A series of hindered phenols were investigated as hypolipidemic and/or hypoglycemic agents with ability to inhibit lipid peroxidation. 1,3-Benzoxathioles (9 and 22), phenoxypentanoic acid (34), phenoxypentanol (35a), phenoxynonanol (35b), phenylchloropropionic acid having a chromanyl group (25), and a thiazolidine compound (27) derived from 25, all having a hindered phenol group, were prepared and examined. Compound 27 showed the expected biological properties in vivo and in vitro without any liver weight increase. Biological activities of the analogous thiazolidine compounds, 43-58, were compared. Thus, (+/-)-5-[4-[(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy]- benzyl]-2,4-thiazolidinedione (27) (CS-045) was found to have all of our expected properties and was selected as a candidate for further development as a hypoglycemic and hypolipidemic agent.

A series of hindered phenolic 1,3-benzoxathioles (7a-l) were prepared and investigated for biological properties. Many compounds had LPO-lowering, antisuperoxide inhibiting, SRS-A inhibiting, and 5-lipoxygenase inhibiting activities. Among them, 5-hydroxy-4,6,7-trimethyl-2-propyl-1,3-benzoxathiole (7d) and 3-(5-hydroxy-4,6,7-trimethyl-1,3-benzoxathiol-2-yl)propanol (7j) were most potent in SRS-A inhibiting and 5-lipoxygenase inhibiting activities, respectively, and were selected for further development as candidate drugs for the treatment of asthma.

A synthetic procedure for producing (±)‐5‐[4‐(6‐hydroxy‐2, 5, 7, 8‐tetramethylchroman‐2‐ylmethoxy) benzyl]‐5‐14C‐thiazolidine‐2, 4‐dione (14C‐labelled CS‐045) is described. The radiolabel is introduced using [5‐14C] thiazolidine‐2, 4‐dione, as shown in the scheme.

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