CN101784268B - 使用辐射敏化剂使肿瘤对辐射敏化的方法 - Google Patents
使用辐射敏化剂使肿瘤对辐射敏化的方法 Download PDFInfo
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Abstract
本发明涉及使用PARP抑制剂作为肿瘤辐射敏化剂治疗癌的方法。具体地,本发明涉及使用式(I)的化合物或其药学可接受的盐使肿瘤对辐射敏化的方法:本发明还涉及用于使肿瘤对辐射敏化的PARP抑制剂的药物组合物。
Description
技术领域
本发明涉及使用PARP抑制剂作为肿瘤辐射敏化剂治疗癌的方法。具体地,本发明涉及使用下式(I)的化合物或其药学可接受的盐使肿瘤对辐射敏化的方法:
本发明还涉及用于使肿瘤对辐射敏化的PARP抑制剂的药物组合物。
背景技术
辐射是一种通过产生DNA链断裂碎片来诱导细胞损伤的细胞毒治疗形式。聚(ADP-核糖)聚合酶1(PARP-1)是核锌指DNA结合蛋白,其被DNA辐射诱导的损伤和修复所活化或与之有牵连。PARP结合于DNA链断裂碎片,这可用于保护它们免于核酸酶的攻击或重组。因为PARP用于帮助DNA修复,抑制剂具有增强胞毒剂的化学和辐射敏化能力(Curtin,2005)。
治疗失败和癌死亡率的最重要的原因是辐射/化疗抗性。克服癌细胞对胞毒剂的抗性的试剂在成功的癌治疗中可以是关键因素。在治疗方面作为化疗和辐射敏化剂的PARP抑制剂的潜在应用直到相对最近局限于这些试剂的效力、选择性和药学性质(Griffin等人,1998;Bowman等人,1998;Bowman等人,2001,Chen & Pan,1998;Delany等人,2000;Griffin等人,1995;Lui等人,1999)。最近,已经开发了更具效力和选择性的PARP抑制剂(苯并咪唑-4-甲酰胺和喹唑啉-4-[3H]-酮),在人和鼠的白血病、淋巴瘤转移到中枢神经系统、结肠癌、肺癌和乳癌试剂的肿瘤模型中,其已经显示出增强放疗剂和化疗剂诸如喜树碱(CPT)、拓扑替康、伊立替康、顺铂、依托泊苷、博来霉素、BCNU和替莫唑胺(TMZ)在体外和体内的效果(Griffin等人,1998;Bowman等人,1998;Bowman等人,2001,Chen & Pan,1998;Delany等人,2000;Griffin等人,195;Lui等人,1999,Tentori等人,2002)。能够使得肿瘤细胞对不同类别的化疗剂和/或辐射的作用敏化的PARP抑制剂可增加制定的癌疗法的成功率。
PARP-1是116kD核锌指DNA结合蛋白,其采用NAD+作为底物以将ADP-核糖转移到受体蛋白诸如组蛋白、聚合酶、连接酶和PARP自身(自修饰)(Griffin等人,1998;Tentori等人,2002;Baldwin等人,2002)。PARP-1属于目前包括18个成员的蛋白质家族,在这些中,PARP-1和PARP-2是仅被DNA损伤活化的酶(Curtin,2005;Tentori等人,2002)。PARP-2的活化还可诱导促炎活性(Jagtap和Szabo,2005),表明在肿瘤细胞中PARP-2的抑制可具有附加的治疗益处。尽管由各种PARP同工酶调节的病理和生理过程是广泛研究的对象(Ame等人,2004),该家族的被充分表征的成员以及在肿瘤学治疗努力的有目标的药物发现中的主要集中点是PARP-1。
PARP在调节许多不同的生物过程中具有活性,所述生物过程包括在转录水平的蛋白质表达、复制和分化、端粒酶活性和细胞骨架组构。然而,应PARP抑制剂作为化疗/辐射敏化剂的要求,感兴趣的是PARP在DNA修复和保持基因组完整性中的作用(Smith,2001)。这一作用借助于使用缺乏PARP-1的细胞进行说明,该细胞当暴露于电离辐射或烷化剂治疗下时显示出延迟的碱基切割修复和高频率的姐妹染色单体交换。另外,高水平的电离辐射和烷化剂在缺乏PARP-1的小鼠中比在野生型小鼠中引起更高的致死率(Smith,2001;Virag & Szabo,2002)。
在PARP家族成员中,PARP-1(和PARP-2)由于以下被特别地活化并且与之有牵连:直接由电离辐射引起的DNA链断裂碎片的修复,或在由于甲基化剂、拓扑异构酶I抑制剂和其它化疗剂诸如顺铂和博来霉素导致的DNA损伤的酶修复之后间接引起的DNA链断裂碎片的修复。(Griffin等人,1998;Delany等人,2000;Tentori等人,2002;de Murcia等人,1997)。有相当大量的生化和遗传证据显示PARP-1在亚致死量的DNA损伤后的细胞存活和修复中起作用。另外,正如在PARP-1剃除小鼠中所被例证的,在没有DNA损伤的情况下PARP-1的功能对于细胞存活不是关键性的已经使得PARP-1的抑制成为供化疗和/或放疗使用的一种可能的可行治疗策略(Delany等人,2000;Burkle等人,1993)。
早期获得的PARP-1抑制剂诸如3-氨基苯甲酰胺、烟酰胺和相关衍生物,在体外和体内的人和鼠肿瘤模型中,增强了辐射、博来霉素、CPT、顺铂和TMZ的体外和体内的细胞毒活性。这些化合物在效力、选择性和递送能力方面的固有限制妨碍了特异性地针对这些分子的非特异性活性将在体外和体内观察到的抗肿瘤效力的增强明确归属到PARP-1的抑制(Griffin等人,1998;Griffin等人,1995;Masuntani等人,2000;Kato等人,1988)。这些问题在开发更具效力和选择性结构类别的包括苯并咪唑-4-甲酰胺和喹唑啉-4-[3H]-酮衍生物在内的PARP-1抑制剂方面具有影响。体外和体内分析揭示了这些化合物能够增强使用人和鼠肿瘤模型的化疗剂的效力(Griffin等人,1998;Bowman等人,1998;Bowman等人,2001;Chen & Pan,1998;Delany等人,2000;Griffin等人,1995;Liu等人,1999)。2001年11月15日公开的PCT公报WO2001085686公开了具有PARP抑制活性的咔唑化合物。
需要发现和开发作为辐射敏化剂的PARP抑制剂用于治疗对PARP具有高选择性、高效力、改善的递送能力和改善的耐受性模式的癌治疗。
发明概述
本发明提供了使用4-甲氧基-咔唑通过体内抑制PARP-1使肿瘤对辐射敏化的方法。该方法包括式(Ia)的4-甲氧基-咔唑:
及其前体药物,优选其曼尼希碱前体药物,以提供溶解度和稳定性,和用于帮助活性药物7-甲氧基-1,2,3,11-四氢-5,11-二氮杂苯并[a]三茚-4,6-二酮的体内递送。
本发明还提供了通过给予式(I)的辐射敏化剂或其药学可接受的盐到罹患癌的哺乳动物;并对所述哺乳动物组织施加电离辐射而治疗癌的方法:
其中,X是H或本文定义的前体药物部分。
本发明的另一个目的是提供包括本发明化合物的药物组合物,其中该组合物包括一种或多种药学可接受的赋形剂和治疗有效量的至少一种本发明的化合物或其药学可接受的盐或酯形式。
本发明的另一个目的是提供下式(II)的化合物:
或其药学可接受的盐。
在另一个实施方案中,本发明提供了式(I)的化合物用于制备治疗癌的药物的用途。
本发明的这些和其它目的、特征和优点将在以下的详细说明中被公开。
附图说明
图1:表示使用耐辐射U87MG胶质母细胞瘤异种移植瘤,曼尼希碱前体药物结合辐射对肿瘤的生长延迟的效果,
图2:联合治疗的效果幅度比仅采用放疗或前体药物的可比方案获得的效果幅度更强,图3:在裸鼠的U87MG人胶质母细胞瘤异种移植瘤中实施例7的辐射敏化效应(未优化方案),
图4表示包括本发明范围内的化合物及其前体在内的合成方案,
图5:在裸鼠的U87MG人胶质母细胞瘤异种移植瘤中经口给予的实施例7的辐射敏化效应。
