昂丹司琼 | 99614-02-5

• 物质功能分类: 原料药 - 消化系统用药 - 止吐催吐药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 中文名称: 昂丹司琼
• 中文别名: 昂旦司琼；恩丹西酮；1,2,3,9-四氢-9-甲基-3-[(2-甲基-1H-咪唑-1-基)甲基]-4H-咔唑-4-酮；蒽丹西酮
• 英文名称: ondanserton
• 英文别名: Ondansetron；zofran；9-methyl-3-((2-methyl-1H-imidazol-1-yl)methyl)-2,3-dihydro-1H-carbazol-4(9H)-one；9-methyl-3-((2-methyl-1H-imidazol-1-yl)methyl)-1,2,3,9-tetrahydro-4H-carbazol-4-one；doran；1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)-methyl]-4H-carbazol-4-one；9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1H-carbazol-4-one
• CAS: 99614-02-5
• 化学式: C₁₈H₁₉N₃O
• mdl: MFCD00833882
• 分子量: 293.368
• InChiKey: FELGMEQIXOGIFQ-UHFFFAOYSA-N

物化性质

• 熔点：
  231-232°
• 沸点：
  435.21°C (rough estimate)
• 密度：
  1.1385 (rough estimate)
• 溶解度：
  H2O:>5 mg/mL
• 物理描述：
  Solid
• 颜色/状态：
  Crystals from methanol
• 蒸汽压力：
  3.7X10-10 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable under recommended storage conditions. /Ondansetron hydrochloride dihydrate/
• 解离常数：
  pKa1 = 7.34 (imine); pKa2 = 15.39 (est)
• 碰撞截面：
  171.7 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)：
  2.3
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.333
• 拓扑面积：
  39.8
• 氢给体数：
  0
• 氢受体数：
  2

ADMET

代谢

体外代谢研究表明，昂丹司琼是人类肝脏细胞色素P450酶的底物，包括CYP1A2、CYP2D6和CYP3A4。在昂丹司琼的整体转化中，CYP3A4起主导作用。由于有多种代谢酶能够代谢昂丹司琼，因此一个酶的抑制或缺失（例如CYP2D6酶缺乏）可能会被其他酶补偿，可能导致昂丹司琼清除率整体变化不大。口服或静脉给药后，昂丹司琼被广泛代谢并在尿液和粪便中排泄。在人体中，不到10%的剂量以原形在尿液中排泄。主要的尿液代谢物是葡萄糖苷酸结合物（45%）、硫酸盐结合物（20%）和羟基化产物（10%）。主要的代谢途径是随后在吲哚环上进行羟基化，然后进行葡萄糖苷酸或硫酸盐结合。尽管一些非结合代谢物具有药理活性，但这些物质在血浆中的浓度不太可能对昂丹司琼的生物活性产生显著贡献。

In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P450 enzymes, including CYP1A2, CYP2D6 and CYP3A4. In terms of overall ondansetron turnover, CYP3A4 played the predominant role. Because of the multiplicity of metabolic enzymes capable of metabolizing ondansetron, it is likely that inhibition or loss of one enzyme (e.g. CYP2D6 enzyme deficiency) will be compensated by others and may result in little change in overall rates of ondansetron clearance. Following oral or IV administration, ondansetron is extensively metabolised and excreted in the urine and faeces. In humans, less than 10% of the dose is excreted unchanged in the urine. The major urinary metabolites are glucuronide conjugates (45%), sulphate conjugates (20%) and hydroxylation products (10%). The primary metabolic pathway is subsequently hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation. Although some nonconjugated metabolites have pharmacologic activity, these are not found in plasma at concentrations likely to significantly contribute to the biological activity of ondansetron.

