In the search for new antibiotics active against macrolide-resistant pneumococci and Haemophilus influenzae, we synthesized a new class of 3-oxo-6-O-methylerythromycin derivatives, so-called "ketolides". A keto function was introduced in position 3 after removal of L-cladinose, a sugar which has long been thought essential. Further modifications of the macrolactone backbone allowed us to obtain three different series of 9-oxime, 11,12-carbamate, and 11, 12-hydrazonocarbamate ketolides. These compounds were found to be very active against penicillin/erythromycin-resistant pneumococci and noninducers of MLSB resistance. The 11,12-substituted ketolide 61 (HMR 3004) demonstrated a potent activity against multiresistant pneumococci associated with a well-balanced activity against all bacteria involved in respiratory infections including H. influenzae, Mycoplasma catarrhalis, group A streptococci, and atypical bacteria. In addition HMR 3004 displayed high therapeutic activity in animals infected by all major strains, irrespective of their resistance phenotype.

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A series of 4-hydroxy-3-quinolinecarboxamides has been synthesized and evaluated by the oral route as antiinflammatory agents in carrageenin-induced foot edema and adjuvant-induced arthritis and as analgesic agents in the acetic acid induced writhing test. Among the most active molecules, some have shown both analgesic and acute antiinflammatory activities. Others, such as compounds 24, 37, and 52, were only powerful peripherally acting analgesics. Compound 52, being active at 1 mg/kg (ED50), is the most potent compound in the series. Some analogues, substituted in the 2-position by an alcohol, ester, or amine function, displayed potent antiarthritic activity in the same range as that of piroxicam and were also active in acute tests of inflammation and nociception. They inhibited the activity of both cyclooxygenase and 5-lipoxygenase at micromolar concentrations. Compound 102 (RU 43526) showed potent antiarthritic activity (adjuvant-induced arthritis, ED50 = 0.7 mg/kg, po) and gastrointestinal tolerance (ED100 greater than 250 mg/kg, po) and thus it is presently undergoing an extensive pharmacological evaluation.

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The synthesis of N‐aryl and N‐heteroaryl substituted 4‐hydroxy‐3‐quinolinecarboxamides 1 is described. The attack of dianions 12 of N‐aryl substituted acetamides on the C‐4 carbonyl of 4H‐3,1‐benzoxazin‐4‐ones 11 gave rise to ketoamides 13, which smoothly cyclised in the presence of bases to afford quinolinecarboxamides 1. By this method, a large number of 2‐substituted 4‐hydroxyquinolinecarboxamides can be prepared.