CN101827839B - 1,3,5-三取代的三唑衍生物 - Google Patents
1,3,5-三取代的三唑衍生物 Download PDFInfo
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- CN101827839B CN101827839B CN2008801119538A CN200880111953A CN101827839B CN 101827839 B CN101827839 B CN 101827839B CN 2008801119538 A CN2008801119538 A CN 2008801119538A CN 200880111953 A CN200880111953 A CN 200880111953A CN 101827839 B CN101827839 B CN 101827839B
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Abstract
本发明涉及1,3,5-三取代的三唑衍生物。本发明涉及2-[3-(2,2-二氟-苯并[1,3]间二氧杂环戊烯-5-基氨基)-5-(2,6-二甲基-吡啶-4-基)-[1,2,4]三唑-1-基]-N-乙基-乙酰胺及其类似物或其药学上可接受的盐,它们的制备方法,含有它们的药物组合物以及它们在治疗中的用途。本发明特别涉及烟碱样乙酰胆碱受体的有效的正变构调节剂,其具有增加烟碱样受体激动剂的效力的性能。
Description
技术领域
本发明涉及2-[3-(2,2-二氟-苯并[1,3]间二氧杂环戊烯-5-基氨基)-5-(2,6-二甲基-吡啶-4-基)-[1,2,4]三唑-1-基]-N-乙基-乙酰胺及其药学上可接受的盐,它们的制备方法,含有它们的药物组合物以及它们在治疗中的用途。本发明涉及α7烟碱样(nicotinic)乙酰胆碱受体的选择性的、有效的正变构调节剂,其具有增加烟碱样受体激动剂的效力的性能。
背景技术
EP 1044970描述了作为神经肽Y受体配体的3-烷基氨基-1,2,4-三唑类化合物。
Makara G.M.,等的论文(Organic Letters(2002)Vol.4(10);1751-1754)描述了3-烷基氨基-1,2,4-三唑类化合物的固相合成并举例说明了N-(4-甲氧基苯基)-1-甲基-5-(4-甲基苯基)-1H-1,2,4-三唑-3-胺[CAS No:433710-55-5]的不成功合成,却没有关于此化合物的潜在治疗应用的记载,特别是没有关于此化合物作为α7烟碱样乙酰胆碱受体的正变构调节剂的用途的记载。
Chen Chen等人在Bioorganic&Medicinal Chemistry Letters 11(2001)3165-3168中描述了1-烷基-3-氨基-5-芳基-1H-[1,2,4]三唑类化合物,特别是N-(2-甲氧基苯基)-1-甲基-5-(2,4-二氯苯基)-1H-1,2,4-三唑-3-胺的合成,并描述了它们作为促肾上腺皮质激素释放因子-1(CRF1)拮抗剂的用途。
发明背景
胆碱能受体通常结合内源性神经递质乙酰胆碱(ACh),由此引起离子通道的开放。分别基于蝇蕈碱和烟碱的激动剂活性,哺乳动物中枢神经系统中的ACh受体可以被分成毒蕈碱亚型(mAChR)和烟碱样亚型(nAChR)。所述烟碱样乙酰胆碱受体是含有五个亚单元的配体门控离子通道。基于它们的氨基酸序列,nAChR亚单元基因家族成员已经被分成两组;一组含有所谓的β亚单元,以及第二组含有α亚单元。三种α亚单 元,α7、α8和α9,当单独表达时已经表明形成了功能性受体,并由此推测生成同源低聚五聚受体。
现已开发出nAChR的变构转变状态模型,其涉及至少一种静止状态,一种活化状态和一种″脱敏″封闭的通道状态,一种过程,通过该过程使得受体变为对激动剂不敏感。不同的nAChR配体可以使与其优先结合的受体的构象状态稳定。例如,激动剂ACh和(-)-烟碱分别使活性化和脱敏化状态稳定。
烟碱样受体的活性的改变与许多疾病有关。其中一些,例如重症肌无力和常染色体显性遗传的夜间额叶癫痫(ADNFLE)与烟碱样传递活性的减少有关,或者由于受体数量的减少或脱敏增加。
烟碱样受体减少还被假设是调节认知缺陷,在疾病如阿尔茨海默氏病和精神分裂症中可见。
来自烟草的烟碱的作用同样被烟碱样受体调节,由于烟碱的作用是稳定处于脱敏状态的受体,因此烟碱样受体的活性增加可以降低吸烟的欲望。
结合nAChRs的化合物已经被建议用于治疗一定范围的涉及胆碱能功能减少的疾病,例如学习缺陷、认知缺陷、注意力缺陷或记忆丧失。α7烟碱样受体活性的调节在许多疾病中被期望是有益的,所述疾病包括阿尔茨海默氏病、莱维体痴呆、注意力缺陷活动过强症、焦虑症、精神分裂症、躁狂症、躁狂性抑郁症、帕金森病、亨廷顿舞蹈病、图雷特(氏)综合征、脑损伤或其它其中存在胆碱能突触丧失的神经病学、变性或精神障碍,包括时差综合征、烟碱成瘾、疼痛。
