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Four new 3,4-di­hydro-1-benzoxepin-5(2H)-one derivatives, namely (E)-4-(5-bromo-2-hy­droxy­benzyl­idene)-6,8-dimeth­oxy-3,4-di­hydro­benzo[b]oxepin-5(2H)-one, (7), (E)-4-[(E)-3-(5-bromo-2-hy­droxy­phen­yl)allyl­idene]-6,8-dimeth­oxy-3,4-di­hydro­benzo[b]oxepin-5(2H)-one, (8), (E)-4-(5-bromo-2-hy­droxy­benzyl­idene)-6-hy­droxy-8-meth­oxy-3,4-di­hydro­benzo[b]oxepin-5(2H)-one, C18H15BrO5, (9), and (E)-4-[(E)-3-(5-bromo-2-hy­droxy­phen­yl)allyl­idene]-6-hy­droxy-8-meth­oxy-3,4-di­hydro­benzo[b]oxepin-5(2H)-one, (10), have been synthesized and characterized by FT–IR, NMR and MS. The structure of (9) was confirmed by single-crystal X-ray diffraction. Crystal structure analysis shows that mol­ecules of (9) are connected into a one-dimensional chain in the [010] direction through classical hydrogen bonds and these chains are further extended into a three-dimensional network via C—H...O inter­actions. The inhibitory activities of these compounds against protein–tyrosine kinases (PTKs) show that 6-hy­droxy-substituted compounds (9) and (10) are more effective for inhibiting ErbB1 and ErbB2 than are 6-meth­oxy-substituted compounds (7) and (8). This may be because (9) and (10) could effectively bind to the active pockets of the protein through inter­molecular inter­actions.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S2053229617015145/sk3671sup1.cif
Contains datablocks I, global

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S2053229617015145/sk3671Isup2.hkl
Contains datablock I

CCDC reference: 1563964

Computing details top

Data collection: APEX2 (Bruker, 2007); cell refinement: APEX2 (Bruker, 2007); data reduction: SAINT (Bruker, 2012); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015); molecular graphics: DIAMOND (Brandenburg, 2012); software used to prepare material for publication: SHELXTL (Sheldrick, 2008) and publCIF (Westrip, 2010).

(E)-4-(5-Bromo-2-hydroxybenzylidene)-6-hydroxy-8-methoxy-3,4-dihydrobenzo[b]oxepin-5(2H)-one top
Crystal data top
C18H15BrO5F(000) = 792
Mr = 391.21Dx = 1.618 Mg m3
Monoclinic, P21/nMo Kα radiation, λ = 0.71073 Å
a = 11.960 (4) ÅCell parameters from 2479 reflections
b = 9.025 (3) Åθ = 2.3–24.1°
c = 14.981 (4) ŵ = 2.59 mm1
β = 96.768 (6)°T = 296 K
V = 1605.9 (8) Å3Block, yellow
Z = 40.14 × 0.12 × 0.12 mm
Data collection top
Bruker SMART CCD area detector
diffractometer
Rint = 0.046
Radiation source: fine-focus sealed tubeθmax = 25.5°, θmin = 2.1°
