具有潜在生物活性的咪唑或噻唑类衍生物的合成与结构表征
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摘要
含氮杂环化合物及其衍生物作为医药、农药、染料及其它精细化工产品的中间体，应用越来越广泛。在有机化合物中引入含氮杂环化合物及其衍生物，常常会引起有机化合物的生物活性增加。苯并含氮杂环化合物由于其高选择性和生物活性，在药物的研究和开发中发挥着重要的作用，从而成为农药和医药研究的一大热点。但对苯并杂环化合物3，4-二氢-2(1氢)羰基喹喔啉、1，2，3，4-四氢喹喔啉、2，3-二氢-1，4-苯并噁嗪、2，3-二氢苯并噁唑以及2，3-二氢-1，4-苯并噻嗪的研究相对较少。实际上，它们在一些药物中也发挥着重要作用，可能是这些药物的活性中心，所以它们可能具有生物活性。
咪唑类和噻唑类化合物广泛存在于自然界，在药物研究和开发中占有非常重要的地位，对其研究也非常活跃。许多临床药物都含有咪唑环或噻唑环。同时，含有咪唑环或噻唑环的新研制的众多化合物也具有生物活性。因而我们可以确信咪唑环和噻唑环是具有生物活性的。
现代药物设计理论，例如定量构效关系(QSAR)，在预测化合物的生物活性、帮助了解药物的作用机理方面有一定的作用，能够指导目标分子的设计。本文结合Free-Wilson模式的基本思想，设计了两类具有潜在生物活性的新型目标分子。它们的结构式如下：
1 X=NH；Y=0；n=1 6 X=NH；Y=0：n=1
2 X=NH；Y=2H；n=1 7 X=NH；Y=2H；n=1
3 X=O；Y=2H；n=1 8 X=O；Y=2H；n=1
4 X=O；Y=2H；n=0 9 X=O；Y=2H；n=1
5 X=S；Y=2H；n=1
为了得到目标分子，我们首先设计并合成了五个苯并含氮杂环化合物。通过对这些化合物不同合成方法的比较，结合本研究室以前的研究成果，我们对这些合成方法进行了优化。我们现在可以利用价廉易得的原料来制备它们。在室温条件下，用N，N-二甲基乙酰胺(DMAC)作溶剂，这些苯并含氮杂环化合物各自与氯乙酰氯或溴乙酰氯反应可以得到相应的N-氯乙酰或N-溴乙酰取代的苯并含氮杂环化合物。
含咪哇或曝哇杂环类化合物的合成与结构表征
用乙睛作溶剂，加入KZCo3和四丁基碘化胺(T BAI)，咪畔与N一溟乙酞或N，N’-
二嗅乙酞取代的苯并含氮杂环化合物发生亲核取代反应，从而可以得到目标化合
物TMI一TMS。
在丙酮中，以NaZCO:作碱，通过硫醚键的形成，将四个N一氯乙酞或N，N’-
二氯乙酞取代的苯并含氮杂环中间体导入咪吟结构。通过柱层析或重结晶，我们
可以在较高的产率下得到TM6一TMg。
总之，通过不同的方法我们合成了9个具有潜在生物活性的未见文献报道的
化合物，它们的结构已经得到MS、’HNMR、’3eNMR、DEPT、xR谱和元素分析
的确证。
Nitrogen-containing heterocyclic compounds and their derivatives have found greater and greater application as intermediates of medicine, pesticide, dye and other fine chemical engineering's products. The introduction of nitrogen-containing heterocyclic compounds and their derivatives into some organic compounds generally brings about increased bioactivity of the organic compounds. Because of their high selectivity and bioactivity, nitrogen-containing benzoheterocyclic compounds play an important role in the research and exploitation of drugs and have become the focus of research in pesticides and medicines. However, according to our knowledge, relatively less research has been carried out on nitrogen-containing benzoheterocyclic compounds, such as 3,4-dihydro-2(1H)quinoxalinone, 1,2,3,4-tetrahydroquinoxaline, 2,3-dihydro-l,4-benzoxazine, 2,3-dihidrobenzoxazole and 2,3-dihydro-l,4-benzo-thiazine. In fact, they play an important role in the medicine. Probably they are pharmacological active centers and posses
s bioactivity.
