Two polymorphs of N-(2-meth­oxy­phen­yl)-4-oxo-4H-chromone-3-car­box­amide

Neurodegenerative diseases, such as Alzheimer's and Parkinson's, are growing in incidence with the increase in life expe­cta­ncy of the human population. They remain an unmet clinical need, and the search for new targets and effective treatments with disease-modifying properties is still an incomplete endeavour.

Mono­amine oxidase (MAO), a mammalian enzyme present in two isoforms (MAO-A and MAO-B), is an attractive drug target as it plays a central role in neurotransmitter metabolism. In fact, MAO-B inhibitors are relevant drugs in the therapy of Parkinson's disease (Edmondson et al., 2004; Youdim & Buccafusco, 2005; Riederer et al., 2004) as they have the capacity to prolong the action of dopamine in the brain. However, the MAO-B inhibitors that are currently used in therapy have several associated side effects as they are of the irreversible type [The inhibitors or the side effects?] (Gaspar, Reis et al., 2011; Gaspar, Silva et al., 2011; Gaspar, Teixeira et al., 2011; Reis et al., 2012). Therefore, there is still a great need for the discovery of MAO-B inhibitors with an enhanced and a safer pharmacological profile.

The chromone scaffold has emerged as a fruitful approach to the discovery of novel drugs as it allows the attainment of a versatile chemistry platform and putative potent and selective agents for a range of different biological targets. In fact, the chromone scaffold has been the central core in diverse medicinal chemistry programmes (Alcaro et al., 2010; Gaspar, Reis, Kachler et al., 2012), for the development of novel MAO-B inhibitors (Alcaro et al., 2010; Gaspar, Reis et al., 2011; Gaspar, Silva et al., 2011; Gaspar, Teixeira et al., 2011) as well as of adenosine receptor ligands (Gaspar, Reis, Kachler et al., 2012; Gaspar, Reis, Matos et al., 2012). In this context, the structural characterization of the polymorphic forms of the title novel chromone carboxamide derivative, (I), is presented in this work. Unequivocal characterization of chromones is of the utmost importance in medicinal chemistry projects as it allows the speeding up of studies of structure–activity relationships and molecular docking. In fact, polymorphism has a special relevance in pharmaceutical processing and formulation due to its impact on key drug properties, such as dissolution rate and stability.

Crystal data, data collection and structure refinement details are summarized in Table 1.

All chemicals were of analysis grade and were purchased from Sigma–Aldrich Química S.A. (Sintra, Portugal) and used without additional purification.

For the synthesis of (I), POCl₃ (2.6 mmol) was added to a solution of chromone-3-carb­oxy­lic acid (1.3 mmol) in di­methyl­formamide (2 ml). The mixture was stirred at room temperature for 30 min, resulting in the formation of the corresponding acyl chloride in situ. 2-Meth­oxy­aniline (1.9 mmol) was then added and the solution stirred for 1 h. The mixture was then diluted with di­chloro­methane (20 ml) and washed with H₂O (3 × 10 ml) and saturated NaHCO₃ solution (3 × 10 ml). The organic phase was dried with Na₂SO₄, filtered and concentrated under reduced pressure. Crystals of (I) suitable for X-ray diffraction were obtained by recrystallization from ethyl acetate (for polymorph A) or CH₂Cl₂/n-hexane [Solvent ratio?] (for polymorph B).

H atoms were located in difference maps and treated as riding atoms, with aromatic C—H = 0.95 Å and N—H = 0.88 Å, with U_iso(H) = 1.2U_eq(C), and with methyl C—H = 0.98 Å, with U_iso(H) = 1.5U_eq(C). The positions of the N-bound H atom and the methyl groups were checked on a final difference map.

The title compound, (I), crystallizes in two polymorphic forms (Figs. 1 and 2), referred to as polymorphs A and B. In both structures, the compound crystallizes in the space group P2₁/c with two molecules (1 and 2) in the asymmetric unit. Here, atom labels have the general notation nx, where n = 1 or 2 referring to molecules 1 or 2 and x refers to the numbering of the atom, so that molecules 1 are labelled 1x and molecules 2 as 2x, in both polymorphs.

Molecular conformation may be the most relevant information that solid-state X-ray analysis can give with respect to the prediction of pharmacological activity of chromones and to give an insight concerning their structure–activity profiles, while the supra­molecular strucure may condition the bioavailability of the compound. The conformation of these molecules is driven by the carboxamide residue: they exhibit an anti configuration with respect to the C—N rotamer of the amide, which allows for the establishment of three or four intra­molecular hydrogen bonds. As can be seen by the information given in Table 1 and Fig. 3, amide atom Nn3 acts as a donor to the O atom of the meth­oxy group and to the carbonyl O atom of the chromone ring. This donation allows the formation of a six-membered S(5) ring (R₃ in Fig. 3) and a five-membered S(6) ring (R₁), respectively (Bernstein et al., 1995). Also, the amide O atom acts as an acceptor for a weak hydrogen-bond inter­action (Cn36—Hn36···On3; ortho position of the benzyl ring), forming another S(6) ring (Fig. 3). A fourth hydrogen-bond inter­action involving the amide O atom may also be considered, viz. Cn2—Hn2(ortho-chromene), giving an S(5) ring (Fig. 3).

