Anxiolytic activity of analogues of 4-benzylamino-2-methyl-7H-pyrrolo[2,3- d]pyrimidines

Abstract

An extensive series of analogues of the lead anxiolytic 4-benzylamino-2-methylpyrrolo[2,3- d]pyrimidine 1 was synthesized and evaluated in the Geller-Seifter conflict test for anxiolytic activity to discover a less toxic derivative. Analysis of the SAR revealed that the most potent compounds were those with meta substituents on the benzylamino ring. In this group the most promising derivatives were 4-[bis(3,5-dimethylamino)]benzylamino-2-methyl-7 H-pyrrolo[2,3- d]pyrimidine 12 and 4-(3,5-dimethylbenzyl-amino)-2-rnethyl-7 H-pyrrolo[2,3- d]pyrimidine 24. Potential metabolites of 12 were synthesized and checked for their anxiolytic activity. Less toxic analogues of the second lead 24 were prepared by extending the alkyl groups attached to the benzene ring moiety. The addition of a fluoro substituent to the benzene moiety in the extended alkyl chain analogue 4-(3,5-diethyl-2-fluorobenzylamino)-2-methyl-7 H-pyrrolo[2,3- d]pyrimidine 34 resulted in a compound with a longer duration of activity relative to its analogue 4-(3,5-diethylbenzylamino)-2-methyl-7 H-pyrrolo[2,3- d]pyrimidine 26.