Crystal structures of 2-methoxyisoindoline-1,3-dione, 1,3-dioxoisoindolin-2-yl methyl carbonate and 1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-2-yl methyl carbonate: three anticonvulsant compounds

In three potentially anticonvulsant compounds, of which two are isoindoline derivatives and one an isoquinoline derivative, the central moiety is planar. In the crystals of all three compounds, there are C—H⋯O hydrogen bonds present linking the molecules into two-dimensional slabs for the isoindoline derivatives, and into a three-dimensional framework for the isoquinoline derivative.


Chemical context
Traumatic brain injury (TBI) is a neurological disorder that is defined as damage to the brain resulting from external mechanical force, including accelerating, decelerating and rotating forces (Langlois et al., 2003(Langlois et al., , 2005Ashman et al., 2006;Coronado et al., 2011). TBI also exacerbates seizure severity in individuals with pre-existing epilepsy (Ferraro et al., 1999), being one example of the process of epileptogenesis (Christensen et al., 2009). In this context, it has been demonstrated that early lesions in the central nervous system (CNS) alter the transport dynamic of the blood-brain barrier (BBB) and deteriorate the balance of the inhibitory and excitatory neurotransmitter system (Scantlebury et al., 2005]. This neuronal dysfunction predisposes to subsequent development of spontaneous recurrent seizures in the presence of prior subtle brain malformation (Love, 2005]. TBI is the major cause of death in young individuals (14-24 years) from industrialized countries, with head injuries accounting for 25-33% of all trauma-related deaths (Abdul-Muneer et al., 2014). Disorders like memory loss, depression and seizures are some of the side effects to TBI. TBI affects people over 75 years of age because of falls and of 17-25 years of age because of accidents (Langlois et al., 2003(Langlois et al., , 2005Ashman et al., 2006;Coronado et al., 2011). At present, there are no effective treatments available for TBI and there is thus a critical need to develop novel and effective strategies to alter the disease course. As indicated above, this health condition is quite similar to epilepsy in some instances and thus our earlier work (Alexander et al., 2013;Jackson et al., 2012;Edafiogho et al., 2007) on developing anticonvulsant compounds for the treatment of epilepsy is relevant.
Our research on pharmacologically active compounds is a multi-pronged approach, which involves synthesis, chemical characterization, computer modeling, pharmacological evaluation, and structure determination (North et al., 2012;Gibson et al., 2009). From this comprehensive approach, structure-activity correlations can be made to improve the existing pharmacologically active compounds. From our studies, we identified three imidooxy derivatives as potential drug candidates for TBI that underwent anticonvulsant evaluation to test their ability to inhibit the onset of seizures in the in vivo MES, scPTZ test models. The MES (maximal electroshock seizure evaluation) test presented activity in animals in phase 1 testing.
2-Methoxyisoindoline-1,3-dione, (1), studied by X-ray techniques, was inactive in MES and scPTZ in mice, but showed MES protection in rat studies at 50 mg kg À1 at 4 h and also protected 1/4 mice at three different time intervals (0.50, 1 and 2 h) in the 6 Hz test (Jackson, 2009). For scPTZ studies, the compound was Class III (no activity at 300 mg kg À1 ). The compound is a dual MES/6Hz active compound. Compounds (2) and (3) showed similar activity.

Structural commentary
In compound (1), the isoindoline ring is planar [r.m.s. deviation = 0.017 (4) Å ]. The methoxy O atom, O3, deviates from this plane by 0.176 (6) Å while the methyl C atom, C9, is out of the plane by 1.105 (9) Å . The methoxy substituent is oriented almost perpendicular to the indoline ring with the dihedral angle between the mean planes of the indoline ring and the methoxy substituent being 89.7 (3) .
In compound (2), there are two molecules (A and B) in the asymmetric unit. The isoindoline ring is planar [r.m.s. deviation = 0.0327 (9) for A and 0.0147 (9) Å for B] with the dione O atoms significantly out of the plane for molecule A but not for molecule B [0.172 (1) and 0.123 (1) Å for atoms O1 and The molecular structure of compound (1), with atom labelling. Displacement ellipsoids are drawn at the 30% probability level.

