CN112351985B - 吡啶并嘧啶酮衍生物用作axl抑制剂 - Google Patents
吡啶并嘧啶酮衍生物用作axl抑制剂 Download PDFInfo
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- CN112351985B CN112351985B CN201980043846.4A CN201980043846A CN112351985B CN 112351985 B CN112351985 B CN 112351985B CN 201980043846 A CN201980043846 A CN 201980043846A CN 112351985 B CN112351985 B CN 112351985B
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Abstract
公开了吡啶并嘧啶酮衍生物和包含其的药物组合物,其用作Axl抑制剂,用于治疗由Axl介导的疾病或病症,例如多种类型的癌症和转移。还公开了通过向受试者施用治疗有效量的吡啶并嘧啶酮衍生物来治疗Axl介导的疾病或病症的方法。
Description
技术领域
本发明涉及吡啶并嘧啶酮衍生物和包含其的组合物,它们可用作Axl抑制剂,用于治疗由Axl介导的疾病或病症。
背景技术
蛋白激酶在调节多种细胞过程和维持对细胞功能的控制中起着核心作用。蛋白激酶催化并调节磷酸化过程,从而激酶响应各种细胞外信号将磷酸基团共价结合到蛋白质或脂质靶标上。细胞外刺激,例如激素,神经递质,生长和分化因子,细胞周期事件,环境压力和营养压力,可能会影响与细胞生长,迁移,分化,激素分泌,转录因子激活,肌肉收缩,葡萄糖代谢,蛋白质合成控制和细胞周期调节有关的一种或多种细胞反应。
Axl是受体酪氨酸激酶TAM(Tyro3-Axl-Mer)家族的成员,该酪氨酸激酶在激活后可以调节肿瘤细胞的存活,增殖,迁移和侵袭,血管生成以及肿瘤与宿主的相互作用。已经从上皮和血液学起源的多种恶性肿瘤中描述了Axl的过表达,并且通常与不良的预后有关。而且,Axl表达与上皮到间质转化(EMT)有关,这是转移性肿瘤的常见特征,通常与耐药性相关。
大多数Axl信号以一种依赖于生长停滞特异性6(GAS6)介导的配体方式发生。当GAS6与Axl结合后,Axl随后激活下游的信号传导途径,例如磷酸肌醇3-激酶(PI3K),RAt肉瘤(RAS)和细胞外信号调节激酶(ERK)。在癌症中,Axl信号传导可以被GAS6以自分泌或旁分泌的方式激活。
在临床上,与正常组织相比,Axl在原发肿瘤和转移中高表达。对原发肿瘤的免疫组织化学分析表明,在肺腺癌,多形胶质母细胞瘤,乳腺癌,胰腺癌,肾细胞癌,食道腺癌,口腔鳞状癌,胸膜间皮瘤,卵巢腺癌,结肠癌,头颈部鳞状细胞癌,尿路上皮癌,食道细胞癌和肝细胞癌患者中,Axl表达与肿瘤转移和/或低存活相联系。此外,在乳腺癌,黑色素瘤,髓样白血病,肺癌和肾细胞癌患者中,Axl表达与耐药性相关(参见Rankin和Giaccia,癌症,2016,103:1-16)。因此,GAS6/Axl信号作为驱动肿瘤生长,转移和耐药性的重要途径。
另外,Axl是肿瘤细胞上调的以促进对多种抗癌策略(包括髓样白血病,非小细胞肺癌,三阴性乳腺癌(TNBC),食道癌和卵巢癌)的抗性的关键因素。例如,Axl的水平与非小细胞肺癌中的表皮生长因子受体(EGFR)抑制剂抗性,黑色素瘤中的促***原活化蛋白激酶(MAPK)抑制剂抗性和乳腺癌患者中的人类EGFR 2型(HER2)抑制高度相关。最重要的是,Axl的遗传和治疗抑制足以敏感化这些抑制,这表明Axl抑制可改善对抗癌疗法的反应,这是预防和抑制多种癌症中耐药性和复发的有效策略。
同时,PCT公开号WO 2013/142382公开了4-苯基氨基-吡啶并[4,3,-d]嘧啶-5-酮衍生物及其作为FLT3抑制剂的用途,但是未公开其作为Axl抑制剂的用途或用于Axl介导的疾病的治疗。
发明公开
技术问题
本发明的发明人已经研究了可用作Axl抑制剂的化合物,并且通过确认具有特定结构的4-苯基氨基-吡啶并[4,3,-d]嘧啶-5-酮衍生物有效地抑制Axl受体酪氨酸激酶的活性,因此可以有效地用于治疗与其相关的疾病,来完成了本发明。
因此,本发明的目的是提供吡啶并嘧啶酮衍生物和包含其的组合物,其用作Axl抑制剂,用于治疗由Axl介导的疾病或病症,例如多种类型的癌症和转移。
解决问题方案
一方面,本发明提供式(I)代表的化合物或其药学上可接受的盐作为Axl抑制剂在治疗由Axl介导的疾病或病症中的用途:
其中
R1是C6-C10芳基,C6-C10芳基C1-C6烷基,C5-C6环烷基或C5-C6环烷基甲基,其任选地被一个或两个R3取代;
R3独立地为氟,氯,溴,碘,C1-C6烷基或三氟甲基;
X是H,氟,氯,溴,碘,甲基或三氟乙基;
Y是氯,溴,碘,C1-C3烷基或苯基;
R2为C3-C6环烷基或4至7元杂环烷基,其中C3-C6环烷基在碳原子上任选被一个或两个R4取代,且其中4至7元杂环烷基具有1或2个选自下组的杂原子:氮、氧,硫,砜和亚砜,并且任选地在碳原子上被R4取代或在氮原子上被R5取代;
R4独立地是羟基,羟基C1-C6烷基,氨基,氨基C1-C6烷基,-NH(-C1-C3烷基),-N(-C1-C3烷基)2,C1-C3烷基或卤素;和
R5为H,C1-C3烷基或-C(=O)(-C1-C3烷基),其中C1-C3烷基任选被1-3个氟取代。
在另一方面,本发明提供了如上定义的式(I)化合物的单独的立体异构体,立体异构体的混合物,前药衍生物,被保护的衍生物,N-氧化物衍生物,溶剂化物或氢化物作为Axl抑制剂用于治疗Axl介导的疾病或病症的用途。
在另一方面,本发明提供了如上定义的化合物或其药学上可接受的盐在制备用于治疗由Axl介导的疾病或病症的药物中的用途。
在另一方面,本发明提供了一种药物组合物,其包含如上定义的式(I)的化合物或其药学上可接受的盐,以及药学上可接受的载体,稀释剂,佐剂或赋形剂。
另一方面,本发明提供了一种药物组合物,其包含如上定义的式(I)的化合物或其药学上可接受的盐作为活性成分,用于治疗由Axl介导的疾病或病症。
在另一方面,本发明提供了一种治疗由Axl介导的疾病或病症的方法,其包括向有需要的受试者施用有效量的如上定义的式(I)的化合物或其药学上可接受的盐。
在另一方面,本发明提供了抑制Axl受体酪氨酸激酶或抑制癌细胞生长的方法。
发明的有益效果
如上定义的式(I)的化合物或其药学上可接受的盐,以及包含该化合物的药物组合物,抑制Axl受体酪氨酸激酶,并且可用于治疗由Axl介导的疾病或病症,例如细胞增殖性疾病例如多种类型的癌症和转移。
附图说明
图1a至1c显示了化合物238和R428的迁移和侵袭测定的结果。
图2a和2b显示化合物238在乳腺4T1同基因体内癌症模型中的抗肿瘤活性。
图3a至3c显示了化合物226对B16F10肺体内转移模型的抗转移活性。
图4a和4b显示化合物226对CT26腹膜体内转移模型的抗转移活性。
图5a显示了4T1自发转移模型。
