CN115448906B - 一种2-苯胺基嘧啶类衍生物及其制备方法与应用 - Google Patents
一种2-苯胺基嘧啶类衍生物及其制备方法与应用 Download PDFInfo
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- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
Abstract
本发明属于医药领域,涉及一种2‑苯胺基嘧啶类衍生物及其制备方法与应用。所述2‑苯胺基嘧啶类衍生物为式I所示化合物,或其可药用盐或互变异构体或其前药分子。实验表明式Ⅰ所示化合物对表皮生长因子受体具有一定的抑制活性,并且可以有效地抑制多种肿瘤细胞的增殖,具有作为肿瘤药物研发的潜力。
Description
技术领域
本发明属于医药领域,具体地,涉及一种具有EGFR和ALK抑制活性的2-苯胺基嘧啶类衍生物及其制备方法与应用。
背景技术
肿瘤分子靶向治疗是近几年发展迅速的一类新型肿瘤治疗手段,其原理是基于对肿瘤生长、发育密切相关的关键因子或蛋白通过靶向性的化学或生物学手段抑制达到选择性杀伤肿瘤细胞的一种治疗方法。相比于传统的抗癌小分子药物,肿瘤靶向药物具有针对性强、副作用相对较少和治疗效果好等特点,因此受到了广泛关注,肿瘤的靶向治疗也是肿瘤治疗的发展趋势之一。
表皮生长因子受体(EGFR)是一种受体型酪氨酸蛋白激酶,在增殖、分化、凋亡以及血管生成等生命活动中发挥了重要作用,同时也被发现在多种肿瘤细胞如肺癌、乳腺癌、***癌中存在过度活化或持续活化的情况。其中在肺癌患者中,EGFR的突变是最重要的驱动因子之一,尤其在亚洲人中其突变比例达到了50%以上。2003年上市的EGFR小分子抑制剂吉非替尼(Gefitinib)被用于非小细胞肺癌(NSCLC)晚期的治疗中,现在还常用作EGFR突变的NSCLC患者的一线用药。
EGFR抑制剂发展至今按照上市药物分为了三代。第一代EGFR包括前面提到的Gefitinib还有Erlotinib、Icontinib等,其针对的是存在L858R或者del19突变的EGFR的NSCLC患者,获得了显著的临床疗效。但部分患者在使用药物的10~12个月后会产生耐药性,经过基因测序等可以发现其主要发生了T790M突变,超过50%的耐药患者发生了T790M的二次突变。为了解决第一代抑制剂耐药问题,发展了第二代EGFR抑制剂。第二代抑制剂属于不可逆抑制剂,其对野生型EGFR(EGFRwt)也有较强的抑制作用,因此具有较大毒性。已经上市的第二代EGFR抑制剂包括Afatinib和Dacomtinib,但在临床最大耐受剂量(MTD)下,还是无法很好的解决T790M突变带来的耐药性问题。而真正解决T790M突变导致的耐药问题的则是第三代EGFR抑制剂,在2015年11月获得美国FDA加速批准上市的奥希替尼(Osimertinib),其在临床上能够有效治疗T790M突变导致耐药的NSCLC患者,取得了较大成功。但不可避免的是部分受益患者在经过9~14个月治疗后又出现了新的耐药现象,经过研究发现,20~40%的患者是因为发生了C797S点突变导致了Osimertinib的耐药。C797S点突变指的是EGFR797位的半胱氨酸转变成丝氨酸,而797位又是Osimertinib与EGFR共价结合的重要位点之一,因此两者无法结合,最终导致Osimertinib的耐药。目前尚未有针对C797S突变的EGFR抑制剂上市,因此迫切需要对C797S具有高选择性的EGFR抑制剂解决三代抑制剂的耐药性问题。
间变性淋巴瘤激酶(ALK)也属于受体型酪氨酸激酶,棘皮动物微管结合蛋白(EML4)和ALK融合基因突变生成的EML4-ALK嵌合蛋白会促使ALK的二聚化,导致相关信号通路持续激活,从而促进癌症的发生与发展。在NSCLC的吸烟患者中,有2.9%发生了EML4-ALK基因融合突变;在未吸烟的患者中,则有9.4%发生了EML4-ALK突变,因此ALK也是除EGFR突变外的主要突变类型之一。随着基因测序技术的发展,EGFR和ALK重排同时存在的情况被不断发现。有文献报道在对14名奥希替尼耐药的患者进行基因测序后发现有2名患者发生了EML4-ALK融合突变,这也暗示着,EGFR/ALK双靶点抑制剂未来不仅可以用于肺癌的靶点药物治疗,也有一定潜力用于解决EGFR的耐药性问题。
发明内容
本发明的目的是提供一类具有EGFR和ALK抑制活性的2-苯胺基嘧啶类衍生物抑制剂及其制备方法。
为了实现上述目的,本发明提供一种2-苯胺基嘧啶类衍生物,所述2-苯胺基嘧啶类衍生物为式I所示化合物,或其可药用盐或互变异构体或其前药分子;
其中:
R1为
R2为
R3为氢、卤素(Cl或Br)、三氟甲基、硝基、取代或未取代C1-C6烷基、取代或未取代C3-C6环烷基、取代或未取代C1-C6烷氧基、取代或未取代C3-C6环烷氧基;
X、Y、Z各自独立地为CH或N。优选地,X为N,Y、Z为CH。
本发明中,所述药学上可接受的盐可以为无机酸盐或有机酸盐;具体地,所述无机酸盐选自下述任意一种无机酸形成的盐:盐酸、硫酸和磷酸;所述有机酸盐选自下述任意一种有机酸形成的盐:乙酸、三氟乙酸、丙二酸、柠檬酸和对甲苯磺酸。
本发明的化合物可以以不同的多晶型物形式存在。
根据本发明一种优选实施方式,式I所示化合物选自下述任意一种:
本发明还提供所述2-苯胺基嘧啶类衍生物的制备方法,包括下述步骤:
式IA所示化合物与式IB所示化合物在酸性条件下、在溶剂中进行反应,获得式I所示化合物:
R1、R2、R3、X、Y和Z如权利要求1所定义。
更具体地,可按照下述反应路线制备得到:
其中R1、R2、R3、X、Y和Z如上所述。
反应路线主要包括以下反应步骤:
步骤a)式Ia所示化合物与含氟芳香环在碱性条件下发生取代反应得到式Ib所示化合物。优选地,反应以N,N-二甲基甲酰胺作溶剂,碳酸铯为碱试剂,反应温度为90℃,反应时间为24小时。
步骤b)式Ib所示化合物在催化剂作用下与氢气发生还原反应得到式Ic所示化合物。优选地,反应在无水乙醇中进行;催化剂为10%的钯碳;反应温度为室温;反应时间为6小时。
步骤c)式Ic所示化合物在碱性条件下与相应的含脂肪杂环的乙醇衍生物的末端羟基发生亲核取代反应得到式Id所示化合物。优选地,反应所需碱为氢化钠;反应在无水乙醇中进行;反应温度为0℃;反应时间为8-12小时。
步骤d)式Ie所示化合物在碱性条件下与相应的包含R2基团的末端伯胺发生亲核取代反应得到式If所示化合物。优选地,反应所需碱可以从三乙胺、二异丙基乙基胺、氨水、甲醇钠、乙醇胺、叔丁醇钠、叔丁醇钾、四丁基碘化铵等中选择一种或多种;反应温度为80℃;反应时间为0.5-3小时。
步骤e)式If所示化合物在酸性条件下与式Id化合物的末端伯胺发生取代反应得到式I所示化合物。优选地,反应所需酸为对甲苯磺酸一水化合物;反应在2-戊醇中进行;反应温度为90℃;反应时间为5小时。
