芬乙茶碱 | 3736-08-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 中文名称: 芬乙茶碱
• 中文别名: 苯丙胺乙茶碱；苄乙胺嘌呤
• 英文名称: fenetylline
• 英文别名: Fenetyllin；fenethylline；Amfetyline；1,3-dimethyl-7-[2-(1-phenylpropan-2-ylamino)ethyl]purine-2,6-dione
• CAS: 3736-08-1
• 化学式: C₁₈H₂₃N₅O₂
• 分子量: 341.413
• InChiKey: NMCHYWGKBADVMK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  70.5
• 氢给体数：
  1
• 氢受体数：
  4

ADMET

代谢

7-[2-(α-甲基苯乙基氨基)乙基]茶碱氢氯酸盐(芬乙茶碱)在雄性Sprague-Dawley大鼠和三名男性志愿者体内的代谢命运进行了研究。在大鼠尿液中通过光谱特性以及高效液相色谱(HPLC)和气相色谱(GC)与真实样本的特征比较，鉴定出6种代谢物，分别为苯丙胺(AP)、对羟基-AP、乙酰氨基乙基-茶碱(TP)、氨基乙基-TP、羟乙基-TP和羧甲基-TP。这些代谢物也出现在接受芬乙茶碱的人类尿液中。使用HPLC和GC对这些代谢物进行定量分析显示，在大鼠0-24小时尿液中，羧甲基-TP、对羟基-AP和乙酰氨基乙基-TP是主要代谢物，分别占剂量的13.7%、11.2%和9.3%。在人类中，0-48小时尿液中的主要代谢物是羧甲基-TP(占剂量的39-43%)和AP(占剂量的23-33%)。这些结果表明，芬乙茶碱的代谢通过在两个不同位点进行氧化裂解，分别产生氨基乙基-TP和AP。产生AP的途径在人类和大鼠中均占主导地位，但在人类中更为显著。

Metabolic fate of 7-[2-(alpha-methylphenylethylamino)ethyl]theophylline hydrochloride (fenetylline) was investigated in male Sprague-Dawley rats and three male volunteers. Six metabolites were identified in the rat urine as amphetamine (AP), p-hydroxy-AP, acetylaminoethyl-theophylline(TP), aminoethyl-TP, hydroxyethyl-TP and carboxymethyl-TP by comparison of their spectral properties and H.P.L.C. and G.L.C. characteristics with those of authentic samples. All these metabolites was also detected in the urine of humans receiving fenetylline. Quantification of these metabolites using H.P.L.C. and G.L.C. showed that carboxymethyl-TP, p-hydroxy-AP and acetylaminoethyl-TP were the major metabolites in 0-24 hr rat urine at 13.7%, 11.2% and 9.3% of dose, respectively. In men, carboxymethyl-TP(39-43% dose) and AP(23-33% dose) were the major metabolites in 0-48 hr urine. These results suggest that fenetylline metabolism proceeds via oxidative cleavage at two different sites to produce aminoethyl-TP and AP, respectively. The pathway producing AP predominates, in both man and rat, but is more predominant in the former.

来源:Hazardous Substances Data Bank (HSDB)

代谢

芬乙茶碱在人体内通过两条途径代谢。除了之前描述的降解为安非他命和7-氧乙基茶碱外，芬乙茶碱还会经历氧化的N-脱烷基化，生成7-氨基乙基茶碱和苯乙酮。

Fenetylline is metabolized in humans on two pathways. In addition to previously described degradation to amphetamine and 7-oxyethyltheophylline fenetylline undergoes moreover oxydative N-dealkylation to yield 7-aminoethyltheophylline and phenylacetone.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在fenetylline分子中，茶碱通过一个烷基链与安非他命共价连接。由于早期代谢研究包含了安非他命，有人推测fenetylline可能仅仅是安非他命和/或茶碱的前药。尽管以前的研究与这个假设不一致，但为了比较fenetylline及其两种假定主要代谢物（+/-）-安非他命和茶碱的活动概况，进行了额外的研究。还使用新开发的高压液相色谱（HPLC）技术进行了调查，以进一步表征fenetylline经历的代谢模式，并检查药物的血浆药代动力学与其药效学作用之间的关系。Fenetylline抑制与安非他命相关的活动，在特定的测试系统中，这种效果与以前观察到的fenfluramine类似。理论上可从fenetylline分子中释放的安非他命的数量非常少。与fenetylline给药相关的药效学活动与母体化合物的血浆水平的关系比与产生的（+/-）-安非他命的关系更为密切。

