羟嗪 | 68-88-2

• 物质功能分类: 原料药 - 神经系统用药 - 抗焦虑药
• 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: 羟嗪
• 中文别名: 安泰乐；2-[2-[4-[(4-氯苯基)-苯甲基]哌嗪-1-基]乙氧基]乙醇；盐酸盐酸
• 英文名称: hydroxizine
• 英文别名: 2-{2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy}ethanol；Hydroxyzine；2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)ethoxy)ethanol；2-[2-[4-[(4-chlorophenyl)-phenylmethyl]piperazin-1-yl]ethoxy]ethanol；hydroxyzine pamoate
• CAS: 68-88-2
• 化学式: C₂₁H₂₇ClN₂O₂
• mdl: MFCD00242772
• 分子量: 374.911
• InChiKey: ZQDWXGKKHFNSQK-UHFFFAOYSA-N

物化性质

• 熔点：
  190°C
• 沸点：
  250 °C(Press: 0.1 Torr)
• 密度：
  1.1020 (rough estimate)
• 溶解度：
  可溶于氯仿（少量）、DMSO（少量）、乙醇（少量）、甲醇（少量）
• 物理描述：
  Solid
• 颜色/状态：
  Oil
• 蒸汽压力：
  1.17X10-11 mm Hg at 25 °C (est)
• 解离常数：
  pKa1 = 2.47 (amine); pKa2 = 6.95 (amine) (est)
• 碰撞截面：
  197.4 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]
• 保留指数：
  2871;2820;2874;2874;2832;2876;2884;2867;2849;2871.8;2849;2832;2849

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  26
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  35.9
• 氢给体数：
  1
• 氢受体数：
  4

ADMET

代谢

盐酸羟嗪在肝脏中通过CYP3A4和CYP3A5代谢。尽管盐酸羟嗪的确切代谢命运尚不清楚，但其主要和活性代谢物（口服给药剂量的约45至60%），通过将其醇部分氧化为羧酸生成，是第二代抗组胺药[西替利嗪]。盐酸羟嗪可能分解为其他几种代谢物，尽管在人类中尚未阐明特定的结构和途径。

Hydroxyzine is metabolized in the liver by CYP3A4 and CYP3A5. While the precise metabolic fate of hydroxyzine is unclear, its main and active metabolite (~45 to 60% of an orally administered dose), generated by oxidation of its alcohol moiety to a carboxylic acid, is the second-generation antihistamine [cetirizine]. Hydroxyzine is likely broken down into several other metabolites, though specific structures and pathways have not been elucidated in humans.

来源:DrugBank

代谢

氢化可的松及其活性代谢物西替利嗪的药代动力学参数在给六只健康狗口服和静脉注射2毫克/千克氢化可的松后确定。血浆药物水平用高压液相色谱法测定。药效学研究评估了对组胺和抗犬IgE介导的皮肤风团形成的抑制效果。药代动力学和药效学相关性通过计算机建模确定。口服氢化可的松的平均系统可用性为72%。无论给药途径如何，氢化可的松都会迅速转化为西替利嗪。在静脉和口服给药后，西替利嗪的平均药时曲线下面积分别比氢化可的松高8倍和10倍。口服给药氢化可的松后，西替利嗪的平均峰浓度约为2.2微克/毫升，而氢化可的松为0.16微克/毫升。在静脉注射和口服给药氢化可的松后，西替利嗪的终末半衰期在10到11小时之间变化。将西替利嗪血浆浓度与风团抑制数据进行比较，得到了S型关系。在最初的8小时内观察到最大抑制（组胺和抗犬IgE介导的皮肤反应分别为82%和69%），这与西替利嗪血浆浓度大于1.5微克/毫升相关。药理建模表明，增加氢化可的松的剂量或给药频率不会导致比每日两次2毫克/千克的氢化可的松更好的组胺抑制作用。总之，氢化可的松迅速转化为西替利嗪。风团形成的减少几乎完全是由于西替利嗪。药效学建模预测，每日两次口服2毫克/千克的氢化可的松将产生最大的抗组胺效果。

Pharmacokinetic parameters of hydroxyzine and its active metabolite cetirizine were determined after oral and intravenous administration of 2 mg kg(-1) of hydroxyzine to six healthy dogs. Plasma drug levels were determined with high-pressure liquid chromatography. Pharmacodynamic studies evaluated the suppressive effect on histamine and anticanine IgE-mediated cutaneous wheal formation. Pharmacokinetic and pharmacodynamic correlations were determined with computer modelling. The mean systemic availability of oral hydroxyzine was 72%. Hydroxyzine was rapidly converted to cetirizine regardless of the route of administration. The mean area-under-the-curve was eight and ten times higher for cetirizine than hydroxyzine after intravenous and oral dosing, respectively. After oral administration of hydroxyzine, the mean peak concentration of cetirizine was approximately 2.2 ug mL(-1) and that of hydroxyzine 0.16 ug mL(-1). The terminal half-life for cetirizine varied between 10 and 11 hr after intravenous and oral administration of hydroxyzine. A sigmoidal relationship was fit to the data comparing cetirizine plasma concentration to wheal suppression. Maximum inhibition (82% and 69% for histamine and anticanine IgE-mediated skin reactions, respectively) was observed during the first 8 hr, which correlated with a plasma concentration of cetirizine greater than 1.5 ug mL(-1). Pharmacological modelling suggested that increasing either hydroxyzine dosages or frequencies of administration would not result in histamine inhibition superior to that obtained with twice daily hydroxyzine at 2 mg kg(-1). In conclusion, there was rapid conversion of hydroxyzine to cetirizine. The reduction of wheal formation appeared almost entirely due to cetirizine. Pharmacodynamic modelling predicted that maximal antihistamine effect would occur with twice daily oral administration of hydroxyzine at 2 mg kg(-1).

