CN114644560A - 一种苯基丙烯酸类化合物及其制备方法和应用 - Google Patents
一种苯基丙烯酸类化合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明提供一种苯基丙烯酸类化合物及其制备方法和应用,所述苯基丙烯酸类化合物具有如下式I所示结构,本发明提供的苯基丙烯酸类化合物可以与多个靶点蛋白有较好的结合,并且具有较好的生物利用度,可用于制备预防或治疗肿瘤、自身免疫性疾病、炎症性疾病、神经退行性疾病或抗衰老药物。
Description
技术领域
本发明属于医药技术领域,具体涉及一种苯基丙烯酸类化合物及其制备方法和应用。
背景技术
医学数据表明,炎症是导致肿瘤的危险因素。例如,宫颈癌中由于乳头瘤病毒感染所致的患者较多;胃幽门螺杆菌的感染有增加胃癌风险的趋势;慢性肝炎也可能是诱发肝癌的直接原因。其它因素,如自身免疫性肠病与结肠癌密切相关,空气中的PM2.5也是诱发肺癌的黑手。肿瘤被定义为一种与心脏病、慢性呼吸系统疾病或者糖尿病一样非传染性的疾病。它们大多是长时间的慢性疾病,进展比较缓慢。炎症和肿瘤的相关性是最早在1800年前由Galenus提出的,很多研究已经证实持续的炎症可以使病变从感染或者自身免疫性的炎症进展为肿瘤。
苯基丙烯酸类化合物广泛存在于活性天然产物中,其具有多种生物活性,如抗菌、抗氧化、抗炎、抗肿瘤等,具有非常广阔的研究前景,我们长期从事此类天然产物的结构优化与抗肿瘤活性、治疗自身免疫性疾病和抗炎症的构效关系研究,针对天然产物的结构改造有助于发现比原天然产物具有更强肿瘤抑制活性、治疗自身免疫性疾病和炎症性疾病活性,更低毒性的先导物,而进一步成为抗肿瘤、抗炎免疫药物。
此发明内容所设计的苯基丙烯酸类衍生物在抗肿瘤潜在的靶点概括如下:
Caspase-3是一种与caspase-8和caspase-9相互作用的caspase蛋白。由casp3 基因编码。血液中caspase-3,p17片段的水平升高是最近心肌梗死的一个标志。现在有研究表明caspase-3可能在胚胎和造血干细胞分化、细胞凋亡中起着重要作用。有研究表明头颈癌以及乳腺癌患者中caspase-3的表达量异常的高,因此降低其表达,在一定程度上也是可以减少癌症发病的方法之一。
表皮生长因子受体(EGFR):EGFR的突变活化是导致肿瘤细胞异常生物学活动的重要因素,其中EGFR中T790M突变是一个碱基对发生从胞嘧啶核苷 (C)到胸腺嘧啶(T)的改变,即EGFR酪氨酸激酶功能中790位点的苏氨酸被蛋氨酸取代,这种突变可使得EGFR重新处于被激活状态,从而导致酪氨酸激酶抑制剂(TKI)产生耐药性。而我们将此突变后的蛋白与此类天然产物以及衍生物通过计算机辅助设计的方法对接后发现,此类化合物的打分都很高,提示:苯基丙烯酸类衍生物可以成为此靶点的候选物。
组蛋白-赖氨酸N-甲基转移酶EZH2:EZH2是一个由人类EZH2基因所编码的酶。已鉴定该基因转录出的两种转录物变异体编码不同的亚型;基因序列改变与表观遗传修饰异常有本质的不同。因为DNA序列一旦发生突变,基因就难以修复或变异的基因产物也难以消除。但是表观遗传修饰异常能潜在性地被其相关染色质修饰酶类的抑制剂所逆转。因此,明确肿瘤细胞中的表观遗传修饰酶类的作用机制显得十分重要,进而为阻止表观遗传修饰变异提供相应治疗手段。目前EZH2抑制剂并未有上市药物,共有五种药物正在临床I/II期研究中。
组蛋白去乙酰化酶(histone deacetylase,HDAC):一类蛋白酶,对染色体的结构修饰和基因表达调控发挥着重要的作用。一般情况下,组蛋白的乙酰化有利于 DNA与组蛋白八聚体的解离,核小体结构松弛,从而使各种转录因子和协同转录因子能与DNA结合位点特异性结合,激活基因的转录。在细胞核内,组蛋白乙酰化与组蛋白去乙酰化过程处于动态平衡,并由组蛋白乙酰化转移酶(histone acetyltransferase,HAT)和组蛋白去乙酰化酶(histone deacetylase,HDAC)共同调控。
Src激酶:一种非受体型蛋白激酶,其广泛存在于癌细胞中,并在细胞生长、增殖的各个过程中都起到重要作用,如基因转录、细胞分化、迁移、血管生成、防止细胞凋亡等,Src抑制剂的研究已成为抗肿瘤药物研究的热点。目前已有一系列Src抑制剂处于临床研究阶段。
癌症免疫治疗是一种越来越有效的癌症治疗策略,T细胞在免疫治疗中起着关键作用,众多免疫检查点是有待发掘的宝藏,自CTLA-4和PD-1/PD-L1单抗疗效得到肯定后,在此的单抗轨道上竞争激烈,因此应更关注于其他免疫检查点靶点上,其功能决定了免疫治疗的疗效。
T细胞的生存和发育受到TCR信号的影响,而TCR信号通路依赖于Src 家族激酶(SFK)。Lck是SFK的重要成员,在T细胞的大部分生命周期中都有表达。此外,Lck在激活TCR信号通路以激活T细胞中发挥重要作用。CSK是 SFK的关键调节器,其对Lck(Tyr505)的磷酸化使Lck失活,后者通过TCR 抑制T细胞活化。因此,CSK和p-Lck(Tyr505)可能是未来免疫调节治疗的有效靶点。
CD73是5-主核苷酸水解酶,可将细胞外腺苷一磷酸(AMP)水解为腺苷,腺苷是一种功能强大的免疫抑制性分子,能够抑制CD8阳性T细胞的活化,进而帮助癌细胞逃逸T细胞的“追杀”。浸润肿瘤的NK细胞上调CD73表达,而这些CD73+NK细胞的发生频率与乳腺癌患者肿瘤的大小相关。研究结果支持肿瘤可以劫持NK细胞以免疫逃避,并且CD73表达定义了可诱导的NK细胞群体,在肿瘤微环境中具有免疫调节特性。
KIR,杀伤细胞免疫球蛋白样受体,表达在NK细胞和部分T细胞表面的受体,能特异性识别细胞表面MHC-I类分子,从而发挥免疫调节功能。
LAG-3,淋巴细胞活化因子3蛋白,是分布于活化T细胞、NK细胞和树突状细胞中的一种可与MHC-II类分子结合的免疫负调节分子受体,具有维持内环境稳定和参与免疫调节的功能,与肿瘤的发生发展密切相关。
4-1BB,也称CD137,是表达在活化T细胞表面的TNF家族成员,是一种可诱导的T细胞表面受体,4-1BB及其配体是CD28/B7共刺激信号途径之外的另一重要共刺激分子。
ACAT1属于特异性硫醇酶超家族,中文名称为乙酰乙酰CoA硫化酶,也被称为乙酰CoA乙酰基转移酶(ACAT),许多报道显示ACAT1在肿瘤细胞中表达通常呈现异常状态,并对肿瘤的发生发展起到至关重要的作用。ACAT1的活性在不同的人类癌症细胞中的上调机制值得研究。ACAT1的高表达会降低其总体生存率;MDA-MB-231人乳腺癌细胞中ACAT1过度表达,所导致的酮体再利用驱动肿瘤的进展和转移,因此对以ACAT1为靶点的苯基丙烯酸类衍生物的研究,可能会发现新型抗肿瘤药物。
在抗氧化和抗炎免疫方面与如下有关:
由于苯基丙烯酸结构广泛存在于植物的多酚类次生代谢产物中,具有很强抗氧化和抗炎特性。其能够螯合金属离子和清除自由基[超氧阴离子(O2 -)、过氧化氢(H2O2)、羟基自由基(·OH)、次氯酸(HOCl)、过氧亚硝酸盐阴离子 (ONOO-)和一氧化氮(NO)]。苯基丙烯酸类结构化合物具有很强的抗氧化活性,其清除1,1-二苯基-2-三硝基苯肼(DPPH)自由基的活性是维生素C和E 的2~3倍,清除超氧阴离子自由基的活性是维生素C和E的10~30倍。
在抗炎作用方面,对角叉菜胶致大鼠足跖肿胀炎症模型具有抗炎活性。其机制可通过清除细胞内ROS,抑制p38级联磷酸化和上调核因子κB(nuclear factor kappa-B,NF-κB)信号通路来抑制白介素-8(interleukin-8,IL-8)的产生,从而起到抗炎作用。
然而在硫酸葡聚糖诱导的小鼠溃疡性结肠炎模型中,通过调控丝裂原活化蛋白激酶/ERK/c-Jun氨基末端激酶信号通路来降低组织的炎症反应。为此可称为治疗类风湿关节炎的新型治疗剂,其机制是通过降低了NF-κB与B细胞活化因子启动子区域的DNA结合能力,进而抑制了通过NF-κB途径介导的B细胞活化因子表达。同时具有较强的肝功能保护作用,可有效降低CCl4诱导的急性肝损伤产生TNF-α、IL-6和IL-1β炎症因子,其机制是通过核因子E-2相关因子2(nuclear factor erythroid 2-related factor 2,Nrf2)介导的抗氧化和抑制Nod 样受体家族热蛋白结构域3炎症小体的激活来进行急性肝损伤的保护作用。此类化合物也可以通过增加B淋巴细胞瘤-2(B-cell lymphoma-2,Bcl2)表达并抑制环氧化酶-2、诱导型一氧化氮合酶、Bax(Bcl2 associated X,Bax)和caspases 3、9介导的炎症反应来降低甲氨蝶呤(methotrexate,MTX)诱导的肝毒。
神经退行性疾病阿尔茨海默病和帕金森病的病理学研究表明,慢性氧化应激和炎症反应会导致神经元受损。基于苯基丙烯酸类较强的抗氧化和抗炎作用,发现它具有很好的神经系统保护作用。一些临床和临床前研究表明,苯基丙烯酸类天然产物对阿尔茨海默病和帕金森病展现出很好的治疗效果。可以改善记忆力减退和海马细胞短暂性全脑缺血后死亡,其机制是通过增加Bcl2、超氧化物歧化酶2和血小板-内皮细胞黏附分子CD31表达,并降低内皮素-1表达来改善空间记忆,防止双侧颈总动脉闭塞后CA1锥体细胞死亡。通过激活SIRT1调节的线粒体功能来预防饱和游离脂肪酸(free fatty acid,FFA)诱导的脂毒性。其机制是通过减少ROS的产生以及增加线粒体质量和线粒体膜电位,减轻了氧化应激和线粒体功能障碍;显著降低促细胞凋亡蛋白Bax表达,从而减少线粒体介导的caspase依赖性细胞凋亡。
尽管苯基丙烯酸类衍生物已被证实具有如上较广的活性作用,但其确切的作用机制以及构效关系需要进一步的研究,需要合成其结构衍生物,并研究其药物作用方式以及可用来治疗的疾病,尤其是炎症相关、肿瘤、自身免疫性疾病、神经退行性疾病和衰老等。
发明内容
针对现有技术的不足,本发明的目的在于提供一种苯基丙烯酸类化合物及其制备方法和应用,本发明提供的苯基丙烯酸类化合物可以与多个靶点蛋白有较好的结合,并且具有较好的生物利用度,可用于制备预防或治疗肿瘤、自身免疫性疾病、炎症性疾病、神经退行性疾病或抗衰老药物。
为达此目的,本发明采用以下技术方案:
第一方面,本发明提供一种苯基丙烯酸类化合物,所述苯基丙烯酸类化合物具有如下式I所示结构:
其中,R1、R2、R3、R4、R7、R8、R9各自独立地选自氢、卤素、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、C1-C6 (例如可以是C1、C2、C3、C4、C5、C6等)烷氧羰基、C1-C6(例如可以是 C1、C2、C3、C4、C5、C6等)烷羰基氧基、C1-C6(例如可以是C1、C2、C3、 C4、C5、C6等)烷基、C1-C6(例如可以是C1、C2、C3、C4、C5、C6等) 烷氧基、C1-C6(例如可以是C1、C2、C3、C4、C5、C6等)烷氧基亚甲基氧基、C1-C6(例如可以是C1、C2、C3、C4、C5、C6等)烷酰基、三卤代C1-C6 (例如可以是C1、C2、C3、C4、C5、C6等)烷基或三卤代C1-C6(例如可以是C1、C2、C3、C4、C5、C6等)烷氧基中的任意一种;或者,R1、R2、R7、 R8、R9各自独立地选自-O(CH2)nO-,并与其取代的苯基相连成环,n选自1、2 或3;
R5选自氢、氨基、C1-C6(例如可以是C1、C2、C3、C4、C5、C6等)烷基、C1-C6(例如可以是C1、C2、C3、C4、C5、C6等)烷氧基甲基或C1-C6 (例如可以是C1、C2、C3、C4、C5、C6等)烷基胺基中的任意一种;
R6选自氢、羟基、氨基、羰基、C1-C6(例如可以是C1、C2、C3、C4、C5、C6等)烷基胺基、C1-C6(例如可以是C1、C2、C3、C4、C5、C6等) 烷羰基氧基或C1-C6(例如可以是C1、C2、C3、C4、C5、C6等)烷氧基羰基中的任意一种;
X选自O或NH;
Y选自O、NH、S、亚砜或砜中的任意一种。
在本发明中三卤代C1-C6烷基或三卤代C1-C6烷氧基中三卤指的是含3个卤素,包括F3 C1-C6烷基、Br3 C1-C6烷基、Cl3 C1-C6烷基、I3 C1-C6烷基、 F2Br C1-C6烷基、F2ClC1-C6烷基、F2I C1-C6烷基、FBr2 C1-C6烷基、FCl2 C1-C6 烷基、FI2 C1-C6烷基、ClBr2 C1-C6烷基、ICl2 C1-C6烷基、ClI2 C1-C6烷基; F3 C1-C6烷氧基、Br3 C1-C6烷氧基、Cl3 C1-C6烷氧基、I3 C1-C6烷氧基、F2Br C1-C6烷氧基、F2Cl C1-C6烷氧基、F2I C1-C6烷氧基、FBr2C1-C6烷氧基、FCl2 C1-C6烷氧基、FI2 C1-C6烷基、ClBr2 C1-C6烷氧基、ICl2 C1-C6烷氧基、ClI2 C1-C6 烷氧基。
优选F3 C1-C4烷基、Br3 C1-C4烷基、Cl3 C1-C4烷基、I3 C1-C4烷基、F2Br C1-C4烷基、F2Cl C1-C4烷基、F2I C1-C4烷基、FBr2 C1-C4烷基、FCl2 C1-C4 烷基、FI2 C1-C4烷基、ClBr2 C1-C4烷基、ICl2 C1-C4烷基、ClI2 C1-C4烷基; F3 C1-C4烷氧基、Br3 C1-4烷氧基、Cl3C1-C4烷氧基、I3 C1-C4烷氧基、F2Br C1-C4 烷氧基、F2Cl C1-C4烷氧基、F2I C1-C4烷氧基、FBr2 C1-C4烷氧基、FCl2 C1-C4 烷氧基、FI2 C1-C4烷基、ClBr2 C1-C4烷氧基、ICl2 C1-4烷氧基、ClI2 C1-C4烷氧基。
最优选F3 C、F3CCH2、Br3C、Br3CCH2、Cl3C、Cl3CCH2、I3C、I3CCH2、 F2BrC、F2BrCCH2、F2ClC、F2ClCCH2、F2IC、F2ICCH2、FBr2C、FBr2CCH2、FCl2C、FCl2C CH2、FI2C、FI2CCH2、ClBr2C、ClBr2CCH2、ICl2C、ICl2CCH2、 ClI2C、ClI2CCH2;F3CO、F3CCH2O、Br3CO、Br3CCH2O、Cl3CO、Cl3CCH2O、 I3CO、I3CCH2O、F2BrCO、F2BrCCH2O、F2ClCO、F2ClCCH2O、F2ICO、F2ICCH2O、 FBr2CO、FBr2CCH2O、FCl2CO、FCl2CCH2O、FI2CO、FI2CCH2O、ClBr2CO、 ClBr2CCH2O、ICl2CO、ICl2CCH2O、ClI2CO、ClI2CCH2O。
在本发明中,所述苯基丙烯酸类化合物选自如下式II~式V中的任意一种:
其中,所述R1、R2各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、C1-C4(例如可以是C1、C2、C3、C4等)烷氧羰基、C1-C4(例如可以是C1、C2、C3、C4等) 烷羰基氧基、C1-C4(例如可以是C1、C2、C3、C4等)烷基、C1-C4(例如可以是C1、C2、C3、C4等)烷氧基、C1-C4(例如可以是C1、C2、C3、C4等) 烷氧基亚甲基氧基、三卤代C1-C4(例如可以是C1、C2、C3、C4等)烷基、三卤代C1-C4(例如可以是C1、C2、C3、C4等)烷氧基中的任意一种;
所述R3、R4各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、C1-C4(例如可以是C1、 C2、C3、C4等)烷氧羰基、C1-C4(例如可以是C1、C2、C3、C4等)烷羰基氧基、C1-C4(例如可以是C1、C2、C3、C4等)烷基、C1-C4(例如可以是 C1、C2、C3、C4等)烷氧基、三卤代C1-C4(例如可以是C1、C2、C3、C4 等)烷基或三卤代C1-C4(例如可以是C1、C2、C3、C4等)烷氧基中的任意一种;
所述R5选自氢、氨基、C1-C4(例如可以是C1、C2、C3、C4等)烷基、 C1-C4(例如可以是C1、C2、C3、C4等)烷氧基甲基或C1-C4(例如可以是 C1、C2、C3、C4等)烷基胺基中的任意一种;
所述R6选自氢、羟基、氨基、羰基、C1-C4(例如可以是C1、C2、C3、 C4等)烷基胺基、C1-C4(例如可以是C1、C2、C3、C4等)烷羰基氧基或C1-C4 (例如可以是C1、C2、C3、C4等)烷氧基羰基中的任意一种;
所述R7、R8、R9各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、C1-C4(例如可以是 C1、C2、C3、C4等)烷基、C1-C4(例如可以是C1、C2、C3、C4等)烷氧基、C1-C4(例如可以是C1、C2、C3、C4等)烷氧羰基、C1-C4(例如可以是 C1、C2、C3、C4等)烷羰基氧基、C1-C3(例如可以是C1、C2、C3等)烷酰基、C1-C4(例如可以是C1、C2、C3、C4等)烷氧基亚甲基氧基、三卤代C1-C4 (例如可以是C1、C2、C3、C4等)烷基或三卤代C1-C4(例如可以是C1、C2、 C3、C4等)烷氧基中的任意一种;
所述X选自O或NH;
所述Y选自O、NH、S、亚砜或砜中的任意一种;
所述p1、p2、p3各自独立地选自1、2或3。
在本发明中,所述R1、R2各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲氧羰基、乙氧羰基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、甲基、乙基、甲氧基、乙氧基、C1-C2(例如可以是C1、C2等)烷羰基氧基、C1-C2(例如可以是C1、C2等)烷氧基亚甲基氧基、三卤代C1-C2(例如可以是C1、C2等)烷基或三卤代C1-C2(例如可以是C1、C2等)烷氧基中的任意一种;
所述R3、R4各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲氧羰基、乙氧羰基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、甲基、乙基、甲氧基、乙氧基、C1-C2(例如可以是C1、C2等)烷羰基氧基、三卤代 C1-C2(例如可以是C1、C2等)烷基或三卤代C1-C2(例如可以是C1、C2等) 烷氧基中的任意一种;
所述R5选自氢、氨基、甲基、乙基、C1-C2(例如可以是C1、C2等)烷氧基甲基或C1-C2(例如可以是C1、C2等)烷基胺基中的任意一种;
所述R6选自氢、氨基、羟基、羰基、C1-C2(例如可以是C1、C2等)烷基胺基、C1-C2(例如可以是C1、C2等)烷羰基氧基或C1-C2(例如可以是 C1、C2等)烷氧基羰基中的任意一种;
所述R7、R8、R9各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、甲基、乙基、甲氧基、乙氧基、甲氧羰基、乙氧羰基、甲酰基、乙酰基、丙酰基、丁酰基、戊酰基、异丁酰基、2-甲基丁酰基、C1-C2(例如可以是C1、C2等)烷氧基亚甲基氧基、三卤代C1-C2(例如可以是C1、C2等)烷基或三卤代C1-C2(例如可以是C1、 C2等)烷氧基;
所述X选自O或NH;
所述Y选自O、NH、S、亚砜或砜中的任意一种;
所述p1、p2、p3各自独立地选自1或2。
在本发明中,所述R1、R2各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲氧羰基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、甲基、乙基、甲氧基、乙氧基、三氟甲基、三氟甲氧基或甲氧基亚甲基氧基中的任意一种;
所述R3、R4各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲氧羰基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、甲基、乙基、甲氧基、乙氧基、三氟甲基或三氟甲氧基中的任意一种;
所述R5选自氢、甲基、乙基、甲氧基甲基或氨基中的任意一种;
R6选自氢、羟基、氨基、羰基或C1-C2(例如可以是C1、C2等)烷羰基氧基中的任意一种;
R7、R8、R9各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、甲基、乙基、甲氧基、乙氧基、三氟甲基、三氟甲氧基、甲氧羰基、甲酰基、乙酰基、丙酰基、丁酰基、戊酰基、异丁酰基或甲氧基亚甲基氧基中的任意一种;
X选自O或NH;
Y选自O、NH、S、亚砜或砜中的任意一种或至少两种的组合;
所述p1、p2、p3各自独立地选自1。
在本发明中,所述苯基丙烯酸类化合物选自如下M1-M31中的任意一种:
第二方面,本发明提供一种根据第一方面所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐。
优选地,所述药学上可接受的盐包括盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、甲磺酸盐、对甲苯磺酸盐、乙酸盐、三氟乙酸盐、水杨酸盐、氨基酸盐、枸杞酸盐、马来酸盐、酒石酸盐、富马酸盐、柠檬酸盐、乳酸盐、钠盐、钾盐、钙盐、镁盐、锂盐、铵盐或能提供生理上可接受的阳离子的有机碱的盐中的任意一种或至少两种的组合。
