洛沙平 | 1977-10-2

• 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 - 苯并恶嗪类
• 中文名称: 洛沙平
• 中文别名: 克噻平
• 英文名称: loxapine
• 英文别名: rosup；Loxapin；2-chloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine；2-chloro-11-(4-methyl-1-piperazinyl)-dibenz[b,f][1,4]oxazepine；8-chloro-6-(4-methylpiperazin-1-yl)benzo[b][1,4]benzoxazepine
• CAS: 1977-10-2
• 化学式: C₁₈H₁₈ClN₃O
• 分子量: 327.813
• InChiKey: XJGVXQDUIWGIRW-UHFFFAOYSA-N

物化性质

• 熔点：
  109-110°
• 密度：
  1.2299 (rough estimate)
• 溶解度：
  溶于二甲基亚砜
• 物理描述：
  Solid
• 颜色/状态：
  Pale yellowish crystals from petroleum ether
• 分解：
  When heated to decomposition it emits very toxic fumes of /hydrogen chloride/ and nitroxides.
• 碰撞截面：
  175.7 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]
• 保留指数：
  2542;2577.2;2542;2530

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：
  0.28
• 拓扑面积：
  28.1
• 氢给体数：
  0
• 氢受体数：
  3

ADMET

代谢

肝脏的

Hepatic

来源:DrugBank

代谢

迅速且广泛地在肝脏通过芳香羟基化、N-去甲基化和N-氧化代谢。主要代谢物为...8-羟基氧拉平，7-羟基氧拉平，它们具有活性...8-羟基去甲基氧拉平、7-羟基去甲基氧拉平和氧拉平-N-氧化物，它们不具有活性/人类，口服/

RAPIDLY & EXTENSIVELY METABOLIZED IN LIVER BY AROMATIC HYDROXYLATION, N-DEMETHYLATION & N-OXIDATION. MAJOR METABOLITES...8-HYDROXYLOXAPINE, & 7-HYDROXYLOXAPINE WHICH ARE ACTIVE...8-HYDROXYDESMETHYLLOXAPINE, 7-HYDROXYDESMETHYLLOXAPINE & LOXAPINE-N-OXIDE WHICH ARE INACTIVE /HUMAN, ORAL/

来源:Hazardous Substances Data Bank (HSDB)

代谢

大量N-氧化物/7-羟基-和8-羟基氧化哌嗪，通过羟基化和N-氧化形成的代谢物/存在...氧化哌嗪的代谢物主要以葡萄糖醛酸或硫酸盐结合物形式通过尿液排出/人类，口服/

SIGNIFICANT AMT OF N-OXIDES OF /7-HYDROXY- & 8-HYDROXYLOXAPINES, METABOLITES FORMED BY HYDROXYLATION & N-OXIDATION/, PRESENT...LOXAPINE METABOLITES ARE EXCRETED IN URINE PRIMARILY AS GLUCURONIDE OR SULFATE CONJUGATES /HUMAN, ORAL/

来源:Hazardous Substances Data Bank (HSDB)

代谢

2种代谢物：8-羟基洛沙平 & 8-羟基阿莫沙平，口服药物后增加。

2 METABOLITES: 8-HYDROXYLOXAPINE & 8-HYDROXYAMOXAPINE, INCR ON ORAL MEDICATION.

来源:Hazardous Substances Data Bank (HSDB)

代谢

盐酸洛沙平在肝脏中被迅速且广泛地代谢，通过芳香羟基化、N-氧化等方式。盐酸洛沙平的主要代谢物是8-羟基洛沙平和7-羟基洛沙平，它们具有活性，以及8-羟基去甲基洛沙平、7-羟基去甲基洛沙平和洛沙平N-氧化物，它们不具有活性。大量的羟基洛沙平的N-氧化物也同时存在。

Loxapine is rapidly and extensively metabolized in the liver by aromatic hydroxylation, N-oxidation. The major metabolites of loxapine are 8-hydroxyloxapine and 7-hydroxyloxapine which are active and 8-hydroxydesmethylloxapine, 7-hydroxydesmethylloxapine, and loxapine N-oxide which are inactive. Significant amounts of the N-oxides of the hydroxyloxapines are also present.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

loxapine是一种多巴胺拮抗剂，也是一种5 - HT2血清素阻断剂。loxapine的确切作用机制尚未建立，然而，在几种动物物种中，与镇静的表观现象(如镇静作用和抑制攻击行为)相关，观察到皮质下抑制区兴奋性的变化。

Loxapine is a dopamine antagonist, and also a serotonin 5-HT2 blocker. The exact mode of action of Loxapine has not been established, however changes in the level of excitability of subcortical inhibitory areas have been observed in several animal species in association with such manifestations of tranquilization as calming effects and suppression of aggressive behavior.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

