CN108191874B - 一种C-Kit抑制剂及其应用 - Google Patents
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Abstract
本发明公开了一种式I所示的C‑Kit抑制剂化合物、其立体异构体或药学上可接受的盐，其中，R1为羟基、氰基、C1‑4烷基、卤素或卤素取代的C1‑4烷基；R2为氢、羟基、氰基、烷基、卤素或卤素取代的C1‑4烷基；R3为氢、羟基、氰基、C1‑4烷基、卤素或卤素取代的C1‑4烷基。本发明还提供了所述化合物、其立体异构体或药学上可接受的盐在制备预防或治疗C‑Kit、特别是突变型C‑Kit介导的疾病的药物中的应用。
Description
技术领域
本发明属于药物领域，具体涉及一种C-Kit抑制剂，以及在预防和治疗C-Kit介导的疾病中的应用。
背景技术
KIT属于原癌基因C-kit编码的III型受体酪氨酸激酶家族成员。C-kit基因编码的kit蛋白由胞内的酪氨酸激酶区，跨膜区和带有配体结合位点胞外区构成，KIT受体与配体SCF(干细胞因子)结合后，通过形成二聚体，激活下游信号，包括Ras、Raf、MAPK通路等，最终活化细胞内的转录因子，从而调节基因表达、控制细胞生长和增殖。
伊马替尼是一种酪氨酸蛋白酶抑制剂，能阻断酪氨酸蛋白激酶KIT受体的功能，从而抑制肿瘤的形成。已有研究证实，KIT突变的位置能影响肿瘤患者对伊马替尼的反应。KIT突变位于调控区即非酪氨酸酶结构区，使抑制剂能有效封闭酶位点，对伊马替尼的部分缓解率明显提高，平均生存期延长，病情进展缓慢。
如：胃肠间质瘤是一种较为常见的恶性胃肠道肿瘤。病理学研究证明激酶c-Kit是胃肠间质瘤治疗的有效靶点，在细胞的转移和分化过程中起着重要的作用，它的过量表达与胃肠间质瘤密切相关。目前，伊马替尼是治疗胃肠间质瘤的临床一线用药，但是长期用药后，有近80-85％患者产生耐药性，其中主要的耐药因素是因为C-Kit激酶发生耐药性突变，因此开发一种化合物用于抑制野生型c-Kit和突变型c-Kit是临床治疗非常急需的。
发明内容
针对现有技术的不足，本发明的目的是提供一种同时抑制野生型c-Kit和突变型C-Kit的化合物，用于预防和治疗C-Kit介导的疾病，包括胃肠道间质瘤、天狼疮、白血病、肥大细胞病、黑素瘤、精原细胞瘤、类风湿性关节炎、多发性硬化病、渐冻症、多发性骨髓瘤和胰腺癌等。
本发明的上述目的通过以下技术方案实现：
一种式I的化合物、其立体异构体或药学上可接受的盐：
其中，R1和R2独立地为氢、卤素、硝基、氨基、氰基、取代或未取代的C1-4烷基、取代或未取代的C1-4烷氧基或磺酸基；所述取代是被至少一个下述基团取代：卤素、硝基、氨基、氰基和苯基；m、n独立地为1～4的整数。
根据本发明的一些具体实施例，上式I中，所述R1和R2独立地为氢、卤素、硝基、氰基、取代或未取代的C1-2烷基、取代或未取代的C1-2烷氧基；所述取代是被至少一个下述基团取代：卤素、硝基和苯基；m、n独立地为1～2的整数。
更具体而言，本发明一些优选化合物的结构式如式II所示：
在本发明中，优选所述的立体异构体为光学异构体。
根据本发明的一个实施例，所述化合物为：
进一步地，本发明所述的盐包括但不限于乙酸盐、抗坏血酸盐、苯甲酸盐、苯磺酸盐、柠檬酸盐、富马酸盐、盐酸盐、氢溴酸盐、马来酸盐、甲磺酸盐、硝酸盐、草酸盐、磷酸盐、琥珀酸盐和硫酸盐等。
本发明所述的化合物、其立体异构体或药学上可接受的盐在实际应用过程中以药物组合物的形式存在，所述药物组合物还包含药学上可接受的载体和/或辅料。
本发明还进一步提供了含有上述的化合物、其立体异构体或药学上可接受的盐的药物组合物在制备预防或治疗C-Kit介导的疾病的药物中的应用。
所述C-Kit介导的疾病包括胃肠道间质瘤、天狼疮、白血病、肥大细胞病、黑素瘤、精原细胞瘤、类风湿性关节炎、多发性硬化病、渐冻症、多发性骨髓瘤和胰腺癌等。
更优地，含有本发明所述的化合物、其立体异构体或药学上可接受的盐的药物组合物特别适于在制备预防或治疗突变型C-Kit介导的疾病的药物中的应用。
本发明的化合物为临床用药、特别是为肿瘤耐受性患者提供了更优的选择。
具体实施方式
以下将结合实施例对本发明作进一步的详细描述，本发明的实施例仅用于说明本发明的技术方案，并非对本发明的限制，凡依照本发明公开的内容所作的任何本领域的等同置换，均属于本发明的保护范围。
本发明的化合物、其立体异构体或药学上可接受的盐均可选择实施例的合成路线进行制备，并根据取代基或成盐的需要，对反应原料和反应溶剂的常规条件加以调整，这些都是本领域的技术人员在本发明公开内容的基础上可以实现的。
实施例1化合物II的制备
