CN105753795A - 一种具有1,2,3-三氮唑结构片段的生物碱化合物及其用途 - Google Patents

一种具有1,2,3-三氮唑结构片段的生物碱化合物及其用途 Download PDF

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CN105753795A
CN105753795A CN201610281376.3A CN201610281376A CN105753795A CN 105753795 A CN105753795 A CN 105753795A CN 201610281376 A CN201610281376 A CN 201610281376A CN 105753795 A CN105753795 A CN 105753795A
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江成世
张华�
张娟
刘娜
李家诚
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University of Jinan
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Abstract

本发明公开了一种具有1,2,3?三氮唑结构片段的生物碱化合物及其用途。该类化合物具有如下所示结构通式:

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一种具有1,2,3-三氮唑结构片段的生物碱化合物及其用途
技术领域
本发明涉及一种具有1,2,3三氮唑结构片段的生物碱化合物及其在制备预防和/或治疗肿瘤、炎症、抗帕金森病及抗老年痴呆症的药物中的用途。
背景技术
氧化应激(oxidative stress)直接或者间接地损伤细胞内蛋白质、脂质、核酸等大分子物质的生理功能,被认为与超过200种疾病的发生有关,如肿瘤、炎症、帕金森病和老年痴呆症等。机体形成了一套复杂的氧化应激应答系统,当暴露于亲电试剂或者活性氧刺激时,能诱导出一系列的保护性蛋白,以缓解细胞所受的伤害。Nrf2 (核因子E2相关因子2)是细胞氧化应激反应中的关键因子,受Keap1 (Keleh样环氧氯丙烷相关蛋白-1)蛋白的调控(Free Radic. Biol. Med. 2004, 36, 1208; Genes Des. 1999, 13, 76),通过抗氧化反应原件ARE (antioxidant response element)相互作用,调节抗氧化蛋白和II相解毒酶的表达,如NAD(P)H:醌氧化还原酶(NAD(P)H:quinine oxidoreductase 1, NQO1),血红素加氧酶1(hemoxygenase-1, HO-1)等。
大量研究表明,在正常条件下Nrf2与其抑制蛋白Keap1结合,存在于细胞中。发生氧化应激时,Keap1的半胱氨酸残基被修饰,构象改变后导致Nrf2蛋白释放,进入细胞核中与ARE结合,促进靶基因的表达,从而发挥细胞保护作用。病理条件下,机体无法上Keap1-Nrf2解离。而Nrf2蛋白可以经泛素化降解,不能入核诱导抗氧化基因的表达,导致疾病的发生(Med. Res. Rev. 2012, 32, 687)。过去30多年中多个实验室开展了大量工作,从天然化合物(如sulforaphane,curcumin)或人工合成化合物库(如oltipraz,bardoxolonemethyl)中筛选Nrf2小分子激动剂,通过化学小分子模拟正常机体修饰Keap1的半胱氨酸残基的生物过程,释放Nrf2使其入核,发挥细胞保护作用。但令人遗憾的是,长时间使用共价结合修饰Keap1蛋白,持续激活Nrf2会引起较大的细胞毒性,易导致癌变发生。
近年来,设计直接抑制Keap1-Nrf2蛋白质相互作用的小分子成为了发现Keap1-Nrf2-ARE通路调节的一个新策略(Curr. Top. Med. Chem. 2007, 7, 972)。2006年Mark课题组解析了Keap1和一个Nrf2模拟肽端的晶体复合物,从而揭示了Nrf2与Keap1结合界面。基于此结构基础,Well和Hu两个课题组设计了一系列的多肽,然而肽类化合物的细胞渗透能力差致使细胞水平活性并不理想(Org. Biomol. Chem., 2013, 11, 3553; Bioorg.Med. Chem. Lett. 2013, 23, 3029)。因此,非肽类小分子Keap1-Nrf2结合抑制剂成为该领域研究热点,目前已有多个制药公司及高校都在开展此方面的研究,并报道了一系列Keap1-Nrf2相互作用的小分子直接抑制剂(Bioorg. Med. Chem. Lett., 2013, 23,3039; Medchemcomm., 2014, 5, 93; ChemMedChem., 2014, 9, 699; J. Med. Chem.,2014, 57, 1121; J. Med. Chem., 2016, DOI: 10.1021/acs.jmedchem.6b00228),在治疗肿瘤、炎症、抗帕金森病及抗老年痴呆症药物研发方面显示出极强的应用前景。
发明内容
本发明人经过对大量实验室合成化合物及其结构衍生物的筛选,发现了一类结构相对简单、对Keap1-Nrf2蛋白-蛋白相互作用具有一定的抑制活性的通式I所示的新化合物,由此可能对肿瘤、炎症、抗帕金森病及抗老年痴呆症具有预防和/或治疗作用,从而在制药领域具有潜在的用途。迄今为止,未见关于式I所示化合物的结构、制备方法及用途的报道。
本发明采用以下技术方案:
