Pharmacological properties of MDL 19,301: A novel, nonsteroidal, anti‐inflammatory agent

Abstract

Oral administration of MDL 19,301 (N-(l,3-dithiolan-2-ylidene)-4-hexyl-benzenamine) inhibited rat paw edema induced by carrageenan (ED30 4.8 mg/kg) or an Arthus reaction (ED30 8.2 mgikg p.0.). The oral dose which induced gastric ulceration in 50% of fasted rats (UD50) was greater than 1,000 mgikg, demonstrating a more favorable therapeutic ratio than conventional nonsteroidal anti-inflammatory agents. Its major metabolite (MDLI 6,861, 4[( 1,3-dithiolan-2-yliden)arnino]-benzeneacetic acid) was also a potent inhibitor of carrageenan paw edema (ED50 5.5 mgikg P.o.), although it was more ulcerogenic (UD50 52 mgikg p.0.). The anti-inflammatory activity of MDL 19,301, but not that of MDL 16,861, was attenuated by co-administration of an inhibitor of drug metabolism (SK&F525A 30 mgikg i.p.). This suggests that MDL 19,301 is a prodrug of MDL 16,861 and this phenomenon would explain its lack of ulcerogenicity. Additional anti-inflammatory properties of MDL 19,301 included inhibition of carrageenan pleurisy, adjuvant arthritis, and acetic-acid-induced writhing. Other pharmacological data indicate that MDL 19,301 administration results in inhibition of prostaglandin synthesis; inhibition of arachidonic-acidinduced, but not prostaglandin-E2-induced, diarrhea in mice; and inhibition of ex vivo arachidonic-acid-induced, but not adenosine-diphosphate-induced, rat platelet aggregation. MDL 19,301 and MDL 16,861 were unexpectedly weak antipyretic agents in rats. In summary, MDL 19,301 is an anti-inflammatory, analgesic prodrug which, unlike conventional agents, is devoid of ulcerogenic activity at therapeutic doses.

DBU and DBU‐Derived Ionic Liquid Synergistic Catalysts for the Conversion of Carbon Dioxide/Carbon Disulfide to 3‐Aryl‐2‐oxazolidinones/[1,3]Dithiolan‐2‐ylidenephenyl‐ amine

“…To take full advantage of the catalytic effect, the combination of DBU and HDBUBr was then employed to catalyze the reaction of CS 2 , EO, and aniline, which produced [1,3]dithiolan‐2‐ylidenephenylamine ( 2 a ) as the main product, rather than 3‐phenyl‐2‐thiazolidinethione or 3‐phenyl‐2‐oxazolidinethione. [1,3]Dithiolan‐2‐ylidene aryl amines, as bioactive cyclic dithiocarbonimidates, are effective anti‐inflammatory analgesics with low ulcerogenicity . Traditional methods for the synthesis of [1,3]dithiolan‐2‐ylidene aryl amines rely on the use of toxic isothiocyanates .…”

“…[1,3]Dithiolan-2-ylidene aryl amines,a sb ioactive cyclic dithiocarbonimidates, are effective anti-inflammatory analgesics with low ulcerogenicity. [30] Traditional methods for the synthesis of [1,3]dithiolan-2-ylidene aryl amines rely on the use of toxic isothiocyanates. [31] An alternative method established by the reaction of aromatic amines,C S 2 ,a nd dibromoethane has also been reported.…”

Eco‐Efficient Synthesis of Cyclic Carbamates/Dithiocarbonimidates from Cyclic Carbonates/Trithiocarbonate and Aromatic Amines Catalyzed by Ionic Liquid BmimOAc

“…To our surprise, this reaction produced [1,3]dithiolan‐2‐ylidene‐phenylamine ( 4a ) instead of 3‐phenylthiazolidine‐2‐thione. It should be noted that [1,3]dithiolan‐2‐ylidene‐arylamines, as bioactive cyclic dithiocarbonimidates, are effective anti‐inflammatory analgesics with low ulcerogenicity 14. The known methods for the synthesis of [1,3]dithiolan‐2‐ylidene‐arylamines involve the use of toxic isothiocyanates 4d,15.…”

Nonsteroidal Anti-inflammatory Activity of 1,2,4-Triazolyl-heterocarboxylic Derivatives

“…At the completion of adjuvant arthritis and cotton pellets granuloma assays, animals used in both methods were killed and their stomachs were excised, opened, rinsed and fixed with 1% formalin. The mucous membranes were observed under a stereoscopic microscope and the number and the size of epithelial lesions were counted [18].…”