然而,用烟碱样受体激动剂治疗,其与ACh作用在相同的部位,是成问题的,因为ACh通过过程(包括脱敏)和非竞争性阻断不仅激活而且阻滞受体活性。此外,延长激活似乎引起持久失活。因此,ACh激动剂有望减少活性以及增强活性。
一般地,在烟碱样受体上,以及特别是在α7-烟碱样受体上,脱敏限制了所施加的激动剂的作用的持续时间。
发明概述
我们现已令人惊讶地发现,2-[3-(2,2-二氟-苯并[1,3]间二氧杂环戊烯-5-基氨基)-5-(2,6-二甲基-吡啶-4-基)-[1,2,4]三唑-1-基]-N-乙基-乙酰胺 可以提高激动剂在烟碱样乙酰胆碱受体上的效力。具有这种作用类型的化合物被称为″正变构调节剂″,其可能用于治疗与烟碱样传递减少有关的病症。在治疗背景下,这种化合物可以恢复正常的神经元间传达,而不会影响激活的时间曲线。此外,正变构调节剂预期不会产生在反复或长期施用激动剂后可能出现的受体的长期失活。
本发明的正nAChR调节剂可用于治疗或预防精神障碍、智力损伤障碍或疾病、其中调节α7烟碱样受体是有益的炎性疾病或病症。
本发明涉及具有正变构调节剂性质的2-[3-(2,2-二氟-苯并[1,3]间二氧杂环戊烯-5-基氨基)-5-(2,6-二甲基-吡啶-4-基)-[1,2,4]三唑-1-基]-N-乙基-乙酰胺,其提高激动剂在α7烟碱样受体上的效力。本发明还涉及制备它们的方法以及包含它们的药物组合物。本发明还涉及这种衍生物在制备药物中的用途,所述药物用于治疗或预防精神障碍、智力损伤障碍或疾病、或其中调节α7烟碱样受体是有益的病症。
本发明的化合物及其盐在结构上不同于现有技术的化合物,并且作为α7烟碱样乙酰胆碱受体的正变构调节剂具有其提高的药理学活性,其具有其提高的水溶性和其改善的体外心血管安全参数,特别是降低的对hERG钾通道的亲合力。
本发明涉及化合物(I)
或其药学上可接受的盐或水合物或溶剂化物。
对于治疗用途,式(I)化合物的盐是其中所述抗衡离子是药学上可接受的那些。然而,非药学上可接受的盐也发现是有用的,例如在制备或纯化药学上可接受的化合物的过程中。所有盐,不管它们是药学上可接受的或药学上不可接受的,都包括在本发明的范围内。
在本文的上下文中所述的药学上可接受的加成盐是指包含化合物(I) 能够生成的治疗活性的无毒酸加成盐形式。所述药学上可接受的酸加成盐可以方便地通过将所述碱形式用这些适宜的酸处理来获得。适宜的酸包含,例如,无机酸如氢卤酸,例如盐酸或氢溴酸,硫酸、硝酸、磷酸等酸;或有机酸例如,诸如乙酸、丙酸、羟乙酸、乳酸、丙酮酸、草酸(例如乙二酸)、丙二酸、琥珀酸(即丁二酸)、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、环己烷氨基磺酸、水杨酸、对氨基水杨酸、双羟萘酸等酸。相反地,通过用适宜的碱处理,所述盐形式可以转化成游离碱形式。
术语水合物和溶剂化物是指所述式(I)的化合物以及其盐可以形成的水合物和醇化物。
式(I)的化合物还可以以互变异构体形式存在。虽然没有明确地表示在上面式中的这些形式被旨指包括在本发明的范围内。
化合物的制备
一般地,本发明的化合物可以通过一系列步骤制得,其每个步骤是本领域熟练技术人员已知的。特别地,本专利申请中的化合物可以根据下列制备方法(方案1至5)进行制备。
方案1
所述酰基硫脲(II)以两阶段制得。在第一阶段中,所述酰基氯(I)与一价阳离子硫氰酸盐,例如硫氰酸铵反应,得到相应的酰基异硫氰酸盐。此反应可以使用丙酮作为溶剂并在0℃至70℃的温度、优选在室温下进行。
在第二阶段中,反应可以有利地在相同的反应介质中进行,不需要分离中间体酰基异硫氰酸盐,加入苯胺(III),得到式(II)的N-酰基硫脲。此反应通常在0℃至70℃的温度下进行,优选在室温下进行(方案1)。
方案2
在下一步中,N-酰基硫脲(II)的S-甲基化得到式(IV)的N-酰基碳亚氨基硫代酸(carbomimidothioic acid),甲酯衍生物。此转化需要存在碱,优选强无机碱,如NaH或碳酸钾,并且在非质子传递溶剂例如DMF、THF等中,在-70℃至室温的温度范围内进行,优选在0℃下进行(方案2)。
方案3
使用2-肼基乙酸乙酯盐酸盐,可以将式(IV)的N-酰基碳亚氨基硫代酸甲酯衍生物转化为式(V)的1,2,4-三唑。此转化反应典型地在质子溶剂如甲醇或高级醇中进行并需要室温至150℃的温度。在一种具体实施方案中,所述高级醇是叔丁醇以及所述反应温度在70℃至120℃之间,最优选为100℃。优选加入化学计算量的碱。所述碱可以是无机碱,如乙酸钾或碳酸钾,然而更优选地,所述碱是叔胺,如二异丙基乙胺等等(方案3)。
方案4