在不描述起始原料合成及中间体的情况下,化合物是可以商业购买的或利用标准方法或利用本文实施例的扩展方法利用可商业化购买的化合物来制备。
本发明的再一个目的是提供式Ⅰ所示化合物及其药学上可接受的盐的应用。具体地,本发明所述的2-苯胺基嘧啶类衍生物可应用于制备下述产品:
1)表皮生长因子受体(EGFR)抑制剂;
2)间变性淋巴瘤激酶(ALK)抑制剂;
3)真核生物肿瘤细胞增殖抑制剂;
4)真核生物肿瘤细胞转移抑制剂;
5)血管生成抑制剂;
6)预防和/或***的药物。
所述表皮生长因子受体(EGFR)包括但不限于EGFRL858R、EGFRdel19、EGFRL858R/T790M、EGFRdel19/T790M、EGFRL858R/T790M/C797S和EGFRdel19/T790M/C797S中至少一种。
所述间变性淋巴瘤激酶(ALK)包括但不限于ALKwt、ALK L1196M和EML4-ALK中至少一种。
所述真核生物优选为哺乳动物;所述肿瘤细胞优选为癌细胞;更优选地,所述癌细胞为白血病癌细胞、淋巴瘤细胞、肺癌细胞、乳腺癌细胞、卵巢癌细胞、***细胞、人脑胶质瘤细胞、黑色素癌细胞、胶质母细胞瘤细胞、鼻咽癌细胞、肝癌细胞、脑癌细胞、胰腺癌细胞、子宫癌细胞、睾丸癌细胞、皮肤癌细胞、胃癌细胞、结肠癌细胞、膀胱癌细胞或直肠癌细胞。
所述白血病癌细胞具体为人慢性粒细胞白血病(CML)细胞系K562;所述淋巴瘤细胞具体为人组织细胞淋巴瘤细胞U937;所述肺癌细胞具体为人肺癌细胞株HCC827;所述乳腺癌细胞具体为人乳腺癌细胞MCF-7、T47D和MDA-MB-231;所述卵巢癌细胞具体为A2780;所述***细胞具体为人***细胞系Hela;所述人脑胶质瘤细胞具体为U251;所述黑色素癌细胞具体为A375;所述胶质母细胞瘤细胞具体为人胶质母细胞瘤细胞A172和人脑星形胶质母细胞瘤细胞U-118MG;所述鼻咽癌细胞具体为鼻咽癌细胞株CNE-2;所述肝癌细胞为具体人肝癌细胞HepG2。
所述肿瘤为癌,所述癌具体为白血病、淋巴瘤、肺癌、黑色素癌、胶质母细胞瘤、***、鼻咽癌、肝癌、乳腺癌、脑癌、胰腺癌、卵巢癌、子宫癌、睾丸癌、皮肤癌、胃癌、结肠癌、膀胱癌或直肠癌。
本发明还提供一种产品,其活性成分为所述的2-苯胺基嘧啶类衍生物;所述产品为以下中的至少一种:
1)表皮生长因子受体(EGFR)抑制剂;
2)间变性淋巴瘤激酶(ALK)抑制剂;
3)真核生物肿瘤细胞增殖抑制剂;
4)真核生物肿瘤细胞转移抑制剂;
5)血管生成抑制剂;
6)预防和/或***的药物。
对各产品的限定与前述相同,在此不再赘述。
本发明结构式Ⅰ所示化合物或其药学上可接受的盐也可用于制备预防和/或***的药物。以结构式Ⅰ所示的化合物或其药学上可接受的盐为有效成分制备的预防和/或***的药物,也属于本发明的保护范围。
用式Ⅰ所示化合物或其药学上可接受的盐制备的表皮生长因子(EGFR)抑制剂、间变性淋巴瘤激酶(ALK)抑制剂、真核生物肿瘤细胞增殖抑制剂以及预防和/或***的药物可通过注射、喷射、滴鼻、滴眼、渗透、吸收、物理或化学介导的方法导入机体如肌肉、皮内、皮下、静脉、粘膜组织;或是被其他物质混合或包裹后导入机体。
需要的时候,在上述药物中还可以加入一种或多种药学上可接受的载体。所述载体包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂等。
用结构式Ⅰ所示化合物或其药学上可接受的盐制备的预防和/或***药物可以制成注射液、片剂、粉剂、颗粒剂、胶囊、口服液、膏剂、霜剂等多种形式。上述各种剂型的药物均可以按照药学领域的常规方法制备。
本发明提供的化合物经过测试证明可以抑制多种肿瘤细胞的生长,以及对EGFR家族蛋白酶产生抑制作用,尤其能够有效抑制EGFR蛋白激酶耐药突变体的活性,例如EGFRdel19/T790M/C797S和EGFRL858R/T790M/C797S,可以克服现有第三代EGFR抑制剂药物例如Osimertinib等诱发的NSCLC患者的临床耐药。同时对ALKwt具有较好的抑制效果。本发明提供的化合物原料易得,制备方法简单,实验证明其有良好的抗癌效果,在抗肿瘤药物设计研发领域有着良好的应用前景。
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。
下述实施例中所述实验方法,如无特殊说明,均为有机合成的常规方法;所述试剂和生物材料,如无特殊说明,均从商业途径获得。
实施例1
5-氯-N2-((2-(2-(4-甲基哌嗪-1-基)乙氧基)吡啶-4-基)氧基)苯基-N4-苯基嘧啶-2,4-二胺
实施例1A
2-氟-4-(3-甲氧基-4-硝基苯氧基)吡啶
将2,4-二氟吡啶(0.500g,4.34mmol)用25mL的N,N-二甲基甲酰胺溶解,加入碳酸铯(2.831g,8.68mmol)和3-甲氧基-4-硝基苯酚(0.73g,4.34mmol),升温至90℃,反应时间24个小时。反应完成后用乙酸乙酯和水进行萃取,有机层用水层多次萃取,直至无色,收集有机层,通过硅胶柱色谱分离纯化,得淡黄色固体0.841g,产率73.7%。化合物核磁表征数据:1H NMR(400MHz,Chloroform-d)δ8.17(d,J=5.8Hz,1H),8.00(d,J=8.9Hz,1H),6.84(s,2H),6.74(dd,J=8.9,2.3Hz,1H),6.52(s,1H),3.96(s,3H).13C NMR(101MHz,CDCl3)δ166.73,166.61,166.33,163.97,158.54,155.30,149.28,149.10,128.19,111.38,111.26,111.22,105.63,98.60,98.19,56.87.。
实施例1B
4-((2-氟吡啶-4-基)氧基)-2-甲氧基苯胺
用10mL的无水乙醇溶解实施例1A(0.841g,3.18mmol),加入含有55%水的10%的钯碳试剂(0.170g,原料的20%),用氢气置换空气,重复多次确保氢气置换完全,在室温下反应6小时。反应完成后使用硅藻土过滤除去多余的钯碳,收集滤液,减压旋蒸除去溶剂,得到淡黄色浓稠液态产物0.547g,产率70.7%。化合物核磁表征数据:1H NMR(400MHz,DMSO-d6)δ8.07(d,J=5.8Hz,1H),6.82(dd,J=5.8,1.0Hz,1H),6.72–6.65(m,2H),6.56–6.50(m,2H),4.80(s,2H),3.74(s,3H).13C NMR(101MHz,DMSO)δ170.03,169.91,166.17,163.87,149.16,148.98,147.48,143.54,136.32,113.96,113.09,110.65,110.62,104.76,96.59,96.17,56.03.