图5b和5c显示了与抗PD-1抗体对4T1正交各向异性转移模型的组合作用。
图6显示在4T1正交各向异性转移模型中在原发部位(乳脂垫)上的肿瘤生长抑制。
实施发明的最佳方式
在下文中,将详细描述本发明。
单独或作为较大部分例如芳基烷基或环烷基的一部分使用的术语“烷基”,是指具有1至15个碳原子或1至8个碳原子的直链或支链碳氢自由基(除非另有说明),并且包括例如,甲基,乙基,正-丙基,异-丙基,正-丁基,仲-丁基,异-丁基,叔-丁基,正-戊基,异-戊基,正-己基等。烷基可以是未取代的或被一个或多个合适的取代基取代的。
术语“环烷基”是指单环或多环烃环基,包括例如环丙基,环庚基,环辛基,环癸基,环丁基,金刚烷基,降冰片烷基,十氢化萘基,降冰片基,环己基,环戊基等。环烷基可以未被取代或被一个或多个合适的取代基取代。
术语“杂”是指环***中的至少一个碳原子被至少一个杂原子如氮,硫,砜,亚砜和氧所取代。
术语“杂环烷基”是指包含碳和氢原子以及至少一个,优选地1-4个选自下组氮,硫,氧,砜或亚砜的杂原子的非芳族单环或多环。杂环烷基可以在环基团中具有一个或多个碳-碳双键或碳-杂原子双键,只要该环基团不因其存在而变成芳族即可。
杂环烷基的实例包括氮杂环丁烷基,吖丙啶基,吡咯烷基,哌啶基,哌嗪基,高哌嗪基,吗啉代,硫代吗啉代,四氢呋喃基,四氢硫呋喃基,四氢吡喃基,吡喃基等。杂环烷基可以未被取代或被一个或多个合适的取代基取代。
如本文所用,术语“卤代”包括氟,氯,溴和碘。
如本文所用,术语“烷氧基”是指通过氧结合的上述烷基,其实例包括甲氧基,乙氧基,异-丙氧基,叔-丁氧基等。另外,烷氧基还指聚醚,例如-O-(CH2)2-O-CH3等。烷氧基可以未被取代或被一个或多个合适的取代基取代。
如本文所用,术语“芳基”是指未取代或取代的芳族单环或多环基团,并且包括例如苯基和萘基。术语“芳基”也包括与非芳族碳环或杂环稠合的苯环。术语“芳基”可以与“芳基环”,“芳族基团”和“芳族环”互换使用。杂芳基具有4至14个原子,其中1至9个独立地选自氧,硫和氮。芳基或杂芳基可以是单环或双环芳族基团。典型的芳基和杂芳基包括,例如,苯基,喹啉基,吲唑基,吲哚基,二氢苯并二氧杂环己烯基(dihydrobenzodioxynyl),3-氯苯基,2,6-二溴苯基,吡啶基,嘧啶基,3-甲基吡啶基,苯并噻吩基,2,4,6-三溴苯基,4-乙基苯并噻吩基,呋喃基,3,4-二乙基呋喃基,萘基,4,7-二氯萘基,吡咯基,吡唑基,咪唑基,噻唑基等。芳基或杂芳基可以未被取代或被一个或多个合适的取代基取代。
如本文所用,术语“卤代烷基”是指具有一个或多个氢原子被卤素原子取代的任何烷基自由基。卤代烷基的实例包括-CF3,-CFH2,-CF2H等。
如本文所用,术语“羟基”或“羟基”是指-OH。
如本文所用,术语“氨基”是指-NH2。
如本文所用,术语“羟烷基”是指烷基的任何羟基衍生物。术语“羟烷基”包括具有一个或多个氢原子被羟基取代的任何烷基。
如本文所用,“取代基”是指与目标分子内的原子共价键合的分子部分。例如,环取代基可以是诸如卤素,烷基,卤代烷基或与作为环成员的原子(优选为碳或氮原子)共价键合的其他基团的部分。芳族基团的取代基通常与环碳原子共价键合。术语“取代”是指分子结构中的氢原子被取代基取代,从而使得指定原子上的化合价不会超过,并且化学上稳定的化合物(即,可以分离,表征,并测试其生物活性的化合物)由于取代而产生。
如上所述,某些基团可以未被取代或被一个或多个合适的取代基在一个或多个可用位置(通常为1、2、3、4或5个位置)上的氢以外的一个或多个合适的基团取代(其可以是相同或不同)。某些基团在被取代时,被1、2、3或4个独立选择的取代基取代。合适的取代基包括卤素,烷基,卤代烷基,芳基,羟基,烷氧基,羟烷基,氨基等。
如本文所用,术语“激酶”是指Axl。含有本文描述的激酶的激酶测定法因其选择性可商业上应用于生化分析激酶抑制剂。在某些实施方案中,激酶是哺乳动物激酶,例如人激酶。
如本文所用,术语“皮肤病”是指皮肤病。这种皮肤病包括但不限于皮肤的增生性或炎性疾病,例如特应性皮炎,大疱性疾病,胶原蛋白,接触性皮炎湿疹,川崎病,酒渣鼻,Sjogren-Larsso综合症和荨麻疹。
如本文所用,术语“呼吸***疾病”是指影响呼吸相关器官的疾病,例如鼻子,喉咙,喉,气管,支气管和肺。呼吸***疾病包括但不限于哮喘,成人呼吸窘迫综合征和过敏性(外来)哮喘,非过敏性(内在)哮喘,急性重症哮喘,慢性哮喘,临床哮喘,夜间哮喘,过敏原诱发的哮喘,阿司匹林敏感型哮喘,运动诱发型哮喘,等二氧化碳过度通气,儿童发作性哮喘,成人发作性哮喘,咳嗽变异性哮喘,职业性哮喘,类固醇耐药性哮喘,季节性哮喘,季节性过敏性鼻炎,常年性过敏性鼻炎,慢性阻塞性肺疾病包括慢性支气管炎或肺气肿,肺动脉高压,间质性肺纤维化和/或气道炎症和囊性纤维化,以及缺氧。
如本文所用,术语“癌症”是指细胞的异常生长,其倾向于以不受控制的方式增殖并且在某些情况下转移。癌症的类型包括但不限于实体瘤,例如膀胱,肠,脑,乳腺,子宫内膜,心脏,肾脏,肺,淋巴组织(淋巴瘤),卵巢,胰腺或其他内分泌器官的实体瘤(甲状腺),***,皮肤(黑色素瘤)或血液***肿瘤(例如白血病)。
如本文所用,术语“炎性病症”是指那些以如下的一种或多种体征为特征的疾病或病症:疼痛(疼痛,来自有害物质的产生和神经刺激),热(热量,来自血管舒张),充血(发红,由于血管扩张和血流量增加引起的发红),肿胀(肿瘤,由于过多的流入或有限的液体流出引起的)和功能丧失,这种功能丧失可能是部分或完全的,暂时或永久的。炎症有多种形式,包括但不限于以下一种或多种炎症:急性,粘连性,萎缩性,卡他性,慢性,肝硬化,弥漫性,弥散性,渗出性,纤维蛋白化,纤维化,局灶性,肉芽肿性,增生性,肥厚性,间质性,转移性,坏死性,闭塞性,实质性,可塑性,生产性,增殖性,假膜性,化脓性,硬化性,浆性,浆液性,单纯性,特异性,亚急性,化脓性,中毒性,创伤性和/或溃疡性。炎症性疾病还包括但不限于影响血管的疾病(多动脉炎,颞动脉炎);关节(关节炎:晶体,骨,银屑病,反应性,类风湿,赖特氏病);胃肠道;皮肤(皮炎);或多个器官和组织(***性红斑狼疮)。
如本文所用,术语“心血管疾病”是指影响心脏或血管或两者的疾病,包括但不限于动脉粥样硬化,心律失常,心绞痛,心肌缺血,心肌梗塞,心脏或血管动脉瘤,血管炎,中风,肢体周围梗阻性动脉病,器官或组织缺血后的再灌注损伤,内毒素,外科或外伤性休克,高血压,瓣膜性心脏病,心力衰竭,血压异常,血管收缩,血管异常或炎症。
如本文所用,术语“抑制剂”是指抑制本文所述的一种或多种激酶的化合物。例如,术语“Axl抑制剂”是指抑制Axl受体或降低信号传导作用的化合物。
如本文所用,术语“药学上可接受的”是指不消除本文所述化合物的生物学活性或特性的材料,例如载体或稀释剂。将这样的材料施用于个体,而不会引起不希望的生物学作用或以有害的方式与其中包含该材料的组合物的任何组分相互作用。
如本文所用,术语“药学上可接受的盐”是指不会引起对其施用的有机体的显著刺激并且不会消除本文所述化合物的生物学活性和性质的化合物的制剂。
