CN102675289B - 作为蛋白激酶抑制剂的n-苯基苯甲酰胺衍生物 - Google Patents
作为蛋白激酶抑制剂的n-苯基苯甲酰胺衍生物 Download PDFInfo
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Abstract
本发明涉及式I所表示的一类新的N-苯基苯甲酰胺类衍生物，或其在药学上可接受的盐或其前药，作为蛋白激酶抑制剂。本发明还提供了制备这类化合物的方法，含有它们的药物组合物，以及任选地与一种或多种其他药学活性化合物组合用于治疗对于抑制蛋白激酶活性有响应的疾病、尤其是肿瘤疾病的用途以及治疗所述疾病的方法。
Description
技术领域
本发明涉及新的取代的N-苯基苯甲酰基氨衍生物或其药学上可接受的盐或药物组合物，单独或任选地与一种或多种其他药学活性化合物联合用于治疗对于抑制蛋白激酶活性有响应的疾病，尤其是肿瘤疾病的用途，以及治疗所述疾病的方法。
背景技术
蛋白激酶是一类磷酸转移酶，其作用是将ATP的γ磷酸基转移到底物特定的氨基酸残基上，使蛋白质磷酸化。底物蛋白经过这种修饰后可充当调节细胞增殖、活化/分化的分子开关。蛋白质的磷酸化作用导致细胞传导途径的激活，对细胞的生长、代谢、分化和死亡起着关键的作用。蛋白激酶活性的失常，可以引起许多相关的疾病，如癌症、炎症和心血管疾病等。在很多情况下，可以通过体外和体内利用蛋白激酶抑制剂来治疗这类疾病。
Bcr-Abl基因是费城染色体，是由染色体异变产生的，它表达210KD的蛋白质(p210Bcr-Abl)。Bcr-Abl蛋白质的Abl部分含有Abl的酪氨酸激酶，它在原型的c-Abl中是受严密调节的，但在Bcr-Abl融合蛋白质中被连续地激活，从而导致细胞生长的失控。Bcr-Abl存在于95％慢性髓性白血病的患者中，以及10-25％急性淋巴细胞白血病的患者中。
c-kit是具有酪氨酸激酶活性的一种生长因子受体，是原癌基因c-kit产生的。c-kit及其配体干细胞因子(SCF)对血细胞生成、黑色素生成和生育能力是至关重要的。SCF在血细胞生成发育级序的多重水平上起作用以促进细胞生存、增殖、分化、粘附和功能激活。它在肥大细胞和红细胞系中特别重要的，而且在多重潜在性干细胞和祖细胞、巨核细胞和淋巴祖细胞亚集上起作用。c-kit的自发突变以及SCF/c-kit途径的自分泌/旁分泌激活机制与各种恶性肿瘤有关。通过增强肿瘤生长并且减少细胞凋亡，c-kit激活有助于转移。另外，c-kit经常突变和在胃肠间质瘤中激活，并且配体介导的。c-kit激活存在于某些肺癌当中。c-kit受体也在64％的原发性初治急性髓系白血病和95％的AMLs 中的至少10％的胚细胞中表达。c-kit介导AML中的增值和抗-细胞凋亡作用。c-kit表达已经在各种人恶性肿瘤中被证实，包括肥大细胞增多症、肥大细胞白血病、胃肠道间质瘤、精原细胞瘤、无性细胞瘤、急性骨髓性白血病、卵巢癌、幼年型T细胞急性淋巴细胞白血病(ALL)、淋巴癌、乳腺癌和前列腺癌等。
