8-Chloro-6-(3-di­methyl­amino­propyl­amino)-11H-pyrido­[2,3-b][1,4]­benzodiazepine

The crystal structure determination of the title compound, C₁₇H₂₀ClN₅, has been undertaken as part of studies on antipsychotic drugs. Its structure is compared with that of clozapine (C₁₈H₁₉ClN₄), a well known atypical antipsychotic drug. The side chain is more flexible than in the N-methyl­piperazine analogues, but its folding is influenced by an intramolecular N—H...N hydrogen bond. The distances between the N-distal atom, a possible pharmacophore, and the centres of the two aromatic rings are significantly shorter than in clozapine. The crystal packing involves one N—H...N intermolecular hydrogen bond. The title compound showed no affinity for the receptors tested.

Key indicators

• Single-crystal X-ray study
• T = 293 K
• Mean [sigma](C-C) = 0.003 Å
• R factor = 0.044
• wR factor = 0.122
• Data-to-parameter ratio = 16.2

checkCIF results

No syntax errors found

ADDSYM reports no extra symmetry

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S1. Comment

In the first part of our program, biosteric analogues of dibenzoazepines were synthesized by modulating the tricyclic nucleus (Liégeois et al., 1993, 1994). Later, new entities were further developed by modulating the N-methylpiperazine side chain either by varying the N-substituent or by replacing the piperazine ring by other nitrogen-containing rings or even by aliphatic diamines. The new compounds were used to explore the impact of such modifications on the binding affinities of these molecules for D_4.2, 5-HT_{2 A} and D_{2 L} receptors. The title compound, (I), showed no affinity for the receptors tested. The flexibility of the side chain in the molecule is increased compared to the N-methylpiperazine analogues like, for example, 8-chloro-6-(4-methylpiperazin-1-yl)-11H-pyrido[2,3-b][1,4]benzodiazepine [clozapine drug (II); Petcher & Weber, 1976]. Nevertheless, the folding of the side chain is dominated by the existence of the intramolecular N16—H···N20(distal) hydrogen bond. In (I), the spatial position of the distal N atom, a possible pharmacophore, is modified and thus the interaction with the receptor sites could be compromised. Some geometrical features may be compared between (I) and (II). The dihedral angle between the two aromatic rings are 134.6 (2) in (I) and 115.0 (4)° in (II). The distances D1 and D2 between the N-distal atom and the the centres of the two aromatic rings are 4.754 (2) and 7.669 (2) Å in (I), and 5.972 (5) and 7.716 (5) Å in (II). In the crystal structure of (I), the side chain is more folded: D1 mainly is shorter than in (II) and in other dibenzo- or pyridobenzoazepine derivatives. In amidine moieties, the N═C double bond and C—N single bond are 1.295 (2) and 1.345 (2) Å in (I), and 1.293 (5) and 1.371 (5) in (II). The crystal packing is dominated by one hydrogen bond, viz. N5—H···N12.

S2. Experimental

The title compound was prepared according to previously described methods (Liégeois et al., 1993) using a one-pot synthesis. A mixture of the lactame derivative, the corresponding amine, titanium tetrachloride in toluene–anisole was refluxed for several hours. The product was extracted from basic solution with chloroform and recrystallized from methylene chloride/hexane mixture (Liégeois et al., 2002).

S3. Refinement

All H atoms (with the exception of the nitrogen-bound atoms H5 and H16) were included in the refinement in the riding-model approximation, with isotropic displacement parameters fixed at 1.2U_eq of the parent atom (1.5U_eq for methyl H-atoms). Atoms H5 and H16 were refined isotropically, their displacement parameters being fixed at 1.2U_eq of the nitrogen-bound atom. The two methyl groups were allowed to rotate about their local threefold axis.

Computing details

Data collection: CAD-4 EXPRESS (Enraf-Nonius, 1992); cell refinement: CAD-4 EXPRESS; data reduction: HELENA (Spek, 1997); program(s) used to solve structure: SIR92 (Altomare et al., 1993); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEPIII (Burnett & Johnson, 1996); software used to prepare material for publication: SHELXL97.

