卢帕他定的合成

2-氰基-3-甲基吡啶经Ritter反应、烷基化、氰化、水解后闭环制得8-氯-5,6-二氢苯并[5,6]环庚[1，2-b]吡啶-11-酮，再与3-（4-氯哌啶-1-基甲基）-5-甲基吡啶经Grignard反应和脱水反应制得卢帕他定，总收率18．7％。     

富马酸卢帕他定的合成

以烟酸乙酯(4)和间氯苯乙腈(5)为原料,经克莱森缩合、酸水解脱羧反应,得2-(3-氯苯基)-1-(吡啶-3-基)-1-乙酮(6)。6与水合肼经黄鸣龙还原反应,得3-(3-氯苯乙基)吡啶(7),7在钨酸钠催化下经过氧化氢氧化后,再经Reissert-Henze吡啶氰基化反应,得3-(3-氯苯乙基)-2-氰基吡啶(8),水解后闭环得8-氯-10,11-二氢-4-氮杂-5H-二苯并[a,d]-5-环庚酮(3),再与1-[(5-甲基吡啶-3-基)甲基]-4-哌啶酮(12)经McMurry偶联反应,并与富马酸成盐,得到富马酸卢帕他定(1),总收率28.0%(以4计),纯度99.7%。该路线避免格氏试剂的使用,且环合反应使用“一锅法”,操作方便,适合工业化生产。     

泰妥拉唑的合成

2,3-二氨基-6-甲氧基吡啶和乙氧基荒酸钾经闭环得到5-甲氧基-1H-咪唑并[4，5-自]吡啶-2-硫醇，再与2-氯甲基-3,5-二甲基-4-甲氧基吡啶缩合后氧化得到抗溃疡药泰妥拉唑，总收率48％。     

5-甲氧基-1H-吡咯并[3,2-b]吡啶-2-甲酸的合成

目的制备5-甲氧基-1H-吡咯并[3,2-b]吡啶-2-甲酸。方法以2-甲基-6-氯-3-硝基吡啶为原料,经Williamson合成法制得2-甲基-6-甲氧基-3-硝基吡啶,再经Reissert合成法制得终产物。结果反应总收率33%,产物结构由1H-NMR光谱确证。结论该方法简单、原料价廉易得,后处理容易,副产物较少,适于工业化生产。     

2-氯甲基-3，4-二甲氧基吡啶盐酸盐的制备

2-氯甲基 - 3,4-二甲氧基吡啶盐酸盐 (1 )是制备质子泵抑制剂泮托拉唑的重要中间体。文献 [1,2 ]以3-羟基 - 2 -甲基吡啶为起始原料 ,经氧化、硝化、醚化制得 6,再经乙酸化、水解、氯化制得 1。文献 [3] 报道以 3-甲氧基 - 2 -甲基 - 4-吡啶酮 (3)为起始原料 ,经氯化、氧化、醚化制得 6再制得 1。由于 3-羟基 - 2 -甲基吡啶没有国产品 ,而以国产麦芽酚 (2 -甲基 - 3-羟基 -γ-吡喃酮 ,2 )通过两步反应可制得 3。因此 ,参照文献[1～ 3] ,并对其工艺进行改进 ,制备了 1。文献[4 ] 报道3的制备是在 Ag2 O存在以下以 CH3I醚化 ,本文改用硫酸二…     

埃索美拉唑镁的合成

2-羟甲基-3,5-二甲基-4-硝基吡啶经氯化亚砜氯化后得2-氯甲基-3,5-二甲基-4-硝基吡啶盐酸盐(3),3与5-甲氧基-2-巯基苯并咪唑缩合得5-甲氧基-2[(3,5-二甲基-4-硝基-2-吡啶基)甲硫基]-1H苯并咪唑(4),4经不对称氧化得5-甲氧基-2-[[(3,5-二甲基-4-硝基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑(5),5再通过甲氧基化后得埃索美拉唑钠(6),最后6与氯化镁反应得埃索美拉唑镁,总收率约73.6％(以2-羟甲基-3,5-二甲基-4-硝基吡啶计).     

氯雷他定的合成

2-氰基-3-甲基吡啶经Ritter反应、烷基化、氰化得到2-氰基-3-[2-（3-氯苯基）乙基]吡啶，在PPA／P2O5作用下闭环后和N-乙氧羰基-4-哌啶酮偶合制得氯雷他定，总收率39％。     

奥美拉唑的合成

2,3，5-三甲基吡啶经氧代、硝化、在乙酐中重排、水解及氯代制得2-氯甲基-3，5-二甲基-4-硝幕吡啶盐酸盐，与2-巯基-5-甲氧基苯并咪唑在甲醇钠作用下同时完成缩合、甲氧基化得到5-甲氧基-2-[（4-甲氧基-3，5-二甲基吡啶-2-基）甲硫基]-1H-苯并咪唑，最后氧化得到奥美拉唑，总收率约42％。     

5-羟基-5H-[1]-苯并吡喃[2,3-b]吡啶的制备

目的改进5-羟基-5H-[1]-苯并吡喃[2,3-b]吡啶的合成工艺。方法以2-氯烟酸为起始原料,经亲核取代、环合和还原制得目标化合物。结果总收率68.6%,产物经熔点和1HNMR确证。结论改进后的工艺具有操作简便,对环境友好,收率高等优点。     

8-氯-10,11-二氢-4-氮杂-5H-二苯并[a,d]-5-环庚酮的合成新方法

以2-氰基一3一甲基吡啶为原料，通过自由基反应、Wittig-Homer反应、水解、还原、环化反应合成氯雷他定的重要中间体8-氯-10，11-二氢-4-氮杂-5H-二苯并[a，d]-5-环庚酮，总收率为20％。其结构经元素分析、核磁共振、质谱确证。     

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.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

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.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.