Eth­yl 5-isoprop­oxy-4-meth­yl-β-carboline-3-carboxyl­ate: structural determinants of benzodiazepine-receptor antagonism

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.

S1. Comment

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.

S2. Experimental

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.

S3. Refinement

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

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

	Fig. 1. The molecular structure of ZK 93426, showing 50% probability displacement ellipsoids. H atoms are drawn as small circles of arbitrary radii.
	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.
	Fig. 3. The superposition of ZK 93426 (large circles, filled bonds) with Ro 15–1788.

Ethyl 5-isopropoxy-4-methyl-β-carboline-3-carboxylate

Crystal data

C18H20N2O3	F(000) = 664
Mr = 312.36	Dx = 1.308 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
a = 8.5190 (9) Å	Cell parameters from 32 reflections
b = 16.2110 (15) Å	θ = 10–22°
c = 11.862 (2) Å	µ = 0.09 mm^−1
β = 104.46 (2)°	T = 294 K
V = 1586.3 (4) Å^3	Prism, white
Z = 4	0.50 × 0.30 × 0.25 mm

Data collection

Enraf–Nonius CAD-4 diffractometer	Rint = 0.000
Radiation source: fine-focus sealed tube	θmax = 25.0°, θmin = 2.2°
Graphite monochromator	h = −10→9
ω /2θ scans	k = 0→19
2777 measured reflections	l = 0→14
2777 independent reflections	3 standard reflections every 100 reflections
2135 reflections with I > 2σ(I)	intensity decay: 1%

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)] = 0.039	Hydrogen site location: difference Fourier map
wR(F^2) = 0.107	All H-atom parameters refined
S = 1.01	w = 1/[σ^2(Fo^2) + (0.0451P)^2 + 0.3655P] where P = (Fo^2 + 2Fc^2)/3
2777 reflections	(Δ/σ)max = 0.002
288 parameters	Δρmax = 0.24 e Å^−3
0 restraints	Δρmin = −0.19 e Å^−3

Special details

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 (Ų)

