CN115073353B - 木脂素类衍生物及其制法和其药物组合物与用途 - Google Patents
木脂素类衍生物及其制法和其药物组合物与用途 Download PDFInfo
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- CN115073353B CN115073353B CN202110277262.2A CN202110277262A CN115073353B CN 115073353 B CN115073353 B CN 115073353B CN 202110277262 A CN202110277262 A CN 202110277262A CN 115073353 B CN115073353 B CN 115073353B
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Abstract
本发明属于医药技术领域，公开了木脂素类衍生物及其制法和药物组合物与用途。具体涉及式(I)化合物或其异构体及其药学上可接受的盐，以及其制备方法。一种新的药物组合物，包括有效剂量的式(I)化合物和药效学上可接受的载体。本发明还公开了这类化合物在预防和/或治疗免疫失调，和/或肿瘤疾病方面的的应用。所述的肿瘤包括神经胶质母细胞瘤、黑色素瘤、胃癌、肺癌、乳腺癌、肾癌、肝癌、口腔表皮癌、宫颈癌、卵巢癌、胰腺癌、前列腺癌、结肠癌、直肠腺癌。
Description
技术领域
本发明涉及木脂素类衍生物，其可药用盐，其多晶和共晶，其同样生物功能的前体或衍生物/探针，其制备方法，含它们的药物组合物，及其作为药物，尤其作为预防/抗肿瘤药物的用途，属于医药技术领域。
背景技术
世界卫生组织国际癌症研究机构(IARC)发布了2020年全球最新癌症负担数据。2020年全球新发癌症病例1929万例，其中中国新发癌症457万人，占全球23.7％，由于中国是世界第一人口大国，癌症新发人数远超世界其他国家。癌症新发人数前十的国家分别是：中国457万，美国228万，印度132万，日本103万，德国63万，巴西59万，俄罗斯59万，法国47万，英国46万，意大利42万。抗击癌症，并不仅仅是中国将面临的严峻问题，同时也是全球面临的严峻问题。
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。肿瘤被定义为一种和心脏病、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。
木脂素是一类从裸子植物和被子植物中分离得到的天然产物，其天然组分多数以游离状态存在，也有些与糖结合成苷存在于植物的木部和树脂中。木脂素类化合物广义上可分为二大类，即木脂素类和新木脂素类。木脂素偏亲脂性，不易溶于水，能溶于有机溶剂，少数木脂素与糖结合成苷后水溶性增大。大多数木脂素具有光化学活性，遇酸异构化。木脂素类化合物具有多方面生物活性，如：抗肿瘤，[Xu D,Lu Q,Hu X.Down-regulation of P-glycoprotein expression in MDR breast cancer cell MCF-7/ADR by honokiol[J].Cancer Letters,2006,243(2):274-280]抗病毒，抗菌，抗氧化，保护心脑血管等活性，其有非常大的研究前景，我们长期从事木脂素类天然产物的合成，结构简化与优化，进而发现比原天然产物具有更好肿瘤抑制活性，更低毒性的先导物，而进一步成为抗肿瘤药物。
此发明内容所设计的木脂素类衍生物在抗肿瘤潜在的靶点概括如下：
内皮生长因子受体(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：此类木脂素衍生物可以成为此靶点的筛选候选物。
c-Src蛋白：酪氨酸激酶(Tyrosine protein kinase，TPK)一种，属于胞质非受体类，现已被证明是细胞内信号传导过程(略)中介分子，通过与多种不同受体蛋白相互作用，在细胞生长、增殖、分化、运动和凋亡等生理过程中起着重要调节作用.c-src基因在真核细胞内普遍存在，并且在肿瘤细胞中过量表达，被认(略)生、发展以及转移等密切相关.关于c-Src抑制剂研究也渐成热点，在临床治疗上具有广阔前景.利用基因工程方法大量表达c-Src蛋白，能够大大提高c-Src抑制剂筛选效率，同时为深入研究c-Src抑制剂作用机制提供了可能.
细胞周期蛋白依赖激酶CDK2：CDK2是蛋白质激酶家族中的一员，依赖与细胞周期蛋白的结合来执行细胞周期有序进行中的关键功能。不同的CDK周期蛋白质复合物使特异的靶蛋白质磷酸化而激发细胞周期各期的顺利进行。当缺乏细胞周期蛋白质或CDK抑制物存在时，它们即失去活性，细胞增殖停滞，甚至死亡。CDK通过调节靶蛋白磷酸化而调控细胞周期的运转。
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一期，二期研究中。
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、防止细胞凋亡等等,Src抑制剂的研究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，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。
尽管木脂素类天然产物已被证实具有如上的活性作用，但其确切的作用机制以及在人体内的药物代谢动力学以及药效学需要进一步的研究，由于其亲酯性较大，不易溶于水，因此，本发明提出用引入极性分子到苯丙醇或者苯丙稀的结构中，得到其结构衍生物，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、免疫调节等。
发明内容
本发明要解决的技术问题是提供具有优良疗效且毒性低的具有抗炎、抗肿瘤活性的木脂素类衍生物，其异构体，其可药用盐，其前药，其多晶或共晶。
本发明要解决的另一技术问题是提供这类化合物的制备方法。
本发明要解决的又一技术问题是提供含有这类化合物的药物组合物。
本发明要解决的再一技术问题是提供这类化合物在制备抗/预防肿瘤，以及与免疫相关疾病的药物中的应用。
为解决本发明的技术问题，采用如下技术方案：
式(I)化合物或其异构体及其药学上可接受的盐；
R1和R2独立的选自氢，卤素，羟基，二甲胺基，氰基，硝基，C1-6烷氧羰基，C1-6烷羰基氧基，甲胺基，甲磺酰基，二甲胺磺酰基，氨基，羧基，C1-6烷基，C1-6烷氧基，三卤C1-6烷基，三卤C1-6烷氧基；
或R1和R2选自-O(CH2)nO-，并与其取代的苯基相连成环；n选自1、2或3；
R3和R4独立的选自氢，卤素，羟基，二甲胺基，氰基，硝基，C1-6烷氧羰基，C1-6烷羰基氧基，甲胺基，甲磺酰基，二甲胺磺酰基，氨基，羧基，C1-6烷基，C1-6烷氧基，三卤C1-6烷基，三卤C1-6烷氧基；
R5选自氢，C1-6烷基，C1-6烷氧基甲基，C0-6烷基胺基；
R6选自氢，羟基，C0-6烷基胺基，C1-6烷羰基氧基，C1-6烷氧基羰基，O＝；
R7，R8，R9，R10，R11独立的选自氢，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，C1-6烷基，C1-6烷氧基，三卤C1-6烷基，三卤C1-6烷氧基，C1-6烷氧羰基，C1-6烷羰基氧基，C1-5烷酰基，C1-6烷氧基亚甲基氧基；
或R8和R9选自-O(CH2)n’O-，并与其取代的苯基相连成环；n’选自1、2或3；
三卤C1-6烷基和三卤C1-6烷氧基中三卤指的是含3个卤素，包括F3C1-6烷基、Br3C1-6烷基、Cl3C1-6烷基、I3C1-6烷基、F2BrC1-6烷基、F2ClC1-6烷基、F2IC1-6烷基、FBr2C1-6烷基、FCl2C1-6烷基、FI2C1-6烷基、ClBr2C1-6烷基、ICl2C1-6烷基、ClI2C1-6烷基；F3C1-6烷氧基、Br3C1-6烷氧基、Cl3C1-6烷氧基、I3C1-6烷氧基、F2BrC1-6烷氧基、F2ClC1-6烷氧基、F2IC1-6烷氧基、FBr2C1-6烷氧基、FCl2C1-6烷氧基、FI2C1-6烷基、ClBr2C1-6烷氧基、ICl2C1-6烷氧基、ClI2C1-6烷氧基；
