CN114401948A - 用于改善认知功能和对抗物质成瘾的噻唑和二苯基取代的亚砜 - Google Patents
用于改善认知功能和对抗物质成瘾的噻唑和二苯基取代的亚砜 Download PDFInfo
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- CN114401948A CN114401948A CN202080064509.6A CN202080064509A CN114401948A CN 114401948 A CN114401948 A CN 114401948A CN 202080064509 A CN202080064509 A CN 202080064509A CN 114401948 A CN114401948 A CN 114401948A
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- thiazole
- phenyl
- sulfinyl
- bromophenyl
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Abstract
Description
技术领域
本发明涉及非对映体化合物,其可用于改善人类个体,特别是老龄个体的认知功能,特别是学习能力以及记忆性能,更特别是改善空间记忆。更具体地,本发明涉及可用于治疗认知功能如空间记忆任务的年龄依赖性衰退的新化合物。
背景技术
在预期寿命长的社会中,老龄化期间的认知能力下降意味着严重的医疗和社会经济负担。衰老引起的认知障碍通常伴随着大脑各个区域的多巴胺减少。多巴胺在学习和记忆中起重要作用,涉及前额叶皮层和海马的内在神经元回路以及这些结构之间的神经元网络活动(Werlen等人,调节地图:海马空间编码和相互作用的多巴胺能调节(Modulatingthe map:dopaminergic tuning of hippocampal spatial coding and interactions),脑研究进展(Prog.Brain Res.)219:187-216;2015)。然而,多巴胺作为治疗认知障碍的靶点的作用取决于所使用的记忆系统(Ashby等人,多巴胺导向治疗对认知的不同影响(Differential effects of dopamine-directed treatments on cognition),神经精神疾病和治疗(Neuropsychiatr.Dis.Treat.)11:1859-1875;2015)。结构上涉及海马和前额叶皮层的空间记忆以及陈述性(Linssen等人,哌醋甲酯选择性增强健康志愿者的陈述性记忆巩固(Methylphenidate produces selective enhancement of declarative memoryconsolidation in healthy volunteers),精神药理学(Psychopharmacology)(Berl),221:611-619;2012)和新颖性(Takeuchi等人,突触可塑性和记忆假说:编码、存储和持久性(The synaptic plasticity and memory hypothesis:encoding,storage andpersistence),伦敦皇家学会哲学汇刊B系列生物科学(Philos.Trans.R Soc Lond B BiolSci.)369:20130288;2013)的记忆过程强烈依赖于多巴胺的神经调节功能。此外,这些大脑结构之间的连通性(Bertolino等人,记忆处理过程中的前额叶-海马耦合受COMTval158met基因型的调节(Prefrontal-hippocampal coupling during memoryprocessing is modulated by COMT val158met genotype).生物精神病学(Biol.Psychiatry).60:1250-1258;2006)以及这些结构内的突触谷氨酸能传递受到多巴胺的强烈影响主要受腹侧被盖区释放的影响。基底神经节可以参与非陈述性记忆的调节(Foerde和Shohamy,基底神经节在学习和记忆中的作用:来自帕金森病的见解(The roleof the basal ganglia in learning and memory:insight from Parkinson’sdisease),学习和记忆的神经生物学(Neurobiol.Learn.Mem.)96:624-636;2011),例如伏隔核(Mulder等人,体内海马对伏隔核和前额叶皮层通路的短期和长期可塑性(Short-andlong-term plasticity of the hippocampus to nucleus accumbens and prefrontalcortex pathways in the rat,in vivo),欧洲神经科学杂志(Eur.J.Neurosci)9:1603-1611;1997;Lopez等人,伏隔核壳或核刺激对麻醉大鼠齿状回长时程增强的反作用(Opposite effects of shell or core stimulation of the nucleus accumbens onlong-term potentiation in dentate gyrus of anesthetized rats),神经科学(Neuroscience)151:572-8;2008)和纹状体(Sagratella等人,地方学习受损纹状体损伤大鼠海马齿状频率增强的选择性降低(Selective reduction of hippocampal dentatefrequency-potentiation in striatally lesioned rats with impaired placelearning),脑研究(Brain Res.)660:66-72;1994,结合陈述性记忆(in conjunction withdeclarative memory)。
多巴胺转运蛋白(dopamine transporter,DAT)的抑制旨在规避多巴胺能系统的任务和年龄依赖性功能差异问题。DAT将细胞外多巴胺重新摄取到突触中。因此,多巴胺转运蛋白抑制剂(DAT抑制剂)的应用导致细胞外多巴胺浓度增加(Rowley等人,通过同时双探针微透析和自由移动大鼠的运动活动测量揭示哌醋甲酯和莫达非尼的神经化学和行为特征的差异(Differences in the neurochemical and behavioural profiles oflisdexamfetamine methylphenidate and modafinil revealed by simultaneous dual-probe microdialysis and locomotor activity measurements in freely-movingrats),精神药理学杂志(J.Psy-chopharmacol).28:254-69;2014),多种多巴胺受体可以从中受益。
包括靶向多巴胺转运蛋白(DAT)药物的一系列化合物可以影响和改善认知功能。多巴胺转运蛋白将细胞外多巴胺重新摄取到突触中,抑制剂会增加细胞外多巴胺的浓度(Rowley等人,2014),从而改善学习和记忆力。例如,已经表明DAT抑制剂会影响齿状回的海马突触可塑性(Tsanov等人,精神兴奋剂莫达非促进水迷宫性能并增强齿状回的突触增强(The psychostimulant modafinil facilitates water maze performance andaugments synaptic potentiation in dentate gyrus),神经药理学(Neuropharmacology)59:9-19;2010;Jenson等人,多巴胺和去甲肾上腺素受体参与哌醋甲酯增强体内海马突触可塑性(Dopamine and norepinephrine receptors participate inmethylphenidate enhancement of in vivo hippocampal synaptic plasticity),神经药理学(Neuropharmacology)90:23-32;2015)和CAi(Swant和Wagner,多巴胺转运体阻断通过激活D3多巴胺受体增加大鼠海马CAi区域的LTP(Dopamine transporter blockadeincreases LTP in the CAi region of the rat hippocampus via activation of theD3 dopamine receptor),学习和记忆(Learn Mem).13:161-167;2006)以及啮齿动物(Burgos等人,莫达非尼对大鼠学习能力和新皮质长时程增强的影响(Effect ofmodafinil on learning performance and neocortical long-term potentiation inrats),脑研究公报(Brain Res.Bull).83:238-44;2010;Li等人,平衡的多巴胺对于联想记忆回忆期间的模式完成至关重要(Balanced dopamine is critical for patterncompletion during associative memory recall),公共科学图书馆-综合(PLoS One).5(10)e15401.doi:io.i37i/joumal.pone.ooi540i,2010;Tsanov等人,精神兴奋剂莫达非促进水迷宫性能并增强齿状回的突触增强(The psychostimulant modafinil facilitateswater maze performance and augments synaptic potentiation in dentate gyrus).神经药理学(Neuropharmacology).59:9-19,2010)和人类(Zilles等人,5-HTT和DAT而不是COMT的遗传多态性对语言和视觉空间工作记忆功能有不同的影响(Geneticpolymorphisms of 5-HTT and DAT but not COMT differentially affect verbal andvisuospatial working memory functioning),欧洲精神病学和临床神经科学档案(EurArch Psychiatry Clin Neurosci.),2012Dec;202(8):667-76)的不同学习任务(包括空间任务)中的工作记忆和长期记忆。然而,常用的抑制剂对DAT的特异性不足,并且还抑制去甲肾上腺素和血清素转运蛋白。这种非特异性会导致对一般唤醒水平的严重副作用,并诱发精神类疾病,例如抑郁发作(Wood等人,精神兴奋剂和认知:行为和认知激活的连续统一体(Psychostimulants and cognition:a continuum of behavioral and cognitiveactivation),药理综述(Pharmacol.Rev).66:193-221;2014)。
与衰老相关的认知能力下降伴随着包括海马和前额叶皮层在内的各个大脑区域的多巴胺能系统退化。因此,突触前和突触后的多巴胺能成分在整个生命周期中发生不同的变化,从而在各个年龄段以不同的方式损害认知功能,例如工作和情景记忆以及决策制定(Li和Rieckman,神经调节和衰老:衰老神经元增益控制对认知的影响(Neuromodulationand aging:implications of aging neuronal gain control on cognition),神经生物学的当前观点(Curr.Opin.Neurobiol.)29:148-158;2014)。此外,任务性能的差异也可能仅与动机的差异有关,而不是与认知有关。
