CN105566329B - 一种吡唑[5，6-d]并嘧啶类EGFR抑制剂及其抗肿瘤活性 - Google Patents
一种吡唑[5，6-d]并嘧啶类EGFR抑制剂及其抗肿瘤活性 Download PDFInfo
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Abstract
本发明提供了一种EGFR抑制剂类具有抗肿瘤作用的吡唑[5，6‑d]并嘧啶类化合物。另外，本发明还提供了该化合物的药物组合物以及抗肿瘤用途等。
Description
技术领域
本发明属于药物化学领域，具体而言，本发明涉及一种有良好抗肿瘤活性的吡唑[5，6-d]并嘧啶类化合物。另外，本发明还涉及含有该种化合物的药物组合物及其在制备抗肿瘤药物中的用途等。
背景技术
肺癌是发病率和病死率最高的恶性肿瘤之一，在世界范围内每年因肺癌导致的死亡超过100万人；在我国，肺癌的发病率和死亡率在恶性肿瘤中长期居于首位，其中以非小细胞肺癌(NSCLC)最为普遍，占发病总数的85％以上。目前，经典的手术切除或放化疗往往存在术后复发率高、毒副作用大、转移和耐药等多种缺陷。鉴于EGFR信号途径在诱发NSCLC肿瘤生长和血管增生中的重要作用，EGFR已经成为NSCLC靶向治疗的重要靶点，其相应的小分子抑制剂成为各大医药公司争相研发的重要领域。
目前，已有近20种EGFR抑制剂药物进入临床试验阶段或陆续上市。其中，被认为是第一代EGFR抑制剂的易瑞沙(Gefinitib)、特罗凯(Erlotinib)和我国自主研发上市的凯美纳(Icotinib，2012年上市)等已在临床NSCLC病人治疗中获得巨大成功。但经6～12个月的治疗后往往会发生明显的继发性耐药，极大的限制了患者生存时间的延长，目前研究认为这种耐药通常是由于EGFR 20号外显子T790M错位突变所引起。2013年，BoehringerIngelheim公司成功开发了首个第二代EGFR抑制剂Afatinib(BIBW2992)，其主要特点是可以显著抑制EGFRT790M，有效逆转T790M所引起的耐药。但是，Afatinib同时也强烈抑制野生型EGFR(EGFRWT)，阻止体内正常组织EGFRWT激酶的磷酸化和相关信号通路的激活，从而带来较大的药物毒副作用，临床上表现为皮疹、呕吐等药物毒副反应。因此，开发具有高特异性EGFRT790M突变体抑制剂已成为研发新一代抑制剂的首要目标。
目前，EGFR抑制剂的构效关系并不明朗，有的结构差别很小的化合物，其针对EGFR抑制的效果却相差很大。本发明人经过艰苦努力，令人意外地设计并合成出一种新的吡唑[5，6-d]并嘧啶类化合物，其具有优良的EGFRT790M抑制效果和选择性，属于第三代EGFR抑制剂，能用于治疗各种EGFRT790M高表达的肿瘤。
发明内容
本发明要解决的技术问题是提供新的EGFR抑制剂类抗肿瘤化合物及其药物。
具体而言，本发明提供了式(WZ00411)所示的化合物或者其药学上可接受的盐：
化合物(WZ00411)为：
N6-(1H-吲哚-5)-N2-(4-(4-氮甲基哌嗪苯基)-1H-吡唑[5，6-d]并嘧啶-4，6-二胺
N4-(1H-indol-5-yl)-N6-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[3，4-d]pyrimidine-4，6-diamine
本发明要解决的技术问题在于提供新的含吲哚的嘧啶[5，6-d]并咪唑类化合物和/或提供其在治疗或预防肿瘤(尤其是EGFR依赖性或EGFRT790M突变高表达类肿瘤)方面的新用途。
本发明的目的之一是提供一种新型的吡唑[5，6-d]并嘧啶类EGFR抑制剂。
本发明的目的之二是提供一种新型的吡唑[5，6-d]并嘧啶类EGFR抑制剂的制备方法及抗肿瘤活性。
在本发明中，我们首先利用化学方法合成了一种新型的吡唑[5，6-d]并嘧啶类化合物WZ00411。利用体外激酶层次上的活性筛选实验证实了化合物WZ00411具有强烈的EGFRT790M抑制活性，同时对EGFRWT具有一定选择性并对其他激酶抑制活性较弱，具备良好的激酶选择性和第三代EGFR抑制剂特点(详情见实施例1)。细胞层面上实验也证实该化合物可以有效抑制EGFR及其下游信号p-Akt和p-Erk的磷酸化水平(详情见实施例2)。
附图说明：
这里所列举的化合物只是为了更好地说明本发明的化合物类别和结构形式，并非限制本发明。
图1说明合成的化合物WZ00411化学结构；
图2说明激酶选择性抑制测试；
图3说明化合物细胞水平上化合物的抗肿瘤活性验证。
图4说明化合物在H1975细胞水平上对下游信号通路蛋白磷酸化抑制作用。
实施例1化合物体外抑制EGFR的活性和选择性
