Patent Evaluation: Novel N-Hydroxyureas as 5-Lipoxygenase Inhibitors

Summary

Novelty: N-hydroxyureas are disclosed and are said to inhibit 5-lipoxygenase. Hence, these compounds may be useful for treating rheumatoid arthritis.

Biology: The compounds were tested for their ability to inhibit A23187-induced production of LTB₄ in whole blood (in vitro and ex vivo). 1,5-Dihydro-1,3-diphenyl-4-(N-methylhydroxylamino)-2H-pyrrol-2-one produced 58% inhibition at 10 μM for human blood. In the rat, ex vivo, 10mg/hg iv produced 62% inhibition at 30 minutes, but 100mg/hg po had little effect.

Chemistry: Benzofuranylacetic acids were converted to amides and then cyclized with ethylbromoacetate prior to reaction with N-methylhydroxylamine. Ten illustrative examples are given, but the details refer to compounds in the original application (US502681). The four claimed dibenzofurans are disclosed, including 3-(2-dibenzofuranyl)-1,5-dihydro-4-(N-methylhydroxylamino)-1-phenyl-2H-pyrrol-2-one.

Structure: