organic compounds
4-[4-(4-Fluorophenyl)-2-methyl-5-oxo-2,5-dihydroisoxazol-3-yl]-1-methylpyridinium iodide–4-[3-(4-fluorophenyl)-2-methyl-5-oxo-2,5-dihydroisoxazol-4-yl]-1-methylpyridinium iodide (0.6/0.4)
aInstitute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany, and bDepartment of Organic Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 10-14, D-55099 Mainz, Germany
*Correspondence e-mail: stefan.laufer@uni-tuebingen.de
The 16H16FN2O2+·I−, was determined as part of a study of the biological activity of isoxazolone derivatives as p38 mitogen-activated protein kinase (MAPK) inhibitors. The X-ray of 4-[4-(4-fluorophenyl)-2-methyl-5-oxo-2,5-dihydroisoxazol-3-yl]-1-methylpyridinium iodide showed the presence of the regioisomer 4-[3-(4-fluorophenyl)-2-methyl-5-oxo-2,5-dihydroisoxazol-4-yl]-1-methylpyridinium iodide. The synthesis of the former compound was achieved by reacting 4-(4-fluorophenyl)-3-(4-pyridyl)isoxazol-5(2H)-one after treatment with Et3N in dimethylformamide, with iodomethane. The unexpected formation of the regioisomer could be explained by a rearrangement occurring via aziridine of the isoxazolone compound. The regioisomers have site occupancies of 0.632 (4)/0.368 (4). The two six members rings make a dihedral angle of 66.8 (2)°.
of the title compound, CRelated literature
For general background on the pharmaceutical applications of isoxazolones, see: Laughlin et al. (2005); Clark et al. (2002); Wang et al. (1998); Foster et al. (2000); Adams et al. (1998); Laufer & Wagner (2002); de Laszlo et al. (1998); Laufer et al. (2005, 2006); Revesz et al. (2000); Ohkawa et al. (2001). The aziridine rearrangement of isoxazolones was described by Nishiwaki & Saito (1971) and Sauers (1990).
Experimental
Crystal data
|
Data collection: APEX2 (Bruker, 2006); cell APEX2; data reduction: APEX2; program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP (Johnson, 1968) and PLATON (Spek, 2003); software used to prepare material for publication: SHELXL97.
Supporting information
https://doi.org/10.1107/S1600536807055985/bt2577sup1.cif
contains datablocks I, global. DOI:Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S1600536807055985/bt2577Isup2.hkl
For the synthesis of 2-(4-Fluoro-phenyl)-3-oxo-3-pyridin-4-yl-propionic acid ethyl ester (see scheme 1), to a suspension of 3.3 g (26.8 mmol) of isonicotinic acid in 15 ml of DMF, 7.3 g (45 mmol) of CDI were added. The reaction mixture was stirred at 298 K for 1 h. The limpid solution was then cooled at 273 K and 5 g (27.4 mmol) of (4-Fluoro-phenyl)-acetic acid ethyl and 1.7 g (70.8 mmol) of NaH were added. The reaction mixture was stirred at 273 K for 15 min, then the temperature was raised to 298 K and kept under vigorous stirring for 4 h. The reaction was then poured into water/ice, the pH adjusted to value 6 and extracted with ethylacetate. The combined organic layers were then collected, dried over Na2SO4 and concentrated under vacuum affording an oil that was chromatographed over SiO2 using acetone as
