盐酸帕洛诺司琼的合成工艺研究

目的 研究化疗止吐药盐酸帕洛诺司琼的合成工艺.方法 以1,2,3,4-四氢萘甲酸消旋体和S-3-氨基奎宁环胺为起始物料料,经缩合、还原、缩合关环、成盐、重结晶等多步反应制备盐酸帕洛诺司琼.结果 制备盐酸帕洛诺司琼的总收率为32％.结论 新工艺以1,2,3,4-四氢萘甲酸消旋体原料代替昂贵的手性原料实现手性纯化合物盐酸帕...     

盐酸昂丹司琼合成工艺优化

目的优化盐酸昂丹司琼的合成工艺。方法以1,2,3,9-四氢-4H-咔唑-4-酮为起始原料,经甲基化得9-甲基-1,2,3,9-四氢-4H-咔唑-4-酮(3),3与二甲胺盐酸盐、多聚甲醛、2-甲基咪唑经过"一锅烩"反应得到中间体9-甲基-3-[(2-甲基-1H-咪唑-1-基)甲基]-1,2,3,9-四氢-4H-咔唑-4-酮(4),4经成盐反应得到目标产物盐酸昂丹司琼。结果与结论目标化合物的结构经1H-NM R、M S谱确证,总收率为57.2%,该合成工艺步骤简便,收率较高,易于工业化生产。     

盐酸雷莫司琼对白血病化疗止吐的临床疗效观察

目的观察盐酸雷莫司琼防治化疗所致恶心、呕吐的临床疗效。方法2005-2007年我院诊断为白血病的患者以昂丹司琼(欧贝)作为对照组,利用随机分组对照的方法进行随机对照试验。结果盐酸雷莫司琼对45例白血病患者化疗后呕吐的完全控制率达71.1%、有效率为88.9%,与对照组比较(完全控制率48.8%、有效率65.9%)有显著性差异(P<0.05)。盐酸雷莫司琼不良反应发生率为6.67%、昂丹司琼为9.76%,无显著性差异(P>0.05)。结论盐酸雷莫司琼具有强力、持久的止吐作用,无明显不良反应。     

注射用盐酸雷莫司琼与4种输液配伍的稳定性考察

目的考察注射用盐酸雷莫司琼在5％葡萄糖注射液等4种输液中的稳定性。方法在25℃,将注射用盐酸雷莫司琼加入到4种输液中,模拟临床用药浓度,用高效液相色谱法测定配伍后不同时间配伍液的含量,同时检查配伍液的pH值和外观变化。结果注射用盐酸雷莫司琼与4种输液配伍后在25℃放置10h其外观、pH值和含量基本不变。结论注射用盐酸雷莫司琼与4种输液配伍,在10h内基本稳定。     

高效液相色谱法手性拆分盐酸雷莫司琼对映体

目的手性拆分盐酸雷莫司琼对映体,建立检查盐酸雷莫司琼原料药中S-异构体的HPLC方法.方法采用YMC-Pack K03(用[N-(R)-(+)-1-(1-萘基)乙基]甲基丙烯酰胺聚合物键合硅胶为填充剂)手性柱(250 mm×4.0 mm,5μm),以乙腈-水(含0.05 mol·L-1磷酸氢二钠,磷酸调pH 5.2)(3565)为流动相,检测波长为247 nm,柱温45℃,流速为1.0 mL·min-1.结果S-异构体和R-异构体分离度＞1.8,S-异构体的检测限可达到10 ng·mL-1.结论该方法简便,快速,可用来检查盐酸雷莫司琼原料药中S-异构体的限度.     

