CN115260234A - 一种2-氨基-4-氨基芳基磷氧基嘧啶化合物及其制备方法与应用 - Google Patents
一种2-氨基-4-氨基芳基磷氧基嘧啶化合物及其制备方法与应用 Download PDFInfo
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Abstract
本发明属于药物领域，涉及一种2‑氨基‑4‑氨基芳基磷氧基嘧啶化合物及其制备方法与应用。所述2‑氨基‑4‑氨基芳基磷氧基嘧啶化合物为式I所示化合物：其中，R1选自卤素或者C1‑C4烷基；R2选自H或者C1‑C4烷基。本发明所涉及的一类2‑氨基‑4‑氨基芳基磷氧基嘧啶衍生物及其药学上可接受的盐具有显著的抗肿瘤活性，药理学实验表明，本发明的2‑氨基‑4‑氨基芳基磷氧基嘧啶衍生物对人非小细胞肺癌细胞H1975、人乳腺癌细胞MDA‑MB‑231有显著的抑制作用，且对野生型细胞显示出较高的选择性，具有开发抗肿瘤药物的潜力。
Description
技术领域
本发明属于药物领域，具体地，涉及一种2-氨基-4-氨基芳基磷氧基嘧啶化合物及其制备方法与应用。
背景技术
恶性肿瘤也称作癌症，是一种严重威胁人类生命健康的重大疾病。
肺癌主要分为小细胞肺癌(small cell lung cancer，SCLC)和非小细胞肺癌(non-small cell lung cancer，NSCLC)，其中NSCLC占比约为80-90％。大部分肺癌患者在初次诊断时已为晚期(局部晚期或转移性疾病)，如果无相应治疗措施，NSCLC晚期患者中位生存期(Median Survival Time，MST) 只有5～6个月，患者1年生存率不到10％，5年存活率低于5％。除了外科手术治疗之外，化学药物治疗仍然是NSCLC主要治疗方法，然而传统的化疗药物在杀死肿瘤细胞的同时缺乏对正常细胞的选择性，带来较强的毒副作用，同时还易产生耐药性问题。因此，研究并开发特异性阻断癌细胞生长的“靶向”药物，已经成为抗肿瘤药物研究和发展的重要方向。
门控处EGFRT790M突变是第一代和第二代EGFR抑制剂靶向治疗非小细胞肺癌的最大障碍。基于对T790M突变产生的获得性耐药性机制的理解，以及第一代和第二代EGFR抑制剂的“靶向”剂量限制性毒性的出现，已经开发出第三代EGFR抑制剂，保留对EGFRWT选择性作用，包括含有共价不可逆和非共价可逆的靶向抑制剂作为T790M阳性患者的有效二线疗法。然而，临床治疗过程发现，以AZD9291治疗后EGFRC797S三级突变迅速出现，EGFRT790M/C797S突变可能是不可逆的第三代EGFR-TKI的主要耐药机制，它通过干扰驱动靶效力和选择性的关键共价键的形成而产生抗药性。以第三代EGFR抑制剂治疗后不可避免的出现了EGFRC797S三级突变，阻止了酪氨酸激酶与第三代抑制剂形成共价键，严重制约了EGFRT790M突变患者的临床治疗效果。因此，开发新型克服EGFRL858R/T790M/C797S三级突变体的 EGFR抑制剂，成了第四代EGFR抑制剂研究与开发的主要任务。
以奥希替尼为代表的嘧啶环化合物是许多已上市的治疗非小细胞肺癌药物的经典骨架结构。Brigatinib(5-1，又名布吉他滨，布吉替尼)属于苯胺嘧啶类化合物，化学名称：5-氯-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶 -1-基)苯基)-N4-(2-(二甲基膦酰基)苯基)-2,4-嘧啶二胺，由ARIAD制药公司开发并于2017年4月28日获得美国FDA批准用于治疗克唑替尼耐药后局部进展或转移性非小细胞肺癌患者的二线治疗药物(商品名为Alunbrig)。王义汉等人公开了“用作激酶抑制剂的磷衍生物”，通过对含氮六元杂环取代变换，合成苯氧磷基氯代嘧啶衍生物，但未给出任何活性研究数据 (CN102105150A)。基于Brigatinib嘧啶环结构，吴凌云等人设计并合成了一系列并环芳基磷氧基嘧啶胺化合物(WO2019015655A1)。
酶活性测试、细胞磷酸化抑制实验和体内药效实验研究结果表明，大部分化合物具有良好的抗L858R/T790M/C797S抑制活性，且对A431细胞具有很好的选择性。其中，WO2019015655中含有乙基苯胺取代的化合物对L858R/T790M/C797S三级突变(IC50＝0.16nM)和EGFRWT(IC50＝7.92nM) 具有抑制作用，同时，对A431细胞(IC50＝154nM)表现出良好的选择性。
尽管如此，到目前为止，临床上还没有有效的治疗策略来克服 L858R/T790M/C797S介导的EGFR-TKI的三级突变耐药性。因此，基于嘧啶环结构，通过嘧啶环上取代基改造，开发新型单环嘧啶胺类化合物，研究目标化合物对EGFRL858R/T790M/C797S三级突变体的抑制活性，开发生物活性更高、选择性更好的抗肿瘤化合物，对于嘧啶类化合物合成研究和非小细胞肺癌治疗均具有重要意义。
发明内容
为了克服现有技术的不足，本发明的目的是提供一类抗肿瘤活性较高的2-氨基-4-氨基芳基磷氧基嘧啶化合物及其制备方法与应用。体外EGFR L858R/T790M/C797S抑制活性试验证明本发明提供的化合物具有较好的抑制活性，同时对野生型细胞具有良好的选择性。
