CN115636802A - 白藜芦醇丙烯酰基哌嗪苯磺酰胺衍生物及其制备与应用 - Google Patents
白藜芦醇丙烯酰基哌嗪苯磺酰胺衍生物及其制备与应用 Download PDFInfo
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- CN115636802A CN115636802A CN202211354901.1A CN202211354901A CN115636802A CN 115636802 A CN115636802 A CN 115636802A CN 202211354901 A CN202211354901 A CN 202211354901A CN 115636802 A CN115636802 A CN 115636802A
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- resveratrol
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- nmr
- compound
- acryloyl piperazine
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- -1 Resveratrol acryloyl piperazine benzene sulfonamide derivative Chemical class 0.000 title claims abstract description 48
- 229940016667 resveratrol Drugs 0.000 title claims abstract description 37
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 235000021283 resveratrol Nutrition 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 7
- 229940124599 anti-inflammatory drug Drugs 0.000 claims abstract description 6
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- RFIOZSIHFNEKFF-UHFFFAOYSA-N piperazine-1-carboxylic acid Chemical compound OC(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-N 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 40
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 5
- 238000013461 design Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 description 50
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- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 27
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- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 4
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- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
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Abstract
本发明公开了一种白藜芦醇丙烯酰基哌嗪苯磺酰胺衍生物及其制备与应用,涉及药物化学技术领域,本发明设计并合成了一系列具有新型结构的白藜芦醇丙烯酰基哌嗪苯磺酰胺衍生物,并对其结构进行了表征;制备这些化合物所采用的方法具有原料易得、操作简便、收率高的特点,能够快速合成目标化合物;同时测试了这些化合物的抗炎活性,从中筛选出高活性的化合物以用于开发新型抗炎药物。
Description
技术领域:
本发明涉及药物化学技术领域,具体涉及一种白藜芦醇丙烯酰基哌嗪苯磺酰胺衍生物及其制备与应用。
背景技术:
白藜芦醇(Resveratrol)一种天然二苯乙烯类化合物,常以反式结构广泛存在于自然界的植物中。白藜芦醇具有多种药理活性,如抗炎、降血脂、抗癌、抗氧化、抗神经退行性疾病、调节血糖、抗血小板凝集、抗过敏等,是一种极具开发潜力的先导化合物。由于白藜芦醇稳定性差且生物利用度低,因此,通过对白藜芦醇的结构加以修饰来筛选稳定性和生物利用度较高的白藜芦醇衍生物受到广泛的关注。白藜芦醇的结构中含有3个酚羟基和1个双键,这些官能团不仅使其具有广泛的生物活性,而且为改造分子结构提供了化学上的便利。将白藜芦醇的酚羟基甲基化可以显著提高其生物利用度。研究发现,磺酰胺类化合物具有抗菌、抗炎、抗肿瘤、抗糖尿病等生物活性,因此本发明选择在白藜芦醇母体分子上引入磺酰胺片段,期望可以大大提高化合物的生物活性。
发明内容:
本发明所要解决的技术问题在于设计并合成一种白藜芦醇丙烯酰基哌嗪苯磺酰胺衍生物,并测试这些化合物的抗炎活性,从中筛选出高活性的化合物以用于开发新型抗炎药物。
本发明所要解决的技术问题采用以下的技术方案来实现:
本发明的目的之一是提供一种白藜芦醇丙烯酰基哌嗪苯磺酰胺衍生物,结构如式I所示:
其中,R为苯基、苄基或取代苯基,但不限于此,也可为取代苄基、苯乙基、取代苯乙基等。
所述取代苯基的取代基为甲基、乙基、甲氧基、卤素、硝基、氰基、三氟甲基、三氟甲氧基,但不限于此,也可为其它类型的烷基、烷氧基等。
所述白藜芦醇丙烯酰基哌嗪苯磺酰胺衍生物包括下表1中的化合物1-27:
表1
本发明的第二个目的是提供一种所述白藜芦醇丙烯酰基哌嗪苯磺酰胺衍生物的制备方法,先由哌嗪-1-羧酸叔丁醇和RSO2Cl反应合成中间体1,再将中间体1脱Boc保护基得到中间体2,然后将3,5,4′-三甲氧基-2-丙烯酸白藜芦醇和中间体2反应得到白藜芦醇丙烯酰基哌嗪苯磺酰胺衍生物1-27。
合成路线如下:
本发明的第三个目的是提供一种药物组合物,含有所述白藜芦醇丙烯酰基哌嗪苯磺酰胺衍生物或其药学上可接受的盐。
本发明的第四个目的是提供一种药物制剂,包括有效成分和药学上可接受的辅料和/或载体,所述有效成分含有所述白藜芦醇丙烯酰基哌嗪苯磺酰胺衍生物或其药学上可接受的盐。
本发明的第五个目的是提供所述白藜芦醇丙烯酰基哌嗪苯磺酰胺衍生物在制备抗炎药物中的应用。
本发明的有益效果是:本发明设计并合成了一系列具有新型结构的白藜芦醇丙烯酰基哌嗪苯磺酰胺衍生物,并对其结构进行了表征;制备这些化合物所采用的方法具有原料易得、操作简便、收率高的特点,能够快速合成目标化合物;同时测试了这些化合物的抗炎活性,从中筛选出高活性的化合物以用于开发新型抗炎药物。
附图说明:
图1为本发明化合物1-27对RAW 264.7细胞的安全性评价;
图2为本发明化合物1-27对LPS诱导的RAW 264.7细胞NO释放的抑制率。
具体实施方式:
为了使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解,下面结合具体实施例和图示,进一步阐述本发明。
化合物1-27的合成:
实施例1
1)中间体1的合成
取1mmol哌嗪-1-羧酸叔丁醇和1mmol苯磺酰氯,加入3mLCH2Cl2,室温搅拌溶解,再逐滴加入2mmol三乙胺,在常温下反应15min,结束反应。加入30mL水和10mLCH2Cl2淬灭反应。萃取分液,以饱和NaCl洗涤有机相,无水硫酸钠干燥,旋干,得到中间体1。
2)中间体2的合成
将中间体1加入5mL CH2Cl2搅拌溶解,随后逐滴缓慢加入3mL三氟乙酸,室温搅拌10min,脱Boc完毕。加入10mL CH2Cl2冲淡体系,用90mL饱和NaHCO3溶液和10mL饱和K2CO3溶液淬灭体系。萃取分液,再次加入饱和NaHCO3溶液洗涤有机相一次,最后以水洗涤有机相一次,无水硫酸钠干燥,旋干,得到中间体2。
3)(E)-3-(2,4-dimethoxy-6-((E)-4-methoxystyryl)phenyl)-1-(4-(phenylsulfonyl)piperazin-1-yl)prop-2-en-1-one(化合物1)的合成
取1mmol 3,5,4′-三甲氧基-2-丙烯酸白藜芦醇和1mmol HOAt溶于5mL CH2Cl2中,再逐滴滴入2mmol三乙胺,搅拌至澄清。随后向反应液中加入1mmol EDCI,室温搅拌1h,此时溶液成黄色体系。
将中间体2用4mLCH2Cl2溶解后逐滴加入上述体系中,室温继续反应1h。加入5mL二氯甲烷冲淡体系,随后用水、1M盐酸、饱和NaHCO3溶液、饱和食盐水依次洗涤体系,无水硫酸钠干燥,旋干,得到粗产物。用CH2Cl2:MeOH(v/v)=100:1体系过柱纯化,得到化合物1。
1H NMR(400MHz,CDCl3)δ7.95(d,J=15.4Hz,1H),7.77-7.73(m,2H),7.65(t,J=7.4Hz,1H),7.57(t,J=7.4Hz,2H),7.43(d,J=8.7Hz,2H),7.20(d,J=16.0Hz,1H),6.93-6.87(m,3H),6.75-6.68(m,2H),6.42(d,J=2.4Hz,1H),3.89(s,3H),3.88(s,3H),3.85(s,3H),3.82-3.56(m,4H),2.99(s,4H).13C NMR(101MHz,CDCl3)δ161.0,160.0,159.6,140.6,137.5,135.2,133.2,131.1,129.8,129.3,127.9,127.7,125.9,119.7,116.1,114.2,103.4,97.7,55.7,55.5,55.4.HRMS(ESI):m/z[M+H]+calcd for C31H29NO4,549.6499;found:549.2059.
实施例2
(E)-3-(2,4-dimethoxy-6-((E)-4-methoxystyryl)phenyl)-1-(4-((4-methoxyphenyl)sulfonyl)piperazin-1-yl)prop-2-en-1-one(化合物2)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成4-甲氧基苯磺酰氯,得到化合物2。
1H NMR(400MHz,CDCl3)δ7.95(d,J=15.4Hz,1H),7.68(d,J=8.9Hz,2H),7.43(d,J=8.7Hz,2H),7.20(d,J=16.1Hz,1H),7.04-7.00(m,2H),6.92-6.87(m,3H),6.75-6.69(m,2H),6.42(d,J=2.4Hz,1H),3.90(s,6H),3.88(s,3H),3.86(s,3H),3.63(d,J=19.3Hz,4H),2.96(d,J=36.2Hz,4H).13C NMR(101MHz,CDCl3)δ166.3,163.3,161.0,160.0,159.6,140.6,137.4,131.1,129.9,129.8,127.9,126.7,126.0,119.8,116.1,114.4,114.2,103.4,97.7,55.7,55.7,55.5,55.4.HRMS(ESI):m/z[M+H]+calcd for C31H29NO4,579.6759;found:579.2163.
实施例3
(E)-3-(2,4-dimethoxy-6-((E)-4-methoxystyryl)phenyl)-1-(4-((4-iodophenyl)sulfonyl)piperazin-1-yl)prop-2-en-1-one(化合物3)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成4-碘苯磺酰氯,得到化合物3。
1H NMR(400MHz,CDCl3)δ7.98-7.90(m,3H),7.47-7.40(m,4H),7.20(d,J=16.0Hz,1H),6.93-6.87(m,3H),6.76-6.68(m,2H),6.42(d,J=2.4Hz,1H),3.90(s,3H),3.88(s,3H),3.86(s,3H),3.82-3.50(m,4H),2.98(s,4H).13C NMR(101MHz,CDCl3)δ166.3,161.1,160.0,159.6,140.7,138.6,137.6,135.0,131.2,129.8,129.0,127.9,126.0,119.7,116.1,114.2,103.3,100.9,97.7,55.7,55.5,55.4.HRMS(ESI):m/z[M+H]+calcd forC30H31IN2O6S,675.5464;found:675.1022.
