Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270100009768/bk1544sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S0108270100009768/bk1544PHI492sup2.hkl | |
Structure factor file (CIF format) https://doi.org/10.1107/S0108270100009768/bk1544PHI493sup3.hkl | |
Structure factor file (CIF format) https://doi.org/10.1107/S0108270100009768/bk1544PHI495sup4.hkl |
CCDC references: 152624; 152625; 152626
PHI492 was crystallized through slow evaporation of an ethanol/dichloromethane/dimethylformamide solution (3:2:1 v/v/v); colorless prisms, suitable for diffraction, were obtained after 27 d. PHI493 was crystallized as colorless needles through slow evaporation of tetrahydrofuran. PHI495 was dissolved in acetonitrile and crystallized through vapor diffusion of diethylether at 277 K; colorless prisms, suitable for diffraction, were grown in 18 d.
The H atoms attached to the N and O atoms for all three compounds appeared well resolved in the difference Fourier maps but, with the exception of PHI495, proved difficult to refine freely. The positions of the hydroxyl and amide protons in PHI492 and PHI493 were refined by restrained methods using the DFIX command in SHELXL97? (Sheldrick, 1997), where the distances were restrained to 0.82 Å and 0.86 Å, respectively, and their Ueq values were allowed to refine freely. All H atoms attached to C atoms were placed in ideal positions and refined using a riding model with aromatic C—H = 0.96 Å, methyl C—H = 0.98 Å, and with fixed isotropic displacement parameters equal to 1.2 (1.5 for methyl-H atoms) times the equivalent isotropic displacement parameter of the atom to which they were attached. The methyl groups were allowed to rotate about their local threefold axis during refinement. The H atoms in the methyl group C10 of PHI493 and PHI495 were found to be rotationally disordered, in a 0.6:0.4 ratio in PHI493 and in a 0.3:0.7 ratio in PHI495. The major features in the final difference map of PHI495 were ≤ 1.1 Å from the Br atom.
The title compounds were designed and synthesized as part of our ongoing program on the development of tyrosine kinase inhibitors as anti-cancer agents. The development of inhibitors of the PTK (or BTK?) signaling pathway is an active area of translational (or transnational?) cancer research. The identification of the compounds was guided by structure-based drug design methods, which included the construction of the kinase homology model of BTK (Mahajan et al., 1999) and advanced docking procedures to generate novel molecules that are complementary in shape and electrostatics to the kinase domain topography. Based on these modeling studies, several leflunomide metabolite (LFM) analogs were synthesized and tested for their kinase inhibitory activity on BTK. The three title compounds, PHI492, PHI493 and PHI495, were subsequently found to have micromolar potency towards BTK. \sch
The X-ray crystal structures of PHI492, PHI493 and PHI495 (Figs. 1–3) show that all three molecules contain an intramolecular O—H···O hydrogen bond that locks the compounds in a planar conformation. The presence of this intramolecular hydrogen bond is consistent with the results from docking studies of LFM analogs at the catalytic sites of several protein tyrosine kinases (Ghosh et al., 1998; Ghosh, Narla et al., 1999; Mahajan et al., 1999). These studies reveal that the planar conformation of these inhibitors resulting from the intramolecular hydrogen bond would allow the molecules to fit snugly into the shallow catalytic sites of EGFR (define?) and BTK. This binding mode is such that the title compounds can maintain close contact with the hinge region of the receptor on the edge of the inhibitor, and the aromatic rings of the inhibitors are sandwiched between hydrophobic residues at the catalytic site of the receptor.
The electronegative SO2 group of PHI492 and PHI493 is involved in hydrogen bonding with Lys430 and Arg525, respectively, on BTK, while in PHI495 the CF3 group is oriented towards Val416. In all three crystal structures, the molecules pack to form hydrogen-bonded dimers about inversion centers.
Compound PHI492 does not display O—H···O intermolecular hydrogen bonds and the intramolecular O9···O7 distance is 2.534 (2) Å. The compound forms a centrosymmetrically related dimer via an N1—H1···N11i intermolecular hydrogen bond [N1···N11i 3.132 (2) Å; symmetry code: (i) 1 - x, 4 - y, -z]. In compound PHI493, the intramolecular O9···O7 hydrogen-bond distance is 2.510 (2)%A and the dimers are linked by an N1···N11ii intermolecular hydrogen bond [N1···N11ii 3.060 (2) Å; symmetry code: (ii) -1 - x, 2 - y, 1 - z] and an O7···O9iii intermolecular contact [O7···O9iii 3.046 (2) Å; symmetry code: (iii) -x, 3 - y, 1 - z]. In PHI495, the intramolecular O9···.·O7 distance is 2.508 (4) Å and the dimers are linked by an N1···N11v intermolecular hydrogen bond [N1···N11v 3.218 (5) Å; symmetry code: (v) 2 - x, 1 - y, -z] and an O7···O9iv intermolecular contact [O7···O9iv 3.027 (4) Å; symmetry code: (iv) 1 - x, -y, -z]. These hydrogen-bond interactions observed in the crystal packing are similar for the three title compounds and similar to the six other leflunomide metabolite analogs reported earlier (Ghosh, Zheng & Uckun, 1999; Ghosh & Uckun, 1999).
The dihedral angle of the plane of the phenyl ring with the plane formed by atoms N1, C7, C8, C9 and C10 is 2.3 (3)° for PHI492, 2.4 (3)° for PHI493, and 2.5 (7)° for PHI495. The planarity of the molecules is extended to the hydroxyl, cyano and methyl groups via the intramolecular O9—H9···O7 hydrogen bond. The mean-plane deviation for each of the molecules as a whole is 0.0422 Å for PHI492, 0.0368 Å for PHI493 and 0.0372 Å for PHI495.
There is no significant difference in the corresponding bond lengths and angles in the three structures. However, the C8—C11 (Csp2—Csp1) bond distances are 1.424 (3) Å for PHI492, 1.424 (2) Å for PHI493 and 1.427 (6) Å for PHI495, and are slightly longer than the expected Csp2—Csp1 bond length of 1.416 Å. The C11≡N11 bond distances, on the other hand, are significantly shorter than the expected C≡N bond length of 1.165 Å; they are 1.138 (2) Å for PHI492, 1.136 (2) Å for PHI493 and 1.134 (5) Å for PHI495. A similar lengthening of the C8—C11 bond and shortening of the C≡N bond has been observed in the molecular structures of the six LFM analogs reported earlier (Ghosh, Zheng & Uckun, 1999; Ghosh & Uckun, 1999).
For all compounds, data collection: SMART (Bruker, 1998); cell refinement: SAINT (Bruker, 1998); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL (Bruker, 1997); software used to prepare material for publication: SHELXTL.
