CN105348219B - 姜黄素类似物及其制备和应用 - Google Patents
姜黄素类似物及其制备和应用 Download PDFInfo
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- CN105348219B CN105348219B CN201410418432.4A CN201410418432A CN105348219B CN 105348219 B CN105348219 B CN 105348219B CN 201410418432 A CN201410418432 A CN 201410418432A CN 105348219 B CN105348219 B CN 105348219B
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- curcumin
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- heptadiene
- phenyl
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Abstract
本发明属于医药技术领域,涉及一系列姜黄素类似物的制备及应用,具有如式I、式II及式III的结构,其中R、R1、R2如说明书所述。所述姜黄素类似物药学上可接受的盐和溶剂化物,以及含有所述姜黄素类似物或其药学上可接受的盐作为活性成分的药物,可用于治疗癌症。本发明所述的姜黄素类似物及其药用盐类具有较好的抗癌活性,其制备方法简单可行,易操作。
Description
技术领域:
本发明涉及新的姜黄素类似物及其制备方法,还涉及合成所述姜黄素类似物的中间体及其制备方法和作为抗肿瘤药物的应用。
背景技术:
姜黄是姜科姜黄属多年生草本植物。《本草纲目》中记载,姜黄释名宝鼎香,气味辛、苦、大寒、无毒,用于心痛难忍以及胎寒腹痛的治疗。姜黄素是姜黄发挥药理作用最重要的活性成分且具有广泛的药理作用。研究表明姜黄素对人类的胃癌、肝癌以及白血病等多种癌症均有明显的抑制作用并且毒副作用小(崔淑香,金东庆,周玲等.姜黄素抗肿瘤作用试验观察.肿瘤防治杂志,2002,9(1):50-52.)。美国国立癌症研究所(national cancerinstitute,NCI)已将其列为第三代肿瘤化学预防药物(Chauhan DP.Chemotherapeuticpotential of curcumin for colorectal cancer[J].Curr Pharm Des,2002,8(19):1695-1706.),现已进入临床Ⅰ期和临床Ⅱ期试验。但姜黄素同时也存在水溶性低、稳定性差、体内代谢迅速等缺陷。因此,本发明以姜黄素为先导化合物,对其进行结构改造与修饰,以期望提高其稳定性、水溶性以及抗肿瘤活性。
体外研究表明,α,β-不饱和β-二酮结构是造成姜黄素不稳定的主要原因。在日光照射以及碱性条件下姜黄素在此部位分解,日光照射降解产物为香草醛、香草酸、2-羟基-香荚兰乙酮、原儿茶醛、去氢姜油酮、反式阿魏酸以及顺式阿魏酸;碱性条件下降解产物为香草醛、香草酸以及反式阿魏酸(冯生光,罩耿幸,邱峰等.姜黄素降解产物的分离鉴定及姜黄素的稳定性考察[J].沈阳药科大学学报,2004,26(5):361-366.)。另外,β-二酮结构还是aldo-keto还原酶的底物,在体内能被迅速代谢分解(Grogan G.Emergent mechanisticdiversity of enzyme-catalysedβ–diketone cleavage[J].Biochemical Journal.2005,388:721-730.)。Anand等研究发现β-二酮结构及其活性亚甲基有助于姜黄素在生理条件下被迅速代谢(Anand P,Kunnumakkara AB,Newman RA,et al.Bioavailability ofcurcumin:problems and promises[J].Molecular Pharmacology.2007,4:807-818.),Gupta等也进一步证实了这个结论(Gupta SC,Prasad S,Kim JH,et al.Multitargetingby curcumin as revealed by molecular interaction studies[J].Natural productreports.2011,28:1937-1955.)。
姜黄素的酚羟基既是其活性基团也是其代谢基团。研究发现,酚羟基可在体内相关酶的催化下,与内源性物质葡糖糖醛酸、硫酸及甘氨酸结合,使其极性增大,易于排出体外,导致代谢迅速。Tamvakopoulos等研究发现,将姜黄素两端的酚羟基转化为甲氧基后,其体外抗肿瘤活性是姜黄素的2~4倍(Tamvakopoulos C,Dimas K,Sofianos ZD,etal.Metabolism and Anticancer Activity of the Curcumin Analogue,Dimethoxycurcumin[J].Clin.Cancer Res,2007,13:1269-1277.)。本实验室前期工作也在姜黄素或四氢姜黄素两侧苯环的酚羟基上引入极性基团,即氨烷基,药理结果显示它们都具有良好的药理活性,即将苯环酚羟基烃化引入亲水的氨烷基侧链能够显著提高其抗肿瘤活性(Liu BM,Xia MY,Ji XL,et al.Synthesis and antiproliferative effect ofnovel curcumin analogues.Chem.Pharm.Bull.2013,61(7):757-763.)因此为提高姜黄素的稳定性、改善极性或亲水性、延长体内代谢时间,增强其抗癌活性,本发明合成了具有式I、式II及式III的结构的姜黄素类似物。
发明内容:
本发明所解决的技术问题是以姜黄素为先导化合物,为提高姜黄素的稳定性、极性或亲水性、增强其抗癌活性,设计合成了三种类型的姜黄素类似物及其盐类或它们的溶剂化物。
本发明的第二个目的是提供该类似物的制备方法。
本发明的第三个目的是提供含有该类似物的药物组合物。
本发明的第四个目的是提供该类似物的用途,具体为所述姜黄素类似物或组合物在制备各种抗肿瘤药物中的应用。
本发明是通过如下技术方案实现的:
1.在姜黄素β-二酮亚甲基位置引入双甲基或双苄基,并在一侧苯环的酚羟基上引入甲基,阻止在体内被迅速代谢,而在另一侧苯环的酚羟基上引入氨烷基侧链,以提高化合物的极性或亲水性。合成了式I化合物。
2.将影响姜黄素稳定性和代谢动力学性质的α,β-不饱和β-二酮结构的二个羰基还原为醇羟基,并对两端的酚羟基进行胺烷基化修饰,合成了式II化合物。
3.将影响姜黄素稳定性和代谢动力学性质的α,β-不饱和β-二酮结构的二个羰基还原为醇羟基,碳-碳双键还原为饱和键,并对两端的酚羟基进行胺烷基化修饰,合成了式III化合物。
本发明提供的姜黄素类似物具有如下结构特征的化合物或其药学上可接受的药用盐或溶剂化物:
其中R为Bn,CH3;R1、R2独立地为C1-C4烷基、C1-C4羟基烷基,或NR1R2为取代或未取代的含氮和/或氧的5-10元杂环基,所述取代基为C1-C4烷基、C1-C4羟基烷基。
优选地,NR1R2为N(CH3)2,N(C2H5)2,N(C2H4OH)2,
其中R1、R2独立地为C1-C4烷基、C1-C4羟基烷基,或NR1R2为取代或未取代的含氮和/或氧的5-10元杂环基,所述取代基为C1-C4烷基、C1-C4羟基烷基。
优选地,NR1R2为N(CH3)2,N(C2H5)2,N(C2H4OH)2,
其中R1、R2独立地为C1-C4烷基,或NR1R2为取代或未取代的含氮和/或氧的5-10元杂环基,所述取代基为C1-C4烷基;
优选地,NR1R2为N(C2H5)2,
本发明所提供的实施方案中,本发明的化合物含有碱性基团,则可与酸成盐,采用本领域技术人员所熟知的方法可以制备姜黄素类似物的药用盐。
本发明提供了含上述姜黄素的类似物及其药用盐类,其特征在于,所述的药用盐为与合适的非毒性有机酸或无机酸成的盐。
本发明还提供了上述姜黄素类似物的制备方法。
式I姜黄素类似物的制备方法,其特征在于:以3,4-二甲氧基苯甲醛为原料,先与乙酰丙酮缩合得中间体A1,再与香兰素缩合得到中间体A2。以醋酐对其酚羟基进行保护,再在β-二酮位置引入双烃基,最后在无水碳酸钾的条件下脱去保护基得到关键中间体A5/A8。以A5/A8为原料,与1,3-溴氯丙烷反应,在酚羟基上引入氯丙烷基侧链得中间体A6/A9,最后再与脂肪胺类、取代哌嗪、吗啉、四氢吡咯、哌啶、氮杂环庚烷进行组合反应得到式I化合物。
式II姜黄素类似物的制备方法,其特征在于:以姜黄素为原料,将其结构中的酚羟基以乙酰基保护,然后用碘甲烷对其活性亚甲基的两个氢原子进行亲核取代以引入双甲基,最后脱去乙酰基保护基而得关键中间体B4。以B4为原料,与1,3-溴氯丙烷反应,在酚羟基上引入氯丙烷基侧链。然后,在冰浴条件下,经硼氢化钠还原,将两个酮羰基还原为醇羟基,得关键中间体B6。最后再与脂肪胺类、取代哌嗪、吗啉、四氢吡咯、哌啶进行组合反应得到式II化合物。
式III姜黄素类似物的制备方法,其特征在于:以姜黄素为原料,先以醋酐将酚羟基保护,在β-二酮亚甲基位置位引入双苄基,脱保护得到双苄基姜黄素C1。经催化氢化将双键还原生成四氢双苄基姜黄素,再与1,3-溴氯丙烷反应并用硼氢化钠将羰基还原得到C4,最后与不同的仲胺反应得到式III化合物。
本发明上述姜黄素类似物及其药用盐类的制备过程中反应条件为常规反应条件,所用溶剂为常用的反应溶剂,无特殊要求。
本发明所述姜黄素类似物具有较好的水溶性,通过MTT法对人宫颈癌细胞HeLa,人肝癌细胞HepG2,人纤维肉瘤细胞HT-1080,人结肠癌细胞HCT116,人黑色素瘤细胞A375-S2,人乳腺癌细胞MCF-7,人肺癌细胞A549,人组织细胞淋巴瘤细胞U-937,人慢性髓原白血病细胞K562,人原髓细胞白血病细胞HL60等十类细胞的体外活性测试,与姜黄素相比,活性和选择性都有很大提高,因此,可以用于制备抗肿瘤的药物。
