4-Hydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-[4-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide

The title compound, C20H17F3N2O4, named tasquinimod, is a second-generation oral quinoline-3-carboxamide analogue, which is currently in phase III clinical trials for the treatment of metastatic prostate cancer. The quinoline unit is almost planar (r.m.s. deviation of fitted atoms = 0.0075 Å). The carboxamide side chain, substituted at position 3, is tilted by 88.07 (7)° to the quinoline plane. Both the methyl and carbonyl groups of this carboxamide side chain are in a syn conformation. The 4-(trifluoromethyl)phenyl plane is inclined at 50.62 (17)° to the plane of the carboxamide side chain, and at 87.14 (4)° to the plane of the quinoline ring system. The 4-hydroxy H atom acts as a double proton donor in an intramolecular hydrogen bond to the 5-position methoxy O atom and in an intermolecular contact to the 2-oxo group, generating a chain along [010] in the crystal structure.

The title compound, C 20 H 17 F 3 N 2 O 4 , named tasquinimod, is a second-generation oral quinoline-3-carboxamide analogue, which is currently in phase III clinical trials for the treatment of metastatic prostate cancer. The quinoline unit is almost planar (r.m.s. deviation of fitted atoms = 0.0075 Å ). The carboxamide side chain, substituted at position 3, is tilted by 88.07 (7) to the quinoline plane. Both the methyl and carbonyl groups of this carboxamide side chain are in a syn conformation. The 4-(trifluoromethyl)phenyl plane is inclined at 50.62 (17) to the plane of the carboxamide side chain, and at 87.14 (4) to the plane of the quinoline ring system. The 4hydroxy H atom acts as a double proton donor in an intramolecular hydrogen bond to the 5-position methoxy O atom and in an intermolecular contact to the 2-oxo group, generating a chain along [010] in the crystal structure.
Ultimately, tasquinimod will be optimally used in combination with other therapeutic agents. To identify the optimal combinational regime, the identification of the molecular target(s) involved in its mechanism of action is critical. Similar structures have been previously reported (Dasari et al., 2002;Jönsson et al., 2004;Jansson et al., 2006).
As a lead for defining pharmacophoric features of tasquinimod, its three-dimensional structure was determined by X-ray structure analysis. The molecular structure shows that quinoline ring is almost planar (rms deviation of fitted atoms = 0.0075 Å). The carboxamide side chain at position 3, is tilted by 88.07 (7)° to the quinoline plane. Both, the methyl and carbonyl groups of this carboxamide side chain are in a syn conformation. The N-[4-trifluoromethyl)phenyl] plane is inclined at 50.62 (17)° to the plane of the carboxamide side chain, and 87.14 (4)° to the plane of the quinoline ring. The 4-hydroxy proton forms intramolecular hydrogen bond with the 5-position methoxy oxygen being planar to the quinoline ring ( Fig. 1, Table 1). In the crystal packing molecules are linked by an intermolecular hydrogen bond between 4-hydroxy and 2-oxo groups generating a chain in the direction [010] (Fig. 2, Table 1).

Experimental
The preparation of the titled compound was reported by Jönsson et al. (2004).
To obtain crystal of this compound, a saturated solution of a pure sample of the title compound was made in 5 mL of acetonitrile (HPLC grade) at room temperature. The solution was filtered, and 2.5 mL of this saturated solution was transferred into a transparent 2 dram glass vial. Crystallization of this sample was by vapor diffusion in diethyl ether at room temperature over a period of 48 h. Crystal growth was observed within 24 h, but the experiment was left to stand for 48 h. A gentle vacuum filtration of the sample followed by air drying afforded white crystals of the compound for Xray diffraction studies.

Refinement
H atoms were positioned geometrically and refined using the riding model, with C-H distance of 0.93-0.96 Å, with U iso (H) = 1.20 U eq (C) or 1.50 U eq (C) for methyl H atoms. Hydrogen atoms involved in hydrogen bonding were refined  Crystal packing of the title compound viewed along the a axis. Hydrogen bonding is shown by dashed lines.

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. 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 expression of F 2 > σ(F 2 ) is used only for calculating R-factors(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.