Design, synthesis, and calcium channel antagonist activity of new 1,4-dihydropyridines containing 4-(5)-chloro-2-ethyl-5-(4)-imidazolyl substituent

Article abstract of DOI:10.1002/ardp.200600013

A series of dialkyl, dicycloalkyl, and diaryl ester analogues of nifedipine, in which the ortho-nitro phenyl group at position 4 is replaced by the 4-(5)-chloro-2-ethyl-5-(4)-imidazolyl substituent, were synthesized and evaluated as calcium channel antago

Full text of DOI:10.1002/ardp.200600013

Arch. Pharm. Chem. Life Sci. 2006, 339, 299–304
A. Davood et al.
299
Full Paper
Design, Synthesis, and Calcium Channel Antagonist Activity of
New 1,4-Dihydropyridines Containing 4-(5)-Chloro-2-ethyl-5-
(4)-imidazolyl Substituent
Asghar Davood1, Niloufar Mansouri2, Ahmad Rerza Dehpour2, Hamed Shafaroudi3, Eskandar Ali-
pour4, and Abbas Shafiee5
1 Department of Medicinal Chemistry, Faculty of Pharmacy, Islamic Azad University, Tehran, Iran
2 Department of Pharmacology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
3 Department of Pharmacology, Faculty of Medicine, Islamic Azad University, Tehran, Iran
4 Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan,
Iran
5 Department of Medicinal Chemistry, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center,
Tehran University of Medical Sciences, Tehran, Iran
A series of dialkyl, dicycloalkyl, and diaryl ester analogues of nifedipine, in which the ortho-nitro
phenyl group at position 4 is replaced by the 4-(5)-chloro-2-ethyl-5-(4)-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 ester series showed
that increasing the length of the chain in C3- and C5-ester substituents increased the activity and
the most active compound was the diphenylethyl ester derivative, so it was more active than the
reference drug nifedipine. In unsymmetrical diester series, when R1 is methyl or ethyl, increa-
sing lipophilic properties in the R substituent, increased the activity. The most active com-
pounds were methyl/phenethyl and ethyl/phenethyl ester derivatives, being slightly more active
than nifedipine.
Keywords: Calcium channel blockers / Dihydropyridines / Chloroimidazole / Nifedipine analogues /
Received: January 18, 2006; accepted: February 7, 2006
DOI 10.1002/ardp.200600013
requirements is that the substituted aromatic ring occu-
pies an axial position perpendicularly bisecting the boat-
like DHP ring with the substituent in a syn-periplanar
orientation. A syn-cis-carbonyl ester orientation with
respect to the olefinic double bond is also needed for a
high activity [7, 8]. It is possible to replace the phenyl ring
on the C-4 position with some heterocyclic rings [9–11].
In previous studies we showed that a C-4 imidazolyl sub-
stituent was isosteric with a nitrophenyl substituent and
they were potent calcium channel blocker [12–15]. We
now describe the synthesis and calcium channel antago-
nist activity for DHPs containing a 4-[4-(5)-chloro-2-ethyl-
5-(4)-imidazolyl] moiety. For the selection of this moiety
in the 4 positions, the following reasons were consid-
ered:
Introduction
The development of 4-aryl-1,4-dihydropyridines (DHPs),
related to the first generation calcium antagonist nifedi-
pine, as therapeutic agents for the treatment of cardio-
vascular disorders [1, 2] has stimulated many structure-
activity relationship studies [3]. Changes in the substitu-
tion pattern at the C-3, C-4, and C-5 positions of nifedi-
pine alter potency [3], tissue selectivity [4, 5], and the con-
formation of the DHP ring [6]. One of the structural
Correspondence: A. Shafiee, PhD, Professor of Medicinal Chemistry,
Department of Medicinal Chemistry, Faculty of Pharmacy, and Pharma-
ceutical Sciences Research Center, Tehran University of Medical
Sciences, Tehran 14174, Iran.
