



Supporting information
![]() | Crystallographic Information File (CIF) https://doi.org/10.1107/S1600536810046969/hg2750sup1.cif |
![]() | Structure factor file (CIF format) https://doi.org/10.1107/S1600536810046969/hg2750Isup2.hkl |
CCDC reference: 803225
Key indicators
- Single-crystal X-ray study
- T = 123 K
- Mean
(C-C) = 0.003 Å
- Disorder in main residue
- R factor = 0.058
- wR factor = 0.160
- Data-to-parameter ratio = 13.8
checkCIF/PLATON results
No syntax errors found
Alert level A PLAT723_ALERT_1_A Torsion Calc 86.00, Rep 9.00 Dev... 77.00 Sigma C9B -C8 -C9A -C10A 1.555 1.555 1.555 1.555 23
Alert level B PLAT230_ALERT_2_B Hirshfeld Test Diff for O3 -- C15 .. 7.72 su PLAT230_ALERT_2_B Hirshfeld Test Diff for C15 -- C11B .. 10.26 su
Alert level C PLAT242_ALERT_2_C Check Low Ueq as Compared to Neighbors for C7 PLAT366_ALERT_2_C Short? C(sp?)-C(sp?) Bond C8 - C13 ... 1.36 Ang. PLAT910_ALERT_3_C Missing # of FCF Reflections Below Th(Min) ..... 1 PLAT911_ALERT_3_C Missing # FCF Refl Between THmin & STh/L= 0.600 3 PLAT912_ALERT_4_C Missing # of FCF Reflections Above STh/L= 0.600 104
Alert level G PLAT301_ALERT_3_G Note: Main Residue Disorder ................... 13.00 Perc. PLAT773_ALERT_2_G Check long C-C Bond in CIF: C11B -- C15 . 1.74 Ang. PLAT720_ALERT_4_G Number of Unusual/Non-Standard Labels .......... 4 PLAT779_ALERT_4_G Suspect or Irrelevant (Bond) Angle in CIF .... # 35 C9B -C8 -C9A 1.555 1.555 1.555 6.00 Deg. PLAT779_ALERT_4_G Suspect or Irrelevant (Bond) Angle in CIF .... # 83 C11B -C12 -C11A 1.555 1.555 1.555 35.10 Deg. PLAT779_ALERT_4_G Suspect or Irrelevant (Bond) Angle in CIF .... # 92 C11A -C15 -C11B 1.555 1.555 1.555 32.10 Deg. PLAT793_ALERT_4_G The Model has Chirality at C10A (Verify) .... S PLAT793_ALERT_4_G The Model has Chirality at C11A (Verify) .... R PLAT811_ALERT_5_G No ADDSYM Analysis: Too Many Excluded Atoms .... !
1 ALERT level A = In general: serious problem 2 ALERT level B = Potentially serious problem 5 ALERT level C = Check and explain 9 ALERT level G = General alerts; check 1 ALERT type 1 CIF construction/syntax error, inconsistent or missing data 5 ALERT type 2 Indicator that the structure model may be wrong or deficient 3 ALERT type 3 Indicator that the structure quality may be low 7 ALERT type 4 Improvement, methodology, query or suggestion 1 ALERT type 5 Informative message, check
4-Carbo-t-butoxy-5-methylcyclohexane-1,3-dione (6.11 g, 27 mmol), mp 145–146°C (lit. mp 130–131.5°C), and 4-trifluoromethoxyaniline (4.428 ml g, 33 mmol) were added to a mixture of absolute EtOH (100 ml) and EtOAc (100 ml), and the solution was refluxed and stirred for 6 h with azeotropic removal of water by Dean-Stark trap. Evaporation under reduced pressure yielded a yellow solid which was recrystallized from 2-PrOH, 47% yield (mp 168–171°C). ).
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 Uiso(H) = 1.2Ueq(C) and 0.98 Å for CH3 [Uiso(H) = 1.5Ueq(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
Our research on enaminones has led to several compounds possessing anticonvulsant properties (Edafiogho et al., 1992; Eddington et al., 2003; Scott et al., 1993, 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 ED50 (median effective dose) of 121.87 mg kg-1 and TD50 (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).
