CN104292139A - 法尼基硫醚取代的查尔酮衍生物及制备方法和用途 - Google Patents
法尼基硫醚取代的查尔酮衍生物及制备方法和用途 Download PDFInfo
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- CN104292139A CN104292139A CN201410422999.9A CN201410422999A CN104292139A CN 104292139 A CN104292139 A CN 104292139A CN 201410422999 A CN201410422999 A CN 201410422999A CN 104292139 A CN104292139 A CN 104292139A
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- phenyl
- ketone
- alkene
- farnesyl
- iii
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Abstract
本发明公开了一种法尼基硫醚取代的查尔酮衍生物及制备方法和用途,是通式(I)、(Ⅱ)、(Ⅲ)所示的法尼基硫醚取代的查尔酮衍生物及其药学上可接受的盐。本发明制备方便,可用于制备治疗肿瘤和炎症药物。
Description
技术领域
本发明涉及生物医药领域,具体涉及含有查尔酮骨架的新型法尼基硫代水杨酸类似物及其药学上可接受的盐,它们的制备方法,含有这些类似物的药用组合物以及它们的医药用途,特别是在制备用于抗肿瘤药物和抗炎症反应药物中的应用。
背景技术
查尔酮类化合物广泛存在于自然界中,属于黄酮类化合物家族具有1,3-二苯基-2-烯-1-酮的母核结构,参与黄酮类化合物的生物合成途径,如查尔酮是黄酮的前体结构。研究表明,查尔酮类化合物表现出多种生物活性,包括抗肿瘤生成活性及抗炎活性[106-107]。查尔酮的抗炎及抗癌作用方式具有多种形式,抑制NF-κB活性是其中一种重要的作用机制。大量的天然的或合成的查尔酮类化合物具有抑制NF-κB活性,Lee等从姜科植物Alpinia conchigera Griff中鉴定得到Cardamomin,可作为NF-κB抑制剂。实验表明,Cardamomin可显著抑制LPS诱导的TNF-α的生成以及iNOS和COX-2的表达,并且Cardamomin不仅抑制LPS诱导的IκBα的磷酸化和降解,还可活化IKK(Lee JH,Jung HS,Giang PM,et al.J Pharmacol Exp Ther,2006,316:271-278)。Shen等证明基于二苯基丙烯酮结构的查尔酮具有抗NF-κB活性,且降低NF-κB下游Bcl-XL的表达。由查尔酮引起的T24和HT-1376细胞凋亡诱导作用可能是因为降低了NF-κB的抗凋亡作用(Shen KH,Chang JK,Hsu YL,et al.Basic Clin Pharmacol Toxicol,2007,101:254-261)。Alcaraz等[109]报道了人工合成的查尔酮化合物3',4',5',3,4,5-hexamethoxy-chalcone显示出抗炎活性,并且抑制NF-κB转移到细胞核中从而抑制其与DNA结合及转录活性(Srinivasan B,Johnson TE,Lad R,et al.J Med Chem,2009,52:7228-7235.)。此外,查尔酮比较容易合成,通过引入这种配体-受体相互作用的相关特征,即疏水性基团,氢键受体和供体,可丰富结构的多样性。查尔酮类化合物可以阻断NF-κB的激活,诱导细胞凋亡并且抑制细胞增殖,侵入,转移和血管生成,因此,查尔酮类化合物有望成为抗肿瘤药物开发的先导物和用于癌症治疗。
另据研究报道,从蛇麻草中分离得到的含异戊烯基片段查尔酮类化合物Xanthohumol,具有抗炎,抗增殖和抗血管生成作用,它下调基本的及可诱导的NF-κB活化,其作用是由于抑制IκBα的磷酸化和降解(Harikumar KB,Kunnumakkara AB,Ahn KS,et al.Blood,2009,113:2003-2013)。类似含有异戊二烯片段的法尼基硫代水杨酸(FTA)是基于法尼基与Galectin结合口袋的竞争性Ras抑制剂,FTA中的硫代法尼基通过竞争性地取代F-Ras与Galectin结合,其可以阻断Ras的各种亚型,从而抑制由Ras引发的下游信号通路,抑制肿瘤细胞的增殖和促进细胞凋亡,已处于II期临床研究(Blum R,Cox AD,Kloog Y.Recent PatAnticancer Drug Discov,2008,3(1):31-47;Goldberg L,Ocherashvilli A,Daniels D,et al.Mol Cancer Ther,2008,7(11):3609-3616;Riely GJ,Johnson ML,Medina C,etal.J Thorac Oncol,2011,6(8):1435-1437)。然而临床治疗效果不高,使用剂量大,临床上通常需要和其他抗肿瘤药联合治疗(Mologni L,Brussolo S,Ceccon M,et al.PLoS One,2012,7(12):e51449;Bustinza-Linares E,Kurzrock R,Tsimberidou AM,et al.Future Oncol,2010,6(6):885–891)。因此,在此基础上,将天然骨架查尔酮与FTA进行拼合,利用合理药物设计原理,将具有Ras抑制活性的法尼基硫醚片段引入到查尔酮的邻位,设计合成了一类法尼基硫醚取代的新型查尔酮衍生物,以期获得活性更好、安全性更高的具有Ras及NF-κB多重生物抑制活性的抗肿瘤候选药物。本发明公开了一类具有药用价值的法尼基硫醚取代的新型查尔酮衍生物及其药学上可接受的盐,目前尚未见对此类化合物的任何报道。
发明内容
本发明目的在于提供一种一类具有抗肿瘤活性的法尼基硫醚取代的查尔酮衍生物及其药学上可接受的盐、其制备方法及其医药用途。
本发明公开的化合物是通式(I)、(Ⅱ)、(Ⅲ)所示的法尼基硫醚取代的新型查尔酮衍生物及其药学上可接受的盐:
通式Ⅱ中:
n=1~3;
Y为含氮的各类基团,可以为形式;
当Y基团为形式时,R1或R2可以分别独立地选自基团选自H,或C1~C12的饱和或不饱和的烷基、环烷基、链烯基,或带有O,N,S,卤素等杂原子的C1~C12的饱和或不饱和的烷基、环烷基、链烯基,或苯基、苄基,或取代苯基及各种杂环基团;
当Y基团为形式时,可为饱和或不饱和的环状基团。其中R3可以分别独立地选自基团选自H,或C1~C12的饱和或不饱和的烷基、环烷基、链烯基,或带有O,N,S,卤素等杂原子的C1~C12的饱和或不饱和的烷基、环烷基、链烯基,或苯基、取代苯基,及各种杂环基团;Z可以为O,或S,或NH,或取代的N原子等。
Y基团为形式时,R1或R2尤其可独立地选自:H或X(CH2)m-(m=0,1,2,3,4;X=H,NH2,SH,OH),如特别优选基团为:-NH2,CH3NH-,CH3CH2NH-,CH3CH2CH2NH-,CH3CH2CH2CH2NH-,HOCH2CH2NH-,HOCH2CH2CH2NH-,CH3CH(CH2OH)NH-,HOCH2CH(CH2OH)NH-,[HOCH2(CHOH)CH2]CH3N-,(HOCH2CH2)2N-。
Y基团为形式时,Y基团尤其特别优选的是含有各种羟基、巯基、氨基、卤素及烷基取代的饱和含氮杂环如哌啶环、吡咯环、哌嗪环、吗啉环,以及含有各种羟基、巯基、氨基、卤素及烷基取代的不饱和含氮杂环如噻唑环、噁唑环、吡唑环、咪唑环、三氮唑环,四氮唑环,噁嗪环,噻嗪环。
通式Ⅲ中:
n=0~1;
Y为含氮的各类基团,可以为形式;
当Y基团为形式时,R1或R2可以分别独立地选自基团选自H,或C1~C12的饱和或不饱和的烷基、环烷基,或带有O,N,S,卤素等杂原子的C1~C12的饱和或不饱和的烷基、环烷基,或苯基、苄基,或取代苯基及各种杂环基团;
当Y基团为形式时,可为饱和或不饱和的环状基团。其中R3可以分别独立地选自基团选自H,或C1~C12的饱和或不饱和的烷基、环烷基,或带有O,N,S,卤素等杂原子的C1~C12的饱和或不饱和的烷基、环烷基,或苯基、取代苯基,及各种杂环基团;Z可以为O,或S,或NH,或取代的N原子等。
Y基团为形式时,R1或R2尤其可独立地选自:H或X(CH2)m-(m=0,1,2,3,4;X=H,NH2,OH),如特别优选基团为:-NH2,CH3NH-,CH3CH2NH-,CH3CH2CH2NH-,HOCH2CH2NH-,HOCH2CH2CH2NH-,HOCH2CH(CH2OH)NH-,[HOCH2(CHOH)CH2]CH3N-,(HOCH2CH2)2N-。
Y基团为形式时,Y基团尤其特别优选的是含有各种羟基、巯基、氨基、卤素及烷基取代的饱和含氮杂环如哌啶环、吡咯环、哌嗪环、吗啉环,以及含有各种羟基、巯基、氨基、卤素及烷基取代的不饱和含氮杂环如噻唑环、噁唑环、吡唑环、咪唑环、三氮唑环,四氮唑环。
具体的说,通式(I)中所示的法尼基硫醚取代的新型查尔酮衍生物如下:
(E)-1-(4-羟苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(化合物编号:I,下同)
通式(Ⅱ)中所示的法尼基硫醚取代的新型查尔酮衍生物特别优选的化合物如下:
(E)-1-(4-(2-(二乙胺基)乙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ1)
(E)-1-(4-(2-(1-哌啶基)乙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ2)
(E)-1-(4-(2-(1-(4-甲哌嗪基))乙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ3)
(E)-1-(4-(3-(1-吡咯烷)丙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ4)
(E)-1-(4-(3-(双(2-羟乙基)氨基)丙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ5)
(E)-1-(4-(3-(1-哌啶基)丙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ6)
