新型CETP小分子抑制剂的合成及活性评价
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摘要
胆固醇酯转移蛋白(CETP)是一种血浆糖蛋白,它的主要作用是调节中性类脂类化合物在血液脂蛋白中的转移。中性类脂一般有较差水溶性,如甘油三酸酯(TG),自由胆固醇(FC)和胆固醇酯(CE)等,它们在血液中不能自由循环。它们要包裹在具有两亲结构的大的脂蛋白中进行转移。如高密度脂蛋白(HDL)和低密度脂蛋白(LDL),它们的功能是分别从周围组织转移胆固醇至肝脏和转移胆固醇至周围组织。而CETP负责调节这种转移,它有利于胆固醇酯从高密度脂蛋白转移至低密度脂蛋白,同时甘油三酸酯从低密度脂蛋白转移至高密度脂蛋白。因此人们认为CETP抑制剂可以提高血浆中高密度脂蛋白胆固醇(HDLc)水平,降低低密度脂蛋白胆固醇(LDLc)水平,从而为心血管疾病提供了一种潜在的治疗方法。
本文依据已有对含硫CETP抑制剂的合成及药性研究,合成了一系列含硫类苯并含氮杂环的CETP抑制剂:3-[1-(2-乙基丁基)环己甲酰胺基]-2-喹啉硫酚(化合物1-7)、3-[1-(2-乙基丁基)环己甲酰胺基]-4-喹啉硫酚(化合物2-7)和S-[2-[1-(2-乙基丁基)甲酰胺基]-1-异喹啉基]硫代异丁酸酯(化合物3-9),并测试了化合物1-7、2-7的抑制活性,另外还改进了苄基保护路线,不仅有效解决了合成过程中存在很大异味的问题,而且缩短了反应时间,提高了反应收率。
Cholesteryl ester transfer protein(CETP) is a plasma glycoprotein which can mediate the transfer of neutral lipids in the blood among various lipoproteins.Neutral lipids can't circulate freely in plasma for their poor water solubility,such as triglycerides(TG),free cholesterol (FC) and cholesteryl esters(CE).As a result,they packed together and transported in larger lipoprotein particles that have amphipathic lipids and proteins as surface components. High-density lipoproteins(HDL) and low-density lipoproteins(LDL) help move cholesterol from and to the periphery respectively.This process is regulated by CETP which facilitates the transfer of CE from HDL to LDL with a balanced exchange of TG.Therefore,CETP inhibitor could be expected to raise plasma HDL cholesterol(HDLc) levels,lower LDL cholesterol(LDLc) levels,and provide a potential therapeutic benefit for patient with heart artery disease.
A series of thio-based benzaza-heterocyclic CETP inhibitors were synthesized in this paper:3-[1-(2-ethylbutyl)cyclohexamido]-2-mercapto quinoline(compound 1-7),3-(1-(2-ethylbutyl)cyclohexamido)-4-mercapto quinoline(compound 2-7) and S-(2-(1-(2-ethylbutyl) cyclohexamido)-1-isoquinolyl) isobutanethioate(compound 3-9),and their activity as CETP inhibitors was evaluated.What's more,a novel environment friendly synthesis route by which the mercapto group could be protected was reported and optimized.By this route,the problem that there was great off odor in the experimentation was solved perfectly while the reaction time was shorted and the yields was elevated.
本文依据已有对含硫CETP抑制剂的合成及药性研究,合成了一系列含硫类苯并含氮杂环的CETP抑制剂:3-[1-(2-乙基丁基)环己甲酰胺基]-2-喹啉硫酚(化合物1-7)、3-[1-(2-乙基丁基)环己甲酰胺基]-4-喹啉硫酚(化合物2-7)和S-[2-[1-(2-乙基丁基)甲酰胺基]-1-异喹啉基]硫代异丁酸酯(化合物3-9),并测试了化合物1-7、2-7的抑制活性,另外还改进了苄基保护路线,不仅有效解决了合成过程中存在很大异味的问题,而且缩短了反应时间,提高了反应收率。
Cholesteryl ester transfer protein(CETP) is a plasma glycoprotein which can mediate the transfer of neutral lipids in the blood among various lipoproteins.Neutral lipids can't circulate freely in plasma for their poor water solubility,such as triglycerides(TG),free cholesterol (FC) and cholesteryl esters(CE).As a result,they packed together and transported in larger lipoprotein particles that have amphipathic lipids and proteins as surface components. High-density lipoproteins(HDL) and low-density lipoproteins(LDL) help move cholesterol from and to the periphery respectively.This process is regulated by CETP which facilitates the transfer of CE from HDL to LDL with a balanced exchange of TG.Therefore,CETP inhibitor could be expected to raise plasma HDL cholesterol(HDLc) levels,lower LDL cholesterol(LDLc) levels,and provide a potential therapeutic benefit for patient with heart artery disease.