y ielding 75% of 2-(4-Fluoro-phenyl)-3-oxo-3-pyridin-4-yl-propionic acid ethyl ester. For the synthesis of (I), a suspension of 5.2 g (18.1 mmol) of 2-(4-Fluoro-phenyl)-3-oxo-3-pyridin -4-yl-propionic acid ethyl ester and 1.41 g (20.27 mmol) of hydroxylamine hydrochloride in 1.5 ml of H2O was warmed to 353 K. 8 ml of MeOH were added and the resulting solution allowed to reflux 4 h. The reaction mixture was then cooled to 298 K and stored at 277 K overnight whereupon a yellow solide precipitated, yielding 75% of (I). For the synthesis of (II) and (III), a suspension of 620 mg (2.5 mmol) of (I) in 1 ml of DMF was added of 0.620 ml (4.5 mmol) of Et3N and refluxed for 2 h. The reaction mixture was then cooled at 298 K, added of 0.231 ml (3.75 mmol) of iodomethane and stirred at 298 K for 2 h. The reaction mixture was then added of ethylacetate and the resulting precipitate separated by filtration and then crystalized from MeOH yielding 54% of (II) and (III).Hydrogen atoms attached to carbons were placed at calculated positions with C—H = 0.95 A% (aromatic) or 0.99–1.00 Å (sp3 C-atom). All H atoms were refined with isotropic displacement parameters (set at 1.2–1.5 times of the Ueq of the parent atom). The regioisomers (II) and (III) have s.o.f.s of 0.632 (4)/0.368 (4). The coordinates and a.d.p.'s of the disorderd C, N and F atoms were constrained to be equal to achieve a good convergence of the
procedure.Compound (II) (Scheme 1) was prepared in the course of our study on isoxazolones derivatives bearing the typical vicinal 4-pyridyl and 4-fluorophenyl pharmacophores of MAP Kinase inhibitors. Isoxazolones are described in the literature as inhibitors for p38 MAP Kinase (Laughlin et al., 2005; Clark et al., 2002).
The prototypical pyridinylimidazole SB 203580 is one of the best studied p38 inhibitors reported until now. Fig. 1 shows the most important interactions between the ATP binding sites of p38 kinase and the imidazole inhibitor SB203580 (Wang et al., 1998). The 4-fluorophenyl ring of SB203580 occupies a hydrophobic back pocket gaining selectivity. Vicinal to this interaction site, 4-pyridinyl moiety forms a hydrogen bond from the backbone NH group of Met 109 of p38 MAP Kinase (Fig. 1).
However, certain liver toxicities, such as increased liver size and increased
induction, have been reported (Foster et al., 2000; Adams et al., 1998). In light of this potential toxicity and the risks associated with developing human drugs, a continuing need exist for potent new small molecules inhibitors of cytokine production with improved pharmacokinetic and safety profiles.Several research groups have undertaken studies in which the imidazole ring was replaced by other 5- or 6- membered heterocycles (Laufer & Wagner, 2002; de Laszlo et al., 1998; Laufer et al., 2006; Revesz et al., 2000; Ohkawa et al., 2001). Replacement of the core heterocycle representing a strategy to dissect inhibition of p38 from interferences with
(CYP450).Accordingly, and based on the research published by Laughlin and co-authors (Laughlin et al., 2005), we plane to prepare N-alkylated derivatives of compound (I) in order to get more accurate and comparable information about isoxazolones as p38 MAP Kinase inhibitors in terms of biological activity.
By testing compounds (I) and (II) in the in vitro p38-alpha MAPK assay (Laufer et al., 2005), only compound (I) was found to posses biological activity.
The loss of the biological activity of compound (II) can be attributed to the absence of hydrogen bond donor on the pyridine ring and, consequentely, impossibility of interaction with Met109.
