一种香豆素衍生物及其制备方法和作为抗癌药物的用途转让专利
申请号 : CN201010297276.2
文献号 : CN101985449B
文献日 : 2012-08-22
发明人 : 黄志纾 , 吴伟彬 , 古练权 , 谭嘉恒 , 欧田苗 , 黄世亮
申请人 : 中山大学
摘要 :
权利要求 :
1.一种香豆素衍生物,其特征在于其结构式为:式中R1为H或O(CH2)nNR3;R2为H或O(CH2)nNR3;R1或R2中至少有一个为O(CH2)nNR3;
其中n=1、2、3、4或5;NR3表示C1-6的烷基胺、C3-6的环烷基胺或哌嗪基。
2.一种如权利要求1所述的香豆素衍生物的制备方法,其特征在于:(1)当R1=H,R2=O(CH2)nNR3时,制备方法包括以下步骤:将水杨醛、氰基乙酸乙酯、单羟基取代苯甲醛、醋酸铵进行反应,得到化合物 然后与Br(CH2)nBr反应得到化合物 再与NHR3反应获得香豆素衍生物,结构式为 其中n=1、2、3、4或5;NR3表示C1-6的烷基胺、C3-6的环烷基胺或哌嗪基;
(2)当R1=O(CH2)nNR3,R2=H时,制备方法包括以下步骤:将4-苄氧基水杨醛、氰基乙酸乙酯、苯甲醛、醋酸铵进行反应,得到化合物 然后在三氟乙酸中回流,得到化合物 再与Br(CH2)nBr反应得到化合物 再与NHR3反应获得香豆素衍生物,结构式为 其中n=1、2、3、4或5;NR3表示C1-6的烷基胺、C3-6的环烷基胺或哌嗪基;
(3) 当 R1 = O(CH2)nNR3,R2 = O(CH2)nNR3 时,制 备 方 法 包 括 以 下 步 骤:将4-苄氧基水杨醛、氰基乙酸乙酯、单羟基取代苯甲醛、醋酸铵进行反应,得 到 化 合 物 然 后 在 三 氟 乙 酸 中 回 流,得 到化 合 物 再 与 Br(CH2)nBr 反 应 得 到 化 合 物 最后与NHR3反应获得香豆素衍生物,结构式为 其中n=1、2、3、4或5;NR3表示C1-6的烷基胺、C3-6的环烷基胺或哌嗪基。
3.如权利要求2所述的制备方法,其特征在于所述反应获得的香豆素衍生物经过柱层析纯化得到纯品。
4.如权利要求1所述的香豆素衍生物在制备抗癌药物中的用途。
说明书 :
一种香豆素衍生物及其制备方法和作为抗癌药物的用途
技术领域
背景技术
发明内容
具体实施方式
13
7.9Hz,1H),7.00(ddd,J=8.1,2.4,1.0Hz,1H). C NMR(101MHz,DMSO) 166.06,163.13,
160.79,158.97,157.49,153.35,138.13,133.74,129.41,124.94,124.72,119.54,118.78,+
118.12,116.84,115.36,95.38.MS(ESI+)m/z 306[M+H]
=8.8,2.4Hz,1H),7.03(d,J=2.3Hz,1H),5.20(s,2H). C NMR(101MHz,DMSO) 165.86,
163.11,162.73,160.97,158.94,154.91,136.81,136.12,131.57,128.55,128.47,128.37,+
128.08,127.90,126.31,113.29,111.20,101.56,93.87,69.95.MS(ESI+)m/z 396[M+H][0036]
2H),7.36(dd,J = 15.8,7.7Hz,2H),7.09(dd,J = 8.8,2.2Hz,1H),7.04(d,J = 2.1Hz,
13
1H),7.00(dd,J=7.9,1.4Hz,1H),5.21(s,2H). C NMR(101MHz,DMSO) 165.99,163.07,
162.70,160.98,158.83,157.43,154.88,138.25,136.09,129.30,128.45,128.07,127.93,
126.12,119.54,118.65,115.36,113.27,111.21,101.52,93.82,69.95.MS(ESI+)m/z +
412[M+H]
13
4.5Hz,1H),6.93(dd,J=8.7,2.3Hz,1H),6.77(d,J=2.2Hz,1H). C NMR(101MHz,DMSO)
165.81,163.15,162.72,161.17,159.18,155.06,136.88,131.49,128.52,128.33,127.95,+
126.63,126.35,113.48,109.84,102.30,93.47.MS(ESI+)m/z 306[M+H]
7.8Hz,1H),6.98(ddd,J= 8.1,2.4,0.9Hz,1H),6.94(dd,J= 8.7,2.3Hz,1H),6.78(d,J
13
= 2.2Hz,1H). C NMR(101MHz,DMSO) 165.98,163.14,162.70,161.20,159.14,157.43,
