CN105473547A - 阿戈美拉汀和磺酸的新复合物、其制备方法和包含其的药物组合物 - Google Patents
阿戈美拉汀和磺酸的新复合物、其制备方法和包含其的药物组合物 Download PDFInfo
- Publication number
- CN105473547A CN105473547A CN201480042633.7A CN201480042633A CN105473547A CN 105473547 A CN105473547 A CN 105473547A CN 201480042633 A CN201480042633 A CN 201480042633A CN 105473547 A CN105473547 A CN 105473547A
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- Prior art keywords
- agomelatine
- mixture
- sulfonic acid
- formula
- disorder
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- 229960002629 agomelatine Drugs 0.000 title claims abstract description 82
- YJYPHIXNFHFHND-UHFFFAOYSA-N agomelatine Chemical compound C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 YJYPHIXNFHFHND-UHFFFAOYSA-N 0.000 title claims abstract description 79
- 239000002253 acid Substances 0.000 title claims abstract description 4
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- 238000000034 method Methods 0.000 title claims description 12
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- 239000003814 drug Substances 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims description 72
- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 claims description 28
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 20
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 12
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 11
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Classifications
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- C07C309/01—Sulfonic acids
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- 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
式(I)的阿戈美拉汀和磺酸的新复合物。药物。
Description
本发明涉及阿戈美拉汀和磺酸的新复合物、其制备方法,还涉及包含其的药物组合物。
阿戈美拉汀或N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺具有式(II)的结构:
阿戈美拉汀作为褪黑激素能***受体激动剂和5-HT2C受体拮抗剂由法国公司Servier以商品名或在市场销售。它是首个褪黑激素能类型的抗抑郁药,可用于治疗重性抑郁症、改善睡眠和性功能。
欧洲专利说明书EP0447285和EP1564202中描述了阿戈美拉汀、其制备及其治疗应用。
本发明涉及阿戈美拉汀和磺酸的复合物的制备,其具有特定的化学计量:每1摩尔当量磺酸2摩尔当量阿戈美拉汀。这些复合物在溶解度、稳定性和纯度方面具有优越的性质,使得将它们设计用于制备含阿戈美拉汀的药物组合物成为可能。此外,本发明的复合物的化学计量提供了在复合物的活性组分(即阿戈美拉汀)的重量方面的优势,使得制备包含较低量的复合物的药物制剂成为可能。
本发明涉及阿戈美拉汀和磺酸的复合物,其具有式(I)的结构:
其中x表示0或1,且RSO3H表示1,5-萘二磺酸或苯磺酸。
优选的本发明化合物是以下的阿戈美拉汀和磺酸的复合物:
-阿戈美拉汀/1,5-萘二磺酸(2/1)复合物,
-阿戈美拉汀/1,5-萘二磺酸(2/1)一水合物复合物,
-阿戈美拉汀/苯磺酸(2/1)复合物。
阿戈美拉汀/1,5-萘二磺酸(2/1)复合物特征为图1中显示的X-射线粉末衍射图,其使用PanalyticalXpertProMPD衍射仪(铜对阴极)进行测定。主要谱线用晶面间距d、布拉格角2θ(以°±0.2表示)和相对强度(以相对于最强谱线的百分比表示)表示,且它们在表1列出:
表1:阿戈美拉汀/1,5-萘二磺酸(2/1)复合物的衍射峰的表
当通过X-射线衍射测定来表征本发明的复合物时,可能存在所鉴定的峰的测定误差,这有时归咎于使用的设备或环境。更加尤其是,即使使用精良的设备,2θ值也可以具有约±0.2的误差,有时具有约±0.1的误差。因此当鉴定复合物的结构时,必须相应地考虑测定误差。
测定了阿戈美拉汀/1,5-萘二磺酸(2/1)复合物的晶体结构,并鉴定了以下的参数:
-空间群:P121/c1(14)
-晶胞参数:α=90°,β=93.059(2)°,γ=90°
-晶胞体积:
还通过DSC(差示扫描量热法)在图2中显示的谱中表征了阿戈美拉汀/1,5-萘二磺酸(2/1)复合物,图2在约237℃的温度显示对应于复合物的熔化的吸热峰。
本发明还涉及阿戈美拉汀/1,5-萘二磺酸(2/1)一水合物复合物,其特征为图3中显示的它的X-射线粉末衍射图,其使用PanalyticalXpertProMPD衍射仪(铜对阴极)进行测定。主要谱线用晶面间距d、布拉格角2θ(以°±0.2表示)和相对强度(以相对于最强谱线的百分比表示)表示,且在表2中列出:
表2:阿戈美拉汀/1,5-萘二磺酸(2/1)一水合物复合物的衍射峰的表
当通过X-射线衍射测定来表征本发明的复合物时,可能存在所鉴定的峰的测定误差,这有时归咎于使用的设备或环境。更加尤其是,即使使用精良的设备,2θ值也可以具有约±0.2的误差,有时具有约±0.1的误差。因此当鉴定复合物的结构时,必须相应地考虑测定误差。
测定了阿戈美拉汀/1,5-萘二磺酸(2/1)一水合物复合物的晶体结构,并鉴定了以下的参数:
-空间群:P-1(2)
-晶胞参数:α=76.967(2)°,β=75.339(1)°,γ=78.675(2)°
-晶胞体积:
还通过DSC(差示扫描量热法)在图4中显示的谱中表征了阿戈美拉汀/1,5-萘二磺酸(2/1)一水合物复合物,图4显示两个吸热峰:一个在约116℃,对应于复合物的脱水,另一个在约238℃,对应于复合物的熔化。
