CN111333655A - 一种三唑并嘧啶类化合物及其制备方法和应用 - Google Patents
一种三唑并嘧啶类化合物及其制备方法和应用 Download PDFInfo
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- CN111333655A CN111333655A CN202010287331.3A CN202010287331A CN111333655A CN 111333655 A CN111333655 A CN 111333655A CN 202010287331 A CN202010287331 A CN 202010287331A CN 111333655 A CN111333655 A CN 111333655A
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Abstract
本发明公开了一种三唑并嘧啶类化合物及其制备方法和应用,所述的三唑并嘧啶类化合物是一类结构新颖的mTOR抑制剂,该类先导化合物具有利用虚拟筛选和药效团的方法寻找的新化合物骨架,且根据PI3K和mTOR蛋白结构的不同进行的针对性设计,因而具有高活性,高选择性的特点。而且,本发明创造性的将其作为放射增敏剂用于癌症的治疗中,可增加癌细胞对放疗的敏感性,大大降低放疗中的放射剂量,降低副作用,提高放射治疗的效果。
Description
技术领域
本发明涉及医药化工技术领域,具体涉及一种三唑并嘧啶类化合物及其制备方法和应用。
背景技术
雷帕霉素(mTOR)是一种丝氨酸/苏氨酸蛋白激酶,分子量约为280kda。它在多种信号通路中发挥着重要作用,影响着多种生理功能,如生长、增殖、蛋白质合成、自噬、代谢和存活等。过度活化mTOR是导致细胞过度增殖和恶性转化的重要原因之一,而抑制mTOR活性可达到抗肿瘤、抗炎、免疫抑制和抗衰老的作用。
晚期肝癌(Hepatocellular carcinoma)是一种非常可怕的疾病,由于肝癌细胞对细胞化疗的耐药以及患者对分子靶向药物敏感性的个体差异,其预后或临床预后仍然很差。放射治疗是一种非侵入性的治疗方法,可以选择性地破坏肝细胞癌患者肝器官中的小瘤体,是一种有希望的晚期肝癌治疗策略。然而,据报道,晚期肝癌对电离辐射(IR)不太敏感,整个肝脏分别只能承受90Gy剂量的IR进行安全照射,而这些安全剂量只能达到癌症控制所需剂量的一部分。因此,开发新的治疗策略,有效地提高肝癌的放射治疗效果是非常有价值的。
过去,mTOR抑制剂往往被用来直接抑制肿瘤的增殖,但是人们发现选择性mTOR抑制剂还具有对放射治疗增敏的效果,这意味着mTOR抑制剂有望被开发成为新型放射增敏剂。因此,设计一种具有放射治疗增敏效果的高活性,高选择性的mTOR抑制剂是非常有必要的。
发明内容
基于以上现有技术的不足,本发明所解决的技术问题在于提供一种处理效果好的三唑并嘧啶类化合物及其制备方法和应用,该三唑并嘧啶类化合物及其制备方法和应用能有效的对含有化学成分的废气进行合理利用,并达到安全排放的标准。
为了解决上述技术问题,本发明提供一类结构新颖的mTOR抑制剂,该类先导化合物具有利用虚拟筛选和药效团的方法寻找的新化合物骨架,且根据PI3K和mTOR蛋白结构的不同进行的针对性设计,因而具有高活性,高选择性的特点。而且,本发明创造性的将其作为化疗增敏剂和放射增敏剂用于癌症的治疗中,可增加癌细胞对化疗和放疗的敏感性,大大降低放疗中的放射剂量和化疗药物的IC50值,降低副作用,提高放射治疗的效果。
一种三唑并嘧啶类化合物,所述三唑并嘧啶类化合物的化学式具有如下的通式:
或者是式I化合物的异构体、可药用的盐或水合物;
其中:
n=0-5;
R1为C1-C6烷氧基、C1-C6酯基、C1-C6醛基、C1-C6酮基、取代或未取代的杂环烷基、取代或未取代芳香杂环,其中所述取代的杂环烷基、取代芳香杂环为被1个、2个、3个、4个或5个独立地选自下列的取代基取代:-F、-Cl、-Br、-I、硝基、羟基、氨基、氰基;
R2为取代或未取代的杂环烷基、取代或为取代的芳香环、取代或未取代芳香杂环,其中所述取代的杂环烷基、取代或为取代的芳香环、取代芳香杂环为被1个、2个、3个、4个或5个独立地选自下列的取代基取代:-F、-Cl、-Br、-I、硝基、羟基、氨基、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、C1-C6醛基、C1-C6酮基;
R3为取代或未取代的杂环烷基、取代或为取代的芳香环、取代或未取代芳香杂环,其中所述取代的杂环烷基、取代或为取代的芳香环、取代芳香杂环为被1个、2个、3个、4个或5个独立地选自下列的取代基取代:-F、-Cl、-Br、-I、硝基、羟基、氨基、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、C1-C6醛基、C1-C6酮基。
作为上述技术方案的优选,本发明提供的三唑并嘧啶类化合物进一步包括下列技术特征的部分或全部:
其中*表示连接位点。
作为上述技术方案的改进,优选的,所述三唑并嘧啶类化合物为:
7-(3-甲氧苯基)-2-((3-甲氧丙基)硫基)-5-甲基-N-(吡啶-3-基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-6-甲酰胺(1a);
2-((2-(1,3-二氧戊环-2-基)乙基)硫基)-7-(3-甲氧苯基)-5-甲基-N-(吡啶-3-基)-4,7-二氢-[1,2,4]三唑并[1,5-a]嘧啶-6-甲酰胺(1b);
甲基3-((7-(3-甲氧苯基)-5-甲基-6-(吡啶-3-基氨甲酰基)-4,7-二氢-[1,2,4]三唑并[1,5-a]嘧啶-2-基)硫基)丙酸酯(1c);
7-(3-甲氧苯基)-5-甲基-N-(吡啶基3-基)-2-((吡啶-4-基甲基)硫基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-6-甲酰胺(1d);
甲基3-((7-(3-甲氧苯基)-5-甲基-6-((5-甲基吡啶3-基)氨甲酰基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫)丙酸酯(2a);
甲基3-((6-((3-氟苯)氨甲酰基)-7-(3-甲氧苯基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(2b);
甲基3-((7-(3-甲氧苯基)-6-((4-甲氧苯基)氨甲酰基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(2c);
甲基3-((6-((3-乙酰苯基)氨甲酰基)-7-(3-甲氧苯基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(2d);
甲基3-((6-((4-乙酰苯基)氨甲酰基)-7-(3-甲氧苯基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(2e);
2-((2-(1,3-二氧戊环-2-基)乙基)硫基)-7-(3-甲氧苯基)-5-甲基-N-(5-甲基吡啶基3-基)-4,7-二氢-[1,2,4]三唑并[1,5-a]嘧啶-6-甲酰胺(2f);
2-((2-(1,3-二氧戊环-2-基)乙基)硫基)-N-(3-氟苯基)-7-(3-甲氧苯基)-5-甲基-4,7-二氢-[1,2,4]三唑并[1,5-a]嘧啶-6-甲酰胺(2g);
2-((2-(1,3-二氧戊环-2-基)乙基)硫基)-7-(3-甲氧苯基)-N-(4-甲氧苯基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-6-甲酰胺(2h);
2-((2-(1,3-二氧戊环-2-基)乙基)硫基)-N-(3-乙酰苯基)-7-(3-甲氧苯基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-6-甲酰胺(2i);
2-((2-(1,3-二氧戊环-2-基)乙基)硫基)-N-(4-乙酰苯基)-7-(3-甲氧苯基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-6-甲酰胺(2j);
甲基3-((7-(3-羟苯基)-5-甲基-6-((5-甲基吡啶3-基)氨甲酰基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(3a);
甲基3-((7-(4-羟苯基)-5-甲基-6-((5-甲基吡啶基3-基)氨甲酰基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(3b);
