The glycogen phospho­rylase inhibitor 2-(3-benzyl­amino-2-oxo-1,2-di­hydro­pyridin-1-yl)-N-(3,4-di­chloro­benz­yl)acetamide

The molecular structure of the title compound, C₂₁H₁₉Cl₂N₃O₂, a potent glycogen phospho­rylase a (GPa) inhibitor (IC₅₀ of 6.3 µM), consists of four distinct conjugated π systems separated by rotatable C—C bonds at the methylene groups. Mol­ecules are linked into dimers disposed about a crystallographic centre of symmetry through a cyclic N—H...O hydrogen-bonding motif [graph set R₂²(10)]. These dimers are further connected along the crystallographic c axis by N—H...O hydrogen bonding between the amide groups [graph set C(4)]. A comparison of this structure with that of the monohydrate of the significantly less active analogue (S)-2-(3-benzyl­amino-2-oxo-1,2-di­hydro­pyridin-1-yl)-N-(2-hy­droxy-1-phenyl­eth­yl)acetamide (IC₅₀ of 120 µM) is presented.

Computing details

Cell refinement: CrysAlis PRO (Agilent, 2012); data reduction: CrysAlis PRO (Agilent, 2012); program(s) used to solve structure: TEXSAN (Molecular Structure Corporation, 2001) and SIR97 (Altomare et al., 1999); program(s) used to refine structure: TEXSAN (Molecular Structure Corporation, 2001) and SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012); software used to prepare material for publication: PLATON (Spek, 2009).

2-(3-Benzylamino-2-oxo-1,2-dihydropyridin-1-yl)-N-(3,4-dichlorobenzyl)acetamide

Crystal data

C21H19Cl2N3O2	F(000) = 864
Mr = 416.29	Dx = 1.418 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71070 Å
Hall symbol: -P 2ybc	Cell parameters from 1947 reflections
a = 18.9215 (8) Å	θ = 3.5–28.9°
b = 11.5507 (5) Å	µ = 0.36 mm^−1
c = 8.9392 (3) Å	T = 200 K
β = 93.874 (3)°	Plate, colourless
V = 1949.26 (14) Å^3	0.29 × 0.18 × 0.06 mm
Z = 4

Data collection

Oxford GEMINI S Ultra diffractometer	4456 independent reflections
Radiation source: Enhance (Mo) X-ray Source	3126 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.035
Detector resolution: 16.0774 pixels mm^-1	θmax = 27.5°, θmin = 3.1°
ω and φ scans	h = −24→16
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2012)	k = −13→15
Tmin = 0.904, Tmax = 0.979	l = −11→10
8900 measured reflections

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)] = 0.051	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.116	H atoms treated by a mixture of independent and constrained refinement
S = 1.04	w = 1/[σ^2(Fo^2) + (0.0454P)^2 + 0.3413P] where P = (Fo^2 + 2Fc^2)/3
4456 reflections	(Δ/σ)max < 0.001
261 parameters	Δρmax = 0.32 e Å^−3
0 restraints	Δρmin = −0.30 e Å^−3

Special details

Geometry. Bond distances, angles etc. have been calculated using the rounded fractional coordinates. All su's are estimated from the variances of the (full) variance-covariance matrix. The cell e.s.d.'s are taken into account in the estimation of distances, angles and torsion angles