The imidazoles and the thiazoles, existing in nature, are of great significance in the research and exploitation of drugs. There are imidazole or thiazole rings in the structures of many clinic medicines. At the same time, many newly developed compounds containing imidazole ring or thiazole ring also have bioactivity. Therefore, it can be concluded that both imidazole ring and thiazole ring have bioactivity.
The theories about drug design, such as Quantitative Structure-Activity Relationship (QSAR), have some effects on forecasting the bioactivity of compounds and helping us to understand pharmic mechanism, and can direct us to design target molecule (TM). Combined with the idea of Free-Wilson model, two kinds of molecules owning potential bioactivity were designed, and their structures are shown as follows:
Five types of nitrogen-containing benzoheterocyclic compounds were designed and synthesized in order to obtain target molecules. Based on the previous researches in our laboratory, synthetic methods of these compounds were optimized by comparing different synthetic methods. Now these compounds can be prepared from inexpensive and available materials. The reactions of these nitrogen-containing benzoheterocyclic compounds with chloracetyl chloride or chloracetyl bromide at room temperature in DMAC can produce the corresponding N-chloracetyl or N-bromoacetyl-substiuted nitrogen-containing benzoheterocyclic compounds.
In the presence of K2CO3 and TBAI in CH3CN, TM1-TM5 were synthesized through nucleophilic substitution reaction between imidazole and N-bromoacetyl or N,N'-dibromoacetyl substituted nitrogen-containing benzoheterocyclic compounds.
By using Na2CO3 as a base in acetone, four types of N-chloroacetyl or N,N'-dichloroacetyl substituted nitrogen-containing benzoheterocycles were introduced into thiazole through the formation of thio-ether. TM6-TM9 were obtained in good yields after column chromatography or recrystallization.
In conclusion, nine novel compounds with potential bioactivity were synthesized through different approaches. MS, 1H NMR, 13C NMR, DEPT, IR and elementary analysis have identified the structures of them.
咪唑类和噻唑类化合物广泛存在于自然界，在药物研究和开发中占有非常重要的地位，对其研究也非常活跃。许多临床药物都含有咪唑环或噻唑环。同时，含有咪唑环或噻唑环的新研制的众多化合物也具有生物活性。因而我们可以确信咪唑环和噻唑环是具有生物活性的。
现代药物设计理论，例如定量构效关系(QSAR)，在预测化合物的生物活性、帮助了解药物的作用机理方面有一定的作用，能够指导目标分子的设计。本文结合Free-Wilson模式的基本思想，设计了两类具有潜在生物活性的新型目标分子。它们的结构式如下：
1 X=NH；Y=0；n=1 6 X=NH；Y=0：n=1
2 X=NH；Y=2H；n=1 7 X=NH；Y=2H；n=1
3 X=O；Y=2H；n=1 8 X=O；Y=2H；n=1
4 X=O；Y=2H；n=0 9 X=O；Y=2H；n=1
5 X=S；Y=2H；n=1
为了得到目标分子，我们首先设计并合成了五个苯并含氮杂环化合物。通过对这些化合物不同合成方法的比较，结合本研究室以前的研究成果，我们对这些合成方法进行了优化。我们现在可以利用价廉易得的原料来制备它们。在室温条件下，用N，N-二甲基乙酰胺(DMAC)作溶剂，这些苯并含氮杂环化合物各自与氯乙酰氯或溴乙酰氯反应可以得到相应的N-氯乙酰或N-溴乙酰取代的苯并含氮杂环化合物。
含咪哇或曝哇杂环类化合物的合成与结构表征
用乙睛作溶剂，加入KZCo3和四丁基碘化胺(T BAI)，咪畔与N一溟乙酞或N，N’-
二嗅乙酞取代的苯并含氮杂环化合物发生亲核取代反应，从而可以得到目标化合
物TMI一TMS。
在丙酮中，以NaZCO:作碱，通过硫醚键的形成，将四个N一氯乙酞或N，N’-
二氯乙酞取代的苯并含氮杂环中间体导入咪吟结构。通过柱层析或重结晶，我们
可以在较高的产率下得到TM6一TMg。
总之，通过不同的方法我们合成了9个具有潜在生物活性的未见文献报道的
化合物，它们的结构已经得到MS、’HNMR、’3eNMR、DEPT、xR谱和元素分析
的确证。
