CN115260179A - 一种2-氨基嘧啶衍生物及其制备方法和应用 - Google Patents
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Abstract
本发明属于制药领域,公开了一种2‑氨基嘧啶衍生物及其制备方法和应用。以达拉菲尼和对醛基苯甲酸为原料,反应后,经无水乙醇、硼氢化钠处理后得化合物4;然后在二氯甲烷中加入化合物4,1‑(3‑二甲氨基丙基)‑3‑乙基碳二亚胺盐酸盐EDC,4‑二甲氨基吡啶DMAP,邻苯二胺,搅拌反应后,减压回收溶剂,硅胶柱层析得目标化合物,即2‑氨基嘧啶衍生物。所得的2‑氨基嘧啶衍生物或其药学上可接受的盐,均可以用于制备治疗肿瘤的药物,尤其是治疗黑色素瘤的药物。
Description
技术领域
本发明属于制药领域,涉及一种2-氨基嘧啶衍生物及其制备方法和应用。
背景技术
黑色素瘤,又称恶性黑色素瘤,是来源于黑色素细胞的一类恶性肿瘤,常见于皮肤,亦见于黏膜、眼脉络膜等部位。
达拉菲尼(Dabrafenib,2)一种BRAFV600突变型特异性抑制剂,无细胞试验中IC50为0.8nM,作用于B-Raf(wt)和c-Raf的IC50分别低4和6倍。达拉菲尼已获FDA批准,用于携带BRAFV600E突变的手术不可切除性黑色素瘤或转移性黑色素瘤成人患者的治疗。常见的不良反应(≥20%)角化过度,头痛,发热,关节痛,乳头状瘤,脱发和掌跖erythrodysesthesia综合征。
Mocetinostat(3)是一种有效的HDAC抑制剂,对非小细胞肺癌具有明确的细胞毒性。
因此,制备一种新的治疗肿瘤的药物,对BRAFV600E突变黑色素瘤具有比达拉菲尼、Mocetinosta更好的抗肿瘤效果,意义重大。
发明内容
本发明提供一种2-氨基嘧啶衍生物及其制备方法和应用。该化合物对BRAFV600E突变黑色素瘤具有比达拉菲尼、Mocetinosta更好的抗肿瘤效果,可用于制备治疗肿瘤的药物,该化合物对黑色素瘤具有显著的细胞毒性,
一种2-氨基嘧啶衍生物,结构式为(1):
一种2-氨基嘧啶衍生物的制备方法,合成路线为:
步骤为:
(1)将达拉菲尼(化合物2)的甲醇溶液和对醛基苯甲酸的甲醇溶液混合,一定温度下反应后,冷却至室温,过滤,固体加入无水乙醇,分批加入硼氢化钠,至红色褪色,继续反应后,冷却至室温;加入水,然后用盐酸调节pH,过滤,固体烘干,得白色固体,为化合物4;
(2)在二氯甲烷中加入化合物4,1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐EDC,4-二甲氨基吡啶DMAP,室温搅拌,加入邻苯二胺,继续室温搅拌,减压回收溶剂,硅胶柱层析得目标化合物1,即2-氨基嘧啶衍生物。
进一步地,具体步骤为:
(1)将含有1.0mmol的达拉菲尼的10mL甲醇溶液和含有1.1mmol的对醛基苯甲酸的5mL甲醇溶液混合,于50℃反应5h,冷却至室温,过滤,所得固体中加入10mL无水乙醇,分批加入1.0g的硼氢化钠,至红色褪色,于50℃反应1h,冷却至室温,加入10mL的水,先破坏大部分没有反氢化钠,然后用6M的盐酸调节pH至5,过滤,固体烘干,得白色固体,为化合物4;
(2)在10mL的二氯甲烷中,加入0.5mmol的化合物4,0.55mmol的1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐EDC,0.55mmol的4-二甲氨基吡啶DMAP,室温搅拌20min,加入0.55mmol的邻苯二胺,室温搅拌24小时,减压回收溶剂,硅胶柱层析得目标化合物,即2-氨基嘧啶衍生物。
本发明制备的2-氨基嘧啶衍生物或其药学上可接受的盐在制备治疗肿瘤药物中的应用。
本发明制备的2-氨基嘧啶衍生物或其药学上可接受的盐在制备治疗黑色素瘤药物中的应用。
治疗肿瘤药物,有效成分为上述2-氨基嘧啶衍生物或其药学上可接受的盐。
需要特别指出的是,化合物1的类似物1-1,1-2,1-3,1-4没有显示出类似的良好的抗肿瘤作用,提示化合物1的结构具有特异性。
本发明的有益效果为:
本发明获得的2-氨基嘧啶衍生物,对BRAFV600E突变黑色素瘤具有比达拉菲尼、Mocetinosta更好的抗肿瘤效果,可用于制备治疗肿瘤的药物。
具体实施方式
下面的实施例可使本专业技术人员可全面的理解本发明,但不以任何方式限制本发明。
实施例1:
化合物1的合成路线
实验操作:
达拉菲尼(2)0.518g(1.0mmol)的10mL的甲醇溶液和0.165g(1.1mmol)的对醛基苯甲酸的5mL的甲醇溶液混合,于50℃反应5h,冷却至室温,过滤,固体加入10mL的无水乙醇,溶液,分批加入1.0g的硼氢化钠,至红色褪色,于50℃反应1h,冷却至室温,加入10mL的水,用6M的盐酸PH至5,过滤,固体烘干,得白色固体(化合物4)0.45g。
10mL的二氯甲烷中加入0.376g(0.5mmol)的化合物4,0.11g(0.55mmol)的1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC),0.067g(0.55mmol)的4-二甲氨基吡啶(DMAP)室温搅拌20min,加入0.12g(0.55mmol)的邻苯二胺,室温搅拌24小时,减压回收溶剂,硅胶柱层析得目标化合物,即2-氨基嘧啶衍生物。
将分析测定:
1HNMR(DMSO-d6,δ,ppm,300MHz):8.42(s,1H),8.42(s,1H),8.03(t,1H),7.97(d,1H),7.92(d,2H),7.53-7.50(m,2H),7.68(t,1H),7.43(t,1H),7.35(t,1H),7.28-7.21(m,4H),7.14(d,1H),6.96(t,1H),6.77-6.75(m,3H),6.58(t,1H),4.65(d,2H)1.40(s,9H),1.55(d,3H)。
实施例2:
目标化合物1对A-375黑色素肿瘤细胞抑制作用研究
取对数生长期肿瘤细胞,加入0.25wt.%胰酶消化3min,用含10wt.%小牛血清RPMI-1640悬浮细胞,计数,调细胞浓度为1×105个/mL,以100μL/孔接种于Top-count专用96孔细胞培养板中,37℃,5%CO2孵育24h。然后将细胞分为实验组和对照组,实验组加入目标化合物1溶液,每一浓度均为四复孔,且每孔体积均补足200μL。各组加样后分别继续培养72h,于培养结束前,每孔分别加入3H-TdR 3×105Bq,用Top-count测定各孔CPM(count perminute)值。计算各实验组药物对细胞增殖的半数抑制浓度(median inhibitionconcentration,IC50)。
表1目标化合物对A-375黑色素肿瘤细胞增殖(72小时)的半数抑制浓度(IC50,μmol/L)
化合物 | IC<sub>50</sub>(μmol/L) |
Dabrafenib | 0.03 |
Mocetinostat | >0.1 |
化合物1 | 0.008 |
化合物1-1 | >0.1 |
化合物1-2 | >0.1 |
化合物1-3 | >0.1 |
化合物1-4 | >0.1 |
以上实验结果显示:化合物1对A-375黑色素肿瘤细胞增殖体外抑制作用明显高于Dabrafenib、Mocetinostat。提示本发明的实施例化合物对A-375黑色素肿瘤细胞有更强的细胞毒性。而化合物1的类似物1-1,1-2,1-3,1-4没有显示出良好的对A-375黑色素肿瘤细胞增殖体外抑制作用。
Claims (7)
3.如权利要求2所述的制备方法,其特征在于:具体步骤为:
(1)将含有1.0mmol的达拉菲尼的10mL甲醇溶液和含有1.1mmol的对醛基苯甲酸的5mL甲醇溶液混合,于50℃反应5h,冷却至室温,过滤,所得固体中加入10mL无水乙醇,分批加入1.0g的硼氢化钠,至红色褪色,于50℃反应1h,冷却至室温,加入10mL的水,先破坏大部分没有反氢化钠,然后用盐酸调节pH至5,过滤,固体烘干,得白色固体,为化合物4;
(2)在10mL的二氯甲烷中,加入0.5mmol的化合物4,0.55mmol的1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐EDC,0.55mmol的4-二甲氨基吡啶DMAP,室温搅拌20min,加入0.55mmol的邻苯二胺,室温搅拌24小时,减压回收溶剂,硅胶柱层析得目标化合物,即2-氨基嘧啶衍生物。
4.如权利要求3所述的制备方法,其特征在于:步骤(1)中,所述盐酸的浓度为6M。
5.治疗肿瘤药物,其特征在于,有效成分为权利要求1所述化合物或其药学上可接受的盐。
6.权利要求1所述化合物或其药学上可接受的盐在制备治疗肿瘤药物中的应用。
7.权利要求1所述化合物或其药学上可接受的盐在制备治疗黑色素瘤药物中的应用。
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