CN114829352A - 新型氘代嘧啶衍生物及包含其的药物组合物 - Google Patents
新型氘代嘧啶衍生物及包含其的药物组合物 Download PDFInfo
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- CN114829352A CN114829352A CN202080086685.XA CN202080086685A CN114829352A CN 114829352 A CN114829352 A CN 114829352A CN 202080086685 A CN202080086685 A CN 202080086685A CN 114829352 A CN114829352 A CN 114829352A
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- methyl
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- 229910052805 deuterium Inorganic materials 0.000 claims description 27
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- -1 2- ((5-chloro-2- ((2-methoxy-4- (4- (4- (methyl-d 3) piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl Chemical group 0.000 claims description 22
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
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- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims description 3
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Abstract
本发明提供一种化学式1表示的新型氘代嘧啶衍生物或其药学上可接受的盐,以及包含该衍生物的用于治疗肺癌的药物组合物。具体而言,所述化学式1表示的氘代嘧啶衍生物有效地抑制AKL突变和EGFR突变的癌细胞的生长。
Description
技术领域
本发明涉及一种新型氘代嘧啶衍生物和包含该衍生物的药物组合物。
背景技术
非小细胞肺癌(NSCLC)是近年来全球癌症相关疾病发病率和死亡率都非常高的疾病。非小细胞肺癌是由多种因素引起的,但主要是由酪氨酸激酶或间变性淋巴瘤激酶基因的突变、过度表达等引起的,正在开发治疗它们的抗癌药,以对这些酶的活性进行靶向抑制。
已知主要发生在包括韩国在内的东亚地区的非小细胞肺癌往往具有上皮生长因子受体(EGFR)基因突变;已发现表皮生长因子受体(EGFR)激酶区的活化突变是一些非小细胞肺癌患者的致癌基因,并且吉非替尼、厄洛替尼等被用作治疗剂,即,用于治疗它们的低分子量表皮生长因子受体(EGFR)激酶抑制剂(Science 2004,304:1497-500;和NewEngland Journal of Medicine 2004,350:2129-39)。在证实具有EGFR活性突变的非小细胞肺癌患者中,使用吉非替尼和厄洛替尼作为治疗剂会在一年内在多数患者中引起耐药性(Clinical Cancer Research 2013,19:2240-7)。在这些耐药机制中,观察到表皮生长因子受体的T790M突变率最高达到60%。因此,已开发出靶向肺癌中T790M突变型表皮生长因子受体(EGFR)的第三代EGFR抑制剂。代表药物包括奥希替尼、拉泽替尼(lazertinib)等,它们靶向T790M突变,显示的毒性相对较低,因此在临床上用于治疗非小细胞肺癌(J ThoracDis.2018Jul 2018);10(7):3909-3921)。然而,不可避免的是,已报道了第三代EGFR抑制剂的耐药性,并且已报道C797S突变、MET扩增等是主要耐药机制(J Hematol Oncol.2016,Jul22,9(1):59;Nature Medicine 2015,21:560-562;Lung Cancer 2018,118:105-110;和ASCO 2017,abstract 2572,9020)。已报道,C797S突变和MET扩增是分开出现的,但有时是同时出现的。
在一些非小细胞肺癌患者中观察到间变性淋巴瘤激酶(ALK)基因异常(EML4-ALK融合(transfusion)),且临床上正在使用各种酪氨酸激酶抑制剂(TKI)等来治疗这些癌症。ALK阳性的非小细胞肺癌是由ALK和EML4基因融合引起的,并且由于正常潜伏的ALK基因通过这两种基因的融合加快了细胞生长速度,因此接收到这种信号的细胞迅速转移到癌细胞。作为代表性治疗药物,克唑替尼(crizotinib)于2011年被美国FDA批准为多靶点抗癌药。该药物用于通过抑制MET、ALK、ROS1等的活性而治疗转移性ALK阳性非小细胞肺癌等。从克唑替尼的临床研究结果来看,参与者以腺癌组织型肺癌患者为主,其中亚裔占46%。其显示出非常好的疗效:肿瘤响应率约为65%,无进展生存期为7.7个月(化疗组为3个月),所报道的最常见的不良反应为视野异常、腹泻、呕吐、水肿、恶心等(J Thorac Oncol 2012;7(7):1086-90)。使用克唑替尼时,不可避免地产生耐药性,并且已主要报道了ALK激酶结构域中的二次突变(约30%)、ALK融合基因突变扩增、旁路信号传导途径的激活等。虽然突变种类繁多,但存在包括L1196M和G1269A在内的次级突变,L1196M位于最常见的守门残基上,从而诱导克唑替尼与ALK的结合障碍(J Clin Oncol 2013;31(8):1105-11)。
据报道,所有由ALK突变或EGFR突变(或两者兼有)引起的非小细胞肺癌都存在抑制激酶-药物结合力的次级突变,这是主要耐药机制,这些突变影响细胞内下游信号传导(Eur Med Chem.2017Aug 18;136:497-510)。尽管在不断开发各种ALK和EGFR抑制剂,但同时抑制这两种激酶的抑制剂的开发进展非常缓慢。因此,需要开发有效抑制具有上述主要耐药机制的ALK突变或EGFR突变癌细胞的生长的药物。
此外,非小细胞肺癌是由多种癌基因的表达、重排等引起的,这些癌基因的实例包括KRAS、ROS1、RET等(Lancet Oncol 2011;12(2):175-80).
