间三氟甲基苯胺的合成

以三氟甲苛来起始原料，经混酸硝化和加氢还原反应合成间三氟甲基苯胺，总收率达８３％，产品纯度９８％以上。     

间三氟甲基溴苯的合成新方法

间三氟甲基溴苯 ( 1 )是合成医药中间体间三氟甲基苯乙酮[1] ,进而合成嘧啶类和抗精神病类药物 [2 ] 的原料。文献报道其合成路线主要有两条 :( 1 )由三氟甲基苯 ( 2 )经硝化、还原后 ,经 Sandmeyer反应合成 [3] ;( 2 )由 2直接溴化制备 [4 ]。前者路线长 ,三废量大 ,总收率低 ,几无实用价值 ;后者的收率仅5 0 % ,而且由于三氟甲基的钝化作用 ,直接溴化所需要的温度高 ,易导致三氟甲基的水解 ,约生成 35 %左右的间溴苯甲酸 [4 ] ,同时对玻璃反应瓶也有明显的腐蚀作用。我们在研究中发现 ,使用 KBr O3-H2 SO4 体系能很好地溴化 2 ,收率可…     

间三氟甲基苯胺的合成

以三氟甲苯为起始原料,经混酸硝化和加氢还原反应合成间三氟甲基苯胺,总收率达83%,产品纯度98%以上。     

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%.     

来氟米特的合成

来氟米特 (leflunomide,1 ) ,化学名为 :N- (4-三氟甲基苯基 ) - 5-甲基异唑 - 4-甲酰胺 ,由德国Hoechst Marion Roussel公司开发 ,其片剂 (1 0 ,2 0和 1 0 0 mg) 1 998年经美国 FDA批准在美国以商品名 Arava上市 ,临床用作治疗类风湿性关节炎病人关节疼痛和肿胀以及关节延迟性损害的口服药物 [1] 。本文参考文献[2～ 4 ] ,以乙酰乙酸乙酯和原甲酸三乙酯缩合得α-乙氧亚甲基乙酰乙酸乙酯 (2 ) ,再成肟环合成 5-甲基异唑 - 4-甲酸乙酯 (3) ,水解后再转变为其酰氯 ,最后与对三氟甲基苯胺缩合制备1。本文用甲醇代替文献中的乙醇作为制…     

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。     

抗疟药的研究——ⅩⅣ.三氟甲基喹啉四氢萘酚类及氨基酚类化合物的合成

前文报道2-特丁氨甲基-4-(7′-氯-4′-喹啉氨基)-5,6,7,8-四氢-1-萘酚盐酸盐对伯氏鼠疟原虫敏感株的作用较强,但对抗氯喹株有一定的抗性,在一些抗疟药中单边或双边取代的氨基苯酚侧链对抗疟作用也有一定的影响。Ohnmach等报道的甲氟喹,在其母核的2位和8位各为三氟甲基取代,与同类化合物相比,有较强的抗疟作用,并与氯喹无交叉抗药性,已在临床试用。因此,我们用三氟甲基代替喹啉核7位上的氯原子,并在喹啉核的4     

芬氟拉明的新合成方法

本文报道了一种新的合成芬氟拉明的方法，用一般方法制备的间－溴三氟甲苯的Ｇｒｉｇｎａｒｄ试剂与１，２－环氧丙烷反应得到１－（ｍ－三氟甲基苯基）－２－丙醇（Ⅱ），氧化（Ⅱ）得到１－（ｍ－三氟甲基苯基）－２－丙酮（Ⅲ），（Ⅲ）经与乙胺缩合还原得（Ⅳ），（Ⅳ）被盐酸化给出盐酸芬氟拉明．     

来氟米特的合成

以N，N－二甲基甲酰胺缩醛与乙酰乙酸乙酯综合后无需分离，经环合、水解得到5－甲基异恶唑－4－甲酸，收率56％，再经酰氯化、与对三氟甲基苯胺反应得到来氟米特。总收率47．8％（按乙酰乙酸乙酯计）。     

5-三氟甲基-3-(4-甲基-1H-咪唑-1-基)苯胺的合成

3,5-二硝基三氟甲苯(2)与氟化四甲铵进行氟代反应,所得单氟中间体再与4-甲基-1H-咪唑进行取代反应得到5-三氟甲基-3-(4-甲基-1H-咪唑-1-基)-硝基苯(3),然后在Pd/C催化下氢化还原制得抗肿瘤药尼罗替尼的中间体5-三氟甲基-3-(4-甲基-1H-眯唑-1-基)-苯胺(1),总收率约50％(以2计).     

