Matsumoto J, Miyamoto T, Minamida A, Nishimura Y, Egawa H, Nishimura H
J Med Chem. 1984 Mar;27(3):292-301. doi: 10.1021/jm00369a011.
The title compounds having nitro, amino, cyano, chloro, or fluoro as the C-6 substituent were prepared. Introduction of the chloro and cyano groups at C-6 was accomplished by the Sandmeyer reaction of 6-amino-1,8-naphthyridine derivatives 9 via their 6-diazonium salts. The reaction was extended to the synthesis of the 6-fluoro analogues, involving the Balz-Schiemann reaction of the diazonium tetrafluoroborate. Furthermore, a series of the 1-ethyl, 1-vinyl, 1-(2-fluoroethyl), and 1-(difluoromethyl) analogues of 7-substituted 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids was prepared. 1-Pyrrolidinyl and, particularly, N-substituted or unsubstituted 1-piperazinyl groups were introduced as the C-7 variants. As a result of this study, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1, 8-naphthyridine-3-carboxylic acid (named enoxacin, originally AT-2266) was found to show the most broad and potent in vitro antibacterial activity, an excellent in vivo efficacy on systemic infections, and a weak acute toxicity. Structure-activity relationships of compounds with variations of substituents at C-1, C-6, and C-7 are also discussed.
制备了以硝基、氨基、氰基、氯或氟作为C-6取代基的目标化合物。通过6-氨基-1,8-萘啶衍生物9的6-重氮盐的桑德迈尔反应，在C-6处引入氯和氰基。该反应扩展至6-氟类似物的合成，涉及重氮四氟硼酸盐的巴尔兹-施iemann反应。此外，还制备了一系列7-取代的6-氟-1,4-二氢-4-氧代-1,8-萘啶-3-羧酸的1-乙基、1-乙烯基、1-(2-氟乙基)和1-(二氟甲基)类似物。引入了1-吡咯烷基，特别是N-取代或未取代的1-哌嗪基作为C-7变体。作为该研究的结果，发现1-乙基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)-1,8-萘啶-3-羧酸（命名为依诺沙星，最初为AT-2266）显示出最广泛和有效的体外抗菌活性、对全身感染的优异体内疗效以及较弱的急性毒性。还讨论了在C-1、C-6和C-7处具有取代基变化的化合物的构效关系。