A series of thio-based benzaza-heterocyclic CETP inhibitors were synthesized in this paper:3-[1-(2-ethylbutyl)cyclohexamido]-2-mercapto quinoline(compound 1-7),3-(1-(2-ethylbutyl)cyclohexamido)-4-mercapto quinoline(compound 2-7) and S-(2-(1-(2-ethylbutyl) cyclohexamido)-1-isoquinolyl) isobutanethioate(compound 3-9),and their activity as CETP inhibitors was evaluated.What's more,a novel environment friendly synthesis route by which the mercapto group could be protected was reported and optimized.By this route,the problem that there was great off odor in the experimentation was solved perfectly while the reaction time was shorted and the yields was elevated.
引文
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[2]于新民,宋文芳.动脉粥样硬化的特征和发生机理[J].生物学通报,1994,29(7):29.
[3]宋剑南.中医药防治动脉硬化研究进展[J].中国中医基础医学杂志,2003,9(11):71-79.
[4]马剑飞.胆固醇酯转移蛋白小分子抑制剂的设计与合成[J].辽宁:大连理工大学,2008.
[5]Sikorski James A.Oral cholesteryl ester transfer protein(CETP) inhibitors:A potential new approach for treating coronary artery disease[J].J.Med.Chem.,2006,49:1-22.
[6]Evans M,Roberts A,Davies Set al.Medical lipid-regulating therapy:Current evidence,ongoing trials and future developments[J].Drugs,2004,64:1181-1196.
[7]Clader J W.The discovery of ezetimibe:a view from outside the receptor[J].J.Med.Chem.,2004,47:1-9.
[8]Pederson T R,Olsson A G,Faergeman O et al.Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinanavian simvistatin surviaval study(4S)[J].Circulation,1998,97:1453-1460.
[9]The West of Scotland Coronary Prevention Study Group.Influence of pravaststin and plasma lipids on clinical events in the west of Scotland coronary prevention study (WOSCOPS)[J].Circulation,1998,97:1440-1445.
[10]Knopp R H.Drug treatment of lipid disorders[J].N.Engl.J.Med.,1999,341:498-511.
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[13]de Grooth G J,Kuivenhoven J A,Stalenhoef A F H et al.Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor,JTT-705,in humans:A randomized phase Ⅱ dose-response study[J].Circulation,2002,105:2159-2165.
[14]Clark R W,Sutfin T A,Ruggeri R B et al.Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein:An initial multidose study of torcetrapib[J].Arterioscler.Thromb.Vasc.Biol.,2004,24:490-497.
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[16]孟怀东.动脉粥样硬化是如何形成的[N].民族医药报,2008,6,6(002).
[17]任丽丽.动脉粥样硬化疫苗的研究进展[J].中国生物制品学杂志,2005,18(2):171-173.
[18]宋涛,尹蕾蕾.胆固醇酯转运蛋白抑制剂的研究进展[J].国际心血管病杂志,2007,34(3):177-179.
[19]梁芳,王学东.CETP、CETP抑制剂与动脉粥样硬化[J].中国心血管病研究杂志,2006,4(7):557-559.
[20]Shinkai H,Maeda K,Yamasaki T et al.Bis(2-(Acylamino)phenyl) Disulfides,2-(Acylamino)benzenethiols,and S-(2-(Acylamino)phenyl) Alkanethioates as Novel Inhibitors of Cholesteryl Ester Transfer Protein[J].J.Med.Chem.,2000,43:3566-3572.
[21]Connolly D T,Heuvelman D,Glenn K.Inactivation of cholesteryl ester transfer Protein by cysteine modification[J].Biochem.Biophys.Res.Commun.,1996,223:42-47.
[22]Hope H R,Heuvelman D,Duffin K et al.Inhibition of cholesteryl ester transfer protein by substituted dithiobisnicotinic acid dimethyl ester:involvement of a critical cysteine[J].J.Lipid Res.,2000,41:1604-1610.