肝脏测试异常在长期使用loxapine治疗的小部分患者中被报道，但升高的情况很少超过正常上限的3倍。氨基转移酶异常通常是轻微的、无症状的，并且是短暂的，即使在继续用药的情况下也会逆转。据报道，由于loxapine以及与之结构相关的三环类化合物amoxapine（在美国不可用）导致临床上明显的急性肝损伤的情况非常罕见。在报告的病例中，黄疸的出现通常在4到8周内，血清酶升高的模式通常是肝细胞型的。免疫过敏特征和自身抗体的形成并不突出。所有病例都是自限性的，没有死亡或残留的慢性肝损伤。

Liver test abnormalities have been reported to occur in a small proportion of patients on long term therapy with loxapine, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually mild, asymptomatic and transient, reversing even with continuation of medication. Instances of clinically apparent acute liver injury have been reported due to loxapine and to the structurally related tricylic amoxapine (not available in the United States), but cases are rare. In reported cases, the onset of jaundice was within 4 to 8 weeks, and the pattern of serum enzyme elevations was typically hepatocellular. Immunoallergic features and autoantibody formation were not prominent. All cases were self-limited without fatalities or residual chronic liver injury.

来源:LiverTox

毒理性

• 药物性肝损伤

药物：洛沙平

Compound:loxapine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：模糊的 DILI 关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重等级：5

Severity Grade:5

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

亲本药物的系统性生物利用度仅约为男性志愿者肌肉注射等效剂量（25毫克基础）的三分之一。

Systemic bioavailability of the parent drug was only about one third that after an equivalent intramuscular dose (25 mg base) in male volunteers

来源:DrugBank

吸收、分配和排泄

• 消除途径

代谢物以结合形式通过尿液排出，以非结合形式通过粪便排出。

Metabolites are excreted in the urine in the form of conjugates and in the feces unconjugated.

来源:DrugBank

吸收、分配和排泄

动物研究中，放射性药物研究表明loxapine及其代谢物广泛分布于身体各组织中，以脑、肺、心脏、肝脏和胰腺中浓度最高。该药物出现在脑脊液中。

Animal studies with radioactive drug indicate that loxapine and/or its metabolites are widely distributed in body tissues with highest concentrations in brain, lungs, heart, liver, and pancreas. The drug appears in the CSF.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

loxapine从胃肠道(GI)快速且几乎完全吸收。该药物在肌内(IM)给药后也几乎完全吸收。

Loxapine is rapidly and almost completely absorbed from the GI tract. The drug is also almost completely absorbed following IM administration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

从消化道快速且几乎完全吸收。服用25毫克口服剂量后，2小时内达到峰值，血清中loxapine的水平在0.006至0.013微克/毫升之间...血清中的主要/活性/代谢物是8-羟基loxapine，服用loxapine后2-4小时内的最大浓度为0.012-0.038微克/毫升。人类/

RAPIDLY & ALMOST COMPLETELY ABSORBED FROM GI TRACT. PEAK LOXAPINE SERUM LEVELS /WITHIN 2 HR, RANGE FROM 0.006 TO 0.013 MCG/ML AFTER/ 25 MG ORAL DOSE...MAJOR /ACTIVE/ METABOLITE IN SERUM IS 8-HYDROXYLOXAPINE /MAX CONCN 0.012-0.038 MCG/ML WITHIN 2-4 HR AFTER ORAL LOXAPINE. HUMAN/

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 储存条件：
  2-8℃

制备方法与用途

洛沙平简介

洛沙平是一种苯氧氮平类三环衍生物，其主要作用机制为阻断多巴胺2型（D2）受体。此外，它还具有其他中枢和外周作用，包括抗胆碱能和α肾上腺素能神经阻断作用。洛沙平于1976年在美国获批上市，并主要用于治疗精神分裂症。

用途

洛沙平属于传统抗精神病药物，其主要用途是治疗精神分裂症。在使用过程中，可能会导致血清转氨酶轻微升高，极少情况下会引起急性肝损伤的临床症状。

生物活性

洛沙平琥珀酸盐作为D2DR/D4DR抑制剂和5-羟色胺受体拮抗剂，表现出显著的抗精神病活性。

反应信息

• 作为反应物：
  描述：

  洛沙平 在 盐酸 、 N,N-二甲基苯胺 、 三氯氧磷 作用下， 以 xylene 为溶剂， 反应 26.0h， 生成 阿莫沙平
  参考文献：
  名称：

  在11-Stellung氨基取代基Dibenzo [b，f] -1，4-thiazepine和-oxazep​​ine中使用Über。9. Mitteilungübersiebengliedrige杂环†

  摘要：

  在11-氨基取代的二苯并[b，f] -1、4-噻氮平和二苯并[b，f] -1、4-氧杂氮平系列III中发现了抗精神病药。它们可以通过亚氨基氯化物VI的氨解和/或尿素II的Bischler-Napieralski用POCl 3闭环合成。