[现有技术文献]
[专利文献]
PCT国际公开WO 2009/143389 A1
发明内容
[技术问题]
本发明人寻求开发一种有效抑制ALK突变和EGFR突变的癌的新化合物。结果证实,一种新型氘代嘧啶衍生物在肺癌治疗中表现出优异的效果。
因此,本发明的一个目的在于提供一种在肺癌的治疗中具有优异效果的新型氘代嘧啶衍生物以及包含该衍生物的药物组合物。
本发明的另一个目的是提供一种在肺癌的治疗中具有优异效果的新型氘代嘧啶衍生物以及包含该衍生物的药物组合物,所述肺癌是表达肺癌中的ALK突变或EGFR突变的肺癌。
[技术方案]
为了实现上述目的,本发明提供了一种下式1表示的化合物或其药学上可接受的盐:
[式1]
其中,
X是未取代或被氘取代的C1-C4烷基磺酰基或未取代或被氘取代的C1-C4二烷基磷酰基;并且
Y1、Y2和Y3各自独立地是未取代或被氘取代的C1-C4烷基,
其中,式1的化合物含有一个或多个氘。
此外,本发明提供了一种用于治疗肺癌的药物组合物,其包含上式1所示的化合物或其药学上可接受的盐作为活性成分,以及药学上可接受的载体。
此外,本发明提供了上式1表示的化合物或其药学上可接受的盐,其用于治疗肺癌。
此外,本发明提供了一种治疗患有肺癌的动物的方法,所述方法包括向所述动物施用有效量的上式1表示的化合物或其药学上可接受的盐。
[有益效果]
本发明的新型氘代嘧啶衍生物和包含其的药物组合物在肺癌的治疗中提供了优异的效果。
此外,所述氘代嘧啶衍生物和包含其的药物组合物特别有效地抑制ALK突变或EGFR突变的癌细胞的生长。
附图说明
图1至4显示了针对本发明实施例1和2中获得的化合物在大鼠中测量的药代动力学元素的结果。
具体实施方式
在下文中,将参考实施方式更详细地描述本发明。然而,本发明不受已通过实例表示的实施方式的限制,并且本发明仅由所附权利要求的范围限定。另外,即使是实施本发明所必需的构成,也会省略本领域技术人员容易实施的对该构成的详细说明。
除非下文另有说明,否则术语“本发明的化合物”或“式1的化合物”用作包括该化合物本身及其药学上可接受的盐的概念。
如本文所用,术语“烷基”是指具有特定碳原子数的直链和支链烃基。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。
如本文所用,术语“烷基磺酰基”是指烷基-S(O2)-。在这种情况下,烷基如上所定义。
本发明涉及由下式1表示的化合物或其药学上可接受的盐:
[式1]
其中,
X是未取代或被氘取代的C1-C4烷基磺酰基或未取代或被氘取代的C1-C4二烷基磷酰基;和
Y1、Y2和Y3各自独立地是未取代或被氘取代的C1-C4烷基,
其中,式1的化合物含有一个或多个氘。
在式1的化合物中,Y1、Y2和Y3中的任何一个或多个可以是被氘取代的C1-C4烷基。
在式1的化合物中,未取代或被氘取代的C1-C4烷基中的烷基可以优选为甲基。
在式1的化合物中,X可以是未取代的或被氘取代的C1-C4烷基磺酰基。
上述式1的化合物优选为以下化合物中的任一种:
N-(2-((5-氯-2-((2-甲氧基-4-(4-(4-(甲基-d3)哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺(化合物1);
N-(2-((5-氯-2-((2-(甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-(甲基-d3)甲磺酰胺(化合物2);
N-(2-((5-氯-2-((2-(甲氧基-d3)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺(化合物3);
N-(2-((5-氯-2-((2-甲氧基-4-(4-(4-(甲基-d3)哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-(甲基-d3)甲磺酰胺(化合物4);
N-(2-((5-氯-2-((2-(甲氧基-d3)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-(甲基-d3)甲磺酰胺(化合物5);
N-(2-((5-氯-2-((2-甲氧基-d3)-4-(4-(4-(甲基-d3)哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺(化合物6);和
N-(2-((5-氯-2-((2-(甲氧基-d3)-4-(4-(4-(甲基-d3)哌嗪-1-基)哌啶-1-基)苯基))氨基)嘧啶-4-基)氨基)苯基)-N-(甲基-d3)甲磺酰胺(化合物7)。
