3-芳基/芳氧甲基-6-芳基-1,2,4-三唑并[3,4-b]-1,3,4-噻二唑衍生物的合成及生物活性
作者：史海健 王忠义 史好新
单位：史海健 史好新 安徽师范大学化学系，芜湖 241000；王忠义 中国科技大学化学系，合肥 230026
关键词：3,6-二芳基-1,2,4-三唑并[3,4-b]-1,3,4-噻二唑；合成；生物活性
药学学报990217 SYNTHESIS AND BIOLOGICAL ACTIVITIES OF DERIVATIVES OF
3-ARYL/ARYLOXYMETHYL-6-ARYL-1,2,4-TRIAZOLO[3,4-B]-1,3,4-THIADIAZOLES
Shi Haijian (Shi HJ) and Shi Haoxin (Shi HX)
, 百拇医药 Department of Chemistry, Anhui Normal University, Wuhu 241000
Wang Zhongyi (Wang ZY)
Department of Chemistry, The University of Science and Technology of China, Hefei 230026
ABSTRACT AIM: To synthesize a number of novel heterocyclic compounds and screen for their biological activities. Sixteen title compounds were prepared. METHODS: These novel compounds were prepared by the reaction of 3-aryl/aryloxymethyl-4-amino-5-mercapto-1,2,4-triazoles with aryl carboxylic acids in the presence of phosphorus oxychloride. The structures of these compounds were confirmed by elemental analysis, IR, 1HNMR and MS. The reaction conditions for the synthesis had been investigated. All the compounds were screened for antimicrobial activity against bacteria S.aureus, E.coli and B.subilis. The concentration of the test compounds was 0.002%. The antibacterial activities of the test compounds were compared with those of penicillin and gentamicin. RESULTS: The results display that some of them possess strong biological activities.CONCLUSION: Syntheses of these novel heterocyclic compounds and study on their biological activities are very important and valuable in medicine.
, 百拇医药
KEY WORDS 3,6-diaryl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles; synthesis; biological activity
噻二唑类杂环化合物有广泛的生物活性，如消炎、驱虫、除草、调节植物生长、防止水稻白叶枯病、柑桔溃疡病、蕃茄青枯病等[1～3]。而1,2,4-三唑类杂环化合物也有相当广泛的生物活性,如抗菌、抗痉挛、消炎、抗血小板凝聚及调节植物生长等[4～6]。如果合成既含有1,2,4-三唑环，又含有1,3,4-噻二唑环的新型稠杂环化合物，同时改变取代基，有可能产生新的生物活性，这对于寻找新药和探索构效关系，有一定的意义。本文研究了3-芳基/芳氧甲基-4-氨基-5-巯基-1,2,4-三唑和羧酸在三氯氧磷作用下合成的16个新的化合物及其生物活性。并研究了反应温度对反应产率的影响。结果表明，有些化合物有较强的生物活性。所有化合物均经元素分析、红外光谱、核磁共振氢谱和质谱鉴定其结构。
, 百拇医药
实验部分
X4型显微熔点测定仪测定熔点，温度未校正；元素分析仪为PE-2400型；红外光谱用FTS-40型红外光谱仪(美国Bio-rad公司)测定,KBr压片；1HNMR用EM-360，60 MHz核磁共振仪测定，TMS为内标；MS用HP5989A型质谱仪测定。试剂一般为分析纯或化学纯。
1 3-芳基-4-氨基-5-巯基-1，2，4-三唑的合成
参考文献[7]合成。
2 3a～i的合成(图1)
Ar-: 3a～g: β-Py-; 3h～i: Ph-; 3j～p: PhOCH2-.
Ar′-: 3a,3h: 3,4-(CH3)2C6H3-; 3b: 3-CH3C6H4-;
, 百拇医药
3c: 3,4-(HO)2C6H3-; 3d: o-O2NC6H4-; 3e: m-O2NC6H4-;
3f: p-O2NC6H4-; 3g,3i,3m: 3-O2N-p-ClC6H3-;
3j: α-C10H7-; 3k: 3,4-(CH3O)2C6H3-; 3l: o-ClC6H4-;
, 百拇医药 3n: β-Py-; 3o: p-H2NC6H4-; 3p: Ph-CH=CH-.
Fig 1 Route of synthesis of compounds 3a～i.
