CN115368349A - 一种新型n-取代靛红衍生物及其制备以及其在制备抗肿瘤药物中的应用 - Google Patents
一种新型n-取代靛红衍生物及其制备以及其在制备抗肿瘤药物中的应用 Download PDFInfo
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- CN115368349A CN115368349A CN202110533123.1A CN202110533123A CN115368349A CN 115368349 A CN115368349 A CN 115368349A CN 202110533123 A CN202110533123 A CN 202110533123A CN 115368349 A CN115368349 A CN 115368349A
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Abstract
本发明提供一种新型N‑取代靛红衍生物及其制备以及其在制备抗肿瘤药物中的应用。N‑取代靛红衍生物,其结构式如式I所示。N‑取代的靛玉红衍生物,其结构式如式II所示:所合成的新型N‑2,1‑苯并异噁唑靛红和新型N‑2,1‑苯并异噁唑靛玉红化合物具有肿瘤细胞抑制活性,进一步拓宽了治疗肿瘤候选药物的种类。
Description
技术领域
本发明涉及药物合成领域,尤其涉及一种新型N-取代靛红衍生物及其制备以及其在制备抗肿瘤药物中的应用。
背景技术
肿瘤是世界范围内死亡率极高的疾病,恶性肿瘤(癌症)已成为严重威胁世界各国人民身心健康的重大疾病之一,且发病例数逐年增加。目前,癌症的临床治疗方法有手术治疗、放射治疗、免疫治疗、化疗、癌症疫苗接种、光动力治疗等,而每种方法都有各自的优缺点。而当前治疗的难题还是围绕在愈后肿瘤复发、转移或药物缺乏选择性、副作用大等。化疗药物作为治疗方法中的一种,近些年来发展迅速,有许多的新药陆续进入临床,它不仅可以单独使用,还是其他疗法必不可少的辅助治疗手段[3]。近年来,越来越多药物化学家开始选择以特定药效团分子为基本骨架,通过各类衍生合成方法来改善原有药物分子的局限性和毒副作用,在保留原有药效特征的基础上,设计合成出新的具有潜在抗癌活性的化合物。
靛红是现代药物化学中一个具有广泛生物活性和化学修饰可能性的特殊支架,多年来被广泛用于化工和医药等领域[刘丰喜.多取代靛红衍生物的合成与抗肿瘤活性研究[D].天津科技大学,2014;闫玮.靛红衍生物的合成研究及抑菌活性研究[D].西北大学,2009]。据报道,靛红及其衍生物具有广泛的生物学活性,包括抗肿瘤[Ding Z,Zhou M,ZengC.Recent advances in isatin hybrids as potential anticancer agents[J].Archivder Pharmazie,2020,353(3)],抗菌[Ayman E F,Hozzein W N,Wadaan M,etal.Microwave Synthesis,Characterization,and Antimicrobial Activity of SomeNovel Isatin Derivatives[J].Journal of Chemistry,2015,2015:1-8],抗疟疾[Chinnasamy,Rajaram,Prakash,et al.Synthesis,characterization and in vitroantimicrobial activity of some novel5-substituted Schiff and Mannich base ofisatin derivatives[J].Journal of Saudi Chemical Society,2013.],抗结核[Raj R,Gut J,Rosenthal P J,et al.1H-1,2,3-Triazole-tethered isatin-7-chloroquinolineand 3-hydroxy-indole-7-chloroquinoline conjugates:Synthesis and antimalarialevaluation[J].Bioorganic&Medicinal Chemistry Letters,2014,24(3):756-759]和抗病毒[Pandeya S N,Sriram D,Nath,et al.Synthesis,antibacterial,antifungal andanti-HIV activities of norfloxacin Mannich bases[J].European Journal ofMedicinal Chemistry,2000]等。靛红作为一类重要的氮杂环药效团,其被广泛应用于抗肿瘤药物研究领域。靛红不仅是我国I类抗癌新药靛玉红(Indirubin)的化学前体,还是许多临床抗癌药物的基本母核。例如Semaxanib、Sunitinib、Nintedanib和Hesperadin都含有靛红的片段,这表明靛红是开发新型抗癌药物的有效基团。
双吲哚生物碱靛玉红及其类似物(统称靛玉红)是靛红的化学二聚体,被发现的早期周期蛋白依赖性激酶(CDK)抑制剂之一。靛玉红是传统中药方剂当归龙荟丸的有效成分,临床用于治疗慢性粒细胞白血病[Ying-Sing Li a,Qi-Zheng Yao b,Zhao-Hui Wang b,etal.Vibrational spectroscopic studies of N1-ethyl-5′-bromo-7-azaindirubin-3′-oxime and N1-ethyl-indirubin-3′-monooxime[J].Journal of Molecular Structure,2015,1087:51-59]。但靛玉红的水溶性差,口服生物利用度低,且具有胃肠道副作用,影响了其治疗效果[Xi K W,Yeo W K,Bing Z,et al.Synthesis and evaluation offunctionalized isoindigos as antiproliferative agents[J].Bioorganic&MedicinalChemistry,2009,17(21):7562-7571]。因此对靛玉红原有结构进行衍生修饰,提高其生物利用度及抗癌活性成为越来越多研究者的关注点。
因此,我们以靛红母核为基础对其进行结构修饰改造,研究开发具有潜在抗癌活性的先导化合物,对现有药物药效的改进提升及抗癌新药的创制具有重要意义。
N-取代靛红是靛红衍生物中活性较好的一类化合物,它不仅保留了靛红母核的基本活性,而且降低了靛红母核对碱基的不稳定性,大大增加了反应底物范围和生物活性的拓展可能[Shmidt,María Sol,Reverdito,Ana María,Kremenchuzky L,et al.Simple andEfficient Microwave Assisted N-Alkylation of Isatin[J].Molecules,2008,13(4):831-840]。目前文献中报道得N-取代靛红衍生物的合成主要是以碱催化和过渡金属催化的两种方法来实现的。早在1966年,Autrey等[Autrey R L,Tahk F C.The synthesis andstereochemistry of some isatylideneacetic acid derivatives[J].Tetrahedron,1967,23(2):901-917]利用金属氢化物NaH和溴苄1-2合成出1-苄基靛红1-3(图1)。
Radul等[Radul O M,Zhungietu G I,Rekhter M A,et al.Simple method forthe preparation of 1-substituted isatins[J].Chemistry of HeterocyclicCompounds,1983,19(3):286-288]开发出一种合成N-烷基和N-酰基化靛红的方法(图2)。此方法以二甲基甲酰胺(DMF)为溶剂,以碳酸钾为碱,使靛红与烷基溴、碘化物和酰氯在室温下进行N-烷基化,与烷基氯在70-80℃高温下进行N-烷基化。
Devarajan等[Devarajan N,Sures P.Framework-Copper-Catalyzed C-N Cross-Coupling of Arylboronic Acids with Imidazole:Convenient and Ligand-FreeSynthesis of N-Arylimidazoles[J].ChemCatChem,2016,8:1-9]使用对苯二甲酸铜金属有机骨架(Cu(tpa)-MOF)作为非均相催化剂,利用不饱和配位的Cu可催化得到N-芳基靛红(图3)。
Majumder等[Babu,Madhu,Gupta,et al.Air-stable palladium(0)phosphinesulfide catalysts for Ullmann-type C-N and C-O coupling reactions[J].Journalof Organometallic Chemistry,2015,781:23-34]以碘苯或溴苯1-7为原料与靛红反应,通过钯催化的Ullmann型交叉偶联反应,实现了N-芳基靛红的合成(图4)。
尽管现有制备N-取代靛红的方法已经取得了一定进展,但是,这些经典方法大多涉及繁琐的多步骤过程,通常使N-烷基靛红的总收率较低。它们通常存在以下缺点:1)靛红核的基础不稳定;2)使用金属氢化物危险试剂;3)使用质子与高水溶性和高沸点有机溶剂;4)使用致癌溶剂;5)由于酮羰基的存在而产生的副反应;6)过渡金属和配体的高成本和毒性,以及最终产品中的微量金属污染,都需要耗费大量的时间和财力去处理。
发明内容
本发明的目的之一是提供一种新型的N-取代靛红衍生物及其制备方法,本发明的制备新型N-取代靛红衍生物的方法条件温和、工艺简单、成本低、环境友好,克服现有N-取代靛红制备技术中因过渡金属、质子性溶剂、金属氢化物等危险试剂的使用而产生的问题及困难。
本发明所提供的N-取代靛红衍生物,其结构式如式I所示:
式I中,R1代表C1-C4直链或支链烷基,具体可为甲基或乙基;R2代表H、卤素、C1-C4烷氧基、酯基、硝基中的任意一种,具体可为H、甲氧基、F、-CO2Me、Br、-NO2;R3代表H、卤素、C1-C4直链或直链烷基、C1-C4烷氧基中的任意一种,具体可为H、甲基、甲氧基、F、Br或I;X代表氧原子、羰基、含氧杂环(具体可为)中的任意一种。
具体地,式I所示N-取代靛红衍生物为下述化合物中的任意一种:
上述式I所示N-取代靛红衍生物通过包括如下步骤的方法制备得到:以式III所示化合物和式IV所示化合物为原料,在化学计量的路易斯碱的作用下,在溶剂中,惰性气体保护下,反应,即得,
式III中,R1代表C1-C4直链或直链烷基,具体可为甲基或乙基;R2代表H、卤素、C1-C4烷氧基、酯基、硝基中的任意一种,具体可为H、甲氧基、F、-CO2Me、Br、-NO2;
式IV中,R3代表H、卤素、C1-C4直链或直链烷基、C1-C4烷氧基中的任意一种,具体可为H、甲基、甲氧基、F、Br或I;X代表氧原子、羰基、含氧杂环中的任意一种;
所述路易斯碱可选自碳酸钠、碳酸铯、叔丁醇钾、磷酸钾、乙酸钾、三乙胺、TMEDA、DIPEA和DMAP中的任意一种或几种的混合物,具体可为DMAP;
所述溶剂可选自二氯甲烷、三氯甲烷、四氯化碳、四氢呋喃、乙腈、1,4-二氧六环、乙酸乙酯、DCE、TBME和DMSO中的任意一种或几种的混合物,具体可为三氯甲烷;
式III所示化合物与式IV所示化合物的摩尔比可为1:1.2~1.5,路易斯碱的加入量可为式III所示化合物的2倍当量;
所述反应在室温下进行,所述反应的时间可为12-24小时;
所述反应完成还包括对粗产物进行硅胶色谱纯化得到式I所示目标化合物的操作。
本发明的另一目的是针对现有技术和方法的不足,以式I所示新型N-取代靛红为前体合成新型N-取代的靛玉红衍生物,并提供其在抗肿瘤方面的应用。
本发明所述提供的新型N-取代的靛玉红衍生物,其结构式如式II所示:
式II中,R1代表C1-C4直链或支链烷基,具体可为甲基;R2代表H、卤素、C1-C4烷氧基、酯基、硝基中的任意一种,具体可为H、甲氧基、F;R3代表H、卤素、C1-C4直链或直链烷基、C1-C4烷氧基中的任意一种,具体可为H、甲基或F。
具体地,式II所示N-取代的靛玉红衍生物为下述化合物中的任意一种:
上述式II所示N-取代的靛玉红衍生物通过包括如下步骤的方法制备得到:
式I’中,R1代表C1-C4直链或支链烷基,具体可为甲基;R2代表H、卤素、C1-C4烷氧基、酯基、硝基中的任意一种,具体可为H、甲氧基、F;R3代表H、卤素、C1-C4直链或直链烷基、C1-C4烷氧基中的任意一种,具体可为H、甲基或F;
在惰性气氛下,Na2CO3存在下,使得式I’所示化合物与式V所示3-乙酸吲哚酯反应,得到式II所示N-取代的靛玉红衍生物;
