喹唑啉酮衍生物的合成研究
摘要
喹唑啉酮类生物碱是生物碱中的一大类,是中药成分常山碱、异常山碱、色胺酮等的主要结构单元。这些成分主要存在于常山、大青叶等中药中,具有广泛的生物活性。近年来的研究表明,含有此类结构的化合物具有多重生物活性,主要表现在对表皮生长因子受体(EGFR)或其酪氨酸激酶(EGFR-TK)、血管内皮生长因子受体(VEGFR)、血小板衍生生长因子受体(PDGFR)、神经生长因子受体(NGFR)及其他多个作用靶点有抑制活性,从而发挥抗癌、抗菌、抗病毒等多种药理作用。由于此类结构化合物具有优异的药理活性,从而引起了医药研究人员的极大兴趣。对以喹唑啉酮类化合物为基础的衍生物研究成为热点,特别是对4(3H)喹唑啉酮类衍生物进行结构修饰和改造。目前报道的喹唑啉酮类化合物的合成方法较多,这些方法各有优缺点。本文利用微波辅助合成的方法,以邻氨基苯甲酸、2-氨基-5-硝基苯甲酸、2-氨基-4-硝基苯甲酸、邻氨基对苯二甲酸、2-氨基-4-羟基苯甲酸、2-氨基-5-溴苯甲酸、2-氨基-5-碘苯甲酸、5-甲基-2-氨基苯甲酸等为原料与甲酰胺反应,以及以1,4-丁炔二醇、L-谷氨酰胺与靛红酸酐反应,共合成了13个喹唑啉酮衍生物。这些合成反应条件简单,后处理简便,产率较高。其中4-oxo-3,4-dihydroquinazoline-5-carboxylic acid、2,3-bis(hydroxylmethyl)-2,3-dihydroquinolin-4(1H)-one、5-羟基-4(3H)-喹唑酮、7-iodoquinazolin-4(3H)-one、7-甲基-4(3H)-喹唑酮、7-bromoquinazolin-4(3H)-one等未见文献报道。限于时间关系本文所合成的喹唑啉酮类化合物未来得及进行生物活性评价。
Quinazoline is a class of alkaloids,exist in some plants,such as Saxifragaceae, Folium etc.They have similar core structure and a wide range of biological activity,mainly in the epidermal growth factor receptor(EGFR) or the tyrosine kinase(EGFR-TK),vascular endothelial growth factor receptor(VEGFR),platelet-derived growth factor receptor (PDGFR),nerve growth factor receptor(NGFR) and other targets and thus play anti-cancer, antibacterial,antiviral and other pharmacological effects.Therefore,the quinazolinone compounds attracted the interest of medicinal researchers.There are a lot of reports of synthesis of quinazolinone.In this dissertation,4(3H) quinazolinone、7-nitro-4(3H) quinazolinone,6-nitro--4(3H) quinazolinone,6-amino-4(3H) quinazolinone、7-amino -4(3H)-quinazolinone,4-oxo-3,4-dihydroquinazolinone-5-carboxylic acid,5-amin o-2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-5-oxopentanoic acid、2,3-bis (hydroxymethyl)-2,3-dihydroquinolin-4(1H)-one[1,3],5-hydroxy-4(3H) quinazolinone, 7-iodoquinazolin-4(3H)-one,7-methyl-4(3H)-quinazolinone,7-bromoquinazolin-4(3H)-one were synthesized by using anthranilic acid、2-amino-5-nitrobenzoic acid、2-amino-4-nitrobenzoic acid,6-nitro--4(3H)-quinazoline-one、o-amino-terephthalic acid, 2-amino-4-hydroxy benzoic acid、2-amino-5-bromo-benzoic acid、2-amino-5-iodine acid,1、4-butynediol、L-glutamine、isatin anhydride、formamide as starting materials and utilizing microwave-assisted synthetic approach.Among them,the 4-oxo-3,4-dihydroquinazoline-5-carboxylic acid,5-amino-2-(2,4-dioxo-1,2-dihydroquinazolin-3 (4H)-yl)-5-oxopentanoic acid,2,3-bis(hydroxymethy 1)-2,3-dihydroquinolin-4(1H)-one [1,3],5-hydroxy-4(3H) quinazoline-one,2-amino-5-bromobenzoic acid, 7-iodoquinazolin-4(3H)-one,7-methyl-4(3H)-quinazolinone,7-bromoquinazolin-4 (3H)-one were not been reported in the literature.
Quinazoline is a class of alkaloids,exist in some plants,such as Saxifragaceae, Folium etc.They have similar core structure and a wide range of biological activity,mainly in the epidermal growth factor receptor(EGFR) or the tyrosine kinase(EGFR-TK),vascular endothelial growth factor receptor(VEGFR),platelet-derived growth factor receptor (PDGFR),nerve growth factor receptor(NGFR) and other targets and thus play anti-cancer, antibacterial,antiviral and other pharmacological effects.Therefore,the quinazolinone compounds attracted the interest of medicinal researchers.There are a lot of reports of synthesis of quinazolinone.In this dissertation,4(3H) quinazolinone、7-nitro-4(3H) quinazolinone,6-nitro--4(3H) quinazolinone,6-amino-4(3H) quinazolinone、7-amino -4(3H)-quinazolinone,4-oxo-3,4-dihydroquinazolinone-5-carboxylic acid,5-amin o-2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-5-oxopentanoic acid、2,3-bis (hydroxymethyl)-2,3-dihydroquinolin-4(1H)-one[1,3],5-hydroxy-4(3H) quinazolinone, 7-iodoquinazolin-4(3H)-one,7-methyl-4(3H)-quinazolinone,7-bromoquinazolin-4(3H)-one were synthesized by using anthranilic acid、2-amino-5-nitrobenzoic acid、2-amino-4-nitrobenzoic acid,6-nitro--4(3H)-quinazoline-one、o-amino-terephthalic acid, 2-amino-4-hydroxy benzoic acid、2-amino-5-bromo-benzoic acid、2-amino-5-iodine acid,1、4-butynediol、L-glutamine、isatin anhydride、formamide as starting materials and utilizing microwave-assisted synthetic approach.Among them,the 4-oxo-3,4-dihydroquinazoline-5-carboxylic acid,5-amino-2-(2,4-dioxo-1,2-dihydroquinazolin-3 (4H)-yl)-5-oxopentanoic acid,2,3-bis(hydroxymethy 1)-2,3-dihydroquinolin-4(1H)-one [1,3],5-hydroxy-4(3H) quinazoline-one,2-amino-5-bromobenzoic acid, 7-iodoquinazolin-4(3H)-one,7-methyl-4(3H)-quinazolinone,7-bromoquinazolin-4 (3H)-one were not been reported in the literature.
