奥氮平 | 132539-06-1

• 物质功能分类: 原料药 - 循环系统用药 - 抗休克血管活性药
• 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: 奥氮平
• 中文别名: 奥兰扎平；2-甲基-4-(4-甲基-1-哌嗪基)-10H-噻吩并[2,3-b][1,5]苯并二氮杂；2-甲基-4-(4-甲基-1-哌嗪基)-10H-thieno[2,3-b][1,5]苯二氮
• 英文名称: zyprexa
• 英文别名: Olanzapine；2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine；OLZ；2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine
• CAS: 132539-06-1
• 化学式: C₁₇H₂₀N₄S
• mdl: MFCD00866702
• 分子量: 312.439
• InChiKey: KVWDHTXUZHCGIO-UHFFFAOYSA-N

物化性质

• 熔点：
  195°C
• 沸点：
  476.0±55.0 °C(Predicted)
• 密度：
  1.32±0.1 g/cm3(Predicted)
• 闪点：
  2℃
• 溶解度：
  二甲基亚砜：>15mg/mL
• 物理描述：
  Solid
• 颜色/状态：
  Yellow crystalline solid
• 蒸汽压力：
  1.04X10-8 mm Hg at 25 °C (est)
• 亨利常数：
  Henry's Law constant = 7.52X10-15 atm-cu m/mol at 25 °C (est)
• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxides and sulfur oxides/.
• 解离常数：
  pKa1 = 4.01; pKa2 = 7.24; pKa3 = 14.17 (est)
• 碰撞截面：
  175.5 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]
• 保留指数：
  2844.1;2738.1;2738.7

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.352
• 拓扑面积：
  59.1
• 氢给体数：
  1
• 氢受体数：
  4

ADMET

代谢

奥氮平在肝脏中大量代谢，约占给药剂量的40%，主要由葡萄糖醛酸酶和细胞色素P450系统的活性实现。在CYP系统中，主要的代谢酶是CYP1A2和CYP2D6。作为第一阶段代谢的一部分，奥氮平的主要循环代谢物约占这一阶段的50-60%，是10-N-葡萄糖苷酸和4'-N-去甲基奥氮平，这些代谢物在临床上不活跃，由CYP1A2的活性形成。另一方面，CYP2D6催化形成2-OH奥氮平，黄素含单加氧酶（FMO3）负责N-氧化物奥氮平的形成。在奥氮平的第二阶段代谢中，UGT1A4是关键参与者，通过生成奥氮平的直接结合形式。

Olanzapine is greatly metabolized in the liver, which represents around 40% of the administered dose, mainly by the activity of glucuronide enzymes and by the cytochrome P450 system. From the CYP system, the main metabolic enzymes are CYP1A2 and CYP2D6. As part of the phase I metabolism, the major circulating metabolites of olanzapine, accounting for approximate 50-60% of this phase, are the 10-N-glucuronide and the 4'-N-desmethyl olanzapine which are clinically inactive and formed by the activity of CYP1A2. On the other hand, CYP2D6 catalyzes the formation of 2-OH olanzapine and the flavin-containing monooxygenase (FMO3) is responsible for N-oxide olanzapine. On the phase II metabolism of olanzapine, UGT1A4 is the key player by generating direct conjugation forms of olanzapine.

来源:DrugBank

代谢

肌肉内给药后的代谢轮廓与口服给药后的代谢轮廓在质量上相似。

Metabolic profiles after intramuscular administration are qualitatively similar to metabolic profiles after oral administration.

