CN103848827A - 一种含苯并三氮唑类衍生物在抗癌药物中的应用 - Google Patents
一种含苯并三氮唑类衍生物在抗癌药物中的应用 Download PDFInfo
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Abstract
一类苯并三氮唑类衍生物,其特征是它有如下通式:R为:
Description
技术领域
本发明涉及苯并三氮唑类衍生物及其制备方法与用途。
背景技术
苯并三氮唑,是医药工业上常用的一类原料,可以衍生出苯并三氮唑类衍生物。其具有显著的生物活性,一直是药物化学领域研究的热点,在临床上广泛运用于肿瘤疾病的治疗。选择性作用于特定靶点的高效、低毒、特异性强的新型抗癌药物已成为当今抗肿瘤药物研究开发的重要方向。目前为止,已有十多种蛋白酪氨酸激酶抑制剂和抗体进入I-II期临床试验阶段,个别的已经上市,并取得了令人鼓舞的治疗结果。
FAK在不同的组织中有表达,在恶性转移肿瘤中的表达特别高。FAK在不同肿瘤组织中的表达是不同的,在前列腺癌、乳腺癌、结肠癌、卵巢癌、口腔癌和甲状腺癌的发生过程中,FAK的表达均有提高。尤其是在乳腺癌和结肠癌组织中,FAK表达极高。铃蟾肽、肝细胞生长因子(HGF)、促乳素等可以刺激肿瘤细胞中FAK的表达。FAK不具有经典的癌蛋白功能,但它在整合素信号转导和整合素所参与肿瘤发展过程及转移进程中都起着重要作用,这意味着FAK可能成为针对恶性细胞多元发展过程中的一个靶点。
发明内容
本发明的目的在于提供一类本病三氮唑类衍生物以及它们的制备方法与用途。
本发明的技术方案如下:
1.一类苯并三氮唑类衍生物,其特征是它有如下通式:
式中R为:
R为:
一种上述的苯并三氮唑类衍生物的制法,它由下列步骤组成:
步骤1.在反应容器中加入邻苯二胺和适量的有机溶剂,搅拌使之溶解,再加入适量亚硝酸钠,加热回流一段时间(用TLC跟踪反应,直至至少一种原料 很少甚至没有),用40%氢氧化钠溶液将产物的PH调至酸性,再用氯化钠溶液水洗,最后重结晶得化合物2苯并三氮唑。
步骤2.将上面合成的化合物2和氯乙酸乙酯,碳酸钾混合起来加入到适量的有机溶剂中溶解,加热回流一段时间,(用TLC跟踪反应,有两种产物)用旋转蒸发仪蒸去机溶剂,用柱层析分离得到化合物3
步骤3.将合成的化合物3溶于有机溶剂中,在冰水浴中滴加水合肼,在冰浴中搅拌2~10小时,有白色固体析出,将白色固体过滤出来即得到化合物4.
步骤4.将化合物4溶于有机溶剂中,再向其中加入含各种不同取代基的苯乙酸,加热回流5~10小时。用碳酸钾溶液将反应产物溶液调至合适的PH值,即有固体析出,过滤可得终产物。
本发明的磺胺类衍生物对人乳腺癌细胞(MCF-7)有明显的抑制作用,因此本发明的磺胺类衍生物可以应用于制备抗肿瘤药物。
具体实施方式
实施例一:2-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-5-benzyl-1,3,4-oxadiazole
(化合物1)的制备步骤1.在反应容器中加入邻苯二胺和适量的有机溶剂,搅拌使之溶解,再加入适量亚硝酸钠,加热回流一段时间(用TLC跟踪反应,直至至少一种原料很少甚至没有),用40%氢氧化钠溶液将产物的PH调至4.4-4.6,再用氯化钠溶液水洗,最后重结晶得化合物2苯并三氮唑。
步骤2.将上面合成的化合物2和氯乙酸乙酯,碳酸钾混合起来加入到适量的有机溶剂中溶解,加热回流一段时间,(用TLC跟踪反应,有两种产物)用旋转蒸发仪蒸去机溶剂,用柱层析分离得到化合物3
步骤3.将合成的化合物3溶于有机溶剂中,在冰水浴中滴加水合肼,在冰浴中搅拌5~6小时,有白色固体析出,将白色固体过滤出来即得到化合物4.