优选F3C1-4烷基、Br3C1-4烷基、Cl3C1-4烷基、I3C1-4烷基、F2BrC1-4烷基、F2ClC1-4烷基、F2IC1-4烷基、FBr2C1-4烷基、FCl2C1-4烷基、FI2C1-4烷基、ClBr2C1-4烷基、ICl2C1-4烷基、ClI2C1-4烷基；F3C1-4烷氧基、Br3C1-4烷氧基、Cl3C1-4烷氧基、I3C1-4烷氧基、F2BrC1-4烷氧基、F2ClC1-4烷氧基、F2IC1-4烷氧基、FBr2C1-4烷氧基、FCl2C1-4烷氧基、FI2C1-4烷基、ClBr2C1-4烷氧基、ICl2C1-4烷氧基、ClI2C1-4烷氧基；
最优选F3C、F3CCH2、Br3C、Br3CCH2、Cl3C、Cl3CCH2、I3C、I3CCH2、F2BrC、F2BrCCH2、F2ClC、F2ClCCH2、F2IC、F2ICCH2、FBr2C、FBr2CCH2、FCl2C、FCl2CCH2、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；
X选自O，NH；
Y选自O，NH，S，亚砜，砜。
在通式(I)的衍生物的实施方案中：
优选的R1，R2独立的选自氢，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，C1-4烷基，C1-4烷氧基，三卤C1-4烷基，三卤C1-4烷氧基，C1-4烷氧羰基，C1-4烷羰基氧基，C1-3烷酰基，C1-4烷氧基亚甲基氧基；
优选的R1，R2或选自-O(CH2)n’O-，并与其取代的苯基相连成环；n选自1、2或3；
优选的R3和R4独立的选自氢，氟，氯，溴，羟基，二甲胺基，氰基，硝基，C1-4烷氧羰基，C1-4烷羰基氧基，甲胺基，甲磺酰基，二甲胺磺酰基，氨基，羧基，C1-4烷基，C1-4烷氧基，三卤C1-4烷基，三卤C1-4烷氧基；
优选的R5选自氢，C1-4烷基，C1-4烷氧基甲基，C0-4烷基胺基；
优选的R6选自氢，羟基，C0-4烷基胺基，C1-4烷羰基氧基，C1-4烷氧基羰基，O＝；
优选的R7，R8，R9，R10，R11独立的选自氢，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，C1-4烷基，C1-4烷氧基，三卤C1-4烷基，三卤C1-4烷氧基，C1-4烷氧羰基，C1-4烷羰基氧基，C1-3烷酰基，C1-4烷氧基亚甲基氧基，
优选的R8和R9或选自-O(CH2)n’O-，并与其取代的苯基相连成环；n’选自1、2或3；
优选的X选自O，NH；
优选的Y选自O，NH，S，亚砜，砜。
在通式(I)的衍生物的实施方案中：
更优选的R1，R2独立的选自氢，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，三卤C1-2烷基，三卤C1-2烷氧基，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，C1-2烷氧基亚甲基氧基；
更优选的R1，R2或选自-OCH2O-，-OCH2CH2O-并与其取代的苯基相连成环；
更优选的R3和R4独立的选自氢，氟，氯，溴，羟基，二甲胺基，氰基，硝基，甲氧羰基，乙氧羰基，C1-2烷羰基氧基，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，三卤C1-2烷基，三卤C1-2烷氧基；
更优选的R5选自氢，C1-2烷基，C1-2烷氧基甲基，C0-2烷基胺基；
更优选的R6选自氢，羟基，O＝，C0-2烷基胺基，C1-2烷氧基羰基，C1-2烷羰基氧基；
更优选的R7，R8，R9，R10，R11独立的选自氢，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，三卤C1-2烷基，三卤C1-2烷氧基，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，C1-2烷氧基亚甲基氧基；
更优选的R8和R9或选自-OCH2O-，-OCH2CH2O-并与其取代的苯基相连成环；
更优选的X选自O，NH；
更优选的Y选自O，NH，S，亚砜，砜。
在通式(I)的衍生物的实施方案中：
最优选的R1，R2独立的选自氢，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，甲氧基亚甲基氧基；
最优选的R1，R2或选自-OCH2O-，-OCH2CH2O-，并与其取代的苯基相连成环；
最优选的R3和R4独立的选自氢，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；
最优选的R5选自氢，甲基，乙基，甲氧基甲基，氨基；
最优选的R6选自氢，羟基，O＝，氨基，C1-2烷羰基氧基；
最优选的R7，R8，R9，R10，R11独立的选自氢，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，甲氧基亚甲基氧基；
最优选的R8和R9或选自-OCH2O-，-OCH2CH2O-，并与其取代的苯基相连成环；
最优选的X选自O，NH；
最优选的Y选自O，NH，S，亚砜，砜。
最优选的化合物，包括但不限定于如下化合物
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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。
本发明还公开了制备本发明化合物的方法，包括如下路线步骤：
i:取代；ii:缩合；
A:式(II)化合物在有机碱，如吡啶，哌啶，二异丙胺，乙二胺等；无机碱，如氢氧化钠，氢氧化钾，氢氧化锂，碳酸铯，碳酸钾等碱性条件下与式(III)化合物反应生成式(IV)化合物；
B:式(IV)化合物在有机碱，如吡啶，哌啶，二异丙胺，乙二胺等；无机碱，如氢氧化钠，氢氧化钾，氢氧化锂，碳酸铯，碳酸钾等碱性条件下于甲醇，乙醇，异丙醇，丁醇等醇溶剂中于40℃-70℃加热反应得到式(I)化合物；
其中R1，R2，R3，R4，R5，R6，R7，R8，R9，R10，R11，X，Y如权利要求1-6任一项所定义；Z选自：羟基，氯，溴，碘，对甲苯磺酰基，甲磺酰基。
式(I)化合物或其异构体及其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，铵盐和能提供生理上可接受的阳离子的有机碱的盐，如甲胺，二甲胺，三甲胺，哌啶，吗啉及三(2-羟乙基)胺的盐。本发明专利的所有盐都可以采用常规方法制备。另外，式(I)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。
本发明再一方面还涉及一种药物组合物，包括有效剂量的本发明化合物和药效学上可接受的载体。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物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。本发明化合物在其药物组合物中的含量通常为0.1-95重量％。
本发明化合物或含有它的药物组合物可以单位剂量形式给药，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。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂，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。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、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。
为将本发明化合物制成注射剂，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。
根据本发明，式(I)化合物或其异构体及其药学上可接受的盐在抗肿瘤中显示出优良效果。因而可作为抗肿瘤药用于动物，优选用于哺乳动物，特别是人。本发明的化合物可用于制备预防和/或治疗肿瘤的药物中的应用。所述的肿瘤选自胶质母细胞瘤、黑色素瘤、胃癌、肺癌、乳腺癌、肾癌、肝癌、口腔上皮癌、宫颈癌、卵巢癌、胰腺癌、前列腺癌、结肠癌或直肠腺癌。优选的肿瘤选自肝癌。
本发明化合物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，本发明化合物的每天的合适剂量范围为0.001-150mg/Kg体重，优选为0.1-100mg/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。
本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
本发明的优点
本发明的化合物是木脂素类的衍生物，此类衍生物与以往的结构改造多有不同，引入取代的吲哚环或取代的苯并呋喃酮而得到新型衍生物。此类化合物对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，可用于多种人类恶性肿瘤的治疗，以及肿瘤的预防，其中所述的肿瘤疾病是肺癌、肾癌、肝癌、胰腺癌、结肠癌、膀胱癌、乳腺癌、卵巢癌、及胶质母细胞瘤、白血病、头颈部癌。在炎症治疗中也觉有较好的效果。
具体实施方式
下面的实施例及药物活性实验用来进一步说明本发明，但这并不意味着对本发明的任何限制。
下面的实施例用来解释本发明，但对本发明无任何限制。
使用的原料为已知化合物或按已知方法制备。
步骤A:
(450mg,3mmol)香草醛，(1.2g,4.38mmol)3，4，5-三甲氧基溴代苯乙醇，(1.65g,12mmol)碳酸钾，于20mL DMF中，50℃反应4h，冷却至室温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)得0.63g化合物51，白色固体，收率60.5％。
1H NMR(400MHz,CDCl3)δ9.85(s,1H),7.42-7.44(m,2H),6.96(d,J＝8.8Hz,1H),6.55(s,2H),4.29(t,J＝7.2Hz,2H),3.93(s,3H),3.86(s,6H),3.83(s,3H),3.13(t,J＝7.2Hz,2H)；
13C NMR(100MHz,CDCl3)δ190.8,153.7,153.2,149.8,136.8,133.4,130.1,126.7,111.4,109.3,106.1,99.9,69.7,60.8,56.0,56.0,35.9.
以(300mg,2mmol)香草醛为原料，采用与制备化合物51相似操作步骤，与(402mg,2mmol)4-氟溴代苯乙醇在碳酸钾(1.1g,8mmol),10mL DMF中反应得到化合物52，305mg白色固体，收率55.7％。
1H NMR(400MHz,CDCl3)δ9.80(s,1H),7.37-7.39(m,2H),7.20-7.23(m,2H),6.89-6.99(m,3H),4.21(t,J＝7.2Hz,2H),3.89(s,3H),3.12(t,J＝7.2Hz,2H)；
13C NMR(100MHz,CDCl3)δ190.9,163.0,160.6,153.8,149.9,133.2,130.6,130.2,126.7,115.5,115.3,111.6,109.5,69.7,56.1,34.8.
以(300mg,2mmol)香草醛为原料，采用与制备化合物51相似操作步骤，与(960mg,4mmol)3,4-二甲氧基溴代苯乙醇在碳酸钾(1.1g,8mmol),10mLDMF中反应得到化合物53，445mg白色固体，收率70.4％。
1HNMR(400MHz,CDCl3)δ9.85(s,1H),7.42-7.44(m,2H),6.94-6.96(m,1H),6.88(m,1H),6.83(m,2H),4.27(t,J＝7.2Hz,2H),3.93(s,3H),3.89(s,3H),3.87(s,3H),3.14(t,J＝7.2Hz,2H)；
13C NMR(100MHz,CDCl3)δ190.9,153.8,149.8,148.9,147.8,130.1,130.1,126.8,120.9,112.5,111.4,111.3,109.3,70.0,56.0,55.9,55.8,35.1.
以(300mg,2mmol)香草醛为原料，采用与制备化合物51相似操作步骤，与(800mg,4mmol)4-甲基溴代苯乙醇在碳酸钾(1.1g,8mmol),10mLDMF中反应得到化合物54，285mg白色固体，收率52.8％。
1H NMR(400MHz,CDCl3)δ9.81(s,1H),7.38-7.40(m,2H),7.10-7.17(m,4H),6.91-6.93(m,1H),4.23(t,J＝7.2Hz,2H),3.90(s,3H),3.13(t,J＝7.2Hz,2H),2.31(s,3H)；
13C NMR(100MHz,CDCl3)δ190.9,153.8,149.8,136.3,134.2,130.1,129.3,128.9,126.8,111.4,109.3,69.9,56.0,35.1,21.0.
以(300mg,2mmol)香草醛为原料，采用与制备化合物51相似操作步骤，与(740mg,4mmol)溴代苯乙醇在碳酸钾(1.1g,8mmol),10mLDMF中反应得到化合物55，400mg白色固体，收率78.1％。
1H NMR(400MHz,CDCl3)δ9.83(s,1H),7.39-7.42(m,2H),7.24-7.34(m,5H),6.93-6.95(m,1H),4.28(t,J＝7.6Hz,2H),3.92(s,3H),3.19(t,J＝7.6Hz,2H)；
13C NMR(100MHz,CDCl3)δ191.0,153.8,149.9,137.4,130.2,129.1,128.7,126.8,126.8,111.6,109.4,69.8,56.1,35.6.
以(300mg,2mmol)香草醛为原料，采用与制备化合物51相似操作步骤，与(860mg,4mmol)4-甲氧基溴代苯乙醇在碳酸钾(1.1g,8mmol),10mLDMF中反应得到化合物56，414mg白色固体，收率72.4％。
1HNMR(400MHz,CDCl3)δ9.83(s,1H),7.39-7.42(m,2H),7.19-7.21(m,2H),6.92-6.94(m,1H),6.84-6.86(m,2H),4.23(t,J＝7.6Hz,2H),3.92(s,3H),3.78(s,3H),3.12(t,J＝7.6Hz,2H)；
13C NMR(100MHz,CDCl3)δ191.0,158.5,153.9,149.9,130.1,130.1,129.4,126.8,114.1,111.5,109.4,70.1,56.1,55.3,34.7.
以(380mg,2mmol)4-羟基-3-三氟甲基苯甲醛为原料，采用与制备化合物51相似操作步骤，与(0.55ml,4mmol)溴代苯乙醇在碳酸钾(1.1g,8mmol),10mL DMF中反应得到化合物57，572mg白色固体，收率97.3％。
1HNMR(400MHz,CDCl3)δ9.90(s,1H),8.09-8.10(m,1H),8.00(dd,J＝2.0Hz,8.4Hz,1H),7.24-7.35(m,5H),7.07(d,J＝8.4Hz,1H),4.37(t,J＝7.2Hz,2H),3.17(t,J＝7.2Hz,2H)；
13C NMR(100MHz,CDCl3)δ189.7,137.4,135.1,129.2,128.9,128.6,126.9,112.8,70.3,35.5.