来源:Hazardous Substances Data Bank (HSDB)

代谢

直接葡糖苷酸化和细胞色素P450（CYP）介导的氧化是奥氮平的主要代谢途径。体外研究表明，CYP1A2和2D6以及黄素含单加氧酶系统参与奥氮平的氧化。由于奥氮平的清除在缺乏该酶的受试者中并未减少，CYP2D6介导的氧化在体内似乎是一个次要的代谢途径。

Direct glucuronidation and cytochrome P450 (CYP) mediated oxidation are the primary metabolic pathways for olanzapine. In vitro studies suggest that CYPs 1A2 and 2D6, and the flavin-containing monooxygenase system are involved in olanzapine oxidation. CYP2D6 mediated oxidation appears to be a minor metabolic pathway in vivo, because the clearance of olanzapine is not reduced in subjects who are deficient in this enzyme.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在单次口服给予14C标记的奥氮平后，剂量的7%以原药形式在尿液中回收，表明奥氮平被高度代谢。大约57%和30%的剂量分别在尿液和粪便中回收。在血浆中，奥氮平仅占总放射性AUC的12%，表明代谢物的显著暴露。在多次给药后，主要循环代谢物是10-N-葡萄糖苷酸，稳态时浓度为奥氮平的44%，以及4'-N-去甲基奥氮平，稳态时浓度为奥氮平的31%。在观察到的浓度下，这两种代谢物均无药理活性。

Following a single oral dose of (14)C labeled olanzapine, 7% of the dose of olanzapine was recovered in the urine as unchanged drug, indicating that olanzapine is highly metabolized. Approximately 57% and 30% of the dose was recovered in the urine and feces, respectively. In the plasma, olanzapine accounted for only 12% of the AUC for total radioactivity, indicating significant exposure to metabolites. After multiple dosing, the major circulating metabolites were the 10-N-glucuronide, present at steady state at 44% of the concentration of olanzapine, and 4'-N-desmethyl olanzapine, present at steady state at 31% of the concentration of olanzapine. Both metabolites lack pharmacological activity at the concentrations observed.

来源:Hazardous Substances Data Bank (HSDB)

代谢

奥氮平已知的人类代谢物包括2-羟甲基奥氮平、7-羟基奥氮平、N-去甲基奥氮平和奥氮平N-氧化物。

Olanzapine has known human metabolites that include 2-Hydroxymethyl Olanzapine, 7-Hydroxyolanzapine, N-Desmethylolanzapine, and Olanzapine N-Oxide.

来源:NORMAN Suspect List Exchange

毒理性

• 毒性总结

奥氮平的毒性症状包括嗜睡、瞳孔扩大、视力模糊、呼吸抑制、低血压、锥体外系症状和抗胆碱能效应。儿童过量服用通常与更严重的副作用相关。临床试验中记录的奥氮平最大注册剂量为300毫克，据报道会出现嗜睡和言语不清。然而，在上市后监测中，出现了一系列症状，包括激动、构音障碍、心动过速、锥体外系症状和意识降低。有一起过量服用450毫克奥氮平后死亡的报告。在急性过量情况下，建议建立充分的氧合和通气、洗胃以及使用泻药给予活性炭。在致癌性研究中，奥氮平显示出增加了肝脏血管瘤和血管肉瘤以及乳腺腺瘤和腺癌的发生率。在生育能力研究中，仅在雄性交配表现受损和排卵延迟方面发现影响。没有证据表明奥氮平具有致突变、遗传毒性潜力或对生育能力有不利影响。

The toxicity symptoms of olanzapine are known to include somnolence, mydriasis, blurred vision, respiratory depression, hypotension, extrapyramidal symptoms and anticholinergic effects. The overdosage effects in children are generally associated with more significant side effects. The maximum registered dosage of olanzapine in clinical trials was of 300 mg and it was reported to present drowsiness and slurred speech. However, on post-marketing surveillance, a wide range of symptoms have been presented including agitation, dysarthria, tachycardia, extrapyramidal symptoms, and reduced consciousness. One case of overdosage-driven death was reported after ingestion of 450 mg of olanzapine. In the cases of acute overdosage, the establishment of adequate oxygenation and ventilation, gastric lavage and administration of activated charcoal with a laxative is recommended. In carcinogenesis studies, olanzapine was showed to present an increase in the incidence of liver hemangiomas and hemangiosarcomas as well as mammary gland adenomas, and adenocarcinomas. On fertility studies, there was solely found impairment in male mating performance and delays in ovulation. There is no evidence of mutagenic, genotoxic potential not adverse events on fertility.

