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

Alan J Lough; Justin W Hicks; John F Valliant; Alan A Wilson; Neil Vasdev

doi:10.1107/S1600536810032186

. 2010 Aug 18;66(Pt 9):o2339. doi: 10.1107/S1600536810032186

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

Alan J Lough ^a,^*, Justin W Hicks ^b, John F Valliant ^c, Alan A Wilson ^b, Neil Vasdev ^b

PMCID: PMC3008116 PMID: 21588684

Abstract

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].

Related literature

For background information on the preparation and activity of AR-A014418, see: Bhat et al. (2003 ▶); Inestrosa et al. (2006 ▶). For the radiolabelling procedure of AR-A014418 with carbon-11, see: Vasdev et al. (2005 ▶). For the crystal structure of AR-A014418, see: Vasdev et al. (2007 ▶).

Experimental

Crystal data

C₁₁H₁₀N₄O₄S
M _r = 294.29
Monoclinic,
a = 6.8740 (3) Å
b = 12.5840 (7) Å
c = 14.6861 (5) Å
β = 101.622 (3)°
V = 1244.34 (10) Å³
Z = 4
Mo Kα radiation
μ = 0.28 mm⁻¹
T = 150 K
0.28 × 0.24 × 0.22 mm

Data collection

Nonius KappaCCD diffractometer
Absorption correction: multi-scan (SORTAV; Blessing, 1995 ▶) T _min = 0.718, T _max = 0.948
8106 measured reflections
2825 independent reflections
1979 reflections with I > 2σ(I)
R _int = 0.053

Refinement

R[F ² > 2σ(F ²)] = 0.050
wR(F ²) = 0.145
S = 1.07
2825 reflections
190 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.38 e Å⁻³
Δρ_min = −0.51 e Å⁻³

Data collection: COLLECT (Nonius, 2002 ▶); cell refinement: DENZO-SMN (Otwinowski & Minor, 1997 ▶); data reduction: DENZO-SMN; program(s) used to solve structure: SIR92 (Altomare et al., 1994 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: PLATON (Spek, 2009 ▶); software used to prepare material for publication: SHELXTL (Sheldrick, 2008 ▶).

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536810032186/su2205sup1.cif

e-66-o2339-sup1.cif^{(15.8KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810032186/su2205Isup2.hkl

e-66-o2339-Isup2.hkl^{(138.7KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N2—H2N⋯O4ⁱ	0.86 (3)	1.97 (3)	2.817 (3)	168 (3)
N3—H3N⋯O3ⁱ	0.87 (3)	2.30 (3)	3.168 (2)	174 (2)

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Symmetry code: (i) Inline graphic .

Acknowledgments

We thank Dr Sylvain Houle for allowing the CAMH PET Centre facilities to be used for this research. Funding was provided by the Ontario Ministry for Research and Innovation (Early Researcher Award to NV).

supplementary crystallographic information

Comment

N-(4-methoxybenzyl)-N'--(5-nitro-1,3-thiazol-2-yl)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, [¹¹C]-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, C₁₁H₁₀N₄O₄S, 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 (MgSO₄), filtered, and concentrated prior to purification by silica chromatography (Biotage Isolera Flash system, 98% dichloromethane and 2% methanol). C₁₁H₁₀N₄O₄S 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 (50/50) containing 5% ethanol. ¹H NMR (DMSO d₆, 400 MHz) δ 11.75 (s, 1 H, NH), 9.28 (s, 1H, NH), 8.53 (s, 1H, thiazole), 7.41 (d, J = 8.9 Hz, 2H, Ar), 6.91 (d, J = 8.9 Hz, 2H, Ar), 3.73 (s, 3H, CH₃). HRMS (ESI) m/z calcd for C₁₁H₁₁N₄O₄S, 295.0495; found 295.0483 (M⁺+H), m.p. = 454–456 K.