Anticonvulsant Profiles of Certain New 6-Aryl-9-substituted-6,9-diazaspiro-[4.5]decane-8,10-diones and 1-Aryl-4-substituted-1,4-diazaspiro[5.5]undecane-3,5-diones

Abstract

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.

Synthesis, molecular modeling studies, and anticonvulsant evaluation of novel 1‐((2‐hydroxyethyl)(aryl)amino)‐N‐substituted cycloalkanecarboxamides and their acetate esters

“…Representative examples of anticonvulsants (training set) with their ED 50 values in scPTZ test. 2 : ED 50 = 0.49 mmol/kg; 3 : ED 50 = 0.0056 mmol/kg; 4 : ED 50 = 0.45 mmol/kg; 5 : ED 50 = 0.011 mmol/kg; 6 : ED 50 = 0.017 mmol/kg; 7 : ED 50 = 0.19 mmol/kg; 8 : ED 50 = 0.012 mmol/kg; 9 : ED 50 = 0.071 mmol/kg; 10 : ED 50 = 0.15 mmol/kg; 11 : ED 50 = 0.019 mmol/kg…”

“…Compounds IIIa–e , IVa–f , Va–d , VIa–d , VIIa–d , VIIIa–f were prepared according to adopted procedures . Please also see the Supporting Information for further details.…”

“…Besides, it was previously disclosed the anticonvulsant potential of certain diazaspiroalkanediones 1 (Figure ) . Accordingly, it was found of interest to design and synthesize a set of novel 1‐((2‐hydroxyethyl)(aryl)amino)‐ N ‐substituted cycloalkanecarboxamides ( IXa–l ).…”

Synthesis and Anticonvulsant Activity of Substituted‐1,3‐diazaspiro[4.5]decan‐4‐ones

“…scPTZ test : To determine the production of threshold or minimal clonic seizures, 85 mg/ kg PTZ was injected subcutaneously in a loose fold of skin on the back of the mice neck 30 min after individually i.p. injection of the reference drugs ethosuximide (150 mg/kg ≡ 1.06 mmol/kg) , phenobarbital (30 mg/kg ≡ 0.13 mmol/kg) , or one of the test compounds in the dose range of 4–37 mg/ kg. Meanwhile, the control experiments were performed using the solvent alone.…”

“…Moreover, many geminally disubstituted cyclohexane derivatives have been proven to elicit anticonvulsant profile such as gabapentin ( VI ) . In the same vein, Aboul‐Enein et al disclosed the preparation and the anticonvulsant potential of several geminally disubstituted cyclohexane derivatives VII , VIII , XI , and X in the PTZ and maximal electroshock‐induced seizure tests . In addition, it was reported that some compounds bearing the pharmacophoric aminoacyl moiety such as remacemide XI , safinamide XII , XIII , and XIV possessed pronounced anticonvulsant profile (Fig.…”