来源:DrugBank

毒理性

• 肝毒性

肝脏测试异常在接受奥氮平长期治疗的病人中报告发生率为10%到50%。这些异常通常是轻微的、无症状的、短暂的，甚至在继续用药的情况下也可以逆转。此外，在接受奥氮平治疗的病人中还报告了血清转氨酶水平显著升高和临床明显的肝炎伴随黄疸的情况。血清酶升高的模式范围从肝细胞型到混合型甚至胆汁淤积型。过敏表现（皮疹、发热、嗜酸性粒细胞增多）和自身免疫标志物是不常见的。奥氮平治疗引起肝损伤的发生时间差异很大，从开始用药后几周到一年不等。在所有病例中，停药后损伤迅速解决。那些潜伏期长且伴随显著体重增加的病例可能代表非酒精性脂肪肝病，而不是奥氮平的肝毒性。

Liver test abnormalities have been reported to occur in 10% to 50% of patients on long term therapy with olanzapine. These abnormalities are usually mild, asymptomatic and transient, and can reverse even with continuation of medication. In addition, instances of more marked elevations in serum aminotransferase levels and clinically apparent hepatitis with jaundice have been reported in patients taking olanzapine. The pattern of serum enzyme elevations has ranged from hepatocellular to mixed and even cholestatic. Allergic manifestations (rash, fever, eosinophilia) and autoimmune markers are uncommon. The time to onset of liver injury with olanzapine therapy has varied widely, from a few weeks to a year after starting. In all cases, the injury has resolved rapidly with drug discontinuation. Cases with a long latency and accompanied by significant weight gain may represent nonalcoholic fatty liver disease, rather than olanzapine hepatotoxicity.

来源:LiverTox

毒理性

• 药物性肝损伤

药物名称：奥氮平

Compound:olanzapine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：较少的药物性肝损伤关注

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

吸收、分配和排泄

• 吸收

奥氮平呈现线性的药代动力学特征，每日给药后大约一周达到稳态。在正常剂量的奥氮平给药下，稳态血浆浓度似乎不会超过150 ng/ml，且药时曲线下面积（AUC）为333 ng/h/ml。奥氮平的吸收不受食物同服的影响。奥氮平的药代动力学特征是在口服给药后大约6小时达到156.9 ng/ml的峰血浆浓度。

Olanzapine presents a linear pharmacokinetic profile and, after daily administration, it reaches steady-state in about a week. Under the administration of a normal dosage of olanzapine, the steady-state plasma concentration does not seem to exceed 150 ng/ml with an AUC of 333 ng/h/ml. The absorption of olanzapine is not affected by the concomitant administration of food. The pharmacokinetic profile of olanzapine is characterized by reaching peak plasma concentration of 156.9 ng/ml approximately 6 hours after oral administration.

来源:DrugBank

吸收、分配和排泄

• 排除途径

奥氮平主要通过代谢消除，因此，只有7%的消除药物能以原型形式找到。它主要在尿液中排泄，约占排泄剂量的53%，其次是粪便，约占30%。

Olanzapine is mainly eliminated through metabolism and hence, only 7% of the eliminated drug can be found as the unchanged form. It is mainly excreted in the urine which represents around 53% of the excreted dose followed by the feces that represent about 30%.

来源:DrugBank

吸收、分配和排泄

• 分布容积

奥氮平的分布容积据报道为1000升，这表明它在体内有广泛的分布。

The volume of distribution of olanzapine is reported to be of 1000 liters which indicate a large distribution throughout the body.