来源:Hazardous Substances Data Bank (HSDB)

代谢

尽管羟嗪的确切代谢命运尚未明确建立，但看来该药物被完全代谢，主要在肝脏中进行。在动物中，羟嗪及其代谢物通过胆汁消除在粪便中排出。羟嗪的羧酸代谢物，西替利嗪，是一种长效抗组胺药。

Although the exact metabolic fate of hydroxyzine is not clearly established, it appears that the drug is completely metabolized, principally in the liver. In animals, hydroxyzine and its metabolites are excreted in feces via biliary elimination. The carboxylic acid metabolite of hydroxyzine, cetirizine, is a long-acting antihistamine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏 半衰期：20到25小时

Hepatic Half Life: 20 to 25 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

盐酸羟嗪与组胺竞争在效应细胞表面的H1受体位点，从而抑制组胺引起的血管性水肿、红斑和瘙痒。盐酸羟嗪的镇静作用发生在中枢神经系统的皮层下水平。由于其中枢抗胆碱能作用，盐酸羟嗪可能作为一种镇吐药有效。

Hydroxyzine competes with histamine for binding at H₁-receptor sites on the effector cell surface, resulting in suppression of histaminic edema, flare, and pruritus. The sedative properties of hydroxyzine occur at the subcortical level of the CNS. Secondary to its central anticholinergic actions, hydroxyzine may be effective as an antiemetic.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

尽管广泛使用，羟嗪并未与肝功能测试异常或临床上明显的肝损伤有关联。实际上，羟嗪常用于治疗与肝病相关的瘙痒。其安全性可能与每日低剂量和有限的使用期限有关。 可能性评分：E（不太可能是临床上明显肝损伤的原因）。 关于抗组胺药的安全性和潜在肝毒性的参考资料，在抗组胺药概述部分之后一起给出。 药物类别：抗组胺药

Despite widespread use, hydroxyzine has not been linked to liver test abnormalities or to clinically apparent liver injury. Indeed, hydroxyzine is commonly used for the pruritus associated with liver disease. The reason for its safety may relate to low daily dose and limited duration of use. Likelihood score: E (unlikely to be a cause of clinically apparent liver injury). References on the safety and potential hepatotoxicity of antihistamines are given together after the Overview section on Antihistamines. Drug Class: Antihistamines

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：羟嗪

Compound:hydroxyzine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：没有匹配项

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

氢化可的松的绝对生物利用度尚未确定，因为静脉注射制剂由于溶血风险而不可用。氢化可的松在口服给药后从胃肠道迅速吸收，大约在给药后2小时达到最大血浆浓度（Tmax）。

The absolute bioavailability of hydroxyzine has not been ascertained, as intravenous formulations are unavailable due to a risk of hemolysis. Hydroxyzine is rapidly absorbed from the gastrointestinal tract upon oral administration, reaching its maximum plasma concentration (Tmax) approximately 2 hours following administration.

来源:DrugBank

吸收、分配和排泄

• 消除途径

大约70%的羟嗪活性代谢物，西替利嗪，以不变的形式通过尿液排出。在人体中，肾和粪便排泄的确切程度尚未确定。

Approximately 70% of hydroxyzine's active metabolite, cetirizine, is excreted unchanged in the urine. The precise extent of renal and fecal excretion in humans has not been determined.

来源:DrugBank

吸收、分配和排泄

• 分布容积

平均分布容积为16.0 ± 3.0 L/kg。在皮肤中的浓度高于血浆。

The mean volume of distribution is 16.0 ± 3.0 L/kg. Higher concentrations are found in the skin than in the plasma.

来源:DrugBank

吸收、分配和排泄

• 清除

氢化可的松在儿童中的清除率为31.1 ± 11.1 mL/min/kg，在成人中为9.8 ± 3.3 mL/min/kg。

Clearance of hydroxyzine has been reported to be 31.1 ± 11.1 mL/min/kg in children and 9.8 ± 3.3 mL/min/kg in adults.