(E)-1-(4-(3-(1-吗啉基)丙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ7)
(E)-1-(4-(3-(1-(4-甲哌嗪基))丙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ8)
(E)-1-(4-(3-(4-羟甲基哌啶基)丙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ9)
(E)-1-(4-(3-(N-(羟乙基(甲基))胺基)丙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ10)
(E)-1-(4-(4-(二乙胺基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ11)
(E)-1-(4-(4-(二丙氨基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ12)
(E)-1-(4-(4-(二丁氨基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ13)
(E)-1-(4-(4-(1-吡咯烷)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ14)
(E)-1-(4-(4-(1-哌啶基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ15)
(E)-1-(4-(4-(1-吗啉基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ16)
(E)-1-(4-(4-(双(2-羟乙基)氨基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ17)
(E)-1-(4-(4-(1-(4-甲哌嗪基))丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ18)
(E)-1-(4-(4-(1-(4-乙基哌嗪基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ19)
(E)-1-(4-(4-(1-(4-羟基哌啶基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ20)
(E)-1-(4-(4-(1-(4-苄基哌嗪基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ21)
(E)-1-(4-(4-(1-(4-羟乙基哌嗪基))丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ22)
(E)-1-(4-(4-(1-(4-叔丁氧羰基哌嗪基))丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ23)
(E)-1-(4-(4-(1-哌嗪基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ24)
通式(Ⅲ)所示的法尼基硫醚取代的新型查尔酮衍生物特别优选的化合物如下:
(E)-1-(4-(4-羟基-3-(二乙胺基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ1)
(E)-1-(4-(4-羟基-3,5-二(二乙胺基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ2)
(E)-1-(4-(4-羟基-3-(二羟乙胺基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ3)
(E)-1-(4-(4-羟基-3,5-二(二羟乙胺基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ4)
(E)-1-(4-(4-羟基-3-(N-(羟乙基(甲基))胺基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ5)
(E)-1-(4-(4-羟基-3,5-二(N-(羟乙基(甲基))胺基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ6)
(E)-1-(4-(4-羟基-3-(哌啶基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ7)(E)-1-(4-(4-羟基-3,5-二(哌啶基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ8)
(E)-1-(4-(4-羟基-3-(吗啉基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ9)(E)-1-(4-(4-羟基-3,5-二(吗啉基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ10)
(E)-1-(4-(4-羟基-3-(甲哌嗪基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ11)
(E)-1-(4-(4-羟基-3,5-二(甲哌嗪基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ12)
(E)-1-(4-(4-羟基-3-(对羟基哌啶-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ13)
(E)-1-(4-(4-羟基-3,5-二(对羟基哌啶-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ14)
(E)-1-(4-(4-羟基-3-((4-叔丁氧羰基哌嗪基)-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ15)
(E)-1-(4-(4-羟基-3,5-二((4-叔丁氧羰基哌嗪基)-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ16)
(E)-1-(4-(4-羟基-3-(哌嗪基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ17)
(E)-1-(4-(4-羟基-3,5-二(哌嗪基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ18)
上述结构通式Ⅱ优选化合物代号及其对应的结构如表1所示
表1 通式Ⅱ优选化合物代号及其对应的结构
上述结构通式Ⅱ优选化合物代号及其对应的结构如表1所示
表2 通式Ⅱ优选化合物代号及其对应的结构
本发明的另一目的在于提供本发明通式Ⅰ、Ⅱ和Ⅲ所述化合物的制备方法。
通式Ⅰ所示新型查尔酮衍生物或其药学上可接受的盐的制备方法,其特征是:包括下列步骤:
采用法尼基硫代水杨醛1与对甲基苯乙酮2在10%NaOH作用下生成目标化合物Ⅰ,合成路线如下所示:
通式Ⅱ所示新型查尔酮衍生物或其药学上可接受的盐的制备方法,其特征是:包括下列步骤:
首先采用对羟基苯乙酮2与不同链长的二溴烷烃反应得到O-溴烷基取代的对溴烷氧基苯乙酮3,再与不同取代的仲胺反应得到中间体4,再将其与法尼基硫代水杨醛1反应得到目标化合物Ⅱ,合成路线为:
其中Y参照上述。
通式Ⅲ所示新型查尔酮衍生物或其药学上可接受的盐的制备方法,其特征是:包括下列步骤:
将通式Ⅰ化合物、37%甲醛和不同取代的仲胺进行mannish反应,得到目标化合物Ⅲa(通式Ⅲ中n=0)和Ⅲb(通式Ⅲ中n=1),合成路线为:
其中,Y参照上述。
本发明的再一目的是提供本发明通式Ⅰ、Ⅱ和Ⅲ化合物在制备治疗肿瘤和炎症药物中的应用。
本发明的进一步目的在于提供一种含有效剂量的本发明通式Ⅰ、Ⅱ和Ⅲ化合物或其医学上可接受的盐及药学上可接受的载体或辅料的药物组合物。
本发明的再一目的是提供本发明通式Ⅰ、Ⅱ和Ⅲ化合物在制备抗肿瘤药物和治疗炎症药物中的应用,尤其是治疗肝癌,结肠癌,乳腺癌,肺癌,胃癌及脑癌等肿瘤药物中的应用和炎症损伤保护药物中的应用。
由于本发明通式Ⅰ、Ⅱ和Ⅲ化合物,是根据生命科学和信息科学最新研究进展,应用新药设计的先进理念和手段对FTA结构进行修饰、改造,引入其它药效基团得到的,其具有和FTA相似的结构,从化学结构和空间结构上可推测本发明通式Ⅰ、Ⅱ和Ⅲ化合物具有FTA相似的药理作用。
本发明化合物可以单独或与一种或一种以上的药学上可接受的载体组合制成制剂以供给药。例如,溶剂、稀释剂等,可以用口服剂型给药,如片剂、胶囊、可分散粉末、颗粒剂等。本发明药物组合物的各种剂型可以按照药学领域中熟知的方法进行制备。这些药用制剂中可以含有与载体组合的例如0.05%~90%重量的活性成分,更常见约15%~60%之间重量的活性成分。本发明化合物剂量可以是0.005~5000mg/kg/天,也可根据疾病严重程度或剂型的不同使用剂量超出此剂量范围。
本发明化合物可以与其他抗肿瘤药物例如烷化剂(如环磷酰胺或顺铂)、抗代谢药(如5-氟尿嘧啶或羟基脲)、拓扑异构酶抑制剂(如喜树碱)、有丝分裂抑制剂(如紫杉醇或长春碱)、DNA插入剂(如阿霉素)联合应用,另外还可以与放射治疗联合应用。这些其他抗肿瘤药物或放射治疗可以与本发明化合物同时或在不同时间给予。这些联合治疗可以产生协同作用从而有助于改善治疗效果。
本发明化合物的部分药理试验结果如下:
1、采用MTT法对本发明化合物的肿瘤细胞增殖抑制率测定研究
经过一系列肿瘤细胞测试,发现这些本发明通式Ⅰ、Ⅱ和Ⅲ化合物在25μmol/L浓度下对大部分肿瘤细胞增殖抑制作用较强,且肿瘤细胞抑制率显著比先导化合物FTA强2-4倍左右;在这些肿瘤细胞中,发明化合物对结肠癌、肝癌和胃癌细胞敏感程度要略高于其他肿瘤细胞(见表3和4)。药理实验结果表明,本发明化合物对人肿瘤细胞的增殖具有较强程度的抑制作用,大部分化合物抗肿瘤活性均显著强于FTA。
表3 本发明通式Ⅰ和Ⅱ化合物对部分肿瘤细胞增殖的抑制率%(25μmol/L)
ND:未检测.
表4 本发明通式Ⅲ化合物对部分肿瘤细胞增殖的抑制率%(25μmol/L)
ND:未检测.