一种具有1,2,3-三氮唑结构片段的生物碱化合物,其特征在于,它具有如下通式I所示的结构:
其中,A为芳香环,具体为苯基、吡啶基、萘基、吲哚、喹啉、苯并呋喃、苯并吡喃或苯并吡喃酮;R1和R2为芳环上邻位、间位及对位取代基团,R1或R2可分别或同时为氢、甲基、甲氧基、乙基、乙氧基、丙基、丙氧基、异丙基、丁基、羟基、氨基、二甲氨基、氟、氯、溴、三氟甲基、三氟甲氧基、腈基、甲氧羰基、甲氧羰乙烯基、吗啉基、甲基哌嗪基或氨基磺酰基。
作为本发明的一种优选,所述A为苯基或萘基。
本发明还提供了一种上述的化合物在制备抗肿瘤、抗炎、抗帕金森病及抗老年痴呆症药物中的应用。
本发明还提供了一种用于预防和/或治疗肿瘤、炎症、抗帕金森病及抗老年痴呆症的药物组合物,它是由上述通式I所示的化合物为活性成分或主要活性成分,辅以药学上可接受的辅料制成。
本发明所涉及化合物的制备方法如下:
a) 卤代苯甲酸酯(式1)和三甲基硅乙炔在催化剂作用下经Sonogashira偶联反应得到式2化合物。其中,式1化合物为溴(碘)代苯甲酸及其甲酯、乙酯及丙酯,所述催化剂为四(三苯基膦)钯、二氯化钯、双(三环己基膦)二氯化钯、双(三苯基膦)二氯化钯(II)、醋酸钯、碘化亚铜、碳酸钾中至少一种;反应溶剂为N,N-二甲基甲酰胺、三乙胺、二异丙胺、二异丙基乙胺、四氢呋喃、甲醇及甲苯中至少一种;该反应温度为0 ℃~120 ℃,反应时间为1~12小时。
b) 式2化合物在碱催化作用下,脱去三甲基硅基并进行酯水解反应得到式3化合物。其中,所用碱为氢氧化钠、氢氧化钾或碳酸钾;该反应所用溶剂为甲醇、乙醇、乙腈、N,N-二甲基甲酰胺、四氢呋喃、1,4-二氧六环或水,该反应温度为0 ℃~120 ℃,反应时间为1~24小时。
c) 式3化合物与2-吗啡乙胺进行缩合得到式4所示的酰胺化合物。其中,所用缩合剂为N,N'-二环己基碳二亚胺(DCC)、N,N'-二异丙基碳二亚胺(DIC)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)、偶氮二甲酸二乙酯(DEAD)、偶氮二甲酸二异丙酯(DIAD)、1-羟基-7-偶氮苯并三氮唑(HOAT)、1-羟基苯并三氮唑(HOBT)、O-(7-氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(HBTU)、N-羟基丁二酰亚胺(NHS)、N,O-二甲基羟胺盐酸盐;该反应所用溶剂为N,N-二甲基甲(乙)酰胺、乙腈、1,4-二氧六环、二氯乙烷、三乙胺、N,N-二异丙基乙胺,该反应温度为0℃~120 ℃,反应时间为1~24小时。
d) 式4化合物与相应溴化物式5进行Click Chemistry反应得到通式I所示的结构衍生物。其中,Click Chemistry反应作用试剂为叠氮化钠、碘化亚铜、氯化亚铜、抗坏血酸钠、硫酸铜、醋酸铜、三苯基膦溴化亚铜、三苯基膦钯、双(三苯基膦)二氯化钯(II)、醋酸钯中至少一种;该反应所用溶剂为水、甲醇、乙醇、叔丁醇、二甲基亚砜、甲苯、N,N-二甲基甲(乙)酰胺、乙腈、二氯乙烷、N,N-二异丙基乙胺、四氢呋喃、1,4-二氧六环,该反应温度为0℃~120 ℃,反应时间为1~24小时。
反应流程如下式所示:
本发明的有益效果是:本发明的化合物为首次合成的具有全新结构的一类生物碱化合物,在对合成化合物体外模型测试实验中,首次发现该类化合物对Keap1-Nrf2蛋白-蛋白相互作用具有一定的抑制活性,因而它们在制备预防和/或治疗肿瘤、炎症、帕金森病及老年痴呆症的药物中具有潜在的应用前景。
具体实施方式
下面结合具体实施例对本发明做进一步的详细说明。
实施例1
式2-1化合物的制备
将5.0 g式1-1化合物和2.57 g三甲基硅乙炔溶于25 mL N,N-二甲基甲酰胺和5 mL三乙胺的混合溶液中,氮气保护,随后加入1.53 g四(三苯基膦)钯和0.4 g碘化亚铜,加热至50oC并在此温度下搅拌6小时。之后将反应液浓缩,乙酸乙酯/水萃取有机相。有机相依次用水、饱和食盐水洗涤,浓缩。残余物经柱层析纯化后得到3.90 g无色油状化合物式2-1,产率73%。1H NMR (400 MHz, CDCl3) δ 7.84 (1H, d, J = 9 Hz), 7.34 (1H, s), 7.31 (1H,d, J = 9 Hz), 3.88 (3H, s), 2.56 (3H, s), 0.25, (9H, s). 13C NMR (100 MHz,CDCl3) δ167.4, 140.2, 135.0, 130.5, 129.2, 129.0, 126.7, 104.1, 96.9, 51.9,21.5, 0.2.
实施例2
式3化合物的制备
将3.90 g式2-1化合物溶于50 mL甲醇中,冰浴至0oC,加入2.48 g 氢氧化钾。待反应进行2小时,加热升温使其回流4小时。反应液减压浓缩后,加入50 mL水,水相用乙酸乙酯萃取三次。之后用10% 盐酸溶液将水相酸化至pH~3,再用乙酸乙酯萃取三次,有机相依次用饱和碳酸氢钠、饱和食盐水、水洗涤,无水硫酸镁干燥。最后经过滤、有机相浓缩得到2.5 g淡黄色固体化合物式3,产率98%。可直接用于下一步反应。1H NMR (400 MHz, CDCl3) δ 8.03(1H, d, J = 8 Hz), 7.41 (1H, s), 7.39 (1H, d, J = 8 Hz), 3.22 (1H, s), 2.64(3H, s). 13C NMR (100 MHz, CDCl3) δ172.8, 141.4, 135.4, 131.5, 129.4, 128.3,126.8, 82.7, 79.9, 21.9.
