氯氮平 | 5786-21-0

• 物质功能分类: 原料药 - 神经系统用药 - 抗精神病药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 中文名称: 氯氮平
• 中文别名: 氯扎平
• 英文名称: clozaril
• 英文别名: clozapin；clozapine；Clozapine；3-chloro-6-(4-methylpiperazin-1-yl)-11H-benzo[b][1,4]benzodiazepine
• CAS: 5786-21-0
• 化学式: C₁₈H₁₉ClN₄
• mdl: MFCD00153785
• 分子量: 326.829
• InChiKey: QZUDBNBUXVUHMW-UHFFFAOYSA-N

物化性质

• 熔点：
  182-185°C
• 沸点：
  482.71°C (rough estimate)
• 密度：
  1.1327 (rough estimate)
• 闪点：
  9℃
• 溶解度：
  乙醇：1 mg/mL
• 物理描述：
  Solid
• 颜色/状态：
  Yellow crystals from acetone-petroleum ether
• 蒸汽压力：
  1.12X10-8 mm Hg at 25 °C (est)
• 亨利常数：
  Henry's Law constant = 9.29X10-15 atm-cu m/mol at 25 °C (est)
• 稳定性/保质期：
  常温常压下，这种物质稳定存在，呈现淡黄色结晶性粉末状。其熔点为183-184℃。易溶于氯仿，可溶于乙醇，几乎不溶于水。无特殊气味。
• 解离常数：
  pKa = 7.50
• 碰撞截面：
  178.8 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]
• 保留指数：
  2859;2873;2893;2915

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  23
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.277
• 拓扑面积：
  30.9
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

代谢

肝脏的

Hepatic

来源:DrugBank

代谢

狂躁症和精神分裂症患者每天给予神经阻滞剂氯氮平300-500毫克，并从尿液中分离出氯氮平的代谢物，通过气相色谱-质谱法进行分析。氯氮平转化为2种代谢物，通过氯原子被羟基或甲硫基团取代。进一步的代谢物是前两个代谢物的N-去甲基衍生物。还发现了一个具有氧化哌嗪环的代谢物，并提示可能存在一个具有氧化硫的代谢物。

Manic and schizophrenic patients were given neuroleptic clozapine at 300-500 mg daily and metabolites of clozapine were isolated from urine and analyzed by gas chromatography-mass spectrometry. Clozapine was converted into 2 metabolites by replacement of chlorine atom by a hydroxyl or methylsulfide group. Further metabolites were the N-demethyl deriv of 1st two metabolites. A metabolite with an oxidized piperazine ring was also found, and possibility of a metabolite with an oxidized sulfur is suggested.

来源:Hazardous Substances Data Bank (HSDB)

代谢

/Clozapine/ 被代谢成 N-氧化氯氮平和 N-去甲基氯氮平，这两种代谢物的药理活性低于原化合物，并通过尿液排出，较少部分通过粪便排出。

/Clozapine/ is metabolized to N-oxideclozapine and N-desmethylclozapine, which have less pharmacological activity than the parent compound and are excreted in the urine and, to a lesser extent, in the feces.

来源:Hazardous Substances Data Bank (HSDB)

代谢

氯氮平已知的人类代谢物包括氯氮平N-葡萄糖苷酸、氯氮平-N-氧化物和N-去甲基氯氮平。

Clozapine has known human metabolites that include Clozapine N-glucuronide, Clozapine-N-oxide, and N-Desmethylclozapine.

来源:NORMAN Suspect List Exchange

毒理性

• 毒性总结

氯氮平因粒细胞缺乏症而带有黑盒警告。

Clozapine carries a black-box warning for agranulocytosis.

