替普瑞酮合成工艺的改进

橙花叔醇与乙酰乙酸甲酯进行Carroll反应制得(5E,9E)-和(5Z,9E)-法昵基丙酮,经分馏纯化得到含量较高的(5E,9E)-法呢基丙酮后再经Grignard反应、Carroll反应制得抗溃疡药替普瑞酮,总收率18%,产品纯度98%.     

法呢醇X受体激动剂研究进展

法呢醇X受体（FXR）通过调节胆汁酸的合成、分泌和吸收来调节胆汁酸的代谢和稳态。法呢醇X受体激动剂有望成为治疗胆汁酸代谢相关疾病的新型药物。该文对近年来报道的法呢醇X受体激动剂进行简要综述。     

法呢基转移酶抑制剂抗癌机理及筛选方法的研究进展

综述了法呢基转移酶抑制剂的抗癌机理、筛选方法和开发前景.法呢基转移酶抑制剂通过抑制癌细胞中功能异常的ras蛋白的法呢基化发挥作用.     

砜的简便合成

芳族磺酰氯与活泼的溴代烷或碘甲烷于四氢呋喃－饱和氯化铵水溶液或四氢呋喃－水中,在锌粉参与下,反应温度０°Ｃ到室温,时间２～３ｈ,进行偶合反应合成砜。１４例收率５１％～８２％。砜的简便合成@张庆文     

阿扎胞苷的合成工艺研究

目的 研究阿扎胞苷的合成工艺.方法以5-氮杂胞嘧啶为原料,在硫酸铵的催化下用双三甲基二硅胺(HMDS)保护其羰基和氨基,再与四乙酰核糖缩合,在甲醇中进行醇解,吡啶重结晶得阿扎胞苷.结果本工艺的总收率为58.8％.结论该合成工艺反应条件温和,操作简便,阿扎胞苷产品质量分数和收率较高,适合于工业化生产.     

DCC/DMAP催化制备乙酰阿魏酸苯丙醇酯

目的改进乙酰阿魏酸苯丙醇酯的合成工艺。方法以N,N-二环己基碳二亚胺（DCC）和4-二甲胺基吡啶（DMAP）为催化剂,以乙酰阿魏酸和1-苯丙醇（又名利胆醇）在室温下制备乙酰阿魏酸苯丙醇酯。结果该方法反应条件比较温和,均可合成乙酰阿魏酸苯丙醇酯,DCC/DMAP法反应3h,产率73.4%。结论以DCC/DMAP法合成乙酰阿魏酸苯丙醇酯,反应时间更短、收率更高。     

选择性内皮素受体阻滞剂darusentan的合成

目的:合成ETA选择性内皮素受体阻滞剂darusentan,降低合成的成本和操作难度.方法:以二苯甲酮为原料,经与氯乙酸乙酯在无溶剂的条件下进行Darzens缩合;对甲苯磺酸的催化下醇解;甲基亚硫酸钠的催化下与2-氯4,6-二甲氧基嘧啶进行亲核取代反应;碱性条件下水解得到目标化合物.结果:目标化合物经红外光谱、核磁共振氢谱、质谱确证其化学结构.结论:该法操作简便,成本低,总收率达53.5%.     

N-叔丁氧羰基-O-苄基-L-苏氨醇的制备及其在合成奥曲肽中的应用研究

目的：合成N-叔丁氧羰基-O-苄基-L-苏氨醇（化合物1）,并将其作为原料合成多肽药物奥曲肽。方法：以侧链羟基和氨基均被保护的苏氨酸为原料,分别采用混合酸酐法、四氢锂铝（LiAlH4）法以及卡特缩合剂（BOP）法进行还原反应,柱层析分离纯化,合成目标化合物,经红外光谱（IR）、核磁共振氢谱（1H-NMR）及质谱（MS）进行表征。合成的目标化合物经脱除氨基保护,用于奥曲肽合成。结果：混合酸酐法、LiAlH4法、BOP法合成目标化合物1的收率分别为83.2%、73.4%、69.5%,纯度分别为99.0%、98.8%、98.5%,并经过结构表征确证;奥曲肽合成收率为6%,纯度〉98%。结论：混合酸酐法合成化合物1的操作简便、收率高、纯度高,并成功应用于奥曲肽的合成。     

癸异戊二烯醇的合成

(E)-4-氯-3-甲基-2-丁烯-1-醇乙酸酯经磺酰化、水解和THP保护羟基得到的四氢吡喃醚与茄呢基溴进行偶联,再脱除磺酰基和THP保护基得到癸异戊二烯醇,总收率54%,茄呢醇利用率77%.     

