Synthesis of 2-Alkoxy 1,4-Naphthoquinone Derivatives as Antiplatelet, Antiinflammatory, and Antiallergic Agents.

In a previous paper, 1,2) a series of 2,3-disubstituted 1,4naphthoquinones were synthesized and their antiplatelet, antiinflammatory, and antiallergic activities were evaluated.Among them, compounds 1-4 (Chart 1) showed potent inhibitory effect on neutrophil and mast cell degranulation.In particular, 2-chloro-3-methoxy-1,4-naphthoquinone (1) had impressive IC 50 values of 0.5 and 0.9 mM against neutrophil and mast cell degranulation, respectively.Encouraged by this preliminary result, in this investigation we explored further the chain length of compounds 1 and 3.During the screening for antiplatelet, antiinflammatory, and antiallergic activities, we found that some of the target compounds demonstrated improved and more potent activity in comparison with 1 and 3. Our findings are summarized in this report. ChemistryThe target compounds, 2-alkoxy-3-chloro-1,4-naphthoquinones (5-9) and 2-alkoxy-1,4-naphthoquinones (10-14), were synthesized as shown in Charts 2 and 3.The preparation of two typical compounds, 2-chloro-3-propoxy-1,4naphthoquinone (5) and 2-propoxy-1,4-naphthoquinones (10), is described to illustrate the general procedures.As shown in Chart 2, the starting 2,3-dichloro-1,4-naphthoquinone was treated with sodium propoxide in propanol to form 5. As illustrated in Chart 3, the starting 2-hydroxy-1,4naphthoquinone was treated with propyl iodide in the presence of silver oxide to afford 10.Antiplatelet Activity 3,4) As indicated in Table 1, all of the synthesized compounds significantly inhibited arachidonic acid (AA)-, collagen-, and platelet-activating factor (PAF)-induced platelet aggregation.On the contrary, they did not inhibit thrombin-induced aggregation at concentractions up to 100 mg/ml (not shown in Table 1).In other words, these compounds showed similar patterns of preferential inhibition toward platelet aggregation to that of compound 1.Their inhibitory potency is greatest against AA-and collagen-induced platelet aggregation, whereas their potency is only moderate against PAF-induced aggregation, and the weakest toward thrombin-induced aggregation.Among compounds 5-7, the inhibitory potency against AA-, collagen-, and PAF-induced platelet aggregation was found to increase with increasing 2-alkoxy chain length.Alternatively, the phenoxy group was introduced into the 2-po-