发明的详细说明
在第一实施方案中,本发明提供了通过给予式(I)的辐射敏化剂或其药学可接受的盐到罹患癌的哺乳动物;并对所述哺乳动物施加电离辐射而治疗癌的方法:
其中,X是H或前体药物部分。
在优选方案中,辐射敏化剂存在于所述组织内或其附近以增加所述被施加的电离辐射向局部化治疗效果的转化效率。
在优选方案中,辐射敏化剂以有效使癌细胞对辐射敏化的量存在。
在优选方案中,所述组织的电离辐射采用有效破坏所述细胞的剂量的辐射进行。
在优选方案中,电离辐射对于给定的癌类型是临床上可接受的或被推荐的放疗规程。
在优选方案中,癌是恶性的。
在优选方案中,癌是良性的。
在优选方案中,前体药物部分选自:-CH2NR1R2,-CH2OC(=O)R3,-CH2OP(=O)(OH)2和-C(=O)R4;
其中;
R1是H或C1-4烷基;
R2是H或C1-4烷基;
作为替代,R1和R2与其所连接的氮原子一起形成选自吡咯基、吡咯烷基、哌啶基、吗啉基、硫代吗啉基和哌嗪基的杂环基,其中所述杂环基任选地被C1-4烷基取代;
R3选自-C1-4烷基-NR1R2,-C1-4烷基-OR5,吡啶基,-苯基(CH2NR1R2)和-CH(R6)NH2;
R4选自-O-(C1-4烷基)-NR1R2,-O-(C1-4烷基)-OR5和-CH(R6)NH2;
R5是H或C1-4烷基;和
R6是天然存在的氨基酸的侧链。
在优选方案中,前体药物部分是-CH2NR1R2,R1是H或C1-4烷基;R2是H或C1-4烷基;并且,作为替代,R1和R2与其所连接的氮原子一起形成选自吡咯基、吡咯烷基、哌啶基、吗啉基、硫代吗啉基和哌嗪基的杂环基,其中所述杂环基任选地被C1-4烷基取代。
在优选方案中,前体药物部分是曼尼希碱。
在优选方案中,曼尼希碱选自:4-甲基-哌嗪-1-基甲基-,吗啉-4-基甲基-和5-二乙基氨基甲基-。
在优选方案中,曼尼希碱是4-甲基-哌嗪-1-基甲基。
在优选方案中,给药途径是静脉内、皮下、经口和腹膜内途径。
在优选方案中,给药途径是静脉内途径。
在优选方案中,癌选自头颈鳞状细胞癌(眼癌、唇癌、口癌、咽癌、喉癌、鼻癌、舌癌和食管癌),黑素瘤,鳞状细胞癌(表皮),胶质母细胞瘤,星形细胞瘤,少突胶质细胞瘤,少突星形细胞瘤,脑膜瘤,神经母细胞瘤,横纹肌肉瘤,软组织肉瘤,骨肉瘤,在中枢神经系统部位的血液恶性病、乳癌(导管癌和原位癌),甲状腺癌(甲状腺乳头状癌和甲状腺滤泡型癌),肺癌(细支气管肺泡癌、小细胞肺癌、混合型小细胞/大细胞癌、复合性小细胞癌,非小细胞肺癌,鳞状细胞癌,大细胞癌,和肺腺癌),肝细胞癌,结肠直肠癌,宫颈癌,卵巢癌,前列腺癌,睾丸癌,胃癌,胰腺癌,胆管瘤(cholangiosarcoma),淋巴瘤(T细胞和B细胞由来的霍奇金型和非霍奇金型淋巴瘤),白血病(骨髓和淋巴由来的急性和慢性白血病),和膀胱癌。
在优选方案中,癌选自头颈鳞状细胞癌(眼癌、唇癌、口癌、咽癌、喉癌、鼻癌、舌癌和食管癌),黑素瘤,鳞状细胞癌(表皮),胶质母细胞瘤,神经母细胞瘤,横纹肌肉瘤,肺癌(细支气管肺泡癌癌,小细胞肺癌,混合型小细胞/大细胞癌,复合性小细胞癌,非小细胞肺癌,鳞状细胞癌,大细胞癌和肺腺癌),淋巴瘤(T细胞和B细胞由来的霍奇金型和非霍奇金型淋巴瘤),和白血病(骨髓和淋巴由来的急性和慢性白血病)。
在优选方案中,本发明提供了通过给予式7-甲氧基-1,2,3,11-四氢-5,11-二氮杂苯并[a]三茚-4,6-二酮的辐射敏化剂治疗癌的方法。
在优选方案中,本发明提供了通过给予式7-甲氧基-5-(4-甲基-哌嗪-1-基甲基)-1,2,3,11-四氢-5,11-二氮杂苯并[a]三茚-4,6-二酮的辐射敏化剂治疗癌的方法。
在第二实施方案中,本发明提供了用于使癌细胞对辐射敏化的药物组合物,其包括辐射敏化量的下式(I)的化合物或其药学可接受的盐;和药学可接受的载体:
其中X是H或前体药物部分。
在优选方案中,前体药物部分选自:-CH2NR1R2,-CH2OC(=O)R3,-CH2OP(=O)(OH)2和-C(=O)R4;
R1是H或C1-4烷基;
R2是H或C1-4烷基;
作为替代,R1和R2与其所连接的氮原子一起形成选自吡咯基、吡咯烷基、哌啶基、吗啉基、硫代吗啉基和哌嗪基的杂环基,其中所述杂环基任选地被C1-4烷基取代;
R3选自-C1-4烷基-NR1R2,-C1-4烷基-OR5,吡啶基,-苯基(CH2NR1R2)和-CH(R6)NH2;
R4选自-O-(C1-4烷基)-OR1R2,O-(C1-4烷基)-OR5和-CH(R6)NH2;
R5是H或C1-4烷基;和
R6是天然存在的氨基酸的侧链。
在优选方案中,前体药物部分是-CH2NR1R2,
R1是H或C1-4烷基;
R2是H或C1-4烷基;并且,
作为替代,R1和R2与其所连接的氮原子一起形成选自吡咯基、吡咯烷基、哌啶基、吗啉基、硫代吗啉基和哌嗪基的杂环基,其中所述杂环基任选地被C1-4烷基取代。
在优选方案中,化合物是:
或其药学可接受的盐形式。
在优选方案中,化合物是:
或其药学可接受的盐形式。
在第三实施方案中,本发明提供了下式(II)的化合物:
或其药学可接受的盐。
在第四实施方案中,本发明提供了式(I)的化合物用于制备治疗癌的药物的用途。
在优选方案中,本发明提供了式(II)的化合物用于制备治疗癌的药物的用途。
可理解的是,本发明的某些特征,其在分开的实施方案的上下文中为了清楚目的被描述,还以单个实施方案的组合形式被提供,相反地,本发明的多个特征,其在单个的实施方案的上下文中为了清楚目的被描述,为了简便起见,也可以分开的或以任何适当的亚组合的形式被提供。
本文包含的以下的术语和表述如下定义:
本文使用的术语“约”是指给定值±10%的值范围。例如,措词“约50mg”包括50±10%mg,或表示45到55mg。
本文使用的术语“烷基”是指含1-4个碳原子的直链或支链烷基,诸如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基。诸如“C1-4烷基”是指含1-4个碳原子的烷基。
本文使用的术语“氨基酸”是指既包含氨基又包含羧基的分子。其包括本领域技术人员公知的“α-氨基酸”,其是在与羧基相邻的碳上携带氨基官能度的羧酸。氨基酸可以是天然存在的或非天然存在。“天然存在的氨基酸”包括丙氨酸、精氨酸、天门冬酰胺、门冬氨酸、半胱氨酸、谷氨酸、谷氨酰胺、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、蛋氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸和缬氨酸。
本文使用的术语“杂环基”是指含碳原子和至少选自O、N或S的杂原子的5或6元环状基团,其中所述杂环基可以是饱和的或不饱和的并且其中所述杂环基可以是被取代的或未被取代的。氮和硫杂原子可任选被氧化。杂环基的实例包括吡咯基、吡咯烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基和甲基哌嗪基。本文使用的术语“哺乳动物”是指温血动物,诸如小鼠、大鼠、猫、狗、猴或人,优选是人,或人类儿童,其罹患或可能罹患本文所述的一种或多种疾病和病况。
本文使用的“药学可接受”的组分是适合用于人和/或动物而无不适当的不良副作用(诸如毒性、刺激和变态反应)并与合理的利益/风险比相称的组分。
本文使用的术语“安全和有效的量”是指当以本发明的方式被使用时组分的足够引起所需的治疗应答而无不适当的不良副作用(诸如毒性、刺激或变态反应)并与合理的利益/风险比相称的量。“治疗有效量”是指本发明的化合物有效获得所需治疗应答的量。例如,有效延迟癌(肉瘤或淋巴瘤)生长或引起癌(肉瘤或淋巴瘤)缩小或预防其转移的量。具体的安全和有效的量或治疗有效量将根据诸如以下因素的不同而异:被治疗的特定病况,患者的物理状态,被治疗的哺乳动物或动物的种类,治疗的持续时间,同时进行的治疗(如果有的话)的性质,和所用的特定的制剂以及化合物或其衍生物的结构。
