CN102153508B - 3,5-(e)-二亚苄基-n-环丙基哌啶-4-酮及其在制备治疗抗肿瘤药物中的应用 - Google Patents
3,5-(e)-二亚苄基-n-环丙基哌啶-4-酮及其在制备治疗抗肿瘤药物中的应用 Download PDFInfo
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Abstract
本发明公开一种3,5-(E)-二亚苄基-N-环丙基哌啶-4-酮及其在制备治疗抗肿瘤药物中的应用,本发明的3,5-(E)-二亚苄基-N-环丙基哌啶-4-酮类化合物可由芳醛与N-环丙基-4-哌啶酮进行Claisen-Schimidt反应得到。本发明的3,5-(E)-二亚苄基-N-环丙基哌啶-4-酮类化合物能够显著抑制多种人肿瘤细胞的增殖,该化合物可用于制备治疗白血病、结肠癌、肝癌、皮肤癌、胃癌、乳腺癌、***癌或其他恶性肿瘤的药物。
Description
技术领域:
本发明涉及合成抗肿瘤药物及制备方法,具体涉及合成3,5-(E)-二亚苄基-N-环丙基哌啶-4-酮类化合物及其用于制备抗肿瘤药物的应用。
背景技术:
以4-哌啶酮为中间体与芳香醛缩合得到一系列化合物具有抗肿瘤、抗炎、抗菌等活性,其中代表化合物EF-24(结构式如下)体内外具有较好的抗肿瘤活性[文献1,2]。但目前未有文献报道3,5-(E)-二亚苄基-N-环丙基哌啶-4-酮类化合物的合成及其在制备治疗抗肿瘤药物中的应用。
EF-24的化学结构式
参考文献
1.Subramaniam D,May R,Sureban SM,et al.Diphenyl difluoroketone:a curcumin derivative with potent in vivo anticancer activity.[J].Cancer Res.,2008,68(6):1962-1969.
2.Adams BK,Ferstl EM,Davis MC,etal.Synthesis and biological evaluation ofnovel curcumin analogs as anti-cancer and anti-angiogenesis agents[J].Bioorg Med Chem,2004,12(14):3871-3883.
发明内容:
本发明的目的之一在于提供一种3,5-(E)-二亚苄基-N-环丙基哌啶4-酮化合物。
本发明的3,5-(E)-二亚苄基-N-环丙基哌啶-4-酮化合物通式如下:
本发明也可采用含有治疗有效量的3,5-(E)-二亚苄基-N-环丙基哌啶4-酮类化合物和药学上可接受的载体来组成组合物。式(I)中的Ar所代表的基团为:取代苯基或杂环,苯基上的取代基可以是R1,R2,R3,R4,R5中的至少一个非氢取代基,若全是氢,取代苯基即为苯基(见实施例7),或者有两个取代基如R1,R3,也可以三个取代基如R3,R4,R5,最多可以有五个取代基R1,R2,R3,R4,R5,R1,R2,R3,R4,R5可以是相同的基团也可以是不同的基团,如可以R1=R2,也可以,R1≠R2,所述的取代基优选烷基,烷氧基,卤素,卤代烷基或硝基,最优选甲氧基,1-4个碳的烷基,氟,三氟甲基或硝基;最优选的苯基上的取代基为2-甲氧基(见实施例5);2,5-二甲氧基(见实施例4);3,4-二甲氧基(见实施例3);2,4,5-三甲氧基(见实施例1);2-氟(见实施例2);2-氯(见实施例9);2-溴(见实施例8);4-甲基(见实施例12);2-三氟 甲基(见实施例6);3,4-甲撑二氧基(见实施例10);取代苯基Ar为2-亚萘基(见实施例11)。所述的杂环优选吡啶基,吡咯基或呋喃基,最优选3-吡啶基。
本发明目的之二在于提供3,5-(E)-二亚苄基-N-环丙基哌啶-4-酮类化合物的制备方法。本发明的化合物3,5-(E)-二亚苄基-N-环丙基哌啶-4-酮化合物可由芳醛与N-环丙基-4-哌啶酮进行Claisen-Schimidt反应得到。反应方程式示意如下:
