CN104610170B - 2,5‑二酮哌嗪衍生物及其制备方法和应用 - Google Patents
2,5‑二酮哌嗪衍生物及其制备方法和应用 Download PDFInfo
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- CN104610170B CN104610170B CN201510018622.1A CN201510018622A CN104610170B CN 104610170 B CN104610170 B CN 104610170B CN 201510018622 A CN201510018622 A CN 201510018622A CN 104610170 B CN104610170 B CN 104610170B
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- chlorophenyl
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- trifluoromethylphenyl
- bromophenyl
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- BXRNXXXXHLBUKK-UHFFFAOYSA-N piperazine-2,5-dione Chemical class O=C1CNC(=O)CN1 BXRNXXXXHLBUKK-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- -1 p-trifluoromethylphenyl Chemical group 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 13
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims abstract description 10
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims abstract description 10
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims abstract description 10
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims abstract description 10
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims abstract description 10
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims abstract description 10
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims abstract description 10
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims abstract description 10
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims abstract description 10
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims abstract description 10
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims abstract description 10
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims abstract description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims abstract description 9
- 230000008569 process Effects 0.000 claims abstract description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 37
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- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 4
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- 239000003744 tubulin modulator Substances 0.000 description 1
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Abstract
本发明公开了2,5‑二酮哌嗪衍生物及其制备方法和应用。其结构如式1所示，其中：R为甲基或烯丙基；Ar1为苯基，邻、间或对甲苯基，邻、间或对甲氧苯基，邻、间或对氯苯基，邻、间或对溴苯基，邻、间或对氟苯基，邻、间或对三氟甲基苯基，或，邻或间二氯苯基等；Ar2为苯基，邻、间或对甲苯基，邻、间或对甲氧苯基，邻、间或对氯苯基，邻、间或对溴苯基，邻、间或对氟苯基，邻、间或对三氟甲基苯基，或，邻或间二氯苯基等。本发明公开了一类易溶的、具有抗肿瘤活性和的抗污损生物附着活性的2,5‑二酮哌嗪衍生物的合成方法，该方法流程简单，价格低廉，适合于大规模生产，来源可靠稳定，推广应用潜力大，此方法可以大大拓展其应用前景。
Description
技术领域：
本发明属于药物小分子制备领域，具体涉及一类易溶、具有抗肿瘤与抗污损生物附着活性的2,5-二酮哌嗪衍生物及其制备方法和应用。
背景技术：
2.5-二酮哌嗪是由两分子甘氨酸通过自身环合而形成的一类有机小分子，由于这种小分子中存在两对羰基氧(C＝O)和两对酰胺氢(N-H)，因而分子间容易形成氢键，进而通过π-π堆积作用而形成一种白色的晶体(式2)，这种晶体结构难溶解任何常见的溶剂中，因而其利用价值不大。但在其1、3、4、6位置有取代基的衍生物则常见于许多天然产物中，并且具有抗菌、抗病毒、抗肿瘤、抗污损生物附着等广泛的生物活性。如具有咪唑基团的天然产物Phenylahistin和aurantiamine等具有较强的抑制肿瘤细胞活性，以它们为先导物修饰的化合物如Plinabulin具有更强活性的抗肿瘤活性，目前其三期临床已接近结束，而用苯甲酰基修饰的Plinabulin衍生物则具有更强的抑制癌细胞生长活性(IC50＝0.5nM)。对这些衍生物的作用机制研究表明，这类化合物是一类微管蛋白抑制剂，其通过抑制微管蛋白聚集而抑制血管的生成，从而使癌细胞的营养供应受阻，引起细胞的凋亡而达到抑制癌细胞生长的目标。这类N原子未保护的化合物的合成一般经多步进行，合成过程麻烦，但其更大的缺陷在于这类化合物的脂溶性非常差，除含有咪唑的衍生物能溶解在DMSO、DMF及DCM和MeOH的混合溶剂中外，其它芳香基团的化合物不溶解在任何常规溶剂中，脂溶性非常差，因而严重影响其生物利用度。因此合成脂溶性好、具有良好的抗肿瘤与抗污损生物附着活性的2,5-二酮哌嗪衍生物非常重要，且具有广泛的应用前景和市场价值。
发明内容：
本发明的第一个目的是提供一种脂溶性好、具有良好的抗肿瘤与抗污损生物附着活性的2,5-二酮哌嗪衍生物。
本发明的2,5-二酮哌嗪衍生物，其特征在于，其结构式如式1所示：
其中：
R为甲基或烯丙基；
Ar1为苯基，邻、间或对甲苯基，邻、间或对甲氧苯基，邻、间或对氯苯基，邻、间或对溴苯基，邻、间或对氟苯基，邻、间或对三氟甲基苯基，或，邻或间二氯苯基等；
Ar2为苯基，邻、间或对甲苯基，邻、间或对甲氧苯基，邻、间或对氯苯基，邻、间或对溴苯基，邻、间或对氟苯基，邻、间或对三氟甲基苯基，或，邻或间二氯苯基等。
Ar1与Ar2可以相同，也可以不同。
本发明的第二个目的是提供一种上述脂溶性好、具有良好的抗肿瘤与抗污损生物附着活性的2,5-二酮哌嗪衍生物的一锅法合成的制备方法，其合成过程如下：
其合成步骤如下：
将双乙酰甘氨酸酐Ar、卤代烃和碱置于二甲基甲酰胺(DMF)中，经反应得到2,5-二酮哌嗪衍生物；
所述的卤代烃为溴丙烯或碘甲烷，所述的碱为NaOH或Cs2CO3；
所述的Ar为其中Ar1为苯基，邻、间或对甲苯基，邻、间或对甲氧苯基，邻、间或对氯苯基，邻、间或对溴苯基，邻、间或对氟苯基，或，邻、间或对三氟甲基苯基，或，邻或间二氯苯基等基团中的一种；Ar2为苯基，邻、间或对甲苯基，邻、间或对甲氧苯基，邻、间或对氯苯基，邻、间或对溴苯基，邻、间或对氟苯基，邻、间或对三氟甲基苯基，或，邻或间二氯苯基等基团中的一种。
所述的反应，其反应条件优选为：室温搅拌3～24h或60°加热24h，待反应完成后，倒入到水中，质量百分数10％盐酸调pH值至4～5，乙酸乙酯萃取，干燥，最后柱层析，得到2,5-二酮哌嗪衍生物。
