CN108658914B - 一种单羰基姜黄素-香豆素杂合体及其制备方法和用途 - Google Patents
一种单羰基姜黄素-香豆素杂合体及其制备方法和用途 Download PDFInfo
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Abstract
本发明涉及药物化学和药物治疗学领域,具体涉及一种单羰基姜黄素‑香豆素杂合体及其制备方法和用途,特别涉及一种红外荧光诊疗一体化化合物的制备方法,制备方法以及医药用途,特别是在荧光诊断及肿瘤相关活性等方面的应用。
Description
技术领域
本发明涉及一种红外荧光诊疗一体化化合物,具体涉及一种单羰基姜黄素-香豆素杂合体及其制备方法和用途,特别是在荧光诊断及肿瘤相关活性等方面的应用,属于药学技术领域。
背景技术
癌症是威胁人类的重要疾病之一。尽管近几十年来在肿瘤治疗领域有突飞猛进的进展,肿瘤治疗常因缺乏亚细胞器专属性使得治疗窗较窄且有一定的毒副作用。因此,开发一种新型的诊疗方案,即同时能够递送至特殊的亚细胞器并用自身荧光进行检测的新型方法可以实现个体化精准治疗的目的。
线粒体,是维持细胞内代谢平衡的主要细胞器。它们能通过氧化磷酸化提供代谢能量,通过ROS产生细胞内信号,并调节细胞凋亡。线粒体同时响应不同类型的刺激,包括死亡信号、营养因子剥夺、DNA损伤和释放线粒体介导的凋亡蛋白。更重要的是,线粒体调节由Bcl-2/Bax家族的蛋白质调控的内在凋亡途径。Caspase级联的激活导致细胞死亡。癌细胞的线粒体在正常的细胞中起着不同的作用,它们参与癌变和癌症发展进程。线粒体膜电位下降引起的细胞ROS应激主要是由TrxR/Trx和谷胱甘肽还原酶(GR)/谷胱甘肽(GSH)抗氧化系统在生理条件下调控的。TrxR是唯一已知的催化还原反应的还原酶。硫氧还蛋白系统的功能受到TrxR活性的严格控制。结构上,所有哺乳动物TrxR异构体的特征是在其保守的C-末端(Gly-Cys-Sec-Gly)序列的倒数第二个硒代半胱氨酸残基(Sec498)为主要靶点。因此,许多TrxR靶向化合物,特别是α,β-不饱和酮(如姜黄素及其衍生物)已被开发为潜在的不可逆的抗肿瘤治疗的TrxR抑制剂。线粒体中缺乏TrxR/Trx可能引起肿瘤细胞严重凋亡现象。因此,由于TrxR/Trx的重要作用,线粒体靶向的TrxR抑制剂是一种潜在的化疗方法来根除癌细胞,然而目前却鲜有报道。
天然的和合成的香豆素衍生物具有多种生物活性,如抗癌、抗炎、抗氧化等。有文献表明,香豆素衍生物具有荧光特性如7-二乙氨基香豆素类化合物。单羰基姜黄素衍生物是一种已报道的TrxR抑制剂。
本发明依据药物设计中的常用拼合原理,将姜黄素部分和7-二乙氨基香豆素进行杂合可能会获得新的线粒体靶向性的荧光诊疗一体的TrxR抑制剂KY-6。
发明内容
目的:本发明提供一种单羰基姜黄素-香豆素杂合体及其制备方法和用途。
技术方案:为解决上述技术问题,本发明采用的技术方案为:
本发明的化合物如式I所示:
光学实验证明,该化合物具有红色发射波长和较长的斯托克斯位移、良好的生理pH稳定性和抗血清中蛋白的干扰能力、细胞膜通透性和细胞内线粒体聚集作用及在体成像。药理实验证明,该化合物具有抑制TrxR活性的作用。诱导肿瘤细胞内活性氧水平升高,激活caspase凋亡通路诱导肿瘤细胞凋亡,并具有良好的体内抗肿瘤活性等。
