Synthesis, QSAR and calcium channel antagonist activity of new 1,4-dihydropyridine derivatives containing 1-methy 1-4,5-dichloroimidazolyl substituents

Article abstract of DOI:10.1002/ardp.200600211

A group of dialkyl and diarylester analogues of nifedipine, in which the ortho-nitrophenyl group at position 4 was replaced by a 1-methyl-4,5- dichloroimidazolyl substituent, were synthesized and evaluated as calcium-channel antagonists using the high K⁺ concentration of guinea-pig ileum longitudinal smooth muscle. The structure of all compounds was confirmed by IR, ¹H-NMR, and mass spectra. The calcium-channel antagonist activity of compounds 10a-f demonstrated that compound 10b was the most active and 10f the least active one. With unsymmetrical diesters 12a-k, the most active compound was the ethyl, phenethyl derivative. Structural parameters on the calcium-channel antagonist activity were evaluated by QSAR analysis and a linear correlation was found between the -log IC₅₀ values of these compounds and their constitutional and topological properties.

Full text of DOI:10.1002/ardp.200600211

Arch. Pharm. Chem. Life Sci. 2007, 340, 549–556
M. Hosseini et al.
549
Full Paper
Synthesis, QSAR and Calcium Channel Antagonist Activity of
New 1,4-Dihydropyridine Derivatives Containing 1-Methyl-4,5-
dichloroimidazolyl Substituents
Maryam Hosseini1, Ramin Miri2,3, Mohsen Amini2, Hossein Mirkhani3, Bahram Hemmateenejad3,4
Shahram Ghodsi5, Eskandar Alipour1, and Abbas Shafiee2
,
1 Faculty of Chemistry, Islamic Azad University, North Tehran Branch, Tehran, Iran
2 Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center,
Tehran University of Medical Science, Tehran, Iran
3 Medicinal & Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz,
Iran
4 Department of Chemistry, Shiraz University, Shiraz, Iran
5 Department of Chemistry, Islamic Azad University, Karaj Branch, Karaj, Iran
A group of dialkyl and diarylester analogues of nifedipine, in which the ortho-nitrophenyl group
at position 4 was replaced by a 1-methyl-4,5-dichloroimidazolyl substituent, were synthesized
and evaluated as calcium-channel antagonists using the high K+ concentration of guinea-pig
1
ileum longitudinal smooth muscle. The structure of all compounds was confirmed by IR, H-
NMR, and mass spectra. The calcium-channel antagonist activity of compounds 10a–f demon-
strated that compound 10b was the most active and 10f the least active one. With unsymmetri-
cal diesters 12a–k, the most active compound was the ethyl, phenethyl derivative. Structural
parameters on the calcium-channel antagonist activity were evaluated by QSAR analysis and a
linear correlation was found between the –log IC50 values of these compounds and their consti-
tutional and topological properties.
Keywords: Calcium antagonist / Dichloroimidazole / Dihydropyridine / QSAR analysis /
Received: December 19, 2006; accepted: May 30, 2007
DOI 10.1002/ardp.200600211
9 3, nicardipine 4, and other DHPs caused to refocus on
synthesis of novel DHP derivatives [3].
Introduction
Felodipine 5 (having two chloro substituents) (Fig. 1)
has a high calcium-antagonist potency that is compara-
ble to that nifedipine [4]. Therefore, chlorine substitution
in the aryl rings on the C-4 position lead to potent com-
pounds. Other studies suggested that C-4 heterocyclic
substituents gave compounds as calcium-channel antago-
nists [5–7]. Changes in the substitution pattern at C-3
and C-5 position of DHP alter activity and tissue selectiv-
ity. Parallel to this finding, we were able to prove that the
bioisosteric replacement of the 4-aryl moiety with a 4-
imidazolyl group yields 4-imidazolyl-1,4-dihydropyri-
dines which retain potent calcium-channel antagonist
activity [8–11]. The dihydropyridine class of compounds,
in which nifedipine is the prototype, has been the aim of
many structure-activity relationship studies [12–19].
The discovery that the 1,4-dihydropyridine class of cal-
cium-channel antagonists inhibits the Ca2+ influx, repre-
sents a major therapeutic advance in the treatment of
cardiovascular diseases, such as hypertension, angina
pectoris, and other spastic smooth muscle diseases [1].
Dihydropyridine (DHP) derivatives substituted in posi-
tion 4 are analogues of nifedipine 1 and an important
class of drugs [2]. Introducing of potent multiple drug
resistance (MDR) reversal agents such as NIK-250 2, N276-
Correspondence: R. Miri, Faculty of Pharmacy, Tehran University of
Medical Sciences, Medicinal Chemistry, P. O. Box 14155-6451, Tehran
14174, Iran.
E-mail: mirir@tums.ac.ir
Fax: +98 21 664-61178
i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

550
M. Hosseini et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 549–556
They concluded that the biological activity of DHPs is
dependent on the lipophilic as well as the electronic and
esteric properties of the substituents on 4-phenyl DHP
analogues of nifedipine.