上述方法中,所述惰性气氛具体可为氩气气氛;
所述反应在溶剂中进行,所述溶剂具体可为甲醇;
式I’所示化合物与碳酸钠、式V所示3-乙酸吲哚酯的摩尔比可依次为1:2.5:1;
所述反应的温度可为室温,所述反应的时间可为1-24h,具体地,先在室温下搅拌反应1h,再静置24h。
反应结束后,将反应体系过滤,收集固体产物,再水和甲醇洗,干燥,得到式II所示N-取代的靛玉红衍生物,
具体可为:反应结束后,通过布氏漏斗过滤,残渣用甲醇和冷水洗涤,直到滤液反应中性。然后在干燥器中氢氧化钾上干燥,得到的紫红色固体极为产物。
式I所示N-取代靛红衍生物和式II所示N-取代的靛玉红衍生物在制备抗肿瘤药物中的应用也属于本发明的保护范围。
所述应用中,所述肿瘤为癌,所述癌具体可为卵巢癌、白血病。
本发明还提供一种治疗卵巢癌的药物,所述药物含有式I所示N-取代靛红衍生物或式II所示N-取代的靛玉红衍生物。
本发明还提供一种治疗白血病的药物,所述药物含有式I所示N-取代靛红衍生物或式II所示N-取代的靛玉红衍生物。
本发明涉及所述化合物对人卵巢癌细胞SKOV3和人白血病细胞K562的抑制活性。
肿瘤细胞抑制率=[1-(实验孔-空白孔)/(对照孔-空白孔)]*100%。
术语解释:
“烷基”是包括具有特定数目碳原子的支链和直链饱和烃基。“卤素”指氟、氯、溴和碘原子。
英文缩写:DMAP指4-二甲氨基吡啶,TMEDA指N,N,N',N'-四甲基乙二胺,DIPEA指N,N-二异丙基乙胺;DCE指1,2-二氯乙烷,TBME指叔丁基甲基醚,DMSO指二甲亚砜。
与现有技术相比具有的有益效果:
(1)本发明提供了一种条件温和、工艺简单、成本低、环境友好的制备新型N-2,1-苯并异噁唑靛红衍生物的方法;
(2)该方法在化学计量的路易斯碱的作用下进行,方便,廉价,易于处理,避免了过渡金属及昂贵配体的使用;反应条件温和,常温下即可高效反应;无危险致癌试剂的使用,且具有良好的底物适用性;
(3)本发明还提供了在抗肿瘤药物合成制备上的应用,所合成的新型N-2,1-苯并异噁唑靛红和新型N-2,1-苯并异噁唑靛玉红化合物具有肿瘤细胞抑制活性,进一步拓宽了治疗肿瘤候选药物的种类。
附图说明
图1为现有技术中Autrey等利用金属氢化物NaH和溴苄1-2合成出1-苄基靛红1-3的反应方程式。
图2为现有技术中Radul等开发出的N-烷基和N-酰基化靛红的反应方程式。
图3为现有技术中Devarajan等使用对苯二甲酸铜金属有机骨架(Cu(tpa)-MOF)作为非均相催化剂,利用不饱和配位的Cu可催化得到N-芳基靛红的反应方程式。
图4为现有技术中Majumder等发现的N-芳基靛红的合成示意图。
具体实施方式
下述实施例中所使用的实验方法如无特殊说明,均为常规方法。
下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
本发明提供一种N-取代靛红衍生物,其结构式如式I所示:
式I中,R1代表C1-C4直链或支链烷基,具体可为甲基或乙基;R2代表H、卤素、C1-C4烷氧基、酯基、硝基中的任意一种,具体可为H、甲氧基、F、-CO2Me、Br、-NO2;R3代表H、卤素、C1-C4直链或直链烷基、C1-C4烷氧基中的任意一种,具体可为H、甲基、甲氧基、F、Br或I;X代表氧原子、羰基、含氧杂环中的任意一种。
上述式I所示N-取代靛红衍生物通过包括如下步骤的方法制备得到:以式III所示化合物和式IV所示化合物为原料,在化学计量的路易斯碱的作用下,在溶剂中,惰性保护下,反应,即得,
本发明还提供一种新型N-取代的靛玉红衍生物,其结构式如式II所示:
式II中,R1代表C1-C4直链或支链烷基,具体可为甲基;R2代表H、卤素、C1-C4烷氧基、酯基、硝基中的任意一种,具体可为H、甲氧基、F;R3代表H、卤素、C1-C4直链或直链烷基、C1-C4烷氧基中的任意一种,具体可为H、甲基或F。
上述式II所示N-取代的靛玉红衍生物通过包括如下步骤的方法制备得到:
在惰性气氛下,Na2CO3存在下,使得式I’所示化合物与式V所示3-乙酸吲哚酯反应,得到式II所示N-取代的靛玉红衍生物;
式I所示N-取代靛红衍生物和式II所示N-取代的靛玉红衍生物在制备抗肿瘤药物中的应用也属于本发明的保护范围。
所述应用中,所述肿瘤为癌,所述癌具体可为卵巢癌、白血病。
本发明还提供一种治疗卵巢癌的药物,所述药物含有式I所示N-取代靛红衍生物或式II所示N-取代的靛玉红衍生物。
本发明还提供一种治疗白血病的药物,所述药物含有式I所示N-取代靛红衍生物或式II所示N-取代的靛玉红衍生物。
本发明所合成的新型N-2,1-苯并异噁唑靛红和新型N-2,1-苯并异噁唑靛玉红化合物具有肿瘤细胞抑制活性,进一步拓宽了治疗肿瘤候选药物的种类。
化合物III的制备方法(以1-甲基-2,1-苯并异恶唑四氟硼酸盐为例)(参见:J.Org.Chem.1984,49,3367-3372,Synthesis,Stability,Structure,Reactivity,andChemistry of N-Alkylbenzoazetinones):
将Me3O+BF4 -(20mmol,1equiv.)的CH3NO2(8mL)缓慢加入到搅拌的冷却的2,1-苯并异噁唑(20mmol,1equiv.)的CH3NO2(2mL)溶液中,将混合物放在冰箱(4℃)中过夜。然后在干冰-丙酮(-78℃)中冷却,同时将产物III用EtOAc缓慢沉淀,再用CH2Cl2洗涤沉淀得到纯净的化合物III。
以1-烷基-2,1-苯并恶唑四氟硼酸盐(III)和靛红(IV)为反应原料,以DMAP为碱,以CHCl3为溶剂,在室温Ar保护下,获得了不同取代的N-2,1-苯并异噁唑靛红衍生物。下面选择了其中具有代表性的实施例1-11,对以靛红为原料对2,1-苯丙异恶唑盐进行功能化的合成策略进行说明。
实施例1
名称:1-(1-甲基-1,3-二氢苯并[c]异恶唑-3-基)二氢吲哚-2,3-二酮
向5mL干净的反应瓶中加入1-甲基-2,1-苯并异恶唑四氟硼酸盐(44.2mg,0.2mmo1)、靛红(44.1mg,0.3mmol)、DMAP(48.9mg,0.4mmol)和CHCl3(1mL),然后在氩气气氛下,将反应瓶置于室温条件下搅拌反应。反应体系持续12h后停止反应,减压蒸馏出去溶剂,将残余物经柱层析分离(石油醚/乙酸乙酯)得到目标产物1-(1-甲基-1,3-二氢苯并[c]异恶唑-3-基)二氢吲哚-2,3-二酮,黄色固体,产率为74%。
Melting Point:127–129℃.
