来氟米特的合成

以价廉易得的乙酰乙酸乙酯为起始原料,缩合、环合后中国产物3不分离,水解得到68%的5-甲基-4-异恶唑甲酸,经氯化、纯化后与对三氟甲基苯胺反应得到来氟米特,两步收率60.8%,总收率41%,操作简便,反应副产物少。     

氟罗沙星的合成

以２,３,４－三氟硝基苯为原料,经还原、与ＥＭＭＥ缩合、环合、氟乙基化、与Ｎ－甲基哌嗪缩玫水解６步反应制得氟罗沙星,合成工艺有所改进,总收率为５５．５％。     

来氟米特的合成工艺研究

以乙酰乙酸乙酯与原甲酸三乙酯为起始原料,经缩合得到相应的乙氧亚甲基衍生物,然后与盐酸羟胺环合形成５－甲基异恶唑－４－甲酸乙酯,再通过水解、氯化得到酰氯,最后与４－三氟甲基苯胺反应得到来氟米特,总收率为３２．２％。     

托曲珠利的合成

对硝基苯硫酚经甲基化、氯化、氟代、还原、重氮化及水解制得4-三氟甲硫基苯酚，与3-甲基4-氯硝基苯缩合、还原、异氰酸酯化后再与甲基脲反应、环合制得抗球虫药托曲珠利，总收率接近19％。     

氟伐他汀钠的合成

氟苯和氯乙酰氯经付-克酰化、与N-异丙基苯胺缩合后环合，得3-（4-氟苯基）-1-异丙基-1H-吲哚，再经Vilsmeier-Haack反应、与乙酰乙酸甲酯缩合、选择性还原后水解成盐得HMG CoA还原酶抑制剂类降血脂药氟伐他汀钠，总收率约26％。     

2-三氟甲基噻吨-9-酮合成工艺的改进

目的 改进2-三氟甲基噻吨-9-酮的合成工艺.方法 以邻氨基苯甲酸为原料,经重氮化、还原、偶合和环合四步反应制备2-三氟甲基噻吨-9-酮.结果 与结论通过改进合成2-三氟甲基噻吨-9-酮的投料方法和后处理方法,使反应产率由36.8%提高到48%.     

马来酸氟伏沙明的合成

1-氯-4-甲氧基丁烷与对三氟甲基苄腈经格氏反应得到5-甲氧基-1-(4-三氟甲基苯基)戊酮,与盐酸羟胺成肟后经与2-氯乙胺盐酸盐缩合及成盐反应制得抗抑郁药马来酸氟伏沙明,总收率40%(以对三氟甲基苄腈计).     

普卢利沙星的合成

用3,4-二氟苯胺制得6,7-二氟-4-羟基-2-甲氧甲硫基喹啉-3-羧酸乙酯,在乙醇中与盐酸反应得到巯基化合物后,经与1,1-二碘乙烷环合、与哌嗪缩合、酸性水解得到6-氟-1-甲基-4-氧代-7-(1-哌嗪基)-1H,4H-[1,3]硫氮杂环丁烷并[3,2-a]喹啉-3-羧酸,最后与由3-羟基-2-丁酮和三光气反应后溴代得到的4-溴甲基-5-甲基-1,3-二噁环戊烯-2-酮缩合,得到氟喹诺酮类抗菌药普卢利沙星,总收率26%(以3,4-二氟苯胺计).     

氟罗布芬的合成

用衣康酸酐经异构化、还原、环合得到甲基丁二酸酐,与由2,4-二氟苯胺经Gomberg-Bachmann-Hey反应得到的2,4-二氟联苯进行付-克反应,制得COX/5-LO双重抑制剂氟罗布芬,总收率49%(以衣康酸酐计).     

巴洛沙星的合成

1-环丙基-6,7-二氟-1,4-二氢-8-甲氧基-4-氧代喹啉-3-羧酸乙酯在乙酐中与硼酸螯合后与3-甲胺基哌啶缩合,再经水解得到氟喹诺酮类抗菌药巴洛沙星,总收率74.4%.其合成关键中间体3-甲胺基哌啶可用γ-丁内酯经胺解、水解、酯化、与溴乙酸乙酯缩合、环合、酯水解并脱羧、还原胺化和氢解脱苄基等反应得到,收率11.5%.     

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.     

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.     

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.