E-mail: ashafiee@ams.ac.ir
Fax: +98 21 664-61178
a) substitution of chlorine instead of NO2 in the 4-aryl
ring produces active compounds [8]; b) a bulky substitu-
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300
A. Davood et al.
Arch. Pharm. Chem. Life Sci. 2006, 339, 299–304
Figure 1. COSMIC optimized geometric for lowest energy tau-
tomeric forms (A, B) of compound 4a.
ent in the 2- and 5-position of imidazole was tolerated by
the receptor [13–15]; c) considering the tautomeric
forms of the 2-ethyl-4-(5)-chloro-5-(4)-imidazolyl moiety,
both of the nitrogen atoms probably can interact with
the receptor via hydrogen bonding (donor, acceptor) and,
therefore, both tautomeric forms should be pharmacolo-
gically active. Our molecular modeling studies indicate
that the 4-chloro tautomer is the main form and is more
stable than the 5-chloro tautomer (Fig. 1). 4-H is syn-per-
pendicular and has good compatibility with the refer-
ence drug nifedipine. In addition, it has been shown that
4-aryl in DHPs have a lipophilic pocket in the DHP recep-
tor [16]. In order to adjust the lipophilic property of the
imidazole ring, ethyl and chloro groups were inserted in
the 2- and 4-(5) position of the imidazole ring, respec-
tively.
Results and discussion
The synthesis method used is represented in Scheme 1.
The compounds (1–5) were readily characterized by con-
ventional spectral and analytical data.
Scheme 1. Synthesis of new 1,4-dihydropyridines containing 4-
(5)-chloro- 2-ethyl-5-(4)-imidazolyl substituent.
The conformational study of compound 4a was done
by COSMIC molecular mechanics calculations and two
favored tautomers were found for this compound. They
were labeled as A when the imidazole substituent at C-4
lies in a 4-chloro tautomeric form and B when the imida-
zole substituent lies in a 5-chloro tautomeric form
(Fig. 1).
In both cases the DHP ring showed a twisted boat con-
formation and the imidazole ring occupies an axial posi-
tion perpendicularly bisecting the boat-like DHP ring.
The carbonyl ester orientation is syn-cis with respect to
the olefinic double bond. In the A-form 4-H is syn-perpen-
dicular (sp) but in B-form 4-H is anti-perpendicular (ap).
The energy of formation for the two possible tauto-
mers A and B was calculated. Tautomer A (10.101 kcal/
mol) was found to be about 1.1 kcal more stable than tau-
tomer B (11.221 kcal/mol). 4-H is syn-perpendicular and
had good compatibility with nifedipine. In addition, ab
initio calcalution at 298 K gives 1.73 kcal/mol for the
interconversion of tautomers A and B. Therefore, the two
possible tautomers are converted into each other at
room temperature.
The Ca2+ channel antagonist activities of 4a–l and 5a–
m determined as the contraction needed to produce 50%
inhibition of the guinea pig ileal longitudinal smooth
muscle contractility, are summarized in Table 1 (symme-
trical compounds) and Table 2 (unsymmetrical com-
pounds).
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Arch. Pharm. Chem. Life Sci. 2006, 339, 299–304
Calcium Channel Antagonist Activity
301
Table 1. Physical properties and calcium channel antagonist activity of symmetrical esters.
No
R
M. p. (08C)
Yield (%)
Formulaa)
Calcium channel
antagonist activity: IC50
b)
4a
4b
4c
4d
4e
4f
4g
4h
4i
CH3
CH2CH3
CH2CH2CH3
CH(CH3)2
CH2CH(CH3)CH3
C(CH3)3
Cyclopentyl
Cyclohexyl
Cyclohexylmethyl
Benzyl
Phenethyl
Phenpropyl
263–266
245–249
204–207
212–216
179–183
214–216
212–217
189–191
147–150
160–171
186–189
162–164
67
54
52
72
71
54
84
60
70
76
88
49
C16H20ClN3O4
C18H24ClN3O4
C20H28ClN3O4
C20H28ClN3O4
C22H32ClN3O4
C22H32ClN3O4
C24H32ClN3O4
C26H36ClN3O4
C28H40ClN3O4
C28H28ClN3O4
C30H32ClN3O4
C32H36ClN3O4
0.596 l 0.112
0.158 l 0.026
0.130 l 0.018
0.749 l 0.010
2.64 l 0.55
34.2 l 10.5
0.212 l 0.045
0.132 l 0.013
not tested
0.905 l 0.108
0.0437 l 0.0070
0.0668 l 0.0069
0.0582 l 0.0106
4j
4k
4l
Nifc)
a)
Microanalytical analyses were within l0.4% of theoretical values.
The nanomolar concentration of antagonist test compound causing a 50% rise in the tonic contractile response (IC50 l SEM) in
b)
guinea pig ileal smooth muscle by KCl (80 mM) was determined graphically from the dose-response curve. The number of experi-
ment was six for all compounds.