实施例1C
2-甲氧基-4-((2-(2-(4-甲基哌嗪-1-基)乙氧基)吡啶-4-基)氧基)苯胺
先用8mL的N,N-二甲基甲酰胺溶解1-羟乙基-4-甲基哌嗪(0.389g,2.69mmol),在0℃条件下乙醇溶液中搅拌10分钟后,加入60%的氢化钠(0.112g,2.81mmol),搅拌20分钟后让其缓慢升温,1小时后,用4mL的N,N-二甲基甲酰胺溶解实施例1B(0.547g,2.25mmol)并加入反应液中,温度上升至室温时,过夜。反应完成后用乙酸乙酯和水萃取,水层用乙酸乙酯多次萃取,收集有机层,通过硅胶柱色谱分离纯化,得到淡黄色油状产物0.572g,产率71.1%。化合物核磁表征数据:1H NMR(400MHz,CDCl3)δ7.92(d,J=5.9Hz,1H),6.65(s,1H),6.49(d,J=9.2Hz,3H),6.10(d,J=2.0Hz,1H),4.35(t,J=5.7Hz,2H),3.77(s,3H),2.73(d,J=5.8Hz,2H),2.51(d,J=33.7Hz,8H),2.26(s,3H).
实施例1D
2,5-二氯-N-苯基嘧啶-4-胺
用5mL的二甲基亚砜溶解2,4,5-三氯嘧啶(0.500g,2.73mmol),加入少量的四丁基碘化铵,待溶液变为黄色后再加入苯胺(0.281g,3.00mmol)及三乙胺(0.302g,3.00mmol),升温至80℃,过夜反应。反应完成后用乙酸乙酯和水萃取,多次用乙酸乙酯重复萃取水层,收集有机层,用硅胶柱分离产物,得黄色固体产物0.455g,产率85.1%。化合物核磁表征数据:1H NMR(400MHz,DMSO-d6)δ9.53(s,1H),7.58(dd,J=8.6,1.1Hz,2H),7.46–7.31(m,2H),7.19(d,J=7.4Hz,1H).13C NMR(101MHz,DMSO)δ157.64,157.38,155.84,137.88,129.00,125.46,123.93,114.05.
5-氯-N2-((2-(2-(4-甲基哌嗪-1-基)乙氧基)吡啶-4-基)氧基)苯基-N4-苯基嘧啶-2,4-二胺
将实施例1C(0.171g,0.477mmol)、实施例1D(0.137g,0.572mmol)及其他试剂包括三(二亚苄基丙酮)二钯(0.022g,2.39x10-3 mmol)、1,1'-联萘-2,2'-双二苯膦(0.030g,47.7×10-3mmol)和叔丁醇钾(0.077g,0.687mmol)放入封管中,氩气保护,加入5mL的1,4-二氧六环后再用氩气通入溶液中除气。120℃条件下反应24小时,反应完成后用乙酸乙酯和水进行萃取,收集有机层用硅胶柱方法分离产物,收集淡黄色固体产物0.151g,产率56.3%。核磁表征数据如下:1H NMR(400MHz,Chloroform-d)δ8.30(d,J=8.6Hz,1H),8.09(s,1H),7.99(d,J=5.9Hz,1H),7.59(d,J=7.6Hz,2H),7.49(s,1H),7.38(t,J=7.9Hz,2H),7.17(t,J=7.4Hz,1H),7.09(s,1H),6.63–6.57(m,2H),6.55(d,J=2.2Hz,1H),6.19(d,J=2.1Hz,1H),4.41(t,J=5.8Hz,2H),3.85(s,3H),2.77(t,J=5.8Hz,2H),2.53(d,J=40.1Hz,8H),2.28(s,3H).13C NMR(101MHz,CDCl3)δ167.51,165.54,157.65,155.86,154.32,149.03,148.27,147.86,137.72,128.91,126.61,124.61,122.26,119.72,112.62,107.09,103.77,97.19,63.62,57.10,55.90,54.96,53.38,45.99.高分辨质谱HRMS(ESI)m/z计算值[M+H]+562.2333,实测值562.2289。
实施例2
(2-((5-氯-2-((2-甲氧基-4-((2-(2-(4-甲基哌嗪-1-基)乙氧基)吡啶-4-基)氧基)苯基)胺基)嘧啶-4-基)胺基)苯基)二甲基氧磷
实施例2与实施例1合成方法基本一致,将实施例1D中的苯氨换成2-(二甲基氧磷基)苯胺,其余合成步骤及条件与实施例1基本一致。核磁表征及高分辨质谱数据如下:1HNMR(400MHz,Chloroform-d)δ10.78(s,1H),8.50(ddd,J=8.6,4.4,1.1Hz,1H),8.31–8.25(m,1H),8.05(s,1H),7.92(d,J=5.9Hz,1H),7.43(s,2H),7.28–7.19(m,1H),7.05(tdd,J=7.5,2.4,1.1Hz,1H),6.57(d,J=2.3Hz,2H),6.47(d,J=2.2Hz,1H),6.13(d,J=2.1Hz,1H),4.34(s,2H),3.79(s,3H),2.69(s,2H),2.57–2.45(m,4H),2.44–2.33(m,4H),2.21(d,J=2.5Hz,3H),1.78(s,3H),1.75(s,3H).13C NMR(101MHz,CDCl3)δ167.95,167.44,165.50,165.45,157.34,155.92,154.87,149.18,148.37,147.84,147.68,145.67,143.57,119.87,114.80,113.12,112.48,107.05,104.37,103.83,97.18,63.58,57.04,55.89,54.90,53.31,45.92,18.87,18.16.高分辨质谱HRMS(ESI)m/z计算值[M+H]+638.2411,实测值638.2369。
实施例3
(6-((5-氯-2-((2-甲氧基-4-((2-(2-(4-甲基哌嗪-1-基)乙氧基)吡啶-4-基)氧基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧磷
部分合成路线如下:
实施例3A
5-碘基-6-氨基喹喔啉
用5mL的1,4-二氧六环加水溶液(4:1)溶解6-氨基喹喔啉(0.100g,0.689mmol),在0℃条件下,先加入碳酸氢钠(0.144g,1.722mmol)和入碘单质(0.437g,1.722mmol),搅拌半小时后,转移至室温4小时;反应完全后用水和乙酸乙酯萃取,收集有机层,用硅胶柱分离产物,得深黄色固体0.122g。化合物核磁表征数据:1H NMR(400MHz,Chloroform-d)δ8.74(d,J=2.0Hz,1H),8.53(d,J=2.0Hz,1H),7.83(d,J=9.0Hz,1H),7.31–7.22(m,1H).13C NMR(101MHz,CDCl3)δ171.21,149.46,145.51,144.22,141.27,138.61,130.30,120.70,67.08.
