CN110511214B - 二胺基取代芳杂环类化合物及其制备方法和应用 - Google Patents
二胺基取代芳杂环类化合物及其制备方法和应用 Download PDFInfo
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Abstract
一种如式(III)所示的二胺基取代芳杂环类化合物,其制备方法为:化合物(I)与化合物(II)在溶剂1,4‑二氧六环中,在钌金属催化剂和叔丁醇钾作用下,于90~140℃反应16~30h,之后反应液经后处理,得到产物(III);该工艺反应条件温和,原料易得,操作方便,成本低,有着较好的工业应用前景,制备的二胺基取代芳杂环类化合物显示一定的抗人骨肉瘤细胞和抗人乳腺导管瘤细胞活性,为新药筛选及开发奠定了基础,具有较好的实用价值;
Description
(一)技术领域
本发明涉及一种二胺基取代芳杂环类化合物及其制备方法,以及在制备抗肿瘤药物中的应用。
(二)背景技术
芳杂环类化合物作为多种具有生物活性的天然产物及药物的基本骨架,是一类重要的有机合成中间体,其中三嗪类化合物具有抗菌等多种生物活性。因此,研究该类化合物及其应用具有重要的实际应用价值。
(三)发明内容
本发明的目的在于提供一种二胺基取代芳杂环类化合物及其制备方法,以及在制备抗肿瘤药物中的应用。
本发明的技术方案如下:
一种如式(III)所示的二胺基取代芳杂环类化合物:
式(III)中,
R1为苯基或苯甲基;
R2、R3各自独立为氢、甲基、苯基或者R2、R3和两者之间的N组合形成哌啶环;
R4为庚基、苯乙基、苯乙烯基、3-吡啶乙基或3,4-亚甲二甲氧基苯乙烯基。
本发明所述式(III)所示的二胺基取代芳杂环类化合物的制备方法为:
化合物(I)与化合物(II)在溶剂1,4-二氧六环中,在钌金属催化剂和叔丁醇钾作用下,于90~140℃(优选120℃)反应16~30h(优选16h),之后反应液经后处理,得到产物(III);
所述化合物(I)、化合物(II)、钌金属催化剂、叔丁醇钾的物质的量之比为1:2~4:0.02:1,特别优选1:2:0.02:1;
所述钌金属催化剂例如:三(三苯基膦)二氯化钌或三氯化钌;
所述溶剂1,4-二氧六环的体积用量以化合物(I)的物质的量计为5~10mL/mmol;
所述后处理的方法为:反应结束后,待反应液冷却至室温(20~30℃),加入甲醇和二氯甲烷(溶解目标产物),搅拌,过滤,取滤液浓缩后进行柱层析分离,以乙酸乙酯/石油醚体积比1:10的混合液为洗脱剂,收集含目标化合物的洗脱液,蒸除溶剂并干燥,得到产物(III);
式(I)中,R1、R2、R3的定义与式(III)中相同;
式(II)中,R5为戊基、苯基、3-吡啶基或3,4-亚甲二甲氧基苯基。
本发明还提供了所述式(III)所示的二胺基取代芳杂环类化合物的应用,具体的,所述应用为:
(1)在制备真核生物肿瘤细胞增殖抑制剂中的应用;
其中,所述真核生物为哺乳动物;所述肿瘤细胞为癌细胞,所述癌细胞可为骨肉瘤细胞癌细胞或乳腺导管癌细胞,所述骨肉瘤细胞癌细胞可为人骨肉瘤细胞株U2OS;所述乳腺导管癌细胞可为人乳腺导管癌细胞株T47D;
(2)在制备预防和/或治疗肿瘤药物中的应用;
其中,所述肿瘤为癌,所述癌为骨癌或乳腺癌。
本发明还涉及一种真核生物肿瘤细胞增殖抑制剂或预防和/或治疗肿瘤药物,其包含式(III)所示的二胺基取代芳杂环类化合物。
本发明的有益效果在于:本发明开发了二胺基取代的芳杂环类化合物及其制备方法,该工艺反应条件温和,原料易得,操作方便,成本低,有着较好的工业应用前景。本发明所提供的二胺基取代芳杂环类化合物显示一定的抗人骨肉瘤细胞和抗人乳腺导管瘤细胞活性,为新药筛选及开发奠定了基础,具有较好的实用价值。
