3,4-二氯-N-(2-二甲氨基环己基)-N-甲基苯甲酰胺 | 121348-98-9

• 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: 3,4-二氯-N-(2-二甲氨基环己基)-N-甲基苯甲酰胺
• 英文名称: 3,4-dichloro-N-(2-(dimethylamino)cyclohexyl)-N-methylbenzamide
• 英文别名: U-47700；3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide
• CAS: 121348-98-9
• 化学式: C₁₆H₂₂Cl₂N₂O
• 分子量: 329.269
• InChiKey: JGPNMZWFVRQNGU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  23.6
• 氢给体数：
  0
• 氢受体数：
  2

ADMET

代谢

最近，涉及新型阿片类药物的不良事件数量持续增加，包括死亡，为法医和医疗界带来了额外的持续挑战。确定新兴新型阿片类药物可能会很困难，由于检测窗口和未知的代谢概况而变得复杂。在这项研究中，使用了人肝微粒体来生成U-47700和U-49900的体外代谢概况。生成的代谢物通过SCIEX TripleTOF 5600+四级飞行时间质谱仪进行分析，所得数据文件使用MetabolitePilot进行处理。通过分析在U-47700或U-49900过量服用案例中收集到的真实人尿样本来验证了确定的代谢物。总共，U-47700在尿样中确定了四个代谢物，而U-49900确定了五个代谢物。确定了N-Desmethyl-U-47700为U-47700的主要代谢物。亲本U-47700在所有尿样中都被识别出来。在获得标准参考材料后，首次在本次研究中确认了N-Desmethyl-U-47700和N,N-didesmethyl-U-47700的结构。确定了N-Desethyl-U-49900为U-49900微粒体培养后的主要代谢物，而N,N-didesethyl-N-desmethyl-U-49900在尿样中含量最丰富。在U-47700和U-49900之间发现了相似的代谢转化，产生了一个共同的代谢物和同分异构体物种。在涉及U-47700或U-49900的案件中，应考虑这些现象。这是首次使用人肝微粒体绘制U-47700和U-49900的代谢概况的研究，也是首次报告涉及U-49900和案例分析的案件文献。

Recently, the number of adverse events, including death, involving novel opioids has continued to increase, providing additional and sustained challenges for forensic and medical communities. Identification of emerging novel opioids can be challenging, compounded by detection windows and unknown metabolic profiles. In this study, human liver microsomes were used for the generation of in vitro metabolic profiles of U-47700 and U-49900. Generated metabolites were analyzed via a SCIEX TripleTOF 5600+ quadrupole time-of-flight mass spectrometer and resulting data files were processing using MetabolitePilot. Characterized metabolites were verified in vivo by analysis of authentic human urine specimens collected after analytically confirmed cases of overdose involving U-47700 or U-49900. In total, four metabolites were identified and present in urine specimens for U-47700, and five metabolites for U-49900. N-Desmethyl-U-47700 was determined to be the primary metabolite of U-47700. Parent U-47700 was identified in all urine specimens. N-Desmethyl-U-47700 and N,N-didesmethyl-U-47700 were structurally confirmed for the first time during this study following acquisition of standard reference material. N-Desethyl-U-49900 was determined to be the primary metabolite of U-49900 following microsomal incubations, while N,N-didesethyl-N-desmethyl-U-49900 was the most abundant in a urine specimen. Similarities in metabolic transformation were identified between U-47700 and U-49900, resulting in a common metabolite and isomeric species. These phenomena should be considered in cases involving U-47700 or U-49900. This study is the first to map the metabolic profiles of U-47700 and U-49900 using human liver microsomes, as well as the first to report any literature involving U-49900 and analysis of case specimens.

