CN111936173A - 过渡金属与环戊二烯基阴离子的苯并杂环衍生物的三羰基复合物 - Google Patents
过渡金属与环戊二烯基阴离子的苯并杂环衍生物的三羰基复合物 Download PDFInfo
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- CN111936173A CN111936173A CN201980020996.3A CN201980020996A CN111936173A CN 111936173 A CN111936173 A CN 111936173A CN 201980020996 A CN201980020996 A CN 201980020996A CN 111936173 A CN111936173 A CN 111936173A
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Abstract
Description
技术领域
本发明涉及适当设计的过渡金属的复合物,其呈现出高的血脑屏障渗透性并且可以用作CNS疾病的诊断剂/治疗剂。更具体地,涉及a)普遍的CNS疾病(包括阿尔茨海默病和脑肿瘤)的放射诊断,和b)这些复合物的治疗性应用。
背景技术
血脑屏障和CNS药物
血脑屏障(BBB)的穿透是用于中枢神经系统(CNS)并且尤其是用于脑的药物研发中的瓶颈[1]。血脑屏障的特征在于CNS毛细血管中内皮细胞的紧密排列和致密连接,并且用于维持脑腔微环境的稳定和防止有毒物质的进入。BBB给予的保护对于用于对抗脑病理学的治疗性干预的药物的有效运输形成了大的障碍。其特征在于BBB的存在防止了>98%的全部低分子量药物(400-500Da)和~100%的高分子量药物以及生物技术制品(单克隆抗体、蛋白质、基因治疗剂)达到脑部。除了低分子量以外,一系列的物理化学特征影响了BBB穿透,其中亲脂性是最重要的[2]。Comprehensive Medicinal Chemistry数据库(https:/ www.sciencedirect.com/science/referenceworks/9780080450445#,2007)中记录的~7000种小分子药物中,仅有5%到达了CNS,且治疗了有限类型的病状(精神分裂症、抑郁、癫痫、慢性疼痛)。尽管获得了CNS药物研究的成功结果,但新的治疗剂通过BBB的有效运输的缺乏阻碍了它们从实验室运用到临床上。因此,并且主要是由于BBB的存在,对于大量的CNS疾病(包括阿尔茨海默病、亨廷顿病、肌肉萎缩侧索硬化(A.L.S.)、脑肿瘤、脑和CSF损伤、细菌感染等)还没有有效的临床治疗性处理。因此,对于穿透BBB的药物的需求是合理且巨大的。
阿尔茨海默病
阿尔茨海默病(AD)呈现了非常普遍的CNS疾病的特征性实例,对其所有治疗方法都受到BBB存在的限制[3]。AD是痴呆的主要形式(总病例的~70%),并且主要是影响老年人。全世界大约有4千6百万人受痴呆之苦,使其成为全球第7大死因,同时由于预期寿命的增加,预期受害者的数量在不久的将来会显著增加(https://www.alz.co.uk/research/statistics,http://www.who.int/gho/mortality_burden_disease/en/)。AD的主要组织病理学特征之一是脑的胞外空间中存在淀粉样斑块[4]。淀粉样斑块的主要蛋白质成分是40-或42-个氨基酸的β-淀粉样肽。β-淀粉样肽在尚未完全了解的条件下聚集成不溶性纤丝,其随着其它物质的参与逐渐累积形成淀粉样斑块。根据关于AD发病机理的主要理论(淀粉样蛋白级联假设),β-淀粉样蛋白聚集成纤丝并随后形成淀粉样斑块与AD的病理学相关[5,6]。因此,它们构成了对抗AD的诊断和治疗方法的靶标。迄今为止,没有临床实验室检查和测试方案能够提高早期的、准确的和选择性的AD诊断。临床实践已经建立了一套诊断标准,其包括目的在于区分AD与呈现相似症状的其它密切相关疾病(如生理学衰老、血管性痴呆、缺血性事件、抑郁等)的神经心理学、生物化学和成像检查[7,8]。在2012年,FDA(食品与药品管理局,USA)批准了florbetapir F-18(商业名称:Amyvid,示意图1A)作为第一个放射诊断探针,用于使用正电子发射断层扫描(PET)示踪AD的淀粉样斑块,接着是2013年的flutametamol F-18(Visamyl,示意图1B)和2014年的florbetaben F-18(Neuraceq,示意图1C)[9]。使用PET成像不是常规检查,而是最常用于证实负荷的临床病症[10]。然而,最近NIH支持的聚焦于精神衰退前的早期诊断的阿尔茨海默病诊断指南版本变得明显,强调了对于更广泛地使用成像形式的需求(https://www.nia.nih.gov/news/alzheimers-diagnostic-guidelines-updated-first-time-decades)[11]。