优选，所述的双乙酰甘氨酸酐的物质的量(mol)分别与的物质的量之比都为1.0:1.0～1.15，与卤代烃的物质的量之比为1:1.5～1.8，与碱的物质的量之比为1:2.0～3.0。
本发明的第三个目的是提供上述2,5-二酮哌嗪衍生物在制备抗肿瘤药物或抗污损生物附着药物中的应用。
优选，所述的化合物8：化合物11：或化合物14：在制备抗污损生物附着药物中的应用。进一步优选，所述的抗污损生物附着药物为抗藤壶或抗草台虫附着药物。
本发明公开了一类易溶的、具有抗肿瘤活性和的抗污损生物附着活性的2,5-二酮哌嗪衍生物的合成方法，该方法流程简单，价格低廉，适合于大规模生产，来源可靠稳定，推广应用潜力大，此方法可以大大拓展其应用前景。
具体实施方式：
以下实施例是对本发明的进一步说明，而不是对本发明的限制。
实施例1：化合物1的合成
将双乙酰甘氨酸酐100.0mg(0.51mmol,1.0eq.)、苯甲醛130.0μL(1.28mmol，2.5eq.)、碘甲烷57.2μL(0.92mmol,1.8eq.)、Cs2CO3500.0mg(1.53mmol，3.0eq.)及3.0mL二甲基甲酰胺(DMF)中60°搅拌24h，待完成后冷却至室温，加水加稀盐酸调pH值至4～5，乙酸乙酯萃取，硅胶柱层析得82mg无色油状物，室温放置数天后变为淡黄色固体(化合物1)，产率：53％。
1H NMR(500MHz,CDCl3)δ:8.12(d,J＝5Hz,2H),8.09(s,1H),7.46～7.31(m,9H),6.60(s,1H),4.07(s,3H)；13C NMR(125MHz,CDCl3)δ:160.46,154.50,135.38,133.51,132.15,131.80,129.80,129.34,128.85,128.77,128.69,124.63,111.17,100.31,54.92；MS-ESI m/z:305.2[M+H]+。
实施例2：化合物2的合成
将双乙酰甘氨酸酐100.0mg(0.51mmol,1.0eq.)、苯甲醛106.0μL(1.02mmol，2.0eq.)、溴丙烯64.7μL(0.77mmol,1.5eq.)、Cs2CO3500.0mg(1.53mmol，3.0eq.)及3.0mLDMF中60°搅拌24h，待完成后冷却至室温，加水加稀盐酸调pH值至4～5，乙酸乙酯萃取，硅胶柱层析得99mg淡黄色固体(化合物2)，产率：59％。
1H NMR(500MHz,CDCl3)δ:8.20(s,1H),8.09(d,J＝10Hz,2H),7.46～7.33(m,9H),7.31(s,1H),6.65(s,1H),6.21～6.13(m,1H),5.50(d,J＝20Hz,1H),5.37(d,J＝20Hz,1H),4.96(d,J＝20Hz,2H)；13C NMR(125MHz,CDCl3)δ:160.49,153.63,135.34,133.48,132.69,132.07,131.74,130.44,129.78,129.36,128.98,128.79,128.73,128.68,124.63,118.90,111.38,68.23；MS-ESI m/z:331.2[M+H]+。
实施例3：化合物3的合成
用邻甲基苯甲醛替换苯甲醛，合成方法同实施例2，得95mg淡黄色固体(化合物3)，产率：52％。
1H NMR(500MHz,CDCl3)δ:8.41(t,J＝5.0Hz,1H),7.83(s,1H),7.55(s,1H),7.32～7.22(m,7H),7.31(s,1H),6.64(s,1H),6.15～6.08(m,1H),5.45(d,J＝20Hz,1H),5.33(d,J＝20Hz,1H),4.91(d,J＝5Hz,2H),2.47(s,3H),2.31(s,3H)；13C NMR(125MHz,CDCl3)δ:160.45,153.63,139.09,137.69,133.79,132.84,132.07,131.75,131.46,131.35,130.55,129.10,129.00,128.11,126.95,126.34,125.77,124.98,118.85,110.41,67.91,20.72,20.34；MS-ESI m/z:358.1[M+H]+。
实施例4：化合物4的合成
用对甲基苯甲醛替换苯甲醛，合成方法同实施例2，得104mg淡黄色固体(化合物4)，产率：57％。