phi and ω scansh = 1413
8968 measured reflectionsk = 910
2985 independent reflectionsl = 1815
2155 reflections with I > 2σ(I)
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.038Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.094H-atom parameters constrained
S = 1.02 w = 1/[σ2(Fo2) + (0.0422P)2 + 0.3742P]
where P = (Fo2 + 2Fc2)/3
2985 reflections(Δ/σ)max = 0.001
220 parametersΔρmax = 0.28 e Å3
0 restraintsΔρmin = 0.47 e Å3
Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds 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 > 2sigma(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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
Br10.11150 (3)1.16571 (4)0.10415 (2)0.05918 (16)
C10.3910 (3)0.4235 (3)0.14028 (19)0.0370 (7)
C20.3849 (2)0.3774 (3)0.05003 (18)0.0345 (7)
C30.4234 (3)0.2323 (3)0.03582 (19)0.0396 (7)
C40.4552 (3)0.1360 (3)0.1060 (2)0.0419 (8)
H40.47660.03930.09490.050*
C50.4545 (3)0.1861 (3)0.1924 (2)0.0389 (7)
C60.4230 (3)0.3311 (3)0.2102 (2)0.0404 (7)
H60.42390.36400.26910.049*
C70.3422 (3)0.4691 (3)0.02609 (19)0.0361 (7)
C80.2722 (3)0.6018 (3)0.01220 (18)0.0346 (7)
C90.1977 (3)0.5903 (3)0.0613 (2)0.0444 (8)
H9A0.16420.49230.05960.053*
H9B0.13710.66180.05010.053*
C100.2587 (3)0.6170 (4)0.1540 (2)0.0554 (10)
H10A0.25550.72160.16830.067*
H10B0.22130.56270.19780.067*
C110.2795 (3)0.7156 (3)0.06838 (18)0.0381 (7)
H110.32570.69920.11320.046*
C120.2267 (3)0.8612 (3)0.07056 (19)0.0360 (7)
C130.2054 (3)0.9343 (3)0.15327 (19)0.0402 (7)
C140.1617 (3)1.0753 (3)0.1591 (2)0.0458 (8)
H140.15151.12350.21430.055*
C150.1327 (3)1.1460 (3)0.0829 (2)0.0461 (8)
H150.10141.24040.08660.055*
C160.1510 (3)1.0740 (3)0.0019 (2)0.0405 (7)
C170.1989 (3)0.9352 (3)0.00498 (19)0.0399 (7)
H170.21280.89030.06110.048*
C180.5233 (3)0.0463 (4)0.2550 (2)0.0624 (10)
H18A0.46270.10250.22380.094*
H18B0.54580.09080.31260.094*
H18C0.58600.04550.22050.094*
O10.37413 (19)0.5711 (2)0.15975 (13)0.0459 (6)
O20.3591 (2)0.4338 (2)0.10358 (12)0.0489 (6)
O30.4301 (2)0.1809 (2)0.04798 (14)0.0567 (7)
H30.41780.24880.08420.085*
O40.48642 (19)0.1033 (2)0.26751 (14)0.0518 (6)
O50.2319 (2)0.8596 (2)0.22711 (14)0.0559 (6)
H50.21210.90840.27240.084*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
Br10.0866 (3)0.0395 (2)0.0552 (2)0.00133 (18)0.02430 (19)0.00907 (16)
C10.0422 (19)0.0321 (15)0.0378 (16)0.0008 (13)0.0090 (14)0.0019 (13)
C20.0426 (19)0.0283 (14)0.0332 (15)0.0014 (13)0.0068 (13)0.0019 (12)
C30.046 (2)0.0349 (15)0.0383 (16)0.0038 (14)0.0058 (14)0.0062 (13)
