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Ropinirole hydrochloride, or diethyl[2-(2-oxo-2,3-dihydro-1
H-indol-4-yl)ethyl]ammonium chloride, C
16H
25N
2O
+·Cl
-, belongs to a class of new non-ergoline dopamine agonists which bind specifically to D2-like receptors with a selectivity similar to that of dopamine (D3 > D2 > D4). The N atom in the ethylamine side chain is protonated and there is a hydrogen bond between it and the Cl
- ion. In the crystal structure, two cations and two anions form inversion-related cyclic dimers
via N-H
Cl hydrogen bonds.
Supporting information
CCDC reference: 609418
To obtain crystals of (I) suitable for X-ray studies, ropinirole hydrochloride (Pharmacology Department, IICT, Hyderabad) was dissolved in a misture of methanol and water (95:5) and the solution was allowed to evaporate slowly.
The H atoms on N were located in a difference density map and were refined freely with isotropic displacement parameters. All other H atoms were included in calculated positions, with C—H = 0.93–0.98 Å, and refined using a riding model, with Uiso(H) values set at 1.2 (C atoms) or 1.5 (CH3) times Ueq of the parent atoms. The methyl groups were allowed to rotate but not to tip.
Data collection: SMART (Bruker, 2001); cell refinement: SAINT (Bruker, 2001); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL/PC (Sheldrick, 1990) and Mercury (Bruno et al., 2002); software used to prepare material for publication: SHELXL97.
4-[2-(dipropylamino)ethyl]-2,3-dihydro-1
H-indol-2-ol hydrochloride
top
Crystal data top
C16H25N2O+·Cl− | Z = 2 |
Mr = 296.83 | F(000) = 320 |
Triclinic, P1 | Dx = 1.228 Mg m−3 |
Hall symbol: -P 1 | Mo Kα radiation, λ = 0.71073 Å |
a = 7.5388 (11) Å | Cell parameters from 4700 reflections |
b = 8.9545 (13) Å | θ = 2.3–28.0° |
c = 12.1647 (18) Å | µ = 0.24 mm−1 |
α = 80.005 (2)° | T = 273 K |
β = 85.968 (2)° | Needle, colourless |
γ = 83.504 (2)° | 0.21 × 0.11 × 0.08 mm |
V = 802.5 (2) Å3 | |
Data collection top
Bruker SMART APEX CCD area-detector diffractometer | 2582 reflections with I > 2σ(I) |
Radiation source: fine-focus sealed tube | Rint = 0.021 |
Graphite monochromator | θmax = 25.0°, θmin = 1.7° |
ω scans | h = −8→8 |
7757 measured reflections | k = −10→10 |
2825 independent reflections | l = −14→14 |
Refinement top
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.037 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.101 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.05 | w = 1/[σ2(Fo2) + (0.0547P)2 + 0.173P] where P = (Fo2 + 2Fc2)/3 |
2825 reflections | (Δ/σ)max < 0.001 |
191 parameters | Δρmax = 0.27 e Å−3 |
0 restraints | Δρmin = −0.18 e Å−3 |
Crystal data top
C16H25N2O+·Cl− | γ = 83.504 (2)° |