155.09,138.32,129.33,126.53,119.49,118.63,115.33,113.52,109.89,102.36,93.47.+
MS(ESI+)m/z 322[M+H]
2.6,1.5Hz,1H),7.75(ddd,J=8.3,7.3,1.7Hz,1H),7.51-7.43(m,3H),7.20(ddd,J=8.2,
13
2.7,0.9Hz,1H),4.44(t,J=5.2Hz,2H),3.88(t,J=5.4Hz,2H). C NMR(101MHz,DMSO)
165.53,163.11,160.74,159.05,158.08,153.33,138.27,133.78,129.68,125.13,124.76,
121.49,118.03,117.79,116.79,114.64,95.51,67.87,31.45.MS(ESI+)m/z 412and +
414[M+H]
2.5,1.5Hz,1H),7.73(ddd,J=8.8,7.4,1.7Hz,1H),7.50-7.41(m,3H),7.17(ddd,J=8.2,
13
2.7,0.9Hz,1H),4.18(t,J = 6.0Hz,2H),3.74(t,J = 6.5Hz,2H),2.38-2.28(m,2H). C NMR(101MHz,DMSO) 165.57,163.08,160.72,158.97,158.45,153.29,138.17,133.71,
129.53,125.08,124.68,121.20,118.01,117.75,116.74,114.24,95.43,65.35,31.86,+
31.26.MS(ESI+)m/z 426 and 428[M+H]
6.96(d,J = 2.4Hz,1H),4.43(t,2H),3.85(t,J = 5.4Hz,2H). C NMR(101MHz,DMSO)
165.83,163.07,162.21,160.91,158.85,154.86,136.77,131.56,128.53,128.36,126.32,+
113.01,111.37,101.31,93.88,68.32,30.87.MS(ESI+)m/z 412and 414[M+H][0066]
1
154.81,136.79,131.48,128.52,128.29,126.17,112.81,111.06,101.04,93.75,66.08,+
31.60,30.86.MS(ESI+)m/z426and 428[M+H]
8.0Hz,1H),7.19(ddd,J=8.2,2.6,0.7Hz,1H),7.06(dd,J=8.8,2.4Hz,1H),7.02(d,J=
13
2.4Hz,1H),4.51-4.39(m,4H),3.92-3.81(m,4H). CNMR(101MHz,DMSO) 165.48,163.06,
162.29,160.93,158.91,158.04,154.94,138.36,129.62,126.45,121.47,117.69,114.64,
113.14,111.40,101.39,94.04,68.39,67.85,31.45,30.93.MS(ESI+)m/z 534,536and +
538[M+H]
1
7.11(dd,J = 8.1,2.0Hz,1H),6.91(dd,J = 8.8,2.4Hz,1H),6.85(d,J = 2.3Hz,1H),
4.14(t,J= 5.9Hz,2H),4.11(t,J = 5.9Hz,2H),3.70(t,J= 6.5Hz,2H),3.65(t,J =
13
6.6Hz,2H),2.34-2.27(m,2H),2.27-2.20(m,2H). C NMR(101MHz,DMSO) 165.45,162.98,
162.64,160.88,158.77,158.37,154.82,138.26,129.39,126.22,121.16,117.56,114.21,
112.83,111.05,101.04,93.81,66.11,65.32,31.88,31.60,31.24,30.86.MS(ESI+)m/z
562,564and 566[M+H]+
13
2.32(s,3H). C NMR(101MHz,CDCl3) 167.25,163.52,161.85,159.88,158.97,153.81,
138.42,133.62,129.43,125.75,124.79,121.81,118.57,117.03,114.64,95.97,66.02,
57.23,55.06,53.59,46.02.HRMS(ESI+)m/z:Calc.for C24H25N5O3:432.2036[M+H]+.Found
432.2030[M+H]+.
