Several 9-alkyl-6-substituted-purines were synthesized and tested for anticonvulsant activity against maximal electroshock-induced seizures (MES) in rats. Most compounds were prepared in three steps from 5-amino-4,6-dichloropyrimidine or in two steps via alkylation of 6-chloropurine. Potent anticonvulsant activity against MES resided in compounds that contain a benzyl substituent at the 9-position of 6-(methylamino)- or 6-(dimethyl-amino)purine. Among commonly used agents for control of seizures, this type of structure represents a new class of potent anticonvulsant agents.

A number of pyrimidine acyclic nucleosides were synthesized and tested for activity against herpes simplex virus type 1. Synthesis of 1-[(2-hydroxyethoxy)methyl]cytosine (8) and 1-[(2-hydroxyethoxy)methyl]uracil (14) was accomplished in two or three steps from 2,4-diethoxypyrimidine and 2-(benzoyloxy)ethoxymethyl chloride. The 5-methyl (20), 5-(trifluoromethyl) (21), and 5-fluoro (22) analogues of 14 were available in two steps form the appropriate bis(trimethylsilyl)ated 5-substituted uracil and 2-(acetoxymethoxy)ethyl acetate or 2-(benzoyloxy)ethoxymethyl chloride. Bromination of 8 and 14 or iodination of 14 gave the 5-halogeno-1-[(2-hydroxyethoxy)methyl]pyrimidines 9, 23, and 24. These pyrimidine acyclic nucleosides exhibited little or no activity against herpes simplex virus type 1 or against a range of other DNA and RNA viruses. This is compatible with their lack of substrate properties toward herpes simplex virus induced thymidine kinase.

A series of 9-benzyl-6-(dimethylamino)-9H-purines and 9-benzyl-2-chloro-6-(dimethylamino)-9H-purines were synthesized and tested in cell culture for activity against rhinovirus type 1B. The 9-benzylpurines that were unsubstituted in the 2-position had weak activity. However, introduction of a 2-chloro substituent resulted in a substantial increase in antiviral activity. One of the most active compounds, 2-chloro-6-(dimethylamino)-9-(4-methylbenzyl)-9H-purine (29), had an IC50 value of 0.08 microM against serotype 1B. Four compounds were tested against 18 other rhinovirus serotypes, but the majority tested were less sensitive than type 1B. The range of serotype sensitivity for 29 varied from 0.08 to 14 microM. These 9-benzyl-2-chloro-9H-purines represent a new class of antiviral agents with in vitro activity against rhinoviruses.

A series of 8-substituted analogues of 9-(3-aminobenzyl)-6-(dimethylamino)-9H-purine (8) were synthesized and tested for their ability to bind to the benzodiazepine receptor (BZR) in rat brain tissue. The most active compound was the 8-bromo-9-(3-formamidobenzyl) analogue 16 (IC50 = 0.011 microM), which was 1000-fold more active than the parent 9-benzyl-6-(dimethylamino)-9H-purine (1) and nearly as active as diazepam. Although substitution of a m-formamido group and an 8-bromo substituent on 1 imparted potent BZR binding activity, neither 16 nor 11 analogues exhibited significant anxiolytic activity on a modified Geller-Seifter conflict schedule.

Several 5-substituted analogues of the acyclic aminonucleoside 1-[2-aminoethoxy)methyl]uracil (5) were prepared for evaluation as antivirals. The uracil and thymine analogues were prepared in two steps from N-[2-(chloromethoxy)ethyl]phthalimide (1). The 5-chloro, 5-bromo, and 5-iodo analogues were prepared by halogenation of 5. These acyclic aminonucleosides exhibited neither cell toxicity nor antiviral activity. This is compatible with their lack of substrate properties toward herpes simplex virus thymidine kinase.