来源:DrugBank

吸收、分配和排泄

• 清除

奥氮平的平均清除率为29.4 L/小时，然而，一些研究报告称明显的清除率为25 L/h。

The mean clearance rate of olanzapine is of 29.4 L/hour however, some studies have reported an apparent clearance of 25 L/h.

来源:DrugBank

吸收、分配和排泄

这项研究检查了患有产后精神病的五位哺乳期妇女奥氮平排入母乳中的情况。收集了九对血浆和母乳样本，并使用高效液相色谱法测定了奥氮平的浓度。计算了单点乳浆比，范围从0.2到0.84，平均值为0.46。婴儿的中间相对剂量是母体体重调整剂量的1.6%（范围0-2.5%）。在研究期间，婴儿暴露于这些剂量的奥氮平后，没有出现明显的副作用。与其他抗精神病药物一样，这项研究表明奥氮平会进入母乳中。

The excretion of olanzapine into the breast milk of five lactating women with postpartum psychosis was examined in this study. Nine pairs of plasma and breast-milk samples were collected and the concentration of olanzapine determined by high-performance liquid chromatography. Single-point milk-to-plasma ratios were calculated and ranged from 0.2 to 0.84 with a mean of 0.46. The median relative infant dose was 1.6% (range 0-2.5%) of the weight-adjusted maternal dose. During the study period, there were no apparent ill effects on the infant as a consequence of exposure to these doses of olanzapine. As with other antipsychotic drugs this study demonstrates that olanzapine passes into breast milk. ...

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1
• 危险品标志：
  Xi,Xn,F
• 安全说明：
  S22,S24/25
• 危险类别码：
  R36/38,R36,R20/21/22,R11
• WGK Germany：
  3
• 海关编码：
  2934999090
• 危险品运输编号：
  UN 2811 6.1 / PGIII
• 储存条件：
  |-20°C freezer|

SDS

Olanzapine Revision number: 5
SAFETY DATA SHEET

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Section 1. IDENTIFICATION
Product name: Olanzapine

Revision number: 5

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Section 2. HAZARDS IDENTIFICATION
GHS classification
PHYSICAL HAZARDS Not classified
HEALTH HAZARDS
Acute toxicity (Oral) Category 3
Category 2
Skin corrosion/irritation
Serious eye damage/eye irritation Category 2A
Not classified
ENVIRONMENTAL HAZARDS
GHS label elements, including precautionary statements
Pictograms or hazard symbols
Signal word Danger
Hazard statements Toxic if swallowed
Causes skin irritation
Causes serious eye irritation
Precautionary statements:
Do not eat, drink or smoke when using this product.
[Prevention]
Wash hands thoroughly after handling.
Wear protective gloves/eye protection/face protection.
[Response] IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. Rinse
mouth.
IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses,
if present and easy to do. Continue rinsing.
If eye irritation persists: Get medical advice/attention.
IF ON SKIN: Gently wash with plenty of soap and water.
If skin irritation occurs: Get medical advice/attention.
Take off contaminated clothing and wash before reuse.
[Storage] Store locked up.
[Disposal] Dispose of contents/container through a waste management company authorized by
the local government.

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Section 3. COMPOSITION/INFORMATION ON INGREDIENTS
Substance/mixture: Substance
Olanzapine
Components:
Olanzapine

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Section 3. COMPOSITION/INFORMATION ON INGREDIENTS
Percent: >98.0%(GC)(T)
CAS Number: 132539-06-1
Synonyms: 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine
Chemical Formula: C17H20N4S

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Section 4. FIRST AID MEASURES
Remove victim to fresh air and keep at rest in a position comfortable for breathing.
Inhalation:
Get medical advice/attention if you feel unwell.
Remove/Take off immediately all contaminated clothing. Gently wash with plenty of
Skin contact:
soap and water. If skin irritation or rash occurs: Get medical advice/attention.
Eye contact: Rinse cautiously with water for several minutes. Remove contact lenses, if present
and easy to do. Continue rinsing. If eye irritation persists: Get medical
advice/attention.
Ingestion: Immediately call a POISON CENTER or doctor/physician. Rinse mouth.
Protection of first-aiders: A rescuer should wear personal protective equipment, such as rubber gloves and air-
tight goggles.

