CN108484613B - 一种吡唑并[1,5-a]嘧啶类化合物及其应用 - Google Patents
一种吡唑并[1,5-a]嘧啶类化合物及其应用 Download PDFInfo
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- CN108484613B CN108484613B CN201810494219.XA CN201810494219A CN108484613B CN 108484613 B CN108484613 B CN 108484613B CN 201810494219 A CN201810494219 A CN 201810494219A CN 108484613 B CN108484613 B CN 108484613B
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- cdk2
- pyrazolo
- pyrimidine
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- cancer
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Abstract
本发明公开了一种吡唑并[1,5‑a]嘧啶类化合物及其应用,属于医药领域。本发明的部分吡唑并[1,5‑a]嘧啶类化合物对CDK2的抑制活性达到40%以上,因此,本发明的化合物呈现较好的CDK2的抑制活性,可以被用作CDK2的抑制剂。本发明要求保护的化合物具有较强的对CDK2的抑制活性。对于开发适于用作CDK2抑制剂的药物方面具有重要的指导意义。
Description
技术领域
本发明涉及一种吡唑并[1,5-a]嘧啶类衍生物及其应用。属于医药领域。
技术背景
恶性肿瘤是一种危害人类健康的重大疾病,其发生发展是一个复杂的多级网络进程。基因突变及原癌基因异常激活都可能导致细胞异常增殖,进而引发肿瘤。细胞周期的调节是在检查点的监控下,各级调节因子依次激活或失活,从而推动细胞完成DNA复制以及细胞分裂的过程。在多种细胞周期调控因子中,细胞周期蛋白依赖性激酶(Cyclin dependentkinase,CDKs)处于核心位置,与细胞周期蛋白(Cyclins)、细胞周期依赖性激轉抑制因子(CKIs)等组成细胞周期调控网络系统。CDKs主要通过与相关周期蛋白,特异性内源抑制剂结合,改变自身磷酸化状态及其泛素降解等过程,在推动细胞周期进程中发挥关键作用。据统计,超过90%的人类癌症中出现CDK、Cyclin、CKI和Rb(retinobalastoma gene)途径中相关蛋白的异常表达,引发CDK功能失调的现象。基于CDKs在细胞周期调控中所处的核心地位,对肿瘤细胞中过度表达的CDKs进行抑制,从而有效遏制肿瘤细胞增殖已成为一种极具潜力的癌症治疗策略。
细胞周期蛋白依赖性激酶(Cyclin-dependent kinases,CDKs)属于丝氨酸/苏氨酸蛋白激酶家族,直接参与细胞周期的调控,促进细胞有序的生长、增殖和凋亡。细胞分裂周期分为4期:G1期、S期、G2期和M期,其中以G1-S调控点最为重要,其调控与CDKs紧密相关。CDKs通过与周期蛋白结合形成蛋白激酶复合物,该复合物可以催化底物磷酸化,控制细胞周期进程,依次完成DNA的复制与有丝分裂,引起细胞的分裂增殖。细胞分裂周期受到两种调控:抑制和促进,正常情况下两者处于动态平衡。但当促进细胞增殖的信号增强,或是抑制细胞增殖的信号减弱时,平衡就会被打破,细胞增殖就会失控,导致肿瘤的发生。研究表明,许多恶性肿瘤中都存在着CDKs的过度表达,如肝癌、乳腺癌、肺癌、淋巴癌等。