本发明对2-氨基-4-芳基磷氧基嘧啶骨架进行修饰，设计并合成了一系列具有抗肿瘤活性的2-氨基-4-氨基芳基磷氧基嘧啶化合物，及其药学上可接受的盐，所述2-氨基-4-氨基芳基磷氧基嘧啶化合物为式I所示化合物：
其中，R1选自卤素或者C1-C4烷基；R2选自H或者C1-C4烷基。
本发明中，C1-C4烷基可以为甲基、乙基、正丙基、异丙基、正丁基、异丁基。
进一步地，R1选自Br或者CH3；R2选自H或者CH3。
本发明的所述2-氨基-4-氨基芳基磷氧基嘧啶化合物优选下列化合物或其药学上可接受的盐：
2-((5-溴-2-((2-甲氧基-5-甲基-4-(4-吗啉基哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦(I-a)；
2-((2-((2-甲氧基-5-甲基-4-(4-吗啉代哌啶-1-基)苯基)氨基)-5-甲基嘧啶 -4-基)氨基)苯基)二甲基氧化膦(I-b)；
2-((5-溴-2-((2-甲氧基-4-(4-吗啉代哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦(I-c)；
2-((2-((2-(2-甲氧基-4-(4-吗啉代哌啶-1-基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯基)二甲基氧化膦(I-d)。
本发明还提供所述的2-氨基-4-氨基芳基磷氧基嘧啶化合物的制备方法，包括以下步骤：
通过式II中间体和式III中间体通过缩合反应a得到：
其中R1、R2如权利要求1或2所定义；
所述式II中间体通过以下步骤b制备得到：
所述式III中间体通过以下步骤c和d制备得到：
进一步地，步骤a中所用的催化剂选自氢氧化钠、三乙胺、N,N-二异丙基乙胺、叔丁醇钾和甲醇钠中的一种或多种。
进一步地，步骤b中，利用式IV化合物的嘧啶环上氯与磷氧基苯胺上的氨基在溶剂中，一定的碱催化剂条件下发生取代反应得到式II中间体，所述溶剂选自乙腈、二氯甲烷、四氢呋喃和甲苯中的一种或多种，所述碱催化剂选自氢氧化钠、三乙胺、N,N-二异丙基乙胺、叔丁醇钾和甲醇钠中的一种或多种。
进一步地，步骤c中，式V化合物与哌啶基吗啉化合物在碱催化下缩合得到式VI化合物，所述碱选自碳酸钠、碳酸钾、碳酸氢钠、三乙胺、吡啶、4-二甲胺基吡啶和DBU中的一种或多种。
进一步地，步骤d中，式VI化合物的硝基经还原反应得到式III中间体，所述还原反应的还原剂选自氢气、水合肼、甲酸铵、硼氢化钠和硼氢化钾中的一种或多种。
具体地，化合物I-a、I-b、I-c、I-d的合成路线如下：
本发明中，所述药学上可接受的盐包括所有无毒的药学上可接受的加成盐。在某些实施方案中，药学上可接受的加成盐可以是无机和有机酸的加成盐和碱性盐。在某些实施方案中，药学上可接受的盐可以是金属盐，例如钠盐、钾盐、铯盐等；碱土金属盐，如钙盐、镁盐等；有机胺盐如三乙胺盐、吡啶盐、甲基吡啶盐、乙醇胺盐、三乙醇胺盐、二环己胺盐、N,N'- 二苄基乙二胺盐等；无机酸盐如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐等；有机酸盐如柠檬酸盐、乳酸盐、酒石酸盐、马来酸盐、富马酸盐、扁桃酸盐、乙酸盐、二氯乙酸盐、三氟乙酸盐、草酸盐、甲酸盐等；磺酸盐如甲磺酸盐、苯磺酸盐、对甲苯磺酸盐等；和氨基酸盐，如精氨酸盐、天冬氨酸盐、谷氨酸盐等。
由于它们的活性，本发明的化合物有利地可用于医药中。因此本发明还提供所述的2-氨基-4-氨基芳基磷氧基嘧啶化合物在制备治疗肿瘤的药物和/或制备肿瘤细胞抑制剂中的应用。
本发明的化合物可用于治疗有此需要的受试者的癌症。如本文所用的术语“受试者”是指可以经历本发明化合物的有益效果的任何动物。首要的动物是哺乳动物，例如人类和伴侣动物，但是本发明内容并不限于此。
经体外EGFR L858R/T790M/C797S三级突变体抑制活性筛选实验，结果表明本发明的式I化合物对EGFR L858R/T790M/C797S激酶具有较好的抑制活性。该结果提示本发明的化合物或其药学上可接受的盐在制备治疗肿瘤有关的疾病或病症的药物中的用途，所述肿瘤为EGFR介导的癌症，优选非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌、头颈部肿瘤、结肠癌、直肠癌、胶质瘤等过度增殖性疾病，进一步优选非小细胞肺癌和乳腺癌，更进一步优选EGFR L858R/ T790M/C797S突变的非小细胞肺癌。
所述肿瘤细胞为人非小细胞肺癌细胞H1975或人乳腺癌细胞 MDA-MB-231，再进一步地，所述人非小细胞肺癌细胞优选为野生型H1975 细胞、H1975(L858R/T790M)突变型细胞和H1975(L858R/T790M/C797S)突变型细胞中的任意一种。
为了检测EGFR的表达或活性，从受试者获得的组织(癌组织、血管壁组织、皮肤、口腔粘膜等)或体液(血液，淋巴)等可应用于检测EGFR 的表达或活性的测试。这些测试是本领域技术人员已知的。
本发明提供一种药物组合物，以所述的2-氨基-4-氨基芳基磷氧基嘧啶化合物为活性组分，并包括药学上可接受的辅料。
本发明的药物组合物可以采取溶液、悬浮液、乳液、片剂、丸剂、颗粒剂、粉末、多颗粒、胶囊、含有液体的胶囊、含有粉末的胶囊、含有多颗粒的胶囊、含片、持续释放制剂、栓剂、透皮贴剂、透粘膜薄膜、舌下片、气溶胶、喷雾剂、或任何其他适合使用的形式。在一个实施方案中，组合物是呈片剂形式。
