7—乙基吲哚的合成

以邻硝基乙苯为原料，经过还原、Ｓａｎｄｍｅｙｅｒ反应、环合、还原四步合成了７－乙基吲哚，总收率达１６％，质量与文献相符。     

4-羟基吲哚和4-甲氧基吲哚的合成

目的 寻找操作方便、反应路线短且成本低的工艺路线。方法 通过取代酚的醚化，再在苯环上直接引入腈乙基，然后水解、环合等反应，直接生成吲哚衍生物。结果 采用氢的亲核取代反应(VNS)，直接制得4-羟基吲哚和4-甲氧基吲哚，操作方便，反应路线短且成本较低。结论 4-羟基吲哚和4-甲氧基吲哚的收率分别达57．4％和28．8％，是值得研究推广的新工艺。     

以L-半胱氨酸和吲哚酶法合成L-色氨酸

用色氨酸酶基因工程菌ＷＷ－４催化Ｌ－半胱氨酸和吲哚合成Ｌ－色氨酸。８０ｍｌ反应液（Ｌ－半胱氨酸０．７５ｇ，吲哚０．７５ｇ）３７℃反应４８ｈ，可积累Ｌ－色氨酸１．１８ｇ。Ｌ－半胱氨酸转化率为９３．２％，吲哚转化率为９０．１％。产品总回收率达７０％，所得晶体在熔点、旋光性和红外吸收光谱等方面与标准品完全一致。     

7-氮杂吲哚的合成

目的 研究医药中间体7-氮杂吲哚的合成方法.方法 以2-氨基-3-甲基吡啶为起始原料,经与二碳酸二叔丁酯反应保护2位氨基,然后在丁基锂的作用下得到二锂盐,二锂盐在稀盐酸中闭环反应,得7-氮杂吲哚.结果 反应总收率63%.结论 合成路线设计合理,条件温和,收率较好.     

奥氮平的合成

以丙二腈,丙醛,硫化原料在三乙胺存在下缩合制得2－氨基－3－氰基－5－甲基噻吩,再与邻氯硝基苯缩合制得2－（邻硝基苯胺基）－3－氰基－5－甲基噻吩,用氯化亚锡还原合环合制得2－甲基－4－氨基－10H－噻吩并[2,3-b][1,5]苯二氮杂Chuo,最后与哌嗪缩合并甲基化制得奥氮平,总收率29％。     

FDA审查结果表明舍吲哚片可能导致心脏性猝死

2009年4月6日《今日医学要闻》（MedPage Today）报道,根据FDA的一项审查结果,作为治疗精神分裂症的有效安定药——舍吲哚片（sertindole,商品名：Serdolect）可能会导致心脏性猝死。在发布此项审查结果后,FDA将召开药品咨询委员会会议,决定这一风险是否会影响该药品的上市。该药品现已在其他国家用于治疗精神分裂症。     

顺式全氢异吲哚的合成

目的 合成降糖药米格列奈的重要中间体顺式全氢异吲哚.方法 以邻苯二甲酰亚胺为原料,经过苄基保护、羰基还原、脱保护和苯环还原四步反应合成目标产物.结果 四步总收率为28.3%.结论 所用方法原料易得,条件温和,操作简便,适于放大制备.     

吲哚美辛衍生物的合成及其抗炎活性

目的:合成吲哚美辛衍生物,以寻找新的对胃肠道毒不良反应更小的非甾体抗炎药.方法:吲哚美辛与卤代烃、硝基苄醇、硝基苄基氯等化合物进行缩合以及硝酸酯化反应,制备相应结构的衍生物.结果与结论:合成的6个化合物中,化合物3a,3c和5b的抗炎活性明显高于吲哚美辛.     

Sertindole for the treatment of schizophrenia

Importance of the field: Despite considerable progress in the pharmacological treatment of schizophrenia, unmet needs remain concerning refractory patients, as well as improvement of negative symptoms, cognition, quality of life, adherence and tolerability. Sertindole, a second-generation antipsychotic with high affinity for dopamine D₂, serotonin 5-HT_2A, 5-HT_2C, and α₁-adrenergic receptors, is the first phenylindole-derived antipsychotic agent.

Areas covered in this review: Pharmacodynamics, pharmacokinetics, clinical efficacy, safety and cost-effectiveness of sertindole are covered based on a literature review (PubMed) from 1990 to 2010. Pivotal as well as supportive randomized controlled trials are reviewed along with observational and/or naturalistic safety studies.

What the reader will gain: This review of sertindole will allow the reader to determine the place for sertindole in the schizophrenia treatment landscape.