For general background on the pharmaceutical applications of isoxazolones, see: Laughlin et al. (2005); Clark et al. (2002); Wang et al. (1998); Foster et al. (2000); Adams et al. (1998); Laufer & Wagner (2002); de Laszlo et al. (1998); Laufer et al. (2005, 2006); Revesz et al. (2000); Ohkawa et al. (2001). The aziridine rearrangement of isoxazolones was described by Nishiwaki & Saito (1971) and Sauers (1990). [These last two references are not cited anywhere but here. Please provide revised text to be added to the appropriate section of the
or they will be removed]Data collection: APEX2 (Bruker, 2006); cell
APEX2 (Bruker, 2006); data reduction: APEX2 (Bruker, 2006); program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP (Johnson, 1968) and PLATON (Spek, 2003); software used to prepare material for publication: SHELXL97 (Sheldrick, 1997).C15H12FN2O2+·I− | F(000) = 776 |
Mr = 398.17 | Dx = 1.680 Mg m−3 |
Monoclinic, P21/c | Mo Kα radiation, λ = 0.71069 Å |
Hall symbol: -P 2ybc | Cell parameters from 6868 reflections |
a = 10.2804 (4) Å | θ = 2.7–28.3° |
b = 20.5895 (9) Å | µ = 2.05 mm−1 |
c = 7.4907 (3) Å | T = 193 K |
β = 96.8828 (14)° | Block, brown |
V = 1574.12 (11) Å3 | 0.52 × 0.20 × 0.08 mm |
Z = 4 |
Bruker APEXII CCD diffractometer | 3897 independent reflections |
Radiation source: sealed Tube | 3369 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.126 |
CCD scan | θmax = 28.4°, θmin = 2.0° |
Absorption correction: multi-scan (APEX2; Bruker, 2006) | h = −13→13 |
Tmin = 0.415, Tmax = 0.853 | k = −27→27 |
27681 measured reflections | l = −9→9 |
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)] = 0.040 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.115 | H-atom parameters constrained |
S = 1.07 | w = 1/[σ2(Fo2) + (0.0617P)2 + 2.8681P] where P = (Fo2 + 2Fc2)/3 |
3897 reflections | (Δ/σ)max = 0.001 |
188 parameters | Δρmax = 1.60 e Å−3 |
0 restraints | Δρmin = −0.51 e Å−3 |
C15H12FN2O2+·I− | V = 1574.12 (11) Å3 |
Mr = 398.17 | Z = 4 |
Monoclinic, P21/c | Mo Kα radiation |
a = 10.2804 (4) Å | µ = 2.05 mm−1 |
b = 20.5895 (9) Å | T = 193 K |
c = 7.4907 (3) Å | 0.52 × 0.20 × 0.08 mm |
β = 96.8828 (14)° |
Bruker APEXII CCD diffractometer | 3897 independent reflections |
Absorption correction: multi-scan (APEX2; Bruker, 2006) | 3369 reflections with I > 2σ(I) |
Tmin = 0.415, Tmax = 0.853 | Rint = 0.126 |
27681 measured reflections |
R[F2 > 2σ(F2)] = 0.040 | 0 restraints |
wR(F2) = 0.115 | H-atom parameters constrained |
S = 1.07 | Δρmax = 1.60 e Å−3 |
3897 reflections | Δρmin = −0.51 e Å−3 |
188 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) | |
F1A | 1.0107 (3) | 0.20467 (16) | 1.6192 (4) | 0.0292 (4) | 0.632 (4) |