实施例4
(E)-3-(2,4-dimethoxy-6-((E)-4-methoxystyryl)phenyl)-1-(4-((4-ethylphenyl)sulfonyl)piperazin-1-yl)prop-2-en-1-one(化合物4)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成4-乙基苯磺酰氯,得到化合物4。
1H NMR(400MHz,CDCl3)δ7.95(d,J=15.4Hz,1H),7.65(d,J=8.3Hz,2H),7.40(dd,J=19.1,8.5Hz,4H),7.20(d,J=16.1Hz,1H),6.93-6.86(m,3H),6.76-6.68(m,2H),6.42(d,J=2.4Hz,1H),3.89(s,3H),3.88(s,3H),3.85(s,3H),3.74(d,J=7.0Hz,4H),2.99(s,4H),2.75(q,J=7.6Hz,2H),1.30(d,J=7.6Hz,2H).13C NMR(101MHz,CDCl3)δ166.3,161.0,160.0,159.6,150.2,140.6,137.5,132.3,131.2,129.8,128.7,127.9,125.9,119.8,116.1,114.2,103.4,97.7,55.7,55.5,55.4,28.8,15.1.HRMS(ESI):m/z[M+H]+calcd forC32H36N2O6S,577.2294;found:577.2371.
实施例5
(E)-1-(4-((4-bromophenyl)sulfonyl)piperazin-1-yl)-3-(2,4-dimethoxy-6-((E)-4-methoxystyryl)phenyl)prop-2-en-1-one(化合物5)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成4-溴苯磺酰氯,得到化合物5。
1H NMR(400MHz,CDCl3)δ7.96(d,J=15.4Hz,1H),7.71(d,J=8.6Hz,2H),7.60(d,J=8.6Hz,2H),7.43(d,J=8.7Hz,2H),7.20(d,J=16.1Hz,1H),6.94-6.87(m,3H),6.76-6.69(m,2H),6.42(d,J=2.4Hz,1H),3.90(s,3H),3.88(s,3H),3.86(s,3H),3.84-3.52(m,4H),2.98(d,J=45.0Hz,4H).13C NMR(101MHz,CDCl3)δ166.3,161.1,160.0,159.6,140.7,137.6,134.4,132.6,131.2,129.8,129.2,128.4,127.9,126.0,119.7,116.1,114.2,103.4,97.7,55.7,55.5,55.4.HRMS(ESI):m/z[M+H]+calcd for C30H31BrN2O6S,628.5459;found:628.1178.
实施例6
(E)-3-(2,4-dimethoxy-6-((E)-4-methoxystyryl)phenyl)-1-(4-((4-nitrophenyl)su lfonyl)piperazin-1-yl)prop-2-en-1-one(化合物6)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成4-硝基苯磺酰氯,得到化合物6。
1H NMR(400MHz,CDCl3)δ7.96(d,J=15.4Hz,1H),7.79-7.73(m,2H),7.43(d,J=8.7Hz,2H),7.28-7.17(m,3H),6.93-6.86(m,3H),6.77-6.65(m,2H),6.42(d,J=2.4Hz,1H),3.89(s,3H),3.88(s,3H),3.86(s,3H),3.83-3.52(m,4H),2.98(s,4H).13C NMR(101MHz,CDCl3)δ166.4,161.1,160.0,159.6,150.4,141.4,140.7,137.8,131.2,129.8,128.9,127.9,126.0,124.5,119.5,116.0,114.2,103.5,97.7,55.7,55.5,55.4,46.0.HRMS(ESI):m/z[M+H]+calcd for C30H31N3O8S,594.6474;found:594.1189.
实施例7
(E)-3-(2,4-dimethoxy-6-((E)-4-methoxystyryl)phenyl)-1-(4-((4-fluorophenyl)sulfonyl)piperazin-1-yl)prop-2-en-1-one(化合物7)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成4-氟苯磺酰氯,得到化合物7。
1H NMR(400MHz,CDCl3)δ7.96(d,J=15.4Hz,1H),7.79-7.73(m,2H),7.43(d,J=8.7Hz,2H),7.28-7.17(m,3H),6.93-6.86(m,3H),6.77-6.65(m,2H),6.42(d,J=2.4Hz,1H),3.89(s,3H),3.88(s,3H),3.86(s,3H),3.83-3.52(m,4H),2.98(s,4H).13C NMR(101MHz,CDCl3)δ166.7,164.2,161.1,160.0,159.6,140.6,137.6,131.2,130.5,130.4,129.8,127.9,126.0,119.7,116.7,116.5,116.1,114.2,103.4,97.7,55.7,55.5,55.4.HRMS(ESI):m/z[M+H]+calcd for C30H31FN2O6S,567.6404;found:567.1955.
实施例8
(E)-1-(4-((4-chlorophenyl)sulfonyl)piperazin-1-yl)-3-(2,4-dimethoxy-6-((E)-4-methoxystyryl)phenyl)prop-2-en-1-one(化合物8)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成4-氯苯磺酰氯,得到化合物8。
1H NMR(400MHz,CDCl3)δ7.95(d,J=15.4Hz,1H),7.68(d,J=8.6Hz,2H),7.55(d,J=8.6Hz,2H),7.43(d,J=8.7Hz,2H),7.20(d,J=16.1Hz,1H),6.94-6.86(m,3H),6.76-6.68(m,2H),6.42(d,J=2.4Hz,1H),3.90(s,3H),3.88(s,3H),3.86(s,3H),3.84-3.51(m,4H),2.98(s,4H).13C NMR(101MHz,CDCl3)δ166.3,161.1,160.0,159.6,140.7,139.9,137.6,133.8,131.2,129.8,129.6,129.1,127.9,126.0,119.7,116.1,114.2,103.4,97.7,55.7,55.5,55.4.HRMS(ESI):m/z[M+H]+calcd for C30H31ClN2O6S,583.1591;found:583.1661.