引文
[1]南京大学化学系有机化学教研室。有机化学(下册M) 北京:高等教育出版杜,1988.329
[2]全国中等卫生学校统编教材《中草药化学》编写组.中草药化学(M)南京:江苏科学技术出版杜,1980.2
[3]陈友梅.中药化学(M)济南:山东科学技术出版社,1988.51
[4]马养民,傅建熙1,生物碱的研究概况(J),陕西林业科技,1997.1:75
[5]Lee J Y,Park Y K,Seo S H,et al.1,4-Dioxane-fused 4-anilinoquinazoline as inhibitors of epidermal growth factor receptor kinase[J].Arch Pharm(Weinheim),2001,334(11):35723601
[6]LeeJY,LeeYS,Park H K,etal.4-(Phenylamino)[1,4]dioxano[2,3-g]quinazoline derivatives and process for prepar2ing the same:US,2003045537[P].20032032061
[7]侯廷军,朱丽荔,陈丽蓉,等.EGFR和4-苯胺喹唑啉类抑制剂之间相互作用模式的研究[J].化学学报,2002,60(6):1023210281
[8]EI2Sharief AM S,Ammar YA,Zahran MA,et al.Aminoacids in the synthesis of heterocyclic system:the synthesis of triazinoquinazolinones,triazepinoquinazolinones and triazocinoquinazolinones of potential biological interest[J].Molecules,2001,6(3):26722781
[9]Xu G F,Song B A,Bhadury P S,et al.Synthesis and antifungal activity of novel ssubstituted 6-fluoro-4-alkyl(aryl)thioquinazoline derivatives[J].Bioorg Med Chem,2007,15(11):3768237741
[10]Marsham PR,Hughes LR,Jackman AL,etal.Quinazoline antifolate thymidylate synthase inhibitors:heterocyclic benzoyl ring modifications[J].J MedChem,1991,34:1594 - 1605
[11]Cunningham D,Zalcberg J,Maroun J,et al.Efficacy,tolerability and management of raltitrexed monotherapy inpatients with advanced colorectal cancer:a review of phase Ⅱ/Ⅲtrials[J].Eur J Cancer,2002,38:478 -486
[12]Witt,Bergman J,Recent Developments in the Field of Quinazoline Chemistry.Current Organic Chemistry,2003,7:659-677
[13]Koepfly JB,Mead JF,Brokman J A.An alkaloid with high antimalarial activity from Dichroa febrifuge.J.Am.Chem.Soc.,1947,69:1837-146
[14]Koepfly JB,Mead JF,Brokman J A.An alkaloid with high antimalarial activity from Dichroa febrifuge.J.Am.Chem.Soc.,1947,69:1048-1056
[15]Kobayyashi S,Ueno M,Suzuki R,etal.Catalytic asymmetric synthesis of antimalari alalkaloids.febrifugine and isofebrifugine and their biological itivity.J.Ofg.Chem.1999,64:6833-6841
[16]Bergrnan J,Brynolf A.Synthesis of chrysogine,a metalolite of Penicillium chrysogenum and somerelated 2-substituted-4-(3H)-quinazolinones.Tetrahedron,1990.46:1295-1310
[17]Hikino H,Nabetani S,Takemoto T.Yakugaku Za sshi,1973,93:619
[18]Chadwick DJ,Easton IW.Acta Crystallogr.,Sect.C,1983,39:454
[19]Bergman J,Brynolf A.Synthesis of Chrysogine:a Metabolite of Penicillium chrsogenum and somerelated2-substituted 4-(3H)-Quinazolinoes.Tetrahedron,1990,46(4):1295-1310
[20]Bergman J.Comments on the Asymmetric Synthesis of Chrysogine.JChen.Res.(s),1997:224
[21]李清华,金继曙,种明才,等.青黛抗真菌成份的研究[J].中草药,1983,14(10):8-9
[22]Oberth(u∣¨)r C,J3/4 ggi R,HamburgerM.HPLC based activity p rofilingfor 521ipoxygenase inhibitory activity in Isatis tinctoria leaf extracts[J].Fitoterapia,2005,76(3-4):324-32
[23]Sharma V M,Prasanna P,Seshu K V,et al.Novel indolo[2,1-b]quinazoline analogues as cytostatic agents:synthesis,biological e2valuation and structure2activity relationship[J].B ioorg Med ChemLett,2002,12(17):2303-7
[24]王振义.白血病的诱导凋亡疗法[N].中国医学论坛报,2003,29(1):72-5
[25]Mu B Z.A new cytotoxic active principle isolated from Polygonumtinctorium[J].N atMed,1999,53(2):72-9
[26]Bhattacharjee A K,Skanchy D J,JenningsB,et al.Analysis of stereoelectronic p roperties,mechanism of action and pharmacophore ofsynthetic indolo[2,1-b]quinazoline-6,1-2dione derivatives in relation to antileishmanial activity using quantum chemical,cyclicvoltammetry and 3DQSAR CATALYST Procedures[J].J B ioorg Med Chem,2002,10:1979 - 89
[27]Scovill J,Blank E,KonnickM,et al.Antitrypanosomal activities of tryp tanthrins[J].Antim icrob Agents Chem other,2002,46(3):8823
[28]Li Q H,J in J S,ZhongM C,et al.Study on antifungal constituentsof indigo pulverata levis [J]. Chin Trad Herb D rug, 1983, 14(10):8-9
[29] Lee E S, Park J G, Jahng Y D. A facile synthesis of simple alkaloids synthesis of 2,3-polymethylene-4 (3H)-quinazolinones and related alkaloids [J].Tetrah Lett, 2003, 44 (9):1883 - 6.