如本文所用,术语“药物组合”是指通过混合或组合一种以上活性成分得到的产品。
如本文所用,术语“药物组合物”是指本文所述的化合物与其他化学组分的混合物,所述其他化学组分例如为载体,稳定剂,稀释剂,分散剂,助悬剂,增稠剂和/或赋形剂。
如本文所用,术语前药是指在体内转化为活性或“母体”药物的试剂。
如本文所用,术语“溶剂化物”是指由溶质(在本发明中,式(I)的化合物或其药学上可接受的盐)和溶剂形成的可变化学计量的复合物。用于本发明目的的此类溶剂可以不干扰溶质的生物学活性。合适溶剂的非限制性实例包括水,丙酮,甲醇,乙醇和乙酸。优选地,所使用的溶剂是药学上可接受的溶剂。合适的药学上可接受的溶剂的非限制性实例包括水,乙醇和乙酸。
如本文所用,术语“蛋白激酶介导的疾病”或“由不适当的蛋白激酶活性介导的病症或疾病或病状”是指由本文描述的蛋白激酶介导或调节的任何疾病状态。这些疾病状态包括但不限于淋巴瘤,骨肉瘤,黑素瘤,乳腺癌,肾癌,***癌,结肠直肠癌,甲状腺癌,卵巢癌,胰腺癌,神经元癌,肺癌,子宫癌和胃肠道癌。
如本文所用,术语“Axl介导的疾病”或“由不适当的Axl活性介导的疾病或病症”是指由Axl激酶机制介导或调节的任何疾病状态。此类疾病状态包括但不限于AML,ALL,实体瘤,其他增生性疾病或与Axl激酶水平异常升高有关的疾病。
如本文所用,术语“治疗”、“治疗”、“疗法”是指缓解,减轻或改善疾病或病症症状,预防其他症状,改善或预防症状的潜在代谢原因,抑制疾病或病症,阻止疾病或病症的发展,缓解疾病或状况,引起疾病或状况消退,缓解由疾病或病症引起的状况,或预防性和/或治疗性地停止疾病或状况的症状。
如本文所用,术语“有需要的受试者”是指已经或可能发展出与蛋白激酶活性有关的疾病的任何动物,例如猴子,牛,马,绵羊,猪,鸡,火鸡,鹌鹑,猫,狗,小鼠,大鼠,兔子和豚鼠以及人类(患者);特别地,可能是哺乳动物。另外,有需要的受试者可以是生物学样品。
如本文所用,术语“有效量”或“治疗有效量”是指给予足够量的本文描述的化合物,其将在某种程度上减轻所治疗的疾病或病症的一种或多种症状。结果可以是降低和/或减轻疾病的体征,症状或原因,或生物***的任何其他期望的改变。例如,用于治疗用途的“有效量”是包含本文公开的化合物以提供临床上显著减轻疾病症状所需的量。在任何个体案例中,都可以使用诸如剂量递增研究等技术确定适当的“有效”量。仅作为举例,式(I)化合物的治疗有效量可以在例如约0.01mg/kg/天至约100mg/kg/天的范围内,或从约0.1mg/kg/天至约10mg/kg/天的范围内。
一方面,本发明提供式(I)代表的化合物或其药学上可接受的盐作为Axl抑制剂在治疗由Axl介导的疾病或病症中的用途:
其中
R1是C6-C10芳基,C6-C10芳基C1-C6烷基,C5-C6环烷基或C5-C6环烷基甲基,其任选地被一个或两个R3取代;
R3独立地为氟,氯,溴,碘,C1-C6烷基或三氟甲基;
X是H,氟,氯,溴,碘,甲基或三氟乙基;
Y是氯,溴,碘,C1-C3烷基或苯基;
R2为C3-C6环烷基或4至7元杂环烷基,其中C3-C6环烷基在碳原子上任选被一个或两个R4取代,且其中4至7元杂环烷基具有1或2个选自下组的杂原子:氮、氧,硫,砜和亚砜,并且任选地在碳原子上被R4取代或在氮原子上被R5取代;
R4独立地是羟基,羟基C1-C6烷基,氨基,氨基C1-C6烷基,-NH(-C1-C3烷基),-N(-C1-C3烷基)2,C1-C3烷基或卤素;和
R5为H,C1-C3烷基或-C(=O)(-C1-C3烷基),其中C1-C3烷基任选被1-3个氟取代。
在某些实施方案中,R1为苯基,苄基,环戊基,环己基,环戊基甲基或环己基甲基,其任选地被一个或两个R3取代。
在某些实施方案中,R3独立地为氟,氯,甲基或异丙基。
在某些实施方案中,R3独立地为氯,氟或甲基。
在某些实施方案中,R3独立地为氯或氟。
在某些实施方案中,X是氟或甲基。
在某些实施方案中,Y是氯,溴,碘,甲基或苯基。
在进一步的实施方案中,Y是氯或溴。
在进一步的实施方案中,Y是溴。
在某些实施方案中,R2是吡咯烷基或哌啶基。
在某些实施方案中,R2是N-甲基吡咯烷基或N-甲基哌啶基。
在某些实施方案中,R2是氮原子上被R5取代的哌啶基或吡咯烷基。
在某些实施方案中,R5是甲基,乙基,三氟乙基或异丙基。
在某些实施方案中,R5是甲基。
在某些实施方案中,R4独立地为羟基,氨基或N-甲基氨基。
在某些实施方案中,式(I)的化合物或其药学上可接受的盐是8-溴-2-((1-甲基哌啶-4-基)氨基)-4-((3-苯氧基苯基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮盐酸盐或8-溴-4-((4-(3-氟苯氧基)苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮盐酸盐。
在某些实施方案中,式(I)的化合物或其药学上可接受的盐是8-溴-4-((3-氟-4-苯氧基苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮盐酸盐。
在另一方面,本发明提供了如上定义的式(I)化合物的单独的立体异构体,立体异构体的混合物,前药衍生物,被保护的衍生物,N-氧化物衍生物,溶剂化物或氢化物作为Axl抑制剂治疗Axl介导的疾病或病症的用途。在某些实施方案中,式(I)的化合物包含其立体异构体。
在另一方面,本发明提供了如上定义的式(I)的化合物或其药学上可接受的盐在制备用于治疗由Axl介导的疾病或病症的药物中的用途。
如上定义的式(I)的化合物或其药学上可接受的盐可用于治疗与Axl功能亢进相关,伴随和/或由其引起的过度增殖疾病,特别是Axl受体酪氨酸激酶诱导的过度增殖疾病。
如上定义的式(I)的化合物或其药学上可接受的盐能够抑制细胞增殖,因此适合于治疗和/或预防Axl受体酪氨酸激酶诱导的过度增殖性疾病,特别是选择的癌症和原发性肿瘤转移。
在某些实施方案中,该疾病或病状是由Axl介导的多种类型的癌症。