1H NMR(600MHz,CDCl3):δ=7.78(s,1H),7.62(dd,J=7.4,0.8Hz,1H),7.43(t,J=7.6Hz,1H),7.38-7.35(m,1H),7.23(d,J=7.6Hz,1H),7.12–7.06(m,2H),6.92(d,J=8.0Hz,1H),6.69(d,J=8.1Hz,1H),3.26(s,3H)ppm.
13C NMR(151MHz,CDCl3):δ=183.02,158.53,151.63,148.44,138.72,130.96,125.53,124.44,124.22,123.55,123.24,118.23,113.34,110.89,83.75,45.41ppm.
HRMS(ESI):calcd for C16H12N2O3[M+K]+:319.3818,found 319.3034.
实施例2
名称:1-(5-甲氧基-1-甲基-1,3-二氢苯并[c]异恶唑-3-基)吲哚啉-2,3-二酮在实施例1中所用的1-甲基-2,1-苯并异恶唑四氟硼酸盐用等摩尔量的5-甲氧基-1-甲基-2,1-苯并异恶唑四氟硼酸盐代替,反应时间延长至13h,其余步骤与实施例1相同,得到结构如上的目标产物1-(5-甲氧基-1-甲基-1,3-二氢苯并[c]异恶唑-3-基)吲哚啉-2,3-二酮,橘黄色固体,产率为73%。
Melting Point:108–110℃.
1H NMR(400MHz,CDCl3):δ=7.72(s,1H),7.59(d,J=8.0Hz,1H),7.38(t,J=7.5Hz,1H),7.06(t,J=7.5Hz,1H),6.97(d,J=8.6Hz,1H),6.84(d,J=8.6Hz,1H),6.76(d,J=8.0Hz,1H),6.72(s,1H),3.72(s,3H),3.18(s,3H)ppm.
13C NMR(151MHz,CDCl3):δ=182.95,158.47,157.38,148.30,145.20,138.76,125.39,124.39,124.17,118.12,117.79,113.41,112.02,107.41,83.80,55.90,46.38ppm.
HRMS(ESI):calcd for C17H14N2O4[M+Na]+:333.0844,found 333.0842.
实施例3
名称:1-(5-溴-1-甲基-1,3-二氢苯并[c]异恶唑-3-基)吲哚啉-2,3-二酮
在实施例1中所用的1-甲基-2,1-苯并异恶唑四氟硼酸盐用等摩尔量的5-氟-1-甲基-2,1-苯并异恶唑四氟硼酸盐代替,反应时间延长至14h,其余步骤与实施例1相同,得到结构如上的目标产物1-(5-溴-1-甲基-1,3-二氢苯并[c]异恶唑-3-基)吲哚啉-2,3-二酮,黄色固体,产率为74%。
Melting Point:118–120℃.
1H NMR(400MHz,CDCl3):δ=7.72(s,1H),7.64(d,J=7.5Hz,1H),7.52(d,J=8.5Hz,1H),7.41(t,J=7.8Hz,1H),7.35(s,1H),7.11(t,J=7.5Hz,1H),6.81–6.76(m,2H),3.24(s,3H)ppm.
13C NMR(151MHz,CDCl3):δ=182.66,158.35,150.72,148.09,138.80,133.97,126.52,125.72,125.51,124.46,118.26,116.67,113.18,112.26,83.13,45.18ppm.
HRMS(ESI):calcd for C16H11BrN2O3[M+H]+:360.1870,found 360.3231.
实施例4
名称:3-(2,3-二氧吲哚-1-基)-1-甲基-1,3-二氢苯并[c]异恶唑-6-羧酸甲酯
在实施例1中所用的1-甲基-2,1-苯并异恶唑四氟硼酸盐用等摩尔量的6-(甲氧羰基)-1-甲基-2,1-苯并异恶唑四氟硼酸盐代替,反应时间延长至13h,其余步骤与实施例1相同,得到结构如上的目标产物3-(2,3-二氧吲哚-1-基)-1-甲基-1,3-二氢苯并[c]异恶唑-6-羧酸甲酯,黄色固体,产率为81%。
Melting Point:142–144℃.
1H NMR(400MHz,CDCl3):δ=7.79-7.77(m,2H),7.63(d,J=7.5Hz,1H),7.58(s,1H),7.37(t,J=7.4Hz,1H),7.29(d,J=8.0Hz,1H),7.09(t,J=7.4Hz,1H),6.71(d,J=8.0Hz,1H),3.95(s,3H),3.30(s,3H)ppm.
13C NMR(151MHz,CDCl3):δ=182.64,166.24,158.38,151.91,148.12,138.77,133.18,127.89,125.85,125.68,124.43,123.59,118.23,113.15,111.78,83.38,52.75,45.02ppm.
HRMS(ESI):calcd for C18H14N2O5[M+Na]+:361.0793,found 361.0790.
实施例5
名称:1-(6-氟-1-甲基-1,3-二氢苯并[c]异恶唑-3-基)吲哚啉-2,3-二酮
在实施例1中所用的1-甲基-2,1-苯并异恶唑四氟硼酸盐用等摩尔量的6-溴-1-甲基-2,1-苯并异恶唑四氟硼酸盐代替,反应时间缩短至11h,其余步骤与实施例1相同,得到结构如上的目标产物1-(6-氟-1-甲基-1,3-二氢苯并[c]异恶唑-3-基)吲哚啉-2,3-二酮,橘黄色固体,产率为77%。
Melting Point:108–110℃.
