Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270100007496/bk1527sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S0108270100007496/bk1527WHI-P131sup2.hkl |
CCDC reference: 152639
Yellow needles of WHI-P131 were grown from methanol/dichloromethane by vapor diffusion at room temperature. The hydrochloride salt crystallized as a methanol solvate.
H atoms were placed at calculated positions, except for H1 and H4, which were located in the electron-density difference map and refined isotropically. The hydroxyl H3 and H26 atoms were not observed in the electron-density map but were included at calculated positions based on an assessment of the best hydrogen-bond interactions to nearby N, O or Cl atoms.
Data collection: SMART (Bruker, 1998); cell refinement: SMART; data reduction: SHELXTL (Bruker, 1998); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.
C16H16N3O3+·Cl−·CH4O | Dx = 1.374 Mg m−3 |
Mr = 365.81 | Melting point: 245-248°C K |
Monoclinic, P21/n | Mo Kα radiation, λ = 0.71073 Å |
a = 7.4128 (7) Å | Cell parameters from 2622 reflections |
b = 10.7752 (10) Å | θ = 2.6–25.0° |
c = 22.337 (2) Å | µ = 0.24 mm−1 |
β = 97.538 (2)° | T = 297 K |
V = 1768.8 (3) Å3 | Needle, yellow |
Z = 4 | 0.45 × 0.15 × 0.12 mm |
F(000) = 768 |
CCD area-detector diffractometer | 3117 independent reflections |
Radiation source: fine-focus sealed tube | 2087 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.050 |
ϕ and ω scans | θmax = 25.0°, θmin = 1.8° |
Absorption correction: empirical (using intensity measurements) (SADABS; Sheldrick, 1996) | h = −8→8 |
Tmin = 0.90, Tmax = 0.97 | k = −12→12 |
8982 measured reflections | l = −26→22 |
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)] = 0.048 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.12 | H atoms treated by a mixture of independent and constrained refinement |
S = 0.99 | w = 1/[σ2(Fo2) + (0.0672P)2] where P = (Fo2 + 2Fc2)/3 |
3117 reflections | (Δ/σ)max = 0.003 |
239 parameters | Δρmax = 0.33 e Å−3 |
0 restraints | Δρmin = −0.26 e Å−3 |
C16H16N3O3+·Cl−·CH4O | V = 1768.8 (3) Å3 |
Mr = 365.81 | Z = 4 |
Monoclinic, P21/n | Mo Kα radiation |
a = 7.4128 (7) Å | µ = 0.24 mm−1 |
b = 10.7752 (10) Å | T = 297 K |
c = 22.337 (2) Å | 0.45 × 0.15 × 0.12 mm |
β = 97.538 (2)° |
CCD area-detector diffractometer | 3117 independent reflections |
Absorption correction: empirical (using intensity measurements) (SADABS; Sheldrick, 1996) | 2087 reflections with I > 2σ(I) |
Tmin = 0.90, Tmax = 0.97 | Rint = 0.050 |
8982 measured reflections |
R[F2 > 2σ(F2)] = 0.048 | 0 restraints |
wR(F2) = 0.12 | H atoms treated by a mixture of independent and constrained refinement |
S = 0.99 | Δρmax = 0.33 e Å−3 |
3117 reflections | Δρmin = −0.26 e Å−3 |
239 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 | ||
Cl1 | 0.52383 (11) | 0.62330 (7) | 0.19676 (3) | 0.0574 (3) | |
