CN110357885A - 一种蝶啶类化合物及其在药学上的应用 - Google Patents
一种蝶啶类化合物及其在药学上的应用 Download PDFInfo
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- CN110357885A CN110357885A CN201910672270.XA CN201910672270A CN110357885A CN 110357885 A CN110357885 A CN 110357885A CN 201910672270 A CN201910672270 A CN 201910672270A CN 110357885 A CN110357885 A CN 110357885A
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- pharmaceutically acceptable
- acceptable salt
- stereoisomer
- alkyl
- pteridine
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Abstract
本发明公开了一种蝶啶类化合物及其在药学上的应用,属于医药领域。本发明蝶啶类衍生物或其立体异构体或其药学上可接受的盐具有通式(I)或(II)所示的结构,对CDK4的抑制活性均达47%以上,较高可达79%,呈现非常好的CDK4/6的抑制活性,可以被用作CDK4/6的高效抑制剂,具有非常广阔的应用前景。
Description
技术领域
本发明涉及一种蝶啶类化合物及其在药学上的应用,属于医药领域。
背景技术
癌症是影响人类健康的主要疾病之一,现已成为全球重要的公共卫生问题。据2015年国家统计局数据显示,我国恶性肿瘤的发病率约占全球恶性肿瘤发病率的21.8%,总体位于中等偏上水平。恶性肿瘤死亡率在中国居民各类疾病的死亡率中位列第一,主要包括肺癌、肝癌、胃癌、食道癌、结直肠癌和乳腺癌,是一种严重威胁居民公共健康的重大疾病。在女性肿瘤患者中,乳腺癌发病率最高。每年我国女性乳腺癌发病人数达16.9万,占全球总发病人数的12.2%。目前,晚期乳腺癌常用的治疗方式有化疗、内分泌治疗、抗人类表皮生长因子受体2(HER2)治疗等。
随着肿瘤分子生物学与肿瘤药理学的研究与发展,恶性肿瘤的治疗药物也从传统的细胞毒性药物逐步向特异性强的分子靶向药物过渡。所谓分子靶向治疗就是针对肿瘤发生、发展过程中的关键大分子,通过特异性阻断肿瘤细胞的信号转导,来控制其基因表达并改变其生物学行为;或是阻止肿瘤血管的生成从而抑制肿瘤细胞的生长和增殖,达到抗肿瘤的作用。大多数靶向治疗药物都是单克隆抗体或小分子激酶抑制剂,单克隆抗体主要与细胞表面特异性分子结合,而小分子抑制剂则是进入细胞内发挥特定的作用。细胞周期是生命体内的一个基本过程,细胞周期控制细胞从静止期或胞质分裂期到细胞增殖的转变,在各个检查点严格把控,确保基因组稳定遗传。细胞周期素依赖性激酶(CDK)和细胞周期素(cyclin)是参与调控细胞周期的关键分子,CDK处于整个调控网络的核心,并且大多数肿瘤细胞中的CDK有过度表达的现象。研究统计显示,有超过90.0%的人类癌症中Cdks、Cyclins和Rb(人视网膜母细胞瘤蛋白)途径中相关基因发生了变异,其中Cdk和其相应的调节亚基Cyclin的失常最为频繁。因此恢复细胞周期正常的Cdk-Cyclin活性调控是治疗肿瘤的策略之一。因此,Cdks成为抗肿瘤治疗中令人关注的分子治疗靶点。
细胞周期蛋白依赖性激酶(Cyclin dependent kinases,Cdks)属于丝/苏氨酸蛋白激酶家族,是参与细胞周期调节的关键激酶,在细胞周期的各个阶段发挥着不同的作用。细胞的增殖和分裂需要有序地经过细胞周期,该进程主要由周期素(cyclin)和周期素依赖性激酶(Cyclin-dependent kinase,CDK)复合物驱动。CDK-cyclin复合物在发挥生理功能时需要与ATP结合,若能阻碍ATP进入CDK-cyclin复合物的活化区域,就能阻碍肿瘤细胞增殖的过程。
