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为了提高美罗培南口服吸收,本课题合成并研究了一系列在其羰基和吡咯烷基上引入脂溶性修饰基前药。在这些前药中,对特戊酰甲氧基-(1R,5S,6S)-2-[(3S,5S)-5-(N,N-二甲氨基甲酰基-1-(异丁酰氧甲氧基羰基)吡咯烷-3-硫代-6-[(1R)-1-羟乙基]-1-甲基羧苄青霉素-2-烯-3-羧酸酯(4)和1-吡咯烷氧羰基氧甲基(1R,5S,6S)-2-[(3S,5S)-5-(N,N-二甲基氨基甲酰基)-1-(异丁酰氧甲基氧羰基)吡咯烷-3-硫代]-6-[(1R)-1-甲基羧苄青霉素-2-烯-3-羧酸酯(8)作了深入研究。研究发现,在鼠和犬的动物实验中,口服前药4和8,其生物利用度为18.2%～38.4%,且对包括耐青霉素肺炎链球菌和β-内酰胺酶阴性耐氨苄西林流感嗜血杆菌在内的各种病原体均有效。
In order to improve the oral absorption of meropenem, a series of prodrugs were introduced and introduced into its carbonyl and pyrrolidino groups. Among these prodrugs, pivaloylmethoxy- (1R, 5S, 6S) -2 - [(3S, 5S) -5- (N, N-dimethylcarbamoyl-1- Oxymethyloxycarbonyl) pyrrolidine-3-thio-6 - [(1R) -1-hydroxyethyl] -1-methylcarbenicillin-2-em-3-carboxylate (4) and 1 -pyrrolidyloxycarbonyloxymethyl (1R, 5S, 6S) -2 - [(3S, 5S) -5- (N, N-dimethylcarbamoyl) -1- (isobutyryloxymethyl oxy Carbonyl) pyrrolidine-3-thio] -6 - [(1R) -1-methylcarbenicillin-2-em-3-carboxylate (8) Animal experiments, oral prodrugs 4 and 8, the bioavailability of 18.2% to 38.4%, and including penicillin-resistant Streptococcus pneumoniae and beta-lactamase-resistant ampicillin-resistant Haemophilus influenzae, including various Pathogens are effective.