微波及离子液体条件下香豆素类化合物的合成研究

目的：探索操作简便、环境友好的香豆素衍生物的合成方法：方法：以乙酰乙酸乙酯和苯酚类化合物为原料,通过Pechmann反应,在4种不同的反应条件（浓硫酸催化、Lewis酸三氯化铋催化、微波Lewis酸三氯化铋催化、微波离子液体催化）下催化合成多种香豆素衍生物,并对4种方法进行对比。结果：微波离子液体条件下的Pechmann反应与传统方法相比革除了有机溶剂的使用,缩短了反应时间且产率较高。结论：微波及离子液体条件下合成香豆素类化合物是一种条件简单、环境友好的合成方法。     

Announcing a New Editor-in-Chief

An examination of the properties and reactivity of S-carboxymethylcysteine sulfone indicated that, unlike S-carboxymethylcysteine, the sulfone is not stable under acid hydrolysis conditions and decomposes to yield alanine. Unlike S-carboxymethylcysteine, the sulfone is resistant to N-derivatization by the dansyl reagent or by phenylisothiocyanate. Efforts were made to determine if spontaneous cyclization of the sulfone to the corresponding thiazane (lactam) accounts for lack of reactivity. These included i.r. spectroscopy, natural abundance ¹³C-n.m.r. spectroscopy and differential scanning calorimetry, but yielded equivocal results concerning the existence of the cyclic form in solution. Solubility behavior of the sulfone after lyophilization from strongly acid solutions was consistent with conversion of the open chain form to the cyclic form on addition of water.     

茶多酚对兰索拉唑及其代谢产物在大鼠体内药动学的影响

目的:研究茶多酚对兰索拉唑及其代谢产物5-羟基兰索拉唑和兰索拉唑砜在大鼠体内药动学的影响.方法:16只SD雄性大鼠随机分为单独用药组和联合用药组,前14 d联合用药组灌胃给予茶多酚400 mg·kg-1,单独用药组灌胃给予等体积生理盐水,qd.第15天两组给予兰索拉唑8 mg·kg-1,给药后不同时间点采取血样,LC-MC/MS法测定兰索拉唑及其代谢产物血药浓度,用DAS2.0软件分析其药动学参数,以考察茶多酚对兰索拉唑代谢的影响.结果:茶多酚(400 mg·kg-1·d-1)显著降低兰索拉唑(8 mg·kg-1)的AUC(0-4)、Cmax和t1/2Z(P<0.05),显著升高5-羟基兰索拉唑与兰索拉唑的AUC(0-4)比值R1(P<0.05),但对兰索拉唑砜的药动学无显著影响(P>0.05).结论:茶多酚能够显著降低兰索拉唑在大鼠体内的口服生物利用度,其原因可能与茶多酚诱导CYP2C19有关.     

Effect of clotrimazole on microsomal metabolism and pharmacokinetics of albendazole

Albendazole is a broad spectrum anthelmintic drug widely used in human and veterinary medicine. Intestinal and hepatic albendazole metabolism leads to albendazole sulfoxide (active metabolite) and albendazole sulfone (inactive metabolite) formation. Microsomal sulfonase activity can be abolished by in-vitro interaction with clotrimazole and pharmacokinetic studies confirm this interaction. After albendazole incubation, albendazole sulfone formation was completely inhibited by 50 microM clotrimazole in intestinal incubations and a 50% inhibition was observed in hepatic incubations. The lower inhibition constant (K(i)) value observed in the intestinal incubations (9.4 +/- 1.0 microM) compared with the hepatic counterparts (23.3 +/- 15.8 microM) pointed to a greater affinity of the enzymatic systems in the intestine. Regarding the formation of albendazole sulfoxide, an inhibition close to 50% was observed in liver and intestine at 10 microM clotrimazole. The pharmacokinetic parameters obtained following the oral co-administration of albendazole sulfoxide and clotrimazole corroborated the in-vitro inhibition of albendazole sulfone formation, since the ratio of the area under the plasma concentration-time curves for the sulfoxide/sulfone (AUC(ABZSO)/AUC(ABZSO2)) was significantly higher (38.1%). In addition, the AUC and C(max) for albendazole sulfone were significantly lower. The effect of clotrimazole was also studied after prolonged treatment. Hepatic microsomal metabolism of albendazole was induced after 10 days of clotrimazole administration, with significant increases in formation of albendazole sulfoxide (40%) and sulfone (27%). These results offer further insight into the metabolism of benzimidazole drugs and highlight the difficulty involved in human therapy with these anthelmintics, since after prolonged treatment the drug interactions are affected differentially.     