1H NMR(500MHz,CDCl3)δ:8.15(s,1H),7.99(d,J＝10.0Hz,2H),7.28(t,J＝5.0Hz,3H),7.24(s,1H),7.22(s,1H),7.21(s,1H),6.59(s,1H),6.19～6.13(m,1H),5.49(d,J＝20Hz,1H),5.35(d,J＝20Hz,1H),4.93(d,J＝5Hz,2H),2.39(s,3H),2.38(s,3H)；13C NMR(125MHz,CDCl3)δ:160.05,153.37,139.59,138.81,132.78,132.63,132.01,131.11,130.59,130.40,129.44,128.80,128.61,124.17,118.72,111.12,68.07,21.82,21.63；MS-ESI m/z:358.1[M+H]+。
实施例5：化合物5的合成
用间氯苯甲醛替换苯甲醛，合成方法同实施例5，得126mg淡黄色固体(化合物5)，产率：62％。
1H NMR(500MHz,CDCl3)δ:8.35(s,1H),8.24(s,1H),7.73(d,J＝5.0Hz,1H),7.36(s,2H),,7.31(s,2H),7.25(t,J＝5Hz,2H),6.60(s,1H),6.19～6.13(m,1H),5.49(d,J＝20Hz,1H),5.37(d,J＝10Hz,1H),4.96(d,J＝5Hz,2H)；13C NMR(125MHz,CDCl3)δ:160.08,153.75,136.89,134.56,132.32,131.49,130.98,130.32,130.19,129.81,129.21,129.12,128.91,128.88,127.43,126.69,125.25,119.04,110.30,68.47；MS-ESI m/z:399.2[M+H]+。
实施例6：化合物6的合成
用邻溴苯甲醛替换苯甲醛，合成方法同实施例2，得136mg淡黄色固体(化合物6)，产率：55％。
1H NMR(500MHz,CDCl3)δ:8.04(s,1H),7.69(d,J＝10Hz,1H),7.63(d,J＝5Hz,1H),7.42(t,J＝5.0Hz,2H),7.35(t,J＝5.0Hz,1H),7.27(s,2H),7.25～7.22(m,3H),7.12(s,1H),5.55～5.47(m,1H),4.74(d,J＝25Hz,1H),4.24(d,J＝5Hz,1H)；13C NMR(125MHz,CDCl3)δ:159.36,158.77,135.27,134.14,133.47,133.17,131.12,131.08,130.62,130.47,129.62,129.21,128.38,127.35,127.11,124.90,124.82,121.20,118.91,117.34,48.97；MS-ESI m/z:487.1[M+H]+,489.1[M+3H]+。
实施例7：化合物7的合成
用邻氟苯甲醛替换苯甲醛，合成方法同实施例2，得94mg淡黄色固体(化合物7)，产率：50％。
1H NMR(500MHz,CDCl3)δ:8.65(t,J＝10Hz,1H),8.20(s,1H),7.58(s,1H),7.42(t,J＝10Hz,1H),7.38～7.34(m,1H),7.31(t,J＝10.0Hz,1H),7.23(t,J＝10.0Hz,1H),7.20～7.13(m,2H),7.09(t,J＝10.0Hz,1H),6.64(s,1H),6.18～6.11(m,1H),5.48(d,J＝20Hz,1H),5.36(d,J＝10Hz,1H),4.93(d,J＝5Hz,2H)；13C NMR(125MHz,CDCl3)δ:161.87(d,JFC＝253Hz),160.27(d,JFC＝248Hz),159.99,153.77,132.75,132.50,132.28,130.89,130.83,130.76,130.01,125.73,125.21(d,JFC＝3.75Hz),124.06(d,JFC＝3.75Hz),123.35(d,JFC＝10Hz),121.13(d,JFC＝15Hz),120.10(d,JFC＝6.25Hz),118.95,118.27,116.81(d,JFC＝22.5Hz),115.63(d,JFC＝22.5Hz),104.79,68.31；MS-ESI m/z:367.2[M+H]+。
实施例8：化合物8的合成
用间氟苯甲醛替换苯甲醛，合成方法同实施例2，得112mg淡黄色固体(化合物8)，产率：60％。