来源:DrugBank

代谢

昂丹司琼在人体内广泛代谢，大约5%的放射性剂量以原型药物形式从尿液中回收。主要的代谢途径是在吲哚环上进行羟基化，随后进行葡萄糖醛酸或硫酸结合。尽管一些非结合型代谢物具有药理活性，但这些物质在血浆中的浓度不太可能对昂丹司琼的生物活性产生显著贡献。

Ondansetron is extensively metabolized in humans, with approximately 5% of a radiolabeled dose recovered as the parent compound from the urine. The primary metabolic pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation. Although some nonconjugated metabolites have pharmacologic activity, these are not found in plasma at concentrations likely to significantly contribute to the biological activity of ondansetron.

来源:Hazardous Substances Data Bank (HSDB)

代谢

丹蒽司琼已知的人类代谢物包括7-羟基-丹蒽司琼、6-羟基-丹蒽司琼和8-羟基-丹蒽司琼。

Ondansetron has known human metabolites that include 7-hydroxy-ondansetron, 6-hydroxy-ondansetron, and 8-hydroxy-ondansetron.

来源:NORMAN Suspect List Exchange

代谢

肝脏 半衰期：5.7小时

Hepatic Half Life: 5.7 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

识别和使用：昂丹司琼从甲醇中形成晶体。它是一种用于预防与高度催吐性癌症化疗相关的人类和兽医病例的恶心和呕吐的药物。接受昂丹司琼治疗的患者中已有QT间期延长和尖端扭转型室速的报道。在接受昂丹司琼与其他药物联合治疗的患者中，包括可能具有肝毒性的细胞毒化疗和抗生素，罕见有肝衰竭和死亡的报道。昂丹司琼盐酸盐可能引起严重的过敏性反应。在一项研究中，对母亲在怀孕期间接受异丙嗪或昂丹司琼的儿童进行了研究，没有发现具有临床意义的负面神经行为效应或产科结果。根据另一项研究，昂丹司琼的致畸风险较低，但心脏间隔缺损的风险增加。在用人外周淋巴细胞进行的体外染色体畸变试验中，也没有遗传物质损伤的证据。动物研究：在配子发生、交配、怀孕和哺乳期间，将昂丹司琼以1、4和15 mg/kg的剂量口服给予大鼠。建议昂丹司琼对F0代动物的一般毒性和生殖能力的最大无效剂量分别为4和15 mg/kg。建议F1和F2代动物发育的最大无效剂量为15 mg/kg。在怀孕和哺乳期间每天静脉注射0.5、1.5和4 mg/kg的昂丹司琼后，结果表明，昂丹司琼对母体的一般毒性的最大无效剂量为1.5 mg/kg，对母体的生殖毒性和胎儿的发育毒性的最大无效剂量为4 mg/kg。在兔子的静脉器官发生（4.0 mg/kg/天）研究中，最高剂量水平观察到轻微的母体毒性。影响包括母体体重减轻和早期胎儿死亡率的增加。在V-79哺乳动物细胞突变研究的体外试验或小鼠骨髓的体内染色体畸变分析中，没有遗传物质损伤的证据。在使用突变株的微生物突变试验中，包括或不包括大鼠肝脏微粒体代谢系统，没有观察到致突变性。在大鼠和小鼠的2年研究中，口服昂丹司琼剂量高达10和30 mg/kg/天，没有观察到致癌作用。

