4-(2-methoxynaphthalen-6-yl)butan-2-one

Indications

Nabumetone (Relafen) is approved for rheumatoid arthritis, osteoarthritis, and pain management. Its long half-life allows for once-daily dosing. Although this drug is a weak inhibitor of COX, it is metabolized in the liver to 6-methoxy-2-naphthylacetic acid (6-MNA), a strong COX inhibitor that is chemically similar to naproxen. As with most NSAIDs, GI side effects are most commonly reported. The incidence of gastric ulceration is lower with nabumetone than with many other NSAIDs.This is due to its nature as a prodrug, not to COX-2 selectivity. Lower-bowel complaints, rashes, and CNS disturbances are common adverse effects.

Manufacturing Process

4-(5-Bromo-6-methoxy-2-naphthyl)-4-hydroxybut-3-en-2-one50 grams (0.179 moles) of 2-acetyl-5-bromo-6-methoxynaphthalene and 200 ml of n-butyl acetate are placed in a flask equipped with refrigerator and stirrer and, under stirring and at the temperature of 15°C, 14.5 g (0.268 moles) of sodium methoxide are added. The temperature of the reaction mixture goes up to 25°C and is kept at this value for 30 minutes, then the mixture is warmed at 65°C for one hour, is added with 100 ml of water and is brought to pH 4 by adding a concentrated aqueous solution of hydrochloric acid. The reaction mixture is then cooled to 0°-5°C and kept at this temperature for one hour. The solid is filtered, abundantly washed with water on the filter, then washed with butyl acetate and dried in oven under vacuum obtaining 53 g of product with a yield equal to 92%.Example 1. 4-(6-Methoxy-2-naphthyl)butan-2-one48 grams (0.150 moles) of 4-(5-bromo-6-methoxy-2-naphthyl)-4-hydroxybut- 3-en-2-one, 6.1 g of sodium acetate hydrate containing 32.4% of water, equivalent to 0.050 moles of sodium acetate, 4 g of a 50% suspension in water of 10% palladium on carbon, equivalent to 0.0019 moles of palladium, and 500 ml of methanol are put in a hydrogenator. The hydrogenator is washed with nitrogen in order to eliminate the oxygen and then hydrogen is introduced at the pressure of 2 atmospheres. The temperature of reaction is kept at 40°C for a period of time of 6 hours, then the hydrogen is let off, the hydrogenator is washed with nitrogen and the reaction mixture is filtered to eliminate the catalyst. The solution is brought to pH 6 with a 5% aqueous solution of sodium hydroxide and concentrated under vacuum. The oily residue is dissolved into 130 ml of isopropanol and 30 ml of N,Ndimethylformamide and the solution is added with 45 ml of water and 17.6 g of sodium bisulfite obtaining a suspension that is stirred for one hour at 60°C, then is cooled to 5°C and is filtered. The obtained solid is washed with 75 ml of methanol, suspended in 200 ml of a 5% aqueous solution of sodium hydroxide and kept under stirring at room temperature for three hours. The suspension is then filtered, the solid is washed with water until neutrality and dried in oven under vacuum obtaining 18 g of product with a yield equal to 52.8%.Example 2. 4-(6-Methoxy-2-naphthy)butan-2-oneThe reaction described above is repeated with the sole changes of doubling the amount of sodium acetate hydrate containing 32.4% of water, 12.22 g equivalent to 0.100 moles of sodium acetate, and of lowering the hydrogenation time to five hours. In this way 22.5 g of product are obtained with a yield equal to 66%.Example 3. 4-(6-Methoxy-2-naphthyl)butan-2-oneThe reaction described in example 3 is repeated with the sole changes of nearly triplicating the amount of sodium acetate hydrate containing 32.4% of water, 17.60 g equivalent to 0.145 moles of sodium acetate, and of lowering the hydrogenation time to five hours. The oil obtained by evaporating the solvent at the end of the reaction is treated with 300 ml of toluene and 100 ml of water and after 15 minutes of stirring the two layers are separated. The aqueous phase is discarded while the organic phase is evaporated under vacuum at 70°C obtaining an oil that is dissolved into 100 ml of methanol. The solution is kept at 0°C for two hours and the precipitated solid is filtered, washed with 15 ml of methanol cooled to 0°C and dried in oven under vacuum. In this way 21.7 g of product are obtained. The methanolic filtrates from crystallization and washing are concentrated under vacuum to half volume so obtaining, after cooling to 0°C, the crystallization of other 4 g of product with an overall yield equal to 75.3%.

