CN113840823A - 显示癌细胞生长抑制效果的新型杂环取代的嘧啶衍生物,以及包含其的药物组合物 - Google Patents
显示癌细胞生长抑制效果的新型杂环取代的嘧啶衍生物,以及包含其的药物组合物 Download PDFInfo
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- CN113840823A CN113840823A CN202080034942.5A CN202080034942A CN113840823A CN 113840823 A CN113840823 A CN 113840823A CN 202080034942 A CN202080034942 A CN 202080034942A CN 113840823 A CN113840823 A CN 113840823A
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Abstract
本发明提供一种化学式1表示的新型化合物或其盐以及包含其的肺癌治疗用药物组合物。化学式1表示的嘧啶衍生物化合物有效抑制具有ALK突变和EGFR突变的癌细胞的生长,从而可有效用于肺癌的治疗。
Description
[技术领域]
本申请要求基于2019年10月31日提交的韩国专利申请第10-2019-0137489号的优先权权益,其全部内容通过引用并入本文。
本发明涉及有效抑制癌细胞生长的新型杂环取代嘧啶衍生物以及包含其的药物组合物。
[背景技术]
非小细胞肺癌(NSCLC)是一种最近在世界上癌症相关疾病的患病率和死亡率非常高的疾病。NSCLC主要是由酪氨酸激酶的突变和过度表达等引起的,并且用于治疗NSCLC的抗癌剂已通过靶向这些酶的活性抑制而开发。主要发生在包括韩国在内的东亚地区的NSCLC有许多表皮生长因子受体(EGFR)基因突变的情况,并且已开发出毒性相对较低且治疗效果好的药物。
另外,NSCLC是由各种肿瘤基因的表达、重排等引起的,这些基因对应于间变性淋巴瘤激酶(ALK)、KRAS、ROS1等(LANCET ONCOL 2011;12(2):175-80.)。
在一些NSCLC患者中,观察到ALK异常(EML4-alk输血等),并且临床上使用各种酪氨酸激酶抑制剂(TKI)等来治疗癌症。ALK-阳性NSCLC是由ALK-EML4融合引起的,并且当通常由两个基因的融合而潜伏的ALK基因迅速提高细胞的生长速度时,接收到这种信号的细胞会迅速转移到癌细胞。作为具有突变的患者的代表性治疗药物,克唑替尼于2011年被美国FDA批准为多靶点抗癌治疗剂。这些药物已通过对MET、ALK和ROS1等的活性抑制而用于治疗转移性、ALK阳性NSCLC等。作为克唑替尼的临床研究结果,具有腺癌组织形式的肺癌患者主要参与,其中46%为亚洲人。克唑替尼具有非常优异的疗效,例如约65%的肿瘤反应率、7.7个月(化疗组3个月)的无进展生存时间等,并且最常报告的异常反应是视野异常、腹泻、呕吐、水肿或恶心等(J Thorac Oncol 2012;7(7):1086-90.)。
使用克唑替尼会不可避免地引起耐性,并且据报道,主要导致ALK激酶结构域中发生二次突变(约30%)、ALK融合突变基因扩增,以及旁路信号过程激活等。存在非常多样的突变,但在这些突变中,有包括L1196M和G1269A在内的二次突变、位于最常见的守门员残基(gate-keeper residue)以诱导ALK与克唑替尼的结合干扰的L1196M等(J Clin Oncol2013;31(8):1105-11.)。
在表皮生长因子受体(EGFR)的激酶区域,已发现激活突变del119和L858R是一些NSCLC患者中的致癌基因,并且已使用吉非替尼和厄洛替尼等(其为治疗肺癌的低分子EGFR抑制剂)作为治疗剂(Science 2004,304:1497-500;和New England Journal of Medicine2004,350:2129-39)。
当使用吉非替尼和厄洛替尼作为EGFR激活突变得到确认的NSCLC患者的治疗剂时,大多数患者在一年内表现出对药物的耐性(Clinical Cancer Research 2013;19:2240-7)。观察到在这种耐性机制中表皮生长因子受体的T790M突变率高达60%。因此,已开发出靶向肺癌中T790M突变EGFR的第三代EGFR抑制剂。作为代表性药物,存在奥希替尼和拉泽替尼等,并且这些药物靶向T790M突变,表现出相对较低的毒性,从而临床上用于治疗NSCLC(J Thorac Dis.2018Jul;10(7):3909-3921)。
然而,据报道,第三代EGFR抑制剂的耐药性是不可避免的,并且作为主要耐性机制,已报道C797S突变和MET扩增等(J Hematol Oncol.2016,Jul 22;9(1):59;NatureMedicine 2015,21,560-562;Lung Cancer 2018,118,105-110;和ASCO2017abstract2572,9020)。据报道,C797S突变和MET扩增是分开发现的,但有时是同时发现的。
据报道,在由ALK突变或EGFR突变(或两者)引起的非小细胞肺癌(NSCLC)中,所有抑制激酶-药物的结合力的二次突变作为主要耐性机制影响细胞内亚信号(subsignaling)(Eur Med Chem.2017Aug 18;136:497-510.)。尽管不断开发出各种ALK和EGFR抑制剂,但同时抑制两种激酶的抑制剂的开发却非常缓慢。因此,需要开发有效抑制作为上述主要耐药机制的ALK突变或EGFR突变癌细胞生长的药物。
