CN115698015A - 选择性cdk4/6抑制剂癌症治疗 - Google Patents
选择性cdk4/6抑制剂癌症治疗 Download PDFInfo
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- CN115698015A CN115698015A CN202180039343.7A CN202180039343A CN115698015A CN 115698015 A CN115698015 A CN 115698015A CN 202180039343 A CN202180039343 A CN 202180039343A CN 115698015 A CN115698015 A CN 115698015A
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- 238000000034 method Methods 0.000 claims abstract description 41
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Abstract
本公开描述了选择性且有效的CDK4/6抑制剂的实施方案,所述CDK4/6抑制剂即使在低浓度下显示出对癌症生长的有利抑制。如本文所述,本方法的化合物包含具有脂肪酸部分的经取代的吡啶基哌嗪‑吡咯并嘧啶化合物。本文所述的化合物可用作抗癌疗法的药物化合物,并且可用于治疗、预防和/或减轻癌症。式(a)
Description
领域
本公开涉及用于抗癌疗法的药物化合物,并且更具体地涉及经取代的吡啶基哌嗪-吡咯并嘧啶化合物,其是有效的CDK4/6抑制剂并且还可以用于治疗、预防和/或减轻癌症。
背景
癌症干细胞(CSC)是肿瘤起始细胞(TIC),它们对化学疗法和放射疗法等常规癌症疗法具有抗性。因此,CSC是导致肿瘤复发和远处转移的原因,导致癌症患者的治疗失败和临床结果不佳。因此,必须采用创新方法来了解如何解决CSC问题。从机制上讲,这可能与CSC在严苛条件和不同微环境下生存和繁衍的能力有关。由于CSC是肿瘤细胞群中特别小的子集,因此直到最近,它们的代谢和表型特性在很大程度上仍未得到表征。
此外,CSC具有惊人的复原力和对细胞应激的高度抵抗力,这使它们能够进行不依赖锚定的生长,尤其是在低附着条件下生长。因此,它们形成3D球体,保留了CSC和干细胞祖细胞的特性。相反,当在悬浮液中生长时,大多数“主体”癌细胞会通过失巢凋亡(一种特化类型的细胞凋亡)而死亡。因此,单个CSC的克隆繁殖导致3D球体的产生,并且不涉及癌细胞的自我聚集。因此,3D球体形成是上皮癌细胞的干性的功能读出,并允许人们富集具有干细胞样表型的上皮样细胞群。这些3D球体在使用乳腺癌细胞(例如MCF7等)制备时也被称为乳腺球。
以前,3D球体是从2个不同的ER(+)细胞系(MCF7和T47D)生成的,并进行了无偏无标签蛋白质组学分析。这项工作开始于在分子水平上分析CSC的表型行为。将3D球体与这些细胞系的单层直接比较并且平行处理。这允许鉴定相对于单层的蛋白质组学特征,这些特征是3D球体中CSC表型的特征。基于这种分子分析,观察到乳腺球极大地富集线粒体蛋白。这些线粒体相关蛋白包括参与β氧化和酮代谢/再利用、线粒体生物发生、电子传递、ADP/ATP交换/运输、CoQ合成和ROS产生以及线粒体自噬抑制的分子。因此,线粒体蛋白合成增加或线粒体自噬减少能够允许CSC中线粒体质量的积累。
鉴于CSC的增加,线粒体质量被认为是纯化CSC的新代谢生物标志物。使用这种整体方法,已经观察到仅使用MitoTracker作为ER(+)(MCF7)和ER(-)(MDA-MB-231)乳腺癌细胞系的单一标志物,就有可能极大富集CSC活性。值得注意的是,发现MitoTracker高的细胞对紫杉醇具有化学抗性,表现出对紫杉醇诱导的DNA损伤反应的抗性。
然而,需要的是用于根除CSC、预防或降低转移和/或复发的可能性以及降低或消除癌症对化学疗法和其他抗癌疗法的抗性的抗癌疗法的新药物化合物。此外,还需要治疗策略和抗癌疗法以专门靶向“最适生存的(fittest)”CSC,并消除进一步的癌症生长,包括不依赖锚定的生长、肿瘤复发和远处转移。
概述
癌症干细胞(CSC)现在被认为是全世界癌症患者治疗失败的主要根本原因之一。从机制上讲,这可能与CSC在严苛条件和不同微环境下生存和繁衍的能力有关。本发明人提出了这样的理论,即CSC可能通过使用升高的线粒体OXPHOS代谢“促进”ATP产生而对常规疗法产生抗性。与这一观点一致,多种线粒体抑制剂成功阻断了3D肿瘤球的形成,包括i)FDA批准的抗生素(多西环素、替加环素、阿奇霉素、恩波维铵、阿托伐醌、贝达喹啉),ii)天然化合物(放线菌素、CAPE、小檗碱、brutieridin和melitidin),以及iii)实验化合物(寡霉素和AR-C155858(一种MCT1/2抑制剂))等。