实施例9
(E)-3-(2,4-dimethoxy-6-((E)-4-methoxystyryl)phenyl)-1-(4-tosylpiperazin-1-yl)prop-2-en-1-one(化合物9)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成4-甲基苯磺酰氯,得到化合物9。
1H NMR(400MHz,CDCl3)δ7.95(d,J=15.4Hz,1H),7.62(d,J=8.1Hz,2H),7.43(d,J=8.5Hz,2H),7.36(d,J=8.0Hz,2H),7.20(d,J=16.1Hz,1H),6.93-6.87(m,3H),6.76-6.67(m,2H),6.42(d,J=2.3Hz,1H),3.89(s,3H),3.88(s,3H),3.86(s,3H),3.82-3.53(m,4H),2.97(s,4H),2.46(s,3H).13C NMR(101MHz,CDCl3)δ161.0,160.0,159.6,144.1,140.6,137.4,132.1,131.1,129.9,129.8,127.9,127.8,125.9,119.8,116.1,114.2,103.4,97.7,55.7,55.5,55.4,21.6.HRMS(ESI):m/z[M+H]+calcd for C31H34N2O6S,563.6765;found:563.2206.
实施例10
(E)-1-(4-((3-chlorophenyl)sulfonyl)piperazin-1-yl)-3-(2,4-dimethoxy-6-((E)-4-methoxystyryl)phenyl)prop-2-en-1-one(化合物10)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成3-氯苯磺酰氯,得到化合物10。
1H NMR(400MHz,CDCl3)δ7.96(d,J=15.5Hz,1H),7.74(t,J=1.9Hz,1H),7.64-7.60(m,2H),7.53(d,J=7.9Hz,1H),7.43(d,J=8.8Hz,2H),7.20(d,J=16.1Hz,1H),6.94-6.89(m,3H),6.76-6.69(m,2H),6.42(d,J=2.3Hz,1H),3.89(s,3H),3.88(s,3H),3.86(s,3H),3.64(d,J=14.7Hz,4H),3.01(d,J=44.3Hz,4H).13C NMR(101MHz,CDCl3)δ166.4,161.1,160.0,159.6,140.7,137.6,137.1,135.6,133.4,131.2,130.6,129.8,127.9,127.7,125.9,125.8,119.6,116.0,114.2,103.4,97.7,55.7,55.5,55.4.HRMS(ESI):m/z[M+H]+calcd for C30H31ClN2O6S,583.1591;found:583.1660.
实施例11
(E)-3-(2,4-dimethoxy-6-((E)-4-methoxystyryl)phenyl)-1-(4-((3-nitrophenyl)sulfonyl)piperazin-1-yl)prop-2-en-1-one(化合物11)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成3-硝基苯磺酰氯,得到化合物11。
1H NMR(400MHz,CDCl3)δ8.59(s,1H),8.50(dd,J=7.6,1.9Hz,1H),8.07(d,J=7.5Hz,1H),7.95(d,J=15.3Hz,1H),7.81(t,J=7.9Hz,1H),7.43(d,J=8.3Hz,2H),7.19(d,J=16.1Hz,1H),6.95-6.86(m,3H),6.78-6.67(m,2H),6.42(d,J=2.3Hz,1H),3.89(s,3H),3.88(s,3H),3.86(s,3H),3.83-3.47(m,4H),3.06(s,4H).13C NMR(101MHz,CDCl3)δ161.1,160.0,159.63,148.4,140.8,137.8,137.8,133.1,131.3,130.8,129.8,127.9,127.7,125.9,122.8,115.9,114.2,103.5,97.7,55.7,55.5,55.4.HRMS(ESI):m/z[M+H]+calcd for C30H31N3O8S,594.6474;found:594.1907.
实施例12
(E)-3-(2,4-dimethoxy-6-((E)-4-methoxystyryl)phenyl)-1-(4-((2-fluorophenyl)sulfonyl)piperazin-1-yl)prop-2-en-1-one(化合物12)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成2-氟苯磺酰氯,得到化合物12。
1H NMR(400MHz,CDCl3)δ7.98(d,J=15.3Hz,1H),7.84(d,J=8.0Hz,1H),7.62(ddd,J=8.1,5.7,3.2Hz,1H),7.44(d,J=8.6Hz,2H),7.32(td,J=7.7,1.0Hz,1H),7.24(dd,J=17.4,8.8Hz,2H),6.93-6.88(m,3H),6.76(d,J=15.5Hz,1H),6.70(d,J=2.3Hz,1H),6.43(d,J=2.3Hz,1H),3.90(s,3H),3.87(s,3H),3.87(s,3H),3.80-3.63(m,4H),3.19(s,4H).13C NMR(101MHz,CDCl3)δ166.5,161.0,160.0,159.6,140.8,140.7,139.6,137.7,137.6,135.8,134.1,133.1,131.8,131.3,131.2,131.0,130.9,130.5,129.8,127.9,127.9,125.8,125.7,124.2,119.7,119.5,116.1,115.9,114.2,103.4,97.7,55.7,55.5,55.4.HRMS(ESI):m/z[M+H]+calcd for C30H31FN2O6S,567.6404;found:567.1956.