通过用过量的乙胺在质子溶剂中在0℃至80℃的温度下处理,优选在室温(方案4)下处理,式(V)的[1,2,4]三唑-1-基]-乙酸乙酯被转化为相应的[1,2,4]三唑-1-基]-N-乙基-乙酰胺(VI)。
方案5
最终的式(I)的二甲基-取代的吡啶并三唑可以通过将2-氯吡啶基前体(VI)用过量(3-15当量)的格利雅试剂MeMgBr在催化量的乙酰丙酮铁(III)存在下在由75%至85体积%THF和15%至25体积%NMP组成的溶剂系统中处理制备。所述转化可以在0℃至50℃的温度范围内进行,最优选在0℃至25℃的温度范围内进行(方案5)。
药理学
本发明的化合物被发现是α7烟碱样受体的正变构调节剂。α7烟碱样受体(α7nAChR)属于cys-loop,离子移变(ionotropic)的配体门控离子通道的超家族,其包括5-HT3、GABAA和甘氨酸受体家族。它被乙酰胆碱及其分解(breakdown)产物胆碱激活,且α7nAChR的一个主要特点是其在激动剂长期存在下它的快速脱敏作用。其是在脑中的第二种最丰富的烟碱样受体亚型且是释放许多神经递质的重要调节剂。其离散分布在与注意力和认知历程相关的数个脑结构中,例如海马和额叶前部的皮质,并在人类中涉及各种精神和神经障碍。它还涉及到胆碱能炎性途径。
其与精神分裂症相关的遗传学证据是见于精神分裂症标记(感觉门控缺陷)与α7基因的核心启动子区域中的15q13-14和多晶型现象上的α7位置之间的强烈连接的形式。
病理学证据指向在精神分裂症患者大脑的海马、前叶和有色带的皮质、在帕金森氏病和阿尔茨海默氏病和在自闭症的脑室壁核和核心(nucleus reuniens)中失去α7免疫反应性和α-Btx-结合。
药理学证据例如与正常者比较,精神分裂症患者的明显抽烟习惯已经被解释成患者试图自身投药医治(medicate)以补偿在α7烟碱能(nicotinergic)传递中的缺乏。在当前脑胆碱能活性低(例如第2睡眠阶段)时给药烟碱并在精神分裂症患者中暂时恢复正常感觉门控的动物和人类二者的模型中,感觉门控中缺陷的瞬时正常化(脉冲前抑制PPI)已经被解释成α7烟碱样受体的瞬时激活接着进行脱敏的结果。
因此,有充分的理由来推测,激活α7nAChR对于许多CNS(精神病学的和神经病学的)障碍将具有治疗上有益的效果。
正如已提及的那样,所述α7nAChR在天然递质乙酰胆碱以及外源性配体如烟碱的持续存在下迅速脱敏。在脱敏状态下,所述受体保持配体结合但在功能上是失活的。这对天然递质如乙酰胆碱和胆碱不是太大的问题,因为这些是非常强烈的分解(乙酰胆碱酯酶)和清除(胆碱运输者(transporter))机理的底物。这些递质分解/清除机理在生理学有用范围内可能保持在可激活和脱敏的α7nAChRs之间的平衡。然而,合成的激动剂,其不是天然分解和清除机理的底物,可以理解为具有潜在的能力,以进行可过度刺激并且还将α7nAChR群体平衡推向持续地脱敏状态,这在其中在α7nAChR表达或功能方面中的缺陷起作用的疾病中是不合意的。激动剂在本质上必须靶向ACh结合袋,其对于不同的烟碱样受体亚型高度地保守,导致其它烟碱样受体亚型的非专一性激活作用的潜在危害反应。因此,为了避免这些潜在倾向性,对于α7激动作用的一个替代治疗策略是增强受体对于具有正变构调节剂(PAM)的天然激动剂的反应。PAM定义为一种药剂,其结合至与激动剂结合部位不同的位置,且因此不能预期具有激动剂或脱敏性质,但是增强α7nAChR对于天然递质的反应。该策略的价值是对于给定量的递质,α7nAChR反应的大小在PAM存在下大于没有PAM时可能的传递水平。所以对于其中在α7nAChR蛋白中有缺陷的障碍,在α7烟碱能传递中PAM诱发的增加可能是有利的。因为PAM依赖于天然递质的存在,过度刺激的可能性受到天然递质的分解/清除机理的限制。
基于定性的动力学性质,本发明的化合物分为类型1-4,其根据全细胞电压钳记录进行测定。这种分类基于如上文所述的α7PAM化合物对于由激动剂使用所引起的信号的作用。特别地,所述激动剂是浓度为1mM的胆碱。在一种优选的实验背景中,如下文所述,所述α7PAM化 合物和胆碱同时给予所述细胞。如下文所述的脱敏作用是在全细胞电压钳电生理学测定中使用激动剂期间当激活时受体的关闭,被视为通过激动剂最初激活后外向电流的减少。
PAM类型1-4的定义如下文所述:
类型1化合物提高由1mM胆碱引起的电流的作用大小,但是最低限度地改变所述受体的动力学。特别地,由激动剂引起的脱敏的速度和程度没有受影响。因此,对1mM胆碱的化合物调节的响应在不存在α7PAM化合物的情况下为1mM胆碱响应的线性比例之结束。
类型2化合物提高由1mM胆碱引起的电流的作用大小,同时减小脱敏的速度和/或程度。
类型3化合物提高由1mM胆碱引起的电流的作用大小。当在最高达10μM的较高浓度下进行测试时,它们完全抑制脱敏,特别是1mM胆碱应用250毫秒。
