Synthesis and Anticonvulsant Activities of .alpha.-Acetamido-N-benzylacetamide Derivatives Containing an Electron-Deficient .alpha.-Heteroaromatic Substituent

Abstract

Recent studies have demonstrated that C(alpha)-substituted alpha-acetamido-N-benzylacetamides displayed excellent anticonvulsant activities in mice. Analysis of the structure-activity relationship for this series of compounds has shown that placement of small, electron-rich aromatic and heteroaromatic groups at the C(alpha) site led to pronounced protection against MES-induced seizures. In this note, synthetic protocols are reported for the preparation of three novel nonnaturally occurring electron-deficient C(alpha)-aza aromatic alpha-acetamido-N-benzylacetamides (i.e., pyrid-2-yl (11), pyrazin-2-yl (12), pyrimid-2-yl (13)). Expedient syntheses for 12 and 13 were developed using a phase-transfer, nucleophilic aromatic substitution process. All three adducts exhibited potencies comparable to or greater than phenytoin in the MES test (mice, ip). These findings required us to modify in part the previously proposed structure-activity relationship for this class of anticonvulsants.

Merging the Structural Motifs of Functionalized Amino Acids and α-Aminoamides: Compounds with Significant Anticonvulsant Activities

“…We also found that MES seizure protection significantly increased upon the inclusion of a C(2)-substituted heteroatom group one atom removed from the C(2) center (( R,S )- 9 , MES ED 50 = 28 mg/kg; ( R )- 10 , MES ED 50 = 13 mg/kg versus ( R )- 6 , MES ED 50 = >30, <100 mg/kg; ( R )- 7 , MES ED 50 = >300 mg/kg; ( R )- 8 , MES ED 50 = >300 mg/kg). Similar SAR patterns were observed for 1 compounds 7,11–14. Furthermore, for both 6 and 10 , we tested the ( R )- and ( S )-enantiomers and found that the principal activity resided in the ( R )-stereoisomer (D-configuration) (MES ED 50 (mice, ip): ( R )- 6 , >30, <100 mg/kg vs ( S )- 6 , >100, <300 mg/kg, and ( R )- 10 , 13 mg/kg vs ( S )- 10 , >300 mg/kg).…”

Synthesis and Anticonvulsant Activities of N-Benzyl-2-acetamidopropionamide Derivatives

“…Our structure−activity studies indicated two important trends. First, in cases where an aromatic moiety was positioned at the C(2) site improved activity was noted for those compounds that contained a small, electron-rich R 2 substituent. , Second, enhanced protection against MES-induced seizures was observed for C(2) cyclic and acyclic R 2 groups that contained a substituted heteroatom one atom from the C(2) site. ,, Consistent with these contentions were the relative activities (mice, ip) of 3 (ED 50 = 10 mg/kg) versus the 2-tetrahydrofuran-2-yl diastereomers ( 7 ) (ED 50 = 52−90 mg/kg), the relative potencies of 2-furan-2-yl ( 3 ) (ED 50 = 10 mg/kg), 2-pyrrol-2-yl ( 4 ) (ED 50 = 16 mg/kg), and 2-thien-2-yl ( 5 ) (ED 50 = 45 mg/kg) N -benzyl-2-acetamidoacetamide derivatives, the decrease in activity of the 2-thien-3-yl ( 6 ) (ED 50 = 88 mg/kg) adduct versus the isomeric 2-thien-2-yl ( 5 ) (ED 50 = 45 mg/kg) compound, and the dramatic increase in activity for the O -methylhydroxylamine ( 9 ) (ED 50 = 6.2 mg/kg) and O , N -dimethylhydroxylamine ( 10 ) (ED 50 = 6.7 mg/kg) derivatives versus the C(2) hydroxylamine compound ( 8 ) (ED 50 ≈ 100 mg/kg) ,,, These differences in activities were the greatest eudismic ratio reported to date for MES-selective anticonvulsant agents.…”

“…Recently, we found that the three C(2) electron-deficient heteroaromatic compounds ( 11 − 13 ) possessed outstanding anticonvulsant activities . This discovery ran counter to our original projections of the beneficial properties that accompany incorporation of an electron-rich aromatic substituent at this site and challenged the validity of this aspect of our structure−activity relationship.…”

“…Over the past 10 years we have reported on the anticonvulsant properties of functionalized amino acid derivatives that conform to the general structure 1 . − Systematic evaluation of over 100 derivatives has led to our proposal that stringent steric and electronic requirements exist for this novel class of compounds for protection against maximal electroshock (MES)-induced seizure. Our structure−activity studies indicated two important trends.…”

New Anticonvulsant Agents

“…In the recent years, Kohn and coworkers have reported on the anticonvulsant activity of a series of functionalized amino acids [47][48][49][50][51][52][53][54][55][56][57][58][59][60][61] (FAA) 5 ( Fig. 6).…”