细胞周期蛋白依赖性激酶(CDK)4和6是已知可促进正常细胞和癌细胞中的细胞有丝分裂和减数分裂的酶。这些酶负责磷酸化视网膜母细胞瘤蛋白,从而使其失活,视网膜母细胞瘤蛋白在从G1期到S期的细胞周期进程中发挥作用。研究已经发现癌细胞中会增加CDK的活性的异常。这种增加的活性导致各种肿瘤抑制基因失活,从而为癌症干细胞的快速增殖和肿瘤生长铺平了道路。天然存在的CDK蛋白抑制剂,如p16和p27,已显示可体外抑制肺癌细胞系的生长。某些CDK抑制剂可通过其抑制正常未转化细胞的细胞周期进程的能力用作化学保护剂。
对这些酶的靶向抑制,无论是单独使用还是与其他疗法联合使用,是抗癌治疗剂和疗法的一种潜在策略。阻断CDK4/6通路防止细胞进入S期,从而通过细胞凋亡实现细胞死亡。本文描述的是吡咯并嘧啶化合物的实施方案,这些吡咯并嘧啶化合物是CDK抑制剂,主要是CDK4和CDK6(“CDK4/6”)的抑制剂,其作为癌症治疗剂具有很强的功效。更具体地,根据本方法的抗癌CDK4/6抑制剂的实施方案是具有脂肪酸部分的经取代的吡啶基哌嗪-吡咯并嘧啶化合物。下面显示的化合物(其中“m”是0-4,更优选0-2的整数,“n”是13-22,更优选12-20的整数)是第一类抗癌CDK 4/6抑制剂的一些实施方案的例示。
下面的化合物(其中‘m’是0并且‘n’是13)是本文描述的吡啶基哌嗪-吡咯并嘧啶抗癌CDK4/6抑制剂的示例性实施方案。
下面显示的化合物是根据本方法的经取代的吡啶基哌嗪-吡咯并嘧啶化合物的另一个说明性实施方案。在本实施方案中,“m”是2,“n”是14。
本文所述的化合物,包括其盐,可用作治疗癌症的药物化合物。本方法还提供具有治疗有效量的化合物或其治疗上可接受的一种或多种盐和药学上可接受的载剂、稀释剂或赋形剂的药物制剂。所有这些形式都在本方法范围之内。应当理解,可以使用本领域已知的药学上可接受的载剂。
本文所述的化合物可与治疗哺乳动物(包括人)癌症的方法联合使用,包括向哺乳动物施用有效治疗此类疾患或病症的量的经取代的吡啶基哌嗪-吡咯并嘧啶化合物或其药学上可接受的盐。例如,本方法可用于治疗异常细胞增殖,如癌症。本文所述的化合物可用于治疗异常细胞增生疾患、并且尤其是选自由以下组成的组的癌症:乳腺癌、卵巢癌、宫颈癌癌、前列腺癌、睾丸癌、食管癌、胃癌、皮肤癌、肺癌、骨癌、结肠癌、胰腺癌、甲状腺癌、胆道癌、口腔和咽部(口腔)癌、唇癌、舌癌、口癌、咽癌、小肠癌、结直肠癌、大肠癌、直肠癌、脑和中枢神经系统癌、胶质母细胞瘤、成神经细胞瘤、角化棘皮瘤、表皮样癌、大细胞癌、腺癌、腺癌、腺瘤、腺癌、滤泡癌、未分化癌、乳头状癌、精原细胞瘤、黑色素瘤、肉瘤、膀胱癌、肝癌、肾癌、骨髓疾患、淋巴疾患、霍奇金病、毛细胞癌、和白血病,所述治疗通过将治疗有效量的第一类、第二类或第三类化合物或其药学上可接受的盐施用给已被诊断患有此类癌症的受试者。在一些实施方案中,本方法可以与其他疗法组合使用和/或用于提高其他疗法的有效性。
本领域的普通技术人员在阅读了以下详细描述后可以认识到本方法的实施方案。
描述
以下描述包括当前设想的执行本方法的示例性实施方案的模式。下面的描述不应以限制性意义理解,而仅仅是为了例示本发明的一般原理。
根据本方法,一种或多种经取代的吡啶基哌嗪-吡咯并嘧啶CDK4/6抑制剂可用作抗癌治疗剂。根据本方法,吡啶基哌嗪部分被脂肪酸部分取代,优选脂肪酸部分具有至少14个碳,优选14个至约22个碳。本文所述的化合物具有有用的药学和医学特性。许多化合物表现出显著的选择性CDK4/6抑制活性,因此在以下各种临床病症中具有价值:其中CDK4/6激酶异常升高、异常激活或以正常量和活性存在,但其中需要抑制CDK来治疗细胞增生性疾患。特别是,这些化合物有望作为抗癌治疗剂。每一类中的化合物在以下定义中描述,这些定义适用于本方法的实施方案。
如本文所用,符号C(O)是指碳氧双键。本文所用的术语“卤代”是指卤素,包括如本领域所理解地键合的氟、氯、溴或碘。
本文所用术语“烷基”是指饱和脂肪族基团,包括直链烷基基团(例如甲基、乙基等)、支链烷基基团(异丙基、叔丁基等)、环烷基(脂环族)基团(环丙基、环戊基、环己基、环庚基、环辛基)、烷基取代的环烷基基团和环烷基取代的烷基基团。术语“烷基”还包括烯基基团和炔基基团。通式可使用术语“Cn-烷基”,其中n是例如1-20的整数,以表示基团中具有特定范围或数量的碳的特定烷基基团(直链或支链)。例如,术语C1-C3-烷基包括但不限于甲基、乙基、丙基和异丙基。类似地,术语C3-6-环烷基包括但不限于环丙基、环戊基和环己基。烷基以及环烷基基团可以是未取代的或经取代的。因此,术语烷基包括“未取代的烷基”和“经取代的烷基”,后者是指有取代基取代烃主链的一个或多个碳上的氢的部分。
