tert-Butyl 6-methyl-2-oxo-4-[4-(trifluoromethoxy)anilino]cyclohex-3-ene-1-carboxylate

In the title compound, C19H22F3NO4, the dihedral angle between the benzene ring and the conjugated part of the enaminone ring is 42.5 (1)°. The ester substituent makes a dihedral angle of 81.3 (2)° with this latter moiety. The crystal structure is held together by strong N—H⋯O and weak C—H⋯O intermolecular interactions. The enaminone ring is disordered over two orientations with relative occupancies of 0.794 (4) and 0.206 (4).

In the title compound, C 19 H 22 F 3 NO 4 , the dihedral angle between the benzene ring and the conjugated part of the enaminone ring is 42.5 (1) . The ester substituent makes a dihedral angle of 81.3 (2) with this latter moiety. The crystal structure is held together by strong N-HÁ Á ÁO and weak C-HÁ Á ÁO intermolecular interactions. The enaminone ring is disordered over two orientations with relative occupancies of 0.794 (4) and 0.206 (4).

Comment
Our research on enaminones has led to several compounds possessing anticonvulsant properties (Edafiogho et al., 1992;Eddington et al., 2003;Scott et al., 1993Scott et al., , 1995. The present work is part of a structural study of enaminones. Our group has extensively studied the effects of modification of the enaminone with substitutions at the methyl ester, ethyl ester, and without the ester group. We synthesized a series of carbo-tert-butoxy esters to evaluate the effect of added bulk and lipophilicity to the ester functionality. The title compound, tert-butyl-4-(4-trifluoromethoxyphenylamino)-6-methyl-2-oxocyclohex-3-en-1-oate (10) is highly active, with activity at <100 mg kg -1 .
The compound was exclusively active in maximal electroshock seizure evaluation (MES) in mice, indicative of protection against tonic-clonic convulsions in humans (1/4 rats were protected at 15 min then 3/4 rats at 2 h and 4 hrs at post dose 50 mg kg -1 in rats, orally). The MES test with mice revealed no activity in the 30 minute study, however in the 4 h MES test 1/1 animals were protected at 30 mg kg -1 , 3/3 animals protected at 100 mg kg -1 , and 1/1 at 300 mg kg -1 with no toxicity. The scMET (subcutaneous phentylenetetrazole assessment), indicative of protection against absence seizures was 0/2 animals protected in doses of 62.5 to 500 mg kg -1 . The compound displayed no toxicity from 62.5 to 500 mg kg -1 from 15 min to 24 h time range in all doses. A four hour MES test showed 4/16 mice protected at 100 mg kg -1 dose and maximium protection (7/8 mice protected) at 150 and 200 mg kg -1 . In mice, a MES ED 50 (median effective dose) of 121.87 mg kg-1 and TD 50 (median toxic dose) of >500 mg kg-1, provided a protective index PI (defined as the ration of the median toxic dose to the median effective dose) at 95% confidence interval.
In view of the therapeutic interest in this compound its structure was determined. The conformation adopted by the molecule is such that the dihedral angle between the phenyl ring and conjugated part of the enaminone ring is 42.5 (1)°. The ester substituent makes a dihedral angle of 81.3 (2)° with this latter moiety. The crystal structure is held together by strong N-H···O and weak C-H···O intermolecular interactions. The enaminone ring is disordered over two conformations with relative occupancies of 0.794 (4)/0.206 (4).
supplementary materials sup-2 Refinement H atoms were placed in geometrically idealized positions and constrained to ride on their parent atoms with a C-H distances of 0.95 to 1.00 Å U iso (H) = 1.2U eq (C) and 0.98 Å for CH 3 [U iso (H) = 1.5U eq (C)]. The H atoms attached to N were idealized with an N-H distance of 0.88 Å. The enaminone ring is disordered over two conformations with relative occupancies of 0.794 (4)/0.206 (4). Each component was constrained to have similar metrical and thermal parameters Figures Fig. 1. Diagram of tert-butyl-4-(4-trifluoromethoxyphenylamino)-6-methyl-2-oxocyclohex-3-en-1-oate showing atom labeling scheme. Thermal ellipsoids drawn at the 30% probability level.