Acemetacin

Description

Acemetacin is used in the treatment of pain and restricted mobility resulting from chronic articular rheumatism, degenerative articular disease, gout, and inflammation of muscle, joints, and tendons. Acemetacin causes less gastrointestinal blood loss than indomethacin. Its anti-inflammatory activity results from liberation of the parent compound, indomethacin.

Chemical Properties

Light Yellow Solid

Originator

Rantudil ,Bayer ,W. Germany ,1980

Uses

A potent inhibitor of COX-2 found to have anti-tumor activity in the colon

Uses

Cyclo-oxygenase inhibitor; analgesic; anti-inflammatory.

Definition

ChEBI: A carboxylic ester that is the carboxymethyl ester of indometacin. A non-steroidal anti-inflammatory drug, it is used in the treatment of rheumatoid arthritis, osteoarthritis, and low back pain, as well as for postoperative pain and inflammation. Its activ ty is due to both acemetacin and its major metabolite, indometacin.

Manufacturing Process

25.4 g (0.050 mol) of [1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3- indoleacetoxy]-benzyl acetate were dissolved in 400 ml of glacial acetic acid and hydrogenated on 2.0 g of palladium carbon at room temperature. After the absorption of hydrogen had finished (1 hour), the catalyst was filtered off, the filtrate was concentrated by evaporation under vacuum and the compound was caused to crystallize by adding petroleum ether. The compound melted at 149.5-150.5°C (determined on the micro-Kofler bench); the yield was 19.4 g which corresponds to 93% of the theoretical yield.
The starting material for the above step may be prepared as follows: 5 g (0.016 mol) of N1-(p-methoxyphenyl)-p-chlorobenzhydrazide hydrochloride and 4.75 g (0.018 mol) of benzyl levulinoyloxyacetate were heated in 25 ml of glacial acetic acid for 3 hours at 80°C. The solvent was then evaporated off under vacuum. The residue was taken up in chloroform and the solution was washed neutral by shaking with sodium bicarbonate solution and thereafter with water. After drying the chloroform solution, this was subjected to chromatography on aluminium oxide, the eluate was concentrated by evaporation and the viscous oil remaining as residue was crystallized by adding ether. The compound melted at 94-95°C. The yield was 4.1 g which corresponds to 50.7% of the theoretical yield.

Therapeutic Function

Antiinflammatory

Trade name

Acemetacin (Heumann, Stada, Germany), Acemix (Bioprogress, Italy), Altren (Rhone-Poulenc Rorer, Belgium), Emflex (Merck, UK), Rantudil (Bayer Pharma Deutschland, Germany)

Clinical Use

Acemetacin is a nonsteroidal anti-inflammatory drug acting directly and via its major metabolite indomethacin. Acemetacin is used in chronic joint pain as well as in postoperative pain.

Safety Profile

Poison by ingestion, subcutaneous,intraperitoneal, intravenous, and intramuscular routes. Anexperimental teratogen. Other experimental reproductiveeffects. When heated to decomposition it emits toxic fumesof Cl and NOx. An anti-inflammatory agent.

Synthesis

alkylation of indomethacin with benzyl bromoacetate in K2CO3/N,N-dimethylformamide gives the corresponding benzyl glycolate ester, which is hydrogenated over 10 % palladium on charcoal in acetic acid to yield acemetacin.

References

[1] Patent: CN108440374, 2018, A. Location in patent: Paragraph 0023-0028; 0030-0035; 0037-0042; 0044-0049; 0051-0
[2] Journal of Medicinal Chemistry, 2009, vol. 52, # 10, p. 3348 - 3353
[3] Arzneimittel-Forschung/Drug Research, 1980, vol. 30, # 8 A, p. 1314 - 1325