在一个实施方案中，组合物是呈胶囊形式(参见例如美国专利 No.5,698,155)。其他合适的药物赋形剂实例描述于Remington's Pharmaceutical Sciences 1447-1676(Alfonso R.Gennaro ed.,19th ed.1995)，作为引文引入。
本发明的药物组合物可包含合适量的药学上可接受的赋形剂，以提供用于向受试者合适施用的形式。在某些实施方案中，药物赋形剂可以是稀释剂、悬浮剂、增溶剂、粘合剂、崩解剂、防腐剂、着色剂、润滑剂等。药物赋形剂可以是液体，例如水或油，包括石油、动物、植物、或合成来源的那些，例如花生油、大豆油、矿物油、芝麻油等。药物赋形剂可以是盐水，阿拉伯树胶、明胶、淀粉糊、滑石、角蛋白、胶体二氧化硅、尿素等。可以使用辅助剂、稳定剂、增稠剂、润滑剂和着色剂。在某些实施方案中，当给予受试者时，药学上可接受的赋形剂可以是无菌的。当静脉内施用本发明的化合物时，水可以是赋形剂。盐水溶液和葡萄糖水溶液和甘油溶液也可用作液体赋形剂，例如用于可注射溶液。在某些实施方案中，药物赋形剂可包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸钠、甘油单硬脂酸酯、滑石、氯化钠、干脱脂乳、甘油、丙二醇、水、乙醇等。在某些实施方案中，组合物可含有少量润湿剂或乳化剂、或pH缓冲剂。可用于配制口服剂型的药学上可接受的载体和赋形剂的具体实例描述于Handbook of Pharmaceutical Excipients,American PharmaceuticalAssociation(1986)。
在某些实施方案中，本发明的化合物可以配制用于口服给药制剂。待口服递送的本发明化合物例如可以是片剂，胶囊，软胶囊，囊片，锭剂，水性或油性溶液，悬浮液，颗粒，粉末，乳液，糖浆或酏剂的形式。当将本发明的化合物掺入口服片剂中时，可将这种片剂压制，片剂粉碎，肠溶包衣，糖包衣，薄膜包衣，多重压片或多层包裹。
本发明的口服给药化合物可以含有一种或多种另外的辅剂，例如甜味剂，例如果糖、阿斯巴甜或糖精；调味剂例如薄荷、冬青油或樱桃；着色剂；和保存剂和稳定剂，以提供稳定的，药学上可口服的剂型。用于制备固体口服剂型的技术和组合物描述于Pharmaceutical Dosage Forms:Tablets(Lieberman,Lachman和Schwartz,eds.,2nded.)，由Marcel Dekker,Inc出版。制备片剂(压缩和模塑)，胶囊(硬和软明胶)和丸剂的技术和组合物也描述于Remington's Pharmaceutical Sciences 1553-1593(Arthur Osol,ed.,16th ed.,Mack Publishing,Easton,PA1980)。液体口服剂型可包括水性和非水性溶液、乳液、悬浮液、和由非泡腾颗粒重构的溶液和/或悬浮液，任选地含有一种或多种合适的溶剂、防腐剂、乳化剂、悬浮剂、稀释剂、甜味剂、着色剂、调味剂等。用于制备液体口服剂型的技术和组合物描述于Pharmaceutical Dosage Forms:Disperse Systems,(Lieberman,Rieger and Banker,eds.)由Marcel Dekker,Inc出版。
当本发明的化合物配制成用于通过注射(例如，连续输注或推注)进行肠胃外给药时，制剂可以是油性或水性载体中的悬浮液、溶液、或乳液的形式，并且这样的制剂可以进一步包含药学上必需的添加剂，例如一种或多种稳定剂、悬浮剂、分散剂等。当肠胃外注射本发明的化合物时，其可以是例如等渗无菌溶液的形式。本发明的化合物还可以是粉末形式，用于重构为可注射制剂。
在某些实施方案中，可以将本发明的化合物配制成用于静脉内施用的药物组合物。在某些实施方案中，此类组合物包含无菌等渗水性缓冲液。在某些实施方案中，组合物可包含增溶剂。用于静脉内施用的本发明的化合物可包括局部麻醉剂，例如苯佐卡因或丙胺卡因，以减轻注射部位的疼痛。在某些实施方案中，所述成分可以以单独或混合在一起的单位剂量形式提供，例如，在密封容器如安瓿或小药囊中表明活性剂的量的作为干燥的冻干粉末或无水浓缩物。当通过输注施用本发明的化合物时，其可以例如用含有无菌药用级水或盐水的输液瓶分配。当通过注射施用本发明的化合物时，可以提供安瓿的无菌注射用水或盐水，使得可以在施用之前混合成分。
当通过吸入给予本发明的化合物时，可将其配制成干燥气溶胶，或水性或部分水性溶液。
在另一个实施方案中，本发明的化合物可以在囊泡中递送，特别是脂质体。(参见Langer,Science249:1527-1533(1990)和Treat et al.,Liposomes in the Therapy ofInfectious Disease and Cancer 317-327and 353-365(1989))。
在某些实施方案中，本发明的化合物可以局部给药。这可以通过例如手术期间的局部输注，局部施用，例如与手术后的伤口敷料结合，通过注射，借助于导管，通过栓剂或灌肠，或通过植入物实现，所述植入物是多孔的，非多孔的或凝胶状的材料，包括膜，例如弹性膜或纤维。
