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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
Author(s) -
Anana Raymond D.,
Knaus Edward E.
Publication year - 1996
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.19963290807
Subject(s) - chemistry , substituent , moiety , knoevenagel condensation , stereochemistry , isopropyl , alkyl , calcium channel , medicinal chemistry , calcium , organic chemistry , catalysis
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‐amine ( 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 (IC 50 = 1.43 × 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 R 2 ‐subsituent, the relative potency order was i ‐Bu ( 11c ) ≥ 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 ) ≥ 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‐pyridinecarboxylate ( 11f ) produced a modest 10% increase in the in vitro contractile force of guinea pig left atrium at a concentration of 1.64 × 10 −7 M, relative to the reference 3‐nitro analogue 1 (EC 50 = 9.6 × 10 −6 M).