Ropinirole hydro­chloride, a dopamine agonist

Ropinirole hydro­chloride, or diethyl[2-(2-oxo-2,3-dihydro-1H-indol-4-yl)ethyl]ammonium chloride, C₁₆H₂₅N₂O⁺·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.

S1. Comment

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.

S2. Experimental

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.

S3. Refinement

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 U_iso(H) values set at 1.2 (C atoms) or 1.5 (CH₃) times U_eq of the parent atoms. The methyl groups were allowed to rotate but not to tip.

Computing details

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.

Figures

	Fig. 1. A view of (I), with the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as small spheres of arbitrary radii. The intramolecular hydrogen bond is drawn as a dashed line.
	Fig. 2. An overlay of dopamine with the title compound (red), along with other dopamine derivatives: dopamine HCl (Klein, 1991) (green, r.m.s. deviation 0.023 Å); Compound? (Boivin et al., 1987) (yellow, r.m.s deviation 0.040 Å) and the methoxy derivative of dopamine perchlorate (Okabe & Mori, 1992) (violet, r.m.s. deviation 0.028 Å) by superimposing the aromatic moieties. H atoms have been omitted for clarity.
	Fig. 3. Orthogonal orientations of the ethylamine side chain to the plane of the aromatic ring for (a) dopamine hydrochloride and (b) ropinirole hydrochloride. H atoms have been omitted for clarity.
	Fig. 4. A packing diagram for (I), viewed down the b axis, showing the hydrogen-bond networks (dashed lines) involving two Cl^− ions that bridge two molecules of the cation to form centrosymmetric dimers. H atoms not involved in hydrogen bonding have been omitted for clarity.

4-[2-(dipropylamino)ethyl]-2,3-dihydro-1H-indol-2-ol hydrochloride

Crystal data

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) Å^3

Data collection

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

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)] = 0.037	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.101	H atoms treated by a mixture of independent and constrained refinement
S = 1.05	w = 1/[σ^2(Fo^2) + (0.0547P)^2 + 0.173P] where P = (Fo^2 + 2Fc^2)/3
2825 reflections	(Δ/σ)max < 0.001
191 parameters	Δρmax = 0.27 e Å^−3
0 restraints	Δρmin = −0.18 e Å^−3

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.

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

	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 (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
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)

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)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1N···Cl1^i	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.