引入苯并含氮杂环的嘧啶及咪唑类衍生物的合成
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摘要
在医药和农药的研究和开发中，含氮杂环化合物发挥着重要作用，是当今药物研究的一大热点。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-苯并噁嗪和2，3-二氢苯并噁唑的研究相对较少。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，具有生物活性。
嘧啶类及咪唑类化合物广泛存在于自然界、结构简单，在药物开发和研究中占有非常突出的地位，对其研究也非常活跃。许多临床药物都含有嘧啶及咪唑。同时含有嘧啶或咪唑的新研制的众多化合物也具有生物活性。因而可以确信嘧啶或咪唑是具有生物活性的。
定量构效关系研究在预测化合物的生物活性、帮助了解药物的作用机制方面有一定的作用，能够指导目标分子设计。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。
为了进行目标分子的合成研究，首先研究了苯并杂环化合物的合成。通过对它们不同的合成方法的比较，结合本研究室以前的研究，优化和完善了这四种苯并杂环化合物的合成方法，可以用价廉易得的原料简单直接地制备它们。同时利用其具有的仲胺性质，成功地制备了几个相关衍生物。
设计并合成了四个N-氯乙酰和N，N’-二氯乙酰取代的苯并含氮杂环中间体。它们分别与2-巯基-4，6-二甲基嘧啶反应被导入嘧啶结构中，与2-巯基苯并咪唑反应被导入咪唑结构中。新化合物的结构经MS高分辨NMR和元素分析得到确证。
In the research and exploitation of medicine and pestcide, hetrocyclic compounds containing nitrogen play an important role. It is a focus of the research of novel Pharmaceuticals. But there are a little research on nitrogen-containing benzoheterocyclic compounds: 3,4-dihydro-2(1H) quinoxalinone, 1,2,3,4-tetrahydro-quino-xaline, 2,3-dihydro-l,4-benzo- xazine, and 2,3-dihydrobenzoxazole. In fact, they play an important role in many Pharmaceuticals, perhaps are their bioactivity's center. Therefore they maybe have potential bioactiviry.
The pyrimidines or the imidazolines, whose structures are simple, exist in nature wildly. They are vital role in the research and exploitation of Pharmaceuticals. The research on them is hot. Pyrimidine and imidazoline exist in a large number of medicines. Meantime, lots of new compounds containing pyrimidinecycle or Imidazolinecycle own potential bioactivity. So it is sure to say that They have bioactivity.
The research of quantitative structure-activity relationships(QSAR), which can predict compound's bioactivity, helps to know the pharmaceutical effect and design target molecular(TM). On the basis of free-wilson model, two kinds of target molecular owning potential bioactiviry are designed, as following:
In order to research the synthesis of target molecular, the synthesis of nitrogen-containing benzoheterocyclic compounds has been synthsized firstly. Compared with different synthetic methods and based on the preceding researches in our laboratory, the synthesis method of those nitrogen-containing benzoheterocyclic compounds was optimized. It is simple and direct to prepare from inexpensive and ease materials. Several derivates were prepared successfully on their properties of
secondary ammonia.
Four types of N-chloroacetyl and N, N'-dichloroacetyl substituted nitrogen-Containing intermediate compounds were successfully designed and synthesized. Their were treated with 2-mercapto-4,6-dimethy pyrimidine respectively, they were introduced into pyrimide structure. In same method, reated with 2-mercapto-benzoic-midazoles respectively, they were introduced into imidazoline structure. The structures of all new compounds were identified by MS, high resolution-NMR and elemental analysis.
嘧啶类及咪唑类化合物广泛存在于自然界、结构简单，在药物开发和研究中占有非常突出的地位，对其研究也非常活跃。许多临床药物都含有嘧啶及咪唑。同时含有嘧啶或咪唑的新研制的众多化合物也具有生物活性。因而可以确信嘧啶或咪唑是具有生物活性的。
定量构效关系研究在预测化合物的生物活性、帮助了解药物的作用机制方面有一定的作用，能够指导目标分子设计。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。
为了进行目标分子的合成研究，首先研究了苯并杂环化合物的合成。通过对它们不同的合成方法的比较，结合本研究室以前的研究，优化和完善了这四种苯并杂环化合物的合成方法，可以用价廉易得的原料简单直接地制备它们。同时利用其具有的仲胺性质，成功地制备了几个相关衍生物。
设计并合成了四个N-氯乙酰和N，N’-二氯乙酰取代的苯并含氮杂环中间体。它们分别与2-巯基-4，6-二甲基嘧啶反应被导入嘧啶结构中，与2-巯基苯并咪唑反应被导入咪唑结构中。新化合物的结构经MS高分辨NMR和元素分析得到确证。
In the research and exploitation of medicine and pestcide, hetrocyclic compounds containing nitrogen play an important role. It is a focus of the research of novel Pharmaceuticals. But there are a little research on nitrogen-containing benzoheterocyclic compounds: 3,4-dihydro-2(1H) quinoxalinone, 1,2,3,4-tetrahydro-quino-xaline, 2,3-dihydro-l,4-benzo- xazine, and 2,3-dihydrobenzoxazole. In fact, they play an important role in many Pharmaceuticals, perhaps are their bioactivity's center. Therefore they maybe have potential bioactiviry.
