Synthesis and structure-activity relationships of new 7-[3-(fluoromethyl)piperazinyl]- and -(fluorohomopiperazinyl)quinolone antibacterials

Abstract

Some novel 6-fluoro-7-substituted-1,4-dihydro-4-oxoquinoline-3-carboxylic acids have been prepared. At the N-1 position "standard" substitution was employed with the ethyl, cyclopropyl, and p-fluorophenyl groups being used. At C-7 the introduction of some novel piperazines was made. Most notably, 2-(fluoromethyl)piperazine (10) and hexahydro-6-fluoro-1H-1,4-diazepine (16, fluorohomopiperazine) at the quinolone C-7 position produced products with similar in vitro antibacterial activity as the ciprofloxacin reference. The in vivo efficacy of 1-cyclopropyl-6-fluoro-7-[3-(fluoromethyl)piperazinyl]-1,4-dihydro-4- oxoquinoline-3-carboxylic acid (20) was excellent with better oral absorption than ciprofloxacin (2).

Synthesis and Application of [1,2,5]Triazepane and [1,2,5]Oxadiazepane as Versatile Structural Units for Drug Discovery

“…The bulky Boc group at the 1-position is expected to decrease the basicity and nucleophilicity of the 2-position relative to the 5-position. As expected, selective arylation under basic conditions proceeded at the 5-position to afford nitrobenzene 4a, and catalytic hydrogenation of 4a provided aniline 5a without cleavage of the N-N bond of the [1,2,5]triazepane framework. Compound 5a should be a useful building block for N-aryl-type compounds.…”

“…Six-membered saturated heterocycles represented by piperazine or morpholine have been widely applied as functional or linker units to develop antihistamines, 1,2) antipsychotics, 3,4) and antibacterial agents. 5,6) Two examples are shown in Fig. 1.…”

“…Piperazine has two N atoms that can be readily functionalized and can be used to improve both lipophilicity 9) and hydrophilicity, 10) which in turn can improve bioavailability 11) and pharmaceutical formulation properties. 12) We thought that the seven-membered heterocycles [1,2,5]triazepane and [1,2,5]oxadiazepane, which could be considered homologues of piperazine, might be similarly useful (Fig. 2).…”

“…Since [1,2,5]triazepane contains three N atoms, a wide range of chemical modifications should be available. Only a few monocyclic [1,2,5]triazepane-type compounds have been synthesized so far, 13) and no [1,2,5]oxadiazepane derivatives have been reported. Accordingly, we set out to synthesize several N-protected derivatives and to examine whether they might be useful in medicinal chemistry.…”

“…First, we attempted to synthesize [1,2,5]triazepane and [1,2,5]oxadiazepane frameworks bearing t-butoxycarbonyl (Boc) protective groups. As shown in Chart 1, cyclization precursors, di-protected hydrazine 1a 14) and bis(2-chloroethyl)carbamic acid benzyl ester, 15) were treated with NaH in N,N-dimethylformamide (DMF) to afford all N-protected [1,2,5]triazepane 2a in good yield, followed by catalytic hydrogenation to obtain 3a protected with a Boc group at the 1-position.…”