与PET放射诊断发展相平行,对用于淀粉样斑块检测的99mTc(γ-发射体)放射诊断与γ-相机断层扫描(单光子发射计算机断层扫描,SPECT)的探索已经吸引了全世界的科学兴趣。这是由于临床上最广泛使用的放射性核素99mTc具有用于体内成像的理想性质的事实,其通过便携式99Mo/99mTc发生器可广泛和更经济地利用,而对于其产生不需要回旋加速器基础构造,而PET同位素需要。已经针对研发具有淀粉样斑块亲和力和令人满意的BBB渗透性的放射剂合成了大量99mTc标记的各种结构(包括苯并呋喃、黄酮、查耳酮、苯并噻唑、苯并噁唑、姜黄素、菊花胺、Congo红的衍生物)和各种配位方式的化合物[9,12]。在已经用于针对AD诊断的99mTc放射剂寻求中的各种99mTc核中,特别提及环戊二烯基三羰基金属核[Cp99mTc(CO)3],其也用于本发明中[13]。这种有机金属核对于CNS放射药物的研发呈现出非常有利的特性,因为其低分子量和小的尺寸、合适的亲脂性、稳定性和易于缀合生物活性分子的特征能够结合淀粉样斑块[14]。文献中的环戊二烯基三羰基复合物包括查耳酮模拟物(示意图2A)或通过酯(示意图2B,2C)或酰胺(示意图2D)键连接的2-(4’-氨基苯基)苯并噻唑缀合物[15-18]。
通过测定其对淀粉样斑块的化学亲和力(体外和离体)、测定其对淀粉样纤丝的结合常数Ki、和通过小鼠中的生物分布实验评估其脑吸收(表达为%注射的剂量/g器官,%ID/g)来进行目的在于作为放射诊断剂的新99mTc复合物的评价[17]。在最近的概括了现有文献数据的综述中[9],表明了环戊二烯基三羰基99mTc复合物对β-淀粉样聚集物呈现出中到高的亲和力(Ki=12.4-204.1nM)并且在体外将淀粉样斑块染色的潜能。然而,在生物分布实验中,对于它们中的大部分,只有有限的脑吸收,最高为1.06%ID/g。迄今为止,不存在集合了所有所需特性以进入作为AD早期诊断试剂的临床评估阶段的99mTc复合物。
迄今为止,阿尔茨海默病尚不能治愈。目前可用的治疗仅仅是针对症状的,并且目的在于通过增强神经传递来减轻认知受损[19]。尽管投入了很大的科学研究,但目前仅有五种药物可用于治疗与记忆和思维相关的症状https://www.alz.org/research/ science/_alzheimers_treatment_horizon.asp。对抗AD的主要治疗方法之一是抑制β-淀粉样肽聚集成可溶性寡聚物(其也与神经毒性相关[20])或聚集成不溶性淀粉样纤丝。已经针对其与β-淀粉样肽的相互作用及其具有振奋人心结果的干扰β-淀粉样肽聚集过程的潜能,在体外研究了大量合成的小分子和天然产物[21,22]。用检测淀粉样纤丝的硫黄素T(ThT)荧光测定和电子显微镜技术来评估潜在抑制剂在防止β-淀粉样肽聚集中的效力[23]。还通过测定其从β-淀粉样肽细胞毒性拯救神经元细胞的潜能来进行评估[24]。尽管文献中的许多化合物已知能干预β-淀粉样蛋白质聚集并且其中许多(>400)处于临床试验中([25],https://clinicaltrials.gov/),但它们的低BBB渗透性通常是阻止它们发展成治疗AD的药剂的主要原因[3]。
脑癌
脑癌(原发性和转移性)的特征在于短的存活预期,发达国家中仅有总数14%的患者在最初诊断后存活达10年(http://www.cancerresearchuk.org/health-professional/cancer-statistics/)。值得注意的是尽管全世界CNS肿瘤的发病率仅为1.8%[26],但它们的频率在较年轻的年龄中不断上升。根据2016年的统计,脑癌是儿童(0-14岁的年龄)中最常见的类型,并且是15-39岁年龄组中第三大常出现的类型[26,27]。
尽管存在有效抗癌药物的事实,但它们在神经肿瘤学中的应用主要受到BBB存在的限制[28]。作为它们通过BBB的有限渗透及其在肿瘤部位的低浓度的结果,用于全身性治疗的选择极少,并且它们对患者存活的影响是有争议的[29,30]。因此,用于脑肿瘤的主要治疗策略是放疗和外科手术,在两种情况中治愈率都是很低。因此,很明显的是,脑肿瘤的有效抗争与穿过BBB的运送密切相关,穿过BBB运送是过去十年药物研究的主要目标[31]。
目前,脑肿瘤诊断是基于特征性的临床症状、神经学检查和脑成像,主要是使用磁共振成像(MRI)[32]。使用放射性药物(PET、SPECT)的成像在肿瘤部位发炎或坏死组织的存在使得使用MRI难以观察肿瘤时在治疗或外科手术后追踪疾病进展中极其重要。在已经临床用于脑肿瘤成像的放射性标记的化合物中(如121TICI或18F-FDG),包括各种99mTc示踪剂,如99mTc-替曲磷(tetrofosmin)、99mTc-塞斯塔米比(sestamibi)、99mTc-葡庚糖酸盐[33]。这些药物不是特异性的并且它们在肿瘤部位的定位主要是由于肿瘤部位增加的血液供应。基于这些事实,任何能够以临床上足够的程度成功穿过BBB的99mTc复合物-作为新分子,其是本发明的主题-可以导致更清楚的成像和更安全的诊断。铼的放射性同位素186Re和188Re(其与99mTc获得相同结构的复合物并发射适用于治疗干预的β-辐射[34])用作金属核时,所得到的复合物是用于脑肿瘤治疗的强候选物。最后,众所周知的是,各种呈现抗肿瘤活性的分子在其结构中含有苯并噻唑、苯并咪唑或苯并噁唑药效团[35-38]。
发明内容
本发明提供了过渡金属与环戊二烯基阴离子的苯并杂环衍生物的三羰基复合物。本发明的化合物呈现出高的血脑屏障渗透性并且可以用作CNS疾病(如阿尔茨海默病或CNS肿瘤)的诊断剂或治疗剂。
附图说明
图1呈现了FDA批准的用于使用PET示踪阿尔茨海默病的淀粉样斑块的18F标记的放射诊断剂的化学结构。