来源:DrugBank

毒理性

• 毒性总结

识别和使用：氯氮平在未经控制和控制的研究中已被证明是一种有效的、相对快速作用的、广谱的抗精神病药物，适用于精神分裂症患者的治疗。氯氮平在有限数量的晚期特发性帕金森综合症患者中使用，用于管理抗帕金森病药物治疗相关的多巴胺能精神病态，但镇静、混乱和帕金森症状加重等不良反应可能会限制这些患者中氯氮平治疗的益处。氯氮平用于降低精神分裂症或分裂情感障碍患者复发性自杀行为的风险，这些患者根据病史和近期临床状态被判定为长期风险。尽管氯氮平在16岁以下儿童和青少年中的安全性和有效性尚未确立，但该药物已成功用于治疗难治性儿童和青少年的儿童期发病精神分裂症。氯氮平用于症状性管理严重精神病患者的精神分裂症，这些患者的疾病对其他抗精神病治疗反应不足。人类暴露和毒性：氯氮平最常见的不良反应涉及中枢和自主神经系统（例如，嗜睡或镇静，过度流涎）和心血管系统（例如，心动过速，低血压）。尽管一些不良反应（例如，外周抗胆碱能反应，迟发性运动障碍）的频率和严重程度在氯氮平中似乎低于其他抗精神病药物，但其他可能严重的不良反应（例如，粒细胞缺乏症，癫痫）在氯氮平治疗中可能更频繁发生，因此在考虑使用该药物治疗时应仔细评估潜在的风险和益处。尽管有人建议芬兰病例中可能涉及局部遗传或环境因素，但尚未证实存在此类因素。在芬兰的2个月期间，有18例与氯氮平相关的严重血液障碍报告（9例致命）。粒细胞缺乏症导致8人死亡，白血病可能导致第九人死亡。在芬兰以外22个国家的氯氮平市场经验表明，粒细胞缺乏症的发病率为0.3/1000，而在芬兰的发病率几乎高出20倍，其他三环类神经安定剂的发病率为0.1至0.8/1000。接受氯氮平灵活剂量的患者（平均剂量：每日274.2毫克）大约2年，与接受奥氮平灵活剂量的患者（平均剂量：每日16.6毫克）相比，自杀尝试或为预防自杀而住院的风险降低了26%；患者的难治性状态并不预示对氯氮平或奥氮平的反应。动物研究：连续口服给予大鼠（6个月）和狗（3个月）剂量为20毫克/千克或更多的大鼠和10毫克/千克的狗，体重增加减少。肝肥大并非严格剂量依赖性，且未与组织学变化或血液化学变化相关，并在停药后完全可逆。在大鼠或狗中没有观察到毒性迹象。大鼠和兔子的每日口服剂量为20或40毫克/千克的氯氮平没有致畸作用，对雄性和雌性大鼠的生育能力也没有影响。然而，在40毫克/千克时，氯氮平抑制了接受治疗母亲的哺乳幼崽的生长。F1代治疗母亲的生育能力正常，F2代的发展没有异常。氯氮平盐酸盐抑制了大鼠的条件性回避行为，还抑制了小鼠由苯基苯并喹啉诱导的扭动综合症，并降低了体温。氯氮平盐酸盐拮抗了小鼠由氧化震颤素诱导的震颤和流泪，降低了毒扁豆碱的急性毒性和大脑中5-羟基吲哚乙酸的浓度。

