齐拉西酮 | 146939-27-7

• 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 - 二嗪烷类
• 中文名称: 齐拉西酮
• 中文别名: 齐哌西酮；5-(2-(4-(1,2-苯并异噻唑-3-基)-1-哌嗪基)乙基)-6-氯-1,3-二氢-2H-吲哚-2-酮；噻帕西酮
• 英文名称: ziprazidone
• 英文别名: Ziprasidone；anhydrous 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one；5-[2-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]ethyl]-6-chloro-1,3-dihydroindol-2-one
• CAS: 146939-27-7
• 化学式: C₂₁H₂₁ClN₄OS
• 分子量: 412.943
• InChiKey: MVWVFYHBGMAFLY-UHFFFAOYSA-N

物化性质

• 熔点：
  213-215°C
• 沸点：
  554.8±50.0 °C(Predicted)
• 密度：
  1.369±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）
• 物理描述：
  Solid
• 闪点：
  -2 °C (28 °F) - closed cup
• 蒸汽压力：
  1.02X10-13 mm Hg at 25 °C (est)
• 稳定性/保质期：
  盐酸噻帕西酮：C21H21ClN4OS·HCl·H2O，[138982-67-9]。它也可存在半水合物形式，熔点超过300℃。
• 解离常数：
  pKa1 = 2.03 (amine); pKa2 = 7.09 (amine); pKa3 = 14.89 (secondary amine) (est)
• 碰撞截面：
  192.6 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)：
  4
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  76.7
• 氢给体数：
  1
• 氢受体数：
  5

ADMET

代谢

齐拉西酮在肝脏中大量代谢，小于5%的药物以原形通过尿液排出。主要的还原途径由乙醛氧化酶催化，而另外两个不太显著的氧化途径由CYP3A4催化。由于只有1/3的抗精神病药物通过CYP3A4系统代谢，齐拉西酮不太可能与通过CYP3A4代谢的其他药物发生相互作用。已鉴定出12种齐拉西酮代谢物（斜体字为缩写）：齐拉西酮亚砜、齐拉西酮砜、(6-氯-2-氧代-2,3-二氢-1H-吲哚-5-基)乙酸(_OX-COOH_)、OX-COOH葡萄糖苷酸、3-(哌嗪-1-基)-1,2-苯并异噻唑(_BITP_)、BITP亚砜、BITP砜、BITP砜内酰胺、S-甲基-二氢-齐拉西酮、S-甲基-二氢-齐拉西酮亚砜、6-氯-5-(2-哌嗪-1-基-乙基)-1,3-二氢-吲哚-2-酮(_OX-P_)和二氢-齐拉西酮砜。根据代谢物的数量，齐拉西酮通过多种不同的途径进行代谢。齐拉西酮依次被氧化为齐拉西酮亚砜和齐拉西酮砜，而齐拉西酮的氧化N-脱烷基化产生OX-COOH和BITP。OX-COOH经历第二阶段代谢产生葡萄糖苷酸化代谢物，而BITP依次被氧化为BITP亚砜、BITP砜，然后是BITP砜内酰胺。齐拉西酮还可以经历还原裂解和甲基化，产生S-甲基-二氢-齐拉西酮，然后进一步氧化产生S-甲基-二氢-齐拉西酮亚砜。最后，齐拉西酮的脱芳香化产生OX-P，而水合和氧化过程将母药转化为二氢-齐拉西酮砜。尽管CYP3A4和乙醛氧化酶是齐拉西酮代谢的主要酶，但与每种酶相关的代谢途径尚未明确指定。

