CN106459011A - 作为抗肿瘤化合物的σ‑2受体配体药物缀合物、其合成方法及其用途 - Google Patents
作为抗肿瘤化合物的σ‑2受体配体药物缀合物、其合成方法及其用途 Download PDFInfo
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Abstract
公开了用于治疗如胰腺癌和滑膜肉瘤的癌症的方法和组合物。描述了包含σ‑2受体结合部分和铁死亡诱导部分的化合物。至少一种所描述的分子物质在体外针对人胰腺癌细胞展现低于5μM的IC50值。施用这一物质在鼠模型系统中在体内促进胰腺癌肿瘤收缩,并在一定时程内引起实验动物的100%存活,而在所述时程内,对照疗法仅提供30%或40%存活率。还公开了分子物质的合成方法。
Description
相关申请的交叉引用
本申请要求2014年4月1日提交的美国临时申请号61/973,366的权益,该案内容据此以引用的方式并入。
有关联邦资助的研究或开发的声明
本研究获得了国立卫生研究院(NIH)拨款号5R01CA163764-03的支持。美国政府在本发明中可享有某些权利。
领域
本公开涉及σ-2受体结合化合物和组合物,及其作为药物用于治疗疾病的应用。更确切地说,实施方案涉及σ-2受体配体-药物缀合物、其合成及其用于治疗如癌症的过度增生性疾病的用途。
相关技术的说明
胰腺癌是癌症死亡的第四大主导原因,并且预计到2020年将成为第二大主导原因。利用当前的治疗选择,胰腺癌的五年存活率仅仅是5.8%,并且迫切需要新的疗法。
σ-2受体(S2R)在胰腺导管腺癌(PDAC)细胞中过表达并且对于S2R配体具有高亲和力。S2R配体局限于PDAC细胞并且迅速被癌细胞内化,最终引起细胞凋亡和细胞死亡。在胰腺癌模型中,S2R配体还使常规抗癌化学疗法更有效力,并提高存活率。
使用连接至小分子成像标签的S2R配体已经证实,S2R配体优先结合至胰腺癌,并且可以用于显现癌细胞上的S2R。类似地,S2R配体可以连接至能够选择性递送到癌细胞中的细胞凋亡诱导肽或拟肽。
埃拉汀(Erastin),具有结构:
是通过称为铁死亡(ferroptosis)的铁依赖性非细胞凋亡过程介导细胞死亡,由此选择性杀伤带有致癌K-ras突变的细胞的一种药物。然而,这一药物在初始临床试验中表现不佳。
已经在Stockwell,B.R.的美国专利申请公布2007/0161644中将埃拉汀描述为具有非细胞凋亡性的细胞杀伤特性。这一参考文献还公开了某些埃拉汀类似物,如以下结构的埃拉汀A
以下结构的埃拉汀B
及以下结构的脱甲基埃拉汀(称为“化合物21”)
(本文中又称SW V-27)。该申请的发明人声称,脱甲基埃拉汀的肿瘤细胞杀伤活性与埃拉汀相当。Dixon,S.J.等人在Cell 149:1060-1072,2012中将埃拉汀描述为介导非细胞凋亡性、铁依赖性氧化性细胞死亡(“铁死亡”)。然而,这些参考文献都未描述包含双环部分的化合物,而且所描述的化合物也不介导细胞凋亡性细胞死亡。
McDunn,J.E.等人的美国专利8,143,222,以及Spitzer,D.等人,Cancer Res.72:201-209,2012和Hornick,J.R.等人,Molecular Cancer 9:298,2010公开了用于治疗癌症的化合物。这些参考文献中公开的化合物包括了具有结合σ-2受体的靶向部分(Zeng,C.等人,Cancer Res,67:6708-6716,2007)及如细胞凋亡诱导肽等细胞凋亡诱导部分的分子。公开的化合物包括σ-2受体配体,如具有以下结构的N-取代的9-氮杂双环[3.3.1]壬-3α-基苯基氨基甲酸酯部分:
其中R可以选自由键、C1-C10烷基、C1-C10烷基胺、C1-C10烷基酰胺、C1-C10杂烷基、C1-C10芳基、C1-C10杂芳基、酯及亲水性聚合物组成的群组。在一些构型中,该专利的化合物包括双环苯基氨基甲酸酯部分的烷基胺衍生物,如
(当n=1时,称为SV119)及具有以下结构的SW43
尽管在这些参考文献中公开的一些化合物被描述为具有肿瘤细胞杀伤活性,但公开的这些化合物都不介导铁依赖性氧化性细胞死亡(铁死亡)。
概述
因此,本发明人在本文中公开了新的组合物和化合物,及其合成方法,以及用于治疗包括各种癌症在内的过度增生性病症的方法。
在各种实施方案中,本教导包括结构式I的化合物
及其盐,其中:W可以是芳基,如C5-C10芳基或C5-C10杂芳基,其中任一个可以被取代;X可以是连接部分,如但不限于,直链烷基链;并且Y可以是铁死亡诱导部分,如埃拉汀、埃拉汀类似物如埃拉汀-A、埃拉汀-B、脱甲基埃拉汀,或埃拉汀模拟物。
在各种实施方案中,本教导包括了包含式I化合物及药学上可接受的载剂、佐剂或媒介物的组合物。
在各种实施方案中,本教导包括了治疗有需要的受试者的过度增生性病症的方法,所述方法包括向该受试者施用式I化合物的步骤。
在各种实施方案中,本教导包括了治疗有需要的受试者的过度增生性病症的方法,所述方法包括依序施用或共施用式I化合物或其药学上可接受的盐,及另一治疗剂。
在各种实施方案中,本教导包括了用于人疗法中的式I化合物。
在各种实施方案中,本教导包括了用于治疗过度增生性病症中的任何式I化合物。
在各种实施方案中,本教导包括了式I化合物用于制造供治疗过度增生性病症用的药物的用途。
在各种实施方案中,本教导包括以下结构的化合物或其盐
其中n是1至5的整数,并且R1可以是H或甲基。在一些构型中,这些实施方案的化合物或盐包括化合物和盐,n可以是1并且R1可以是H。在一些构型中,这些实施方案的化合物或盐包括化合物和盐,n可以是5并且R1可以是H。在各种构型中,这些实施方案的化合物的盐可以是草酸盐。
在各种实施方案中,这些化合物和其盐可以用于治疗癌症的方法中。在各种构型中,这些方法可以包括向有需要的受试者施用治疗有效量的这些化合物或其盐中的任一种。在各种构型中,可以用这些化合物或其盐中的任一种治疗的癌症可以是任何癌症,如但不限于,胰腺癌或滑膜肉瘤。
在各种实施方案中,这些化合物和其盐可以通过本文公开的方法合成。在一些构型中,这些方法可以包括使结构的化合物与结构的化合物反应,其中n可以是1至5的整数,并且R1可以是甲基或H。在一些构型中,n可以是1并且R1可以是H。在一些构型中,n可以是5并且R1可以是H。
在一些构型中,本教导包括用于治疗癌症的这些化合物或其盐。在一些方面,癌症可以是但不限于,胰腺癌或滑膜肉瘤。
在一些构型中,本教导包括这些化合物或其盐用于制造供治疗癌症用的药物的用途。在一些方面,癌症可以是但不限于,胰腺癌或滑膜肉瘤。
在各种实施方案中,本教导包括了合成式IV化合物的方法:
所述方法包括以下步骤:使结构式V的化合物:
与结构式VI的化合物反应:
其中n是1至5的整数;并且R2可以是H或甲基。
附图简述
图1示出埃拉汀和脱甲基埃拉汀(SW V-27)。
图2A-C示出了本教导的化合物SW V-49s和SW V-50s的合成。
图3示出了SW V-49s对Panc-1细胞中荧光σ-2配体SW120内化的竞争性抑制作用。
图4A-F示出了在体外在各种人(A-D)和鼠(E)胰腺癌细胞系上SW V-49s的活力分析。
图5A-B示出在24小时(A)或7小时(B)治疗后分析的由SW V-49s诱导的细胞凋亡性细胞死亡增加。
图6示出了由SW V-49s诱导的铁死亡性细胞死亡。
图7示出在鼠模型系统中施用SW V-49s之后胰腺癌的肿瘤大小减小。
图8示出在鼠模型系统中施用SW V-49s之后胰腺癌存活率是100%。
图9示出SW V-49s和对照的细胞杀伤特征。
图10示出用埃拉汀处理的细胞的细胞活力分析。
图11A-B示出SW V-49s抑制胱氨酸摄取导致产生ROS。
图12A-C示出SW V-49s处理诱导固有的细胞凋亡途径。
图13示出SW V-49s诱导细胞凋亡性和ROS依赖性细胞死亡。
图14A-E示出SW V 49s减少肿瘤生长并增加存活率。
详述
缩写和定义
为便于了解本公开,本文中使用的多个术语和缩写定义如下:
在介绍本公开或其优选实施方案的要素时,冠词“一个”、“一种”“该”及“所述”意图指存在一个或多个要素。
化学物质和部分是根据Naming and Indexing of Chemical Substances forChemical AbstactsTM 2007版,American Chemical Society,2008命名,除非以下具体说明。
在未另外具体定义时,本文中单独或组合使用的术语“低级”是指含有1至多至6个碳原子并且包括6个在内。
本文中单独或组合使用的术语“低级芳基”是指苯基或萘基,其中任一个可以任选被取代。
本文中单独或组合使用的术语“低级杂芳基”是指1)包含五个或六个环成员的单环杂芳基,其中介于一个与四个之间的成员可以是选自由O、S及N组成的群组的杂原子;或2)双环杂芳基,其中稠合环的每一个包含五个或六个环成员,其间包含一至四个选自由O、S及N组成的群组的杂原子。
本文中单独或组合使用的术语“低级环烷基”是指具有介于三个与六个之间的环成员的单环环烷基。低级环烷基可以是不饱和的。低级环烷基的实例包括环丙基、环丁基、环戊基及环己基。
本文中单独或组合使用的术语“低级杂环烷基”是指具有介于三个与六个之间的环成员的单环杂环烷基,其中介于一个或四个之间的环成员可以是选自由O、S及N组成的群组的杂原子。低级杂环烷基的实例包括吡咯烷基、咪唑烷基、吡唑烷基、哌啶基、哌嗪基及吗啉基。低级杂环烷基可以是不饱和的。
本文中单独或组合使用的术语“低级氨基”是指-NRR′,其中R和R′独立地选自由氢、烷基及低级杂烷基组成的群组,其中任一个可以任选被取代。此外,低级氨基的R和R′可以组合形成五元或六元杂环烷基,其中任一个可以任选被取代。
本文中单独或组合使用的术语“氧基”或“氧杂”是指-O-。
本文中单独或组合使用的术语“氧代”是指=O。
术语“全卤代烷氧基”是指所有氢原子都被卤素原子置换的烷氧基。
本文中单独或组合使用的术语“全卤代烷基”是指所有氢原子都被卤素原子置换的烷基。
本文中单独或组合使用的术语“磺酸酯”、“磺酸”及“磺酸的”是指-SO3H基团及其阴离子,如用于形成盐的磺酸。
本文中单独或组合使用的术语“硫基”是指-S-。
本文中单独或组合使用的术语“亚磺酰基”是指-S(O)-。
术语“N-磺酰胺基”是指RS(=O)2NR′-基团,其中R和R′如本文所定义。
术语“S-磺酰胺基”是指-S(=O)2NRR’基团,其中R和R′如本文所定义。
本文中单独或组合使用的术语“硫杂”和“硫代”是指-S-基团或氧原子被硫置换的醚。硫代基团的氧化衍生物,即,亚磺酰基和磺酰基,包括在硫杂和硫代的定义中。
如本文中所使用,术语“硫代羰基”当单独使用时包括硫代甲酰基,即,-C(S)H,并且当组合使用时是-C(S)-基团。
术语“N-硫代氨甲酰基”是指ROC(S)NR′-基团,其中R和R′如本文所定义。
术语“O-硫代氨甲酰基”是指-OC(S)NRR’基团,其中R和R′如本文所定义。
术语“硫代氰酰”是指-CNS基团。
术语“三卤代甲烷磺酰胺基”是指X3CS(O)2NR-基团,其中X是卤素并且R如本文所定义。
术语“三卤代甲烷磺酰基”是指X3CS(O)2-基团,其中X是卤素。
术语“三卤代甲氧基”是指X3CO-基团,其中X是卤素。
本文中单独或组合使用的术语“三取代的甲硅烷基”是指在三个自由价键处被本文在被取代的氨基定义下所列的基团取代的硅酮基团。实例包括三甲基甲硅烷基、叔丁基二甲基甲硅烷基、三苯基甲硅烷基等。
本文中的任一定义都可以与任何其它定义组合使用以描述复合结构基团。按照惯例,任何此类定义的后缀元素是附接至母体部分的元素。举例来说,复合基团烷基酰胺基表示烷基通过酰胺基团附接至母体分子,而术语烷氧基烷基表示烷氧基通过烷基附接至母体分子。
术语“任选被取代”是指其之前的基团可以是被取代或未取代的。当被取代时,“任选被取代”的基团的取代基可以包括但不限于,独立地选自单独或组合的以下基团或一组特定基团的一个或多个取代基:烷基、低级烯基、低级炔基、低级烷酰基、低级杂烷基、低级杂环烷基、低级卤代烷基、低级卤代烯基、低级卤代炔基、低级全卤代烷基、低级全卤代烷氧基、低级环烷基、苯基、芳基、芳氧基、低级烷氧基、低级卤代烷氧基、氧代、低级酰氧基、羰基、羧基、烷基羰基、低级羧基酯、低级羧酰胺基、氰基、氢、卤素、羟基、氨基、烷基氨基、芳基氨基、酰胺基、硝基、硫醇、烷硫基、低级卤代烷硫基、低级全卤代烷硫基、芳硫基、磺酸酯、磺酸、三取代的甲硅烷基、N3、SH、SCH3、C(O)CH3、CO2CH3、CO2H、吡啶基、噻吩、呋喃基、低级氨基甲酸酯及低级脲。两个取代基可以接合在一起形成由零个至三个杂原子组成的稠合五元、六元或七元碳环或杂环,例如形成亚甲基二氧基或亚乙基二氧基。任选被取代的基团可以是未取代的(例如-CH2CH3)、完全取代的(例如-CF2CF3)、单取代的(例如-CH2CH2F),或以介于完全取代与单取代之间的任何水平取代的(例如-CH2CF3)。当陈述取代基,但未关于取代作出限定时,涵盖被取代的形式和未取代的形式。当限定取代基为“被取代的”时,特指被取代的形式。另外,必要时,可以针对特定部分界定几组不同的可选取代基;在这些情况下,可选取代将如通常紧跟在短语“任选被......取代”之后定义。