细胞周期素依赖性激酶(CDK)是细胞周期进程中的一个正性调控蛋白激酶家族。直接参与调节细胞周期的CDK有CDK1、CDK2、CDK4、CDK6和CDK7。CDK4/6与细胞周期蛋白cyclin D结合,主要调控G1期,为DNA复制储备RNA和蛋白质;而后CDK2-cyclin E调控细胞由G1期进入S期,细胞处于S期时由CDK2-cyclin A调控,合成DNA并为有丝分裂做准备;进入G2/M期后由CDK1-cyclin A、B所控制,细胞进行有丝分裂;CDK7-cyclin H在整个细胞周期中一直保持活化状态,通过磷酸化T-loop的苏氨酸进一步促进CDK的激活。与癌症有关的细胞周期突变主要存在于G1期和G1/S期转化过程中,而CDK4/6主要调控这个过程,因此,CDK4/6成为一种新的抗肿瘤靶点。
自发现Cdks以来,研究者们一直致力于寻找其抑制剂,期望通过抑制Cdks的作用来杀死肿瘤细胞。通过对Cdks作用机制及构效关系的研究,新的Cdk抑制剂被不断发现,根据这些抑制剂的的发展历程、结构类型及目前临床的研究现状,可将其分为三代:第一代泛Cdk抑制剂,比如Flavopiridol,是一种半合成黄酮类化合物,是由印度本地植物分离得到的一种生物碱Rohitukine经过结构修饰得到。它属于广谱的激酶抑制剂,纳摩尔浓度的Flavopiridol可抑制Cdks 1、2、4、6、7和9的活性诱导G1或G2/M期的细胞周期停滞。Flavopiridol是第一个进入临床试验的Cdk抑制剂,并且已经进行了多项临床试验,在肿瘤学领域已有数年的发展。但是其对靶点的选择性低,发生许多副作用;第二代较低选择性抑制剂,比如嘌呤类、嘧啶类、吡唑并喹唑啉类等。6-N,N-二甲基腺嘌呤(IC50=16.0μM)是最早的嘌呤类抑制剂,最初它是作为嘌呤霉素被人们熟知。研究者利用生物电子等排体原理合成吡唑并嘧啶类衍生物,其中药效活性最好的是SCH-727965,它对多个靶点都有较高的抑制活性,如Cdk1、Cdk2、Cdk5和Cdk9等。对Cdk2的抑制活性非常好,IC50达到1.0nM。第三代Cdk抑制剂主要是对Cdk4/6高选择性的抑制剂,它们的毒性副作用相比于前两代大大减小。比如Cdk4/6抑制剂Palbociclib、Ribociclib等。因此,有望在临床上得到广泛的应用。由于这类抑制剂研发难度较高,目前已经上市的仅有三种Cdk4/6抑制剂:Palbociclib、Ribociclib和Abemaciclib。这三种化合物对Cdk4和Cdk6半数抑制浓度(IC50)值均小于40.0nM,对其他Cdk家族成员的选择性要高得多。
Cdk4/6即细胞周期依赖性激酶4/6,是细胞周期中G1期重要的调控分子,能特异性地和Cyclin D1结合形成复合物。Cdk4的基因位于12q,编码分子量为33×103kDa的蛋白质。可磷酸化人视网膜母细胞瘤蛋白(Retinoblastoma protein,Rb),释放E2Fs转录因子,使细胞顺利通过细胞周期G1/S检测点,细胞周期得以继续进行。抑制Cdk4/6则可通过Cdk4-Rb通路诱导细胞周期停滞于G1/S期,从而抑制细胞增殖。研究发现,Cdk4/6在许多肿瘤细胞中高表达,Cdk4/6选择性抑制剂的抗癌作用已得到临床验证。来自辉瑞公司的全球首款Cdk4/6抑制剂Palbociclib的加速获批上市也进一步证明Cdk4/6是一类重要的抗肿瘤作用靶点。
Cdk4/6信号通路是当细胞受到外界信号如表皮生长因子(Epidermal growthfactor,EGF)等刺激时,催化亚基Cdk4/6就会与调节亚基Cyclin D结合,形成的Cdk4/6-CyclinD复合物,该复合物能够催化激活Rb蛋白并使其磷酸化,磷酸化的Rb(Retinoblastoma gene)蛋白释放出转录因子E2F,E2F诱导调节亚基CyclinE与催化亚基Cdk2结合并形成Cdk2-CyclinE复合物,该复合物使Rb蛋白磷酸化,从而充分释放出E2F转录因子,推进细胞周期由G1期进入S期,随后Cdk2/CyclinE复合物因为CyclinE自身的泛素化而降解,由催化亚基Cdk2与调节亚基CyclinA形成新的复合物,参与到DNA复制的进程中。因此,可以通过切断Cdk4/6信号通路来阻止肿瘤细胞快速分裂。已上市的小分子抑制剂主要针对CDK4/6这个亚型,代表药物有:帕博西尼(Palbociclib,18,2015年批准上市,Pfizer)、瑞博西尼(Ribociclib,19,2017年批准上市,Novartis)、玻玛西尼(Abemaciclib,20,2017年批准上市,Lilly)。这类药物主要用于治疗雌激素受体阳性、HER2阴性的晚期乳腺癌患者,临床上与来曲唑、氟维司群等抗肿瘤药物联用可有效地延长患者的无进展生存期。