血小板衍生生长因子受体(PDGFR)是跨膜酪氨酸激酶受体。其配体由两个A链形成，或两个B链形成。或一个A链和一个B链的异型二聚物形成。PDGF一旦与配体结合，血小板衍生生长因子受体形成二聚，其酪氨酸激酶被激活，向下游区发出信号。血小板衍生生长因子信号与一系列疾病有关。生长因子信号通路的自分泌激活与某些脑胶质瘤、骨髓增生性疾病、肿瘤、多发性骨髓瘤和肉瘤有关。旁分泌生长因子信号常见于上皮癌，在那里它引发基质的吸入，并且可能参与上皮细胞间质转型，从而影响肿瘤的生长、血管生成、侵袭和转移。血小板衍生生长因子驱动血管疾病的器质病变反应，如动脉粥样硬化、动脉狭窄、肺动脉高压、视网膜疾病以及肝纤维化的疾病，包括肺间质纤维化、肝硬化、硬皮病、肾小球硬化和心肌纤维化。
伊马替尼是一种特异的酪氨酸抑制剂，它除了抑制BCR-ABL酪氨酸激酶活力外，对血小板衍化生长因子β(PDGF2β)受体酪氨酸激酶和干细胞因子(SCF)的c-kit配体酪氨酸激酶活力也存在同等程度的抑制。然而，随后的临床研究表明，BCR-ABL基因发生了包括Y253H、E255V、E255K、F359V、T315I、G250E、F317L、E355G、H396P、M351T、M253H、L248V、Q252H、Y253H和Y253C等15种突变，BCR-ABL基因的突变导致伊马替尼出现耐药性。
鉴于蛋白激酶抑制剂数量之大和增殖性及其他蛋白激酶相关的疾病种类之多，而且现有药物出现了耐药性等问题，我们需要开发新的种类的化合物，以用作蛋白激酶抑制剂，用于治疗这些蛋白激酶相关的疾病。因此，本发明发现了一种新的N-苯基苯甲酰胺类衍生物，用于预防或治疗与蛋白激酶活性异常或失控相关的疾病，特别是涉及Bcr-Abl，c-kit和PDGF蛋白激酶活性异常的疾病。
发明内容
本发明公开了一种新型的N-苯基苯甲酰胺衍生物，其具有通式(I)表示的化合物或药学上可接受的盐或其前药，
式(I)
其中
R1可以任意地被氢原子，羟基，腈基，C1-6的烷基，C1-6的羟烷基，C1-6的氨代烷基，C1-6的卤代烷基，C1-6的腈代烷基，C2-6的烯基，C2-6的炔基，芳基，杂环基，环烷基或杂环烷基所取代；其中所述的芳基、杂环基、环烷基、杂环烷基可任意地被1、2或3个卤素，羟基，氨基，腈基，C1-3的烷基、烯基、炔基的基团所取代；
R2，R4可以任意地被氢原子，卤素，腈基，C1-6的烷基，C1-6的羟烷基，C1-6的氨代烷基，C1-6的卤代烷基，C1-6的腈代烷基，C2-6的烯基，C2-6的炔基，环烷基或杂环烷基，ORa，SRa，NRbRc，NRbC(O)Rd，NRbS(O)2Rd，C(O)NRbRc，S(O)2NRbRc，C(O)Rd，S(O)2Rd的基团所取代；
R3可以任意地被氢原子，卤素，羟基，腈基，氨基，C1-6的烷基，C1-6的羟烷基，C1-6的氨代烷基，C1-6的卤代烷基，C1-6的腈代烷基，C2-6的烯基，C2-6的炔基，环烷基或杂环烷基所取代；
或者两个R3基团和它们连接的原子一起形成3、4、5、6、7元环的环烷基或杂环烷基，并可任意地被1、2、3个独立选自于羟基，腈基，卤素，C1-6的烷基，C1-6的羟烷基，C1-6的氨代烷基，C1-6的卤代烷基，C1-6的腈代烷基，C2-6的烯基，C2-6的炔基，环烷基或杂环烷基，ORa，SRa，NRbRc，NRbC(O)Rd，NRbS(O)2Rd，C(O)NRbRc，S(O)2NRbRc，C(O)Rd，S(O)2Rd的基团所取代；
X是杂环基，可任意地被1、2或3个R5所取代；