将1(3 mmol)放入园底烧瓶中,再加入2(3.5 mmol)及POCl3 5 ml,在(95～98)℃搅拌反应(4～6) h。然后减压蒸去过量的POCl3，剩余物倒入50 ml冰水中，搅拌、静置、抽滤，用10%NaOH溶液洗涤反应产物，再用水洗至中性，干燥得粗产品，在乙醇中重结晶得纯品。3a，产率43%，mp 120～122℃; 3b，产率45%，mp 101～102.5℃; 3c，产率38%，mp 236～238℃; 3d，产率46%，mp 208～210℃; 3e，产率45%，mp 178～180℃; 3f，产率51%，mp 248～250℃; 3g，产率52%，mp 282～284℃; 3h，产率36%，mp 159～160℃; 3i，产率42.6%，mp 226～228℃。
, 百拇医药
3 1’的合成[8～10](图2)
Fig 2 Route of synthesis of compound 1'.
4 3j～p的合成
1’与羧酸的反应合成3j～p与前法相同。3j，产率85.20%，mp 139～141℃; 3k，产率90.6%，mp 171～171.5℃; 3l,产率83.5%，mp 88～90℃; 3m，产率77.5%，mp 87～89℃; 3n，产率35.1%，mp 103～105℃; 3o，产率34.4%，mp 190℃(dec.); 3p，产率49.9%，mp 141～143℃。
结果与讨论
元素分析的实验值与计算值虽有一定误差，但均在允许范围内；核磁共振氢谱与各化合物的结构相符合；质谱的分子离子峰均出现，有的为基峰，说明这类化合物较稳定。
, 百拇医药
生物活性 用平皿试验法，以青霉素、庆大霉素和链霉素为参比，药液浓度为0.002%，研究了这些化合物对金黄色葡萄球菌(G+)、大肠杆菌(G-)和枯草芽胞杆菌的抑菌作用。结果表明,3b和3g对3种菌都有较强的抑菌活性；3c,3h,3j,3k,3n和3o对金黄色葡萄球菌有较强的抑菌活性；3a对大肠杆菌有较强抑菌作用;3a,3h,3i,3k,3n,3o对枯草芽胞杆菌有较强抑菌作用。其余对3种菌的抑菌作用都较弱。
Tel:(0553)3869920(H)
基金项目：安徽省自然科学基金和安徽省教委科学基金资助项目
参考文献
1 Dahle Norman, A. 3-Benzyl-2-methylimine-5-phenyl-Δ4-1,3,4-thiadiazolines for combationg undesired plant growth, U.S. 4,104,053,1979(C.A.1979,90∶103962c)
, 百拇医药
2 Velsicol. Thiadiazolylimidazolinones. Chemical Corp., Austrian, 345,816,1979 (C.A. 1979,90∶121604s)
3 张自义，杨虎.酰氨基硫脲及其杂环衍生物研究II.1-[5-(α-萘)-2H-四唑-2-乙酰]-4-苯基硫脲及其相关杂环衍生物的合成.有机化学，1986，3∶184
4 Chaaban I, Oji OO. Synthesis and preliminary antibacterial activity of 3-(2-arylamino-1,3,4-thiadiazol-5-yl)-4-hydroxy-4′-substituted. J Indian Chem Soc, 1984,61∶523
5 Omar A, Mohsen ME, Aboulwata OM, et al. Synthesis and anticonvulsant properties of a novel series of 2-(substituted amino)-5-aryl-1,3,4-oxadiazole derivatives. J Heterocycl Chem, 1984,21∶1415
, 百拇医药
6 Clemence F, Joliveau C, Fouranx R. et al. 4H-1,2,4-Triazole derivatives and their use as medicines. C.A. 1985,102∶95677n
7 张自义，李明，赵岚，等.3-烷基/芳基-6-(3′-吡啶基均三唑并[3,4-b]-1,3,4-噻二唑类化合物的合成.有机化学，1993，13∶397
8 Wang ZY, Shi HJ, Shi HX, et al. The synthesis of aryloxy-carboxylic acid under microwave, solid base as a support. Chin Chem Letters, 1996,7∶527
9 史海健，王忠义，史好新.微波辐射下的芳基甲酰氨基硫脲的合成.有机化学,1996，16∶242
10 王忠义，史海健，史好新.微波炉加热法合成3-芳基-1,2,4-三唑啉-5-硫酮.有机化学，1997，17∶271
收稿日期：1998-02-05, http://www.100md.com
单位：史海健 史好新 安徽师范大学化学系，芜湖 241000；王忠义 中国科技大学化学系，合肥 230026
关键词：3,6-二芳基-1,2,4-三唑并[3,4-b]-1,3,4-噻二唑；合成；生物活性
药学学报990217 SYNTHESIS AND BIOLOGICAL ACTIVITIES OF DERIVATIVES OF
