WO2010097052A1 - 阿戈美拉汀卤化氢复合物及其制备方法 - Google Patents

阿戈美拉汀卤化氢复合物及其制备方法 Download PDF

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Publication number
WO2010097052A1
WO2010097052A1 PCT/CN2010/070780 CN2010070780W WO2010097052A1 WO 2010097052 A1 WO2010097052 A1 WO 2010097052A1 CN 2010070780 W CN2010070780 W CN 2010070780W WO 2010097052 A1 WO2010097052 A1 WO 2010097052A1
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agomelatine
preparation
ethyl acetate
complex
hydrogen halide
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French (fr)
Inventor
张鹏
单汉滨
袁哲东
蒋旭东
黄雨
王胡博
曹旭峰
程兴栋
潘红娟
俞雄
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Shanghai Institute of Pharmaceutical Industry
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Shanghai Institute of Pharmaceutical Industry
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Priority to BRPI1008767-2A priority Critical patent/BRPI1008767B1/pt
Priority to EA201101208A priority patent/EA021939B1/ru
Priority to KR1020117021812A priority patent/KR101284202B1/ko
Priority to RS20150040A priority patent/RS53751B1/sr
Priority to EP10745836.6A priority patent/EP2418195B1/en
Priority to PL10745836T priority patent/PL2418195T3/pl
Priority to UAA201111232A priority patent/UA97619C2/ru
Priority to AP2011005845A priority patent/AP3048A/xx
Priority to SG2011058542A priority patent/SG173691A1/en
Priority to ES10745836T priority patent/ES2530730T3/es
Priority to HRP20150072AT priority patent/HRP20150072T1/hr
Priority to DK10745836T priority patent/DK2418195T3/en
Priority to US13/138,511 priority patent/US8524949B2/en
Priority to SI201030872T priority patent/SI2418195T1/sl
Priority to JP2011551399A priority patent/JP5426693B2/ja
Priority to NZ594773A priority patent/NZ594773A/xx
Priority to CA2753449A priority patent/CA2753449C/en
Priority to MA34120A priority patent/MA33063B1/fr
Priority to MX2011008946A priority patent/MX2011008946A/es
Priority to AU2010217082A priority patent/AU2010217082B2/en
Application filed by Shanghai Institute of Pharmaceutical Industry filed Critical Shanghai Institute of Pharmaceutical Industry
Publication of WO2010097052A1 publication Critical patent/WO2010097052A1/zh
Priority to IL214682A priority patent/IL214682A/en
Priority to ZA2011/06048A priority patent/ZA201106048B/en
Priority to TN2011000425A priority patent/TN2011000425A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B7/00—Halogens; Halogen acids
    • C01B7/01—Chlorine; Hydrogen chloride
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B7/00—Halogens; Halogen acids
    • C01B7/09—Bromine; Hydrogen bromide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups

Definitions

  • the invention relates to a composite of agomelatine and a technical field thereof.
  • Agomelatine (1) chemical name N-[2-(7-methoxyl_naphthyl)ethyl]acetamide, has the structural formula shown below in Formula II. Its trade name is Valdoxan, a melatonin agonist developed by Servier of France, which acts as an antagonist of 5HT2C receptor. It is the first melatonin antidepressant that is effective in treating depression, improving sleep parameters and maintaining sexual function.
  • the object of the present invention is to provide a agomelatine hydrogen halide complex which has high solubility, good stability and high purity, and is advantageous for the practical application of agomelatine as a pharmaceutical preparation.
  • Another object of the present invention is to provide a process for the preparation of the above-mentioned agomelatine hydrogen halide complex.
  • agomelatine can be mixed with a mineral acid such as hydrochloric acid, hydrobromic acid or hydroiodic acid to form a physicochemically stable complex.
  • This complex is suitable for the preparation of pharmaceutical preparations.
  • other commonly used inorganic acids such as: sulfuric acid, phosphoric acid, perchloric acid, etc.
  • organic acids such as acetic acid, oxalic acid, tartaric acid, fumaric acid, etc.
  • agomelatine hydrogen halide complex is represented by the following formula:
  • X represents halogen.
  • X is preferably C1 or Br.
  • a method for preparing a agomelatine hydrogen halide complex by reacting agomelatine with various forms of HX to form a complex may be first dissolved in an organic solvent, and then the HX gas is introduced to wash and dry the crystallized solid; or the agomelatine may be added to the organic solution containing HX. After crystallization, it is washed and dried. The control of the HX concentration is based on the requirement that the precipitated complex be the lowest concentration. After many times of experimental results, the yield of agomelatine hydrochloride complex precipitated in ethyl acetate is relatively high, so the most preferred method is to add agomelatine to ethyl acetate and crystallize it. After washing and drying, the target product is obtained.
  • the preparation method of the above-mentioned agomelatine hydrogen halide complex has no particular limitation on the selection of the organic solvent, as long as it can dissolve the reaction raw material agomelatine and hydrogen halide, and at the same time, can make the agomelatine hydrogen halide complex.
  • the matter can be precipitated.
  • Solvents which may be used include: ethyl acetate, methyl acetate, n-butyl acetate, acetone, acetonitrile and the like, preferably ethyl acetate. Solvents with lower polarity, such as alcohols (ethanol, methanol, etc.), DMF, DMS0, etc., are not suitable.
  • agomelatine can only react with hydrohalic acid to produce a stable complex in many common acids, and is superior to other physical properties in stability, solubility, hygroscopicity and the difficulty of preparation.
  • the reaction product of a common acid with agomelatine is superior to other physical properties in stability, solubility, hygroscopicity and the difficulty of preparation.
  • the agomelatine hydrogen halide complex prepared by the invention has a significantly higher solubility than agomelatine, and is suitable for the application of the finished pharmaceutical preparation; and the product has good stability and high purity. It is also very simple in the preparation process, and it can be obtained with high purity without special operation.
  • Og agomelatine was stirred and dissolved in 10 ml of ethyl acetate, and dry hydrogen chloride gas was slowly introduced at room temperature until the solution was no longer weighted, filtered, and the solid was washed with ethyl acetate 2 ml * 2 at 30 ° C 7% ⁇ Purification to give a white solid 1. 05g; purity: 99. 7%.
  • Og agomelatine was stirred and dissolved in 30 ml of ethyl acetate, and dried at room temperature. The hydrogen chloride gas was dried until the solution was no longer weight-increased, filtered, and the solid was washed with ethyl acetate 5 ml*2 and dried at 30 ° C to give a white solid 3.2 g; purity: 99.8%.
  • agomelatine 10 g was added to a saturated solution of 100 ml of ethyl hydrogen chloride, and stirred at room temperature for 1 h, filtered, and the solid was washed with ethyl acetate 10 ml*2, and dried at 30 ° C to give a white solid 10.9 g; purity: 99.8 %.
  • the lg agomelatine was dissolved and dissolved in 10 ml of ethyl acetate, and concentrated sulfuric acid was added dropwise at room temperature, and no precipitate was precipitated at all times.
  • the lg agomelatine was dissolved and dissolved in 10 ml of ethyl acetate, and concentrated sulfuric acid was added dropwise at -10 °C, and no precipitation was observed at all.
  • the lg agomelatine was dissolved and dissolved in 10 ml of ethyl acetate, and glacial acetic acid was added dropwise at -10 °C, and no precipitation was observed at all.
  • the hydrogen chloride and hydrogen bromide complexes of agomelatine were placed in an incubator at 40 ° C for 30 days, and the stability of these crystal forms was investigated by high performance liquid chromatography.
  • Chromatographic conditions using octadecyl silicon germanium bonded silica as a filler; a mixed solution of 10 mM / L phosphate buffer salt (pH adjusted to 7.0 with sodium hydroxide) and acetonitrile volume ratio of 2: 7 as mobile phase
  • the column temperature is 40 ° C; the detection wavelength is 220 nm.
  • the purity was determined by an internal standard method.
  • the solution was set to a lmg/mL solution with a mobile phase, and 10 ⁇ L of each solution was injected into the liquid chromatograph to record the chromatogram.
  • the measurement method is determined by the method of measuring the purity of the sample by an external standard method. The results are as shown in Table 1 below:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

