N-(4-Methoxyphenyl)-N′-(5-nitro-1,3-thiazol-2-yl)urea

The title compound, C11H10N4O4S, is a derivative of N-(4-methoxybenzyl)-N′-(5-nitro-1,3-thiazol-2-yl)urea (AR-A014418), a known glycogen synthase kinase 3β (GSK-3β) inhibitor. All non-H atoms in the molecule are essentially coplanar, with an r.m.s. deviation of 0.045 Å and a maximum deviation of 0.115 (2) Å for the carbonyl O atom. In the crystal structure, molecules are linked via N—H⋯O hydrogen bonds into one-dimensional chains along [101].


N-(4-Methoxyphenyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea
A. J. Lough, J. W. Hicks, J. F. Valliant,urea (AR-A014418, Bhat et al., 2003) is a selective glycogen synthase kinase-3β (GSK-3β) inhibitor (Inestrosa et al., 2006). Our initial work on AR-A014418 was to radiolabel this compound with carbon-11 at the methoxy position for positron emission tomography (PET) imaging of brain pathologies (Vasdev et al., 2005). To our surprise, [ 11 C]-AR-A014418 had insignificant brain uptake in rodents despite literature precedence (Bhat et al., 2003). To further understand the role of AR-A014418 and GSK-3β, a single-crystal X-ray structure of AR-A014418 was obtained (Vasdev et al., 2007) and overlaid with the structural determination of the co-crystal of GSK-3β and AR-A014418 (Bhat et al., 2003). For that structure, the benyzl ring was bent out of the binding pocket of the kinase. We now endeavour to explore the binding affinity of an analogous molecule which has reduced flexibility (i.e. the benzyl group is replaced with a phenyl group). Biological assays are underway to determine whether the increased rigidity decreases the binding affinity for GSK-3β. Data from these biological studies as well as the crystal structure determinations will assist in designing future ligands for imaging GSK-3β with PET.
The molecular structure of the title compound is shown in Fig. 1. All non-hydrogen atoms in the molecule are essentially co-planar with a r.m.s. deviation of 0.045 Å and a maximum deviation of 0.115 (2)Å for atom O1.
In the crystal symmetry related molecules are linked via N-H···O hydrogen bonds, to form one-dimensional chains propagating along [101] (Table 1, Fig. 2).

Experimental
The title compound, C 11 H 10 N 4 O 4 S, was obtained by heating equimolar amounts of 2-amino-5-nitrothiazole (0.65 mmol) and 4-methoxyphenyl isocyanate (0.65 mmol) in dry N,N-dimethyl formamide (5 ml) in a Biotage Initiator Microwave for 1 h at 403 K under nitrogen. Upon cooling, the reaction mixture was partitioned between ethyl acetate and water and the aqueous layer was further extracted with more ethyl acetate (15 ml). The combined organic layers were washed with brine (3 × 30 ml), dried (MgSO 4 ), filtered, and concentrated prior to purification by silica chromatography (Biotage Isolera Flash system, 98% dichloromethane and 2% methanol). C 11 H 10 N 4 O 4 S was obtained as a red solid in 39% yield (not optimized).
X-ray quality crystals were obtained by slow evaporation of a solution of the title compound in ethyl acetate/hexane ( supplementary materials sup-2 Refinement H atoms bonded to C atoms were placed in calculated positions with C-H = 0.95Å or 0.98Å for methyl groups and included in the refinement with U iso (H) = 1.2U eq (C) or 1.2U eq (C methyl ). H atoms bonded to N atoms were refined independently with isotropic displacement parameters. Fig. 1. The molecular structure of the title compound with probability ellipsoids drawn at the 30% level.  Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expr ession of F 2 > σ(F 2 ) is used only for calculating Rfactors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.