实施例3
式4化合物的制备
将2.50 g式3化合物溶于30 mL二氯甲烷中,冰浴至0oC,随后加入2.33 g HOBT、4.1 mLN,N-二异丙基乙胺(DIEPA)和3.28 g EDCI。待反应进行0.5小时,加入4.06 g 与2-吗啡乙胺。反应搅拌过夜,有机相依次用饱和食盐水、水洗涤,无水硫酸镁干燥。过滤、浓缩得残余物。残余物经柱层析纯化后得到3.60 g白色固体化合物式4,产率85%。1H NMR (400 MHz,CDCl3) δ 7.32 (2H, d, J = 12 Hz), 7.31 (1H, s), 6.41 (1H, s), 3.68 (4H, dd, J= 4, 4 Hz), 3.51 (2H, m), 3.11 (1H, s), 2.36 (2H, t, J = 4 Hz), 2.47 (4H, m),2.41 (3H, s). 13C NMR (100 MHz, CDCl3) δ169.2, 136.7, 136.1, 134.5, 129.4,126.9, 123.6, 82.8, 78.3, 66.8, 56.9, 53.3, 35.9, 19.6. ESI-MS: 273.0 [M+H+]
实施例4
式I化合物的制备
将相应式5化合物(1.1 equiv)溶于4 mL二甲基亚砜中,加入24 mg叠氮化钠,室温搅拌1小时。之后加入4 mL水、29 mg抗坏血酸钠、100 mg式4化合物(1 equiv)和14 mg碘化亚铜,室温搅拌过夜。反应结束后,加入30 mL乙酸乙酯,依次用饱和食盐水、水洗涤。有机相用无水硫酸镁干燥,过滤、浓缩得残余物。残余物经柱层析纯化后得到相应的式I化合物。其式5中所示化合物,A为苯基、吡啶基、萘基、吲哚、喹啉、苯并呋喃、苯并吡喃或苯并吡喃酮;R1和R2为芳环上邻位、间位及对位取代基团,R1或R2可分别或同时为氢、甲基、甲氧基、乙基、乙氧基、丙基、丙氧基、异丙基、丁基、羟基、氨基、二甲氨基、氟、氯、溴、三氟甲基、三氟甲氧基、腈基、甲氧羰基、甲氧羰乙烯基、吗啉基、甲基哌嗪基或氨基磺酰基。
本发明按照上述方法具体还制备了一系列具有通式I所示结构的化合物,其化合物具体结构式及波谱数据如下所示:
白色固体(130 mg, 79%). 1H NMR (400 MHz, CDCl3) δ8.21 (2H, d, J = 8.0 Hz),7.80 (1H, s), 7.65 (1H, s), 7.60 (1H, d, J = 8.0 Hz), 7.43 (2H, d, J = 8.0Hz), 7.40 (2H, d, J = 8.0 Hz), 6.55 (1H, t, J = 4.0 Hz), 5.68 (2H, s), 3.67(O-CH2-×2, t, J = 4.0 Hz), 3.52 (2H, td, J = 4.0, 4.0 Hz), 2.57 (2H, t, J =4.0 Hz), 2.49 (N-CH2-×2, t, J = 4.0 Hz), 2.46 (3H, s). 13C NMR (100 MHz,CDCl3) δ169.5, 148.0, 147.7, 141.5, 136.7, 136.2, 131.4, 128.6, 128.1, 127.6,124.3, 123.0, 66.7, 57.0, 53.2, 53.1, 40.8, 35.9, 19.9. ESI-MS m/z: 451 [M+H]+.
白色固体(74 mg, 47%). 1H NMR (400 MHz, CDCl3) δ7.77 (1H, s), 7.67 (1H,s), 7.66 (2H, d, J = 8.0 Hz), 7.61 (1H, d, J = 8.0 Hz), 7.41 (1H, d, J = 8.0Hz), 7.37 (1H, d, J = 8.0 Hz), 6.41 (1H, t, J = 4.0 Hz), 5.64 (2H, s), 3.67(O-CH2-×2, t, J = 4.0 Hz), 3.52 (2H, td, J = 4.0, 4.0 Hz), 2.57 (2H, t, J =4.0 Hz), 2.47 (N-CH2-×2, -CH3, s). 13C NMR (100 MHz, CDCl3) δ169.4, 147.7,139.7, 136.7, 136.2, 132.9, 131.4, 128.3, 128.1, 127.6, 123.0, 120.1, 118.0,112.7, 66.9, 56.9, 53.4, 53.2, 35.9, 19.9. ESI-MS m/z: 431 [M+H]+.
白色固体(32 mg, 19%). 1H NMR (400 MHz, CDCl3) δ7.97 (2H, d, J = 8.0 Hz),7.78 (1H, s), 7.69 (1H, s), 7.64 (1H, d, J = 8.0 Hz), 7.49 (2H, d, J = 8.0Hz), 7.44 (2H, d, J = 8.0 Hz), 6.48 (1H, s), 5.69 (2H, s), 3.70 (O-CH2-×2,t, J = 4.0 Hz), 3.56 (2H, td, J = 4.0, 4.0 Hz), 2.63 (2H, t, J = 4.0 Hz),2.52 (N-CH2-×2, s), 2.49 (3H, s). 13C NMR (100 MHz, CDCl3) δ169.5, 148.0,147.7, 141.5, 136.7, 136.2, 131.4, 128.6, 128.1, 127.6, 124.3, 123.0, 66.7,57.0, 53.2, 53.1, 40.8, 35.9, 19.9. ESI-MS m/z: 483.9 [M+H]-.
白色固体(73 mg, 46%). 1H NMR (400 MHz, CDCl3) δ7.79 (1H, s), 7.64 (1H,s), 7.60 (1H, d, J = 8.0 Hz), 7.40-7.34 (2H, m), 7.98 (2H, m), 6.55 (1H, s),5.64 (2H, s), 3.67 (O-CH2-×2, t, J = 4.0 Hz), 3.50 (2H, td, J = 4.0, 4.0Hz), 2.54 (2H, t, J = 4.0 Hz), 2.48 (N-CH2-×2, s), 2.45 (3H, s). 13C NMR (100MHz, CDCl3) δ169.5, 162.6, 160.0, 147.1, 136.6, 135.9, 131.7, 128.0, 127.5,122.9, 119.9, 1117, 110.6, 66.7, 57.0, 53.2, 41.4, 35.9, 19.9. ESI-MS m/z:442 [M+H]+.
白色固体(93 mg, 61%). 1H NMR (400 MHz, CDCl3) δ7.65 (1H, s), 7.61 (1H,s),7.55 (1H, d, J = 8.0 Hz), 7.37 (1H, d, J = 8.0 Hz), 7.16 (4H, m), 6.60(1H, t, J = 4.0 Hz), 5.47 (2H, s), 3.66 (O-CH2-×2, t, J = 4.0 Hz), 3.49 (2H,td, J = 4.0, 4.0 Hz), 2.54 (2H, t, J = 4.0 Hz), 2.45 (N-CH2-×2, s), 2.42(3H, s), 2.31 (3H, s). 13C NMR (100 MHz, CDCl3) δ169.5, 147.1, 138.7, 136.5,135.8, 131.7, 131.3, 129.7, 127.9, 127.5, 122.8, 119.8, 66.7, 56.9, 53.9,53.2, 35.8, 21.0, 19.9. ESI-MS m/z: 420 [M+H]+.
白色固体(121 mg, 68%). 1H NMR (400 MHz, CDCl3) δ7.70 (1H, s), 7.62 (1H,s),7.56 (1H, d, J = 8.0 Hz), 7.47 (2H, d, J = 8.0 Hz), 7.37 (1H, d, J = 8.0Hz), 7.15 (2H, d, J = 8.0 Hz), 6.60 (1H, s), 5.49 (2H, s), 3.66 (O-CH2-×2,s), 3.50 (2H, td, J = 4.0, 4.0 Hz), 2.47 (N-CH2-×2, s), 2.43 (3H, s). 13C NMR(100 MHz, CDCl3) δ169.5, 147.3, 141.0, 136.6, 136.0, 133.4, 132.2, 131.6,129.6, 128.0, 127.5, 122.8, 119.9, 66.7, 56.9, 53.4, 53.2, 35.8, 19.9. ESI-MSm/z: 486 [M+H]+.