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
Cl17	0.01187 (4)	0.39204 (8)	−0.18149 (7)	0.0617 (3)
Cl18	0.04090 (3)	0.12847 (7)	−0.10599 (7)	0.0523 (2)
O2	0.47878 (7)	0.38715 (12)	0.36430 (15)	0.0292 (4)
O12	0.36288 (7)	0.17730 (13)	0.43693 (14)	0.0299 (5)
N1	0.49932 (8)	0.19497 (14)	0.33929 (17)	0.0223 (5)
N3	0.60227 (10)	0.41821 (17)	0.5336 (2)	0.0341 (6)
N11	0.31490 (9)	0.24570 (17)	0.2172 (2)	0.0284 (6)
C2	0.51697 (10)	0.30181 (18)	0.3965 (2)	0.0223 (6)
C3	0.58202 (10)	0.30810 (18)	0.4918 (2)	0.0234 (6)
C4	0.61913 (11)	0.20999 (19)	0.5276 (2)	0.0298 (6)
C5	0.59536 (11)	0.10202 (19)	0.4706 (2)	0.0317 (7)
C6	0.53699 (11)	0.09613 (18)	0.3768 (2)	0.0284 (6)
C11	0.43813 (10)	0.19012 (19)	0.2318 (2)	0.0269 (6)
C12	0.36871 (10)	0.20587 (18)	0.3054 (2)	0.0234 (6)
C13	0.24491 (11)	0.2561 (2)	0.2742 (2)	0.0334 (7)
C14	0.18896 (10)	0.2890 (2)	0.1548 (2)	0.0279 (6)
C15	0.17688 (13)	0.4037 (2)	0.1177 (3)	0.0368 (7)
C16	0.12307 (13)	0.4348 (2)	0.0138 (3)	0.0397 (8)
C17	0.08051 (11)	0.3512 (2)	−0.0545 (2)	0.0355 (8)
C18	0.09268 (10)	0.2355 (2)	−0.0206 (2)	0.0314 (7)
C19	0.14641 (10)	0.20476 (19)	0.0839 (2)	0.0281 (6)
C31	0.66989 (12)	0.4393 (2)	0.6130 (3)	0.0369 (7)
C32	0.73130 (11)	0.41581 (19)	0.5170 (3)	0.0321 (7)
C33	0.72526 (12)	0.4363 (2)	0.3636 (3)	0.0392 (8)
C34	0.78102 (14)	0.4140 (2)	0.2756 (3)	0.0467 (9)
C35	0.84427 (13)	0.3723 (2)	0.3401 (3)	0.0499 (9)
C36	0.85115 (13)	0.3511 (2)	0.4922 (3)	0.0501 (9)
C37	0.79493 (12)	0.3720 (2)	0.5794 (3)	0.0395 (8)
H3	0.5730 (13)	0.466 (2)	0.540 (3)	0.040 (7)*
H4	0.66130	0.21420	0.59140	0.0360*
H5	0.62070	0.03340	0.49840	0.0380*
H6	0.52170	0.02360	0.33630	0.0340*
H11	0.3211 (12)	0.262 (2)	0.138 (3)	0.029 (7)*
H11A	0.43750	0.11690	0.18320	0.0320*
H11B	0.44230	0.24970	0.15970	0.0320*
H13A	0.23250	0.18380	0.31600	0.0400*
H13B	0.24670	0.31380	0.35030	0.0400*
H15	0.20610	0.46190	0.16450	0.0440*
H16	0.11550	0.51410	−0.01070	0.0480*
H19	0.15440	0.12540	0.10740	0.0340*
H31A	0.67430	0.39040	0.69870	0.0440*
H31B	0.67190	0.51800	0.64410	0.0440*
H33	0.68220	0.46630	0.31850	0.0470*
H34	0.77580	0.42740	0.17060	0.0560*
H35	0.88290	0.35800	0.28010	0.0600*
H36	0.89460	0.32250	0.53710	0.0600*
