Rosen T, Chu D T, Lico I M, Fernandes P B, Shen L, Borodkin S, Pernet A G
Abbott Laboratories, Illinois 60064.
J Med Chem. 1988 Aug;31(8):1586-90. doi: 10.1021/jm00403a017.
Compound 1 [7-(3-aminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-1,4-dihydro-6-f luoro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride] is a potent member of the quinolonecarboxylic acid class of antibacterial agents and is currently undergoing clinical evaluation. We have developed efficient asymmetric syntheses of the enantiomers of this agent. The S-(+) enantiomer 1a is 1-2 log2 dilutions more active than the R-(-) enantiomer 1b against aerobic bacteria and 1-2 or more log2 dilutions more active against anaerobic bacteria in vitro. The enantiomer 1a shows significantly better in vivo activity in a Pseudomonas aeruginosa mouse protection model compared to racemic 1. Coupled with the improved solubility profile of 1a relative to racemic material, these features may be of practical significance from a clinical standpoint.
化合物1 [7-(3-氨基吡咯烷-1-基)-1-(2,4-二氟苯基)-1,4-二氢-6-氟-4-氧代-1,8-萘啶-3-羧酸盐酸盐] 是喹诺羧酸类抗菌剂中的一种强效成员，目前正在进行临床评估。我们已经开发出了该药物对映体的高效不对称合成方法。在体外，S-(+)对映体1a对需氧菌的活性比R-(-)对映体1b高1 - 2个log₂稀释度，对厌氧菌的活性高1 - 2个或更多log₂稀释度。与外消旋体1相比，对映体1a在铜绿假单胞菌小鼠保护模型中显示出显著更好的体内活性。再加上1a相对于外消旋体材料改善的溶解度，从临床角度来看，这些特性可能具有实际意义。