白色固体(75 mg, 43%). 1H NMR (400 MHz, CDCl3) δ7.74 (1H, s), 7.73 (1H, d,J = 8.0 Hz), 7.67 (1H, s), 7.61 (2H, d, J = 8.0 Hz), 7.53 (1H, dd, J = 8.0,8.0 Hz), 7.46 (1H, dd, J = 8.0, 8.0 Hz), 7.40 (1H, d, J = 8.0 Hz), 7.24 (1H,d, J = 8.0 Hz), 6.47 (1H, s), 5.77 (2H, s), 3.67 (O-CH2-×2, J = 4.0 Hz),3.52 (2H, td, J = 4.0, 4.0 Hz), 2.58 (2H, t, J = 4.0 Hz), 2.48 (N-CH2-×2,s), 2.47 (3H, s). 13C NMR (100 MHz, CDCl3) δ169.5, 147.5, 136.7, 136.1, 133.0,132.7, 131.6, 130.0, 128.8, 128.1, 127.6, 126.2, 125.4, 122.9, 122.7, 120.3,66.8, 56.9, 53.2, 50.1, 35.9, 19.9. ESI-MS m/z: 474.3 [M+H]+.
白色固体(123 mg, 72%). 1H NMR (400 MHz, CDCl3) δ8.05 (1H, dd, J = 4.0,4.0 Hz), 7.87 (1H, s), 7.60 (1H, s), 7.53 (1H, d, J = 8.0 Hz), 7.35 (1H, d, J= 8.0 Hz), 7.30 (1H, d, J = 8.0 Hz), 6.58 (1H, s), 5.61 (2H, s), 3.66 (O-CH2-×2, t, J = 4.0 Hz), 3.52 (2H, td, J = 4.0, 4.0 Hz), 2.58 (2H, t, J = 4.0Hz), 2.49 (N-CH2-×2, s), 2.41 (3H, s). 13C NMR (100 MHz, CDCl3) δ169.4,156.7, 154.0, 136.6, 136.2, 135.1, 135.0, 131.9, 131.8, 131.3, 128.0, 127.5,125.6, 122.9, 120.2, 119.5, 119.3, 66.7, 56.9, 53.2, 52.4, 35.9, 21.0, 19.8.ESI-MS m/z: 469.2 [M+H]+.
白色固体(124 mg, 79%). 1H NMR (400 MHz, CDCl3) δ7.92 (1H, s), 7.68 (1H,d, J = 8.0 Hz), 7.62 (1H, s), 7.58 (1H, d, J = 8.0 Hz), 7.56 (1H, d, J = 4.0Hz), 7.44 (1H, dd, J = 4.0, 8.0 Hz), 7.35 (1H, dd, J = 4.0, 8.0 Hz), 6.63(1H, t, J = 4.0 Hz), 5.74 (2H, s), 3.63 (O-CH3, s), 3.48 (O-CH2-×2, t, J =4.0 Hz), 3.52 (2H, td, J = 4.0, 4.0 Hz), 2.44 (N-CH2-×2, s), 2.42 (3H, s).13C NMR (100 MHz, CDCl3) δ169.5, 147.3, 137.8, 136.5, 136.1, 133.6, 133.0,131.3, 129.5, 129.3, 127.9, 127.5, 122.8, 120.5, 116.9, 111.6, 66.7, 56.9,53.1, 51.7, 35.8, 19.8. ESI-MS m/z: 431.3 [M+H]+.
白色固体(50.6 mg, 30%). 1H NMR (400 MHz, CDCl3) δ7.80 (1H, s), 7.66 (1H,s), 7.61 (1H, d, J = 8.0 Hz), 7.48 (1H, d, J = 8.0 Hz), 7.40 (1H, d, J = 8.0Hz), 6.78-6.74 (2H, m), 6.54 (1H, t, J = 4.0 Hz), 5.63 (2H, s), 3.71 (O-CH3,s), 3.67 (O-CH2-×2, t, J = 4.0 Hz), 3.52 (2H, td, J = 4.0, 4.0 Hz), 2.57(2H, t, J = 4.0 Hz), 2.47 (N-CH2-×2, s), 2.46 (3H, s). 13C NMR (100 MHz,CDCl3) δ169.5, 159.4, 147.2, 136.6, 136.0, 134.7, 133.8, 131.7, 128.0, 127.6,122.9, 120.1, 116.2, 115.9, 113.5, 66.7, 57.0, 55.5, 53.9, 53.2, 35.9, 19.9.ESI-MS m/z: 514.2, 515.2, 516.2 [M+H]+.
白色固体(94.9 mg, 59%). 1H NMR (400 MHz, CDCl3) δ7.78 (1H, s), 7.63 (1H,s), 7.58 (1H, dd, J = 4.0, 4.0 Hz), 7.38 (1H, d, J = 8.0 Hz), 7.34-7.28 (1H,m), 6.90-6.83 (1H, m), 6.58 (1H, s), 5.55 (2H, s), 3.56 (O-CH2-×2, t, J =4.0 Hz), 3.50 (2H, td, J = 4.0, 4.0 Hz), 2.55 (2H, t, J = 4.0 Hz), 2.46 (N-CH2-×2, s), 2.44 (3H, s). 13C NMR (100 MHz, CDCl3) δ169.4, 164.3, 162.0,199.5, 147.3, 136.6, 136.0, 131.6, 131.5, 128.0, 127.5, 122.9, 119.9, 117.8,112.2, 104.3, 66.7, 56.9, 53.2, 47.1, 35.8, 19.8. ESI-MS m/z: 442.9 [M+H]+.
