Synthesis and hypolipidemic activities of novel 2-[4-[diethoxyphosphoryl)methyl]phenyl]quinazolines and 4(3H)-quinazolinones.
The novel compound NO-1886, 4-[(diethoxyphosphoryl)methyl]-N-(4-bromo-2-cyanophenyl)-ben zamide, is a hypolipidemic agent, which appears to increase lipoprotein lipase activity in rats. Various analogs of NO-1886 were synthesized to study the structure-activity relationship of this hypolipidemic drug. A novel series of quinazolines and 4(3H)-quinazolinones were prepared by cyclization of NO-1886 derivatives. Derivatives bearing a 4-[(diethoxyphosphoryl)-methyl]phenyl] group at the 2-position were found to lower triglyceride and total cholesterol levels. In accord with the decrease in log P*, quinazolines and 4(3H)-quinazolinones showed good absorption and hypolipidemic activity. When the quinazolinone ring system is substituted at positions 6 and 7 with methoxy groups, increased hypolipidemic activity was observed. The highest hypolipidemic activity was observed when the 3-position was substituted by a methyl or benzyl group.
Kurogi
Y
Y
Nutrition Research Institute, Otsuka Pharmaceutical Factory, Inc., Tokushima, Japan.
Inoue
Y
Y
Tsutsumi
K
K
Nakamura
S
S
Nagao
K
K
Yoshitsugu
H
H
Tsuda
Y
Y
D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D001682:Biological Availability; D002784:Cholesterol / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D006949:Hyperlipidemias / Q000188:drug therapy / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000097:blood
D001549:Benzamides; D000960:Hypolipidemic Agents; D009943:Organophosphorus Compounds; D011799:Quinazolines; D014280:Triglycerides; C082137:4-diethoxyphosphorylmethyl-N-(4-bromo-2-cyanophenyl)benzamide; D011092:Polyethylene Glycols; D002784:Cholesterol; C016811:tyloxapol