H37	0.79990	0.35590	0.68380	0.0470*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl17	0.0435 (4)	0.0931 (6)	0.0472 (4)	0.0309 (4)	−0.0053 (3)	0.0138 (4)
Cl18	0.0337 (3)	0.0666 (5)	0.0553 (4)	−0.0130 (3)	−0.0075 (3)	−0.0132 (4)
O2	0.0312 (8)	0.0235 (8)	0.0326 (7)	0.0081 (6)	0.0002 (6)	−0.0003 (6)
O12	0.0303 (8)	0.0386 (9)	0.0212 (7)	0.0026 (7)	0.0038 (5)	0.0015 (7)
N1	0.0217 (8)	0.0216 (9)	0.0238 (8)	−0.0001 (7)	0.0034 (6)	−0.0033 (7)
N3	0.0215 (10)	0.0257 (10)	0.0546 (12)	0.0021 (8)	−0.0002 (8)	−0.0136 (9)
N11	0.0233 (9)	0.0429 (12)	0.0191 (9)	−0.0034 (8)	0.0026 (7)	0.0025 (9)
C2	0.0244 (10)	0.0218 (10)	0.0212 (9)	0.0013 (8)	0.0048 (7)	0.0018 (8)
C3	0.0219 (10)	0.0227 (11)	0.0261 (10)	−0.0001 (8)	0.0045 (8)	−0.0015 (9)
C4	0.0228 (10)	0.0301 (12)	0.0361 (11)	0.0027 (9)	−0.0015 (8)	0.0026 (10)
C5	0.0319 (12)	0.0203 (11)	0.0430 (12)	0.0073 (9)	0.0035 (9)	0.0069 (10)
C6	0.0325 (12)	0.0169 (10)	0.0366 (11)	−0.0001 (9)	0.0089 (9)	−0.0029 (9)
C11	0.0263 (11)	0.0320 (12)	0.0224 (10)	−0.0016 (9)	0.0009 (8)	−0.0060 (9)
C12	0.0255 (10)	0.0224 (11)	0.0223 (9)	−0.0033 (8)	0.0014 (7)	−0.0067 (9)
C13	0.0253 (11)	0.0504 (15)	0.0245 (10)	−0.0044 (10)	0.0025 (8)	0.0023 (11)
C14	0.0216 (10)	0.0387 (13)	0.0237 (10)	−0.0002 (9)	0.0047 (8)	−0.0003 (10)
C15	0.0405 (13)	0.0345 (13)	0.0358 (12)	−0.0049 (11)	0.0052 (10)	−0.0055 (11)
C16	0.0454 (14)	0.0321 (13)	0.0427 (13)	0.0120 (11)	0.0104 (11)	0.0038 (11)
C17	0.0269 (12)	0.0524 (16)	0.0276 (11)	0.0119 (11)	0.0044 (8)	0.0059 (11)
C18	0.0222 (10)	0.0428 (14)	0.0292 (10)	−0.0015 (10)	0.0026 (8)	−0.0030 (10)
C19	0.0231 (10)	0.0308 (12)	0.0307 (10)	0.0002 (9)	0.0031 (8)	0.0012 (10)
C31	0.0278 (12)	0.0368 (13)	0.0457 (13)	−0.0043 (10)	−0.0010 (9)	−0.0134 (11)
C32	0.0246 (11)	0.0261 (12)	0.0454 (13)	−0.0056 (9)	0.0003 (9)	−0.0099 (10)
C33	0.0309 (12)	0.0371 (14)	0.0491 (14)	−0.0056 (10)	−0.0017 (10)	−0.0008 (12)
C34	0.0428 (15)	0.0522 (17)	0.0456 (14)	−0.0134 (12)	0.0076 (11)	−0.0044 (13)
C35	0.0336 (14)	0.0531 (17)	0.0645 (17)	−0.0069 (12)	0.0153 (12)	−0.0158 (15)
C36	0.0280 (13)	0.0509 (17)	0.0708 (18)	0.0051 (12)	−0.0019 (12)	−0.0109 (15)
C37	0.0332 (13)	0.0378 (14)	0.0469 (13)	−0.0016 (10)	−0.0021 (10)	−0.0061 (12)