2H).13C NMR(101MHz,CDCl3) 167.32,163.53,161.84,159.88,159.20,153.83,138.42,
133.60,129.42,125.74,124.77,121.65,118.55,118.39,117.03,114.69,95.96,66.35,
55.12,54.98,52.98,45.86,26.75.HRMS(ESI+)m/z:Calc.for C25H27N5O3:446.2192[M+H]+.Found446.2191[M+H]+.
13
4.20(t,J=5.7Hz,2H),2.88(t,J=5.7Hz,2H),2.68(s,4H),2.55(s,4H),2.34(s,3H). C NMR(101MHz,CDCl3) 167.55,163.62,163.41,162.17,159.91,155.49,137.20,131.72,
129.11,128.44,126.97,113.38,111.87,101.46,94.63,66.69,56.84,54.95,53.41,+ +
45.85.HRMS(ESI+)m/z:Calc.forC24H25N5O3:432.2036[M+H].Found 432.2020[M+H].[0096]
6.81(d,J=2.3Hz,0H),6.05(s,0H),4.11(t,J=6.3Hz,1H),2.73-2.36(m,5H),2.31(s,
13
2H),2.07-1.99(m,1H). C NMR(101MHz,CDCl3) 167.48,163.72,163.59,162.19,159.91,
155.51,137.21,131.69,129.09,128.43,126.87,113.34,111.61,101.28,94.54,66.93,+
55.14,54.85,53.21,46.03,26.54.HRMS(ESI+)m/z:Calc.for C25H27N5O3:446.2192[M+H].+
Found 446.2178[M+H].
1H),4.18(t,J = 6.1Hz,2H),4.07(t,J = 5.7Hz,2H),2.96(t,J = 6.0Hz,2H),2.89(t,J = 5.9Hz,2H),2.72(q,J = 14.3,7.2Hz,4H),2.66(q,J = 14.4,7.2Hz,4H),1.12(t,
13
J = 8.0Hz,6H),1.08(t,J = 8.0Hz,6H). C NMR(101MHz,CDCl3) 166.90,163.42,
163.31,162.00,159.58,158.80,155.26,138.54,129.29,126.73,121.70,118.37,114.27,
113.14,111.53,101.19,94.43,67.12,66.17,51.64,51.49,47.81,47.70,11.67,11.48.+ +
HRMS(ESI+)m/z:Calc.for C27H39N5O4:520.2900[M+Na].Found 520.2918[M+Na].[0106]
7.08(dd,J = 8.2,1.8Hz,1H),6.94(dd,J = 8.9,2.4Hz,1H),6.76(d,J = 2.3Hz,1H),
6.32(d,J= 4.0Hz,1H),4.24(t,J =5.9Hz,2H),4.17(t,J = 5.8Hz,2H),2.99(t,J =
5.9Hz,2H),2.94(t,J = 5.8Hz,2H),2.70(t,J = 6.8Hz,4H),2.67(t,J = 6.9Hz,5H),
13
1.91-1.84(m,4H),1.84-1.77(m,4H). C NMR(101MHz,CDCl3) 167.04,163.47,163.37,
162.08,159.67,158.92,155.31,138.54,129.30,126.81,121.68,118.39,114.52,113.25,
111.62,101.26,94.49,67.67,66.98,55.09,54.75,54.72,23.51.HRMS(ESI+)m/z:Calc.+ +
for C29H33N5O4:516.2611[M+H].Found 516.2610[M+H].