[现有技术文献]
[专利文献]
(专利文献1)PCT专利公报No.WO/2009/143389A1
[发明内容]
[技术问题]
本发明人致力于开发一种有效抑制ALK突变癌和EGFR突变癌的新型化合物。结果,发现了新型杂环取代嘧啶衍生物在癌症治疗中是有效的。特别是,确认了新型杂环取代嘧啶衍生物对肺癌的治疗表现出优异的效果。
因此,本发明的目的在于提供一种对癌症治疗有效果的新型杂环取代嘧啶衍生物。
本发明的另一个目的是提供一种包含该杂环取代嘧啶衍生物的肺癌治疗用药物组合物。
本发明的再一个目的是提供一种甚至在肺癌中表达ALK突变或EGFR突变的肺癌治疗用药物组合物。
本发明的又一个目的是提供一种甚至在肺癌中表达ALK突变和EGFR突变的肺癌治疗用药物组合物。
[技术方案]
为了实现上述目的,本发明提供了一种下述化学式1表示的化合物或其盐:
[化学式1]
X是氧、取代有或未取代有C1至C4的烷基的胺基或C1至C4的烷基,
R1是C1至C4的烷基、C3至C6的环烷基、CF3、或二甲胺基,
R2是H或C1至C4的烷基,
R3是氢或卤素基团,
R4是氢、卤素基团、CN、CF3、C1至C4的烷基、或氨基羰基,
R5是氢或C1至C4的烷基,
R6是氢或C1至C4的烷基,
R7是取代有或未取代有C1至C4的烷基并由一个或多个氮原子和2至10个碳原子组成的杂环化合物,
R8是取代有或未取代有C1至C4的烷基并由选自氮原子、氧原子和硫原子中的一个或多个杂原子和2至10个碳原子组成的脂族杂环化合物;或N1,N1,N2-三(C1至C4烷基)乙二胺基,
其中,当X为氧时,X与S形成双键,S与N形成单键,且当X为取代有或未取代有C1至C4的烷基的胺基或C1至C4的烷基时,X与S形成单键,S与N形成双键。
本发明还提供了一种用于治疗肺癌的化学式1表示的化合物或其盐。
此外,本发明提供了一种肺癌治疗用药物组合物,其包含化学式1表示的化合物或其药学上可接受的盐和药学上可接受的载体作为有效成分。
此外,本发明提供了一种治疗患有肺癌的动物的方法,其包括将化学式1表示的化合物以有效剂量施用于动物。
此外,本发明提供了化学式1表示的化合物用于治疗肺癌的用途。
[有益效果]
根据本发明,新型杂环取代嘧啶衍生物化合物对癌症治疗提供优异的效果。
此外,根据本发明,包含该杂环取代嘧啶衍生物化合物的肺癌治疗用药物组合物对肺癌的治疗提供优异的活性,特别是有效抑制ALK突变癌细胞和EGRF突变癌细胞的生长。
[具体实施方式]
在下文中,将详细描述本发明的示例性实施方式。然而,示例性实施方式是说明性的,因此,本发明不限于此,并且本发明将仅由下面描述的权利要求的范围来限定。此外,尽管是实施本发明的构成,但是对于能够由本领域技术人员根据已知技术容易地实施的构成,将省略详细描述。
在下文中,除非另有说明,否则术语“本发明的化合物”或“化学式1的化合物”用作同时包括化合物本身及其盐的概念。
在本说明书中,术语“烷基”是指具有特定数量的碳原子的直链和支链烃基。烷基可以是例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基等。
在本说明书中,术语“烷基磺酰基”是指烷基-S(O2)-。此处,烷基如上定义。
本发明涉及一种下述化学式1表示的化合物或其盐:
以下化学式1表示的化合物或其盐:
[化学式1]
X是氧、取代有或未取代有C1至C4的烷基的胺基或C1至C4的烷基,
R1是C1至C4的烷基、C3至C6的环烷基、CF3、或二甲胺基,
R2是H或C1至C4的烷基,
R3是氢或卤素基团,
R4是氢、卤素基团、CN、CF3、C1至C4的烷基、或氨基羰基,
R5是氢或C1至C4的烷基,
R6是氢或C1至C4的烷基,
R7是取代有或未取代有C1至C4的烷基并由一个或多个氮原子和2至10个碳原子组成的杂环化合物,
R8是取代有或未取代有C1至C4的烷基并由选自氮原子、氧原子和硫原子中的一个或多个杂原子和2至10个碳原子组成的脂族杂环化合物;或N1,N1,N2-三(C1至C4烷基)乙二胺基,
其中,当X为氧时,X与S形成双键,S与N形成单键,且当X为取代有或未取代有C1至C4的烷基的胺基或C1至C4的烷基时,X与S形成单键,S与N形成双键。
此外,对于R7和R8,
所述R7可以是取代有或未取代有C1至C4的烷基并由一个或多个氮原子和2至10个碳原子组成的杂环化合物,并且
所述R8可以是取代有或未取代有C1至C4的烷基并由选自氮原子、氧原子和硫原子中的两个以上的杂原子和2至10个碳原子组成的脂族杂环化合物;或N1,N1,N2-三(C1至C4烷基)乙二胺基。
此外,对于R7和R8,
所述R7可以是取代有或未取代有C1至C4烷基的吡唑基、取代有或未取代有C1至C4烷基的咪唑基、或取代有或未取代有C1至C4烷基的***基,并且
所述R8可以是取代有或未取代有C1至C4烷基的吗啉基、取代有或未取代有C1至C4烷基的硫代吗啉基、取代有或未取代有C1至C4烷基的哌嗪基、取代有或未取代有C1至C4烷基的C5至C10的二氮杂螺环化合物、取代有或未取代有C1至C4烷基的C5至C10氧氮杂螺环化合物、取代有或未取代有C1至C4烷基的C5至C10硫氮杂螺环化合物、或N1,N1,N2-三(C1至C4烷基)乙二胺基。