2、利用Western blot实验检测活性较好的本发明通式Ⅰ、Ⅱ和Ⅲ部分化合物对结肠癌HCT116细胞Ras相关下游信号通路及炎症NF-κb通路相关蛋白IKκB和p65表达的影响。结果表明,细胞在TNF-α10ng/ml刺激下,化合物Ⅰ、Ⅱ2-Ⅱ8、Ⅱ15-Ⅱ18、Ⅲ3-Ⅲ8和Ⅲ11-Ⅲ14在2.0、4.0和8.0μmol/L分别对总的NF-B表达影响不大,但是能够显著抑制炎症相关蛋白Ikb和p65表达,且呈现剂量依赖性,条带灰度扫描量化后发现在4.0和8.0μmol/L的抑制效果尤其明显。同时化合物Ⅰ、Ⅱ2-Ⅱ8、Ⅱ15-Ⅱ18、Ⅲ3-Ⅲ8和Ⅲ11-Ⅲ14在4.0和8.0μmol/L分别对Ras相关下游信号通路中磷酸化c-Raf、ERK和Akt均具有显著抑制作用。Actin显示各组所含总蛋白量大体一致,提示本发明通式通式Ⅰ、Ⅱ和Ⅲ化合物不仅保留了对Ras蛋白及相关下游信号通路抑制活性,而且能够抑制炎症NF-κb通路相关蛋白,从而协同发挥显著抗肿瘤效果,促使肿瘤细胞凋亡和抑制炎症反应发生。
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。本发明所用法尼基硫代水杨醛为实验室自制,含量>98%。
实施例1 (E)-1-(4-羟苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(I)的制备
将法尼基硫代水杨醛(0.18g,0.52mmol),对羟基苯乙酮(68mg,0.5mmol)溶于2mL乙醇溶液中,加入10%的NaOH(3mmol)溶液0.6mL,于20-25℃搅拌过夜,反应完毕。将反应液调pH=9,加入10mL水,乙酸乙酯萃取(20mL×3)萃取,有机层浓缩得粗品。粗品用硅胶柱层析纯化得亮黄色油状物(I),产率83%。IR(KBr,cm-1):3445,2929,1736,1628,1418,1209,1005;1H NMR(DMSO-d6,300MHz):δ8.18(d,1H,J=12 Hz,Ar-CH=CH),8.06(d,2H,J=6 Hz,Ar-H),8.03(m,1H,Ar-H),7.93(d,1H,J=12 Hz,Ar-CH=CH),7.51(m,1H,Ar-H),7.40(m,1H,Ar-H),7.34(m,1H,Ar-H),7.05(d,2H,J=6 Hz,Ar-H),5.23(m,1H,SCH2CH),5.00(m,2H,2×CH2CH=CCH3),3.60(m,2H,SCH 2CH),1.89-1.96(m,8H,2×CCH 2CH 2),1.49-1.87(m,12H,4×CH=CCH 3);MS(ESI)m/z=461[M+H]+.
实施例2 (E)-1-(4-(2-(二乙胺基)乙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ1)的制备
2-溴乙氧基苯乙酮(3a)
向对羟基苯乙酮(1.36g,10mmol),1,2-二溴乙烷(7.51g,40mmol),K2CO3(3.45g,25mmol),KI(0.17g,1mmol)中加入30mL乙腈,加热回流3h,反应完毕,减压浓缩溶剂。快速柱层析(石油醚/乙酸乙酯=10/1,v/v)得到黄色油状物(3a),产率85%。
3-溴丙基氧基苯乙酮(3b)
参照(3a)的制备方法,由1,3-二溴丙烷替代方法中的1,2-二溴乙烷,与4-羟基苯乙酮反应制得亮黄色油状物(3b),收率82%。
4-溴丁基氧基苯乙酮(3c)
参照(3a)的制备方法,由1,4-二溴丁烷替代方法中的1,2-二溴乙烷,与4-羟基苯乙酮反应制得亮黄色油状物(3c),收率80%。
(E)-1-(4-(2-(二乙胺基)乙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ1)的制备
2-溴乙氧基苯乙酮(3a,3mmol),二乙胺(12mmol),KI(0.3mmol),K2CO3(7.5mmol)溶于10mL乙腈,加热回流3h,反应完毕冷却抽滤,滤液减压浓缩,得4-(2-(二乙胺基)乙氧基)苯乙酮,不经纯化用于下一步。然后将法尼基硫代水杨醛(1.05mmol),4-(2-(二乙胺基)乙氧基)苯乙酮(1mmol)溶于3mL乙醇溶液中,加入10%的NaOH(3mmol)溶液1.2mL,于20-25℃搅拌过夜,反应完毕。将反应液调pH=9,加入20mL水,乙酸乙酯萃取(40mL×3)萃取,有机层浓缩得粗品。粗品用硅胶柱层析纯化得亮黄色油状物(Ⅱ1),产率78%。
1H NMR(DMSO-d6,300 MHz):δ8.19(d,1H,J=12 Hz,Ar-CH=CH),8.13(d,2H,J=6 Hz,Ar-H),8.01(m,1H,Ar-H),7.86(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.33-7.40(m,1H,Ar-H),7.05(m,2H,Ar-H),5.23(m,1H,SCH2CH),4.99(m,2H,2×CH2CH=CCH3),4.12(m,2H,OCH2),3.61(m,2H,SCH2),2.97(m,2H,NCH2),2.53-2.58(m,4H,N(CH 2)2),1.93-1.99(m,8H,2×CCH 2CH 2),1.51-1.69(m,12H,4×CH=CCH 3),0.98-1.07(m,6H,N(CH2CH 3)2);MS(ESI)m/z=560[M+H]+.
实施例3 (E)-1-(4-(2-(1-哌啶基)乙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ2)的制备
参照(Ⅱ1)的制备方法,由哌啶替代方法中的二乙胺,与2-溴乙氧基苯乙酮(3a)和法尼基硫代水杨醛反应制得亮黄色油状物(Ⅱ2),收率80%。
1H NMR(DMSO-d6,300 MHz):δ8.21(d,1H,J=12 Hz,Ar-CH=CH),8.15(m,2H,Ar-H),8.04(m,1H,Ar-H),7.82(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.34-7.41(m,2H,Ar-H),7.10(d,2H,J=6 Hz,Ar-H),5.24(m,1H,SCH2CH),5.01(m,2H,2×CH2CH=C),4.11(m,2H,OCH2),3.60(m,2H,SCH2),2.31-2.36(m,4H,N(CH2)2),1.92-1.95(m,8H,2×CCH 2CH 2),1.47-1.66(m,16H,4×CH=CCH 3,2×NCH2CH 2),1.34(m,2H,NCH2CHCH 2);MS(ESI)m/z=572[M+H]+.
实施例4 (E)-1-(4-(2-(1-(4-甲哌嗪基))乙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ3)的制备
参照(Ⅱ1)的制备方法,由甲基哌嗪替代方法中的二乙胺,与2-溴乙氧基苯乙酮(3a)和法尼基硫代水杨醛反应制得亮黄色油状物(Ⅱ3),收率80%。MS(ESI)m/z=587[M+H]+.
实施例5 (E)-1-(4-(3-(1-吡咯烷)丙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ4)的制备
参照(Ⅱ1)的制备方法,由吡咯烷替代方法中的二乙胺,3-溴丁氧基苯乙酮(3b)替代方法中的2-溴乙氧基苯乙酮(3a),与法尼基硫代水杨醛反应制得亮黄色油状物(Ⅱ4),收率80%。MS(ESI)m/z=572[M+H]+.
实施例6 (E)-1-(4-(3-(双(2-羟乙基)氨基)丙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ5)的制备
参照(Ⅱ1)的制备方法,由二乙醇胺替代方法中的二乙胺,3-溴丁氧基苯乙酮(3b)替代方法中的2-溴乙氧基苯乙酮(3a),与法尼基硫代水杨醛反应制得亮黄色油状物(Ⅱ5),收率82%。
1H NMR(DMSO-d6,300 MHz):δ8.23(d,1H,J=12 Hz,Ar-CH=CH),8.17(d,2H,J=6 Hz,Ar-H),8.06(m,1H,Ar-H),7.87(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.42(m,1H,Ar-H),7.37(m,1H,Ar-H),7.09(d,2H,J=6 Hz,Ar-H),5.28(m,1H,SCH2CH),4.98(m,2H,2×CH2CH=CCH3),4.08-4.15(m,6H,3×OCH2),3.61(m,2H,SCH2),3.16-3.22(m,6H,3×NCH2),1.90-2.02(m,8H,2×CCH2CH2),1.50-1.61(m,14H,4×CH=CCH3,OCH2CH2);MS(ESI)m/z=620[M+H]+.
实施例7 (E)-1-(4-(3-(1-哌啶基)丙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ6)的制备
参照(Ⅱ1)的制备方法,由哌啶替代方法中的二乙胺,3-溴丁氧基苯乙酮(3b)替代方法中的2-溴乙氧基苯乙酮(3a),与法尼基硫代水杨醛反应制得亮黄色油状物(Ⅱ6),收率78%。
1H NMR(DMSO-d6,300 MHz):δ8.20(d,1H,J=12 Hz,Ar-CH=CH),8.12(d,2H,J=6 Hz,Ar-H),8.05(m,1H,Ar-H),7.86(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.40(m,1H,Ar-H),7.34(m,1H,Ar-H),7.07(d,2H,J=6 Hz,Ar-H),5.22(m,1H,SCH2CH),5.00(m,2H,2×CH2CH=CCH3),4.10(m,2H,CH 2CH2CH2),3.59(m,2H,SCH 2CH),2.33-2.40(m,6H,N(CH2)3),1.89-1.96(m,8H,2×CCH 2CH 2),1.37-1.65(m,18H,4×CH=CCH 3,CH2CH 2CH2,N(CH2CH 2)2CH 2);MS(ESI)m/z=586[M+H]+.
实施例8 (E)-1-(4-(3-(1-吗啉基)丙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ7)
参照(Ⅱ1)的制备方法,由吗啉替代方法中的二乙胺,3-溴丁氧基苯乙酮(3b)替代方法中的2-溴乙氧基苯乙酮(3a),与法尼基硫代水杨醛反应制得亮黄色油状物(Ⅱ7),收率79%。
1H NMR(DMSO-d6,300 MHz):δ8.21(d,1H,J=12 Hz,Ar-CH=CH),8.15(d,2H,J=6 Hz,Ar-H),8.05(m,1H,Ar-H),7.86(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.40(m,1H,Ar-H),7.34(m,1H,Ar-H),7.07(d,2H,J=6 Hz,Ar-H),5.22(m,1H,SCH2CH),5.00(m,2H,2×CH2CH=CCH3),4.10(m,2H,CH 2CHCH2),3.60(m,2H,SCH 2CH),3.56(m,4H,O(CH2)2),2.36(m,4H,N(CH2)2),1.89-1.96(m,8H,2×CCH 2CH 2),1.37-1.65(m,14H,4×CH=CCH 3,CH2CH 2CH2,);MS(ESI)m/z=588[M+H]+.