作为学习和记忆形成的关键机制的海马谷氨酸能活性受树突棘、肌动蛋白结合蛋白大脑发育调节蛋白的调节(Merriam等人,钙对树突棘微管动力学的突触调节,F-肌动蛋白,和脑发育调节蛋白(Synaptic regulation of microtubule dynamics in dendriticspines by calcium,F-actin,and drebrin),神经科学杂志(J.Neurosci.),八月16;33(42):16471-82;2013)。海马多巴胺-谷氨酸相互作用是通过许多突触后蛋白实现的,如荷马(homer)(de Bartolomeis和Tomasetti,多巴胺-谷氨酸相互作用中的钙依赖性网络:突触后支架蛋白的作用(Calcium-dependent networks in dopamine-glutamateinteraction:the role of postsynaptic scaffolding proteins),分子神经生物学(Mol.Neurobiol.),Oct:46(2):275-96;2012)和神经传递素释放的突触前调节器,如巴松管(Gundelfinger等人,巴松管和短笛在活动区组装和分子组织中的作用(Role ofBassoon and Piccolo in Assembly and Molecular Organization of the ActiveZone).计算神经科学前沿(Front Synaptic Neurosci.),Jan 12;7:19.doi:10.3389/fsnyn.2015.00019;2016)。cAMP作为多巴胺激活的腺苷酸环化酶的第二信使,介导多巴胺下游信号传导,涉及在长期记忆形成中起关键作用的蛋白激酶A(PKA)和cAMP反应元件-结合蛋白(CREB)。此外,在认知和精神疾病的背景下,已经报道了多巴胺通过异源受体复合物的功能变化(Fuxe等人,了解异受体复合物在中枢神经系统中的作用(Understanding therole of heteroreceptor complexes in the central nervous system),当前的蛋白质和肽科学(Curr Protein Pept.Sci.)2014;15(7):647;Fuxe等人,多巴胺异源受体复合物作为帕金森病的治疗靶点(Dopamine heteroreceptor complexes as therapeutictargets in Parkinson’sdisease),治疗靶点专家意见(Expert Opin.Ther.Targets.)19:377-98;2015;Martinez-Pinilla,多巴胺D2和血管紧张素II 1型受体在大鼠纹状体中形成功能性异聚体(Dopamine D2 and angiotensin II type 1receptors form functionalheteromers in rat striatum),生化药理学(Biochem.Pharmacol.)96:131-42;2015)。
术语“工作记忆”可以被认为是一种特定形式的短期记忆,指的是在一次试验中保留信息的能力,即在头脑中主动保存多条暂时信息,以便它们可以以一种使它们对目标导向行为有用的方式进行操作。根据Alan Baddeley(工作记忆、阅读和阅读障碍(Workingmemory,reading and dyslexia).心理学进展(Advances in Psychology)34:141-152,1986.)。工作记忆可以定义为“在执行一系列认知任务(如理解、学习和推理)期间临时保存和操纵信息的系统”。随着时间的推移保持不变并且在许多训练课程中逐渐获得的信息的长期存储通常被分配给“参照记忆”(D.S.Olton,迷宫、地图和记忆(Mazes,maps,andmemory),美国心理学家(American Psychologist)34:583,1979)。也就是说,与工作记忆相比,参照记忆似乎更类似于长期记忆,因为它指的是存储有关特定固定情况的信息的能力。根据Fauci等人(“Harrison’s Principles of Internal Medicine(哈里森内科医学原理)”,第1卷,第142至150页,1988),参照记忆是指从以前的(无论是最近的还是遥远的)经验中获得的信息,即参照记忆是指随着时间的推移保持不变的特定情况的知识。正如A.N.Guitar在"径向迷宫大鼠空间工作与参考记忆的相互作用(The Interaction BetweenSpatial Working and Reference Memory in Rats on a Radial Maze)"(Paper 4,2014;http://ir.lib.uwo.ca/psychd_uht)中所说,工作记忆和参照记忆可以定义为认知和物理上的独立系统。因此,参照记忆是或可以与长期记忆进行比较。参照记忆通常是在许多训练课程中逐渐获得的。一旦存储,参照记忆被认为是相对稳定且抗干扰的。在空间任务中,参照记忆模仿情景记忆的两个方面,即事件的“什么”(内容)和“哪里”(地点)维度。
人们认识到,立体异构体如手性药物的对映异构体可能具有与其外消旋体不同的药代动力学和药效学性质。因此,使用非立体选择性测定法产生的外消旋药物的药物处置和血浆药物浓度效应数据存在误解的风险。为药物的外消旋形式收集的数据对于单个对映异构体通常在数量和质量上都不准确。例如,未解析药物的清除可能表明浓度和时间依赖性,即使这种药代动力学过程对于每种对映体而言是浓度和时间无关的。
C.J.Loland等人,生物精神病学(Biol.Psychiatry),2012九月1,72(5)第405至413页(“R-莫达非(Armodafinil):一种独特的多巴胺摄取抑制剂和潜在的精神兴奋剂滥用药物(R-Modafinil(Armodafinil):A unique dopamine up-take inhibitor andpotential medication for psychostimulant abuse)”),发现R-莫达非在体外显示概况不同于可卡因。然而,得出的结论是,有必要使用R-莫达非尼作为替代疗法进行进一步的试验。
在WO 03/059873A1中公开了药物化合物,其包含噻唑基团和季碳,该季碳包含与亚砜部分相邻的三个苯基。这些化合物提供调节钙激活钾通道并充当SKca和/或IKca通道调节剂的药物。根据该文件,所提出的药物化合物适用于治疗疾病或病症,例如呼吸系统疾病如哮喘、囊性纤维化、慢性阻塞性肺病和鼻漏、抽搐、血管痉挛、冠状动脉痉挛、肾病、多囊肾病、膀胱痉挛、尿失禁、膀胱流出阻塞、肠易激综合征、胃肠功能障碍、分泌性腹泻、缺血、脑缺血、缺血性心脏病、心绞痛、冠心病、脑外伤、精神病、焦虑症、抑郁症、痴呆症、记忆力和注意力缺陷、阿尔茨海默病、痛经、嗜睡病、雷诺病、间歇性跛行、干燥综合征、偏头痛、心律失常、高血压、失神发作、强直性肌营养不良、口干症、11型糖尿病、高胰岛素血症、早产、秃顶、癌症和免疫抑制,特别是减少或抑制不良免疫调节作用,艾迪生病、斑秃、强直性脊柱炎、溶血性贫血(anemia haemolytica)、恶性贫血(anemia perniciosa)、口疮、口疮性口腔炎、关节炎、动脉硬化性疾病、骨关节炎、类风湿性关节炎、无精子症、支气管哮喘、自身免疫性哮喘、自身免疫性溶血、贝切特氏病、博克氏病、炎症性肠病、伯基特氏淋巴瘤、Chron病、绒毛膜炎、溃疡性结肠炎、腹腔疾病、冷球蛋白血症、疱疹样皮炎、皮肌炎、胰岛素依赖型I型糖尿病、青少年糖尿病、特发性尿崩症、胰岛素依赖型糖尿病、自身免疫性脱髓鞘疾病、杜普伊特伦氏挛缩症(Dupuytren's contracture)、脑脊髓炎、过敏性脑脊髓炎、过敏性眼内炎、过敏性肠炎、自身免疫性肠病综合征、麻风结节性红斑、特发性面瘫、慢性疲劳综合征、风湿性发热、肾小球肾炎、古德帕斯丘综合征(Goodpasture's syndrome)、格雷夫斯病、Hamman-Rich病、桥本氏病、桥本甲状腺炎、突发性听力丧失、感觉神经性听力丧失、慢性肝炎、霍奇金病、阵发性血红蛋白尿、性腺功能减退、区域性回肠炎、虹膜炎、白细胞减少、白血病、广布性红斑狼疮、系统性红斑狼疮、皮肤红斑狼疮、恶性淋巴肉芽肿、传染性单核细胞增多症、重症肌无力、横贯性脊髓炎、原发性特发性粘液性水肿、肾病、交感性眼炎、肉芽肿性睾丸炎、胰腺炎、天疱疮、寻常型天疱疮、结节性多动脉炎、慢性原发性多关节炎、多发性肌炎、急性多发性神经根炎、银屑病、紫癜、坏疽性脓皮病、奎文氏甲状腺炎、赖特综合征、结节病、共济失调性硬化症、进行性系统性硬化症、巩膜炎、硬皮病、多发性硬化症、广布性硬化症、获得性脾萎缩、抗精子抗体引起的不孕症、血小板减少症、特发性血小板减少性紫癜、胸腺瘤、急性前葡萄膜炎、白癜风、AIDS、HIV、SCID和爱泼斯坦-巴尔病毒(Epstein Barrvirus)相关疾病如干燥综合征、病毒(AIDS或EBV)相关B细胞淋巴瘤、寄生虫病如利士曼原虫(Le-sihmania)和免疫抑制疾病状态,例如同种异体移植后的病毒感染、移植物抗宿主综合征、移植排斥或AIDS、癌症、慢性活动性肝炎糖尿病、中毒性阻塞综合征、食物中毒和移植排斥。
US 2002/0183334是关于取代的硫代乙酰胺。US 2002/0183334中公开的相当广泛的一组化合物适用于治疗嗜睡、疲倦、帕金森病、脑缺血、中风、睡眠呼吸暂停、饮食失调、注意力缺陷多动障碍、认知功能障碍、大脑皮层功能低下相关疾病、抑郁症、精神分裂症和慢性疲劳综合征的合理性,以及促进不眠、刺激食欲或刺激体重增加。
在WO 03/066035中公开了范围广泛的硫醚磺酰胺,它们适用于治疗糖尿病。
US 2005/0234040涉及三环芳族和双-苯基亚磺酰基衍生物。本文件中规定的化合物提供适用于治疗过度嗜睡、促进和/或改善不眠,优选改善与嗜睡症、睡眠呼吸暂停优选阻塞性睡眠呼吸暂停/呼吸不足和轮班工作紊乱相关的过度嗜睡患者的药物)、帕金森病、阿尔茨海默病、脑缺血、中风、饮食失调、注意力缺陷障碍(“ADD”)、注意力缺陷多动障碍(“ADHD”)、抑郁症、精神分裂症(schizophrenia)、疲劳,优选与癌症或神经系统疾病相关的疲劳,例如多发性硬化症和慢性疲劳综合征、刺激食欲和体重增加以及改善认知功能障碍。
从EP2292213A1可以得到由特定多晶型R-(-)-莫达非尼和一种或多种药学上可接受的载体、稀释剂或赋形剂组成的药物组合物,使用这些药物组合物可以治疗嗜睡症患者,确保与等量的外消旋形式的莫达非尼相比,在高剂量下更持久的血浆浓度和更高的总体暴露量。
发明内容
尽管已经进行了许多尝试,但希望提供一种允许高效且有效地应对已知的学习和/或记忆缺陷的方法。仍在寻找表现出进一步改善记忆和学习功能的化合物和方法。因此,本发明的一个目的是提供增加学习能力以及记忆性能的药剂,特别是在老年个体中。本发明的另一个目的是治疗认知功能的年龄依赖性衰退,并提供一种有效的药剂,其可用于治疗年龄依赖性衰退和/或反过来需要改善学习能力以及记忆性能的障碍。
因此,本发明提供了具有通式(I)的化合物:
其中
R1是苯基,并且
R2是间位取代的苯基;和
RTA是取代的或未取代的噻唑环,
其中取代的是指被选自由烃基、环烃基、杂环烃基、羟烃基、烷硫基、醚、羟基、氟、氯、溴和碘所组成的组中的残基取代。
已发现式(I)的那些化合物是优选的,其中
RTA是具有通式(IIa)的2-1,3-或4-1,3-或5-1,3-噻唑环,
其中R3相同或独立地,在根据式(IIa)的环上存在1次或2次,并且其中R3选自由氢、烃基、环烃基、杂环烃基、烃基氨基,特别是二烃基氨基、芳基氨基,特别是二芳基氨基、羟烃基氨基、烷氧基、芳烃基、羟烃基、硫代烃基、卤代烃基、卤代芳基、卤代芳烃基、卤代烷氧基、单取代或多取代的烃基,单取代或多取代的环烃基、单取代或多取代的杂环烃基、单取代或多取代的烃基氨基,特别是二烃基氨基、单取代或多取代的芳基氨基,特别是二芳基氨基、单取代或多取代的羟烃基氨基、单取代或多取代的烷氧基、单取代或多取代的芳烃基、单取代或多取代的羟烃基、单取代或多取代的硫代烃基、单取代或多取代的卤代烃基、单取代或多取代的卤芳基、单取代或多取代的卤芳烃基、单取代或多取代的卤代烷氧基和羧酸酯所组成的组中。
已经发现,另外或可选地,根据式(I)的那些化合物是优选的,其中
残基R2的间位取代基选自由烃基、环烃基、杂环烃基、烃基氨基,特别是二烃基氨基、芳基氨基,特别是二芳基氨基、羟烃基氨基、烷氧基、羟基、羧酸基团、羧酸酯基团、卤素,特别是溴取代基、芳烃基、羟烃基、硫代烃基、卤代烃基、卤代芳基、卤代芳烃基、卤代烷氧基、单取代或多取代的烃基、单取代或多取代的环烃基、单取代或多取代的杂环烃基、单取代或多取代的烃基氨基,特别是二烃基氨基、单取代或多取代的芳基氨基,特别是二芳基氨基、单取代或多取代的羟烃基氨基、单取代或多取代的烷氧基、单取代或多取代的芳烃基、单取代或多取代的羟烃基、单取代或多取代的硫代烃基、单取代或多取代的卤代烃基、单取代或多取代的卤芳基、单取代或多取代的卤芳基烃基、单取代或多取代的卤代烷氧基和羧酸酯所组成的组中,
其中取代的是指被选自由烃基、环烃基、杂环烃基、羟烃基、烷硫基、醚、羟基、氟、氯、溴和碘所组成的组中的残基取代,和/或其中
R3是氢或烃基,特别是甲基,或氧烃基,特别是氧甲基,或被选自由杂环烃基、羧酸、酰胺和酯所组成的组中的至少一个残基取代的烃基,特别是被杂环烃基,优选含有至少两个杂原子的杂环烃基取代的甲基。
在这方面甚至更优选的是残基RTA,其代表2-1,3-噻唑基团或5-1,3-噻唑基团,特别是5-1,3-噻唑基团。