到目前为止,科学家发现的CDKs有13种亚型,其中,直接调控细胞周期的CDKs主要有CDK1、CDK2、CDK4和CDK6。它们在结构上有着共同的特征:都是由α-螺旋组成的C末端和β-折叠组成的N末端组成,ATP结合口袋位于这两末端的形成域之间。CDKs抑制剂可以占据ATP结合口袋的活性空腔,抑制蛋白激酶复合物的激活,诱导细胞凋亡,达到抗肿瘤的目的。
研究表明直接参与细胞周期调控的CDKs主要包括CDK1、CDK2、CDK4和CDK6,在调控细胞周期中发挥关键作用。细胞受到外界信号如生长因子等刺激时,催化亚基CDK4/6与调节亚基Cyclin结合,形成的复合物催化Rb蛋白使之磷酸化,磷酸化的Rb蛋白释放转录因子E2F,诱导Cyclin E和CDK2结合并形成CDK2/Cyclin E复合物,后者进一步磷酸化Rb蛋白,充分释放E2F,推动细胞周期由G1期进入S期,随后CDK2/Cyclin E复合物由于Cyclin E自身泛素化降解,由CDK2与Cyclin A形成复合物,参与DNA复制。
CDK2属于CDKs家族中的一员。它是细胞有丝分裂完成G1期和由G1期进入S期至关重要的细胞周期依赖性激酶。在G1后期,CDK2与Cyclin E结合并活化,促使pRb持续磷酸化,保证细胞顺利通过G1期并进入S期。E2F的钝化是S期完成的首要条件,在S期初期,CDK2与Cyclin A结合使E2F转录因子钝化,从而促使细胞顺利完成S期。然而E2F持续的活性将导致细胞凋亡,所以,选择性地抑制CDK2/Cylin A的活性,使E2F的浓度升高,进而导致细胞周期停滞在S期或发生凋亡,从而达到治疗肿瘤细胞的目的。
迄今为止,国内外已报道的小分子抑制剂均为竞争性抑制刘,具有多种不同的结构类型,主要包括:嘌呤衍生物及其类似物、黄酮类衍生物、吲哚及吲哚酮衍生物、吲唑及氮杂吲唑类衍生物、吡唑衍生物等,其中嘌呤衍生物R-roscovitine、黄酮类衍生物flavopiridol、氨基吡唑类化合物AT7519、氨基噻唑类化合物SNS-032和氮杂吲唑类化合物AG024322等多个小分子抑制剂目前正处于期临床试验,对多种恶性胖瘤具有较好的治疗作用。嘌呤衍生物及其类似物是一类最早出现的CDKs抑制剂,由于嘌呤类似物与ATP母核具有极大相似性,并且在目前进入临床试验及临床前研究的小分子抑制剂中占据较大的比例,所以一直以来是小分子抑制剂的研究热点之一。
发明内容
本发明的目的在于提供一种新型吡唑并[1,5-a]嘧啶类似物,其结构如式I所示的化合物或其药学上可接受的盐,该类新型小分子活性化合物具有抑制细胞周期蛋白依赖性酶家族(CDKs)的生物学功能,从而为寻找新的治疗癌症、代谢与免疫疾病、心血管病以及神经性疾病等开辟新途径。
本发明的第一个目的是提供一种吡唑并[1,5-a]嘧啶类似物或其药学上可接受的盐,如以下通式I所示。
在通式I中,
R1选自-CN、-COOH、-CH2NH2、-COOR、未取代或卤素取代的C1-C8直链或支链烷基或者未取代或卤素取代的C3-C6环烷基;R2选自H、芳香环及芳杂环、卤素或-CF3;R3、R4、R5、R6各自独立地选自H、卤素、-CF3、未取代或卤素取代的C1-C6直链或支链烷基;R7为C1-C8直链或支链烷基胺、C3-C6环烷基胺、C1-C8氧基、C1-C8直链或支链烷基氨基醇、C3-C6环烷基氨基醇、C1-C5烷氧基醇、杂环基醇、氨基芳香酚及醇、巯基芳香酚及醇、哌嗪、吗啉。其中,卤素表示氟、氯、溴或碘。
在本发明的一种实施方式中,R1选自-CN、-CH2NH2、未取代或卤素取代的C1-C5直链或支链烷基或者未取代或卤素取代的C3-C5环烷基;R2选自H、芳香环及芳杂环、卤素。其中,卤素表示氟、氯、溴或碘。
在本发明的一种实施方式中,R3、R4、R5、R6各自独立地选自H、卤素、未取代或卤素取代的C1-C3直链或支链烷基或-CF3,R7选自C1-C5直链或支链烷基胺、C3-C6环烷基胺、C1-C5烷氧基、C1-C5直链或支链烷基氨基醇、C3-C6环烷基氨基醇、C1-C5烷氧基醇、杂环基醇、氨基芳香酚及醇、巯基芳香酚及醇、哌嗪、吗啉。其中,卤素表示氟、氯、溴或碘。
在本发明的一种实施方式中,R1选自-CN、-CH2NH2、正丁基、异丙基或环戊基。
在本发明的一种实施方式中,R2选自H、苯基及吡啶基、氯、氟。
在本发明的一种实施方式中,R3、R4、R5、R6各自独立地为H或卤素。
在本发明的一种实施方式中,R7选自乙醇氨、乙二醇、3-氨基-1-丙醇、4-氨基-1-丁醇、5-氨基-1-戊醇、1-氨基-2-甲基丙-2-醇、4-氨基苯酚、4-羟甲基哌啶、3-羟甲基哌啶、1-氨基-2-丙醇、2-氨基-1-丁醇、4-羟基哌啶、(R)-(-)-2-氨基-1-丁醇、3-氨基正丁醇、DL-亮氨醇、吗啉、乙二醇胺、3-羟基哌啶、D-缬氨醇、2-氨基-3,3-二甲基丁-1-醇、DL-苯甘氨醇、4-氨基环己醇。
在本发明的一种实施方式中,a为0。
在本发明的一种实施方式中,a为1。
本发明的第二个目的是提供了一种药物组合物,包含所述吡唑并[1,5-a]嘧啶类似物或其药学可接受的盐。
在本发明的一种实施方式中,所述组合物含有所述化合物或其衍生物,以及药学上可接受的载体。
在本发明的一种实施方式中,所述组合物包含通式I的化合物或其药学可接受的盐以及至少一种药学可接受的赋形剂、载体和/或稀释剂。
本发明的第三个目的是提供一种制备所述化合物的方法,所述方法通过以下反应式进行:
其中,以上反应式中,R1、R2、R3、R4、R5、R6、R7与上文定义相同。X为卤素。
本发明的第四个目的是提供所述通式I的化合物或其药学可接受的盐在制备用作CDK抑制剂的药物中的用途。
本发明的第五个目的是提供所述通式I的化合物或其药学可接受的盐在制备用于预防或治疗癌症的药物中的用途。
另一方面,本发明提供了上述通式I的化合物或其药学可接受的盐在制备用作CDK2抑制剂的药物中的用途。
特别地,所述癌症选自膀胱癌、乳腺癌、结肠癌、直肠癌、肾癌、表皮癌、肝癌、肺癌、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌、鼻癌、头颈癌、前列腺癌、皮肤癌、淋巴系的造血细胞肿瘤、髓系造血细胞肿瘤、甲状腺滤泡癌、源于间质细胞肿瘤、中枢或周围神经系统肿瘤、黑素瘤、神经胶质瘤、精原细胞瘤、畸胎瘤、骨肉瘤、着色性干皮病、角化棘细胞瘤、甲状腺滤泡癌或卡波西肉瘤。
在本发明的一种实施方式中,所述淋巴系的造血细胞肿瘤选自白血病、急性淋巴性白血病、慢性淋巴细胞白血病、B-细胞淋巴瘤、T-细胞淋巴瘤、多发性骨髓瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤或伯基特氏淋巴瘤。
本发明的第六个目的是提供所述通式I的化合物在制备食品、保健品方面的应用。
有益效果:
本发明的化合物多数具有较好的CDK2抑制活性。因此,本发明的的化合物可以被用作CDK2的抑制剂。本发明要求保护的化合物具有较强的对CDK2的抑制活性。这在开发适于用作CDK2抑制剂的药物方面是有利的。
具体实施方式
术语“药学上可接受的”是指当给入施用时生理上可耐受的并且一般不产生过敏或相似不适当的反应,例如肠胃不适、眩晕等的分子实体和组合物。优选地,本文所用的术语“药学上可接受的”是指联邦监管机构或国家政府批准的或美国药典或其他一般认可的药典上列举的在动物中、更特别在人体中使用的。
本文所用的“烷基”是指直链或支链饱和烃基基团。在一些实施方案中,烷基基团可具有1至10个碳原子(例如1至8个碳原子)。烷基基团的实例包括甲基(Me)、乙基(Et)、丙基(例如,正丙基和异丙基)、丁基(例如,正丁基、异丁基、仲丁基、叔丁基)、戊基基团(例如,正戊基、异戊基、新戊基)、己基(例如,正己基及其异构体)等。低级烷基基团一般最多有4个碳原子。低级烷基基团的实例包括甲基、乙基、丙基(例如正丙基和异丙基)和丁基基团(例如正丁基、异丁基、仲丁基、叔丁基)。在一个实施方案中一个烷基基团或两个或多个烷基基团可形成桥连的烷基基团。即其中烷基基团经另一个基团连接(特别显示于环状基团),通过烷基链桥连形成环,即,形成桥连的稠合环。
如本文所用,“环烷基”是指非芳香碳环基团,包括环状烷基、链烯基和炔基基团。环烷基基团可以是单环(例如环己基)或多环(例如,包含稠合、桥连和/或螺环体系),其中碳原子位于环体系内部或外部。环烷基基团作为整体可具有3至14个环原子(例如,3至8个碳原子用于单环环烷基基团和7至14个碳原子用于多环环烷基基团)。环烷基基团的任何适宜环上位置可与所定义的化学结构共价连接。环烷基基团的实例包括环丙基、环丁基、环戊基、环己基、环庚基、环戊烯基、环己烯基、环己二烯基、环庚三烯基、冰片基、norpinyl、norcaryl、金刚烷基和螺[4.5]癸基,及其同系物、异构体等。
本发明包括化合物的全部药学上可接受的同位素标记化合物,其中一个或多个原子被有相同原子数的原子替换,但原子质量或质量数与通常见于自然中的原子质量或质量数不同。
适于包含在本发明化合物中的同位素实例包括氢的同位素,例如2H和3H,碳,例如11C、13C和14C氮例如13N和15N,氧例如15O、17O和18O。
用较重的同位素例如氘即2H取代可提供某些治疗优势,其有更好的代谢稳定性,例如,体内半衰期增加或降低了剂量需求,并因此在某些情况下优选。
以下将通过实施例详细描述本发明的以上化合物1-38的合成方法。
制备实施例
中间体的制备
氨基-1H-吡唑-4-甲腈
将丙二腈(16.5g,0.25mol),原甲酸三乙酯(38g,0.29mol)和乙酸酐(55g,0.54mol)加入到1L的三颈瓶中,缓慢加热至115℃,回流反应2h。将混合物温度降到20℃,40分钟内滴加水合肼(15.5g,0.31mol),温度保持在18-22℃。然后20-30℃下反应18h。TLC监测反应,于25℃下用氢氧化钠水溶液(36g氢氧化钠溶解在72ml水中)中和得到奖状混合物,加热混合物,共沸蒸馏,共收集45ml馏分。此馏分在0-5℃下冷却1.5h,收集浅褐色固体,用冷水淋洗,自然干燥,得到产品(19.2g,72%收率)。MS(ESI)m/z:109.5[M+H]+。1H-NMR(DMSO,400MHz)δ:12.51(s,1H),8.94(s,1H),6.27(s,1H)。
3-氰基-5-氯甲基-7-羟基吡唑并[1,5-a]嘧啶
在250ml三颈瓶中用100ml冰乙酸作为溶剂,加入3-氨基-4-氰基-吡唑(10.8g,0.1mol)和氯乙酸乙酰乙酯(23g,0.15mol),加热至80℃左右原料基本溶解,回流反应4小时,有固体生成,TLC监测反应完毕后将反应液冷却至室温,过滤,用冰醋酸淋洗,自然干燥,得到乳黄色固体(19.7g,95%收率)。MS(ESI)m/z:209.1[M+H]+。1H-NMR(DMSO,400MHz)δ:11.20(s,1H),8.72(s,1H),5.34(s,1H),4.34(d,J=8,2H)。