类型4化合物允许受体的最初脱敏作用,接着在激动剂使用期间受体再打开。在α7PAM化合物的低效力浓度下,激动剂诱导的激活,接着是脱敏,仍然可以从化合物诱导的再打开分离而作为最初内向电流的最大值。在α7PAM化合物的较高效力浓度下,由于脱敏作用使得再打开发生得比关闭更快,以便初始电流最大值消失。
因此,本发明的一个目的是提供一种治疗方法,其包括给药或者正变构调节剂作为唯一的活性物质,由此调节内源性烟碱样受体激动剂如乙酰胆碱或胆碱的活性,或给药正变构调节剂以及烟碱样受体激动剂。在本发明此方面的一种具体形式中,所述治疗方法包含用在此所述的α7烟碱样受体的正变构调节剂和α7烟碱样受体激动剂或部分激动剂进行治疗。具有α7烟碱样受体激动活性的适宜化合物的实例包括,但不局限于:
-1,4-二氮杂双环[3.2.2]壬烷-4-羧酸,4-溴苯基酯,一盐酸盐(SSR180711A);
-(-)-螺[1-氮杂双环[2.2.2.]辛烷-3,5′-噁唑烷]-2′-酮;
-3-[(2,4-二甲氧基)亚苄基]-假木贼因二盐酸盐(GTS-21);
-[N-[(3R)-1-氮杂双环[2.2.2]辛-3-基]-4-氯苯甲酰胺盐酸 盐]PNU-282987)。
本发明的化合物可用于治疗或预防精神障碍、智力损伤障碍或疾病、或其中调节α7烟碱样受体活性是有益的病症。本发明的方法的一个具体方面是一种治疗学习缺陷、认知缺陷、注意力缺陷或记忆丧失的方法,在许多疾病中调节α7烟碱样受体活性被期望是有益的,所述疾病包括阿尔茨海默氏病、莱维体痴呆、注意力缺陷活动过强症、焦虑症、精神分裂症、躁狂症、躁狂性抑郁症、帕金森病、亨廷顿舞蹈病、图雷特(氏)综合征、脑损伤或其它其中存在胆碱能突触丧失的神经病学、变性或精神疾病,包括时差综合征、烟碱成瘾、疼痛。
所述化合物还可以发现作为抗炎药物的治疗用途,因为所述烟碱样乙酰胆碱受体a7亚单元对通过胆碱能炎性途径抑制细胞因子合成来说是必不可少的。其中可以用所述化合物进行治疗的适应症的实例是内毒素血症、内毒素休克、败血病、类风湿性关节炎、哮喘、多发性硬化、炎性肠病、炎性胆病、克罗恩病、胰腺炎、心力衰竭和同种异体移植排斥。
鉴于上述药理学性质,所述化合物及其药学上可接受的加成盐可以用作药物。特别地,本发明的化合物可用于制备药物,所述药物用于治疗或预防精神障碍、智力损伤障碍或疾病或其中调节α7烟碱样受体是有益的病症。
鉴于所述化合物的用途,本发明提供了一种治疗患有下述疾病的温血动物包括人类的方法,或防止温血动物包括人类的方法,所述温血动物患有其中调节α7烟碱样受体是有益的疾病,例如精神分裂症、躁狂症和躁狂性抑郁症、焦虑症、阿尔茨海默氏病、学习缺陷、认知缺陷、注意力缺陷、记忆丧失、莱维体痴呆、注意力缺陷活动过强症、帕金森病、亨廷顿舞蹈病、图雷特(氏)综合征、脑损伤、时差综合征、烟碱成瘾和疼痛。所述方法包含给药于包括人类在内的温血动物,即全身性或局部给药,优选口服给药,有效量的式(I)化合物,包括其所有立体化学异构形式、其药学上可接受的加成盐、溶剂化物或水合物。
本领域熟练技术人员将会认识到,本发明的PAM’s的治疗有效量是足以调节α7烟碱样受体活性的数量并且该数量尤其是可以根据疾病的类型、治疗制剂中化合物的浓度以及患者的状况进行改变。一般地,作 为治疗剂所给予的PAM的数量以用于治疗其中调节α7烟碱样受体是有益的疾病,例如精神分裂症、躁狂症和躁狂性抑郁症、焦虑症、阿尔茨海默氏病、学习缺陷、认知缺陷、注意力缺陷、记忆丧失、莱维体痴呆、注意力缺陷活动过强症、帕金森病、亨廷顿舞蹈病、图雷特(氏)综合征、脑损伤、时差综合征、烟碱成瘾和疼痛,将由主治医师根据具体情况而确定。
一般地,适宜的剂量是在治疗位点产生0.5nM至200μM,更通常5nM至50μM的PAM的浓度的剂量。为了获得这些治疗浓度,向需要治疗的患者可能给药0.005mg/kg至10mg/kg体重,特别是0.1mg/kg至0.50mg/kg体重。实现治疗效果所需要的本发明化合物,在本文中也被称为活性组分,的数量当然随具体情况而改变,随具体的化合物、给药途径、接受者的年龄和状况以及所治疗的具体障碍或疾病而改变。治疗方法还可以包括以每日摄取1-4次之间的给药方案给予所述活性组分。在这些治疗方法中,本发明的化合物优选在给药(admission)前进行配制。如下文所述,适宜的药物制剂是通过已知方法使用公知的和容易得到的组分进行制备。
本发明还提供用于预防或治疗其中调节α7烟碱样受体是有益的疾病的组合物,所有疾病为例如精神分裂症、躁狂症和躁狂性抑郁症、焦虑症、阿尔茨海默氏病、学习缺陷、认知缺陷、注意力缺陷、记忆丧失、莱维体痴呆、注意力缺陷活动过强症、帕金森病、亨廷顿舞蹈病、图雷特(氏)综合征、脑损伤、时差综合征、烟碱成瘾和疼痛。所述组合物包含治疗有效量的式(I)化合物和药学上可接受的载体或稀释剂。
