安他唑啉 | 91-75-8

• 物质功能分类: 原料药 - 循环系统用药 - 抗心律失常药
• 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: 安他唑啉
• 中文别名: 盐酸安太林；N-苄基-N-(4,5-二氢-1H-咪唑-2-基甲基)苯胺
• 英文名称: antazoline
• 英文别名: N-benzyl-N-(4,5-dihydro-1H-imidazol-2-ylmethyl)phenylamine；N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-N-(phenylmethyl)aniline；N-benzyl-N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-aniline；N-Benzyl-N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-anilin；benzyl-(4,5-dihydro-1H-imidazol-2-ylmethyl)-phenyl-amine；N-benzyl-N-(4,5-dihydro-1H-imidazol-2-ylmethyl)aniline
• CAS: 91-75-8
• 化学式: C₁₇H₁₉N₃
• mdl: MFCD00047013
• 分子量: 265.358
• InChiKey: REYFJDPCWQRWAA-UHFFFAOYSA-N

物化性质

• 熔点：
  120-122°
• 沸点：
  398.57°C (rough estimate)
• 密度：
  0.9786 (rough estimate)
• 物理描述：
  Solid
• 颜色/状态：
  White, crystalline powder
• 气味：
  Odorless
• 味道：
  Bitter
• 溶解度：
  663 mg/L (at 30 °C)
• 蒸汽压力：
  2.3X10-8 mm Hg at 25 °C (est)
• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxides/.
• 解离常数：
  pKa = 4.90 (non-cyclic tertiary nitrogen); pKa = 10.68 (tertiary imidazoline nitrogen) (est)
• 保留指数：
  2280;2315;2295;2320;2330;2328

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.235
• 拓扑面积：
  27.6
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

毒理性

• 相互作用

这项研究的目的旨在探究安他唑啉和酮替芬（两种H1受体拮抗剂）对 抗癫痫药物 抗电惊厥活性的影响，该抗癫痫药物用于对抗 小鼠由最大电休克（MES）引发的惊厥。所使用的抗癫痫药物包括：丙戊酸、卡马西平、二苯乙内酰脲和苯巴比妥。此外，研究还考察了 抗癫痫药物单独使用或与安他唑啉或酮替芬联合使用时，对长期记忆（在被动回避任务中测试）和运动性能（在烟囱测试中评估）的影响，以及这些H1受体拮抗剂的急性作用和连续治疗7天后的影响。还评估了安他唑啉和酮替芬对抗癫痫药物的自由血浆和脑水平的影响。安他唑啉（0.5 mg/kg），在急性给药和连续治疗7天后，显著降低了电惊厥阈值。同样，酮替芬在急性剂量和慢性剂量8 mg/kg后，显著降低了电惊厥的阈值。在这两种情况下，安他唑啉和酮替芬在较低剂量时对此参数没有影响。安他唑啉（0.25 mg/kg）显著提高了卡马西平对MES的ED50值（急性给药和连续治疗7天后）。此外，安他唑啉（0.25 mg/kg）也降低了二苯乙内酰脲的抗惊厥活性，但仅在重复给药后，并未改变该药物的脑部和自由血浆水平。而且，丙戊酸和苯巴比妥在与安他唑啉联合使用时，并未改变它们的保护活性。... 只有急性安他唑啉（0.25 mg/kg）与丙戊酸联合使用时，在烟囱测试中评估的小鼠表现受损。酮替芬（4 mg/kg）与常规抗癫痫药物联合使用时，损害了服用丙戊酸、苯巴比妥或二苯乙内酰脲的小鼠的运动协调能力。急性安他唑啉（0.25 mg/kg）单独使用或与抗癫痫药物联合使用时，并未干扰在被动回避任务中测试的长期记忆。... 本研究的结果表明，穿过血脑屏障的H1受体拮抗剂在癫痫患者中使用时应谨慎，因为安他唑啉降低了二苯乙内酰脲和卡马西平的保护潜力。