本发明具有如下有益技术效果:
1.在β-二酮亚甲基位置引入双甲基或双苄基,以破坏姜黄素的α,β-不饱和β-二酮结构,消除二个羰基之间的亚甲基这一反应活性位点,提高其稳定性,改善代谢动力学性质。
2.为了避免酚羟基与葡萄糖醛酸或硫酸等内源性物质结合而发生迅速代谢,对酚羟基进行烷基化保护。
3.通过酚羟基的胺烷基化引入亲水的碱性基团来增加水溶性,并且氮原子的引入,通常能够提高与受体的结合能力,增强抗肿瘤活性。
式I类型化合物的设计:在姜黄素β-二酮亚甲基位置引入双甲基或双苄基,并在一侧苯环的酚羟基上引入甲基,阻止在体内被迅速代谢,而在另一侧苯环的酚羟基上引入氨烷基侧链,以提高化合物的极性或亲水性。
此类化合物与其它姜黄素类似物的不同之处在于其具有不对称结构。因为本实验室前期的研究是同时在两端的酚羟基上引入氨烷基侧链,结果发现其中的大部分化合物体外对10种人癌细胞株的增殖抑制活性都要强于姜黄素。但在体内研究实验过程中发现,正常剂量下小鼠的死亡率偏高,这说明二侧同时引入氨烷基侧链的化合物虽然有着较好的抗肿瘤活性,但也有着较强的毒副作用。所以本实验中只对一端苯环的酚羟基进行氨烷基化,而对另外一端苯环的酚羟基甲基化,以期望在保留良好抗肿瘤作用的同时降低毒副作用。此外,此类化合物具有明显的不对称结构,一侧具有亲水性,而另一侧具有亲脂性,使得分子具有良好的两亲性,有利于透过细胞膜,从而增加药理活性。体外抑制肿瘤细胞增殖的药理试验数据已经证明双甲基取代的单侧引入氨烷基侧链的目标化合物对HT-1080、HL-60和U397肿瘤细胞的生长抑制活性要明显优于双甲基或双苄基取代的双侧引入氨烷基侧链的目标化合物,即本发明中式I类型化合物的新颖性在于只在一侧苯环的酚羟基上引入氨烷基侧链,且证明比双侧引入更有助于提高抗肿瘤活性。
式II类型化合物的设计:α,β-不饱和β-二酮结构是造成姜黄素不稳定的主要原因,α,β-不饱和酮结构,曾被认为是姜黄素发挥抗肿瘤作用的重要药效团。但Weber等研究发现,不含有α,β-不饱和酮结构的四氢姜黄素及其类似物对TNF-α诱导NF-ΚB活化的抑制活性几乎与姜黄素相当。故他们认为α,β-不饱和酮不是活性必要基团(Wber WM,HunsakerLA,Limtrakul P.Tetrahydrocurcumin inhibits HT1080cell migration and invasionvia downregulation of MMPs and uPA1[J].Acta pharmacologica sinica.2008,29,853-860.)。本实验室前期研究也表明四氢姜黄素衍生物对10种人癌细胞株的生长抑制活性都要强于姜黄素,甚至要优于一些抗癌活性较好的姜黄素类似物(Liu BM,Xia MY,JiXL,et al.Synthesis and antiproliferative effect of novel curcuminanalogues.Chem.Pharm.Bull.2013,61(7):757-763.)。因此设计式II类型化合物的新颖性在于通过将β-二酮的两个酮羰基还原为醇羟基,保留碳碳双键,来消除不稳定的α,β-不饱和β-二酮结构,并对两端的酚羟基进行烷基化和胺烷基化修饰。结果表明此类化合物仍然具有体外抗肿瘤活性,且表现出对HeLa和HepG2细胞的选择性,即与抑制其它种类的肿瘤细胞相比,抑制HeLa和HepG2细胞增殖作用要明显优于羰基还原前所相对应的化合物以及姜黄素。
式III类型化合物的设计:基于α,β-不饱和酮不是活性的必要基团,将式II类型化合物的碳-碳双键还原,以增加分子的柔性,希望能更好的与受体结合,提高抗癌活性。药理数据显示与对应的只将其双键还原的四氢姜黄素类似物相比,仅对A375-S2和K562细胞的增殖抑制作用稍有下降,而对其它种类的肿瘤细胞的增殖抑制作用无明显差异。
具体实施方式:
下面通过实施例来说明本发明的可实施性,本领域的技术人员应当理解,根据现有技术的教导,对相应的技术特征进行修改或替换,仍然属于本发明要求保护的范围。
实施例1 1-(3,4-二甲氧基苯基)-3,5-二酮-1-己烯(A1)的制备
将乙酰丙酮(16.3mL,160mmol)和三氧化二硼(7.8g,112mmol)加入到100mL的乙酸乙酯中,升温70℃反应0.5h。缓慢加入3,4-二甲氧基苯甲醛(13.2g,80mmol)和硼酸三正丁酯(21.6mL,80mmol),于70℃下反应0.5h。正丁胺8mL加入乙酸乙酯10mL,滴毕。100℃下反应1.5h。降温至60℃,加入50mL0.4mol·L-1盐酸,反应0.5h。反应毕,冷却至室温,水洗,水层用乙酸乙酯(30mL×3)萃取,合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥。过滤,减压浓缩,所得油状物经柱层析分离纯化(洗脱剂为石油醚-乙酸乙酯)。得到黄色晶状固体6.4g,收率32.4%,m.p.127-129℃(Lit,128-130℃)。
实施例2 1-(3,4-二甲氧基苯基)-7-(3-甲氧基-4-羟基苯基)-1,6-庚二烯-3,5-二酮(A2)的制备
将6-(3,4-二甲氧基苯基)己-5-烯-2,4-二酮(10.0g,40.3mmol)(A1)和三氧化二硼(4.8g,68.5mmol)加入到160mL的乙酸乙酯中,升温至70℃反应0.5h。缓慢加入3-甲氧基-4-羟基苯甲醛(6.1g,40.3mmol)和硼酸三正丁酯(18.4g,79.0mmol),于70℃下反应0.5h。滴加哌啶(4mL,40.5mmol),滴毕,升温至100℃,反应1.5h。然后降温至60℃,加入80mL0.4mol·L-1盐酸,反应0.5h,反应毕,冷却至室温,水洗,水层用乙酸乙酯(30mL×3)萃取,合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥。过滤,减压浓缩,所得油状物经柱层析分离纯化(洗脱剂为石油醚-乙酸乙酯)。得到桔红色固体5.4g,收率35.1%,m.p.85-88℃(Lit,89-91℃)。
实施例3 1-(3,4-二甲氧基苯基)-7-(3-甲氧基-4-乙酰氧基苯基)-1,6-庚二烯-3,5-二酮(A3)的制备
将1-(3,4-二甲氧基苯基)-7-(3-甲氧基-4-羟基苯基)-1,6-庚二烯-3,5-二酮(A2)(5.0g,13.1mmol)、乙酸酐(3.0mL,32.8mmol)和吡啶(2.6mL,32.8mmol)加入到50mL的二氯甲烷中,回流5h。反应毕,冷却至室温,用饱和碳酸氢钠水溶液调节pH至中性,无水硫酸钠干燥。过滤,减压浓缩,得到黄色固体,用乙酸乙酯和石油醚重结晶,得到黄色固体4.8g,收率86.4%。m.p.133-136℃,ESI-MS,m/z:425.2[M+H]+。
实施例4 1-(3,4-二甲氧基苯基)-7-(3-甲氧基-4-乙酰氧基苯基)-4,4-二甲基-1,6-庚二烯-3,5-二酮(A4)的制备
将1-(3,4-二甲氧基苯基)-7-(3-甲氧基-4-乙酰氧基苯基)-1,6-庚二烯-3,5-二酮(A3)(5.0g,11.8mmol)、无水碳酸钾(4.1g,29.5mmol)加入到30mL的丙酮中,滴加碘甲烷(29.5mmol),回流30h。反应毕,冷却至室温,过滤,滤液减压浓缩,加入水50mL,用二氯甲烷(30mL×3)萃取,合并有机相,再用饱和食盐水洗涤,无水硫酸钠干燥。过滤,减压浓缩,得到黄色固体,用乙醇重结晶,得到淡黄色固体3.8g,收率71.2%。
m.p.113-115℃,ESI-MS,m/z:453.2[M+H]+;1H-NMR(400MHz,CDCl3)δ:1.48(s,6H),2.31(s,3H),3.85(s,3H),3.90(s,3H),3.91(s,3H),6.63(d,J=15.6Hz,1H),6.71(d,J=15.6Hz,1H),6.84(d,J=8.0Hz,1H),7.02(d,J=8.0Hz,1H),7.00(d,J=2.0Hz,1H),7.06(d,J=2.0Hz,1H),7.12(dd,J1=2.0Hz,J2=8.0Hz,1H),7.14(dd,J1=2.0Hz,J2=8.0Hz,1H),7.68(d,J=15.6Hz,1H),7.69(d,J=15.6Hz,1H).
实施例5 1-(3,4-二甲氧基苯基)-7-(3-甲氧基-4-羟基苯基)-4,4-二甲基-1,6-庚二烯-3,5-二酮(A5)的制备
将1-(3,4-二甲氧基苯基)-7-(3-甲氧基-4-乙酰氧基苯基)-4,4-二甲基-1,6-庚二烯-3,5-二酮(A4)(3.6g,8.0mmol)、无水碳酸钾(2.2g,16.0mmol)加入到20mL的无水甲醇中,室温反应1.5h。反应毕,用冰乙酸调节pH为中性,加入50mL水,分取水相,用二氯甲烷(20mL×2)萃取,合并有机相,再用饱和食盐水洗涤,无水硫酸钠干燥。过滤,滤液减压浓缩,所得油状物经柱层析分离(洗脱剂为石油醚-乙酸乙酯),得到黄色固体2.0g,收率60.9%。
m.p.85-89℃,ESI-MS,m/z:411.2[M+H]+;1H-NMR(400MHz,CDCl3)δ:1.47(s,6H),2.31(s,3H),3.85(s,3H),3.90(s,3H),3.92(s,6H),6.63(d,J=15.6Hz,1H),6.64(d,J=15.6Hz,1H),6.83(d,J=8.0Hz,1H),6.90(d,J=8.0Hz,1H),6.99(d,J=2.0Hz,1H),7.00(d,J=2.0Hz,1H),7.09(dd,J1=2.0Hz,J2=8.0Hz,1H),7.12(dd,J1=2.0Hz,J2=8.0Hz,1H),7.67(d,J=15.6Hz,1H),7.78(d,J=15.6Hz,1H).
