Synthesis and anticonvulsant activity of enaminones. 4. Investigations on isoxazole derivatives.
Due to the exceptional anticonvulsant activity displayed by substituted aniline enaminones, related pyridine derivatives and phenothiazines synthesised in our laboratories, the further investigation of various aromatic heterocycles was undertaken. Condensation of cyclic 1,3-diketo esters with 3-, and 5-aminoisoxazole derivatives led to a series of potent anti-maximal electroshock (MES) analogues, three of which occurred in the 3-amino series: ethyl ester (10), orally (po) active in rats [ED(50) 68.9 mg kg(-1), TD(50) > 500 mg kg(-1), protective index (PI = TD(50)/ED(50)) > 49.6]; methyl ester (9), ED(50) 68.9 mg kg(-1) intraperitoneally (ip) in mice, TD(50) > 500 mg kg(-1), PI > 7.3, and tert-butyl ester (8), ED(50) 28.1 mg kg(-1) po in rats, TD(50) > 500 mg kg(-1), PI > 17.8. Sodium channel binding studies, as well as evaluations against pentylenetetrazol, bicuculline, and picrotoxin on isoxazole 10 were all negative, leading to an unknown mechanism of action. X-ray diffraction patterns of a representative of the 3-amino series (isoxazoles 6-11) unequivocally display the existence of intramolecular hydrogen bonding of the nitrogen to the vinylic proton in the cyclohexene ring, providing a pseudo three ring structure which was also shown previously with the vinylic benzamides. Physicochemical-permeability across the BBB suggested an efflux mechanism for the previously synthesised aniline enaminones, but not with isoxazole 10.
Eddington
Natalie D
ND
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201-4403, USA.
Cox
Donna S
DS
Roberts
Ralph R
RR
Butcher
Raymond J
RJ
Edafiogho
Ivan O
IO
Stables
James P
JP
Cooke
Neville
N
Goodwin
Angela M
AM
Smith
Carlynn A
CA
Scott
K R
KR
D000588:Amines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000166:cytology; D018360:Crystallography, X-Ray; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D009498:Neurotoxins / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D000588:Amines; D000927:Anticonvulsants; D007555:Isoxazoles; D009498:Neurotoxins; D015222:Sodium Channels