本发明化合物与可药用酸的加合盐构成了本发明的完整部分;在可药用酸中有盐酸,氢溴酸,硫酸,磷酸,乙酸,三氟乙酸,乳酸,丙酮酸,丙二酸,琥珀酸,戊二酸,富马酸,酒石酸,马来酸,柠檬酸,抗坏血酸,甲磺酸,樟脑酸,草酸等。
本发明的另一目的在于提供本发明式I化合物的制备方法,化合物合成路线如下:
包括以下步骤:
步骤(1)4-(二乙氨基)-2-羟基苯甲醛和丙二酸二乙酯反应制得7-(二乙氨基)-2-氧代-2H-苯并吡喃-3-羧酸乙酯;
步骤(2)7-(二乙氨基)-2-氧代-2H-苯并吡喃-3-羧酸乙酯经酸化、脱羧得到7-(二乙氨基)-2-氧代-2H-苯并吡喃;
步骤(3)7-(二乙氨基)-2-氧代-2H-苯并吡喃经甲酰基化得到7-(二乙氨基)-2-氧代-2H-苯并吡喃-3-甲醛;
步骤(4)7-(二乙氨基)-2-氧代-2H-苯并吡喃-3-甲醛反应后得到(E)-7-(二乙基氨基)-3-(3-丁酮-1-烯)-2H-苯并吡喃-2-酮;
步骤(5)(E)-7-(二乙基氨基)-3-(3-丁酮-1-烯)-2H-苯并吡喃-2-酮与3-羟基-4-甲氧基苯甲醛反应制得目标化合物。
所述化合物的制备方法,步骤(1)具体是指:将4-(二乙氨基)-2-羟基苯甲醛加入到盛有溶剂的反应器中,搅拌,再滴加入丙二酸二乙酯和哌啶,滴加完毕后,回流反应,反应完成后,减压蒸馏,析出固体,过滤,真空干燥,得7-(二乙氨基)-2-氧代-2H-苯并吡喃-3-羧酸乙酯;
步骤(2)具体是指:将7-(二乙氨基)-2-氧代-2H-苯并吡喃-3-羧酸乙酯加入盛有有机溶剂的反应器中,控温100~110℃并搅拌;10-24小时后停止反应,将反应液倒入提前准备好的冰水中淬灭,用氢氧化钠水溶液调pH 4.0-6.0,析出固体,过滤,真空干燥,得7-(二乙氨基)-2-氧代-2H-苯并吡喃;
步骤(3)具体是指:于有机溶剂中加入三氯氧磷,反应温度20-50℃,氮气保护下反应30-90分钟后,将溶于有机溶剂的7-(二乙氨基)-2-氧代-2H-苯并吡喃缓慢滴加入反应瓶,60-90℃加热反应,该温度下搅拌反应2~8小时;将反应液倒入提前准备好的冰水中淬灭,析出固体,过滤,真空干燥,得7-(二乙氨基)-2-氧代-2H-苯并吡喃-3-甲醛;
步骤(4)具体是指:用有机溶剂溶解7-(二乙氨基)-2-氧代-2H-苯并吡喃-3-甲醛,随后加入乙酰三苯基溴化膦,60-70℃回流搅拌,反应结束后,减压蒸馏除去有机溶剂,加入适量丙三醇,过滤,真空干燥,得(E)-7-(二乙基氨基)-3-(3-丁酮-1-烯)-2H-苯并吡喃-2-酮;
步骤(5)具体是指:用有机溶剂溶解(E)-7-(二乙基氨基)-3-(3-丁酮-1-烯)-2H-苯并吡喃-2-酮,随后加入催化剂和3-羟基-4-甲氧基苯甲醛,回流搅拌,反应结束后,减压蒸馏除去有机溶剂,分离出化合物,即得7-(二乙胺基)-3-((1E,4E)-5-(3-羟基-4-甲氧基苯基)-3-氧代-1,4-戊二烯)-2H-苯并吡喃-2-酮。
作为优选方案,步骤(1)中,所述的溶剂选用甲醇、乙醇、丙醇、正丁醇中的一种或几种。更优选为乙醇。
步骤(2)中,所述有机溶剂为冰醋酸和盐酸的混合物,更为优选的冰醋酸和盐酸两者体积比为1:1。