白色固体(129 mg, 70%). 1H NMR (400 MHz, CDCl3) δ7.78 (1H, s), 7.78 (1H,s), 7.65 (1H, s), 7.60 (1H, d, J = 8.0 Hz), 7.40 (1H, d, J = 8.0 Hz), 7.31-7.28 (2H, m), 7.18 (1H, dd, J = 8.0, 8.0 Hz), 6.48 (1H, t, J = 4.0 Hz), 5.56(2H, s), 3.66 (O-CH2-×2, t, J = 4.0 Hz), 3.50 (2H, td, J = 4.0, 4.0 Hz),2.56 (2H, t, J = 4.0 Hz), 2.47 (N-CH2-×2, s), 2.46 (3H, s). 13C NMR (100 MHz,CDCl3) δ169.5, 161.4, 158.9, 147.4, 136.6, 136.0, 131.6, 131.5, 128.2, 128.0,127.6, 123.6, 122.9, 121.0, 120.0, 119.6, 119.4, 66.8, 57.0, 53.2, 53.1,47.2, 35.9, 19.9. ESI-MS m/z: 502.2, 502.4 [M+H]-.
白色固体(32 mg, 19%). 1H NMR (400 MHz, CDCl3) δ7.97 (2H, d, J = 8.0 Hz),7.78 (1H, s), 7.69 (1H, s), 7.64 (1H, d, J = 8.0 Hz), 7.49 (2H, d, J = 8.0Hz), 7.44 (2H, d, J = 8.0 Hz), 6.48 (1H, s), 5.69 (2H, s), 3.70 (O-CH2-×2,t, J = 4.0 Hz), 3.56 (2H, td, J = 4.0, 4.0 Hz), 2.63 (2H, t, J = 4.0 Hz),2.52 (N-CH2-×2, s), 2.49 (3H, s). 13C NMR (100 MHz, CDCl3) δ169.5, 148.0,147.7, 141.5, 136.7, 136.2, 131.4, 128.6, 128.1, 127.6, 124.3, 123.0, 66.7,57.0, 53.2, 53.1, 40.8, 35.9, 19.9. ESI-MS m/z: 483.9 [M+H]-.
白色固体(94 mg, 58%). 1H NMR (400 MHz, CDCl3) δ7.75 (1H, s), 7.62 (1H,s), 7.57 (1H, dd, J = 4.0, 4.0 Hz), 7.37 (1H, d, J = 8.0 Hz), 7.18-7.09 (2H,m), 7.04 (1H, m), 6.62 (1H, s), 5.49 (2H, s), 3.66 (O-CH2-×2, t, J = 4.0Hz), 3.50 (2H, td, J = 4.0, 4.0 Hz), 2.57 (2H, t, J = 4.0 Hz), 2.48 (N-CH2-×2, s), 2.43 (3H, s). 13C NMR (100 MHz, CDCl3) δ169.5, 151.7, 149.2, 147.5,136.6, 136.1, 131.5, 131.5, 128.0, 127.5, 124.2, 122.9, 119.9, 118.0, 117.2,66.6, 57.0, 53.2, 53.0, 35.8, 19.8. ESI-MS m/z: 442.2 [M+H]+.
白色固体(71 mg, 40%). 1H NMR (400 MHz, CDCl3) δ7.75 (1H, s), 7.70 (1H,s),7.65 (1H, d, J = 8.0 Hz), 7.50 (2H, d, J = 4.0 Hz), 7.48 (1H,s), 7.30-7.24(2H, m), 6.50 (1H, s), 5.56 (2H, s), 3.71 (O-CH2-×2, s), 3.56 (2H, td, J =4.0, 4.0 Hz), 2.50 (2H, t, J = 4.0 Hz), 2.51 (N-CH2-×2+-CH3, s). 13C NMR (100MHz, CDCl3) δ169.5, 147.5, 136.7, 136.6, 136.1, 132.0, 131.6, 131.0, 130.7,128.1, 127.6, 126.6, 123.1, 123.0, 119.9, 66.8, 57.0, 53.4, 53.2, 35.9, 19.9.ESI-MS m/z: 484.3, 486.1 [M+H]+.
白色固体(128 mg, 64%). 1H NMR (400 MHz, CDCl3) δ7.87 (1H, s), 7.84 (1H,s), 7.76 (2H, s), 7.65 (1H, s), 7.60 (1H, d, J = 8.0 Hz), 7.39 (1H, d, J =8.0 Hz), 6.56 (1H, s), 5.69 (2H, s), 3.65 (O-CH2-×2, t, J = 4.0 Hz), 3.50(2H, td, J = 4.0, 4.0 Hz), 2.55 (2H, t, J = 4.0 Hz), 2.45 (N-CH2-×2, s),2.44 (3H, s). 13C NMR (100 MHz, CDCl3) δ169.4, 147.7, 137.2, 136.6, 136.3,133.0, 132.6, 132.3, 132.0, 131.3, 128.1, 127.6, 126.8, 124.1, 123.0, 122.7,121.4, 120.2, 66.8, 57.0, 53.2, 52.9, 35.9, 19.8. ESI-MS m/z: 542.3 [M+H]+.
白色固体(98 mg, 61%). 1H NMR (400 MHz, CDCl3) δ7.61 (1H, s), 7.57 (1H, d,J = 8.0 Hz), 7.56 (1H, s), 7.18 (1H, m), 6.93-6.87 (2H, m), 6.56 (1H, s),5.50 (2H, s), 3.65 (O-CH2-×2, t, J = 4.0 Hz), 3.50 (2H, td, J = 4.0, 4.0Hz), 2.55 (2H, t, J = 4.0 Hz), 2.46 (N-CH2-×2, s), 2.43 (3H, s), 2.26 (3H,s). 13C NMR (100 MHz, CDCl3) δ169.5, 164.0, 162.5, 147.1, 139.6, 136.6, 135.9,131.6, 131.2, 128.2, 127.9, 127.5, 122.8, 119.5, 117.9, 113.4, 66.7, 56.9,53.2, 51.7, 35.9, 19.8, 19.1. ESI-MS m/z: 438.3 [M+H]+.
白色固体(75 mg, 43%). 1H NMR (400 MHz, CDCl3) δ7.74 (1H, s), 7.73 (1H, d,J = 8.0 Hz), 7.67 (1H, s), 7.61 (2H, d, J = 8.0 Hz), 7.53 (1H, dd, J = 8.0,8.0 Hz), 7.46 (1H, dd, J = 8.0, 8.0 Hz), 7.40 (1H, d, J = 8.0 Hz), 7.24 (1H,d, J = 8.0 Hz), 6.47 (1H, s), 5.77 (2H, s), 3.67 (O-CH2-×2, J = 4.0 Hz),3.52 (2H, td, J = 4.0, 4.0 Hz), 2.58 (2H, t, J = 4.0 Hz), 2.48 (N-CH2-×2,s), 2.47 (3H, s). 13C NMR (100 MHz, CDCl3) δ169.5, 147.5, 136.7, 136.1, 133.0,132.7, 131.6, 130.0, 128.8, 128.1, 127.6, 126.2, 125.4, 122.9, 122.7, 120.3,66.8, 56.9, 53.2, 50.1, 35.9, 19.9. ESI-MS m/z: 474.3 [M+H]+.
