Synthesis and smooth muscle calcium channel antagonist effects of alkyl 1,4-dihydro-2,6-dimethyl-4-(pyridinyl)-5-[2-(4,5-dihydro- 4,4-dimethyloxazolin-2-yl)]-3-pyridinecarboxylates.

Abstract

A group of racemic alkyl 1,4-dihydro-2,6-dimethyl-4-(3- or 4-pyridinyl)-5-[2-(4,5-dihydro-4,4-dimethyloxazolin-2-yl)-3- pyridinecarboxylates 11a-e were prepared by using the Hantzsch reaction involving condensation of the Knoevenagel adducts 9a-e with 1-[2-(4,5-dihydro-4,4-dimethyloxazolin-2-yl)]-1-propen-2-ami ne (10). In contrast, the 4-(2-pyridinyl) analogue 11f was prepared by thionyl chloride mediated cyclization of the 5-¿N-(1,1-dimethyl-2-hydroxyethyl)aminocarbonyl¿ moiety of 16 to the 5-[2-(4,5-dihydro-4,4-dimethyloxazolin-2-yl)] ring system (11f). In vitro calcium channel antagonist activity was determined by using the guinea pig ileum longitudinal smooth muscle (GPILSM) assay. Compared to the reference drug nifedipine (IC50 = 1.43 x 10(-8) M), the title compounds 11 exhibited weak calcium channel antagonist activity (10(-5) to 10(-6) M range). A comparison of compounds 11 having a C-4 3-pyridinyl substituent showed that with respect to the alkyl ester R2-substituent, the relative potency order was i-Bu (11c) > or = i-Pr (11e) > Me (11a). The point of attachment of the C-4 pyridinyl substituent in the isopropyl ester isomeric series of compounds was a determinant of activity where the potency profile was 4-py (11d) > or = 3-py (11e) > 2-py (11f). Although less effective, the 4,5-dihydro-4,4-dimethyloxazolin-2-yl moiety acts as a bioisostere of the alkyl ester substituent present in classical 1,4-dihydropyridine calcium channel antagonists. The 4,5-dihydro-4,4-dimethyl-oxaxolin-2-yl ring system is not an effective bioisostere of the 3-nitro group present in 1,4-dihydropyridine calcium channel agonists since isopropyl 1,4-dihydro-2,6-dimethyl-4-(2-pyridinyl)-5- [2-(4,5-dihydro-4,4-dimethyloxazolin-2-yl)]-3-pyridinecarboxyla te (11f) produced a modest 10% increase in the in vitro contractile force of guinea pig left atrium at a concentration of 1.64 x 10(-7) M, relative to the reference 3-nitro analogue 1 (EC50 = 9.6 x 10(-6) M).