甲基3-((5-甲基-6-((5-甲基吡啶基3-基)氨甲酰基)-7-苯基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(3c);
甲基3-((5-甲基-6-((5-甲基吡啶基3-基)氨甲酰基)-7-(对-甲苯基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(3d);
甲基3-((5-甲基-6-((5-甲基吡啶基3-基)氨甲酰基)-7-(邻-甲苯基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(3e);
甲基3-((7-(3,5-二甲苯基)-5-甲基-6-((5-甲基吡啶基3-基)氨甲酰基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(3f);
甲基3-((7-(4-氟苯基)-5-甲基-6-((5-甲基吡啶基3-基)氨甲酰基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(3g);
或者,
甲基3-((7-(3-氟苯基)-5-甲基-6-((5-甲基吡啶基3-基)氨甲酰基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(3h)。
一种三唑并嘧啶类化合物的制备方法,所述三唑并嘧啶类化合物是如上所述的任一化合物;
其制备方法按照如下反应式进行:
其中:步骤a中,采用氢氧化钠的乙醇溶液作为溶剂,以物质的量计,三唑衍生物:溴代衍生物:氢氧化钠:乙醇的用量为1:1-2:1-2:30-80,室温下反应20-60分钟,反应产物经过萃取、洗涤和干燥步骤得到中间体1;步骤b中,采用三乙胺和甲苯作为溶剂,以物质的量计,胺类衍生物:乙酸乙酯:三乙胺:甲苯的用量为1:1-2:3-5:5-10,100℃下反应10-20小时,反应产物经过沉淀、过滤、洗涤步骤得到中间体2;步骤c中,以物质的量计,中间体1:中间体2:醛类衍生物:乙醇的用量为1:1-2:1-2:30-80乙醇溶剂在80℃下反应2-5小时,反应产物经过滤洗涤得到终产物。
作为上述技术方案的优选,本发明提供的三唑并嘧啶类化合物的制备方法进一步包括下列技术特征的部分或全部:
作为上述技术方案的改进,所述三唑并嘧啶类化合物可以用作制备抗癌药物、免疫抑制剂、PI3K抑制剂、mTOR抑制剂、抑制PI3K-Akt-mTOR通路信号的药物、抑制T淋巴细胞增殖的药物、抗菌药物、抗病毒药物、促进肿瘤细胞凋亡的药物、使细胞周期停滞在G1期的药物、防止器官排斥反应的药物、降低动脉栓塞的药物、抗衰老药物、抗阿尔茨海默病药物、抗炎药物、放射增敏剂或抗菌药物。
作为上述技术方案的改进,所述三唑并嘧啶类化合物可以作为放射增敏剂,与放疗联合使用治疗癌症。
作为上述技术方案的改进,所述三唑并嘧啶类化合物可以作为化疗增敏剂,与分子靶向药物联合使用治疗癌症。
本发明提供的化合物对多种肿瘤细胞具有明显的抑制活性,这些肿瘤细胞包括但不限于:人高转移性肝癌细胞(MHCC97-H细胞)、人肺癌细胞系(A549细胞)、人乳腺癌细胞(MCF7)、人白血病细胞(K562)、子宫颈癌细胞(Hela)、卵巢癌细胞(SKOV3)、胃腺癌细胞(AGS)、前列腺细胞(PC-3)。因此,上述化合物及其可药用盐、水合物或者本发明的药物组合物可以用于治疗肝癌、肺癌、乳腺癌、白血病、子宫颈癌、卵巢癌、胃腺癌、前列腺癌。
此外,本发明提供的化合物其可药用的盐用于生产可抑制哺乳动物体内PI3K/Akt/mTOR信号的药物。
一种如上任一所述的三唑并嘧啶类化合物的应用,本发明提供的化合物为ATP类似物,可作用于各种激酶(kinase)类靶点,作为激酶抑制剂使用,所述三唑并嘧啶类化合物可以作为ATP类似物用于治疗激酶失调相关疾病或病症。
一种药物组合物,包含如上任一所述的化合物或其可药用的盐、异构体、水合物以及至少一种可药用的载体。
需要说明的是,本发明提供的化合物为采用虚拟筛选和药效团的方式筛选而来。首先,将本课题组自有分子库中的小分子化合物与mTOR进行柔性虚拟对接。这些化合物使用3个评分规则进行排序,包括碰撞、极性和目视检查。通过聚类分析,选出了5类结构中排名前的50位的化合物,通过聚类分析,去除已经被报道过的骨架结构化合物,进行初始mTOR酶抑制率试验,通过酶抑制活性试验(mTOR IC50=167nm)初步证实了上述化合物为一种具有全新型骨架的mTOR抑制剂。
且上述化合物为mTOR的选择性抑制剂,对mTOR的选择性较高,由于其与mTOR/PI3K双重抑制剂比较,参与的信号通路较少,因而成药后会具有更少的副作用。上述选择特异性由如下具体方法得来:首先,将mTOR和PI3K蛋白的三维晶体结构进行了比较,我们可以观察到:PI3K和mTOR蛋白腔的底部有很高的相似性,但开口处结构性差异较大。PI3K蛋白结构为发夹状结构(如图1所示),由LEU766、GLU767和GLU768组成,这使PI3K的β折叠结构单元较mTOR单元的同一位置前倾。PI3K的ATP结合口袋部分被遮挡,使PI3K的结合口袋开口小于mTOR。经测量,PI3K的ATP结合口袋开口距离为mTOR的ATP结合口袋开口距离为较PI3K宽27%。这个差异意味着立体结构较大的化合物较难进入PI3K结合口袋。事实上,根据以往的报道,PI3K选择性抑制剂在大多数情况下确实具有更扁平的分子结构,而mTOR选择性抑制剂则往往倾向于具有更大的分子体积。由于分子间的结构差异,一些分子可以进入mTOR的结合口袋,但不能进入PI3K的口袋。上述可能是mTOR选择性抑制剂产生的主要原因。一些已报到的抑制剂可以证实我们的猜想,它们的结构被列举如下:LY294002、PI-103、TGX-221、Torin1、Wye-125132、Way-600。这些先导化合物与mTOR中的重要氨基酸残基SER2165、LYS2187、VAL2240和ASN2343形成稳定的氢键。
其次,在本发明提供的化合物中,R1位置引入的侧链都是柔性的,并且具有至少一个氢键受体结构,以形成与mTOR中的Ser2165相互作用的氢键。而且,从分子对接中也可以看出,侧链需要适当的疏水性和长度才能伸入mTOR狭窄的疏水空腔。R2可以与mTOR中的ASN2343相互作用,明确的形成一个氢键。在结合位口袋R2部分占据了一个宽的疏水空穴,因此这个基团必须具有较大的体积。上述先导化合物与mTOR和PI3K的对接显示R3具有相对于化合物骨架的垂直结构,这是化合物能够特异性与mTOR空腔结合的关键原因。苯环上的取代基进一步增大了体积,使化合物难以进入PI3K空腔,增加了对mTOR的选择性。另一方面,mTOR上的氨基酸VAL2240残基通过氢键作用稳定了R3基团的空间构型。
基于上述通过虚拟对接特征的研究,本发明在新型化合物骨架式I的基础上,针对性的对取代基R1、R2、R3的取代基团进行了特异性设计,从而提高其对mTOR的选择性和活性。
与现有技术相比,本发明的技术方案具有如下有益效果:本申请基于虚拟对接的方法,通过构建药效团模型法针对性的改造先导化合物,得到具有全新结构骨架化合物,该类化合物对mTOR抑制活性好,且选择性好。同时,根据实验发现,该类化合物具有较好的抗癌效果以及放射增敏和化疗增敏活,因此该类化合物具有更好的成药前景。
上述说明仅是本发明技术方案的概述,为了能够更清楚了解本发明的技术手段,而可依照说明书的内容予以实施,并且为了让本发明的上述和其他目的、特征和优点能够更明显易懂,以下结合优选实施例,详细说明如下。
附图说明
为了更清楚地说明本发明实施例的技术方案,下面将对实施例的附图作简单地介绍。
图1(a)实施例化合物2a与mTOR蛋白的虚拟对接飘带图;
图1(b)实施例化合物2a与mTOR蛋白的虚拟对接蛋白表面图;
图2实施例化合物2a对MHCC97-H细胞的放射增敏效果测试的平板克隆实验效果图;其中图2(a)是MHCC97-H细胞在溶剂对照试验中接受计量为0Gy的60Co-γIR辐射时的抑制效果;图2(b)是MHCC97-H细胞在溶剂对照试验中接受计量为2Gy的60Co-γIR辐射时的抑制效果;图2(c)是MHCC97-H细胞在溶剂对照试验中接受计量为4Gy的60Co-γIR辐射时的抑制效果;图2(d)是MHCC97-H细胞在溶剂对照试验中接受计量为8Gy的60Co-γIR辐射时的抑制效果;图2(e)是MHCC97-H细胞在加入了0.03μM的化合物2a的试验中接受计量为0Gy的60Co-γIR辐射时的抑制效果;图2(f)是MHCC97-H细胞在加入了0.03μM的化合物2a的试验中接受计量为2Gy的60Co-γIR辐射时的抑制效果;图2(g)是MHCC97-H细胞在加入了0.03μM的化合物2a的试验中接受计量为4Gy的60Co-γIR辐射时的抑制效果;图2(h)是MHCC97-H细胞在加入了0.03μM的化合物2a的试验中接受计量为0、2、4、8Gy的60Co-γIR辐射时的抑制效果;
