Naproxen and Ibuprofen

At present much research is being directed to the development of catalytic routes to a series of asymmetric carboxylic acids that lack the acidamido ligand as additional functionality. Four are listed in Fig. 6.29, which are important as 

The aluminium salt obtained is acidified and dehydrated to give the unsaturated (atropic type) acid precursor. This can be asymmetrically hydrogenated in methanol under 7 bar of H2 with an enantiomeric excess of 98.5%. A turnover of 3000 was most efficient. The reaction scheme is shown in Fig. 6.31. 

6 — HOMOGENEOUS CATALYSIS WITH TRANSITION METAL COMPLEXES 

---

Given the role of prostaglandins in the pathophysiology of I dysmenorrhea, NSAIDs are the treatment of choice. There does not appear to be a difference between agents in efficacy. Choice of one agent over another may be based on cost, convenience, and patient preference.17 The most commonly used agents are naproxen and ibuprofen. 

Other similar lipase/esterase resolution processes have been developed such as the use of Bacillus that esterase to produce the substituted propanoic acids that are precursors of non-steroidal anti-inflammatory drags, snch as naproxen and ibuprofen etc., and the formation of chiral amines by Celgene. Other methods start from prochiral precursors and have the advantage that enantioselective synthesis allows the production of particular isomers in yields approaching 100%, rather than the 50% yields characteristic of resolution processes. For instance Hoechst have patented the production of enantiomers using Pseudomonas fluorescens lipase to either acylate diols or hydrolyse diacetate esters. 

The enzymatic enantioselective hydrolysis of esters of naproxen and ibuprofen has attracted considerable attention because the (S)-enantiomers of these nonsteroidal anti-inflammatory drugs (NSAIDs) are the pharmacologically active isomers. These reactions have been successfully performed in a range of ionic liquids (Figure 10.10) [60, 65, 121]. 

Figure 10.10 Enantioselective hydrolysis of naproxen and ibuprofen esters. ...

Rofecoxib is approved for the treatment of acute pain and dysmenorrhea at a dose of 50 mg for up to 5 days. The clinical studies indicate that rofecoxib shows efficacy similar to that produced by the maximum analgesic doses of naproxen and ibuprofen (Ehrich et al., 1999). The pain settings in which rofecoxib has been tested include acute postoperative dental pain, the pain of dysmenorrhea for up to 3 days, and postoperative pain for 5 days following surgical replacement of the knee or hip. In contrast, celecoxib is not approved in the United States for the treatment of acute pain, and it appears to be less effective when given acutely than rofecoxib, ibuprofen, or naproxen. The explanation for the differences between rofecoxib and celecoxib in acute pain is not known. 

The asymmetric hydroformylation of vinyl arenes can provide a route to the preparation of the profen class of drugs. Naproxen and ibuprofen, two examples in the profen class, are NSAIDs on the market.50... 

FIGURE 27.4 Deracemization of protected forms of te/t-leucine, naproxen, and ibuprofen. 

Both naproxen and ibuprofen are chiral but, while both enantiomers of ibuprofen are effective painkillers, and the drug is sold as a racemic mixture (and anyway racemizes in the body) only the (S) enantiomer of naproxen has anti-inflammatory activity. When the American pharmaceutical company Syntex first marketed the drug they needed a way of resolving the racemic naproxen they synthesized in the laboratory,... 

Naproxen and ibuprofen are nonsteroidal antiinflammatory drugs (NSAIDs) widely available as and OTC medications. In both cases the active (S)-enantiomer is far more potent. Selective hydrolysis of racemic esters of these drugs enables the production of both (S)-naproxen and (S)-ibuprofen. A number of... 

Nonsteroidal Anti-Inflammatory Drugs NSAIDs have now become the drugs of choice over colchicine because of the severe gastrointestinal side effects associated with colchicine and its lack of efficacy to resolve the gouty pain unless used within 24 hours after the occurrence of the initial attack. NSAIDs such as indomethacin, naproxen, and ibuprofen are effective because they have a short r/2, a rapid onset of action, and are better tolerated by patients. 