所述R7选自下述化合物,并且
所述R8可以选自下述化合物。
在本发明的化学式1表示的化合物或其盐中,
X是氧,
R1是C1至C4的烷基,
R2是H或C1至C4的烷基,
R3是氢或卤素基团,
R4是氢或卤素基团,
R5是氢或C1至C4的烷基,
R6是C1至C4的烷基,
R7选自下述化合物,并且
R8可以选自下述化合物。
具体而言,上述化学式1表示的化合物可以选自下述化合物:
N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-吗啉苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺(化学式1),
N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-吗啉苯基)氨基)嘧啶-4-基)氨基)苯基)甲磺酰胺(化学式2),
N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-硫代吗啉苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲氧基甲磺酰胺(化学式3),
N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲氧基甲磺酰胺(化学式4),
N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(2-氧杂-6-氮杂螺环[3.3]庚烷-6-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺(化学式5),
N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(6-甲基-2,6-二氮杂螺环[3.3]庚烷-2-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺(化学式6),
N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-硫代吗啉苯基)氨基)嘧啶-4-基)氨基)苯基)甲磺酰胺(化学式7),
N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)甲磺酰胺(化学式8),
N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(2-氧杂-6-氮杂螺环[3.3]庚烷-6-基)苯基)氨基)嘧啶-4-基)氨基)苯基)甲磺酰胺(化学式9),和
N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(6-甲基-2,6-二氮杂螺环[3.3]庚烷-2-基)苯基)氨基)嘧啶-4-基)氨基)苯基)甲磺酰胺(化学式10)。
在本发明中,盐可以是由选自由以下组成的组的至少一种酸诱导的盐形式:盐酸、氢溴酸、硫酸、磷酸、硝酸、乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、丁二酸、戊二酸、富马酸、苹果酸、扁桃酸、酒石酸、柠檬酸、抗坏血酸、棕榈酸、马来酸、苯甲酸、羟基苯甲酸、苯乙酸、肉桂酸、水杨酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸等。
此外,本发明涉及一种肺癌治疗用药物组合物,其包含化学式1表示的化合物或其药学上可接受的盐和药学上可接受的载体作为有效成分。
肺癌可以是ALK突变或表皮生长因子受体(EGFR)突变表达肺癌。
肺癌可以是非小细胞肺癌。
本发明的药物组合物可特别用于治疗肺癌,并且可有效用于治疗甚至在肺癌中具有ALK突变或EGFR突变癌细胞的肺癌。
本发明的药物组合物具有同时对ALK(L1196M或EML4-AlK扩增突变)和EGFR(C797S)具有抑制活性的效果。
在本发明中,化学式1表示的化合物可以以由无机酸或有机酸诱导的盐形式使用,并且例如,可以以由选自由以下组成的组的至少一种酸诱导的盐形式使用:盐酸、氢溴酸、硫酸、磷酸、硝酸、乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、丁二酸、戊二酸、富马酸、苹果酸、扁桃酸、酒石酸、柠檬酸、抗坏血酸、棕榈酸、马来酸、苯甲酸、羟基苯甲酸、苯乙酸、肉桂酸、水杨酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸等。
此外,本发明涉及一种用于治疗肺癌的化学式1表示的化合物或其盐。
此外,本发明涉及一种治疗患有肺癌的动物的方法,其包括将化学式1表示的化合物以有效剂量施用于动物。
此外,本发明涉及化学式1表示的化合物治疗肺癌,特别是非小细胞肺癌的用途。
动物可以是人,并且肺癌可以是具有ALK突变或EGFR突变癌细胞的肺癌。
ALK突变可以是L1196M和EML4-AlK融合突变,EGFR突变可以是选自L858R、T790M、del19和C797S中的一个或多个突变。
本发明的药物组合物可根据常规方法配制,并且可以制备成各种口服给药形式,例如片剂、丸剂、散剂、胶囊剂、糖浆剂、乳剂、微乳剂等,也可以制备成肠胃外给药形式,例如静脉注射、皮下注射、肌肉注射、腹腔注射、经皮注射和直接组织注射。