实施例3B
5-二甲基氧磷基-6-氨基喹喔啉
实施例3A(0.100g,0.37mmol)、二甲基氧膦(0.043g,0.55mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.021g,0.037mmol),醋酸钯(0.008g,0.037mmol)和磷酸钾(0.117g,0.550mmol)放入封管中,氩气保护。加入2mL的N,N-二甲基甲酰胺和0.4mL的水后再次进行氩气保护,密封,120℃条件下,反应过夜。反应完成后用乙酸乙酯和水萃取,收集有机层,通过硅胶柱色谱方法分离产物,得黄色固体产物0.112g。化合物核磁表征数据:1H NMR(400MHz,Chloroform-d)δ8.63–8.40(m,2H),7.84(s,1H),7.03(d,J=4.6Hz,1H),2.04–1.95(m,6H).13C NMR(101MHz,CDCl3)δ155.72,145.78,143.13,139.74,137.63,134.05,134.03,124.88,124.79,20.21,19.49.
实施例3C
(6-((2,5-二氯-4-基)氨基)喹喔啉-5-基)二甲基氧磷
实施例3C的合成方法参照实施例1D,将苯胺换成实施例3B,其他反应条件和实施例1D合成条件基本一致。化合物核磁表征数据:1H NMR(400MHz,Chloroform-d)δ13.22(s,1H),9.15(dd,J=9.5,4.2Hz,1H),8.81–8.78(m,1H),8.74(d,J=1.8Hz,1H),8.27(d,J=0.9Hz,1H),8.25(d,J=9.6Hz,1H),2.12(dd,J=14.3,0.8Hz,7H).13C NMR(101MHz,CDCl3)δ157.26,156.90,156.90,156.37,155.99,155.00,147.84,143.63,143.61,139.44,139.37,133.98,133.96,125.68,125.59,116.46,20.72,19.99.
实施例3
(6-((5-氯-2-((2-甲氧基-4-((2-(2-(4-甲基哌嗪-1-基)乙氧基)吡啶-4-基)氧基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧磷
实施例1C(0.144g,0.402mmol)、实施例3C(0.147g,0.402mmol)、对甲苯磺酸一水化合物(0.153g,0.804mmol)用6mL的2-戊醇溶解,在90℃条件下反应5小时。反应完成后用乙酸乙酯和水萃取,多次用乙酸乙酯对水层进行萃取,收集有机层,用硅胶柱分离产物,得黄色固体产物80mg。化合物核磁表征数据:1H NMR(400MHz,Chloroform-d)δ12.75(s,1H),9.13(dd,J=9.5,4.1Hz,1H),8.75(s,1H),8.72(s,1H),8.35–8.29(m,1H),8.19(s,1H),8.13(d,J=9.5Hz,1H),7.98(d,J=5.9Hz,1H),7.51(s,1H),6.67–6.64(m,2H),6.54(dd,J=5.9,2.2Hz,1H),6.17(d,J=2.1Hz,1H),4.40(t,J=5.7Hz,2H),3.87(s,3H),2.80–2.55(m,11H),2.38(s,3H),2.14(s,3H),2.11(s,3H).13C NMR(101MHz,CDCl3)δ167.47,165.43,157.22,155.89,155.80,149.31,148.90,148.88,148.64,147.90,143.86,143.80,143.35,142.96,139.27,139.20,132.98,132.95,126.82,126.73,126.50,119.88,112.62,112.49,111.60,108.01,107.16,103.99,97.23,63.44,56.84,55.98,54.55,52.42,45.27,20.76,20.03.
实施例4
5-氯-4-(1-(乙基磺酰基)-1H-吲哚-3-基)-N-(2-甲氧基-4-((2-(2-(4-甲基哌嗪-1-基)乙氧基)吡啶-4-基)氧基)苯基)嘧啶-2-胺
部分合成路线如下:
实施例4A
3-(2,5-二氯嘧啶-4-基)-1H-吲哚
用6mL的四氢呋喃溶解吲哚(1.28g,10.79mmol),0℃下将甲基溴化镁(3.37mL,10.78mmol)缓慢滴加进去,搅拌30分钟;再加入2,4,5-三氯嘧啶(1g,5.4mmol),室温下搅拌1小时,升温至60℃后继续搅拌1.5小时。反应结束后,待冷却至室温后滴加634μL的乙酸(11.06mmol)、9.9mL水及2mL的四氢呋喃,在60℃搅拌20分钟。收集有机层,加入11mL的庚烷后产生白色固体,收集产物1.51g。化合物核磁表征数据:1H NMR(400MHz,DMSO-d6)δ8.69(d,J=1.4Hz,2H),8.50(d,J=6.9Hz,1H),7.55(s,1H),7.24(d,J=0.6Hz,2H).
实施例4B
3-(2,5-二氯嘧啶-4-基)-1-(乙基磺酰基)-1H-吲哚
用1.5mL的四氢呋喃溶解实施例4A(0.100g,0.379mmol),0℃下加入氢化钠(0.037g,0.946mmol),关闭制冷后3个小左右后加入乙基磺酰氯(0.058g,0.454mmol),室温条件下过夜。反应完成后用乙酸乙酯和水萃取,收集有机层,通过硅胶柱色谱方法分离产物,得淡黄色固体产物0.155g。化合物核磁表征数据:1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),8.57(s,1H),8.37(d,J=7.9Hz,1H),7.92(d,J=8.2Hz,1H),7.46(dd,J=13.1,7.8Hz,2H),3.87–3.71(m,2H),1.11(t,J=7.3Hz,3H).
实施例4
5-氯-4-(1-(乙基磺酰基)-1H-吲哚-3-基)-N-(2-甲氧基-4-((2-(2-(4-甲基哌嗪-1-基)乙氧基)吡啶-4-基)氧基)苯基)嘧啶-2-胺
实施例4的合成方法参照实施例3,将实施例3C换成实施例4B,其他反应条件和实施例3合成条件基本一致。核磁表征数据如下:1H NMR(400MHz,Chloroform-d)δ8.48(d,J=0.8Hz,2H),8.41(d,J=0.8Hz,2H),7.99(d,J=6.0Hz,2H),7.76(s,1H),7.44–7.34(m,2H),6.68(d,J=2.4Hz,2H),6.59–6.54(m,1H),6.19(d,J=2.1Hz,1H),4.41(t,J=5.7Hz,2H),3.91(s,3H),3.42(q,J=7.4Hz,2H),2.79–2.54(m,10H),2.38(s,3H),1.30–1.27(m,4H).13CNMR(101MHz,CDCl3)δ167.42,165.46,158.19,149.30,148.82,147.90,134.87,130.44,128.74,126.33,125.55,124.07,123.37,119.70,112.94,112.75,107.21,103.95,97.29,63.52,56.90,56.02,54.63,52.57,49.01,45.37,8.12.
