Synthesis of C3 heteroatom-substituted azetidinones that display potent cholesterol absorption inhibitory activity.
The C3 phenylpropyl side chain of N-phenylazetidinones related to SCH 56524 was modified by replacing the hydroxymethylene with various isoelectronic or isosteric groups. Modifications at the 3' position led to less-active compounds; however, modifications at the 1' position provided compounds with improved cholesterol absorption inhibitory activity. An enantioselective route for the synthesis of C3 1'-sulfur-substituted azetidinones and the development of structure-activity relationships for this series of compounds are presented.
McKittrick
B A
BA
Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
Ma
K
K
Huie
K
K
Yumibe
N
N
Davis
H
H
Clader
J W
JW
Czarniecki
M
M
McPhail
A T
AT
D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001384:Azetidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001646:Bile / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C111317:3-(2-phenethylsulfinyl)-4-(4-hydroxyphenyl)-N-(4-fluorophenyl)-2-azetidinone; C111316:3-(2-phenethylthio)-4-(4-hydroxyphenyl)-N-(4-fluorophenyl)-2-azetidinone; D000924:Anticholesteremic Agents; D001384:Azetidines; C095487:1,4-bis(4-methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone; D002784:Cholesterol