术语“烯基”包括在长度和可能的取代方面与上述烷基类似,但包含至少一个双键的不饱和脂肪族基团。烯基还包括“未取代的烯基”和“经取代的烯基”,后者是指有取代基取代烃主链的一个或多个碳上的氢的部分。
例如,术语“烯基”包括直链烯基基团(例如,乙烯基、丙烯基、丁烯基、戊烯基、己烯基、庚烯基、辛烯基、壬烯基、癸烯基等)、支链烯基基团、环烯基(脂环族)基团(环丙烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基)、烷基或烯基取代的环烯基基团、和环烷基或环烯基取代的烯基基团。术语烯基还包括这样的烯基基团,其包括替代烃主链的一个或多个碳的氧、氮、硫或磷原子。在某些实施方案中,直链或支链烯基基团在其主链中具有6个或更少的碳原子(例如,对于直链,C2-6,对于支链,C3-6)。同样,环烯基基团在其环结构中可具有3-8个碳原子,更优选在环结构中具有5或6个碳原子。术语C2-C6包括含有2至6个碳原子的烯基基团。
术语“炔基”包括在长度和可能的取代方面与上述烷基类似,但包含至少一个三键的不饱和脂肪族基团。此外,术语炔基包括“未取代的炔基”和“经取代的炔基”,后者是指有取代基取代烃主链的一个或多个碳上的氢的炔基部分。
例如,术语“炔基”包括直链炔基基团(例如,乙炔基、丙炔基、丁炔基、戊炔基、己炔基、庚炔基、辛炔基、壬炔基、癸炔基等)、支链炔基基团、和环烷基或环烯基取代的炔基基团。术语炔基还包括这样的炔基基团,其包括替代烃主链的一个或多个碳的氧、氮、硫或磷原子。在某些实施方案中,直链或支链炔基基团在其主链中具有6个或更少的碳原子(例如,对于直链,C2-6,对于支链,C3-6)。术语C2-C6包括含有2至6个碳原子的炔基基团。
术语“经取代的”旨在描述有取代基取代分子的一个或多个原子(例如C、O或N)上的氢的部分。这样的取代基可以包括,例如但不限于烷基、烷氧基、烯基、炔基、卤代、羟基、烷基羰基氧基、芳基羰基氧基、烷氧基羰基氧基、芳氧基羰基氧基、羧酸基、烷基羰基、芳基羰基、烷氧基羰基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、烷硫基羰基、烷氧基、磷酸基、膦酸基、亚膦酸基、氨基(包括烷基氨基、二烷基氨基、芳基氨基、二芳基氨基、和烷基芳基氨基)、酰基氨基(包括烷基羰基氨基、芳基羰基氨基、氨基甲酰基和脲基)、脒基、亚氨基、巯基、烷硫基、芳硫基、硫代羧酸基、硫酸基、烷基亚磺酰基、磺酸基、氨磺酰基、磺酰胺基、硝基、三氟甲基、氰基、叠氮基、杂环基、烷基芳基、吗啉代、苯酚、苄基、苯基、哌嗪、环戊烷、环己烷、吡啶、5H-四唑、三唑、哌啶、或芳族或杂芳族部分,及其组合。如本文所述,吡啶基哌嗪部分上的取代包括脂肪酸部分。脂肪酸部分优选具有至少14个碳原子,并且优选包括14个碳原子至约22个碳原子。
如本领域通常理解的,术语“胺”或“氨基”应指分子或部分或官能团,并且可以是伯、仲或叔胺。术语“胺”或“氨基”包括其中氮原子与至少一个碳、氢或杂原子共价键合的化合物。这些术语包括,例如但不限于,“烷基氨基”、“芳基氨基”、“二芳基氨基”、“烷基芳基氨基”、“烷基氨基芳基”、“芳基氨基烷基”、“烷氨基烷基”、“酰胺”、“酰胺基”和“氨基羰基”。术语“烷基氨基”包括其中氮与至少一个另外的烷基基团键合的基团和化合物。术语“二烷基氨基”包括其中氮原子与至少两个另外的烷基基团键合的基团。术语“芳基氨基”和“二芳基氨基”包括其中氮分别与至少一个或两个芳基基团键合的基团。术语“烷基芳基氨基”、“烷基氨基芳基”或“芳基氨基烷基”是指与至少一个烷基基团和至少一个芳基基团键合的氨基基团。术语“烷氨基烷基”是指与氮原子键合的烷基、烯基或炔基基团,该氮原子还与烷基基团键合。
术语“酰胺”、“酰胺基”或“氨基羰基”包括含有与羰基或硫代羰基基团的碳键合的氮原子的化合物或部分。该术语包括“烷氨基羰基”或“烷基氨基羰基”基团,其包括与羰基基团键合的氨基基团键合的烷基、烯基、芳基或炔基。它包括芳基氨基羰基和芳基羰基氨基基团,这些基团包括与氨基基团键合的芳基或杂芳基部分,该氨基基团又与羰基或硫代羰基的碳键合。术语“烷基氨基羰基”、“烯基氨基羰基”、“炔基氨基羰基”、“芳基氨基羰基”、“烷基羰基氨基”、“烯基羰基氨基”、“炔基羰基氨基”和“芳基羰基氨基”包括在术语“酰胺”中。酰胺还包括脲基团(氨基羰基氨基)和氨基甲酸酯(氧基羰基氨基)。