[30] Witt A, Bergman J.Recent development in the field of quinazolinechemistry [J].Curreng O ry Chem, 2003, 7:659-77
[31]王翠玲,刘建利,沈小莉.天然产物色胺酮及其衍生物合成的研究进展[J].化学通报,2007, 70(2):89-95
[32] Ma Z Z, Hano Y, Nomura T , et al.J.Heterocycles,1997,51(7):1593-1596.
[33] Noonbery S B , Benz C C. Tyrosine kinase inhibitors targetedto the epidermal growth factor recptor subfamily[J].Drugs, 2000, 59(4):75327671
[34] Morin M J. From oncogene to drug: development of smallmolecule tyrosine kinase inhibitors as anti2tumor and antiangiogcnic agents [J]. Oncogene, 2000, 19 (56): 6574265831
[35] Nakamura K, Yamamoto A, Kamishohara M, et al.KRN633: A selective inhibitor of vascular endothelial growthfactor receptor tyrosine kinase that suppresses tumor angiogenesis and growth [J]. Mol Cancer Ther, 2004, 3 (12):1639216491
[36] Williams KJ , Telfer B A , Brave S, et al. ZD6474, a potentinhibitor of vascular endothelial growth factor signaling , combined with radiotherapy : chedule dependent enhancement ofantitumor activity [J]. Clin Cancer Res, 2004, 10 (24):8587285931
[37] McCartyM F, Wey J, Stoeltzing O, et al.ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitorwith additional activity against epidermal growth factor receptor tyrosine kinase, inhibits orthotopic growth and angiogenesis of gastric cancer [J].Mol CancerThe, 2004, 3 (9): 1041210481
[38] Wedge S R, KendrewJ, Hennequin L F, et al. AZD2171:ahighly potent, orally bioavailable, vascular endothelial growthfactor receptor tyrosine kinase inhibitor for the treatment ofcancer[J].Cancer Res, 2005, 65(10):4389244001
[39] Jin Y, Zhou Z Y, Tian W, et al. 4'- Alkoxyl substitution enhancing the antimitotic effect of 52(3', 4', 5'2 substituted)aniline-4-hydroxy-8-nitroquinazolines as a novel class of anti2microtubule agents [J] . Bioorg Med Chem Lett, 2006, 16(22): 5864258691
[40] Soelaiman S , Wei B Q , Bergson P, et al. Structure based inhibitor discovery against adenylyl cyclase toxins from pathogenic bacteria that cause anthrax and whooping cough[J] .J Biol Chem, 2003, 278 (28): 2599022599
[41]Lokker N A,Sullivan C M,Hollenbach S J,etal.Platelet2derived growth factor (PDGF) autocrine signaling regulatessurvival and mitogenic pathways in glioblastoma cells:Evidence that the novel PDGF-C and PDGF-D ligands may play arole in the development of brain tumors[J].Cance Re,2002,62(13):3729237351
[42]Kyprianou N,Chon J,Benning CM.Effects of alphal ad renoceptor antagonists on cultured prostatic smooth muscle cells[J].Prostate Sup,2000,9(1):342411
[43]Keledjian K,Borkowski A,Kim G,et al.Reduction of human prostate tumor vascularity by the alphaadrenoceptor antagonist terazosin[J].Prostate,2,001,48(2):712781
[44]Fox D N A.Quinoline and quinazoline compounds useful intherapy:US,2002040028[P].20022042041
[45]R(?)dl S,Hezky P,ProIka J,et al.Synthesis and analgesic activity of some quinazoline analogs of anpirtoline[J].ArchPharm(Weinheim),2000,333(11):38123861
[46]Colquhoun A,Lawrance GM,Shamovsky I L,etal.Differential activity of thenerve growth factor(NGF) antagonist PD90780[7-(benzolylamino)-4,dihydro-4-methyl-9-oxo-Py razolo[5,1-b]quinazoline-2-carboxylicacid]suggestsaltered NGF-p75NTR interactions in the presence of TrkA[J].JPharmacol Exp Ther,2004,310(2):50525111
[47]Gineinah MM,EL 2Sherbeny MA,Nasr MN,etal.Synthe2sis and antiinflammatory screening of some quinazoline andquinazolyl242oxoquinazoline derivatives[J].Arch Pharm(Weinheim),2002,335(11):55625621
[48]刘志红,孙晓莉,张生勇.对Niementowski反应的改进[J].有机化学,2001,21(12):116121163
[49]许志锋,邝代治,张复兴,等.串连aza2Wittig反应合成2-芳氧(硫)基-3-苯基喹唑啉-4-酮[J].化学试剂,2004,26(3):1632164
[50]丁明武,杨尚君,陈云峰.2-烷氧基-3H-喹唑啉-4-酮的合成与杀菌活性[J].有机化学,2004,24(8):9232926
[51]施沁清,刘志平.喹唑啉酮类化合物的合成[J].上海化,2000,9(9):18220.
