CN104016986B - 3-取代-6-(1-取代哌嗪基)-1,2,4-三氮唑并[3,4-a]酞嗪类化合物、其制备方法和用途 - Google Patents
3-取代-6-(1-取代哌嗪基)-1,2,4-三氮唑并[3,4-a]酞嗪类化合物、其制备方法和用途 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
本发明属于药物化学领域,公开了具有抗肿瘤活性的3-取代-6-(1-取代哌嗪基)-1,2,4-三氮唑并[3,4-a]酞嗪类化合物、其制备方法及其用途。所述化合物具有通式<b>Ⅰ</b>结构,通式<b>Ⅰ</b>中:R1为氢、甲基、苯基;R2为氢、4-氟苯基、4-氯苯基、3-三氟甲基苯基、2-氟苯基。初步的体外抗肿瘤活性评价发现该系列化合物对多种肿瘤细胞具有明显的抑制和杀伤作用。可作为活性成分开发成为新药后应用于临床预防和癌症治疗。
Description
技术领域
本发明属于药物化学领域,涉及1,2,4-三氮唑并[3,4-a]酞嗪类衍生物,具体涉及抗肿瘤活性的3-取代-6-(1-取代哌嗪基)-1,2,4-三氮唑并[3,4-a]酞嗪类化合物、其制备方法及其用途。
背景技术
目前有大量的文献报道了酞嗪衍生物的生物活性及其药理活性。酞嗪类化合物有一系列的生物活性:如抗微生物、抗真菌、抗细菌、抗肿瘤及抗癫痈活性等,因此,在药物分子设计方面得到了广泛的应用,其抗肿瘤活性的优秀代表为:琥珀酸瓦他拉尼(vatalanib/PTK787),目前正在进行III期临床试验,并且一系列的II和I期研究正在进行中。三氮唑类化合物由于其生物活性的多样性而备受重视,不同结构的三氮唑类化合物具有不同的生物活性,文献报道了该类化合物具有广谱的抗菌活性、抗肿瘤活性、抗炎活性、抗HIV活性、抗血小板聚集等活性,比如:“三氮唑类化合物的合成及抗真菌活性研究,胡晓燕,孙翠兰等,《化学研究与应用》,2010年12期”,“三氮唑衍生物抗肿瘤作用及其机制的研究进展,刘彬,胡国强等《药物生物技术》,2009年05期,472-477”。而哌嗪及其系列化合物是化工产业和医药产业之间承上启下的重要产品,广泛应用于医药、农药,参见文献“哌嗪及其衍生物的合成,高俊文,张勇,《精细与专用化学品》,2001,11期,13-15”,“哌嗪类药物的现状及其研究进展,《山西大同大学学报(自然科学版)》,韩生华,温雪山等,2009年第3期,公开日期2009年6月”。因此,依据药物分子合成设计拼合原理,合成一系列的3-取代-6-(1-取代哌嗪基)-1,2,4-三氮唑并[3,4-a]酞嗪类化合物,探讨其药物活性,为药物开发及形成我国自主知识产权保护具有重要意义。
发明内容
为开发利用现有的临床药物资源,本发明目的在于提供一类3-取代-6-(1-取代哌嗪基)-1,2,4-三氮唑并[3,4-a]酞嗪类化合物,从而为寻找新的抗肿瘤活性化合物开辟一条新途径;本发明另一目的在于提供其制备方法及其在制备抗肿瘤药物中的应用。
本发明所述3-取代-6-(1-取代哌嗪基)-1,2,4-三氮唑并[3,4-a]酞嗪类化合物结构通式如下:
通式Ⅰ
R1为氢、甲基、苯基;R2为氢、4-氟苯基、4-氯苯基、3-三氟甲基苯基、2-氟苯基。
优选如下化合物之一:
1、2-{4-(1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}-N-(4-氟苯基)乙酰胺
2、2-{4-(1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}-N-(4-氯苯基)乙酰胺
3、2-{4-(1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}-N-(3-三氟甲基苯基)乙酰胺
4、2-{4-(1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}-N-(2-氟苯基)乙酰胺
5、N-(4-氯苯基)-2-{4-(3-甲基-1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}乙酰胺
6、N-(2-氟苯基)-2-{4-(3-甲基-1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}乙酰胺
7、N-(4-氟苯基)-2-{4-(3-甲基-1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}乙酰胺
8、2-{4-(3-甲基-1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}-N-(3-三氟甲基苯基)乙酰胺
9、N-(4-氯苯基)-2-{4-(3-苯基-1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}乙酰胺
10、N-(2-氟苯基)-2-{4-(3-苯基-1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}乙酰胺
11、2-{4-(3-苯基-1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}-N-(3-三氟甲基苯基)乙酰胺
12、N-(4-氟苯基)-2-{4-(3-苯基-1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}乙酰胺。
其制备路线:
具体包括如下步骤:
1、将邻苯二甲酸酐溶于冰醋酸中,滴加水合肼,加热回流。反应结束后,将反应液冷至室温,抽滤,洗涤,真空干燥,得2,3-二氢酞嗪-1,4-二酮;
2、在2,3-二氢酞嗪-1,4-二酮中加入三氯氧磷,搅拌升温反应,反应结束后,将反应液冷至室温,加入水中析出乳白色固体,抽滤,洗至中性,真空干燥,得产物1,4-二氯酞嗪;
3、无水乙醇中,加入水合肼和1,4-二氯酞嗪,加热反应。反应结束后,冷却至室温,抽滤,真空干燥,得1-氯-4-肼基酞嗪;
4、含1-氯-4-肼基酞嗪的三乙胺溶液中加入二氧六环和原甲酸三乙酯或乙酰氯或苯甲酰氯,升温反应,反应结束后,冷却至室温,经萃取,干燥,抽滤,减压蒸馏,得式1化合物;
5、将式1化合物的N,N-二甲基甲酰胺溶液中加入NaOH和哌嗪,升温反应,反应结束后,冷却至室温,经抽滤,得化合物式2化合物。
6、将式2化合物的丙酮溶液中加入到乙酰胺或2-氯-N-(取代苯基)乙酰胺和K2CO3,升温反应,反应结束后,冷却至室温,经抽滤,洗涤,减压蒸馏。柱分离得式3目标化合物。
2-氯-N-(取代苯基)乙酰胺采用如下方法制备:在取代苯胺的三乙胺溶液中加入丙酮,然后缓慢加入氯乙酰氯,室温下反应。减压蒸馏。将残余物倾入冰水,室温搅拌,抽滤,得到2-氯-N-(取代苯基)乙酰胺。所述的取代苯胺为4-氟苯胺、4-氯苯胺、3-三氟甲基苯胺、2-氟苯胺。
本发明所述3-取代-6-(1-取代哌嗪基)-1,2,4-三氮唑并[3,4-a]酞嗪类化合物对胃癌细胞(MGC-803)、食管鳞癌细胞(EC9706)、人宫颈癌(Hela)、乳腺癌(MCF-7)、有很好的抑制作用。其中有些化合物对胃癌细胞(MGC-803)、食管鳞癌细胞(EC9706)、人宫颈癌(Hela)、乳腺癌(MCF-7)的IC50值小于10(μmol/L),与正在临床试验的抗肿瘤药物瓦他拉尼和临床上已使用的抗肿瘤药物5-氟尿嘧啶做对照,优于其活性。因此,本发明提供的此类3-取代-6-(1-取代哌嗪基)-1,2,4-三氮唑并[3,4-a]酞嗪类化合物为开发新型抗肿瘤药物和联合用药开辟了新途径。
具体实施方式
下面结合具体实施例,进一步阐述本发明。这些实施例仅用于说明本发明而不用于限制本发明要求保护的范围。
合成化合物表征使用的仪器:NMR谱使用瑞典BrukerDPX-400型超导核磁共振仪测定,TMS为内标;高分辨质谱使用Waters-Micromass公司Q-Tof质谱仪测定。
实施例1
2-{4-(1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}-N-(4-氟苯基)乙酰胺的制备
取邻苯二甲酸酐6.00g(40mmol)于100mL单口瓶中,加入22mL冰醋酸搅拌,随着温度的上升溶解速度逐渐加快,至120℃原料全部溶解,缓慢滴加水合肼2.81mL(44mmol),反应液变成淡黄色乳状,而后又变成白色乳状,继续加热回流约4h。将反应液冷至室温,抽滤,用石油醚洗涤两次,真空干燥,得白色产物2,3-二氢酞嗪-1,4-二酮。
取1.68g(10mmol)上述2,3-二氢酞嗪-1,4-二酮于50mL三口瓶中,加入三氯氧磷15mL搅拌,温度至80℃时原料完全溶解,再缓慢升温至110℃,反应约1h后TLC(V石油醚:V乙酸乙酯=3:1)显示反应完全。将反应液冷至室温,逐滴加入到碎冰上,边滴加边搅拌,析出乳白色固体,抽滤,水洗至中性,真空干燥,得产物1,4-二氯酞嗪。