As a part of our ongoing program to design new DHPs,
we reported in a previous paper [11] that imidazole with
a free NH has considerable calcium-channel antagonist
activity. We postulated that the nitrogen atom can inter-
act with the receptor via hydrogen bonding. To test our
hypothesis, here, we report the synthesis, calcium-chan-
nel antagonist activity, and QSAR of symmetrical and
unsymmetrical esters of 2,6-dimethyl-1,4-dihydro-4-(1-
methyl-4,5-dichloroimidazole-2-yl)-3,5-pyridine dicarbox-
ylates.
Chemistry
The symmetrical diesters 10a–f (Table 1) and unsymmet-
rical diesters 12a–k (Table 2) are synthesized according
to Scheme 1. N-Methylation of 6 with methyl iodide was
performed to give compound 7. Oxidation of the hydrox-
ymethyl group of the latter with MnO2 resulted in alde-
hyde 8. The symmetrical analogues 10a–f (Table 1) was
prepared by classical Hantzsch condensation in which 1-
methyl-4,5-dicholoroimidazol-2-carboxaldehyde
8 was
reacted with acetoacetic acid esters and ammonium
hydroxide in 29–55% yield [20].
Figure 1. The structure of compounds 1–5.
Table 1. Physicochemical and calcium channel modulation data for compounds 10a–h.
No
R
Mp (8C)
Reflux
Time (h)
Yield
(%)
Formulaa)
MW
Calcium-chan-
nel antagonist
activity
IC50 (lM)b)
10a
10b
10c
10d
10e
10f
Nif
Me
Et
isopropyl
t-butyl
isobutyl
benzyl
310–315
260–264
209–213
240–244
225–230
169–171
12
12
24
24
12
12
29
43
55
143
37
50
C15H17Cl2N3O4
C17H21Cl2N3O4
C19H25Cl2N3O4
C21H29Cl2N3O4
C27H37Cl2N3O4
C27H25Cl2N3O4
C17H18N2O2
374.22
402.27
430.33
458.38
538.51
526.42
3.32 l 1.11
0.882 l 0.162
1.29 l 0.92
5.31 l 0.4
2.18 l 0.21
5.08 l 1.44
0.0314 l 0.014
a)
Micro-analytical analysis were within l 0.35%.
b)
The molar concentration of antagonist test compound causing a 50% decrease in the tonic contractile response l IC50% (SEM) in
GPILSM by KCl (80 mmol) was determined graphically from dose-response curve. The number of experiments was six for all com-
pounds.
i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2007, 340, 549–556
New 1,4-Dihydropyridine Derivatives
551
Table 2. Physicochemical and calcium channel modulation data for compounds 12a–k.
No
R1
R2
Mp (8C)
Reflux
Time (h)
Yield
(%)
Formulaa)
MW
Calcium-chan-
nel antagonist
activity IC50
(lM)b)
12a
12b
12c
12d
12e
12f
12g
12h
12i
Et
Et
Et
Et
Et
Et
Et
Me
Me
Me
Me
Me
235–240
162–167
190–195
194–99
24
24
24
15
48
17
48
24
24
24
24
48
56.5
49
C16H19Cl2N3O4
C18H23Cl2N3O4
C18H23Cl2N3O4
C19H25Cl2N3O4
C22H23Cl2N3O4
C19H25Cl2N3O4
C23H25Cl2N3O4
C21H21Cl2N3O4
C18H23Cl2N3O4
C17H21Cl2N3O4
C18H23Cl2N3O4
C17H18N2O2
388.24
416.30
416.30
430.33
464.35
430.33
478.37
450.32
416.30
402.27
416.30
1.28 l 0.69
1.37 l 0.38
0.955 l 0.27
2.7 l 0.7
isopropyl
n-propyl
isobutyl
benzyl
t-butyl
phenethyl
benzyl
isobutyl
isopropyl
t-butyl
33
70–75
47.2
52.8
79
61.5
63
1.8 l 0.4
128–133
150–155
172–175
197–199
227–230
212–218
1.88 l 0.79
0.090 l 0.023
1.22 l 0.94
1.99 l 1.1
8.3 l 0.2
0.87 l 0.02
0.0314 l 0.014
12j
12k
Nif
17.7
7.6
a)
Microanalytical analysis were within l0.35%.
The molar concentration of antagonist test compound causing a 50% decrease in the tonic contractile response l SEM in GPILSM
b)
by KCl (80 mmol) was graphically determined from dose-response curves. The number of experiments was six for all compounds.