将化合物1(10.83mmol)，化合物2(10.83mmol)，PdCl2(dppf)(527mg,0.72mmol)和KOAc(235mg,2.4mmol)在甲苯(30ml)中的混合物加热至110℃保持6小时。将反应液蒸发并加入水(100ml)，将其用乙酸乙酯(2×40ml)萃取。分离有机相，用无水Na2SO4干燥，过滤并蒸发。通过柱色谱法用乙酸乙酯/石油醚＝1：4～1：1进行纯化，得到2g固体，在THF:H 20(24ml:6ml)的混合溶剂中的溶液中加入NaIO4(18.6mmol)，并在室温下搅拌30分钟。加入2NHCl水溶液。将其在室温下搅拌3小时。将混合物用乙酸乙酯稀释，用盐水洗涤，然后分离并用无水Na2SO4干燥，过滤并浓缩。通过使用MeOH/DCM＝1：10的柱色谱法纯化得到化合物4。
将化合物4(0.21mmol)、化合物5(0.21mmol)和二异丙基乙胺(0.84mmol)于二噁烷(10ml)中的混合物在室温下搅拌过夜，LC-MS监测反应完全，浓缩反应混合物得到目标化合物(II)。
MS：m/z(ES):499.5[M+1]。
1H NMR：(300MHz,d6-DMSO):8.58(m,2H),8.22(m,1H),7.91-7.96(m,2H),7.19-7.28(m,4H),6.41(s,1H),5.10(t,2H),5.01(s,1H)，3.95(m,3H)，3.26(m,4H)，3.18-3.22((m,4H)，1.76(s,3H)。
实施例2化合物II的光学异构体：(S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethanamine的制备
根据实施例1合成化合物II 100mg，再通过手性HPLC分离得到40mg白色固体，为上式的异构体化合物III。
MS m/z(ES):499.5[M+1]。
1H NMR(300MHz,d6-DMSO):8.59(m,2H),8.21(m,1H),7.91-7.96(m,2H),7.19-7.28(m,4H),6.41(s,1H),5.10(t,2H),5.01(s,1H)，3.95(m,3H)，3.26(m,4H)，3.18-3.21((m,4H))，1.76(s,3H)。
试验例1体外酶抑制活性测试
1.试验原理：
通过Envision检测Assay plate中的化学发光，以化合物的IC50值为指标，来评价化合物对c-Kit(WT)、c-Kit突变D861V和PDGFRα突变D842V激酶的抑制作用。
2.试验方法：
将待测化合物III以DMSO稀释到1mM备用。在使用前，再用超纯水将待测化合物稀释25倍，室温平衡30min待用。在Assay plate中，每个待测化合物进行3倍梯度稀释，获得终浓度从1uM到0.017nM的11个浓度梯度；加入c-Kit(WT)或c-Kit(D861V)或PDGFRα(D842V)激酶混合物到Assay plate中，室温孵育30min，再加入底物ATP混合物启动反应，室温孵育90min，加入终止液终止反应，室温孵育1小时，Envision读板，分析数据，计算化合物的IC50值。
表1实施化合物对体外酶的抑制作用
由表1可知，实施例化合物III对野生型c-Kit(WT)、和突变型c-Kit(D861V)及PDGFRα(D842V)激酶均具有很强的抑制作用，这意味着本发明化合物不仅对c-Kit野生型介导的疾病有治疗作用，对突变的c-Kit介导的疾病将同样有效，且效果较佳。
Claims (9)
1.式I的化合物、其立体异构体或药学上可接受的盐：
其中，R1和R2独立地为氢、卤素、硝基、氰基、取代或未取代的C1-2烷基、取代或未取代的C1-2烷氧基；所述取代是被至少一个下述基团取代：卤素、硝基和苯基；m、n独立地为1～2的整数。
2.根据权利要求1所述的化合物、其立体异构体或药学上可接受的盐，其特征在于，所述化合物的结构式如式II所示：
3.根据权利要求1或2所述的化合物、其立体异构体或药学上可接受的盐，其特征在于，所述的立体异构体为光学异构体。
4.根据权利要求3所述的化合物、其立体异构体或药学上可接受的盐，其特征在于，所述化合物为：
5.根据权利要求1或2所述的化合物、其立体异构体或药学上可接受的盐，其特征在于，所述盐为乙酸盐、抗坏血酸盐、苯甲酸盐、苯磺酸盐、柠檬酸盐、富马酸盐、盐酸盐、氢溴酸盐、马来酸盐、甲磺酸盐、硝酸盐、草酸盐、磷酸盐、琥珀酸盐或硫酸盐。
6.一种药物组合物，其特征在于，所述组合物含有权利要求1或2所述的化合物、其立体异构体或药学上可接受的盐，以及药学上可接受的载体和/或辅料。
7.如权利要求6所述的药物组合物在制备预防或治疗C-Kit介导的疾病的药物中的应用。
8.根据权利要求7所述的应用，其特征在于，所述C-Kit介导的疾病包括胃肠道间质瘤、天狼疮、白血病、肥大细胞病、黑素瘤、精原细胞瘤、类风湿性关节炎、多发性硬化病、渐冻症、多发性骨髓瘤和胰腺癌。
9.根据权利要求7所述的应用，其特征在于，所述C-Kit为突变型C-Kit。
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