Efficient synthesis of bicyclic oxazolino- and thiazolino[3,2-c]pyrimidine-5,7-diones and its application to the synthesis of GnRH antagonists.
Treatment of various 2-methyl oxazolines or thiazolines with chlorocarbonyl isocyanate gives the corresponding bicyclic oxazolino- or thiazolino[3,2-c]pyrimidin-5,7-dione derivatives in very good yield. This reaction has been applied to the rapid syntheses of human gonadotropin-releasing hormone (hGnRH) receptor antagonists for SAR study, resulting in 13e with binding affinity in the low nanomolar range (4.5 nM).
Pontillo
Joseph
J
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA. jpontillo@neurocrine.com
Chen
Chen
C
D001667:Binding, Competitive; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D003500:Cyclization; D006801:Humans; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis / Q000494:pharmacology; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000494:pharmacology; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology
D001643:Bridged Bicyclo Compounds; D010080:Oxazoles; D011744:Pyrimidinones; D011966:Receptors, LHRH; D013844:Thiazoles