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Mol­ecules of the title compound, C18H20N2O3, are linked into ribbons by N—H...O and N—H...N hydrogen bonds. Stereochemical comparison with Ro 15-1788 (viz. eth­yl 8-fluoro-5,6-dihydro-5-meth­yl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxyl­ate) has identified three electronegative N and O atoms in the mol­ecule as features likely to be responsible for its activity as a benzodiazepine-receptor antagonist.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270105005457/gd1376sup1.cif
Contains datablocks I, global

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S0108270105005457/gd1376Isup2.hkl
Contains datablock I

CCDC reference: 269053

Comment top

The title compound, (I), is a member of the β-carbolines, a class of compounds that bind to the benzodiazepine receptor (BDZR) and elicit a wide range of neurological effects, i.e. agonist (anxiolytic, sedative and anticonvulsant), antagonist and inverse agonist (anxiogenic and convulsant) activities (Braestrup & Nielsen, 1993). Compound (I) (ZK 93426) was reported to bind with high affinity to benzodiazepine receptors and act as a BDZR antagonist (Jensen et al., 1984). The structure of ZK 93426 is presented in Fig. 1. Bond distances and angles in the molecule are consistent with normal values. The 13-atom ring system shows a slightly bowed configuration, with a maximum deviation of 0.11 (s.u.?) Å for atom?, significantly higher than in the more planar systems found in other reported β-carboline crystal structures (Bertolasi et al., 1984; Kubicki & Codding, 2001). The two O atoms of the ethyl carboxylate moiety are not coplanar with the tricyclic system, with atoms O2 and O3 lying 1.12 and −0.5 Å out of the mean plane, in contrast to the situation in the previously reported structures. Atoms O1 and C9 of the isopropoxy group deviate from the plane of the tricyclic system by 0.2 and 0.3 Å respectively.

Like in other β-carboline carboxylate structures, the H atom at atom N9 in (I) forms two (bifurcated) hydrogen bonds, one with the carbonyl O atom and another with atom N2 of a symmetry-related molecule (Table 1). The crystal packing is presented in Fig. 2. The hydrogen-bonded molecules form infinite ribbons running parallel to the c axis, with van der Waals interactions between them.

We have compared (Fig. 3) the structure of ZK 93426 with that of Ro 15–1788, (II) (ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylate; Hempel et al., 1987), a chemically different BDZR antagonist, in order to correlate pharmacological properties with stereochemical features. The structures were superposed by maximizing the fit of four atoms in each (N2, O2, O1 and C5 in ZK 93426, with similar functions in Ro 15–1788). No bond rotations or other molecular alterations were performed. As is evident from the superposition, hydrophobic portions of both structures occupy similar regions in space, and three electronegative N and O atoms in each molecule superpose closely. The results are persuasive that these common features are the likely determinants for the common pharmacological activity of these compounds.

Experimental top

The title compound was crystallized from a methanol–benzene mixture. Compound (I) was warmed first in methanol to dissolve all of the powder, and benzene was added until slight cloudiness appeared; the mixture was then filtered through a glass frit and allowed to stand in a covered beaker. White hexagonal needle-shaped [prism below?] crystals grew in about 5 d.

Refinement top

Since all H atoms were refined independently, it is not surprising that some heavy-atom–hydrogen geometrical parameters may differ slightly from standard values [C—H = 0.94 (3)–1.05 (2) Å].

Computing details top

Data collection: CAD-4 Software (Enraf–Nonius, 1989); cell refinement: CAD-4 Software; data reduction: DATRDN The X-ray System, (Stewart, 1976); program(s) used to solve structure: MULTAN80 (Main et al., 1980); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997); software used to prepare material for publication: SHELXL97.

