CN114685507B - 嘌呤胺衍生物类cdk2抑制剂及其制备方法和应用 - Google Patents
嘌呤胺衍生物类cdk2抑制剂及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及嘌呤胺衍生物类CDK2抑制剂、其药学上可接受的盐、其立体异构体或其溶剂化合物，其中R1和R2如说明书中所定义；本发明还涉及这些化合物的制备方法，含有这些化合物的药物组合物，以及这些化合物在制备用于治疗和/或预防与由CDK2介导的信号通路有关的疾病的药物中的应用。
Description
技术领域
本发明属于医药技术领域，具体涉及嘌呤胺类衍生物、其药学上可接受的盐或其溶剂化物，这些化合物的制备方法和含有这些化合物的药物组合物，以及这些化合物、其药学上可接受的盐或其溶剂化物在制备用于治疗和/或预防与细胞周期依赖性激酶，尤其是CDK2，活性有关的疾病药物中的应用。
背景技术
自上世纪70年代，哺乳动物的细胞周期调控机制逐渐被阐明。细胞周期调控依赖的调控因子主要有三大类：细胞周期蛋白依赖性激酶(Cyclin-dependent kinases,CDKs)、细胞周期蛋白(Cyclins)、细胞周期蛋白依赖性激酶抑制剂(Cyclin-dependent kinaseinhibitor,CDKI)。
CDKs属于丝氨酸/苏氨酸激酶，在细胞周期的各个阶段发挥作用。CDKs必须与相应的Cyclins形成异二聚体复合物才能发挥作用,并通过Cyclins的周期性表达和降解,推动细胞周期各时相的有序进行。目前，已经发现有20个CDKs和29个相应的Cyclins。其中，CDK1～6和CDK14～18直接参与细胞周期调控和细胞分裂，而CDK7～13以及CDK19～20则主要调控基因转录。
CDK2在细胞周期调节中起关键作用。CDK2与Cyclin E形成复合物，然后磷酸化Rb蛋白，并激活转录因子E2F。CDK2-Cyclin A复合物促进细胞通过S/G2检查点。CDK2还控制许多转录因子的磷酸化，包括Smad3、FoxM1、FoxO1、NFY、B-Myb、Myc，并促进细胞周期。CDK2是多种致癌信号通路的重要调控因子。CDK2及其相关的Cyclin A或Cyclin E的过度表达与多种肿瘤的发生和发展密切相关。目前，CDK2已被公认为抗肿瘤药物开发的潜在靶点，有必要研究和开发新的CDK2抑制剂。
发明内容
本发明的一个目的是提供一种嘌呤胺衍生物类CDK2抑制剂或其药学上可接受的盐。
本发明的另一个目的是提供制备本发明的嘌呤胺衍生物类CDK2抑制剂或其药学上可接受的盐的制备方法和应用。
针对上述目的，本发明提供以下技术方案：
一、嘌呤胺衍生物类CDK2抑制剂
通式(Ⅰ)所示的嘌呤胺衍生物类CDK2抑制剂、其药学上可接受的盐、其立体异构体或其溶剂化物：
其中，
R1选自氨基、羧基、羟基、卤素，或者末端被氨基、羧基、羟基、卤素原子取代的C1-8烷基、C1-8烷胺基和C1-8烷氧基。
R2选自硝基、磺酰胺基，或者N原子被一个或两个C1-8烷基取代的磺酰胺基。
根据本发明优选的，
R1选自氨基、羧基，或者末端被氨基、羧基取代的C1-5烷基。
R2选自硝基、磺酰胺基。
根据本发明进一步优选的，嘌呤胺衍生物类CDK2抑制剂为如下之一：
本发明所述“卤素原子”指氟原子、氯原子、溴原子或碘原子。
本发明所述“C1-8烷基”指含有1-8个碳原子的直链或支链的烷基，其实例包括但不限于例如甲基、乙基、正丙基、异丙基、正丁基、2-甲基丙基、1-甲基丙基、1,1-二甲基乙基、正戊基、3-甲基丁基、2-甲基丁基、1-甲基丁基、1-乙基丙基、正己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基、庚基、辛基等。
本发明所述“C1-8烷胺基”是指以“C1-8烷基-NH-”方式连接的基团，“C1-8烷基”的定义如前文所述；其中包括例如“C1-6烷胺基”、“C1-4烷胺基”、“C1-3烷胺基”、“C2-4烷胺基”、“C2-5烷胺基”等。
