1.2.4- Triazolo quinazolin-8-ones

Reaetion of l,3-benzoxazin-4-ones (43, 44) or trithioisatoie anhydride (45) with amidrazones (46, 47) or thiosemiearbazide (48) resulted in the formation of 3-(l-amidino)- (49-51) and 3-(l-thioureido)pyrimidines (52) respeetively. Compounds 49-52 underwent thermal intramoleeular ey-elization to the eorresponding l,2,4-triazolo[l,5-c]quinazolines (53-56) [68CB2106 76MI1 80PHA582 83MI1 85H(23)2357] (Seheme 18). 

A series of novel l-substituted-4-phenyl-l,2,3-triazolo(4,3-a)quinazolin-5(4H)-ones 1 were synthesized by the cyclization of 2-hydrazino-3-phenyl-quinazolin-4(3H) 2 with various one carbon donors. The starting material 2-hydrazino-3-phenylquinazolin-4(3H)-one 2, was synthesized from aniline 7 by a novel innovative route. When tested for their in vivo Hi-antihistaminic activity on conscious guinea pigs all the test compounds protected the animals from histamine-induced bronchospasm significantly, whereas the compound l-methyl-4-phenyl-l,2,3-triazolo(4,3-a)quinazolin-5(4H)-one lb (percentage protection 70.7%) was found to be equipotent with the reference standard chlorpheniramine maleate (percentage protection 71%). These compounds show negligible sedation (5%) when compared to the reference standard (26%). Hence they could serve as prototype molecules for future development [1,4,5]. 

The reaction of 2,3-diaminoquinazolin-4-one 404 with aryl aldehydes and thioglycolic acid gives 2-substituted 1,3-dihydro-thiazolo[3, 4 2,3][l,2,4]triazolo[5,l-A]quinazolin-5-ones 405 (Equation 79) <2004MI10>. 

In one synthesis [76JAP(K)76100098], l,2,4-triazolo[4,3-a]quinazolines (304) were prepared from 1,2,4-triazole precursors when 2-(l, 2,4-triazol-3-yl)benzophenones (303, LG = OR,SH, or SR) were cyclized with ammonia. 

Finally, the reduced 1,2,4-triazolo[5,1 -fc]quinazolin-9-ones (310) were prepared from 1,2,4-triazole precursors when 3-amino-l,2,4-triazole (309) was cyclocondensed with 2-ethoxycarbonylcyclohexanones (72MI1 890PP163). 

Treatment of 2-mercapto-4(3W)-quinazolinone (52) with hydrazonoyl halides affords 1,3-disubstituted l,2,4-triazolo[4,3-a]quinazolin-5-ones 53 [95H(41)1999]. Hydrazones derived from [(2-methyl-4-quinazolinyl)oxy]acetic acid hydrazide and aldehydes or ketones were shown to give 4-thiazolidinones and pyrazoles under cyclization conditions [95UC(B)537]. 

Reaction of 2-amino-2-(2-aminophenyl)acetaldehyde aroylhydrazones (109) with ethyl chloroformate gave the urethane derivatives 110. The latter underwent condensative double ring-closure to the l,2,4-triazolo[l,5-c]quinazolin-5-ones 86. Carrying out a similar reaction between 109 and guanidine furnished the 5-amino congener 111 (93JHC11) (Scheme 40). 

Generation of the carbodiimide from the 3-amino group in 618, followed by ring closure affords l,2,4-triazolo[5,l-b]quinazolin-9-(3H)-ones in 63-88 % yield. 

In the reaction of the heterocyclic N-substituted iminophosphorane 9 with aryl isocyanates, 2-arylamino-l,2,4-triazolo[5,l-b]quinazolin-9(3H)-ones 10 are formed in 86-94 % yield. ... 

Synthesis of 9-substituted tetrahydroazepinopurines as asmarine analogs has been described <03T6493>. In relation to adenosine receptor antagonists, new derivatives of pyrazolo[4,3-c][l,2,4]triazolo[l,5-c]pyrimidines have been synthesized <03IMC1229, 4287>. A one-pot synthesis of l,2,4-triazolo[l,5-c]quinazoline thiones 65, consisting of a domino cyclization of 2-isothiocyanatobenzonitrile 63 with hydrazides 64 has been published <03EJO182>. 

The l,2,4-triazolo[2,3-fl]quinazoline 532 was obtained by reaction of 1 with 3-amino-l,2,4-triazole 531 in DMF (05RJOC114). In the presence of p-substituted benzaldehyde, the condensation with equimolar amounts of 531 and 1 in DMF or methanol gave l,2,4-triazolo[5,l-fr]quinazolin-8-ones 533 (03CHE1213, 07MI11). Also, the reaction can take place under MW irradiation (07MI287227). Alternatively, 533 were obtained from the condensation of 531 with arylidinedimedone 328 or xanthenedione 402 (R = Ar), via a loss of a molecule of dimedone from the latter compound... 

A three-component condensation of 3-amino-l, 2,4-triazole (or its 5-Me and 5-methylthio derivatives), 1 and DMF-dimethylacetal afforded 8,9-dihydro[l,2,4]triazolo[l,5-fl]quinazolin-6(7H)-ones (06RCB1224). Condensation of 3,4,5-triamino-l,2,4-triazole with aromatic aldehydes and dimedone afforded partially hydrogenated 9-aryl-[l,2,4]triazolo[5,l-frJquinazolin-8-ones. The structure of 2-amino-6,6-dimethyl-3-(4-nitro-benzylidene)amino-9-(4-nitrophenyl)-5,6,7,9-tetrahydro[l,2,4]triazolo[5,l-fr]-quinazolin-8-one was confirmed by X-ray analysis (05RCB2903). 

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