F1B | 0.3217 (5) | 0.1835 (3) | 0.8219 (7) | 0.0292 (4) | 0.368 (4) |
C1 | 0.9450 (4) | 0.08719 (19) | 0.9398 (5) | 0.0327 (7) | |
C2 | 0.8322 (4) | 0.07466 (19) | 0.8261 (5) | 0.0333 (7) | |
N3 | 0.8565 (3) | 0.0373 (2) | 0.6894 (5) | 0.0458 (9) | |
O4 | 0.9887 (3) | 0.02271 (16) | 0.7079 (4) | 0.0439 (7) | |
C5 | 1.0475 (4) | 0.0546 (2) | 0.8619 (6) | 0.0384 (8) | |
C6 | 0.7766 (4) | 0.0089 (2) | 0.5375 (6) | 0.0408 (9) | |
H6A | 0.8320 | −0.0168 | 0.4667 | 0.061* | |
H6B | 0.7337 | 0.0435 | 0.4623 | 0.061* | |
H6C | 0.7100 | −0.0191 | 0.5806 | 0.061* | |
O7 | 1.1646 (3) | 0.04901 (16) | 0.8994 (5) | 0.0489 (8) | |
C8 | 0.9607 (4) | 0.12052 (18) | 1.1149 (5) | 0.0332 (8) | |
C9 | 0.8538 (4) | 0.1315 (2) | 1.2097 (6) | 0.0359 (8) | |
H9 | 0.7687 | 0.1187 | 1.1584 | 0.043* | |
C10 | 0.8700 (4) | 0.1609 (2) | 1.3781 (6) | 0.0399 (9) | |
H10 | 0.7969 | 0.1691 | 1.4412 | 0.048* | |
C11A | 0.9937 (5) | 0.1776 (2) | 1.4501 (6) | 0.0462 (9) | 0.632 (4) |
N11B | 0.9937 (5) | 0.1776 (2) | 1.4501 (6) | 0.0462 (9) | 0.368 (4) |
H11B | 1.0046 | 0.1958 | 1.5571 | 0.055* | 0.368 (4) |
C12 | 1.1020 (4) | 0.1672 (2) | 1.3625 (6) | 0.0458 (10) | |
H12 | 1.1868 | 0.1795 | 1.4162 | 0.055* | |
C13 | 1.0846 (4) | 0.1386 (2) | 1.1952 (6) | 0.0413 (9) | |
H13 | 1.1586 | 0.1310 | 1.1333 | 0.050* | |
C15 | 0.6988 (4) | 0.10094 (19) | 0.8287 (5) | 0.0312 (7) | |
C16 | 0.5906 (4) | 0.06123 (19) | 0.8311 (5) | 0.0336 (7) | |
H16 | 0.6003 | 0.0153 | 0.8348 | 0.040* | |
C17 | 0.4681 (4) | 0.0892 (2) | 0.8282 (5) | 0.0352 (8) | |
H17 | 0.3932 | 0.0623 | 0.8308 | 0.042* | |
N18A | 0.4542 (3) | 0.15364 (17) | 0.8217 (4) | 0.0292 (4) | 0.632 (4) |
H18A | 0.3753 | 0.1705 | 0.8193 | 0.035* | 0.632 (4) |
C18B | 0.4542 (3) | 0.15364 (17) | 0.8217 (4) | 0.0292 (4) | 0.368 (4) |
C19 | 0.5569 (4) | 0.1931 (2) | 0.8188 (6) | 0.0364 (8) | |
H19 | 0.5441 | 0.2388 | 0.8156 | 0.044* | |
C20 | 0.6822 (4) | 0.16808 (19) | 0.8204 (5) | 0.0354 (8) | |
H20 | 0.7552 | 0.1961 | 0.8160 | 0.042* | |
I1 | 0.47781 (2) | 0.126317 (12) | 0.31747 (3) | 0.03385 (11) |
U11 | U22 | U33 | U12 | U13 | U23 | |
F1A | 0.0284 (10) | 0.0371 (11) | 0.0211 (9) | 0.0016 (8) | −0.0013 (7) | −0.0038 (8) |
F1B | 0.0284 (10) | 0.0371 (11) | 0.0211 (9) | 0.0016 (8) | −0.0013 (7) | −0.0038 (8) |
C1 | 0.0289 (17) | 0.0352 (19) | 0.0353 (18) | 0.0032 (14) | 0.0087 (14) | 0.0040 (14) |
C2 | 0.0329 (18) | 0.0339 (19) | 0.0339 (18) | 0.0020 (14) | 0.0065 (14) | 0.0026 (14) |
N3 | 0.0312 (17) | 0.061 (2) | 0.045 (2) | 0.0125 (16) | 0.0037 (15) | −0.0117 (17) |
O4 | 0.0336 (14) | 0.0525 (18) | 0.0474 (17) | 0.0086 (13) | 0.0122 (12) | −0.0064 (14) |
C5 | 0.0325 (19) | 0.038 (2) | 0.045 (2) | 0.0013 (16) | 0.0092 (16) | 0.0042 (16) |