Nitrogen-containing heterocyclic compounds and their derivatives have found greater and greater application as intermediates of medicine, pesticide, dye and other fine chemical engineering's products. The introduction of nitrogen-containing heterocyclic compounds and their derivatives into some organic compounds generally brings about increased bioactivity of the organic compounds. Because of their high selectivity and bioactivity, nitrogen-containing benzoheterocyclic compounds play an important role in the research and exploitation of drugs and have become the focus of research in pesticides and medicines. However, according to our knowledge, relatively less research has been carried out on nitrogen-containing benzoheterocyclic compounds, such as 3,4-dihydro-2(1H)quinoxalinone, 1,2,3,4-tetrahydroquinoxaline, 2,3-dihydro-l,4-benzoxazine, 2,3-dihidrobenzoxazole and 2,3-dihydro-l,4-benzo-thiazine. In fact, they play an important role in the medicine. Probably they are pharmacological active centers and posses
s bioactivity.
The imidazoles and the thiazoles, existing in nature, are of great significance in the research and exploitation of drugs. There are imidazole or thiazole rings in the structures of many clinic medicines. At the same time, many newly developed compounds containing imidazole ring or thiazole ring also have bioactivity. Therefore, it can be concluded that both imidazole ring and thiazole ring have bioactivity.
The theories about drug design, such as Quantitative Structure-Activity Relationship (QSAR), have some effects on forecasting the bioactivity of compounds and helping us to understand pharmic mechanism, and can direct us to design target molecule (TM). Combined with the idea of Free-Wilson model, two kinds of molecules owning potential bioactivity were designed, and their structures are shown as follows:
Five types of nitrogen-containing benzoheterocyclic compounds were designed and synthesized in order to obtain target molecules. Based on the previous researches in our laboratory, synthetic methods of these compounds were optimized by comparing different synthetic methods. Now these compounds can be prepared from inexpensive and available materials. The reactions of these nitrogen-containing benzoheterocyclic compounds with chloracetyl chloride or chloracetyl bromide at room temperature in DMAC can produce the corresponding N-chloracetyl or N-bromoacetyl-substiuted nitrogen-containing benzoheterocyclic compounds.
In the presence of K2CO3 and TBAI in CH3CN, TM1-TM5 were synthesized through nucleophilic substitution reaction between imidazole and N-bromoacetyl or N,N'-dibromoacetyl substituted nitrogen-containing benzoheterocyclic compounds.
By using Na2CO3 as a base in acetone, four types of N-chloroacetyl or N,N'-dichloroacetyl substituted nitrogen-containing benzoheterocycles were introduced into thiazole through the formation of thio-ether. TM6-TM9 were obtained in good yields after column chromatography or recrystallization.
In conclusion, nine novel compounds with potential bioactivity were synthesized through different approaches. MS, 1H NMR, 13C NMR, DEPT, IR and elementary analysis have identified the structures of them.
引文
[1] 张华，宋宝安．杂环类植物抗病毒剂的研究进展．Pesticides，2002，41(2)：6-9
[2] 柏再苏，王大翔．杂环、基因工程和二十一世纪的农药．中国化工学会农药专业委员会第九届年会论文集，上海：1998，1-8
[3] Acharya A N, Thai C, Ostresh J M, et al. Use of Vilsmeier Reagent for the Solid-Phase Synthesis of 1,5-Disubstituted 4,5-Dihydro-1H-imidazoles and Disubstituted 4,5-Dihydro-1H-imidazolylbenzimidazoles. J. Comb. Chem., 2002, 4:496-500
[4] Gilman A G, Goodman L S. In The Pharmacological Basis of Therapeutics. 10th ed, Macmillan & Co., New York: 2001
[5] Greenhill J V, Lue L. In Progress in Medicinal Chemistry. Ellis, G. P., Luscombe, D. K., Eds., Elsevier Science, New York: 1993, V30:22-32
[6] 李再峰，罗富英．含氮杂环及其衍生物的氮氧化方法研究进展．有机化学，2002，22(4)：233-238
[7] 陈立功，王东华，宋传君等．药物中间体合成工艺．北京：化学工业出版社，2001，98
[8] 杨松，宋宝安，李正名等．2(1H-咪唑-1-基)-1-(2，3，4-三甲氧基)苯乙酮肟酯新化合物合成与生物活性研究．有机化学，2002，22(5)：345-349
[9] 谢如观，苏晓谕，游劲松．咪唑环番仿生新体系研究进展．化学研究与应用，1999，11(5)：449-451
[10] 刘长令，刘晓南，李斌．新型咪唑并三嗪化合物的设计与合成．中国化工学会农药专业委员会第九届年会论文集，上海：1998，11-12
[11] Lermer L, Roupioz Y, Ting R, et al. Toward an RNaseA Mimic: A DNAzyme with Imidazoles and Cationic Amines. J. Am. Chem. Soc., 2002, 124:9960-9961
[12] 陈立功，王东华，宋传君等．药物中间体合成工艺．北京：化学工业出版社，2001，109
[13] Sarges R, Lyga J W. Preparation of 4-(arylsulfony) quinoxalin-2-one-l-alkyl-carboxylates for treatment of complications of diabetes. J. Heterocylcl. Chem., 1988, 25:1475
[14] Tenbrink R E, Im W B, Sethy V H, et al. Antagonist, partial agonist, and full agonist imidazo[1,5-a] quinoxaline amides and carbamates acting through the
GABA_A/benzodiazepine receptor. J. Med. Chem., 1994, 37:758
[15] Mickelson J W, Jacobsem E J, Carter D B, et al. Sysnthesis of an azasteroid using an acyl iminicion. J. Med. Chem., 1996, 39:4654
[16] 陈洪超，罗娟，曹红梅等．异烟噻的合成．Pesticides，2002，43(9)：10-11
[17] 黄琮耀，黄力军，朱正芳．3，4-二氢-2-喹喔啉酮尿类衍生物的合成及其生物活性的测定．中国化工学会农药专业委员会第九届年会论文集，上海：1998，22-23
[18] Holmes K, Richard C. Antifungal Agents. 10, Synthesis, Anti-Candida Activity, and Quantitative Structure-Analysis Relationship Studies. EP: 772154, 1973
[19] 任天，周家驹．三唑并嘧啶类化合物的合成和除草活性研究．中国化工学会农药专业委员会第九届年会论文集，上海：1998，34-35
[20] Wyvratl M J,Patchett A A. Preparation of Antitumor. Med. Res. Rev.,1985, 5(4):483
[21] 陈凯先，罗小明，蒋华良．计算机辅助药物设计．原理方法及应用．中国科学院院刊，2000，4：266