本发明的式1中所含的氘是氢的同位素之一,在氢原子中含有1个质子和1个中子,因此其原子核的质量是一般氢的2倍。氘通常用D表示,是一种稳定的元素,不衰变,并且在自然界中的含量非常低。氘主要是通过电解和浓缩水产生的,是通过利用轻硬水先与电极反应并分解、然后重水以较慢速率与电极反应进行电解的反应速率差异而获得的。对于重元素,它不受中子数带来的质量的影响,因此同位素之间的化学性质差异不大。然而,对于质量较小的氢,中子数变化所引起的质量变化对例如反应性和扩散速率等化学和物理性质具有非常敏感的影响。这被称为同位素效应,已知它在氢和氘中表现突出。
本发明的特征在于,式1的化合物及其药学上可接受的盐的抗癌活性通过利用氘的这种性质而提高。
本发明的式1表示的化合物的盐可以是衍生自无机酸或有机酸的盐的形式,并且在这种情况下,优选的盐包括盐酸、氢溴酸、硫酸、磷酸、硝酸、乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、琥珀酸、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药物组合物,其包含式1表示的化合物或其药学上可接受的盐作为活性成分,以及药学上可接受的载体。
特别地,该药物组合物可以有效地用于治疗ALK突变和表皮生长因子受体(EGFR)突变的肺癌。
本发明的药物组合物可用于非小细胞肺癌和小细胞肺癌。
本发明的式1表示的化合物可以以源自无机酸或有机酸的药学上可接受的盐的形式使用,并且在这种情况下,优选的盐包括源自盐酸、氢溴酸、硫酸、磷酸、硝酸、乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、琥珀酸、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、甲苯磺酸等的盐。
本发明的药物组合物可按常规方法配制,并且可以制成多种口服剂型,例如片剂、丸剂、散剂、胶囊、糖浆剂、乳液、微乳液,也可以制成肠胃外剂型,例如静脉输注、皮下输注、肌内输注、腹膜内输注、透皮输注和直接输注到组织中。
当本发明的药物组合物制备成口服制剂形式时,本领域已知的成分可以不受限制地用作药学上可接受的载体,只要它们不干扰活性成分的活性表达即可。
载体可以包括例如赋形剂、稀释剂、崩解剂、粘合剂、助流剂、表面活性剂、乳化剂、助悬剂等,但不限于此。
当本发明的药物组合物制备成注射剂形式时,本领域已知的成分可以不受限制地用作药学上可接受的载体,只要它们不干扰活性成分的活性表达即可。
具体地,载体可以包括例如水、盐水、葡萄糖水溶液、假糖水溶液、醇、乙二醇、醚(例如,聚乙二醇400)、油、脂肪酸、脂肪酸酯、甘油酯、表面活性剂、助悬剂、乳化剂等,但不限于此。
本发明的药物组合物的剂量优选考虑患者的年龄、性别和状况、活性成分在体内的吸收程度、灭活率以及所要联用的药物来确定,并且基于式1表示的化合物,可以为每次0.0001mg/kg(体重)至100mg/kg(体重)。施用次数为每天约1至3次是合适的。
此外,本发明涉及式1表示的化合物或其药学上可接受的盐,其用于治疗肺癌。
此外,本发明涉及一种治疗患有肺癌的动物的方法,所述方法包括向所述动物施用有效量的上述式1表示的化合物或其药学上可接受的盐。
所述动物可以是人,并且肺癌可以是具有ALK突变或EGFR突变的癌细胞的肺癌。
实施例
在下文中,将通过实施例更详细地描述本发明。对于本领域技术人员来说显而易见的是,这些实施例仅用于更详细地说明本发明,并且根据本发明的主旨,本发明的范围不限于这些实施例。
本发明的式1表示的化合物可以通过以下方案中示出的方法制备,但不限于此。
[方案]
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(1.0eq)溶解在乙腈中,在室温下向其中加入碳酸钾(2.0eq)和N-甲基甲磺酰胺(1.4eq)。此后,将其在80℃搅拌过夜。反应完成后,将温度降至室温并进行过滤。滤液减压蒸发得到化合物,其不经任何分离过程即用于下一步反应。
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(1.0eq)溶解在甲醇和乙酸乙酯(1:1)的混合溶液中,向其中加入10%钯/木炭(0.2eq)。在氢气下搅拌2小时。反应完成后,通过硅藻土过滤。滤液减压蒸发,用乙醚和戊烷固化。之后,过滤得到目标化合物,其不经任何分离过程即用于下一步反应。