C12H12N2O4S | F(000) = 584 |
Mr = 280.30 | Dx = 1.492 Mg m−3 |
Monoclinic, P21/n | Mo Kα radiation, λ = 0.71073 Å |
a = 8.8002 (10) Å | Cell parameters from 5320 reflections |
b = 5.5336 (6) Å | θ = 1.6–26.4° |
c = 25.852 (3) Å | µ = 0.27 mm−1 |
β = 97.644 (1)° | T = 295 K |
V = 1247.7 (2) Å3 | Prism, colorless |
Z = 4 | 0.34 × 0.31 × 0.28 mm |
Bruker SMART CCD area-detector diffractometer | 2157 reflections with I > 2σ(I) |
ω scans | Rint = 0.030 |
Absorption correction: empirical (using intensity measurements) (SADABS; Sheldrick, 1996) | θmax = 26.4°, θmin = 1.6° |
Tmin = 0.913, Tmax = 0.928 | h = −11→10 |
10595 measured reflections | k = −6→6 |
2503 independent reflections | l = −32→31 |
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)] = 0.044 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.113 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.07 | w = 1/[σ2(Fo2) + (0.057P)2 + 0.5101P] where P = (Fo2 + 2Fc2)/3 |
2503 reflections | (Δ/σ)max = 0.003 |
182 parameters | Δρmax = 0.23 e Å−3 |
2 restraints | Δρmin = −0.45 e Å−3 |
C12H12N2O4S | V = 1247.7 (2) Å3 |
Mr = 280.30 | Z = 4 |
Monoclinic, P21/n | Mo Kα radiation |
a = 8.8002 (10) Å | µ = 0.27 mm−1 |
b = 5.5336 (6) Å | T = 295 K |
c = 25.852 (3) Å | 0.34 × 0.31 × 0.28 mm |
β = 97.644 (1)° |
Bruker SMART CCD area-detector diffractometer | 2503 independent reflections |
Absorption correction: empirical (using intensity measurements) (SADABS; Sheldrick, 1996) | 2157 reflections with I > 2σ(I) |
Tmin = 0.913, Tmax = 0.928 | Rint = 0.030 |
10595 measured reflections |
R[F2 > 2σ(F2)] = 0.044 | 2 restraints |
wR(F2) = 0.113 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.07 | Δρmax = 0.23 e Å−3 |
2503 reflections | Δρmin = −0.45 e Å−3 |
182 parameters |
x | y | z | Uiso*/Ueq | ||
S1 | 0.92302 (6) | 0.96106 (9) | 0.186661 (18) | 0.03941 (17) | |
O1 | 0.7903 (2) | 0.8542 (3) | 0.20405 (7) | 0.0594 (4) | |
O2 | 1.04355 (19) | 0.8031 (3) | 0.17545 (6) | 0.0555 (4) | |
O7 | 0.82385 (16) | 1.4044 (3) | −0.06543 (5) | 0.0446 (4) | |
O9 | 0.75956 (19) | 1.5746 (3) | −0.15671 (6) | 0.0540 (4) | |
H9 | 0.799 (3) | 1.485 (5) | −0.1335 (9) | 0.076 (9)* | |
N1 | 0.71869 (19) | 1.5741 (3) | 0.00206 (6) | 0.0389 (4) | |
H1 | 0.657 (2) | 1.682 (3) | 0.0096 (9) | 0.043 (6)* | |
N11 | 0.5095 (2) | 2.0899 (4) | −0.05154 (8) | 0.0566 (5) | |
C1 | 0.7722 (2) | 1.4183 (3) | 0.04377 (7) | 0.0347 (4) | |
C2 | 0.8655 (2) | 1.2177 (4) | 0.03973 (8) | 0.0404 (4) | |
H2 | 0.8960 | 1.1769 | 0.0078 | 0.048* | |
C3 | 0.9123 (2) | 1.0798 (3) | 0.08344 (8) | 0.0388 (4) | |
H3 | 0.9761 | 0.9475 | 0.0810 | 0.047* | |
C4 | 0.8650 (2) | 1.1370 (3) | 0.13082 (7) | 0.0337 (4) | |
C5 | 0.7714 (2) | 1.3354 (4) | 0.13495 (8) | 0.0413 (5) | |
H5 | 0.7389 | 1.3734 | 0.1668 | 0.050* | |
C6 | 0.7270 (2) | 1.4751 (4) | 0.09191 (8) | 0.0422 (5) | |
H6 | 0.6658 | 1.6100 | 0.0949 | 0.051* | |
C7 | 0.7434 (2) | 1.5618 (3) | −0.04842 (8) | 0.0355 (4) | |
C8 | 0.6686 (2) | 1.7474 (3) | −0.08386 (8) | 0.0366 (4) | |
C9 | 0.6804 (2) | 1.7415 (4) | −0.13599 (8) | 0.0405 (4) | |
C10 | 0.6065 (3) | 1.9207 (4) | −0.17414 (9) | 0.0530 (6) | |
H10A | 0.5829 | 1.8454 | −0.2077 | 0.079* | |
H10B | 0.6752 | 2.0537 | −0.1767 | 0.079* | |
H10C | 0.5138 | 1.9788 | −0.1627 | 0.079* | |
C11 | 0.5806 (2) | 1.9372 (4) | −0.06545 (8) | 0.0407 (4) | |
C12 | 0.9998 (3) | 1.1723 (4) | 0.23398 (8) | 0.0517 (5) | |
H12A | 1.0518 | 1.0884 | 0.2637 | 0.078* | |
H12B | 0.9184 | 1.2682 | 0.2446 | 0.078* | |
H12C | 1.0710 | 1.2754 | 0.2195 | 0.078* |
U11 | U22 | U33 | U12 | U13 | U23 | |
S1 | 0.0506 (3) | 0.0333 (3) | 0.0355 (3) | 0.0060 (2) | 0.0100 (2) | 0.00012 (18) |
O1 | 0.0708 (10) | 0.0500 (9) | 0.0616 (10) | −0.0100 (8) | 0.0247 (8) | 0.0067 (8) |
O2 | 0.0685 (10) | 0.0520 (9) | 0.0462 (8) | 0.0283 (8) | 0.0079 (7) | 0.0012 (7) |
O7 | 0.0515 (8) | 0.0398 (8) | 0.0448 (8) | 0.0173 (6) | 0.0143 (6) | 0.0045 (6) |
O9 | 0.0674 (10) | 0.0517 (9) | 0.0441 (9) | 0.0244 (8) | 0.0125 (8) | 0.0043 (7) |
N1 | 0.0438 (9) | 0.0332 (8) | 0.0403 (9) | 0.0129 (7) | 0.0079 (7) | −0.0003 (7) |
N11 | 0.0625 (12) | 0.0487 (11) | 0.0594 (12) | 0.0251 (10) | 0.0112 (10) | 0.0002 (9) |
C1 | 0.0353 (9) | 0.0301 (9) | 0.0388 (10) | 0.0029 (7) | 0.0055 (7) | −0.0017 (7) |
C2 | 0.0456 (10) | 0.0404 (10) | 0.0365 (10) | 0.0123 (9) | 0.0105 (8) | −0.0025 (8) |
C3 | 0.0431 (10) | 0.0346 (10) | 0.0397 (10) | 0.0115 (8) | 0.0088 (8) | −0.0017 (8) |
C4 | 0.0344 (9) | 0.0309 (9) | 0.0363 (9) | 0.0017 (7) | 0.0068 (7) | −0.0014 (7) |
C5 | 0.0488 (11) | 0.0390 (10) | 0.0378 (10) | 0.0097 (9) | 0.0122 (9) | −0.0038 (8) |
