CN112867728B - 与铜螯合的(吡啶基亚甲基)丁二胺衍生物 - Google Patents
与铜螯合的(吡啶基亚甲基)丁二胺衍生物 Download PDFInfo
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- CN112867728B CN112867728B CN201980060977.3A CN201980060977A CN112867728B CN 112867728 B CN112867728 B CN 112867728B CN 201980060977 A CN201980060977 A CN 201980060977A CN 112867728 B CN112867728 B CN 112867728B
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Abstract
如该式所示化合物：
Description
相关申请
本申请要求2018年7月20日提交的美国临时申请序列号62/700,968和2019年5月31日提交的美国临时申请序列号62/855,031的优先权。所述专利申请各自通过引用整体并入本文。
政府权利声明
本发明是在政府的支持下由美国国立卫生研究院授予的编号为CA053840和GM055989的发明。政府拥有本发明的某些权利。
技术领域
本文公开的主题涉及用于与铜离子络合的化合物及其用途。该化合物是N1-(取代的)-N4-(吡啶-2-基甲基)丁烷-1,4-二胺。因其具有选择性与铜螯合的能力，该化合物可用于治疗与铜相关的疾病，并可用作铜依赖性酶活性的抑制剂。
发明背景
铜通过控制激酶(如MEK)的活性参与调控信号转导，从而将自身与控制细胞生长联系起来。铜的生理水平处于复杂的稳态控制下，包括控制流入和流出的转运蛋白，以及将金属输送到其作用部位的专属伴侣蛋白。这些稳态机制会在多种疾病状态下遭到破坏。在铜排泄中起作用的ATP7B突变导致金属累积，从而导致威尔逊氏病(一种严重的常染色体隐性遗传疾病)。这种疾病的物理负担出现在肝脏中，特别是当肝脏高水平表达ATP7B时。初期显示前期症状，在此期间，铜在肝脏中积累。然后发生一系列肝病，从肝脏肿大到肝炎和肝硬化，甚至急性肝衰竭。当前的治疗策略取决于充当“脱铜剂”的螯合剂，其目的是降低金属含量并尝试恢复正常的体内稳态。不幸的是，青霉素和曲恩汀虽是最常使用的药物，但它们均会产生严重的不良反应。因此，需要寻找新的强效铜螯合剂专门用来治疗威尔逊氏病。
铜稳态机制的破坏也与肿瘤发生和转移有关。
选择性铜螯合剂在其他领域中有很高应用价值，在这些领域中，需要精确测量极少量的铜，例如放射性金属的生产【Dearling等，《当代放射药物》2017年；第10卷，第1期，第59-64页】。在这方面，铜螯合配体可与荧光素或其他紫外荧光部分偶联，产生一类试剂，该类试剂既具有高紫外吸收率和高量子产率，也能在其他金属离子的存在下选择性地螯合铜。这种材料可以测量低至ppm量级的Cu(II)浓度。
发明概述
一方面，本发明涉及式I化合物：
其中R1、R2、R3和R4独立选自氢、(C1-C6)烷基、(C1-C6)氧杂烷基和(C1-C6)氨基烷基，或两个相邻的R1、R2、R3和R4可形成五、六或七元环，所述五元环、六元环或七元环任选地被一个或两个选自卤素、氰基、羟基、(C1-C6)烷基、(C1-C6)氧杂烷基和(C1-C6)氨基烷基的取代基取代；