C6 | 0.040 (2) | 0.042 (2) | 0.042 (2) | 0.0019 (17) | 0.0108 (17) | −0.0077 (17) |
O7 | 0.0292 (14) | 0.0528 (18) | 0.067 (2) | 0.0032 (12) | 0.0151 (14) | 0.0009 (16) |
C8 | 0.0303 (18) | 0.0346 (19) | 0.0349 (19) | −0.0006 (14) | 0.0047 (15) | 0.0048 (14) |
C9 | 0.0286 (17) | 0.046 (2) | 0.0336 (19) | 0.0007 (15) | 0.0036 (15) | 0.0009 (15) |
C10 | 0.037 (2) | 0.048 (2) | 0.035 (2) | 0.0035 (17) | 0.0049 (16) | −0.0002 (17) |
C11A | 0.055 (2) | 0.043 (2) | 0.039 (2) | −0.0025 (18) | −0.0002 (18) | 0.0000 (17) |
N11B | 0.055 (2) | 0.043 (2) | 0.039 (2) | −0.0025 (18) | −0.0002 (18) | 0.0000 (17) |
C12 | 0.037 (2) | 0.050 (3) | 0.048 (2) | −0.0095 (18) | −0.0029 (18) | 0.0029 (19) |
C13 | 0.0297 (19) | 0.048 (2) | 0.047 (2) | −0.0043 (16) | 0.0057 (17) | 0.0058 (18) |
C15 | 0.0331 (17) | 0.0352 (18) | 0.0257 (16) | 0.0025 (14) | 0.0045 (13) | −0.0009 (14) |
C16 | 0.0372 (19) | 0.0332 (18) | 0.0313 (17) | −0.0009 (15) | 0.0079 (15) | −0.0007 (14) |
C17 | 0.0360 (19) | 0.038 (2) | 0.0323 (18) | −0.0024 (15) | 0.0063 (15) | −0.0016 (14) |
N18A | 0.0284 (10) | 0.0371 (11) | 0.0211 (9) | 0.0016 (8) | −0.0013 (7) | −0.0038 (8) |
C18B | 0.0284 (10) | 0.0371 (11) | 0.0211 (9) | 0.0016 (8) | −0.0013 (7) | −0.0038 (8) |
C19 | 0.0344 (18) | 0.0363 (19) | 0.0381 (19) | 0.0028 (15) | 0.0025 (15) | 0.0013 (15) |
C20 | 0.0318 (18) | 0.0329 (19) | 0.041 (2) | −0.0005 (14) | 0.0037 (15) | −0.0014 (15) |
I1 | 0.03172 (15) | 0.03684 (16) | 0.03268 (16) | −0.00256 (9) | 0.00260 (10) | −0.00114 (9) |
F1A—C11A | 1.376 (5) | C10—C11A | 1.365 (6) |
C1—C2 | 1.378 (5) | C10—H10 | 0.9500 |
C1—C5 | 1.431 (5) | C11A—C12 | 1.375 (7) |
C1—C8 | 1.472 (5) | C12—C13 | 1.378 (7) |
C2—N3 | 1.328 (5) | C12—H12 | 0.9500 |
C2—C15 | 1.477 (5) | C13—H13 | 0.9500 |
N3—O4 | 1.383 (4) | C15—C16 | 1.383 (5) |
N3—C6 | 1.444 (6) | C15—C20 | 1.393 (6) |
O4—C5 | 1.400 (5) | C16—C17 | 1.382 (5) |
C5—O7 | 1.208 (5) | C16—H16 | 0.9500 |
C6—H6A | 0.9800 | C17—N18A | 1.336 (6) |
C6—H6B | 0.9800 | C17—H17 | 0.9500 |
C6—H6C | 0.9800 | N18A—C19 | 1.334 (5) |
C8—C13 | 1.392 (6) | N18A—H18A | 0.8800 |
C8—C9 | 1.397 (6) | C19—C20 | 1.386 (5) |
C9—C10 | 1.390 (6) | C19—H19 | 0.9500 |
C9—H9 | 0.9500 | C20—H20 | 0.9500 |
C2—C1—C5 | 105.4 (3) | C10—C11A—C12 | 122.8 (4) |
C2—C1—C8 | 129.2 (3) | C10—C11A—F1A | 118.4 (4) |
C5—C1—C8 | 125.1 (4) | C12—C11A—F1A | 118.8 (4) |
N3—C2—C1 | 111.3 (3) | C11A—C12—C13 | 118.5 (4) |
N3—C2—C15 | 118.9 (3) | C11A—C12—H12 | 120.8 |
C1—C2—C15 | 129.6 (4) | C13—C12—H12 | 120.8 |
C2—N3—O4 | 108.8 (3) | C12—C13—C8 | 121.3 (4) |
C2—N3—C6 | 134.4 (4) | C12—C13—H13 | 119.4 |
O4—N3—C6 | 116.8 (3) | C8—C13—H13 | 119.4 |
N3—O4—C5 | 107.6 (3) | C16—C15—C20 | 119.5 (3) |