虽然所述活性组分有可能单独给药,但是所述活性组分优选以药物组合物的形式存在。因此,本发明还提供一种药物组合物,其包含本发明的化合物以及药学上可接受的载体或稀释剂。所述载体或稀释剂必须是″可接受的″,在这种意义上其与组合物的其它组分相容并且对于其接受者是无毒害作用的。
本发明的药物组合物可以通过药学领域中公知的任何方法进行制备,例如,使用Gennaro等人Remington’s Pharmaceutical Sciences(第18版,Mack出版社,1990,尤其是参见第8部分:药物制剂及其制备)中所述的那些方法。作为活性组分的治疗有效量的具体化合物,其以碱形式或加成盐形式存在,与药学上可接受的载体以密切混合的形式结 合,根据给药所期望的制剂形式,所述药学上可接受的载体可以呈宽范围的各种形式。这些药物组合物理想地是呈单元剂型,其优选适于全身性给药如口服、经皮或肠胃外给药;或局部给药如通过吸入、鼻喷雾、滴眼剂或通过乳剂、凝胶、香波等等。例如,在制备口服剂型的组合物中,可以使用任何常见的药物介质,诸如,例如,水、二元醇类、油类、醇类等,在口服液体制剂例如混悬液、糖浆、酏剂和溶液的情况中:或固体载体例如淀粉、糖、高岭土、润滑剂、粘合剂、崩解剂等,在粉剂、丸剂、胶囊和片剂的情况中。因为它们易于给药,片剂和胶囊代表最有利的口服单位剂型,在这种情况下,很明显使用固体药物载体。对于肠胃外组合物,所述载体通常包含无菌水,至少在很大程度上,尽管还可以包括其它组分,例如,以用以帮助溶解。可以制备可注射溶液,例如,其中载体包含盐水溶液、葡萄糖溶液或盐水和葡萄糖溶液的混合物。可注射混悬液也是可以制备的,在此情况中,可以使用适宜的液体载体、悬浮剂等。在适合于经皮给药的组合物中,所述载体任选包含渗透增强剂和/或适宜的可湿润剂,任选与少比例的任何性质的适宜添加剂混合,所述添加剂应不会对皮肤造成任何明显的有害作用。所述添加剂可以有助于向皮肤给药和/或可以有助于制备所需的组合物。这些组合物可以以各种方式给药,例如作为经皮贴片、作为点片、或作为软膏剂的形式给药。
为了易于给药和剂量均匀,将上述药物组合物配制成剂量单位形式是特别有利的。在本说明书和权利要求书中使用的剂量单位形式是指适合作为单元剂量的物理上不连续(discrete)的单位,每一单位含有计算产生所需治疗效果的预先确定量的活性组分,以及所需的药物载体。这些剂量单位形式的实例是片剂(包括划痕的(scored)或包衣的片剂),胶囊,丸剂,粉袋,扁片(wafers),可注射溶液或混悬液,一茶匙容量,一汤匙容量等,以及其单独的(segregated)倍数。
本发明的化合物可用于全身性给药,例如口服、经皮或肠胃外给药;或局部给药如通过吸入、鼻喷雾、滴眼剂或通过乳剂(cream)、凝胶、香波等等。所述化合物优选通过口服给药。给药的准确剂量和频率取决于所使用的具体的式(I)化合物,被治疗的具体病症,被治疗的病症的严重程度,具体患者的年龄、体重、性别、疾病的程度、和一般身体状况以及个体可能正在采取的其它药疗法(medication),其为本领域熟练技术人 员众所周知。此外,显而易见的是,所述有效的每日用量可以根据被治疗的患者的反应和/或根据处方本发明化合物的医生的评估而减低或增加。
式(I)的化合物还可以与其它常规的α7烟碱样受体激动剂联合应用,诸如,例如1,4-二氮杂双环[3.2.2]壬烷-4-羧酸,4-溴苯基酯,一盐酸盐(SSR180711A);(-)-螺[1-氮杂双环[2.2.2.]辛烷-3,5′-噁唑烷]-2′-酮;3-[(2,4-二甲氧基)亚苄基]-假木贼因二盐酸盐(GTS-21);或[N-[(3R)-1-氮杂双环[2.2.2]辛-3-基]-4-氯苯甲酰胺盐酸盐]PNU-282987)。因此,本发明还涉及式(I)化合物与α7烟碱样受体激动剂的联合。所述联合可以用作药物。本发明还涉及一种产品,其包含(a)式(I)化合物,和(b)α7烟碱样受体激动剂,作为混合制剂,用于同时、分开或连续给药以治疗其中调节α7烟碱样受体是有益的疾病。不同的药物可以与药学上可接受的载体一起合并成单一制剂。
具体实施方式
实验部分
下面实施例说明本发明化合物的几种制备方法。除非另有说明,所有起始原料得自市购供应商并且其使用无需进一步纯化。
在上下文中,″DMF″是指N,N-二甲基甲酰胺;″NMP″是指1-甲基-2-吡咯烷酮;″THF″是指四氢呋喃和″DIPE″是指二异丙醚。
对于本发明的中间体和化合物的LCMS-表征,使用下列方法。
一般程序
HPLC测定使用Alliance HT 2790(Waters)系统进行,如在下面各方法中所述,其包含具有脱气装置的四元泵、自动进样器、柱恒温箱(对于LCMS的程序1设在60℃,对于LCMS程序2设在40℃)、二极管-阵列检测器(DAD)和柱。来自柱的液流被分流至MS光谱仪(spectrometer)。MS检测器配置有电喷射离子化源。质谱通过在1秒内从100扫描到1000获得,使用0.1秒的停留时间。毛细管针电压是3kV,源温维持在140℃。氮气被用作喷雾器气体。数据获取使用Waters-MicromassMassLynx-Openlynx数据系统来进行。