5种5-HT_3受体拮抗药治疗化疗所致呕吐的最小成本分析

目的:比较5种5-HT3受体拮抗药治疗化疗所致呕吐的经济学效果。方法:128例化疗患者分为5组,分别应用盐酸昂丹司琼(A组)、盐酸格拉司琼(B组)、盐酸托烷司琼(C组)、盐酸阿扎司琼(D组)、盐酸雷莫司琼(E组)5种5-HT3受体拮抗药治疗化疗所致呕吐,观察疗效,采用药物经济学最小成本法进行比较。结果:A、B、C、D、E组有效率分别为75.00%、81.48%、84.62%、88.00%、86.36%,差异无统计学意义(P>0.05);成本分别为223.80、213.90、459.00、345.00、414.00元。结论:盐酸格拉司琼是治疗化疗所致呕吐较经济有效的药物。     

盐酸阿洛司琼合成工艺改进

目的 :改进盐酸阿洛司琼的合成工艺 ,以利于工业生产。方法 :以 2 ,4 -哌啶二酮 - 3-羧酸甲酯与 N -甲基苯肼缩合后在硫酸和醋酸存在下环合得制 2 ,3,4 ,5 -四氢 - 5 -甲基 - 1H-吡啶并 [4、3- b]吲哚 - 1-酮 ,然后甲基化 ,再与 4 -羟甲基 - 5 -甲基咪唑在对甲苯磺酸催化下缩合。结果 :制得合格的盐酸阿洛司琼 ,总收率 38%。结论 :经改进的工艺操作简便 ,比原工艺更易于工业化生产     

盐酸雷莫司琼口腔崩解片预防恶性血液疾病联合化疗所致的胃肠反应

目的：观察盐酸雷莫司琼口腔崩解片预防恶性血液疾病患者联合化疗所致胃肠反应的疗效和安全性。方法：采用随机、对照方法，将入选病例随机分为治疗组（含服盐酸雷莫司琼口腔崩解片0．1mg）和对照组（静脉注射盐酸托烷司琼5mg）。结果：可评价疗效及安全性病例110例。两种药物对控制化疗所致食欲缺乏、恶心和呕吐的有效率相似。第1～7天盐酸雷莫司琼对食欲缺乏的完全控制率（52．7％～63．6％）、第4～7天对恶心的完全控制率（43．6％～56．4％）及第3、4、6天对呕吐的完全控制率（80．0％、87．3％和90．9％）明显优于盐酸托烷司琼注射剂，差异有显著性（P〈0．05）。盐酸雷莫司琼不良反应轻，主要为便秘、头痛、体热感和疲倦，为一过性，其发生率与盐酸托烷司琼注射剂相似。结论：盐酸雷莫司琼口腔崩解片能有效预防恶性血液病患者联合化疗所致的胃肠反应，适用于因各种原因不能吞服药片的患者。     

阿哌沙班的合成工艺改进研究

目的对阿哌沙班的合成工艺进行改进研究。方法以4,5,6,7-四氢-1-(4-甲氧基苯基)-6-(4-硝基苯基)-7-氧代-1H-吡唑并[3,4-C]吡啶-3-羧酸乙酯为起始原料,通过还原、取代、环合、胺化反应得到阿哌沙班。结果合成了目标化合物阿哌沙班,经MS、~1H-NMR确证了结构,质量分数为99.2%,本合成工艺的总收率为76.4%。结论该合成工艺改进后操作简单、安全,适合工业化生产。     

44例5-HT3受体拮抗剂不良反应文献分析

目的探讨5-羟色胺3(5-HT3)受体拮抗剂致药品不良反应(ADR)的特点及相关因素,为临床合理用药提供参考。方法利用"维普医药信息资源服务系统"、"万方数据医药信息系统"、"中华医学会全文期刊"、"中国医院数字图书馆",以"昂丹司琼"、"格拉司琼"、"托烷司琼"、"阿扎司琼"、"雷莫司琼"、"5-HT3受体拮抗剂"等为题名进行全面搜索,对2000年1月~2011年12月国内公开报道的5-HT3受体拮抗剂所致的ADR44例进行统计分析。结果 44例ADR患者中男性20例(45.45%),女性24例(54.55%),格拉司琼发生ADR的例数最高30例(68.18%),临床主要累及皮肤及附件、心血管系统、呼吸系统等。结论临床应高度重视5-HT3受体拮抗剂的ADR,以确保安全用药。     

