CN103826622A - 用于预防或治疗情感障碍的n-取代的苯丙酰胺或苯丙烯酰胺 - Google Patents
用于预防或治疗情感障碍的n-取代的苯丙酰胺或苯丙烯酰胺 Download PDFInfo
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- CN103826622A CN103826622A CN201280045760.3A CN201280045760A CN103826622A CN 103826622 A CN103826622 A CN 103826622A CN 201280045760 A CN201280045760 A CN 201280045760A CN 103826622 A CN103826622 A CN 103826622A
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Abstract
用于治疗或预防情感障碍的化合物,该化合物表示为通式I:其中:虚线代表单键或双键;并且R5和R5'独立地是-H、-OH或-OR6,其中R6是直链的或支链的C1-C4烷基;X是-CH2O-;Z是-CH2CH2O-、-CH(CH3)CH2O-或-CH2CH(CH3)O-;m是1;并且n是1-5的整数;或其药学上可接受的盐、前药、代谢物或水合物。
Description
技术领域
本发明涉及情感障碍如焦虑和抑郁的治疗或预防并且提供治疗或预防情感障碍的方法以及某些化合物在制备用于治疗或预防人类和非人类动物中的情感障碍的药物中的用途。
背景技术
情感障碍是多方面(包括生物的、行为的、社会的和心理的因素)的精神病学疾病。情感障碍的特征在于作为主要的临床表现的情绪变化。这类障碍包括抑郁、焦虑、双相型障碍、产后抑郁、心境恶劣、季节性情感障碍、情感分离障碍、惊恐性障碍、进食障碍、强迫症和创伤后应激障碍。情绪紊乱(抑郁、焦虑、得意和兴奋)很严重的情况下,患者可能另外经历精神病症状。
重度抑郁症(MDD)、双相型障碍和焦虑症是最常见的情感障碍。这类复发性情绪障碍能够具有毁灭性的长期效应,并且这些疾病在人类受难、生产力和卫生保健方面的花费是巨大的。情感障碍可以导致从温和和不方便到严重和威胁生命范围的症状;由于罹患所述障碍之一的患者的自杀,后者导致15%以上的死亡。
重度抑郁症(MDD),也被称为单相抑郁或单极情感障碍,是常见的、严重的,并且有时威胁生命的精神病学疾病,MDD导致长时间的情绪的、精神的和身体的衰竭,具有自我摧残和自杀的高风险。主要研究已经确认MDD是工作障碍和早逝的主要原因之一,其代表越来越多的全球性健康和经济问题。
双相情感障碍依据所表现的症状被划分为不同类型:类型I(双相I或BPI)和类型II(双相II或BPII)疾病,循环情感性精神障碍和轻度躁狂症。双相情感障碍的其他名称包括躁狂-抑郁症、循环性精神病、躁狂-抑郁疾病(MDI)和双相型障碍。双相型疾病的人们经历一段时间的躁狂的(过度兴奋的)发作与一段时间的深度抑郁的交替。双相型障碍是慢性的和复发性的情感疾病,其如果不治疗随时可能有严重程度加重的趋势。严重的危险可以导致在抑郁发作期间自杀的企图或在躁狂发作期间对自己或他人的身体暴力。然而,在许多患者中,发作是温和和稀少的。混合的状态也可能发生,伴随躁狂和抑郁的元素同时存在。一些双相情感障碍的人们表现出在躁狂和抑郁状态之间快速循环。
焦虑症也是常见的精神障碍,并且被认为是最治疗不足和被忽视的健康问题之一。其最常见的临床表现是恐慌型症状、恐惧症、慢性广泛性焦虑症、强迫症和创伤后障碍。焦虑症是其他疾病如高血压、消化和进食障碍、和心律失常的重要原因。严重的焦虑症通常导致烟草成瘾、酒精滥用和药物滥用。
除了自杀,情感障碍的许多其他有害的健康相关的作用已经越来越多地被认识到。远远不是纯粹的心理临床表现,情感障碍是有害作用于多个器官系统的全身性疾病。例如,MDD代表心血管疾病发展以及心肌梗塞指标之后死亡的主要风险因素。而且,一项控制了身体疾病、吸烟和酒精消费的近期研究发现高度抑郁症状的存在导致的死亡风险增加的幅度与中风和充血性心脏衰竭导致的死亡风险增加的幅度相似。
许多患者现在已经认识到长期结果通常远差于先前所想,具有不完全的发作期内(interepisode)恢复,所观察的整体功能内逐步下降。事实上,根据全球疾病负担研究,情绪障碍在全球是失能的主要原因之一,并且在即将到来的几年可能代表越来越多的更大健康的、社会的和经济的问题。
情感障碍往往与中枢神经系统中某些生物胺神经递质,如多巴胺、去甲肾上腺素和血清素的减少相关。因此,许多目前可用的治疗主要是通过提高生物胺神经递质的水平(无论是抑制其吸收或阻止其新陈代谢)而起作用。情感障碍通常用抗抑郁药治疗,包括三环抗抑郁药(TCA)、单胺氧化酶抑制剂(MAOI)、选择性五羟色胺再摄取抑制剂(SSRI)、结合的再摄取抑制剂和受体阻滞剂、血清素和去甲肾上腺素再摄取抑制剂(SNRI)、去甲肾上腺素和多巴胺再摄取抑制剂(NDRI)和四环抗抑郁药。
不幸的是,目前用于治疗情感障碍的可用药物遭受延迟起效、疗效不佳、以及各种副作用。此外,大量的个体对目前可用的治疗保持耐受。鉴于在现有方法的缺点,存在改进用于治疗情感障碍,特别是抑郁症、焦虑症和精神病症状的组合物和方法的需要。
因此,本发明的目的是提供用于治疗或预防焦虑或抑郁的可选择的化合物。本发明的另一个目的是提供用于治疗或预防焦虑或抑郁的可选择的方法。
PCT/IB2009/000448涉及化合物用于治疗疼痛的用途。该申请的实施例涉及以下实验,其中已发现对热板或其他刺激表现出延迟应答的动物,当在旷场实验时没有在它们的常规运动性上表现出变化并且没有被化合物镇静。由于大多数抗抑郁药(例如SSRI和三环药剂)在高剂量使用时表现出一些镇静作用,据此推论:由该申请的化合物导致的镇痛活性不依赖于中枢神经系统的作用。
然而,本发明人现已惊奇地发现,通过进行广泛的前期研究,相比于对照动物,在与焦虑和抑郁相关的行为测试中发现了效果。得到的结果表明,本发明的化合物积极参与CNS中。这已经通过在研究的高级阶段获得的PK数据得到支持。因此,本发明人现在已经得出结论,本发明的化合物可以用于治疗情感障碍如焦虑和抑郁和强迫症。
发明内容
因此,根据本发明的一个方面,提供了用于治疗或预防情感障碍的化合物,所述化合物可以表示为以下通式I:
其中:
虚线代表单键或双键;并且R5和R5'独立地是-H、-OH或-OR6,其中R6是直链的或支链的C1-C4烷基;
X是-CH2O-,
Z是-CH2CH2O-、-CH(CH3)CH2O-或-CH2CH(CH3)O-;m是1;并且n是1-5的整数,优选地n是1或2。