实施例5
5-氯-N2-(2-甲氧基-4-((2-(2-吗啉乙氧基)吡啶-4-基)氧基)苯基)-N4-苯基嘧啶-2,4-二胺
合成方法参考实施例1,产率61.2%。核磁表征及高分辨质谱数据如下:1H NMR(400MHz,Chloroform-d)δ8.29(d,J=8.7Hz,1H),8.07(s,1H),7.99(d,J=5.9Hz,1H),7.57(d,J=8.0Hz,2H),7.51(s,1H),7.37(t,J=7.9Hz,2H),7.14(d,J=11.5Hz,2H),6.63–6.52(m,3H),6.19(d,J=2.1Hz,1H),4.41(s,2H),3.84(s,3H),3.73–3.68(m,4H),2.74(t,J=5.7Hz,2H),2.53(dd,J=5.7,3.7Hz,4H).13C NMR(101MHz,CDCl3)δ167.57,165.49,157.64,155.89,154.28,149.08,148.28,147.86,137.75,128.88,126.63,124.60,122.31,119.80,112.60,107.16,105.08,103.77,97.17,66.83,63.32,57.58,55.90,53.92.高分辨质谱HRMS(ESI)m/z计算值[M+H]+549.2017,实测值549.1949。
实施例6
(2-((5-氯-2-((2-甲氧基-4-((2-(2-吗啉乙氧基)吡啶-4-基)氧基)苯基)胺基)嘧啶-4-基)胺基)苯基)二甲基氧磷
合成方法参考实施例2,产率63.3%,核磁表征数据如下:1H NMR(400MHz,Chloroform-d)δ10.78(s,1H),8.54–8.45(m,1H),8.28(d,J=9.5Hz,1H),8.05(s,1H),7.92(d,J=5.9Hz,1H),7.45(s,2H),7.22(d,J=14.0Hz,1H),7.06(ddt,J=8.8,6.7,1.6Hz,1H),6.58(s,2H),6.48(d,J=2.2Hz,1H),6.14(d,J=2.2Hz,1H),4.35(t,J=5.7Hz,2H),3.79(s,3H),3.65–3.58(m,4H),2.68(t,J=5.7Hz,2H),2.46(s,4H),1.79(s,3H),1.75(s,3H).13C NMR(101MHz,CDCl3)δ167.49,165.46,157.33,155.93,154.86,149.21,148.36,147.85,143.59,132.25,129.67,126.65,123.17,122.80,121.02,119.90,112.48,107.11,106.76,103.84,97.15,66.80,63.31,57.55,55.90,53.89,18.85,18.14.高分辨质谱HRMS(ESI)m/z计算值[M+H]+625.2095,实测值625.2046。
实施例7
(6-((5-氯-2-((2-甲氧基-4-((2-(2-(4-甲基哌嗪-1-基)乙氧基)吡啶-4-基)氧基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧磷
合成方法参考实施例3,产率38.1%,核磁表征数据如下:1H NMR(400MHz,Chloroform-d)δ12.75(s,1H),9.13(dd,J=9.5,4.1Hz,1H),8.73(d,J=11.2Hz,2H),8.36–8.28(m,1H),8.19(s,1H),7.98(dd,J=5.9,1.4Hz,2H),7.51(s,1H),6.64(s,2H),6.55(dd,J=5.9,2.2Hz,1H),6.18(d,J=2.1Hz,1H),4.42(t,J=5.7Hz,3H),3.87(s,3H),3.71(d,J=4.6Hz,4H),2.77(d,J=5.7Hz,2H),2.55(s,4H),2.12(d,J=14.3Hz,6H).13C NMR(101MHz,CDCl3)δ167.47,165.43,157.21,155.89,155.80,149.30,148.63,147.90,143.35,142.96,132.96,132.94,126.82,126.73,126.50,119.87,112.61,108.01,107.17,103.99,97.23,66.71,63.18,57.55,55.97,53.85,20.76,20.03.
实施例8
5-氯-N4-(1-(乙基磺酰基)-1H-吲哚-3-基)-N2-(2-甲氧基-4-((2-(2-吗啉乙氧基)吡啶-4-基)氧基)苯基)嘧啶-2,4-二胺
合成方法参考实施例4,产率22.4%,核磁表征数据如下:1H NMR(400MHz,Chloroform-d)δ8.49–8.44(m,2H),8.40(s,2H),7.97(dd,J=12.6,7.0Hz,2H),7.76(s,1H),7.47–7.32(m,2H),6.67(dd,J=4.7,2.3Hz,2H),6.56(dd,J=5.9,2.2Hz,1H),6.20(d,J=2.1Hz,1H),4.45(t,J=5.6Hz,2H),3.89(s,3H),3.76–3.70(m,4H),3.41(q,J=7.4Hz,2H),2.81(t,J=5.6Hz,2H),2.60(d,J=4.7Hz,4H),1.29(t,J=7.4Hz,3H).13C NMR(101MHz,CDCl3)δ167.46,165.36,158.18,157.90,156.95,149.31,148.80,147.91,134.87,130.45,128.73,126.34,125.54,124.05,123.38,119.73,118.15,116.52,112.94,112.72,107.28,103.94,97.28,66.55,63.04,57.50,56.01,53.79,49.01,8.12.
实施例9
5-氯-N2-(2-甲氧基-4-((2-(2-(吡咯烷-1-基)乙氧基)吡啶-4-基)氧基)苯基)-N4-苯基嘧啶-2,4-二胺
合成方法参考实施例1,产率60.8%,核磁表征及高分辨质谱数据如下:1H NMR(400MHz,Chloroform-d)δ8.26(d,J=8.5Hz,1H),8.03(s,1H),7.97(d,J=5.8Hz,1H),7.59–7.46(m,3H),7.33(t,J=7.7Hz,2H),7.14(d,J=11.0Hz,2H),6.62–6.48(m,3H),6.19(s,1H),4.42(t,J=5.4Hz,2H),3.80(s,3H),2.89(t,J=5.4Hz,2H),2.64(s,4H),1.78(s,4H).13C NMR(101MHz,CDCl3)δ167.54,165.42,157.58,155.84,154.25,149.01,148.21,147.84,137.73,128.85,126.58,124.56,122.30,119.72,112.57,107.14,105.02,103.73,97.19,64.50,55.87,54.88,54.48,23.40.高分辨质谱HRMS(ESI)m/z计算值[M+H]+533.2068,实测值533.2021
实施例10
(2-((5-氯-2-((2-甲氧基-4-((2-(2-(吡咯烷-1-基)乙氧基)吡啶-4-基)氧基)苯基)胺基)嘧啶-4-基)胺基)苯基)二甲基氧磷
合成方法参考实施例2,产率59.2%,核磁表征及高分辨质谱数据如下:1H NMR(400MHz,Chloroform-d)δ10.77(s,1H),8.45(dd,J=8.4,4.3Hz,1H),8.23(d,J=9.4Hz,1H),7.99(s,1H),7.87(d,J=5.9Hz,1H),7.40(d,J=19.0Hz,2H),7.23–7.12(m,1H),7.06–6.96(m,1H),6.56–6.49(m,2H),6.46–6.39(m,1H),6.11(d,J=2.1Hz,1H),4.34(t,J=5.7Hz,2H),3.73(s,3H),2.79(s,2H),2.55(s,4H),1.71(d,J=13.2Hz,10H).13C NMR(101MHz,CDCl3)δ167.52,165.40,157.37,155.98,154.91,149.19,148.38,147.87,143.65,132.28,129.63,126.71,123.24,122.68,121.09,119.84,112.52,107.19,106.84,103.86,97.25,64.32,55.93,54.87,54.48,23.42,18.90,18.19.高分辨质谱HRMS(ESI)m/z计算值[M+H]+609.2146,实测值609.2089。
实施例11
(6-((5-氯-2-((2-甲氧基-4-((2-(2-(吡咯烷-1-基)乙氧基)吡啶-4-基)氧基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧磷
合成方法参考实施例3,产率50.6%,核磁表征数据如下:1H NMR(400MHz,Chloroform-d)δ12.70(s,1H),9.07(dd,J=9.5,4.1Hz,1H),8.69(d,J=9.7Hz,2H),8.25(d,J=9.4Hz,1H),8.11(s,1H),8.06(d,J=9.5Hz,1H),7.90(d,J=5.9Hz,1H),7.48(s,1H),6.62–6.57(m,2H),6.51(s,1H),6.15(d,J=2.2Hz,1H),4.71–4.62(m,2H),3.82(s,3H),3.37–3.30(m,2H),3.20(s,4H),2.06(d,J=14.2Hz,6H),1.99(s,4H).13C NMR(101MHz,CDCl3)δ167.62,164.28,157.11,155.79,155.67,149.31,148.71,148.42,147.92,143.77,143.72,143.49,143.05,139.11,139.05,132.90,128.76,126.67,126.59,126.46,125.79,119.82,112.43,111.51,107.89,107.68,103.89,97.16,61.74,56.00,54.27,53.91,23.23,20.71,19.98.