实施例6 1-(3,4-二甲氧基苯基)-7-[3-甲氧基-4-(3-氯丙基)苯基]-4,4-二甲基-1,6-庚二烯-3,5-二酮(A6)的制备
将1-(3,4-二甲氧基苯基)-7-(3-甲氧基-4-羟基苯基)-4,4-二甲基-1,6-庚二烯-3,5-二酮(A5)(2.1g,5.1mmol)、无水碳酸钾(2.2g,8.0mmol)加入到30mL的乙腈中,70℃下反应10min,滴加1,3-溴氯丙烷(1mL,10.2mmol),回流6h。反应毕,滤液减压浓缩,残余物加入50mL水和50mL二氯甲烷,水相再用二氯甲烷(20mL×2)萃取,合并有机相,再用饱和食盐水洗涤,无水硫酸钠干燥。过滤,滤液减压浓缩,所得油状物经柱层析分离(洗脱剂为石油醚-乙酸乙酯),得到黄色油状物1.45g,收率58.6%。
ESI-MS,m/z:486.2[M+H]+;1H-NMR(500MHz,CDCl3)δ:1.50(s,6H),2.27-2.32(m,J=6.0Hz,2H),3.77(t,J=6.0Hz,3H),3.89(t,3H),3.91(t,3H),4.20(t,J=6.0Hz,2H),6.65(d,J=15.5Hz,1H),6.68(d,J=15.5Hz,1H),6.84(d,J=8.0Hz,1H),6.87(d,J=8.0Hz,1H),7.02(d,J=2.0Hz,1H),7.02(d,J=2.0Hz,1H),7.12(dd,J1=2.0Hz,J2=8.5Hz,1H),7.14(dd,J1=2.0Hz,J2=8.5Hz,1H),7.69(d,J=15.5Hz,1H),7.70(d,J=15.5Hz,1H).
实施例7式I化合物1-(3,4-二甲氧基苯基)-7-(3-甲氧基-4-取代氨基烷氧基苯基)-4,4-二甲基-1,6-庚二烯-3,5-二酮(I-1~I-9)的制备通法:
将1-(3,4-二甲氧基苯基)-7-[3-甲氧基-4-(3-氯丙基)苯基]-4,4-二甲基-1,6-庚二烯-3,5-二酮(A6)(0.4mmol)、碘化钾(0.17g,1.0mmol)加入到10mL的乙腈中,70℃下反应10min,加入无水碳酸钾(0.14g,1.0mmol),继续反应10min。最后加入取代仲胺(1.0mmol),回流24h。反应毕,滤液减压浓缩,残余物加入20mL二氯甲烷溶解,水洗(20mL×2),饱和食盐水洗涤,无水硫酸钠干燥。过滤,滤液减压浓缩,所得油状物经柱层析分离(洗脱剂为二氯甲烷-甲醇),制得式I化合物I-1~I-9。
实施例7-1 1-(3,4-二甲氧基苯基)-7-{3-甲氧基-4-[3-(吗啉-4-基)丙氧基]苯基}-4,4-二甲基-1,6-庚二烯-3,5-二酮(I-1)的制备
以中间体A6和吗啉为原料,按照制备通法制得黄色油状物,收率40.9%。
ESI-MS,m/z:538.3[M+H]+;1H-NMR(400MHz,CDCl3)δ:1.48(s,6H),2.02~2.05(m,2H),2.47~2.53(m,6H),3.70~3.73(m,4H),3.87(s,3H),3.90(s,6H),4.11(t,2H),6.64(d,J=15.6Hz,1H),6.65(d,J=15.6Hz,1H),6.83(d,J=8.0Hz,1H),6.86(d,J=8.0Hz,1H),7.00(d,J=2.0Hz,1H),7.01(d,J=2.0Hz,1H),7.09(dd,J1=2.0Hz,J2=8.0Hz,1H),7.13(dd,J1=2.0Hz,J2=8.0Hz,1H),7.67(d,J=15.6Hz,1H),7.68(d,J=15.6Hz,1H).
实施例7-2 1-(3,4-二甲氧基苯基)-7-{3-甲氧基-4-[3-(4-甲基哌嗪-1-基)丙氧基]苯基}-4,4-二甲基-1,6-庚二烯-3,5-二酮(I-2)的制备
以中间体A6和4-甲基哌嗪为原料,按照制备通法制得黄色油状物,收率30.1%。
ESI-MS,m/z:551.3[M+H]+;1H-NMR(500MHz,CDCl3)δ:1.49(s,6H),2.04~2.06(m,2H),2.40(s,3H),2.54~2.69(m,10H),3.86(s,3H),3.91(s,6H),4.11(t,2H),6.65(d,J=15.5Hz,1H),6.66(d,J=15.5Hz,1H),6.85(d,J=8.0Hz,1H),6.86(d,J=8.0Hz,1H),7.01(d,J=2.0Hz,1H),7.02(d,J=2.0Hz,1H),7.11(dd,J1=2.0Hz,J2=8.0Hz,1H),7.14(dd,J1=2.0Hz,J2=8.0Hz,1H),7.69(d,J=15.5Hz,1H),7.70(d,J=15.5Hz,1H).
实施例7-3 1-(3,4-二甲氧基苯基)-7-{3-甲氧基-4-[3-(哌啶-1-基)丙氧基]苯基}-4,4-二甲基-1,6-庚二烯-3,5-二酮(I-3)的制备
以中间体A6和哌啶为原料,按照制备通法制得黄色油状物,收率36.4%。
ESI-MS,m/z:536.3[M+H]+;1H-NMR(500MHz,CDCl3)δ:1.45~1.47(m,2H),1.49(s,6H),1.53~1.69(m,4H),2.11~2.13(m,2H),2.54~2.61(m,6H),3.88(s,3H),3.91(s,6H),4.12(t,2H),6.64(d,J=15.5Hz,1H),6.67(d,J=15.5Hz,1H),6.86(d,J=8.0Hz,1H),6.87(d,J=8.0Hz,1H),7.01(d,J=2.0Hz,1H),7.02(d,J=2.0Hz,1H),7.10(dd,J1=2.0Hz,J2=8.0Hz,1H),7.12(dd,J1=2.0Hz,J2=8.0Hz,1H),7.68(d,J=15.5Hz,1H),7.69(d,J=15.5Hz,1H).
实施例7-4 1-(3,4-二甲氧基苯基)-7-{3-甲氧基-4-[3-(四氢吡咯-1-基)丙氧基]苯基}-4,4-二甲基-1,6-庚二烯-3,5-二酮(I-4)的制备
以中间体A6和四氢吡咯为原料,按照制备通法制得黄色油状物,收率32.7%。
ESI-MS,m/z:522.3[M+H]+;1H-NMR(500MHz,CDCl3)δ:1.50(s,6H),1.83~2.00(m,4H),2.21~2.23(m,2H),2.75~2.95(m,6H),3.88(s,3H),3.91(s,6H),4.14(t,2H),6.65(d,J=15.5Hz,1H),6.68(d,J=15.5Hz,1H),6.85(d,J=8.0Hz,1H),6.87(d,J=8.0Hz,1H),7.01(d,J=2.0Hz,1H),7.02(d,J=2.0Hz,1H),7.12(dd,J1=2.0Hz,J2=8.0Hz,1H),7.14(dd,J1=2.0Hz,J2=8.0Hz,1H),7.68(d,J=15.5Hz,1H),7.70(d,J=15.5Hz,1H).
实施例7-5 1-(3,4-二甲氧基苯基)-7-[3-甲氧基-4-(3-二乙胺基丙氧基)苯基]-4,4-二甲基-1,6-庚二烯-3,5-二酮(I-5)的制备
以中间体A6和二乙胺为原料,按照制备通法制得黄色油状物,收率31.6%。
ESI-MS,m/z:524.3[M+H]+;1H-NMR(500MHz,CDCl3)δ:1.43~1.46(m,6H),1.49(s,6H),2.40~2.42(m,2H),3.15~3.18(m,4H),3.25~3.26(m,2H),3.87(s,3H),3.91(s,6H),4.17(t,2H),6.65(d,J=15.5Hz,1H),6.67(d,J=15.5Hz,1H),6.85(d,J=8.0Hz,1H),6.88(d,J=8.0Hz,1H),7.01(d,J=2.0Hz,1H),7.02(d,J=2.0Hz,1H),7.11(dd,J1=2.0Hz,J2=8.0Hz,1H),7.14(dd,J1=2.0Hz,J2=8.0Hz,1H),7.67(d,J=15.5Hz,1H),7.69(d,J=15.5Hz,1H).
实施例7-6 1-(3,4-二甲氧基苯基)-7-[3-甲氧基-4-(3-二甲胺基丙氧基)苯基]-4,4-二甲基-1,6-庚二烯-3,5-二酮(I-6)的制备
以中间体A6和二甲胺为原料,按照制备通法制得黄色油状物,收率23.8%。
ESI-MS,m/z:496.3[M+H]+;1H-NMR(500MHz,CDCl3)δ:1.49(s,6H),2.22~2.25(m,2H),2.56(s,6H),2.77~2.90(m,2H),3.88(s,3H),3.91(s,6H),4.16(t,2H),6.65(d,J=15.5Hz,1H),6.68(d,J=15.5Hz,1H),6.85(d,J=8.0Hz,1H),6.87(d,J=8.0Hz,1H),7.01(d,J=2.0Hz,1H),7.02(d,J=2.0Hz,1H),7.11(dd,J1=2.0Hz,J2=8.0Hz,1H),7.12(dd,J1=2.0Hz,J2=8.0Hz,1H),7.68(d,J=15.5Hz,1H),7.69(d,J=15.5Hz,1H).