O1 | 0.0122 (3) | −0.26977 (16) | 0.40580 (8) | 0.0491 (5) | |
N1 | 0.3539 (3) | 0.03508 (19) | 0.58342 (10) | 0.0393 (5) | |
H1 | 0.376 (3) | 0.011 (2) | 0.6238 (12) | 0.047 (8)* | |
O2 | 0.0802 (2) | −0.35313 (15) | 0.51354 (8) | 0.0440 (5) | |
C2 | 0.4062 (4) | 0.1486 (2) | 0.57080 (12) | 0.0429 (7) | |
H2 | 0.4627 | 0.1959 | 0.6027 | 0.051* | |
O3 | 0.4681 (3) | 0.64338 (16) | 0.32994 (8) | 0.0616 (6) | |
H3 | 0.4754 | 0.6383 | 0.2937 | 0.074* | |
N3 | 0.3850 (3) | 0.19951 (19) | 0.51742 (9) | 0.0405 (5) | |
O4 | 0.9139 (3) | 0.5371 (2) | 0.20208 (9) | 0.0689 (6) | |
H26 | 0.8101 | 0.5608 | 0.2048 | 0.083* | |
N4 | 0.2750 (3) | 0.18402 (19) | 0.41662 (10) | 0.0395 (5) | |
H4 | 0.211 (4) | 0.145 (2) | 0.3866 (12) | 0.044 (8)* | |
C4 | 0.2978 (3) | 0.1321 (2) | 0.47112 (11) | 0.0347 (6) | |
C5 | 0.1492 (3) | −0.0703 (2) | 0.43343 (11) | 0.0353 (6) | |
H5 | 0.1254 | −0.0404 | 0.3941 | 0.042* | |
C6 | 0.0990 (3) | −0.1886 (2) | 0.44617 (11) | 0.0360 (6) | |
C7 | 0.1341 (3) | −0.2351 (2) | 0.50644 (11) | 0.0343 (6) | |
C8 | 0.2178 (3) | −0.1611 (2) | 0.55155 (11) | 0.0364 (6) | |
H8 | 0.2411 | −0.1910 | 0.5909 | 0.044* | |
C9 | 0.2680 (3) | −0.0403 (2) | 0.53817 (10) | 0.0328 (6) | |
C10 | 0.2371 (3) | 0.0070 (2) | 0.47959 (11) | 0.0321 (6) | |
C11 | 0.3347 (3) | 0.3031 (2) | 0.39844 (11) | 0.0348 (6) | |
C12 | 0.3854 (4) | 0.3097 (2) | 0.34094 (11) | 0.0413 (6) | |
H12 | 0.3884 | 0.2379 | 0.3180 | 0.050* | |
C13 | 0.4315 (4) | 0.4224 (2) | 0.31758 (11) | 0.0429 (7) | |
H13 | 0.4645 | 0.4266 | 0.2789 | 0.052* | |
C14 | 0.4285 (4) | 0.5286 (2) | 0.35173 (11) | 0.0403 (6) | |
C15 | 0.3821 (4) | 0.5219 (2) | 0.40931 (12) | 0.0425 (7) | |
H15 | 0.3829 | 0.5936 | 0.4325 | 0.051* | |
C16 | 0.3346 (4) | 0.4102 (2) | 0.43303 (12) | 0.0409 (6) | |
H16 | 0.3026 | 0.4066 | 0.4719 | 0.049* | |
C17 | −0.0109 (5) | −0.2350 (3) | 0.34362 (12) | 0.0655 (9) | |
H19 | −0.0816 | −0.2970 | 0.3203 | 0.098* | |
H18 | 0.1061 | −0.2279 | 0.3299 | 0.098* | |
H17 | −0.0728 | −0.1566 | 0.3389 | 0.098* | |
C18 | 0.1278 (4) | −0.4089 (2) | 0.57202 (12) | 0.0518 (8) | |
H22 | 0.0917 | −0.4946 | 0.5704 | 0.078* | |
H21 | 0.0664 | −0.3661 | 0.6012 | 0.078* | |
H20 | 0.2569 | −0.4034 | 0.5835 | 0.078* | |
C20 | 0.9658 (8) | 0.4476 (4) | 0.24667 (19) | 0.1060 (15) | |
H25 | 1.0956 | 0.4375 | 0.2514 | 0.23 (3)* | |
H24 | 0.9085 | 0.3699 | 0.2348 | 0.22 (3)* | |
H23 | 0.9289 | 0.4740 | 0.2843 | 0.24 (3)* |
U11 | U22 | U33 | U12 | U13 | U23 | |
Cl1 | 0.0729 (6) | 0.0585 (5) | 0.0396 (4) | 0.0129 (4) | 0.0023 (3) | 0.0048 (3) |
O1 | 0.0663 (13) | 0.0346 (11) | 0.0434 (11) | −0.0119 (9) | −0.0042 (9) | −0.0042 (8) |
N1 | 0.0491 (14) | 0.0325 (13) | 0.0356 (13) | −0.0049 (10) | 0.0031 (10) | −0.0044 (10) |
O2 | 0.0541 (12) | 0.0287 (10) | 0.0474 (11) | −0.0091 (8) | −0.0002 (9) | 0.0028 (8) |
