FENOPROFEN

Description

Fenoprofen is used as its calcium salt dihydrate in the treatment of rheumatoid arthritis and osteoarthritis at a daily dose of 1.2 – 3.0 g. The drug is rapidly absorbed and excreted with a plasma half-life of about 3 h despite being extensively bound (99 %) to plasma protein. Fenoprofen is well tolerated, with dyspepsia being the chief adverse effect.

Originator

Fenopron,Dista,UK,1974

The Uses of FENOPROFEN

Fenoprofen is used in treating symptoms of rheumatoid arthritis and osteoarthritis; however, fenoprofen exhibits a number of undesirable side effects.

The Uses of FENOPROFEN

antiinflammatory

Definition

ChEBI: Propanoic acid in which one of the hydrogens at position 2 is substituted by a 3-phenoxyphenyl group. A non-steroidal anti-inflammatory drug, the dihydrate form of the calcium salt is used for the management of mild to moderate pain and for the relief of p in and inflammation associated with disorders such as arthritis. It is pharmacologically similar to aspirin, but causes less gastrointestinal bleeding.

Indications

Fenoprofen (Nalfon) is chemically and pharmacologically similar to ibuprofen and is used in the treatment of rheumatoid arthritis, osteoarthritis, and mild to moderate pain. GI effects such as dyspepsia and pain are most common, although dizziness, pruritus, and palpitations may occur. GI bleeding, sometimes severe, has been reported, and interstitial nephritis has been rarely associated with this drug. Concomitant administration of aspirin decreases the biological half-life of fenoprofen by increasing the metabolic clearance of hydroxylated fenoprofen. Chronic administration of phenobarbital also decreases the drug’s half-life.

Manufacturing Process

3-Phenoxyacetophenone: A mixture consisting of 908 grams (6.68 mols) of m-hydroxyacetophenone, 4,500 grams (28.6 mols) of bromobenzene, 996 grams (7.2 mols) of anhydrous potassium carbonate, and 300 grams of copper bronze was heated under reflux with stirring until water evolution was complete, using a Dean-Stark water separator. The mixture was then stirred and refluxed for 24 hours. After cooling to room temperature, the reaction was diluted with an equal volume of CHCl3 and filtered. The filtrate was washed with 5% HCl, then with 5% NaOH, with water, dried over Na2SO4 and evaporated in vacuo. The residual oil was distilled through a 15 cm Vigreux column, yielding 918 grams of 3-phenoxy-acetophenone, BP 120° to 121°C (0.09 mm).
α-Methyl-3-Phenoxybenzyl Alcohol: A stirred solution of 700 grams of mphenoxyacetophenone in 3,000 ml anhydrous methanol was cooled to 0°C in an ice-acetone bath. Sodium borohydride, 136 grams (3.6 mols) was added to this solution in small portions at such a rate that the temperature never rose above 10°C. After borohydride addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 18 hours. It was then stirred and refluxed for 8 hours. About 400 ml of methanol was distilled out and the remaining solution was evaporated to about one-third its original volume in vacuo and poured into ice water. This mixture was extracted twice with ether, acidified with 6 N HCl, and again extracted with ether. The ether extracts were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residual oil was distilled through a 15 cm Vigreux column, yielding 666 grams of α-methyl-3- phenoxybenzyl alcohol, BP 132° to 134°C (0.35 mm), nD 25 = 1.5809.
α-Methyl-3-Phenoxybenzyl Bromide: A stirred solution of 1,357 grams of α- methyl-3-phenoxybenzyl alcohol in 5,000 ml anhydrous CCl4 (predriedover molecular sieve) was cooled to 0°C. To this was added 1,760 grams PBr3,stirring and cooling being maintained at such a rate that the temperature remained at 0° to 5°C, during the addition. The reaction mixture was then allowed to warm to room temperature and was stirred at room temperature overnight (ca 12 hours). The reaction mixture was then poured into ice water and the organic phase separated. The aqueous phase was extracted with CCl4 and the combined extracts were washed three times with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to yield 1,702 grams of α-methyl-3-phenoxybenzyl bromide as a heavy viscous oil, nD 25=1.5993.
2-(3-Phenoxyphenyl)Propionitrile: A well-stirred suspension of 316 grams of 98% sodium cyanide in 5,000 ml of anhydrous dimethyl sulfoxide (previously dried over molecular sieve) was warmed to 55° to 60°C and maintained at this temperature while 1,702 grams of α-methyl-3-phenoxybenzyl bromide was slowly added. After the bromide addition was completed, the temperature was raised to 75°C and the mixture stirred at this temperature for 1.5 hours. The mixture was then allowed to cool to room temperature and was stirred overnight at room temperature and then poured into ice water. The resulting aqueous suspension was extracted twice with ethyl acetate, and then with ether. The organic extract was washed twice with a sodium chloride solution, once with water, and dried over anhydrous sodium sulfate. Evaporation of the solvent in vacuo left an oily residue which was distilled through a 15 cm Vigreux column to yield 1,136 grams of 2-(3-phenoxyphenyl)propionitrile, BP 141° to 148°C (0.1 mm), nD 25 = 1.5678.
2-(3-Phenoxyphenyl)Propionic Acid: A mixture of 223 grams of 2-(3- phenoxyphenyl)propionitrile and 400 grams of sodium hydroxide in 1,600 ml of 50% ethanol was refluxed with stirring for 72 hours. After cooling to room temperature, the reaction mixture was poured into ice water. The resulting solution was washed with ether, acidifed with concentrated HCl, and extracted with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo. The residual oil was distilled to yield 203.5 grams (84%) of 2-(3-phenoxyphenyl)propionic acid as a viscous oil; BP 168° to 171°C (0.11 mm), nD 25 = 1.5742.