步骤(3)中,所述有机溶剂为N,N-二甲基甲酰胺。
步骤(4)中,所述有机溶剂为四氢呋喃。
步骤(5)中,所述有机溶剂为甲苯,正丁醇,乙腈中的一种或几种,更优选为正丁醇。所述催化剂优选为哌啶、冰醋酸或一种或两种混合物;更优选为哌啶和冰醋酸的混合物。
本发明的进一步目的在于提供一种药物组合物,其中含有治疗有效量的所述的化合物,或其药学上可接受的盐、酯及可药用的载体、佐剂或媒剂。
本发明的再一目的是提供所述的化合物在制备预防或治疗与肿瘤有关疾病的药物中的应用。以及所述的化合物作为与肿瘤有关的荧光诊断剂的应用。
有益效果:本发明设计、合成了化合物,该化合物具有红色发射波长和较长的斯托克斯位移、良好的生理pH稳定性和抗血清中蛋白的干扰能力、细胞膜通透性和细胞内线粒体聚集作用及在体成像。药理实验证明,该化合物具有抑制TrxR活性的作用。诱导肿瘤细胞内活性氧水平升高,激活caspase凋亡通路诱导肿瘤细胞凋亡,并具有良好的体内抗肿瘤活性等。
附图说明
图1是对本发明化合物对TrxR的酶活性抑制作用和蛋白表达水平的筛选的实验结果;A:以姜黄素为参照,KY-6对HCT116细胞中TrxR的抑制作用;B:不同浓度KY-6对HCT116细胞内TrxR蛋白水平的抑制作用。
图2是对本发明化合物光学性能的评价结果;A:KY-6的光谱学性质;B:KY-6的荧光性能在pH5.0-9.0的稳定性;C:KY-6的荧光强度不受不同分析物的干扰;D:KY-6的荧光强度不受5%的血清的PBS溶液干扰;
图3是对本发明化合物细胞内荧光成像实验结果;
图4是对本发明化合物亚细胞器定位作用考察实验结果。A:KY-6与商用线粒体探针的细胞共定位成像;B:KY-6与商用溶酶体探针的细胞共定位成像;
图5是对本发明化合物对肿瘤细胞内ROS水平影响的评价实验结果。A:DCFH-DA探针考察KY-6对肿瘤细胞内活性氧的影响;B:乙酰半胱氨酸对KY-6细胞毒活性的影响;
图6是对本发明化合物体内抗肿瘤评价;A:KY-6抑制肿瘤的生长;B:KY-6抑制肿瘤体积增大;C:KY-6对小鼠体重的影响;
图7是对本发明化合物对瘤内细胞增殖活性的考察;
图8是对本发明化合物对瘤内荧光成像的考察。
具体实施方式
为了进一步阐明本发明,下面给出一系列实施例,这些实施例完全是例证性的,它们仅用来对本发明具体描述,不应当理解为对本发明的限制。
化合物KY-6的合成路线为:
实施例1
7-(二乙氨基)-2-氧代-2H-苯并吡喃-3-羧酸乙酯:
将4-(二乙氨基)-2-羟基苯甲醛(4.0g)加入到盛有乙醇的反应器中,搅拌,再滴加入丙二酸二乙酯(9.47mL)和哌啶(1mL),滴加完毕后,回流反应,薄层跟踪检测反应,反应完成后,减压蒸馏,析出固体,过滤,真空干燥,得7-(二乙氨基)-2-氧代-2H-苯并吡喃-3-羧酸乙酯。(5.2g,收率86.8%)。该化合物无需进一步纯化,直接用于下一步反应。实验数据如下:1H NMR(600MHz,DMSO)δ8.54(s,1H),7.62(d,J=9.0Hz,1H),6.76(d,J=9.0Hz,1H),6.53(s,1H),4.22(q,J=7.1Hz,2H),3.47(q,J=6.9Hz,4H),1.28(t,J=7.1Hz,3H),1.12(dd,J=12.5,5.6Hz,6H).