Therapeutic Function

Antiinflammatory

Pharmacokinetics

Nabumetone is absorbed primarily from the duodenum. Milk and food increase the rate of absorption and the bioavailability of the active metabolite. Plasma concentrations of unchanged drug are too low to be detected in most subjects after oral administration, so most pharmacokinetic studies have involved the disposition of the active metabolite. Pharmacokinetic properties are altered in elderly patients, with higher plasma levels of the active metabolite being noted. Nabumetone undergoes rapid and extensive metabolism in the liver, with a mean absolute bioavailability of the active metabolite of 38%. The metabolism of nabumetone is illustrated in Figure 36.15. The major, most active metabolite is 6MNA, but the initial alcohol metabolite, a minor product, and its esters also possess significant anti-inflammatory properties.

Drug interactions

Potentially hazardous interactions with other drugs ACE inhibitors and angiotensin-II antagonists: antagonism of hypotensive effect; increased risk of nephrotoxicity and hyperkalaemia Analgesics: avoid concomitant use of 2 or more NSAIDs, including aspirin (increased side effects); avoid with ketorolac (increased risk of side effects and haemorrhage). Antibacterials: possibly increased risk of convulsions with quinolones. Anticoagulants: effects of coumarins and phenindione enhanced; possibly increased risk of bleeding with heparin, dabigatran and edoxaban - avoid long term use with edoxaban. Antidepressants: increased risk of bleeding with SSRIs and venlaflaxine. Antidiabetic agents: effects of sulphonylureas enhanced. Antiepileptics: possibly increased phenytoin concentration. Antivirals: increased risk of haematological toxicity with zidovudine; concentration possibly increased by ritonavir. Ciclosporin: may potentiate nephrotoxicity. Cytotoxics: reduced excretion of methotrexate; increased risk of bleeding with erlotinib. Diuretics: increased risk of nephrotoxicity; antagonism of diuretic effect; hyperkalaemia with potassium-sparing diuretics. Lithium: excretion decreased. Pentoxifylline: increased risk of bleeding. Tacrolimus: increased risk of nephrotoxicity.

Metabolism

Nabumetone is rapidly metabolised in the liver to the main active metabolite 6-methoxy-2-naphthylacetic acid (6-MNA). The metabolite is a potent inhibitor of prostaglandin synthesis. Excretion of the metabolite is predominantly in the urine.

Definition

ChEBI: A methyl ketone that is 2-butanone in which one of the methyl hydrogens at position 4 is replaced by a 6-methoxy-2-naphthyl group. A prodrug that is converted to the active metabolite, 6-methoxy-2-naphthylacetic acid, following oral administration. It is s own to have a slightly lower risk of gastrointestinal side effects than most other non-steroidal anti-inflammatory drugs.

Brand name

Relafen (Smith-Kline Beecham);RELIFEX.

General Description

Nabumetone (Relafen), a nonacidic NSAID prodrug, isclassified as an arylacetic acid, because it undergoes rapidhepatic metabolism to its active metabolite, 6-methoxy-2-naphthylacetic acid. Similar to the other arylacetic aciddrugs, it is used in short- or long-term management of RAand OA. Being nonacidic, it does not produce significantprimary insult to the GI mucosa lining and also has no effecton prostaglandin synthesis in gastric mucosa, thus producingminimum secondary GI damage when comparedwith other conventional NSAIDs.