brand name

Nalfon (Dista, Pedinol, USA, Austria, Canada), Fenopron (Lilly, South Africa, United Kingdom), Fepron (Lilly, Italy), Nalgesic (Lilly, France), Progesic (Lilly, United Kingdom).

Therapeutic Function

Antiinflammatory

General Description

Fenoprofen (Nalfon), is rapidly absorbed orally, reachespeak plasma levels within 2 hours, and has a short plasmahalf-life (3 hours). It is highly protein bound, just like theother NSAIDs, thus caution is needed when it is used concurrentlywith other medications including hydantoins, sulfonamides,and sulfonylureas. It is recommended for RAand OA, at an oral dose of 300 to 600 mg for 3 or 4 timesper day, but not exceeding 3 g/d to avoid any serious side effects.It should be noted that in a comparison study of allNSAIDs, fenoprofen is the one that has been most closelyassociated with a rare acute interstitial nephritis.188 For mildto moderate pain relief, the recommended dosage is 200 mggiven every 4 to 6 hours, as needed.

Clinical Use

Clinical use NSAID and analgesic

Synthesis

Fenoprofen, 2-(3-phenoxyphenyl)propionic acid (3.2.32), is synthesized from 3-hydroxyacetophenone, which is esterfied by bromobenzene in the presence of potassium carbonate and copper filings, forming 3-phenoxyacetophenone (3.2.28). The carbonyl group of the resulting product is reduced by sodium borohydride and the resulting alcohol (3.2.29) is brominated by phosphorous tribromide. The reaction of the resulting bromo derivative (3.2.20) with sodium cyanide gives 2-(3-phenoxyphenyl)propionitrile (3.2.31), which is hydrolyzed into the desired fenoprofen (3.2.32) [102,103].

Drug interactions

Potentially hazardous interactions with other drugs
ACE inhibitors and angiotensin-II antagonists: increased risk of hyperkalaemia and nephrotoxicity; reduced hypotensive effect.
Analgesics: avoid concomitant use with other NSAIDs or aspirin; avoid concomitant use with ketorolac (increased 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 or venlafaxine.
Antidiabetics: effects of sulphonylureas enhanced.
Antiepileptics: possibly enhanced effect of phenytoin.
Antivirals: concentration possibly increased by ritonavir; increased risk of haematological toxicity with zidovudine.
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 reduced.
Pentoxifylline: increased risk of bleeding.
Tacrolimus: increased risk of nephrotoxicity

Metabolism

Approximately 90% of a dose is excreted in the urine in 24 hours, chiefly as the glucuronide and the glucuronide of hydroxylated fenoprofen.