Pyrazolo[3,4-d]pyrimidine ribonucleosides as anticoccidials. 3. Synthesis and activity of some nucleosides of 4-[(arylalkenyl)thio]pyrazolo[3,4-d]pyrimidines.

Abstract

Ribonucleosides of 4-(alkylthio)-1H-pyrazolo[3,4-d]pyrimidines have been shown to be useful anticoccidial agents [Krenitsky, T. A.; Rideout, J. L.; Koszalka, G. W.; Inmon, R. B.; Chao, E. Y.; Elion, G. B.; Latter, V. S.; Williams, R. B. J. Med. Chem. 1982, 25, 32. Rideout, J. L.; Krenitsky, T. A.; Elion, G. B. U.S. Patent 4299 283, 1981]. In that study, the unsaturated 4-allylthio and 4-crotylthio derivatives (19 and 20) were shown to be more active in vivo against Eimeria tenella than their saturated congeners; therefore, some unsaturated (arylalkyl)thio derivatives were synthesized and investigated as anticoccidial agents. The novel compounds in this study (2 to 18) were prepared by the alkylation of 4-mercapto-1-beta-D-ribofuranosyl-1H-pyrazolo[3,4-d]pyrimidine (1), which was prepared by an enzymatic method. The (E)-4-cinnamylthio derivative (2) and the 5'-monophosphate (18) were the most active compounds against E. tenella in vivo. None of the analogues with substituents in the aryl moiety (3 to 13) was more active than 2 in vivo. The geometry about the double bond was important, since the (Z)-4-cinnamylthio derivative (14) was inactive both in vitro and in vivo. The 4-(3-phenylpropynyl)thio and 4-(5-phenyl-2,4-pentadienyl)thio derivatives (15 and 16) were at least as active as 2 in vitro; however, they were less active than 2 in vivo. Compound 2 was effective in vivo against E. tenella, E. necatrix, E. maxima, and E. brunetti; these species of Eimeria were controlled when 2 was given in the diet at levels upt to 100 ppm. Infections in vivo due to E. acervulina were controlled by 2 only at about 800 ppm. The broad spectrum of anticoccidial activity shown by 2 represents a significant improvement over the activities reported for related compounds [Krenitsky, T. A.; Rideout, J. L.; Koszalka, G. W.; Inmon, R. B.; Chao, E. Y.; Elion, G. B.; Latter, V. S.; Williams, R. B. J. Med. Chem. 1982, 25, 32].