Synthesis, physicochemical and anticonvulsant properties of new N-phenylamino derivatives of 2-azaspiro[4.4]nonane- and [4.5]decane-1,3-diones: Part V

• Published in: European journal of medicinal chemistry 2008, Vol.43 (1), p.53-61
• Main Authors: Kamiński, Krzysztof, Obniska, Jolanta, Dybała, Małgorzata
• Format: Article
• Language: English
• Subjects: 2-Azaspiro[4.4]nonane- and [4.5]decane-1,3-diones; 3-Cyclohexyl-pyrrolidine-2,5-diones; Animals; Anticonvulsant activity; Anticonvulsants - chemical synthesis; Anticonvulsants - metabolism; Anticonvulsants - pharmacology; Anticonvulsants - toxicity; Aza Compounds - chemical synthesis; Aza Compounds - metabolism; Aza Compounds - pharmacology; Aza Compounds - toxicity; Electroshock; Mice; N-phenylamino derivatives; Pentylenetetrazole - antagonists & inhibitors; Receptors, GABA-A - metabolism; RP-HPLC; Seizures - drug therapy; Spiro Compounds - chemical synthesis; Spiro Compounds - metabolism; Spiro Compounds - pharmacology; Spiro Compounds - toxicity
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2007.02.024

The synthesis, physicochemical and pharmacological properties of new N-phenylamino derivatives of 2-azaspiro[4.4]nonane-1,3-dione ( 8– 10), 2-azaspiro[4.5]decane-1,3-dione ( 11– 18) and 3-cyclohexyl-pyrrolidine-2,5-dione ( 19, 20) derivatives were described. The anticonvulsant properties of those compounds were examined by a maximal electroshock (MES) and a pentylenetetrazole ( scPTZ) tests, and their neurotoxicity was determined using a rota-rod test. The most active was N-[(2,4-dichlorophenyl)-amino]-2-azaspiro[4.4]nonane-1,3-dione ( 9), which exhibited anti-seizure properties in the MES model at a dose of 100 mg/kg in mice and at a dose of 30 mg/kg in rats. To explain the possible mechanism of action, for chosen active derivatives N-[(2,4-dichlorophenyl)-amino]-2-azaspiro[4.4]nonane-1,3-dione ( 9), N-[(4-bromophenyl)-amino]-2-azaspiro[4.4]nonane-1,3-dione ( 10), N-[(2,4-dichlorophenyl)-amino]-2-azaspiro[4.5]decane-1,3-dione ( 12) and N-[(4-bromophenyl)-amino]-2-azaspiro[4.5]decane-1,3-dione ( 13) their influence on GABA A receptors were tested in vitro. Moreover, for all compounds obtained the lipophilic properties were determined by use of RP-HPLC method. Several compounds investigated were effective in the MES and/or scPTZ screens. The presence of spirocycloalkyl system was essential for anticonvulsant activity. [Display omitted]