3-ARYL/ARYLOXYMETHYL-6-ARYL-1,2,4-TRIAZOLO[3,4-B]-1,3,4-THIADIAZOLES
Shi Haijian (Shi HJ) and Shi Haoxin (Shi HX)
, 百拇医药 Department of Chemistry, Anhui Normal University, Wuhu 241000
Wang Zhongyi (Wang ZY)
Department of Chemistry, The University of Science and Technology of China, Hefei 230026
ABSTRACT AIM: To synthesize a number of novel heterocyclic compounds and screen for their biological activities. Sixteen title compounds were prepared. METHODS: These novel compounds were prepared by the reaction of 3-aryl/aryloxymethyl-4-amino-5-mercapto-1,2,4-triazoles with aryl carboxylic acids in the presence of phosphorus oxychloride. The structures of these compounds were confirmed by elemental analysis, IR, 1HNMR and MS. The reaction conditions for the synthesis had been investigated. All the compounds were screened for antimicrobial activity against bacteria S.aureus, E.coli and B.subilis. The concentration of the test compounds was 0.002%. The antibacterial activities of the test compounds were compared with those of penicillin and gentamicin. RESULTS: The results display that some of them possess strong biological activities.CONCLUSION: Syntheses of these novel heterocyclic compounds and study on their biological activities are very important and valuable in medicine.
, 百拇医药
KEY WORDS 3,6-diaryl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles; synthesis; biological activity
噻二唑类杂环化合物有广泛的生物活性，如消炎、驱虫、除草、调节植物生长、防止水稻白叶枯病、柑桔溃疡病、蕃茄青枯病等[1～3]。而1,2,4-三唑类杂环化合物也有相当广泛的生物活性,如抗菌、抗痉挛、消炎、抗血小板凝聚及调节植物生长等[4～6]。如果合成既含有1,2,4-三唑环，又含有1,3,4-噻二唑环的新型稠杂环化合物，同时改变取代基，有可能产生新的生物活性，这对于寻找新药和探索构效关系，有一定的意义。本文研究了3-芳基/芳氧甲基-4-氨基-5-巯基-1,2,4-三唑和羧酸在三氯氧磷作用下合成的16个新的化合物及其生物活性。并研究了反应温度对反应产率的影响。结果表明，有些化合物有较强的生物活性。所有化合物均经元素分析、红外光谱、核磁共振氢谱和质谱鉴定其结构。
, 百拇医药
实验部分
X4型显微熔点测定仪测定熔点，温度未校正；元素分析仪为PE-2400型；红外光谱用FTS-40型红外光谱仪(美国Bio-rad公司)测定,KBr压片；1HNMR用EM-360，60 MHz核磁共振仪测定，TMS为内标；MS用HP5989A型质谱仪测定。试剂一般为分析纯或化学纯。
1 3-芳基-4-氨基-5-巯基-1，2，4-三唑的合成
参考文献[7]合成。
2 3a～i的合成(图1)
Ar-: 3a～g: β-Py-; 3h～i: Ph-; 3j～p: PhOCH2-.
Ar′-: 3a,3h: 3,4-(CH3)2C6H3-; 3b: 3-CH3C6H4-;
, 百拇医药
3c: 3,4-(HO)2C6H3-; 3d: o-O2NC6H4-; 3e: m-O2NC6H4-;
3f: p-O2NC6H4-; 3g,3i,3m: 3-O2N-p-ClC6H3-;
3j: α-C10H7-; 3k: 3,4-(CH3O)2C6H3-; 3l: o-ClC6H4-;
, 百拇医药 3n: β-Py-; 3o: p-H2NC6H4-; 3p: Ph-CH=CH-.
Fig 1 Route of synthesis of compounds 3a～i.