在本发明中,术语“电离辐射”是指包括借助于核相互作用可具有足够能量或者产生电离(电子的获得或丧失)而产生足够能量的粒子或光子的辐射。示例性的和优选的电离辐射是X射线辐射。递送X射线辐射到靶组织或细胞的手段是本领域所公知的。在给定细胞内所需的电离辐射的量通常根据该细胞的性质的不同而异。测定辐射的有效量的手段是本领域所公知的。本文使用的术语“有效剂量”的电离辐射是指一定剂量的电离辐射,其当与本发明的化合物联合给予时导致细胞损伤或死亡的增加。
X-射线的日剂量范围是50至200伦琴,持续延长时段(3-4周),到2000至6000伦琴的单个剂量。辐射性同位素的剂量范围可根据同位素的半衰期、被发射的辐射的强调和类型、以及赘生性细胞的摄取的不同而广泛不同。
任何适当的用于递送辐射到组织的手段可用于本发明中。递送辐射到组织的常用手段是在被治疗体之外的电离辐射源。用于递送辐射到组织的备选方法包括例如,首先体内递送与肿瘤的抗原发生免疫反应的辐射性标记抗体,然后体内递送有效量的辐射性标记抗体到肿瘤。另外,辐射性同位素可用于递送电离辐射到组织或细胞。另外,辐射可借助于拟辐射剂(radiomimetic agent)被递送。本文使用的“拟辐射剂”是指化疗剂,例如美法仑,其引起与辐射治疗相同类型的细胞损伤,但是不施加辐射。
本文使用的术语“前体药物部分”是指该前体药物在生理学条件下可通过许多的化学和生物学机理被转化为生物活性药物。在一个实施方案中,前体药物向生物活性药物的转化可通过前体药物部分的水解完成,条件是该前体药物部分可被水进行化学或酶促水解。与水的反应典型地导致前体药物部分的除去和生物活性药物的释放。本发明的又一个方面提供了通过前体药物部分的还原发生的前体药物向生物活性药物的转化。典型地,在该实施方案中,前体药物部分在生理学条件下在还原酶过程存在的条件下可被还原。还原优选地导致前体药物部分的除去和生物活性药物的释放。在另一个实施方案中,前体药物向生物活性药物的转化还可通过前体药物部分的氧化完成。典型地,在该实施方案中,前体药物部分在生理学条件下在氧化酶过程存在的条件下可被氧化。氧化优选地导致前体药物部分的除去和生物活性药物的释放。本发明的另一个方面涵盖了通过前体药物部分的消除发生的前体药物向生物活性药物的转化。一般而言,在该实施方案中,前体药物部分在生理学条件下利用化学反应或生物反应被消除。消除导致前体药物部分的除去和生物活性药物的释放。当然,本发明的任何前体药物化合物可经历任何上述机理的组合以使该前体药物转化为生物活性化合物。例如,特定化合物可经历水解、氧化、消除和还原以将前体药物转化为生物活性化合物。同样地,特定化合物可仅经历这些机理之一以将该前体药物转化为生物活性化合物。
本文使用的“癌”是指在哺乳动物中发现的所有类型的癌或赘生物或恶性肿瘤或良性肿瘤,包括癌肿和肉瘤。癌的实例是脑癌、乳癌、胰腺癌、颈癌、结肠癌、头颈癌、肾癌、肺癌、非小细胞肺癌、黑素瘤、间皮瘤、卵巢癌、肉瘤、胃癌、子宫癌和成神经管细胞瘤。
术语“白血病”广泛地是指造血器官的进行性恶性疾病并且通常以血液和骨髓中的白细胞及其前体的异常增殖和发展为特征。白血病通常基于以下进行临床分类(1)疾病的持续时间和特征-急性的或慢性的;(2)所牵涉细胞的类型;骨髓性的(骨髓源的),淋巴性的(淋巴源的)或单核细胞性的;和(3)在血液白血病性或非白血病性(亚白血病性)中异常细胞数目的增加或非增加。P388白血病模型作为体内抗白血病活性的预测模型被广泛接受。相信在P388试验中被检验为阳性的化合物将通常表现出一定程度的体内抗白血病活性,而与被治疗的白血病的类型无关。因此,本发明包括治疗白血病的方法,优选治疗以下白血病的方法:急性非淋巴细胞性白血病,慢性淋巴细胞性白血病,急性粒细胞性白血病,慢性粒细胞性白血病,急性早幼粒细胞性白血病,成人T细胞白血病,非白血性白血病,白血性白血病,嗜碱性粒细胞性白血病,胚细胞白血病,牛白血病,慢性粒细胞性白血病,皮肤白血病,干细胞性白血病,嗜酸细胞性白血病,Gross白血病,毛状细胞白血病,成血细胞性白血病,血胚细胞性白血病,组织细胞性白血病,干细胞性白血病,急性单核细胞性白血病,白细胞减少性白血病,淋巴性白血病,淋巴母细胞性白血病,淋巴细胞性白血病,淋巴源性白血病(lymphogenous leukemia),淋巴细胞性白血病(lymphoid leukemia),淋巴肉瘤细胞性白血病,肥大细胞白血病,巨核细胞白血病,小原粒型白血病,单核细胞性白血病,成髓细胞白血病,骨髓性白血症,骨髓性粒细胞性白血病,单核细胞性白血病,内格利型白血病,浆细胞白血病,浆细胞性白血病,早幼粒细胞性白血病,李德尔氏细胞白血病,先令氏白血病,干细胞性白血病,亚白血性白血病和未分化细胞性血病。
术语“肉瘤”泛指由诸如胚性结缔组织的物质组成的肿瘤并且通常由被包埋在原纤维或均质物质中的密堆积的细胞组成。可用4-甲氧基-咔唑和放疗进行治疗的肉瘤包括软骨肉瘤,胆管瘤,纤维肉瘤,淋巴肉瘤,黑肉瘤,粘液肉瘤,骨肉瘤,阿伯内西肉瘤,脂肉瘤,脂肪肉瘤,肺泡软组织肉瘤,成釉细胞肉瘤,葡萄簇状肉瘤,绿色肉瘤,绒毛膜肉瘤,胚胎性肉瘤,维尔姆斯肉瘤,子宫内膜肉瘤,间质肉瘤,尤因肉瘤,筋膜肉瘤,成纤维细胞肉瘤,巨细胞肉瘤,粒细胞肉瘤,霍奇金肉瘤,特发性多发性色素沉着性出血性肉瘤,B细胞免疫母细胞性肉瘤,淋巴瘤,T细胞免疫母细胞性肉瘤,延森肉瘤,卡波西肉瘤,科普弗细胞肉瘤,血管肉瘤,白血病性肉瘤,恶性间叶瘤性肉瘤,骨膜外肉瘤,网状细胞肉瘤,劳斯肉瘤,浆液囊性肉瘤,软组织肉瘤,滑膜肉瘤和毛细管扩张性肉瘤。
术语“黑素瘤”是指从皮肤和其它器官的黑素细胞系统产生的肿瘤。可用4-甲氧基-咔唑和放疗治疗的黑素瘤包括例如肢端色斑样黑素瘤,无黑色素性黑素瘤,良性幼年型黑色素瘤,Cloudman黑素瘤,S91黑素瘤,哈-腊黑素瘤,幼年型黑色素瘤,恶性着色斑型黑素瘤,恶性黑素瘤,结节型黑素瘤,甲床黑素瘤和表浅蔓延型黑素瘤。
术语“癌肿”是指由倾向于渗透周围组织并引起转移的上皮细胞组成的恶性新生物。可用4-甲氧基-咔唑和放疗进行治疗的示例性的癌肿包括例如腺泡癌(acinar carcinoma),腺泡癌(acinous carcinoma),腺囊癌(adenocystic carcinoma),腺囊癌(adenoid cystic carcinoma),乳腺癌,腺癌(carcinoma adenomatosum),肾上腺皮质癌,肺泡癌,肺泡细胞癌,基底细胞癌(basal cell carcinoma),基底细胞癌(carcinomabasocellulare),移行细胞癌,基底鳞状细胞癌,膀胱癌,细支气管肺泡癌(bronchioalveolar carcinoma),细支气管癌(bronchiolar carcinoma),支气管癌,髓样癌(cerebriform carcinoma),胆管细胞癌,绒癌,胶样癌,结肠-直肠癌,宫颈癌,粉刺癌,子宫体癌,筛状癌,铠甲状癌,癌疮,皮肤癌,柱状细胞癌,导管癌(duct carcinoma),硬纤维瘤(carcinomadurum),胚胎样癌,髓样癌(encephaloid carcinoma),表皮样癌,腺样上皮癌,外生型癌,恶性溃疡性癌(carcinoma ex ulcere),硬癌,胃癌,胶样癌(gelatiniform carcinoma),胶样癌(gelatinous carcinoma),巨细胞癌(giant cell