图3实施例化合物2a对MHCC97-H细胞的放射增敏效果测试的平板克隆实验抑制率;
图4实施例化合物2a对MHCC97-H细胞在放疗下DNA双链断裂的增强效果图;其中图4(a)是MHCC97-H细胞在γ-H2aX染色组中使用0Gy剂量IR治疗和溶剂对照时的抑制效果;其中图4(b)是MHCC97-H细胞在γ-H2aX染色组中使用化合物2a治疗时的抑制效果;其中图4(c)是MHCC97-H细胞在γ-H2aX染色组中使用4Gy剂量IR治疗时的抑制效果;其中图4(d)是MHCC97-H细胞在γ-H2aX染色组中同时使用4Gy剂量IR和化合物2a治疗时的抑制效果;其中图4(e)是MHCC97-H细胞在Hoechst3342组中使用0Gy剂量IR治疗和溶剂对照时的抑制效果;其中图4(f)是MHCC97-H细胞在Hoechst3342组中使用化合物2a治疗时的抑制效果;其中图4(g)是MHCC97-H细胞在Hoechst3342组中使用4Gy剂量IR治疗时的抑制效果;其中图4(h)是MHCC97-H细胞在Hoechst3342组中同时使用4Gy剂量IR和化合物2a治疗时的抑制效果;
图5实施例化合物2a对MHCC97-H细胞在放疗下DNA双链断裂的增强结果(γ-H2aX病灶颗粒总面积)。
具体实施方式
下面详细说明本发明的具体实施方式,其作为本说明书的一部分,通过实施例来说明本发明的原理,本发明的其他方面、特征及其优点通过该详细说明将会变得一目了然。
实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
实施例1:
甲基3-((7-(3-甲氧苯基)-5-甲基-6-((4-甲基吡啶-3-基)氨基甲酰)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫)丙酸酯(2a)的合成
步骤1:甲基3-((5-氨基-1H-1,2,4-三唑-3-基)硫基)丙酸酯(中间体1)的制备
3-溴丙酸甲酯(14.36g,0.086mol)溶解至40ml的无水乙醇中备用。在500ml的反应容器中,NaOH(3.44g,0.086mol)溶解在200ml的纯净水中,搅拌至完全溶解。然后加入3-氨基-5-硫基-1,2,4-三唑(10.00g,0.086mol)并搅拌。30分钟后,加入3-溴丙酸甲酯和乙醇的混合物。室温下反应过夜。反应完成后,使用乙酸乙酯萃取、用饱和氯化钠洗涤并用Na2SO4干燥。得到甲基3-((5-氨基-1H-1,2,4-三唑-3-基)硫基)丙酸(11.65g,收率67%)。
步骤2:N-(5-甲基吡啶基3-基)-3-乙酰乙酰胺(中间体2)的制备
5-甲基吡啶基3-胺(10.00g,0.092mol)与200ml甲苯在500ml的反应器中混合,搅拌至完全溶解。然后,加入乙酰乙酸乙酯(11.97g,0.092mol),混合物在加热至100℃反应10小时,然后静置过夜会有沉淀析出。过滤沉淀,滤饼用石油醚洗涤并收集。在40℃下真空干燥30分钟,得到N-(5-甲基吡啶基3-基)-3-乙酰乙酰胺(13.26g,收率:75%)。
步骤3:甲基3-((7-(3-甲氧苯基)-5-甲基-6-((5-甲基吡啶基3-基)氨甲酰基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(2a)的制备.
在500ml的反应容器中,将N-(5-甲基吡啶基3-基)-3-乙酰乙酰胺(5.00g,0.026mol)与80ml的无水乙醇混合,搅拌至完全溶解。随后,依次加入3-甲氧苯基甲醛(3.54g,0.026mol)和甲基3-((5-氨基-1H-1,2,4-三唑-3-基)硫基)丙酸酯(5.26g,0.026mol),并在80℃下反应3小时。30分钟后,有白色晶体析出,当白色晶体停止析出时停止反应。过滤,并使用无水乙醇洗涤滤饼并收集固体。反应产物在40℃下烘干20分钟,得到目标化合物2a(5.40g,收率42%)。m.p.:221.7–222.4℃.1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.87(s,1H),8.47(d,J=2.3Hz,1H),8.11–8.05(m,1H),7.81(d,J=2.3Hz,1H),7.25(t,J=7.9Hz,1H),6.85(ddd,J=8.3,2.6,0.9Hz,1H),6.83–6.71(m,2H),6.50–6.44(m,1H),3.68(s,3H),3.60(s,3H),3.17(td,J=7.0,2.2Hz,2H),2.73(t,J=6.9Hz,2H),2.21(d,J=24.9Hz,6H).13C NMR(101MHz,DMSO-d6)δ172.12,165.61,159.72,157.85,149.07,145.08,142.41,138.81,137.53,135.70,133.26,130.26,127.22,119.55,113.55,113.50,103.87,60.44,55.47,51.99,34.45,26.57,18.34,18.31,17.82.MS(ESI)m/z:495.57[M+H]+.Anal.C24H26N6O4S:C 58.29,H 5.30,N 16.99.Found:C 58.32,H 5.30,N17.02.
化合物对mTOR酶抑制活性和选择性测试:
化合物的mTOR酶抑制活性用赛默飞公司的ultra time-resolvedfluorescence resonance energy transfer(TR-FRET)测试(Invitrogen,Carlsbad,CA,USA),按赛默飞公司提供的说明书进行操作,选择已经报道的化合物WYE-125132为阳性对照化合物。操作时,首先将mTOR酶(0.1μg/mL,Invitrogen,Carlsbad,CA,USA)、ATP(3μM)、GFP-4EBP1 Peptide(0.4μM)以及测试化合物溶于酶缓冲液(50mM HEPES pH 7.5,1mMEGTA,3mM MnCl2,10mM MgCl2,2mM DTT and 0.01%Tween-20)。该反应在384孔板(Corning,New York,NY,USA)中,常温反应一小时。然后加EDTA至10mM停止反应。接下来向每个孔中加入指定浓度的Tb-antiphospho-4EBP1(Thr37/46)抗体(PerkinElmer,Fremont,CA,USA),将反应液在室温下混合30分钟。测试化合物的浓度梯度为10000、2500、625、156.25、39.06、9.77、2.44、0.61、0.15、0.04、0.01nmol/L。荧光强度用Spectramax 190酶标仪测量(Molecular Devices,Valley,CA,USA)的TR-FRET模式进行测试(激发波长320nm,散射波长665nm)。所有化合物活性测试两次,结果用IC50表达(抑制50%细胞时候的浓度),取两次测试结果的平均值。酶抑制活性测试结果见表1。
化合物对PI3K酶抑制活性和选择性测试:
采用ADP-Glo激酶法(美国Promega公司PI3Kα酶)测定PI3Kα活性的抑制作用。根据Promega提供的方案,在实验前应准备试剂。在310μL 2.5×激酶反应缓冲液(promega,V1691)中稀释10微升(1μg,promega#V1691)的PI3K酶,得到2.5×激酶溶液。将微量PIP2:3PS底物和ATP在100μL 10×脂质稀释缓冲液和250μL水中稀释,得到2.5×PIP2:3PS脂质激酶底物工作液。在975微升水中稀释25微升超纯ATP(10mM),得到250μM的ATP水溶液。
实验开始时,将受试化合物连续稀释至所需浓度,然后将1μL的每种化合物的添加至384孔板(Corning,New York,NY,USA)作为实验板。测试化合物的浓度梯度为10000、2500、625、156.25、39.06、9.77、2.44、0.61、0.15、0.04、0.01nmol/L。每个实验孔加入4μL的PIP2:3PS脂质激酶底物。然后,将4μL的激酶溶液添加到实验板的每个孔中,除了对照孔添加4μL的1×激酶反应缓冲液(酶对照组)。当激酶反应开始时,向实验板加入1μL 250μM的ATP,然后盖住,混合30至60s,并在23℃(室温)下孵育1小时。在反应混合物中加入10微升ADP-GloTM试剂(Promega,Madison,WI,USA,#V1691),用于停止酶反应并消耗掉多余的ATP。40分钟后,在反应混合物中加入20μL激酶检测试剂(Promega,Madison,WI,USA,#V1691),将ADP转化为ATP。在平板阅读器上进行荧光读数之前,将混合物摇动1分钟并平衡40分钟。最后,在Flex站上收集转换数据,使用(max-Sample RLU)/(max-min)×100%的公式将RLU(相对光单位)值转换为抑制值。其中,“max”表示DMSO对照的RLU值,“min”表示无酶控制的RLU值。所有化合物都进行了两次测试,IC50(抑制浓度50%)结果是两次测定的平均值。化合物WYE-125132为阳性对照。