适宜地,所述化合物可以是如上述式I表示的化合物的S-对映异构体。本发明还包含式I的化合物各自的药学上可接受的盐、前药、代谢物和水合物的用途。
术语“情感障碍”是指任何类型的情绪障碍,其症状包括,但不限于,抑郁、焦虑、双相型障碍、产后抑郁、心境恶劣、季节性情感障碍、情感分离障碍、惊恐性障碍、进食障碍、强迫症、创伤后应激障碍,和由酒精或精神活性物质,如苯丙胺、甲基苯丙胺和可卡因诱导的障碍。这些障碍的特征是多种症状,包括但不限于,干扰工作、学习、睡觉、吃饭,并享受一次愉快的活动的能力。
这些疾病是有据可查的,这些疾病的诊断通常是由心理健康提供者使用由美国精神病学协会(American Psychiatric Association)华盛顿特区出版的精神疾病诊断与统计手册(Diagnostic and Statistical Manual of Mental Disorders,DSM)来完成。
本发明的化合物可用于治疗或预防急性或慢性情感障碍。举例来说,该化合物可用于治疗抑郁、焦虑或强迫症。
该化合物可单独使用或与其它抗焦虑或抗抑郁药物联合使用,如磷酸二酯酶抑制剂(例如PDE3、PDE4、PDE5、PDE7和PDE10抑制剂),白三烯D4合成抑制剂,或其他有效治疗情感障碍的药剂,包括但不限于,抗抑郁药(例如选择性血清素再摄取抑制剂(SSRI)例如西酞普兰,依他普仑,氟西汀,三氟戊肟胺,帕罗西汀或舍曲林;三环抗抑郁药(TCA)例如阿米替林,氯米帕明,多塞平,丙咪嗪,三甲丙咪嗪,地昔帕明,去甲替林,普罗替林;四环抗抑郁药(TeCA)例如阿莫沙平,马普替林,马吲哚,米安色林,米氮平,司普替林,单胺氧化酶(MAO)抑制剂例如异唑肼,吗氯贝胺,苯乙肼,司来吉兰,反苯环丙胺;去甲肾上腺素再摄取抑制剂(NRI)例如阿托西汀,马吲哚,瑞波西汀,维洛沙秦;五羟色胺-去甲肾上腺素再摄取抑制剂(SNRI),如去甲文拉法辛,度洛西汀,米那普仑,文拉法辛;和非典型抗抑郁药),抗焦虑药(如苯二氮类如氯硝西泮,地西泮,艾司唑仑,氟硝西泮,劳拉西泮,咪达唑仑,硝西泮,奥沙西泮,三唑仑,替马西泮,氯氮,阿普唑仑;增强γ-氨基丁酸酯活性的药剂;氮哌酮类化合物例如丁螺环酮或坦度螺酮);抗精神病药(如氟哌啶醇,氟哌利多,吩噻嗪,氯丙嗪,氟奋乃静,奋乃静,普鲁氯嗪、甲硫达嗪、三氟拉嗪,美索达嗪,哌氰嗪,普马嗪,三氟丙嗪,左美丙嗪,异丙嗪,哌迷清,噻吨,氯普噻吨,氯噻吨,氟哌噻吨,氨砜噻吨,珠氯噻醇),安定药,镇静药(如异戊巴比妥,戊巴比妥,司可巴比妥,苯巴比妥),肌肉松弛剂(如卡利普多,环苯扎林,美他沙酮,和美索巴莫),抗痉挛药(如加巴喷丁或普加巴林),情绪稳定剂(例如丙戊酸盐,锂或立痛定)和失眠治疗剂(如苯二氮类,唑吡坦,扎来普隆,佐匹克隆和左旋佐匹克隆)。
因此,根据本发明的另一个方面,提供了一种用于治疗或预防人类或非人类动物患者中的情感障碍的方法,所述方法包含向有所需要的所述患者施用治疗有效量的一种或多种本发明的化合物。
对于人类患者而言,所述一种或多种化合物可以适宜地以日剂量1.0mg至15g施用,所述化合物以如下更详述的纯净的、基本上纯净的或部分纯净的形式存在。所述化合物可以在执业医师的监督下以足够实现有效的治疗焦虑或抑郁的量来施用。在某些实施方案中,所述一种或多种化合物的日剂量可以被滴定来检测所述有效量。所述日剂量可以包含大约5.0mg至1g,典型地大约5mg至500mg。在某些实施方案中,所述剂量可以包含每天10mg至100mg的所述一种或多种化合物。所述化合物可以按照每天一至四次的方案来施用。
所述一种或多种化合物可以非肠道、透皮、肌肉内、静脉内、皮内、鼻内、皮下、腹腔内、心室内或直肠内施用。优选地,所述一种或多种化合物为口服施用。
任选地,本发明的一种或多种化合物可以与至少一种其他抗抑郁或抗焦虑药物同时、相继或分别施用。
在本发明的其他另一个方面中,提供了本发明的一种或多种化合物在制备用于治疗或预防焦虑或抑郁的药物中的用途。所述药物可以被制备用于与一种或多种其他抗焦虑或抗抑郁药物共同施用。
如上所述,n可以是1至5,优选1至2。
在本发明的某些实施方案中,本发明的化合物可以表示为以下通式II:
其中n、Z、R5和R5'如上所定义。
Z可以是-CH2CH(CH3)O-。
Z可以是-CH(CH3)CH2O-。
在本发明的某些实施方案中,本发明的化合物因此可以表示为以下通式III:
其中n、R5和R5'如上所定义。
R5可以是H。可选择地,R5可以是OH。
R5'可以是H。可选择地,R5'可以是OH。
适宜地,n可以是1-5的整数,优选1-3的整数,更优选1-2的整数。例如,n可以是1、2、3、4或5。有利地,n可以是1-2,例如,1。
可选择地,本发明的化合物可以是以下通式IV、V、VI和VII表示的化合物的S-对映异构体:
其中R是具有n个单元的聚烷二醇聚合物,其中n如上所定义,特别地n=1-5。
适宜地,所述聚烷二醇聚合物可以是聚异丙二醇。
在一个优选的方面中,本发明的化合物是式VII的化合物,更优选具有以下式中的一种的化合物。
化合物1 (NRD71) 化合物2(NRD135)
化合物3 (NRD175)
除非具体地指出特定的立体化学或异构形式,本发明旨在结构的所有手性的、非对映异构的、外消旋的和几何异构的异构形式。例如,对于化合物2而言,旨在下列异构形式:
化合物1的某些异构形式的例子如下所示:
化合物1的异构形式还包括如下所示的几何异构体,包括所有的R和S排列。
例如,化合物3(NRD175)的某些异构形式如下所示:
用于获得并纯化本发明的化合物的适宜的合成法在下文中详细公开。然而,对于本领域技术人员而言,使用任何其他可行的合成法可以制备所述化合物是显而易见的。
本发明的化合物可以合成为聚烷二醇(PAG)轭合物。可用于所述轭合的聚合物包括聚(乙二醇)(PEG),也被称为聚(环氧乙烷)(PEO)和聚丙二醇(包括聚异丙二醇)。
聚烷二醇(PAG),如PEG,是在每个末端采用羟基封端的直链聚合物:
HO-CH2CH2O-(CH2CH2O)p-CH2CH2-OH。
上述聚合物,α,ω-二羟基聚(乙二醇),还可能表示为HO-PEG-OH,其中可以理解的是,所述-PEG-符号表示下列结构单元:
-CH2CH2O-(CH2CH2O)p-CH2CH2-
其中p可以在0至大约48的范围内变化。PEG可以用作甲氧基-PEG-OH,或mPEG,其中一个末端是相对惰性的甲氧基,而另一个末端是容易被化学修饰的羟基。此外,在化学上与PEG密切相关的不同环氧烷(例如,环氧乙烷和环氧丙烷)的无规或嵌段共聚物可以替代PEG。
所述PAG聚合物可以是直链的或支链的。
