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CN107011313B - 取代桂皮酰胺衍生物在制备抗焦虑药物中的应用 - Google Patents

取代桂皮酰胺衍生物在制备抗焦虑药物中的应用 Download PDF

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CN107011313B
CN107011313B CN201710038281.3A CN201710038281A CN107011313B CN 107011313 B CN107011313 B CN 107011313B CN 201710038281 A CN201710038281 A CN 201710038281A CN 107011313 B CN107011313 B CN 107011313B
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anxiety
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韩民
马晓慧
周王谊
刘雁勇
李彦川
王晶
周水平
孙鹤
朱永宏
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Jiangsu Hongtai Pharmaceutical Co.,Ltd.
Jiangsu Tasly Diyi Pharmaceutical Co Ltd
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Abstract

本发明提供了一种取代桂皮酰胺衍生物在制备抗焦虑药物中的应用，所述的取代桂皮酰胺衍生物为式(Ⅰ)结构的化合物或其可药用盐作为药物活性成分，具体如下：式中：R1为‑H、‑OH、‑F、‑Cl、‑Br、‑I、‑OCH3、‑OCF3、‑OCHF2、‑OCH2F、‑CF3、‑CHF2、‑CH2F、‑CH3、‑CH3CH2、‑CF3CH2、‑CN、‑NO2、‑NH2或‑COOR5；R2为H、C1‑C10直链烃基、C3‑C10支链烃基、C3‑C10环烃基、C1‑C10羟烷基或N‑取代哌嗪衍生基团；或R2为与相邻的X形成四氢吡咯基、哌啶基或环己亚胺基的基团。

Description

取代桂皮酰胺衍生物在制备抗焦虑药物中的应用
技术领域：
本发明涉及一种药物新用途，特别涉及一种取代桂皮酰胺衍生物在制备抗焦虑药物中的应用。
背景技术：
焦虑症，又称为焦虑性神经症，是神经症这一大类疾病中最常见的一种，以焦虑情绪体验为主要特征。可分为慢性焦虑(广泛性焦虑)和急性焦虑发作(惊恐障碍)两种形式。主要表现为：无明确客观对象的紧张担心，坐立不安，还有植物神经症状(心悸、手抖、出汗、尿频等)。
具体的，
慢性焦虑，又称广泛性焦虑，在没有明显诱因的情况下，患者经常出现过分担心、紧张害怕，但紧张害怕常常没有明确的对象和内容。主要表现为：(1)情绪症状：紧张不安、提心吊胆，恐惧、害怕、忧虑。(2)植物神经症状：头晕、胸闷、心慌、呼吸急促、口干、尿频、尿急、出汗、震颤等躯体方面的症状。(3)运动性不安：坐立不安，坐卧不宁，烦躁，很难静下心来。
急性焦虑发作，又称惊恐发作、惊恐障碍，在正常的日常生活环境中，并没有恐惧性情境时，患者突然出现极端恐惧的紧张心理，伴有濒死感或失控感，同时有明显的植物神经系统症状，主要表现为：(1)濒死感或失控感：突然出现极度恐惧的心理，体验到濒死感或失控感。(2)植物神经系统症状同时出现：如胸闷、心慌、呼吸困难、出汗、全身发抖等。(3)一般持续几分钟到数小时：发作开始突然，发作时意识清楚。