步骤4.将化合物4溶于有机溶剂中,再向其中加入苯乙酸,加热回流7~8小时。用碳酸钾溶液将反应产物溶液调至合适的PH值,即有固体析出,过滤可得终产物。
放入产率69%。Mp 230-232℃.1H-NMR(300MHz,DMSO3,δppm):5.4364-5.5723(d,J=40.77Hz,2H),7.2128-7.2414(m,1H),7.1774-7.2914(m,4H),7.2914-7.3591(m,1H),7.3591-7.3835(m,2H).7.3835-7.4097(m,2H);7.4097-7.4341(m,1H)MS(ESI):291.31([M+H]+).Anal.calc.for C16H13N5O:C,65.97;H,4.50;N,24.04;O,5.49%;found:C,65.60;H,4.52;N,24.03%。
实施例二:2-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-5-(3-bromobenzyl)-1,3,4-oxadiazole
制备方法同实施例一。以间溴苯乙酸代替苯乙酸,得到白色粉末状目标化合物。产率65%。Mp 242℃.1H-NMR(300MHz,DMSO-d6,δppm):4.2781(s,2H),6.3795(s,2H),7.2846-7.2895(m,2H),7.4471-7.4593(m,1H),7.4664-7.8418(m, 2H),7.5721-7.5990(m,2H),7.8345-7.8623(m,1H);8.0752-8.1031(d,J=8.37,1H)MS(ESI):370.20([M+H]+).Anal.calc.forC16H12BrN5O:C,51.91;H,3.27;Br,21.58;N,18.92;O,4.32;found:C,51.94;H,3.31;Br,21.60;N,18.89;O,4.33
实施例三:2-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-5-(4-bromobenzyl)-1,3,4-oxadiazole
制备方法同实施例一。以对溴苯乙酸代替苯乙酸,得到白色粉末状目标化合物。产率62%。Mp 230-232℃.1H-NMR(300MHz,DMSO-d6,δppm):5.6543-5.6762(m,2H);6.3772(s,2H),7.2591-7.316(m,2H),7.4487-7.4586(m,3H),7.4873-7.5031(m,2H),8.0653-8.1041(m,1H).MS(ESI):370.20([M+H]+).Anal.calc.forC16H12BrN5O:C,51.91;H,3.27;Br,21.58;N,18.92;O,4.32%;found:C,51.90;H,3.28;N,18.91%。
实施例四:2-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-5-(3-chlorobenzyl)-1,3,4-oxadiazole(化合物4)的制备
制备方法同实施例一。间氯苯乙酸代替苯乙酸,得到白色粉末状状目标化合物。产率65%。Mp 235-237℃.1H-NMR(300MHz,DMSO-d6,δppm):5.6743-5.6845(m,2H);6.0834(s,2H),7.3822-7.4533(m,2H),7.5432-7.5983(m,3H),7.6634-7.7072(m,1H),8.0453-8.0718(m,2H).MS(ESI):325.75([M+H]+).Anal.calc.For C16H12ClN5O:C,58.99;H,3.71;Cl,10.88;N,21.50;O,4.91%;found:C,56.01;H,3.73;N,21.48%。
实施例五:2-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-5-(3-fluorobenzyl)-1,3,4-oxadiazole(化合物5)的制备
制备方法同实施例一。以间氟苯乙酸胺代替苯乙酸,得到白色粉末状目标化合物。产率63%。Mp 240-242℃.1H-NMR(300MHz,DMSO,δppm):5.6182-5.6771(m,4H);7.2225-7.3841(m,5H),7.4353-7.5298(m,1H),7.5556-7.5804(m,1H),8.0388-8.0668(m,1H).MS(ESI):309.30([M+H]+).Anal.calc.for C16H12FN5O:C,62.13;H,3.91;F,6.14;N,22.64;O,5.17%;found:C,62.14;H,3.90;N,22.66%。
