Synthesis, crystal structure and activity evaluation of novel 3,4-di­hydro-1-benzoxepin-5(2H)-one derivatives as protein–tyrosine kinase (PTK) inhibitors

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.

Computing details

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

Crystal data

C18H15BrO5	F(000) = 792
Mr = 391.21	Dx = 1.618 Mg m^−3
Monoclinic, P21/n	Mo Kα radiation, λ = 0.71073 Å
a = 11.960 (4) Å	Cell parameters from 2479 reflections
b = 9.025 (3) Å	θ = 2.3–24.1°
c = 14.981 (4) Å	µ = 2.59 mm^−1
β = 96.768 (6)°	T = 296 K
V = 1605.9 (8) Å^3	Block, yellow
Z = 4	0.14 × 0.12 × 0.12 mm

Data collection

Bruker SMART CCD area detector diffractometer	Rint = 0.046
Radiation source: fine-focus sealed tube	θmax = 25.5°, θmin = 2.1°
phi and ω scans	h = −14→13
8968 measured reflections	k = −9→10
2985 independent reflections	l = −18→15
2155 reflections with I > 2σ(I)

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.038	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.094	H-atom parameters constrained
S = 1.02	w = 1/[σ^2(Fo^2) + (0.0422P)^2 + 0.3742P] where P = (Fo^2 + 2Fc^2)/3
2985 reflections	(Δ/σ)max = 0.001
220 parameters	Δρmax = 0.28 e Å^−3
0 restraints	Δρmin = −0.47 e Å^−3

Special details

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 (Ų)