[23]Kuivenhoven J A,de Grooth G J,Kawamura H etal.Effectiveness of inhibition of cholesteryl ester transfer protein by JTT-705 in combination with Pravastatin in type Ⅱ dyslipidemia[J].Am.J.Cardiol.,2005,95:1085-1088.
[24]Maeda K,Okamoto H et al.S-(2-(acylamino)phenyl)-2,2- dimethylpropanethioates as CETP inhibitors[J].Bioorg.Med.Chem.Lett.,2004,14:2589-2591.
[25]Paulsen H,Schmeck C,Brandes A et al.Fluorine-substitution in cholesteryl ester transfer protein inhibitors(CETP-inhibitors):biology,chemistry,SAR,and properties[J].Chimia,2004,58(3):123-127.
[26]Gielen H,Goldmann S.3-Hydroxy-(-4-trifluoromethylphenyl)-methyl-7- spirocyclobutyl -5,6,7,8-tetra hydroquinolin-5-nol derivatives and the use of the same as cholesterol ester transfer protein(CETP) inhibitors[P].WO 2003028727,2003.
[27]徐柏玲.胆同醇酯转移蛋白小分子抑制剂的研究进展[J].中国药物化学杂志,2007,17(6):395-402.
[28]王迪,余如瑾.辉瑞研发线失火[N].医药经济报,2006,12,8(A08).
[29]Tall A R,Yvan-Charvet L,Wang N.The failure of torcetrapib-Was it the molecule or the mechanism[J].Arterioscler.Thromb.Vasc.Biol.,2007,27:257-260.
[30]Durley R C,Grapperhaus M L,Hickory B Set al.Chiral N,N-disubstituted trifluoro-3-amino-2-propanols are potent inhibitors of cholesteryl ester transfer protein[J].J.Med.Chem.,2002,45:3891-3904.
[31]Maeda K,Nagamori H,Nakamura H et al.Dibenzylamine compound and medicinal use thereof[P].WO 2004020393,2004.
[32]Kori M,Hamaura K,Fuse H et al.Aminoethanol derivatives[P].WO 2002059077,2002.
[33]Br(u|¨)ckner D,Hafner F T,Li V et al.Dibenzodioxocinones-A new class of CETP inhibitors[J].Bioorg.Med.Chem.Lett.,2005,15:3611-3614.
[34]Hua D H,Huang X,Chen Y.Total syntheses of(+)-chloropuupehenone and(+)-Chloropuupehenol and their analogues and evaluation of their bioactivities[J].J.Org.Chem.,2004,69:6065-6078.
[35]熊绪琼,赵冬梅,程卯生.胆固醇酯转运蛋白抑制剂的研究进展[J].沈阳药科大学学报.2004,21(4):314-320.
[36]乔荣章.新型CETP抑制剂的化学合成及活性评价[D].北京:北京化工大学,2007.
[37]Prout F S,Cason J.Branched-chain fatty acids.ⅷ.Synthesis of two acids containing a 3-phentyl symmetrical end-grouping[J].J.Org.Chem.,1949,14:132-136.
[38]Noller C R,Dinsmore R.Isobutyl bromide[J].Org.Synth.,1943,2:358-360.
[39]Hess R W,Leaper J M F.Process of making mercaptans[P].US 1729615,1929.
[40]韩广甸等.有机制备化学手册[M].化学工业出版社,1980.
[41]Wujiong Xia,Scheffer J R,Botoshansky M et al.Photochemistry of 1-Isopopylcycloalkyl aryl ketones:ring size effects,medium effects,and asymmetric induction[J].Org.Lett.,2005,7:1315-1318.
[42]Ochiai E.Recent Japanese work on the chemistry of pyridine 1-oxide and related compounds[J].J.Org.Chem.,1953,18:534-551.
[43]Sharma K S,Kumari S,Singh R K.Condensed Heterocycles;Xl.Synthesis of 1,2,5-thia(selena)diazolo[3,4-b]quinolines and 1,2,5-thia(selena)diazolo[3,4-h]quinolines[J].Synthesis,1981,4:316-318.
[44]Kurz M E,Yang L T A,Zahora E P et al.Nitration by Aroyl Nitrates[J].J.Org.Chem.,1973,38:2271-2277.
[45]Kharasch N,Langford R B.Derivatives of sulfenic acids.XLⅢ.The chlorinolysis of certain aryl benzyl sulfides as a route to sulfenyl chlorides[J].J.Org.Chem.,1936,28:1903-1905.
[46]Shinkai H,Maeda K.CETP activity inhibitors[P].EP 1710231,2006.
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