取50ml无水乙醇于100mL单口瓶中,加入3.73ml(76.51mmol)水合肼,升温至78℃,缓慢加入2.01g(10mmol)1,4-二氯酞嗪,溶解3min后,有絮状物析出,反应0.5h后,TLC(V石油醚:V乙酸乙酯=3:1)显示反应完全。冷却至室温,抽滤,然后将固体加入20ml无水乙醚中超声10min,抽滤,真空干燥,得黄色产物1-氯-4-肼基酞嗪。
取1.5g(7.73mmol)化合物1-氯-4-肼基酞嗪于50mL单口瓶中,加入25ml二氧六环,1.44mL(9.28mmol)原甲酸三乙酯,1.08ml(7.73mmol)三乙胺,然后缓慢升温至100℃,反应约6h后TLC(V石油醚:V乙酸乙酯=1:2)显示反应完全,冷却至室温,用二氯?与水萃取,无水硫酸镁干燥,抽滤,减压蒸馏,得淡黄色固体6-氯-1,2,4-三氮唑并[3,4-a]酞嗪。
取0.20g(1mmol)化合物6-氯-1,2,4-三氮唑并[3,4-a]酞嗪于25ml单口瓶中,加入1.51mlN,N-二甲基甲酰胺,溶解后,加入0.12g(3mmol)NaOH,加入1.20eq的哌嗪,缓慢升温至100℃,1h后TLC(V石油醚:V丙酮=5:3)显示反应完全。冷却至室温,加入少量水,析出沉淀,抽滤,取少量N,N-二甲基甲酰胺于25ml单口瓶中,加入滤饼,超声5min,加入少量水超声5min后,抽滤,得6-(哌嗪-1-基)-1,2,4-三唑并[3,4-a]酞嗪。
取3.60ml(30mmol)三乙胺和1.90ml(20mmol)4-氟苯胺于50ml的单口瓶中,加入25ml丙酮,然后在0-10℃温度下缓慢加入2.14ml(26mmol)氯乙酰氯,室温下反应8h。将混合物在减压下浓缩。将残余物倾入冰水(5ml),在室温下搅拌1h,过滤分离,得到2-氯-N-(4-氟苯基)乙酰胺。
取0.25g(1mmol)6-(哌嗪-1-基)-1,2,4-三唑并[3,4-a]酞嗪于25ml的单口瓶中,加入4ml丙酮和0.28g(1.5mmol)2-氯-N-(4-氟苯基)乙酰胺,然后加入0.35g(2.5mmol)K2CO3,加热至60℃反应8h,冷却至室温,抽滤,少量丙酮洗涤,滤液减压下浓缩。二氯甲烷:甲醇=40:1进行柱分离得2-{4-(1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}-N-(4-氟苯基)乙酰胺。
产物为黄色胶状固体。1HNMR(400MHz,CDCl3)δ9.09(s,1H,NH),8.89(s,1H,CH),8.68(d,J=7.7Hz,1H,ArH),8.05(d,J=8.0Hz,1H,ArH),7.92(t,J=7.4Hz,1H,ArH),7.79(t,J=7.4Hz,1H,ArH),7.58(dd,J=8.0,4.6Hz,2H,ArH),7.06(t,J=8.4Hz,2H,ArH),3.52(s,4H,CH2),3.33(s,2H,),2.97(s,4H,CH2).13CNMR(101MHz,CDCl3)δ167.67,160.61,158.13,139.36,133.51,133.29,130.42,126.31,124.68,124.16,121.23,121.16,120.48,115.87,115.64,61.95,53.19,51.42.HR-MS(ESI):Calcd.C21H20FN7O,[M+H]+m/z:406.1792,found:406.1788.。
实施例22-{4-(1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}-N-(4-氯苯基)乙酰胺的制备
用4-氯苯胺替代4-氟苯胺,制备方法同实施例1。
产物为黄色胶状固体。1HNMR(400MHz,CDCl3)δ9.15(s,1H,NH),8.86(s,1H,ArH),8.63(d,J=7.8Hz,1H,ArH),8.03(d,J=8.1Hz,1H,ArH),7.89(m,1H,ArH),7.77(dt,J=22.4,7.6Hz,1H,ArH),7.55(m,2H,ArH),7.30(m,2H,ArH),3.50(s,4H,CH2),3.31(s,2H,),2.95(m,4H,CH2).13CNMR(101MHz,CDCl3)δ167.88,158.12,142.31,139.31,136.06,133.27,130.46,129.25,129.05,126.35,124.56,124.04,120.72,120.46,61.97,53.15,51.38.HR-MS(ESI):Calcd.C21H20ClN7O,[M+H]+m/z:422.1496,found:422.1494.。