杂环烃基优选选自由吗啉基、哌嗪基和甲基哌嗪基所组成的组中。
芳基,即本发明含义中的芳基优选表示苯基,并且取代的芳基优选表示单取代或多取代的苯基。示例性取代的苯基包括例如-o-C6H4-R’、-m-C6H4-R’和-p-C6H4-R’,其中R’是如本文所定义或如对残基R3、R4、R5、R6和R7所定义的烃基。在本发明的含义中,稠合芳基优选表示与至少一种芳环系统稠合的芳环,该稠合芳基特别是由5至15个碳原子组成,例如萘基和蒽基。这些稠合芳基也可以是单取代或多取代的,例如如本文所定义的1-萘基、2-萘基、1-蒽基(1-anthracenyl)或2-蒽基。
杂芳基,即本发明含义中的杂芳基优选表示含有至少一个选自O、N和S的杂原子的3至8元杂环芳基。本发明含义中的杂芳基还包括与另一个芳环稠合的杂芳基环。杂芳基和稠合杂芳基也可以是如本文所定义的单取代或多取代。
烃基,即本发明含义中的烃基优选包含烷基、烯基和炔基残基,特别是C1-C6-烷基、C2-C6-烯基和C2-C6-炔基残基。合适的残基选自由以下所组成的组中:-CH3、-C2H5、-CH=CH2、-C≡CH、-C3H7、-CH(CH3)2、-CH2-CH=CH2、-C(CH3)=CH2、-CH=CH-CH3、-C≡C-CH3、-CH2-C≡CH、-C4H9、-CH2-CH(CH3)2、-CH(CH3)-C2H5、-C(CH3)3、-C5H11、-C6H13、-C(R’)3、-C2(R’)5、-CH2-C(R’)3、-C3(R’)7、-C2H4-C(R’)3、-C2H4-CH=CH2、-CH=CH-C2H5、-CH=C(CH3)2、-CH2-CH=CH-CH3、-CH=CH-CH=CH2、-C2H4-C≡CH、-C≡C-C2H5、-CH2-C≡C-CH3、-C≡C-CH=CH2、-CH=CH-C≡CH、-C≡C-C≡CH、-C2H4-CH(CH3)2、-CH(CH3)-C3H7、-CH2-CH(CH3)-C2H5、-CH(CH3)-CH(CH3)2、-C(CH3)2-C2H5、-CH2-C(CH3)3、-C3H6-CH=CH2、-CH=CH-C3H7、-C2H4-CH=CH-CH3、-CH2-CH=CH-C2H5、-CH2-CH=CH-CH=CH2、-CH=CH-CH=CH-CH3、-CH=CH-CH2-CH=CH2、-C(CH3)=CH-CH=CH2、-CH=C(CH3)-CH=CH2、-CH=CH-C(CH3)=CH2、-CH2-CH=C(CH3)2、C(CH3)=C(CH3)2、-C3H6-C≡CH、-C≡C-C3H7、-C2H4-C≡C-CH3、-CH2-C≡C-C2H5、-CH2-C≡C-CH=CH2、-CH2-CH=CH-C≡CH、-CH2-C≡C-C≡CH、-C≡C-CH=CH-CH3、-CH=CH-C≡C-CH3、-C≡C-C≡C-CH3、-C≡C-CH2-CH=CH2、-CH=CH-CH2-C≡CH、-C≡C-CH2-C≡CH、-C(CH3)=CH-CH=CH2、-CH=C(CH3)-CH=CH2、-CH=CH-C(CH3)=CH2、-C(CH3)=CH-C≡CH、-CH=C(CH3)-C≡CH、-C≡C-C(CH3)=CH2、-C3H6-CH(CH3)2、-C2H4-CH(CH3)-C2H5、-CH(CH3)-C4H9、-CH2-CH(CH3)-C3H7、-CH(CH3)-CH2-CH(CH3)2、-CH(CH3)-CH(CH3)-C2H5、-CH2-CH(CH3)-CH(CH3)2、-CH2-C(CH3)2-C2H5、-C(CH3)2-C3H7、-C(CH3)2-CH(CH3)2、-C2H4-C(CH3)3、-CH(CH3)-C(CH3)3、-C4H8-CH=CH2、-CH=CH-C4H9、-C3H6-CH=CH-CH3、-CH2-CH=CH-C3H7、-C2H4-CH=CH-C2H5、-CH2-C(CH3)=C(CH3)2、-C2H4-CH=C(CH3)2、-C4H8-C≡CH、-C≡C-C4H9、-C3H6-C≡C-CH3、-CH2-C≡C-C3H7、和-C2H4-C≡C-C2H5;
其中R’可以定义为如上文针对式(I)概述的残基R3。如上所述的R’优选是氢、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、仲丁基或异丁基,特别是氢、甲基或异丙基(i-propyl)。
根据式(I)的优选实施方式的烃基,特别是对于残基R3,是甲基、乙基、丙基、异丙基、正丁基、叔丁基、仲丁基和异丁基,优选甲基或异丙基,更优选烃基选自甲基、乙基、异丙基和叔丁基。
芳烃基,即本发明含义中的芳烃基优选表示被至少一个如上定义的芳基取代的直链或支链C1-C6-烃基,优选苄基或苯乙基。合适的单取代或多取代的芳烃基包括例如4-羟基苄基、3-氟苄基或2-氟苯基乙基。
环烃基,即本发明含义中的环烃基优选表示含有三至八个碳原子,优选四至八个碳原子的非芳族环系统。对于单取代或多取代的环烃基,环中的一个或多个碳原子可以被如上定义的基团R’取代,优选甲基、乙基、正丙基、异丙基、正-丁基、异-丁基或叔-丁基。合适的C3-C8-环烃基可选自由-环-C3H5、-环-C4H7、-环-C5H9、-环-C6H11、-环-C7H13和-环-C8H15所组成的组中。
杂环烃基,即本发明含义中的杂环烃基优选表示非芳族碳环体系,其中一个或多个环碳原子已被杂原子官能团如O、S、SO、SO2、N或NR’2,其中R’定义如上。优选的杂环烃基可选自由吗啉-4-基、哌嗪基和异烃基哌嗪-4-基所组成的组中。
羟烃基,即本发明含义中的羟烃基优选表示其中烃基如上文所述定义的羟烃基,其中烃基优选为甲基、乙基、正丙基、异丙基、正-丁基、异-丁基或叔-丁基。合适的羟烃基选自由羟甲基、羟乙基、羟丙基和羟基-异丙基所组成的组中。根据式(I)的优选实施方式的羟烃基是羟甲基。一旦键合,烃基或甲基也可分别表示为亚烃基(alkylene)或亚甲基(methylene)。
烷硫基,即本发明含义中的烷硫基优选表示其中烃基如上文所述定义的烷硫基(alkylthio group),优选是对于R3,特别是硫甲基(thiomethyl)。
卤代烃基,即本发明含义中的卤代烃基优选表示其中烃基如上文所述特别是对于R3定义的卤代烃基,并且其中所述烃基被一个或多个卤原子取代,优选被取代一到五个卤原子,特别是氟或氯原子。在一个优选的实施方式中,卤代烃基选自由-C(R10)3、-C R10(R10’)2、-CR10(R10’)R10”、-C2(R10)5、-CH2-C(R10)3、-C(R10’)2-CH(R10’)2、-CH2-CR10(R10’)2、-CH2-CR10(R10’)R10”、-C3(R10)7或-C2H4-C(R10)3,其中R10、R10’、R10”代表F、Cl、Br或I,优选F。
卤代芳基,即本发明含义中的卤代芳基优选表示其中至少一个芳族碳原子被一个或多个卤原子取代,优选被1-5个卤原子取代的卤代芳基。优选地,卤原子选自氟、氯和溴原子,优选氟。
卤代芳基烃基,即本发明含义中的卤代芳基烃基优选表示其中芳基烃基如上文所述定义并且其中所述芳基的至少一个芳族碳原子被一个或多个卤原子取代的卤代芳基烃基,优选被一到五个卤素原子取代。优选地,卤素原子选自氟、氯、溴和碘原子,更优选地选自氟和氯原子。
卤代烷氧基,即本发明含义中的卤代烷氧基优选表示其中烷氧基如上文所述定义并且其中所述烷氧基被一个或多个卤原子取代,优选被1-5个卤原子特别是氟、氯、溴和/或碘原子,更优选氟和/或氯原子取代的卤代烷氧基。优选地,卤代烷氧基选自由OC(R10)3、-OCR10(R10’)2、-OCR10(R10’)R10”、-OC2(R10)5、-OCH2-C(R10)3、-OCH2-CR10(R10’)2、-OCH2-CR10(R10’)R10”、-OC3(R10)7或-OC2H4-C(R10)3所组成的组中,其中R10、R10’、R10”代表F、Cl、Br或I,优选F。
烃基氨基,即本发明含义中的烃基氨基优选表示其中烃基如上文所述特别是对于R3定义的烃基氨基。本发明含义中的烃基氨基优选表示(烃基)2-N-基团,即二烃基氨基,或烃基-NH-基团。优选二烃基氨基。烃基优选如上所述定义。
芳基氨基,即本发明含义中的二芳基氨基优选表示芳基氨基,其中芳基如上文所述定义。芳基氨基表示(芳基)2-N-基团,即二芳基氨基或芳基-NH-基团。优选二芳基氨基,特别是二苯基氨基。芳基优选如上所述定义。
羟烃基氨基,即本发明含义中的羟烃基氨基优选表示其中烃基如上文所述特别是对于R3定义的羟烃基氨基,并且其中羟烃基氨基表示(HO-烃基)2-N-基团或HO-烃基-NH-基团,或(HO-烃基)-N-(烃基)-基团。烃基优选如上所述定义。
本发明不包括具有由例如重复的R1、R2、R3单元等组成的无限链的化合物。
除非另有说明,如本文所述任选取代的成分可以在任何化学上可能的位置被取代。
此外,根据式(I)的那些非对映异构体富集的或非对映异构体纯的化合物在学习能力、特别是空间学习能力和/或记忆功能、特别是参照记忆方面提供特别改进的结果,特别是通过使用那些根据式(I)的化合物,其中RTA是具有通式(IIa)的2-1,3-或4-1,3-或5-1,3-噻唑环。
特别优选根据式(I)的那些化合物,其中R2是在间位具有氯、溴或碘取代基,特别是溴取代基的苯环。
在另一个优选的实施方式中,根据式(I)的化合物是非对映异构体混合物,所述混合物是5-((((R),(R)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,特别是5-((((R),(R)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,以及更特别是5-((((R),(R)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑、
5-((((R),(S)-3-卤苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,特别是5-((((R),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,以及更特别是5-(((((R),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,以及
5-((((S),(R)-3-卤苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,特别是5-((((S),(R)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,以及更特别是5-((((S),(R)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,和
5-(((((S),(S)3-卤苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,以及更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑的非对映异构体混合物。
在另一个优选的实施方式中,根据式(I)的化合物代表富含5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,特别是富含5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,以及更特别地富含5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑的非对映异构体混合物。
甚至更优选地,根据式(I)的化合物是具有通式(I)的四种非对映体之一的基本上非对映体纯的化合物,特别是5-((((S),(S)-3-卤苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,以及甚至更特别5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,即它基本上不含任何5-((((R),(R)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,特别是任何5-((((R),(R)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,5-((((R),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,特别是任何5-((((R),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,和5-((((S),(R)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,特别是任何5-(((((S),(R)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑。