在某些实施方案中,所述疾病或病状是急性淋巴细胞白血病,急性髓细胞性白血病,肾上腺皮质癌,与艾滋病有关的癌症,与艾滋病有关的淋巴瘤,***癌,阑尾癌,星形细胞瘤,非典型畸胎瘤/横纹肌瘤,基底细胞癌,胆管癌症,膀胱癌,骨癌,骨肉瘤和恶性纤维组织细胞瘤,脑干神经胶质瘤,脑瘤,中枢神经***非典型畸胎瘤/横纹肌瘤,星形细胞瘤,颅咽管瘤,成室管膜细胞瘤,室管膜瘤,髓母细胞瘤,髓上皮瘤,中间分化的松果体实质瘤,慕上原始神经外胚层肿瘤和松母细胞瘤,脑和脊髓肿瘤,乳腺癌,支气管肿瘤,伯基特淋巴瘤,类癌,胃肠道癌,中枢神经***(CNS)淋巴瘤,子***,脊索瘤,慢性淋巴细胞性白血病,慢性粒细胞性白血病,慢性骨髓增生性疾病,结肠癌,大肠癌症,颅咽管瘤,皮肤T细胞淋巴瘤,蕈样肉芽肿,Sezary综合征,子宫内膜癌,成室管膜细胞瘤,室管膜瘤,食道癌,鼻腔神经胶质瘤,尤因肉瘤家族肿瘤,颅外生殖细胞瘤,性腺外生殖细胞癌,肝外胆管癌,眼内黑色素瘤,视网膜母细胞瘤,胆囊癌,胃(腹部)癌,胃肠道类癌,胃肠道间质瘤(GIST),胃肠道***瘤,颅外生殖细胞瘤,性腺外生殖细胞瘤,卵巢生殖细胞瘤,妊娠滋养细胞肿瘤,神经胶质瘤,毛细胞白血病,头颈癌,心脏病,肝细胞癌(肝癌),组织细胞增生症,霍奇金淋巴瘤,咽喉癌,眼内黑色素瘤,胰岛细胞瘤(内分泌胰腺),卡波西肉瘤,肾细胞癌,肾癌,朗格罕斯细胞组织细胞增生症,喉癌,急性淋巴细胞白血病,急性髓细胞性白血病,慢性淋巴细胞白血病,慢性粒细胞性白血病,白血病,嘴唇和口腔癌,肝癌,肺癌,非小细胞肺癌,小细胞肺癌,与艾滋病有关的淋巴瘤,伯基特淋巴瘤,皮肤性T细胞淋巴瘤,霍奇金淋巴瘤,非霍奇金淋巴瘤,原发性中枢神经***淋巴瘤,巨球蛋白血症,骨和骨肉瘤的恶性纤维组织细胞瘤,髓母细胞瘤,髓上皮瘤,黑色素瘤,眼内(眼)黑色素瘤,默克尔细胞癌,间皮瘤,原发性隐匿性转移性鳞状颈癌,口腔癌,多发性内分泌肿瘤综合征,多发性骨髓瘤,浆细胞瘤,骨髓增生异常综合征,骨髓增生异常/骨髓增生性肿瘤,骨髓性白血病,髓样白血病,骨髓增生性疾病,鼻腔和鼻旁鼻窦癌,鼻咽癌,神经母细胞瘤,非霍奇金淋巴瘤,非小细胞肺癌,口腔癌,口腔癌,口咽癌,骨肉瘤和骨恶性纤维组织细胞瘤,卵巢癌,卵巢上皮癌,卵巢生殖细胞瘤,卵巢低度恶性潜能肿瘤,胰腺癌,***瘤病,甲状旁腺癌,***癌,咽癌,松母细胞瘤和慕上原始神经外胚层肿瘤,垂体瘤,胸膜肺母细胞瘤,妊娠和乳腺癌,***癌,直肠癌,肾细胞(肾)癌,移行细胞癌,呼吸道癌,视网膜母细胞瘤,横纹肌肉瘤,唾液腺癌,肉瘤,尤因肉瘤,卡波西肉瘤,子宫肉瘤,非黑素瘤皮肤癌,黑色素瘤皮肤癌,皮肤癌,小细胞肺癌,小肠癌,软组织肉瘤,鳞状细胞癌,鳞状颈癌,腹部(胃)癌,幕上原始神经外胚层肿瘤,T细胞淋巴瘤,睾丸癌,喉癌,胸腺瘤和胸腺癌,甲状腺癌,肾盂和输尿管的移行细胞癌,滋养细胞肿瘤,妊娠癌,输尿管和肾盂癌,移行细胞癌,尿道癌,子宫癌,子宫内膜癌,子宫肉瘤,***癌,外阴癌,瓦尔登斯特伦(Waldenstrom)巨球蛋白血症或威尔姆斯(Wilms)肿瘤。
在另一方面,本发明提供了一种药物组合物,其包含如上所定义的式(I)的化合物或其药学上可接受的盐,以及药学上可接受的载体,稀释剂或赋形剂。
另一方面,本发明提供了一种药物组合物,其包含如上定义的式(I)的化合物或其药学上可接受的盐作为活性成分,用于治疗由Axl介导的疾病或病症。
在某些实施方案中,药物组合物包含如上定义的式(I)化合物的单独的立体异构体,立体异构体的混合物,前药衍生物,被保护的衍生物,N-氧化物衍生物,溶剂化物或氢化物。
药学上可接受的盐形式包括药学上可接受的酸性/阴离子或碱性/阳离子盐。药学上可接受的酸性/阴离子盐包括乙酸盐,苯磺酸盐,苯甲酸盐,碳酸氢盐,酒石酸氢盐,溴化物,乙二胺四乙酸钙,樟脑磺酸盐,碳酸盐,氯化物,柠檬酸盐,二盐酸盐,乙二胺四乙酸盐,乙二磺酸盐,丙酸酯月桂硫酸盐(estolate),乙磺酸盐,富马酸盐,甘油酸盐(glyceptate),葡糖酸盐,谷氨酸盐,对羟基乙酰氨基苯胂酸盐(glycollylarsanilate),己基间苯二酚盐,氢溴酸盐,盐酸盐,羟萘甲酸盐,碘化物,羟乙基磺酸盐,乳酸盐,乳糖酸盐,苹果酸盐,马来酸盐,丙二酸盐,扁桃酸盐,甲磺酸盐,甲基硫酸盐,粘液酸盐,萘磺酸盐,硝酸盐,双羟萘酸盐,泛酸盐,磷酸盐/二磷酸盐,聚半乳糖醛酸盐,水杨酸盐,硬脂酸盐,亚乙酸盐,琥珀酸盐,硫酸盐,硫酸氢盐,丹宁酸盐,酒石酸盐,茶氯酸盐,甲苯磺酸盐和三乙基碘盐。药学上可接受的碱性/阳离子盐包括钠,钾,钙,镁,二乙醇胺,N-甲基-D-葡萄糖胺,L-赖氨酸,L-精氨酸,铵,乙醇胺,哌嗪和三乙醇胺盐。
药学上可接受的酸加成盐是通过使式(I)化合物的游离碱形式与合适的无机或有机酸反应而形成的,所述无机或有机酸包括但不限于氢溴酸,盐酸,硫酸,硝酸,磷酸,琥珀酸,马来酸,甲酸,乙酸,丙酸,富马酸,柠檬酸,酒石酸,乳酸,苯甲酸,水杨酸,谷氨酸,天冬氨酸,对甲苯磺酸,苯磺酸,甲磺酸,乙磺酸,萘磺酸(例如2-萘磺酸)或己酸。
式(I)化合物的药学上可接受的酸加成盐可以包括或为例如氢溴酸盐,盐酸盐,硫酸盐,硝酸盐,磷酸盐,琥珀酸盐,马来酸盐,甲酸盐,乙酸盐,丙酸盐,富马酸盐,柠檬酸盐,酒石酸盐,乳酸盐,苯甲酸盐,水杨酸盐,谷氨酸盐,天冬氨酸盐,对甲苯磺酸盐,苯磺酸盐,甲磺酸盐,乙磺酸盐,萘磺酸盐(例如2-萘磺酸盐)或己酸盐。
式(I)化合物的游离酸或游离碱形式可以分别由相应的碱加成盐或酸加成盐制备。例如,可以通过用合适的碱(例如氢氧化铵溶液,氢氧化钠等)处理,将酸加成盐形式的式(I)化合物转化为相应的游离碱。碱加成盐形式的式(I)化合物可以通过用合适的酸(例如盐酸等)处理而转化为相应的游离酸。
式(I)化合物的前药衍生物可以通过本领域普通技术人员已知的方法制备(例如,有关更多细节,参见Saulnier等人,(1994),生物有机和药物化学快报,1985年第4卷;其全部教导通过引用并入本文)。
式(I)化合物的被保护的衍生物可以通过本领域普通技术人员已知的方法来制备。可以在T.W.Greene的“有机化学中的保护基团”,第三版,约翰·威利父子出版公司(John Wiley and Sons,Inc.,)1999中,找到适用于创建保护基团和去除保护基团的技术的详细说明,在这里,该专利的全部内容通过引用均已并入本文。
可以通过使化合物的外消旋混合物与旋光性拆分剂反应形成一对非对映异构体化合物,分离非对映异构体并回收光学纯的对映异构体而将式(I)化合物制备为它们的单独的立体异构体。对映异构体的拆分可使用式(I)化合物的共价非对映异构体衍生物,或通过使用可解离的配合物(例如,结晶非对映异构体盐)来进行。非对映异构体具有独特的物理性质(例如,熔点,沸点,溶解度,反应性等),并且可以利用这些差异来容易地分离。非对映异构体可以通过色谱法或基于溶解度差异的分离/拆分技术来分离。然后通过不会导致外消旋作用的任何实用手段,将旋光纯的对映异构体与拆分剂一起回收。可以从JeanJacques,Andre Collet,Samuel H.Wilen的“对映异构体,外消旋体和拆分物”,约翰·威利父子出版公司(John Wiley and Sons,Inc.,),1981年中,找到适用于从其外消旋混合物中拆分化合物的立体异构体的技术的更详细说明,其全部教导在此通过引用作为参考。
药物组合物被配制成片剂,丸剂,胶囊剂,液体,吸入剂,鼻喷雾剂,栓剂,溶液,凝胶,乳剂,软膏剂,滴眼剂或滴耳剂。
用于本发明药物组合物的合适的药学上可接受的载体,稀释剂,助剂或赋形剂包括由以下制成的片剂(包衣片剂):例如可立酮或紫胶,***树胶,滑石粉,二氧化钛或糖,胶囊剂(明胶),溶液(水溶液或乙醇水溶液),含有活性物质的糖浆,乳剂或可吸入性粉剂(各种糖类如乳糖或葡萄糖,这些赋形剂的一种和另一种的盐和混合物)和气雾剂(含推进剂的或自由吸入的溶液)。
可以使用的赋形剂包括例如水,药学上可接受的有机溶剂,例如石蜡(例如,石油馏分),植物油(例如,花生油或芝麻油),单或多官能醇(例如,乙醇或甘油),载体如天然矿物粉末(例如高岭土,粘土,滑石粉,白垩),合成矿物粉末(例如高度分散的硅酸和硅酸盐),糖类(例如蔗糖,乳糖和葡萄糖),乳化剂(例如木质素,废亚硫酸盐溶液,甲基纤维素,淀粉和聚乙烯吡咯烷酮)和润滑剂(例如硬脂酸镁,滑石粉,硬脂酸和十二烷基硫酸钠)。
