An improved method for the synthesis of benzamides from 3-amino-2-cyclohexenones is presented. Using sodium hydride, a base-catalyzed N-benzoylation provided significantly higher yields (71-79%) for the reported compounds. This novel protocol was applied in the solution-phase parallel synthesis of a 12-member library of vinylic benzamide derivatives of 3-amino-2-cyclohexenones in 63-90% yield, using a Radley's Carousel Reaction Station.

Benzamides↗

PubMedDate not supplied

Pharmacokinetics and pharmacodynamics of valproate analogues in rats. I. Spiro[4.6]undecane-2-carboxylic acid.

The pharmacokinetic and pharmacodynamic properties of the spiro carboxylic acid, spiro[4.6]undecane-2-carboxylic acid (SUCA, ADD 93024), were investigated in rats and compared with those of the standard anticonvulsant carboxylic acid, valproate (VPA). The clearance of SUCA was dose-dependent, although the observed nonlinearity did not appear to be due to classical saturable elimination. The change in clearance across doses was consistent with end-product inhibition or cosubstrate depletion. The volume of distribution of the spiro compound also evidenced nonlinearity, possibly due to concentration-dependent binding to serum proteins. In contrast, the dose-dependent clearance displayed by VPA was composed of both saturable and nonsaturable components. Furthermore, the disposition of VPA was characterized by a significant enterohepatic recirculation, whereas no such recirculatory process was apparent for SUCA. Both compounds afforded significant protection from pentylenetetrazol (PTZ)-induced seizures, and the time course of anticonvulsant effect did not correspond to that of drug concentrations in serum for either anticonvulsant. The apparent dissociation between the pharmacokinetics and pharmacodynamics of VPA may be a function of the mechanism of antiepileptic action and not due to the presence of active metabolites of the drug.

Animals↗

PubMedDate not supplied

Profile of anticonvulsant activity and minimal toxicity of methyl 4-[(p-chlorophenyl)amino]-6-methyl-2-oxo-cyclohex-3-en-1-oate and some prototype antiepileptic drugs in mice and rats.

The anticonvulsant and toxic properties of methyl 4-[(p-chlorophenyl)amino]-6-methyl-2-oxocyclohex-3-en-1-oate (ADD 196022), were compared with those of phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA). These compounds were evaluated in mice and rats using well-standardized anticonvulsant testing procedures. Results indicate that ADD 196022 is a very potent anticonvulsant in the maximal electroshock seizure (MES) model. The compound was effective in nontoxic doses after intraperitoneal (i.p.) administration in mice and oral administration in rats. In mice, i.p. administration of ADD 196022 resulted in an ED50 value of 26.2 mg/kg as compared with a value of 6.48 mg/kg for PHT in the same assay. ADD 196022 was more potent that PHT in the oral rat model, having an ED50 value of 5.79 mg/kg as compared to 23.2 mg/kg for PHT. ADD 196022 was ineffective in nontoxic doses against all other seizure models evaluated and thus has a pharmacologic profile similar to that of PHT.

Administration, Oral↗