Ziprasidone is heavily metabolized in the liver with less than 5% of the drug excreted unchanged in the urine. The primary reductive pathway is catalyzed by aldehyde oxidase, while 2 other less prominent oxidative pathways are catalyzed by CYP3A4. Ziprasidone is unlikely to interact with other medications metabolized by CYP3A4 since only 1/3 of the antipsychotic is metabolized by the CYP3A4 system. There are 12 identified ziprasidone metabolites (abbreviations italicized): Ziprasidone sulfoxide, ziprasidone sulfone, (6-chloro-2-oxo-2,3-dihydro-1H-indol-5-yl)acetic acid (_OX-COOH_), OX-COOH glucuronide, 3-(piperazine-1-yl)-1,2-benzisothiazole (_BITP_), BITP sulfoxide, BITP sulfone, BITP sulfone lactam, S-Methyl-dihydro-ziprasidone, S-Methyl-dihydro-ziprasidone-sulfoxide, 6-chloro-5-(2-piperazin-1-yl-ethyl)-1,3-dihydro-indol-2-one (_OX-P_), and dihydro-ziprasidone-sulfone. As suggested by the quantity of metabolites, ziprasidone is metabolized through several different pathways. Ziprasidone is sequentially oxidized to ziprasidone sulfoxide and ziprasidone sulfone, and oxidative N-dealkylation of ziprasidone produces OX-COOH and BITP. OX-COOH undergoes phase II metabolism to yield a glucuronidated metabolite while BITP is sequentially oxidized into BITP sulfoxide, BITP sulfone, then BITP sulfone lactam. Ziprasidone can also undergo reductive cleavage and methylation to produce S-Methyl-dihydro-ziprasidone and then further oxidation to produce S-Methyl-dihydro-ziprasidone-sulfoxide. Finally dearylation of ziprasidone produces OX-P, and the process of hydration and oxidation transforms the parent drug into dihydro-ziprasidone-sulfone. Although CYP3A4 and aldehyde oxidase are the primary enzymes involved in ziprasidone metabolism, the pathways associated with each enzyme have not been specified.

来源:DrugBank

代谢

Ziprasidone在肝脏中被广泛代谢，主要通过醛氧化酶的还原，尿液中或粪便中几乎没有未改变的药物排泄。大约三分之一的Ziprasidone的代谢清除是通过细胞色素P-450 (CYP) 3A4同工酶介导的。

Ziprasidone is extensively metabolized in the liver principally via reduction by aldehyde oxidase with minimal excretion of unchanged drug in urine or feces. About one-third of ziprasidone's metabolic clearance is mediated by the cytochrome P-450 (CYP) 3A4 isoenzyme.

来源:Hazardous Substances Data Bank (HSDB)

代谢

喹硫平主要通过三条代谢途径产生四种主要循环代谢物，包括苯并异噻唑（BITP）亚砜、BITP-砜、喹硫平亚砜和S-甲基-二氢喹硫平。

Ziprasidone is primarily cleared via three metabolic routes to yield four major circulating metabolites, benzisothiazole (BITP) sulphoxide, BITP-sulphone, ziprasidone sulphoxide, and S-methyl-dihydroziprasidone.

来源:Hazardous Substances Data Bank (HSDB)

代谢

体外使用人肝亚细胞组分的研究表明，S-甲基-二氢齐拉西酮是通过两步生成的。数据显示，还原反应由醛氧化酶介导，随后的甲基化由硫醇甲基转移酶介导。

In vitro studies using human liver subcellular fractions indicate that S-methyl-dihydroziprasidone is generated in two steps. The data indicate that the reduction reaction is mediated by aldehyde oxidase and the subsequent methylation is mediated by thiol methyltransferase.