实施例32-{4-(1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}-N-(3-三氟甲基苯基)乙酰胺的制备
用3-三氟甲基苯胺替代4-氟苯胺,制备方法同实施例1。
产物为黄色胶状固体。1HNMR(400MHz,CDCl3)δ9.29(s,1H,NH),8.87(s,1H,CH),8.65(d,J=7.8Hz,1H,ArH),8.04(d,J=8.0Hz,1H,ArH),7.90(m,2H,ArH),7.80(m,2H,ArH),7.47(t,J=7.8Hz,1H,ArH),7.38(d,J=7.5Hz,1H,ArH),3.52(s,4H,CH2),3.34(s,2H,),2.97(s,4H,CH2).13CNMR(101MHz,CDCl3)δ168.17,158.13,142.32,139.32,137.99,133.29,131.41,130.47,129.65,126.34,124.56,124.09,122.57,120.91,120.47,116.18,61.98,53.17,51.35.HR-MS(ESI):Calcd.C22H20F3N7O,[M+H]+m/z:456.1760,found:456.1760.。
实施例42-{4-(1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}-N-(2-氟苯基)乙酰胺的制备
用2-氟苯胺替代4-氟苯胺,制备方法同实施例1。
产物为黄色胶状固体。1HNMR(400MHz,CDCl3)δ9.53(s,1H,NH),8.89(s,1H,CH),8.66(d,J=7.9Hz,1H,ArH),8.39(t,J=7.5Hz,1H,ArH),8.05(d,J=8.1Hz,1H,ArH),7.90(t,J=7.5Hz,1H,ArH),7.78(t,J=7.5Hz,1H,ArH),7.12(m,3H,ArH),3.53(s,4H,CH2),3.35(s,2H,),2.97(s,4H,CH2).13CNMR(101MHz,CDCl3)δ167.91,158.07,153.72,151.30,142.33,139.38,133.21,130.37,126.35,125.94,124.66,124.49,124.11,121.32,120.50,114.87,61.99,53.09,51.43.HR-MS(ESI):Calcd.C21H20FN7O,[M+H]+m/z:406.1792,found:406.1789.。
实施例5N-(4-氯苯基)-2-{4-(3-甲基-1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}乙酰胺的制备
用乙酰氯替代原甲酸三乙酯,反应时间延长14h,制备方法同实施例1,得3-甲基-6-(哌嗪-1-基)-1,2,4-三唑并[3,4-a]酞嗪。用4-氯苯胺替代4-氟苯胺,3-甲基-6-(哌嗪-1-基)-1,2,4-三唑并[3,4-a]酞嗪替代6-(哌嗪-1-基)-1,2,4-三唑并[3,4-a]酞嗪制备方法同实施例1。
产物为黄色胶状固体。1HNMR(400MHz,CDCl3)δ9.15(s,1H,NH),8.63(d,J=7.9Hz,1H,ArH),8.03(d,J=8.1Hz,1H,ArH),7.88(t,J=7.4Hz,1H,ArH),7.76(dd,J=11.3,4.0Hz,1H,ArH),7.56(dd,J=9.5,6.7Hz,2H,ArH),7.33(t,J=5.8Hz,2H,ArH),3.52(s,4H,CH2),3.32(s,2H,),2.96(dd,J=11.5,7.0Hz,4H,CH2),2.77(s,3H,CH3).13CNMR(101MHz,CDCl3)δ167.85,157.42,147.69,142.46,136.05,133.07,130.05,129.33,129.09,126.17,125.08,123.90,120.71,119.89,62.02,53.22,51.37,9.80.HR-MS(ESI):Calcd.C22H22ClN7O,[M+H]+m/z:436.1653,found:436.1650.。
实施例6N-(2-氟苯基)-2-{4-(3-甲基-1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}乙酰胺的制备
用2-氟苯胺替代4-氯苯胺,制备方法同实施例5。