In the fenetylline molecule, theophylline is covalently linked with amphetamine via an alkyl chain. The inclusion of amphetamine and results from early metabolic studies have led to speculation that fenetylline may be merely a prodrug for amphetamine and/or theophylline. Although previous studies are not consistent with this hypothesis, additional studies were conducted to comparatively evaluate the profiles of activity exhibited by fenetylline and its two postulated primary metabolites, (+/-)-amphetamine and theophylline. Investigations were also initiated using newly developed high pressure liquid chromatography (HPLC) techniques to further characterize the metabolic pattern that fenetylline undergoes and to examine the relationship between plasma pharmacokinetics and the pharmacodynamic actions of the drug. Fenetylline inhibits activity associated with amphetamine in certain test systems, an effect similar to that previously observed with fenfluramine. Only small amounts of the amphetamine theoretically available in the fenetylline molecule are released. Pharmacodynamic activity associated with fenetylline administration is more closely tied to plasma levels of the parent compound than to any (+/-)-amphetamine produced.

来源:Hazardous Substances Data Bank (HSDB)

代谢

甲基苯丙胺和苯丙胺阳性检测结果在生物样本中的解释对临床和法医毒理学构成了挑战，原因有几个。必须考虑到尿液样本的pH值和稀释的影响，以及关于合法和非法来源的知识。除了可能合法开具的苯丙胺处方外，许多物质在体内代谢为甲基苯丙胺或苯丙胺：安非他明、苯甲非他明、克罗苯甲非他明、脱氧苯丙胺、二甲基安非他明、乙基安非他明、法莫非他明、芬那明、芬乙茶碱、芬普罗非他明、呋芬非他明、美芬非他明、美索卡宾和普瑞尼胺。特别是对甲基苯丙胺和苯丙胺可能来源的了解变得非常重要，以防止对周围环境的误解并证明非法滥用药物。在这篇综述中，描述了潜在的precursor compounds（前体化合物），包括它们的医疗用途和主要临床效果以及它们的代谢概况，以及一些帮助识别来源的线索。

The interpretation of methamphetamine and amphetamine positive test results in biological samples is a challenge to clinical and forensic toxicology for several reasons. The effects of pH and dilution of urine samples and the knowledge about legitimate and illicit sources have to be taken into account. Besides a potentially legal prescription of amphetamines, many substances metabolize to methamphetamine or amphetamine in the body: amphetaminil, benzphetamine, clobenzorex, deprenyl, dimethylamphetamine, ethylamphetamine, famprofazone, fencamine, fenethylline, fenproporex, furfenorex, mefenorex, mesocarb, and prenylamine. Especially the knowledge of potential origins of methamphetamine and amphetamine turns out to be very important to prevent a misinterpretation of the surrounding circumstances and to prove illegal drug abuse. In this review, potential precursor compounds are described, including their medical use and major clinical effects and their metabolic profiles, as well as some clues which help to identify the sources.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用： Fenetylline 是一种 I 类管制物质，也是一种中枢神经系统兴奋剂。人类暴露和毒性： Fenetylline 的效果与amphetamine（安非他命）相似。在小到中等剂量下，amphetamine会导致心率、体温、呼吸和血压升高。此外，使用者最初会经历支气管血管扩张、额外能量和食欲抑制。然而，长期使用amphetamine可能会有多种副作用，包括但不限于极度抑郁、乏力、睡眠剥夺、心脏和血管毒性以及营养不良。据报道，在连续使用Fenetylline盐酸后，有三例中央视网膜静脉阻塞出血的情况。在一例中，停药和激光治疗后，出血、水肿和静脉充血明显改善。动物研究：无信息可用。