1H NMR(500MHz,CDCl3)δ:8.19(s,1H),8.07(d,J＝10Hz,1H),7.61(d,J＝10Hz,1H),7.44～7.40(m,1H),7.37～7.33(m,1H),7.25(s,1H),7.18(d,J＝5.0Hz,1H),7.09～7.03(m,3H),6.61(s,1H),6.18～6.11(m,1H),5.51(d,J＝15Hz,1H),5.37(d,J＝10Hz,1H),4.95(d,J＝5Hz,2H)；13C NMR(125MHz,CDCl3)δ:164.21(d,JFC＝92.5Hz),162.25(d,JFC＝76.25Hz),160.06,153.74,137.18,135.51,132.38(d,JFC＝15Hz),131.42,129.96,128.15,127.70,125.18,124.29,119.09,117.97(d,JFC＝22.5Hz),116.30(d,JFC＝22.5Hz),115.90,115.73,110.39,68.45；MS-ESI m/z:367.2[M+H]+。
实施例9：化合物9的合成
用对氟苯甲醛替换苯甲醛，合成方法同实施例2，得117mg淡黄色固体(化合物9)，产率：62％。
1H NMR(500MHz,CDCl3)δ:8.09(t,J＝5.0Hz,2H),8.04(s,1H),7.37(t,J＝10Hz,2H),7.14(t,J＝10.0Hz,2H),7.09(t,J＝10.0Hz,2H),6.59(s,1H),6.18～6.11(m,1H),5.49(d,J＝10Hz,1H),5.37(d,J＝5.0Hz,1H),4.93(d,J＝5Hz,2H)；13C NMR(125MHz,CDCl3)δ:166.95,160.35,153.60,150.48,133.97,132.51,131.56,131.18,130.57,129.42,127.78,124.60,119.03,116.95,115.85,110.27,68.27；MS-ESI m/z:367.1[M+H]+。
实施例10：化合物10的合成
用邻、间二氯苯甲醛替换苯甲醛，合成方法同实施例2，得162mg淡黄色固体(化合物10)，产率：68％。
1H NMR(500MHz,CDCl3)δ:7.73(s,1H),7.49(d,J＝10Hz,2H),7.28(t,J＝10.0Hz,2H),7.21(s,2H),7.15(s,1H),6.53(s,1H),5.95～5.87(m,1H),5.37(d,J＝10Hz,1H),5.32(d,J＝15.0Hz,1H),4.63(d,J＝5Hz,2H)；13C NMR(125MHz,CDCl3)δ:156.85,156.16,137.95,135.10,134.57,133.70,133.13,131.15,130.96,130.30,129.14,128.25,127.96,127.86,127.44,126.96,121.24,118.56,114.39,100.31,47.39；MS-ESI m/z:467.1[M+H]+。
实施例11：化合物11的合成
用间三氟甲基苯甲醛替换苯甲醛，合成方法同实施例2，得171mg淡黄色固体(化合物11)，产率：72％。
1H NMR(500MHz,CDCl3)δ:8.19(s,1H),8.17(d,J＝5Hz,2H),7.71(d,J＝10.0Hz,2H),7.65(d,J＝10.0Hz,2H),7.51(d,J＝10.0Hz,2H),7.31(s,1H),6.68(s,1H),6.20～6.12(m,1H),5.50(d,J＝15Hz,1H),5.39(d,J＝10.0Hz,1H),4.95(d,J＝5Hz,2H)；13C NMR(125MHz,CDCl3)δ:160.05,153.37,139.59,138.81,132.78,132.63,132.01,131.11,130.59,130.40,129.44,128.80,128.61,127.15,124.44,124.17,118.72,111.12,68.33；MS-ESI m/z:467.2[M+H]+。
实施例12：化合物12的合成
将双乙酰甘氨酸酐100.0mg(0.51mmol,1.0eq.)、对甲氧基苯甲醛72.0μL(0.59mmol，1.15eq.)、溴丙烯64.7μL(0.77mmol,1.5eq.)、Cs2CO3500.0mg(1.53mmol，3.0eq.)及3.0mL DMF中室温搅拌2h，后加入2,3-二氯苯甲醛89mg(0.51mmol，1.0eq.)于60°搅拌24h，待完成后冷却至室温，加水加稀盐酸调pH值至4～5，乙酸乙酯萃取，硅胶柱层析得98mg淡黄色固体(化合物12)，产率：45％。