本发明还涉及阿戈美拉汀/苯磺酸(2/1)复合物,其特征为图5中显示的它的X-射线粉末衍射图,其使用PanalyticalXpertProMPD衍射仪(铜对阴极)进行测定。主要谱线用晶面间距d、布拉格角2θ(以°±0.2表示)和相对强度(以相对于最强谱线的百分比表示)表示,且在表3中列出:
表3:阿戈美拉汀/苯磺酸(2/1)复合物的衍射峰的表
当通过X-射线衍射测定来表征本发明的复合物时,可能存在所鉴定的峰的测定误差,这有时归咎于使用的设备或环境。更加尤其是,即使使用精良的设备,2θ值也可以具有约±0.2的误差,有时具有约±0.1的误差。因此当鉴定复合物的结构时,必须相应地考虑测定误差。
测定了阿戈美拉汀/苯磺酸(2/1)复合物的晶体结构,并鉴定了以下的参数:
-空间群:P-1(2)
-晶胞参数:α=100.445(2)°,β=99.470(2)°,γ=89.054(3)°
-晶胞体积:
还通过DSC(差示扫描量热法)在图6中显示的谱中表征了阿戈美拉汀/苯磺酸(2/1)复合物,图6在约116℃显示对应于复合物的熔化的吸热峰。
本发明还涉及得到阿戈美拉汀和磺酸的复合物的方法,其中:
-将这两种组分在有机溶剂或含水-有机溶剂中以所需比例混合;
-将得到的溶液搅拌,并任选地在不超过所选溶剂沸点的温度加热;
-将该混合液在搅拌下冷却,复合物自然沉淀,或者在加入第二种溶剂中后沉淀;
-将得到的沉淀过滤,并干燥。
在本发明的方法中,使用的溶剂优选为酮,例如丙酮;醚,例如二异丙醚、四氢呋喃或甲基叔丁基醚;或芳烃,例如甲苯。当使用第二种溶剂以促进复合物的沉淀时,所选择的溶剂是醇,例如,甲醇、乙醇或叔丁醇;烷烃,例如正己烷或正庚烷;或苄腈。
备选的方法包括将共晶(co-crystal)的两种组分共同研磨。所述共同研磨优选在钢罐中进行。该方法的变通方案包括在研磨过程中加入有机溶剂;在该情况中,然后将得到的共晶干燥。在使用的溶剂中,可提及的更尤其是酮,例如丙酮;或醚,例如二异丙醚或甲基叔丁基醚。还可以使用醇,例如甲醇,乙醇或叔丁醇。
有利地使用不可氧化的球进行所述研磨。使用振动进行所述研磨,优选地振动频率范围为20至30Hz。振动可施加5分钟至3小时范围的时间。
另一个备选方法包括将含每种组分的两种溶液混合,并将得到的混合液在非常低的温度快速冷冻,然后在相同低的温度将由此得到的共晶干燥。将所述两种组分有利地在有机溶剂或含水-有机溶剂中混合。冷冻和干燥优选在-40℃至-60℃、最优选在-40℃进行。
另一个有利的本发明方法包括将阿戈美拉汀粉末和所述酸的粉末在混合器中混合,然后通过没有冲模的双螺旋挤出方式将混合物挤出以直接在挤出机出口得到固体颗粒。使用的螺旋模式(profil)优选为高剪切模式,任选地使用捏和机组件以使得各组分间的接触面得到改善。螺旋的L/D参数可从10至40变化,且旋转速度为10至200rpm。使用的温度在40至100℃变化。
所得到的阿戈美拉汀和磺酸的复合物的溶解度相比阿戈美拉汀本身有非常显著的提高,这使得它们更加适合用于制备药物制剂。本发明的阿戈美拉汀和磺酸的复合物还展现出优秀的稳定性和非常好的纯度。此外,它们通过不包括任何困难步骤的简单方法获得。
包含本发明复合物的药物形式用于治疗褪黑激素能***障碍,更加尤其是用于治疗应激、睡眠障碍、焦虑症、尤其是广泛性焦虑症、强迫症、心境障碍、尤其是双相性精神障碍、重性抑郁症、季节性情感障碍、心血管病变、消化***病变、由时差综合征导致的失眠和疲劳、精神***症、惊恐发作、忧郁症、食欲障碍、肥胖、失眠、疼痛、精神病性精神障碍、癫痫、糖尿病、帕金森病、老年性痴呆、与正常或病理性老化相关的各种障碍、偏头痛、记忆丧失、阿尔茨海默病,还用于脑循环障碍。在另一个活性领域,可能的是将本发明的共晶用于性功能障碍,作为***抑制剂和免疫调节剂,以及用于治疗癌症。