	x	y	z	Uiso*/Ueq
Br1	0.11150 (3)	1.16571 (4)	0.10415 (2)	0.05918 (16)
C1	0.3910 (3)	0.4235 (3)	0.14028 (19)	0.0370 (7)
C2	0.3849 (2)	0.3774 (3)	0.05003 (18)	0.0345 (7)
C3	0.4234 (3)	0.2323 (3)	0.03582 (19)	0.0396 (7)
C4	0.4552 (3)	0.1360 (3)	0.1060 (2)	0.0419 (8)
H4	0.4766	0.0393	0.0949	0.050*
C5	0.4545 (3)	0.1861 (3)	0.1924 (2)	0.0389 (7)
C6	0.4230 (3)	0.3311 (3)	0.2102 (2)	0.0404 (7)
H6	0.4239	0.3640	0.2691	0.049*
C7	0.3422 (3)	0.4691 (3)	−0.02609 (19)	0.0361 (7)
C8	0.2722 (3)	0.6018 (3)	−0.01220 (18)	0.0346 (7)
C9	0.1977 (3)	0.5903 (3)	0.0613 (2)	0.0444 (8)
H9A	0.1642	0.4923	0.0596	0.053*
H9B	0.1371	0.6618	0.0501	0.053*
C10	0.2587 (3)	0.6170 (4)	0.1540 (2)	0.0554 (10)
H10A	0.2555	0.7216	0.1683	0.067*
H10B	0.2213	0.5627	0.1978	0.067*
C11	0.2795 (3)	0.7156 (3)	−0.06838 (18)	0.0381 (7)
H11	0.3257	0.6992	−0.1132	0.046*
C12	0.2267 (3)	0.8612 (3)	−0.07056 (19)	0.0360 (7)
C13	0.2054 (3)	0.9343 (3)	−0.15327 (19)	0.0402 (7)
C14	0.1617 (3)	1.0753 (3)	−0.1591 (2)	0.0458 (8)
H14	0.1515	1.1235	−0.2143	0.055*
C15	0.1327 (3)	1.1460 (3)	−0.0829 (2)	0.0461 (8)
H15	0.1014	1.2404	−0.0866	0.055*
C16	0.1510 (3)	1.0740 (3)	−0.0019 (2)	0.0405 (7)
C17	0.1989 (3)	0.9352 (3)	0.00498 (19)	0.0399 (7)
H17	0.2128	0.8903	0.0611	0.048*
C18	0.5233 (3)	−0.0463 (4)	0.2550 (2)	0.0624 (10)
H18A	0.4627	−0.1025	0.2238	0.094*
H18B	0.5458	−0.0908	0.3126	0.094*
H18C	0.5860	−0.0455	0.2205	0.094*
O1	0.37413 (19)	0.5711 (2)	0.15975 (13)	0.0459 (6)
O2	0.3591 (2)	0.4338 (2)	−0.10358 (12)	0.0489 (6)
O3	0.4301 (2)	0.1809 (2)	−0.04798 (14)	0.0567 (7)
H3	0.4178	0.2488	−0.0842	0.085*
O4	0.48642 (19)	0.1033 (2)	0.26751 (14)	0.0518 (6)
O5	0.2319 (2)	0.8596 (2)	−0.22711 (14)	0.0559 (6)
H5	0.2121	0.9084	−0.2724	0.084*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Br1	0.0866 (3)	0.0395 (2)	0.0552 (2)	−0.00133 (18)	0.02430 (19)	−0.00907 (16)
C1	0.0422 (19)	0.0321 (15)	0.0378 (16)	0.0008 (13)	0.0090 (14)	−0.0019 (13)
C2	0.0426 (19)	0.0283 (14)	0.0332 (15)	0.0014 (13)	0.0068 (13)	−0.0019 (12)
C3	0.046 (2)	0.0349 (15)	0.0383 (16)	0.0038 (14)	0.0058 (14)	−0.0062 (13)
C4	0.048 (2)	0.0307 (16)	0.0474 (19)	0.0056 (14)	0.0054 (15)	0.0000 (13)
C5	0.0371 (19)	0.0364 (16)	0.0439 (18)	0.0027 (13)	0.0082 (14)	0.0066 (14)
C6	0.047 (2)	0.0430 (17)	0.0322 (15)	0.0018 (14)	0.0096 (14)	−0.0006 (14)
C7	0.0419 (19)	0.0322 (15)	0.0352 (16)	−0.0024 (13)	0.0083 (13)	−0.0026 (12)
C8	0.0418 (18)	0.0308 (15)	0.0312 (15)	0.0011 (13)	0.0048 (13)	−0.0001 (12)
C9	0.047 (2)	0.0300 (16)	0.060 (2)	0.0060 (14)	0.0184 (16)	0.0087 (14)
C10	0.081 (3)	0.0506 (19)	0.0391 (18)	0.0231 (19)	0.0260 (18)	0.0071 (15)
C11	0.048 (2)	0.0374 (16)	0.0297 (15)	0.0003 (14)	0.0080 (13)	−0.0006 (13)
C12	0.0454 (19)	0.0300 (15)	0.0334 (16)	−0.0040 (13)	0.0074 (13)	0.0032 (12)
C13	0.050 (2)	0.0372 (17)	0.0347 (16)	−0.0025 (14)	0.0087 (14)	0.0032 (13)
C14	0.056 (2)	0.0398 (18)	0.0419 (18)	−0.0012 (15)	0.0060 (15)	0.0108 (14)
C15	0.054 (2)	0.0300 (16)	0.055 (2)	0.0026 (14)	0.0093 (16)	0.0069 (14)
C16	0.051 (2)	0.0324 (16)	0.0397 (17)	−0.0052 (14)	0.0103 (14)	−0.0002 (13)
C17	0.057 (2)	0.0274 (15)	0.0356 (16)	−0.0014 (14)	0.0060 (15)	0.0044 (12)
C18	0.080 (3)	0.0409 (19)	0.067 (2)	0.0162 (18)	0.010 (2)	0.0171 (17)
O1	0.0684 (16)	0.0332 (11)	0.0371 (11)	0.0077 (11)	0.0112 (11)	−0.0065 (9)
O2	0.0737 (17)	0.0434 (12)	0.0302 (11)	0.0126 (11)	0.0077 (11)	−0.0024 (9)
O3	0.0887 (19)	0.0438 (13)	0.0369 (12)	0.0232 (13)	0.0045 (12)	−0.0079 (10)
O4	0.0620 (16)	0.0468 (13)	0.0476 (13)	0.0128 (11)	0.0105 (11)	0.0129 (11)
O5	0.0854 (19)	0.0522 (14)	0.0304 (11)	0.0119 (13)	0.0083 (12)	0.0026 (10)