来源:Hazardous Substances Data Bank (HSDB)

代谢

体外使用人肝微粒体和重组酶的研究表明，CYP3A4是主要的CYP，参与ziprasidone的氧化代谢。CYP1A2的贡献要小得多。根据体内排泄代谢物的丰富度，ziprasidone代谢清除率不到三分之一是通过细胞色素P450催化的氧化，大约三分之二通过醛氧化酶还原。目前没有已知的具有临床相关性的醛氧化酶抑制剂或诱导剂。

In vitro studies using human liver microsomes and recombinant enzymes indicate that CYP3A4 is the major CYP contributing to the oxidative metabolism of ziprasidone. CYP1A2 may contribute to a much lesser extent. Based on in vivo abundance of excretory metabolites, less than one-third of ziprasidone metabolic clearance is mediated by cytochrome P450 catalyzed oxidation and approximately two-thirds via reduction by aldehyde oxidase. There are no known clinically relevant inhibitors or inducers of aldehyde oxidase.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：齐拉西酮用于治疗精神分裂症。齐拉西酮作为单药治疗，用于双相情感障碍I型的急性躁狂或混合发作。齐拉西酮作为锂或丙戊酸盐的辅助药物，用于双相情感障碍I型的维持治疗。人类暴露和毒性：服用最大确认量的患者（3240毫克）报告的唯一症状是最轻微的镇静、言语含糊和暂时性高血压（200/95）。在上市后使用中，与齐拉西酮过量相关的不良事件通常包括锥体外系症状、嗜睡、震颤和焦虑。先前报告的儿童齐拉西酮过量描述了一组症状，包括镇静、心动过速、肌张力减退和昏迷。在儿童齐拉西酮过量中，还观察到QTc间期延长和低血压，但未报告癫痫发作。有一例有趣的齐拉西酮中毒案例，涉及瞳孔针尖样缩小，对纳洛酮无反应。这种现象以前在过量使用类似的非典型抗精神病药物奥氮平中也有报道。过量使用非典型抗精神病药物引起的缩瞳机制尚不清楚，但可能与干扰瞳孔中央神经支配有关。患有痴呆相关精神病的老年患者使用非典型抗精神病药物似乎比使用安慰剂的患者死亡风险增加。在一项研究中，口服齐拉西酮在心电图上延长QT间期的平均时间比接受利培酮、奥氮平、喹硫平或氟哌啶醇的患者多9-14毫秒，但比接受硫利达嗪的患者少大约14毫秒。一例儿童患者服用齐拉西酮过量，定量血清水平显示昏迷和瞳孔针尖样缩小，说明仅服用1片药物可能会导致儿童出现深刻的意识状态和呼吸抑制。在人类淋巴细胞的体外染色体畸变试验中得到了阳性结果。接受非典型抗精神病药物治疗的的精神病患者在纠正低钠血症期间应密切监测横纹肌溶解症，以便及时治疗以限制其并发症。动物研究：在大鼠和小鼠中进行了齐拉西酮的终身致癌性研究。在大鼠研究中，通过饮食给药24个月，剂量为2、6或12毫克/千克/天，小鼠的剂量为50、100或200毫克/千克/天（分别为最大推荐人类剂量[MRHD] 200毫克/天的0.1至0.6倍和1至5倍）。在大鼠研究中，与对照组相比，没有发现肿瘤发生率增加的证据。在雄性小鼠中，与对照组相比，肿瘤发生率没有增加。在雌性小鼠中，所有测试剂量（50至200毫克/千克/天，或MRHD的1至5倍）的垂体腺瘤和腺癌以及乳腺腺癌的发生率都有剂量相关性增加。在慢性给药其他抗精神病药物后，已在啮齿动物的垂体和乳腺中观察到增生性改变，这些改变被认为是催乳素介导的。在一项为期1个月的饮食研究中，雌性小鼠（而非雄性小鼠）在100和200毫克/千克/天（或MRHD的2.5和5倍）的剂量下观察到血清催乳素增加。在为期5周的饮食研究中，齐拉西酮在用于致癌性研究的剂量下对大鼠的血清催乳素没有影响。齐拉西酮在治疗的前3周内没有引起显著体重增加，然而，在第28天时，2.5毫克/千克的剂量观察到显著体重增加（p < 0.05）。齐拉西酮在任何时间点对食物摄入都没有影响。在治疗的第一周，2.5毫克/千克齐拉西酮显著减少了饮水摄入量（p < 0.05）。齐拉西酮对腹内脂肪重量、湿或干子宫重量或血浆催乳素水平没有影响。所有接受齐拉西酮治疗的动物都表现出正常的四天发情周期。在大鼠中，胚胎胎儿毒性（胎儿体重减轻、骨骼钙化延迟）在器官形成期或整个妊娠期间给予10至160毫克/千克/天的剂量后观察到，但没有证据表明有致畸性。40和160毫克/千克/天的剂量与母体毒性相关。齐拉西酮在 Ames 细菌突变试验、体外哺乳动物细胞基因突变小鼠淋巴瘤试验和体内小鼠骨髓染色体畸变试验中进行了测试。在没有代谢激活的情况下，一种沙门氏菌菌株在Ames试验中出现了可重复的突变反应。在体外哺乳动物细胞基因突变试验中得到了阳性结果。