Figures

Fig. 1. The molecular structure of (I) with the atom-labelling scheme. Displacement ellipsoids are shown at the 50% probability level.

8-Chloro-6-(3-dimethylaminopropylamino)-11H-pyrido[2,3-b][1,4]benzodiazepine

Crystal data

C17H20ClN5	F(000) = 696
Mr = 329.83	Dx = 1.273 Mg m^−3
Monoclinic, P21/n	Mo Kα radiation, λ = 0.71069 Å
a = 9.001 (1) Å	Cell parameters from 25 reflections
b = 20.421 (3) Å	θ = 20–23°
c = 9.935 (1) Å	µ = 0.23 mm^−1
β = 109.545 (6)°	T = 293 K
V = 1720.9 (4) Å^3	Prism, yellow
Z = 4	0.50 × 0.50 × 0.50 mm

Data collection

Enraf-Nonius CAD-4 diffractometer	Rint = 0.022
Radiation source: fine-focus sealed tube	θmax = 26.3°, θmin = 2.0°
Graphite monochromator	h = 0→11
θ/2θ scans	k = −25→25
7197 measured reflections	l = −12→11
3511 independent reflections	3 standard reflections every 200 reflections
3036 reflections with I > 2σ(I)	intensity decay: 4%

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: H atoms were placed at standard calculated positions, except atoms H(N5) and H(N16), which were obtained from difference map.
R[F^2 > 2σ(F^2)] = 0.044	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.122	w = 1/[σ^2(Fo^2) + (0.0528P)^2 + 0.2131P] where P = (Fo^2 + 2Fc^2)/3
S = 1.11	(Δ/σ)max < 0.001
3511 reflections	Δρmax = 0.34 e Å^−3
217 parameters	Δρmin = −0.16 e Å^−3
0 restraints	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.078 (4)

Special details

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.