由于CDK活性在调节细胞中的重要性以及该途径在癌症中被激活的机制,CDK抑制剂成为一种有吸引力的治疗手段。一个主要的理论问题是,CDKs在正常细胞以及癌细胞的增殖中起关键作用,可能造成治疗窗口狭窄,其毒性将影响临床治疗水平。为了达到更好的治疗肿瘤的目的,更好的满足市场需求,我们希望能够开发出新的高效低毒的CDK4/6抑制剂。本发明将提供一种新型结构的CDK4/6抑制剂,并发现此类结构的化合物表现出优异的效果和作用,希望为治疗癌症提供更多的药物。
发明内容
本发明的第一个目的在于一种蝶啶类衍生物或其立体异构体或其药学上可接受的盐,具有如下通式(I)或(II)所示的结构:
其中,R1和R1’分别独立地选自未取代或卤素取代的C1-C8直链或支链烷基,或未取代或卤素取代的C3-C6环烷基;R2为羟基或卤素;R2’选自氢、烷基、-C(O)R4中任意一种;其中R4为H或C1-C5烷基;R3和R3’分别独立地选自C1-8烷基或C1-8氨基烷基取代的伯氨基或仲氨基、C3-6环烷基取代的伯氨基、N上未取代或C1-3有烷基取代的哌嗪基;X为CH或N。
在本发明的一种实施方式中,R1优选甲基、乙基、叔丁基、异丙基、环戊烷基。
在本发明的一种实施方式中,通式(I)中,当R2为羟基时,X优选CH;当R2为卤素时,X优选N。
在本发明的一种实施方式中,R3优选C1-8烷基取代的仲氨基或者N上未取代或C1-3有烷基取代的哌嗪基。
在本发明的一种实施方式中,蝶啶类衍生物可以选自以下具体化合物:
在本发明的一种实施方式中,所述药学上可接受的盐包括:钾盐、钠盐、盐酸盐、甲酸盐,三氟醋酸盐、磷酸盐和硫酸盐等。
本发明的第二个目的是提供一种组合物,含有上述蝶啶类衍生物或其立体异构体或其药学上可接受的盐。
在本发明的一种实施方式中,所述组合物含有上述蝶啶类衍生物或其立体异构体或其药学上可接受的盐,以及药学上可接受的载体。
在本发明的一种实施方式中,所述药学上可接受的载体是指药学领域常规的药物载体,例如:稀释剂、赋形剂、水等,填充剂如:淀粉、蔗糖、乳糖、微晶纤维素等:粘合剂如纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮;润湿剂如甘油;崩解剂如羧甲基淀粉钠、羟丙纤维素、琼脂、碳酸钙和碳酸氢钠;吸收促进剂如季胺化合物;表面活性剂如十六烷醇、十二烷基硫酸钠;
在本发明的一种实施方式中,所述组合物包含上述蝶啶类衍生物或其立体异构体或其药学上可接受的盐以及至少一种药学可接受的赋形剂或载体。
在本发明的一种实施方式中,上述蝶啶类衍生物或其立体异构体或其药学上可接受的盐的制备是通过以下反应式进行:
其中,以上反应式中,R1、R2、R3、R1’、R2’、R3’、X与上文定义相同。
本发明的第三个目的是提供上述蝶啶类衍生物或其立体异构体或其药学上可接受的盐在制备用作CDK抑制剂的药物中的用途。
本发明的第四个目的是提供上述蝶啶类衍生物或其立体异构体或其药学上可接受的盐在制备用于预防或治疗癌症的药物中的用途。
在本发明的一种实施方式中,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。
本发明的五个目的是提供上述蝶啶类衍生物或其立体异构体或其药学上可接受的盐在食品、保健品方面的应用。
有益效果:
本发明蝶啶类衍生物或其立体异构体或其药学上可接受的盐对CDK4的抑制活性均达47%以上,较高可达79%,呈现非常好的CDK4/6的抑制活性,可以被用作CDK4/6的高效抑制剂。本发明要求保护的化合物具有很强的药效和对CDK4/6的选择性,这在开发适于用作CDK4/6抑制剂的药物方面是有利的,具有非常广阔的应用前景。
具体实施方式
本发明所述“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。
本发明所述“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。
本发明所述通式I和通式Ⅱ化合物,还包括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。适于包含在本发明通式I和通式Ⅱ化合物中的同位素包括氢的同位素,例如2H和3H,碳的同位素,例如11C、13C和14C,氮的同位素,例如13N和15N,氧的同位素,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的合成方法。
实施例1化合物I-1的制备
(1)中间体化合物2-氯-N4–异丙基嘧啶-4,5-二胺的制备
将5-氨基-2,4-二氯嘧啶(25.0g,0.15mol)溶于无水四氢呋喃中(100mL),室温搅拌下,采用恒压滴液漏斗向反应体系中逐滴滴加三乙胺(30.4g,0.3mol)和异丙胺(17.7g,0.3mol)的混合溶液,滴毕,将反应体系移至80℃油浴中反应8h。TLC检测反应完全,冷却至室温后,加入水(100mL),用乙酸乙酯(100mL×3)萃取,合并有机相。有机相经饱和氯化钠水洗,无水硫酸钠干燥后,减压浓缩,经硅胶柱层析分离纯化,得到红棕色固体(22.1g,收率78.8%)。
MS-ESI(m/z):187.1[M+H]+;1H NMR(400MHz,DMSO-d6)δ:7.59(d,1H),7.28(s,1H),5.82(s,2H),3.95(m,1H),1.17(d,6H)。
(2)中间体化合物2-氯-8-异丙基-6-羟基蝶啶-7(8H)-酮的制备
将2-氯-N4–异丙基嘧啶-4,5-二胺(0.12mol)溶于二氯甲烷(150mL)中,加入三乙胺(24.28g,0.24mol),在冰浴条件下缓慢滴加草酰氯单乙酯(24.6g,0.18mol),控制温度不超过5℃。滴毕,升至常温反应24h。TLC检测大部分原料反应完全,有固体析出,抽滤,烘干后得到淡黄色固体(20.7g,收率73.1%)。
MS-ESI(m/z):241.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ:12.57(s,1H),7.49(s,1H),3.80(m,1H),1.26(d,6H)。
(3)化合物I-1的制备
将2-氯-8-异丙基-6-羟基蝶啶-7(8H)-酮(0.5g,2.1mmol)溶于1,4-二氧六环(10mL),再依次加入对甲苯磺酸(0.72g,4.2mmol)、4-(4-甲基哌嗪)苯胺(0.80g,4.2mmol)。升温至回流反应8h。TLC检测反应结束,冷却至室温,有固体析出,抽滤,滤饼用水淋洗,烘干后得到黄色固体I-1(收率62.2%)。
MS-ESI(m/z):395.2[M+H]+;1H NMR(400MHz,DMSO)δ:12.57(s,1H),8.86(s,1H),7.32(s,1H),7.00(d,2H),6.76(d,2H),3.80(q,1H),3.44(t,4H),2.35(t,4H),2.21(s,3H),1.26(d,6H)
实施例2化合物I-2的制备
参照实施例1,将步骤(3)中的4-(4-甲基哌嗪)苯胺替换为等摩尔量的N,N-二甲基-1,4-苯二胺,其他条件不变,得到化合物I-2(收率72%)。
MS-ESI(m/z):340.2[M+H]+;1H NMR(400MHz,DMSO)δ:12.57(s,1H),8.86(s,1H),7.32(s,1H),7.00(d,2H),6.76(d,2H),3.80(q,1H),3.02(s,6H),1.26(d,6H)
实施例3化合物I-3的制备
(1)中间体2-氯-N4–叔丁基嘧啶-4,5-二胺的制备
将5-氨基-2,4-二氯嘧啶(0.15mol)溶于无水四氢呋喃中(100mL),室温搅拌下,采用恒压滴液漏斗向反应体系中逐滴滴加三乙胺(30.4g,0.3mol)和叔丁胺(21.9g,0.3mol)的混合溶液,滴毕,将反应体系移至100℃油浴中反应16h。TLC检测反应完全,冷却至室温后,加入水(100mL),用乙酸乙酯(100mL×3)萃取,合并有机相。有机相经饱和氯化钠水洗,无水硫酸钠干燥后,减压浓缩,经硅胶柱层析分离纯化,得到红棕色固体(21.0g,收率69.8%)。MS-ESI(m/z):201.1[M+H]+;1H NMR(400MHz,DMSO-d6)δ:7.28(s,1H),5.82(s,2H),3.41(s,1H),1.38(d,9H)。
(2)中间体2-氯-8-叔丁基-6-羟基蝶啶-7(8H)-酮的制备
将2-氯-N4–叔丁基嘧啶-4,5-二胺(0.12mol)溶于二氯甲烷(150mL)中,加入三乙胺(24.28g,0.24mol),在冰浴条件下缓慢滴加草酰氯单乙酯(24.6g,0.18mol),控制温度不超过5℃。滴毕,升至常温反应24h。TLC检测大部分原料反应完全,有固体析出,抽滤,烘干后得到淡黄色固体(16.63g,收率62.4%)。MS-ESI(m/z):255.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ:12.57(s,1H),7.49(s,1H),1.42(s,9H)。
(3)化合物I-3的制备:
将2-氯-8-叔丁基-6-羟基蝶啶-7(8H)-酮(2.1mmol)溶于1,4-二氧六环(10mL),再依次加入对甲苯磺酸(0.72g,4.2mmol)、4-(4-甲基哌嗪)苯胺(4.2mmol)。升温至回流反应8h。TLC检测反应结束,冷却至室温,有固体析出,抽滤,滤饼用水淋洗,烘干后,然后与三氯氧磷(5mL)混合,加热至60℃反应4h。反应完全,将反应液冷却至室温,逐滴加入到冰水中,有固体析出。充分搅拌30min后,抽滤,滤饼烘干后得到黄色固体I-3(收率75%)。
MS-ESI(m/z):427.2[M+H]+;1H NMR(400MHz,DMSO)δ:8.86(s,1H),7.32(s,1H),7.00(d,2H),6.76(d,2H),3.44(t,4H),2.35(t,4H),2.21(s,3H),1.42(s,9H)。
实施例4化合物I-4的制备
将2-氯-8-叔丁基-6-羟基蝶啶-7(8H)-酮(2.1mmol)溶于DMSO(10mL),再依次加入2-氨基-5-(N-甲基哌嗪基)吡啶(2.8mmol))、碳酸钾(0.52g,3.8mmol)、氟化钾(44mg,0.76mmol)。升温至120℃加热反应8h。TLC检测反应结束,冷却至室温,有固体析出,抽滤,滤饼用水淋洗,烘干后,与三氯氧磷(5mL)混合,加热至60℃反应4h。反应完全,将反应液冷却至室温,逐滴加入到冰水中,有固体析出。充分搅拌30min后,抽滤,滤饼烘干后得到黄色固体I-4(收率69.8%)。MS-ESI(m/z):428.2[M+H]+;1H NMR(400MHz,DMSO)δ:10.18(s,1H),7.32(s,1H),7.17(s,1H),6.79(d,1H),6.65(d,1H),3.15(t,4H),2.35(t,4H),2.21(s,3H),1.42(s,9H)
实施例5化合物I-5的制备
(1)中间体2-氯-N4–环戊基嘧啶-4,5-二胺的制备:
将5-氨基-2,4-二氯嘧啶(25.0g,0.15mol)溶于无水四氢呋喃中(100mL),室温搅拌下,采用恒压滴液漏斗向反应体系中逐滴滴加三乙胺(30.4g,0.3mol)和环戊胺(25.5g,0.3mol)的混合溶液,滴毕,将反应体系移至100℃油浴中反应8h。TLC检测反应完全,冷却至室温后,加入水(100mL),用乙酸乙酯(100mL×3)萃取,合并有机相。有机相经饱和氯化钠水洗,无水硫酸钠干燥后,减压浓缩,经硅胶柱层析分离纯化,得到红棕色固体(26.3g,收率82.3%)。MS-ESI(m/z):214.1[M+H]+;1H NMR(400MHz,DMSO-d6)δ:7.59(d,1H),7.28(s,1H),5.82(s,2H),2.64(m,1H),1.83-1.58(m,4H),1.73-1.63(m,4H)。
(2)中间体2-氯-8-环戊基-6-羟基蝶啶-7(8H)-酮的制备
将2-氯-N4–环戊基嘧啶-4,5-二胺(26.3g,0.12mol)溶于二氯甲烷(150mL)中,加入三乙胺(24.28g,0.24mol),在冰浴条件下缓慢滴加草酰氯单乙酯(24.6g,0.18mol),控制温度不超过5℃。滴毕,升至常温反应24h。TLC检测大部分原料反应完全,有固体析出,抽滤,烘干后得到白色固体(24.1g,收率75.2%)。MS-ESI(m/z):267.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ:8.29(s,1H),5.49(m,1H),2.06-2.12(m,4H),1.97-1.98(m,2H),1.59-1.63(m,2H)。
(3)化合物I-5的制备