在另一方面,本发明提供了一种治疗由Axl介导的疾病或病症的方法,其包括向有需要的受试者施用有效量的如上定义的式(I)的化合物或其药学上可接受的盐。
在另一方面,本发明提供了抑制Axl受体酪氨酸激酶或抑制癌细胞生长的方法。
另外,该化合物单独或与一种或多种其他治疗剂例如免疫疗法(抗PD-1和/或抗CTLA4),化学疗法和辐照组合给药。
在某些实施方案中,将化合物单独施用或与一种或多种免疫检查点阻断剂(抗PD-1,抗PDL,抗CLTA4)和其他化疗剂联合施用。
此类化合物和组合物的给药方法包括但不限于静脉内给药,吸入,口服给药,直肠给药,肠胃外,玻璃体内给药,皮下给药,肌内给药,鼻内给药,皮肤给药,局部给药,眼科给药,口腔给药,气管给药,支气管给药,舌下给药或耳部给药。本文提供的化合物通过已知的药物制剂给药,包括用于口服给药的片剂,胶囊剂或酏剂,用于直肠给药的栓剂,用于肠胃外或肌内给药的无菌溶液或悬浮液,用于局部给药的乳液,凝胶剂,软膏剂或乳膏剂等。
在某些实施方案中,化合物通过静脉内给药,皮下给药,吸入,口服给药,直肠给药,肠胃外,玻璃体内给药,肌肉内给药,鼻内给药,皮肤给药,局部给药,光学给药,眼科给药,口腔给药,气管给药,支气管给药或舌下给药。
在以上方法中,将如上定义的式(I)的化合物或其药学上可接受的盐施用于包含细胞或组织的***。在某些实施方案中,将如上定义的式(I)的化合物或其药学上可接受的盐施用于人或动物受试者。
治疗有效量将取决于以下因素而变化,其中尤其是所指示的疾病,疾病的严重程度,受试者的年龄和相对健康,所施用化合物的效力,所施用的方式和所需的治疗。
所需剂量也将根据给药方式,待治疗的特定病症和所需的效果而变化。
如上定义的式(I)化合物通过以下方法制备:
(a)任选地将式(I)的化合物转化为药学上可接受的盐;
(b)任选地将式(I)化合物的盐形式转化为非盐形式;
(c)任选地将式(I)化合物的非氧化形式转化成药学上可接受的N-氧化物;
(d)任选地从异构体的混合物中拆分式(I)化合物的单个异构体;
(e)任选地将未衍生的式(I)化合物转化为药学上可接受的前药衍生物;和
(f)任选地将式(I)化合物的前药衍生物转化为其非衍生形式。
本发明的方式
在下文中,将参考实施例详细描述本发明。但是,以下实施例仅用于说明目的,并不意图限制本发明的范围。本领域技术人员将理解,可以在不改变本发明范围的情况下进行变化和修改。
液相色谱-质谱法(LC-MS):
1.样品在配备Zorbax Eclipse XDB-C18(3.5μm)反相色谱柱(4.6x50mm)的Agilent Technologies 6120MSD***上,在室温下,以1.5mL/min的流速运行。
2.流动相使用溶剂A(水/0.1%甲酸)和溶剂B(乙腈/0.1%甲酸):95%/5%至0%/100%(A/B)5分钟。
3.使用电喷雾电离(ESI)记录质谱(m/z)。
4.电离数据四舍五入到最接近的整数。
如上定义的式(I)化合物或其药学上可接受的盐的制备描述于2013年3月15日提交的PCT公开号WO 2013/142382的实施例和表1中,并且在许多其他国家,具有等同的申请和专利,例如在美国专利号8,877,763,澳大利亚专利号2013235344,日本专利号6101341和中国专利号104428298。本文引用的所有专利,公开的申请和参考文献的教导通过引用整体并入本文。
某些式(I)化合物或其药学上可接受的盐如下命名:
221. 4-((4-(苄氧基)苯基)氨基)-8-溴-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮;
222. 8-溴-2-(((1-甲基哌啶-4-基)氨基)-4-((4-苯氧基苯基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮;
223. 8-溴-4-((4-(环戊氧基)苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮;
224. 8-溴-4-((4-(环己基甲氧基)苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮;
225. 8-溴-2-(((1-甲基哌啶-4-基)氨基)-4-((4-(对甲苯氧基)苯基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮;
226. 8-溴-2-((1-甲基哌啶-4-基)氨基)-4-((4-苯氧基苯基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮盐酸盐;
227. 8-溴-4-((4-(环戊基甲氧基)苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮;
228. 8-溴-4-((4-(环己氧基)苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮;
229. 8-氯-4-((4-(环己氧基)苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮;
230. 8-溴-4-((4-(4-异丙基苯氧基)苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮;
231. 8-溴-2-(((1-甲基哌啶-4-基)氨基)-4-((4-(对甲苯氧基)苯基)氨基)吡啶基[4,3-d]嘧啶-5(6H)-酮盐酸盐
232. 8-溴-4-((4-(4-氟苯氧基)苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮盐酸盐
233. 8-溴-4-((4-(环己氧基)苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮盐酸盐;
234. 4-((4-(苄氧基)苯基)氨基)-8-溴-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮盐酸盐;
235. 8-溴-4-((4-(环戊基甲氧基)苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮盐酸盐;
236. 8-溴-4-((4-(4-异丙基苯氧基)苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮盐酸盐
237. 8-溴-4-((4-(环戊氧基)苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮盐酸盐;