当本发明的药物组合物以口服制剂的形式制备时,作为药学上可接受的载体,可以使用本领域已知的成分而没有限制,除非干扰有效成分的活性表达。
载体的实例包括赋形剂、稀释剂、崩解剂、粘合剂、润滑剂、表面活性剂、乳化剂、悬浮剂、稀释剂等,但不限于此。
当本发明的药物组合物以注射剂的形式制备时,作为药学上可接受的载体,可以使用本领域已知的成分而没有限制,除非干扰有效成分的活性表达。
具体而言,药学上可接受的载体可包括例如水、盐水、葡萄糖水溶液、类糖水溶液、醇、二醇、醚(例如,聚乙二醇400)、油、脂肪酸、脂肪酸酯、甘油酯、表面活性剂、悬浮剂、乳化剂等,但不限于此。
本发明的药物组合物的剂量可通过考虑患者的年龄、性别和状况、有效成分在体内的吸收度、非活性(inactivity)以及联用的药物来确定,并且可基于化学式1的化合物以0.0001mg/kg(体重)至100mg/kg(体重)注射一次。给药次数以每天1至3次左右为宜。
[具体实施方式]
在下文中,将通过实施例更详细地描述本发明。这些实施例是为了更详细地解释本发明,并且对于本领域技术人员将显而易见的是,根据本发明的要旨,本发明的范围不受这些实施例的限制。
<化学式1表示的化合物的合成方法>
本发明的下述化学式1表示的化合物可参考例如下述反应式1表示的方法容易地制备:
[反应式1]
合成例1.N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-吗啉苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺的合成
步骤A-1:N-甲基-N-(2-硝基苯基)甲磺酰胺的合成
将1-氟-2-硝基苯(1.0当量)溶解在乙腈中,并在室温下添加碳酸钾(2.0当量)和N-甲基甲磺酰胺(1.4当量)。然后,将该混合物在80℃下搅拌过夜。反应完成后,将温度降至室温并过滤该混合物。减压蒸发滤液以获得化合物。将该化合物用于下一个反应而无需分离过程。
步骤A-2:N-(2-氨基苯基)-N-甲基甲磺酰胺的合成
将N-甲基-N-(2-硝基苯基)甲磺酰胺(1.0当量)溶解在甲醇和乙酸乙酯(1:1)中,并添加10%钯/木炭(0.2当量)。将该混合物在氢气下搅拌2小时。反应完成后,使用硅藻土过滤该混合物。减压蒸发滤液。使用***和戊烷使该混合物固化。过滤该混合物以获得目标化合物。将该化合物用于下一个反应而无需分离过程。
步骤A-3:N-(2-((2,5-二氯嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺的合成
将N-(2-氨基苯基)-N-甲基甲磺酰胺(1.0当量)溶解在异丙醇中,并在室温下添加2,4,5-三氯嘧啶(1.1当量)和N,N-二异丙基乙胺(2.5当量)。将该混合物在80℃下搅拌过夜。反应完成后,减压蒸发该混合物并用水和二氯甲烷提取。使用2N盐酸洗涤有机层。减压蒸发该有机层以获得目标化合物。将该化合物用于下一个反应而无需分离过程。
步骤B-1:4-溴-5-氟-2-硝基苯酚的合成
将4-溴-3-氟苯酚溶解在二氯甲烷中。在0℃下添加浓硫酸和硝酸。在相同温度下搅拌该混合物2小时。反应完成后,使用在水中饱和的碳酸氢钠中和该混合物。该混合物用二氯甲烷提取。收集有机层并减压蒸发以获得目标化合物。将该化合物用于下一个反应而无需分离过程。
步骤B-2:1-溴-2-氟-4-甲氧基-5-硝基苯的合成
将4-溴-5-氟-2-硝基苯酚(1.0当量)溶解在N,N-二甲基甲酰胺中,并在室温下添加碳酸钾(2.0当量)和碘甲烷(1.5当量)。将该混合物在45℃下搅拌2小时。反应完成后,用水和乙酸乙酯提取该混合物以收集有机层。减压蒸发该有机层,以通过使用柱色谱法获得目标化合物(己烷:乙酸乙酯=10:1)。
步骤B-3:4-(2-氟-4-甲氧基-5-硝基苯基)-1-甲基-1H-吡唑的合成
将1-溴-2-氟-4-甲氧基-5-硝基苯(1.0当量)溶解在1,4-二氧六环和水中,并在室温下添加1-甲基吡唑-4-硼酸频哪醇酯(1.2当量)、碳酸钠(2.0当量)和钯催化剂(0.1当量)。将该混合物回流并搅拌过夜。反应完成后,用水和乙酸乙酯提取该混合物以收集有机层。减压蒸发该有机层,以通过使用柱色谱法获得目标化合物(己烷:乙酸乙酯=5:1至3:1)。
步骤B-4:4-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)吗啉的合成
将4-(2-氟-4-甲氧基-5-硝基苯基)-1-甲基-1H-吡唑(1.0当量)溶解在N,N-二甲基甲酰胺中,并在室温下添加碳酸钾(1.2当量)和吗啉(1.2当量)。将该混合物在130℃下搅拌过夜。反应完成后,用水和乙酸乙酯提取该混合物以收集有机层。减压蒸发该有机层,以通过使用柱色谱法获得目标化合物(己烷:乙酸乙酯=1:1至1:2)。
步骤B-5:2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-吗啉代苯胺的合成
将4-(5-甲氧基-2-(1-甲基-1H-吡唑-4-基)-4-硝基苯基)吗啉(1.0当量)溶解在甲醇和乙酸乙酯(1:1)中并添加10%钯/木炭(0.2当量)。将该混合物在氢气下搅拌2小时。反应完成后,使用硅藻土过滤该混合物。减压蒸发滤液。使用己烷使该混合物固化并且将制成的固体用于下一个反应而无需分离过程。
步骤C-1:最终化合物的合成
