Arch. Pharm. Chem. Life Sci. 2008, 341, 81 – 89 A. A. Kadi et al. 81 Full Paper Synthesis, Ultra-Short Acting Hypnotic Activity, and Metabolic Profile of Ethyl 8-Oxo-5,6,7,8-tetrahydro-thiazolo[3,2-a] [1,3]diazepin-3-carboxylate (HIE-124) Adnan A. Kadi 1 , Hassan A. El-Kashef 2 , Alaa A.-M. Abdel-Aziz 1 , Ghada S. Hassan 3 , Justice Tettey 4 , Mary H. Grant 5 , Jochen Lehmann 6 , Hussein I. El-Subbagh 1 1 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia 2 Department of Pharmacology, College of Pharmacy, Mansoura University, Mansoura, Egypt 3 Department of Medicinal Chemistry, College of Pharmacy, Mansoura University, Mansoura, Egypt 4 Institute of Pharmaceutical and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom 5 Department of Bioengineering, University of Strathclyde, Glasgow, United Kingdom 6 Institut of Pharmacy, Friedrich-Schiller-University Jena, Jena, Germany The synthesis and biological evaluation of ethyl 8-oxo-5,6,7,8-tetrahydro-thiazolo[3,2-a][1,3]diaze- pin-3-carboxylate (HIE-124, 4), as a member of a new generation of ultra-short acting hypnotics is described. HIE-124 4 exhibited potent in-vivo activity with a very rapid onset of action and a shorter duration of action with no acute tolerance or noticeable side effects than thiopental sodium. The rat in-vivo and in-vitro metabolic profile of 4 is also described. Urine was pooled from a number of animals and analyzed using electrospray liquid chromatography mass spec- trometry (ESI LC-MS). HIE-124 4 was incubated with rat-liver microsomal and rat-liver hepatocyte preparations then similarly analyzed. The only metabolic product of both in-vitro and in-vivo experiments is the carboxylic acid derivative 5. HIE-124 4 has the potential use not only as a pre- anesthetic medication and as anesthesia inducer but also has the potential to be used with thio- pental sodium to maintain anesthesia for longer duration. Keywords: Metabolic profile / Synthesis / Thiazolo[3,2-a][1,3]diazepine / Ultra-short acting hypnotic / Received: June 28, 2007; accepted: November 5, 2007 DOI 10.1002/ardp.200700132 Introduction Surgical procedures require the administration of several intravenous drugs to ensure hypnosis, analgesia, relaxa- tion, and control of visceral reflex responses. The use of intravenous drugs adds flexibility and permits the administration of lower doses of inhalational anesthetic agents. General anesthesia most often is initiated by an injection of thiopental, an ultra-short acting barbiturate, to induce sleep prior to administration of the agents that are necessary for maintaining anesthesia during the sur- gical procedure. Ultra-short acting barbiturates and ben- zodiazepines have an important place in the practice of anesthesiology. Thiopental sodium remains the standard for comparison with new agents. Single intravenous anesthetic dose of thiopental pro- duces unconsciousness within 10 – 20 seconds. The depth of anesthesia may increase for up to 40 seconds then decreases progressively until consciousness returns in 20 – 30 minutes. However, recovery may require many hours if a large dose of thiopental sodium is adminis- tered [1]. Thiopental is metabolized slowly in the liver, which together with other factors, may influence the depth of anesthesia, time of recovery, and duration of action [2]. The concentration employed of thiopental should not exceed 2.5% in aqueous solution. When greater concentration is injected extravascularly, severe Correspondence: Hussein I. El-Subbagh, Department of Pharmaceuti- cal Chemistry, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia. E-mail: subbagh@yahoo.com Fax: +966 1 467-6383 Abbreviations: ethyl 8-oxo-5,6,7,8-tetrahydro-thiazolo[3,2-a][1,3]diaze- pin-3-carboxylate (HIE-124); total ion current (TIC); rat liver microsomes (RLM's); glutathione (GSH); Troglitazone (TGZ); single ion monitoring (SIM) i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim