溴甲纳曲酮的合成

盐酸纳曲酮与乙二醇缩合、叔丁基二甲基氯硅烷保护,再与碘甲烷进行N-甲基化反应得(R)-3-[(叔丁基二甲基硅基)氧基]-17-环丙甲基-4,5a-环氧-14-羟基-6-(1,3-二氧戊烷-2-基)-N-甲基吗啡喃碘化物,再经氢溴酸水解、溴离子交换得溴甲纳曲酮,总收率53％,HPLC纯度大于99％.     

溴甲纳曲酮可用于晚期重症病人使用阿片所致的便秘

惠氏（Wyeth）公司和Progenics公司联合开发的μ阿片受体拮抗剂溴甲纳曲酮（methyhaaltrexone bromide，Relistor）皮下注射剂最近已获美国FDA批准及欧盟CHMP的支持性批件，可用于接受姑息疗法的晚期重症患者因阿片所致的便秘（OIC）而使用轻泻药又无效的情况，并将很快在美国和欧盟上市。此前，该产品已在加拿大首次获准用于OIC。     

溴甲纳曲酮有关物质的HPLC-MS分析

目的:建立梯度洗脱反相高效液相色谱法测定溴甲纳曲酮中的有关物质。方法:采用高效液相色谱法,色谱柱为Shim-pack CLC-ODS(4.6 mm×150 mm,5μm),以甲醇-水-三氟乙酸(5:95:0.1)为流动相A,以甲醇-水-三氟乙酸(65:35:0.1)为流动相B,以1.0 mL.min-1的流速进行梯度洗脱,进样量20μL,检测波长230 nm。电喷雾电离源(ESI),电离源电压4.0 kV,喷雾气氮气的流速为9.0 L.min-1,干燥气温度为325℃,柱后分流;质谱扫描质量范围m/z 100～1000。结果:各有关物质与主成分均达到基线分离,分析了溴甲纳曲酮粗品中的杂质可能结构。结论:本法灵敏、专属,能有效分离降解产物及有关物质,可用于有关物质及降解产物检查。     

双硬脂酸纳曲酮的合成

对吗啡受体拮抗剂纳曲酮生物降解分散系的深入研究表明 ,纳曲酮的长效缓释制剂可克服病人在长达数月乃至数年的阿片成瘾治疗过程中产生的不适应。纳曲酮的结构与吗啡极为相似 [1] ,目前初步研究所得剂型为固形植入剂 ,需手术皮下埋植。因而 ,需探索可注射用的植入剂 :小颗粒混悬液供皮下注射 ,或是酯类前药 ,以油溶液供皮下或肌肉注射。将纳曲酮结构的 3位和 1 4位分别连接乙酰基和琥珀酰基后 ,其在狗体内的活性和生物利用度均比未修饰的纳曲酮高出 60 % ,并达到了一定的缓释和控释效果[2 ,3] 。本文以纳曲酮盐酸盐 (3)为原料 ,合成了 3位和…     

毛细管气相色谱法测定溴甲基纳曲酮中有机溶剂残留量

目的 建立以毛细管气相色谱法测定溴甲基纳曲酮中二氯甲烷、丙酮、甲醇、甲基叔丁基醚、乙酸乙酯和甲苯6种有机溶剂残留量的方法。 方法 采用DB-WAX(30.0 m×0.25 mm,0.25 μm)毛细管柱,氢火焰离子化检测器(FID),载气为氮气,柱流量为1.0 mL·min^-1,进样口温度为240 ℃,检测器温度为250 ℃,柱温为程序升温。 结果 甲基叔丁基醚、丙酮、乙酸乙酯、甲醇、二氯甲烷和甲苯6种有机溶剂均得到有效分离,回收率及线性关系皆良好,且3批样品中有机溶剂残留量均符合规定。 结论 该方法操作简便,精密度好,准确可靠,可用于溴甲基纳曲酮中有机溶剂残留量的测定。     

溴化甲基纳曲酮

溴化甲基纳曲酮（methylnaltrexone bromide）商品名为Relistor，由美国Wyeth公司和Progenies公司联合研究开发。2008年4月经美国FDA批准上市，用于治疗阿片类药物引起的便秘（opioid-indueed constipation，OIC）。Wyeth公司申请了世界专利WO2008／030567和美国专利US2008／0064743对Relistor进行了专利保护。     

新药纳曲酮中间体合成方法的改进

较系统地探索了用氯甲酸酯类化合物脱Ｎ－甲基的反应条件及中间体氨基酸甲酸酯的水解条件，以Ｌｅｗｉｓ及软硬酸碱理论为指导成功地改进了三溴化硼脱Ｏ－甲基方法，提出以氯甲酸－α－氯乙酯代替溴化氯以及改进的三溴化硼法作为新药纳曲酮合成中相应的方法。     