将1(3 mmol)放入园底烧瓶中,再加入2(3.5 mmol)及POCl3 5 ml,在(95～98)℃搅拌反应(4～6) h。然后减压蒸去过量的POCl3，剩余物倒入50 ml冰水中，搅拌、静置、抽滤，用10%NaOH溶液洗涤反应产物，再用水洗至中性，干燥得粗产品，在乙醇中重结晶得纯品。3a，产率43%，mp 120～122℃; 3b，产率45%，mp 101～102.5℃; 3c，产率38%，mp 236～238℃; 3d，产率46%，mp 208～210℃; 3e，产率45%，mp 178～180℃; 3f，产率51%，mp 248～250℃; 3g，产率52%，mp 282～284℃; 3h，产率36%，mp 159～160℃; 3i，产率42.6%，mp 226～228℃。
, 百拇医药
3 1’的合成[8～10](图2)
Fig 2 Route of synthesis of compound 1'.
4 3j～p的合成
1’与羧酸的反应合成3j～p与前法相同。3j，产率85.20%，mp 139～141℃; 3k，产率90.6%，mp 171～171.5℃; 3l,产率83.5%，mp 88～90℃; 3m，产率77.5%，mp 87～89℃; 3n，产率35.1%，mp 103～105℃; 3o，产率34.4%，mp 190℃(dec.); 3p，产率49.9%，mp 141～143℃。
结果与讨论
元素分析的实验值与计算值虽有一定误差，但均在允许范围内；核磁共振氢谱与各化合物的结构相符合；质谱的分子离子峰均出现，有的为基峰，说明这类化合物较稳定。
, 百拇医药
生物活性 用平皿试验法，以青霉素、庆大霉素和链霉素为参比，药液浓度为0.002%，研究了这些化合物对金黄色葡萄球菌(G+)、大肠杆菌(G-)和枯草芽胞杆菌的抑菌作用。结果表明,3b和3g对3种菌都有较强的抑菌活性；3c,3h,3j,3k,3n和3o对金黄色葡萄球菌有较强的抑菌活性；3a对大肠杆菌有较强抑菌作用;3a,3h,3i,3k,3n,3o对枯草芽胞杆菌有较强抑菌作用。其余对3种菌的抑菌作用都较弱。
Tel:(0553)3869920(H)
基金项目：安徽省自然科学基金和安徽省教委科学基金资助项目
参考文献
1 Dahle Norman, A. 3-Benzyl-2-methylimine-5-phenyl-Δ4-1,3,4-thiadiazolines for combationg undesired plant growth, U.S. 4,104,053,1979(C.A.1979,90∶103962c)
, 百拇医药
2 Velsicol. Thiadiazolylimidazolinones. Chemical Corp., Austrian, 345,816,1979 (C.A. 1979,90∶121604s)
3 张自义，杨虎.酰氨基硫脲及其杂环衍生物研究II.1-[5-(α-萘)-2H-四唑-2-乙酰]-4-苯基硫脲及其相关杂环衍生物的合成.有机化学，1986，3∶184
4 Chaaban I, Oji OO. Synthesis and preliminary antibacterial activity of 3-(2-arylamino-1,3,4-thiadiazol-5-yl)-4-hydroxy-4′-substituted. J Indian Chem Soc, 1984,61∶523
5 Omar A, Mohsen ME, Aboulwata OM, et al. Synthesis and anticonvulsant properties of a novel series of 2-(substituted amino)-5-aryl-1,3,4-oxadiazole derivatives. J Heterocycl Chem, 1984,21∶1415
, 百拇医药
6 Clemence F, Joliveau C, Fouranx R. et al. 4H-1,2,4-Triazole derivatives and their use as medicines. C.A. 1985,102∶95677n
7 张自义，李明，赵岚，等.3-烷基/芳基-6-(3′-吡啶基均三唑并[3,4-b]-1,3,4-噻二唑类化合物的合成.有机化学，1993，13∶397
8 Wang ZY, Shi HJ, Shi HX, et al. The synthesis of aryloxy-carboxylic acid under microwave, solid base as a support. Chin Chem Letters, 1996,7∶527
9 史海健，王忠义，史好新.微波辐射下的芳基甲酰氨基硫脲的合成.有机化学,1996，16∶242
10 王忠义，史海健，史好新.微波炉加热法合成3-芳基-1,2,4-三唑啉-5-硫酮.有机化学，1997，17∶271
收稿日期：1998-02-05, http://www.100md.com