Synthesis and smooth muscle calcium channel effects of dialkyl 1,4-dihydro-2,6-dimethyl-4-aryl-3,5-pyridinedicarboxylates containing a nitrone moiety in the 4-aryl substituent.

A group of dialkyl 1,4-dihydro-2,6-dimethyl-4-¿3-(or 4-)[[(Z)-N- oxo-N-[4-substituted-phenylmethylene (or vinylmethylene)]-lambda 5- azanyl]phenyl¿-3,5-pyridinedicarboxylates 7a-n were synthesized. Reaction of the C-4 nitrophenyl compounds 6a-d with an aryl Grignard reagent afforded the corresponding nitrone derivatives 7a-e. Alternatively, reaction of the aryl hydroxylamine compounds 8a-b prepared by reduction of the nitrophenyl compounds 6c-d with Zn/NH4Cl, or the aryl hydroxylamine compounds 8c-d prepared by reduction of the nitrophenyl compounds 6e-f with 5% rhodium-on-charcoal and 65% hydrazine hydrate, with a 4-substituted-benzaldehyde, benzaldehyde or acrolein afforded the respective nitrone compounds 7f-n. In vitro calcium channel (CC) antagonist activities were determined using the guinea pig ileum longitudinal smooth muscle assay. This class of compounds containing a nitrone moiety on the 1,4-dihydropyridine C-4 phenyl ring exhibited CC antagonist activities (10(-5) to 10(-9) M range) relative to the reference drug nifedipine (IC50 = 1.43 x 10(-8) M). Structure-activity relationships showed that the position of the nitrone moiety on the C-4 phenyl ring was a determinant of CC antagonist activity where the potency order was always meta-nitrone > para-nitrone. The effect of the ester alkyl substituent was variable depending upon whether the nitrone substituent was at the meta or para-position (meta-nitrone, Et > i-Pr approximately Me; para-nitrone, i-Pr > Me approximately Et). In the diethyl ester series of compounds having a meta-nitrone moiety, the difference in potency for the various R2-nitrone substituents varied by a factor of 15-fold (IC50 = 1.51 x 10(-7) to 9.84 x 10(-9) M range) (4-Cl-C6H4- > or = 4-Me-C6H4- approximately C6H5- > or = 4-O2N-C6H4- 4-F3C-C6H4- > > CH2 = CH-). Whole-cell voltage-clamp studies using isolated guinea pig ventricular myocytes indicated that the 4-¿3-[(Z)-N-oxo-N-(phenylmethylene)-lambda 5-azanyl]-phenyl¿ compound 7c (10 microM) is a calcium channel antagonist which decreased the calcium current (ICa).

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.

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).