Synthesis and anti-influenza virus activity of novel pyrimidine derivatives

Efficient synthetic routes of 2-amino-4-(omega-hydroxyalkylamino)pyrimidine derivatives were investigated in relation to the anti-influenza virus acti vity of these compounds. The derivatives in which cyclobutyl and cyclopenty l groups were introduced to the beta-position of the aminoalkyl group (espe cially the cyclobutyl group substituted by a phenylalkyl group at the 3'-po sition) resulted in improved antiviral potency: i.e. an average 50% effecti ve concentration for inhibition of plaque formation (EC50, mu M) of 0.1-0.0 1 mu M for both types A and B influenza virus. The antiviral efficacies wer e in the order of amino group > hydroxyiminomethyl group > halogen substitu tion at the 5-position, and chlorine or methoxy group > hydrogen at the 6-p osition of the pyrimidine ring. The antiviral indices of these compounds we re 2-6 with respect to the 50% inhibitory concentration for cell proliferat ion (IC50, mu M) for growing cells, but > 500 to > 10(4) with respect to th e IC50 for stationary cells, indicating that these compounds may be efficac ious for the topical treatment of influenza virus infection. (C) 1999 Elsev ier Science B.V. All rights reserved.