Geometric parameters (Å, º)

Cl17—C17	1.732 (2)	C31—C32	1.515 (3)
Cl18—C18	1.723 (2)	C32—C37	1.388 (3)
O2—C2	1.244 (2)	C32—C33	1.389 (4)
O12—C12	1.233 (2)	C33—C34	1.382 (4)
N1—C2	1.369 (3)	C34—C35	1.380 (4)
N1—C6	1.375 (3)	C35—C36	1.379 (4)
N1—C11	1.455 (2)	C36—C37	1.382 (3)
N3—C3	1.373 (3)	C4—H4	0.9500
N3—C31	1.441 (3)	C5—H5	0.9500
N11—C12	1.327 (3)	C6—H6	0.9500
N11—C13	1.456 (3)	C11—H11A	0.9500
N3—H3	0.79 (2)	C11—H11B	0.9500
N11—H11	0.75 (3)	C13—H13A	0.9500
C2—C3	1.451 (3)	C13—H13B	0.9500
C3—C4	1.360 (3)	C15—H15	0.9500
C4—C5	1.409 (3)	C16—H16	0.9500
C5—C6	1.343 (3)	C19—H19	0.9500
C11—C12	1.519 (3)	C31—H31A	0.9500
C13—C14	1.501 (3)	C31—H31B	0.9500
C14—C19	1.388 (3)	C33—H33	0.9500
C14—C15	1.381 (3)	C34—H34	0.9500
C15—C16	1.379 (4)	C35—H35	0.9500
C16—C17	1.374 (3)	C36—H36	0.9500
C17—C18	1.386 (3)	C37—H37	0.9500
C18—C19	1.380 (3)
Cl17···Cl18	3.1584 (12)	C32···C4	3.193 (3)
Cl17···Cl18^i	3.4362 (11)	C33···C3	3.357 (3)
Cl17···C16^ii	3.645 (3)	C2···H11B^ix	2.8900
Cl17···C19^iii	3.585 (2)	C4···H31A	2.7500
Cl18···Cl17	3.1584 (12)	C5···H31A^iii	2.9400
Cl18···Cl17^iv	3.4362 (11)	C16···H34^xi	3.0600
Cl18···H35^v	3.1000	C19···H13B^iii	2.9200
O2···N3	2.721 (2)	C31···H4	2.6100
O2···C12	2.975 (2)	C32···H4	2.7800
O2···N3^vi	2.903 (2)	C34···H19^vii	2.8900
O2···C6^vii	3.236 (2)	C34···H4^iii	3.0900
O12···C2	3.293 (2)	C35···H19^vii	2.9600
O12···C5^viii	3.410 (3)	C35···H37^iii	3.0700
O12···C11^ix	3.288 (2)	C37···H15^vi	2.9900
O12···N11^ix	2.864 (2)	H3···O2	2.47 (3)
O12···N1	2.788 (2)	H3···O2^vi	2.16 (2)
O2···H11B	2.4800	H4···C31	2.6100
O2···H3^vi	2.16 (2)	H4···C32	2.7800
O2···H3	2.47 (3)	H4···H31A	2.2600
O2···H6^vii	2.3900	H4···C34^ix	3.0900
O12···H13A	2.6300	H5···O12^viii	2.5200
O12···H5^viii	2.5200	H6···H11A	2.3000
O12···H13B	2.7700	H6···O2^x	2.3900
O12···H11^ix	2.13 (3)	H11···H11B	2.2900
O12···H11B^ix	2.5600	H11···O12^iii	2.13 (3)
N1···O12	2.788 (2)	H11A···H6	2.3000
N3···O2	2.721 (2)	H11B···O2	2.4800
N3···O2^vi	2.903 (2)	H11B···H11	2.2900
N3···C6^ix	3.388 (3)	H11B···O12^iii	2.5600
N11···O12^iii	2.864 (2)	H11B···C2^iii	2.8900
N3···H33	2.5900	H13A···O12	2.6300
C2···O12	3.293 (2)	H13A···H19	2.4000
C2···C11^ix	3.438 (3)	H13B···O12	2.7700