将2-氯-8-环戊基-6-羟基蝶啶-7(8H)-酮(0.5g,1.9mmol)溶于DMSO(10mL),再依次加入2-氨基-5-[(二甲氨基乙基-甲基)氨基]吡啶(2.8mmol))、碳酸钾(0.52g,3.8mmol)、氟化钾(44mg,0.76mmol)。升温至120℃加热反应8h。TLC检测反应结束,冷却至室温,有固体析出,抽滤,滤饼用水淋洗,烘干后,与三氯氧磷(5mL)混合,加热至60℃反应4h。反应完全,将反应液冷却至室温,逐滴加入到冰水中,有固体析出。充分搅拌30min后,抽滤,滤饼烘干后得到黄色固体I-5(收率69.8%)。
MS-ESI(m/z):442.2[M+H]+;1H NMR(400MHz,DMSO)δ:10.18(s,1H),7.32(s,1H),7.17(s,1H),6.79(d,1H),6.65(d,1H),3.61(m,1H),3.16(t,2H),2.76(s,3H),2.50(t,2H),2.21(s,6H),2.04~1.78(q,4H),1.73~1.63(m,4H)。
实施例6化合物I-6的制备
参照实施例5,将步骤(3)中的2-氨基-5-[(二甲氨基乙基-甲基)氨基]吡啶替换为2-氨基-5-(N-甲基哌嗪基)吡啶,其他条件不变,制备得到黄色固体I-6(收率73.5%)。
MS-ESI(m/z):440.2[M+H]+;1H NMR(400MHz,DMSO)δ:10.18(s,1H),7.32(s,1H),7.17(s,1H),6.79(d,1H),6.65(d,1H),3.61(m,1H),3.15(t,4H),2.35(t,4H),2.21(s,3H),2.04~1.78(q,4H),1.73~1.63(m,4H)。
实施例7化合物II-1的制备
将2-氯-N4–环戊基嘧啶-4,5-二胺(0.5g,1.9mmol)溶于DMSO(10mL),再依次加入2-氨基-5-二甲氨基吡啶(0.26g,2.8mmol))、碳酸钾(0.52g,3.8mmol)、氟化钾(44mg,0.76mmol)。升温至120℃加热反应8h。TLC检测反应结束,冷却至室温,有固体析出,抽滤,滤饼用水淋洗,烘干后得到黄色固体II-1(收率76.7%)。
MS-ESI(m/z):367.2[M+H]+;1H NMR(400MHz,DMSO)δ:11.24(s,1H),10.18(s,1H),7.97(s,1H),7.17(s,1H),6.79(d,1H),6.65(d,1H),3.61(m,1H),2.92(s,6H),2.04~1.78(m,4H),1.73~1.63(m,4H)。
对比化合物C1-C4的制备:
C-1化合物的制备:
(1)将2-氯-8-环戊基-6-羟基蝶啶-7(8H)-酮(1.0g,3.8mmol)溶于1,4-二氧六环(20mL),再依次加入对甲苯磺酸(1.4g,7.4mmol)、4-(2-羟基乙基氨基)苯胺(7.4mmol)。升温至回流反应8h。TLC检测反应结束,冷却至室温,有固体析出,抽滤,滤饼用水淋洗,烘干后得到黄色固体中间产物(0.58g,收率45.3%)。MS-ESI(m/z):342.1[M+H]+;1H NMR(400MHz,DMSO)δ:12.57(s,1H),9.43(s,1H),7.41(d,2H),7.32(s,1H),7.31(d,2H),3.61(m,1H),2.04~1.78(q,4H),1.73~1.63(m,4H)。
(2)将中间产物(0.5g,1.5mmol)、三氯氧磷(5mL)依次加入反应瓶,加热至60℃反应4h。TLC检测反应完全,将反应液冷却至室温,逐滴加入到冰水中,有固体析出。充分搅拌30min后,抽滤,滤饼烘干后得到黄色固体C-1(收率68.8%)。
MS-ESI(m/z):400.1[M+H]+;1H NMR(400MHz,DMSO)δ:8.96(t,1H),8.86(s,1H),7.32(s,1H),7.08(d,2H),6.63(d,2H),4.92(t,1H),3.67(q,2H),3.61(m,1H),3.55(q,2H),2.04~1.78(q,4H),1.73~1.63(m,4H)。
C-2化合物的制备:
参照C-1的制备过程,将步骤(1)中的4-(2-羟基乙基氨基)苯胺替换为等摩尔量的4-吗啉基苯胺,其他条件不变,得到黄色固体C-2化合物(收率76.8%)