Geometric parameters (Å, º)

Br1—C16	1.900 (3)	C10—H10A	0.9700
C1—C6	1.358 (4)	C10—H10B	0.9700
C1—O1	1.383 (3)	C11—C12	1.457 (4)
C1—C2	1.408 (4)	C11—H11	0.9300
C2—C3	1.413 (4)	C12—C17	1.388 (4)
C2—C7	1.452 (4)	C12—C13	1.400 (4)
C3—O3	1.349 (3)	C13—O5	1.364 (3)
C3—C4	1.383 (4)	C13—C14	1.375 (4)
C4—C5	1.371 (4)	C14—C15	1.387 (4)
C4—H4	0.9300	C14—H14	0.9300
C5—O4	1.368 (4)	C15—C16	1.370 (4)
C5—C6	1.396 (4)	C15—H15	0.9300
C6—H6	0.9300	C16—C17	1.376 (4)
C7—O2	1.243 (3)	C17—H17	0.9300
C7—C8	1.490 (4)	C18—O4	1.439 (4)
C8—C11	1.337 (4)	C18—H18A	0.9600
C8—C9	1.500 (4)	C18—H18B	0.9600
C9—C10	1.510 (5)	C18—H18C	0.9600
C9—H9A	0.9700	O3—H3	0.8200
C9—H9B	0.9700	O5—H5	0.8200
C10—O1	1.434 (4)
C6—C1—O1	117.6 (3)	C9—C10—H10B	109.3
C6—C1—C2	122.5 (3)	H10A—C10—H10B	108.0
O1—C1—C2	119.6 (2)	C8—C11—C12	130.3 (3)
C1—C2—C3	116.0 (3)	C8—C11—H11	114.9
C1—C2—C7	124.0 (2)	C12—C11—H11	114.9
C3—C2—C7	120.1 (2)	C17—C12—C13	117.3 (3)
O3—C3—C4	116.8 (3)	C17—C12—C11	124.1 (3)
O3—C3—C2	121.0 (3)	C13—C12—C11	118.6 (3)
C4—C3—C2	122.2 (3)	O5—C13—C14	121.9 (3)
C5—C4—C3	118.6 (3)	O5—C13—C12	116.7 (3)
C5—C4—H4	120.7	C14—C13—C12	121.4 (3)
C3—C4—H4	120.7	C13—C14—C15	120.2 (3)
O4—C5—C4	124.3 (3)	C13—C14—H14	119.9
O4—C5—C6	114.2 (3)	C15—C14—H14	119.9
C4—C5—C6	121.4 (3)	C16—C15—C14	118.8 (3)
C1—C6—C5	119.0 (3)	C16—C15—H15	120.6
C1—C6—H6	120.5	C14—C15—H15	120.6
C5—C6—H6	120.5	C15—C16—C17	121.3 (3)
O2—C7—C2	120.4 (3)	C15—C16—Br1	120.3 (2)
O2—C7—C8	119.5 (3)	C17—C16—Br1	118.4 (2)
C2—C7—C8	120.0 (2)	C16—C17—C12	120.9 (3)
C11—C8—C7	116.7 (3)	C16—C17—H17	119.5
C11—C8—C9	127.2 (3)	C12—C17—H17	119.5
C7—C8—C9	116.1 (2)	O4—C18—H18A	109.5
C8—C9—C10	113.6 (3)	O4—C18—H18B	109.5
C8—C9—H9A	108.9	H18A—C18—H18B	109.5
C10—C9—H9A	108.9	O4—C18—H18C	109.5