实施例2
7-(二乙氨基)-2-氧代-2H-苯并吡喃:
将7-(二乙氨基)-2-氧代-2H-苯并吡喃-3-羧酸乙酯加入盛20mL冰醋酸和20mL盐酸的反应器中,控温100~110℃并搅拌;18小时后停止反应,将反应液倒入提前准备好的冰水中淬灭,用氢氧化钠水溶液调pH 5.0,析出固体,过滤,真空干燥,得7-(二乙氨基)-2-氧代-2H-苯并吡喃(2.8g,收率93.2%)。直接用于下一步反应无需纯化。实验数据如下:1HNMR(500MHz,CDCl3)δ7.52(d,J=9.3Hz,1H),7.23(d,J=8.8Hz,1H),6.60–6.53(m,1H),6.49(d,J=1.8Hz,1H),6.02(d,J=9.3Hz,1H),3.40(q,J=7.1Hz,4H),1.20(t,J=7.1Hz,6H).
实施例3
制备7-(二乙氨基)-2-氧代-2H-苯并吡喃-3-甲醛
于无水的N,N-二甲基甲酰胺中加入三氯氧磷(5.36mL),反应温度20-50℃,氮气保护下反应45分钟后,将溶于N,N-二甲基甲酰胺的7-(二乙氨基)-2-氧代-2H-苯并吡喃(2.5g)缓慢滴加入反应瓶,60℃加热回反应,该温度下搅拌反应2~3小时;将反应液倒入提前准备好的冰水中淬灭,析出固体,过滤,真空干燥,得7-(二乙氨基)-2-氧代-2H-苯并吡喃-3-甲醛(2.1g,收率74.4%)。实验数据如下:1H NMR(500MHz,CDCl3)δ7.52(d,J=9.3Hz,1H),7.23(d,J=8.8Hz,1H),6.60–6.53(m,1H),6.49(d,J=1.8Hz,1H),6.02(d,J=9.3Hz,1H),3.40(q,J=7.1Hz,4H),1.20(t,J=7.1Hz,6H).
实施例4
(E)-7-(二乙基氨基)-3-(3-丁酮-1-烯)-2H-苯并吡喃-2-酮
用四氢呋喃溶解7-(二乙氨基)-2-氧代-2H-苯并吡喃-3-甲醛(1.0g),随后加入乙酰三苯基溴化膦(1.37),60-70℃回流搅拌,薄层跟踪检测反应;反应结束后,减压蒸馏除去有机溶剂,加入适量丙三醇,过滤,真空干燥,得(E)-7-(二乙基氨基)-3-(3-丁酮-1-烯)-2H-苯并吡喃-2-酮。(1.0g,收率85.9%)。实验数据如下:1H NMR(500MHz,CDCl3)δ7.76(s,1H),7.71(d,J=16.0Hz,1H),7.31(d,J=8.7Hz,1H),7.13(d,J=16.0Hz,1H),6.62(dd,J=8.7,2.1Hz,1H),6.50(d,J=2.1Hz,1H),3.44(q,J=7.0Hz,4H),2.35(s,3H),1.23(t,J=7.0Hz,6H).