盐酸纳曲酮防复吸初步研究

用盐酸纳曲酮胶囊对１８２例海洛因依赖者脱毒后防复吸治疗，经１２个月临床观察，结果显示：１年内防复吸治疗巩固率为２７．５％。多数人在坚持服药２个月后，恶劣心境、人格扭曲、烦躁不安等精神症状改善，提示盐酸纳曲酮是一种有效的防复吸药物，它给有戒毒愿望的海洛因依赖者摆脱毒品困扰带来一线曙光     

盐酸纳曲酮有关物质的合成

为了有效控制盐酸纳曲酮的质量,该研究合成了7个有关物质：17-(1-丁烯基)-4,5-环氧-3,14-二羟基吗啡烷-6-酮(有关物质C)、双纳曲酮(有关物质D)、3-环丙甲氧基-17-(环丙甲基)-4,5-环氧-14-羟基吗啡烷-6-酮(有关物质E)、17-正丁基-4,5-环氧-3,14-二羟基吗啡烷-6-酮(有关物质H)、17-(环丙甲基)-3-甲氧基-4,5-环氧-14-羟基吗啡烷-6-酮(有关物质J)、17-(环丙甲基)-4,5-环氧-3,14-二羟基吗啡-7-烯-6-酮(有关物质K)、纳曲酮氮氧化物(有关物质L)。其中,有关物质K、L未收录进《欧洲药典》10.0中,有关物质C、D、H的合成路线未见文献报道。上述有关物质结构均经MS、¹H NMR、¹³C NMR确证。     

顶空毛细管气相色谱法测定溴化甲基纳曲酮中的残留溶剂

目的建立溴化甲基纳曲酮中有机残留溶剂的顶空毛细管气相色谱测定法。方法使用PEG-20M毛细管色谱柱(30m×0.25mm×0.25μm)进行分离;检测器为FID;进样口温度为200℃;检测器温度为250℃;柱温为35℃;顶空进样,80℃平衡40min;双蒸水为溶剂。结果有机残留溶剂能得到很好的分离,线性关系和精密度良好,平均回收率为95.1%～101.6%。结论该方法简单、准确、可靠,可用于溴化甲基纳曲酮中的残留溶剂的测定。     

溴丙胺太林杂质A的合成

目的为加强对溴丙胺太林原料药的质量控制,合成溴丙胺太林杂质A以作为对照品使用。方法以呫吨酸(3)为起始原料,采用两条合成路线合成关键中间体9-羟基丙胺太林:1)首先氧化引入羟基,然后再经过甲酯化和酯交换反应得到9-羟基丙胺太林;2)首先进行酯化反应,再经过氧化反应引入羟基得到9-羟基丙胺太林。最后经过季铵盐化反应得到终产物。结果与结论相比第一条合成路线,第二条路线更简短,收率更高。目标化合物结构经1H-NM R、13C-NM R和M S确证,HPLC检测纯度达到98%以上,合成的杂质可以作为溴丙胺太林原料药质量控制的杂质对照品。     

匹维溴铵的合成

目的研究肠易激综合征治疗药物匹维溴铵的合成工艺。方法以诺卜醇为起始原料,与4-(2-氯乙基)吗啉缩合,氢化后再与2-溴-4,5-二甲氧基溴苄反应制得目标化合物。结果以诺卜醇计三步反应总收率83.3%,目标化合物的结构经元素分析、红外、核磁共振氢谱、核磁共振碳谱、DEPT-135、HMQC和HMBC、质谱确证。结论该方法条件温和、操作简单、收率高,适合工业化生产。     

奥替溴铵的合成研究

目的研究肠易激综合征治疗药奥替溴铵的合成工艺。方法以水杨酸和正溴辛烷为原料经成酯保护、醚化及水解脱保护得到邻辛氧基苯甲酸,将其制成酰氯后与普鲁卡因缩合,再与溴甲烷反应制得目标化合物。结果与结论目标化合物的结构经IR、MS、元素分析和1H-NMR谱确证。合成工艺路线操作比文献报道的方法更简便,成本低,总收率达36.3%（以水杨酸计算）,适合工业化生产。     

Methylnaltrexone bromide for the treatment of opioid-induced constipation

Introduction: The extensive and alarming use of opioids for pain management in patients with chronic pain receiving palliative care is associated with non-tolerable gastrointestinal (GI) adverse effects. Opioid-induced constipation (OIC) is the most common adverse effect impairing patient quality of life (QOL). In addition, OIC is one of the treatment limiting consequences of opioid analgesics. Management of OIC is becoming a challenge since traditional laxatives have limited efficiency. Peripherally acting mu-opioid receptor antagonists (PAMORA) have been developed for the treatment of OIC with methylnaltrexone bromide being the first approved to treat OIC in adults with advanced illness undergoing palliative care.

