7-AZETIDINYLQUINOLONES AS ANTIBACTERIAL AGENTS .3. SYNTHESIS, PROPERTIES AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF THE STEREOISOMERS CONTAINING A 7-(3-AMINO-2-METHYL-1-AZETIDINYL) MOIETY

A series of stereochemically pure ino-2-methyl-1-azetidinyl)-1,4-dihyd ro-6-fluoro-4- oxoquinoline- and -1,8-naphthyridine-3-carboxylic acids , with varied substituents at the 1-, 5-, and 8-positions, was prepare d to determine the effects of chirality on potency and in vivo efficac y relative to the racemic mixtures (for part 2, see: J. Med. Chem. 199 4, 37, 4195-4210). A series of chiral -7H-pyridol[1,2,3-de]-1,4-benzox azine-6-carboxylic acids was synthesized to study the effect of the az etidine moiety on tricyclic quinolone antibacterial agents. A series o f amino acid prodrugs of chiral naphthyridines 24a and 24b and quinolo ne 33a (cetefloxacin) was prepared and evaluated for antibacterial act ivity, solubility, and pharmacokinetic behavior. The absolute configur ation of the new azetidinylquinolones was established by X-ray analysi s of one of the diastereomeric salts of the resolved azetidinols (15) and of compound 25a (E-4767), which showed the best in vitro and in vi vo overall profile. Structure-activity relationship studies indicated that the absolute stereochemistry at the asymmetric centers of both th e azetidine and the oxazine rings was critical to increase in vitro ac tivity and oral efficacy. The 3S configuration in the pyridobenzoxazin e series and the (2S,3R) configuration of the 3-amino-2-methylazetidin e moiety for all new compounds conferred the best antibacterial activi ty.