The purpose of this study was to investigate the effects of antazoline and ketotifen (two H1 receptor antagonists) on the anticonvulsant activity of antiepileptic drugs against maximal electroshock (MES)-induced convulsions in mice. The following antiepileptic drugs were used: valproate, carbamazepine, diphenylhydantoin and phenobarbital. In addition, the effects of antiepileptic drugs alone or in combination with antazoline or ketotifen were studied on long-term memory (tested in the passive avoidance task) and motor performance (evaluated in the chimney test), acutely and after 7-day treatment with these H1 receptor antagonists. The influence of antazoline and ketotifen on the free plasma and brain levels of the antiepileptics was also evaluated. Antazoline (at 0.5 mg/kg), given acutely and after 7-day treatment, significantly diminished the electroconvulsive threshold. Similarly, ketotifen, after acute and chronic doses of 8 mg/kg markedly reduced the threshold for electroconvulsions. In both cases, antazoline and ketotifen were without effect upon this parameter at lower doses. Antazoline (0.25 mg/kg) significantly raised the ED50 value of carbamazepine against MES (both, acutely and after 7-day treatment). Furthermore antazoline (0.25 mg/kg) also reduced the anticonvulsant activity of diphenylhydantoin, but only after repeated administration, without modifying the brain and free plasma level of this drug. Moreover, valproate and phenobarbital did not change their protective activity when combined with antazoline. ... Only acute antazoline (0.25 mg/kg) applied with valproate impaired the performance of mice evaluated in the chimney test. Ketotifen (4 mg/kg) co-administered with conventional antiepileptic drugs impaired motor coordination in mice treated with valproate, phenobarbital or diphenylhydantoin. Acute and chronic antazoline (0.25 mg/kg) alone or in combination with antiepileptic drugs did not disturb long-term memory, tested in the passive avoidance task. ... The results of this study indicate that H1 receptor antagonists, crossing the blood brain barrier, should be used with caution in epileptic patients. This is because antazoline reduced the protective potential of diphenylhydantoin and carbamazepine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

咪唑啉类药物在脑缺血模型中发挥神经保护作用。它们还通过阻断N-甲基-D-天门冬氨酸（NMDA）电流，对抗由NMDA引起的小鼠小脑和纹状体神经细胞死亡。在这里，我们研究了安他唑啉对大鼠海马神经元培养中的NMDA毒性和电流的影响，以及在场癫痫状态体内的模型中的作用。在海马培养中，安他唑啉（30 uM）减少了NMDA介导的神经毒性，并且以电压依赖性和快速可逆的方式阻断了NMDA电流（在-60 mV时抑制了85+/- 3%）。通过向雄性成年大鼠的右侧梨状皮质直接注射毛果芸香碱（200 nmol）诱导癫痫状态。然后大鼠立即接受间隔30分钟的连续三次i.p.注射PBS（对照组）或安他唑啉10 mg/kg（低剂量组）或45 mg/kg（高剂量组）。在6小时的记录期间，所有组的癫痫状态持续了超过200分钟。只有在高剂量组中，第三次注射安他唑啉后1小时，癫痫完全停止，然后1小时后又开始。大鼠在一周后被处死，并对他们的大脑进行 Cresyl Violet 染色的切片分析以量化损伤。在毛果芸香碱注射的同侧，梨状皮质和海马的CA1和CA3区域在两个安他唑啉处理组中均显著受到保护，而前梨状和外侧膝状皮质仅在安他唑啉高剂量组中受到保护。在毛果芸香碱注射的对侧，只有海马的CA3区域在低剂量组中显著受到保护，但在高剂量组中所有调查的结构均受到保护。总之，安他唑啉在不同神经细胞原代培养模型中是一种强效的神经保护药物，之前在纹状体和小脑颗粒神经元中已经显示过，这里在海马神经元中也显示了同样的效果。安他唑啉在体内模型中也是神经保护的，即在梨状皮质内注射毛果芸香碱诱导的癫痫状态模型中。

Imidazoline drugs exert neuroprotective effects in cerebral ischaemia models. They also have effects against mouse cerebellar and striatal neuronal death induced by N-methyl-D-aspartate (NMDA) through the blockade of NMDA currents. Here, we investigated the effects of antazoline on NMDA toxicity and current in rat hippocampal neuronal cultures, and on an in vivo model of status epilepticus. In hippocampal cultures, antazoline (30 uM) decreased NMDA-mediated neurotoxicity and also blocked the NMDA current with voltage-dependent and fast-reversible action (inhibition by 85+ or - 3% at -60 mV). Status epilepticus was induced by injecting pilocarpine (200 nmol) directly into the right pyriform cortex of male adult rats. The rats then received immediately three consecutive i.p. injections at 30-min intervals of either PBS (control group) or antazoline at 10 mg/kg (low-dose group) or at 45 mg/kg (high-dose group). During the 6-hr recording, status epilepticus lasted more than 200 min in all groups. In the high-dose group only, seizures completely ceased 1 hr after the third injection of antazoline, then started again 1 hr later. Rats were killed 1 week later, and Cresyl Violet-stained sections of their brain were analysed for damage quantification. On the ipsilateral side to the pilocarpine injection, pyriform cortex and hippocampal CA1 and CA3 areas were significantly protected in both antazoline-treated groups, whilst prepyriform and entorhinal cortices were only in the high-dose group. On the contralateral side to the pilocarpine injection, only the hippocampal CA3 area was significantly protected in the low-dose group, but all investigated structures were in the high-dose group.In conclusion, antazoline is a potent neuroprotective drug in different models of neuronal primary culture, as previously shown in striatal and cerebellar granule neurons, and here in hippocampal neurons. Antazoline is also neuroprotective in vivo in the intra-pyriform pilocarpine-induced status epilepticus model.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

大多数患者只需要对症和支持性治疗。治疗重点在于控制激动、维持呼吸道通畅、逆转高热，并支持血流动力学功能。胃肠道净化并非必要，但如果药物摄入后不超过1小时，可以考虑使用活性炭。鉴于潜在的心脏毒性，除了维持患者的呼吸道、呼吸和循环状态外，还需要观察是否有心律失常。临床评估可能表明即将发生癫痫活动的迹象（高张力、反射亢进或肌阵挛抽动）是很重要的。... /抗组胺药/

Most patients require only symptomatic and supportive care. Treatment is focused on controlling agitation, maintaining airway, reversing hyperthermia, and supporting hemodynamic function. Gastrointestinal decontamination is not essential, but if not more than 1 hours has elapsed since ingestion of the drug, activated charcoal may be considered. In view of the potential cardiac toxicity in addition to maintenance of the airway, breathing, and circulatory status of the patients, observation for dysrhythmia is warranted. Clinical assessment for signs that may indicated impending seizure activity (hypertonicity, hyperreflexia, or myoclonic jerking) is important. ... /Antihistamines/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

基本治疗：建立专利气道（如需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。密切观察呼吸不足的迹象，并在需要时辅助通气。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，并在必要时进行治疗……。监测休克，并在必要时进行治疗……。预防癫痫发作，并在必要时进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在转运过程中，用0.9%的生理盐水（NS）连续冲洗每只眼睛……。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……。/毒物A和B/

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

高级治疗：对于昏迷的患者、严重肺水肿的患者或严重呼吸窘迫的患者，考虑进行口咽或鼻咽气管插管以控制气道。使用带气囊的面罩进行正压通气技术可能有益。考虑对肺水肿进行药物治疗...。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”，最小流量/。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。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/

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)

安全信息

• 安全说明：
  S22,S24/25
• 储存条件：
  -20°C

制备方法与用途

盐酸安他唑啉概述

盐酸安他唑啉（4,5-二氮-N-苯甲基-1H-咪唑-2-甲胺盐酸盐）是一种乙二胺类组胺受体拮抗剂，具有抗组胺和抗胆碱作用。它能干扰心肌细胞膜对钾、钠等离子的渗透，从而减缓心肌纤维间的传导速度。临床上主要用于治疗室性早搏以及洋地黄毒苷引起的心动过速，属IA类抗心律失常药。目前关于盐酸安他唑啉的研究侧重于其临床应用的安全性和有效性，以及采用光谱法和色谱法测定制剂中药物含量，但有关生物样品中的药物浓度测定及药代动力学研究尚未见报道。