(四)具体实施方式
下面将通过实施例对本发明作进一步的说明,但本发明的保护范围不限于此。
实施例1:化合物(III-1)的制备
在反应容器中加N2-苄基-N4,N4,6-三甲基-1,3,5-三嗪(60.8mg,0.250mmol),3,4-二亚甲氧基苄醇(76.8mg,0.50mmol),三氯化钌(1.9mg,0.005mmol),叔丁醇钾(28.0mg,0.25mmol),在1,4-二氧六环(2mL)中混合,140℃油浴中搅拌反应16小时;反应结束后,加甲醇和二氯甲烷(溶解目标产物),搅拌,过滤,浓缩滤液,柱层析(乙酸乙酯:石油醚=1:10),收集Rf值0.3~0.35的洗脱液,减压蒸馏,干燥得到目标化合物(III-1),64.0mg,收率为69%。
1H NMR(500MHz,CDCl3)δ7.85(d,J=15.2Hz,1H),7.37(d,J=7.5Hz,2H),7.34(t,J=7.5Hz,2H),7.30-7.25(m,1H),7.11(s,1H),7.04(d,J=8.0Hz,1H),6.81(d,J=8.0Hz,1H),6.66(d,J=15.2Hz,1H),5.99(s,2H),5.64(br,1H),4.78-4.56(m,2H),3.23(s,3H),3.16(s,3H)。
实施例2:化合物(III-2)的制备
操作同实施例1,只是将N2-苄基-N4,N4,6-三甲基-1,3,5-三嗪换成N2-苯基-N4,N4,6-三甲基-1,3,5-三嗪(61.6mg,0.25mmol),3,4-二亚甲氧基苄醇环换成苯甲醇(57.2mg,0.5mmol),制得目标化合物(III-2),79.8mg,收率为93%。
1H NMR(500MHz,CDCl3)δ8.00(d,J=15.9Hz,1H),7.68(dd,J=8.4,0.8Hz,2H),7.61(dd,J=7.1,1.3Hz,2H),7.40(t,J=7.3Hz,2H),7.37-7.33(m,3H),7.11-7.00(m,2H),6.90(d,J=15.9Hz,1H),3.30(s,3H),3.25(s,3H)。
实施例3:化合物(III-3)的制备
操作同实施例1,只是将N2-苄基-N4,N4,6-三甲基-1,3,5-三嗪换成N2,N4-二苯基-6-甲基-1,3,5-三嗪(69.0mg,0.25mmol),3,4-二亚甲氧基苄醇环换成苯甲醇(83.2mg,0.75mmol),制得目标化合物(III-3),90.3mg,收率为98%。
1H NMR(500MHz,CDCl3)δ8.04(d,J=15.9Hz,1H),7.66(d,J=7.9Hz,4H),7.57(d,J=7.2Hz,2H),7.46-7.32(m,9H),7.13(tt,J=7.2,1.0Hz,2H),6.90(d,J=15.9Hz,1H)。
实施例4:化合物(III-4)的制备
操作同实施例1,只是将3,4-二亚甲氧基苄醇换成3-吡啶甲醇(107.6mg,1.00mmol),三氯化钌换成三(三苯基膦)二氯化钌(4.9mg,0.005mmol),制得目标化合物(III-4),35.9mg,收率为43%。
1H NMR(600MHz,CDCl3)δ8.50(d,J=1.6Hz,1H),8.41(dd,J=5.0,1.6Hz,1H),7.54(d,J=5.0Hz,1H),7.34-7.28(m,4H),7.28-7.22(m,1H),7.17(t,J=5.0Hz,1H),5.46(br,1H),4.60(d,J=5.3Hz,2H),3.14(s,3H),3.10(s,3H),3.07(t,J=7.6Hz,2H),2.93-2.72(m,2H)。