The pyrimidines or the imidazolines, whose structures are simple, exist in nature wildly. They are vital role in the research and exploitation of Pharmaceuticals. The research on them is hot. Pyrimidine and imidazoline exist in a large number of medicines. Meantime, lots of new compounds containing pyrimidinecycle or Imidazolinecycle own potential bioactivity. So it is sure to say that They have bioactivity.
The research of quantitative structure-activity relationships(QSAR), which can predict compound's bioactivity, helps to know the pharmaceutical effect and design target molecular(TM). On the basis of free-wilson model, two kinds of target molecular owning potential bioactiviry are designed, as following:
In order to research the synthesis of target molecular, the synthesis of nitrogen-containing benzoheterocyclic compounds has been synthsized firstly. Compared with different synthetic methods and based on the preceding researches in our laboratory, the synthesis method of those nitrogen-containing benzoheterocyclic compounds was optimized. It is simple and direct to prepare from inexpensive and ease materials. Several derivates were prepared successfully on their properties of
secondary ammonia.
Four types of N-chloroacetyl and N, N'-dichloroacetyl substituted nitrogen-Containing intermediate compounds were successfully designed and synthesized. Their were treated with 2-mercapto-4,6-dimethy pyrimidine respectively, they were introduced into pyrimide structure. In same method, reated with 2-mercapto-benzoic-midazoles respectively, they were introduced into imidazoline structure. The structures of all new compounds were identified by MS, high resolution-NMR and elemental analysis.
引文
[1] 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．上海出版社，1998．
[2] 谢如观，苏晓渝，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．
[3] 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．上海出版社，1998．
[4] 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．
[5] 杨南林．含氮杂环新农药的设计与研制．[硕士学位论文]．长沙：湖南大学，1999．
[6] 王大翔．杂环化合物在农药发展中的重要作用．农药．1995，34(1)：6-9．
[7] 安守忠，城田靖彦．含氮有机化合物的物性化学．科学出版社，1983．
[8] 李正化药物化学．人民出版社，1993．
[9] BocK.M,Riebenfekd.D.Clasen.B,Clin Ther.1994,16(4):653-654.
[10] 李正化．药物化学．人民出版社，1993．
[11] 孙仲实．优匹敌-新型α-受体佶抗剂．中国医学杂志，1991，26(5)：30-32．
[12] 万保坤，邢维绷，刘芳．新型α_1-肾上腺素受体阻滞剂．中国医学杂志，2000，31(9)：385-388．
[13] 施佩君．国外医药-合成药．生化药．制剂手册，1990，11(4)：237-238．
[14] 霍红武，周青青．具有生物活性有机磷化合物研究．中国化工学会农药专业委员会第九届年会论文集．上海出版社，1998．
[15] 尚尔才，刘长令，杜英娟．嘧啶类农药的研究进展．化工进展．1995，5：8-15．
[16] 柳爱平，邓金保．LGC-40863-一种光谱选择性芽后除草剂．农药译丛．1998，4：59-63．
[17] 亦冰．水杨酸嘧啶类除草剂-Pyriminobac-methyl．农药译丛．1998，6：63-65．
[18] 李琮成．近年来开发的农药新品种．农药．2001，40(2)：44-47．
[19] Maeno. S, Brighton. C, A synthesis of Mepaniprim J.org. chem. 1990, 5(3): 415-418.
[20] 林学圃．杀菌剂嘧菌胺的开发．农药译丛．1998，20(1)：30-36．
[21] Bhaua. M, Naithani. D. K, Bhalla. N, A Facile synthesis of pimethyl N-Aryldithio corbonimidates and z-Arylaminobenzimidazoles. Indian. Chem. Soc. 1992, 69: 594-598.
