1-Ethyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. New quinolone antibacterial with potent gram-positive activity

Journal of Medicinal Chemistry
1986.0

Abstract

In recent years, an old class of antibacterials known collectively as the quinolones has aroused a great deal of new interest. The original members of this class, oxolinic acid (3) and nalidixic acid (4), have been used for certain clinical indications for over 20 years but suffer from a rather limited antibacterial spectrum. The current derivatives, shown in Figure 1, possess exceptional Gram-negative activity but still have weaknesses in their Gram-positive spectrum. Analysis of the compounds in Figure 1 reveals remarkable structural similarities. All possess a fluorine atom at the 6-position and a piperazine moiety at the 7-position. The only structural deviations observed in these drugs is found at the 8-position (X in 1) and the group appended to N1. During the course of our work we observed that the piperazine group, although beneficial, was not essential for displaying low minimum inhibitory concentrations (MICs) against bacteria or against the target enzyme DNA gyrase. The piperazine, possibly through the basic nitrogen, did confer proportionally good in vivo activity to those derivatives to which it was appended. In order to improve the spectrum of antibacterial activity without losing the obvious benefits of the piperazine moiety, we sought a new side chain that might satisfy both requirements. With the aid of molecular modelling and computer graphics it appeared to us that the amino group in the 3-(aminomethyl)pyrrolidines 5 might mimic the 4-piperazinyl nitrogen present in the known active drugs. Certainly the amino group in 5 would have several degrees of freedom relative to the piperazinyl nitrogen and might possess properties unique to this feature. In this communication we report our results from the synthesis and evaluation of a series of quinolones containing these 3-(aminomethyl)pyrrolidine heterocycles at the 7-position and, in particular, the discovery of 1-ethyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (CI-934), a new quinolone with excellent Gram-positive activity.

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