以(380mg,2mmol)4-羟基-3-三氟甲基苯甲醛为原料，采用与制备化合物51相似操作步骤，与(700mg,3mmol)3,4-二甲氧基溴代苯乙醇在碳酸钾(1.1g,8mmol),10mLDMF中反应得到化合物58，670mg白色固体，收率94.6％。
1HNMR(400MHz,CDCl3)δ9.91(s,1H),8.10-8.11(m,1H),8.01(dd,J＝2.0Hz,8.4Hz,1H),7.08(d,J＝8.4Hz,1H),6.83-6.86(m,3H),4.32(t,J＝6.4Hz,2H),3.89(s,3H),3.86(s,3H),3.12(t,J＝6.4Hz,2H)；
13C NMR(100MHz,CDCl3)δ189.7,161.4,149.0,148.0,135.1,130.2,129.4,128.9,121.0,112.8,112.5,111.3,70.6,56.0,55.8,35.2.
以(244mg,2mmol)4-羟基苯甲醛为原料，采用与制备化合物51相似操作步骤，与(555mg,3mmol)溴代苯乙醇在碳酸钾(1.1g,8mmol),10mLDMF中反应得到化合物59，390mg白色固体，收率86.3％。
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1HNMR(400MHz,CDCl3)δ9.88(s,1H),7.81-7.83(m,2H),7.28-7.35(m,5H),6.98-7.00(m,2H),4.26(t,J＝6.8Hz,2H),3.13(t,J＝6.8Hz,2H)；
13C NMR(100MHz,CDCl3)δ190.9,163.9,137.7,132.0,130.0,129.0,128.6,126.8,114.8,69.0,35.6.
以(244mg,2mmol)4-羟基苯甲醛为原料，采用与制备化合物51相似操作步骤，与(732mg,3mmol)3,4-二甲氧基溴代苯乙醇在碳酸钾(1.1g,8mmol),10mL DMF中反应得到化合物60，373mg白色固体，收率65.2％。
1HNMR(400MHz,CDCl3)δ9.88(s,1H),7.82(d,J＝6.8Hz,2H),6.99(d,J＝6.8Hz,2H),6.81-6.83(m,3H),4.24(t,J＝6.8Hz,2H),3.89(s,3H),3.87(s,3H),3.08(t,J＝6.8Hz,2H)；
13C NMR(100MHz,CDCl3)δ190.8,163.9,149.0,147.9,132.0,130.3,130.0,121.0,114.8,112.4,111.4,69.23,56.0,55.9,35.2.
实施例1：
步骤B操作:
50mL圆底瓶中装有(50mg,0.14mmol)化合物51，(16mg,0.12mmol)2-吲哚酮，5滴哌啶，乙醇5mL加入，回流反应4h，TLC显示完全，冷却后过滤得47mg化合物1，收率84.8％。
1H NMR(400MHz,CDCl3)δ10.54(s,1H),8.67(s,1H),7.82(d,J＝10.4Hz,1H),7.73(s,1H),7.66(d,J＝7.2Hz,1H),7.17(t,J＝7.6Hz,1H),7.09(d,J＝8.4Hz,1H),6.97(t,J＝7.6Hz,1H),6.82(d,J＝7.6Hz,1H),6.68(s,2H),4.25(t,J＝7.2Hz,2H),3.83(s,3H),3.76(s,6H),3.62(s,3H),3.00(t,J＝6.8Hz,2H)；
13C NMR(100MHz,CDCl3)δ168.0,153.2,150.8,148.6,140.7,137.9,136.5,134.4,128.7,128.0,127.8,126.0,124.4,121.4,119.7,115.7,112.6,109.7,106.9,100.0,69.3,60.5,56.0,35.7,19.1.
HR-MS(ESI)calcd for C27H28O6N(M+H)+:462.1911,found 462.1903.
实施例2：
以(50mg,0.14mmol)化合物51，(18mg,0.12mmol)5-氟吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物2，黄色固体收率84.2％。
1H NMR(400MHz,CDCl3)δ10.54(s,1H),8.69(s,1H),7.81-7.83(m,2H),7.58(d,J＝9.2Hz,1H),7.11(d,J＝8.8Hz,1H),6.98-7.01(m,1H),6.77-6.80(m,1H),6.68(s,2H),4.25(t,J＝6.8Hz,2H),3.83(s,3H),3.76(s,6H),3.62(s,3H),3.00(t,J＝6.8Hz,2H)；
13C NMR(100MHz,CDCl3)δ168.1,153.1,150.7,148.5,140.7,137.9,136.5,134.4,128.7,128.0,127.8,126.0,124.4,121.4,119.7,115.7,112.6,109.7,106.9,100.0,69.3,60.5,56.0,35.6,19.0.
HR-MS(ESI)calcd for C27H27O6NF(M+H)+:480.1817,found480.1807.
实施例3：
以(50mg,0.14mmol)化合物51,(18mg,0.12mmol)5-甲基吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物3，33mg黄色固体，收率56.9％。
1HNMR(400MHz,CDCl3)δ10.38(s,1H),8.63(s,1H),8.58(s,1H),6.63-7.8(m,9H),4.16-4.22(m,2H),3.83(s,3H),3.76(s,6H),3.62(s,3H),2.95(t,J＝6.8Hz,2H)；
HR-MS(ESI)calcd for C28H30O6N(M+H)+:476.2068,found 476.2065.
实施例4：
以(50mg,0.14mmol)化合物51,(20mg,0.12mmol)5-甲氧基吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物4，20mg黄色固体，收率33.3％。
1H NMR(400MHz,CDCl3)δ10.28(s,1H),8.62(s,1H),7.78-7.80(m,1H),7.70(s,1H),7.30(s,1H),7.04-7.06(m,1H),6.63-6.71(m,4H),4.20(t,J＝6.8Hz,2H),3.78(s,3H),3.71(s,6H),3.70(s,3H),3.57(s,3H),2.95(t,J＝6.8Hz,2H)；
HR-MS(ESI)calcd for C28H30O7N(M+H)+:492.2017,found492.2007.
实施例5：
以(50mg,0.18mmol)化合物52,(20mg,0.15mmol)吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物5，56mg黄色固体，收率95.9％。
1HNMR(400MHz,CDCl3)δ10.48(s,1H),8.61(s,1H),7.59-7.77(m,3H),7.31-7.35(m,2H),6.75-7.14(m,6H),4.19(t,J＝7.6Hz,2H),3.76(s,3H),3.01(t,J＝6.8Hz,2H)；
实施例6：
以(50mg,0.18mmol)化合物52,(20mg,0.15mmol)5-氟吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物6，44mg黄色固体，收率72.1％。
1HNMR(400MHz,d-DMSO)δ10.50(s,1H),8.63(s,1H),7.76(m,2H),7.53-7.55(m,1H),7.33-7.35(m,2H),7.07-7.11(m,3H),6.92-6.96(m,1H),6.72-6.76(m,1H),4.22(t,J＝6.8Hz,2H),3.77(s,3H),3.02(t,J＝6.8Hz,2H)；
实施例7：
以(50mg,0.18mmol)化合物52,(22mg,0.15mmol)5-甲基吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物7，40mg黄色固体，收率66.7％。
1H NMR(400MHz,CDCl3)δ8.74(m,1H),7.52-7.54(m,1H),7.42-7.45(m,1H),7.25-7.33(m,4H),6.99-7.03(m,3H),6.88-6.90(m,1H),6.72-6.74(m,1H),4.22(t,J＝6.8Hz,2H),3.77(s,3H),3.02(t,J＝6.8Hz,2H)；
HR-MS(ESI)calcd for C25H23O3NF(M+H)+:404.1656,found404.1636.