IDENTIFICATION AND USE: Ziprasidone is indicated for the treatment of schizophrenia. Ziprasidone is indicated as monotherapy for the acute treatment of manic or mixed episodes associated with bipolar I disorder. Ziprasidone is indicated as an adjunct to lithium or valproate for the maintenance treatment of bipolar I disorder. HUMAN EXPOSURE AND TOXICITY: In the patient taking the largest confirmed amount, 3240 mg, the only symptoms reported were minimal sedation, slurring of speech, and transitory hypertension (200/95). In post-marketing use, adverse events reported in association with ziprasidone overdose generally included extrapyramidal symptoms, somnolence, tremor, and anxiety. Previously reported pediatric ziprasidone overdoses describe a syndrome of sedation, tachycardia, hypotonia, and coma. In pediatric ziprasidone overdose, QTc prolongation and hypotension have also been illustrated, but seizures have not been reported. An interesting case of ziprasidone intoxication involving the development of pinpoint pupils unresponsive to naloxone has been reported. This phenomenon has been reported before with overdose of olanzapine, a similar atypical antipsychotic. The mechanism of miosis associated with overdose of atypical antipsychotics is unclear but is likely related to interference with central innervation of the pupil. Geriatric patients with dementia-related psychosis treated with atypical antipsychotic drugs appear to be at an increased risk of death compared with that among patients receiving placebo. In one study, oral ziprasidone prolonged the QT interval on ECG by a mean of 9-14 msec more than that observed in patients receiving risperidone, olanzapine, quetiapine, or haloperidol, but approximately 14 msec less than that observed in patients receiving thioridazine. A ziprasidone overdose with quantitative serum levels of a pediatric patient in coma and with pinpoint pupils illustrating that ingestion of just 1 pill may result to profound mental status and respiratory depression in a child. Positive results were obtained in an in vitro chromosomal aberration assay in human lymphocytes. Psychiatric patients treated with atypical antipsychotic medications should be closely monitored for rhabdomyolysis during correction of hyponatremia, thus permitting prompt therapy to limit its complications. ANIMAL STUDIES: Lifetime carcinogenicity studies were conducted with ziprasidone in rats and mice. Ziprasidone was administered for 24 months in the diet at doses of 2, 6, or 12 mg/kg/day to rats, and 50, 100, or 200 mg/kg/day to mice (0.1 to 0.6 and 1 to 5 times the maximum recommended human dose [MRHD] of 200 mg/day on a sq m basis, respectively). In the rat study, there was no evidence of an increased incidence of tumors compared to controls. In male mice, there was no increase in incidence of tumors relative to controls. In female mice, there were dose-related increases in the incidences of pituitary gland adenoma and carcinoma, and mammary gland adenocarcinoma at all doses tested (50 to 200 mg/kg/day or 1 to 5 times the MRHD on an mg/sq m basis). Proliferative changes in the pituitary and mammary glands of rodents have been observed following chronic administration of other antipsychotic agents and are considered to be prolactin-mediated. Increases in serum prolactin were observed in a 1-month dietary study in female, but not male, mice at 100 and 200 mg/kg/day (or 2.5 and 5 times the MRHD on an mg/sq m basis). Ziprasidone had no effect on serum prolactin in rats in a 5-week dietary study at the doses that were used in the carcinogenicity study. Ziprasidone failed to induce significant weight gain during weeks 1-3, however, significant weight gain was observed on day 28 at 2.5 mg/kg (p < 0.05). Ziprasidone had no effect on food intake at any time point. A significant reduction in water intake (p < 0.05) was observed during the first week of treatment with 2.5 mg/kg ziprasidone. Ziprasidone had no effect on intra-abdominal fat weight, wet or dry uterine weight or plasma prolactin levels. All ziprasidone treated animals displayed a normal four-day estrous cycle. In rats, embryofetal toxicity (decreased fetal weights, delayed skeletal ossification) was observed following administration of 10 to 160 mg/kg/day during organogenesis or throughout gestation, but there was no evidence of teratogenicity. Doses of 40 and 160 mg/kg/day were associated with maternal toxicity. Ziprasidone was tested in the Ames bacterial mutation assay, the in vitro mammalian cell gene mutation mouse lymphoma assay, and the in vivo chromosomal aberration assay in mouse bone marrow. There was a reproducible mutagenic response in the Ames assay in one strain of S. typhimurium in the absence of metabolic activation. Positive results were obtained in the in vitro mammalian cell gene mutation assay.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