在当今社会，伴随着人们生活节奏的加快和工作压力增大，社会竞争日益激烈，焦虑症的患病率逐年上升。
焦虑症的治疗，通常采用心理治疗和药物治疗，其中：
心理治疗，找出生活中的压力源，避开压力，学习放松技巧，减轻压力；
药物治疗，用抗焦虑药物去平静脑中过度活跃的部分，较为典型的药物苯二氮卓类药物(BDZ)，其抗焦虑作用强，起效快，但长期服用有成瘾性、耐药性及戒断反应等副作用；三环类抗抑郁药(TCAs)对广泛性焦虑有良好疗效，但有较强的抗胆碱能副作用和心脏毒性作用，限制了它们的应用；其他用于抗焦虑的药物也或多或少的存在起效缓慢、药物间相互作用和不良反应等问题。以上副作用常令患者十分顾虑，这种担忧反而加重焦虑，或被迫放弃治疗。停药反应更是医生面临的难中之难。
因此，亟需一种可以有效治疗焦虑，且副作用少的药物。本发明桂皮酰胺衍生物在单次经口给药后能快速跨过血脑屏障从而发挥其抗焦虑效果。
桂皮酰胺，又称苯丙烯酰胺，肉桂酰胺，3-苯基丙烯酰胺，其取代桂皮酰胺衍生物曾经在CN102850317A(申请号为CN201210123842.7)和CN104513172A(申请号为CN201410504555.X)中公开了一系列取代的桂皮酰胺衍生物及其制备方法，动物实验研究发现，取代桂皮酰胺衍生物具有明显的抗抑郁活性。
未见到取代的桂皮酰胺衍生物在抗焦虑方面的报道。
本发明涉及取代桂皮酰胺衍生物在制备抗焦虑药物中的应用。本发明通过考察取代桂皮酰胺衍生物对小鼠在高架十字迷宫实验中进入开臂次数和在开臂停留时间的影响，以及对大鼠在饮水冲突实验中惩罚期饮水次数的影响，验证其在抗焦虑方面的作用，实验证明取代桂皮酰胺衍生物中有17种化合物在给药7天后能在不同程度上增加小鼠进入开臂的次数，并延长小鼠在开臂停留的时间，且能明显增加大鼠在饮水冲突实验中惩罚期饮水次数，从而证明取代桂皮酰胺衍生物可以开发为抗焦虑药物。
发明内容：
本发明涉及取代桂皮酰胺衍生物的新应用。
具体的，本发明提供了取代桂皮酰胺衍生物在制备抗焦虑药物中的应用。
其中，所述焦虑是指慢性焦虑(广泛性焦虑)或者急性焦虑(惊恐发作、惊恐障碍)。
所述的取代桂皮酰胺衍生物为式(Ⅰ)结构的化合物或其可药用盐作为药物活性成分，具体如下：
Figure BDA0001213574530000021
式中：
R1为-H、-OH、-F、-Cl、-Br、-I、-OCH3、-OCF3、-OCHF2、-OCH2F、-CF3、-CHF2、-CH2F、-CH3、-CH3CH2、-CF3CH2、-CN、-NO2、-NH2或-COOR5；
R2为H、C1-C10直链烃基、C3-C10支链烃基、C3-C10环烃基、C1-C10羟烷基或N-取代哌嗪衍生基团；或R2为与相邻的X形成四氢吡咯基、哌啶基或环己亚胺基的基团；
R3或R4各自独立地为H、OH、OR5、F、Cl、Br、I、C1-C10直链烃基、C3-C10支链烃基、CF3、CHF2、CH2F、NO2、NH2、OCF3、OCHF2、OCH2F、OOCR5或COOR5；
或，R3与R4相连形成-OCH2O-、-OCH2CH2O-；
其中，R5为C1-C10直链烃基、C3-C10支链烃基、C3-C10环烃基、C1-C10羟烷基；
n为1、2或3，-(C2-C3)n-单元最少含有一个碳碳单键或者一个碳碳双键；
X为＝O、＝S、H、SH或SR6；
Y为N或NR6、O或S；
R6为H、C1-C10直链烃、C3-C10支链烃、C3-C10环烃或C6-C10芳香烃；
优选的，所述取代桂皮酰胺衍生物如式(Ⅱ)所示，
Figure BDA0001213574530000031
其中，
R1为-H、-OH、-F、-Cl、-Br、-I、-OCH3、-OCF3、-OCHF2、-OCH2F、-CF3、-CHF2、-CH2F、-CH3、-CH3CH2、-CF3CH2、-CN、-NO2、-NH2或-COOR5；