实施例13
(E)-1-(4-((2-chlorophenyl)sulfonyl)piperazin-1-yl)-3-(2,4-dimethoxy-6-((E)-4-methoxystyryl)phenyl)prop-2-en-1-one(化合物13)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成2-氯苯磺酰氯,得到化合物13。
1H NMR(400MHz,CDCl3)δ8.06(dd,J=7.7,1.4Hz,1H),7.99(d,J=15.4Hz,1H),7.54(dd,J=6.7,1.7Hz,2H),7.46-7.41(m,3H),7.23(d,J=16.1Hz,1H),6.94-6.88(m,3H),6.77(d,J=15.4Hz,1H),6.71(d,J=2.4Hz,1H),6.43(d,J=2.4Hz,1H),3.90(s,3H),3.87(s,6H),3.81-3.56(m,4H),3.29(s,4H).13C NMR(101MHz,CDCl3)δ161.0,160.0,159.6,140.6,137.5,135.7,134.0,132.4,132.3,132.2,131.2,129.8,127.9,127.2,125.8,119.9,116.1,114.2,103.4,97.7,55.7,55.5,55.4.HRMS(ESI):m/z[M+H]+calcd forC30H31ClN2O6S,583.1591;found:583.1668.
实施例14
(E)-1-(4-(benzylsulfonyl)piperazin-1-yl)-3-(2,4-dimethoxy-6-((E)-4-methoxystyryl)phenyl)prop-2-en-1-one(化合物14)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成苄基苯磺酰氯,得到化合物14。
1H NMR(400MHz,CDCl3)δ8.00(d,J=15.4Hz,1H),7.46-7.38(m,7H),7.23(d,J=16.1Hz,1H),6.95-6.89(m,3H),6.77-6.69(m,2H),6.44(d,J=2.4Hz,1H),4.24(s,2H),3.90(s,3H),3.87(s,3H),3.86(s,3H),3.62(d,J=36.1Hz,4H),3.08(s,4H).13C NMR(101MHz,CDCl3)δ166.4,161.0,160.0,159.6,140.7,137.5,131.3,130.7,129.8,129.0,129.0,128.4,127.9,125.8,119.9,116.1,114.2,103.4,97.7,57.2,55.7,55.5,55.4.HRMS(ESI):m/z[M+H]+calcd for C31H34N2O6S,563.6765;found:563.2210.
实施例15
2-((4-((E)-3-(2-((E)-4-hydroxystyryl)-4,6-dimethoxyphenyl)acryloyl)piperazin-1-yl)sulfonyl)benzonitrile(化合物15)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成2-氰基苯磺酰氯,得到化合物15。
1H NMR(400MHz,CDCl3)δ8.07-8.04(m,1H),7.99(d,J=15.4Hz,1H),7.54(dd,J=6.6,1.6Hz,2H),7.44(dd,J=8.4,1.9Hz,3H),7.23(d,J=16.1Hz,1H),6.93-6.88(m,3H),6.77(d,J=15.5Hz,1H),6.71(d,J=2.4Hz,1H),6.43(d,J=2.3Hz,1H),3.90(s,3H),3.87(s,6H),3.80-3.52(m,4H),3.29(s,4H).13C NMR(101MHz,CDCl3)δ166.5,166.5,161.1,160.1,160.0,159.6,148.4,140.8,140.7,139.6,137.7,135.8,134.1,133.1,131.7,131.3,131.2,131.0,130.5,129.8,127.9,127.9,125.8,125.7,124.2,119.7,119.4,116.2,116.1,115.9,114.3,111.0,103.4,97.7,55.7,55.5,55.4,29.7.HRMS(ESI):m/z[M+H]+calcd for C31H31N3O6S,574.6593;found:574.2010.
实施例16
(E)-3-(2-((E)-4-hydroxystyryl)-4,6-dimethoxyphenyl)-1-(4-((2-nitrophenyl)sulfonyl)piperazin-1-yl)prop-2-en-1-one(化合物16)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成2-硝基苯磺酰氯,得到化合物16。
1H NMR(400MHz,CDCl3)δ7.99(d,J=15.6Hz,2H),7.78-7.70(m,2H),7.67-7.63(m,1H),7.45(d,J=8.7Hz,2H),7.23(d,J=16.0Hz,1H),6.94–6.89(m,3H),6.78(d,J=15.4Hz,1H),6.71(d,J=2.4Hz,1H),6.43(d,J=2.4Hz,1H),3.90(s,3H),3.87(s,6H),3.85-3.60(m,4H),3.30(s,4H).13C NMR(101MHz,CDCl3)δ166.4,161.1,160.0,159.6,140.7,137.6,135.5,135.4,131.3,131.2,129.8,127.9,125.8,124.7,119.8,117.6,117.4,116.1,114.2,103.4,97.7,55.7,55.5,55.4.HRMS(ESI):m/z[M+H]+calcd forC30H31N3O8S,594.6474;found:594.1905.
实施例17
(E)-3-(2-((E)-4-hydroxystyryl)-4,6-dimethoxyphenyl)-1-(4-((2-(trifluoromethoxy)phenyl)sulfonyl)piperazin-1-yl)prop-2-en-1-one(化合物17)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成2-三氟甲氧基苯磺酰氯,得到化合物17。
1H NMR(400MHz,CDCl3)δ8.02-7.95(m,2H),7.69-7.63(m,1H),7.47-7.41(m,4H),7.24(d,J=16.1Hz,1H),6.94-6.87(m,3H),6.78(d,J=15.5Hz,1H),6.71(d,J=2.4Hz,1H),6.43(d,J=2.4Hz,1H),3.90(s,3H),3.87(d,J=0.9Hz,6H),3.82-3.57(m,4H),3.23(s,4H).13C NMR(101MHz,CDCl3)δ166.50,161.0,160.0,159.6,140.7,137.5,134.8,132.0,131.3,130.0,129.8,127.9,126.8,125.7,120.9,119.8,116.1,114.2,103.4,97.7,55.7,55.5,55.4.HRMS(ESI):m/z[M+H]+calcd for C31H31F3N2O7S,633.6473;found:633.1883.
实施例18
(E)-1-(4-((2-bromophenyl)sulfonyl)piperazin-1-yl)-3-(2-((E)-4-hydroxystyryl)-4,6-dimethoxyphenyl)prop-2-en-1-one(化合物18)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成2-溴苯磺酰氯,得到化合物18。
1H NMR(400MHz,CDCl3)δ8.10(dd,J=7.7,1.8Hz,1H),7.99(d,J=15.5Hz,1H),7.78(dd,J=7.8,1.4Hz,1H),7.46(ddd,J=14.9,7.5,1.6Hz,4H),7.24(d,J=16.1Hz,1H),6.94-6.89(m,3H),6.77(d,J=15.5Hz,1H),6.71(d,J=2.4Hz,1H),6.43(d,J=2.3Hz,1H),3.90(s,3H),3.87(s,6H),3.82-3.54(m,4H),3.30(s,4H).13C NMR(101MHz,DMSO-d6)δ165.6,161.1,160.1,159.6,140.3,137.4,136.4,136.2,135.1,132.1,131.6,130.0,128.9,128.4,125.4,120.9,120.0,115.7,114.6,103.9,98.2,56.3,55.9,55.6.HRMS(ESI):m/z[M+H]+calcd for C30H31BrN2O6S,629.1070;found:629.1157.
实施例19
(E)-1-(4-((3-bromophenyl)sulfonyl)piperazin-1-yl)-3-(2-((E)-4-hydroxystyryl)-4,6-dimethoxyphenyl)prop-2-en-1-one(化合物19)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成3-溴苯磺酰氯,得到化合物19。
1H NMR(400MHz,CDCl3)δ7.96(d,J=15.4Hz,1H),7.89(t,J=1.8Hz,1H),7.77(ddd,J=8.0,1.9,1.0Hz,1H),7.69-7.65(m,1H),7.48-7.41(m,3H),7.20(d,J=16.1Hz,1H),6.93-6.88(m,3H),6.74(d,J=15.4Hz,1H),6.70(d,J=2.4Hz,1H),6.42(d,J=2.3Hz,1H),3.90(s,3H),3.88(s,3H),3.86(s,3H),3.85-3.56(m,4H),3.01(d,J=40.4Hz,4H).13CNMR(101MHz,DMSO-d6)δ165.6,161.1,160.2,159.7,140.4,137.4,136.8,136.1,132.2,131.7,130.1,130.0,128.5,127.1,125.4,123.0,120.8,115.6,114.6,103.9,98.2,56.3,55.9,55.7.HRMS(ESI):m/z[M+H]+calcd for C30H31BrN2O6S,629.1070;found:629.1170.
实施例20
(E)-3-(2-((E)-4-hydroxystyryl)-4,6-dimethoxyphenyl)-1-(4-((3-(trifluoromethyl)phenyl)sulfonyl)piperazin-1-yl)prop-2-en-1-one(化合物20)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成3-三氟甲基苯磺酰氯,得到化合物20。
1H NMR(400MHz,CDCl3)δ8.01(s,1H),7.99-7.89(m,3H),7.74(t,J=7.8Hz,1H),7.43(d,J=8.7Hz,2H),7.20(d,J=16.1Hz,1H),6.93-6.87(m,3H),6.74(d,J=15.4Hz,1H),6.69(d,J=2.4Hz,1H),6.42(d,J=2.4Hz,1H),3.90(s,3H),3.88(s,3H),3.86(s,3H),3.64(s,4H),3.02(d,J=25.7Hz,4H).13C NMR(101MHz,DMSO-d6)δ165.6,161.2,160.1,159.7,140.4,136.7,136.1,132.1,131.7,131.7,130.7,130.5,130.0,128.5,125.4,124.3,120.7,115.6,114.6,103.9,98.2,56.2,55.9,55.6.HRMS(ESI):m/z[M+H]+calcdfor C31H31F3N2O6S,617.6479;found:617.1929.
实施例21
(E)-3-(2-((E)-4-hydroxystyryl)-4,6-dimethoxyphenyl)-1-(4-((4-(trifluoromethyl)phenyl)sulfonyl)piperazin-1-yl)prop-2-en-1-one(化合物21)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成4-三氟甲基苯磺酰氯,得到化合物21。
1H NMR(400MHz,CDCl3)δ7.95(d,J=15.4Hz,1H),7.89-7.81(m,4H),7.43(d,J=8.6Hz,2H),7.19(d,J=16.1Hz,1H),6.93-6.86(m,3H),6.75-6.67(m,2H),6.42(d,J=2.4Hz,1H),3.89(s,3H),3.88(s,3H),3.85(s,3H),3.84-3.50(m,4H),3.02(d,J=41.2Hz,4H).13C NMR(101MHz,DMSO-d6)δ165.5,161.1,160.1,159.7,140.4,139.4,136.1,131.7,130.0,129.0,128.5,127.2,127.2,125.4,120.7,115.6,114.7,104.0,98.2,56.3,55.9,55.6.HRMS(ESI):m/z[M+H]+calcd for C31H31F3N2O6S,617.6479;found:617.1927.
