利奈唑胺

[通用名称]linezolid,利奈唑胺 [化学名称](S)-N-{[3-(3-氟4-(4-吗啉基>苯)2-氧-5 唑啉]甲基}-乙酰胺.利奈唑胺的分子式为C16H20FN3O4,相对分子质量为337.35. [药理作用]本品为合成的抗G+菌药,其作用为抑制细菌蛋白质合成.其突出特点是与细菌50S亚基附近界面的30S亚基结合,阻止70S初始复合物的形成而发挥杀菌作用.对葡萄球菌、链球菌(包括肠球菌)敏感.由于本品的特殊结构,因此与其他抗菌药无交叉耐药性[1].特别对耐甲氧西林金葡球菌(MRSA)、耐万古霉素肠球菌(VREF)等微生物有良好的抗菌作用,为治疗耐万古霉素肠球菌感染的惟一药物.     

Ezetimibe的合成

(4S)-3-[(5S)-5-(4-氟苯基)-5-羟基-1-氧代戊基]-4-苯基-2-(?)唑烷酮与4-(4-氟苯基亚氨基)甲酚缩合后再经环合、脱硅烷保护得ezetimibe。前一中间体可以氟苯为原料,与戊二酸酐经付-克反应得到的5-(4-氟苯基)-5-氧代戊酸,与特戊酰氯缩合得到混合酸酐,再与(4S)-4-苯基-2-(?)唑烷酮缩合得(4S)-3-[5-(4-氟苯基)-1,5-二氧代戊基]-4-苯基-2-(?)唑烷酮,经(3αR)-1-甲基-3,3-二苯基-1H,3H-四氢吡咯并[1,2-c][1.3.2](?)唑硼烷[(R)-MeCBS]／BH3·S(CH3)2催化还原制得。总收率24％。     

噁唑烷酮类抗菌剂雷得唑来的合成

目的研究噁唑烷酮类抗菌剂雷得唑来的合成。方法以间氟苯胺为起始原料,依次经取代、碘代、环合、Suzuki偶联反应得到中间体(5S)-N-{[3-[4-(4-甲酰基苯基)-3-氟苯基]-2-氧代噁唑烷-5-基]甲基}乙酰胺(5);以对甲氧基氯苄为原料,经取代、Husigen-Click环加成反应得到中间体[1-(4-甲氧基苄基)-1H-1,2,3-三氮唑-4-基]甲胺(8);中间体5和8经还原胺化反应得到中间体(5S)-N-{[3-[2-氟-4'-({[1-(4-甲氧基苄基)-1H-1,2,3-三氮唑-4-基甲基]氨基}甲基)联苯-4-基]-2-氧代噁唑烷-5-基]甲基}乙酰胺(10),再经脱保护得到雷得唑来。结果与结论雷得唑来的结构经MS、IR、~1H-NMR和~(13)C-NMR确证,纯度经HPLC测定。其收率为40.7%(以间氟苯胺计)。该路线未见文献报道,所用原料价廉易得,反应条件温和可控,后处理简便,为其工业化生产奠定了基础。     

泊沙康唑

泊沙康唑(posaconazole)是2006年9月15日由美国FDA批准的一种广谱三唑类抗真菌药,用于难治性疾病或其他药物耐药所引起的真菌感染(如曲霉菌病、结核菌病和镰刀菌病等),该药由美国Scher-ing-Plough公司研制上市,商品名为Noxafil[1]。泊沙康唑化学名称:(-)-4-[4-[4-[4-[(2R-顺)-5-(2,4-二氟苯基)四氢-5-(1H-1,2,4-三唑-1-基甲基)呋喃-3-基]甲氧基]苯基]-1-哌嗪基]苯基-2,4-二氢-2-[(S)-1-乙基-2(S)-羟基丙基]-3H-1,2,4-三唑-3-酮;英文化学名称:(-)-4-[4-[4-[4-[(2R-cis)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-yl-met…     

利奈唑胺降解杂质的合成研究

目的为了加强对利奈唑胺注射液的质量控制,合成了口恶唑烷酮类抗生素利奈唑胺的两个特定杂质。方法以利奈唑胺为起始原料,经水解制备得到降解杂质(2S)-1-氨基-3-{[3-氟-4-(4-吗啉基)苯基]氨基}-2-丙醇,再经Boc保护、乙酰化、脱Boc制得降解杂质N-[(2S)-3-氨基-2-羟基丙基]-N-[3-氟-4-(4-吗啉基)苯基]-乙酰胺。结果与结论合成的两种降解杂质的结构经1H-NMR、MS确证,可以作为利奈唑胺注射液质量控制的杂质对照品。     

伏立康唑

[通用名称] voriconazole,伏立康唑 [商品名称] Vfend [化学名称] (2R,3S)-2-(2,4-二氟苯基)-3-(5-氟-4-嘧啶)-1-(1H-1,2,4-三唑-1-基)-2-丁醇     

