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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
Author(s) -
Anana Raymond D.,
Ng Helen,
Howlett Susan E.,
Knaus Edward E.
Publication year - 1997
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.19973300303
Subject(s) - nitrone , chemistry , moiety , substituent , aryl , benzaldehyde , medicinal chemistry , hydroxylamine , stereochemistry , cycloaddition , organic chemistry , alkyl , catalysis
A group of dialkyl 1,4‐dihydro‐2,6‐dimethyl‐4‐{3‐ (or 4‐)[[( Z )‐ N ‐oxo‐ N ‐[4‐substituted‐phenylmethylene (or vinylmethylene)]‐λ 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/NH 4 Cl, 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 (IC 50 = 1.43 × 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 ≈ Me; para ‐nitrone, i ‐Pr > Me ≈ Et). In the diethyl ester series of compounds having a meta ‐nitrone moiety, the difference in potency for the various R 2 ‐nitrone substituents varied by a factor of 15‐fold (IC 50 = 1.51 × 10 −7 to 9.84 × 10 −9 M range) (4‐Cl‐C 6 H 4 ‐±4‐Me‐C 6 H 4 ‐ ≈ C 6 H 5 ‐≥4‐O 2 N‐C 6 H 4 ‐ 4‐F 3 C‐C 6 H 4 ‐>CH 2 =CH‐). Whole‐cell voltage‐clamp studies using isolated guinea pig ventricular myocytes indicated that, the 4‐{3‐[( Z )‐ N ‐oxo‐ N ‐(phenylmethylene)‐λ 5 ‐azanyl]‐phenyl} compound 7c (10 μM) is a calcium channel antagonist which decreased the calcium current ( I ca).