IDENTIFICATION AND USE: Ondansetron forms as crystals from methanol. It is a drug used for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy in both human and veterinary cases. Prolongation of the QT interval and cases of torsades de pointes have been reported in patients receiving ondansetron. Liver failure and death have been reported rarely in patients with cancer receiving ondansetron concomitantly with other drugs, including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. Ondansetron hydrochloride may cause a serious anaphylactic reaction. In a study of children whose mothers received promethazine or ondansetron during pregnancy, no clinically significant adverse neurobehavioral effects or obstetric outcomes were identified. According to a different study, the teratogenic risk with ondansetron is low but an increased risk for a cardiac septum defect is likely. There was also no evidence of damage to genetic material noted in in vitro chromosome aberration tests using human peripheral lymphocytes. ANIMAL STUDIES: Ondansetron was administered orally to rats at doses of 1, 4, and 15 mg/kg during gametogenesis, mating, pregnancy, and lactation periods. It is proposed that the maximum noneffective dose of ondansetron was 4 and 15 mg/kg with respect to general toxicity and reproductive capacity in F0 animals respectively. The maximum noneffective dose with respect to development in F1 and F2 animals was suggested to be 15 mg/kg. After IV administration of 0.5, 1.5, and 4 mg/kg of ondansetron daily during gestation and lactation period, the results suggest that the maximum noneffective dose of ondansetron for general toxicity in dams was 1.5 mg/kg and that for reproduction toxicity in dams and developmental toxicity in fetuses and offspring was 4 mg/kg. A slight maternal toxicity was observed at the highest dose level in intravenous organogenesis (4.0 mg/kg/day) studies in the rabbit. Effects included maternal body weight loss and increased incidence of early fetal death. There was no evidence of damage to genetic material noted in in vitro V-79 mammalian cell mutation studies or in vivo chromosome aberration assays in mouse bone marrow. No evidence of mutagenicity was observed in microbial mutagen tests using mutant strains of Salmonella typhimurium, Escherichia coli or Saccharomyces cerevisiae, with or without a rat liver post-mitochondrial metabolizing system. Carcinogenic effects were not seen in 2-year studies in rats and mice with oral ondansetron doses up to 10 and 30 mg/kg/day, respectively.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

昂丹司琼是一种选择性的5-HT₃受体拮抗剂。该药物的抗呕吐作用是通过抑制中枢（延髓化学感受区）和周围（胃肠道）存在的5-HT₃受体实现的。这种对5-HT₃受体的抑制反过来又抑制了呕吐中枢的内脏传入刺激，可能是通过间接在呕吐中枢后区（area postrema）的水平上，以及通过直接抑制延髓化学感受区（chemoreceptor trigger zone）和呕吐中枢后区的血清素活性实现的。

Ondansetron is a selective serotonin 5-HT₃ receptor antagonist. The antiemetic activity of the drug is brought about through the inhibition of 5-HT₃ receptors present both centrally (medullary chemoreceptor zone) and peripherally (GI tract). This inhibition of 5-HT₃ receptors in turn inhibits the visceral afferent stimulation of the vomiting center, likely indirectly at the level of the area postrema, as well as through direct inhibition of serotonin activity within the area postrema and the chemoreceptor trigger zone.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 药物性肝损伤

化合物：昂丹司琼

Compound:ondansetron

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

严重等级：7

Severity Grade:7

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

昂丹司琼从胃肠道吸收并经历一定程度的首过代谢。在健康受试者中，单次服用8毫克片剂后的平均生物利用度记录为大约56%至60%。食物的存在也能略微提高生物利用度。昂丹司琼的系统暴露量并不会与剂量成正比增加。从16毫克片剂得出的药时曲线下面积（AUC）比从8毫克片剂剂量预测的值高出24%。这可能是由于在高剂量口服时首过代谢有所减少。

Ondansetron is absorbed from the gastrointestinal tract and undergoes some limited first-pass metabolism. Mean bioavailability in healthy subjects, following administration of a single 8-mg tablet, was recorded as being approximately 56% to 60%. Bioavailability is also slightly enhanced by the presence of food. Ondansetron systemic exposure does not increase proportionately to dose. The AUC from a 16-mg tablet was 24% greater than predicted from an 8-mg tablet dose. This may reflect some reduction of first-pass metabolism at higher oral doses.

来源:DrugBank

吸收、分配和排泄

• 消除途径

口服或静脉给药后，昂丹司琼在体内广泛代谢，并经尿液和粪便排出。

Following oral or IV administration, ondansetron is extensively metabolised and excreted in the urine and faeces.

来源:DrugBank

吸收、分配和排泄

• 分布容积

丹蒽司琼的分布容积已记录为大约160升。

The volume of distribution of ondansetron has been recorded as being approximately 160L.

来源:DrugBank

吸收、分配和排泄

• 清除

各患者年龄组奥丹司琼的清除率值记录如下：正常成年志愿者（19-40岁）约为0.38 L/h/kg，正常成年志愿者（61-74岁）约为0.32 L/h/kg，正常成年志愿者（75岁及以上）约为0.26 L/h/kg。

The clearance values determined for ondansetron in various patient age groups were recorded as approximately 0.38 L/h/kg in normal adult volunteers aged 19-40 yrs, 0.32 L/h/kg in normal adult volunteers aged 61-74 yrs, 0.26 L/h/kg in normal adult volunteers aged >=75 yrs.

来源:DrugBank

吸收、分配和排泄

奥丹西隆是一种有效的5-HT3受体拮抗剂，用于猫的抗呕吐。本研究的目的是评估奥丹西隆在健康猫体内的药代动力学。六只具有正常血常规、血清生化指标和尿液分析的猫分别以交叉方式口服(平均0.43毫克/公斤)、皮下(平均0.4毫克/公斤)和静脉(平均0.4毫克/公斤)给药奥丹西隆，并设有5天的清洗期。在给药奥丹西隆前和给药后的0.25、0.5、1、2、4、8、12、18和24小时收集血清。使用液相色谱串联质谱法测量奥丹西隆的浓度。进行非房室药代动力学建模和给药间隔建模。使用重复测量方差分析比较不同给药途径之间的参数。奥丹西隆的口服生物利用度为32%，皮下为75%。计算得出的奥丹西隆消除半衰期为静脉给药1.84 ± 0.58小时，口服给药1.18 ± 0.27小时，皮下给药3.17 ± 0.53小时。皮下给药的消除半衰期显著长于口服或静脉给药(P < 0.05)。与健康猫口服给药相比，皮下给药奥丹西隆的生物利用度更高，暴露时间更长。这些信息将有助于管理猫患者的呕吐症状。

Ondansetron is a 5-HT3 receptor antagonist that is an effective anti-emetic in cats. The purpose of this study was to evaluate the pharmacokinetics of ondansetron in healthy cats. Six cats with normal complete blood count, serum biochemistry, and urinalysis received 2 mg oral (mean 0.43 mg/kg), subcutaneous (mean 0.4 mg/kg), and intravenous (mean 0.4 mg/kg) ondansetron in a cross-over manner with a 5-day wash out. Serum was collected prior to, and at 0.25, 0.5, 1, 2, 4, 8, 12, 18, and 24 hr after administration of ondansetron. Ondansetron concentrations were measured using liquid chromatography coupled to tandem mass spectrometry. Noncompartmental pharmacokinetic modeling and dose interval modeling were performed. Repeated measures anova was used to compare parameters between administration routes. Bioavailability of ondansetron was 32% (oral) and 75% (subcutaneous). Calculated elimination half-life of ondansetron was 1.84 + or - 0.58 hr (intravenous), 1.18 + or - 0.27 hr (oral) and 3.17 + or - 0.53 hr (subcutaneous). The calculated elimination half-life of subcutaneous ondansetron was significantly longer (P < 0.05) than oral or intravenous administration. Subcutaneous administration of ondansetron to healthy cats is more bioavailable and results in a more prolonged exposure than oral administration. This information will aid management of emesis in feline patients.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xi,T
• 安全说明：
  S45
• 危险类别码：
  R25
• WGK Germany：
  3
• 海关编码：
  2933990090
• 危险品运输编号：
  UN 2811 6.1/PG 3
• RTECS号：
  FE6375500
• 包装等级：
  II
• 危险类别：
  6.1
• 危险性防范说明：
  P301+P310
• 危险性描述：
  H301
• 储存条件：
  | -20°C |

SDS

Material Safety Data Sheet

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Section 1. Identification of the substance
Product Name: Ondansetron
Synonyms:

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Section 2. Hazards identification
Harmful by inhalation, in contact with skin, and if swallowed.

