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Chapter 1
Synthesis of functionalized pyrimidines
Figure-7
Authors modified the structure of previously described DHPM i.e. 3-
substituted 1,4-dihydropyrimidines. Structure-activity studies using potassiumdepolarized
rabbit aorta show that ortho, meta-disubstituted aryl derivatives are more
potent than either ortho or meta-monosubstituted compounds. While vasorelaxant
activity was critically dependent on the size of the C5 ester group, isopropyl ester
being the best, a variety of substituents (carbamate, acyl, sulfonyl, and alkyl) were
tolerated at N3. The results showed that DHPMs are significantly more potent than
corresponding 2- heteroalkyl-l,4-dihydropyrimidines and only slightly less potent than
similarly substituted 2-heteroalkyl-1-4-dihydropyridines (Figure-8). Where as DHP
enantiomer usually show 10-15-fold difference in activity, the enantiomer of DHPM
show more than a 1000-fold difference in activity. These results strengthen the
requirement of an enaminoester for binding to the dihydropyridine receptor and
indicate a nonspecific role for the N3-substituent.
Figure 8
2-Heterosubstituted-4-aryl-l,4-dihydro-6-methyl-5-pyrimidinecarboxylicesters
(Figure 9), which lack the potential symmetry of DHP calcium channel blockers,
were prepared and evaluated for biological activity. Biological assays using
potassium-depolarized rabbit aorta and radio ligand binding techniques showed that
some of these compounds are potent mimics of DHP calcium channel blockers. 25
Figure 9
Department of Chemistry, Saurashtra University, Rajkot-360005 5