在某些实施方案中，本发明的化合物可以立即释放形式递送。在其他实施方案中，本发明的化合物可以在控释系统或持续释放系统中递送。控释或持续释放的药物组合物可具有改善药物治疗的共同目标，不同于通过其非对照或非持续释放对应物实现的结果。在某些实施方案中，控释或持续释放组合物可包含最少量的本发明化合物，以在最短的时间内治疗。控释或持续释放组合物的优点包括延长药物活性，降低剂量频率和增加依从性。控释或持续释放组合物可有利地影响作用开始的时间或其他特征，例如本发明化合物的血液水平，并因此可减少不良副作用的发生。
控释或持续释放组合物可以最初立即释放一定量的本发明化合物，其迅速产生所需的治疗效果，并逐渐和持续释放其它量的本发明化合物，以在延长的时间内保持治疗效果水平。为了在体内维持本发明的化合物的恒定水平，本发明的化合物可以以一定的速率从制剂中释放，所述速率将取代被代谢和从体内排泄的本发明化合物的量。可以通过各种条件刺激活性成分的控制或持续释放，包括但不限于pH的变化，温度的变化，酶的浓度或可获得性，水的浓度或可获得性，或其他生理条件或化合物。
当施用于受试者时，本发明的化合物可以作为包含药学上可接受的载体或赋形剂的组合物的组分施用。本发明的化合物可以通过任何适当的途径施用，如医师所确定的。给药方法可包括皮内、肌肉内、腹膜内、肠胃外、静脉内、皮下、鼻内、硬膜外、口服、舌下、口腔、脑内、阴道内、透皮、经粘膜、直肠、吸入或局部(如耳朵、鼻子、眼睛或皮肤)。分布可以是局部的或系统的。在某些实施方案中，施用可导致本发明化合物释放到血流中。
本发明所提供的一类2-氨基-4-氨基芳基磷氧基嘧啶衍生物及其药学上可接受的盐具有显著的抗肿瘤活性，药理学实验表明，本发明的2-氨基-4- 氨基芳基磷氧基嘧啶衍生物对人非小细胞肺癌细胞H1975、人乳腺癌细胞 MDA-MB-231有显著的抑制作用，且对野生型细胞显示出较高的选择性，具有开发抗肿瘤药物的潜力。
本发明的其它特征和优点将在随后具体实施方式部分予以详细说明。
具体实施方式
下面将更详细地描述本发明的优选实施方式。虽然以下描述了本发明的优选实施方式，然而应该理解，可以以各种形式实现本发明而不应被这里阐述的实施方式所限制。
实施例1
制备2-((5-溴-2-((2-甲氧基-5-甲基-4-(4-吗啉基哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦(I-a)
步骤a：2-((5-溴-2-氯嘧啶-4-基)氨基)苯基)二甲基膦氧化物(I-3)的合成：
向50mL三口烧瓶中加入25mL DMF，搅拌下加入8.9mmol 2-(二甲基氧磷基)苯胺，8.9mmol 5-溴-2,4-二氯嘧啶，缓慢滴加17.7mmol N,N-二异丙基乙胺，滴毕，80-85℃反应8h，TLC监测反应完成(展开剂：乙酸乙酯/石油醚＝1/2)，反应液减压浓缩至干，粗品经柱层析纯化得到灰色固体，收率：77.8％,熔点:121-123℃.1H NMR(400MHz,DMSO-d6,ppm)δ:1.79(s,3H),1.82(s,3H),7.23-7.27(m,1H),7.59-7.67(m,2H),8.30-8.33(m, 1H),8.52(s,1H),11.53(s,1H).13C NMR(100MHz,DMSO-d6,ppm)δ: 159.12,158.04,157.85,142.42(d,J＝2Hz),132.57(d,J＝2Hz),131.31(d,J＝10 Hz),124.27(d,J＝11Hz),123.19,122.54(d,J＝7Hz),122.28,105.08,18.92, 18.21.HRMS(ESI):359.9668 calcd forC12H13BrClN3PO[M+H]+,found: 359.9668.
步骤b：4-(1-(5-甲氧基-2-甲基-4-硝基苯基)哌啶-4-基)吗啉(I-7)的合成：
向50mL三口烧瓶中加入30mL DMF，17.6mmol 4-(哌啶-4-基)吗啉， 35.3mmol碳酸钾，磁力搅拌下加入17.6mmol 4-氟-2-甲氧基-5-甲基-1-硝基苯(I-5)，加毕，升温至60℃反应4h，TLC监测反应完成(展开剂：乙酸乙酯/石油醚＝4/1)，反应液减压浓缩至干，加入20mL水，二氯甲烷萃取(20 mL×3)，合并有机相，无水硫酸钠干燥后，减压浓缩至干，得到黄色固体，再以60mL乙酸乙酯/甲醇(5/1)混合溶剂重结晶，得到淡黄色固体。收率: 88.0％,熔点:133.2-135.9℃.1H NMR(400MHz,DMSO-d6,ppm)δ: 1.50-1.61(m,2H),δ1.88-1.91(m,2H),2.20-2.24(m,3H),2.28-2.34(m,1H), 2.49-2.51(m,2H),2.70-2.75(m,2H),3.31-3.35(m,4H),3.56-3.60(m,4H), 3.91(s,3H),6.69(s,1H),7.76(s,1H).13C NMR(100MHz,DMSO-d6,ppm) δ:158.33 153.15,132.43,128.51,123.05,104.18,67.04,61.37,56.86,50.61, 49.95,49.71,28.65,17.75.HRMS(ESI):336.1923,calcd for C17H26N3O4 [M+H]+,found:336.1924.