C40.048 (2)0.0307 (16)0.0474 (19)0.0056 (14)0.0054 (15)0.0000 (13)
C50.0371 (19)0.0364 (16)0.0439 (18)0.0027 (13)0.0082 (14)0.0066 (14)
C60.047 (2)0.0430 (17)0.0322 (15)0.0018 (14)0.0096 (14)0.0006 (14)
C70.0419 (19)0.0322 (15)0.0352 (16)0.0024 (13)0.0083 (13)0.0026 (12)
C80.0418 (18)0.0308 (15)0.0312 (15)0.0011 (13)0.0048 (13)0.0001 (12)
C90.047 (2)0.0300 (16)0.060 (2)0.0060 (14)0.0184 (16)0.0087 (14)
C100.081 (3)0.0506 (19)0.0391 (18)0.0231 (19)0.0260 (18)0.0071 (15)
C110.048 (2)0.0374 (16)0.0297 (15)0.0003 (14)0.0080 (13)0.0006 (13)
C120.0454 (19)0.0300 (15)0.0334 (16)0.0040 (13)0.0074 (13)0.0032 (12)
C130.050 (2)0.0372 (17)0.0347 (16)0.0025 (14)0.0087 (14)0.0032 (13)
C140.056 (2)0.0398 (18)0.0419 (18)0.0012 (15)0.0060 (15)0.0108 (14)
C150.054 (2)0.0300 (16)0.055 (2)0.0026 (14)0.0093 (16)0.0069 (14)
C160.051 (2)0.0324 (16)0.0397 (17)0.0052 (14)0.0103 (14)0.0002 (13)
C170.057 (2)0.0274 (15)0.0356 (16)0.0014 (14)0.0060 (15)0.0044 (12)
C180.080 (3)0.0409 (19)0.067 (2)0.0162 (18)0.010 (2)0.0171 (17)
O10.0684 (16)0.0332 (11)0.0371 (11)0.0077 (11)0.0112 (11)0.0065 (9)
O20.0737 (17)0.0434 (12)0.0302 (11)0.0126 (11)0.0077 (11)0.0024 (9)
O30.0887 (19)0.0438 (13)0.0369 (12)0.0232 (13)0.0045 (12)0.0079 (10)
O40.0620 (16)0.0468 (13)0.0476 (13)0.0128 (11)0.0105 (11)0.0129 (11)
O50.0854 (19)0.0522 (14)0.0304 (11)0.0119 (13)0.0083 (12)0.0026 (10)
Geometric parameters (Å, º) top
Br1—C161.900 (3)C10—H10A0.9700
C1—C61.358 (4)C10—H10B0.9700
C1—O11.383 (3)C11—C121.457 (4)
C1—C21.408 (4)C11—H110.9300
C2—C31.413 (4)C12—C171.388 (4)
C2—C71.452 (4)C12—C131.400 (4)
C3—O31.349 (3)C13—O51.364 (3)
C3—C41.383 (4)C13—C141.375 (4)
C4—C51.371 (4)C14—C151.387 (4)
C4—H40.9300C14—H140.9300
C5—O41.368 (4)C15—C161.370 (4)
C5—C61.396 (4)C15—H150.9300
C6—H60.9300C16—C171.376 (4)
C7—O21.243 (3)C17—H170.9300
C7—C81.490 (4)C18—O41.439 (4)
C8—C111.337 (4)C18—H18A0.9600
C8—C91.500 (4)C18—H18B0.9600
C9—C101.510 (5)C18—H18C0.9600
C9—H9A0.9700O3—H30.8200
C9—H9B0.9700O5—H50.8200
C10—O11.434 (4)
C6—C1—O1117.6 (3)C9—C10—H10B109.3
C6—C1—C2122.5 (3)H10A—C10—H10B108.0
O1—C1—C2119.6 (2)C8—C11—C12130.3 (3)
C1—C2—C3116.0 (3)C8—C11—H11114.9
C1—C2—C7124.0 (2)C12—C11—H11114.9
C3—C2—C7120.1 (2)C17—C12—C13117.3 (3)
O3—C3—C4116.8 (3)C17—C12—C11124.1 (3)
O3—C3—C2121.0 (3)C13—C12—C11118.6 (3)
C4—C3—C2122.2 (3)O5—C13—C14121.9 (3)
C5—C4—C3118.6 (3)O5—C13—C12116.7 (3)
C5—C4—H4120.7C14—C13—C12121.4 (3)
C3—C4—H4120.7C13—C14—C15120.2 (3)
O4—C5—C4124.3 (3)C13—C14—H14119.9
O4—C5—C6114.2 (3)C15—C14—H14119.9
C4—C5—C6121.4 (3)C16—C15—C14118.8 (3)
