Description
Naramig was launched in Germany, Sweden and the UK for use in migraine.
It is chemically available via a number of related synthetic routes all having about
three steps starting from 5-bromoindole. It is a new serotonin 5-HT1B/1D receptor
antagonist with modest affinity for 5-HT1a, and very weak affinity for 5-HT3 receptors. It
has little or no affinity for a wide range of non-serotonin receptors including a- and padrenoceptors,
dopamine, neurokinin NK1, and opiate receptors. It mediates
vasoconstriction in cerebral vasculature (extra cerebral intracranial vessels), reduces
neurogenic inflammation, and inhibits responses mediated by the trigeminal nerves. It
has a 6- and 3-fold greater affinity for 5-HT1B, and 5-HT1D, receptors, respectively, than
sumatriptan which translates to a 2-3 fold increase in potency. The reoccurance of
headache was less compared to sumatriptan, zolmitriptan and rizatriptan. Naramig
had no clinical effects on blood pressure or heart rate, had a long duration of action
with very good tolerability, and has high oral bioavailability.
Synthesis
General procedure for the synthesis of N-methyl-2-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)ethane-1-sulfonamide hydrochloride from N-methyl-3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-1H-indole-5-ethane sulfonamide:
1. Compound VIII (50 g, 1501 mmol) was dissolved in a mixed solvent of methanol and acetic acid (0.2L:0.2L) and 2.5 g of platinum oxide catalyst was added. The hydrogenation reaction was carried out at 50 to 60°C for 6 to 8 hours under 5 kg/cm2 hydrogen pressure. After completion of the reaction, the reaction mixture was filtered and distilled to remove the solvent to obtain an oily product.
2. The above oily product was vaporized with isopropanol, followed by addition of 125 ml of ethanolic hydrochloric acid solution and refluxing the reaction mixture for 1 hour. The solid was stirred at 5 to 20°C for 1 hr to precipitate, filtered and washed with cold ethanol to give N-methyl-2-(3-(1-methylpiperidin-4-yl)-1H-indol-5-yl)ethane-1-sulfonamide hydrochloride (I). [Yield 50 g, 89.76%].
3. Compound I (50 g, 1347 mmol) was dissolved in a mixed solvent of 400 ml of ethanol and 100 ml of water and 2 g of activated carbon was added. It was refluxed at 78-80°C for half an hour. After completion of the reaction, it was filtered through hyflow and washed with 100 ml of ethanol. The filtrate was stirred at 5 to 20°C for half an hour to precipitate a solid, filtered, washed with cold ethanol and dried. [Yield 42.5 g, 85%]. Purity: 99.8%.
References
[1] Patent: WO2009/118753, 2009, A2. Location in patent: Page/Page column 28
[2] Patent: WO2011/21000, 2011, A2
