No abstract

A series of N-phenyl-N'-pyridinylureas was examined for anticonvulsant activity. Extensive structure/activity investigations revealed optimal activity in the N-(2,6-disubstituted-phenyl)-N'-(4-pyridinyl)urea series, with 37 exhibiting the best overall anticonvulsant profile. Compound 37 was effective against seizures induced by maximal electroshock but did not protect mice from clonic seizures produced by the convulsant pentylenetetrazol. The overall pharmacological profile suggests that 37 would be of therapeutic use in the treatment of generalized tonic-clonic and partial seizures. Compound 37 was selected for Phase 1 clinical trials.

Durch Acylierung von (I) zu den Ketonen (II) und weitere Umsetzung mit den 1,2‐Diaminen (III) erhält man die Pyrazolodiazepine (IV).

The introduction of lipophilic groups onto the ring nitrogen of nipecotic acid and guvacine, two known GABA uptake inhibitors, afforded potent, orally-active anticonvulsant drugs. A series of compounds is reported which explores the structure-activity relationships (SAR) in this series. Among the areas explored: side-chain SAR (aromatic-, heterocyclic-, and tricyclic-containing side chains) and modifications to the tetrahydropyridine ring. The benzhydrol ether-containing side chains afforded the most potent compounds with several exhibiting in vitro IC50 values for GABA uptake of < 1 microM (including 5, Table I; 37, 43, Table IV; and 44, Table V). Compound 44 was selected for extensive evaluation and subsequently progressed to Phase 1 clinical trials with severe adverse effects seen after single dose administration to humans.

A lipophilic derivative of the known GABA uptake inhibitor guvacine has been prepared. The synthesis of this compound, [1-[2-bis[4-(trifluoromethyl)]phenyl]-methoxy]ethylj-l,2,5,6-tetrahydro-3-pyridine carboxylic acid, monohydrochloride, Cl-966, is described. Studies were carried out to determine the metabolic profile of Cl-966 in rats. Two metabolites, one less polar and the other more polar than Cl-966, were identified and their structures assigned by spectroscopic methods and confirmed by comparison to synthetic material.