CN102892749A - 阿戈美拉汀溴化氢水合物及其制备方法 - Google Patents
阿戈美拉汀溴化氢水合物及其制备方法 Download PDFInfo
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- agomelatine
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- 229960002629 agomelatine Drugs 0.000 title claims abstract description 70
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- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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Abstract
本发明涉及式(I)的阿戈美拉汀溴化氢水合物，其中X是Br，其制备方法和应用，以及包含其的药物组合物。本发明方法得到的阿戈美拉汀卤化氢水合物溶解性比阿戈美拉汀有显著提高，因而更加适合于制备药物制剂；且产品稳定性好、纯度高。制备工艺简便，无需特殊的操作，即可得到高纯度的产品。
Description
技术领域
本发明涉及阿戈美拉汀溴化氢的一种水合物、其制备方法和应用，以及包含其的药物组合物。
背景技术
阿戈美拉汀（agomelatine），化学名为N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺，其结构式如下式Ⅱ所示。其商品名为Valdoxan，是法国Servier公司研发的褪黑激素激动剂，兼有拮抗5HT2C受体作用。它是第一个褪黑激素类抗抑郁药，能有效治疗抑郁症，改善睡眠参数和保持性功能。
鉴于该化合物的药学价值，获得纯度优良、溶解度更好、具有很确定且重现性极好的化合物或复合物是相当重要的。
发明内容
本发明的目的就是提供一种阿戈美拉汀溴化氢水合物，该新的化合物溶解度高、稳定性好、纯度高，利于阿戈美拉汀做成药物制剂的实际应用。
本发明的发明人在进行阿戈美拉汀产品纯化时，惊喜的发现阿戈美拉汀能与氢溴酸混合形成物理化学性质稳定的阿戈美拉汀溴化氢水合物，所述阿戈美拉汀溴化氢水合物适用于药物制剂的制备。而使用其它常用的多种无机酸（如：硫酸、磷酸、过氯酸等）和有机酸（如：乙酸、草酸、酒石酸、富马酸等），均不易得到阿戈美拉汀溴化氢水合物或者得到的阿戈美拉汀溴化氢水合物物理化学性质不稳定。
本发明提供的阿戈美拉汀溴化氢水合物，如下式（I）所示：
其中X为Br。
本发明的另一目的是提供上述阿戈美拉汀溴化氢水合物的制备方法，该方法是将阿戈美拉汀与各种形式的HBr反应形成阿戈美拉汀溴化氢水合物。具体步骤可为两种：先将阿戈美拉汀溶解于含水有机溶剂，然后通入HBr气体，再将结晶析出的固体洗涤、干燥；或者将阿戈美拉汀加入到含有HBr的溶剂中，再将结晶析出的固体洗涤、干燥。经过多次的实验，本发明的发明人发现，如果使用第一种方法通入HBr过多反而会造成收率降低，而第二种方法对于溶剂中HBr的量则容易控制，所以优选第二种方法。
其中，也可以将阿戈美拉汀加入到含水的有机溶剂中，再滴加含HBr的溶剂，再将结晶析出的固体洗涤、干燥。
或者，也可以将阿戈美拉汀加入到有机溶剂中，再滴加HBr水溶液，再将结晶析出的固体洗涤、干燥。
本制备方法的反应温度可以是本领域反应时的常见温度，只要低于溶剂的沸点即可，但为了提高反应收率，反应温度为室温或室温以下，较佳的为室温以下，更佳的为0-20℃。
上述阿戈美拉汀溴化氢水合物的制备方法，其有机溶剂的选择没有特别限制，只要能够溶解反应原料阿戈美拉汀及HBr，同时又能使阿戈美拉汀溴化氢水合物析出即可。可使用的有机溶剂包括：乙酸乙酯、乙酸甲酯、乙酸正丁酯、丙酮、乙腈等，优选乙酸乙酯。而如极性较高的有机溶剂，如醇类（乙醇、甲醇等）、DMF、DMSO等都不太合适。
本发明的有益效果：本发明人在众多常用酸中发现阿戈美拉汀能与溴化氢反应生产稳定的阿戈美拉汀溴化氢水合物，且无论是在稳定性、溶解度、吸湿性等物理性质，还是制备难度上均显著优于其它的常用酸与阿戈美拉汀的反应产物。