C6 | 0.0472 (11) | 0.0352 (10) | 0.0451 (11) | 0.0141 (9) | 0.0095 (9) | −0.0032 (8) |
C7 | 0.0339 (9) | 0.0305 (9) | 0.0425 (10) | 0.0028 (7) | 0.0063 (8) | −0.0001 (8) |
C8 | 0.0349 (9) | 0.0312 (9) | 0.0439 (11) | 0.0053 (8) | 0.0065 (8) | 0.0009 (8) |
C9 | 0.0399 (10) | 0.0371 (10) | 0.0449 (11) | 0.0073 (8) | 0.0069 (8) | 0.0021 (8) |
C10 | 0.0597 (13) | 0.0518 (13) | 0.0473 (12) | 0.0182 (11) | 0.0070 (10) | 0.0093 (10) |
C11 | 0.0403 (10) | 0.0379 (10) | 0.0436 (11) | 0.0072 (8) | 0.0039 (8) | 0.0036 (8) |
C12 | 0.0640 (13) | 0.0536 (13) | 0.0370 (11) | 0.0040 (11) | 0.0045 (10) | −0.0069 (9) |
S1—O2 | 1.4336 (15) | C3—H3 | 0.9300 |
S1—O1 | 1.4339 (16) | C4—C5 | 1.385 (3) |
S1—C4 | 1.7596 (19) | C5—C6 | 1.368 (3) |
S1—C12 | 1.760 (2) | C5—H5 | 0.9300 |
O7—C7 | 1.239 (2) | C6—H6 | 0.9300 |
O9—C9 | 1.313 (2) | C7—C8 | 1.472 (3) |
O9—H9 | 0.819 (10) | C8—C9 | 1.366 (3) |
N1—C7 | 1.353 (3) | C8—C11 | 1.424 (3) |
N1—C1 | 1.412 (2) | C9—C10 | 1.486 (3) |
N1—H1 | 0.851 (10) | C10—H10A | 0.9600 |
N11—C11 | 1.138 (2) | C10—H10B | 0.9600 |
C1—C6 | 1.392 (3) | C10—H10C | 0.9600 |
C1—C2 | 1.393 (2) | C12—H12A | 0.9600 |
C2—C3 | 1.380 (3) | C12—H12B | 0.9600 |
C2—H2 | 0.9300 | C12—H12C | 0.9600 |
C3—C4 | 1.382 (3) | ||
O2—S1—O1 | 117.86 (10) | C5—C6—C1 | 121.01 (17) |
O2—S1—C4 | 108.26 (9) | C5—C6—H6 | 119.5 |
O1—S1—C4 | 109.02 (9) | C1—C6—H6 | 119.5 |
O2—S1—C12 | 108.63 (11) | O7—C7—N1 | 123.37 (17) |
O1—S1—C12 | 108.03 (11) | O7—C7—C8 | 119.91 (17) |
C4—S1—C12 | 104.20 (10) | N1—C7—C8 | 116.72 (16) |
C9—O9—H9 | 109 (2) | C9—C8—C11 | 117.63 (17) |
C7—N1—C1 | 128.78 (16) | C9—C8—C7 | 120.73 (17) |
C7—N1—H1 | 116.6 (15) | C11—C8—C7 | 121.64 (17) |
C1—N1—H1 | 114.4 (15) | O9—C9—C8 | 122.25 (18) |
C6—C1—C2 | 119.22 (18) | O9—C9—C10 | 114.07 (18) |
C6—C1—N1 | 116.07 (16) | C8—C9—C10 | 123.69 (18) |
C2—C1—N1 | 124.71 (17) | C9—C10—H10A | 109.5 |
C3—C2—C1 | 119.60 (17) | C9—C10—H10B | 109.5 |
C3—C2—H2 | 120.2 | H10A—C10—H10B | 109.5 |
C1—C2—H2 | 120.2 | C9—C10—H10C | 109.5 |
C2—C3—C4 | 120.46 (17) | H10A—C10—H10C | 109.5 |
C2—C3—H3 | 119.8 | H10B—C10—H10C | 109.5 |
C4—C3—H3 | 119.8 | N11—C11—C8 | 178.9 (2) |
C3—C4—C5 | 120.13 (18) | S1—C12—H12A | 109.5 |
C3—C4—S1 | 120.80 (14) | S1—C12—H12B | 109.5 |
C5—C4—S1 | 119.07 (14) | H12A—C12—H12B | 109.5 |
C6—C5—C4 | 119.56 (17) | S1—C12—H12C | 109.5 |
C6—C5—H5 | 120.2 | H12A—C12—H12C | 109.5 |
C4—C5—H5 | 120.2 | H12B—C12—H12C | 109.5 |
D—H···A | D—H | H···A | D···A | D—H···A |
O9—H9···O7 | 0.82 (1) | 1.80 (2) | 2.534 (2) | 148 (3) |
N1—H1···N11i | 0.85 (1) | 2.31 (1) | 3.132 (2) | 164 (2) |
Symmetry code: (i) −x+1, −y+4, −z. |
C12H12N2O4S | Z = 2 |
Mr = 280.30 | F(000) = 292 |
Triclinic, P1 | Dx = 1.450 Mg m−3 |
a = 5.4734 (3) Å | Mo Kα radiation, λ = 0.71073 Å |
b = 11.4048 (6) Å | Cell parameters from 4558 reflections |
c = 11.5200 (6) Å | θ = 2.0–25.7° |
α = 115.478 (1)° | µ = 0.26 mm−1 |
β = 95.941 (1)° | T = 295 K |
γ = 93.035 (1)° | Needle, colorless |
V = 641.88 (6) Å3 | 0.55 × 0.35 × 0.17 mm |
Bruker SMART CCD area-detector diffractometer | 2428 independent reflections |
Radiation source: fine-focus sealed tube | 2152 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.022 |
ω scans | θmax = 25.7°, θmin = 2.0° |
Absorption correction: empirical (using intensity measurements) (SADABS; Sheldrick, 1996) | h = −6→6 |
Tmin = 0.869, Tmax = 0.957 | k = −13→13 |
6510 measured reflections | l = −14→14 |
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)] = 0.034 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.102 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.05 | w = 1/[σ2(Fo2) + (0.0546P)2 + 0.1902P] where P = (Fo2 + 2Fc2)/3 |
2428 reflections | (Δ/σ)max = 0.002 |
182 parameters | Δρmax = 0.22 e Å−3 |
2 restraints | Δρmin = −0.28 e Å−3 |
C12H12N2O4S | γ = 93.035 (1)° |
Mr = 280.30 | V = 641.88 (6) Å3 |
Triclinic, P1 | Z = 2 |
a = 5.4734 (3) Å | Mo Kα radiation |
b = 11.4048 (6) Å | µ = 0.26 mm−1 |
c = 11.5200 (6) Å | T = 295 K |
α = 115.478 (1)° | 0.55 × 0.35 × 0.17 mm |
β = 95.941 (1)° |
Bruker SMART CCD area-detector diffractometer | 2428 independent reflections |
Absorption correction: empirical (using intensity measurements) (SADABS; Sheldrick, 1996) | 2152 reflections with I > 2σ(I) |
Tmin = 0.869, Tmax = 0.957 | Rint = 0.022 |
6510 measured reflections |
R[F2 > 2σ(F2)] = 0.034 | 2 restraints |
wR(F2) = 0.102 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.05 | Δρmax = 0.22 e Å−3 |
2428 reflections | Δρmin = −0.28 e Å−3 |
182 parameters |
x | y | z | Uiso*/Ueq | Occ. (<1) | |
S1 | 0.18636 (8) | 0.72706 (4) | 0.08772 (4) | 0.04348 (16) | |