术语“芳基”包括以下基团,其包括可包含零至四个杂原子的5元和6元单环芳族基团,例如苯基、吡咯、呋喃、噻吩、噻唑、异噻唑、咪唑、三唑、四唑,吡唑、噁唑、异噁唑、吡啶、吡嗪、哒嗪和嘧啶等。此外,术语“芳基”包括多环芳基基团,例如三环、双环,例如萘、苯并噁唑、苯并二噁唑、苯并噻唑、苯并咪唑、苯并噻吩、亚甲基二氧基苯基、喹啉、异喹啉、蒽基、菲基、萘啶、吲哚、苯并呋喃、嘌呤、苯并呋喃、脱氮嘌呤或吲哚嗪。在环结构中具有杂原子的那些芳基基团也可称为“芳基杂环”、“杂环”、“杂芳基”或“杂芳族”。芳族环可以在一个或多个环位置被如上所述的取代基取代,例如,烷基、卤素、羟基、烷氧基、烷基羰基氧基、芳基羰基氧基、烷氧基羰基氧基、芳氧基羰基氧基、羧酸基、烷基羰基、烷基氨基羰基、芳烷基氨基羰基、烯基氨基羰基、烷基羰基、芳基羰基、芳烷基羰基、烯基羰基、烷氧基羰基、氨基羰基、烷硫基羰基、磷酸基、膦酸基、亚膦酸基、氰基、氨基(包括烷基氨基、二烷基氨基、芳基氨基、二芳基氨基、和烷基芳基氨基)、酰基氨基(包括烷基羰基氨基、芳基羰基氨基、氨基甲酰基和脲基)、脒基、亚氨基、巯基、烷硫基、芳硫基、硫代羧酸基、硫酸基、烷基亚磺酰基、磺酸基、氨磺酰基、磺酰胺基、硝基、三氟甲基、氰基、叠氮基、杂环基、烷基芳基、或芳族或杂芳族部分。芳基基团也可以与非芳族的脂环或杂环稠合或桥连以形成多环(例如四氢化萘)。
如本文所用,术语杂芳基表示每个环至多7个原子的稳定单环或双环,其中至少一个环是芳族的并且含有1至4个选自由O、N和S组成的组的杂原子。该定义的范围内的杂芳基基团包括但不限于:吖啶基、咔唑基、噌啉基、喹喔啉基、吡唑基、吲哚基、苯并三唑基、呋喃基、噻吩基、苯并噻吩基、苯并呋喃基、喹啉基、异喹啉基、噁唑基、异噁唑基、吲哚基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基、四氢喹啉。正如下面杂环的定义,“杂芳基”也应理解为包括任何含氮杂芳基的N-氧化衍生物。在杂芳基取代基是双环且一个环是非芳族或不含杂原子的情况下,应理解连接分别通过芳族环或通过含杂原子的环。
本文所用的术语“杂环”或“杂环基”意指含有1至4个选自由O、N和S组成的组的杂原子的5至10元芳族或非芳族杂环,并且包括双环基团。因此,“杂环基”包括上述杂芳基及其二氢和四氢类似物。“杂环基”的其他实例包括,但不限于以下:苯并咪唑基、苯并呋喃基、苯并呋咱基、苯并吡唑基、苯并三唑基、苯并噻吩基、苯并噁唑基、咔唑基、咔啉基、噌啉基、呋喃基、咪唑基、吲哚啉基、吲哚基、吲嗪基、吲唑基、异苯并呋喃基、异吲哚基、异喹啉基、异噻唑基、异噁唑基、萘吡啶基、噁二唑基、噁唑基、噁唑啉、异噁唑啉、氧杂环丁烷基、吡喃基、吡嗪基、吡唑基、哒嗪基,吡啶并吡啶基、哒嗪基、吡啶基、嘧啶基,吡咯基、喹唑啉基、喹啉基、喹喔啉基、四氢吡喃基、四唑基、四唑并吡啶基、噻二唑基、噻唑基、噻吩基、三唑基、氮杂环丁烷基(azetidinyl)、1,4-二噁烷基、六氢氮杂环庚烯基(hexadydroazepinyl)、哌嗪基、哌啶基、吡啶-2-酮基、吡咯烷基、吗啉基、硫代吗啉基、二氢苯并咪唑基、二氢苯并呋喃基、二氢苯并噻吩基、二氢苯并噁唑基、二氢呋喃基、二氢咪唑基、二氢吲哚基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢喹啉基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢噻吩基、二氢三唑基、二氢氮杂环丁烷基、亚甲基二氧基苯甲酰基、四氢呋喃基、和四氢噻吩基、及其N-氧化物。杂环基取代基的连接可通过碳原子或杂原子发生。
术语“酰基”包括含有酰基基团(CH3CO-)或羰基基团的化合物和部分。术语“经取代的酰基”包括其中一个或多个氢原子被例如以下取代的酰基基团:烷基基团、炔基基团、卤素、羟基、烷基羰基氧基、芳基羰基氧基、烷氧基羰基氧基、芳氧基羰基氧基、羧酸基、烷基羰基、芳基羰基、烷氧基羰基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、烷硫基羰基、烷氧基、磷酸基、膦酸基、亚膦酸基、氰基、氨基(包括烷基氨基、二烷基氨基、芳基氨基、二芳基氨基、和烷基芳基氨基)、酰基氨基(包括烷基羰基氨基、芳基羰基氨基、氨基甲酰基和脲基)、脒基、亚氨基、巯基、烷硫基、芳硫基、硫代羧酸基、硫酸基、烷基亚磺酰基、磺酸基、氨磺酰基、磺酰胺基、硝基、三氟甲基、氰基、叠氮基、杂环基、烷基芳基、或芳族或杂芳族部分。
术语“酰基氨基”包括其中酰基部分与氨基基团键合的部分。例如,该术语包括烷基羰基氨基、芳基羰基氨基、氨基甲酰基和脲基基团。
