盐酸西布曲明的合成

以对氯氯苄为原料 ,经取代、环合、加成、还原、二甲基化及成盐等反应合成盐酸西布曲明。还原反应改用成本较低的硼氢化钾 ;二甲基化反应改用条件温和、对环境污染少的甲醛 -硼氢化钾系统 ,使该步收率可达 92 %。方法操作简便 ,条件温和 ,成本较低 ,总收率 44 % (以 2计 )     

盐酸西布曲明的合成工艺改进

目的研究盐酸西布曲明适合工业化大生产的方法。方法以对氯氯苄为原料,经取代、环合、加成、还原、二甲基化及成盐等反应合成盐酸西布曲明,并对反应条件进行了改进和优化。结论工艺经改进和优化后,反应条件温和,操作简便,工艺稳定,总收率达到57.8%,大幅度的降低了生产成本,更加适合工业化生产。     

盐酸西布曲明的合成

目的：改进肥胖症治疗药盐酸西布曲明（ｓｉｂｕｔｒａｍｉｎｅ ｈｙｄｒｏｃｈｌｏｒｉｄｅ）的合成方法。方法：以４－氨苄腈为起始原料,经环烃化、Ｇｒｉｇｎａｒｄ反应、还原、Ｅｓｃｈｗｅｉｌｅｒ－ｃｌａｒｋｅ甲基化和成盐等反应合成了盐酸西布曲明。结果：合成产物经熔点、元素分析、红外光谱和核磁共振谱等确证,总收率３６．３％。结论：此合成工艺简便,易于工业化生产。     

抗抑郁药盐酸氟西汀的合成

目的：研究盐酸氟西汀的合成工艺。方法：以苯乙酮为起始原料，经Mannich反应、还原、醚化、去甲基、水解、成盐6步合成盐酸氟西汀。结果：合成盐酸氟西汀的总收率为41．9％。改进了中间体3，4和6的合成工艺。结论：该方法原料易得，操作方便，条件温和，收率较高，适于工业化生产。     

班布特罗合成的改进

以３‘,５’－二羟基苯乙酮为起始原料,经酯化,溴化,还原,缩合,成盐５步反应合成了盐酸班布特罗,工艺简便,条件温和,总收率达１９％。     

5-甲基吡嗪-2-羧酸的合成研究

目的：研究５－甲基吡嗪－２－羧酸的合成方法。方法：以２,５－二甲基吡嗪和Ｎ－氯代琥珀酰亚胺为原料,经氯代酯化、碱解、氧化四步反应合成５－甲基吡嗪－２－羧酸。结果：合成的５－甲基吡嗪－２－羧酸的总收率为５２．０％,结构经元素分析,ＭＳ,＾１ＨＮＭＲ确证。结论：设计的合成路线合理,反应条件温和,收率高,适合于工业生产。     

盐酸莫雷西嗪的合成

目的：合成抗心律失常药盐酸莫雷西嗪。方法：以3-溴硝基苯、乙酰苯胺为原料经烃化、水解反应得3-硝基二苯胺，经硫化亚铁-氯化铵-甲醇-水体系还原得3-氨基二苯胺，再经酰化、环合、烃化和成盐反应得盐酸莫雷西嗪。结果：合成了盐酸莫雷西嗪，9步反应总收率为35．8％。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，适合大规模制备。     

盐酸赛洛唑啉的合成工艺

目的合成盐酸赛洛唑啉并对其工艺进行研究。方法以间二甲苯为起始原料,经叔丁基化、氯甲基化、环合、成盐精制等6步反应合成盐酸赛洛唑啉,并对氯甲基化反应进行了工艺改进。结果合成了盐酸赛洛唑啉,总收率为18.95%。结论工艺改进后,简化了操作过程,提高了收率。     

抗心律失常药盐酸索他洛尔的合成

合成盐酸索他洛尔。方法　以苯胺为原料,经甲烷磺酰氯的酰化反应,溴乙酰溴的傅 -克酰化反应和异丙胺的分子间亲核取代反应及还原四步合成盐酸索他洛尔。结果及结论　经工艺改进,各步收率均有较大的提高,总收率达到 4 6 4 0 %。     

盐酸丙帕他莫的合成

目的：改进盐酸丙帕他莫的合成方法。方法：以对乙酰氨基苯酚为原料,经氯乙酰化、氨化、成盐三步反应制得盐酸丙帕他莫。结果：最终产品质量符合《欧洲药典》5．0版（EP5．0）质量标准,收率52．3％。结论：改进后工艺产品质量好,反应溶媒污染少,产品收率亦较高。     

