Niflumic acid

Bossert, F. and Vater, W. U.S. Patent 3,485,847 December 23, 1969 assigned to Farbenfabriken Bayer AG, Germany 

Chemical Name 2-[[3-(trifluoromethyl)phenyl] amino]-3-pyridinecarboxylic acid Common Name 2-[3-(trifluoromethyl)anilino] nicotinic acid Structural Formula  

Niflumic acid Is prepared as follows Nicotinic acid, m-trifluoromethylanlline, and potassium Iodide are intimately mixed and heated on an oil bath at 140 C. The mixture melts 

Hoffmann.C.and Faure, A. U.S. Patent 3,415,834 December 10,1968 assigned to Societe anonymedite Laboratoires UPSA, France 

Chemicel Name 2-[ [3-(trifluoromethyl)phenyl] amino]-3-pyridinecarboxylic acid 

Common Name 2-[3-(trifluoromethyl)anilino] nicotinic acid Structural Formula cr 

Chemical Abstracts Registry No. 4394-00-7 Trade Name Manufacturer 

Nifluril Actol Flamlnon Forenol Landruma Nifluran NIflux 

---

Pyridine A Oxides. Analgesic and antiinflammatory dmgs niflumic acid [4394-00-7] (68) and pranoprofen [52549-17-4] (69) are manufactured from nicotinic acid N-oxide [2398-81 -4]. The antiulcer dmg omeprazole (66) is produced from 2,3,5-trimethylpyridine N-oxide [74409-42-0]. Zinc pyrithione, the zinc salt of pyrithione (45), is a fungicide derived from 2-chloropyridine N-oxide (45). 

Fontego - Bumetanide Fonzylane - Buflomedil Forane Isoflurane Fordex - Tolbutamide Fordiuran Bumetanide Foreart Inosine Forenol -Niflumic acid Forhistal Dimethindene maleata Foristal - Dimethindene maleate Formaftil - Formocortal acetate Formulex Dicyclomine HCI Fortabol -Methenolona acetate Fortabolin - Nandrolone decanoate Fortapen - Ampicillin Fortasec - Loperamide HCI Fortecortin Dexamethasone acetate Fortesul Sulfameter... 

Unfortunately, the pharmacology of chloride channels is poorly developed. Specific and highly useful inhibitors or modulators (e.g. strychnine, picrotoxin, diazepams) are only available for ligand-gated chloride channels (but these are covered in a different chapter). There are several chloride channel inhibitors such as the stilbene-disulfonates DIDS and SITS, 9-antracene-carboxylic acid (9-AC), arylaminobenzoates such as DPC and NPPB, niflumic acids and derivates, sulfony-lureas, and zinc and cadmium. All of these inhibitors, however, are not veiy specific. Several of these inhibitors (e.g. DIDS) inhibit many chloride channels only partially even at millimolar concentrations and have effects on other types of transport proteins. 

C7HjFjN 98-16-8) see Bendroflumethiazide Flufenamic acid Flutamide Hydroflumethiazide Niflumic acid... 

Fig. 16.3 ionization scheme of niflumic acid (CAS-RN 4394-00-7). The macro- (pfCJ and microprotonation (p(t ) schemes of the compound are shown. The logP value is determined by partition of neutral species (dubbed as NO) only. The microconstants and partition coefficients of each microspecies as well as the nature and the concentration of... 

Niflumic acid, which has two pKa values, was studied both pH-metrically and spectroscopically using the shake-flask method [224]. The monoprotonated species can exist in two forms (1) zwitterion, XH 1 and (2) ordinary (uncharged) ampholyte, XH°. The ratio between the two forms (tautomeric ratio) was measured spectroscopically to be 17.4. On assuming that a negligible amount of zwitterion XH partitions into octanol, the calculated micro-log/1 for XH° was 5.1, quite a bit higher than the macro-log/1 3.9 determined pH-metrically in 0.15 M NaCl. It is noteworthy that the distribution coefficient D is the same regardless of whether the species are described with microconstants or macroconstants [275]. 

Takacs-Novak, K. Avdeef, A. Podanyi, B. Szasz, G., Determination of protonation macro- and microconstants and octanol/water partition coefficient of anti-inflammatory niflumic acid, J. Pharm. Biomed. Anal. 12, 1369-1377 (1994). 

A number of compounds activate TRPA1 without any apparent ability to form covalent adducts, including nonelectrophilic fenamate nonsteroidal anti-inflammatory drugs (NSAIDs), such as flufenamic acid (17, FFA), niflumic acid (18, NFA), and mefenamic acid (19, MFA) [13]. Phenols such as thymol (20) and 2-ferf-butyl-5-methylphenol (21) have been shown to activate human TRPA1 with micromolar EC50 values in stably transfected HEK293 cells [14]. 

Poulsen, M. V. and Vandenberg, R. J. (2001) Niflumic acid modulates uncoupled substrategated conductances in the human glutamate transporter EAAT4. J. Physiol. (Lond). 534, 159-167. 

Niflumic acid Niflumic acid, 2-3-(trifluoromethyl)anilino nicotinic acid (3.2.21), is synthesized either by the reaction of 2-chloronicotinic acid with 3-trifluoromethylaniline [84-86], or 2-aminonicotinic acid with l-bromo-3-trifluoromethylbenzene [87]. 

D. Bilecen, A.C. Schulte, A. Kaspar, E. Kustermann, J. Seelig, D. von Elverfeldt, K. Scheffler, Detection of the non-steroidal anti-inflammatory drug niflumic acid in humans A combined F-19-MRS in vivo and in vitro study, NMR Biomed. 16 (2003) 144-151. 

Synthesis Condensation of 2-chloronicotinic acid with 3-trifluoromethylaniline or reaction of 2-aminonicotinic acid with 1-bromo-3-trifluoromethylbenzene yields niflumic acid (Sherlock and Sperber (Schering Corp.), 1967 Faure and Hoffman (Labs. U.P.S.A.), 1968 Kleemann et al., 1999). 

Clinical use Niflumic acid (Auclair et al., 1989) is a nonsteroidal anti-inflammatory drug used for the treatment of inflammation and pain in musculoskeletal and joint disorders such as rheumatoid arthritis as well as traumatic and postoperative pain. Niflumic acid is used in oral, rectal or topical preparations (up to 750 mg/day). 

Auclair, J., Georges, M., Grapton, X., Gryp, L., D Hooghe, M., Meiser, R. G., Noto, R., Schmidtmayer, B. A double-blind controlled multicenter study of percutaneous niflumic acid gel and placebo in the treatment ofachilles heel tendinitis, Curr. Ther. Res. 1989, 46, 782-788. 

Gogelein, H., Dahlem, D., Englert, H. C., Lang, H. J. Flufenamic acid, mefenamic acid and niflumic acid inhibit single nonselective cation channels in the rat exocrine pancreas, FEBS Lett. 1990,268, 79-82. 

---