The unsymmetrical analogues 12a–k were synthesized compounds). A comparison of the activity of the symmet-
by modified Hantzsch reaction using a procedure rical series of ester (Table 1) shows that increasing the
reported by Meyer [21]. Thus, condensation of acetoacetic length or lipophilicity of the methylene chain (except for
esters 9 with 1-methyl-4,5-dicholoroimidazole-2-carboxal- 10b) in C3 and C5 ester substituents is not accompanied
dehyde 8 afforded the intermediate which was con- with variations in biological activity. In the unsymmetri-
densed with alkyl acetoacetate in the presence of ammo- cal series (Table 2), compound 12g was the most active
nium acetate to give the desired compounds 12. Since the one. In general, for most compounds a change of the
DHP compounds undergo oxidation during synthesis, alkyl or aryl esters series in the C5 or C3 position caused
the preparation, collection, and purification of the prod- no significant variation in biological activity.
uct should be carried out in the absence of oxidizing
Our previous study showed [7] that when the 4-aryl
agents and in darkness. Alkyl acetoacetate was synthe- moiety of 1,4-DHP was replaced by a 1H-4,5-dichloroimi-
sized by known methods [22, 23] in which 2,2,6-tri- dazole ring, the activity of some C3- and C5- alkyl or aryl
methyl-4H-1,3-dioxane-4-one was used as starting mate- esters were almost the same as observed in the reference
rial.
drug (nifedipine). Comparison of the activity of com-
The structure of all compounds was confirmed by ele- pounds (Tables 1 and 2) to their analogous (1H-4,5-
mental analyses, IR,1H-NMR, and Mass spectroscopy.
dichloroimidazole) showed considerable reduction in
Ca2+-antagonist activity.
The results of this study are in good agreement with
our previous findings [11] in which the importance of
hydrogen bonding between N-H of the imidazole ring
Results and discussion
The Ca2+-channel antagonist activity of 10a–f and 12a–k and the receptor was proposed. Considering the tauto-
was determined as the concentration needed to produce meric forms of the 1H-4,5-dichloroimidazolyl moiety,
50% inhibition of the guinea-pig ileum longitudinal both nitrogen atoms can interact with the receptor via
smooth muscle contractility, are summarized in Table 1 hydrogen bonding and, therefore, both tautomeric forms
(symmetrical compounds) and Table 2 (unsymmetrical should be pharmacologically active. However, in the 1-
i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

552
M. Hosseini et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 549–556
Scheme 1. Synthesis of 1,4-dihydropyridine derivatives containing 1-methyl-4,5-dichloroimidazolyl substituents.
methyl-4,5-dichloro imidazolyl group hydrogen bonding bonyl group has preferred the trans-configuration and
cannot be formed. Therefore, these compounds are that of molecules with small –R groups is adapted to cis-
assumed to be less active.
configuration. However, no systematic relationship is
In order to investigate the relationships between struc- observed between the cis/trans-orientation of the car-
ture and biological activity, the QSAR of the synthesized bonyl group on the C-3 position (left site) and the bulki-
compounds were studied. The superimposed three- ness of –R substituents.
dimensional structure of molecules is represented in
To obtain the quantitative effects of the structural
Fig. 2. The DHP ring is adapted to a semi-boat conforma- parameters of the 4-chloroimidazolyl DHP derivatives on
tion in which the chloroimidazolyl ring has occupied the their calcium-channel antagonist activity, QSAR analysis
axial position of the C-4 atom of DHP. Indeed, the dihe- with different types of molecular descriptors including
dral angle between the chloroimidazolyl aromatic ring electronic, physicochemical, and topological parameters
and the DHP ring is not fixed and is varied by a change in was operated. HOMO and LUMO energies and dipole
the substitution patterns on the C-3 and C-5 atoms of moment (DM) were used to account for the electronic fea-
DHP ring. The carbonyl groups on the C-3 and C-5 posi- ture of the molecules. Molecular surface area (SA), molar
tions are oriented in both cis- and trans-configurations volume (MV), molar refractivity (MR), lipophilicity (log P),
with respect to the C2-C3 and C5-C6 double bonds, respec- and hydration energy (HE) are the physicochemical prop-
tively. It is interesting to note that for all molecules with erties that were calculated for each molecule. The cal-
bulky –R groups on the C-5 position (right site), the car- cium-channel antagonist activity of the molecules was
i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2007, 340, 549–556
New 1,4-Dihydropyridine Derivatives
553
Figure 2. Superimposed three-dimensional structures of the
DHP derivatives obtained from semi-empirical AM1 calculation.
Figure 3. Scatter plot of the cross-validation predicted activity of
the DHP derivatives correlating to their corresponding experi-
mental values.
expressed in pIC50 (-logarithm of IC50) scale. As it is shown
in Tables 1 and 2, pIC50 data are varied between 4.90 and
7.0. This indicates that calcium-channel antagonist activ-
ity of the studied DHP derivatives is affected by substitu-
tion patterns on the C-3 and C-5 of the DHP ring.