The title compound posseses significant anticonvulsant properties. For the anticonvulsant properties of enaminones, see: Edafiogho et al. (1992); Eddington et al. (2003); Scott et al. (1993, 1995).
Data collection: CrysAlis PRO (Oxford Diffraction, 2007); cell refinement: CrysAlis PRO (Oxford Diffraction, 2007); data reduction: CrysAlis PRO (Oxford Diffraction, 2007); 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 (Sheldrick, 2008).
C19H22F3NO4 | F(000) = 808 |
Mr = 385.38 | Dx = 1.397 Mg m−3 |
Monoclinic, P21/c | Cu Kα radiation, λ = 1.54184 Å |
Hall symbol: -P 2ybc | Cell parameters from 4437 reflections |
a = 13.7896 (3) Å | θ = 4.9–74.0° |
b = 12.0820 (2) Å | µ = 1.01 mm−1 |
c = 11.0023 (2) Å | T = 123 K |
β = 91.1978 (18)° | Needle plate, colorless |
V = 1832.65 (6) Å3 | 0.48 × 0.18 × 0.08 mm |
Z = 4 |
Oxford Diffraction Xcalibur Ruby Gemini diffractometer | 3607 independent reflections |
Radiation source: Enhance (Cu) X-ray Source | 3095 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.018 |
Detector resolution: 10.5081 pixels mm-1 | θmax = 74.1°, θmin = 4.9° |
ω scans | h = −16→14 |
Absorption correction: multi-scan (CrysAlis PRO; Oxford Diffraction, 2007) | k = −14→8 |
Tmin = 0.852, Tmax = 1.000 | l = −13→13 |
7085 measured reflections |
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.058 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.160 | H-atom parameters constrained |
S = 1.06 | w = 1/[σ2(Fo2) + (0.0769P)2 + 1.5676P] where P = (Fo2 + 2Fc2)/3 |
3607 reflections | (Δ/σ)max < 0.001 |
262 parameters | Δρmax = 0.66 e Å−3 |
0 restraints | Δρmin = −0.39 e Å−3 |
C19H22F3NO4 | V = 1832.65 (6) Å3 |
Mr = 385.38 | Z = 4 |
Monoclinic, P21/c | Cu Kα radiation |
a = 13.7896 (3) Å | µ = 1.01 mm−1 |
b = 12.0820 (2) Å | T = 123 K |
c = 11.0023 (2) Å | 0.48 × 0.18 × 0.08 mm |
β = 91.1978 (18)° |
Oxford Diffraction Xcalibur Ruby Gemini diffractometer | 3607 independent reflections |
Absorption correction: multi-scan (CrysAlis PRO; Oxford Diffraction, 2007) | 3095 reflections with I > 2σ(I) |
Tmin = 0.852, Tmax = 1.000 | Rint = 0.018 |
7085 measured reflections |
R[F2 > 2σ(F2)] = 0.058 | 0 restraints |
wR(F2) = 0.160 | H-atom parameters constrained |
S = 1.06 | Δρmax = 0.66 e Å−3 |
3607 reflections | Δρmin = −0.39 e Å−3 |
262 parameters |
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 F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger. |