Y是杂环基，或杂环烷基，可任意地被1、2或3个R6所取代；
R5可以任意地被氢原子，卤素，羟基，腈基，氨基，C1-6的烷基，C1-6的羟烷基，C1-6的氨代烷基，C1-6的卤代烷基，C1-6的腈代烷基，C2-6的烯基，C2-6的炔基，环烷基或杂环烷基，ORa，SRa，NRbRc，NRbC(O)Rd，NRbS(O)2Rd，C(O)NRbRc，S(O)2NRbRc，C(O)Rd，S(O)2Rd的基团所取代；
R6可以任意地被氢原子，卤素，羟基，腈基，氨基，C1-6的烷基，C1-6的羟烷基，C1-6的氨代烷基，C1-6的卤代烷基，C1-6的腈代烷基，C2-6的烯基，C2-6的炔 基，环烷基或杂环烷基，ORa，SRa，NRbRc，NRbC(O)Rd，NRbS(O)2Rd，C(O)NRbRc，S(O)2NRbRc，C(O)Rd，S(O)2Rd的基团所取代；
Ra，Rb，Rc，Rd可以任意地被氢原子，卤素，羟基，腈基，氨基，C1-6的烷基，C1-6的羟烷基，C1-6的氨代烷基，C1-6的卤代烷基，C1-6的腈代烷基，C2-6的烯基，C2-6的炔基，环烷基或杂环烷基的基团所取代；
m是0到4的整数
n是0到5的整数。
式(I)化合物的成盐基团是碱性基团，具有至少一个碱性基团如游离氨基团、吡嗪基或吡啶基，可以与下列酸生成盐，如无机酸：盐酸、硫酸、磷酸；有机羧酸：乙酸、丙酸、三氟乙酸、乙醇酸、琥珀酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、草酸、各种天然的或合成的氨基酸、苯甲酸、水杨酸、4-氨基水杨酸、扁桃酸、肉桂酸、烟酸、异烟酸；有机磺酸：甲磺酸、三氟甲磺酸、乙磺酸、2-羟基乙磺酸、苯磺酸、对甲苯磺酸、2-萘磺酸。当存在多个碱性基团是，可以生成多酸加成盐。
式(I)化合物具有宝贵的药理性质，如可以用作抗癌药物、治疗动脉粥样硬化的药物、用于移植诱发的障碍如闭塞性细支气管炎的预防。
PDGF是一种非常常见的生长因子，它在正常生长和病理性细胞增殖中起着重要的作用，如在癌发生和血管平滑肌细胞的疾病。PDGF受体酪氨酸激酶的抑制作用使式(I)化合物适合治疗肿瘤疾病，如神经胶质瘤、肉瘤、前列腺肿瘤和结肠、乳腺、卵巢肿瘤。
式(I)化合物还可抑制涉及所谓干细胞生长因子(SCF)的细胞进程。例如SCF受体(kit)的自磷酸化作用和SCF刺激的MAPK激酶(促分裂原活化蛋白激酶)活化作用。
式(I)化合物还抑制Bcr-Abl激酶，因而适合治疗Bcr-Abl-阳性癌症和肿瘤疾病，如白血病，尤其是慢性骨髓性白血病和急性淋巴细胞型白血病。而且还显示出对白血病性干细胞亚群的效果以及对在除去所述细胞后体外纯化这些细胞和一旦清除癌细胞再植入细胞的潜力。
式(I)化合物还能够抑制血管的生成，其对三种生长因子VEGF、PDGF和bFGF的血管生成有抑制效果。
本发明尤其涉及式(I)化合物或者其药学上可接受的盐用于治疗对于抑制蛋白激酶活性有响应的疾病的药物组合物中的用途，其中所述的疾病是一种 肿瘤疾病。更具体地讲，本发明涉及式(I)化合物或者其药学上可接受的盐在制备用于治疗对于抑制Raf和Abl酪氨酸激酶活性有响应的白血病的药物组合物中的用途。