阿戈美拉汀卤化氢复合物及其制备方法 技术领域
本发明涉及阿戈美拉汀的一种复合物及其制备方法技术领域。
阿戈美拉汀 ( agomelatine, 1 )， 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。
Figure imgf000002_0001
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及其重要的。 发明概要
本发明的目的就是提供一种阿戈美拉汀卤化氢复合物，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。
本发明的另一目的是提供上述阿戈美拉汀卤化氢复合物的制备 方法。 本申请的发明人在进行阿戈美拉汀产品纯化时，惊喜的发现阿戈 美拉汀能与如下的无机酸， 如盐酸、氢溴酸或氢碘酸混合形成物理化 学性质稳定的复合物， 此复合物适用于药物制剂的制备。使用其它常 用的多种无机酸（如： 硫酸、 磷酸、 过氯酸等）或有机酸（如： 乙酸、 草酸、 酒石酸、 富马酸等）， 均不易得到复合物。
上述的阿戈美拉汀卤化氢复合物， 如下式所示：
Figure imgf000003_0001
其中 X代表卤素。 X优选 C1或 Br。
阿戈美拉汀卤化氢复合物的制备方法，该方法是将阿戈美拉汀与 各种形式的 HX反应形成复合物。 具体操作时， 既可以先将阿戈美拉 汀溶解于有机溶剂， 然后通入 HX气体， 将结晶析出的固体洗涤、 干 燥； 也可以是将阿戈美拉汀加入到含有 HX的有机溶液中， 结晶析出 后洗涤、 干燥。 HX浓度的控制是以能析出复合物为最低浓度要求为 准。经过多次的实验结果比较， 盐酸乙酸乙酯中析出的阿戈美拉汀盐 酸复合物收率比较高，所以最优选的方法是将阿戈美拉汀加入到盐酸 乙酸乙酯中， 结晶析出后洗涤、 干燥得到目标产物。
上述阿戈美拉汀卤化氢复合物的制备方法，其有机溶剂的选择没 有特别限制， 只要是能够溶解反应原料阿戈美拉汀及卤化氢， 同时又 能使阿戈美拉汀卤化氢复合物析出即可。可使用的溶剂包括： 乙酸乙 酯、 乙酸甲酯、 乙酸正丁酯、 丙酮、 乙腈等， 优选乙酸乙酯。 像极性 较低的溶剂， 如醇类 （乙醇， 甲醇等）、 DMF、 DMS0等都不太合适。 本发明的有益效果：
本发明在众多常用酸中发现阿戈美拉汀仅能与氢卤酸反应生产 稳定的复合物， 且无论是在稳定性、 溶解度、 吸湿性等物理性质， 以 及制取难度上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卤化氢复合物，溶解性比阿戈美拉汀有 显著提高， 适合成品药物制剂时的应用需要； 且产品稳定性好、 纯度 高。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 广叩
发明内容
下面通过几个优选的具体实施例进一歩说明本发明，对于实施例 中涉及的具体数据和操作等并不构成本发明要求保护范围的限制。
实施例 1：
将 1. Og阿戈美拉汀搅拌溶解于 10ml乙酸乙酯中，室温下缓慢通 入干燥的氯化氢气体直至溶液不再增重，过滤，固体用乙酸乙酯 2ml*2 洗涤， 30°C下干燥得到白色固体 1. 05g; 纯度： 99. 7%。
分析结果 (C15H17N02 - HC1 )
计算值： C1 % ( 12. 69%)
实测值： C1 % ( 12. 44%)
熔点： 64- 66°C
实施例 2:
将 3. Og阿戈美拉汀搅拌溶解于 30ml乙酸乙酯中，室温下通入干 燥的氯化氢气体直至溶液不再增重， 过滤，固体用乙酸乙酯 5ml*2洗 涤， 30°C下干燥得到白色固体 3.2g; 纯度： 99.8%。
分析结果 (C15H17N02 - HC1)
计算值： C1 % (12.69%)
实测值： C1 % (12.60%)
熔点： 64- 66°C
实施例 3:
将 10g阿戈美拉汀搅拌溶解于 100ml乙酸乙酯中，室温下通入干 燥的氯化氢气体直至溶液不再增重，过滤，固体用乙酸乙酯 10ml*2洗 涤， 30°C下干燥得到白色固体 10.8g。
分析结果 (C15H17N02 · HC1); 纯度： 99.8%
计算值： C1 % (12.69%)