白色固体(71 mg, 39%). 1H NMR (400 MHz, CDCl3) δ7.75 (1H, m), 7.64 (1H,s), 7.59 (1H, d, J = 8.0 Hz), 7.53 (1H, dd, J = 4.0, 8.0 Hz), 7.39 (1H, d, J= 8.0 Hz), 7.05 (1H, dd, J = 4.0, 8.0 Hz), 6.96 (1H, dd, J = 4.0, 8.0 Hz),6.53 (1H, t, J = 4.0 Hz), 5.51 (2H, s), 3.66 (O-CH2-×2, t, J = 4.0 Hz), 3.51(2H, td, J = 4.0, 4.0 Hz), 2.56 (2H, t, J = 4.0 Hz), 2.46 (N-CH2-×2, s),2.45 (3H, s). 13C NMR (100 MHz, CDCl3) δ169.5, 160.4, 157.9, 147.5, 136.6,136.1, 126.0, 134.2, 128.0, 127.6, 124.6, 122.9, 120.0, 116.2, 109.6, 66.8,57.0, 53.2, 53.0, 35.9, 19.9. ESI-MS m/z: 502.3, 504.1 [M+H]+.
白色固体(87 mg, 52%). 1H NMR (400 MHz, CDCl3) δ7.97 (1H, m), 7.91-7.87(2H, m), 7.57 (1H, s), 7.54-7.46 (6H, m), 7.43 (1H, d, J = 8.0 Hz), 6.51 (1H,t, J = 4.0 Hz), 5.99 (2H, s), 3.64 (O-CH2-×2, t, J = 4.0 Hz), 3.47 (2H, td,J = 4.0, 4.0 Hz), 2.53 (2H, t, J = 4.0 Hz), 2.45 (N-CH2-×2, s), 2.40 (3H,s). 13C NMR (100 MHz, CDCl3) δ169.5, 140.7, 136.5, 135.9, 133.8, 131.7, 131.1,131.1, 130.1, 129.6, 128.9, 127.9, 127.9, 127.5, 127.3, 126.3, 122.8, 122.8,119.8, 66.7, 57.0, 53.2, 52.4, 35.9, 19.8. ESI-MS m/z: 456.3 [M+H]+.
白色固体(105 mg, 57%). 1H NMR (400 MHz, CDCl3) δ7.79 (1H, s), 7.64 (1H,s), 7.59 (1H, d, J = 4.0), 7.38 (1H, d, J = 8.0 Hz), 7.34 (1H, dd, J = 4.0,4.0 Hz), 7.22 (1H, dd, J = 8.0, 8.0 Hz), 7.01 (1H, td, J = 4.0, 8.0 Hz), 6.58(1H, t, J = 4.0 Hz), 5.63 (2H, s), 3.56 (O-CH2-×2, t, J = 4.0 Hz), 3.50 (2H,td, J = 4.0, 4.0 Hz), 2.55 (2H, t, J = 4.0 Hz), 2.45 (N-CH2-×2, s), 2.44(3H, s). 13C NMR (100 MHz, CDCl3) δ169.5, 163.6, 161.0, 147.2, 136.6, 136.0,131.6, 131.5, 130.0, 128.0, 127.5, 123.7, 122.9, 120.6, 120.1, 115.6, 66.7,56.9, 53.2, 50.3, 35.9, 19.8. ESI-MS m/z: 502.2, 504.1 [M+H]+.
白色固体(50 mg, 28%). 1H NMR (400 MHz, CDCl3) δ7.71 (1H, s), 7.68 (1H,s), 7.66 (1H, d, J = 16.0 Hz), 7.62 (1H, d, J = 8.0 Hz), 7.54 (1H, d, J = 8.0Hz), 7.40 (1H, d, J = 8.0 Hz), 7.32 (2H, d, J = 8.0 Hz), 6.64 (1H, d, J =16.0 Hz), 6.64 (1H, s), 5.59 (2H, s), 3.80 (3H, s), 3.69 (O-CH2-×2, d, J =4.0 Hz), 3.52 (2H, dd, J = 4.0, 4.0 Hz), 2.58 (2H, d, J = 4.0 Hz), 2.49 (N-CH2-×2, s), 2.48 (3H, s). 13C NMR (100 MHz, CDCl3) δ169.5, 167.1, 147.5,143.6, 139.7, 136.5, 136.1, 135.0, 131.8, 128.7, 128.5, 128.2, 127.6, 123.0,119.9, 118.9, 66.9, 57.0, 53.8, 53.3, 35.9, 20.0. ESI-MS m/z: 490.3 [M+H]+.
白色固体(102 mg, 66%). 1H NMR (400 MHz, CDCl3) δ7.73 (1H, s), 7.64 (1H,d, J = 4.0 Hz), 7.62 (1H, dd, J = 4.0, 4.0 Hz), 7.44 (1H, dd, J = 4.0, 4.0Hz), 7.34 (1H, m), 7.15 (2H, d, J = 8.0 Hz), 6.53 (1H, d, J = 4.0 Hz), 5.54(2H, s), 3.68 (O-CH2-×2, s), 3.52 (2H, m), 2.47 (7H, m). 13C NMR (100 MHz,CDCl3) δ169.5, 164.2, 161.7, 147.4, 136.9, 136.7, 136.0, 131.6, 130.8, 128.1,127.6, 123.5, 122.9, 120.0, 115.9, 115.1, 66.8, 57.9, 53.5, 53.2, 35.9, 19.9.ESI-MS m/z: 424.5 [M+H]+.