此外，本发明还涉及式(I)化合物或者其药学上可接受的盐在治疗对于抑制蛋白激酶有响应的疾病中的用途；相关的疾病有癌症、炎症、自身免疫性疾病、感染和心血管疾病；其中癌症包括白血病、骨髓增生性疾病、神经胶母细胞瘤、肥大细胞肿瘤、生殖细胞肿瘤、脑瘤、黑色素瘤、胃肠道间质瘤、结肠癌、胃癌、肺癌、肾癌、乳腺癌、卵巢癌、宫颈癌、前列腺癌、膀胱癌；炎症包括类风湿性关节炎、鼻炎、哮喘、牛皮癣和克罗恩病；心血管疾病包括动脉粥样硬化、肺动脉高压、视网膜疾病、肝硬化和心肌纤维化。
本发明还提供了治疗患有所述疾病，尤其是患有肿瘤疾病的包括人在内的温血动物的方法，其中将有效对抗有关疾病量的式I化合物对需要这类治疗的包括人在内的温血动物给药。根据物种、年龄、个体条件、给药模式和有关临床表现，对体重约65kg的包括人在内的温血动物给药有效剂量的药，如每日剂量约为1-2500mg，优选5-500mg。
本发明还涉及药物制剂，该制剂含有有效量的式I化合物或其药学上可接受的盐或其前药以及至少一种药学上可接受的载体。这些载体可通过口服，针剂注射，喷雾吸入，皮外用，直肠用，鼻腔用，腹腔用，或通过植入储液囊或透皮贴剂等途径使用。
具体实施方式
实施例1
4-[(4-甲基-1-高哌嗪基)甲基]-N-{4-甲基-3-[4-(3-吡啶基)-2-嘧啶基氨基]苯基}苯甲酰胺的制备
步骤A：4-氯甲基-N-{4-甲基-3-[4-(3-吡啶基)-2-嘧啶基氨基]苯基}苯甲 酰胺
将N-(5-氨基-2-甲基苯基)-4-(3-吡啶基)-2-氨基嘧啶2.77g(0.01mol)溶于20ml氯仿中，加入二异丙基乙胺3ml，搅拌，在冰浴下滴加对氯甲基苯甲酰氯2.27g/氯仿20ml溶液，滴完后，撤去冰浴，室温反应1h，TLC跟踪。反应结束后，用去离子水(40ml×3)洗涤，无水硫酸镁干燥，减压蒸馏脱去溶剂，柱色谱分离提纯，以二氯甲烷/甲醇(v/v，15/1)为洗脱剂，得到产物2.5g，产率58％。MS(M+1)＝430.14。
步骤B：4-[(4-甲基-1-高哌嗪基)甲基]-N-{4-甲基-3-[4-(3-吡啶基)-2-嘧啶基氨基]苯基}苯甲酰胺
将步骤A产物4.3g溶于100ml 1，2-二氯乙烷中，加入N-甲基高哌嗪1.7g，碳酸钾10g，搅拌，升温至80℃反应6h，TLC跟踪。反应完成后用水洗涤3次，收集有机相，无水硫酸镁干燥，减压浓缩，柱色谱分离，洗脱剂为二氯甲烷/甲醇(v/v，9/1)，得到目标产物3.3g，产率65％。MS(M+1)＝508.6。
实施例2-4
类似于实施例1合成下列化合物
实施例2
4-[(4-乙基-1-高哌嗪基)甲基]-N-{4-甲基-3-[4-(3-吡啶基)-2-嘧啶基氨基]苯基}苯甲酰胺
实施例3
4-[(4-异丙基-1-高哌嗪基)甲基]-N-{4-甲基-3-[4-(3-吡啶基)-2-嘧啶基氨基]苯基}苯甲酰胺
实施例4
4-[(4-羟乙基-1-高哌嗪基)甲基]-N-{4-甲基-3-[4-(3-吡啶基)-2-嘧啶基氨基]苯基}苯甲酰胺的
实施例5
4-[(4-甲基-1-高哌嗪基)甲基]-N-{4-甲基-3-[4-(3-吡啶基)-2-嘧啶基氨基]苯基}苯甲酰胺甲磺酸盐
将4-[(4-甲基-1-高哌嗪基)甲基]-N-{4-甲基-3-[4-(3-吡啶基)-2-嘧啶基氨基]苯基}苯甲酰胺5g在加热下溶于20ml乙醇中，然后加入0.99g甲磺酸，反应0.5h后，冷却，加入乙酸乙酯析出晶体。将晶体真空干燥，即得目标产物。