IDENTIFICATION AND USE: Clozapine has been shown to be an effective, relatively rapid-acting, broad-spectrum antipsychotic agent in both uncontrolled and controlled studies of patients with schizophrenia.Clozapine has been used in a limited number of patients with advanced, idiopathic parkinsonian syndrome for the management of dopaminomimetic psychosis associated with antiparkinsonian drug therapy, but adverse effects such as sedation, confusion, and increased parkinsonian manifestations may limit the benefit of clozapine therapy in these patients. Clozapine is used to reduce the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for such behavior, based on history and recent clinical state. Although the safety and efficacy of clozapine in children and adolescents younger than 16 years of age have not been established, the drug has been successfully used for the management of childhood-onset schizophrenia in a limited number of treatment-resistant children and adolescents. Clozapine is used for the symptomatic management of schizophrenia in severely ill patients whose disease fails to respond adequately to other antipsychotic therapy. HUMAN EXPOSURE AND TOXICITY: The most frequent adverse effects of clozapine involve the central and autonomic nervous systems (e.g., drowsiness or sedation, hypersalivation) and the cardiovascular system (e.g., tachycardia, hypotension). While the frequency and severity of some adverse effects (e.g., extrapyramidal reactions, tardive dyskinesia) appear to be less with clozapine than with other antipsychotic agents, other potentially serious adverse effects (e.g., agranulocytosis, seizures) may occur more frequently with clozapine therapy, and the potential risks and benefits should be evaluated carefully whenever therapy with the drug is considered. Although it has been suggested that a local genetic or environmental factor or factors may have been involved in the Finnish cases, the existence of such a factor has not been documented. During a 2 month period in Finland there were 18 reports of severe blood disorders (9 fatal) associated with clozapine. Agranulocytosis accounted for 8 of the deaths and leukemia probably for the ninth. Experience in 22 other countries outside Finland where clozapine had been marketed indicated an incidence of agranulocytosis of 0.3 per 1000 compared with an incidence almost 20 times as high in Finland and with 0.1 to 0.8 per 1000 for other tricyclic neuroleptics. patients who received flexible dosages of clozapine (mean dosage: 274.2 mg daily) for approximately 2 years had a 26% reduction in their risk for suicide attempts or hospitalization to prevent suicide compared with those who received flexible dosages of olanzapine (mean dosage: 16.6 mg daily); the treatment-resistant status of patients was not predictive of response to clozapine or olanzapine. ANIMAL STUDIES: Repeated oral administration to rats (6 months) and to dogs (3 months) decreased wt gain with doses of 20 mg/kg or more in rats and of 10 mg/kg or more in dogs. Hepatic hypertrophy, which was not strictly dose-dependent, was not associated with either histological changes or changes in blood chemistry and was completely reversible after discontinuation of treatment. No toxic signs were observed in rats or in dogs. Clozapine in daily oral doses of 20 or 40 mg/kg to rats and rabbits had no teratogenic effects and no influence on the fertility of male and female rats. At 40 mg/kg, however, clozapine inhibited growth of suckling young of treated mothers. Fertility of F1 treated mothers was normal and development of F2 showed no abnormalities. Clozapine hydrochloride inhibited conditioned avoidance behavior in rats, also inhibited writhing syndrome induced by phenylbenzoquinone in mice, and decreased body temp. Clozapine hydrochloride antagonized tremor and lacrimation induced by oxotremorine in mice, decreased the acute toxicity of physostigmine and 5-hydroxyindol acetate level in brain.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

血清酶水平升高在服用氯氮平的患者中多达三分之二，但通常升高幅度不大，且在6到12周内会自行缓解，通常不需要调整剂量或停药。偶尔，血清酶水平升高会伴随恶心、虚弱和腹部不适的症状，应停止治疗或在仔细减少剂量的情况下进行管理。 在接受氯氮平治疗的超过十几例患者中报告了急性、临床上明显的肝脏损伤事件，表现为肝酶显著升高和黄疸，估计在约每2000名治疗患者中发生1例。损伤的发生通常在开始治疗后的几天到几周内，血清酶升高的典型模式是肝细胞型或混合型，尽管也有胆汁淤积的病例描述。还描述了急性肝损伤的严重病例，包括进行性肝衰竭、死亡或需要紧急移植。嗜酸性粒细胞增多或白细胞增多并不少见，还报告了发热和皮疹，尽管通常较轻。自身免疫标记物罕见。 可能性评分：B（很可能是临床上明显肝损伤的原因）。

Serum enzyme elevations arise in up to two-thirds of patients on clozapine but are usually modest and resolve spontaneously after 6 to 12 weeks, often not requiring dose modification or discontinuation. Occasionally, serum enzyme elevations are associated with symptoms of nausea, weakness and abdominal discomfort, and therapy should be discontinued or managed with careful dose reduction. Acute, clinically apparent episodes of liver injury with marked liver enzyme elevations and jaundice have been reported in more than a dozen patients receiving clozapine and is estimated to occur in ~1:2000 treated patients. The onset of injury is usually within a few days to several weeks after starting, and the typical pattern of serum enzyme elevations is hepatocellular or mixed, although cholestatic cases have also been described. Severe instances of acute liver injury with progressive hepatic failure and death or need for emergency transplantation have also been described. Eosinophilia or leukocytosis are not uncommon and fever and rash have been reported, although generally mild. Autoimmune markers are rare. Likelihood score: B (very likely cause of clinically apparent liver injury).

