Synthesis, physicochemical and anticonvulsant properties of N-benzyl and N-aminophenyl derivatives of 2-azaspiro[4.4]nonane and [4.5]decane-1,3-dione. Part I.
To continue our systematic SAR studies, two series of N-benzyl- (X=CH2) and N-aminophenyl- (X=NH) derivatives of 2-azaspiro[4.4]nonane (1a-1j) and 2-azaspiro[4.5]decane-1,3-dione (2a-2j) were synthesized, and evaluated in maximum electroshock seizure (MES), subcutaneous pentylenetetrazole (sc.MET) and rotorod (TOX) tests for their anticonvulsant activity. Among those derivatives, the most potent N-aminophenyl-2-azaspiro[4.4]nonane-1,3-dione 1j had ED50=76.27 mg kg-1. X-ray structures for two pairs of derivatives with a different linker were solved. Then 3-D data for the active 1j versus less active 2j, both having an imine linker (X=NH), and the respective parent of compounds with a methylene linker (X=CH2) (1a and 2a) were discussed.
Obniska
Jolanta
J
Department of Pharmaceutical Chemistry, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland. mfobnisk@cyf-kr.edu.pl
Dzierzawska-Majewska
Agnieszka
A
Zagorska
Agnieszka
A
Zajdel
Pawel
P
Karolak-Wojciechowska
Janina
J
D000473:Alkanes / Q000138:chemical synthesis* / Q000494:pharmacology; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D018360:Crystallography, X-Ray / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004597:Electroshock / Q000009:adverse effects / Q000379:methods; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010433:Pentylenetetrazole / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D045442:Rotarod Performance Test; D012640:Seizures / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000473:Alkanes; D000814:Aniline Compounds; D000927:Anticonvulsants; D001372:Aza Compounds; C510599:N-aminophenyl-(4,5)decane-1,3-dione; C510598:N-benzyl-phenyl-2-azaspiro(4,4)nonane; D013141:Spiro Compounds; D010433:Pentylenetetrazole