R2为H、C1-C10直链烃、C3-C10支链烃、C3-C10环烃、C6-C10芳香烃或C1-C10烷基醇或N-取代哌嗪衍生物，或R2为与相邻的X形成四氢吡咯基、哌啶基或环己亚胺基的基团。
R5为C1-C10直链烃基、C3-C10支链烃基、C3-C10环烃基、C1-C10羟烷基；
n为1、2或3，-(C2-C3)n-单元最少含有一个碳碳单键或者一个碳碳双键；
X为＝O、＝S、H、SH或SR6；
Y为N或NR6、O或S；其中R6为H、C1-C10直链烃、C3-C10支链烃、C3-C10环烃或C6-C10芳香烃；
或优选的，所述取代桂皮酰胺衍生物如式(Ⅲ)所示，
Figure BDA0001213574530000041
其中，
R3为H、OH、OR5、F、Cl、Br、I、C1-C10直链烃基、C3-C10支链烃基、CF3、CHF2、CH2F、NO2、NH2、OCF3、OCHF2、OCH2F、OOCR5或COOR5；
R4为H、OH、OR5、F、Cl、Br、I、C1-C10直链烃基、C3-C10支链烃基、CF3、CHF2、CH2F、NO2、NH2、OCF3、OCHF2、OCH2F、OOCR5或COOR5；
R5为C1-C10直链烃基、C3-C10支链烃基、C3-C10环烃基、C1-C10羟烷基；
n为1、2或3，-(C2-C3)n-单元最少含有一个碳碳单键或者一个碳碳双键；
X为N或NH；
R2为H、C1-C10直链烃、C3-C10支链烃、C3-C10环烃、C6-C10芳香烃或C1-C10烷基醇或N-取代哌嗪衍生物，或R2为与相邻的X形成四氢吡咯基、哌啶基或环己亚胺基的基团。
本发明的化合物或其可药用酸加成盐，特别优选的是以下化合物：
5′-碘-3′，4′-次甲二氧基桂皮酸异丁基酰胺(Ⅱ-3)
Figure BDA0001213574530000042
5′-氯-3′，4′-次甲二氧基桂皮酸异丁基酰胺(Ⅱ-4)
Figure BDA0001213574530000043
5′-三氟甲基-3′，4′-次甲二氧基桂皮酸异丁基酰胺(Ⅱ-5)
Figure BDA0001213574530000051
5′-三氟甲基-3′，4′-次甲二氧基桂皮酸哌啶基酰胺(Ⅱ-10)
Figure BDA0001213574530000052
3-(5′-三氟甲基-3′，4′-次甲二氧基苯基)-丙酸异丁基酰胺(Ⅱ-11)
Figure BDA0001213574530000053
5-三氟甲基-3，4-次甲二氧基苯甲酸异丁基酰胺(Ⅱ-12)
Figure BDA0001213574530000054
(E)-N-(4-甲基哌嗪基)-5-(5′-三氟甲基-3′，4′-次甲二氧基苯基)-1-戊烯酰胺盐酸盐(Ⅱ-13)
Figure BDA0001213574530000055
(2E,4E)-N-异丁基-7-(5′-三氟甲基-3′，4′-次甲二氧基苯基)-2，4-庚二烯酰胺
(Ⅱ-14)
Figure BDA0001213574530000056
(2E,4E)-N-(4-甲基哌嗪基)-7-(5′-三氟甲基-3′，4′-次甲二氧基苯基)-2，4-庚二烯酰胺胺盐酸盐(Ⅱ-15)
Figure BDA0001213574530000061
N-甲基-(5′-三氟甲基-3′，4′-次甲二氧基)-苯丙胺盐酸盐(Ⅱ-16)
Figure BDA0001213574530000062
3′,4′-二甲氧基-5′-三氟甲基-桂皮酸异丁基酰胺(Ⅲ-2)
Figure BDA0001213574530000063
3′-羟基-4′-甲氧基-5′-三氟甲基-桂皮酸异丁基酰胺(Ⅲ-4)
Figure BDA0001213574530000064