Role of 3,5-dichlorophenyl methyl sulfone, a metabolite of m-dichlorobenzene, in the induction of hepatic microsomal drug-metabolizing enzymes by m-dichlorobenzene in rats

The increases in the hepatic microsomal aminopyrine N-demethylase activity and in the content of cytochrome P-450 produced by m-dichlorobenzene (m-DCB) occurred after increases in the hepatic concentration of 3,5-dichlorophenyl methyl sulfone, a minor metabolite. The extent of increases in aminopyrine N-demethylase activity and in the content of cytochrome P-450 at 48 hr after po administration of 200 mg/kg (1.36 mmol/kg) of m-DCB was almost equal to that 72 hr after the ip administration of 25 mumol/kg of the sulfone (Kimura et al., 1983). m-DCB in liver was not detectable at that time, and the concentration of sulfone was 63 to 70% of that 48 to 72 hr after the ip administration of 50 mumol/kg of sulfone. Administration of m-DCB (200 mg/kg) produced a significant reduction in hexobarbital sleeping time, but this reduction was less than that produced by administration of the sulfone (50 mumol/kg). The protein band patterns by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the microsomes from rats treated with the sulfone and m-DCB were similar to those of phenobarbital-treated rats but were different from those of 3-methylcholanthrene-treated rats. The sulfone showed type I interaction with the cytochrome P-450 (Ks, 0.17 mM). The sulfone was formed from the sulfide but reduction of the sulfone was not observed when it was incubated in a hepatic microsomal preparation. The pattern of induction by the sulfone and m-DCB was similar to that by phenobarbital and differed from that by 3-methylcholanthrene. From these results, 3,5-dichlorophenyl methyl sulfone is considered to be a major contributing factor of the inducing activity of m-DCB and to be a potent phenobarbital-like inducer.     

克拉霉素对兰索拉唑及其代谢产物在大鼠体内药动学特征的影响

目的研究克拉霉素对兰索拉唑及其代谢产物5-羟基兰索拉唑和兰索拉唑砜药动学特征的影响。方法 24只大鼠随机分为4组,分别十二指肠给予兰索拉唑(8 mg·kg^-1)+生理盐水、兰索拉唑(8 mg·kg^-1)+酮康唑(5 mg·kg^-1)、兰索拉唑(8 mg·kg^-1)+反苯环丙胺(5 mg·kg^-1)、兰索拉唑(8 mg·kg^-1)+克拉霉素(8 mg·kg^-1)。于给药后不同时间点采集血样,用LC-MS/MS法测定药物浓度。通过对兰索拉唑及5-羟基兰索拉唑和兰索拉唑砜血药浓度的测定,计算大鼠体内药动学参数。以5-羟基兰索拉唑、兰索拉唑砜与兰索拉唑AUC_0→4h的比值分别作为原药经CYP2C19和CYP3A4代谢程度的指标,研究克拉霉素对兰索拉唑代谢的影响。结果克拉霉素显著增加兰索拉唑的AUC_0→4h、MRT和t_1/2,显著降低其CLz。克拉霉素显著降低兰索拉唑砜与兰索拉唑AUC_0→4h的比值,从0.63±0.17降至0.15±0.09（P<0.05）,兰索拉唑砜的ρ_max显著降低,MRT和t_1/2显著延长。克拉霉素对5-羟基兰索拉唑的药动学参数无明显影响。结论克拉霉素在大鼠体内对兰索拉唑CYP3A4主导的磺化代谢抑制作用明显,可明显增加兰索拉唑的生物利用度,对临床治疗消化性溃疡有积极意义。     

Metabolism of diphenyl sulfoxide in perfused guinea pig liver. Involvement of aldehyde oxidase as a sulfoxide reductase