实施例12
5-氯-N4-(1-(乙基磺酰基)-1H-吲哚-3-基)-N2-(2-甲氧基-4-((2-(2-(吡咯烷-1-基)乙氧基)吡啶-4-基)氧基)苯基)嘧啶-2,4-二胺
合成方法参考实施例4,产率51.5%,核磁表征数据如下:1H NMR(400MHz,Chloroform-d)δ8.51–8.45(m,2H),8.39(d,J=7.2Hz,2H),7.96(dd,J=7.0,3.5Hz,2H),7.76(s,1H),7.45–7.32(m,2H),6.70–6.64(m,2H),6.58(dd,J=5.9,2.2Hz,1H),6.21(d,J=2.1Hz,1H),4.75(t,J=5.1Hz,2H),3.91(s,3H),3.48–3.18(m,8H),2.07(s,4H),1.29(t,J=7.4Hz,3H).13C NMR(101MHz,CDCl3)δ167.69,164.30,158.18,157.90,156.99,149.34,148.67,147.98,134.87,130.44,128.71,126.46,125.56,124.05,123.33,119.67,118.20,116.51,112.95,112.65,107.83,103.90,97.27,61.59,56.07,54.24,53.93,49.02,23.29,8.11,1.00.
实施例13
5-氯-N2-(2-甲氧基-4-((2-(2-(哌啶-1-基)乙氧基)吡啶-4-基)氧基)苯基)-N4-苯基嘧啶-2,4-二胺
合成方法参考实施例1,产率46.4%,核磁表征及高分辨质谱数据如下:1H NMR(400MHz,Chloroform-d)δ8.28(d,J=8.7Hz,1H),8.05(s,1H),7.98(d,J=5.9Hz,1H),7.58–7.54(m,2H),7.49(s,1H),7.38–7.32(m,3H),7.18–7.10(m,4H),6.60(t,J=2.8Hz,2H),6.52(dd,J=5.9,2.2Hz,1H),6.19(d,J=2.2Hz,1H),4.42(s,2H),3.82(s,3H),2.74(s,2H),2.50(s,5H),1.60(d,J=5.6Hz,4H),1.42(d,J=5.1Hz,2H).13C NMR(101MHz,CDCl3)δ167.48,165.56,157.66,155.87,154.29,149.07,148.35,147.89,137.78,128.85,128.60,126.60,124.55,122.28,119.92,119.80,112.56,107.05,103.75,97.20,63.54,57.75,55.88,53.48,25.67,24.10.高分辨质谱HRMS(ESI)m/z计算值[M+H]+547.2224,实测值547.2161。
实施例14
(2-((5-氯-2-((2-甲氧基-4-((2-(2-(哌啶-1-基)乙氧基)吡啶-4-基)氧基)苯基)胺基)嘧啶-4-基)胺基)苯基)二甲基氧磷
合成方法参考实施例2,产率40.3%,核磁表征及高分辨质谱数据如下:1H NMR(400MHz,Chloroform-d)δ10.79(s,1H),8.49(dd,J=8.5,4.4Hz,1H),8.27(d,J=9.5Hz,1H),8.04(s,1H),7.92(d,J=5.9Hz,1H),7.44(s,2H),7.22(ddd,J=14.0,7.7,1.6Hz,1H),7.06(dd,J=7.6,2.2Hz,1H),6.57(d,J=6.7Hz,2H),6.47(dd,J=5.7,2.2Hz,1H),6.13(d,J=2.2Hz,1H),4.36(d,J=5.9Hz,2H),3.78(s,3H),2.69(s,3H),2.45(s,4H),1.76(d,J=13.1Hz,6H),1.53(d,J=5.6Hz,5H),1.35(s,2H).13C NMR(101MHz,CDCl3)δ167.72,164.43,157.34,155.99,154.80,149.27,148.28,147.94,147.78,143.62,132.23,129.72,126.80,123.08,122.70,121.07,119.89,112.45,107.64,106.93,103.83,97.11,61.12,56.51,55.97,53.92,23.42,22.42,18.92,18.21.高分辨质谱HRMS(ESI)m/z计算值[M+H]+623.2302,实测值623.2257。
实施例15
(6-((5-氯-2-((2-甲氧基-4-((2-(2-(哌啶-1-基)乙氧基)吡啶-4-基)氧基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧磷
合成方法参考实施例3,产率42.5%,核磁表征数据如下:1H NMR(400MHz,Chloroform-d)δ12.76(s,1H),9.14(dd,J=9.5,4.1Hz,1H),8.79–8.69(m,2H),8.32(d,J=8.4Hz,1H),8.20(s,1H),8.16–8.12(m,1H),7.99(d,J=6.0Hz,1H),7.51(s,1H),6.66(d,J=8.1Hz,2H),6.54(dd,J=5.8,2.1Hz,1H),6.18(d,J=2.2Hz,1H),4.42(t,J=5.9Hz,3H),3.87(s,3H),3.64(s,3H),2.76(s,3H),2.52(s,5H),2.13(d,J=14.3Hz,6H),1.62–1.57(m,5H),1.43(d,J=6.0Hz,3H).13C NMR(101MHz,CDCl3)δ167.43,165.47,157.24,155.90,155.81,149.31,148.91,148.71,147.94,143.81,143.34,142.97,139.28,132.99,126.83,126.47,119.91,112.61,108.01,107.11,103.99,97.25,63.31,57.60,55.97,54.66,25.47,23.96,20.77,20.04.
实施例16
5-氯-N4-(1-(乙基磺酰基)-1H-吲哚-3-基)-N2-(2-甲氧基-4-((2-(2-(哌啶-1-基)乙氧基)吡啶-4-基)氧基)苯基)嘧啶-2,4-二胺
合成方法参考实施例4,产率38.8%,核磁表征数据如下::1H NMR(400MHz,Chloroform-d)δ8.49–8.44(m,2H),8.40–8.36(m,2H),7.98–7.93(m,2H),7.76(s,1H),7.39(dddd,J=28.0,8.2,7.2,1.2Hz,2H),6.67(dd,J=4.6,2.3Hz,2H),6.57(dd,J=5.9,2.1Hz,1H),6.19(d,J=2.1Hz,1H),4.76(t,J=5.0Hz,2H),3.90(s,3H),3.42(q,J=7.3Hz,2H),3.27(t,J=5.0Hz,2H),3.06(s,3H),1.96(s,4H),1.58(s,2H),1.28(d,J=7.3Hz,3H).13C NMR(101MHz,CDCl3)δ167.68,164.30,158.17,157.89,156.99,149.33,148.66,148.00,134.87,130.45,128.71,126.46,125.55,124.03,123.32,119.66,118.21,116.49,112.95,112.66,107.79,103.89,97.21,60.80,56.35,56.06,53.82,49.03,23.14,22.24,8.11.
