Design and synthesis of methyl 2-methyl-7,7-dihalo-5-phenyl-2-azabicyclo[4. 1.0]hept-3-ene-4-carboxylates with calcium channel antagonist activity

Abstract

A group of methyl 2-methyl-7,7-dihalo-5-(substituted-phenyl)-2- azabicyclo[4.1.0]hept-3-ene-4-carboxylates were prepared by reaction of dihalocarbenes (:CX2, X=Br, Cl) with methyl 1-methyl-4-(substituted- phenyl)-1,4-dihydropyridine-3-carboxylates. In vitro calcium channel antagonist activities were determined using a guinea pig ileum longitudinal smooth muscle assay. The title compounds exhibited weaker CC antagonist activity (10 -5-10-6M range) than the reference drug nifedipine (1.4أ—10-8M). Structure-activity relationship studies showed that the position of a nitro substituent on the C-5 phenyl ring where the relative potency order was ortho>meta>para, and the size and/or electronegativity of the C-7 geminal-dihalo substituents (Br>Cl), were determinants of calcium channel antagonist activity. This class of compounds did not exhibit any inotropic effect on guinea pig left atria. A dihalocyclopropyl moiety is a potential bioisostere for the 2-methyl-3-methoxycarbonylvinyl moiety present in the calcium channel antagonist nifedipine. é 2004 Elsevier Ltd. All rights reserved.