SYNTHESIS AND BIOLOGICAL EVALUATION OF 5H-INDOLO[3,2-B][1,5]BENZOTHIAZEPINE DERIVATIVES, DESIGNED AS CONFORMATIONALLY CONSTRAINED ANALOGS OF THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REVERSE-TRANSCRIPTASE INHIBITOR L-737,126

In the presence of sodium hydride, reaction of aryl-disulphides with e thyl esters of indole-2-carboxylic acids furnished ethyl 3-arylthioind ole-2-carboxylates, which were cyclized intramolecularly to afford 5H- indolo[3,2-b][1,5]benzothiazepin-6(7H)-ones or hydrolysed in alkaline medium to give 3-arylthioindole-2-carboxylic acids. These acids, also obtained by the action of aryldisulphides on indole-2-carboxylic acids , afforded tetracyclic 5H-indolo [3,2-b][1,5]benzothiazepin-6(7H)-ones upon treatment with EDCI-DMAP. Transformation of cyclic sulphides int o the required sulphones was achieved by treatment with hydrogen perox ide or with m-chloroperbenzoic acid. The title derivatives are conform ationally constrained analogues of the potent human immunodeficiency v irus type 1 (HIV-1) reverse transcriptase inhibitor 3-benzene-sulphony l-5-chloroindole-2-carboxamide (L-737, 126). Although the indolobenzot hiazepine derivatives, as well as the indolyl aryl sulphones used for their synthesis, were endowed with anti-HIV-l activities in the submic romolar and micromolar range, none of them proved more potent than L-7 37,126.