实施例六:2-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-5-(3-methoxybenzyl)-1,3,4-oxadiazole(化合物6)的制备
制备方法同实施例一。以间甲氧苯乙酸代替苯乙酸,得到白色粉末状目标化合物。产率67%。Mp 240-242℃.1H-NMR(300MHz,DMSO,δppm):5.5413-5.6168(m, 2H),6.8342-6.8623(m,3H),7.1780-7.2055(m,3H),7.3841-7.4072(m,1H),7.4322-7.5462(m,1H),7.5718-7.7736(m,1H),8.0363-8.0638(m,1H),10.0121(s,1H);10.2376(s,1H);10.6527(s,1H)MS(ESI):321.33([M+H]+).Anal.calc.forC17H15N5O2:C,63.54;H,4.71;N,21.79;O,9.96%;found:C,63.50;H,4.73;N,21.80%。
实施例七:2-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-5-(4-nitrobenzyl)-1,3,4-oxadiazole
制备方法同实施例一。以对硝基苯乙酸代替苯乙酸,得到白色粉末状目标化合物。产率64%。Mp 235-237℃.1H-NMR(300MHz,DMSO,δppm):5.6492(s,2H),7.5786-7.6030(m,1H),7.8370-7.8651(m,2H),8.0449-8.0705(m,2H),8.1420-8.2119(m,3H),8.3217-8.4655(m,2H).MS(ESI):336.30([M+H]+).Anal.calc.for C16H12N6O3:C,57.14;H,3.60;N,24.99;O,14.27%;found:C,57.18;H,3.58;N,25.01%。
实施例八:2-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-5-(4-methoxybenzyl)-1,3,4-oxadiazole(化合物8)的制备
制备方法同实施例一。以对甲氧苯乙酸代替苯乙酸,得到白色粉末状目标化合物。产率62%。Mp 169-170℃.1H-NMR(300MHz,DMSO,δppm):5.6719-5.7853(m,3H),6.8107-6.8393(m,2H),7.0643-7.0929(m,3H),7.4221-7.4489(m,3H),7.5458-7.5702(m,3H),7.5702-7.8232(m,1H),8.0518-8.0792(s,1H).MS(ESI):321.33([M+H]+).Anal.calc.forC17H15N5O2:C,63.54;H,4.71;N,21.79;O,9.96%;found:C,63.51;H,4.73;N,21.80%。
实施例九:2-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-5-(2-methoxybenzyl)-1,3,4-oxadiazole(化合物8)的制备
制备方法同实施例一。以临甲氧苯乙酸代替苯乙酸,得到白色粉末状目标化合物。产率64%。Mp 170-172℃.1H-NMR(300MHz,DMSO,δppm):5.6424-5.6428(s,3H),6.4284-6.4286(m,2H),7.0982-7.1493(m,4H),7.4648-7.5452(m,3H),8.0163-8.2064(m,2H),8.6754-8.8802(s,1H).MS(ESI):307.11([M+H]+).Anal.calc.for C16H13N5O2:C,62.53;H,4.26;N,22.79;O,10.41%;found:C,62.56;H,4.28;N,22.77%。
实施例十:苯并三氮唑生物体外抗肿瘤活性研究