本发明还涉及药物组合物,其包含作为活性成分的本发明的阿戈美拉汀和磺酸的复合物,以及一种或多种辅助剂或赋形剂。
在本发明的药物组合物中更特别地可提及的是适用于经口、胃肠外(静脉内或皮下)或经鼻施用的那些、片剂或糖锭剂、颗粒剂、舌下片、胶囊剂、锭剂、栓剂、霜剂、软膏剂、皮肤凝胶剂、注射剂、可饮用混悬剂和咀嚼胶。
可用的剂量可以根据障碍的性质和严重性、施用途径和患者的年龄和体重而改变。剂量为0.1mg至1g阿戈美拉汀每天,分一次或多次施用。
本发明的代表性的实施例使用相应的附图阐示,以便更好的评价本发明的主题、特征和优势。
图1:实施例1的阿戈美拉汀/1,5-萘二磺酸(2/1)复合物的X-射线粉末衍射图。
图2:实施例1的阿戈美拉汀/1,5-萘二磺酸(2/1)复合物的DSC热分析图。
图3:实施例2的阿戈美拉汀/1,5-萘二磺酸(2/1)一水合物复合物的X-射线粉末衍射图。
图4:实施例2的阿戈美拉汀/1,5-萘二磺酸(2/1)一水合物复合物的DSC热分析图。
图5:实施例3的阿戈美拉汀/苯磺酸(2/1)复合物的X-射线粉末衍射图。
图6:实施例3的阿戈美拉汀/苯磺酸(2/1)复合物的DSC热分析图。
实施例1:阿戈美拉汀/1,5-萘二磺酸(2/1)复合物
操作1
将阿戈美拉汀(5.00g,2当量)和无水1,5-萘二磺酸(2.96g,1当量)置于反应器中。加入20ml丙酮。将该混悬液在回流下搅拌1小时,然后立即过滤。将滤饼用丙酮洗涤两次,然后干燥1小时。得到对应标题产物的25g白色固体。
收率:78.5%
熔点:237℃
操作2
将阿戈美拉汀(2.98g,2当量)和1,5-萘二磺酸四水合物(2.18g,1当量)转移至250-ml烧瓶中。加入100ml丙酮,并将该反应混合液回流3小时(在约1小时后发生结晶)。将该混悬液冷却至环境温度,并搅拌1小时。通过过滤分离出4.03g对应于标题产物的白色固体,并在真空下(10毫巴)在40℃干燥15小时。
收率:85.0%
熔点:237℃
操作3
将阿戈美拉汀(5.00g,2当量)和无水1,5-萘二磺酸(2.96g,1当量)置于反应器中。加入40ml甲基叔丁基醚。将该混悬液在回流下搅拌3小时,然后立即过滤。将滤饼用甲基叔丁基醚洗涤两次,然后干燥1小时。得到5.28g对应标题产物的白色固体。
收率:66.3%
熔点:237℃
实施例2:阿戈美拉汀/1,5-萘二磺酸(2/1)一水合物复合物
操作1
将阿戈美拉汀(5.00g,1当量)和无水1,5-萘二磺酸(5.92g,1当量)置于反应器中。加入10ml乙醇和20ml水。将该混悬液在回流下搅拌0.5小时,以使其变澄清。然后将该混合物在搅拌下自然冷却0.5小时,并将该混悬液过滤。将滤饼用乙醇和水洗涤,然后干燥1小时。得到5.15g白色固体。
收率:63.2%
熔点:116℃(脱水吸热),238℃
操作2
将阿戈美拉汀(5.00g,1当量)和1,5-萘二磺酸四水合物(7.40g,1当量)转移至反应器中。加入10ml乙醇和20ml水。将该混悬液在回流下搅拌0.5小时以使得其变澄清。然后将该混合液在搅拌下自然冷却0.5小时,并将该混悬液过滤。将滤饼用乙醇和水洗涤,然后干燥1小时。得到4.90g白色固体。
收率:60.2%
熔点:116℃(脱水吸热),238℃
操作3
将阿戈美拉汀(0.5g)和1,5-萘二磺酸四水合物(0.370g)置于50-ml不可氧化的罐中。加入两个12mm直径的不锈钢球,并将该罐封闭。施加频率30Hz的振动达15分钟,在环境温度干燥过夜后,得到0.805g固体。
熔点:116℃(脱水吸热),238℃
操作4
将阿戈美拉汀(0.5g)和1,5-萘二磺酸四水合物(0.370g)置于50-ml不可氧化的罐中。加入两个12mm直径的不锈钢球,并将该罐封闭。加入100μl甲基叔丁基醚。施加频率30Hz的振动达30分钟,在环境温度干燥过夜后,得到0.803g固体。
熔点:116℃(脱水吸热),238℃
实施例3:阿戈美拉汀/苯磺酸(2/1)复合物
将阿戈美拉汀(5.00g,2当量)和苯磺酸(1.62g,1当量)转移至反应器中。加入10ml乙醇和15ml(10ml+5ml)甲苯。将该混悬液在回流下搅拌0.5小时以使其变澄清(如果溶液不澄清,加入更多的乙醇直至其变得澄清)。然后将该混合液在搅拌下自然冷却0.5小时至5℃,并将该混悬液过滤。将滤饼干燥1小时。得到4.31g对应标题产物的白色固体。
收率:65.2%
熔点:116℃
在以上实施例中,可能使用可商购的阿戈美拉汀或通过现有技术中所述的方法之一制备的阿戈美拉汀。
实施例4:药物组合物:含25mg阿戈美拉汀的剂量的胶囊剂
含实施例1的化合物的药物组合物
含实施例2的化合物的药物组合物
含实施例3的化合物的药物组合物
实施例5:药物组合物:片剂各自包含25mg剂量的阿戈美拉汀制备1000片的配方,每片含25mg阿戈美拉汀
制备1000片的配方,每片含25mg阿戈美拉汀
制备1000片的配方,每片含25mg阿戈美拉汀
测定方法和结果
1.样品纯度
色谱条件:C18柱;移动相:磷酸盐缓冲液10mmol/L(用NaOH调节至pH7.0):乙腈2:7(v/v);柱温:40℃;测定波长:220nm;内标法,使用实施例1的化合物。
使用移动相制备1mg/ml本发明的各化合物的溶液。将10μl的每种溶液注入液相色谱***,并记录色谱。
本发明的各化合物均具有超过或等于99%的纯度。
2.稳定性
将实施例1、2和3的化合物的样品在变性条件下置于恒温箱中,在2个月的时间通过DSC测量来测定稳定性。结果在表4中呈现:
表4
25℃,60%RH OB | 50℃ CB | 70℃ CB | |
实施例1的化合物 | 稳定 | 稳定 | 稳定 |
实施例2的化合物 | 稳定 | 稳定 | 稳定 |
实施例3的化合物 | 稳定 | 稳定 | 稳定 |
RH=相对湿度;OB=开口瓶;CB=封闭瓶
本发明的化合物在高度变性条件下稳定,这有利于它们在药物组合物中的应用。
3.溶解度
使用外标法,通过HPLC来测试实施例1、2和3的化合物,并与形式II的阿戈美拉汀比较。结果以溶解度的%增加的形式在表5中呈现,所述溶解度的%增加是相对于形式II的阿戈美拉汀的溶解度而言的:
表5
结果显示,在水中、在类似于人胃液的0.1NHCl中、或在pH6.8的缓冲液中,本发明的阿戈美拉汀和磺酸的复合物均具有比形式II的阿戈美拉汀本身更高的溶解度。这些结果显示所述复合物在生物利用度方面具有远胜于形式II的阿戈美拉汀的潜力。
4.DSC分析
除非另外说明,称量约5-10mg实施例1、2和3的化合物至用穿孔的(不密闭的)铝盖封盖的铝坩埚中。将样品引入TAQ1000装置(装备有冷却器)中,冷却,并保持在25℃。在热稳定后,将样品和参考以10℃/min的速度从200℃加热至250℃,并记录对热流的响应。将氮气以100cm3/min的流速用作净化气体。
在图2、4和6中显示使用实施例1、2和3的化合物获得的DSC热分析图。
5.晶体结构的分析
实施例1、2和3的产物的X-射线粉末衍射图的测定条件如下:
将约50mg实施例1、2和3的化合物置于两个膜之间,并固定于样品载体。然后在以下的条件下将样品置于传输模式的PANALYTICALXPERT-PROMPD衍射仪中:
发生器的参数:45kV/40mA
配置θ/θ
阳极:Cu
1.54060
1.54443
1.39225
K-A2/K-A1比率0.50000
扫描模式:连续,从3°至55°(布拉格角2θ)
步长[°2θ]0.0170
步持续时间[s]35.5301
起始角度[°2θ]3.0034
完成角度[°2θ]54.9894
旋转:是
在图1、3和5中显示实施例1、2和3得到的X-射线粉末衍射图。
