A New Route to Substituted Pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones and Facile Extension to 5,7(6H,8H) Isomers

A new route to substituted pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones is outlined. The synthesis proceeds via pre-formed hydrazone intermediates, which are then condensed with an activated chlorouracil to build up the entire molecular framework, followed by a reductive ring closure to provide the parent series. The route has been extended to the isomeric pyrimido[5,4-e]-1,2,4-triazine-5,7(6H,8H)-dione class via the use of methylhydrazine as hydrazine surrogate, followed by regiospecific alkylation of the N(8)-H pyrimidotriazinediones with a range of alkyl and alkaryl substituents. This new methodology permits the generation of a wide range of compounds with variable substitution at the N(1), C(3), and N(8) positions for a heterocyclic scaffold with demonstrated pharmacological activity.     

Synthesis of 1,3-dialkylpyrazolo [1,5-a]-1,3,5-triazine-2,4-diones isomers of 1,3-dialkylxanthines

The synthesis of a new series of alkylxanthine analogs containing a bridgehead nitrogen atom is reported. 1,3-Dialkylpyrazolo[1,5-a]-1,3,5-triazine-2,4-diones, were prepared by the treatment of 3-methylpyrazolo[1,5-a]-1,3,5-triazine-2,4-dione (3) with the corresponding alkyl iodide. Similarly, the reaction of 3-methyl-7-phenylpyrazolo[1,5-a]-1,3,5-dialkyl-7-phenylpyrazolo[1,5-a]-1,3,5-triazine-2,4-diones. The starting materials, 3 and 17 , were prepared via the reaction of an appropriate 3-aminopyrazole with ethoxycarbonyl isothiocyanate. Several 8-bromo derivatives were prepared by direct bromination of the 1,3-dialkylpyrazolo[1,5-a]-1,3,5-triazine-2,4-diones.     

Diethylamine and triethylamine as sources of the dienophile component in the reverse azadiene synthesis with dimethylpyrimido[4,5-e]- and-[5,4-e]-1,2,4-triazinediones and 1,2,4,5-tetrazines

Diethylamine (DEA) and triethylamine (TEA) can function as sources for the two-carbon component in the reverse azadiene synthesis. Reaction of 5,7-dimethylpyrimido[4,5-e]-1,2,4-triazine-6,8-dione, 6,8-dimethylpyrimido-[5,4-e]-1,2,4-triazine-5,7-dione, or 1,2,4,5-tetrazine with an excess of DEA or TEA gives, respectively, the pyrido[2,3-d]pyrimidine-2,4-dione,pyrido[3,2-d]pyrimidine-2,4-dione, or pyridazine. The presence of an oxidant (atmospheric oxygen, MnO₂, or an electron-acceptor solvent) is required for the reaction to occur. Reaction of 5,7-dimethylpyrimido[4,5-e]-1,2,4-triazinedione with piperidine, morpholine, or under certain conditions DEA, results in opening of the triazine ring to give uracils with an amidine group in the 6-position.For preliminary communication, see [1, 2].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1545–1558, November, 1990.     

Reactivity of 7-amino-3-tert-butyl-4-oxo-4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-8-carbonitrile

By reaction of carbonyl compounds with 7-amino-3-tert-butyl-4-oxo-4,6-dihydropyrazolo[5,1-c]-[1,2,4]triazine-8-carbonitrile 3-tert-butyl-8-R-4,6,9,10-tetrahydropyrimido[4′,5′:3,4]pyrazolo[5,1-c][1,2,4]-triazine-4,10-diones and (3-tert-butyl-4-oxo-8-cyano-4,6-dihydropyrazolo[5,1-c][1,2,4]triazin-7-yl)acetamide were obtained.     