A为至多五个环的聚环体系，其任选地被一个或多个选自卤素、羟基、(C1-C6)烷基、氧代基、(C1-C6)氧杂烷基、羧基、(C1-C6)烷氧羰基、(C1-C6)烷氧基羰基、(C1-C6)烷基、羧基(C1-C6)烷基、氨基和(C1-C6)氨基烷基的取代基取代；
n为0或1；和
p为1或2。
另一方面，本发明涉及螯合铜的方法，该方法包括使含铜的样品与上述化合物接触，形成该化合物和铜的络合物。
另一方面，本发明涉及在诊断出患有癌症的患者中治疗癌症，其包括向所述患者施用上述化合物。
另一方面，本发明涉及治疗患有威尔逊氏病的患者，包括向患者施用上述化合物。
具体实施方式
本文公开了能够与铜形成络合物的化合物，或已经与铜形成络合物的化合物及其用途。该类化合物可以配制成药物组合物，施用给需要医学治疗的患者。例如，可以将化合物施用于人或动物受试者，或将其与生物组织或细胞的样品或非生物样品接触，以在溶液中形成化合物与铜的络合物。例如，该化合物可用于螯合铜，以防止或减少铜与样品中其他分子相结合。
本发明涉及如上所述式I化合物：
属于上述亲本属及其亚属的所有化合物均可用作铜的螯合剂，但并非所有化合物都具有新颖性。尤其是尽管一些该类别化合物用于络合铜的用途尚未公开，其仍属于第I种属。特别是一类化合物公开于美国专利序列号9,365,608和公开的美国申请申请号2105/0099727中，其中A为下式的全氢环戊[a]菲R1、R2、R3和R4均为氢，p是1，n是0，17位取代基为-CH(CH3)CH2CH2COOH、-CH(CH3)CH2CH2COOCH3、-CH(CH3)CH2CH2CH(OSO3H)CH(CH3)2、/> 经查发现，本申请中从权利要求中排除的化合物对发明人来说是可授予专利权的。还可发现，本申请中目前未被排除的其他种属对发明人来说是不可被授予专利权的。在任一情况下，从申请人权利要求中排除的种属均应视为专利诉讼的产物，无法体现发明人的观点，亦无法描述该发明。从组成方面看，本发明涵盖所有式I化合物，但为公众所得的除外。
在一些实施方式中，A为选自下式的聚环体系：
在一些实施方式中，聚环体系A是下式所示的全氢环戊[a]菲在6或7位被羟基取代，其中17位的取代基是(C3-C8)烷基。
在其他实施方式中，p是1，A是选自下式的聚环体系
在其他实施方式中，A是选自萘、四氢萘、萘烷、菲、全氢菲、八氢菲、四氢菲、茚、茚满、芴、四氢芴、四氢蒽、八氢蒽和蒽的聚环体系。
在其他实施方式中，A是选自喹啉、异喹啉、吲哚、咔唑、四氢喹啉、四氢异喹啉、二氢吲哚和异吲哚啉的聚环体系。
在其他实施例中，p是1并且A是
其中虚线代表任选的双键，并且Q1和Q2独立地选自碳和氮。例如，A可以是萘、四氢萘、十氢化萘、喹啉、异喹啉、四氢喹啉或四氢异喹啉。
在任何前述实施方式中，聚环体系可被一个或多个选自羟基、甲基、氧代基、氨基、(C1-C6)氨基烷基、(C1-C6)氧代烷基、羧基、甲氧基羰基、甲氧基羰基(C1-C6)烷基和羧基(C1-C6)烷基的取代基取代。聚环体系也可以为未取代的。
在一些实施方式中，R1、R2、R3和R4的任何相邻对一起形成苯环。在其他实施方式中，R1、R2、R3和R4均为氢。
如本文公开，式I化合物与铜的络合物具有抗肿瘤活性。例如，所述化合物可用于治疗乳腺癌和胃肠道(GI)癌症。某些类型的乳腺癌细胞表达蛋白HER2(也称为受体酪氨酸蛋白激酶erbB-2、CD340、原癌基因Neu、ERBB2)，并且HER2的表达激发癌症表型和肿瘤生长。在某些HER2阳性乳腺癌细胞中，PTP1B是过表达的。缺乏PTP1B表达已被证明可以防止因HER2过表达引起的乳腺肿瘤生长。三阴性乳腺癌细胞的细胞内铜水平升高，并且铜转运蛋白水平升高致使铜进入细胞。使三阴性乳腺癌细胞与式I化合物接触会降低细胞铜水平。
而且，一些糖尿病患者也表现出铜水平升高。与威尔逊氏病患者类似，糖尿病患者体内铜水平升高会产生细胞毒性作用，引发组织或器官损伤或功能障碍。上述方法通过向体内铜水平升高的患者给予式I化合物，形成该化合物与铜的络合物也适用于糖尿病患者的治疗。
螯合是指化合物以高亲和力与金属离子结合，形成络合物，从而使金属保持与化合物相结合，而不是以游离金属离子的形式存在于与化合物的溶液中。该类络合物是在生理条件下形成的，例如当将式I化合物施用于培养基中的细胞或哺乳动物动物或人类受试者时。该类复合物也在非生物溶液中形成。非生物溶液或样品是指非来自活体受试者或曾经的活体受试者，且没有故意加入活细胞或组织或体液的样品。非生物样品可以是可能需要去除铜或需要测量铜水平的溶液。通常亲和力测量并表示为其倒数、解离常数Kd。有用的化合物具有低于250nM的Kd，本文所述的化合物的Kd通常在25至250nM的范围内。
式I化合物可用于任何需要与铜结合或螯合的样品，或需要抑制本文所述的酶活性的样品，或需要测试铜的潜在作用或存在的重要性的任何样品。如上所述，样品可以包括非生物样品。也可以是从活的生物体或曾经活的生物体获取或取得的细胞、组织或体液样本。样品还可以包括意指生物体的受试者，包括人类或非人类动物。例如，受试者可以包括需要医学治疗的人类或非人类动物。样品还可以包括生物溶液、生物材料或组织的悬液，例如从活细胞或曾经的活细胞、或从培养有活细胞或组织的培养物或组织中间物中提取的成分配制成的溶液或悬液。样品也可包括体液，例如血液、唾液、脑脊髓液、腹水、淋巴液、血浆、血清、粘液或其他体液或分泌物。生物样品可以是活细胞产生的有机分子或其他化合物制成的溶液或悬液。包含除通过活细胞、组织或生物以外的其他方式(例如通过人工方法)合成的有机分子的样品(包括其他天然存在的化合物的合成副本)不会形成生物溶液或悬液。
作为非限制性实例，包含式I化合物的药物组合物包括所述化合物为冻干或干燥形式，在将所述干燥形式溶解于溶剂中时(包括口服给予受试者时)，所述化合物在溶液中与铜结合。通常，络合物的Kd优选为100nM或更小。给予受试者的制剂包括适于口服、肠胃外(包括皮下、皮内、肌内、静脉内和关节内)、直肠和局部(包括皮肤、颊、舌下和眼内)给药的制剂。最合适的途径可以取决于受试者的状况和病情或给药的预期目的。制剂可以制成方便使用的单位剂型，并且可以通过药学领域公知的任何方法制备。该方法可包括使式I化合物或其药学上可接受的盐(“活性成分”)与构成一种或多种辅助成分的载体结合。通常，制剂还可以通过将活性成分与液体载体或细分的固体载体或两者均匀且紧密地结合在一起，且如需要，将产品成型为所需制剂来制备。
本发明公开的适合于口服给药的制剂可被制成离散单位，如胶囊、扁囊剂或片剂，其各自包含预定量的活性成分；粉末或颗粒；水性液体或非水性液体中的溶液或悬液；或水包油型液体乳剂或油包水型液体乳剂。式I化合物也可以制成丸剂、沉淀剂或糊剂。对于口服或其他方式给药，可将式I化合物悬浮于溶液中或溶解于溶剂中，所述溶剂包括乙醇、DMSO、水、盐水或其他溶剂，可将其进一步稀释或溶解于另一种溶液或溶剂中。在一些示例中，其还可以或可以包含载体或其他赋形剂。