O7—C5—O4 | 117.8 (4) | C16—C15—C2 | 122.2 (4) |
O7—C5—C1 | 135.3 (4) | C20—C15—C2 | 118.1 (3) |
O4—C5—C1 | 106.9 (3) | C17—C16—C15 | 119.1 (4) |
N3—C6—H6A | 109.5 | C17—C16—H16 | 120.4 |
N3—C6—H6B | 109.5 | C15—C16—H16 | 120.4 |
H6A—C6—H6B | 109.5 | N18A—C17—C16 | 120.5 (4) |
N3—C6—H6C | 109.5 | N18A—C17—H17 | 119.7 |
H6A—C6—H6C | 109.5 | C16—C17—H17 | 119.7 |
H6B—C6—H6C | 109.5 | C19—N18A—C17 | 121.6 (3) |
C13—C8—C9 | 118.2 (4) | C19—N18A—H18A | 119.2 |
C13—C8—C1 | 120.4 (4) | C17—N18A—H18A | 119.2 |
C9—C8—C1 | 121.3 (4) | N18A—C19—C20 | 120.7 (4) |
C10—C9—C8 | 121.1 (4) | N18A—C19—H19 | 119.6 |
C10—C9—H9 | 119.5 | C20—C19—H19 | 119.6 |
C8—C9—H9 | 119.5 | C19—C20—C15 | 118.5 (4) |
C11A—C10—C9 | 118.2 (4) | C19—C20—H20 | 120.7 |
C11A—C10—H10 | 120.9 | C15—C20—H20 | 120.7 |
C9—C10—H10 | 120.9 | ||
C5—C1—C2—N3 | 0.7 (5) | C1—C8—C9—C10 | 177.6 (4) |
C8—C1—C2—N3 | −173.3 (4) | C8—C9—C10—C11A | −1.2 (6) |
C5—C1—C2—C15 | −173.3 (4) | C9—C10—C11A—C12 | 0.7 (7) |
C8—C1—C2—C15 | 12.7 (7) | C9—C10—C11A—F1A | −177.8 (4) |
C1—C2—N3—O4 | 0.6 (5) | C10—C11A—C12—C13 | −0.1 (7) |
C15—C2—N3—O4 | 175.3 (3) | F1A—C11A—C12—C13 | 178.4 (4) |
C1—C2—N3—C6 | 178.3 (5) | C11A—C12—C13—C8 | 0.2 (7) |
C15—C2—N3—C6 | −7.0 (8) | C9—C8—C13—C12 | −0.7 (6) |
C2—N3—O4—C5 | −1.7 (5) | C1—C8—C13—C12 | −177.1 (4) |
C6—N3—O4—C5 | −179.9 (4) | N3—C2—C15—C16 | 60.6 (5) |
N3—O4—C5—O7 | −178.4 (4) | C1—C2—C15—C16 | −125.8 (5) |
N3—O4—C5—C1 | 2.1 (4) | N3—C2—C15—C20 | −116.6 (4) |
C2—C1—C5—O7 | 178.9 (5) | C1—C2—C15—C20 | 57.0 (6) |
C8—C1—C5—O7 | −6.8 (8) | C20—C15—C16—C17 | −1.0 (5) |
C2—C1—C5—O4 | −1.7 (4) | C2—C15—C16—C17 | −178.1 (3) |
C8—C1—C5—O4 | 172.6 (3) | C15—C16—C17—N18A | 0.5 (5) |
C2—C1—C8—C13 | −168.6 (4) | C16—C17—N18A—C19 | −0.4 (5) |
C5—C1—C8—C13 | 18.5 (6) | C17—N18A—C19—C20 | 0.7 (6) |
C2—C1—C8—C9 | 15.1 (6) | N18A—C19—C20—C15 | −1.2 (6) |
C5—C1—C8—C9 | −157.8 (4) | C16—C15—C20—C19 | 1.4 (6) |
C13—C8—C9—C10 | 1.3 (6) | C2—C15—C20—C19 | 178.6 (4) |
Experimental details
Crystal data | |
Chemical formula | C15H12FN2O2+·I− |
Mr | 398.17 |
Crystal system, space group | Monoclinic, P21/c |
Temperature (K) | 193 |
a, b, c (Å) | 10.2804 (4), 20.5895 (9), 7.4907 (3) |
β (°) | 96.8828 (14) |
V (Å3) | 1574.12 (11) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 2.05 |
Crystal size (mm) | 0.52 × 0.20 × 0.08 |
Data collection | |
Diffractometer | Bruker APEXII CCD |
Absorption correction | Multi-scan (APEX2; Bruker, 2006) |
Tmin, Tmax | 0.415, 0.853 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 27681, 3897, 3369 |
Rint | 0.126 |
(sin θ/λ)max (Å−1) | 0.668 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.040, 0.115, 1.07 |
No. of reflections | 3897 |