C3···C33	3.357 (3)	H13B···H15	2.4700
C3···C11^ix	3.578 (3)	H13B···H31B^vi	2.4800
C4···C32	3.193 (3)	H13B···C19^ix	2.9200
C5···O12^viii	3.410 (3)	H15···H13B	2.4700
C6···O2^x	3.236 (2)	H15···C37^vi	2.9900
C6···C31^iii	3.585 (3)	H15···H37^vi	2.5100
C6···N3^iii	3.388 (3)	H19···H13A	2.4000
C6···C6^viii	3.487 (3)	H19···C34^x	2.8900
C11···O12^iii	3.288 (2)	H19···C35^x	2.9600
C11···C3^iii	3.578 (3)	H31A···C4	2.7500
C11···C2^iii	3.438 (3)	H31A···H4	2.2600
C12···O2	2.975 (2)	H31A···H37	2.4200
C13···C18^ix	3.519 (3)	H31A···C5^ix	2.9400
C13···C19^ix	3.470 (3)	H31B···H13B^vi	2.4800
C14···C18^ix	3.540 (3)	H33···N3	2.5900
C16···Cl17^ii	3.645 (3)	H34···C16^xi	3.0600
C18···C14^iii	3.540 (3)	H35···Cl18^xii	3.1000
C18···C13^iii	3.519 (3)	H37···H31A	2.4200
C19···Cl17^ix	3.585 (2)	H37···H15^vi	2.5100
C19···C13^iii	3.470 (3)	H37···C35^ix	3.0700
C31···C6^ix	3.585 (3)
C2—N1—C6	123.23 (16)	C34—C35—C36	119.7 (2)
C2—N1—C11	116.41 (16)	C35—C36—C37	120.0 (2)
C6—N1—C11	120.35 (16)	C32—C37—C36	121.1 (2)
C3—N3—C31	120.85 (18)	C3—C4—H4	120.00
C12—N11—C13	120.01 (17)	C5—C4—H4	120.00
C3—N3—H3	119.0 (18)	C4—C5—H5	120.00
C31—N3—H3	116.8 (18)	C6—C5—H5	120.00
C13—N11—H11	120.9 (18)	N1—C6—H6	120.00
C12—N11—H11	119.1 (17)	C5—C6—H6	120.00
O2—C2—C3	123.54 (18)	N1—C11—H11A	109.00
N1—C2—C3	116.14 (17)	N1—C11—H11B	109.00
O2—C2—N1	120.31 (17)	C12—C11—H11A	109.00
N3—C3—C2	114.61 (18)	C12—C11—H11B	109.00
C2—C3—C4	120.04 (19)	H11A—C11—H11B	109.00
N3—C3—C4	125.30 (18)	N11—C13—H13A	109.00
C3—C4—C5	120.35 (18)	N11—C13—H13B	109.00
C4—C5—C6	120.0 (2)	C14—C13—H13A	109.00
N1—C6—C5	120.08 (19)	C14—C13—H13B	109.00
N1—C11—C12	112.47 (15)	H13A—C13—H13B	109.00
O12—C12—C11	121.10 (17)	C14—C15—H15	119.00
N11—C12—C11	115.80 (16)	C16—C15—H15	120.00
O12—C12—N11	123.00 (18)	C15—C16—H16	120.00
N11—C13—C14	112.75 (15)	C17—C16—H16	120.00
C13—C14—C15	120.7 (2)	C14—C19—H19	120.00
C13—C14—C19	120.4 (2)	C18—C19—H19	120.00
C15—C14—C19	118.77 (19)	N3—C31—H31A	109.00
C14—C15—C16	121.0 (2)	N3—C31—H31B	109.00
C15—C16—C17	120.0 (2)	C32—C31—H31A	109.00
Cl17—C17—C16	119.41 (18)	C32—C31—H31B	109.00
Cl17—C17—C18	120.80 (16)	H31A—C31—H31B	109.00
C16—C17—C18	119.79 (19)	C32—C33—H33	119.00