[22] 李志安，刘树彬，次立杰．2-叔丁基-4-氯-3-哒嗪酮硫代磷酸酯的合成及质谱研究．合成化学，1998，6(1)：95-99
[23] 林学圃，张一兵．杀菌剂嘧菌胺的开发．中国化工学会农药专业委员会第九届年会论文集，上海：1998，30-36
[24] 李正化．药物化学．北京：人民出版社，1993，99-102
[25] Bhaua M, Naithani D K, Bhalla N. Synthesis and Physiologically Active Compound Indian. Chem. Soc., 1992, 6(9): 594
[26] 曲凡歧，刘芳．植物病毒病化学防治剂的探寻．中国化工学会农药专业委员会第九届年会论文集，上海：1998，44-47
[27] Bihan G L, Rondu F, Pele-Tounian A, etal. Design and Synthesis of Imidazoline Derivatives Active on Glucose Homeostasis in a Rat Model of Type Ⅱ Diabetes. 2. Syntheses and Biological Activities of 1,4-Dialkyl-, 1,4-Dibenzyl, and 1-Benzyl-4-alkyl-2-(4,5-dihydro-1Himidazol-2-yl)piperazines and Isosteric Analogues of Imidazoline. J. Med. Chem. 1999, 42:1587-1603
[28] Tebbe M J, Spitzer W A, Victor F, etal. Antirhino/Enteroviral Vinylacetylene Benzimidazoles: A Study of Their Activity and Oral Plasma Levels in Mice. J. Med. Chem. 1997, 40:3937-3946
[29] 曹明章．植物抗病激活剂苯并噻二唑类．农药译丛，1998，20(5)：38-44
[30] 苏少泉．除草剂作用靶标与新品种创制．北京：化学工业出版社，2001，5-7
[31] 宫平，赵燕芳，冯润良．盐酸头孢吡肟的合成．中国药物化学杂志，2002，12(6)：
350-352
[32] 张致平．抗菌药物研究进展．中国抗生素杂志，2002，27(2)：67-79
[33] Hutchinson I, Jennings S A, Vishnuvajjala B R. Antitumor Benzothiazoles, 16, Synthesis and Pharmaceutical Properties of Antitumor 2-(4-Aminophenyl)-benzothiazole Amino Acid Prodrugs. J. Med. Chem., 2002, 4(5): 744-747
[34] 刘长令．浅谈国内外农药开发现状与发展趋势．新农药研究开发文集，北京：化学工业出版社，2002，45-47
[35] 徐基东．浅谈新农药创制策略．中国化工学会农药专业委员会第九届年会论文集，上海：1998，10-11
[36] 陈凯先，蒋华良，嵇汝运．计算机辅助药物设计-原理方法及应用．上海：2000，78-79
[37] 矶文升，李志良．药物化学．北京：2002，12-15
[38] 陈凯先，罗小明，蒋华良．药物分子设计的发展．中国科学院院刊，2000，4(1)：268-269
[39] 安德烈，叶方国．具有潜在生物活性的含氮杂环化合物的合成研究．[硕士学位论文]，长沙：湖南大学，2001，4(1)：15-16
[40] Cavagnol J C, Wiselogle F Y. 1-Alkyl-1,2,3,4-tetrahydroquinoxalines. J. Am. Chem. Soc., 1947, 69(4): 795-799
[41] Hamer J, Holliday. On the Reduction of Quinoxaline Carngnaol. J. Org. Chem., 1963, 28(9): 2488
[42] Robert C B, Robert A, Osteryoun. Reduction of azanaphthalenes by sodium borohydride in trifluoroacetic acid. J. Org. Chem., 1979, 44(10): 1719-1720
[43] Ramage G R, Trappe G. Tetrahydroquinoxalines, a new route from O-amino-N-2-hydroxyethyl-anilines. J. Chem. Soc., 1952, 4406