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(1.0eq)溶解在异丙醇中,在室温下向其中加入2,4,5-三氯嘧啶(1.1eq)和N,N-二异丙基乙胺(2.5eq)。将其在80℃搅拌过夜。反应完成后,减压蒸发,用水和二氯甲烷萃取。有机层用2N盐酸洗涤。将有机层减压蒸发,得到目标化合物,其不经任何分离过程即用于下一步反应。
步骤A'-1:N-(2-硝基苯基)甲磺酰胺的合成
将1-氟-2-硝基苯(1.0eq)溶解在乙腈中,在室温下向其中加入碳酸钾(2.0eq)和甲磺酰胺(1.4eq)。此后,将其在80℃搅拌过夜。反应完成后,将温度降至室温并进行过滤。滤液减压蒸发得到目标化合物,其不经任何分离过程即用于下一步反应。
步骤A'-2:N-(甲基-d3)-N-(2-硝基苯基)甲磺酰胺的合成
将N-(2-硝基苯基)甲磺酰胺(1.0eq)溶解在N,N-二甲基甲酰胺中,在室温下向其中加入碳酸钾(1.2eq)和碘甲烷-d3(1.1eq)。在70℃搅拌2小时后,反应完成,将温度降至室温并加入水。将所得固体过滤,用水充分洗涤,不经任何分离过程即用于下一步反应。
步骤A'-3:N-(2-氨基苯基)-N-(甲基-d3)甲磺酰胺的合成
将N-甲基-N-(2-硝基苯基)甲磺酰胺(1.0eq)溶解在甲醇和乙酸乙酯(1:1)中,并向其中加入10%钯/木炭(0.2eq)。在氢气下搅拌2小时。反应完成后,通过硅藻土过滤。减压蒸发滤液。用乙醚和戊烷固化后,将其过滤得到目标化合物,其不经任何分离过程即用于下一步反应。
步骤A'-4:N-(2-((2,5-二氯嘧啶-4-基)氨基)苯基)-N-(甲基-d3)甲磺酰胺的合成
将N-(2-氨基苯基)-N-甲基甲磺酰胺(1.0eq)溶解在异丙醇中,在室温下向其中加入2,4,5-三氯嘧啶(1.1eq)和N,N-二异丙基乙胺(2.5eq)。将其在80℃搅拌过夜。反应完成后,减压蒸发,用水和二氯甲烷萃取。有机层用2N盐酸洗涤,有机层减压蒸发,得到目标化合物。其不经任何分离过程即用于下一步反应。
步骤B-1:1-(1-(3-甲氧基-4-硝基苯基)哌啶-4-基)-4-甲基哌嗪的合成
将4-氟-2-甲氧基-1-硝基苯(1.0eq)溶解在乙腈中,在室温下向其中加入碳酸钾(2.5eq)和哌嗪中间体(1.1eq)。在回流下搅拌过夜。反应完成后,将温度降至室温并进行过滤。滤液减压蒸发得到目标化合物,其不经任何分离过程即用于下一步反应。
步骤B-2:2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺的合成
将1-(1-(3-甲氧基-4-硝基苯基)哌啶-4-基)-4-甲基哌嗪(1.0eq)溶于甲醇和二氯甲烷(1:1)的混合溶剂中,向其中添加10%钯/木炭(0.2eq)。在氢气下搅拌2小时。反应完成后,经硅藻土过滤,滤液减压蒸发。使用己烷固化,所得固体不经任何分离过程即用于下一步反应。
步骤B'-1:1-(3-甲氧基-4-硝基苯基)哌啶-4-酮的合成
将4-氟-2-甲氧基-1-硝基苯(1.0eq)溶解在乙腈中。在室温下向其中加入N,N-二异丙基乙胺(3.0eq)和4-哌啶酮一水合物盐酸盐(1.2eq)。将其在80℃搅拌过夜。反应完成后,减压蒸发溶剂,用水和二氯甲烷萃取。收集有机层,减压蒸发,得到目标化合物。其不经任何分离过程即用于下一步反应。
步骤B'-2:4-(1-(3-甲氧基-4-硝基苯基)哌啶-4-基)哌嗪-1-甲酸叔丁酯的合成
将1-(3-甲氧基-4-硝基苯基)哌啶-4-酮(1.0eq)溶解于甲苯,并在室温下向其中添剂哌嗪-1-甲酸叔丁酯(1.97eq)、三乙胺(2.58eq)和乙酸(1.53eq)。在室温下搅拌30分钟后,向其中加入三乙酰氧基硼氢化钠(0.83eq)。这个过程再重复两次。添加完成后,在室温下搅拌过夜。反应完成后,用水和乙酸乙酯萃取,收集有机层。减压蒸发有机层,得到标题化合物。其不经任何分离过程即用于下一步反应。
步骤B'-3:1-(1-(3-甲氧基-4-硝基苯基)哌啶-4-基)哌嗪的合成
将4-(1-(3-甲氧基-4-硝基苯基)哌啶-4-基)哌嗪-1-甲酸叔丁酯(1.0eq)溶于三氟乙酸和二氯甲烷(1:1)的混合溶剂中,并在室温下搅拌。反应完成后,减压蒸发。用2N氢氧化钾溶液和二氯甲烷萃取,收集有机层。减压蒸发有机层,得到标题化合物。其不经任何分离过程即用于下一步反应。
步骤B'-4:1-(1-(3-甲氧基-4-硝基苯基)哌啶-4-基)-4-(甲基-d3)哌嗪的合成
将1-(1-(3-甲氧基-4-硝基苯基)哌啶-4-基)哌嗪(1.0eq)溶解在乙腈中,在0℃向其中加入三乙胺(1.2eq)和碘甲烷-d3(1.1eq)。在相同温度下搅拌。反应完成后,用水和乙酸乙酯萃取,收集有机层。减压蒸发有机层,使用柱色谱法(10%甲醇/二氯甲烷)得到目标化合物。
