含噁二唑杂环取代的新型三唑并嘧啶衍生物的合成及其生物活性

2-肼羰基亚甲硫基-5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶与二硫化碳在乙醇溶液中回流制得化合物2-(5-巯基-1,3,4-噁二唑-2-亚甲硫基)-5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶, 后者在碱性环境中与卤化苄反应得到17种新型双杂环化合物. 对所得化合物结构均经元素分析, ¹H NMR和MS确认. 初步生物活性测试表明这些化合物具有一定的杀菌活性.     

5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶-2-甲酰腙类化合物的合成与生物活性

以5-氨基-1H-1,2,4-三唑-3-羧酸为起始原料, 设计合成了13个新型的5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶-2-甲酰腙类化合物, 通过¹H NMR, MS和元素分析对所合成的化合物进行了结构表征. 初步的生物活性测试结果表明, 所合成的化合物均表现出不同程度的除草及杀菌活性, 其中化合物4b, 4h和5m的活性较好, 在50 mg/L浓度下对水稻纹枯病菌的抑制率达90 %以上.     

新型1,2,4-三唑[3,4-b]-1,3,4-噻二嗪的合成及表征

以3-(2-苯基-1,2,3-三唑-4-基)-4-氨基-5-巯基-1,2,4-三唑(1)为原料分别与ω-溴代芳基乙酮、ω-溴代-ω-(1H-1,2,4-三 唑-1-基)芳基乙酮反应, 合成了一系列新的1,2,4-三唑[3,4-b]-1,3,4-噻二嗪类化合物2a～2e和3a～3e. 其结构经IR, ¹H NMR和MS及元素分析确证.     

2-甲硫基-7(5)-取代-3-吡唑并[1,5-a]嘧啶甲酸乙酯的区域选择性合成与2D NMR 研究

利用3-甲硫基-4-乙氧羰基-5-氨基-1H-吡唑分别与甲基/芳基烯胺酮反应, 合成了8种新的化合物2-甲硫基-7-取代-3-吡唑并[1,5-a]嘧啶甲酸乙酯(3a～3g)和2-甲硫基-5-甲基-3-吡唑并[1,5-a]嘧啶甲酸乙酯(4a). 化合物的结构均经元素分析, IR, ¹H NMR, MS所证实, 异构体3a和4a的结构进一步由¹³C NMR, HMQC和HMBC确认. 同时, 探讨了区域选择性合成吡唑并[1,5-a]嘧啶类化合物可能的反应机理, 并对部分化合物杀菌活性进行了测试.     

含三唑基的新型咪唑[2,1-b]-1,3,4-噻二唑的合成及表征

以2-(2-苯基-1,2,3-三唑-4-基)-5-氨基-1,3,4-噻二唑(1)为原料分别与ω-溴代芳基乙酮、ω-溴代-ω-(1H-1,2,4-三唑-1-基)芳基乙酮反应, 合成了一系列新型咪唑[2,1-b]-1,3,4-噻二唑类化合物2a～2e和3a～3e. 其结构经IR, ¹H NMR和MS及元素分析确证.     

3-(4-氯苯基)-6-取代苯氧乙酰氨基均三唑并[3,4-b]-1,3,4-噻二唑类化合物的合成

将取代苯氧乙酰氨基引入到3,6-二取代均三唑并噻二唑的分子骨架中, 设计合成了8个未见文献报道的3-(4-氯苯基)-6-取代苯氧乙酰氨基均三唑并[3,4-b]-1,3,4-噻二唑类化合物5a～5h, 结构经元素分析、IR和¹H NMR等测试得到确证.     

新型3-取代-6-(4-氯苯基)-7-(1H-1,2,4-三唑-1-基)-1',2',4'-三唑[3,4-b]-1",3",4"-噻二嗪衍生物的合成及抗菌活性

通过3-取代-4-氨基-5-巯基-1,2,4-三唑(3a～3m)和2-溴-2-(1H–1,2,4-三唑-1-基)-4′-氯代苯乙酮(2)的缩合反应, 合成了13个新型3-取代-6-(4-氯苯基)-7-(1H-1,2,4-三唑-1-基)-1',2',4'-三唑[3,4-b]-1",3",4"-噻二嗪衍生物4a～4m. 化合物结构经元素分析, ¹H NMR, IR和MS进行了表征. 抗菌试验表明所合成的化合物对细菌表现出中等程度的抑制活性.     