C2 | 0.0500 (17) | 0.0341 (16) | 0.0439 (16) | −0.0071 (13) | 0.0030 (13) | −0.0107 (12) |
O3 | 0.1116 (19) | 0.0324 (11) | 0.0422 (11) | −0.0181 (11) | 0.0155 (11) | −0.0015 (8) |
N3 | 0.0469 (14) | 0.0329 (12) | 0.0406 (13) | −0.0083 (10) | 0.0018 (10) | −0.0052 (10) |
O4 | 0.0756 (16) | 0.0705 (16) | 0.0584 (13) | 0.0149 (12) | 0.0003 (11) | 0.0030 (11) |
N4 | 0.0513 (15) | 0.0276 (12) | 0.0378 (13) | −0.0081 (10) | −0.0006 (11) | −0.0022 (10) |
C4 | 0.0336 (14) | 0.0296 (14) | 0.0414 (15) | 0.0003 (11) | 0.0066 (11) | −0.0023 (12) |
C5 | 0.0406 (16) | 0.0300 (14) | 0.0344 (14) | −0.0009 (11) | 0.0022 (12) | −0.0011 (11) |
C6 | 0.0374 (15) | 0.0295 (14) | 0.0402 (14) | −0.0010 (12) | 0.0012 (11) | −0.0071 (12) |
C7 | 0.0319 (14) | 0.0271 (14) | 0.0445 (15) | −0.0012 (11) | 0.0073 (11) | −0.0008 (11) |
C8 | 0.0399 (15) | 0.0327 (14) | 0.0369 (14) | 0.0007 (11) | 0.0065 (12) | 0.0016 (11) |
C9 | 0.0318 (14) | 0.0314 (14) | 0.0356 (14) | −0.0013 (11) | 0.0062 (11) | −0.0048 (11) |
C10 | 0.0309 (13) | 0.0266 (13) | 0.0391 (14) | −0.0002 (11) | 0.0061 (11) | −0.0013 (11) |
C11 | 0.0377 (15) | 0.0235 (13) | 0.0426 (15) | −0.0025 (11) | 0.0033 (11) | 0.0003 (11) |
C12 | 0.0532 (17) | 0.0290 (14) | 0.0408 (15) | −0.0008 (12) | 0.0031 (12) | −0.0066 (12) |
C13 | 0.0598 (19) | 0.0322 (15) | 0.0372 (15) | −0.0063 (13) | 0.0080 (13) | −0.0025 (12) |
C14 | 0.0511 (17) | 0.0268 (14) | 0.0418 (15) | −0.0053 (12) | 0.0017 (12) | 0.0003 (11) |
C15 | 0.0565 (18) | 0.0257 (14) | 0.0457 (16) | −0.0020 (13) | 0.0082 (13) | −0.0071 (12) |
C16 | 0.0479 (16) | 0.0315 (15) | 0.0445 (15) | 0.0006 (12) | 0.0111 (12) | −0.0027 (12) |
C17 | 0.097 (3) | 0.0485 (19) | 0.0452 (18) | −0.0110 (17) | −0.0114 (16) | −0.0070 (14) |
C18 | 0.060 (2) | 0.0354 (16) | 0.0578 (18) | −0.0065 (14) | −0.0003 (15) | 0.0131 (13) |
C20 | 0.148 (5) | 0.085 (3) | 0.075 (3) | 0.043 (3) | −0.023 (3) | 0.013 (2) |
O1—C6 | 1.357 (3) | C5—C6 | 1.368 (3) |
O1—C17 | 1.427 (3) | C5—C10 | 1.416 (3) |
N1—C2 | 1.324 (3) | C6—C7 | 1.428 (3) |
N1—C9 | 1.385 (3) | C7—C8 | 1.368 (3) |
O2—C7 | 1.349 (3) | C8—C9 | 1.397 (3) |
O2—C18 | 1.439 (3) | C9—C10 | 1.395 (3) |
N3—C2 | 1.303 (3) | C11—C12 | 1.386 (3) |
N3—C4 | 1.356 (3) | C11—C16 | 1.389 (3) |
O3—C14 | 1.375 (3) | C12—C13 | 1.383 (3) |
O4—C20 | 1.404 (4) | C13—C14 | 1.377 (3) |
N4—C4 | 1.330 (3) | C14—C15 | 1.376 (4) |
N4—C11 | 1.433 (3) | C15—C16 | 1.380 (3) |
C4—C10 | 1.442 (3) | ||
C6—O1—C17 | 117.6 (2) | N1—C9—C10 | 118.3 (2) |
C2—N1—C9 | 120.4 (2) | N1—C9—C8 | 120.0 (2) |
C7—O2—C18 | 117.4 (2) | C10—C9—C8 | 121.7 (2) |
N3—C2—N1 | 125.5 (2) | C9—C10—C5 | 118.2 (2) |
C2—N3—C4 | 117.4 (2) | C9—C10—C4 | 116.7 (2) |
C4—N4—C11 | 129.0 (2) | C5—C10—C4 | 125.2 (2) |
N4—C4—N3 | 117.6 (2) | C12—C11—C16 | 119.5 (2) |
N4—C4—C10 | 120.6 (2) | C12—C11—N4 | 116.1 (2) |
N3—C4—C10 | 121.8 (2) | C16—C11—N4 | 124.3 (2) |