carcinoma),巨细胞癌(carcinoma gigantocellulare),腺癌(glandular carcinoma),卵巢颗粒细胞瘤,基底细胞癌,血样癌,肝细胞癌,胡尔特尔细胞腺癌,hyaline carcinoma,肾上腺样癌(hypemephroidcarcinoma),幼稚性胚胎性癌,原位癌,表皮内癌,上皮内癌,Krompecher癌,库尔契茨基细胞癌,大细胞癌,豆状癌(lenticular carcinoma),豆状癌(carcinoma lenticulare),脂瘤癌,肺癌,淋巴上皮癌,甲状腺髓样癌,髓样癌,黑色素瘤,软癌,粘液癌(mucinous carcinoma),粘液癌(carcinoma muciparum),粘液细胞癌,粘液表皮样癌,粘液癌(carcinomamucosum),粘液癌(mucous carcinoma),粘液瘤样癌,鼻咽癌,燕麦细胞癌,骨样癌(carcinoma ossificans),骨样癌(osteoid carcinoma),卵巢癌,胰腺癌,前列腺癌,乳头状癌,门静脉周癌,原位癌,棘状细胞癌,髓样癌,肾的肾细胞癌,补充细胞癌,肉瘤样癌,schneideriancarcinoma,硬癌,阴囊癌,印指环状细胞癌,单纯癌,小细胞癌,马铃薯状癌,球状细胞癌,梭形细胞癌,骨样癌,鳞状癌,鳞状细胞癌,string carcinoma,血管扩张性癌(carcinoma telangiectaticum),血管扩张性癌(carcinoma telangiectodes),睾丸癌,转移细胞癌,甲状腺癌,结节性皮癌(carcinoma tuberosum),结节性皮癌(tuberous carcinoma),疣状癌和绒毛状癌。
优选的可用本发明的化合物治疗的癌包括:头颈鳞状细胞癌(眼癌、唇癌、口癌、咽癌、喉癌、鼻癌、舌癌和食管癌),黑素瘤,鳞状细胞癌(表皮),胶质母细胞瘤,星形细胞瘤,少突胶质细胞瘤,少突星形细胞瘤,脑膜瘤,神经母细胞瘤,横纹肌肉瘤,软组织肉瘤,骨肉瘤,在中枢神经系统部位的血液恶性病、乳癌(导管癌和原位癌),甲状腺癌(甲状腺乳头状癌和甲状腺滤泡型癌),肺癌(细支气管肺泡癌、小细胞肺癌、混合型小细胞/大细胞癌、复合性小细胞癌,非小细胞肺癌,鳞状细胞癌,大细胞癌和肺腺癌),肝细胞癌,结肠直肠癌,宫颈癌,卵巢癌,前列腺癌,睾丸癌,胃癌,胰腺癌,胆管瘤(cholangiosarcoma),淋巴瘤(T细胞和B细胞由来的霍奇金型和非霍奇金型淋巴瘤),白血病(骨髓和淋巴由来的急性和慢性白血病),和膀胱癌。
更优选的可用本发明的化合物治疗的癌包括:头颈鳞状细胞癌(眼癌、唇癌、口癌、咽癌、喉癌、鼻癌、舌癌和食管癌),黑素瘤,鳞状细胞癌(表皮),胶质母细胞瘤,神经母细胞瘤,横纹肌肉瘤,肺癌(细支气管肺泡癌癌,小细胞肺癌,混合型小细胞/大细胞癌,复合性小细胞癌,非小细胞肺癌,鳞状细胞癌,大细胞癌和肺腺癌),淋巴瘤(T细胞和B细胞由来的霍奇金型和非霍奇金型淋巴瘤),和白血病(骨髓和淋巴由来的急性和慢性白血病)。
本文的术语“4-甲氧基-咔唑”是指下式所示的那些化学物质或其药学可接受的盐形式:
其中,X是H或前体药物部分。
本发明的化合物可包括前体药物部分。被本发明所涵盖的前体药物部分的实例可选自磷酸酯,氨基酸酯,氨基酸酰胺,氨基烷基氨基甲酸酯,烷氧基烷基氨基甲酸酯,羟烷基氨基甲酸酯,烷氧基烷基酯,羟烷基酯,苯甲酸酯,烟酸酯,哌嗪醋酸酯,吗啉醋酸酯和曼尼希碱。被本发明所涵盖的前体药物部分的实例可选自:
优选的前体药物部分是曼尼希碱。优选的曼尼希碱包括但不限于4-甲基-哌嗪-1-基甲基-,吗啉-4-基甲基-和二乙基氨基甲基-。
本发明的化合物还可是药理学可接受的盐、水合物、溶剂合物或代谢物的形式。药理学可接受的盐包括无机酸和有机酸的碱盐,所述酸包括但不限于盐酸,氢溴酸,硫酸,磷酸,甲磺酸,乙磺酸,苹果酸,乙酸,草酸,酒石酸,枸橼酸,乳酸,富马酸,琥珀酸,马来酸,水杨酸,苯甲酸,苯乙酸,扁桃酸,抗坏血酸,葡糖酸等等。当本发明的化合物包括酸性官能团诸如羧基时,则用于羧基的适当的药学可接受的阳离子是本领域技术人员公知的并且包括碱金属、碱土金属、铵、季铵的阳离子等等。本发明涵盖了当本发明的化合物为药理学可接受的盐形式,所述盐形式可原地产生或作为分离的固体。
本发明的化合物,特别是刚刚描述的盐形式,可与本领域公知的各种赋形剂和/或助剂组合使用,它们充当药学可接受的载体以允许药物作为例如注射剂、悬浮剂、乳剂、片剂、胶囊和膏剂的形式被给药。这些药物组合物,包括辐射敏化量的所述化合物,可通过导致乏氧肿瘤细胞对辐射敏化的任何可接受的手段被给予。对于恒温动物,特别是对于经历放疗的人,给药可以是经口、皮下、腹膜内或静脉内途径。为了破坏乏氧肿瘤细胞,包含辐射敏化剂的药物组合物以有效使乏氧肿瘤细胞对辐射敏化的量被给予。被给予的该特定剂量将根据诸如以下因素的不同而异:患者的总体健康和物理条件以及他们的年龄和体重,患者疾病病况的阶段,以及任何同时发生的治疗的存在。
给予有效量的方法还可根据被治疗的病症或疾病的不同而异。相信通过静脉内给用4-甲氧基-咔唑进行治疗,该4-甲氧基-咔唑与适当的载体、另外的一种或多种癌抑制化合物或帮助给用的稀释剂进行配制,是给予该化合物至温血动物的优选方法。
本文所述的化合物可以纯形式、结合其它活性成分、或结合药学可接受的无毒的赋形剂或载体的形式被给予。口服组合物通常包括惰性稀释剂载体或食用载体。药学相容性的粘合剂和/或助剂可作为组合物的一部分被包括在内。片剂、丸剂、胶囊、锭剂等可包含以下的任何成分或具有类似性质的化合物:粘合剂诸如微晶纤维素、黄蓍胶或明胶;赋形剂诸如淀粉或乳糖,分散剂诸如海藻酸,Primogel或玉米淀粉;润滑剂诸如硬脂酸镁;助流剂诸如胶体二氧化硅;甜味剂诸如蔗糖或糖精;或芳香剂诸如胡椒薄荷、水杨酸甲酯或橙味调味剂。当剂量单位形式是胶囊时,胶囊除了上述类型的材料之外还可包含液体载体诸如脂肪油。另外,剂量单位形式可包含修饰剂量单位的物理形式的多种其它材料,例如糖、虫胶或肠溶试剂的包衣。另外,糖浆剂除了活性化合物之外还可包含蔗糖作为甜味剂和某些防腐剂、染料、着色剂和调味剂。
被给予到患者的化合物的量足够使待治疗的恶性赘生物对辐射敏化但是低于可引起毒性效果的量。该量将根据肿瘤的类型、被治疗患者的物种、预定的适应症剂量和患者的体重或体表面的不同而异。辐射可以多种不同的分次方案被给予至患者,即,总的辐射剂量在若干天到若干星期的时段内被给予。这些剂量从每天(即,每周5次)剂量持续长达六周到一周一次剂量持续4-6周。
被给予至患者的辐射敏化化合物的量可在辐射治疗前、辐射治疗期间或辐射治疗之后被给予。然而,优选本发明的化合物在辐射治疗之前被给予。
在给予辐射敏化组合物到乏氧肿瘤细胞并且经过足够增强乏氧肿瘤细胞对辐射敏化的时段后,乏氧肿瘤细胞用有效破坏乏氧肿瘤细胞的剂量的辐射进行照射。通常,患者接受每天约2Gy达5天的辐射剂量。通常,患者接受在7-8周内的约70至约80Gy的总辐射剂量,待给予的每个单独辐射剂量在给予辐射敏化剂后的约1-4小时内被给予。根据需要重复辐射敏化治疗和照射的这一顺序以减轻并且最佳地减小或消除恶性肿瘤的蔓延。然而,本领域技术人员可理解的是,日辐射剂量和总辐射剂量将根据患者的肿瘤类型、治疗方案和物理状态的不同而异。例如,本发明化合物的日剂量通常不受具体限制,但是可因患者的年龄、癌、体重和目前的治疗方案和/或药物的不同而异。另外,本发明的化合物可用作辐射敏化剂并且可以在暴露于辐射之前以一个或多个剂量即一个到若干个剂量被给予。
在裸鼠中使用U87MG耐辐射异种移植瘤的初始辐射敏化研究(未优化的剂量给药方案)