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Section 3. Composition/information on ingredients.
Ingredient name: Ondansetron
CAS number: 99614-02-5

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Section 4. First aid measures
Skin contact: Immediately wash skin with copious amounts of water for at least 15 minutes while removing
contaminated clothing and shoes. If irritation persists, seek medical attention.
Eye contact: Immediately wash skin with copious amounts of water for at least 15 minutes. Assure adequate
flushing of the eyes by separating the eyelids with fingers. If irritation persists, seek medical
attention.
Inhalation: Remove to fresh air. In severe cases or if symptoms persist, seek medical attention.
Ingestion: Wash out mouth with copious amounts of water for at least 15 minutes. Seek medical attention.

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Section 5. Fire fighting measures
In the event of a fire involving this material, alone or in combination with other materials, use dry
powder or carbon dioxide extinguishers. Protective clothing and self-contained breathing apparatus
should be worn.

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Section 6. Accidental release measures
Personal precautions: Wear suitable personal protective equipment which performs satisfactorily and meets local/state/national
standards.
Respiratory precaution: Wear approved mask/respirator
Hand precaution: Wear suitable gloves/gauntlets
Skin protection: Wear suitable protective clothing
Eye protection: Wear suitable eye protection
Methods for cleaning up: Mix with sand or similar inert absorbent material, sweep up and keep in a tightly closed container
for disposal. See section 12.
Environmental precautions: Do not allow material to enter drains or water courses.

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Section 7. Handling and storage
Handling: This product should be handled only by, or under the close supervision of, those properly qualified
in the handling and use of potentially hazardous chemicals, who should take into account the fire,
health and chemical hazard data given on this sheet.
Store in closed vessels.
Storage:

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Section 8. Exposure Controls / Personal protection
Engineering Controls: Use only in a chemical fume hood.
Personal protective equipment: Wear laboratory clothing, chemical-resistant gloves and safety goggles.
General hydiene measures: Wash thoroughly after handling. Wash contaminated clothing before reuse.

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Section 9. Physical and chemical properties
Appearance: Not specified
Boiling point: No data
No data
Melting point:
Flash point: No data
Density: No data
Molecular formula: C18H19N3O
Molecular weight: 293.4

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Section 10. Stability and reactivity
Conditions to avoid: Heat, flames and sparks.
Materials to avoid: Oxidizing agents.
Possible hazardous combustion products: Carbon monoxide, nitrogen oxides.

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Section 11. Toxicological information
No data.

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Section 12. Ecological information
No data.

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Section 13. Disposal consideration
Arrange disposal as special waste, by licensed disposal company, in consultation with local waste
disposal authority, in accordance with national and regional regulations.

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Section 14. Transportation information
Non-harzardous for air and ground transportation.

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Section 15. Regulatory information
No chemicals in this material are subject to the reporting requirements of SARA Title III, Section
302, or have known CAS numbers that exceed the threshold reporting levels established by SARA
Title III, Section 313.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

昂丹司琼

昂丹司琼和格拉司琼、多拉司琼是临床上常用的三种止吐药。昂丹司琼是一种有效的、具有选择性和可逆性的5-羟色胺（5-HT3）受体阻滞剂，对α1、α2、β1、β2肾上腺素能受体及组胺H1、H2受体作用极小，对中枢和末梢多巴胺能受体无拮抗作用。它能够抑制由化疗及放射治疗引起的恶心和呕吐。相较于胃复安，昂丹司琼的止吐效果更强且无锥体外系反应，尤其对于顺铂、环磷酰胺、阿霉素等药物导致的呕吐具有快速而强烈的止呕作用。适用于治疗细胞毒药物化疗和放射治疗引起的恶心呕吐，并可预防和治疗手术后引起的恶心呕吐。

昂丹司琼的作用机制是作为胃肠道内激活的内脏传入神经与脊髓内的呕吐中枢间的中转站，从而通过腹肌和膈肌运动来抑制呕吐反射。化疗药物和放射治疗可导致小肠5-HT释放，并通过5-HT3受体引起迷走神经兴奋，进而引发呕吐反应。昂丹司琼可以阻断这一反射的发生，同时也可能通过中枢作用触发呕吐。