实施例5
7-(二乙胺基)-3-((1E,4E)-5-(3-羟基-4-甲氧基苯基)-3-氧代-1,4-戊二烯)-2H-苯并吡喃-2-酮
用正丁醇溶解(E)-7-(二乙基氨基)-3-(3-丁酮-1-烯)-2H-苯并吡喃-2-酮,随后加入催化剂(哌啶和冰醋酸)和3-羟基-4-甲氧基苯甲醛,120℃回流搅拌,薄层跟踪检测反应;反应结束后,减压蒸馏除去有机溶剂,液相色谱分离出化合物,即得7-(二乙胺基)-3-((1E,4E)-5-(3-羟基-4-甲氧基苯基)-3-氧代-1,4-戊二烯)-2H-苯并吡喃-2-酮。收率38%,red solid;m.p.120-121℃;IR(KBr)v3458.9,1709.6,1580.2,1512.5,1415.6,1354.8,1260.5,1192.3,1104.9,988.9,870.0,799.2,771.1,725.2,466.2cm-1;1H NMR(500MHz,CDCl3)δ7.79(d,J=7.7Hz,1H),7.67(dd,J=15.7,6.1Hz,2H),7.58(t,J=11.8Hz,1H),7.34(d,J=8.9Hz,1H),7.22(d,J=1.8Hz,1H),7.13(dd,J=8.3,1.8Hz,1H),6.92(d,J=15.9Hz,1H),6.87(d,J=8.3Hz,1H),6.68(d,J=8.7Hz,1H),6.56(s,1H),5.65(s,1H),3.94(s,3H),3.45(q,J=7.1Hz,5H),1.24(t,J=7.1Hz,6H).13C NMR(151MHz,CDCl3)δ189.56(s),160.16(s),156.47(s),148.75(s),145.99(s),145.44(s),143.08(s),137.97(s),130.11(s),128.74(s),126.49(s),125.19(s),122.43(s),115.25(s),113.97–113.49(m),110.72(s),110.60(s),56.17(s),45.48(s),12.56(s).MS(ESI)m/z420.2[M+H]+;HRMS(ESI)m/z 420.1807[M+H]+(calcd for 420.1805C25H26NO5).
实施例6下面是本发明的化合物KY-6部分荧光成像实验和药理试验及结果:
1、荧光性能考察
1.1光学性能评价:选取含有0.1%DMSO的PBS溶液作为光学检测体系,5μM的化合物为检测所以浓度,在荧光分光光度计上进行激发波长和发射波长测定。如图2所示,化合物的荧光激发波长优选480nm,发射波长为650nm。
1.2pH稳定性评价:选取含有0.1%DMSO的PBS溶液作为光学检测体系,5μM的化合物为检测所以浓度,选取激发波长优选480nm,发射波长为650nm,测定化合物在pH5-9的酸碱缓冲溶液的稳定性。如图2所示,发现荧光信号几乎没有改变。测定化合物在5%的FBS的缓冲液中荧光信号也无明显的改变。化合物表现出良好的生理条件下的荧光信号稳定性。
1.3细胞成像试验:给予肿瘤细胞0-10μM的KY-6,用高内涵荧光呈现系统采集细胞内荧光信号。如图3所示,在给药60min后,细胞内荧光信号强度随着KY-6浓度的升高逐渐增强,呈现出良好的浓度响应性。
1.4亚细胞器定位试验:给予肿瘤细胞5μM的KY-6孵育,再给予商业化线粒体和溶酶体荧光探针孵育30min,用高内涵荧光呈现系统采集细胞内荧光信号。如图4所示,KY-6发出的红色荧光信号主要聚集在细胞的线粒体部位,说明化合物有一定的线粒体靶向作用。
2、抗肿瘤活性评价
