Synthesis and Calcium Channel Antagonist Activities of New Derivatives of Dialkyl
1,4-Dihydro-2,6-dimethyl-4-(5-phenylisoxazol-3-yl)pyridine-3,5-dicarboxylates

N. Daryabari ^a, T. Akbarzadeh^a, M. Amini^a, R. Miri ^a,b, H. Mirkhani ^b and A. Shafiee^a,*

^aDepartment of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Science, Tehran, 14174, Iran^bMedicinal & Natural Product Chemistry Research Centre, Shiraz University of Medical Science, Shiraz, Iran

(Received 28 January 2007, Accepted 3 February 2007)

The new analogues of nifedipine, in which 2-nitrophenyl group at position 4 is replaced by phenylisoxazolyl substituent, were synthesized. The symmetrical dialkyl 1,4-dihydro-2,6-dimethyl-4-(5-phenylisoxazol-3-yl)pyridine-3,5-dicarboxylates were prepared by classical Hantzsch condensation, and the asymmetrical analogues were synthesized using a procedure reported by Dagnino that involved the condensation of alkyl acetoacetate with alkyl 3-aminocrotonate and 5-phenylisoxazole-3-carboxaldehyde. The structure of all compounds was confirmed by IR, ¹H NMR and Mass spectra. In vitro calcium channel antagonist activities were evaluated as calcium channel antagonists using the high K⁺ concentration of guinea-pig ileum longitudinal smooth muscle (GPILSM) assay. These compounds exhibited moderate calcium antagonist activity (IC₅₀ = 10^-7 to 10^-5 M range) relative to the reference drug nifedipine (IC₅₀ = 1.10 � 0.40 � 10^-8 M).

Keywords:�Dihydropyridine, Ca²⁺ channels antagonist, Phenylisoxazole