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Section 5. FIRE-FIGHTING MEASURES
Suitable extinguishing Dry chemical, foam, water spray, carbon dioxide.
media:
Specific hazards arising Take care as it may decompose upon combustion or in high temperatures to
from the chemical: generate poisonous fume.
Precautions for firefighters: Fire-extinguishing work is done from the windward and the suitable fire-extinguishing
method according to the surrounding situation is used. Uninvolved persons should
evacuate to a safe place. In case of fire in the surroundings: Remove movable
containers if safe to do so.
Special protective When extinguishing fire, be sure to wear personal protective equipment.
equipment for firefighters:

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Section 6. ACCIDENTAL RELEASE MEASURES
Use extra personal protective equipment (P3 filter respirator for toxic particles). Keep
Personal precautions,
protective equipment and people away from and upwind of spill/leak. Entry to non-involved personnel should
emergency procedures: be controlled around the leakage area by roping off, etc.
Environmental precautions: Prevent product from entering drains.
Methods and materials for Sweep dust to collect it into an airtight container, taking care not to disperse it.
containment and cleaning Adhered or collected material should be promptly disposed of, in accordance with
up: appropriate laws and regulations.

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Section 7. HANDLING AND STORAGE
Precautions for safe handling
Technical measures: Handling is performed in a well ventilated place. Wear suitable protective equipment.
Prevent dispersion of dust. Wash hands and face thoroughly after handling.
Use a closed system if possible. Use a local exhaust if dust or aerosol will be
generated.
Advice on safe handling: Avoid contact with skin, eyes and clothing.
Conditions for safe storage, including any
incompatibilities
Storage conditions: Keep container tightly closed. Store in a refrigerator.
Store locked up.
Store away from incompatible materials such as oxidizing agents.
Heat-sensitive
Packaging material: Comply with laws.

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Section 8. EXPOSURE CONTROLS / PERSONAL PROTECTION
Engineering controls: Install a closed system or local exhaust. Also install safety shower and eye bath.
Personal protective equipment
Olanzapine

---

Section 8. EXPOSURE CONTROLS / PERSONAL PROTECTION
Respiratory protection: Dust respirator, self-contained breathing apparatus(SCBA), supplied air respirator,
etc. Use respirators approved under appropriate government standards and follow
local and national regulations.
Hand protection: Impervious gloves.
Eye protection: Safety goggles. A face-shield, if the situation requires.
Skin and body protection: Impervious protective clothing. Protective boots, if the situation requires.

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Section 9. PHYSICAL AND CHEMICAL PROPERTIES
Solid
Physical state (20°C):
Form: Crystal- Powder
Colour: Pale yellow - Deep yellow
Odour: No data available
pH: No data available
Melting point/freezing point:194°C (dec.)
Boiling point/range: No data available
Flash point: No data available
Flammability or explosive
limits:
Lower: No data available
Upper: No data available
Relative density: No data available
Solubility(ies):
[Water] Insoluble
[Other solvents]
Soluble: Hot acetone
Log Pow: 4.09

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Section 10. STABILITY AND REACTIVITY
Chemical stability: Stable under proper conditions.
Possibility of hazardous No special reactivity has been reported.
reactions:
Incompatible materials: Oxidizing agents
Hazardous decomposition Carbon monoxide, Carbon dioxide, Nitrogen oxides (NOx), Sulfur oxides
products:

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Section 11. TOXICOLOGICAL INFORMATION
Acute Toxicity: orl-man LDLo:7067 ug/kg
Skin corrosion/irritation: No data available
Serious eye No data available
damage/irritation:
Germ cell mutagenicity: No data available
Carcinogenicity:
IARC = No data available
NTP = No data available
Reproductive toxicity: No data available
RTECS Number: XJ9007750