微波辐射下合成5-(2-甲基/三氟甲基-苯并咪唑-1-亚甲基)-3-(苯基/p-取代苯基)-2H-1',2',4'-三唑[3,4-b]-1

分别采用微波辐射法和加热回流的常规方法, 将1-氨基-2-(2-甲基/三氟甲基-苯并咪唑-1-亚甲基)-5-巯基-1,3,4-三唑与α-溴代芳基乙酮3a～3e反应, 合成了一系列未见文献报道的1,2,4-三唑[3,4-b]-1',3',4'-噻二嗪类化合物4a～4e 和5a～5e. 微波辐射法具有反应时间短、产率高、副反应少等优点. 标题化合物经元素分析, IR, ¹H NMR, MS确证结构.     

7-取代苯氧基-4,5-二氢-1,2,4-三唑并[4,3-a]喹啉和喹啉-1(2H)-酮衍生物的合成及抗惊厥活性

合成了7-取代苯氧基-4,5-二氢-1,2,4-三唑并[4,3-a]喹啉(3a～3g)和7-取代苯氧基-4,5-二氢-1,2,4-三唑并[4,3-a]喹表明啉-1(2H)-酮(4a～4g)类衍生物. 以最大电惊厥法和戊四唑法测定了抗惊厥活性, 以旋转棒法测定了神经毒性. 结果表明, 化合物7-(4-氟苯氧基)-4,5-二氢-1,2,4-三唑并[4,3-a]喹啉-1(2H)-酮(4c)显示最强的抗惊厥作用和低的神经毒性, 其抗电惊厥ED₅₀为6.8 mg/kg, 神经毒性TD₅₀为88.0 mg/kg, 保护指数PI为12.9, 明显优于对照药苯妥英钠.     

2-取代氨基-6-甲基-5-氧代-4-正丁基-4,5-二氢-1,2,4-三氮唑并[1,5-a]嘧啶类衍生物的合成

以2-溴丙酸甲酯、α,α-二氯甲基甲醚和胍唑为原料, 经缩合以及环化反应制得2-氨基-6-甲基-5-氧代-4,5-二氢-1,2,4-三氮唑并[1,5-a]嘧啶. 为了提高其在有机溶剂中的溶解性, 该化合物再同1-溴丁烷发生亲核取代反应得到了2-氨基-6-甲基-5-氧代-4-正丁基-4,5-二氢-1,2,4-三氮唑并[1,5-a]嘧啶, 然后与芳基醛和叔丁基异氰发生Ugi多组分反应, 合成了一系列具有潜在催吐活性的2-取代氨基-6-甲基-5-氧代-4-正丁基-4,5-二氢-1,2,4-三氮唑并[1,5-a]嘧啶类衍生物, 产品结构经质谱、核磁共振谱及元素分析确认.     

Synthesis of Some 1,3-Thiazole, 1,3,4-Thiadiazole, Pyrazolo[5,1-c]-1,2,4-triazine, and 1,2,4-Triazolo[5,1-c]-1,2,4-triazine Derivatives Based on the Thiazolo[3,2-a]benzimidazole Moiety

Summary. 3-(3-Methylthiazolo[3,2-a]benzimidazol-2-yl)-3-oxopropionitrile was synthesized by refluxing ethyl 3-methylthiazolo[3,2-a]benzimidazole-2-carboxylate, acetonitrile, and sodium hydride. Treatment of 3-(3-methylthiazolo[3,2-a]benzimidazol-2-yl)-3-oxopropionitrile with phenyl isothiocyanate, in the presence of KOH, furnished the corresponding potassium salt which was converted into thioacetanilide derivative upon neutralization. The thioacetanilide derivative reacts with α-chloroacetylacetone and ethyl α-chloroacetoacetate to give the 1,3-thiazole derivatives, while the reaction of the'thioacetanilide derivative with hydrazonyl chlorides gave 1,3,4-thiadiazole derivatives. On the other hand, 3-(3-methylthiazolo[3,2-a]benzimidazol-2-yl)-3-oxopropionitrile reacted with the diazonium salt of both 3-phenyl-5-amino-(1H)-pyrazole and 5-amino-l,2,4-(1H)-triazole to afford the corresponding hydrazones. The latter hydrazones underwent an intramolecular cyclization upon boiling in pyridine to give pyrazolo[5,1-c]-1,2,4-triazine and 1,2,4-triazolo[5,1-c]-1,2,4-triazine derivatives. Moreover, the behavior of thiazolo[3,2-a]benzimidazol-3(2H)-one towards phenyl isothiocyanate followed by the reaction with α-chloroketones or hydrazonyl chlorides was investigated. Some of the latter compounds exhibited moderate effects against some bacterial and fungal species.     

