Frovatriptan

Originator

Frova,Elan Corporation

Definition

ChEBI: Frovatriptan is a member of carbazoles.

Manufacturing Process

4-Carboxamidophenylhydrazine hydrochloride (2.87 g) and 4- phthalimidocyclohexanone (3.00 g) were mixed in acetic acid and the mixture was heated under reflux for 2 h. After cooling, the mixture was neutralized using aq. potassium carbonate solution, and the yellow solid thus obtained was filtered, washed with water, and dried. Purification by column chromatography (SiO2; CHCl3/CH3OH) gave 6-carboxamido-3-phthalimido- 1,2,3,4-tetrahydrocarbazole (2.8 g).
The 6-carboxamido-3-phthalimido-1,2,3,4-tetrahydrocarbazole (1.0 g) was suspended in ethanol (10 ml) and hydrazine hydrate (5 ml) was added. A clear solution was obtained, and the mixture was left to stir overnight, to yield a precipitate. The whole mixture was evaporated to dryness, washed with aq. K2CO3 solution, and water, to leave the (+/-)-3-amino-6-carboxamido-1,2,3,4- tetrahydrocarbazole (0.44 g), melting point 146°-148°C.
Separation of diastereoisomers of a chiral derivative of a 3-amino-6- carboxamido-1,2,3,4-tetrahydrocarbazole e.g. by crystallisation, or by chromatography.
Benzaldehyde (10.6 g) was added to a suspension of (+)-3-amino-6- carboxamido-1,2,3,4-tetrahydrocarbazole (12.35 g) in methanol (100 ml). The mixture was stirred for 1 h, sodium cyanoborohydride (9.3 g) added over 1 h and the clear solution stirred for 24 h. The solution was cooled (ice bath) and formaldehyde (37% aqueous methanolic, 9:1 solution, 5.5 ml) added. After 30 min stirring at room temperature water (100 ml) was added, stirring continued for 30 min followed by extraction with dichloromethane (3 times 150 ml). The combined organic extracts were washed with water (2 times 200 ml), dried (Na2SO4), filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, dichloromethane-10% ethanol/dichloromethane) to give 3-N-benzyl-6-carboxamido-3-Nmethylamino-1,2,3,4-tetrahydrocarbazole (9.4 g) as a foam. The succinate salt (1:1) was recrystallised from methanol, melting point 175°-182°C.
To a solution of 3-N-benzyl-6-carboxamido-3-N-methylamino-1,2,3,4- tetrahydrocarbazole (1.0 g) in ethanol (100 ml) containing succinic acid (0.39 g), Pearlmans catalyst (1.0 g) was added and the mixture shaken under an atmosphere of hydrogen at 45 psi and 50°C for 2 h. The mixture was filtered (celite pad) and the pad washed thoroughly with ethanol. The combined flitrate and washings were evaporated to dryness, coevaporated with ethanol (3 times 100 ml) and recrystallised from methanol to give the (+)-6- carboxamido-3-N-methylamino-1,2,3,4-tetrahydrocarbazole succinate (1:1) salt, melting point 148°-155°C.

Therapeutic Function

Migraine therapy

Clinical Use

5HT1 receptor agonist:
Acute relief of migraine

Drug interactions

Potentially hazardous interactions with other drugs
Antidepressants: increased CNS toxicity with citalopram - avoid; blood levels of frovatriptan increased 27-49% by fluvoxamine - avoid; possibly increased serotonergic effects with duloxetine, venlafaxine and SSRIs; increased serotonergic effects with St John’s wort - avoid.
Dapoxetine: possible increased risk of serotonergic effects - avoid for 2 weeks after stopping 5HT1 agonists.
Ergot alkaloids: increased risk of vasospasm - avoid.

Metabolism

Following oral administration of radiolabelled frovatriptan, 32% of the dose was recovered in urine and 62% in faeces. Radiolabelled compounds excreted in urine were unchanged frovatriptan, hydroxy frovatriptan, N-acetyl desmethyl frovatriptan, hydroxy N-acetyl desmethyl frovatriptan, and desmethyl frovatriptan, together with several other minor metabolites formed under the action of CYP1A2. Desmethyl frovatriptan had about 3-fold lower affinity at 5-HT1 receptors than the parent compound. N-acetyl desmethyl frovatriptan had negligible affinity at 5-HT1 receptors. The activity of other metabolites has not been studied. Renal clearance accounted for 38% (82 mL/min) and 49% (65 mL/min) of total clearance in males and females, respectively.

Raw materials

Preparation Products