利培酮治疗的患者中报告了肝功能测试异常，但文献中对这些异常的描述并不充分，而且升高频率似乎与安慰剂治疗相似。在接受利培酮治疗的患者中报告了几例超敏反应，这些反应在开始治疗后的1到4周内出现，至少在一例中再次接触利培酮后迅速复发。在几例中，超敏反应被归类为药物反应伴嗜酸性粒细胞增多和系统症状（DRESS）综合征，表现为皮疹、嗜酸性粒细胞增多和伴随的肝脏损伤，形式为中度血清酶升高或伴有黄疸的混合性肝炎。在所有情况下，停止利培酮治疗后，症状、体征和实验室异常迅速缓解。因此，在罕见的情况下，利培酮可以引起急性超敏反应，可能伴有肝炎，但肝脏损伤通常是轻微和自限性的。

Liver test abnormalities have been reported in patients taking ziprasidone, but they have not been well characterized in the literature and the frequency of elevations appears to be similar to placebo therapy. Several instances of hypersensitivity reactions have been reported in patients taking ziprasidone, arising within 1 to 4 weeks of starting therapy and with rapid recurrence on reexposure in at least one case. In several instances, the hypersensitivity reaction qualified as DRESS syndrome with rash, eosinophilia and an accompanying liver injury either in the form of moderate serum enzymes or a mixed hepatitis with jaundice. In all instances, the symptoms, signs and laboratory abnormalities resolved rapidly with stopping ziprasidone. Thus, on rare occasions, ziprasidone can cause acute hypersensitivity reactions that can be accompanied by hepatitis, but the liver injury is usually mild and self-limited.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：齐拉西酮

Compound:ziprasidone

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

严重程度等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

在未进食的情况下，齐拉西酮的口服生物利用度为60%，如果与至少含有500千卡热量的餐食一起服用，吸收率可能达到100%。生物利用度的差异与食物的脂肪含量关系不大，似乎与食物的体积有关，因为齐拉西酮在胃中停留的时间越长，吸收越多。

In the absence of food, ziprasidone's oral bioavailability is 60%, and absorption may reach 100% if ziprasidone is taken with a meal containing at least 500 kcal. The difference in bioavailability has little to do with the fat content of the food and appears to be related to the bulk of the meal since more absorption occurs the longer ziprasidone remains in the stomach.

