1,2,5-BENZOTHIADIAZEPINE AND PYRROLO[2,1-D][1,2,5]BENZOTHIADIAZEPINE DERIVATIVES WITH SPECIFIC ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ACTIVITY

We synthesized and tested as novel inhibitors of human immunodeficienc y virus type 1 (HIV-1) bi-and tricyclic thiadiazine ring homologues of chloro-2-ethyl-2H-1,2,4-benzothiadiazin-3-(4H)-one 1,l-dioxide, which is a compound endowed with anti-HIV-l activity at low micromolar conc entrations. Benzothiadiazepine derivatives were obtained by alkylation of dihydro-3-methyl-1,2,5-benzothiadiazepin-4(5H)-one 1,l-dioxide, wh ich was obtained by intramolecular cyclization of 2-(2-amino-5-chloro- benzenesulphonamido) propanoic acid. Pyrrolobenzothiadiazepines were s ynthesized from N-substituted 5-chloro-2-(1H-pyrrol-1-yl)benzenesulpho namides by treating with triphosgene. N-6- substituted pyrrolo[2,1-d][ 1,2,5]benzothiadiazepin-7(6H)-one 5,5-dioxides were active, though not very potent. Both a chlorine atom and an unsaturated alkyl chain were found to be determinants of anti-HIV-l activity. The highest potency was shown by a derivative with a TIBO-related 3,3-dimethylallyl chain. 2,3-Dihydro-1,2,5-benzothiadiazepin-4(5H)-one 1,l-dioxides were scarc ely active in HIV-l-infected MT-4 cell assays; however, the introducti on of the dimethylallyl chain into 7-chloro-1,2,5-benzothiadiazepine m oiety led to a bicyclic derivative which was more potent and less cyto toxic than the tricyclic pyrrole-containing counterpart.