x | y | z | Uiso*/Ueq | Occ. (<1) | |
F1 | 0.10734 (15) | 0.64674 (16) | 1.23883 (16) | 0.0709 (6) | |
F2 | 0.04027 (13) | 0.49236 (14) | 1.20234 (15) | 0.0589 (5) | |
F3 | 0.19525 (14) | 0.5113 (2) | 1.1945 (2) | 0.0850 (7) | |
O1 | 0.09751 (12) | 0.58259 (15) | 1.05175 (15) | 0.0420 (4) | |
O2 | 0.59047 (12) | 0.50627 (12) | 0.62115 (16) | 0.0397 (4) | |
O3 | 0.66640 (13) | 0.58950 (15) | 0.36210 (19) | 0.0490 (5) | |
O4 | 0.75913 (13) | 0.67009 (14) | 0.50910 (16) | 0.0437 (4) | |
N1 | 0.38563 (13) | 0.78606 (14) | 0.78117 (17) | 0.0301 (4) | |
H1A | 0.3844 | 0.8587 | 0.7870 | 0.036* | |
C1 | 0.31707 (15) | 0.72966 (17) | 0.85070 (19) | 0.0272 (4) | |
C2 | 0.28473 (16) | 0.78157 (17) | 0.95577 (19) | 0.0305 (5) | |
H2A | 0.3124 | 0.8503 | 0.9803 | 0.037* | |
C3 | 0.21290 (16) | 0.73416 (19) | 1.0246 (2) | 0.0336 (5) | |
H3A | 0.1906 | 0.7702 | 1.0955 | 0.040* | |
C4 | 0.17405 (15) | 0.63344 (18) | 0.9886 (2) | 0.0310 (5) | |
C5 | 0.20450 (16) | 0.58090 (18) | 0.8851 (2) | 0.0315 (5) | |
H5A | 0.1766 | 0.5121 | 0.8615 | 0.038* | |
C6 | 0.27590 (15) | 0.62856 (17) | 0.81557 (19) | 0.0295 (4) | |
H6A | 0.2969 | 0.5926 | 0.7440 | 0.035* | |
C7 | 0.11132 (18) | 0.5574 (2) | 1.1683 (2) | 0.0422 (6) | |
C8 | 0.45375 (14) | 0.74432 (16) | 0.70599 (18) | 0.0262 (4) | |
C9A | 0.5003 (12) | 0.8322 (14) | 0.6279 (13) | 0.0279 (12) | 0.794 (4) |
H9AA | 0.5105 | 0.8995 | 0.6778 | 0.033* | 0.794 (4) |
H9AB | 0.4546 | 0.8515 | 0.5606 | 0.033* | 0.794 (4) |
C10A | 0.5972 (2) | 0.7986 (2) | 0.5737 (3) | 0.0267 (6) | 0.794 (4) |
H10A | 0.6476 | 0.7949 | 0.6403 | 0.032* | 0.794 (4) |
C11A | 0.58523 (18) | 0.6829 (2) | 0.5167 (2) | 0.0256 (5) | 0.794 (4) |
H11A | 0.5310 | 0.6865 | 0.4550 | 0.031* | 0.794 (4) |
C14A | 0.6263 (10) | 0.8853 (13) | 0.4833 (13) | 0.0344 (13) | 0.794 (4) |
H14A | 0.6888 | 0.8651 | 0.4486 | 0.052* | 0.794 (4) |
H14B | 0.6323 | 0.9571 | 0.5242 | 0.052* | 0.794 (4) |
H14C | 0.5769 | 0.8901 | 0.4182 | 0.052* | 0.794 (4) |
C9B | 0.505 (5) | 0.834 (6) | 0.641 (5) | 0.0279 (12) | 0.206 (4) |
H9BA | 0.5494 | 0.8727 | 0.6977 | 0.033* | 0.206 (4) |
H9BB | 0.4569 | 0.8878 | 0.6086 | 0.033* | 0.206 (4) |
C10B | 0.5616 (9) | 0.7870 (10) | 0.5372 (11) | 0.0267 (6) | 0.206 (4) |
H10B | 0.5148 | 0.7565 | 0.4752 | 0.032* | 0.206 (4) |
C11B | 0.6240 (7) | 0.6924 (8) | 0.5856 (9) | 0.0256 (5) | 0.206 (4) |
H11B | 0.6718 | 0.7133 | 0.6513 | 0.031* | 0.206 (4) |
C14B | 0.630 (4) | 0.878 (5) | 0.471 (6) | 0.0344 (13) | 0.206 (4) |
