西替利嗪 | 83881-51-0

• 物质功能分类: 原料药 - 抗变态反应药 - 抗组胺药
• 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: 西替利嗪
• 中文别名: 赛特赞；2-[2-[4-[(4-氯苯基)苯甲基]-1-哌嗪基]乙氧基]乙酸；盐酸西替利嗪
• 英文名称: cetirizine
• 英文别名: 2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)ethoxy)acetic acid；(+/-)-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid；zyrtec；CTZ；2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid；2-[2-[4-[(4-chlorophenyl)-phenylmethyl]piperazin-1-ium-1-yl]ethoxy]acetate
• CAS: 83881-51-0
• 化学式: C₂₁H₂₅ClN₂O₃
• mdl: MFCD00800721
• 分子量: 388.894
• InChiKey: ZKLPARSLTMPFCP-UHFFFAOYSA-N

物化性质

• 熔点：
  110-115°C
• 沸点：
  542.1±45.0 °C(Predicted)
• 密度：
  1.237±0.06 g/cm3(Predicted)
• 溶解度：
  不溶于乙醇；水中≥122 mg/mL； DMSO 中≥19.44 mg/mL
• 物理描述：
  Solid
• 颜色/状态：
  Crystals from ethanol
• 蒸汽压力：
  2.98X10-11 mm Hg at 25 °C (est)
• Caco2细胞的药物渗透性：
  1.14
• 解离常数：
  pKa1 = 2.70 (amine); pKa2 = 3.57 (carboxylic acid); pKa3 = 7.56 (amine) (est)
• 碰撞截面：
  200.8 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  27
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  53
• 氢给体数：
  1
• 氢受体数：
  5

ADMET

代谢

一项由6名健康男性志愿者参与的质量平衡临床试验显示，服用西替利嗪后，70%的放射性剂量在尿液中测量到，10%在粪便中测量到。大约50%的放射性剂量以未改变的西替利嗪形式在尿液中测量到。血浆中放射性峰值快速增加的大部分与母药有关，这意味着首次通过肝脏的代谢水平较低。这阻止了西替利嗪与与肝细胞色素酶相互作用的药物发生潜在的相互作用。西替利嗪部分通过氧化O-脱烷基化代谢为一种不具有显著抗组胺活性的代谢物。负责西替利嗪这一代谢步骤的酶或酶尚未被鉴定。

A mass balance clinical trial comprised of 6 healthy male study volunteers showed that 70% of the administered radioactivity was measured in the urine and 10% in the feces after cetirizine administration. About 50% of the radioactivity was measured in the urine as unchanged cetirizine. Most of the rapid increase in peak plasma radioactivity was related to the parent drug, implying a low level of first pass metabolism. This prevents potential interactions of cetirizine with drugs interacting with hepatic cytochrome enzymes. Cetirizine is metabolized partially by oxidative O-dealkylation to a metabolite with insignificant antihistaminic activity. The enzyme or enzymes responsible for this step in cetirizine metabolism have not yet been identified.

来源:DrugBank

代谢

在一项针对6名健康男性志愿者的质量平衡研究中，给药的放射性活性的70%在尿液中回收，10%在粪便中回收。大约50%的放射性活性在尿液中以未改变的药物形式被鉴定。血浆中放射性活性的快速增加主要与母药相关，这表明首次通过代谢的程度较低。西替利嗪通过氧化O-脱烷基化有限地代谢为一个几乎无抗组胺活性的代谢物。负责这种代谢的酶或酶尚未被鉴定。

A mass balance study in 6 healthy male volunteers indicated that 70% of the administered radioactivity was recovered in the urine and 10% in the feces. Approximately 50% of the radioactivity was identified in the urine as unchanged drug. Most of the rapid increase in peak plasma radioactivity was associated with parent drug, suggesting a low degree of first-pass metabolism. Cetirizine is metabolized to a limited extent by oxidative O-dealkylation to a metabolite with negligible antihistaminic activity. The enzyme or enzymes responsible for this metabolism have not been identified.

来源:Hazardous Substances Data Bank (HSDB)

代谢

氢xyzine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xyzine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用计算机建模确定。口服氢xyzine的平均系统可用性为72%。氢xyzine迅速转化为西替利嗪，无论给药途径如何。西替利嗪的平均曲线下面积在静脉给药和口服给药后分别比氢xyzine高8倍和10倍。口服给药氢xyzine后，西替利嗪的平均峰浓度约为2.2微克/毫升，而氢xyzine为0.16微克/毫升。静脉注射和口服给药氢xyzine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的数据进行比较，得到了一个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xyzine的剂量或给药频率并不会获得优于每次2毫克/千克、每日两次的氢xyzine给药的组胺抑制作用。总之，氢xyzine迅速转化为西替利嗪。风团形成的减少几乎完全归因于西替利嗪。药效学建模预测，每次2毫克/千克、每日两次口服给药氢xyzine可实现最大的抗组胺效果。

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 microg 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

半衰期：8.3小时

Half Life: 8.3 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

Cetirizine与组胺竞争结合在效应细胞表面的H1受体位点，从而抑制组胺引起的血管水肿、红斑和瘙痒。由于其侧链上的乙胺部分带有较少亲脂性的羧基，导致Cetirizine进入中枢神经系统的渗透减少，因此其引起镇静的几率较低。

Cetirizine competes with histamine for binding at H₁-receptor sites on the effector cell surface, resulting in suppression of histaminic edema, flare, and pruritus. The low incidence of sedation can be attributed to reduced penetration of cetirizine into the CNS as a result of the less lipophilic carboxyl group on the ethylamine side chain.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 药物性肝损伤

化合物：西替利嗪

Compound:cetirizine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：低药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重性等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

不良反应部分

Label Section:Adverse reactions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

西替利嗪口服给药片剂或糖浆制剂后，在成年志愿者中迅速吸收，达到最高浓度（Tmax）的时间大约为1小时。研究发现，片剂和糖浆剂型的生物利用度相似。当健康的研究志愿者接受多次剂量的西替利嗪（10毫克片剂，每日一次，连续10天），测得的平均峰血浆浓度（Cmax）为311 ng/mL。**食物对吸收的影响**食物对西替利嗪暴露（AUC）没有影响，然而，在饱食状态下，Tmax延迟了1.7小时，Cmax降低了23%。

Cetirizine was rapidly absorbed with a time to maximum concentration (Tmax) of about 1 hour after oral administration of tablets or syrup formulation in adult volunteers. Bioavailability was found to be similar between the tablet and syrup dosage forms. When healthy study volunteers were given several doses of cetirizine (10 mg tablets once daily for 10 days), a mean peak plasma concentration (Cmax) of 311 ng/mL was measured. **Effect of food on absorption** Food had no effect on cetirizine exposure (AUC), however, Tmax was delayed by 1.7 hours and Cmax was decreased by 23% in the fed state.

来源:DrugBank

吸收、分配和排泄

• 消除途径

主要经尿液排出，70-85%的口服剂量可以在尿液中找到，10-13%在大便中。

Mainly eliminated in the urine,. Between 70 – 85% of an orally administered dose can be found in the urine and 10 – 13% in the feces.

来源:DrugBank

吸收、分配和排泄

• 分布容积

表观分布容积：0.44 +/- 0.19 L/kg。

Apparent volume of distribution: 0.44 +/- 0.19 L/kg.

来源:DrugBank

吸收、分配和排泄

• 清除

表观总身体清除率：大约53毫升/分钟。西替利嗪主要通过肾脏消除，中到重度肾功能损害患者以及接受血液透析的患者需要调整剂量。

Apparent total body clearance: approximately 53 mL/min. Cetirizine is mainly eliminated by the kidneys,. Dose adjustment is required for patients with moderate to severe renal impairment and in patients on hemodialysis.

