Cyclo­oxygenase-1-selective inhibitor SC-560

Sihui Long; Kathryn L Theiss; Tonglei Li; Charles D Loftin

doi:10.1107/S1600536809001779

. 2009 Jan 23;65(Pt 2):o360. doi: 10.1107/S1600536809001779

Cyclooxygenase-1-selective inhibitor SC-560

Sihui Long ^a, Kathryn L Theiss ^a, Tonglei Li ^a, Charles D Loftin ^a,^*

PMCID: PMC2968361 PMID: 21581958

Abstract

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.

Related literature

For background literature, see: Choi et al. (2008 ▶); Cusimano et al. (2007 ▶); Kundu & Fulton (2002 ▶); Penning et al. (1997 ▶); Smith et al. (2000 ▶); Teng et al. (2003 ▶); Tiano et al. (2002 ▶); For related structures, see: Allen (2002 ▶); Charlier et al. (2004 ▶); Norris et al. (2005 ▶); Sonar et al. (2004 ▶); Zhu et al. (2004 ▶).

Experimental

Crystal data

C₁₇H₁₂ClF₃N₂O
M _r = 352.74
Monoclinic,
a = 15.585 (3) Å
b = 7.1671 (14) Å
c = 15.789 (3) Å
β = 116.81 (3)°
V = 1574.1 (5) Å³
Z = 4
Mo Kα radiation
μ = 0.28 mm⁻¹
T = 90 (2) K
0.20 × 0.10 × 0.10 mm

Data collection

Nonius KappaCCD diffractometer
Absorption correction: multi-scan (SCALEPACK; Otwinowski & Minor, 1997 ▶) T _min = 0.946, T _max = 0.972
6895 measured reflections
3608 independent reflections
3030 reflections with I > 2σ(I)
R _int = 0.020

Refinement

R[F ² > 2σ(F ²)] = 0.035
wR(F ²) = 0.094
S = 1.04
3608 reflections
218 parameters
H-atom parameters constrained
Δρ_max = 0.34 e Å⁻³
Δρ_min = −0.29 e Å⁻³

Data collection: COLLECT (Hooft, 1998 ▶); cell refinement: DENZO-SMN (Otwinowski & Minor, 1997 ▶); data reduction: DENZO-SMN; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: SHELXTL (Sheldrick, 2008 ▶); software used to prepare material for publication: SHELXTL and local procedures.

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536809001779/pv2130sup1.cif

e-65-0o360-sup1.cif^{(19KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809001779/pv2130Isup2.hkl

e-65-0o360-Isup2.hkl^{(176.9KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Acknowledgments

SL and TL are grateful for financial support by the NSF (DMR– 0449633). The authors also thank Dr Sean Parkin for providing laboratory facilities and for helpful discussions.

supplementary crystallographic information

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.