Synthesis and calcium antagonist activity of 1,4-dihydropyridines containing phenylaminoimidazolyl substituents

Article abstract of DOI:10.1016/S0014-827X(03)00159-9

Alkyl ester analogues of nifedipine, in which the ortho-nitrophenyl group at position 4 is replaced by 2-methylthio-1-phenylamino-5-imidazolyl substituent, were synthesized and evaluated as calcium-channel antagonists using the high K⁺ contraction of guinea-pig ileal longitudinal smooth muscle. The results for the symmetrical esters showed that in the series of alkyl esters increasing the length of methylene chain in C-3 and C-5 ester substituents for more than two methylene units decreases activity. In the phenylalkyl ester series increasing the length of methylene chain also decreases activity. The results demonstrate that most of the compounds had similar activity to the reference drug nifedipine. In addition, two compounds, 5b and 5f were more active than the nifedipine.

Full text of DOI:10.1016/S0014-827X(03)00159-9

Il Farmaco 58 (2003) 1077Á1081
/
www.elsevier.com/locate/farmac
Synthesis and calcium antagonist activity of 1,4-dihydropyridines
containing phenylaminoimidazolyl substituents
A. Zarghi a, H. Sadeghi b, A. Fassihi b, M. Faizi c, A. Shafiee d,*
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Shaheed Beheshti University of Medical Sciences, Tehran, Iran
b Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran
c Department of Pharmacology, Faculty of Pharmacy, Shaheed Beheshti University of Medical Sciences, Kerman, Iran
d Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155/6451, Tehran 14174, Iran
Received 7 March 2003; accepted 26 April 2003
Abstract
Alkyl ester analogues of nifedipine, in which the ortho-nitrophenyl group at position 4 is replaced by 2-methylthio-1-
phenylamino-5-imidazolyl substituent, were synthesized and evaluated as calcium-channel antagonists using the high Kꢀ
contraction of guinea-pig ileal longitudinal smooth muscle. The results for the symmetrical esters showed that in the series of
alkyl esters increasing the length of methylene chain in C-3 and C-5 ester substituents for more than two methylene units decreases
activity. In the phenylalkyl ester series increasing the length of methylene chain also decreases activity. The results demonstrate that
most of the compounds had similar activity to the reference drug nifedipine. In addition, two compounds, 5b and 5f were more
active than the nifedipine.
´
# 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: Dihyropyridines; Phenylaminoimidazoles; Nifedipine analogues; Calcium channel anatagonists
1. Introduction
even for the vascular bed upon which they act. Changes
in the substitution pattern at the C3, C4, C5 positions of
1,4-Dihydropyridine calcium channel antagonists are
an important class of drugs which induce relaxation of
vascular smooth muscle, preferentially in arteries, and
display a negative inotropic effect on isolated cardiac
muscle [1]. They exert these effects by binding to a high
affinity binding site in L-type voltage-dependent Ca2ꢀ
channels [2]. In therapy, this class of drugs is effective in
the treatment of hypertension, angina pectoris and other
cardiovascular disorders [3]. Because the prototype of
1,4-dihydropyridines, nifedipine, does not have the
optimum pharmacokinetic and pharmacodynamic char-
acteristics, several attempts have been made to introduce
other drugs in this class with improved properties. The
results of these efforts are new drugs with a slower onset,
longer duration of action and fewer side effects [4,5].
Some of these drugs have selectivity for the vessels and
nifedipine alter activity and tissue selectivity [4Á
Several papers illustrated that C4 heterocycle substitu-
ents of dihydropyridine were potent antagonists [11Á
13]. In previous studies, we reported that a C4 imidazole
substituent gave very active compounds as calcium
/
10].
/
channel antagonist [13Á16]. It was therefore of interest
/
to determine the effect of selected C3 and C5 substitu-
ents, in conjugation with 2-methylthio-1-phenylamino-
5-imidazolyl as C4 substituent on calcium channel
antagonist activity. We now report the synthesis and
calcium antagonist activities of new alkyl 1,4-dihydro-
2,6-dimethyl-4-(2-methylthio-1-phenylamino-5-imidazo-
lyl)-3,5-pyridinedicarboxylates.
2. Chemistry
The synthesis of the 1,4-dihydropyridine derivatives
5aÁ
/
h (Table 1) was achieved following the steps outlined
* Corresponding author.
E-mail address: ashafiee@ams.ac.ir (A. Shafiee).
in Fig. 1. 5-Hydroxymethyl-2-mercapto-1-phenylami-
´
0014-827X/03/$ - see front matter # 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
doi:10.1016/S0014-827X(03)00159-9

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A. Zarghi et al. / Il Farmaco 58 (2003) 1077Á1081
/
Table 1
Physical and calcium channel modulation data for compounds 5aÁh
/
Comp.
R1
Mp (8C)
Yield (%)
Formula a
Calcium channel antagonist activity b
5a
5b
Me
Et
197Á
142Á
141Á
186Á
227Á
176Á
133Á
132Á
/
198
143
142
188
228
177
134
133
50
35
56
35
23
52
23
44
C21H24N4O4S
C23H28N4O4S
C25H32N4O4S
C25H32N4O4S
C27H36N4O4S
C33H32N4O4S
C35H36N4O4S
C37H40N4O4S
3.549
1.6990.43ꢁ
2.2990.79ꢁ
2.1690.76ꢁ
1.2190.27ꢁ
1.4990.39ꢁ
2.7990.69ꢁ
3.1590.71ꢁ
2.5590.21ꢁ
/
0.85ꢁ
/
10ꢂ9
10ꢂ9
10ꢂ9
10ꢂ9
10ꢂ7
10ꢂ9
10ꢂ9
10ꢂ9
10ꢂ9
/
/
/
5c
Pr
/
/
/
5d
i-Pr
/
/
/
5e
t-Bu
/
/
/
5f
5g
Benzyl
Phenylethyl
Phenylpropyl
/
/
/
/
/
/
5h
/
/
/
Nifedipine
/
/
a
Microanalyses were within 9
/
0.4% of theoretical values.
The molar concentration of antagonist test compound causing a 50% in the tonic contractile response (IC50
longitudinal smooth muscle by KCl (80 mmol/l) was determined graphically from dose-response curve (nꢃ6).
b
9/SEM) in guinea-pig ileal
/
noimidazole (2) was prepared according to the proce-
dure described by Dener et al. [17]. Reaction of 2 with
methyl iodide afforded corresponding substituted
methylthio imidazole 3. Oxidation of 3 with manganese
dioxide in chloroform gave the corresponding aldehyde
acetate. The compounds were characterized by 1H
nuclear magnetic resonance, infrared and mass spectro-
scopy. The purity of all products was determined by thin
layer chromatography using several solvent systems of
different polarity. The physical properties of final
compounds are summarized in Table 1. All final
products were pure and stable compounds. Similar to
other analogues of nifedipine, they are lipophilic com-
pounds with very slight solubility in water.
4. The symmetrical 1,4-dihydropyridine derivatives 5aÁ
/
h were prepared (23Á56% yield) by the classical Hantzch
/
condensation [18,19] in which the aldehyde 4 was
reacted with the acetoacetate ester and ammonium
Fig. 1. Synthesis of nifedipine analogues.

A. Zarghi et al. / Il Farmaco 58 (2003) 1077Á
/1081
1079
3. Experimental
1H, CHO), 7.8Á/7.2 (m, 6H, H4-imidazole and phenyl),
2.8 (s, 3H, SCH3).
3.1. Chemistry
3.1.4. General procedure for the synthesis of
dihydropyridine derivatives (5aÁh)
/
Melting points were determined using a Mettler FP61
capillary apparatus. Infrared spectra acquired on a
A mixture of compound 4 (100 mg, 0.429 mmol),
appropriate acetoacetate ester (0.858 mmol) and ammo-
nium acetate (33 mg, 0.429 mmol) in 3 ml of methanol
was refluxed for 24 h. The solvent was evaporated and
the residue was purified by preparative thin-layer
chromatography. Silica gel GF254 was used as adsor-
bent and chloroform was used as mobile phase.
PerkinÁElmer 1420 recording spectrometer. A Bruker
/
FT-80 instrument was used to acquire 1H NMR spectra;
with tetramethylsilane as the internal standard. Mass
spectra were acquired with a Finnigan TSQ-70 mass
spectrometer. Electron-impact ionization was performed
at an ionizing energy of 70 eV. Elemental analyses were
carried out with a PerkinÁ
tus. Elemental microanalyses were within 9
theoretical values for C, H and N.
