Lurasidone hydro­chloride

Hua Zhang; Hubo Wang; Xueyan Zhu; Zhedong Yuan; Huijuan Jiang

doi:10.1107/S1600536812012883

. 2012 Apr 13;68(Pt 5):o1357. doi: 10.1107/S1600536812012883

Lurasidone hydrochloride

Hua Zhang ^a, Hubo Wang ^a, Xueyan Zhu ^a, Zhedong Yuan ^a,^*, Huijuan Jiang ^a

PMCID: PMC3344489 PMID: 22590251

Abstract

In the crystal structure of the title compound, C₂₈H₃₇N₄O₂S⁺·Cl⁻ [systematic name: 4-(1,2-benzothiazol-3-yl)-1-({2-[(3,5-dioxo-4-azatricyclo[5.2.1.0^2,6]decan-4-yl)methyl]cyclohexyl}methyl)piperazin-1-ium chloride], the anions and cations are linked by N—H⋯Cl hydrogen bonds. The crystal structure is further stabilized by C—H⋯π and C—H⋯O interactions.

Related literature

For the background to the biological activity of the title compound, an antipsychotic drug, see: Ishibashi et al. (2002 ▶); Ishiyama et al. (2003 ▶); Ohno et al. (1997 ▶).

Experimental

Crystal data

C₂₈H₃₇N₄O₂S⁺·Cl⁻
M _r = 529.13
Orthorhombic,
a = 11.2039 (10) Å
b = 12.2665 (11) Å
c = 19.9774 (18) Å
V = 2745.5 (4) Å³
Z = 4
Mo Kα radiation
μ = 0.25 mm⁻¹
T = 293 K
0.22 × 0.12 × 0.10 mm

Data collection

Bruker SMART CCD area-detector diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2000 ▶) T _min = 0.452, T _max = 1.000
15020 measured reflections
5384 independent reflections
4649 reflections with I > 2σ(I)
R _int = 0.028

Refinement

R[F ² > 2σ(F ²)] = 0.047
wR(F ²) = 0.108
S = 1.10
5384 reflections
329 parameters
1 restraint
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.24 e Å⁻³
Δρ_min = −0.14 e Å⁻³
Absolute structure: Flack (1983 ▶), 2338 Friedel pairs
Flack parameter: 0.03 (6)

Data collection: SMART (Bruker, 2000 ▶); cell refinement: SAINT (Bruker, 2000 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: SHELXTL (Sheldrick, 2008 ▶); software used to prepare material for publication: SHELXTL.

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536812012883/bt5835sup1.cif

e-68-o1357-sup1.cif^{(36.5KB, cif)}

Supplementary material file. DOI: 10.1107/S1600536812012883/bt5835Isup2.cml

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812012883/bt5835Isup3.hkl

e-68-o1357-Isup3.hkl^{(263.7KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

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

Cg is the centroid of the S1/ N4/C22/C23/C28 ring.

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N2—H2A⋯Cl1	0.80 (2)	2.15 (2)	2.9426 (19)	168 (2)
C21—H21A⋯O1ⁱ	0.97	2.38	3.289 (3)	156
C5—H5A⋯Cgⁱⁱ	0.97	2.89	3.802 (4)	157

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

Acknowledgments

The authors thank the Shanghai Institute of Organic Chemistry for providing the infrastructure.

supplementary crystallographic information

Comment

Lurasidone hydrochloride is a benzisothiazole derivative and an atypical antipsychotic drug. This drug has high affinities for dopamine D₂ (K_i =1.68nM), serotonin 5-HT_{2 A} (K_i =2.03nM), 5-HT_{1 A} (K_i =6.75nM), 5-HT₇ receptors (K_i =0.495nM), and α_2c adrenoceptor (K_i =10.8nM), but only weak or negligible interactions with serotonin 5-HT_2c, histamine H₁, acetylcholine M₁ receptors, and α₁ adrenoceptor (Ishibashi et al., 2002; Ishiyama et al., 2003). Interestingly, despite its potent D₂-blocking actions in vivo, Lurasidone has little propensity to induce extrapyramidal symptoms (Ohno et al., 1997).

The United States Food and Drug Administration (US FDA) approved Lurasidone hydrochloride (brand name: Latuda) in 2010 as an immediate release oral tablet for the treatment of schizophrenia. Lurasidone hydrochloride was developed by Dainippon Sumitomo Pharma in collaboration with Merck Research Laboratories during the initial IND stages. No data about crystal structure of Lurasidone hydrochloride has been reported yet.

Lurasidone hydrochloride consists of six chiral centres, e. g. C1, C2, C11, C12, C15 and C16. Currently, the clinically used form is a single isomer. The crystal structure of the title compound is built up of discrete lurasidium anions and chloride cations (Fig. 1).

There are two systems of hydrogen-bond interactions, viz. N2—H2A···Cl1 and C21—H21A···O1Aⁱ [symmetry code: (i) x + 1/2, -y + 3/2, -z + 1] (Table 1 and Fig. 2).

The crystal structure is further stabilized by weak C—H···π interactions [symmetry code: 1/2 - x, 1 - y, -1/2 + z] between the cyclohexyl (C5—H5A) and the isothiazole ring.

Experimental

Lurasidone hydrochloride (10 g, 18.9 mmole) was dissolved in a hot solution in a 3:1 mixture of acetone and water. After cooling to ambient temperature, the solvent was allowed to evaporate slowly. Colourless crystals of (1) appeared after 5 days.