白色固体(114 mg, 64%). 1H NMR (400 MHz, CDCl3) δ7.79 (1H, s), 7.65 (1H,s), 7.60 (2H, d, J = 8.0 Hz), 7.39 (1H, d, J = 8.0 Hz), 7.29 (1H, dd, J =8.0, 8.0 Hz), 7.23-7.17 (2H, m), 6.59 (1H, s), 5.67 (2H, s), 3.71 (O-CH2-×2,t, J = 4.0 Hz), 3.51 (2H, td, J = 4.0, 4.0 Hz), 2.48 (4H, s), 2.45 (3H, s).13C NMR (100 MHz, CDCl3) δ169.5, 147.1, 136.6, 135.9, 133.9, 133.2, 131.7,130.4, 130.3, 128.2, 128.0, 127.6, 123.4, 122.9, 120.2, 66.7, 56.9, 53.8,53.2, 35.8, 19.9. ESI-MS m/z: 484.2, 486.1 [M+H]+.
白色固体(153 mg, 98%). 1H NMR (400 MHz, CDCl3) δ7.68 (1H, s), 7.66 (1H,s), 7.61 (1H, d, J = 8.0 Hz), 7.41 (1H, d, J = 8.0Hz), 7.32-7.28 (2H, m),7.09-7.05 (2H, m), 6.47 (1H, t, J = 4.0 Hz), 5.74 (2H, s), 3.68 (O-CH2-×2, J= 4.0 Hz), 3.53 (2H, td, J = 4.0, 4.0 Hz), 2.57 (2H, t, J = 4.0 Hz), 2.47 (N-CH2-×2, -CH3, s),. 13C NMR (100 MHz, CDCl3) δ169.5, 164.1, 161.6, 147.5,136.7, 136.0, 131.7, 130.3, 130.0, 128.1, 127.6, 122.9, 119.8, 116.3, 66.8,57.0, 53.3, 50.6, 35.9, 19.9. ESI-MS m/z: 424.3 [M+H]+.
白色固体(157 mg, 94%). 1H NMR (400 MHz, CDCl3) δ7.84-7.79 (3H, m), 7.76(1H, s), 7.70 (1H, s), 7.63 (1H, s), 7.57 (1H, d, J = 8.0 Hz), 7.50-7.48 (2H,m), 7.38-7.34 (2H, m), 6.51 (1H, s), 5.69 (2H, s), 3.65 (O-CH2-×2, t, J =4.0 Hz), 3.50 (2H, td, J = 4.0, 4.0 Hz), 2.54 (2H, t, J = 4.0 Hz), 2.45 (N-CH2-×2, s), 2.43 (3H, s). 13C NMR (100 MHz, CDCl3) δ169.5, 147.2, 136.5,135.9, 131.7, 131.7, 129.1, 128.0, 127.8, 127.7, 127.5, 127.4, 126.3, 122.8,120.0, 66.7, 56.9, 54.4, 53.2, 35.9, 19.8. ESI-MS m/z: 456.3 [M+H]+.
白色固体(123 mg, 79%). 1H NMR (400 MHz, CDCl3) δ7.77 (1H, s), 7.62 (1H,s), 7.57 (1H, d, J = 4.0 Hz), 7.34 (1H, d, J = 4.0 Hz), 7.31 (1H, m), 7.25(1H, m), 7.13-7.06 (2H, m), 6.61 (1H, d, J = 4.0 Hz), 5.58 (2H, s), 3.64 (O-CH2-×2, s), 3.48 (2H, dd, J = 4.0, 4.0 Hz), 2.35 (2H, d, J = 4.0 Hz), 2.44(4H, s), 2.42 (3H, s). 13C NMR (100 MHz, CDCl3) δ169.5, 161.6, 159.2, 147.2,136.5, 136.0, 131.6, 130.9, 130.5, 127.9, 127.5, 124.8, 121.7, 120.0, 115.9,66.7, 57.0, 53.2, 47.7, 35.9, 19.8. ESI-MS m/z: 424.2 [M+H]+.
白色固体(132 mg, 83%). 1H NMR (400 MHz, CDCl3) δ7.67 (1H, s), 7.60 (1H,s), 7.54 (1H, d, J = 8.0 Hz), 7.34 (1H, d, J = 8.0 Hz), 6.92 (1H, s), 6.86(2H, s), 6.64 (1H, t, J = 4.0 Hz), 5.41 (2H, s), 3.62 (O-CH2-×2, t, J = 4.0Hz), 3.46 (2H, td, J = 4.0, 4.0 Hz), 2.50 (2H, t, J = 4.0 Hz), 2.42 (N-CH2-×2, s), 2.40 (3H, s), 2.23 (6H, s). 13C NMR (100 MHz, CDCl3) δ169.5, 147.0,138.6, 136.4, 135.8, 134.1, 131.7, 130.2, 127.8, 127.4, 125.7, 122.7, 119.9,66.6, 56.9, 54.0, 53.1, 35.8, 21.0, 19.7. ESI-MS m/z: 434.3 [M+H]+.
白色固体(116 mg, 72%). 1H NMR (400 MHz, CDCl3) δ7.74 (1H, s), 7.63 (1H,s), 7.57 (1H, d, J = 8.0 Hz), 7.37 (1H, d, J = 8.0 Hz), 7.29-7.25 (3H, m),7.15 (1H, d, J = 4.0 Hz), 6.61 (1H, s), 5.50 (2H, s), 3.63 (O-CH2-×2, t, J =4.0 Hz), 3.49 (2H, td, J = 4.0, 4.0 Hz), 2.54 (1H, d, J = 4.0 Hz), 2.45 (4H,s), 2.42 (3H, s). 13C NMR (100 MHz, CDCl3) δ169.5, 147.3, 136.5, 136.4, 136.0,134.8, 131.5, 130.3, 128.9, 127.9, 127.5, 126.0, 122.8, 120.2, 66.7, 56.9,53.4, 53.1, 35.8, 19.8. ESI-MS m/z: 440.3 [M+H]+.
白色固体(94 mg, 56%). 1H NMR (400 MHz, CDCl3) δ7.78 (1H, s), 7.64 (1H,s), 7.59 (1H, d, J = 8.0 Hz), 7.41 (1H, d, J = 8.0 Hz), 7.38 (1H, d, J = 8.0Hz), 7.31-7.20 (3H, m), 6.57 (1H, s), 5.67 (2H, s), 3.65 (O-CH2-×2, t, J =4.0 Hz), 3.50 (2H, td, J = 4.0, 4.0 Hz), 2.54 (1H, d, J = 4.0 Hz), 2.44 (N-CH2-×2,-CH3, s). 13C NMR (100 MHz, CDCl3) δ169.5, 147.1, 136.6, 136.0, 133.4,132.2, 131.7, 130.3, 130.2, 129.9, 128.0, 127.6, 127.5, 122.9, 120.2, 66.7,57.0, 53.2, 51.4, 35.9, 19.8. ESI-MS m/z: 440.3 [M+H]+.
