新型催眠镇静药佐匹克隆类似物的合成

本文根据环吡咯酮类催眠药佐匹克隆的构效关系及作用机制，合成了八个未见文献报道的环吡咯酮类化合物，并进行了初步的药效研究。     

新型催眠镇静药佐匹克隆类似物的合成

本文根据环吡络酮类催眠药佐匹克隆的构效关系及作用机制，合成了八个未见文献报道的环吡咯酮类新化合物，并进行了初步的药效研究。     

环吡咯酮类化合物的合成及其与苯二氮卓受体结合 的活性研究

目的 设计并合成环吡咯酮类化合物,并评价其与苯二氮卓受体的结合活性。方法 根据环吡咯酮类镇静催眠药佐匹克隆(zopiclone)的基本活性结构特征,设计了17个改变酯键侧链的环吡咯酮类化合物。以2,3-吡嗪二酸酐、2-氨基-5-氯吡啶为起始原料,经过5步反应得到目标产物。以苯二氮卓受体拮抗剂氚标氟马西尼([3H] Ro 15-1788)为工具药,氟马西尼为阳性对照药,通过测试所合成化合物与苯二氮卓受体竞争性结合活性,对目标化合物进行了初步的活性评价。结果与结论 合成得到了17个未见文献报道的环吡咯酮类化合物,结构均经MS和1H-NMR确证。活性筛选实验表明,部分化合物表现出一定的活性。     

佐匹克隆治疗失眠的药理学,临床疗效和耐受性

佐区克隆为一非苯二氮Ｚｈｏｕ类的吡咯环酮类类化合物，其治疗失眠的疗效与苯二氮Ｚｈｏｕ类相似，激动γ－氨基丁酸，受体，增强ＧＡＢＡ的抑制作用，是一种有效，耐受性良好的催眠药。     

2-甲基-3-取代苯基吡咯并吡嗪酮类化合物的合成及抗癌活性研究

目的 寻找具有抗癌活性的新吡咯并吡嗪酮类化合物。方法 以吡咯、对氨基苯乙酮为原料,经Friedel-Crafts酰化、醇解、亲核取代、环合及醇解反应制得母体化合物2-甲基-3-对氨基苯基吡咯并[1,2-a]吡嗪-1(2H)-酮,再通过酰基化/磺酰基化和烷基化反应引入酰基和烷基即制得系列吡咯并吡嗪酮类化合物。结果 合成了8个未见文献报道的吡咯并吡嗪酮类化合物,其结构经¹H-NMR、MS和IR谱确证。结论 8个目标化合物的体外抗乳腺癌细胞、肝癌细胞和肺癌细胞的活性试验结果显示,化合物4、5 具有明显的抗癌活性。     

佐匹克隆(Zopiclone)

异名 RP-27267,Imovane,Imovance 化学名 6-(5-氯-2-吡啶基)-7-[(4-甲基哌嗪-1-基)羰基氧]-5,6-二氢吡咯并[3,4-b]吡嗪-5-酮药效分类催眠药开发单位 (法)Rhone-Poulenc Phar-ma 上市厂商预计1985年初在法国上市文献 Pharmacology 1983,27(sup2):1～248 药理本品是环吡咯酮类催眠药中的第     

5-苯硫基吡哩酮及其异构体的合成研究

目的研究1H-2，3-二氢-1-吡咯里嗪酮类衍生物的构效关系，设计合成了5-苯硫基-2，3-二氢-1-吡咯里嗪酮(1)。方法 以吡咯为原料经Michael加成、苯硫化、分子内Hoesch反应合成目标化合物。结果 在生成目标化合物的同时，生成了其同分异构体7-苯硫基-2，3-二氢-1-吡咯里嗪酮(5)。结论 推测其生成机制为中间体2-苯硫基-1-氰乙基吡咯在酸性下的异构化反应。     

佐匹克隆

佐匹克隆Zopiclone，由法国罗钠普朗克公司研制，1987年首次在法国上市，商品名Imovan“忆梦返”。佐匹克隆是非苯并二氮杂类药物，为激动GABAA受体，增强GABA抑制作用的吡咯环酮类化合物：作用于苯二氮卓受体，但结合方式不同于苯二氮卓类药物，为速效催眠药，能延长睡眠时间，提高睡眠质量，减少夜间觉醒和早醒次数。     

5-芳基-1,2-二氢-1-吡咯里嗪酮类化合物的合成及抗炎镇痛作用

目的 研究5-芳基-1，2-二氢-1-吡咯里嗪酮类化合物的抗炎镇痛作用构效关系，寻找高效低毒、具有抗炎镇痛活性的新型吡咯里嗪酮衍生物。方法 以吡咯里嗪酮为母体，设计并合成了5-芳基-1，2-二氢-1-吡咯里嗪酮类化合物。用二甲苯致小鼠耳肿胀法和小鼠醋酸扭体法测定了该类化合物的抗炎及镇痛活性。结果 用两条路线合成了10个目标化合物，经1H-NMR和MS确证其结构。小鼠试验表明，一些所合成的化合物具有明显的抗炎和／或镇痛作用。结论 化合物Ⅲ1及Ⅲ5的抗炎活性优于对照药布洛芬；化合物Ⅲ5的镇痛活性优于对照药布洛芬；其中化合物Ⅲ5的抗炎及镇痛活性均强于对照药布洛芬，值得进一步研究。     

对氯苯基氨基酮类化合物的合成及镇痛作用

对氯苯基氨基酮类化合物的合成及镇痛作用郭玉红１）王玉玲张守芳（沈阳药科大学有机化学教研室，沈阳１１００１５）作者曾经报道，一些１，２－二氢吡咯哩嗪酮类化合物具有良好的解热镇痛作用〔１〕，如氯苯酰酮（Ⅰ）．参照氯苯酰酮的基本结构，曾设计合成了对氯苯基氨...     