实测值： C1 % (12.21%)
熔点： 64- 66°C
实施例 4:
将 10g阿戈美拉汀加入到饱和的 100ml氯化氢乙酸乙酯溶液中， 室温下搅拌 lh， 过滤， 固体用乙酸乙酯 10ml*2洗涤， 30°C下干燥得 到白色固体 10.9g; 纯度： 99.8%。
分析结果 (C15H17N02 - HC1)
计算值： C1 % (12.69%)
实测值： C1 % (12.39%)
熔点： 64- 66°C 根据专利 CN1680284A制备阿戈美拉汀的方法， 将 17.3g 2- (7- 甲氧基 -1-萘基） 乙胺盐酸盐和 6.6g 乙酸钠的乙醇溶液加入反应器 中， 搅拌混合物， 然后加入 7.9g乙酸酐。 对反应混合物加热回流， 加入 60ml水。 将反应混合物回复至室温， 滤出所获沉淀物， 母液用 20ml X3乙酸乙酯萃取， 蒸干溶剂， 所获固体搅拌溶解于 100ml乙酸 乙酯中， 室温下通入干燥的氯化氢气体直至溶液不再增重， 过滤，固 体用乙酸乙酯 10ml*2洗涤， 30°C下干燥得到白色固体 18.5g。
收率： 91%, 纯度： 99.1%。
分析结果 (C15H17N02-HC1)
计算值： C1 % (12.69%)
实测值： C1 % (12.57%)
熔点： 64- 66°C
实施例 6:
根据专利 CN1680284A制备阿戈美拉汀的方法， 将 17.3g 2- (7- 甲氧基 -1-萘基） 乙胺盐酸盐和 6.6g 乙酸钠的乙醇溶液加入反应器 中， 搅拌混合物， 然后加入 7.9g乙酸酐。 对反应混合物加热回流， 加入 60ml水。 将反应混合物回复至室温， 滤出所获沉淀物， 母液用 20mlX3乙酸乙酯萃取， 蒸干溶剂， 所获固体加入到 100ml饱和氯化 氢乙酸乙酯溶液中， 室温下搅拌 lh， 过滤， 固体用乙酸乙酯 10ml*2 洗涤， 30°C下干燥得到白色固体 18.7g， 收率： 92%, 纯度： 99.8%。
分析结果 (C15H17N02-HC1) 计算值： CI % ( 12. 69%)
实测值： C1 % ( 12. 70%)
熔点： 64- 66°C
实施例 7:
将 10g阿戈美拉汀搅拌溶解于 100ml乙酸乙酯中，室温下干燥的 溴化氢气体直至溶液不再增重， 过滤，固体用乙酸乙酯 10ml*2洗涤， 30°C下干燥得到白色固体 11. 2g; 纯度： 99. 3%。
分析结果 （C15H17N02 · HBr)
计算值： Br% (24. 6%)
实测值： Br% (23. 8%)
熔点： 85-87 °C
实施例 8:
将 lg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 9:
将 lg阿戈美拉汀搅拌溶解于 10ml乙酸乙酯中， 在 -10度下逐滴 滴入浓硫酸， 始终无沉淀析出。
实施例 10
将 lg阿戈美拉汀搅拌溶解于 10ml乙酸乙酯中， 在 -10度下逐滴 滴入冰醋酸， 始终无沉淀析出。
实施例 11
将 lg阿戈美拉汀搅拌溶解于 10ml乙酸乙酯中， 在 -10度下逐滴 滴入富马酸， 始终无沉淀析出。
测试方法：
分别将阿戈美拉汀的氯化氢和溴化氢复合物放入 40°C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。
1、 样品纯度测定
色谱条件： 用十八垸基硅垸键合硅胶为填充剂； 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°C ; 检测波长为 220nm。 通过内标法测定纯度。
用流动相分别配置成 lmg/mL的溶液，各取 10 μ L注入液相色谱仪， 记录色谱图。
2、 样品含量测定
测定方法参考样品纯度测定的方法， 用外标法进行测定。结果如 下表 1 :
Figure imgf000008_0001
Figure imgf000008_0002
3、 水溶性测定
测定方法采用 HPLC方法， 用外标法进行测定。 结果如下表 2 : 阿戈美拉汀 阿戈美拉汀 样品名称 阿戈美拉汀
HBr复合物 HC1复合物 纯度 99. 79% 99. 77% 99. 82%
、)Q*用午 1*
1. 11 2. 14 1. 60
(mg/ml )