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Section 12. ECOLOGICAL INFORMATION
Ecotoxicity:
Fish: No data available
No data available
Crustacea:
Algae: No data available
Persistence / degradability: No data available
Bioaccumulative No data available
potential(BCF):
Mobility in soil
Olanzapine

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Section 12. ECOLOGICAL INFORMATION
Log Pow: 4.09
Soil adsorption (Koc): No data available
Henry's Law No data available
constant(PaM3/mol):

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Section 13. DISPOSAL CONSIDERATIONS
Recycle to process, if possible. Consult your local regional authorities. You may be able to dissolve or mix material
with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber system.
Observe all federal, state and local regulations when disposing of the substance.

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Section 14. TRANSPORT INFORMATION
Hazards Class: 6.1: Toxic substance.
UN-No: 2811
Proper shipping name: Toxic solid, organic, n.o.s.
Packing group: III

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Section 15. REGULATORY INFORMATION
Safe management ordinance of dangerous chemical product (State Council announces on January 26, 2002
and revised on February 16,2011): Safe use and production, the storage of a dangerous chemical, transport,
loading and unloading were prescribed.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

抗精神病药：奥氮平

奥氮平（又称为奥兰扎平、奥兰氮平）是一种常用的抗精神病药物。临床上主要用于控制精神分裂症、双极性躁狂症和痴呆症患者的激越症状，能显著改善精神分裂症的阴性症状（如情感淡漠、情感和社会退缩、言语贫乏）、阳性症状（如妄想、幻觉、思维障碍、敌意和猜疑），并缓解精神分裂症及相关疾病常见的继发性情感症状。

口服吸收良好，约5至8小时达到血浆峰值浓度，并不受进食影响。奥氮平在肝脏中通过结合和氧化反应代谢，主要循环代谢产物是10-N-葡萄糖苷酸。

动物试验表明，奥氮平对多种受体具有亲和力，包括5-HT、多巴胺D2、α-肾上腺素和组胺H等。其体外和体内对5-HT2受体的亲和力大于对多巴胺D2受体的亲和力。

动物行为研究表明，奥氮平表现出5-HT、多巴胺及胆碱能拮抗作用，与上述受体结合情况相符。电生理研究进一步表明，奥氮平选择性地减少间脑边缘系统（A10）多巴胺能神经元放电，而对纹状体（A9）的运动功能通路影响较小，在低于产生僵住反应剂量水平时可减少条件性回避反应。

与其它抗精神病药物不同的是，奥氮平在抗焦虑测试中也能增加反应。

化学性质

从乙腈结晶得到，熔点为195℃。

用途

• 作为5-HT2-D2拮抗剂用于治疗精神分裂症。
• 主要用于治疗精神分裂症。
• 具有一定的抗抑郁作用。
• 控制精神分裂症、双极性躁狂症等疾病症状。

生产方法

4-氨基-2-甲基-10H-噻吩并[2,3-b][1,5]苯并二氮杂革盐酸盐和N-甲基哌嗪，在二甲亚砜和甲苯中，氮气保护下回流20小时后得到奥氮平。

反应信息

• 作为反应物：
  描述：

  奥氮平 在 水 作用下， 反应 730.5h， 生成 2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine dihydrate
  参考文献：
  名称：

  [EN] NOVEL CRYSTAL FORMS OF OLANZAPINE, METHODS FOR THEIR PREPARATION AND METHOD FOR THE PREPARATION OF KNOWN OLANZAPINE CRYSTAL FORMS
  [FR] NOUVELLES FORMES CRISTALLINES D'OLANZAPINE, PROCEDES POUR LES PREPARER ET PROCEDE POUR PREPARER DES FORMES CRISTALLINES D'OLANZAPINE CONNUES