步骤c：2-甲氧基-5-甲基-4-(4-吗啉哌啶-1-基)苯胺(I-9)的合成：
向50mL三口烧瓶中加入25mL乙醇，9.3mmol 4-(1-(3-甲氧基-4-硝基苯基)哌啶-4-基)吗啉I-7，5％Pd-C(0.3g,60％水分)，磁力搅拌下升温至 55-60℃开始滴加37.3mmol水合肼(80％)，滴毕，保温反应4h，TLC监测反应完成(展开剂：乙酸乙酯/甲醇＝8/1)，趁热过滤除去Pd-C，滤液减压浓缩至干，得到紫红色固体，收率:77.6％,熔点>220℃.1H NMR(400 MHz,DMSO-d6,ppm)δ:1.96-2.02(m,2H),δ2.20-2.25(m,5H),2.73-2.79(m, 2H),3.09-3.14(m,2H),3.24-3.31(m,3H),3.43-3.46(m,2H),3.86-3.87(m, 3H),3.96-3.98(m,4H),4.72(s,2H),6.86(s,1H),7.26(s,1H).13C NMR (100MHz,DMSO-d6,ppm)δ:151.30,126.24,124.27,104.80,63.66,62.64, 56.69,50.73,48.68,43.00,26.31,17.27.HRMS(ESI):306.2182,calcd for C17H28N3O2[M+H]+,found:306.2178.
步骤d：2-((5-溴-2-((2-甲氧基-5-甲基-4-(4-吗啉基哌啶-1-基)苯基)氨基) 嘧啶-4-基)氨基)苯基)二甲基氧化膦(I-a)的合成：
向25mL三口烧瓶中加入10mL乙腈，磁力搅拌下加入1.39mmol I-3， 1.68mmol I-9，缓慢加入2.10mmol碳酸钾，加毕，80℃反应4h，TLC监测反应完成(展开剂：乙酸乙酯/石油醚＝1/1)，反应液减压浓缩至干，粗品经柱层析纯化得到灰色固体，收率:38.6％,m.p:214-216℃.1H NMR(400 MHz,CDCl3,ppm)δ:8.54(dd,J＝8.4,4.4Hz,1H),8.22(s,1H),8.05(s,1H), 7.53(t,J＝7.6Hz,1H),7.34(t,J＝6.8Hz,1H),7.16(t,J＝7.4Hz,1H),6.63(s, 1H),3.87(s,3H),3.81-3.78(m,4H),3.17(d,J＝11.7Hz,2H),2.65-2.63(m,5 H),2.18(s,3H),1.98(d,J＝11.5Hz,3H),1.88(s,3H),1.85(s,3H),1.66-1.76 (m,3H).13C NMR(100MHz,CDCl3,ppm)δ:158.06,157.96(d,J＝6.9Hz), 156.68,146.81,146.26,143.77(d,J＝2.6Hz),132.63,129.56(d,J＝10.7Hz), 124.4,124.42,124.18,123.14,121.59(d,J＝5.2Hz),121.16,120.21,102.21(d, J＝9.4Hz),94.72,67.35,62.17,55.88(d,J＝13.8Hz),52.04(d,J＝3.1Hz),49.98, 29.07,18.81,18.10,17.27(d,J＝6.0Hz).HRMS(ESI):651.1824 calcd for C29H38NaBrN6O3P[M+Na]+,found:651.1819.
实施例2
2-((2-((2-甲氧基-5-甲基-4-(4-吗啉代哌啶-1-基)苯基)氨基)-5-甲基嘧啶 -4-基)氨基)苯基)二甲基氧化膦(I-b)的合成
2-((2-氯-5-甲基嘧啶-4-基)氨基)苯基)二甲基膦氧化物(I-4)的合成
向50mL三口烧瓶中加入20mL DMF，搅拌下加入8.9mmol(2-氨基苯基)二甲基膦氧化物，8.9mmol 2,4-二氯-5-甲基嘧啶I-2，缓慢加入17.7 mmol碳酸钾，加毕，80-85℃反应8-9h，TLC监测反应完成(展开剂：乙酸乙酯/石油醚＝1/2)，反应液减压浓缩至干，粗品经柱层析纯化得到灰色固体，收率：79.8％,熔点:147-149℃.1H NMR(400MHz,DMSO-d6,ppm)δ:1.81(s,3H),1.84(s,3H),2.17(s,3H),7.16-7.20(m,1H),7.58-7.65(m,2H), 8.13(d,J＝4.0Hz,2H),8.57-8.60(m,1H),11.41(s,1H).13C NMR(100MHz, DMSO-d6,ppm)δ:160.20,157.00,156.82,143.79(d,J＝3Hz),132.81(d,J＝2 Hz),131.45(d,J＝11Hz),123.12(d,J＝12Hz),121.33(t,J＝7Hz),120.43, 116.05,19.14,18.44,13.64.HRMS(ESI):318.0539calcd for C13H16ClN3PO [M+Na]+,found:318.0553.
2-((2-((2-甲氧基-5-甲基-4-(4-吗啉代哌啶-1-基)苯基)氨基)-5-甲基嘧啶 -4-基)氨基)苯基)二甲基氧化膦(I-b)的合成：
合成方法参考I-a的合成，以I-4和I-9为原料，反应得到灰黄色固体，收率:44.4％,熔点:219-221℃.1H NMR(400MHz,CD3OD,ppm)δ:8.47 (dd,J＝8.4,4.5Hz,1H),7.87(s,1H),7.80(s,1H),7.62(m,1H),7.53(t, J＝7.9Hz,1H),7.24-7.26(m,1H),6.74(s,1H),5.52(s,1H),3.88(s,3H), 3.77(t,J＝4.7Hz,4H),3.16(d,J＝11.7Hz,2H),2.69(s,5H),2.36(t,J＝11.3 Hz,1H),2.18(s,3H),2.14(s,3H),2.05(d,J＝11.4Hz,2H),1.90(s,3H),1.86(s,3H),1.70(dd,J＝11.8,3.8Hz,1H).13C NMR(100MHz,CD3OD,ppm) δ:159.69,158.38,154.75,147.78,146.55,143.62,137.73,132.69,130.41, 124.16,123.95,122.62,120.53,109.03,106.29,102.25,66.37,62.30,55.05, 53.41,51.72,49.71,28.56,16.89,16.18,12.23,10.70.HRMS(ESI):565.3056 calcd for C30H42N6O3P[M+H]+,found:565.3053.