Figures top
[Figure 1] Fig. 1. The molecular structure of ZK 93426, showing 50% probability displacement ellipsoids. H atoms are drawn as small circles of arbitrary radii.
[Figure 2] Fig. 2. A stereoview of the molecular packing and hydrogen-bond scheme. All atoms are drawn as spheres of arbitrary radii. Only the H atoms involved in hydrogen bonds are shown.
[Figure 3] Fig. 3. The superposition of ZK 93426 (large circles, filled bonds) with Ro 15–1788.
Ethyl 5-isopropoxy-4-methyl-β-carboline-3-carboxylate top
Crystal data top
C18H20N2O3F(000) = 664
Mr = 312.36Dx = 1.308 Mg m3
Monoclinic, P21/cMo Kα radiation, λ = 0.71073 Å
a = 8.5190 (9) ÅCell parameters from 32 reflections
b = 16.2110 (15) Åθ = 10–22°
c = 11.862 (2) ŵ = 0.09 mm1
β = 104.46 (2)°T = 294 K
V = 1586.3 (4) Å3Prism, white
Z = 40.50 × 0.30 × 0.25 mm
Data collection top
Enraf–Nonius CAD-4
diffractometer
Rint = 0.000
Radiation source: fine-focus sealed tubeθmax = 25.0°, θmin = 2.2°
Graphite monochromatorh = 109
ω /2θ scansk = 019
2777 measured reflectionsl = 014
2777 independent reflections3 standard reflections every 100 reflections
2135 reflections with I > 2σ(I) intensity decay: 1%
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)] = 0.039Hydrogen site location: difference Fourier map
wR(F2) = 0.107All H-atom parameters refined
S = 1.01 w = 1/[σ2(Fo2) + (0.0451P)2 + 0.3655P]
where P = (Fo2 + 2Fc2)/3
2777 reflections(Δ/σ)max = 0.002
288 parametersΔρmax = 0.24 e Å3
0 restraintsΔρmin = 0.19 e Å3
Crystal data top
C18H20N2O3V = 1586.3 (4) Å3
Mr = 312.36Z = 4
Monoclinic, P21/cMo Kα radiation
a = 8.5190 (9) ŵ = 0.09 mm1
b = 16.2110 (15) ÅT = 294 K
c = 11.862 (2) Å0.50 × 0.30 × 0.25 mm
β = 104.46 (2)°
Data collection top
Enraf–Nonius CAD-4
diffractometer
Rint = 0.000
2777 measured reflections3 standard reflections every 100 reflections
2777 independent reflections intensity decay: 1%
2135 reflections with I > 2σ(I)
Refinement top
R[F2 > 2σ(F2)] = 0.0390 restraints
wR(F2) = 0.107All H-atom parameters refined
S = 1.01Δρmax = 0.24 e Å3
2777 reflectionsΔρmin = 0.19 e Å3
288 parameters
Special details top

Experimental. There were no reflections above background at angles higher than θ = 24.97°

