WO2012126386A1 - 阿戈美拉汀的混晶(形式-ⅷ)、其制备方法、应用和包含其的药物组合物 - Google Patents

阿戈美拉汀的混晶(形式-ⅷ)、其制备方法、应用和包含其的药物组合物 Download PDF

Info

Publication number
WO2012126386A1
WO2012126386A1 PCT/CN2012/072818 CN2012072818W WO2012126386A1 WO 2012126386 A1 WO2012126386 A1 WO 2012126386A1 CN 2012072818 W CN2012072818 W CN 2012072818W WO 2012126386 A1 WO2012126386 A1 WO 2012126386A1
Authority
WO
WIPO (PCT)
Prior art keywords
agomelatine
mixed crystal
preparation
crystals
water
Prior art date
Application number
PCT/CN2012/072818
Other languages
English (en)
French (fr)
Inventor
黄雨
龙青
朱雪焱
单汉滨
袁哲东
俞雄
Original Assignee
上海医药工业研究院
瑟维尔实验室
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US14/006,484 priority Critical patent/US20140088197A1/en
Priority to EA201301065A priority patent/EA023278B1/ru
Priority to CN201280013429.3A priority patent/CN103476743B/zh
Priority to CA2829690A priority patent/CA2829690C/en
Priority to JP2014500244A priority patent/JP6203171B2/ja
Priority to EP12761142.4A priority patent/EP2690088B1/en
Priority to MX2013010634A priority patent/MX355551B/es
Priority to LTEP12761142.4T priority patent/LT2690088T/lt
Priority to AU2012231548A priority patent/AU2012231548B2/en
Priority to DK12761142.4T priority patent/DK2690088T3/en
Priority to SG2013066600A priority patent/SG193305A1/en
Priority to MA36226A priority patent/MA34959B1/fr
Application filed by 上海医药工业研究院, 瑟维尔实验室 filed Critical 上海医药工业研究院
Priority to RS20170307A priority patent/RS55918B1/sr
Priority to NZ615714A priority patent/NZ615714B2/en
Priority to MDA20130074A priority patent/MD4484C1/ro
Priority to BR112013024022A priority patent/BR112013024022A2/pt
Priority to ES12761142.4T priority patent/ES2626030T3/es
Priority to SI201230949A priority patent/SI2690088T1/sl
Priority to KR1020137027641A priority patent/KR20130136546A/ko
Publication of WO2012126386A1 publication Critical patent/WO2012126386A1/zh
Priority to ZA2013/06761A priority patent/ZA201306761B/en
Priority to HK14106352.3A priority patent/HK1193086A1/zh
Priority to CY20171100351T priority patent/CY1118751T1/el
Priority to HRP20170575TT priority patent/HRP20170575T1/hr
Priority to MEP-2017-109A priority patent/ME02731B/me

Links

Classifications

    • 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
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/08—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a mixed crystal of agomelatine or N-[ 2- ( 7 -methoxy-1-naphthyl)ethyl]acetamide, a process for the preparation thereof, use thereof and a pharmaceutical composition comprising the same. Background technique
  • melatonin has a dual role, not only an agonist of melatonin system receptors, but also an antagonist of 5HT 2C receptors, its properties make it active in the central nervous system, especially in severe depression, seasonal affective disorder, It is active in the treatment of sleep disorders, cardiovascular diseases, digestive diseases, insomnia and fatigue caused by jet lag, appetite disorders and obesity. It is the first melatonin antidepressant that can effectively treat depression, improve sleep parameters and not affect sexual function.
  • the crystal form VI disclosed in the patent CN200910047329.2 is obtained by recrystallization from acetic acid and water, and is superior in solubility to most of the crystal forms disclosed so far, so it has unique value in the preparation, but the crystal form VI is under extremely harsh conditions ( After 10 days at high temperature, a small amount of crystal form will occur. Change. In order to find a crystal form or mixed crystal with better stability without lowering the solubility, it has become another focus of researchers.
  • the object of the present invention is to provide a mixed crystal (form-) of agomelatine, and to provide a preparation method thereof, and the form -VIII is more stable under high temperature conditions than the crystal form of VI, and shows in formulation. A valuable feature.
  • the mixed crystal (form-coated) of agomelatine of the present invention can be used for treating melatonin system diseases, sleep disorders, nervousness, anxiety disorders, seasonal affective disorders, severe depression, cardiovascular diseases, digestive diseases Insomnia or fatigue caused by jet lag, schizophrenia, phobia or depression.
  • Another object of the present invention is to provide a form-cover preparation method of agomelatine which is simple in operation and good in reproducibility.
  • a further object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the mixed crystal (form-coated) of agomelatine of the present invention together with a pharmaceutically acceptable adjuvant or excipient.
  • compositions can be formulated for use in a variety of routes of administration, particularly for oral administration or injection.
  • the dosage can be adjusted depending on the nature and severity of the disease, the route of administration, and the age and weight of the patient.
  • the dose varies between 0.1 mg and 1 g per day and can be administered in one or more divided doses.
  • agomelatine of the present invention is characterized by the following X-ray diffraction pattern, which is expressed by the interplanar spacing d, the cloth ⁇ 2 angle and the relative intensity (1%):
  • the crystal of the present invention is measured by X-ray diffraction, there may be a slight measurement error for the measured peak due to the measured instrument or the measurement conditions. Specifically, for example, the measurement error of the 2 ⁇ value may be Approximately ⁇ 0.2, sometimes using an extremely precise device, an error of about ⁇ 0.1 is sometimes generated. Therefore, this error should be taken into account when determining each crystal structure.
  • Scan range: 3° ⁇ 45°
  • test conditions of the DSC endothermic transition pattern of the form -VIII of the agomelatine of the present invention are: Instrument model: NETZSCH DSC 204 F1
  • ⁇ type aluminum ⁇ (needle piercing)
  • Purge gas high purity nitrogen, 60 ml/min
  • the DSC endothermic transition according to the present invention is characterized by the onset value of the endothermic main peak in the spectrum, the onset value ranges from 97 to 98 " €, and the area of the endothermic main peak is not less than 90%, and the preferred ratio is 95-99. %.
  • the crystal of the present invention When the crystal of the present invention is measured by DSC, there may be a slight measurement error with respect to the measured peak due to the measured instrument or the measurement conditions. Specifically, for example, the measurement error of the onset value may be about ⁇ 1, even if When using very sophisticated equipment, an error of about ⁇ 0.5" € is sometimes generated. Therefore, this error should be taken into account when determining each crystal structure.
  • the TGA test conditions are: Instrument model NETZSCH TG 209F1
  • a method for preparing a form-cover of the present invention which comprises dissolving the agomelatine complex of the formula (Agomelatine-HCl-H 2 0) in acetic acid, and then adding sodium acetate thereto, by reacting the obtained reaction Add water to the solution and add it at 7-13. C is stirred to precipitate crystals, and then the crystals are separated from the liquid phase.
  • the acetic acid according to the present invention has no special requirement for the amount of acetic acid to be added, and the raw material can be dissolved, and can be appropriately heated and dissolved according to the demand.
  • the molar ratio of the agomelatine complex of the formula II to sodium acetate is preferably from 1:1 to 1.5, particularly preferably from 1:1 to 1.1.
  • the volume fraction ratio of acetic acid to water is 1: 15-30.
  • the obtained reaction liquid is 12-18. C, especially at about 15. In the case of C, crystals are precipitated by dropwise addition of water thereto.
  • crystals are precipitated by dropwise addition of water to the obtained reaction liquid and stirring at about 10 ° C, for example, for 1.5 hours.
  • reaction solution is heated to 40-80 after the addition of sodium acetate.
  • an appropriate amount of activated carbon is optionally added thereto and stirred, followed by filtration; then the solution is naturally cooled, and crystals are precipitated by dropwise addition of water thereto.
  • the form of agomelatine provided by the present invention can be used together with various pharmaceutically acceptable excipients or excipients to prepare various pharmaceutical dosage forms.
  • the invention obtains a form-covering of agomelatine, which is superior to the crystal form of VI, and has the advantage of good stability in preparation.
  • the above-mentioned formula II agomelatine complex can be produced by the following preparation method, which comprises reacting agomelatine with various forms of HC1 to form a hydrate.
  • preparation method which comprises reacting agomelatine with various forms of HC1 to form a hydrate.
  • agomelatine may be added to an aqueous organic solvent, and a solvent containing HC1 may be added dropwise, and the solid precipitated and washed may be washed and dried.
  • agomelatine can be added to an organic solvent, an aqueous solution of HC1 is added dropwise, and the solid precipitated is washed and dried.
  • Figure 1 is an X-ray diffraction pattern of Form-VIII obtained in Example 1 of the present invention.
  • Figure 2 is a DSC endothermic transition map of Form-VIII obtained in Example 1 of the present invention.
  • Figure 3 is an X-ray diffraction pattern of Form-VIII obtained in Example 2 of the present invention.
  • Figure 4 is a DSC endothermic transition map of Form-VIII obtained in Example 2 of the present invention.
  • Figure 5 is an X-ray diffraction pattern of Form-VIII obtained in Example 3 of the present invention.
  • Figure 6 is a DSC endothermic transition pattern of Form-VIII obtained in Example 3 of the present invention.
  • Figure 7 is a TGA graph of the thermogravimetric analysis of the product of Example 5 of the present invention. detailed description
  • Example 1 The agmelatin complex of formula II (14 g ) was dissolved in acetic acid (55 ml), sodium acetate (4.5 g) was added; heated to 60 X, activated carbon (0.5 g) was added, stirred for 2 hours, and filtered; When the filtrate reached 15", start to add water (1L), the solution gradually became turbid, and stirred at ⁇ 10" for 1.5 hours; filtered, washed with water filter cake, dried under vacuum at 45 to constant weight to obtain 9.6 g of white solid. ;
  • the agmelatin complex of formula II (140 g) was dissolved in acetic acid (490 ml), sodium acetate (60 g) was added; heated to 60" C, activated carbon (1.4 g) was added, stirred for 1 hour, filtered When the filtrate reaches 15", start to add water (8.8 L), the solution gradually becomes cloudy, and stir at ⁇ 10 for 1.5 hours; filter, wash the filter cake with water, and dry under vacuum to constant weight for 45 g to obtain a white solid 94 g ;
  • the crystal form VI and form-cover of Agmelatine were placed in a 4 (TC incubator, placed for 20 days, and the stability of these samples was studied by high performance liquid chromatography. .
  • Color transfer conditions using octadecylsilane bonded silica as a filler; a mixed solution of 10 mmol/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 220 nm at the detection wavelength. The purity was determined by an internal standard method.
  • Form VI and Form-VIII were separately prepared into a 1 m g /mL solution using a mobile phase, each taking 10 Inject liquid phase color, record chromatogram
  • the measurement method refers to the method for determining the purity of the sample, and the measurement is performed by an external standard method. The results are shown in Table 1: Table 1
  • the method of determination uses the stability assessment method in the pharmacopoeia:
  • the form of agomelatine of the present invention is superior in stability to the crystalline form VI under high temperature conditions, and is also equivalent in solubility to the crystalline form VI; the reproducibility of the preparation method is good, It shows valuable properties in terms of formulation.
  • CMS-Na Sodium carboxymethyl starch
  • C1 content is 11.91wt%
  • Example 5 The product of Example 5 was tested according to the Fisher's method, and the measured crystal water content was 6.15 wt %.
  • Example 5 The product of Example 5 was tested according to the thermal analysis method, and the amount of loss of crystal water was measured to be 6.67 wt%, i.e., the original product contained 6.67 wt% of crystal water. See Figure 7 for the TGA curve.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Anesthesiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明提供了阿戈美拉汀混晶(形式-Ⅷ)、其制备方法、应用和包含其的药物组合物，其中所述混晶主要含阿戈美拉汀Ⅵ晶型。该混晶晶型稳定且重现性好，通过稳定性实验发现在稳定性方面优于Ⅵ晶型。因此，本发明的形式-Ⅷ在制剂方面具有优势。

Description

阿戈美拉汀的混晶 (形式 -νιπ)、 其制备方法、 应用和包含其的药物组合物 技术领域
本发明涉及阿戈美拉汀或 N-[2-(7_甲氧基 -1-萘基)乙基】乙酰胺的一种 混晶、 其制备方法、 应用和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 商品名 Valdoxan, 化
Figure imgf000002_0001
它具有双重作用， 不仅是褪黑激素能系统受体的激动剂， 还有拮抗 5HT2C受体的作用， 其性质使其在中枢神经系统具备活性， 尤其在严重抑 郁症、 季节性情感障碍、 睡眠障碍、 心血管疾病、 消化系统疾病、 飞行时 差引起的失眠和疲劳、 食欲紊乱和肥胖症的治疗中具有活性。 它是第一个 褪黑激素类抗抑郁药， 能有效治疗抑郁症， 改善睡眠参数和不影响性功能。
阿戈美拉汀、其制备及其治疗用途在欧洲专利说明书 EP0447285中已 有报道。
鉴于该化合物的药学价值， 获得纯度好、 晶形稳定且重现性好的该化 合物是重要的， 使其在制剂方面具有优势， 并且足够稳定可以长期存储， 且对温度、 光、 湿度或氧气水平没有特定要求。
对于阿戈美拉汀已有多篇文献艮道， 例如在专利 CN200510071611.6、 CN200610108396.7 、 CN200610108394.8 、 CN200610108395.2 、 CN200910047329.2, CN200910245029.5 等公开了阿戈美拉汀的多种晶形 及其制备方法。
其中， CN200910047329.2 专利公开的晶型 VI通过醋酸和水重结晶所 得， 在溶解度方面优于目前公开的大多数晶型， 因此在制剂具有独特的价 值，但晶型 VI在极端恶劣条件下 (高温 放置 10天，会发生少量晶型转 变。 为了寻找出稳定性更好的， 而不降低溶解度的晶型或混晶， 成为研究 人员又一关注点。
令人欣喜的是， 本发明人通过制备工艺的摸索， 通过稳定性对比， 发 现了一种在恶劣条件下稳定性更优于晶型 VI的一种混晶。 该混晶不仅没降 低晶型 VI溶解度优良的特性， 而且稳定性更好， 制备方法重现好， 制备的 制剂在恶劣条件下的稳定性均良好， 因此大大增加了其成药的可能性。 发明内容
本发明的目的是提供一种阿戈美拉汀的一种混晶 (形式 - )， 并提供其 制备方法， 且该形式 -VIII与 VI晶型比较在高温条件下更加稳定， 在制剂方面 显示出有价值的特性。
本发明的阿戈美拉汀的混晶 (形式 -覆)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。
本发明的另一目的是提供阿戈美拉汀的形式-覆制备方法，该制备方法 操作简单， 重现性好。
本发明的又一目的是提供药物组合物， 其包含本发明的阿戈美拉汀的 混晶 (形式 -覆)以及可药用辅料或赋形剂。
可配制所述药物组合物以用于各种施用途径， 尤其是用于口服施用或 注射。
可根据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施 用剂量。 剂量在每天 0.1 mg至 l g之间变化， 可以一次或分多次施用。
本发明的阿戈美拉汀的形式 -覆以下列的 X射线衍射图表征，其以晶面 间距 d、 布 ^ 2 Θ角和相对强度 (1%)来表示：
2Θ° d (A) 相对强度 (1%)
9.493 9.3085 12.86 9.809 9.0096 15.62
10.815 8.1735 13.10
11.171 7.9141 17.53
11.879 7.4439 64.67
12.770 6.9264 17.90
13.811 6.4065 17.10
14.939 5.9255 12.14
15.315 5.7808 10.48
16.085 5.5057 19.89
17.544 5.0510 48.47
18.491 4.7943 66.41
19.065 4.6512 24.02
19.538 4.5398 99.39
19.774 4.4861 100.00
20.801 4.2668 50.35
21.156 4.1961 30.66
21.807 4.0722 37.31
22.499 3.9486 22.63
23.032 3.8583 31.18
23.780 3.7387 39.67
24.610 3.6144 21.02
25.419 3.5011 30.30
27.075 3.2906 14.67
31.931 2.8004 14.14 用 X射线衍射测定本发明的结晶时， 有时由于测定的仪器或测定的条 件， 对于所测得的峰而言稍有测定误差， 具体来说， 例如， 2Θ值的测定误 差有时为约 ±0.2, 即使使用非常精密的设备时， 有时也会产生约 ±0.1 的误 差。 因此， 在确定每种结晶结构时， 应该将此误差考虑在内。
本发明所述阿戈美拉汀的形式 -VIII的 XRD测试条件：
仪器型号： Bruker D8 ADVANCE X射线衍射仪 实验 ：
检测器： LynxEye检测器
光源： CuKoi 40 kV 40 mA
单色器： M滤片
发散狭缝： 1。
DivH丄 .Slit: 1.0 mm
探测器： LynxEye探测器
扫描方式： Θ-Θ连续扫描
扫描范围： 3°~45°
步长： 0.02°
扫描速度： 8.0°/min
扫描时间： 5 min
扫描温度： 室温
本发明所述阿戈美拉汀的形式 -VIII的 DSC吸热转变图谱的测试条件为: 仪器型号： NETZSCH DSC 204 F1
实验糾：
坩埚类型： 铝坩埚 (针刺穿孔）
保护气： 高纯氮， 20 ml/min
吹扫气： 高纯氮， 60 ml/min
升温速度： lO'C/min
温度范围： 室温〜 140*€
本发明所述的 DSC吸热转变以图谱中吸热主峰的 onset值表征， onset 值的范围在 97-98 "€， 且吸热主峰的面积不低于 90%， 优选的比率为 95-99%。
用 DSC测定本发明的结晶时，有时由于测定的仪器或测定的条件，对 于所测得的峰而言稍有测定误差， 具体来说， 例如， onset值的测定误差有 时为约 ±1 ， 即使使用非常精密的设备时， 有时也会产生约 ±0.5"€的误差。 因此， 在确定每种结晶结构时， 应该将此误差考虑在内。
在本发明中 TGA测试条件为： 仪器型号 NETZSCH TG 209F1
实验糾
坩埚类型： A1203
吹扫气： N2 20 ml/min; 保护气： N2 10 ml/min
温度范围： 室温〜 300 "C
升温速率： 10"C/min
本发明的形式-覆的制备方法， 该方法是将式 Π的阿戈美拉汀复合物 (Agomelatine-HCl-H20)溶于醋酸， 然后向其中加入醋酸钠， 通过向所得到 的反应液中滴加水并在 7-13。C进行搅拌， 使结晶析出， 然后将结晶与液相 分离。
Figure imgf000006_0001
( II )
本发明所述的醋酸， 其加入量无特殊要求， 以能溶解原料为准， 并可 根据需求适当加热助溶。
式 II的阿戈美拉汀复合物与醋酸钠的摩尔比优选为 1 ： 1-1.5， 特别优 选 1： 1-1.1。
本发明所述制备方法中， 醋酸与水的体积份数比为 1： 15-30。
本发明的阿戈美拉汀的形式 -覆的制备方法的一个优选的实施方案中， 在所得到的反应液为 12-18。C、 特别是在约 15。C时， 通过向其中滴加水使 结晶析出。
在另一个优选的实施方案中， 通过向所得到的反应液中滴加水并在约 10°C进行搅拌， 例如搅拌 1.5小时， 使结晶析出。
在另一个优选的实施方案中， 在加入醋酸钠后将反应液加热至 40-80。C , 任选地向其中加入适量的活性炭并进行搅拌、 而后过滤； 然后使 该溶液自然冷却， 通过向其中滴加水使结晶析出。
本发明所提供的阿戈美拉汀的形式 - ，可与药学上的各种辅料或赋性 剂一起制得各种药物剂型。 本发明得到了一种阿戈美拉汀的形式 -覆， 稳定性优于 VI晶型， 在制剂 方面具有稳定性良好的优势。
根据中国专利申请 CN 201010126254.X, 上述式 II阿戈美拉汀复合物 可通过以下的制备方法来制备， 该方法是将阿戈美拉汀与各种形式的 HC1 反应形成水合物。具体步骤为两种：先将阿戈美拉汀溶解于含水有机溶剂， 然后通入 HC1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 HC1的溶剂中， 再将结晶析出的固体洗涤、 干燥。 如果使用第 一种方法通入 HC1过多反而会造成收率降低， 而第二种方法对于溶剂中 HC1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有机溶剂中， 再滴加含 HC1的 溶剂， 再将结晶析出的固体洗涤、 干燥。
同样也可以将阿戈美拉汀加入到有机溶剂中， 再滴加 HC1水溶液， 再 将结晶析出的固体洗涤、 干燥。
所引用或提及的参考文献的全部内容引入本申请作为参考。 附图说明
图 1是本发明实施例 1所得的形式 -VIII的 X射线衍射图谱；
图 2是本发明实施例 1所得的形式 -VIII的 DSC吸热转变图谱；
图 3是本发明实施例 2所得的形式 -VIII的 X射线衍射图谱；
图 4是本发明实施例 2所得的形式 -VIII的 DSC吸热转变图谱；
图 5是本发明实施例 3所得的形式 -VIII的 X射线衍射图谱；
图 6是本发明实施例 3所得的形式 -VIII的 DSC吸热转变图谱；
图 7为本发明实施例 5产物进行热重分析的 TGA曲线图。 具体实施方式
下面通过实施例的方式进一步说明本发明， 但并不因此将本发明限制 在所述的实施例范围之中。 实施例 1: 将式 II阿戈美拉汀复合物 (14 g)溶于醋酸 (55 ml)溶液中， 加入醋酸钠 (4.5 g); 加热至 60 X， 加入活性炭 (0.5 g)， 搅拌 2小时， 过滤； 当滤液达到 15"€时， 开始滴加水 (1L)， 溶液逐渐变浑浊， 同时在〜 10"€搅拌 1.5小时； 过滤， 用水洗涤滤饼， 45 下真空干燥至恒重， 得到白色固体 9.6g;
(X射线衍射图谱见图 1; DSC吸热转变图谱见图 2) 实施例 2:
将式 II阿戈美拉汀复合物 (140 g)溶于醋酸 (490 ml)溶液中，加入醋酸钠 (60 g); 加热至 60"C， 加入活性炭 (1.4 g)， 搅拌 1小时， 过滤； 当滤液达到 15"€时， 开始滴加水 (8.8 L), 溶液逐渐变浑浊， 同时在〜 10 搅拌 1.5小时； 过滤， 用水洗涤滤饼， 45 下真空干燥至恒重， 得到白色固体 94g;
(X射线衍射图谱见图 3; DSC吸热转变图谱见图 4) 实施例 3:
将式 II阿戈美拉汀复合物 (66 g)溶于醋酸 (230 ml)溶液中， 加入醋酸钠 (21 g); 加热至 60"€， 加入活性炭 (1.3 g)， 搅拌 1小时， 过滤； 当滤液达到 到 15"€时， 开始滴加水 (6.9 L), 溶液逐渐变浑浊， 同时在〜 搅拌 1.5小 时； 过滤， 用水洗涤滤饼， 50 下真空干燥至恒重， 得到白色固体 49g;
(X射线衍射图谱见图 5; DSC吸热转变图谱见图 6) 实施例 4:
将阿戈美拉汀的晶型 VI和形式 -覆 （得自实施例 2)分别放入 4(TC的恒 温箱中， 放置 20天， 通过高效液相色谱法对这些样品的稳定性进行研究。
1、 样品纯度测定
色傳条件： 用十八烷基硅烷键合硅胶为填充剂； 以 10 mmol/L磷酸緩 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 检测波长为 220 nm。 通过内标法测定纯度。
用流动相分别将晶型 VI和形式 -VIII配置成 1 mg/mL的溶液，各取 10 注入液相色^义， 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，结果见表一: 表一
Figure imgf000009_0001
3、 水溶性测定
测定方法采用 HPLC方法， 用外标法进行测定。 结果如下表二:
表二
Figure imgf000009_0002
4、 晶型稳定性测定
测定方法采用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 (45001x)， 高湿 (92.5%RH, 25"C)
2 ) 加速实验 (密闭 6个月）： 温度为 30"€, 湿度为 65%RH
3 ) 长期实验 (密闭 12个月）： 温度为 25*€, 湿度为 60%RH
样品名称 晶型 VI 形式 -VIII
*
面温 X
影响因素 光照 V V
高湿 V V 加速实验 V V
长期实验 (6个月） V V
长期实验 (9个月） V V
长期实验 (12个月） X V
*: -稳定； X -不稳定
根据测试结果看到，本发明的阿戈美拉汀的形式 -覆在高温条件下的在 稳定性优于晶型 VI，并且溶解度上也与晶型 VI相当；制备方法的重现性好， 在制剂方面显示出有价值的特性。
5、 药物组合物的制备及稳定性研究 (晶型、 纯度和含量)
1000粒胶嚢处方 （剂量： 25 mg)
形式 -VIII 25 mg
乳糖 71.2 mg
硬脂酸镁 1 3 mg
1 3 mg
淀粉 (Starch 1500) 19.5 mg
羧甲基淀粉钠 (CMS-Na) 6.5 mg 按照药典稳定性考核研究方法， 经过影响因素实验 (敞口 10天)： 高温 (60"€)， 光照 (45001x)， 高湿 (92.5%RH， 25"€)； 加速实验 (密闭 6个月）： 温度为 30"€， 湿度为 65%RH; 长期实验 (密闭 12个月）： 温度为 25 ， 湿 度为 60%RH, 考核结果显示在上述条件下本品的晶型、 纯度和含量均未 发生改变。
因此，本品原料药与胶嚢的各项试验结果显示形式 -VIII具有优良的成药 前景。 实施例 5: 式 II阿戈美拉汀复合物
将 10 g阿戈美拉汀加入到 100 ml乙酸乙酯溶液中， 10"€条件下逐滴 加入 HC1 (36%)水溶液 4.6 g,搅摔 1个小时；过滤， 固体用乙酸乙酯 10 ml 洗涤两次， 40 下干燥得到式 II的白色固体 10.2 g; 纯度： 99.8%, 收率： 88.7%。
C1元素分析：
理 十算值： C1含量为 11.91wt %
实测值： C1含量为 11.86 wt % 式 II阿戈美拉汀复合物结晶水含量测定：
根据计算得 Ci5H17N02 HC1 H20中结晶水的理论含量为 6.06 wt %。
5.1 费休氏法（《中国药典》 2010版 附录 VIII M)
取实施例 5产物按照所述费休氏法测试， 实测结晶水含量： 6.15 wt %
5.2 热重分析（《中国药典》 2010版 附录 VIII Q)
取实施例 5产物按照所述热分析法测试，测得结晶水损失量 6.67 wt %, 即 原产物中含有结晶水 6.67 wt %。 TGA曲线请参见图 7。