实施例3
2-((5-溴-2-((2-甲氧基-4-(4-吗啉代哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦(I-c)的合成：
4-(1-(3-甲氧基-4-硝基苯基)哌啶-4-基)吗啉(I-8)的合成：
向50mL三口烧瓶中加入30mL DMF，17.6mmol 4-(哌啶-4-基)吗啉， 35.3mmol碳酸钾，磁力搅拌下加入17.6mmol 4-氟-2-甲氧基-1-硝基苯 (I-6)，加毕，升温至60℃反应4h，TLC监测反应完成(展开剂：乙酸乙酯/石油醚＝4/1),反应液减压浓缩至干，加入20mL水，二氯甲烷萃取(20 mL×3)，合并有机相，无水硫酸钠干燥后，减压浓缩至干，得到黄色固体，再以60mL乙酸乙酯/甲醇(5/1)混合溶剂重结晶，得到淡黄色固体，收率: 91.5％,熔点>230℃.1H NMR(400MHz,DMSO-d6,ppm)δ:1.36-1.46(m,2 H),1.84-1.87(m,2H),2.41(t,J＝3.8Hz,1H),2.45(t,J＝4.7Hz,4H), 2.92-2.98(m,2H),3.56(t,J＝4.4Hz,4H),3.90(s,3H),4.02(d,J＝13.2Hz,2 H),6.48(d,J＝2.6,1H),6.57(dd,J＝2.5,9.5Hz,1H),7.87(d,J＝9.4Hz,1H). 13C NMR(100MHz,DMSO-d6,ppm)δ:156.65,155.55,128.79,128.03,105.74,97.15,66.97,61.10,56.68,49.86,46.42,27.78.HRMS(ESI):322.1767 calcd forC16H24N3O4[M+H]+,found:322.1772.
2-甲氧基-4-(4-吗啉哌啶-1-基)苯胺(I-10)的合成：
向50mL三口烧瓶中加入25mL乙醇，9.3mmol 4-(1-(3-甲氧基-4-硝基苯基)哌啶-4-基)吗啉I-8，5％Pd-C(0.3g,60％水分)，磁力搅拌下升温至 55-60℃开始滴加37.3mmol水合肼(80％)，滴毕，保温反应4h，TLC监测反应完成(展开剂：乙酸乙酯/甲醇＝8/1)，趁热过滤除去Pd-C，滤液减压浓缩至干，得到棕色固体，收率:89.3％,熔点>230℃.1H NMR(400MHz, CDCl3,ppm)δ:6.65(d,J＝8.3Hz,1H),6.54(d,J＝1.6Hz,1H),6.42-6.45(m,1H),3.85(s,3H),3.77(t,J＝4.6Hz,4H),3.54(d,J＝11.8Hz,2H),2.61-2.63(m, 6H),2.29-2.37(m,1H),1.95(d,J＝12.3Hz,2H),1.67-1.77(m,2H).13C NMR(100MHz,CDCl3,ppm)δ:147.97,145.21,130.08,115.43,109.80, 102.86,67.27,62.11,55.47,51.44,49.75,28.32.HRMS(ESI):291.1947 calcd for C16H26N3O2[M+H]+,found:291.1924.
2-((5-溴-2-((2-甲氧基-4-(4-吗啉代哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦(I-c)的合成：
合成方法参考I-a的合成，以I-3和I-10为原料，反应得到灰黄色固体，收率:40.9％,熔点:95-98℃.1H NMR(400MHz,CDCl3,ppm)δ:8.55(dd, J＝8.4,4.4Hz,1H),8.21(s,1H),8.11(d,J＝8.8Hz,1H),7.53(t,J＝7.9Hz,1 H),7.38-7.30(m,1H),7.16(t,J＝8.2Hz,1H),6.58(d,J＝2.4Hz,1H),6.50(dd, J＝8.8,2.4Hz,1H),3.89(s,3H),3.82-3.73(m,4H),3.67(d,J＝12.3Hz,2H), 2.73(t,J＝11.2Hz,2H),2.66-2.58(m,4H),1.99(d,J＝12.1Hz,2H),1.88(s,3 H),1.84(s,3H),1.73(dd,J＝11.8,3.4Hz,2H).13C NMR(100MHz,CDCl3, ppm)δ:158.15,157.93,156.64,149.20,147.43,143.76(d,J＝2.8Hz), 132.43-132.10(m),129.44(d,J＝10.8Hz),123.51(d,J＝7.1Hz),122.59(d, J＝12.1Hz),122.10,121.16,120.43,120.20,108.39,101.03,94.57,67.32,62.03, 55.61(d,J＝6.1Hz),50.41,49.78,28.27(d,J＝14.7Hz),18.80,18.08.HRMS (ESI):615.1848 calcd forC28H37BrN6O3P[M+H]+,found:615.1836.
实施例4
2-((2-((2-(2-甲氧基-4-(4-吗啉代哌啶-1-基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯基)二甲基氧化膦(I-d)的合成：
合成方法参考I-a的合成，以I-4和I-10为原料，反应得到浅黄色固体，收率:37.7％,熔点:72-74℃.1H NMR(400MHz,CDCl3,ppm)δ:10.39(s,1 H),8.76(dd,J＝8.5,4.5Hz,1H),7.93(s,1H),7.44-7.58(m,2H),7.29(s,1H), 7.07-7.11(m,1H),6.59(d,J＝2.5Hz,1H),6.54(dd,J＝8.8,2.6Hz,1H),3.89 (s,3H),3.79(t,J＝9.3Hz,4H),3.67(d,J＝11.9Hz,2H),2.73(t,J＝11.4Hz,2 H),2.64(t,J＝4.6Hz,2H),2.34-2.40(m,1H),2.21(s,3H),1.99(d,J＝11.7Hz, 2H),1.87(s,3H),1.83(s,3H),1.69-1.79(m,2H).13C NMR(100MHz, CDCl3,ppm)δ:159.20,158.36,157.88,155.83,155.69,149.13,146.97,145.60,144.99,132.85,132.53,129.50,108.61,108.47,107.06,101.36,67.28,62.13, 55.61,50.66,49.76,31.96,29.73,28.20,22.73,18.98,18.27,13.64.HRMS (ESI):551.2900calcd for C29H40N6O3P[M+H]+,found:551.2890.
