Synthesis and Biological Evaluation of Five‐Atom‐Linker‐Based Arylpiperazine Derivatives with an Atypical Antipsychotic Profile

Abstract

Herein we describe a focused set of new arylpiperazine derivatives as potential broad-spectrum antipsychotics. The general structure contains a quinolinone-like moiety, an arylpiperazine moiety, and a five-atom linker. Among them,isothiazol-4-yl)piperazin-1-yl)pentyl)quinolin-2(1H)-one (S6) shows a promising preclinical profile. Compound S6, characterized by partial D 2 R agonism, 5-HT 1A R agonism, 5-HT 2A R antagonism, and blockade of SERT activities, was found to decrease psychosis-and depressive-like symptoms in rodents. The polypharmacological profile of S6 could provide opportunities for the treatment of various other central nervous system disorders such as anxiety, depression, and psychoses associated with dementia. Furthermore, S6 demonstrated acceptable safety, toxicology, and pharmacokinetic profiles, and has been selected as a preclinical candidate for further evaluation in schizophrenia.[a] Dr.previous SAR studies on antipsychotic drugs indicated that an appropriate linker is of great importance for desired multireceptor activity, we also explored the influence of linker flexibility of the new derivatives on receptor function profiles. [18] Among the derivatives prepared, compound S6 manifested a unique polypharmacological antipsychotic profile. It displayed much higher potency for the desired targets (D 2 , 5-HT 1A , 5-HT 2A , and SERT) than other off-target receptors (α 1A , H 1 , 5-HT 2C , M 3 , hERG). Thus, compound S6 was developed as an atypical antipsychotic candidate to treat schizophrenia based on the D 2 R, 5-HT 1A R, 5-HT 2A R and SERT multi-target profile. 2 3 4 5 6 7 8

Total Synthesis of 1”‐ and 2”‐Hydroxycannabidiol Metabolites

“…[12] Under these conditions the formation of the compound 7 was observed, but only in trace amounts. Finally, a slight modification of the Shen's conditions [13] permitted to produce ketones 7 and 8 in almost 1 : 1 ratio and in a 72 % of overall yield. Specifically, the hydration of 6 was attempted using a 4 % sulfuric acid water solution, HgSO 4 and ethanol as solvent at 70 °C.…”

“…Both metabolites were isolated as an inseparable ca. 1 : 1 epimeric mixture, as determined by the analysis of the 13 C{H} NMR spectra (see Supporting Information).…”

“…1 H NMR analyses were recorded at 400 MHz on a Varian Mercury Plus 400. 13 C NMR analyses were recorded at 100 MHz. NMR calibration was accomplished by referring to the TMS signal.…”

“…1 H NMR (CDCl 3 , 400 MHz): δ = 6.83 (s, 2H), 5.26 (s, 1H), 4.57-4.54 (m, 2H), 3.54 (d, 1H, J = 10.0 Hz), 2.73-2.65 (m, 1H), 2.35 (t, 2H, J = 5.6 Hz), 2.19-2.09 (m, 1H), 2.08-2.00 (m, 1H), 1.87-1.80 (m, 1H), 1.76-1.66 (m, 1H), 1.64-1.58 (m, 5H), 1.56 (s, 3H), 1.35 (s, 18H), 1.04 (t, 3H, J = 6.0 Hz). 13 Synthetic procedure for the preparation of 7 and 8. To a solution of 6 (0.30 g, 0.61 mmol) in EtOH (6 mL) an aqueous 4 % H 2 SO 4 solution (3 mL, 0.365 mmol, 0.6 eq.)…”

“…1 H NMR (CDCl 3 , 400 MHz): δ = 7.36 (s, 2H), 5.24 (s, 1H), 4.55 (s, 2H), 3.63 (d, 1H, J = 12.5 Hz), 2.91 (t, 2H, J = 7.5 Hz), 2.79-2.71 (m, 1H), 2.21-2.11 (m, 1H), 2.09-2.03 (m, 1H), 1.89-1.82 (m, 1H), 1.76-1.67 (m, 3H), 1.64 (s, 3H), 1.56 (s, 3H), 1.48-1.29 (m, 20H), 0.96 (t, 3H, J = 7.5 Hz). 13 Synthetic procedure for the preparation of 1"-OH-CBD and 2"-OH-CBD. LiAlH 4 (0.031 g, 0.805 mmol, 5 eq.)…”