C1—C6—C5119.0 (3)C16—C15—H15120.6
C1—C6—H6120.5C14—C15—H15120.6
C5—C6—H6120.5C15—C16—C17121.3 (3)
O2—C7—C2120.4 (3)C15—C16—Br1120.3 (2)
O2—C7—C8119.5 (3)C17—C16—Br1118.4 (2)
C2—C7—C8120.0 (2)C16—C17—C12120.9 (3)
C11—C8—C7116.7 (3)C16—C17—H17119.5
C11—C8—C9127.2 (3)C12—C17—H17119.5
C7—C8—C9116.1 (2)O4—C18—H18A109.5
C8—C9—C10113.6 (3)O4—C18—H18B109.5
C8—C9—H9A108.9H18A—C18—H18B109.5
C10—C9—H9A108.9O4—C18—H18C109.5
C8—C9—H9B108.9H18A—C18—H18C109.5
C10—C9—H9B108.9H18B—C18—H18C109.5
H9A—C9—H9B107.7C1—O1—C10115.4 (2)
O1—C10—C9111.5 (2)C3—O3—H3109.5
O1—C10—H10A109.3C5—O4—C18117.8 (2)
C9—C10—H10A109.3C13—O5—H5109.5
O1—C10—H10B109.3
C6—C1—C2—C35.2 (4)C7—C8—C9—C1080.4 (3)
O1—C1—C2—C3168.7 (3)C8—C9—C10—O130.7 (4)
C6—C1—C2—C7174.6 (3)C7—C8—C11—C12177.1 (3)
O1—C1—C2—C711.5 (5)C9—C8—C11—C125.4 (5)
C1—C2—C3—O3174.5 (3)C8—C11—C12—C1730.2 (5)
C7—C2—C3—O35.7 (5)C8—C11—C12—C13151.8 (3)
C1—C2—C3—C45.8 (4)C17—C12—C13—O5179.2 (3)
C7—C2—C3—C4174.0 (3)C11—C12—C13—O52.6 (4)
O3—C3—C4—C5177.1 (3)C17—C12—C13—C141.9 (5)
C2—C3—C4—C53.3 (5)C11—C12—C13—C14176.3 (3)
C3—C4—C5—O4178.5 (3)O5—C13—C14—C15178.1 (3)
C3—C4—C5—C60.3 (5)C12—C13—C14—C153.1 (5)
O1—C1—C6—C5172.0 (3)C13—C14—C15—C161.6 (5)
C2—C1—C6—C52.0 (5)C14—C15—C16—C171.1 (5)
O4—C5—C6—C1179.2 (3)C14—C15—C16—Br1179.5 (2)
C4—C5—C6—C10.9 (5)C15—C16—C17—C122.2 (5)
C1—C2—C7—O2165.9 (3)Br1—C16—C17—C12178.3 (2)
C3—C2—C7—O214.3 (5)C13—C12—C17—C160.7 (5)
C1—C2—C7—C817.5 (5)C11—C12—C17—C16178.8 (3)
C3—C2—C7—C8162.3 (3)C6—C1—O1—C10105.0 (3)
O2—C7—C8—C1134.3 (4)C2—C1—O1—C1080.8 (3)
C2—C7—C8—C11149.1 (3)C9—C10—O1—C158.6 (3)
O2—C7—C8—C9143.4 (3)C4—C5—O4—C180.1 (5)
C2—C7—C8—C933.2 (4)C6—C5—O4—C18178.2 (3)
C11—C8—C9—C10102.2 (4)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O5—H5···O2i0.821.962.723 (3)154
O3—H3···O20.821.822.541 (3)146
C10—H10B···O4ii0.972.623.288 (4)126
C9—H9A···Br1iii0.973.104.039 (3)163
C4—H4···O3iv0.932.423.332 (4)165
Symmetry codes: (i) x+1/2, y+1/2, z1/2; (ii) x+1/2, y+1/2, z+1/2; (iii) x, y1, z; (iv) x+1, y, z.
Inhibitory activity against PTKs for (7)–(10) presented as IC50M) top
CompoundErbB1ErbB2c-MetALKRETFGFR1KDR
(7)7.17±0.286.27±1.0537.29±2.8079.17±2.61?100?100?100
(8)3.47±0.152.17±0.2816.82±1.0136.59±2.37?10068.37±4.01?100
(9)0.82±0.360.69±0.0912.19±0.8157.27±2.7918.79±0.5961.18±1.1759.36±3.17
(10)0.31±0.080.16±0.057.38±0.8213.22±0.9416.39±1.1429.13±3.15?100
Lapatinib0.024±0.0120.013±0.007
PF-23410660.0052±0.0120.014±0.00350.016±0.003
AZD45470.019±0.0030.009±0.003
 

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