对细胞照射以诱导检查点抑制,这允许细胞修复DNA损伤,采用活化的PARP帮助修复DNA损伤。假设地,给予与单剂量或分剂量的辐射联合使用的PARP抑制剂将降低被照射细胞修复DNA损伤的能力并增加细胞杀死。因此,PARP抑制剂将与分剂量的辐射协同地增加瘤生长延迟。使用实施例7/实施例6进行这一假设的初始实验在裸鼠的耐辐射U87MG人胶质母细胞瘤异种移植瘤中进行。如图3所示,单独给予实施例7,单独给予辐射,给予实施例7结合辐射(100mg/kg剂量当量的实施例6,s.c.,每日一次,在辐射前两天,和结合7.5Gy辐射持续3天),在携带定制肿瘤的小鼠中进行。作为单独试剂给予的实施例7对瘤生长没有影响。用媒介物或实施例7治疗的肿瘤在10.0天或9.6天内分别达到2000立方毫米的肿瘤体积(p=0.798,相对于对照)。单独给予的辐射使达到2000立方毫米所需的时间增加到16.1天,使瘤生长延迟(TGD)增加6.1天(p=0.033,相对于对照)。相比之下,给予实施例7结合辐射治疗,使肿瘤达到2000立方毫米所需的时间增加到24.8天,对应于14.8天的TGD。联合治疗的效果幅度比仅仅给予实施例7的可比方案(p=0.001)或仅仅给予辐射的可比方案(p=0.006)中所观察到的效果幅度更强,表明实施例7表现为真实的辐射敏化剂的模式。实施例6的与效力有关的血浆水平Cmax(在100mg/kg的实施例7)是23μM,与在该剂量下的化学敏化研究中所实现的那些是可相比的。
在裸鼠中使用U87MG耐辐射异种移植瘤使用实施例7和临床相关分次放疗剂量给药方案进行的辐射敏化研究。
随后评价了实施例7(30和100mg/kg,s.c.)结合临床相关分次放疗方案(2Gy×5天)的辐射敏化研究。在辐射后0.5小时给予实施例7达5天,并且在辐射方案完成后继续剂量给药实施例7达16天。这一剂量给药方案的基本原理基于从辐射后10-12天发生的辐射损伤中进行DNA修复的事实,因此,连续地剂量给药实施例7并调节PARP活性覆盖了细胞周期停滞和DNA修复时间,它们将与分次辐射协同地增加辐射敏感性和瘤生长延迟。如图1和2所示,给予单独的辐射(2Gy×5天)与用媒介物处理的肿瘤相比产生2.5天的TGD。给予实施例7(CEP 30;30mg/kg,s.c.),与单独辐射(p≤0.05)相比,增加TGD到15天,即增加4倍;和与单独的实施例7(p≤0.001)相比,增加TGD到26天。实施例6的与辐射敏化效力有关的血浆水平Cmax是5.5μM。给予实施例7(100mg/kg,s.c.)与分次放疗产生显著的抗肿瘤效力,但是在第11天有80%的死亡率。在100mg/kg,s.c.剂量下的血浆水平Cmax是21uM,与在该剂量下在化学敏化研究和如上所述的初始辐射敏化研究中的暴露水平一致。
这些数据显示了在使用临床相关分剂量给药方案的更低浓度的实施例7(CEP 30;30mg/剂量当量的实施例6,s.c.,每日一次,×21天)下,观察到TGD有更高的增加。另外,单独的实施例7(CEP 30;30mg/kg剂量当量的实施例,s.c.,每日一次,×21天)对瘤生长抑制没有效果,显示了实施例7作为“真实的”辐射敏化剂起作用。
为了评价治疗受益,在骨髓和空肠隐窝试验中评价了实施例7(30和100mg/kg剂量当量的实施例6,sc)加上2Gy辐射×5天,以确定实施例7是否增强辐射诱导的正常组织(NT)毒性。骨髓和肠粘膜的评价揭示了实施例7(30和100mg/kg剂量当量的实施例6,sc)不增强这些组织中的辐射毒性,研究指出CEP-9722当口服给予时发挥辐射敏化效应。这些联合数据指明了在耐照射神经胶质瘤模型中实施例7通过增加分次放疗的有效性而以大于加合的方式起到辐射敏化剂的作用而且不增强辐射诱导的NT毒性。
实施例
本发明的化合物可以采用本领域技术人员公知的许多方法制备,所述方法不限于如下所述的那些,或者通过采用有机合成领域技术人员已知的标准技术对这些方法进行改进下方法。与本发明有关而公开的所有方法被认为以任何比例实践,包括毫克、克、数克、千克、数千克和商业级的工业规模。
本发明的特征在于制备可用作PARP的抑制剂的本文所述的多环化合物的方法。该方法包括从4-甲氧基吲哚开始的多步骤合成。具体而言,4-甲氧基吲哚A用例如丁基锂、二氧化碳、叔丁基锂和酮B连续处理,得到2位被取代的4-甲氧基吲哚叔醇C。该叔醇在例如使用盐酸或甲苯磺酸的酸性条件下倍消除,得到被取代的2-乙烯剂吲哚D。D与亲二烯体诸如但不限于马来酰亚胺(E)进行的狄尔斯-阿德耳环加成得到环加成中间体F。环加成中间体例如与氧在催化剂诸如钯或铂的存在的条件下或与氧化剂诸如DDQ或四氯对醌进行芳构化,得到咔唑G。
进一步用烷基化试剂或酰化试剂处理G得到本发明的吲哚-N-取代的咔唑衍生物。用于适当的前体药物衍生物的选择和制备的常规方法例如描述在Prodrugs,Sloane,K.B.编;Marcel Dekker:New York,1992中,其作为参考全文并入本文。
本发明的化合物是PARP抑制剂。抑制剂的效力可通过测量体外或体内的PARP活性进行检测。优选的试验监控辐射性标记的ADP-核糖单元从[32p]NAD向蛋白质受体诸如组蛋白或PARP自身的转移。PARP的常规试验公开在Purnell和Whish的Biochem.J.1980,185,775中,其作为参考并入本文。
实施例1
细胞系
在市售的含1.5g/L碳酸氢钠、0.1nM非必需氨基酸、1.0nM丙酮酸钠以及10%胎牛血清(FBS)的极限必需培养基(MEM)中培养U87MG人胶质母细胞瘤细胞。
实施例2
肿瘤细胞移植和生长
按指数规律生长的细胞被收获并被注射((2×106)个细胞/小鼠)进入到市售的无胸腺的NCR NUM裸鼠的右侧腹中。携带200-400立方毫米肿瘤的动物根据大小被随机分成适当的治疗组(n=10)。每3-4天使用游标卡尺测量肿瘤。使用下式计算肿瘤体积:
V(mm3)=0.5236×长(mm)×宽(mm)[长(mm)+宽(mm)/2]。
实施例3
方法:将U87MG人胶质母细胞瘤细胞皮下(s.c.)注射进入无胸腺的NCR NUM小鼠的右后肢中并允许生长到200立方毫米的平均肿瘤体积。接受放疗的小鼠在辐射前用100mg/kg氯胺酮+10mg/kg赛拉嗪或37.5mg/kg氯胺酮+0.2mg/kg乙酰丙嗪s.c.进行麻醉,以提供25-30分钟的镇静。将被麻醉的小鼠置于适形性的、与动物的体格大小和形状相符的具展延性的铅护罩中而不产生不适当的压力。用铅将躯体掩蔽。携带肿瘤的腿或被暴露出来的肿瘤用适当剂量进行照射。在肿瘤被照射后,将小鼠送返回笼的加热垫上直到从麻醉药中恢复知觉。实施例7在照射(RT)后尽可能快地(30分钟内)被给予。图3:小鼠被随机分成以下的处理组(n=10)∶1)媒介物,2)仅给予照射(7.5Gy持续3天),3)仅给予实施例7(100mg/kg剂量当量的实施例,s.c,每日一次,持续5天),和4)实施例7+照射。在第1-5天给予和在第2、3和4天在照射后的30分钟s.c.给予单独的实施例7或者媒介物。使用混合效果回归到log10肿瘤体积作为处理时间的函数进行数据分析。在SAS8.3(SAS Institute Inc.,Cary,NC)上进行分析。图1和2:将小鼠随机分成以下的处理组并给予:1)媒介物,2)RT(5×2Gy),3)RT+实施例7(30或100mg/kg s.c.剂量当量的实施例6,每天一次,×21天)或4)仅给予实施例7(30或100mg/kg剂量当量的实施例6,s.c,每天一次,×21天)。实施例7在第1-21天被给予并且RT在第1-5天被给予。所有动物在相同日子进行测量。在log转化线性模型中对单独的肿瘤体积量度进行模型化处理并且测定了肿瘤达到约2000立方毫米的最佳配合时间。单因素方差分析和post hoc分析用于测定显著性。≤0.05的p值被认为具有显著性。