术语“烷氧基”包括与氧原子共价连接的经取代和未取代的烷基、烯基和炔基。烷氧基基团的实例包括甲氧基、乙氧基、异丙氧基、丙氧基、丁氧基和戊氧基基团,并且可以包括环状基团例如环戊氧基。经取代的烷氧基基团的实例包括卤代烷氧基基团。烷氧基基团可以被例如以下基团取代:烯基、炔基、卤素、羟基、烷基羰基氧基、芳基羰基氧基、烷氧基羰基氧基、芳氧基羰基氧基、羧酸基、烷基羰基、芳基羰基、烷氧基羰基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、烷硫基羰基、烷氧基、磷酸基、膦酸基、亚膦酸基、氰基、氨基(包括烷基氨基、二烷基氨基、芳基氨基、二芳基氨基、和烷基芳基氨基)、酰基氨基(包括烷基羰基氨基、芳基羰基氨基、氨基甲酰基和脲基)、脒基、亚氨基、巯基、烷硫基、芳硫基、硫代羧酸基、硫酸基、烷基亚磺酰基、磺酸基、氨磺酰基、磺酰胺基、硝基、三氟甲基、氰基、叠氮基、杂环基、烷基芳基、或芳族或杂芳族部分。卤素取代的烷氧基基团的实例包括但不限于氟甲氧基、二氟甲氧基、三氟甲氧基、氯甲氧基、二氯甲氧基、三氯甲氧基等。
术语“羰基”或“羧基”包括含有碳通过双键连接到氧原子的化合物和部分,及其互变异构形式。含有羰基的部分的实例包括醛、酮、羧酸(例如脂肪酸部分)、酰胺、酯、酸酐等。术语“脂肪酸部分”、“羧基部分”和“羰基部分”是指以下基团,例如“烷基羰基”基团(其中烷基基团与羰基基团共价键合)、“烯基羰基”基团(其中烯基基团与羰基基团共价键合)、“炔基羰基”基团(其中炔基基团与羰基基团共价键合)、“芳基羰基”基团(其中芳基基团共价连接至羰基基团)。此外,该术语还指其中一个或多个杂原子共价键合至羰基部分的基团。例如,该术语包括以下部分,例如氨基羰基部分(其中氮原子与羰基基团的碳键合,例如酰胺)、氨基羰基氧基部分(其中氧和氮原子都键合至羰基基团的碳)(例如,也称为“氨基甲酸酯”)。此外,还包括氨基羰基氨基基团(例如脲)以及羰基基团与杂原子(例如氮、氧、硫等以及碳原子)键合的其他组合。此外,杂原子可进一步被一个或多个烷基、烯基、炔基、芳基、芳烷基、酰基等部分取代。
术语“硫代羰基”或“硫代羧基”包括含有碳通过双键连接至硫原子的化合物和部分。术语“硫代羰基部分”包括类似于羰基部分的部分。例如,“硫代羰基”部分包括氨基硫代羰基,其中氨基基团与硫代羰基基团的碳原子键合,此外其他硫代羰基部分包括氧基硫代羰基(氧与碳原子键合)、氨基硫代羰基氨基基团等。
术语“醚”包括含有与两个不同碳原子或杂原子键合的氧的化合物或部分。例如,该术语包括“烷氧基烷基”,其是指与氧原子共价键合的烷基、烯基或炔基基团,该氧原子还与另一个烷基基团共价键合。
术语“酯”包括含有与氧原子键合的碳或杂原子的化合物和部分,该氧原子还与羰基基团的碳键合。术语“酯”包括烷氧基羧基基团,例如甲氧基羰基、乙氧基羰基、丙氧基羰基、丁氧基羰基、戊氧基羰基等。烷基、烯基或炔基基团如上所定义。
术语“硫醚”包括含有与两个不同碳原子或杂原子键合的硫原子的化合物和部分。硫醚的实例包括但不限于烷硫基烷基、烷硫基烯基和烷硫基炔基。术语“烷硫基烷基”包括具有与硫原子(该硫原子与烷基基团键合)键合的烷基、烯基或炔基的化合物。类似地,术语“烷硫基烯基”和“烷硫基炔基”是指其中烷基、烯基或炔基与硫原子(该硫原子与炔基基团共价键合)键合的化合物或部分。
术语“羟基(hydroxy或hydroxyl)”包括具有-OH或-O-的基团。
术语“多环基”或“多环基团”包括具有两个或更多个环的部分(例如,环烷基、环烯基、环炔基、芳基和/或杂环基),其中两个或更多个碳是两个相邻环共有的,例如,环是“稠合环”。通过非相邻原子连接的环称为“桥接”环。多环的每个环可被如上所述的取代基取代,例如,卤素、羟基、烷基羰基氧基、芳基羰基氧基、烷氧基羰基氧基、芳氧基羰基氧基、羧酸基、烷基羰基、烷氧基羰基、烷基氨基羰基、芳烷基氨基羰基、烯基氨基羰基、烷基羰基、芳基羰基、芳烷基羰基、烯基羰基、氨基羰基、烷硫基羰基、烷氧基、磷酸基、膦酸基、亚膦酸基、氰基、氨基(包括烷基氨基、二烷基氨基、芳基氨基、二芳基氨基、和烷基芳基氨基)、酰基氨基(包括烷基羰基氨基、芳基羰基氨基、氨基甲酰基和脲基)、脒基、亚氨基、巯基、烷硫基、芳硫基、硫代羧酸基、硫酸基、烷基亚磺酰基、磺酸基、氨磺酰基、磺酰胺基、硝基、三氟甲基、氰基、叠氮基、杂环基、烷基、烷基芳基、或芳族或杂芳族部分。
术语“杂原子”包括碳或氢以外的任何元素的原子。优选的杂原子是氮、氧、硫和磷。
此外,短语“其任何组合”意味着可以组合任何数量的所列官能团和分子以产生更大的分子结构。例如,术语“苯基”、“羰基”(或“=O”)、“-O-”、“-OH”和C1-6(即,—CH3和—CH2CH2CH2—)可以组合形成3-甲氧基-4-丙氧基苯甲酸取代基。应当理解,当将官能团和分子组合以产生更大的分子结构时,可以根据需要去除或添加氢以满足每个原子的化合价。