来源:Hazardous Substances Data Bank (HSDB)

代谢

一名23岁的女性在使用“U4”通过鼻吸和注射后前来就诊。... 使用质谱分析法对尿液和血清样本进行了分析，确认了3,4-二氯-N-[(1R,2R)-2-(二甲氨基)环己基]-N-甲基苯甲酰胺或U-47700。样本进一步分析阐明了代谢特异性。随后测量了药物及其代谢物在血清和尿液中的浓度。U-47700的母化合物在血清和尿液中的浓度分别为394 ng/mL和228 ng/mL。在尿液中检测到的代谢物包括去甲基（1964 ng/mL）、双去甲基（618 ng/mL）、去甲基羟基（447 ng/mL）和双去甲基羟基形式（247 ng/mL）的U-47700。...

A 23-year-old female presented after using "U4" by nasal insufflation and injection. ... Urine and serum samples were analyzed using mass spectrometry, confirming 3,4-dichloro-N-[(1R,2R)-2-(dimethylamino)cyclohexyl]-N-methylbenzamide or U-47700. The sample was further analyzed elucidating metabolism specifics. Drug and metabolite concentrations were subsequently measured in both serum and urine. The parent compound of U-47700 was detected at 394 ng/mL and 228 ng/mL in serum and urine, respectively. Metabolites detected in appreciable amounts included the desmethyl (1964 ng/mL in urine), bisdesmethyl (618 ng/mL), desmethyl hydroxy (447 ng/mL), and bisdesmethyl hydroxy forms (247 ng/mL) of U-47700. ...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：U-47700 是一种白色或浅粉色粉末。它是一种第一类受控物质。人体研究：有报道称U-47700作为一种新型精神活性物质被滥用，导致致命中毒的情况。也有非致命中毒的案例。在一个案例中，一名男性被发现皮肤发青，呼吸困难，他被插管并送往医院，在支持性治疗下恢复良好。一名女性出现焦虑、震颤和嗜睡，被收治观察。动物研究：U-47700在体外结合和在体外功能性活动方面，对μ、κ和δ阿片受体的报道。受体结合研究是使用转染了中国仓鼠卵巢（CHO）细胞的人δ阿片受体（DOR）和κ阿片受体（KOR），以及转染了CHO细胞的大鼠μ阿片受体（MOR）进行的。

IDENTIFICATION AND USE: U-47700 is a white or light pink powder. It is is a Schedule I controlled substance. HUMAN STUDIES: There are case reports of a fatal intoxication involving U-47700 abused as a new psychotropic substance. There are also cases of nonfatal intoxication. In one case, a man was found down with cyanosis and agonal respirations. He was intubated and taken to hospital where he recovered well with supportive care. A woman presented with anxiety, tremors and drowsiness and was admitted for observation. ANIMAL STUDIES: In vitro binding and in vitro functional activity reported for U-47700 at mu, kappa, and delta opioid receptors. Receptor binding studies were conducted using human delta opioid receptors (DOR) and kappa opioid receptors (KOR) transfected into Chinese hamster ovary (CHO) cells, and rat mu opioid receptor (MOR) transfected into CHO cells.

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毒物清除。如果患者停止呼吸，开始人工呼吸，最好使用需求阀复苏器、袋阀面罩装置或口袋面罩，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，协助通气。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……。预期癫痫发作，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，如果患者能够吞咽、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"，最低流量/。如果出现低血容量的迹象，使用0.9%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……。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

我们报告了一位患者，在娱乐性使用一种新型合成阿片类药物U-47700后，出现了呼吸衰竭和意识水平下降的情况。急救人员给予的一剂纳洛酮完全逆转了他的阿片类药物中毒。

... We report a patient who suffered respiratory failure and depressed level of consciousness after recreationally using a novel synthetic opioid labeled U-47700. A single dose of naloxone administered by paramedics completely reversed his opioid poisoning. ...