H14D | 0.6391 | 0.8572 | 0.3861 | 0.052* | 0.206 (4) |
H14E | 0.6933 | 0.8818 | 0.5133 | 0.052* | 0.206 (4) |
H14F | 0.5989 | 0.9513 | 0.4742 | 0.052* | 0.206 (4) |
C12 | 0.55529 (16) | 0.60027 (17) | 0.6181 (2) | 0.0329 (5) | |
C13 | 0.48038 (15) | 0.63603 (16) | 0.69731 (19) | 0.0281 (4) | |
H13A | 0.4482 | 0.5826 | 0.7453 | 0.034* | |
C15 | 0.67459 (18) | 0.64028 (19) | 0.4539 (3) | 0.0421 (6) | |
C16 | 0.85219 (18) | 0.6464 (2) | 0.4484 (2) | 0.0421 (6) | |
C17 | 0.8520 (2) | 0.6974 (2) | 0.3218 (3) | 0.0543 (7) | |
H17A | 0.8062 | 0.6571 | 0.2687 | 0.081* | |
H17B | 0.9172 | 0.6927 | 0.2886 | 0.081* | |
H17C | 0.8323 | 0.7752 | 0.3267 | 0.081* | |
C18 | 0.9252 (3) | 0.7032 (3) | 0.5303 (4) | 0.0734 (10) | |
H18A | 0.9232 | 0.6706 | 0.6118 | 0.110* | |
H18B | 0.9099 | 0.7823 | 0.5350 | 0.110* | |
H18C | 0.9903 | 0.6937 | 0.4976 | 0.110* | |
C19 | 0.86786 (19) | 0.5226 (2) | 0.4465 (2) | 0.0435 (6) | |
H19A | 0.8613 | 0.4929 | 0.5288 | 0.065* | |
H19B | 0.9330 | 0.5065 | 0.4173 | 0.065* | |
H19C | 0.8195 | 0.4881 | 0.3921 | 0.065* |
U11 | U22 | U33 | U12 | U13 | U23 | |
F1 | 0.0923 (14) | 0.0713 (12) | 0.0501 (10) | −0.0257 (10) | 0.0258 (9) | −0.0172 (9) |
F2 | 0.0668 (10) | 0.0592 (10) | 0.0515 (9) | −0.0206 (8) | 0.0218 (8) | 0.0063 (8) |
F3 | 0.0611 (11) | 0.1082 (17) | 0.0865 (14) | 0.0289 (11) | 0.0204 (10) | 0.0574 (13) |
O1 | 0.0411 (9) | 0.0485 (10) | 0.0367 (9) | −0.0135 (8) | 0.0053 (7) | 0.0018 (7) |
O2 | 0.0395 (9) | 0.0199 (7) | 0.0601 (11) | 0.0059 (6) | 0.0104 (8) | 0.0037 (7) |
O3 | 0.0455 (10) | 0.0339 (9) | 0.0674 (12) | 0.0013 (8) | −0.0016 (9) | −0.0065 (9) |
O4 | 0.0535 (11) | 0.0357 (9) | 0.0425 (9) | 0.0030 (8) | 0.0121 (8) | −0.0088 (7) |
N1 | 0.0375 (10) | 0.0172 (8) | 0.0358 (9) | 0.0011 (7) | 0.0060 (7) | −0.0013 (7) |
C1 | 0.0280 (10) | 0.0223 (9) | 0.0315 (10) | 0.0030 (8) | 0.0007 (8) | 0.0014 (8) |
C2 | 0.0344 (11) | 0.0230 (10) | 0.0342 (11) | −0.0017 (8) | −0.0001 (9) | −0.0034 (8) |
C3 | 0.0378 (12) | 0.0333 (11) | 0.0299 (10) | −0.0012 (9) | 0.0034 (9) | −0.0049 (9) |
C4 | 0.0299 (10) | 0.0315 (11) | 0.0316 (10) | −0.0039 (9) | 0.0019 (8) | 0.0039 (9) |
C5 | 0.0331 (11) | 0.0240 (10) | 0.0372 (11) | −0.0014 (8) | −0.0021 (9) | −0.0015 (8) |
C6 | 0.0335 (11) | 0.0249 (10) | 0.0301 (10) | 0.0012 (8) | 0.0008 (8) | −0.0031 (8) |
C7 | 0.0416 (13) | 0.0422 (13) | 0.0432 (13) | 0.0024 (11) | 0.0114 (10) | 0.0049 (11) |
