Description
Naproxen(22204-53-1) is synthesized from 2-methoxynaphthalene and the (+)-isomer obtained by resolution with cinchonidine
(61). It was introduced in the United States in 1976 and, as a generic drug, has consistently been among the more
popular NSAIDs. It is marketed as the S-(+)-enantiomer, but interestingly, the sodium salt of the (–)-isomer also is on
the market as Anaprox. As an inhibitor of prostaglandin biosynthesis, it is 12 times more potent than aspirin, 10 times
more potent than phenylbutazone, three to four times more potent than ibuprofen, and four times times more potent
than fenoprofen, but it is approximately 300 times less potent than indomethacin.
Originator
Naprosyn,Syntex,UK,1973
Definition
ChEBI: A methoxynaphthalene that is 2-methoxynaphthalene substituted by a carboxy ethyl group at position 6. Naproxen is a non-steroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such a
osteoarthritis, kidney stones, rheumatoid arthritis, psoriatic arthritis, gout, ankylosing spondylitis, menstrual cramps, tendinitis, bursitis, and for the treatment of primary dysmenorrhea. It works by inhibiting both the COX-1 and COX-2 enzymes.
Indications
Naproxen (Naprosyn,22204-53-1) also has pharmacological
properties and clinical uses similar to those of ibuprofen.
It exhibits approximately equal selectivity for
COX-1 and COX-2 and is better tolerated than certain
NSAIDs, such as indomethacin. Adverse reactions related
to the GI tract occur in about 14% of all patients,
and severe GI bleeding has been reported. CNS complaints
(headache, dizziness, drowsiness), dermatological
effects (pruritus, skin eruptions, echinoses), tinnitus,
edema, and dyspnea also occur.
Manufacturing Process
According to US Patent 3,658,858, a solution of 24 grams of 2-bromo-6-
methoxynaphthalene in 300 ml of tetrahydrofuran is slowly added to 2.5
grams of magnesium turnings and 100 ml of tetrahydrofuran at reflux
temperature. After the addition is complete, 20 grams of cadium chloride is
added, and the resultant mixture is refluxed for 10 minutes to yield a solution
of di-(6-methoxy-2-naphthyl)cadmium (which can be separated by
conventional chromatography, although separation is unnecessary).
A solution of 18 grams of ethyl 2-bromopropionate in 20 ml of tetrahydrofuran
is then added to the cooled reaction mixture. After 24 hours at 20°C, the
product is hydrolyzed by adding 200 ml of 5 weight percent methanolic
sodium hydroxide followed by heating to reflux for 1 hour. The reaction
mixture is then diluted with excess 1 N sulfuric acid and extracted with ether.
The ether phase is separated, evaporated to dryness and the residue is
recrystallized from acetone-hexane to yield 2-(6-methoxy-2-
naphthyl)propionic acid.
Brand name
Naprosyn (Roche).
Therapeutic Function
Antiinflammatory
General Description
Naproxen (Naprosyn, Anaprox,22204-53-1), marketed as the (S)-enantiomer,is well absorbed after oral administration, givingpeak plasma levels in 2 to 4 hours and a half-life of 13 hours.Naproxen is highly protein bound and displaces most protein-bound drugs. It is recommended for use in RA, OA, acute gouty inflammation, and in primary dysmenorrhea. Itshows good analgesic activity (i.e., 400 mg is comparable to75–150 mg of oral meperidine and superior to 65 mg ofpropoxyphene and 325 mg of aspirin plus 30 mg of codeine).It is also available OTC as 200-mg tablets (Aleve).
Pharmacokinetics
Naproxen is almost completely absorbed following oral administration. Peak plasma levels are achieved within 2 to 4
hours following administration. Like most of the acidic NSAIDs (pKa = 4.2), it is highly bound (99.6%) to plasma
proteins. Approximately 70% of an administered dose is eliminated as either unchanged drug (60%) or as conjugates
of unchanged drug (10%). The remainder is converted to the 6-O-desmethyl metabolite by both CYP3A4 and CYP1A2
and, further, to the glucuronide conjugate of the demethylated metabolite. The 6-O-desmethyl metabolite lacks
anti-inflammatory activity. Like most of the arylalkanoic acids, the most common side effect associated with the use
of naproxen is irritation to the GI tract. The most common other adverse reactions are associated with CNS
disturbances (e.g., nausea and dizziness).