In the QSAR-model development, first the correlation
of each one of the descriptors with each other and with
pIC50 was calculated. Among the collinear descriptors,
one of them, which had the highest correlation with
pIC50, was retained and the others were removed. The
remaining descriptors were used to find a multilinear
equation of the form
the calcium-channel antagonist activity of the studied
DHP. Our attempts to derive equations from the use of
chemical and electronic parameters failed. The above
equation has high statistical quality and can describe the
quantitative effects of molecular structure on the cal-
cium-channel antagonist activity of the studied DHP
derivative in a useful manner. Because of the low number
of molecules, we did not use an external test set to vali-
date the prediction ability of the model, rather this QSAR
model was evaluated by leave-one-out cross-validation
method. Root mean square error of cross-validation
(RMSCV) and square of cross-validate correlation coeffi-
cient (R2CV) was used to measure the model predictivity. As
is observed from the above equation, R2CV is 0.854, which
means that the resulted QSAR equation could reproduce
more than 85% of variances in the experimental calcium-
channel antagonist data. The plot of cross-validated pre-
dicted activities against the experimental values are rep-
resented in Fig. 3. It can clearly be observed that the data
are distributed around a straight line without significant
outliers.
log MIC = b0 + b1DES1 + b2DES2 + . . .
between activity and structural parameters. The stepwise
selection and elimination of variable procedure of SPSS
software (SPSS Inc., version 11) was used to find the best
set of descriptors. The resulted QSAR model is as follow-
ing:
pIC50 = –12.610 + 0.169 (nCs) – 134.396 (X5A) + 136.568
(MSD) + 0.399 (nCq)
N = 16 R2 = 0.911 Se = 0.151 R2CV = 0.856 RMSCV = 0.189
F = 30.2
This research was supported by grants from the Research Coun-
cil of Tehran University of Medical Sciences and Shiraz Univer-
sity of Medical Sciences.
In this three-parametric equation, nCs is the total num-
ber of secondary carbon atoms, X5A is the fifth-order
average connectivity index, and nCq is the total number
of quaternary carbon atoms. The first and third descrip-
tors are constitutional and the second one is a topologi-
cal index. This equation explains the significant impact
of topological indices and constitutional descriptors on
Experimental
Reagent and solvents were obtained from Merck (Darmstadt,
Germany). Melting points were taken on a Kofler hot stage appa-
i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

554
M. Hosseini et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 549–556
ratus (Reichert, Vienna, Austria) and were uncorrected. 1H-NMR
spectra were recorded on a Bruker FT-80 spectrometer (Bruker,
Rheinstetten, Germany) and TMS was used as an internal stand-
ard. Infrared spectra were acquired on a Nicolet 550-FT spec-
trometer. (Nicolet, Maidson, WI, USA). Mass Spectra were meas-
ured with a Finnigan TSQ-70 spectrometer (Finnigan, Bremen,
Germany) at 70 eV. Elemental analysis was carried out with a
Perkin-Elmer Model 240-C apparatus (Perkin-Elmer, England).
The results of elemental analyses (C, H, N) were within l0.4% of
theoretical values for C, H and N.
Diisopropyl-1,4-dihydro-2,6-dimethyl-4-(1-methyl-4,5-
dichloroimidazole-2-yl)-3,5-pyridine dicarboxylate 10c
1
IR (KBr): m cm– 1 3410 (NH), 1673 (CO). H-NMR (CDCl3): d = 1.20
(dd, 12H, J = 6.4 Hz, CH(CH3)2], 2.20 (s, 6H, C2,C6-CH3), 3.87 (s, 3H,
N-CH3), 4.90-5.2 (m, 3H, H4 –DHP and OCH), 9.90 (bs, 1H, NH). MS:
m/z (%) 429[M+] (70), 370 (18), 342 (100), 255 (42), 282 (98), 198
(94), 150 (58).
Di-tert-butyl-1,4-dihydro-2,6-dimethyl-4-(1-methyl-4,5-
dichloroimidazole-2-yl)-3,5-pyridine dicarboxylate 10d
IR (KBr): m cm– 1 3385 (NH), 1670 (CO). 1H-NMR (CDCl3): d = 1.43 (s,
18H, C(CH3)3), 2.17 (s, 6H, C2,C6-CH3), 3.76 (s, 3H, N-CH3), 5.0 (1H,
H4-DHP), 9.70 (bs, 1H, NH). MS: m/z (%) 457 [M+] (45), 356 (40), 300
(100), 196 (98), 151 (69), 106 (20), 57 (72).
Synthesis
4,5-Dichloro-2-hydroxymethyl-1-methyl -imidazole 7
To a stirred solution of compound 6 (5.01 g, 0.03 mol) in 50 mL
of methanol were added sodium hydroxide (1.2 g, 0.03 mol) and
methyl iodide (8.52 g, 0.06 mol). The reaction was monitored by
TLC. The solvent was removed under reduced pressure. The resi-
due was crystallized from methanol and water to give 4.5 g
(83%) of compound 7, mp. 165–1678C. IR (KBr): m cm– 1 3350
(OH). 1H-NMR (CDCl3): d = 3.80 (s, 3H, CH3), 4.58 (s, 2H, CH2), 5.07
(bs, 1H, OH). Anal. Calcd. C5H6Cl2N2O requires C, 33.18; H, 3.34;
N, 15.48; found C, 33.36; H, 3.15; N, 15.22.