利奈唑胺的合成

(S)-环氧氯丙烷(2)用叠氮钠开环得到(S)-1-叠氮基-3-氯-2-丙醇(3);另用3,4-二氟硝基苯(4)经与吗啉反应后以铁粉还原硝基,再与氯甲酸乙酯反应得到N-[3-氟-4- (4-吗啉基)苯基]氨基甲酸乙酯(7).3和7经环合反应制得(S)-3-[3-氟-4- (4-吗啉基)苯基]-5-叠氮甲基-1,3-噁唑烷-2-酮后,再经水合肼还原、氨基乙酰化得到抗菌剂利奈唑胺,总收率约40％(以4计).     

利伐沙班（rivaroxaban）

利伐沙班（rivaroxaban）是由拜耳公司和强生公司共同研发的一种小分子口服抗凝药,商品名为Xarelto。2011年7月1日FDA批准该药用于预防膝或髋取代手术患者深部静脉血栓形成。 利伐沙班的中文化学名称：5-氯-N-[2-氧代-3-[4-(3-羰基吗啉-4-基)苯基]唑烷-5(S)-基甲基]噻吩-2-甲酰胺;英文化学名称：5-chloro-N-({5(S)-2-oxo-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-1,3- oxazolidin-5-yl}methyl)thiophene-2-carboxamide;分子式：C19H18ClN3O5S;分子量：435.89;CAS登记号：366789-02-8。     

抗菌药利奈唑胺有关物质的合成

目的合成利奈唑胺的四个有关物质。方法利奈唑胺在碱性条件下五元环水解,再经N-甲酰化、酸化,得到有关物质N-[(2S)-3-乙酰胺基-2-羟丙基]-N-[3-氟-4-(4-吗琳基)苯基]氨甲酸(Ⅰ);利奈唑胺经H2O2氧化,得到其氧化杂质(S)-N-[[3-[3-氟-4-(4-吗琳基)苯基]-2-氧代-5-口恶唑烷基]甲基]乙酰胺氮氧化物(Ⅱ);以N-(3-氟-4-吗啉苯基)氨基甲酸苄酯为原料,与S-正丁酸缩水甘油酯成环,经磺酰化、叠氮化后还原,得到(S)-3-(3-氟-4-吗啉苯基)-5-氨甲基-1,3-口恶唑烷-2-酮(Ⅲ);N-(3-氟-4-吗啉苯基)氨基甲酸苄酯与R-正丁酸缩水甘油酯成环,经磺酰化、叠氮化后还原,再经乙酰化,得到(R)-N-{{3-[3-氟-4-(4-吗啉基)苯基]-2-氧-5-口恶唑基}甲基}乙酰胺(Ⅳ)。结果与结论有关物质Ⅰ~Ⅳ的结构经MS、1H-NM R谱确证,可作为利奈唑胺质量控制的杂质对照品。     

利伐沙班中间体的合成

4-(3-氧代-4-吗啉基)苯胺与氯甲酸苄酯发生取代反应制得N-[4-(3-氧代-4-吗啉基)苯基]氨基甲酸苄酯,后者与(S)-N-[(2-乙酰氧基-3-氯)丙基]乙酰胺经缩合制得(S)-3-[4-(3-氧代-4-吗啉基)苯基]-5-乙酰胺甲基-1,3-噁唑烷-2-酮,再经酸性水解即可制得合成利伐沙班的重要中间体(S)-3-[4-(3-氧代-4-吗啉基)苯基]-5-氨甲基-1,3-噁唑烷-2-酮,总收率约35％.     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.     

Gender-related symptoms and correlates of alcohol dependence among men and women with a lifetime diagnosis of alcohol use disorders

This study explored gender-related symptoms and correlates of alcohol dependence in a crosssectional study of 150 men and 150 women with a lifetime diagnosis of alcohol use disorders (AUD). Participants were recruited in equal numbers from treatment settings, correctional centres and the general community. Standardized measures were used to determine participants' use of substances, history of psychiatric disorders and psychosocial stress, their sensation seeking and family history of substance use and mental health disorders. Multivariate analyses were used to detect patterns of variables associated with gender and the lifetime severity of AUD. Men had a longer history of severe AUD than women. Women had similar levels of alcohol dependence and medical and psychological sequelae as men, despite 6 fewer years of AUD. More women than men had a history of severe psychosocial stress, severe dependence on other substances and antecedent mental health problems, especially mood and anxiety disorders. There were differences in family history of alcohol-related problems approximating same-gender aggregation. The severity of a lifetime AUD was predicted by its earlier age at onset and the occurrence of other disorders, especially anxiety, among both men and women. The limitations in the generalizability of these findings due to sample idiosyncrasies are discussed.