[52]Akazome M,Kondo T,WatanabeY.Transitionmetal complex catalyzed reductive N-heterocyclization:Synthesis of 4(3H)-quinazolinone derivativesfrom N-(2-nitrobenzoyl)amides[J].J.Org.Chem,1993,58(2):3102312.
[53]Larksarp C,Alper H.Palladium catalyzed cyclocarbonylationof oiodoanlin with heterocumulenes:Regioselective preparation of 4(3H)-quinazolinone derivatives[J].J. Org.Chem.2000,65(9):277322777.
[54]CoutureA,CornetH,Grandclaudon P.Anexpeditious synthesis of 2-aryl and 2-alkylquinazolin-4(3H)-ones[J].Synthesis,1991:100921010.
[55]史达清,王香善,屠树江,等.32苯基喹唑啉24(3H)2酮的合成及晶体结构[J].结构化学,2003,22(5):581-584.
[56]O'Mahony R J D,Krchnak V.Traceless synthesis of 3H-quinazolin-4-ones via a combination of solidphase and solution methodologies[J].TetrahedronLett.,2002,43(6):9392942.
[57]R.Soliman,F.S.G.Soliman,A facile synthesis of 2,3-disubstituted4-oxo-3,4-dihydroquinazolines,synthesis.1979,803-804
[58]D.V.Ramana,E.Kantharaj,Facile Synthesis of 2-alky-3-ary-4(3H)-quinazolinones Indian J.Heterocycl.Chem.1994(3)215-218
[59]Saito T,Tsuda K.Stato Y.,A Facile and Efficient Carbodiimide-Mediated Synthesis Of Dihydrooquinazolines via a Tandem Nuclephilic Addition Intramolecular Hetero Conyugate Addition Annulation Strategy.Tetrahedron Lett.,1996,37,209
[60]Wang F,Hauske,J.R.,Solide-Phase Synthesis Of 2,3-disebtituted Tetrahedron Lett.1997,38,8651
[61]R.Soliman,F.S.G.Soliman,A facile synthesis of 2,3-disubstituted4-oxo-3,4-dihydroquinazolines,synthesis.1979,803-804
[62]D.V.Ramana,E.Kantharaj,Facile Synthesis of 2-alky-3-ary-4(3H)-quinazolinones Indian J.Heterocycl.Chem.994(3),215-218
[63]R.Soliman,F.S.G.Soliman,A facile synthesis of 2,3-disubstituted
[64]D.V.Ramana,E.Kantharaj,Facile Synthesis of 2-alky-3-ary-4(3H)-quinazolinones Indian J.Heterocycl.Chem.1994(3),215-218
[65]Saito T,Tsuda K.Stato Y.,A Facile and Efficient Carbodiimide-Mediated Synthesis Of Dihydrooquinazolines via a Tandem Nuclephilic Addition Intramolecular Hetero Conyugate Addition Annulation Strategy.Tetrahedron Lett.,1996,37,209
[66]Wang F,Hauske,J.R.,Solide-Phase Synthesis Of 2,3-disebtituted Tetrahedron Lett.1997,38,8651
[67]CRC Hand Book of Data on Organic Compouds
[68] K.Kottoke, H, kuhmstedt. Pharmazie [J], 1984, 39(12), 868
[69] Saito T, Tsuda K. Stato Y., A Facile and Efficient Carbodiimide-Mediated Synthesis Of Dihydrooquinazolines via a Tandem Nuclephilic Addition Intramolecular Hetero Conyugate Addition Annulation Strategy.Tetrahedron Lett., 1996 , 37, 209
[70] Wang F, Hauske, J.R., Solide-Phase Synthesis Of 2, 3-disebtituted Tetrahedron Lett. 1997, 38, 8651
[71] V anderhoff J. W. arrying out Chemical Reactions Using Microwave Energy [P].US 432413, 1969.203-211
[72]Gedye, R.; Smith, F.; Westaway, K.TetrahedronLet .1986, 27(3), 279.(b)Gedye ,R.; Smith, F.;Westaway, K.Can. J.Chem. 1988, 66, 17
[73] Gedye R., Sm ith F., Westaway K, A li H., et al.The uses of m icrow ave ovens fo r rap id o rganic syn2thesis [J]. Tetrahedron Lett., 1986, 27 (3): 279-282
[74] 金钦汉,微波化学page147
[75] Giguere RJ, Bray TL, Majetich G, etal.Application of commercial microwave ovens to organic synthesis. Tetrahedron Lett , 1986 , 27:4945—4948
[76] Srikrishna, A.;Nagaraju, S.J. Chem. Soc Perkin.Trans. 1, 1992, 311
[77]V.Sridar and V.S.S.Rao, J. Chem.Set.B, 1994, 33B(2), 184
[78] Strauss, C. R; Trainor, R.W. Aus. J. Chem. 1995, 48, 1665
[79] R.J.Giguere, T.L.Bray, S. M. Duncan and G.Majetich, Tetrahedron Lett., 1986, 27,4945.
[80] S.Caddick, Tetrahedron, 1995, 51(8), 10403.
[81] M.W.Lu, W, X, HuandL.H.Yun, Firs tNational ConferenceonMicrowave Chemistry,1996, 54
[82] Giguere RJ , Bray TL , Majetich G, et al.Application of commercial microwave ovens to organic synthesis. Tetrahedron Lett , 1986 , 27 :4945-4948
[83] Srikrishna, A.;Nagaraju, S.J. Chem. Soc., Perkin.Trans. 1, 1992, 311
[84] Caddick, S. Tetrahedron 1995, 51 , 10403
[85] Gordon, E.M.; Gaba, D.C; Jebber, K.A.Organometallics 1993 , 12 , 5020.
