Synthesis of Chiral 1-[ω-(4-Chlorophenoxy)alkyl]-4-methylpiperidines and Their Biological Evaluation at σ₁, σ₂, and Sterol Δ₈−Δ₇ Isomerase Sites

Abstract

Sumitomo's patented sigma ligand 1-[3-(4-chlorophenoxy)propyl]-4-methylpiperidine (15), which has been claimed as agent for CNS disorders and neuropathies, and its lower homologue 12 were prepared along with related chiral (4-chlorophenoxy)alkylpiperidines. They were tested at sigma1, sigma2, and sterol Delta8-Delta7 isomerase (SI) sites by in vitro radioligand binding assays, to evaluate the influence of a chiral center in the alkyl chain on the selective sigma(1) binding relative to other sigma family sites. Generally high sigma1-site affinities were found, so that the chirality introduced by a methyl substitution resulted in slight differences. Nevertheless, the shorter oxyethylenic chain was beneficial to increase sigma1 selectivity. However, the (-)-(S)-4-methyl-1-[2-(4-chlorophenoxy)-1-methylethyl]piperidine ((-)-(S)-17) reached the highest sigma1 affinity (K(i) = 0.34 nM) and the best selectivity relative to the sigma2 site (547-fold). Compound (-)-(S)-17 displayed also a moderate selectivity (11-fold) relative to the SI site.

Pharmacophore Identification for Sigma-1 (σ1) Receptor Binding: Application of the "Deconstruction - Reconstruction - Elaboration" Approach

“…Piperazines 95 where n = 1-6 bind in the low nanomolar range [37], and 96 (Ki ca 12 nM) [38] might be viewed as an additional example of a arylalkylamines bearing a heteroatom (i.e., N atom) in the chain. Compounds 97, which also bind in the low nanomolar range when n = 1 or 2 [39], bears an oxygen atom in the chain and possesses a piperidinyl 4-methyl group as found in 57. Spiro compound 98 (which binds with a Ki = 1.29 nM and displays >2,700-fold selectivity over σ 2 receptors) [40], and 99 [41] represents a sulfur-…”

One-step synthesis of homochiral O-aryl and O-heteroaryl mandelic acids and their use as efficient 1H NMR chiral solvating agents

“…However, when applied to the formation of diastereomeric salts with mexiletine, an antiarrhythmic drug, and related compounds, they caused only poor chemical shift non-equivalences and were unable to offer sufficient chiral discrimination for ee value determinations, regardless of the experimental conditions used. 15 Over the last few years, O-aryl mandelic acids 3 have been reported as efficient CSAs for the determination of the ee values of some clinically [15][16][17][18] or pharmacologically 15,16,19,20 relevant amines. In particular, (S)-O-(p-chlorophenyl)mandelic acid 3a was successfully used to assess the ee values of mexiletine and two of its analogs, 15,16 para-hydroxymexiletine, a major mexiletine metabolite, 18 a prolinoxylidide acting as a voltage-gated sodium channel blocking agent, 19 and some 4-methylpiperidine derivatives reported as rreceptor ligands.…”

“…In particular, (S)-O-(p-chlorophenyl)mandelic acid 3a was successfully used to assess the ee values of mexiletine and two of its analogs, 15,16 para-hydroxymexiletine, a major mexiletine metabolite, 18 a prolinoxylidide acting as a voltage-gated sodium channel blocking agent, 19 and some 4-methylpiperidine derivatives reported as rreceptor ligands. 20 (R)-O-(2-Naphthyl)mandelic acid 3b was used as an alternative to chiral CZE analysis to assess the ee value of the so-called hydroxymethylmexiletine, one of the major metabolites of mexiletine. 18 Homochiral forms of 3a were obtained in yields ranging from low to moderate by chemical, 21 lipase-mediated, 22 and dynamic kinetic 23 resolution of racemic 3a, 3a methyl ester, and the 3a imido derivative of (S)-4-isopropyl-1,3-oxazolidin-2-one, respectively.…”

H-NMR determination of the enantiomeric excess of the antiarrhytmic drug Mexiletine by using mandelic acid analogues as chiral solvating agents

“…54c On the other hand, we had previously reported the application of (S)-2a for the direct determination of the enantiomeric excesses of some tocainide analogues 60 and 4-methylpiperidine derivatives with high σ receptors affinity. 58 In the NMR experiment related to racemic 1a in the presence of (S)-2a, both methyl doublets and methine multiplets of 1a were shifted to higher frequencies of 0.09 ppm and 0.15 ppm, respectively; a similar effect was also observed for the methyl singlets (0.12 ppm). This finding was probably related to a high percentage of diastereomeric salt formation, at working stoichiometry.…”

“…Our first attempts of direct 1 H-NMR 1a ee determination used either commercially available (+)- (Figure 2), recently synthesized in our laboratory in optically pure form, 58 as CSAs. Their use was suggested by the number of applications of some CDAs structurally related to the former 15,33,59 and by the reported efficacy of 2-phenoxypropionic acids as CSAs, 54c respectively.…”