Synthesis and anticonvulsant activity of enaminones. 2. Further structure-activity correlations

Abstract

This report continues the in-depth evaluation of methyl 4-[(p-chlorophenyl)amino]-6-methyl-2-oxocyclohex-3-en-1-oate , 1 (ADD 196022), and methyl 4-(benzylamino)-6-methyl-2-oxocyclohex-3-en-1-oate, 2, two potent anticonvulsant enaminones. These compounds were evaluated employing the amygdala kindling model. Neither 1 nor 2 was active against amygdala kindled seizures, further supporting the corneal kindled model as a definitive tool for antielectroshock seizure evaluation as previously reported. Additional intraperitoneal (ip) data on 1 revealed toxicity at 24 h at 100 mg/kg. Several active analogs have been prepared with the view to minimizing toxicity. In a special ip rat screen developed by the Antiepileptic Drug Development (ADD) Program, these newer analogs were evaluated for protection against maximal electroshock seizures (MES) at 10 mg/kg and neurotoxicity at 100 mg/kg. From this screen, several compounds were shown to be safer alternatives, the most notable was methyl 4-[(p-bromophenyl)amino]-6-methyl-2-oxocyclohex-3-en-1-oate, 13. Compound 13 had an ip ED50 of 4 mg/kg in the rat and a TD50 of 269 mg/kg, providing a protective index (TD50/ED50) of > 67. By variation in the ring size, additional aromatic substitutions and the synthesis of acyclic analogs, these newer compounds provide a more definitive insight into the structure-activity correlation. CLOGP evaluation and molecular modeling studies are also provided to further elaborate the molecular characteristics of potential anticonvulsant enaminones.

Effect of P-Glycoprotein on the Pharmacokinetics and Tissue Distribution of Enaminone Anticonvulsants: Analysis by Population and Physiological Approaches

“…Enaminone anticonvulsants have been previously evaluated as compounds with potent anticonvulsant activity at the sodium channel binding site in a manner similar to class I anticonvulsants such as phenytoin, carbamazepine, and lamotrigine (Scott et al, 1993(Scott et al, , 1995. The prototype anticonvulsant of this series DM5 (calculated log P oct/water ϭ 3.23) was tested in this study.…”

“…1, synthesized by Scott and investigators, represent a new and potentially active series of compounds for the treatment of generalized tonic-clonic and complex partial seizures (Scott et al, 1993(Scott et al, , 1995. The prototype anticonvulsant of the series methyl 4-[(4Ј-chlorophenyl)amino]-6-methyl-2-oxo-3-cyclohexene-1-carboxylate (DM5) was found to be active intraperitoneally in mice (ED 50 26.2 mg/kg) and orally (p.o.)…”

The chemistry of enaminones, diazocarbonyls and small rings: our contribution

“…Thus, methyl 4-(p-chlorophenylamino)-6-methyl-2-oxocyclohex-3-ene-1-oate and methyl 4-(benzylamino)-6-methyl-2-oxocyclohex-3-ene-1-oate are two anticonvulsant enaminones. 79 Azirinomicine, the first naturally occurring 1-azirine (isolated from the Steptomyces aureaus bacteria) is an antibiotic 80 and dysidazirine, the first example of this strained ring class of heterocycles from a marine source, has citotoxic activity. 80 The cyclopropenone penitricine has antibiotic activity and has been used as a model for other biologically active cyclopropenones.…”

Preparation of beta-enamino carbonylic compounds using microwave radiation/K-10

“…4,5 Anticonvulsivant activity of several secondary enaminones has been reported. 6 Scott et al 7 identified several relationships between chemical features and activity: (i) the separation between the amino group and the aromatic ring should not exceed two methylene units; (ii) the presence of a carbomethoxy group enhances activity; and (iii) the cyclic enaminones are generally more active than the acyclic ones, the restrict conformation provides a more rigid frame of interaction.…”