本发明制备的阿戈美拉汀溴化氢水合物，溶解性比阿戈美拉汀有显著提高，因而更加适合于制备药物制剂；且产品稳定性好、纯度高、溶解度好。在制备工艺上也非常简便，无需特殊的操作，即可得到高纯度的产品。
所述阿戈美拉汀溴化氢水合物的药理研究结果显示，其可用于治疗褪黑素能系统疾病，睡眠障碍、紧张、焦虑症、季节性情感障碍、严重抑郁症、心血管疾病、消化系统疾病、飞行时差引起的失眠或疲劳、精神分裂症、恐惧症或抑郁症。
本发明还提供了药物组合物，其包含本发明的阿戈美拉汀溴化氢水合物以及可药用辅料或赋形剂。
所述药物组合物可被配制以用于各种施用途径，尤其是用于口服或注射施用。
可根据待治疗疾病的性质和严重性、施用途径以及患者的年龄及体重调节有用剂量。日剂量为0.1mg至1g，且可分一次或多次施用。
附图简述
为能更清楚理解本发明的目的、特点和优点，以下将结合附图对本发明的较佳实施例进行详细描述，其中：
图1为本发明实施例1产物进行热重分析的TGA曲线图；
图2为本发明单晶分子立体结构投影图；以及
图3为本发明阿戈美拉汀溴化氢水合物的晶胞堆积投影图。
实施例
实施例1
将1g阿戈美拉汀搅拌溶解于10ml乙酸乙酯中，10℃条件下逐滴加入HBr水溶液（0.92g，40%），搅拌1个小时；过滤，固体用乙酸乙酯1ml洗涤两次，40℃下干燥得到白色固体1.1g；纯度：99.6%，收率：78.2%。
分析结果（C15H17NO2·HBr·H2O）
理论计算值：Br含量为23.35wt%
实测值：Br含量为23.27wt%
熔点：88-90℃
实施例2
将10g阿戈美拉汀搅拌溶解于100ml乙酸乙酯中，低温下逐滴加入HBr水溶液（8.32g，40%），搅拌1个小时；过滤，固体用乙酸乙酯10ml洗涤两次，40℃下干燥得到白色固体11.2g；纯度：99.7%，收率：84%。
分析结果（C15H17NO2·HBr·H2O）
计算值：Br%（23.35%）
实测值：Br%（23.19%）
熔点：87-89℃
实施例3
将1g阿戈美拉汀搅拌溶解于10ml乙酸乙酯中，室温下逐滴滴入浓硫酸，始终无沉淀析出。
实施例4
将1g阿戈美拉汀搅拌溶解于10ml乙酸乙酯中，在-10℃逐滴滴入浓硫酸，始终无沉淀析出。
实施例5
将1g阿戈美拉汀搅拌溶解于10ml乙酸乙酯中，在-10℃逐滴滴入冰醋酸，始终无沉淀析出。
实施例6
将1g阿戈美拉汀搅拌溶解于10ml乙酸乙酯中，在-10℃逐滴滴入富马酸，始终无沉淀析出。
实施例7
将100g阿戈美拉汀搅拌溶解于800ml乙酸乙酯中，低温下逐滴加入HBr水溶液（84g，40%），搅拌1个小时；过滤，固体用乙酸乙酯100ml洗涤两次，40℃下干燥得到白色固体120g；纯度：99.9%，收率：85.3%。
分析结果（C15H17NO2·HBr·H2O）
计算值：Br%（23.35%）
实测值：Br%（23.21%）
熔点：88-90℃
上述实施例中所用的阿戈美拉汀为市售可得，或者也可以按照现有的制备方法制得。
实施例8：药物组合物
检测方法及其结果
1、样品纯度测定
色谱条件：用十八烷基硅烷键合硅胶为填充剂；以10mM/L磷酸缓冲盐（用氢氧化钠调节pH至7.0）和乙腈体积比为2：7的混合溶液作为流动相；柱温为40℃；检测波长为220nm。分别取实施例1和实施例2产物，通过内标法测定纯度。
用流动相分别配置成1mg/mL的溶液，各取10μL注入液相色谱仪，记录色谱图，所得纯度结果如上述实施例1和实施例2所示。
2、样品稳定性测定
取实施例1产物若干放入40℃的恒温箱中，放置30天，通过高效液相色谱法对这些晶型的稳定性进行研究，结果如下表1：
表1
| 实施例1产物 | 0天 | 5天 | 10天 | 30天 |
| AG·HBr·H2O | 99.7% | 99.7% | 99.6% | 99.6% |
其中，AG代表阿戈美拉汀C15H17NO2。
3、水溶性测定
测定方法采用HPLC方法，取实施例1产物用外标法进行测定，并与阿戈美拉汀晶型II进行比较，结果如下表2：
表2
可见，本发明的阿戈美拉汀溴化氢水合物不论在水中，还是在与人体胃液环境接近的0.1N HCl，或者pH为7.0的缓冲盐溶液中，其溶解度都要比阿戈美拉汀好，也就是说其具有较好生物利用度的潜力。
4、结晶水含量测定
根据计算得C15H17NO2·HBr·H2O中结晶水的理论含量为5.26wt%。
4.1费休氏法（《中国药典》2010版附录VIII M）