采用MTT[3-(4.5)-双甲基-2-噻唑-(2,5)-苯基溴化四氮唑蓝]法来测定苯并三氮唑类衍生物对宫颈癌细胞株(Hela)和肝癌细胞株(HepG2)的半数抑制浓度(IC50)。
(1)培养液(每升)的配制:①悬浮细胞:RPMI-1640培养粉一袋(10.4g),新生牛血清100ml,青霉素溶液(20万U/ml)0.5ml,链霉素溶液(20万U/ml)0.5ml,加三蒸水溶解后,用5.6%的NaHCO3溶液调PH值至7.2-7.4,最后定容至1000ml。过滤灭菌。②贴壁细胞:同上,再加入NaHCO32.00g,HEPES 2.38g。
(2)D-Hanks缓冲液(每升)的配制:NaCl 8.00g,KCl 0.40g,Na2HPO4·12H2O 0.06g,KH2PO4 0.06g,NaHCO3 0.35g。高压灭菌。
(3)胰蛋白酶液的配制:利用D-Hanks缓冲液配成浓度为0.5%胰蛋白酶 液。过滤除菌。
(4)实验药液的配制:将测试样品用少量的三蒸水溶解配成储备液,一般按实验最高浓度的10倍配制储备液。根据化合物溶解性不同,可用三蒸水直接溶解,或用少量DMSO助溶,再加三蒸水溶解。DMSO在培养液中的浓度不宜过大,加药后的每孔细胞悬液中DMSO的终浓度一般不超过0.05%-0.1%。储备液保存于-20℃冰箱中备用。
(5)人宫颈癌细胞Hela以及肝癌细胞HepG的培养:为贴壁生长细胞,常规培养于DMEM培养液内(含10%胎牛血清、100U/ml链霉素),置于37℃、5%CO2培养箱中培养,每隔1-2天传代一次。传代时将原瓶中培养液转移至离心管中,1000rpm离心5min,弃去原培养液,加入等量新鲜培养液,吹打均匀,移取适量至新鲜培养瓶中,再补充新鲜培养液至原体积(培养液体积约为培养瓶容量的1/10)。
(6)细胞孵育:取对数生长期的肿瘤细胞,调细胞悬液浓度为1-1.5×105个ml-1。在96孔培养板中每孔加细胞悬液100μl,置37℃,5%CO2培养箱中培养24h。培养24h后,分别按设计加入药液。
(8)加药:将测试药液按照最终浓度的浓度梯度分别加入到各个孔中,每个浓度设6个平行孔。实验分为药物试验组(分别加入不同浓度的测试药)、对照组(只加培养液和细胞,不加测试药)和空白组(只加培养液,不加细胞和测试药)。将加药后的96孔板置于37℃,5%CO2培养箱中培养48h。阳性对照药物的活性按照测试样品的方法测定。
(9)存活细胞的测定:在培养了24h后的96孔板中,每孔加MTT 40μl(用D-Hanks缓冲液配成4mg/ml)。在37℃放置4h后,移去上清液。每孔加150μl DMSO,振荡5min,使formazan结晶溶解。最后,利用自动酶标仪在570nm波长处检测各孔的光密度(OD值)。
抑制率的计算:细胞生长的抑制率按照下列公式计算:
生长抑制率=(1-存活率)×100%=[1-(OD实验-OD空白)/(OD对照-OD空白)]×100%(OD实验表示测试药物组的平均光密度,OD对照表示对照组的平均光密度,OD空白表示对照组的平均光密度)。
半数抑制浓度(IC50)定义为当50%的肿瘤细胞存活时的药物浓度。根据测 定的光密度(OD值),制作细胞生长抑制率的标准曲线,在标准曲线上求得其对应的药物浓度。
测得的IC50见表1所示。
表1本发明所列苯并三氮唑类化合物的对肿瘤细胞的抑制IC50值(μg/ml)
Claims (3)
2.一种权利要求1所述的苯并三氮唑类衍生物的制法,其特征是它由下列步骤组成:
步骤1.在反应容器中加入邻苯二胺和适量的有机溶剂,搅拌使之溶解,再加入适量亚硝酸钠,加热回流一段时间(用TLC跟踪反应,直至至少一种原料很少甚至没有),用40%氢氧化钠溶液将产物的PH调至4.4-4.6,再用氯化钠溶液水洗,最后重结晶得化合物2苯并三氮唑。
步骤2.将上面合成的化合物2和氯乙酸乙酯,碳酸钾混合起来加入到适量的有机溶剂中溶解,加热回流一段时间,(用TLC跟踪反应,有两种产物)用旋转蒸发仪蒸去机溶剂,用柱层析分离得到化合物3
步骤3.将合成的化合物3溶于有机溶剂中,在冰水浴中滴加水合肼,在冰浴中搅拌5~6小时,有白色固体析出,将白色固体过滤出来即得到化合物4.
步骤4.将化合物4溶于有机溶剂中,再向其中加入含各种不同取代基的苯乙酸,加热回流7~8小时。用碳酸钾溶液将反应产物溶液调至合适的PH值,即有固体析出,过滤可得终产物。
3.根据权利要求所述的苯并三氮唑类衍生物在制备抗肿瘤药物中的应用。
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