来源:LiverTox

毒理性

• 药物性肝损伤

药物名称：氯氮平

Compound:clozapine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：最令人关注的药物性肝损伤

DILI Annotation:Most-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

快速而几乎完整

Rapid and almost complete

来源:DrugBank

吸收、分配和排泄

• 消除途径

大约50%的给药剂量通过尿液排出，30%通过粪便排出。

Approximately 50% of the administered dose is excreted in the urine and 30% in the feces.

来源:DrugBank

吸收、分配和排泄

氯氮平在排泄前几乎完全代谢，尿和粪便中仅能检测到微量的未改变药物。大约50%的给药剂量通过尿液排泄，30%通过粪便排泄。脱甲基、羟基化和N-氧化物衍生物是尿液和粪便中的组成部分。药理测试表明，去甲基代谢物仅具有有限活性，而羟基化和N-氧化物衍生物则无活性。

Clozapine is almost completely metabolized prior to excretion and only trace amounts of unchanged drug are detected in the urine and feces. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. The demethylated, hydroxylated and N-oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite to have only limited activity, while the hydroxylated and N-oxide derivatives were inactive.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在人体中，氯氮平片剂（25毫克和100毫克）相对于氯氮平溶液具有相同的生物利用度。在每次服用100毫克，每日两次的剂量后，平均稳态峰值血浆浓度为319纳克/毫升（范围：102至771纳克/毫升），平均在给药后2.5小时（范围：1至6小时）出现。在每次服用100毫克，每日两次的剂量后，稳态下的平均最低浓度为122纳克/毫升（范围：41至343纳克/毫升）。食物似乎不会影响氯氮平的系统生物利用度。因此，氯氮平可以在有食物或无食物的情况下服用。氯氮平大约有97%与血清蛋白结合。

In man, clozapine tablets (25 mg and 100 mg) are equally bioavailable relative to a clozapine solution. Following a dosage of 100 mg b.i.d., the average steady-state peak plasma concentration was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2.5 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady-state was 122 ng/mL (range: 41 to 343 ng/mL), after 100 mg b.i.d. dosing. Food does not appear to affect the systemic bioavailability of clozapine. Thus, clozapine may be administered with or without food. Clozapine is approximately 97% bound to serum proteins.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Clozapine是一种抗精神病药物，口服给药后能够迅速吸收，无论是单次给药还是多次给药。在开始治疗后的八到十天内，Clozapine可以达到稳态血药浓度。

Clozapine is rapidly absorbed after both single and repeated oral doses, with steady-state concentrations attained within eight to ten days after beginning therapy.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(b)
• 危险品标志：
  Xi
• 安全说明：
  S26
• 危险类别码：
  R22,R36/37/38
• WGK Germany：
  3
• 海关编码：
  2933990090
• 危险品运输编号：
  UN 2811 6.1/PG 3
• 危险类别：
  6.1(b)
• RTECS号：
  HP1750000
• 包装等级：
  III
• 危险标志：
  GHS06,GHS08
• 危险性描述：
  H301,H341,H361
• 危险性防范说明：
  P281,P301 + P310
• 储存条件：
  常温、避光、存放在阴凉干燥处，并密封保存。

SDS

氯氮平 修改号码：5

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模块 1. 化学品
产品名称： Clozapine
修改号码： 5

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模块 2. 危险性概述
GHS分类
物理性危害 未分类
健康危害
急性毒性（经口） 第3级
皮肤腐蚀/刺激 第2级
严重损伤/刺激眼睛 2A类
环境危害 未分类
GHS标签元素
图标或危害标志
信号词 危险
危险描述 吞咽会中毒。
造成皮肤刺激
造成严重眼刺激
防范说明
[预防] 使用本产品时切勿吃东西，喝水或吸烟。
处理后要彻底清洗双手。
穿戴防护手套/护目镜/防护面具。
[急救措施] 食入：立即呼叫解毒中心/医生。
眼睛接触：用水小心清洗几分钟。如果方便，易操作，摘除隐形眼镜。继续冲洗。
眼睛接触：求医/就诊
皮肤接触：用大量肥皂和水轻轻洗。
若皮肤刺激：求医/就诊。
脱掉被污染的衣物，清洗后方可重新使用。
[储存] 存放处须加锁。
[废弃处置] 根据当地政府规定把物品/容器交与工业废弃处理机构。
氯氮平 修改号码：5

