托品酸的制备

托品酸(tropic acid,3-羟基-2-苯丙酸,1)是山莨菪碱(anisodamine)和托吡卡胺(tropicamide)的重要中间体。可由苯乙酸甲酯(2)和甲酸乙酯在醇钠作用下缩合得到的a-甲酰基苯乙酸甲酯经KBH4还原得托品酸甲酯(3),然后碱性水解得到,收率56%(全国原料药工艺汇编,1980. 1141)。本文用2和多聚甲醛在碳酸氢钠作用下缩合直接得到3[1],再经水解得到1(图1),操作简便,收率67.8%。实验部分托品酸甲酯(3)室温及氮气保护下将碳酸氢钠(0.17g,2mmol)、多聚甲醛(2.8g,0.09mol)、二甲亚砜(16ml)和苯乙酸甲酯(12g,0.08mol)混合后缓慢升温至34℃,保温反应1h后升温…     

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).     

(±)-瑞枯灵的合成

4-羟基-3-甲氧基苯乙胺和3-羟基-4-甲氧基苯乙酸经缩合、O-苄基保护得到2-(3-苄氧基-4-甲氧基苯基)-N-[2-(4-苄氧基-3-甲氧基苯基)乙基]乙酰胺,在POCl3作用下进行Bischler-Napieralski环合反应后,不经分离纯化直接与氯甲酸甲酯进行N-酰化得到7-苄氧基-1-(3-苄氧基-4-甲氧基苯亚甲基)-6-甲氧基-3,4-二氢-1H-异喹啉-2-羧酸甲酯,再经Pd-C氢化脱苄基和用四氢铝锂还原得到(±)-瑞枯灵,总收率23%.     

伐昔洛韦的合成

2-氯乙醇经氯甲基化、与乙醇钠反应制得1-氯-2-(乙酰氧基甲氧基)乙烷,与2,9-二乙酰鸟嘌呤经缩合、脱乙酰化得到9-(2-氯乙氧基甲基)鸟嘌呤,再与N-[(1-乙氧羰基)烯丙-2-基]-L-缬氨酸钠反应后水解得到伐昔洛韦,总收率约18.4% (按2,9-二乙酰鸟嘌呤计)。     

磷酸西他列汀的合成

2,4,5-三氟苯乙酸与丙二酸单乙酯钾盐经亲核取代、脱羧、不对称还原、酯水解、与苄氧胺盐酸盐反应后经Mitsunobu反应得到(R)-1-苄氧基-4-(2,4,5-三氟苄基)-氮杂环丁烷-2-酮,再经水解开环后与5,6,7,8-四氢-3-三氟甲基-1,2,4-三唑并[4,3-α]吡嗪盐酸盐经缩合并脱保护基得到西他列汀,最后与磷酸成盐得到磷酸西他列汀,总收率约58%,光学纯度99.8%.     

非索非那定的合成

α,α-二甲基苯乙酸经硅胶负载磷钨酸(PW/SiO2)固体酸催化酯化、与4-氯丁酰氯反应生成α,α-二甲基-4-(4-氯-1-氧代丁基)苯乙酸乙酯,用硼氢化钠还原后与α,α-二苯基-4-哌啶甲醇反应、碱性水解制得抗组胺药非索非那定,总收率约48%.     

阿伐麦布的合成

1,3,5-三异丙基苯经氯甲基化、氰化和水解得到2,4,6-三异丙基苯乙酸,酰氯化后和氨基磺酸2,6-二异丙基苯酯缩合得到降血脂药阿伐麦布,总收率50%.     

吡贝地尔的合成工艺研究

目的 改进吡贝地尔的合成工艺。方法 以邻苯二酚和二氯甲烷为原料经环和反应合成胡椒环,胡椒环与多聚甲醛经Blanc氯甲基化反应合成重要中间体胡椒基氯(3);以哌嗪和二氯嘧啶为原料经氮烷基化反应合成重要中间体1-(2-嘧啶基)哌嗪(4);(3)和(4)经氮烷基化反应得到目标化合物。结果与讨论 目标化合物的结构经1H-NMR、GC-MS谱确证,总收率为44.2%,改进后的工艺操作简便,成本低廉,有利于工业化生产。     

盐酸洛美利嗪的合成

焦性没食子酸经醚化、氯甲基化得2，3，4-三甲氧基氯苄(4)，双(4-氟苯基)甲醇(5)依次与氯化亚砜、哌嗪反应得到N’-双(4-氟苯基)甲基哌嗪，以甲醇为溶剂，在三乙胺存在下与4反应后成盐制得盐酸洛美利嗪，总收率46％(以5计)。     

阿克他利的合成

阿克他利(actarit,1),化学名:4-乙酰胺基苯乙酸,是一种免疫调节剂,用于慢性类风湿性关节炎[1]。由日本新药/三菱两家公司开发并于1994年在日本首次上市,商品名为Orkal、Mover、Mor-var。文献[1]以4-氨基苯乙酸(3)为起始原料,本文由4-硝基苯乙酸(2)经还原得3,再依次经酯化、酰化、水解等四步制得1,总收率为67%。在还原反应中,文献[1]介绍可以Pd-C催化氢化,本文以醋酸和铁粉还原,收率为85%。在酰化反应中,文献[1]将醋酐溶于乙酸乙酯中一次性加入,本文采用醋酐直接滴加减少了乙酸乙酯用量。丆H2COOHNO2　　2FeCH3COOH丆H2COOHNH2　…     

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.