此外，昂丹司琼与地塞米松合用时，止吐效果会更强。

生物活性

Ondansetron (GR 38032F, GR-C507/75)是一种5-羟色胺（5-HT3）受体拮抗剂，主要用于止吐作用。

靶点

Target	Value
5-HT3

化学性质

昂丹司琼从甲醇结晶，熔点为231-232℃。盐酸昂丹司琼二水合物 (Ondansetron Hydrochloride Dihydrate)：C₁₈H₁₉N₃O·HCl·2H₂O，白色结晶性固体，熔点178.5～179.5℃。盐酸昂丹司琼-水合物 (Ondansetron Hydrochloride Monohydrate)：C₁₈H₁₉N₃O·HCl·H₂O，结晶，熔点186～187℃。

3S-型：[α]²₅D -14°(C=0.19，甲醇)。3R-型：[α]²₆D +12° (C=1.55，氯仿)。

制备方法

昂丹司琼的制备可以通过多种合成路线实现。以下是其中三种方法：

方法一

环己酮和苯肼反应得到四氢咔唑（收率85%）。接着在0℃下滴加2,3,5,6-四氯-1,4-苯醌，得氧化产物(Ⅱ)，收率67.4%。然后与乙醇、浓盐酸、多聚甲醛和盐酸二甲胺回流反应（收率71.7%）。化合物(V)在水中与2-甲基咪唑反应得到化合物(Ⅵ)，收率70.9%。化合物(Ⅵ)与碘甲烷和碳酸钾室温搅拌至固体消失，再倾入水中，过滤、水洗、甲醇重结晶得昂丹司琼（收率57.2%）。溶于丙酮和水中加入浓盐酸反应可得盐酸昂丹司琼二水合物（收率92.6%）。

方法二

化合物(II)与碳酸钾、丙酮和硫酸二甲酯室温搅拌得到化合物(Ⅶ)，收率91%。然后在回流下加入聚甲醛和盐酸二甲胺，得化合物(Ⅷ)，收率67%。处理后，溶于无水乙醇通入氯化氢气体得到其盐酸盐，并在50℃加入2-甲基咪唑回流，得昂丹司琼（收率70%）。溶于异丙醇、水和浓盐酸中室温搅拌可得盐酸昂丹司琼二水合物（收率90.5%）。

方法三

化合物(II)与碳酸钾、丙酮和硫酸二甲酯在室温搅拌得到化合物(Ⅶ)，收率91%。然后溶于乙醇中分批加入聚甲醛和盐酸二甲胺，回流反应后处理得化合物(Ⅷ)，收率67%。再溶于无水乙醇通入氯化氢气体，在50℃加入2-甲基咪唑回流，得到昂丹司琼（收率70%）。将该盐酸盐溶于异丙醇、水和浓盐酸中室温搅拌可得盐酸昂丹司琼二水合物（收率90.5%）。

反应信息

• 作为反应物：
  描述：

  昂丹司琼 在 aluminum (III) chloride 、 双氧水 作用下， 以 水 为溶剂， 反应 8.0h， 以56.8%的产率得到3-[(二甲基氨基)甲基]-9-甲基-1,2,3,9-四氢-4H-咔唑-4-酮
  参考文献：
  名称：

  一种昂丹司琼杂质A的制备方法

  摘要：

  本发明公开了一种昂丹司琼杂质A的制备方法，包括如下步骤：先称取昂丹司琼原料和适量氯化铝，加过氧化氢水溶液溶解制成昂丹司琼溶液，过氧化氢水溶液中过氧化氢的质量分数为12％；将该溶液转移至带有聚四氟乙烯内衬的反应釜，密封后放入烘箱中在140℃反应8h；反应完成，冷却到室温后，乙酸乙酯萃取，收集乙酸乙酯部分，浓缩干燥得到水热反应萃取物；再用HSCCC法对水热反应萃取物进行分离纯化得到杂质A。本发明提供的方法先通过水热反应使得昂丹司琼降解得到杂质A、D，以水为介质，经济环保；再通过HSCCC一步即可分别分离纯化得到杂质A、D，纯度在98％以上。