实施例7-7 1-(3,4-二甲氧基苯基)-7-{3-甲氧基-4-[3-二(2-羟乙基)胺基丙氧基]苯基}-4,4-二甲基-1,6-庚二烯-3,5-二酮(I-7)的制备
以中间体A6和二乙醇胺为原料,按照制备通法制得黄色油状物,收率30.7%。
ESI-MS,m/z:556.3[M+H]+;1H-NMR(500MHz,CDCl3)δ:1.49(s,6H),2.02~2.07(m,2H),2.70~2.75(m,6H),3.64~3.68(m,4H),3.89(s,3H),3.91(s,6H),4.14(t,2H),6.64(d,J=15.5Hz,1H),6.66(d,J=15.5Hz,1H),6.84(d,J=8.0Hz,1H),6.86(d,J=8.0Hz,1H),7.01(d,J=2.0Hz,1H),7.02(d,J=2.0Hz,1H),7.12(dd,J1=2.0Hz,J2=8.0Hz,1H),7.14(dd,J1=2.0Hz,J2=8.0Hz,1H),7.68(d,J=15.5Hz,1H),7.69(d,J=15.5Hz,1H).
实施例7-8 1-(3,4-二甲氧基苯基)-7-{3-甲氧基-4-{3-[4-(2-羟乙基)哌嗪-1-基]丙氧基}苯基}-4,4-二甲基-1,6-庚二烯-3,5-二酮(I-8)的制备
以中间体A6和4-羟乙基哌嗪为原料,按照制备通法制得黄色油状物,收率55.2%。
ESI-MS,m/z:581.3[M+H]+;1H-NMR(500MHz,CDCl3)δ:1.49(s,6H),2.02~2.08(m,2H),2.57~2.66(m,12H),3.66~3.69(m,3H),3.88(s,3H),3.91(s,6H),4.11(t,2H,J=6.8Hz),6.65(d,J=15.5Hz,1H),6.66(d,J=15.5Hz,1H),6.85(d,J=8.0Hz,1H),6.86(d,J=8.0Hz,1H),7.01(d,J=2.0Hz,1H),7.02(d,J=2.0Hz,1H),7.10(dd,J1=2.0Hz,J2=8.0Hz,1H),7.12(dd,J1=2.0Hz,J2=8.0Hz,1H),7.68(d,J=15.5Hz,1H),7.69(d,J=15.5Hz,1H).
实施例7-9 1-(3,4-二甲氧基苯基)-7-{3-甲氧基-4-[3-(环己亚胺-1-基)丙氧基]苯基}-4,4-二甲基-1,6-庚二烯-3,5-二酮(I-9)的制备
以中间体A6和环己亚胺为原料,按照制备通法制得黄色油状物,收率42.6%。
ESI-MS,m/z:550.3[M+H]+;1H-NMR(500MHz,CDCl3)δ:1.49(s,6H),1.60~1.62(m,4H),1.66~1.69(m,4H),2.04~2.06(m,2H),2.70~2.73(m,6H),3.89(s,3H),3.91(s,6H),4.12(t,2H),6.65(d,J=15.5Hz,1H),6.66(d,J=15.5Hz,1H),6.85(d,J=8.0Hz,1H),6.88(d,J=8.0Hz,1H),7.01(d,J=2.0Hz,1H),7.02(d,J=2.0Hz,1H),7.11(dd,J1=2.0Hz,J2=8.0Hz,1H),7.13(dd,J1=2.0Hz,J2=8.0Hz,1H),7.68(d,J=15.5Hz,1H),7.69(d,J=15.5Hz,1H).
实施例8 1-(3,4-二甲氧基苯基)-7-(3-甲氧基-4-乙酰氧基苯基)-4,4-二苄基-1,6-庚二烯-3,5-二酮(A7)的制备
将1-(3,4-二甲氧基苯基)-7-(3-甲氧基-4-乙酰氧基苯基)-1,6-庚二烯-3,5-二酮(A3)(5.0g,11.8mmol)、无水碳酸钾(4.1g,29.5mmol)加入到30mL的丙酮中,滴加溴苄(29.5mmol),回流36h。反应毕,冷却至室温,过滤,滤液减压浓缩,加入水50mL,用二氯甲烷(30mL×3)萃取,合并有机相,再用饱和食盐水洗涤,无水硫酸钠干燥。过滤,减压浓缩,所得油状物经柱层析分离(洗脱剂为石油醚-乙酸乙酯),得到淡黄色固体4.7g,收率65.9%。
m.p.107-110℃,ESI-MS,m/z:605.2[M+H]+;1H-NMR(400MHz,CDCl3)δ:2.30(s,3H),3.38(s,4H),3.81(s,3H),3.87(s,3H),3.89(s,3H),6.49(d,J=15.6Hz,1H),6.56(d,J=15.6Hz,1H),6.82(d,J=8.4Hz,1H),6.85(d,J=2.0Hz,1H),6.91(d,J=2.0Hz,1H),7.01(d,J=8.4Hz,1H),7.04(dd,J1=2.0Hz,J2=8.4Hz,1H),7.08(dd,J1=2.0Hz,J2=8.4Hz,1H),7.10~7.12(m,4H),7.20~7.24(m,6H),7.67(d,J=15.6Hz,1H),7.70(d,J=15.6Hz,1H).
实施例9 1-(3,4-二甲氧基苯基)-7-(3-甲氧基-4-羟基苯基)-4,4-二苄基-1,6-庚二烯-3,5-二酮(A8)的制备
将1-(3,4-二甲氧基苯基)-7-(3-甲氧基-4-乙酰氧基苯基)-4,4-二苄基-1,6-庚二烯-3,5-二酮(A7)(4.8g,8.0mmol)、无水碳酸钾(2.2g,16.0mmol)加入到30mL的无水甲醇中,室温反应1.5h。反应毕,用冰乙酸调节pH为中性,加入50mL水,分取水相,用二氯甲烷(20mL×2)萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥。过滤,滤液减压浓缩,得到黄色固体3.1g,收率68.9%。
m.p.159-162℃,ESI-MS,m/z:563.3[M+H]+;1H-NMR(500MHz,CDCl3)δ:3.40(s,4H),3.88(s,3H),3.90(s,6H),6.54(d,J=15.5Hz,1H),6.56(d,J=15.5Hz,1H),6.84(d,J=8.0Hz,1H),6.88(d,J=2.0Hz,1H),6.91(d,J=2.0Hz,1H),7.01(d,J=8.0Hz,1H),7.04(dd,J1=2.0Hz,J2=8.0Hz,1H),7.08(dd,J1=2.0Hz,J2=8.0Hz,1H),7.11~7.12(m,4H),7.21~7.23(m,6H),7.69(d,J=15.5Hz,1H),7.71(d,J=15.5Hz,1H).
实施例10 1-(3,4-二甲氧基苯基)-7-[3-甲氧基-4-(3-氯丙基)苯基]-4,4-二苄基-1,6-庚二烯-3,5-二酮(A9)的制备
将1-(3,4-二甲氧基苯基)-7-(3-甲氧基-4-羟基苯基)-4,4-二苄基-1,6-庚二烯-3,5-二酮(A8)(2.9g,5.1mmol)、无水碳酸钾(2.2g,8.0mmol)加入到30mL的乙腈中,70℃下反应10min,滴加1,3-溴氯丙烷(1mL,10.2mmol),回流6h。反应毕,滤液减压浓缩,残余物加入50mL水和50mL二氯甲烷,水相再用二氯甲烷(20mL×2)萃取,合并有机相,再用饱和食盐水洗涤,无水硫酸钠干燥。过滤,滤液减压浓缩,所得油状物经柱层析分离(洗脱剂为石油醚-乙酸乙酯),得到黄色油状物1.45g,收率44.5%。
ESI-MS,m/z:639.3[M+H]+;1H-NMR(500MHz,CDCl3)δ:2.67~2.31(m,2H),3.40(s,4H),3.75(t,2H),3.85(s,3H),3.88(s,3H),3.90(s,3H),4.20(t,2H),6.54(d,J=15.5Hz,1H),6.57(d,J=15.5Hz,1H),6.82(d,J=8.0Hz,1H),6.85(d,J=2.0Hz,1H),6.91(d,J=2.0Hz,1H),7.01(d,J=8.0Hz,1H),7.12(dd,J1=2.0Hz,J2=8.0Hz,1H),7.13(dd,J1=2.0Hz,J2=8.0Hz,1H),7.20~7.21(m,4H),7.27~7.28(m,6H),7.69(d,J=15.5Hz,1H),7.70(d,J=15.5Hz,1H).