MS-ESI(m/z):426.1[M+H]+;1H NMR(400MHz,DMSO)δ:8.86(s,1H),7.32(s,1H),7.00(d,2H),6.76(d,2H),3.73(t,4H),3.61(m,1H),3.15(t,4H),2.04~1.78(q,4H),1.73~1.63(m,4H)。
C-3化合物的制备:
将2-氯-8-环戊基-6-羟基蝶啶-7(8H)-酮(1.0g,3.8mmol)溶于1,4-二氧六环(20mL),再依次加入对甲苯磺酸(1.4g,7.4mmol)、N,N-二甲基-1,4-苯二胺(7.4mmol)。升温至回流反应8h。TLC检测反应结束,冷却至室温,有固体析出,抽滤,滤饼用水淋洗,烘干后得到中间体1(收率55.3%)。MS-ESI(m/z):366.4[M+H]+;1H NMR(400MHz,DMSO)δ:12.57(s,1H),8.86(s,1H),7.32(s,1H),7.00(d,2H),6.76(d,2H),3.61(m,1H),3.02(s,6H),2.04~1.78(q,4H),1.73~1.63(m,4H)。
向中间体1(0.2g,0.59mmol)中加入N,N-二甲基甲酰胺二甲基缩醛(8mL),120℃反应4h。TLC监测反应结束,待冷却至室温后,向反应液中逐滴缓慢加入水,有固体析出,抽滤,干燥,得到白色固体。MS-ESI(m/z):380.2[M+H]+;1H NMR(400MHz,DMSO)δ:8.86(s,1H),7.32(s,1H),7.00(d,2H),6.76(d,2H),3.95(s,3H),3.61(m,1H),3.02(s,6H),2.04~1.78(m,4H),1.73~1.63(m,4H)。
C-4化合物的制备:
将2-氯-8-环戊基-6-羟基蝶啶-7(8H)-酮(0.5g,1.9mmol)溶于DMSO(10mL),再依次加入3-氨基吡啶(2.8mmol))、碳酸钾(0.52g,3.8mmol)、氟化钾(44mg,0.76mmol)。升温至120℃加热反应8h。TLC检测反应结束,冷却至室温,有固体析出,抽滤,滤饼用水淋洗,烘干后得到黄色固体C-4(收率69.8%)。MS-ESI(m/z):324.1[M+H]+;1H NMR(400MHz,DMSO)δ:11.24(s,1H),8.18(s,1H),8.04(s,1H),7.97(s,1H),7.92(d,1H),7.36(t,1H),7.15(d,1H),3.61(m,1H),2.04~1.78(m,4H),1.73~1.63(m,4H)。
实施例21生物学活性评价
1.CDK4激酶抑制活性评价
①化合物的配制:将化合物粉末溶解在100%DMSO中,配制成10mM的储存液。受试化合物测试浓度为500nM,复孔检测。在384孔板中用100%DMSO将储存液稀释100倍。用分液器Echo 550向目的板转移250nL 100倍终浓度的化合物。阴性对照孔和阳性对照孔中分别加250nL的100%DMSO。
②激酶的配制:配制1×Kinase buffer,用其配制2.5倍终浓度的激酶溶液。
③在化合物孔和阳性对照孔分别加10μL的2.5倍终浓度的激酶溶液;在阴性对照孔中加10μL的1×Kinase buffer。1000rpm离心30秒,振荡混匀后室温孵育10分钟。
④用1×Kinase buffer配制25/15倍终浓度的ATP和Kinase substrate 18的混合溶液,取10μL加入到上述孔中,起始反应。将384孔板1000rpm离心30秒,振荡混匀后室温孵育30分钟。
⑤终止反应:加入30μL终止检测液停止激酶反应,1000rpm离心30秒,振荡混匀后用酶标仪读取转化率。计算公式:
Inhibition%=(Conversion%max-Conversion%sample)/(Conversion%max-Conversion%min)×100,其中Inhibition%表示抑制率,Conversion%max表示阳性对照孔转化率读数,Conversion%sample表示样品转化率读数,Conversion%min表示阴性对照孔转化率读数。
2.MCF-7和HCT 116细胞增殖抑制活性评价
①细胞复苏:从液氮中取出细胞冻存管,迅速放入37℃恒温水浴锅中,不断摇晃使其快速解冻。将细胞悬液加入含10倍体积细胞培养基的离心管中,混匀,转速1000rpm离心5min。小心弃去上清,加入对应的细胞培养基,轻轻吹匀后加至无菌培养瓶中,在37℃,5%CO2条件下培养。
