Cyclooxygenase-1-selective inhibitor SC-560

In the title compound, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560), C17H12ClF3N2O, a COX-1-selective inhibitor, the dihedral angles between the heterocycle and the chlorobenzene and methoxybenzene rings are 41.66 (6) and 43.08 (7)°, respectively. The dihedral angle between the two phenyl rings is 59.94 (6)°. No classic hydrogen bonds are possible in the crystal, and intermolecular interactions must be mainly of the dispersion type. This information may aid the identification of dosage formulations with improved oral bioavailability.


Experimental
Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: PV2130).

Comment
Inhibition of the two cyclooxygenase (COX) isoforms is considered the primary mechanism responsible for both the therapeutic and toxic effects of nonsteroidal anti-inflammatory drugs (NSAIDS) (Smith, et al., 2000). Both of the COX isoforms have been shown to contribute to inflammation and tumor genesis, and therapeutic benefits may result from either COX-1 or COX-2 selective inhibition (Tiano, et al. 2002;Choi, et al. 2008;Kundu & Fulton, 2002;Cusimano, et al. 2007). The development of the COX-2-selective inhibitor celecoxib led to identification of a variety of structurally related compounds with varying selectivity for the COX isoforms, SC-560 was one of them (Penning, et al. 1997;Choi, et al. 2008). However, SC-560's poor bioavailability may limit its effects (Teng, et al. 2003). The information from crystal structure may provide direction in suitable dosage formulation. Herein, we describe the first crystal structure of SC-560, (I), a selective and potent inhibitor of the cyclooxygenase-1 isoform (Penning, et al. 1997).
The crystal structure of (I) is presented in Fig. 1. The structure lacks the moieties necessary for hydrogen-bonding to occur between molecules (Fig. 2). Thus, the lattice energy mainly consists of dispersion energies, which typically result in a low melting point because of the weak intermolecular interactions (as confirmed by melting point measurement). Despite the entire chemical structure being fused together by three aromatic rings, a large conjugate system between the rings is not seen due to steric repulsion between the two phenyl rings. Similar structures are abundant in the Cambridge Structural Database (CSD -Version 5.29; Allen, 2002), EYISAG (Sonar, et al. 2004), IZAYUD (Charlier, et al. 2004), JAQBIN (Norris, et al. 2005), and MAJGUA (Zhu, et al. 2004) are few of them. To conclude, the single-crystal structure of SC-560 was solved. Because there is no hydrogen bonding in the structure, the major contribution for the lattice energy stems from weak dispersion energies leading to its low melting point at 335.5 K.

Experimental
Commercial SC-560 was dissolved in HPLC grade methanol in a glass vial at room temperature. The vial was sealed with Parafilm with numerous pin-size holes introduced to allow for evaporation of the solvent. Colorless block crystals were obtained following approximately one week of slow evaporation.

Refinement
H atoms were found in difference Fourier maps and those on the aromatic ring subsequently placed in idealized positions with C-H distances of 0.95 Å and isotropic displacement parameters equal to 1.2U eq of the attached carbon atom. Hydrogen atom coordinates in the methyl group were placed in idealized positions with C-H distances of 0.98 Å and isotropic displacement parameters of 1.5U eq of the carbon atom.
supplementary materials sup-2 Figures Fig. 1. The molecular structure of (I), showing atom displacement ellipsoids at the 50% probability level.