Synthesis, Crystal Structure and URAT1 Inhibitory Activity of 2-((5-Bromo-4-((4-cyclobutylnaphth-1-yl)methyl)-4H-1,2,4-triazol-3-yl)thio)acetic Acid

摘要

The title compound 1 was prepared from 1-bromonaphthalene and cyclobutanone in 11 steps,and its structure was determined by single-crystal X-ray diffraction for its monohydrate.The title compound 1 crystallizes as its monohydrate (C19H18BrN3O2S·H2O,Mr =450.35) in triclinic,space group P1 with a =8.195(3),b =8.703(3),c =14.610(4) (A),a =90.290(4),β =93.764(9),γ =116.435(10)°,V =930.3(5) (A)3,Z =2,Do =1.608 g/cm3,F(000) =460,μ =2.347 mm-1,the final R =0.0314 and wR =0.0746 for 3368 observed reflections (I ＞ 2σ(I)).The cyclobutane ring adopts a puckered conformation.The crystal lattice is stabilized by three intermolecular hydrogen bonds involving the existing water molecule.1 was a highly active urate transporter 1 (URAT1) inhibitor as it was 14-fold more active in in vitro human URAT1 inhibitory assay versus positive control lesinurad (IC50 =0.51μM for 1 vs.7.18μM for lesinurad against human URAT1).The single-crystal structure for the monohydrate of 1 reported herein represents the tirst unambiguous structural determination of a novel flexible molecular scaffold we discovered earlier that was very promising for the design of highly active URAT 1 inhibitors.