LCMS程序1
除一般程序外:反相HPLC在Xterra MS C18柱(3.5μm,4.6x100mm)上以1.6ml/min的流速进行。使用三种流动相(流动相A:95%25mM乙酸铵+5%乙腈;流动相B:乙腈;流动相C:甲醇),以运行梯度条件:在6.5分钟内以100%A至50%B和50%C运行,在0.5分钟内至100%B,接着保持这些条件1分钟,然后用100%A再平衡1.5分钟。使用10μl的注射体积。对于正电离模式,锥电压是10V,对于负电离模式,锥电压是20V。
LCMS程序2(仅用于中间体)
除一般程序外:反相HPLC在Chromolith(4.6x25mm)上以3ml/min的流速进行。使用三种流动相(流动相A:95%25mM乙酸铵+5%乙腈;流动相B:乙腈;流动相C:甲醇),以运行梯度条件:在0.9分钟内96%A、2%B和2%C,至49%B和49%C,在0.3分钟内至100%B,然后保持0.2分钟。使用2μl的注射体积。对于正电离模式,锥电压是10V,对于负电离模式,锥电压是20V。
熔点
熔点(m.p.)用DSC823e(Mettler-Toledo)进行测定。熔点用30℃/分钟的温度梯度进行测量。最高温度是400℃。获得的数值存在通常与这种分析方法相关的实验不确定性。
A.中间体的制备
描述1
1-(2-氯-6-甲基-吡啶-4-羰基)-3-(2,2-二氟-苯并[1,3]间二氧杂环戊烯-5-基)-硫脲(D1)
硫氰酸,铵盐(1∶1)(9.35g;0.1230mol)在2-丙酮(300ml)中在室温下进行搅拌。然后,加入2-氯-6-甲基-4-吡啶碳酰氯(22.2g;0.1170mol),将所述反应混合物在室温下搅拌2小时。加入在一些2-丙烷中的2,2-二氟-1,3-苯并间二氧杂环戊烯-5-胺(19.2g;0.1110mol),所述反应混合物在室温下搅拌1小时。然后,将反应混合物倾倒冰上,滤出残余物并干躁。收率:38.1g中间体D 1。
LCMS 保留时间:1.03;[M-H]-峰:384;LCMS步骤2
描述2
2-氯-N-[(2,2-二氟-苯并[1,3]间二氧杂环戊烯-5-基氨基)-甲基硫烷基-甲基]-6-甲基-异烟酰胺(D2)
NaH,60%(2.2g;0.0550mol)在THF(170ml)中在冰浴上在N2中进行搅拌。然后,加入中间体D1(19.3g;0.500mol),并在0℃下搅拌1小时。然后,加入CH3I(7.8g;0.0550mol),将所述反应混合物温热至室温过夜。加入水,在真空中蒸除THF。滤出沉淀,用水洗涤并干燥。收率:22.86g中间体D2。
LCMS 保留时间:1.15;[M-H]-峰:398;LCMS步骤2
描述3
[5-(2-氯-6-甲基-吡啶-4-基)-3-(2,2-二氟-苯并[1,3]间二氧杂环戊烯-5-基氨基)-[1,2,4]三唑-1-基]-乙酸乙酯(D3)
将中间体D2(13.6g;0.0340mol)、2-肼基乙酸乙酯,盐酸盐(1∶1)(10.5g;0.0680mol)、N-乙基-N-(1-甲基乙基)-2-丙胺(13.2g;0.1020mol)和t-BuOH(400ml)回流2小时。然后,将反应混合物蒸发。加入水,所述产物用CH2Cl2萃取。有机层在MgSO4中干燥,过滤,在真空中蒸发。然后,将残余物在乙醇/HCl中加热到60℃达1小时。将反应混合物部分蒸发,滤出沉淀并干燥。收率:4.57g中间体D3。
LCMS 保留时间:1.03;[M-H]-峰:450;LCMS步骤2
描述4
2-[5-(2-氯-6-甲基-吡啶-4-基)-3-(2,2-二氟-苯并[1,3]间二氧杂环戊烯-5-基氨基)-[1,2,4]三唑-1-基]-N-乙基-乙酰胺(D4)
在CH3OH(40ml;2M)中的中间体D3(1g;0.0022mol)和乙胺在室温下搅拌过夜。由反应混合物中结晶出产物。滤出晶体,并干燥。收率:700mg中间体D4。
LCMS 保留时间:0.95;[M-H]-峰:449;LCMS步骤2
B.最终化合物的制备
2-[3-(2,2-二氟-苯并[1,3]间二氧杂环戊烯-5-基氨基)-5-(2,6-二甲基-吡啶-4-基)-[1,2,4]三唑-1-基]-N-乙基-乙酰胺(E1)
中间体D4(0.70g;0.0016mol)、乙酰丙酮铁(III)(0.067g;0.0002mol)、THF(20ml)和1-甲基-2-吡咯烷酮(5ml)在0℃下在N2中进行搅拌。加入在乙醚中的过量CH3MgBr(2M),将所述混合物带至室温。然后,所述反应混合物用CH3OH分解,在真空中蒸发。加入水和CH2Cl2,所述混合物在dicalite中过滤。滤液蒸发,加入水和DIPE。滤出沉淀,溶于CH2Cl2中,在MgSO4中干燥,过滤并在真空中蒸发。将所述残余物在水中搅拌,滤出沉淀并干燥。收率:400mg化合物E1。