优选地,所示能提供生理上可接受的阳离子的有机碱的盐包括甲胺盐、二甲胺盐、三甲胺盐、哌啶盐、吗啉盐或三(2-羟乙基)胺盐中的任意一种或至少两种的组合。
在本发明中,术语“卤素"是指氟、氯、溴、碘。
根据本发明,式I化合物可以异构体的形式存在,式I化合物连接R5、R6基团的碳的构型可为R或S构型。
本发明包括所有可能的立体异构体以及两种或多种异构体的混合物。
如果存在顺/反异构体,本发明涉及顺式形式和反式形式以及这些形式的混合物,如果需要单一异物体可根据常规方法分离或通过立体选择合成制备。
本发明中的所有盐都可以采用常规方法制备。另外,式I所示化合物溶剂化物和其盐的制备过程中,不同结晶条件可能出现多晶或共晶。
第三方面,本发明提供一种根据第一方面所述的苯基丙烯酸类化合物的制备方法,所述制备方法包括以下步骤:
(1)将式a所示化合物与式b所示化合物进行缩合反应,得到式c所示化合物,反应式如下所示:
(2)将式c所示化合物进行脱保护基,得到式d所示化合物,反应式如下所示:
(3)将式d所示化合物和式e所示化合物进行取代反应,得到式I所示化合物,反应式如下所示:
或者,所述制备方法包括以下步骤:将式f所示化合物与式g所示化合物进行缩合反应,得到式I所示化合物,反应式如下所示:
其中,所述X’选自OH或NH2;
Y’选自叔丁基二甲基硅氧基、叔丁基二苯基硅氧基、三甲基硅氧基、三乙基硅氧、苄氧基、对甲氧基卞氧基、甲氧基亚甲基氧基、苄氧羰酰基氧基或叔丁氧羰基氧基中的任意一种;
Y”选自OH、NH2或SH中的任意一种;
Z选自羟基、氯、溴、碘、对甲苯磺酰基或甲磺酰基中的任意一种。
在本发明中,步骤(1)中,所述缩合反应在碱性条件下进行。
优选地,步骤(1)中,所述缩合反应在缩合剂的存在下进行,所述缩合剂包括EDCI和/或DMAP。
优选地,步骤(1)中,所述缩合反应的温度为0-30℃(例如可以是0℃、5℃、10℃、15℃、20℃、25℃、30℃等),时间为5-15h(例如可以是5h、7h、 9h、11h、13h、15h等)。
优选地,步骤(1)中,所述式a所示化合物与式b所示化合物的摩尔比为 1:(0.8-1.5);
其中,“0.8-1.5”可以是0.8、0.9、1、1.1、1.2、1.3、1.4、1.5等。
优选地,步骤(2)中,所述脱保护基通过水解反应或氢化反应进行。
优选地,步骤(2)中,所述脱保护基通过水解反应进行,所述水解反应在酸性条件或碱性条件下进行。
优选地,步骤(3)中,所述取代反应在碱性条件下进行。
优选地,步骤(3)中,所述取代反应的温度为60-100℃(例如可以是60℃、 65℃、70℃、75℃、80℃、85℃、90℃、95℃、100℃等),时间为2-6h(例如可以是2、2.5、3、3.5、4、4.5、5、5.5、6等)。
优选地,步骤(3)中,所述式d所示化合物与式e所示化合物的摩尔比为 1:(1-2);
其中,“1-2”可以是1、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2等。
优选地,所述式f所示化合物与式g所示化合物在碱性条件下进行缩合反应。
优选地,所述式f所示化合物与式g所示化合物在缩合剂的存在下进行缩合反应,所述缩合剂包括EDCI和/或DMAP。
优选地,所述式f所示化合物与式g所示化合物的摩尔比为1:(0.8-1.5);
其中,“0.8-1.5”可以是0.8、1、1.1、1.2、1.3、1.4、1.5等。
第四方面,本发明提供一种药物组合物,所述药物组合物包括活性成分和药效学上可接受的载体,所述活性成分包括第一方面所述的苯基丙烯酸类化合物或第二方面所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐。
优选地,所述药物组合物中所述活性成分的质量百分含量为0.1-95%,例如可以是0.1、1、10、20、30、40、50、60、70、80、90、95等。
本发明提供的药物组合物可根据本领域公知的方法制备,可通过将活性成分与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合,制成适于人或动物使用的任何剂型。
本发明第一方面所述的苯基丙烯酸类化合物、第二方面所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐或第四方面所述的药物组合物可以采用单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明第一方面所述的苯基丙烯酸类化合物、第二方面所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐或第四方面所述的药物组合物可以制成普通制剂、也可以制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明第一方面所述的苯基丙烯酸类化合物、第二方面所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐或第四方面所述的药物组合物制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;湿润剂可以是水、乙醇、异丙醇等;粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
为了将第一方面所述的苯基丙烯酸类化合物、第二方面所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐或第四方面所述的药物组合物制成胶囊剂,可以将其与稀释剂、助流剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将其先与稀释剂、黏合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明第一方面所述的苯基丙烯酸类化合物、第二方面所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐或第四方面所述的药物组合物制成注射剂,可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等;pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂,还可加入甘露醇、葡萄糖等作为支撑剂。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
第五方面,本发明提供一种根据第一方面所述的苯基丙烯酸类化合物、第二方面所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐或第四方面所述的药物组合物在制备预防或治疗肿瘤、自身免疫性疾病、炎症性疾病、神经退行性疾病或抗衰老药物中的应用。
优选地,所述肿瘤选自神经胶质瘤、黑色素瘤、胃癌、肺癌、乳腺癌、肾癌、肝癌、口腔上皮癌、头颈部肿瘤、宫颈癌、卵巢癌、胰腺癌、前列腺癌、结肠癌、直肠腺癌、白血病或淋巴瘤中的任意一种或至少两种的组合。
优选地,所述自身免疫性疾病包括类风湿关节炎、系统性红斑狼疮、溃疡性结肠炎、银屑病、皮炎或脊髓侧索硬化症中的任意一种或至少两种的组合。
优选地,所述炎症性疾病包括多发性动脉炎、静脉炎、反流性食管炎中的任意一种或至少两种的组合。
优选地,所述神经退行性疾病包括老年性痴呆和/或帕金森病。
本发明第一方面所述的苯基丙烯酸类化合物、第二方面所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐或第四方面所述的药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度,患者或动物的个体情况,给药途径和剂型等可以有大范围的变化。一般来讲,本发明第一方面所述的苯基丙烯酸类化合物、第二方面所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐或第四方面所述的药物组合物的每天的合适剂量范围为0.001-150mg/Kg体重,优选为0.1-100 mg/Kg体重,更优选为1-70mg/Kg体重,最优选为2-30mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药,这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明第一方面所述的苯基丙烯酸类化合物、第二方面所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐或第四方面所述的药物组合物可单独服用,或与其他治疗药物或对症药物合并使用。当其它治疗药物存在协同作用时,应根据实际情况调整其剂量。
相对于现有技术,本发明具有以下有益效果:
本发明提供的苯基丙烯酸类化合物与多个靶点蛋白都有较好的结合,并且具有较好的生物利用度,可用于制备预防或治疗肿瘤、自身免疫性疾病、炎症性疾病、神经退行性疾病或抗衰老药物,其中所述的肿瘤疾病是神经胶质瘤、黑色素瘤、胃癌、肺癌、乳腺癌、肾癌、肝癌、口腔上皮癌、头颈部肿瘤、宫颈癌、卵巢癌、胰腺癌、前列腺癌、结肠癌、直肠腺癌、白血病或淋巴瘤等。
具体实施方式
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了,所述实施例仅仅是帮助理解本发明,不应视为对本发明的具体限制。
以下实施例中反应原料均为商购可获得的常规产品。
制备例1
本制备例提供化合物c-1,所述化合物c-1的制备方法包括以下步骤:
将(536mg,2mmol)(E)-3-(3,4-bis(methoxymethoxy)phenyl)acrylic acid (a-1)、(559mg,2.2mmol)4-tert-butyldimethylsilyloxy-3-methoxyphenol(b-1)、 (575mg,3mmol)EDCI、10mg DMAP溶于20mL二氯甲烷中,0℃滴入三乙胺 (0.56mL,4mmol)25℃反应10h;反应结束后加入乙酸乙酯和水,分液,取有机相,无水硫酸钠干燥,过滤,浓缩,柱层析(PE:EA=5:1)分离得0.63g化合物c-1,黄色固化油,收率62.4%。
1H NMR(500MHz,CDCl3)δ7.79(s,1H),7.42(s,1H),7.19(s,2H),6.83(d,J =8.5Hz,1H),6.69(s,1H),6.63(dd,J=8.6,2.7Hz,1H),6.49(d,J=15.9Hz,1H), 5.27(d,J=5.3Hz,4H),3.79(s,3H),3.54(s,3H),3.52(s,3H),1.00(s,9H),0.16(s, 6H).
