阿的芬宁 | 64-95-9

• 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: 阿的芬宁
• 中文别名: 解痉素；屈阿生丁
• 英文名称: adiphenine
• 英文别名: Adiphenin；Diphenyl-essigsaeure-(2-diaethylamino-aethylester)；2-(diethylamino)ethyl 2,2-diphenylacetate
• CAS: 64-95-9
• 化学式: C₂₀H₂₅NO₂
• 分子量: 311.424
• InChiKey: JGOAIQNSOGZNBX-UHFFFAOYSA-N

物化性质

• 熔点：
  113.5°C
• 沸点：
  451.46°C (rough estimate)
• 密度：
  1.0899 (rough estimate)
• 溶解度：
  In water, 1.89X10+1 mg/L at 25 °C (est)
• 蒸汽压力：
  1.56X10-6 mm Hg at 25 °C (est)
• 分解：
  When heated to decomposition it emits toxic fumes of NOx.
• 保留指数：
  2210;2192;2193;2186;2220;2250

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  23
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  3

ADMET

代谢

单次给药(14C)阿地芬宁或(3H)阿地芬宁后，从大鼠尿液中分离出的主要代谢物通过色谱和核磁共振光谱法以及与化学合成的真实参考化合物进行比较而得以鉴定。阿地芬宁通过酯键的水解被广泛代谢为二乙氨基乙醇、二苯乙酸、二苯乙酸葡萄糖苷酸，以及少量相应的甘氨酸和谷氨酰胺结合物。

Major metabolites isolated from rat urine after administration of a single dose of (14C)adiphenine or (3H)adiphenine were identified by chromatography and n.m.r. spectrometry, and by comparison with authentic reference compounds chemically synthesized. Adiphenine was extensively metabolized by hydrolysis of the ester bond into diethylaminoethanol, diphenylacetic acid, diphenylacetic acid glucuronide and, in small quantities, the corresponding glycine and glutamine conjugates.

来源:Hazardous Substances Data Bank (HSDB)

代谢

14C标记在两个位置的阿片芬太尼在大鼠和小鼠静脉给药后的分布情况已经进行了研究...在初步代谢研究中，已经鉴定出三种主要代谢物：二苯乙酸、二乙基乙醇胺和二苯乙酸葡萄糖苷酸。

The disposition of adiphenine labelled with 14C in two positions has been investigated in rats and mice after iv administration ... In preliminary metabolic studies, three major metabolites have been identified: diphenylacetic acid, diethylethanolamine and a diphenylacetic acid glucuronide.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

尽管这种药物相对无毒，但不应与吗啡连续使用；这两种药物的组合似乎会导致焦虑和心动过速。/盐酸阿尼芬/

ALTHOUGH THE DRUG IS RELATIVELY NONTOXIC, IT SHOULD NOT BE USED IN CLOSE SEQUENCE WITH MORPHINE; THE COMBINATION APPEARS TO CAUSE APPREHENSION & TACHYCARDIA. /ADIPHENINE HYDROCHLORIDE/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

痉挛素（阿地芬尼盐酸）和托品碱通过肌肉注射给予白化病大鼠，这些大鼠通过胃管接受了硫酸阿那巴碱的剂量，分别为346、519和692毫克/千克。在阿地芬尼盐酸治疗下，硫酸阿那巴碱的LD50（致死剂量50%）确定为570毫克/千克，而在托品碱治疗下为403毫克/千克。在阿地芬尼盐酸和托品碱治疗下确定的LD16（致死剂量16%）和LD84（致死剂量84%）值分别为460和712毫克/千克以及288和498毫克/千克。通过肌肉注射20毫克/千克的阿地芬尼盐酸和托品碱，分别将硫酸阿那巴碱的LD50降低了271%和191%。/阿地芬尼盐酸/

Spasmolytin (adiphenine hydrochloride) and tropicine were administered im to albino rats poisoned with anabasine sulfate doses of 346, 519, and 692 mg/kg administered through gastric tube. The LD50 of anabasine sulfate, determined for treatment with adiphenine hydrochloride, was 570 mg/kg, and 403 mg/kg for treatment with tropacine. The LD16 and LD84 values determined for treatment with adiphenine hydrochloride and tropacine were 460 and 712 mg/kg and 288 and 498 mg/kg, respectively. Adiphenine hydrochloride and tropacine, administered im in 20 mg/kg doses, reduced the LD50 of anabasine sulfate by 271% and 191%, respectively./Adiphenine hydrochloride/