IDENTIFICATION AND USE: Fenetylline is a Schedule I Controlled Substance and a central nervous system stimulant. HUMAN EXPOSURE AND TOXICITY: The effects of fenetylline are similar to those of amphetamine. In small to moderate doses, amphetamine causes elevations in heart rate, body temperature, respiration, and blood pressure. In addition, a user initially experiences a dilation of bronchial vessels, extra energy, and appetite suppression. Over the long-term, however, amphetamine use can have a number of side effects, including, but not limited to, extreme depression, lethargy, sleep deprivation, heart and blood vessel toxicity, and malnutrition. There have been three reported cases of hemorrhagic central retina vein occlusion following continuous use of fenetylline hydrochloride. The hemorrhage, the edema and the engorged veins showed marked improvement after discontinuing the drug and laser supplement in one case. ANIMAL STUDIES: No information available.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中和。如果患者停止呼吸，请开始人工呼吸，最好使用需求阀复苏器、球囊阀面罩设备或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果发生呕吐，让患者前倾或将其置于左侧（如果可能的话，头部向下）以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗帮助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，辅助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……。监测休克，如有必要，进行治疗……。预防癫痫发作，如有必要，进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的干呕反射且不流口水，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于昏迷、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W TKO /SRP: "保持开放"，最低流速/。如果出现低血容量的迹象，使用0.9%的生理盐水（NS）或乳酸钠林格氏液（LR）。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。使用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。/毒物A和B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

紧急和支持性措施。1. 保持呼吸道通畅，必要时协助通气。2. 如有激动、惊厥、昏迷和发热，进行治疗。3. 持续监测体温、其他生命体征和心电图至少6小时。/安非他命/

Emergency and supportive measures. 1. Maintain an open airway and assist ventilation if necessary. 2. Treat agitation, seizures, coma, and hyperthermia if they occur. 3. Continuously monitor the temperature, other vital signs, and the ECG for a minimum of 6 hours. /Amphetamines/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

芬乙茶碱及其代谢物安非他命的气相色谱N-FID检测限在纳克级别。在给予六名志愿者不同剂量的Captagon后，测量了尿液中这些物质的消除情况。尿液中芬乙茶碱和安非他命的浓度可以在一定程度上限制地估计出为了法医目的摄入Captagon的时间和数量。

The limit for detecting fenethylline and its metabolite amphetamine in GLC with N-FID is in the range of nanograms. The elimination of these substances in urine was measured after giving different quantities of Captagon to six volunteers. The concentrations of fenethylline and amphetamine in urine allow to estimate with some limitations time and amount of consuming Captagon for forensic purposes

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

本研究描述了fenethylline（FNT）及其代谢物在大鼠毛发中的掺入趋势，以及通过气相色谱-质谱联用技术结合选择离子监测来区分FNT使用和安非他明（AP）使用的方法。在给有色毛大鼠腹膜内给药FNT（5 mg/kg/天，10天，n = 3）后，比较了大鼠新生毛发中FNT及其代谢物AP在4周内的浓度与药物在大鼠血浆中的浓度-时间曲线下面积（AUCs）。FNT和AP的毛发浓度分别为52 +/- 1.4和4.9 +/- 0.6 ng/mg，而血浆AUCs分别为55.9 +/- 23.1和22.3 +/- 4.9微克·分钟/mL。FNT和AP的毛发浓度与AUCs的比值分别为0.93和0.22。这表明FNT倾向于从血液中高度掺入毛发。该方法应用于口服多剂量FNT（50 mg/天，3天，n = 5）或单剂量FNT（50 mg/天，1天，n = 1）的人的头皮毛发中代谢物的测定。口服FNT 3天的人在近端1厘米毛发段中检测到的FNT和AP分别为0.51 +/- 0.23和0.35 +/- 0.12 ng/mg，而在单剂量样本中分别为0.25和0.11 ng/mg。此外，尽管FNT相对于AP迅速从尿液中消失，但在除了一个样本之外的所有人类毛发样本中，FNT的浓度是AP的1.2至2.7倍。因此，得出结论，毛发是揭示FNT药物历史和区分FNT使用与AP滥用的良好样本。