[22] 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．上海出版社，1998．
[23] 任天，周家驹．三唑并嘧啶类化合物的合成合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，上海出版社，1998．
[24] 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．上海出版社，1998．
[25] Sarges. R, Lyga. J. W, Prepartion of 4-(arylsulfonyl)quinoxalin-2-one-1-alkylcarboxylates for treatment of complications of diabetes. J. Heterocylcl. Chem., 1988, 25: 1475-1478.
[26] 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 brough the GABA_A/ benzodiazepine receptor, J. Med. Chem., 1994, 37: 758-761.
[27] Mickelson. J. W, Jacobsem. E. J, Carter. D. B, et al, Sysnthesis of an azasteroid using an acyl iminicion, J. Med. Chem., 1996, 39, 4654-4658.
[28] 黄琮耀，黄力军，朱正芳．3，4-二氢-2-喹喔啉酮脲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．上海出版社，1998．
[29] Holmes. K, Richard. C, EP: 772154(1973).
[30] 陈海涛．国外医学—医学分册．1990，117(3)，144-146．
[31] Desiraju. R. K, et al, Pharmacokinetics of chlozoxazone in humans. J. Pharm. Sci., 1983, 72, 9911-9914.
[32] Klintz. R, Goetz. N, Schaefer. D, Some Reactions of steroidal 1,2-Diazabicyclo[3.2.0] heptenone J.org.chem.. 1966,42-47.
[33] Kojima. K, Aoizawa. Y, Samacota N, et al, WO: 96--23789(1996).
[34] 陈凯先，罗小民，蒋华良．药物分子设计的发展．中国科学院院刊．2000，4：265-269．
[35] Hansch. C, A methed for the correlation of biological and chemical struacture, J. Am. Chem, Soc., 1964, 86(8): 1616-1626.
[36] Free. S. M, Wilson, A Mathematical contribution to structure-activity J. Med. Chem, 1964, 7(4): 395-398.
[37] Kier. L. B, Hall, Molecuiar connectivity and drugres, J. Med. Chem. 1944 6(3):420-424.
[38] 杨南林．含氮杂环新农药的设计与研制．[硕士学位论文]．长沙：湖南大学，1999．
[39] Carngnal. J. C, Wiselogle. E Y, 1-Alkyl-1,2,3,4-tetrahydroquinoxalines, J. Am. Chem. Soc., 1947, 69: 795-799.
[40] Haqmer. J, Holliday. R.E, On the Reduction of Quinpnxaline, J.Org. Chem, 1963, 28:2488-2491.
[41] Bugle.R.C,Osteryoung. R.A,Reduction of Azanaphtnalenes by solidium Borohydride in Trifluoroacetic Acid. J. Med. Chem. 1939 7(4): 390-395.
[42] Ramage. G. R, Trappe. G, Tetrahydroquinoxalines, A new route from O-amino-N-2 hydroxyethyl-anilines, J. Chem. Soc., 1952. 4406-4409.
[43] Clarke. P, Moorhouse.. K., The syntyesis of some 6-substituted 1,2,3,4-tetrahydro-quinoxdines, J. Chem. Soc., 1963, 4763-4767.
[44] Kremer, Physiologically active compounds. J. Am. Chem. Soc., 1939, 61: 1321-1324.
[2] 谢如观，苏晓渝，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．
[3] 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．上海出版社，1998．
[4] 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．
[5] 杨南林．含氮杂环新农药的设计与研制．[硕士学位论文]．长沙：湖南大学，1999．
[6] 王大翔．杂环化合物在农药发展中的重要作用．农药．1995，34(1)：6-9．
[7] 安守忠，城田靖彦．含氮有机化合物的物性化学．科学出版社，1983．
[8] 李正化药物化学．人民出版社，1993．
[9] BocK.M,Riebenfekd.D.Clasen.B,Clin Ther.1994,16(4):653-654.