取实施例1产物按照所述费休氏法测试，实测结晶水含量：5.10wt%
取实施例7产物按照所述费休氏法测试，实测结晶水含量：5.25wt%
4.2热重分析（《中国药典》2010版附录VIII Q）
取实施例1产物按照所述热分析法测试，测得结晶水损失量5.70wt%，即原产物中含有结晶水5.70wt%，TGA曲线请参见图1。
TGA方法的测试条件如下：
仪器型号NETZSCH TG 209F1
坩埚类型：Al2O3
吹扫气：N2 20ml/分钟；
保护气：N2 10ml/分钟。
温度范围：室温~300℃
升温速率：10℃/分钟
5、晶体结构分析
5.1衍射实验
晶体制备：将含有阿戈美拉汀溴化氢水合物的甲醇的饱和溶液自然析晶，挑选出实验所用晶体。
衍射实验用晶体呈白色透明块状，晶体大小为0.10×0.20×0.40mm，晶体属单斜晶系，空间群为P21/c，晶胞参数：a＝7.5943(7)，b＝23.4046(19)，
β＝1613.9(2)°，晶胞体积
晶胞内分子数Z＝4。
用Bruker SMART APEX-II衍射仪收集衍射强度数据，CuKα辐射，石墨单色器，单导管直径Ф＝0.50mm，晶体与CCD探测器距离d＝60.3mm，管压40kV，管流30mA，扫描方式：Ф/ω扫描，收集独立衍射点为2154个，可观察点(|F|2≥2σ|F|2)为2074个。
5.2结构解析
采用直接法(Shelxs97)解析晶体结构，从E图上获得全部20个非氢原子位置，使用最小二乘法修正结构参数和判别原子种类，使用几何计算法和差值Fourier法获得全部氢原子位置，最终可靠因子R1＝0.0302，wR2＝0.0868(w＝1/σ|F|2)，S＝1.092。最终确定1个不对称单位内化学计量式为C15H17O2N·HBr·H2O，计算晶体密度为1.404g/cm3。
分子立体结构投影图请参阅图2，晶胞堆积投影图请参阅图3。
6、阿戈美拉汀溴化氢水合物稳定性测定
测定方法采用中国药典中稳定性考核方法
1）影响因素实验（敞口10天）：高温（60℃），光照（4500lx），高湿（92.5%RH在25℃）
2）加速实验（密闭6个月）：温度为40℃，湿度为75%RH
3）长期实验（密闭9个月）：温度为25℃，湿度为60%RH
结果如下表3
表3
可见在稳定性考察中，阿戈美拉汀溴化氢复合物是稳定的，利于制剂方面的应用。
Claims (13)
1.式I所示的阿戈美拉汀溴化氢水合物：
其中X为Br。
2.结晶形式的权利要求1所述的阿戈美拉汀溴化氢水合物，其具有以下晶体参数：空间群为P21/c，晶胞参数：a＝7.5943(7)，b＝23.4046(19)，
β＝1613.9(2)°。
3.权利要求1或2所述的阿戈美拉汀溴化氢水合物的制备方法，其中，将阿戈美拉汀与HBr反应形成所述阿戈美拉汀溴化氢水合物。
4.根据权利要求3所述的阿戈美拉汀溴化氢水合物的制备方法，其中，将阿戈美拉汀与HBr在含水有机溶剂中反应形成所述阿戈美拉汀溴化氢水合物。
5.根据权利要求4所述的阿戈美拉汀溴化氢水合物的制备方法，其中，将阿戈美拉汀溶解于有机溶剂，然后加入HBr水溶液，从而析出产物的结晶。
6.根据权利要求5所述的阿戈美拉汀溴化氢水合物的制备方法，其中，采用滴加的方式加入HBr水溶液。
7.根据权利要求4所述的阿戈美拉汀溴化氢水合物的制备方法，其中，将阿戈美拉汀加入到含有HBr的含水有机溶剂中，从而析出产物的结晶。
8.根据权利要求5或7所述的阿戈美拉汀溴化氢水合物的制备方法，其还包括：结晶析出后将固体洗涤、干燥。
9.根据权利要求5或7所述的阿戈美拉汀溴化氢水合物的制备方法，其中，所述反应的反应温度为0-20℃。
10.根据权利要求5或7所述的阿戈美拉汀溴化氢水合物的制备方法，其中，所述有机溶剂为乙酸乙酯、乙酸甲酯、乙酸正丁酯、丙酮或乙腈。
11.根据权利要求10所述的阿戈美拉汀溴化氢水合物的制备方法，其中，所述有机溶剂为乙酸乙酯。
12.药物组合物，其包含根据权利要求1或2所述的阿戈美拉汀溴化氢水合物和可药用的辅料或赋形剂。
13.权利要求1或2所述的阿戈美拉汀溴化氢水合物用于治疗褪黑素能系统疾病，睡眠障碍、紧张、焦虑症、季节性情感障碍、严重抑郁症、心血管疾病、消化系统疾病、飞行时差引起的失眠或疲劳、精神分裂症、恐惧症或抑郁症的应用。
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