238. 8-溴-4-((4-(3-氟苯氧基)苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮盐酸盐
239. 8-溴-2-(((1-甲基哌啶-4-基)氨基)-4-((4-(邻甲苯氧基)苯基)氨基)吡啶基[4,3-d]嘧啶-5(6H)-酮盐酸盐
240. 8-溴-4-((4-(3-氟苯氧基)苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮;
241. 8-溴-4-((4-(3,4-二氟苯氧基)苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮盐酸盐;
242. 8-溴-4-((4-(4-氯苯氧基)苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮盐酸盐
243. 8-溴-4-((4-(3,5-二氟苯氧基)苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮盐酸盐;
244. 8-溴-4-((4-(3-氟苯氧基)-3-甲基苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮盐酸盐;
245. 8-溴-4-((3-氟-4-苯氧基苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮盐酸盐;
246. 8-溴-4-((3-甲基-4-苯氧基苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮盐酸盐;
247. 8-溴-4-((3-氟-4-(3-氟苯氧基)苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮盐酸盐;
248. 8-溴-2-(1-异丙基哌啶-4-基氨基)-4-(4-苯氧基苯基氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮;
249. 8-溴-2-(1-乙基哌啶-4-基氨基)-4-(4-苯氧基苯基氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮;和
250. 8-溴-4-(4-苯氧基苯基氨基)-2-(1-(2,2,2-三氟乙基)哌啶-4-基氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮。
表1显示了式(I)的化合物的结构。
所有数据均列在IC50值(Axl)的范围内。
每个++++,+++,++和+分别表示1-10nM,11-100nM,101-1000nM,1001-10000nM。
[表1]
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本文列出的所有专利,专利申请和出版物的内容均通过引用并入本文。
生物测定
1.激酶抑制测定(酶促Axl激酶活性抑制)
分析如上获得的式(I)的化合物以测量其抑制Axl激酶的能力。Axl属于最近鉴定的TYRO-3,Axl,MERTK(TAM)受体酪氨酸激酶(RTK)家族。生长停滞特异性6(GAS6)蛋白充当每个TAM激酶的共同配体,并显示出对Axl的最高亲和力。在GAS6结合后,Axl均二聚化,并随后诱导一些下游信号通路,涉及细胞增殖,迁移,侵袭,抗凋亡,血管生成,转移和治疗抗性。在多种癌细胞系以及乳腺癌,急性白血病,结肠直肠癌,肺癌,黑素瘤,卵巢癌或***癌等患者的癌症标本中,已经报道了Axl的上调。
方法
首先将如上获得的式(I)化合物在100%DMSO(CALBIOCHEMTM)中稀释至10mM以进行存储,并制成激酶缓冲溶液以产生1μm至10μm的化合物浓度。将化合物的系列稀释液分别以6μL分配到96孔板(GREINER BIOSCIENCESTM)中。将截短的人Axl(CARNA BIOSCIENCESTM)在激酶缓冲液中稀释,然后添加至化合物溶液中,并在室温下预孵育30分钟。接下来,将Axl(PerkinElmerTM)的ATP(TEKNOVATM)和底物溶液(PerkinElmerTM的建议生产底物,例如UlightTM-TK肽)添加到含有化合物溶液和酶的孔中(每个12μL)。将反应混合物温育1小时。孵育后,添加由EDTA,水和Lance检测缓冲液(PerkinElmerTM)制成的终止溶液(各12μL)以终止磷酸化。加入终止液并摇晃5分钟后,将含有铕标记的抗体(建议使用PerkinElmerTM的生产底物,例如Axl的PT66)的检测溶液,水和Lance检测缓冲液(12μL)添加至反应混合物中并再次温孵育50分钟。加入检测溶液并孵育50分钟后,底物磷酸化是665nm发射光的函数。
结果
式(I)的化合物表现出有用的药理性质。如本文所用,描述抑制活性(nM)的能力的方法是50%抑制活性范围(IC50),如表2所示。为了Axl使用参考化合物ASP2215(吉替利尼(gilteritinib),阿斯特拉斯(Astellas)),R428(BGB324,BerGenBio)和星形孢菌素(泛激酶抑制剂)来判断式(I)化合物的抑制活性。
例如,式(I)的化合物238,即,8-溴-4-((4-(3-氟苯氧基)苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮盐酸盐,显示出对Axl激酶活性的强抑制作用。它在生化测定中的功效可与临床开发的Axl抑制剂APS2215和R428媲美。表2说明了式(I)的代表性化合物的Axl的IC50值的范围。如表2所示,参考化合物星形孢菌素是最有效的,而如上获得的式(I)化合物显示出比参考化合物更好的选择性,并且显示出与ASP2215和R428相似的效能。此外,式(I)的化合物还显示出比由星号表示并在WO 2011/053861和PCT/US2010/054853的现有技术中描述的那些化合物更好的选择性。综上,这些数据表明,与已知的Axl抑制剂ASP2215和R428相比,式(I)的化合物显著提高了Axl的选择性以及抑制效力。
在WO 2011/053861中描述的8和136号化合物显示出对包括JAK2的各种测试激酶的多种抑制活性。特别地,它们在大鼠口服10mg/kg的后未显示药物暴露,表明它们没有被肠道吸收或被极快地从体内清除。
表2显示了代表性的式(I)化合物对Ax1和JAK2的生化抑制。
[表2]
化合物 | Axl | JAK2 | 化合物 | Axl | JAK2 |
ASP2215 | +++ | +++ | 223 | ++ | ++ |
R428 | +++ | ++ | 225 | +++ | + |
*8 | +++ | +++ | 226 | +++ | ++ |
*136 | +++ | ++++ | 228 | ++ | ++ |
*203 | +++ | ++ | 233 | ++ | ++ |
222 | +++ | ++ | 240 | +++ | ++ |
