Synthesis and CLOGP correlation of imidooxy anticonvulsants.
Continuing structure-activity studies on the anticonvulsant activity of analogs of N-(benzyloxy)-2-azaspiro[4.4]nonane-1,3-dione (2a), which displayed anti-electroshock seizure (MES) activity and a protective index (TD50/ED50) of > 4.5 are reported. An in-depth analysis of this moiety was studied employing the Topliss structure activity and the Craig plot analytical approaches as well as a semiempirical method. CLOG P analysis was also applied to this series after experimentally determining the NOR fragment. All compounds were minimized and these physicochemical parameters correlated to anticonvulsant activity. Several interesting substituted benzyloxy compounds emerged from this study: the 2',4'-dichloro (2b), 4'-(trifluoromethyl) (2c), 2'-bromo (2d), 3'-chloro (2o), 2'-chloro (2r), 2'-fluoro (2p), and 3'-fluoro (2w) analogs, all of which had comparable, or better activity than the parent unsubstituted analog (2a). X-ray crystal analysis of the active 2a versus inactive N-benzyl-2-azaspiro[4.4]nonane-1,3-dione (10) is discussed.
Farrar
V A
VA
Department of Medicinal Chemistry, College of Pharmacy and Pharmacal Sciences, Howard University, Washington, D.C. 20059.
Ciechanowicz-Rutkowska
M
M
Grochowski
J
J
Serda
P
P
Pilati
T
T
Filippini
G
G
Hinko
C N
CN
el-Assadi
A
A
Moore
J A
JA
Edafiogho
I O
IO
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018360:Crystallography, X-Ray; D004597:Electroshock; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011760:Pyrrolidinones / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy / Q000209:etiology; D013141:Spiro Compounds / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D013329:Structure-Activity Relationship
D000927:Anticonvulsants; D011760:Pyrrolidinones; D013141:Spiro Compounds; C084465:N-(benzyloxy)-2-azaspiro(4.4)nonane-1,3-dione