3′,4′-二羟基-5′-三氟甲基-桂皮酸异丁基酰胺(Ⅲ-7)
Figure BDA0001213574530000065
3′,4′-二羟基-5′-三氟甲基-桂皮酰基哌啶(Ⅲ-9)
Figure BDA0001213574530000066
3-(3′,4′-二羟基-5′-三氟甲基苯基)-丙酸异丁基酰胺(Ⅲ-10)
Figure BDA0001213574530000067
3,4-二羟基-5-三氟甲基-苯甲酸异丁基酰胺(Ⅲ-11)
Figure BDA0001213574530000071
5-(5′-三氟甲基-3′,4′-二甲氧基苯基)戊二烯酸异丁基酰胺(Ⅲ-13)
Figure BDA0001213574530000072
本发明所述的应用，其中所述药物可以是含有本发明化合物或其药用盐的药物组合物，可以被制备成任何一种可药用的剂型，这些剂型包括：片剂、胶囊剂、颗粒剂、丸剂、散剂、膏剂、丹剂、粉剂、溶液剂、注射剂、栓剂、喷雾剂、滴剂、贴剂。
本发明的药物组合物，其口服给药的制剂可含有常用的赋形剂，诸如粘合剂、填充剂、稀释剂、压片剂、润滑剂、崩解剂、着色剂、调味剂和湿润剂。适用的填充剂包括淀粉、蔗糖、纤维素、甘露糖醇、乳糖和其它类似的填充剂。适宜的崩解剂包括淀粉、聚乙烯吡咯烷酮和淀粉衍生物，例如羟基乙酸淀粉钠。适宜的润滑剂包括，例如硬脂酸镁。可通过混合，填充，压片等常用的方法制备固体口服组合物。进行反复混合可使活性物质分布在整个使用大量填充剂的那些组合物中；常用的辅料成分包括：甘露醇、山梨醇、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素C、EDTA二钠、EDTA钙钠，一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、吐温80、琼脂、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β-环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁等。
本发明的制剂在使用时根据况确定用法用量，可以每日服1-5次。
本发明提供的取代桂皮酰胺衍生物的新应用具有以下优点：
1、发明人发现本发明提供的化合物能够改善焦虑症，并发现该衍生物能快速透过血脑屏障，具有起效快的特点。同时，对焦虑导致的睡眠障碍也有较明显的改善作用。
2、经动物自主活动评估证实，本发明提供的化合物抗焦虑活性不是化合物对动物活动度抑制作用的继发结果；此外以5g/kg的剂量灌服该化合物，动物未见明显不良反应，说明其安全性高，耐受性好。
3、传统的中枢苯二氮卓类抗焦虑药物如地西泮具有镇静、肌肉松弛等副作用，从而限制了其在临床中的应用。
经利用Western-blot技术检测相关基因的表达变化，发现本发明所述的17种化合物可调节线粒体自噬相关基因的表达，可能为外周型苯二氮卓受体的结合性配体。外周型苯二氮卓受体与本发明所述的化合物结合后，能刺激线粒体分泌类固醇，调节生物的行为，表现出明显的抗焦虑作用，且无镇静、肌松等副作用。
所以，相比于传统的中枢苯二氮卓类抗焦虑药物，本发明所述的化合物可能具有起效快，副反应少且不易产生耐受性等优势。
具体实施方式
以下通过实施例进一步说明本发明。
化合物Ⅱ-3、Ⅱ-4、Ⅱ-5、Ⅱ-10、Ⅱ-11、Ⅱ-12及其制备方法见CN201210123842.7(公开号为CN102850317A)；
化合物Ⅲ-2、Ⅲ-4、Ⅲ-7、Ⅲ-9、Ⅲ-10、Ⅲ-11、Ⅲ-13及其制备方法见CN201410504555.X(公开号为CN104513172A)；
化合物Ⅱ-13、Ⅱ-14、Ⅱ-15、Ⅱ-16的制备方法见实施例1-4。
实施例1：(E)-N-(4-甲基哌嗪基)-5-(5′-三氟甲基-3′，4′-次甲二氧基苯基)-1-戊烯酰胺盐酸盐(Ⅱ-13)