本发明所述“C1-8烷氧基”是指以“C1-8烷基-O-”方式连接的基团，“C1-8烷基”的定义如前文所述；其中包括例如“C1-6烷氧基”、“C1-4烷氧基”、“C1-3烷氧基”、“C2-4烷氧基”、“C2-5烷氧基”等。
本发明上述任一化合物的“药学上可接受的盐”包括根据本文中所述化合物上存在的特定取代基采用相对无毒的酸或碱制备的活性化合物的盐。当本发明化合物含相对酸性的官能团时，可通过使中性形式的这种化合物与足量的需要的碱单独或在合适的惰性溶剂中接触得到碱加成盐。由药学上可接受的无机碱衍生的盐的实例包括铝、铵、钙、铜、三价铁、亚铁、锂、镁、锰、二价锰、钾、钠、锌等。由药学上可接受的有机碱衍生的盐包括伯、仲和叔胺的盐，它们包括取代的胺、环胺、天然胺等，例如精氨酸、甜菜碱、咖啡因、胆碱、N,N’-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、甲基葡糖胺、组氨酸、赖氨酸、异丙胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。当本发明化合物含有相对碱性的官能团时，可通过使中性形式的这种化合物与足量的需要的酸单独或在合适的惰性溶剂中接触得到酸加成盐。药学上可接受的酸加成盐的实例包括由无机酸衍生的盐，例如盐酸盐、氢溴酸盐、硝酸盐、碳酸盐、碳酸氢盐、磷酸盐、磷酸氢盐、磷酸二氢盐、硫酸盐、硫酸氢盐、氢碘酸盐或亚磷酸盐等；由相对无毒的有机酸衍生的盐，所述的有机酸为例如乙酸、丙酸、异丁酸、丙二酸、苹果酸、琥珀酸、辛二酸、富马酸、扁桃酸、苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸等。还包括氨基酸例如精氨酸等的盐以及有机酸例如葡糖醛酸或半乳糖酸等的盐。本发明某些化合物含有碱性或酸性官能团，使得化合物可以转化为碱或酸加成盐。
本发明上述任一化合物的“溶剂化物”是指本发明化合物与一个或多个溶剂分子的物理结合。这种物理结合涉及不同程度的离子和共价键，包括氢键合。在某些情况中，溶剂化物能够分离，例如，当一个或多个溶剂分子结合进结晶固体的晶格中时。“溶剂化物”包括溶液相和可分离的溶剂化物二者。合适的溶剂化物的非限制性例子包括乙醇化物，甲醇化物，等等。“水合物”是其中溶剂分子是水的溶剂化物。
可以任选将本发明的一个或多个化合物转变为溶剂化物。溶剂化物的制备通常是已知的。典型的非限制性方法涉及：在高于环境温度下，将本发明的化合物溶解在目标数量的目标溶剂(有机溶剂或水或其混合物)中，以足以形成晶体的速度冷却该溶液，然后通过标准方法分离。分析技术例如，例如I.R.光谱，显示溶剂(或水)在溶剂化物(或水合物)形式的晶体中存在。
二、嘌呤胺衍生物类CDK2抑制剂的制备方法
本发明要求嘌呤胺衍生物类CDK2抑制剂(Ⅰ)的制备方法，式(Ⅰ)化合物可以采用下述流程中描述的方法和/或本领域普通技术人员已知的其它技术来合成，但不仅限于以下方法。
反应方程式：
步骤1：将原料1溶于乙酸乙酯中，加入DL-樟脑磺酸和3,4-2H-吡喃，65℃反应18-20小时，纯化，得到中间体1；
步骤2：将中间体1与原料2溶于二氧六环和水的混合溶液中，加入钯催化剂和碳酸钾，在氮气保护下于80-100℃反应6-12小时，纯化，得到中间体2；
步骤3：将中间体2与原料3溶于超干燥二氧六环中，加入钯催化剂和碳酸铯，在氮气保护下于100℃反应10-12小时，纯化，得到中间体3或将中间体2与原料3溶于二甲基亚砜中，加入三乙胺，于100℃反应6-20小时，纯化，得到中间体3；
步骤4：将中间体3加入氯化氢饱和的乙酸乙酯溶液中，室温搅拌过夜，过滤，干燥滤饼，纯化，得式(Ⅰ)化合物。
