15-Lipooxygenase inhibitors

Activated hydroxylamines react as able nucleophilic partners in the Mitsunobu reaction to provide key intermediates for further elaboration. The 5-lipooxygenase inhibitor CMI-977 was prepared using two sequential Mitsunobu reactions.After initial coupling of 4-fluorophenol to the lactone fragment, the homopropargyl alcohol was installed this intermediate, upon reaction with the phenoxycarbonyl activated hydroxylamine equivalent gave intermediate 188, which upon further reaction with ammonium hydroxide provided CMI-977 (189) in good yield. 

Horie and coworkers synthesized a series of flavones that showed promising inhibitory activity against archidonate 5-lipooxygenase. This enzyme is responsible for the initiation of bioactive leukotrienes that are chemical mediators of anaphylaxis and inflammation. Under standard K-R conditions o-hydroxyarylketone 66 and anhydride 67 in presence of the corresponding anhydride 68 delivered flavones 69 in yields of 42-65%. Subsequent hydrogenation of 69 afforded the flavone inhibitors 70. 

Compounds 111 having structural features of the dual cyclooxygenase (COX)/5-lipooxygenase (5-LO) inhibitor tepoxalin and the 5-LO inhibitor ABT-761 were prepared. Many of these hybrid compounds are potent COX and 5-LO inhibitors two compounds (111, r =McO, R = R" = R = H, R = NH2, R = Me and r = MeO, R = R = Me, R" = R = H, R = Cl) inhibited eicosanoid biosynthesis in an ex vivo assay, but neither improved on the main deficiency of tepoxalin, duration of 5-LO inhibitory activity (99BMCL979). Compounds 111 inhibit the production of arachidonic acid products associated with 5-lipoxygenase and cyclooxygenase and are useful in the treatment of inflammatory disorders (99USP5925769). 

Leukotriene inhibitors, one leukotriene inhibitor blocks leukotriene synthesis by inhibiting the action of 5-lipooxygenase (Zileuton Zyflo). Another blocks leukotriene receptors on the surface of smooth-muscle cells and eosinophils (Montelukast Singulair). 

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