Figure BDA0001213574530000081
步骤1：将化合物1(1.53g，4.0mmol)置于100ml的单口瓶中，加入15ml氯仿溶解，再将化合物2(1g，4.0mmol)加到反应体系中，室温搅拌反应14h；TLC监测(展开剂PE:EA＝5:1)显示反应完全；然后将反应物直接浓缩得粗产物化合物3，经硅胶柱色谱纯化(PE:EA＝5:1)后，得到1.1g白色固体化合物3，收率78.87％。
步骤2：把化合物3(0.3g，0.87mmol)溶于5ml二氯甲烷中，降温至0℃；将三氟乙酸(1ml)滴加到反应体系中，然后将反应体系升温的室温下反应；1h后TLC显示原料反应完毕，把反应体系直接浓缩，得到化合物4白色固体0.21g(84％)。
步骤3：把化合物4(0.48g，1.66mmol)、N-甲基哌嗪(0.5g，5mmol)、DIPEA(0.43g，3.34mmol)、加到二氯甲烷中，氮气置换三次，然后加入HATU(0.95g，2.5mmol)室温下搅拌6h；反应体系经水洗涤，有机相干燥浓缩得到粗品，经硅胶柱色谱纯化后得到400mg无色油状物；然后用2ml的二氧六环溶解，再加入4ml的二氧六环的盐酸溶液，室温下搅拌30min，浓缩干燥得到43mg化合物Ⅱ-13(65％)。
1H NMR(DMSO,400MHz):δ11.28-11.27.00(1H,NH,br),7.11(1H,s),6.94(1H,s),6.70(1H,d,J＝15.2Hz),6.50(1H,d,J＝15.2Hz),6.17(2H,s),4.33(2H,br),3.42-3.20(6H,br),2.75(4H,s),2.51(3H,s)；
ESI-MS:371.1[M+H]+
实施例2：(2E,4E)-N-异丁基-7-(5′-三氟甲基-3′，4′-次甲二氧基苯基)-2，4-庚二烯酰胺(Ⅱ-14)
Figure BDA0001213574530000091
步骤1：50ml三口瓶中加入化合物5(650mg，2.6mmol)、20ml无水四氢呋喃、氢氧化锂(326mg，7.8mmol)，N2保护下加热至70℃反应1小时。将化合物1(0.76g，2.0mmol)溶于10ml无水四氢呋喃中，0.5小时内将其滴入反应瓶中。反应液于70℃反应10小时。薄层色谱检测，反应完全后停止加热。将反应液旋转蒸发浓缩至干，加入20ml蒸馏水使固体溶解。向上述溶液中慢慢滴加2N盐酸至pH 2.0，继续搅拌1小时，析出淡黄色固体，减压抽滤收集固体，真空干燥得到化合物6(400mg,65％)。
步骤2：把物料6(400mg，1.4mmol)、EDCI(410mg，2.14mmol)、异丁胺(310mg，4.2mmol)溶到20ml二氯甲烷中，室温搅拌反应6后TLC显示原料反应完，然后把反应体系直接缩干，粗产品经硅胶柱色谱纯化(正己烷：乙酸乙酯＝3:1)后，得到270mg白色固体Ⅱ-14(52％)。
1H NMR(DMSO,400MHz):δ7.18(1H,dd,J1＝10.8Hz,J2＝4.4Hz),6.80(1H,d,J＝5.6Hz),6.11(2H,m),6.06(2H,s),5.76(1H,d,J＝15.2Hz),5.46(1H,s),3.17(2H,t,J＝6.0Hz),2.68(2H,t,J＝7.6Hz),2.44(2H,m),1.80(1H,m),0.94(3H,s),0.92(3H,s)；
ESI-MS:370.1[M+H]+
实施例3：(2E,4E)-N-(4-甲基哌嗪基)-7-(5′-三氟甲基-3′，4′-次甲二氧基苯基)-2，4-庚二烯酰胺盐酸盐(Ⅱ-15)
Figure BDA0001213574530000101
