Synthesis of some substituted triazolo[4,3-b][1,2,4]triazines as potential anticancer agents

The synthesis of some 3-substituted amino-6,7-diphenyl-1,2,4-triazolo[4,3-b][1,2,4]triazines (15) by cyclodesulfurisation of the corresponding N-(5,6-diphenyl-1,2,4-triazin-3-yl)-N-[substituted thio (carbamoyl)]hydrazines (3) using dicyclohexylcarbodiimid (DCC) and mercuric chloride is described. Moreover, trials to prepare 3-substituted amino-7-hydroxy-6-methyl-1,2,4-triazolo[4,3-b][1,2,4]triazines were not successful.

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Synthese einiger substituierter Triazolo[4,3-b][1,2,4]-triazine als potentielle Antikrebswirkstoffe

Zusammenfassung Es wird die Synthese einiger 3-substituierter Amino-6,7-diphenyl-1,2,4-triazolo[4,3-b][1,2,4]-triazine (15) mittels Cyclodesulfurisierung der entsprechenden N-(5,6-Diphenyl-1,2,4-triazin-3-yl)-N-[subst.thio(carbamoyl)]-hydrazine (3) unter Verwendung von Dicyclohexylcarbodiimid (DDQ) beschrieben. Versuche zur Herstellung von 3-substituierten Amino-7-hydroxy-6-methyl-triazolo[4,3-b][1,2,4]-triazinen schlugen fehl.

     

SNH-Reactions of triazolo[4,3-b]- and tetrazolo[1,5-b]-1,2,4-triazines with methylene-active carbonyl compounds

Unsubstituted triazolo[4,3-b]- and tetrazolo[1,5-b]-1,2,4-triazines react with carbanions generated from dimedone and barbituric acid to give adducts of a C-nucleophile with the heterocyclic system through the C=N double bond. The adducts can be oxidized under mild conditions into products of nucleophilic hydrogen substitution. Analogous adducts with carbanions produced in the reactions of ethyl cyanoacetate and ethyl malonate with Bu^tOK proved to be unstable; in this case, the title azolotriazines immediately yield products of nucleophilic hydrogen substitution in position 7. Tautomerism of the S _N ^H products obtained is discussed.     

4,5二氢[1,2,4]三氮唑并[4-3-a]喹林衍生物的合成

为了寻找正性肌力作用更强、副作用较小的治疗充血性心力衰竭的正性肌力药物 ,本文参照有关二氢喹啉酮类化合物的结构与正性肌力活性的文献报道[1- 5] ,在喹啉环上并入三氮唑 ,设计合成了 4,5二氢 [1 ,2 ,4]三氮唑并 [4 3 ａ]喹啉衍生物 ,以进一步探索二氢喹啉酮并入三唑环对其活性的影响。其结构经质谱、红外光谱和核磁共振氢谱表征。1　合成路线以苯胺为起始原料 ,经酰化、环合、硝化、还原、硫代、环合得 6 氨基 4,5二氢 [1 ,2 ,4]三氮唑并 [4 3 ａ]喹啉衍生物 :2　实验部分熔点用毛细管法测定 ,温度计未校正。红外光谱仪为ＦＴ ＩＲ1 …     

Synthesis of [1,2,4]triazolo[4,3-alpha]piperazines via highly reactive chloromethyloxadiazoles

[reaction: see text] A concise, modular approach for the synthesis of [1,2,4]triazolo[4,3-alpha]piperazines via condensation of highly reactive chloromethyloxadiazoles with ethylenediamines is described. NMR studies of this reaction provide evidence that suggests a novel activation mechanism for electron-deficient chloromethyloxadiazoles.     

Synthesis and tuberculostatic activity of new 3-alkylthio-6-R-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazines

Russian Chemical Bulletin - A number of new 3-alkylthio-6-(3,5-dimethylpyrazol-1-yl)[1,2,4]triazolo[4,3-b][1,2,4,5]-tetrazines were synthesized and modified in nucleophilic substitution reactions...     

Synthesis of arylamino-substituted pyrazolo[3,4-d][1,2,4]triazolo[4,3-a]pyrimidinones,pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidinones,and their thermal isomerization

The reaction of 1-(4-oxo-1-R-5H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-arylthiosemicarbazides with methyl iodide gave rise to 1,2,4-triazolo-pyrazolopyrimidinones of linear structure, and with dicyclohexylcarbodiimide the products had angular and linear structure. The heating of compounds obtained higher than their melting point resulted in their isomerization into 7-aryl-amino-1-R-1,8-dihydro-4H-pyrazolo[3,4-d]-[1,2,4]triazolo[1,5-a]pyrimidin-4-ones.     

Facile synthesis of some novel triazolo[3,4-b]thiadiazines and triazolo[4,3-b]tetrazines

4-Amino-5-ethyl-4H-1,2,4-triazole-3-thiol was used as a key intermediate for the synthesis of triazolo[3,4-b][1,3,4]thiadiazines, triazolo[4,3-b][1,2,4,5]tetrazines and Schiff’s base via reactions with various hydrazonoyl halides and salicyaldehyde, respectively. Moreover triazolyl-N-N′-triazole derivatives were prepared from reaction of Schiff’s base with various hydrazonoyl halides. The structures of all the newly synthesized heterocyclic compounds were established by considering elemental analysis and spectral data.     

Synthesis of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines

Starting from 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-ones, a synthesis pathway to the tricyclic pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines is described. Reaction of 1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-ones with phosphoryl chloride afforded the corresponding 4-chloro-1H-pyrazolo[3,4-d]pyrimidines. Treatment of these compounds with hydrazine hydrate at reflux temperature gave the hydrazino derivatives, which were subsequently cyclized to the titled compounds on heating with orthoesters in ethanol.     