盐酸西布曲明与牛血清白蛋白结合作用的光谱学研究

目的运用光谱学方法研究在生理pH值条件下盐酸西布曲明与牛血清白蛋白之间的结合作用。方法 通过荧光法和吸收光谱法确定了盐酸西布曲明对牛血清白蛋白的荧光猝灭机制。依据Scatchard方程测定了不同温度下该结合反应的结合常数和结合位点数。根据热力学方程讨论了两者间的主要作用力类型。结合同步荧光分析了盐酸西布曲明对牛血清白蛋白构象的影响。结果盐酸西布曲明对牛血清白蛋白的荧光猝灭机制为静态猝灭。在8，25和37 ℃时盐酸西布曲明与牛血清白蛋白的结合常数分别为1.21×10⁵，8.31×10⁴和6.97×10⁴ L·mol^-1，结合位点数均为1。结合反应的热力学参数为ΔH=-9.70 kJ·mol^-1，ΔS=56.41 J·mol^-1·K^-1。结论 两者结合的主要作用力类型是静电作用。盐酸西布曲明在体内能够被血清蛋白存储和转运且结合时对蛋白构象无影响。     

检测中药保健品中非法掺入的盐酸西布曲明

目的检查某些中药减肥保健品中非法掺入的化学药品盐酸西布曲明。方法采用高效液相色谱法测定中药保健品中掺入盐酸西布曲明的含量,并用薄层色谱、高效液相色谱、红外光谱以及质谱技术进行定性鉴别。结果抽取的15种样品中,有13种检出了盐酸西布曲明。结论所建方法专属性强、灵敏度高,操作简便,可作为中药保健品中掺入盐酸西布曲明监督检查的有效方法。     

Crystal chemistry of sibutramine: thermal, diffractometric and spectroscopic characterization

Monohydrated sibutramine hydrochloride is a widely used active ingredient for the treatment of obesity. An anhydrous form of sibutramine hydrochloride was prepared starting from its monohydrate form upon heating it at 140 degrees C for 15 min. This dehydration process was monitored using conventional TG/DSC methods. Heated above 190 degrees C, sibutramine hydrochloride sublimes and recrystallizes on the cold walls of the test tube, giving platelet shaped crystals suitable for single crystal X-ray diffraction analysis: monoclinic, P2(1)/n, a = 7.321(2) A, b = 25.456(5) A, c = 9.750(3) A, beta = 101.60(2) degrees , V = 1779.9(8) A(3), Z = 4. At variance, sibutramine free base was typically recovered as a viscous oily material, upon treatment of its hydrochloride salt in ethyl acetate solution. Recrystallization from hexane yielded a white polycrystalline powder, the structure of which was determined by unconventional ab initio X-ray powder diffraction analysis: triclinic, P-1, a = 8.6578(3) A, b = 9.3318(3) A, c = 11.1224(4) A, alpha = 110.434(3) degrees , beta = 100.159(3) degrees , gamma = 89.201(2) degrees , V = 827.76(5) A(3), Z = 2. Sibutramine, in its different crystalline environments, was also fully characterized by solid state (13)C NMR analyses. Additional spectral information was obtained by collecting spectra of a metastable, oily sample, before it slowly recrystallizes (within hours).     

盐酸西布曲明对高脂肥胖大鼠下丘脑增食欲素系统的影响

目的观察盐酸西布曲明对高脂饮食肥胖大鼠下丘脑增食欲素系统基因表达的变化。方法建立高脂饮食肥胖大鼠模型,分组连续灌胃给药4wk,观察盐酸西布曲明给药对高脂饮食肥胖大鼠体重、血脂、血糖及下丘脑前增食欲素原及增食欲素受体mRNA表达的影响。结果盐酸西布曲明8mg·kg-1能明显降低高脂肥胖大鼠体重、血糖和血脂;升高肥胖大鼠下丘脑前增食欲素原mRNA表达水平;各组间增食欲素受体1和2mRNA表达无变化。结论盐酸西布曲明具有减重、降脂和增加高脂饮食肥胖大鼠下丘脑前增食欲素原基因表达的作用。     

减肥类保健食品中非法添加盐酸西布曲明和酚酞的定性定量检测

目的建立准确检测减肥类保健食品中非法添加盐酸西布曲明和酚酞的定性定量方法。方法采用超高效液相色谱-串联质谱(UPLC-MS/MS)法,以0.1%甲酸的甲醇溶液和水溶液为流动相,通过分子离子峰、二级质谱的碎片离子、多反应检测模式的色谱峰等信息,对盐酸西布曲明和酚酞进行定性鉴别和定量测定。结果 4批保健食品中均检出盐酸西布曲明和酚酞。结论该方法准确可靠、专属性强、灵敏度高,可作为检测减肥类保健食品中非法添加盐酸西布曲明和酚酞的有效方法。     