除非另外定义,否则单独并且无数字指示的术语R或术语R’是指选自由氢、烷基、环烷基、杂烷基、芳基、杂芳基及杂环烷基组成的群组的部分,其中任一个可以任选被取代。此类R和R’基团应理解为如本文所定义的任选被取代的。无论R基团是否具有数字指示,每个R基团,包括R、R′及Rn(其中n是整数),每个取代基,及每个术语都应理解为就从一个群组选择来说是彼此独立的。在任何变量、取代基或术语(例如芳基、杂环、R等)在化学式或通用结构中出现超过一次的情况下,其在每次出现时的定义与在其它时候出现的定义无关。本领域技术人员应进一步认识到,某些基团可以附接至母体分子或者可以从书写的任一端占据元素链中的位置。因此,仅举例来说,不对称基团,如-C(O)N(R)-,可以在碳或氮处附接至母体部分。
本文所公开的化合物中存在不对称中心。化合物的个别立体异构体可以由含有手性中心的可商购的起始物质,以合成方式制备,或者通过制备对映异构产物的混合物,随后分离,如转化成非对映异构体混合物随后分离或再结晶、色谱技术、在手性色谱柱上直接分离对映异构体,或本领域中已知的任何其它适当方法来制备。呈特定立体化学的起始化合物是可商购的,或者可以通过本领域中已知的技术制备和拆分。另外,本文所公开的化合物可以呈几何异构体存在。另外,化合物可以呈互变异构体存在;本公开提供所有互变异构体。另外,本文所公开的化合物可以呈其未溶剂化形式以及用药学上可接受的溶剂(如水、乙醇等)溶剂化的形式。一般来说,溶剂化形式被认为与未溶剂化形式相当。
术语“键”是指两个原子,或当由键接合的原子被视为较大子结构的一部分时两个部分之间的共价键联。除非另外说明,否则键可以是单键、双键或三键。在分子图中,两个原子之间的虚线指示可以在该位置存在或不存在另外的键。
本文中使用的术语“疾病”与术语“病症”和“病况”(如在医学病况中)同义并且可互换使用,因为这些术语都反映了人体或动物体或其损害正常功能的部分之一的异常状况,典型地由有区别的征象和症状表现,并且使人或动物的寿命缩短或生活质量降低。
术语“组合疗法”是指施用两种或更多种治疗剂治疗本公开中所描述的治疗性病况或病症。此类施用涵盖以基本上同时的方式共施用这些治疗剂,如在具有固定比率活性成分的单一胶囊中,或在各活性成分分开的多个胶囊中。此外,此类施用也涵盖依序使用每一类治疗剂。
短语“治疗有效”意图限定用于治疗疾病或病症或实现临床终点的活性成分的量。
术语“治疗学上可接受”是指化合物(或盐、前药、互变异构体、两性离子形式等)适于与患者的组织接触使用而无过度毒性、刺激及过敏反应,与合理的效益/风险比相称并且有效用于预定用途。
在本公开中,术语“辐射”是指包含粒子或光子的电离辐射,这些粒子或光子具有足够能量或者可以经由核相互作用产生足够能量以引起电离(电子增加或损失)。示例性并且优选的电离辐射是x辐射。用于将x辐射递送到靶组织或细胞的方式是本领域中众所周知的。给定细胞所需的电离辐射的量一般取决于该细胞的性质。用于确定辐射的有效量的方式是本领域中众所周知的。本文中使用的术语电离辐射的“有效剂量”是指使细胞损伤或死亡增加的电离辐射剂量。
术语“辐射疗法”是指使用电磁辐射或粒子辐射来治疗瘤形成并且包括使用电离辐射和非电离辐射。
本文所公开的化合物可以呈治疗学上可接受的盐形式存在。本公开包括呈盐形式,包括酸加成盐形式的以上所列的化合物。适合盐包括与有机和无机酸形成的盐。此类酸加成盐通常是药学上可接受的。不过,非药学上可接受的盐可以用于制备和纯化所论及的化合物。也可以形成碱加成盐并且可以是药学上可接受的。有关盐的制备和选择的更完整论述,参见Pharmaceutical Salts:Properties,Selection,and Use (Stahl,P.Heinrich.Wiley-VCHA,Zurich,Switzerland,2002)。
如本文所使用,术语“治疗学上可接受的盐”表示本文所公开的化合物的盐或两亲离子形式,这些形式是水或油可溶或可分散的并且是如本文所定义的治疗学上可接受的。这些盐可以在化合物的最终分离和纯化过程中制备,或者单独通过使呈游离碱形式的适当化合物与适合酸反应来制备。代表性酸加成盐包括乙酸盐、己二酸盐、海藻酸盐、L-抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐(苯磺酸盐(besylate))、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、二葡糖酸盐、甲酸盐、反丁烯二酸盐、龙胆酸盐、谷氨酸盐、甘油磷酸盐、乙醇酸盐、半硫酸盐、庚酸盐、己酸盐、马尿酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙烷磺酸盐(羟乙基磺酸盐)、乳酸盐、顺丁烯二酸盐、丙二酸盐、DL-扁桃酸盐、均三甲苯磺酸盐、甲烷磺酸盐、萘磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基并酸盐、膦酸盐、苦味酸盐、特戊酸盐、丙酸盐、焦谷氨酸盐、琥珀酸盐、磺酸盐、酒石酸盐、L-酒石酸盐、三氯乙酸盐、三氟乙酸盐、磷酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐(对甲苯磺酸盐(p-tosylate))及十一烷酸盐。另外,本文所公开的化合物中的碱性基团可以用甲基、乙基、丙基及丁基氯化物、溴化物及碘化物;二甲基、二乙基、二丁基及二戊基硫酸酯;癸基、月桂基、肉豆蔻基及硬脂基氯化物、溴化物及碘化物;以及苯甲基和苯乙基溴化物四级化。可以用于形成治疗学上可接受的加成盐的酸的实例包括无机酸,如盐酸、氢溴酸、硫酸及磷酸;及有机酸,如草酸、顺丁烯二酸、琥珀酸及柠檬酸。还可以通过使化合物与碱金属或碱土金属离子配位来形成盐。因此,本公开涵盖本文所公开的化合物的钠盐、钾盐、镁盐及钙盐等。
碱加成盐可以在化合物的最终分离和纯化过程中,通过使羧基与适合碱,如金属阳离子的氢氧化物、碳酸盐或碳酸氢盐,或者与氨或有机伯胺、仲胺或叔胺反应来制备。治疗学上可接受的盐的阳离子包括锂、钠、钾、钙、镁及铝,以及无毒季铵阳离子,如铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺、二乙胺、乙胺、三丁胺、吡啶、N,N-二甲基苯胺、N-甲基哌啶、N-甲基吗啉、二环己胺、普鲁卡因、二苯甲胺、N,N-二苯甲基苯乙胺、1-二苯羟甲胺及N,N′-二苯甲基乙二胺。可用于形成碱加成盐的其它代表性有机胺包括乙二胺、乙醇胺、二乙醇胺、哌啶及哌嗪。
化合物
本公开提供一种结构式I的化合物
或其盐,其中:W选自任选被取代的C5-C10芳基和C5-C10杂芳基;X是连接部分;并且Y是铁死亡诱导部分,该部分选自埃拉汀、埃拉汀类似物如埃拉汀-A、埃拉汀-B或脱甲基埃拉汀,或简化的合成埃拉汀模拟物。
在一些构型中,W可以是C5-C10芳基。
在一些构型中,W可以是被取代的C5-C10芳基。
在一些构型中,W可以是σ-2受体配体。
在一些构型中,连接部分可以包含C1-C12直链。
在一些构型中,连接部分可以另外包含1个或多个杂原子。在一些构型中,该1个或多个杂原子的每一个可以独立地选自由氧、硫及氮组成的群组。
在一些构型中,连接部分可以具有结构
其中是键,并且n是1至10的整数,即,1、2、3、4、5、6、7、8、9或10。9。在一些构型中,n=1。在一些构型中,n=5。
在一些构型中,结构式I化合物的铁死亡诱导部分可以选自由埃拉汀、埃拉汀-A、埃拉汀-B及脱甲基埃拉汀组成的群组。
在一些构型中,结构式I化合物的铁死亡诱导部分可以是埃拉汀。
在一些实施方案中,本教导包括式II的化合物
或其盐,其中:W选自任选被取代的C5-C10芳基和C5-C10杂芳基;X是连接部分;并且R2选自氢和甲基。
在一些实施方案中,本教导包括式III的化合物:
或其盐,其中:Z1和Z3的每一个独立地选自由以下组成的群组:键、C1-C10烷基、C1-C10烯基、C1-C10炔基、C5-C10芳基、C5-C10杂芳基、芳基烷基、杂芳基烷基、烷基芳基、烷基杂芳基、杂环烷基烷基、烷基杂环烷基、环烷基烷基、烷基环烷基、-(CH2)a(OCH2CH2)b(CH2)c-、-(CH2)a(CH2CH2O)b(CH2)c-、-(CH2)aO(CH2)c-、-(CH2)aS(CH2)c-、-(CH2)aS(O)2(CH2)c-、-(CH2)aS(O)(CH2)c-、-(CH2)aN(R1)(CH2)c-、-(CH2)aN(R1)C(O)(CH2)c-、-(CH2)aC(O)N(R1)(CH2)c-、-(CH2)aN(R1)C(O)N(R1)(CH2)c-、-(CH2)aS(O2)N(R1)(CH2)c-、-(CH2)aN(R)S(O2)(CH2)c-;Z2选自C1-C10烷基、C1-C10烯基、C1-C10炔基、C5-C10芳基、C5-C10杂芳基、芳基烷基、杂芳基烷基、烷基芳基、烷基杂芳基、杂环烷基烷基、烷基杂环烷基、环烷基烷基、烷基环烷基、-(CH2)a(OCH2CH2)b(CH2)c-及-(CH2)a(CH2CH2O)b(CH2)c-、-(CH2)aO(CH2)c-、-(CH2)aS(CH2)c-、-(CH2)aS(O)2(CH2)c-、-(CH2)aS(O)(CH2)c-、-(CH2)aN(R1)(CH2)c-、-(CH2)aN(R1)C(O)(CH2)c-、-(CH2)aC(O)N(R1)(CH2)c-、-(CH2)aN(R1)C(O)N(R1)(CH2)c-、-(CH2)aS(O2)N(R1)(CH2)c-、-(CH2)aN(R)S(O2)(CH2)c-;其中Z1、Z2及Z3的每一个可以任选被一个或多个选自卤素、氧代及C1-C10烷基的基团取代;各R1独立地选自氢、C1-C10烷基及C1-C10酰基;a和c各自是独立地选自0、1、2、3及4的整数;各b是独立地选自1、2、3、4、5及6的整数;并且Y是铁死亡诱导部分,该部分选自埃拉汀、埃拉汀类似物如埃拉汀-A、埃拉汀-B或脱甲基埃拉汀,或简化合成的埃拉汀模拟物。
在某些实施方案中,本教导的化合物具有结构式IV:
或其盐,其中:n是选自1、2、3、4及5的整数;并且R2可以选自氢和甲基。
在一些构型中,n可以是1;并且R2可以是氢。
在一些构型中,n可以是5;并且R2可以是氢。
在一些构型中,盐可以是草酸盐。
在一些构型中,化合物可以选自如本文所公开的化合物1-24。
药物组合物
尽管本教导的化合物可以按原料化合物形式施用,但也可以使其呈药物制剂形式。因此,本文提供了药物制剂,这些药物制剂包含一种或多种本教导的化合物,或一种或多种其药学上可接受的盐、酯、前药、酰胺或溶剂化物,以及一种或多种其药学上可接受的载剂和任选地一种或多种其它治疗成分。从与制剂中的其它成分可相容并且对其接受者无害的意义上说,载剂必须是“可接受的”。适当的制剂取决于所选施用途径。适当时并且如本领域中所了解,任何众所周知的技术、载剂及赋形剂都可以使用;例如在Remington′sPharmaceutical Sciences中。本文公开的药物组合物可以通过本领域中已知的任何方式,例如借助于常规混合、溶解、制粒、制糖衣丸、粉碎、乳化、囊封、包封或压缩方法制造。
制剂包括适于经口、胃肠外(包括皮下、皮内、肌肉内、静脉内、关节内及髓内)、腹膜内、透粘膜、透皮、直肠及局部(包括真皮、颊、舌下及眼内)施用的那些,但最适合的途径可以取决于例如接受者的病况和病症。制剂宜呈单位剂型并且可以通过药学领域众所周知的任何方法制备。典型地,这些方法包括使本公开的化合物或其药学上可接受的盐、酯、酰胺、前药或溶剂化物(“活性成分”)与构成一种或多种辅助成分的载剂结合的步骤。一般来说,制剂是通过使活性成分与液体载剂或适时分开的细粉状固体载剂或两者均匀并紧密地结合,随后视需要使产物成型成希望的制剂来制备。
本文所描述的化合物可以如下施用:
经口施用
本教导的化合物可以经口施用,包括吞咽,因此,该化合物进入胃肠道,或直接从口吸收到血流中,包括舌下或颊施用。
适于经口施用的组合物包括固体制剂,如片剂、丸剂、药囊、糖锭以及硬质或软质胶囊,这些制剂可以含有液体、凝胶、粉末或颗粒。
在片剂或胶囊剂型中,存在药物量可以是该剂型重量的约0.05%至约95%,更典型地是约2%至约50%。
此外,片剂或胶囊可以含有以重量计占该剂型约0.5%至约35%,更典型地约2%至约25%的崩解剂。崩解剂的实例包括甲基纤维素、羧甲基纤维素钠或羧甲基纤维素钙、交联羧甲基纤维素钠、聚乙烯吡咯烷酮、羟丙基纤维素、淀粉等。
适用于片剂中的粘合剂包括明胶、聚乙二醇、糖、树胶、淀粉、羟丙基纤维素等。适用于片剂中的稀释剂包括甘露糖醇、木糖醇、乳糖、葡聚糖、蔗糖、山梨糖醇及淀粉。
适用于片剂或胶囊中的表面活性剂和助流剂以重量计可以是约0.1%至约3%的量,并且包括聚山梨醇酯80、十二烷基硫酸钠、滑石及二氧化硅。
适用于片剂或胶囊中的润滑剂以重量计可以是约0.1%至约5%的量,并且包括硬脂酸钙、硬脂酸锌或硬脂酸镁、硬脂基反丁烯二酸钠等。
片剂可以任选在一种或多种辅助成分存在下,通过压缩或模制制成。压缩片剂可以通过在适合机器中,压缩呈自由流动形式,如呈粉末或颗粒状的活性成分,任选混入粘合剂、惰性稀释剂或润滑剂、表面活性剂或分散剂来制备。模制片剂可以通过在适合机器中模制用液体稀释剂润湿的粉末状化合物的混合物来制造。可以向片剂中添加染料或颜料以标识或表征不同的活性化合物剂量组合。
液体制剂可以包括乳液、溶液、糖浆、酏剂及悬浮液,这些制剂可以用于软质或硬质胶囊中。此类制剂可以包括药学上可接受的载剂,例如水、乙醇、聚乙二醇、纤维素或油。制剂还可以包括一种或多种乳化剂和/或悬浮剂。
经口施用的组合物可以配制成立即释放或改良释放形式,包括延迟释放或持续释放形式,任选包覆肠衣。
在另一个实施方案中,药物组合物包含治疗有效量的式(I)化合物或其药学上可接受的盐,及药学上可接受的载剂。
胃肠外施用
本教导的化合物可以通过注射,例如通过推注或连续输注直接施用于血流、肌肉或内脏中。适于胃肠外施用的方式包括静脉内、肌肉内、皮下、动脉内、腹膜内、鞘内、颅内等。适于胃肠外施用的装置包括注射器(包括有针和无针注射器)和输注方法。制剂可以提供于单位剂量或多剂量容器中,例如密封安瓿和小瓶中。
大多数胃肠外制剂是含有赋形剂,包括盐、缓冲剂、悬浮剂、稳定剂和/或分散剂、抗氧化剂、抑菌剂、防腐剂及使制剂与预定接受者的血液等渗的溶质,及碳水化合物的水溶液。
胃肠外制剂还可以制备为脱水形式(例如通过冻干)或无菌非睡醒溶液形式。这些制剂可以在适合媒介物,如无菌水存在下使用。也可以使用增溶剂制备胃肠外溶液。
胃肠外施用的组合物可以配制成立即释放或改良释放形式,包括延迟释放或持续释放形式。化合物还可以配制为储积式制剂形式。此类长效制剂可以通过植入(例如皮下或肌肉内植入)或通过肌肉内注射进行施用。因此,例如,化合物可以用适合的聚合物质或疏水性物质(例如,如在可接受的油中的乳液)或离子交换树脂配制,或以难溶衍生物,例如难溶盐形式配制。
局部施用
在一些构型中,本教导的化合物可以局部(例如用于皮肤、粘膜、耳、鼻或眼)或透皮施用。供局部施用的制剂可以包括但不限于,洗液、溶液、乳膏、凝胶、水凝胶、油膏、泡沫剂、植入物、贴片等。供局部施用制剂的药学上可接受的载剂可以包括水、醇、矿物油、甘油、聚乙二醇等。局部施用还可以通过例如电穿孔、离子电渗透、超声透入疗法等进行。
典型地,供局部施用的活性成分可以占制剂的0.001%至10%w/w(以重量计)。在某些实施方案中,活性成分可以占制剂多达10%w/w;低于5%w/w;2%w/w至5%w/w;或0.1%w/w至1%w/w。
局部施用的组合物可以配制成立即释放或改良释放形式,包括延迟释放或持续释放形式。
直肠、颊及舌下施用
供直肠施用本教导的化合物的栓剂可以通过将活性剂与适合的无刺激性赋形剂,如可可脂、合成单酸甘油酯、二酸甘油酯或三酸甘油酯、脂肪酸或聚乙二醇混合来制备,聚乙二醇在常温下是固体,但在直肠温度下是液体,并因此将在直肠中熔融并释放出药物。
对于颊或舌下施用,组合物可以呈通过常规方式配制的片剂、糖锭、锭剂或凝胶形式。此类制剂可以包含以如蔗糖和阿拉伯胶或黄芪胶调味的活性成分。
通过吸入施用
对于通过吸入施用,在一些构型中,本教导的化合物可以由吹药器、喷雾器加压包装或其它递送气雾剂喷雾或粉末的惯用构件递送。加压包装可以包含适合推进剂,如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它适合气体。在加压气雾剂的情况下,可以通过提供阀递送定计量来确定剂量单位。或者,对于通过吸入或吹入施用,根据本公开的化合物可以呈干粉组合物,例如化合物和适合粉末基质(如乳糖或淀粉)的粉末混合物的形式。在例如胶囊、药筒、明胶或泡罩包装中,粉末组合物可以呈单位剂型,借助于吸入器或吹药器,可以由这些包装施用粉末。
也可以使用制药领域中已知的其它载剂物质和施用模式。本教导的药物组合物可以通过众所周知的制药技术,如有效配制和施用程序制备。优选的单位剂量制剂是含有如本文所陈述的有效剂量,或其适当分数的活性成分的制剂。施用给患者的确切剂量将是主治医师的职责。对于任何特定患者的具体剂量水平将取决于多种因素,包括所用具体化合物的活性、年龄、体重、一般健康状况、性别、饮食、施用时间、施用途径、排泄速率、药物组合、所治疗的确切病症,及所治疗的适应症或病况的严重程度。此外,施用途径可以取决于病况及其严重程度而变化。以上有关有效配制和施用程序的考虑是本领域中众所周知的并且描述于标准教科书中。药物的配制论述于例如Hoover,John E.,Remington′sPharmaceutical Sciences,Mack Publishing Co.,Easton,Pa.,1975;Liberman等人编,Pharmaceutical Dosage Forms,Marcel Decker,New York,N.Y.,1980;及Kibbe等人编,Handbook of Pharmaceutical Excipients(第3版),American PharmaceuticalAssociation,Washington,1999中。
治疗方法
本公开提供特征为结合σ-2受体的靶向部分并因此可以用于治疗或预防与表达σ-2受体的细胞有关的病症的化合物和药物组合物,且所述病症包括但不限于,癌症。
癌症
在一些实施方案中,本公开的化合物和药物组合物可以用于治疗或预防癌症。
在某些实施方案中,癌症可以选自腺癌、成人T细胞白血病/淋巴瘤、膀胱癌、胚细胞瘤、骨癌、乳癌、脑癌、癌瘤、髓样肉瘤、子宫颈癌、结肠直肠癌、食道癌、胃肠癌、多形性胶质母细胞瘤、神经胶质瘤、胆囊癌、胃癌、头颈癌、霍奇金氏淋巴瘤(Hodgkin′s lymphoma)、非霍奇金氏淋巴瘤、肠癌、肾癌、喉癌、白血病、肺癌、淋巴瘤、肝癌、小细胞肺癌、非小细胞肺癌、间皮瘤、多发性骨髓瘤、眼癌、视神经肿瘤、口腔癌、卵巢癌、垂体肿瘤、原发性中枢神经系统淋巴瘤、前列腺癌、胰腺癌、咽癌、肾细胞癌瘤、直肠癌、肉瘤、皮肤癌、脊髓肿瘤、小肠癌、胃癌、滑膜肉瘤、T细胞淋巴瘤、睾丸癌、甲状腺癌、咽喉癌、泌尿生殖道癌症、尿路上皮癌、子宫癌、阴道癌或威尔姆氏肿瘤(Wilms’tumor)。
在特定实施方案中,癌症可以是胰腺癌。在特定实施方案中,癌症可以是滑膜肉瘤。
组合和组合疗法
本教导的化合物可以单独使用,或者与其它药物活性化合物组合使用,以治疗如先前在上文描述的那些病况。本教导的化合物及其它药物活性化合物可以同时(以相同剂型或以分开的剂型)或依序施用。因此,在一个实施方案中,本教导包含了通过向受试者施用治疗有效量的一种或多种本教导的化合物及一种或多种另外的药物活性化合物来治疗病况的方法。
在另一实施方案中,提供了一种药物组合物,该药物组合物包含一种或多种本教导的化合物、一种或多种另外的药物活性化合物,及药学上可接受的载剂。
在另一实施方案中,该一种或多种另外的药物活性化合物选自由抗癌药、抗增生药及抗炎药组成的群组。
本文所描述的σ-2受体结合组合物还任选与其它治疗试剂组合使用,这些治疗试剂是针对其对有待治疗的病况的治疗价值进行选择。一般来说,在采用组合疗法的实施方案中,本文所描述的化合物与其它药剂不以同一药物组合物施用,而且由于物理和化学特征不同,这些药剂任选通过不同途径施用。初始施用一般是根据确定的方案进行,而且随后基于观察的效果、剂量、施用模式及施用时间进行修改。在某些情形中,如本文所描述的σ-2受体结合化合物宜与另一治疗剂组合施用。仅举例来说,通过施用也具有治疗益处的另一治疗剂(也包括治疗方案)来增进σ-2受体结合化合物的治疗效用。不管所治疗的疾病、病症或病况如何,患者所经历的总体益处是两种治疗剂的简单加和,或患者经历增强的(即,协同)益处。或者,如果本文所公开的化合物具有副作用,那么宜施用一种降低该副作用的药剂;或者可以通过施用佐剂来增强本文所描述的化合物的治疗效用。
当药物是以治疗组合使用时,治疗有效剂量不同。以实验方式确定在组合治疗方案中使用的药物及其它药剂的治疗有效剂量的方法是有文献记载的方法。组合治疗另外包括周期治疗,这些治疗在各种时间开始和结束以帮助患者的临床管理。在任何情形中,可以按任一次序或同时施用多种治疗剂(其中之一是本文所描述的σ-2受体结合化合物)。如果同时施用,那么该多种治疗剂任选是以单一形式或以多种形式(仅举例来说,以单一丸剂或两粒分开的丸剂)提供。
在一些实施方案中,治疗剂之一是以多次剂量给予,或都以多次剂量给予。如果不是同时施用,那么这多次剂量之间的时间任选在超过零周至少于十二周之间变化。
此外,组合方法、组合物及制剂不仅仅限于使用两种药剂,也预期施用多种治疗剂组合。应了解,用于治疗、预防或改善有待减轻的病况的剂量方案任选根据多种因素进行修改。这些因素包括受试者所患病症,以及受试者的年龄、体重、性别、饮食及医学病况。因此,实际采用的剂量方案在一些实施方案中变化极大,并由此偏离本文所陈述的剂量方案。
构成本文所公开的组合疗法的药剂任选是预定用于基本上同时施用的组合剂量形式或独立剂量形式。构成组合疗法的药剂还任选依序施用,其中任一药剂是根据需要两步施用的方案施用。该两步施用方案任选要求依序施用活性剂或间隔分开施用个别活性剂。取决于每一药剂的特性,如药剂的效力、溶解性、生物利用率、血浆半衰期及动力学型态,多个施用步骤之间的时间在数分钟至数小时范围内。
在另一实施方案中,σ-2受体结合化合物抑制剂任选与向患者提供另外益处的程序组合使用。σ-2受体结合化合物抑制剂和任何另外的疗法任选在疾病或病况发生之前、期间或之后施用,并且在一些实施方案中,施用含σ-2受体结合化合物的组合物的时程不同。因此,例如,σ-2受体结合化合物是作为预防措施使用并且向有发生病况或疾病的倾向的受试者连续施用,以防止疾病或病况的发生。σ-2受体结合化合物及组合物任选在症状发作期间或在症状发作后尽可能快地施用给受试者。尽管本文中已显示并描述本教导的优选实施方案,但本领域技术人员将显而易见,这些实施方案仅借助实施例提供。在不偏离本教导的情况下,本领域技术人员可以作出多种变更、改变及取代。在本教导的一些实施方案中,可以采用本文所描述的实施方案的各种替代方案实践本教导。
σ-2受体结合化合物可以与抗癌药组合使用,这些抗癌药包括但不限于以下类别:烷化剂、血管生成素1和/或2抑制剂、蒽环类药物、抗代谢药物、极光激酶抑制剂、B-raf抑制剂、BTK抑制剂、c-met抑制剂、CDK 4和/或6抑制剂、CDK4和/或CDK6抑制剂、cFMS抑制剂、交联剂、DNA复制抑制剂、内皮生长因子(EGF)抑制剂、肝细胞生长因子/分散因子(HGF/SF)抑制剂、HER2和HER3抑制剂、类胰岛素生长因子1受体(IGFR-1)抑制剂、嵌入剂、MEK抑制剂、微管破坏剂、mTOR抑制剂、全ErbB酪氨酸激酶抑制剂、PARP抑制剂、P13K抑制剂、PKB抑制剂、PKB抑制剂、类polo激酶抑制剂、拟辐射剂、辐射增敏剂、重组人apo2配体、断链剂、拓扑异构酶II抑制剂、肿瘤坏死因子相关细胞凋亡诱导性配体(TRAIL)激动剂,及血管内皮生长因子(VEGF)抑制剂。
本文所公开的化合物,包括式I化合物在内,也可用作癌症治疗的化学增敏剂和辐射增敏剂。这些化合物可用于治疗先前曾经历或正在经历或即将经历癌症治疗的哺乳动物。此类其它治疗包括化学疗法、辐射疗法、手术或免疫疗法,如癌症疫苗。
本发明化合物特别适于与治疗性抗癌剂和/或辐射治疗剂组合使用。因此,本公开提供了用于同时、分开或依序施用的本发明式I化合物与治疗性抗癌剂和/或辐射治疗剂的组合。本公开的化合物及另一抗癌剂可以加和地或协同地起作用。本发明化合物与另一抗癌剂的协同组合允许使用这些药剂之一或两种的较低剂量和/或本发明化合物与其它抗癌剂之一或两种的不太频繁的剂量,和/或不太频繁地施用这些药剂可以减少与施用这些药剂给受试者相关的任何毒性,同时不会降低这些药剂在癌症治疗中的功效。此外,协同作用可以提高这些药剂在癌症治疗中的功效和/或减少与单独使用任一药剂有关的任何不良或不想要的副作用。