步骤B'-5:2-甲氧基-4-(4-(4-(甲基-d3)哌嗪-1-基)哌啶-1-基)苯胺的合成
将1-(1-(3-甲氧基-4-硝基苯基)哌啶-4-基)-4-(甲基-d3)哌嗪(1.0eq)溶于甲醇和乙酸乙酯(1:1)的混合溶剂中,并向其中加入10%钯/木炭(0.2eq)。在氢气下搅拌2小时。反应完成后,通过硅藻土过滤。减压蒸发滤液。使用己烷固化,所得固体不经任何分离过程即用于下一步反应。
步骤B SM-1:4-氟-2-(甲氧基-d3)-1-硝基苯
将1-(1-(3-甲氧基-4-硝基苯基)哌啶-4-基)哌嗪(1.0eq)溶解在乙腈中,室温下向其中加入碳酸钾(2.0eq)和碘甲烷-d3(1.3eq)。将其在60℃搅拌2小时。反应完成后,减压蒸发,用水和乙酸乙酯萃取,收集有机层。减压蒸发有机层,使用柱色谱法(25%乙酸乙酯/正己烷)得到目标化合物。
步骤C-1:最终化合物的合成
将嘧啶衍生物(1.0eq)溶解在异丙醇中,在室温下向其中加入苯胺衍生物(1.0eq)和甲磺酸(1.3eq)。将其在80℃搅拌过夜。反应完成后,减压蒸发以去除溶剂,用水和10%甲醇/二氯甲烷混合溶液萃取。减压蒸发有机层,使用柱色谱法(10%甲醇/二氯甲烷)得到目标化合物。
实施例1:N-(2-((5-氯-2-((2-甲氧基-4-(4-(4-(甲基-d3)哌嗪-1-基)哌啶-1-基)苯基)氨基))嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺(化合物1)
步骤A、步骤B'和步骤C用于合成该化合物。
收率:22.5%,白色固体,
1H NMR(400MHz,DMSO-d6)δ8.23(m,2H),8.07-8.06(m,2H),7.54(dd,J=7.9,1.6Hz,1H),7.32(d,J=8.6Hz,1H),7.21(t,J=7.8Hz,1H),7.12(td,J=7.6,1.5Hz,1H),6.57(d,J=2.5Hz,1H),6.41(dd,J=8.7,2.6Hz,1H),3.71-3.66(m,5H),3.14(s,3H),3.06(s,3H),2.62(t,J=11.7Hz,3H),2.52-2.43(m,4H),2.29-2.23(m,5H),1.85-1.79(m,2H),1.54-1.41(m,2H).MS:ESI m/z 618.20[M+H]+
实施例2:N-(2-((5-氯-2-((2-(甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4)-基)氨基)苯基)-N-(甲基-d3)甲磺酰胺(化合物2)
步骤A'、步骤B和步骤C用于合成该化合物。
收率:25.5%,白色固体,
1H NMR(400MHz,DMSO-d6)δ8.24-8.22(m,2H),8.06(s,2H),7.54(dd,J=7.9,1.6Hz,1H),7.32(d,J=8.6Hz,1H),7.21(t,J=7.7Hz,1H),7.12(td,J=7.6,1.5Hz,1H),6.58(d,J=2.5Hz,1H),6.41(dd,J=8.8,2.6Hz,1H),3.71-3.66(m,5H),3.06(s,3H),2.65-2.60(m,2H),2.53-2.43(m,4H),2.29-2.24(m,5H),2.10(s,3H),1.86-1.79(m,2H),1.53-1.43(m,2H).MS:ESI m/z 618.20[M+H]+
实施例3:N-(2-((5-氯-2-((2-(甲氧基-d3)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺(化合物3)
步骤A'、步骤B SM、步骤B和步骤C用于合成该化合物。
收率:40.3%,白色固体,
1H NMR(400MHz,DMSO-d6)δ8.23(m,2H),8.07-8.06(m,2H),7.54(dd,J=7.9,1.6Hz,1H),7.32(d,J=8.6Hz,1H),7.21(t,J=7.8Hz,1H),7.12(td,J=7.6,1.5Hz,1H),6.57(d,J=2.5Hz,1H),6.41(dd,J=8.7,2.6Hz,1H),3.70-3.66(m,2H),3.14(s,3H),3.06(s,3H),2.62(t,J=11.7Hz,3H),2.52-2.43(m,4H),2.29-2.23(m,5H),2.10(s,3H),1.85-1.79(m,2H),1.54-1.41(m,2H).MS:ESI m/z 618.20[M+H]+