On Triazoles. XIII. The reaction of 5-benzalimino-1,2,4-triazoles with substituted acetyl chlorides

The reaction of Schiff bases prepared from 1- and 2-substituted-5-amino-1,2,4-triazoles with phenoxyacetyl chlorides in the presence of triethylamine and a mixture of phosphorus oxychloride and dichloroacetic acid in dimethylformamide to yield β-lactam 4 , a dihydro-1,2,4-triazolo[4,3-a]pyrimidine-5(1H)-one 5, a 1,2,4-triazolo[1,5-a]pyrimidin-5(3H)-one 9 and the corresponding 1,2,4-triazolo[4,3-a]pyrimidine-5(1H)-one 10 derivatives was studied.     

Synthesis of 1,2,4-Triazol-3-ylmethyl-, 1,3,4-Oxa-, and -Thiadiazol-2-ylmethyl-1<Emphasis Type="Italic">H</Emphasis>-[1,2,3]-triazolo[4,5-<Emphasis Type="Italic">d</Emphasis>]pyrimidinediones

Summary. 1-Carbethoxymethyl-4,6-dimethyl-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione was synthesized and treated with hydrazine hydrate to give the corresponding hydrazide. The latter hydrazide was treated either with phenylisothiocyanate or with carbon disulfide/alc. KOH to afford the corresponding thiosemicarbazide and oxadiazole derivatives. Alkylation of 2-mercapto-1,3,4-oxadiazole with dimethyl sulfate or ethyl chloroacetate gave the corresponding 2-methylthio-, and 2-ethylthioglycolate derivatives. Formation of 1,3,4-thiadiazole, 5-mercapto-1,2,4-triazole, and 1,3,4-oxadiazole were carried out by treating of the latter thiosemicarbazide with conc. H₂SO₄, NaOH/HCl, and HgO. Treating of 5-mercapto-1,2,4-triazole with ethyl chloroacetate afforded the thioglycolate ester. Hydrolysis of the latter with hydrazine hydrate afforded the hydrazide derivatives. Condensation of these hydrazides with monosaccharide aldoses gave the corresponding sugar hydrazones. The novel compounds were tested for antiviral activity against hepatitis B virus and showed moderate activities.     

5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶-2-氧乙酰腙类衍生物的合成与生物活性

以5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶-2-甲硫醚为起始原料, 设计合成了15个新型的5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶-2-氧乙酰腙及10个(R)-5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶-2-氧(α-甲基)乙酰腙类化合物, 通过元素分析、 MS和 1H NMR对所合成的化合物进行了结构表征. 初步生物活性测试结果表明, 部分化合物表现出不同程度的除草及杀菌活性. 目标化合物中引入手性中心有利于生物活性的提高.     

Synthesis of Some 1,3-Thiazole, 1,3,4-Thiadiazole, Pyrazolo[5,1-c]-1,2,4-triazine, and 1,2,4-Triazolo[5,1-c]-1,2,4-triazine Derivatives Based on the Thiazolo[3,2-a]benzimidazole Moiety

