Carbamate derivatives of felbamate as potential anticonvulsant agents

Abstract

Several monocarbamate compounds derived from felbamate were synthesized and 11 target compounds (1, 4, and 6-14) were initially evaluated in mice MES and PTZ models in our laboratory. Carbamate compounds with varying substituents on the oxygen (1-4) gave anticonvulsant activity with a wide range of ED 50 in MES test from \20 mg/kg (2) to [300 mg/kg (4) and compounds with different groups on the nitrogen (5-14) also were quite active in the range of 15 mg/ kg (14) to 170.5 mg/kg (6). This suggested that the spatial limitation in the MES model seemed flexible especially on the nitrogen end. All tested compounds showed some activity against mice scPTZ test, but none had the ED 50 value\50 mg/kg. Ten selected compounds (1 and 6-14) for subsequent pharmacological evaluation in NIH all gave positive mice MES activity except 8 and 9, which were unexpectedly active in rats after further evaluations. Among the compounds, 1, 8, and 9 advanced to the quantitative study and 1 and 9 provided the highest PI values, 15 and 21, respectively, in the rat oral MES test.

Synthesis and Reactivity of N-Alkyl Carbamoylimidazoles: Development of N-Methyl Carbamoylimidazole as a Methyl Isocyanate Equivalent

“…The scope of the reactivity of 4 has also been extended to a variety of other nucleophile classes to give biologically relevant molecules in good to excellent yields (Table ). Among these are anticonvulsant carbamate 7 , thiocarbamates 8 and 9 investigated for their nematicidal and antimycotic activities, respectively, and benzthiazuron ( 10 ), a potent broad leaf and grass herbicide derived from 2-aminobenzthiazole. The lack of reactivity of 4 with alcohols had previously been displayed in the reaction of ephedrine (Table , entry 8).…”

Mechanochemical 1,1′-Carbonyldiimidazole-Mediated Synthesis of Carbamates

“…We were pleased to find that Method B applied straightforward, also for the mechanochemical preparation of N-methyl-O-benzyl carbamate 5 (entry 5), biologically relevant for its anticonvulsant properties, 37 in higher yield (99%) and milder reaction conditions compared to solution synthesis (87%) according to Method A, 38 requiring long reaction times (18 h) and activation of the alcohol by hydrides. The nucleophilic MeNH 2 is a gas at room temperature or above, thus not suitable as reactant, escaping the shocks 55 during the milling.…”

“…36 We report herein a systematic investigation for the CDImediated mechanochemical preparation of various carbamates using different primary or secondary alcohol/amine combinations. The revisited and new synthesis of the anticonvulsant drug N-methyl-O-benzyl carbamate 37,38 was successful in a vibrational ball-mill, while N-protected benzyloxycarbonyl-(Z)-, allyloxycarbonyl-(Alloc), or methoxycarbonyl-(Moc) amino esters were prepared in a planetary ball-mill, with no racemisation. To the best of our knowledge, this represents the first report on the CDI-mediated N-carbamoylation of amino esters by mechanochemistry.…”

The enthalpies of formation of alkyl carbamates: Experimental and computational redetermination

“…They are valuable scaffolds used as intermediates in the synthesis of biologically active compounds [1,2]. The carbamate moiety, ÀHNÀC(@O)ÀOÀR, is often found in many therapeutic active compounds, such as anti-cancer drugs [3][4][5][6] anticonvulsants [7,8], hypnotics [9], local anesthetics [10,11], anti-epileptics [12,13] muscle relaxants [14,15] and sedatives [16] as well as in the industry, in the synthesis of organic polymer polyurethane [17,18].…”