以上反应方程式中的R1和R2如前文所定义。必要时，可对需要保护的官能团进行保护，此后通过常规方法脱去保护基团；必要时，可根据化合物的性质，对反应溶剂进行适当的替换；必要时，根据化合物的性质，可省去某些化合物或者增加某些化合物的制备。
三、嘌呤胺衍生物类CDK2抑制剂的应用
以下通过部分本发明化合物的体外药理活性进一步阐述本发明化合物的有益效果，本发明其它化合物与试验中所列举的化合物具有相同的有益效果，但不应将此理解为本发明化合物仅具有下列有益效果。
实验例1：嘌呤胺衍生物类CDK2抑制剂的体外药理活性实验
供试品：本发明部分化合物，按照实施例方法制备；
实验方法：目标化合物酶学实验(enzyme assay)
本实验采用Kinase-Glo Plus发光激酶测定试剂盒。准确称取供试品，加入10％DMSO溶解，充分混匀并将5μL稀释液加入到50μL反应液中，使DMSO在所有反应中的最终浓度为1％。50μL反应混合物含有40mM Tri s、pH 7.4、10mM MgCl2、0.1mg/ml BSA、1mM DTT、10μM ATP、0.2μg/ml激酶和100μM底物。使用Kinase-Glo Plus发光激酶测定试剂盒进行测定。通过量化激酶反应后溶液中剩余的ATP量来测量激酶活性。测定的发光信号与溶液中存在的ATP的量相关，并且与激酶活性的量成反比。使用Prism GraphPad软件使用具有归一化剂量反应拟合的非线性回归计算IC50值。
采用GraphPad 5.0软件进行曲线拟合，拟合方程为Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))，得出IC50值。
表1.本发明化合物对CDK2的IC50值
表中数据均为三次实验结果平均值
结论，由表1数据可见，本发明化合物对CDK2有很好的抑制活性，化合物H4的抑制活性优于阳性药Roscovitine。
实验例2：嘌呤胺衍生物类CDK2抑制剂抑制肿瘤细胞增殖实验
选取CDK2抑制活性较好的目标化合物进行体外抑制肿瘤细胞增殖实验，结果见表2
1.[材料]
HCT-116,MDA-MB-231,MTT,10％胎牛血清,2.5g/L胰蛋白酶，改良型RPMI1640培养基，阳性对照药塞利西利(Roscovitine)，96孔板；
2.[方法]
常规培养细胞，用RPMI 1640培养基将对数生长期的细胞稀释至4×104个/mL，之后将细胞接种于96孔板中(每孔加100μL)，不加细胞的作为空白孔，放于恒温孵育箱(37℃，5％二氧化碳)中培养8小时；加入用培养基配制的目标化合物溶液和阳性药(Roscovitine)溶液，不加药的作为100％孔，于恒温孵育箱(37℃,5％二氧化碳)中培养48小时后加入30μLMTT，四小时后除去孔中液体(悬浮细胞需离心)，加150μL DMSO，最后于恒温摇床中振摇10min用酶标仪于570nm波长处测定每孔的吸光度值，计算抑制率和IC50值；
表2.目标化合物进行体外抑制肿瘤细胞增殖实验结果
表中数据均为三次实验的平均值，且偏差值不超过10％。
术语说明：人结肠癌细胞HCT116，人乳腺癌细胞MDA-MB-231。
结论：CDK2抑制活性较好的目标化合物H4对不同的肿瘤细胞均表现出较好的抗增殖活性，且优于阳性药Roscovit ine。
这些化合物可深入进行活性研究，开发出更有活性的化合物用于制备预防和治疗与CDK2功能异常相关的肿瘤等疾病。
因此，本发明还提供嘌呤胺衍生物类CDK2抑制剂在制备用于治疗和/或预防与由CDK2介导的信号通路有关的疾病的药物中的应用。
一种治疗和/或预防与由CDK2介导的信号通路有关的疾病的药物组合物，含有上述的嘌呤胺衍生物类CDK2抑制剂及其药学上可接受的盐与药用辅料，制成不同剂型的药物。
具体实施方式
以下通过实施例对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下实施例。
实施例1：3-(2-((3-硝基苯基)氨基)-9H-嘌呤-6-基)苯甲酸的制备2,6-二氯-9-(四氢-2H-吡喃-2-基)-9H-嘌呤的制备