3-氰基-5-氯甲基-7-氯吡唑并[1,5-a]嘧啶
将3-氰基-5-氯甲基-7-羟基吡唑并[1,5-a]嘧啶(82g,0.36mol)和吡啶(34g,0.43mol)加入1L三颈瓶中,滴加POCl3(90g,0.59mol),缓慢加热,当温度到达85℃时,开启搅拌,在120℃下反应1小时,当反应液变成黑亮浆状物时TLC监测反应完毕。将反应液冷却至室温,缓慢倒入冰水中,加入二氯甲烷(100ml×3)萃取,分液,合并有机层,有机层干燥旋干,通过柱层析(洗脱剂:石油醚:乙酸乙酯=1:1)纯化,得到土黄色固体(70g,78%收率)。MS(ESI)m/z:228.15[M+H]+。1H-NMR(CDCl3,400MHz)δ:8.70(s,1H),7.42(s,1H),4.32(s,2H)。
3-氰基-5-氯甲基-7-苯胺基吡唑并[1,5-a]嘧啶(中间体A1)
将3-氰基-5-氯甲基-7-氯吡唑并[1,5-a]嘧啶(5g,17mmol)和正丁醇(50ml)加入单口烧瓶中,开启搅拌,向其中滴加苯胺(2.5g,27mmol)和三乙胺(2.74g,27mmol),逐渐升温至110℃,在该条件下反应3h,TLC监测反应,混合物冷却至20℃,有固体析出,固体抽滤,用正丁醇(10ml×3)洗,然后真空干燥得产物(4.42g,92%收率)。MS(ESI)m/z:284.15[M+H]+。1H-NMR(CDCl3,400MHz)δ:8.32(s,1H),8.20(s,1H),7.56–7.52(t,J=8,2H),7.42–7.38(t,J=8,3H),6.71(s,2H),4.61(s,2H)。
3-氰基-5-氯甲基-7-苄胺基吡唑并[1,5-a]嘧啶(中间体A2)
除了使用苄胺代替苯胺以外,以与3-氰基-5-氯甲基-7-苯胺基吡唑并[1,5-a]嘧啶的合成方法类似的方法合成3-氰基-5-氯甲基-7-苄胺基吡唑并[1,5-a]嘧啶。MS(ESI)m/z:298.05[M+H]+。1H-NMR(CDCl3,400MHz)δ:8.24(s,1H),7.44–7.37(m,5H),6.44(s,1H),4.67–4.66(d,J=4,2H),4.62(s,2H)。
3-氰基-5-氯甲基-7-对氟苯胺基吡唑并[1,5-a]嘧啶(中间体A3)
除了使用对氟苯胺代替苯胺以外,以与3-氰基-5-氯甲基-7-苯胺基吡唑并[1,5-a]嘧啶的合成方法类似的方法合成3-氰基-5-氯甲基-7-对氟苯胺基吡唑并[1,5-a]嘧啶。MS(ESI)m/z:302.05[M+H]+。1H-NMR(CDCl3,400MHz)δ:8.32(s,1H),8.10(s,1H),7.40–7.36(m,2H),7.25–7.23(d,J=8,2H),6.56(s,1H),4.60(s,2H)。
3-氰基-5-氯甲基-7-对氯苯胺基吡唑并[1,5-a]嘧啶(中间体A4)
除了使用对氯苯胺代替苯胺以外,以与3-氰基-5-氯甲基-7-苯胺基吡唑并[1,5-a]嘧啶的合成方法类似的方法合成3-氰基-5-氯甲基-7-对氯苯胺基吡唑并[1,5-a]嘧啶。MS(ESI)m/z:319.02[M+H]+。1H-NMR(CDCl3,400MHz)δ:8.32(s,1H),8.14(s,1H),7.52–7.50(m,2H),7.35–7.33(d,J=8,2H),6.67(s,1H),4.62(s,2H)。
除了使用联苯胺代替苯胺以外,以与3-氰基-5-氯甲基-7-苯胺基吡唑并[1,5-a]嘧啶的合成方法类似的方法合成3-氰基-5-氯甲基-7-联苯胺基吡唑并[1,5-a]嘧啶。MS(ESI)m/z:360.10[M+H]+。1H-NMR(CDCl3,400MHz)δ:8.32(s,1H),7.91–7.55(m,9H),6.67(s,1H),4.62(s,2H)。