产物为黄色胶状固体。1HNMR(400MHz,CDCl3)δ9.54(s,1H,NH),8.66(d,J=7.9Hz,1H,ArH),8.41(t,J=8.0Hz,1H,ArH,ArH),8.04(d,J=8.1Hz,1H,ArH,ArH),7.89(t,J=7.6Hz,1H,ArH),7.76(t,J=7.7Hz,1H,ArH),7.14(m,3H,ArH),3.55(s,4H,CH2),3.36(s,2H,),2.99(d,J=4.3Hz,4H,CH2),2.79(s,3H,CH3).13CNMR(101MHz,CDCl3)δ168.00,157.48,147.64,142.44,133.04,130.01,126.19,125.14,124.71,124.42,123.97,121.36,119.93,114.96,62.07,53.15,51.41,9.81.HR-MS(ESI):Calcd.C22H22FN7O,[M+H]+m/z:420.1948,found:420.1943.。
实施例7N-(4-氟苯基)-2-{4-(3-甲基-1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}乙酰胺的制备
用4-氟苯胺替代4-氯苯胺,制备方法同实施例5。
产物为黄色胶状固体。1HNMR(400MHz,CDCl3)δ9.12(s,1H,NH),8.60(d,J=7.9Hz,1H,ArH),8.02(d,J=8.1Hz,1H,ArH),7.86(t,J=7.3Hz,1H,ArH),7.74(m,1H,ArH),7.56(m,2H,ArH),7.03(m,2H,ArH),3.51(s,4H,CH2),3.31(s,2H,),2.95(m,4H,CH2),2.74(s,3H,CH3).13CNMR(101MHz,CDCl3)δ167.82,160.59,158.15,157.47,147.69,142.45,133.53,133.07,130.09,126.21,124.99,123.87,121.24,119.91,115.70,61.97,53.22,51.38,9.78.HR-MS(ESI):Calcd.C22H22FN7O,[M+H]+m/z:420.1948,found:420.1946.。
实施例82-{4-(3-甲基-1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}-N-(3-三氟甲基苯基)乙酰胺的制备
用3-三氟甲基苯胺替代4-氯苯胺,制备方法同实施例5。
产物为黄色胶状固体。1HNMR(400MHz,CDCl3)δ9.26(s,1H,NH),8.65(d,J=7.8Hz,1H,ArH),8.04(d,J=8.1Hz,1H,ArH),7.89(dd,J=13.6,6.2Hz,3H,ArH),7.77(t,J=7.7Hz,1H,ArH),7.50(t,J=8.2Hz,1H,ArH),7.41(d,J=7.7Hz,1H,ArH),3.55(s,4H,CH2),3.35(s,2H,),2.98(m,4H,CH2),2.78(s,3H,CH3).13CNMR(101MHz,CDCl3)δ168.16,157.45,147.74,142.48,137.95,133.14,131.68,131.33,130.11,129.70,126.16,125.07,123.98,122.57,121.00,119.91,116.14,62.05,53.27,51.36,9.80.HR-MS(ESI):Calcd.C23H22F3N7O,[M+H]+m/z:470.1916,found:470.1915.。
实施例9N-(4-氯苯基)-2-{4-(3-苯基-1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}乙酰胺的制备
用苯甲酰氯替代原甲酸三乙酯,反应时间延长14h,制备方法同实施例1,得3-苯基-6-(哌嗪-1-基)-1,2,4-三唑并[3,4-a]酞嗪。用4-氯苯胺替代4-氟苯胺,3-苯基-6-(哌嗪-1-基)-1,2,4-三唑并[3,4-a]酞嗪替代6-(哌嗪-1-基)-1,2,4-三唑并[3,4-a]酞嗪制备方法同实施例1。