There are slight differences in geometry between the molecules, although the hydrogen-bonding network restrains their geometry, particularly the rotation of the aromatic rings around the carboxamide group. The chromone rings are mostly planar, as expected. For polymorph A, the mean planes formed by all the non-H atoms of the chromone ring in molecules 1 and 2 have maximum deviations of -0.020 (1) and -0.017 (1) Å, respectively, for atoms C14 and C24, while for polymorph B the corresponding values are -0.044 (4) and -0.011 (4) Å, respectively, for atoms C12 and C27. Table 3 gives the values calculated for the dihedral angles between the mean planes of the chromone and benzene rings, θ₁, between the mean plane of the chromone and the plane defined by atoms On31/Cn37/Nn3, θ₂, and between the mean plane of the benzene ring and that defined by atoms On31/Cn37/Nn3 of the amide group, θ₃. Molecule 2 of polymorph A is practically planar, whereas the remaining ones present slight torsions between the defined planes. In molecule 2 of polymorph B, the amide group is practically coplanar with the chromone ring, with the overall deviation from planarity being due to the torsion of the benzene substituent in relation to the On31—Cn37—Nn3 residue. In contrast, the deviations from planarity that both molecules 1 exhibit are due to some degree of bending of the Cα and Cα' atoms (Cn31 and Cn3) out of the On31—Cn37—Nn3 plane of the amide. This bending is followed by a lengthening of the inter­nal hydrogen-bond contacts involving carbonyl atom O131, thus making the pseudo-rings R₂ and R₄ less flat in these molecules.

The differences in conformation between molecules 1 and 2 of the polymorphs can be assessed by the quaternion fit method (Mackay, 1984), which fits molecule 1 onto molecule 2 of polymorph A with a rotation angle of -174° about the (pseudo)axis, giving a weighted fit of 0.131 Å and a unit weight r.m.s. fit of 0.137 Å for 22 fitted atoms. In polymorph B, molecule 1 fits onto molecule 2 with a rotation angle of -31° about the (pseudo)axis, with a weighted fit of 0.187 Å and a unit weight r.m.s. fit of 0.181 Å for the 22 fitted atoms (Figs. 4 and 5). Table 3 gives the quaternion fit parameters for all pairs of molecules. These values indicate that the differences in conformation are slightly greater for the molecules 1 and 2 of polymorph B and these differences can be appreciated graphically in Figs. 4 and 5. However, when the molecules of polymorph A are compared with those of polymorph B (Table 3), it can be seen that molecule 1 of polymorph A is very close in conformation to molecule 2 of polymorph B and, to a lesser extent, the conformation of molecule 2 of polymorph A is close to that of molecule 1 of polymorph B.

It is inter­esting to compare the inter­nal hydrogen-bond network presented by this compound with the analogous N-(2-meth­oxy­phenyl)-4-oxo-4H-2-chromone carboxamide (Gomes et al., 2013) having the same configuration (see Fig. 6). As can be seen, the amidic substitution at the 3-position of the chromone system `inverts' the relative position of the O-atom pair On1/On4 of the chromone ring with respect to the phenyl­amide, compared with the structure of the 2-chromone carboxamide. From a structural point of view, this inversion permits the formation of two pseudo-six-membered rings in the chrom-3-one, in contrast with one pseudo-six-membered ring and one pseudo-five-membered ring in the 2-substituted compound. Moreover, in the 3-substituted compound, the acceptor for the N-bound H atom is the oxo O atom of the chromone ring, instead of the heteroatom in the 2-substituted compounds. These differences suggest that 3-substituted chromones may be structurally more stable than their 2-substituted analogues. These particular differences may also determine the availability for docking when their pharmacological activities are kept in mind.

In polymorph A, the molecules of the selected asymmetric unit are linked by weak C12—H12···O231 and C22—H22···O131 hydrogen bonds to form dimers (Fig. 1). In polymorph B, the molecules within the selected asymmetric unit are connected by a weak C25—H25···O11 hydrogen bond.

Details for both compounds are given in Table 2. There are no inter­molecular hydrogen bonds in polymorph A other than those which form the dimer described above. The supra­molecular structure is determined by π–π stacking inter­actions as described below. In polymorph B, the supra­molecular hydrogen-bond pattern is best described in terms of the individual structures which comprise it. As described above, the molecules within the selected asymmetric unit are connected by a weak C25—H25···O11 hydrogen bond. The molecules in the asymmetric unit are linked to form a centrosymmetric R₄⁴(24) quadrimer [tetra­mer?] across a centre of symmetry at (1/2, 1/2, 1/2) by a C22—H22···O131 hydrogen bond (Fig. 7). In addition, the molecules in the asymmetric unit are linked by a weak C16—H16···O231(x + 1, y, z) hydrogen bond to form C₂²(13) chains, which run parallel to the a axis (Fig. 8). A weak C133—H133···O132(x, -y + 3/2, z + 1/2) hydrogen bond links molecules 1 into a C(4) chain produced by the action of a c-glide at y = 3/4 which runs along the c axis (Fig. 9).

Table 5 gives details for the π–π stacking parameters between the chromone rings in both compounds. In all cases, packing takes place between centrosymetrically related molecules of the same type. Views of the packing perpendicular to the chromone rings are shown in Fig. 10 for polymorph A and in Fig. 11 for polymorph B. In polymorph A, in the case of molecule 2, there is a possible inter­action between the chromone ring and the 2-meth­oxy­phenyl ring at (-x + 1, -y + 1, -z + 1). The pyran ring is inclined to this latter ring at an angle of 2.82 (6)° [centroid separation 3.5263 (10) Å] and to the benzene ring of the chromone system at 2.14 (6)° [centroid separation 3.6509 (11) Å]. In all cases, the perpendicular distances between the centroids and the planes are less than 3.5 Å.

There are similar inter­actions between the chromone and meth­oxy­phenyl rings in polymorph B, where the centroid-to-centroid distance is less than 4 Å but the angles between the planes lie in the range 5–11°. In all cases, the perpendicular distances between the centroids and the planes are less than 3.5 Å. This overlap of rings for molecule 2 is shown in Fig. 7.