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模块 3. 成分/组成信息
单一物质/混和物 单一物质
化学名(中文名)： 氯氮平
百分比： >98.0%(GC)(T)
CAS编码： 5786-21-0
俗名： 8-Chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine
分子式： C18H19ClN4

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模块 4. 急救措施
吸入： 将受害者移到新鲜空气处，保持呼吸通畅，休息。若感不适请求医/就诊。
皮肤接触： 立即去除/脱掉所有被污染的衣物。用大量肥皂和水轻轻洗。
若皮肤刺激或发生皮疹：求医/就诊。
眼睛接触： 用水小心清洗几分钟。如果方便，易操作，摘除隐形眼镜。继续清洗。
如果眼睛刺激：求医/就诊。
食入： 立即呼叫解毒中心/医生。漱口。
紧急救助者的防护： 救援者需要穿戴个人防护用品，比如橡胶手套和气密性护目镜。

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模块 5. 消防措施
合适的灭火剂： 干粉，泡沫，雾状水，二氧化碳
特殊危险性： 小心，燃烧或高温下可能分解产生毒烟。
特定方法： 从上风处灭火，根据周围环境选择合适的灭火方法。
非相关人员应该撤离至安全地方。
周围一旦着火：如果安全，移去可移动容器。
消防员的特殊防护用具： 灭火时，一定要穿戴个人防护用品。

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模块 6. 泄漏应急处理
个人防护措施，防护用具， 使用特殊的个人防护用品（针对有毒颗粒的P3过滤式空气呼吸器）。远离溢出物/泄露
紧急措施： 处并处在上风处。
泄露区应该用安全带等圈起来，控制非相关人员进入。
环保措施： 防止进入下水道。
控制和清洗的方法和材料： 清扫收集粉尘，封入密闭容器。注意切勿分散。附着物或收集物应该立即根据合适的
法律法规处置。

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模块 7. 操作处置与储存
处理
技术措施： 在通风良好处进行处理。穿戴合适的防护用具。防止粉尘扩散。处理后彻底清洗双手
和脸。
注意事项： 如果可能，使用封闭系统。如果粉尘或浮质产生，使用局部排气。
操作处置注意事项： 避免接触皮肤、眼睛和衣物。
贮存
储存条件： 保持容器密闭。存放于凉爽、阴暗处。
存放处须加锁。
远离不相容的材料比如氧化剂存放。
包装材料： 依据法律。

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模块 8. 接触控制和个体防护
工程控制： 尽可能安装封闭体系或局部排风系统。同时安装淋浴器和洗眼器。
个人防护用品
呼吸系统防护： 防尘面具，自携式呼吸器（SCBA），供气呼吸器等。使用通过政府标准的呼吸器。依
据当地和政府法规。
氯氮平 修改号码：5

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模块 8. 接触控制和个体防护
手部防护： 防渗手套。
眼睛防护： 护目镜。如果情况需要，佩戴面具。
皮肤和身体防护： 防渗防护服。如果情况需要，穿戴防护靴。

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模块 9. 理化特性
固体
外形（20°C）：
外观： 晶体-粉末
颜色： 浅黄色-深黄色
气味： 无资料
pH: 无数据资料
熔点： 185°C
沸点/沸程 无资料
闪点： 无资料
爆炸特性
爆炸下限： 无资料
爆炸上限： 无资料
密度： 无资料
溶解度：
[水] 不溶于
[其他溶剂]
溶于： 甲醇, 丙酮, 氯仿, 热乙酸
微溶于： 乙腈
log水分配系数 = 17.4

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模块 10. 稳定性和反应性
化学稳定性： 一般情况下稳定。
危险反应的可能性： 未报道特殊反应性。
须避免接触的物质 氧化剂
危险的分解产物: 一氧化碳, 二氧化碳, 氮氧化物 (NOx), 氯化氢

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模块 11. 毒理学信息
急性毒性： orl-rat LD50:251 mg/kg
ipr-mus LD50:90 mg/kg
ivn-rat LD50:41600 ug/kg
scu-rat LD50:240 mg/kg
对皮肤腐蚀或刺激： 无资料
对眼睛严重损害或刺激： 无资料
生殖细胞变异原性： cyt-hmn-lym 10 mg/L
sln-dmg-orl 2 mg/2D
致癌性：
IARC = 无资料
NTP = 无资料
生殖毒性： 无资料
RTECS 号码: HP1750000