产物为绿色胶状固体。1HNMR(400MHz,CDCl3)δ9.12(s,1H,NH),8.68(d,J=7.9Hz,1H,ArH),8.45(d,J=7.2Hz,2H,ArH),8.04(d,J=8.1Hz,1H,ArH),7.87(dd,J=14.1,6.8Hz,1H,ArH),7.77(t,J=7.7Hz,1H,ArH),7.54(m,5H,ArH),7.31(m,2H,ArH),3.55(s,4H,CH2),3.33(s,2H,),2.98(m,4H,CH2).13CNMR(101MHz,CDCl3)δ167.85,157.58,152.67,148.67,143.36,136.03,133.23,130.30,129.97,129.37,129.11,128.63,127.69,126.71,126.10,125.07,124.12,120.72,119.68,62.06,53.24,51.43.HR-MS(ESI):Calcd.C27H24ClN7O,[M+H]+m/z:498.1809,found:498.1806.。
实施例10N-(2-氟苯基)-2-{4-(3-苯基-1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}乙酰胺的制备
用2-氟苯胺替代4-氯苯胺,制备方法同实施例9。
产物为白色胶状固体。1HNMR(400MHz,CDCl3)δ9.51(s,1H,NH),8.69(d,J=7.7Hz,1H,ArH),8.49(m,2H,ArH),8.38(tt,J=12.8,6.5Hz,1H,ArH),8.03(d,J=8.1Hz,1H,ArH),7.87(dd,J=11.2,4.0Hz,1H,ArH),7.76(m,1H,ArH),7.53(m,3H,ArH),7.16(m,1H,ArH),7.09(m,2H,ArH),3.55(d,J=19.4Hz,4H,CH2),3.34(d,J=12.0Hz,2H,),2.99(m,4H,CH2).13CNMR(101MHz,CDCl3)δ167.99,157.54,153.73,151.31,148.61,143.34,133.13,130.21,129.89,128.61,127.68,126.78,126.13,125.08,124.64,124.50,124.10,121.38,119.70,114.88,62.05,53.11,51.46.HR-MS(ESI):Calcd.C27H24FN7O,[M+H]+m/z:482.2105,found:482.2100.。
实施例112-{4-(3-苯基-1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}-N-(3-三氟甲基苯基)乙酰胺的制备
用3-三氟甲基苯胺替代4-氯苯胺,制备方法同实施例9。
产物为白色胶状固体。1HNMR(400MHz,CDCl3)δ9.28(s,1H,NH),8.68(d,J=7.4Hz,1H,ArH),8.45(dd,J=8.2,1.2Hz,2H,ArH),8.04(d,J=8.0Hz,1H,ArH),7.86(m,3H,ArH),7.77(m,1H,ArH),7.52(m,4H,ArH),7.38(m,1H,ArH),3.56(s,4H,CH2),3.35(s,2H,),2.99(m,4H,CH2).13CNMR(101MHz,CDCl3)δ168.22,157.59,148.62,143.35,138.01,133.20,131.45,130.29,129.94,129.64,128.61,127.66,126.71,126.12,125.03,124.08,122.62,120.90,119.67,116.24,62.05,53.23,51.36.HR-MS(ESI):Calcd.C28H24F3N7O,[M+H]+m/z:532.2073,found:532.2070.。
应用实例
体外抗肿瘤活性测试:以MTT法采用五种细胞系,分别为胃癌细胞(MGC-803)、食管鳞癌细胞(EC9706)、人宫颈癌(Hela)、乳腺癌(MCF-7)。
收集对数期细胞,调整细胞悬液浓度,每孔加入100μl,铺板调整待测细胞密度,(边缘孔用PBS填充)。5%CO2下37℃孵育24h,至细胞单层铺满孔底(96孔平地板),加入浓度梯度本发明化合物,一般设9个浓度,每孔200μl,设3个复孔。5%CO2下37℃孵育72h,倒置显微镜下观察,每孔加入20μlMTT溶液(5mg/ml,即0.5%MTT),继续培养4h。终止培养,小心吸去孔内培养液,每孔加入150μl二甲基亚砜,置摇床上低速振荡10min,使结晶物充分溶解。在酶联免疫检测仪OD490nm处测量各孔的吸光值。用SPSS软件对实验结果进行统计并计算IC50值(μM)。结果如下表。
