CN106279190B - 香豆素并咪唑衍生物或其可药用盐及用途 - Google Patents
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Abstract
本发明属于化学医药技术领域,特别涉及一种抗肿瘤化合物或其可药用盐及用途。本发明要求保护的化合物具有如式式I所示的结构,药理学实验表明,这些化合物在多种肿瘤细胞株上具有良好的抑制活性。本发明所得化合物具有对于结直肠癌、乳腺癌的选择性抑制活性,同时还具有可以抑制结直肠癌细胞HCT116细胞群落生成的能力,以及可以将SW620细胞周期阻滞在G0/G1期,同时促进HCT116细胞和SW620两种结直肠癌细胞凋亡。
Description
技术领域
本发明属于化学医药技术领域,特别涉及一种香豆素并咪唑衍生物或其可药用盐及用途。
背景技术
癌症,是危害人类健康的重大疾病,现已成为当今世界发达国家和欠发达国家的第一大死因。随着人口增长和老龄化,特别是在欠发达国家,很多不健康的生活方式:吸烟,营养不良,缺乏运动更有可能引发癌症。根据全球癌症数据统计,2012年全球癌症预计新增病例1410万,死亡人数达到820万。随着世界人口日趋老龄化,世界卫生组织估计:预计全世界癌症死亡人数将继续上升,到2030年可能将超过1310万。全球恶性肿瘤患者人数大大增加,癌症治疗策略迫在眉睫。全球男性中,肺癌、前列腺癌、结直肠癌、胃癌以及肝癌位于发病率的前五位,而在女性中,乳腺癌、结直肠癌、肺癌、子宫癌以及胃癌发病率最高。
目前对于癌症的临床治疗,主要采用手术治疗、放射治疗和化学治疗。其中,化学治疗指的是采用化学药物阻止癌细胞的增殖、浸润、转移,直至最终杀灭癌细胞的一种治疗方式。由于目前一线的抗肿瘤化疗药物选择性低,在杀死肿瘤细胞的同时,损伤机体的正常细胞,从而表现出较大的毒副作用,限制其临床应用。如今,一类新型的靶向化疗药物选择性的作用于肿瘤细胞、组织、器官,同时降低对于正常细胞的损伤,具有较低的毒副作用,成为抗肿瘤药物研发的热点。分子靶向药物不同于化疗药物,化疗药物以肿瘤缩小评价疗效;靶向药物既能使肿瘤缩小,又能更多地使肿瘤稳定,延迟复发且一般能保持较好的生活质量,获得较高的临床收益率。
发明内容
本发明针对上述缺陷,提供一种新型的抗肿瘤化合物,具有广泛的抗肿瘤活性。
本发明的技术方案:
本发明要求保护的化合物或其可药用盐具有如式I所示的结构:
其中,
R1为-H,直链或支链、饱和或不饱和、取代或不取代的具有1至10个C原子的烃基,带有或不带取代基的芳环基,带有或不带取代基的芳杂环基;
R2为卤素,直链或支链、饱和或不饱和、取代或不取代的具有1至10个C原子的烃基,氨基,羟基,磺酸基,磺酰胺基,取代或不取代的苯磺酰基,取代或不取代的苯磺酰胺基,羧基,硝基,醛基,酮基,酰胺基,酯基,巯基,氰基,-CF3,C1~C8烷氧基,3~10个碳原子的带有取代基的芳香环基,3~10个碳原子的带有取代基的脂肪环基,1~9个碳原子的带有取代基的芳香族杂环基或1~9个碳原子的带有取代基的脂肪族杂环基。
优选的,所述R1为带有或不带取代基的芳环基、带有或不带取代基的芳杂环基。
更优选的,所述R1
优选的,所述R2为3~10个碳原子的带有取代基的芳香环基,1~9个碳原子的带有取代基的芳香族杂环基。
更优选的,所述R2为Br-,
进一步,所述抗肿瘤化合物优选的具有下述结构式:
本发明还提供了上述化合物的制备方法:采用五元脲环并香豆素衍生物与叔丁醇钾反应得到式I所述化合物。
进一步,上述化合物的制备方法为:将五元脲环并香豆素衍生物(1mmol)与叔丁醇钾(3mmol)溶解于DMF(2mL)中,0℃下缓慢滴加溶解有CH3I(1mmol)的DMF(mL)2溶液,TLC监测;反应至原料反应完全,将反应液导入水中分散,乙酸乙酯萃取至少三次,饱和食盐水反洗至少三次,无水硫酸钠干燥,旋干,石油醚/乙酸乙酯体系过柱,得黄色油状液体即为本发明要求保护的化合物。
