Synthesis and antibacterial activity of C11, C12-cyclic urea analogues of ketolides

New chemistry was developed to introduce a nitrogen substituent at the C12 position of ketolide template. This led to syntheses of novel C11, C12-cyclic urea analogues of ketolides that exhibited potent in vitro antibacterial activity. C11, C12-cyclic urea analogues of ketolides were designed and synthesized by use of a novel ketene acetal intermediate. This intermediate enabled introduction of an amino group at C12 stereospecifically and in high yield. The resulting cyclic urea ketolides appear to have in vitro activity similar to that of telithromycin which contains a C11, C12 cyclic carbamate moiety. Some of the C2 fluorinated compounds have improved potency against erm-containing Streptococcus pyogenes.