治疗剂、抗癌剂和/或辐射疗法可以根据本领域中众所周知的治疗方案施用。本领域技术人员显而易见的是,治疗剂、抗癌剂和/或辐射疗法的施用可以取决于所治疗的疾病以及该抗癌剂和/或辐射疗法对该疾病的已知作用而变化。另外,根据熟练临床医师的技能,治疗方案(例如施用剂量和时间)可以根据观察到的所施用的治疗剂(即,抗赘生剂或辐射)对患者的影响,以及根据观察到的疾病对所施用的治疗剂的反应,和观察到的不良作用而变化。
x射线的剂量范围是50至200伦琴的日剂量持续较长时间段(3至4周)到2000至6000伦琴的单次剂量。放射性同位素的剂量范围变化极大,并且取决于同位素的半衰期、所发射的辐射的强度和类型,及赘生性细胞的吸收情况。
用于将辐射递送至组织的任何适合方式都可以用于本公开中。将辐射递送至组织的常用方式是在所治疗的身体外部的电离辐射源。用于将辐射递送至组织的替代方法包括例如,首先在体内递送与肿瘤抗原免疫反应的经放射性标记的抗体,随后在体内将有效量的放射性标记的抗体递送至组织中。此外,可以使用放射性同位素将电离辐射递送至组织或细胞。另外,辐射可以借助于拟辐射剂递送。如本文所使用,“拟辐射剂”是引起与辐射疗法相同类型的细胞损害,但无需施加辐射的一种化学治疗剂,例如美法兰(melphalan)。
就用于癌症和赘生性疾病来说,σ-2受体结合化合物最佳与以下抗癌剂的非限制性实例中的一种或多种结合使用:(1)烷化剂,包括但不限于,顺铂(PLATIN)、卡铂(PARAPLATIN)、奥沙利铂(oxaliplatin;ELOXATIN)、链佐星(streptozocin;ZANOSAR)、白消安(busulfan;MYLERAN)及环磷酰胺(ENDOXAN);(2)抗代谢物,包括但不限于,巯基嘌呤(PURINETHOL)、硫鸟嘌呤、喷司他汀(pentostatin;NIPENT)、胞嘧啶阿拉伯糖苷(ARA-C)、吉西他滨(gemcitabine;GEMZAR)、氟尿嘧啶(CARAC)、左亚叶酸(leucovorin;FUSILEV)及甲氨蝶呤(methotrexate;RHEUMATREX);(3)植物生物碱及萜类化合物,包括但不限于,长春新碱(vincristine;ONCOVIN)、长春花碱(vinblastine)及紫杉醇(paclitaxel;TAXOL);(4)拓扑异构酶抑制剂,包括但不限于,伊立替康(irinotecan;CAMPTOSAR)、拓扑替康(topotecan;HYCAMTIN)及依托泊苷(etoposide;EPOSIN);(5)细胞毒性抗生素,包括但不限于,放线菌素D(actinomycin D;COSMEGEN)、多柔比星(doxorubicin;ADRIAMYCIN)、博莱霉素(bleomycin;BLENOXANE)及丝裂霉素(mitomycin;MITOSOL);(6)血管生成抑制剂,包括但不限于,舒尼替尼(sunitinib;SUTENT)和贝伐单抗(bevacizumab;AVASTIN);及(7)酪氨酸激酶抑制剂,包括但不限于,伊马替尼(imatinib;GLEEVEC)、厄洛替尼(erlotinib;TARCEVA)、拉帕替尼(lapatininb;TYKERB)及阿西替尼(axitinib;INLYTA)。
该另外的治疗剂可以选自5-氟尿嘧啶、阿霉素(adriamycin)、阿法替尼(afatinib)、艾图单抗(alemtuzmab)、六甲密胺(altretamine)、氨鲁米特(aminoglutethimide)、氨基乙酰丙酸、安吖啶(amsacrine)、阿那曲唑(anastrozole)、阿瑞匹坦(aprepitant)、天冬酰胺酶(asparaginase)、阿西替尼、阿扎胞苷(azacitidine)、bcg、bertozimib、贝伐单抗、倍萨罗丁(bexarotene)、比卡鲁胺(bicalutamide)、博莱霉素、硼替佐米(bortezomib)、博舒替尼(bosutinib)、布舍瑞林(buserelin)、白消安、喜树碱(campothecin)、卡培他滨(capecitabine)、卡铂、卡博替尼(carbozantimib)、卡非佐米(carfilzomib)、卡莫司汀(carmustine)、色瑞替尼(ceritinib)、西妥昔单抗(cetuximab)、苯丁酸氮芥(chlorambucil)、氯喹(chloroquine)、顺铂、卡迪NaCl水溶液(cladisat.aq.NaCl solution)、克拉屈滨(cladribine)、氯屈膦酸盐(clodronate)、氯法拉滨(clofarabine)、考比替尼(cobimetinib)、秋水仙碱(colchicine)、克唑替尼(crizotinib)、环磷酰胺、环磷酸胺(cyclophosphamine)、环丙孕酮(cyproterone)、阿糖胞苷(cytarabine)、达卡巴嗪(dacarbazine)、放线菌素D(dactinomycin)、达沙替尼(dasatinib)、道诺霉素(daunorubicin)、debratinib、decarazine、地西他滨(decitabine)、脱甲绿胶酶素(demethoxyviridin)、达萨替尼(desatinib)、右雷佐生(dexrazoxane)、二氯乙酸盐、己二烯雌酚(dienestrol)、己烯雌酚(diethylstilbestrol)、多西他赛(docetaxel)、多柔比星、恩杂鲁胺(enzalutamide)、表柔比星(epirubicin)、厄洛替尼、雌二醇(estradiol)、雌莫司汀(estramustine)、依托泊苷、依维莫司(everolimus)、依西美坦(exemestane)、非格司亭(filgrastim)、氟达拉滨(fludarabine)、氟氢可的松(fludrocortisone)、氟尿嘧啶、氟甲睾酮(fluoxymesterone)、氟他胺(flutamide)、氟维司群(fulvestrant)、吉非替尼(gefitinib)、吉西他滨、吉妥珠单抗(gemtuzumab)、金雀异黄酮(genistein)、戈合瑞林(goserelin)、羟基脲(hydroxyurea)、依鲁替尼(ibrutanib)、伊达比星(idarubicin)、idelalisib、异环磷酰胺(ifosfamide)、伊马替尼、咪喹莫特(imiquimod)、干扰素、伊立替康(irinotecan)、伊诺替康(ironotecan)、伊沙匹隆(ixabepilone)、拉帕替尼(lapatinib)、来那度胺(lenalidomide)、来曲唑(letrozole)、亚叶酸(leucovorin)、亮丙瑞林(leuprolide)、左旋咪唑(levamisole)、洛莫司汀(lomustine)、氯尼达明(lonidamine)、氮芥(mechlorethamine)、甲羟孕酮(medroxyprogesterone)、甲地孕酮(megestrol)、美法兰、巯基嘌呤、美司钠(mesna)、二甲双胍(metformin)、甲氨蝶呤、甲氨蝶呤、米拉霉素(mithram)、丝裂霉素、mitosmycin、米托坦(mitotane)、mitoxane、米托蒽醌(mitoxantrone)、奈拉滨(nelarabine)、来那替尼(neratinib)、尼洛替尼(nilotinib)、尼鲁米特(nilutamide)、诺考达唑(nocodazole)、奥曲肽(octreotide)、奥拉帕利(olaparib)、奥沙利铂、紫杉醇、帕米膦酸盐(pamidronate)、帕唑帕尼(pazopanib)、培门冬酶(pegaspargase)、培美曲塞(pemetrexed)、喷司他丁、哌立福辛(perifosine)、普卡霉素(plicamycin)、泊马度胺(pomalidomide)、帕纳替尼(ponatinib)、卟吩姆(porfimer)、丙卡巴肼(procarbazine)、雷洛昔芬(raloxifene)、雷替曲赛(raltitrexed)、瑞格非尼(regorafinib)、利妥昔单抗(rituximab)、索拉非尼(sorafenib)、链佐星、舒尼替尼、舒拉明(suramin)、他莫昔芬(tamoxifen)、替莫唑胺(temozolomide)、西罗莫司(temsirolimus)、替尼泊苷(teniposide)、睾酮(testosterone)、沙立度胺(thalidomide)、硫鸟嘌呤、噻替哌(thiotepa)、二氯二茂钛(titanocene dichloride)、拓扑替康、曲美替尼(trametinib)、曲妥珠单抗(trastuzumab)、维甲酸(tretinoin)、维利帕尼(veliparib)、长春花碱、长春新碱、长春地辛(vindesine)、长春瑞滨(vinorelbine)、伏拉塞替(volasertib)、伏立诺他(vorinostat)及唑来膦酸(zoledronic acid)。
当受试者罹患炎症性病况或有患炎症性病况的风险时,本文所描述的σ-2受体结合化合物任选与一种或多种治疗炎症性病况的药剂或方法以任何组合结合使用。用于治疗自身免疫和/或炎症性病况的治疗剂/治疗方法包括但不限于,以下实例中的任一种:(1)皮质类固醇,包括但不限于,可的松(cortisone)、地塞米松(dexamethasone)及甲泼尼龙(methylprednisolone);(2)非类固醇抗炎药(NSAID),包括但不限于,布洛芬(ibuprofen)、萘普生(naproxen)、对乙酰氨基酚(acetaminophen)、阿司匹林(aspirin)、非诺洛芬(fenoprofen;NALFON))、氟比洛芬(flurbiprofen;ANSAID)、酮洛芬(ketoprofen)、奥沙普秦(oxaprozin;DAYPRO)、双氯芬酸钠(diclofenac sodium;VOLTAREN)、双氯芬酸钾(CATAFLAM)、依托度酸(etodolac;LODINE)、吲哚美辛(indomethacin;INDOCIN))、酮洛酸(ketorolac;TORADOL))、舒林酸(sulindac;CLINORIL))、托美丁(tolmetin;TOLECTIN)、甲氯灭酸盐(meclofenamate;MECLOMEN)、甲芬那酸(mefenamic acid;PONSTEL)、萘丁美酮(nabumetone;RELAFEN)及吡罗昔康(piroxicam;FELDENE);(3)免疫抑制剂,包括但不限于,甲氨蝶呤(RHEUMATREX)、来氟米特(leflunomide;ARAVA)、硫唑嘌呤(azathioprine;IMURAN)、环孢素(cyclosporine;NEORAL、SANDIMMUNE)、他克莫司(tacrolimus)及环磷酰胺(CYTOXAN);(4)CD20阻断剂,包括但不限于,利妥昔单抗(RITUXAN);(5)肿瘤坏死因子(TNF)阻断剂,包括但不限于,依他普特(etanercept;ENBREL)、英利昔单抗(infliximab;REMICADE)及阿达木单抗(adalimumab;HUMIRA);(6)白细胞介素-1受体拮抗剂,包括但不限于,阿那白滞素(anakinra;KINERET);(7)白细胞介素-6抑制剂,包括但不限于,托珠单抗(tocilizumab;ACTEMRA);(8)白细胞介素-17抑制剂,包括但不限于,AIN457;(9)Janus激酶抑制剂,包括但不限于,托法替尼(tasocitinib);(10)syk抑制剂,包括但不限于,福他替尼(fostamatinib)。
化合物合成
本教导的化合物可以使用以下详述的通用合成方案及实验程序制备。通用合成方案和实验程序是出于说明的目的提供,并且不打算作限制。用于制备本教导的化合物的起始物质是可商购的或者可以使用本领域中已知的常规方法制备。
缩写清单
aq.=水溶液;CDCl3=氘化氯仿;DMSO-d6=氘化二甲亚砜;DMSO=二甲亚砜;h=小时;THF=四氢呋喃。
本教导的一些实施方案包括了合成式IV的化合物的方法:
在各种构型中,这些方法包括使结构式V的化合物:
与结构式VI的化合物反应:
其中n是1至5的整数,并且R2是氢或甲基。
在一些构型中,n可以是1;并且R2可以是氢。
在一些构型中,n可以是5;并且R2可以是氢。
