新型苯并呋喃并嘧啶酮衍生物的抑菌活性研究

呋喃嘧啶衍生物是重要的含氮杂环化合物,其类似嘌呤结构具有良好的杀菌、抗病毒、防辐射、抗凝血作用以及具有除草、杀虫活性,是一类具有良好生物活性和药理活性的杂环化合物,早在20世纪30年代就备受人们的关注。研究表明一些呋喃并嘧啶衍生物通过抑制血管内皮细     

我国吡啶碱产业技术发展现状

吡啶碱属含氮杂环类共性化合物,它是农药、医药、兽药等三药及三药中间体的关键共性化合物,是日用化工、饲料、食品添加剂、子午轮胎工业的     

环维黄杨星D的结构修饰及耐缺氧活性的研究

目的 以环维黄杨星D为先导化合物进行结构修饰,以寻求更好的耐缺氧活性的衍生物.方法 将能改变药物活性和水溶性的含氮杂环化合物用于环维黄杨星D的结构修饰,合成目标化合物Ⅱa～Ⅱg.结果 合成了7个未见报道的环维黄杨星D衍生物,其结构经1 HNMR、”CNMR、MS和IR表征;同时进行了小鼠耐缺氧活性的研究.结论 合成的新化合物具有一定的生物活性,其中,含吗啉基、咪唑基、哌嗪基取代的衍生物具有较好的生物活性.     

4-(4-吡啶基)-1-丁醇的制备方法及在药物合成中的应用现状

4-(4-吡啶基)-1-丁醇是一种应用范围广、附加值高的含氮杂环化合物.依据起始物料综述了以4-甲基吡啶、4-溴吡啶、4-乙烯基吡啶、4-(4-氰基丁基)吡啶为原料制备4-(4-吡啶基)-1-丁醇的合成方法,分析比较了每种路线的优势与不足.同时归纳了其在特异性抗血小板药物、磷酸二酯酶抑制剂、含碘BODIPY光敏剂等药物...     

含有吡唑结构单元的化合物及其抗结核活性

杂环化合物广泛存在于天然产物中,目前临床上使用的90％以上的药物为杂环化合物.因此,杂环化合物对新药的发现至关重要.作为一类极其重要的杂环化合物,吡唑类衍生物具有抗肿瘤、抗病毒、抗炎、抗菌、抗氧化和抗结核(TB)等多种生物活性,众多含有吡唑结构单元的药物在临床上广泛使用.特别值得一提的是,含有吡唑结构单元的化合物在抗TB领域的研究引起了药物化学家的持续关注.药物化学家有针对性的设计合成了众多含有吡唑结构单元的化合物,以期从中筛选出具有优秀抗TB活性的先导物.本文将着重探讨此类化合物的抗结核分枝杆菌构-效关系,为寻找疗效更高、毒副作用更小的含有吡唑结构单元的化合物抗TB新药提供理论依据.     

苯并噻唑衍生物抗肿瘤活性研究进展

杂环化合物的生物活性研究一直受到药物化学家的重视。苯并噻唑属于苯环并五元杂环,其衍生物易于合成,已被广泛应用于抗肿瘤尤其是具有分子靶向性抗肿瘤药物的研发。苯并噻唑衍生物可以通过多种途径发挥抗肿瘤作用,如激酶抑制、诱导凋亡、作用于DNA等。本文简要综述了近几年(2010²014年)苯并噻唑衍生物在抗肿瘤药物研究方面的一些新发现。     

基于吡咯［1, 2-α］吲哚的生物碱的生物活性研究进展

吡咯[1, 2-α]吲哚是一种结构新颖的融合杂环骨架, 也是许多天然活性产物和药物的基本结构单元及合成中间体。吡咯[1, 2-a]吲哚杂环衍生物因其具有广泛而显著的生物活性, 在有机合成和药物化学中备受关注。植物提取物一直以来都是活性化合物的重要来源, 目前从植物提取物中发现并分离得到的基于吡咯[1, 2-a]吲哚杂环结构的生物碱有Isatisine、isoborreverine、flinderoles、polyavolensin和yuremamine。笔者综述了国内外对吡咯[1, 2-a]吲哚杂环衍生物的生物活性研究进展, 在筛选活性化合物和候选药物方面具有良好的发展前景。     

