Hypolipidemic 2-[4-(1,1-dimethylethyl)phenyl]-4H-3,1-benzoxazin-4-ones. Structure-activity relationships of a novel series of high-density lipoprotein elevators

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Abstract
The preparation and plasma lipid altering characteristics of a series of 4H-3,1-benzoxazin-4 ones are discribed. Hypocholesterolemic, hypotriglyceridemic, and high-density-lipoprotein elevating properties are found for derivatives bearing a 4-(1,1-dimethylethyl)phenyl group at the 2-position, and this activity is displayed in boht hypercholesterolemic and in normolipidemic rats when the ring system is substituted at position 6 with hydrogen, methyl, chloro, or iodo groups, and is optimal when the 6-position is substituted by a bromine atom. Evidence is presented suggesting that a metabolite or degradation product is responsible for the changes in lipoprotein concentration observed with active molecules of this type. Synthesis of anticipated degradation products of the active molecule gave products displaying the expected in vivo activity, but no improvement in the narrow therapeutic margin of the best compound, 6-bromo-2-[4-(1,1-dimethylethyl)phenyl]-4H-3,1-benzoxazin-4-one, was obtained.

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