Reaction of 5-substituted-2-amino-2-oxazolines with ethoxycarbonyl isocyanate. A route to 2,3,6,7-tetrahydro-4H-oxazolo[3,2-a]-1,3,5-triazine-2,4-diones

The reaction of 2-amino-2-oxazolines with ethoxycarbonyl isocyanate was investigated in order to access to fused 1,3,5-triazine-2,4-diones with a potential 5-HT₂ antagonist activity. The reaction leads to 2,3,6,7-tetrahydro-4H-oxazolo[3,2-a]-1,3,5-triazine-2,4-diones and to 1-carbethoxy-3-(2-iminooxazolidine)ureas. During the carbamoylation the regioselectivity seems to be related to the strong nucleophilic character of the endo nitrogen atom of 2-amino-2-oxazolines. The structures of two compounds were studied by X-ray crystallography. N-Substituted compounds have been prepared by alkylation of the 2,3,6,7-tetrahydro-7-phenoxymethyl-4H-oxazolo[3,2-a]-1,3,5-triazine-2,4-dione.     

Syntheses based on 8-substituted 3-bromoacetyl-3,8-dimethyl-2,7-dioxaspiro[4,4]nonane-1,6-diones

By reaction of 8-substituted 3-bromoacetyl-3,8-dimethyl-2,7-dioxaspiro[4,4]nonane-1,6-diones with thiourea and substituted thioureas under Hansch reaction conditions, we have obtained the novel heterocycles 3-[2′-amino(arylamino)thiazol-4-yl]-3,8-dimethyl-2,7-dioxaspiro[4,4]nonane-1,6-diones. By reacting the above-indicated bromoacetyl spirodilactones with 5-aryl-3-mercapto-1,2,4-triazoles, we obtained 8-substituted 3-(aryl-3,8-dimethyl-1′,2′,4′-triazol-3′-yl)thioacetyl-2,7-dioxaspiro[4,4]nonane-1,6-diones. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 123–129, January, 2006.     

新型2H-噻唑[3,2-b][1,2,4]三嗪-3,7-二酮的超声辅助一锅法合成及乙酰胆碱酯酶抑制活性研究

以取代苯甲醛、溴乙腈和6-苄基-3-硫代-3,4-二氢-1,2,4-三嗪-5(2H)-酮为起始原料,在超声辅助下,一锅合成了9个新型6-苄基-2-亚苄基-2H-噻唑[3,2-b][1,2,4]三嗪-3,7-二酮类化合物,结构经_¹H NMR,_¹³C NMR和MS（ESI）表征并对其合成机理进行了初步研究。测试了目标化合物(4a~4i)的体外乙酰胆碱酯酶的抑制活性,其中4a和4d抑制活性最好,有进一步研究的价值。     

Intramolecular cyclization of hydrazides of (2-alkylthio-3,4-dihydro-6-methyl-4-oxo-3-pyrimidml)acetic acids to 1,2,3,4-tetrahydropyrimido[2,1-c]-1,2,4-triazine-3,6-diones

A method has been developed for the synthesis of 1,2,3,4-tetrahydropyrimido[2, 1-c]-1,2,4-triazine-3,6-diones by intramolecullar cyclization of hydrazides of (2-alkylthio-3,4-dihydro-6-methyl-4-oxo-3-pyrimidinyl)acetic acids in benzylamine.Vilnius University, Vilnius 2734. Translated Born Khimiya Geterotsiklicheskikh Soedinenii, No, 7, pp. 967–970, July, 1994. Original article submitted April 4, 1994.     

9H-Pyrimido[4,5-b]indole-2,4-diones. The acid-catalyzed cyclization of 6-(phenylhydrazino)uracils

6-(Phenylhydrazino)uracils undergo facile Fischer-type cyclization in both N hydrochloric acid and in formic acid at reflux to give 9H-pyrimido[4,5-b]indole-2,4-diones. Yields appear to be related to substituent effects and side reactions, and these are discussed in light of the mechanism of this reaction. In the reaction of 6-(phenylhydrazino)uracil itself with hydrochloric acid, the major competing reaction is hydrolysis to barbituric acid and phenylhydrazine, whereas in formic acid a novel cyclization occurs to give I-phenyl-3-carboxamidomethyl-1,2,4-triazole as the major product. Nmr spectra of pyrimido[4,5-b]indole-2,4-diones provide interesting examples of peri effects on proton chemical shifts.     