来源:DrugBank

吸收、分配和排泄

在一项针对6名健康男性志愿者的质量平衡研究中，给药的放射性活性的70%在尿液中回收，10%在粪便中回收。大约50%的放射性活性在尿液中以未改变的药物形式被鉴定。血浆中放射性活性的快速增加主要与母药相关，这表明首次通过代谢的程度较低。西替利嗪通过氧化O-脱烷基化有限地代谢为一个几乎无抗组胺活性的代谢物。负责这种代谢的酶或酶尚未被鉴定。

A mass balance study in 6 healthy male volunteers indicated that 70% of the administered radioactivity was recovered in the urine and 10% in the feces. Approximately 50% of the radioactivity was identified in the urine as unchanged drug. Most of the rapid increase in peak plasma radioactivity was associated with parent drug, suggesting a low degree of first-pass metabolism. Cetirizine is metabolized to a limited extent by oxidative O-dealkylation to a metabolite with negligible antihistaminic activity. The enzyme or enzymes responsible for this metabolism have not been identified.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• WGK Germany：
  3
• RTECS号：
  AG0977500
• 海关编码：
  2933599090
• 危险性防范说明：
  P261,P264,P271,P280,P302+P352,P304+P340,P305+P351+P338,P312,P332+P313,P337+P313,P362,P403+P233,P405,P501
• 危险性描述：
  H315,H319,H335
• 储存条件：
  2-8℃

制备方法与用途

概述了西替利嗪的基本信息、化学性质、用途及生产工艺。具体包括：

1. 基本信息：介绍了药物的用法用量、不良反应及其注意事项。

2. 化学性质与结构：详细描述了二盐酸西替利嗪的分子式和熔点。

3. 药理作用与临床应用：强调其抗过敏效果，适用于呼吸系统、皮肤及眼部疾病的治疗，并提及一些副作用如嗜睡等需注意的情况。

4. 生产方法：简要说明了西替利嗪的合成过程。

反应信息

• 作为反应物：
  描述：

  西替利嗪 在 锰 、 氯化镍二甲氧基乙烷 、 4,4'-二甲氧基-2,2'-联吡啶 、 1,8-双二甲氨基萘 、 fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate 作用下， 以 N-甲基吡咯烷酮 为溶剂， 反应 24.0h， 生成 4-(benzo[d][1,3]dioxol-5-yl)-1-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)ethoxy)butan-2-one
  参考文献：
  名称：

  镍催化 N-烷基吡啶鎓盐与活化羧酸偶联合成二烷基酮。

  摘要：

  虽然酮是最通用的官能团之一，但它们的合成仍然依赖于反应性和低丰度的起始材料。相比之下，酰胺形成是药物化学中最常用的键构建方法，因为该化学反应可靠并且利用大量多样的底物库。这里提出了一种合成酮的新方法，该方法利用与酰胺键合成相同的底物：胺和羧酸。三联吡啶镍催化剂在还原条件下（锰金属）将 N-烷基吡啶鎓盐与原位形成的羧酰氟或 2-吡啶酯偶联。该反应范围广泛，合成了 35 种带有多种官能团的不同酮，平均产率为 60±16%。这种方法能够偶联不同的底物，包括药物中间体，以快速形成复杂的酮。

  DOI：

  10.1002/anie.202002271
• 作为产物：
  描述：

  2-{2-[4-[(4-氯苯基)苯基甲基]-1-哌嗪基]乙氧基}乙醛二乙基缩醛 在 盐酸 、 sodium hydroxide 、 双氧水 作用下， 以 水 、 乙醇 为溶剂， 反应 0.5h， 以85.3%的产率得到西替利嗪
  参考文献：
  名称：