2.1化合物TrxR抑制活性评价试验:HCT116细胞接种于6孔板中每孔30万。用不同浓度的KY-6处理细胞24小时,胰蛋白酶消化后收获细胞,用1×RIPA裂解缓冲液(50mM TrI-HCl,pH 7.4,150mM氯化钠,0.25%脱氧胆酸,1%NP40,1mM EDTA和蛋白酶抑制剂)处理细胞,提取总蛋白。用BCA蛋白测定试剂盒定量测定。如图1所示,测得化合物KY-6抑制TrxR的半数抑制浓度为1.22μM。
2.2蛋白印记试验:给予不同浓度的KY-6孵育HCT116细胞培养24h,胰蛋白酶消化后收获细胞,用1×RIPA裂解缓冲液(50mM Tr-HCl,pH 7.4,150mM氯化钠,0.25%脱氧胆酸,1%NP40,1mm EDTA和蛋白酶抑制剂)提取细胞。蛋白质。用十二烷基硫酸钠(10%)聚丙烯酰胺凝胶电泳(SDS-PAGE)分离,分离到总细胞裂解物(30至60μg/泳道)中的蛋白质,湿转移到NC膜。特异性的TrxR,cleaved-PARP,cleaved-Caspase3,cleaved-Caspase9,Bcl-2,Bax和GAPDH。结合CyoDoc XRS+系统检测结合免疫复合物。化合物KY-6浓度依赖性的抑制TrxR水平,诱导cleaved-PARP,cleaved-Caspase3,cleaved-Caspase9蛋白表达升高。并有效促进凋亡蛋白Bax升高,下调抗凋亡蛋白Bcl-2的表达水平。
2.3活性氧试验:HCT116细胞以1.5×104每孔的密度铺在96孔板或3×105每孔的密度铺在6孔板中。用不同浓度的KY-6处理细胞24h,将商业化DCFH-DA探针溶解于无血清培养基中,稀释至10μM的终浓度,用含有探针的无血清培养基代替生长培养基。在37℃培养30分钟后,用无血清培养基洗涤两次,用胰蛋白酶消化,再悬浮于预热的PBS缓冲液中。然后用流式细胞仪或高内涵对样品进行分析。如图5所示,化合物KY-6可以诱导肿瘤细胞内升高,这一现象可以被预孵的NAC抑制。
2.4体内药效评价和荧光成像试验:裸鼠皮下注射16-18g的人乳腺肿瘤HCT116(体积为0.2ml含有3×106个细胞)进入小鼠右辅助区皮下组织。瘤细胞接种三天后,将小鼠随机分为三组,每组六只。给予荷瘤小鼠腹腔注射30mg/kg化合物KY-6,每天只注射一次。当小鼠的肿瘤负荷达到约80立方毫米时开始治疗。每周测量3次直径,记录肿瘤生长情况,用长×宽的平方的1/2公式计算,记录体重。根据体重下降、肿瘤生长抑制(用卡尺测定)并用公式计算:肿瘤抑制率(%)=(空白组肿瘤体积-给药组肿瘤)/空白组肿瘤体积。在第二十二天,处死小鼠,肿瘤分离,称重,并保存在-80℃,以备以后使用。30毫克/公斤的KY-6给药组显著降低了小鼠肿瘤的体积(图6)。重要的是,KY-6处理的小鼠的肿瘤重量比对照组显著降低了60.8%,体重没有显著变化。免疫组化染色分析对照组和KY-6给药组小鼠肿瘤组织中Ki67的表达,KY-6抑制肿瘤细胞增殖(图7)。接着,将探针应用于HCT116荷瘤小鼠的肿瘤区域,然后用小动物体内成像系统进行荧光成像。如图8所示,在荷瘤裸鼠皮下注射KY-6(50μM)4h后,肿瘤区的红荧光反应增强。
以上所述仅是本发明的优选实施方式,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润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (10)
3.根据权利要求2所述化合物的制备方法,其特征在于,包括以下步骤:
步骤(1)4-(二乙氨基)-2-羟基苯甲醛和丙二酸二乙酯反应制得7-(二乙氨基)-2-氧代-2H-苯并吡喃-3-羧酸乙酯;