图2呈现了文献中已经报道了作为潜在的对抗阿尔茨海默病的放射诊断剂的环戊二烯基复合物的化学结构。
图3呈现了非放射性Re复合物在淀粉样斑块的体外成像研究中的应用,通过共聚焦荧光显微镜(DAPI滤器,激发365nm,发射445nm)来成像,实施例10。更具体地,显示了来自AD患者的颞皮质脑组织切片(6μm厚)的复合物Re-2(A)、Re-3(B)、Re-4(D)和Re-5(E)染色。为了比较目的,相应的组织切片用硫黄素S染色(C、F)。比例尺在A、B、C中对应于100μm,在D、E、F中对应于50μm。
图4呈现了:(A)复合物Re-2和Re-3(1和2μM)对在37℃温育24h后的鼠原代海马细胞系中由Aβ42诱发的细胞毒性的作用,通过MTT来评估(实施例12);(B)复合物Re-2和Re-3(1和2μM)对在37℃温育24h后的鼠原代海马细胞系中由Aβ42诱发的ROS产生的作用。通过DCF荧光方法进行了所产生的ROS含量的评价(实施例13)。记录的结果(来自n=3的独立实验,其中每个条件重复6次)呈现为平均值±SEM。对于Aβ42(1μM),*p≤0.05,**p≤0.01,***p≤0.001,ns(不显著)>0.05,对于仅生长在培养基中的细胞(对照),#p<0.01,##p<0.01,###p<0.001。
发明详述
本发明涉及呈现出高的血脑屏障(BBB)渗透性并且可以用作一般的脑和CNS疾病的诊断探针或治疗剂的金属复合物的研发和应用。更具体地,本发明描述了与化合物的苯并噻唑、苯并咪唑和苯并噁唑家族的小分子量杂环部分直接键合的环戊二烯基阴离子作为三羰基金属核M(CO)3 +的配体并导致由通用结构式1表示的复合物的形成的用途。因此,本发明提供了式1的化合物或其药学上可接受的盐,
其中
-M是能够形成CpM(CO)3 +类型的三羰基环戊二烯基实体的Re、Tc、Mn或其它过渡金属;
-X是S(苯并噻唑家族)、N(苯并咪唑家族)、O(苯并噁唑家族);
-A是N或C-RA,B是N或C-RB,C是N或C-RC,D是N或C-RD,其中RA、RB、RC、RD相同或不同,并且选自氢、卤素、硝基-、烷基-、每个碳原子上具有0至3个卤原子的卤代烷基-、氨基烷基-、烷基氨基-、羟基、烷氧基-、苄氧基-、芳氧基-、-SO2-C(=O)NR4R5、-C(=S)NR4R5、-SO2NR4R5、-NC(=O)R4,其中R4、R5相同或不同,并且是氢或C1-C6烷基-;
-当X=N时,R1是氢、烷基-、烯基-、每个碳原子上具有0至3个卤原子的卤代烷基-、烷氧基烷基-、环烷基-、芳烷基-,而当X=S、O时,R1不存在;
-R2、R3相同或不同,并且选自氢、-NR4R5、-NC(=O)R4,其中R4、R5相同或不同,并且是氢或C1-C6烷基-。
式1的化合物可以按照本领域公知的程序来合成,例如,如以下示意图1中所示的。使用适当取代的芳香族氨基硫醇、二胺或氨基醇,使适当取代的二茂铁基甲醛经历氧化环化,以获得相应的带有所需取代基的二茂铁基苯并噻唑、苯并咪唑、苯并噁唑。后者中的任一个随后与带有金属三羰基的前体复合物反应,以引起铁-Cp部分被金属三羰基核取代,并产生最终的环戊二烯基金属三羰基苯并噻唑、苯并咪唑、苯并噁唑。
本发明的复合物呈现出高的BBB渗透性(实施例9)并且可以用作CNS疾病(如阿尔茨海默病或CNS肿瘤)的诊断或治疗剂。即,通式1的化合物对表征AD病理的淀粉样斑块呈现出高的亲和力(实施例10)并且因此可以用作成像剂/诊断剂,通过使用放射性99mTc用于SPECT诊断。此外,它们显示出与淀粉样纤丝的强烈相互作用(实施例11),它们在原代神经元细胞中抑制β-淀粉样肽诱发的毒性(实施例12)并且它们还显示出对抗活性氧物质(ROS)的抗氧化活性,活性氧物质(ROS)在AD中大幅增加(实施例13)。因此,本发明的化合物用作对抗AD的治疗剂。除了在AD中的应用,通过生长中肿瘤增加的脉管系统吸收通式结构1的化合物,提高的BBB穿透对于本发明延伸至脑肿瘤的诊断和治疗也是重要的发现。优选通过使用放射性金属99mTc和SPECT成像来实现诊断应用,而治疗应用优选通过使用铼放射性同位素186Re和188Re来实现,所述同位素发射适用于放疗的β-辐射。
本发明化合物的最大优点是其高的BBB渗透潜力,对于化合物99mTc-2,其达到例如7.04%ID/gr(实施例9)。该渗透率显著高于设计为用于AD的潜在放射诊断剂的99mTc复合物的任何其它报道,99mTc复合物在给药后2分钟内最好达到1.21%ID/gr[9],与临床上使用的用于脑灌注的放射诊断剂的渗透相当,如99mTc-HMPAO(给药后60分钟内5%ID/gr[39])和99mTc-ECD(给药后2分钟内1.32%ID/器官[40],大约4.4%ID/gr)。大脑对于生命的首要重要性以及由于BBB的存在到达闭合的颅脑腔的困难性,加重了本发明的重要性,特别是考虑到几乎没有可用于对抗脑疾的治疗干预的药物时。
本发明的化合物以药学上可接受的盐的形式使用时,这样的盐例如可以通过将化合物与合适的药学上可接受的酸或碱结合来制备。这样的酸或碱是本领域公知的。
本发明的化合物优选以药物组合物或诊断组合物的形式来施用。这样的组合物是本领域技术人员公知的。对于诊断应用,优选以生理盐水溶液静脉内施用本发明的放射性标记的化合物。调节注射的剂量的放射性(通常范围在5-15mCi之间),以使淀粉样斑块或脑肿瘤或能使用SPECT的其它损伤成像。