实施例4:N-(2-((5-氯-2-((2-甲氧基-4-(4-(4-(甲基-d3)哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-(甲基-d3)甲磺酰胺
步骤A'、步骤B'和步骤C用于合成该化合物。
收率:20.2%,白色固体,1H NMR(400MHz,DMSO-d6)δ8.26-8.23(m,2H),8.08-8.06(m,2H),7.54(dd,J=7.9,1.6Hz,1H),7.32(d,J=8.6Hz,1H),7.21(t,J=7.7Hz,1H),7.12(td,J=7.6,1.5Hz,1H),6.58(d,J=2.5Hz,1H),6.41(dd,J=8.8,2.6Hz,1H),3.71-3.66(m,5H),3.06(s,3H),2.66-2.59(m,2H),2.53-2.43(m,4H),2.37-2.25(m,5H),1.87-1.80(m,2H),1.52-1.44(m,2H).MS:ESI m/z 621.20[M+H]+
实施例5:N-(2-((5-氯-2-((2-(甲氧基-d3)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-(甲基-d3)甲磺酰胺
步骤A'、步骤B SM、步骤B和步骤C用于合成该化合物。
收率:38.9%,白色固体,
1H NMR(400MHz,DMSO-d6)δ8.26-8.23(m,2H),8.08-8.06(m,2H),7.54(dd,J=7.9,1.6Hz,1H),7.32(d,J=8.6Hz,1H),7.21(t,J=7.7Hz,1H),7.12(td,J=7.6,1.5Hz,1H),6.58(d,J=2.5Hz,1H),6.41(dd,J=8.8,2.6Hz,1H),3.70-3.66(m,2H),3.06(s,3H),2.66-2.59(m,2H),2.53-2.43(m,4H),2.37-2.25(m,5H),2.10(s,3H),1.87-1.80(m,2H),1.52-1.44(m,2H).MS:ESI m/z 621.20[M+H]+
实施例6:N-(2-((5-氯-2-((2-甲氧基-4-(4-(4-(甲基-d3)哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-(甲基-d3)甲磺酰胺
步骤A、步骤B SM、步骤B'和步骤C用于合成该化合物。
收率:41.3%,白色固体,
1H NMR(400MHz,DMSO-d6)δ8.26-8.23(m,2H),8.08-8.06(m,2H),7.54(dd,J=7.9,1.6Hz,1H),7.32(d,J=8.6Hz,1H),7.21(t,J=7.7Hz,1H),7.12(td,J=7.6,1.5Hz,1H),6.58(d,J=2.5Hz,1H),6.41(dd,J=8.8,2.6Hz,1H),3.70-3.66(m,2H),3.14(s,3H),3.06(s,3H),2.66-2.59(m,2H),2.53-2.43(m,4H),2.37-2.25(m,5H),1.87-1.80(m,2H),1.52-1.44(m,2H).MS:ESI m/z 621.20[M+H]+
实施例7:N-(2-((5-氯-2-((2-(甲氧基-d3)-4-(4-(4-(甲基-d3)哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-(甲基-d3)甲磺酰胺(化合物7)
步骤A'、步骤B SM、步骤B'和步骤C用于合成该化合物。
收率:38.1%,白色固体,
1H NMR(400MHz,DMSO-d6)δ8.26-8.23(m,2H),8.08-8.06(m,2H),7.54(dd,J=7.9,1.6Hz,1H),7.32(d,J=8.6Hz,1H),7.21(t,J=7.7Hz,1H),7.12(td,J=7.6,1.5Hz,1H),6.58(d,J=2.5Hz,1H),6.41(dd,J=8.8,2.6Hz,1H),3.70-3.66(m,2H),3.06(s,3H),2.66-2.59(m,2H),2.53-2.43(m,4H),2.37-2.25(m,5H),1.87-1.80(m,2H),1.52-1.44(m,2H).MS:ESI m/z 624.30[M+H]+
实施例8:N-(2-((5-氯-2-((2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-(甲基-d3)甲磺酰胺的甲磺酸盐的合成
