Chemical Properties
White, granular, crystalline substance;
camphor-like odor. Soluble in water; freely soluble in alcohol, chloroform, and ether; pH
6.0 (5% solution).
Originator
Tridione,Abbott,US,1946
Uses
3,5,5-Trimethyloxazolidine-2,4-dione is used in the control of absence (petit mal) seizures that are refractory to treatment with other medications. It is used in the treatment of epilepsy.
Uses
Trimethadione is used in minor forms of epilepsy that does not respond to treatment of
other drugs.
Definition
ChEBI: Trimethadione is an oxazolidinone that is 1,3-oxazolidine-2,4-dione substituted by methyl groups at positions 3, 5 and 5. It is an antiepileptic agent. It has a role as a geroprotector and an anticonvulsant.
Manufacturing Process
To a cooled solution of 23 parts of sodium in 400 parts of dry ethanol are
added 60 parts of dry urea and 132 parts of ethyl α-hydroxy-isobutyrate. The
mixture is heated on a steam bath under reflux for about 16 hours and the
liberated ammonia is removed from the solution by drawing a current of dry
air through it at the boiling point. The solution of the sodium salt of 5,5-
dimethyloxazolidine-2,4-dione so obtained is cooled and treated with 284 parts of methyl iodide. The mixture is allowed to stand at room temperature
for 3 days, excess methyl iodide and ethanol are then removed by distillation
under reduced pressure.
The residue is dissolved in ether and the solution is washed with sodium
chloride solution and then with a little sodium thiosulfate solution. The
ethereal solution is dried over sodium sulfate and ether removed by
distillation. A yield of 108 parts of 3,5,5-trimethyloxazolidine-2,4-dione is
obtained having a melting point of 45° to 46°C with slight softening at 43°C.
This represents a 75% theory yield on the ethyl α-hydroxy-iso-butyrate taken.
The product may be further purified by dissolving the minimum quantity of
dry ether and cooling to -10°C. The product so obtained melts sharply at
45.5° to 46.5°C according to US Patent 2,559,011.
Brand name
Tridione (Abbott).
Therapeutic Function
Anticonvulsant
Hazard
May have adverse side effects; toxic in
overdose.
Clinical Use
Trimethadione is indicated only for control of absence seizures refractory to treatment with other AEDs. It
is ineffective against other seizure types. Trimethadione is a pro-drug and is metabolized by N-demethylation to dimethadione,
which is effective in the pentylenetetrazole test, which acts by decreasing T-type calcium currents. Trimethadione is rapidly
absorbed, is not protein bound, and has a half-life of 16 to 24 hours. The half-life of dimethadione, however, is substantially
longer (i.e., 6–13 days), and dimethadione accumulates to concentrations greater than the parent drug. Because of its
potentially fatal side effects. including aplastic anemia, nephrosis, idiosyncratic rashes, and exfoliative dermatitis,
trimethadione rarely is used today.
Synthesis
Trimethadione, 3,5,5-trimethyloxazolidine-2,4-dione (9.8.2), is synthesized by methylating 5,5-trimethyloxazolidine-2,4-dione (9.8.1) with dimethylsulfate.Starting 5,5-trimethyloxazolidine-2,4-dione (9.8.1) is in turn synthesized by the cyclocondensation of the ester of 2-hydroxyisobutyric acid with urea [26¨C28].