实施例11式I化合物1-(3,4-二甲氧基苯基)-7-(3-甲氧基-4-取代氨基丙氧基苯基)-4,4-二苄基-1,6-庚二烯-3,5-二酮(I-10~I-18)的制备通法:
将1-(3,4-二甲氧基苯基)-7-[3-甲氧基-4-(3-氯丙基)苯基]-4,4-二苄基-1,6-庚二烯-3,5-二酮(A9)(0.4mmol)、碘化钾(0.17g,1.0mmol)加入到10mL的乙腈中,70℃下反应10min,加入无水碳酸钾(0.14g,1.0mmol),继续反应10min。最后加入取代仲胺(1.0mmol),回流24h。反应毕,滤液减压浓缩,残余物加入20mL二氯甲烷溶解,水洗(20mL×2),饱和食盐水洗涤,无水硫酸钠干燥。过滤,滤液减压浓缩,所得油状物经柱层析分离(洗脱剂为二氯甲烷-甲醇),制得式I化合物I-10~I-18。
实施例11-1 1-(3,4-二甲氧基苯基)-7-{3-甲氧基-4-[3-(吗啉-4-基)丙氧基]苯基}-4,4-二苄基-1,6-庚二烯-3,5-二酮(I-10)的制备
以中间体A9和吗啉为原料,按照制备通法制得黄色油状物,收率21.6%。
ESI-MS,m/z:690.4[M+H]+;1H-NMR(500MHz,CDCl3)δ:2.03~2.05(m,2H),2.46~2.48(m,6H),3.40(s,4H),3.72~3.73(m,4H),3.85(s,3H),3.88(s,3H),3.90(s,6H),4.12(t,2H),6.54(d,J=15.5Hz,1H),6.57(d,J=15.5Hz,1H),6.86(d,J=8.0Hz,1H),6.88(d,J=2.0Hz,1H),6.94(d,J=2.0Hz,1H),7.02(d,J=8.0Hz,1H),7.07(dd,J1=2.0Hz,J2=8.0Hz,1H),7.09(dd,J1=2.0Hz,J2=8.0Hz,1H),7.11~7.13(m,4H),7.19~7.24(m,6H),7.69(d,J=15.5Hz,1H),7.70(d,J=15.5Hz,1H).
实施例11-2 1-(3,4-二甲氧基苯基)-7-{3-甲氧基-4-[3-(4-甲基哌嗪-1-基)丙氧基]苯基}-4,4-二苄基-1,6-庚二烯-3,5-二酮(I-11)的制备
以中间体A9和4-甲基哌嗪为原料,按照制备通法制得黄色油状物,收率22.5%。
ESI-MS,m/z:703.4[M+H]+;1H-NMR(500MHz,CDCl3)δ:2.06~2.08(m,2H),2.53(s,3H),2.67~2.79(m,10H),3.40(s,4H),3.84(s,3H),3.88(s,3H),3.90(s,3H),4.10(t,2H),6.53(d,J=15.6Hz,1H),6.57(d,J=15.5Hz,1H),6.83(d,J=8.0Hz,1H),6.85(d,J=2.0Hz,1H),6.91(d,J=2.0Hz,1H),7.01(d,J=8.0Hz,1H),7.06(dd,J1=2.0Hz,J2=8.0Hz,1H),7.09(dd,J1=2.0Hz,J2=8.0Hz,1H),7.11~7.13(m,4H),7.19~7.23(m,6H),7.69(d,J=15.5Hz,1H),7.70(d,J=15.5Hz,1H).
实施例11-3 1-(3,4-二甲氧基苯基)-7-{3-甲氧基-4-[3-(哌啶-1-基)丙氧基]苯基}-4,4-二苄基-1,6-庚二烯-3,5-二酮(I-12)的制备
以中间体A9和哌啶为原料,按照制备通法制得黄色油状物,收率59.1%。
ESI-MS,m/z:688.4[M+H]+;1H-NMR(500MHz,CDCl3)δ:1.46~1.47(m,2H),1.62~1.65(m,4H),2.06~2.08(m,2H),2.44~2.47(m,6H),3.40(s,4H),3.85(s,3H),3.88(s,3H),3.90(s,3H),4.11(t,2H),6.54(d,J=15.5Hz,1H),6.55(d,J=15.5Hz,1H),6.83(d,J=8.0Hz,1H),6.87(d,J=2.0Hz,1H),6.91(d,J=2.0Hz,1H),7.01(d,J=8.0Hz,1H),7.07(dd,J1=2.0Hz,J2=8.0Hz,1H),7.09(dd,J1=2.0Hz,J2=8.4Hz,1H),7.10~7.13(m,4H),7.18~7.24(m,6H),7.69(d,J=15.5Hz,1H),7.70(d,J=15.5Hz,1H).
实施例11-4 1-(3,4-二甲氧基苯基)-7-{3-甲氧基-4-[3-(四氢吡咯-1-基)丙氧基]苯基}-4,4-二苄基-1,6-庚二烯-3,5-二酮(I-13)的制备
以中间体A9和四氢吡咯为原料,按照制备通法制得黄色油状物,收率20.4%。
ESI-MS,m/z:674.3[M+H]+;1H-NMR(500MHz,CDCl3)δ:1.83~1.87(m,4H),2.10~2.14(m,2H),2.62~2.65(m,4H),2.71~2.72(m,2H),3.40(s,4H),3.85(s,3H),3.88(s,3H),3.90(s,6H),4.12(t,2H),6.55(d,J=15.5Hz,1H),6.57(d,J=15.5Hz,1H),6.83(d,J=8.0Hz,1H),6.85(d,J=2.0Hz,1H),6.88(d,J=2.0Hz,1H),7.00(d,J=8.0Hz,1H),7.07(dd,J1=2.0Hz,J2=8.0Hz,1H),7.09(dd,J1=2.0Hz,J2=8.0Hz,1H),7.11~7.13(m,4H),7.19~7.24(m,6H),7.69(d,J=15.5Hz,1H),7.70(d,J=15.5Hz,1H).
实施例11-5 1-(3,4-二甲氧基苯基)-7-[3-甲氧基-4-(3-二乙胺基丙氧基)苯基]-4,4-二苄基-1,6-庚二烯-3,5-二酮(I-14)的制备
以中间体A9和二乙胺为原料,按照制备通法制得黄色油状物,收率25.2%。
ESI-MS,m/z:676.4[M+H]+;1H-NMR(500MHz,CDCl3)δ:1.06~1.08(m,6H),2.00~2.02(m,2H),2.59~2.61(m,4H),2.66~2.67(m,2H),3.40(s,4H),3.85(s,3H),3.88(s,3H),3.90(s,3H),4.10(t,2H),6.54(d,J=15.5Hz,1H),6.57(d,J=15.5Hz,1H),6.82(d,J=8.0Hz,1H),6.85(d,J=2.0Hz,1H),6.88(d,J=2.0Hz,1H),7.04(d,J=8.0Hz,1H),7.07(dd,J1=2.0Hz,J2=8.0Hz,1H),7.09(dd,J1=2.0Hz,J2=8.0Hz,1H),7.11~7.13(m,4H),7.18~7.24(m,6H),7.69(d,J=15.5Hz,1H),7.70(d,J=15.5Hz,1H).
实施例11-6 1-(3,4-二甲氧基苯基)-7-[3-甲氧基-4-(3-二甲胺基丙氧基)苯基]-4,4-二苄基-1,6-庚二烯-3,5-二酮(I-15)的制备
以中间体A9和二甲胺为原料,按照制备通法制得黄色油状物,收率25.9%。
ESI-MS,m/z:648.3[M+H]+;1H-NMR(500MHz,CDCl3)δ:2.24~2.26(m,2H),2.58(s,6H),2.90~2.92(m,2H),3.40(s,4H),3.84(s,3H),3.88(s,3H),3.90(s,3H),4.13(t,2H),6.53(d,J=15.5Hz,1H),6.56(d,J=15.5Hz,1H),6.83(d,J=8.0Hz,1H),6.84(d,J=2.0Hz,1H),6.88(d,J=2.0Hz,1H),7.05(d,J=8.0Hz,1H),7.07(dd,J1=2.0Hz,J2=8.0Hz,1H),7.09(dd,J1=2.0Hz,J2=8.0Hz,1H),7.11~7.13(m,4H),7.17~7.24(m,6H),7.68(d,J=15.5Hz,1H),7.70(d,J=15.5Hz,1H).
实施例11-7 1-(3,4-二甲氧基苯基)-7-{3-甲氧基-4-[3-二(2-羟乙基)胺基丙氧基]苯基}-4,4-二苄基-1,6-庚二烯-3,5-二酮(I-16)的制备
以中间体A9和二乙醇胺为原料,按照制备通法制得黄色油状物,收率37.1%。
ESI-MS,m/z:708.3[M+H]+;1H-NMR(500MHz,CDCl3)δ:2.00~2.04(m,2H),2.67(t,2H),2.75(t,2H),3.40(s,4H),3.61(t,2H),3.86(s,3H),3.88(s,3H),3.90(s,3H),4.13(t,2H),6.53(d,J=15.5Hz,1H),6.57(d,J=15.5Hz,1H),6.82(d,J=8.0Hz,1H),6.83(d,J=2.0Hz,1H),6.88(d,J=2.0Hz,1H),7.04(d,J=8.0Hz,1H),7.08(dd,J1=2.0Hz,J2=8.0Hz,1H),7.09(dd,J1=2.0Hz,J2=8.0Hz,1H),7.11~7.13(m,4H),7.18~7.23(m,6H),7.69(d,J=15.5Hz,1H),7.70(d,J=15.5Hz,1H).
实施例11-8 1-(3,4-二甲氧基苯基)-7-{3-甲氧基-4-{3-[4-(2-羟乙基)哌嗪-1-基]丙氧基}苯基}-4,4-二苄基-1,6-庚二烯-3,5-二酮(I-17)的制备
以中间体A9和4-羟乙基哌嗪为原料,按照制备通法制得黄色油状物,收率31.4%。
ESI-MS,m/z:733.4[M+H]+;1H-NMR(500MHz,CDCl3)δ:2.01~2.05(m,2H),2.55~2.63(m,12H),3.40(s,4H),3.67(t,3H),3.85(s,3H),3.87(s,3H),3.90(s,3H),4.10(t,2H),6.54(d,J=15.5Hz,1H),6.57(d,J=15.5Hz,1H),6.82(d,J=8.0Hz,1H),6.83(d,J=2.0Hz,1H),6.88(d,J=2.0Hz,1H),7.04(d,J=8.0Hz,1H),7.07(dd,J1=2.0Hz,J2=8.0Hz,1H),7.09(dd,J1=2.0Hz,J2=8.0Hz,1H),7.11~7.13(m,4H),7.18~7.23(m,6H),7.69(d,J=15.5Hz,1H),7.70(d,J=15.5Hz,1H).