如本领域普通技术人员所理解的,本文所述的化合物根据需要包括相邻原子和/或氢之间的键以满足每个原子的化合价。如有必要,添加键和/或氢原子,以对以下类型的原子中的每一种提供以下总键数:碳:四个键;氮:三个键;氧:两个键;和硫:2-6个键。
如本文所用的短语“药学有效量”表示施用给宿主或施用给宿主的细胞、组织或器官以达到治疗结果如调节、调控或抑制蛋白激酶活性(例如抑制蛋白激酶的活性)或治疗癌症所必需的量。具有本领域普通技能的医师或兽医可以容易地确定并且开出所需药物组合物的有效量。例如,医师或兽医可以以比实现所期望治疗效果所需的水平低的水平来开始在药物组合物中使用的本发明化合物的剂量,并且逐渐增加剂量直至达到所期望效果。
术语“治疗(treat)”、“被治疗的(treated)”、“治疗(treating)”和“治疗(treatment)”包括减少或减轻至少一种与所治疗的状态、疾患或疾病,尤其是癌症相关或由其引起的症状。在某些实施方案中,治疗包括通过本发明的化合物减少和/或减轻至少一种与正在治疗的癌症相关或由其引起的症状。例如,治疗可以是减少癌症的一种或几种症状或完全根除癌症。
本文所述的化合物包括本公开内容所提及的脂肪酸部分,也称为羰基部分。如本文所用,脂肪酸是具有脂族链的羧酸,其可以是饱和的或不饱和的,但优选饱和链。饱和脂肪酸的实例包括月桂酸(CH3(CH2)10C(O)OH)、棕榈酸(CH3(CH2)14C(O)OH)、硬脂酸(CH3(CH2)16C(O)OH)和肉豆蔻酸(CH3(CH2)12C(O)OH)。油酸(CH3(CH2)7CH=CH(CH2)7C(O)OH)是天然存在的不饱和脂肪酸的实例。还可以提及脂肪酸的盐或酯,以及它的脂肪酰胺部分,但为简单起见,这些包括在本文所用的脂肪酸部分的含义中。例如,肉豆蔻酸可称为肉豆蔻酸盐或酯,而油酸可称为油酸盐或酯。脂肪酸部分也可以是脂肪酸的碳酰基,即通过失去羧酸的羟基形成的基团。在一些实施方案中,脂肪酸部分可通过酰胺键键合至治疗剂。例如,肉豆蔻酸缀合物可具有脂肪酸部分CH3(CH2)12CO-NH-,其中叔氮键合至治疗剂:并且n是1-20,优选是10-20的整数。当肉豆蔻酸酯部分通过豆蔻酰化缀合时,可能会产生这种情况,从而产生十四酰胺(或肉豆蔻酰胺)基团。
根据本方法,抗癌CDK4/6抑制剂包括如下通式[1]所示的经取代的吡啶基哌嗪-吡咯并嘧啶化合物。
如通式[1]中所用,脂肪酸部分中的‘m’是0-4的整数,更优选0-2,使得当m是0时,直接键合至哌嗪中的氮;脂肪酸部分中的n表示13至22的整数,优选14至20,并且可以是14、15、16、17、18、19、20、21或22;并且优选是饱和直链;
R1选自由以下组成的组:氢、C1-C8-烷基、经取代的C1-C8-烷基、C3-C8-环烷基、经取代的C3-C8-环烷基、芳基、经取代的芳基、杂芳基和经取代的杂芳基、卤代取代的烷氧基基团。
在本方法的一个优选实施方案中,抗癌CDK4/6抑制剂具有如下所示的化学式[2]。在这样的实施方案中,‘m’是0,‘n’是12,导致脂肪酸部分包含肉豆蔻酸酯部分,并且R1是氢。该实施方案类似于曲拉西利(Trilaciclib),曲拉西利是一种目前处于2期临床试验的CDK4/6抑制剂,用于减少与化学疗法相关的副作用。然而,式[2]在吡啶基哌嗪上包括肉豆蔻酸酯部分。应当理解,式2中的R1是H,但如本文所述其可是C1-C8-烷基、经取代的C1-C8-烷基(例如卤代烷基)、C3-C8-环烷基、经取代的C3-C8-环烷基、芳基、经取代的芳基、杂芳基和经取代的杂芳基。
本方法的实施方案包括具有上式[2]和下式[3]中所示结构的实施方案,包括本公开所称的在吡啶基哌嗪处取代的脂肪酸。脂肪酸部分,特别是在该结构上的这个位置,显著提高了化合物的细胞摄取,大大增加了其对癌症干细胞增殖的抑制,以及其他有益作用。结果,根据本方法的化合物体外抑制肺癌细胞系的生长。并且可以通过它们抑制正常未转化细胞的细胞周期进程的能力用作化学保护剂,以及用于治疗癌症,降低癌症对治疗的抗性,预防转移性疾病,预防肿瘤复发,预防放射疗法抗性、化学疗法抗性和激素疗法抗性中的至少一种,和/或预防或减少癌细胞、癌症干细胞和循环肿瘤细胞中至少一种的增殖。
第二说明性实施方案如上式[3]所示,其中R1是氢,m是2,n是14。因此,该实施方案具有14碳饱和脂肪酸(即棕榈酸酯)部分。与曲拉西利相比,式[2]和[3]中所示的化合物在乳腺球测定中引人注目地提到了对MCF7细胞的抑制。应当理解类似的结果对于具有少至11个碳、优选至少14个碳且多至22个碳的其他脂肪酸部分被预期。