No. of parameters | 188 |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 1.60, −0.51 |
Computer programs: APEX2 (Bruker, 2006), SIR92 (Altomare et al., 1994), SHELXL97 (Sheldrick, 1997), ORTEP (Johnson, 1968) and PLATON (Spek, 2003).
Acknowledgements
The authors thank the EU-Craft Programme, Project Macrocept (FP6), for funding.
References
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This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.
Compound (II) (Scheme 1) was prepared in the course of our study on isoxazolones derivatives bearing the typical vicinal 4-pyridyl and 4-fluorophenyl pharmacophores of MAP Kinase inhibitors. Isoxazolones are described in the literature as inhibitors for p38 MAP Kinase (Laughlin et al., 2005; Clark et al., 2002).
The prototypical pyridinylimidazole SB 203580 is one of the best studied p38 inhibitors reported until now. Fig. 1 shows the most important interactions between the ATP binding sites of p38 kinase and the imidazole inhibitor SB203580 (Wang et al., 1998). The 4-fluorophenyl ring of SB203580 occupies a hydrophobic back pocket gaining selectivity. Vicinal to this interaction site, 4-pyridinyl moiety forms a hydrogen bond from the backbone NH group of Met 109 of p38 MAP Kinase (Fig. 1).
However, certain liver toxicities, such as increased liver size and increased cytochrome P450 induction, have been reported (Foster et al., 2000; Adams et al., 1998). In light of this potential toxicity and the risks associated with developing human drugs, a continuing need exist for potent new small molecules inhibitors of cytokine production with improved pharmacokinetic and safety profiles.
Several research groups have undertaken studies in which the imidazole ring was replaced by other 5- or 6- membered heterocycles (Laufer & Wagner, 2002; de Laszlo et al., 1998; Laufer et al., 2006; Revesz et al., 2000; Ohkawa et al., 2001). Replacement of the core heterocycle representing a strategy to dissect inhibition of p38 from interferences with cytochrome P450 (CYP450).
Accordingly, and based on the research published by Laughlin and co-authors (Laughlin et al., 2005), we plane to prepare N-alkylated derivatives of compound (I) in order to get more accurate and comparable information about isoxazolones as p38 MAP Kinase inhibitors in terms of biological activity.
By testing compounds (I) and (II) in the in vitro p38-alpha MAPK assay (Laufer et al., 2005), only compound (I) was found to posses biological activity.
The loss of the biological activity of compound (II) can be attributed to the absence of hydrogen bond donor on the pyridine ring and, consequentely, impossibility of interaction with Met109.