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。如果患者呕吐，让患者向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：对于无意识、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 /SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸林格氏液。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……。 /Poisons A and 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 /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's 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)

吸收、分配和排泄

这项研究描述了一种双标记药物阿地芬尼在大鼠大脑中的行为。宏观放射自显影显示了注射后不同时间的大脑图像。在大脑水平上识别出一些组织代谢物，并比较了通过血脑屏障的药物与氚水。获得的数据为血脑分布和大脑水平的代谢提供了非常有趣的指示。不同的高压液相色谱技术、宏观和放射自显影技术允许可视化药物如何固定在大脑结构上，从而提供了其作用机制的指示。

This study describes the behavior of a dual labelled drug, adiphenine, in the rat brain. Macroautoradiographies show images of the brain at different times after injection. Some of the tissue metabolites are identified at the brain level and the passage of the blood brain barrier is compared with tritiated water. The obtained data give very interesting indications on the blood brain distribution and on the metabolism at the brain level. Different techniques of high pressure liquid chromatography, macro- and histoautoradiographies allowed /visualization of/ how the drug is fixed on cerebral structures, giving indications on its mechanism of action.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

14C 标记的两个位置的阿地平在静脉注射后在大鼠和小鼠体内的分布情况已经进行了研究，并且与[14C]二乙基乙醇胺 HCl 和 [14C]二苯乙酸进行了比较。血液中的放射性以双相方式下降。胆汁消除取决于所给予的14C标记化合物的种类：二乙基乙醇胺部分少于5%的剂量，羧酸部分为100%的剂量。在大鼠胆汁中出现的放射性中，不到1%与未改变的阿地平有关。...在给药后不久，大脑对[14C]阿地平的摄取是血液的15倍。放射性也出现在垂体、肾上腺和黑色素色素中，其浓度是血液中发现的浓度的30倍。

The disposition of adiphenine labelled with 14C in two positions has been investigated in rats and mice after iv administration, and has been compared with that of the [14C]diethylethanolamine HCl and of the [14C]diphenylacetic acid. Radioactivity in the blood declined in a biphasic manner. Biliary elimination depended upon the 14C-labelled compound administered: less than 5% dose for the diethylethanolamine moiety, 100% dose for the carboxylic moiety. Of the radioactivity appearing in rat bile, less than 1% is associated with unchanged adiphenine. ... Uptake by the brain of [14C]adiphenine shortly after dosing is 15 times greater than that of blood. Radioactivity is also found in the hypophysis, the adrenals and melanoid pigments, with a concentration up to 30 times greater than that found in the blood.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  阿的芬宁 在 potassium hydroxide 作用下， 以 甲醇 为溶剂， 以92%的产率得到二苯基羟基乙酸
  参考文献：
  名称：

  蓝光辐照增强了芳基重氮乙酸酯与硼酸的室温偶联。

  摘要：

  据报道可见光促进的光化学方案用于芳基重氮乙酸酯与硼酸的偶联。与没有光照的相同方案相比，这种光化学反应显示出极大的增强。除少数情况外，在黑暗（热过程）中的室温耦合通常不起作用。如果这样做的话，很可能还涉及到游离卡宾作为关键中间体。可替代地，光化学反应显示出广泛的范围，可以在空气中进行并且耐受各种各样的官能团。反应进化监测，DFT计算和控制实验已用于评估这种复杂机制的主要方面。具有生物活性的分子阿迪芬，苯那西嗪和阿普生已经被制备为合成应用的实例。

  DOI：

  10.1002/chem.201905812
• 作为产物：
  描述：

  苯乙酸甲酯 在 4-乙酰氨基苯磺酰叠氮 、 sodium carbonate 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 potassium hydroxide 作用下， 以 甲烷磺酸 、 二氯甲烷 、 1,2-二氯乙烷 、 乙腈 为溶剂， 反应 24.0h， 生成 阿的芬宁
  参考文献：
  名称：

  蓝光辐照增强了芳基重氮乙酸酯与硼酸的室温偶联。

  摘要：

  据报道可见光促进的光化学方案用于芳基重氮乙酸酯与硼酸的偶联。与没有光照的相同方案相比，这种光化学反应显示出极大的增强。除少数情况外，在黑暗（热过程）中的室温耦合通常不起作用。如果这样做的话，很可能还涉及到游离卡宾作为关键中间体。可替代地，光化学反应显示出广泛的范围，可以在空气中进行并且耐受各种各样的官能团。反应进化监测，DFT计算和控制实验已用于评估这种复杂机制的主要方面。具有生物活性的分子阿迪芬，苯那西嗪和阿普生已经被制备为合成应用的实例。

  DOI：

  10.1002/chem.201905812

文献信息

• Protecting-group-free synthesis of hydroxyesters from amino alcohols
  作者：Guillaume Reynard、Eve-Marline Joseph-Valcin、Hélène Lebel

  DOI：10.1039/d0cc03242e

  日期：——

  The synthesis of hydroxyesters from carboxylic acids and unprotected amino alcohols in both continuous flow and batch processes is reported. The formation of a transient diazonium species with a dinitrite reagent is key in this transformation. The reaction conditions are compatible with a variety of functional groups.