优选的,当所述化合物结构式为Ia时,其制备方法为:
先采用申请号201310205309.X的方法制备化合物再与叔丁醇钾反应得到结构式Ia的化合物。
上述化合物或其可药用盐在制备抗肿瘤药物中的用途。
上述化合物或其可药用盐在制备抗肿瘤药物中的用途,所述抗肿瘤药物为拮抗肺癌,胃癌,结直肠癌,肝癌,食道癌、鼻咽癌,胰腺癌,宫颈癌,前列腺癌,子宫内膜癌,卵巢癌、乳腺癌、黑色素瘤或白血病的药物。
更优选的,所述抗肿瘤药物为结直肠癌或乳腺癌。
所述抗肿瘤药物的抗肿瘤活性主要针对人结肠癌细胞(SW620,HCT116,SW480),鼠结直肠癌细胞(CT26),人乳腺癌细胞(MCF-7)、人肺癌细胞(A549)以及人正常肝细胞(LO2)。
本发明通过药理学实验表明,这些化合物在多种肿瘤细胞株上具有良好的抑制活性。
所述抗肿瘤的药物,其活性成分含有上述化合物或其可药用盐中的至少一种。
本发明的有益效果:
本发明在申请号为201310205309.X的专利申请(名称为五元脲环并香豆素衍生物或其可药用盐及用途)的基础上,提供了一种新的结构式的抗肿瘤化合物;即将脲环上的羰基打开,在咪唑环的3位引入甲基和叔丁氧基,同时保留了咪唑环4位N原子上的甲基。本发明所得化合物具有对于结直肠癌、乳腺癌的选择性抑制活性,同时还具有可以抑制结直肠癌细胞HCT116细胞群落生成的能力,以及可以将SW620细胞周期阻滞在G0/G1期,同时促进HCT116细胞和SW620两种结直肠癌细胞凋亡。
附图说明
图1为化合物II b抑制HCT116细胞群落生成演示图。
图2为化合物II b的细胞周期实验,由图可知,IIb可以将SW620细胞周期阻滞在G0/G1期。
图3A为化合物II b对于SW620细胞的凋亡实验图,图3B为化合物II b对于HCT116细胞的凋亡实验图。
具体实施方式
下面结合实施例对本发明的具体实施方式做进一步的描述,并不因此将本发明限制在所述的实施例范围之中。
实施例1
化合物Ia:结构式为其制备方法为:
先采用申请号201310205309.X公开的方法制备化合物
化合物Ia的制备方法:
将5-苯基-4-氧代-7-溴-3,4-二氢咪唑并[4,5-c]香豆素(375mg,1mmol)与叔丁醇钾(336mg,3mmol)溶解于2mL DMF中,0℃下缓慢滴加溶解有CH3I(142mg,1mmol)的2mL的DMF溶液,TLC监测;40分钟左右,有产物生成,但存在反应物,若延长反应时间,产物转变为副产物,产率下降;处理反应:即反应40分钟左右后将反应液导入水中分散,乙酸乙酯萃取三次,饱和食盐水反洗三次,无水硫酸钠干燥,旋干,石油醚/乙酸乙酯体系过柱,得黄色油状液体30mg,产率7%。
1H NMR(400MHz,DMSO)δ7.38(m,5H),7.22(d,J=6.7Hz,2H),6.83(d,J=8.9Hz,1H),3.51(s,3H),2.17(s,3H),1.22(s,9H)ppm.ESI-MS:481,483[M+K]+.
实施例2
化合物II a的制备:反应原理同实施例1,先采用申请号201310205309.X公开的方法制备化合物再参照实施例1的制备方法制得化合物II a:
1H NMR(400MHz,DMSO)δ7.55(d,J=8.3Hz,2H),7.44(dd,J=8.8,2.3Hz,1H),7.37(d,J=2.3Hz,1H),7.29(d,J=8.2Hz,2H),6.84(d,J=8.9Hz,1H),3.49(s,3H),2.18(s,3H),1.66(s,6H),1.23(s,9H)ppm.ESI-MS:510,512[M+H]+.