Take home message: Studies conducted so far suggest a beneficial effect of sertindole on positive and negative symptoms as well as on cognition, relapse prevention and quality of life. There is also some evidence for the treatment of refractory patients. Sertindole induces moderate weight gain, with few extrapyramidal symptoms and metabolic changes. More head-to-head comparisons with other second-generation antipsychotics are, however, still needed as well as further clarification on cardiac safety.     

Sertindole in the long-term treatment of schizophrenia

This study assessed the safety and tolerability of sertindole in the long-term treatment of schizophrenia. An open-label, noncomparative, flexible-dose study was carried out in 11 European countries. Upon completion of an 8-week, haloperidol-referenced randomized clinical trial with sertindole, patients were offered sertindole maintenance treatment up to 18 months. In total, 294 patients were enrolled, of whom 237 (81%) had received sertindole and 57 (19%) had received haloperidol in the lead-in trial. The modal dose during the maintenance period was 16 mg/day. Patients showed therapeutic improvement indicated by significant decreases in the Positive And Negative Syndrome Scale and Clinical Global Impression 'severity-of-illness' scores. An adverse event was the primary reason for withdrawal in 13% of patients. The most common adverse events were fatigue and weight gain, both with incidences of 14%. The incidence of extrapyramidal symptoms was 18%, and 11% of the patients required anticholinergic medication. No statistically significant changes were observed in laboratory values or vital signs, but the mean serum prolactin levels decreased. The mean change in weight from baseline to the last assessment was 2.7 kg. The largest weight increase was observed in patients who were underweight at baseline. Long-term treatment with sertindole was safe and well tolerated, and patients showed clinical improvement beyond acute treatment.     

Sertindole: efficacy and safety in schizophrenia

The most commonly prescribed class of medications in the United States for chronic severe pain is opioid analgesics. Due to their low cost and widespread availability, the synthetic opioids are popular choices among clinicians and patients. However, there is an increasingly recognized risk of QT prolongation with several drugs in this class, and recently propoxyphene (Darvon) was withdrawn from the market by the Food and Drug Administration (FDA) due to, in part, the risk of QT prolongation and ventricular arrhythmias Updated Epidemiological Review of Propoxyphene Safety. [FDA Alert]. Rockville, MD: U.S. Food and Drug Administration; 2010. Available from: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM234383.pdf on 5 May 2012.     

Sertindole: efficacy and safety in schizophrenia

Sertindole is an antipsychotic drug with affinity for dopamine D2, serotonin 5-HT2A and 5-HT2C, and alpha1-adrenoreceptors. Preclinical studies suggest that sertindole acts preferentially on limbic and cortical dopaminergic neurons and clinical trials have confirmed that sertindole is effective at a low dopamine D2 occupancy level. The active substance has a long half-life. Oral administration once daily yields highly stable plasma levels. These features may explain the clinically observed low frequency of extrapyramidal side effects, including tardive dyskinesia. In contrast to most antipsychotics, sertindole seems to be void of sedative effects. However, although not strictly proven by objective neuropsychological tests, this asset of sertindole does not add to the cognitive problems inherent in schizophrenia. Administration of sertindole is more often associated with prolongation of QTc compared with most other currently used antipsychotics. However, large cohort analyses do not suggest that all-cause mortality is higher with sertindole than with, for example, risperidone or olanzapine. The effective antipsychotic dose range of sertindole is 12-20 mg/day, with small variations among patients. The frequency of most adverse events, for example extrapyramidal symptoms and somnolence, with such a dose does not differ from placebo. Three side effects have been more common than with placebo/haloperidol in short-term studies: weight gain, rhinitis and a decreased ejaculation volume. Two head-to-head comparisons (one in treatment-resistant patients) of sertindole and risperidone showed equivalent effects on positive symptoms. For negative symptoms, one study obtained equivalent effects and one a superior effect of sertindole. Sertindole should not be used as first-line treatment for first-episode patients with schizophrenia because of the QTc prolongation. It has a side-effect profile that makes it an interesting alternative for many patients who do not respond well to the initial choice of antipsychotic drug.     