Long-lasting effects of an acute stress on the neurochemistry and function of 5-hydroxytryptaminergic neurones in the mouse brain

The present experiments investigated the effects of a novel stress challenge (6-min swim test) on behaviour (immobility) and the neurochemistry of cortical 5-hydroxytryptaminergic neurones in CD1 mice. The influence of previous experience of stress (once-daily saline injection) or administration of the noradrenaline and 5-hydroxytryptamine (5-HT) uptake blocker, sibutramine hydrochloride, on any changes was also evaluated. 5-HT_2A receptor binding was unchanged 24 h after the last injection of either saline or sibutramine alone but immobility in the swim test was reduced to the same extent by these pretreatments. Seven days, but not 3 h, after the swim test, the density of 5- HT_2A receptors and the frequency of 5-HT_2A receptor-mediated head-twitches were increased significantly. These increases were prevented by saline injection, but sibutramine prevented the increase in head-twitches only. Sibutramine, but not saline, reduced 5-HT synthesis and 5-HT_2A receptor-mediated head-twitches 3 h after the swim and increased synthesis at 7 days. The results indicate that a brief stress can have long-term effects on central 5-hydroxytryptaminergic neurones. Previous experience of stress or sibutramine has marked, but dissimilar, effects on these changes. These findings might be relevant to long-lasting CNS disorders provoked, or aggravated, by stress.     

Sibutramine: new preparation. Slight weight loss; but also a slight rise in blood pressure ..

(1) The reference treatment for achieving weight loss by obese patients is a combination of dietary measures, exercise and behavioural interventions. There is currently no drug treatment with demonstrated efficacy on the morbidity or mortality associated with excess body weight. (2) Sibutramine, a serotonin- and noradrenaline-reuptake inhibitor structurally related to the amphetamines has been granted marketing authorisation in France for the treatment of obesity and excess body weight in patients with associated risk factors. (3) The clinical file on sibutramine contains no trial focusing on morbidity or mortality end points. (4) According to comparative clinical trials, weight loss during a 6-12 month course of sibutramine is, on average, between 3 and 9 kg greater than that on placebo. Patients regain weight after sibutramine cessation. (5) Sibutramine has little or no benefit on blood sugar or lipid parameters. (6) The main known adverse effect of sibutramine is increased blood pressure. Sibutramine also has amphetamine-like side effects. (7) In practice, sibutramine currently has no place in the management of obesity.     

Effects of sibutramine alone and with alcohol on cognitive function in healthy volunteers

AIMS: To investigate the effects of sibutramine in combination with alcohol in a double-blind, randomised, placebo-controlled, four-way crossover study in 20 healthy volunteers. METHODS: On each study day each volunteer received either: sibutramine 20 mg+0.5 g kg-1 alcohol; sibutramine 20 mg+placebo alcohol; placebo capsules+0.5 g kg-1 alcohol; or placebo capsules+placebo alcohol. Alcohol was administered 2 h following ingestion of the study capsules. During each study day, assessments of cognitive performance were made prior to dosing, and at 3, 4.5, 6 and 10 h post dosing. Blood alcohol concentration was estimated using a breath alcometer immediately prior to each cognitive performance test session. Each study day was followed by a minimum 7 day washout period. RESULTS: Alcohol was found to produce statistically significant impairments in tests of attention (maximum impairment to speed of digit vigilance=49 ms) and episodic memory (maximum impairment to speed of word recognition=74 ms). Alcohol also increased body sway (maximum increase 17.4 units) and lowered self rated alertness (maximum decrease 13.6 mm). These effects were produced by an inferred blood alcohol level of 53.2 mg dl-1. Sibutramine was not found to potentiate any of the effects of alcohol. There was a small, yet statistically significant, interaction effect observed on the sensitivity index of the picture recognition task. In this test, the combined effects of sibutramine and alcohol were smaller than the impairments produced by alcohol alone. Sibutramine, when dosed alone, was associated with improved performance on several tasks. Sibutramine improved attention (mean speed of digit vigilance improved by 21 ms), picture recognition speed (improvement at 3=81) and motor control (tracking error at 3 h reduced by 1.58 mm). Also sibutramine improved postural stability (reducing body sway at 3 h by 14.2 units). Adverse events reported were unremarkable and consistent with the known pharmacology of sibutramine and alcohol. CONCLUSIONS: There was little evidence of a clinically relevant interaction of sibutramine with the impairment of cognitive function produced by alcohol in healthy volunteers. The single statistically significant interaction indicated a reduction, rather than a worsening, of alcohol-induced impairment when sibutramine is taken concomitantly. Sibutramine when administered alone is associated with improved performance on several tasks.