Condensed naphtho[1,8-de][1,3]thiazines. 1. Synthesis of naphtho[1,8-de][1,2,4]triazolo[3,4-b][1,3]thiazine derivatives and their inhibitory activityon human platelet aggregation

Our previous research dealing with heterocycles containing a built-in pseudothiourea or thiosemicarbazide as pharmacophore led to the synthesis of the title compounds. The syntheses were performed starting from 8-amino-1-naphthalenesulfonic acid (6), which was converted to the cyclic sulfonamide 7 by treating with phosphorus oxychloride and then reduced with lithium aluminum hydride to give 8-amino-1-naphthalenethiol (8). Compound 8 was cyclized to naphtho[1,8-de][1,3]thiazine-2(3H)thione (5a) and then transformed to 2-hydrazinonaphtho[1,8-de][1,3]-thiazine (5b). Cyclocondensation of 5b with carboxylic acid orthoesters (9a-d), chlorides (9e-g), anhydrides (9h,i) and allied reagents (9j,k) afforded the target compounds 10a-e,h,j,k and some uncyclized intermediates 11 f,g,i, respectively. The pharmacological evaluation revealed that these compounds are potent inhibitors of platelet aggregation induced by collagen, epinephrine, ADP, PAF, thrombin, AA and ionophore A-23187. The mode of action was found to be direct suppressing the ATP release from platelets, subduing the increase of intracellular Ca + + concentration and inhibiting the TXA 2 formation caused by the above inducers.