13C NMR(101MHz,CDCl3)δ165.8,151.2,149.5,147.5,146.0,145.1,142.7,128.7,123.8,120.6,116.2,115.9,115.8,113.6,106.2,95.6,94.8,56.4,56.3,55.6,25.7,18.5,-4.6.
制备例2
本制备例提供化合物c-2,以化合物a-1(536mg,2mmol)和化合物b-2(557 mg,2.2mmol)为原料,所述化合物c-2的制备方法同化合物c-1,得化合物c-2 白色固体600mg,收率62%,所述化合物c-2的反应式如下所示:
1H NMR(400MHz,CDCl3)δ7.75(d,J=15.2Hz,1H),7.65-7.67(m,2H), 7.47(m,1H),7.42(d,J=15.2Hz,1H),7.26-7.28(m,1H),7.19(d,J=8.0Hz,1H), 7.05(d,J=8Hz,1H),5.22(s,2H),5.22(s,2H),3.90(s,3H),3.60(s,3H),3.53(s, 3H),1.03(s,9H),0.33(s,6H).
制备例3
本制备例提供化合物c-3,以化合物a-1(536mg,2mmol)和化合物b-3(490 mg,2.2mmol)为原料,所述化合物c-3的制备方法同化合物c-1,得化合物c-3 白色固体650mg,收率68.4%,所述化合物c-3的反应式如下所示:
1H NMR(400MHz,CDCl3)δ7.80(d,J=15.6Hz,1H),7.63-7.68(m,2H), 7.49(m,1H),7.41(d,J=15.6Hz,1H),7.26-7.28(m,1H),7.19(d,J=8.8Hz,1H), 7.05(d,J=8.8Hz,1H),5.24(s,2H),5.24(s,2H),3.60(s,3H),3.53(s,3H),1.02(s, 9H),0.34(s,6H).
制备例4
本制备例提供化合物d-1,所述化合物d-1的制备方法包括以下步骤:
将(500mg,1mmol)化合物c-1溶于THF中,0℃下加入四丁基氟化铵(1.5 mL,1.5mmol),30min后加入饱和氯化铵中止反应,乙酸乙酯加入,分液,有机相用无水硫酸钠干燥,过滤,浓缩,柱层析(PE:EA=5:1)得0.35g化合物 d-1,黄色固体,收率89.7%。
1H NMR(400MHz,CDCl3)δ7.77(d,J=15.9Hz,1H),7.42(s,1H),7.18(s, 2H),6.90(d,J=8.5Hz,1H),6.70(d,J=2.6Hz,1H),6.65(dd,J=8.5,2.6Hz, 1H),6.49(d,J=15.9Hz,1H),5.68(s,1H),5.27(d,J=4.2Hz,4H),3.85(s,3H), 3.53(s,3H),3.52(s,3H).
13C NMR(101MHz,CDCl3)δ166.1,149.6,147.5,146.7,146.1,143.8,143.4,128.7,123.8,116.2,115.8,115.8,114.4,113.8,105.3,95.6,95.1,77.4,77.1,76.8,56.4,56.3,56.0.
制备例5
本制备例提供化合物d-2,以化合物c-2(500mg,1mmol)为原料,所述化合物d-2的制备方法同化合物d-1,得化合物d-2淡黄色固体352mg,收率 90.1%,所述化合物d-2的反应式如下所示:
1H NMR(400MHz,CDCl3)δ9.90(s,1H),9.17(s,1H),7.48(d,J=8.9Hz, 2H),7.45(d,J=15.7Hz,1H),7.38(d,J=2.0Hz,1H),7.25–7.09(m,1H),6.73(d, J=8.9Hz,1H),6.65(d,J=15.6Hz,1H),5.29(s,2H),5.29(s,2H),4.12(s,3H), 3.56(s,3H),3.53(s,3H).
制备例6
本制备例提供化合物d-3,以化合物c-3(470mg,1mmol)为原料,所述化合物d-3的制备方法同化合物d-1,得化合物d-3淡黄色固体340mg,收率 94.7%,所述化合物d-3的反应式如下所示:
1H NMR(400MHz,d-DMSO)δ9.91(s,1H),9.16(s,1H),7.47(d,J=8.9Hz, 2H),7.43(d,J=15.7Hz,1H),7.36(d,J=2.0Hz,1H),7.21–7.09(m,1H),6.70(d, J=8.9Hz,1H),6.64(d,J=15.6Hz,1H),5.24(s,2H),5.22(s,2H),3.42(s,3H), 3.40(s,3H).
13C NMR(101MHz,d-DMSO)δ163.0,153.3,148.2,147.0,139.0,131.1, 129.1,122.9,120.9,120.7,116.8,115.1,115.1,94.8,94.6,55.8,40.2,39.9,39.7, 39.5,39.3,39.1,38.9.
实施例1
本实施例提供化合物M1,所述化合物M1的制备方法包括以下步骤:
50mL圆底瓶中装有(50mg,0.13mmol)化合物d-1,(50mg,0.2mmol) 3,4-二甲氧基苯乙基溴(e-1),(85mg,0.26mmol)碳酸铯和5mL乙腈,回流反应4h,TLC显示完全,冷却后过滤得粗品60mg,溶于5mL四氢呋喃中,加入0.3mL浓盐酸,搅拌1h后,浓缩得47mg化合物M1,收率78.3%。
1H NMR(400MHz,CDCl3)δ7.71(d,J=15.9Hz,1H),7.09(d,J=2.0Hz, 1H),7.03(dd,J=8.2,2.0Hz,1H),6.89(d,J=2.1Hz,1H),6.85(d,J=7.9Hz, 2H),6.80(d,J=1.1Hz,2H),6.73–6.67(m,2H),6.36(d,J=15.9Hz,1H),5.97– 5.86(m,2H),4.16(t,J=7.3Hz,2H),3.88–3.84(m,9H),3.09(t,J=7.3Hz,2H);
13C NMR(151MHz,CDCl3)δ166.3,149.3,148.6,147.6,147.0,146.7,146.6,144.9,143.9,131.4,127.3,123.6,121.0,116.5,114.6,114.3,113.2,112.5,111.9,111.3,107.4,70.0,58.0,55.9,55.3,35.2.
实施例2
本实施例提供化合物M2,以化合物d-1(50mg,0.13mmol)和化合物e-2(80 mg,0.22mmol)为原料,所述化合物M2的制备方法同化合物M1,得化合物M2 黄色固体54mg,收率84.2%,所述化合物M2的反应式如下所示:
1H NMR(400MHz,CDCl3)δ7.73(d,J=15.9Hz,1H),7.11(d,J=2.0Hz, 1H),7.06(dd,J=8.2,2.1Hz,1H),7.01(d,J=1.8Hz,1H),6.93(d,J=8.9Hz, 1H),6.90–6.85(m,3H),6.83(dd,J=8.6,2.7Hz,2H),6.39(d,J=15.8Hz,1H), 4.89(d,J=3.2Hz,1H),4.43(qd,J=6.3,3.1Hz,1H),3.91–3.83(m,9H),1.20(d, J=6.4Hz,3H).
13C NMR(151MHz,CDCl3)δ166.2,149.4,148.8,148.3,146.9,146.0,144.9,143.9,132.2,127.2,122.8,118.7,115.6,114.5,113.1,112.6,110.8,109.6,82.0, 74.6,58.3,53.9,28.7,12.4.