1H NMR(500MHz,CDCl3)δ:8.02(s,1H),7.46(d,J＝10Hz,1H),7.35(d,J＝10.0Hz,1H),7.28(s,1H),7.27(s,1H),7.25(s,1H),7.17(s,1H),7.10(s,1H),6.94(s,1H),6.92(s,1H),5.61～5.53(m,1H),5.04(d,J＝10Hz,1H),4.82(d,J＝10.0Hz,1H),4.31(d,J＝5Hz,2H),3.86(s,3H)；13C NMR(125MHz,CDCl3)δ:160.83,160.54,159.38,134.86,134.00,133.07,131.72,131.56,130.86,128.42,128.12,127.70,126.61,126.07,123.45,118.85,114.34,114.19,55.70,48.37；MS-ESI m/z:429.1[M+H]+。
实施例13：化合物13的合成
将双乙酰甘氨酸酐100.0mg(0.51mmol,1.0eq.)、苯甲醛61.0μL(0.59mmol，1.15eq.)、碘甲烷57.2μL(0.92mmol,1.8eq.)、NaOH 86.0mg(1.53mmol，3.0eq.)及3.0mLDMF中室温搅拌2h，后加入对氟苯甲醛55μL(0.51mmol，1.0eq.)于室温搅拌24h，待完成后冷却至室温，加水加稀盐酸调pH值至4～5，乙酸乙酯萃取，硅胶柱层析得79mg淡黄色固体(化合物13)，产率：48％。
1H NMR(500MHz,CDCl3)δ:8.17(s,1H),7.44～7.38(m,4H),7.34(t,J＝10Hz,1H),7.28(d,J＝10.0Hz,3H),7.15(t,J＝10.0Hz,2H),7.03(s,1H),3.00(s,3H)；13C NMR(125MHz,CDCl3)δ:162.90(d,JFC＝250Hz),159.90,159.72,134.13,130.83,129.91(d,JFC＝155Hz),129.77,128.93,128.64,126.12,121.58,116.98,116.81,116.59,37.10；MS-ESIm/z:323.1[M+H]+。
实施例14：化合物14的合成
将双乙酰甘氨酸酐100.0mg(0.51mmol,1.0eq.)、邻氧基苯甲醛72.0μL(0.59mmol，1.15eq.)、溴丙烯64.7μL(0.77mmol,1.5eq.)、Cs2CO3500.0mg(1.53mmol，3.0eq.)及3.0mLDMF中室温搅拌2h，后加入苯甲醛53μL(0.51mmol，1.0eq.)于60°搅拌24h，待完成后冷却至室温，加水加稀盐酸调pH值至4～5，乙酸乙酯萃取，硅胶柱层析得86mg淡黄色固体(化合物14)，产率：47％。
1H NMR(500MHz,CDCl3)δ:8.04(s,1H),7.46～7.40(m,4H),7.37～7.34(m,3H)7.22(d,J＝5Hz,1H),7.07(s,1H),6.98(t,J＝5Hz,1H),6.91(d,J＝5Hz,1H),5.58～5.51(m,1H),5.00(d,J＝15.0Hz,1H),4.77(d,J＝15.0Hz,1H),4.24(d,J＝5Hz,2H),3.86(s,3H)；13CNMR(125MHz,CDCl3)δ:160.33,160.56,159.78,135.34,133.78,132.07,131.44,130.74,129.78,129.56,128.98,128.79,128.63,128.65,124.64,118.90,111.31,66.03；MS-ESIm/z:361.1[M+H]+。
实施例15：化合物的细胞毒活性
正常培养条件下，癌细胞K562,Hela,U937,H1975,SGC-7901,A549,MCF-7,DU145和HL60在RPMI或DMEM的10％FBS和1％penicillin/streptomycin的条件下培养(5％CO2，37℃)。用CCK8(DOjinDo,Japan)方法计算细胞成活率。在384孔板中每孔中放置400-800个癌细胞及各浓度的化合物，空白液作为对照，计算72h后细胞增殖并计算化合物的IC50值，具体结果如表1所示：
表1化合物的抗癌细胞活性
从表1可以看出化合物1-13对肿瘤细胞具有细胞毒活性，能够用于制备治疗相应的肿瘤药物中应用。
实施例16：化合物抗附着实验
使用附着生物：网纹藤壶金星幼虫与草苔虫幼虫；
使用抗附着的化合物：2,5-二酮哌嗪衍生物；
金星幼虫的获取方法如下：首先从大亚湾潮间带中采集成年网纹藤壶，将其于室温下暴露于空气中12小时候后，再置于用0.22μm过滤膜过滤了的海水中，让其缓慢孵化出无节幼虫，然后用纤细角毛藻为饵料，将无节幼虫置于恒温培养箱内在26-28℃的条件下，将其培养至金星幼虫，新培养的金星幼虫立即用于抗附着实验。
抗附着实验是在一种24孔聚苯乙烯板中进行，化合物首先溶解在DMSO中，然后用过滤的海水稀释至所需要的浓度：25,10,5,2.5,1.25,0.625,0.31,0.15μg/mL.