来源:DrugBank

吸收、分配和排泄

• 消除途径

齐拉西酮口服给药后广泛代谢，只有极少量的药物以原形药物的形式从尿液中排泄（<1%）或粪便中排泄（<4%）。

Ziprasidone is extensively metabolized after oral administration with only a small amount excreted in the urine (<1%) or feces (<4%) as unchanged drug.

来源:DrugBank

吸收、分配和排泄

• 分布容积

齐拉西酮的平均表观分布容积为1.5 L/kg。

The mean apparent volume of distribution of Ziprasidone is 1.5 L/kg.

来源:DrugBank

吸收、分配和排泄

• 清除

平均表观系统清除率为7.5 mL/min/kg。

The mean apparent systemic clearance is 7.5 mL/min/kg.

来源:DrugBank

吸收、分配和排泄

喹硫平口服给药后吸收良好，在6到8小时内达到血浆峰浓度。在进食条件下，20毫克剂量的绝对生物利用度大约为60%。食物的存在可使喹硫平的吸收增加至两倍。

Ziprasidone is well absorbed after oral administration, reaching peak plasma concentrations in 6 to 8 hours. The absolute bioavailability of a 20 mg dose under fed conditions is approximately 60%. The absorption of ziprasidone is increased up to two-fold in the presence of food.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  C,N
• 安全说明：
  S45
• 危险类别码：
  R19,R11,R61,R38,R60
• WGK Germany：
  2
• RTECS号：
  JR6475000
• 海关编码：
  29211980
• 危险类别：
  8
• 包装等级：
  II
• 储存条件：
  | 冰箱 |

制备方法与用途

齐拉西酮

齐拉西酮是一种非典型抗精神病药，属于苯并异噻唑基哌嗪类化合物。其对多巴胺D2、D3、5-HT2A、5-HT2C、5-HT1A、5-HT1D和α1肾上腺素受体的亲和力很强，在体外表现出显著的拮抗或激动作用，并抑制突触前膜对5-HT和去甲肾上腺素的再摄取。其确切的作用机制尚不明确，但通过联合拮抗多巴胺D2和5-HT2受体产生抗精神分裂症疗效。齐拉西酮主要阻断多巴胺D2和5-HT2受体，比其他非典型抗精神病药物如奥氮平、奎硫平和氯氮平更加强烈，主要用于治疗急性或慢性初发或复发的精神分裂症，尤其对阴性症状更为有效。

非典型抗精神病药概述

非典型抗精神病药又称为新一代抗精神病药，是指对多巴胺D2受体的阻断作用较弱，而5-HT2受体的阻断作用较强的药物。齐拉西酮正是这类药物中的一种。它适用于治疗成人精神分裂症，并且可以用于双相障碍急性躁狂发作、混合性发作和双相障碍维持治疗。

不良反应

常见的不良反应包括思睡、静坐不能、椎体外系症状、头晕、肌张力障碍、头痛、胃肠道不适、衰弱、激动、高张力状态。少数患者可能出现SGPT升高、骨骼肌肉不适、中枢神经系统异常、鼻炎、斑丘疹、风疹、视力异常和尿失禁。

药物相互作用

齐拉西酮不应与延长QT间期的药物合用，与其他作用于中枢神经系统的药物合用时需谨慎。它可能诱发低血压，并增强某些抗高血压药物的效果，同时可能会拮抗左旋多巴胺和多巴胺激动剂的作用。

用量与用法

初始剂量为每日2次，每次20mg。调整剂量可在2天后进行，一般剂量范围是20～80mg，最大剂量可达100mg。轻、中度肝肾损害患者无需调整剂量。齐拉西酮主要在肝脏中代谢，并通过尿液和粪便排出体外。

