1-GLYCERYL N-[7-CHLORO-4-QUINOLYL]ANTHRANILATE HYDROCHLORIDE

Glifanan,Roussel,France,1965

Glafenine is a non-narcotic analgesic agent. Glafenine shows significant antiinflammatory activity. Glafenine is widely used for the treatment of pains of various origins.

ChEBI: A carboxylic ester that is 2,3-dihydroxypropyl anthranilate in which the amino group is substituted by a 7-chloroquinolin-4-yl group. A non-steroidal anti-inflammatory drug, glafenine and its hydrochloride salt were used for the relief of all types of pain but high incidence of anaphylactic reactions resulted in their withdrawal from the market.

Step A: Preparation of (2,3-isopropylidenedioxy)-propyl o-nitrobenzoate - 59.6 g of 2,2-dimethyl-4hydroxymethyl-1,3-dioxolane were dissolved under agitation in 60 cc of anhydrous pyridine. The solution was cooled to +5°c and 86.5 g of o-nitrobenzoyl chloride (prepared by Leckermann et al., Ber. vol.80, p.488, 1947) were slowly introduced into it. The reaction mixture was agitated for a period of two hours at room temperature and then was poured into 500 cc of ether. The mixture was filtered and the filtrate was washed successively with 0.5 N sulfuric acid solution, with aqueous sodium bicarbonate solution and finally with water until the wash waters were neutral. The washed solution was dried over sodium sulfate and filtered again. The filtrate was distilled to dryness under vacuum to obtain 116.5 g (being a yield of 92%) of (2,3- isopropylidenedioxy)-propyl o-nitrobenzoate in the form of a yellow oil which distilled at 178°C to 180°C at a pressure of 1 mm.
Step B: Preparation of (2,3-isopropylidenedioxy)-propyl anthranilate - 80 g of (2,3-isopropyl-idenedioxy)propyl o-nitrobenzoate, obtained as described in Step A, were subjected to hydrogenation for a period of one hour in 800 cc of absolute alcohol in the presence of 2 g of palladized carbon black as catalyst. The reaction mixture was filtered and the filtrate was evaporated under vacuum to obtain 70.5 g (being a yield of 98.5%) of (2,3- isopropylidenedioxy)-propyl anthranilate in the form of a yellow oil which distilled at 159°C to 160°C under 0.5 mm of pressure.
Step C: Preparation of the (α-monoglyceride of 4-(2'-carboxyphenylamino)-7- chloro-quinoline - A mixture of 48 g of (2,3-isopropylidenedioxy)-propyl anthranilate, 36 g of 4.7-dichloro-quinoline, 36 cc of concentrated hydrochloric acid and 300 cc of water was agitated while heating to reflux for a period of two hours. The reaction mixture was filtered and the filtrate was allowed to stand at a temperature of 0°C for a period of three hours. The hydrochloride salt was then vacuum filtered and the salt was taken up in 600 cc 50% methanol at reflux. The solution was made alkaline by the addition of 120 cc of ammonia solution and iced for a period of one hour. The crystalline precipitate obtained was vacuum filtered, washed with water and dried to obtain 38.5 g (being a yield of 56%) of the α-monoglyceride of 4-(2'- carboxyphenylamino-7-chloro-quinoline having a melting point of 165°C.
The product occurred in the form of pale yellow prisms and was insoluble in water, ether, benzene, diluted alcohols, olive oil and chloroform, slightly soluble in absolute alcohol, dioxane, tetrahydrofuran and acetone, and soluble in dilute aqueous acids and alkalis.

Disipan;Espasmo-giliganan;Exidol;Glafezon;Glifadex;Glifanan;Glifarelax;Osodent.

Analgesic

Glafenine, a quinolylanthranilate derivative, was introduced in 1965 for use as an analgesic. By the late 1970s its use had been associated with severe allergic responses, including anaphylactoid reactions, which led to its withdrawal in one country whereas in others a warning to this effect is required in the product information. In 1992, on the advice of the Committee for Proprietary Medicinal Products of the European Communities, glafenine was eventually withdrawn worldwide by the major manufacturer.

Moderately toxic by ingestion. Human systemic effects.