N1 | −0.1711 (3) | 1.13535 (12) | 0.39287 (14) | 0.0403 (3) | |
H1 | −0.247 (3) | 1.0773 (15) | 0.407 (2) | 0.054 (6)* | |
N11 | −0.6427 (4) | 1.10486 (15) | 0.57420 (18) | 0.0662 (5) | |
O1 | 0.1075 (3) | 0.67815 (13) | 0.17522 (14) | 0.0622 (4) | |
O2 | 0.4265 (3) | 0.70436 (14) | 0.04929 (16) | 0.0710 (5) | |
O7 | −0.1032 (3) | 1.35314 (11) | 0.44916 (14) | 0.0564 (4) | |
O9 | −0.3146 (3) | 1.51540 (11) | 0.62330 (14) | 0.0560 (4) | |
H9 | −0.223 (4) | 1.485 (2) | 0.5662 (18) | 0.074 (7)* | |
C1 | −0.0055 (3) | 1.08639 (15) | 0.30128 (15) | 0.0370 (4) | |
C2 | 0.1493 (4) | 1.16422 (16) | 0.26817 (18) | 0.0481 (4) | |
H2B | 0.1434 | 1.2542 | 0.3050 | 0.058* | |
C3 | 0.3124 (4) | 1.10813 (18) | 0.1803 (2) | 0.0586 (5) | |
H3A | 0.4151 | 1.1612 | 0.1589 | 0.070* | |
C4 | 0.3252 (4) | 0.97491 (18) | 0.12390 (19) | 0.0527 (5) | |
H4A | 0.4359 | 0.9378 | 0.0655 | 0.063* | |
C5 | 0.1686 (3) | 0.89833 (15) | 0.15682 (16) | 0.0394 (4) | |
C6 | 0.0049 (3) | 0.95122 (15) | 0.24385 (16) | 0.0395 (4) | |
H6A | −0.0982 | 0.8975 | 0.2643 | 0.047* | |
C7 | −0.2140 (3) | 1.26115 (15) | 0.46070 (16) | 0.0386 (4) | |
C8 | −0.3970 (3) | 1.28887 (15) | 0.55049 (15) | 0.0375 (4) | |
C9 | −0.4378 (3) | 1.41522 (15) | 0.62732 (16) | 0.0405 (4) | |
C10 | −0.6188 (4) | 1.45202 (18) | 0.72103 (19) | 0.0523 (5) | |
H10A | −0.7170 | 1.5144 | 0.7093 | 0.078* | 0.59 (2) |
H10B | −0.5323 | 1.4899 | 0.8080 | 0.078* | 0.59 (2) |
H10C | −0.7241 | 1.3756 | 0.7065 | 0.078* | 0.59 (2) |
H10D | −0.5986 | 1.4055 | 0.7732 | 0.078* | 0.41 (2) |
H10E | −0.7833 | 1.4300 | 0.6745 | 0.078* | 0.41 (2) |
H10F | −0.5915 | 1.5443 | 0.7760 | 0.078* | 0.41 (2) |
C11 | −0.5334 (3) | 1.18660 (16) | 0.56395 (17) | 0.0440 (4) | |
C12 | −0.0315 (4) | 0.66208 (19) | −0.05261 (19) | 0.0553 (5) | |
H12A | −0.0330 | 0.5688 | −0.0947 | 0.083* | |
H12B | 0.0112 | 0.6978 | −0.1105 | 0.083* | |
H12C | −0.1922 | 0.6840 | −0.0296 | 0.083* |
U11 | U22 | U33 | U12 | U13 | U23 | |
S1 | 0.0465 (3) | 0.0326 (2) | 0.0486 (3) | 0.01200 (17) | 0.01693 (18) | 0.01218 (19) |
N1 | 0.0526 (8) | 0.0252 (6) | 0.0454 (8) | 0.0040 (6) | 0.0247 (6) | 0.0137 (6) |
N11 | 0.0868 (13) | 0.0383 (8) | 0.0797 (12) | 0.0061 (8) | 0.0514 (10) | 0.0231 (8) |
O1 | 0.0955 (11) | 0.0397 (7) | 0.0585 (8) | 0.0151 (7) | 0.0223 (8) | 0.0248 (6) |
O2 | 0.0498 (8) | 0.0541 (8) | 0.0941 (11) | 0.0194 (6) | 0.0265 (8) | 0.0135 (8) |
O7 | 0.0747 (9) | 0.0282 (6) | 0.0703 (9) | 0.0050 (6) | 0.0417 (7) | 0.0184 (6) |
O9 | 0.0733 (9) | 0.0265 (6) | 0.0641 (9) | 0.0037 (6) | 0.0336 (7) | 0.0111 (6) |
C1 | 0.0444 (9) | 0.0307 (8) | 0.0369 (8) | 0.0049 (6) | 0.0149 (7) | 0.0134 (6) |
C2 | 0.0651 (11) | 0.0307 (8) | 0.0508 (10) | 0.0047 (7) | 0.0275 (9) | 0.0158 (7) |
C3 | 0.0731 (13) | 0.0432 (10) | 0.0667 (12) | 0.0020 (9) | 0.0400 (10) | 0.0247 (9) |
C4 | 0.0617 (11) | 0.0433 (10) | 0.0554 (11) | 0.0099 (8) | 0.0342 (9) | 0.0176 (8) |
C5 | 0.0449 (9) | 0.0318 (8) | 0.0408 (9) | 0.0063 (6) | 0.0150 (7) | 0.0130 (7) |
C6 | 0.0462 (9) | 0.0297 (8) | 0.0448 (9) | 0.0033 (6) | 0.0188 (7) | 0.0157 (7) |
C7 | 0.0478 (9) | 0.0281 (8) | 0.0405 (8) | 0.0032 (6) | 0.0146 (7) | 0.0139 (7) |
C8 | 0.0467 (9) | 0.0283 (7) | 0.0380 (8) | 0.0031 (6) | 0.0147 (7) | 0.0131 (6) |
C9 | 0.0484 (9) | 0.0310 (8) | 0.0403 (9) | 0.0043 (7) | 0.0128 (7) | 0.0126 (7) |
C10 | 0.0606 (11) | 0.0393 (9) | 0.0521 (10) | 0.0096 (8) | 0.0248 (9) | 0.0113 (8) |
C11 | 0.0552 (10) | 0.0318 (8) | 0.0458 (9) | 0.0081 (7) | 0.0260 (8) | 0.0133 (7) |
C12 | 0.0591 (12) | 0.0445 (10) | 0.0528 (11) | 0.0084 (8) | 0.0117 (9) | 0.0114 (8) |
S1—O2 | 1.4312 (14) | C4—C5 | 1.384 (2) |
S1—O1 | 1.4360 (14) | C4—H4A | 0.9300 |
S1—C12 | 1.750 (2) | C5—C6 | 1.377 (2) |
S1—C5 | 1.7768 (16) | C6—H6A | 0.9300 |
N1—C7 | 1.354 (2) | C7—C8 | 1.463 (2) |
N1—C1 | 1.412 (2) | C8—C9 | 1.374 (2) |
N1—H1 | 0.844 (9) | C8—C11 | 1.425 (2) |
N11—C11 | 1.136 (2) | C9—C10 | 1.483 (2) |
O7—C7 | 1.2472 (19) | C10—H10A | 0.9600 |
O9—C9 | 1.316 (2) | C10—H10B | 0.9600 |
O9—H9 | 0.833 (10) | C10—H10C | 0.9600 |
C1—C2 | 1.389 (2) | C10—H10D | 0.9600 |
C1—C6 | 1.399 (2) | C10—H10E | 0.9600 |
C2—C3 | 1.386 (2) | C10—H10F | 0.9600 |
C2—H2B | 0.9300 | C12—H12A | 0.9600 |
C3—C4 | 1.381 (3) | C12—H12B | 0.9600 |
C3—H3A | 0.9300 | C12—H12C | 0.9600 |
O2—S1—O1 | 118.71 (10) | C11—C8—C7 | 121.35 (14) |
O2—S1—C12 | 108.16 (10) | O9—C9—C8 | 121.60 (15) |
O1—S1—C12 | 107.80 (10) | O9—C9—C10 | 114.07 (14) |
O2—S1—C5 | 107.75 (8) | C8—C9—C10 | 124.33 (15) |
O1—S1—C5 | 108.60 (8) | C9—C10—H10A | 109.5 |
C12—S1—C5 | 105.01 (9) | C9—C10—H10B | 109.5 |