本发明目的之三在于提供3,5-(E)-二亚苄基-N-环丙基哌啶-4-酮类化合物及其组成的组合物在制备抗肿瘤药物中的应用。
本发明的3,5-(E)-二亚苄基-N-环丙基哌啶-4-酮类化合物,可用于但不局限于作为制备治疗白血病、结肠癌、皮肤癌、胃癌、肝癌、乳腺癌或***癌的药物。
本发明提供用于治疗抗肿瘤的药物组合物,其中含有治疗有效量的权利要求1~5中任意一项的化合物和药学上可接受的载体。所述的治疗有效量为药物学上在临床上有治疗效果的最低药量。
本发明提供用于治疗自血病、结肠癌、皮肤癌、胃癌、肝癌、乳腺癌、***癌的药物组合物,其中含有治疗有效量的权利要求1~5中任意一项的化合物和药学上可接受的载体。所述的治疗有效量为药物学上在临床上有治疗效果的最低药量。
根据本发明的实施方案,本发明所述的治疗癌症的3,5-(E)-二亚苄基-N-环丙基哌啶-4-酮类化合物的药物或组合物,可以治疗的癌症的例子包括但不局限于自血病、结肠癌、皮肤癌、胃癌、肝癌、乳腺癌、***癌。
本发明的有益效果为:本发明的3,5-(E)-二亚苄基-N-环丙基哌啶-4-酮一类化合物体外能够显著抑制多种人肿瘤细胞的增殖,见表1;体内口服给药以化合物2为例加100mg·Kg-1·d-1量能对H22肝癌移植瘤小鼠抑瘤率达48.4%,见表2,图1,说明本发明的3,5-(E)-二亚苄基-N-环丙基哌啶-4-酮类化合物可用于作为制备治疗自血病、结肠癌、肝癌、皮肤癌、胃癌、乳腺癌或***癌等的药物。
而且本发明的制备方法与背景技术中的EF-24化合物制备方法不同,EF-24化合物制备方法不能用于本发明的制备,EF-24合成是用饱和HCl的冰醋酸等作催化剂和反应溶剂,反应时间一般为2d。本发明的目标化合物3,5-(E)-二亚苄基-N-环丙基哌啶-4-酮是用碱催化,乙醇为溶剂,反应时间明显缩短,一般在30min-1d,分离纯化简单,并且溶剂无腐蚀性,绿色安全。本发明制备的时间短,效能高,制备工艺简单,收率高,达到60%以上,最高可达到88%。
附图说明:
图1为本发明的化合物2对小鼠H22腹水型肝癌移植瘤的抑制作用图,
图中上排的为未加化合物2的肝癌移植瘤形状图,图中与上排对照的下排为添加化合物2后肝癌移植瘤的抑制形状图,上下图相比可知添加化合物2后小鼠H22腹水型肝癌移植瘤受到明显抑制。
具体实施方式:
下面结合实施例对本发明进行详细说明:
熔点用上海精密仪器厂X-4型显微熔点仪测定,温度未经校正。1H、13C NMR谱采用Bruker Avance III型核磁共振仪(400MHz)测定,TMS为内标。质谱采用Agilent 1100LC/MSD Trap离子阱液质联用仪测定。所用原料1-环丙基4-哌啶酮、芳醛购自阿法埃莎(天津)化学有限公司,氢氧化钠、无水乙醇、浓盐酸、醋酸购自国药化学试剂公司。
3,5-(E)-二亚苄基-N-环丙基哌啶4-酮的合成通法
N-环丙基-4-哌啶酮348mg(2.5mmol),氢氧化钠20mg(0.5mmol),无水乙醇20mL,混合后室温搅拌,待澄清后加入芳醛(5mmol),室温下反应0.5h~24h,有固体析出。抽滤,滤饼用无水乙醇洗涤,真空干燥。本实例中所采用的各种芳醛(其摩尔数均为5mmol),参见如下:实施例一~十二所合成的1~12化合物的化学结构式如下:
即1-12种3,5-(E)-二亚苄基-N-环丙基哌啶-4-酮类化合物的化学结构式为:
1-12种3,5-(E)-二亚苄基-N-环丙基哌啶-4-酮类化合物经熔点仪、核磁共振仪和质谱仪测定,其测定值如下:
实施例一、当芳醛是2,4,5-三甲氧基苯甲醛时,制得3,5-(E)-二(2,4,5-三甲氧基亚苄基)-N-环丙基哌啶-4-酮(化合物1),为桔红色粉末,收率60%,mp150~153℃,ESI-MS:496.3(M+1);1H-NMR(CDCl3,ppm)δ:8.02(2H,s,-CH=),6.82(2H,s,Ar-H),6.55(2H,s,Ar-H),4.63(4H,s,-CH2-),3.86(18H,s,-OCH3),1.93(s,1H,-N-CH(CH2)2),0.44-0.39(m,4H, -CH(CH2)2).δ:87.99,154.18,151.13,142.54,131.93,116.36,114.32,109.17,97.27,56.86,56.35,56.21,55.19,37.42,6.67
实施例二、当芳醛是2-氟苯甲醛时,制得3,5-(E)-二(2-氟亚苄基)-N-环丙基哌啶-4-酮(化合物2),为淡黄色粉末,收率88%,mp169~172℃,ESI-MS:352.3(M+1);1H-NMR(CDCl3,ppm)δ:7.88(2H,s,-CH=),7.39~7.31(4H,m,Ph-H),7.22~7.11(4H,m,Ph-H),3.86(s,4H,-CH2-),1.90(s,1H,-N-CH(CH2)2),0.47-0.40(m,4H,-CH(CH2)2).13C-NMR(100MHz,CDCl3,ppm)δ:186.71,162.22,159.72,135.09,130.76,129.25,123.99,123.25,115.82,54.98,37.70,6.77.
实施例三、当芳醛是3,4-二甲氧基苯甲醛时,制得3,5-(E)-二(3,4-二甲氧基亚苄基)-N-环丙基哌啶-4-酮(化合物3),为黄色粉末,收率66%,mp195~198℃,ESI-MS:436.3(M+1);1H-NMR(CDCl3,ppm)δ:7.75(2H,s,-CH=),7.06(2H,d,J=8Hz,Ar-H),6.97(2H,s,Ar-H),6.93(2H,d,J=8Hz,Ar-H),4.01(4H,s,-CH2-),3.92(12H,s,-OCH3),1.97(s,1H,-N-CH(CH2)2),0.53-0.48(m,4H,-CH(CH2)2).13C-NMR(100MHz,CDCl3,ppm)δ:187.16,150.01,148.86,136.26,128.40,124.04,123.89,114.04,111.13,55.99,55.75,55.12,37.90,6.73
实施例四、当芳醛是2,5-二甲氧基苯甲醛时,制得3,5-(E)-二(2,5-二甲氧基亚苄基)-N-环丙基哌啶-4-酮(化合物4),为金黄色粉末,收率77%,mp138~141℃,ESI-MS:436.3(M+1);1H-NMR(CDCl3,ppm)δ:7.99(2H,s,-CH=),6.91-6.84(4H,m,Ar-H),6.81(2H,s,Ar-H),3.89(4H,s,-CH2-),3.80(12H,s,-OCH3),1.89(s,1H,-N-CH(CH2)2),0.43-0.37(m,4H,-CH(CH2)2).13C-NMR(100MHz,CDCl3,ppm)δ:187.43,152.99,152.96,133.70,132.14,125.38,116.34,114.88,111.89,56.17,55.87,55.05,37.59,6.77
实施例五、当芳醛是2-二甲氧基苯甲醛时,制得3,5-(E)-二(2-甲氧基亚苄基)-N-环丙基哌啶-4-酮(化合物5),为淡黄色针状晶体,收率80%,mp178~181℃,ESI-MS:476.3(M+1);1H NMR(CDCl3,ppm)δ:8.05(2H,s,-CH=),7.36(2H,t,J=8Hz,Ar-H),7.25(2H,d,J=8Hz,Ar-H),6.99(2H,t,J=8Hz,Ar-H),6.92(2H,d,J=8Hz,Ar-H),3.88(4H,s,-CH2-),3.85(6H,s,-OCH3),1.88(s,1H,-N-CH(CH2)2),0.42-0.35(m,4H,-CH(CH2)2).13C-NMR(100MHz,CDCl3,ppm)δ:187.56,158.52,133.40,132.19,130.39,130.31,124.63,120.09,110.82,55.52,55.15,37.67,6.72