Di-isobutyl-1,4-dihydro-2,6-dimethyl-4-(1-methyl-4,5-
dichloroimidazole-2-yl)-3,5-pyridine dicarboxylate 10e
IR (KBr): m cm– 1 3451 (NH), 1677 (CO). 1H-NMR (CDCl3): d = 0.90 (d,
12H, J = 6.4 Hz, CH(CH3)2), 1.70-1.90 (m, 2H, CH), 2.2 (s, 6H, C2,C6-
CH3), 3.42–3.68 (m, 7H, N-CH3 and CH2), 5.10 (s, 1H, H4-DHP),
10.09 (bs, 1H, NH). MS: m/z (%) 457 [M+] (40), 383 (17), 356 (38),
300 (100), 256 (98), 196 (97), 151 (67), 106 (20), 57 (70).
4,5-Dichloro-1-methyl-2-imidazolecarboxaldehyde 8
A mixture of compound 7 (7.24 g, 0.04 mol) and activated man-
ganese(IV)oxide (28 g) in 70 mL methylene chloride was stirred
at room temperature for 12 hours. The mixture was filtered and
the solvent was removed under the reduced pressure. The resi-
due was crystallized from water to give 5.01 g (70%) of 8, mp.
81–828C. IR (KBr): m cm– 1 1675 (CO). 1H-NMR (CDCl3): d = 3.89 (s,
3H, CH3), 9.90 (s, 1H, CHO). Anal. Calcd.: C5H4Cl2N2O requires C,
33.55; H, 2.25; N, 15.65; found C, 33.37; H, 2.44; N, 15.83.
Dibenzyl-1,4-dihydro-2,6-dimethyl-4-(1-methyl-4,5-
dichloroimidazole-2-yl)-3,5-pyridine dicarboxylate 10f
IR (KBr): m cm– 1 3450 (NH), 1676 (CO). 1H-NMR (CDCl3): d = 2.20 (s,
6H, C2, C6-CH3), 3.80 (s, 3H, N-CH3), 4.90–5.16 (m, 5H, H4-DHP and
CH2 benzyl), 7.12–7.30 (m, 10H, phenyl), 9.8 (bs, 1H, NH). MS:
m/z (%) 523 [M+] (25), 390 (57), 314 (38), 282 (95), 241 (45), 150 (49),
91 (100).
General procedure for the preparation of symmetrical
Dialkyl- and Diaryl-1,4-dihydro-2,6-dimethyl-4(1-methyl-
4,5-dichloroimidazole-2-yl)-3,5-pyridinedicarboxylate
General procedure for the preparation of unsymmetrical
Dialkyl- or Alky-aryl-1,4-dihydro-2,6-dimethyl-4(1-
methyl)-4,5-dichloroimidazole-2-yl)-3,5-pyridine
10a–f
dicarboxylate 12
To a solution of 8 (4.33 mol) and alkyl acetoacetate (8.66 mol) in
30 L methanol was added 10 mL ammonia solution (37%) and
refluxed for 12–24 h in the darkness and under argon. The sol-
vent was removed under reduced pressure and the residue was
crystallized from methanol to give the title compound.
A solution of compound 8 (5 mmol), methyl acetoacetate (for
11h–i) or ethylacetoacetate (for 11a–g) (5 mmol), glacial acetic
acid (0.5 mL), piperidine (0.2 mL), and benzene (100 mL) were
refluxed for 3 h during which the water was removed via a
Dean–Stark trap. The benzene was removed and the oily residue
was directly used in next step. To a stirring solution of com-
pound 11 in methanol (20 mL), alkyl acetoacetates (5 mmol) and
ammonium acetate (0.8 g) were added. The solution was
refluxed for 15–48 h in the darkness and under argon. After
cooling, the solvent was removed and the residue was purified
by column chromatography (ethyl acetate; CH2Cl2), to give the
title compounds.
Dimethyl-1,4-dihydro-2,6-dimethyl-4-(1-methyl-4,5-
dichloroimidazole-2-yl)-3,5-pyridine dicarboxylate 10a
IR (KBr): m cm– 1 3455 (NH), 1678 (CO). 1H-NMR (CDCl3): d = 2.21 (s,
6H, C2, C6-CH3), 3.68 (s, 6H, OCH3), 3.85 (s,3H, N-CH3), 4.99 (s,1H,
H4-DHP). MS: m/z (%) 373 [M+] (30), 314 (60), 282 (70), 224 (100),
192 (23), 150 (16).
Diethyl-1,4-dihydro-2,6-dimethyl-4-(1-methyl-4,5-
Ethylmethyl-1,4-dihydro-2,6-dimethyl-4-(1-methyl-4,5-
dichloroimidazole-2-yl)-3,5-pyridine dicarboxylate 10b
IR (KBr): m cm– 1 3451 (NH), 1678 (CO). 1H-NMR (CDCl3): d = 1.20 (t,
6H, J = 7.2 Hz, CH3), 2.26 (s, 6H, C2, C6-CH3), 3.81 (s, 3H, N-CH3), 4.1
(q, 4H, J = 7.2 Hz, OCH2), 5.09 (s, 1H, H4-DHP), 9.96 (bs, 1H, NH).
