SYNTHESIS AND SMOOTH-MUSCLE CALCIUM-CHANNEL EFFECTS OF DIALKYL DRO-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 ambda(5)-azanyl]phenyl}-3,5-pyridi nedicarboxylates 7a-n were synthesized. Reaction of the C-4 nitropheny l compounds 6-d with an aryl Grignard reagent afforded the correspondi ng nitrone derivatives 7a-e. Alternatively, reaction of the aryl hydro xylamine compounds 8a-b prepared by reduction of the nitrophenyl compo unds 6c-d with Zn/NH4Cl, or the aryl hydroxylamine compounds 8c-d prep ared 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 7 f-n. In vitro calcium channel (CC) antagonist activities were determin ed using the guinea pig ileum longitudinal smooth muscle assay. This c lass of compounds containing a nitrone moiety on the 1,4-dihydropyridi ne C-4 phenyl ring exhibited CC antagonist activities (10(-5) to 10(-9 ) M range) to the reference drug nifedipine (IC50 = 1.43 x 10(-8) M). Structure-activity relationships showed that the position of the nitro ne moiety on the C-4 phenyl ring was a determinant of CC antagonist ac tivity 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 (met a-nitrone, Et > i-Pr approximate to Me; para-nitrone, i-Pr > Me approx imate to Et). In the diethyl ester series of compounds having a meta-n itrone moiety, the difference in potency for the various R-2-nitrone s ubstituents varied by a factor of 15-fold (IC50 = 1.51 x 10(-7) to 9.8 4 x 10(-9) M range) (4-Cl-C6H4- greater than or equal to 4-Me-C6H4- ap proximate to C6H5- greater than or equal to 4-O2N-C6H4- 4-F3C-C6H4- mu ch greater than CH2=CH-). Whole-cell voltage-clamp studies using isola ted guinea pig ventricular myocytes indicated that the N-oxo-N-(phenyl methylene)-lambda(5)-azanyl]phenyl} compound 7c (10 mu M) is a calcium channel antagonist which decreased the calcium current (I-Ca).