Pelanserin: 3-[3-(4-phenyl­piperazin-1-yl)prop­yl]quinazoline-2,4(1H,3H)-dione

Gerardo Aguirre Hernández; Ratnasamy Somanathan; Sylvain Bernès

doi:10.1107/S160053681401602X

. 2014 Jul 23;70(Pt 8):o878. doi: 10.1107/S160053681401602X

Pelanserin: 3-[3-(4-phenylpiperazin-1-yl)propyl]quinazoline-2,4(1H,3H)-dione

Gerardo Aguirre Hernández ^a,^*, Ratnasamy Somanathan ^a, Sylvain Bernès ^b,^‡

PMCID: PMC4158516 PMID: 25249922

Abstract

The title compound, C₂₁H₂₄N₄O₂, is a potent serotonin 5-HT₂ and α₁-adrenoceptor antagonist. The n-propyl chain links the quinazolinedione heterocycle and the phenylpiperazine group in which the benzene ring is equatorially located and the piperazine ring has the expected chair conformation. The dihedral angle between the planes of the benzene ring and the quinazolinedione ring system is 74.1 (1)°. In the crystal, molecules form centrosymmetric dimers through R ₂ ²(8) hydrogen-bonded rings involving the amine and one carbonyl group of the quinazolinedione moiety. These dimers are extended into chains extending along the a-axis direction through expanded centrosymmetric cyclic C—H⋯O associations involving the second carbonyl group, giving R ₂ ²(20) and R ₁ ²(7) motifs.

Keywords: crystal structure

Related literature

For the synthesis of pelanserin, see: Cortez et al. (1991 ▶); Garcia et al. (2000 ▶); Li et al. (2011 ▶). For the pharmacology of pelanserin, see: Flores-Murrieta et al. (1990 ▶, 1992 ▶); Villalobos-Molina et al. (1995 ▶). For the structure of quinazoline-2,4(1H,3H)-dione, see: Liu (2008 ▶). graphic file with name e-70-0o878-scheme1.jpg

Experimental

Crystal data

C₂₁H₂₄N₄O₂
M _r = 364.44
Monoclinic,
a = 15.7531 (17) Å
b = 5.4345 (10) Å
c = 22.756 (3) Å
β = 104.506 (9)°
V = 1886.0 (5) Å³
Z = 4
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 296 K
0.60 × 0.30 × 0.10 mm

Data collection

Bruker P4 diffractometer
3452 measured reflections
3323 independent reflections
1301 reflections with I > 2σ(I)
R _int = 0.077
3 standard reflections every 97 reflections intensity decay: 1%

Refinement

R[F ² > 2σ(F ²)] = 0.072
wR(F ²) = 0.148
S = 0.99
3323 reflections
247 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.18 e Å⁻³
Δρ_min = −0.19 e Å⁻³

Data collection: XSCANS (Siemens, 1996 ▶); cell refinement: XSCANS; data reduction: XSCANS; program(s) used to solve structure: SHELXS2013 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL2013 (Sheldrick, 2008 ▶); molecular graphics: Mercury (Macrae et al., 2008 ▶); software used to prepare material for publication: SHELXL2013.

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S160053681401602X/zs2304sup1.cif

e-70-0o878-sup1.cif^{(136.5KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S160053681401602X/zs2304Isup2.hkl

e-70-0o878-Isup2.hkl^{(182.5KB, hkl)}

Click here for additional data file.^{(7.6KB, cml)}

Supporting information file. DOI: 10.1107/S160053681401602X/zs2304Isup3.cml

CCDC reference: 1013055

Additional supporting information: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N3—H3⋯O2ⁱ	0.95 (4)	1.85 (4)	2.799 (5)	171 (4)
C18—H18A⋯O10ⁱⁱ	0.97	2.71	3.625 (6)	157
C25—H25A⋯O10ⁱⁱ	0.93	2.59	3.404 (6)	147

Open in a new tab

Symmetry codes: (i) Inline graphic ; (ii) .

supplementary crystallographic information

S1. Comment

Quinazolinediones are important heterocycles, which have been shown to possess pharmacologically interesting properties, displaying for example anti-hypertensive, or antidiabetic activity. Among these, synthetic pelanserin (TR-2515) is a well-established potent antihypertensive agent, a feature attributed to its 5-HT₂ and α₁-adrenoceptor antagonist activity (Flores-Murrieta et al., 1990, 1992; Villalobos-Molina et al., 1995). Indeed, this molecule presents an activity comparable to that of ketanserin, a clinically used drug. Both molecules also share the quinazoline-2,4-dione scaffold.

We synthesized pelanserin via a ring closure procedure we have developed, based on the reaction between an o-aminobenzamide and triphosgene (Cortez et al., 1991; Garcia et al., 2000). Such a strategy has also been used starting from isatoic anhydride and a readily available primary amine, with triphosgene as ring closure agent (Li et al., 2011).

The title compound has the expected conformation, with the extended n-propyl chain linking the heterocyclic systems (Fig. 1). The quinazolinedione group has the same geometry as that observed for free quinazoline-2,4(1H,3H)-dione (Liu, 2008), and the piperazine ring is found in the chair conformation, with the phenyl substituent group equatorially located. Both lone pairs in the piperazine ring are thus placed in axial positions. The dihedral angle between phenyl and quinazolinedione rings is 74.1 (1)°, giving a twisted conformation for the overall molecule. The crystal structure is dominated by common intermolecular R₂²(8) hydrogen-bonded ring motifs formed through N3—H···O2ⁱ hydrogen bonds (Table 2). These centrosymmetric dimers are extended through weak C—H···O hydrogen-bonding associations involving the second carbonyl group in a bifurcated R₁²(7) motif (C18—H···O10ⁱⁱ, C25—H···O10ⁱⁱ), giving an expanded cyclic R₂²(20) motif in one-dimensional chains extending along a (Fig. 2).

S2. Experimental

2-Amino-N-[3-(4-phenhylpiperazin-1-yl)propyl]benzamide (1.7 g, 5 mmol) was stirred in CH₂Cl₂ (50 ml) at room temperature and triphosgene (0.5 g, 1.7 mmol) in CH₂Cl₂ (10 ml) was added. The mixture was refluxed for 2 h. The organic phase was washed with water and dried over MgSO₄. The solvent was removed under reduced pressure, to give a solid product, which was recrystallized from ethanol, affording pure pelanserin. M.p. 190–192 °C, yield 88%; IR (KBr): 3358 (NH), 2982 (CH), 1737 cm^-1 (C═O). ¹H-NMR (200 MHz, CDCl₃, p.p.m.): δ 10.70 (s, 1H), 8.12 (d, 1H, J = 8.0 Hz), 7.0 (t, 1H, J = 8.4 Hz), 7.25 (m, 4H), 6.87 (m, 3H), 4.19 (t, 2H, J = 6.9 Hz), 3.12 (t, 4H, J = 6.0 Hz), 2.61 (m, 6H), 1.95 (q, 2H); ¹³C-NMR (50 MHz, CDCl₃, p.p.m.): δ 162, 152, 151, 139, 135, 129, 128, 123, 119, 116, 114, 56, 53, 49, 30, 25. EIMS (m/z): 364 [M⁺, 3], 175 [100]. Anal. calcd. for C₂₁H₂₄N₄O₂: C 69.21, H 6.64%; found: C 69.23, H 6.58%.