实施例3
本实施例提供化合物M3,以化合物d-1(50mg,0.14mmol)和化合物e-3(80 mg,0.22mmol)为原料,所述化合物M3的制备方法同化合物M1,得化合物M3 黄色固体45mg,收率64.3%,所述化合物M3的反应式如下所示:
1H NMR(400MHz,CDCl3)δ7.73(d,J=15.9Hz,1H),7.11(d,J=2.0Hz, 1H),7.04(dd,J=8.2,2.1Hz,1H),6.95–6.89(m,3H),6.89–6.78(m,4H),6.38 (d,J=16.0Hz,1H),4.68(d,J=8.4Hz,1H),4.26–4.18(m,1H),3.90(s,3H),3.87 (s,3H),3.85(s,3H),1.18(d,J=6.3Hz,3H).
实施例4
本实施例提供化合物M4,以化合物d-3(130mg,0.36mmol)和化合物 e-4(100mg,0.54mmol)为原料,所述化合物M4的制备方法同化合物M1,得化合物M4黄色固体100mg,收率88.5%,所述化合物M4的反应式如下所示:
1H NMR(400MHz,Acetone-d6)δ7.63(d,J=9.1Hz,2H),7.48(d,J=15.5 Hz,1H),7.37–7.25(m,4H),7.19(t,J=6.3Hz,1H),7.07(d,J=2.1Hz,1H),6.95 (dd,J=8.2,2.1Hz,1H),6.89–6.76(m,3H),6.54(d,J=15.5Hz,1H),4.16(t,J= 6.9Hz,2H),3.04(t,J=6.9Hz,3H).
13C NMR(101MHz,Acetone-d6)δ164.3,156.7,149.0,146.0,140.6,138.9, 133.8,130.1,129.0,128.3,127.0,122.5,121.3,119.7,116.2,115.3,113.3,68.5, 36.3.
实施例5
本实施例提供化合物M5,以化合物d-3(150mg,0.42mmol)和化合物 e-5(134mg,0.63mmol)为原料,所述化合物M5的制备方法同化合物M1,得化合物M5黄色固体150mg,收率88.2%,所述化合物M5的反应式如下所示:
1H NMR(400MHz,Acetone-d6)δ8.05(d,J=3.6Hz,1H),7.61(s,2H),7.47 (d,J=15.5Hz,1H),7.22(d,J=8.5Hz,2H),7.06(s,1H),6.94(d,J=8.1Hz,1H), 6.87–6.77(m,5H),6.53(d,J=15.5Hz,1H),4.10(t,J=6.9Hz,2H),2.96(t,J= 6.9Hz,2H).
13C NMR(101MHz,Acetone-d6)δ163.9,158.4,155.0,147.0,145.4,140.6, 130.5,129.9,127.5,120.9,120.6,120.5,119.0,115.5,115.4,114.5,114.0,113.9, 113.7,68.9,55.0,36.2.
实施例6
本实施例提供化合物M6,以化合物d-3(150mg,0.42mmol)和化合物 e-6(126mg,0.63mmol)为原料,所述化合物M6的制备方法同化合物M1,得化合物M6黄色固体100mg,收率60.6%,所述化合物M6的反应式如下所示:
1H NMR(400MHz,Acetone-d6)δ9.07(s,1H),8.30(s,1H),8.06(s,1H),7.63 (d,J=9.0Hz,2H),7.46(s,1H),7.35(dd,J=8.5,5.7Hz,2H),7.10–7.00(m,3H), 6.94(dd,J=8.2,2.1Hz,1H),6.86–6.77(m,2H),6.54(d,J=15.6Hz,1H),4.15(t, J=6.8Hz,2H),3.04(d,J=6.8Hz,2H).
13C NMR(101MHz,Acetone)δ165.0,162.8,160.9,155.4,147.9,145.4, 139.6,134.9,134.8,133.1,130.8,130.7,127.5,120.9,120.6,120.5,119.0,115.5, 115.0,114.7,114.5,114.0,66.1,34.6.
实施例7
本实施例提供化合物M7,以化合物d-3(150mg,0.42mmol)和化合物 e-7(125mg,0.63mmol)为原料,所述化合物M7的制备方法同化合物M1,得化合物M7黄色固体101mg,收率61.9%,所述化合物M7的反应式如下所示:
1H NMR(400MHz,Acetone-d6)δ9.06(s,1H),8.30(s,1H),8.06(d,J=3.5 Hz,1H),7.63(d,J=8.5Hz,2H),7.48(d,J=15.5Hz,1H),7.19(d,J=8.0Hz,2H), 7.12–7.03(m,3H),6.94(dd,J=8.1,2.1Hz,1H),6.84(dd,J=14.3,8.6Hz,3H), 6.54(d,J=15.5Hz,1H),4.12(t,J=6.9Hz,2H),2.99(t,J=7.0Hz,2H).
13C NMR(101MHz,Acetone)δ164.1,153.4,147.1,145.9,140.6,136.4, 133.7,128.9,127.5,120.9,120.6,119.0,115.5,114.5,111.9,70.5,68.8,38.0,21.4.
实施例8
本实施例提供化合物M8,以化合物d-3(150mg,0.42mmol)和化合物 e-8(126mg,0.63mmol)为原料,所述化合物M8的制备方法同化合物M1,得化合物M8黄色固体80mg,收率50%,所述化合物M8的反应式如下所示:
1H NMR(400MHz,Acetone-d6)δ9.07(s,1H),8.33(s,1H),8.09(s,1H),7.63 (d,J=9.0Hz,2H),7.48(d,J=15.5Hz,1H),7.13(d,J=8.4Hz,2H),7.07(d,J= 2.1Hz,1H),6.94(dd,J=8.2,2.1Hz,1H),6.84(dd,J=14.4,8.6Hz,3H),6.75(d,J =8.5Hz,2H),6.49(s,1H),4.09(t,J=7.0Hz,2H),2.94(t,J=7.0Hz,2H).
13C NMR(101MHz,Acetone)δ161.4,156.0,153.7,148.1,143.8,140.6, 130.5,128.5,125.5,121.6,120.6,118.3,115.5,115.1,114.5,114.0,69.1,35.3.
实施例9
本实施例提供化合物M9,以化合物d-3(150mg,0.42mmol)和化合物 e-1(153mg,0.63mmol)为原料,所述化合物M9的制备方法同化合物M1,得化合物M9淡黄色固体100mg,收率54.6%,所述化合物M9的反应式如下所示:
1H NMR(400MHz,Acetone-d6)δ9.05(s,1H),8.30(s,1H),8.05(s,1H),7.63 (d,J=8.6Hz,2H),7.48(d,J=15.5Hz,1H),7.06(d,J=2.1Hz,1H),6.95(d,J= 9.0Hz,2H),6.89–6.78(m,4H),6.54(d,J=15.5Hz,1H),4.13(t,J=7.0Hz,2H), 2.97(t,J=7.0Hz,2H).
13C NMR(101MHz,Acetone)δ164.0,155.0,150.6,148.6,147.1,144.7, 141.3,135.2,131.1,128.1,121.0,120.6,119.0,116.1,114.5,114.0,113.2,112.1, 68.9,55.3,55.2,37.4.
实施例10
本实施例提供化合物M10,以化合物d-3(150mg,0.42mmol)和化合物 e-9(173mg,0.63mmol)为原料,所述化合物M10的制备方法同化合物M1,得化合物M10淡黄色固体95mg,收率48.7%,所述化合物M10的反应式如下所示:
1H NMR(400MHz,Acetone-d6)δ9.15(s,1H),8.32(s,1H),8.08(s,1H),7.61 (s,2H),7.46(d,J=15.6Hz,1H),7.04(s,1H),6.92(d,J=6.3Hz,1H),6.83(d,J= 17.2Hz,3H),6.61(s,2H),6.53(d,J=15.2Hz,1H),4.13(s,2H),3.76(s,7H),3.65 (s,3H),2.95(s,2H).
13C NMR(101MHz,Acetone)δ163.7,155.0,152.4,147.2,145.4,141.3, 136.9,134.2,133.1,127.9,121.3,120.7,118.4,115.5,114.6,113.7,107.0,68.4, 59.0,56.3,37.3.
实施例11
本实施例提供化合物M11,以化合物d-3(130mg,0.36mmol)和化合物 e-4(100mg,0.54mmol)为原料,所述化合物M11的制备方法同化合物M1,不经酸化,得化合物M11淡黄色固体110mg,收率66.3%,所述化合物M11的反应式如下所示:
1H NMR(400MHz,Chloroform-d)δ7.63(d,J=15.5Hz,1H),7.49(d,J=8.3 Hz,2H),7.38–7.20(m,8H),7.12(d,J=5.8Hz,2H),6.86(d,J=9.0Hz,2H),6.38 (d,J=15.4Hz,1H),5.25(s,4H),4.15(t,J=7.1Hz,2H),3.52(s,2H),3.50(s,3H), 3.08(t,J=7.1Hz,2H).
13C NMR(101MHz,CDCl3)δ162.9,157.4,148.8,146.2,142.1,137.7,132.3,129.7,129.0,128.5,126.5,123.5,121.6,119.9,116.2,115.0,95.9,94.4,70.9,56.4,34.8.
实施例12
本实施例提供化合物M12,以化合物d-3(150mg,0.42mmol)和化合物 e-5(134mg,0.63mmol)为原料,所述化合物M12的制备方法同化合物M1,不经酸化,得化合物M12淡黄色固体180mg,收率87%,所述化合物M12的反应式如下所示:
1H NMR(400MHz,Chloroform-d)δ7.64(d,J=15.4Hz,1H),7.49(d,J= 10.3Hz,2H),7.37(s,1H),7.19(d,J=8.6Hz,3H),7.13(d,J=3.9Hz,2H),6.85 (dd,J=8.7,6.2Hz,4H),6.38(d,J=15.5Hz,1H),5.25(s,5H),4.10(d,J=7.1Hz, 2H),3.02(d,J=7.0Hz,2H).