[86]Kundu, M. K.; Mukherjee, S. B.; Balu, N. Synlett 1994 , 444
[87] S. addick, Tetrahedron 1995, 51(8), 10403.
[88]R.Baghurst,D.M.P.Mingos and M.J.Watson,J.Organomet.Chem.,1989,C43,368
[89]王静,姜凤超.微波有机合成反应的新进展[J].有机化学,2002,22(3):212-219.
[90]LeeJY,LeeYS,Park H K,et al.4-(Phenylamino)[1,4]dioxano[2,3-g]quinazoline derivatives and process for preparing the same:US,2003045537[P].20032032061
[91]侯廷军,朱丽荔,陈丽蓉,等.EGFR和4-苯胺喹唑啉类抑制剂之间相互作用模式的研究[J].化学学报,2002,60(6):1023210281
[92]EISharief A M S,Ammar YA,Zahran MA,et al.Aminoacids in the synthesis of heterocyclic systems:the synthesis of triazinoquinazolinones,triazepinoquinazolinones and triazocinoquinazolinones of potential biological interest[J].Molecules,2001,6(3):26722781
[93]Xu G F,Song B A,Bhadury P S,et al.Synthesis and antifungal activity of novel ssubstituted 62fluoro242 alkyl(aryl)thioquinazoline derivatives[J].Bioorg Med Chem,2007,15(11):3768237741
[94]Marsham PR,Hughes LR,Jackman AL,et al.Quinazoline antifolate thymidylate synthase inhibitors:heterocyclic benzoyl ring modifications[J].J MedChem,1991,34:1594 -1605.
[95]Gedye R.,Sm ith F.,WestawayK.,A li H.,et al..The uses of m icrow ave ovens fo r rap id o rganic syn2thesis[J].Tet rahedron L et al.,1986,27(3):279 -282,
[96]金钦汉,戴树珊,黄卡玛.微波化学[M].北京:科学出版社,1999:4.
[97]Chakrabarty,M.;Monatshefte fuer Chemie 1995,Ⅴ 126(6/7),P789-94
[98]King,R.R.;Phytochemistry 1998,V49(5),P1265-1267
[99]Yong,Jian-Ping;Acta Crystallographica,Section E:Structure Reports Online 2008,VE64(2),Po427,o427/1-o427/7
[100]Schmidt,Anne-Christine;Rapid Communications in Mass Spectrometry 2006,V20(15),P2293-2302
[101]Rachid,Zakaria;Journal of Medicinal Chemistry 2003,V46(20),P4313-4321
[102]Wu,Yao-Hua;Journal of the American Chemical Society 1952,V74,P1863-4
[103]Photographic layers for the silver decolorizati on process.CIBALtd.).(1962),30 pp.BE 611898 19620622 Patent language unavailable.
[104]Leysen,D.L.;Journal of Heterocyclic Chemistry 1987,V24(6),P1611-16
[105]Mahindroo,Neeraj;Medicinal Chemistry Research 2006,V14(6),P347-368
[106]Llinas,Antonio;Journal of Chemical Information and Modeling 2008,V48(7),P1289-1303
[107]Singh,Tripti;Indian Journal of Chemistry,Section B:Organic Chemistry Including Medicinal Chemistry 2006,V45B(11),P2558-2565
[108]Guise,G.Bruce;Journal of the Chemical Society,Perkin Transactions 1:Organic and Bio-Organic Chemistry(1972-1999) 1982,(8),P1637-48
[2]全国中等卫生学校统编教材《中草药化学》编写组.中草药化学(M)南京:江苏科学技术出版杜,1980.2
[3]陈友梅.中药化学(M)济南:山东科学技术出版社,1988.51
[4]马养民,傅建熙1,生物碱的研究概况(J),陕西林业科技,1997.1:75
[5]Lee J Y,Park Y K,Seo S H,et al.1,4-Dioxane-fused 4-anilinoquinazoline as inhibitors of epidermal growth factor receptor kinase[J].Arch Pharm(Weinheim),2001,334(11):35723601
[6]LeeJY,LeeYS,Park H K,etal.4-(Phenylamino)[1,4]dioxano[2,3-g]quinazoline derivatives and process for prepar2ing the same:US,2003045537[P].20032032061
[7]侯廷军,朱丽荔,陈丽蓉,等.EGFR和4-苯胺喹唑啉类抑制剂之间相互作用模式的研究[J].化学学报,2002,60(6):1023210281
[8]EI2Sharief AM S,Ammar YA,Zahran MA,et al.Aminoacids in the synthesis of heterocyclic system:the synthesis of triazinoquinazolinones,triazepinoquinazolinones and triazocinoquinazolinones of potential biological interest[J].Molecules,2001,6(3):26722781
[9]Xu G F,Song B A,Bhadury P S,et al.Synthesis and antifungal activity of novel ssubstituted 6-fluoro-4-alkyl(aryl)thioquinazoline derivatives[J].Bioorg Med Chem,2007,15(11):3768237741
[10]Marsham PR,Hughes LR,Jackman AL,etal.Quinazoline antifolate thymidylate synthase inhibitors:heterocyclic benzoyl ring modifications[J].J MedChem,1991,34:1594 - 1605
[11]Cunningham D,Zalcberg J,Maroun J,et al.Efficacy,tolerability and management of raltitrexed monotherapy inpatients with advanced colorectal cancer:a review of phase Ⅱ/Ⅲtrials[J].Eur J Cancer,2002,38:478 -486
[12]Witt,Bergman J,Recent Developments in the Field of Quinazoline Chemistry.Current Organic Chemistry,2003,7:659-677
[13]Koepfly JB,Mead JF,Brokman J A.An alkaloid with high antimalarial activity from Dichroa febrifuge.J.Am.Chem.Soc.,1947,69:1837-146
[14]Koepfly JB,Mead JF,Brokman J A.An alkaloid with high antimalarial activity from Dichroa febrifuge.J.Am.Chem.Soc.,1947,69:1048-1056
[15]Kobayyashi S,Ueno M,Suzuki R,etal.Catalytic asymmetric synthesis of antimalari alalkaloids.febrifugine and isofebrifugine and their biological itivity.J.Ofg.Chem.1999,64:6833-6841
[16]Bergrnan J,Brynolf A.Synthesis of chrysogine,a metalolite of Penicillium chrysogenum and somerelated 2-substituted-4-(3H)-quinazolinones.Tetrahedron,1990.46:1295-1310