C8 | 0.0269 (10) | 0.0222 (10) | 0.0295 (10) | −0.0001 (8) | −0.0014 (8) | −0.0007 (8) |
C9A | 0.0309 (19) | 0.0166 (10) | 0.036 (3) | −0.0004 (13) | 0.0004 (19) | 0.000 (2) |
C10A | 0.0268 (16) | 0.0212 (12) | 0.0321 (16) | −0.0029 (11) | −0.0003 (11) | −0.0011 (11) |
C11A | 0.0264 (13) | 0.0200 (11) | 0.0303 (13) | −0.0010 (9) | −0.0018 (9) | −0.0006 (10) |
C14A | 0.0413 (17) | 0.022 (2) | 0.040 (3) | −0.0023 (16) | 0.009 (2) | 0.0008 (19) |
C9B | 0.0309 (19) | 0.0166 (10) | 0.036 (3) | −0.0004 (13) | 0.0004 (19) | 0.000 (2) |
C10B | 0.0268 (16) | 0.0212 (12) | 0.0321 (16) | −0.0029 (11) | −0.0003 (11) | −0.0011 (11) |
C11B | 0.0264 (13) | 0.0200 (11) | 0.0303 (13) | −0.0010 (9) | −0.0018 (9) | −0.0006 (10) |
C14B | 0.0413 (17) | 0.022 (2) | 0.040 (3) | −0.0023 (16) | 0.009 (2) | 0.0008 (19) |
C12 | 0.0289 (10) | 0.0196 (10) | 0.0503 (13) | −0.0002 (8) | 0.0050 (9) | 0.0015 (9) |
C13 | 0.0313 (10) | 0.0191 (9) | 0.0340 (10) | −0.0007 (8) | 0.0020 (8) | 0.0017 (8) |
C15 | 0.0382 (13) | 0.0247 (11) | 0.0641 (17) | 0.0021 (9) | 0.0184 (11) | 0.0109 (11) |
C16 | 0.0371 (13) | 0.0393 (13) | 0.0499 (14) | 0.0003 (10) | 0.0023 (10) | −0.0053 (11) |
C17 | 0.0510 (16) | 0.0486 (15) | 0.0641 (18) | 0.0055 (13) | 0.0220 (13) | 0.0111 (13) |
C18 | 0.064 (2) | 0.0525 (18) | 0.102 (3) | −0.0054 (16) | −0.0229 (19) | −0.0140 (18) |
C19 | 0.0424 (13) | 0.0411 (13) | 0.0470 (14) | 0.0055 (11) | 0.0003 (10) | −0.0025 (11) |
F1—C7 | 1.331 (3) | C11A—C12 | 1.559 (3) |
F2—C7 | 1.316 (3) | C11A—H11A | 1.0000 |
F3—C7 | 1.311 (3) | C14A—H14A | 0.9800 |
O1—C7 | 1.328 (3) | C14A—H14B | 0.9800 |
O1—C4 | 1.416 (3) | C14A—H14C | 0.9800 |
O2—C12 | 1.235 (3) | C9B—C10B | 1.50 (7) |
O3—C15 | 1.185 (3) | C9B—H9BA | 0.9900 |
O4—C15 | 1.352 (3) | C9B—H9BB | 0.9900 |
O4—C16 | 1.487 (3) | C10B—C11B | 1.520 (15) |
N1—C8 | 1.361 (3) | C10B—C14B | 1.63 (7) |
N1—C1 | 1.405 (3) | C10B—H10B | 1.0000 |
N1—H1A | 0.8800 | C11B—C12 | 1.510 (10) |
C1—C2 | 1.396 (3) | C11B—C15 | 1.740 (10) |
C1—C6 | 1.398 (3) | C11B—H11B | 1.0000 |
C2—C3 | 1.384 (3) | C14B—H14D | 0.9800 |
C2—H2A | 0.9500 | C14B—H14E | 0.9800 |
C3—C4 | 1.384 (3) | C14B—H14F | 0.9800 |
C3—H3A | 0.9500 | C12—C13 | 1.432 (3) |
C4—C5 | 1.377 (3) | C13—H13A | 0.9500 |
C5—C6 | 1.385 (3) | C16—C18 | 1.503 (4) |
C5—H5A | 0.9500 | C16—C19 | 1.512 (3) |
C6—H6A | 0.9500 | C16—C17 | 1.523 (4) |
C8—C13 | 1.363 (3) | C17—H17A | 0.9800 |
C8—C9B | 1.48 (7) | C17—H17B | 0.9800 |
