7-取代-[1,2,4]三唑[1,5-a]嘧啶-5(4H)-酮衍生物的合成及抗炎活性的研究
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摘要
本文设计合成一系列7-取代-[1,2,4]三唑[1,5-a]嘧啶-5(4H)-酮(1a-p)类衍生物,并用小鼠耳肿胀法测定其抗炎活性。其中,在100 mg·kg~(-1)剂量下,三个化合物的抗炎活性优于阳性对照药吲哚美辛,而化合物7-(4-甲氧基苯基)-[1,2,4]三唑[1,5-a]嘧啶-5(4H)-酮(1k)表现出最强的抗炎活性,其耳肿胀抑制率为70.71%,具有进一步研究的价值。
A series of 7-substitued-[1,2,4]triazolo[1,5-a]pyrimidin-5( 4 H)-one( 1 a-p) were synthesized and evaluated the antiinflammatory activity via the method of the xylene-induced ear edema in mice. Among them,three compounds were demonstrated more effective anti-inflammatory activity than the reference anti-inflammatory drug indomethacin.7-( 4-methoxyphenoxy)-[1,2,4]triazolo[1,5-a]pyrimidin-5( 4 H)-one( 1 k) exhibited the potent anti-inflammatory activity and 70. 71%inhibition at dose of 100 mg·kg~(-1)( 30 min after i.p administration),it was worth studying further.
A series of 7-substitued-[1,2,4]triazolo[1,5-a]pyrimidin-5( 4 H)-one( 1 a-p) were synthesized and evaluated the antiinflammatory activity via the method of the xylene-induced ear edema in mice. Among them,three compounds were demonstrated more effective anti-inflammatory activity than the reference anti-inflammatory drug indomethacin.7-( 4-methoxyphenoxy)-[1,2,4]triazolo[1,5-a]pyrimidin-5( 4 H)-one( 1 k) exhibited the potent anti-inflammatory activity and 70. 71%inhibition at dose of 100 mg·kg~(-1)( 30 min after i.p administration),it was worth studying further.
引文
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[12]Sanchez RM,Erhard K,Hardwicke MA,et al.Synthesis and structure-activity relationships of 1,2,4-triazolo[1,5-a]pyrimidin-7(3H)-ones as novel series of potentβisoform selective phosphatidylinositol 3-kinase inhibitors[J].Bioorg Med Chem Lett,2012,22:3 198-3 202.
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[2]PraticòD,DognéJM.Selective cyclooxygenase-2 inhibitors development in cardiovascular medicine[J].Circulation,2005,112(7):1 073-1 079.
[3]戚繁,周金培,丁一为,等.咪唑并[1,2-a]嘧啶类化合物的合成和抗炎活性[J].中国药科大学学报,2009,40(1):16-20.
[4]Song MX,Zheng CJ,Deng XQ,et al.Synthesis and antibacterial evaluation of rhodanine-based 5-aryloxy pyrazoles against selected methicillin resistant and quinolone-resistant Staphylococcus aureus(MRSA and QRSA)[J].Eur J Med Chem,2013,60:376-385.
[5]Ahmed S,Zayed MF,El-Messery SM,et al.Design,synthesis,antimicrobial evaluation and molecular modeling study of 1,2,4-triazole-based 4-thiazolidinones[J].Molecules,2016,21(5):568-568.
[6]Shi JB,Tang WJ,Qi XB,et al.Novel pyrazole-5-carboxamide and pyrazole-pyrimidine derivatives:synthesis and anticancer activity[J].Eur J Med Chem,2015,90:889-896.
[7]Wang B,Chu D,Feng Y,et al.Discovery and characterization of(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one(BMN 673,talazoparib),a novel,highly potent,and orally efficacious poly(ADP-ribose)polymerase-1/2 inhibitor,as an anticancer agent[J].J Med Chem,2016,59(1):335-357.
[8]Abdel-Aziz M,Abuo-Rahma Gel-D,Hassan AA.Synthesis of novel pyrazole derivatives and evaluation of their antidepressant and anticonvulsant activities[J].Eur J Med Chem,2009,44:3 480-3 487.
[9]Wang SB,Piao GC,Zhang HJ,et al.Synthesis of 5-alkoxythieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives and evaluation of their anticonvulsant activities[J].Molecules,2015,20(4):4 627-4 683.
[10]Bekhit AA,Ashour HM,Bekhit Ael-D,et al.Synthesis and biological evaluation of novel pyrazole derivatives as anti-inflammatory antimicrobial agents[J].Med Chem,2009,5:103-117.
[11]Liu DC,Gong GH,Wei CX,et al.Synthesis and anti-inflammatory activity evaluation of a novel series of 6-phenoxy-[1,2,4]triazolo[3,4-a]phthalazine-3-carboxamide derivatives[J].Bioorg Med Chem Lett,2016,26(6):1576-1 579.
[12]Sanchez RM,Erhard K,Hardwicke MA,et al.Synthesis and structure-activity relationships of 1,2,4-triazolo[1,5-a]pyrimidin-7(3H)-ones as novel series of potentβisoform selective phosphatidylinositol 3-kinase inhibitors[J].Bioorg Med Chem Lett,2012,22:3 198-3 202.
[13]Sun XY,Wei CX,Deng XQ,et al.Evaluation of the anticonvulsant activity of 6-(4-chlorophenyoxy)-tetrazolo[5,1-a]phthalazine in various experimental seizure models in mice[J].Pharmacol Rep,2010,62:273-277.
[14]Kumpan K,Nathubhai A,Zhang C,et al.Structure-based design,synthesis and evaluation in vitro of arylnaphthyridinones,arylpyridopyrimidinones and their tetrahydro derivatives as inhibitors of the tankyrases[J].Bioorg Med Chem,2015,23:3 013-3 032.
[15]徐淑云,卞如濂,陈修.药理试验方法学第三版[M].北京:人民卫生出版社,2001:9-11.