Mr = 296.83 | V = 802.5 (2) Å3 |
Triclinic, P1 | Z = 2 |
a = 7.5388 (11) Å | Mo Kα radiation |
b = 8.9545 (13) Å | µ = 0.24 mm−1 |
c = 12.1647 (18) Å | T = 273 K |
α = 80.005 (2)° | 0.21 × 0.11 × 0.08 mm |
β = 85.968 (2)° | |
Data collection top
Bruker SMART APEX CCD area-detector diffractometer | 2582 reflections with I > 2σ(I) |
7757 measured reflections | Rint = 0.021 |
2825 independent reflections | |
Refinement top
R[F2 > 2σ(F2)] = 0.037 | 0 restraints |
wR(F2) = 0.101 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.05 | Δρmax = 0.27 e Å−3 |
2825 reflections | Δρmin = −0.18 e Å−3 |
191 parameters | |
Special details top
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. |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top | x | y | z | Uiso*/Ueq | |
C1 | 0.7696 (2) | 1.16992 (19) | −0.01182 (13) | 0.0460 (4) | |
C2 | 0.7515 (2) | 1.01633 (17) | 0.06263 (12) | 0.0432 (3) | |
H2A | 0.8591 | 0.9807 | 0.1027 | 0.052* | |
H2B | 0.6505 | 1.0229 | 0.1161 | 0.052* | |
C3 | 0.72299 (18) | 0.91279 (17) | −0.01796 (11) | 0.0393 (3) | |
C4 | 0.69272 (19) | 0.76036 (17) | −0.00258 (12) | 0.0421 (3) | |
C5 | 0.6720 (2) | 0.6978 (2) | −0.09775 (14) | 0.0509 (4) | |
H5 | 0.6558 | 0.5950 | −0.0901 | 0.061* | |
C6 | 0.6750 (2) | 0.7852 (2) | −0.20271 (14) | 0.0563 (4) | |
H6 | 0.6589 | 0.7406 | −0.2644 | 0.068* | |
C7 | 0.7016 (2) | 0.9384 (2) | −0.21836 (13) | 0.0514 (4) | |
H7 | 0.7024 | 0.9976 | −0.2892 | 0.062* | |
C8 | 0.72677 (18) | 0.99950 (17) | −0.12510 (12) | 0.0409 (3) | |
C9 | 0.6786 (2) | 0.66338 (19) | 0.11171 (13) | 0.0479 (4) | |
H9A | 0.6369 | 0.5670 | 0.1049 | 0.058* | |
H9B | 0.5914 | 0.7146 | 0.1588 | 0.058* | |
C10 | 0.85595 (19) | 0.63334 (17) | 0.16639 (12) | 0.0413 (3) | |
H10A | 0.9439 | 0.5871 | 0.1170 | 0.050* | |
H10B | 0.8946 | 0.7300 | 0.1754 | 0.050* | |
C11 | 0.7134 (2) | 0.58428 (16) | 0.36201 (12) | 0.0417 (3) | |
H11A | 0.7245 | 0.5144 | 0.4322 | 0.050* | |
H11B | 0.5958 | 0.5797 | 0.3359 | 0.050* | |
C12 | 0.7263 (2) | 0.74295 (19) | 0.38298 (15) | 0.0547 (4) | |
H12A | 0.7037 | 0.8155 | 0.3151 | 0.066* | |
H12B | 0.8457 | 0.7513 | 0.4047 | 0.066* | |
C13 | 0.5905 (3) | 0.7789 (2) | 0.47503 (16) | 0.0652 (5) | |
H13A | 0.4723 | 0.7744 | 0.4520 | 0.098* | |
H13B | 0.6012 | 0.8793 | 0.4898 | 0.098* | |
H13C | 0.6120 | 0.7058 | 0.5416 | 0.098* | |
C14 | 0.8372 (2) | 0.36918 (17) | 0.26843 (13) | 0.0466 (4) | |
H14A | 0.9093 | 0.3449 | 0.2034 | 0.056* | |
H14B | 0.7139 | 0.3575 | 0.2567 | 0.056* | |
C15 | 0.8971 (2) | 0.25807 (18) | 0.37001 (14) | 0.0533 (4) | |
H15A | 0.8319 | 0.2858 | 0.4364 | 0.064* | |
H15B | 1.0235 | 0.2617 | 0.3783 | 0.064* | |
C16 | 0.8635 (3) | 0.0983 (2) | 0.35772 (19) | 0.0721 (6) | |