241 | +++ | + | 238 | +++ | ++ |
星形孢菌素 | ++++ | ++++ |
*8、136和203号化合物在WO 2011/053861和PCT/US2010/054853中被描述。
所有数据均在IC50值的范围内列出。++++,+++,++和+分别表示1-10nM,11-100nM,101-1000nM,1001-10000nM。
2.细胞活力测定:抑制Axl阳性细胞的增殖
测试如上获得的式(I)的化合物对抑制具有Axl的三阴性乳腺癌细胞系(MDA-MB-231和Hs578T)和具有Axl阴性的乳腺癌细胞系(MCF7)增殖的效果。Axl是TAM(TYRO3-Axl-MER)受体酪氨酸激酶家族的成员,该酪氨酸激酶在激活后可以增加肿瘤细胞的存活率,增殖,迁移和侵袭,血管生成以及肿瘤与宿主的相互作用。当GAS6与Axl结合后,Axl随后激活下游的信号传导途径,例如磷酸肌醇3-激酶(PI3K),RAt肉瘤(RAS)和细胞外信号调节激酶(ERK)。
Axl的过表达或异常激活已在上皮和血液学起源的多种恶性肿瘤中进行了描述,通常与预后不良,复发率增加,无病生存率降低和总体生存率降低有关。而且,Axl表达与上皮到间质转化(EMT)有关,这是转移性肿瘤的常见特征,通常与耐药性相关。因此,Axl是包括乳腺癌在内的多种实体瘤的有吸引力的分子靶标。
方法
测试如上获得的式(I)的化合物对MDA-MB-231和Hs578T细胞的细胞活力作用。对于细胞活力测定,表达人Axl的MDA-MB-231和Hs578T细胞获自美国典型培养物保藏中心(ATCC,马纳萨斯,弗吉尼亚)。该细胞系用含有10%牛犊血清(BCS;HycloneTM)补充的铁的(罗斯威尔公园纪念研究所(RPMI))培养基(HyCloneTM)维持。将细胞接种在96孔培养板上的2x104细胞中,然后添加连续稀释的化合物。在37℃孵育72小时后,使用ATPLite 1步测定(Perkin-ElmerTM)测量细胞活力,该测定基于活细胞中ATP的定量。使用非线性回归计算50%的最大细胞增殖抑制浓度(GI50值),并将其定义为处理过的对照细胞与未处理对照细胞的发光度或吸光度降低50%所需的浓度(PrismTM软件)。
结果
表3中示出了式(I)的代表性化合物的GI50抑制数据。式(I)化合物在其GI50值小于3μM下,显示出对细胞增殖的抑制。特别地,化合物237,8-溴-4-((4-(环戊氧基)苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮盐酸盐在具有Axl的乳腺癌细胞系中显示出比参考ASP2215和R428更高的抑制水平。如此强的抗肿瘤活性表明,式(I)的化合物比现有技术(PCT申请号PCT/US2010/054853)中所述的参比化合物和由星号表示的化合物203具有更好的治疗价值。
表3显示了通过式(I)的代表性化合物的Axl阳性癌细胞系的细胞活力。
[表3]
*化合物203在WO 2011/053861和PCT/US2010/054853中进行了描述。
所有数据都在GI50值的范围内列出。++++,+++,++和+分别表示0.1-1.0μM,1.1-3.0μM,3.1-10μM,11-30μM。
3.迁移和侵袭检测:抑制转移潜能
为了测试式(I)的化合物是否显示出对转移抑制的作用,使用Transwell和基质胶侵袭测定法分析了MDA-MB-231乳腺癌细胞系中的细胞迁移和侵袭行为。
方法
使用MDA-MB-231乳腺癌细胞系对上获得的式(I)的化合物在迁移和侵袭测定中进行测试。通过transwell测定法(BD生物科学,加利福尼亚,美国)进行细胞迁移测试。简而言之,将无血清RPMI-1640中的5×104细胞接种到插在24孔板孔中的膜(孔径为8.0μm)上。将含有10%FBS的RPMI-1640添加到每个孔的下腔室中。24小时后,用棉签除去上室中的细胞,将到达膜下侧的细胞固定,并用结晶紫(1%的甲醇溶液)染色10分钟。计数位于过滤器下侧的细胞(5场/过滤器)。除了在将细胞接种在膜上之前6小时,将基质胶(BD生物科学,加利福尼亚,美国)添加到每个孔中,以类似方式进行细胞侵袭测定。48小时后,用棉签去除基质胶和上腔室中的所有剩余细胞。如上所述,将膜下表面上的细胞固定并染色。化合物238和参考化合物R428如图1a至1c所示孵育。数据代表来自染色膜的三个独立领域的结果。
结果
如图1a-1c所示,式(I)的代表性化合物238显示MDA-MB-231细胞的迁移和侵袭能力受损,其优于参考化合物R428。有趣的是,与R428相比,式(I)的代表性化合物238即使在0.03μM下也显著抑制迁移和侵袭。使用MDA-MB-231细胞,这些结果表明代表性的化合物具有非常强的抗转移活性。此外,如上获得的式(I)的化合物将赋予与Axl表达相关的转移的治疗选择,例如在乳腺癌中具有侵袭性。
4.乳腺癌4T1同基因体内癌症模型中的抗肿瘤活性
为了测试式(I)化合物在乳腺癌4T1同基因体内癌症模型中是否显示抗肿瘤活性,对其进行了如下测试。
方法
使用小鼠乳腺4T1癌细胞在同系模型中测试如上获得的式(I)化合物。使4T1细胞在补充有10%FBS(Invitrogen,目录号10438-026)和1%青霉素链霉素(赛默飞世尔科技,目录号15140-122)的RPMI1640培养基(Sigma,目录号R6504)中生长。当细胞达到70-80%汇合时,通过胰蛋白酶消化收集细胞。在细胞接种的前一天,使用毛发修剪器将BALB/C小鼠右侧腹的毛发脱毛。在第二天,用手术酒精轻轻擦拭消毒注射部位周围的皮肤区域。为了建立同种异体移植,将细胞悬浮在无血清培养基中,并与基质胶(Mattriel)1:1混合,以获得1x106细胞/100μL。使用连接到24号针头(BD精密滑行针头,0.55mm x 25mm,REF#302805)的1mL BD注射器皮下植入悬浮在基质胶中的细胞。根据肿瘤体积将小鼠随机分组,每组分配六只小鼠约5天后,当肿瘤移植物明显时,测量肿瘤移植物。每天一次,动物口服载体对照或化合物238(QD,30mg/kg/天),持续14天。口服载体由在50mM柠檬酸盐缓冲液(pH 3.0)中的10%磺基丁基醚β-环糊精钠(SBECD)组成。肿瘤生长抑制(TGI)的计算如下:%TGI=[1-(治疗TV最终–治疗TV初始)/(控制TV最终–控制TV初始)]*100
结果
这项研究的目的是在***4T1同基因肿瘤模型中测试化合物238独立的抗肿瘤功效。与载体对照相比,所有治疗均耐受良好,因为没有临床异常迹象,动物体重也没有明显变化。在第15天,治疗组#2的平均肿瘤体积(化合物238)为669±60mm3,其导致肿瘤生长抑制(TGI)为59%(见图2a)。总的来说,这些结果表明化合物238在BALB/C小鼠的免疫竞争性4T1同基因肿瘤模型中显示出良好的抗肿瘤活性。
有趣的是,在免疫缺陷小鼠中,30mg/kg/天的化合物238没有抗肿瘤作用(见图2b),表明它可以通过直接增加免疫反应来抑制肿瘤的生长。
5.乳腺癌4T1同基因体内癌症模型中的抗转移活性