将2,6-二氯嘌呤(10.00g,52.91mmol)溶于100mL的乙酸乙酯中，加入DL-樟脑磺酸和3,4-2H-吡喃(4.45g,52.91mmol)，65℃反应18小时，反应结束加入50mL的水，萃取三次，收集乙酸乙酯层，用无水硫酸镁干燥，浓缩经过柱层析纯化得8.05g白色固体。
3-(2-氯-9-(四氢-2H-吡喃-2-基))-9H-嘌呤-6-基苯甲酸甲酯的制备
将2,6-二氯-9-(四氢-2H-吡喃-2-基)-9H-嘌呤(1.00g,3.66mmol),3-甲氧基羰基苯硼酸(0.79g,4.39mmol),碳酸钾(1.52g,10.98mmol)和钯催化剂溶于30mL的二氧六环和水的混合溶液中，在氮气保护下于100℃反应10小时，反应结束后旋干有机溶剂，加入20mL的乙酸乙酯，萃取三次，收集乙酸乙酯层，用无水硫酸镁干燥，浓缩经过柱层析纯化得1.12g白色固体。
3-(2-(3-硝基苯基)氨基-9-(四氢-2H-吡喃-2-基))-9H-嘌呤-6-基苯甲酸甲酯的制备
将3-(2-氯-9-(四氢-2H-吡喃-2-基))-9H-嘌呤-6-基苯甲酸甲酯(1.00g,2.68mmol),间硝基苯胺(0.44g,3.22mmol),碳酸铯(2.62g,8.05mmol)和钯催化剂溶于30mL的超干二氧六环中，在氮气保护下于100℃反应10小时，反应结束后旋干有机溶剂，加入20mL的乙酸乙酯，萃取三次，收集乙酸乙酯层，用无水硫酸镁干燥，浓缩经过柱层析纯化得0.98g白色固体。
3-(2-((3-硝基苯基)氨基)-9H-嘌呤-6-基)苯甲酸甲酯的制备
将3-(2-(3-硝基苯基)氨基-9-(四氢-2H-吡喃-2-基))-9H-嘌呤-6-基苯甲酸甲酯(1.00g,2.11mmol)溶于10mL的氯化氢饱和的乙酸乙酯溶液中，室温搅拌过夜，过滤得0.78g黄色固体。
3-(2-((3-硝基苯基)氨基)-9H-嘌呤-6-基)苯甲酸的制备
将3-(2-((3-硝基苯基)氨基)-9H-嘌呤-6-基)苯甲酸甲酯(0.50g,1.28mmol)溶于30mL的甲醇和水的混合溶液中，室温搅拌过夜，旋干有机溶剂，用1M盐酸将溶液pH调至3～5，有固体析出，过滤得0.30g黄色固体。
LC/MS(M+H+):377.0998.
1H NMR(400MHz,DMSO)δ13.30(s,1H),13.15(s,1H),10.19(s,1H),9.51(s,1H),9.11(d,J＝7.8Hz,1H),9.08(s,1H),8.42(s,1H),8.16(dd,J＝16.5,7.9Hz,2H),7.80(d,J＝8.0Hz,1H),7.75(t,J＝7.6Hz,1H),7.60(t,J＝8.1Hz,1H).
实施例2：N-(3-硝基苯基)-6-(3-(氨基甲基)苯基)-9H-嘌呤-2-胺的制备
(3-((N-(3-硝基苯基)-9-(四氢-2H-吡喃-2-基)-9H-嘌呤-2-胺)-6-基)苄基)氨基甲酸叔丁酯的制备
将(3-(2-氯-9-(四氢-2H-吡喃-2-基)-9H-嘌呤-6-基)苄基)氨基甲酸叔丁酯(1.00g,2.25mmol),间硝基苯胺(0.37g,2.70mmol),碳酸铯(2.20g,6.76mmol)和钯催化剂溶于30mL的超干二氧六环中，在氮气保护下于100℃反应10小时，反应结束后旋干有机溶剂，加入20mL的乙酸乙酯，萃取三次，收集乙酸乙酯层，用无水硫酸镁干燥，浓缩经过柱层析纯化得0.88g白色固体。
N-(3-硝基苯基)-6-(3-(氨基甲基)苯基)-9H-嘌呤-2-胺的制备
将(3-((N-(3-硝基苯基)-9-(四氢-2H-吡喃-2-基)-9H-嘌呤-2-胺)-6-基)苯基)氨基甲酸叔丁酯(0.50g,0.92mmol)溶于10mL的氯化氢饱和的乙酸乙酯溶液中，室温搅拌过夜，过滤得0.25g黄色固体。
LC/MS(M+H+):362.1358.