7.09(dd,J = 8.0,2.1Hz,1H),6.98(dd,J = 8.9,2.3Hz,1H),6.82(d,J = 2.3Hz,1H),
6.05(d,J= 4.3Hz,1H),4.33(t,J =5.7Hz,2H),4.23(t,J = 5.8Hz,2H),2.96(t,J =
5.3Hz,2H),2.86(t,J = 5.8Hz,2H),2.69(s,4H),2.58(s,4H),1.81-1.68(m,J = 12.3,
13
7.0Hz,4H),1.69-1.59(m,J=11.0,5.5Hz,4H),1.56-1.41(m,4H). C NMR(101MHz,CDCl3)
165.90,162.40,162.25,161.00,158.54,157.83,154.23,137.51,128.26,125.70,120.65,
117.31,113.45,112.16,110.52,100.18,93.41,65.45,64.78,56.92,56.63,54.09,+
54.03,24.80,24.77,23.10,23.09.HRMS(ESI+)m/z:Calc.for C31H37N5O4:544.2924[M+H].+
Found544.2926[M+H].
1H),7.39(t,J = 7.9Hz,1H),7.06(dd,J = 7.8,2.2Hz,1H),6.91(dd,J = 8.8,2.4Hz,
1H),6.75(d,J = 2.3Hz,1H),6.40(d,J = 4.3Hz,1H),4.13(t,J = 6.3Hz,2H),4.07(t,
13
J = 6.3Hz,2H),2.75-2.41(m,20H),2.31(s,3H),2.30(s,3H),2.08-1.98(m,4H). C NMR(101MHz,CDCl3) 167.00,163.46,163.25,162.04,159.64,158.87,155.30,138.56,
129.34,126.80,121.74,118.36,114.55,113.25,111.65,101.24,94.51,66.49,65.92,
57.21,56.86,55.00,54.96,53.57,53.56,45.99.HRMS(ESI+)m/z:Calc.for C31H39N7O4:
+ +
574.3142[M+H].Found 574.3155[M+H].
1H),7.08(dd,J = 8.1,2.3Hz,1H),6.96(dd,J = 8.9,2.3Hz,1H),6.80(d,J = 2.3Hz,
1H),6.16(d,J = 4.2Hz,1H),4.24(t,J = 5.7Hz,2H),4.18(t,J = 5.6Hz,2H),3.63(t,J=5.4Hz,4H),2.89(t,J =4.2Hz,2H),2.86(t,J= 4.1Hz,2H),2.70-2.34(m,21H).13C NMR(101MHz,CDCl3) 166.13,162.47,162.31,161.08,158.75,157.88,154.38,137.57,
128.40,125.89,120.77,117.38,113.60,112.30,110.71,100.33,93.57,76.33,76.21,
76.01,75.69,65.55,64.95,58.25,58.22,56.71,56.20,55.85,52.67,52.63,51.78,+ +
51.73.HRMS(ESI+)m/z:Calc.for C33H43N7O6:634.3353[M+H].Found 634.3378[M+H].[0126]
4.21-4.04(m,4H),2.70(t,J = 7.4Hz,2H),2.64(t,2H),2.63-2.51(m,8H),2.05-1.93(m,
13
4H),1.08(t,J = 4.7Hz,6H),1.05(t,J = 4.7Hz,6H). CNMR(101MHz,CDCl3) 167.27,
163.76,163.51,162.17,159.85,159.23,155.48,138.58,129.34,126.85,121.54,
118.33,114.61,113.28,111.51,101.27,94.54,67.02,66.52,49.47,49.18,47.02,47.00,+
26.98,26.86,11.75,11.63.HRMS(ESI+)m/z:Calc.for C31H41N5O4:548.3237[M+H].Found +
548.3248[M+H].