熔点:242.28℃
LCMS 保留时间:5.12;[M+H]+峰:431;LCMS步骤1
1H NMR(Bruker DPX 360MHz,DMSO-d6)δppm 9.62(s),8.37(t,J=5.4Hz),7.67(d,J=2.1Hz),7.38(s),7.29(d,J=8.8Hz),7.22(dd,J=8.8,2.2Hz),4.84(s),3.13(qd,J=7.2,5.5Hz),2.50(s),1.03(t,J=7.2Hz)
C.药理学实施例
实施例C.1b:Ca
2+
通量成像(FDSS)
材料
a)分析缓冲液
Hanks缓冲盐水溶液(HBSS,Invitrogen,比利时),补充以10mMHEPES(Invitrogen,比利时),CaCl2至最终浓度5mM,0.1%牛血清白蛋白(Sigma-Aldrich NV,比利时)。
b)钙敏感染料-Fluo-4AM
将Fluo-4AM(Molecular Probes,USA)溶于含有10%Pluronicacid(Molecular Probes,USA)的DMSO中,得到一种储备液,将该储备液在补充以5mM probenicid(Sigma,Aldrich NV,比利时)的分析缓冲液中进行稀释,以得到最终浓度2μM。
c)384-孔板
黑色384孔板黑色/透明板,PDL预涂覆(Corning,Incorporated,USA)
d)钙通量测量
使用功能性药物筛选系统(FDSS,Hamamatsu)测量胞内游离钙通量信号。
方法
使hα7-wt nAChR-表达GH4C1细胞的单层在多孔板(特别是涂覆有聚-D-赖氨酸的黑边、透明底的384孔板)中生长24小时,然后填装荧光钙指示剂,在一种具体实施方案中是装填fluo-4AM达最高120分钟。
在持续监视FDSS中的由荧光的细胞钙活动期间,通过将待测试化合物和α7烟碱样受体激动剂施加至装载的细胞而实时检测PAM活性。当化合物给出的峰荧光响应大于激动剂单独的响应时,被认为是α7nAChR PAM’s。在一种具体实施方案中,所述α7烟碱样受体激动剂是胆碱,在一个更具体的实施方案中,胆碱以100μM的亚最大浓度施加。在本发明的另一环境(setting)中,待测试化合物在α7烟碱样受体激动剂之前施加,在一种具体实施方案中,在所述激动剂之前最高达10分钟施加。
从单独接受胆碱或分析缓冲液的孔中的荧光峰差异,计算各板上对胆碱的对照响应。本发明的化合物在从0.01μM至30μM的浓度范围内进行测试。当在30μM浓度进行测试时,当其强化胆碱信号至少250%时,化合物被认为是具有使人感兴趣的活性(在没有PAM的情况下,100μM胆碱的效力被定义为100%)。
EC50值(效力),最大作用(%效力)和Hill斜率通过拟合sigmoidal方程对数据进行估算,使用GraphPad Prism(GraphPad Software,Inc.,SanDiego,CA)。当获得清晰的顶端平台的sigmoidal曲线时,EC50(或pEC50)以涉及半最大作用的浓度进行测定。
当经由在稳定过度表达人类野生型α7受体的GH4C1细胞中的全细胞电压钳电生理学测量时,本发明的化合物对于胆碱的响应也具有增强的作用,正如下文所述。
实施例C.2:全细胞电压钳记录
来自哺乳动物细胞的全细胞电压钳记录提供强力的方法以评价认为是配体门控离子通道的亚单元的膜蛋白的功能。这些蛋白通过内源性或外源性配体进行的激活造成与受体相关的孔的开启,离子由此流下至其电化学梯度。在hα7-wt nAChR表达GH4C1重组细胞系的情况中,对比受体的钙的优先渗透性表示钙经由ACh、胆碱以及其它烟碱样配体激活后流入细胞内,造成钙电流。因为这种受体在激动剂存在下迅速脱敏,所以重要的是使用能够非常快速的转换溶液(<100ms)的应用系统,以 防止受体响应在施加激动剂的时间的同时部分或全部被脱敏。因此,评价烟碱效力增强的第二种方便技术是来自偶合有快速应用系统的hα7-wt nAChR表达GH4C1细胞的全细胞电压钳记录。
材料
a)分析缓冲液
外部记录溶液由152mM NaCl、5mM KCl、1mM MgCl2、1mM钙、10mM HEPES组成;pH 7.3。内部记录溶液由140mM CsCl、10mMHEPES、10mM EGTA、1mM MgCl2组成,pH 7.3。