表1部分化合物的mTOR酶抑制活性和选择性
以上mTOR和PI3K酶抑制活性实验结果(表1)说明本发明中所述化合物1c,2a,4c具有较好的对mTOR酶的抑制活性,且对mTOR酶具有选择性。4c与对比化合物WYE-125132相比,具有显著更好的对mTOR酶的抑制活性以及选择性。
化合物2a对分子靶向药物的化疗增敏实验
实验材料与方法:
本发明所用的抗肿瘤药物如索拉非尼、瑞戈非尼、阿帕替尼从selleck公司购买。将MHCC97-H细胞以每孔5000个的数量接种于白壁底透96孔板(Corning,NY,USA)。该细胞系在DMEM(Invitrogen,USA)中与10%胎牛血清(FBS,Invitrogen,Carlsbad,CA,USA)在37℃和5%CO2条件下培养24小时。受试化合物用DMSO溶解,用DMEM稀释。用指定浓度(10.0μmol/L、3.0μmol/L、1.0μmol/L、0.3μmol/L、0.1μmol/L、0.03μmol/L、0.01或0.003μmol/L)的分子靶向药物处理MHCC97-H细胞12h,然后用MTT法(Amresco,Washington,USA)测试细胞的存活。用O.D.490nm波长检测吸光度,分子靶向剂对MHCC97-H细胞的抑制率计算方法为:(对照组的O.D.490nm-给药组的O.D.490nm)/(对照组的O.D.490nm)×100%。通过抑制率计算MHCC97-H细胞上分子靶向药物的IC50值
结果:
将30nmol/L的化合物2a分别与3种分子靶向药物联合给药,以不加化合物2a作为对照组,获得的IC50值见表。该实验显示,化合物2a的处理明显增强了多种分子靶向药物对MHCC97-H细胞的抑制作用,从而降低了3种分子靶向药物索拉非尼、瑞戈非尼、阿帕替尼的IC50值。
表2.化合物2a对分子靶向药物的化疗增敏效果
体外辐射增敏实验-平板克隆实验
首先,将MHCC97-H细胞株使用不同浓度的化合物2a的进行处理,结果如下表3所示:
表3不同浓度的化合物2a的对mTOR酶和MHCC97-H细胞株的抑制活性
根据上表可知,化合物2a的浓度为0.03μM时,对mTOR酶有明显的抑制效果,但不直接影响MHCC97-H细胞,因此,将该浓度设定为实验浓度。
平板克隆实验材料与方法
在菌落形成实验中,MHCC97-H细胞(每孔2×103细胞)被接种于6孔板(Corning,USA)中,培养3~4周。将化合物2a的DMSO溶液(化合物2a的浓度为30nM,DMSO的最终浓度为1‰)加入细胞中,孵育12h,然后用不同剂量(0、2、4或8Gy)的60Co-γ电离辐射的照射细胞5分钟。分为溶剂对照+分次照射、化合物2a+分次照射两组,结果显示为图像或柱状图。抑制率计算方法为[(对照组在546nm处的吸光度)-(给药组在546nm处的吸光度)]/(对照组在546nm处的吸光度)×100%。实验结果如图2所示,图2表面,浓度为0.03μM的化合物2a能够明显提高辐射对MHCC97-H细胞株的抑制效果,抑制率大大提高。
体外辐射增敏实验-免疫荧光实验
免疫荧光实验被用来考察放射对MHCC97-H细胞的损伤程度。在γ-H2aX染色组(图4a、b、c、d)中,MHCC97-H细胞(每孔5×103细胞)接种于96孔板(Corning,USA)中培养3~4周。将化合物2a的DMSO溶液(化合物2a的浓度为30nM,DMSO的最终浓度为1‰)加入细胞中,孵育12h,然后用4Gy剂量的60Co-γ电离辐射处理细胞5分钟。3%多聚甲醛固定30分钟,Triton X-100(0.5%)在4℃下渗透10分钟,然后用10%牛血清白蛋白(BSA)在磷酸盐缓冲液(PBS)中稀释。封闭后,用FITC(荧光素异硫氰酸酯异构体I;3',6'-二羟基-5-异硫氰酸酯-3H-螺环[异苯并呋喃-1,9'-黄原]-3-酮)结合抗体(抗γ-H2AX[1:500])在PBS中于37℃稀释1h,同时避光。使用荧光显微镜观察荧光信号。在Hoechst3342组(图4e、f、g、h)中,用类似的方法检测MHCC97-H细胞的细胞核损伤程度。实验共包括4组:0Gy+溶剂对照组(DMSO稀释1‰浓度)治疗组(图4a和4e)、化合物2a治疗组(图4b和4f)、4Gy剂量IR治疗组(图4c和4g)、4Gy剂量IR+化合物2a治疗组(图4d和4h),结果显示为图像或柱状图。对FITC强度使用Image J软件进行定量分析。
实验结果如图4b和4f所示,单独使用化合物2a给药不能诱导MHCC97-H细胞核内γ-H2aX的形成。用4Gy剂量的IR治疗可诱导少量γ-H2AX的形成(图4c和4g),不出所料,用化合物2a和IR联合作用可显著增强IR诱导的γ-H2AX病灶的形成(图4d和4h)。
在这两个体外细胞实验中,我们研究了化合物2a对IR治疗效果的增强作用。结果表明,给予化合物2a可以在非细胞毒性浓度(0.03μm/L)下的增强IR对HCC细胞的抑制作用。本研究为开发mTOR特异性抑制剂用于放射增敏剂治疗癌症提供了依据。
肿瘤细胞抑制实验
实验材料:DMEM高糖细胞培养基(Hyclone公司),胎牛血清(FBS)(Gibco公司),青霉素、链霉素购自华北制药股份有限公司,磷酸生理盐水缓冲液(PBS)购自Gibco公司,Cell细胞活力检测试剂购自Promega公司,胰酶以及二甲亚砜(DMSO)为Sigma公司产品。人高转移性肝癌细胞(MHCC97-H细胞)、人肺癌细胞系(A549细胞)、人乳腺癌细胞(MCF7)、人白血病细胞(K562)、MDA231、卵巢癌细胞(SKOV3)、胃腺癌细胞(AGS)、前列腺细胞(PC-3)均购自ATCC公司。阳性对照化合物选择WYE-125132。
实验方法:
以每孔5000个细胞的数量接种白壁底透96孔板(Costar),37℃5%CO2条件下培养24h。利用DMSO将待测化合物溶解至100mM,作为化合物母液。
利用含有2%FBS的DMEM培养液稀释化合物,浓度梯度为3,浓度范围为100μM~3nM。将各稀释度化合物加入培养好的96孔板细胞中,每孔100μl。37℃CO2条件下培养指定时间,弃去上清液后,进行细胞活力检测实验。测试肿瘤细胞抑制活性时给药孵育72h,测试肿瘤增敏活性时给药孵育12h。
根据每孔的化学发光检测值,计算每个化合物各稀释度的抑制率,利用Origin8.0软件对每个化合物的不同梯度进行S型曲线拟合,计算IC50值。结果见表4。
表4实施例化合物对多种肿瘤细胞的体外增值抑制能力
体外抗肿瘤实验实验的结果证明,优选化合物1c、2a、4c对多个肿瘤细胞系如:MHCC97-H,A549,MCF7,K562,MDA231,SKOV3,AGS,PC-3的抑制活性均较好。
以下为优选化合物的结构信息:
1a:7-(3-甲氧苯基)-2-((3-甲氧基丙基)巯基)-5-甲基-N-(吡啶-3-基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-6-甲酰胺
m.p.:232.2–233.4℃.1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),9.90(s,1H),8.68(s,1H),8.24(d,J=4.6Hz,1H),7.94(d,J=8.3Hz,1H),7.30(dd,J=8.4,4.7Hz,1H),7.25(t,J=8.0Hz,1H),6.85(d,J=8.2Hz,1H),6.79(d,J=7.7Hz,1H),6.74(s,1H),6.48(s,1H),3.69(s,3H),3.37(t,J=6.3Hz,2H),3.01(h,J=7.0,6.5Hz,2H),2.19(s,3H),1.84(p,J=6.8Hz,2H).13C NMR(101MHz,DMSO-d6)δ165.65,159.72,158.30,149.01,144.73,142.52,141.60,137.70,136.08,130.24,126.95,123.98,119.51,113.49,103.79,70.65,60.40,58.28,55.47,29.74,28.30,17.83.MS(ESI)m/z:467.69[M+H]+.
