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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)
Author(s) -
Kadi Adnan A.,
ElKashef Hassan A.,
AbdelAziz Alaa A.M.,
Hassan Ghada S.,
Tettey Justice,
Grant Mary H.,
Lehmann Jochen,
ElSubbagh Hussein I.
Publication year - 2008
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.200700132
Subject(s) - in vivo , chemistry , hypnotic , pharmacology , anesthetic , in vitro , microsome , metabolic pathway , hepatocyte , chromatography , metabolism , biochemistry , anesthesia , medicine , biology , microbiology and biotechnology
The synthesis and biological evaluation of ethyl 8‐oxo‐5,6,7,8‐tetrahydro‐thiazolo[3,2‐ a ][1,3]diazepin‐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 spectrometry (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 thiopental sodium to maintain anesthesia for longer duration.