  DOI：

  10.1002/hlca.19670500131
• 作为产物：
  描述：

  2-chlorodibenzo[b,f][1,4]oxazepin-11-amine 以85.2的产率得到洛沙平
  参考文献：
  名称：

  洛沙平的制备方法及其关键中间体

  摘要：

  本发明属于药物化学领域，公开了一种洛沙平的制备方法，其包含下述步骤：在有机溶剂中，化合物I与化合物II发生缩合反应得到中间体III；将步骤（1）制得的中间体III还原缩合反应，得到中间体IV；将步骤（2）制得的中间体IV与 N -甲基哌嗪反应得到目标化合物TM。洛沙平用于精神分裂症的极性短期和长期维持性治疗，本发明所提供的制备发法具有所用试剂和原料易得，产品的产率和纯度较高，适合工业化生产的优点。

  公开号：

  CN103570641A

文献信息

• [EN] AZA PYRIDONE ANALOGS USEFUL AS MELANIN CONCENTRATING HORMONE RECEPTOR-1 ANTAGONISTS<br/>[FR] ANALOGUES D'AZAPYRIDONE UTILES COMME ANTAGONISTES DU RÉCEPTEUR 1 DE L'HORMONE CONCENTRANT LA MÉLANINE
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2010104818A1

  公开（公告）日：2010-09-16

  MCHR1 antagonists are provided having the following Formula (I): A1 and A2 are independently C or N; E is C or N; Q1, Q2, and Q3 are independently C or N provided that at least one of Q1, Q2, and Q3 is N but not more than one of Q1, Q2, and Q3 is N; D1 is a bond, -CR8R9 X-, -XCR8R9-, -CHR8CHR9-, -CR10=CR10'-, -C≡C-, or 1,2-cyclopropyl; X is O, S or NR11; R1, R2, and R3 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, lower cycloalkyl, -CF3, -OCF3, -OR12 and -SR12; G is O, S or -NR15; D2 is lower alkyl, lower cycloalkyl, lower alkylcycloalkyl, lower cycloalkylalkyl, lower cycloalkoxyalkyl or lower alkylcycloalkoxy or when G is NR15, G and D2 together may optionally form an azetidine, pyrrolidine or piperidine ring; Z1 and Z2 are independently hydrogen, lower alkyl, lower cycloalkyl, lower alkoxy, lower cycloalkoxy, halo, -CF3, -OCONR14R14', -CN, -CONR14R14', -SOR12, -SO2R12, -NR14COR14', -NR14CO2R14', -CO2R12, NR14SO2R12 or COR12; R5, R6, and R7 are independently selected from the group consisting of hydrogen lower alkyl, lower cycloalkyl, -CF3, -SR12, lower alkoxy, lower cycloalkoxy, -CN, -CONR14R14', SOR12, SO2R12, NR14COR14', NR14CO2R12, CO2R12, NR14SO2R12 and -COR12; R8, R9, R10, R10', R11 are independently hydrogen or lower alkyl; R12 is lower alkyl or lower cycloalkyl; R14 and R14' are independently H, lower alkyl, lower cycloalkyl or R14 and R14' together with the N to which they are attached form a ring having 4 to 7 atoms; and R15 is independently selected from the group consisting of hydrogen and lower alkyl. Such compounds are useful for the treatment of MCHR1 mediated diseases, such as obesity, diabetes, IBD, depression, and anxiety.

  MCHR1拮抗剂具有以下化学式（I）：A1和A2独立地为C或N；E为C或N；Q1、Q2和Q3独立地为C或N，但至少其中一个为N，但不超过一个为N；D1为键，-CR8R9 X-，-XCR8R9-，-CHR8CHR9-，-CR10=CR10'-，-C≡C-，或1,2-环丙基；X为O、S或NR11；R1、R2和R3独立地从氢、卤素、低烷基、低环烷基、-CF3、-OCF3、-OR12和-SR12组成的群体中选择；G为O、S或-NR15；D2为低烷基、低环烷基、低烷基环烷基、低环烷基烷基、低环烷氧基烷基或低烷基环烷氧基，或当G为NR15时，G和D2一起可以选择形成氮杂环丙烷、吡咯烷或哌啶环；Z1和Z2独立地为氢、低烷基、低环烷基、低烷氧基、低环烷氧基、卤素、-CF3、-OCONR14R14'、-CN、-CONR14R14'、-SOR12、-SO2R12、-NR14COR14'、-NR14CO2R14'、-CO2R12、NR14SO2R12或COR12；R5、R6和R7独立地从氢、低烷基、低环烷基、-CF3、-SR12、低烷氧基、低环烷氧基、-CN、-CONR14R14'、SOR12、SO2R12、NR14COR14'、NR14CO2R12、CO2R12、NR14SO2R12和-COR12组成的群体中选择；R8、R9、R10、R10'、R11独立地为氢或低烷基；R12为低烷基或低环烷基；R14和R14'独立地为H、低烷基、低环烷基或R14和R14'与其连接的N一起形成具有4至7个原子的环；R15独立地从氢和低烷基组成的群体中选择。这些化合物对于治疗MCHR1介导的疾病，如肥胖症、糖尿病、炎症性肠病、抑郁症和焦虑症非常有用。
• [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。
• 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