1H NMR(400MHz,CDCl3):δ=7.72(s,1H),7.63(d,J=8.0Hz,1H),7.41(t,J=7.5Hz,1H),7.19–7.15(m,1H),7.10(t,J=7.5Hz,1H),6.79(t,J=8.6Hz,1H),6.72(d,J=8.0Hz,1H),6.62(d,J=8.6Hz,1H),3.24(s,3H).ppm.
13C NMR(151MHz,CDCl3):δ=182.84,164.83(d,J=249.0Hz),158.47,153.32(d,J=11.1Hz),148.24,138.75,125.65,124.87(d,J=10.5Hz),124.38,118.24,113.20,112.41,111.58(d,J=23.8Hz),98.75(d,J=27.4Hz),83.43,44.89.
HRMS(ESI):calcd for C16H11FN2O3[M+Na]+:321.0644,found 321.0645.
实施例6
名称:1-(1-甲基-6-硝基-1,3-二氢苯并[c]异恶唑-3-基)吲哚啉-2,3-二酮
在实施例1中所用的1-甲基-2,1-苯并异恶唑四氟硼酸盐用等摩尔量的1-甲基-6-硝基-2,1-苯并异恶唑四氟硼酸盐代替,反应时间延长至16h,其余步骤与实施例1相同,得到结构如上的目标产物1-(1-甲基-6-硝基-1,3-二氢苯并[c]异恶唑-3-基)吲哚啉-2,3-二酮,黄色固体,产率为48%。
Melting Point:203–205℃.
1H NMR(400MHz,CDCl3):δ=7.97(d,J=8.1Hz,1H),7.77(s,1H),7.74(s,1H),7.66(d,J=7.5Hz,1H),7.45–7.38(m,2H),7.14(t,J=7.5Hz,1H),6.77(d,J=8.1Hz,1H),3.35(s,3H)ppm.
13C NMR(151MHz,CDCl3):δ=182.22,158.23,152.53,150.50,147.81,138.85,129.55,125.92,124.73,124.46,119.64,118.27,112.84,105.79,83.08,44.50ppm
HRMS(ESI):calcd for C16 H11 O5 N3[M+Na]+:348.0591,found 348.0589.
实施例7
名称:1-(1-乙基-1,3-二氢苯并[c]异恶唑-3-基)二氢吲哚-2,3-二酮
在实施例1中所用的1-甲基-2,1-苯并异恶唑四氟硼酸盐用等摩尔量的1-乙基-2,1-苯并异恶唑四氟硼酸盐代替,反应时间延长至13h,其余步骤与实施例1相同,得到结构如上的目标产物1-(1-乙基-1,3-二氢苯并[c]异恶唑-3-基)二氢吲哚-2,3-二酮,橘黄色固体,产率为72%。
Melting Point:120–122℃.
1H NMR(400MHz,CDCl3):δ=7.79(s,1H),7.61(d,J=7.5Hz,1H),7.43–7.34(m,2H),7.21(d,J=7.5Hz,1H),7.07(q,J=7.3Hz,2H),6.91(d,J=8.0Hz,1H),6.71(d,J=8.0Hz,1H),3.63–3.54(m,1H),3.49–3.40(m,1H),1.27(t,J=7.0Hz,3H)ppm.
13C NMR(151MHz,CDCl3):δ=183.12,158.56,150.21,148.41,138.73,130.86,125.45,124.38,124.18,123.63,123.49,118.20,113.50,111.25,84.05,53.26,11.56ppm.
HRMS(ESI):calcd for C17H14N2O3[M+H]+:295.1084,found 295.2035.
实施例8
名称:5-甲基-1-(1-甲基-1,3-二氢苯并[c]异恶唑-3-基)吲哚啉-2,3-二酮
在实施例1中所用的靛红用等摩尔量的5-甲基靛红代替,反应时间延长至16h,其余步骤与实施例1相同,得到结构如上的目标产物5-甲基-1-(1-甲基-1,3-二氢苯并[c]异恶唑-3-基)吲哚啉-2,3-二酮,橘黄色固体,产率为86%。
Melting Point:124–126℃.
1H NMR(400MHz,CDCl3):δ=7.71(s,1H),7.42–7.38(m,2H),7.20(d,J=8.0Hz,1H),7.14(d,J=8.2Hz,1H),7.07(t,J=7.4Hz,1H),6.91(d,J=8.0Hz,1H),6.52(d,J=8.2Hz,1H),3.23(s,3H),2.23(s,3H)ppm.
13C NMR(151MHz,CDCl3):δ=183.13,158.67,151.57,146.22,139.22,133.99,130.85,125.61,124.29,123.43,123.19,118.19,113.06,110.82,83.57,45.28,20.62ppm.
HRMS(ESI):calcd for C17H14N2O3[M+H]+:295.1084,found 295.2006.
实施例9
名称:6-甲氧基-1-(1-甲基-1,3-二氢苯并[c]异恶唑-3-基)二氢吲哚-2,3-二酮
在实施例1中所用的靛红用等摩尔量的6-甲氧基靛红代替,反应时间延长至16h,其余步骤与实施例1相同,得到结构如上的目标产物6-甲氧基-1-(1-甲基-1,3-二氢苯并[c]异恶唑-3-基)二氢吲哚-2,3-二酮,黄色固体,产率为85%。
Melting Point:148–150℃.
1H NMR(400MHz,CDCl3):δ=7.74(s,1H),7.56(d,J=8.5Hz,1H),7.42(t,J=7.5Hz,1H),7.24(d,J=8.0Hz,1H),7.11(t,J=7.5Hz,1H),6.91(d,J=8.0Hz,1H),6.51(d,J=8.5Hz,1H),6.24(s,1H),3.66(s,3H),3.25(s,3H)ppm.
13C NMR(151MHz,CDCl3):δ=180.16,168.25,159.93,151.59,151.03,130.97,127.86,124.50,123.69,123.48,111.83,110.61,109.88,99.48,83.59,55.91,45.37ppm.
