LIPOPHILIC, ACID-STABLE, ADENOSINE DEAMINASE-ACTIVATED ANTI-HIV PRODRUGS FOR CENTRAL-NERVOUS-SYSTEM DELIVERY .3. 6-AMINO PRODRUGS OF 2'-BETA-FLUORO-2',3'-DIDEOXYINOSINE

A series of 6-substituted amino analogs of (2,3-dideoxy-2-fluoro-beta- D-threo-pentofuranosyl) purines (F-ddN) has been synthesized and chara cterized with the objective of finding compounds which might be superi or to existing chugs for the treatment of HIV in the central nervous s ystem. These compounds are intended to be more lipophilic than the cur rently approved anti-HIV drugs for better blood-brain barrier penetrat ion. Subsequent adenosine deaminase (ADA)-catalyzed hydrolysis of thes e prodrugs in the brain is expected to produce the anti-HIV agent, -2- fluoro-beta-D-threo-pentofuranosyl)hypoxanthine (F-ddI). The new compo unds, synthesized from the corresponding 6-chloro analog, include F-dd N which contain methylamino, ethylamino, dimethylamino, hydroxylamino, methoxyamino, benzyloxyamino, hydrazino, and nitro substituents in th e 6-position. The 6-nitro analog was isolated as an unexpected product during the preparation of the 6-chloro derivative. Among the analogs with anti-HIV activity, the ethylamino and dimethylamino compounds are ca. 100 times more Lipophilic than ddI or F-ddI. As expected, 2'-fluo ro substitution protects the compounds from acid-catalyzed glycosylic cleavage. Only the hydroxylamino and nitro analogs underwent any nonen zymatic hydrolysis at pH 1.0 or 7.4. This reaction, however, results i n hydrolysis of the group in the 6-position rather than glycosylic bon d cleavage. ADA catalyzes the hydrolysis of the 6-substituents at rate s which vary from slightly slower (NO2, 1.7x) to much slower (NHEt, 50 00 x) than F-ddA. The 6-dimethylamino analog is the only compound whic h possesses anti-HIV activity (ED(50) is mu M) without ADA hydrolysis. With the exception of the two inactive alkoxyamino compounds, the oth er prodrugs exhibited cellular protection in the HIV-1/PHA-PBM system with IC50 potencies of 7-40 mu M.