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

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.

The title compound, C 21 H 24 N 4 O 2 , is a potent serotonin 5-HT 2 and 1 -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-HÁ Á ÁO associations involving the second carbonyl group, giving R 2 2 (20) and R 1 2 (7) motifs.
Supporting information for this paper is available from the IUCr electronic archives (Reference: ZS2304).

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-HT 2 and α 1 -adrenoceptor antagonist activity (Flores-Murrieta et al., 1990, 1992Villalobos-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 R 2 2 (8) hydrogen-bonded ring motifs formed through N3-H···O2 i 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 R 1 2 (7) motif (C18-H···O10 ii , C25-H···O10 ii ), giving an expanded cyclic R 2 2 (20) motif in one-dimensional chains extending along a (Fig. 2).

S3. Refinement
Crystals were thin plates (0.1 mm) and as a consequence, only poorly diffracting samples were obtained, hence roomtemperature collected data had resolution limited to sin(θ)/λ = 0.59 Å -1 , with 97.5% completeness. All H atoms bonded to supporting information sup-2 Acta Cryst. (2014). E70, o878 C atoms were placed in idealized positions and refined as riding on their carrier atoms, with bond lengths fixed to 0.93 Å (aromatic CH) or 0.97 Å (methylene CH 2 ). The amine H atom (H3) was found in a difference map and refined freely. For all H atoms, isotropic displacement parameters were calculated as U iso (H) = 1.2U eq (carrier atom).

Figure 1
Molecular structure of the title compound, with 30% probability level displacement ellipsoids for non-H atoms.

Figure 2
Part of the crystal structure, showing hydrogen bonds as dashed lines.