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Chapter 1
Synthesis of functionalized pyrimidines
Structure-activity studies showed that l-(phenylmethyl)-4-piperidinylcarbamate
moiety at N3 and sulfur at C2 are optimal for vasorelaxant activity in vitro and impart
potent and long-acting antihypertensive activity in vivo. One of these compounds was
identified as a lead, and the individual enantiomers were synthesized. Two key steps
of the synthesis were (1) the efficient separation of the diastereomeric ureido
derivatives and (2) the high-yield transformation of 2-methoxy intermediate to the
(p-methoxybenzyl)thio intermediates. Chirality was demonstrated to be a significant
determinant of biological activity, with the DHP receptor recognizing the enamines
ester moiety but not the carbamate moiety. DHPM is equipotent to nifidepine and
amlodipine in vitro. In the spontaneously hypertensive rat, DHPM is more potent and
longer acting than both nifidepine and the long-acting amlodipine (DHP derivative).
DHPM has the potential advantage of being a single enantiomer. 23,24
F 3 C
i-PrO 2 C
N
H
N
O 2
C
S
N
F 3 C
R i-PrO 2 C
Figure-6
N
H
N
O 2
C
S
N
HCl
F
In order to explain the potent antihypertensive activity of the modestly active
(ICw = 3.2 pM) DHPM calcium channel blocker, Atwal et al. carried out drug
metabolism studies in the rat and found that two of the metabolites (ICw = 16 nM)
and (ICw = 12 nM), were responsible for antihypertensive activity of compound.
Potential metabolism in vivo precluded interest in pursuing compounds related to it.
Structure-activity studies aimed at identifying additional aryl-substituted analogues
led to comparable potential in vivo, though these compounds were less potent in vitro.
To investigate the effects of absolute stereochemistry on potency, authors resolved via
diastereomeric ureas, prepared by treatment with (R)-α-methylbenzylamine. The
results demonstrate that the active R-(-)-enantiomer is more potent and longer acting
than nifedipine as an antihypertensive agent in the SHR. The in vivo potency and
duration is comparable to the long-acting DHP amlodipine. The superior oral
antihypertensive activity compared to that of previously described carbamates
(R 2 =COOEt) could be explained by its improved oral bioavailability, possibly
resulting from increased stability of the urea functionality (Figure-7). 6
Department of Chemistry, Saurashtra University, Rajkot-360005 4