7.06(dd,J = 7.4,2.6Hz,1H),6.85(dd,J = 8.8,2.4Hz,1H),6.67(d,J = 2.3Hz,1H),
6.60(d,J = 4.1Hz,1H),4.15(t,J = 6.3Hz,2H),4.07(t,J = 6.2Hz,2H),2.72(t,2H),
13
2.68(t,2H),2.65-2.51(m,8H),2.14-2.00(m,4H),1.88-1.72(m,8H). C NMR(101MHz,CDCl3) 166.97,163.50,163.46,162.04,159.56,159.12,155.27,138.60,129.28,126.70,
121.55,118.28,114.41,113.03,111.39,101.12,94.36,77.36,77.25,77.04,76.73,
66.73,66.41,54.25,54.17,53.20,52.72,28.81,28.46,23.47,23.46.HRMS(ESI+)m/z:
+ +
Calc.for C31H37N5O4:544.2924[M+H].Found 544.2932[M+H].
1H),7.06(dd,J = 8.1,2.5Hz,1H),6.87(dd,J = 8.8,2.4Hz,1H),6.70(d,J = 2.3Hz,
1H),6.45(d,J = 4.0Hz,1H),4.12(t,J = 6.3Hz,2H),4.04(t,J = 6.3Hz,2H),2.56(t,
2H),2.51(t,2H),2.50-2.32(m,J = 16.4Hz,8H),2.10-1.97(m,4H),1.69-1.57(m,J
13
= 10.5,5.2Hz,8H),1.52-1.39(m,J = 4.6Hz,4H). CNMR(101MHz,CDCl3) 166.96,
163.53,163.42,162.04,159.58,159.10,155.29,138.54,129.28,126.69,121.54,118.23,
114.47,113.09,111.39,101.10,94.38,66.91,66.50,56.02,55.59,54.60,26.71,26.43,+
25.84,25.77,24.36,24.32.HRMS(ESI+)m/z:Calc.for C33H41N5O4:572.3237[M+H].Found +
572.3249[M+H].
1H),7.39(t,J = 7.9Hz,1H),7.06(dd,J = 7.8,2.2Hz,1H),6.91(dd,J = 8.8,2.4Hz,
1H),6.75(d,J = 2.3Hz,1H),6.40(d,J = 4.3Hz,1H),4.13(t,J = 6.3Hz,2H),4.07(t,J = 6.3Hz,2H),2.75-2.41(m,20H),2.31(s,3H),2.30(s,3H),2.08-1.98(m,4H).13C NMR(101MHz,CDCl3) 167.08,163.56,163.47,162.09,159.69,159.11,155.36,138.56,
129.33,126.78,121.56,118.21,114.56,113.20,111.47,101.14,94.45,66.79,66.33,
55.16,54.99,54.78,53.08,45.93,26.76,26.43.HRMS(ESI+)m/z:Calc.for C33H43N7O4:
+ +
602.3455[M+H].Found 602.3472[M+H].
7.01(dd,J = 8.1,2.0Hz,1H),6.82(dd,J = 8.8,2.3Hz,1H),6.65(d,J = 2.3Hz,1H),
6.57(d,J=3.5Hz,1H),4.07(t,J=6.1Hz,2H),3.99(t,J=6.2Hz,2H),3.66-3.56(m,
13
J = 5.5,2.5Hz,4H),3.15(s,2H),2.65-2.36(m,24H),2.03-1.92(m,4H). C NMR(101MHz,CDCl3) 166.92,163.46,163.40,161.98,159.54,159.05,155.27,138.53,129.29,126.69,
121.54,118.09,114.55,113.09,111.39,101.05,94.36,66.68,66.25,59.47,57.83,
55.18,54.76,53.19,53.16,52.86,26.74,26.37.HRMS(ESI+)m/z:Calc.for C35H47N7O6:
+ +
662.3666[M+H].Found662.3670[M+H].