Synthesis and anticonvulsant activity of N,N-phthaloyl derivatives of central nervous system inhibitory amino acids

In order to study the influence of the length of the amino acid chain of N,N‐phthaloylamino acid amides as analogues of the former anticonvulsant taltrimide on the seizureantagonizing activity glycine, β‐alanine and γ‐aminobutyric acid (GABA) derivatives were synthesized. The corresponding taurine derivatives were also included. Generally, the glycine‐derived amides showed a higher activity than the β‐alanine and GABA derivatives in the maximal electroshock seizure (MES) test in mice upon intraperitoneal administration. The activity was comparable to the respective taurine derivatives. The N,N‐phthaloyl‐glycine amides were also active in the MES test upon oral administration to rats. No significant activity was noted in the seizure threshold test with subcutaneous pentylenetetrazole. The ED50 of N,N‐phthaloyl‐glycine ethyl amide (4b) in the MES test upon intraperitoneal administration to mice was 19.1 mg/kg. On a molar basis this activity is comparable to the activity of phenytoin with little toxicity in the rotorod test. In conclusion, N,N‐phthaloyl‐glycine amides might represent promising antiepileptic drugs.