Related to Arylsulfonic Acids

The potential antimetastatic activity of inhibitors of metalloproteinases has generated considerable work in the area as noted in the discussion of tanomastat (34). The very different stmcture of the inhibitor prinomastat (107) illustrates the considerable structural freedom that seems to exist for inhibitors of these enzymes. Displacement of halogen in 4-chloropyridine (99) by phenoxide leads to the diaryl ether (100). Reaction of intermediate 100 with chlorosulfonic acid affords the sulfonyl chloride (101). 

Construction of the thiomorpholine moiety starts by protection of the carboxylic acid in penicillamine (102) by reaction with hexyl dimethylsUane (Dmhs). Condensation of 103 with 1,2-dichloroethane leads to formation of the heterocychc ring by sequential displacement of halogen by nitrogen and sulfur to yield 104. Reaction of intermediate 104 with the benzophe-none (101), leads to formation of the sulfonamide (105). Mild acid then serves to reveal the free carboxyhc acid (106). This function is then converted to the acid chloride with oxalyl chloride. Treatment of this reactive intermediate with hydroxylamine leads to acylation on nitrogen to afford the proteinase inhibitor 107.  

115 with methylamine gives intermediate 116. Acylation of the secondary amine with pivaloyl chloride affords the corresponding amide and thus the endothelin receptor antagonist edonentan (117).  

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