[44] Clarke P, Moorhouse K. The synthesis of some 6-substituted 1,2,3,4-tetrahydro-quinoxdines. J. Chem. Soc., 1963, 4763
[45] Chester B K. Alkanolamines, Ⅵ, Physiologically Active Compound, Ⅰ, The Preparation of Subtituted Anilino Alcohols. J. Am. Chem. Soc., 1939, 61(6): 1321-1324
[46] Albert L. Synthesis and Chemical Transformations of 1,5-Benzothiazepones. J. Heterocycl. Chem., 2000, 3(7): 199-213
[47] Sarges R, LygaJ W. Prepartion of 4-(arylsulfonyl)quinoxalin-2-one-1-alkylcarboxylates gor treatment of complications of diabetes. J. Heterocycl. Chem., 1988, 25: 1475
[48] 陈芬儿．有机药物合成法．1999，北京：102-107
[49] 陈芬儿．有机药物合成法．1999，北京：831-833
[50] 罗铁军，欧晓明．哒嗪酮的乙酰胺类化合物的合成及生物活性．中国化工学会农药专业委员会第九届年会论文集，上海：1998，90-98
[51] 安德烈，彭志鸿．引入苯并含氮杂环的嘧啶及咪唑类衍生物的合成．[硕士学位论文]，长沙：湖南大学，2002，4(1)：45-46
[52] 袁开基，夏鹏．有机杂环化学．第一版，北京：1984，117-127
[53] 陈芬儿．有机药物合成法．第一卷，北京：1999，69-77
[54] 傅德才，楼杨通，李忠民．头孢地嗪钠中间体2-巯基-4-甲基-5-噻唑乙酸的合成．中国药物化学杂志，2000，12(2)：105-106
[55] 茹德新．2-氨基-5-甲基噻唑的合成及应用研究．化学反应工程与工艺，2002，18(1)：94-95
[56] 陈敏为，甘礼．有机含氮杂环化合物．第一版，北京：1990，56-57
[57] 陈芬儿．有机药物合成法．第一版，中国医药科技出版社：1999，85-91
[58] 杨日芳，恽榴红，丁振．邻二甲胺基苄氯衍生物与取代的2-巯基苯并咪唑反应规律探索．有机化学，1998，1(8)：437-441
[2] 柏再苏，王大翔．杂环、基因工程和二十一世纪的农药．中国化工学会农药专业委员会第九届年会论文集，上海：1998，1-8
[3] Acharya A N, Thai C, Ostresh J M, et al. Use of Vilsmeier Reagent for the Solid-Phase Synthesis of 1,5-Disubstituted 4,5-Dihydro-1H-imidazoles and Disubstituted 4,5-Dihydro-1H-imidazolylbenzimidazoles. J. Comb. Chem., 2002, 4:496-500
[4] Gilman A G, Goodman L S. In The Pharmacological Basis of Therapeutics. 10th ed, Macmillan & Co., New York: 2001
[5] Greenhill J V, Lue L. In Progress in Medicinal Chemistry. Ellis, G. P., Luscombe, D. K., Eds., Elsevier Science, New York: 1993, V30:22-32
[6] 李再峰，罗富英．含氮杂环及其衍生物的氮氧化方法研究进展．有机化学，2002，22(4)：233-238
[7] 陈立功，王东华，宋传君等．药物中间体合成工艺．北京：化学工业出版社，2001，98
[8] 杨松，宋宝安，李正名等．2(1H-咪唑-1-基)-1-(2，3，4-三甲氧基)苯乙酮肟酯新化合物合成与生物活性研究．有机化学，2002，22(5)：345-349
[9] 谢如观，苏晓谕，游劲松．咪唑环番仿生新体系研究进展．化学研究与应用，1999，11(5)：449-451
[10] 刘长令，刘晓南，李斌．新型咪唑并三嗪化合物的设计与合成．中国化工学会农药专业委员会第九届年会论文集，上海：1998，11-12
[11] Lermer L, Roupioz Y, Ting R, et al. Toward an RNaseA Mimic: A DNAzyme with Imidazoles and Cationic Amines. J. Am. Chem. Soc., 2002, 124:9960-9961
