Fenamic acids

The relatively low potency of aspirin in overcoming the symptoms of inflammatory diseases has led to a continuing search for new antiinflammatory agents. Although many more potent agents have been introduced to clinical practice, most of these elicit some side effects that limit their use. Derivatives of iv-aryl anthra-nillic acids have provided a series of quite effective antiinflammatory drugs, the so-called fenamic acids. 

Ullman condensation of m-trifluoromethylaniline (13) with o-iodobenzoic acid in the presence of copper-bronze affords flu-fenamic acid (14). An analogous reaction of o-chlorobenzolc acid with 2,3-dimethylaniline (15) gives mefenamic acid (16) meclofenamic acid (18) is obtained by Ullman condensation employing 2,6-dlchloro-3-methylaniline (17). 

Replacement of one of the benzene rings by pyridine in the fenamic acid-type analgesics leads to an agent with full pharmacologic activity. Treatment of the N-oxide of nicotinic acid with phosphorus trichloride followed by hydrolysis of the acid... 

Replacement of one of the benzene rings in a fenamic acid by pyridine interestingly leads to a compound which exhibits antiliypertensive rather than antiinflammatory activity. Preparation of this agent starts with nucleophilic aroniatic substitution of anthranilic acid (8) on 4-chloropyri-dine. The product (9) is converted to its acid chloride (10), and this is condensed with piperidine. There is thus obtained ofornine (11) f31. 

Tryptophan—a single strong binding site that coincides with or overlaps the binding site for NphOAc, small fatty acid anions, benzodiazepines, fenamic acids, naproxen, ibuprofen,... 

As shown in Equations 20 and 21, the uncoupling activity and antiinflammatory activity of fenamic acid analogs, including flufenamic and mefenamic acids, are very similar in their dependence on both hydro-phobic and electronic effects of substituents. In these equations, the subscript, i, means that the drug activities are calculated on the basis of concentration of the ionized form. It has been suggested that these two biological effects, which are also observed in many other acidic antiinflammatory drugs, have similar physicochemical mechanisms in the interaction with receptors (44). 

SYNS o-ANILINOBENZOIC ACID 2-ANILINO-BENZOIC ACID O 2-CARBOXYDIPHENYLAMINE DIPHENYLAMINE-2-CARBOXYLICACID FENAMIC ACID PA 2-(PHENYLAMINO)BENZOICACID PHENYLANTHRANILIC ACID... 

Fenamic acid. The principal adverse effects of mefenamic acid are diarrhoea, upper abdominal discomfort, peptic ulcer and haemolytic anaemia. Elderly patients who take mefenamic acid may develop nonoliguric renal failure especially if they become dehydrated, e.g. by diarrhoea the drug should be avoided or used with close supervision in the elderly. 

Another important example of the importance of chirality, related to rheumatology, is that shown by some members of the NSAID family of aryl acids. Certain molecules which inhibit prostaglandin synthetase in vitro show in vivo antiinflammatory actions. Such compounds include several families of acidic NSAIDs, particularly the aryl acids salicylates, indomethacin analogs, phenylacetic acids, fenamic acids and enolic compounds. With respect to the indomethacin analogs, an important characteristic has emerged, namely, the requirement for a sinister absolute configuration (the S form, which happens to be -t-) at the chiral centre. For these drugs the (5)-(-l-) enantiomers show dominant, if not exclusive, activity. ... 

Fenamic acid (fenemate) derivatives include mefenamic acid and meclofenamic acid. These, too, are very powerful NSAIDs, but their GI side-effects seriously limit their use as antirheumatics. 

Grage, S. L., Gauger, D. R., et al. (2000). The amphiphilic drug flu-fenamic acid can induce a hexagonal phase in DMPC A solid state 31P- and 19F-NMR study. Physical Chemistry Chemical Physics, 2, 4574-4579. 

The list of compounds presented in Table 6.4 includes copper complexes of well-known antiarthritic drugs, including salicylic acid, aspirin, diflunisal, niflumic acid, D-penicillamine, hydrocortisone, dexamethasone, dimethyl-sul-phoxide, clopirac, ketoprofen, ibuprofen, (+ )-naproxen, indomethacin, me-fenamic acid, thiomalic acid, phenylbutazone, lonazolac, isoxicam and azo-propazone. While there has been much discussion concerning the qualitative and quantitative activities of these complexes [136, 152-156, 164, 187], it is... 

Tolfenamic Acid. 2-[(3-Chioro-2.methylphenyl)-aminojbenzoic acid V-(3-clj loro f-totyl >anthranilic acid JV-C2-methyl-3-chlorophenyl)anthranilic acid GEA 6414 Clotam Tolfedine. CMHuCINO, mol wt 261.71. C 64.25%, H 4.62%, Cl 13.55%, N 5.35%, O 12.23%, Deriv of anthranilic acid, related structurally to merenamic and flu-fenamic acids, q.q. v. Prepn Neth. pat. Appl, 6,680,251... 

Simultaneous aprobarbital, butabarbital, chlordiazepoxide, chloroj lenol, chlorproma-zine, clenbuterol, cortisone, danazol, diflunisal, doxapram, estrone, fluoxymesterone, me-fenamic acid, methyltestosterone, nicotine, oxazepam, phentermine, phenylpropanolamine, progesterone, sulfamethazine, sulfanilamide, testosterone, testosterone propionate, tranylcypromine, tripelennamine Interfering N-acetylprocainamide... 

Kim, M. Stewart, J.T. HPLC post-column ion-pair extraction of acidic drugs using a substituted a-phenylcinnamonitrile quaternary ammonium salt as a new fluorescent ion-pair reagent. J.Liq.Chromatogr., 1990, 13, 213-237 [derivatization fluorescence detection also benzoic acid, flu-fenamic acid, ibuprofen, ketoprofen, mefenamic acid, probenecid, salicylic acid, valproic acid]... 

Mefenamic acid is synthesized from o-chlorobenzoic acid and 2,3-dimethylaniline under catalytic conditions (66). Mefenamic acid is the only fenamic acid derivative that produces analgesia centrally and peripherally. Mefenamic acid is indicated for the short-term relief of moderate pain and for primary dysmenorrhea. 

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