四氢唑林 | 84-22-0

• 物质功能分类: 原料药 - 神经系统用药 - 拟胆碱药
• 分子结构分类: 有机化合物 - 苯类化合物 - 四氢化萘
• 中文名称: 四氢唑林
• 中文别名: 四氢唑啉；4,5-二氢-2-(1,2,3,4-四氢-1-萘基)-1H-咪唑；四氢萘咪唑
• 英文名称: tetrahydrozoline
• 英文别名: 2-(1,2,3,4-tetrahydro-1-naphthyl)-2-imidazoline；Tetryzoline；2-(1,2,3,4-tetrahydronaphthalen-1-yl)-4,5-dihydro-1H-imidazole；2-tetralin-1-yl-4,5-dihydro-1H-imidazole；2-(1,2,3,4-tetrahydro-naphthalen-1-yl)-4,5-dihydro-1H-imidazole
• CAS: 84-22-0
• 化学式: C₁₃H₁₆N₂
• 分子量: 200.283
• InChiKey: BYJAVTDNIXVSPW-UHFFFAOYSA-N

物化性质

• 熔点：
  117-119 °C(Solv: heptane (142-82-5); ethanol (64-17-5))
• 沸点：
  393.5±21.0 °C(Predicted)
• 密度：
  1.20±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少许）、DMSO（少许）
• 蒸汽压力：
  6.5X10-7 mm Hg at 25 °C (est)
• 稳定性/保质期：

  Commercial products stored up to 3 yr at room temperature demonstrated no significant degradation.

• 解离常数：
  pKa = 10.17 (est)
• 保留指数：
  1833

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  24.4
• 氢给体数：
  1
• 氢受体数：
  1

ADMET

代谢

没有可用的信息。

No information is available.

来源:DrugBank

毒理性

• 毒性总结

识别和使用：盐酸四氢唑啉是一种咪唑啉衍生物，局部应用于眼部，用于自我药物治疗，以暂时缓解充血、瘙痒和轻微刺激，并控制患有表层角膜血管扩张患者的充血。眼部血管收缩剂在治疗迟发性超敏反应，如接触性皮炎结膜炎方面无效。在 一些眼部诊断程序中可能会使用四氢唑啉的血管收缩效果，但一些临床医生更喜欢使用苯肾上腺素而不是四氢唑啉。人类研究：据报道，儿科患者因意外摄入含有咪唑啉衍生物，包括四氢唑啉的非处方眼药水或鼻喷剂后，发生了需要住院治疗的严重不良事件。从1985年到2012年10月，报告了96起1个月至5岁儿童的意外摄入案例。摄入的药物量从0.6-45毫升不等。虽然未报告死亡案例，但超过一半的案例报告了需要住院治疗的严重不良事件，包括恶心、呕吐、嗜睡、心动过速、呼吸减慢、心动过缓、低血压、高血压、镇静、嗜睡、瞳孔扩大、昏迷、体温过低、流涎和昏迷。动物研究：在狗身上，中毒迹象可能包括呕吐、心动过缓、心律失常、毛细血管充盈时间延长、低血压或高血压、喘息、上呼吸道声音增加、抑郁、虚弱、紧张、过度活跃或颤抖。这些症状出现在暴露后30分钟至4小时内。一般来说，咪唑啉类血管收缩剂暴露可能影响胃肠道、心肺和神经系统。

IDENTIFICATION AND USE: Tetrahydrozoline hydrochloride, an imidazoline derivative, is applied topically to the eye for self-medication to temporarily relieve congestion, itching, and minor irritation, and to control hyperemia in patients with superficial corneal vascularity. Ocular decongestants are ineffective in the treatment of delayed hypersensitivity reactions such as contact dermatoconjunctivitis. The vasoconstrictor effect of tetrahydrozoline may be used during some ocular diagnostic procedures, but some clinicians prefer phenylephrine to tetrahydrozoline for this use. HUMAN STUDIES: Serious adverse events requiring hospitalization have been reported in pediatric patients following accidental ingestion of nonprescription ophthalmic solutions or nasal sprays containing imidazoline derivatives including tetrahydrozoline. Between 1985 and October 2012, 96 cases of accidental ingestion were reported in children 1 month to 5 years of age. The amount of drug ingested ranged from 0.6-45 mL. While no deaths were reported, more than half of these cases reported serious adverse events requiring hospitalization, including nausea, vomiting, lethargy, tachycardia, decreased respiration, bradycardia, hypotension, hypertension, sedation, somnolence, mydriasis, stupor, hypothermia, drooling, and coma. ANIMAL STUDIES: In dogs, signs of intoxication may include vomiting, bradycardia, cardiac arrhythmias, poor capillary refill time, hypotension or hypertension, panting, increased upper respiratory sounds, depression, weakness, nervousness, hyperactivity, or shaking. These signs appear within 30 min to 4 hr postexposure. In general, imidazoline decongestant exposure may affect the GI, cardiopulmonary, and nervous systems.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

背景：我们报告了两例药物促进性侵犯的案例，这些案例表现为中枢神经系统抑制，使受害者容易受到性侵犯，并无法回忆起犯罪事件周围的情况。在每个案例中，四氢唑啉（THZ）被量化。 案例报告：案例1摄入了含有THZ的未知数量的眼药水，并与酒精饮料混合。案例1在据报道遭受性侵犯大约7小时后出现在急诊科（ED），在ED时没有症状。早期来自看到她的人的报告中指出受害者“严重醉酒”。案例2也摄入了含有THZ的未知数量的眼药水，并与酒精饮料混合。案例2在据报道遭受性侵犯大约23小时后没有症状地出现在急诊科。从两个案例中获得的尿液被用气相色谱-质谱法评估THZ浓度。 案例讨论：案例1的尿液乙醇浓度为0.15克%（按体积计），尿THZ浓度为1.481纳克/毫升，摄入后大约7小时。案例2对乙醇呈阴性，但在摄入后23小时尿THZ浓度为108纳克/毫升。很少有案例报告记录了使用THZ促进性侵犯的情况。 结论：我们报告了两例涉及同时饮用酒精饮料的药物促进性侵犯案例，使用了THZ。据我们所知，这是第一篇讨论THZ摄入的药理学以及酒精存在的重要性的论文。

BACKGROUND: We report two cases of drug-facilitated sexual assault which presented with CNS depression rendering the victims vulnerable to sexual assault and unable to recall the events surrounding the crimes. In each tetrahydrozoline (THZ) was quantified. CASE REPORT: Case #1 ingested an unknown amount of eye drops containing THZ mixed with alcoholic beverages. Case #1 presented to the emergency department (ED) approximately 7 hr after reportedly being sexually assaulted and was without symptoms in the ED. Earlier reports from individuals who saw her indicated the victim to be "heavily intoxicated". Case #2 also ingested an unknown amount of eye drops containing THZ mixed with alcoholic beverages. Case #2 presented to an ED without symptoms approximately 23 hr after reportedly being sexually assaulted. Urine obtained from both cases was assessed for THZ concentrations using gas-chromatography-mass spectrometry. CASE DISCUSSION: Case #1 had a 0.15 g% (by weight by volume) urine ethanol concentration and a urinary THZ concentration of 1.481 ng/mL, approximately 7h after ingestion. Case #2 was negative for ethanol but had a urine THZ concentration of 108 ng/mL at 23 hr post-ingestion. Few case reports have been published documenting the use of THZ to facilitate sexual assault. CONCLUSION: We report two cases of drug-facilitated sexual assault involving the use of THZ where alcoholic beverages were concomitantly consumed. This is the first paper to our knowledge which discusses pharmacology of THZ ingestion and the significance of alcohol being present.

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，让患者身体前倾或置于左侧（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。寻求医疗救助。 /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 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5%葡萄糖溶液（D5W），以“保持开放”，最小流量/ SRP。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……。使用地西泮（安定）或劳拉西泮（安定）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 (Valium) or lorazepam (Ativan) ... . 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

• 吸收

当口服四氢唑啉时，它能够从胃肠道迅速吸收并穿越血脑屏障。在给予0.05%四氢唑啉眼内给药后，Cmax（最高血药浓度）的范围为0.068至0.380纳克/毫升。

When consumed orally, tetryzoline is rapidly absorbed from the gastrointestinal tract and can cross the blood-brain barrier. Following ocular administration of 0.05% tetryzoline, Cmax ranged from 0.068 to 0.380 ng/mL.

来源:DrugBank

吸收、分配和排泄

• 消除途径

在给予0.05%四氢唑啉眼内给药后，24小时内在尿液中检测到四氢唑啉。

Following ocular administration of 0.05% tetryzoline, tetryzoline was detected in urine at 24 hours.

来源:DrugBank

吸收、分配和排泄

• 分布容积

没有可用的信息。

No information is available.

来源:DrugBank

吸收、分配和排泄

• 清除

没有可用的信息。

No information is available.

来源:DrugBank

吸收、分配和排泄

背景：儿童过量使用四氢唑啉（THZ）可能会导致严重症状，需要重症监护管理。我们报告了三例出现中枢神经系统抑制和心血管效应的病例，其中进行了血清浓度的检测。 病例报告：病例1摄入了含有THZ的眼药水，数量不详，导致意识状态改变、心动过缓、低体温和低血压。病例2和病例3摄入了含有THZ的7.5毫升眼药水。病例2在急诊科（ED）就诊时无症状，但摄入后90分钟变得昏睡和心动过缓。相比之下，病例3在摄入后15分钟变得昏睡，到达急诊科时需要气管插管。所有儿童都被收入重症监护室进行观察，并在摄入后24小时内有所改善。用于药物筛查的尿液对THZ呈阳性。采集血液以使用气相色谱-质谱（GC-MS）评估水平。 病例讨论：病例1在摄入后7小时和12小时的血浆水平分别为51.4和23.6 ng/mL，揭示了一半的生命期为4.4小时。已经发表了许多病例报告，记录了摄入这些局部非处方（OTC）产品的危险。然而，人类的药代动力学（PK）数据不可用，无法帮助我们了解摄入后THZ的毒代动力学和人体内的处置。 结论：我们报告了三例儿童摄入THZ后的病例，其中一例的血浆浓度得到了计算，半衰期为4.4小时。

BACKGROUND: Major symptoms can occur from tetrahydrozoline (THZ) overdoses in young children, requiring intensive care management. We report three cases that presented with CNS depression and cardiovascular effects where serum concentrations were performed. CASE REPORT: Case 1 ingested an unknown amount of eye drops containing THZ, resulting in altered mental status, bradycardia, hypothermia, and hypotension. Cases 2 and 3 ingested 7.5 mL of eye drops containing THZ. Case 2 presented to the emergency department (ED) without symptoms but became lethargic and bradycardic 90 min after ingestion. By contrast, Case 3 became lethargic 15 min after ingestion and required intubation on arrival to the ED. All children were admitted to ICU for observation and improved within 24 hr of ingestion. Urine obtained for drug screening was positive for THZ. Blood was obtained to assess level using gas-chromatography mass-spectrometry (GC-MS). CASE DISCUSSION: Case 1 had plasma levels of 51.4 and 23.6 ng/mL at 7 and 12 hr, respectively, after ingestion, revealing a half-life of 4.4 hr. Numerous case reports have been published documenting the dangers of ingesting these topical over-the-counter (OTC) products. However, human PK data are not available to help in our understanding of THZ toxicokinetics and disposition in humans after ingestion. CONCLUSION: We report three pediatric cases after ingestion of THZ where plasma concentrations were obtained with a calculated half-life of 4.4 hr in one case.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302
• 储存条件：
  -20℃

制备方法与用途

概述

四氢唑啉的作用与萘甲唑啉相似。临床常用其0.1%的溶液作为滴鼻剂，用于治疗鼻炎和鼻窦炎；也可用0.05%的溶液滴眼，以治疗眼结膜充血。药物可从用药部位吸收，也可通过胃肠道吸收。注意事项与萘甲唑啉相同。

用途

四氢唑啉是一种化学品，其闪点为191.8°C，是一种白色结晶性粉末化合物。临床上，它被归类为拟交感神经药，具有血管收缩作用，能够迅速消除鼻粘膜和眼结膜的充血。

生物活性

Tetrahydrozoline (Tetryzoline) 是咪唑啉的衍生物，是一种 α-肾上腺素能（α-adrenergic）激动剂，能够引起血管收缩。它广泛用于研究鼻充血和结膜充血。

体外研究

在体外实验中，0.05% HCl-Tetrahydrozoline 溶液（稀释至1:20浓度，在DMEM中孵育24小时）可诱导原代人类牙龈成纤维细胞合成胶原类型I和III。

反应信息

• 作为反应物：
  描述：

  四氢唑林 在 nitric oxide 作用下， 以 乙腈 为溶剂， 20.0 ℃ 、506.62 kPa 条件下， 反应 24.0h， 以82%的产率得到(Z)-[1-(4,5-dihydro-1H-imidazol-2-yl)-3,4-dihydro-2H-naphthalen-1-yl]-hydroxyimino-oxidoazanium
  参考文献：
  名称：

  一氧化氮与Am反应制得的碳键重氮二醇

  摘要：

  各种取代的脒游离碱发生反应的乙二胺互变异构体与一氧化氮（NO）以产生含有碳-二醇二氮烯结合化合物[R 1 - [R 2 - [R 3 C-N（O）NO -官能团（以前称为“亚硝基羟胺”）。尽管产物的性质确实有所不同，但新反应已被证明是相当普遍的。含有不止一个可取代氢的produce会生成聚间二烯二醇盐作为分子间盐，而仅能发生一次二one烯二胺化的those提供两性离子盐。这些二氮杂二氮杂ated化are显示为有用的NO供体化合物，当溶解于pH 7.4磷酸盐缓冲液中时，它会经历非常缓慢的自解离，从而生成NO和主要含有NO的一氧化二氮的混合物。该新发现的最有利的体现是单重氮二烯丙基化am两性离子的制备。医学上相关的α-肾上腺素能激动剂四氢唑啉与伊达唑烷的反应产生了单重氮二醇二am化z两性离子，从中观察到长达28天的NO释放，并且几乎没有终止的迹象。该反应应适用于多种药物，包括NO合酶抑制剂，抗肿瘤剂和抗菌剂。

  DOI：

  10.1021/jo050921y
• 作为产物：
  描述：

  1-氰基四氢化萘 、 ethylene diamine mono-p-toluenesulfonic acid salt 生成 四氢唑林
  参考文献：
  名称：

  DE1009189

  摘要：

  公开号：

文献信息

• SUBSTITUTED INDOLES
  申请人：Gant Thomas G.

  公开号：US20090191183A1

  公开（公告）日：2009-07-30

  Disclosed herein are substituted indole cysteinyl leukotriene receptor modulators of Formula I, process of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.

  本文揭示了Formula I的替代吲哚半胱氨酸白三烯受体调节剂，其制备方法，药物组合物以及使用方法。
• New CRTh2 antagonists
  申请人：Almirall, S.A.

  公开号：EP2548876A1

  公开（公告）日：2013-01-23

  The present invention relates to compounds of formula (I), to the process for preparing such compounds and to their use in the treatment of a pathological condition or disease susceptible to amelioration by CRTh2 antagonist activity.

  本发明涉及式(I)的化合物，制备这种化合物的方法以及它们在治疗病理状况或疾病中的应用，该病理状况或疾病容易通过CRTh2拮抗活性得到改善。
• [EN] NEW CRTh2 ANTAGONISTS<br/>[FR] NOUVEAUX ANTAGONISTES DE CRTH2
  申请人：ALMIRALL SA

  公开号：WO2013010881A1

  公开（公告）日：2013-01-24

  The present invention relates to compounds of formula (I), to the process for preparing such compounds and to their use in the treatment of a pathological condition or disease susceptible to amelioration by CRTh2 antagonist activity.

  本发明涉及公式(I)的化合物，制备此类化合物的方法以及它们在治疗可通过CRTh2拮抗剂活性改善的病理状况或疾病中的用途。
• New bicyclic compounds as crac channel modulators
  申请人：Almirall, S.A.

  公开号：EP2738172A1

  公开（公告）日：2014-06-04

  The present invention relates to novel compounds which are inhibitors of CRAC channel activity. This invention also relates to pharmaceutical compositions containing them, process for their preparation and their use in therapy.

  这项发明涉及一种新型化合物，它们是CRAC通道活性的抑制剂。该发明还涉及含有这些化合物的药物组合物，它们的制备方法以及它们在治疗中的应用。
• CONJUGATE-BASED ANTIFUNGAL AND ANTIBACTERIAL PRODRUGS
  申请人：Bapat Abhijit S.

  公开号：US20140364595A1

  公开（公告）日：2014-12-11

  The invention provides conjugate-based antifungal or antibacterial prodrugs formed by coupling at least one anti-fungal agent or antibacterial agent with at least one linker and/or carrier. The prodrugs are of formula: (i) (AFA) m -X-(L) n ; (ii) [(AFA) m′ -X] p -L; (iii) AFA-[X-(L) n′ ] q ; or (iv) (AFA) m″ -X, wherein: AFA is an antifungal agent or an antibacterial agent; L is a carrier; X is a linker; m ranges from 1 to 10; n ranges from 2 to 10; m′ is 1 to 10; p is 1 to 10; n′ is 1 to 10; and q is 1 to 10, provided that q′ and n are not both 1; and m″ is 1 to 10. The invention also provides nanoparticles comprising the conjugate-based prodrugs. Additionally, the invention also provides non-conjugated antifungal and antibacterial agents in the form of nanoparticles.

  该发明提供了由至少一种抗真菌剂或抗菌剂与至少一种连接剂和/或载体偶联形成的基于共轭的抗真菌或抗菌前药。这些前药的公式为：(i) (AFA) m -X-(L) n ; (ii) [(AFA) m′ -X] p -L; (iii) AFA-[X-(L) n′ ] q ; 或 (iv) (AFA) m″ -X，其中：AFA是抗真菌剂或抗菌剂；L是载体；X是连接剂；m范围从1到10；n范围从2到10；m′为1到10；p为1到10；n′为1到10；q为1到10，前提是q'和n不同时为1；m″为1到10。该发明还提供了包含基于共轭的前药的纳米粒子。此外，该发明还提供了以纳米粒子形式的非共轭抗真菌和抗菌剂。

表征谱图