Clinical Use
Naproxen(22204-53-1) is indicated for the treatment of rheumatoid arthritis, osteoarthritis, juvenile arthritis, ankylosing
spondylitis, tendinitis, bursitis, acute gout, and primary dysmenorrhea and for the relief of mild to moderate pain.
Side effects
Common side effects of Naproxen(22204-53-1) may include indigestion, heartburn, stomach pain, nausea, headache, dizziness, drowsiness, bruising, itching, rash, swelling, or ringing in the ears. Seek immediate medical attention if you have any of the following serious drug reactions. For example: shortness of breath, swelling or rapid weight gain, rash, signs of stomach bleeding (bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds), liver problems (nausea, upper stomach pain, itching, feeling tired, flu-like symptoms, loss of appetite, dark urine, clay-coloured stools, jaundice), kidney problems (little or no urination, pain or difficulty in urinating, swelling of the feet or ankles, feeling tired or shortness of breath), low red blood cells (anaemia), etc. In addition, in rare cases, a severe allergic reaction to naproxen may occur. You may also suffer from stomach ulcers and other adverse reactions when taking it for a long time.
Synthesis
Naproxene, 2-(6-methoxy-2-naphthyl)-propionic acid (3.2.15) can be synthesized by the methods of synthesis described for ibuprofen as well as by the methods of
fenoprofen (3.2.21) and ketoprofen (3.2.27) synthesis that will be described below from
2-acetyl or 2-chloromethyl-6-methoxynaphthaline [99–101].
Veterinary Drugs and Treatments
The manufacturer lists the following indications: “…for the relief
of inflammation and associated pain and lameness exhibited with
myositis and other soft tissue diseases of the musculoskeletal system
of the horse.” (Package Insert; Equiproxen?—Syntex). It has
also been used as an antiinflammatory/analgesic in dogs for the
treatment of osteoarthritis and other musculoskeletal inflammatory
diseases (see adverse reactions below).
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 heparins, 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.
Probenecid: excretion reduced by probenecid.
Tacrolimus: increased risk of nephrotoxicity.
Metabolism
Naproxen(22204-53-1) is extensively metabolised in the liver
to 6-0-desmethyl naproxen. Both naproxen and
6-0-desmethyl naproxen are further metabolised to their
respective acylglucuronide conjugated metabolites.
About 95% of a dose is excreted in urine as naproxen and
6-O-desmethylnaproxen and their conjugates. Less than
5% of a dose appears in the faeces.
References
[1] barnett j, chow j, ives d, et al. purification, characterization and selective inhibition of human prostaglandin g/h synthase 1 and 2 expressed in the baculovirus system[j]. biochimica et biophysica acta (bba)-protein structure and molecular enzymology, 1994, 1209(1): 130-139.
[2] laneuville o, breuer d k, dewitt d l, et al. differential inhibition of human prostaglandin endoperoxide h synthases-1 and-2 by nonsteroidal anti-inflammatory drugs[j]. journal of pharmacology and experimental therapeutics, 1994, 271(2): 927-934.
[3] dubois r n, abramson s b, crofford l, et al. cyclooxygenase in biology and disease[j]. the faseb journal, 1998, 12(12): 1063-1073.
[4] agdeppa e d, kepe v, petri a, et al. in vitro detection of (s)-naproxen and ibuprofen binding to plaques in the alzheimer’s brain using the positron emission tomography molecular imaging probe 2-(1-{6-[(2-[18 f] fluoroethyl)(methyl) amino]-2-naphthyl} ethylidene) malononitrile[j]. neuroscience, 2003, 117(3): 723-730.