Effect of ramosetron on short-circuit current response in rat colonic mucosa

We investigated the effects of ramosetron (YM060, (−)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole monohydrochloride) on the short-circuit current (I_sc) responses to 5-HT receptor agonists in the rat distal colon, and compared its potency to that of other 5-HT₃ receptor antagonists. 5-Hydroxytryptamine (5-HT) concentration-dependently increased I_sc. The I_sc response to 5-HT was partially reduced by tetrodotoxin and ramosetron, and strongly inhibited by GR113808 ([[1-[(2-methylsulphonyl)amino]ethyl]-4-piperidin-yl]methyl 1-methyl-1H-indole-3-carboxylate). 2-Methyl-5-HT and 5-methoxytryptamine also increased I_sc. The former response was inhibited by ramosetron, and the latter was abolished by GR113808. Ramosetron, YM114 (KAE-393, (−)-(R)-5-[(1-indolinyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole monohydrochloride) and granisetron concentration-dependently antagonized the I_sc responses to 2-methyl-5-HT with reduction in the maximal response at higher concentrations. Apparent pA₂ values for these antagonists were 10.40, 10.37 and 8.99, respectively. Ondansetron produced clear rightward shifts of the concentration-response curves to 2-methyl-5-HT, with a pA₂ value of 8.53. These results suggest that 5-HT increases I_sc through the 5-HT₃ and 5-HT₄ receptors, and that ramosetron is a potent and selective 5-HT₃ receptor antagonist in rat colonic mucosa.     

Structure-activity relationship of histamine analogues, XVIII: Absolute configuration and histamin-like activity of the enantiomers of 5-amino-4,5,6,7-tetrahydrobenzimidazole

Structure-Activity Relationship of Histamine Analogues, XVIII: Absolute Configuration and Histamine-like Activity of the Enantiomers of 5-Amino-4,5,6,7-tetrahydrobenzimidazole The resolution of 5-amino-4,5,6,7-tetrahydrobenzimidazole (3) , the determination of the absolute configuration and the histamine-like activity of the enantiomers on the guinea-pig ileum (H₁) and atrium (H₂) are reported.     

Bicyclic compounds with potential antiulcer and/or antisecretory activity. II. 1(or 3),4,6,7-Tetrahydro-1(3)H-pyrano[3,4-d]imidazoles and 1(or 3),4,6,7-tetrahydro-1(3)H-thiopyrano[3,4-d]imidazoles

Owing to our current interest in synthesizing and evaluating the antiulcer and antisecretory activity of bicyclic compounds, a series of 1(or 3),4,6,7-tetrahydropyrano- and 1(or 3),4,6,7-tetrahydrothiopyrano-[3,4-d]imidazoles was synthesized and tested. The biological results were compared with those of some previously described 4,5,6,7-tetrahydroimidazo-[4,5-c]pyridine and 4,5,6,7-tetrahydrobenzimidazole derivatives.     

替比培南匹伏酯侧链的合成

目的:合成替比培南匹伏酯侧链1-(4,5-二氢-2-噻唑啉基)-3-巯基吖丁啶盐酸盐。方法:以2-甲硫基-2-噻唑啉为原料,经与3-羟基吖丁啶盐酸盐,甲烷磺酰氯,硫代乙酸钾以及水解4步反应合成1-(4,5-二氢-2-噻唑啉基)-3-巯基吖丁啶盐酸盐。结果:合成了1-(4,5-二氢-2-噻唑啉基)-3-巯基吖丁啶盐酸盐,总收率42%。结论:本方法可以方便地得到替比培南匹伏酯侧链1-(4,5-二氢-2-噻唑啉基)-3-巯基吖丁啶盐酸盐,提高了反应收率,简化了操作,降低了成本。     

雷莫司琼降低幼鼠内脏痛觉敏感性

目的:采用行为学和电生理学评价方法,探讨应用5-羟色胺3(5-HT3)受体拮抗剂雷莫司琼对幼鼠内脏痛觉敏感性影响。方法:新生期反复结直肠刺激(colorectal irritation,CI)建立幼鼠内脏痛觉高敏感性模型。32只SD新生大鼠按2×2析因设计分成4组,每组8只,A1B1组:新生期反复CI,15～21d腹腔注射雷莫司琼;A1B2组:新生期反复CI,15～21d腹腔注射生理盐水;A2B1组:新生期未接受CI,15～21d腹腔注射雷莫司琼;A2B2组:新生期未接受CI,15～21d腹腔注射生理盐水。常规饲养到幼鼠期(6周龄),通过观察幼鼠在不同压力结直肠扩张(colorectaldistension,CRD)刺激后的腹壁撤退反射(AWR)评分、内脏痛阈和腹外斜肌放电测量进行内脏痛觉敏感性评价。结果:幼鼠痛阈受建立内脏痛敏化模型和早期雷莫司琼干预两因素影响。建立内脏痛敏化模型可使幼鼠痛阈降低11.56mm Hg,早期雷莫司琼干预则使幼鼠痛阈提高9.06mm Hg,两者存在交互作用。应用雷莫司琼使AWR评分及腹外斜肌放电幅值降低,对于AWR评分的主效应在各个CRD压力下有统计学意义;对腹外斜肌放电幅值的主效应在各不同CRD压力下亦有统计学意义。结论:应用5-HT3受体拮抗剂雷莫司琼能够降低幼鼠内脏痛觉的高敏感性。     

Analysis of 5-HT3 receptor antagonist, ramosetron hydrochloride, based on receptor occupancy considering its active metabolite]

Severe nausea and vomiting induced by antineoplastics diminish the patient's quality of life and the ability to tolerate further chemotherapy. Ramosetron hydrochloride is a 5-HT3 receptor antagonist, which has an active metabolite (M-1), expected to be useful in the inhibition of chemotherapy-induced nausea and vomiting. In the present study, in order to analyze the pharmacological effect of ramosetron hydrochloride in a comprehensive manner, we estimated the 5-HT3 receptor occupancy after intravenous administration of ramosetron hydrochloride using pharmacokinetic parameters and the dissociation constants for the 5-HT3 receptor. The average total receptor occupancy after intravenous administration of 0.3 mg of ramosetron hydrochloride to human was calculated to be 82.9% (ramosetron, 77.8%; M-1, 5.1%), thus exhibiting a significant antiemetic activity. Furthermore, the estimated time course of 5-HT3 receptor occupancies after intravenous administration of 0.3 mg of ramosetron hydrochloride suggested a substantial impact of the active metabolite (M-1). It suggested that M-1 contributed to the long duration of binding on the 5-HT3 receptor. The present analysis method should be useful for designing the rational dosage regimen of ramosetron hydrochloride and predicting the duration of its antiemetic activity in a quantitative manner.     

盐酸达泊西汀的合成

目的:合成盐酸达泊西汀.方法:以苯甲醛和丙二酸为原料,经八步反应合成目标化合物.结果:目标化合物经旋光度测定及1H NMR,13C NMR,2D-NMR确证其化学结构,总收率达到15.08%.结论:该合成方法操作简单、收率高、适合工业化生产.     

Struktur-Wirkungsbeziehungen bei Histaminanaloga, 14. Mitt. 4-Aminomethyl-benzimidazole und 9-Amino-naphth[1,2-d]imidazole

4-(Aminomethyl)benzimidazoles and 9-Aminonaphth[1,2-d]imidazoles Syntheses of the bicyclic histamine analogues 4-(aminomethyl)benzimidazole ( 3a ) and 4-aminomethyl-4,5,6,7-tetrahydrobenzimidazole ( 3b ) and of the tricyclic analogues 9-amino-6,7,8,9-tetrahydronaphth[1,2-d]imidazole (6b) and 9-amino-4,5,5a,6,7,8,9,9a-octahydronaphth[1,2-d]-imidazole ( 6c ) are described.