[12] 陈立功，王东华，宋传君等．药物中间体合成工艺．北京：化学工业出版社，2001，109
[13] Sarges R, Lyga J W. Preparation of 4-(arylsulfony) quinoxalin-2-one-l-alkyl-carboxylates for treatment of complications of diabetes. J. Heterocylcl. Chem., 1988, 25:1475
[14] Tenbrink R E, Im W B, Sethy V H, et al. Antagonist, partial agonist, and full agonist imidazo[1,5-a] quinoxaline amides and carbamates acting through the
GABA_A/benzodiazepine receptor. J. Med. Chem., 1994, 37:758
[15] Mickelson J W, Jacobsem E J, Carter D B, et al. Sysnthesis of an azasteroid using an acyl iminicion. J. Med. Chem., 1996, 39:4654
[16] 陈洪超，罗娟，曹红梅等．异烟噻的合成．Pesticides，2002，43(9)：10-11
[17] 黄琮耀，黄力军，朱正芳．3，4-二氢-2-喹喔啉酮尿类衍生物的合成及其生物活性的测定．中国化工学会农药专业委员会第九届年会论文集，上海：1998，22-23
[18] Holmes K, Richard C. Antifungal Agents. 10, Synthesis, Anti-Candida Activity, and Quantitative Structure-Analysis Relationship Studies. EP: 772154, 1973
[19] 任天，周家驹．三唑并嘧啶类化合物的合成和除草活性研究．中国化工学会农药专业委员会第九届年会论文集，上海：1998，34-35
[20] Wyvratl M J,Patchett A A. Preparation of Antitumor. Med. Res. Rev.,1985, 5(4):483
[21] 陈凯先，罗小明，蒋华良．计算机辅助药物设计．原理方法及应用．中国科学院院刊，2000，4：266
[22] 李志安，刘树彬，次立杰．2-叔丁基-4-氯-3-哒嗪酮硫代磷酸酯的合成及质谱研究．合成化学，1998，6(1)：95-99
[23] 林学圃，张一兵．杀菌剂嘧菌胺的开发．中国化工学会农药专业委员会第九届年会论文集，上海：1998，30-36
[24] 李正化．药物化学．北京：人民出版社，1993，99-102
[25] Bhaua M, Naithani D K, Bhalla N. Synthesis and Physiologically Active Compound Indian. Chem. Soc., 1992, 6(9): 594
[26] 曲凡歧，刘芳．植物病毒病化学防治剂的探寻．中国化工学会农药专业委员会第九届年会论文集，上海：1998，44-47
[27] Bihan G L, Rondu F, Pele-Tounian A, etal. Design and Synthesis of Imidazoline Derivatives Active on Glucose Homeostasis in a Rat Model of Type Ⅱ Diabetes. 2. Syntheses and Biological Activities of 1,4-Dialkyl-, 1,4-Dibenzyl, and 1-Benzyl-4-alkyl-2-(4,5-dihydro-1Himidazol-2-yl)piperazines and Isosteric Analogues of Imidazoline. J. Med. Chem. 1999, 42:1587-1603
[28] Tebbe M J, Spitzer W A, Victor F, etal. Antirhino/Enteroviral Vinylacetylene Benzimidazoles: A Study of Their Activity and Oral Plasma Levels in Mice. J. Med. Chem. 1997, 40:3937-3946
[29] 曹明章．植物抗病激活剂苯并噻二唑类．农药译丛，1998，20(5)：38-44
[30] 苏少泉．除草剂作用靶标与新品种创制．北京：化学工业出版社，2001，5-7
[31] 宫平，赵燕芳，冯润良．盐酸头孢吡肟的合成．中国药物化学杂志，2002，12(6)：
350-352
[32] 张致平．抗菌药物研究进展．中国抗生素杂志，2002，27(2)：67-79
