Prodrugs for amidines: Synthesis and anti-Pneumocystis carinii activity ofcarbamates of 2,5-bis(4-amidinophenyl)furan

Syntheses of several carbamate analogues of 2,5-bis(4-amidinophenyl)furan ( 1) under mild conditions and their evaluation as prodrugs against Pneumocys tis carinii pneumonia (PCP) in an immunosuppressed rat model are described. Thus, nine new bis-carbamates: methoxycarb onyl (2), 2,2,2-trichloroethoxy carbonyl (3), ethylthiocarbonyl (4), benzyloxycarbonyl (5), (4-methyl-2-oxo -1,3-dioxol-4-en-5-yl)methoxycarbonyl (6), phenoxycarbonyl (7), 4-fluorophe noxycarbonyl (8), 4-methoxyphenoxycarbonyl (8), and (1-acetoxy)ethoxycarbon yl (10) and a biscarbonate ethoxycarbonyloxy (11) of the bis-amidine 1 have been synthesized and evaluated. The in vivo results show that the 4-fluoro phenyl carbamate 8 and the Q-methoxyphenyl carbamate 9 in this series had t he best anti-PCP activity by bath intravenous and oral administration at a dosage level of 22 mol and 33 mu mol/kg/day, respectively. Compounds 3-7 we re also more active than the parent drug (1) on oral administration. The ac ute toxicity usually exhibited by the parent amidine 1 at a dosage level of 22 mu mol/kg/day on intravenous administration has been significantly redu ced by the prodrug modifications, with the exception of compound 10 which e xhibited some toxicity. This report also describes the synthesis of several aryl-alkyl and aryl-aryl carbonates (12-14, 16-23) as efficient reagents f or the preparation of carbamate derivatives from bis-arylamidines.