A series of 6-(dimethylamino)-2-(trifluoromethyl)-9-(substituted benzyl)purines was synthesized and tested for antirhinovirus activity. Most of the compounds were synthesized by alkylation of 6-chloro-2-(trifluoromethyl)-9H-purine with the appropriate benzyl halide followed by displacement of the chloro group with dimethylamine. Alternatively, 6-(dimethylamino)-2-(trifluoromethyl)purine was alkylated with the appropriate benzyl halide. Although several different aryl substituents provided compounds with IC50's = 0.03 microM against rhinovirus serotype 1B, no congener was significantly more active than the parent 2. Twenty-three compounds were tested against 18 other serotypes, but none exhibited a uniform profile of activity.

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.

2-Amino-9-benzyl-6-chloro-9H-purine 1 is hydrolysed in refluxing water in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) to give 2-amino-9-benzyl-I ,6-dihydro-6-oxo-SH-purine 3; however, 1 reacts with hydroxide ion at ambient temp., or an alcohol and potassium carbonate at elevated temperatures, in the presence of DABCO to give 3 or 6-alkoxy-2-amino-9-benzyl-9H-purines 4-8, respectively.The development of efficient methods for the synthesis of N(9)-substituted guanines (2-amino-6-oxopurines) continues to receive much attention, in part due to the pivotal role of acyclovir and ganciclovir in the treatment of herpes virus infections. 1 Synthetic routes to N(9)-substituted guanines often proceed via 9-substituted 2-amino-6-chloropurines. Conversion of the 6-chloro moiety to the 6-0x0 function of guanine usually requires treatment with acid or base at elevated temp.2 Milder conditions for the conversion of 9-substituted 2-amino-6-chloropurines to 9-substituted guanines include the use of alkaline 2-hydroxyethanethiol3 and 6-pyridinium salts.4Ashwell et al., recently reported a two-stage procedure for the preparation of guanines from 2-amino-6-chloropurines.5The 6-chloro group was displaced with trimethylamine at 0°C to give a 2-amino-6-trimethylammonium purine salt. This salt was treated with 3-hydroxypropionitrile in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to give 9-(substituted)guanine derivatives. We applied this method to the preparation of 2-amino-6-oxopurines but the method was problematic owing to the high volatility of trimethylamine. Substitution of the less volatile triethylamine for trimethylamine was not successful; a triethylammonium salt did not form. However, the bicyclic tertiary amine 1,4-diazabicyclo-[2.2.2]octane (DABCO), which has a high melting point, worked very well to form an in situ ammonium salt from 2-amino-9-benzyl-6-chloropurine 1 (see Scheme 1). The CI cr G I +N R Scheme 1Table 1~' Compound R Yieldh (YO) mpPC 3c OH(oxo) 40d, 34e 302-304 Compounds 3-8 were homogeneous by TLC [silica gel 60 (40-63 pm); ethyl acetate-hexanes]; 2 was an origin spot. All compounds gave combustion C, H and N analyses data to within 0.4% of theoretical values. Mass spectra and IH NMR spectra were consistent with the assigned structures. h The reported yields are for recrystallized material and are non-optimized. c See ref. 6. d Recrystallized from 80% aq. propan-2-01; 75% crude yield before recrystallization. See footnote 7 . c' Recrystallized from ethanol; 57% crude yield before recrystallization. See footnote Q . f Recrystallized from ethyl acetatehexanes. R See ref. 8 (lit.8 mp 95.5-99 "C non-recrystallized; purified by silica gel chromatography).DABCO moiety was easily hydrolysed in refluxing water or by using aqueous sodium hydroxide in dichloromethane at ambient temp. to provide the 9-substituted guanine. In addition, the DABCO-purine salt could be displaced with alcohols to give 6-alkoxy-2-aminopurines. This method represents a mild and efficient process for the synthesis of 9-su...

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