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

	x	y	z	Uiso*/Ueq
C1	0.1994 (2)	0.07844 (9)	0.63588 (19)	0.0541 (4)
C2	0.0909 (2)	0.12621 (10)	0.57305 (18)	0.0558 (5)
H2	0.0271	0.1224	0.4780	0.067*
C3	0.0776 (2)	0.17979 (9)	0.65227 (17)	0.0491 (4)
H3	0.0031	0.2119	0.6103	0.059*
C4	0.17410 (19)	0.18683 (8)	0.79491 (16)	0.0402 (3)
N5	0.15959 (18)	0.24356 (7)	0.86991 (14)	0.0464 (3)
H5	0.094 (2)	0.2720 (10)	0.817 (2)	0.056*
C6	0.1401 (2)	0.23693 (8)	1.00457 (16)	0.0416 (4)
N7	0.02017 (18)	0.27092 (8)	1.01874 (15)	0.0513 (4)
C8	−0.0044 (2)	0.26769 (10)	1.1445 (2)	0.0591 (5)
H8	−0.0867	0.2919	1.1561	0.071*
C9	0.0854 (2)	0.23063 (10)	1.25634 (19)	0.0574 (5)
H9	0.0621	0.2282	1.3406	0.069*
C10	0.2120 (2)	0.19673 (9)	1.24123 (17)	0.0504 (4)
H10	0.2756	0.1716	1.3166	0.061*
C11	0.24474 (18)	0.19994 (8)	1.11439 (16)	0.0407 (3)
N12	0.38923 (16)	0.17396 (7)	1.11346 (14)	0.0436 (3)
C13	0.40794 (18)	0.14789 (8)	1.00144 (16)	0.0414 (3)
C14	0.28679 (18)	0.13908 (8)	0.85719 (16)	0.0402 (3)
C15	0.2966 (2)	0.08439 (8)	0.77592 (18)	0.0481 (4)
H15	0.3696	0.0516	0.8168	0.058*
N16	0.54988 (17)	0.12354 (8)	1.01059 (16)	0.0524 (4)
H16	0.567 (2)	0.1146 (10)	0.937 (2)	0.063*
C17	0.6895 (2)	0.12695 (11)	1.1369 (2)	0.0594 (5)
H171	0.6638	0.1130	1.2197	0.071*
H172	0.7267	0.1718	1.1524	0.071*
C18	0.8176 (2)	0.08352 (12)	1.1188 (2)	0.0708 (6)
H181	0.9130	0.0905	1.1997	0.085*
H182	0.7864	0.0382	1.1218	0.085*
C19	0.8555 (2)	0.09373 (12)	0.9846 (3)	0.0715 (6)
H191	0.8782	0.1398	0.9770	0.086*
H192	0.9501	0.0692	0.9916	0.086*
N20	0.72907 (19)	0.07374 (8)	0.85317 (17)	0.0573 (4)
C21	0.7089 (3)	0.00392 (12)	0.8365 (3)	0.0850 (7)
H211	0.6264	−0.0055	0.7483	0.128*
H212	0.6813	−0.0136	0.9147	0.128*
H213	0.8055	−0.0156	0.8355	0.128*
C22	0.7641 (4)	0.10054 (13)	0.7309 (3)	0.0897 (8)
H221	0.8576	0.0802	0.7244	0.135*
H222	0.7804	0.1469	0.7429	0.135*
H223	0.6773	0.0921	0.6451	0.135*
Cl1	0.21868 (8)	0.01038 (3)	0.53802 (6)	0.0864 (2)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0612 (11)	0.0547 (10)	0.0499 (9)	−0.0064 (8)	0.0231 (8)	−0.0148 (8)
C2	0.0648 (11)	0.0632 (11)	0.0383 (8)	−0.0051 (9)	0.0156 (8)	−0.0055 (8)
C3	0.0549 (10)	0.0533 (9)	0.0398 (8)	0.0016 (8)	0.0166 (7)	0.0039 (7)
C4	0.0466 (8)	0.0418 (8)	0.0379 (7)	−0.0032 (6)	0.0218 (6)	0.0013 (6)
N5	0.0616 (9)	0.0421 (7)	0.0409 (7)	0.0071 (6)	0.0244 (7)	0.0038 (5)
C6	0.0486 (9)	0.0412 (8)	0.0393 (7)	−0.0044 (6)	0.0202 (7)	−0.0046 (6)
N7	0.0536 (9)	0.0570 (8)	0.0468 (8)	0.0084 (7)	0.0215 (7)	−0.0040 (6)
C8	0.0581 (11)	0.0700 (12)	0.0573 (10)	0.0058 (9)	0.0300 (9)	−0.0101 (9)
C9	0.0603 (11)	0.0756 (12)	0.0452 (9)	−0.0028 (9)	0.0295 (8)	−0.0068 (8)
C10	0.0549 (10)	0.0608 (10)	0.0379 (8)	−0.0037 (8)	0.0186 (7)	−0.0009 (7)
C11	0.0414 (8)	0.0444 (8)	0.0389 (7)	−0.0059 (6)	0.0169 (6)	−0.0058 (6)
N12	0.0420 (7)	0.0498 (8)	0.0398 (6)	−0.0022 (6)	0.0147 (5)	−0.0036 (6)
C13	0.0418 (8)	0.0416 (8)	0.0437 (8)	−0.0028 (6)	0.0184 (6)	−0.0013 (6)
C14	0.0433 (8)	0.0416 (8)	0.0396 (7)	−0.0056 (6)	0.0192 (6)	−0.0025 (6)
C15	0.0505 (9)	0.0469 (9)	0.0495 (9)	−0.0025 (7)	0.0204 (7)	−0.0066 (7)
N16	0.0440 (8)	0.0687 (10)	0.0451 (8)	0.0057 (7)	0.0159 (6)	−0.0072 (7)
C17	0.0499 (10)	0.0700 (12)	0.0540 (10)	0.0053 (9)	0.0117 (8)	−0.0081 (9)
C18	0.0539 (11)	0.0812 (14)	0.0674 (12)	0.0137 (10)	0.0072 (9)	−0.0108 (11)
C19	0.0508 (11)	0.0738 (14)	0.0917 (16)	0.0047 (10)	0.0263 (11)	−0.0112 (12)
N20	0.0578 (9)	0.0575 (9)	0.0621 (9)	0.0071 (7)	0.0272 (8)	−0.0035 (7)
C21	0.0978 (19)	0.0627 (13)	0.0983 (18)	−0.0005 (13)	0.0377 (15)	−0.0068 (12)
C22	0.119 (2)	0.0746 (15)	0.1017 (19)	0.0139 (15)	0.0724 (17)	0.0053 (13)
Cl1	0.1033 (5)	0.0785 (4)	0.0739 (4)	0.0039 (3)	0.0250 (3)	−0.0389 (3)