3-氰基-5-氯甲基-7-联苯胺基吡唑并[1,5-a]嘧啶(中间体A5)
除了使用联苯胺代替苯胺以外,以与3-氰基-5-氯甲基-7-苯胺基吡唑并[1,5-a]嘧啶的合成方法类似的方法合成3-氰基-5-氯甲基-7-联苯胺基吡唑并[1,5-a]嘧啶。MS(ESI)m/z:360.10[M+H]+。1H-NMR(CDCl3,400MHz)δ:8.32(s,1H),7.91–7.55(m,9H),6.67(s,1H),4.62(s,2H)。
5-(氯甲基)-7-((4-(吡啶-4-基)苯基)氨基)吡唑并[1,5-a]嘧啶-3-腈(中间体A6)
除了使用4-吡啶苯胺代替苯胺以外,以与3-氰基-5-氯甲基-7-苯胺基吡唑并[1,5-a]嘧啶的合成方法类似的方法合成5-(氯甲基)-7-((4-(吡啶-4-基)苯基)氨基)吡唑并[1,5-a]嘧啶-3-腈。MS(ESI)m/z:361.10[M+H]+。1H-NMR(CDCl3,400MHz)δ:8.32(s,1H),8.71(d,J=7.9Hz,2H),8.0(d,J=7.9Hz,2H),7.55(d,J=7.9Hz,2H),7.37(d,J=7.9Hz,2H),6.67(s,1H),4.62(s,2H)。
3-(氨基甲基)-N-苄基-5-(氯甲基)吡唑并[1,5-a]嘧啶-7-胺(中间体A7)
将中间体A4(1.04g,3.3mmol)溶解在无水的THF中,冰浴条件下,缓慢加入四氢铝锂(0.25g,6.6mmol),加毕,移至室温下,缓慢加热至50℃反应5h。TLC监测反应,冷却至室温,缓慢倒入冰水中淬灭反应,加入二氯甲烷(20mL×3)进行萃取,分液,合并有机层,无水硫酸钠干燥,柱层析纯化(二氯甲烷:甲醇=10:1)得到白色产物(0.86g,87%收率)。1H-NMR(CDCl3,400MHz)δ:8.24(s,1H),7.44–7.37(m,4H),6.44(s,1H),4.67–4.66(d,J=4,2H),4.62(s,2H),4.31(s,2H)。
叔丁基哌嗪-1-甲酸叔丁酯(中间体B1)
将哌嗪(1g,11.6mmol)、二碳酸二叔丁酯(2.52g,11.6mmol)和DCM(10mL)加入25mL反应瓶中,搅拌溶解,反应体系冷却至0℃,滴加三乙胺(1.75g,17.4mmol),滴毕,反应体系移至室温下搅拌反应过夜。TLC监测反应,加入水(10mL)稀释,用二氯甲烷(10mL×3)进行萃取,分液,合并有机层,干燥,减压蒸除大部分溶剂,逐滴滴加正己烷有固体析出,抽滤,固体用正己烷洗三次,烘干得白色固体(1.94g,90%收率)。MS(ESI)m/z:187.4[M+H]+。1H-NMR(CDCl3,400MHz)δ:3.21(t,J=8.6Hz,4H),2.81(t,J=8.6Hz,4H),1.42(s,9H)。
实施例1
7-(苄基氨基)-5–(((2-羟基乙基)氨基)甲基)吡唑并[1,5-a]嘧啶-3-腈(化合物1)的合成
将中间体A2(1.0g,3.3mmol)、乙醇胺(2.0g,33mmol)、乙醇(5mL)加入25mL反应瓶中,搅拌溶解,加热回流至100℃反应5h。TLC监测反应,冷却至室温,将反应液转移到100mL锥形瓶,加入水(20mL),然后用二氯甲烷(20mL×3)进行萃取,分液,合并有机层,干燥,柱层析纯化(二氯甲烷:甲醇=10:1)得淡黄色固体(0.96g,90%收率)。MS(ESI)m/z:323.1[M+H]+。
实施例2
7-(苄基氨基)-5–((2-羟基乙氧基)甲基)吡唑并[1,5-a]嘧啶-3-腈(化合物2)的合成