MS: m/z (%) 401 [M+] (27), 328 (65), 282 (100), 252 (36), 124 (27),
196 (24), 150 (19).
dichloroimidazole-2-yl)-3,5-pyridine dicarboxylate 12a
IR (KBr): m cm– 1 3410 (NH), 1677 (CO). 1H-NMR (CDCl3): d = 1.26 (t, J
= 7.2 Hz, 3H, OCH2CH3), 2.24 (s, 6H, C2,C6-CH3), 3.70 (s, 3H, OCH3),
3.87 (s, 3H, N-CH3), 4.10 (q, J = 7.2 Hz, 2H, OCH2CH3), 5.12 (s, 1H,
H4-DHP), 10.0 (bs, 1H, NH). MS: m/z (%) 387 [M+] (30), 330 (23), 282
(83), 210 (55), 150 (33), 91 (29), 69 (75), 55 (100).
i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2007, 340, 549–556
New 1,4-Dihydropyridine Derivatives
555
Ethyl-isopropyl-1,4-dihydro-2,6-dimethyl-4-(1-methyl-4,5-
Methylisobutyl-1,4-dihydro-2,6-dimethyl-4-(1-methyl-4,5-
dichloroimidazole-2-yl)]-3,5-pyridine dicarboxylates 12b
IR (KBr): m cm– 1 3415 (NH), 1680 (CO). 1H-NMR (CDCl3): d = 1.28 (t, J
= 7.2 Hz, 3H, CH3), 1.39 (d, J = 6.4 Hz, 6H, CH(CH3)2), 2.38 (s, 6H,
C2,C6-CH3), 3.78 (s, 3H, N-CH3), 3.9–4.4 (m, 2H, OCH2), 5.0–5.4 (m,
2H, H4-DHP and OCH), 9.8 (bs, 1H, NH). MS: m/z (%) 415 [M+] (16),
342 (56), 282 (100), 196 (56), 150 (45).
dichloroimidazole-2-yl)-3,5-pyridine dicarboxylates 12i
IR (KBr): m cm– 1 3450 (NH), 1674, (CO). 1H-NMR (CDCl3): d = 0.90 (d,
J = 6.1 Hz, 6H, CH(CH3)2), 1.7–2.05 (m, 1H, CH2CH(CH3)2), 2.22 (s,
6H, C2,C6-CH3), 3.80 (s, 3H, N-CH3), 3.88 (s, 3H, OCH3), 5.1 (s, 1H,
H4-DHP), 10.0 (bs, 1H, NH). MS: m/z (%) 415 [M+] (2), 328 (41), 282
(100), 267 (27), 197 (76), 150 (51), 100 (33).
Methylisopropyle-1,4-dihydro-2,6-dimethyl-4-(1-methyl-
Ethyl-n-propyl-1,4-dihydro-2,6-dimethyl-4-[1-methyl-4,5-
4,5-dichloroimidazole-2-yl)-3,5-pyridine dicarboxylate 12j
IR (KBr): m cm– 1 3373 (NH), 1671 (CO). 1H-NMR (CDCl3): d = 1.27 (d,
J = 6.8 Hz, 6H, CH(CH3)2), 2.21 (s, 6H, C2,C6-CH3), 3.78 (s, 3H, N-
CH3), 3.90 (s, 3H, OCH3), 5.05-5.15 (m, 2H, CH(CH3)2 and H4-DHP),
9.95 (bs, 1H, NH). MS: m/z (%) 401 [M+] (19), 242 (77), 311 (59), 279
(100), 196 (97), 148 (70), 104 (29).
dichloroimidazole-2-yl]-3,5-pyridine dicarboxylate 12c
IR (KBr): m cm– 1 3450 (NH), 1671 (CO). 1H-NMR (CDCl3): d = 0.93 (t, J
= 7.1 Hz, 3H, CH3CH2CH2), 1.15 (t, J = 7.2 Hz, 3H, OCH2CH3), 1.4–
1.90 (m, 2H, CH2-CH2-CH3), 2.23 (s, 6H, C2, C6-CH3), 3.84 (s, 3H, N-
CH3), 3.9–4.4 (m, 5H, H4-DHP, OCH2CH3 and OCH2CH2CH3), 5.09 (s,
1H, H4-DHP), 9.90 (bs, 1H, NH). MS: m/z (%) 415 [M+] (24), 342 (90),
282 (100), 196 (73), 150 (59).
Methyl-tert-butyl-1,4-dihydro-2,6-dimethyl-4-(1-methyl-
Ethylisobutyl-1,4-dihydro-2,6-dimethyl-4-(1-methyl-4,5-
4,5-dichloroimidazole-2-yl)-3,5-dicarboxylates 12k
IR (KBr): m cm– 1 3386 (NH), 1669 (CO). 1H-NMR (CDCl3): d = 1.24 (s,
9H, tBu), 2.17 (s, 6H, C2,C6-CH3), 3.79 (s, 3H, N-CH3), 3.87 (s, 3H,
OCH3), 5.01 (s, 1H, H4-DHP), 9.58 (bs, 1H, NH). MS: m/z (%) 415 [M+]
(2), 328 (40), 282 (100), 267 (28), 197 (72), 150 (50), 106 (35).