Areas covered: The authors systematically review the clinical evidence for methylnaltrexone bromide including a review of the pharmacokinetic and pharmacodynamic data along with clinical effectiveness and cost-effectiveness. Though there is a need for further long-term clinical investigation, there is a large body of evidence for both its efficacy and safety in the treatment of OIC.

Expert opinion: Methylnaltrexone has both subcutaneous injection and oral dosage forms available in the market. The lack of more evidence in specific populations such as pregnant women, pediatrics and elderly still remains. The global consumption of methylnaltrexone shows a projection of increased use since its approval worldwide in 2008.     

药物中基因毒性杂质检测方法研究进展

基因毒性杂质由于对DNA的破坏作用而具有一定的致癌性,危害极大.因其结构众多,患者在服药过程中有摄入该类杂质的风险.部分国家对基因毒性杂质的限度控制已成为药品上市时必须考察的指标.本文概述了基因毒性杂质的基本概念、相关法规标准、部分杂质检测方法限度等内容,以期为控制药品中基因毒性杂质的含量提供参考和依据,保证患者用药安...     

Pharmacokinetic study of methylnaltrexone after single and multiple subcutaneous administrations in healthy Chinese subjects

1. Pharmacokinetics of methylnaltrexone (MNTX) were evaluated after subcutaneous administrations (s.c.) in healthy Chinese subjects.

2. In a cross-over single dose study, 12 subjects were given 0.075, 0.15, and 0.3?mg/kg of MNTX bromide injection. In a multiple doses study, another 12 subjects subcutaneously received 0.15?mg/kg of MNTX bromide injection every 48?h, in total five administrations. The concentrations of MNTX in plasma were quantified by LC–MS/MS.

3. After single s.c. administrations of 0.075, 0.15, and 0.3?mg/kg of MNTX bromide, C_max values of MNTX were 93.5?±?28.6, 191?±?37, and 364?±?54?ng/mL, respectively, and AUC_0–∞ were 88.8?±?8.8, 181?±?16, and 357?±?34?ng?h/mL, respectively. The t_1/2 of MNTX was about 7.7?h. After multiple doses administration, the C_max, C_av, AUC_ss, and MRT_0–∞ values were 191?±?50, 3.79?±?0.40?ng/mL, 182?±?19?ng?h/mL, and 3.56?±?1.17?h, respectively.

4. Methylnaltrexone bromide displayed dose-proportional pharmacokinetics in the dose range of 0.075–0.3?mg/kg. After multiple doses administration, t_1/2 was slightly prolonged, with the cumulative factor of 1.02. This study provides a pharmacokinetic reference after a single dose and multiple doses of MNTX bromide in Chinese subjects.     

Development and use of methylnaltrexone,a peripherally acting opioid antagonist,to treat side effects related to opioid use

Opioid medications are used extensively as potent analgesics for treating moderate to severe pain. Although opioids offer reliable pain relief, their use is associated with a number of adverse effects, especially constipation. Conventional measures for ameliorating opioid‐induced adverse effects are often insufficient. Thus, reducing the severity of these adverse effects is of utmost importance for patients who require the benefits of opioid analgesics. Since opioids mediate pain‐relieving and adverse effects through the same classes of receptors, i.e., mu, delta, and kappa, it has been challenging to dissociate beneficial effects from detrimental ones. Methylnaltrexone is the first peripherally acting opioid receptor antagonist to receive FDA approval. This compound offers the therapeutic potential to block or reverse the undesired side effects of opioids that are mediated by receptors located in the periphery (e.g., in the gastrointestinal tract), without affecting analgesia or precipitating opioid withdrawal symptoms, which are mediated predominantly by receptors in the central nervous system. This review provides a history of the development of methylnaltrexone, discusses studies that relate to opioid bowel dysfunction, and explores other uses of this compound. Drug Dev Res, 2009. © 2009 Wiley‐Liss, Inc.     

基因毒性杂质的毒理学评估策略

基因毒性杂质的限度确定是药物安全研究的重要内容.有潜在基因毒性的杂质根据其结构特征和毒理学数据可分为5类:已知有致突变性及致癌性的杂质、有致突变性但致癌性未知的杂质、含有与药物活性成分结构无关的警示结构但无致突变性数据的杂质、含与药物活性成分相关警示结构的杂质以及致癌风险高的特殊杂质.本文以毒理学评价的方法,分类对基因...