在一些构型中,该反应可以在还原剂存在下发生,如但不限于,氢氧化铝、硼烷-四氢呋喃、儿茶酚硼烷、二异丁基氢化铝、二异戊基硼烷、肼、氢化锂铝、硼氢化锂、三叔丁氧基氢化铝锂、三乙基硼氢化锂、三仲丁基硼氢化钾、硼氢化钠、氰基硼氢化钠、三乙酰氧基硼氢化钠或其混合物。
用于制备化合物的通用方法
可以使用以下方案实践本教导的合成方法。可以并入另外的结构基团,包括但不限于,在本说明书别处定义并且未在方案中描述的化合物中显示的那些,以得到本文所公开的各种化合物,或在使用本领域技术人员已知的技术进一步操作后可以转化成本教导的化合物的中间化合物。
实施例1:3-(邻乙氧基苯基)-2-{[4-(2-{对-[(6-{3-(2-甲氧基氨基甲苯羰氧基)-9-氮杂双环[3.3.1]壬-9-基}己基氨基)甲基]苯氧基)乙酰基)-1-哌嗪基]甲基}-3H-喹唑啉-4-酮)(SW V-49s)
中间体1A.N-9-苯甲基-9-氮杂双环[3.3.1]壬-3α-醇(2)。
在冰浴中冷却LiAlH(o-tert-Bu)3(20.0g,78.5mmol)于无水THF(30mL)中的混合物。逐滴添加化合物9-氮杂双环[3.3.1]壬-3-酮(1)(5.0g,21.8mmol)于无水THF(45mL)中的溶液。在室温下搅拌混合物过夜。用饱和NH4Cl水溶液中止反应。滤出固体并用THF洗涤。合并的有机层经Na2SO4干燥,过滤并蒸发至干,得到呈浅黄色油状的N-9-苯甲基-9-氮杂双环[3.3.1]壬-3α-醇(4.8g,95%产率)。1H NMR(CDCl3)δ7.20-7.35(m,5H),4.22-4.32(m,.1H),3.79(s,2H),3.02-3.06(m,2H),2.33-2.43(m,2H),2.12-2.26(m,1H),1.85-1.99(m,3H),1.30-1.54(m,3H),1.08-1.13(m,2H)。
中间体1B.N-(9-苯甲基-9-氮杂双环[3.3.1]壬-3α-基)-N’-(2-甲氧基-5-甲基-苯基)氨基甲酸酯(3)
在室温下,将中间体1A(4.8g,20.6mmol)、异氰酸2-甲氧基-5-甲基苯酯(3.8g,23.5mmol)、二乙酸二丁基锡(几滴)于CH2Cl2(45ml)中的混合物搅拌过夜。用水、饱和NaHCO3水溶液及盐水洗涤反应混合物,然后经Na2SO4干燥。减压去除溶剂并且残余物通过硅胶柱色谱法(己烷/乙酸乙酯/三乙胺,80∶20∶1)纯化,得到呈白色固体状的N-(9-苯甲基-9-氮杂双环[3.3.1]壬-3α-基)-N’-(2-甲氧基-5-甲基-苯基)氨基甲酸酯(6.8g,83%产率)。1H NMR(CDCl3)δ7.97(s,1H),7.16-7.37(m,6H),6.73-6.80(m,2H),5.22-5.30(m,1H),3.84(s,3H),3.81(s,2H),3.04-3.07(m,2H),2.42-2.52(m,2H),2.30(s,3H),1.91-2.20(m,3H),1.48-1.56(m,3H),1.15-1.18(m,2H)。
中间体1C.O-(9-氮杂双环[3.3.1]壬-3α-基)-N-(2-甲氧基-5-甲基苯基)-氨基甲酸酯(4)。
向中间体1B(6.8g,17.3mmol)于甲醇/乙酸乙酯(1∶1,160mL)中的溶液中添加20%w/w的氢氧化钯/碳(1.35g)和甲酸铵(5.4g,86.5mmol)。使混合物回流6小时,冷却,经由硅藻土垫过滤并蒸发。将所得残余物溶解于乙酸乙酯中,用饱和NaHCO3水溶液、水及盐水洗涤,然后经Na2SO4干燥。去除溶剂,得到呈浅褐色油状的脱保护的双环胺O-(9-氮杂双环[3.3.1]壬-3α-基)-N-(2-甲氧基-5-甲基苯基)-氨基甲酸酯4(定量)。1H NMR(CDCl3)δ7.94(s,1H),7.16(s,1H),6.73-6,80(m,2H),4.96-5.04(m,1H),3.84(s,3H),3.33-3.36(m,2H),2.33-2.41(m,2H),2.30(s,3H),2.06-2.14(m,1H),1.45-1.75(m,8H)。
中间体1D.N-(9-(6-氨基己基)-9-氮杂双环[3.3.1]壬-3α-基)-N’-(2-甲氧基-5-甲基-苯基)氨基甲酸酯(6a)。
将来自中间体1C的仲胺(3.3g,11.0mmol)、N-(6-溴己基)邻苯二甲酰亚胺(3.5g,11.3mmol)、KI(2.0g,12.4mmol)及K2CO3(7.8g,56.5mmol)于乙腈(90mL)中的混合物在回流下搅拌过夜。过滤后,在真空中蒸发挥发性组分。所得残余物通过硅胶柱色谱法(5%甲醇于二氯甲烷中)纯化,得到呈浅褐色油状的所希望的中间体受邻苯二甲酰亚胺基保护的胺5a(5.8g,96%产率)。
使化合物5a(2.8g,5.3mmol)与水合肼(540mg,10.7mmol)一起于乙醇(100mL)中回流5小时。蒸发溶剂并添加10%的NaOH水溶液(20mL)。用CH2Cl2萃取混合物,经Na2SO4干燥并蒸发,得到呈浅黄色油状的所希望的伯胺N-(9-(6-氨基己基)-9-氮杂双环[3.3.1]壬-3α-基)-N’-(2-甲氧基-5-甲基-苯基)氨基甲酸酯6a(1.9g,88%产率)。1H NMR(CDCl3)δ7.96(s,1H),7.14(s,1H),6.72-6.80(m,2H),5.10-5.18(m,1H),3.84(s,3H),3.05-3.07(m,2H),2.66-2.71(m,2H),2.55-2.59(m,2H),2.39-2.49(m,2H),2.29(s,3H),2.10-2.20(m,1H).1.81-1.94(m,2H),1.18-1.54(m,15H)。
中间体1E.2-(4-甲酰基苯氧基)乙酸乙酯(7)。
将2-溴乙酸乙酯(3.7g,22.0mmol)和碳酸钾(8.3g,60.0mmol)添加至4-羟基苯甲醛(2.4g,20.0mmol)于乙腈(60mL)中的溶液中。使反应混合物回流24小时。冷却后,过滤反应混合物,并蒸发,得到呈浅黄色液体状的2-(4-甲酰基苯氧基)乙酸乙酯(定量)。1H NMR(CDCl3)δ9.90(s,1H),7.85(d,J=8.4Hz,2H),7.01(d,J=8.4Hz,2H),4.71(s,2H),4.28(q,J=7.1Hz,2H),1.31(t,J=7.1Hz,3H)。
中间体1F.2-(4-甲酰基苯氧基)乙酸(8)。
在甲醇/水(2∶1,90mL)中,用氢氧化钠(2.2eq)水解中间体1E达24小时,随后用10%HCl溶液酸化,得到呈灰白色固体状的2-(4-甲酰基苯氧基)乙酸(3.1g,87%产率)。1HNMR(DMSO-d6)δ13.18(br s,1H),9.91(s,1H),7.89(d,J=8.6Hz,2H),7.13(d,J=8.6Hz.2H),4.86(s,2H)。
中间体1G.2-(2-氯乙酰胺基)苯甲酸(9)。
将三乙胺(4.06g,40.1mmol)添加至2-氨基苯甲酸(5.0g,36.5mmol)于二氯甲烷(90mL)中的溶液中,并在冰浴中冷却该混合物。逐滴添加氯乙酰氯(4.5g,40.1mmol)于二氯甲烷(40mL)中的溶液并在环境温度下,使混合物搅拌过夜。过滤固体并依序用冷水和含5%乙醚的己烷洗涤,并且空气干燥,得到呈白色固体状的2-(2-氯乙酰胺基)苯甲酸(7.4g,95%产率)。1H NMR(DMSO-d6)δ11.82(s,1H),8.52(d,J=7.5Hz,1H).8.01(d,J=7.5Hz,1H),7.63(t,J=7.5Hz,1H),7.21(t,J=7.5Hz,1H),4.45(s,2H)。
中间体1H.2-(氯甲基)-3-(2-乙氧基苯基)喹唑啉-4(3H)-酮(10)。
将磷酰氯(6.5g,42.4mmol)逐滴添加至中间体1G(3.1g,14.5mmol)和2-乙氧基苯胺(2.0g,14.5mmol)于乙腈(50mL)中的混合物中。在回流下加热混合物过夜。将反应混合物冷却至室温,倒入冰/饱和Na2CO3溶液的浆液中。过滤所得固体,用水洗涤并空气干燥,得到呈褐色固体状的2-(氯甲基)-3-(2-乙氧基苯基)喹唑啉-4(3H)-酮(10)(2.5g,53%产率)。1H NMR(CDCl3)δ8.31(d,J=7.8Hz,1H),7.78-7.82(m,2H),7.47-7.55(m,2H),7.35(d,J=7.4Hz,1H),7.06-7.14(m,2H),4.35(d,J=11.9Hz,1H),4.17(d,J=11.9Hz,1H),4.06(q,J=6.9Hz,2H),1.23(t,J=6.9Hz,3H)。
中间体1L.3-(2-乙氧基苯基)-2-(哌嗪-1-基-甲基)喹唑啉-4(3H)-酮(11)。
将哌嗪(2.7g,32.0mmol)添加至中间体1H(2.5g,8.0mmol)、K2CO3(4.4g,32.0mmol)及KI(1.7g,10.4mmol)于乙腈(75mL)中的混合物中。在85-90℃下,将反应混合物加热过夜。冷却后,将其过滤并用乙腈洗涤固体。蒸发合并的有机层。使所得残余物分散于水中并用乙酸乙酯萃取。用盐水洗涤有机层,经Na2SO4干燥,过滤并蒸发。粗残余物通过柱色谱法(10%甲醇、0.5%NH4OH于二氯甲烷中)纯化,得到呈黄色油状的3-(2-乙氧基苯基)-2-(哌嗪-1-基-甲基)喹唑啉-4(3H)-酮(2.3g,79%产率)。1H NMR(CDCl3)δ8.30(d,J=7.8Hz,1H),7.75-7.77(m,2H),7.39-7.50(m,2H),7.28(d,J=7.0Hz,1H),7.01-7.08(m,2H),4.05(q,J=6.8Hz,2H),3.18-3.28(m,2H),2.73(s,4H),2.33-2.37(m,2H),2.17-2.20(m,2H),1.22(t,J=6.8Hz,3H)。
中间体1J.4-(2-(4-((3-(2-乙氧基苯基)-4-氧代-3,4-二氢喹唑啉-2-基)甲基)-哌嗪-1-基)-2-氧代乙氧基)苯甲醛(12)。
将酸8(360mg,2.0mmol)、N-羟基琥珀酰亚胺(280mg,2.4mmol)于乙腈(12mL)中的冷却的混合物添加至DCC(500mg,2.4mmol)于乙腈(4mL)中的溶液中。在室温下搅拌45分钟后,添加中间体H(800mg,2.2mmol)于乙腈(10mL)中的溶液,随后继续搅拌过夜。滤出固体并蒸发滤液。所得残余物通过柱色谱法(8%甲醇于二氯甲烷中)纯化,得到呈灰白色固体状的4-(2-(4-((3-(2-乙氧基苯基)-4-氧代-3,4-二氢喹唑啉-2-基)甲基)-哌嗪-1-基)-2-氧代-乙氧基)苯甲醛(847mg,80%产率)。1H NMR(CDCl3)δ9.89(s,1H),8.27-8.31(m,1H),7.72-7.84(m,4H),7.42-7.52(m,2H),7.25(d,J=6.3Hz,1H),7.02-7.09(m,4H),4.74(s,2H),4.05(q,J=7.0Hz,2H),3,42-3.49(m,4H),3.22-3.31(m,2H),2.18-2.46(m,4H),1.22(t,J=7.0Hz,3H)。
9-(6-((4-(2-(4-((3-(2-乙氧基苯基)-4-氧代-3,4-二氢喹唑啉-2-基)甲基)-哌嗪-1-基)-2-氧代乙氧基)苯甲基)氨基)己基)-N-(9-氮杂双环[3.3.1]壬-3α-基)-N-(2-甲氧基-5-甲基苯基)氨基甲酸酯草酸盐(SW V-49s)。
将胺中间体1D(6a)(386mg,0.95mmol)于二氯甲烷(4mL)中的溶液添加至中间体1J(12)(480mg,0.91mmol)于二氯甲烷(4mL)中的溶液中。搅拌混合物4小时,然后蒸发溶剂。将残余物溶解于乙醇(5mL)中,然后添加NaBH4(100mg,2.6mmol)。搅拌混合物6小时,随后用10%HCl溶液中止。蒸发溶剂后,将其用10%NaOH溶液碱化,用二氯甲烷萃取并蒸发。所得残余物通过柱色谱法(10%甲醇、0.5%NH4OH于二氯甲烷中)纯化,得到呈游离胺形式的产物(460mg,55%产率)。1H NMR(CDCl3)δ8.30(d,J=7.8Hz,1H),7.94(s,1H),7.74-7.78(m,2H),7.41-7.51(m,2H),7.23-7.26(m,3H),7.14(s,1H),7.03-7.09(m,2H),6.86(d,J=8.6Hz,2H),6.73-6.79(m,2H),5.10-5.16(m,1H),4.62(s,2H),4.04(q,J=6.9Hz,2H),3.85(s,3H),3.74(s,2H),3.43-3.48(m,4H),3.22-3.30(m,2H),3.12(br s,2H),2.60-2.64(m,4H),2.37-2.50(m,4H),2.29(s,3H),2.19-2.25(m,3H),1.90-1.96(m,2H),1.48-1.58(m,7H),1.28-1.34(m,6H),1.22(t,J=6.9Hz,3H)。使用1当量草酸在乙醇中制备草酸盐,得到呈灰白色固体状的SW V-49s(470mg,93%产率)。熔点164-165℃。分析(C55H69N7O11·2H2O):计算值,%:C 63.51,H 7.07,N 9.43;实验值,%:C 63.54,H 7.06,N 9.76。
实施例2:3-(邻乙氧基苯基)-2-{[4-(2-(对-[(10-{3-(2-甲氧基氨基甲苯羰氧基)-9-氮杂双环[3.3.1]壬-9-基}癸基氨基)甲基]苯氧基)乙酰基)-1-哌嗪基]甲基}-3H-喹唑啉-4-酮)草酸盐(SW V-50s)
中间体2A.N-(9-(10-氨基癸基)-9-氮杂双环[3.3.1]壬-3α-基)-N’-(2-甲氧基-5-甲基苯基)氨基甲酸酯(6b)。
在回流下,将来自中间体1C的仲胺(3.6g,11.8mmol)、N-(10-溴癸基)邻苯二甲酰亚胺(4.4g,12.0mmol)、KI(2.0g,12.4mmol)及K2CO3(8.2g,59.4mmol)于乙腈(90mL)中的混合物搅拌过夜。过滤后,在真空中蒸发挥发性组分。所得残余物通过硅胶柱色谱法(5%甲醇于二氯甲烷中)纯化,得到呈浅褐色油状的所希望的受邻苯二甲酰亚胺基保护的中间体5b(6.0g,86%产率)。
使化合物5b(2.9g,4.9mmol)与水合肼(700mg,13.9mmol)一起于乙醇(100mL)中回流5小时。蒸发溶剂并添加10%的NaOH水溶液(20mL)。用CH2Cl2萃取混合物,经Na2SO4干燥并蒸发,得到呈浅黄色油状的伯胺N-(9-(10-氨基癸基)-9-氮杂双环[3.3.1]壬-3α-基)-N’-(2-甲氧基-5-甲基苯基)氨基甲酸酯6b(2.2g,95%产率)。1H NMR(CDCl3)δ7.96(s,1H),7.14(s,1H),6.72-6.80(m,2H),5.10-5.18(m,1H),3.84(s,3H),3.04-3.07(m,2H),2.65-2.70(m,2H),2.53-2.58(m,2H),2.39-2.49(m,2H),2.29(s,3H),2.08-2.20(m,1H),1.83-1.94(m,2H),1.18-1.54(m,23H)。
将胺中间体2A(343mg,0.74mmol)于二氯甲烷(4mL)中的溶液添加至12(380mg,0.72mmol)于二氯甲烷(4mL)中的溶液中。搅拌混合物4小时,然后蒸发溶剂。将残余物溶解于乙醇(5mL)中,然后添加NaBH4(100mg,2.6mmol)。搅拌混合物6小时,随后用10%HCl溶液中止。蒸发溶剂后,将其用10%NaOH溶液碱化,用二氯甲烷萃取并蒸发。所得残余物通过柱色谱法(10%甲醇、0.5%NH4OH于二氯甲烷中)纯化,得到呈游离胺形式的产物(295mg,42%产率)。1H NMR(CDCl3)δ8.29(d,J=7.8Hz,1H),7.95(s,1H),7.73-7.78(m,2H),7.41-7.51(m,2H),7.21-7.24(m,3H),7.14(s,1H),7.02-7.08(m,2H),6.86(d,J=8.2Hz,2H),6.73-6.79(m,2H),5.10-5.16(m,1H),4.61(s,2H),4.04(q,J=6.9Hz,2H),3.84(s,3H),3.72(s,2H),3.44-3.48(m,4H),3.21-3.31(m,2H),3.09(br s,2H),2.59-2.62(m,4H),2.36-2.50(m,4H),2.29(s,3H),2.17-2.24(m,3H),1.88-1.94(m,2H),1.40-1.57(m,7H),1.24-1.30(m,6H),1.21(t,J=6.9Hz,3H)。使用1当量草酸在乙醇中制备草酸盐,得到呈浅褐色固体状的SW V-50(308mg,95%产率),熔点183-184℃。分析(C59H77N7O11·2H2O):计算值,%:C64.64,H 7.45,N 8.94;实验值,%:C 64.84,H 7.41,N 8.62。
表1.双结构域σ-2受体配体药物缀合物化合物,包括σ-2受体配体埃拉汀缀合物化合物和σ-2受体配体埃拉汀类似物缀合物化合物的另外的实例。
生物活性分析
以下分析可以用于评价式(I)化合物的生物功效。
本文所描述的方法和组合物利用了熟练技术人员众所周知的实验室技术,并且可以见于实验室手册,如Sambrook,J.等人,Molecular Cloning:A Laboratory Manual,第3版,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY,2001;Spector,D.L.等人,Cells:A Laboratory Manual,Cold Spring Harbor Laboratory Press,ColdSpring Harbor,NY,1998;Nagy,A.,Manipulating the Mouse Embryo:A LaboratoryManual(第三版),Cold Spring Harbor,NY,2003;Harlow,E.,Using Antibodies:ALaboratory Manual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY,1999;及Carruthers,W.,和Coldham,I.,Modern Methods of Organic Synthesis(第4版),Cambridge University Press,Cambridge,U.K.,2004。药物的施用方法及剂量方案可以根据熟练技术人员众所周知的标准药理学原理,使用如Remington:the Science andPractice of Pharmacy(Alfonso R.Gennaro编,第19版,1995);Hardman,J.G.等人,Goodman&Gilman′s The Pharmacological Basis of Therapeutics,第九版,McGraw-Hill,1996;及Rowe,R.C.等人,Handbook of Pharmaceutical Excipients,第四版,Pharmaceutical Press,2003等标准参考书提供的方法来测定。如本说明和所附权利要求书中所使用,单数形式“一个(种)”和“所述”意图也包括复数形式,除非上下文另作指示。
毒性研究方法
将六只成年雌性小鼠送去尸检。这些小鼠的品系名称是C57BL/6。先前的程序包括在2周时间内每日腹膜内施用铁死亡诱导药物或媒介物对照。另外,预先对小鼠皮下移植KCKO异种移植物(Besmer,D.M.等人,Cancer Res.17:4432-4442,2011)。
细胞系
CFPAC-1、BxPC-3、AsPC-1、PANC-1及Mia PaCa-2细胞系是从美国典型培养物保藏中心(ATCC,Manasas,VA)获得。SYO-1细胞系,一种滑膜肉瘤细胞系(Kawai,A.等人,CancerLett 204:105-113,2004)是由Brian Van Tine博士(Washington University School ofMedicine,St.Louis,MO)提供。KCKO细胞系是从表达人MUC1的转基因小鼠的胰腺肿瘤分离(Besmer等人,Cancer Research 2011;71:4432-4442;Tinder等人,J Immunol 2008;181:3116-3125)。KCKO细胞系是由Pinku Mukherjee博士(University of North Carolina,Charlotte,NC)提供。PANC-1细胞在含有4mM L-谷氨酰胺、1.5g/L碳酸氢钠及10%胎牛血清(FBS)的Dulbecco改良型Eagle培养基中培养。Mia PaCa-2细胞系是在含10%FBS和2.5%马血清的Dulbecco改良型Eagle培养基中培养。BxPC-3、AsPC-1及KCKO细胞系是在含10%FBS的RPMI-1640培养基中培养。SYO-1滑膜肉瘤细胞是在含10%FBS的Dulbecco改良型Eagle培养基中培养。向培养基中添加抗生素青霉素(100mg/ml)和链霉素(100mg/ml)并将细胞维持在37℃并含5%CO2的潮湿恒温箱中。
统计学
统计学分析和数据作图是使用第6版GraphPad Prism软件(San Diego,CA)进行。结果表示为至少3次生物重复实验的平均值±SEM。IC50值是通过拟合正规化活力随药物浓度变化的曲线来计算。使用单因素ANOVA,利用NAC和ZVAD测试分析IC50值和SW V-49s抑制作用的差异。使用不成对双尾t测试评价CBC和生物化学分析的差异,并确认胱氨酸摄取、胱天蛋白酶及ROS检测分析亚组的差异。使用双因素ANOVA分析肿瘤体积差异。使用Kaplan-Meier存活率分析并用对数秩测试比较各组之间的差异。对于所有分析,p值<0.05被认为是显著的。
尸检前检查
小鼠A(ID:732)是媒介物对照。剃除右侧腹上的被毛,其中部分再生长。在右侧腹中可触知极小的皮下增厚。未出现鼻或眼分泌物或腹泻。水合作用和体脂正常。体重是21克。
小鼠B(ID:727)用测试药物处理。剃除右侧腹上的被毛,其中部分再生长。在腰脊柱上观察到1.5×0.6cm大小的皮下肿块,并且紧密地粘附于下伏的肌肉组织中。在此肿块上覆的皮肤中观察到4-5mm直径的渍疡。未出现鼻或眼分泌物或腹泻。水合作用和体脂正常。体重是21克。
小鼠C(ID:735)是媒介物对照。在此动物中观察到后部麻痹,并且拖拽后肢。深部痛觉反应可以从左后腿引起,但不从右后腿引起。使右侧腹上的被毛略微变薄。在腰脊柱上观察到坚硬的皮下肿块。此肿块牢固地附着于下伏组织。在右侧腹上观察到0.2-0.3cm直径的皮肤增厚,其内是0.1cm直径的溃疡。未出现鼻或眼分泌物或腹泻。水合作用和体脂正常。体重是20克。
小鼠D(ID:737)用测试药物处理。在脊柱上可触知皮下肿块。被毛正常。未出现鼻或眼分泌物或腹泻。水合作用和体脂正常。体重是19克。
小鼠E(ID:746)是媒介物对照。剃除右侧腹上的被毛,其中部分再生长。在右侧腹中观察到0.6cm直径的坚硬皮下结节。未出现鼻或眼分泌物或腹泻。水合作用和体脂正常。体重是23克。
小鼠F(ID:738)用测试药物处理。被毛正常。在腰脊柱上方可触知坚硬的皮下肿块。脊柱易于触知,表明可能发生肌肉消瘦。未出现鼻或眼分泌物或腹泻。水合作用和体脂正常。体重是22克。
肉眼尸检检查
关于小鼠A,在尸检前检查时观察到的皮下增厚是0.5×0.1cm大小的坚硬肿块。不受理论限制,在靠近远端结肠的肠系膜中观察到的0.4×0.1cm增厚区域可能是淋巴结增大的结果。在左肺中观察到2mm直径的发红病灶。心脏和肝脏轻微泛白。在肠道、肌肉骨骼系统、泌尿系统、生殖系统、脑、胸腺、脾、肾上腺、甲状腺、垂体、中耳或眼中无肉眼病变。
关于小鼠B,皮下肿块是具有多小叶的,并且大小是1.8×0.6cm,附有1.0cm直径结节。皮下肿块位于皮下腰脊柱和右侧背上方。脊柱中未发生浸润。该肿块向腹侧突出,碰撞腹部。肝脏略微泛白。心脏轻微泛白。在呼吸系统、肠道、泌尿系统、生殖系统、脑、胸腺、脾、淋巴结、肾上腺、甲状腺、垂体、中耳或眼中无肉眼病变。
关于小鼠C,皮下肿块大小是1.8×1.7×1.5cm并且看来覆盖中部腰脊柱。肿块呈浅棕褐色、坚硬并且略带结节。心脏和肝脏轻微泛白。在呼吸系统、肠道、泌尿系统、生殖系统、脑、胸腺、脾、淋巴结、肾上腺、甲状腺、垂体、中耳或眼中无肉眼病变。
关于小鼠D,皮下肿块大小是1.2×0.8cm并且覆盖腰脊柱。不受理论束缚,椎骨的背部棘状突起可能被肿瘤侵蚀。肝脏轻微泛白。在呼吸系统、肠道、泌尿系统、生殖系统、心脏、脑、胸腺、脾、淋巴结、肾上腺、甲状腺、垂体、中耳或眼中无肉眼病变。
关于小鼠E,肺呈斑点状红色。肝脏略微泛白。在肠道、肌肉骨骼系统、泌尿系统、生殖系统、心脏、脑、胸腺、脾、淋巴结、肾上腺、甲状腺、垂体、中耳或眼中无肉眼病变。
关于小鼠F,在皮肤和皮下组织中观察到两个肿块。一个大小是0.5×0.5×0.3cm并且位于皮肤中,而另一个大小是0.5×0.5×0.2cm并且在皮下组织中,上覆腰脊柱。在呼吸系统、肠道、泌尿系统、生殖系统、心脏、脑、胸腺、脾、淋巴结、肾上腺、甲状腺、垂体、中耳或眼中无肉眼病变。
组织病理学检查.