  报道了在连续流动和间歇过程中由羧酸和未保护的氨基醇合成羟基酯的方法。用亚硝酸盐试剂形成瞬态重氮物质是该转化的关键。反应条件与各种官能团相容。
• NOVEL BRONCHODILATING DIAZAHETEROARYLS
  申请人：Johansson Martin

  公开号：US20120040942A1

  公开（公告）日：2012-02-16

  The invention relates to novel compounds having the general formula (I), and which compounds are useful to treat a disorder or disease characterized by bronchoconstriction, e.g. COPD and asthma.

  这项发明涉及具有通式（I）的新化合物，这些化合物可用于治疗由支气管痉挛引起的疾病或疾病，例如慢性阻塞性肺疾病（COPD）和哮喘。
• Molecular modification of anticholinergics as probes for muscarinic receptors. 1. Amino esters of .alpha.-substituted phenylacetic acid and related analogs
  作者：Matthias C. Lu、Walley E. Wung、Lisa B. Shih、Soledad Callejas、James E. Gearien、Emmanuel B. Thompson

  DOI：10.1021/jm00385a008

  日期：1987.2

  Two series of compounds having the general structure of C6H5CRR'COOCH2CH2NEt2 were synthesized and examined for their antispasmodic activities. These compounds were selected as structural probes for exploring the nature of muscarinic cholinergic receptor binding sites that interact with atropine-like anticholinergics. These studies indicate a rather strict size limitation for the hydrophobic region

  合成了具有C6H5CRR'COOCH2CH2NEt2的一般结构的两个系列的化合物，并研究了它们的解痉活性。选择这些化合物作为结构探针，以探索与阿托品样抗胆碱能药物相互作用的毒蕈碱胆碱能受体结合位点的性质。这些研究表明，对于受体的疏水区域存在相当严格的尺寸限制，并建议分子内氢键作为解释观察到的立体选择性的可能手段。
• [EN] NOVEL BRONCHODILATING DIAZAHETEROARYLS<br/>[FR] NOUVEAUX DIAZAHÉTÉROARYLES BRONCHODILATATEURS
  申请人：RESPIRATORIUS AB

  公开号：WO2010097410A1

  公开（公告）日：2010-09-02

  The invention relates to novel compounds having the general formula (I), and which compounds are useful to treat a disorder or disease characterized by bronchoconstriction, e.g. COPD and asthma.

  这项发明涉及具有通式（I）的新化合物，这些化合物可用于治疗由支气管痉挛引起的疾病或疾病，例如慢性阻塞性肺疾病（COPD）和哮喘。
• Ruthenium-catalyzed umpolung carboxylation of hydrazones with CO₂
  作者：Si-Shun Yan、Lei Zhu、Jian-Heng Ye、Zhen Zhang、He Huang、Huiying Zeng、Chao-Jun Li、Yu Lan、Da-Gang Yu

  DOI：10.1039/c8sc01299g

  日期：——

  The first ruthenium-catalyzed umpolung carboxylation of hydrazones with CO2 to generate important aryl acetic acids is reported. Besides aldehyde hydrazones, a variety of ketone hydrazones, which have not been successfully applied in previous umpolung reactions with other reactive electrophiles, also show high reactivity and selectivity under mild conditions. Moreover, this operationally simple protocol

  报道了第一次钌催化腙与 CO 2的 umpolung 羧化生成重要的芳基乙酸。除醛腙外，多种酮腙在与其他反应性亲电试剂的超微球反应中尚未成功应用，在温和条件下也表现出高反应性和选择性。此外，这种操作简单的协议具有良好的官能团耐受性，易于扩展，并提供了重要结构的简单推导，包括生物活性联苯乙酸和阿地芬。计算研究表明，这种 umpolung 反应通过生成 Ru-nitrenoid 然后与 CO 2协同 [4 + 2] 环加成反应进行。

表征谱图