	x	y	z	Uiso*/Ueq
C1	0.6498 (2)	0.21411 (11)	0.49394 (17)	0.0528 (5)
C10	0.7388 (4)	−0.21408 (17)	0.2541 (2)	0.0764 (7)
C11	0.8882 (3)	−0.22835 (14)	0.4631 (2)	0.0628 (6)
C12	0.7451 (3)	−0.03996 (11)	0.58904 (18)	0.0475 (4)
C13	0.6586 (2)	0.09037 (10)	0.74506 (15)	0.0456 (4)
C14	0.5658 (3)	−0.00089 (12)	0.87194 (16)	0.0523 (5)
C15	0.6280 (4)	−0.08641 (15)	0.8955 (2)	0.0687 (6)
C1A	0.6988 (2)	0.16165 (10)	0.41721 (15)	0.0424 (4)
C3	0.6691 (2)	0.10716 (10)	0.62352 (15)	0.0428 (4)
C4	0.71324 (19)	0.04818 (9)	0.55135 (13)	0.0373 (4)
C4A	0.73351 (19)	0.07764 (9)	0.44350 (13)	0.0375 (4)
C4B	0.79049 (19)	0.04506 (10)	0.34598 (14)	0.0382 (4)
C5	0.8418 (2)	−0.03229 (10)	0.31260 (14)	0.0416 (4)
C6	0.8980 (2)	−0.03733 (12)	0.21282 (16)	0.0506 (5)
C7	0.9000 (2)	0.03217 (13)	0.14373 (17)	0.0558 (5)
C8	0.8450 (2)	0.10704 (12)	0.16920 (16)	0.0523 (5)
C8B	0.7903 (2)	0.11227 (10)	0.27037 (14)	0.0435 (4)
C9	0.8712 (2)	−0.17976 (11)	0.35241 (17)	0.0511 (5)
N2	0.6396 (2)	0.18814 (8)	0.59746 (13)	0.0527 (4)
N9	0.73122 (19)	0.18096 (9)	0.31324 (13)	0.0485 (4)
O1	0.83126 (17)	−0.09749 (7)	0.38157 (11)	0.0533 (3)
O2	0.7162 (3)	0.13545 (9)	0.82477 (13)	0.0911 (6)
O3	0.57885 (16)	0.02307 (8)	0.75695 (10)	0.0559 (4)
H1	0.624 (2)	0.2695 (13)	0.4752 (16)	0.054 (5)*
H10	0.977 (2)	−0.1771 (11)	0.3318 (17)	0.057 (5)*
H10A	0.721 (3)	−0.1802 (16)	0.185 (2)	0.090 (8)*
H10B	0.773 (3)	−0.266 (2)	0.235 (2)	0.110 (10)*
H10C	0.630 (4)	−0.2174 (17)	0.279 (2)	0.113 (10)*
H11A	0.784 (3)	−0.2314 (13)	0.4842 (18)	0.069 (6)*
H11B	0.962 (3)	−0.2019 (15)	0.528 (2)	0.082 (7)*
H11C	0.919 (3)	−0.2860 (16)	0.4506 (19)	0.081 (7)*
H12A	0.843 (3)	−0.0582 (13)	0.5718 (19)	0.070 (6)*
H12B	0.767 (3)	−0.0479 (15)	0.672 (2)	0.086 (7)*
H12C	0.662 (3)	−0.0754 (16)	0.550 (2)	0.094 (8)*
H14A	0.442 (3)	0.0039 (12)	0.8691 (17)	0.063 (6)*
H14B	0.626 (2)	0.0377 (13)	0.9284 (19)	0.064 (6)*
H15A	0.747 (3)	−0.0892 (16)	0.894 (2)	0.096 (8)*
H15B	0.567 (3)	−0.1247 (15)	0.834 (2)	0.083 (7)*
H15C	0.622 (3)	−0.1040 (16)	0.975 (2)	0.093 (8)*
H6	0.941 (2)	−0.0896 (12)	0.1910 (16)	0.050 (5)*
H7	0.943 (2)	0.0277 (12)	0.0734 (18)	0.059 (5)*
H8	0.844 (2)	0.1561 (13)	0.1207 (18)	0.062 (6)*
H9	0.717 (2)	0.2282 (13)	0.2815 (17)	0.055 (6)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0715 (12)	0.0313 (9)	0.0582 (12)	0.0059 (8)	0.0210 (10)	0.0032 (8)
C10	0.110 (2)	0.0596 (14)	0.0592 (14)	−0.0152 (14)	0.0196 (14)	−0.0109 (12)
C11	0.0738 (15)	0.0445 (11)	0.0691 (15)	0.0044 (10)	0.0162 (12)	0.0026 (10)
C12	0.0679 (13)	0.0364 (9)	0.0424 (10)	0.0063 (9)	0.0215 (9)	0.0029 (8)
C13	0.0611 (11)	0.0347 (9)	0.0448 (10)	0.0009 (8)	0.0202 (8)	−0.0073 (7)
C14	0.0688 (13)	0.0532 (11)	0.0382 (10)	−0.0071 (10)	0.0195 (9)	−0.0024 (8)
C15	0.0861 (17)	0.0633 (14)	0.0586 (14)	0.0098 (12)	0.0219 (12)	0.0049 (11)
C1A	0.0496 (9)	0.0365 (9)	0.0411 (9)	−0.0019 (7)	0.0111 (7)	0.0012 (7)
C3	0.0519 (10)	0.0347 (9)	0.0443 (10)	−0.0012 (7)	0.0164 (8)	−0.0027 (7)
C4	0.0412 (9)	0.0337 (8)	0.0370 (9)	−0.0029 (6)	0.0096 (7)	−0.0030 (6)
C4A	0.0405 (9)	0.0336 (8)	0.0380 (9)	−0.0028 (7)	0.0089 (7)	−0.0024 (6)
C4B	0.0404 (8)	0.0389 (9)	0.0351 (8)	−0.0045 (7)	0.0088 (7)	0.0000 (7)
C5	0.0460 (9)	0.0410 (9)	0.0378 (9)	−0.0029 (7)	0.0104 (7)	−0.0024 (7)
C6	0.0560 (11)	0.0534 (11)	0.0464 (10)	−0.0004 (9)	0.0204 (8)	−0.0057 (8)
C7	0.0595 (12)	0.0694 (13)	0.0438 (10)	−0.0075 (10)	0.0230 (9)	−0.0008 (9)
C8	0.0605 (11)	0.0557 (11)	0.0432 (10)	−0.0061 (9)	0.0179 (8)	0.0079 (9)
C8B	0.0476 (10)	0.0430 (9)	0.0391 (9)	−0.0061 (7)	0.0095 (7)	0.0031 (7)
C9	0.0614 (12)	0.0381 (9)	0.0588 (11)	0.0040 (8)	0.0244 (9)	−0.0062 (8)
N2	0.0737 (10)	0.0359 (8)	0.0534 (9)	0.0051 (7)	0.0254 (8)	−0.0018 (7)
N9	0.0662 (10)	0.0350 (8)	0.0448 (9)	0.0003 (7)	0.0147 (7)	0.0073 (7)
O1	0.0814 (9)	0.0357 (6)	0.0492 (7)	0.0037 (6)	0.0285 (7)	−0.0025 (5)
O2	0.1681 (18)	0.0595 (9)	0.0555 (9)	−0.0426 (10)	0.0458 (10)	−0.0233 (7)
O3	0.0729 (9)	0.0596 (8)	0.0379 (7)	−0.0212 (7)	0.0187 (6)	−0.0064 (6)