关于小鼠A,在包括巨噬细胞、嗜中性粒细胞、淋巴细胞及浆细胞的肠系膜脂肪中观察到轻微的多灶性炎症性浸润。观察到反应性肠系膜淋巴结,伴随的淋巴样增生、组织细胞增多及髓窦扩张。在不受理论束缚情况下,在一个肺叶中观察到的中度灶性出血可能与CO2安乐死有关。在脑、心脏、肝脏、肾脏、脾、胰脏或胃肠道中无明显病变。
关于小鼠B,在肠系膜中并且沿小肠道和大肠道及胃以及在胰脏周围观察到轻度至中度慢性腹膜炎。这以巨噬细胞、嗜中性粒细胞、淋巴细胞及浆细胞的浸润以及纤维化区域为特征。在回肠中观察到轻度粘膜增生。如先前所描述,位于胰脏附近的肠系膜淋巴结具有反应性。在胰实质内未观察到病变。在胆囊周围以及沿右肾小囊表面观察到轻度腹膜炎。在肝脏或肾脏中未观察到其它病变。沿脾观察到轻度囊性增厚和间皮细胞性增生。在脾髓中出现髓外红细胞生成的中度增加。在脑、心脏或肺中无明显病变。
关于小鼠C,肺检查揭露原发肿瘤的几个小转移灶。不受理论限制,原发肿瘤看来侵袭到骨骼,因为在肿块内观察到较小骨骼片段。在脑、心脏、肝脏、肾脏、脾、胰脏或胃肠道中无明显病变。
关于小鼠D,沿胃、小肠的浆膜表面以及在胰脏周围观察到微小至轻度慢性腹膜炎,并且如先前所述,存在炎性细胞和纤维化区域。沿肝脏和肾脏的囊性表面也观察到腹膜炎病灶。在胃肠道、胰脏、肝脏及肾脏中未观察到其它病变。在脾中,出现髓外红细胞生成的中度增加。在一个肺叶中观察到2个较小的化脓性肉芽肿病灶。其病因未知;未观察到相关外来物质。肿瘤明显侵入腰部肌肉组织。肿瘤细胞还紧密接近椎体并且包围较小骨骼片段,不受理论限制,推测此表示椎体的背部棘状突起。在脑或心脏中无明显病变。
关于小鼠E,在肠系膜脂肪中,出现微小至轻度巨噬细胞、淋巴细胞、嗜中性粒细胞及浆细胞浸润。如先前所描述,在胰脏附近观察到轻度反应性淋巴结。在脑、心脏、肺、肝脏、肾脏、胰脏、脾或胃肠道中未观察到明显病变。
关于小鼠F,如先前所描述,沿肠道浆膜表面并且在胰脏周围的肠系膜中观察到轻度慢性腹膜炎。在一个胰小叶中出现腺细胞损失及巨噬细胞和成纤维细胞替代,这可能表示在肠系膜中观察到的反应的扩展。在肾小囊上及肾脏周围的肠系膜中也观察到轻度腹膜炎。在肠道、肝脏及肾脏中未观察到其它病变。在脾中,出现髓外红细胞生成和粒细胞生成的中度增加。在脑、心脏、肺或胃中无肉眼病变。
血液学检验
药物处理的动物与对照动物之间的差异是在药物处理的动物中,沿肠道和腹部器官的浆膜表面以及在胰脏周围的肠系膜中微小至中度慢性腹膜炎的存在。而对照动物在肠系膜中显示微小至轻度多灶性炎性浸润,无纤维组织增生。其它发现包括在小鼠C中观察到的ALT和AST升高。不受理论限制,此发现的病因尚不明了。正如所预期的,无肝细胞损伤的组织学证据。不受理论限制,其它可能原因包括血液样品的溶血,或由肿瘤侵袭引起的骨骼损伤。
在小鼠C中,肿瘤侵入腰部肌肉组织中,并出现骨骼片段化,不受理论限制,这可能与椎体突起的情形相同,并且发生肺转移。在小鼠D中,肿瘤侵入腰部肌肉组织中并且背部棘状突起片段化。
表2:全血细胞计数结果
*观察到轻度血小板凝块。
表3:差异结果
表4:临床化学结果
化合物SW V-49s的σ-2受体结合特性
在这些实验中,在以下结构的荧光标记的σ-2配体SW120存在下,对SW V-49s进行竞争性结合分析:
将AsPC-1细胞(5×105个/孔)接种于6孔板中,保持24小时,随后进行处理。接着,在37℃下,将细胞与0、10、30及50μM的SW V-49s一起孵育30分钟。随后,向含有SW V-49s的细胞培养基中添加10nM荧光标记的σ-2配体SW120。在37℃下孵育30分钟之后,用磷酸盐缓冲生理盐水(PBS)洗涤细胞两次,并用0.05%胰蛋白酶EDTA(Life Technologies,GrandIsland,NY)收获。此后,以1000×g离心细胞5分钟,并用PBS洗涤细胞团两次。SW 120的内化通过流式细胞仪(FACSCaliburTM,BD Biosciences,San Jose,CA)测定。
图3显示在人Panc-1细胞中10μM荧光标记的SW 120的内化(Spitzer,D.等人,Cancer Res.72:201-209,2012)与SW V-49s的竞争性抑制作用。这些数据指示在递增浓度的SW V-49s存在下,SW 120内化得到有效阻断。这些结果表明,SW V-49s有效结合σ-2受体。
SW V-49s在体外对癌细胞系展现致死作用
在这些实验中,在用SW V-49s或其单独或组合的母体化合物SV 119和埃拉汀处理人和鼠胰腺癌细胞系和滑膜肉瘤细胞系24小时后进行活力分析。数据显示,SW V-49s针对人胰腺癌细胞系Panc-1(CRL-1469TM)的IC50浓度是4.3μM(图4A);SW V-49s针对人胰腺癌细胞系BxPC-3(CRL-1687TM)的IC50浓度是2.3μM(图4B);SW V-49s针对人胰腺癌细胞系MIA PaCa-2(CRL-1420TM)的IC50浓度是2.3μM(图4C);SW V-49s针对人胰腺癌细胞系AsPC-1(CRL-1682TM)的IC50浓度是3μM(图4D);及SW V-49s针对鼠胰腺癌细胞系(KCKO细胞)的IC50浓度是2.2μM(图4E)。相比之下,单独埃拉汀针对测试的所有人和鼠胰腺癌细胞系展现的IC50>100μMM;单独SV 119针对测试的所有人和鼠胰腺癌细胞系展现的IC50>54μM;并且埃拉汀与SV 119的等摩尔浓度混合物针对测试的所有人和鼠胰腺癌细胞系展现的IC50>44μM。
滑膜肉瘤细胞系(图4F,SYO-1,ME1缺陷型)对SW V-49s如此敏感以致难以测量杀伤50%的癌细胞所需的最低药物浓度,但测量的IC50是约1.0μM。相比之下,测试的其它化合物针对滑膜肉瘤细胞的IC50如下:埃拉汀,>16μM;SV 119,6.2μM;埃拉汀+SV119,4.9μM。
这些数据表明,SW V-49s针对癌细胞,包括人和鼠胰腺癌细胞和滑膜肉瘤细胞的致死作用远高于其单独或组合的组分母体化合物。
SW V-49s的双重功能
在这些实验中,本发明人研究了本教导的化合物是通过触发细胞凋亡性细胞死亡途径、铁死亡性细胞死亡途径还是其组合而对胰腺癌细胞产生致死作用。本发明人因此进行了以胱天蛋白酶3/7作为细胞凋亡性细胞死亡的指示的分析,及以活性氧物质(ROS)的产生作为铁死亡性细胞死亡的指示的分析。如图5A中所示,用50μM埃拉汀、SV 119或埃拉汀加SV 119的等摩尔浓度混合物处理AsPC-1细胞24小时所引起的胱天蛋白酶活性远低于4μM的SW V-49s。在图5B中,显示了用8μM SW V-49s、8μM埃拉汀、8μM SV 119或8μM埃拉汀与SV119的等摩尔浓度混合物处理Aspc-1细胞7小时的(Promega)分析的结果。相较于所有对照,用SW V-49s处理的细胞中胱天蛋白酶3/7活性显著增加(约3倍),*p<0.0001。
在图6中,显示了用8μM 8μM SW V-49s、8μM埃拉汀、8μM SV 119或8μM埃拉汀与SV119的等摩尔浓度混合物,或阳性对照处理Aspc-1细胞30分钟的活性氧物质(ROS)分析的结果。相较于所有埃拉汀、SV 119或其组合,用SW V-49s处理的细胞中ROS胱天蛋白酶显著(50%)增加,*p<0.0001,与铁死亡性细胞死亡相符。用于细胞的单独或组合的母体化合物SV 119和埃拉汀在相同浓度下没有影响。
不受理论限制,这些数据表明,SW V-49s在胰腺癌细胞中同时诱导细胞凋亡性和铁死亡性细胞死亡途径。
施用SW V-49s可以在体内减小胰腺肿瘤大小
图7示出在向带有确定的同基因皮下KCKO鼠胰腺肿瘤的C57BL/6小鼠施用10天的SW V-49s、埃拉汀、SV119、埃拉汀与SV119的混合物及媒介物对照之后平均肿瘤体积(以mm3表示)的变化。SW V-49s处理引起肿瘤体积的显著减小,但其它处理则不然(p<0.05)。这些处理引起极小脱靶效应。在图7中观察到,在SW V 49s处理的小鼠中肿瘤体积从约40mm3减小到约20mm3,而其它处理从约40mm3增加至约140mm3。
在鼠模型系统中施用SW V-49s可以增加胰腺癌的存活率
在这些实验中,在实施例9中所报导的小鼠存活率研究中,接受SW V-49s的组100%存活(图8)。在所有其它组中,平均存活期集中在约18天。
SW V-49s诱导胰腺癌的细胞死亡
利用发光细胞活力分析(Promega,Madison,WI)评价药物的细胞毒性。将胰腺细胞系以2×104个/孔的密度涂铺于底部透明的白色96孔板中,保持24小时,随后处理。将药物溶解于DMSO中并在培养基中连续稀释以使DMSO的最终浓度低于1%。接着,处理细胞24小时,并向每个孔中添加100μl试剂。施用回转式振荡器混合板的内含物,随后在室温下孵育10分钟。使用多模式微量板读取器(BioTekinstruments,Winooski,VT)测量发光信号。一式三份分析不同药物浓度。为了评价药物的功效,在体外计算化合物针对一组人和鼠来源的胰腺癌细胞系的IC50。用SW V-49s、SV119、埃拉汀及SV119与埃拉汀的等摩尔浓度混合物处理细胞24小时,随后进行活力分析。埃拉汀是活性最低的化合物,并且IC50>150μM。SV119展现适度功效,该功效因添加埃拉汀而增大。然而,SW V-49s显示稳健的细胞毒性,并且IC50相较于用SV119与埃拉汀的等摩尔浓度混合物处理有17-20倍减小(表4和图9)。这些结果表明,SW V49s选择性递送至胰腺癌细胞中。
表5.用不同化合物处理胰腺细胞系24小时的IC50(μM).
