The synthesis steps of Tecovirimat are as follows: A mixture of cycloheptatriene (5 g, 54.26 mmol) and maleic anhydride (6.13 g, 62.40 mmol) was placed in 35 mL of xylene, and the reaction mixture was heated under argon protection and refluxed overnight. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered to collect the brownish-yellow precipitate, and dried to give 2.94 g (28%) of the target product, which is a mixture of intermediates I and II (compound I usually dominates in this mixture, at least 80% by weight. If necessary, the purity of compound I can be further improved by recrystallization. The weight of the isomer of compound I, compound II, is generally less than 20% and varies with reaction conditions). The mother liquor was concentrated to dryness, and the residue was separated by column chromatography to obtain pure compound II, which can be further purified by recrystallization if necessary.
The intermediate compound I (150 mg, 0.788 mmol) prepared in the previous step and 4-trifluoromethylbenzoylhydrazine (169 mg, 0.827 mmol) were mixed in ethanol (10 mL), and then transferred to acetone and heated overnight. After the reaction was complete, the solvent was removed from the resulting reaction mixture by rotary evaporation under vacuum. Purification by silica gel column chromatography with 1/1 n-hexane/ethyl acetate yielded 152 mg (51%) of the product Tecovirimat.
Figure: Synthetic Route of Tecovirimat
The water solubility of ST-246 is very poor, the solubility in water is about 3 μg/ml, which is a low solubility drug; the solubility of ST-246 increases with the increase of p H, and the solubility in alkaline environment is higher than that in weakly alkaline and acidic environment.
Tecovirimat is an orally bioavailable antipoxvirus compound inhibits extracellular virus formation and protects mice from lethal orthopoxvirus, including vaccinia, monkeypox, camelpox, cowpox, ectromelia (mousepox), and variola viruses.
At the recommended oral dosage of 600 mg every 12 hours administered in healthy adults weighing less than 120 kg, the mean steady-state values of tecovirimat AUC0-24hr, Cmax, and Ctau/trough are 29816 hr¤ng/mL (n, CV: 43, 34%), 2159 ng/mL (n, CV: 46, 32%), and 845 ng/mL (n, CV: 45, 47%), respectively. At the recommended intravenous dosage of 200 mg every 12 hours administered by IV infusion over 6 hours in healthy adults, the mean steady-state values of tecovirimat AUC0-24hr, Cmax, and Cmin are 39405 hr.ng/mL (n, CV: 22, 23%), 2630 ng/mL (n, CV: 22, 22%), and 747 ng/mL (n, CV: 22, 29%). Refer to Table 7 for pharmacokinetic parameters of tecovirimat. Tecovirimat steady-state is achieved by Day 4-6.
Common side effects of TPOXX (Tecovirimat) include: headache, nausea, abdominal pain, and vomiting.
TPOXX (Tecovirimat) may cause serious side effects, including: hives, difficulty breathing, and swelling of your face, lips, tongue, or throat.