Physicochemical properties of maltosyl and glucosaminyl derivatives of beta-lactoglobulin

Maltosyl and glucosaminyl derivatives of beta-lactoglobulin (b-LG) were analyzed for their physicochemical properties: reduced viscosity, ultraviolet difference spectra, intrinsic fluorescence, hydrophobicity and circular dichroism. The viscosity of these derivatives increased as the mass of the carbohydrates covalently linked to b-LG increased. The ultraviolet difference spectra and the intrinsic fluorescence of these proteins revealed that the microenvironments of aromatic amino acid residues of b-LG were increasingly exposed to the surface of the protein as the extent of modification increased; and the polarity of these residues also increased as modification increased. The hydrophobicities of M-b-LG derivatives decreased as the extent of modification increased while the hydrophobicities of G-b-LG derivatives were relatively unchanged. The circular dichroic analysis of these proteins indicated that the ordered secondary structures of the extensively modified derivatives of b-LG were partially unfolded. Thus, the carbohydrates covalently linked to b-LG altered many physiochemical properties. These physicochemical changes of b-LG apparently resulted from an alteration of forces stabilizing the structure of the protein.     

Differential effects of serotonergic and catecholaminergic drugs on ingestive behavior

The serotonergic agonists fenfluramine and fluoxetine and the catecholaminergic agonists amphetamine and phenylpropanolamine are well known to cause a reduction in intake in rats. In the studies reported here we investigated the effects of these drugs on the microstructure of licking behavior of the rat ingesting 0.4 M sucrose. The purpose was to examine the similarities in the behavioral effects within and between these two classes of anorectic agents. The serotonergic agonists fenfluramine and fluoxetine caused a reduction in intake primarily by reducing the size of bursts and clusters of licking within the test meal without affecting the duration of the meal, suggesting a reduction in the palatability of the test solution. The catecholamine agonists amphetamine and phenylpropanolamine reduced intake primarily by reducing the number of bursts and clusters without affecting their size, suggesting a fractionation in the organization of the normal pattern of ingestion. The differences between the two serotonin and the two catecholamine agonists on the microstructure of the licking behavior suggest a different effect of the two neurotransmitters on the motor system that controls ingestive behavior. The similarities between the two different agonists within each class suggests a common neurotransmitter mechanism responsible for these two different effects on the behavior of the animals.Supported by NIH Grant DK41563 (JDD).     

Extrapyramidal and mesolimbic involvement with the stereotypic activity of D- and L-amphetamine

The electrolytic brain lesion technique was use to investigate the role of the dopamine-containing areas and pathways of the extrapyramidial and mesolimbic systems in the mediation of the stereotyped behaviour patterns induced by D- and L-amphetamine in the rat.Interruption of the ascending dopaminergic neurones from the mesencephalon at the level of the lateral hypothalamus did not modify the dose-dependent stereotypy induced by D- or L-amphetamine, whilst a lesion placed in the rostral hypothalamus to interrupt the dopaminergic innervation to the mesolimbic brain areas was shown to abolish the wearker intensity component of stereotypy (sniffing and repetitive head movements). Of the areas innervated by this pathway, lesion of the tuberculum olfactorium, but not the nucleus interstitialis stria terminalis or nucleus accumbens septi, also abolished sniffing behaviour. Lesions placed in the neostriatal area of the extrapyramidal system were without significant effect whilst lesion of the paleostriatum abolished all components of stereotypy. Lesion of the central amygdaloid nucleus only abolised the more intense components of both D- and L-amphetamine stereotypy (bitting, gnawing and licking).The brain studies demonstrate a differential involvement of the dopamine-containing areas of the mesolimbic and extrapyramidal brain regions, and the associated dopaminergic neurones which ascend from the mesencephalon, with the stereotyped behaviour patterns induced by both D- and L-amphetamine.     

The historical delivery of antibiotics from microbial natural products--can history repeat?