将中间体A2(1.0g,3.3mmol)、乙二醇(0.41g,6.6mmol)、无水THF(5mL)加入25mL反应瓶中,搅拌溶解,室温条件下加入NaH(0.16g,6.6mmol),反应体系升温至50℃反应10h。TLC监测反应,冷却至室温,将反应体系缓慢加入冰水中淬灭。加入二氯甲烷(30mL×3)进行萃取,减压蒸除大部分溶剂,向浓缩液中逐滴滴加石油醚(10mL),有固体析出,抽滤,石油醚洗三次,烘干得白色固体(0.91g,0.85%收率)。MS(ESI)m/z:324.1[M+H]+。
实施例3
7-(苄基氨基)-5–(((4-羟基苯基)硫基)甲基)吡唑并[1,5-a]嘧啶-3-腈(化合物20)的合成
将中间体A2(1.0g,3.3mmol)、4-羟基苯硫酚(0.62g,4.95mmol)、碳酸钾(0.68g,4.95mmol)和丙酮(5mL)加入25mL反应瓶中,搅拌溶解,反应体系加热至回流持续24h,然后冷却至室温,TLC监测反应,向反应体系中加入正己烷(10mL),有固体析出,抽滤,正己烷洗涤固体三次,烘干得白色固体(1.0g,80%收率)。MS(ESI)m/z:388.2[M+H]+。
实施例4
7-(苄基氨基)-5-(哌嗪-1-基甲基)吡唑并[1,5-a]嘧啶-3-腈(化合物22)的合成
将中间体A2(1.0g,3.3mmol)、中间体B1(6.13g,33mmol)、乙醇(10mL)加入25mL反应瓶中,搅拌溶解,反应体系加热至100℃回流反应5h。TLC监测反应,冷却至室温,加入水(20mL),用二氯甲烷(20mL×3)进行萃取,分液,合并有机层,干燥,柱层析纯化(二氯甲烷:甲醇=10:1)得白色固体。将该白色固体溶解在氯化氢的1,4-二氧六环溶液中,室温下搅拌反应1h,有固体析出,抽滤,用1,4-二氧六环洗三次得白色固体(0.86g,75%收率)。MS(ESI)m/z:348.6[M+H]+。
实施例5
化合物3-19、21、23-44的合成
分别采用不同的中间体,按照与上述化合物1或2类似的合成方法,合成以下表1中的化合物。
表1
在以下表2中列出通过以上方法制备的化合物的氢谱数据。
表2
实施例6:化合物对CDK2的抑制实验
实验材料
CDK2/CycA2((eurofins,Cat.No:14-448M,Lot.No:D8CN058U,GST-CDK2(1-298(end)))
Peptide FAM-P8(GL Biochem,Cat.No.114202,Lot.No.P080319-XY114202)
ATP(Sigma,Cat.No.A7699-1G,CAS No.987-65-5)
DMSO(Sigma,Cat.No.D2650,Lot.No.474382)
EDTA(Sigma,Cat.No.E5134,CAS No.60-00-4)
96孔板(Corning,Cat.No.3365,Lot.No.22008026)
384孔板(Corning,Cat.No.3573,Lot.No.12608008)
Staurosporine(MCE,Cat.No.HY-15141,Lot.No.19340)
实验操作
1.配制1x激酶碱性缓冲液以及终止缓冲液
1)用于CDK2的1x激酶碱性缓冲液
用纯化水配制10ml溶液,包括50mM HEPES,,pH 7.5,0.0015%Brij-35。
2)用于CDK2的1x激酶碱性终止液
用纯化水配制10ml溶液,包括100mM HEPES,pH 7.5,0.015%Brij-35、0.2%涂层试剂#3以及50mM EDTA。
2.准备化合物