用于肠胃外或其他方式给药的制剂包括水性和非水性无菌注射液，其中可包含抗氧化剂、缓冲液、抑菌剂和溶质，这些成分会使制剂与预期接受者的血液等渗。用于肠胃外或其他方式给药的制剂还可以包括水性和非水性无菌悬液，可包含悬浮剂和增稠剂。所述制剂可以在多剂量容器中以单位剂量存在，例如密封的安瓶和小瓶。应在冷冻干燥(冻干)条件下储存，使用前仅需添加盐水、磷酸盐缓冲液(PBS)等无菌液体载体。临时注射溶液和悬液可以由前述类型的无菌粉末、颗粒和片剂制备。
如本文所用术语“药学上可接受的载体”是指无菌的水性或非水性溶液、分散液、悬液或乳剂，以及使用前制成无菌可注射溶液或分散液的无菌粉末。
合适的水性和非水性载体、稀释剂、溶剂或载体的实例包括水、乙醇、多元醇(如甘油、丙二醇、聚乙二醇等)，羧甲基纤维素及其合适的混合物、植物油(如橄榄油)和可注射有机酯，如油酸乙酯。例如可以通过使用包衣材料如卵磷脂，在分散液的情况下通过维持所需的粒度以及通过使用表面活性剂来维持适当的流动性。这些组合物还可包含佐剂，例如防腐剂、湿润剂、乳化剂和分散剂。可以通过包含各种抗菌和抗真菌剂，例如对羟基苯甲酸酯、三氯叔丁醇、苯酚、山梨酸等来确保抗微生物的效果。最好还包括糖、氯化钠等等渗剂。其包含的单硬脂酸铝和明胶等延迟吸收的试剂可以延长可注射药物形式的吸收时间。通过在可生物降解的聚合物(例如聚丙交酯-聚乙交酯、聚原酸酯和聚酐)中形成药物微胶囊基质来制备可注射的储库形式。根据式I化合物与聚合物的比例和所使用的特定聚合物的性质，可以控制式I化合物的释放速率。还可以将药物截留在与身体组织相容的脂质体或微乳状液中，用以制备储库型可注射制剂。可注射制剂可经由如细菌保留过滤器过滤或掺入无菌固体组合物形式的灭菌剂进行灭菌，该灭菌剂可在使用前立即溶解或分散在无菌水或其他无菌可注射介质中。合适的惰性载体可包括糖，例如乳糖。
式I化合物制剂可包括不同类型的载体，这取决于它是以固体、液体还是气雾剂形式给药，以及对于诸如注射这样的给药途径是否需要无菌。本发明可用于静脉内、皮内、透皮、鞘内、动脉内、腹膜内、鼻内、阴道内、直肠内、局部、肌肉内、皮下、粘膜、口服、局部、定位给药，通过吸入(例如气雾剂吸入)、注射、点滴、持续点滴、定位灌注的方式，直接或通过导管、灌洗、乳脂、脂质组合物(例如脂质体)，或本领域普通技术人员已知的其他方法或上述方法的任意组合浸浴靶细胞(例如参见《雷明顿药物科学》，第18版，麦克印刷公司，1990年)。
术语“药学上可接受的盐”是指由药学上可接受的无毒酸或碱(包括无机酸和碱以及有机酸和碱)制备的盐。除非另有说明，本文所述式I化合物或任何此类化合物均包括其药学上可接受的盐。当本发明化合物为碱性时，可以从药学上可接受的无毒酸(包括无机和有机酸)制备盐。用于本发明化合物的合适的药学上可接受的酸加成盐包括乙酸、己二酸、藻酸、抗坏血酸、天冬氨酸、苯磺酸(贝磺酸盐)、苯甲酸、桦木酸、硼酸、丁酸、樟脑、樟脑磺酸、碳酸、柠檬酸、乙二磺酸、乙磺酸、乙二胺四乙酸、甲酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、氢溴酸、盐酸、氢碘酸、羟萘酸、羟乙磺酸、乳酸、乳酸、乳酸、月桂基磺酸、马来酸、苹果酸、扁桃酸、甲磺酸、半乳糖二酸、萘、亚砜基、硝酸、油酸、扑酸、泛酸、磷酸、特戊酸、多半乳糖醛酸、水杨酸、硬脂酸、琥珀酸、硫酸、单宁酸、酒石酸、磷壁酸、对甲苯磺酸、乌索酸等。当化合物包含酸性侧链时，适用于本发明化合物的药学上可接受的碱加成盐包括但不限于由铝、钙、锂、镁、钾、钠和锌制成的金属盐，或由赖氨酸、精氨酸、N,N'-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、葡甲胺(N-甲基葡糖胺)和普鲁卡因制成的有机盐。另外的药学上可接受的盐包括，当合适时，无毒的铵阳离子和与具有1至20个碳原子的烷基连接的羧酸根、磺酸根和膦酸根阴离子。