因此,根据式(I)的化合物优选为5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,以及甚至更优选5-(((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑。后一种化合物也可以通过下式来描述:
已经发现,当根据式(I)的化合物是5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,以及更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑时,在改善空间记忆方面,尤其是对于年老的个体或遭受与年龄相关的认知衰退的那些个体而言,可以获得最有希望的结果。
替代地,也可以使用富含5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-(((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑的非对映异构体混合物,其含有5-((((R),(R)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑、5-((((R),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑和/或5-((((S),(R)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑。一般而言,本发明提供如本文所定义的式(I)化合物用于治疗,即用作药物,特别是用于治疗与年龄相关的认知衰退,更特别是用于治疗根据2018ICD-10-CM诊断代码(Diagnosis Code)R41.81,例如根据美国版2018ICD-10-CM诊断代码R41.81的与年龄相关的认知衰退。
特别令人感兴趣的是,使用式(I)的化合物,优选非对映体纯的5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,或富含5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,在特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑的非对映异构体混合物在学习能力,特别是空间学习能力以及记忆性能,特别是参照记忆方面的改善,可以通过没有记忆缺陷和/或认知缺陷的人类个体来实现。
因此,这些结果也可以在没有参照记忆缺陷和/或由脑部疾病引起的认知缺陷的个体中获得。因此,本发明的化合物也可以施用于健康个体并且对健康个体也有效,以改善参照记忆和/或其他认知能力,例如学习能力(或克服各自的缺陷)。因此,本发明因此还涉及根据本发明的化合物用于改善健康个体,特别是健康老龄个体的学习能力,特别是空间学习能力,以及记忆性能,特别是参照记忆。
此外,本发明还涉及根据本发明的化合物用于改善学习能力,特别是空间学习能力,以及记忆性能,特别是具有参照记忆缺陷和/或认知缺陷的人类个体的参照记忆,特别是由大脑疾病引起的参照记忆缺陷。在这方面,可以用根据式(I)的化合物治疗具有参照记忆缺陷和/或认知缺陷,特别是和/或参照记忆缺陷的患者,其由阿尔茨海默病;唐氏综合症;血管性认知障碍;中风;额颞叶痴呆;行为、语义或进行性失语型痴呆;路易体痴呆;皮层下痴呆;帕金森病痴呆;酒精相关性痴呆;外伤性脑损伤引起的痴呆;亨廷顿病相关痴呆;AIDS相关痴呆症;注意缺陷障碍;或精神分裂症,或有任何形式的认知障碍引起。
本发明的式(I)化合物,特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,可以单独或与其他认知增强化合物组合使用,如利伐斯的明、多奈哌齐、加兰他明、氯氮平、利培酮、美金刚、奥氮平、阿立哌唑、喹硫平、氯氮平、二激动剂、烟碱型阿尔法7-激动剂、d-丝氨酸、d-环丝氨酸、PDE2、4,9抑制剂、AMPA激动剂、拉莫三嗪、n-去甲基氯氮平、mGlu受体激动剂、GABA A受体激动剂、毒蕈碱1和4受体激动剂,用于治疗缺乏认知障碍和改善参照记忆。
根据本发明的化合物特别适用于治疗具有学习缺陷和/或记忆缺陷,特别是空间学习和记忆任务缺陷的患者,这是由于健康和老龄个体的特殊需求、脑部疾病、精神障碍或认知障碍缺陷,特别是患有阿尔茨海默病、唐氏综合症、中风(血管性认知障碍)、额颞叶痴呆、行为、语义和进行性失语型痴呆、路易体痴呆、皮层下痴呆和帕金森病痴呆、酒精相关性痴呆、创伤性痴呆脑损伤、亨廷顿病相关痴呆、AIDS相关痴呆、注意力缺陷障碍;或精神分裂症(schizophrenia)的患者。
根据式(I)的化合物,优选5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更优选5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑可以以有效量施用于患有或有风险发展上述任何疾病的患者。还可以将化合物施用于健康个体以改善学习能力和/或记忆性能,特别是参照记忆,更优选空间学习能力和参照记忆。
根据一个优选的实施方式,根据本发明的化合物的给药是方便的,特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)-亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,以单一剂量单位形式,特别是作为胶囊剂或药片。优选的制剂包括软明胶胶囊,该胶囊含有至少一种根据式(I)的化合物与一种或多种乳化剂一起溶解在胶囊内的油中。因此,优选明胶胶囊,其包含一种或多种乳化剂以及溶解在至少一种油中的至少一种根据式(I)的化合物。
优选的剂量包括约1mg/kg至约25mg/kg体重的给药剂量。合适的剂型还包括含有至少一种根据式(I)的化合物的制剂,其量为约0.1mg至约10g,优选约1mg至约1g,更优选约10mg至约200mg。
根据一个优选的实施方式,根据本发明的式(I)化合物,特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑可以是制剂的一部分,该制剂至少含有或可以与一种或多种化合物一起施用,该化合物也称为助剂,选自利伐斯的明、多奈哌齐、加兰他明、氯氮平、利培酮、美金刚、奥氮平、阿立哌唑、喹硫平、氯氮平、二激动剂、烟碱阿尔法7-激动剂、d-丝氨酸、d-环丝氨酸、PDE2、4,9抑制剂、AMPA激动剂、拉莫三嗪、n-去甲基氯氮平、mGlu受体激动剂、GABA A受体激动剂和毒蕈碱1和4激动剂或其他潜在的认知增强化合物。
本发明的目的还通过使用根据式(I)的化合物,特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)-甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑解决,用于制备改善学习能力,特别是空间学习能力,以及记忆能力,特别是参照记忆,更特别是空间学习能力和参照记忆的药物。
根据本发明的另一方面,根据式(I)的化合物,特别是5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,已被发现可用于,特别是选择性地,抑制哺乳动物,特别是人类个体大脑突触中DAT介导的多巴胺再摄取,以及在制造用于抑制哺乳动物,特别是人类个体大脑中突触中DAT介导的多巴胺再摄取的药物中。对于根据式(I)的化合物,特别是5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,对DAT的抑制不仅非常有效,而且对SERT和NET抑制具有高度特异性。用根据式(I)的化合物,特别是5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,可以实现高特异性的DAT抑制,IC50不超过7.5μM,特别是不超过4.5μM,更特别是不超过2.5μM,甚至更特别地不超过1.75μM,更优选地不超过1.0μM。与5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,特异性DAT抑制作用甚至可以以不超过0.75μM、优选不超过0.5μM、甚至更优选不超过0.3μM的浓度完成。测量基于使用体外再摄取抑制测定(如实验部分所述)。
令人惊讶地发现,5-(((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,特别是5-(((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑在选择性抑制大脑突触中DAT介导的多巴胺再摄取方面的效果是5-((((R),(R)-3)-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑、5-(((((R),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑、5-((((S),(R)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑和(S)-5-(二苯基甲烷亚磺酰基甲基)-1,3-噻唑的至少5倍,特别是至少8倍,更特别是至少10倍。
此外,本发明的目的还通过药物制剂解决,本文也称为药物组合物,其包含至少一种根据式(I)的化合物,特别是5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-(((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,甚至更多特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,和至少一种药学上可接受的载体和/或稀释剂。因此,根据另一方面,本发明涉及包含根据本发明的化合物和药学上可接受的载体或稀释剂的药物制剂。
药物“载体”、“稀释剂”以及“赋形剂”是作为根据本发明的化合物或具有药学作用的其他化合物(例如也具有神经学或行为学作用)的辅助物质混入药物组合物中的物质。这些辅助物质本身不具有药学作用(它们本身不是“活性物质”),但可以帮助优化根据本发明的化合物的有效性。用作“载体”、“稀释剂”和“赋形剂”的物质通常可以互换使用(即用作“稀释剂”的物质也可以用作“赋形剂”和/或“载体”)。
一般来说,“载体”是改善药物输送和有效性的物质;“稀释剂”是稀释药物制剂中活性物质的物质;“赋形剂”是混合到药物制剂中以定义其释放特性的物质。
如前所述,所有此类“载体”、“稀释剂”和“赋形剂”(即辅助物质,有时也将术语“赋形剂”用作包括所有此类物质的通用术语)都是与活性成分一起配制的药物的非活性物质(“API”),用于填充含有强效活性成分(因此通常也称为“膨胀剂”、“填充剂”或“稀释剂”)的配方。膨胀允许在生产剂型时方便且准确地分配药物物质。它们还可以用于各种治疗增强目的,例如促进药物吸收或溶解,或其他药代动力学考虑。此类物质也可用于制造过程,以帮助处理相关的活性物质,例如通过促进粉末流动性或不粘特性,还帮助体外稳定性,例如在预期的保质期内防止变性。合适的赋形剂、载体和稀释剂的选择还取决于给药途径和剂型,以及活性成分和其他因素。此类物质,例如用作抗粘附剂、粘合剂、涂料、崩解剂、填充剂、香料、色素、润滑剂、助流剂、吸附剂、防腐剂、甜味剂等。
药物“载体”是用作改善药物输送和有效性的机制的物质。药物载体通常用于各种药物递送系统,例如:延长体内药物作用的控释技术;降低药物代谢,降低药物毒性。
载体通常也用于设计中以提高药物递送至药理作用目标部位的有效性。
药物“稀释剂”通常是简单地稀释或重构药物组合物(例如以干燥形式储存后)的物质。
具有至少一种根据式(I)的化合物的药物组合物,特别是5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,通常在固体组合物中包含约0.01(%w/w)至约80(%w/w)或在液体组合物中包含约0.001(%w/v)至约80(%w/v)的所述化合物。优选地,根据本发明的化合物的存在量在固体组合物中为约0.1(%w/w)至约50(%w/w)或在液体组合物中的存在量为约0.01(%w/v)至约10(%w/v),特别是在固体组合物中为约1(%w/w)至约0(%w/w)或在液体组合物中为约0.1(%w/v)至约5(%w/v)。