实施例17
(2-((5-溴-2-((2-甲氧基-4-((2-(2-(吡咯烷-1-基)乙氧基)吡啶-4-基)氧基)苯基)胺基)嘧啶-4-基)胺基)苯基)二甲基氧磷
合成方法参考实施例10,产率38.8%,核磁表征数据如下:1H NMR(400MHz,Chloroform-d)δ10.62(s,1H),8.45(dd,J=8.5,4.3Hz,1H),8.34(d,J=8.6Hz,1H),8.24–8.20(m,1H),7.97(d,J=5.9Hz,1H),7.54–7.45(m,2H),7.34–7.26(m,1H),7.16–7.06(m,1H),6.65–6.58(m,2H),6.55(dd,J=5.9,2.2Hz,1H),6.19(s,1H),4.56(t,J=5.4Hz,2H),3.86(s,3H),3.09(d,J=5.9Hz,2H),2.90(s,4H),1.91(s,4H),1.83(d,J=13.1Hz,6H).13CNMR(101MHz,CDCl3)δ167.61,165.02,157.92,157.84,156.80,149.16,148.31,147.90,143.57,143.55,132.16,132.13,129.58,129.48,126.73,123.69,123.62,122.98,122.86,121.64,120.69,119.80,112.53,107.40,103.84,97.22,95.45,63.35,55.95,54.51,54.34,23.38,18.80,18.09,0.99.
实施例18
(6-((5-溴-2-((2-甲氧基-4-((2-(2-(吡咯烷-1-基)乙氧基)吡啶-4-基)氧基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧磷
合成方法参考实施例11,产率35.6%,核磁表征数据如下:1H NMR(400MHz,Chloroform-d)δ12.57(s,1H),8.98(dd,J=9.5,4.1Hz,1H),8.73(dd,J=14.8,1.9Hz,2H),8.29(s,2H),8.12(d,J=9.5Hz,1H),7.97(d,J=5.9Hz,1H),7.53(s,1H),6.62(d,J=7.6Hz,2H),6.54(dd,J=5.9,2.2Hz,1H),6.18(d,J=2.2Hz,1H),4.53(t,J=5.5Hz,2H),3.86(s,3H),3.05(t,J=5.6Hz,2H),2.85(s,4H),2.12(d,J=14.3Hz,6H),1.88(s,4H).13CNMR(101MHz,CDCl3)δ167.52,165.09,158.76,157.67,156.75,149.25,148.93,148.91,148.58,147.92,143.86,143.81,143.32,142.99,139.34,139.27,132.75,132.73,127.12,127.03,126.47,119.81,112.77,112.60,111.87,107.34,103.96,97.26,96.61,63.54,55.98,54.58,54.35,23.38,20.77,20.04.
实施例19
5-溴-N4-(1-(乙基磺酰基)-1H-吲哚-3-基)-N2-(2-甲氧基-4-((2-(2-(吡咯烷-1-基)乙氧基)吡啶-4-基)氧基)苯基)嘧啶-2,4-二胺
合成方法参考实施例12,产率37.1%,核磁表征数据如下:1H NMR(400MHz,Chloroform-d)δ8.58(s,1H),8.47(d,J=8.5Hz,1H),8.38(s,1H),8.26(d,J=7.9Hz,1H),8.00–7.91(m,2H),7.79(s,1H),7.38(d,J=28.2Hz,2H),6.65(d,J=9.7Hz,2H),6.56(dd,J=5.8,2.0Hz,1H),6.20(d,J=2.1Hz,1H),4.83–4.69(m,2H),3.89(s,3H),3.42(t,J=7.1Hz,4H),3.32(s,2H),2.09(d,J=3.4Hz,4H),1.28(t,J=7.4Hz,3H).13C NMR(101MHz,CDCl3)δ167.67,164.20,160.79,158.34,158.26,149.31,148.67,147.97,134.89,130.11,128.71,126.40,125.51,123.99,123.03,119.62,117.65,112.99,112.64,107.86,107.04,103.88,97.30,61.31,56.08,54.18,53.80,49.02,23.27,8.14.
测试例1、MTT法细胞增殖抑制活性测试
体外细胞增殖抑制实验采用MTT法,采用以下5种细胞系:BaF3_EGFRdTC(dTC代表del19/T790M/C797S三突变)、BaF3_EGFRLTC(LTC代表L8585R/T790M/C797S三突变)、H1975(EGFR的L858R/T790M突变型)、H820(EGFR的del19/T790M突变型)、A549(EGFR野生型)。
其中两类BaF3细胞为悬浮细胞,用含有10%胎牛血清(体积分数)及1%的puro的PRIM-1640培养液,在37℃乙基5%的CO2(体积分数)条件下常规培养。。
其他为贴壁细胞,其中A549用含体积分数为10%胎牛血清的F12K培养液,H1975和H820采用10%胎牛血清的PRIM-1640培养液。
具体操作如下:
将所有化合物配置成浓度为10mM的DMSO(二甲基亚砜)溶液,然后通过梯度稀释法得到一系列浓度逐渐降低的化合物溶液。
培养细胞,取对数期的细胞,计数后将肿瘤细胞以每孔1.2×104-1.5×104个(悬浮细胞)或者6×103-9×103个(贴壁细胞)的密度稀释,之后加入99μL含有细胞的培养基接种于96孔板中。接下来是加药步骤,对于悬浮细胞,铺板4小时后进行加药;对于贴壁细胞,则需细胞贴壁后加药,一般为铺板后12-16小时加药。之后每孔加1μL的化合物溶液,因此化合物终浓度相当于原浓度稀释100倍,每个浓度设置3个复孔,IC50测试时设置8~9个浓度梯度。同时实验加入两个阳性药组,分别是第一代EGFR抑制剂Gefinitinb和具有三突变EGFR抑制活性的Brigatinib;以及设置对照组和空白组,都是加入1μL的纯DMSO溶液。所有处理后的细胞培养3天后,向化合物组和对照组每孔加入10μL的5mg/mL的MTT的PBS溶液,空白组则不加。然后继续培养4小时。之后悬浮细胞的需线进行离心处理,而贴壁细胞则无须离心;吸除每孔的培养基,再加入100μL的DMSO溶液;之后分别在微量振荡器上振荡5分钟及摇床上摇5分钟;最后使用酶标仪测试490nm处OD值,从而计算处不同浓度下化合物对肿瘤细胞的抑制率(Inh%),再通过绘制抑制率-浓度曲线获得IC50值。测试结果如表1所示,可以看到大部分化合物都具有一定的肿瘤细胞抑制活性,其中11、12、17、18等化合物表现较好,对大部分肿瘤细胞都有不错的抑制活性,其IC50值达到了微摩尔级。
