5-(4-Chlorophenyl)-5,6-dihydro-1,3-oxazepin-7(4H)-one derivatives as lipophilic cyclic analogues of baclofen: design, synthesis, and neuropharmacological evaluation.
In trials to preserve the pharmacological profile and improve the bioavailability via lipophilicity increment of baclofen 1 and searching for more potent and less toxic muscle relaxants and analgesics, nine substituted cyclic analogues of 1 were designed and synthesized. The target derivatives 5-(4-chlorophenyl)-5,6-dihydro-1,3-oxazepin-7(4H)-one (11-19) were obtained through amide formation to the corresponding intermediates (2-10) followed by cyclization using acetic anhydride. The structures of the target compounds (11-19) were confirmed by IR, (1)H NMR, MS, and elemental analyses. The neuropharmacological activities of these lipophilic cyclic analogues (11-19) were assessed for their effects on motor activity, muscle relaxation, pain relief and impaired cognition, by intraperitoneal administration at a dose of 3mg/kg with reference to those of baclofen 1. Our results showed that compounds 11-14 are devoid of all of the tested pharmacological effects associated with 1. In all paradigms tested, undecyl, tridecyl, heptdec-8-enyl and benzyl substituted analogue derivatives (15, 16, 18, and 19) revealed a significant neurological activity being vividly favorable comparable with baclofen 1. 2-Benzyl-5-(4-chlorophenyl)-5,6-dihydro-1,3-oxazepin-7(4H)-one derivative 19 is the most active candidate with high significant neurological potencies, while 5-(4-chlorophenyl)-2-(dec-8-enyl)-5,6-dihydro-1,3-oxazepin-7(4H)-one derivative 17 displayed activity at relatively higher time interval. These results probe a new structurally distinct class incorporating 1,3-oxazepine nucleus as promising candidates as GABA(B) agonists for further investigations.
Abdel-Hafez
Atef A
AA
Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt. atef@aun.edu.eg
Abdel-Wahab
Basel A
BA
D000818:Animals; D001418:Baclofen / Q000737:chemistry* / Q000494:pharmacology; D003072:Cognition Disorders / Q000188:drug therapy*; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D018755:GABA Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D058786:GABA-B Receptor Agonists; D057927:Hydrophobic and Hydrophilic Interactions; D007274:Injections, Intraperitoneal; D009682:Magnetic Resonance Spectroscopy / Q000379:methods / Q000592:standards; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects*; D010077:Oxazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy*; D018080:Receptors, GABA-B / Q000737:chemistry; D012015:Reference Standards; D013237:Stereoisomerism
D018755:GABA Agonists; D058786:GABA-B Receptor Agonists; D010077:Oxazepines; D018080:Receptors, GABA-B; D001418:Baclofen