实施例9 (E)-1-(4-(3-(1-(4-甲哌嗪基))丙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ8)
参照(Ⅱ1)的制备方法,由4-甲基哌嗪替代方法中的二乙胺,3-溴丁氧基苯乙酮(3b)替代方法中的2-溴乙氧基苯乙酮(3a),与法尼基硫代水杨醛反应制得亮黄色油状物(Ⅱ8),收率83%。
1H NMR(DMSO-d6,300 MHz):δ8.21(d,1H,J=12 Hz,Ar-CH=CH),8.14(d,2H,J=6 Hz,Ar-H),8.05(m,1H,Ar-H),7.86(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.40(m,1H,Ar-H),7.34(m,1H,Ar-H),7.07(d,2H,J=6 Hz,Ar-H),5.22(m,1H,SCH2CH),5.00(m,2H,2×CH2CH=CCH3),4.10(m,2H,CH2CH2CH2),3.59(m,2H,SCH2CH),2.95(m,2H,NCH2),2.37(m,8H,2×NCH2CH2),2.20(s,3H,NCH3),1.89-1.96(m,8H,2×CCH2CH2),1.36-1.65(m,14H,4×CH=CCH3,CH2CH2CH2);MS(ESI)m/z=601[M+H]+.
实施例10 (E)-1-(4-(3-(4-羟甲基哌啶基)丙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ9)的制备
参照(Ⅱ1)的制备方法,由4-羟甲基哌啶替代方法中的二乙胺,3-溴丁氧基苯乙酮(3b)替代方法中的2-溴乙氧基苯乙酮(3a),与法尼基硫代水杨醛反应制得亮黄色油状物(Ⅱ9),收率75%。MS(ESI)m/z=616[M+H]+.
实施例11 (E)-1-(4-(3-(N-(羟乙基(甲基))胺基)丙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ10)的制备
参照(Ⅱ1)的制备方法,由N-甲基乙醇胺替代方法中的二乙胺,3-溴丁氧基苯乙酮(3b)替代方法中的2-溴乙氧基苯乙酮(3a),与法尼基硫代水杨醛反应制得亮黄色油状物(Ⅱ7),收率78%。
1H NMR(DMSO-d6,300 MHz):δ8.22(d,1H,J=12 Hz,Ar-CH=),8.08(d,2H,J=6 Hz,Ar-H),8.04(m,1H,Ar-H),7.84(d,1H,J=12 Hz,CH=),7.51(m,1H,Ar-H),7.42(m,1H,Ar-H),7.30-7.34(m,3H,Ar-H),5.25(m,1H,SCH2CH),5.01(m,2H,2×CH2CH=C),4.10(m,2H,OCH2),3.50-3.58(m,7H,SCH2,NCH2,CH2CH 2OH),2.45-2.48(m,2H,CH 2CH2OH),2.16(s,3H,NCH3),1.86-1.93(m,8H,2×CCH 2CH 2),1.47-1.59(m,14H,4×CH=CCH 3,OCH2CH 2);MS(ESI)m/z=576[M+H]+.
实施例12 (E)-1-(4-(4-(二乙胺基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ11)的制备
参照(Ⅱ1)的制备方法,由4-溴丁氧基苯乙酮(3c)替代方法中的2-溴乙氧基苯乙酮(3a),与二乙胺和法尼基硫代水杨醛反应制得亮黄色油状物(Ⅱ11),收率85%。
1H NMR(DMSO-d6,300 MHz):δ8.21(d,1H,J=12 Hz,Ar-CH=CH),8.15(d,2H,J=6 Hz,Ar-H),8.06(m,1H,Ar-H),7.86(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.40(m,1H,Ar-H),7.35(m,1H,Ar-H),7.08(d,2H,J=6 Hz,Ar-H),5.22(m,1H,SCH2CH),5.00(m,2H,2×CH2CH=CCH3),4.10(m,2H,OCH2),3.60(m,2H,SCH 2CH),2.95(m,2H,NCH2),2.51-2.57(m,4H,N(CH 2)2),1.92-1.95(m,8H,2×CCH 2CH2),1.48-1.61(m,14H,4×CH=CCH 3,OCH2CH 2),1.14-1.17(m,2H,CH2CHCH 2CH2),0.96-1.05(m,6H,N(CH2CH 3)2);MS(ESI)m/z=588[M+H]+.
实施例13 (E)-1-(4-(4-(二丙氨基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ12)
参照(Ⅱ1)的制备方法,由二丙胺替代方法中的二乙胺,4-溴丁氧基苯乙酮(3c)替代方法中的2-溴乙氧基苯乙酮(3a),与法尼基硫代水杨醛反应制得亮黄色油状物(Ⅱ12),收率84%。
1H NMR(DMSO-d6,300 MHz):δ8.21(d,1H,J=12 Hz,Ar-CH=CH),8.14(d,2H,J=6 Hz,Ar-H),8.06(m,1H,Ar-H),7.86(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.41(m,1H,Ar-H),7.34(m,1H,Ar-H),7.07(d,2H,J=6 Hz,Ar-H),5.22(m,1H,SCH2CH),5.00(m,2H,2×CH2CH=CCH3),4.10(m,2H,CH 2CHCH2CH2),3.59(m,2H,SCH 2CH),2.39(m,2H,CH2CHCH2CH 2),2.31(m,4H,N(CH 2)2),1.90-1.95(m,8H,2×CCH 2CH 2),1.50-1.65(m,16H,4×CH=CCH 3,CH2CH 2CH 2CH2),1.37(m,4H,2×NCH2CH 2),0.83(m,6H,2×CH3);MS(ESI)m/z=616[M+H]+.
实施例14 (E)-1-(4-(4-(二丁氨基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ13)
参照(Ⅱ1)的制备方法,由二丁胺替代方法中的二乙胺,4-溴丁氧基苯乙酮(3c)替代方法中的2-溴乙氧基苯乙酮(3a),与法尼基硫代水杨醛反应制得亮黄色油状物(Ⅱ13),收率76%。MS(ESI)m/z=644[M+H]+.
实施例15 (E)-1-(4-(4-(1-吡咯烷)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ14)
参照(Ⅱ1)的制备方法,由吡咯烷替代方法中的二乙胺,4-溴丁氧基苯乙酮(3c)替代方法中的2-溴乙氧基苯乙酮(3a),与法尼基硫代水杨醛反应制得亮黄色油状物(Ⅱ14),收率79%。
1H NMR(DMSO-d6,300 MHz):δ8.20(d,1H,J=12 Hz,Ar-CH=CH),8.13(d,2H,J=6 Hz,Ar-H),8.05(m,1H,Ar-H),7.86(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.40(m,1H,Ar-H),7.35(m,1H,Ar-H),7.08(d,2H,J=6 Hz,Ar-H),5.22(m,1H,SCH2CH),5.00(m,2H,2×CH2CH=C),4.10(m,2H,OCH2),3.60(m,2H,SCH 2CH),2.34(m,4H,N(CH2)2),1.92-1.95(m,8H,2×CCH 2CH 2),1.43-1.65(m,16H,4×CH=CCH 3,2×NCH2CH 2);MS(ESI)m/z=586[M+H]+.
实施例16 (E)-1-(4-(4-(1-哌啶基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ15)
参照(Ⅱ1)的制备方法,由哌啶替代方法中的二乙胺,4-溴丁氧基苯乙酮(3c)替代方法中的2-溴乙氧基苯乙酮(3a),与法尼基硫代水杨醛反应制得亮黄色油状物(Ⅱ15),收率78%。
1H NMR(DMSO-d6,300 MHz):δ8.23(d,1H,J=12 Hz,Ar-CH=CH),8.17(d,2H,J=6 Hz,Ar-H),8.07(m,1H,Ar-H),7.86(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.43(m,1H,Ar-H),7.36(m,1H,Ar-H),7.08(d,2H,J=6 Hz,Ar-H),5.22(m,1H,SCH2CH),5.00(m,2H,2×CH2CH=CCH3),4.10(m,2H,OCH2),3.60(m,2H,SCH 2CH),2.34(m,4H,N(CH2)2),1.92-1.95(m,8H,2×CCH 2CH 2),1.48-1.61(m,18H,4×CH=CCH 3,3×NCH2CH 2),1.37(m,2H,NCH2CHCH 2),1.16(m,2H,CH2CHCH 2CH2);MS(ESI)m/z=600[M+H]+.
实施例17 (E)-1-(4-(4-(1-吗啉基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ16)
参照(Ⅱ1)的制备方法,由吗啉替代方法中的二乙胺,4-溴丁氧基苯乙酮(3c)替代方法中的2-溴乙氧基苯乙酮(3a),与法尼基硫代水杨醛反应制得亮黄色油状物(Ⅱ16),收率79%。
1H NMR(DMSO-d6,300 MHz):δ8.21(d,1H,J=12 Hz,Ar-CH=),8.15(d,2H,J=6 Hz,Ar-H),8.07(m,1H,Ar-H),7.88(d,1H,J=12 Hz,CH=),7.51(m,1H,Ar-H),7.41(m,1H,Ar-H),7.35(m,1H,Ar-H),7.08(d,2H,J=6 Hz,Ar-H),5.26(m,1H,SCH2CH),5.03(m,2H,2×CH2CH=CCH3),4.10(m,2H,CH 2CHCH2CH2),3.61(m,2H,SCH 2CH),3.56(m,4H,O(CH2)2),3.34(m,2H,CH2CHCH2CH 2),2.36(m,4H,N(CH2)2),1.89-1.96(m,8H,2×CCH 2CH 2),1.49-1.60(m,14H,4×CH=CCH 3,CH2CHCH2CH2),1.16-1.18(m,2H,CH2CHCH 2CH2);MS(ESI)m/z=603[M+H]+.