[4+2] Cycloaddition of 2(1H)-pyrazinones and 1,2,4-triazoline-3,5-diones

The reaction of 2(1H)-pyrazinones 1 and 1,2,4-triazoline-3,5-diones 3 was investigated by comparing that of 1 with singlet oxygen. 2(1H)-Pyrazinones 1 reacted in Diels-Alder fashion with 1,2,4-triazoline-3,5-diones 3 to afford [4+2]-adducts 4–17 in high yields.     

Synthesis of selected 3-substituted-pyrimido[5,4-e]1,2,4-triazine-5,7-diamines as potential folate antagonists

3-(Anilinomethy1) 3-[(arylthio)methy1]pyrimido[5,4-e]-1,2,4-triazine-5,7-diamines were prepared by ring closure of 6-hydrazino-4-[(phenylmethy1)thio]-2.5-pyrimidinediamine. these nonclassical analogs of known potent dihydrofolate reductase inhibitors were inactive against malarial infections in mice and L1210 leukemia in vitro.     

Purines,pyrimidines, and condensed systems based on them. 9. Concerning the synthesis of 1-r-pyrazolo[3,4-d]pyrimidine-4,6-diones

1-Ethyl-3-aryl-5-methylpyrazolo[3,4-d]pyrimidine-4,6-diones are formed in small amounts, together with the expected hydrazones, in the reaction of 3-methyl-6-(1-ethylhydrazino)uracil with aromatic aldehydes in ethanol The yield of these diones increases substantially when the reaction is carried out in acetic acid and sodium nitrite is subsequently added to the mixture. A change in the temperature conditions makes it possible to direct this reaction toward the formation of 1-ethyl-3-aryl-6-methylpyrimido[5,7-e]as-triazine-5,7-diones.For Communication 8, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 219–224, February, 1992.     

Synthesis of benzo[f]isoindole-4,9-diones

A synthesis of benzo[f]isoindole-4,9-diones 1 is presented starting from the reaction of 2,3-bis(bromomethyl)-1,4-dimethoxynaphthalene 15 with primary amines affording 2,3-bis(aminomethyl)-1,4-dimethoxynaphthalenes 14, which could be converted by CAN-mediated oxidation in one step to benzo[f]isoindole-4,9-diones 1. An alternative synthesis of benzo[f]isoindole-4,9-diones 1 starts from 2,3-bis(bromomethyl)-1,4-naphthoquinone 9 via 2,3-dihydrobenzo[f]isoindoles 10 which spontaneously oxidize.     

Synthesis of 2-R-3-Hydroxy[1,2,4]triazino[6,1-b]-quinazoline-4,10-diones

A preparation method was developed for [1,2,4]triazino[6,1-b]quinazoline-4,10-diones using isatoic anhydride, carboxylic acids hydrazides, ethyl oxalyl chloride, and hydroxylamine.     

Pyrazolo[1,5-d]triazines-1,2,4. II étude des pyrazolo[1,5-d]triazinones,des pyrazolo[1,5-d]triazinediones et des pyrazolo[1,5-d]triazinethiones

The synthesis of 1,2-dihydro-l-oxopyrazolo[1,5-d]-1,2,4-triaxine was achieved by rerrangment of 2-(5-pyrazolyl)-1,3,4-oxadiazole under alkaline condition. The cyclization of the N-carbethoxyhydrazone of the pyrazole-5-carboxaldehyde gave the 3,4-dihydro-4-oxopyrazolo[1,5-d]1,2,4-triazine. Electrophilic substitutions of the l-pyrazolotriazinome were made either on the lactam nitrogen with methylsulfate, benzylchloride and monochloracetic axid or on the pyrazole ring with bromine. The synthesis of pyrazolo[1,5-d]-1,2,4-triazine was made from teh l-pyrazolotrizinone via the l-pyrazolotrizinone. The methylation of l-pyrazolotrizinone and 8-bromo-l-pyrazolotrizinone afforded N-and S-methyl derivatives. The sysnthesis of 1,2,3,4-tetrahydropyrazolo[1,5-d]-1,2,4-triazine-1,4-diones was axhived by cyclising N-carbethoxyhydrazides of pyrrole-5-carboxylic acid. The structures of the derivatives were determined by ¹H-nmr.     