实施例11-9 1-(3,4-二甲氧基苯基)-7-{3-甲氧基-4-[3-(环己亚胺-1-基)丙氧基]苯基}-4,4-二苄基-1,6-庚二烯-3,5-二酮(I-18)的制备
以中间体A9和环己亚胺为原料,按照制备通法制得黄色油状物,收率32.6%。
ESI-MS,m/z:702.4[M+H]+;1H-NMR(500MHz,CDCl3)δ:1.60~1.62(m,4H),1.66~1.69(m,4H),2.03~2.06(m,2H),2.68~2.75(m,6H),3.40(s,4H),3.85(s,3H),3.88(s,3H),3.90(s,6H),4.12(t,2H),6.54(d,J=15.5Hz,1H),6.57(d,J=15.5Hz,1H),6.83(d,J=8.0Hz,1H),6.85(d,J=2.0Hz,1H),6.88(d,J=2.0Hz,1H),7.05(d,J=8.0Hz,1H),7.07(dd,J1=2.0Hz,J2=8.0Hz,1H),7.09(dd,J1=2.0Hz,J2=8.0Hz,1H),7.11~7.13(m,4H),7.19~7.24(m,6H),7.69(d,J=15.5Hz,1H),7.70(d,J=15.5Hz,1H).
实施例12 1,7-二(3-甲氧基-4-乙酰氧基苯基)-1,6-庚二烯-3,5-二酮(B2)的制备
将姜黄素(20.0g,54.2mmol)乙酸酐(15.4mL,162.6mmol)和吡啶(13.2mL,162.6mmol)加入到300mL的二氯甲烷中,回流5h。反应毕,冷却至室温,用饱和碳酸氢钠水溶液调节pH至中性,有机相用饱和食盐水洗涤,无水硫酸钠干燥。过滤,减压浓缩,得到黄色固体,用乙酸乙酯和石油醚重结晶,得到黄色固体23.0g,收率93.6%,m.p.156-159℃。
实施例13 1,7-二(3-甲氧基-4-乙酰氧基苯基)-4,4-二甲基-1,6-庚二烯-3,5-二酮(B3)的制备
将1,7-二(3-甲氧基-4-乙酰氧基苯基)-1,6-庚二烯-3,5-二酮(15.0g,33.3mmol)、无水碳酸钾(11.5g,83.3mmol)加入到100mL的丙酮中,滴加碘甲烷(83.3mmol),回流48h。反应毕,冷却至室温,过滤,滤液减压浓缩,残余物加入100mL的二氯甲烷,水洗,饱和食盐水洗涤,无水硫酸钠干燥。过滤,减压将溶剂二氯甲烷蒸除得到大量黄色固体,经丙酮-乙醇重结晶,得到乳白色固体8.4g,产率52.9%,m.p.160-163℃。
实施例14 1,7-二(3-甲氧基-4-羟基苯基)-4,4-二甲基-1,6-庚二烯-3,5-二酮(B4)的制备
将1,7-二(3-甲氧基-4-乙酰氧基苯基)-4,4-二甲基-1,6-庚二烯-3,5-二酮(9.6g,20.0mmol)、无水碳酸钾(11.0g,80.0mmol)加入到60mL的无水甲醇中,室温反应2h。反应毕,过滤,滤液减压浓缩,得到红色固体。用50mL二氯甲烷溶解,用冰乙酸调节pH为中性,此时,红色固体全部溶解,溶液颜色呈黄色。加入100mL水,分取水相,用二氯甲烷(30mL×2)萃取。合并有机相,饱和食盐水洗涤,无水硫酸钠干燥。过滤,滤液减压浓缩,得到油状物,用乙酸乙酯和石油醚重结晶,得到黄色固体6.0g,收率75.9%。
m.p.136-138℃.ESI-MS,m/z:481.2[M+H]+.1H-NMR(300MHz,CDCl3)δ:1.47(s,3H),3.91(s,3H),6.62(d,J=15.6Hz,1H),6.89(d,J=8.1Hz,1H),6.99(d,J=1.8Hz,1H),7.08(dd,J1=1.8Hz,J2=8.1Hz,1H),7.68(d,J=15.6Hz,1H).
实施例15 1,7-二[3-甲氧基-4-(3-氯丙氧基)苯基]-4,4-二甲基-1,6-庚二烯-3,5-二酮(B5)的制备
将1,7-二(3-甲氧基-4-羟基苯基)-4,4-二甲基-1,6-庚二烯-3,5-二酮(4.0g,10.0mmol)、无水碳酸钾(5.5g,40.0mmol)加入到50mL的乙腈中,70℃下反应10min,然后滴加1,3-溴氯丙烷(4.0mL,40.0mmol),回流6h。反应毕,滤液减压浓缩,残余物加入50mL水和50mL二氯甲烷,水相再用二氯甲烷(20mL×2)萃取,合并有机相,再用饱和食盐水洗涤,无水硫酸钠干燥。过滤,滤液减压浓缩,所得油状物不经纯化直接应用到下一步反应中。
实施例16 1,7-二[3-甲氧基-4-(3-氯丙氧基)苯基]-4,4-二甲基-1,6-庚二烯-3,5-二醇(B6)的制备
将1,7-二[3-甲氧基-4-(3-氯丙氧基)苯基]-4,4-二甲基-1,6-庚二烯-3,5-二酮(5.5g,10.0mmol)加入到30mL的四氢呋喃中,再加入15mL的甲醇。于0℃下分批加入硼氢化钠(0.76g,20.0mmol),反应4h。反应毕,将大部分的溶剂蒸除,残余物加入50mL水和50mL二氯甲烷,水相再用二氯甲烷(20mL×3)萃取,合并有机相,再用饱和食盐水洗涤,无水硫酸钠干燥。过滤,滤液减压浓缩,所得油状物经柱层析分离(洗脱剂为石油醚-乙酸乙酯),得到黄色油状物4.5g,收率81.5%。
ESI-MS,m/z:553.2[M+H]+,575.2[M+Na]+.1H-NMR(500MHz,CDCl3)δ:1.00~1.06(m,3H),2.26~2.31(m,2H),3.78~3.80(m,2H),3.90(s,3H),4.19(t,2H),4.29(t,2H),5.98~6.14(m,1H),6.61(dd,1H),6.89(d,J=8.0Hz,1H),6.99(d,J=2.0Hz,1H),7.08(dd,J1=2.0Hz,J2=8.0Hz,1H).
实施例17式II化合物1,7-二(3-甲氧基-4-取代氨基丙氧基苯基)-4,4-二甲基-1,6-庚二烯-3,5-二醇(II-1~II-8)制备通法:
将1,7-二[3-甲氧基-4-(3-氯丙氧基)苯基]-4,4-二甲基-1,6-庚二烯-3,5-二醇(1.25mmol)、碘化钾(0.82g,5.0mmol)加入10mL的乙腈中,于70℃下反应10min,加入无水碳酸钾(0.68g,5.0mmol),继续反应10min。最后加入取代仲胺(5.0mmol),回流24h。反应毕,滤液减压浓缩,残余物加入20mL二氯甲烷溶解,水洗(20mL×2),饱和食盐水洗涤,无水硫酸钠干燥。过滤,滤液减压浓缩,所得油状物经柱层析分离(洗脱剂为二氯甲烷-甲醇),制得式II化合物II-1~II-8。
实施例17-1 1,7-二{3-甲氧基-4-[3-(吗啉-4-基)丙氧基]苯基}-4,4-二甲基-1,6-庚二烯-3,5-二醇(II-1)的制备
以1,7-二[3-甲氧基-4-(3-氯丙氧基)苯基]-4,4-二甲基-1,6-庚二烯-3,5-二醇和吗啉为原料,按照制备通法制得淡黄色固体,收率22.1%。
m.p.137~139℃.ESI-MS,m/z:553.2[M+H]+,575.2[M+Na]+.1H-NMR(500MHz,CDCl3)δ:1.02~1.04(m,3H),2.17~2.18(m,2H),2.70~2.78(m,6H),3.82~3.89(m,2H),3.91(s,3H),4.11(t,2H),4.30(t,2H),6.18~6.26(m,1H),6.57(dd,1H),6.83(d,J=8.0Hz,1H),6.85(d,J=2.0Hz,1H),6.94(dd,J1=2.0Hz,J2=8.0Hz,1H).
实施例17-2 1,7-二{3-甲氧基-4-[3-(4-甲基哌嗪-1-基)丙氧基]苯基}-4,4-二甲基-1,6-庚二烯-3,5-二醇(II-2)的制备
以1,7-二[3-甲氧基-4-(3-氯丙氧基)苯基]-4,4-二甲基-1,6-庚二烯-3,5-二醇和4-甲基哌嗪为原料,按照制备通法制得淡黄色固体,收率25.2%。
m.p.89~92℃.ESI-MS,m/z:681.2[M+H]+.1H-NMR(500MHz,CDCl3)δ:1.01~1.09(m,3H),2.02~2.06(m,2H),2.36(s,4H),2.57~2.60(m,10H),3.90(s,3H),4.09(t,2H),4.29(t,2H),6.18~6.26(m,1H),6.55(dd,1H),6.84(d,J=8.0Hz,1H),6.93(d,J=2.0Hz,1H),6.95(dd,J1=2.0Hz,J2=8.0Hz,1H).
实施例17-3 1,7-二{3-甲氧基-4-[3-(哌啶-1-基)丙氧基]苯基}-4,4-二甲基-1,6-庚二烯-3,5-二醇(II-3)的制备
以1,7-二[3-甲氧基-4-(3-氯丙氧基)苯基]-4,4-二甲基-1,6-庚二烯-3,5-二醇和哌啶为原料,按照制备通法制得淡黄色固体,收率30.1%。
m.p.101~104℃.ESI-MS,m/z:652.4[M+H]+.1H-NMR(500MHz,CDCl3)δ:1.02~1.05(m,3H),1.48(m,2H),1.62~1.68(m,4H),2.04~2.09(m,2H),2.40~2.60(m,6H),3.90(s,3H),4.08(t,2H),4.29(t,2H),6.17~6.26(m,1H),6.56(dd,1H),6.85(d,J=8.0Hz,1H),6.93(d,J=2.0Hz,1H),6.95(dd,J1=2.0Hz,J2=8.0Hz,1H).