可以理解的是,本发明的化合物包含PAG部分,所述PAG部分可以包括聚合物的混合物,所述混合物具有不同数目的单体单位。PAG轭合的化合物的合成可以在轭合物的每个聚合物中产生具有泊松分布数目的单体单位的分子群。因此,被描述为具有n=2单体单位的聚合物的根据本发明的化合物不但是指在那个群体中被描述为具有n=2单体单位的实际聚合物,而且是指分布峰为2或接近于2的分子群。可以通过例如,核磁共振(NMR)或者质谱(MS)测定在给定的群中单体单位的分布。
在本发明的另一个方面中,提供了用于治疗或预防焦虑或抑郁的药物组合物,所述组合物包含药学上有效量的一种或多种本发明的化合物。所述组合物可以进一步包含一种或多种药学上可接受的赋形剂。在某些实施方案中,所述组合物还可以包含另一种抗焦虑或抗抑郁药物,如磷酸二酯酶抑制剂(例如,PDE3、PDE4、PDE5、PDE7和PDE10抑制剂),白三烯D4合成抑制剂,或其他有效治疗情感障碍的药剂,包括但不限于,抗抑郁药、抗精神病药、安定药、镇静药、肌肉松弛剂、抗痉挛药和失眠治疗剂。
“其他抗焦虑或抗抑郁药”包括神经胶质衰减剂,如米诺环素、氟代柠檬酸、MWO1-5-188WH、丙戊茶碱(也是PDE抑制剂)、已酮可可碱(也是PDE抑制剂)、咯利普兰(也是PDE抑制剂)、IL-10,IL-1受体拮抗剂)、TNF-α受体拮抗剂包括中sTNFR、MAP激酶抑制剂、育亨宾、神经胶质细胞氯化物拮抗剂、半胱天冬酶抑制剂、MMP抑制剂、大麻素受体(例如,2型)激动剂、arundic acid(无对应中英文)、他汀类药物、沙利度胺和相关的类似物;磷酸二酯酶抑制剂,如咯利普兰、阿罗茶碱、多索茶碱、西潘茶碱、罗氟司特、替托司特、阿替唑兰、CC-1088、托非米拉斯(Tofimilast)、托拉芬群、已酮可可碱、双嘧达莫、西洛他唑、茶碱、西洛司特、AWE-12-28、丙戊茶碱;抗抑郁药,如三环抗抑郁药,包括但不限于,阿米替林、阿莫沙平、地昔帕明()、多塞平()、丙咪嗪()、去甲替林()、普罗替林()、和三甲丙咪嗪();单胺氧化酶抑制剂,包括但不限于,异卡波肼、优降宁、司来吉兰、呋喃唑酮和苯乙肼;选择性血清素再摄取抑制剂,包括但不限于,西酞普兰()、依他普仑()、氟西汀(Prozac)、帕罗西汀(Paxil)、舍曲林();合并的再摄取抑制剂和受体阻断剂,包括但不限于,曲唑酮、奈法唑酮、和马普替林;5-羟色胺和去甲肾上腺素再摄取抑制剂,包括但不限于,度洛西汀()和文拉法辛(郁复伸(Effexor)、Effexor);去甲肾上腺素和多巴胺再摄取抑制剂,包括但不限于,安非他酮(WellbutrinWellbutrin);和四环抗抑郁药,包括但不限于,米氮平(Reraeron);苯二氮,如地西泮、甲氨二氮、阿普唑仑、氯硝西泮、替马西泮、劳拉西泮、氟西泮、奥沙西泮、氯氮和三唑仑;失眠治疗剂,如氟西泮、替马西泮、酒石酸唑吡坦、右佐匹克隆、苯海拉明和抗敏安。
当然,在联合治疗期间第二活性药剂的准确量将进行相应的调整,并且将取决于如下因素,如针对的患者群体,待治疗的特定的情感障碍的症状或病症,所施用的活性药剂之间潜在的协同作用,并会容易地由本领域技术人员根据本文提供的指导确定。
本发明的药物组合物可以包含以纯净的、基本上纯净的或部分纯净的形式的一种或多种本发明的化合物。在某些实施方案中,所述基本上纯净的形式可以包含至少95重量%的所述一种或多种化合物,例如,96重量%、97重量%、98重量%或多于99重量%的所述化合物。
所述化合物的所述基本上或部分纯净的形式可以进一步包含一部分游离聚烷二醇,例如,聚乙二醇(PEG)或聚丙二醇(PPG)。所述聚烷二醇本身可以是生物学上有活性的。游离聚烷二醇的链长度可以在1-50的范围内变化,优选1-25,更优选1-5或1或2。在某些实施方案中,所述聚烷二醇可以具有1、2、3、4或5个单体单位的链长度。所述游离聚烷二醇可以包含不同链长度的混合物。因此,对于所述一种或多种化合物的基本上纯净的形式而言,所述形式可以包含至多5重量%的游离聚烷二醇,例如,至多4重量%、3重量%、2重量%或少于1重量%,在所述形式中,所述一种或多种化合物和所述游离聚烷二醇的总量为100重量%。
所述一种或多种化合物的所述部分纯净的形式可以包含大约5-60重量%的一种或多种根据本发明的化合物和大约95-40重量%的游离聚烷二醇,总量为100重量%。典型地,所述部分纯净的形式可以包含大约45-55重量%的所述一种或多种化合物和大约55-45重量%的所述一种或多种聚烷二醇。可选择地,所述形式可以包含大约80-95重量%的所述一种或多种化合物和大约20-5重量%的所述聚烷二醇。
适宜地,本发明的组合物可以被配制成单位剂型。每一个单位剂型可以包含一种或多种本发明的化合物的日剂量的全部或预先确定的部分,例如,日剂量的二分之一或四分之一。
因此,组合物可以被配制成片剂、丸剂、胶囊剂、粉剂、颗粒剂、无菌的非肠道溶液剂或混悬剂、计量气雾剂或液体喷雾剂、滴剂、安瓿、自动注射装置、栓剂、霜剂或凝胶剂。所述组合物可以适用于口服、肠内、非肠道、囊内、鼻内、舌下、直肠或局部施用,或者用于通过吸入或吹入施用。特别优选地是口服组合物如片剂、丸剂、胶囊剂或威化。
为了制备固体剂型如片剂,可以将所述一种或多种化合物与一种或多种药物赋形剂(例如,常规的压片成分如玉米淀粉、乳糖、蔗糖、山梨糖醇、滑石、硬脂酸、硬脂酸镁、磷酸二钙或树胶)或其他的药物稀释剂(例如,水)混合来形成固体预制剂组合物,所述固体预制剂组合物含有所述一种或多种化合物的基本上均匀的混合物,以便所述一种或多种化合物均匀地分散在组合物中,以致于所述组合物可以轻易地细分成均等有效的单位剂型如片剂、丸剂和胶囊剂。
然后将所述固体预制剂组合物细分成如上所述的单位剂型,每一个单位剂型可以含有从0.1至大约500mg的一种或多种化合物。优选的单位剂型含有从1至500mg(例如,1、5、10、25、50、100、300或500mg)的化合物。
当被配制成片剂或丸剂时,所述片剂或丸剂可以被包衣或者被混合来提供剂型,所述剂型给予延长作用的优势。例如,所述片剂或丸剂能够包含内剂(innerdosage)和外剂(outer dosage)成分,后者以包层的形式包裹前者。这两种成分可以通过肠溶衣分隔,所述肠溶衣用于抵抗在胃中的崩解并允许内部成分完好无损地进入十二指肠或者延迟释放。用于所述肠溶衣或包衣的各种材料是已知的,所述材料包括多种聚酸和聚酸混合物连同如虫漆、鲸蜡醇和纤维素乙酸酯的材料。
可选择地,本发明的药物组合物可以被配制成用于口服或注射施用的液体剂型;例如水溶液剂、适宜地矫味的糖浆剂、水性或油性混悬剂或采用食用油(例如,棉籽油、芝麻油、椰油或花生油)矫味的乳剂,以及酏剂或类似的药物载体。用于水性混悬剂的适宜的分散剂或助悬剂包括合成的和天然的树胶,例如,黄耆胶、阿拉伯胶、藻朊酸盐、右旋糖酐、羧甲基纤维素钠、甲基纤维素、聚维酮或明胶。
