CN1907958A - 阿戈美拉汀的新晶形ⅴ、它的制备方法和包含它的药物组合物 - Google Patents
阿戈美拉汀的新晶形ⅴ、它的制备方法和包含它的药物组合物 Download PDFInfo
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Abstract
式(I)化合物的晶形V以及含有它的药物，该晶形以其粉末X射线衍射图表征。
Description
技术领域
本发明涉及阿戈美拉汀或式(I)的N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺的新晶形V：
它的制备方法以及包含它的药物组合物。
背景技术
阿戈美拉汀，或N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺，具有有价值的药理性质。
它确实具有双重的特征，一方面，它是褪黑激素能系统受体的激动剂，另一方面，它是5-HT2C受体的拮抗剂。这些性质使得它在中枢神经系统中具有活性，更特别是在严重抑郁症(severe depression)、季节性情感障碍、睡眠紊乱、心血管疾病、消化系统疾病、由时差导致的失眠和疲劳、食欲紊乱和肥胖症的治疗中有活性。
阿戈美拉汀、它的制备和它的治疗用途在欧洲专利说明书EP 0 447285中已有描述。
鉴于该化合物的药学价值，获得纯度优良、具有很确定晶形且重现性极好的该化合物是重要的，其结果是在溶出和制剂方面呈现出有价值的特性，并且足够稳定以使得它可长时间储存而没有对温度、光、湿度或氧气水平的特定要求。
专利说明书EP 0 447 285描述了阿戈美拉汀从7-甲氧基-1-四氢萘酮起始的八步制备。但是，该文件中没有具体说明以可重现方式获得呈现这些特性的阿戈美拉汀的条件。
发明内容
本申请人现已开发了新的合成方法，该方法可以以很确定的、重现性极好的晶形获得阿戈美拉汀，所述晶形在溶出和制剂方面尤其显示出有价值的特性。
更具体而言，本发明涉及式(I)化合物的晶形V，其以下列的粉末X射线衍射图表征，使用西门子D5005衍射计(铜对阴极)进行测定，以晶面间距d、布拉格2θ角、强度和相对强度(以最强射线的百分数表示)表示：
| 2θ角(°)实测值 | d(_)实测值 | 强度(％) |
| 9.8412.4013.3115.1415.9816.6217.9518.8820.4920.9923.0723.4424.2825.1026.0226.8227.51 | 8.9797.1346.6465.8485.5435.3294.9394.6974.3324.2283.8523.7923.6633.5453.4223.3223.239 | 17151918181910065243439365819151916 |
本发明还涉及式(I)化合物的晶形V的制备方法，该方法的特征在于，对阿戈美拉汀进行所谓的“高能”机械研磨。在本发明的结晶方法中，使用通过任何方法获得的式(I)化合物是可能的。
本发明还涉及式(I)化合物的晶形V的另一制备方法，该方法特征在于，加热阿戈美拉汀直至完全熔化，然后立即置于室温下并同时加入少量新制备的式(I)化合物的晶形V，冷却混合物直至结晶完成。优选在本发明的第二种结晶方法中，阿戈美拉汀在110℃熔化。在本发明的第二种方法中加入的晶形V的量优选在阿戈美拉汀重量的1/100和1/50之间。在本发明的第二种结晶方法中，使用通过任何方法获得的式(I)化合物是可能的。
获得这种晶形的优点是其允许制备具有一致且可重现组成的药物制剂，其结果是就溶出而言呈现有价值的特性，当制剂用于口服施用时这是特别有益的。
对如此获得的晶形V的药理研究已经证实它在中枢神经系统和微循环中具有重要活性，这使得阿戈美拉汀的晶形V被确立可用于治疗下列病症：紧张、睡眠紊乱、焦虑、严重抑郁症、季节性情感障碍、心血管疾病、消化系统疾病、由时差导致的失眠和疲劳、精神分裂症、恐慌发作、忧郁症、食欲紊乱、肥胖症、失眠、疼痛、精神紊乱、癫痫、糖尿病、帕金森病、老年性痴呆、与正常或病理性老化有关的各种紊乱、偏头痛、记忆丧失、阿尔茨海默病以及脑循环紊乱。在另一个活性领域，表明阿戈美拉汀的晶形V可用于治疗性功能障碍，具有排卵抑制和免疫调节的性质，并且可用于治疗癌症。
阿戈美拉汀的晶形V优选用于治疗严重抑郁症、季节性情感障碍、睡眠紊乱、心血管疾病、由时差导致的失眠和疲劳、食欲紊乱和肥胖症。
本发明还涉及包含作为活性成分的阿戈美拉汀的晶形V以及一种或多种适宜的惰性无毒赋形剂的药物组合物。在本发明的药物组合物中，可以提及的更特别是适于口服、胃肠道外(静脉内或皮下)或经鼻施用的那些，例如片剂或糖衣丸、颗粒剂、舌下片、明胶胶囊、锭剂、栓剂、乳膏剂、软膏剂、皮肤凝胶、可注射制剂、可饮用混悬剂和可崩解糊剂。
根据紊乱的性质和严重性、施用途径以及患者的年龄及体重调节有用剂量。剂量在每天0.1mg至1g之间变化，一次或多次施用。
具体实施方式
下列的实施例说明本发明，但不以任何方式限制本发明。
实施例1：N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺的晶形V
将100g N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺置于可变速高能行星磨(vario-planetary mill)型的机械研磨机中研磨约6小时，所得固体以下列的粉末X射线衍射图表征，其使用西门子D5005衍射计(铜对阴极)进行测定，并以晶面间距d、布拉格2θ角、强度和相对强度(以最强射线的百分数表示)来表示：
| 2θ角(°)实测值 | d(_)实测值 | 强度(％) |
| 9.8412.4013.3115.1415.9816.6217.9518.8820.4920.9923.0723.4424.2825.1026.0226.8227.51 | 8.9797.1346.6465.8485.5435.3294.9394.6974.3324.2283.8523.7923.6633.5453.4223.3223.239 | 17151918181910065243439365819151916 |
实施例2：N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺的晶形V