H16A | 0.7380 | 0.0946 | 0.3512 | 0.108* | |
H16B | 0.9031 | 0.0278 | 0.4222 | 0.108* | |
H16C | 0.9282 | 0.0713 | 0.2920 | 0.108* | |
Cl1 | 1.22426 (5) | 0.59313 (5) | 0.33513 (3) | 0.05399 (16) | |
N1 | 0.75689 (18) | 1.14855 (16) | −0.11869 (11) | 0.0472 (3) | |
H1N | 0.758 (2) | 1.215 (2) | −0.1679 (16) | 0.052 (5)* | |
N2 | 0.85164 (16) | 0.53150 (13) | 0.27847 (9) | 0.0370 (3) | |
H2N | 0.961 (2) | 0.5337 (19) | 0.3051 (14) | 0.050 (4)* | |
O1 | 0.79325 (18) | 1.28825 (14) | 0.01737 (11) | 0.0644 (3) | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
C1 | 0.0388 (8) | 0.0513 (9) | 0.0465 (9) | −0.0058 (7) | 0.0004 (6) | −0.0043 (7) |
C2 | 0.0412 (8) | 0.0522 (9) | 0.0353 (7) | −0.0071 (6) | −0.0036 (6) | −0.0030 (6) |
C3 | 0.0322 (7) | 0.0508 (8) | 0.0331 (7) | −0.0043 (6) | −0.0030 (5) | −0.0016 (6) |
C4 | 0.0349 (7) | 0.0507 (9) | 0.0392 (8) | −0.0048 (6) | −0.0072 (6) | −0.0009 (6) |
C5 | 0.0501 (9) | 0.0527 (9) | 0.0519 (9) | −0.0078 (7) | −0.0079 (7) | −0.0105 (7) |
C6 | 0.0574 (10) | 0.0747 (12) | 0.0403 (9) | −0.0066 (8) | −0.0045 (7) | −0.0181 (8) |
C7 | 0.0505 (9) | 0.0693 (11) | 0.0312 (8) | −0.0034 (8) | −0.0026 (6) | −0.0013 (7) |
C8 | 0.0332 (7) | 0.0503 (8) | 0.0358 (7) | −0.0021 (6) | −0.0007 (6) | 0.0003 (6) |
C9 | 0.0414 (8) | 0.0541 (9) | 0.0459 (9) | −0.0127 (7) | −0.0092 (6) | 0.0064 (7) |
C10 | 0.0371 (7) | 0.0473 (8) | 0.0368 (8) | −0.0083 (6) | −0.0021 (6) | 0.0033 (6) |
C11 | 0.0435 (8) | 0.0432 (8) | 0.0373 (7) | −0.0075 (6) | −0.0005 (6) | −0.0025 (6) |
C12 | 0.0617 (11) | 0.0459 (9) | 0.0571 (10) | −0.0078 (7) | 0.0029 (8) | −0.0114 (7) |
C13 | 0.0790 (13) | 0.0560 (10) | 0.0591 (11) | 0.0021 (9) | 0.0048 (9) | −0.0150 (8) |
C14 | 0.0531 (9) | 0.0432 (8) | 0.0456 (9) | −0.0083 (7) | −0.0053 (7) | −0.0100 (7) |
C15 | 0.0644 (10) | 0.0426 (9) | 0.0520 (10) | −0.0051 (7) | −0.0039 (8) | −0.0053 (7) |
C16 | 0.0841 (14) | 0.0455 (10) | 0.0855 (14) | −0.0093 (9) | −0.0071 (11) | −0.0051 (9) |
Cl1 | 0.0458 (2) | 0.0664 (3) | 0.0472 (3) | −0.01706 (19) | −0.01301 (17) | 0.00918 (19) |
N1 | 0.0464 (7) | 0.0500 (8) | 0.0401 (7) | −0.0059 (6) | −0.0011 (6) | 0.0067 (6) |
N2 | 0.0361 (6) | 0.0404 (7) | 0.0343 (6) | −0.0077 (5) | −0.0048 (5) | −0.0016 (5) |
O1 | 0.0758 (9) | 0.0552 (7) | 0.0647 (8) | −0.0179 (6) | 0.0015 (6) | −0.0118 (6) |
Geometric parameters (Å, º) top
C1—O1 | 1.210 (2) | C11—N2 | 1.4996 (19) |
C1—N1 | 1.358 (2) | C11—C12 | 1.501 (2) |
C1—C2 | 1.524 (2) | C11—H11A | 0.9700 |
C2—C3 | 1.502 (2) | C11—H11B | 0.9700 |
C2—H2A | 0.9700 | C12—C13 | 1.515 (2) |
C2—H2B | 0.9700 | C12—H12A | 0.9700 |
C3—C4 | 1.388 (2) | C12—H12B | 0.9700 |
C3—C8 | 1.397 (2) | C13—H13A | 0.9600 |
C4—C5 | 1.396 (2) | C13—H13B | 0.9600 |