附图说明
下面仅以举例的方式说明随附的本发明的实施方案的附图。
在附图中:
图1a显示出135S(0.1、5mg/kg)、175S(0.1、5mg/kg)和双氯芬酸(10mg/kg)(口服,-60,亚慢性的)在旷场实验中对Balb/c小鼠在20分钟的时间内的移动距离(cm)的作用。
图1b显示出135S(0.1、5mg/kg)、175S(0.1、5mg/kg)和双氯芬酸(10mg/kg)(口服,-60,亚慢性的)在旷场实验中对Balb/c小鼠在20分钟的时间内的速度(cm/秒)的作用。
图1c显示出135S(0.1、5mg/kg)、175S(0.1、5mg/kg)和双氯芬酸(10mg/kg)(口服,-60,亚慢性的)在旷场实验中对Balb/c小鼠在20分钟的时间内的强移动性(30%)的作用。
图1d显示出135S(0.1、5mg/kg)、175S(0.1、5mg/kg)和双氯芬酸(10mg/kg)(口服,-60,亚慢性的)在旷场实验中对Balb/c小鼠在20分钟的时间内的不动性(10%)的作用。
图1e显示出采用135S(0.1、5mg/kg)、175S(0.1、5mg/kg)和双氯芬酸(10mg/kg)(口服,-60亚慢性的)治疗Balb/c小鼠之后区域2和3相比于区域1的总持续时间的比例。
图1f显示出采用135S(0.1、5mg/kg)、175S(0.1、5mg/kg)和双氯芬酸(10mg/kg)(口服,-60亚慢性的)治疗的Balb/c小鼠在区域2和3中的总持续时间(秒)。
图2a显示出135S(0.1、0.5和2.5mg/kg)和氟西汀(10mg/kg)(口服,-180)在强迫游泳实验中对Balb/c小鼠的强移动性(30%)的作用。
图2b显示出135S(0.1、0.5和2.5mg/kg)和氟西汀(10mg/kg)(口服,-180)在强迫游泳实验中对Balb/c小鼠的不动性(10%)的作用。
图2c显示出135S(0.1、0.5和2.5mg/kg)和氟西汀(10mg/kg)(口服,-180)在强迫游泳实验中对Balb/c小鼠的移动性的作用。
图3a显示出氟西汀10mg/kg和135S(0.1、0.5和2.5mg/kg)9-180分钟,口服)在高架十字迷宫在开放臂中对Balb/c小鼠有关进入开放臂区域的频率的作用。
图3b显示出氟西汀10mg/kg和135S(0.1、0.5和2.5mg/kg)9-180分钟,口服)在高架十字迷宫在开放臂中对Balb/c小鼠有关在开放臂区域花费的总持续时间的作用。
图3c显示出氟西汀10mg/kg和135S(0.1、0.5和2.5mg/kg)9-180分钟,口服)在高架十字迷宫在开放臂中对Balb/c小鼠有关小鼠速度(cm/秒)的作用。
图3d显示出氟西汀10mg/kg和135S(0.1、0.5和2.5mg/kg)9-180分钟,口服)在高架十字迷宫在开放臂中对Balb/c小鼠有关小鼠移动距离(cm)的作用。
图4显示出施用氟西汀10mg/kg和135S(0.1、0.5和2.5mg/kg)(-180分钟,口服)之后对Balb/c小鼠的弹珠埋藏行为的作用。
具体实施方式
聚烷二醇化合物的合成
通常,通过制备适当的醇化合物,然后将所述醇与所需长度的聚烷二醇(PAG)聚合物(例如,聚乙二醇(PEG)或聚丙二醇(PPG))轭合来合成聚烷二醇化合物。
合成a:化合物a(苯基丙氨醇)
将1.2g、32mM LiAlH4加入到50ml干燥乙醚中的2.3g、10mM苯基丙氨酸乙酯盐酸盐中。于室温搅拌2小时之后,加入水和KOH并采用乙酸乙酯萃取反应产物。蒸发之后,得到0.8g化合物a,浅黄色油。
将化合物a静置结晶。Mp-70。
NMR CDCl37.30(5H,m),3.64(1H,dd,J=10.5,3.8Hz)3.40(1H,dd,J=10.5,7.2Hz)3.12(1H,m),2.81(1H,dd,J=13.2,5.2Hz),2.52(1H,dd,J=13.2,8.6Hz)
NMR丙酮d67.30(5Hm)3.76(1Hdt)3.60(1H m)3.30(1Ht)2.85(2Hm)。Helv.Chim.Acta,31,1617(1948).Biels.–E3,Vol.13,p1757。
合成b:化合物b(酪氨醇)
向50ml干燥乙醚中的3g、12mM L-酪氨酸乙酯盐酸盐中加入1.2g、32mMLiAlH4。于室温搅拌3小时之后,加入水和KOH并采用乙酸乙酯萃取反应。蒸发得到1.1g淡黄色油,收率54%,将其静置结晶。mp-85。
NMR CDCl37.20(4H,AB q,J=8.6Hz),3.50(2H,m)3.20(1H,m),2.81(2H,m)。
NMR酪氨酸乙酯游离碱CDCl37.0,6.56(4H,AB q,J=8.8Hz),4.20(2H,q,J=7,0Hz),3.70,3.0,2.80(3H,12条线ABXm),1.28.(3H,t,J=7.0Hz).JACS71,305(1949).Biels.–E3,Vol.13,p2263。
合成1:化合物2
化合物2(NRD135)具有通式IV的结构,其中R=PPG并且n=1。MW=354。
化合物2如下合成。
A)i)
将L-酪氨醇(24.4g)与氢化肉桂酸(HCA,1.02eq)、DCC(1.1eq)、HOBT(1.1eq)和NaHCO3(4.0eq)在室温反应过夜。在室温过夜反应进行完全。将反应过滤并且进行从THF至EA的溶剂交换。采用1N HCl、饱和NaHCO3、盐水洗涤EA层,并且采用Na2SO4干燥有机层。通过蒸馏除去部分EA,然后缓慢加入庚烷得到33.82g(94.1%收率)所需产物。HPLC:纯度=≥92%。
ii)
制备AV74S的苄醚。在50℃将1.33eq氯化苄加载于在丙酮中的AV74S(50.90g)、1.33eq碳酸钾、0.1eq碘化钾。在50℃20小时之后,将反应加热回流另外的7小时以消耗所有的起始原料。将反应冷却至室温并且采用水淬灭反应。将浆液冷却至<5℃并且搅拌1.5小时,然后过滤。经过周末将固体在真空下(70℃)干燥以得到62.98g粗固体。AUC纯度为94.4%。1H NMR分析支持指定的结构。
B)i)
在室温在DMF中在吡啶和DMAP存在下采用三苯甲基氯(246.7g,885mmol)处理5倍过量的丙二醇。经过周末在室温搅拌反应。将混合物用3倍体积的水稀释并且用EA萃取。从乙腈/水中重结晶得到235.04g(83.4%产率,纯度=98.7%)的所需产物。
ii)
