SYNTHESIS AND ANTI-HIV ACTIVITY OF CARBOCYCLIC 2',3'-DIDEHYDRO-2',3'-DIDEOXY 2,6-DISUBSTITUTED PURINE NUCLEOSIDES

(±)-cis-[4-[(2,5-Diamino-6-chloropyrimidinyl)amino]-2-cyclopentenyl]carbinol (5a) was synthesized from 2-amino-4,6-dichloropyrimidine and cis-4-(hydroxymethyl)cyclopentenylamine (2a) by subsequent preparation of the 5-[(4-chlorophenyl)azo] derivative of the resulting pyrimidine (3a) and reduction of the azo moiety with zinc and acetic acid. The carbocyclic analogue of 2′,3/-didehydro-2′,3′-dideoxy 2-amino-6-chloropurine (6a) and the corresponding 8-azapurine (9a) were prepared from 5a. The carbocyclic 2′,3/-didehydro-2′,3′-dideoxy analogues of guanine (7a) and 2,6-diaminopurine (8a), and 8-azaguanine (10a) and 8-aza-2,6-diaminopurine (11a) were prepared from 6a and 9a, respectively. The corresponding 2′,3′-saturated series of 2-amino-6-substituted-purine carbocyclic nucleosides was prepared following the same scheme starting with cis-4-(hydroxymethyl)cyclopentylamine (2b). Carbocyclic 2′,3,-didehydro-2′,3′-dideoxyguanosine (carbovir, 7a) emerged as a potent and selective anti-HIV agent. Its hydrolytic stability and its ability to inhibit the infectivity and replication of HIV in T-cells at concentrations of approximately 200–400-fold below toxic concentrations make carbovir an excellent candidate for development as a potential antiretroviral agent. © 1990, American Chemical Society. All rights reserved.