After women have tried lifestyle changes, nutritional supplements, and nonpharmacologic treatment approaches, some may require pharmacologic therapies if there is limited response. Women with less severe PMS generally self-treat headaches and cramps with aspirin, acetaminophen, and nonsteroidal anti-inflammatory drugs (NSAlDs). NSAIDs, such as naproxen and ibuprofen, are the treatments of choice for dysmenorrhea, menstrual headaches or migraines, and mastalgia. 

Nonsteroidal anti-inflammatory drugs (naproxen and ibuprofen) Penicillins Phenylbutazone Probenecid Salicylates Sulfonamides Barbitu rates Phenytoin Probenecid Retinoids Salicylates Sulfonamides Sulfonylureas Tetracycline Ethanol Retinoids Dipyridamole... 

There has been considerable academic and industrial effort to produce chiral, nonsteroidal anti-inflammatory agents such as Naproxen and Ibuprofen via the stereoselective hydroformyiation of vinyl aromatics. Such a process requires not only a high enatiomeric excess (i.e. optical yield) of the branched isomer but also a high branched to normal (b/n) regioselectivity ... 

Both naproxen and ibuprofen are chiral but, while both enantiomers of ibuprofen are effective painkillers, and the drug is sold as a racemic mixture (and anyway racemizes in the body) only the... 

Several variations of these CSPs have been developed, such as the phosphonate ester CSP 30 and the tetrahydrophenanthryl amide CSP 33. These compounds are used in pharmaceutical studies. The former CSP is a good resolving agent for the (3-adrenergic blocker class of compounds, such as propanolol, whereas the latter is a good CSP for separation of NSAIDs, such as naproxen and ibuprofen. ... 

Figure 20. Stereoselective synthesis of naproxen and ibuprofen by hydrogenation. Reagents a, C02, electrolysis b, H30 + c, H +, -H20 d, H2, Ru(acac)2/BINAP.

The choice of drugs for children is considerably restricted, and only drugs that have been extensively tested in children should be used. This commonly points toward naproxen and ibuprofen. 

The risk of serious upper gastrointestinal bleeding was inereased by the use of more than one NSAID in a meta-analysis of data from three ease-eontrolled studies (odds ratio 4.9 with one NSAID and 10.7 with two). Another study provided similar findings the odds ratio was 7.1 with one NSAID and 12.3 with two or more NSAIDs. Similar findings have been reported with aspirin and NSAIDs, see NSAIDs + Aspirin Anti-inflammatory dose , p.l42. Analysis of yellow eard reports to the CSM in the UK, of gastrointestinal perforation, obstruetion, uleeration or bleeding with diclofenac, naproxen, and ibuprofen, revealed that 6% of the patients were reeeiving another non-aspirin NSAID. ... 

There is evidence that most NSAIDs can increase blood pressure in patients taking antihypertensives, although some studies have not found the increase to be clinically relevant In various small studies, indometacin reduced the antihypertensive effects of the beta biockers. There is some evidence that piroxicam usually interacts similarly. Ibuprofen and naproxen have reduced the effect of beta blockers in some small studies but not others. Two isolated cases of hypertension have been reported with naproxen and ibuprofen in patients treated with propranolol and pindolol, respectively. Celecoxib, but not rofecoxib, inhibits the metabolism of metoprolol. Limited information su ests that normally di-... 

Conversions, yields, and selectivities in the synthesis of (.S)-naproxen and (. ibuprofen... 

Patients with osteoarthritis or rheumatoid arthritis are randomized to one of three treatments, celecoxib, ibuprofen, or naproxen, and the primary endpoint is the occurrence of a cardiovascular endpoint a nonfatal myocardial infarction, a nonfatal stroke, or any cardiovascular death. Non-inferiority will be assessed for three different pairwise comparisons celecoxib versus ibuprofen, celecoxib versus naproxen, and ibuprofen versus naproxen. The definition of non-inferiority differs somewhat from the fixed margin approach describe earlier in that there are separate criteria for the confidence interval and the point estimate. The hazard ratio for each comparison will be calculated, and non-inferiority will be concluded if the upper end of the... 

---