对于治疗应用,优选将本发明的化合物结合一种或多种赋形剂,以形成药物组合物。根据给药方式和组合物的形式,一种或多种赋形剂优选选自:pH调节剂、渗透剂、乳化剂、分散剂、表面活性剂、增溶剂、缓冲剂、防腐剂、润湿剂、胶凝剂、稠度剂、螯合剂、悬浮剂、增稠剂,或其组合。在其中将放射性188Re或186Re化合物用于脑肿瘤或其它损伤的放疗的情况中,优选以生理盐水溶液并且以治疗有效的放射性剂量静脉内施用化合物。
具体实施方案
为了实现本发明,给出以下具有实验结果的实施例:
·前体分子Fe-2-Fe-6的合成(实施例1-5)
·所需的与稳定(非放射性)Re的复合物的合成(Re-2-Re-6,实施例6)
·所需的与放射性99mTc的复合物的合成(99mTc-2-99mTc-5,实施例7)
·99mTc-2-99mTc-4的稳定性和亲脂性的评估(实施例8)
·使用鼠的生物分布实验的血脑屏障渗透的评估(实施例9)
·复合物在阿尔茨海默病相关挑战中的应用,包括使用复合物Re-2-Re-5的脑组织中的淀粉样斑块的染色(实施例10),复合物99mTc-2-99mTc-4与淀粉样纤丝的结合的亲和力常数的测定(实施例11),使用复合物Re-2,Re-3的原代神经元细胞中淀粉样纤丝诱发的毒性的抑制(实施例12),以及复合物Re-2,Re-3对抗ROS的抗氧化活性的测定(实施例13)。
必须注意到Re和99mTc金属具有非常相似的物理和化学性质,并且它们形成具有可比生物学行为的复合物。在此,出于合成、分离和表征化合物的目的(实施例6)以及出于实际原因在许多生物学评估程序中使用非放射性Re金属代替放射性99mTc,以减轻实验要求和减少不必要的放射性暴露(实施例10、12、13),而对于实验动物中的生物分布实验,99mTc是不可替代的(实施例9)。
实施例1
二茂铁基-苯并噻唑(Fe-2)的合成
将乙醇(40mL)中的二茂铁甲醛(1.1g,5mmol)和2-氨基苯硫酚(600μL,5.6mmol,1.1eq)在回流下搅拌16小时。将反应回至r.t,出现了棕红色固体沉淀。通过用己烷:乙酸乙酯(98:2至96:4)洗脱的沉淀物快速柱色谱获得了最终产物。产量:92%。NMR(DMSO-d6,ppm):1Η(500ΜΗz)8.03,7.92,7.47,7.39,5.02,4.60,4.16;13C(126MHz)153.43,126.24,124.52,121.96,121.80,70.82,70.13,68.50.MS(ESI)m/z:[M+H]+计算值C17H14NS56Fe,320.0188;测定值,320.0188。
实施例2
二茂铁基-苯并咪唑(Fe-3)的合成
将二茂铁甲醛(0.76g,4mmol)和亚硫酸氢钠(1.44g,1.4mmol)的混合物溶解于20mL无水乙醇和水(1:1)的混合物中。将反应混合物回流1小时。在室温下加入o-苯二胺(0.4g,4mmol)并将混合物再回流另1小时。随后冷却至室温并最后冷藏。将形成的沉淀过滤,随后依次用冰冷水和冷的无水乙醇洗涤。通过用二氯甲烷:乙酸乙酯(96:4)洗脱的沉淀物的快速柱色谱分离纯的产物。产量:62%。NMR(DMSO-d6,ppm):1Η(500ΜΗz)12.35,7.54,7.44,7.13,5.04,4.47,4.10;13C NMR(126MHz)152.92,120.86,117.50,110.15,69.31,68.91,66.90。
实施例3
二茂铁基-N-甲基-苯并咪唑(Fe-4)的合成
在NaOH(0.535g,13.4mmol)的水(1mL)溶液中,加入丙酮(7.5mL)和二茂铁基-苯并咪唑(Fe-3)(0.54g,1.8mmol)的溶液并搅拌5分钟,接着在0℃下逐滴添加甲基碘(145μL,2.3mmol)。将反应混合物在r.t下搅拌1h,随后在真空下蒸发丙酮,并用水(50mL)稀释混合物,并且随后用二氯甲烷萃取(3×30mL)。用盐水洗涤合并的有机相,用Na2SO4干燥并真空蒸发溶剂,以产生浅棕色油状产物。通过用二氯甲烷:乙酸乙酯(96:4)洗脱的快速柱色谱获得了纯的产物。产量:95%。NMR(DMSO-d6,ppm):1Η(500ΜΗz)7.55,7.22,7.17,4.99,4.53,4.21,4.03;13C NMR(126MHz)152.74,142.57,136.71,121.51,118.04,69.80,69.25,68.77,31.19。
实施例4
二茂铁基-苯并噁唑(Fe-5)的合成
将二茂铁甲醛(642mg,3.00mmol)和2-氨基苯酚(330mg,3.00mmol)的混合物在5mL乙酸中在室温下搅拌15min。这之后在30min内将20mL PbAc4(1350mg,3.03mmol)的热乙酸溶液逐滴加入体系中,并随后将混合物倒至50g冰上。用二氯甲烷(3×30mL)萃取水相,并用盐水洗涤合并的有机相,用Na2SO4干燥并在真空下除去溶剂。通过二氯甲烷:己烷(10:90)洗脱的快速柱色谱纯化剩余的固体。产量:42%。NMR(DMSO-d6,ppm):1Η(500ΜΗz)7.69,7.35,5.06,4.62,4.20;13C(126MHz)165.53,150.00,141.86,124.46,124.34,118.83,110.47,71.10,69.62,68.24。