实施例17-4 1,7-二{3-甲氧基-4-[3-(四氢吡咯-1-基)丙氧基]苯基}-4,4-二甲基-1,6-庚二烯-3,5-二醇(II-4)的制备
以1,7-二[3-甲氧基-4-(3-氯丙氧基)苯基]-4,4-二甲基-1,6-庚二烯-3,5-二醇和四氢吡咯为原料,按照制备通法制得淡黄色油状物,收率29.8%。
ESI-MS,m/z:623.3[M+H]+.1H-NMR(500MHz,CDCl3)δ:1.00~1.03(m,3H),1.73~1.82(m,4H),2.07~2.11(m,2H),2.71~2.74(m,6H),3.90(s,3H),4.10(t,2H),4.29(t,2H),6.17~6.26(m,1H),6.57(dd,1H),6.85(d,J=8.0Hz,1H),6.93(d,J=2.0Hz,1H),6.95(dd,J1=2.0Hz,J2=8.0Hz,1H).
实施例17-5 1,7-二[3-甲氧基-4-(3-二乙胺基丙氧基)苯基]-4,4-二甲基-1,6-庚二烯-3,5-二醇(II-5)的制备
以1,7-二[3-甲氧基-4-(3-氯丙氧基)苯基]-4,4-二甲基-1,6-庚二烯-3,5-二醇和二乙胺为原料,按照制备通法制得淡黄色固体,收率33.2%。
m.p.83~85℃.ESI-MS,m/z:627.4[M+H]+.1H-NMR(500MHz,CDCl3)δ:1.01~1.04(m,3H),1.40~1.75(m,6H),2.08~2.11(m,2H),2.70~2.74(m,4H),2.80~2.83(m,2H),3.89(s,3H),4.09(t,2H),4.30(t,2H),6.17~6.26(m,1H),6.56(dd,1H),6.85(d,J=8.0Hz,1H),6.93(d,J=2.0Hz,1H),6.95(dd,J1=2.0Hz,J2=8.0Hz,1H).
实施例17-6 1,7-二[3-甲氧基-4-(3-二甲胺基丙氧基)苯基]-4,4-二甲基-1,6-庚二烯-3,5-二醇(II-6)的制备
以1,7-二[3-甲氧基-4-(3-氯丙氧基)苯基]-4,4-二甲基-1,6-庚二烯-3,5-二醇和二甲胺为原料,按照制备通法制得淡黄色油状物,收率26.7%。
ESI-MS,m/z:571.3[M+H]+.1H-NMR(500MHz,CDCl3)δ:1.02~1.09(m,3H),2.03~2.08(m,2H),2.31(s,6H),2.52~2.60(t,2H),3.90(s,3H),4.08(t,2H),4.28(t,1H),6.17~6.25(m,1H),6.56(dd,1H),6.84(d,J=8.0Hz,1H),6.93(d,J=2.0Hz,1H),6.95(dd,J1=2.0Hz,J2=8.0Hz,1H).
实施例17-7 1,7-二{3-甲氧基-4-[3-二(2-羟乙基)胺基丙氧基]苯基}-4,4-二甲基-1,6-庚二烯-3,5-二醇(II-7)的制备
以1,7-二[3-甲氧基-4-(3-氯丙氧基)苯基]-4,4-二甲基-1,6-庚二烯-3,5-二醇和二乙醇胺为原料,按照制备通法制得淡黄色油状物,收率25.4%。
ESI-MS,m/z:691.4[M+H]+.1H-NMR(500MHz,CDCl3)δ:1.03(s,3H),2.02~2.05(m,2H),2.70~2.73(m,4H),2.80~2.83(m,2H),3.56(s,3H),3.90(s,3H),4.12(t,2H),4.27(t,2H),6.17~6.24(m,1H),6.56(dd,1H),6.84(d,J=8.0Hz,1H),6.93(d,J=2.0Hz,1H),6.95(dd,J1=2.0Hz,J2=8.0Hz,1H).
实施例17-8 1,7-二{3-甲氧基-4-{3-[4-(2-羟乙基)哌嗪-1-基]丙氧基}苯基}-4,4-二甲基-1,6-庚二烯-3,5-二醇(II-8)的制备
以1,7-二[3-甲氧基-4-(3-氯丙氧基)苯基]-4,4-二甲基-1,6-庚二烯-3,5-二醇和4-羟乙基哌嗪为原料,按照制备通法制得淡黄色固体,收率38.2%。
m.p.112~115℃.ESI-MS,m/z:741.5[M+H]+.1H-NMR(400MHz,CDCl3)δ:1.02(s,3H),1.99~2.04(m,2H),2.50~2.56(m,12H),3.62(t,2H),3.86(s,3H),4.04(t,2H),4.26(t,2H),6.14~6.25(m,1H),6.53(dd,1H),6.82(d,J=8.1Hz,1H),6.93(d,J=1.8Hz,1H),6.95(dd,J1=1.8Hz,J2=8.1Hz,1H).
实施例18 1,7-二(3-甲氧基-4-乙酰氧基苯基)-4,4-二苄基-1,6-庚二烯-3,5-二酮的制备
将1,7-二(3-甲氧基-4-乙酰氧基苯基)-1,6-庚二烯-3,5-二酮(B2)(16.0g,35.4mmol)、无水碳酸钾(14.7g,106.2mmol)加入到100mL的丙酮中,滴加溴苄(18.2g,106.2mmol),回流12h。反应毕,冷却至室温,过滤,滤液减压浓缩,残余物加入100mL的二氯甲烷,水洗,饱和食盐水洗涤,无水硫酸钠干燥。过滤,减压将溶剂二氯甲烷蒸除得到大量棕色油状物,经丙酮-乙醇重结晶,得到白色固体15.2g,产率68.0%,m.p.178~180℃。
实施例19 1,7-二(3-甲氧基-4-羟基苯基)-4,4-二苄基-1,6-庚二烯-3,5-二酮(C1)的制备
将1,7-二(3-甲氧基-4-乙酰氧基苯基)-4,4-二苄基-1,6-庚二烯-3,5-二酮(14.0g,22.1mmol)、无水碳酸钾(12.3g,88.4mmol)加入到100mL的无水甲醇中,室温反应2h。反应毕,过滤,滤液减压浓缩,得到红色固体。用50mL二氯甲烷溶解,用冰乙酸调节pH为中性,此时,红色固体全部溶解,溶液颜色呈黄色。加入100mL水,分取水相,用二氯甲烷(30mL×2)萃取。合并有机相,饱和食盐水洗涤,无水硫酸钠干燥。过滤,滤液减压浓缩,得到油状物,用乙酸乙酯和石油醚重结晶,得到黄色固体10.1g,收率83.2%,m.p.113~1116℃。
实施例20 1,7-二(3-甲氧基-4-羟基苯基)-4,4-二苄基-3,5-庚二酮(C2)的制备
将1,7-二(3-甲氧基-4-羟基苯基)-4,4-二苄基-1,6-庚二烯-3,5-二酮(C1)(5.5g,10.0mmol)、10%Pd-C(0.6g)加入到50mL无水乙醇中,通入氢气,室温条件下反应24h。反应毕,过滤,滤饼用20mL二氯甲烷溶解,再抽滤,回收钯碳,滤液减压浓缩,得乳白色固体,用乙醇重结晶,得到白色固体3.4g,收率61.4%,m.p.73-75℃。
实施例21 1,7-二[3-甲氧基-4-(3-氯丙氧基)苯基]-4,4-二苄基-3,5-庚二酮(C3)的制备
将1,7-二(3-甲氧基-4-羟基苯基)-4,4-二甲基-3,5-庚二酮(5.5g,10.0mmol)(C2)、无水碳酸钾(5.5g,40.0mmol)加入到40mL的乙腈中,70℃下反应10min,然后滴加1,3-溴氯丙烷(4.0mL,40.0mmol),回流12h。反应毕,滤液减压浓缩,残余物加入50mL水和50mL二氯甲烷,水相再用二氯甲烷(20mL×2)萃取,合并有机相,再用饱和食盐水洗涤,无水硫酸钠干燥。过滤,滤液减压浓缩,得到白色固体5.0g,收率71.4%,m.p.96-99℃。
实施例22 1,7-二[3-甲氧基-4-(3-氯丙氧基)苯基]-4,4-二苄基-3,5-庚二醇(C4)的制备
将1,7-二[3-甲氧基-4-(3-氯丙氧基)苯基]-4,4-二苄基-3,5-庚二酮(C3)(3.6g,5.0mmol)加入到20mL四氢呋喃中,再加入10mL甲醇。于0℃下分批加入硼氢化钠(0.38g,10.0mmol),反应4h。反应毕,将大部分的溶剂蒸除,残余物加入50mL水和50mL二氯甲烷,水相再用二氯甲烷(20mL×3)萃取,合并有机相,再用饱和食盐水洗涤,无水硫酸钠干燥。过滤,滤液减压浓缩,所得油状物经柱层析分离(洗脱剂为石油醚-乙酸乙酯),得到无色油状物1.5g,收率41.4%。
ESI-MS,m/z:710.2[M+H]+.1H-NMR(500MHz,CDCl3)δ:1.82~1.88(m,2H),2.05~2.16(m,2H),3.00(t,1H),3.77(s,3H),4.07(t,2H),6.77~6.82(m,2H),6.88(d,J=8.5Hz,1H),7.01~7.04(m,2H),7.19~7.23(m,3H).
