Naratriptan

Originator

Amerge,Glaxo Wellcome,UK

Uses

Antimigraine.

Uses

Naratriptan is a triptan drug that is used for the treatment of migraine headaches.

Definition

ChEBI: Naratriptan is a sulfonamide, a member of tryptamines and a heteroarylpiperidine. It has a role as a serotonergic agonist and a vasoconstrictor agent.

Manufacturing Process

N-Methyl-3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-1H-indole-5- ethanesulphonamide oxalate
A solution of N-methyl-1H-indole-5-ethanesulphonamide (1.0 g) in methanol (50 ml) containing potassium hydroxide (5.6 g) and N-methyl-4-piperidone (1.0 ml) was heated at reflux for 24 h, cooled, and the resulting solid filtered off (1.0 g). A sample of the solid (0.2 g) was dissolved in a hot methanolic solution of oxalic acid (0.06 g), the solution cooled, and the salt precipitated by adding ethyl acetate (20 ml) and dry ether (50 ml). The salt was filtered off, and dried in vacuo to give the title compound as a solid (0.12 g), m.p. 87°-90°C (shrinks).
Analysis Found: C,52.2; H,5.6; N,9.5. C17H23N3O2S · C2H2O4 · 0.6H2O requires C,52.5; H,6.0; N,9.7%.
N-Methyl-3-(1-methyl-4 -piperidinyl)-1H-indole-5-ethansulphonamide
N-Methyl-3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-1H-indole-5- ethanesulphonamide oxalate (as the free base) (0.36 g, 0.001 mol) in absolute alcohol (70 ml) and anhydrous dimethylformamide (5 ml) was hydrogenated, in the presence of 5% palladium on activated carbon (0.36 g) at ambient temperature and atmospheric pressure. After 20 h, hydrogen absorption (25 cm3, theoretical = 24 cm3) ceased. The catalyst was filtered off and the solvent removed in vacuo to given an opaque gum which solidified as a soft white solid (0.3 g). Purification by flash chromatography (Sorbsil C60 silica gel, CH2Cl2/EtOH/0.88 ammonia; 50:80:1) gave a colorless oil (0.21 g) that was triturated with ether to give the title compound (0.17 g) m.p. 156°- 158°C. TLC SiO2(CH2Cl2/EtOH/0.88 ammonia; 50:8:1) Rf 0.4.
N-Methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethanesulphonamide may be prepared the another way.
A solution of 4-hydrazino-N-methyl-benzenethanesulphonamide (0.5 g) and 1- methyl-4-piperidineacetaldehyde (0.35 g) in a mixture of water (10 ml) of 2 N hydrochloric acid (1.0 ml, 2.00 mmol) was stirred for 2 days at room temperature. A further quantity of the aldehyde (0.35 g) was added and stirring continued for a further 30 min. The solution was then basified with 8% sodium bicarbonate to pH 8 and extracted with chloroform (3 times 50 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give the crude hydrazone as an oil (1.0 g). A solution of the hydrazone (1.0 g) in chloroform (20 ml) containing polyphosphate ester (10 g) was heated at reflux for 8 min. The solution was poured onto ice (200 g), stirred for 2 h treated with 2 M sodium carbonate (20 ml) and extracted with chloroform (3 times 50 ml). The combined organic extracts were dried (Na2SO4), evaporated in vacuo and the residue purified by flash chromatography (silica 9385, 100 g) eluting with CH2Cl2/EtOH/NH3(75:8:1) to give impure material as a yellow oil. Further flash chromatography (silica 9385, 100 g) eluting with CH2Cl2/EtOH/NH3 (100:8:1) gave the product as an oil (0.05 g). This was crystallised from ethyl acetate to give the title compound solid m.p. 156°-157°C. TLC SiO2(CH2Cl2/EtOH/NH3(50:8:1)) Rf 0.6.

brand name

Amerge (GlaxoSmithKline).

Therapeutic Function

Serotonin antagonist, Migraine therapy

General Description

Naratriptan, the third triptan approved in 1998, is one of themost lipophilic triptans marketed to date. It has a much improvedbioavailability (63% in men and 74% in women), agreater affinity for 5-HT1B/1D receptors (3–6 times), and alower recurrence rate than sumatriptan because of its muchlonger elimination half-life. Naratritan also has a favorableCNS side effect profile when compared with sumatriptanor zolmitriptan because of its metabolic stability,thereby lacking a N-demethylated active metabolite and asignificant renal excretion ( 70% of naratriptan is excretedunchanged and the rest of the administered dose is degradedvia several CYP isozymes).

Clinical Use

5HT1 receptor agonist:
Acute treatment of migraine

Drug interactions

Potentially hazardous interactions with other drugs
Antidepressants: increased CNS toxicity with citalopram - avoid; possibly increased serotonergic effects with duloxetine, SSRIs and venlafaxine; 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

Naratriptan undergoes some hepatic metabolism via a wide range of cytochrome P450 isoenzymes to form inactive metabolites. Naratriptan is excreted by glomerular filtration and active secretion into the renal tubules. It is mainly excreted in the urine with 50% of a dose being recovered as unchanged drug and 30% as inactive metabolites.

Raw materials

Preparation Products