2,5-二甲基-3-苯基-1,5-苯并硫氮杂卓-4(5H)-酮的合成研究

以2-甲硫基苯胺为原料,反应通过酰化、碘环化以及Suzuki交叉偶联反应,合成了2,5-二甲基-3-苯基-1,5-苯并硫氮杂卓-4(5H)-酮,该方法反应步骤少,产物立体选择性好,反应总收率为70.8%,产物结构经NMR和MS得以确证.     

3-(1-氯-亚庚基)吲哚酮的合成研究

以邻碘苯胺为原料,经Sonogashira交叉偶联反应、羰基化环合反应两步合成了3-(1-氯-亚庚基)吲哚酮,该方法 反应步骤少,产物市体选择性好,反应总收率为84.1%,产物结构经南NMR和MS确证.     

5-苯基-[1,4]硫氮杂卓并[2,3,4-de]菲啶-7(9H)-酮的合成研究

以2-甲硫基苯胺为原料,通过酰化、碘环化以及分子内氧化偶联反应,合成了5-苯基-[1,4]硫氮杂卓并[2,3,4-de]菲啶-7(9H)-酮(4).在最佳的反应条件下,化合物4总收率为48.1%.中间产物及目标产物的结构经由IR、NMR和MS得以确证.     

1,2,6,7-四甲氧基-9H-咔唑和2,3,6,7-四甲氧基-9H-咔唑的合成方法研究

目的 研究1，2，6，7-四甲氧基-9H-咔唑和2，3，6，7-四甲氧基-9H-咔唑的合成方法。方法 以4,5-二甲氧基-2-溴硝基苯和4-碘-1，2．二甲氧基苯为原料，经Ullmann反应得2-(3，4-二甲氧基苯基)-4．5．二甲氧基硝基苯(3)，再经亚磷酸三乙酯还原环合得1，2，6，7-四甲氧基-9H-咔唑(1)和2，3，6，7-四甲氧基-9H-咔唑(2)。结果 以4，5-二甲氧基-2-溴硝基苯和4-碘-1，2-二甲氧基苯为原料，制得3的收率为42％，3经环合制备l和2的收率分别为38％和39％。结论 化合物3经亚磷酸三乙酯还原环合时。等量得到l和2。研究发现化合物2还可由Ullmann反应的副产物4，4′，5，5′-四甲氧基-2，2′-二硝基联苯4经亚磷酸三乙酯还原环合制得。     

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。     

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。     

改进顺-[2-(2,4-二氯苯基)-2-(1H-咪唑基-1-甲基)-1,3-二氧戊环-4-]对甲苯磺酸酯的合成工艺

目的 改进酮康唑的重要中间体顺-[2-(2,4-二氯苯基)-2-(1H-咪唑基-1-甲基)-1,3-二氧戊环-4-]对甲苯磺酸酯的合成工艺.方法 以间二氯苯为原料,经过傅-克酰基化、甘油环合、溴代、苯甲酰化、异构体分离、咪唑烷基化、水解、对甲苯磺酰化等八步反应合成目标产物.结果 合成的目标化合物的熔点和核磁共振氢谱与相关文献一致,总收率为19.1%.结论 改进后的合成工艺条件温和,操作简便,适用于放大制备.     

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。     

3,4-二甲基-2-碘代苯甲酸的合成

目的研究合成肿瘤血管破坏剂Vadimeza的关键中间体3,4-二甲基-2-碘代苯甲酸的合成方法。方法以乙醛酸(2)为起始原料,首先与乙酸酐反应生成2,2-二乙酰氧基乙酸(3),然后与氯化亚砜反应得到相应的酰氯后,与2,3-二甲基苯胺(5)进行酰化反应得到N-(2,2-二乙酰氧基)乙酰基-2,3-二甲基苯胺(6),再与盐酸羟胺反应得到N-(2-羟亚氨基)乙酰基-2,3-二甲基苯胺(7);最后经甲磺酸脱水环合、双氧水氧化开环和Sandmeyer反应得到目标产物3,4-二甲基-2-碘代苯甲酸(1)。结果合成了3,4-二甲基-2-碘代苯甲酸,7步反应总收率达到45.0%,目标产物结构经ESI-MS、1H-NMR确证。结论本合成方法原料易得,反应条件温和,适合大规模制备。     

1H-吲唑-3-羧酸的合成工艺研究

目的选择了所需原料廉价,并对反应条件进行优化与改进,反应设备与条件要求低,反应步骤较少。方法以苯肼为原料,以醋酸乙酰化反应得乙酰苯肼,再与水合氯醛,盐酸羟胺反应,最后通过浓硫酸环合、Beckmann重排水解得到1H-吲唑-3-羧酸。结果该合成方法合成的产品1H-吲唑-3-羧酸熔点为256-260℃,合成的总收率为28.2%。结论简化了操作,适合于工业生产。     

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.     

Pharmacological treatment of COVID-19: an opinion paper

The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation.     

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.