将嘧啶衍生物(1.0当量)溶解在异丙醇中,并在室温下添加苯胺衍生物(1.0当量)和甲磺酸盐(1.3当量)。将该混合物在80℃下搅拌过夜。反应完成后,减压蒸发该混合物以去除溶剂并用水和10%甲醇/二氯甲烷混合溶液提取。减压蒸发有机层,以使用柱色谱法获得目标化合物(10%甲醇/二氯甲烷)。
实施例1:N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-吗啉苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺(化学式1)
通过上述方法制备最终化合物。
产率:69.5%,白色固体,
1H NMR(400MHz,DMSO-d6)δ8.25(d,J=2.4Hz,2H),8.16(d,J=8.6Hz,1H),8.10(s,1H),8.00(s,1H),7.79(d,J=0.8Hz,1H),7.56(s,1H),7.52(dd,J=8.0,1.5Hz,1H),7.02(t,J=7.6Hz,1H),6.83(bs,1H),6.76(s,1H),3.80(s,3H),3.76(s,3H),3.70(m,4H),3.14(s,3H),3.05(s,3H),2.80(m,4H).MS:ESI m/z 599.04[M+H]+
实施例2:N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-吗啉苯基)氨基)嘧啶-4-基)氨基)苯基)甲磺酰胺(化学式2)
在步骤A-1中,使用甲磺酰胺合成该化合物。
产率:62.6%,白色固体,
1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.42(s,1H),8.08(d,J=1.8Hz,2H),7.98-7.87(m,2H),7.77(d,J=0.8Hz,1H),7.56(s,1H),7.26(dd,J=8.0,1.5Hz,1H),6.99(t,J=7.6Hz,1H),6.80(s,1H),6.73(s,1H),3.80(s,3H),3.75(s,3H),3.68(m,4H),2.92(s,3H),2.83-2.72(m,4H).MS:ESI m/z 585.05[M+H]+
实施例3:N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-硫代吗啉苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲氧基甲磺酰胺(化学式3)
在步骤B-4中,使用硫代吗啉合成该化合物。
产率:58.9%,白色固体,
1H NMR(400MHz,DMSO-d6)δ8.26(d,J=2.4Hz,2H),8.14(d,J=8.6Hz,1H),8.09(s,1H),8.01(s,1H),7.79(d,J=0.8Hz,1H),7.56(s,1H),7.52(dd,J=8.0,1.5Hz,1H),7.02(t,J=7.6Hz,1H),6.83(bs,1H),6.76(s,1H),3.94(s,3H),3.86(s,3H),3.72(m,4H),3.33(d,J=12.0Hz,5H),2.95(m,4H).MS:ESI m/z 615.04[M+H]+
实施例4:N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲氧基甲磺酰胺(化学式4)
在步骤B-4中,使用N-甲基哌嗪合成该化合物。
产率:61.5%,灰白色固体,
1H NMR(400MHz,DMSO-d6)δ8.24(d,J=2.4Hz,2H),8.13(d,J=8.6Hz,1H),8.11(s,1H),7.98(s,1H),7.77(d,J=0.8Hz,1H),7.53(s,1H),7.51(dd,J=8.0,1.5Hz,1H),7.02(t,J=7.6Hz,1H),6.83(bs,1H),6.76(s,1H),3.94(s,3H),3.87(s,3H),3.42-3.25(m,11H),3.19-3.07(m,2H),2.96(m,2H),2.26(s,3H).MS:ESI m/z 612.02[M+H]+
实施例5:N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(2-氧杂-6-氮杂螺环[3.3]庚烷-6-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺(化学式5)
在步骤B-4中,使用2-氧杂-6-氮杂螺环[3.3]庚烷合成该化合物。
产率:45.3%,白色固体,
1H NMR(400MHz,DMSO-d6)δ8.28(d,J=2.4Hz,2H),8.14(d,J=8.6Hz,1H),8.12(s,1H),8.02(s,1H),7.81(bs,1H),7.57(s,1H),7.54(m,1H),7.02(t,J=7.6Hz,1H),6.83(bs,1H),6.76(s,1H),4.61(s,4H),3.94(s,3H),3.87(s,3H),3.59(s,4H),3.32(s,3H),3.31(s,3H).MS:ESI m/z 611.09[M+H]+
实施例6:N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(6-甲基-2,6-二氮杂螺环[3.3]庚烷-2-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺(化学式6)