C8—C9A | 1.516 (18) | C17—H17C | 0.9800 |
C9A—C10A | 1.530 (17) | C18—H18A | 0.9800 |
C9A—H9AA | 0.9900 | C18—H18B | 0.9800 |
C9A—H9AB | 0.9900 | C18—H18C | 0.9800 |
C10A—C14A | 1.504 (17) | C19—H19A | 0.9800 |
C10A—C11A | 1.540 (4) | C19—H19B | 0.9800 |
C10A—H10A | 1.0000 | C19—H19C | 0.9800 |
C11A—C15 | 1.515 (3) | ||
C7—O1—C4 | 118.68 (19) | H9BA—C9B—H9BB | 108.1 |
C15—O4—C16 | 119.42 (19) | C9B—C10B—C11B | 108 (2) |
C8—N1—C1 | 129.19 (17) | C9B—C10B—C14B | 113 (4) |
C8—N1—H1A | 115.4 | C11B—C10B—C14B | 110 (2) |
C1—N1—H1A | 115.4 | C9B—C10B—H10B | 108.4 |
C2—C1—C6 | 119.10 (19) | C11B—C10B—H10B | 108.4 |
C2—C1—N1 | 117.59 (18) | C14B—C10B—H10B | 108.4 |
C6—C1—N1 | 123.18 (19) | C12—C11B—C10B | 106.5 (8) |
C3—C2—C1 | 120.8 (2) | C12—C11B—C15 | 101.2 (6) |
C3—C2—H2A | 119.6 | C10B—C11B—C15 | 102.4 (8) |
C1—C2—H2A | 119.6 | C12—C11B—H11B | 115.0 |
C2—C3—C4 | 119.0 (2) | C10B—C11B—H11B | 115.0 |
C2—C3—H3A | 120.5 | C15—C11B—H11B | 115.0 |
C4—C3—H3A | 120.5 | C10B—C14B—H14D | 109.5 |
C5—C4—C3 | 121.3 (2) | C10B—C14B—H14E | 109.5 |
C5—C4—O1 | 116.67 (19) | H14D—C14B—H14E | 109.5 |
C3—C4—O1 | 122.0 (2) | C10B—C14B—H14F | 109.5 |
C4—C5—C6 | 119.9 (2) | H14D—C14B—H14F | 109.5 |
C4—C5—H5A | 120.1 | H14E—C14B—H14F | 109.5 |
C6—C5—H5A | 120.1 | O2—C12—C13 | 123.3 (2) |
C5—C6—C1 | 120.0 (2) | O2—C12—C11B | 115.9 (4) |
C5—C6—H6A | 120.0 | C13—C12—C11B | 112.7 (4) |
C1—C6—H6A | 120.0 | O2—C12—C11A | 119.9 (2) |
F3—C7—F2 | 110.1 (2) | C13—C12—C11A | 116.59 (18) |
F3—C7—O1 | 114.7 (2) | C11B—C12—C11A | 35.1 (4) |
F2—C7—O1 | 108.6 (2) | C8—C13—C12 | 122.08 (19) |
F3—C7—F1 | 105.3 (3) | C8—C13—H13A | 119.0 |
F2—C7—F1 | 106.2 (2) | C12—C13—H13A | 119.0 |
O1—C7—F1 | 111.7 (2) | O3—C15—O4 | 125.9 (2) |
N1—C8—C13 | 126.06 (19) | O3—C15—C11A | 120.0 (2) |
N1—C8—C9B | 111 (2) | O4—C15—C11A | 114.0 (2) |
C13—C8—C9B | 122 (2) | O3—C15—C11B | 149.8 (4) |
N1—C8—C9A | 113.0 (6) | O4—C15—C11B | 83.5 (4) |
C13—C8—C9A | 121.0 (6) | C11A—C15—C11B | 32.1 (3) |
C9B—C8—C9A | 6 (3) | O4—C16—C18 | 102.5 (2) |
C8—C9A—C10A | 114.8 (10) | O4—C16—C19 | 108.8 (2) |
C8—C9A—H9AA | 108.6 | C18—C16—C19 | 111.5 (2) |
C10A—C9A—H9AA | 108.6 | O4—C16—C17 | 110.3 (2) |
C8—C9A—H9AB | 108.6 | C18—C16—C17 | 110.6 (3) |
C10A—C9A—H9AB | 108.6 | C19—C16—C17 | 112.6 (2) |
H9AA—C9A—H9AB | 107.5 | C16—C17—H17A | 109.5 |
C14A—C10A—C9A | 108.7 (8) | C16—C17—H17B | 109.5 |
C14A—C10A—C11A | 113.0 (5) | H17A—C17—H17B | 109.5 |
