A series of 1-aryl-2,3-bis(hydroxymethyl)naphthalene lignans have been synthesized and evaluated for their ability to selectively inhibit PDE IV isolated from guinea pig. Replacement of the 1-phenyl ring by a pyridone ring led to marked improvement of their selectivity for PDE IV over PDE III. The compounds that were most potent and selective involved those bearing an N-alkylpyridone ring at C-1. These compounds also showed potent antispasmogenic activity without causing significant changes in heart rate in the guinea pig. The most potent compound was 6,7-diethoxy-2,3-bis(hydroxymethyl)-1-[1-(2-methoxyethyl)-2-oxo-pyrid-4-yl]naphthalene (17f), ED50 values of histamine-induced and antigen-induced bronchoconstriction in the guinea pig being 0.08 and 2.3 mg/kg iv, respectively. This compound was chosen as a candidate for further pharmacological evaluation.

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a-C-Acylamino acid esters (3-oxo-2-amino acid esters, 6) were prepared in good yields by the acid hydrolysis of a-acyl-a-isocyanoacetate analogs (5) and oxazole-4-carboxylate derivatives (4), which were easily obtained by the reaction of -isocyanoacetate analogs (1) with acyl halides (2) or acid anhydrides (3) in the presence of metallic or organic bases. Further, the hydrolysis of 6 and 4 gave the -amino ketones (7) in high yields.

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