化合物6(0.52g，1.66mmol)、N-甲基哌嗪(0.5g，5mmol)、DIPEA(0.43g，3.34mmol)加到二氯甲烷中，然后加入HATU(0.95g，2.5mmol)室温下搅拌6h；反应体系经水洗涤，有机相干燥浓缩得到粗品，经硅胶柱色谱纯化后得到350mg无色油状物；然后用2ml的二氧六环溶解，再加入4ml的二氧六环的盐酸溶液，室温下搅拌30min，浓缩干燥得到370mg化合物Ⅱ-15(53％)。
1H NMR(MeOD,400MHz):δ7.25(1H,dd,J1＝10.8Hz,J2＝4.4Hz),6.96(1H,s),6.87(1H,s),6.48(1H,d,J＝14.8Hz),6.31(1H,dd,J1＝10.8Hz,J2＝4.4Hz),6.21(1H,m),6.10(2H,s),4.87(2H,br),3.77-3.50(3H,br),3.40-3.10(3H,br),3.15(3H,s),2.76(2H,t,J＝7.2Hz),2.50(2H,t,J＝7.2Hz)；
ESI-MS:397.1[M+H]+
实施例4：N-甲基-(5′-三氟甲基-3′，4′-次甲二氧基)-苯丙胺盐酸盐(Ⅱ-16)
Figure BDA0001213574530000102
50ml三口瓶中加入化合物1(650mg，2.6mmol)、甲胺溶液(0.4ml，5.1mmol)，氰基硼氢化钠(430mg，5.2mmol)加入至20ml无水甲醇中，室温反应6小时。反应液加入50ml水，乙酸乙酯(50ml×2)萃取后，浓缩有机相得粗产物，粗产物经硅胶柱色谱(正己烷：乙酸乙酯＝1:1)纯化后得320mg油状物；
然后用2ml的二氧六环溶解，再加入4ml的二氧六环的盐酸溶液，室温下搅拌30min，浓缩干燥得到340mg化合物Ⅱ-16(47％)。
1H NMR(D2O,400MHz):δ6.93(1H,s),6.92(1H,s),6.01(2H,s),2.93(2H,t,J＝8.0Hz),2.62(2H,t,J＝8.0Hz),2.61(3H,s),1.90(2H,m)；
ESI-MS:263.2[M+H]+
实施例5：滴丸制剂的制备
取化合物Ⅱ-3、Ⅱ-4、Ⅱ-5、Ⅱ-10、Ⅱ-11、Ⅱ-12、Ⅱ-13、Ⅱ-14、Ⅱ-15、Ⅱ-16，Ⅲ-2、Ⅲ-4、Ⅲ-7、Ⅲ-9、Ⅲ-10、Ⅲ-11、或Ⅲ-13 0.5g，与10.5g聚乙二醇-6000混合均匀，加热熔融，化料后移至滴丸滴灌中，药液滴至6-8℃液体石蜡中，除油，制得滴丸500粒。
实施例6：注射剂
取化合物Ⅱ-3、Ⅱ-4、Ⅱ-5、Ⅱ-10、Ⅱ-11、Ⅱ-12、Ⅱ-13、Ⅱ-14、Ⅱ-15、Ⅱ-16，Ⅲ-2、Ⅲ-4、Ⅲ-7、Ⅲ-9、Ⅲ-10、Ⅲ-11、或Ⅲ-13 0.5g，以及葡萄糖4.5g、硫代硫酸钠0.9g和蒸馏水1ml，上述组分混合均匀后，冷冻干燥，分装500支，即得。
以下通过实验数据说明本发明的有益效果：
实验例1：小鼠高架十字迷宫实验
(一)实验材料
1、待测样品
取代桂皮酰胺衍生物如化合物Ⅱ-3、Ⅱ-4、Ⅱ-5、Ⅱ-10、Ⅱ-11、Ⅱ-12、Ⅱ-13、Ⅱ-14、Ⅱ-15，Ⅱ-16，Ⅲ-2、Ⅲ-4、Ⅲ-7、Ⅲ-9、Ⅲ-10、Ⅲ-11、Ⅲ-13：由天士力控股集团有限公司研究院中药所提供。
样品处理：向2wt％的吐温80水溶液中加入化合物Ⅱ-3、Ⅱ-4、Ⅱ-5、Ⅱ-10、Ⅱ-11、Ⅱ-12、Ⅱ-13、Ⅱ-14、Ⅱ-15，Ⅱ-16，Ⅲ-2、Ⅲ-4、Ⅲ-7、Ⅲ-9、Ⅲ-10、Ⅲ-11、Ⅲ-13，分别将上述化合物配制成浓度为0.5mg/ml的溶液。
地西泮，生产厂家：北京益民药业有限公司，规格：2.5mg/片，国药准字H11020898，临用时通过2wt％的吐温80水溶液配制成含有0.075mg/ml药品的溶液。
2、实验动物