Geometric parameters (Å, º)

N9—C1A	1.366 (2)	O1—C9	1.440 (2)
N9—C8B	1.371 (2)	C9—C11	1.507 (3)
N9—H9	0.85 (2)	C9—C10	1.511 (3)
C8B—C8	1.394 (3)	C9—H10	0.99 (2)
C8B—C4B	1.411 (2)	C10—H10A	0.97 (3)
C8—C7	1.362 (3)	C10—H10B	0.94 (3)
C8—H8	0.98 (2)	C10—H10C	1.04 (3)
C7—C6	1.396 (3)	C11—H11A	0.99 (2)
C7—H7	1.00 (2)	C11—H11B	0.97 (3)
C6—C5	1.386 (2)	C11—H11C	0.99 (2)
C6—H6	0.982 (19)	C12—H12A	0.96 (2)
C5—O1	1.353 (2)	C12—H12B	0.96 (3)
C5—C4B	1.416 (2)	C12—H12C	0.94 (3)
C4B—C4A	1.461 (2)	C13—O2	1.199 (2)
C4A—C1A	1.412 (2)	C13—O3	1.311 (2)
C4A—C4	1.416 (2)	O3—C14	1.449 (2)
C4—C3	1.396 (2)	C14—C15	1.485 (3)
C4—C12	1.502 (2)	C14—H14A	1.05 (2)
C3—N2	1.358 (2)	C14—H14B	0.96 (2)
C3—C13	1.492 (2)	C15—H15A	1.02 (3)
N2—C1	1.321 (2)	C15—H15B	1.00 (3)
C1—C1A	1.384 (2)	C15—H15C	1.00 (3)
C1—H1	0.94 (2)
C1A—N9—C8B	108.94 (14)	O1—C9—C10	110.52 (18)
C1A—N9—H9	124.7 (13)	C11—C9—C10	111.74 (19)
C8B—N9—H9	126.4 (13)	O1—C9—H10	107.7 (11)
N9—C8B—C8	126.96 (16)	C11—C9—H10	110.0 (11)
N9—C8B—C4B	109.49 (15)	C10—C9—H10	112.0 (11)
C8—C8B—C4B	123.55 (16)	C9—C10—H10A	111.9 (15)
C7—C8—C8B	116.91 (17)	C9—C10—H10B	107.6 (18)
C7—C8—H8	123.1 (12)	H10A—C10—H10B	107 (2)
C8B—C8—H8	120.0 (12)	C9—C10—H10C	110.0 (16)
C8—C7—C6	122.26 (18)	H10A—C10—H10C	108 (2)
C8—C7—H7	118.1 (11)	H10B—C10—H10C	112 (2)
C6—C7—H7	119.6 (11)	C9—C11—H11A	110.6 (13)
C5—C6—C7	120.76 (18)	C9—C11—H11B	111.5 (14)
C5—C6—H6	120.4 (11)	H11A—C11—H11B	105.7 (19)
C7—C6—H6	118.8 (11)	C9—C11—H11C	109.5 (13)
O1—C5—C6	124.02 (15)	H11A—C11—H11C	106.2 (18)
O1—C5—C4B	116.80 (14)	H11B—C11—H11C	113.1 (19)
C6—C5—C4B	119.18 (16)	C4—C12—H12A	109.5 (13)
C8B—C4B—C5	117.22 (15)	C4—C12—H12B	113.9 (14)
C8B—C4B—C4A	106.04 (14)	H12A—C12—H12B	102.8 (18)
C5—C4B—C4A	136.74 (15)	C4—C12—H12C	112.2 (16)
C1A—C4A—C4	117.32 (14)	H12A—C12—H12C	107 (2)
C1A—C4A—C4B	105.46 (13)	H12B—C12—H12C	111 (2)
C4—C4A—C4B	137.16 (15)	O2—C13—O3	122.90 (17)
C3—C4—C4A	115.80 (14)	O2—C13—C3	122.67 (16)
C3—C4—C12	121.70 (15)	O3—C13—C3	114.42 (14)