生物活性试验
试验例1：激酶活性检测
采用均相时间分辨荧光(HTRF)的方法建立EGFR (L858R/T790M/C797S)三级突变型以及EGFR(wild type)的激酶活性检测方法，测定化合物的抑制活性。配制8μL的反应液，包括1×enzymatic buffer(Cisbio,HTRF KinEASETM-TK)，5mM MgCl2，1mM MnCl2，1mM DTT，0.5μM TK substrate-biotin(Cisbio,HTRF KinEASETM-TK)，4μM ATP (EGFR wild type为10μM)，梯度浓度的化合物以及0.2ng/μL EGFR (L858R/T790M/C797S)或者0.04ng/μL的EGFR(wild type)。反应体系中DMSO浓度为2％。酶和化合物预孵育5分钟，然后加入ATP和底物开始反应。所有酶催化反应都在25℃下进行60分钟。酶催化反应结束后，反应液中加入4μL TK antibody-cryptate和4μL streptavidin-XL665(反应浓度为62.5nM)，继续在25℃孵育60分钟。孵育结束后在CLARIOstar(BMG LABTECH)上检测HTRF荧光值，并使用GraphPadPrism 5.0计算IC50。结果见表1。
表1目标化合物对不同类型EGFRa的抑制作用
N.D.:Not determined
a这些值是三个独立实验的平均值±标准偏差.
bIC50用HTRF(均相时间分辨荧光)KinEASE-TK法测定EGFR-L858R/T790M/C797S.每一个反应都是一式两份，每个IC50至少有三个独立的测定.
cL：L858R一级突变
dTL：T790M/L858R二级突变
eCTL：EGFR L858R/T790M/C797S三级突变.
fWT：wild type
gWT/CTL：wild type/EGFR L858R/T790M/C797S三级突变.
由表1中结果可以看出，2-氨基-4-氨基芳基磷氧基嘧啶衍生物中，当嘧啶环2位被芳胺基取代，无论R1是CH3还是Br取代基，所有化合物对 EGFRL858R、EGFRL858R/T790M二级突变体和EGFRL858R/T790M/C797S三级突变体都有明显的抑制活性。其中，当R1为Br取代基，无论R2为CH3取代(I-a， EGFRL858R/T790M IC50＝32.70nM，EGFRL858R/T790M/C797S IC50＝9.90nM，WT/CTL＝15.37)还是H取代(I-c，EGFRL858R/T790M IC50＝31.76nM， EGFRL858R/T790M/C797S IC50＝23.53nM，WT/CTL＝6.77)，化合物对 EGFRL858R/T790M/C797S三级突变体抑制活性均高于EGFRL858R/T790M二级突变体，且对于野生型EGFR都具有较好选择性。对于EGFRL858R/T790M/C797S三级突变体抑制活性，R2为CH3取代较H取代的活性更好，选择性也更强。
当R1为CH3取代基，R2为CH3取代，化合物I-b对EGFRL858R/T790M/C797S三级突变体(IC50＝12.11nM)、EGFRL858R/T790M二级突变体(IC50＝27.56nM) 和EGFRL858R突变(IC50＝13.06nM)抑制活性都较好，但是活性相差不大。 R2为H取代时，化合物I-d对EGFRL858R/T790M/C797S三级突变体(IC50＝122 nM)、EGFRL858R/T790M二级突变体(IC50＝210.72nM)和EGFRL858R突变 (IC50＝85.17nM)抑制活性较差。对于EGFRL858R/T790M/C797S三级突变体抑制活性，R1为CH3取代基，无论R2为CH3(I-b，WT/CTL＝3.07)还是H(I-d， WT/CTL＝2.53)，对于野生型EGFR选择性都不高。
试验例2化合物对不同细胞系的评价
方法：
人非小细胞肺癌细胞系NCI-H1975(TL)表达EGFR(T790M/L858R) 双突变型，从中国科学院细胞库购买；NCI-H1975(CTL)表达EGFR (L858R/T790M/C797S)三级突变，为通过慢病毒转染方式将EGFR (L858R/T790M/C797S)稳定过表达至NCI-H1975(TL)中。MDA-MB-231 细胞从中国科学院细胞库购买。将各细胞维持在含有10％胎牛血清 RPMI1640培养基中。使细胞在有5％CO2的加湿培养箱中于37℃生长。依照Phospho-EGFR HTRF kit(Cisbio，货号#64HR1PEG)中描述的方案，检测细胞裂解液中内源性p-EGFR。将90μL细胞接种于96孔板中(50000 细胞/孔)，于37℃，5％CO2细胞培养箱中培养过夜。将连续4倍稀释的化合物加入细胞中，10μL/孔，继续培养2h。继续培养2小时后弃去培养液，并立即加入25μL/孔裂解液，于室温裂解细胞10分钟，然后取12μL/孔加入Greiner白色低体积384孔板中，加入检测抗体(Anti-phospho EGFR-d2 以及Anti-EGFR-Tb)，在25℃孵育60分钟。孵育结束后在CLARIOstar(BMG LABTECH)上检测HTRF荧光值，并使用GraphPad Prism 5.0计算IC50。结果见表2。
表2代表性化合物的细胞活性
a所有的实验都重复了至少三次。
b TL,T790M/L858R二级突变。
c CTL,EGFR L858R/T790M/C797S三级突变。
由表2测试结果可以看出，化合物I-a对非小细胞肺癌H1975(TL) (IC50＝468.2nM)和H1975(CTL)(IC50＝330.5nM)细胞都具有良好的增殖抑制活性，且对CTL细胞抑制活性更好。相比于化合物AZD9291，化合物I-a对人非小细胞肺癌细胞H1975(TL)细胞及H1975(CTL)细胞的抗增殖活性更好。细胞增殖抑制活性结果与化合物I-a对EGFRL858R/T790M/C797S三级突变体表现出良好的活性抑制结果相一致。
试验例3不同种类肝微粒体的稳定性
方法：
将还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)和化合物(1μM)在PBS缓冲液(pH＝7.4)中混合后于37℃中预孵育3分钟。孵育结束后加入各种属肝微粒体(0.5mg/mL)以起始反应。反应的温度为37℃，反应的最终体系是200μL。分别在0，2，5，10，20，30和60分钟时，将含有内标的冷的终止液加入到反应板中以终止反应。T0板样品先加入终止液后再添加还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)工作液。将终止后的所有反应板摇匀，并在4℃，12000转，离心10分钟。将上清溶液稀释一定比例后进行LC-MS/MS分析。结果见表3。
表3化合物I-a在不同种类肝微粒体的稳定性.