为了测试式(I)的化合物在B16F10肺和CT-26腹膜转移模型中是否显示抗癌转移活性,对其进行如下测试。
方法
使用小鼠B16F10黑素瘤和CT26-荧光素酶结肠癌细胞在转移模型中测试如上获得的式(I)化合物。两种细胞均在补充有10%FBS(Invitrogen,目录号10438-026)和1%青霉素链霉素(赛默飞世尔科技,目录号15140-122)的RPMI1640培养基(Sigma,目录号R6504)中生长。当它们达到70-80%汇合时,通过胰蛋白酶消化收获细胞系。在细胞接种的前一天,根据SPF指南(室温,40-60%湿度)将C57BL/6小鼠维持在无病原体的条件下,并饲养在延世大学的ABMRC中。为了建立转移,将B16F10细胞(1x106细胞/小鼠,n=3/组)悬浮在无血清培养基中,并使用连接到24号针头(BD精密滑行针头,0.55毫米x25毫米,REF#302805)的1mL BD注射器在尾部静脉注射。30mg/kg/天的化合物226预处理24小时后,将CT-26-荧光素酶细胞(1x104细胞/小鼠,n=5/组)移植到腹膜腔内。
将小鼠随机分组,每组分配三只用于B16F10模型的小鼠和五只用于CT26腹膜转移模型的小鼠。接种细胞14天后测量肺转移情况。在所示的日子中每天一次对动物口服载体对照或化合物226(30mg/kg/天)。口服载体由在50mM柠檬酸盐缓冲液(pH 3.0)中的10%磺基丁基醚β-环糊精钠(SBECD)组成。在整个研究过程中每天监测动物的死亡率和临床体征(例如疾病和行为改变)。在B16F10模型中,处死小鼠后,将器官用10%的***溶液固定1天。将FFPE块在涂布载玻片上切成4μm的厚度,以进行H&E染色。然后,计算肿瘤结节计数。CT26转移是通过测量腹膜腔内的发光强度来确定的。
结果
这项研究的目的是评估化合物226对B16F10肺和CT-26腹膜转移模型的预防作用。化合物226的治疗耐受性良好,因为与载体对照相比,没有临床异常迹象。在第9天,在载体组中的两只小鼠在CT26转移模型中被发现死亡。在B16F10转移模型中,如黑色区域显示,口服30mg/kg/天的化合物226在所有大肺标本中均显着抑制了肺转移,并且没有肿瘤结节(参见图3a至图3c)。在CT-26腹膜转移模型中,化合物226的治疗可大大降低腹膜腔内的发光强度。另外,载体组中的小鼠从CT26-萤光素酶细胞移植后的第9天开始死亡,而用化合物226(QD,30mg/kg/天)处理的小鼠在治疗期间还活着(见图4a和4b)。因此,这些结果表明式(I)的化合物226将具有预防Axl阳性癌症患者转移的治疗潜力。
6.与抗PD-1抗体在转移模型中的联合作用
为了测试式(I)的化合物在4T1自发转移模型中是否显示与小鼠抗PD-1抗体的组合作用,对其进行如下测试。
方法
使用小鼠4T1乳腺癌细胞在自发转移模型中测试如上获得的式(I)的化合物。使4T1细胞在补充有10%FBS(Invitrogen,目录号10438-026)和1%青霉素链霉素(赛默飞世尔科技,目录号15140-122)的RPMI1640培养基(Sigma,目录号R6504)中生长。当它们达到70-80%汇合时,通过胰蛋白酶消化收获细胞系。在细胞接种的前一天,使用毛发修剪器将BALB/C小鼠右侧腹的毛发脱毛。在第二天,用手术酒精轻轻擦拭消毒注射部位周围的皮肤区域。为了建立同种异体移植,将BALB/c雌性小鼠(7周龄)与5x106同系4T1细胞原位植入乳腺。当平均肿瘤体积达到1500mm3时处死小鼠。
根据肿瘤体积(~50mm3)将小鼠随机分组,每组分配五只小鼠。接种约2天后,当可触摸时,测量肿瘤移植物。在指定的天数内,给动物口服载体对照或式(I)化合物226(30mg/kg/天)和/或抗小鼠PD-1抗体。口服载体由在50mM柠檬酸盐缓冲液(pH 3.0)中的10%磺基丁基醚β-环糊精钠(SBECD)组成。在整个研究过程中每天监测动物的死亡率和临床体征(例如疾病和行为改变)。处理28天后,处死所有小鼠。通过H&E染色计数肿瘤结节来确定4T1肺转移。通过肿瘤3D扫描仪TM900(Peria,比利时)对原位4T1实体瘤进行了测量。收集小鼠肺并用10%***溶液固定24小时。将FFPE块在涂布载玻片上切成4μm的厚度,以进行H&E染色。通过显微镜观察测量转移结节。
结果
将BALB/c雌性小鼠(7周龄)与5x106同基因4T1细胞原位植入乳腺。当肿瘤达到约50mm3的大小时,用载体,抗PD-1抗体(100mg两次/周),式(I)化合物226(30mg/kg/天)或式(I)的化合物226和抗PD-1抗体的组合治疗小鼠持续4周。在第28天处死小鼠,并通过计数结节评估肺转移。单独使用化合物226可以显著减少向肺的转移,并且与单独使用化合物226的治疗相比,抗PD1抗体和化合物226的组合可提高更高的肿瘤结节减少率(参见图5a至5c)。抗PD-1抗体治疗组对肺转移没有显著疗效。化合物226显著抑制了总转移负担和较大转移的数量(中+大转移,直径≥5mm;见图5c)。关于原发部位的肿瘤生长,单独的化合物226和联合组显示出对肿瘤生长的抑制,各组之间没有不同的功效,这表明联合作用将在转移性肿瘤而不是原发性肿瘤上起作用(见图6)。综上所述,这些结果表明式(I)的化合物226对于免疫肿瘤学在转移治疗中的应用显示出高潜力。
Claims (7)
1.一种式(I)代表的化合物或其药学上可接受的盐的用途,用于制备一制剂,所述的制剂用于治疗由Axl介导的乳腺癌、结肠癌、肺癌或黑色素瘤:
其中
R1是C6芳基,C5-C6环烷基或C5-C6环烷基甲基,其任选地被一个R3取代;
R3独立地为氟或甲基;
Y是溴;
R2为6元杂环烷基,其中所述6元杂环烷基具有1个氮原子,并且在氮原子上被R5取代;
和R5为C1-C3烷基,其中所述C1-C3烷基任选被3个氟取代。
2.如权利要求1所述的用途,其中R1是苯基,环戊基,环己基,环戊基甲基或环己基甲基,其任选地被一个R3取代;且R3独立地为氟或甲基。
3.如权利要求1所述的用途,其中R2是在氮原子上被R5取代的哌啶基;R5是C1-C3烷基。
4.如权利要求1所述的用途,其中R5为甲基,乙基,三氟乙基或异丙基。
5.如权利要求1所述的用途,其中R3独立地是氟。
6.如权利要求1所述的用途,其中式(I)的化合物或其药学上可接受的盐是8-溴-2-((1-甲基哌啶-4-基)氨基)-4-((4-苯氧基苯基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮盐酸盐。
7.如权利要求1所述的用途,其中式(I)的化合物或其药学上可接受的盐是8-溴-4-((4-(环戊氧基)苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮盐酸盐;或8-溴-4-((4-(3-氟苯氧基)苯基)氨基)-2-((1-甲基哌啶-4-基)氨基)吡啶并[4,3-d]嘧啶-5(6H)-酮一盐酸盐。
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