如前所述,优选根据式(I)的化合物,特别是5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑作为药物组合物,特别是作为药物单一单位剂型提供。本文提供的药物组合物和单一单位剂型包含预防或治疗有效量的一种或多种根据式(I)的化合物和任选地还包含一种或多种另外的预防或治疗剂(例如,特别是本文提供的化合物,或其他预防或治疗剂),以及一种或多种药学上可接受的载体或赋形剂或稀释剂。在一个特别优选的实施方式中并且在本文中,术语“药学上可接受的”是指由联邦或州政府的监管机构批准或列在欧洲或美国药典或其他公认的用于动物更具体地在人类的药典中。
术语“载体”在一个实施方式中是指稀释剂、佐剂(例如,弗氏佐剂(完全和不完全))或与治疗剂一起施用的载体。这样的药物载体可以是无菌液体,例如水和油,包括石油、动物、植物或合成来源的那些,例如花生油、大豆油、矿物油、芝麻油等。当药物组合物静脉内给药时,水是一种特殊的载体。盐水溶液和含水葡萄糖和甘油水溶液也可以用作液体载体,特别是用于可注射溶液。
在一个实施方式中,药物组合物和剂型包含一种或多种赋形剂。合适的赋形剂是药学领域技术人员熟知的,合适的赋形剂的非限制性实例包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙烯、乙二醇、水、乙醇等。特定赋形剂是否适合掺入药物组合物或剂型通常取决于本领域熟知的多种因素,包括但不限于将剂型施用于患者的方式和具体的剂型中的活性成分。如果需要,组合物或单一单位剂型还可以包含少量的润湿剂或乳化剂,或pH缓冲剂。
剂型的例子包括但不限于:片剂;囊片;胶囊,例如软弹性明胶胶囊;扁囊剂;锭剂;含片;分散体;栓剂;药膏;巴布剂(药膏);糊状物;粉末;敷料;面霜;膏药;溶液剂;药贴;气雾剂(例如,鼻喷雾剂或吸入器);凝胶;适合于向患者口服或粘膜给药的液体剂型,包括混悬剂(例如,水性或非水性液体混悬剂、水包油乳剂或油包水液体乳剂)、溶液剂和酏剂;适用于对患者进行肠胃外给药的液体剂型;和无菌固体(例如结晶或无定形固体),它们可以被重构以提供适合于对患者进行肠胃外给药的液体剂型。
可用于口服剂型的合适赋形剂的实例包括但不限于粘合剂、填充剂、崩解剂和润滑剂。适用于药物组合物和剂型的粘合剂包括但不限于玉米淀粉、马铃薯淀粉或其他淀粉、明胶、天然和合成树胶如阿拉伯胶、海藻酸钠、海藻酸、其他海藻酸盐、粉状黄蓍胶、瓜尔豆胶、纤维素及其衍生物(例如乙基纤维素、醋酸纤维素、羧甲基纤维素钙、羧甲基纤维素钠)、聚乙烯吡咯烷酮、甲基纤维素、预糊化淀粉、羟丙基甲基纤维素(例如,Nos.2208、2906、2910)、微晶纤维素及其混合物。
适用于本文公开的药物组合物和剂型的填充剂的实例包括但不限于滑石、碳酸钙(例如,颗粒或粉末)、微晶纤维素、粉状纤维素、葡聚糖、高岭土、甘露醇、硅酸、山梨糖醇、淀粉、预糊化淀粉及其混合物。本文提供的药物组合物中的粘合剂或填充剂通常以药物组合物或剂型的约50至约99重量%存在。
微晶纤维素的合适形式包括但不限于以AVICEL-PH-101、AVICEL-PH-103AVICELRC-581、AVICEL-PH-105出售的材料(可从FMC公司(FMC Corporation)、美国粘胶部(American Viscose Division)、Avicel Sales、马库斯胡克(Marcus Hook)、PA获得)及其混合物。一种特定的粘合剂是微晶纤维素和羧甲基纤维素钠的混合物,以AVICEL RC-581出售。合适的无水或低水分赋形剂或添加剂包括AVICEL-PH-103TM和Starch 1500LM。
崩解剂可用于本发明的组合物中以提供固体剂型,例如当暴露于水性环境时崩解的片剂。崩解剂含量过多的片剂可能会在储存中崩解,而崩解剂含量过少的片剂可能无法以所需的速率或在所需的条件下崩解。因此,应使用足够量的崩解剂,既不过多也不过少而不会有害地改变活性成分的释放,来形成本文提供的固体口服剂型。崩解剂的使用量根据制剂的类型而变化,并且对于本领域普通技术人员来说是容易辨别的。典型的药物组合物包含约0.5至约15重量百分比的崩解剂,特别是约1至约5重量百分比的崩解剂。
可用于药物组合物和剂型的合适崩解剂包括但不限于琼脂、海藻酸、碳酸钙、微晶纤维素、交联羧甲基纤维素钠、交联聚维酮、波拉克林钾、淀粉乙醇酸钠、马铃薯或木薯淀粉、预糊化淀粉、其他淀粉、粘土、其他藻类、其他纤维素、树胶及其混合物。
可用于药物组合物和剂型的合适润滑剂包括但不限于硬脂酸钙、硬脂酸镁、矿物油、轻质矿物油、甘油、山梨醇、甘露醇、聚乙二醇、其他二醇、硬脂酸、月桂酸钠硫酸盐、滑石粉、氢化植物油(例如,花生油、棉籽油、葵花油、芝麻油、橄榄油、玉米油和大豆油)、硬脂酸锌、油酸乙酯、月桂酸乙酯、琼脂及其混合物。另外的润滑剂包括例如syloid硅胶(AEROSIL200,由马里兰州巴尔的摩的WR Grace Co.制造)、合成二氧化硅的凝结气雾剂(由德克萨斯州皮亚诺的Degussa Co.销售)、CAB-O-SIL(马萨诸塞州波士顿的卡博特公司出售的热解二氧化硅产品)及其混合物。如果使用的话,润滑剂的使用量通常少于其所加入的药物组合物或剂型的约1重量百分比。
本文所述的活性成分如根据式(I)的化合物和/或本文提供的助剂可以通过控释方式或通过本领域普通技术人员熟知的递送装置给药。此类剂型可用于提供一种或多种活性成分的缓释或控释,使用例如羟丙基甲基纤维素、其他聚合物基质、凝胶、渗透膜、渗透系统、多层包衣、微粒、脂质体、微球或它们的组合以提供不同比例的所需释放曲线。可以容易地选择本领域普通技术人员已知的合适的控释制剂,包括本文所述的那些,以与活性成分一起使用。因此提供了适用于口服给药的单一单位剂型,例如但不限于适用于控释的片剂、胶囊、凝胶胶囊和囊片。
所有控释药物产品都有一个共同的目标,即与非受控同类产品相比,改善药物治疗。理想情况下,在医学治疗中使用优化设计的控释制剂的特点是在最短时间内使用最少的药物来治愈或控制病情。控释制剂的优点包括延长药物活性、降低给药频率和提高患者依从性。此外,控释制剂可用于影响起效时间或其他特性,例如药物的血液水平,从而影响副作用(例如不良反应)的发生。
大多数控释制剂设计为首先释放一定量的药物(活性成分),从而迅速产生所需的治疗效果,然后逐渐和持续释放其他量的药物,以在较长时间内保持这种水平的治疗或预防效果。为了在体内维持这种恒定的药物水平,药物必须以一定速度从剂型中释放出来,以取代正在代谢和从体内排出的药物量。可以通过各种条件刺激活性成分的控释,包括但不限于pH、温度、酶、水或其他生理条件或化合物。
肠胃外剂型可以通过多种途径施用于患者,包括但不限于口服、皮下、静脉内(包括推注)、肌内和动脉内。因为它们的施用通常绕过患者对污染物的天然防御,所以在某些实施方式中,肠胃外剂型是无菌的或能够在施用给患者之前被灭菌。肠胃外剂型的实例包括但不限于准备注射的溶液、准备溶解或悬浮在药学上可接受的注射载体中的干燥产品、准备注射的混悬剂和乳剂。
可用于提供肠胃外剂型的合适载体是本领域技术人员熟知的。示例包括但不限于:注射用水USP;水性载体,例如但不限于氯化钠注射液、林格注射液、葡萄糖注射液、葡萄糖和氯化钠注射液和乳酸林格注射液;与水混溶的载体,例如但不限于乙醇、聚乙二醇和聚丙二醇;和非水载体,例如但不限于玉米油、棉籽油、花生油、芝麻油、油酸乙酯、肉豆蔻酸异丙酯和苯甲酸苄酯。
根据一个优选的实施方式,本发明的药物制剂还包含一种或多种选自下组的化合物:利伐斯的明、多奈哌齐、加兰他明、氯氮平、利培酮、美金刚、奥氮平、阿立哌唑、喹硫平、氯氮平、二激动剂、烟碱阿尔法7-激动剂、d-丝氨酸、d-环丝氨酸、PDE2、4,9抑制剂、AMPA激动剂、拉莫三嗪、n-去甲基氯氮平、mGlu受体激动剂、GABA A受体激动剂和毒蕈碱1和4激动剂或其他潜在的认知增强化合物、药剂。
根据式(I)的化合物,特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑的优选剂量为0.1mg至10g,优选1mg至1g,特别是10mg至200mg根据本发明的化合物。如前所述,本发明涉及根据式(I)的组合物在制备药物中的用途。并且,本发明还涉及包含至少一种根据式(I)的化合物的组合物在制备药物中的用途,即药物治疗或预防认知障碍、痴呆和/或参照记忆缺陷。
式(I)化合物,特别是5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,可用于人类、啮齿类动物和其他哺乳动物,可作为治疗剂本身,也可作为彼此的混合物或药物制剂的形式,其允许肠内或肠胃外使用并且作为活性成分含有有效剂量的式(I)化合物。有效剂量范围可以很容易地适应个体患者的严重程度和需要。除了常规的药学上无害的赋形剂和添加剂之外,优选的剂量是1mg至10mg/kg体重。
所提出的治疗剂可以口服给药,例如以丸剂、片剂、包衣片剂、糖衣片剂、硬胶囊和软胶囊、溶液剂、糖浆、乳剂或混悬剂的形式。然而,给药也可以通过直肠进行,例如以栓剂的形式,或通过肠胃外进行,例如以注射或输注或经皮的形式,例如以软膏、乳膏或酊剂的形式。
除了式(I)的活性化合物之外,药物组合物还可以包含其他常用的、通常是惰性的载体材料或赋形剂,特别是如上所述的。因此,药物制剂还可以包含添加剂,例如用于填充剂、增量剂、崩解剂、粘合剂、助流剂、润湿剂、稳定剂、乳化剂、防腐剂、甜味剂、着色剂、调味剂或芳香剂、缓冲物质和用于实现贮藏效果的溶剂或增溶剂或试剂,以及用于改变渗透压的盐、包衣剂或抗氧化剂。
本发明的化合物可以以一种物质的形式单独使用或与其他活性化合物组合使用——例如与已知的改善健康个体,特别是健康老龄个体的参照记忆的药物一起使用。
本发明还提供了一种药物组合物,其包含式(I)化合物,特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,以游离形式或以药学上可接受的制剂形式以及与药学上可接受的稀释剂或载体一起。
所述式(I)化合物,特别是5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,以及更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑及其药学上可接受的盐或溶剂化物可用作活性成分以改善学习能力特别是空间学习能力,以及记忆性能特别是参照记忆,也用于健康或未受损个体中。
根据式(I)的本发明化合物,特别是5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,比莫达非尼(Modafinil)(2-(二苯甲基)亚磺酰基乙酰胺)的效果好很多倍,选择性也高很多倍。
本发明还涉及根据式(I)的化合物,特别是5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更在特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,并且还涉及生理功能衍生物在制备用于改善健康个体或老龄个体或具有认知障碍的个体的学习能力,特别是空间学习能力,以及记忆性能,特别是参照记忆的药物中的用途,或用于治疗疾病或治疗适应症,其中学习能力和记忆能力的改善,更特别是空间学习和记忆任务的改善是有益的。
优选地,根据本发明的药物组合物包含如式(I)所定义的化合物,特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,以游离形式和药学上可接受的稀释剂或载体用于治疗健康个体或老龄个体或治疗伴有学习能力和记忆能力尤其是空间学习和记忆任务的缺陷的疾病或医疗状况。
然而,一般而言,本发明还提供了一种药物组合物,其包含根据式(I)的化合物的S对映异构体和至少一种如本文所定义的药学上可接受的载体和/或稀释剂,用于治疗,即用作药物,特别是用于治疗与年龄相关的认知衰退,更特别是用于治疗根据2018ICD-10-CM诊断代码R41.81,例如根据美国版2018ICD-10-CM诊断代码R41.81的与年龄相关的认知衰退。
根据式(I)的化合物,特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,特别可以用于提高没有认知功能缺陷和/或参照记忆缺陷或任何由脑部疾病引起的不足或缺陷的人类个体的学习能力,特别是空间学习能力,以及记忆性能,特别是参照记忆。或者,式(I)的化合物,特别是5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,可用于因脑部疾病导致认知功能缺陷和/或参照记忆缺陷的人类个体。这种认知功能缺陷和/或参照记忆缺陷的原因如上所述。