结果:所有的组以200立方毫米的相似大小的肿瘤开始治疗(P=0.83,在第0天比较各组)。如图3所示,单独给予实施例7,单独给予辐射,给予实施例7结合辐射(100mg/kg剂量当量的实施例6,s.c.,每日一次,在辐射前两天,和结合7.5Gy辐射持续3天),在携带定制肿瘤的小鼠中进行。作为单独试剂给予的实施例7对瘤生长没有影响。仅用媒介物或实施例7处理的肿瘤分别在第10.0天或9.6天达到2000立方毫米的肿瘤体积(P=0.798,相对于对照)。单独给予照射使达到2000立方毫米所需的时间增加到16.1天,使瘤生长延迟(TGD)增加了6.1天(P=0.033,相对于对照)。给予实施例7结合辐射治疗,使肿瘤达到2000立方毫米所需的时间增加到24.8天,对应于14.8天的TGD。联合治疗的效果幅度比仅仅给予实施例7的可比方案(p=0.001)或仅仅给予辐射的可比方案(p=0.006)中所观察到的效果幅度更强,表明实施例7表现为真实的辐射敏化剂的模式。如图1和图2所示,给予实施例7(CEP 30;30mg/kg剂量当量的实施例6,s.c.)结合RT,与给予单独的照射(p≤0.05)相比,增加TGD到15天,即增加4倍;和与给予单独的实施例7(p≤0.001)相比,增加TGD到26天,即增加6倍。给予实施例7(100mg/kg,s.c.)与分次放疗,产生显著的抗肿瘤效力,但是在第11天有80%的死亡率。这些数据显示了在使用临床相关分剂量给药方案的更低浓度的实施例7(CEP 30;30mg/kg)下,观察到TGD有更高的增加。另外,给予单独的实施例7对瘤生长抑制没有效果,显示了实施例7作为“真实的”辐射敏化剂的起作用。
实施例4
DNA损伤的评价
抗体:可使用一次抗体对抗磷酸组蛋白H2AX(Cell Signaling,#2577,1∶1000)和GAPDH(Abeam,#9484,1∶5000)。二次抗体可以是山羊抗小鼠IRDye800(Rockland,#610-132-121)和山羊抗兔Alexa fluor700(Molecular Probes,#A21038)。
U87MG细胞可用3Gy或5Gy辐射进行照射,然后在辐射后的0.5小时用实施例6(300nM和1μM)进行处理。然后可在加入实施例6后的0.5、1和4小时收集样品。细胞可在冰上在RIPA缓冲液(150mMNaCl、1% NP-40、0.5%脱氧胆酸钠、0.1% SDS、50mM Tris pH 8.0)加上抑制剂鸡尾酒(蛋白酶抑制剂鸡尾酒Set III,Calbiochem)和1mMNa3VO4中进行细胞溶解,并且可使用BCA蛋白质试验试剂盒(Pierce#23225)进行定量分析。样品采用4-12% bis tris胶凝(Novex #NP0336)与MES SDS缓冲液(Novex,#NP0002)在140伏特下进行电泳分析(15μg蛋白质),然后使用2倍转移缓冲液(Novex,#NP0006)通过半干转移器(18伏特,持续35天)被转移到硝化纤维膜(Biorad,#162-0145)中。然后将膜在用1倍TBS以1∶1稀释的Odyssey阻断缓冲液(Licor#927-40000)中在室温下阻断1小时,然后与一次抗体在用1倍TBS-T 0.05%以1∶1稀释的Odyssey阻断缓冲液中在4℃下培养过夜。第二天,膜可以用1倍TBS-T洗涤4次,每次洗涤10分钟,然后与两个二次抗体以1∶10,000(在用1倍TBS-T 0.05%以1∶1稀释的Odyssey阻断缓冲液中)在室温下避光培养1.5小时。斑点可用1X倍TBS-T 0.2%洗涤四次,每次洗涤10分钟(避光),然后在Odyssey红外成象仪上读数。GAPDH可使用800nm信号目测并且磷酸-H2AX可使用700nm信号进行检测。对于磷酸组蛋白H2AX期望的大小为15kDa,对于GAPDH期望的大小为36kDa。
实施例5
细胞周期分析
U87MG细胞可以用3Gy或5Gy辐射进行照射,然后在照射后0.5小时用实施例6(300nM和1μM)处理。然后可在加入实施例6的8、24和48小时(和由本领域技术人员确定的任何时间)收集样品。细胞在100%乙醇中在4℃下固定过夜。第二天,细胞与细胞周期试剂(GuavaTechnologies#4500-0220)在室温下避光培养1小时。被染色的核可采用流式细胞光度术(Guava EasyCyte;使用本领域技术人员已知的设定,例如427X8;探测数据5,000次事件/样品)进行分析。在细胞周期的每个阶段中的细胞的百分数可以采用细胞周期分析软件(Guava技术)来测定。
实施例6
7-甲氧基-1,3,5,11-四氢-5,11-二氮杂苯并[a]三茚-4,6-二酮
步骤1:向冷却(-78℃)的4-甲氧基吲哚(2.0g,13.1mmol)在无水THF(20mL)中的溶液中缓慢加入含nBuLi的己烷(2.5M,5.2mL,13.1mmol),混合物在-78℃搅拌另外30分钟,然后将CO2气鼓入反应混合物中达15分钟,然后另外搅拌15分钟,减压除去过量的二氧化碳和半数THF体积,向反应混合物中加入另外的无水THF(10mL)并将反应混合物冷却回到-78℃,在30分钟内向反应混合物中缓慢加入1.7M叔丁基锂(7.7mL,13.1mmol),在-78℃下继续搅拌2小时,然后缓慢加入环戊酮(1.7g,20.4mmol)在无水THF(5mL)中的溶液,在-78℃下另外搅拌1小时后,通过滴加水(5mL)、然后滴加饱和的NH4Cl溶液(20mL)将反应混合物淬灭,加入乙醚(50mL)并将混合物在室温下搅拌10分钟,分离有机层,干燥(MgSO4)并浓缩,得到醇(1-(4-甲氧基-1H-吲哚-2-基)-环戊醇)和二烯(2-环戊-1-烯基-4-甲氧基-1H-吲哚)的混合物。向含该混合物的丙酮(15mL)中加入2N HCl(5mL),混合物搅拌另外10分钟,加入水(50mL),然后收集二烯产物2-环戊-1-烯基-4-甲氧基-1H-吲哚并真空干燥,产物通过硅胶色谱纯化(EtOAC/己烷9∶1)。1H NMR(DMSO-d6)δ1.9-2.1(m,3H),2.6-2.75(m,3H),3.9(s,3H),6.1(s,1H),6.3(s,1H),6.4(m,1H),6.9-7.0(m,2H),11.1(s,1H)。这一产物直接用于下一步。
步骤2:2-环戊-1-烯基-4-甲氧基-1H-吲哚(0.1g,0.47mmol)和马来酰亚胺(0.0.9g,0.91mmol)在乙酸(5mL)中的混合物在室温下搅拌1小时,加入水并用EtOAc提取产物,其用2N Na2CO3溶液、水和饱和NaCl溶液洗涤,并干燥(MgSO4),干燥剂被过滤除去并且将溶剂浓缩以得到0.13g。MS:m/z 309(M-H)。
步骤3:向在甲苯(2mL)和乙酸(3mL)中的得自步骤2的产物(0.123g,0.4mmol)中加入2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ,185mg,0.8mmol),在0℃搅拌30分钟后,将混合物浓缩并用EtOAC和抗坏血酸处理,在30分钟后,将混合物用2N Na2CO3碱化,EtOAc层用水、饱和NaCl溶液洗涤,干燥(MgSO4)并浓缩,得到产物0.095mg;MS:m/z305(M-H)+。1H NMR(DMSO-d6)δ2.26-2.31(m,2H),3.1-3.2(m,2H),3.3-3.4(m,2H),3.9(s,3H),6.7(m,1H),7.1(m 1H),6.4(m,1H),7.4(m,1H),10.6(s,1H),11.9(s,1H)。
实施例7