实施例6
含有100mg式I化合物例如实施例1中所述的化合物片剂通常按照下列组成制备：
原料与所有辅料混合后总重450g，将其粉碎、过筛后混合均匀，经制粒压片成1000片，每片100mg。
实施例7
含有100mg式I化合物例如实施例1中所述的化合物胶囊通常按照下列组成制备：
将以上各种组分混合均匀，然后将混合物填充在1号胶囊内。
实施例8激酶酶活性的测试
将测试化合物溶解在DMSO中。加入384孔黑色聚苯乙烯培养板的干燥孔中。将激酶Abl、c-kit、PDGFR溶解在含有50mM HEPES(pH 7.0)、1mM DTT、5mM MgCl2、0.02％NaN3、0.1mg/ml BSA、0.1mM Na3VO4、和辅酶缓冲液的介质中(10微升)，然后加到培养板的孔中。其次加入10微升的1mM ATP、500nM生物素酰化酪氨酸激酶底物的溶液。反应在室温进行90分钟，然后停止，将10微升的反应液转移到黑培养板上，该培养板上含有10微升的检测溶液，由50mM HEPES、1mg/ml血清白蛋白、0.8M KF、20mM EDTA、62.5nM Sa-XL665和TK-Ab-Cryptate组成。将培养板密封，离心分离1分钟，在室温下培养60分钟。测试板在Fusion微板读取仪上读取。抑制百分比值是根据化合物的平均荧光强度相对于没有测试化合物(空白)情况下和没有激酶情况下的平均荧光强度计算出来的。同时利用伊马替尼(Imatinib)进行了对照试验。测试结果如下表所示。
试验结果表明，本发明实施例化合物对激酶Abl、c-Kit和PDGFR的抑制活性(IC50)略优于伊马替尼或与伊马替尼相当。
以上所述仅为本发明的较佳实施例而已，并非用以限定本发明的实质技术内容范围，本发明的实质技术内容是广义地定义于申请的权利要求范围中，任何他人完成的技术实体或方法，若是与申请的权利要求范围所定义的完全相同，也或是一种等效的变更，均将被视为涵盖于该权利要求范围之中。
Claims (5)
1.一种有下面通式(Ⅰ)表示的化合物或药学上可接受的盐，
其中
R1是甲基，乙基，丙基，或羟乙基；
R2，R4是甲基，或乙基；
R3是氢原子；
X选自于嘧啶基；
Y选自于吡啶基；
m，n分别是0到1的整数。
2.根据权利要求1所述的化合物或药学上可接受的盐，其成盐基团是碱性基团，具有至少一个吡啶基，可以与甲磺酸成盐。
3.一种化合物或药学上可接受的盐，其中所述化合物优选自：
4-[(4-甲基-1-高哌嗪基)甲基]-N-{4-甲基-3-[4-(3-吡啶基)-2-嘧啶基氨基]苯基}苯甲酰胺，
4-[(4-乙基-1-高哌嗪基)甲基]-N-{4-甲基-3-[4-(3-吡啶基)-2-嘧啶基氨基]苯基}苯甲酰胺，或
4-[(4-异丙基-1-高哌嗪基)甲基]-N-{4-甲基-3-[4-(3-吡啶基)-2-嘧啶基氨基]苯基}苯甲酰胺。
4.一种药物组合物，包括权利要求1-3任一项所述的化合物或其药学上可接受的盐，和至少一种药学上可接受的载体。
5.根据权利要求1-3任一项所述的化合物或其药学上可接受的盐在制备用于治疗与Bcr-Abl，c-kit和PDGF蛋白激酶活性异常相关的疾病的抑制剂中的用途。
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