如本文所述，术语“有效量”是指例如由研究人员或临床医生引起所寻求的细胞、组织、系统、动物或人的生物学或医学反应的式I药剂的化合物的量。术语“治疗有效量”是指与没有接受该量的相应受试者相比，提升疗效，治愈、预防或减轻疾病、病症或副作用，或减缓疾病或病症的进展速度的任何量。该术语还包括在其范围内有效增强正常生理功能的量。为了用于治疗，可以将治疗有效量的式I化合物及其盐、溶剂化物和生理功能性衍生物作为原料化学品施用。另外，活性成分可以作为药物组合物存在。
本发明的药物组合物包括有效量的式I化合物和任选地一种或多种另外的溶解或分散在药学上可接受的载体中的试剂。术语“药学上或药理学上可接受的”是指当施用于动物(如视情况施用于人)时不产生不利的、过敏的或其他不良反应的分子实体和组合物。根据本申请，本领域技术人员知道如何制备包含式I化合物和任选地一种或多种其他活性成分的药物组合物，如《雷明顿药物科学》(第18版，麦克印刷公司，1990年)举例说明的。此外，对于动物(例如人)给药，应当理解为制剂应符合美国食品及药物管理局生物标准办公室要求的无菌性、热原性、一般安全性和纯度标准。
以下实施例旨在说明本申请的特定实施方案，绝非意在限制其范围。
可将叔丁基(4-氧代丁基)(吡啶-2-基甲基)氨基甲酸酯(4)用适当的胺或N1-(吡啶-2-基甲基)丁烷-1,4-二胺(8)用适当的醛还原胺化来制备I类化合物。
例如，可以通过常规方法制备n为0或1的化合物：
或者，可以通过常规方法制备n为1的化合物：
且n为0，A不完全为芳族的化合物可以类似地由酮A(如四氢萘酮和癸酮)制备。
通过方案1a或方案1b制备(4-氧代丁基)(吡啶-2-基甲基)氨基甲酸叔丁酯(4)：
方案1a
方案1b
N1-(吡啶-2-基甲基)丁烷-1,4-二胺(8)由方案2制备：
方案2
R1、R2、R3和/或R4不是氢的化合物可以适当取代的吡啶-2-羧醛为原料制备。
上述合成的示例为：
方案3
方案4
方案5
以类似的方式，其中p为2的T-7的对应化合物可以由可商购的2,6-萘二甲醛基甲醛制备。
其中A是取代的全氢环戊[a]菲的化合物可以通过以下通用方案6制备：
方案6
在一个特定的实施方案中，(C3-C8)烷基为–(CH)(CH2)3CH(CH3)2，且产物为：
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8的制备：
向吡啶甲酸醛(5.0g，46.7mmol)的CH2Cl2(300mL)溶液中加入(4-氨基丁基)氨基甲酸叔丁酯(8.8g，46.74mmol)，然后在氮气氛下加入NaB(OAc)3H(19.8g，93.42mmol)。将混合物在室温搅拌5小时。将反应混合物倒入饱和NaHCO3溶液(300mL)中，并搅拌10分钟。分离有机层，用饱和NaHCO3溶液，用盐水洗涤，并经无水Na2SO4干燥，然后过滤和蒸发。粗产物通过硅胶快速色谱法纯化，用5-10％MeOH-CH2Cl2洗脱，得到一种黄色油7(6.9g，53％)。TLC：Rf＝0.4(硅胶，MeOH：CH2Cl2，10:90)。1H-NMR(300MHz，CDCl3)δ8.54(m，1H，H-6)，7.64(m，1H，H-4)，7.20(m，1H，H-3)，7.18-7.13(m，1H)，3.89(s，2H，-CH2N-)，3.2-3.05(m，2H，-CH2NHBoc)，2.67(t，2H，-CH2NH)，1.55-1.53(m，4H，-CH2-CH2-)，1.42(s，9H，-C(CH3)3)。APCI+＝280。