dichloroimidazole-2-yl)-3,5-pyridine dicarboxylate 12d
IR (KBr): m cm– 1 3451 (NH), 1703, 1672 (CO). 1H-NMR (CDCl3): d =
0.90 (d, J = 6.4 Hz, 6H, CH(CH3)2), 1.26 (t, J = 7.2 Hz, 3H, OCH2CH3),
1.5-1.9 (m, 1H, CH2CH(CH3)2), 2.26 (s, 6H, C2,C6-CH3), 3.88 (s, 3H,N-
CH3), 3.90 (d, J = 6.5 Hz, 2H, OCH2CH(CH3)2), 4.10 (q, J = 7.2 Hz, 2H,
OCH2CH3), 5.12 (s, 1H, H4-DHP), 10.02 (bs, 1H, NH). MS: m/z (%) 429 [M+]
(10), 356 (50), 328 (25), 282 (100), 196 (45), 150 (24), 57 (70).
Pharmacology
Investigations on isolated ileum of guinea pigs
Male guinea pigs, weighing 300–400 g, were killed by a blow on
the head. The animals were deprived from food 18 h before sacri-
fice but had free access to water. The non-terminal part of the
ileum was removed and cut into segments of 10–15 mm length.
Each ileal segment was suspended in an organ bath and con-
nected to an isometric transducer (K30, Hugo Sachs Electronic,
Germany). The organ bath contained 20 mL physiological solu-
tion of the following composition (in mM): NaCl 119, KCl 2.7,
CaCl2 2, MgCl2 0.88, NaH2PO4 0.36, NaHCO3 12, glucose 5.5. The
physiological salt solution was continuously gassed with a mix-
ture of 95% O2 and 5% CO2 and its temperature was held at 378C.
The fluid of the organ bath was changed every 15 min. A resting
tension of 0.5 g was applied to the ileal segments and they were
allowed to equilibrate for 1 h. Contractions of the ileal segments
were recorded, using an amplifier (Plugsys, Hugo Sachs Elec-
tronic, Germany) and a recorder (Graphtec, model WR3320). In
order to study the effects of the synthesized dihydropyridines on
KCl-induced contractions of the ileum, at the first step, several
contractions with KCl (40 mM) were made. Finding no signifi-
cant differences between the KCl-induced contractions were con-
sidered as tissue stability and thereafter, the main experiments
were started. At this step, KCl (40 mM)-induced contraction was
recorded again and the peak of the first phase (phasic contrac-
tion) was considered as control. Then, tissues were pre-incubated
with one particular concentration of each compound (for
15 min.) and then the effect of KCl (40 mM) was assessed once
again. Each segment was treated with only one compound. From
the concentration-response curves, the pIC50 (–log IC50) value of
each compound was calculated. Nifedipine was used as refer-
ence compound.
Ethylbenzyl-1,4-dihydro-2,6-dimethyl-4-(1-methyl-4,5-
dichloroimidazole-2-yl)-3,5-pyridine diicarboxylate 12e
IR (KBr): m cm– 1 3405 (NH), 1698, 1669 (CO). 1H-NMR (CDCl3): d =
1.23 (t, J = 7 Hz, 3H, OCH2CH3), 2.24 (s, 6H, C2,C6-CH3), 3.8 (s, 3H, N-
CH3), 4.17 (q, J = 7 Hz, OCH2CH3), 4.9-5.3 (m, 3H, H4-DHP and
CH2Ph), 7.1–7.4 (m, 5H, phenyl), 10.0 (bs, 1H, NH). MS: m/z (%)
463 [M+] (9), 282 (25), 150 (11), 91 (100).
Ethyl-t-butyl-1,4-dihydro-2,6-dimethyl-4-[1-methyl-4,5-
dichloroimidazole-2-yl]-3,5-diicarboxylates 12f
IR (KBr): m cm– 1 3400 (NH), 1688, 1670 (CO). 1H-NMR (CDCl3): d =
1.1 (t, J = 7.2 Hz, 3H, OCH2CH3), 1.42 (s, 9H, tBu), 2.2 (s, 6H, C2,C6-
CH3), 3.9 (s, 3H, N-CH3), 4.12 (q, J = 7.2 Hz, 2H, OCH2CH3), 5.1 (s,
1H, H4-DHP), 9.9 (bs, 1H, NH). MS: m/z (%) 429 [M+] (18), 259 (73),
328 (40), 282 (100), 196 (4), 57 (90).
Ethylphenethyl-1,4-dihydro-2,6-dimethyl-4-(1-methyl-4,5-
dichloroimidazole-2-yl)-3,5-pyridine dicarboxylates 12g
IR (KBr): m cm– 1 3322 (NH), 1672, 1678 (CO). 1H-NMR (CDCl3): d =
1.35 (t, J = 7 Hz, 3H, CH2CH3), 2.14 (t, J = 7 Hz, 2H, CH2Ph), 2.25 (s,
6H, C2,C6-CH3), 3.66 (s, 3H, N-CH3), 4.10 (q, 2H, OCH2CH3), 4.35 (t, J
= 7 Hz, OCH2CH2-), 4.89 (s, 1H, H4-DHP), 7.1 (m, 5H, phenyl), 8.9
(bs, 1H, NH). MS: m/z (%) 475 [M+] (1), 401 (8), 328 (27), 282 (31),
150 (11), 106 (100).