实施例六、当芳醛是2-三氟甲基苯甲醛时,制得3,5-(E)-二(2-三氟甲基亚苄基)-N-环丙基哌啶-4-酮(化合物6),为黄色针晶,收率60%,mp152~154℃,ESI-MS:452.3(M+1); 1H-NMR(400MHz,CDCl3,ppm)δ:8.04(2H,s,-CH=),7.75(2H,d,Ph-H,J=7.6Hz),7.59(2H,t,Ph-H,J=7.6Hz),7.48(2H,t,Ph-H,J=7.6Hz),7.30(2H,d,Ph-H,J=7.6Hz),3.73(s,4H,-CH2-),1.86(s,1H,-N CH(CH2)2),0.39-0.33(m,4H,-CH(CH2)2).13C-NMR(100MHz,CDCl 3,ppm)δ:186.11,162.22,159.72,135.09,130.76,129.25,123.99,123.25,115.82,54.05,36.65,6.62.
实施例七、当芳醛是苯甲醛时,制得3,5-(E)-二(2-亚苄基)-N-环丙基哌啶-4-酮(化合物7),淡黄色粉末,收率80%,mp 156~159℃,ESI-MS:316.3(M+1);1H-NMR(400MHz,CDCl3,ppm)δ7.80(2H,s,-CH=),7.46~7.35(10H,m,Ph-H),3.99(s,4H,-CH2-),1.97~1.92(m,1H,-N-CH(CH2)2),0.50-0.38(m,4H,-CH(CH2)2).13C-NMR(100MHz,CDCl3,ppm)δ:187.54,136.26,135.37,133.50,13 0.49,128.97,128.59,128.23,127.25,55.18,38.03,6.81
实施例八、当芳醛是2-溴苯甲醛时,制得3,5-(E)-二(2-溴亚苄基)-N-环丙基哌啶4-酮(化合物8),黄色粉末,收率77%,mp130~135℃,ESI-MS:492.3(M+1);1H-NMR(400MHz,CDCl3,ppm)δ:7.94(2H,s,-CH=),7.66(2H,d,Ph-H,J=8Hz),7.37(2H,t,Ph-H,J=7.6Hz),7.27~7.21(4H,q,Ph-H,J=7.2Hz),3.82(s,4H,-CH2-),1.88(s,1H,-N-CH(CH2)2),0.44-0.37(m,4H,-CH(CH2)2).13C-NMR(100MHz,CDCl3,ppm)δ:186.81,136.30,135.52,134.25,133.19,130.32,130.09,127.10,125.24,54.51,37.49,6.74
实施例九、当芳醛是2-氯苯甲醛时,制得3,5-(E)-二(2-氯亚苄基)-N-环丙基哌啶4-酮(化合物9),淡黄色粉末,收率74%,mp 152~155℃,ESI-MS:384.3(M+1); 1H-NMR(400MHz,CDCl3,ppm)δ:7.99(2H,s,-CH=),7.34~7.26(8H,m,Ph-H),3.83(s,4H,-CH2-),1.88(m,1H,-N-CH(CH2)2),0.45-0.35(m,4H,-CH(CH2)2).13C-NMR(100MHz,CDCl3,ppm)δ:186.81,135.21,134.63,133.89,133.74,130.34,129.97,129.95,126.47,54.67,37.58,6.76
实施例十、当芳醛是胡椒醛时,制得3,5-(E)-二(3,4-甲撑二氧基亚苄基)-N-环丙基哌啶-4-酮(化合物10),黄色粉末,收率68%,mp215~218℃,ESI-MS:404.3(M+1); 1H-NMR(400MHz,CDCl3,ppm)δ:7.68(2H,s,-CH=),6.97(2H,d,Ph-H,J=8Hz),6.93(2H,s,Ph-H),6.88(2H,d,Ph-H,J=8Hz),6.03(4H,s,O-CH2-O),3.94(s,4H,-CH2-),1.95(m,1H,-N-CH(CH2)2),0.54-0.40(m,4H,-CH(CH2)2)。13C-NMR(100MHz,CDCl3,ppm)δ:187.24,148.38,147.91,135.93,132.02,129.62,126.09,110.06,108.61,101.48,55.26,38.14,6.87
实施例十一、当芳醛是2-萘甲醛时,制得3,5-(E)-二(2-亚萘基)-N-环丙基哌啶4-酮(化合物11),淡黄色粉末,收率82%,mp 199~202℃,ESI-MS:416.3(M+1); 1H-NMR(400MHz,CDCl3,ppm)δ:7.99(2H,s,-CH=),7.92~7.98(4H,m,Ph-H),7.88~7.85(4H,m,Ph-H),7.56~7.51(6H,m,Ph-H),4.14(s,4H,-CH2-),2.02(m,1H,-N-CH(CH2)2),0.50-0.40(m,4H,-CH(CH2)2).13C-NMR(100MHz,CDCl3,ppm)δ:136.61,133.76,133.26,133.14,132.93,130.58,128.58,128.23,127.72,127.50,127.13,126.58,55.19,37.91,6.85
实施例十二、当芳醛是4-甲基苯甲醛时,制得3,5-(E)-二(4-甲基亚苄基)-N-环丙基哌啶-4-酮(化合物12),淡黄色粉末,收率88%,mp 196~199℃,ESI-MS:344.3(M+1); 1H-NMR(400MHz,CDCl3,ppm)δ:7.76(2H,s,-CH=),7.33(4H,d,Ph-H,J=8Hz),7.24(4H,d,Ph-H,J=8Hz),3.99(s,4H,-CH2-),2.40(s,6H,Ph-CH3)1.95(m,1H,-N-CH(CH2)2),0.45-0.35(m,4H,-CH(CH2)2).13C-NMR(100MHz,CDCl3,ppm)δ:187.49,139.27,136.22,132.78,132.62,130.60,129.36,55.22,38.01,21.45,6.78
实施例十三
体外抗肿瘤活性的检测:
使用的肿瘤细胞株有:人类慢性粒细胞白血病急变细胞K562,人原髓细胞白血病细胞HL60,人结肠癌细胞SW480,人结肠癌细胞SW1116,以上细胞均来源于中科院上海细胞库。
细胞培养于添加10%小牛血清的RPMI1640培养中,在37℃,5%CO2培养箱中培养,取对数生长期细胞用于实验。
将一定数量处于对数生长期的细胞,按一定密度接种于96孔板里(贴壁细胞待贴壁后), 实验组分别加入不同浓度的受试药物,对照组加同浓度溶剂,另设空白组(只加培养基,无细胞),每组设三个平行孔,37℃培养48h,加入5mg/ml的MTT溶液20ul/孔,继续培养4h后,离心弃上清,加入DMSO 150ul,振荡10min,充***解后,用全自动酶标仪(美国BIO-RAD公司生产)检测570nm处的吸光度(OD570)值。根据吸光度计算细胞生长抑制率。细胞生长抑制率=[OD对照-OD实验]/[OD对照-OD空白]×100%。
以同一药物的不同浓度对肿瘤细胞生长抑制率作图,可得到剂量反应曲线,根据线性回归方程求出该药物对细胞生长抑制率为50%的浓度即半数抑制浓度IC50。结果见表1,表1中的化合物编号1~12代表实施例一~十二所合成的化合物,EF-24做为对照。从表1可以看到,化合物2对HL60细胞抑制活性比EF-24强,化合物7对K562细胞抑制活性比EF-24强,化合物3、化合物9对SW1116细胞抑制活性比EF-24强,说明3,5-(E)-二亚苄基-N-环丙基哌啶-4-酮类化合物能够显著抑制多种人肿瘤细胞的增殖。本发明的保护范围不仅限于以上所述的实施例。