实施例8：
以(50mg,0.18mmol)化合物52,(25mg,0.15mmol)5-甲氧基吲哚-2-酮为原料，采用实施例1相似操作步骤，并重结晶两次，得到化合物8，22mg黄色固体，收率34.4％。
1H NMR(400MHz,d-DMSO)δ10.33(s,1H),8.66(s,1H),7.83-7.85(m,1H),7.75(m,1H),7.34-7.40(m,3H),7.08-7.15(m,3H),6.70-6.77(m,2H),4.25(t,J＝6.8Hz,2H),3.82(s,3H),3.76(s,3H),3.06(t,J＝6.8Hz,2H)；
HR-MS(ESI)calcd for C25H23O4NF(M+H)+:420.1606,found420.1600.
实施例9：
以(100mg,0.32mmol)化合物53，(35mg,0.26mmol)吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物9，100mg淡黄色固体，收率88.5％。
1H NMR(400MHz,d-DMSO)δ10.54(s,1H),8.67(d,J＝2.0Hz,1H),7.81(dd,J＝2.0Hz,6.8Hz,1H),7.28(s,1H),7.66(d,J＝7.6Hz,1H),7.15-7.19(m,1H),7.08(d,J＝8.4Hz,1H),6.94-6.99(m,2H),6.81-6.88(m,3H),4.21(t,J＝6.8Hz,2H),3.83(s,3H),3.75(s,3H),3.71(s,3H),2.99(t,J＝6.8Hz,2H)；
13C NMR(100MHz,CDCl3)δ167.9,150.8,149.0,148.5,147.9,140.6,137.9,131.0,128.6,127.9,127.7,125.9,124.4,121.4,119.6,115.7,113.5,112.5,112.3,109.7,56.0,55.9,55.8.
实施例10：
以(100mg,0.32mmol)化合物53，(40mg,0.26mmol)5-氟吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物10，85mg淡黄色固体，收率80.5％。
1H NMR(400MHz,d-DMSO)δ10.51(s,1H),8.65(d,J＝2.0Hz,1H),7.71-7.79(m,2H),7.55(dd,J＝2.0Hz,9.2Hz,1H),7.07(d,J＝9.2Hz,1H),6.92-6.97(m,2H),6.73-6.84(m,3H),4.19(t,J＝7.2Hz,2H),3.79(s,3H),3.71(s,3H),3.67(s,3H),2.96(t,J＝7.2Hz,2H)；
实施例11：
以(100mg,0.32mmol)化合物53，(38mg,0.26mmol)5-甲基吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物11，90mg淡黄色固体，收率53％。
1H NMR(400MHz,d-DMSO)δ10.42(s,1H),8.62-8.66(m,1H),7.81-7.83(m,1H),7.69(s,1H),7.48-7.49(m,2H),7.07-7.09(m,2H),6.83-6.88(m,3H),4.21-4.24(m,2H),3.82(s,3H),3.75(s,3H),3.71(s,3H),2.97-3.01(m,2H),2.29(s,3H)；
HR-MS(ESI)calcd for C27H28O5N(M+H)+:446.1962,found 446.1958.
实施例12：
以(100mg,0.32mmol)化合物53，(38mg,0.26mmol)5-甲氧基吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物12，重结晶两次后得到55mg淡黄色固体，收率46.6％。
1H NMR(400MHz,d-DMSO)δ10.33(s,1H),8.66(d,J＝2.0Hz,1H),7.83(dd,J＝2.0Hz,8.4Hz,1H),7.75(s,1H),7.34(d,J＝2.0Hz,1H),7.08(d,J＝8.4Hz,1H),6.99(d,J＝1.6Hz,1H),6.84-6.88(m,2H),6.70-6.76(m,2H),4.22(t,J＝7.2Hz,2H),3.82(s,3H),3.76(s,3H),3.75(s,3H),3.71(s,3H),2.99(t,J＝7.2Hz,2H)；
13C NMR(100MHz,d-DMSO)δ168.1,155.1,150.8,149.0,148.5,147.9,138.1,134.5,131.0,128.0,127.7,126.9,124.9,121.3,115.8,114.5,113.5,112.5,112.3,110.2,105.8,69.5,56.1,56.0,55.9,55.8,34.9.
实施例13：
以(60mg,0.22mmol)化合物54，(25mg,0.26mmol)吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物13，63mg淡黄色固体，收率87.1％。
1HNMR(400MHz,d-DMSO)δ10.54(s,1H),8.66(d,J＝2.0Hz,1H),7.83(dd,J＝2.0Hz,8.8Hz,1H),7.73(s,1H),7.66(d,J＝7.6Hz,1H),7.21-7.23(m,2H),7.07-7.19(m,4H),6.94-6.98(m,1H),6.82(d,J＝7.6Hz,1H),4.22(t,J＝7.2Hz,2H),3.82(s,3H),3.02(t,J＝7.2Hz,2H),2.26(s,3H)；
实施例14：
以(60mg,0.22mmol)化合物54，(27mg,0.18mmol)5-氟吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物14，60mg淡黄色固体，收率82.6％。
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)；
实施例15：
以(60mg,0.22mmol)化合物54，(26mg,0.18mmol)5-甲基吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物15，60mg淡黄色固体，收率83.4％。
1H NMR(400MHz,d-DMSO)δ10.42(s,1H),8.61-8.66(m,1H),7.81-7.83(m,1H),7.69(s,1H),7.21-7.49(m,7H),6.70(d,J＝8.0Hz,1H),4.20-4.24(m,2H),3.81(m,3H),3.02(t,J＝6.8Hz,2H),2.29(s,3H),2.27(s,3H)；
HR-MS(ESI)calcd for C26H26O3N(M+H)+:400.1907,found 400.1902.