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 (Å2) top
xyzUiso*/Ueq
C10.6498 (2)0.21411 (11)0.49394 (17)0.0528 (5)
C100.7388 (4)0.21408 (17)0.2541 (2)0.0764 (7)
C110.8882 (3)0.22835 (14)0.4631 (2)0.0628 (6)
C120.7451 (3)0.03996 (11)0.58904 (18)0.0475 (4)
C130.6586 (2)0.09037 (10)0.74506 (15)0.0456 (4)
C140.5658 (3)0.00089 (12)0.87194 (16)0.0523 (5)
C150.6280 (4)0.08641 (15)0.8955 (2)0.0687 (6)
C1A0.6988 (2)0.16165 (10)0.41721 (15)0.0424 (4)
C30.6691 (2)0.10716 (10)0.62352 (15)0.0428 (4)
C40.71324 (19)0.04818 (9)0.55135 (13)0.0373 (4)
C4A0.73351 (19)0.07764 (9)0.44350 (13)0.0375 (4)
C4B0.79049 (19)0.04506 (10)0.34598 (14)0.0382 (4)
C50.8418 (2)0.03229 (10)0.31260 (14)0.0416 (4)
C60.8980 (2)0.03733 (12)0.21282 (16)0.0506 (5)
C70.9000 (2)0.03217 (13)0.14373 (17)0.0558 (5)
C80.8450 (2)0.10704 (12)0.16920 (16)0.0523 (5)
C8B0.7903 (2)0.11227 (10)0.27037 (14)0.0435 (4)
C90.8712 (2)0.17976 (11)0.35241 (17)0.0511 (5)
N20.6396 (2)0.18814 (8)0.59746 (13)0.0527 (4)
N90.73122 (19)0.18096 (9)0.31324 (13)0.0485 (4)
O10.83126 (17)0.09749 (7)0.38157 (11)0.0533 (3)
O20.7162 (3)0.13545 (9)0.82477 (13)0.0911 (6)
O30.57885 (16)0.02307 (8)0.75695 (10)0.0559 (4)
H10.624 (2)0.2695 (13)0.4752 (16)0.054 (5)*
H100.977 (2)0.1771 (11)0.3318 (17)0.057 (5)*
H10A0.721 (3)0.1802 (16)0.185 (2)0.090 (8)*
H10B0.773 (3)0.266 (2)0.235 (2)0.110 (10)*
H10C0.630 (4)0.2174 (17)0.279 (2)0.113 (10)*
H11A0.784 (3)0.2314 (13)0.4842 (18)0.069 (6)*
H11B0.962 (3)0.2019 (15)0.528 (2)0.082 (7)*
H11C0.919 (3)0.2860 (16)0.4506 (19)0.081 (7)*
H12A0.843 (3)0.0582 (13)0.5718 (19)0.070 (6)*
H12B0.767 (3)0.0479 (15)0.672 (2)0.086 (7)*
H12C0.662 (3)0.0754 (16)0.550 (2)0.094 (8)*
H14A0.442 (3)0.0039 (12)0.8691 (17)0.063 (6)*
H14B0.626 (2)0.0377 (13)0.9284 (19)0.064 (6)*
H15A0.747 (3)0.0892 (16)0.894 (2)0.096 (8)*
H15B0.567 (3)0.1247 (15)0.834 (2)0.083 (7)*
H15C0.622 (3)0.1040 (16)0.975 (2)0.093 (8)*
H60.941 (2)0.0896 (12)0.1910 (16)0.050 (5)*
H70.943 (2)0.0277 (12)0.0734 (18)0.059 (5)*
H80.844 (2)0.1561 (13)0.1207 (18)0.062 (6)*
H90.717 (2)0.2282 (13)0.2815 (17)0.055 (6)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0715 (12)0.0313 (9)0.0582 (12)0.0059 (8)0.0210 (10)0.0032 (8)
C100.110 (2)0.0596 (14)0.0592 (14)0.0152 (14)0.0196 (14)0.0109 (12)
C110.0738 (15)0.0445 (11)0.0691 (15)0.0044 (10)0.0162 (12)0.0026 (10)
C120.0679 (13)0.0364 (9)0.0424 (10)0.0063 (9)0.0215 (9)0.0029 (8)
C130.0611 (11)0.0347 (9)0.0448 (10)0.0009 (8)0.0202 (8)0.0073 (7)
C140.0688 (13)0.0532 (11)0.0382 (10)0.0071 (10)0.0195 (9)0.0024 (8)
C150.0861 (17)0.0633 (14)0.0586 (14)0.0098 (12)0.0219 (12)0.0049 (11)
C1A0.0496 (9)0.0365 (9)0.0411 (9)0.0019 (7)0.0111 (7)0.0012 (7)
C30.0519 (10)0.0347 (9)0.0443 (10)0.0012 (7)0.0164 (8)0.0027 (7)
C40.0412 (9)0.0337 (8)0.0370 (9)0.0029 (6)0.0096 (7)0.0030 (6)
C4A0.0405 (9)0.0336 (8)0.0380 (9)0.0028 (7)0.0089 (7)0.0024 (6)
C4B0.0404 (8)0.0389 (9)0.0351 (8)0.0045 (7)0.0088 (7)0.0000 (7)
C50.0460 (9)0.0410 (9)0.0378 (9)0.0029 (7)0.0104 (7)0.0024 (7)
C60.0560 (11)0.0534 (11)0.0464 (10)0.0004 (9)0.0204 (8)0.0057 (8)
C70.0595 (12)0.0694 (13)0.0438 (10)0.0075 (10)0.0230 (9)0.0008 (9)
C80.0605 (11)0.0557 (11)0.0432 (10)0.0061 (9)0.0179 (8)0.0079 (9)
C8B0.0476 (10)0.0430 (9)0.0391 (9)0.0061 (7)0.0095 (7)0.0031 (7)
C90.0614 (12)0.0381 (9)0.0588 (11)0.0040 (8)0.0244 (9)0.0062 (8)
N20.0737 (10)0.0359 (8)0.0534 (9)0.0051 (7)0.0254 (8)0.0018 (7)
N90.0662 (10)0.0350 (8)0.0448 (9)0.0003 (7)0.0147 (7)0.0073 (7)
O10.0814 (9)0.0357 (6)0.0492 (7)0.0037 (6)0.0285 (7)0.0025 (5)
O20.1681 (18)0.0595 (9)0.0555 (9)0.0426 (10)0.0458 (10)0.0233 (7)
O30.0729 (9)0.0596 (8)0.0379 (7)0.0212 (7)0.0187 (6)0.0064 (6)
Geometric parameters (Å, º) top