/
Elmer Model 240-C appara-
3.1.5. 3,5-Dimethyl-1,4-dihydro-2,6-dimethyl-4-(2-
methylthio-1-phenylamino-5-imidazolyl)-3,5-
pyyridinedicarboxylate (5a)
/
0.4% of the
Mp: 197Á
/
198 8C; IR (KBr): n (cmꢂ1) 3348 (NH),
3.1.1. 5-Hydroxymethyl-2-mercapto-1-
phenylaminoimidazole (2)
1704 (CO); 1H NMR (CDCl3): d 7.60Á
/7.20 (m, 5H,
phenyl), 6.90 (s, 1H, H-C4 imidazole), 6.55 (bs, 1H,
NH), 5.40 (s, 1H, H-C4 dihydropyridine), 3.70 (s, 6H,
To a mixture of dihydroxyacetone (4.26 g, 46 mmol),
potassium thiocyanate (6.9 g, 70 mmol) and phenylhy-
drazine (8.66 g, 60 mmol) in 30 ml of butanol, 5.4 ml of
glacial acetic acid was added. The reaction mixture was
stirred at room temperature for 72 h and the precipitate
was collected. After washing with ether, the precipitate
was dried under reduce pressure to give 12.7 g (65%) of
OCH3), 2.65 (s, 3H, SCH3), 2.30 (s, 6H, CH3Ã
/
C2 and
C6). Mass; m/z (%): 428 (Mꢀ,10), 414 (86), 400
(21), 383 (19), 382 (40), 355 (100), 335 (31), 325 (13), 323
(74), 224 (35).
CH3Ã
/
3.1.6. 3,5-Diethyl-1,4-dihydro-2,6-dimethyl-4-(2-
methylthio-1-phenylamino-5-imidazolyl)-3,5-
pyridinedicarboxylate (5b)
2. Mp 133Á
/
134 8C; 1H NMR (CDCl3): d 8.2 (s, 1H, H4-
8.1 (m, 2H, phenyl), 7.1Á7.5 (m, 3H,
phenyl), 6.0 (s, 1H, SH), 4.6 (s, 2H, CH2O), 3.7 (s, 1H,
imidazole), 7.9Á
/
/
Mp: 142Á
/
143 8C; IR (KBr): n (cmꢂ1) 3343 (NH),
OH).
1692 (CO); 1H NMR (CDCl3): 7.60Á
/7.20 (m, 5H,
phenyl), 6.90 (s, 1H, H-C4 imidazole), 6.55 (bs, 1H,
NH), 5.40 (s, 1H, H-C4 dihydropyridine), 4.20 (q, 4H,
3.1.2. 5-Hydroxymethyl-2-methylthio-1-
phenylaminoimidazole (3)
OCH2), 2.65 (s, 3H, SCH3), 2.25 (s, 6H, CH3Ã
/
C2 and
C6), 1.30 (t, 6H, CH3). MS; m/z (%): 456 (Mꢀ,8),
442 (37), 396 (20), 369 (100), 349.0 (26), 323 (64), 252
(37).
To a stirring solution of compound 2 (2.81 g, 10
mmol) and potassium hydroxide (1.4 g, 25 mmol) in 5
ml of methanol a solution of methyl iodide (2.13 g, 15
mmol) in 2.5 ml of methanol was added drop-wise. After
2 h the mixture was poured into water and the
precipitate was collected, washed with water, and dried.
CH3Ã
/
3.1.7. 3,5-Dipropyl-1,4-dihydro-2,6-dimethyl-4-(2-
methylthio-1-phenylamino-5-imidazolyl)-3,5-
pyridinedicarboxylate (5c)
The residue was recrystallized from acetoneÁ
ether to give 1.58 g (67%) of 3, mp: 92Á93 8C.
1H NMR (CDCl3): d 7.3Á
7.7 (m, 6H, H4-imidazole
/
petroleum
142 8C; IR (KBr): n (cmꢂ1) 3206, 3270
/
Mp: 141Á
/
1
/
(NH), 1694 (CO). H NMR (CDCl3): d 7.60Á
/7.20 (m,
and phenyl), 4.8 (s, 2H, CH2O), 3.2 (bs, 1H, OH), 2.7 (s,
3H, SCH3).
5H, phenyl), 6.90 (s, 1H, H-C4 imidazole), 6.50 (bs, 1H,
NH), 5.40 (s, 1H, H-C4 dihydropyridine), 4.05 (t, 4H,
OCH2), 2.50 (s, 3H, SCH3), 2.10 (s, 6H, CH3Ã
/
C2 and
3.1.3. 2-Methylthio-1-phenylaminoimidazole-5-
carboxaldehyde (4)
CH3Ã
/
C6), 1.65 (m, 4H, CH2), 0.90 (t, 6H, CH3). MS; m/
z (%): 484 (Mꢀ,5), 470 (34), 410 (18), 385 (18), 383
(100), 363 (30), 323 (68), 280 (54), 196 (24).