在0℃下向7(6.9g，24.69mmol)的CH2Cl2(60mL)溶液添加TFA:CH2Cl2(1:1，40mL)30分钟。使混合物温热至室温，搅拌过夜，并在旋转蒸发仪上与作为助溶剂的甲苯(5×100mL)一起浓缩。将粗产物溶于水中，冻干过夜，得到棕色油，将其与EtOAc(500mL)一起搅拌。将分离出的固体过滤，用EtOAc洗涤，并在真空下干燥，得到一种白色固体8(8.2g，64％)。1H NMR(300MHz，CD3OD)δ8.66-8.62(m，1H，H-6)，7.91-7.82(m，1H，H-4)，7.48-7.39(m，2H，H-3，H-5)，4.38(s，2H，-CH2N-)，3.2-3.12(m，2H，-CH2N)，3.03-2.94(m，2H，-CH2N)，1.91-1.70(m，4H，-CH2-CH2)。APCI+＝180。
T-11和T-12的制备：
向二氢胆固醇酯(0.71mmole)和9(160mg，0.35mmole)在CH3OH：THF(1:1，8mL)的混合物中加入分子筛(1g)，然后加入DIPEA(0.55g，4.26mmol)，将混合物搅拌过夜。如果反应不完全，则再加入1克/>分子筛，并将混合物再搅拌7小时。添加NaBH3CN(71mg，1.13mmol)。将混合物置于室温搅拌2天。通过硅藻土垫过滤反应混合物，并用二氯甲烷和甲醇洗涤。浓缩滤液得到粗产物，将其重新溶解于二氯甲烷中，用水和5％NaOH溶液洗涤；将水相用二氯甲烷再萃取，并将合并的有机相用盐水洗涤，干燥(Na2SO4)，并在减压下除去溶剂以分离粗产物。可以使用1-10％MeOH/CHCl3和1-2％NH3的MeOH溶液通过FCC纯化该物质，以分离3α-异构体(T-11)和3β-异构体(T-12)。
在其他特定的实施方案中，A为取代的全氢环戊[a]菲，其C-7位是羟基，17位是(C3-C8)烷基，T-13、T-14、T-15和T-16的实例如方案7和8所示。
方案7
方案8
利用以上合成方法制备如下化合物：
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铜结合实验：
使用放射标记的铜(64Cu2+)进行直接结合实验。将不同浓度的放射性标记的铜(0-100nM)与待测化合物(100nM)一同培养。使样品通过脱盐柱除去多余的铜。通过闪烁计数直接测定与化合物结合的金属量。通常，式I化合物的结合常数(κd)在亚微摩尔范围内，并且在存在其他二价金属(例如镍、锰、镁和钴)的情况下，其对铜的选择性至少显示为铜的κd比其他金属低100倍。除了其中A是喹啉或异喹啉的亚属以外，本发明的化合物选择性地结合铜，且在所测试的浓度下(最多超过金属盐8当量)并不结合钴、锰、铁或镁离子。还对一些样品针对银、钼、锑、镍、铬、锌、钙和钌进行了测试，结果显示，其结合水平均未达到与铜结合的水平。