1b:2-((2-(1,3-二氧戊环-2-基)乙基)巯基)-7-(3-甲氧苯基)-5-甲基-N-(吡啶-3-基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-6-甲酰胺
m.p.:227.4–229.0℃.1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.93(s,1H),8.68(d,J=2.5Hz,1H),8.23(dd,J=4.7,1.4Hz,1H),7.94(ddd,J=8.4,2.6,1.5Hz,1H),7.34–7.20(m,2H),6.85(dd,J=8.2,2.5Hz,1H),6.82–6.71(m,2H),6.49(s,1H),4.87(t,J=4.6Hz,1H),3.93–3.70(m,4H),3.33(s,2H),3.02(td,J=7.2,2.1Hz,2H),2.54–2.47(m,1H),2.19(s,3H),1.92(td,J=7.6,4.7Hz,2H).13C NMR(101MHz,DMSO-d6)δ165.64,159.73,158.17,149.04,144.73,142.49,141.60,137.71,136.08,130.25,126.95,123.98,119.50,113.54,113.46,103.79,102.68,64.76,60.40,55.47,34.13,26.09,17.83.MS(ESI)m/z:495.35[M+H]+.
1c:甲基3-((7-(3-甲氧苯基)-5-甲基-6-(吡啶-3-基氨基甲酰基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)巯基)丙酸酯
m.p.:229.5–229.2℃.1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),9.94(s,1H),8.68(d,J=2.5Hz,1H),8.23(dd,J=4.7,1.5Hz,1H),7.94(ddd,J=8.4,2.6,1.5Hz,1H),7.34–7.20(m,2H),6.85(ddd,J=8.3,2.6,0.9Hz,1H),6.83–6.71(m,2H),6.49(s,1H),3.68(s,3H),3.60(s,3H),3.18(td,J=7.0,2.1Hz,2H),2.73(t,J=6.9Hz,2H),2.19(s,3H).13C NMR(101MHz,DMSO-d6)δ172.11,165.63,159.74,157.87,149.08,144.75,142.42,141.61,137.65,136.07,130.25,126.96,123.98,119.52,113.58,113.47,103.82,60.43,55.47,51.97,34.46,26.58,17.83.MS(ESI)m/z:481.52[M+H]+.
1d:7-(3-甲氧苯基)-5-甲基-N-(吡啶-3-基)-2-((吡啶-4-基甲基)巯基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-6-甲酰胺
m.p.:222.3–223.6℃.1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),9.95(s,1H),8.68(dd,J=2.6,0.7Hz,1H),8.43–8.36(m,2H),8.23(dd,J=4.7,1.5Hz,1H),7.94(ddd,J=8.4,2.6,1.5Hz,1H),7.34–7.22(m,4H),6.88(ddd,J=8.3,2.6,0.9Hz,1H),6.83–6.72(m,2H),6.48(d,J=1.1Hz,1H),4.26(d,J=14.1Hz,1H),4.18(d,J=14.1Hz,1H),3.69(s,3H),2.19(d,J=0.9Hz,3H).13C NMR(101MHz,DMSO-d6)δ165.61,159.75,157.33,149.91,149.09,147.79,144.75,142.37,141.60,137.58,136.05,130.26,126.95,124.21,123.99,119.64,113.61,113.54,103.82,60.51,55.50,33.86,17.84.MS(ESI)m/z:486.22[M+H]+.
2a:甲基3-((7-(3-甲氧苯基)-5-甲基-6-((5-甲基吡啶-3-基)氨基甲酰基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)巯基)丙酸酯
m.p.:221.7–222.4℃.1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.87(s,1H),8.47(d,J=2.3Hz,1H),8.11–8.05(m,1H),7.81(d,J=2.3Hz,1H),7.25(t,J=7.9Hz,1H),6.85(ddd,J=8.3,2.6,0.9Hz,1H),6.83–6.71(m,2H),6.50–6.44(m,1H),3.68(s,3H),3.60(s,3H),3.17(td,J=7.0,2.2Hz,2H),2.73(t,J=6.9Hz,2H),2.21(d,J=24.9Hz,6H).13C NMR(101MHz,DMSO-d6)δ172.12,165.61,159.72,157.85,149.07,145.08,142.41,138.81,137.53,135.70,133.26,130.26,127.22,119.55,113.55,113.50,103.87,60.44,55.47,51.99,34.45,26.57,18.34,18.31,17.82.MS(ESI)m/z:495.57[M+H]+.
2b:甲基3-((6-((3-氟代苯基)氨基甲酰基)-7-(3-甲氧苯基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)巯基)丙酸酯
m.p.:240.3–242.5℃.1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),9.94(s,1H),7.51(ddd,J=11.4,3.4,1.9Hz,1H),7.36–7.20(m,3H),6.91–6.80(m,2H),6.84–6.70(m,2H),6.46(d,J=1.2Hz,1H),3.68(s,3H),3.60(s,3H),3.17(td,J=7.1,2.5Hz,2H),2.73(t,J=6.8Hz,2H),2.17(s,3H).13C NMR(101MHz,DMSO-d6)δ172.11,165.45,163.69,161.29,159.72,157.83,149.09,142.38,141.21,141.10,137.34,130.76,130.66,130.24,119.54,115.63,113.55,113.49,110.32,110.11,106.78,106.52,104.07,60.47,55.45,51.97,34.46,26.57,17.79.MS(ESI)m/z:498.42[M+H]+.
2c:甲基3-((7-(3-甲氧苯基)-6-((4-甲氧苯基)氨基甲酰基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)巯基)丙酸酯
m.p.:254.3–256.1℃.1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),9.61(s,1H),7.47–7.38(m,2H),7.24(t,J=7.9Hz,1H),6.89–6.80(m,3H),6.81–6.70(m,2H),6.43(s,1H),3.69(d,J=5.9Hz,6H),3.60(s,3H),3.17(td,J=7.0,2.6Hz,2H),2.77–2.66(m,2H),2.18–2.13(m,3H).13C NMR(101MHz,DMSO-d6)δ172.12,164.74,159.70,157.71,155.83,149.22,142.45,136.14,132.49,130.15,121.63,119.58,114.21,113.51,113.48,104.50,60.59,55.64,55.47,51.97,34.47,26.57,17.70.MS(ESI)m/z:510.67[M+H]+.
2d:甲基3-((6-((3-乙酰苯基)氨基甲酰基)-7-(3-甲氧苯基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)巯基)丙酸酯
m.p.:212.7–213.0℃.1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),9.95(s,1H),8.13(t,J=2.0Hz,1H),7.81(ddd,J=8.2,2.3,1.1Hz,1H),7.64(dt,J=7.8,1.3Hz,1H),7.42(t,J=7.9Hz,1H),7.25(t,J=7.9Hz,1H),6.88–6.76(m,2H),6.76(dd,J=2.5,1.6Hz,1H),6.49(d,J=1.1Hz,1H),3.68(s,3H),3.60(s,3H),3.17(td,J=7.0,2.4Hz,2H),2.77–2.66(m,2H),2.54(s,3H),2.21–2.16(m,3H).13C NMR(101MHz,DMSO-d6)δ198.07,172.12,165.43,159.71,157.81,149.07,142.41,139.82,137.69,137.31,130.23,129.53,124.41,123.88,119.58,119.08,113.55,113.52,104.03,60.45,55.45,51.98,34.45,27.17,26.56,17.82.MS(ESI)m/z:522.24[M+H]+.
2e:甲基3-((6-((4-乙酰苯基)氨基甲酰基)-7-(3-甲氧苯基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)巯基)丙酸酯
m.p.:229.8–231.6℃.1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),10.07(s,1H),7.89(d,J=8.3Hz,2H),7.68(d,J=8.4Hz,2H),7.24(t,J=7.9Hz,1H),6.84(dd,J=8.2,2.5Hz,1H),6.81–6.71(m,2H),6.49(s,1H),3.67(s,3H),3.60(s,3H),3.22–3.11(m,2H),2.73(t,J=7.0Hz,2H),2.18(s,3H).13C NMR(101MHz,DMSO-d6)δ196.94,172.12,165.58,159.71,157.86,149.03,143.82,142.41,137.80,132.19,130.26,129.81,119.52,119.09,113.55,113.46,103.98,60.45,55.45,51.99,34.44,26.88,26.56,17.83.MS(ESI)m/z:522.27[M+H]+.
2f:2-((2-(1,3-二氧戊环-2-基)乙基)巯基)-7-(3-甲氧苯基)-5-甲基-N-(5-甲基吡啶-3-基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-6-甲酰胺
m.p.:224.5–226.7℃.1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),9.87(s,1H),8.47(d,J=2.3Hz,1H),8.08(dd,J=1.9,0.9Hz,1H),7.84–7.78(m,1H),7.25(t,J=7.9Hz,1H),6.89–6.75(m,2H),6.74(dd,J=2.5,1.6Hz,1H),6.47(d,J=1.1Hz,1H),4.86(t,J=4.6Hz,1H),3.93–3.80(m,2H),3.83–3.70(m,2H),3.68(s,3H),3.02(td,J=7.2,2.2Hz,2H),2.25(s,3H),2.21–2.15(m,3H),1.92(ddd,J=8.3,7.1,4.7Hz,2H).13C NMR(101MHz,DMSO-d6)δ165.62,159.72,158.15,149.03,145.07,142.48,138.83,137.59,135.71,133.24,130.25,127.23,119.52,113.53,113.50,103.85,102.68,64.76,60.42,55.47,34.13,26.08,18.34,17.81.MS(ESI)m/z:509.45[M+H]+.
2g:2-((2-(1,3-二氧戊环-2-基)乙基)巯基)-N-(3-氟代苯基)-7-(3-甲氧苯基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-6-甲酰胺
m.p.:227.3–238.9℃.1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),9.93(s,1H),7.55–7.46(m,1H),7.36–7.20(m,3H),6.91–6.80(m,2H),6.84–6.70(m,2H),6.46(d,J=1.1Hz,1H),4.86(t,J=4.6Hz,1H),3.93–3.78(m,2H),3.80–3.70(m,2H),3.68(s,3H),3.01(tt,J=8.4,4.3Hz,2H),2.19–2.14(m,3H),1.92(td,J=7.6,4.6Hz,2H).13C NMR(101MHz,DMSO-d6)δ165.47,163.69,161.30,159.72,158.14,149.05,142.45,141.23,141.12,137.40,130.76,130.66,130.24,119.52,115.64,113.53,113.49,110.31,110.10,106.78,106.52,104.05,102.68,64.76,60.44,55.46,34.13,26.08,17.78.MS(ESI)m/z:512.84[M+H]+.
2h:2-((2-(1,3-二氧戊环-2-基)乙基)巯基)-7-(3-甲氧苯基)-N-(4-甲氧苯基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-6-甲酰胺
m.p.:251.9–253.1℃.1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),9.61(s,1H),7.47–7.38(m,2H),7.24(t,J=7.9Hz,1H),6.88–6.79(m,3H),6.81–6.70(m,2H),6.46–6.41(m,1H),4.86(t,J=4.6Hz,1H),3.93–3.80(m,2H),3.83–3.72(m,2H),3.69(d,J=6.3Hz,6H),3.01(tt,J=8.3,4.3Hz,2H),2.18–2.13(m,3H),1.92(ddd,J=8.1,7.1,4.7Hz,2H).13C NMR(101MHz,DMSO-d6)δ164.76,159.69,158.01,155.82,149.19,142.52,136.19,132.51,130.15,121.63,119.56,114.21,113.48,104.48,102.69,64.76,60.56,55.64,55.46,34.14,26.09,17.69.MS(ESI)m/z:524.55[M+H]+.
2i:2-((2-(1,3-二氧戊环-2-基)乙基)巯基)-N-(3-乙酰苯基)-7-(3-甲氧苯基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-6-甲酰胺
m.p.:212.5–213.8℃.1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),9.92(s,1H),8.10(t,J=1.9Hz,1H),7.78(ddd,J=8.1,2.2,1.0Hz,1H),7.62(dt,J=7.8,1.3Hz,1H),7.40(t,J=7.9Hz,1H),7.22(t,J=7.9Hz,1H),6.82(ddd,J=8.3,2.6,0.9Hz,1H),6.81–6.70(m,2H),6.49–6.44(m,1H),4.84(t,J=4.6Hz,1H),3.91–3.68(m,4H),3.30(d,J=1.8Hz,3H),2.99(tt,J=8.3,4.2Hz,2H),2.51(s,3H),2.16(s,3H),2.00–1.85(m,2H).13C NMR(101MHz,DMSO-d6)δ198.07,165.45,159.70,158.11,149.02,142.49,139.83,137.69,137.37,130.23,129.52,124.40,123.86,119.56,119.08,113.52,104.01,102.67,64.76,60.43,55.44,34.12,27.17,26.07,17.82.MS(ESI)m/z:536.71[M+H]+.
2j:2-((2-(1,3-二氧戊环-2-基)乙基)巯基)-N-(4-乙酰苯基)-7-(3-甲氧苯基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-6-甲酰胺
m.p.:224.7–226.3℃.1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),10.07(s,1H),7.89(d,J=8.4Hz,2H),7.68(d,J=8.4Hz,2H),7.23(d,J=8.0Hz,1H),6.88–6.80(m,1H),6.81–6.71(m,2H),6.50(s,1H),4.86(t,J=4.7Hz,1H),3.86(d,J=6.5Hz,2H),3.77(d,J=6.2Hz,2H),3.67(s,3H),3.01(tt,J=9.0,4.6Hz,2H),2.18(s,3H),1.92(tt,J=7.7,4.6Hz,2H).13C NMR(101MHz,DMSO-d6)δ196.92,165.60,159.71,158.16,148.99,143.84,142.48,137.87,132.18,130.26,129.81,119.49,119.09,113.52,113.46,103.96,102.66,64.76,60.42,55.45,34.11,26.88,26.07,17.84.MS(ESI)m/z:536.32[M+H]+.
3a:甲基3-((7-(3-羟基苯基)-5-甲基-6-((5-甲基吡啶-3-基)氨基甲酰基)-4,7–二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)巯基)丙酸酯
m.p.:236.7–238.1℃.1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),9.86(s,1H),9.44(s,1H),8.48(d,J=2.3Hz,1H),8.08(dd,J=1.9,0.8Hz,1H),7.85–7.79(m,1H),7.10(t,J=7.8Hz,1H),6.69–6.55(m,3H),6.43(d,J=1.1Hz,1H),3.61(s,3H),3.24–3.12(m,2H),2.73(t,J=7.0Hz,2H),2.25(s,3H),2.20–2.14(m,3H).13C NMR(101MHz,DMSO-d6)δ172.12,165.60,157.95,157.78,149.13,145.04,142.41,138.88,137.38,135.74,133.23,130.03,127.27,117.80,115.67,114.11,104.15,60.48,51.99,34.48,26.58,18.35,17.77.MS(ESI)m/z:481.53[M+H]+.
3b:甲基3-((7-(4-羟基苯基)-5-甲基-6-((5-甲基吡啶-3-基)氨基甲酰基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)巯基)丙酸酯
m.p.:259.6–261.1℃.1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),9.81(s,1H),9.46(s,1H),8.46(d,J=2.3Hz,1H),8.07(d,J=1.9Hz,1H),7.80(d,J=2.3Hz,1H),7.10–7.01(m,2H),6.73–6.64(m,2H),6.40(s,1H),3.60(s,3H),3.15(d,J=5.0Hz,1H),2.77–2.66(m,2H),2.24(s,3H),2.17(s,3H).13C NMR(101MHz,DMSO-d6)δ172.13,165.74,157.79,157.55,148.81,145.01,138.81,137.15,135.75,133.22,131.33,128.85,127.20,115.66,104.25,60.16,51.98,34.48,26.57,18.34,17.76.MS(ESI)m/z:481.21[M+H]+.
3c:甲基3-((5-甲基-6-((5-甲基吡啶-3-基)氨基甲酰基)-7-苯基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)巯基)丙酸酯
m.p.:231.7–233.5℃.1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.88(s,1H),8.46(d,J=2.3Hz,1H),8.07(dd,J=1.9,0.9Hz,1H),7.82–7.76(m,1H),7.37–7.19(m,4H),6.50(d,J=1.1Hz,1H),3.60(s,3H),3.16(dd,J=7.0,2.1Hz,1H),2.72(t,J=6.9Hz,2H),2.24(s,3H),2.21–2.16(m,3H).13C NMR(101MHz,DMSO-d6)δ172.11,165.61,157.85,149.05,145.07,140.89,138.84,137.45,135.68,133.23,129.06,128.68,127.43,127.23,103.99,60.63,51.98,34.46,26.57,18.33,17.80.MS(ESI)m/z:465.10[M+H]+.