A mixture of compound 3 (5 g, 21.3 mmol) and
activated magnesium dioxide (7.4 g, 85.2 mmol) in 35 ml
of acetonitrile was refluxed for 9 h. After cooling, the
mixture was filtered on diatomaceous earth and the
solvent removed under reduced pressure. The residue
was crystallized in a mixture of acetone and petroleum
ether to yield 4.2 g (85%) white needle crystals of
3.1.8. 3,5-Diisopropyl-1,4-dihydro-2,6-dimethyl-4-(2-
methylthio-1-phenylamino-5-imidazolyl)-3,5-
pyridinedicarboxylate (5d)
Mp: 186Á
1688 (CO); 1H NMR (CDCl3): d 7.55Á
phenyl), 6.85 (s, 1H, HÃC4 imidazole), 6.50 (bs, 1H,
NH), 5.40 (s, 1H, HÃC4 dihydropyridine), 5.05 (m, 2H,
/
188 8C; IR (KBr): n (cmꢂ1) 3252 (NH),
/7.20 (m, 5H,
compound 4; mp: 84Á
/
85 8C; IR (KBr): n (cmꢂ1) 3300
(NH), 1710 (CO); H NMR (CDCl3): d (ppm) 10.0 (s,
/
1
/

1080
A. Zarghi et al. / Il Farmaco 58 (2003) 1077Á1081
/
OCH), 2.60 (s, 3H, SCH3), 2.10 (s, 6H, CH3Ã
/
C2 and
ileocaecal junction and longitudinal smooth muscle
segments of 2 cm length were mounted under a resting
CH3Ã
/
C6), 1.30 (d, 12H, CH3). MS; m/z (%): 484
(Mꢀ,5), 473 (26), 470 (57), 411 (31), 410 (19), 383
(100), 364 (23), 341 (66), 297 (62), 280 (29), 196 (19).
tension of 400Á500 mg. The segments were maintained
/
at 37 8C in a 20 ml jacketed organ bath containing
oxygenated (100% O2) physiological saline solution at
the following millimolar composition: NaCl, 137; CaCl2,
1.8; KCl, 2.7; MgSO4, 1.1; NaH2PO4, 0.4; NaHCO3, 12;
and glucose, 5. The muscles were equilibrated for 1 h
with a solution change every 15 min. The concentrations
were recorded with a force displacement transducer (F-
50) on a NARCO physiograph. Test agents were
dissolved in dimethylsulfoxide and the same volume of
the solvent was used as a control in the absence of the
test compounds. The contractile response was taken as
the 100% value for the tonic (slow) component of the
response. The contraction was elicited with 80 mmol/l
KCl. Test compounds were cumulatively added and
compound-induced relaxation of contracted muscle was
expressed as percent of control. The IC50 of each
compound was graphically determined from the
concentration-response curves [20,21]. Results are ex-
3.1.9. 3,5-Ditertiarybutyl-1,4-dihydro-2,6-dimethyl-4-(2-
methylthio-1-phenylamino-5-imidazolyl)-3,5-
pyridinedicarboxylate (5e)
Mp: 227Á
1690 (CO); 1H NMR (CDCl3): d 7.55Á
phenyl), 6.85 (s, 1H, HÃC4 imidazole), 6.40 (bs, 1H,
NH), 5.40 (s, 1H, HÃC4 dihydropyridine), 2.65 (s, 3H,
/
228 8C; IR (KBr): n (cmꢂ1) 3270 (NH),
/
7.20 (m, 5H,
/
/
SCH3), 2.25 (s, 6H, CH3Ã
/
C2 and CH3Ã
/
C6), 1.50 (s, 18H,
CH3). MS; m/z (%): 512 (Mꢀ), 502 (34), 499 (100), 441
(20), 429 (30), 425 (86).
3.1.10. 3,5-Dibenzyl-1,4-dihydro-2,6-dimethyl-4-(2-
methylthio-1-phenylamino-5-imidazolyl)-3,5-
pyridinedicarboxylate (5f)
Mp: 176Á
/
177 8C; IR (KBr): n (cmꢂ1) 3210, 3280
1
(NH), 1698 (CO); H NMR (CDCl3): d 7.65Á
/
7.05 (m,
C4 imidazole), 6.40 (bs,
C4 dihydropyridine), 5.20 (s,
4H, CH2C6H5), 2.50 (s, 3H, SCH3), 2.25 (s, 6H, CH3Ã
C6). MS; m/z (%): 580 (Mꢀ,8), 566 (25),
15H, phenyl), 6.85 (s, 1H, HÃ
/
pressed as mean9s.e. Differences between the IC50 and
/
1H, NH), 5.45 (s, 1H, HÃ
/
response percentage ratio values of compounds in each
preparation were compared by use of two-tailed Stu-
/
C2 and CH3Ã
/
dents’ t-test. A P value B0.05 was considered to be
/
433 (22), 431 (100), 376 (42), 323 (23).
indicative of significance. The research protocol and
experimental animals have been approved by ethics
committee of Shaheed Beheshti University of Medical
Sciences.