来源:DrugBank

吸收、分配和排泄

尚不清楚羟嗪是否穿过胎盘或分布到乳汁中。

It is not known if hydroxyzine crosses the placenta or is distributed into milk.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2933599090
• 安全说明：
  S16,S23,S26,S3
• 危险类别码：
  R20/22,R11,R35
• 危险品运输编号：
  1106
• 储存条件：
  2-8℃

制备方法与用途

生物活性

Hydroxyzine 是一种苯二氮卓抗组胺剂，作为口服活性组胺 H1 受体拮抗剂和血清素拮抗剂。Hydroxyzine 具有抗焦虑作用，适用于广泛性焦虑障碍的研究。

靶点

• H1 Receptor

体外研究

Hydroxyzine 氢溴酸盐在膀胱切片中抑制了乙酰胆碱（10 μM）诱导的血清素释放。其抑制作用随浓度增加而减弱：在 10 μM 浓度下抑制 34%，1 μM 下抑制 25%，0.1 μM 下抑制 17%。

体内研究

Hydroxyzine 氢溴酸盐（剂量分别为 12.5 mg/kg、25 mg/kg 和 50 mg/kg 腹腔注射）表现出微弱的直接镇痛作用，但显著增强了吗啡对小鼠发声后放电的影响，这代表了疼痛的情绪成分。Hydroxyzine 氢溴酸盐（50 mg/kg 腹腔注射）与吗啡联合使用时，在尾部触碰试验中显示出增强效果；然而，Hydroxyzine （12.5 mg/kg 腹腔注射）却减少了吗啡在小鼠中的镇痛作用。

反应信息

• 作为反应物：
  描述：

  羟嗪 生成 2-(2-(4-((4-Chlorophenyl)(phenyl)methyl)piperazin-1-yl)ethoxy)acetaldehyde
  参考文献：
  名称：

  一种合成盐酸西替利嗪的新的工艺

  摘要：

  一种合成盐酸西替利嗪的新的工艺。该工艺以羟嗪为原料，首先将羟嗪氧化为醛基物，之后该醛基物再经进一步氧化为西替利嗪，最后经成盐纯化得到盐酸西替利嗪。该合成方法总收率高达80％以上。同时该合成方法具有操作简单，生产周期短，能耗少，成本低，三废少的特点，适合大规模工业化生产。

  公开号：

  CN104130211A
• 作为产物：
  描述：

  alkaline earth salt of/the/ methylsulfuric acid 在 氯化亚砜 、 苯 作用下， 生成 羟嗪
  参考文献：
  名称：

  Morren et al., Industrie Chimique Belge, 1954, vol. 19, p. 1176,1181

  摘要：

  DOI：
• 作为试剂：
  描述：

  ketoprofen chloride 、 羟嗪 在 羟嗪 作用下， 生成 Benzeneacetic acid, 3-benzoyl-alpha-methyl-, 2-(2-(4-((4-chlorophenyl)phenylmethyl)-1-piperazinyl)ethoxy)ethyl ester, (2Z)-2-butenedioate (1:2)
  参考文献：
  名称：

  GB2043626A

  摘要：

  公开号：

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。
• [EN] COMPOUNDS AND THEIR USE AS BACE INHIBITORS<br/>[FR] COMPOSÉS ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE BACE
  申请人：ASTRAZENECA AB

  公开号：WO2016055858A1

  公开（公告）日：2016-04-14

  The present application relates to compounds of formula (I), (la), or (lb) and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing Αβ-related pathologies such as Down's syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease.

  本申请涉及式(I)、(Ia)或(Ib)的化合物及其药物组合物/制剂。本申请进一步涉及治疗或预防与Αβ相关的病理学，如唐氏综合症，β-淀粉样蛋白血管病，如但不限于脑淀粉样蛋白血管病或遗传性脑出血，与认知损害相关的疾病，如但不限于MCI（“轻度认知损害”），阿尔茨海默病，记忆丧失，与阿尔茨海默病相关的注意力缺陷症状，与疾病如阿尔茨海默病或痴呆症相关的神经退行性疾病，包括混合性血管性和退行性起源的痴呆，早老性痴呆，老年性痴呆和与帕金森病相关的痴呆的方法。
• [EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
  申请人：MERCK SHARP & DOHME

  公开号：WO2016089721A1

  公开（公告）日：2016-06-09

  The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

  本发明涉及甲基噁唑化合物，其为促进睡眠的受体拮抗剂。本发明还涉及所述化合物在潜在治疗或预防涉及促进睡眠的神经和精神疾病和疾病中的用途。本发明还涉及包含这些化合物的组合物。本发明还涉及这些组合物在潜在预防或治疗涉及促进睡眠的疾病中的用途。
• 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。
• HETEROBICYCLIC COMPOUNDS
  申请人：Amgen Inc.

  公开号：US20130225552A1

  公开（公告）日：2013-08-29

  Heterobicyclic compounds of Formula (I): or a pharmaceutically-acceptable salt, tautomer, or stereoisomer thereof, as defined in the specification, and compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, Huntington's Disease, and the like.

  Formula (I)的杂环化合物： 或其药用可接受的盐、互变异构体或立体异构体，如规范中所定义，并含有它们的组合物，以及制备这种化合物的方法。本文还提供了通过抑制PDE10来治疗由此可治疗的疾病或疾病的方法，如肥胖症、非胰岛素依赖型糖尿病、精神分裂症、躁郁症、强迫症、亨廷顿病等。

表征谱图