实施例18 (E)-1-(4-(4-(双(2-羟乙基)氨基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ17)
参照(Ⅱ1)的制备方法,由二乙醇胺替代方法中的二乙胺,4-溴丁氧基苯乙酮(3c)替代方法中的2-溴乙氧基苯乙酮(3a),与法尼基硫代水杨醛反应制得亮黄色油状物(Ⅱ17),收率76%。
1H NMR(DMSO-d6,300 MHz):δ8.21(d,1H,J=12 Hz,Ar-CH=CH),8.17(d,2H,J=6 Hz,Ar-H),8.06(m,1H,Ar-H),7.87(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.42(m,1H,Ar-H),7.37(m,1H,Ar-H),7.09(d,2H,J=6 Hz,Ar-H),5.28(m,1H,SCH2CH),4.98(m,2H,2×CH2CH=CCH3),4.14(m,2H,OCH2),3.61(m,2H,SCH 2CH),3.16-3.22(m,6H,N(CH2)3),1.90-1.96(m,8H,2×CCH 2CH 2),1.50-1.61(m,16H,4×CH=CCH 3,CH2CH 2CH 2CH2),1.20(m,4H,2×NCH2CH 2);MS(ESI)m/z=620[M+H]+.
实施例19 (E)-1-(4-(4-(1-(4-甲哌嗪基))丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ18)
参照(Ⅱ1)的制备方法,由N-甲基哌嗪替代方法中的二乙胺,4-溴丁氧基苯乙酮(3c)替代方法中的2-溴乙氧基苯乙酮(3a),与法尼基硫代水杨醛反应制得亮黄色油状物(Ⅱ18),收率75%。
1H NMR(DMSO-d6,300 MHz):δ8.21(d,1H,J=12 Hz,Ar-CH=CH),8.15(d,2H,J=6 Hz,Ar-H),8.06(m,1H,Ar-H),7.86(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.40(m,1H,Ar-H),7.35(m,1H,Ar-H),7.08(d,2H,J=6 Hz,Ar-H),5.22(m,1H,SCH2CH),5.00(m,2H,2×CH2CH=CCH3),4.10(m,2H,OCH2),3.60(m,2H,SCH 2CH),2.95(m,2H,NCH2),2.37(m,8H,2×NCH 2CH 2),2.21(s,3H,NCH3),1.92-1.95(m,8H,2×CCH 2CH2),1.48-1.61(m,14H,4×CH=CCH 3,CH2CH 2CH2CH2),1.14-1.17(m,2H,CH2CHCH 2CH2);MS(ESI)m/z=615[M+H]+.
实施例20 (E)-1-(4-(4-(1-(4-乙基哌嗪基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ19)
参照(Ⅱ1)的制备方法,由4-乙基哌嗪替代方法中的二乙胺,4-溴丁氧基苯乙酮(3c)替代方法中的2-溴乙氧基苯乙酮(3a),与法尼基硫代水杨醛反应制得亮黄色油状物(Ⅱ19),收率80%。
1H NMR(DMSO-d6,300 MHz):δ8.21(d,1H,J=12 Hz,Ar-CH=CH),8.14(d,2H,J=6 Hz,Ar-H),8.06(m,1H,Ar-H),7.86(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.41(m,1H,Ar-H),7.34(m,1H,Ar-H),7.07(d,2H,J=6 Hz,Ar-H),5.22(m,1H,SCH2CH),5.00(m,2H,2×CH2CH=CCH3),4.10(m,2H,OCH2),3.59(m,2H,SCH 2CH),2.29-2.40(m,6H,N(CH2)3),1.90-1.95(m,8H,2×CCH 2CH 2),1.35-1.61(m,20H,4×CH=CCH 3,CH2CH 2CH 2CH2,2×NCH2CH 2),0.83(m,6H,2×CH3);MS(ESI)m/z=629[M+H]+.
实施例21 (E)-1-(4-(4-(1-(4-羟基哌啶基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ20)
参照(Ⅱ1)的制备方法,由4-羟基哌啶替代方法中的二乙胺,4-溴丁氧基苯乙酮(3c)替代方法中的2-溴乙氧基苯乙酮(3a),与法尼基硫代水杨醛反应制得亮黄色油状物(Ⅱ20),收率76%。
1H NMR(DMSO-d6,300 MHz):δ8.21(d,1H,J=12 Hz,Ar-CH=CH),8.15(d,2H,J=6 Hz,Ar-H),8.06(m,1H,Ar-H),7.86(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.40(m,1H,Ar-H),7.35(m,1H,Ar-H),7.08(d,2H,J=6 Hz,Ar-H),5.22(m,1H,SCH2CH),5.00(m,2H,2×CH2CH=CCH3),4.10(m,2H,OCH2),3.60(m,2H,SCH 2CH),3.52(m,2H,Ar-CH2),2.34(m,4H,N(CH2)2),1.92-1.95(m,8H,2×CCH 2CH 2),1.48-1.61(m,14H,4×CH=CCH 3,CH2CH 2CH2CH2),1.14-1.17(m,2H,CH2CHCH 2CH2);MS(ESI)m/z=616[M+H]+.
实施例22 (E)-1-(4-(4-(1-(4-苄基哌嗪基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ21)
参照(Ⅱ1)的制备方法,由苄基哌嗪替代方法中的二乙胺,4-溴丁氧基苯乙酮(3c)替代方法中的2-溴乙氧基苯乙酮(3a),与法尼基硫代水杨醛反应制得亮黄色油状物(Ⅱ21),收率81%。
1H NMR(DMSO-d6,300 MHz):δ8.19(d,1H,J=12 Hz,Ar-CH=CH),8.14(d,2H,J=6 Hz,Ar-H),7.91(m,1H,Ar-H),7.85(d,1H,J=12 Hz,Ar-CH=CH),7.29-7.33(m,4H,Ar-H),7.27(d,2H,J=6 Hz,Ar-H),7.07(d,2H,J=6 Hz,Ar-H),7.02(d,2H,J=6 Hz,Ar-H),5.21(m,1H,SCH2CH),5.02(m,2H,2×CH2CH=CCH3),4.09(m,2H,CH 2CHCH2CH2),3.59(m,2H,SCH 2CH),3.43(s,2H,Ar-CH2),2.32-2.33(m,10H,CH2CH2CH2CH 2,2×NCH 2CH 2),1.90-1.95(m,8H,2×CCH 2CH 2),1.48-1.61(m,16H,CH2CH 2CH 2CH2,4×CH=CCH 3);MS(ESI)m/z=691[M+H]+.
实施例23 (E)-1-(4-(4-(1-(4-羟乙基哌嗪基))丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ22)
参照(Ⅱ1)的制备方法,由羟乙基哌嗪替代方法中的二乙胺,4-溴丁氧基苯乙酮(3c)替代方法中的2-溴乙氧基苯乙酮(3a),与法尼基硫代水杨醛反应制得亮黄色油状物(Ⅱ22),收率72%。
1H NMR(DMSO-d6,300 MHz):δ8.19(d,1H,J=12 Hz,Ar-CH=CH),8.15(d,2H,J=6 Hz,Ar-H),7.92(m,1H,Ar-H),7.86(d,1H,J=12 Hz,Ar-CH=CH),7.51(m,1H,Ar-H),7.41(m,1H,Ar-H),7.36(m,1H,Ar-H),7.08(d,2H,J=6 Hz,Ar-H),5.22(m,1H,SCH2CH),5.05(m,2H,2×CH2CH=CCH3),4.09(m,2H,CH 2CH2CH2CH2),3.60(m,2H,SCH 2CH),3.52(m,2H,CH2CH 2OH),3.35(s,1H,OH),2.51(m,8H,2×NCH 2CH 2),1.92-1.96(m,10H,2×CCH 2CH 2,CH2CH2CH2CH 2),1.49-1.74(m,18H,CH2CH 2CH 2CH2,4×CH=CCH 3,CH 2CH2OH);MS(ESI)m/z=645[M+H]+.
实施例24 (E)-1-(4-(4-(1-(4-叔丁氧羰基哌嗪基))丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ23)
参照(Ⅱ1)的制备方法,由4-叔丁氧羰基哌嗪替代方法中的二乙胺,4-溴丁氧基苯乙酮(3c)替代方法中的2-溴乙氧基苯乙酮(3a),与法尼基硫代水杨醛反应制得亮黄色油状物(Ⅱ23),收率77%。
1H NMR(DMSO-d6,300 MHz):δ8.21(d,1H,J=12 Hz,Ar-CH=CH),8.15(d,2H,J=6 Hz,Ar-H),8.06(m,1H,Ar-H),7.86(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.40(m,1H,Ar-H),7.35(m,1H,Ar-H),7.08(d,2H,J=6 Hz,Ar-H),5.22(m,1H,SCH2CH),5.00(m,2H,2×CH2CH=CCH3),4.10(m,2H,CH 2CHCH2CH2),3.60(m,2H,SCH 2CH),2.95(m,2H,NCH2),2.37(m,8H,2×NCH 2CH 2),2.11(s,1H,NH),1.92-1.95(m,8H,2×CCH 2CH 2),1.48-1.61(m,14H,4×CH=CCH 3,CH2CH 2CH2CH2),1.14-1.17(m,2H,CH2CHCH 2CH2);MS(ESI)m/z=701[M+H]+.
