胃肠道动力促进剂Fedotozine Tartrate

化学名 (+)-(R)-a-乙基-N,N-二甲基-a-(3,4,5-三甲氧基苯甲氧基甲基)苯甲醇胺l-酒石酸盐药效分类胃肠道动力促进剂开发单位 (法国)Joureinal实验室合成本品由二种不同途径制备: a)消旋(±)-N,N-二甲基-1-[(3,4,5-三甲氧基苄基)氧甲基]-1-苯基-n-丙胺在乙醇中用(一)酒石酸拆分 b)(+)-二甲基胺基-2-苯基-n-丁醇与     

枸橼酸托法替尼的合成工艺改进

目的改进Janus激酶抑制剂枸橼酸托法替尼的合成工艺。方法以3-氨基-4-甲基吡啶为原料,经与碳酸二甲酯反应、LiAlH_4还原、与溴苄反应、NaBH_4还原再成盐酸盐,最后用L-二对甲基苯甲酰酒石酸(L-DTTA)拆分得到(3R,4R)-(1-苄基-4-甲基哌啶-3-基)甲胺-L-二对甲苯甲酰酒石酸盐(1);以4-氯-7H-吡咯并[2,3-d]嘧啶为原料,先经Ts保护,再与中间体1经亲核取代、脱Ts保护、脱苄基保护,最后与氰基乙酸缩合再与枸橼酸成盐制得枸橼酸托法替尼。结果与结论该工艺路线实现了无氢气参与的枸橼酸托法替尼的合成,优化后的工艺路线更易于大量制备,总收率为16.9%(以3-氨基-4-甲基吡啶计)。     

盐酸维那卡兰的合成

(-)-(4R)-羟基-L-脯氨酸(2)经脱羧、二碳酸二叔丁酯保护、与溴苄反应及脱Boc保护基得(3R)-苄氧基吡咯烷,然后与顺-1,2-环氧环己烷经开环反应、D-二对甲基苯甲酰酒石酸拆分、与2-(3,4-二甲氧基苯基)乙基甲磺酸酯成醚及Pd/C催化下氢解脱苄,制得维那卡兰,最后成盐酸盐制得盐酸维那卡兰,总收率约12％.     

盐酸度洛西汀的波谱学特征和结构确证

目的:建立利用分析仪器确证盐酸度洛西汀化学结构的方法。方法:通过元素分析仪分析盐酸度洛西汀的元素组成,运用旋光仪测定其旋光性,并利用核磁共振(NMR)、质谱(MS)、红外光谱(IR)、差热(DSC)、X-射线粉末衍射对盐酸度洛西汀进行结构分析。结果:通过实验证实盐酸度洛西汀的结构为(+)-(S)-N-甲基-γ-(1-萘氧基)-2-噻吩丙胺盐酸盐。结论:该方法准确可行,可为盐酸度洛西汀的结构鉴定提供依据。     

度洛西汀合成路线图解

度洛西汀(duloxetine,1),化学名为(γS)-N-甲基-γ-(1-萘氧基)-2-噻吩丙胺,是由美国Eli Lilly公司研发的5-羟色胺(5-HT)和去甲肾上腺素(NE)双重再摄取抑制剂[1].2002年9月美国FDA批准用于治疗重型抑郁症,临床用盐酸盐,商品名Cymblta.     

(±)-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%.     

哌马色林酒石酸盐合成路线图解

<正>哌马色林酒石酸盐(1)由美国Acadia制药公司研发,并于2016年4月29日经美国食品药品监督管理局(FDA)批准上市,其商品名称为Nuplazid。该药是美国FDA批准的首个治疗帕金森氏病并发的幻觉和妄想等精神症状的药物[1]。哌马色林酒石酸盐的中文化学名称为N-(4-氟苯甲基)-N-(1-甲基哌啶-4-基)-N'-(4-(2-甲基丙氧基)苯基甲基)脲酒石酸盐;英文化学名称     

盐酸决奈达隆的合成

2-正丁基-5-乙酰胺基苯并呋喃和4-(3-氯丙氧基)苯甲酰氯经Friedel-Crafts反应,与二正丁胺缩合得2-正丁基-3- [4- (3-二正丁胺基丙氧基)苯甲酰基]-5-乙酰胺基苯并呋喃,再经盐酸水解、与草酸成盐精制得2-正丁基-3-[4-(3-二正丁胺基丙氧基)苯甲酰基]-5-氨基苯并呋喃二草酸盐,最后经甲磺酰化、成盐制得盐酸决条达隆,总收率约41％.     

盐酸尼非卡兰的合成

以3-苯基丙酸为原料，经硝化、N-酰化和还原反应合成中间体N-(2-羟乙基)-N-[3-(4-硝基苯基)丙基]胺（Ⅰ），Ⅰ与1，3-二甲基-6-[[2-(p-甲苯磺酰)氧基]乙基]氨基-2，4(1H，3H)-嘧啶二酮（Ⅱ）缩合、成盐得盐酸尼非卡兰。     

米罗那非的合成工艺改进

目的改进米罗那非的合成工艺。方法以2-羟基苯甲酸甲酯为原料,经醚化、氯磺化、N-酰化得到中间体2-丙氧基-5-[[4-(2-羟乙基)-1-哌嗪基]磺酰基]苯甲酸甲酯,水解后与4-丙基-1-苄基-3-氨基-1H-吡咯-2-甲酰胺发生酰化反应,再经O-乙酰化、N-脱苄基、N-乙基化、酯水解"一锅法"得到1-乙基-4-丙基-3-[5-[[4-(2-羟乙基)-1-哌嗪基]磺酰]-2-丙氧基苯甲酰胺基]-1H-吡咯-2-甲酰胺,最后经环合生成米罗那非。关键中间体4-丙基-1-苄基-3-氨基-1H-吡咯-2-甲酰胺的合成以甘氨酸为原料,经甲酯化、还原胺化、烯胺化、氨解、环合反应得到。结果与结论经5步反应合成目标化合物,收率为25.9%(以2-羟基苯甲酸甲酯计)。关键中间体经6步反应合成,收率为36.5%,目标化合物和中间体的结构经1H-NMR和MS谱确证。     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

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.

     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.     

Gender-related symptoms and correlates of alcohol dependence among men and women with a lifetime diagnosis of alcohol use disorders

This study explored gender-related symptoms and correlates of alcohol dependence in a crosssectional study of 150 men and 150 women with a lifetime diagnosis of alcohol use disorders (AUD). Participants were recruited in equal numbers from treatment settings, correctional centres and the general community. Standardized measures were used to determine participants' use of substances, history of psychiatric disorders and psychosocial stress, their sensation seeking and family history of substance use and mental health disorders. Multivariate analyses were used to detect patterns of variables associated with gender and the lifetime severity of AUD. Men had a longer history of severe AUD than women. Women had similar levels of alcohol dependence and medical and psychological sequelae as men, despite 6 fewer years of AUD. More women than men had a history of severe psychosocial stress, severe dependence on other substances and antecedent mental health problems, especially mood and anxiety disorders. There were differences in family history of alcohol-related problems approximating same-gender aggregation. The severity of a lifetime AUD was predicted by its earlier age at onset and the occurrence of other disorders, especially anxiety, among both men and women. The limitations in the generalizability of these findings due to sample idiosyncrasies are discussed.     

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.