C9A—C10A—C11A | 108.2 (7) | C16—C17—H17C | 109.5 |
C14A—C10A—H10A | 108.9 | H17A—C17—H17C | 109.5 |
C9A—C10A—H10A | 108.9 | H17B—C17—H17C | 109.5 |
C11A—C10A—H10A | 108.9 | C16—C18—H18A | 109.5 |
C15—C11A—C10A | 114.4 (2) | C16—C18—H18B | 109.5 |
C15—C11A—C12 | 109.83 (19) | H18A—C18—H18B | 109.5 |
C10A—C11A—C12 | 108.5 (2) | C16—C18—H18C | 109.5 |
C15—C11A—H11A | 108.0 | H18A—C18—H18C | 109.5 |
C10A—C11A—H11A | 108.0 | H18B—C18—H18C | 109.5 |
C12—C11A—H11A | 108.0 | C16—C19—H19A | 109.5 |
C8—C9B—C10B | 111 (4) | C16—C19—H19B | 109.5 |
C8—C9B—H9BA | 109.5 | H19A—C19—H19B | 109.5 |
C10B—C9B—H9BA | 109.5 | C16—C19—H19C | 109.5 |
C8—C9B—H9BB | 109.5 | H19A—C19—H19C | 109.5 |
C10B—C9B—H9BB | 109.5 | H19B—C19—H19C | 109.5 |
C8—N1—C1—C2 | 153.2 (2) | C14B—C10B—C11B—C15 | −61 (2) |
C8—N1—C1—C6 | −31.0 (3) | C10B—C11B—C12—O2 | 157.3 (6) |
C6—C1—C2—C3 | 0.0 (3) | C15—C11B—C12—O2 | 50.7 (6) |
N1—C1—C2—C3 | 176.0 (2) | C10B—C11B—C12—C13 | −52.9 (8) |
C1—C2—C3—C4 | 0.7 (3) | C15—C11B—C12—C13 | −159.6 (3) |
C2—C3—C4—C5 | −1.0 (3) | C10B—C11B—C12—C11A | 51.5 (7) |
C2—C3—C4—O1 | −177.2 (2) | C15—C11B—C12—C11A | −55.2 (5) |
C7—O1—C4—C5 | 123.9 (2) | C15—C11A—C12—O2 | −14.0 (3) |
C7—O1—C4—C3 | −59.7 (3) | C10A—C11A—C12—O2 | −139.7 (2) |
C3—C4—C5—C6 | 0.5 (3) | C15—C11A—C12—C13 | 171.5 (2) |
O1—C4—C5—C6 | 176.93 (19) | C10A—C11A—C12—C13 | 45.8 (3) |
C4—C5—C6—C1 | 0.2 (3) | C15—C11A—C12—C11B | 79.3 (7) |
C2—C1—C6—C5 | −0.4 (3) | C10A—C11A—C12—C11B | −46.4 (7) |
N1—C1—C6—C5 | −176.20 (19) | N1—C8—C13—C12 | −177.9 (2) |
C4—O1—C7—F3 | −44.1 (3) | C9B—C8—C13—C12 | −4 (3) |
C4—O1—C7—F2 | −167.7 (2) | C9A—C8—C13—C12 | 2.3 (7) |
C4—O1—C7—F1 | 75.5 (3) | O2—C12—C13—C8 | 169.1 (2) |
C1—N1—C8—C13 | −11.5 (4) | C11B—C12—C13—C8 | 22.0 (5) |
C1—N1—C8—C9B | 174 (2) | C11A—C12—C13—C8 | −16.5 (3) |
C1—N1—C8—C9A | 168.4 (6) | C16—O4—C15—O3 | 4.9 (4) |
N1—C8—C9A—C10A | 161.2 (6) | C16—O4—C15—C11A | −172.1 (2) |
C13—C8—C9A—C10A | −19.0 (11) | C16—O4—C15—C11B | 177.6 (4) |
C9B—C8—C9A—C10A | 85 (30) | C10A—C11A—C15—O3 | −141.6 (2) |
C8—C9A—C10A—C14A | 170.9 (8) | C12—C11A—C15—O3 | 96.1 (3) |
C8—C9A—C10A—C11A | 47.8 (9) | C10A—C11A—C15—O4 | 35.6 (3) |
C14A—C10A—C11A—C15 | 56.9 (7) | C12—C11A—C15—O4 | −86.7 (2) |
C9A—C10A—C11A—C15 | 177.4 (6) | C10A—C11A—C15—C11B | 55.1 (6) |
C14A—C10A—C11A—C12 | 179.9 (6) | C12—C11A—C15—C11B | −67.2 (6) |
C9A—C10A—C11A—C12 | −59.6 (6) | C12—C11B—C15—O3 | 36.2 (11) |
N1—C8—C9B—C10B | −166 (2) | C10B—C11B—C15—O3 | −73.7 (10) |