实施例16：
以(60mg,0.22mmol)化合物54，(26mg,0.18mmol)5-甲氧基吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物16，55mg淡黄色固体，收率72.4％。
1H NMR(400MHz,d-DMSO)δ10.33(s,1H),8.68(d,J＝2.0Hz,1H),7.83(dd,J＝2.0Hz,8.8Hz,1H),7.74(s,1H),7.34(d,J＝3.0Hz,1H),7.21-7.23(m,2H),7.07-7.12(m,3H),6.70-6.77(m,2H),4.22(t,J＝7.2Hz,2H),3.82(s,3H),3.76(s,3H),3.02(t,J＝7.2Hz,2H),2.26(s,3H)；
实施例17：
以(100mg,0.39mmol)化合物55，(44mg,0.33mmol)吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物17，106mg淡黄色固体，收率86.5％。
1H NMR(400MHz,d-DMSO)δ10.54(s,1H),8.66(d,J＝2.0Hz,1H),7.82(dd,J＝1.6Hz,7.6Hz,1H),7.73(s,1H),7.66(d,J＝7.6Hz,1H),7.29-7.36(m,4H),7.15-7.24(m,2H),7.09(d,J＝8.4Hz,1H),6.97(t,J＝7.2Hz,1H),6.82(d,J＝8.0Hz,1H),4.26(t,J＝7.2Hz,2H),3.82(s,3H),3.07(t,J＝7.2Hz,2H)；
实施例18：
以(100mg,0.39mmol)化合物55，(44mg,0.33mmol)5-氟吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物18，77mg淡黄色固体，收率62.9％。
1H NMR(400MHz,d-DMSO)δ10.55(s,1H),8.68(d,J＝2.0Hz,1H),7.80-7.83(m,2H),7.59(dd,J＝2.4Hz,8.8Hz,1H),7.29-7.36(m,4H),7.22-7.34(m,1H),7.11(d,J＝8.4Hz,1H),6.96-7.01(m,1H),6.77-6.80(m,1H),4.27(t,J＝7.2Hz,2H),3.82(s,3H),3.07(t,J＝7.2Hz,2H)；
实施例19：
以(100mg,0.39mmol)化合物55，(49mg,0.33mmol)5-甲基吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物19，94mg淡黄色固体，收率73.4％。
1H NMR(400MHz,d-DMSO)δ10.42(s,1H),8.65(d,J＝2.0Hz,1H),7.82(dd,J＝1.6Hz,8.4Hz,1H),7.69(s,1H),7.49(s,1H),7.20-7.36(m,5H),7.08(d,J＝8.4Hz,1H),6.97(d,J＝8.0Hz,1H),6.70(d,J＝8.0Hz,1H),4.26(t,J＝6.8Hz,2H),3.81(s,3H),3.07(t,J＝7.2Hz,2H),2.29(s,3H)；
13C NMR(100MHz,d-DMSO)δ168.0,150.7,148.5,138.6,138.4,137.5,130.1,129.5,129.0,128.8,127.8,126.8,126.0,124.6,120.2,115.8,112.6,109.4,69.3,56.0,35.4,21.3.
实施例20：
以(100mg,0.39mmol)化合物55，(53mg,0.33mmol)5-甲氧基吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物20，77mg淡黄色固体，收率59.2％。
1H NMR(400MHz,d-DMSO)δ10.33(s,1H),8.66(d,J＝2.0Hz,1H),7.83(dd,J＝2.0Hz,6.8Hz,1H),7.75(s,1H),7.29-7.36(m,5H),7.20-7.24(m,1H),7.09(d,J＝8.8Hz,1H),6.70-6.77(m,2H),4.26(t,J＝7.2Hz,2H),3.82(s,3H),3.76(s,3H),3.07(t,J＝6.8Hz,2H)；
HR-MS(ESI)calcd for C25H24O4N(M+H)+:402.1700,found 402.1696.
实施例21：
以(80mg,0.28mmol)化合物56，(31mg,0.23mmol)吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物21，80mg淡黄色固体，收率86％。
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)；
HR-MS(ESI)calcd for C25H23O4NNa(M+Na)+:424.1519,found424.1513.
实施例22：
以(80mg,0.28mmol)化合物56，(35mg,0.23mmol)5-氟吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物22，85mg淡黄色固体，收率87.6％。
1H NMR(400MHz,d-DMSO)δ10.55(s,1H),8.68(d,J＝2.0Hz,1H),7.80-7.82(m,2H),7.58(dd,J＝2.4Hz,8.8Hz,1H),7.24-7.27(m,2H),7.09(d,J＝8.4Hz,1H),6.96-7.01(m,1H),6.85-6.89(m,2H),6.77-6.80(m,1H),4.21(t,J＝7.2Hz,2H),3.82(s,3H),3.72(s,3H),3.00(t,J＝6.8Hz,2H)；
HR-MS(ESI)calcd for C25H23O4NF(M+H)+:420.1606,found 420.1588.
实施例23：
以(80mg,0.28mmol)化合物56，(34mg,0.23mmol)5-甲基吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物23，80mg淡黄色固体，收率83.3％。
1H NMR(400MHz,d-DMSO)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),4.21-4.22(m,2H),3.82(s,3H),3.72(s,3H),3.00(t,J＝6.8Hz,2H)；
HR-MS(ESI)calcd for C26H26O4N(M+H)+:416.1856,found 416.1847.
实施例24：
以(80mg,0.28mmol)化合物56，(38mg,0.23mmol)5-甲氧基吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物24，84mg淡黄色固体，收率84％。
1H NMR(400MHz,d-DMSO)δ10.33(s,1H),8.66(d,J＝2.0Hz,1H),7.83(dd,J＝1.6Hz,8.4Hz,1H),7.74(s,1H),7.24-7.35(m,3H),7.08(d,J＝8.4Hz,1H),6.86-6.88(m,2H),6.70-6.77(m,2H),4.21(t,J＝7.2Hz,2H),3.82(s,3H),3.76(s,3H),3.72(s,3H),3.07(t,J＝6.8Hz,2H)；
HR-MS(ESI)calcd for C26H26O5N(M+H)+:432.1806,found 432.1800.
实施例25：
以(100mg,0.34mmol)化合物57，(28mg,0.28mmol)吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物25，48mg淡黄色固体，收率55.8％。
1H NMR(500MHz,d-DMSO)δ10.61(s,1H),8.98(s,1H),8.59(d,J＝8.5Hz,1H),7.82(s,1H),7.67(d,J＝7.5Hz,1H),7.18-7.38(m,7H),6.98(d,J＝7.5Hz,1H),6.82(d,J＝8.0Hz,1H),4.40(t,J＝6.5Hz,2H),3.07(t,J＝6.5Hz,2H)；
HR-MS(ESI)calcd for C24H19O2NF3(M+H)+:410.1362,found 410.1349.
实施例26：
以(100mg,0.25mmol)化合物57，(28mg,0.21mmol)5-氟吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物26，63mg淡黄色固体，收率79.7％。
1H NMR(400MHz,d-DMSO)δ10.63(s,1H),8.98(d,J＝2.0Hz,1H),8.60(dd,J＝2.4Hz,8.8Hz,1H),7.90(s,1H),7.59(dd,J＝2.4Hz,8.8Hz,1H),7.20-7.41(m,6H),6.99-7.04(m,1H),6.78-6.81(m,1H),4.41(t,J＝6.8Hz,2H),3.82(s,3H),3.07(t,J＝6.8Hz,2H)；
HR-MS(ESI)calcd for C24H18O2NF4(M+H)+:428.1268,found 428.1275.
实施例27：
以(100mg,0.25mmol)化合物57，(32mg,0.22mmol)5-甲基吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物27，77mg淡黄色固体，收率83.7％。
1H NMR(500MHz,d-DMSO)δ10.49(s,1H),8.95(m,1H),8.56-8.61(m,1H),8.07-8.11(m,1H),7.78(s,1H),7.51(s,1H),7.22-7.42(m,6H),7.00-7.01(m,1H),6.70-6.71(m,1H),4.40(m,2H),3.07(t,J＝6.5Hz,2H)；
HR-MS(ESI)calcd for C25H21O2NF3(M+H)+:424.1519,found 424.1515.
实施例28：
以(100mg,0.25mmol)化合物57，(34mg,0.22mmol)5-甲氧基吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物28，34mg淡黄色固体，收率37.2％。
1H NMR(400MHz,CDCl3)δ8.35(s,1H),7.99(d,J＝1.6Hz,1H),7.76(dd,J＝2.0Hz,8.8Hz,1H),7.71(s,1H),7.26-7.34(m,5H),7.21(s,1H),7.04-7.06(m,1H),6.80(d,J＝1.6Hz,2H),4.32(t,J＝6.8Hz,2H),3.69(s,3H),3.18(t,J＝6.8Hz,2H)；
HR-MS(ESI)calcd for C25H21O3NF3(M+H)+:440.1468,found 440.1458.
实施例29：
以(100mg,0.28mmol)化合物58，(31mg,0.23mmol)吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物29，76mg淡黄色固体，收率69.7％。
1H NMR(500MHz,d-DMSO)δ10.61(s,1H),8.98(s,1H),8.60(d,J＝9.0Hz,1H),7.83(s,1H),7.67(d,J＝7.5Hz,1H),7.37(d,J＝9.0Hz,1H),7.19(t,J＝7.5Hz,1H),6.94-7.00(m,2H),6.81-6.88(m,4H),4.37(t,J＝6.0Hz,2H),3.74(s,3H),3.71(s,3H),3.00(t,J＝6.5Hz,2H)；
HR-MS(ESI)calcd for C26H23O4NF3(M+H)+:470.1574,found 470.1566.
实施例30：
以(100mg,0.28mmol)化合物58，(35mg,0.23mmol)5-氟吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物30，95mg淡黄色固体，收率84.1％。
1H NMR(500MHz,d-DMSO)δ10.63(s,1H),8.99(s,1H),8.61(d,J＝8.5Hz,1H),7.90(s,1H),7.59(d,J＝9.0Hz,1H),7.39(d,J＝9.0Hz,1H),7.00-7.04(m,1H),6.94(s,1H),6.78-6.88(m,3H),4.37(t,J＝6.5Hz,2H),3.73(s,3H),3.71(s,3H),3.00(t,J＝6.5Hz,2H)；
HR-MS(ESI)calcd for C26H22O4NF4(M+H)+:488.1480,found 488.1480.
实施例31：
以(100mg,0.28mmol)化合物58，(34mg,0.23mmol)5-甲基吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物30，95mg淡黄色固体，收率70.8％。
1H NMR(400MHz,d-DMSO)δ10.49(s,1H),8.95(m,1H),8.56-8.61(m,1H),8.07-8.11(m,1H),7.78(s,1H),7.51(s,1H),7.22-7.42(m,5H),7.00-7.01(m,1H),6.70-6.71(m,1H),4.40(m,2H),3.73(s,3H),3.71(s,3H),3.00(t,J＝6.5Hz,2H),2.26(s,3H)；
HR-MS(ESI)calcd for C27H25O4NF3(M+H)+:484.1730,found 484.1710.
实施例32：
以(100mg,0.28mmol)化合物58，(38mg,0.23mmol)5-甲氧基吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物32，65mg淡黄色固体，收率56％。
1H NMR(400MHz,d-DMSO)δ10.41(s,1H),8.97(s,1H),8.64(d,J＝10.0Hz,1H),7.84(s,1H),7.37-7.39(m,2H),6.71-6.94(m,5H),4.37(t,J＝6.8Hz,2H),3.75(s,3H),3.74(s,3H),3.71(s,3H),3.00(t,J＝6.8Hz,2H)；
HR-MS(ESI)calcd for C27H25O5NF3(M+H)+:500.1679,found 500.1669.
实施例33：
以(80mg,0.35mmol)化合物59，(40mg,0.3mmol)吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物33，52mg淡黄色固体，收率75.5％。
1H NMR(400MHz,d-DMSO)δ10.56(s,1H),8.45(d,J＝9.6Hz,2H),7.73(s,1H),7.66(d,J＝7.2Hz,1H),7.29-7.35(m,4H),7.15-7.24(s,2H),7.03(d,J＝8.8Hz,2H),6.96(t,J＝7.6Hz,1H),6.80(d,J＝7.6Hz,1H),4.28(t,J＝6.8Hz,2H),3.00(t,J＝6.8Hz,2H)；
HR-MS(ESI)calcd for C23H20O2N(M+H)+:342.1489,found 342.1484.
实施例34：
以(80mg,0.35mmol)化合物59，(44mg,0.3mmol)5-氟吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物34，80mg淡黄色固体，收率74％。
1H NMR(400MHz,d-DMSO)δ10.57(s,1H),8.46(d,J＝8.8Hz,2H),7.81(s,1H),7.59(dd,J＝2.8Hz,9.0Hz,1H),7.29-7.35(m,4H),7.20-7.24(m,1H),6.96-7.06(m,3H),6.75-6.79(m,1H),4.29(t,J＝6.8Hz,2H),3.06(t,J＝6.8Hz,2H)；
HR-MS(ESI)calcd for C23H19O2NF(M+H)+:360.1394,found 360.1388.
实施例35：
以(80mg,0.35mmol)化合物59，(44mg,0.3mmol)5-甲基吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物35，30mg淡黄色固体，收率28.3％。
1H NMR(400MHz,CDCl3)δ8.25(s,1H),7.75(s,1H),7.64-7.66(m,2H),7.56(s,1H),7.28-7.36(m,5H),6.97-7.02(m,3H),6.78(d,J＝7.6Hz,1H),4.26(t,J＝6.8Hz,2H),3.15(t,J＝6.8Hz,2H),2.24(s,3H)；
HR-MS(ESI)calcd for C24H22O2N(M+H)+:356.1645,found 356.1631.
实施例36：
以(80mg,0.35mmol)化合物59，(49mg,0.3mmol)5-甲氧基吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物36，81mg淡黄色固体，收率73％。
1H NMR(400MHz,d-DMSO)δ10.34(s,1H),7.68(d,J＝8.4Hz,2H),7.55(s,1H),7.29-7.35(m,4H),7.20-7.24(m,2H),7.09(d,J＝8.4Hz,2H),6.76-6.83(m,2H),4.28(t,J＝6.8Hz,2H),3.63(s,3H),3.06(t,J＝6.8Hz,2H)；
HR-MS(ESI)calcd for C24H22O3N(M+H)+:372.1594,found 372.1588.
实施例37：
以(80mg,0.27mmol)化合物60，(30mg,0.23mmol)吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物37，80mg淡黄色固体，收率88.8％。
1H NMR(400MHz,d-DMSO)δ10.53(s,1H),7.68(d,J＝8.8Hz,2H),7.63(d,J＝8.0Hz,2H),7.56(s,1H),7.18-7.22(m,1H),7.08(d,J＝8.8Hz,2H),6.95(m,1H),6.82-6.89(m,4H),4.25(t,J＝6.8Hz,2H),3.75(s,3H),3.71(s,3H),3.00(t,J＝6.8Hz,2H)；
HR-MS(ESI)calcd for C25H24O4N(M+H)+:402.1700,found 402.1691.
实施例38：
以(80mg,0.27mmol)化合物60，(30mg,0.23mmol)5-氟吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物38，81mg淡黄色固体，收率89％。
1H NMR(400MHz,d-DMSO)δ10.58(s,1H),7.68(d,J＝8.8Hz,2H),7.63(s,1H),7.34(dd,J＝2.4Hz,8.8Hz,1H),7.11(d,J＝8.8Hz,2H),7.05-7.10(m,1H),6.95-6.96(m,1H),6.83-6.89(m,3H),4.26(t,J＝6.8Hz,2H),3.75(s,3H),3.72(s,3H),3.00(t,J＝6.8Hz,2H)；
HR-MS(ESI)calcd for C25H23O4NF(M+H)+:420.1606,found 420.1596.
