N-烯丙基-N-(1-(5-溴-2-((4-氯苄基)氧基)苄基)-4-哌啶基)吡啶甲酰胺的合成及表征
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摘要
趋化因子受体CCR5是HIV-1病毒进入人体细胞的主要辅助受体,CCR5拮抗剂可作为一种靶向制剂,以防治人类HIV-1感染.目前,非肽类小分子化合物CCR5拮抗剂的研究占据主导地位.以4-氯苄氯、5-溴水杨醛为原料,通过消去、还原及溴化合成了4-溴-2-溴甲基-1-((4-溴苄基)氧)苯(中间体3),以哌啶-4-酮合成了N-烯丙基-N-(4-哌啶基)吡啶甲酰胺(中间体7),通过中间体3和7合成了一种有望用作CCR5拮抗剂的非肽类小分子化合物N-烯丙基-N-(1-(5-溴-2-((4-氯苄基)氧基)苄基)-4-哌啶基)吡啶甲酰胺,该产物有一定的生物活性,并对该产物进行了1H NMR、13C NMR、IR及MS表征.
Chemokine receptor CCR5 is a major coreceptor for HIV-1 entry into cell,CCR5 antagonists can be used as a targeting preparation in the prevention of human HIV-1 infection. At present,the peptide of small molecule compounds CCR5 antagonists research occupy the leading position. 4-bromo-2-( bromomethyl)-1-(( 4-chlorobenzyl)oxy) benzene( intermediate 3) was synthesized from 1-chloro-4-( chloromethyl) benzene and 5-bromo-2-hydroxybenzaldehyde by elimination reaction,reduction reaction and bromization. N-allyl-N-( piperidin-4-yl) picolinamide( intermediate 7) was prepared from piperidin-4-one. Further reaction of intermediate 3 with intermediate 7 gave a novel non-peptide CCR5 antagonist N-allyl-N-( 1-( 5-bromo-2-(( 4-chlorobenzyl) oxy) benzyl) piperidin-4-yl) picolinamide. The product has a certain biological activity,the compounds were characterized by1 H NMR,13 C NMR,IR and MS.
Chemokine receptor CCR5 is a major coreceptor for HIV-1 entry into cell,CCR5 antagonists can be used as a targeting preparation in the prevention of human HIV-1 infection. At present,the peptide of small molecule compounds CCR5 antagonists research occupy the leading position. 4-bromo-2-( bromomethyl)-1-(( 4-chlorobenzyl)oxy) benzene( intermediate 3) was synthesized from 1-chloro-4-( chloromethyl) benzene and 5-bromo-2-hydroxybenzaldehyde by elimination reaction,reduction reaction and bromization. N-allyl-N-( piperidin-4-yl) picolinamide( intermediate 7) was prepared from piperidin-4-one. Further reaction of intermediate 3 with intermediate 7 gave a novel non-peptide CCR5 antagonist N-allyl-N-( 1-( 5-bromo-2-(( 4-chlorobenzyl) oxy) benzyl) piperidin-4-yl) picolinamide. The product has a certain biological activity,the compounds were characterized by1 H NMR,13 C NMR,IR and MS.
引文
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[9]Paul E F,Bryan O,Sander G M.Antagonists of the human CCR5 receptor as anti-HIV-1 agents.Part 4:Synthesis and structure-activity relationships for 1-[N-(methyl)-N-(phenylsulfonyl)amino]-2-(phenyl)-4-(4-(N-(alkyl)-N-(benzyloxycarbonyl)amino)piperidin-1-yl)butanes[J].Bioorganic&Medicinal Chemistry Letters,2001,11(18):2475-2479.
[10]Christopher K A,Saheem A Z,Zhang Zhu,et al.Design syntheses,and characterization of pharmacophore based chemokine receptor CCR5 antagonists as anti prostate cancer agents[J].European Journal of Medicinal Chemistry,2013,69:647-658.