将三苯甲基醚(99.82g,313.5mmol)转化为正交保护的双醚。向<10℃2当量在DMF中的NaH浆液,以控制气体逸出的速度滴加三苯甲基醚。在<10℃搅拌15分钟之后,通过注射器加入对甲氧苯甲基氯。使混合物升至室温(温和的放热)并且在室温置于搅拌1.5小时。HPLC分析表明起始原料被消耗完全。后处理由以下组成:采用3倍体积的水小心淬灭混合物并EA萃取。采用水洗涤EA层以去除DMF并且采用Na2SO4干燥以得到浑浊的油(150.95g)。
iii)
将受保护的双醚暴露于催化量的对甲苯磺酸以使三苯甲基基团脱三苯甲基。向甲醇和THF中的受保护的双醚(150.95g,PR030-084-2),加入催化量的对甲苯磺酸(0.1eq)。在室温60分钟之后,薄层色谱法和HPLC分析表明反应已经完全。加入三乙胺淬灭反应并且通过DURP去除溶剂。从硅胶塞分离所需产物以得到51.74g(84%产率,纯度=98.4%)。1H NMR分析支持指定的结构。
iv)
使用2.0eq甲磺酰氯和2.25eq三乙胺在<5℃进行PPG-1-羟基-2-OPMB(20.1g)的甲磺酰化以得到向所需产物的完全转化,108%粗产率,油状。该原料的纯度足够下面步骤使用。
C)i)
在室温经1.6小时向DMSO中的20.13g OBn-酪氨醇核(得自步骤A)和2.25eq PPG-1-O甲磺酰基-2-OPMB(得自步骤B)加入2.0eq1M叔丁醇钾(在THF中)。在室温15.5小时之后,已经形成91.9%所需产物并且8.1%的OBn-酪氨醇核没有被完全消耗。加入另外的0.3eq1M叔丁醇钾并且在45℃搅拌反应。在45℃另外的18小时之后,已经形成98.3%所需产物并且1.7%OBn-酪氨醇核没有被完全消耗。在室温采用USP水淬灭反应混合物并且采用乙酸乙酯萃取反应混合物。相继采用USP水、饱和NaHCO3水溶液、盐水洗涤合并的有机层并且采用硫酸钠干燥以得到39.00g油。从甲苯/庚烷重结晶的尝试经证明是不成功的并且得到的25.8g固体是77.4%纯度的所需产物。
将硅藻土加至溶解在热MTBE/庚烷(1:1)中的25.3g PR030-114-12。经过一层硅藻土热过滤混合物。将滤液冷却至室温并且通过真空过滤收集固体以提供13.1g白色固体(52.4%产率)。第二次收集获得另外的2.75g白色固体(另外的11%收率)。这两步收集的纯度分别为98.8%和98.1%。1H NMR和质谱分析支持了所需产物的指定结构。合并的产率为63.5%。
iii)
将双保护的醚(15.7g)暴露于在甲醇中的一锅法氢化-脱苄基条件(10%负载10%Pd/C和0.25eq对甲苯磺酸)。在氢气氛下60℃2小时之后,HPLC分析表明苄基的氢化和PMB环的脱苄基已进行完全。经过硅藻土过滤反应混合物并且在减压下浓缩反应混合物。将残余物溶解于乙酸乙酯并且进行饱和碳酸氢钠水溶液处理以有效去除对甲苯磺酸,然后除去DURP以得到12.13g油(pR030-120-4)。从EA/庚烷重结晶分离所需的产物以得到8.83g白色固体(PR030-120-6,89.4%产率)。经过HPLC分析PR030-120-6的纯度为99.3%。1H NMR和质谱分析支持了所需产物的指定结构。
合成2:化合物1
化合物1具有通式IV的结构,其中R=PPG并且n=2。MW=413。
使用如上在合成1中所述相同的程序制备化合物1,其中从PPG,n=1换成了PPG,n=2。
因此,将能理解合成1的程序可以用来产生式VII的化合物其中Z为PPG。通过用合适的氨基醇(例如在合成a中制备的苯基氨基丙醇)替换在步骤(A)中L-酪氨醇可以制备落入式I的可选择化合物。
合成1的程序还可以适应如下在合成3中所述,以使其导致产生式I化合物其中Z为PEG。
合成3:化合物3
化合物3具有通式IV的结构,其中R=PPG并且n=1。MW=413。
使用下列程序制备化合物3。
A)如化合物2那样进行步骤A。
B)i)
在室温在DMF中在吡啶和DMAP存在下采用三苯甲基氯(22.9g,82.13mmol)处理5倍过量的乙二醇。在室温将反应搅拌过夜。将混合物用3倍体积的水稀释并且用EA萃取。通过从乙腈/水中重结晶分离到所需产物,得到22.87g固体(91.5%产率)。通过HPLC确定纯度为97.8%。1H NMR和质谱分析支持了所需产物的指定结构。
ii)
在<5℃使用2.0eq甲磺酰氯和2.25eq三乙胺进行化合物A-1(11.00g)的甲磺酰化以得到向所需产物以定量产率的完全转化,固体状(13.85g)。AUC纯度=97.5%。质谱和1H NMR分析支持了指定结构。
C)i)在室温经45分钟向DMSO中的2.29g OBn-酪氨醇核(得自步骤A)和2.25eq化合物B-1(得自步骤B)加入2.0eq1M叔丁醇钾(在THF中)。35℃12.25小时之后,在室温采用USP水淬灭反应混合物并且采用乙酸乙酯萃取反应混合物。相继采用USP水、饱和NaHCO3水溶液、盐水洗涤合并的有机层并且采用硫酸钠干燥以得到5.05g油。经过柱色谱法纯化该产物以分离到固体状的所需产物(2.07g)。AUC纯度=97.5%。1H NMR分析支持了指定结构。
ii)
2.07g C-1。在60℃将C-1溶解于30倍体积甲醇中。60℃时加入10重量%Pd/C然后是0.25eq pTSA。维持氢气氛3小时。通过热过滤去除催化剂。滤液经DURP以获得固体。将固体溶解于乙酸乙酯中并且用碳酸氢钠洗涤。通过硫酸钠干燥有机相和DURP以得到胶粘的固体。
实施例
使用下列化合物,进行如下所述的实验来证明本发明的化合物在治疗焦虑或抑郁中的实用性。
化合物1(NRD71) 化合物2(NRD135)
化合物3(NRD175)
实施例1
旷场实验:探索性运动活性。
该方法是最流行的评价动物行为的方法之一。其既测试运动参数又测试焦虑(Prut等人)。将个体小鼠置于新的50x50cm树脂玻璃平台,其底板被划分为3个数字区域;外周区1,中间区2和最中心区3。通过录像记录在旷场中的动物行为20分钟并且随后使用Noldus软件数字分析动物行为。测定包括常规运动性:移动距离,速度和强移动性,以及焦虑参数包括访问中心区的频率,在内部区域花费的时间和在中心饲喂事件的次数。动物停留和活动于中心越多,其越少焦虑。
如下使用该方法评价本发明化合物的抗焦虑作用。
将40只9周龄首次接受试验的雄性Balb/c小鼠划分为5组(每组8只小鼠)并且如下每天治疗(0min,口服)持续两周:
1、对照-0.5%DMSO0.3ml/小鼠,口服(3ml/10只小鼠)(15μl DMSO+2994μlDDW),n=8。
2、双氯芬酸10mg/Kg=0.3mg/0.3ml/小鼠,腹腔注射(3ml/10小鼠),n=8