抑制率公式如下:Inh%=(对照组OD490-实验组OD490)/(对照组OD490-空白组OD490)×100%。
实验后获得了本发明制备的化合物的体外细胞增殖抑制活性,结果如表1、表2所示。
表1实施例制备的化合物的体外肿瘤细胞增殖抑制活性
表2部分实施例制备的化合物的体外肿瘤细胞增殖抑制活性
注:IC50表示半数抑制浓度
测试例2、EGFR酶抑制活性实验
以EGFR为研究对象,测试化合物对L858R/T790M/C797S的亚型以及野生型的抑制活性,该项测试与上海睿智化学研究有限公司负责和桑迪亚医药技术(上海)有限责任公司都有合作,采用了Mobility Shift Assay方法(仪器迁移率改变法)。基本操作流程如下:首先将化合物用缓冲液配置成化合物溶液,并转移至微孔板中;用缓冲液配置激酶溶液,往化合物租、阳性对照租加入激酶溶液,阴性对照组加入缓冲液;室温下反应10分钟;用缓冲液将ATP和底物配置成混合液,再滴入各组中;室温下再反应60分钟;用缓冲液配置反应终止液,并加入各组中;使用Caliper仪器读取数据,计算抑制率。
表3所有实施例的EGFRLTC酶抑制活性
表4部分实施例的EGFRwt酶抑制活性
表5部分实施例的EGFRLTC酶抑制活性
测试例3、ALK酶抑制活性实验
该项ALK抑制活性测试与桑迪亚医药技术(上海)有限责任公司合作,采用了Mobility Shift Assay方法(仪器迁移率改变法)对ALK靶点抑制活性进行测试。测试方法与EGFR酶抑制活性测试基本一致。
表6实施例的ALK酶抑制活性
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 (9)
1.一种2-苯胺基嘧啶类衍生物或其可药用盐,所述2-苯胺基嘧啶类衍生物为式I所示化合物;
式I所示化合物选自下述任意一种:
。
2.根据权利要求1所述的2-苯胺基嘧啶类衍生物或其可药用盐,其中,药学上可接受的盐为无机酸盐或有机酸盐;
所述无机酸盐选自下述任意一种无机酸形成的盐:盐酸、硫酸和磷酸;
所述有机酸盐选自下述任意一种有机酸形成的盐:乙酸、三氟乙酸、丙二酸、柠檬酸和对甲苯磺酸。
3.一种权利要求1至2任一项所述2-苯胺基嘧啶类衍生物的制备方法,包括下述步骤:
式IA所示化合物与式IB所示化合物在酸性条件下、在溶剂中进行反应,获得式I所示化合物:
R1、R2、R3、X、Y和Z如权利要求1所定义。
4.权利要求1至2中任一项所述的2-苯胺基嘧啶类衍生物在制备下述产品中的应用:
1)表皮生长因子受体(EGFR)抑制剂;
2)间变性淋巴瘤激酶(ALK)抑制剂;
3)真核生物肿瘤细胞增殖抑制剂;
4)真核生物肿瘤细胞转移抑制剂;
5)血管生成抑制剂;
6)预防和/或***的药物。
5.根据权利要求4所述的应用,其中,
所述表皮生长因子受体(EGFR)为EGFRL858R、EGFRdel19、EGFRL858R/T790M、EGFRdel19/T790M、EGFRL858R/T790M/C797S和EGFRdel19/T790M/C797S中至少一种;
所述间变性淋巴瘤激酶(ALK)为ALKwt、ALKL1196M和EML4-ALK中至少一种;
所述真核生物为哺乳动物;
所述肿瘤细胞为癌细胞;所述癌细胞为白血病癌细胞、淋巴瘤细胞、肺癌细胞、乳腺癌细胞、卵巢癌细胞、***细胞、人脑胶质瘤细胞、黑色素癌细胞、胶质母细胞瘤细胞、鼻咽癌细胞、肝癌细胞、脑癌细胞、胰腺癌细胞、子宫癌细胞、睾丸癌细胞、皮肤癌细胞、胃癌细胞、结肠癌细胞、膀胱癌细胞或直肠癌细胞;
所述肿瘤为癌。
6.根据权利要求5所述的应用,其中,
所述白血病癌细胞为人慢性粒细胞白血病(CML)细胞系K562;
所述淋巴瘤细胞为人组织细胞淋巴瘤细胞U937;
所述肺癌细胞为人肺癌细胞株HCC827;
所述乳腺癌细胞为人乳腺癌细胞MCF-7、T47D和MDA-MB-231;
所述卵巢癌细胞为A2780;
所述***细胞为人***细胞系Hela;
所述人脑胶质瘤细胞为U251;
所述黑色素癌细胞为A375;
所述胶质母细胞瘤细胞为人胶质母细胞瘤细胞A172和人脑星形胶质母细胞瘤细胞U-118MG;
所述鼻咽癌细胞为鼻咽癌细胞株CNE-2;
所述肝癌细胞为人肝癌细胞HepG2;
所述癌为白血病、淋巴瘤、肺癌、黑色素癌、胶质母细胞瘤、***、鼻咽癌、肝癌、乳腺癌、脑癌、胰腺癌、卵巢癌、子宫癌、睾丸癌、皮肤癌、胃癌、结肠癌、膀胱癌或直肠癌。
7.一种产品,其活性成分为权利要求1至2中任一项所述的2-苯胺基嘧啶类衍生物;所述产品为以下中的至少一种:
1)表皮生长因子受体(EGFR)抑制剂;
2)间变性淋巴瘤激酶(ALK)抑制剂;
3)真核生物肿瘤细胞增殖抑制剂;
4)真核生物肿瘤细胞转移抑制剂;
5)血管生成抑制剂;
6)预防和/或***的药物。
8.根据权利要求7所述的产品,其中,
所述表皮生长因子受体(EGFR)为EGFRL858R、EGFRdel19、EGFRL858R/T790M、EGFRdel19/T790M、EGFRL858R/T790M/C797S和EGFRdel19/T790M/C797S中至少一种;
所述间变性淋巴瘤激酶(ALK)为ALKwt、ALKL1196M和EML4-ALK中至少一种;
所述真核生物为哺乳动物;
所述肿瘤细胞为癌细胞;所述癌细胞为白血病癌细胞、淋巴瘤细胞、肺癌细胞、乳腺癌细胞、卵巢癌细胞、***细胞、人脑胶质瘤细胞、黑色素癌细胞、胶质母细胞瘤细胞、鼻咽癌细胞、肝癌细胞、脑癌细胞、胰腺癌细胞、子宫癌细胞、睾丸癌细胞、皮肤癌细胞、胃癌细胞、结肠癌细胞、膀胱癌细胞或直肠癌细胞;
所述肿瘤为癌。
9.根据权利要求8所述的产品,其中,
所述白血病癌细胞为人慢性粒细胞白血病(CML)细胞系K562;
所述淋巴瘤细胞为人组织细胞淋巴瘤细胞U937;
所述肺癌细胞为人肺癌细胞株HCC827;
所述乳腺癌细胞为人乳腺癌细胞MCF-7、T47D和MDA-MB-231;
所述卵巢癌细胞为A2780;
所述***细胞为人***细胞系Hela;
所述人脑胶质瘤细胞为U251;
所述黑色素癌细胞为A375;
所述胶质母细胞瘤细胞为人胶质母细胞瘤细胞A172和人脑星形胶质母细胞瘤细胞U-118MG;
所述鼻咽癌细胞为鼻咽癌细胞株CNE-2;
所述肝癌细胞为人肝癌细胞HepG2;
所述癌为白血病、淋巴瘤、肺癌、黑色素癌、胶质母细胞瘤、***、鼻咽癌、肝癌、乳腺癌、脑癌、胰腺癌、卵巢癌、子宫癌、睾丸癌、皮肤癌、胃癌、结肠癌、膀胱癌或直肠癌。
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