HRMS(ESI):calcd for C17H14N2O4[M+H]+:311.3170,found 311.3145.
实施例10
名称:6-氟-1-(1-甲基-1,3-二氢苯并[c]异恶唑-3-基)吲哚啉-2,3-二酮在实施例1中所用的靛红用等摩尔量的6-氟靛红代替,反应时间延长至14h,其余步骤与实施例1相同,得到结构如上的目标产物6-氟-1-(1-甲基-1,3-二氢苯并[c]异恶唑-3-基)吲哚啉-2,3-二酮,黄色固体,产率为(46mg,77%)。
Melting Point:125–127℃.
1H NMR(600MHz,CDCl3):δ=7.76(s,1H),7.66–7.63(m,1H),7.44(t,J=7.4Hz,1H),7.24(d,J=7.6Hz,1H),7.13–7.11(m,1H),6.93(d,J=8.0Hz,1H),6.76-6.72(m,1H),6.58-6.56(m,1H),3.26(s,3H)ppm.
13C NMR(151MHz,CDCl3):δ=180.99,169.11(d,J=260.6Hz),158.62,151.36,150.73(d,J=13.8Hz),131.22,128.14(d,J=11.8Hz),124.62,123.51,122.89,114.73(d,J=2.4Hz),111.47(d,J=23.6Hz),110.86,102.45(d,J=29.3Hz),83.81,45.24ppm.
HRMS(ESI):calcd for C16H11FN2O3[M+Na]+:321.0644,found 321.1339.
实施例11
名称:4-溴-1-(1-甲基-1,3-二氢苯并[c]异恶唑-3-基)吲哚啉-2,3-二酮
在实施例1中所用的靛红用等摩尔量的4-溴靛红代替,反应时间延长至16h,其余步骤与实施例1相同,得到结构如上的目标产物4-溴-1-(1-甲基-1,3-二氢苯并[c]异恶唑-3-基)吲哚啉-2,3-二酮,黄色固体(47mg,66%)。
Melting Point:108–110℃.
1H NMR(400MHz,CDCl3):δ=7.80(s,1H),7.42(t,J=7.6Hz,1H),7.22-7.16(m,3H),7.10(t,J=7.6Hz,1H),6.91(d,J=8.0Hz,1H),6.74(d,J=7.3Hz,1H),3.25(s,3H)ppm.
13C NMR(151MHz,CDCl3):δ=180.45,157.53,151.48,149.92,138.70,131.09,128.95,124.57,123.52,123.08,121.68,116.95,112.15,110.88,83.93,45.39ppm.
HRMS(ESI):calcd for C16H11BrN2O3[M+Na]+:382.1680,found 382.3041.
实施例12
名称:5-碘-1-(1-甲基-1,3-二氢苯并[c]异恶唑-3-基)吲哚啉-2,3-二酮,橘黄色固体。
在实施例1中所用的靛红用等摩尔量的5-碘靛红代替,反应时间延长至16h,其余步骤与实施例1相同,得到结构如上的目标产物5-碘-1-(1-甲基-1,3-二氢苯并[c]异恶唑-3-基)吲哚啉-2,3-二酮,黄色固体(54mg,66%)。
Melting Point:109–111℃.
1H NMR(400MHz,CDCl3):δ=7.89(s,1H),7.75(s,1H),7.66(d,J=8.5Hz,1H),7.42(t,J=7.5Hz,1H),7.21(d,J=8.0Hz,1H),7.10(t,J=7.5Hz,1H),6.91(d,J=8.0Hz,1H),6.54(d,J=8.5Hz,1H),3.24(s,3H)ppm.
13C NMR(151MHz,CDCl3):δ=181.76,157.46,151.47,147.72,146.78,133.86,131.13,124.55,123.50,122.89,119.76,115.61,110.82,87.03,83.76,45.28ppm.
HRMS(ESI):calcd for C16H11IN2O3[M+Na]+:429.1685,found 429.3221.
实施例13
在实施例1中所用的靛红用等摩尔量的苯并[d]恶唑-2(3H)-one代替,反应时间延长至20h,其余步骤与实施例1相同,得到结构如上的目标产物3-(1-甲基-1,3-二氢苯并[c]异恶唑-3-基)苯并[d]恶唑-2(3H)-one,橙黄色固体(26mg,48%)。
Melting Point:90–92℃.
1H NMR(600MHz,CDCl3):δ=7.60(s,1H),7.47-7.44(m,1H),7.27(d,J=7.5Hz,1H),7.17(d,J=8.0Hz,1H),7.12(d,J=7.5Hz,1H),7.05-7.03(m,1H),6.94(d,J=8.0Hz,1H),6.92-6.90(m,1H),6.33(dd,J=8.0,0.5Hz,1H),3.23(s,3H)ppm.
13C NMR(151MHz,CDCl3):δ=154.27,151.63,142.70,131.13,124.28,124.15,123.88,123.10,110.92,110.71,110.36,110.16,109.97,85.38,45.14ppm.
HRMS(ESI):calcd for C15H12N2O3[M+Na]+:291.2720,found 291.2711.
实施例14
在实施例1中所用的靛红用等摩尔量的螺[吲哚啉-3,2'-[1,3]二氧戊环]-2-one代替,反应时间延长至18h,其余步骤与实施例1相同,得到结构如上的目标产物1-(1-甲基-1,3-二氢苯并[c]异恶唑-3-基)螺[吲哚啉-3,2'-[1,3]二氧戊环]-2-one,淡黄色固体(34mg,52%)。
Melting Point:113–115℃.
1H NMR(600MHz,CDCl3):δ=7.63(s,1H),7.39–7.34(m,2H),7.18(d,J=7.5Hz,1H),7.12-7.09(m,1H),7.06-7.04(m,1H),7.03-7.00(m,1H),6.89(d,J=8.0Hz,1H),6.48(d,J=8.0Hz,1H),4.62-4.59(m,2H),4.35-4.33(m,2H),3.22(s,3H)ppm.
13C NMR(151MHz,CDCl3):δ=173.85,151.68,141.27,131.71,130.50,124.84,124.04,123.75,123.73,123.64,123.50,111.78,110.72,102.08,83.15,66.02,65.84,45.33ppm.