将4g N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺置于110℃的通风培养箱中。在110℃1小时后，将产品立即放置于室温下，并用0.05g通过高能机械研磨获得的在结构上是纯的N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺的晶形V。5分钟后，结晶完成，所得固体以下列的粉末X射线衍射图表征，其使用西门子D5005衍射计(铜对阴极)进行测定，并以晶面间距d、布拉格2θ角、强度和相对强度(以最强射线的百分数表示)来表示：
| 2θ角(°)实测值 | d(_)实测值 | 强度(％) |
| 9.8412.4013.3115.1415.9816.6217.9518.8820.4920.9923.0723.4424.2825.1026.0226.8227.51 | 8.9797.1346.6465.8485.5435.3294.9394.6974.3324.2283.8523.7923.6633.5453.4223.3223.239 | 17151918181910065243439365819151916 |
实施例3：药物组合物
制备1000片片剂的处方，每片含有25mg剂量：
实施例1或2的化合物………………………………………25g
乳糖一水合物…………………………………………………62g
硬脂酸镁………………………………………………………1.3g
玉米淀粉………………………………………………………26g
麦芽糖糊精合剂………………………………………………9g
无水胶体二氧化硅……………………………………………0.3g
A型淀粉羟乙酸钠……………………………………………4g
硬脂酸…………………………………………………………2.6g
实施例4：药物组合物
制备1000片片剂的处方，每片含有25mg剂量：
实施例1或2的化合物……………………………………………25g
乳糖一水合物…………………………………………………62g
硬脂酸镁………………………………………………………1.3g
聚维酮…………………………………………………………9g
无水胶体二氧化硅……………………………………………0.3g
羧甲基纤维素钠………………………………………………30g
硬脂酸…………………………………………………………2.6g。
Claims (6)
1.式(I)的阿戈美拉汀的晶形V：
以下列的粉末X射线衍射图表征，使用衍射计(铜对阴极)进行测定，并以晶面间距d、布拉格2θ角、强度和相对强度(以最强射线的百分数表示)来表示：
2θ角(°)实测值
d(_)实测值
强度(％)
9.8412.4013.3115.1415.9816.6217.9518.8820.4920.9923.0723.4424.2825.1026.0226.8227.51
8.9797.1346.6465.8485.5435.3294.9394.6974.3324.2283.8523.7923.6633.5453.4223.3223.239
17151918181910065243439365819151916
2.权利要求1的式(I)化合物的晶形V的制备方法，其特征在于对阿戈美拉汀进行所谓的“高能”机械研磨。
3.权利要求1的式(I)化合物的晶形V的制备方法，其特征在于加热阿戈美拉汀直至完全熔化，然后立即放置于室温下并同时加入少量新制备的式(I)化合物的晶形V，冷却混合物直至结晶完成。
4.药物组合物，包含作为活性成分的权利要求1的阿戈美拉汀的晶形V以及一种或多种可药用的惰性无毒载体。
5.权利要求4的药物组合物，用于制造治疗褪黑激素能紊乱的药物。
6.权利要求4的药物组合物，用于制造治疗下列病症的药物：睡眠紊乱、紧张、焦虑、季节性情感障碍或严重抑郁症、心血管疾病、消化系统疾病、由时差导致的失眠和疲劳、精神分裂症、恐慌发作、忧郁症、食欲紊乱、肥胖症、失眠、精神紊乱、癫痫、糖尿病、帕金森病、老年性痴呆、与正常或病理性老化有关的各种紊乱、偏头痛、记忆丧失、阿尔茨海默病、脑循环紊乱，性功能障碍，用作排卵抑制剂和免疫调节剂，以及癌症。
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| WO2011050742A1 (zh) * | 2009-10-29 | 2011-05-05 | 重庆医药工业研究院有限责任公司 | 阿戈美拉汀的新晶型及其制备方法 |
| MD4391C1 (ro) * | 2011-03-23 | 2016-08-31 | Hanghai Institute Of Pharmaceutical Industry | Formă cristalină nouă VII a agomelatinei, procedeu de preparare şi utilizarea acesteia, şi compoziţie farmaceutică care o conţine |
| MD4484C1 (ro) * | 2011-03-23 | 2017-12-31 | Hanghai Institute Of Pharmaceutical Industry | Forma cristalină VIII a agomelatinei, procedeu de preparare, utilizarea acesteia şi compoziţie farmaceutică care o conţine |
| CN103360275A (zh) * | 2012-03-30 | 2013-10-23 | 上海希迈医药科技有限公司 | 一种制备阿戈美拉汀ⅰ型晶体的方法 |
| CN103360275B (zh) * | 2012-03-30 | 2015-04-22 | 上海创诺制药有限公司 | 一种制备阿戈美拉汀ⅰ型晶体的方法 |
| CN113952323A (zh) * | 2021-12-10 | 2022-01-21 | 李甜 | 阿戈美拉汀在抑制Ube2c蛋白表达中的应用 |
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