C8—C9—H9B	108.9	H18A—C18—H18C	109.5
C10—C9—H9B	108.9	H18B—C18—H18C	109.5
H9A—C9—H9B	107.7	C1—O1—C10	115.4 (2)
O1—C10—C9	111.5 (2)	C3—O3—H3	109.5
O1—C10—H10A	109.3	C5—O4—C18	117.8 (2)
C9—C10—H10A	109.3	C13—O5—H5	109.5
O1—C10—H10B	109.3
C6—C1—C2—C3	−5.2 (4)	C7—C8—C9—C10	80.4 (3)
O1—C1—C2—C3	168.7 (3)	C8—C9—C10—O1	−30.7 (4)
C6—C1—C2—C7	174.6 (3)	C7—C8—C11—C12	−177.1 (3)
O1—C1—C2—C7	−11.5 (5)	C9—C8—C11—C12	5.4 (5)
C1—C2—C3—O3	−174.5 (3)	C8—C11—C12—C17	30.2 (5)
C7—C2—C3—O3	5.7 (5)	C8—C11—C12—C13	−151.8 (3)
C1—C2—C3—C4	5.8 (4)	C17—C12—C13—O5	−179.2 (3)
C7—C2—C3—C4	−174.0 (3)	C11—C12—C13—O5	2.6 (4)
O3—C3—C4—C5	177.1 (3)	C17—C12—C13—C14	1.9 (5)
C2—C3—C4—C5	−3.3 (5)	C11—C12—C13—C14	−176.3 (3)
C3—C4—C5—O4	−178.5 (3)	O5—C13—C14—C15	178.1 (3)
C3—C4—C5—C6	−0.3 (5)	C12—C13—C14—C15	−3.1 (5)
O1—C1—C6—C5	−172.0 (3)	C13—C14—C15—C16	1.6 (5)
C2—C1—C6—C5	2.0 (5)	C14—C15—C16—C17	1.1 (5)
O4—C5—C6—C1	179.2 (3)	C14—C15—C16—Br1	−179.5 (2)
C4—C5—C6—C1	0.9 (5)	C15—C16—C17—C12	−2.2 (5)
C1—C2—C7—O2	165.9 (3)	Br1—C16—C17—C12	178.3 (2)
C3—C2—C7—O2	−14.3 (5)	C13—C12—C17—C16	0.7 (5)
C1—C2—C7—C8	−17.5 (5)	C11—C12—C17—C16	178.8 (3)
C3—C2—C7—C8	162.3 (3)	C6—C1—O1—C10	−105.0 (3)
O2—C7—C8—C11	−34.3 (4)	C2—C1—O1—C10	80.8 (3)
C2—C7—C8—C11	149.1 (3)	C9—C10—O1—C1	−58.6 (3)
O2—C7—C8—C9	143.4 (3)	C4—C5—O4—C18	0.1 (5)
C2—C7—C8—C9	−33.2 (4)	C6—C5—O4—C18	−178.2 (3)
C11—C8—C9—C10	−102.2 (4)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O5—H5···O2^i	0.82	1.96	2.723 (3)	154
O3—H3···O2	0.82	1.82	2.541 (3)	146
C10—H10B···O4^ii	0.97	2.62	3.288 (4)	126
C9—H9A···Br1^iii	0.97	3.10	4.039 (3)	163
C4—H4···O3^iv	0.93	2.42	3.332 (4)	165

Symmetry codes: (i) −x+1/2, y+1/2, −z−1/2; (ii) −x+1/2, y+1/2, −z+1/2; (iii) x, y−1, z; (iv) −x+1, −y, −z.