[11]Mark A Ashwell,Jean-Marc Lapierre,Alan Kaplan.The design preparation and SAR of novel small molecule sodium(Na+)channel blockers[J].Bioorganic&Medicinal Chemistry Letters,2004,14(9):2025-2030.
[12]王涛,黄海金,罗劲,等.2E-3-苯基丙烯酰氧基烃基膦酸二乙酯的合成与生物活性研究[J].江西师范大学学报:自然科学版,2011,35(1):15-17.
[13]汪淼.CCR5受体拮抗剂的设计、合成与生物活性研究[D].沈阳:沈阳药科大学,2009.
[2]Mohsen Shahaei,Alireza Pourhossein.Modeling of CCR5antagonists as anti HIV agents using combined genetic algorithm and adaptive neuro-fuzzy inference system(GAANFIS)[J].Med Chem Res,2013,22(9):4423-4436.
[3]Mohammed Abdul Rasheed,Nagul Meera Shaik,Nirogl R.Concise and aimple synthesis of M1 allosteric agonist TBPB[J].Synthetic Communications,2013,43(13):1796-1801.
[4]Ji Yongjun,Shu Mao,Lin Yong,et al.Combined 3D-QSAR modeling and molecular docking study on azacycles CCR5antagonists[J].Journal of Molecular Structure,2013,1045(3):35-41.
[5]Renato Skerlj,Gary Bridger,Zhou Yuanxi,et al.Design and synthesis of pyridin-2-ylmethylaminopiperidin-1-ylbutyl amide CCR5 antagonists that are potent inhibitors of M-tropic(R5)HIV-1 replication[J].Bioorganic&Medicinal Chemistry Letters,2011,21(23):6950-6954.
[6]Lavina Gharu,Rajesh Ringe,Jayanta Bhattacharya.HIV-1clade C envelopes obtained from late stage symptomatic Indian patients varied in their ability towards relative CD4usages and sensitivity to CCR5 antagonist TAK-779[J].Virus Research,2011,158(1):216-224.
[7]Lu Shoufu,Chen Binglong,Dave Davey,et al.CCR5 receptor antagonists:Discovery and SAR of novel 4-hydroxypiperidine derivatives[J].Bioorganic&Medicinal Chemistry Letters,2007,17(7):1883-1887.
[8]Richard R G,John F W W,Brown K,et al.1,3-dihydro-2,1,3-benzothiadiazol-2,2-diones and 3,4-dihydro-1H-2,1,3-benzothidiazin-2,2-diones as ligands for the NOP receptor[J].Bioorganic&Medicinal Chemistry Letters,2004,14(20):5045-5050.
[9]Paul E F,Bryan O,Sander G M.Antagonists of the human CCR5 receptor as anti-HIV-1 agents.Part 4:Synthesis and structure-activity relationships for 1-[N-(methyl)-N-(phenylsulfonyl)amino]-2-(phenyl)-4-(4-(N-(alkyl)-N-(benzyloxycarbonyl)amino)piperidin-1-yl)butanes[J].Bioorganic&Medicinal Chemistry Letters,2001,11(18):2475-2479.
[10]Christopher K A,Saheem A Z,Zhang Zhu,et al.Design syntheses,and characterization of pharmacophore based chemokine receptor CCR5 antagonists as anti prostate cancer agents[J].European Journal of Medicinal Chemistry,2013,69:647-658.
[11]Mark A Ashwell,Jean-Marc Lapierre,Alan Kaplan.The design preparation and SAR of novel small molecule sodium(Na+)channel blockers[J].Bioorganic&Medicinal Chemistry Letters,2004,14(9):2025-2030.
[12]王涛,黄海金,罗劲,等.2E-3-苯基丙烯酰氧基烃基膦酸二乙酯的合成与生物活性研究[J].江西师范大学学报:自然科学版,2011,35(1):15-17.
[13]汪淼.CCR5受体拮抗剂的设计、合成与生物活性研究[D].沈阳:沈阳药科大学,2009.