因此,本发明的问题还通过使用根据式(I)的化合物,特别是5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,甚至更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,用于制备提高学习能力,特别是空间学习能力,以及记忆性能,特别是参照记忆的药物,在人类个体中,特别是在老龄个体中。优选地,所述制备的药物用于没有认知功能缺陷和/或参照记忆缺陷或任何由脑部疾病引起的不足或缺陷的人类个体。或者,通过使用根据式(I)的化合物,特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑制备的所述药物可以用于治疗有由脑部疾病引起的认知功能缺陷和/或参照记忆缺陷的人类个体。这种认知功能缺陷和/或参照记忆缺陷的原因如上所述。
还令人惊讶地发现根据式(I)的化合物,特别是5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,甚至更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,可用于提高学习能力,特别是学习能力,以及记忆能力,特别是参照记忆,即使在与年龄有关的记忆衰退的情况下。对于根据式(I)的化合物,特别是5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,甚至更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,例如仅使用l0mg/kg甚至1mg/kg体重就可以获得惊人的效果。还令人惊讶地发现根据式(I)的化合物,特别是5-((((S),(S)-3-卤苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,甚至更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,具有非常高的特异性和DAT抑制的潜力,并且没有表现出任何意外的脱靶活性。例如,在功能性细胞试验中,没有发现5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑)对157个G蛋白偶联受体(GPCR)(来自66个GPCR家族)中的任何一个有激动剂或拮抗剂活性。已知GPCR可以检测细胞外的分子并激活导致细胞反应的内部信号转导途径。式(I)的化合物,特别是其(S),(S)-非对映异构体,优选为非对映异构纯的形式,令人惊讶地表现出非常低的风险或甚至基本上没有副作用的风险。通过在2.0%DMSO/Tris缓冲液中连续稀释DMSO储备溶液至最终测定浓度,得到最终浓度为0.22μmol/l的5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)-甲基)噻唑)。细胞激动剂效应计算为每个靶标对已知参考激动剂的对照反应的百分比,细胞拮抗剂效应计算为每个靶标的对照参考激动剂反应的抑制百分比。因此,根据式(I)的化合物,特别是5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,甚至更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑似乎具有极低的脱靶交叉潜力。
还令人惊讶地发现根据式(I)的化合物,特别是5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,甚至更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,可用于治疗和/或预防酒精成瘾、尼古丁成瘾或药物成瘾,特别是用于治疗和/或预防可卡因和/或甲基苯丙胺成瘾,甚至特别是在治疗和/或预防可卡因和甲基苯丙胺成瘾方面。此外,本发明还提供了一种药物制剂,其包含根据式(I)的化合物,特别是5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,甚至更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,用于治疗和/或预防酒精成瘾、尼古丁成瘾或药物成瘾,特别是用于治疗和/或预防可卡因和/或甲基苯丙胺成瘾,特别是在治疗和/或预防可卡因和甲基苯丙胺成瘾方面。
而且,还令人惊讶地发现根据式(I)的化合物,特别是5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,没有或基本上没有任何副作用,例如觉醒状态增加、抑郁发作或成瘾问题。
不受任何理论约束的情况下,认为根据式(I)的本发明化合物,特别是5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,甚至更特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,不会引起早期后除极(EAD)或hERG(人类Ether-a-go-go相关基因)。这种动作电位是hERG特有的。在这方面,还认为这些化合物对hERG没有任何作用。
“药学上可接受的盐”是指本文提供的化合物的任何盐,其保留其生物学特性,且无毒或没有在其他方面不适合药物使用。此类盐可以衍生自本领域熟知的多种有机和无机抗衡离子并且包括:(l)与有机酸或无机酸形成的酸加成盐,例如盐酸、氢溴酸、硫酸、硝酸、磷酸、氨基磺酸、乙酸、三氟乙酸、三氯乙酸、丙酸、已酸、环戊基丙酸、乙醇酸、戊二酸、丙酮酸、乳酸、丙二酸、琥珀酸、山梨酸、抗坏血酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、苦味酸、肉桂酸、扁桃酸、邻苯二甲酸、月桂酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟脑、樟脑磺酸、4-甲基双环[2.2.2]-辛-2-烯-1-羧酸、葡庚糖、3-苯丙酸、三甲基乙酸、叔丁基乙酸、月桂基硫酸、葡萄糖酸、苯甲酸、谷氨酸、羟基萘酸、水杨酸、硬脂酸、环已基氨基磺酸、奎宁酸、粘康酸等酸;或(2)当母体化合物(a)中存在的酸质子被金属离子例如碱金属离子、碱土金属离子或铝离子,或碱金属或碱土金属氢氧化物例如钠、钾、钙、镁、铝、锂、锌和氢氧化钡、氨取代时形成的盐,或(b)与有机碱例如脂肪族、脂环族或芳香族有机胺,例如氨、甲胺、二甲胺、二乙胺、甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、乙二胺、赖氨酸、精氨酸、鸟氨酸、胆碱、N,N’-二苄基乙二胺、氯普鲁卡因、二乙醇胺、普鲁卡因、N-苄基苯乙胺、N-甲基葡萄糖胺哌嗪、三(羟甲基)-氨基甲烷、四甲基氢氧化铵等配位时形成的盐。特别优选的盐形式是六氟磷酸盐和氯化物盐。
此类盐还包括,仅举例来说,钠、钾、钙、镁、铵、四烃基铵等,并且当该化合物含有碱性官能团时,包括无毒有机或无机酸的盐,例如盐酸盐、氢溴酸盐、酒石酸盐、甲磺酸盐、苯磺酸盐、乙酸盐、马来酸盐、草酸盐等。术语“生理上可接受的阳离子”是指酸性官能团的无毒、生理上可接受的阳离子平衡离子。这种阳离子的例子有钠、钾、钙、镁、铵和四烃基铵阳离子等。
根据本发明的化合物也可以作为溶剂化物提供。“溶剂化物”是指本文提供的化合物或其盐,其还包括由非共价分子间力结合的化学计量或非化学计量量的溶剂。在溶剂是水的情况下,溶剂化物是水合物。
具体实施方式
实施例
实验步骤
反应条件和产率没有系统优化。无水溶剂购自西格玛奥德里奇(Sigma-Aldrich),无需进一步纯化即可直接使用。所有其他化学品和试剂均购自VWR国际(VWRInternational)、TCI欧洲/德国(TCI Europe/Germany)、Synthonix、Acros Organics、激活科技(Activate Scientific)、荧光化学(Fluorochem)、Enamine和阿法埃莎(AlfaAesar)。1H和13C核磁共振(NMR)光谱在Bruker Avance 500NMR光谱仪(UltraShield)上使用5-mm可切换探头(PA BBO 500SB BBF-HD-05-Z,1H,BB=19F和31P-15N)与z轴梯度和自动调谐和匹配附件(Bruker BioSpin)。1H NMR的共振频率为500.13MHz,且13C NMR的共振频率为125.75MHz。所有测量均针对298K下的完全氘代氯仿或DMSO溶液进行。标准1D和梯度增强(gradient-enhanced,ge)2D实验,如双量子过滤(DQF)COSY、NOESY、HSQC和HMBC,由生产厂家提供的方式使用。化学位移在内部参考氯仿lH(δ=7.26ppm)或DMSO lH(δ=2.50ppm)的残留非氘化溶剂信号和氯仿13C(δ=77.00ppm)或DMSO 13C(δ=39.57ppm)的溶剂碳信号。HRESIMS光谱在maXis HD ESI-Qq-TOF质谱仪(布鲁克·道尔顿(Bruker Daltonics),不莱梅(Bremen),德国(Germany))上获得。将样品在溶解至20μg/mL MeOH中,并使用注射泵以3μL/min的流速直接注入ESI源。ESI离子源操作如下:毛细管电压:0.9至4.0kV(单独优化),雾化器:0.4bar(N2),干燥气体流量:4L/min(N2),干燥温度:200℃。质谱在正离子模式下记录在m/z 50-1550的范围内。使用基于质量精度(△m/z≤2ppm)的Bruker CompassDataAnalysis 4.2和同位素模式匹配(SmartFormula算法)确定总和公式。化合物的纯度通过HPLC在配备有VWD检测器(Dionex/Thermo Fisher Scientific,Germering,Germany)的UltiMate 3000系列系统上或在LC-2010A HT液相色谱仪设备(日本东京岛津公司(Shimadzu Corporation,Tokyo,Japan))上测定。分别使用LC-MS级水和乙腈作为流动相A和B,在Acclaim 120C18、2.1x 150mm、3μm HPLC柱(Thermo Fisher Scientific)上进行分离。样品组分在25分钟内用10%至90%B的线性梯度进行分离和洗脱,然后进行等度柱清洗和再平衡步骤。流速为0.2mL/min,柱温箱温度设置为25℃。纯度由UV色谱图(254nm)确定,即确定为化合物的峰面积与总峰面积(即溶剂空白中不存在的所有峰面积之和)的比值。根据HPLC数据,所有最终化合物的纯度均>95%。
5-((((3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑非对映异构体的合成
非对映异构体的合成如图1所示。在第一步(a)中,5-(氯甲基)噻唑盐酸盐1和硫代乙酸2反应生成S-(噻唑-5-基甲基)乙硫酯(S-(thiazol-5-ylmethyl)ethanethioate)3。在后续步骤(b)中,将酰化中间体脱保护并分离所需的噻唑-5-基甲硫醇(thiazol-5-ylmethanethiol)5,在缩合反应(c)中,将其进一步与市售的(3-溴苯基)(苯基)甲醇4和BF3·Et2O在CH3COOH中反应以提供具有亚磺酰基部分的化合物6。随后的半-制备手性HPLC分离(d)使得具有在碳原子(C1)上分别为S和R构型的单个对映异构体7和8分离。用H2O2在CH3COOH中氧化亚磺酰基中间体7和8(e),生成含有亚砜的产物,记为_mix_1和_mix_2。两种产物都是2种立体异构体的混合物。在最后一步(f)中,半-制备手性分离使得个体立体异构体分离,分别为来自mix_1的1_1和1_2,以及来自mix_2的2_1和2_2。所有化合物均已明确表征(高分辨率质谱、高分辨率NMR-1D和2D、HPLC-确定的纯度)。
用于图1中描述的各个反应步骤的试剂和条件可总结如下:(a)K2CO3、NaI、丙酮,35-40℃,3h;(b)NaOH、EtOH,回流,2h;(c)BF3·Et2O、CH3COOH,室温过夜;(d)手性分离,Chiralpack IA柱,等度100%EtOH作为流动相;(e)CH3COOH、H2O2、室温过夜;(f)手性分离,Chiralpack IA色谱柱,(i)等度100%EtOAC作为1_1和1_2的流动相,(ii)100%EtOAC作为2_1和2_2的流动相。立体异构体化合物的纯度通过RP-HPLC法测定,立体异构体化合物的对映体过量(ee)通过手性HPLC法测定。
原料合成:
S-(噻唑-5-基甲基)乙硫酯(S-(thiazol-5-ylmethyl)ethanethioate)(3)