An Improved Synthesis of 3-Substituted 1,2,4-Triazolo[4,3-a]pyridines and 1,2,4-Triazolo[4,3-b]pyridazines

The preliminary results of a simple and versatile one-pot procedure for the preparation of 3-substituted 1,2,4-triazolo[4,3-a] pyridines and 1,2,4-triazolo[4,3-b]pyridazines are described. Intramolecular cyclization of nitrile imine ylides are carried out by treatment of 2-pyridyl- and 3-pyridazinylhydrazones with chloramine T.     

5-取代-1,2,4-三唑并[4,3-a]喹唑啉衍生物的合成及抗惊厥活性

合成了5-取代-1,2,4-三唑并[4,3-a]喹唑啉衍生物2a～2q.利用最大电惊厥法(MES)和旋转棒法(Rotarod Test),以小鼠腹腔给药,分别测定了其抗惊厥活性和神经毒性.药理实验结果表明,化合物5-正庚氧基-1,2,4-三唑并[4,3 -a]喹唑啉(2d)的抗惊厥活性最强,其半数有效量EDso为19.7 mg/kg,保护指数PI为6.2.由化学物质诱发的抗惊厥实验结果表明,化合物2d能对抗由戊四唑、异烟肼、硫代氨基脲和3-巯基丙酸诱发的惊厥作用,推测其抗惊厥作用是通过增强γ-aminobutyric acid (GABA)神经能系统和活化谷氨酸脱羧酶或抑制GABA转氨酶而起抗惊厥作用.     

Synthesis and chemical transformations of partially hydrogenated [1,2,4]triazolo[5,1-b]quinazolines

The reaction of 5-methyl-7-phenyl-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine with α,β-unsaturated carbonyl compounds in MeOH in the presence of MeONa affords partially hydrogenated aryl-substituted [1,2,4]triazolo[5,1-b]quinazolines. Hydrolysis, oxidation, reduction, and alkylation of 5,6,8-triphenyl-5,6,7,10-tetrahydro[1,2,4]triazolo[5,1-b]quinazoline were studied. The structure of one oxidation product, viz., 7-hydroxy-5,6,8-triphenyl-6,7-dihydro[1,2,4]triazolo[5,1-b]quinazoline, was established by X-ray diffraction. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 335—340, February, 2006.     

Synthesis and in vitro cytotoxicity studies of novel triazolo[4,3-b]pyridazinones

New triazolo[4,3-b]pyridazinones were synthesized and evaluated for their potential in vitro cytotoxic antitumor properties. The compounds were prepared by 1,3-dipolar cycloaddition of pyridazin-3-ones with N-aryl-C-ethoxycarbonylnitrile imines, generated in situ from ethylhydrazono-á-bromoglyoxylates. The peri- and regioselectivity of the reaction were ascertained by ¹H and ¹³C NMR spectroscopy of the cycloadducts.     

New thieno[2,3-b]pyridine-fused [1,2,4]triazolo[4,3-a]pyrimidinone hybrids as potential MRSA and VRE inhibitors

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Synthesis of new 1,2,4-triazolo[4,3-b]pyridazines and related compounds

The synthesis of novel 6-[4-(1H-imidazol-1-yl)phenyl]-1,2,4-triazolo[4,3-b]pyridazines 8a-f and related compounds is described. Although the intermediate hydrazine derivatives 7 and 9 possess good positive inotropic activity, the fused bicyclic pyridazines 8a-f are significantly less potent than the 3(2H)-pyridazinone 5. Compounds 8a-f are potent but nonselective inhibitors of cardiac phosphodiesterase.     

MAOS ls for the general synthesis and lead optimization of 3,6-disubstituted-[1,2,4]triazolo[4,3-b]pyridazines

General, high-yielding MAOS protocols for the expedient synthesis of functionalized 3,6-disubstituted-[1,2,4]triazolo[4,3-b]pyridazines are described amenable to an iterative analog library synthesis strategy for the lead optimization of an M1 antagonist screening hit. Optimized compounds proved to be highly selective M1 antagonists.     

Synthesis of Substituted 5,6-Dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepines

A one-pot synthetic approach to the novel 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepines by thermal cyclization of 4-acylhydrazino-2,3-dihydro-1H-1,5-benzodiazepines is described.     

Synthesis and opening of the thiadiazine ring in 6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines

A reaction of 3-benzylthiotriazole-4-amines with aromatic aldehydes leads to the formation of 6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines. A dihydrothiadiazine ring opening along the N-N bond occurs by the action of strong bases. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1249–1252, June, 2008.     

Synthesis and rearrangements of 7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]-and 7h-pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidines

7H-Pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines were synthesized by the reactions of 2-ethoxymethyleneamino-1H-pyrrole-3-carbonitriles with acid hydrazides and by the reactions of aminoiminopyrimidines (prepared based on the above-mentioned carbonitriles) with acid chlorides. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1438–1443, August, 2006.     

新型[1,2,4]三唑[4,3-b]均四嗪类化合物的合成及其抗癌活性

以6-(3,5-二甲基吡唑-1-基)-3-肼基均四嗪和芳醛为原料,经Schiff碱缩合和环合反应合成了6个新型的6-芳基-3-(3,5-二甲基吡唑-1-基)[1,2,4]三唑[4,3-b]均四嗪类化合物(4a～4f),其结构经1HNMR,MS,IR和元素分析表征。以顺铂为对照,采用MTT法测试了体外4a～4f对人白血病细胞株,人肺癌,人乳腺癌和人子宫颈癌细胞株的抗癌活性。结果表明,4a～4f对四种癌细胞均具有较强的抑制活性。