C4—C9 | 1.510 (2) | C13—H13C | 0.9600 |
C5—C6 | 1.377 (2) | C14—N2 | 1.4962 (19) |
C5—H5 | 0.9300 | C14—C15 | 1.507 (2) |
C6—C7 | 1.388 (3) | C14—H14A | 0.9700 |
C6—H6 | 0.9300 | C14—H14B | 0.9700 |
C7—C8 | 1.375 (2) | C15—C16 | 1.515 (2) |
C7—H7 | 0.9300 | C15—H15A | 0.9700 |
C8—N1 | 1.395 (2) | C15—H15B | 0.9700 |
C9—C10 | 1.511 (2) | C16—H16A | 0.9600 |
C9—H9A | 0.9700 | C16—H16B | 0.9600 |
C9—H9B | 0.9700 | C16—H16C | 0.9600 |
C10—N2 | 1.5035 (17) | N1—H1N | 0.770 (19) |
C10—H10A | 0.9700 | N2—H2N | 0.913 (19) |
C10—H10B | 0.9700 | | |
| | | |
O1—C1—N1 | 126.04 (15) | N2—C11—H11B | 108.7 |
O1—C1—C2 | 127.20 (15) | C12—C11—H11B | 108.7 |
N1—C1—C2 | 106.76 (14) | H11A—C11—H11B | 107.6 |
C3—C2—C1 | 103.86 (12) | C11—C12—C13 | 109.59 (14) |
C3—C2—H2A | 111.0 | C11—C12—H12A | 109.8 |
C1—C2—H2A | 111.0 | C13—C12—H12A | 109.8 |
C3—C2—H2B | 111.0 | C11—C12—H12B | 109.8 |
C1—C2—H2B | 111.0 | C13—C12—H12B | 109.8 |
H2A—C2—H2B | 109.0 | H12A—C12—H12B | 108.2 |
C4—C3—C8 | 120.34 (13) | C12—C13—H13A | 109.5 |
C4—C3—C2 | 132.31 (13) | C12—C13—H13B | 109.5 |
C8—C3—C2 | 107.33 (13) | H13A—C13—H13B | 109.5 |
C3—C4—C5 | 117.51 (14) | C12—C13—H13C | 109.5 |
C3—C4—C9 | 122.54 (13) | H13A—C13—H13C | 109.5 |
C5—C4—C9 | 119.93 (14) | H13B—C13—H13C | 109.5 |
C6—C5—C4 | 121.34 (16) | N2—C14—C15 | 112.97 (13) |
C6—C5—H5 | 119.3 | N2—C14—H14A | 109.0 |
C4—C5—H5 | 119.3 | C15—C14—H14A | 109.0 |
C5—C6—C7 | 121.37 (15) | N2—C14—H14B | 109.0 |
C5—C6—H6 | 119.3 | C15—C14—H14B | 109.0 |
C7—C6—H6 | 119.3 | H14A—C14—H14B | 107.8 |
C8—C7—C6 | 117.45 (14) | C14—C15—C16 | 109.77 (15) |
C8—C7—H7 | 121.3 | C14—C15—H15A | 109.7 |
C6—C7—H7 | 121.3 | C16—C15—H15A | 109.7 |
C7—C8—N1 | 128.46 (14) | C14—C15—H15B | 109.7 |
C7—C8—C3 | 121.95 (15) | C16—C15—H15B | 109.7 |
N1—C8—C3 | 109.59 (13) | H15A—C15—H15B | 108.2 |
C4—C9—C10 | 111.84 (12) | C15—C16—H16A | 109.5 |
C4—C9—H9A | 109.2 | C15—C16—H16B | 109.5 |
C10—C9—H9A | 109.2 | H16A—C16—H16B | 109.5 |
C4—C9—H9B | 109.2 | C15—C16—H16C | 109.5 |
C10—C9—H9B | 109.2 | H16A—C16—H16C | 109.5 |
H9A—C9—H9B | 107.9 | H16B—C16—H16C | 109.5 |
N2—C10—C9 | 114.15 (12) | C1—N1—C8 | 112.43 (13) |
N2—C10—H10A | 108.7 | C1—N1—H1N | 121.4 (14) |
C9—C10—H10A | 108.7 | C8—N1—H1N | 125.9 (14) |
N2—C10—H10B | 108.7 | C14—N2—C11 | 110.81 (11) |
C9—C10—H10B | 108.7 | C14—N2—C10 | 112.04 (11) |
H10A—C10—H10B | 107.6 | C11—N2—C10 | 114.73 (11) |
N2—C11—C12 | 114.32 (12) | C14—N2—H2N | 106.4 (10) |
N2—C11—H11A | 108.7 | C11—N2—H2N | 107.7 (11) |
C12—C11—H11A | 108.7 | C10—N2—H2N | 104.5 (11) |
| | | |
O1—C1—C2—C3 | 179.56 (16) | C2—C3—C8—N1 | 0.53 (16) |
N1—C1—C2—C3 | −1.44 (15) | C3—C4—C9—C10 | −68.85 (19) |
C1—C2—C3—C4 | −177.96 (15) | C5—C4—C9—C10 | 112.28 (16) |
