Patent Evaluation: Indole Derivatives which Inhibit Leukotriene Biosynthesis

Summary

Novelty: Substituted indolyl compounds are claimed. They are said to be potent inhibitors of the lipoxygenase enzymes. These compounds may be useful for the treatment or amelioration of inflammatory disease states, in which leukotrienes play a role.

Biology: Inhibition of leukotriene biosynthesis was evaluated in vitro. Calcium ionophore-induced LTB₄ biosynthesis which is expressed by human polymorphonuclear leukocytes (PMNL) or whole human blood was also assayed. Inhibition of in vivo leukotriene biosynthesis, after oral administration of the compound, was determined using a rat peritoneal anaphylaxis model. These compounds were found to be orally effective in preventing in vivo leukotriene biosynthesis.

Chemistry: The syntheses of the compounds are described in several reaction schemes. All compounds are prepared using conventional methods. Two-hundred and seventy-eight examples are given. Twenty-four compounds are specifically claimed, including N′-hydroxy-N′-methyl-N-2-[2-methyl-3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethyl-ethylthio)-5-(1-methylethyl)indol-2-yl)]propyl urea.

Structure: