Drug compounds ibuprofen

For therapeutical purposes, a likewise frequently used group of drug compounds are the nonsteroidal anti-inflammatory drugs (NSAID). Among the best known representatives of the aryl acetic acid derivatives is diclofenac as well as ibuprofen, an aryl propionic acid derivative. As both have acidic properties, they dissociate while being dissolved and may form salts with amphiphilic properties. Together with appropriate counterions these amphiphilic organic acids may form lyotropic mesophases with water even at room or body temperature, for example, diclofenac diethylamine... 

Many drug compounds are racemic mixtures of stereoisomers. In most cases, one of the isomers is more pharmacologically active than the other isomer, and each isomer may exhibit different pharmacokinetic properties. Warfarin, propranolol, verapamil, and ibuprofen are aU racemic mixtures of stereoisomers. Some drug interactions inhibit or increase the elimination of only one stereoisomer. The importance of the drug interaction depends on which isomer is affected. Other drugs, such as dextromethorphan, levofloxacin, and dUtiazem, are composed of just one stereoisomer. 

By these procedures, the anti-inflammatory drugs (S)-ibuprofen and (S)-naproxen (Equation 15.41) can be synthesized by asymmetric hydrogenation. Again, one challenging aspect of this route to naproxen is the synthesis of the substrate, and for this reason, asymmetric hydrogenation has not become the major commercial route to this compound. 

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). 

There are several hundred reported NF-kB inhibitors (see www.nf-kb.org for a complete and updated list). These inhibitors include natural products, chemicals, metabolites, and synthetic compounds. A large majority of these products, in particular commonly used antiinflammatory drugs such as corticosteroids and the nonsteroidal antiinflammatory drugs (NSADDs) aspirin, sulindac, ibuprofen and sulphasalazine, have the ability to partially inhibit NF-kB activity in cell culture. However, the precise mechanism of action and the specific molecular targets of most of these inhibitors remain unclear. 

FIGURE 2.20 Schematic presentation of the hydrogen-bonded cyclic dimers of enantiomeric antipodes of 2-phenylpropionic acid, Ibuprofen, and Naproxen (the latter two compounds are drugs from the group of profens). 

Anti-inflammatory drugs such as Ibuprofen, acetaminophen, diclofenac, atorvastatin, and hydrochlorthiazide were detected in the highest concentrations in samples from three WWTPs in Spain [93]. These compounds were present in average concentrations from 43 to 117 ng/g, 42 to 103 ng/g, 28 to 75 ng/g, 21 to 65 ng/g, and 29 to 126 ng/g, respectively. 

For therapeutic drugs, the highest concentrations in the raw sludge corresponded to the analgesics diclofenac (209 ng g ) and ibuprofen (135 ng g-1), and the sulfonamide antibiotic sulfathiazole (143.0 ng g-1). Next in abundance were the diuretic compounds furosemide (79.9 ng g-1) and hydrochlorothiazide (41.3 ng g-1), and the analgesic ketoprofen (42.4 ng g-1). The remaining PhC were found at concentrations below 40 ng g The list of the 24 detected... 

Non steroidal antiinflammatory drugs were among the first classes of chiral compounds investigated in the early stages of the application of macrocyclic antibiotics as chiral selectors therefore, they were screened on vancomycin [7], teicoplanin [30], ristocetin A [33] CSPs under RPmode systems, and on avoparcin CSP under NP mode systems [37]. The enantioresolution of a variety of pro fens was later reported on commercially available vancomycin CSPs [128, 168], and recently on a ME-TAG CSP [58]. Ibuprofen enantiomers were also separated on a CDP-1-containing CSP [55]. Glycopeptide A-40,926 CSP was successfully employed in the analytical and semipreparative separation of 2-arylpropionic acids [63]. 

Most of the nonsteroidal anti-inflammatory drugs (NSAIDs) are carboxylic acids. Aspirin (8.69) (acetylsalicylic acid, ASA) has been used since the turn of the last century to reduce pain and fever, but the parent compound, salicylic acid, has been known and used since antiquity, owing to its common occurrence as a glycoside in willow bark. Acetylation merely decreases its irritating effect. Among the numerous other salicylates known and used, flufenisal (8.70) has a longer duration of activity and fewer side effects than aspirin. Mefenamic acid (8.71) and flufenamic acid (8.72) are derivatives of anthranilic acid, while ibuprofen (8.73) and naproxen (8.74) are derivatives of phenylacetic and naphthylacetic acids, respectively. 

The prototype for this class of compounds is ibufenac (42-3), developed by a group at Boots in the UK. This drug was to be quickly superseded by its a-methylated congener, ibuprofen, from the same laboratory [43]. The mechanistically very complex Wilgerodt reaction constitutes the key to the preparation of ibufenac. Thus, reaction of the acetylation product (42-1) from isobutyl benzene and acetyl chloride with sulfur and morpholine leads to the transposition of the oxidized function to the terminal carbon and formation of thiomorpholide (42-2). Hydrolysis of the thioamide... 

---