Syntheses and Evaluation of Anticonvulsant Activity of Novel Branched Alkyl Carbamates

Abstract

A novel class of 19 carbamates was synthesized, and their anticonvulsant activity was comparatively evaluated in the rat maximal electroshock (MES) and subcutaneous metrazol (scMet) seizure tests and pilocarpine-induced status epilepticus (SE) model. In spite of the alkyl-carbamates' close structural features, only compounds <b>34</b>, <b>38</b>, and <b>40</b> were active at the MES test. The analogues 2-ethyl-3-methyl-butyl-carbamate (<b>34</b>) and 2-ethyl-3-methyl-pentyl-carbamate (<b>38</b>) also exhibited potent activity in the pilocarpine-SE model 30 min postseizure onset. Extending the aliphatic side chains of homologous carbamates from 7 to 8 (<b>34</b> to <b>35</b>) and from 8 to 9 carbons in the homologues <b>38</b> and <b>43</b> decreased the activity in the pilocarpine-SE model from ED₅₀ = 81 mg/kg (<b>34</b>) to 94 mg/kg (<b>35</b>) and from 96 mg/kg (<b>38</b>) to 114 mg/kg (<b>43</b>), respectively. The most potent carbamate, phenyl-ethyl-carbamate (<b>47</b>) (MES ED₅₀ = 16 mg/kg) contains an aromatic moiety in its structure. Compounds <b>34</b>, <b>38</b>, <b>40</b>, and <b>47</b> offer the optimal efficacy–safety profile and, consequently, are promising candidates for development as new antiepileptics