C1—C2—C3—C8 | 0.54 (15) | C4—C9—C10—N2 | −177.48 (12) |
C8—C3—C4—C5 | 1.9 (2) | N2—C11—C12—C13 | −175.44 (14) |
C2—C3—C4—C5 | −179.81 (15) | N2—C14—C15—C16 | 175.13 (15) |
C8—C3—C4—C9 | −177.05 (13) | O1—C1—N1—C8 | −179.10 (15) |
C2—C3—C4—C9 | 1.3 (2) | C2—C1—N1—C8 | 1.88 (17) |
C3—C4—C5—C6 | −2.3 (2) | C7—C8—N1—C1 | 177.82 (15) |
C9—C4—C5—C6 | 176.65 (15) | C3—C8—N1—C1 | −1.58 (17) |
C4—C5—C6—C7 | 1.0 (3) | C15—C14—N2—C11 | −70.87 (16) |
C5—C6—C7—C8 | 0.7 (3) | C15—C14—N2—C10 | 159.59 (13) |
C6—C7—C8—N1 | 179.59 (15) | C12—C11—N2—C14 | 176.12 (13) |
C6—C7—C8—C3 | −1.1 (2) | C12—C11—N2—C10 | −55.79 (17) |
C4—C3—C8—C7 | −0.2 (2) | C9—C10—N2—C14 | 72.40 (17) |
C2—C3—C8—C7 | −178.92 (14) | C9—C10—N2—C11 | −55.08 (17) |
C4—C3—C8—N1 | 179.24 (13) | | |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1N···Cl1i | 0.770 (19) | 2.43 (2) | 3.1955 (15) | 173.9 (18) |
N2—H2N···Cl1 | 0.913 (19) | 2.180 (19) | 3.0701 (13) | 164.7 (15) |
Symmetry code: (i) −x+2, −y+2, −z. |
Experimental details
Crystal data |
Chemical formula | C16H25N2O+·Cl− |
Mr | 296.83 |
Crystal system, space group | Triclinic, P1 |
Temperature (K) | 273 |
a, b, c (Å) | 7.5388 (11), 8.9545 (13), 12.1647 (18) |
α, β, γ (°) | 80.005 (2), 85.968 (2), 83.504 (2) |
V (Å3) | 802.5 (2) |
Z | 2 |
Radiation type | Mo Kα |
µ (mm−1) | 0.24 |
Crystal size (mm) | 0.21 × 0.11 × 0.08 |
|
Data collection |
Diffractometer | Bruker SMART APEX CCD area-detector diffractometer |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 7757, 2825, 2582 |
Rint | 0.021 |
(sin θ/λ)max (Å−1) | 0.595 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.037, 0.101, 1.05 |
No. of reflections | 2825 |
No. of parameters | 191 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.27, −0.18 |
Selected geometric parameters (Å, º) topC10—N2 | 1.5035 (17) | C14—N2 | 1.4962 (19) |
C11—N2 | 1.4996 (19) | | |
| | | |
N2—C10—C9 | 114.15 (12) | C14—N2—C11 | 110.81 (11) |
N2—C11—C12 | 114.32 (12) | C14—N2—C10 | 112.04 (11) |
N2—C14—C15 | 112.97 (13) | C11—N2—C10 | 114.73 (11) |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1N···Cl1i | 0.770 (19) | 2.43 (2) | 3.1955 (15) | 173.9 (18) |
N2—H2N···Cl1 | 0.913 (19) | 2.180 (19) | 3.0701 (13) | 164.7 (15) |
Symmetry code: (i) −x+2, −y+2, −z. |
Selected topographical X-ray structural features of the title compound and dopamine derivatives (Å and °) topRef | τ1 | τ2 | d1 | d2 | ϕ |
a | -177.5 (1) | -68.9 (2) | 5.214 | 6.946 | 67.4 (1) |
b | -168.32 | -120.92 | 5.172 | 7268 | 64.36 |
c | 178.98/-177.24 | -94.47/137.00 | 5.122/5.196 | 6.874/7.165 | 84.49/43.99i |
d | -171.78 | -76.66 | 5.119 | 6.808 | 77.04 |
e | -179.27 | -72.68 | 5.134 | 6.894 | 72.55 |
f | 178.71 | -175.83 | 5.202 | 7.415 | 4.27 |
