Fenamic acid derivatives

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. 

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. 

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. 

The eight groups of nonsteroidal anti-inflammatory drugs are salicylates, parachlorobenzoic acid derivatives, pyrazolone derivatives, propionic acid derivatives, fenamates, oxicams, phenylacetic acid, and selective COX-2 inhibitors. 

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... 

About 10% of asthmatics are hypersensitive to aspirin, and in some individuals life-threatening bronchoconstriction can occur. This is not a drug-drug interaction but an adverse response of asthmatic patients to aspirin, whether taking an anti-asthmatic drug or not. The reasons are not fully understood. Those known to be sensitive to aspirin may also possibly react to other NSAIDs, in particular the acetylated salicylates, the indole and indene acetic acids, and the propionic acid derivatives (see Table 6.1 , (p.l34)). The fenamates, oxicams, pyrazolones and pyrazolidinediones are better tolerated. The nonacetylated salicylates (sodium salicylate, salicylamide, choline magnesium trisalicylate) are normally well tolerated. Aspirin-sensitive individuals are also less likely to react to nimesulide. ... 

Fenamic Acids and Aza Analogs - The N-nitroso derivative 1 (ITF 611) was reported to have twice the potency (CE) of flufenamic acid, with less toxicity.61, 62 Clonixin (12) had 0.5 tiroes the potency (CE) of flufenamic acid, 63 and in a clinical trial 600 mg of 22. found comparable to 12 mg of morphine sulfate (i.m.) in the relief of postsurgical pain.64 At daily doses of 0.75-1.0 g, niflumic acid (18) was shown to be of some benefit in a wide variety of rheumatic afflictions.65... 

Flufenamic acid (162) is a reasonably well-established NSAID (Non Steroidal Anti Inflammatory Drug). Alkylation of its potassiuni salt with the hydroxyethyl ethyl ether of ethylenechlo-rohydrin affords the latendated derivative etofenamate (163) [41]. Antiinflammatory activity is apparently retained when both rings in the fenamate series carry carboxyl groups. Thus, condensation of dichlorobenzoic acid 164 with anthranilic acid (165) by means of nucleophilic aromatic... 

The fenamates are a family of NSAIDs first discovered in the 1950s that are derivatives of N-phenylanthranilic acid. They include mefenamic, meclofenamic, and flufenamic acids. They have no clear advantages over several other NSAIDs, and frequently cause GI side effects. 

These agents are considered to be 7/-aryl-substituted derivatives of anthranilic acid, which itself is a bioisostere of salicylic acid. These agents retain the acidic properties that are characteristic of this class of agents though mefenamic acid and meclofenamic acid are derivatives of anthranilic acid, diclofenac is derived from 2-arylacetic acid (Figure 13.10). The most active fenamates have small alkyl or halogen substituents at the 2, 3, or 6 position of the iV-aryl moiety... 

---