1.2.4- Triazolo triazin-8-ones

Di-tert-butyl-4-hydroxyphenyl)-7//-triazolo [3,2-b][l, 2,4]triazin-7-one (HWA-131)is anon-immunosuppressive drug that effectively inhibited carrageenan-induced paw edema, attenuated the active Arthus reaction, and demonstrated antierythema as well as antipyretic activity. Part of the antiinflammatory effect of this new compound is most probably related to its antioxidative activity as well as inhibition of lipoxygenase... 

Thioxo-l,2,4-triazin-5-ones and hydrazonyl halides react together in the presence of triethylamine in dichloromethane to yield l,2,4-triazolo[4,3-ftHl,2,4]-triazin-5-ones 81 <95M105 96CA(124)317107>. 

The synthesis and structures of 6-amino-l,2,4-triazolo[3,4-/][l,2,4]triazin-8(7i/)-one derivatives <06MI169 06MI444> and of dihydrotetrazolo[5,l-c][l,2,4]triazines have been described <06H1595>. 

Some N-glycosides have been synthesized as nucleoside analogues by Vilarrasa and co-workers <1996TL901>, the result is shown in Scheme 8. The starting compound, [l,2,4]triazolo[5,l-c][l,2,4]triazine-4(l//)-one 54, was reacted with tri-0-benzoyl-/3-diribofuranosyl bromide under two different reaction conditions. In the presence of silver triflate at low temperature, the zwitterionic 2-substituted compound 55 was obtained, whereas under reflux conditions in acetonitrile the neutral 1-substituted compound 56 was formed. 

Four different ring systems belonging to this category have been published during the past period synthesis of [l,3,4]oxadiazolo[3,2-tf]triazines, [l,3,4]thiadiazolo[3,2-tf]triazines, and two [l,2,4]triazolo[l,3,5]triazines, the [1,5-a) and [4,3-a] fused ones, are discussed here (Scheme 31). 

A special approach to [l,2,4]triazolo[3,2-c][l,2,4]triazine derivatives is the transformation of 3-diazo[l,2,4]triazoles, easily available by diazotation of aminotriazoles. These compounds already contain the five nitrogen atoms in the correct sequence in order to form the desired bicyclic ring system and, thus, their reaction with proper bifunctional reagents can give rise the cyclized products in one single step. Such transformations are collected in Scheme 50. 

A new cyclization method for [l,2,4]triazolo[5,l-c]triazines (ring system 26) starting from trifluoromethylated 1,2,3-triketones and resulting in formation of 4,7-dihydro derivatives has recently been published <2005JFC1230>. The structure of one representative derivative has also been investigated by X-ray crystallography. 

When the synthesis of a heterocyclic system containing a diazole fused onto l,2,3-triazin-4-one (e.g., imidazo[4,5-i [l,2,3]tnazin-4-one (Section 10.13.9.1.l(i)) and pyrazolo[3,4-rf [l,2,3]triazin-4-one (Section 10.13.9.1.1(ii))) or 1,2,3-triazole fused onto pyrimidin-4(7)-(di)one (e.g., [l,2,3]triazolo[4,5-rf pyrimidin-4(7)-(di)one (Section 10.13.9.1.l(iv))) is required, the synthesis of the six-membered ring is the most reliable method. There are several recent accounts of six-membered annulations onto 1,2,3-triazoles to give [l,2,3]triazolo[4,5-r/ pyrimidines (Section 10.13.9.1.l(iv)), which are valuable alternatives to 1,2,3-triazole annulation using nitrosation techniques <1996CHEC-II(7)489>. 

Two reaction centers of 477-furo[3,2-6]pyrrole-5-carboxyhydrazide (228) (Scheme 15) <84CCC65> were utilized in cyclization reactions with either triethyl orthoformate or orthoacetate, leading to furo[2, 3 4,5]pyrrolo[l,2-d][l,2,4]triazine-8(7H)-one (229). Phosphorus pentasulfide treatment of this product (229) gave the corresponding thione (230) which with hydrazine hydrate gave (231). This compound (231) with triethyl orthoformate gave furo[2, 3 4,5]pyrrolo[l,2- /][l,2,4]triazolo]3,4-/][l,2,4]triazine (232) the 3-methyl (233), 6-methyl (234) and 3,6-dimethyl (235) derivatives were also made. 

Other claims are the isothiazolo[4,5-d][l,2,3]triazine-4-ones (170) for the treatment of gout and eschemia <86EUP274654>, the 3-aryl[l,2,5]thiadiazolo[3,4-d]pyrimidine-7-ones as antiallergics <90EUP349239>, 3-dialkylaminoethyl-l,2,3-triazolo[4,5-d]pyrimidine-5,7-diones as bronchodilators <88EUP272226>, and the 5-aryl-1,2,3-triazolo[4,5-d]pyrimidines as antihypertensives <88USP4923874>. 

Reaction of 1,2,4-triazol-4-ylamidines (473) with diethyl carbonate in the presence of sodium ethoxyethoxide led (70JPR669) to intermediate 474 which, upon cyclization, gave the l,2,4-triazolo[3,4-/]l,2,4-triazino-8-ones (475). Kurasawa and his group (85JHC1715) reported that the reaction of 3-(a-hydroxyimino-4-amino-5-methyl-4//-l,2,4-triazol-3-ylmethyl)2-oxo-l,2-dihydroquinoxaline (476) with orthoesters and iron powder in acetic acid gave l,2,4-triazolo[3,4-/]l,2,4-triazines 480 and its 7,8-dihydro isomers 479. 

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