13C NMR(101MHz,CDCl3)δ163.9,158.3,155.7,149.6,148.1,140.5,131.3,130.7,130.0,127.7,122.9,121.6,120.3,117.2,114.6,114.0,100.1,94.7,68.1,57.2,55.3,34.9.
实施例13
本实施例提供化合物M13,以化合物d-3(150mg,0.42mmol)和化合物 e-6(125mg,0.62mmol)为原料,所述化合物M13的制备方法同化合物M1,不经酸化,得化合物M13淡黄色固体120mg,收率59.4%,所述化合物M13的反应式如下所示:
1H NMR(400MHz,CDCl3)δ7.67(s,1H),7.51(d,J=8.2Hz,2H),7.38(s, 1H),7.28–7.18(m,4H),7.14(d,J=4.0Hz,2H),7.00(t,J=8.7Hz,2H),6.87(d,J =9.0Hz,2H),6.40(d,J=15.4Hz,1H),5.27(s,4H),4.14(t,J=6.9Hz,2H),3.53 (d,J=9.6Hz,6H).
13C NMR(101MHz,CDCl3)δ163.8,162.9,159.6,154.0,148.8,146.7,141.5,134.7,131.4,130.4,130.3,128.3,123.5,121.5,119.4,116.2,115.3,115.1,114.9,68.4,53.6,36.0.
实施例14
本实施例提供化合物M14,以化合物d-3(150mg,0.42mmol)和化合物 e-7(125mg,0.62mmol)为原料,所述化合物M14的制备方法同化合物M1,不经酸化,得化合物M14淡黄色固体150mg,收率75%,所述化合物M14的反应式如下所示:
1H NMR(400MHz,d-DMSO)δ10.55(s,1H),8.68(d,J=1.6Hz,1H), 7.80-7.82(m,2H),7.58(dd,J=3.0Hz,8.8Hz,1H),7.21-7.23(m,2H),7.09-7.12 (m,3H),6.96-7.01(m,1H),6.77-6.80(m,1H),4.23(t,J=7.2Hz,2H),3.82(s,3H), 3.02(t,J=7.2Hz,2H),2.26(s,3H);
13C NMR(101MHz,CDCl3)δ165.4,154.8,148.8,147.1,142.0,136.1,133.6,129.8,128.4,123.5,121.5,119.5,116.2,112.0,95.5,94.8,68.3,56.4,35.4,20.5.
实施例15
本实施例提供化合物M15,以化合物d-3(60mg,0.22mmol)和化合物e-8(25 mg,0.18mmol)为原料,所述化合物M15的制备方法同化合物M1,不经酸化,得化合物M15淡黄色固体60mg,收率83.4%,所述化合物M15的反应式如下所示:
1H NMR(400MHz,Chloroform-d)δ7.65(d,J=15.4Hz,1H),7.54–7.33(m, 3H),7.15(dd,J=13.9,6.6Hz,5H),6.92–6.73(m,5H),6.40(d,J=13.7Hz,1H), 5.26(s,5H),4.11(t,J=6.3Hz,3H),3.54(s,3H),3.52(s,3H),3.01(t,J=7.0Hz, 3H).
13C NMR(101MHz,CDCl3)δ164.0,156.7,155.8,154.8,149.4,147.4,141.1,131.2,130.1,130.0,129.2,123.6,122.1,119.4,117.0,115.4,115.0,114.7,95.5, 94.8,77.3,69.3,68.4,56.3,34.9.
实施例16
本实施例提供化合物M16,以化合物d-3(150mg,0.42mmol)和化合物 e-1(206mg,0.84mmol)为原料,所述化合物M16的制备方法同化合物M1,不经酸化,得化合物M16淡黄色固体150mg,收率68.2%,所述化合物M16的反应式如下所示:
1H NMR(400MHz,Chloroform-d)δ7.65(d,J=15.3Hz,1H),7.51(d,J=8.2 Hz,2H),7.35(d,J=20.2Hz,2H),7.13(q,J=8.1Hz,2H),6.88(d,J=9.0Hz,2H), 6.82(s,3H),6.40(d,J=15.4Hz,1H),4.14(t,J=7.0Hz,2H),3.88(s,3H),3.87(s, 3H),3.54(s,3H),3.51(s,3H),3.03(t,J=7.0Hz,2H).
13C NMR(101MHz,CDCl3)δ163.5,156.1,149.6,147.7,147.4,138.2,130.8,128.4,123.5,122.5,120.9,119.0,117.3,113.9,112.4,110.8,96.0,93.9,68.1,57.7,55.9,36.1,29.7.
实施例17
本实施例提供化合物M17,以化合物d-3(150mg,0.42mmol)和化合物 e-9(173mg,0.63mmol)为原料,所述化合物M17的制备方法同化合物M1,不经酸化,得化合物M17淡黄色固体106mg,收率45.7%,所述化合物M17的反应式如下所示:
1H NMR(400MHz,Chloroform-d)δ7.66(d,J=15.4Hz,1H),7.51(d,J=7.9 Hz,2H),7.39(s,1H),7.23–7.11(m,3H),6.89(d,J=8.8Hz,2H),6.50(s,2H), 6.40(d,J=15.4Hz,1H),5.27(s,4H),4.17(t,J=7.0Hz,2H),3.86(s,6H),3.84(s, 3H),3.54(s,3H),3.52(s,3H),3.03(t,J=7.0Hz,2H).
13C NMR(101MHz,CDCl3)δ152.0,148.9,147.5,141.6,135.4,132.8,127.2,123.1,120.6,119.4,117.3,115.0,113.5,106.0,95.9,95.2,77.3,69.1,68.6,62.2,59.4,56.4,54.8.
实施例18
本实施例提供化合物M18,以化合物d-1(50mg,0.13mmol)和化合物e-4(37 mg,0.2mmol)为原料,所述化合物M18的制备方法同化合物M1,得化合物M18 淡黄色固体30mg,收率56.6%,所述化合物M18的反应式如下所示:
1H NMR(400MHz,Acetone-d6)δ7.60(d,J=9.1Hz,2H),7.45(d,J=15.5 Hz,1H),7.34–7.25(m,4H),7.16(t,J=6.3Hz,1H),7.04(d,J=2.1Hz,1H),6.95 (dd,J=8.2,2.1Hz,1H),6.89–6.76(m,3H),6.54(d,J=15.5Hz,1H),4.13(t,J= 6.9Hz,2H),3.84(s,3H),3.01(t,J=6.9Hz,3H).
实施例19
本实施例提供化合物M19,以化合物d-1(100mg,0.26mmol)和化合物 e-6(66mg,0.33mmol)为原料,所述化合物M19的制备方法同化合物M1,得化合物M19淡黄色固体60mg,收率54.4%,所述化合物M19的反应式如下所示:
1H NMR(400MHz,Acetone-d6)δ9.05(s,1H),8.32(s,1H),8.04(s,1H),7.63 (d,J=9.0Hz,2H),7.46(s,1H),7.35(dd,J=8.5,5.7Hz,2H),7.10–7.00(m,3H), 6.94(dd,J=8.2,2.1Hz,1H),6.86–6.77(m,2H),6.54(d,J=15.6Hz,1H),4.15(t, J=7.2Hz,2H),3.84(s,3H),3.02(d,J=6.8Hz,2H).
实施例20
本实施例提供化合物M20,以化合物d-1(50mg,0.13mmol)和化合物e-5(70 mg,0.33mmol)为原料,所述化合物M20的制备方法同化合物M1,得化合物 M20淡黄色固体40mg,收率70.2%,所述化合物M20的反应式如下所示:
1H NMR(400MHz,Acetone-d6)δ8.07(d,J=3.6Hz,1H),7.63(s,2H),7.47 (d,J=15.6Hz,1H),7.22(d,J=8.6Hz,2H),7.06(s,1H),6.94(d,J=8.1Hz,1H), 6.87–6.77(m,5H),6.53(d,J=15.5Hz,1H),4.12(t,J=6.9Hz,2H),3.84(s,3H), 2.96(t,J=6.9Hz,2H).
实施例21
本实施例提供化合物M21,以化合物d-1(50mg,0.13mmol)和化合物e-7(45 mg,0.23mmol)为原料,所述化合物M21的制备方法同化合物M1,得化合物 M21淡黄色固体40mg,收率72.7%,所述化合物M21的反应式如下所示:
1H NMR(400MHz,d-DMSO)δ10.54(s,1H),8.66(d,J=2.0Hz,1H),7.81 (dd,J=2.0Hz,8.8Hz,1H),7.72(s,1H),7.65(d,J=7.6Hz,1H),7.24-7.27(m, 2H),7.15-7.19(m,1H),7.07(d,J=8.8Hz,1H),6.94-6.98(m,1H),6.85-6.89(m, 2H),6.81(d,J=7.6Hz,1H),4.21(t,J=7.2Hz,2H),3.82(s,3H),3.72(s,3H), 3.00(t,J=6.8Hz,2H).
实施例22
本实施例提供化合物M22,以化合物d-1(80mg,0.28mmol)和化合物 e-9(104mg,0.38mmol)为原料,所述化合物M22的制备方法同化合物M1,得化合物M22淡黄色固体85mg,收率61.6%,所述化合物M22的反应式如下所示:
1H NMR(400MHz,CDCl3)δ7.64(d,J=15.4Hz,1H),7.50(d,J=7.9Hz, 2H),7.35(s,1H),7.25–7.11(m,3H),6.89(d,J=8.8Hz,2H),6.50(s,2H),6.40(d, J=15.4Hz,1H),5.27(s,4H),4.17(t,J=7.0Hz,2H),3.86(s,6H),3.84(s,3H), 3.54(s,3H),3.52(s,3H),3.01(t,J=7.0Hz,2H).