目标化合物的制备
实施例23式III化合物1,7-二(3-甲氧基-4-取代氨基丙氧基苯基苯基)-4,4-二苄基-3,5-庚二醇(III-1~III-5)制备通法:
将1,7-二[3-甲氧基-4-(3-氯丙氧基)苯基]-4,4-二苄基-3,5-庚二醇(C4)(1.25mmol)、碘化钾(0.82g,5.0mmol)加入到10mL的乙腈中,70℃下反应10min,加入无水碳酸钾(0.68g,5.0mmol),继续反应10min。最后加入取代仲胺(5.0mmol),回流24h。反应毕,滤液减压浓缩,残余物加入20mL二氯甲烷溶解,水洗(20mL×2),饱和食盐水洗涤,无水硫酸钠干燥。过滤,滤液减压浓缩,所得油状物经柱层析分离(洗脱剂为二氯甲烷-甲醇),制得目标化合物III-1~III-5。
实施例23-1 1,7-二{3-甲氧基-4-[3-(吗啉-4-基)丙氧基]苯基}-4,4-二苄基-3,5-庚二醇(III-1)的制备
以中间体(C4)和吗啉为原料,按照制备通法制得白色固体,收率40.5%。
m.p.176-180℃.ESI-MS,m/z:811.4[M+H]+.1H-NMR(500MHz,CDCl3)δ:1.65~1.67(m,2H),2.06~2.10(m,2H),2.60~2.68(m,6H),2.37~2.75(m,2H),2.91(s,2H),3.04(s,1H),3.75~3.80(m,4H),3.81(s,3H),4.05(t,2H),6.58~6.63(m,2H),6.79(d,J=8.5Hz,1H),7.13~7.15(m,2H),7.19~7.25(m,3H).
实施例23-2 1,7-二{3-甲氧基-4-[3-(4-甲基哌嗪-1-基)丙氧基]苯基}-4,4-二苄基-3,5-庚二醇(III-2)的制备
以中间体(C4)和4-甲基哌嗪为原料,按照制备通法制得白色固体,收率23.1%。
m.p.123-127℃.ESI-MS,m/z:837.5[M+H]+.1H-NMR(500MHz,CDCl3)δ:1.67~1.72(m,2H),1.82~1.92(m,2H),2.16(s,3H),2.30~2.32(m,8H),2.46~2.50(m,2H),2.58~2.66(m,2H),2.81(s,2H),2.84~2.87(m,1H),3.85(s,3H),4.09(t,2H),6.71~6.78(m,2H),6.84(d,J=8.5Hz,1H),7.09~7.15(m,2H),7.19~7.24(m,3H).
实施例23-3 1,7-二{3-甲氧基-4-[3-(哌啶-1-基)丙氧基]苯基}-4,4-二苄基-3,5-庚二醇(III-3)的制备
以中间体(C4)和哌啶为原料,按照制备通法制得白色固体,收率46.3%。
m.p.169-171℃.ESI-MS,m/z:808.5[M+H]+.1H-NMR(500MHz,CDCl3)δ:1.49~1.50(m,2H),1.65~1.69(m,4H),2.09~2.12(m,2H),2.45~2.69(m,8H),2.80(s,2H),2.89~2.92(m,1H),3.81(s,3H),4.05(t,2H),6.58~6.63(m,2H),6.79(d,J=8.5Hz,1H),7.13~7.15(m,2H),7.19~7.25(m,3H).
实施例23-4 1,7-二{3-甲氧基-4-[3-(四氢吡咯-1-基)丙氧基]苯基}-4,4-二苄基-3,5-庚二醇(III-4)的制备
以中间体(C4)和四氢吡咯为原料,按照制备通法制得白色固体,收率22.2%。
m.p.132~135℃.ESI-MS,m/z:780.3[M+H]+.1H-NMR(500MHz,CDCl3)δ:1.63~1.69(m,4H),1.80~1.91(m,4H),2.40~2.68(m,8H),2.74(s,2H),2.77~2.85(m,1H),3.74(s,3H),4.03(t,2H),6.74~6.79(m,2H),6.82(d,J=8.5Hz,1H),7.13~7.15(m,2H),7.19~7.25(m,3H).
实施例23-5 1,7-二[3-甲氧基-4-(3-二乙胺基丙氧基)苯基]-4,4-二苄基-3,5-庚二醇(III-5)的制备
以中间体(C4)和二乙胺为原料,按照制备通法制得白色固体,收率34.6%。
m.p.166-170℃.ESI-MS,m/z:781.3[M-H]+.1H-NMR(500MHz,CDCl3)δ:1.27~1.33(m,6H),1.89~2.01(m,4H),2.58~2.62(m,2H),2.70~2.74(m,2H),2.94(s,2H),3.10~3.19(m,5H),3.88(s,3H),4.17(t,2H),6.86~6.88(m,2H),6.92(d,J=8.5Hz,1H),7.13~7.15(m,2H),7.27~7.32(m,3H).
实施例24
实验所用肿瘤细胞株:人宫颈癌细胞(HeLa),人肝癌细胞(HepG2),人纤维肉瘤细胞(HT-1080),人结肠癌细胞(HCT116),人黑色素瘤细胞(A375-S2),人乳腺癌细胞(MCF-7),人肺癌细胞(A549),人组织细胞淋巴瘤细胞(U-937),人慢性髓原白血病细胞(K562),人原髓细胞白血病细胞(HL60)购于American Type Culture Collection(ATCC,Rockville,MD,USA)。细胞接种在含10%胎牛血清、2%谷氨酰胺的RPMI-1640培养液中,在37℃,5%CO2培养箱中培养。各化合物于无菌条件下,用二甲基亚砜(DMSO)溶解后,用RPMI1640培养液稀释至所需浓度,DMSO终浓度小于0.5%。胎牛血清,北京元亨圣马生物技术研究所。
贴壁细胞选用对数生长期的贴壁肿瘤细胞,用胰酶消化后,用含10%小牛血清的RPMIl640培养基配成5×104/mL的细胞悬液,接种在96孔培养板中,每孔100μL,37℃,5%CO2培养24h。实验组更换新的含不同浓度被测样品的培养液,对照组则更换含等体积溶剂的培养液,每组设3个平行孔,37℃,5%CO2培养48h。弃去上清液,用PBS小心洗2次,每孔加入100μL新鲜配制的含0.5mg/mL MTT的培养基,37℃继续培养4h。小心弃去上清,并加入150μLDMSO,用微型振荡器混匀10min后,用酶标仪在492nm处测定光密度值。
悬浮细胞选用对数生长期的细胞,用含10%小牛血清的RPMIl640培养基配成1×104/mL的细胞悬液,接种在96孔培养板中,每孔50μL,37℃,5%CO2培养24h。实验组加入含不同浓度被测样品的培养液50μL,对照组则加入含等体积溶剂的培养液,每组设3个平行孔,37℃,5%CO2培养48h,每孔加入10L新鲜配制的含5mg/mL MTT的培养基,37℃继续培养4h。用三联液(SDS10g,10M HCl0.1mL,异丁醇5mL,用蒸馏水稀释至100mL)100μL溶解结晶,37℃孵育12h。用酶标仪在492nm处测定光密度值。
按下式计算药物对肿瘤细胞生长的抑制率:
肿瘤细胞生长抑制率(%)=[A492(阴性对照)-A492(加药组)]/A492(阴性对照)×100%,从中求出样品的半数抑制浓度(IC50)。
以HeLa、MCF-7、HepG2、HCT116、A549、A375-S2、HT1080、HL60、U937及K562细胞对部分所合成的化合物进行体外抗增殖活性的评价(评价结果见下表)。
表1.式Ⅰ、式II及式III化合物、中间体和姜黄素对肿瘤细胞的IC50值
Claims (8)
1.姜黄素类似物及其药用盐,
其中R1、R2独立地为C1-C4烷基、C1-C4羟基烷基,或NR1R2为取代或未取代的含氮和/或氧的5-10元杂环基,所述取代基为C1-C4烷基、C1-C4羟基烷基;
其中R1、R2独立地为C1-C4烷基,或NR1R2为取代或未取代的含氮和/或氧的5-10元杂环基,所述取代基为C1-C4烷基。
2.如权利要求1所述的姜黄素类似物及其药用盐,其特征在于,式II中,NR1R2为N(CH3)2,N(C2H5)2,N(C2H4OH)2,
3.如权利要求1所述的姜黄素类似物及其药用盐,其特征在于,式III中,NR1R2为N(C2H5)2,
4.一种药物组合物,包含权利要求1-3任何一项所述的姜黄素类似物及其药用盐和药学上可被接受的赋形剂。
5.权利要求1-3任何一项所述姜黄素类似物及其药用盐或权利要求4所述的组合物在制备抗癌药物中的应用。
6.如权利要求5所述的应用,其特征在于,所述的癌症为宫颈癌、肝癌、纤维肉瘤、结肠癌、黑色素瘤、乳腺癌、肺癌、组织细胞淋巴瘤、慢性髓原白血病、原髓细胞白血病。
7.一种如权利要求1所述姜黄素类似物的制备方法,其特征在于:式II通过如下方法制备:以姜黄素为原料,将其结构中的酚羟基以乙酰基保护,然后用碘甲烷对其活性亚甲基的两个氢原子进行亲核取代以引入双甲基,最后脱去乙酰基保护基而得关键中间体B4,以1,3-溴氯丙烷对B4酚羟基烃化,在酚羟基位置引入氯丙烷基侧链,然后,经硼氢化钠还原,将两个酮羰基还原为醇羟基,得关键中间体B6,最后再与不同的取代仲胺反应得到式II化合物;
8.一种如权利要求1所述姜黄素类似物的制备方法,其特征在于:式III的制备方法如下:以姜黄素为原料,先以醋酐将酚羟基保护,在β-二酮亚甲基位置位引入双苄基,脱保护得到双苄基姜黄素C1,经催化氢化将双键还原生成四氢双苄基姜黄素C2,再以1,3-溴氯丙烷对C2酚羟基烃化,并用硼氢化钠将羰基还原得到C4,最后与不同的仲胺反应得到式III化合物;
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