C7—N1—C1 | 127.91 (13) | H10A—C10—H10B | 109.5 |
C7—N1—H1 | 118.3 (14) | C9—C10—H10C | 109.5 |
C1—N1—H1 | 113.7 (14) | H10A—C10—H10C | 109.5 |
C9—O9—H9 | 107.1 (17) | H10B—C10—H10C | 109.5 |
C2—C1—C6 | 118.99 (14) | C9—C10—H10D | 109.5 |
C2—C1—N1 | 124.02 (14) | H10A—C10—H10D | 141.1 |
C6—C1—N1 | 116.97 (13) | H10B—C10—H10D | 56.3 |
C3—C2—C1 | 120.13 (15) | H10C—C10—H10D | 56.3 |
C3—C2—H2B | 119.9 | C9—C10—H10E | 109.5 |
C1—C2—H2B | 119.9 | H10A—C10—H10E | 56.3 |
C4—C3—C2 | 121.28 (16) | H10B—C10—H10E | 141.1 |
C4—C3—H3A | 119.4 | H10C—C10—H10E | 56.3 |
C2—C3—H3A | 119.4 | H10D—C10—H10E | 109.5 |
C3—C4—C5 | 118.02 (15) | C9—C10—H10F | 109.5 |
C3—C4—H4A | 121.0 | H10A—C10—H10F | 56.3 |
C5—C4—H4A | 121.0 | H10B—C10—H10F | 56.3 |
C6—C5—C4 | 122.02 (15) | H10C—C10—H10F | 141.1 |
C6—C5—S1 | 119.22 (12) | H10D—C10—H10F | 109.5 |
C4—C5—S1 | 118.73 (12) | H10E—C10—H10F | 109.5 |
C5—C6—C1 | 119.54 (14) | N11—C11—C8 | 179.7 (2) |
C5—C6—H6A | 120.2 | S1—C12—H12A | 109.5 |
C1—C6—H6A | 120.2 | S1—C12—H12B | 109.5 |
O7—C7—N1 | 122.34 (14) | H12A—C12—H12B | 109.5 |
O7—C7—C8 | 119.39 (14) | S1—C12—H12C | 109.5 |
N1—C7—C8 | 118.27 (13) | H12A—C12—H12C | 109.5 |
C9—C8—C11 | 117.83 (14) | H12B—C12—H12C | 109.5 |
C9—C8—C7 | 120.80 (14) |
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1···N11i | 0.84 (1) | 2.24 (1) | 3.060 (2) | 164 (2) |
O9—H9···O7 | 0.83 (1) | 1.75 (2) | 2.5102 (17) | 151 (2) |
O9—H9···O7ii | 0.83 (1) | 2.57 (2) | 3.0464 (18) | 118 (2) |
Symmetry codes: (i) −x−1, −y+2, −z+1; (ii) −x, −y+3, −z+1. |
C12H8BrF3N2O3 | Z = 2 |
Mr = 365.11 | F(000) = 360 |
Triclinic, P1 | Dx = 1.750 Mg m−3 Dm = 1.76 (2) Mg m−3 Dm measured by flotation in phenyliodide and hexane |
a = 5.2834 (4) Å | Mo Kα radiation, λ = 0.71073 Å |
b = 10.8265 (8) Å | Cell parameters from 1906 reflections |
c = 13.1634 (10) Å | θ = 1.7–25.7° |
α = 69.009 (1)° | µ = 3.01 mm−1 |
β = 81.085 (1)° | T = 295 K |
γ = 83.238 (1)° | Needle, colorless |
V = 692.91 (9) Å3 | 0.45 × 0.11 × 0.10 mm |
Bruker SMART CCD area-detector diffractometer | 2643 independent reflections |
Radiation source: fine-focus sealed tube | 1364 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.037 |
ω scans | θmax = 25.7°, θmin = 1.7° |
Absorption correction: empirical (using intensity measurements) (SADABS; Sheldrick, 1996) | h = −6→6 |
Tmin = 0.344, Tmax = 0.753 | k = −13→13 |
7235 measured reflections | l = −16→16 |
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)] = 0.045 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.131 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.01 | w = 1/[σ2(Fo2) + (0.0639P)2] where P = (Fo2 + 2Fc2)/3 |
2643 reflections | (Δ/σ)max = 0.004 |
200 parameters | Δρmax = 0.61 e Å−3 |
0 restraints | Δρmin = −0.51 e Å−3 |
C12H8BrF3N2O3 | γ = 83.238 (1)° |
Mr = 365.11 | V = 692.91 (9) Å3 |
Triclinic, P1 | Z = 2 |
a = 5.2834 (4) Å | Mo Kα radiation |
b = 10.8265 (8) Å | µ = 3.01 mm−1 |
c = 13.1634 (10) Å | T = 295 K |
α = 69.009 (1)° | 0.45 × 0.11 × 0.10 mm |
β = 81.085 (1)° |
Bruker SMART CCD area-detector diffractometer | 2643 independent reflections |
Absorption correction: empirical (using intensity measurements) (SADABS; Sheldrick, 1996) | 1364 reflections with I > 2σ(I) |
Tmin = 0.344, Tmax = 0.753 | Rint = 0.037 |
7235 measured reflections |
R[F2 > 2σ(F2)] = 0.045 | 0 restraints |
wR(F2) = 0.131 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.01 | Δρmax = 0.61 e Å−3 |
2643 reflections | Δρmin = −0.51 e Å−3 |
200 parameters |
x | y | z | Uiso*/Ueq | Occ. (<1) | |
Br1 | 0.18630 (13) | 0.49058 (6) | 0.37570 (5) | 0.1136 (4) | |
F1 | −0.2881 (9) | 0.0828 (5) | 0.5088 (3) | 0.1625 (17) | |
F2 | −0.3853 (8) | 0.2333 (4) | 0.5740 (3) | 0.1645 (17) | |
F3 | −0.0019 (9) | 0.1602 (5) | 0.5507 (3) | 0.1481 (16) | |
O4 | −0.1978 (6) | 0.2863 (4) | 0.4107 (3) | 0.0898 (10) | |
O7 | 0.5577 (5) | 0.1190 (3) | 0.0302 (2) | 0.0699 (9) | |
O9 | 0.8665 (6) | 0.0708 (3) | −0.1182 (3) | 0.0754 (10) | |
H9 | 0.727 (10) | 0.068 (5) | −0.070 (5) | 0.109 (19)* | |
N1 | 0.6152 (7) | 0.2897 (4) | 0.0847 (3) | 0.0552 (9) | |
H1 | 0.696 (7) | 0.355 (3) | 0.070 (3) | 0.042 (11)* | |
N11 | 1.1555 (8) | 0.4453 (4) | −0.0794 (3) | 0.0810 (12) | |
C1 | 0.4079 (7) | 0.2789 (4) | 0.1688 (3) | 0.0515 (10) | |
C2 | 0.2253 (8) | 0.1866 (4) | 0.1979 (3) | 0.0601 (11) | |
H2 | 0.2345 | 0.1250 | 0.1630 | 0.072* | |
C3 | 0.0286 (8) | 0.1882 (5) | 0.2803 (3) | 0.0700 (12) | |
H3 | −0.0972 | 0.1278 | 0.2997 | 0.084* | |
C4 | 0.0153 (8) | 0.2761 (5) | 0.3334 (3) | 0.0666 (12) | |
C5 | 0.1969 (9) | 0.3664 (4) | 0.3048 (3) | 0.0652 (12) | |