实施例3
化合物I b的制备:反应原料参照实施例1。
1H NMR(400MHz,DMSO)δ9.14(s,1H),8.52(s,1H),8.01(t,J=7.8Hz,2H),7.83(d,J=10.6Hz,1H),7.75(m,2H),7.63(t,J=7.4Hz,1H),7.40(m,3H),7.30(d,J=7.4Hz,2H),7.05(d,J=8.6Hz,1H),3.63(s,3H),2.21(s,3H),1.19(s,9H)ppm.
实施例4
化合物I c的制备:反应原理参照实施例1。
1H NMR(400MHz,CDCl3)δ7.43(m,6H),7.31(m,4H),7.10(m,2H),6.78(d,J=8.6Hz,1H),3.60(s,3H),2.33(s,3H),1.33(s,9H)ppm.ESI-MS:463.4[M+Na]+.
实施例5
化合物II b的制备:将2-甲基-2-[4-(2-氧代-8-溴-2,3-二氢咪唑并[4,5-c]香豆素-1-基)苯基]丙腈(423mg,1mmol)与叔丁醇钾(336mg,3mmol)溶解于2mL DMF中,0℃下缓慢滴加CH3I(142mg,1mmol)的2mL DMF溶液,TLC监测;40分钟左右,有产物生成,但存在反应物,若延长反应时间,产物转变为副产物,产率下降;处理反应,即反应40分钟左右后将反应液导入水中分散,乙酸乙酯萃取三次,饱和食盐水反洗三次,无水硫酸钠干燥,旋干,石油醚/乙酸乙酯体系过柱,得黄色油状液体31mg,产率6%。
1H NMR(400MHz,CDCl3)δ9.03(s,1H),8.16(s,1H),8.11(d,J=8.4Hz,1H),7.84(d,J=8.1Hz,1H),7.71(t,J=7.6Hz,1H),7.64(d,J=8.5Hz,1H),7.57(t,J=7.5Hz,1H),7.52(s,1H),7.46(d,J=8.2Hz,2H),7.16(d,J=8.1Hz,2H),6.90(d,J=8.6Hz,1H),3.64(s,3H),2.36(s,3H),1.68(s,6H),1.36(s,9H)ppm.
实施例6
化合物II c的制备:反应原理参照实施例1。
1H NMR(400MHz,CDCl3)δ8.63(d,J=4.5Hz,2H),7.58(dd,J=8.6,2.3Hz,1H),7.44(d,J=8.7Hz,3H),7.37(d,J=5.5Hz,3H),7.13(d,J=8.3Hz,3H),6.85(d,J=8.7Hz,1H),3.63(s,3H),2.36(s,3H),1.68(s,36H),1.33(s,9H)ppm.
实施例7
化合物II d的制备:反应原理参照实施例1。
1H NMR(400MHz,CDCl3)δ8.69(s,1H),8.55(d,J=4.1Hz,1H),7.73(d,J=7.6Hz,1H),7.48(dd,J=18.6,8.2Hz,3H),7.35(m,2H),7.14(d,J=7.8Hz,2H),6.86(d,J=8.5Hz,1H),3.63(s,3H),2.37(s,3H),1.69(s,6H),1.34(s,9H)ppm.
实施例8
化合物II e的制备:反应原理参照实施例1。
1H NMR(400MHz,DMSO)δ9.44(s,1H),7.54(d,J=8.3Hz,2H),7.46(d,J=8.3Hz,1H),7.30(m,5H),6.92(d,J=8.7Hz,1H),6.78(d,J=8.0Hz,2H),3.56(s,3H),2.20(s,3H),1.64(s,6H),1.19(s,9H)ppm.
实施例9
化合物II f的制备:反应原理参照实施例1。
1H NMR(400MHz,CDCl3)δ7.44(m,3H),7.32(s,1H),7.15(m,3H),6.78(dd,J=17.5,9.1Hz,3H),6.62(d,J=7.9Hz,1H),3.61(s,3H),2.34(s,3H),1.68(s,6H),1.30(s,9H)ppm.