作为药物释放系统的前体药物4-咪唑酮可能成为肽类α-氨基酰胺部位的生物可逆性衍生物

肽类化合物在胃肠道易被酶破坏,吸收也很差;注射给药时,肽类一旦进入血流,可因血浆与组织肽酶而引起水解代谢而导致半衰期缩短。故注射给药存在问题。将生物活性肽制成前体药物是解决药物释放及输送的一种有效方法。作者发现,4-咪唑酮在几乎所有肽的α-氨基酰胺结构部位是一种有效的前体药物。本文通过丙酮和不同的二肽类(丙氨酸-甘氨酸,丙氨酸-丙氨酸,苯丙氨酸-亮氨酸,亮氨酸-甘氨酸,门冬氨酸-苯丙氯酸甲基酯)缩合的5种4-咪唑酮水解动力学的研究,与对苯丙氨酸-亮氨酸衍生物及其母体二肽     

2,4,6-三(1H-苯并咪唑-2-基)吡啶和2,4,6-三(1H-咪唑并[4,5-c]吡啶-2-基)吡啶的微波辐射合成

苯并咪唑类衍生物及其金属配合物具有良好的生物活性,可用作抗寄生虫药和质子泵抑制剂等。近年来的药理研究证明,此类化合物对肝炎、骨炎、脾炎等也具有治疗和预防作用,还可作为有机合成反应的中间体。三苯并咪唑类和三吡啶并咪唑类化合物亦具有类似的生理活性。     

喹诺酮类抗菌药研究开发近况

喹诺酮(Quinolones)是吡啶酮酸类系列衍生物的泛称。八十年代以来,在陆续地开发了一系列高效广谱的含氟衍生物以后,这类化合物一跃而成为举世瞩目的新型抗感染药物。新一代的含氟喹诺酮衍生物最初是由日本几家较小的制药公司研制成功的,美国、西德、     

Heterocyclic compounds as inflammation inhibitors

Clinical use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with significant toxicity particularly in the gastrointestinal tract and kidney. Various approaches such as formulation co-administration (of agents to protect the stomach), chemical manipulation and synthesis of new safer anti-inflammatory drugs reported in the literature to overcome the toxicity of NSAIDs have been summarized. As far as synthesis of new more effective and safer anti-inflammatory drugs is concerned, we have reported recent findings in the area of synthesis of heterocyclic compounds such as pyrimidines, imidazole, benzimidazole, thiazole, thiazolidine, acridine, thiourea, alkanoic acid derivatives and other related heterocyclic compounds and their role as inflammation inhibitors.     

Stress Degradation Behavior of Atorvastatin Calcium and Development of a Suitable Stability-Indicating LC Method for the Determination of Atorvastatin,its Related Impurities,and its Degradation Products

A rapid, reversed-phase liquid chromatographic method was developed for the quantitative determination of Atorvastatin calcium, its related substances (12 impurities), and degradation impurities in bulk drugs. The chromatographic separation was achieved on a Zorbax Bonus-RP column by employing a gradient elution with water–acetonitrile–trifluoroacetic acid as the mobile phase in a shorter run time of 25 min. The flow rate was 1.0 mL/min and the detection wavelength was 245 nm. The drug substance was subjected to stress studies such as hydrolysis, oxidation, photolysis, and thermal degradation, and considerable degradation was observed in acidic hydrolysis, oxidative, thermal, and photolytic stress conditions. The formed degradation products were reported and were well-resolved from the Atorvastatin and its related substances. The stressed samples were quantified against a qualified reference standard and the mass balance was found to be close to 99.5% (w/w) when the response of the degradant was considered to be equal to the analyte (i.e. Atorvastatin), which demonstrates the stability-indicating capability of the method. The method was validated in agreement with ICH requirements. The method developed here was single and shorter (25 min method for the determination of all 12 related impurities of Atorvastatin and its degradation products), with clearly better resolution and higher sensitivity than the European (85 min method for the determination of six impurities) and United States pharmacopeia (115 min and 55 min, two different methods for the determination of six related substances).     