Nifedipine.
c)
The results reveal that the test compounds show a sig- ethyl and when the lipophilic property in the R substitu-
nificant calcium cannel antagonist activity in compari- ent is increased, this leads to increased activity if no
son to the reference drug nifedipine. Comparison of the steric hindrance occurs. Here again, t-butyl derivatives
activities of symmetrical esters in the alkyl ester series 5d and 5j have weak activities. In the unsymmetrical ser-
(Table 1, 4a–d) indicates that increasing the length of ies of esters, the results show that compound 5g and 5m
the chain in C3- and C5- ester substituents increase the are the most active compounds. They are slightly more
activity (4c A 4b A 4a). When increasing of the length active than the reference drug nifedipine.
accompanied by increasing the hindrance, the activity
decreases (4d–4f). In addition, the t-butyl ester (4f) is the
weakest compound in the dialkyl ester series. In the
cycloalkyl ester series 4g–i, cyclohexyl is more potent
than cyclopentyl. Comparison of the activity of phenyl
relative to the cycloalkyl substituent, namely 4g, 4h with
4j, 4k, 4l, shows that phenethyl and phenpropyl deriv-
atives are more active than cycloalkyl derivatives. Finally,
the results show that compound 4k is the most active
compound. The latter is more active than the reference
drug nifedipine. In addition, the activity of compound 4l
is comparable to nifedipine.
Experimental
General
Reagents and solvents were obtained from Merck (Darmstadt,
Germany). Melting points were determined using a Thomas
Hoover capillary apparatus (Philadelphia, PA, USA) and were
1
uncorrected. H-NMR and 13C-NMR spectra were recorded on a
Bruker FT-500 spectrometer (Bruker) and TMS was used as an
internal standard. Infrared spectra were acquired on a Nicolet
550-FT spectrometer (Nicolet, Madison, WI, USA). Mass spectra
were measured with a Finnigan TSQ-70 spectrometer (Thermo
Electron Company) at 70 eV. Elemental analysis was carried out
with a Perkin-Elmer model 240-C apparatus (Perkin-Elmer). The
A comparison of the activity of the unsymmetrical ser-
ies of esters (Table 2) shows that, when R1 is methyl or
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302
A. Davood et al.
Arch. Pharm. Chem. Life Sci. 2006, 339, 299–304
Table 2. Physical properties and calcium channel antagonist activity of symmetrical esters.
No
R1
R
M. p. (0C)
Yield
(%)
Formulaa)
Calcium channel
antagonist activity: IC50
b)
5a
5b
5c
5d
5e
5f
5g
5h
5i
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH2CH3
CH(CH3)2
C(CH3)3
Cyclohexylmethyl
Benzyl
Phenethyl
CH2CH2CH3
CH(CH3)2
C(CH3)3
Cyclohexylmethyl
Benzyl
236–239
211–214
233–238
238–242
147–152
127–130
177–180
227–231
217–221
207–210
204–206
207–209
153–157
61
52
42
46
24
52
50
50
48
50
12
18
26
C17H22ClN3O4
C18H24ClN3O4
C18H24ClN3O4
C19H26ClN3O4
C22H30ClN3O4
C22H24ClN3O4
C23H26ClN3O4
C19H26ClN3O4
C19H26ClN3O4
C20H28ClN3O4
C23H32ClN3O4
C23H26ClN3O4
C24H28ClN3O4
2.02 l 0.40
0.146 l 0.035
0.487 l 0.12
50.8 l 21.0
not tested
1.75 l 0.49
0.0309 l 0.0034
0.543 l 0.115
0.564 l 0.105
99.7 l 1.2
1.07 l 0.28
2.66 l 0.30
5j
5k
5l
5m
Phenethyl
0.0457 l 0.0074
0.0582 l 0.0106
Nif c
a)
Microanalytical analyses were within l0.4% of theoretical values.
The nanomolar concentration of antagonist test compound causing a 50% rise in the tonic contractile response ( IC50 l SEM) in
b)
guinea pig ileal smooth muscle by KCl (80 mM) was determined graphically from the dose-response curve. The number of experi-
ment was six for all compounds.