实施例5:化合物(III-5)的制备
操作同实施例1,只是将3,4-二亚甲氧基苄醇换成正己醇(51.6mg,0.5mmol),N2-苄基-N4,N4,6-三甲基-1,3,5-三嗪换成N2-苄基-4-甲基-6-哌啶-1,3,5-三嗪(70.9mg,0.25mmol),三氯化钌换成三(三苯基膦)二氯化钌(4.9mg,0.005mmol),制得目标化合物(Ⅱ-13),30.9mg,收率为33%。
1H NMR(500MHz,CDCl3)δ7.37-7.30(m,4H),7.29-7.26(m,1H),5.33(br,1H),4.65-4.54(m,2H),3.87-3.66(m,4H),2.61-2.37(m,2H),1.77-1.68(m,2H),1.60-1.48(m,4H),1.40-1.22(m,10H),0.89(t,J=8.8Hz,3H)。
实施例6:化合物(III-6)的制备
操作同实施例1,只是将N2-苄基-N4,N4,6-三甲基-1,3,5-三嗪换成N2-苯基-N4,N4,6-三甲基-1,3,5-三嗪(57.2mg,0.25mmol),三氯化钌换成三(三苯基膦)二氯化钌(4.9mg,0.005mmol),3,4-二亚甲氧基苄醇环换成苯甲醇(57.2mg,0.5mmol),制得目标化合物(III-6),61.0mg,收率为77%。
1H NMR(500MHz,CDCl3)δ7.64(d,J=7.8Hz,2H),7.34(t,J=7.8Hz,2H),7.31-7.27(m,4H),7.23-7.18(m,1H),7.06(t,J=7.4Hz,1H),7.03(br,1H),3.22(s,3H),3.21(s,3H),3.16-3.09(m,2H),2.95-2.87(m,2H)。
实施例7:抗人骨肉瘤细胞U2OS生物活性测试
体外抗人骨肉瘤细胞(U2OS)活性测试方法:MTT法
实验步骤:
1)样品的准备:对于可溶样品,每1mg用20μL DMSO溶解,取2uL用1000μL培养液稀释,使浓度为100μg/mL,再用培养液连续稀释至使用浓度。
2)细胞的培养
2.1)培养基的配制:每1000mL培养基中含80万单位青霉素,1.0g链霉素,10%灭活胎牛血清。
2.2)细胞的培养:将肿瘤细胞接种于培养基中,置37℃,5%CO2培养箱中培养,3~5d传代。
3)测定样品对肿瘤细胞生长的抑制作用
将细胞用EDTA-胰酶消化液消化,并用培养基稀释成1×105/mL,加到96孔细胞培养板中,每孔100uL,置37℃,5%CO2培养箱中培养。接种24h后,加入用培养基稀释的样品,每孔100μL,每个浓度加3孔,置37℃,5%CO2培养箱中培养,72h后在细胞培养孔中加入5mg/mL的MTT,每孔10μL,置37℃孵育4h,加入DMSO,每孔150μL,用振荡器振荡,使甲臢完全溶解,用酶标仪在570nm波长下比色。以同样条件用不含样品,含同样浓度DMSO的培养基培养的细胞作为对照,计算样品对肿瘤细胞生长的抑制率,结果如表1所示。
以骨肉瘤细胞U2OS为模型,测定了实施例中制备的化合物(III-1)~(III-6)6个样品体外对人骨肉瘤细胞生长的抑制作用。结果显示,本实验所测试的样品中,化合物(III-1)、(III-2)、(III-4)、(III-5)对实验所用的人骨肉瘤细胞U2OS有一定的抑制作用(结果详见表1)。
表1各化合物对人骨肉瘤细胞U2OS的IC50
化合物 | IC<sub>50</sub>(μM) |