C6 | 0.3926 (8) | 0.3670 (4) | 0.2232 (3) | 0.0611 (11) | |
H6 | 0.5170 | 0.4280 | 0.2045 | 0.073* | |
C7 | 0.6795 (7) | 0.2146 (4) | 0.0208 (3) | 0.0518 (10) | |
C8 | 0.9063 (7) | 0.2481 (4) | −0.0615 (3) | 0.0507 (10) | |
C9 | 0.9902 (8) | 0.1735 (4) | −0.1260 (3) | 0.0582 (11) | |
C10 | 1.2180 (9) | 0.1980 (5) | −0.2098 (4) | 0.0747 (13) | |
H10A | 1.2344 | 0.1339 | −0.2458 | 0.112* | 0.29 (5) |
H10B | 1.3690 | 0.1904 | −0.1752 | 0.112* | 0.29 (5) |
H10C | 1.1982 | 0.2856 | −0.2628 | 0.112* | 0.29 (5) |
H10D | 1.3000 | 0.2727 | −0.2101 | 0.112* | 0.71 (5) |
H10E | 1.1654 | 0.2162 | −0.2807 | 0.112* | 0.71 (5) |
H10F | 1.3362 | 0.1211 | −0.1931 | 0.112* | 0.71 (5) |
C11 | 1.0481 (8) | 0.3575 (4) | −0.0728 (3) | 0.0568 (11) | |
C12 | −0.2141 (14) | 0.1923 (7) | 0.5082 (6) | 0.0981 (19) |
U11 | U22 | U33 | U12 | U13 | U23 | |
Br1 | 0.1548 (7) | 0.1008 (5) | 0.0998 (5) | −0.0162 (4) | 0.0380 (4) | −0.0721 (4) |
F1 | 0.192 (4) | 0.161 (4) | 0.140 (3) | −0.090 (3) | 0.061 (3) | −0.068 (3) |
F2 | 0.175 (3) | 0.192 (4) | 0.109 (3) | −0.017 (3) | 0.084 (3) | −0.072 (3) |
F3 | 0.137 (3) | 0.218 (5) | 0.070 (2) | −0.035 (3) | −0.002 (2) | −0.025 (3) |
O4 | 0.076 (2) | 0.117 (3) | 0.068 (2) | 0.0010 (19) | 0.0266 (18) | −0.039 (2) |
O7 | 0.0687 (18) | 0.078 (2) | 0.079 (2) | −0.0349 (17) | 0.0287 (15) | −0.0525 (17) |
O9 | 0.071 (2) | 0.084 (2) | 0.091 (2) | −0.0331 (18) | 0.0266 (19) | −0.0607 (19) |
N1 | 0.057 (2) | 0.060 (2) | 0.057 (2) | −0.0201 (19) | 0.0132 (17) | −0.0339 (19) |
N11 | 0.088 (3) | 0.084 (3) | 0.081 (3) | −0.038 (2) | 0.017 (2) | −0.041 (2) |
C1 | 0.050 (2) | 0.061 (3) | 0.047 (2) | −0.011 (2) | 0.0060 (19) | −0.025 (2) |
C2 | 0.058 (3) | 0.071 (3) | 0.060 (3) | −0.017 (2) | 0.010 (2) | −0.036 (2) |
C3 | 0.067 (3) | 0.087 (3) | 0.059 (3) | −0.026 (2) | 0.019 (2) | −0.033 (3) |
C4 | 0.059 (3) | 0.082 (3) | 0.053 (3) | 0.000 (3) | 0.016 (2) | −0.026 (2) |
C5 | 0.077 (3) | 0.066 (3) | 0.057 (3) | 0.000 (2) | 0.011 (2) | −0.036 (2) |
C6 | 0.072 (3) | 0.061 (3) | 0.057 (3) | −0.018 (2) | 0.014 (2) | −0.033 (2) |
C7 | 0.049 (2) | 0.061 (3) | 0.051 (2) | −0.015 (2) | 0.0087 (19) | −0.027 (2) |
C8 | 0.050 (2) | 0.056 (2) | 0.049 (2) | −0.0156 (19) | 0.0088 (19) | −0.025 (2) |
C9 | 0.060 (3) | 0.064 (3) | 0.055 (3) | −0.014 (2) | 0.008 (2) | −0.030 (2) |
C10 | 0.073 (3) | 0.088 (3) | 0.068 (3) | −0.020 (3) | 0.024 (2) | −0.042 (3) |
C11 | 0.060 (3) | 0.064 (3) | 0.052 (3) | −0.020 (2) | 0.011 (2) | −0.028 (2) |
C12 | 0.096 (5) | 0.129 (5) | 0.074 (4) | −0.035 (4) | 0.033 (4) | −0.050 (4) |
Br1—C5 | 1.884 (4) | C1—C6 | 1.372 (5) |
F1—C12 | 1.288 (7) | C1—C2 | 1.383 (5) |
F2—C12 | 1.305 (6) | C2—C3 | 1.384 (6) |
F3—C12 | 1.286 (7) | C3—C4 | 1.358 (6) |
O4—C12 | 1.319 (7) | C4—C5 | 1.365 (6) |
O4—C4 | 1.418 (5) | C5—C6 | 1.368 (5) |
O7—C7 | 1.241 (5) | C7—C8 | 1.469 (5) |
O9—C9 | 1.320 (5) | C8—C9 | 1.364 (5) |
N1—C7 | 1.349 (5) | C8—C11 | 1.427 (6) |
N1—C1 | 1.415 (5) | C9—C10 | 1.479 (6) |
N11—C11 | 1.134 (5) | ||
C12—O4—C4 | 117.6 (4) | O7—C7—C8 | 119.7 (3) |
C7—N1—C1 | 128.8 (4) | N1—C7—C8 | 117.5 (4) |
C6—C1—C2 | 119.5 (3) | C9—C8—C11 | 118.7 (3) |
C6—C1—N1 | 116.4 (4) | C9—C8—C7 | 121.1 (4) |
C2—C1—N1 | 124.1 (4) | C11—C8—C7 | 120.2 (3) |
C1—C2—C3 | 118.4 (4) | O9—C9—C8 | 121.0 (4) |
C4—C3—C2 | 121.4 (4) | O9—C9—C10 | 114.0 (4) |
C3—C4—C5 | 119.9 (4) | C8—C9—C10 | 125.1 (4) |
C3—C4—O4 | 121.6 (4) | N11—C11—C8 | 177.9 (4) |
C5—C4—O4 | 118.2 (4) | F3—C12—F1 | 105.1 (7) |
C4—C5—C6 | 119.7 (4) | F3—C12—F2 | 108.6 (6) |
C4—C5—Br1 | 121.4 (3) | F1—C12—F2 | 106.6 (5) |
C6—C5—Br1 | 118.8 (3) | F3—C12—O4 | 114.2 (5) |
C5—C6—C1 | 121.0 (4) | F1—C12—O4 | 113.7 (6) |
O7—C7—N1 | 122.7 (4) | F2—C12—O4 | 108.2 (6) |
D—H···A | D—H | H···A | D···A | D—H···A |
O9—H9···O7 | 0.89 (6) | 1.70 (6) | 2.508 (4) | 150 (5) |
O9—H9···O7i | 0.89 (6) | 2.52 (5) | 3.027 (4) | 117 (4) |
N1—H1···N11ii | 0.82 (3) | 2.44 (4) | 3.218 (5) | 161 (3) |
Symmetry codes: (i) −x+1, −y, −z; (ii) −x+2, −y+1, −z. |
Experimental details
(PHI492) | (PHI493) | (PHI495) | |
Crystal data | |||
Chemical formula | C12H12N2O4S | C12H12N2O4S | C12H8BrF3N2O3 |
Mr | 280.30 | 280.30 | 365.11 |
Crystal system, space group | Monoclinic, P21/n | Triclinic, P1 | Triclinic, P1 |
Temperature (K) | 295 | 295 | 295 |
a, b, c (Å) | 8.8002 (10), 5.5336 (6), 25.852 (3) | 5.4734 (3), 11.4048 (6), 11.5200 (6) | 5.2834 (4), 10.8265 (8), 13.1634 (10) |
α, β, γ (°) | 90, 97.644 (1), 90 | 115.478 (1), 95.941 (1), 93.035 (1) | 69.009 (1), 81.085 (1), 83.238 (1) |
V (Å3) | 1247.7 (2) | 641.88 (6) | 692.91 (9) |
Z | 4 | 2 | 2 |
Radiation type | Mo Kα | Mo Kα | Mo Kα |
µ (mm−1) | 0.27 | 0.26 | 3.01 |
Crystal size (mm) | 0.34 × 0.31 × 0.28 | 0.55 × 0.35 × 0.17 | 0.45 × 0.11 × 0.10 |
Data collection | |||
Diffractometer | Bruker SMART CCD area-detector | Bruker SMART CCD area-detector | Bruker SMART CCD area-detector |
Absorption correction | Empirical (using intensity measurements) (SADABS; Sheldrick, 1996) | Empirical (using intensity measurements) (SADABS; Sheldrick, 1996) | Empirical (using intensity measurements) (SADABS; Sheldrick, 1996) |
Tmin, Tmax | 0.913, 0.928 | 0.869, 0.957 | 0.344, 0.753 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 10595, 2503, 2157 | 6510, 2428, 2152 | 7235, 2643, 1364 |
Rint | 0.030 | 0.022 | 0.037 |
(sin θ/λ)max (Å−1) | 0.626 | 0.610 | 0.611 |
Refinement | |||
R[F2 > 2σ(F2)], wR(F2), S | 0.044, 0.113, 1.07 | 0.034, 0.102, 1.05 | 0.045, 0.131, 1.01 |
No. of reflections | 2503 | 2428 | 2643 |
No. of parameters | 182 | 182 | 200 |
No. of restraints | 2 | 2 | 0 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement | H atoms treated by a mixture of independent and constrained refinement | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.23, −0.45 | 0.22, −0.28 | 0.61, −0.51 |
Computer programs: SMART (Bruker, 1998), SAINT (Bruker, 1998), SAINT, SHELXS97 (Sheldrick, 1990), SHELXL97 (Sheldrick, 1997), SHELXTL (Bruker, 1997), SHELXTL.
S1—O2 | 1.4336 (15) | N1—C7 | 1.353 (3) |
S1—O1 | 1.4339 (16) | N1—C1 | 1.412 (2) |
S1—C4 | 1.7596 (19) | N11—C11 | 1.138 (2) |
S1—C12 | 1.760 (2) | C7—C8 | 1.472 (3) |
O7—C7 | 1.239 (2) | C8—C9 | 1.366 (3) |
O9—C9 | 1.313 (2) | C8—C11 | 1.424 (3) |
O9—H9 | 0.819 (10) | C9—C10 | 1.486 (3) |
O2—S1—O1 | 117.86 (10) | O7—C7—N1 | 123.37 (17) |
O2—S1—C4 | 108.26 (9) | O7—C7—C8 | 119.91 (17) |
O1—S1—C4 | 109.02 (9) | N1—C7—C8 | 116.72 (16) |
O2—S1—C12 | 108.63 (11) | C9—C8—C11 | 117.63 (17) |
O1—S1—C12 | 108.03 (11) | C9—C8—C7 | 120.73 (17) |
C4—S1—C12 | 104.20 (10) | C11—C8—C7 | 121.64 (17) |
C7—N1—C1 | 128.78 (16) | O9—C9—C8 | 122.25 (18) |
C6—C1—N1 | 116.07 (16) | O9—C9—C10 | 114.07 (18) |
C2—C1—N1 | 124.71 (17) | C8—C9—C10 | 123.69 (18) |
C3—C4—S1 | 120.80 (14) | N11—C11—C8 | 178.9 (2) |
C5—C4—S1 | 119.07 (14) |
D—H···A | D—H | H···A | D···A | D—H···A |
O9—H9···O7 | 0.819 (10) | 1.800 (18) | 2.534 (2) | 148 (3) |
N1—H1···N11i | 0.851 (10) | 2.307 (11) | 3.132 (2) | 164 (2) |
Symmetry code: (i) −x+1, −y+4, −z. |
S1—O2 | 1.4312 (14) | O7—C7 | 1.2472 (19) |
S1—O1 | 1.4360 (14) | O9—C9 | 1.316 (2) |
S1—C12 | 1.750 (2) | C7—C8 | 1.463 (2) |
S1—C5 | 1.7768 (16) | C8—C9 | 1.374 (2) |
N1—C7 | 1.354 (2) | C8—C11 | 1.425 (2) |
N1—C1 | 1.412 (2) | C9—C10 | 1.483 (2) |
N11—C11 | 1.136 (2) | ||
O2—S1—O1 | 118.71 (10) | O7—C7—N1 | 122.34 (14) |
O2—S1—C12 | 108.16 (10) | O7—C7—C8 | 119.39 (14) |
O1—S1—C12 | 107.80 (10) | N1—C7—C8 | 118.27 (13) |
O2—S1—C5 | 107.75 (8) | C9—C8—C11 | 117.83 (14) |
O1—S1—C5 | 108.60 (8) | C9—C8—C7 | 120.80 (14) |
C12—S1—C5 | 105.01 (9) | C11—C8—C7 | 121.35 (14) |
C7—N1—C1 | 127.91 (13) | O9—C9—C8 | 121.60 (15) |
C2—C1—N1 | 124.02 (14) | O9—C9—C10 | 114.07 (14) |
C6—C1—N1 | 116.97 (13) | C8—C9—C10 | 124.33 (15) |
C6—C5—S1 | 119.22 (12) | N11—C11—C8 | 179.7 (2) |
C4—C5—S1 | 118.73 (12) |
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1···N11i | 0.844 (9) | 2.239 (11) | 3.060 (2) | 164.2 (19) |
O9—H9···O7 | 0.833 (10) | 1.749 (15) | 2.5102 (17) | 151 (2) |
O9—H9···O7ii | 0.833 (10) | 2.57 (2) | 3.0464 (18) | 117.5 (19) |
Symmetry codes: (i) −x−1, −y+2, −z+1; (ii) −x, −y+3, −z+1. |
Br1—C5 | 1.884 (4) | N1—C7 | 1.349 (5) |
F1—C12 | 1.288 (7) | N1—C1 | 1.415 (5) |
F2—C12 | 1.305 (6) | N11—C11 | 1.134 (5) |
F3—C12 | 1.286 (7) | C7—C8 | 1.469 (5) |
O4—C12 | 1.319 (7) | C8—C9 | 1.364 (5) |
O4—C4 | 1.418 (5) | C8—C11 | 1.427 (6) |
O7—C7 | 1.241 (5) | C9—C10 | 1.479 (6) |
O9—C9 | 1.320 (5) | ||
C12—O4—C4 | 117.6 (4) | C9—C8—C7 | 121.1 (4) |
C7—N1—C1 | 128.8 (4) | C11—C8—C7 | 120.2 (3) |
C6—C1—N1 | 116.4 (4) | O9—C9—C8 | 121.0 (4) |
C2—C1—N1 | 124.1 (4) | O9—C9—C10 | 114.0 (4) |
C3—C4—O4 | 121.6 (4) | C8—C9—C10 | 125.1 (4) |
C5—C4—O4 | 118.2 (4) | N11—C11—C8 | 177.9 (4) |
C4—C5—Br1 | 121.4 (3) | F3—C12—F1 | 105.1 (7) |
C6—C5—Br1 | 118.8 (3) | F3—C12—F2 | 108.6 (6) |
O7—C7—N1 | 122.7 (4) | F1—C12—F2 | 106.6 (5) |
O7—C7—C8 | 119.7 (3) | F3—C12—O4 | 114.2 (5) |
N1—C7—C8 | 117.5 (4) | F1—C12—O4 | 113.7 (6) |
C9—C8—C11 | 118.7 (3) | F2—C12—O4 | 108.2 (6) |
D—H···A | D—H | H···A | D···A | D—H···A |
O9—H9···O7 | 0.89 (6) | 1.70 (6) | 2.508 (4) | 150 (5) |
O9—H9···O7i | 0.89 (6) | 2.52 (5) | 3.027 (4) | 117 (4) |
N1—H1···N11ii | 0.82 (3) | 2.44 (4) | 3.218 (5) | 161 (3) |