C17—C18—C19	120.00 (19)	C34—C33—H33	119.00
Cl18—C18—C17	120.91 (15)	C33—C34—H34	120.00
Cl18—C18—C19	119.08 (17)	C35—C34—H34	120.00
C14—C19—C18	120.4 (2)	C34—C35—H35	120.00
N3—C31—C32	112.3 (2)	C36—C35—H35	120.00
C31—C32—C33	120.9 (2)	C35—C36—H36	120.00
C31—C32—C37	121.0 (2)	C37—C36—H36	120.00
C33—C32—C37	118.1 (2)	C32—C37—H37	119.00
C32—C33—C34	121.0 (2)	C36—C37—H37	119.00
C33—C34—C35	120.1 (2)
C6—N1—C2—O2	−176.31 (17)	N11—C13—C14—C19	97.2 (2)
C6—N1—C2—C3	4.8 (3)	C13—C14—C15—C16	−176.5 (2)
C11—N1—C2—O2	4.9 (3)	C19—C14—C15—C16	0.9 (3)
C11—N1—C2—C3	−174.02 (16)	C13—C14—C19—C18	176.80 (17)
C2—N1—C6—C5	−1.9 (3)	C15—C14—C19—C18	−0.6 (3)
C11—N1—C6—C5	176.85 (17)	C14—C15—C16—C17	0.0 (4)
C2—N1—C11—C12	−72.9 (2)	C15—C16—C17—Cl17	178.50 (19)
C6—N1—C11—C12	108.3 (2)	C15—C16—C17—C18	−1.2 (3)
C31—N3—C3—C2	−172.51 (19)	C16—C17—C18—C19	1.4 (3)
C31—N3—C3—C4	4.7 (3)	Cl17—C17—C18—Cl18	1.1 (2)
C3—N3—C31—C32	67.5 (3)	Cl17—C17—C18—C19	−178.24 (15)
C13—N11—C12—O12	−0.7 (3)	C16—C17—C18—Cl18	−179.23 (17)
C13—N11—C12—C11	175.69 (18)	Cl18—C18—C19—C14	−179.90 (14)
C12—N11—C13—C14	−173.21 (19)	C17—C18—C19—C14	−0.5 (3)
N1—C2—C3—N3	173.08 (16)	N3—C31—C32—C37	−146.1 (2)
N1—C2—C3—C4	−4.3 (3)	N3—C31—C32—C33	33.2 (3)
O2—C2—C3—N3	−5.8 (3)	C31—C32—C33—C34	−179.4 (2)
O2—C2—C3—C4	176.87 (18)	C31—C32—C37—C36	−179.6 (2)
N3—C3—C4—C5	−176.03 (18)	C33—C32—C37—C36	1.1 (3)
C2—C3—C4—C5	1.0 (3)	C37—C32—C33—C34	−0.2 (3)
C3—C4—C5—C6	2.0 (3)	C32—C33—C34—C35	−0.9 (4)
C4—C5—C6—N1	−1.7 (3)	C33—C34—C35—C36	1.1 (4)
N1—C11—C12—N11	155.49 (18)	C34—C35—C36—C37	−0.2 (4)
N1—C11—C12—O12	−28.1 (3)	C35—C36—C37—C32	−0.9 (4)
N11—C13—C14—C15	−85.5 (2)

Symmetry codes: (i) −x, y+1/2, −z−1/2; (ii) −x, −y+1, −z; (iii) x, −y+1/2, z−1/2; (iv) −x, y−1/2, −z−1/2; (v) x−1, −y+1/2, z−1/2; (vi) −x+1, −y+1, −z+1; (vii) −x+1, y+1/2, −z+1/2; (viii) −x+1, −y, −z+1; (ix) x, −y+1/2, z+1/2; (x) −x+1, y−1/2, −z+1/2; (xi) −x+1, −y+1, −z; (xii) x+1, −y+1/2, z+1/2.

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N3—H3···O2	0.79 (2)	2.47 (3)	2.721 (2)	100 (2)
N3—H3···O2^vi	0.79 (2)	2.16 (2)	2.903 (2)	157 (2)
N11—H11···O12^iii	0.75 (3)	2.13 (3)	2.864 (2)	166 (2)

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