ロフェコキシブ 化学特性,用途語,生産方法
外観
白色～黄色、結晶性粉末～粉末
溶解性
ジメチルスルホキシド溶状：試験適合
用途
シクロオキシゲナーゼ2
（COX-2）選択的阻害剤です。抗炎症・鎮痛
作用を示します。長期使用による心血管リス
クの増加が確認されています。
効能
鎮痛薬, 抗炎症薬, シクロオキシゲナーゼ2阻害薬
説明
Rofecoxib ts a non-steroidal anti-inflammatory drug (NSAID) launched
in Mexico, its first market, for the management of acute pain and the treatment
of osteoarthritis (OA) and primary dysmenorrhea. Rofecoxib can be obtained by
several different ways; one example is by arylation of a 4-bromofuranone with a
phenylboronic acid under Suzuki conditions. Rofecoxib is a highly selective
inhibitor of COX-2, the inducible isoform of cyclooxygenase and therefore
exhibits a potent antiinflammatory activity without concomitant gastric or renal
toxicities linked to the non-specific COX-1/2 inhibitors. In several clinical studies
in patients with knee or hip osteoarthritis, Rofecoxib was evaluated at 12.5-50
mg doses once daily: it demonstrated efficacy for all primary and secondary endpoints at doses considerably weaker than those for classical non-specific
NSAIDs, with good tolerance and less adverse effects. Selective COX-2
inhibitors potentially have a large spectrum of activity including new indications
such as Alzheimer's disease, colorectal cancer, irritable bowel disease or
urinary incontinence.
化学的特性
Off-White (Pale Yellow) Crystalline Powder
使用
Rofecoxib has been used in high performance bioaffinity chromatography.
定義
ChEBI: A butenolide that is furan-2(5H)-one that is substituted by a phenyl group at position 3 and by a p-(methylsulfonyl)phenyl group at position 4. A selective cyclooxygenase 2 inhibitor, it was used from 1999 to 2004 for the tr
atment of ostoarthritis, but was withdrawn following concerns about an associated increased risk of heart attack and stroke.
適応症
Rofecoxib is approved for the treatment of osteoarthritis,
dysmenorrhea, and acute pain. The most
common adverse reactions to rofecoxib are mild to
moderate GI irritation (diarrhea, nausea, vomiting, dyspepsia,
abdominal pain). Lower extremity edema and
hypertension occur relatively frequently (about 3.5%).
It is not metabolized by CYP2C9, so rofecoxib should
not be subject to some of the interactions seen with
celecoxib. However, its metabolism is increased by the
coadministration of rifampin, which acts as a nonspecific
inducer of hepatic metabolism.
作用機序
Rofecoxib is excreted primarily in the urine (72%) as metabolites. Less than 1% is excreted in the urine as
unchanged drug, whereas approximately 14% is excreted in the feces as unchanged drug. Although the metabolism
of rofecoxib has not been fully determined, the microsomal cytochrome P450 system appears to play only a minor
role—a major difference in the metabolic routes of rofecoxib and celecoxib. The major metabolic route appears to
form reduction of the dihydrofuranone ring system by cystolic enzymes to the to cis- and trans- dihydro derivatives.
Also isolated is the glucuronide of a hydroxy derivative that results from CYP2C9 oxidative metabolism. None of the
isolated metabolites of rofecoxib possess pharmacological activity as COX-1 or COX-2 inhibitors.
薬物動態学
Rofecoxib has been synthesized by a number of synthetic routes that have been summarized elsewhere. It was
the second selective COX-2 inhibitor to be marketed. Rofecoxib is well absorbed from the GI tract on oral
administration, with peak plasma levels generally being attained within 2 to 3 hours of dosing. Bioavailability
averages 93% following administration of a single dose. The area under the plasma concentration–time curve is
increased in patients older than 65 years compared to younger adults and is increased slightly in black and Hispanic
patients compared with white patients, but the difference is not considered to be clinically significant.
臨床応用
Rofecoxib was indicated for the relief of the signs and symptoms of osteoarthritis, for the management of acute pain
in adults, and for the treatment of primary
dysmenorrhea.
合成
Rofecoxib can be obtained by
different synthetic routes, e.g., by condensation of phenylacetic acid with ethyl bromoacetate to ethyl 2-phenylacetoxyacetate,
which is then cyclized to a hydroxyfuranone. Subsequently, the hydroxyfuranone reacts with trifluoromethanesulfonic (triflic) anhydride to the corresponding triflate which
reacts with LiBr to yield a bromofuranone.
The bromofuranone is condensed with 4-
(methylsulfanyl)phenylboronic acid to give
4-[4-(methylsulfanyl)phenyl]-3-phenylfuran-
2(5H)-one which is finally oxidized to rofecoxib.
ロフェコキシブ 上流と下流の製品情報
原材料
準備製品