Crystal structure of 5-{4′-[(2-{2-[2-(2-ammonioethoxy)ethoxy]ethoxy}ethyl)carbamoyl]-4-methoxy-[1,1′-biphenyl]-3-yl}-3-oxo-1,2,5-thiadiazolidin-2-ide 1,1-dioxide: a potential inhibitor of the enzyme protein tyrosine phosphatase 1B (PTP1B)

A variety of 5-aryl-1,2,5-thiadiazolidin-3-one 1,1-dioxides have been developed as inhibitors of the enzyme protein tyrosine phosphatase 1B (PTP1B). For the title compound, there is the expected twisted relationship between the plane of the 1,2,5-thiadiazolidin-3-one 1,1-dioxide ring and the aryl ring to which it is attached, although the dihedral angle of 62.87 (8)° is substantially less than that seen in certain protein–ligand structures.

The title compound, C 24 H 32 N 4 O 8 S, (I), crystallizes as a zwitterion. The terminal amine N atom of the [(2-{2-[2-(2-ammonioethoxy)ethoxy]ethoxy}ethyl)carbamoyl] side chain is protonated, while the 1,2,5-thiadiazolidin-3-one 1,1-dioxide N atom is deprotonated. The side chain is turned over on itself with an intramolecular N-HÁ Á ÁO hydrogen bond. The 1,2,5-thiadiazolidin-3-one 1,1-dioxide ring has an envelope conformation with the aryl-substituted N atom as the flap. Its mean plane is inclined by 62.87 (8) to the aryl ring to which it is attached, while the aryl rings of the biphenyl unit are inclined to one another by 20.81 (8) . In the crystal, molecules are linked by N-HÁ Á ÁO and N-HÁ Á ÁN hydrogen bonds, forming slabs lying parallel to (010). Within the slabs there are C-HÁ Á ÁO and C-HÁ Á ÁN hydrogen bonds and C-HÁ Á Á interactions present.

Chemical context
A variety of 5-aryl-1,2,5-thiadiazolidin-3-one 1,1-dioxides have been developed as inhibitors of the enzyme protein tyrosine phosphatase 1B (PTP1B) (Combs, 2010). In this capacity, the 5-aryl-1,2,5-thiadiazolidin-3-one 1,1-dioxide core serves as a structural mimic of the phosphoryl tyrosine unit that is present in the endogenous substrates of the enzyme. The parent compound, 5-phenyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide 1 (Fig. 1), is a rather weak inhibitor of PTP1B, displaying a K i value of approximately 2 mM (Black et al., 2005). Docking studies predicted that this compound must bind to the enzyme active site in a conformation where the planes of the 1,2,5-thiadiazolidin-3-one 1,1-dioxide and aryl The parent compound 1 and related compounds. rings are twisted, rather than co-planar (Black et al., 2005). It was further anticipated that installation of substituents such as methyl or methoxy groups on the aryl ring at the position ortho to the 1,2,5-thiadiazolidin-3-one 1,1-dioxide substituent would bias the conformation of the free ligand toward the twisted form, thus serving to 'pre-organize' the compounds for binding to the enzyme active site (Black et al., 2005). Indeed, compounds 2 and 3 (K i values of 100 and 70 mM, respectively) display substantially higher affinities for PTP1B than does 1 (Black et al., 2005). X-ray crystal structure analysis confirmed the twisted conformation of the 1,2,5-thiadiazolidin-3-one 1,1-dioxide and aryl ring systems in the protein-ligand cocrystal structure of 4 bound to PTP1B (Black et al., 2005). The planes of these two rings are nearly perpendicular in the protein-ligand complex (dihedral angle of ca 88 , see: pdb code 2bgd). The ability of methyl and methoxy substituents to favor the twisted relationship between the 1,2,5-thiadiazolidin-3-one 1,1-dioxide and aryl rings in compounds like 2 and 3 has been studied computationally and the twisted relationship of these rings has been experimentally observed in the protein-ligand co-crystal structure of 4 with the enzyme PTP1B. However, to the best of our knowledge no crystal structures of free 5-aryl-1,2,5-thiadiazolidin-3-one 1,1-dioxides have been published. Herein, we describe the crystal structure of the title compound (I), shown in the scheme below, a derivative of compound 4.

Supramolecular features
In the crystal of (I), molecules are linked by N-HÁ Á ÁO and N-HÁ Á ÁN hydrogen bonds, forming slabs lying parallel to the ac plane ( Fig. 3  A view of the molecular structure of the title compound (I), showing the atom labelling. Displacement ellipsoids are drawn at the 50% probability level. The intramolecular N-HÁ Á ÁO hydrogen bond is shown as a dashed line (see Table 1 for details) and C-bound H atoms have been omitted for clarity. Table 1 Hydrogen-bond geometry (Å , ).

Figure 3
A view along the c axis of the crystal packing of the title compound. The N-HÁ Á ÁO and N-HÁ Á ÁO hydrogen bonds are shown as dashed lines (see Table 1 for details) and C-bound H atoms have been omitted for clarity.

Database survey
A search of the Cambridge Structural Database (Version 5.36; Groom & Allen, 2014) revealed no crystal structures of free 5-aryl-1,2,5-thiadiazolidin-3-one 1,1-dioxides. It did reveal the presence of five 1,2,5-thiadiazolidin-3-one 1,1-dioxide compounds substituted at the N atom in the 2-position. In the majority of these compounds, the five-membered 1,2,5-thiadiazolidine rings also have envelope conformations, with the N atom in the 5-position, as in compound (I), as the flap.

Refinement details
Crystal data, data collection and structure refinement details are summarized in Table 2. The N-bound H atoms were located in a difference Fourier map and freely refined. The Cbound H atoms were included in calculated positions and treated as riding: C-H = 0.95-0.99 Å with U iso (H) = 1.5U eq (C) for methyl H atoms and = 1.2U eq (C) for other H atoms.

Special details
Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes. Refinement. Maximum electron density of 0.56 e is in the vicinity of C21 in the extended chain and may represent very minor disorder.