[17]Hikino H,Nabetani S,Takemoto T.Yakugaku Za sshi,1973,93:619
[18]Chadwick DJ,Easton IW.Acta Crystallogr.,Sect.C,1983,39:454
[19]Bergman J,Brynolf A.Synthesis of Chrysogine:a Metabolite of Penicillium chrsogenum and somerelated2-substituted 4-(3H)-Quinazolinoes.Tetrahedron,1990,46(4):1295-1310
[20]Bergman J.Comments on the Asymmetric Synthesis of Chrysogine.JChen.Res.(s),1997:224
[21]李清华,金继曙,种明才,等.青黛抗真菌成份的研究[J].中草药,1983,14(10):8-9
[22]Oberth(u∣¨)r C,J3/4 ggi R,HamburgerM.HPLC based activity p rofilingfor 521ipoxygenase inhibitory activity in Isatis tinctoria leaf extracts[J].Fitoterapia,2005,76(3-4):324-32
[23]Sharma V M,Prasanna P,Seshu K V,et al.Novel indolo[2,1-b]quinazoline analogues as cytostatic agents:synthesis,biological e2valuation and structure2activity relationship[J].B ioorg Med ChemLett,2002,12(17):2303-7
[24]王振义.白血病的诱导凋亡疗法[N].中国医学论坛报,2003,29(1):72-5
[25]Mu B Z.A new cytotoxic active principle isolated from Polygonumtinctorium[J].N atMed,1999,53(2):72-9
[26]Bhattacharjee A K,Skanchy D J,JenningsB,et al.Analysis of stereoelectronic p roperties,mechanism of action and pharmacophore ofsynthetic indolo[2,1-b]quinazoline-6,1-2dione derivatives in relation to antileishmanial activity using quantum chemical,cyclicvoltammetry and 3DQSAR CATALYST Procedures[J].J B ioorg Med Chem,2002,10:1979 - 89
[27]Scovill J,Blank E,KonnickM,et al.Antitrypanosomal activities of tryp tanthrins[J].Antim icrob Agents Chem other,2002,46(3):8823
[28]Li Q H,J in J S,ZhongM C,et al.Study on antifungal constituentsof indigo pulverata levis [J]. Chin Trad Herb D rug, 1983, 14(10):8-9
[29] Lee E S, Park J G, Jahng Y D. A facile synthesis of simple alkaloids synthesis of 2,3-polymethylene-4 (3H)-quinazolinones and related alkaloids [J].Tetrah Lett, 2003, 44 (9):1883 - 6.
[30] Witt A, Bergman J.Recent development in the field of quinazolinechemistry [J].Curreng O ry Chem, 2003, 7:659-77
[31]王翠玲,刘建利,沈小莉.天然产物色胺酮及其衍生物合成的研究进展[J].化学通报,2007, 70(2):89-95
[32] Ma Z Z, Hano Y, Nomura T , et al.J.Heterocycles,1997,51(7):1593-1596.
[33] Noonbery S B , Benz C C. Tyrosine kinase inhibitors targetedto the epidermal growth factor recptor subfamily[J].Drugs, 2000, 59(4):75327671
[34] Morin M J. From oncogene to drug: development of smallmolecule tyrosine kinase inhibitors as anti2tumor and antiangiogcnic agents [J]. Oncogene, 2000, 19 (56): 6574265831
[35] Nakamura K, Yamamoto A, Kamishohara M, et al.KRN633: A selective inhibitor of vascular endothelial growthfactor receptor tyrosine kinase that suppresses tumor angiogenesis and growth [J]. Mol Cancer Ther, 2004, 3 (12):1639216491
[36] Williams KJ , Telfer B A , Brave S, et al. ZD6474, a potentinhibitor of vascular endothelial growth factor signaling , combined with radiotherapy : chedule dependent enhancement ofantitumor activity [J]. Clin Cancer Res, 2004, 10 (24):8587285931
[37] McCartyM F, Wey J, Stoeltzing O, et al.ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitorwith additional activity against epidermal growth factor receptor tyrosine kinase, inhibits orthotopic growth and angiogenesis of gastric cancer [J].Mol CancerThe, 2004, 3 (9): 1041210481
[38] Wedge S R, KendrewJ, Hennequin L F, et al. AZD2171:ahighly potent, orally bioavailable, vascular endothelial growthfactor receptor tyrosine kinase inhibitor for the treatment ofcancer[J].Cancer Res, 2005, 65(10):4389244001
[39] Jin Y, Zhou Z Y, Tian W, et al. 4'- Alkoxyl substitution enhancing the antimitotic effect of 52(3', 4', 5'2 substituted)aniline-4-hydroxy-8-nitroquinazolines as a novel class of anti2microtubule agents [J] . Bioorg Med Chem Lett, 2006, 16(22): 5864258691
[40] Soelaiman S , Wei B Q , Bergson P, et al. Structure based inhibitor discovery against adenylyl cyclase toxins from pathogenic bacteria that cause anthrax and whooping cough[J] .J Biol Chem, 2003, 278 (28): 2599022599
[41]Lokker N A,Sullivan C M,Hollenbach S J,etal.Platelet2derived growth factor (PDGF) autocrine signaling regulatessurvival and mitogenic pathways in glioblastoma cells:Evidence that the novel PDGF-C and PDGF-D ligands may play arole in the development of brain tumors[J].Cance Re,2002,62(13):3729237351
[42]Kyprianou N,Chon J,Benning CM.Effects of alphal ad renoceptor antagonists on cultured prostatic smooth muscle cells[J].Prostate Sup,2000,9(1):342411
[43]Keledjian K,Borkowski A,Kim G,et al.Reduction of human prostate tumor vascularity by the alphaadrenoceptor antagonist terazosin[J].Prostate,2,001,48(2):712781