临床研究

盐酸安他唑啉（安他唑啉）是一种治疗多种心律失常的药物。本研究旨在观察其在不伴有明显器质性心脏病患者中的安全性和有效性。采用双盲、随机、阳性对照试验，对照药物为稳心颗粒。共入选60例不伴有明显器质性心脏病的室性早搏（简称室早）患者，并于停用其他抗心律失常药2周后随机分为安他唑啉治疗组和稳心颗粒治疗组。服药治疗第2周进行随访记录不良反应等临床资料，满4周后复查Holter。疗效结果为对比治疗前后24小时室早的数目；安全性指标则包括治疗前后患者的生化检查结果。

共入选72例患者，其中男性37例（51.39%），平均年龄(45.06±12.33)岁。实际完成随访67例（研究组34例）。两组间基本临床资料匹配。治疗4周后，安他唑啉治疗组与稳心颗粒治疗组24小时室早数目均有明显降低，分别为70.11%和67.80%，但两者之间没有统计学差异（P=0.35）。此外，研究组中有88.24%的患者24小时室早减少超过75%，对照组为78.79%，同样未见显著性差异（P=0.61）。两组均无严重不良反应。结论认为，在临床实践中，安他唑啉对于治疗一些不合并严重心脏疾病的室性早搏具有较好的有效性和较高的安全性。

生物活性 Argireline

Argireline是一种新型的神经肽，广泛应用于局部皮肤护理。

化学性质

盐酸安他唑啉为白色结晶性粉末，熔点237-241℃。它溶于乙醇，略溶于水，不溶于氯仿、乙醚和苯。

用途

盐酸安他唑啉作为抗心律失常药物，用于治疗房性和室性早搏、阵发性心动过速等。此外，也可用作抗组织胺药物，适用于过敏性疾病。

反应信息

• 作为反应物：
  描述：

  安他唑啉 在 碘 作用下， 以 氯仿 为溶剂， 反应 0.5h， 生成 Antazolin-Iod-Komplex
  参考文献：
  名称：

  Charge-Transfer-Complexes, 2nd Mitt. 具有咪唑啉部分结构的药物的分子复合物和自由基形成

  摘要：

  根据 UV/Vis、IR、FIR、1H NMR 和 13C NMR 数据，tolazoline (1)、naphazoline (2)、xylometazoline (3)、oxymetazoline (4) 和antazoline (5) 与碘形成电荷转移络合物 (CT) ) 的结构 6, 7 和 8 来自, 而 7,7,8,8-四氰基醌二甲烷 (TCNQ), 2,3-二氯-5,6-二氰基-对苯醌 (DDQ), 对氯苯醌, 2, 4,5,7-四硝基芴酮（TeNF）和9-二氰基芴酮-2,4,7-三硝基芴酮（DTF）主要是电子供体受体复合物（EDA）和自由基阴离子（Scheme 3-8）之间的溶剂依赖性平衡产生的。结果被转移到 1-5 的直流检测，并用于 Priscol® 片剂和 Otriven® 滴剂的质量控制。

  DOI：

  10.1002/ardp.19843170311
• 作为产物：
  描述：

  N-苄基-4,5-二氢-N-苯基-1H-咪唑-2-甲胺磷酸盐 在 sodium hydroxide 作用下， 以 水 为溶剂， 生成 安他唑啉
  参考文献：
  名称：

  The Preparation and Characterization of New Antazoline Salts with Dicarboxylic Acids

  摘要：

  New antazoline salts with organic acids (fumaric acid, oxalic acid, and maleic acid) were prepared. The effect of the crystallization solvent and mechanochemical treatment on the crystalline forms of these salts was studied. Two polymorphs of antazoline hydrogen maleate were identified and their relative stability was determined. The molecular structures of antazoline hydrogen oxalate and antazoline hydrogen maleate showed differences in antazoline cation conformation. In crystal structures of all salts both imidazoline nitrogens of antazoline cation are involved in hydrogen bond formation with carboxyl groups of the acid.