结果表明，化合物I-a具有良好的代谢稳定性，在人，大鼠和小鼠肝微粒体中的所有半衰期均超过30min，这表明该化合物在后续研究中可进一步开发作为口服药物。
以上已经描述了本发明的各实施例，上述说明是示例性的，并非穷尽性的，并且也不限于所披露的各实施例。在不偏离所说明的各实施例的范围和精神的情况下，对于本技术领域的普通技术人员来说许多修改和变更都是显而易见的。
Claims (10)
1.一种具有抗肿瘤活性的2-氨基-4-氨基芳基磷氧基嘧啶化合物，及其药学上可接受的盐，所述2-氨基-4-氨基芳基磷氧基嘧啶化合物为式I所示化合物：
其中，R1选自卤素或者C1-C4烷基；R2选自H或者C1-C4烷基。
2.根据权利要求1所述的2-氨基-4-氨基芳基磷氧基嘧啶化合物，其特征在于，R1选自Br或者CH3；R2选自H或者CH3。
3.根据权利要求1所述的2-氨基-4-氨基芳基磷氧基嘧啶化合物，其特征在于，所述2-氨基-4-氨基芳基磷氧基嘧啶化合物选自以下化合物中的至少一种：
2-((5-溴-2-((2-甲氧基-5-甲基-4-(4-吗啉基哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦；
2-((2-((2-甲氧基-5-甲基-4-(4-吗啉代哌啶-1-基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯基)二甲基氧化膦；
2-((5-溴-2-((2-甲氧基-4-(4-吗啉代哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦；
2-((2-((2-(2-甲氧基-4-(4-吗啉代哌啶-1-基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯基)二甲基氧化膦。
4.权利要求1-3中任意一项所述的2-氨基-4-氨基芳基磷氧基嘧啶化合物的制备方法，其特征在于，包括以下步骤：
通过式II中间体和式III中间体通过缩合反应a得到：
其中R1、R2如权利要求1或2所定义；
所述式II中间体通过以下步骤b制备得到：
所述式III中间体通过以下步骤c和d制备得到：
5.根据权利要求4所述的2-氨基-4-氨基芳基磷氧基嘧啶化合物的制备方法，其特征在于，
步骤a中所用的催化剂选自氢氧化钠、三乙胺、N,N-二异丙基乙胺、叔丁醇钾和甲醇钠中的一种或多种；
步骤b中，利用式IV化合物的嘧啶环上氯与磷氧基苯胺上的氨基在溶剂中，一定的碱催化剂条件下发生取代反应得到式II中间体，所述溶剂选自乙腈、二氯甲烷、四氢呋喃和甲苯中的一种或多种，所述碱催化剂选自氢氧化钠、三乙胺、N,N-二异丙基乙胺、叔丁醇钾和甲醇钠中的一种或多种；
步骤c中，式V化合物与哌啶基吗啉化合物在碱催化下缩合得到式VI化合物，所述碱选自碳酸钠、碳酸钾、碳酸氢钠、三乙胺、吡啶、4-二甲胺基吡啶和DBU中的一种或多种；
步骤d中，式VI化合物的硝基经还原反应得到式III中间体，所述还原反应的还原剂选自氢气、水合肼、甲酸铵、硼氢化钠和硼氢化钾中的一种或多种。
6.权利要求1-3中任意一项所述的2-氨基-4-氨基芳基磷氧基嘧啶化合物在制备治疗肿瘤的药物和/或制备肿瘤细胞抑制剂中的应用。
7.根据权利要求6所述的应用，其特征在于，所述肿瘤为EGFR介导的癌症；优选为非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌、头颈部肿瘤、结肠癌、直肠癌和胶质瘤中的至少一种。
8.根据权利要求7所述的应用，其特征在于，所述肿瘤为EGFR L858R/T790M/C797S突变的非小细胞肺癌。
9.根据权利要求7所述的应用，其特征在于，所述肿瘤细胞为人非小细胞肺癌细胞H1975或人乳腺癌细胞MDA-MB-231；所述人非小细胞肺癌细胞优选为野生型H1975细胞、H1975(L858R/T790M)突变型细胞和H1975(L858R/T790M/C797S)突变型细胞中的任意一种。
10.一种药物组合物，以权利要求1-3中任意一项所述的2-氨基-4-氨基芳基磷氧基嘧啶化合物为活性组分，并包括药学上可接受的辅料。
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