[44]Fox D N A.Quinoline and quinazoline compounds useful intherapy:US,2002040028[P].20022042041
[45]R(?)dl S,Hezky P,ProIka J,et al.Synthesis and analgesic activity of some quinazoline analogs of anpirtoline[J].ArchPharm(Weinheim),2000,333(11):38123861
[46]Colquhoun A,Lawrance GM,Shamovsky I L,etal.Differential activity of thenerve growth factor(NGF) antagonist PD90780[7-(benzolylamino)-4,dihydro-4-methyl-9-oxo-Py razolo[5,1-b]quinazoline-2-carboxylicacid]suggestsaltered NGF-p75NTR interactions in the presence of TrkA[J].JPharmacol Exp Ther,2004,310(2):50525111
[47]Gineinah MM,EL 2Sherbeny MA,Nasr MN,etal.Synthe2sis and antiinflammatory screening of some quinazoline andquinazolyl242oxoquinazoline derivatives[J].Arch Pharm(Weinheim),2002,335(11):55625621
[48]刘志红,孙晓莉,张生勇.对Niementowski反应的改进[J].有机化学,2001,21(12):116121163
[49]许志锋,邝代治,张复兴,等.串连aza2Wittig反应合成2-芳氧(硫)基-3-苯基喹唑啉-4-酮[J].化学试剂,2004,26(3):1632164
[50]丁明武,杨尚君,陈云峰.2-烷氧基-3H-喹唑啉-4-酮的合成与杀菌活性[J].有机化学,2004,24(8):9232926
[51]施沁清,刘志平.喹唑啉酮类化合物的合成[J].上海化,2000,9(9):18220.
[52]Akazome M,Kondo T,WatanabeY.Transitionmetal complex catalyzed reductive N-heterocyclization:Synthesis of 4(3H)-quinazolinone derivativesfrom N-(2-nitrobenzoyl)amides[J].J.Org.Chem,1993,58(2):3102312.
[53]Larksarp C,Alper H.Palladium catalyzed cyclocarbonylationof oiodoanlin with heterocumulenes:Regioselective preparation of 4(3H)-quinazolinone derivatives[J].J. Org.Chem.2000,65(9):277322777.
[54]CoutureA,CornetH,Grandclaudon P.Anexpeditious synthesis of 2-aryl and 2-alkylquinazolin-4(3H)-ones[J].Synthesis,1991:100921010.
[55]史达清,王香善,屠树江,等.32苯基喹唑啉24(3H)2酮的合成及晶体结构[J].结构化学,2003,22(5):581-584.
[56]O'Mahony R J D,Krchnak V.Traceless synthesis of 3H-quinazolin-4-ones via a combination of solidphase and solution methodologies[J].TetrahedronLett.,2002,43(6):9392942.
[57]R.Soliman,F.S.G.Soliman,A facile synthesis of 2,3-disubstituted4-oxo-3,4-dihydroquinazolines,synthesis.1979,803-804
[58]D.V.Ramana,E.Kantharaj,Facile Synthesis of 2-alky-3-ary-4(3H)-quinazolinones Indian J.Heterocycl.Chem.1994(3)215-218
[59]Saito T,Tsuda K.Stato Y.,A Facile and Efficient Carbodiimide-Mediated Synthesis Of Dihydrooquinazolines via a Tandem Nuclephilic Addition Intramolecular Hetero Conyugate Addition Annulation Strategy.Tetrahedron Lett.,1996,37,209
[60]Wang F,Hauske,J.R.,Solide-Phase Synthesis Of 2,3-disebtituted Tetrahedron Lett.1997,38,8651
[61]R.Soliman,F.S.G.Soliman,A facile synthesis of 2,3-disubstituted4-oxo-3,4-dihydroquinazolines,synthesis.1979,803-804
[62]D.V.Ramana,E.Kantharaj,Facile Synthesis of 2-alky-3-ary-4(3H)-quinazolinones Indian J.Heterocycl.Chem.994(3),215-218
[63]R.Soliman,F.S.G.Soliman,A facile synthesis of 2,3-disubstituted
[64]D.V.Ramana,E.Kantharaj,Facile Synthesis of 2-alky-3-ary-4(3H)-quinazolinones Indian J.Heterocycl.Chem.1994(3),215-218
[65]Saito T,Tsuda K.Stato Y.,A Facile and Efficient Carbodiimide-Mediated Synthesis Of Dihydrooquinazolines via a Tandem Nuclephilic Addition Intramolecular Hetero Conyugate Addition Annulation Strategy.Tetrahedron Lett.,1996,37,209
[66]Wang F,Hauske,J.R.,Solide-Phase Synthesis Of 2,3-disebtituted Tetrahedron Lett.1997,38,8651
[67]CRC Hand Book of Data on Organic Compouds
[68] K.Kottoke, H, kuhmstedt. Pharmazie [J], 1984, 39(12), 868
[69] Saito T, Tsuda K. Stato Y., A Facile and Efficient Carbodiimide-Mediated Synthesis Of Dihydrooquinazolines via a Tandem Nuclephilic Addition Intramolecular Hetero Conyugate Addition Annulation Strategy.Tetrahedron Lett., 1996 , 37, 209
[70] Wang F, Hauske, J.R., Solide-Phase Synthesis Of 2, 3-disebtituted Tetrahedron Lett. 1997, 38, 8651
[71] V anderhoff J. W. arrying out Chemical Reactions Using Microwave Energy [P].US 432413, 1969.203-211
[72]Gedye, R.; Smith, F.; Westaway, K.TetrahedronLet .1986, 27(3), 279.(b)Gedye ,R.; Smith, F.;Westaway, K.Can. J.Chem. 1988, 66, 17
[73] Gedye R., Sm ith F., Westaway K, A li H., et al.The uses of m icrow ave ovens fo r rap id o rganic syn2thesis [J]. Tetrahedron Lett., 1986, 27 (3): 279-282
[74] 金钦汉,微波化学page147
[75] Giguere RJ, Bray TL, Majetich G, etal.Application of commercial microwave ovens to organic synthesis. Tetrahedron Lett , 1986 , 27:4945—4948
[76] Srikrishna, A.;Nagaraju, S.J. Chem. Soc Perkin.Trans. 1, 1992, 311
[77]V.Sridar and V.S.S.Rao, J. Chem.Set.B, 1994, 33B(2), 184
[78] Strauss, C. R; Trainor, R.W. Aus. J. Chem. 1995, 48, 1665
[79] R.J.Giguere, T.L.Bray, S. M. Duncan and G.Majetich, Tetrahedron Lett., 1986, 27,4945.