1)用100%DMSO稀释化合物50倍到最终的想要的抑制剂浓度。转移100uL化合物稀释液到96孔板中的一个孔。例如,如果想要的抑制剂浓度是500nM,然后这一步中需要准备25uM。
2)加100uL 100%DMSO到两个空的孔中,没有对照化合物,没有对照酶,标记这个板作为来源板。
3)准备中间板,从来源板中转移10uL到一个新的96孔板中作为中间板,加90uL 1×激酶缓冲液到中间板的每一个孔,在中间板上混合化合物,振动器振动10min。
3.准备实验板
1)从中间96孔板中的每一个孔转移5uL到一个384孔板中,一式两份。例如,96孔板中的所有A1转移到394孔板中的A1和A2。96孔板中的A2转移到384孔板上的A3和A4,依次进行。
4.激酶反应
1)配制2.5x激酶溶液
将5ug的cdk2激酶加入2.5ml的1x激酶碱基缓冲液中配制成酶溶液。
2)配制2.5x多肽溶液
加入FAM标记的多肽和ATP到1×激酶碱性缓冲液。
3)配制500nM的待测化合物的DMSO缓冲液溶液
先配制25uM化合物的DMSO溶液,取10ul的化合物的DMSO溶液,向其中加入90ul的1x激酶碱基缓冲液。混合10min得到化合物在10%DMSO中的溶液。在384孔板上加入5μl的化合物在10%DMSO中的溶液。
4)将2.5x酶溶液转移到测定板上
向384孔分析板的每个孔中加入10μl 2.5x酶溶液。
5)在室温下孵育10分钟。
6)将2.5x肽溶液转移到测定板。向96孔测定板的每个孔中加入10μl的2.5x肽溶液。
7)激酶反应终止
在28℃烘箱中孵育1h。加入25μl终止缓冲液终止反应。用Caliper仪器检测。
抑制率=[(A-B)-(C-D)]/(A-B)*100%
A:不含样品但含CDK2激酶的阴性对照组吸光值;
B:不含样品和CDK2激酶的空白对照组吸光值;
C:包含样品和CDK2激酶的实验组吸光值;
D:包含样品但不含CDK2激酶的空白对照组吸光值。
在以下表3中显示化合物1-38(浓度为500nM)对CDK2的抑制率。
表3
化合物 | CDK2抑制率% | 化合物 | CDK2抑制率% |
1 | 38 | 20 | 49.6 |
2 | 60 | 21 | 34.3 |
3 | 22.4 | 22 | 45.6 |
4 | 30.4 | 23 | 16.2 |
5 | 27.8 | 24 | 15.8 |
6 | 33.8 | 25 | 6.6 |
7 | 18.6 | 26 | 13.8 |
8 | 22.4 | 27 | 11.8 |
9 | 29.2 | 28 | 8.4 |
10 | 36.6 | 29 | 34.4 |
11 | 32.8 | 30 | 27.8 |
12 | 6.4 | 31 | 30.4 |
13 | 40.2 | 32 | 23.8 |
14 | 30.4 | 33 | 33.8 |
15 | 34.6 | 34 | 36.6 |
16 | 23.8 | 35 | 7.6 |
17 | 12.2 | 36 | 41.8 |
18 | 49.4 | 37 | 22.2 |
19 | 28.4 | 38 | 27.4 |
从以上表3可以看出,本发明的多数化合物对CDK2均具有较好的抑制作用,可以用来作为CDK2抑制剂。
以上实施例仅为本发明的示例性实施例,不用于限制本发明,本发明的保护范围由权利要求书限定。本领域技术人员可以在本发明的实质和保护范围内,对本发明做出各种修改或等同替换,这种修改或等同替换也应视为落在本发明的保护范围内。
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