实施例23
本实施例提供化合物M23,以化合物d-3(150mg,0.42mmol)和化合物 e-10(34mg,0.23mmol)为原料,所述化合物M23的制备方法同化合物M1,得化合物M23淡黄色固体80mg,收率83.3%,所述化合物M23的反应式如下所示:
1H NMR(400MHz,CDCl3)δ10.42(s,1H),8.65-8.66(m,1H),7.81-7.83(m, 1H),7.69(s,1H),7.47-7.49(m,1H),7.24-7.27(m,2H),7.06-7.08(m,1H), 6.96-6.99(m,1H),6.86-6.88(m,2H),6.69-6.71(m,1H),5.80(s,2H),4.21-4.22(m, 2H),3.01(t,J=6.8Hz,2H).
实施例24
本实施例提供化合物M24,以化合物d-2(80mg,0.27mmol)和化合物e-1(80 mg,0.33mmol)为原料,所述化合物M24的制备方法同化合物M1,得化合物 M24淡黄色固体84mg,收率66.7%,所述化合物M24的反应式如下所示:
1H NMR(400MHz,Acetone-d6)δ8.95(s,1H),8.25(s,1H),8.00(s,1H),7.60 (d,J=8.6Hz,2H),7.48(d,J=15.6Hz,1H),7.06(d,J=2.4Hz,1H),6.95(d,J= 9.2Hz,2H),6.89–6.78(m,4H),6.54(d,J=15.5Hz,1H),4.13(t,J=7.0Hz,2H), 3.84(s,3H),2.97(t,J=7.0Hz,2H).
实施例25
本实施例提供化合物M25,以化合物d-2(80mg,0.27mmol)和化合物e-4(64 mg,0.35mmol)为原料,所述化合物M25的制备方法同化合物M1,得化合物 M25淡黄色固体80mg,收率73.4%,所述化合物M25的反应式如下所示:
1H NMR(400MHz,Acetone-d6)δ7.60(d,J=9.1Hz,2H),7.50(d,J=15.5 Hz,1H),7.39–7.25(m,4H),7.14(t,J=6.3Hz,1H),7.03(d,J=2.1Hz,1H),6.95 (dd,J=8.2,2.1Hz,1H),6.89–6.76(m,3H),6.54(d,J=15.5Hz,1H),4.16(t,J= 6.9Hz,2H),3.84(s,3H),3.02(t,J=6.9Hz,3H).
实施例26
本实施例提供化合物M26,以化合物f-1(100mg,0.67mmol)和化合物 g-1(233mg,0.77mmol)为原料,所述化合物M26的制备方法同化合物M1,不经酸化,得化合物M26淡黄色固体200mg,收率69%,所述化合物M26的反应式如下所示:
1H NMR(400MHz,CDCl3)δ8.00(s,1H),7.53(d,J=8.6Hz,2H),7.42(d,J =15.6Hz,1H),7.23-7.26(m,2H),7.06(d,J=2.4Hz,1H),6.95(d,J=9.2Hz,2H), 6.89–6.78(m,4H),6.54(d,J=15.5Hz,1H),4.12(t,J=7.0Hz,2H),3.93(s,3H), 3.92(s,3H),3.86(s,3H),2.99(t,J=7.0Hz,2H).
实施例27
本实施例提供化合物M27,以化合物f-2(100mg,0.56mmol)和化合物 g-1(233mg,0.77mmol)为原料,所述化合物M27的制备方法同化合物M26,不经酸化,得化合物M27淡黄色固体106mg,收率40.8%,所述化合物M27的反应式如下所示:
1H NMR(400MHz,CDCl3)δ7.23(s,1H),7.53(d,J=8.6Hz,2H),7.38(d,J =15.6Hz,1H),7.23-7.26(m,1H),7.06(s,1H),6.95(d,J=9.2Hz,2H),6.89–6.78 (m,4H),6.54(d,J=15.5Hz,1H),4.12(t,J=7.0Hz,2H),3.91(s,3H),3.88(s, 3H),3.83(s,3H),2.99(t,J=7.0Hz,2H).
实施例28
本实施例提供化合物M28,以化合物f-3(100mg,0.52mmol)和化合物 g-1(233mg,0.77mmol)为原料,所述化合物M28的制备方法同化合物M26,不经酸化,得化合物M28淡黄色固体180mg,收率72.6%,所述化合物M28的反应式如下所示:
1H NMR(400MHz,CDCl3)δ8.60(m,1H),7.80(m,1H),7.66(s,1H), 7.47-7.49(m,1H),7.24-7.27(m,2H),7.06-7.08(m,1H),6.96-6.99(m,1H), 6.86-6.88(m,2H),6.69-6.71(m,1H),5.77(s,2H),3.91(s,3H),3.88(s,3H),3.83 (s,3H),4.21-4.22(m,2H),2.99(t,J=6.8Hz,2H).
实施例29
本实施例提供化合物M29,以化合物f-4(100mg,0.60mmol)和化合物 g-1(233mg,0.77mmol)为原料,所述化合物M29的制备方法同化合物M26,不经酸化,得化合物M29淡黄色固体150mg,收率55.6%,所述化合物M29的反应式如下所示:
1H NMR(400MHz,CDCl3)δ7.77(m,1H),7.66(s,1H),7.47-7.49(m,2H), 7.24-7.27(m,2H),7.06-7.08(m,2H),6.96-6.99(m,1H),6.86-6.88(m,2H), 6.69-6.71(m,1H),3.89(s,3H),3.86(s,3H),3.80(s,3H),4.21-4.22(m,2H),2.99(t, J=6.8Hz,2H).
实施例30
本实施例提供化合物M30,以化合物f-5(100mg,0.62mmol)和化合物 g-1(233mg,0.77mmol)为原料,所述化合物M30的制备方法同化合物M26,不经酸化,得化合物M30淡黄色固体150mg,收率54.2%,所述化合物M30的反应式如下所示:
1H NMR(400MHz,CDCl3)δ7.88(m,1H),7.49(s,1H),7.47(m,2H),7.20 (m,2H),7.06-7.08(m,2H),6.99(m,1H),6.86-6.88(m,2H),6.69-6.71(m,1H), 3.89(s,3H),3.86(s,3H),3.80(s,3H),3.72(s,3H),4.23(m,2H),2.969(t,J=6.8 Hz,2H).
实施例31
本实施例提供化合物M31,以化合物f-6(100mg,0.55mmol)和化合物 g-1(233mg,0.77mmol)为原料,所述化合物M31的制备方法同化合物M26,不经酸化,得化合物M31淡黄色固体116mg,收率45%,所述化合物M31的反应式如下所示:
HR-MS(ESI)calcd for C26H28O6N2(M+H)+:464.1730,found 464.1710.
药理实验
实验例1
苯基丙烯酸类衍生物对ACAT1靶点的IC50测定
(一)实验方法
ACAT1小分子抑制剂的筛选方法
ACAT1可以催化两分子的乙酰基辅酶A可逆形成乙酰乙酰基辅酶A。其活性测定是通过ACAT1催化底物乙酰乙酰辅酶A与辅酶A反应,生成产物乙酰辅酶A。基于乙酰乙酰辅酶A在特定光谱有特定吸收,因此,通过检测特定光谱吸收的增多或减少来反映对ACAT1酶活性的影响。
ACAT1重组蛋白通过大肠杆菌进行表达纯化,获得的ACAT1重组蛋白浓度为1mg/mL。进行ACAT1小分子抑制剂筛选时,采用的缓冲液为50mM Tris-HCl(pH 8.1),20mMMgCl2,40mM KCl。在200μl的酶催化体系中,分别加入ACAT1重组蛋白1μL,底物乙酰辅酶A终浓度为25μM,加入CPM探针至终浓度为100μM,以及不同浓度的小分子抑制剂。通过酶标仪(Biotek Synergy H1),采用激发光355nm和发射光460nm,进行检测,采用软件Prism 7.0进行抑制剂IC50的计算。
(二)实验结果
体外对ACAT1活性影响的筛选结果见表1。实验结果表明,化合物1、5、 7、9、10、12和17对ACAT1具有较强的抑制活性。
表1
由上述表1数据可知,化合物M1、M5、M7、M9、M10、M12和M17对 ACAT1具有较强的抑制活性,IC50值均在100μmol/L以下。
实验例2
苯基丙烯酸类衍生物对丙酮酸激酶活性影响
(一)实验方法
丙酮酸激酶小分子调节剂筛选方法
原理:在二磷酸腺苷(ADP)存在的条件下丙酮酸激酶(PK)催化磷酸烯醇式丙酮酸(PEP)转化成丙酮酸,在还原型辅酶I(NADH)存在情况下,丙酮酸被 LDH转化为乳酸,若标记荧光于NADH上,此时有荧光的NADH变为荧光的 NAD。
两个重组蛋白丙酮酸激酶亚型:PKLR(15501-H07E)、PKM2(11430-H07E) 均购自北京义翘神州科技股份有限公司。进行PK活性筛选时,缓冲液采用100 mM Tris HCl(pH8.0),100mM KCl,10mM MgCl2。在200μL的酶催化体系中,分别加入各种底物和酶至终浓度为ADP(0.6mM),PEP(0.5mM),NADH(180 mM),FBP(10mM)和LDH(8units),另外添加不同浓度的小分子抑制剂。通过酶标仪(Biotek Synergy H1),检测340nm吸收光的变化,进行检测,采用软件Prism 7.0进行抑制或激活活性的计算。
(二)实验结果
化合物在体外对丙酮酸激酶活性的影响见表2。
表2
化合物 | PKLR(OD值) | PKM2(OD值) |
M1 | 0.957247 | 0.886667 |
M2 | 1.264338 | 1.21125 |
M3 | 0.951512 | 0.872917 |
由表2数据可知,化合物M1和M3对PKM2具有一定的抑制活性,而化合物M2对PKLR和PKM2均具有一定的激活作用。
