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Zolmitriptan

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Zolmitriptan Basic information
Zolmitriptan Chemical Properties
  • Melting point:136-141°C
  • alpha D22 -5.79° (c = 0.5 in methanol)
  • Boiling point:563.3±38.0 °C(Predicted)
  • Density 1.217±0.06 g/cm3(Predicted)
  • storage temp. Refrigerator
  • solubility Soluble in DMSO at 5mg/ml
  • pka9.64(at 25℃)
  • form powder
  • color white to beige
  • optical activity[α]/D -3 to -8°, c = 1 in methanol
  • λmax225nm(lit.)
  • Merck 14,10189
  • InChIKeyULSDMUVEXKOYBU-ZDUSSCGKSA-N
  • CAS DataBase Reference139264-17-8(CAS DataBase Reference)
Safety Information
  • Hazard Codes Xi,Xn
  • Risk Statements 36/37/38-22
  • Safety Statements 26-36
  • WGK Germany 3
  • RTECS RQ2707000
  • HS Code 29349990
MSDS
Zolmitriptan Usage And Synthesis
  • DescriptionZolmitriptan is a selective serotonin receptor agonist of the 1B and 1D subtypes. It is mainly used in the acute treatment of migraine attacks with or without aura and cluster headaches. Zolmitriptan takes effect through binding to human 5-HT1Band 5-HT1Dreceptors, leading to cranial blood vessel constriction and the release of sensory neuropeptides through nerve endings in the trigeminal system. 
  • Chemical PropertiesWhite Crystalline Powder
  • OriginatorZeneca (UK)
  • UsesA Serotonin 5HTID-receptor agonist
  • Usesadrenergic agonist, nasal decongestant
  • Manufacturing Process(S)-4-(4-[N'-(2-Oxotetrahydropyran-3-iliden)hidrazino]benzyl}-1,3-oxazolidin- 2-one
    A solution of 2.8 g (40.6 mmoles) of sodium nitrite in 12 ml of water was added slowly to a solution of 9.1 g (39.8 mmoles) of (S)-4-(4-aminobenzyl)- 1,3-oxazolidyne-2-one hydrochloride in 17 ml of water and 29 ml of concentrated HCl, keeping the reaction temperature below 0°C. The mixture was stirred at this temperature for 15 minutes. Once that time had elapsed the diazonium salt solution was added rapidly to a suspension of 30 g (239 mmoles) of sodium sulphite in 106 ml of water precooled to 0°C under nitrogen atmosphere. The red solution was stirred at 0°C for 10 minutes and then left to reach 65°C in 1 hour. It was stirred at 65°C for 30 minutes, and 18.2 ml of concentrated HCl then added. The mixture was stirred at the same temperature under nitrogen atmosphere for 3 hours and then left to cool to room temperature. To this solution was added a solution of 35 mmoles of α- keto-γ-valerolactone (prepared by decarboxylation of 11.8 g (63.7 mmoles) of a ethoxyalyl-γ-butyrolactone in 15.2 ml of 2 N H 2 SO 4 at reflux) and left under stirring at room temperature for 12 hours. When that time had elapsed the mixture was cooled to 0°C and stirred for one hour. The precipitate formed was filtered, washed with cold water and dried in an hotair oven at 40°C, giving a white solid which was crystallised from ethanol/water to give 10.5 g (87%) of the title hydrazone as a white solid. Melting point 223.3°-224.7°C.
    (S)-6-(2-Oxo-1,3-oxazolidin-4-ylmethyl)-4,9-dihydro-3H-pyrano-[3,4-b]indol- 1-one
    3.8 g (12.5 mmoles) of (S)-4-{4-[N'-(2-oxotetrahydropyran-3-iliden) hydrazino]benzyl}-1,3-oxazolidin-2-one were suspended in 32 ml of a saturated solution of hydrogen chloride in acetic acid. The mixture was stirred at room temperature for 16 h, 10 ml of water/ice was added to the reaction mixture and stirred at 0°C for 20 min. The precipitate was filtered, washed with cold water and dried in hot-air oven at 40°C. The residue was crystallised with methanol to yield 3.3 g (92%) of the title indole as a yellow crystalline solid. Melting point 215°-217°C.