Methylbenzyl-1,4-dihydro-2,6-dimethyl-4-(1-methyl-4,5-
dichloroimidazole-2-yl)-3,5-pyridine dicarboxylate 12h
IR (KBr): m cm– 1 3442 (NH), 1698, 1680 (CO). 1H-NMR (CDCl3): d =
2.21 (s, 6H, C2,C6-CH3), 3.80 (s, 3H, N-CH3), 3.85 (s, 3H, OMe), 5.01–
5.15 (m, 3H, H4-DHP and CH2 benzyl), 7.1–7.3 (m, 5H, phenyl),
9.99 (bs, 1H, NH), MS: m/z (%) 449 [M+] (9), 389 (72), 314 (21), 297
(27), 282 (49), 150 (100).
Statistical methods
Results are expressed as means lS.E. Comparing pIC50 values of
the compounds on isolated guinea pig ileum were performed
using one-way ANOVA following Dunnet test.
i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

556
M. Hosseini et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 549–556
[10] A. Shafiee, A. R. Dehpour, F. Hadizadeh, M. Azimi, Pharm.
Acta. Helv. 1998, 43, 75–79.
QSAR analysis
The chemical structure of the molecules was drawn by the
Hyperchem software (Hypercube Inc. version 7) into the personal
computer. Semi-empirical AM1 calculations were used for geo-
metry optimization of the molecules by the software. The multi-
linear regression equation was obtained by the stepwise variable
selection method of SPSS software (SPSS Inc., version 11).
[11] A. Davood, N. Mansouri, A. R. Dehpour, H. Shafaroudi, et
al., Arch. Pharm. Chem. 2006, 339, 299–304.
[12] B. Hemmateenejad, R. Miri, M. Akhond, M. Shamsipur,
ChemoLab 2002, 64, 91–99.
[13] B. Hemmateenejad, R. Miri, M. Akhond, M. Shamsipur,
Arch. Pharm. Pharm. Med. Chem. 2002, 335, 472–480.
[14] B. Hemmateenejad, M. Akhond, R. Miri, M. Shamsipur, J.
Chem. Inf. Comput. Sci. 2003, 43, 1328–1334.
References
[1] A. Fleckenstein, Ann. Rev. Pharmacol. Toxicol. 1977, 17,
[15] R. Miri, K. Javidnia, A. Kebriaie-Zadeh, H. Niknahad, et al.,
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 422–428.
149–166.
[2] S. Goldman, J. Stoltefub, Angew. Chem. Int. Ed. Engl. 1991,
30, 1559–1578.
[16] M. A. Safarpour, B. Hemmateenejad, R. Miri, M. Jamali,
QSAR Comb. Sci. 2004, 22, 997–1005.
[3] S. Tasaka, H. Ohmori, N. Gomi, M. Iino, et al., Bioorg. Med.
Chem. Lett. 2001, 11, 275–277.
[17] L. Navidpour, H. Shafaroodi, R. Miri, A. R. Dehpour, A.
Shafiee, Il Farmaco 2004, 59, 261–269.
[4] E. Arowsmith, S. F. Campbell, P. E. Cross, J. K. Stubbls, et
al., J. Med. Chem. 1986, 29, 1696–1702.
[18] B. Hemmateenejad, M. A. Safarpour, R. Miri, F. Taghavi, J.
Comput. Chem. 2004, 25, 1495–1503.
[5] M. R. Akula, W. C. Natowe, M. W. Wolowyk, E. E. Knaus,
[19] B. Hemmateenejad, R. Miri, M. A. Safarpour, M. Khoshne-
viszadeh, N. Edraki, J. Mol. Struct: Theochem. 2005, 717,
139–152.
Pharm. Res 1990, 7, 919–922.
[6] F. Pourmorad, F. Hadizade, A. Shafiee, Pharm. Sci. 1997, 3,
165–168.
[20] A. Hantzsch, Justus Liebigs Ann. Chem. 1882, 215, 1–82.
[7] M. Amini, A. Golabdhifar, A. R. Dehpour, M. Pirali Hame-
[21] H. Meyer, F. Boss, E. Wehinger, K. Stoeple, W. Vater, Arz-
neim. Forsch. 1981, 31, 407–409.
dani, A. Shafiee, Arzneim. Forsch. 2002, 51, 21–26.
[8] A. Shafiee, A. Davood, Gh. Khodarahimi, E. Alipour, et al.,
Boll. Chim. Farmac. 2001, 140, 381–386.
[22] R. J. Clemens, Chem. Rev. 1986, 86, 241–318.
[9] A. Shafiee, R. Miri, A. R. Dehpour, F. Soleymani, Pharm.
Sci. 1996, 2, 541–543.
[23] J. A. Hyatt, P. L. Feldman, R. J. Clemens, J. Org. Chem.
1984, 49, 5105–5108.
i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com