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模块 12. 生态学信息
生态毒性：
鱼类： 无资料
甲壳类： 无资料
藻类： 无资料
氯氮平 修改号码：5

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模块 12. 生态学信息
残留性 / 降解性： 无资料
潜在生物累积 （BCF): 无资料
土壤中移动性
log水分配系数： 17.4
土壤吸收系数 （Koc）： 无资料
亨利定律 无资料
constant(PaM3/mol):

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模块 13. 废弃处置
如果可能，回收处理。请咨询当地管理部门。建议在可燃溶剂中溶解混合，在装有后燃和洗涤装置的化学焚烧炉中
焚烧。废弃处置时请遵守国家、地区和当地的所有法规。

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模块 14. 运输信息
联合国分类： 第1项 毒害品。
UN编号： 2811
正式运输名称： 有毒固体, 有机物, 不另作详细说明
包装等级： III

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模块 15. 法规信息
《危险化学品安全管理条例》（2002年1月26日国务院发布，2011年2月16日修订）: 针对危险化学品的安全使用、
生产、储存、运输、装卸等方面均作了相应的规定。

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模块16 - 其他信息
N/A

制备方法与用途

根据提供的信息，我将对氯氮平进行一个总结：

基本信息

化学名称: 10-[3-(2,6-二吗啉乙基)苯并[5,6]二唑-7-基]-8-氯-11H-二苯并[b,e][1,4]二氮杂卓-11-酮

物理化学性质

• 淡黄色结晶性粉末，熔点为183-184℃。
• 易溶于氯仿，能溶于乙醇，几乎不溶于水。

药物分类

• 非典型抗精神病药
• 作用于D4多巴胺受体

主要用途

• 急性及慢性精神分裂症的治疗
• 特别对幻觉妄想型、青春型患者效果较好
• 对精神分裂症的阳性症状和阴性症状均表现出良好的疗效

注意事项与禁忌证

1. 严重不良反应：诱发粒细胞减少或缺乏是最严重的副作用之一。需密切监测血象。
2. 特殊人群慎用/禁用
   • 16岁以下儿童
   • 闭角型青光眼患者
   • 前列腺增生、痉挛性疾病史者
   • 癫痫及严重心血管疾病患者
3. 中枢神经抑制状态的患者、曾有骨髓抑制或血细胞异常病史者禁用

生产方法

• 2-氨基-4-氯二苯胺-2'-羧酸（4''-甲基）哌嗪与三氯氧磷反应生成目标化合物。

注意事项

1. 使用本品期间应定期监测白细胞计数。
2. 粒细胞减少风险高，一旦出现感染或发热症状应及时就医。
3. 用药时需注意与其他中枢神经系统药物之间的相互作用。
4. 哺乳期妇女不宜使用。
5. 有粒细胞减少、严重肝肾疾病史者应慎用。

不良反应

常见的不良反应包括粒细胞减少症，以及嗜睡、恶心等。长期用药可能引起成瘾性。

总结

氯氮平是一种有效的非典型抗精神病药物，适用于治疗精神分裂症患者的阳性及阴性症状。然而，其使用需谨慎，并且需要严密监控潜在的严重不良反应如粒细胞减少。在临床实践中应遵循严格的监测和管理指导原则以确保患者安全有效地接受治疗。

反应信息

• 作为反应物：
  描述：

  氯氮平 在 吡啶 、 溶剂黄146 、 N,N-二异丙基乙胺 、 锌 、 亚硝酸异戊酯 作用下， 以 二氯甲烷 为溶剂， 反应 7.0h， 生成 N1,N18-bis(8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepin-5-yl)octadecanediamide
  参考文献：
  名称：

  Homobivalent Ligands of the Atypical Antipsychotic Clozapine: Design, Synthesis, and Pharmacological Evaluation