g | 179.78 | 73.19 | 5.118 | 6.824 | 74.20 |
h | 60.47 | 68.98 | 3.940 | 5.745 | 77.76 |
i | 55.49 | 58.39 | 3.975 | 5.620 | 89.17 |
τ1 = torsion angle C4—C9—C10—N2, τ2 = torsion angle C3—C4—C9—C10, d1 = distance between the aromatic ring centroid and atom N2, d2 = distance
between N2 and X (X = N or O), and ϕ = dihedral angle between the ethylamine (1/7/8/N) plane and the aromatic ring plane.
(a) Ropinirole hydrochloride, (I) (present work); (b) 5-(2-aminoethyl)-2-hydroxyphenyl hydrogen sulfate (Eggleston et al., 1985); (c) 4-(2-aminoethyl)-2-hydroxyphenyl hydrogen sulfate (Eggleston et al., 1985); (d) dopamine hydrochloride (Klein, 1991); (e) 6-(2-aminoethyl)-3-methyl-2,3-dihydro-1,3-benzoxazole-2-one hydrochloride (Boivin et al., 1987); (f) 2-(4-hydroxy-3-methoxyphenyl)ethylammonium chloride (Okabe et al., 1991); (g) 2-(4-hydroxy-3-methoxyphenyl)ethylammonium perchlorate (Okabe & Mori, 1992); (h) 2-(3,4-dihydroxyphenyl)ethylammonium 3,5-dinitrobenzoate (Ohba & Ito, 2002a); (i) 2-(3,4-dimethoxyphenyl)ethylammonium 3,5-dinitrobenzoate (Ohba & Ito, 2002b).
i Two molecules in the asymmetric unit. |
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Ropinirole hydrochloride (ReQuip; SmithKline Beecham) is a second-generation non-ergoline dopamine agonist (DA) that selectively activates postsynaptic dopamine receptors (Eden et al. 1991). It mimics the role of dopamine in the brain, causing the neurons to react as they would to dopamine. All of the agonists contain a dopamine-like ring structure which is believed to be the portion of the molecule that actually stimulates the dopamine receptor (Tulloch, 1997). In vitro studies have shown that ropinirole binds with high affinity to cloned human D2, D3 and D4 receptors. The activity of ropinirole against Parkinson's disease is believed to be due to its stimulatory effects on central postsynaptic dopamine D2 receptors within the candate-putamen (Kuzel, 1999). Clinical studies have shown that ropinirole can be used for both early and late treatment of Parkinson's disease. Ropinirole, launched as Requip, was recently cleared for marketing by the US Food and Drug Administration for treatment of the signs and symptoms of Parkinson's disease, both as initial therapy and as an adjunctive treatment with levodopa (Rascol et al., 1996). It was well tolerated and patient withdrawal from clinical trials was rare (Brooks et al., 1995). In a continuation of our ongoing programmes on the structural elucidation of drug molecules and in order to gain further insight into structure–activity relationships, the crystal structure determination of ropinirole hydrochloride, (I), has now been carried out and the results are reported here (Fig. 1, Table 1).