实施例5
2-二甲基氨基二茂铁-苯并噻唑(Fe-6)的合成
合成的方案与实施例1中的相同,使用2-氨基苯硫酚和2-二甲基氨基二茂铁甲醛。使用二氯甲烷:乙酸乙酯(96:4)的快速柱色谱获得了纯的产物。产量:53%。NMR(DMSO-d6,ppm):1Η(500ΜΗz)8.04,7.93,7.47,7.40,4.97,4.58,4.51,4.11,2.16;13C(126MHz)153.02,126.11,124.49,121.85,121.71,97.5,73.64,70.64,69.81,69.09,44.69。
根据以下合成示意图从二茂铁羧酸制备了2-二甲基氨基二茂铁甲醛:
在0℃氮下,添加四滴DMF,用逐滴草酰氯(1.8mL,20mmol)处理无水二氯甲烷(20mL)中的二茂铁羧酸(2.3g,10mmol)溶液。将反应混合物回到室温并搅拌3小时。在氮下除去溶剂和过量的草酰氯,并将所得到的红色固体重新溶解至新鲜的无水二氯甲烷(20mL)中。添加四丁基溴化铵(12mg,0.03mmol),接着添加NaN3(1g,15mmol)的水(5mL)溶液。将反应混合物在氮下并在室温下再搅拌18h。通过添加水(50mL)淬灭反应,并分离有机相,并进一步用二氯甲烷(2×20mL)萃取水。用盐水洗涤合并的有机相,用Na2SO4干燥并在真空下除去溶剂。通过用二氯甲烷:己烷(1:1)洗脱的快速柱色谱分离所需的叠氮化物。产量:78%。NMR(CDCl3,ppm):1H(500MHz)4.78,4.55,4.05;13C(126MHz)176.1,89.0,76.3,78.0,80.1。
将所得到的叠氮化物(2.3mmol)溶解于甲苯(15mL)中并在一次性添加2-(三甲基甲硅烷基)乙醇(4.7mmol)时在氮下加热至回流(105℃)。将反应混合物在回流下搅拌3h,并直至叠氮化物的颜色转至橙色。将反应混合物回到室温并在添加NaOH溶液(1M,50mL)后,再搅拌10分钟。分离有机相并用二氯甲烷(2×20mL)进一步萃取水。用盐水洗涤合并的有机相,用Na2SO4干燥并在真空下除去溶剂,导致带红色的固体的形成,通过二氯甲烷/己烷重结晶获得了纯的产物。
将由此形成的碳酰胺(carbamide)(2.1mmol)溶解于THF中的1M TBAF中,并将反应混合物温热至50℃,持续15min。在真空下除去溶剂,并加入二氯甲烷(50mL)和水(50mL)。分离两相,并进一步用二氯甲烷(2×20mL)萃取水相。用盐水洗涤合并的有机相,用Na2SO4干燥并在真空下除去溶剂,获得带红色的固体的氨基-二茂铁。NMR(CDCl3,ppm):1H(500MHz)4.09,4.00,3.85,260;13C(126MHz)105.63,68.85,63.43,58.80。
将这个氨基-二茂铁(1.07g,5.32mmol)在氮下溶解于乙酸(15mL)中,并加入低聚甲醛(1.59g,53.2mmol)和NaBH3CN(1.67g,26.6mmol),并将反应混合物搅拌16h。加入NaOH6M水溶液,直至pH=12,并通过己烷(3×20mL)萃取溶液。用盐水洗涤合并的有机相,用Na2SO4干燥并在真空下除去溶剂,直至大约5%最初体积。将残余物接受通过硅胶垫的快速过滤,使用己烷洗脱。在真空下除去溶剂,没有至完全干燥,使得纯产物在冰箱中结晶为橙色薄片;mp 69-70℃;NMR(CDCl3,ppm):1H(500MHz)4.25,3.95,3.76,2.59;13C(126MHz)
155.80,66.50,63.07,54.61,41.50。
在0℃和氮下,用BF3·OEt2(1.05eq)处理二甲基氨基-二茂铁(0.229g,1mmol)的THF(0.1M)溶液。搅拌反应溶液,并随后在丙酮-干冰水浴中冷却至-78℃,接着添加n-BuLi(己烷中1.10当量),并使温度达到-40℃。在一小时内,颜色从黄色变成橙红色,并随后将温度回到-78℃,加入DMF(1.20eq)时使反应缓慢回到r.t。通过小心添加己烷和饱和NaHCO3来淬灭反应。分离两相,并进一步用醚(2×20mL)萃取水相。用盐水洗涤合并的有机相,用Na2SO4干燥并在真空下除去溶剂。通过用己烷/Et2O/Et3N 94:5:1洗脱的快速柱色谱分离纯的产物。NMR(CDCl3,ppm):1H(500MHz)10.13,4.63,4.40,4.29,4.27,2.70;13C(126MHz)192.81,117.53,71.81,69.52,67.71,66.23,60.22,45.61。
实施例6
环戊二烯基与三羰基铼的复合物(Re-2-Re-6)的合成
根据对化合物Re-2所述的一般方案:
将实施例1-5制备的二茂铁化合物Fe-2-Fe-6转化成各自由以下结构表示的三羰基铼复合物Re-2-Re-6
在5mL容量的玻璃高压灭菌瓶中的前体复合物[Re(CO)3Br3][NEt4]2(30mg,0.047mmol)和二茂铁衍生物Fe-2(0.098mmol)的DMF(2.5mL)溶液中,加入0.1N HCl(1.8mL)的水溶液。5分钟脱气后,将反应混合物在160℃下搅拌2h。将反应停止加热,使其回到室温,并随后用二氯甲烷(10mL)稀释。用水(3×10mL)、盐水洗涤有机相,用Na2SO4干燥,并在真空下除去溶剂。用二氯己烷:乙酸乙酯或己烷:乙酸乙酯洗脱的快速柱色谱后,获得了纯的产物Re-2。NMR(DMSO-d6,ppm):Re-2 1Η(500ΜΗz)8.11,7.98,7.53,7.46,6.65,5.88;13C(126MHz)193.94,161.06,152.64,134.23,126.86,125.83,122.63,122.48,96.52,87.09,86.65;Re-3 1Η(500ΜΗz)12.79,7.56,7.20,6.50,5.85;13C NMR(126MHz)194.31,145.49,143.11,134.23,122.81,121.83,118.68,111.18,94.96,86.19,85.14;Re-4 1Η(500ΜΗz)7.61,7.28,7.23,6.54,5.90,3.88;13C NMR(126MHz)194.22,145.88,141.80,136.49,122.83,122.30,118.88,110.41,93.94,87.41,86.37,31.50;Re-5 1Η(500ΜΗz)7.37,7.31,6.62,6.60;13C NMR(126MHz)194.22,150.1,141.21,137.19,125.41,124.23,119.90,110.80,94.93,87.35,86.30;Re-6 NMR(DMSO-d6,ppm):1Η(500ΜΗz)8.14,7.98,7.53,7.48,6.60,6.45,5.82,2.32;13C(126MHz)194.22,156.02,128.11,126.49,125.83,123.71,93.54,72.64,70.64,69.79,44.69.MS(ESI)m/z:Re-2[M+H]+ 对C15H9NO3S187Re计算值,469.9861;测定值,469.9852.;Re-3[M+H]对C15H10N2O3 187Re计算值,453.0169,测定值,453.0246。
实施例7
环戊二烯基与三羰基99mTc复合物(99mTc-2-99mTc-5)的合成
根据对化合物99mTc-2描述的一般方案:
将实施例1-4中制备的二茂铁基化合物Fe-2-Fe-5分别转化成由以下结构表示的三羰基99mTc复合物99mTc-2-99mTc-5:
A’方法:将0.5mL DMF中的相应二茂铁前体Fe-2(1.0mg)加入fac-[99mTc(H2O)3(CO)3]+复合物(0.1mL,180MBq)中。随后在油浴中加热,在氮流下,在120℃下3h,获得了相应的99mTc复合物,放射性化合物产率为50%,如通过HPLC所示的。
B’方法:将相应的二茂铁前体Fe-2(1.0mg)和复合物Mn(CO)5Br(1.0mg)溶解于DMF(0.5mL)中,并加入了99mTcO4 -(0.1mL,180MBq)水溶液。将小瓶密封并用氮冲洗10min,并在油浴中在110℃下加热1h,以获得相应的99mTc复合物,放射性化合物产量为96%,如通过HPLC所示的。在两种方法中,使用类似物Re复合物作为参照,通过比较HPLC鉴别了每种99mTc复合物。在用1mL/min流速的二元梯度系统洗脱的C-18反相柱(25.4×0.4cm,5μm)上实现了分离。移动相A是含有0.1%三氟乙酸的甲醇,而移动相B是含有0.1%三氟乙酸的水。
实施例8
99mTc复合物的稳定性和亲脂性
在存在过量的组氨酸和半胱氨酸的情况下评估了99mTc-2-99mTc-4复合物的稳定性,组氨酸和半胱甘酸可以作为三齿取代基来取代复合物的配体[41]。将每种HPLC纯化的99mTc复合物(0.5mL,约10MBq)与组氨酸或半胱氨酸(2mM)在0.1M PBS,pH 7.4(0.5mL)中的溶液混合。将混合物在37℃下温育,并在1、3和6小时后通过HPLC分析。在研究的每个时间点在拮抗剂存在下的完整复合物百分比的记录允许估计标记的99mTc复合物的稳定性。
99mTc-2-99mTc-4复合物的亲脂性是通过估算正辛醇和水(PBS)的双相系统中的分配系数来确定的[42]。分配系数表示为正辛醇相对于PBS的每克计数之比的对数(logPoct/水),其中P为比率。测量一式三份进行,并重复三次。
表1中给出了99mTc-2-99mTc-4复合物的稳定性和亲脂性值。
表1. 37℃下99mTc复合物的稳定性(在过量的组氨酸和半胱氨酸下)和亲脂性(logPoct/水)研究
实施例9
99mTc-2-99mTc-4复合物的血脑屏障渗透性的估算
该评估是通过获自NCSR“Demokritos”的生物科学与应用研究所(Institute ofBiosciences&Applications,NCSR"Demokritos")的繁殖设施的健康瑞士白化小鼠(SwissAlbino mice,5周大,20-30g)中的生物分布研究来进行的。在这些实验中,我们评估了放射性标记化合物施用后动物组织中放射性的分布。为了体内分布数据的可靠性,每次评估需要三个独立实验,其中每个实验中的动物种群范围为9至12只。合成、标记和生物分布的实验在NCSR“Demokritos”的“放射性药物”实验室中进行,所述实验室具有所需的基础设施,可确保使用放射性的实验安全进行。所有生物分布研究都是根据转换了保护用于科学目的的动物的欧盟指令2010/63的第56/2013号总统法令(在希腊官方政府公报106A/30-4-2013中发布)进行的(Presidential Decree56/2013,Official Government Gazette ofGreece 106A/30-4-2013,EU Directive 2010/63)。