每个孔中放入15-20个金星幼虫及1mL的化合物溶液，每个样品重复3次实验，用过滤海水和DMSO替代化合物加入到样品溶液中作为阳性对照。接着，所有的样品溶液置于恒温培养箱内在25℃培养24-48小时。测试结果用解剖镜检测藤壶在固体表面附着的数量、未附着的数量以及藤壶的死亡或病变的数量等。化合物的抑制率通过分别计算单个孔中，附着的幼虫数量或发生病变的幼虫数量与加入藤壶幼虫总数的比值来获得，EC50值用来表示化合物抑制幼虫附着的数量为加入幼虫总数一半时化合物的浓度。最后用Probit软件对3次重复试验进行处理，结果用平均值来表示。
草苔虫收集及抗附着测定试验与网纹藤壶金星幼虫收集及测试方法一致。
表2化合物的抗附着活性
从表2可以看出，化合物8、11和14能够用于制备抗污损生物附着药物。
实施例17：化合物脂溶性实验。
取1mg化合物(化合物1-14)分别置于5mL不同离心管中，分别加入1mL乙酸乙酯，二氯甲烷，氯仿，四氢呋喃，N，N-二甲基甲酰胺，二甲亚砜，甲醇，丙酮，乙腈，上述化合物(化合物1-14中的任一化合物)能很快全部溶解，说明化合物的脂溶性较好。
Claims (4)
1.一种2,5-二酮哌嗪衍生物的制备方法，其特征在于，其合成过程如下：
其合成步骤如下：
将双乙酰甘氨酸酐Ar、卤代烃和碱置于二甲基甲酰胺中，经反应得到2,5-二酮哌嗪衍生物；
所述的卤代烃为溴丙烯或碘甲烷，所述的碱为NaOH或Cs2CO3；
所述的Ar为其中Ar1为苯基，邻、间或对甲苯基，邻、间或对甲氧苯基，邻、间或对氯苯基，邻、间或对溴苯基，邻、间或对氟苯基，或，邻、间或对三氟甲基苯基，或，邻或间二氯苯基基团中的一种；Ar2为苯基，邻、间或对甲苯基，邻、间或对甲氧苯基，邻、间或对氯苯基，邻、间或对溴苯基，邻、间或对氟苯基，邻、间或对三氟甲基苯基，或，邻或间二氯苯基基团中的一种；
所述的2,5-二酮哌嗪衍生物的结构式如式1所示：
其中：
R为甲基或烯丙基；
Ar1为苯基，邻、间或对甲苯基，邻、间或对甲氧苯基，邻、间或对氯苯基，邻、间或对溴苯基，邻、间或对氟苯基，邻、间或对三氟甲基苯基，或，邻或间二氯苯基；
Ar2为苯基，邻、间或对甲苯基，邻、间或对甲氧苯基，邻、间或对氯苯基，邻、间或对溴苯基，邻、间或对氟苯基，邻、间或对三氟甲基苯基，或，邻或间二氯苯基。
2.根据权利要求1所述的制备方法，其特征在于，所述的反应，其反应条件为：室温搅拌3～24h或60°加热24h，待反应完成后，倒入到水中，质量百分数10％盐酸调pH值至4～5，乙酸乙酯萃取，干燥，最后柱层析，得到2,5-二酮哌嗪衍生物。
3.根据权利要求1所述的制备方法，其特征在于，所述的双乙酰甘氨酸酐的物质的量分别与的物质的量之比都为1.0:1.0～1.15，与卤代烃的物质的量之比为1:1.5～1.8，与碱的物质的量之比为1:2.0～3.0。
4.化合物8：化合物11：或化合物14：在制备抗草台虫附着药物中的应用。
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