SPF级ICR雄性小鼠，购买自北京维通利华实验动物技术有限公司，实验动物生产许可证：SCXK(京)2012-0001。
饲养条件：屏障动物房饲养，温度20-25℃，相对湿度40％-60％，每笼12只，自由饮食，饲料为灭菌全价鼠专用饲料，该饲料由北京华埠康生物科技股份有限公司提供；每日更换垫料。
3、实验仪器
高架十字迷宫：北京新天地科技有限责任公司。
(二)实验方法
取247只ICR小鼠，雄性，鼠龄6-8周，体重18-22g，适应性喂养1周。然后，将小鼠按体重随机平均分入19个组中，按表1中所列药物和剂量每日灌胃给药1次，连续给药7天。在第7天给药20min后进行高架十字迷宫实验。
小鼠高架十字迷宫(EPM)，由两个相对的敞开臂(openarms,50cm×10cm)和两个相对的闭臂(en-closedarms，50cm×10cm×40cm)组成，闭臂上部未封顶，迷宫中央为10cm×10cm的开阔部，迷宫离地面50cm。实验于13:00～18:00安静环境下进行。
各给药组连续给药7天，受试物于末次给药后20min，阳性药地西泮于末次给药后60min进行高架十字迷宫实验，将每只小鼠放入一个60cm×60cm×35cm塑料盒中，让其熟悉环境5min后再置于迷宫中央，记录5min内小鼠分别进入开臂和闭臂的次数以及在两臂内的滞留时间，计算各组小鼠进入开臂的次数(open-armsentries，OE)和在开臂停留时间(open-armstime，OT)分别占进入两臂总次数和在两臂停留总时间的百分比(OE％和OT％)。
(三)实验统计
采用SPSS 11.5软件进行分析，数据以x±S表示，用方差分析比较组间差异的显著性，P＜0.05为有显著性差异。
(四)实验结果
本实验评价了本发明17个化合物对小鼠在高架十字迷宫实验中进入开臂次数和在开臂停留时间的影响。
表1各化合物对小鼠进入开臂次数及在开臂停留时间的影响
Figure BDA0001213574530000121
Figure BDA0001213574530000131
注：与溶剂对照组相比，*p<0.05，**p<0.01
表1实验结果显示：将本发明化合物Ⅱ-3、Ⅱ-4、Ⅱ-5、Ⅱ-10、Ⅱ-11、Ⅱ-12、Ⅱ-13、Ⅱ-14、Ⅱ-15，Ⅱ-16，Ⅲ-2、Ⅲ-4、Ⅲ-7、Ⅲ-9、Ⅲ-10、Ⅲ-11、Ⅲ-13，以10mg/kg剂量灌胃给药1周后，与溶剂对照组相比，均能延长小鼠进入开臂的次数，并延长在其在开臂停留的时间，上述结果在统计学上的差异显著(p<0.05，p<0.01)。
实验结论：在高架十字迷宫实验中，以10mg/kg的剂量，将本发明所述的17种化合物给药7天均能在不同程度上增加高架十字迷宫实验中小鼠进入开臂的次数，并延长小鼠在开臂停留的时间。
实验结果可以证明：本发明所述的17种化合物具有显著的抗焦虑活性。
实验例2：大鼠饮水冲突实验
(一)实验材料
1、待测样品
取代桂皮酰胺衍生物如化合物Ⅱ-3、Ⅱ-4、Ⅱ-5、Ⅱ-10、Ⅱ-11、Ⅱ-12、Ⅱ-13、Ⅱ-14、Ⅱ-15，Ⅱ-16，Ⅲ-2、Ⅲ-4、Ⅲ-7、Ⅲ-9、Ⅲ-10、Ⅲ-11、Ⅲ-13：由天士力控股集团有限公司研究院中药所提供。
样品处理：向2wt％的吐温80水溶液中加入化合物Ⅱ-3、Ⅱ-4、Ⅱ-5、Ⅱ-10、Ⅱ-11、Ⅱ-12、Ⅱ-13、Ⅱ-14、Ⅱ-15，Ⅱ-16，Ⅲ-2、Ⅲ-4、Ⅲ-7、Ⅲ-9、Ⅲ-10、Ⅲ-11、Ⅲ-13，分别将上述化合物配制成浓度为0.5mg/ml的溶液。
地西泮，生产厂家：北京益民药业有限公司，规格：2.5mg/片，国药准字H11020898，临用时通过2wt％的吐温80水溶液配制成含有0.01mg/ml药品的溶液。
2、实验动物
SPF级雄性SD大鼠，购买自北京维通利华实验动物技术有限公司，实验动物生产许可证：SCXK(京)2012-0001。