表13,5-(E)-二亚苄基-N-环丙基哌啶-4-酮类化合物对体外培养肿瘤细胞的IC50(μmol·L-1)
化合物编号 | K562 | HL60 | SW480 | SW1116 |
1 | 12.5 | 33.6 | 134 | 49.5 |
2 | 4.22 | 5.13 | 25.8 | 17.25 |
3 | 8.90 | 2.60 | ||
4 | 18.6 | 19.7 | 32.3 | 14.9 |
5 | 17.8 | 44.0 | 49.1 | 35.6 |
6 | 24.0 | 38.6 | ||
7 | 0.559 | 74.0 | ||
8 | 6.86 | 14.1 | ||
9 | 14.2 | 10.4 | ||
10 | 37.2 | 61.0 | ||
11 | 412 | 89.6 | ||
12 | 417 | 37.9 | ||
EF-24 | 1.58 | 11.2 | 10.0 | 11.7 |
*空格为化合物未做该细胞株
实施例十四化合物2对小鼠H22腹水型肝癌细胞生长的影响
按常规方法接种肿瘤细胞:取腹腔传代6~8d生长良好的乳白色腹水,用生理盐水稀释至1×107个/mL,以0.2mL接种于小鼠右腋皮下,接种后动物随机分组。实验分为2组,每组10只,阴性对照组(给予等量溶剂)、化合物2100mg/kg组(化合物2用泊洛沙姆制备成固体分散体)。于接种24h后灌胃给药,每天一次,连续7d。于第8d称体重,颈椎脱臼处死动物。剥离肿瘤组织,用滤纸吸干后称重。计算肿瘤抑制率。
抑瘤率=(1-实验组瘤重/阴性对照组瘤重)×100%
化合物2对小鼠H22腹水型皮下移植瘤的抑制作用明显,100mg/kg/d灌胃的抑制率为48.4%,差别具有显著性(P<0.01)(结果见表2、图1)。
表2化合物2对小鼠H22腹水型肝癌移植瘤的抑制作用
**:p<0.01,*:p<0.05 vs control.t test
Claims (8)
2.根据权利要求1所述的化合物,其特征在于苯基上的取代基为2-甲氧基;2,5-二甲氧基;3,4-二甲氧基;2,4,5-三甲氧基;2-氟;2-氯;2-溴;4-甲基;2-三氟甲基。
4.用于治疗抗肿瘤的药物组合物,其中含有治疗有效量的权利要求1~3中任意一项的化合物和药学上可接受的载体。
5.用于治疗白血病、结肠癌、皮肤癌、胃癌、肝癌、乳腺癌或***癌的药物组合物,其中含有治疗有效量的权利要求1~3中任意一项的化合物和药学上可接受的载体。
6.权利要求4所述的药物组合物在制备治疗白血病、结肠癌、皮肤癌、胃癌、肝癌、乳腺癌或***癌药物中的应用。
7.权利要求1~3中任意一项的化合物在制备抗肿瘤药物中的应用。
8.根据权利要求7所述的应用,其特征在于肿瘤为白血病、结肠癌、皮肤癌、胃癌、肝癌、乳腺癌或***癌。
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CN101434600A (zh) * | 2008-12-25 | 2009-05-20 | 福建医科大学 | 姜黄素哌啶酮结构类似物及其用于制备抗肿瘤药物的应用 |
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刘洋 等.3, 5-二亚苄基哌啶- 4-酮类化合物的合成及其体外抗肿瘤活性.《中国药物化学杂志》.2009,第19卷(第5期),全文. * |
刘洋等.3 5-二亚苄基哌啶- 4-酮类化合物的合成及其体外抗肿瘤活性.《中国药物化学杂志》.2009 |
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