3d:甲基3-((5-甲基-6-((5-甲基吡啶-3-基)氨基甲酰基)-7-(对甲苯基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)巯基)丙酸酯
m.p.:235.8–236.9℃.1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),9.86(s,1H),8.47(d,J=2.4Hz,1H),8.07(dd,J=2.0,0.8Hz,1H),7.84–7.77(m,1H),7.12(s,4H),6.46(d,J=1.1Hz,1H),3.60(s,3H),3.17(dd,J=7.1,1.3Hz,1H),2.72(t,J=7.0Hz,2H),2.24(s,6H),2.18(d,J=0.9Hz,3H).13C NMR(101MHz,DMSO-d6)δ172.12,165.64,157.74,148.95,145.03,138.78,138.01,137.38,135.73,133.23,129.58,127.40,127.16,104.04,60.37,51.98,34.47,26.56,21.13,18.34,17.80.MS(ESI)m/z:479.69[M+H]+.
3e:甲基3-((5-甲基-6-((5-甲基吡啶-3-基)氨基甲酰基)-7-(邻甲苯基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)巯基)丙酸酯
m.p.:236.4–238.1℃.1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),9.91(s,1H),8.41(d,J=2.3Hz,1H),8.06(dd,J=2.0,0.8Hz,1H),7.79–7.73(m,1H),7.28–7.18(m,1H),7.21–7.08(m,3H),6.70(d,J=1.2Hz,1H),3.60(s,3H),3.15(td,J=7.1,1.2Hz,2H),2.71(t,J=7.0Hz,2H),2.37(s,3H),2.25–2.16(m,6H).13C NMR(101MHz,DMSO-d6)δ172.10,165.70,157.65,148.81,145.05,138.87,138.65,137.14,136.33,135.64,133.27,131.02,128.59,128.55,127.03,126.81,103.94,57.84,51.97,34.44,26.60,19.14,18.32,17.69.MS(ESI)m/z:479.83[M+H]+.
3f:甲基3-((7-(3,5-二甲基苯基)-5-甲基-6-((5-甲基吡啶-3-基)氨基甲酰基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)巯基)丙酸酯
m.p.:237.4–238.9℃.1H NMR(400MHz,DMSO-d6)δ6.83(d,J=1.6Hz,2H),3.60(s,3H),3.25–3.08(m,2H),2.72(td,J=7.1,1.5Hz,2H),2.27–2.15(m,12H).13C NMR(101MHz,DMSO-d6)δ172.11,165.68,157.65,148.97,145.08,140.81,138.90,138.01,137.13,135.68,133.23,130.20,127.31,125.24,104.09,60.68,51.97,34.44,26.60,21.34,18.34,17.82.MS(ESI)m/z:493.70[M+H]+.
3g:甲基3-((7-(4-氟代苯基)-5-甲基-6-((5-甲基吡啶-3-基)氨基甲酰基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)巯基)丙酸酯
m.p.:241.5–242.7℃.1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),9.87(s,1H),8.07(d,J=1.9Hz,1H),7.78(s,1H),7.39–7.06(m,3H),6.50(s,1H),3.60(s,3H),3.16(d,J=2.6Hz,1H),2.71(s,1H),2.21(d,J=24.4Hz,6H).13C NMR(101MHz,DMSO-d6)δ172.11,165.55,161.07,157.96,148.91,145.12,138.85,137.57,137.11,135.62,133.26,129.70,129.62,127.26,116.00,115.78,103.76,59.93,51.98,34.43,26.55,18.33,17.82.MS(ESI)m/z:483.65[M+H]+.
3h:甲基3-((7-(3-氟代苯基)-5-甲基-6-((5-甲基吡啶-3-基)氨基甲酰基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)巯基)丙酸酯
m.p.:235.4–237.2℃.1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),9.89(s,1H),8.45(d,J=2.3Hz,1H),8.08(dd,J=1.9,0.8Hz,1H),7.78(d,J=2.3Hz,1H),7.47–7.25(m,1H),7.23–6.96(m,3H),6.50(s,1H),3.60(s,3H),3.17(td,J=7.0,3.3Hz,2H),2.71(t,J=7.0Hz,2H),2.32–2.11(m,6H).13C NMR(101MHz,DMSO-d6)δ172.10,165.52,163.81,161.38,158.09,148.98,145.16,143.54,143.48,138.84,137.75,135.59,133.28,131.16,131.08,127.27,123.75,123.72,115.77,115.56,114.37,114.15,103.43,60.11,51.97,34.42,26.56,18.33,17.86.MS(ESI)m/z:483.78[M+H]+.
4a:甲基3-((7-(3-甲氧基苯基)-6-((6-甲氧基吡啶-3-基)氨基甲酰基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)巯基)丙酸酯
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.47(s,1H),8.81(d,J=1.9Hz,1H),7.58(dd,J=8.4,1.9Hz,1H),7.26(t,J=7.8Hz,1H),7.16(ddt,J=8.0,2.3,1.1Hz,1H),7.10(td,J=2.2,1.0Hz,1H),6.88–6.79(m,2H),6.31(h,J=1.1Hz,1H),3.86(s,2H),3.78(s,2H),3.61(dt,J=14.3,5.8Hz,1H),3.59(s,3H),3.51(dt,J=14.3,5.9Hz,1H),2.76(q,J=5.8Hz,2H),2.28(d,J=0.9Hz,3H).
13C NMR(100MHz,DMSO-d)δ172.01,166.06,163.02,159.59,159.58,147.60,147.41,141.43,138.75,130.24,129.53,128.38,122.46,113.88,113.83,113.81,111.05,60.56,55.25,54.78,51.69,34.03,27.44,18.85.
4b:甲基3-((7-(3-乙酰苯基)-6-((6-甲氧基吡啶-3-基)氨基甲酰基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)巯基)丙酸酯
1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),10.43(s,1H),8.76(d,J=1.9Hz,1H),8.12(td,J=2.2,1.0Hz,1H),7.91(ddd,J=7.6,2.3,1.6Hz,1H),7.66(dd,J=8.4,1.9Hz,1H),7.63–7.50(m,2H),6.85(d,J=8.5Hz,1H),6.36(h,J=1.0Hz,1H),3.86(s,2H),3.63(dt,J=14.2,5.8Hz,1H),3.60(s,3H),3.52(dt,J=14.3,5.9Hz,1H),2.78(t,J=5.8Hz,2H),2.57(s,2H),2.29(d,J=0.9Hz,3H).
13C NMR(100MHz,DMSO-d)δ196.93,172.19,166.06,163.02,159.58,147.59,147.41,141.43,137.36,136.51,133.01,131.67,129.06,128.39,127.84,127.58,113.83,111.05,60.63,54.84,51.70,34.02,27.44,26.46,18.86.
4c:甲基3-((7-(3-乙酰苯基)-5-甲基-6-((5-甲基吡啶-3-基)氨基甲酰基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)巯基)丙酸酯(4c)
1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),10.04(s,1H),9.17(d,J=1.4Hz,1H),8.23(d,J=1.5Hz,1H),8.10(td,J=2.1,0.9Hz,1H),7.90(ddd,J=7.8,2.2,1.3Hz,1H),7.75(t,J=1.6Hz,1H),7.60(t,J=7.8Hz,1H),7.51(ddt,J=7.8,2.1,1.1Hz,1H),6.36(h,J=1.1Hz,1H),3.60(s,3H),3.59(dt,J=14.3,5.7Hz,1H),3.49(dt,J=14.3,5.8Hz,1H),2.76(td,J=5.8,1.2Hz,2H),2.58(s,2H),2.42(s,3H),2.30(d,J=0.9Hz,3H).
13C NMR(100MHz,DMSO-d)δ196.93,172.01,165.86,159.58,147.59,147.41,144.82,139.86,137.36,136.51,134.30,133.18,131.67,129.08,127.90,127.58,123.86,113.83,60.63,51.69,34.03,27.44,26.46,18.85,18.24.
4d:甲基3-((7-(3-甲氧基-4-甲基苯基)-5-甲基-6-((5-甲基吡啶-3-基)氨基甲酰基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)巯基)丙酸酯(4d)
1H NMR(400MHz,DMSO-d6)δ11.35(s,1H),10.29(s,1H),9.25(d,J=1.4Hz,1H),8.25(d,J=1.4Hz,1H),7.73–7.67(m,1H),7.08(q,J=0.8Hz,2H),7.02(q,J=1.1Hz,1H),6.28(q,J=0.9Hz,1H),3.75(s,2H),3.59(s,3H),3.64–3.53(m,1H),3.47(dt,J=14.3,5.8Hz,1H),2.87–2.68(m,2H),2.42(s,3H),2.28(d,J=0.9Hz,3H),2.20(d,J=0.5Hz,3H).
