Synthesis and Biological Evaluation of Some New Thiazolodiazepine Analogues as CNS Active Agents

Abstract

PhDThe ultra‐short ac ng ac vity of ethyl 8‐oxo‐5,6,7,8‐tetrahydro‐thiazolo[3,2‐a] [1,3]diazepin‐3‐carboxylate (HIE‐124, 12), as a member of a novel class, which might overcome many of the disadvantages and problems that usually associated the use of thiopental or benzodiazepines as intravenous anesthetic agents has been reported. The present investigation is directed toward the synthesis of new derivatives of the parent thiazolo[3,2‐a][1,3]diazepine (HIE‐124, 12), in continuation to the previous patented efforts in this area. These derivatives possess the potential to exhibit a promising and varying range of CNS activities, including, among others, hypnotic and anticonvulsant activities. The proposed compounds were synthesized according to the designed strategy. Structure elucidation of the synthesized intermediates and final products was attained by the aid of IR, 1H, 13C NMR, and mass spectrometry. The synthesized compounds were evaluated for various CNS activities. The new analogues Ethyl 3‐methyl‐8‐oxo‐5,6,7,8‐tetrahydro‐thiazolo[3,2‐a] [1,3]diazepine‐2‐carboxylate (35) and 2‐Bromo‐3‐methyl‐6,7‐dihydro‐thiazolo[3,2‐a] [1,3]diazepin‐8(5H)‐one (40) showed marginal hypnotic potency compared to what was reported about the parent compound HIE‐124 (12). Biological screening results allowed the allocation of two potent anticonvulsant agents worth patency. Compounds 35 and 40 proved to be the most active compounds in the present inves ga on as an convulsants with remarkable 100% protec on against PTZ induced convulsions as compared with the standard drug valproic acid. It is worth mentioning that compounds 35 (0.78 mmole/kg) and 40 (0.39 mmole/kg) proved to be almost two and four fold more ac ve, respec vely; than the used posi ve control sodium valproate (1.38 mmole/kg). Structure activity correlation of the obtained results revealed that, CNS activity is embedded in the structure core (8‐oxo‐5,6,7,8‐tetrahydro‐thiazolo[3,2‐a][1,3]diazepine) of the investigated compounds. Structure activity relationships (SAR) were deduced from the obtained data. These studied 8‐oxo‐5,6,7,8‐tetrahydro‐thiazolo[3,2‐a][1,3]diazepine analogues could be considered as useful templates for future development and further derivatization or modification to obtain more potent CNS active compounds