Five analogs of the active metabolite of leflunomide

Abstract

The title compounds, 2-cyano-3-hydroxy-N-(4-bromo-phenyl)but-2-enamide, C 11 H 9 BrN 2 O 2 (LFM-A1), 2-cyano-3-hydroxy-N-(2-fluorophenyl)but-2-enamide, C 11 H 9 FN 2 O 2 (LFM-A7), 2-cyano-3-hydroxy-N-(3-bromophenyl)but-2-enamide, C 11 H 9 BrN 2 O 2 (LFM-A9), 2-cyano-3 -hydroxy-N-(3 -chlorophenyl)but-2-enamide, C 11 H 9 ClN 2 O 2 (LFM-A10), and 2-cyano-3-hydroxy-N-(3-fluorophenyl)but-2-enamide, C 11 H 9 FN 2 O 2 (LFM-A11), 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 structures 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-CH 3 group are 4.8(8)° for LFM-A1, 12.5 (2)° for LFM-A7, 6.2(6)° for LFM-A9, 5.5 (3)° for LFM-A10 and 4.4(3)° for LFM-A11. The intramolecular hydrogen bond between the O atoms observed in all the compounds locks them into a planar conformation and may contribute to a conformation which is favorable for binding the shallow ATP-binding pocket of EGFR.