本文所述的化合物可降低威尔逊氏病动物模型中的铜含量。TX小鼠是威尔逊氏病的自然遗传和表型模型。从Gly到Asp的取代(G775D)会使ATP7B蛋白失效，导致铜积累。该模型已被广泛用于了解人类疾病。TX和野生型小鼠表现出不同的寿命。可以测量接受待测化合物或盐水的TX小鼠和野生型小鼠的存活率。接受盐水或待测化合物的野生型小鼠在一岁时存活率较高。
组织铜含量可以由两种单独方法分别评估。从已经给予盐水或待测化合物的野生型小鼠和TX小鼠中切除肝脏组织，将其分别固定并用罗丹宁染色，该染料可染色铜结合蛋白。与盐水处理的TX小鼠相比，从盐水处理或待测化合物处理的野生型小鼠获得的肝样品中检测到的信号显着降低，观察到该染料的明亮染色，表明铜水平升高。相反，在由本发明化合物治疗的小鼠的肝脏样品中，罗丹宁的染色大为减少或没有出现。
尽管在此已经详细叙述和描述了优选实施例，但是对于相关领域的技术人员来说显而易见的是，在不脱离本申请的主旨和范围的前提下，可以进行各种修改、增加和替换。因此，认定这些修改、增加和替换在所附权利要求书限定的本申请范围内。
Claims (14)
1.一种式I化合物：
其中R1、R2、R3和R4独立选自氢、(C1-C6)烷基、(C1-C6)氧杂烷基和(C1-C6)氨基烷基；
A是选自萘、四氢萘、十氢化萘、菲、全氢菲、八氢菲、四氢菲、四氢蒽、八氢蒽和蒽的聚环体系，其任选地被一个或多个选自卤素、羟基、(C1-C6)烷基、氧代基、(C1-C6)氧杂烷基、羧基、(C1-C6)烷氧羰基、(C1-C6)烷氧基羰基、(C1-C6)烷基、羧基(C1-C6)烷基、氨基和(C1-C6)氨基烷基的取代基取代；
n为0或1；和
p为1。
2.根据权利要求1的化合物，其中A是选自萘、四氢萘和十氢化萘的聚环体系。
3.根据权利要求1的化合物，其中p是1，A是萘。
4.根据权利要求1-3中任一项的化合物，其中所述聚环体系被一个或多个选自羟基、甲基、氧代基、氨基、(C1-C6)氨基烷基、(C1-C6)氧代烷基、羧基、甲氧基羰基、甲氧基羰基(C1-C6)烷基和羧基(C1-C6)烷基的取代基取代。
5.根据权利要求1-3中任一项的化合物，其中所述聚环体系是未取代的。
6.根据权利要求1的化合物，其中R1、R2、R3和R4都是氢。
7.根据权利要求1-3和6中任一项的化合物，其中n为1。
8.根据权利要求1-3和6中任一项的化合物，其中n为0。
9.一种螯合铜的方法，包括使含铜样品与根据权利要求1的化合物接触，从而在所述化合物和铜之间形成络合物。
10.根据权利要求9所述的螯合铜的方法，其中所述含铜样品是非生物溶液或悬液。
11.权利要求1-3和6中任意一项所述的化合物在制备用于治疗威尔逊氏病的药物中的用途。
12.权利要求1-3和6中任意一项所述的化合物在制备用于治疗癌症的药物中的用途。
13.根据权利要求12所述的用途，其中所述癌症是乳腺癌或胃肠癌。
14.一种药物组合物，包含药学上可接受的载体和根据权利要求1-3和6中任一项的化合物。
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| WO2019090331A1 (en) * | 2017-11-06 | 2019-05-09 | Cold Spring Harbor Laboratory | Method and compositions for forming a copper-containing complex and uses thereof |
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