Microbial natural products are the origin of most of the antibiotics on the market today. However, research in antibiotics and natural products has declined significantly during the last decade as a consequence of diverse factors, among which the lack of interest of industry in the field and the strong competition from collections of synthetic compounds as source of drug leads. As a consequence, there is an alarming scarcity of new antibiotic classes in the pipelines of the pharmaceutical industry. Still, microbial natural products remain the most promising source of novel antibiotics, although new approaches are required to improve the efficiency of the discovery process. The impact of microbial biodiversity, the influence of growth conditions on the production of secondary metabolites, the choice of the best approach at the screening step and the challenges faced during the isolation and identification of the active compounds are examined in this review as the critical factors contributing to success in the effort of antibiotic discovery from microbial natural products.     

不同剂量大枣对D-半乳糖衰老小鼠SOD活性和MDA含量影响的实验研究

本实验以昆明种小鼠为研究对象,颈背部注射 Ｄ－ｇａｌ建立衰老模型,同时以大枣作为抗衰老实验药物灌服,测定了脑组织内超氧化物歧化酶（ＳＯＤ）活性、丙二醛（ＭＤＡ）含量．实验结果表明：不同剂量大枣均可提高小鼠脑组织 ＳＯＤ活性,并能降低脑组织 ＭＤＡ含量．说明不同剂量大枣均可提高小鼠脑组织ＳＯＤ活性,并能降低脑组织ＭＤＡ含量,大枣具有一定的抗衰老作用．     

Berberine ameliorates the neurological dysfunction of the gastric fundus by promoting calcium channels dependent release of ACh in STZ-induced diabetic rats

BackgroundIt has been reported diabetic gastroparesis is related to diabetic autonomic neuropathy of the gastrointestinal tract, and berberine (BBR) could ameliorate diabetic central and peripheral neuropathy. However, the influence of BBR on the function and motility of the gastric fundus nerve is unclear.MethodsA diabetic rat model was constructed, and HE staining was used to observe the morphological changes in the gastric fundus. The changes in cholinergic and nitrogen-related neurochemical indexes and the effects of BBR on them were measured using Elisa. The effects of BBR on the neural function and motility of gastric fundus were investigated by electric field stimulation (EFS) induced neurogenic response in vitro.ResultsIn the early stage of STZ-induced diabetic rats, the contractile response of gastric fundus induced by EFS was disorder, disturbance of contraction amplitude, and the cell bodies of neurons in the myenteric plexus of gastric fundus presented vacuolar lesions. Administration with BBR could improve the above symptoms. BBR further enhanced the contraction response in the presence of a NOS inhibitor or the case of inhibitory neurotransmitters removal. Interestingly, the activity of ACh could affect NO release directly and the enhancement of BBR on contractile response was canceled by calcium channel blockers completely.ConclusionsIn the early stage of STZ-induced diabetic rats, the neurogenic contractile response disorder of the gastric fundus is mainly related to cholinergic and nitrergic nerve dysfunction. BBR promotes the release of ACh mainly by affecting the calcium channel to improve the neurological dysfunction of the gastric fundus.     

Cadmium-metallothionein interactions in the olfactory pathways of rats and pikes.

Deposition of cadmium onto the olfactory epithelium results in transport of the metal along the primary olfactory neurons to the olfactory bulbs of the brain. The present investigation was undertaken to determine the intracellular ligand binding of cadmium during this process. (109)Cd(2+) was applied on the olfactory epithelium of rats and pikes, and the subcellular distribution of the metal in the olfactory pathways was then examined. Two groups of rats were used: one pretreated with intranasal instillations of nonlabeled cadmium and the other given physiological saline (controls). Cellular fractionations showed that the (109)Cd(2+) was predominantly present in the cytosol of all samples, both in the rats and the pikes. Gel filtrations of the olfactory epithelium of control rats killed 2 h after the (109)Cd(2+) instillation showed that the metal was recovered in two peaks with elution volumes corresponding to metallothionein (MT) and glutathione (GSH)-the latter peak being the predominant one. However, in the epithelium of the cadmium-pretreated rats killed at 2 h, (109)Cd(2+) was recovered in one peak corresponding to MT. In the olfactory epithelium and bulbs of both groups of rats killed at 48 h, as well as in the olfactory epithelium, nerves, and bulbs of pikes killed at this interval, (109)Cd(2+) was recovered in one peak corresponding to MT. Immunohistochemistry of the olfactory system of rats given cadmium in the right nasal cavity showed induction of MT in the neuronal, sustentacular, and basal cells of the right olfactory epithelium, in the nerve fascicles in the lamina propria of the right olfactory mucosa, and in the olfactory nerve layer of the right olfactory bulb. On the left side, the immunoreactivity was low in these structures. MT immunoreactivity was observed in the glomeruli of both the right and the left olfactory bulbs. However, the staining was homogeneously distributed within the entire glomeruli of the right bulb, whereas it showed a mesh-like pattern corresponding to the localization of astrocytes in the glomeruli of the left bulb. We conclude that exposure of the olfactory epithelium to cadmium results in induction of MT in the primary olfactory neurons and a transport of the metal in these neurons as a cadmium-metallothionein (CdMT) complex. Our results further indicate that GSH is a ligand that can interact with cadmium before the metal binds to MT.     

