2-苯基-1-丁醇与2-二甲氨基-2-苯基丁腈的合成

目的为马来酸曲美布汀的重要中间体2-二甲氨基-2-苯基-1-丁醇的合成奠定基础。方法苯乙腈与溴乙烷进行烃化反应得2-苯基-1-丁腈,所得产物经水解得2-苯基-1-丁酸,然后通过硼氢化钠-碘体系还原得2-苯基-1-丁醇;苯乙腈与N-溴代丁二酰亚胺进行卤代反应得溴代苯乙腈,所得产物与二甲胺进行烃化反应得2-二甲氨基苯乙腈,然后与溴乙烷进行烃化反应得2-二甲氨基-2-苯基丁腈。结果合成了2-苯基-1-丁醇和2-二甲氨基-2-苯基丁腈,总收率为分别为51%和59.4%。目标产物的结构经核磁共振氢谱、质谱确证。结论本合成方法原料易得,操作简单,收率较高,适合于工业化生产。     

3,6-二甲氧基-2,5-二氢吡嗪-2-羧酸乙酯的合成

用苄氧羰基氨基乙酸在N-甲基吗啉的催化下与氯甲酸异丁酯反应后,无需分离直接与氨基丙二酸二乙酯盐酸盐反应得到(2-苄氧羰基氨基乙酰胺基)丙二酸二乙酯,经Pd/C催化氢解、环合后在二氯甲烷中与Me3OBF4反应制得α-取代丝氨酸的合成中间体3,6-二甲氧基-2,5-二氢吡嗪-2-羧酸乙酯,总收率35.1%.     

2,2-二甲基-4-(2,5-二氟苯基)-5-[(4-氨基磺酰基)苯基]-3(2H)-呋喃酮的合成

用2,5-二氟苯乙酸与茴香硫醚经傅-克反应、与3-溴-3-甲基-2-氧代丁腈成环及硝酸氧化制得2,2-二甲基-4-(2,5-二氟苯基)-5-[(4-甲磺酰基)苯基]-3(2H)-呋喃酮(7),7与乙酐反应后再经过硫酸氢钾复合盐氧化、氢氧化钠水解得4-[2,2-二甲基-3-氧代-4-(2,5-二氟苯基)-3(2H)-呋喃-5-基]苯磺酸钠(9),最后依次与磺酰氯和氨水反应制得2,2-二甲基-4-(2,5-二氟苯基)-5-[(4-氨基磺酰基)苯基]-3(2H)-呋喃酮,总收率约46％.     

2-氯-4-氨基-6,7-二甲氧基喹唑啉的合成

目的合成2-氯-4-氨基-6,7-二甲氧基喹唑啉。方法以香草醛为原料,经甲基化、硝化、氧化、还原、环合、氯化、胺化等反应制得目标化合物。结果及结论该实验方法总收率26%,反应条件温和,操作简便,适合工业化生产。     

(2E,6E)-3,7-二甲基-8-羟基-2,6-辛二烯-1-醇乙酸酯的合成

目的合成(2E,6E)-3,7-二甲基-8-羟基-2,6-辛二烯-1-醇乙酸酯。方法以香叶醇为起始原料,经酯化、加成-消除、取代、氧化、重排反应制得目标化合物。结果各步中间体结构经核磁共振谱确证,最终目标产物结构经红外光谱和核磁共振谱确证,总收率为49.7%。结论通过实验探索出一条新的合成(2E,6E)-3,7-二甲基-8-羟基-2,6-辛二烯-1-醇乙酸酯的路线。     

4-(4,6-二吗啉-1,3,5-三嗪-2-基)苯胺的合成

目的合成4-(4,6-二吗啉-1,3,5-三嗪-2-基)苯胺。方法三氯聚氰与吗啉在冰浴条件下经取代反应制得4,4’-(6-氯-1,3,5-三嗪-2,4-二基)二吗啉,再与苯胺-4-硼酸频那醇酯经Suzuki反应制得4-(4,6-二吗啉-1,3,5-三嗪-2-基)苯胺。结果与结论结构经核磁及质谱确证,总收率约61.7%。     

7,8-二甲氧基-3-(3-碘丙基)-1,3-二氢-2H-3-苯并氮杂革-2-酮的制备

目的合成抗心绞痛的新药伊伐布雷定的关键中间体7,8-二甲氧基-3-(3-碘丙基)-1,3-二氢-2H-3-苯并氮杂--2-酮。方法以3,4-二甲氧基苯乙酸为原料,经卤化、酰化、环合、烷基化、碘取代等反应制得目标化合物。结果五步反应总收率为63.6%,产物经MS1、HNMR确证结构。结论所用工艺路线具有原料易得、操作简便、收率较高的特点,适用于该中间体的放大制备。     

7,8-二甲氧基-3-(3-碘丙基)-1,3-二氢-2H-3-苯并氮杂-2-酮的制备

目的合成抗心绞痛的新药伊伐布雷定的关键中间体7,8-二甲氧基-3-(3-碘丙基)-1,3-二氢-2H-3-苯并氮杂--2-酮。方法以3,4-二甲氧基苯乙酸为原料,经卤化、酰化、环合、烷基化、碘取代等反应制得目标化合物。结果五步反应总收率为63.6%,产物经MS1、HNMR确证结构。结论所用工艺路线具有原料易得、操作简便、收率较高的特点,适用于该中间体的放大制备。     

5-氟-2,3-二氢苯并呋喃的合成

对氟苯酚经溴化制得的邻溴对氟苯酚,与1,2-二氯乙烷反应制得2-(2-溴-4-氟苯氧基)氯乙烷,再经格氏反应制得5-氟-2,3-二氢苯并呋喃,总收率79%.     

取代-1,3-二氢吲哚-2-酮化合物的合成

取代苯胺经酰化、环合反应制得关键中间体取代靛红衍生物4a～4k,再用三乙基硅烷/三氟乙酸体系室温还原制得取代-1,3-二氢吲哚-2-酮类化合物1a～1k,后者可用于合成舒尼替尼等酪氨酸激酶抑制剂类抗肿瘤药.     

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.

---

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.     

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.     

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.