  公开号：

  CN109020871A
• 作为产物：
  描述：

  盐酸枢复宁 在 无水氯化钙 、 盐酸 、 氟化钾，无水 作用下， 以 乙醇 为溶剂， 反应 42.0h， 以to give 3.7 g of ondansetron Form B, HCl, KF =0.4%的产率得到昂丹司琼
  参考文献：
  名称：

  Novel crystal and solvate forms of ondansetron hydrochloride and processes for their preparation

  摘要：

  本发明提供了新型的奥曲肽盐酸盐结晶多态形式和溶剂化物。同时还提供了制备和相互转化多态形式的过程。此外，还提供了使用新型多态形式和水合物的制药组合物和治疗方法。

  公开号：

  US20020107275A1
• 作为试剂：
  描述：

  2-甲基咪唑 、 1,2,3,9-四氢-9-甲基-3-亚甲咔唑酮 在 昂丹司琼 、 甲醇 作用下， 生成 昂丹司琼
  参考文献：
  名称：

  Novel crystal forms of ondansetron, processes for their preparation, pharmaceutical compositions containing the novel forms and methods for treating nausea using them

  摘要：

  Ondansetron结晶形式A和B在治疗恶心和呕吐方面非常有用。形式B的熔点非常高，约为244°C。这两种形式在30°C以上直到它们的熔点都稳定，不会发生热诱导多形转变。

  公开号：

  US20040019093A1

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] COMPOUNDS AND COMPOSITIONS COMPRISING CDK INHIBITORS AND METHODS FOR THE TREATMENT OF CANCER<br/>[FR] COMPOSÉS ET COMPOSITIONS COMPRENANT DES INHIBITEURS DES CDK ET MÉTHODES DE TRAITEMENT DU CANCER
  申请人：UNIV GEORGIA STATE RES FOUND

  公开号：WO2010129858A1

  公开（公告）日：2010-11-11

  Disclosed herein are compounds suitable for use as antitumor agents, methods for treating cancer wherein the disclosed compounds are used in making a medicament for the treatment of cancer, methods for treating a tumor comprising, administering to a subject a composition comprising one or more of the disclosed cytotoxic agents, and methods for preparing the disclosed antitumor agents.

  本文披露了适用作抗肿瘤药剂的化合物，用于治疗癌症的方法，其中所披露的化合物用于制备治疗癌症的药物，治疗肿瘤的方法包括向受试者施用包含一种或多种所披露的细胞毒性药剂的组合物，以及制备所披露的抗肿瘤药剂的方法。
• [EN] INHIBITORS OF BRUTON'S TYROSINE KINASE<br/>[FR] INHIBITEURS DE TYROSINE KINASE DE BRUTON
  申请人：BIOCAD JOINT STOCK CO

  公开号：WO2018092047A1

  公开（公告）日：2018-05-24

  The present invention relates to a new compound of formula I: or pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: V1 is C or N, V2 is C(R2) or N, whereby if V1 is C then V2 is N, if V1 is C then V2 is C(R2), or if V1 is N then V2 is C(R2); each n, k is independently 0, 1; each R2, R11 is independently H, D, Hal, CN, NR'R", C(O)NR'R", C1-C6 alkoxy; R3 is H, D, hydroxy, C(O)C1-C6 alkyl, C(O)C2-C6 alkenyl, C(O)C2-C6 alkynyl, C1-C6 alkyl; R4 is H, Hal, CN, CONR'R", hydroxy, C1-C6 alkyl, C1-C6 alkoxy; L is CH2, NH, O or chemical bond; R1 is selected from the group of the fragments, comprising: Fragment 1, Fragment 2, Fragment 3 each A1, A2, A3, A4 is independently CH, N, CHal; each A5, A6, A7, A8, A9 is independently C, CH or N; R5 is H, CN, Hal, CONR'R", C1-C6 alkyl, non-substituted or substituted by one or more halogens; each R' and R" is independently selected from the group, comprising H, C1-C6 alkyl, C1-C6 cycloalkyl, aryl; R6 is selected from the group: [formula II] each R7, R8, R9, R10 is independently vinyl, methylacetylenyl; Hal is CI, Br, I, F, which have properties of inhibitor of Bruton's tyrosine kinase (Btk), to pharmaceutical compositions containing such compounds, and their use as pharmaceuticals for treatment of diseases and disorder.