步骤(2)7-(二乙氨基)-2-氧代-2H-苯并吡喃-3-羧酸乙酯经酸化、脱羧得到7-(二乙氨基)-2-氧代-2H-苯并吡喃;
步骤(3)7-(二乙氨基)-2-氧代-2H-苯并吡喃经甲酰基化得到7-(二乙氨基)-2-氧代-2H-苯并吡喃-3-甲醛;
步骤(4)7-(二乙氨基)-2-氧代-2H-苯并吡喃-3-甲醛反应后得到(E)-7-(二乙基氨基)-3-(3-丁酮-1-烯)-2H-苯并吡喃-2-酮;
步骤(5)(E)-7-(二乙基氨基)-3-(3-丁酮-1-烯)-2H-苯并吡喃-2-酮与3-羟基-4-甲氧基苯甲醛反应制得目标化合物。
4.根据权利要求3所述化合物的制备方法,其特征在于,步骤(1)具体是指:将4-(二乙氨基)-2-羟基苯甲醛加入到盛有溶剂的反应器中,搅拌,再滴加入丙二酸二乙酯和哌啶,滴加完毕后,回流反应,反应完成后,减压蒸馏,析出固体,过滤,真空干燥,得7-(二乙氨基)-2-氧代-2H-苯并吡喃-3-羧酸乙酯;和/或,
步骤(2)具体是指:将7-(二乙氨基)-2-氧代-2H-苯并吡喃-3-羧酸乙酯加入盛有有机溶剂的反应器中,控温100~110℃并搅拌;10-24小时后停止反应,将反应液倒入提前准备好的冰水中淬灭,用氢氧化钠水溶液调pH 4.0-6.0,析出固体,过滤,真空干燥,得7-(二乙氨基)-2-氧代-2H-苯并吡喃;和/或,
步骤(3)具体是指:于有机溶剂中加入三氯氧磷,反应温度20-50℃,氮气保护下反应30-90分钟后,将溶于有机溶剂的7-(二乙氨基)-2-氧代-2H-苯并吡喃缓慢滴加入反应瓶,60-90℃加热反应,该温度下搅拌反应2~8小时;将反应液倒入提前准备好的冰水中淬灭,析出固体,过滤,真空干燥,得7-(二乙氨基)-2-氧代-2H-苯并吡喃-3-甲醛;和/或,
步骤(4)具体是指:用有机溶剂溶解7-(二乙氨基)-2-氧代-2H-苯并吡喃-3-甲醛,随后加入乙酰三苯基溴化膦,60-70℃回流搅拌,反应结束后,减压蒸馏除去有机溶剂,加入适量丙三醇,过滤,真空干燥,得(E)-7-(二乙基氨基)-3-(3-丁酮-1-烯)-2H-苯并吡喃-2-酮;和/或,
步骤(5)具体是指:用有机溶剂溶解(E)-7-(二乙基氨基)-3-(3-丁酮-1-烯)-2H-苯并吡喃-2-酮,随后加入催化剂和3-羟基-4-甲氧基苯甲醛,回流搅拌,反应结束后,减压蒸馏除去有机溶剂,分离出化合物,即得7-(二乙胺基)-3-((1E,4E)-5-(3-羟基-4-甲氧基苯基)-3-氧代-1,4-戊二烯)-2H-苯并吡喃-2-酮。
5.根据权利要求4所述化合物的制备方法,其特征在于:步骤(1)中,所述的溶剂选用甲醇、乙醇、丙醇、正丁醇中的一种或几种;和/或,步骤(2)中,所述有机溶剂为冰醋酸和盐酸的混合物,冰醋酸和盐酸两者体积比为1:1。
6.根据权利要求4所述化合物的制备方法,其特征在于,步骤(3)中,所述有机溶剂为N,N-二甲基甲酰胺;和/或,步骤(4)中,所述有机溶剂为四氢呋喃。
7.根据权利要求4所述化合物的制备方法,其特征在于:步骤(5)中,所述有机溶剂为甲苯、正丁醇、乙腈中的一种或几种。
8.根据权利要求4所述化合物的制备方法,其特征在于:步骤(5)中,所述催化剂为哌啶、冰醋酸中的一种或两种混合物。
9.一种药物组合物,其中含有治疗有效量的权利要求1所述的化合物,或其药学上可接受的盐及可药用的载体、佐剂或媒剂。
10.权利要求1所述的化合物在制备预防或治疗与肿瘤有关疾病的药物中的应用。
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