N9—C1A1.366 (2)O1—C91.440 (2)
N9—C8B1.371 (2)C9—C111.507 (3)
N9—H90.85 (2)C9—C101.511 (3)
C8B—C81.394 (3)C9—H100.99 (2)
C8B—C4B1.411 (2)C10—H10A0.97 (3)
C8—C71.362 (3)C10—H10B0.94 (3)
C8—H80.98 (2)C10—H10C1.04 (3)
C7—C61.396 (3)C11—H11A0.99 (2)
C7—H71.00 (2)C11—H11B0.97 (3)
C6—C51.386 (2)C11—H11C0.99 (2)
C6—H60.982 (19)C12—H12A0.96 (2)
C5—O11.353 (2)C12—H12B0.96 (3)
C5—C4B1.416 (2)C12—H12C0.94 (3)
C4B—C4A1.461 (2)C13—O21.199 (2)
C4A—C1A1.412 (2)C13—O31.311 (2)
C4A—C41.416 (2)O3—C141.449 (2)
C4—C31.396 (2)C14—C151.485 (3)
C4—C121.502 (2)C14—H14A1.05 (2)
C3—N21.358 (2)C14—H14B0.96 (2)
C3—C131.492 (2)C15—H15A1.02 (3)
N2—C11.321 (2)C15—H15B1.00 (3)
C1—C1A1.384 (2)C15—H15C1.00 (3)
C1—H10.94 (2)
C1A—N9—C8B108.94 (14)O1—C9—C10110.52 (18)
C1A—N9—H9124.7 (13)C11—C9—C10111.74 (19)
C8B—N9—H9126.4 (13)O1—C9—H10107.7 (11)
N9—C8B—C8126.96 (16)C11—C9—H10110.0 (11)
N9—C8B—C4B109.49 (15)C10—C9—H10112.0 (11)
C8—C8B—C4B123.55 (16)C9—C10—H10A111.9 (15)
C7—C8—C8B116.91 (17)C9—C10—H10B107.6 (18)
C7—C8—H8123.1 (12)H10A—C10—H10B107 (2)
C8B—C8—H8120.0 (12)C9—C10—H10C110.0 (16)
C8—C7—C6122.26 (18)H10A—C10—H10C108 (2)
C8—C7—H7118.1 (11)H10B—C10—H10C112 (2)
C6—C7—H7119.6 (11)C9—C11—H11A110.6 (13)
C5—C6—C7120.76 (18)C9—C11—H11B111.5 (14)
C5—C6—H6120.4 (11)H11A—C11—H11B105.7 (19)
C7—C6—H6118.8 (11)C9—C11—H11C109.5 (13)
O1—C5—C6124.02 (15)H11A—C11—H11C106.2 (18)
O1—C5—C4B116.80 (14)H11B—C11—H11C113.1 (19)
C6—C5—C4B119.18 (16)C4—C12—H12A109.5 (13)
C8B—C4B—C5117.22 (15)C4—C12—H12B113.9 (14)
C8B—C4B—C4A106.04 (14)H12A—C12—H12B102.8 (18)
C5—C4B—C4A136.74 (15)C4—C12—H12C112.2 (16)
C1A—C4A—C4117.32 (14)H12A—C12—H12C107 (2)
C1A—C4A—C4B105.46 (13)H12B—C12—H12C111 (2)
C4—C4A—C4B137.16 (15)O2—C13—O3122.90 (17)
C3—C4—C4A115.80 (14)O2—C13—C3122.67 (16)
C3—C4—C12121.70 (15)O3—C13—C3114.42 (14)
C4A—C4—C12122.43 (15)C13—O3—C14119.20 (14)
N2—C3—C4125.82 (15)O3—C14—C15108.67 (17)
N2—C3—C13110.15 (14)O3—C14—H14A105.2 (11)
C4—C3—C13123.91 (15)C15—C14—H14A112.6 (11)
C1—N2—C3117.95 (15)O3—C14—H14B109.1 (12)
N2—C1—C1A121.05 (16)C15—C14—H14B111.8 (12)
N2—C1—H1117.4 (11)H14A—C14—H14B109.2 (16)
C1A—C1—H1121.6 (12)C14—C15—H15A110.3 (15)
N9—C1A—C1127.97 (16)C14—C15—H15B110.2 (14)
N9—C1A—C4A110.01 (15)H15A—C15—H15B107 (2)
C1—C1A—C4A121.89 (16)C14—C15—H15C110.3 (15)
C5—O1—C9121.53 (14)H15A—C15—H15C107 (2)
O1—C9—C11104.58 (15)H15B—C15—H15C112 (2)
C1A—N9—C8B—C8176.75 (17)C12—C4—C3—N2179.27 (18)
C1A—N9—C8B—C4B2.4 (2)C4A—C4—C3—C13173.41 (15)
N9—C8B—C8—C7179.50 (18)C12—C4—C3—C133.7 (3)
C4B—C8B—C8—C70.4 (3)C4—C3—N2—C11.6 (3)
C8B—C8—C7—C61.9 (3)C13—C3—N2—C1177.69 (17)
C8—C7—C6—C51.2 (3)C3—N2—C1—C1A4.0 (3)
C7—C6—C5—O1177.73 (17)C8B—N9—C1A—C1174.50 (18)
C7—C6—C5—C4B1.9 (3)C8B—N9—C1A—C4A1.3 (2)
N9—C8B—C4B—C5177.46 (14)N2—C1—C1A—N9172.66 (18)
C8—C8B—C4B—C53.3 (3)N2—C1—C1A—C4A2.7 (3)
N9—C8B—C4B—C4A2.55 (18)C4—C4A—C1A—N9177.30 (14)
C8—C8B—C4B—C4A176.69 (16)C4B—C4A—C1A—N90.26 (18)
O1—C5—C4B—C8B175.69 (14)C4—C4A—C1A—C11.2 (2)
C6—C5—C4B—C8B3.9 (2)C4B—C4A—C1A—C1176.39 (16)
O1—C5—C4B—C4A4.3 (3)C6—C5—O1—C93.2 (3)
C6—C5—C4B—C4A176.07 (18)C4B—C5—O1—C9176.40 (15)
C8B—C4B—C4A—C1A1.68 (17)C5—O1—C9—C11165.06 (17)
C5—C4B—C4A—C1A178.33 (19)C5—O1—C9—C1074.5 (2)
C8B—C4B—C4A—C4175.13 (18)N2—C3—C13—O242.8 (3)
C5—C4B—C4A—C44.9 (3)C4—C3—C13—O2133.4 (2)
C1A—C4A—C4—C33.4 (2)N2—C3—C13—O3136.04 (16)
C4B—C4A—C4—C3173.17 (17)C4—C3—C13—O347.8 (2)
C1A—C4A—C4—C12179.59 (16)O2—C13—O3—C143.3 (3)
C4B—C4A—C4—C123.9 (3)C3—C13—O3—C14177.89 (15)
C4A—C4—C3—N22.2 (3)C13—O3—C14—C15124.7 (2)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N9—H9···O2i0.85 (2)2.27 (2)2.984 (2)141.9 (17)
N9—H9···N2i0.85 (2)2.51 (2)3.266 (2)148.2 (17)
Symmetry code: (i) x, y+1/2, z1/2.