Claims (16)
1.式(I)的阿戈美拉汀和磺酸的复合物:
其中x表示0或1,且RSO3H表示1,5-萘二磺酸或苯磺酸。
2.依据权利要求1的式(I)的阿戈美拉汀复合物,其是阿戈美拉汀/1,5-萘二磺酸(2/1)复合物。
3.依据权利要求2的式(I)的阿戈美拉汀复合物,其通过其X-射线粉末衍射图表征,所述衍射图用如下的晶面间距d、布拉格角2θ(以°±0.2表示)和相对强度表示:
其包括衍射角对应于±0.2°之内的形式。
4.依据权利要求1的式(I)的阿戈美拉汀复合物,其是阿戈美拉汀/1,5-萘二磺酸(2/1)一水合物复合物。
5.依据权利要求4的式(I)的阿戈美拉汀复合物,其通过其X-射线粉末衍射图表征,所述衍射图用如下的晶面间距d、布拉格角2θ(以°±0.2表示)和相对强度表示:
其包括衍射角对应于±0.2°之内的形式。
6.依据权利要求1的式(I)的阿戈美拉汀复合物,其是阿戈美拉汀/苯磺酸(2/1)复合物。
7.依据权利要求6的式(I)的阿戈美拉汀复合物,其通过其X-射线粉末衍射图表征,所述衍射图用如下的晶面间距d、布拉格角2θ(以°±0.2表示)和相对强度表示:
其包括衍射角对应于±0.2°之内的形式。
8.用于得到依据权利要求1至7中的一项的阿戈美拉汀和磺酸的复合物的方法,其特征在于:
-将阿戈美拉汀和磺酸在有机溶剂或含水-有机溶剂中以所需比例混合;
-将得到的溶液搅拌,并任选地在不超过所选溶剂沸点的温度加热;
-将该混合液在搅拌下冷却,共晶自然沉淀,或者在加入第二种溶剂中后沉淀;
-将得到的沉淀过滤,并干燥。
9.依据权利要求1至7中的一项的阿戈美拉汀和磺酸的复合物的制备方法,其特征在于将两种组分共同研磨。
10.依据权利要求1至7中的一项的阿戈美拉汀和磺酸的复合物的制备方法,其特征在于将这两种组分在有机或含水-有机溶剂中混合,然后在非常低的温度冷冻并干燥。
11.依据权利要求1至7中的一项的阿戈美拉汀和磺酸的复合物的制备方法,其特征在于将阿戈美拉汀粉末和所述酸的粉末在混合器中混合,然后通过没有冲模的双螺旋挤出方式将混合物挤出,以直接在挤出机出口得到固体颗粒。
12.药物组合物,其包含作为活性成分的依据权利要求1至7中的一项的阿戈美拉汀和磺酸的复合物之一,以及一种或多种惰性、无毒的可药用载体。
13.用于制备用于治疗褪黑激素能***障碍的药物的依据权利要求12的药物组合物。
14.用于制备药物的依据权利要求12的药物组合物,所述药物用于治疗应激、睡眠障碍、焦虑症、尤其是广泛性焦虑症、强迫症、心境障碍、尤其是双相性精神障碍、重性抑郁症、季节性情感障碍、心血管病变、消化***病变、由时差综合征导致的失眠和疲劳、精神***症、惊恐发作、忧郁症、食欲障碍、肥胖、失眠、疼痛、精神病性精神障碍、癫痫、糖尿病、帕金森病、老年性痴呆、与正常或病理性老化相关的各种障碍、偏头痛、记忆丧失、阿尔茨海默病,还用于脑循环障碍,还用于治疗性功能障碍,作为***抑制剂和免疫调节剂以及用于治疗癌症。
15.用于治疗褪黑激素能***障碍的依据权利要求1至7中的一项的式(I)的戈美拉汀和磺酸的复合物。
16.依据权利要求1至7中的一项的式(I)的阿戈美拉汀和磺酸的复合物,其用于治疗应激、睡眠障碍、焦虑症、尤其是广泛性焦虑症、强迫症、心境障碍、尤其是双相性精神障碍、重性抑郁症、季节性情感障碍、心血管病变、消化***病变、由时差综合征导致的失眠和疲劳、精神***症、惊恐发作、忧郁症、食欲障碍、肥胖、失眠、疼痛、精神病性精神障碍、癫痫、糖尿病、帕金森病、老年性痴呆、与正常或病理性老化相关的各种障碍、偏头痛、记忆丧失、阿尔茨海默病,还用于脑循环障碍,还用于治疗性功能障碍,作为***抑制剂和免疫调节剂以及用于治疗癌症。
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