Claims

权利要求
1. 阿戈美拉汀的混晶， 其以用布拉格 2Θ角来表示的如下 X射线衍射 图表征：
9.493
9.809
10.815
11.171
11.879
12.770
13.811
14.939
15.315
16.085
17.544
18.491
19.065
19.538
19.774
20.801
21.156
21.807
22.499
23.032
23.780
24.610
25.419
27.075
31.931
并且其还包括峰衍射角在上述 2Θ±0.2°的误差内匹配的晶体。
2. 阿戈美拉汀的混晶，其以用晶面间距 布拉格 2Θ角和相对强度来 表示的如下 X射线衍射图表征:
Figure imgf000013_0001
并且其还包括峰衍射角在上述 2Θ±0.2°的误差内匹配的晶体。
3.如权利要求 1或 2所述的阿戈美拉汀的混晶， 其特征在于： 在其 DSC吸热转变图傳中， onset值的范围在 97-98*€, 且主峰面积比率不低于 90%； 优选的比率为 95-99%。
4.如权利要求 1-3中任意一项所述的阿戈美拉汀的混晶的制备方法， 将式 II阿戈美拉汀复合物溶于醋酸， 然后向其中加入醋酸钠， 通过向所得 到的反应液中滴加水并在 7-13。C进行搅拌， 使结晶析出， 然后将结晶与液 相分离
Figure imgf000014_0001
5.如权利要求 4所述的制备方法， 其中， 式 II阿戈美拉汀复合物与醋 酸钠的摩尔比为 1： 1-1.5， 特别是 1： 1-1.1。
6.如权利要求 4或 5所述的制备方法， 其中， 醋酸与水的体积份数比 为 1： 15-30。
7.如权利要求 4-6中任意一项所述的制备方法， 其中， 在所得到的反 应液为 12-18。C、 特别是 15。C时， 通过向其中滴加水使结晶析出。
8.如权利要求 4-7中任意一项所述的制备方法， 其中， 通过向所得到 的反应液中滴加水并在 10。C进行搅拌， 使结晶析出。
9.如权利要求 4-8中任意一项所述的制备方法， 其中， 在加入醋酸钠 后将反应液加热至 40-80Ό;然后使该溶液自然冷却，通过向其中滴加水使 结晶析出。
10. 药物组合物，其包含如权利要求 1-3中任意一项所述的阿戈美拉汀 的混晶以及可药用辅料或赋形剂。
11. 用于制备药物的如权利要求 10所述的药物组合物， 所述药物用于 治疗褪黑素能系统疾病。
12. 用于制备药物的如权利要求 10所述的药物组合物， 所述药物用于 治疗睡眠障碍、 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。
13.如权利要求 1-3 中任意一项所述的阿戈美拉汀的混晶在制备药物 中的应用， 所述药物用于治疗褪黑素能系统疾病。
14.如权利要求 1-3 中任意一项所述的阿戈美拉汀的混晶在制备药物 中的应用， 所述药物用于治疗睡眠障碍、 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。
PCT/CN2012/072818 2011-03-23 2012-03-22 阿戈美拉汀的混晶(形式-ⅷ)、其制备方法、应用和包含其的药物组合物 WO2012126386A1 (zh)

Priority Applications (24)

Application Number Priority Date Filing Date Title
RS20170307A RS55918B1 (sr) 2011-03-23 2012-03-22 Mešani kristal agomelatina (oblik-viii), postupak dobijanja i njegova upotreba i farmaceutske kompozicije koje ga sadrže
EA201301065A EA023278B1 (ru) 2011-03-23 2012-03-22 Кристаллический агомелатин (форма-viii), способ его получения, применение и содержащая его фармацевтическая композиция
NZ615714A NZ615714B2 (en) 2011-03-23 2012-03-22 Mixed crystalline form-VIII of agomelatine, its method of preparation, application and pharmaceutical use
JP2014500244A JP6203171B2 (ja) 2011-03-23 2012-03-22 混晶アゴメラチン（ｖｉｉｉ型）、その調製方法及び使用、並びにこれを含有する医薬組成物
EP12761142.4A EP2690088B1 (en) 2011-03-23 2012-03-22 Mixed crystal agomelatine (form-viii), preparation method and use thereof and pharmaceutical composition containing same
MX2013010634A MX355551B (es) 2011-03-23 2012-03-22 Cristal mixto de agomelatina (forma-viii), sus métodos de preparación y aplicaciones y composiciones farmacéuticas que le contienen.
LTEP12761142.4T LT2690088T (lt) 2011-03-23 2012-03-22 Mišri kristalinė agomelatino forma-viii, jos gamybos būdas bei panaudojimas ir ją turinti farmacinė kompozicija
AU2012231548A AU2012231548B2 (en) 2011-03-23 2012-03-22 Mixed crystal agomelatine (Form-VIII), preparation method and use thereof and pharmaceutical composition containing same
DK12761142.4T DK2690088T3 (en) 2011-03-23 2012-03-22 MIXED CRYSTAL OF AGOMELATIN (FORM-VIII), PROCEDURE FOR ITS PREPARATION, APPLICATION THEREOF AND PHARMACEUTICAL COMPOSITION CONTAINING SAME
SG2013066600A SG193305A1 (en) 2011-03-23 2012-03-22 Mixed crystal agomelatine (form-viii), preparation method and use thereof and pharmaceutical composition containing same
MA36226A MA34959B1 (fr) 2011-03-23 2012-03-22 Agomelatine cristalline mixte (forme viii) ,son procede de preparation et utilisation et composistion pharmaceutique la contenant
US14/006,484 US20140088197A1 (en) 2011-03-23 2012-03-22 Mixed crystal agomelatine (form viii), preparation method and use thereof and pharmaceutical composition containing same
CN201280013429.3A CN103476743B (zh) 2011-03-23 2012-03-22 阿戈美拉汀的混晶(形式-ⅷ)、其制备方法、应用和包含其的药物组合物
CA2829690A CA2829690C (en) 2011-03-23 2012-03-22 Mixed crystal agomelatine (form-viii), preparation method and use thereof and pharmaceutical composition containing same
MDA20130074A MD4484C1 (ro) 2011-03-23 2012-03-22 Forma cristalină VIII a agomelatinei, procedeu de preparare, utilizarea acesteia şi compoziţie farmaceutică care o conţine
BR112013024022A BR112013024022A2 (pt) 2011-03-23 2012-03-22 agomelatina cristalina misturada (forma-viii), método de preparação e uso da mesma e composição farmacêutica contendo a mesma
ES12761142.4T ES2626030T3 (es) 2011-03-23 2012-03-22 Agomelatina cristalina mixta (forma VIII), método de preparación y utilización de la misma, así como composición farmacéutica que la contiene
SI201230949A SI2690088T1 (sl) 2011-03-23 2012-03-22 Mešani kristal agomelatina (oblika viii), postopek njegove priprave in njegova uporaba ter farmacevtski sestavek, ki ga vsebuje
KR1020137027641A KR20130136546A (ko) 2011-03-23 2012-03-22 혼합된 결정성 아고멜라틴 (형태-viii), 및 이의 제조 방법 및 용도 및 이를 함유하는 약학적 조성물
ZA2013/06761A ZA201306761B (en) 2011-03-23 2013-09-09 Mixed crystal agomelatine (form-viii), preparation method and use thereof and pharmaceutical composition containing same
HK14106352.3A HK1193086A1 (zh) 2011-03-23 2014-06-24 阿戈美拉汀的混晶 形式- 、其製備方法、應用和包含其的藥物組合物
CY20171100351T CY1118751T1 (el) 2011-03-23 2017-03-20 Μεικτος κρυσταλλος αγομελατινης (μορφη-viii), μεθοδος παρασκευης και χρηση αυτου και φαρμακευτικη συνθεση που περιεχει τον ιδιο
HRP20170575TT HRP20170575T1 (hr) 2011-03-23 2017-04-11 Miješani kristalni (oblik-viii) agomelatina, postupak njegove priprave i farmaceutski pripravak koji ga sadrži
MEP-2017-109A ME02731B (me) 2011-03-23 2017-06-12 Mješoviti kristalni oblik agomelatina. (oblik-viii), postupak pripreme i njegove primjene i farmaceutski pripravak koji ga sadrži