7-甲氧基-5-(4-甲基-哌嗪-1-基甲基)-1,2,3,11-四氢-5,11-二氮杂苯并[a]三茚-4,6-二酮
在0.5小时内向实施例6(10.0g,30mmol)和N-甲基哌嗪(12.4g,124mmol)在乙醇(950mL)的淤浆中加入多聚甲醛(5.60g,62.4mmol)并搅拌24小时,将淤浆蒸发至干,向残余物中加入己烷(500mL),声处理15分钟,并搅拌1.5小时,并在0℃冷却15分钟,收集黄色固体并用冷己烷洗涤,该产物被溶解在温暖的四氢呋喃(THF)(250mL)中并过滤,将滤液滴加到己烷(3L)中,搅拌15分钟,并收集实施例7的沉淀物并用己烷洗涤。(12.0g,96%收率)。1H NMR(DMSO-d6)2.12(s,3H),2.35(m,8H),2.53(m,4H),3.18(m,2H),4.44(s,3H),6.70(d,1H),7.10(d,1H),7.40(t,1H),11.96(s,1H)。MS m/z 419(M+H)。
实施例8
7-甲氧基-5-(二乙基氨基甲基)-1,2,3,11-四氢-5,11-二氮杂苯并[a]三茚-4,6-二酮(实施例8a)
7-甲氧基-5,11-(双-二乙基氨基甲基)-1,2,3,11-四氢-5,11-二氮杂苯并[a]三茚-4,6-二酮(实施例8b)
向实施例6(50mg,0.16mmol)在DMF(5mL)中的淤浆中加入多聚甲醛(73mg,0.81mmol)、二乙胺(84μL,0.81mmol)并在室温下搅拌1天,将反应蒸发,将残余物与己烷研磨并蒸发,得到两个产物,为油状物,(比率6-1,16b:16c)。1H-NMR(DMSO-d6)0.98(t,3H),1.11(t,3H),2.27(m,2H),2.53(m,8H),2.57(m,15H),3.17(t,2H),3.50(m,1H),3.97(s,3H),4.14(d,2H),4.71(d,2H),6.82(t,2H),6.75(d,2H),7.13(d,2H),7.33(m,1H),7.46(t,3H),7.52(m,1H),11.95(s,1H)。16b:MS m/z 392。16cMS m/z 476。
实施9
7-甲氧基-5,11-(双-吗啉-4-基甲基)-1,2,3,11-四氢-5,11-二氮杂苯并[a]三茚-4,6-二酮
向实施例6(15mg,0.049mmol)在DMF(1mL)中的淤浆中加入多聚甲醛(42mg,0.05μL)、吗啉(160mg,1.9mmol)并在70℃加热18小时,将混合物蒸发,将残余物与己烷研磨,然后溶解在CH2Cl2中,过滤并蒸发,将残余物与Et2O研磨,并收集实施例9,为黄色固体(5mg,20%),1H NMR(DMSO-d6)7.52(t,1H),7.39(d,1H),6.82(d,1H),5.0(s,2H),4.46(s,2H),3.98(s,3H),3.56(s,6H),3.49(s,4H),2.50(s,6H),2.49(s,4H),2.45(m,2H);MS m/z 505(M+H)。
实施例10
7-甲氧基-5-(吗啉-4-基甲基)-1,2,3,11-四氢-5,11-二氮杂苯并[a]三茚-4,6-二酮
向实施例6(50mg,0.16mmol)在乙醇(10mL)中的淤浆中加入多聚甲醛(72mg,0.8mmol)、吗啉(100g,1.1mol)并在50℃加热5小时,蒸发反应,并加入水(15mL),收集黄色固体(59mg)。1H NMR(DMSO-d6)11.98(s,1H),7.45(t,1H),7.13(d,1H),6.75(d,1H),4.44(s,2H),3.97(s,3H),3.56(s,4H),3.18(t,2H),2.29(t,2H)。MS m/z 406(M+H)。
实施例11
PARP酶活性的测量
PARP活性如下进行监控:将辐射性标记的ADP-核糖单元从[32P]NAD+转移到蛋白质受体诸如组蛋白或PARP自身上。试验混合物包含100mM Tris(pH 8.0)、2mM DTT、10mM MgCl2、20ug/ml DNA(通过声处理使其带缺口)、20mg/ml组蛋白H1、5ng重组人PARP,和抑制剂或DMSO(<2.5%(v/v)),最终体积为100uL。通过加入补充有2uCi[32P]NAD+/mL的100μM NAD+并保持在室温下达12分钟引发反应。通过加入100μM的50%TCA使试验终止并且在96孔滤板(Millipore,MADP NOB 50)上收集辐射性标记的沉淀物,用25%TCA洗涤。酸不溶性辐射性的量,相当于聚ADP-核糖化蛋白质,在WallacMicroBeta闪烁计数器中定量表示。
抑制剂的IC50的测定。
通过比较在抑制剂存在的条件下的PARP、VEGFR2或MLK3活性与仅存在DMSO的条件下的活性计算单点抑制数据。通过绘制抑制百分数-log10化合物浓度产生化合物的抑制曲线。IC50值通过使用S形剂量-反应(可变斜率)方程式在GraphPad Prism中如下进行非线性回归进行计算:
其中y是在给定浓度下的活性%,x是化合物浓度的对数,底部是在最低供试化合物浓度下的抑制%,以及顶部是在最高供试化合物浓度下的抑制%。底部和顶部的值分别固定在0和100。IC50值作为至少三次单独测定的平均数被报道。
使用本文公开的试验,下表2显示了本发明的化合物用于PARP抑制的实用性。如果本发明的化合物的IC50值低于50uM则被认为具有活性。在下表中,对于PARP的抑制,具有“+”的本发明的化合物的PARP抑制IC50低于10000nM;具有″++″的本发明的化合物的PARP抑制的IC50低于1000nM;具有″+++″的本发明的化合物的PARP抑制的IC50低于100纳米。当没有IC50值时,数据还有待于确定。
表2
实施例 | 编号 | PARP IC50(nM) |
6 | 6 | +++ |
7 | 7 | +++ |
8 | 8a/8b | +++ |
9 | 9 | +++ |
10 | 10 | +++ |
实施例12
进行初步研究旨在确定口服给药的实施例7的辐射敏化能力。
肿瘤细胞移植和生长
按指数规律生长的细胞被收获并被注射(2×106个细胞/小鼠)进入到市售的无胸腺的NCR nu/nu裸鼠的右侧腹中。将携带200-400立方毫米肿瘤的动物根据大小被随机分成适当的处理组(n=4)。每3-4天使用游标卡尺测量肿瘤体积。使用下式计算肿瘤体积:
V=a2b/2,其中a和b分别表示短尺寸和长尺寸。
方法:将U87MG人胶质母细胞瘤细胞皮下(s.c.)注射进入无胸腺的NCR nu/nu裸鼠的右后肢中并允许生长到200立方毫米的平均肿瘤体积。接受放疗的小鼠在辐射前用100mg/kg氯胺酮+10mg/kg赛拉嗪或37.5mg/kg氯胺酮+0.2mg/kg乙酰丙嗪s.c.进行麻醉,以提供25-30分钟的镇静。将被麻醉的小鼠置于适形性的、与动物的体格大小和形状相符的具展延性的铅护罩中而不产生不适当的压力。用铅将躯体掩蔽。携带肿瘤的腿或被暴露出的肿瘤用适当的剂量进行照射。在照射肿瘤后,将小鼠送返回笼的加热垫上直到从麻醉药中恢复知觉。实施例7在照射(RT)之后尽可能快地(在30分钟内)被给予。将小鼠随机分成以下的处理组并给予:1)媒介物,2)RT(2Gy×5天),3)RT+实施例7(200或300mg/kg p.o.剂量当量的实施例6,每天一次,×21天)或4)仅仅给予实施例7(200或300mg/kg剂量当量的实施例6,p.o.,每天一次,×21天)。实施例7在第1-21天被给予并且RT在第1-5天被给予。所有动物在相同日子进行测量。在log转化线性模型中对单独的肿瘤体积量度进行模型化处理并且测定了肿瘤达到约2000立方毫米的最佳配合时间。