  本发明涉及一种新的化合物，其化学式为I：或其药学上可接受的盐、溶剂化合物或立体异构体，其中：V1为C或N，V2为C(R2)或N，如果V1为C，则V2为N，如果V1为C，则V2为C(R2)，或者如果V1为N，则V2为C(R2)；每个n，k独立地为0或1；每个R2，R11独立地为H，D，Hal，CN，NR'R"，C(O)NR'R"，C1-C6烷氧基；R3为H，D，羟基，C(O)C1-C6烷基，C(O)C2-C6烯基，C(O)C2-C6炔基，C1-C6烷基；R4为H，Hal，CN，CONR'R"，羟基，C1-C6烷基，C1-C6烷氧基；L为CH2，NH，O或化学键；R1从包括的片段组中选择：片段1，片段2，片段3，每个A1，A2，A3，A4独立地为CH，N，CHal；每个A5，A6，A7，A8，A9独立地为C，CH或N；R5为H，CN，Hal，CONR'R"，C1-C6烷基，未取代或被一个或多个卤素取代；每个R'和R"独立地从包括H，C1-C6烷基，C1-C6环烷基，芳基的组中选择；R6从组中选择：[化学式II]每个R7，R8，R9，R10独立地为乙烯基，甲基乙炔基；Hal为CI，Br，I，F，具有布鲁顿酪氨酸激酶（Btk）抑制剂的性质，以及含有这种化合物的药物组合物，以及它们作为治疗疾病和紊乱的药物的用途。
• Eflornithine Prodrugs, Conjugates and Salts, and Methods of Use Thereof
  申请人：Xu Feng

  公开号：US20100120727A1

  公开（公告）日：2010-05-13

  In one aspect, the present invention provides a composition of a covalent conjugate of an eflornithine analog with an anti-inflammatory drug. In another aspect, the present invention provides a composition of an eflornithine prodrug. In another aspect, the present invention provides a composition of an eflornithine or its derivatives aspirin salt. In another aspect, the present invention provides methods for treating or preventing cancer using the conjugates or salts of eflornithine analogs or eflornithine prodrugs.

  在一个方面，本发明提供了一种氟硝西汀类似物与抗炎药物的共价结合物的组合物。在另一个方面，本发明提供了一种氟硝西汀前药的组合物。在另一个方面，本发明提供了一种氟硝西汀或其衍生物水杨酸盐的组合物。在另一个方面，本发明提供了使用氟硝西汀类似物或氟硝西汀前药的共轭物或盐来治疗或预防癌症的方法。
• [EN] SULFONYL COMPOUNDS THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN<br/>[FR] COMPOSÉS DE SULFONYLE QUI INTERAGISSENT AVEC LA PROTÉINE RÉGULATRICE DE LA GLUCOKINASE
  申请人：AMGEN INC

  公开号：WO2013123444A1

  公开（公告）日：2013-08-22

  The present invention relates to sulfonyl compounds that interact with glucokinase regulatory protein. In addition, the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where glucokinase regulatory protein is involved using the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions that contain the compounds, or pharmaceutically acceptable salts thereof.

  本发明涉及与葡萄糖激酶调节蛋白相互作用的磺酰基化合物。此外，本发明涉及使用这些化合物或其药学上可接受的盐治疗2型糖尿病和其他涉及葡萄糖激酶调节蛋白的疾病和/或症状的方法，以及含有这些化合物或其药学上可接受的盐的药物组合物。