Figure 2
The molecular structures of the two independent molecules (A and B) of compound (2), with atom labelling. Displacement ellipsoids are drawn at the 30% probability level. The C-HÁ Á ÁO hydrogen bond is shown as a dashed line (see Table 2 for details).
O2, respectively, in A but by only 0.013 (1) and 0.002 (1) Å , respectively, in B]. The carbonato moiety is planar in both molecules [r.m.s. deviations of 0.0066 (2) and 0.0027 (5) Å for A and B, respectively] and makes dihedral angles of 71.50 (3) and 80.03 (4) with the benzoisoquinoline ring in A and B, respectively, indicating that these substituents are oriented almost perpendicular to the benzoisoquinoline ring system.
In compound (3), there are also two molecules (A and B) in the asymmetric unit. In both molecules, the benzoisoquinoline ring systems are planar (r.m.s. deviations for A and B = 0.033 and 0.015 Å , respectively). The methoxy O atom deviates from this plane by 0.126 (1) for atom O5A in A and 0.156 (1) Å for atom O5B in B. The methyl carbonate moieties are planar [r.m.s. deviations of 0.007 (1) and 0.003 (1) Å for A and B, respectively] and these substituents are oriented almost perpendicular to the isoquinoline rings, making dihedral angles of 71.50 (3) and 80.04 (4) for A and B, respectively. As in (2), these dihedral angles are significantly smaller than that found for (1).
In the crystal of (2), the A and B molecules are linked by C-HÁ Á ÁO hydrogen bonds (Fig. 5 and Table 2), forming slabs parallel to (101). The slabs are in turn linked viainteractions, forming a three-dimensional structure with centroidcentroid distances of 3.4202 (7) for Cg1Á Á ÁCg5 ii and 3.5445 (7)   The molecular structures of the two independent molecules (A and B) of compound (3), with atom labelling. Displacement ellipsoids are drawn at the 30% probability level. The C-HÁ Á ÁO hydrogen bond is shown as a dashed line (see Table 3 for details).

Figure 5
A view along the a axis of the crystal packing of compound (2), showing the three-dimensional array formed by an extensive network of C-HÁ Á ÁO hydrogen bonds (dashed lines; see Table 2 for details).

Database survey
A search of the Cambridge Structural Database (Version 5.35; Groom & Allen, 2014) for the indoline skeleton gave 26 hits. In all cases, the geometrical parameters of the indoline skeleton are similar to those observed in compounds (1) and (2). In the case of the isoquinoline structure, there are only two structures containing the planar isoquinoline moiety with similar geometrical parameters to the present structure, (3).

Synthesis and crystallization
Compound (1): To a freshly prepared solution of sodium (2.3 g, 0.10 mol) in absolute ethanol (60 ml) was added a solution of N-hydroxy- For molecule A in compound (2), perpendicular interactions between atoms O1A and C9A (shown as dashed lines) link the molecules into inversion dimers [symmetry code: (A) À x + 1, À y + 2, Àz].

Figure 8
A view along the a axis of the crystal packing of compound (3), showing the formation of the three-dimensional array by an extensive network of C-HÁ Á ÁO hydrogen bonds (dashed lines; see Table 3 for details). phthalimide (16.3 g, 0.10 mol) in absolute ethanol (350 ml), and the red reaction mixture was stirred at room temperature for 30 min. The brick-red precipitate was collected, washed with water, and dried in the oven at 373 K for 30 min to give 17.45 g (95%) of sodium phthalimide oxide as brick-red crystals; m.p. > 573 K. To the solution of sodium phthalimide oxide (0.92 g, 5 mmol) in water (15 ml) was added acetone (10 ml), followed by a solution of bromomethane (0.66 g, 7 mmol). The reaction mixture was stirred at room temperature for 16 h, during which the red color disappeared. On standing at room temperature for 48 h, the product solidified in the aqueous mixture and was collected. Recrystallization from 2-propanol gave 0.72 g (78%) of compound (1) as platelike colorless crystals: m.p. 395-397 K; 1 H NMR (CDC1 3 ) 3.36 (s, 3H, J = 6 Hz, OCH 3 ), 5.52, s, 1 H,CH, 7.87 (m, 4 H, phthalimido ring).
(1) 2-Methoxyisoindoline-1,3-dione where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.50 e Å −3 Δρ min = −0.34 e Å −3 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.