[80] S.Caddick, Tetrahedron, 1995, 51(8), 10403.
[81] M.W.Lu, W, X, HuandL.H.Yun, Firs tNational ConferenceonMicrowave Chemistry,1996, 54
[82] Giguere RJ , Bray TL , Majetich G, et al.Application of commercial microwave ovens to organic synthesis. Tetrahedron Lett , 1986 , 27 :4945-4948
[83] Srikrishna, A.;Nagaraju, S.J. Chem. Soc., Perkin.Trans. 1, 1992, 311
[84] Caddick, S. Tetrahedron 1995, 51 , 10403
[85] Gordon, E.M.; Gaba, D.C; Jebber, K.A.Organometallics 1993 , 12 , 5020.
[86]Kundu, M. K.; Mukherjee, S. B.; Balu, N. Synlett 1994 , 444
[87] S. addick, Tetrahedron 1995, 51(8), 10403.
[88]R.Baghurst,D.M.P.Mingos and M.J.Watson,J.Organomet.Chem.,1989,C43,368
[89]王静,姜凤超.微波有机合成反应的新进展[J].有机化学,2002,22(3):212-219.
[90]LeeJY,LeeYS,Park H K,et al.4-(Phenylamino)[1,4]dioxano[2,3-g]quinazoline derivatives and process for preparing the same:US,2003045537[P].20032032061
[91]侯廷军,朱丽荔,陈丽蓉,等.EGFR和4-苯胺喹唑啉类抑制剂之间相互作用模式的研究[J].化学学报,2002,60(6):1023210281
[92]EISharief A M S,Ammar YA,Zahran MA,et al.Aminoacids in the synthesis of heterocyclic systems:the synthesis of triazinoquinazolinones,triazepinoquinazolinones and triazocinoquinazolinones of potential biological interest[J].Molecules,2001,6(3):26722781
[93]Xu G F,Song B A,Bhadury P S,et al.Synthesis and antifungal activity of novel ssubstituted 62fluoro242 alkyl(aryl)thioquinazoline derivatives[J].Bioorg Med Chem,2007,15(11):3768237741
[94]Marsham PR,Hughes LR,Jackman AL,et al.Quinazoline antifolate thymidylate synthase inhibitors:heterocyclic benzoyl ring modifications[J].J MedChem,1991,34:1594 -1605.
[95]Gedye R.,Sm ith F.,WestawayK.,A li H.,et al..The uses of m icrow ave ovens fo r rap id o rganic syn2thesis[J].Tet rahedron L et al.,1986,27(3):279 -282,
[96]金钦汉,戴树珊,黄卡玛.微波化学[M].北京:科学出版社,1999:4.
[97]Chakrabarty,M.;Monatshefte fuer Chemie 1995,Ⅴ 126(6/7),P789-94
[98]King,R.R.;Phytochemistry 1998,V49(5),P1265-1267
[99]Yong,Jian-Ping;Acta Crystallographica,Section E:Structure Reports Online 2008,VE64(2),Po427,o427/1-o427/7
[100]Schmidt,Anne-Christine;Rapid Communications in Mass Spectrometry 2006,V20(15),P2293-2302
[101]Rachid,Zakaria;Journal of Medicinal Chemistry 2003,V46(20),P4313-4321
[102]Wu,Yao-Hua;Journal of the American Chemical Society 1952,V74,P1863-4
[103]Photographic layers for the silver decolorizati on process.CIBALtd.).(1962),30 pp.BE 611898 19620622 Patent language unavailable.
[104]Leysen,D.L.;Journal of Heterocyclic Chemistry 1987,V24(6),P1611-16
[105]Mahindroo,Neeraj;Medicinal Chemistry Research 2006,V14(6),P347-368
[106]Llinas,Antonio;Journal of Chemical Information and Modeling 2008,V48(7),P1289-1303
[107]Singh,Tripti;Indian Journal of Chemistry,Section B:Organic Chemistry Including Medicinal Chemistry 2006,V45B(11),P2558-2565
[108]Guise,G.Bruce;Journal of the Chemical Society,Perkin Transactions 1:Organic and Bio-Organic Chemistry(1972-1999) 1982,(8),P1637-48