将N-(2-((5-氯-2-((2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-(甲基-d3)甲磺酰胺(实施例2中制备的化合物,24.0mg,0.039mmol)溶于乙醇(1mL)中,室温下向其中加入甲磺酸(3.8mg,0.039mmol)温度。此后,搅拌直至形成固体。当形成固体时,向其中加入庚烷(1mL)并搅拌2小时。搅拌完成后,过滤并用庚烷洗涤。将滤出的固体在70℃下干燥以合成目标化合物。
收率:97.4%;浅灰色粉末;1H NMR(400MHz,DMSO-d6)δ8.35(s,1H),8.20(m,2H),8.08(s,1H),7.56(dd,J=7.9,1.5Hz,1H),7.36(s,1H),7.24(m,1H),7.15(t,J=7.6Hz,1H),6.63(s,1H),6.47(s,1H),3.83-3.65(m,5H),3.10-2.89(s,7H),2.84-2.63(s,6H),2.31-2.27(m,1H),2.27(s,3H),1.91(d,J=32.1Hz,2H),1.58(s,2H),1.31-1.07(m,2H).MS:ESI m/z 714.05[M+H]+
试验例1:对癌细胞生长的抑制效果的测定
针对上述实施例1和2中获得的化合物、实施例2的化合物中氘被氢取代的化合物(氢取代的参照物质)和对照药无第3代奥希替尼,测量了对含有C797S的上皮生长因子受体(EGFR)激酶的抑制活性,结果示于下表1中。激酶抑制活性的测量方法如下:
1.将每种激酶在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下温育。
2.向其中加入待评价的化合物(DMSO溶液)和Mg/ATP以进行反应。
3.室温下约40分钟后,向其中加入10μL 0.5%的磷酸以完成反应。
4.将0.5%的反应液分割为10μL,并点样于P30滤垫上。
5.用0.425%的磷酸洗涤4次,时间约4分钟。
6.用甲醇洗涤一次,而后干燥,并用闪烁计数法分析以测定IC50值。
7.计算各化合物的GI50值,GI50值为抑制50%细胞生长的浓度,结果如下表1中的A、B、C、D所示。
<评价标准>
A:GI50≤500nM,B:500nM<GI50≤1000nM,C:GI50>1000nM
表1
实施例 | BaF3(del19/T790M/C797S) |
实施例1的化合物 | A |
实施例2的化合物 | A |
氘被氢取代的实施例2化合物(氢取代的参照物质) | A |
奥希替尼 | C |
如上表1所示,本发明实施例1和2中制备的化合物1和2对表达C797S突变表皮生长因子受体的癌细胞系表现出优异的活性。另一方面,作为第3代抗癌剂的奥希替尼活性较差。因此,从这些实验结果可以证实,本发明的化合物是能够治疗由现有第三代药物的耐药机制引起的C797S突变肺癌的新型嘧啶衍生物。
试验例2:药代动力学评价
针对上述实施例1和2中获得的化合物以及氘被氢取代的实施例2化合物(氢取代的参照物质),在大鼠中如下进行了药代动力学试验。
用WFI(注射用水)将受试物质制备成2.5或5mg/mL,而后按规定剂量(10mL/kg)以单剂量施用给大鼠,并在预定时间(0、0.25、0.5、1、2、4、6、8、10、24小时)采血,然后分离血浆。使用HPLC(XBridge C18柱,Waters,流动相为0.1%甲酸:乙腈(30:70,%/%))和MS/MS(ESI阳性,MRM)对药物进行分析,并通过将大鼠空白血浆和每种商业标准溶液以9:1的比例混合来制备5、50、100、500、1000和5000ng/ml的浓度并进行测量。此外,通过以9:1的比例混合大鼠空白血浆和QC标准溶液,制备浓度为100、750和2500ng/ml的QC样品制剂。对于预处理方法,将100μl血浆样品转移至离心管中,向其中加入10μl内标溶液和300μl甲醇,然后混合约30秒。使用离心机以12000rpm的转速(4℃)将管离心约5分钟,取上清液,转移到LC小瓶中,然后注入装置中。此后,通过应用先前验证的测定法来量化大鼠血浆中的药物浓度。对于药代动力学参数,使用WinNonlin 5.2(Pharsight,USA)程序,通过非隔室建模(最佳拟合)来计算AUC0-t、AUC0-∞、Cmax、Tmax和t1/2。药代动力学参数结果表示为平均值和标准差(SD),并使用SPSS程序(Statistical Package for the Social Sciences,10.0K,USA)进行统计学处理。