HRMS(ESI):calcd for C18H16N2O4[M+Na]+:347.1110,found 347.0986.
在氩气保护条件下,将上述所得的化合物I、碳酸钠和3-乙酸吲哚酯(V)加入到甲醇中,室温下搅拌1h,静置24h后过滤,用水和甲醇洗并干燥得到化合物II。下面选择了其中具有代表性的实施例15-19,对新型N-2,1-苯并异噁唑靛玉红衍生物的合成进行说明。
实施例15
名称:(Z)-5-甲基-1-(1-甲基-1,3-二氢苯并[c]异恶唑-3-基)-[2,3'-联吲哚基亚烷基]-2',3-二酮
向50mL干净的反应瓶中加入(化合物8)(0.2mmo1)、3-乙酸吲哚酯(0.2mmol)、碳酸钠(0.5mmol)和甲醇(1mL),然后在氩气气氛下,将反应瓶置于室温条件下搅拌1h反应,待反应完全后,静置24h。过滤得到紫红色固体,用水和甲醇洗,干燥后得到得到目标产物(Z)-5-甲基-1-(1-甲基-1,3-二氢苯并[c]异恶唑-3-基)-[2,3'-联吲哚基亚烷基]-2',3-二酮,紫红色固体,59mg,70%。
Melting Point:200–202℃.
1H NMR(600MHz,CDCl3):δ=10.58(s,1H),8.76(s,1H),7.80(s,1H),7.74–7.73(m,1H),7.53-7.50(m,1H),7.41(t,J=7.5Hz,1H),7.17(d,J=7.5Hz,1H),7.09–7.05(m,1H),7.02–6.99(m,2H),6.93(d,J=8.0Hz,1H),6.87(dd,J=8.1,0.9Hz,1H),6.38(d,J=8.1Hz,1H),3.25(s,3H),2.34(s,3H)ppm.
13C NMR(151MHz,CDCl3):δ=188.39,171.52,151.84,151.62,139.64,137.12,136.61,132.52,130.44,129.99,125.99,125.38,124.39,124.02,123.49,121.87,121.74,120.15,112.09,110.87,110.42,106.74,83.16,45.40,21.43ppm.
HRMS(ESI):calcd for C25H19N3O3[M+H]+:410.1506,found 410.1901.
实施例16
名称:(Z)-6-氟-1-(1-甲基-1,3-二氢苯并[c]异恶唑-3-基)-[2,3'-联吲哚基亚烷基]-2',3-二酮
在实施例12中所用的5-甲基-1-(1-甲基-1,3-二氢苯并[c]异恶唑-3-基)吲哚啉-2,3-二酮用等摩尔量的(化合物10)代替,其余步骤与实施例12相同,得到结构如上的目标产物(Z)-6-氟-1-(1-甲基-1,3-二氢苯并[c]异恶唑-3-基)-[2,3'-联吲哚基亚烷基]-2',3-二酮,紫红色固体,58mg,产率为70%。
Melting Point:205–207℃.
1H NMR(600MHz,CDCl3):δ=10.46(s,1H),8.93-8.91(m,1H),7.83(s,1H),7.74(d,J=7.5Hz,1H),7.53(t,J=7.6Hz,1H),7.43(t,J=7.6Hz,1H),7.18(d,J=7.5Hz,1H),7.09(t,J=7.4Hz,1H),7.04–7.01(m,2H),6.94(d,J=8.0Hz,1H),6.78-6.74(m,1H),6.37-6.35(m,1H),3.26(s,3H)ppm.
13C NMR(151MHz,CDCl3):δ=188.14,171.56,163.20(d,J=248.4Hz),151.51,151.49,139.93(d,J=11.8Hz),139.23,137.11,130.67,126.84(d,J=9.3Hz),125.40,124.11,123.78,123.35,121.90,120.03,117.71,112.02,110.79,109.52(d,J=22.4Hz),105.61,99.55(d,J=29.1Hz),83.13,45.16ppm.
HRMS(ESI):calcd for C24H16FN3O3[M+H]+:414.1256,found 414.2284.
实施例17
名称:(Z)-1-(5-甲氧基-1-甲基-1,3-二氢苯并[c]异恶唑-3-基)-[2,3'-联吲哚基亚烷基]-2',3-二酮
在实施例12中所用的5-甲基-1-(1-甲基-1,3-二氢苯并[c]异恶唑-3-基)吲哚啉-2,3-二酮用等摩尔量的(化合物2)代替,其余步骤与实施例12相同,得到结构如上的目标产物(Z)-1-(5-甲氧基-1-甲基-1,3-二氢苯并[c]异恶唑-3-基)-[2,3'-联吲哚基亚烷基]-2',3-二酮,紫红色固体,62mg,产率为73%。
Melting Point:148–150℃.
1H NMR(600MHz,CDCl3):δ=10.58(s,1H),8.93–8.91(m,1H),7.81(s,1H),7.74(d,J=7.5Hz,1H),7.52-7.50(m,1H),7.09–7.08(m,2H),7.03–6.96(m,3H),6.86(d,J=8.5Hz,1H),6.69(d,J=2.3Hz,1H),6.62–6.60(m,1H),3.71(s,3H),3.21(s,3H)ppm.
13C NMR(151MHz,CDCl3):δ=188.28,171.40,157.22,151.56,145.50,139.81,138.62,137.12,129.41,125.60,125.47,125.45,123.11,121.94,121.66,120.12,117.36,112.08,112.02,110.84,107.54,106.35,83.32,55.91,46.46ppm.
HRMS(ESI):calcd for C25H19N3O4[M+Na]+:448.4330,found 448.3993.
实施例18
名称:(Z)-1-(6-氟-1-甲基-1,3-二氢苯并[c]异恶唑-3-基)-[2,3'-联吲哚基亚烷基]-2',3-二酮
在实施例12中所用的5-甲基-1-(1-甲基-1,3-二氢苯并[c]异恶唑-3-基)吲哚啉-2,3-二酮用等摩尔量的1-(6-氟-1-甲基-1,3-二氢苯并[c]异恶唑-3-基)吲哚啉-2,3-二酮(化合物5)代替,其余步骤与实施例12相同,得到结构如上的目标产物(Z)-1-(6-氟-1-甲基-1,3-二氢苯并[c]异恶唑-3-基)-[2,3'-联吲哚基亚烷基]-2',3-二酮,紫红色固体,64mg,产率为77%。
Melting Point:206–208℃.
