Synthesis and antifilarial activity of N-[4-[[4-alkoxy-3-[(dialkylamino)methyl]phenyl]amino]-2-pyrimidinyl]-N'-phenylguanidines

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Abstract
A series of N-[4-[[4-alkoxy-3-[(dialkylamino)methyl]phenyl]amino]-2-pyrimidinyl]-N''-phenylguanidines were synthesized for antifilarial evaluation. Reaction of the appropriate benzenamines with N-cyanoguanidine, followed by condensation of the resultant N-phenylimidodicarbonimidic diamides with ethyl 4,4,4-trifluoro-3-oxobutanoate provided the intermediate N-(4-hydroxy-2-pyrimidinyl)-N''-phenylguanidines. These compounds VIa were also synthesized by reaction of the requisite .beta.-keto esters with N-cyanoguanidine to give the (4-hydroxy-2-pyrimidinyl)cyanamides, followed by treatment with the desired benzenamines. Chlorination with POCl3 and condensation with the appropriate benzenamines generated the desired guanidines. Antifilarial activity [in jirds] was confined to adult Litomosoides carinii infections, and a structure-activity relationship for this activity was discussed. Lack of activity against L. carinii microfilaria and adult Brugia pahangi infections precludes further work in this area pending evaluation in additional experimental models.