实施例22
(E)-3-(2-((E)-4-hydroxystyryl)-4,6-dimethoxyphenyl)-1-(4-((3-(trifluoromethoxy)phenyl)sulfonyl)piperazin-1-yl)prop-2-en-1-one(化合物22)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成3-三氟甲氧基苯磺酰氯,得到化合物22。
1H NMR(400MHz,CDCl3)δ7.96(d,J=15.4Hz,1H),7.69-7.60(m,3H),7.52-7.47(m,1H),7.43(d,J=8.6Hz,2H),7.20(d,J=16.1Hz,1H),6.93-6.86(m,3H),6.76-6.68(m,2H),6.42(d,J=2.4Hz,1H),3.89(s,3H),3.88(s,3H),3.86(s,3H),3.84-3.55(m,4H),3.01(d,J=29.7Hz,4H).13C NMR(101MHz,DMSO-d6)δ132.54,128.5,127.1,126.6,125.4,114.6,103.9,56.3,55.9,55.6.HRMS(ESI):m/z[M+H]+calcd for C31H31F3N2O7S,633.6473;found:633.1871.
实施例23
(E)-3-(2-((E)-4-hydroxystyryl)-4,6-dimethoxyphenyl)-1-(4-((4-(trifluoromethoxy)phenyl)sulfonyl)piperazin-1-yl)prop-2-en-1-one(化合物23)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成4-三氟甲氧基苯磺酰氯,得到化合物23。
1H NMR(400MHz,CDCl3)δ7.96(d,J=15.4Hz,1H),7.80(d,J=8.8Hz,2H),7.44-7.38(m,4H),7.20(d,J=16.1Hz,1H),6.93-6.87(m,3H),6.76-6.68(m,2H),6.42(d,J=2.4Hz,1H),3.89(s,3H),3.88(s,3H),3.86(s,3H),3.84-3.49(m,4H),3.00(d,J=45.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ165.6,161.2,160.1,159.6,152.0,151.9,136.1,134.3,131.69,130.7,130.0,128.4,125.4,122.0,120.7,115.6,114.6,103.9,98.2,56.3,55.9,55.6.HRMS(ESI):m/z[M+H]+calcd for C31H31F3N2O7S,633.6473;found:633.1879.
实施例24
(E)-3-(2-((E)-4-hydroxystyryl)-4,6-dimethoxyphenyl)-1-(4-((2-(trifluoromethyl)phenyl)sulfonyl)piperazin-1-yl)prop-2-en-1-one(化合物24)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成2-三氟甲基苯磺酰氯,得到化合物24。
1H NMR(400MHz,CDCl3)δ8.14-8.09(m,1H),7.99(d,J=15.5Hz,1H),7.95-7.91(m,1H),7.77-7.72(m,2H),7.44(d,J=8.7Hz,2H),7.23(d,J=16.1Hz,1H),6.93-6.88(m,3H),6.77(d,J=15.4Hz,1H),6.71(d,J=2.4Hz,1H),6.43(d,J=2.4Hz,1H),3.90(s,3H),3.87(s,6H),3.82-3.53(m,4H),3.24(s,4H).13C NMR(101MHz,DMSO-d6)δ165.6,161.2,160.1,159.6,140.3,137.1,136.2,134.1,134.0,131.7,131.6,130.0,129.3,129.2,128.4,125.3,120.8,115.7,114.6,103.9,98.2,56.3,55.9,55.6.HRMS(ESI):m/z[M+H]+calcdfor C31H31F3N2O6S,617.6479;found:617.1941.
实施例25
(E)-3-(2-((E)-4-hydroxystyryl)-4,6-dimethoxyphenyl)-1-(4-((2-methoxyphenyl)sulfonyl)piperazin-1-yl)prop-2-en-1-one(化合物25)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成2-甲氧基苯磺酰氯,得到化合物25。
1H NMR(400MHz,CDCl3)δ7.98(d,J=15.4Hz,1H),7.89(dd,J=7.8,1.7Hz,1H),7.55(ddd,J=8.3,7.4,1.7Hz,1H),7.44(d,J=8.7Hz,2H),7.24(d,J=16.1Hz,1H),7.09-7.01(m,2H),6.94-6.87(m,3H),6.77(d,J=15.4Hz,1H),6.71(d,J=2.4Hz,1H),6.43(d,J=2.3Hz,1H),3.91(s,3H),3.90(s,3H),3.87(d,J=1.2Hz,6H),3.82-3.53(m,4H),3.23(d,J=43.9Hz,4H).13C NMR(101MHz,DMSO-d6)δ165.6,161.1,160.1,159.6,157.2,140.3,136.1,135.6,131.6,131.2,130.0,128.4,125.7,125.39,120.9,120.7,115.7,114.6,113.7,103.9,98.2,56.5,56.3,55.9,55.6.HRMS(ESI):m/z[M+H]+calcd for C31H34N2O7S,579.6759;found:579.2159.
实施例26
(E)-3-(2,4-dimethoxy-6-((E)-4-methoxystyryl)phenyl)-1-(4-((3-methoxyphenyl)sulfonyl)piperazin-1-yl)prop-2-en-1-one(化合物26)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成3-甲氧基苯磺酰氯,得到化合物26。
1H NMR(400MHz,CDCl3)δ7.95(d,J=15.4Hz,1H),7.49-7.41(m,3H),7.31(ddd,J=7.8,1.7,1.0Hz,1H),7.15(ddd,J=8.3,2.6,1.0Hz,1H),6.93-6.87(m,3H),6.76-6.69(m,2H),6.42(d,J=2.4Hz,1H),3.89(s,3H),3.88(d,J=1.5Hz,6H),3.86(s,3H),3.83-3.49(m,4H),3.01(d,J=39.7Hz,4H).13C NMR(101MHz,DMSO-d6)δ165.6,161.1,160.1,160.1,159.6,140.4,136.3,136.1,131.7,131.2,130.0,128.5,125.4,120.7,120.0,119.7,115.6,114.6,112.8,104.0,98.2,56.3,56.1,55.8,55.6.HRMS(ESI):m/z[M+H]+calcd forC31H34N2O7S,579.6759;found:579.2151.
实施例27
4-((4-((E)-3-(2,4-dimethoxy-6-((E)-4-methoxystyryl)phenyl)acryloyl)piperazin-1-yl)sulfonyl)benzonitrile(化合物27)的合成
其合成方法和实施例1相同,只是将苯磺酰氯替换成4-氰基苯磺酰氯,得到化合物27。
1H NMR(400MHz,CDCl3)δ7.95(d,J=15.4Hz,1H),7.87(d,J=2.1Hz,4H),7.43(d,J=8.7Hz,2H),7.19(d,J=16.1Hz,1H),6.92-6.87(m,3H),6.74-6.68(m,2H),6.42(d,J=2.3Hz,1H),3.90(s,3H),3.88(s,3H),3.86(s,3H),3.81-3.56(m,4H),3.01(s,4H).13C NMR(101MHz,CDCl3)δ166.3,161.1,160.0,159.6,140.7,139.9,137.8,133.1,133.0,131.2,129.8,128.3,128.1,127.9,126.0,119.5,117.1,117.0,116.0,114.2,114.2,103.5,97.7,55.7,55.5,55.4,29.8.HRMS(ESI):m/z[M+H]+calcd for C31H31N3O6S,574.6693;found:574.2015.
化合物1-27的抗炎活性评价:
1、MTT法检测细胞毒性
采用MTT法来检测化合物1-27对RAW 264.7细胞、HepaRG细胞的毒性。
(1)细胞铺板:根据细胞生长情况将对数生长期细胞收集并细胞计数,每孔加入100μL混合细胞的的培养基,密度控制在每孔5×103个细胞,最外围一圈加PBS防止溶剂挥发,只用中间的60个孔,并同时设空白对照组(培养基)、阴性对照组(培养基+细胞)、实验组(培养基+细胞+化合物)且每组实验均要设置3个副孔。
(2)细胞培养:在二氧化碳恒温培养箱内过夜培养,不同的细胞有专用的培养基,一般化合物浓度按照二倍法设置五个浓度梯度,每组浓度均有三个副孔确保结果的准确。
(3)加入不同浓度的化合物,继续培养24h。
(4)细胞加入事先配制好浓度的MTT(5mg/mL),培养箱培养4h,弃掉培养基加入150μL的DMSO,置于摇床上缓慢震荡10min。
(5)OD值的测量:设置酶标仪波长为492nm。
实验结果表明,化合物在40μM浓度时与RAW264.7共同孵育24h,化合物均表现出较好的安全性。结果如图1所示。
2、Griess实验
采用Griess法检测化合物1-27对LPS诱导的NO产生的抑制作用,在一定程度上可以反应出化合物的抗炎活性。
(1)收集对数生长期的RAW264.7细胞,细胞计数并接种在96孔板上,每孔加入300μL培养基使得细胞密度每孔约为7×104,二氧化碳恒温培养箱中孵育过夜。
(2)隔夜后,向实验组中加入设定好的五个浓度梯度(5,10,20,30,40μM)的药物,空白组和对照组换新鲜的培养基300μL。
(3)培养箱孵育1h,加入LPS(0.5μg/mL)培养24h。
(4)收集细胞上清液,离心检测。
(5)取出Griess Reagent I和II,并且让温度达到室温条件。
(6)按50μL/孔,在各孔中先加入室温Griess Reagent I。随后,同上一步加入等体积Griess Reagent 4I。注意此步骤避光操作。
(7)酶标仪540nm测定吸光度,带入标准曲线,计算每个化合物对NO分泌的抑制率。
在浓度为40μM时,化合物1、化合物2、化合物23对RAW 264.7中NO释放具有较强的抑制作用,结果如图2所示。其中,化合物2的NO抑制率最高,表现出较好的抗炎潜力,且毒性低,能够为后续基于白藜芦醇的新型抗炎药物筛选提供先导化合物。
进一步对化合物的安全性进行检测,发现化合物对HepaRG细胞的IC50值均大于100μM,如表2所示,说明化合物具有较好的安全性。
表2
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (6)
2.根据权利要求1所述的白藜芦醇丙烯酰基哌嗪苯磺酰胺衍生物,其特征在于:所述取代苯基的取代基为甲基、乙基、甲氧基、卤素、硝基、氰基、三氟甲基、三氟甲氧基中的至少一种。
4.一种药物组合物,含有权利要求1所述的白藜芦醇丙烯酰基哌嗪苯磺酰胺衍生物或其药学上可接受的盐。
5.一种药物制剂,包括有效成分和药学上可接受的辅料和/或载体,所述有效成分含有权利要求1所述的白藜芦醇丙烯酰基哌嗪苯磺酰胺衍生物或其药学上可接受的盐。
6.权利要求1所述的白藜芦醇丙烯酰基哌嗪苯磺酰胺衍生物在制备抗炎药物中的应用。
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