYPs催化普罗迷嗪的生物转化（使用的CYPs为Supersomes 1A1, 1A2, 2A6, 2B6, 2C9, 2C19, 2E1, 3A4）；(C) 在人原代肝细胞培养物中，普罗迷嗪在特定诱导剂处理下的代谢（利福霉素——CYP3A4、CYP2B6和CYP2C诱导剂，2,3,7,8-四氯二苯并-dioxin（TCDD）——CYP1A1/1A2诱导剂）。 在人肝微粒体中，普罗迷嗪5-硫氧化物和N-脱甲基普罗迷嗪的形成与CYP1A2的水平以及乙氧基苦味酸O-脱乙基酶和对硝基苯酚N-羟化酶的活性显著相关，同时也与CYP3A4的水平和环孢素A氧化酶的活性显著相关。此外，N-脱甲基普罗迷嗪的形成与S-甲乙双键酶的活性良好相关。 呋拉西林（CYP1A2抑制剂）和酮康唑（CYP3A4抑制剂）显著降低了普罗迷嗪5-硫氧化的速率，而呋拉西林和噻氯匹啶（CYP2C19抑制剂）显著降低了人肝微粒体中普罗迷嗪N-脱甲基的速率。 cDNA表达的人CYPs生成了不同量的普罗迷嗪代谢物，但在治疗浓度（10 μM）下，各CYP异构体催化普罗迷嗪代谢的速率如下：5-硫氧化为1A1 > 2B6 > 1A2 > 2C9 > 3A4 > 2E1 > 2A6 > 2D6 > 2C19；N-脱甲基为2C19 > 2B6 > 1A1 > 1A2 > 2D6 > 3A4 > 2C9 > 2E1 > 2A6。在5-硫氧化中，CYP1A亚家族、CYP3A4和CYP2B6具有最高的固有清除率（V_max/K_m）；在N-脱甲基中，CYP2C19、CYP1A亚家族和CYP2B6具有最高的固有清除率。 在人原代肝细胞培养物中，TCDD（CYP1A亚家族诱导剂）以及利福霉素（主要是CYP3A4诱导剂）诱导了普罗迷嗪5-硫氧化物和N-脱甲基普罗迷嗪的形成。 根据各种CYP在人类肝脏中的相对表达水平，结果显示CYP1A2和CYP3A4是负责5-硫氧化的主要异构体，而CYP1A2和CYP2C19是催化普罗迷嗪N-脱甲基作用的基本异构体。在研究的其他异构体中，CYP2C9和CYP3A4分别对普罗迷嗪的5-硫氧化和N-脱甲基作用有较小的贡献。CYP2A6、CYP2B6、CYP2D6和CYP2E1在普罗迷嗪研究代谢途径中的作用似乎可以忽略不计。 British Journal of Pharmacology (2003) 138, 1465–1474. doi:10.1038/sj.bjp.0705195
• Oligomer-Phenothiazine Conjugates
  申请人：Gu Xuyuan

  公开号：US20120046279A1

  公开（公告）日：2012-02-23

  The invention relates to (among other things) oligomer-phenothiazine conjugates and related compounds. A conjugate of the invention, when administered by any of a number of administration routes, exhibits advantages over un-conjugated phenothiazine compounds.

  本发明涉及（除其他外）寡聚物-苯噻嗪共轭物和相关化合物。本发明的共轭物在通过多种给药途径之一给予时，表现出优于未共轭苯噻嗪化合物的优点。
• Fujii, Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan, 1956, vol. 76, p. 644,647, 648
  作者：Fujii

  DOI：——

  日期：——
• A Focused Library of Psychotropic Analogues with Neuroprotective and Neuroregenerative Potential
  作者：Elisa Uliassi、Luis Emiliano Peña-Altamira、Aixa V. Morales、Francesca Massenzio、Sabrina Petralla、Michele Rossi、Marinella Roberti、Loreto Martinez Gonzalez、Ana Martinez、Barbara Monti、Maria Laura Bolognesi

  DOI：10.1021/acschemneuro.8b00242

  日期：2019.1.16

  Overcoming the lack of effective treatments and the continuous clinical trial failures in neurodegenerative drug discovery might require a shift from the prevailing paradigm targeting pathogenesis to the one targeting simultaneously neuroprotection and neuroregeneration. In the studies reported herein, we sought to identify small molecules that might exert neuroprotective and neuroregenerative potential as tools against neurodegenerative diseases. In doing so, we started from the reported neuroprotective/neuroregenerative mechanisms of psychotropic drugs featuring a tricyclic alkylamine scaffold. Thus, we designed a focused-chemical library of 36 entries aimed at exploring the structural requirements for efficient neuroprotective/neuroregenerative cellular activity, without the manifestation of toxicity. To this aim, we developed a synthetic protocol, which overcame the limited applicability of previously reported procedures. Next, we evaluated the synthesized compounds through a phenotypic screening pipeline, based on primary neuronal systems. Phenothiazine 2Bc showed improved neuroregenerative and neuroprotective properties with respect to reference drug desipramine (2Aa). Importantly, we have also shown that 2Bc outperformed currently available drugs in cell models of Alzheimer's and Parkinson's diseases and attenuates microglial activation by reducing iNOS expression.