Frovatriptan Succinate

Description

Frovatriptan succinate was launched as an oral treatment for acute migraine attacks with or without aura in adults. It is the eighth member of the “triptan” class. Frovatriptan is a conformationally-restricted analog of the 5-HT₁-receptor agonist 5-carboxytryptamine which can be prepared in six steps. The key intermediate (R)-6-cyano-3-N-methylamino- 1,2,3,4-tetrahydrocarbazole is obtained by Fischer reaction of 4-cyanophenylhydrazine with the appropriate ketone followed by resolution using L-pyroglutamic acid. This drug acts as a dual 5-HT_1D/1B receptor partial agonist and has high and selective affinity for 5HT_1B and 5-HT_1D receptors in cranial vessels. It has no significant activity at 5-HT₂, 5-HT₃, 5-HT₄, α-adrenergic, histaminergic or GABA_A receptors. Frovatriptan is also a moderately potent full agonist at 5-HT₇ receptors, which have a dilatory action and are expressed in the human coronary artery. In vitro studies appear to indicate frovatriptan’s functional selectivity for cerebral circulation as shown by the concentrations needed to induce threshold contractile activity and maximum response in basilar arteries as compared with coronary arteries. Frovatriptan is mainly metabolized by CYPlA2 and most of its metabolites are excreted renally. Co-administration of frovatriptan with the monoamine oxidase-A inhibitor moclobemide or with the potent CYPlA2 inhibitor fluvoxamine did not affect its pharmacokinetics parameters. Although frovatriptan has a poor bioavailability (24- 30%), it has a very long half-life compared to other triptans (25 h) and has an onset of action and efficacy similar to those of naratriptan. The most striking features of this drug are the low headache recurrence rate, which is one of the lowest among the triptans and which may be attributed to its long half-life, and excellent tolerance profile. No significant effect on the cardiovascular system was seen after administration of a single oral dose of 14 fold the therapeutic dose of frovatriptan.

Originator

GlaxoSmithKlineNernaIis (UK)

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.

brand name

Frova

Therapeutic Function

Migraine therapy

Synthesis

The synthesis of frovatriptan (11) appeared in a patent in multi-kilo scale. Cyclohexanedione monoketal (121) was converted to amine 122 by reductive amination. The Fischer indolization of amine 122 with hydrazine 123 furnished indole nitrile 124 in 72% yield. The desired R isomer of the indole nitrile was obtained via a chiral salt formation/recrystallization process using chiral lactam 125 and isolated as a L-pyroglutamic acid salt 126. Hydrolysis of the nitrile functional group in 126 provided carboxamido indole 127, which was converted to succinate 11 in situ.