5-(氯甲基)-1,3-噻唑盐酸盐(5-(chloromethyl)-1,3-thiazolehydrochloride)(1)(5.0g,29.4mmol)、硫代乙酸(2)(2.65g,32.11mmol)、碳酸钾(10.5g,76mmol)和丙酮(100ml)的混合物在室温下搅拌过夜。滤出沉淀并用丙酮洗涤。合并滤液和冲洗液并在真空中蒸发至最小体积。向残余物中加入水(50mL)和DCM(50mL)并将混合物搅拌15分钟。分离各层,用水洗涤有机层,用Na2SO4干燥,真空蒸发溶剂。所得褐色油状物通过硅胶(DCM)快速色谱法纯化,得到3.78g的化合物3,为黄色油状物(产率74%)。
噻唑-5-基甲硫醇进一步与(3-溴苯基)(苯基)甲醇(4)缩合,得到外消旋的5-((((3-溴苯基)(苯基)甲基)硫代)甲基)噻唑(6)。
5-(((((3-溴苯基)(苯基)甲基)硫代)甲基)噻唑(6)
将1.0g(6.6mmol)3-溴苯甲醇和(0.88g,6.6mmol)噻唑-5-基甲硫醇溶解在冰醋酸中。将1.1当量(1.9mL,7.3mmol)的BF3·Et2O添加到溶液中并将反应混合物在室温下搅拌过夜。然后将反应混合物倒在冰上,加入少量水并通过加入固体NaHCO3中和乙酸。然后用50ml乙酸乙酯萃取(3x)产物。收集有机层,合并,用无水Na2SO4干燥,过滤并减压浓缩。然后通过硅胶快速柱色谱法纯化粗产物(石油醚/EtOAc=2/1),得到0.48g油状产物6(产率19%)
在接下来的步骤中,使用CHIRALPACK IA半制备柱(直径10mm x长20mm)(日本东京Daicel公司(Daicel Inc,Tokyo,Japan))和乙醇作为流动相将化合物6分离成单独的对映异构体7和8。每次进样40mg/mL的6,EtOH的流速设置为10mL/min。每个对映异构体被进一步氧化,分别再次产生外消旋化合物mix_1和mix_2,最终使用CHIRALPACK IA半制备柱(25mg/mL进样,EtOAc流速为10mL/min)分离成单独的立体异构体1_1、1_2、2_1、2_2。对于所有分离,流速设置为10mL/min,所有分离均在室温下进行。
绝对构型(AC)的归因
使用振动圆二色谱(VCD)方法对化合物1_1、1_2、2_1、2_2的绝对构型(AC)进行归因。非对映异构体1_1的绝对构型指定为S1(S)Cl(S),即1_1=5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑;1_2的绝对构型指定为S1(R)Cl(S),即1_2=5-((((R),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-噻唑;2_1的绝对构型指定为S1(S)Cl(R),即2_1=5-((((S),(R)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑;并且2_2的绝对构型指定为S1(R)C1(R),即2_2=5-((((R),(R)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-噻唑。
非对映异构体1_1的绝对构型通过晶体学数据进一步证实为5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑。
B.孔板测试:
动物和饲养条件:
三组/群雄性斯普拉格道利(Sprague-Dawley大鼠)[每组18个月龄,n=10每组;分组:载体-1毫克/千克体重(mg/kg bw)-10mg/kg bw的1_1-处理,行为无特征的老年群体),24个月龄,记忆力差老年组/弱势(inferior)(n=10,载体组,用1mg/kg bw的非对映异构体1_1处理)和25个月龄的动物(每组n=10;分组:所有具有老年大鼠的中等水平记忆,载体-1mg/kg bw-10mg/kg bw的非对映异构体1_1),在使用维也纳医科大学实验室动物科学与遗传学系生物医学研究核心培育和饲养动物。在实验过程开始前一周将动物转移到一个单独的实验室,并在整个实验过程中单独放置在装有高压灭菌木片的标准模克隆笼(standardMakrolon cage)中,温度:22±2℃;湿度:55±5%;12h人造光/12h暗循环:早上7:00亮灯)。该研究按照维也纳医科大学伦理委员会的指导方针(the guidelines of the Ethicscommittee,Medical University of Vienna)进行,并获得了奥地利联邦教育、科学和文化部(Federal Ministry of Education,Science and Culture,Austria)的批准。
孔板设备和培训:
孔板(1m x 1m)由黑色塑料制成,周围环绕着半透明的有机玻璃墙。墙壁配备了空间提示。远端提示由板外的房间结构提供。十六个规则排列的孔中的四个(直径和深度为7cm)被诱饵(无尘精密颗粒,45mg,)。在整个测试过程中,诱饵孔的图案保持不变。为了避免嗅觉定向,颗粒也存在于板下方的区域中。在为期三天的实验之前,老鼠被处理了15分钟以熟悉实验者,然后是两天对孔板的习惯,在此期间动物可以每天探索迷宫15分钟并获得食物颗粒。在实验开始前,通过限制食物使每只大鼠的体重减少到其初始体重的85%。随意给予自来水。对大鼠进行了三天的训练(第一天进行五次试验,第2天进行四次试验,第3天进行保留试验)。每次试验持续120秒或直到找到所有四个颗粒。在试验之间用0.1%(伊科尔,杜塞尔多夫,德国(Ecolab,Dusseldorf,Germany))清洁该装置以去除气味线索。个体的两次连续试验之间的间隔为20分钟。安装在房间天花板上的摄像机记录了迷宫中老鼠的表现。每次试验都记录了孔的访问和颗粒的去除。为了比较具有相似水平动机的大鼠,在十次试验中总共访问少于40孔的大鼠被排除在分析之外。参照记忆错误被记录为对未诱饵孔的访问次数。参照记忆指数(RMI)使用公式(第一次+诱饵孔的重新访问次数)/所有孔的总访问次数计算。所有行为训练/测试均在明暗循环的亮阶段进行。
孔板学习和记忆的结果:
用非对映体化合物1_1处理的老年群体的中等水平组
用非对映体化合物1_1处理的老年群体的非特征组
用非对映体化合物1_1处理的老年群体的弱势组
单胺转运体再摄取抑制
如S.Sucic等人(单胺转运蛋白的N末端是苯丙胺作用所需的杠杆(The NTerminus of Monoamine Transporters Is a Lever Required for the Action ofAmphetamines).生物化学杂志(J.Biol.Chem.)2010,285(14),10924-10938)和Kalaba等人(莫达非尼的杂环类似物作为新型、非典型多巴胺转运蛋白抑制剂(HeterocyclicAnalogues of Modafinil as Novel,Atypical Dopamine Transporter Inhibitors).药物化学杂志(J.Med.Chem.)2017,60(22),9330-9348)所述进行摄取抑制测量。达尔伯克氏改良伊格尔氏培养基(Dulbecco's Modified Eagle Medium,DMEM)、胰蛋白酶和胎牛血清(FCS)购自西格玛奥德里奇贸易有限公司(Sigma-Aldrich Handels GmbH)奥地利(Austria)。[3H]5-HT(羟基色胺肌酐硫酸盐(Hydroxytryptamine creatinine sulfate);5-[1,2-3H[N]];45.3Ci/mmol),[3H]DA(二羟基苯乙胺;3,4-[环-2,5,6-3[H]]-多巴胺(3,4-[ring-2,5,6-3[H]]-Dopamine);55.8Ci/mmol)和[3H]MPP+(甲基-4-苯基碘化吡啶;1-[甲基-3H];80Ci/mmol)购自珀金埃尔默,波士顿,马塞诸塞州(Perkin Elmer,Boston,MA)。在稳定表达人类多巴胺转运体(DAT)、去甲肾上腺素转运体(NET)和5-羟色胺转运体(SERT)的人类胚胎肾293(HEK 293)中评估了DAT、NET和SERT的抑制作用。细胞在实验前24小时在预先涂有聚-D-赖氨酸(PDL)(4x104细胞/孔)的96孔板中以单层形式生长。实验当天,吸出培养基,每孔用温的(30℃)0.1mL Krebs-HEPES缓冲液(KHB;10mM HEPES、120mM NaCl、3mMKCl、2mM CaCl2·2H2O、2mM MgCl2·6H2O、5mM D-(+)-葡萄糖一水合物,pH 7.3)洗涤。将细胞在含有1%二甲亚砜和浓度增加的待测化合物的KHB中预孵育5分钟。吸出预孵育溶液后,将细胞在含有增加浓度的该化合物的KHB中孵育,添加0.2μM[3H]-多巴胺(对于DAT)、0.02μM[3H]-MPP+(对于NET)和0.2μM[3H]-5-HT(对于SERT)。DAT和SERT的孵育时间为1分钟,NET的孵育时间为3分钟。从总摄取量中减去在30μM可卡因存在下的非特异性[3H]-多巴胺和[3H]-MPP+摄取量。从总摄取量中减去在30μM帕罗西汀(paroxetine)存在下的非特异性[3H]-5-HT摄取量。在室温下孵育后,通过添加0.1mL冰冷的KHB停止反应。最后,用0.3mL的1%SDS裂解细胞,并通过液体闪烁计数器(Tri-carb-2300TR,珀金埃尔默(Perkin Elmer))测量释放的放射性。非线性回归分析(GraphPad Prism 5.0版,GraphPad Software,美国加利福尼亚圣地亚哥(San Diego,CA,USA))用于计算IC50值。
表1)
1)数值是至少三次独立试验的平均值。NS-使用的浓度范围不明确;
2)(1_1、1_2、2_1和2_2)的非对映异构体混合物。
如表所示,本发明的化合物有效且选择性地抑制多巴胺转运体(dopaminetransporter,DAT),从而抑制细胞外多巴胺再摄取到突触中并增加多巴胺的细胞外浓度,从而导致改善的学习能力,特别是空间学习能力,和/或改善的参照记忆。与常用的抑制剂不同,DAT抑制是相当特异的,去甲肾上腺素和血清素转运体(noradrenaline andserotonin transporters)没有或至少没有被本发明的化合物,特别是没有或至少没有显著被5-((((S),(S)-3-卤代苯基)(苯基)甲基)亚磺酰基)甲基)噻唑抑制,更特别地没有或至少没有显著被5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基))甲基)噻唑抑制,甚至更特别地没有或至少没有显著被5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑抑制。因此,使用本发明的化合物可以省略不需要的副作用。
尽管本领域技术人员可能提出修改和改变,但申请人的意图是在本发明所保证的发明中体现所有改变和修改合理且可能落入对本领域的贡献的范围内。本发明的被认为是新颖的特征在所附权利要求中详细阐述。说明书、附图以及权利要求中公开的特征可以单独或以各种组合形式对于在其不同实施方式中实现本发明是必不可少的。
Claims (36)
2.根据权利要求1所述的化合物,其特征在于,所述取代或未取代的噻唑环是具有通式(IIa)的2-1,3-或4-1,3-或5-1,3-噻唑环,
其中R3相同或独立地,在根据式(IIa)的环上存在1次或2次,并且其中
R3选自由氢、烃基、环烃基、杂环烃基、烃基氨基,特别是二烃基氨基、芳烃基氨基,特别是二芳基氨基、羟烃基氨基、烷氧基、芳烃基、羟烃基、硫代烃基、卤代烃基、卤代芳基、卤代芳烃基、卤代烷氧基、单取代或多取代的烃基,单取代或多取代的环烃基、单取代或多取代的杂环烃基、单取代或多取代的烃基氨基,特别是二烃基氨基、单取代或多取代的芳基氨基,特别是二芳基氨基、单取代或多取代的羟烃基氨基、单取代或多取代的烷氧基、单取代或多取代的芳烃基、单取代或多取代的羟烃基、单取代或多取代的硫代烃基、单取代或多取代的卤代烃基、单取代或多取代的卤芳基、单取代或多取代的卤芳烃基、单取代或多取代的卤代烷氧基和羧酸酯所组成的组中。
3.根据权利要求1或2所述的化合物,其特征在于,所述化合物是富含具有通式(I)的化合物的四种非对映异构体之一的非对映异构体混合物或具有通式(I)的四种非对映异构体之一的非对映异构体纯的化合物。
4.根据前述权利要求中任一项所述的化合物,其特征在于,残基R2的间位取代基
选自由烃基、环烃基、杂环烃基、烃基氨基,特别是二烃基氨基、芳基氨基,特别是二芳基氨基、羟烃基氨基、烷氧基、羟基、羧酸基团、羧酸酯基团、卤素,特别是溴取代基、芳烃基、羟烃基、硫代烃基、卤代烃基、卤代芳基、卤代芳烃基、卤代烷氧基、单取代或多取代的烃基、单取代或多取代的环烃基、单取代或多取代的杂环烃基、单取代或多取代的烃基氨基,特别是二烃基氨基、单取代或多取代的芳基氨基,特别是二芳基氨基、单取代或多取代的羟烃基氨基、单取代或多取代的烷氧基、单取代或多取代的芳烃基、单取代或多取代的羟烃基、单取代或多取代的硫代烃基、单取代或多取代的卤代烃基、单取代或多取代的卤芳基、单取代或多取代的卤芳基烃基、单取代或多取代的卤代烷氧基和羧酸酯所组成的组中,