C13—C8—C9B—C10B | 19 (4) | C12—C11B—C15—O4 | −132.0 (5) |
C9A—C8—C9B—C10B | −60 (28) | C10B—C11B—C15—O4 | 118.2 (7) |
C8—C9B—C10B—C11B | −51 (4) | C12—C11B—C15—C11A | 65.9 (6) |
C8—C9B—C10B—C14B | −173 (3) | C10B—C11B—C15—C11A | −44.0 (6) |
C9B—C10B—C11B—C12 | 69 (3) | C15—O4—C16—C18 | 173.6 (2) |
C14B—C10B—C11B—C12 | −167 (2) | C15—O4—C16—C19 | −68.2 (3) |
C9B—C10B—C11B—C15 | 174 (3) | C15—O4—C16—C17 | 55.8 (3) |
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1A···O2i | 0.88 | 2.08 | 2.886 (2) | 153 |
C2—H2A···O2i | 0.95 | 2.58 | 3.333 (3) | 136 |
C6—H6A···O3ii | 0.95 | 2.55 | 3.385 (3) | 147 |
C9B—H9BA···O3iii | 0.99 | 2.44 | 3.40 (6) | 162 |
Symmetry codes: (i) −x+1, y+1/2, −z+3/2; (ii) −x+1, −y+1, −z+1; (iii) x, −y+3/2, z+1/2. |
Experimental details
Crystal data | |
Chemical formula | C19H22F3NO4 |
Mr | 385.38 |
Crystal system, space group | Monoclinic, P21/c |
Temperature (K) | 123 |
a, b, c (Å) | 13.7896 (3), 12.0820 (2), 11.0023 (2) |
β (°) | 91.1978 (18) |
V (Å3) | 1832.65 (6) |
Z | 4 |
Radiation type | Cu Kα |
µ (mm−1) | 1.01 |
Crystal size (mm) | 0.48 × 0.18 × 0.08 |
Data collection | |
Diffractometer | Oxford Diffraction Xcalibur Ruby Gemini |
Absorption correction | Multi-scan (CrysAlis PRO; Oxford Diffraction, 2007) |
Tmin, Tmax | 0.852, 1.000 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 7085, 3607, 3095 |
Rint | 0.018 |
(sin θ/λ)max (Å−1) | 0.624 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.058, 0.160, 1.06 |
No. of reflections | 3607 |
No. of parameters | 262 |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.66, −0.39 |
Computer programs: CrysAlis PRO (Oxford Diffraction, 2007), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), SHELXTL (Sheldrick, 2008).
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1A···O2i | 0.88 | 2.08 | 2.886 (2) | 152.8 |
C2—H2A···O2i | 0.95 | 2.58 | 3.333 (3) | 136.4 |
C6—H6A···O3ii | 0.95 | 2.55 | 3.385 (3) | 147.4 |
C9B—H9BA···O3iii | 0.99 | 2.44 | 3.40 (6) | 162.1 |
Symmetry codes: (i) −x+1, y+1/2, −z+3/2; (ii) −x+1, −y+1, −z+1; (iii) x, −y+3/2, z+1/2. |
Our research on enaminones has led to several compounds possessing anticonvulsant properties (Edafiogho et al., 1992; Eddington et al., 2003; Scott et al., 1993, 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 ED50 (median effective dose) of 121.87 mg kg-1 and TD50 (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).