A series of novel antibacterial quinolones and naphthyridones has been prepared which contain 7-azetidinyl substituents in place of the usual piperazine or aminopyrrolidine groups. These azetidinyl derivatives were evaluated for in vitro activity by determining minimum inhibitory concentrations against a variety of bacteria. In vivo efficacy in the mouse infection model and blood levels in the mouse were determined for several compounds. The influence on the structure-activity relationships of varying substituents in the azetidine ring and at position 8 (CH, CF, CCl, N) and N-1 (ethyl, fluoroethyl, cyclopropyl, tert-butyl, 4-fluorophenyl, and 2,4-difluorophenyl) was also studied. Compounds with outstandingly broad-spectrum activity, particularly against Gram-positive organisms, improved in vivo efficacy, and high blood levels were identified in this work. 7-Azetidinyl-8-chloroquinolones were considered as warranting further development.

A series of 7-(2,3-disubstituted-1-azetidinyl)-1,4-dihydro-6-fluoro-4- oxoquinoline- and -1,8-naphthyridine-3-carboxylic acids, with varied substituents at the 1-, 5-, and 8-positions, was prepared to study the effects on potency and physicochemical properties of the substituent at position 2 of the azetidine moiety. The activity of the title compounds was determined in vitro against Gram-positive and Gram-negative bacteria, and the in vivo efficacy of selected derivatives was determined using a mouse infection model. The X-ray crystal structures of 6b, 6c, and 6d were found to be in reasonable agreement with the corresponding AM1 calculated geometries. Correlations between antibacterial potency of all the synthesized 7-azetidinylquinolones and naphthyridines and their calculated electronic properties and experimental capacity factors were established. Antibacterial efficacy and pharmacokinetic and physicochemical properties of selected derivatives were compared to the relevant 7-(3-amino-1-azetidinyl) and 7-(3-amino-3-methyl-1-azetidinyl) analogues (for Part 1, see: J. Med. Chem. 1993, 36, 801-810). A combination of a cyclopropyl or a substituted phenyl group at N-1 and a trans-3-amino-2-methyl-1-azetidinyl group at C-7 conferred the best overall antibacterial, pharmacokinetic, and physicochemical properties to the azetidinylquinolones studied.

Based on a medicinal-chemistry-guided approach, three novel series of druglike cycloalkyl-annelated pyrazoles were synthesized and display high affinity (pKi>8) for the sigma1 receptor. Structure-affinity relationships were established, and the different scaffolds were optimized with respect to sigma1 binding and selectivity versus the sigma2 receptor and the hERG channel, resulting in selective compounds that have Ki values (for sigma1) in the subnanomolar range. Selected compounds were screened for cytochrome P450 inhibition (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4), metabolic stability (rat and human liver microsomes), and cell-membrane permeability (Caco-2). They showed favorable in vitro ADME properties as well as favorable calculated druglike and experimental physicochemical properties. Furthermore, compounds 7 f and 17 a, for example, displayed high selectivity (affinity) for the sigma1 receptor against a wide range of other receptors (>60). With these valuable tool compounds in hand, we are further exploring the role of the sigma1 receptor in relevant animal models corresponding to such medicinal indications as drug abuse, pain, depression, anxiety, and psychosis.

A series of stereochemically pure 7-(3-amino-2-methyl-1-azetidinyl)-1,4- dihydro-6-fluoro-4-oxoquinoline- and -1,8-naphthyridine-3-carboxylic acids, with varied substituents at the 1-, 5-, and 8-positions, was prepared to determine the effects of chirality on potency and in vivo efficacy relative to the racemic mixtures (for part 2, see: J. Med. Chem. 1994, 37, 4195-4210). A series of chiral 9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-(substituted-1- azetidinyl)-7H-pyrido[1,2,3- de]-1,4-benzoxazine-6-carboxylic acids was synthesized to study the effect of the azetidine moiety on tricyclic quinolone antibacterial agents. A series of amino acid prodrugs of chiral naphthyridines 24a and 24b and quinolone 33a (cetefloxacin) was prepared and evaluated for antibacterial activity, solubility, and pharmacokinetic behavior. The absolute configuration of the new azetidinylquinolones was established by X-ray analysis 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 vivo overall profile. Structure-activity relationship studies indicated that the absolute stereochemistry at the asymmetric centers of both the azetidine and the oxazine rings was critical to increase in vitro activity and oral efficacy. The 3S configuration in the pyridobenzoxazine series and the (2S,3R) configuration of the 3-amino-2-methylazetidine moiety for all new compounds conferred the best antibacterial activity.