Potential antidepressant and anti-inflammatory agents: 4-(2-Propylthio)acetophenone oximes and 4-(2-propylthio)phenylalkanoic acids

Abstract

4-(2-Propylthio)acetophenone oxime (IV) was reacted with 2-aminoethyl chloride and 3-dimethylaminopropyl chloride to give the O-(aminoalkyl)oximes V and VI which are analogues of the antidepressant agent fluvoxamine (I). Kindler-Willgerodt reaction of 4-(2-propylthio)acetophenone (III) gave the thiomorpholide VII which was hydrolyzed to the acid IX. Friedel-Crafts reaction of (2-propylthio)benzene with ethoxalyl chloride afforded ethyl 4-(2-propylthio)benzoylformate (X) which was transformed by reaction with methylmagnesium iodide, by the following hydrolysis and reduction with hydroiodic acid to 2-(4-(2-propylthio)phenyl)propionic acid (XII), a thia isostere of the anti-inflammatory and analgesic agent ibuprofen (II); acid XII was also obtained by reaction of 2-(4-mercaptophenyl)propionic acid (XVII) with 2-bromopropane and by the following hydrolysis. The acids IX and XII were converted to the amides XIII-XV. The fluvoxamine analogue V (V⁄FB-16 650) showed some pharmacological properties of potential antidepressants. The acids IX and XII (V⁄FB-16 603) have comparable anti-inflammatory activity with that of ibuprofen (II); in addition, XII has lower acute toxicity and higher analgetic activity than ibuprofen.