Synthesis and activity of 6-aryl-3-(hydroxypolymethyleneamino)pyridazines in animal models of epilepsy

• Published in: Journal of medicinal chemistry Vol. 29; no. 3; pp. 369 - 375
• Main Authors: Hallot, Andre, Brodin, Roger, Merlier, Josiane, Brochard, Joelle, Chambon, Jean Pierre, Biziere, Kathleen
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.03.1986
• Subjects: Animals; Anticonvulsants - chemical synthesis; Bicuculline - antagonists & inhibitors; Chemistry; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Exact sciences and technology; Female; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Hypnotics and Sedatives; Kindling, Neurologic - drug effects; Male; Mice; Motor Skills - drug effects; Organic chemistry; Papio; Pentylenetetrazole - antagonists & inhibitors; Photic Stimulation; Preparations and properties; Pyridazines - chemical synthesis; Pyridazines - pharmacology; Rats; Rats, Inbred Strains; Seizures - chemically induced; Seizures - drug therapy; Seizures - etiology; Structure-Activity Relationship; In vivo; Nitrogen heterocycle; Animal; Six membered ring; Benzenic compound; Anticonvulsant; Sedative; Biological activity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00153a011

A series of 6-aryl-3-(hydroxypolymethyleneamino)pyridazines derivatives was synthesized and evaluated for anticonvulsant activity. The compounds were screened in mice for their ability to antagonize maximal electroshock- and bicuculline-induced seizures; neurotoxicity was evaluated in the rotorod test. The anticonvulsant activity of the most potent compounds in this series was also examined in kindled amygdaloid rats and in photoepileptic Papio papio baboons. Phenobarbital, diphenylhydantoin, carbamazepine, and sodium valproate were used as standard antiepileptic drugs. The structure-activity relationships in this series were examined by either varying the aryl ring in the 6-position of the pyridazine ring or by modifying the 3-amino side chain. Only the compounds with a phenyl ring in the 6-position of the pyridazine ring exhibited appreciable anticonvulsant activity. Furthermore, a 4-hydroxypiperidine side chain in the 3-position of the pyridazine ring appeared essential for anticonvulsant activity. Substituting the phenyl ring with a Cl in the 2-position led to a substantial increase of activity; disubstituting the phenyl ring with a Cl in the 2- and 4-positions yielded the most potent compounds in this series, some of which were as potent or more potent than phenobarbital. Two compounds, 6-(2-chlorophenyl)-3-(4-hydroxypiperidino)pyridazine (2) and 6-(2,4-dichlorophenyl)-3-(4-hydroxypiperidino)pyridazine (3), were selected for further studies. Clinical evaluation of these compounds is in progress.