  摘要：

  该发明涉及一系列新型结晶奥氮平形式，特别是奥氮平的水合物和溶剂结晶形式，以及在制药组合物中的使用方法，以及使用这些结晶形式治疗精神疾病的方法。其中一系列结晶形式是水合物，即含水晶体，其中水的比例可在大约2:1.5到大约1:3的奥氮平：水比例范围内。另一系列包括溶剂结晶形式，如异丁醇溶剂结晶形式。奥氮平的结晶形式包括H、G、Y、X、K、S、Q、Z和J形式。

  公开号：

  WO2004058773A1
• 作为产物：
  描述：

  2-(2-硝基苯氨基)-5-甲基噻吩-3-甲酸甲酯 在 palladium on charcoal catalyst 、 四氯化钛 氨 作用下， 以 N-甲基哌嗪 、 乙醇乙酸乙酯 、 乙酸乙酯 、 苯甲醚 、 异丙醇 为溶剂， 生成 奥氮平
  参考文献：
  名称：

  2-methyl-thieno-benzodiazepine

  摘要：

  2-甲基-4-(4-甲基-1-哌嗪基)-10H-噻吩-[2,3-b][1,5]苯二氮杂环己烷，或其酸盐，具有药用性质，特别适用于治疗中枢神经系统疾病。该化合物的结构如下：##STR1##

  公开号：

  US05627178A1
• 作为试剂：
  描述：

  Olanzapine oxalate 、 盐酸 、 甲烷 在 甲烷 、 水 、 二氯甲烷 、 sodium hydroxide 、 奥氮平 、 ice 作用下， 以 水 为溶剂， 反应 0.67h， 生成 奥氮平
  参考文献：
  名称：

  Synthesis of 2-Methyl-4-(4-Methyl-1-Piperazinly)-10H-Thieno(2,3-B) (1,5) Benzodiazepine and Salts Thereof

  摘要：

  本发明属于有机化学领域，涉及一种用于纯化奥氮平的新工艺，包括制备奥氮平的酸加成盐，并将其转化为药用可接受的纯净无色最终产品。本发明还涉及制备纯净奥氮平的新工艺。

  公开号：

  US20080161557A1

文献信息

• [EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
  申请人：GILEAD APOLLO LLC

  公开号：WO2017075056A1

  公开（公告）日：2017-05-04

  The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

  本发明提供了化合物I和II，这些化合物可用作乙酰辅酶A羧化酶（ACC）的抑制剂，以及它们的组合物和使用方法。
• [EN] SUBSTITUTED N-HETEROCYCLIC CARBOXAMIDES AS ACID CERAMIDASE INHIBITORS AND THEIR USE AS MEDICAMENTS<br/>[FR] CARBOXAMIDES N-HÉTÉROCYCLIQUES SUBSTITUÉS UTILISÉS EN TANT QU'INHIBITEURS DE LA CÉRAMIDASE ACIDE ET LEUR UTILISATION EN TANT QUE MÉDICAMENTS
  申请人：BIAL BIOTECH INVEST INC

  公开号：WO2021055627A1

  公开（公告）日：2021-03-25

  The invention provides substituted N-heterocyclic carboxamides and related compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat a medical disorder, e.g., cancer, lysosomal storage disorder, neurodegenerative disorder, inflammatory disorder, in a patient.

  这项发明提供了替代的N-杂环羧酰胺和相关化合物，含有这些化合物的组合物，医疗工具包，以及使用这些化合物和组合物治疗患者的医疗疾病（例如癌症、溶酶体贮积症、神经退行性疾病、炎症性疾病）的方法。
• [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。
• New Drug Delivery System for Crossing the Blood Brain Barrier
  申请人：Lipshutz H. Bruce

  公开号：US20070203080A1

  公开（公告）日：2007-08-30

  New ubiquinol analogs are disclosed, as well as methods of using these compounds to deliver drug moieties to the body.

  新的泛醌类似物被披露，以及利用这些化合物将药物基团输送到人体的方法。
• [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。