饲养条件：屏障动物房饲养，温度20-25℃，相对湿度40％-60％，每笼6只，自由饮食，饲料为灭菌全价鼠专用饲料，该饲料由北京华埠康生物科技股份有限公司提供；每日更换垫料。
3、实验仪器
Vogel test(吮水电击)焦虑测试系统，型号：LE100-25，美国哈佛仪器公司生产。
(二)实验方法
230只SD大鼠，雄性，体重180-220g，适应性喂养1周后按体重随机分19组，每组12-13只，按表2中所列药物和剂量每日灌胃给药1次，连续给药10天，末次给药前48h禁水，第9d进行非惩罚性饮水训练；第10d所有组末次灌胃0.5h后，进行惩罚实验测试。
第一阶段，非惩罚饮水训练：将大鼠禁水24h后单个置于操作箱，让其充分探究，直到发现瓶嘴并开始舔水，计数器自动记录无电击条件下大鼠3min的舔水次数设置条件：电击强度0mA)，淘汰舔水少于300次的大鼠。第二阶段，惩罚实验：上述未被淘汰的大鼠继续禁水24h(共48h)后置于操作箱。大鼠能很快找到瓶嘴并开始舔水，舔够20次仪器自动开始计时并给予一次电击(舔水与电击次数之比为20:1)，电击强度为0.3mA，持续2s，但是大鼠可通过脱离瓶嘴来控制受电击时间的长短。记录惩罚期(3min)大鼠的舔水次数。
Vogel饮水冲突模型观察指标：惩罚期内大鼠的舔水次数。
(三)实验统计
采用SPSS 11.5软件进行分析，数据以x±S表示，用方差分析比较组间差异的显著性，P＜0.05为有显著性差异。
(四)实验结果
本实验评价了本发明17个化合物对大鼠饮水冲突实验中惩罚期大鼠舔水次数的影响。
表2各化合物对惩罚期大鼠舔水次数的影响
Figure BDA0001213574530000141
Figure BDA0001213574530000151
注：与溶剂对照组相比，*p<0.05，**p<0.01
表2实验结果显示：将本发明化合物Ⅱ-3、Ⅱ-4、Ⅱ-5、Ⅱ-10、Ⅱ-11、Ⅱ-12、Ⅱ-13、Ⅱ-14、Ⅱ-15，Ⅱ-16，Ⅲ-2、Ⅲ-4、Ⅲ-7、Ⅲ-9、Ⅲ-10、Ⅲ-11、Ⅲ-13，以5mg/kg剂量灌胃给药10d后，与溶剂对照组相比，均能增加大鼠惩罚期饮水次数，上述结果在统计学上的差异显著(p<0.05，p<0.01)。
实验结论：大鼠饮水冲突实验中，以5mg/kg的剂量，将本发明所述的17种化合物给药10天均能在不同程度上增加大鼠惩罚期的饮水次数。
实验结果可以证明：本发明所述的17种化合物具有抗焦虑活性。

Claims (4)

1.取代桂皮酰胺衍生物在制备抗焦虑的药物中的应用，所述取代桂皮酰胺衍生物为以下化合物：
N-甲基-(5′-三氟甲基-3′，4′-次甲二氧基)-苯丙胺盐酸盐(Ⅱ-16)
Figure FDF0000013821900000011
2.取代桂皮酰胺衍生物在制备抗焦虑的药物中的应用，其特征在于，所述取代桂皮酰胺衍生物为以下化合物：
3′-羟基-4′-甲氧基-5′-三氟甲基-桂皮酸异丁基酰胺(Ⅲ-4)
Figure FDF0000013821900000012
3′4′-二羟基-5′-三氟甲基-桂皮酸异丁基酰胺(Ⅲ-7)
Figure FDF0000013821900000013
3-(3′,4′-二羟基-5′-三氟甲基苯基)-丙酸异丁基酰胺(Ⅲ-10)
Figure FDF0000013821900000014
5-(5′-三氟甲基-3′,4′-二甲氧基苯基)戊二烯酸异丁基酰胺(Ⅲ-13)
Figure FDF0000013821900000015
3.根据权利要求1所述的应用，其特征在于，所述焦虑是指慢性焦虑或者急性焦虑。
4.根据权利要求2所述的应用，其特征在于，所述焦虑是指慢性焦虑或者急性焦虑。
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