在三组小鼠(每组三只动物)的尾静脉注射HPLC纯化的99mTc复合物(0.1mL乙醇/盐水1:9中1-2μCi)。在注射后(p.i.)的不同时间点(2、15、90分钟)处死小鼠。切下目标器官,称重,并在自动γ计数器中对放射性进行计数。在进行放射性测量之前,没有排空胃和肠中的食物。血液和肌肉的计算是基于测得的活性、样品重量和身体成分数据,认为血液占体重的7%,肌肉占体重的43%。通过将样品放射性与含有10%注射剂量的标准溶液进行比较,计算出每个器官注射剂量的百分比(%ID/器官)。每克注射剂量的百分比(%ID/g)通过将%ID/器官除以器官或组织的重量来计算。
其中cpm参照=(cpm 10%标准×10)-cpm尾部。
表2和表3给出了瑞士白化小鼠的99mTc-2和99mTc-3复合物的生物分布结果,其中值得注意的是,脑中放射性的百分比非常高,对于99mTc-2为7.04±0.81%ID/g,而对于99mTc-3为3.99±0.60%ID/g。对于99mTc-4,相应的实验显示出在2分钟时同样令人印象深刻的6.14±1.00%ID/g百分比。
表2.健康瑞士白化小鼠中注射复合物99mTc-2后的放射性生物分布(%ID/gr)
表3.健康瑞士白化小鼠中注射复合物99mTc-3后的放射性生物分布(%ID/gr)
实施例10
使用Re-2-Re-5复合物的阿尔茨海默病患者死后脑切片中的淀粉样斑块染色
将固定在白蛋白涂层的载玻片上的颞叶皮质进行AD患者切片(6μm厚)的脱蜡(二甲苯,2×5分钟),然后水合(在100%,80%,60%,然后0%的乙醇-水v/v中浸泡5分钟),随后在磷酸盐缓冲液(PBS;1.3m NaCl,27mm KCl,81mm Na2HPO4、14.7mm KH2PO4,pH 7)中温育30min。用Re复合物以及硫黄素S(Th-S,用于确认Aβ斑块定位)分别在二甲亚砜(DMSO)和PBS(约1mg·mL-1)中的溶液处理组织制备物1h[43]。最后将切片用40%乙醇洗涤2min,然后用自来水冲洗30s,并使用荧光共聚焦显微镜进行观察。示意图3中给出了指示性显微图像,其中显然复合物Re-2-Re-5以类似于临床使用的染料硫黄素S的方式特异性标记了淀粉样斑块。
实施例11
使用Aβ42纤丝聚集物研究99mTc-2-99mTc-4复合物的结合
将淀粉样肽Aβ42溶液(PBS中终浓度为50μΜ)在33℃下温育15d,没有搅拌,所述条件导致纤丝聚集物的形成,如通过分光光度和显微镜技术所示的。根据已发布的经过修改的程序,在12mm×75mm硼硅酸盐玻璃试管中的1毫升PBS溶液中进行了竞争性结合测定研究。每1mL溶液含有适当体积的Re复合物的储液(以产生10-4-10-10M的浓度)、50nM的Aβ42纤丝聚集物和0.2μCi的相应99mTc复合物。将溶液在室温下温育3h,并通过Millex-GV注射器过滤器装置、0.22μm过滤器分离结合的和游离的放射性,然后在室温下用PBS洗涤2×2mL。在γ计数器中测量含有结合的99mTc复合物的滤膜的放射性。结合研究重复三次。使用GraphPad Prism软件分析数据,并使用一站式(one-site)竞争结合线性回归计算IC50值。Ki值是使用Cheng-Prousoff等式计算的[44]:
其中IC50值表示抑制与放射性标记的99mTc复合物结合的50%所需的抑制剂(Re复合物)的浓度,其中[放射性配体]和Kd值分别是放射性标记的99mTc复合物的浓度和解离常数。
在同源竞争结合的情况下,我们假设热配体和冷配体具有相同的亲和力,因此Kd和Ki具有相同的值。因此,以上等式被转换为:
Ki=IC50-[放射性配体]
从竞争性抑制数据计算的Ki值对于复合物99mTC-2、99mTC-3和99mTC-4分别为112.32±12.05nM,7.04±2.85nM和5.74±2.90nM。这些值显示出了Re复合物对Aβ聚集物的高结合亲和力,与[123I]IMPY(12.5±2.8nM)之一相当,[123I]IMPY是临床前试验中唯一的SPECT Aβ成像剂[45]。
实施例12
在Re-2和Re-3复合物存在下的原代神经元细胞中的β-淀粉样肽毒性的抑制
可溶性寡聚物或不溶性纤丝中的β-淀粉样蛋白(Aβ)的聚集与阿尔茨海默病的发病机制相关,并且在使用神经元细胞培养物的系统性体外研究中已经确定了其毒性[46]。在Re-2和Re-3复合物的存在下,在原代海马神经元细胞中评估了Aβ42毒性的抑制能力。根据公开的方案,将出生后0-3天(P0-3)的小鼠安乐死并分离其海马体,获得了海马神经元培养物[47]。特别地,在解剖后,将每个海马体用0.25%胰蛋白酶在37℃下酶消化20min。然后将海马体在10ml含有10%(v/v)热灭活胎牛血清(FBS)的Hibernate-A培养基中冲洗,以去除任何痕量的血清。适当研磨后,将细胞以每孔2×104的密度接种到聚D-赖氨酸96孔板的孔板上。将培养物在37℃和5%CO2下维持在含有2%B-27补充剂,0.5mM Gluta-MAX和1%青霉素/链霉素的Neurobasal-A培养基中,直至适当分化。每周两次更换一半的培养基。在培养孔板中温育7天后,将原代海马神经元用于细胞活力测量。