[10] 李正化．药物化学．人民出版社，1993．
[11] 孙仲实．优匹敌-新型α-受体佶抗剂．中国医学杂志，1991，26(5)：30-32．
[12] 万保坤，邢维绷，刘芳．新型α_1-肾上腺素受体阻滞剂．中国医学杂志，2000，31(9)：385-388．
[13] 施佩君．国外医药-合成药．生化药．制剂手册，1990，11(4)：237-238．
[14] 霍红武，周青青．具有生物活性有机磷化合物研究．中国化工学会农药专业委员会第九届年会论文集．上海出版社，1998．
[15] 尚尔才，刘长令，杜英娟．嘧啶类农药的研究进展．化工进展．1995，5：8-15．
[16] 柳爱平，邓金保．LGC-40863-一种光谱选择性芽后除草剂．农药译丛．1998，4：59-63．
[17] 亦冰．水杨酸嘧啶类除草剂-Pyriminobac-methyl．农药译丛．1998，6：63-65．
[18] 李琮成．近年来开发的农药新品种．农药．2001，40(2)：44-47．
[19] Maeno. S, Brighton. C, A synthesis of Mepaniprim J.org. chem. 1990, 5(3): 415-418.
[20] 林学圃．杀菌剂嘧菌胺的开发．农药译丛．1998，20(1)：30-36．
[21] Bhaua. M, Naithani. D. K, Bhalla. N, A Facile synthesis of pimethyl N-Aryldithio corbonimidates and z-Arylaminobenzimidazoles. Indian. Chem. Soc. 1992, 69: 594-598.
[22] 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．上海出版社，1998．
[23] 任天，周家驹．三唑并嘧啶类化合物的合成合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，上海出版社，1998．
[24] 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．上海出版社，1998．
[25] Sarges. R, Lyga. J. W, Prepartion of 4-(arylsulfonyl)quinoxalin-2-one-1-alkylcarboxylates for treatment of complications of diabetes. J. Heterocylcl. Chem., 1988, 25: 1475-1478.
[26] 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 brough the GABA_A/ benzodiazepine receptor, J. Med. Chem., 1994, 37: 758-761.
[27] Mickelson. J. W, Jacobsem. E. J, Carter. D. B, et al, Sysnthesis of an azasteroid using an acyl iminicion, J. Med. Chem., 1996, 39, 4654-4658.
[28] 黄琮耀，黄力军，朱正芳．3，4-二氢-2-喹喔啉酮脲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．上海出版社，1998．
[29] Holmes. K, Richard. C, EP: 772154(1973).
[30] 陈海涛．国外医学—医学分册．1990，117(3)，144-146．
[31] Desiraju. R. K, et al, Pharmacokinetics of chlozoxazone in humans. J. Pharm. Sci., 1983, 72, 9911-9914.
[32] Klintz. R, Goetz. N, Schaefer. D, Some Reactions of steroidal 1,2-Diazabicyclo[3.2.0] heptenone J.org.chem.. 1966,42-47.
[33] Kojima. K, Aoizawa. Y, Samacota N, et al, WO: 96--23789(1996).
[34] 陈凯先，罗小民，蒋华良．药物分子设计的发展．中国科学院院刊．2000，4：265-269．
[35] Hansch. C, A methed for the correlation of biological and chemical struacture, J. Am. Chem, Soc., 1964, 86(8): 1616-1626.
[36] Free. S. M, Wilson, A Mathematical contribution to structure-activity J. Med. Chem, 1964, 7(4): 395-398.
[37] Kier. L. B, Hall, Molecuiar connectivity and drugres, J. Med. Chem. 1944 6(3):420-424.
[38] 杨南林．含氮杂环新农药的设计与研制．[硕士学位论文]．长沙：湖南大学，1999．
[39] Carngnal. J. C, Wiselogle. E Y, 1-Alkyl-1,2,3,4-tetrahydroquinoxalines, J. Am. Chem. Soc., 1947, 69: 795-799.
[40] Haqmer. J, Holliday. R.E, On the Reduction of Quinpnxaline, J.Org. Chem, 1963, 28:2488-2491.
[41] Bugle.R.C,Osteryoung. R.A,Reduction of Azanaphtnalenes by solidium Borohydride in Trifluoroacetic Acid. J. Med. Chem. 1939 7(4): 390-395.
[42] Ramage. G. R, Trappe. G, Tetrahydroquinoxalines, A new route from O-amino-N-2 hydroxyethyl-anilines, J. Chem. Soc., 1952. 4406-4409.
[43] Clarke. P, Moorhouse.. K., The syntyesis of some 6-substituted 1,2,3,4-tetrahydro-quinoxdines, J. Chem. Soc., 1963, 4763-4767.
[44] Kremer, Physiologically active compounds. J. Am. Chem. Soc., 1939, 61: 1321-1324.