The Design, Synthesis And Antiepileptic Activity Research Of Benzocycloalkane-containing Aminoamide Compounds

Epilepsy, as a most common chronic neurological disorder, is the second most common neurological disorder, whose treatment mainly relies on drugs. So far, there are approximately more than 30 antiepileptic drugs approved for marketing. The primary targets of these drugs are ion channels (including of Na+, Ca2+, K+etc) and γ-amino butyric acid (GABA) receptor. Although many antiepileptic drugs have been applied in clinical treatment, there is still a large portion of epilepsy remained uncontrollable. Thus, it is of great application value to develop novel antiepileptic drugs with high potency. Recently, the indication of Safinamide for anti-PD has been approved by the E.U. and the indication of Safinamide for antiepileptic is in Phase Ⅱ which indicates that Safinamide is a drug with multi-functioning mechanism. Considering the novel regulating effect of Safinamide on dual ion channels (Na+ and Ca2+) and its potent antiepileptic activity, along with its novel scaffold different from existing antiepileptic drugs, we utilized Safinamide as lead structure for antiepileptic drug design. By scientific investigation of numerous literatures and patents, we designed novel benzocycloalkane-containing aminoamide derivatives. The target compounds were divided into four structural modification sites (A-D).54 novel derivatives were designed, synthesized, and tested in rat-MES models. Protection rate of all derivatives for treatment of rat MES were measured. With a dose of 25 mg/kg,14 derivatives showed strong protective effects in rat-MES models. Among them, two derivatives are of 100% protection rate (64 and 108); two derivatives (37 and 80) are of 75%≤protection rate< 100%; ten derivatives (36,43,47,51, 62,68,71,76,77 and 107) are of 50%≤ protection rate< 75%. Three compounds with protection rate over 75% were selected to assay their ED5o in anti-rat MES models. Eventually, the benzocycloheptane-containing derivative 108 demonstrated the strongest antiepileptic activity. Compared with the positive, the antiepileptic activity of 108 decreased less than a half (13.72 mg/kg vs 7.66 mg/kg). Based on the activity results of rat-MES models, the structure-activity relationship of benzocycloalkane-containing aminoamide derivatives was summarized for the guidance of further structural optimization. The compound 108 found in this thesis which had the strongest activity, compared to Safinamide, became non-chiral compound by removing the chiral center of Safinamide. Taking the quality and safety study of new drug development into consideration, we do not need to think over the residue of chiral isomer and the potential toxicity for non-chiral drugs, and the corresponding preclinical research would be greatly simplified. Thus the antiepileptic active compound 108 with novel scaffold structure is of good development advantages. Compound 108 could be carried out in the progress of further structural optimization and druggability evaluation as an antiepileptic drug candidate.