C6—C5—C10 | 120.5 (2) | C13—C12—C11 | 120.3 (2) |
O1—C6—C5 | 125.5 (2) | C14—C13—C12 | 119.9 (2) |
O1—C6—C7 | 114.3 (2) | O3—C14—C15 | 118.0 (2) |
C5—C6—C7 | 120.1 (2) | O3—C14—C13 | 122.1 (2) |
O2—C7—C8 | 125.2 (2) | C15—C14—C13 | 119.9 (2) |
O2—C7—C6 | 114.9 (2) | C14—C15—C16 | 120.8 (2) |
C8—C7—C6 | 119.9 (2) | C15—C16—C11 | 119.5 (2) |
C7—C8—C9 | 119.6 (2) | ||
C9—N1—C2—N3 | −0.4 (4) | N1—C9—C10—C5 | 180.0 (2) |
N1—C2—N3—C4 | 1.9 (4) | C8—C9—C10—C5 | 1.2 (3) |
C11—N4—C4—N3 | 1.9 (4) | N1—C9—C10—C4 | −0.1 (3) |
C11—N4—C4—C10 | −175.9 (2) | C8—C9—C10—C4 | −178.9 (2) |
C2—N3—C4—N4 | 179.6 (2) | C6—C5—C10—C9 | −1.0 (3) |
C2—N3—C4—C10 | −2.5 (3) | C6—C5—C10—C4 | 179.2 (2) |
C17—O1—C6—C5 | 7.6 (4) | N4—C4—C10—C9 | 179.5 (2) |
C17—O1—C6—C7 | −173.7 (2) | N3—C4—C10—C9 | 1.7 (3) |
C10—C5—C6—O1 | 179.0 (2) | N4—C4—C10—C5 | −0.7 (4) |
C10—C5—C6—C7 | 0.3 (4) | N3—C4—C10—C5 | −178.4 (2) |
C18—O2—C7—C8 | −5.4 (3) | C4—N4—C11—C12 | 145.5 (3) |
C18—O2—C7—C6 | 174.1 (2) | C4—N4—C11—C16 | −38.2 (4) |
O1—C6—C7—O2 | 1.7 (3) | C16—C11—C12—C13 | −1.5 (4) |
C5—C6—C7—O2 | −179.4 (2) | N4—C11—C12—C13 | 175.0 (2) |
O1—C6—C7—C8 | −178.7 (2) | C11—C12—C13—C14 | 0.5 (4) |
C5—C6—C7—C8 | 0.1 (4) | C12—C13—C14—O3 | −178.1 (3) |
O2—C7—C8—C9 | 179.6 (2) | C12—C13—C14—C15 | 0.9 (4) |
C6—C7—C8—C9 | 0.1 (4) | O3—C14—C15—C16 | 177.7 (3) |
C2—N1—C9—C10 | −0.5 (4) | C13—C14—C15—C16 | −1.4 (4) |
C2—N1—C9—C8 | 178.3 (2) | C14—C15—C16—C11 | 0.4 (4) |
C7—C8—C9—N1 | −179.5 (2) | C12—C11—C16—C15 | 1.0 (4) |
C7—C8—C9—C10 | −0.8 (4) | N4—C11—C16—C15 | −175.1 (2) |
D—H···A | D—H | H···A | D···A | D—H···A |
O4—H26···Cl1 | ? | ? | 3.024 (2) | ? |
O3—H3···Cl1 | ? | ? | 3.064 (2) | ? |
N1—H1···O4i | 0.93 (3) | 1.81 (3) | 2.742 (3) | 179 (2) |
N4—H4···Cl1ii | 0.88 (3) | 2.39 (3) | 3.206 (2) | 155 (2) |
Symmetry codes: (i) x−1/2, −y+1/2, z+1/2; (ii) −x+1/2, y−1/2, −z+1/2. |
Experimental details
Crystal data | |
Chemical formula | C16H16N3O3+·Cl−·CH4O |
Mr | 365.81 |
Crystal system, space group | Monoclinic, P21/n |
Temperature (K) | 297 |
a, b, c (Å) | 7.4128 (7), 10.7752 (10), 22.337 (2) |
β (°) | 97.538 (2) |
V (Å3) | 1768.8 (3) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 0.24 |
Crystal size (mm) | 0.45 × 0.15 × 0.12 |
Data collection | |
Diffractometer | CCD area-detector diffractometer |
Absorption correction | Empirical (using intensity measurements) (SADABS; Sheldrick, 1996) |
Tmin, Tmax | 0.90, 0.97 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 8982, 3117, 2087 |
Rint | 0.050 |
(sin θ/λ)max (Å−1) | 0.595 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.048, 0.12, 0.99 |
No. of reflections | 3117 |
No. of parameters | 239 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.33, −0.26 |
Computer programs: SMART (Bruker, 1998), SMART, SHELXTL (Bruker, 1998), SHELXS97 (Sheldrick, 1997), SHELXL97 (Sheldrick, 1997), SHELXTL.