本方法描述了药物组合物,该药物组合物包含治疗有效量的来自第一类或第二类的化合物或其药学上可接受的盐,以及药学上可接受的载剂、稀释剂或赋形剂。根据本方法的化合物可用作抗癌治疗剂。可以根据本领域已知的手段对受试者施用在药学上可接受的载剂中的药学上有效量的化合物。在一些实施方案中,本方法的化合物可以与其他癌症疗法联合使用,例如但不限于化学疗法、线粒体生物发生抑制剂(例如,mitoriboscin、mitoketoscin、repurposcin如antimitoscin、放射疗法、光疗法和卡路里限制。
对CDK4/6的选择性抑制还表明本文所述的化合物可用于降低或消除癌症中的药物和/或疗法抗性。由于它们对CDK和其他激酶的抑制活性,本方法的化合物也是研究此类激酶作用机制的有用研究工具,并且可以在体外和体内使用。
本文所述的治疗方法优选通过将治疗有效量的来自第一类或第二类的化合物施用给需要治疗的受试者来进行。这些化合物容易合成,并且可以通过多种途径施用,包括口服和肠胃外,并且毒性很小或没有毒性。
根据本方法的化合物可以从市售的曲拉西利开始合成。可替代地,合成方案是公众可得的,包括例如美国专利8,598,197中公开的合成方案,该专利通过引用以其整体并入本文。从曲拉西利开始,可以使用本领域已知的方法使甲基哌嗪去甲基化。在去甲基化之后,可以使用豆蔻酰化来形成该化合物。
作为另一个实例,对于具有肉豆蔻酸酯部分的实施方案,可使用以下合成方法。肉豆蔻酸可转化为肉豆蔻酰氯,并在4-甲基吗啉(NMM)和二氯甲烷(DCM)存在下与2-甲基-2-丙基1-哌嗪甲酸酯(以下显示为1-BOC-哌嗪)反应,如下所示。
中间产物可以与HCl和二噁烷反应形成1-(1-哌嗪基)-1-十四烷酮。该方法如下所示继续。应理解,DiPEA是Hünig’s碱(N,N-二异丙基乙胺),DMA是二甲基乙酰胺,THF是四氢呋喃。还应理解,脂肪酸部分可在上述初始步骤中使用所期望的烷基进行修饰。
在本方法的实施方案的描述中使用的术语仅用于描述特定实施方案的目的而不旨在限制。如在说明书和所附权利要求中所使用的,单数形式“一个/种(a)”、“一个/种(an)”和“所述/该(the)”也旨在包括复数形式,上下文另外明确指出除外。如通过考虑以下详细描述将变得显而易见的,本方法包含许多备选方案、修改和等同方案。
应当理解,尽管术语“第一”、“第二”、“第三”、“a)”、“b)”和“c)”等可在本文中用于描述本方法的各种要素,但是权利要求书不应受这些术语的限制。这些术语仅用于将本方法的一个要素与另一个要素区分开来。因此,在不脱离本方法的教导的情况下,下面讨论的第一要素可以被称为一个要素方面,并且类似地,第三要素可以被称为一个要素方面。因此,术语“第一”、“第二”、“第三”、“a)”、“b)”和“c)”等并不一定传达关联要素的顺序或其他层次结构,而是仅用于标识目的。操作(或步骤)的顺序不限于权利要求书中给出的顺序。
除非另有定义,否则本文使用的所有术语(包括技术和科学术语)具有与本领域普通技术人员通常所理解的相同的含义。还应理解,术语(如在常用词典中定义的那些术语)应被解释为具有与其在本申请和相关领域的上下文中一致的含义,并且除非本文明确定义,否则不应被解释为理想化或过于正式的意义。本文提及的所有出版物、专利申请、专利和其他参考文献通过引用以其整体并入本文。在术语冲突的情况下,以本说明书为准。
此外,如本文所用的,“和/或”是指并且涵盖一个或多个相关所列项目的任何和所有可能的组合,以及当以替代方式(“或”)解释时不组合。
除非上下文另有说明,否则本文描述的本方法的各种特征特别旨在以任何组合使用。此外,本方法还设想可以在一些实施方案中排除或省略关于示例性实施方案描述的任何特征或特征的组合。
如本文所用,过渡短语“主要由……组成”(和语法变体)应解释为涵盖所引用的材料或步骤“以及那些不会实质性影响权利要求的一个或多个基本和新颖特征的材料或步骤”。因此,本文所用的术语“主要由...组成”不应解释为等同于“包含”。
本文所用的术语“约”当述及可测量值,例如量或浓度等时,意在涵盖规定量的±20%、±10%、±5%、±1%、±0.5%、甚至是±0.1%的变化。本文提供的可测量值的范围可以包括其中的任何其他范围和/或个别值。
虽已经如此描述了本方法的某些实施方案,但应当理解所附权利要求书的范围不受以上描述中阐述的特定细节的限制,因为在不脱离下文要求保护的精神或范围的情况下,其许多明显的变化是可能的。
Claims (11)
2.如权利要求1所述的化合物,其中‘m’是0-2的整数,‘n’是14-20的整数。
3.如权利要求2所述的化合物,其中R1是H、C1-C8-烷基和经取代的C1-C8-烷基中的一种。
4.如权利要求1所述的化合物,其中m是0,n是12,并且R1是氢。
5.一种药物组合物,其包含如权利要求1至4中任一项所述的化合物和药学上可接受的载剂。
6.一种治疗癌症的方法,该方法包括向有需要的患者施用药学有效量的权利要求1至4中任一项所述的化合物和药学上可接受的载剂。
7.一种降低癌症的治疗抗性的方法,该方法包括向有需要的患者施用药学有效量的权利要求1至4中任一项所述的化合物和药学上可接受的载剂。
8.一种治疗或预防转移性疾病的方法,该方法包括向有需要的患者施用药学有效量的权利要求1至4中任一项所述的化合物和药学上可接受的载剂。
9.一种治疗或预防肿瘤复发的方法,该方法包括向有需要的患者施用药学有效量的权利要求1至4中任一项所述的化合物和药学上可接受的载剂。
10.一种治疗或预防放射疗法抗性、化学疗法抗性和激素疗法抗性中的至少一种的方法,该方法包括向有需要的患者施用药学有效量的权利要求1至4中任一项所述的化合物和药学上可接受的载剂。
11.一种预防或减少癌细胞、癌症干细胞和循环肿瘤细胞中的至少一种的增殖的方法,该方法包括向有需要的患者施用药学有效量的权利要求1至4中任一项所述的化合物和药学上可接受的载剂。
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US20140275066A1 (en) * | 2013-03-15 | 2014-09-18 | G1 Therapeutics, Inc. | Transient Protection of Normal Cells During Chemotherapy |
CN105407723A (zh) * | 2013-03-15 | 2016-03-16 | G1治疗公司 | 高效的抗赘生剂和抗增生剂 |
WO2018106870A1 (en) * | 2016-12-08 | 2018-06-14 | Icahn School Of Medicine At Mount Sinai | Compositions and methods for treating cdk4/6-mediated cancer |
WO2020037251A1 (en) * | 2018-08-16 | 2020-02-20 | G1 Therapeutics, Inc. | Benzothiophene estrogen receptor modulators to treat medical disorders |
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US20140275066A1 (en) * | 2013-03-15 | 2014-09-18 | G1 Therapeutics, Inc. | Transient Protection of Normal Cells During Chemotherapy |
CN105407723A (zh) * | 2013-03-15 | 2016-03-16 | G1治疗公司 | 高效的抗赘生剂和抗增生剂 |
WO2018106870A1 (en) * | 2016-12-08 | 2018-06-14 | Icahn School Of Medicine At Mount Sinai | Compositions and methods for treating cdk4/6-mediated cancer |
WO2020037251A1 (en) * | 2018-08-16 | 2020-02-20 | G1 Therapeutics, Inc. | Benzothiophene estrogen receptor modulators to treat medical disorders |
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WO2021250614A1 (en) | 2021-12-16 |
JP2023530096A (ja) | 2023-07-13 |
EP4165046A1 (en) | 2023-04-19 |
CA3185467A1 (en) | 2021-12-16 |
US20240116942A1 (en) | 2024-04-11 |
KR20230023661A (ko) | 2023-02-17 |
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