Anticonvulsant Profiles of Certain New 6-Aryl-9-substituted-69-diazaspiro-4.5decane-810-diones and 1-Aryl-4-substituted-14-diazaspiro5.5undecane-35-diones

摘要

Synthesis and anticonvulsant potential of certain new 6-aryl-9-substituted-6,9-diazaspiro[4.5]decane-8,10-diones (>6a–>l) and 1-aryl-4-substituted-1,4-diazaspiro[5.5]undecane-3,5-diones (>6m–>x) are reported. The intermediates 1-[(aryl)(cyanomethyl)amino]cycloalkanecarboxamides (>3a–>f) were prepared via adopting Strecker synthesis on the proper cycloalkanone followed by partial hydrolysis of the obtained nitrile functionality and subsequent N-cyanomethylation. Compounds >3a–>f were subjected to complete nitrile hydrolysis to give the respective carboxylic acid derivatives >4a–>f which were cyclized under mild conditions to give the spiro compounds >5a–>f. Ultimately, compounds >5a–>f were alkylated or aralkylated to give the target compounds >6a–>i and >6m–>u. On the other hand, compounds >6j–>l and >6v–>x were synthesized from the intermediates >5a–>f through alkylation, dehydration and finally tetrazole ring formation. Anticonvulsant screening of the target compounds >6a–>x revealed that compound >6g showed an ED50 of 0.0043 mmol/kg in the scPTZ screen, being about 14 and 214 fold more potent than the reference drugs, Phenobarbital (ED50 = 0.06 mmol/kg) and Ethosuximide (ED50 = 0.92 mmol/kg), respectively. Compound >6e exhibited an ED50 of 0.019 mmol/kg, being about 1.8 fold more potent than that of the reference drug, Diphenylhydantoin (ED50 = 0.034 mmol/kg) in the MES screen. Interestingly, all the test compounds >6a–>x did not show any minimal motor impairment at the maximum administered dose in the neurotoxicity screen.