3693,5-Disubstituted 1,2,4-oxadiazole is a well utilized scaffold for medicinal chemistry. A class of 3,5-diphenyl-1,2,4-oxadiazole based compounds have been identified as potent sphingosine-1-phosphate-1 (S1P 1 ) receptor agonists with minimal affinity for the S1P 2 and S1P 3 receptor subtypes.
2)Another derivative, 5-(3-chlorothiophen-2-yl)-3-(5-chloropyridin-2-yl)-1,2,4-oxadiazole has been identified as a novel apoptosis inducer.3) These two examples demonstrate the potential of 3,5-disubstituted 1,2,4-oxadiazole use in the development of new pharmaceutics.1,2,4-Oxadiazoles 4) are usually prepared by 1) Paal-Knorr type ring closure of O-acylamide oximes, 5) 2) reaction of imide equivalents with NH 2 OH,6) 3) ring closure of N-acyl NЈ-substituted amidines, 7) or 4) 1,3-dipolar cycloaddition of nitriles and nitrile oxides.8) Additionally, we have reported the pyrimidine ring opening reaction accompanying the formation of the 1,2,4-oxadiazole ring to give N- [2-([1,2,4]oxadiazol-5-yl)cycloalken-1-yl]formamide oximes (1) by the reaction of tricyclic N-(aliphatic ring-fused pyrimidin-4-yl)amidine (2) or its amide oxime with hydroxylamine hydrochloride (Fig. 1). [9][10][11][12] In this paper, we applied this reaction to one of the bicyclic N-(aliphatic (or aromatic) ring-fused pyrimidin-4-yl)amidines, i.e. N-(5,6,7,8-tetrahydroquinazolin-4-yl)amidines (3) and N-(quinazolin-4-yl)-amidines (4). Since current antiplatelet drugs are known to have certain detrimental side effects and reduced efficacy, we tested these new analogues for anti-platelet aggregation activity.
Results and DiscussionChemistry First, we dealt with the aliphatic ring-fused amidines (3). As shown in Chart 1, the requisite amidine 3 starting materials were synthesized by previously reported methods.10-12) Amidines 3a, b were prepared by the reaction of 4-amino-5,6,7,8-tetrahydroquinazoline (5) with commercially available N,N-dimethylformamide (or acetamide) dimethyl acetal in refluxing toluene. Other amidines 3c-g were produced by the reaction of compound 5 with the Vilsmeier reagent prepared from the corresponding N,Ndimethylamide and phosphoryl chloride.When a hydrogen is attached to the amidine moiety (RϭH) the reaction of 3a with 1.2 eq of hydroxylamine hydrochloride in methanol at room temperature gave the amide oxime (6a, 80% yield). 6a was converted to the desired 1,2,4-oxadiazole derivative 7a (22% yield) by reaction with 6 eq of hydroxylamine hydrochloride in a refluxing methanol (Chart 1).In the -25-4 Daigaku-nishi, Gifu 501-1196, Japan: and b Faculty of Pharmaceutical Sciences, Okayama University; 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530
