Arylpropionic acids nonsteroidal antiinflammatory

An hplc assay was developed suitable for the analysis of enantiomers of ketoprofen (KT), a 2-arylpropionic acid nonsteroidal antiinflammatory dmg (NSAID), in plasma and urine (59). Following the addition of racemic fenprofen as internal standard (IS), plasma containing the KT enantiomers and IS was extracted by Hquid-Hquid extraction at an acidic pH. After evaporation of the organic layer, the dmg and IS were reconstituted in the mobile phase and injected onto the hplc column. The enantiomers were separated at ambient temperature on a commercially available 250 x 4.6 mm amylose carbamate-packed chiral column (chiral AD) with hexane—isopropyl alcohol—trifluoroacetic acid (80 19.9 0.1) as the mobile phase pumped at 1.0 mL/min. The enantiomers of KT were quantified by uv detection with the wavelength set at 254 nm. The assay allows direct quantitation of KT enantiomers in clinical studies in human plasma and urine after adrninistration of therapeutic doses. 

Nonsteroidal Antiinflammatory Drugs. Nonsteroidal antiinflammatory dmgs (NSAIDs) include, among the numerous agents of this class, aspirin (acetylsaflcyhc acid), the arylacetic acids indomethacin and sulindac, and the arylpropionic acids, (5)-(147) and (R)-(148) ibuprofen, (5)-(149) and (R)- (150), flurbiprofen naproxen (41), and fenoprofen (see Analgesics, antipyretics, and antiinflammatory agents Salicylic acid and related compounds). 

Asymmetric catalytic hydrogenation is one of the most efficient and convenient methods for preparing a wide range of enantiomerically pure compounds, and Ru-BINAP-catalyzed asymmetric hydrogenation of 2-arylacrylic acids has attracted a great deal of attention,11 as the chiral 2-arylpropionic acid products constitute an important class of nonsteroidal antiinflammatory drugs. 

Many nonsteroidal anti-inflammatory drugs (NSAIDs) are substituted 2-arylpropionic acids. Most NSAIDs also have a chiral carbon next to the carboxylate and are administered as a racemic mixture of the two enantiomers. In general, the (S)-enantiomcr is responsible for most of the antiinflammatory activity of these agents. It was found that the (/ -enantiomer is converted to the (S)-enantiomer but the reverse does not occur (23). As with amino acid conjugation, the pathway involves reaction with ATP to form an AMP ester, which is, in turn, converted to a Co-A ester, and it is the Co-A ester that undergoes chiral inversion (Fig. 7.14). Substrates include ibuprofen, naproxen, and fenoprofen. 

The hydroformylation reaction of vinyl aromatics (Table 4)60 lends itself to the synthesis of a number of 2-arylpropionic acids in high enantiomeric excess that are nonsteroidal antiinflammatory agents.61 Previous asymmetric syntheses of these acids required the use of stoichiometric amounts of chiral auxiliaries, which in most cases are not easily recovered. The branched aldehyde was oxidized to (S)-(+)-na-proxen,62 in 84% yield. 

The reaction of the secondary xanthate 1009 and pyrrole 1008 afforded methyl 2-(5-benzoyl-17/-pyrrol-2-yl)pro-panoate 1010 in high yield, a new representative of 2-arylpropionic acids constituting a large class of nonsteroidal antiinflammatory drugs, which are used worldwide (Equation 238) <2003CC2316>. 

Two groups of chiral aromatic carboxylic acids are important commercial intermediates for the agricultural and pharmaceutical industries. The R enantiomer of a-phenoxypropionic adds confers biological activity for a number of herbiddes. The S enantiomer of a variety of arylpropionic adds is the biologically active form of the nonsteroidal antiinflammatory products labeled profens. Racemic mixtures of the alkyl esters of these propionic add derivatives have been effectiwly resolved to yield the desired optically active carboxylic acids (64-66). Figure 20 shows examples of the resolution of aromatic propionic acid esters. 

In 1992 the world market for arylpropionic acids (profenes) which are used as nonsteroidal antiinflammatory agents was > 2.5 billion ( 2500 million). 

Flurbiprofen is a nonsteroidal antiinflammatory drug of the 2-arylpropionic acid class. The recommended dosages for flurbiprofen are 50 mg q. 4 to 6 hours for analgesia and 100 to 300 mg/day for the treatment of inflammatory conditions (see also Table 3). 

Nonsteroidal antiinflammatory drugs. Pirprofen, naproxen, ibuprofen, and keto-profen can occasionally cause microvesicular steatosis in humans (Bravo et al. 1997 Victorino et al. 1980 Danan et al. 1985 Dutertre et al. 1991). These NSAIDS have a 2-arylpropionate structure, with an asymmetric carbon, and exist as either the S(+)- or the R(—)-enantiomers. Only the S(+)-enantiomer inhibits prostaglandin synthesis, whereas only the R( )-enantiomer is converted into the acyl-CoA derivative. However, both the S(+)-enantiomer and the R( )-enantiomer of ibuprofen inhibit the p-oxidation of medium- and short-chain fatty acids (Freneaux et al. 1990). Pirprofen, tiaprofenic acid, and flurbiprofen also inhibit mitochondrial p-oxidation (Geneve et al. 1987a). 

Many kinetic resolutions of rac-nitriles were performed in search of a method to produce (S)-configurated a-arylpropionic acids, such as ketoprofen, ibuprofen, or naproxen, which are widely used as nonsteroidal antiinflammatory agents. Overall, enantioselectivities depended on the strain used, and whether a nitrilase- or nitrile hydratase-amidase pathway was dominant, which determines the nature of (enantiomeric) products consisting of a mixture of nitrile/carboxylic acid or amide/ carboxylic acid, respectively [687, 693-696]. 

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