(平均值±SEM)。n≥3。P<0.05
由于埃拉汀在所有胰腺细胞系中未展现作用,故本发明人使用SYO-1细胞进行质量控制实验。将AsPC-1和SYO-1细胞涂铺于96孔板中过夜,然后用类似浓度的埃拉汀处理24小时。24小时后进行活力分析。用40μM埃拉汀处理引起84%的SYO-1细胞死亡,与AsPC-1细胞的2%形成对比(p<0.0001)(图10)。本实验证实,所用埃拉汀具有生物活性并且胰腺细胞系对埃拉汀具有抗性。
SW V-49s抑制胱氨酸摄取并产生活性氧物质
在这些实验中,如先前所描述(Dixon,S.J.等人,Cell 2012;149:1060-1072)进行胱氨酸摄取分析。简单点说,将5×105个AsPC-1细胞/孔接种于6孔板中过夜。次日,细胞在预先加温的无Na+摄取缓冲液(137mM胆碱氯化物、3mM KCl、1mM CaCl2、1mM MgCl2、5mM D-葡萄糖、0.7mM K2HPO4及10mM HEPES[pH 7.4])中洗涤两次。随后,在37℃下,细胞在1ml摄取缓冲液中孵育10分钟以耗尽细胞氨基酸。用600μl含有200μM SW V-49s和0.12μCi(80-110mCi/mmol)L-[3,3′-14C]-胱氨酸(American Radiolabeled Chemicals,St Louis,MO)的摄取缓冲液更换该缓冲液,并在37℃下孵育3分钟。之后,用冰冷的摄取缓冲液洗涤细胞三次,并将其溶解于500μl的0.1M NaOH中。向此溶解产物中添加1ml闪烁液,并通过使用闪烁计数器获得每分钟的放射性计数。
经显示,埃拉汀通过抑制胱氨酸/谷氨酸反向转运体(系统xc -),引起ROS依赖性细胞死亡来阻断胱氨酸摄取(Dixon等人,Cell 2012:149:1060-1072)。为了评价此机制,将AsPC-1细胞涂铺于6孔板中,保持24小时。接着用相同浓度的SV119、埃拉汀、SV119与埃拉汀的组合、SW V-49s及作为对照的DMSO处理细胞。随后,进行胱氨酸摄取分析。用SW V-49s处理的细胞展现胱氨酸摄取减少85%(比半胱氨酸摄取低3.7倍),与用SV119、埃拉汀及SV119与埃拉汀的组合处理的细胞各自的25%、41%及44%减少形成对比(p=0.004,图11A)。
使用总ROS/过氧化物检测试剂盒(Enzo life sciences,Farmingdale,NY),根据制造商的说明测量ROS。简单点说,将AsPC-1细胞以2×104个细胞/孔的密度接种于黑色壁、透明底的96孔板中,保持24小时。将化合物溶解于DMSO中并在培养基中稀释以使DMSO的最终浓度低于1%。用8μM SV119、埃拉汀及SV119与埃拉汀的等膜浓度混合物处理AsPC-1细胞。处理一小时后进行ROS分析。处理细胞一小时,随后去除培养基并添加100μL/孔ROS/过氧化物检测混合物。使用多模式微量板读取器(Bio-Tek,Winooski,VT)测量荧光信号。该分析是一式六份进行。
用SW V-49s处理的细胞的ROS水平比其它高1.5倍。在用该浓度的SV119、埃拉汀及SV119与埃拉汀的等摩尔浓度混合物处理的细胞中ROS水平没有增加(图11B,p<0.0001)。
化合物SW V-49s可以诱导固有的细胞凋亡途径
在这些实验中,使用相应的分析,根据制造商的说明(Promega,Madison,WI)测量AsPC-1细胞中胱天蛋白酶-3/7、8及9的活性。本分析是基于胱天蛋白酶特异性底物,该底物被裂解而释放氨基荧光素,这是荧光素酶的底物,会产生胱天蛋白酶特异性发光信号。将细胞以2×104的密度接种于底部透明的白色96孔板中,保持24小时,随后用4μM化合物处理。然后,使用板振荡器混合内含物30秒,随后在室温下孵育90分钟。使用多模式微量板读取器(BioTek)测量法光信号。分析是以一式三份进行,并且DMSO的胱天蛋白酶活性视为基线。
本发明人显示,SV119诱导胱天蛋白酶-3依赖性细胞凋亡(Kashiwagi,H.等人,MolCancer 2007;6:48)。在这些实验中,用4μM SW V-49s、SV119、埃拉汀及SV119与埃拉汀的等摩尔浓度混合物处理AsPC-1细胞24小时。使用分析,测量胱天蛋白酶-3水平以评估SW V-49s化合物的SW119结构域的活性,并测量胱天蛋白酶-8和胱天蛋白酶-9的水平以鉴别所涉及的细胞凋亡途径。用SW V-49s处理的细胞中胱天蛋白酶-3和胱天蛋白酶-9有显著增加(分别高于基线3.4倍和3.2倍,***p<0.001,分别是图12A和图12B)。相比之下,胱天蛋白酶8无显著增加,ns>0.5(图12C)。其它测试化合物在类似浓度下不活化任何胱天蛋白酶(图12A-C)。这些结果表明,SW V-49s可以选择性递送至癌细胞中并且其两个结构域可以协同作用以活化固有的细胞凋亡途径。
SW V-49s可以诱导ROS和细胞凋亡依赖性细胞死亡
本发明人证实,SW V-49s可以诱导细胞凋亡和ROS产生。为了评估这两种机制对诱导细胞死亡的作用,测试了全胱天蛋白酶抑制剂和抗氧化剂对SW V-49s功效的影响。在这些实验中,用10mM抗氧化剂N-乙酰基半胱氨酸(NAC)、20μM全胱天蛋白酶抑制剂ZVAD及作为对照的DMSO对AsPC-1细胞进行预处理,持续1小时。然后,这3组用10μM的SW V-49s处理5小时,随后进行分析。结果表明,用单独SW V-49s处理的细胞的活力降低到39%,与用NAC和ZVAD预处理的细胞分别是63%和91%形成对比(图13,p<0.0001)。由此发现NAC在抑制SW V-49s活性方面更有效(图13,p<0.002)。这些数据证实了SW V-49s的双重功能并且表明它可以同时诱导细胞凋亡依赖性和ROS依赖性细胞死亡。
SW V-49s在小鼠和患者源性胰腺癌异种移植模型中减少肿瘤生长并增加存活率。
根据Washington University institutional Animal Care Facility批准的动物研究方案进行动物研究。用小鼠进行体内研究以比较SW V-49s、SV119、埃拉汀、SV119与埃拉汀的组合及媒介物的作用。在体内研究中使用的媒介物是25%克列莫佛(cremophor)与75%H2O的混合物。向C57BL/6小鼠(6周龄;National Cancer Institute Laboratories)的右侧腹中注射200μL的KCKO细胞于RPMI培养基中的单细胞悬浮液(25×104/105个细胞/小鼠)。将小鼠随机分成四组(n=15)。当平均肿瘤直径达到约5mm时,开始治疗。小鼠每天经腹膜内注射375nmol的SW V-49s以及媒介物、SV119、埃拉汀、SV119与埃拉汀的等摩尔浓度混合物,每剂100μL,持续10天。每隔一天用数显卡尺测量肿瘤。将来自不同治疗组的若干小鼠送至本协会的比较医学分会(Division of Comparative Medicine)进行病理学评价。对收集的血液进行全血细胞计数(CBC)和生化分析(AST、ALT、BUN、总胆红素及Cr)。通过肉眼和组织学方法检查各器官。
在同基因癌症模型(KCKO于C57BL/6中)中,仅SW V-49s能够减小平均肿瘤体积(图14A,p=0.0003)。单独其它试剂或其组合都不会减少肿瘤生长,并且其都与媒介物(对照)具有类似生长速率(图14A,p=0.9)。SW V49s治疗组的中值存活期是48天,与其它组的(18-21)天形成对比(图14B,Kaplan-Meier存活率曲线,p<0.001)。值得注意的是,没有关于肉眼可见的小鼠行为(梳毛)异常或任何药物相关死亡的记录。这一点得到了未改变的血清实验(CBC、AST、ALT、BUN、总胆红素及Cr)的支持(表5和6)。此外,器官分析(脑、心脏、肺、消化道、肾脏、肝脏及胰腺)除轻度腹膜炎外,未显示任何明显的不良药物作用征象。
表6:SW V-49s在治疗C57BL/6小鼠后不诱导血液细胞学(CBC)变化。
表6包含了从SW V-49s和媒介物(对照)处理10天的C57BL/6小鼠得到的CBC数据。2个组之间的细胞计数差异在统计学上不显著。
表7:SW V-49s在治疗带有肿瘤的C57BL/6小鼠之后不诱导血清化学的改变。
表7显示了用SW IV-134和媒介物(对照)处理10天的C57BL/6小鼠的生化分析。2个组之间的实验室值的差异在统计学上不显著。
另外,在临床上更相关的PDAC患者源性小鼠异种移植模型上测试SW V-49s。手术获得PDAC试样(2×2mm薄片)并将其皮下植入麻醉的NOD SCID小鼠的侧腹中。接着,收集肿瘤并植入无胸腺雌性裸小鼠(6周龄,National Cancer Institute Laboratories)的右侧腹中。每天经腹膜内注射SW IV-134和媒介物来处理这些小鼠,持续14天。小鼠随机分成2组(n=15)。当平均肿瘤直径达到约6mm时,开始药物治疗。小鼠每天经腹膜内注射375nmol的SW V-49s和媒介物,每只小鼠100μL,持续2周。每隔一天测量肿瘤。当肿瘤达到2cm直径或溃烂时,对小鼠实施安乐死。
在此模型中,SW V-49s明显减慢确定的肿瘤的生长速率(图14C,p<0.0001)。SWV-49s治疗组的中值存活期是58天,与媒介物组的33天形成对比(图14D,Kaplan-Meier存活率曲线,p=0.0002)。小鼠对治疗的耐受性良好,无明显脱靶效应。
另外,用300nmol SW V-49处理SYO-1滑膜肉瘤(SS)异种移植物。观察到SS的快速生长模型的生长抑制。图14E描绘了用SW V-49(300nmol)处理14天的无胸腺裸小鼠中的SS细胞系SYO-1的异种移植物及后续跟踪,p<0.0001。SYO异种移植物需要较小剂量的SW V-49就能达到与针对PDAC所达到的结果类似的结果。这些结果证实SW V-49s在胰腺癌和滑膜肉瘤中具有高功效并且表明其选择性递送。
其它实施方案
以上陈述的详细说明将帮助本领域技术人员实践本公开。然而,本文描述并且要求的公开内容不打算限制本文公开的具体实施方案的范围,因为这些实施方案打算作为本公开的若干方面的说明。任何等效实施方案都意图在本公开的范围内。实际上,除本文所描述和显示的那些外,本领域技术人员从前述说明将易于了解对本公开的各种修改,而这些修改不偏离本发明的发现的精神或范围。这些修改也打算在所附权利要求书的范围内。
引用的所有参考文献各自通过引用整体并入本文中。申请人有权质疑任何参考文献的作者所呈现的任何结论。
Claims (18)
1.一种具有以下结构的化合物或其盐,
其中n是1至5的整数,并且R1是H或甲基。
2.根据权利要求1所述的化合物或其盐,其中n=1并且R1是H。
3.根据权利要求1所述的化合物或其盐,其中n=5并且R1是H。
4.根据权利要求1至3中任一项所述的化合物或其盐,其中所述盐是草酸盐。
5.一种治疗癌症的方法,所述方法包括向有需要的受试者施用治疗有效量的权利要求1至3中任一项所述的化合物或其盐。
6.根据权利要求5所述的治疗癌症的方法,其中所述化合物或其盐是权利要求2所述的化合物或其盐。
7.根据权利要求5所述的治疗癌症的方法,其中所述化合物或其盐是权利要求3所述的化合物或其盐。
8.根据权利要求5至7中任一项所述的治疗癌症的方法,其中所述癌症是胰腺癌。
9.根据权利要求5至7中任一项所述的治疗癌症的方法,其中所述癌症是滑膜肉瘤。
10.一种合成权利要求1所述的化合物的方法,所述方法包括使结构的化合物与结构的化合物反应,其中n是1至5的整数,并且R1是甲基或H。
11.根据权利要求10所述的方法,其中n=1并且R1是H。
12.根据权利要求10所述的方法,其中n=5并且R1是H。
13.根据权利要求1所述的化合物或其盐,所述化合物或其盐用于治疗癌症。
14.根据权利要求13所述的化合物或其盐,其中所述癌症是胰腺癌。
15.根据权利要求13所述的化合物或其盐,其中所述癌症是滑膜肉瘤。
16.根据权利要求1所述的化合物或其盐用于制造供治疗癌症用的药物的用途。
17.根据权利要求16所述的化合物或其盐的用途,其中所述癌症是胰腺癌。
18.根据权利要求16所述的化合物或其盐的用途,其中所述癌症是滑膜肉瘤。
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