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2011100706340A CN102690209A (zh) 2011-03-23 2011-03-23 阿戈美拉汀的混晶(形式-ⅷ)、其制备方法、应用和包含其的药物组合物
CN201110070634.0 2011-03-23

Publications (1)

Publication Number Publication Date
WO2012126386A1 true WO2012126386A1 (zh) 2012-09-27

Family

ID=46855965

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2012/072818 WO2012126386A1 (zh) 2011-03-23 2012-03-22 阿戈美拉汀的混晶(形式-ⅷ)、其制备方法、应用和包含其的药物组合物

Country Status (30)

Country Link
US (1) US20140088197A1 (zh)
EP (1) EP2690088B1 (zh)
JP (1) JP6203171B2 (zh)
KR (1) KR20130136546A (zh)
CN (2) CN102690209A (zh)
AR (1) AR085915A1 (zh)
AU (1) AU2012231548B2 (zh)
BR (1) BR112013024022A2 (zh)
CA (1) CA2829690C (zh)
CY (1) CY1118751T1 (zh)
DK (1) DK2690088T3 (zh)
EA (1) EA023278B1 (zh)
ES (1) ES2626030T3 (zh)
GE (1) GEP201606567B (zh)
HK (1) HK1193086A1 (zh)
HR (1) HRP20170575T1 (zh)
HU (1) HUE034329T2 (zh)
LT (1) LT2690088T (zh)
MA (1) MA34959B1 (zh)
MD (1) MD4484C1 (zh)
ME (1) ME02731B (zh)
MX (1) MX355551B (zh)
MY (1) MY166444A (zh)
PL (1) PL2690088T3 (zh)
PT (1) PT2690088T (zh)
RS (1) RS55918B1 (zh)
SG (1) SG193305A1 (zh)
SI (1) SI2690088T1 (zh)
WO (1) WO2012126386A1 (zh)
ZA (1) ZA201306761B (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3075724A1 (en) 2015-03-31 2016-10-05 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Solid form of agomelatine

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PH12012000132A1 (en) * 2011-06-09 2014-10-20 Servier Lab New co-crystals of agomelatine, a process for their preparation and pharmaceutical compositions containing them
ME03741B (me) * 2013-07-29 2021-04-20 Shanghai Inst Pharmaceutical Ind Konpleksi agomelatina i sulfonskih kisjelina, postupak njihove proizvodnje i proizvodnje farmaceutskih pripravaka koji ih sadržavaju
CN104529804A (zh) * 2014-12-11 2015-04-22 连云港金康医药科技有限公司 阿戈美拉汀的新晶型
EP3466923A1 (en) * 2017-10-09 2019-04-10 KRKA, d.d., Novo mesto Process for the preparation of agomelatine in crystalline form

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0447285A1 (fr) 1990-02-27 1991-09-18 Adir Et Compagnie Nouveaux dérivés à structure naphtalénique, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
CN101429134A (zh) * 2007-11-09 2009-05-13 瑟维尔实验室 阿戈美拉汀的新晶形vi、它的制备方法和包含它的药物组合物
CN101585779A (zh) * 2009-03-10 2009-11-25 上海医药工业研究院 阿戈美拉汀的新晶型ⅵ及其制备方法和应用
CN101723844A (zh) * 2009-11-21 2010-06-09 浙江华海药业股份有限公司 一种阿戈美拉汀晶形b、它的制备方法和包含它的药物组合物
CN101792400A (zh) * 2010-03-16 2010-08-04 华东师范大学 一种阿戈美拉汀的合成方法
CN101955440A (zh) * 2009-07-17 2011-01-26 北京德众万全药物技术开发有限公司 一种阿戈美拉汀新晶型及其制备方法