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在这份案例报告中，我们展示了对一起主要归因于3,4-二氯-N-[2-(二甲氨基)环己基]-N-甲基苯甲酰胺（U-47700）的死亡案例中，尸体死后浓度分布的评估……通过气相色谱-质谱（GC-MS）的碱性药物筛选测试，最初在外周血液中识别出U-47700，此前进行了固相萃取。随后通过液-液萃取后的GC-MS特定离子监测分析确认并量化了U-47700。外周血液中U-47700的浓度为190 ng/mL，而中心血液浓度为340 ng/mL。肝脏浓度为1,700 ng/g，玻璃体为170 ng/mL，尿液为360 ng/mL，胃中仅含有微量（<1 mg）。

In this case report, we present an evaluation of the distribution of postmortem concentrations of 3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) in a fatality attributed principally to the drug. ... Toxicology screening tests in peripheral blood initially identified U-47700 using an alkaline drug screen with gas chromatography-mass spectrometry (GC-MS) following solid-phase extraction. It was subsequently confirmed and quantitated by GC-MS-specific ion monitoring analysis following liquid-liquid extraction. The U-47700 peripheral blood concentration was quantitated at 190 ng/mL compared to the central blood concentration of 340 ng/mL. The liver concentration was 1,700 ng/g, the vitreous was 170 ng/mL, the urine was 360 ng/mL and the gastric contained only a trace amount (<1 mg). ...

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  3,4-二氯-N-(2-二甲氨基环己基)-N-甲基苯甲酰胺 在 1-氯乙基氯甲酸酯 、 甲醇 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 6.0h， 生成 N-methyl-N-[2-(N'-methylamino)cyclohexyl]-3,4-dichlorobenzamide
  参考文献：
  名称：

  IMMUNOASSAY

  摘要：

  抗体、免疫测定方法和试剂盒用于检测和测定3,4-二氯-N-[2-(二甲氨基)环己基]-N-甲基苯甲酰胺和3,4-二氯-N-[2-(甲基氨基)环己基]-N-甲基苯甲酰胺，以及相关的免疫原被描述。

  公开号：

  US20180237380A1
• 作为产物：
  描述：

  1S,2S-N,N,N'-三甲基-1,2-环己二胺 、 3,4-二氯苯甲酰氯 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 生成 3,4-二氯-N-(2-二甲氨基环己基)-N-甲基苯甲酰胺
  参考文献：
  名称：

  IMMUNOASSAY

  摘要：

  抗体、免疫测定方法和试剂盒用于检测和测定3,4-二氯-N-[2-(二甲氨基)环己基]-N-甲基苯甲酰胺和3,4-二氯-N-[2-(甲基氨基)环己基]-N-甲基苯甲酰胺，以及相关的免疫原被描述。

  公开号：

  US20180237380A1

文献信息

• U-47700 IMMUNOASSAY
  申请人：Randox Laboratories Ltd.

  公开号：EP3366706A1

  公开（公告）日：2018-08-29

  Antibodies, immunoassay methods and kits for the detection and determination of 3,4,-dichloro-N-[2-(dimethylamino)cylohexyl]-N-methylbenzamide and 3,4,-dichloro-N-[2-(methylamino)cylohexyl]-N-methylbenzamide, as well as the precursory immunogens, are described.

  描述了用于检测和测定 3,4,-二氯-N-[2-（二甲基氨基）环己基]-N-甲基苯甲酰胺和 3,4,-二氯-N-[2-（甲基氨基）环己基]-N-甲基苯甲酰胺以及前体免疫原的抗体、免疫测定方法和试剂盒。
• U-47700 immunoassay
  申请人：Randox Laboratories Ltd.

  公开号：US10815192B2

  公开（公告）日：2020-10-27

  Antibodies, immunoassay methods and kits for the detection and determination of 3,4,-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide and 3,4,-dichloro-N-[2-(methylamino)cyclohexyl]-N-methylbenzamide, as well as the precursory immunogens, are described.

  描述了用于检测和测定 3,4,-二氯-N-[2-（二甲基氨基）环己基]-N-甲基苯甲酰胺和 3,4,-二氯-N-[2-（甲基氨基）环己基]-N-甲基苯甲酰胺以及前体免疫原的抗体、免疫测定方法和试剂盒。
• US4098904A
  申请人：——

  公开号：US4098904A

  公开（公告）日：1978-07-04
• US4148914A
  申请人：——

  公开号：US4148914A

  公开（公告）日：1979-04-10
• US4153717A
  申请人：——

  公开号：US4153717A

  公开（公告）日：1979-05-08