Meclofenamic acid

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Meclofenamic acid
Meclofenamic acid.png
Systematic (IUPAC) name
2-[(2,6-dichloro-3-methylphenyl)amino]benzoic acid
Clinical data
Trade names Meclomen
AHFS/Drugs.com International Drug Names
Routes of
administration
Oral
Identifiers
CAS Number 644-62-2
ATC code M01AG04 M02AA18
PubChem CID 4037
IUPHAR/BPS 7219
DrugBank DB00939
ChemSpider 3897
UNII 48I5LU4ZWD YesY
KEGG D02341
ChEBI CHEBI:6710
ChEMBL CHEMBL509 YesY
Chemical data
Formula C14H11Cl2NO2
Molar mass 296.14864 g/mol

Meclofenamic acid (meclofenamate sodium, brand Meclomen) is a drug used for joint, muscular pain, arthritis and dysmenorrhea.[1] It is a member of the anthranilic acid derivatives (or fenamate) class of NSAID drugs and was approved by the FDA in 1980.[2] Like other members of the class, it is a COX inhibitor and prevents formation of prostaglandins.[3]

Scientists led by Claude Winder from Parke-Davis invented meclofenamate sodium in 1964, along with fellow members of the class, mefenamic acid in 1961 and flufenamic acid in 1963.[4]:718

Patents on the drug expired in 1985[5]:295 and several generics were introduced in the US, but as of July 2015 only Mylan still sold it.[6][7]

It is not widely used in humans as it a high rate (30-60%) rate of gastrointestinal side effects.[8]:310

Use in horses[edit]

Meclofenamic acid is sold under the trade name "Arquel" for use in horses, and is administered as an oral granual form at a dose of 2.2 mg/kg/day.[9] It has a relatively slow onset of action, taking 36–48 hours for full effect,[10] and is most useful for treatment of chronic musculoskeletal disease.[11] It has been found to be beneficial for the treatment of navicular syndrome, laminitis, and osteoarthritis,[10] in some cases having a more profound effect than the commonly-used NSAID phenylbutazone.[12] However, due to cost, it is not routinely used in practice. Toxicity due to excessive dosage is similar to that of phenylbutazone, including depression, anorexia, weight loss, edema, diarrhea, oral ulceration, and decreased hematocrit.[12]

Syntheses[edit]

Meclofenamic acid synthesis:[13] Scherrer, Short, DE 1149015  C.A. 61, 1801d (1964) and U.S. Patent 3,313,848 (1963, 1967 to Parke Davis).

Meclofenamic acid (3) is synthesized analogous to flufenamic acid, by reaction of the potassium salt of 2-bromobenzoic acid (2) with 2,6-dichloro-3-methylaniline (1) in the presence of copper(II) bromide in a mixture of N-ethylmorpholine and diglyme.

N-aryl anthranilic acids are frequently found to have antiinflammatory activity and have been studied extensively to maximize potency and decreaase side effects (gastric irritation, ulcers, etc.). These compounds are often synthesized by reacting an ortho-halobenzoate salt with a suitably substituted aniline. This procedure failed because of steric hindrance, in attempting to synthesized meclofenamic acid. The successful synthesis begins by treating 2-methyl-4-hydroxy acetophenone (4) with NaOCl, which both ortho-chlorinates adjacent to the phenolic OH and effects a haloform reaction. Decarboxylation leads to the chlorinated meta cresol (5). When 5 is converted to its sodium salt with NaH in DMF and then treated with 2,4-dichloroquinazoline (6), two molecules of the phenol react with the heterocycle to give the nucleophilic aromatic substitution product (7). When heated, 7 undergoes an O to N-aryl rearrangement (Chapman rearrangement) to give 8. Upon saponification, carbon dioxide and 2,6-dichloro-3-methylaniline (1) are lost and meclofenamic acid (3) results.

References[edit]

  1. ^ http://www.medicinenet.com/meclofenamate/article.htm
  2. ^ FDA Meclomen page at FDA Page accessed July 3, 2015
  3. ^ NIH LiverTox Database Mefenamic Acid Last updated June 23, 2015. Page accessed July 3, 2015
  4. ^ Whitehouse M. Drugs to Treat Inflammation: A Historical Overview. pp 707-729 in Frontiers in Medicinal Chemistry , Volume 4. Eds Rahman A, et al. Bentham Science Publishers, 2009 ISBN 978-1-60805-207-3
  5. ^ United States. Congress. Office of Technology Assessment Pharmaceutical R & D: Costs, Risks & Rewards DIANE Publishing, 1993 ISBN 978-0-7881-0468-8
  6. ^ FDA Meclofenamate sodium ANDAs at FDA Page accessed July 3, 2015
  7. ^ FDA Mylan label for meclofenamate sodium Revised: October 2013, Accessed July 3, 2015
  8. ^ Jeffrey K. Aronson. Meyler's Side Effects of Analgesics and Anti-inflammatory Drugs. Elsevier, 2009 ISBN 978-0-08-093294-1
  9. ^ McIlwraith CW, Frisbie DD, Kawcak CE. Nonsteroidal Anti-Inflammatory Drugs. Proc. AAEP 2001 (47): 182-187.
  10. ^ a b Cotter GH, Riley WF, Beck CC, Coppock RW. Arquel (Cl- 1583). A new nonsteroidal anti-inflammatory drug for horses, in Proceedings. Am Assoc Equine Practnr 1973;19: 81–90.
  11. ^ Snow DH, Baxter P, Whiting B. The pharmacokinetics of meclofenamic acid in the horse. J Vet Pharmacol Ther 1981; 4:147–156.
  12. ^ a b Lees P, Higgins AJ. Clinical pharmacology in therapeutic uses of non-steroidal anti-inflammatory drugs in the horse. Equine Vet J 1985;17:83–96.
  13. ^ Juby, Peter F.; Hudyma, T. W.; Brown, Morton (1968). "Preparation and antiinflammatory properties of some 5-(2-anilinophenyl)tetrazoles". Journal of Medicinal Chemistry 11 (1): 111–7. doi:10.1021/jm00307a025. PMID 5637153.