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7498466B2 (en) * 2004-02-13 2009-03-03 Les Laboratoires Servier Process for the synthesis and crystalline form of agomelatine
FR2866335B1 (fr) * 2004-02-13 2006-05-26 Servier Lab Nouveau procede de synthese de l'agomelatine
FR2889523B1 (fr) * 2005-08-03 2007-12-28 Servier Lab Nouvelle forme cristalline v de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
FR2889522B1 (fr) * 2005-08-03 2007-12-28 Servier Lab Nouvelle forme cristalline iv de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
FR2889521B1 (fr) * 2005-08-03 2007-12-28 Servier Lab Nouvelle forme cristalline iii de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent
WO2011006387A1 (zh) * 2009-07-11 2011-01-20 浙江华海药业股份有限公司 阿戈美拉汀的制备方法、阿戈美拉汀晶形及其制备方法
EP2319827A1 (en) * 2009-11-09 2011-05-11 Ratiopharm GmbH Process for the production of polymorph form I of agomelatine
CN101781226B (zh) * 2009-12-23 2012-03-28 天津泰普药品科技发展有限公司 阿戈美拉汀及其药物组合物
WO2011154140A2 (en) * 2010-06-10 2011-12-15 Gador S.A. New process for the preparation of n-[2-(7-methoxy-1-naphthyl)-ethyl]acetamide and new crystalline form
WO2012046253A2 (en) * 2010-10-08 2012-04-12 Msn Laboratories Limited Process for the preparation of n-[2- (7-methoxy-l-naphthyl) ethyl] acetamide and its novel crystalline forms
CN102452952A (zh) * 2010-11-03 2012-05-16 天津药物研究院 一种高纯度的i型阿戈美拉汀晶体制备方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0447285A1 (fr) 1990-02-27 1991-09-18 Adir Et Compagnie Nouveaux dérivés à structure naphtalénique, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
CN101429134A (zh) * 2007-11-09 2009-05-13 瑟维尔实验室 阿戈美拉汀的新晶形vi、它的制备方法和包含它的药物组合物
CN101585779A (zh) * 2009-03-10 2009-11-25 上海医药工业研究院 阿戈美拉汀的新晶型ⅵ及其制备方法和应用
CN101955440A (zh) * 2009-07-17 2011-01-26 北京德众万全药物技术开发有限公司 一种阿戈美拉汀新晶型及其制备方法
CN101723844A (zh) * 2009-11-21 2010-06-09 浙江华海药业股份有限公司 一种阿戈美拉汀晶形b、它的制备方法和包含它的药物组合物
CN101792400A (zh) * 2010-03-16 2010-08-04 华东师范大学 一种阿戈美拉汀的合成方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Chinese Pharmacopoeia", 2010
See also references of EP2690088A4
TINANT, B. ET AL.: "N-[2-(7-Methoxy-1-naphthyl)ethyl]-acetamide, a potent melatonin analog", ACTA CRYST., vol. C50, 1994, pages 907 - 910, XP055123493 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3075724A1 (en) 2015-03-31 2016-10-05 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Solid form of agomelatine

Also Published As

Publication number Publication date
AU2012231548A1 (en) 2013-10-03
CN103476743A (zh) 2013-12-25
HRP20170575T1 (hr) 2017-06-30
DK2690088T3 (en) 2017-06-06
ZA201306761B (en) 2014-05-25
EA201301065A1 (ru) 2014-02-28
EP2690088A4 (en) 2014-09-17
RS55918B1 (sr) 2017-09-29
HUE034329T2 (en) 2018-02-28
SI2690088T1 (sl) 2017-06-30
NZ615714A (en) 2016-03-31
MX2013010634A (es) 2013-10-07
JP6203171B2 (ja) 2017-09-27
EP2690088B1 (en) 2017-02-22
HK1193086A1 (zh) 2014-09-12
PT2690088T (pt) 2017-03-20
SG193305A1 (en) 2013-10-30
MD20130074A2 (en) 2014-03-31
CN102690209A (zh) 2012-09-26
LT2690088T (lt) 2017-04-10
MY166444A (en) 2018-06-27
BR112013024022A2 (pt) 2016-12-06
CA2829690A1 (en) 2012-09-27
JP2014516921A (ja) 2014-07-17
PL2690088T3 (pl) 2017-09-29
EA023278B1 (ru) 2016-05-31
AU2012231548B2 (en) 2015-11-19
ME02731B (me) 2017-10-20
GEP201606567B (en) 2016-11-10
CN103476743B (zh) 2015-02-25
CA2829690C (en) 2016-08-09
MX355551B (es) 2018-04-23
KR20130136546A (ko) 2013-12-12
MD4484B1 (ro) 2017-05-31
ES2626030T3 (es) 2017-07-21
CY1118751T1 (el) 2017-07-12
US20140088197A1 (en) 2014-03-27
AR085915A1 (es) 2013-11-06
MD4484C1 (ro) 2017-12-31
EP2690088A1 (en) 2014-01-29
MA34959B1 (fr) 2014-03-01

Similar Documents

Publication Publication Date Title
DK2547649T3 (en) Agomelatine Hydrochloride Hydrate and its Preparation
WO2010102554A1 (zh) 阿戈美拉汀的新晶型ⅵ及其制备方法和应用
US20120252901A1 (en) Agomelatine and pharmaceutical compositions thereof
WO2012126385A1 (zh) 阿戈美拉汀的新晶型ⅶ、其制备方法、应用和包含其的药物组合物
WO2012126386A1 (zh) 阿戈美拉汀的混晶(形式-ⅷ)、其制备方法、应用和包含其的药物组合物
JP2015521179A (ja) アゴメラチン酸基複合体およびその製造方法と用途
US9981912B2 (en) Cocrystal of lorcaserin, preparation methods, pharmaceutical compositions and uses thereof
NZ615714B2 (en) Mixed crystalline form-VIII of agomelatine, its method of preparation, application and pharmaceutical use
NZ615707B2 (en) New crystalline form vii of agomelatine, preparation method and use thereof and pharmaceutical composition containing same

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12761142

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2829690

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: MX/A/2013/010634

Country of ref document: MX

ENP Entry into the national phase

Ref document number: 2014500244

Country of ref document: JP

Kind code of ref document: A

REEP Request for entry into the european phase

Ref document number: 2012761142

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 14006484

Country of ref document: US

Ref document number: 2012761142

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2012231548

Country of ref document: AU

Date of ref document: 20120322

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20130074

Country of ref document: MD

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: A 2013 0074

Country of ref document: MD

WWE Wipo information: entry into national phase

Ref document number: 13264

Country of ref document: GE

Ref document number: A201312166

Country of ref document: UA

ENP Entry into the national phase

Ref document number: 20137027641

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 201301065

Country of ref document: EA

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112013024022

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112013024022

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20130919

WWE Wipo information: entry into national phase

Ref document number: P-2017/0307

Country of ref document: RS