A novel synthesis of N(1)-(substituted)-pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones

A new synthesis of N₁-(substituted)-pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones, which are analogues of the natural product toxoflavin, is reported. Condensation of preformed alkyl or aryl hydrazones with 6-chloro-3-methyl-5-nitrouracil efficiently provides pyrimidotriazinediones in a three-step process that broadens the scope of R₁ substituents.     

Condensed imidazo-1,2,4-azines. 21. Synthesis of 2-arylfuro(pyrrolo-, thieno-)[2,3-e]-1,2,4-triazino[2,3-a]benzimidazoles by cyclization of 2-aroyl-1,2,4-triazino[2,3-a]benzimidazol-4H-3-ones

2-[(-Ethyl-, arylimino)phenethyl]-1,2,4-triazino[2,3-a]benzimidazoles were obtained by reaction of 2-aroylmethyl-1,2,4-triazino[2,3-a]benzimidazol-4H-3-ones with ethyl(aryl)amines or urea. By the action of phosphorus oxychloride, these benzimidazoles cyclize into substituted pyrrolo[2,3-e]-1,2,4-triazino[2,3-a]benzimidazoles, heating of which in polyphosphoric acid leads to the formation of furo[2,3-e]-1,2,4-triazino[2,3-a]benzimidazoles, while by the action of P₄S₁₀, they are transformed into thieno[2,3-e]-1,2,4-triazino[2,3-a]benzimidazoles.For Communication 20, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1109–1113, August, 1989.     

Synthesis of spiro[benzopyrazolonaphthyridine-indoline]-diones and spiro[chromenopyrazolopyridine-indoline]-diones by one-pot, three-component methods in water

The synthesis of spiro[benzo[h]pyrazolo[3,4-b][1,6]naphthyridine-7,3′-indoline]-2′,6(5H)-diones and spiro[chromeno[4,3-b]pyrazolo[4,3-e]pyridine-7,3′-indoline]-2′,6(6aH,10H)-diones via a one-pot, three-component reaction of 4-hydroxycoumarin or 4-hydroxy-1-methylquinolin-2(1H)-one, isatins and 1H-pyrazol-5-amines in water is reported.     

Synthesis of new heteroaromatic systems: Naphth[2,1-e]imidazo[5,1-c]-1,2,4-triazines and benz[e]imidazo-[5,1-c]-1,2,4-triazines

Cyclization of azo compounds, synthesized from 5-diazoimidazoles and 2-naphthol or p-substituted phenols, into naphth[2,1-e]imidazo[5,1-c]-1,2,4-triazines and benz[e]imidazo[5,1-c]-1,2,4-triazines occurs only in the presence of p-toluenesulfonic acid. Imidazo[4,5-d]-1,2,3-triazines are also formed in this reaction when an amide substituent is present in the imidazole ring.Ural State Technical University, Ekaterinburg 620002, Russia: e-mail: mokr@htf.ustu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, 540–546, April, 2000.     

Multicomponent Synthesis of 2,3-Dihydrochromeno[4,3-d]pyrazolo[3,4-b]pyridine-1,6-diones: A Novel Heterocyclic Scaffold with Antibacterial Activity

A multicomponent reaction of 3-aminopyrazol-5-ones with substituted salicylic aldehydes and acetylacetic ester leading to the formation of novel 2,3-dihydrochromeno[4,3-d]pyrazolo[3,4-b]pyridine-1,6-diones was discovered. The elucidation of the reaction scope revealed that 5-aminopyrazoles, 3-amino-1,2,4-triazoles and 6-aminouracil could be used as the heterocyclic amine component. Selected heterocyclic products were found to possess notable antibacterial activities.