表1体外抗肿瘤活性实验数据
Claims (5)
1.3-取代-6-(1-取代哌嗪基)-1,2,4-三氮唑并[3,4-a]酞嗪类化合物,其特征在于,具有通式Ⅰ所述结构:
通式Ⅰ
通式Ⅰ中:R1为氢、甲基或苯基;R2为氢、4-氟苯基、4-氯苯基、3-三氟甲基苯基或2-氟苯基。
2.如权利要求1所述的3-取代-6-(1-取代哌嗪基)-1,2,4-三氮唑并[3,4-a]酞嗪类化合物,其特征在于:该化合物是以下化合物之一:
2-{4-(1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}-N-(4-氟苯基)乙酰胺
2-{4-(1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}-N-(4-氯苯基)乙酰胺
2-{4-(1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}-N-(3-三氟甲基苯基)乙酰胺
2-{4-(1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}-N-(2-氟苯基)乙酰胺
N-(4-氯苯基)-2-{4-(3-甲基-1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}乙酰胺
N-(2-氟苯基)-2-{4-(3-甲基-1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}乙酰胺
N-(4-氟苯基)-2-{4-(3-甲基-1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}乙酰胺
2-{4-(3-甲基-1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}-N-(3-三氟甲基苯基)乙酰胺
N-(4-氯苯基)-2-{4-(3-苯基-1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}乙酰胺
N-(2-氟苯基)-2-{4-(3-苯基-1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}乙酰胺
2-{4-(3-苯基-1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}-N-(3-三氟甲基苯基)乙酰胺
N-(4-氟苯基)-2-{4-(3-苯基-1,2,4-三氮唑并[3,4-a]酞嗪-6-基)哌嗪-1-基}乙酰胺。
3.制备如权利要求1所述的3-取代-6-(1-取代哌嗪基)-1,2,4-三氮唑并[3,4-a]酞嗪类化合物的方法,其特征在于:包括如下步骤:
(1)、将邻苯二甲酸酐溶于冰醋酸中,滴加水合肼,加热回流;反应结束后,将反应液冷至室温,抽滤,洗涤,真空干燥,得2,3-二氢酞嗪-1,4-二酮;
(2)、在2,3-二氢酞嗪-1,4-二酮中加入三氯氧磷,搅拌升温反应,反应结束后,将反应液冷至室温,加入水中析出乳白色固体,抽滤,洗至中性,真空干燥,得产物1,4-二氯酞嗪;
(3)、无水乙醇中,加入水合肼和1,4-二氯酞嗪,加热反应;反应结束后,冷却至室温,抽滤,真空干燥,得1-氯-4-肼基酞嗪;
(4)、含1-氯-4-肼基酞嗪的三乙胺溶液中加入二氧六环和原甲酸三乙酯或乙酰氯或苯甲酰氯,升温反应,反应结束后,冷却至室温,经萃取,干燥,抽滤,减压蒸馏,得式1化合物;
(5)、在式1化合物的N,N-二甲基甲酰胺溶液中加入NaOH和哌嗪,升温反应,反应结束后,冷却至室温,经抽滤,得化合物式2化合物;
(6)、在式2化合物的丙酮溶液中加入乙酰胺或2-氯-N-(取代苯基)乙酰胺和K2CO3,升温反应,反应结束后,冷却至室温,经抽滤,洗涤,减压蒸馏,柱分离得通式I目标化合物;
通式I中R1、R2与权利要求1相同。
4.如权利要求1-2其中之一所述的3-取代-6-(1-取代哌嗪基)-1,2,4-三氮唑并[3,4-a]酞嗪类化合物在药物制备中的应用,其特征在于:作为活性成分用于制备抗肿瘤药物。
5.如权利要求4所述的3-取代-6-(1-取代哌嗪基)-1,2,4-三氮唑并[3,4-a]酞嗪类化合物在药物制备中的应用,其特征在于:作为活性成分用于制备抗胃癌细胞、食管鳞癌细胞、人宫颈癌或乳腺癌细胞的药物。
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