9-Benzyl-8-hydroxyadenine (6) was found to possess interferon-inducing activity in vitro as a lead compound. Although replacement of the 9-benzyl group of 6 did not improve the activity, the introduction of a substituent such as alkyl, alkylthio, alkylamino, and alkoxy groups into the 2-position of the adenine ring resulted in a remarkable increase in the activity. The 2-alkylthio (30-32), 2-butylamino (41), and 2-butoxy (47) analogues indicated the highest activities by oral administration to mice.

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Various 6-substituted 9-benzyl-8-hydroxypurines were synthesized in order to investigate the structure-activity relationship at the 6-position of 9-benzyl-8-hydroxyadenine (1), which is a lead compound for the screening of interferon (IFN)-inducing activity. 6-Unsubstituted, mercapto-, methylthio- and hydroxy-9-benzyl-8-hydroxypurines (2-5) were prepared from 5-amino-1-benzyl-4-cyano-2-hydroxyimidazole (9). Synthesis of a 6-methoxy analog (6) was conducted from 5-amino-4-benzylamino-6-chloropyrimidine (13). 6-Alkylamino and acylaminopurines (7 and 8) were also prepared by alkylation and acylation of 1, respectively. Since these compounds (2-8) indicated no activity, it was found that a free amino group of 1 is required for the expression of IFN-inducing activity.

Purine derivativesPurine derivatives R 0540 Efficient Synthesis of 2,9-Disubstituted 8-Hydroxyadenine Derivatives. -A novel synthesis of 8-hydroxyadenine derivatives is developed using compounds (IV) as key intermediates. Treatment of (XXI) with urea and subsequent alkylation results in the formation of (XIX) in an alternative method. Under mild conditions, various types of substituents are directly introduced at the 2-and 9-positions of the 8-hydroxyadenine nucleus. -(HIROTA*, K.; KAZAOKA, K.; NIIMOTO, I.; SAJIKI, H.; Org.