13C NMR(100MHz,DMSO-d)δ172.01,165.85,159.58,157.19,147.60,147.41,144.82,139.86,137.35,134.30,133.18,130.10,126.83,123.86,122.64,113.83,111.62,60.65,55.67,51.69,34.03,27.44,18.85,18.24,16.03.
本发明所列举的各原料,以及本发明各原料的上下限、区间取值,以及工艺参数(如温度、时间等)的上下限、区间取值都能实现本发明,在此不一一列举实施例。
以上所述是本发明的优选实施方式而已,当然不能以此来限定本发明之权利范围,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和变动,这些改进和变动也视为本发明的保护范围。
Claims (10)
1.一种三唑并嘧啶类化合物,其特征在于,所述三唑并嘧啶类化合物的化学式具有如下的通式:
或者是式I化合物的异构体、可药用的盐或水合物;
其中:
n=0-5;
R1为C1-C6烷氧基、C1-C6酯基、C1-C6醛基、C1-C6酮基、取代或未取代的杂环烷基、取代或未取代芳香杂环,其中所述取代的杂环烷基、取代芳香杂环为被1个、2个、3个、4个或5个独立地选自下列的取代基取代:-F、-Cl、-Br、-I、硝基、羟基、氨基、氰基;
R2为取代或未取代的杂环烷基、取代或为取代的芳香环、取代或未取代芳香杂环,其中所述取代的杂环烷基、取代或为取代的芳香环、取代芳香杂环为被1个、2个、3个、4个或5个独立地选自下列的取代基取代:-F、-Cl、-Br、-I、硝基、羟基、氨基、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、C1-C6醛基、C1-C6酮基;
R3为取代或未取代的杂环烷基、取代或为取代的芳香环、取代或未取代芳香杂环,其中所述取代的杂环烷基、取代或为取代的芳香环、取代芳香杂环为被1个、2个、3个、4个或5个独立地选自下列的取代基取代:-F、-Cl、-Br、-I、硝基、羟基、氨基、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、C1-C6醛基、C1-C6酮基。
3.如权利要求2所述的三唑并嘧啶类化合物,其特征在于:优选的,所述三唑并嘧啶类化合物为:
7-(3-甲氧苯基)-2-((3-甲氧丙基)硫基)-5-甲基-N-(吡啶-3-基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-6-甲酰胺(1a);
2-((2-(1,3-二氧戊环-2-基)乙基)硫基)-7-(3-甲氧苯基)-5-甲基-N-(吡啶-3-基)-4,7-二氢-[1,2,4]三唑并[1,5-a]嘧啶-6-甲酰胺(1b);
甲基3-((7-(3-甲氧苯基)-5-甲基-6-(吡啶-3-基氨甲酰基)-4,7-二氢-[1,2,4]三唑并[1,5-a]嘧啶-2-基)硫基)丙酸酯(1c);
7-(3-甲氧苯基)-5-甲基-N-(吡啶基3-基)-2-((吡啶-4-基甲基)硫基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-6-甲酰胺(1d);
甲基3-((7-(3-甲氧苯基)-5-甲基-6-((5-甲基吡啶3-基)氨甲酰基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫)丙酸酯(2a);
甲基3-((6-((3-氟苯)氨甲酰基)-7-(3-甲氧苯基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(2b);
甲基3-((7-(3-甲氧苯基)-6-((4-甲氧苯基)氨甲酰基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(2c);
甲基3-((6-((3-乙酰苯基)氨甲酰基)-7-(3-甲氧苯基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(2d);
甲基3-((6-((4-乙酰苯基)氨甲酰基)-7-(3-甲氧苯基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(2e);
2-((2-(1,3-二氧戊环-2-基)乙基)硫基)-7-(3-甲氧苯基)-5-甲基-N-(5-甲基吡啶基3-基)-4,7-二氢-[1,2,4]三唑并[1,5-a]嘧啶-6-甲酰胺(2f);
2-((2-(1,3-二氧戊环-2-基)乙基)硫基)-N-(3-氟苯基)-7-(3-甲氧苯基)-5-甲基-4,7-二氢-[1,2,4]三唑并[1,5-a]嘧啶-6-甲酰胺(2g);
2-((2-(1,3-二氧戊环-2-基)乙基)硫基)-7-(3-甲氧苯基)-N-(4-甲氧苯基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-6-甲酰胺(2h);
2-((2-(1,3-二氧戊环-2-基)乙基)硫基)-N-(3-乙酰苯基)-7-(3-甲氧苯基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-6-甲酰胺(2i);
2-((2-(1,3-二氧戊环-2-基)乙基)硫基)-N-(4-乙酰苯基)-7-(3-甲氧苯基)-5-甲基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-6-甲酰胺(2j);
甲基3-((7-(3-羟苯基)-5-甲基-6-((5-甲基吡啶3-基)氨甲酰基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(3a);
甲基3-((7-(4-羟苯基)-5-甲基-6-((5-甲基吡啶基3-基)氨甲酰基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(3b);
甲基3-((5-甲基-6-((5-甲基吡啶基3-基)氨甲酰基)-7-苯基-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(3c);
甲基3-((5-甲基-6-((5-甲基吡啶基3-基)氨甲酰基)-7-(对-甲苯基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(3d);
甲基3-((5-甲基-6-((5-甲基吡啶基3-基)氨甲酰基)-7-(邻-甲苯基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(3e);
甲基3-((7-(3,5-二甲苯基)-5-甲基-6-((5-甲基吡啶基3-基)氨甲酰基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(3f);
甲基3-((7-(4-氟苯基)-5-甲基-6-((5-甲基吡啶基3-基)氨甲酰基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(3g);
或者,
甲基3-((7-(3-氟苯基)-5-甲基-6-((5-甲基吡啶基3-基)氨甲酰基)-4,7-二氢-[1,2,4]三唑[1,5-a]嘧啶-2-基)硫基)丙酸酯(3h)。
5.如权利要求4所述的三唑并嘧啶类化合物,其特征在于:步骤a中,采用氢氧化钠的乙醇溶液作为溶剂,以物质的量计,三唑衍生物:溴代衍生物:氢氧化钠:乙醇的用量为1:1-2:1-2:30-80,室温下反应20-60分钟,反应产物经过萃取、洗涤和干燥步骤得到中间体1;步骤b中,采用三乙胺和甲苯作为溶剂,以物质的量计,胺类衍生物:乙酸乙酯:三乙胺:甲苯的用量为1:1-2:3-5:5-10,100℃下反应10-20小时,反应产物经过沉淀、过滤、洗涤步骤得到中间体2;步骤c中,以物质的量计,中间体1:中间体2:醛类衍生物:乙醇的用量为1:1-2:1-2:30-80乙醇溶剂在80℃下反应2-5小时,反应产物经过滤洗涤得到终产物。
6.一种如权利要求1-3任一所述的三唑并嘧啶类化合物的应用,其特征在于:所述三唑并嘧啶类化合物可以用作制备抗癌药物、免疫抑制剂、PI3K抑制剂、mTOR抑制剂、抑制PI3K-Akt-mTOR通路信号的药物、抑制T淋巴细胞增殖的药物、抗菌药物、抗病毒药物、促进肿瘤细胞凋亡的药物、使细胞周期停滞在G1期的药物、防止器官排斥反应的药物、降低动脉栓塞的药物、抗衰老药物、抗阿尔茨海默病药物、抗炎药物、放射增敏剂或抗菌药物。
7.如权利要求6所述的三唑并嘧啶类化合物的应用,其特征在于:所述三唑并嘧啶类化合物可以作为放射增敏剂,与放疗联合使用治疗癌症;所述三唑并嘧啶类化合物可以作为化疗增敏剂,与分子靶向药物联合使用治疗癌症。
8.如权利要求5-7任一所述的三唑并嘧啶类化合物的应用,其特征在于:所述癌症包括肝癌、肺癌、乳腺癌、白血病、子宫颈癌、卵巢癌、胃腺癌、前列腺癌。
9.一种如权利要求1-3任一所述的三唑并嘧啶类化合物的应用,其特征在于:所述三唑并嘧啶类化合物可以作为ATP类似物用于治疗激酶失调相关疾病或病症。
10.一种药物组合物,其特征在于,包含如权利要求1-3任一所述的化合物或其可药用的盐、异构体、水合物以及至少一种可药用的载体。
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