To evaluate the metabolic capacity of intact guinea pig liver under normoxic and hypoxic conditions, oxidative and reductive metabolism of diphenyl sulfoxide (DPSO) was studied by the nonrecirculating perfusion method in situ. DPSO was exclusively converted into diphenyl sulfone (DPSO2), an oxidative metabolite, under normoxia. When diphenyl sulfide (DPS) was infused, DPSO was eliminated as a predominant metabolite. Judging from the susceptibility toward selective inhibitors of cytochrome P-450, both oxidative steps appear to be catalyzed by cytochrome P-450-dependent monooxygenase rather than flavin adenine dinucleotide-containing monooxygenase. Under hypoxic conditions, however, DPSO2 formation was decreased in parallel with reduced oxygen concentration in the influent perfusate, whereas only a trace amount of DPS, a reductive metabolite, was detected. On the other hand, coinfusion of an electron donor for aldehyde oxidase such as 2-hydroxypyrimidine and benzaldehyde, but not xanthine, markedly stimulated the formation of DPS during hypoxia. These results indicate that the oxidative pathway catalyzed by cytochrome P-450-dependent monooxygenase is predominant in DPSO metabolism under normoxic conditions, whereas only under hypoxia does the reductive pathway become the major one if an electron donor for aldehyde oxidase exists in intact guinea pig liver.     

注射用兰索拉唑与0.9%氯化钠注射液的配伍变化

目的：探讨注射用兰索拉唑与0.9％氯化钠注射液配伍液分别在室温、光照、4 ～8℃条件下放置不同时间溶液的变化.方法：模拟临床用药,参照2010年版《中国药典》,对五厂家生产的15批次注射用兰索拉唑与0.9％氯化钠注射液100 ml配伍后在三种条件下放置,对兰索拉唑含量、pH、澄清度和不溶性微粒数进行测定,对含量、pH采用SAS软件进行统计分析.结果：五厂家15批次的注射用兰索拉唑配伍溶液在三种条件放置8h后含量均在90％以上;pH随时间逐渐减小,8h均能维持在pH 9左右;室温光照条件下配伍溶液8h出现浑浊;10 μm和25μm微粒数4h内基本符合《中国药典》要求.结论：注射用兰索拉唑临床上可按说明书配伍使用,但建议与0.9％氯化钠注射液配伍后放置在阴凉处并尽快使用.     

维生素K_1注射液在临床贮存时的稳定性考察

目的:研究维生素K1注射液在临床常规条件下贮存的稳定性。方法:采用高效液相色谱法测定维生素K1注射液在常温且不避光条件下贮存不同时间(24h)后的含量变化,并观察溶液的颜色变化。结果:维生素K1注射液在24h内含量由98.7%下降至81.7%,溶液颜色由黄绿色变为黄棕色。结论:维生素K1注射液在未避光条件下贮存溶液稳定性较差,临床使用时应注意避光贮存。     

芦荟凝胶的稳定性考察及其有效期预测

目的:考察芦荟凝胶在高温、低温、高湿、光照条件下的稳定性,并预测其室温贮存的有效期。方法:采用苯酚-硫酸法测定芦荟凝胶中芦荟多糖的含量;分别在高温、低温、高湿、光照条件下放置,于规定时间取样,观察样品外观、pH值、含量的变化;采用初均速法预测有效期。结果:本品含量与温度相关性较大,光照及湿度的影响不明显;室温(25℃)贮存的有效期为1a。结论:芦荟凝胶宜于常温阴凉处贮藏。     

对某国产盐酸二甲双胍肠溶胶囊溶出度的评价研究

目的：评价盐酸二甲双胍肠溶胶囊在不同p H条件下的溶出曲线。方法：参照2010版《中华人民共和国药典》附录X B、XD,采用桨法考察盐酸二甲双胍肠溶胶囊在pH分别为1.0、4.0、纯水条件下2h后调节为pH6.8磷酸缓冲液再溶出1h的溶出性能, HPLC法测定溶出液中二甲双胍浓度,DDSolver 1.0对溶出曲线进行分析。结果：盐酸二甲双胍肠溶胶囊在pH1.0、pH4.0及纯水2h内几乎不释放,而在pH6.8的磷酸盐缓冲液中45min内释放达90%以上。经软件DDSolver1.0分析3种pH条件下的溶出曲线是相似的。结论：该二甲双胍肠溶胶囊在不同pH条件下的溶出曲线是相似的,对于不同患者溶出性能一致,药品品质较佳。