Estrogen synthetase inhibitors. 2. Comparison of the in vitro aromatase inhibitory activity for a variety of nitrogen heterocycles substituted with diarylmethane or diarylmethanol groups

The preparation and in vitro aromatase inhibitory activity of a wide variety of heterocyclic (4,4'-dichlorodiphenyl)methanes and -methanols are described. The choice of the two diaryl-bearing moieties as a vehicle for the evaluation of the heterocycles was made by the comparison of series of imidazole and pyridine-derived compounds with similar pyrimidine compounds reported previously. A structural model for the most active compounds is also presented. The activity of a related series of the compounds which contain two heterocyclic moieties was found to be consistent with the model. Many of the compounds evaluated, including representatives of the pyridine, imidazole, pyrimidine, pyrazole, triazole, thiazole, and isothiazole classes, exhibit EC50 potencies for aromatase inhibition at low nanomolar levels. These compounds are at least as potent as other nonsteroidal aromatase inhibitors reported previously.     

Naturally occurring and synthetic imidazoles: their chemistry and their biological activities

Imidazoles are an important class of heterocycles and include many substances of both biological and chemical interest. They are part of a large number of highly significant biomolecules such as the essential amino acid histidine and related compounds, biotin, and the imidazole alkaloids. Insertion of the imidazole nucleus is an important synthetic strategy in drug discovery. Imidazole drugs have broad applications in many areas of clinical medicine. The imidazoles are a class of antifungal azole derivatives and have a broad spectrum of activities both in vitro and in vivo. The imidazole moiety is also contained in many histaminergic ligands for histamine H1, H2, and H3 receptors. These are currently used as tools in pharmacological studies. The important therapeutic properties of imidazole related drugs have encouraged the medicinal chemists to synthesize and test a large number of novel molecules. Some of these have chemotherapeutic properties, such as for example several FTase inhibitors with an imidazole moiety. Imidazole derivatives have also been shown to have antibacterial activity and recently several P38 MAP Kinase inhibitors and 5-Lipoxygenase inhibitors containing the imidazole moiety have been synthesized. This review reports current progress in the area of new biologically active imidazoles and recently discovered naturally occurring imidazole.     

Nadolol: high-pressure liquid chromatographic methods for assay, racemate composition and related compounds.

High-pressure liquid chromatographic (HPLC) methods have been developed for the determination of drug content, racemate A and related compounds in nadolol raw materials. The method for drug content and related substances resolved seven related compounds and several unknown impurities from the drug. The minimum quantifiable levels were 0.05% or less for four of the seven related compounds and 0.3% or less for the remainder. Total impurities in eight raw material samples ranged from 0.06 to 0.96% and assay levels ranged from 98.7 to 101.0%. The method was adapted for the determination of nadolol racemate A by a change in mobile phase composition. One raw material sample contained less than 40% of racemate A. Two samples which had a granular appearance were variable in racemate A content. The methods were adapted for the determination of drug and racemate A in nadolol tablets. Drug content in three tablet samples was between 96.2 and 98.4% and racemate A content was about 52%.     

Profiling indomethacin impurities using high-performance liquid chromatography and nuclear magnetic resonance

The anti-inflammatory drug indomethacin was investigated regarding new related impurities. Therefore, related substances 2-9 were prepared by independent synthesis and physicochemically characterized. To determine indomethacin and its related substances, a new HPLC-UV method was developed and validated. Indomethacin and its impurities were eluted on a C(18) column with a mobile phase consisting of methanol and an aqueous solution of 0.2% phosphoric acid at a flow rate of 1.5 ml/min and were quantified by UV detection at 320 nm. Overall, the HPLC-UV method was simple and reliable for the detection of eight impurities in indomethacin. In addition to the HPLC-UV method, 1H nuclear magnetic resonance (NMR) was used to investigate indomethacin regarding impurities. For that purpose, related substances 2-9 were systematically added to indomethacin and investigated. The NMR method was found to be very useful for the identification of impurities in bulk substance without prior separation. Both HPLC-UV and NMR were used to analyze 38 batches of indomethacin available on the European market. The outcome was that 42% of the batches did not meet the compendial requirements although they met the specifications of current compendial methods. Some batches contained the previously undescribed impurity 8, while other batches contained by-products from two distinct synthetic routes. The methods presented herein are important contributions to the ongoing efforts to reduce impurities and therefore the risk of adverse side-effects in drugs that are no longer under patent protection.     