3-(3-Methylthiazolo[3,2-a]benzimidazol-2-yl)-3-oxopropionitrile was synthesized by refluxing ethyl 3-methylthiazolo[3,2-a]benzimidazole-2-carboxylate, acetonitrile, and sodium hydride. Treatment of 3-(3-methylthiazolo[3,2-a]benzimidazol-2-yl)-3-oxopropionitrile with phenyl isothiocyanate, in the presence of KOH, furnished the corresponding potassium salt which was converted into thioacetanilide derivative upon neutralization. The thioacetanilide derivative reacts with α-chloroacetylacetone and ethyl α-chloroacetoacetate to give the 1,3-thiazole derivatives, while the reaction of the'thioacetanilide derivative with hydrazonyl chlorides gave 1,3,4-thiadiazole derivatives. On the other hand, 3-(3-methylthiazolo[3,2-a]benzimidazol-2-yl)-3-oxopropionitrile reacted with the diazonium salt of both 3-phenyl-5-amino-(1H)-pyrazole and 5-amino-l,2,4-(1H)-triazole to afford the corresponding hydrazones. The latter hydrazones underwent an intramolecular cyclization upon boiling in pyridine to give pyrazolo[5,1-c]-1,2,4-triazine and 1,2,4-triazolo[5,1-c]-1,2,4-triazine derivatives. Moreover, the behavior of thiazolo[3,2-a]benzimidazol-3(2H)-one towards phenyl isothiocyanate followed by the reaction with α-chloroketones or hydrazonyl chlorides was investigated. Some of the latter compounds exhibited moderate effects against some bacterial and fungal species.     

The reaction of 2-amino-7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]-pyrimidine with carbon disulfide and alkylation of its products

In the reaction with carbon disulfide, 2-amino-7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine (1) forms the alkaline salts of substituted dithiocarbamic or iminodithiocarbonic acids depending on the molar ratio between1, CS₂, and the alkali. The alkylation of these salts leads to the esters ofN-(7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-2-yl)dithiocarbamic (2) and diesters of (7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-2-yl)iminodithiocarbonic acids (3). The synthesis of asymmetric diesters3 may be fulfilled based on monoesters2.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 14–14, August, 1994.     

1,3-双[3-芳基-1,2,4-三唑并[3,4-b]-1,3,4-噻二唑-6-基]丙烷类化合物的合成

戊二酸(1)与3-芳基-4-氨基-5-巯基-1,2,4-三唑(2a～2o)在相转移催化剂四丁基碘化铵和POCl₃作用下, 高收率合成了一系列新的1,2-双[3-芳基-1,2,4-三唑并[3,4-b]-1,3,4-噻二唑-6-基]丙烷(3a～3o). 其结构经IR, ¹H NMR, MS和元素分析确证.     

Synthesis and pharmacological evaluation of 3-diphenylmethyl-6-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles: A condensed bridgehead nitrogen heterocyclic system

A series of 3-diphenylmethyl-6-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives (4a–j and 5a–d) were synthesized by condensation of 4-amino-5-diphenylmethyl-4H-1,2,4-triazole-3-thiol with various substituted aromatic acids and aryl/alkyl-isothiocyanates. The structures of synthesized compounds were characterized by elemental analysis, IR, ¹H NMR, ¹³C NMR and mass spectroscopic studies. These compounds were tested in vivo for their anti-inflammatory activity. The compounds which showed activity comparable to the standard drug ibuprofen were screened for their analgesic, ulcerogenic, lipid peroxidation and hepatotoxic effects. Compounds 6-(4-chlorophenyl)-3-diphenylmethyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (4a) and 6-(2,4-dichlorophenyl)-3-diphenylmethyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole(4c) emerged as the most active compounds of the series and were moderately more potent than the standard drug ibuprofen.     

Temperature-dependent reaction of 1,4,6-triaminopyrimidine-2(1H)-thiones with vilsmeier reagent. formation of [1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones

5,7-Diamino[1,3,4]thiadiazolo[3,2-a]pyrirnidinium chloride 2 , 7-amino[1,2,4]triazolo[1,5-c]pyrimidine-5(6H)-thiones 3 and the 5(6H)-one derivative 4a were synthesized by the reaction of 1,4,6-triaminopyrimidine-2(1H)-thione 1 with phosphoryl chloride and N,N-dimethylacylamides. Further, compounds 4 were prepared from 2, 3 or 1,4,6-triaminopyrimidin-2(1H)-one 6 by the treatment with the above reagents. Compounds 3 and 4 were converted to 7-amino[1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones 5 .