Geometric parameters (Å, º)

C1—C2	1.374 (3)	C13—C14	1.493 (2)
C1—C15	1.379 (2)	C14—C15	1.398 (2)
C1—Cl1	1.7379 (18)	C15—H15	0.9300
C2—C3	1.376 (2)	N16—C17	1.450 (2)
C2—H2	0.9300	N16—H16	0.82 (2)
C3—C4	1.400 (2)	C17—C18	1.512 (3)
C3—H3	0.9300	C17—H171	0.9700
C4—C14	1.394 (2)	C17—H172	0.9700
C4—N5	1.407 (2)	C18—C19	1.498 (3)
N5—C6	1.4127 (19)	C18—H181	0.9700
N5—H5	0.87 (2)	C18—H182	0.9700
C6—N7	1.330 (2)	C19—N20	1.474 (3)
C6—C11	1.400 (2)	C19—H191	0.9700
N7—C8	1.342 (2)	C19—H192	0.9700
C8—C9	1.363 (3)	N20—C21	1.440 (3)
C8—H8	0.9300	N20—C22	1.459 (3)
C9—C10	1.384 (3)	C21—H211	0.9600
C9—H9	0.9300	C21—H212	0.9600
C10—C11	1.388 (2)	C21—H213	0.9600
C10—H10	0.9300	C22—H221	0.9600
C11—N12	1.407 (2)	C22—H222	0.9600
N12—C13	1.2945 (19)	C22—H223	0.9600
C13—N16	1.345 (2)
C2—C1—C15	120.71 (16)	C1—C15—H15	119.6
C2—C1—Cl1	120.17 (14)	C14—C15—H15	119.6
C15—C1—Cl1	119.10 (15)	C13—N16—C17	124.69 (15)
C1—C2—C3	119.30 (16)	C13—N16—H16	119.0 (15)
C1—C2—H2	120.3	C17—N16—H16	114.4 (15)
C3—C2—H2	120.3	N16—C17—C18	110.11 (16)
C2—C3—C4	121.15 (17)	N16—C17—H171	109.6
C2—C3—H3	119.4	C18—C17—H171	109.6
C4—C3—H3	119.4	N16—C17—H172	109.6
C14—C4—C3	119.37 (14)	C18—C17—H172	109.6
C14—C4—N5	121.58 (14)	H171—C17—H172	108.2
C3—C4—N5	118.99 (15)	C19—C18—C17	115.69 (19)
C4—N5—C6	119.04 (13)	C19—C18—H181	108.4
C4—N5—H5	113.3 (13)	C17—C18—H181	108.4
C6—N5—H5	111.1 (13)	C19—C18—H182	108.4
N7—C6—C11	123.86 (14)	C17—C18—H182	108.4
N7—C6—N5	114.36 (14)	H181—C18—H182	107.4
C11—C6—N5	121.70 (14)	N20—C19—C18	114.33 (18)
C6—N7—C8	117.74 (15)	N20—C19—H191	108.7
N7—C8—C9	123.29 (18)	C18—C19—H191	108.7
N7—C8—H8	118.4	N20—C19—H192	108.7
C9—C8—H8	118.4	C18—C19—H192	108.7
C8—C9—C10	118.32 (16)	H191—C19—H192	107.6
C8—C9—H9	120.8	C21—N20—C22	109.25 (19)
C10—C9—H9	120.8	C21—N20—C19	113.98 (19)
C9—C10—C11	120.50 (17)	C22—N20—C19	108.4 (2)