(III-1) | 8.00 |
(III-2) | 8.69 |
(III-3) | >100 |
(III-4) | 40.98 |
(III-5) | 63.44 |
(III-6) | >100 |
实施例8:抗人乳腺导管癌细胞(T47D)生物活性测试
体外抗人乳腺导管癌细胞(T47D)活性测试方法:MTT法
实验步骤:
1)样品的准备:对于可溶样品,每1mg用20μL DMSO溶解,取2uL用1000μL培养液稀释,使浓度为100μg/mL,再用培养液连续稀释至使用浓度。
2)细胞的培养
2.1)培养基的配制:每1000mL培养基中含80万单位青霉素,1.0g链霉素,10%灭活胎牛血清。
2.2)细胞的培养:将肿瘤细胞接种于培养基中,置37℃,5%CO2培养箱中培养,3~5d传代。
3)测定样品对肿瘤细胞生长的抑制作用
将细胞用EDTA-胰酶消化液消化,并用培养基稀释成1×105/mL,加到96孔细胞培养板中,每孔100uL,置37℃,5%CO2培养箱中培养。接种24h后,加入用培养基稀释的样品,每孔100μL,每个浓度加3孔,置37℃,5%CO2培养箱中培养,72h后在细胞培养孔中加入5mg/mL的MTT,每孔10μL,置37℃孵育4h,加入DMSO,每孔150μL,用振荡器振荡,使甲臢完全溶解,用酶标仪在570nm波长下比色。以同样条件用不含样品,含同样浓度DMSO的培养基培养的细胞作为对照,计算样品对肿瘤细胞生长的抑制率,结果如表2所示。
以人乳腺导管癌细胞(T47D)为模型,测定了实施例中制备的化合物(III-1)~(III-6)6个样品体外对人乳腺导管癌细胞(T47D)生长的抑制作用。结果显示,本实验所测试的样品中,化合物(III-1)、(III-3)、(III-6)对实验所用的人乳腺导管癌细胞(T47D)有一定的抑制作用(结果详见表2)。
表2各化合物对人乳腺导管癌细胞(T47D)的IC50
化合物 | IC<sub>50</sub>(μM) |
(III-1) | 37.39 |
(III-2) | >100 |
(III-3) | 72.43 |
(III-4) | 100 |
(III-5) | >100 |
(III-6) | 66.12 |
Claims (8)
3.如权利要求2所述的制备方法,其特征在于,反应温度为120℃。
4.如权利要求2所述的制备方法,其特征在于,反应时间为16h。
5.如权利要求2所述的制备方法,其特征在于,所述化合物(I)、化合物(II)、钌金属催化剂、叔丁醇钾的物质的量之比为1:2:0.02:1。
6.如权利要求2所述的制备方法,其特征在于,所述溶剂1,4-二氧六环的体积用量以化合物(I)的物质的量计为5~10mL/mmol。
7.如权利要求2所述的制备方法,其特征在于,所述后处理的方法为:反应结束后,待反应液冷却至室温,加入甲醇和二氯甲烷,搅拌,过滤,取滤液浓缩后进行柱层析分离,以乙酸乙酯/石油醚体积比1:10的混合液为洗脱剂,收集含目标化合物的洗脱液,蒸除溶剂并干燥,得到产物(III)。
8.如权利要求1所述式(III)所示的二胺基取代芳杂环类化合物在制备真核生物肿瘤细胞增殖抑制剂中的应用;所述真核生物为哺乳动物;所述肿瘤细胞为癌细胞,所述癌细胞为骨肉瘤细胞癌细胞或乳腺导管癌细胞,所述骨肉瘤细胞癌细胞为人骨肉瘤细胞株U2OS;所述乳腺导管癌细胞为人乳腺导管癌细胞株T47D;
或者,在制备预防和/或治疗肿瘤药物中的应用;所述肿瘤为癌,所述癌为骨癌或乳腺癌。
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