  A PROCESS FOR THE PREPARATION OF 2- 2- 4-(DIPHENYLMETHYL)-1-PIPERAZINYL]ETHOXY ACETIC ACID COMPOUNDS OR SALTS THEREOF

  摘要：

  公开号：

  EP1157016B1
• 作为试剂：
  描述：

  2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)ethoxy)acetamide 、 水 在 西替利嗪 、 halogenated hydrocarbon 、 乙酸盐 、 Sodium sulfate-III 、 magnesium sulfate 作用下， 生成 西替利嗪
  参考文献：
  名称：

  Novel amorphous form of [2-[4-[(4-chlorophenyl)-phenyl methyl]-1-piperazinyl]ethoxy]acetic acid and process for the preparation thereof

  摘要：

  本文描述了赛替利嗪的一种新型非晶形态，以及制备该非晶形态的方法、组合物、药物组合物和利用晶态形态的方法。

  公开号：

  US20040266787A1

文献信息

• [EN] S-NITROSOMERCAPTO COMPOUNDS AND RELATED DERIVATIVES<br/>[FR] COMPOSÉS DE S-NITROSOMERCAPTO ET DÉRIVÉS APPARENTÉS
  申请人：GALLEON PHARMACEUTICALS INC

  公开号：WO2009151744A1

  公开（公告）日：2009-12-17

  The present invention is directed to mercapto-based and S- nitrosomercapto-based SNO compounds and their derivatives, and their use in treating a lack of normal breathing control, including the treatment of apnea and hypoventilation associated with sleep, obesity, certain medicines and other medical conditions.

  本发明涉及基于巯基和S-亚硝基巯基的SNO化合物及其衍生物，以及它们在治疗正常呼吸控制缺失方面的用途，包括治疗与睡眠、肥胖、某些药物和其他医疗状况相关的呼吸暂停和低通气。
• [EN] NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS<br/>[FR] NOUVEAUX COMPOSÉS ET COMPOSITIONS PHARMACEUTIQUES LES COMPRENANT POUR LE TRAITEMENT DE TROUBLES INFLAMMATOIRES
  申请人：GALAPAGOS NV

  公开号：WO2017012647A1

  公开（公告）日：2017-01-26

  The present invention discloses compounds according to Formula (I), wherein R1, R3, R4, R5, L1, and Cy are as defined herein. The present invention also provides compounds, methods for the production of said compounds of the invention, pharmaceutical compositions comprising the same and their use in allergic or inflammatory conditions, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 and/or interferons. The present invention also methods for the prevention and/or treatment of the aforementioned diseases by administering a compound of the invention.

  本发明公开了根据式（I）的化合物，其中R1、R3、R4、R5、L1和Cy如本文所定义。本发明还提供了该发明的化合物、制备该化合物的方法、包括相同化合物的药物组合物以及它们在过敏或炎症症状、自身免疫疾病、增殖性疾病、移植排斥、涉及软骨周转障碍的疾病、先天软骨畸形和/或与IL6和/或干扰素过度分泌相关的疾病中的使用。本发明还提供了通过给予该发明的化合物来预防和/或治疗上述疾病的方法。
• [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。
• SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS
  申请人：BLUM Andreas

  公开号：US20140135309A1

  公开（公告）日：2014-05-15

  This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I wherein Ar, R 1 and R 2 are as defined herein, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及公式I的新型磺酰胺取代的喹唑啉衍生物，其中Ar、R1和R2如本文所定义，并且它们作为MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。
• [EN] SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] QUINAZOLINES SUBSTITUÉES PAR SULFOXIMINE POUR COMPOSITIONS PHARMACEUTIQUES
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2014072244A1

  公开（公告）日：2014-05-15

  This invention relates to novel sulfoximine substituted quinazoline derivatives of formula (I), wherein Ar, R1 and R2 are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及一种新型的配方(I)的磺酰胺取代喹唑啉衍生物，其中Ar、R1和R2如描述和声明中所定义，并且它们作为MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。