其中取代的是指被选自由烃基、环烃基、杂环烃基、羟烃基、烷硫基、醚、羟基、氟、氯、溴和碘所组成的组中的残基取代。
5.根据权利要求2至4中任一项所述的化合物,其特征在于,R3是氢或烃基,特别是甲基,或氧烃基,特别是甲氧基,或被至少一个选自由杂环烃基、羧酸、酰胺和酯所组成的组中的残基取代的烃基,特别是被杂环烃基,优选含有至少两个杂原子的杂环烃基取代的甲基。
6.根据前述权利要求中任一项所述的化合物,其特征在于,RTA是2-1,3-噻唑基团或5-1,3-噻唑基团,特别是5-1,3-噻唑。
7.根据前述权利要求中任一项所述的化合物,其特征在于,R2是在间位具有氯、溴或碘取代基,特别是溴取代基的苯环。
8.根据前述权利要求中任一项所述的化合物,其特征在于,所述化合物是5-(苯基-3-溴苯基-甲亚磺酰基甲基)噻唑,特别是5-(苯基-3-溴苯基-甲亚磺酰基甲基)-1,3-噻唑。
9.根据前述权利要求中任一项所述的化合物,其特征在于,所述化合物是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑。
10.根据权利要求9的化合物,其特征在于,所述化合物基本上不含任何
5-((((R),(R)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,特别是不含任何5-((((R),(R)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑、5-((((R),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,特别是
5-((((R),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑和5-((((S),(R)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,特别是
5-((((S),(R)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑。
11.根据权利要求1至8中任一项所述的化合物,其特征在于,所述化合物是以下化合物的非对映异构体混合物
5-((((R),(R)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,特别是5-((((R),(R)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,
5-((((R),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,特别是5-((((R),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,
5-((((S),(R)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,特别是5-((((S),(R)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,和
5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)-1,3-噻唑,
富含
5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑,特别是5-((((S),(S)-3-溴苯基)(苯基)甲基)亚磺酰基)甲基)噻唑-1,3-噻唑。
12.根据前述权利要求中任一项所述的化合物,用于治疗。
13.根据权利要求12所述的化合物,用于治疗和/或预防与年龄相关的认知衰退。
14.根据权利要求13所述的化合物,用于治疗和/或预防根据2018ICD-10-CM诊断代码R41.81的与年龄相关的认知衰退。
15.根据权利要求1至11中任一项所述的化合物,用于改善人类个体的认知功能,特别是改善学习能力和/或记忆能力。
16.根据权利要求15所述的化合物,用于提高人类个体的空间学习能力和/或参照记忆任务。
17.根据权利要求12至16的使用的化合物,其特征在于,所述人类个体不具有由脑部疾病引起的认知功能缺陷和/或参照记忆缺陷和/或动机缺陷,特别是不具有任何参照记忆缺陷。
18.根据权利要求12或16中任一项所述的使用的化合物,其特征在于,所述人类个体不具有认知功能缺陷和/或参照记忆缺陷和/或动机缺陷,特别是不具有任何参照记忆缺陷。
19.根据权利要求12至16中任一项所述的使用的化合物,其特征在于,所述人类个体具有由脑部疾病引起的认知功能缺陷和/或参照记忆缺陷和/或动机缺陷,特别是参照记忆缺陷。
20.根据权利要求19所述的使用的化合物,其特征在于,所述人类个体具有认知功能缺陷和/或参照记忆缺陷和/或动机缺陷,特别是参照记忆缺陷或认知功能缺陷或参照记忆缺陷和认知功能缺陷,其由阿尔茨海默病;唐氏综合症;血管性认知障碍;中风;额颞叶痴呆;行为、语义或进行性失语型痴呆;路易体痴呆;皮层下痴呆;帕金森病痴呆;酒精相关性痴呆;外伤性脑损伤引起的痴呆;亨廷顿病相关痴呆;AIDS相关痴呆症;注意缺陷障碍;与衰老相关的参照记忆缺陷;与大脑病毒感染有关的参照记忆障碍;内源性精神病例如精神分裂症,或外源性精神病例如由药品消费引起的。
21.根据权利要求20所述的使用的化合物,其特征在于,所述认知功能缺陷和/或参照记忆缺陷和/或动机缺陷,特别是参照记忆缺陷或者认知功能缺陷或者参照记忆缺陷和认知功能缺陷都是由精神分裂症引起的。
22.根据权利要求12至21中任一项所述的使用的化合物,其特征在于,所述人类个体是老龄个体。
23.根据权利要求1至11中任一项所述的化合物,用于特别是选择性地抑制人类个体大脑中的突触中DAT介导的多巴胺再摄取。
24.根据权利要求1至11中任一项所述的化合物在改善认知功能中的用途。
25.根据权利要求24所述的用途,其特征在于,要改善的认知功能是人类个体的学习能力,特别是空间学习能力,和/或记忆能力,特别是参照记忆。
26.根据权利要求24或25所述的用途,其特征在于,所述人类个体不具有认知功能缺陷和/或参照记忆缺陷和/或动机缺陷,特别是不具有认知功能缺陷和/或参照记忆缺陷。
27.药物制剂,所述药物制剂包含至少一种根据权利要求1至11中任一项的化合物和药学上可接受的载体和/或稀释剂。
28.根据权利要求27所述的药物制剂,用于治疗,特别是用于治疗和/或预防年龄相关的认知衰退,更特别是用于治疗和/或预防根据2018ICD-10-CM诊断代码R41.81的年龄相关的认知衰退。
29.根据权利要求27或28的药物制剂,用于改善人类个体的认知功能,特别是学习能力,更特别是空间学习能力,和/或记忆性能,更特别是参照记忆。
30.根据权利要求29所述的药物制剂,用于提高老龄人类个体的学习能力和/或记忆能力,特别是空间学习能力和/或参照记忆,更特别是空间学习能力。
31.根据权利要求27所述的药物制剂,用于特别是选择性地抑制人类个体大脑中突触中DAT介导的多巴胺再摄取。
32.根据权利要求1至11中任一项所述的化合物的用途,特别是选择性地抑制尤其是没有认知功能缺陷和/或参照记忆缺陷和/或动机缺陷的健康个体大脑中突触中DAT介导的多巴胺再摄取。
33.根据权利要求1至11中任一项所述的化合物,用于治疗和/或预防酒精成瘾、尼古丁成瘾或药物成瘾,特别是可卡因和/或甲基苯丙胺成瘾。
34.根据权利要求1至11中任一项所述的化合物在治疗和/或预防酒精成瘾、尼古丁成瘾或药物成瘾,特别是可卡因和/或甲基苯丙胺成瘾中的用途。
35.根据权利要求1至11中任一项所述的化合物在制备用于治疗和/或预防酒精成瘾、尼古丁成瘾或药物成瘾,特别是可卡因和/或甲基苯丙胺成瘾的药物中的用途。
36.根据权利要求27所述的药物制剂,用于治疗和/或预防酒精成瘾、尼古丁成瘾或药物成瘾,特别是可卡因和/或甲基苯丙胺成瘾。
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EP19197359.3 | 2019-09-13 | ||
PCT/EP2020/075338 WO2021048284A1 (en) | 2019-09-13 | 2020-09-10 | Thiazole and diphenyl substituted sulfoxides for use in improving cognition functions and against addictions to substances |
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CN114917350A (zh) * | 2022-06-21 | 2022-08-19 | 重庆医科大学附属第二医院 | Cftr增强剂在注意缺陷与多动障碍中的应用及产品 |
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US6670358B2 (en) | 2000-05-16 | 2003-12-30 | Cephalon, Inc. | Substituted thioacetamides |
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US6958352B2 (en) | 2002-02-08 | 2005-10-25 | Smithkline Beecham Corporation | Compounds for inhibiting insulin secretion and methods related thereto |
EP2292213A1 (en) | 2004-02-06 | 2011-03-09 | Cephalon, Inc. | Compositions comprising a polymorphic form of armodafinil |
US7314875B2 (en) | 2004-04-13 | 2008-01-01 | Cephalon, Inc. | Tricyclic aromatic and bis-phenyl sulfinyl derivatives |
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CN102348457A (zh) * | 2009-03-11 | 2012-02-08 | 奥默罗斯公司 | 预防和治疗成瘾的组合物和方法 |
WO2016023997A1 (en) * | 2014-08-13 | 2016-02-18 | Red Bull Gmbh | Heterocyclic compounds with working memory enhancing activity |
CN107522693A (zh) * | 2017-08-15 | 2017-12-29 | 田野 | 一种6‑元芳香环或杂芳香环化合物及其制备方法和应用 |
WO2019197670A1 (en) * | 2018-04-12 | 2019-10-17 | Red Bull Gmbh | (s)-enantiomeric form of a heterocyclic compound having motivation improving and/or reference memory enhancing activity |
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CN114917350A (zh) * | 2022-06-21 | 2022-08-19 | 重庆医科大学附属第二医院 | Cftr增强剂在注意缺陷与多动障碍中的应用及产品 |
CN114917350B (zh) * | 2022-06-21 | 2023-06-13 | 重庆医科大学附属第二医院 | Cftr增强剂在注意缺陷与多动障碍中的应用及产品 |
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US20220324821A1 (en) | 2022-10-13 |
KR20220062376A (ko) | 2022-05-16 |
WO2021048284A1 (en) | 2021-03-18 |
JP2022548859A (ja) | 2022-11-22 |
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