C4A—C4—C12	122.43 (15)	C13—O3—C14	119.20 (14)
N2—C3—C4	125.82 (15)	O3—C14—C15	108.67 (17)
N2—C3—C13	110.15 (14)	O3—C14—H14A	105.2 (11)
C4—C3—C13	123.91 (15)	C15—C14—H14A	112.6 (11)
C1—N2—C3	117.95 (15)	O3—C14—H14B	109.1 (12)
N2—C1—C1A	121.05 (16)	C15—C14—H14B	111.8 (12)
N2—C1—H1	117.4 (11)	H14A—C14—H14B	109.2 (16)
C1A—C1—H1	121.6 (12)	C14—C15—H15A	110.3 (15)
N9—C1A—C1	127.97 (16)	C14—C15—H15B	110.2 (14)
N9—C1A—C4A	110.01 (15)	H15A—C15—H15B	107 (2)
C1—C1A—C4A	121.89 (16)	C14—C15—H15C	110.3 (15)
C5—O1—C9	121.53 (14)	H15A—C15—H15C	107 (2)
O1—C9—C11	104.58 (15)	H15B—C15—H15C	112 (2)
C1A—N9—C8B—C8	−176.75 (17)	C12—C4—C3—N2	179.27 (18)
C1A—N9—C8B—C4B	2.4 (2)	C4A—C4—C3—C13	−173.41 (15)
N9—C8B—C8—C7	179.50 (18)	C12—C4—C3—C13	3.7 (3)
C4B—C8B—C8—C7	0.4 (3)	C4—C3—N2—C1	1.6 (3)
C8B—C8—C7—C6	1.9 (3)	C13—C3—N2—C1	177.69 (17)
C8—C7—C6—C5	−1.2 (3)	C3—N2—C1—C1A	−4.0 (3)
C7—C6—C5—O1	177.73 (17)	C8B—N9—C1A—C1	174.50 (18)
C7—C6—C5—C4B	−1.9 (3)	C8B—N9—C1A—C4A	−1.3 (2)
N9—C8B—C4B—C5	177.46 (14)	N2—C1—C1A—N9	−172.66 (18)
C8—C8B—C4B—C5	−3.3 (3)	N2—C1—C1A—C4A	2.7 (3)
N9—C8B—C4B—C4A	−2.55 (18)	C4—C4A—C1A—N9	177.30 (14)
C8—C8B—C4B—C4A	176.69 (16)	C4B—C4A—C1A—N9	−0.26 (18)
O1—C5—C4B—C8B	−175.69 (14)	C4—C4A—C1A—C1	1.2 (2)
C6—C5—C4B—C8B	3.9 (2)	C4B—C4A—C1A—C1	−176.39 (16)
O1—C5—C4B—C4A	4.3 (3)	C6—C5—O1—C9	−3.2 (3)
C6—C5—C4B—C4A	−176.07 (18)	C4B—C5—O1—C9	176.40 (15)
C8B—C4B—C4A—C1A	1.68 (17)	C5—O1—C9—C11	165.06 (17)
C5—C4B—C4A—C1A	−178.33 (19)	C5—O1—C9—C10	−74.5 (2)
C8B—C4B—C4A—C4	−175.13 (18)	N2—C3—C13—O2	−42.8 (3)
C5—C4B—C4A—C4	4.9 (3)	C4—C3—C13—O2	133.4 (2)
C1A—C4A—C4—C3	−3.4 (2)	N2—C3—C13—O3	136.04 (16)
C4B—C4A—C4—C3	173.17 (17)	C4—C3—C13—O3	−47.8 (2)
C1A—C4A—C4—C12	179.59 (16)	O2—C13—O3—C14	−3.3 (3)
C4B—C4A—C4—C12	−3.9 (3)	C3—C13—O3—C14	177.89 (15)
C4A—C4—C3—N2	2.2 (3)	C13—O3—C14—C15	−124.7 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N9—H9···O2^i	0.85 (2)	2.27 (2)	2.984 (2)	141.9 (17)
N9—H9···N2^i	0.85 (2)	2.51 (2)	3.266 (2)	148.2 (17)

Symmetry code: (i) x, −y+1/2, z−1/2.