Pagoclone Indevus

Pagoclone is a cyclopyrrolone GABAA receptor modulator under development by Indevus for the potential treatment of panic and anxiety disorders. Indevus initiated phase II/III trials in November 1996. Pfizer had initiated a phase III trial for panic disorder in August 2000 but discontinued development of the compound in June 2002.     

A key role of the mammillary body in mediation of the antianxiety action of zopiclone, a cyclopyrrolone derivative

The present study was designed to elucidate the brain site of the anticonflict action of zopiclone (ZOP), a cyclopyrrolone derivative, using the rat conflict procedure. ZOP at 10 micrograms/microliters, bilaterally injected into the mammillary body (MB), produced a significant increase in the punished responses, with no change in the unpunished responses. There were no significant changes in these responses when ZOP was injected into the central amygdala, frontal cortex or dorsal hippocampus. Attention should be given to the possibility that the MB is the site of the anticonflict action of ZOP.     

(S)-Zopiclone Sepracor

(S)-Zopiclone, a cyclopyrrolone sharing activity with benzodiazepines in the CNS, is a short-acting sedative being developed by Sepracorfor the potential treatment of sleeping disorders. In August 2000, the company had completed phase II trials of (S)-zopiclone for insomnia [380377]; by September 2000, patient enrollmentfor phase III studies for insomnia was completed and the trial initiation was planned for October 2000 [381361]. Merrill Lynch expects US filing to take place in the second half of 2001 [383230]. Sepracor was granted US-05786357 in August 1998 covering methods and compositions of (S)-zopiclone in the treatment of sleeping disorders [342938]. In August 2000, Merrill Lynch predicted (S)-zopiclone sales of US $30 million in 2002, rising to US $150 million in 2004 [383230].     

Eszopiclone: an update on its use in insomnia

Eszopiclone is the single (S)-enantiomer of the cyclopyrrolone hypnotic zopiclone. It was marketed in the U.S. in December 2004. Its kinetics and possible mode of action, pivotal regulatory trials and its use in insomnia comorbid with other conditions are reviewed, together with trials in patients with obstructive sleep apnea syndromes. Safety and tolerability aspects are discussed, including its dysgeusic profile and effects on memory, cognitive and psychomotor function. U.S.-based pharmacoeconomic data are included together with the design features of key regulatory studies submitted for regulatory approval in Japan.     

Suriclone, a new anxiolytic of the cyclopyrrolone family: evidence for possible interference with GABAergic systems

The action of suriclone (R.P. 31,264), a new non-benzodiazepine compound of the cyclopyrrolone family with clinical anxiolytic activity was examined using biochemical and electrophysiological models supposed to be capable of revealing central GABAergic activity. Suriclone, which does not act directly on the gamma-aminobutyric acid (GABA) receptor (muscimol binding assay), markedly reduced the increase of striatal HVA level induced in the rat by a neuroleptic and decreased the cerebellar vermis cGMP content. Moreover, in the cat, suriclone was able to enhance dorsal root potential amplitude which reflects an increase of the presynaptic inhibition. In view of these results, a central GABAergic mechanism of action may be proposed for suriclone.     

Pharmacological and clinical studies of cyclopyrrolones: zopiclone and suriclone

Among the non-benzodiazepine compounds which have been found to interact with the "GABA receptor-BZ receptor-chloride channel complex," the very chemically original cyclopyrrolone family has a special place. This has been demonstrated using selected pharmacological, biochemical and clinical data obtained with two cyclopyrrolones, zopiclone and suriclone, which, in addition to their capacity of displacing BZ from their sites, simultaneously possess the main pharmacological properties of BZ and well established therapeutic activities, as hypnotic and anxiolytic, respectively. However, although cyclopyrrolones recognize BZ receptor sites, their mechanism of action might not exactly fit with that of BZ. Indeed, using tritiated zopiclone and suriclone, it has been shown that they could act on sites distinct from those of BZ or could induce receptor conformational changes different from those induced by BZ.     

The effects of benzodiazepine (triazolam), cyclopyrrolone (zopiclone) and imidazopyridine (zolpidem) hypnotics on the frequency of hippocampal theta activity and sleep structure in rats.

In order to investigate the relative efficacy and safety of zopiclone and zolpidem, we compared the effects of higher doses of zopiclone and zolpidem on the frequency of hippocampal theta activity and sleep structure with that of triazolam. Rats were divided into triazolam treatment group (1 mg/kg, 5 mg/kg), zopiclone treatment group (20 mg/kg, 100 mg/kg) and zolpidem treatment group (20 mg/kg, 100 mg/kg). Rats were injected intraperitoneally with these drugs or their vehicle. Polygraphic sleep recording and visual frequency analysis of the hippocampal EEG activity in REM sleep were carried out for 6 h after each injection. Zolpidem, unlike triazolam and zopiclone, had a much milder reducing-effect on the frequency of hippocampal theta activity and suppressing-effect on REM sleep. These results suggest that zolpidem may prove to be a safer hypnotic drug which has fewer or milder side effects than are benzodiazepine and cyclopyrrolone hypnotics.