  摘要：

  To date all typical and atypical antipsychotics target the dopamine D-2 receptor. Clozapine represents the best-characterized atypical antipsychotic, although it displays only moderate (submicromolar) affinity for the dopamine D-2 receptor. Herein, we present the design, synthesis, and pharmacological evaluation of three series of homobivalent ligands of clozapine, differing in the length and nature of the spacer and the point of attachment to the pharmacophore. Attachment of the spacer at the N4' position of clozapine yielded a series of homobivalent ligands that displayed spacer-length-dependent gains in affinity and activity for the dopamine D-2 receptor. The 16 and 18 atom spacer bivalent ligands were the highlight compounds, displaying marked low nanomolar receptor binding affinity (1.41 and 1.35 nM, respectively) and functional activity (23 and 44 nM), which correspond to significant gains in affinity (75- and 79-fold) and activity (9- and 5-fold) relative to the original pharmacophore, clozapine. As such these ligands represent useful tools with which to investigate dopamine receptor dimerization and the atypical nature of clozapine.

  DOI：

  10.1021/jm201420s
• 作为产物：
  描述：

  氯氮平-N-氧化物 在 盐酸 、 titanium(III) chloride 作用下， 以 水 、 乙腈 为溶剂， 反应 1.0h， 以97%的产率得到氯氮平
  参考文献：
  名称：

  Applications of TiCl₃ as a Diagnostic Reagent for the Detection of Nitro- and N-Oxide-Containing Compounds as Potentially Mutagenic Impurities Using Ultrahigh-Performance Liquid Chromatography Coupled with High-Resolution Mass Spectrometry

  摘要：

  The ICH has strict guidelines for limiting the presence of potentially mutagenic impurities (PMIs) in marketed drugs. Therefore, it is important to fully characterize and quantitate all possible PMIs that could arise during the process of synthesizing and developing a drug. Two important and prevalent examples of PMIs are compounds containing N-oxide and nitro functional groups. TiCl3 derivatization is an established method for determining the presence or absence of N-oxide metabolites by reduction to the corresponding amine. In this study, we demonstrate a novel application of TiCl3 reduction combined with high-resolution UHPLC/HRMS to analyze PMIs. The results indicate that a variety of N-oxide- and nitro-containing compounds can be readily characterized by this facile platform method. In addition, we show that this chemical derivatization method can be utilized to enhance the ionization of nitro-containing compounds for LC/MS analysis.

  DOI：

  10.1021/acs.oprd.5b00312

文献信息

• [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。
• 4' SUBSTITUTED COMPOUNDS HAVING 5-HT6 RECEPTOR AFFINITY
  申请人：Dunn Robert

  公开号：US20080318941A1

  公开（公告）日：2008-12-25

  The present disclosure provides compounds having affinity for the 5-HT 6 receptor which are of the formula (I): wherein R 1 , R 2 , R 5 , R 6 , B, D, E, G, Q, x and n are as defined herein. The disclosure also relates to methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.

  本公开提供了具有亲和力的化合物，其对5-HT 6 受体具有亲和力，其化学式为（I）： 其中R1、R2、R5、R6、B、D、E、G、Q、x和n如本文所定义。本公开还涉及制备这种化合物的方法、含有这种化合物的组合物以及使用这些化合物的方法。
• 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。
• Imidazole derivatives as PDE10A enzyme inhibitors
  申请人：Kehler Jan

  公开号：US20120129836A1

  公开（公告）日：2012-05-24

  This invention is directed to compounds, which are PDE10A enzyme inhibitors. The invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. The present invention also provides processes for the preparation of the compounds of formula I. The present invention further provides a method of treating a subject suffering from a neurodegenerative disorder comprising administering to the subject a therapeutically effective amount of a compound of formula I. The present invention also provides a method of treating a subject suffering from a drug addiction comprising administering to the subject a therapeutically effective amount of a compound of formula I. The present invention further provides a method of treating a subject suffering from a psychiatric disorder comprising administering to the subject a therapeutically effective amount of a compound of formula I.

  这项发明涉及一类PDE10A酶抑制剂化合物。该发明提供了一种包含该发明化合物的治疗有效量和药用载体的药物组合物。本发明还提供了制备式I化合物的方法。本发明还提供了一种治疗神经退行性疾病的方法，包括向患有神经退行性疾病的受试者施用式I化合物的治疗有效量。本发明还提供了一种治疗药物成瘾的方法，包括向患有药物成瘾的受试者施用式I化合物的治疗有效量。本发明还提供了一种治疗精神障碍的方法，包括向患有精神障碍的受试者施用式I化合物的治疗有效量。

表征谱图