②细胞传代:在显微镜下观察细胞生长情况,当细胞在培养瓶中贴壁生长融合达到80%左右时即可进行传代培养。弃去培养液,用PBS润洗1~2遍,加入0.25%胰蛋白酶消化数分钟,待细胞变圆后加入细胞培养基终止消化。轻轻用吸管吹落贴壁的细胞,将细胞悬液加至离心管中1000rpm离心5min。小心弃去上清,加入细胞培养基吹匀后,按照1:3~1:6的比例分装至细胞培养瓶中。
③接种细胞:取对数生长期的细胞,经胰蛋白酶消化后配成单个细胞悬液,计数。调整细胞悬液的密度为5×104个/mL,取每孔100μL细胞悬液接种到96孔板中,并设置空白对照孔,在37℃,5%CO2条件下培养24小时。
④加药:用移液枪轻轻吸去96孔板中的培养基,加入稀释成不同浓度的含药培养基,每孔150μL,并设置阴性对照孔,在37℃,5%CO2条件下培养48小时。
⑤细胞显色:吸去96孔板中的培养基,每孔加入100μL浓度为0.5mg/mL的MTT溶液,在培养箱中孵育4小时。
⑥吸光值读取:吸去96孔板中的MTT溶液,每孔加入100μL DMSO,用于溶解活细胞内部生成的蓝紫色甲臜,充分振荡后用酶标仪在570nM波长下读取吸光值。
⑦IC50计算:利用GraphPad Prism 5软件计算抑制率,通过抑制率绘制曲线,计算IC50值。计算公式:细胞生长抑制率%=(1-(实验孔吸光值-空白孔吸光值)/(阴性对照孔吸光值-空白孔吸光值))×100%。
本实施例公开了部分活性较好的化合物的体外CDK4激酶抑制活性与抗肿瘤细胞增殖活性检测结果,如表1所示:
表1不同蝶啶类化合物的体外CDK4激酶抑制活性与抗肿瘤细胞增殖活性检测结果
其中“-”代表无明显效果。
由表1可知,通式I和通式II化合物均具有明显的抑制作用。目标化合物体外肿瘤细胞抗增殖活性中,I-1对乳腺癌细胞MCF-7和结直肠癌细胞HCT 116都表现出良好的活性,IC50值均小于3μM。在通式I和通式II化合物中,当母核3位(R2)为羟基或卤素取代、7位为芳基胺取代时,对CDK4的抑制活性更佳;在7位芳基胺的对位引入哌嗪等亲水性基团时活性显著增强,当取代基为羟基氨基或者吗啉时活性减弱;当母核3位为甲氧基时,化合物的活性稍弱。
Claims (10)
1.一种蝶啶类化合物或其立体异构体或其药学上可接受的盐,其特征在于,具有如下通式(I)或(II)所示的结构:
其中,R1和R1’分别独立地选自未取代或卤素取代的C1-C8直链或支链烷基,或未取代或卤素取代的C3-C6环烷基;
R2为羟基或卤素;R2’选自氢、烷基、-C(O)R4中任意一种;其中R4为H或C1-C5烷基;
R3和R3’分别独立地选自C1-8烷基或C1-8氨基烷基取代的伯氨基或仲氨基、C3-6环烷基取代的伯氨基、N上未取代或C1-3有烷基取代的哌嗪基;
X为CH或N。
2.根据权利要求1所述的蝶啶类化合物或其立体异构体或其药学上可接受的盐,其特征在于,R1选自甲基、乙基、叔丁基、异丙基、环戊烷基。
3.根据权利要求1所述的蝶啶类衍生物或其立体异构体或其药学上可接受的盐,其特征在于,R3选自C1-8烷基或C1-8氨基烷基取代的仲氨基,N上未取代或C1-3烷基取代的哌嗪基。
4.根据权利要求1所述的蝶啶类化合物或其立体异构体或其药学上可接受的盐,其特征在于,通式(I)中,R2为羟基、X为CH;或者R2为卤素、X为N。
5.根据权利要求1所述的蝶啶类化合物或其立体异构体或其药学上可接受的盐,其特征在于,所述药学上可接受的盐包括:钾盐、钠盐、盐酸盐、甲酸盐,三氟醋酸盐、磷酸盐和硫酸盐。
6.一种组合物,其特征在于,含有权利要求1~5任一所述的蝶啶类化合物或其立体异构体或其药学上可接受的盐。
7.根据权利要求6所述的组合物,其特征在于,还包括药学上可接受的载体。
8.权利要求1~5任一所述的蝶啶类化合物或其立体异构体或其药学上可接受的盐在制备用作CDK抑制剂的药物方面的应用。
9.权利要求1~5任一所述的蝶啶类化合物或其立体异构体或其药学上可接受的盐在制备用于预防或治疗癌症的药物中的应用。
10.权利要求1~5任一所述的蝶啶类化合物或其立体异构体或其药学上可接受的盐在食品、保健品方面的应用。
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