Novel Water-Soluble Sedative-Hypnotic Agents: Isoindolin-1-one Derivatives

Abstract

Currently, propofol is widely used as an intravenous anesthetic and sedative in clinical settings. Propofol is hardly soluble in water in nature and is prescribed as an emulsion formulation containing soybean oil, glycerin, and egg phospholipids.1) As a result, the long-term use of a propofol emulsion, for example in post-operative sedation, may not only lead to overload of the fat nutrition 2) but also an increase in the risk of infection in patients by rapid microbial growth at room temperature.3) In addition, clinical problems that have been noted with propofol include vascular pain on injection 4) and strong respiratory depression.5) Based on the points above-mentioned, aiming at the discovery of an anesthetic and sedative as an easy-to-formulate water-soluble drug with reduced respiratory depression, we initiated a search for a compound suitable as a lead. Recently nonbenzodiazepine compounds with selective pharmacological actions on sedation and anti-anxiety have been developed. 6,7) Therefore, amongst the parent skeletons of these nonbenzodiazepine compounds, we took note of the isoindolin-1-one skeleton 6) ( Fig. 1), and synthesized approximately 170 compounds and evaluated their hypnotic effects in mice after intravenous administration.8) Herein, we report the representative preferred compounds with potent sedative-hypnotic actions. ChemistryThe general synthetic method used to prepare isoindolin-1-one derivatives is as shown in Chart 1. Phthalic anhydride 30 was heated with an appropriate amine to afford phthalimides 31, which were then reduced with sodium borohydride to afford the hemiacetals 32. The hemiacetals 32 and the Wittig reagent (Ph 3 PϭCHCO 2 Et) were heated in toluene to afford the ethyl esters 33, which were then hydrolyzed with potassium carbonate to afford the carboxylic acids 34. In the presence of N-(3-dimethylaminopropyl)-NЈ-ethylcarbodiimide hydrochloride and HOBT (1-hydroxybenzotriazole hydrate), reaction with the appropriate 1-alkylpiperazine 35 We

Anesthetic drug development: Novel drugs and new approaches

“…[30] Although structurally not a benzodiazepine, JM-1232 (-) allosterically modulates GABA A receptor in a manner that seems to be identical to benzodiazepines and its activity can be inhibited by flumazenil, strongly suggesting that it binds to the same site on the GABA A receptor as classic benzodiazepines. [595838] In addition to its sedative–hypnotic actions, JM-1232 (-) has been shown in animals to possess antinociceptive properties and have a therapeutic index of >38.5, which indicates a safety margin that is greater than propofol, midazolam, thiopental, and even etomidate.…”

Does the sedative agent, JM-1232(−) cause QT prolongation with subsequent torsades de pointes?

“…To detect the possible association between a drug and TdP, a guideline, the Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals (ICH S7B), was approved at the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) (Darpo et al 2006). JM-1232(−) ((−)-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-2-phenyl-3,5,6,7-tetrahydrocyclopenta[f] isoindole-1(2H)-one) is a novel isoindoline compound that acts on the benzodiazepine receptor (Kanamitsu et al 2007). Its clinical use as an intravenous anesthetic or sedative drug is currently being studied in clinical trials; therefore, we must determine if this drug induces a fatal arrhythmia.…”

4,5-Dimethylbenzene-1,2-dimethanol

“…Since maleic anhydride (6) is less expensive and more reactive than 3, we explored the use of this dienophile in the Diels-Alder reaction with 2. Following the procedure of Kanamitsu and coworkers [10], cycloaddition of 6 with 2 in benzene at 25 °C for 12 h gave adduct 7 in 96% yield. These authors subsequently aromatized product 7 using Br2 in refluxing acetic acid, but the yield of anhydride 8 was only 37%.…”