Phthalazine PDE IV inhibitors: Conformational study of some 6-methoxy-1,4-disubstituted derivatives

This report describes the detailed conformational analysis and synthesis of a series of phthalazine phosphodiesterase-type (IV) (PDE IV) inhibitors bearing either mono- or dichloro 4-methylenepyridine at the ‘down’ position of the phthalazine nucleus or different heterocycles at the ‘top’ position 4 of the phthalazine moiety. Both the mono- and dichloro 4-methylenepyridine units linked at carbon C1 of the phthalazine nucleus show identical conformational behaviour with the substituent preferentially oriented towards the external part of the molecule and the pyridine plane almost orthogonal to that of phthalazine ring. The heterocyclic five-membered rings linked at carbon C4 of phthalazine show quite different conformational behaviour. The 1,3-thiazole ring exists in a well-defined conformation almost coplanar with respect to the phthalazine nucleus while the 1,2,4-triazole and the 1,3-diazole heterocycles show a great conformational freedom with large torsion angles. Compound 3 bearing the thiazole ring at C4 displays the major biological activity, thus suggesting that a planar and rather rigid conformation of the pentacycle should favour the PDE IV inhibition capacity of this class of compounds.

A conformational investigation on the phthalazine phosphodiesterase inhibitors 2–5 was performed by using NOE experiments and MD computational methods. A correlation was found between the conformational properties of the heterocyclic five-membered ring and PDE IV inhibitory potency.Figure optionsDownload as PowerPoint slide