1H NMR(400MHz,DMSO)δ10.20(s,1H),9.29(s,1H),8.84(d,J＝31.7Hz,2H),8.52(s,4H),8.07(d,J＝8.2Hz,1H),7.81(d,J＝8.1Hz,1H),7.76(s,1H),7.70(t,J＝7.6Hz,1H),7.61(t,J＝8.1Hz,1H),4.19(d,J＝5.4Hz,2H).
实施例3：N-(3-硝基苯基)-6-(4-(氨基甲基)苯基)-9H-嘌呤-2-胺的制备
(4-((N-(3-硝基苯基)-9-(四氢-2H-吡喃-2-基)-9H-嘌呤-2-胺)-6-基)苄基)氨基甲酸叔丁酯的制备
将(4-(2-氯-9-(四氢-2H-吡喃-2-基)-9H-嘌呤-6-基)苄基)氨基甲酸叔丁酯(1.00g,2.25mmol),间硝基苯胺(0.37g,2.70mmol),碳酸铯(2.20g,6.76mmol)和钯催化剂溶于30mL的超干二氧六环中，在氮气保护下于100℃反应10小时，反应结束后旋干有机溶剂，加入20mL的乙酸乙酯，萃取三次，收集乙酸乙酯层，用无水硫酸镁干燥，浓缩经过柱层析纯化得0.86g白色固体。
N-(3-硝基苯基)-6-(4-(氨基甲基)苯基)-9H-嘌呤-2-胺的制备
将(4-((N-(3-硝基苯基)-9-(四氢-2H-吡喃-2-基)-9H-嘌呤-2-胺)-6-基)苯基)氨基甲酸叔丁酯(0.50g,0.92mmol)溶于10mL的氯化氢饱和的乙酸乙酯溶液中，室温搅拌过夜，过滤得0.18g黄色固体。
LC/MS(M+H+):362.1356.
1H NMR(400MHz,DMSO)δ10.24(s,1H),9.23(s,1H),8.82(d,J＝7.7Hz,2H),8.63(s,4H),8.08(d,J＝8.1Hz,1H),7.79(dd,J＝16.3,7.9Hz,3H),7.60(t,J＝8.1Hz,1H).
实施例4:4-((6-(3-(氨基甲基)苯基)-9H-嘌呤-2-基)氨基)苯磺酰胺的制备(3-(2-((4-氨磺酰基苯基)氨基)-9-(四氢-2H-吡喃-2-基)-9H-嘌呤-6-基)苄基)氨基甲酸叔丁酯的制备
将(3-(2-氯-9-(四氢-2H-吡喃-2-基)-9H-嘌呤-6-基)苄基)氨基甲酸叔丁酯(1.00g,2.25mmol),磺胺(0.46g,2.70mmol),碳酸铯(2.20g,6.76mmol)和钯催化剂溶于30mL的超干二氧六环中，在氮气保护下于100℃反应10小时，反应结束后旋干有机溶剂，加入20mL的乙酸乙酯，萃取三次，收集乙酸乙酯层，用无水硫酸镁干燥，浓缩经过柱层析纯化得0.95g白色固体。
4-((6-(3-(氨基甲基)苯基)-9H-嘌呤-2-基)氨基)苯磺酰胺的制备
将(3-(2-((4-氨磺酰基苯基)氨基)-9-(四氢-2H-吡喃-2-基)-9H-嘌呤-6-基)苄基)氨基甲酸叔丁酯(0.50g,0.73mmol)溶于10mL的氯化氢饱和的乙酸乙酯溶液中，室温搅拌过夜，过滤得0.28g黄色固体。
LC/MS(M+H+):396.1164.
1H NMR(400MHz,DMSO)δ10.04(s,2H),8.79(s,3H),8.73–8.59(m,1H),8.50(d,J＝5.42Hz,2H),8.44(s,7H),8.09–8.02(m,4H),7.82–7.63(m,7H),7.20(s,3H),4.18(d,J＝6.00Hz,4H).
Claims (3)
1.嘌呤胺衍生物类CDK2抑制剂，或其药学上可接受的盐，其特征在于，为如下之一：
2.权利要求1所述的嘌呤胺衍生物类CDK2抑制剂在制备用于治疗和/或预防与由CDK2介导的信号通路有关的疾病的药物中的应用。
3.一种治疗和/或预防与由CDK2介导的信号通路有关的疾病的药物组合物，含有权利要求1所述的嘌呤胺衍生物类CDK2抑制剂及其药学上可接受的盐与药用辅料，制成不同剂型的药物。
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