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
Abstract:To investigate the association between streptozotocin (STZ)-induced painful diabetic neuropathy and the antihyperalgesic effect of capsaicin cream in rats, we first examined the antihyperalgesic effect of capsaicin cream and subsequently performed peripheral neurohistochemical examinations of neuropathic rats. Mechanical hyperalgesia occurred 2 weeks after STZ injection and persisted for 8 weeks of testing. The neuropathy was alleviated by a single application of 0.1% capsaicin cream, but not by cream base. The hyperalgesia did not decrease when the capsaicin cream was applied to normal animals. On the other hand, for dorsal root ganglion (DRG) neurons and hind paw cutaneous nerves, the neurohistochemical examination showed no difference between STZ rats and control rats with capsaicin (vanilloid) receptor subtype 1 (VR1) and NF200 double immunohistochemical staining of DRG neurons, but an increase in A-fibers was seen in the hind paw cutaneous nerves of the STZ rats compared to the control rats. Neither STZ rats nor control rats were toxically affected by the single application of 0.1% capsaicin cream. These results suggest that a single application of capsaicin cream exerts an antihyperalgesic effect in rats with painful neuropathy and increases peripheral A-fibers. However, we could not clarify how VR1 was involved in the effect in rats with STZ painful diabetic neuropathy. (J Toxicol Pathol 2008; 21: 97-104)
Aproximately 170 isoindolinone derivatives are synthesized and evaluated for their hypnotic effects by intravenous administration of the compounds to mice. The (-)-enantiomers of derivatives (VIII) show potent sedative-hypnotic activity, good water solubility and a wide safe margin. Among these compounds, (VIIId) is being considered as the most potential candidate for clinical trials in humans. -(KANAMITSU*, N.; OSAKI, T.; ITSUJI, Y.; YOSHIMURA, M.; TSUJIMOTO, H.; SOGA, M.; Chem.
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