实施例25 (E)-1-(4-(4-(1-哌嗪基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅱ24)
将化合物(Ⅱ23,0.14g,0.36mmol)溶于5mL三氟乙酸/甲醇(1:1)溶液中,回流1h,反应液浓缩制砂,柱层析分离得无色透明粘稠液体(Ⅱ24),收率89%。
1H NMR(DMSO-d6,300 MHz):δ8.21(d,1H,J=12 Hz,Ar-CH=CH),8.15(d,2H,J=6 Hz,Ar-H),8.06(m,1H,Ar-H),7.86(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.40(m,1H,Ar-H),7.35(m,1H,Ar-H),7.08(d,2H,J=6 Hz,Ar-H),5.22(m,1H,SCH2CH),5.00(m,2H,2×CH2CH=CCH3),4.10(m,2H,CH 2CHCH2CH2),3.60(m,2H,SCH 2CH),2.95(m,2H,NCH2),2.37(m,8H,2×NCH 2CH 2),2.11(s,1H,NH),1.92-1.95(m,8H,2×CCH 2CH2),1.48-1.61(m,14H,4×CH=CCH 3,CH2CH 2CH2CH2),1.14-1.17(m,2H,CH2CHCH 2CH2);MS(ESI)m/z=601[M+H]+.
实施例26 (E)-1-(4-(4-羟基-3-(二乙胺基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ1)和(E)-1-(4-(4-羟基-3,5-二(二乙胺基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ2)的制备
将化合物Ⅰ(0.23g,0.5mmol),37%甲醛(0.20g,0.18mL,2.5mmol)和二乙胺(2.5mmol)溶于10mL乙腈中,加热回流6-8h,TLC监测至原料完全反应。减压蒸除溶剂,粗品经硅胶柱层析纯化得到单取代目标化合物(Ⅲ1)和双取代目标化合物(Ⅲ2),收率分别为35%和53%。
(Ⅲ1):1H NMR(DMSO-d6,300 MHz):δ8.15(d,1H,J=12 Hz,Ar-CH=CH),7.99(m,1H,Ar-H),7.93(s,2H,Ar-H),7.77(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.40(m,1H,Ar-H),7.34(m,1H,Ar-H),5.22(m,1H,SCH2CH),5.01(m,3H,OH,2×CH2CH=CCH3),3.84-3.98(m,2H,NCH 2),3.59(d,2H,SCH 2CH),2.45-2.54(m,4H,2×N(CH 2)2),1.80-1.97(m,4H,2×CCH 2CH 2),1.50-1.61(m,12H,4×CH=CCH 3),0.96-1.05(m,12H,2×N(CH2CH 3)2);MS(ESI)m/z=545[M+H]+.
(Ⅲ2):1H NMR(DMSO-d6,300 MHz):δ8.15(d,1H,J=12 Hz,Ar-CH=CH),7.99(m,1H,Ar-H),7.93(s,2H,Ar-H),7.77(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.40(m,1H,Ar-H),7.34(m,1H,Ar-H),5.22(m,1H,SCH2CH),5.01(m,3H,OH,2×CH2CH=CCH3),3.74-3.88(m,4H,2×NCH 2),3.59(d,2H,SCH 2CH),2.51-2.57(m,8H,2×N(CH 2)2),1.88-1.96(m,8H,2×CCH 2CH 2),1.50-1.61(m,12H,4×CH=CCH 3),0.96-1.05(m,12H,2×N(CH2CH 3)2);MS(ESI)m/z=631[M+H]+.
实施例27 (E)-1-(4-(4-羟基-3-(二羟乙胺基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ3)和(E)-1-(4-(4-羟基-3,5-二(二羟乙胺基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ4)的制备
参照实例26中(Ⅲ1)和(Ⅲ2)的制备方法,由二乙醇胺替代方法中的二乙胺,与化合物Ⅰ和37%甲醛反应制得单取代目标化合物(Ⅲ3)和双取代目标化合物(Ⅲ4),收率39%和51%。
(Ⅲ3):1H NMR(DMSO-d6,300 MHz):δ8.18(d,1H,J=12 Hz,Ar-CH=CH),8.02(m,1H,Ar-H),7.99(m,1H,Ar-H),7.77(m,2H,Ar-H),7.83(d,1H,J=12 Hz,Ar-CH=CH),7.51(m,1H,Ar-H),7.41(m,1H,Ar-H),7.37(m,1H,Ar-H),7.32(m,1H,Ar-H),6.81(d,2H,Ar-H),5.24(m,1H,SCH2CH),5.01(m,3H,OH,2×CH2CH=CCH3),3.82-3.91(s,2H,NCH 2),3.60(d,8H,SCH 2CH,2×NCH2CH 2OH),2.60-2.67(m,4H,2×NCH 2CH2OH),1.90-1.97(m,8H,2×CCH 2CH 2),1.50-1.62(m,12H,4×CH=CCH 3);MS(ESI)m/z=578[M+H]+.
(Ⅲ4):1H NMR(DMSO-d6,300 MHz):δ8.18(d,1H,J=12 Hz,Ar-CH=CH),8.02(m,1H,Ar-H),7.99(m,1H,Ar-H),7.77(m,2H,Ar-H),7.83(d,1H,J=12 Hz,Ar-CH=CH),7.51(m,1H,Ar-H),7.41(m,1H,Ar-H),7.37(m,1H,Ar-H),7.32(m,1H,Ar-H),6.81(d,2H,Ar-H),5.24(m,1H,SCH2CH),5.01(m,3H,OH,2×CH2CH=CCH3),3.82-3.91(s,4H,NCH 2),3.60(d,8H,SCH 2CH,2×NCH2CH 2OH),2.60-2.67(m,8H,2×NCH 2CH2OH),1.90-1.97(m,8H,2×CCH 2CH 2),1.50-1.62(m,12H,4×CH=CCH 3);MS(ESI)m/z=630[M+H]+.
实施例28 (E)-1-(4-(4-羟基-3-(N-(羟乙基(甲基))胺基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ5)和(E)-1-(4-(4-羟基-3,5-二(N-(羟乙基(甲基))胺基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ6)的制备
参照实例26中(Ⅲ1)和(Ⅲ2)的制备方法,由N-甲基乙醇胺替代方法中的二乙胺,与化合物Ⅰ和37%甲醛反应制得单取代目标化合物(Ⅲ5)和双取代目标化合物(Ⅲ6),收率36%和43%。(Ⅲ5):MS(ESI)m/z=548[M+H]+;(Ⅲ6):MS(ESI)m/z=635[M+H]+.
实施例29 (E)-1-(4-(4-羟基-3-(哌啶基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ7)和(E)-1-(4-(4-羟基-3,5-二(哌啶基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ8)的制备
参照实例26中(Ⅲ1)和(Ⅲ2)的制备方法,由哌啶替代方法中的二乙胺,与化合物Ⅰ和37%甲醛反应制得单取代目标化合物(Ⅲ7)和双取代目标化合物(Ⅲ8),收率32%和51%。
(Ⅲ7):1H NMR(DMSO-d6,300 MHz):δ8.17(d,1H,J=12 Hz,Ar-CH=CH),8.01(m,1H,Ar-H),7.88(s,2H,Ar-H),7.78(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.41(m,1H,Ar-H),7.36(m,1H,Ar-H),5.20(m,1H,SCH2CH),4.95-5.01(m,3H,OH,2×CH2CH=CCH3),3.75(s,2H,NCH 2),3.60(d,2H,SCH 2CH),2.43(m,4H,N(CH 2)2),1.88-1.97(m,8H,2×CCH 2CH 2),1.44-1.65(m,18H,4×CH=CCH 3,CH 2CH 2CH 2);MS(ESI)m/z=558[M+H]+.
(Ⅲ8):1H NMR(DMSO-d6,300 MHz):δ8.16(d,1H,J=12 Hz,Ar-CH=CH),8.00(m,1H,Ar-H),7.89(s,2H,Ar-H),7.78(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.41(m,1H,Ar-H),7.36(m,1H,Ar-H),5.22(m,1H,SCH2CH),4.96-5.02(m,3H,OH,2×CH2CH=CCH3),3.58-3.64(m,6H,2×NCH 2,SCH 2CH),3.56(m,8H,2×O(CH2)2),2.44(m,8H,2×N(CH 2)2),1.86-1.95(m,8H,2×CCH 2CH 2),1.41-1.66(m,12H,4×CH=CCH 3);MS(ESI)m/z=654[M+H]+.
实施例30 (E)-1-(4-(4-羟基-3-(吗啉基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ9)和(E)-1-(4-(4-羟基-3,5-二(吗啉基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ10)
参照实例26中(Ⅲ1)和(Ⅲ2)的制备方法,由吗啉替代方法中的二乙胺,与化合物Ⅰ和37%甲醛反应制得单取代目标化合物(Ⅲ9)和双取代目标化合物(Ⅲ10),收率40%和44%。
(Ⅲ9):1H NMR(DMSO-d6,300 MHz):δ8.16(d,1H,J=12 Hz,Ar-CH=CH),8.00(m,1H,Ar-H),7.89(s,1H,Ar-H),7.78(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.41(m,1H,Ar-H),7.36(m,1H,Ar-H),5.22(m,1H,SCH2CH),4.96-5.02(m,3H,OH,2×CH2CH=CCH3),3.58-3.64(m,4H,NCH 2,SCH 2CH),3.50(m,4H,2×O(CH2)2),2.34(m,4H,2×N(CH 2)2),1.86-1.95(m,8H,2×CCH 2CH 2),1.41-1.66(m,12H,4×CH=CCH 3);MS(ESI)m/z=559[M+H]+.