b)膜片钳记录使用膜片钳放大器(Multiclamp 700A,AxonInstruments,CA,USA)进行。当填充内部记录溶液时,hα7-wt nAChR-表达GH4C1细胞的膜电势在全细胞构象(Hamill等人,1981)中以1.5-3MΩ尖端电阻的硼硅酸盐玻璃电极进行电压钳制。在膜电阻>500MΩ且更优选1GΩ且串联电阻<15MΩ和至少60%串联电阻补偿的细胞上进行记录。膜电势钳在-70mV。
c)激动剂
ACh、胆碱购自Sigma-Aldrich NV,Belgium。
d)化合物施加
使用用于快速转换溶液(转换分解时间<100ms)的16-通道DynflowDF-16微流体系统(Cellectricon,Sweden)来施加对照物、激动剂和PAM化合物至hα7-wt nAChR表达GH4C1细胞。
方法
将hα7-wt nAChR表达GH4C1细胞放在位于Dynaflow灌流腔室内的外部记录溶液中并使其放置最高达20分钟。用膜片吸管将个体细胞为全细胞膜片并温和地提离腔室底部,进入外部记录溶液的连续流动的灌流中(0.75μl/min)。在持续监视细胞膜电流期间,经由预先施加待测试化合物至装填的细胞,随后施加α7烟碱样受体激动剂,实时检测PAM活性。当化合物给出的电流响应大于激动剂单独的响应时,被认为是α7nAChR PAM’s。在一种具体实施方案中,所述α7烟碱样受体激动剂通过非选择性烟碱样激动剂激活,在一种更具体的实施方案中,所述激动剂是胆碱,以及在甚至更具体的实施方案中,以1mM的亚最大浓度施加胆碱。在本发明的另一环境(setting)中,待测试化合物在α7烟碱样受体激动剂之前施加,在一种更具体的实施方案中,在所述激动剂之前最高达30秒施加。从在各细胞中对施加250ms的亚最大胆碱产生的电流曲线下的面积计算对照响应。曲线下的面积是经时间的净电流的积分且是通过通道的总离子通量的常见表示。由正变构调节剂引起的激动剂效力的增加以激动剂响应的″曲线下面积″(AUC)的增强百分比计算。由本发明化合物所引起的大于对照AUC的增强表明,预期具有有用的治疗活性。
表1:对于化合物E1的效力(pEC50)和%功效
类型2化合物减少了脱敏作用的速度和程度。
Claims (6)
2.一种化合物在制备药物中的用途,所述药物用于防止或治疗或预防精神障碍、智力损伤障碍或疾病、其中调节α7烟碱样受体是有益的炎性疾病或病症,其中所述化合物是权利要求1的化合物。
3.一种药物组合物,其包含药学上可接受的载体以及作为活性组分的治疗有效量的权利要求1的化合物。
4.一种制备权利要求3所述的组合物的方法,其特征在于,将药学上可接受的载体与治疗有效量的权利要求1所述的化合物密切混合。
5.一种产品,其包含:
(a)如权利要求1所述的化合物,和
(b)α7烟碱样受体激动剂,作为用于同时、分开或连续使用以预防或治疗其中调节α7烟碱样受体是有益的疾病的组合制剂。
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CA2697982A1 (en) | 2009-04-23 |
IL205102A (en) | 2015-04-30 |
IL205102A0 (en) | 2010-11-30 |
CN101827839A (zh) | 2010-09-08 |
AR068919A1 (es) | 2009-12-16 |
PE20091080A1 (es) | 2009-08-03 |
ATE522523T1 (de) | 2011-09-15 |
CA2697982C (en) | 2015-09-22 |
WO2009050185A1 (en) | 2009-04-23 |
TW200934491A (en) | 2009-08-16 |
US20100240707A1 (en) | 2010-09-23 |
RU2476433C2 (ru) | 2013-02-27 |
US8404851B2 (en) | 2013-03-26 |
PA8799901A1 (es) | 2009-05-15 |
JO2784B1 (en) | 2014-03-15 |
JP2011500624A (ja) | 2011-01-06 |
MX2010004176A (es) | 2010-05-03 |
EP2205594B1 (en) | 2011-08-31 |
ES2371863T3 (es) | 2012-01-10 |
CL2008003067A1 (es) | 2009-11-27 |
RU2010119458A (ru) | 2011-11-27 |
AU2008313775A1 (en) | 2009-04-23 |
EP2205594A1 (en) | 2010-07-14 |
AU2008313775B2 (en) | 2012-12-13 |
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