Prodrugs for amidines:: Synthesis and anti-Pneumocystis carinii activity of carbamates of 2,5-bis(4-amidinophenyl)furan
Prodrugs for amidines:: Synthesis and anti-Pneumocystis carinii activity of carbamates of 2,5-bis(4-amidinophenyl)furan
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DOI：
10.1021/jm990237
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发表时间：
1999-09-23
影响因子：
7.3
通讯作者：
Boykin, DW
中科院分区：
文献类型：
--
作者：
Rahmathullah, SM;Hall, JE;Boykin, DW
在温和条件下合成了几种2，5-双（4-脒基苯基）呋喃（1）的氨基甲酸酯类似物，并在免疫抑制大鼠模型中评价了它们作为抗卡氏肺孢子虫肺炎（PCP）前药的作用。因此，九种新的双氨基甲酸酯：甲氧羰基（2），2，2，2-三氯乙氧羰基（3），乙硫基羰基（4），苄氧羰基（5），（4-甲基-2-氧代-1，3-二氧杂环戊烯-4-烯-5-基）甲氧羰基（6），苯氧羰基（7），4-氟苯氧羰基（8），4-甲氧苯氧羰基（8），和双脒1的（1-乙酰氧基）乙氧羰基（10）和双碳酸酯乙氧羰基氧基（11）。体内试验结果表明，该系列化合物中的4-氟苯基氨基甲酸酯8和Q-甲氧基苯基氨基甲酸酯9分别以22 μ mol/kg/d和33 μ mol/kg/d的剂量水平通过静脉和口服给药具有最佳的抗PCP活性。化合物3-7在口服给药时也比母体药物（1）更有活性。母体脒1在22 μ mol/kg/天的剂量水平下静脉内给药时通常表现出的急性毒性已被前药修饰显著降低，但化合物10除外，其表现出一定的毒性。该报告还描述了几种芳基-烷基和芳基-芳基碳酸酯（12-14，16-23）的合成，其作为从双芳基脒制备氨基甲酸酯衍生物的有效试剂。
Syntheses of several carbamate analogues of 2,5-bis(4-amidinophenyl)furan (1) 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: methoxycarb onyl (2), 2,2,2-trichloroethoxycarbonyl (3), ethylthiocarbonyl (4), benzyloxycarbonyl (5), (4-methyl-2-oxo-1,3-dioxol-4-en-5-yl)methoxycarbonyl (6), phenoxycarbonyl (7), 4-fluorophenoxycarbonyl (8), 4-methoxyphenoxycarbonyl (8), and (1-acetoxy)ethoxycarbonyl (10) and a biscarbonate ethoxycarbonyloxy (11) of the bis-amidine 1 have been synthesized and evaluated. The in vivo results show that the 4-fluorophenyl carbamate 8 and the Q-methoxyphenyl carbamate 9 in this series had the 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 were also more active than the parent drug (1) on oral administration. The acute toxicity usually exhibited by the parent amidine 1 at a dosage level of 22 mu mol/kg/day on intravenous administration has been significantly reduced by the prodrug modifications, with the exception of compound 10 which exhibited some toxicity. This report also describes the synthesis of several aryl-alkyl and aryl-aryl carbonates (12-14, 16-23) as efficient reagents for the preparation of carbamate derivatives from bis-arylamidines.