实验结果如图1至4所示。如图1至4所示,实施例1和2的化合物表现出的绝对吸收率等于或大于对照药物,即氘被氢取代的实施例2化合物(氢取代的参照物质)。特别地,实施例2的化合物与氢取代的参照物质相比显示出111.4%的相对吸收率提高。
Claims (10)
2.如权利要求1所述的式1表示的化合物或其药学上可接受的盐,其特征在于,Y1、Y2和Y3中的任何一个或多个是被氘取代的C1-C4烷基。
3.如权利要求1所述的式1表示的化合物或其药学上可接受的盐,其特征在于,所述未取代或被氘取代的C1-C4烷基中的烷基为甲基。
4.如权利要求1所述的式1表示的化合物或其药学上可接受的盐,其特征在于,X是未取代或被氘取代的C1-C4烷基磺酰基。
5.如权利要求1所述的式1表示的化合物或其药学上可接受的盐,其特征在于,式1表示的化合物是以下化合物中的任一种:
N-(2-((5-氯-2-((2-甲氧基-4-(4-(4-(甲基-d3)哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺(化合物1);
N-(2-((5-氯-2-((2-(甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-(甲基-d3)甲磺酰胺(化合物2);
N-(2-((5-氯-2-((2-(甲氧基-d3)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺(化合物3);
N-(2-((5-氯-2-((2-甲氧基-4-(4-(4-(甲基-d3)哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-(甲基-d3)甲磺酰胺(化合物4);
N-(2-((5-氯-2-((2-(甲氧基-d3)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-(甲基-d3)甲磺酰胺(化合物5);
N-(2-((5-氯-2-((2-甲氧基-d3)-4-(4-(4-(甲基-d3)哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺(化合物6);和
N-(2-((5-氯-2-((2-(甲氧基-d3)-4-(4-(4-(甲基-d3)哌嗪-1-基)哌啶-1-基)苯基))氨基)嘧啶-4-基)氨基)苯基)-N-(甲基-d3)甲磺酰胺(化合物7)。
6.如权利要求1所述的式1表示的化合物或其药学上可接受的盐,其特征在于,所述盐是衍生自选自由盐酸、氢溴酸、硫酸、磷酸、硝酸、乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、琥珀酸、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、苯磺酸和甲苯磺酸组成的组的一种或多种酸的盐。
7.一种用于治疗肺癌的药物组合物,其包含:作为活性成分的权利要求1至6中任一项所述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。
8.如权利要求7所述的用于治疗肺癌的药物组合物,其特征在于,所述药学上可接受的载体是选自由赋形剂、稀释剂、崩解剂、粘合剂、润滑剂、表面活性剂、乳化剂和助悬剂组成的组的一种或多种。
9.如权利要求7所述的用于治疗肺癌的药物组合物,其特征在于,所述药学上可接受的载体是选自由水、盐水、葡萄糖水溶液、假糖水溶液、醇、二醇、醚、油、脂肪酸、脂肪酸酯、甘油酯、表面活性剂、助悬剂和乳化剂组成的组的一种或多种。
10.如权利要求9所述的用于治疗肺癌的药物组合物,其特征在于,所述肺癌是表达ALK突变和表皮生长因子受体(EGFR)的肺癌。
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EP4079730A1 (en) | 2022-10-26 |
EP4079730A4 (en) | 2023-11-29 |
BR112022011857A2 (pt) | 2022-09-06 |
US20230114177A1 (en) | 2023-04-13 |
AU2020406819A1 (en) | 2022-06-16 |
WO2021125758A1 (ko) | 2021-06-24 |
KR20220113933A (ko) | 2022-08-17 |
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