Claims

权利要求
Figure imgf000010_0001
其中 X代表卤素。
2. 如权利要求 1 所述的阿戈美拉汀卤化氢复合物， 其特征在于： X 为 C1或 Br。
3. 权利要求 1或 2所述阿戈美拉汀卤化氢复合物的制备方法， 该方 法是将阿戈美拉汀与各种形式的 HX反应形成复合物。
4. 如权利要求 3所述阿戈美拉汀卤化氢复合物的制备方法， 其特征 在于： 先将阿戈美拉汀溶解于有机溶剂， 然后通入 HX气体， 结晶 析出。
5. 如权利要求 3所述阿戈美拉汀卤化氢复合物的制备方法， 其特征 在于： 将阿戈美拉汀加入到含有 HX的有机溶液中， 结晶析出。
6. 如权利要求 4所述阿戈美拉汀卤化氢复合物的制备方法， 其特征 在于： 通入 HX气体直至饱和。
PCT/CN2010/070780 2009-02-27 2010-02-26 阿戈美拉汀卤化氢复合物及其制备方法 Ceased WO2010097052A1 (zh)

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EA201101208A EA021939B1 (ru) 2009-02-27 2010-02-26 Гидрогалогенидный комплекс агомелатина и его получение
US13/138,511 US8524949B2 (en) 2009-02-27 2010-02-26 Agomelatine hydrohalide complex and preparation method thereof
KR1020117021812A KR101284202B1 (ko) 2009-02-27 2010-02-26 아고멜라틴 할로겐산염 복합체 및 이의 제조 방법
RS20150040A RS53751B1 (sr) 2009-02-27 2010-02-26 Agomelatin hidrohalidni kompleks i postupak njegove izrade
EP10745836.6A EP2418195B1 (en) 2009-02-27 2010-02-26 Agomelatine hydrohalide complex and preparation method thereof
PL10745836T PL2418195T3 (pl) 2009-02-27 2010-02-26 Kompleks halogenowodorowy agomelatyny i sposób jego wytwarzania
UAA201111232A UA97619C2 (ru) 2009-02-27 2010-02-26 Гидрогалогенидный комплекс агомелатина и способ его получения
AP2011005845A AP3048A (en) 2009-02-27 2010-02-26 Agomelatine hydrohalide complex and preparation method thereof
SG2011058542A SG173691A1 (en) 2009-02-27 2010-02-26 Agomelatine hydrohalide complex and preparation method thereof
ES10745836T ES2530730T3 (es) 2009-02-27 2010-02-26 Complejo hidrohalogenuro-agomelatina y preparación del mismo
HRP20150072AT HRP20150072T1 (xx) 2009-02-27 2010-02-26 Agomelatin halogenovodik kompleks i postupak njegove priprave
JP2011551399A JP5426693B2 (ja) 2009-02-27 2010-02-26 アゴメラチンハロゲン化水素複合体及びその製造方法
SI201030872T SI2418195T1 (sl) 2009-02-27 2010-02-26 Agomelatin halogenovodikov kompleks in njegov postopek priprave
BRPI1008767-2A BRPI1008767B1 (pt) 2009-02-27 2010-02-26 Complexo de haleto de hidrogênio de agomelatina e preparação do mesmo
DK10745836T DK2418195T3 (en) 2009-02-27 2010-02-26 Agomelatinhydrogenhalogenidkompleks and manufacturing method thereof
NZ594773A NZ594773A (en) 2009-02-27 2010-02-26 Agomelatine hydrohalide complex and preparation method thereof
CA2753449A CA2753449C (en) 2009-02-27 2010-02-26 Agomelatine hydrohalide complex and preparation method thereof
MA34120A MA33063B1 (fr) 2009-02-27 2010-02-26 Complexe d'hydrohalogenure d'agomelatine et procede de preparation de celui-ci
MX2011008946A MX2011008946A (es) 2009-02-27 2010-02-26 Un complejo de haluro de hidrogeno de agomelatina y la preparacion del mismo.
AU2010217082A AU2010217082B2 (en) 2009-02-27 2010-02-26 Agomelatine hydrohalide complex and preparation method thereof
IL214682A IL214682A (en) 2009-02-27 2011-08-16 Agomalatine hydrohydric linkage and method of preparation thereof
ZA2011/06048A ZA201106048B (en) 2009-02-27 2011-08-17 Agomelatine hydrohalide complex and preparation method thereof
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EP2556824A1 (fr) 2011-08-10 2013-02-13 Les Laboratoires Servier Composition pharmaceutique solide pour administration buccale d'agomelatine
WO2014122405A1 (fr) 2013-02-08 2014-08-14 Les Laboratoires Servier Composition pharmaceutique solide pour l'administration buccale d'agomélatine
JP2014522388A (ja) * 2011-04-28 2014-09-04 ゼンティーバ，カー．エス． Ｎ‐［２‐（７‐メトキシ‐１‐ナフチル）エチル］アセトアミドの医薬的に許容される共結晶及びそれらの調製方法

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CN102190595A (zh) 2010-03-17 2011-09-21 上海医药工业研究院 阿戈美拉汀溴化氢水合物及其制备方法
CN101870662B (zh) * 2010-05-21 2013-03-20 中山大学 结晶型阿戈美拉汀溶剂化物及其制备方法
EP2551257A1 (en) * 2011-07-28 2013-01-30 Laboratorios Del. Dr. Esteve, S.A. Co-crystals of agomelatine with co-crystal-formers
CN102702041B (zh) * 2012-05-14 2013-08-14 上海右手医药科技开发有限公司 阿戈美拉汀苯磺酸类复合物及其制备方法
KR20150020191A (ko) 2012-05-14 2015-02-25 상하이 라이트핸드 팜테크 주식회사 아고멜라틴 산기 복합체와 그의 제조방법 및 용도
CN102718675B (zh) * 2012-06-07 2015-03-25 上海右手医药科技开发有限公司 阿戈美拉汀甲磺酸复合物及其制备方法
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EP2934502A1 (en) 2012-12-21 2015-10-28 Laboratorios Lesvi S.L. Process for prepararing n-(2-(7-methoxy-1-naphthalenyl)ethyl) acetamide and solid forms thereof
HUE049928T2 (hu) * 2013-07-29 2020-11-30 Servier Lab Agomelatin és szulfonsavak komplexei, eljárás elõállításukra, és ezeket tartalmazó gyógyszerészeti készítmények
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012046253A3 (en) * 2010-10-08 2012-05-31 Msn Laboratories Limited Process for preparation of n-[2-(7-methoxy-1-naphtityl)ethyl] acetamide and its novel crystalline forms
JP2014522388A (ja) * 2011-04-28 2014-09-04 ゼンティーバ，カー．エス． Ｎ‐［２‐（７‐メトキシ‐１‐ナフチル）エチル］アセトアミドの医薬的に許容される共結晶及びそれらの調製方法
EP2556824A1 (fr) 2011-08-10 2013-02-13 Les Laboratoires Servier Composition pharmaceutique solide pour administration buccale d'agomelatine
WO2013021139A1 (fr) 2011-08-10 2013-02-14 Les Laboratoires Servier Composition pharmaceutique solide pour administration buccale d'agomelatine
WO2014122405A1 (fr) 2013-02-08 2014-08-14 Les Laboratoires Servier Composition pharmaceutique solide pour l'administration buccale d'agomélatine

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IL214682A0 (en) 2011-11-30
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JP5426693B2 (ja) 2014-02-26
AU2010217082A1 (en) 2011-09-08
IL214682A (en) 2015-10-29
HRP20150072T1 (xx) 2015-03-13
US20110313198A1 (en) 2011-12-22
SI2418195T1 (sl) 2015-03-31
BRPI1008767A2 (pt) 2016-06-28
NI201100163A (es) 2011-12-12
MA33063B1 (fr) 2012-02-01
EA201101208A1 (ru) 2012-04-30
PL2418195T3 (pl) 2015-04-30
BRPI1008767B1 (pt) 2021-06-15
CN101481321B (zh) 2012-04-18
DK2418195T3 (en) 2015-03-02
CA2753449C (en) 2014-01-07
MX2011008946A (es) 2011-09-27
CY1117100T1 (el) 2017-04-05
GEP20156221B (en) 2015-01-26
MY154015A (en) 2015-04-30
PE20120652A1 (es) 2012-06-14
CU20110163A7 (es) 2012-02-15
KR101284202B1 (ko) 2013-07-09
EA021939B1 (ru) 2015-10-30
SG173691A1 (en) 2011-09-29
CA2753449A1 (en) 2010-09-02
AP3048A (en) 2014-11-30
ZA201106048B (en) 2012-10-31
US8524949B2 (en) 2013-09-03
JP2012519155A (ja) 2012-08-23
CN101481321A (zh) 2009-07-15
CL2011002090A1 (es) 2012-02-03
PT2418195E (pt) 2014-12-26
AU2010217082B2 (en) 2012-05-03
ECSP11011290A (es) 2011-09-30
HN2011002291A (es) 2014-04-07
UA97619C2 (ru) 2012-02-27
EP2418195B1 (en) 2014-11-19
CR20110446A (es) 2011-10-18
EP2418195A1 (en) 2012-02-15
KR20110117721A (ko) 2011-10-27
AP2011005845A0 (en) 2011-08-31
EP2418195A4 (en) 2013-01-16

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