1H NMR(600MHz,CDCl3):δ=10.56(s,1H),8.93(s,1H),7.78(s,1H),7.74(d,J=7.6Hz,1H),7.51(t,J=7.5Hz,1H),7.10(s,3H),7.06–6.99(m,2H),6.76(t,J=7.5Hz,1H),6.63(d,J=8.0Hz,1H),6.57(s,1H),3.24(s,3H)ppm.
13C NMR(151MHz,CDCl3):δ=188.26,171.37,165.43,163.79,153.46(d,J=11.0Hz),151.54,139.90,138.50,137.16,129.31,125.53(d,J=7.5Hz),124.71(d,J=10.5Hz),123.23,122.02,121.71,120.11,119.79,112.09,111.11(d,J=23.7Hz),110.58,106.16,98.71(d,J=27.3Hz),82.91,44.88ppm.
HRMS(ESI):calcd for C24H16FN3O3[M+Na]+:436.3266,found 436.2272.
实施例19
名称:(Z)-1-(5-溴-1-甲基-1,3-二氢苯并[c]异恶唑-3-基)-[2,3'-联吲哚基亚烷基]-2',3-二酮
在实施例12中所用的5-甲基-1-(1-甲基-1,3-二氢苯并[c]异恶唑-3-基)吲哚啉-2,3-二酮用等摩尔量的化合物31-(6-溴-1-甲基-1,3-二氢苯并[c]异恶唑-3-基)吲哚啉-2,3-二酮代替,其余步骤与实施例12相同,得到结构如上的目标产物(Z)-1-(5-溴-1-甲基-1,3-二氢苯并[c]异恶唑-3-基)-[2,3'-联吲哚基亚烷基]-2',3-二酮,紫红色固体,69mg,产率为73%。
Melting Point:213–215℃.
1H NMR(600MHz,CDCl3):δ=10.55(s,1H),8.95–8.93(m,1H),7.78(s,1H),7.75(d,J=7.6Hz,1H),7.53–7.50(m,2H),7.30(d,J=1.7Hz,1H),7.12–7.11(m,2H),7.05-7.0(m,2H),6.80(d,J=8.5Hz,1H),6.64–6.63(m,1H),3.24(s,3H)ppm.
13C NMR(151MHz,CDCl3):δ=188.25,171.24,151.54,150.91,139.96,138.36,137.18,133.45,129.35,126.66,126.44,125.60,125.53,123.31,122.05,121.71,120.12,116.29,112.22,112.12,110.55,106.06,82.63,45.18ppm.
HRMS(ESI):calcd for C24H16BrN3O3[M+Na]+:497.3030,found 497.2399.
实施例20
化合物11、12、15-17抗肿瘤活性研究。
检测方法:CCK8试剂盒;
材料:肿瘤细胞:人卵巢癌细胞株SKOV3、人白血病细胞K562、CCK-8试剂盒;
实验方法:用CCK-8试剂盒检测化合物对于肿瘤细胞增殖的影响:将对数生长期的肿瘤细胞SKOV3或者K562,用含10%的FBS的培养基制成单细胞悬液,以每孔8000-10000个细胞/100μL接种于96孔板,在37℃含5%CO2的恒温培养箱中孵育24h。以五个浓度梯度为:20μg/mL,10μg/mL,5μg/mL,2.5μg/mL,1.25μg/mL的不同种类化合物处理细胞48h。培养结束后,加入CCK8溶液,1.5h后用酶标仪检测各孔在450nm的吸光度,按以下方法求得抑制率(%)。
细胞抑制率=[1-(实验孔-空白孔)/(对照孔-空白孔)]100%;
表1化合物11-12与化合物15-19的活性测试结果(如表1所示)。
表1靛红衍生物对肿瘤细胞的抑制活性
Table 1 The antitumor activity of isatin derivatives
由表1中实验数据可见,受试化合物12、17、18、19对人白血病细胞K562的增殖具有明显的抑制作用,其效果均优于靛红;且化合物18和19的效果优于靛玉红。同时,受试化合物15、17、18对人卵巢癌细胞SKOV3的增殖具有明显的抑制作用,其效果明显优于靛红和靛玉红。受试化合物17、18对人卵巢癌细胞SKOV3和人白血病细胞K562的增殖均有抑制作用,尤其是化合物18,其对人白血病细胞K562的抑制效果为对照品靛玉红的2倍,对人卵巢癌细胞SKOV3的抑制作用也远超于靛玉红。
Claims (10)
4.根据权利要求3所述的方法,其特征在于:所述路易斯碱选自碳酸钠、碳酸铯、叔丁醇钾、磷酸钾、乙酸钾、三乙胺、TMEDA、DIPEA和DMAP中的任意一种或几种的混合物;
所述溶剂选自二氯甲烷、三氯甲烷、四氯化碳、四氢呋喃、乙腈、1,4-二氧六环、乙酸乙酯、DCE、TBME和DMSO中的任意一种或几种的混合物;
式III所示化合物与式IV所示化合物的摩尔比为1:1.2~1.5,路易斯碱的加入量为式III所示化合物的2倍当量;
所述反应在室温下进行,所述反应的时间为12-24小时。
8.根据权利要求7所述的方法,其特征在于:所述惰性气氛为氩气气氛;
所述反应在溶剂中进行,所述溶剂具体可为甲醇;
式I’所示化合物与碳酸钠、式V所示3-乙酸吲哚酯的摩尔比依次为1:2.5:1;
所述反应的温度为室温,所述反应的时间为1-24h。
9.权利要求1或2所述的式I所示N-取代靛红衍生物或权利要求5或6所述的式II所示N-取代的靛玉红衍生物在制备抗肿瘤药物中的应用,
具体地所述应用中,所述肿瘤为癌,所述癌为卵巢癌、白血病。
10.一种抗肿瘤药物,含有权利要求1或2所述的式I所示N-取代靛红衍生物或权利要求5或6所述的式II所示N-取代的靛玉红衍生物。
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