(Ⅲ10):1H NMR(DMSO-d6,300 MHz):δ8.16(d,1H,J=12 Hz,Ar-CH=CH),8.00(m,1H,Ar-H),7.89(s,2H,Ar-H),7.78(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.41(m,1H,Ar-H),7.36(m,1H,Ar-H),5.22(m,1H,SCH2CH),4.96-5.02(m,3H,OH,2×CH2CH=CCH3),3.58-3.64(m,6H,2×NCH 2,SCH 2CH),2.44(m,8H,2×N(CH 2)2),1.88-1.96(m,8H,2×CCH 2CH 2),1.42-1.65(m,24H,4×CH=CCH 3,2×CH 2CH 2CH 2);MS(ESI)m/z=658[M+H]+.
实施例31 (E)-1-(4-(4-羟基-3-(甲哌嗪基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ11)和(E)-1-(4-(4-羟基-3,5-二(甲哌嗪基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ12)的制备
参照实例26中(Ⅲ1)和(Ⅲ2)的制备方法,由4-甲基哌嗪替代方法中的二乙胺,与化合物Ⅰ和37%甲醛反应制得单取代目标化合物(Ⅲ11)和双取代目标化合物(Ⅲ12),收率36%和48%。
(Ⅲ11):1H NMR(DMSO-d6,300 MHz):δ8.18(d,1H,J=12 Hz,Ar-CH=CH),8.03(m,1H,Ar-H),7.98(m,1H,Ar-H),7.82(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.41(m,1H,Ar-H),7.34-7.38(m,2H,Ar-H),5.23(m,1H,SCH2CH),5.00(m,3H,OH,2×CH2CH=CCH3),3.74(s,2H,ArCH2),3.60(d,2H,SCH 2CH),2.51(m,8H,2×NCH 2CH 2),2.17(s,3H,NCH3),1.89-1.96(m,8H,2×CCH 2CH 2),1.49-1.65(m,12H,4×CH=CCH 3);MS(ESI)m/z=573[M+H]+.
(Ⅲ12):1H NMR(DMSO-d6,300 MHz):δ8.16(d,1H,J=12 Hz,Ar-CH=CH),8.02(m,1H,Ar-H),7.93(s,2H,Ar-H),7.80(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.40(m,1H,Ar-H),7.35(m,1H,Ar-H),5.22(m,1H,SCH2CH),5.00(m,3H,OH,2×CH2CH=CCH3),3.58-3.68(m,14H,2×NCH 2,2×N(CH 2)2,SCH 2CH),2.47(m,8H,2×N(CH 2)2),2.18(s,6H,2×NCH3),1.88-1.96(m,8H,2×CCH 2CH 2),1.49-1.65(m,12H,4×CH=CCH 3);MS(ESI)m/z=685[M+H]+.
实施例32 (E)-1-(4-(4-羟基-3-(对羟基哌啶-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ13)和(E)-1-(4-(4-羟基-3,5-二(对羟基哌啶-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ14)的制备
参照实例26中(Ⅲ1)和(Ⅲ2)的制备方法,由4-羟基哌啶替代方法中的二乙胺,与化合物Ⅰ和37%甲醛反应制得单取代目标化合物(Ⅲ13)和双取代目标化合物(Ⅲ14),收率42%和46%。
(Ⅲ13):1H NMR(DMSO-d6,300 MHz):δ8.16(d,1H,J=12 Hz,Ar-CH=CH),8.01(m,1H,Ar-H),7.90(s,1H,Ar-H),7.79(d,1H,J=12 Hz,CH=),7.52(m,1H,Ar-H),7.42(m,1H,Ar-H),7.36(m,1H,Ar-H),5.23(m,1H,SCH2CH),5.00(m,3H,OH,2×CH2CH=CCH3),3.60-3.65(m,2H,NCH 2),3.58(d,2H,SCH 2CH),3.50(m,H,CHOH),2.72(m,4H,2×N(CH2)2),2.21(m,4H,N(CH2)2),1.88-1.96(m,4H,2×CCH 2CH 2),1.49-1.65(m,14H,4×CH=CCH 3,2×CHOH);MS(ESI)m/z=573[M+H]+.
(Ⅲ14):1H NMR(DMSO-d6,300 MHz):δ8.16(d,1H,J=12 Hz,Ar-CH=CH),8.01(m,1H,Ar-H),7.90(s,2H,Ar-H),7.79(d,1H,J=12 Hz,Ar-CH=CH),7.52(m,1H,Ar-H),7.41(m,1H,Ar-H),7.36(m,1H,Ar-H),5.23(m,1H,SCH2CH),5.00(m,3H,OH,2×CH2CH=CCH3),3.60-3.66(m,4H,2×NCH 2),3.58(d,2H,SCH 2CH),3.52(m,2H,2×CHOH),2.74(m,8H,2×N(CH2)2),2.21(m,8H,N(CH2)2),1.88-1.96(m,8H,2×CCH 2CH 2),1.49-1.65(m,14H,4×CH=CCH 3,2×CHOH);MS(ESI)m/z=687[M+H]+.
实施例33 (E)-1-(4-(4-羟基-3-((4-叔丁氧羰基哌嗪基)-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ15)和(E)-1-(4-(4-羟基-3,5-二((4-叔丁氧羰基哌嗪基)-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ16)的制备
参照实例26中(Ⅲ1)和(Ⅲ2)的制备方法,由4-叔丁氧羰基哌嗪替代方法中的二乙胺,与化合物Ⅰ和37%甲醛反应制得单取代目标化合物(Ⅲ15)和双取代目标化合物(Ⅲ16),收率33%和42%。
(Ⅲ15):1H NMR(DMSO-d6,300 MHz):δ8.21(d,1H,J=12 Hz,Ar-CH=CH),8.05(m,1H,Ar-H),7.98(s,1H,Ar-H),7.82(d,1H,J=12 Hz,Ar-CH=CH),7.53(m,1H,Ar-H),7.42(m,1H,Ar-H),7.35-7.37(m,2H,Ar-H),5.24(m,1H,SCH2CH),5.02(m,2H,2×CH2CH=CCH3),3.72(s,2H,ArCH2),3.62(m,2H,SCH2),2.41(m,8H,4×NCH2),1.92-2.00(m,8H,2×CCH 2CH 2),1.49-1.67(m,12H,4×CH=CCH 3),1.37(s,9H,3×CH3);MS(ESI)m/z=659[M+H]+.
(Ⅲ16):1H NMR(DMSO-d6,300 MHz):δ8.18(d,1H,J=12 Hz,Ar-CH=CH),8.02(m,1H,Ar-H),7.96(s,2H,Ar-H),7.79(d,1H,J=12 Hz,Ar-CH=CH),7.50(m,1H,Ar-H),7.39(m,1H,Ar-H),7.33(m,1H,Ar-H),5.21(m,1H,SCH2CH),5.01(m,2H,2×CH2CH=C),3.69(s,4H,ArCH2),3.60(m,2H,SCH2),2.35-2.42(m,8H,4×NCH2),1.94-2.02(m,8H,2×CCH 2CH 2),1.46-1.69(m,12H,4×CH=CCH 3),1.37(s,18H,6×CH3);MS(ESI)m/z=857[M+H]+.
实施例34 (E)-1-(4-(4-羟基-3-(哌嗪基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ17)
参照实例25中(Ⅱ24)的制备方法,由化合物(Ⅲ15)与三氟乙酸反应制得脱去叔丁氧羰基的目标化合物(Ⅲ17),收率91%。MS(ESI)m/z=559[M+H]+.
实施例35 (E)-1-(4-(4-羟基-3,5-二(哌嗪基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮(Ⅲ18)
参照实例25中(Ⅱ24)的制备方法,由化合物(Ⅲ16)与三氟乙酸反应制得脱去叔丁氧羰基的目标化合物(Ⅲ18),收率87%。MS(ESI)m/z=657[M+H]+.
实施例36 四甲基氮唑蓝比色法(MTT)体外抗肿瘤试验
按常规采用MTT评价了本发明化合物对5种人癌细胞株的抗增殖活性。MTT法已广泛用于大规模的抗肿瘤药物筛选、细胞毒性试验以及肿瘤放射敏感测定等。选择FTA作为阳性对照药。
人癌细胞株:肝癌细胞Hep G2、结肠癌细胞HCT116、肺癌细胞A549、乳腺癌细胞MCF-7、胃癌细胞SGC7901。
实验方法如下:取处于指数生长期状态良好的细胞一瓶,加入0.25%胰蛋白酶消化,使贴壁细胞脱落,制成每毫升含2×104~4×104个细胞的悬液。取细胞悬液接种于96孔板上,每孔180μL,置恒温CO2培养箱中培养24小时。换液,加入受试化合物Ⅰ、Ⅱ和Ⅲ(化合物用DMSO溶解后用PBS稀释,受试化合物浓度分别为2.5×10-5mol/L),每孔20μL,培养48小时。将MTT加入96孔板中,每孔20μL,培养箱中反应4小时。吸去上清液,加入DMSO,每孔150μL,平板摇床上振摇5分钟。用酶联免疫检测仪在波长为570nm处测定每孔的吸收度,计算细胞抑制率。实验结果如表3-4所示。
细胞抑制率=(阴性对照组OD值–受试物组OD值)/阴性对照组OD值×100%。
实施例37 Western blot检测活性较好的查尔酮衍生物对结肠癌HCT116细胞Ras下游信号通路中磷酸化c-Raf、ERK和Akt蛋白以及炎症NF-κb通路相关蛋白IKκB和p65表达的影响。
a.细胞处理:取处于对数生长期的细胞,用0.25%胰蛋白酶消化后调整细胞密度为106/ml接种于6孔培养板中,每孔1.0ml。
b.总蛋白提取及蛋白浓度测定:加入细胞蛋白裂解液及蛋白酶抑制剂提取总蛋白。以上均于冰浴中进行。4℃离心12000g,15min,吸出上清(细胞裂解液)。
c.BCA法测定总蛋白浓度。
d.SDS-PAGE和Western blot分析:分别使用测试蛋白对应一抗和二抗。
e.进行灰度扫描,PDQuest7.2.0软件分析结果。以β-actin作为内参,相同实验重复3次。
Claims (8)
1.一种法尼基硫醚取代的查尔酮衍生物,其特征是:是下列通式(I)、(Ⅱ)、(Ⅲ)所示的法尼基硫醚取代的查尔酮衍生物及其药学上可接受的盐:
通式Ⅱ中:
n=1~3;
Y为含氮的各类基团,可以为形式;
当Y基团为形式时,R1或R2可以分别独立地选自基团选自H,C1~C12的饱和或不饱和的烷基、环烷基或链烯基,带有O,N,S,卤素杂原子的C1~C12的饱和或不饱和的烷基、环烷基或链烯基,苯基,苄基,取代苯基,各种杂环基团;
当Y基团为形式时,可为饱和或不饱和的环状基团;其中R3可以分别独立地选自基团选自H,C1~C12的饱和或不饱和的烷基、环烷基或链烯基,带有O,N,S,卤素杂原子的C1~C12的饱和或不饱和的烷基、环烷基或链烯基,苯基,取代苯基,各种杂环基团;Z可以为O、S、NH或取代的N原子;
通式Ⅲ中:
n=0~1;
Y为含氮的各类基团,可以为形式;
当Y基团为形式时,R1或R2可以分别独立地选自基团选自H,C1~C12的饱和或不饱和的烷基或环烷基,带有O,N,S,卤素杂原子的C1~C12的饱和或不饱和的烷基或环烷基,及苯基、苄基、取代苯基或各种杂环基团;
当Y基团为形式时,可为饱和或不饱和的环状基团;其中R3可以分别独立地选自基团选自H,C1~C12的饱和或不饱和的烷基或环烷基,带有O,N,S,卤素杂原子的C1~C12的饱和或不饱和的烷基或环烷基,及苯基、取代苯基或各种杂环基团;Z可以为O,或S,或NH,或取代的N原子。
2.根据权利要求1所述的法尼基硫醚取代的查尔酮衍生物,其特征是:通式II中:
Y基团为形式时,Y基团为:-NH2、CH3NH-、CH3CH2NH-、CH3CH2CH2NH-、CH3CH2CH2CH2NH-、HOCH2CH2NH-、HOCH2CH2CH2NH-、CH3CH(CH2OH)NH-、HOCH2CH(CH2OH)NH-、[HOCH2(CHOH)CH2]CH3N-或(HOCH2CH2)2N-;
Y基团为形式时,Y基团是哌啶环、吡咯环、哌嗪环或吗啉环,或者是噻唑环、噁唑环、吡唑环、咪唑环、三氮唑环、四氮唑环、噁嗪环或噻嗪环。
3.根据权利要求1所述的法尼基硫醚取代的查尔酮衍生物,其特征是:通式III中:
Y基团为形式时,Y基团为:-NH2、CH3NH-、CH3CH2NH-、CH3CH2CH2NH-、HOCH2CH2NH-、HOCH2CH2CH2NH-、HOCH2CH(CH2OH)NH-、[HOCH2(CHOH)CH2]CH3N-或(HOCH2CH2)2N-;
Y基团为形式时,Y基团为哌啶环、吡咯环、哌嗪环、吗啉环,或者是噻唑环、噁唑环、吡唑环、咪唑环、三氮唑环或四氮唑环。
4.根据权利要求1所述的法尼基硫醚取代的查尔酮衍生物,其特征是:通式(I)中所示的法尼基硫醚取代的查尔酮衍生物为:
I:(E)-1-(4-羟苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
通式(Ⅱ)中所示的法尼基硫醚取代的查尔酮衍生物为下列化合物之一:
Ⅱ1:(E)-1-(4-(2-(二乙胺基)乙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅱ2:(E)-1-(4-(2-(1-哌啶基)乙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅱ3:(E)-1-(4-(2-(1-(4-甲哌嗪基))乙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅱ4:(E)-1-(4-(3-(1-吡咯烷)丙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅱ5:(E)-1-(4-(3-(双(2-羟乙基)氨基)丙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅱ6:(E)-1-(4-(3-(1-哌啶基)丙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅱ7:(E)-1-(4-(3-(1-吗啉基)丙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅱ8:(E)-1-(4-(3-(1-(4-甲哌嗪基))丙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅱ9:(E)-1-(4-(3-(4-羟甲基哌啶基)丙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅱ10:(E)-1-(4-(3-(N-(羟乙基(甲基))胺基)丙氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅱ11:(E)-1-(4-(4-(二乙胺基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅱ12:(E)-1-(4-(4-(二丙氨基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅱ13:(E)-1-(4-(4-(二丁氨基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅱ14:(E)-1-(4-(4-(1-吡咯烷)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅱ15:(E)-1-(4-(4-(1-哌啶基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅱ16:(E)-1-(4-(4-(1-吗啉基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅱ17:(E)-1-(4-(4-(双(2-羟乙基)氨基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅱ18:(E)-1-(4-(4-(1-(4-甲哌嗪基))丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅱ19:(E)-1-(4-(4-(1-(4-乙基哌嗪基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅱ20:(E)-1-(4-(4-(1-(4-羟基哌啶基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅱ21:(E)-1-(4-(4-(1-(4-苄基哌嗪基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅱ22:(E)-1-(4-(4-(1-(4-羟乙基哌嗪基))丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅱ23:(E)-1-(4-(4-(1-(4-叔丁氧羰基哌嗪基))丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅱ24:(E)-1-(4-(4-(1-哌嗪基)丁氧基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
通式(Ⅲ)所示的法尼基硫醚取代的新型查尔酮衍生物为下列化合物之一:
Ⅲ1:(E)-1-(4-(4-羟基-3-(二乙胺基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅲ2:(E)-1-(4-(4-羟基-3,5-二(二乙胺基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅲ3:(E)-1-(4-(4-羟基-3-(二羟乙胺基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅲ4:(E)-1-(4-(4-羟基-3,5-二(二羟乙胺基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅲ5:(E)-1-(4-(4-羟基-3-(N-(羟乙基(甲基))胺基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅲ6:(E)-1-(4-(4-羟基-3,5-二(N-(羟乙基(甲基))胺基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅲ7:(E)-1-(4-(4-羟基-3-(哌啶基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅲ8:(E)-1-(4-(4-羟基-3,5-二(哌啶基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅲ9:(E)-1-(4-(4-羟基-3-(吗啉基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅲ10:(E)-1-(4-(4-羟基-3,5-二(吗啉基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅲ11:(E)-1-(4-(4-羟基-3-(甲哌嗪基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅲ12:(E)-1-(4-(4-羟基-3,5-二(甲哌嗪基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅲ13:(E)-1-(4-(4-羟基-3-(对羟基哌啶-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅲ14:(E)-1-(4-(4-羟基-3,5-二(对羟基哌啶-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅲ15:(E)-1-(4-(4-羟基-3-((4-叔丁氧羰基哌嗪基)-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅲ16:(E)-1-(4-(4-羟基-3,5-二((4-叔丁氧羰基哌嗪基)-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅲ17:(E)-1-(4-(4-羟基-3-(哌嗪基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮;
Ⅲ18:(E)-1-(4-(4-羟基-3,5-二(哌嗪基-1-甲基)苯基)-3-(2-法尼基硫代苯基)丙-2-烯-1-酮。
5.一种法尼基硫醚取代的查尔酮衍生物制备方法,其特征是:包括下列步骤:
采用法尼基硫代水杨醛与对甲基苯乙酮在10%NaOH作用下生成目标化合物Ⅰ,合成路线如下所示:
6.一种法尼基硫醚取代的查尔酮衍生物制备方法,其特征是:包括下列步骤:
首先采用对羟基苯乙酮与不同链长的二溴烷烃反应得到O-溴烷基取代的对溴烷氧基苯乙酮,再与不同取代的仲胺反应得到中间体,再将中间体与法尼基硫代水杨醛反应得到目标化合物Ⅱ,合成路线为:
其中Y为含氮的各类基团,可以为形式。
7.一种法尼基硫醚取代的查尔酮衍生物制备方法,其特征是:包括下列步骤:
将通式Ⅰ化合物、37%甲醛和不同取代的仲胺进行mannish反应,得到目标化合物Ⅲa和Ⅲb,合成路线为:
其中Y为含氮的各类基团,可以为形式。
8.一种法尼基硫醚取代的查尔酮衍生物在制备治疗肿瘤和炎症药物中的应用;所述法尼基硫醚取代的查尔酮衍生物为通式Ⅰ、通式Ⅱ或通式Ⅲ化合物。
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