Phenyl acetate derivatives, fluorine-substituted on the phenyl group, as rapid recovery hypnotic agents with reflex depression

doi:10.1016/j.ejmech.2014.10.073

European Journal of Medicinal Chemistry

Volume 89, 7 January 2015, Pages 524-539

https://doi.org/10.1016/j.ejmech.2014.10.073 Get rights and content

Highlights

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Fluorine-containing phenyl acetate derivatives with improved hypnotic potencies were synthesized.
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Compound 55 showed apparently longer duration of LORR and maintained the rapid recovery.
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Compound 55 showed NMDA binding and the reflex depression effect.

Abstract

We report the synthesis of novel, potentially hypnotic fluorine-substituted phenyl acetate derivatives. We describe the structure–activity relationship that led us to the promising derivative: ethyl 2-(4-(2-(diethylamino)-2-oxoethoxy)-5-ethoxy-2-fluorophenyl) acetate (55). The unique pharmacological features of compound 55 are its relatively high affinity for the GABA_A receptor, together with a unique affinity for the NMDA receptor, different to propanidid and AZD3043. In animal models, compound 55 showed stronger hypnotic potency and longer duration of LORR than propanidid and AZD3043, but also maintained a rapid recovery time to walking and behavioral recovery. In particular, compound 55 displayed reflex depression during infusion.

Graphical abstract

Introduction

“Soft” drugs are those molecules that are purposefully designed to be rapidly metabolized (metabolically labile) [1]. In anesthesia, a soft drug is useful because it enables precise titration to effect and rapid recovery, which may allow swift and clear-headed recovery of consciousness and early home readiness [2].

Propofol (Fig. 1) has been associated with long-delayed awakening after prolonged infusion [3], which may mean that several days are required for complete dissipation of the drug's effects.

The role of fluorine in medicinal chemistry in recent years has been remarkable [4]. Drug candidates with one or more fluorine atoms have become commonplace [5]. The chief advantage of fluorine, especially as trifluoromethyl- or fluoro-substituted aryl compounds, is that it imparts a variety of properties to medicines, including increased lipid solubility and improved drug transport across the blood–brain barrier [6].

In our previous work [7], we introduced fluorine atoms to the ether (R₁) and ester (R₂) moieties of the parent structure of propanidid. Among the fluorine-containing phenyl acetate derivatives, compound 1 showed a shorter duration of ‘loss of righting reflex’ (LORR) and faster recovery time (time to walking and time to behavioral recovery) than propanidid or AZD3043. This rapid recovery might make compound 1 suitable as a soft drug for precise titration and allow swift and clear-headed recovery of consciousness and early home readiness.

However, there has been controversy about soft drugs, such as AZD3043 and MOC-etomidate, and whether they offer too rapid a recovery from anesthesia. Relatively longer durations of LORR could reduce the dose administered and still be manipulated readily in the clinic [2], [17]. We tested compounds with fluorine-containing alkyl groups at R₂ and they had a shorter duration of LORR than propanidid and AZD3043 because of the faster metabolism by an esterase (compound 1). The faster metabolism may have been due to the improved lipid solubility of the ester moiety (R₂). However, a fluorine atom on the aryl group was at a relatively long distance and would be expected to have little influence on the ester moiety. Thus, we proposed that compounds fluoro-substituted on the aryl group would show longer durations of LORR compared with the introduction of fluorine on the alkyl group on the ester moiety (R₂). Based on animal model tests, we confirmed our hypothesis that the optimized compounds showed longer durations of LORR and, at the same time, maintained rapid recoveries.

Section snippets

Chemistry

Synthesis of the novel fluorine-containing phenyl acetate derivatives was performed according to the reaction pathway illustrated in Scheme 1. Compounds 40–72 were prepared by a six-step reaction. Propanidid, AZD34043, and propofol were also synthesized.

First, 2-bromo-fluorophenols (2) were reacted with haloalkanes to provide 2-bromofluorophenyl ethers (3). Alkoxy fluorophenols (4) were obtained from 3 under n-BuLi, H₂O₂, acetic acid and −78 °C conditions [8]. Subsequently, 4 and glyoxylic acid

In vitro studies

The new compounds were all dissolved in 5% DMSO. The following specific radioligands and tissue sources were used: (a) GABA_A receptor, [³H]EBOB, rat frontoparietal cortex [10], (b) NMDA receptor, [³H]MK-801, cerebral cortex [11], (c) serotonin 5-HT_1A receptor, [³H]8-OH-DPAT, rat brain cortex [12], (d) serotonin 5-HT_2A receptor, [³H]ketanserin, rat brain cortex [12], (e) serotonin 5-HT_2C receptor, [³H]mesulergine, rat brain cortex [12], (f) 5-HTT transporter, [³H]paroxetine, rat cerebral cortex

Hypnotic activity

In our previous study, the compounds with a fluorine-containing alkyl group on R₁ showed decreased hypnotic potency. Thus the fluorine-containing alkyl groups were not selected for R₁. The results showed that the compounds with fluorine substituted at the 2-position of the phenyl group and an Et group at R₁ displayed stronger hypnotic potencies than propanidid (HD₅₀ = 7.9 mg kg⁻¹) and AZD3043 (HD₅₀ = 8.5 mg kg⁻¹) in rat (Table 1). The HD₅₀ values of compounds 55, 56, and 57 were 5.6, 5.3, and

Conclusions

We introduced fluorine to the phenyl group of the propanidid framework. Fluorine at the 1- and 3-positions of the phenyl group decreased the hypnotic potencies, regardless of the ether (R₁) and ester (R₂) residues. However, we found some unexpected results with fluorine at the 2-position of the phenyl group. Compounds 55, 56, and 57 with an Et group at R₁ showed longer durations of LORR than propanidid and AZD3043, but maintained the rapid recovery time to walking and behavioral recovery.

There

Chemistry experimental

Melting points were determined in open capillary tubes and are uncorrected. NMR spectra are recorded at 400 MHz on a Varian Inova Unity 200 spectrometer in CDCl₃ and DMSO-d₆ solution. Chemical shifts are given in δ values (ppm), using tetramethylsilane (TMS) as the internal standard; coupling constants (J) were given in Hz. Signal multiplicities are characterized as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad signal). Reagents were all of analytical grade or of

Acknowledgments

The authors gratefully acknowledge the financial support of Jiangsu Nhwa Pharmaceutical Co., Ltd.

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Citation Excerpt :
In our previous work, we modified the structure of propanidid by introducing trifluoroethyl instead of ethyl to obtain compound 1 and adding fluorine to benzene to give compound 2 (Fig. 1).14,15 Compound 1 displayed favorable characteristics of an ultra-short recovery time compared with AZD3043 and propanidid in rodents and nonrodents.14 Compound 2 showed potent hypnotic effect and longer duration of action than propanidid or AZD3043, and shorter recovery time to walk than propofol, enabling its precise titration in anesthesia.15
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Original articlePhenyl acetate derivatives, fluorine-substituted on the phenyl group, as rapid recovery hypnotic agents with reflex depression

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

In vitro studies

Hypnotic activity

Conclusions

Chemistry experimental

Acknowledgments

Br. J. Anaesth.

Bioorg. Med. Chem. Lett.

Eur. J. Pharmacol.

Bioorg. Med. Chem.

Anesthesiology

Curr. Med. Chem.

J. Med. Chem.

Future Med. Chem.

Chem. Bio. Chem.

PLoS One

Original article
Phenyl acetate derivatives, fluorine-substituted on the phenyl group, as rapid recovery hypnotic agents with reflex depression