    (S)-3-(2-Hydroxyethyl)-5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1-H-indol-2- carboxylicacid methyl ester
    To a suspension of 500 mg (1.74 mmoles) of the (S)-6-(2-oxo-1,3-oxazolidin- 4-ylmethyl)-4,9-dihydro-3-pyrano-[3,4-b]indol-1-one in 10 ml of methanol were added 0.12 ml (1.9 mmoles) of methanesulfonic acid. The mixture was left under stirring at the reflux temperature for 3 hours. The solvent was evaporated to dryness under reduced pressure, the residue dissolved with 10 ml of a saturated bicarbonate solution and extracted three times with dichloromethane. The combined organic phases were dried and evaporated to dryness and the evaporated solid recrystallised from ethanol to give 517 mg (93%) of the title ester as a yellow crystalline solid. Melting point 178°- 180°C.
    (S)-3-(2-Hydroxyethyl)-5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-2- carboxylicacid ethyl ester
    9.5 g (31.3 mmoles) of (S)-4-{4-[N'-(2-oxotetrahydropyran-3-ilyden) hydrazine]benzyl}-1,3-oxazolidin-2-one were suspended in 76 ml of a 2 N solution of hydrogen chloride in absolute ethanol. The mixture was left under stirring at 75°C for 30 min. The solvent was evaporated to dryness under reduced pressure, 50 ml of a saturated solution of potassium carbonate added, and then extracted three times with 50 ml of dichloromethane. The combined organic phases were dried on anhydrous sodium sulphate and recrystallised from methanol to give a yellow crystalline solid. Melting point 154°-156°C. evaporated to dryness. The residue was recrystallised from isopropyl alcohol/heptane to give 9.25 g (89%) of the title indole. The product was
  • brand nameZomig (AstraZeneca); Zomig (IPR).
  • Therapeutic FunctionSerotoninergic
  • General DescriptionZolmitriptan, the second triptan marketed (approved in1997), has a much better bioavailability (40%–48%) thansumatriptan. It is rapidly absorbed after oral or nasal sprayadministration. It also has an orally disintegrating tablet formulation(Zomig ZMT), which can be taken without water.Zolmitriptan undergoes rapid N-demethylation via CYP1A2to a more potent, active metabolite, N-desmethylzolmitriptan,which is 2 to 6 times more potent than the parentdrug. This active metabolite was detected 5 minutesafter dosing and accounts for about two thirds of the plasmaconcentration of the administered dose of the parent drug.284Thus, it is reasonable to assume that the therapeutic effectsand especially the CNS side effects of zolmitriptan must bein part attributed to the plasma levels of this active metabolite,at least until it is further degraded by hepatic MAO-Ato its inactive indole acetic acid derivatives.
  • Clinical UseZomig was launched in Germany, Denmark, Sweden and the UK for use as an antimigraine agent (with and without aura). It can be prepared by three related routes of 5 to 7 steps starting from L-4-nitrophenylalanine. Zomig is a 5-HT1D/1B receptor agonist (10 fold ratio) with modest (< 100x) affinity for 5-HT1A and 5-HT1F receptors. It has no affinity for other serotonin receptors or receptors of other neurotransmitters. It has a novel dual action mechanism: centrally it acts on the trigeminal nucleus caudalis and peripherally is acts on the trigeminovascular system. Zomig was effective in treating headaches and nonheadache (photophobia, phonophobia and nausea) symptoms. It was 2-3 times more potent than sumatriptan and is metabolized to three compounds, one of which is 2-8 times more active than the parent. It caused a 40-50% decrease in headache after 1 h and a 73-77% after 4 h. There was a 30% reoccurance of headache but 90% effective treatment with a second dose. It blocks neurogenic inflammation by inhibiting release of peptides, causes vasoconstriction, and inhibits neuronal depolarization at peripheral sites in the cranium. It is 40% bioavailable and a 10 time theraputic dose showed no safety concerns.
  • Referenceshttps://www.drugbank.ca/drugs/DB00315
    Rothner, A. D., et al. "Zolmitriptan oral tablet in migraine treatment: high placebo responses in adolescents." Headache the Journal of Head & Face Pain 46.1(2006):101.
    Hedlund, C, et al. "Zolmitriptan nasal spray in the acute treatment of cluster headache: a meta-analysis of two studies. " Neurology49.9(2009):1315–1323.
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