The incorporation tendency of fenethylline (FNT) and its metabolite into rat hair and the discrimination between FNT use and amphetamine (AP) use by hair analysis using gas chromatography-mass spectrometry with selected ion monitoring are described. After the intraperitoneal administrations of FNT to pigmented hairy rats (5 mg/kg/day, 10 days, n = 3), concentrations of FNT and its metabolite, AP, in the rat hair newly grown over 4 weeks were compared with area under the concentration versus time curves (AUCs) of the drugs in the rat plasma. The hair concentrations of FNT and AP were 52 +/- 1.4 and 4.9 +/- 0.6 ng/mg, whereas those of plasma AUCs were 55.9 +/- 23.1 and 22.3 +/- 4.9 micrograms.min/mL, respectively. The ratios of the hair concentrations to the AUCs of FNT and AP were 0.93 and 0.22, respectively. This suggests that FNT tends to be highly incorporated into hair from blood. The analytical method was applied to the determination of the metabolites in scalp hair of humans who were given FNT orally in multiple doses (50 mg/day, 3 days, n = 5) or in a single dose (50 mg/day, 1 day, n = 1). FNT and AP were detected at 0.51 +/- 0.23 and 0.35 +/- 0.12 ng/mg, respectively, in the proximal 1-cm hair segments from subjects given FNT orally for 3 days and 0.25 and 0.11 ng/mg, respectively, in the single-dose sample. In addition, it was found that the concentrations of FNT were 1.2 to 2.7 times greater than those of AP in the human hair samples, except for one sample, although FNT rapidly disappeared from the urine compared with AP. It was concluded that hair would be a good specimen for disclosure of drug history of FNT and for discrimination between FNT use and AP abuse.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  芬乙茶碱 在 sodium hydroxide 作用下， 以 乙醇 为溶剂， 反应 18.0h， 以27%的产率得到5-Methylamino-3-<2-(1-methyl-2-phenylethylamino)-ethyl>-3H-imidazol-4-carbonsaeure-methylamid
  参考文献：
  名称：

  关于芬太林的化学稳定性

  摘要：

  在研究苯乙胺衍生物苯乙胺 (1) 在所用反应条件 (100 °C; pH 12–14) 下的化学稳定性时，观察到分子黄嘌呤部分的裂解反应，如咖啡因 2, 3) 所见. 苯丙胺残留物没有分离。

  DOI：

  10.1002/ardp.198700045
• 作为产物：
  描述：

  5-(1,3-Dimethylureido)-3-[2-(1-methyl-2-phenylethylamino)-ethyl]-3H-imidazol-4-carbonsaeuremethylester 以 二氯甲烷 为溶剂， 反应 1.5h， 生成 芬乙茶碱
  参考文献：
  名称：

  关于芬太林的化学稳定性

  摘要：

  在研究苯乙胺衍生物苯乙胺 (1) 在所用反应条件 (100 °C; pH 12–14) 下的化学稳定性时，观察到分子黄嘌呤部分的裂解反应，如咖啡因 2, 3) 所见. 苯丙胺残留物没有分离。

  DOI：

  10.1002/ardp.198700045

文献信息

• Novel Bicyclic Pyridinones
  申请人：Pettersson Martin Youngjin

  公开号：US20120252758A1

  公开（公告）日：2012-10-04

  Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I as defined herein. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  所述化合物及其药用可接受的盐被披露，其中所述化合物具有如本文所定义的Formula I的结构。相应的药物组合物、治疗方法、合成方法和中间体也被披露。
• [EN] PRODRUGS OF SECONDARY AMINE COMPOUNDS<br/>[FR] PROMÉDICAMENTS DE COMPOSÉS AMINE SECONDAIRES
  申请人：ALKERMES PHARMA IRELAND LTD

  公开号：WO2013088255A1

  公开（公告）日：2013-06-20

  The present invention relates to compounds of Formula (I).