化学性质

盐酸噻帕西酮的化学式为C21H21ClN4OS·HCl·H2O，熔点超过300℃。其主要代谢产物经尿液排泄，终末半衰期约为7小时。

生产方法

齐拉西酮通过6-氯-1,3-二氢-2H-吲哚-2-酮(I)和溴乙酸在多聚磷酸作用下的酰化反应制得化合物(Ⅱ)，再与三乙基氢化硅及三氟乙酸在室温下搅拌得到化合物(Ⅲ)，最后在含碳酸钠的MIBK中与N-(3-苯并异噻唑基)哌嗪反应生成齐拉西酮。

反应信息

• 作为反应物：
  描述：

  齐拉西酮 在 氨基磺酸 作用下， 以 乙醇 、 水 为溶剂， 以95.5%的产率得到5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one sulfamate
  参考文献：
  名称：

  [EN] NEW ADDITION SALTS OF ZIPRASIDONE, A PROCESS FOR THE PREPARATION THEREOF AND USE THEREOF IN THERAPY
  [FR] NOUVEAUX SELS D'ADDITION DE ZIPRASIDONE, LEUR PROCÉDÉ DE PRÉPARATION ET LEUR UTILISATION EN THÉRAPIE

  摘要：

  该发明揭示了氯硫嗪的新加合盐，即氨基磺酸盐和N-取代氨基磺酸盐，以非晶和晶体形式及水合物形式存在。它们的制备过程包括氯硫嗪碱与氨基磺酸的1摩尔反应，以及这些盐固态形式的分离方法。该发明还包括一种用于制备制片和封装颗粒的方法，其中在惰性载体上细分布的氯硫嗪盐被获得。根据该发明，氯硫嗪的新盐用于治疗和预防精神障碍和疾病。

  公开号：

  WO2012096632A1
• 作为产物：
  描述：

  5-(2-(4-(7-bromo-1,2-benzisothiazol-3-yl)piperazinyl)-ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one 在 Pd-BaSO₄ 氢气 作用下， 以 四氢呋喃 为溶剂， 反应 6.0h， 生成 齐拉西酮
  参考文献：
  名称：

  Synthesis of 3H- and 14C-labelled CP-88,059: A potent atypical antipsychotic agent

  摘要：

  本文介绍了 3H 和 14C 标记的 CP-88,059 [即 5-(2-(4-(1,2-苯并异噻唑-3-基)哌嗪基)乙基)-6-氯-1, 3-二氢-2H-吲哚-2-酮] 的合成。CP-88,059 (5b)是一种 D2/5-HT2 联合拮抗剂，目前正在作为一种抗精神病药物进行临床评估，这种药物诱发精神分裂症患者 EPS 的可能性较低。通过氚气还原脱氢和 Pd/BaSO4 催化，将溴从苯并异噻唑分子的 7 位置换出来，得到了 3H-CP-88,059 (5c)。通过[2-14C]-氯乙酰氯对 6-氯氧化吲哚进行弗里德尔-卡夫酰化，然后用三乙基硅烷还原芳基羰基，并在回流的 Na2CO3 水溶液中与 N-(1,2-苯并异噻唑-3-基)哌嗪偶联，实现了 14C 与分子乙烯部分的结合。

  DOI：

  10.1002/jlcr.2580340203

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。
• 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。
• [EN] NAPHTHALENE CARBOXAMIDE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS<br/>[FR] COMPOSÉS DE NAPHTHALÈNE CARBOXAMIDE, MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR M1
  申请人：MERCK SHARP & DOHME

  公开号：WO2011149801A1

  公开（公告）日：2011-12-01

  The present invention is directed to naphthalene carboxamide compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimers disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

  本发明涉及式(I)的萘甲酰胺化合物，它们是M1受体阳性变构调节剂，可用于治疗M1受体参与的疾病，如阿尔茨海默病、精神分裂症、疼痛或睡眠障碍。该发明还涉及包含这些化合物的药物组合物，以及在治疗由M1受体介导的疾病中使用这些化合物和组合物。