  DOI：

  10.1080/15421406.2014.905041

文献信息

• [EN] 3,5-DIAMINO-6-CHLORO-N-(N-(4-PHENYLBUTYL)CARBAMIMIDOYL) PYRAZINE-2- CARBOXAMIDE COMPOUNDS<br/>[FR] COMPOSÉS 3,5-DIAMINO -6-CHLORO-N-(N- (4-PHÉNYLBUTYL)CARBAMIMIDOYL) PYRAZINE-2-CARBOXAMIDE
  申请人：PARION SCIENCES INC

  公开号：WO2014099673A1

  公开（公告）日：2014-06-26

  The present invention relates compounds of the formula: or pharmaceutically acceptable salts thereof, useful as sodium channel blockers, as well as compositions containing the same, processes for the preparation of the same, and therapeutic methods of use therefore in promoting hydration of mucosal surfaces and the treatment of diseases including cystic fibrosis, chronic obstructive pulmonary disease, asthma, bronchiectasis, acute and chronic bronchitis, emphysema, and pneumonia.

  本发明涉及以下化合物的公式：或其药学上可接受的盐，用作钠通道阻滞剂，以及含有这些化合物的组合物，制备这些化合物的方法，以及在促进粘膜表面水合和治疗包括囊性纤维化、慢性阻塞性肺病、哮喘、支气管扩张、急性和慢性支气管炎、肺气肿和肺炎等疾病的治疗方法。
• CHLORO-PYRAZINE CARBOXAMIDE DERIVATIVES WITH EPITHELIAL SODIUM CHANNEL BLOCKING ACTIVITY
  申请人：Parion Sciences, Inc.

  公开号：US20140171447A1

  公开（公告）日：2014-06-19

  This invention provides compounds of the formula I: and their pharmaceutically acceptable salts, useful as sodium channel blockers, compositions containing the same, therapeutic methods and uses for the same and processes for preparing the same.

  这项发明提供了式I的化合物及其药用盐，可用作钠通道阻滞剂，包含这些化合物的组合物，以及用于这些化合物的治疗方法和用途，以及制备这些化合物的方法。
• 3-Aminocyclopentanecarboxamides as modulators of chemokine receptors
  申请人：Xue Chu-Biao

  公开号：US20060004018A1

  公开（公告）日：2006-01-05

  The present invention is directed to compounds of Formula I: which are modulators of chemokine receptors. The compounds of the invention, and compositions thereof, are useful in the treatment of diseases related to chemokine receptor expression and/or activity.

  本发明涉及以下式的化合物： 这些化合物是趋化因子受体的调节剂。本发明的化合物及其组合物在治疗与趋化因子受体表达和/或活性相关的疾病方面是有用的。
• CYCLOPROPYLAMINES AS LSD1 INHIBITORS
  申请人：Incyte Corporation

  公开号：US20150225379A1

  公开（公告）日：2015-08-13

  The present invention is directed to cyclopropylamine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.

  本发明涉及环丙胺衍生物，这些衍生物是LSD1抑制剂，可用于治疗癌症等疾病。
• Benzoxazinyl-amidocyclopentyl-heterocyclic modulators of chemokine receptors
  申请人：Goble D. Stephen

  公开号：US20070238723A1

  公开（公告）日：2007-10-11

  Cyclopentyl compounds linked to a benzoxazinyl group through an amido moiety utilizing the ring nitrogen of the benzoxazine, and further substituted with a heterocyclic moiety, such compounds represented by formula I: which are used to modulate the CCR-2 chemokine receptor to prevent or treat inflammatory and immunoregulatory disorders and diseases, allergic diseases, atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis; and pharmaceutical compositions comprising these compounds and the use of these compounds and compositions.

  环戊基化合物通过酰胺基团与苯并噁唑基团相连，利用苯并噁唑环的环氮原子，并进一步用杂环基团取代，这些化合物由式I表示： 用于调节CCR-2趋化因子受体，以预防或治疗炎症和免疫调节性疾病和疾病，过敏性疾病，包括过敏性鼻炎，皮炎，结膜炎和哮喘，以及类风湿性关节炎和动脉粥样硬化等自身免疫病理病变；以及包含这些化合物的药物组合物和这些化合物和组合物的使用。

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