在步骤B-4中,使用2-甲基-2,6-二氮杂螺环[3.3]庚烷合成该化合物。
产率:40.1%,灰白色固体,
1H NMR(400MHz,DMSO-d6)δ8.28(d,J=2.4Hz,2H),8.17(d,J=8.6Hz,1H),8.13(s,1H),8.02(s,1H),7.81(d,J=0.8Hz,1H),7.55(s,1H),7.52(dd,J=8.0,1.5Hz,1H),7.02(t,J=7.6Hz,1H),6.83(bs,1H),6.76(s,1H),3.94(s,3H),3.87(s,3H),3.59(s,4H),3.35(s,3H),3.33(s,3H),3.22(s,4H),2.12(s,3H).MS:ESI m/z 624.08[M+H]+
实施例7:N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-硫代吗啉苯基)氨基)嘧啶-4-基)氨基)苯基)甲磺酰胺(化学式7)
在步骤B-4中,使用N-甲磺酰胺和硫代吗啉合成该化合物。
产率:53.6%,灰白色固体,1H NMR(400MHz,DMSO-d6)δ9.25(s,1H),8.40(s,1H),8.06(d,J=1.8Hz,2H),7.96-7.85(m,2H),7.73(d,J=0.8Hz,1H),7.55(s,1H),7.22(dd,J=8.0,1.5Hz,1H),6.96(t,J=7.6Hz,1H),6.78(s,1H),6.71(s,1H),3.94(s,3H),3.87(s,3H),3.72(m,4H),3.10(m,4H),2.90(s,3H).MS:ESI m/z 601.02[M+H]+
实施例8:N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)甲磺酰胺(化学式8)
在步骤B-4中,使用N-甲磺酰胺和N-甲基哌嗪合成该化合物。
产率:63.4%,白色固体,
1H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.49(s,1H),8.02-7.87(m,4H),7.77(d,J=0.8Hz,1H),7.56(s,1H),7.26(dd,J=8.0,1.5Hz,1H),7.00(t,J=7.6Hz,1H),6.83(s,1H),6.73(s,1H),3.94(s,3H),3.87(s,3H),3.42-3.25(m,5H),3.19-3.07(m,2H),2.96(m,2H),2.90(s,3H),2.16(s,3H).MS:ESI m/z 598.01[M+H]+
实施例9:N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(2-氧杂-6-氮杂螺环[3.3]庚烷-6-基)苯基)氨基)嘧啶-4-基)氨基)苯基)甲磺酰胺(化学式9)
在步骤B-4中,使用N-甲磺酰胺和2-氧杂-6-氮杂螺环[3.3]庚烷合成该化合物。
产率:40.1%,白色固体,
1H NMR(400MHz,DMSO-d6)δ9.25(s,1H),8.40(s,1H),8.07(d,J=1.8Hz,2H),7.97-7.89(m,2H),7.75(d,J=0.8Hz,1H),7.54(s,1H),7.23(dd,J=8.0,1.5Hz,1H),6.98(t,J=7.6Hz,1H),6.81(s,1H),6.71(s,1H),4.61(s,4H),3.94(s,3H),3.87(s,3H),3.59(s,4H),2.90(s,3H).MS:ESI m/z 597.03[M+H]+
实施例10:N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(6-甲基-2,6-二氮杂螺环[3.3]庚烷-2-基)苯基)氨基)嘧啶-4-基)氨基)苯基)甲磺酰胺(化学式10)
在步骤B-4中,使用N-甲磺酰胺和2-甲基-2,6-二氮杂螺环[3.3]庚烷合成该化合物。
产率:37.2%,灰白色固体,
1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),8.82(s,1H),8.28(m,2H),7.94-7.82(m,2H),7.70(d,J=0.8Hz,1H),7.53(s,1H),7.22(dd,J=8.0,1.5Hz,1H),6.94(t,J=7.6Hz,1H),6.81(s,1H),6.70(s,1H),3.94(s,3H),3.87(s,3H),3.59(s,4H),3.22(s,4H),2.92(s,3H),2.15(s,3H).MS:ESI m/z 610.08[M+H]+
实验例1:激酶抑制活性的测量
对于实施例1的化合物,测量了包括ALK突变和EGFR突变的激酶抑制活性,其结果示于下表1中。激酶抑制活性的测量按照下述方法进行。各化合物在抑制激酶抑制活性的浓度下计算IC50值,其结果在下表1中显示为A、B、C和D。此处,A表示IC50≤50nM,B表示IC50 50至100nM,C表示IC50>100nM。作为对照药物,分别使用克唑替尼、阿来替尼和奥希替尼。
1.将各激酶在8mM MOPS、pH 7.0、0.2mM EDTA、250μM KKKGQEEEYVFIE、1mM原钒酸钠、5mM 6-甘油磷酸钠、10mM乙酸镁和[η-33P]-ATP下培养。