Sertindole causes distinct electrocardiographic T-wave morphology changes

Sertindole's propensity to prolong the QT interval relates to blockade of the KCNH2 (HERG) encoded Ikr potassium channel, but there has been limited detailed data on T-wave morphology changes. Digital 12-lead ECG was recorded at baseline and at steady-state in 37 patients switched to sertindole. ECG was analyzed for quantitative T-wave morphology changes and Fridericia-corrected QT duration (QTcF). Prominent T-wave morphology changes occurred during sertindole treatment and in some cases without concomitant prolongation of the QTcF interval. Four patients developed notched T-waves during sertindole treatment. Mean QTc prolongation was 19 ms. The mean effect size was higher for T-wave morphology combination score (MCS) (ES = 1.92; 95% CI: 1.35–2.49) compared to the mean effect size for QTcF (ES = 0.88; 95% CI: 0.52–1.24). The use of T-wave morphology analysis may become clinically relevant, particularly if shown to be associated with drug-induced arrhythmia risk.     

Sertindole : a review of its use in schizophrenia

Oral sertindole (Serdolect) is an atypical antipsychotic approved in the EU for once-daily use in patients with schizophrenia who are intolerant to at least one other antipsychotic agent.Extensive data from post-marketing studies do not indicate an excess of overall mortality with sertindole. Sertindole is at least as effective as haloperidol and risperidone in the treatment of neuroleptic-responsive schizophrenia. Sertindole improves negative symptoms, and is also effective for the treatment of neuroleptic-resistant schizophrenia. Sertindole is generally well tolerated and is associated with a low rate of extrapyramidal symptoms (EPS). Thus, sertindole is a useful option in the treatment of patients with schizophrenia.     

Sertindole: A limbic selective neuroleptic with potent anxiolytic effects

The anxiolytic potential of the putative neuroleptic sertindole was assessed in various animal models of anxiety in rodents and in the marmoset human threat test. Sertindole facilitates the exploratory behaviour of mice and rats in the black and white two-compartment box over a large dose range. Sertindole is more potent than diazepam, i.e., minimal effective doses (MED) in the mouse are 0.00023 nmol (0.1 ng/kg) and 0.46 μmol/kg (0.13 mg/kg), respectively, and MED in the rat are 0.23 nmol/kg (0.10 μg/kg) and 35 nmol/kg (10 μg/kg), respectively. Sertindole increases the time that pairs of rats spend in active social interaction (unfamiliar high light conditions) at extremely low doses (MED = 0.000023 nmol/kg [0.01 ng/kg]) being some 19 million-fold more active than diazepam (MED = 0.44 μmol/kg; 0.13 mg/kg). Sertindole inhibits isolation-induced aggressive behaviour in the mouse, but only at high doses, and sertindole does not inhibit shock-induced suppression of drinking or footschock-induced ultrasonic vocalization in rat. Sertindole similarly shows potent anxiolytic-like activity in the marmoset human threat test (MED = 23 nmol/kg; 10 μg/kg). The range between anxiolytic doses and sedative doses is very large for sertindole, i.e., sedation is observed at 2,300 nmol/kg (1 mg/kg). © Wiley-Liss, Inc.     

Sertindole,a New Atypical Antipsychotic for the Treatment of Schizophrenia

The introduction of antipsychotics for the management of schizophrenia greatly improved the quality of life of many patients suffering from this debilitating disease. Although typical antipsychotic drugs represent a significant advancement in psychopharmacology, they carry a heavy side effect burden, have little efficacy in the management of negative symptoms, and are ineffective in about one-third of patients with schizophrenia. Atypical antipsychotic agents characterized the next major advancement in pharmacotherapy They differ from typical antipsychotics in their mechanism of action, side effect profiles, and clinical efficacy. Sertindole is a new atypical antipsychotic.     

一种新的α1A肾上腺素受体选择性拮抗剂—Sertindole

本工作分别在稳定表达α_1A,α_1B和α_1D肾上腺素受体(adrenoceptor,AR)的人胚胎肾脏细胞( human embryonic kidney 293,HEK 293)和大鼠离体血管上,用放射配体结合实验和离体血管收缩功能实验方法以确定sertindole对α₁-AR亚型的选择性拮抗作用。结果显示sertindole与克隆α_1A-AR的亲和性分别是与克隆α_1B-AR和克隆α_1D-AR的69倍和132倍。Sertindole拮抗去甲肾上腺素引起的主动脉和肾动脉收缩反应的pA₂值分别与其对α_1D和α_1A亚型的pKI值相符。分别稳定表达3种亚型受体的HEK293细胞膜标本经与sertindole预温育30min后,受体与¹²⁵IBE2254结合的B_max值显著降低,KD值无显著变化;而在 sertindole 存在条件下,α₁-AR3种亚型与¹²⁵IBE2254 结合的KD值显著增大,但B_max值无显著改变。上述结果表明sertindole为不可逆性竞争性α₁-AR拮抗剂,并有α_1A亚型选择性。