EGFR激酶体外活性筛选：实验采用方法为Caliper Mobility Shift Assay，该方法是以微流体芯片技术的迁移率检测技术为核心的检测平台。实验步骤：配置1.25x激酶反应缓冲液(62.5mmol/L HEPES，pH 7.5；0.001875％Brij-35；12.5mmol/LMgCl2；2.5mM DTT)和激酶反应终止液(100mmol/L HEPES，pH 7.5；0.015％Brij-35；0.2％Coating Reagent#3)；在5μl的5x浓度的化合物溶液中(用DMSO溶解，用水稀释10倍)加入10μl的2.5x的FGFR1激酶溶液(在1.25x激酶反应缓冲液中加激酶)，室温孵育10min后再加入10μl的2.5x底物肽溶液(在1.25x激酶反应缓冲液中加FAM标记肽和ATP)，在28℃下反应特定的时间后加入25μl激酶反应终止液。在Caliper上测试收集数据，对激酶活性的抑制率＝(max-conversion)/(max-min)*100。“max”为未加化合物的DMSO对照，“min”为低对照。测定IC50时每种样品设10个稀释度各2个复孔，3次重复。
激酶选择性抑制测试：将WZ00411依照上述激酶抑制活性测定方法，测定对VEGFR1、EGFR、PDGFR、FGFR1～2和C-Met等6种常见激酶的抑制活性，同时比较EGFRWT/EGFRT790M激酶IC50活性比值，以表征这些化合物对EGFRWT和其他激酶的选择性。以表征该化合物对激酶的选择性。
激酶实验表明：化合物WZ00411对EGFRWT/EGFRT790M抑制IC50分别为21.33和1156.62nMol。对其它常见5种激酶的抑制活性均大于5000nMol(实验数据见图2)，因此具有良好的EGFRT790M抑制活性和EGFRWT/EGFRT790M及其他激酶选择性。(见图2)
实施例2细胞水平上化合物的抗肿瘤活性验证
采用MTT法化合物WZ00411在细胞层面上的抗肿瘤活性，选用含EGFRT790M高表达的人NSCLC细胞株(H1975)、EGFRWT高表达的人大细胞肺癌细胞株(A549)以及EGFR原发性错位突变的人肺癌细胞株(HCC827)等7种细胞进行增殖抑制活性测试。测定时以PBS为空白对照，EGF为阴性对照，(EGF+WZ4002)为阳性对照，(EGF+待测样品)为实验组，每种样品设6个浓度梯度，计算IC50值。
活性化合物对胞内EGFR促增殖信号通路的影响：选取化合物WZ00411，用EGF联合不同浓度的WZ00411分别处理含EGFRT790M高表达的非小细胞肺癌H1975细胞；提取细胞总蛋白后，经Western blotting检测细胞内EGF/EGFR信号通路中促增殖信号分子EGFR、ERK和AKT磷酸化水平的变化。
细胞实验表明：化合物WZ00411体现了良好的EGFRWT/EGFRT790M选择性。对EGFRT790M激酶抑制活性均达到20nMol，具有潜在的优化前景，并且拥有比WZ4002更优秀的激酶选择性，化合物WZ00411对EGFRWT/EGFRT790M选择性为55倍(见图3)。此外，WZ00411具有较好的抗肿瘤增殖活性，并在1、10、100和1000nMol四种浓度下均可强烈抑制H1975细胞中p-EGFR，p-AKT和p-ERK水平(见图4)。
Claims (12)
1.具有下列化学结构的化合物及其可药用盐：
2.权利要求1所述的化合物，其用于治疗肿瘤相关的疾病。
3.权利要求2所述的化合物，其特征在于，所述的肿瘤为肺癌或乳腺癌。
4.用于治疗肿瘤或与肿瘤相关的疾病的药物组合物，其包括权利要求1所述的化合物和药学上可接受的载体。
5.权利要求4所述的药物组合物，其特征在于，所述的肿瘤为肺癌或乳腺癌。
6.权利要求4所述的药物组合物，其被制成片剂、胶囊、口服液、注射剂、粉剂、膏剂或外用药液。
7.权利要求1中所述的化合物在制备用于治疗肿瘤或与肿瘤相关的疾病的药物中的应用。
8.权利要求7所述的应用，其特征在于，所述的肿瘤为肺癌或乳腺癌。
9.如权利要求7所述的应用，其特征在于，其中肿瘤或与肿瘤相关的疾病是由表皮生长因子受体或T790M突变体超出正常量表达和释放而导致的疾病。
10.权利要求9所述的应用，其特征在于，所述的表皮生长因子受体为EGFR，所述的T790M突变体为EGFRT790M。
11.如权利要求7所述的应用，其中肿瘤或与肿瘤相关的疾病选自肺癌、乳腺癌、骨肉瘤、皮肤癌、阴茎癌、膀胱癌、前列腺癌、宫颈癌、子宫肌瘤、胆管癌、胰腺癌、肝癌、胃癌、大肠癌、肾癌、鼻咽癌、食管癌、白血病、脑膜瘤、淋巴瘤。
12.如权利要求11所述的应用，其特征在于，所述的肺癌选自非小细胞肺癌。
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