2.添加评价化合物(DMSO溶液)和Mg/ATP以进行反应。
3.在室温下约40分钟后,添加10μL 0.5%磷酸以完成反应。
4.将反应溶液分成0.5%10μL并点在P30过滤垫(filtermat)上。
5.反应溶液用0.425%磷酸洗涤4次,约4分钟。反应溶液用甲醇洗涤一次,然后干燥并用闪烁计数分析以测量IC50值。
[表1]
如表1的实验结果所示,确认了与克唑替尼、阿来替尼和奥希替尼相比,通过本发明的实施例制备的化合物具有非常优异的ALK和EGFR激酶抑制活性。
即,与相关技术中分别单独靶向ALK和EGFR的克唑替尼、阿来替尼和奥希替尼不同,确认了本发明的化合物是能够同时靶向ALK和EGFR的靶向治疗剂,并抑制对奥希替尼显示耐性的C797S EGFR突变蛋白,从而具有非常优异的效果。
实验例2:癌细胞生长抑制效果的测量
对于实施例中获得的化合物,测量了ALK突变癌细胞和EGFR突变Ba/F3癌细胞系的生长抑制效果。使用诸如H3122(EML4-ALK v1)、H2228(EML4-ALK v3)等ALK突变细胞系和EGFR突变Ba/F3稳定细胞系通过下述方法进行抗癌功效活性测量。
基因构建:野生型和突变型EGFR购自Addgene(野生型,#11011;L858R,#11012;L858R+T790M,#32073;del19,#32062;del19+T790M,#32072)。所有的构建体作为逆转录病毒载体最终完成了病毒颗粒以用于感染。
Ba/F3稳定细胞系构建:鼠淋巴细胞进行IL-3依赖性生长。在该细胞系中,当感染每个突变型EGFR构建体时,由突变型EGFR的表达进行致癌成瘾,因此细胞即使没有IL-3也能存活。即使没有嘌呤霉素选择,也能使用该原理构建稳定细胞系。简言之,在Ba/F3上感染每个构建体,48小时后,通过培养基交换去除IL-3并培养细胞。然而,在野生型EGFR的情况下,进行了嘌呤霉素选择。
<Ba/F3稳定细胞系的确认>
所有稳定细胞系都进行了蛋白质印迹法以确认各构建的表达和EGFR活性(排除了EGFR野生型和L858R)。
<细胞激酶活性变化的确认(蛋白质印迹法)>
将药物以浓度依赖性方式处理于各稳定细胞系,5小时后获得细胞。使用EBC裂解缓冲液(50mM Tris-HCl[pH 8.0]、120mM NaCl、1%Triton X-100、1mM EDTA,1mM EGTA、0.3mM苯甲基磺酰氟、0.2mM原钒酸钠、0.5%NP-40和5U/mL抑肽酶)制备细胞裂解物。使用EGFR相关信号分子的抗体[p-EGFR(Tyr1173)、EGFR、Akt、p-Erk、Erk、肌动蛋白,来自SantaCruz;p-Akt,来自细胞信号]测量活性。
<通过MTT试验验证抗癌效果>
将2×105个细胞接种在96孔板上。24小时后,将每种药物以剂量依赖性方式处理,孵育72小时后,15μL MTT试剂反应4小时,然后添加100μL 10%SDS,孵育24小时。在595nm处读取最终OD的变化。MTT结果分析通过prism软件测量IC50值。
在由各化合物50%抑制细胞生长的浓度下计算IC50值,结果示于下表2中。作为对照药物,分别使用克唑替尼、阿来替尼和奥希替尼。结果在下表2中显示为A、B、C和D。此处,A表示IC50≤100nM,B表示IC50 50至100nM,C表示IC50>500nM。
[表2]
如下表2的实验结果所示,确认了与克唑替尼、阿来替尼和奥希替尼相比,通过本发明的实施例制备的化合物对于突变表达癌细胞系表现出显著的抑制活性。
与实验例1的体外激酶试验结果一样,本发明的化合物是能够同时靶向ALK和EGFR的靶向治疗剂,并诱导表达对奥希替尼显示耐性的C797S EGFR突变蛋白的癌细胞死亡,从而具有非常优异的效果。
Claims (9)
1.一种以下化学式1表示的化合物或其盐:
[化学式1]
X是氧、取代有或未取代有C1至C4的烷基的胺基或C1至C4的烷基,
R1是C1至C4的烷基、C3至C6的环烷基、CF3、或二甲胺基,
R2是H或C1至C4的烷基,
R3是氢或卤素基团,
R4是氢、卤素基团、CN、CF3、C1至C4的烷基、或氨基羰基,
R5是氢或C1至C4的烷基,
R6是氢或C1至C4的烷基,
R7是取代有或未取代有C1至C4的烷基并由一个或多个氮原子和2至10个碳原子组成的杂环化合物,并且
R8是取代有或未取代有C1至C4的烷基并由选自氮原子、氧原子和硫原子中的一个或多个杂原子和2至10个碳原子组成的脂族杂环化合物;或N1,N1,N2-三(C1至C4烷基)乙二胺基,
其中,当X为氧时,X与S形成双键,S与N形成单键,且当X为取代有或未取代有C1至C4的烷基的胺基或C1至C4的烷基时,X与S形成单键,S与N形成双键。
2.如权利要求1所述的化学式1表示的化合物或其盐,其中
所述R7是取代有或未取代有C1至C4的烷基并由一个或多个氮原子和2至10个碳原子组成的杂环化合物,并且
所述R8是取代有或未取代有C1至C4的烷基并由选自氮原子、氧原子和硫原子中的两个以上的杂原子和2至10个碳原子组成的脂族杂环化合物;或N1,N1,N2-三(C1至C4烷基)乙二胺基。
3.如权利要求1所述的化学式1表示的化合物或其盐,其中
所述R7是取代有或未取代有C1至C4烷基的吡唑基、取代有或未取代有C1至C4烷基的咪唑基、或取代有或未取代有C1至C4烷基的***基,并且