Viewed from an overall perspective, the bond lengths and angles in compound (I) are comparable with those in similar closely related structures (Boivin et al., 1987; Eyley et al., 1986). Ropinirole crystallizes as the HCl salt with one molecule in the asymmetric unit (Fig. 1). The hybridization of the side chain atom N2 appears to be characteristically sp3 from its bond lengths [mean N2—C 1.500 (2) Å] and angles [mean C—N2—C 113.2 (1)°], indicating the protonation site of the molecule (Table 1).
The protonated amine and the N1—H1N group in a meta position relative to the ethylamine side chain comprise the two possible important sites of interaction with the DA receptor (McDermed et al., 1976). An overlay of dopamine with the title compound, along with other dopamine derivatives, by superimposing the aromatic moieties clearly reveals the conformational similarities (Fig. 2). The functional groups superimpose well, viz. the ethylamine side chain, the aromatic ring and the meta-hydroxyl O atom of dopamine hydrochloride with the N atom of the pyrrolidinone, (I).
The solid-state conformation of the ethylamine side chain in (I), which is associated with the area of greatest conformational flexibility, is significantly similar and closely related to the conformations previously found in the dopamine derivatives (Table 3). It is apparent that the ethylamine side chain is in an almost extended conformation [C4—C9—C10—N2 = τ1 = −177.5 (1)°] and also lies in a plane that is nearly orthogonal [C3—C4—C9—C10 = τ2 = −68.9 (2)°] to the phenyl ring plane, a situation that appears to favour biological activity (Fig. 3). However, in the structure of a methoxy derivative of dopamine hydrochloride (Okabe et al., 1991), the side chain is fully extended but oriented in the same plane as the aromatic ring [τ2 −175.8 (6)°]. Incidentally, in the structures of dinitrobenzoate salts of dopamine (Ohba & Ito, 2002a,b), the side chain is in a gauche conformation, perhaps due to the presence of the bulky counter-ions and crystal packing.
The substituted propyl side chains at N2 are in an extended conformation [N2—C11—C12—C13 − 175.4 (1) and N2—C14—C15—C16 175.1 (2)°] and are inclined at an angle of 69.4 (2)° to each other. This orientation of the propyl chains may also facilitate the binding of atom N2 at the receptor site through possible hydrophobic interactions. As in dopamine hydrochloride, the Cl− ion is central to the hydrogen-bonding network, stabilizing the structure by forming covalent bonds with both N atoms, one each from the ethylamine chain and the indole ring (Table 2). In the crystal structure, two cations and two anions form inversion-related cyclic dimers via N—H···Cl hydrogen bonds. The dimers also form stacks along the a axis (Fig. 4).
In an attempt to map the pharmacophoric requirements for dopamine activity, distances describing the position of the protonated amine atom N2 in relation to the aromatic ring (d1) and to the meta-substituted atom (d2), along with the dihedral angle (ϕ) between the aromatic ring and the ethylamine side chain least-squares planes, have been derived and are listed in Table 3. Significant similarities in these structural parameters can be seen. However, it is difficult, from this limited set of data, to suggest what structural or conformational parameters contribute to the observed pharmacological differences. It is difficult to come to any firm conclusion about the relationships between conformation and biological activity when dealing with agonists. Since they produce a response from living tissue, their activity not only depends upon their ability to activate receptors (efficacy) but also to bind to them (affinity). However, some ideas may be speculated by considering the derived structural features. Firstly, there appears to be some preference for the extended conformation of the ethylamine side chain and also for the plane of the ethylamine to lie at near right angles to the plane of the aromatic ring. Also, a favourable disposition (~3.9–5.2 Å) of the charged N atom relative to the aromatic ring, and an optimal distance (\sim 5.6–7.4 Å), may be preferred between the charged N atom and the meta-substituted hydrogen-bonding atom on the aromatic ring.