3.1.11. 3,5-Diphenethyl-1,4-dihydro-2,6-dimethyl-4-(2-
methylthio-1-phenylamino-5-imidazolyl)-3,5-
pyridinedicarboxylate (5g)
Mp: 133Á
/
134 8C; IR (KBr): n (cmꢂ1) 3200, 3270
1
(NH), 1693 (CO); H NMR (CDCl3): d 7.65Á
/
7.00 (m,
C4 imidazole), 6.30 (bs,
C4 dihydropyridine), 4.40 (t,
4H, OCH2), 2.95 (t, 4H, CH2C6H5), 2.55 (s, 3H, SCH3),
4. Results and discussion
15H, phenyl), 6.85 (s, 1H, HÃ
/
1H, NH), 5.45 (s, 1H, HÃ
/
The calcium-channel antagonist activities (IC50) of
5aÁh, determined as the contraction needed to produce
/
2.20 (s, 6H, CH3Ã
/
C2 and CH3Ã
/
C6). MS, m/z (%): 608
(Mꢀ,10), 594 (18), 447 (19), 445 (100), 426 (28), 404
(48), 323 (37).
50% relaxation of contracted guinea pig ileal long-
itudinal smooth muscle, are presented in Table 1.
The results of biological study showed that these new
dihydropyridines caused dose-dependent inhibition of
the contractile responses induced by high Kꢀ concen-
tration, guinea-pig ileum. These effects were similar to
those obtained with nifedipine, and may be explained as
being caused by inhibition of entry of Ca2ꢀ through
voltage-dependent calcium channels in the muscle
membrane. However, it should be taken into account
that a complex network of neuronal and muscular
tissues exists in the intestine and we could not rule out
the possibility of different action of the synthesized
compounds at several neuronal and muscular sites on
which they might act. Comparison of the activities of
3.1.12. 3,5-Diphenpropyl-1,4-dihydro-2,6-dimethyl-4-(2-
methylthio-1-phenylamino-5-imidazolyl)-3,5-
pyridinedicarboxylate (5h)
Mp: 132Á
/
133 8C; IR (KBr): n (cmꢂ1) 3219, 3272
1
(NH), 1692 (CO); H NMR (CDCl3): d 7.65ꢂ
/
7.00 (m,
C4 imidazole), 6.30 (bs,
C4 dihydropyridine), 4.20 (t,
4H, OCH2), 2.70 (t, 4H, CH2C6H5), 2.50 (s, 3H, SCH3),
15H, phenyl), 6.85 (s, 1H, HÃ
/
1H, NH), 5.50 (s, 1H, HÃ
/
2.20 (s, 6H, CH3Ã
/
C2 and CH3Ã
/C6), 1.95 (m, 4H,
CH2CH2). MS, m/z (%): 636.0 (Mꢀ,8), 612 (28), 486
(26), 459 (100), 438 (36), 432 (40), 328 (19), 323 (76), 196
(13), 117 (21), 91 (53).
synthesized symmetrical esters 5aÁh indicated that in
/
aliphatic alkyl esters series, increasing the length of
methylene chain in C-3 and C-5 ester substituents for
more than two methylene units decreases activity
especially when increasing of the length is accompanied
with increasing the hindrance. Therefore, t-butyl ester
3.2. Pharmacology
Male albino guinea pigs (300Á
blow to the head. The intestine was removed above the
/
450 g) were killed by a

A. Zarghi et al. / Il Farmaco 58 (2003) 1077Á
/1081
1081
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5e is the weakest compound in this series. In phenyl
alkyl ester series 5fÁh increasing the length of methylene
/
chain also decreases activity. These results are in
agreement with our previous works, which carried out
on 1,4-dihydropyridines containing nitroimidazolyl or
nitrobenzylimidazolyl [13,14] substituents. Finally, the
results show that most compounds have activity similar
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active than the reference drug nifedipine. Therefore,
they have potential for use in disorders normally treated
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