药效学实验部分
试验例 细胞增殖抑制实验
实验材料
RPMI-1640、DMEM、胎牛血清、胰酶等购自Gibco BRL公司(InvitrogenCorporation,USA),溴化噻唑蓝四唑(MTT)、二甲亚砜(DMSO)为Sigma公司(USA)产品。本试验例涉及的化合物由由上述实施例1-9制备而成,体外实验时用DMSO配制成20mg/ml储存液,置于4℃冰箱避光保存备用,临用时用完全培养液稀释至所需浓度。
细胞系及培养:本实验所用的肿瘤细胞株均购于美国ATCC公司。
实验方法(MTT法)
用完全培养液调整细胞浓度为2×104/ml,接种于96孔板,每孔200μL,培养过夜,次日分别用不同剂量的上述化合物(终浓度分别为20、10、5、2.5、1、25、0.625、0.312μM)处理细胞,同时设等体积的溶剂对照组,DMSO浓度为0.1%(0.1%的DMSO对细胞增殖无影响)。每个组设5个复孔,37℃,5%CO2培养。分别于培养48及72小时后,取1个培养板,每孔加入5mg/ml MTT试剂20μl,继续培养2h,弃上清液,再加入DMSO150μL,振荡摇匀15min,用酶标仪(λ=570nm)测定吸光度(A)值(A值与活细胞数成正比),取其平均值。相对细胞增殖抑制率(%)=(溶剂对照组A570-实验组A570)/溶剂对照组A570×100%。以上各化合物对细胞增殖抑制作用,均采用细胞增殖抑制率(%)表示。然后用IC50计算软件求出半数抑制浓度(IC50,单位为μmol/L)。
实验结果
各化合物在不同肿瘤细胞株上的对细胞增殖抑制作用见表1。从表1可以看出,香豆素并咪唑衍生物中一大部分有较强的体外抗肿瘤活性,初步的体内抗肿瘤实验有明显的抗肿瘤活性特别是对于结直肠癌细胞有专一性;之前的化合物并没有这种专一性。
表1实施例1-9化合物的对细胞增殖抑制作用
-表示未检测
实验发现,IIb化合物对于已测定的三种细胞株有一定的抗肿瘤活性特别是对于结直肠癌有明显的抗肿瘤活性,随后对于IIb化合物的抗肿瘤活性进行了进一步的测试,结果如表2所示。由化合物IIb对于SW620细胞的凋亡实验和化合物IIb对于HCT116细胞的凋亡实验发现,化合物IIb可以促进HCT116细胞和SW620细胞凋亡。
表2 IIb化合物的抗肿瘤活性
化合物 | LO2 | SW620 | SW480 | CT26 |
II b | >40 | 3.55 | 10.0 | 3.5 |
Claims (8)
1.具有如式I所示的结构的化合物或其可药用盐:
其中,
R1为
R2为Br-,
2.根据权利要求1所述的化合物或其可药用盐,其特征在于:所述化合物结构式如下:
3.权利要求1~2任一项所述的化合物或其可药用盐的制备方法,其特征在于:采用五元脲环并香豆素衍生物与叔丁醇钾反应得到式I所述化合物。
4.根据权利要求3所述的化合物或其可药用盐的制备方法,其特征在于:采用五元脲环并香豆素衍生物与叔丁醇钾溶解于DMF中,0℃下缓慢滴加溶解了CH3I的DMF溶液,TLC监测;反应至原料完全反应,将反应液导入水中分散,乙酸乙酯萃取至少三次,饱和食盐水反洗至少三次,无水硫酸钠干燥,旋干,石油醚/乙酸乙酯体系过柱,得黄色油状液体即为化合物或其可药用盐。
5.化合物或其可药用盐在制备抗肿瘤药物中的用途,其中,所述化合物或其可药用盐为权利要求1~2任一项所述的化合物或其可药用盐,或者采用权利要求3或4的方法制得。
6.根据权利要求5所述的化合物或其可药用盐在制备抗肿瘤药物中的用途,其特征在于:所述抗肿瘤药物为拮抗肺癌,胃癌,结直肠癌,肝癌,食道癌、鼻咽癌,胰腺癌,宫颈癌,前列腺癌,子宫内膜癌,卵巢癌、乳腺癌、黑色素瘤或白血病的药物。
7.根据权利要求6所述的化合物或其可药用盐在制备抗肿瘤药物中的用途,其特征在于:抗肿瘤药物为抗结直肠癌或乳腺癌。
8.抗肿瘤的药物,其特征在于:其活性成分含有权利要求1~2任一项所述的化合物或其可药用盐中的至少一种;或者其活性成分含有由权利要求3或4所述方法制得的化合物或其可药用盐中的至少一种。
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