3、135S0.5mg/Kg=0.015mg/0.3ml/小鼠,口服(3ml/10小鼠)(135S0.15mg(储备液50mg/1ml DMSO)3μl+2997μl DDW),n=8
4、135S2.5mg/kg=0.075mg/0.3ml/小鼠,口服(3ml/10小鼠)(175S0.75mg(储备液50mg/1ml DMSO)15μl+2985μl DDW),n=8
5、135S0.1mg/Kg=0.003mg/0.3ml/小鼠,口服(3ml/10小鼠)(135S0.003mg(储备液50mg/1ml DMSO)0.6μl+2999.4μl DDW),n=8
治疗十五天之后上述五组小鼠经受旷场实验60分钟。通过EthoVision视频轨道系统(Noldus Ltd.)评价小鼠的活动。定义中心区(“区域3”;大约占总面积的16%),边框区(“区域1”;在平台边缘周围8cm宽边框)和中间区(“区域2”;其余区域)。记录了中心区和全部平台的定量参数,如移动距离和平均速度。
旷场实验在一个新的环境中测试活动并且可用于评价小鼠的自发活动、探索性驱动、新奇恐怖症、广场恐惧症和焦虑或恐惧的其他方面的组合,以及运动机能。使用0.1mg/kg或5mg/kg剂量的135S或175S化合物的治疗与采用对照物质(DMSO)或双氯芬酸的治疗作用进行对比。将小鼠置于平台的中心并且在20分钟的时间内记录它们的活动和行为,其涉及移动距离(cm)、速度(cm/秒)、强移动性和不动性。记录了内部区域2和3相比于外部区域1的总持续时间的比例。还测定了在内部区域2和3中的总持续时间。结果显示于图1a至1f。
从图1a至1d可以看出相比于对照小鼠,采用本发明化合物135S和175S的治疗没有显示出对小鼠自发活动(即,移动距离、速度、强移动性和不动性)的显著性作用。
然而,当区域2和3的总持续时间对比于区域1的总持续时间的比例进行对比时,在采用本发明化合物治疗的小鼠中可以看到显著作用。小鼠通常对亮堂堂的旷场的中心区有天生的恐惧,但是这与它们渴望探索新环境相矛盾。焦虑小鼠自然趋向于优选呆在靠近旷场的墙壁并且因此通过啮齿动物避开旷场平台的中心的程度可以确定焦虑相关的行为。如图1f所示,相比于对照小鼠,采用135S和175S治疗的小鼠中可以看出在区域2和3花费的时间显著增加。因此,本发明的化合物显示出抗不安或抗焦虑作用因为它们增加了小鼠花费在旷场的开阔、中心区的时间,而不是靠近墙壁的时间。
实施例2
强迫游泳实验
这是临床前在急性实验中用于筛选抗抑郁活性的最广泛使用的工具之一并且第一次被Porsolt等人描述(1977)。该实验基于以下观察:当被置于不可逃避的圆筒水中大鼠或小鼠显露不动姿势。该行为被认为是行为绝望,与应对紧张条件的积极方式截然相反。抗抑郁药将减少不动性并且增加啮齿动物的有积极性的行为以逃脱绝望的条件。这被以下方式证明:游泳时间、移动距离、速度和试图攀爬墙壁(强移动性)的增加。FST被认为是好的筛选工具,并具有良好的可靠性和预测有效性。
在4天的药物施用之后(最后的药物施用90分钟后进行)在雄性小鼠(BalbicHarlan IL)中进行该实验。使用玻璃圆筒(18cm直径和20cm深度)。水温是24-18℃。通过不动性、游泳和强运动性定义有积极性的行为。通过动物吸引去中心运动的活性低于10%定义动物的不动性。通过动物的距离和速度定义游泳,并且攀爬与强移动性有关(吸引去中心运动大于30%)。动物跌落到圆筒6分钟并且在2分钟适应之后在最后4分钟进行记录。通过Noldus(Holland)系统(包括摄像机和动物行为分析软件)分析所有结果。
采用在三种不同浓度(0.1mg/kg、0.5mg/kg和2.5mg/kg)的化合物135S,或采用抗抑郁药氟西汀(10mg/kg)治疗小鼠,口服施用以日剂量计持续14天。强迫游泳实验在第1天进行。
在第一次试验,小鼠被放置于水箱中,从中它们不能逃脱。监测小鼠的移动性和不动性。在第二次试验中,相同的小鼠被放置回水箱。再次监测小鼠的移动性和不动性。结果显示于图2a至2c中。
图2a至2c的结果显示出相比于对照小鼠,用135S治疗导致移动性的增加和不动性的减少,因此证明135S具有抗抑郁作用。所见的作用还大于采用常规抗抑郁药氟西汀治疗小鼠产生的作用。
实施例3
高架十字迷宫
该模型利用了啮齿动物的天然恐惧以逃避开阔和升高的场所。该装置由十字迷宫组成,十字迷宫具有两个闭合的和两个相对的开放臂,升高于底板上。首次接受实验的动物仅仅花费大约30%的测试时间在开放臂,然而采用BDZ的治疗显著增加开放臂的探索(Pellow等人)。这是研究焦虑样行为的最广泛使用的模型之一。迷宫由离地面50cm的平台上的两个相对开放臂(40x10cm)和两个相对的闭合臂(40x10cm,具有40cm墙壁)组成。迷宫是基于对开放区域的厌恶,因此在显示焦虑的小鼠中,限制进入闭合臂的运动是所期望的。
如实施例2那样治疗小鼠的组群并且在第8天进行高架十字迷宫实验。该实验是用作评价本发明药物的抗焦虑作用的又一实验。
将小鼠置于面向开放臂的迷宫的中心并且允许小鼠自由探索迷宫15分钟。在此期间,它们的行为被观察。结果显示于图3a至3d并且显示相比于对照小鼠,采用化合物135S治疗的小鼠导致增加了迷宫的探索并且增加了花费在开放臂的时间。因此,受治疗的小鼠相比于对照小鼠显示出更少的焦虑并且该研究提供本发明化合物抗焦虑特性的进一步证据。
实施例4
弹珠埋藏实验
弹珠埋藏实验是新奇恐怖症、焦虑和强迫性行为的有用模型。人们也已经提出该实验对新的抗抑郁药、抗焦虑药和抗精神病药的筛选可以具有预测有效性。可以预期小鼠能够在30分钟的时间内埋藏大约75%的弹珠,虽然这随负担和性别而变化。在该研究中,使用雄性Balb/c小鼠。
如实施例2那样治疗小鼠的组群并且在第15天进行弹珠埋藏实验。将小鼠单独置于含有20个玻璃弹珠的笼子中并且暴露20分钟。监测被小鼠埋藏的弹珠的数目。结果显示于图4中,其显示采用化合物135S治疗的小鼠相比于对照小鼠埋藏明显较少的弹珠。该实验提供该化合物的抗焦虑特性,特别是有关于强迫症(OCD)的治疗的进一步证据。
Claims (22)
2.根据权利要求1所述的化合物,其中所述情感障碍为焦虑、抑郁或强迫症。
4.根据前述权利要求中任一项所述的化合物,其中Z是-CH2CH(CH3)O-。
6.根据前述权利要求中任一项所述的化合物,其中R5是H或OH。
7.根据前述权利要求中任一项所述的化合物,其中R5'是H或OH。
8.根据前述权利要求中任一项所述的化合物,其中n是1-5的整数,优选1-2的整数。
9.根据权利要求1所述的化合物,所述化合物表示为式IV、V、VI或VII:
其中R是具有n个单元的聚烷二醇聚合物,其中n是1-5的整数,优选1-2的整数。