C9—C10—H10	119.8	N20—C21—H211	109.5
C11—C10—H10	119.8	N20—C21—H212	109.5
C10—C11—C6	116.17 (15)	H211—C21—H212	109.5
C10—C11—N12	117.74 (15)	N20—C21—H213	109.5
C6—C11—N12	125.48 (14)	H211—C21—H213	109.5
C13—N12—C11	123.16 (13)	H212—C21—H213	109.5
N12—C13—N16	119.18 (15)	N20—C22—H221	109.5
N12—C13—C14	127.69 (14)	N20—C22—H222	109.5
N16—C13—C14	113.11 (14)	H221—C22—H222	109.5
C4—C14—C15	118.67 (15)	N20—C22—H223	109.5
C4—C14—C13	122.09 (14)	H221—C22—H223	109.5
C15—C14—C13	118.90 (15)	H222—C22—H223	109.5
C1—C15—C14	120.76 (17)
C15—C1—C2—C3	−1.3 (3)	C11—N12—C13—N16	−179.23 (15)
Cl1—C1—C2—C3	−179.89 (15)	C11—N12—C13—C14	−1.0 (3)
C1—C2—C3—C4	0.9 (3)	C3—C4—C14—C15	−1.9 (2)
C2—C3—C4—C14	0.7 (2)	N5—C4—C14—C15	−178.96 (14)
C2—C3—C4—N5	177.87 (16)	C3—C4—C14—C13	171.37 (14)
C14—C4—N5—C6	−53.9 (2)	N5—C4—C14—C13	−5.7 (2)
C3—C4—N5—C6	129.06 (17)	N12—C13—C14—C4	39.8 (2)
C4—N5—C6—N7	−129.63 (16)	N16—C13—C14—C4	−141.95 (16)
C4—N5—C6—C11	53.3 (2)	N12—C13—C14—C15	−147.01 (17)
C11—C6—N7—C8	−2.2 (3)	N16—C13—C14—C15	31.3 (2)
N5—C6—N7—C8	−179.15 (16)	C2—C1—C15—C14	0.1 (3)
C6—N7—C8—C9	−1.2 (3)	Cl1—C1—C15—C14	178.71 (13)
N7—C8—C9—C10	2.7 (3)	C4—C14—C15—C1	1.5 (2)
C8—C9—C10—C11	−0.8 (3)	C13—C14—C15—C1	−171.99 (16)
C9—C10—C11—C6	−2.2 (2)	N12—C13—N16—C17	−3.2 (3)
C9—C10—C11—N12	169.30 (16)	C14—C13—N16—C17	178.33 (17)
N7—C6—C11—C10	3.8 (2)	C13—N16—C17—C18	168.89 (18)
N5—C6—C11—C10	−179.43 (15)	N16—C17—C18—C19	51.8 (3)
N7—C6—C11—N12	−166.90 (15)	C17—C18—C19—N20	−68.2 (3)
N5—C6—C11—N12	9.8 (2)	C18—C19—N20—C21	−71.8 (2)
C10—C11—N12—C13	148.91 (16)	C18—C19—N20—C22	166.35 (19)
C6—C11—N12—C13	−40.5 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N5—H5···N12^i	0.87 (2)	2.49 (2)	3.332 (2)	162.9 (17)
N16—H16···N20	0.82 (2)	2.08 (2)	2.787 (2)	145 (2)

Symmetry code: (i) x−1/2, −y+1/2, z−1/2.