申请人声明,本发明通过上述实施例来说明本发明的一种苯基丙烯酸类化合物及其制备方法和应用,但本发明并不局限于上述实施例,即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
Claims (10)
1.一种苯基丙烯酸类化合物,其特征在于,所述苯基丙烯酸类化合物具有如下式I所示结构:
其中,R1、R2、R3、R4、R7、R8、R9各自独立地选自氢、卤素、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、C1-C6烷氧羰基、C1-C6烷羰基氧基、C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基亚甲基氧基、C1-C6烷酰基、三卤代C1-C6烷基或三卤代C1-C6烷氧基中的任意一种;或者,R1、R2、R7、R8、R9各自独立地选自-O(CH2)nO-,并与其取代的苯基相连成环,n选自1、2或3;
R5选自氢、氨基、C1-C6烷基、C1-C6烷氧基甲基或C1-C6烷基胺基中的任意一种;
R6选自氢、羟基、氨基、羰基、C1-C6烷基胺基、C1-C6烷羰基氧基或C1-C6烷氧基羰基中的任意一种;
X选自O或NH;
Y选自O、NH、S、亚砜或砜中的任意一种。
2.根据权利要求1所述的苯基丙烯酸类化合物,其特征在于,所述苯基丙烯酸类化合物选自如下式II~式V中的任意一种:
其中,所述R1、R2各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、C1-C4烷氧羰基、C1-C4烷羰基氧基、C1-C4烷基、C1-C4烷氧基、C1-C4烷氧基亚甲基氧基、三卤代C1-C4烷基、三卤代C1-C4烷氧基中的任意一种;
所述R3、R4各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、C1-C4烷氧羰基、C1-C4烷羰基氧基、C1-C4烷基、C1-C4烷氧基、三卤代C1-C4烷基或三卤代C1-C4烷氧基中的任意一种;
所述R5选自氢、氨基、C1-C4烷基、C1-C4烷氧基甲基或C1-C4烷基胺基中的任意一种;
所述R6选自氢、羟基、氨基、羰基、C1-C4烷基胺基、C1-C4烷羰基氧基或C1-C4烷氧基羰基中的任意一种;
所述R7、R8、R9各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、C1-C4烷基、C1-C4烷氧基、C1-C4烷氧羰基、C1-C4烷羰基氧基、C1-C3烷酰基、C1-C4烷氧基亚甲基氧基、三卤代C1-C4烷基或三卤代C1-C4烷氧基中的任意一种;
所述X选自O或NH;
所述Y选自O、NH、S、亚砜或砜中的任意一种;
所述p1、p2、p3各自独立地选自1、2或3。
3.根据权利要求2所述的苯基丙烯酸类化合物,其特征在于,所述R1、R2各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲氧羰基、乙氧羰基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、甲基、乙基、甲氧基、乙氧基、C1-C2烷羰基氧基、C1-C2烷氧基亚甲基氧基、三卤代C1-C2烷基或三卤代C1-C2烷氧基中的任意一种;
所述R3、R4各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲氧羰基、乙氧羰基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、甲基、乙基、甲氧基、乙氧基、C1-C2烷羰基氧基、三卤代C1-C2烷基或三卤代C1-C2烷氧基中的任意一种;
所述R5选自氢、氨基、甲基、乙基、C1-C2烷氧基甲基或C1-C2烷基胺基中的任意一种;
所述R6选自氢、氨基、羟基、羰基、C1-C2烷基胺基、C1-C2烷羰基氧基或C1-C2烷氧基羰基中的任意一种;
所述R7、R8、R9各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、甲基、乙基、甲氧基、乙氧基、甲氧羰基、乙氧羰基、甲酰基、乙酰基、丙酰基、丁酰基、戊酰基、异丁酰基、2-甲基丁酰基、C1-C2烷氧基亚甲基氧基、三卤代C1-C2烷基或三卤代C1-C2烷氧基;
所述X选自O或NH;
所述Y选自O、NH、S、亚砜或砜中的任意一种;
所述p1、p2、p3各自独立地选自1或2。
4.根据权利要求2或3所述的苯基丙烯酸类化合物,其特征在于,所述R1、R2各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲氧羰基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、甲基、乙基、甲氧基、乙氧基、三氟甲基、三氟甲氧基或甲氧基亚甲基氧基中的任意一种;
所述R3、R4各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲氧羰基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、甲基、乙基、甲氧基、乙氧基、三氟甲基或三氟甲氧基中的任意一种;
所述R5选自氢、甲基、乙基、甲氧基甲基或氨基中的任意一种;
R6选自氢、羟基、氨基、羰基、或C1-C2烷羰基氧基中的任意一种;
R7、R8、R9各自独立地选自氢、氟、氯、溴、羟基、二甲胺基、氰基、硝基、甲胺基、甲磺酰基、二甲胺磺酰基、氨基、羧基、甲基、乙基、甲氧基、乙氧基、三氟甲基、三氟甲氧基、甲氧羰基、甲酰基、乙酰基、丙酰基、丁酰基、戊酰基、异丁酰基或甲氧基亚甲基氧基中的任意一种;
X选自O或NH;
Y选自O、NH、S、亚砜或砜中的任意一种或至少两种的组合;
所述p1、p2、p3各自独立地选自1。
6.一种根据权利要求1-5中任一项所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐;
优选地,所述药学上可接受的盐包括盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、甲磺酸盐、对甲苯磺酸盐、乙酸盐、三氟乙酸盐、水杨酸盐、氨基酸盐、枸杞酸盐、马来酸盐、酒石酸盐、富马酸盐、柠檬酸盐、乳酸盐、钠盐、钾盐、钙盐、镁盐、锂盐、铵盐或能提供生理上可接受的阳离子的有机碱的盐中的任意一种或至少两种的组合;
优选地,所示能提供生理上可接受的阳离子的有机碱的盐包括甲胺盐、二甲胺盐、三甲胺盐、哌啶盐、吗啉盐或三(2-羟乙基)胺盐中的任意一种或至少两种的组合。
7.一种根据权利要求1-5中任一项所述的苯基丙烯酸类化合物的制备方法,其特征在于,所述制备方法包括以下步骤:
(1)将式a所示化合物与式b所示化合物进行缩合反应,得到式c所示化合物,反应式如下所示:
(2)将式c所示化合物进行脱保护基,得到式d所示化合物,反应式如下所示:
(3)将式d所示化合物和式e所示化合物进行取代反应,得到式I所示化合物,反应式如下所示:
或者,所述制备方法包括以下步骤:将式f所示化合物与式g所示化合物进行缩合反应,得到式I所示化合物,反应式如下所示:
其中,所述X’选自OH或NH2;
Y’选自叔丁基二甲基硅氧基、叔丁基二苯基硅氧基、三甲基硅氧基、三乙基硅氧、苄氧基、对甲氧基卞氧基、甲氧基亚甲基氧基、苄氧羰酰基氧基或叔丁氧羰基氧基中的任意一种;
Y”选自OH、NH2或SH中的任意一种;
Z选自羟基、氯、溴、碘、对甲苯磺酰基或甲磺酰基中的任意一种。
8.根据权利要求7所述的制备方法,其特征在于,步骤(1)中,所述缩合反应在碱性条件下进行;
优选地,步骤(1)中,所述缩合反应在缩合剂的存在下进行,所述缩合剂包括EDCI和/或DMAP;
优选地,步骤(1)中,所述缩合反应的温度为0-30℃,时间为5-15h;
优选地,步骤(1)中,所述式a所示化合物与式b所示化合物的摩尔比为1:(0.8-1.5);
优选地,步骤(2)中,所述脱保护基通过水解反应或氢化反应进行;
优选地,步骤(2)中,所述脱保护基通过水解反应进行,所述水解反应在酸性条件或碱性条件下进行;
优选地,步骤(3)中,所述取代反应在碱性条件下进行;
优选地,步骤(3)中,所述取代反应的温度为60-100℃,时间为2-6h;
优选地,步骤(3)中,所述式d所示化合物与式e所示化合物的摩尔比为1:(1-2);
优选地,所述式f所示化合物与式g所示化合物在碱性条件下进行缩合反应;
优选地,所述式f所示化合物与式g所示化合物在缩合剂的存在下进行缩合反应,所述缩合剂包括EDCI和/或DMAP;
优选地,所述式f所示化合物与式g所示化合物的摩尔比为1:(0.8-1.5)。
9.一种药物组合物,其特征在于,所述药物组合物包括活性成分和药效学上可接受的载体,所述活性成分包括权利要求1-5中任一项所述的苯基丙烯酸类化合物或权利要求6所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐;
优选地,所述药物组合物中所述活性成分的质量百分含量为0.1-95%。
10.一种根据权利要求1-5中任一项所述的苯基丙烯酸类化合物、权利要求6所述的苯基丙烯酸类化合物的互变异构体、对映体、非对映体或其药学上可接受的盐或权利要求9所述的药物组合物在制备预防或治疗肿瘤、自身免疫性疾病、炎症性疾病、神经退行性疾病或抗衰老药物中的应用;
优选地,所述肿瘤选自神经胶质瘤、黑色素瘤、胃癌、肺癌、乳腺癌、肾癌、肝癌、口腔上皮癌、头颈部肿瘤、宫颈癌、卵巢癌、胰腺癌、前列腺癌、结肠癌、直肠腺癌、白血病或淋巴瘤中的任意一种或至少两种的组合;
优选地,所述自身免疫性疾病包括类风湿关节炎、系统性红斑狼疮、溃疡性结肠炎、银屑病、皮炎或脊髓侧索硬化症中的任意一种或至少两种的组合;
优选地,所述炎症性疾病包括多发性动脉炎、静脉炎、反流性食管炎中的任意一种或至少两种的组合;
优选地,所述神经退行性疾病包括老年性痴呆和/或帕金森病。
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