10.一种用于治疗或预防情感障碍的药物组合物,所述组合物包含药学上有效量的一种或多种根据权利要求1-9中任一项所述的化合物,任选地和一种或多种药学上可接受的赋形剂。
11.根据权利要求10所述的药物组合物,所述组合物包含基本上纯净形式的所述一种或多种化合物,所述基本上纯净形式由至少95重量%的所述一种或多种化合物和至多5重量%的游离聚烷二醇组成,在所述形式中,所述一种或多种化合物和所述游离聚烷二醇的总量为100重量%。
12.根据权利要求10所述的药物组合物,所述组合物包含部分纯净形式的所述一种或多种化合物,所述部分纯净形式由大约5-60重量%的一种或多种化合物和大约95-40重量%的游离聚烷二醇组成,总量为100重量%。
13.根据权利要求10-12中任一项所述的药物组合物,其中所述组合物被配制成单位剂型。
14.根据权利要求10-13中任一项所述的药物组合物,其被配制用于口服施用。
15.根据权利要求10-14中任一项所述的药物组合物,其中所述组合物被配制成包含从0.1至大约500mg的所述一种或多种化合物的单位剂型。
16.根据权利要求10-15中任一项所述的药物组合物,所述组合物包含多种根据权利要求1-9中任一项所述的化合物,所述化合物具有各自不同的n值。
17.根据权利要求16所述的药物组合物,其中所述多种化合物的n的中值在n=1-2的范围内。
18.一种用于治疗或预防有所需要的人类或非人类动物患者中的焦虑或抑郁的方法,所述方法包含向所述患者施用治疗有效量的至少一种根据权利要求1-9中任一项所述的化合物或如权利要求10-17中任一项所述的药物组合物。
19.根据权利要求18所述的方法,其中所述一种或多种化合物以日剂量1.0mg至15g施用。
20.根据权利要求18或权利要求19所述的方法,其中所述一种或多种化合物为口服施用。
21.一种或多种根据权利要求1-9中任一项所述的化合物在制备用于治疗或预防情感障碍的药物中的用途。
22.一种用于治疗或预防情感障碍的基本上如实施例中所描述的化合物。
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CN201280045760.3A Expired - Fee Related CN103826622B (zh) | 2011-09-21 | 2012-09-10 | 用于预防或治疗情感障碍的n-取代的苯丙酰胺或苯丙烯酰胺 |
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US (1) | US9133103B2 (zh) |
EP (1) | EP2758046B1 (zh) |
JP (1) | JP6067022B2 (zh) |
CN (1) | CN103826622B (zh) |
AU (1) | AU2012311183B2 (zh) |
CA (1) | CA2849055C (zh) |
DK (1) | DK2758046T3 (zh) |
ES (1) | ES2559294T3 (zh) |
GB (1) | GB201116335D0 (zh) |
HK (1) | HK1200353A1 (zh) |
IL (1) | IL231609A (zh) |
WO (1) | WO2013042005A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2017129061A1 (zh) * | 2016-01-27 | 2017-08-03 | 天士力制药集团股份有限公司 | 取代桂皮酰胺衍生物在制备抗焦虑药物中的应用 |
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WO2015173813A1 (en) * | 2014-05-14 | 2015-11-19 | Novaremed Ltd. | Pharmaceutical composition comprising stereoisomers of n-(1-(4-hydroxyphenyl)-3-(2-hydroxypropoxy)propan-2-yl)-3-phenylpropanamide for the prevention and treatment of type ii diabetes |
EP3939578A1 (en) * | 2020-07-13 | 2022-01-19 | Novaremed Ltd. | Compounds for treatment or prevention of an infection resulting from a coronavirus and/or a coronavirus-induced disease |
Citations (3)
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WO2005110987A1 (en) * | 2004-05-12 | 2005-11-24 | Pfizer Products Inc. | Piperidine derivatives as nk1 and nk3 antagonists |
CN101180267A (zh) * | 2005-03-25 | 2008-05-14 | 制药有限责任公司 | 胺和氨基酸的苯基-n-酰基衍生物、其制备过程、其药物组合物和用途 |
WO2009109850A2 (en) * | 2008-03-06 | 2009-09-11 | Novaremed Ltd. | A method of treating or preventing pain |
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SI1546088T1 (sl) * | 2002-10-03 | 2015-04-30 | Novaremed Ltd. | Spojine za uporabo v zdravljenju avtoimunskih bolezni, imunoalergijskih bolezni in zavrnitve transpalantata organa ali tkiva |
JP4939396B2 (ja) * | 2004-03-26 | 2012-05-23 | ノヴァレメッド リミテッド | Aids及び他のウイルス性疾患及びhiv関連感染症の改善又はその治療用化合物及びそのような化合物を含む組成物、そのような疾患及び感染症の治療方法及びそのような化合物及び組成物の製造方法 |
