Prodrugs for Amidines:  Synthesis and Anti-Pneumocystis carinii Activity of Carbamates of 2,5-Bis(4-amidinophenyl)furan

Syntheses of several carbamate analogues of 2,5-bis(4-amidinophenyl)furan (<BO>1</BO>) under mild conditions and their evaluation as prodrugs against Pneumocystis carinii pneumonia (PCP) in an immunosuppressed rat model are described. Thus, nine new bis-carbamates:  methoxycarbonyl (<BO>2</BO>), 2,2,2-trichloroethoxycarbonyl (<BO>3</BO>), ethylthiocarbonyl (<BO>4</BO>), benzyloxycarbonyl (<BO>5</BO>), (4-methyl-2-oxo-1,3-dioxol-4-en-5-yl)methoxycarbonyl (<BO>6</BO>), phenoxycarbonyl (<BO>7</BO>), 4-fluorophenoxycarbonyl (<BO>8</BO>), 4-methoxyphenoxycarbonyl (<BO>9</BO>), and (1-acetoxy)ethoxycarbonyl (<BO>10</BO>) and a bis-carbonate ethoxycarbonyloxy (<BO>11</BO>) of the bis-amidine <BO>1</BO> have been synthesized and evaluated. The in vivo results show that the 4-fluorophenyl carbamate <BO>8 </BO>and the 4-methoxyphenyl carbamate <BO>9</BO> in this series had the best anti-PCP activity by both intravenous and oral administration at a dosage level of 22 mol and 33 μmol/kg/day, respectively. Compounds <BO>3</BO>−<BO>7</BO> were also more active than the parent drug (<BO>1</BO>) on oral administration. The acute toxicity usually exhibited by the parent amidine <BO>1</BO> at a dosage level of 22 μmol/kg/day on intravenous administration has been significantly reduced by the prodrug modifications, with the exception of compound <BO>10</BO> which exhibited some toxicity. This report also describes the synthesis of several aryl−alkyl and aryl−aryl carbonates (<BO>12</BO>−<BO>14, 16</BO>−<BO>23</BO>) as efficient reagents for the preparation of carbamate derivatives from bis-arylamidines.