N3—C2 | 1.303 (3) | O4—C20 | 1.404 (4) |
N3—C4 | 1.356 (3) | N4—C4 | 1.330 (3) |
O3—C14 | 1.375 (3) | N4—C11 | 1.433 (3) |
C17—O1—C6—C5 | 7.6 (4) | C4—N4—C11—C16 | −38.2 (4) |
C18—O2—C7—C8 | −5.4 (3) |
D—H···A | D—H | H···A | D···A | D—H···A |
O4—H26···Cl1 | ? | ? | 3.024 (2) | ? |
O3—H3···Cl1 | ? | ? | 3.064 (2) | ? |
N1—H1···O4i | 0.93 (3) | 1.81 (3) | 2.742 (3) | 179 (2) |
N4—H4···Cl1ii | 0.88 (3) | 2.39 (3) | 3.206 (2) | 155 (2) |
Symmetry codes: (i) x−1/2, −y+1/2, z+1/2; (ii) −x+1/2, y−1/2, −z+1/2. |
O4—H26···Cl1 | O3—H3···Cl1 | N1—H1···O4 | N4—H4···Cl1 | |
O4—H26···Cl1 | D11(2) | D21(3) | D22(4) | D21(3) |
O3—H3···Cl1 | D11(2) | D22(14) | C12(9) | |
N1—H1···O4 | D11(2) | D22(9) | ||
N4—H4···Cl1 | D11(2) |
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The title compound, WHI-P131 (Fig. 1), inhibited the kinase activity of Janus kinase 3 (JAK3), with an IC50 of 9.1µM (Sudbeck et al., 1999). Although WHI-P131 inhibited JAK3, it did not inhibit the Janus kinases JAK1 and JAK2, the ZAP/SYK family tyrosine kinase SYK, the TEC family tyrosine kinase BTK, the SRC family tyrosine kinase LYN or the receptor family tyrosine kinase IRK, even at concentrations as high as 350µM. The relatively high potency and selectivity of WHI-P131 for JAK3 makes it a promising candidate for new treatment strategies against acute lymphoblastic leukemia, the most common form of childhood cancer. In addition to its antileukemic properties, WHI-P131 also shows clinical potential for the treatment of mast-cell-mediated immediate hypersensitivity reactions and allergic disorders (Malaviya & Uckun, 1999). \sch
The crystal structure of WHI-P131 contains four different hydrogen bonds: N1—H1···O4, N4—H4···Cl1, O3—H3···Cl1 and O4—H26···Cl1 (Fig. 2 and Table 3). Each of these can be described in graph-set notation (Bernstein et al., 1990, 1995; Etter, 1990, 1991; Etter et al., 1990) as D11(2) (Fig. 2). The second-level motif combining the N1—H1···O4 and N4—H4···Cl1 hydrogen bond is D22(9), the motif combining N4—H4···Cl1 and O3—H3···Cl1 is C12(9), and the motif combining N1—H1···O4 and O3—H3···Cl1 is D22(14). The combination of N1—H1···O4 and O4—H26···Cl1 can be described as a D22(4) pattern, N4—H4···Cl1 plus O4—H26···Cl1 forms a D12(3) pattern, and O3—H3···Cl1 plus O4—H26···Cl1 is D12(3). The complete first-level hydrogen-bond graph-set notation for WHI-P131 is D11(2)D11(2)D11(2)D11(2) and the second-level graph-set notation (for combinations of two hydrogen bonds) is D12(3)D12(3)D22(4)D22(9)D22(14) C12(9).
An alternative way to describe the two-dimensional hydrogen-bonded network in the crystal of WHI-P131 is C21(9)C32(15), which combines the second-level motif for N4—H4···Cl1 and O3—H3···Cl1, C21(9), and the third-level motif for O4—H16···Cl1, O3—H3···Cl1 and N1—H1···O4, C32(15).