[33] Hutchinson I, Jennings S A, Vishnuvajjala B R. Antitumor Benzothiazoles, 16, Synthesis and Pharmaceutical Properties of Antitumor 2-(4-Aminophenyl)-benzothiazole Amino Acid Prodrugs. J. Med. Chem., 2002, 4(5): 744-747
[34] 刘长令．浅谈国内外农药开发现状与发展趋势．新农药研究开发文集，北京：化学工业出版社，2002，45-47
[35] 徐基东．浅谈新农药创制策略．中国化工学会农药专业委员会第九届年会论文集，上海：1998，10-11
[36] 陈凯先，蒋华良，嵇汝运．计算机辅助药物设计-原理方法及应用．上海：2000，78-79
[37] 矶文升，李志良．药物化学．北京：2002，12-15
[38] 陈凯先，罗小明，蒋华良．药物分子设计的发展．中国科学院院刊，2000，4(1)：268-269
[39] 安德烈，叶方国．具有潜在生物活性的含氮杂环化合物的合成研究．[硕士学位论文]，长沙：湖南大学，2001，4(1)：15-16
[40] Cavagnol J C, Wiselogle F Y. 1-Alkyl-1,2,3,4-tetrahydroquinoxalines. J. Am. Chem. Soc., 1947, 69(4): 795-799
[41] Hamer J, Holliday. On the Reduction of Quinoxaline Carngnaol. J. Org. Chem., 1963, 28(9): 2488
[42] Robert C B, Robert A, Osteryoun. Reduction of azanaphthalenes by sodium borohydride in trifluoroacetic acid. J. Org. Chem., 1979, 44(10): 1719-1720
[43] Ramage G R, Trappe G. Tetrahydroquinoxalines, a new route from O-amino-N-2-hydroxyethyl-anilines. J. Chem. Soc., 1952, 4406
[44] Clarke P, Moorhouse K. The synthesis of some 6-substituted 1,2,3,4-tetrahydro-quinoxdines. J. Chem. Soc., 1963, 4763
[45] Chester B K. Alkanolamines, Ⅵ, Physiologically Active Compound, Ⅰ, The Preparation of Subtituted Anilino Alcohols. J. Am. Chem. Soc., 1939, 61(6): 1321-1324
[46] Albert L. Synthesis and Chemical Transformations of 1,5-Benzothiazepones. J. Heterocycl. Chem., 2000, 3(7): 199-213
[47] Sarges R, LygaJ W. Prepartion of 4-(arylsulfonyl)quinoxalin-2-one-1-alkylcarboxylates gor treatment of complications of diabetes. J. Heterocycl. Chem., 1988, 25: 1475
[48] 陈芬儿．有机药物合成法．1999，北京：102-107
[49] 陈芬儿．有机药物合成法．1999，北京：831-833
[50] 罗铁军，欧晓明．哒嗪酮的乙酰胺类化合物的合成及生物活性．中国化工学会农药专业委员会第九届年会论文集，上海：1998，90-98
[51] 安德烈，彭志鸿．引入苯并含氮杂环的嘧啶及咪唑类衍生物的合成．[硕士学位论文]，长沙：湖南大学，2002，4(1)：45-46
[52] 袁开基，夏鹏．有机杂环化学．第一版，北京：1984，117-127
[53] 陈芬儿．有机药物合成法．第一卷，北京：1999，69-77
[54] 傅德才，楼杨通，李忠民．头孢地嗪钠中间体2-巯基-4-甲基-5-噻唑乙酸的合成．中国药物化学杂志，2000，12(2)：105-106
[55] 茹德新．2-氨基-5-甲基噻唑的合成及应用研究．化学反应工程与工艺，2002，18(1)：94-95
[56] 陈敏为，甘礼．有机含氮杂环化合物．第一版，北京：1990，56-57
[57] 陈芬儿．有机药物合成法．第一版，中国医药科技出版社：1999，85-91
[58] 杨日芳，恽榴红，丁振．邻二甲胺基苄氯衍生物与取代的2-巯基苯并咪唑反应规律探索．有机化学，1998，1(8)：437-441