所述R8是取代有或未取代有C1至C4烷基的吗啉基、取代有或未取代有C1至C4烷基的硫代吗啉基、取代有或未取代有C1至C4烷基的哌嗪基、取代有或未取代有C1至C4烷基的C5至C10的二氮杂螺环化合物、取代有或未取代有C1至C4烷基的C5至C10氧氮杂螺环化合物、取代有或未取代有C1至C4烷基的C5至C10硫氮杂螺环化合物、或N1,N1,N2-三(C1至C4烷基)乙二胺基。
6.如权利要求1所述的化学式1表示的化合物或其盐,其中
所述化学式1表示的化合物选自下述化合物:
N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-吗啉苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺(化学式1),
N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-吗啉苯基)氨基)嘧啶-4-基)氨基)苯基)甲磺酰胺(化学式2),
N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-硫代吗啉苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲氧基甲磺酰胺(化学式3),
N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲氧基甲磺酰胺(化学式4),
N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(2-氧杂-6-氮杂螺环[3.3]庚烷-6-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺(化学式5),
N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(6-甲基-2,6-二氮杂螺环[3.3]庚烷-2-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺(化学式6),
N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-硫代吗啉苯基)氨基)嘧啶-4-基)氨基)苯基)甲磺酰胺(化学式7),
N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)甲磺酰胺(化学式8),
N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(2-氧杂-6-氮杂螺环[3.3]庚烷-6-基)苯基)氨基)嘧啶-4-基)氨基)苯基)甲磺酰胺(化学式9),和
N-(2-((5-氯-2-((2-甲氧基-5-(1-甲基-1H-吡唑-4-基)-4-(6-甲基-2,6-二氮杂螺环[3.3]庚烷-2-基)苯基)氨基)嘧啶-4-基)氨基)苯基)甲磺酰胺(化学式10)。
7.如权利要求1所述的化学式1表示的化合物或其盐,其中
所述盐是由选自由以下组成的组的至少一种酸诱导的盐形式:盐酸、氢溴酸、硫酸、磷酸、硝酸、乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、丁二酸、戊二酸、富马酸、苹果酸、扁桃酸、酒石酸、柠檬酸、抗坏血酸、棕榈酸、马来酸、苯甲酸、羟基苯甲酸、苯乙酸、肉桂酸、水杨酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸等。
8.一种肺癌治疗用药物组合物,其包含权利要求1至7中任一项所述的化合物或其药学上可接受的盐和药学上可接受的载体作为有效成分。
9.如权利要求8所述的药物组合物,其中
所述肺癌是ALK突变和表皮生长因子受体(EGFR)表达肺癌。
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KR1020190137489A KR102168179B1 (ko) | 2019-10-31 | 2019-10-31 | 암세포 성장 억제 효과를 나타내는 신규한 헤테로 고리 치환 피리미딘 유도체 및 그를 포함하는 약제학적 조성물 |
KR10-2019-0137489 | 2019-10-31 | ||
PCT/KR2020/013779 WO2021085888A1 (ko) | 2019-10-31 | 2020-10-08 | 암세포 성장 억제 효과를 나타내는 신규한 헤테로 고리 치환 피리미딘 유도체 및 그를 포함하는 약제학적 조성물 |
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WO2021085888A1 (ko) | 2021-05-06 |
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AU2020374269A1 (en) | 2021-12-02 |
JP2023500755A (ja) | 2023-01-11 |
US20220204492A1 (en) | 2022-06-30 |
BR112021021516A2 (pt) | 2022-05-24 |
CA3132640A1 (en) | 2021-05-06 |
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