Intracerebral microdialysis: 30 years as a tool for the neuroscientist

1. Microdialysis is an established technique for studying physiological, pharmacological and pathological changes of a wide range of low molecular weight substances in the brain extracellular fluid. Many studies have proven its sensitivity in sampling the extracellular space in discrete brain locations, such as the striatum, and monitoring the action of exogenous substances. 2. The two main areas of application of microdialysis are the recovery of endogenous substances, primarily the neurotransmitters, and the infusion of drugs through the microdialysis cannula (retrodialysis). 3. Microdialysis in awake animals is the tool of choice for studying the relationship between changes in behaviour and neurotransmitters in certain brain areas. In addition, the concomitant recording of the electroencephalogram at the site of microdialysis has been shown to be extremely useful in determining the role of certain neurotransmitters in paroxysmal activity. 4. Clinical applications of microdialysis have included monitoring of ischaemic injury, subarachnoid haemorrhage, trauma and epilepsy. With the recent availability of standardized equipment, the use of microdialysis in the neurological clinic is likely to become more common.     

Emerging drug treatments for cystic fibrosis

Cystic fibrosis (CF) is one of the most common life-shortening inherited disorders. Mutations in the cystic fibrosis transmembrane regulator (CFTR) gene disrupt the localisation and function of the cAMP-mediated chloride channel. Most of the morbidity and mortality arise from the lung disease which is characterised by excessive inflammation and chronic infection. Research into the mechanisms of wild-type and mutant CFTR biogenesis suggest that multiple drug targets can be identified. This review explores the current understanding of the nature of the different mutant CFTR forms and the potential for repair of the chloride channel defect. High-throughput screening, pharmacogenomics and proteomics bring recent technological advances to the field.     

Environmental modulation of the response to amphetamine: dissociation between changes in behavior and changes in dopamine and glutamate overflow in the rat striatal complex

Rationale: We have previously shown that environmental novelty enhances the behavioral activating effects of amphetamine and amphetamine-induced expression of the immediate early gene c-fos in the striatal complex, particularly in the most caudal portion of the caudate. In contrast, we found no effect of novelty on the ability of amphetamine to induce dopamine (DA) overflow in the rostral caudate or in the core of the nucleus accumbens. Objectives: The twofold aim of the present study was to determine the effect of environmental novelty on (1) amphetamine-induced DA overflow in the shell of the nucleus accumbens and in the caudal portions of the caudate, and (2) glutamate and aspartate overflow in the caudal portions of the caudate. Methods: Two groups of rats with a unilateral 6-hydroxydopamine lesion of the mesostriatal dopaminergic system received amphetamine (0.5 mg/kg, i.v.) in physically identical cages. For one group, the cages were also the home environment, whereas, for the other group, they were a completely novel environment. In vivo microdialysis was used to estimate DA, glutamate, and aspartate concentrations. Results: Environmental novelty enhanced amphetamine-induced rotational behavior (experiments 1–3) but did not alter amphetamine-induced DA overflow in either the shell of the nucleus accumbens (experiment 1) or the caudate (experiment 2). In addition, the ability of environmental novelty to enhance amphetamine-induced behavioral activation was not associated with changes in glutamate or aspartate efflux in the caudate (experiment 3). Conclusions: The present data indicate that the psychomotor activating effects of amphetamine can be modulated by environmental context independent of its primary neuropharmacological actions in the striatal complex. Received: 27 July 1999 / Accepted: 30 November 1999