Meptazinol

Originator

Meptid,Wyeth,UK,1983

Uses

Analgesic.

Definition

ChEBI: 3-(3-ethyl-1-methyl-3-azepanyl)phenol is a member of azepanes.

Manufacturing Process

2-(m-Methoxyphenyl)butyronitrile in dry ether was added to a stirred suspension of sodium amide in liquid ammonia. The mixture was stirred for 30 minutes then ethyl-4-iodobutyrate (99.25 g, 0.4 mol) in dry ether (200 ml) was added dropwise. The mixture was stirred at the temperature of refluxing liquid ammonia for 5 hours. Ammonium chloride (10 g) was added and the mixture allowed to warm to room temperature. Water (300 ml) was added, the organic layer separated, washed with water, 2 N sulfuric acid and water. After drying over magnesium sulfate and removing the ether, the product was distilled yielding ethyl 5-cyano-5-(mmethoxyphenyl)heptanoate.
That material was hydrogenated in cyclohexane using a Raney nickel catalyst. The product after distillation was recrystallized from ethyl acetate affording 10.0 g of 6-ethyl-(m-methoxyphenyl)hexahydro-2H-azepin-2one, MP 87°C to 88°C.
The azepinone (9.1 g) in dry tetrahydrofuran (50 ml) and ether (50 ml) was added dropwise to a stirred suspension of aluminum lithium hydride (7.5 g) in dry ether (50 ml). After heating under reflux for 3 hours the reaction mixture was worked up and distilled yielding 7.66 g of a compound which was a colorless oil, BP 108°C to 110°C/0.01 mm.
That product was then heated under reflux with 50% hydrobromic acid for 1.5 hours. The reaction mixture was evaporated to dryness and reevaporated with three portions of propan-2-ol. The oil obtained was dissolved in propan-2-ol and diluted with ether. 3-Ethyl-3-(m-hydroxyphenyl)hexahydro-1H-azepine was obtained. That material in turn was reductively methylated by hydrogenation in the presence of formaldehyde in absolute ethanol solution to give 3-ethyl-3-(m-methoxyphenyl)-1-methylhexahydro-1H-azepine.
The methoxy group was converted to a hydroxy group by refluxing with 80% HBr giving meptazinol hydrobromide.

Therapeutic Function

Analgesic

Clinical Use

Opioid analgesic used for moderate to severe pain

Drug interactions

Potentially hazardous interactions with other drugs
Antidepressants: possible CNS excitation or depression with MAOIs - avoid; possible CNS excitation or depression with moclobemide; possibly increased sedative effects with tricyclics.
Antihistamines: increased sedative effects with sedating antihistamines.
Antipsychotics: enhanced hypotensive and sedative effects.
Dopaminergics: avoid with selegiline.
Nalmefene: avoid concomitant use.
Sodium oxybate: enhanced effect of sodium oxybate - avoid

Metabolism

Meptazinol is extensively metabolised in the liver and is excreted mainly in the urine as the glucuronide conjugate. Less than 10% of a dose has been recovered from the faeces.