Hypolipidemic activity of cyclic imido alkyl ethers, thioethers, sulfoxides, and sulfones.

N-Substituted alkyl ethers, thioethers, sulfoxides, and sulfones of cyclic imides (e.g., phthalimide, saccharin, 1,8-naphthalimide, succinimide, and 2,3-dihydrophthalazine-1,4-dione) were shown to have potent hypolipidemic activity at doses of 10 and 20 mg/kg/d in rodents. These N-substitutions afforded no improvement over other known N-substitutions (e.g., butyl, 3-butanone, or the propionic acid derivatives of phthalimide, saccharin, and 2,3-dihydrophthalazine-1,4-dione) compared with the respective parent compounds. However, 2-(methoxyethyl)-1H-benz[de]isoquinoline-1,3-(2H)dione (3a), 2-[2-methylsulfinyl]ethyl-1H-benz[de]isoquinoline-1,3-(2H)dione (3c), 1-(2-methylsulfinyl)-2,5-pyrrolidenedione (4c), and 1-(2-methoxyethyl-2,5-pyrrolidenedione (4a) significantly improved activity compared with parent compounds, as well as previously reported N-substituted analogues, reducing serum cholesterol levels and serum triglyceride levels by 40%. The thioether of succinimide afforded a 54% reduction of serum cholesterol and a 41% reduction of serum triglyceride levels in mice after 16 d. The alkyl thioethers of 1,8-naphthalimide and succinimide significantly lowered cholesterol levels in serum VLDL and LDL, while the alkyl thioethers of succinimide elevated HDL cholesterol content. Tissue lipids were reduced in the liver and aorta by these selected derivatives. The activities of regulatory enzymes in de novo synthesis of hepatic cholesterol and triglyceride were inhibited by the selected 1,8-naphthalimide derivatives. In situ cholesterol and cholic acid reabsorption from intestines were suppressed by the presence of the agents.