Symmetry codes: (i) −x+1, −y, −z; (ii) −x+2, −y+1, −z. |
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The title compounds were designed and synthesized as part of our ongoing program on the development of tyrosine kinase inhibitors as anti-cancer agents. The development of inhibitors of the PTK (or BTK?) signaling pathway is an active area of translational (or transnational?) cancer research. The identification of the compounds was guided by structure-based drug design methods, which included the construction of the kinase homology model of BTK (Mahajan et al., 1999) and advanced docking procedures to generate novel molecules that are complementary in shape and electrostatics to the kinase domain topography. Based on these modeling studies, several leflunomide metabolite (LFM) analogs were synthesized and tested for their kinase inhibitory activity on BTK. The three title compounds, PHI492, PHI493 and PHI495, were subsequently found to have micromolar potency towards BTK. \sch
The X-ray crystal structures of PHI492, PHI493 and PHI495 (Figs. 1–3) show that all three molecules contain an intramolecular O—H···O hydrogen bond that locks the compounds in a planar conformation. The presence of this intramolecular hydrogen bond is consistent with the results from docking studies of LFM analogs at the catalytic sites of several protein tyrosine kinases (Ghosh et al., 1998; Ghosh, Narla et al., 1999; Mahajan et al., 1999). These studies reveal that the planar conformation of these inhibitors resulting from the intramolecular hydrogen bond would allow the molecules to fit snugly into the shallow catalytic sites of EGFR (define?) and BTK. This binding mode is such that the title compounds can maintain close contact with the hinge region of the receptor on the edge of the inhibitor, and the aromatic rings of the inhibitors are sandwiched between hydrophobic residues at the catalytic site of the receptor.
The electronegative SO2 group of PHI492 and PHI493 is involved in hydrogen bonding with Lys430 and Arg525, respectively, on BTK, while in PHI495 the CF3 group is oriented towards Val416. In all three crystal structures, the molecules pack to form hydrogen-bonded dimers about inversion centers.
Compound PHI492 does not display O—H···O intermolecular hydrogen bonds and the intramolecular O9···O7 distance is 2.534 (2) Å. The compound forms a centrosymmetrically related dimer via an N1—H1···N11i intermolecular hydrogen bond [N1···N11i 3.132 (2) Å; symmetry code: (i) 1 - x, 4 - y, -z]. In compound PHI493, the intramolecular O9···O7 hydrogen-bond distance is 2.510 (2)%A and the dimers are linked by an N1···N11ii intermolecular hydrogen bond [N1···N11ii 3.060 (2) Å; symmetry code: (ii) -1 - x, 2 - y, 1 - z] and an O7···O9iii intermolecular contact [O7···O9iii 3.046 (2) Å; symmetry code: (iii) -x, 3 - y, 1 - z]. In PHI495, the intramolecular O9···.·O7 distance is 2.508 (4) Å and the dimers are linked by an N1···N11v intermolecular hydrogen bond [N1···N11v 3.218 (5) Å; symmetry code: (v) 2 - x, 1 - y, -z] and an O7···O9iv intermolecular contact [O7···O9iv 3.027 (4) Å; symmetry code: (iv) 1 - x, -y, -z]. These hydrogen-bond interactions observed in the crystal packing are similar for the three title compounds and similar to the six other leflunomide metabolite analogs reported earlier (Ghosh, Zheng & Uckun, 1999; Ghosh & Uckun, 1999).
The dihedral angle of the plane of the phenyl ring with the plane formed by atoms N1, C7, C8, C9 and C10 is 2.3 (3)° for PHI492, 2.4 (3)° for PHI493, and 2.5 (7)° for PHI495. The planarity of the molecules is extended to the hydroxyl, cyano and methyl groups via the intramolecular O9—H9···O7 hydrogen bond. The mean-plane deviation for each of the molecules as a whole is 0.0422 Å for PHI492, 0.0368 Å for PHI493 and 0.0372 Å for PHI495.
There is no significant difference in the corresponding bond lengths and angles in the three structures. However, the C8—C11 (Csp2—Csp1) bond distances are 1.424 (3) Å for PHI492, 1.424 (2) Å for PHI493 and 1.427 (6) Å for PHI495, and are slightly longer than the expected Csp2—Csp1 bond length of 1.416 Å. The C11≡N11 bond distances, on the other hand, are significantly shorter than the expected C≡N bond length of 1.165 Å; they are 1.138 (2) Å for PHI492, 1.136 (2) Å for PHI493 and 1.134 (5) Å for PHI495. A similar lengthening of the C8—C11 bond and shortening of the C≡N bond has been observed in the molecular structures of the six LFM analogs reported earlier (Ghosh, Zheng & Uckun, 1999; Ghosh & Uckun, 1999).