在Re-2和Re-3复合物(Aβ:复合物比例为1:1和1:2)不存在或存在下,将PBS中的Aβ42(10μM)溶液在37℃下预温育1天,然后用新鲜培养基稀释,并以1μM的Aβ终浓度添加到各个孔中。通过标准MTT测定法确定细胞活力[48]。将细胞暴露于Aβ42溶液24h后,将100μLNeurobasal-A中的0.5mg/mLMTT储液添加到原代海马神经元的每个孔中,然后在37℃下温育3h。除去培养基,并将细胞在DMSO中稀释。通过用孔板读数器光度计测定540nm和620nm处的吸光度来测量相对甲臜(formazan)浓度。假设对照(未处理)细胞的吸光度为100%,结果表示为MTT降低的百分比,并且是每个条件下四个重复孔的三个独立实验的平均值。在海马神经元培养物中,通过单向方差分析(ANOVA)评估了不同组中变化的统计显著性。示意图4A给出了细胞活力结果,其中显然Aβ42在原代神经元诱导了巨大毒性(约占细胞活力的50%)。然而,Re-2和Re-3复合物的存在抑制了Aβ42诱导的神经毒性,在2μM的最高测试浓度下,细胞存活率达95%。
实施例13
Re-2和Re-3复合物对抗ROS的抗氧化活性
阿尔茨海默病的发病机制与活性氧物质(ROS)的形成和氧化应激的诱导有关[49,50],并且众所周知β-淀粉样肽(Aβ)在体外细胞培养物中诱导ROS产生[51]。为了确定本发明化合物的抗氧化活性,使用了荧光素衍生物(DCFH-DA),其穿过细胞膜时,与羟基自由基反应并变成荧光的(DCF)。因此,通过这种方式,我们能够监测ROS的存在[52]。如先前在实施例12中所述,在原代海马神经元中研究了Re-2和Re-3复合物对抗ROS的抗氧化活性。与Aβ42溶液温育24h后,用PBS洗涤细胞并在5%CO2的培养箱中在37℃下,用10μMDCFH-DA温育30min。使用孔板读数器光度计在485nm的激发波长和528nm的发射波长下确定DCF的荧光强度(相对荧光单位)。
结果显示于图4B中,其中普通Aβ42存在下的高水平ROS(强DCF荧光强度标准化至100%)以及随后在Re-2和Re-3复合物的存在下ROS产生的极大抑制(>50%)是明显的。
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Claims (18)
1.根据式1的化合物或其药学上可接受的盐
其中
-M是能够形成CpM(CO)3 +类型的三羰基环戊二烯基实体的Re、Tc、Mn或其它过渡金属;
-X是S、N、O;
-A是N或C-RA,B是N或C-RB,C是N或C-RC,D是N或C-RD,其中RA、RB、RC、RD相同或不同,并且选自氢、卤素、硝基-、烷基-、每个碳原子上具有0至3个卤原子的卤代烷基-、氨基烷基-、烷基氨基-、羟基、烷氧基-、苄氧基-、芳氧基-、-SO2-C(=O)NR4R5、-C(=S)NR4R5、-SO2NR4R5、-NC(=O)R4,其中R4、R5相同或不同,并且是氢或C1-C6烷基-;
-当X=N时,R1是氢、烷基-、烯基-、每个碳原子上具有0至3个卤原子的卤代烷基-、烷氧基烷基-、环烷基-、芳烷基-,而当X=S、O时,R1不存在;
-R2、R3相同或不同,并且选自氢、-NR4R5、-NC(=O)R4,其中R4、R5相同或不同,并且是氢或C1-C6烷基。
2.根据权利要求1的化合物或其药学上可接受的盐,其中A是C-RA,B是C-RB,C是C-RC和D是C-RD。
3.根据权利要求1或2的化合物或其药学上可接受的盐,其中M是Re、Tc或Mn。
4.根据之前的权利要求中任一项的化合物或其药学上可接受的盐,其中M是Re或Tc。
5.根据之前的权利要求中任一项的化合物或其药学上可接受的盐,其中R4、R5相同。
6.根据之前的权利要求中任一项的化合物或其药学上可接受的盐,其中所述烷基-、卤代烷基-、氨基烷基-、烷基氨基-、烷氧基-具有1至6个碳原子。
7.根据之前的权利要求中任一项的化合物或其药学上可接受的盐,其中R2和/或R3是氢。
8.根据之前的权利要求中任一项的化合物或其药学上可接受的盐,其中M是Re或Tc,A是C-H,B是C-H,C是C-H,D是C-H,R2是H,R3是H,X是S、O、N,且R3是N时,R1是H或CH3。
9.根据权利要求8的化合物或其药学上可接受的盐,其中Tc是99mTc。
10.根据之前的权利要求中任一项的化合物或其药学上可接受的盐,用于CNS疾病的诊断和/或治疗中。
11.根据之前的权利要求中任一项的化合物或其药学上可接受的盐,用于阿尔茨海默病的诊断和/或治疗中。
12.根据之前的权利要求中任一项的化合物或其药学上可接受的盐,用于CNS癌症的诊断和/或治疗中。
13.根据权利要求12的化合物或其药学上可接受的盐,其中所述CNS癌症是脑癌。
14.药物组合物,其包含根据权利要求1-9任一项的化合物或其药学上可接受的盐作为活性成分。
15.根据权利要求14的药物组合物,用于CNS疾病的诊断和/或治疗中。
16.根据权利要求14的药物组合物,用于阿尔茨海默病的诊断和/或治疗中。
17.根据权利要求14的药物组合物,用于CNS癌症的诊断和/或治疗中。
18.根据权利要求17的药物组合物,其中所述CNS癌症是脑癌。
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