实施例39：
以(80mg,0.27mmol)化合物60，(30mg,0.23mmol)5-甲基吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物39，89mg淡黄色固体，收率93.2％。
1H NMR(400MHz,CDCl3)δ10.38(s,1H),8.57(s,1H),7.63-7.75(m,3H),7.43-7.49(m,2H),6.79(m,4H),6.71(d,J＝8.0Hz,1H),4.19-4.23(m,2H),3.71(s,3H),3.68(s,3H),2.94-2.98(m,2H),2.14(s,3H)；
HR-MS(ESI)calcd for C26H26O4N(M+H)+:416.1856,found 416.1848.
实施例40：
以(80mg,0.27mmol)化合物60，(38mg,0.23mmol)5-甲氧基吲哚-2-酮为原料，采用实施例1相似操作步骤，得到化合物40，89mg淡黄色固体，收率93.2％。
1H NMR(400MHz,CDCl3)δ10.34(s,1H),7.67-7.69(m,2H),7.55(s,1H),7.20-7.76(m,8H),4.24(t,J＝6.8Hz,2H),3.74(s,3H),3.71(s,3H),3.00(t,J＝6.8Hz,2H)；HR-MS(ESI)calcd for C26H26O5N(M+H)+:432.1806,found 432.1798.
实施例41：
以(38mg,0.23mmol)吲哚-2-酮为原料，采用实施例1相似操作步骤，与(72mg,0.23mmol)(S)-4-((1-(3,4-二甲氧基苯基)-1-丙酮基)-2-氧基苯甲醛在5mL无水乙醇中反应得到化合物41，60mg淡黄色固体，收率61.2％。
实施例42：
化合物41加入15mL甲醇溶解后，滴入硼氢化钠的四氢呋喃溶液，反应2h后淬灭反应，浓缩后柱层析，得到化合物42，40mg淡黄色固体，收率60％。
实施例43：
以(38mg,0.23mmol)3,4-亚甲二氧基吲哚-2-酮为原料，采用实施例1相似操作步骤，与(72mg,0.23mmol)化合物53在5mL无水乙醇中反应得到化合物43，65mg淡黄色固体，收率63.7％。
实施例44：
以(38mg,0.23mmol)5-氟吲哚-2-酮为原料，采用实施例1相似操作步骤，与(62mg,0.23mmol)4-(3,4-亚甲二氧基苯基乙基)氧基苯甲醛在5mL无水乙醇中反应得到化合物44，80mg淡黄色固体，收率86％。
实施例45：
以(38mg,0.23mmol)5-氟苯并呋喃-2-酮为原料，采用实施例1相似操作步骤，与(72mg,0.23mmol)化合物53在5mL无水乙醇中反应得到化合物45，20mg淡黄色固体，收率20.8％。
实施例46：
以(38mg,0.23mmol)5-氟苯并呋喃-2-酮为原料，采用实施例1相似操作步骤，与(66mg,0.23mmol)4-(3,4-二甲氧基苯基乙基)氨基苯甲醛在5mL无水乙醇中反应得到化合物46，30mg淡黄色固体，收率30％。
实施例47：
以(38mg,0.23mmol)5-氟吲哚-2-酮为原料，采用实施例1相似操作步骤，与(69mg,0.23mmol)4-(3,4-二甲氧基苯基乙基)巯基苯甲醛在5mL无水乙醇中反应得到化合物47，45mg淡黄色固体，收率45％。
实施例48：
以(43mg,0.1mmol)化合物47为原料，与0.1mL过氧化氢在2mL正丙醇，5mL甲醇混合溶剂中室温反应30h后，析出固体，过滤后得到化合物48，得到40mg淡黄色固体，收率90％。
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实施例49：
以(37mg,0.08mmol)化合物48为原料，与0.2mL次氯酸钠在3mL乙腈中室温反应10h后，析出固体，过滤得到化合物49，得到30mg淡黄色固体，收率75％。
药理实验
实验例1、木脂素类衍生物MTT法测定肿瘤细胞存活率
(一)方法
MTT法测定肿瘤细胞存活率
将对数生长期的细胞用胰酶消化后，配制成一定浓度的单细胞悬液，根据细胞生长速度的差异，按1500-3000个/孔接种于96孔板，每孔加入细胞悬液100μl。次日加入含不同浓度化合物及相应溶剂对照的新鲜培养基，每孔加100μl(DMSO终浓度<0.1％)，每种受试化合物设3个剂量组(0.5，5，50μmol/L)每组设三个平行孔。于37℃，5％CO2继续培养96h后弃上清，每孔加入50μL新鲜配制的含2.0mg/mL MTT(Sigma Chemical)的无血清培养基。继续培养4h，弃上清，每孔加入150μL DMSO溶解MTT甲簪沉淀，微型振荡器振荡混匀后，酶标仪(WD-2102A,中国)在检测波长570nm条件下测定光密度值(OD)，以溶剂对照处理的肿瘤细胞为对照组，按下列公式计算药物对肿瘤细胞的抑制率，并按中效方程计算IC50：
体外抗肿瘤筛选结果见表
表1体外抗肿瘤筛选结果
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HCT116：人结肠癌细胞株
U87-MG：人胶质母细胞瘤细胞株
MGC803:人胃癌细胞株
BGC823：人胃癌细胞株
PC9：人肺癌细胞株
-：未测试。
Claims (6)
1.式(I)化合物及其药学上可接受的盐
化合物
R1和R2独立的选自氢，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；
R3和R4独立的选自氢，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；
R5选自氢，甲基，乙基，甲氧基甲基，氨基；
R6选自氢，羟基，氨基，C1-2烷羰基氧基；
R7，R8，R9，R10，R11独立的选自氢，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，甲氧基亚甲基氧基；
X选自NH；
Y选自O，S。
2.根据权利要求1的化合物及其药学上可接受的盐，其特征在于，所述化合物选自
3.根据权利要求1-2任一项的化合物及其药学上可接受的盐，其特征在于，所述的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。
4.制备权利要求1-3任一项的所述化合物的方法，其特征在于，包括以下步骤：
i:取代；ii:缩合；
A.式(II)化合物在碱性条件下与式(III)化合物反应生成式(IV)化合物；
B.式(IV)化合物在有机碱或者无机碱性条件下于醇溶剂中加热反应得到式(I)化合物；
其中R1，R2，R3，R4，R5，R6，R7，R8，R9，R10，R11，X，Y如权利要求1-3任一项所定义；Z选自：羟基，氯，溴，碘，对甲苯磺酰基，甲磺酰基。
5.一种药物组合物，包括有效剂量的权利要求1-3中任一项的化合物及其药学上可接受的盐和药效学上可接受的载体。
6.权利要求1-3中任一项的化合物及其药学上可接受的盐在制备预防和/或治疗胶质母细胞瘤、胃癌、肺癌或结肠癌的药物中的应用。
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