  本发明涉及式(I)的化合物。
• AMINO-HETEROCYCLIC COMPOUNDS
  申请人：Claffey Michelle M.

  公开号：US20100190771A1

  公开（公告）日：2010-07-29

  The invention provides PDE9-inhibiting compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , A, and n are as defined herein. Pharmaceutical compositions containing the compounds of Formula I, and uses thereof in treating neurodegenerative and cognitive disorders, such as Alzheimer's disease and schizophrenia, are also provided.

  这项发明提供了式（I）中的PDE9抑制化合物，以及其药学上可接受的盐，其中R1、R2、R3、A和n的定义如本文所述。还提供了含有式I中化合物的药物组合物，并且提供了在治疗神经退行性和认知障碍疾病，如阿尔茨海默病和精神分裂症中的用途。
• Sulfur(VI) fluoride compounds and methods for the preparation thereof
  申请人：The Scripps Research Institute

  公开号：US10117840B2

  公开（公告）日：2018-11-06

  This application describes a compound represented by Formula (I): (I) wherein: Y is a biologically active organic core group comprising one or more of an aryl group, a heteroaryl aryl group, a nonaromatic hydrocarbyl group, and a nonaromatic heterocyclic group, to which Z is covalently bonded; n is 1, 2, 3, 4 or 5; m is 1 or 2; Z is O, NR, or N; X1 is a covalent bond or —CH2CH2—, X2 is O or NR; and R comprises H or a substituted or unsubstituted group selected from an aryl group, a heteroaryl aryl group, a nonaromatic hydrocarbyl group, and a nonaromatic heterocyclic group. Methods of preparing the compounds, methods of using the compounds, and pharmaceutical compositions comprising the compounds are described as well.

  该应用描述了由式(I)表示的化合物：(I)其中：Y是一个生物活性有机核心基团，包括芳基、杂芳基、非芳香烃基和非芳香杂环基中的一个或多个，其中Z与之以共价键结合；n为1、2、3、4或5；m为1或2；Z为O、NR或N；X1为共价键或—CH2CH2—，X2为O或NR；R包括H或从芳基、杂芳基、非芳香烃基和非芳香杂环基中选择的取代或未取代基团。还描述了制备这些化合物的方法、使用这些化合物的方法以及包含这些化合物的药物组合物。
• [EN] PYRAZOLO [4, 3-D] PYRIMIDINES USEFUL AS KINASE INHIBITORS<br/>[FR] PYRAZOLO[4,3-D]PYRIMIDINES UTILES EN TANT QU'INHIBITEURS DE KINASES
  申请人：ORIGENIS GMBH

  公开号：WO2012143144A1

  公开（公告）日：2012-10-26

  The present invention relates to novel compounds of formula (I) that are capable of inhibiting one or more kinases, especially SYK (Spleen Tyrosine Kinase), LRRK2 (Leucine-rich repeat kinase 2) and/or MYLK (Myosin light chain kinase) or mutants thereof. The compounds find applications in the treatment of a variety of diseases. These diseases include autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies, asthma, alzheimer's disease, parkinson's disease, skin disorders, eye diseases, infectious diseases and hormone-related diseases.

  本发明涉及一种能够抑制一个或多个激酶，特别是SYK（脾酪氨酸激酶）、LRRK2（富含亮氨酸重复的激酶2）和/或MYLK（肌球蛋白轻链激酶）或其突变体的化合物的新颖化合物（I）的公式。这些化合物在治疗各种疾病中发挥作用。这些疾病包括自身免疫疾病、炎症性疾病、骨疾病、代谢性疾病、神经和神经退行性疾病、癌症、心血管疾病、过敏、哮喘、阿尔茨海默病、帕金森病、皮肤疾病、眼部疾病、传染病和与激素相关的疾病。