Five analogs of the active metabolite of leflunomide

The title compounds, 2-cyano-3-hydroxy-N-(4-bromophenyl)but-2-enamide, C11H 9BrN2O2 (LFM-A1), 2-cyano-3-hydroxy-N-( 2-fluorophenyl)but-2-enamide, C11H9 FN2O2 (LFM-A7), 2-cyano-3-hydroxy-N-(3-bromophenyl)but-2-enamide, C11H9BrN2 O2 (LFM-A9), 2-cyano-3-hydroxy-N-(3-chlorophenyl)but-C11H9ClN2O2 (LFNI-A10) , and 2-cyano-3-hydroxy-N-(3-fluorophenyl)but-2-enamide, C11H9FN2O2 (LFM-A1 1), are analogs of A77 1726, the active metabolite of the immunosupressive drug leflunomide, which is known to act in part by inhibiting the tyrosine kinase epidermal growth factor receptor (EGFR) [Mattar, Kochhar, Bartlett, Bremer & Finnegan (1993), FEBS Lett. 334, 161-164]. The molecular structure s of the title compounds are very similar and they display similar crystal packing and hydrogen-bonding networks. All five molecules are approximately planar; the dihedral angles between the phenyl ring and the plane defined by the N-C-C=C-CH3 group are 4.8(8)degrees for LFM-A1, 12.5 (2)degrees for LFM-A7, 6.2 (6)degrees for LFM-A9, 5.5 (3)degrees for LFM-A10 and 4.4(3)deg rees for LFM-A11. The intramolecular hydrogen bond between the O atoms obse rved in all the compounds locks them into a planar conformation and may con tribute to a conformation which is favorable for binding the shallow ATP-bi nding pocket of EGFR.