结果:如图5所示,给予实施例7(Cep 300;300mg kg剂量当量的实施例6,p.o.,每天一次,×21天)+RT(2Gy×5天)导致在第8天瘤生长停止并持续整个研究(31天),而给予实施例7(Cep 200;200mg/kg剂量当量的实施例6,p.o.,每天一次,×21天)+RT(2Gy×5天)和给予单独的实施例7(200和300mg/kg剂量当量的实施例6,p.o.,每天一次,×21天)与给予单独的RT相比对瘤生长没有效果。所得结果表明单独给予实施例7对瘤生长没有效果,证实了得自s.c.剂量给药的数据。
本领域技术人员可理解的是,可对本发明的优选方案进行许多的变化和修改,并且这些变化和修改不脱离本发明的精神。因此,权利要求书涵盖了落入本发明的精神和范围内的所有这些的等价变体。
本文引用的所有参考文献以全文并入本文作为参考。
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Claims (11)
1.下式(I)的辐射敏化剂或其药学可接受的盐在制备用于使罹患胶质母细胞瘤的哺乳动物的癌细胞对辐射敏化的药物中的应用:
其中,X是H或-CH2NR1R2;
R1是H或C1-4烷基;
R2是H或C1-4烷基;
或者,R1和R2与其所连接的氮原子一起形成选自吡咯基、吡咯烷基、哌啶基、吗啉基、硫代吗啉基和哌嗪基的杂环基,其中所述杂环基任选被C1-4烷基取代。
2.权利要求1的应用,其中X选自4-甲基-哌嗪-1-基甲基-,吗啉-4-基甲基-和5-二乙基氨基甲基-。
3.权利要求1的应用,其中药物的给药途径是静脉内、皮下、经口或腹膜内途径。
4.权利要求1的应用,其中药物的给药途径是静脉内途径。
5.权利要求1的应用,其中所述式I的辐射敏化剂是7-甲氧基-1,2,3,11-四氢-5,11-二氮杂苯并[a]三茚-4,6-二酮或其药学可接受的盐。
6.权利要求1的应用,其中所述式I的辐射敏化剂是7-甲氧基-5-(4-甲基-哌嗪-1-基甲基)-1,2,3,11-四氢-5,11-二氮杂苯并[a]三茚-4,6-二酮或其药学可接受的盐。
8.权利要求7的药物组合物,其中化合物是:
或其药学可接受的盐形式。
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CN101500563A (zh) * | 2006-06-19 | 2009-08-05 | 赛福伦公司 | 环烷酰吡咯并咔唑衍生物及其作为parp、vegfr2和mlk3抑制剂的应用 |
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US6635642B1 (en) * | 1997-09-03 | 2003-10-21 | Guilford Pharmaceuticals Inc. | PARP inhibitors, pharmaceutical compositions comprising same, and methods of using same |
US6197785B1 (en) * | 1997-09-03 | 2001-03-06 | Guilford Pharmaceuticals Inc. | Alkoxy-substituted compounds, methods, and compositions for inhibiting PARP activity |
AU9297998A (en) * | 1998-05-15 | 1999-12-06 | Guilford Pharmaceuticals Inc. | Carboxamide compounds, compositions, and methods for inhibiting parp activity |
JP2005501848A (ja) * | 2001-08-15 | 2005-01-20 | アイコス コーポレイション | 2h−フタラジン−1−オンおよびその使用方法 |
NZ553295A (en) * | 2004-09-22 | 2010-04-30 | Pfizer | Therapeutic combinations comprising poly(ADP-ribose) polymerases inhibitor |
WO2006110683A1 (en) * | 2005-04-11 | 2006-10-19 | Abbott Laboratories | 2-substituted-1h-benzimidazole-4-carboxamides are parp inhibitors |
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WO2001085686A2 (en) * | 2000-05-09 | 2001-11-15 | Cephalon, Inc. | Multicyclic compounds and the use as inhibitors of parp, vegfr2 and mlk3 enzymes |
CN101500563A (zh) * | 2006-06-19 | 2009-08-05 | 赛福伦公司 | 环烷酰吡咯并咔唑衍生物及其作为parp、vegfr2和mlk3抑制剂的应用 |
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MX2009005292A (es) | 2009-08-13 |
CA2671517A1 (en) | 2008-05-29 |
IL198519A0 (en) | 2010-02-17 |
NZ576693A (en) | 2011-12-22 |
PT2086525E (pt) | 2010-12-09 |
AU2007321987A1 (en) | 2008-05-29 |
ATE483456T1 (de) | 2010-10-15 |
JP2010510312A (ja) | 2010-04-02 |
CA2671517C (en) | 2015-01-27 |
JP5542444B2 (ja) | 2014-07-09 |
TW200829276A (en) | 2008-07-16 |
ES2352817T3 (es) | 2011-02-23 |
EP2086525A1 (en) | 2009-08-12 |
US20080146556A1 (en) | 2008-06-19 |
CN101784268A (zh) | 2010-07-21 |
NZ595522A (en) | 2013-04-26 |
DE602007009717D1 (de) | 2010-11-18 |
CL2007003331A1 (es) | 2008-07-04 |
AU2007321987B2 (en) | 2014-01-23 |
WO2008063644A1 (en) | 2008-05-29 |
AR063869A1 (es) | 2009-02-25 |
TWI519313B (zh) | 2016-02-01 |
TWI636795B (zh) | 2018-10-01 |
EP2086525B1 (en) | 2010-10-06 |
IL198519A (en) | 2014-07-31 |
TW201601762A (zh) | 2016-01-16 |
HK1137347A1 (en) | 2010-07-30 |
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