Simple and rapid screening procedure for 143 new psychoactive substances by liquid chromatography‐tandem mass spectrometry

In recent years, many new psychoactive substances (NPS) from several drug classes have appeared on the drug market. These substances, also known as ‘legal highs’, belong to different chemical classes. Despite the increasing number of NPS, there are few comprehensive screening methods for their detection in biological specimens. In this context, the purpose of this study was to develop a fast and simple liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) screening procedure for NPS in blood. The elaborated method allows the simultaneous screening of 143 compounds from different groups (number of compounds): cathinones (36), phenethylamines (26), tryptamines (18), piperazines (9), piperidines (2), synthetic cannabinoids (34), arylalkylamines (7), arylcyclohexylamines (3), aminoindanes (2), and other drugs (6). Blood samples (0.2 mL) were precipitated with acetonitrile (0.6 mL). The separation was achieved with gradient mobile phase of 0.1% formic acid in acetonitrile and 0.1% formic acid in water in 14 min. Detection of all compounds was based on multiple reaction monitoring (MRM) transitions. The total number of transitions monitored in dynamic mode was 432. The whole procedure was rapid and simple. The limits of detection (LODs) estimated for 104 compounds were in the range 0.01–3.09 ng/mL. The extraction recoveries determined for 32 compounds were from 1.8 to 133%. The procedure was successfully applied to the analysis of forensic blood samples in routine casework. The developed method should have wide applicability for rapid screening of new drugs of abuse in forensic or clinical samples. The procedure can be easily expanded for more substances. Copyright © 2015 John Wiley & Sons, Ltd.     

N-亚硝胺类基因毒性杂质的研究进展

自“缬沙坦事件”之后，N-亚硝胺类基因毒性杂质引起了业界的广泛关注。本文概述了药物中N-亚硝胺类基因毒性杂质和相关检测方法的研究进展，以及近20年来国内外有关药物中基因毒性杂质监管指南的完善历程。N-亚硝胺类基因毒性杂质作为一类高反应活性的基因毒性杂质，主要来源于药物合成过程中发生的副反应，以及药物在储存或者运输过程中发生的氧化或还原等反应。所有的动物实验表明，N-亚硝胺类具有很强的致癌性。在理论上，所有药物都存在N-亚硝胺类杂质或被N-亚硝胺类杂质污染的风险，由于该类化合物在药物中常以痕量形式存在，在分析检测过程中药物基质干扰大，因此建立便捷、高效的分析方法是非常有必要的。     

UV-spectrophotometry in drug control. 39. Spectrophotometric behavior of substances with chromophores and auxochromes in aliphatic chains, in saturated heterocyclics and the heterocyclic compounds: furan, imidazole, thiazole, thiadiazole and oxadiazole

The spectra of 22 drug substances with chromophores and auxochromes in the aliphatic chain, in the saturated heterocyclus and in heterocyclic compounds (furan, imidazole, thiazole, thiadiazole and oxadiazole) underwent a systematic investigation and the results obtained were evaluated. Influences of substituents and solvents on shifts of the E, K, B and R bands were discussed.     

The identification of related substances in 9 alpha-fluoroprednisolone-21 acetate by means of high-performance liquid chromatography with diode array detector and mass spectrometry.

A method for the analysis and identification of the principal related substances in 9 alpha-fluoroprednisolone acetate is described. This compound has been chosen as a model for the investigation of related substances which can be originated in the general procedure for introducing a fluorine substituent at position 9 of a corticosteroid molecule. HPLC procedures, both in reversed and in normal phase were used; a rapid scanning UV detector which allows direct spectrophotometric data to be obtained on chromatographic peaks, proved to be a tool of great importance. Thus, after reversed-phase chromatographic separation and observation of the UV spectra and their respective second derivatives, it was possible to characterize some of the principal effective and potential related substances such as 9 alpha-fluorohydrocortisone acetate, 9 alpha-bromoprednisolone acetate, 9 beta, 11 beta-epoxyprednisolone acetate and 9(11)-dehydroprednisolone acetate, emerging as chromatographic peaks. Identification of 9 alpha-bromoprednisolone acetate and of 9 alpha-fluorohydrocortisone acetate which proved to be the most significant impurities, was confirmed by means of an exhaustive study of the mass spectra of these substances conveniently isolated by normal-phase HPLC. The chromatographic, spectrophotometric and mass-spectrometric characteristics of the studied compounds are reported.