DK2475361T3 (da) | 2009-09-09 | 2020-02-17 | Novaremed Ltd | N-substituerede benzenpropanamider til anvendelse inden for behandlingen af smerte og inflammation |
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2011
- 2011-09-21 GB GBGB1116335.9A patent/GB201116335D0/en not_active Ceased
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2012
- 2012-09-10 EP EP12780536.4A patent/EP2758046B1/en active Active
- 2012-09-10 JP JP2014531340A patent/JP6067022B2/ja not_active Expired - Fee Related
- 2012-09-10 CA CA2849055A patent/CA2849055C/en not_active Expired - Fee Related
- 2012-09-10 ES ES12780536.4T patent/ES2559294T3/es active Active
- 2012-09-10 DK DK12780536.4T patent/DK2758046T3/da active
- 2012-09-10 WO PCT/IB2012/054700 patent/WO2013042005A1/en active Application Filing
- 2012-09-10 AU AU2012311183A patent/AU2012311183B2/en not_active Ceased
- 2012-09-10 US US14/346,419 patent/US9133103B2/en not_active Expired - Fee Related
- 2012-09-10 CN CN201280045760.3A patent/CN103826622B/zh not_active Expired - Fee Related
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2014
- 2014-03-19 IL IL231609A patent/IL231609A/en active IP Right Grant
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Patent Citations (3)
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WO2005110987A1 (en) * | 2004-05-12 | 2005-11-24 | Pfizer Products Inc. | Piperidine derivatives as nk1 and nk3 antagonists |
CN101180267A (zh) * | 2005-03-25 | 2008-05-14 | 制药有限责任公司 | 胺和氨基酸的苯基-n-酰基衍生物、其制备过程、其药物组合物和用途 |
WO2009109850A2 (en) * | 2008-03-06 | 2009-09-11 | Novaremed Ltd. | A method of treating or preventing pain |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2017129061A1 (zh) * | 2016-01-27 | 2017-08-03 | 天士力制药集团股份有限公司 | 取代桂皮酰胺衍生物在制备抗焦虑药物中的应用 |
RU2738648C2 (ru) * | 2016-01-27 | 2020-12-15 | Тасли Фармасьютикал Груп Ко., Лтд. | Применение соединения для лечения хронической тревоги или острой тревоги |
US10874636B2 (en) | 2016-01-27 | 2020-12-29 | Tasly Pharmaceutical Group Co., Ltd. | Application of substituted cinnamamide derivatives in preparation of anti-anxiety medication |
Also Published As
Publication number | Publication date |
---|---|
GB201116335D0 (en) | 2011-11-02 |
WO2013042005A1 (en) | 2013-03-28 |
US9133103B2 (en) | 2015-09-15 |
JP2014530200A (ja) | 2014-11-17 |
EP2758046B1 (en) | 2015-10-21 |
AU2012311183B2 (en) | 2016-09-22 |
CA2849055C (en) | 2019-11-26 |
US20140275273A1 (en) | 2014-09-18 |
EP2758046A1 (en) | 2014-07-30 |
IL231609A0 (en) | 2014-05-28 |
CN103826622B (zh) | 2016-06-08 |
CA2849055A1 (en) | 2013-03-28 |
HK1200353A1 (zh) | 2015-08-07 |
JP6067022B2 (ja) | 2017-01-25 |
ES2559294T3 (es) | 2016-02-11 |
DK2758046T3 (da) | 2016-02-01 |
AU2012311183A1 (en) | 2014-04-03 |
IL231609A (en) | 2016-11-30 |
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