Experimental details

Crystal data
Chemical formulaC18H20N2O3
Mr312.36
Crystal system, space groupMonoclinic, P21/c
Temperature (K)294
a, b, c (Å)8.5190 (9), 16.2110 (15), 11.862 (2)
β (°) 104.46 (2)
V3)1586.3 (4)
Z4
Radiation typeMo Kα
µ (mm1)0.09
Crystal size (mm)0.50 × 0.30 × 0.25
Data collection
DiffractometerEnraf–Nonius CAD-4
diffractometer
Absorption correction
No. of measured, independent and
observed [I > 2σ(I)] reflections
2777, 2777, 2135
Rint0.000
(sin θ/λ)max1)0.595
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.039, 0.107, 1.01
No. of reflections2777
No. of parameters288
H-atom treatmentAll H-atom parameters refined
Δρmax, Δρmin (e Å3)0.24, 0.19

Computer programs: CAD-4 Software (Enraf–Nonius, 1989), CAD-4 Software, DATRDN The X-ray System, (Stewart, 1976), MULTAN80 (Main et al., 1980), SHELXL97 (Sheldrick, 1997), ORTEP-3 for Windows (Farrugia, 1997), SHELXL97.

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N9—H9···O2i0.85 (2)2.27 (2)2.984 (2)141.9 (17)
N9—H9···N2i0.85 (2)2.51 (2)3.266 (2)148.2 (17)
Symmetry code: (i) x, y+1/2, z1/2.
 

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