白色固体(101 mg, 56%). δ7.73 (1H, s), 7.63 (1H, s), 7.58 (1H, d, J = 8.0Hz), 7.38 (1H, d, J = 8.0 Hz), 7.32 (2H, d, J =8.0 Hz), 7.20 (2H, d, J = 8.0Hz), 6.60 (1H, s), 5.55 (2H, s), 3.66 (O-CH2-×2, J = 4.0 Hz), 3.52 (2H, td,J = 4.0, 4.0 Hz), 2.58 (2H, t, J = 4.0 Hz), 2.48 (N-CH2-×2, s), 2.44 (3H,s). 13C NMR (100 MHz, CDCl3) δ169.5, 149.3, 147.4, 136.6, 136.0, 133.2, 131.6,129.5, 128.0, 127.6, 122.9, 121.5, 119,9, 118.9, 66.6, 56.9, 53.2, 53.2,35.8, 19.9. ESI-MS m/z: 490.3 [M+H]+.
白色固体(142 mg, 85%). 1H NMR (400 MHz, CDCl3) δ7.77 (1H, s), 7.63 (1H,s), 7.59 (1H, d, J = 8.0 Hz), 7.38 (1H, d, J = 8.0 Hz), 7.24 (1H, dd, J =4.0, 4.0 Hz), 7.16 (1H, dd, J = 4.0, 4.0 Hz), 6.97 (1H, m), 6.59 (1H, t, J =4.0 Hz), 5.62 (2H, s), 3.64 (O-CH2-×2, t, J = 4.0 Hz), 3.50 (2H, td, J =4.0, 4.0 Hz), 2.54 (2H, t, J = 4.0 Hz), 2.45 (N-CH2-×2, s), 2.43 (3H, s). 13CNMR (100 MHz, CDCl3) δ169.5, 163.7, 161.2, 147.2, 136.6, 136.0, 134.3, 131.7,131.5, 128.3, 128.0, 127.5, 122.9, 120.1, 117.4, 115.0, 66.7, 56.9, 53.2,50.7, 35.8, 19.8. ESI-MS m/z: 458.3 [M+H]+.
测试例
荧光偏振法测定化合物对Keap1-Nrf2蛋白结合抑制活性
荧光偏振法测定Keap1-Nrf2蛋白结合抑制活性将荧光探针(FITC–βAla–DEETGEF–OH)溶解于缓冲液(10 mM HEPES, pH 7.4, 3.4 mM EDTA, 150 mMNaCl, 0.005% Tween-20)稀释至10 nM,加入到梯度稀释的Keap1蛋白中,室温避光孵育30分钟,荧光各向异性值用SpectraMax M5e酶标仪读取(ex: 485nm, em: 535 nm)。蛋白结合常数根据荧光各向异性值用Mathematica 7 (Wolfram Research Inc.)拟合得到。具体公式如下:
实验对待测化合物进行单浓度(100μM),以化合物S47作为对照化合物,抑制率为
将化合物溶解于DMSO用缓冲液(10 mM HEPES, pH 7.4, 3.4 mM EDTA, 150 mMNaCl, 0.005% Tween–20)稀释至需要浓度(1%DMSO),20 μL化合物加入到60 μL含有10 nM荧光探针(FITC–βAla–DEETGEF–OH),400 nM的Keap1蛋白的溶液中,室温避光孵育1小时。荧光各向异性值用Bioteck Synergy 2酶标仪读取(ex: 485nm, em: 535 nm)。蛋白结合常数根据荧光各向异性值用Mathematica 7(Wolfram Research Inc.)拟合得到。具体公式如下:
;和
公式中,Q值是荧光探针的与最高蛋白浓度下结合后的荧光强度和自由状态的荧光强度的比值,FSB为荧光探针结合部分,AB和AF分别为结合和自由状态下的探针的各向异性值,KD1是探针的蛋白结合常数), LST为探针浓度,RT为蛋白浓度,KD2为化合物的蛋白结合抑制常数。具体结果如下表1所示。
表1化合物对Keap1-Nrf2蛋白结合抑制活性结果
上述结果表明,所合成的该1,2,3-三氮唑类化合物在100 μM浓度下对Keap1-Nrf2蛋白相互作用具有一定的抑制作用,可为新型Keap-Nrf2相互作用抑制剂或分子探针的研制提供新颖的分子结构骨架。
因而,本发明所制备的一类具有1,2,3-三氮唑结构片段的生物碱化合物在制备抗肿瘤、抗炎、抗帕金森病及抗老年痴呆症药物中具有广阔的应用前景。本发明所述的一系列化合物作为活性成分再添加常规药剂学辅料制备出预防和/或治疗肿瘤、炎症、抗帕金森病及抗老年痴呆症的药物,可制备成常规药剂学上的片剂、颗粒剂、胶囊剂、口服液等任一种剂型。
以上以具体的实施例来举例说明本发明化合物的制备步骤、鉴定过程和药理实验过程,但对本领域的技术人员来说可以对此作出多种修改和变化,在不背离本发明的精神和范围的情况下,所附的权利要求书覆盖本发明范围内的所有这些修改。

Claims (4)

1.一种具有1,2,3-三氮唑结构片段的生物碱化合物,其特征在于,它具有如下通式I所示的结构:
其中,A为芳香环,具体为苯基、吡啶基、萘基、吲哚、喹啉、苯并呋喃、苯并吡喃或苯并吡喃酮;R1和R2为芳环上邻位、间位及对位取代基团,R1或R2可分别或同时为氢、甲基、甲氧基、乙基、乙氧基、丙基、丙氧基、异丙基、丁基、羟基、氨基、二甲氨基、氟、氯、溴、三氟甲基、三氟甲氧基、腈基、甲氧羰基、甲氧羰乙烯基、吗啉基、甲基哌嗪基或氨基磺酰基。
2.根据权利要求1所述的化合物,其特征在于,所述A为苯基或萘基。
3.一种权利要求1或2所述的化合物在制备抗肿瘤、抗炎、抗帕金森病及抗老年痴呆症药物中的应用。
4.一种用于预防和/或治疗肿瘤、炎症、抗帕金森病及抗老年痴呆症的药物组合物,其特征在于,它是以权利要求1-2中任一项所述的化合物为活性成分或主要活性成分,辅以药学上可接受的辅料制成。
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