Nifedipine.
c)
results of elemental analysis (C, H, N) were within l0.4% of the
calculated amounts.
cake was boiled in acetone, filtered, and dried in the oven to give
a green copper complex of imidazole (45 g). A suspension of this
complex in 1.3 L water was treated with H2S gas for 3 h. The mix-
ture was filtered, washed with water, and decolorized with char-
coal to give a pale yellow solution. The solvent was removed
under reduced pressure and the oily residue (29 g, 52%) was crys-
tallized from acetone to give the title compound (25 g) as a white
Chemistry
Symmetrical 4a–l (Table 1) and unsymmetrical diesters 5a–m
(Table 2), analogues of nifedipine, were synthesized according to
Scheme 1. The symmetrical analogues were prepared by classi-
cal Hantzsch condensation [17], in which 4-(5)-chloro-2-ethylimi-
dazole-5-(4)-carboxaldehyde 3 was reacted with 3-oxobutanoic
acid ester and ammonium acetate. The unsymmetrical diesters
were synthesized according to a modified procedure reported by
Meyer et al. [18]. The compound 3 could be prepared in three
steps from propionaldehyde, dihydroxyacetone, and ammonia
[19, 20]. Methyl and ethyl 3-aminocrotonates [21] and some of
the 3-oxobuthanoic acid esters [21] were prepared according to
the literature.
1
crystals: m. p. 86–878C. IR (KBr): m cm– 1 3160 (OH). H-NMR
(DMSO-d6): d = 1.18 (t, J= 7.4 Hz, 3H, CH3), 2.61 (q, J = 7.4 Hz, 2H,
CH2), 4.34 (s, 2H, CH2OH), 4.54 (s, 1H, OH), 6.75 (s, 1H, imidazole).
Anal. Calcd. for C6H10N2O: C, 57.12; H, 7.99; N, 22.21, found C,
57.33; H, 7.75; N, 22.40.
5-(4)-Chloro-2-ethyl-4(5)hydroxymethylimidazole (2)
To a stirred solution of 1 (29.9 g, 0.237 mol) in 2-methoxyethanol
(133 mL) and 1,4-dioxane (133 mL) a solution of N-chlorosuccini-
mide (32.28 g, 0.237 mol) in 2-methoxyethanol (133 mL) and 1,4-
dioxane (133 mL) was added dropwise during 2 h. The mixture
was stirred in the dark at room temperature for 24 h. The sol-
vent was removed under reduced pressure and the residue was
dissolved in water (300 mL) and filtered. To the filtrate brine
(200 mL) was added and extracted with ethyl acetate
(36200 mL). The organic layer was washed with water (50 mL)
and brine (50 mL), dried (Na2SO4), and evaporated under reduced
2-Ethyl-4-(5)-hydroxymethylimidazole (1)
To a stirred solution of copper acetate(II)monohydrate (177.28 g,
0.88 mol) and propionaldehyde (63.7 mL, 0.87 mol) in concen-
trated ammonia (25%, 1.3 L), a solution of dihydroxyacetone
(40 g, 0.44 mol) in 25 mL water was added dropwise during
15 min and heated with stirring for 5 h. The mixture was cooled
in an ice bath, filtered, and washed with water three times. The
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Arch. Pharm. Chem. Life Sci. 2006, 339, 299–304
Calcium Channel Antagonist Activity
303
pressure to give a yellow solid. This was triturated twice with
CH2Cl2 to give the title compound as a white solid (21 g, 56%),
m.p. 130–1318C. IR (KBr): m cm– 1 3100 (OH). 1H-NMR (DMSO-d6): d
= 1.2 (t, 3H, CH3), 2.6 (q, 2H, CH2), 4.35 (d, 2H, CH2OH), 5.1 (t, 1H,
OH), 11.05 (s, 1H, NH). Anal. Calcd. for C6H9Cl N2O: C, 44.87; H,
5.65; N, 17.44, found C, 44.68; H, 5.80; N, 17.63.
146.57 (C2, C6, DHP), 141 (C1, phenyl), 128.85 (C4, imidazole and
C3, C5, phenyl), 128.76 (C2, C6, phenyl), 126.41 (C4, phenyl), 124.68
(C5, imidazole), 100.06 (C3, C5, DHP), 63.98 (–O–CH2), 32.71 (–CH2–
Ph), 31.69 (CH2, imidazole), 30.85 (–CH2–CH2–Ph), 22.24 (C4,
DHP), 19.76 (C2, C6-CH3, DHP), 12.43 (CH3, imidazole). MS: m/z (%)
561 [M+] (4), 526 (72), 398 (22), 261 (15), 195 (10), 119 (10), 118
(100), 50 (25). Anal. Calcd. for C32H36ClN3O4: C, 68.38; H, 6.46; N,
7.48; found C, 68.49; H, 6.62; N, 7.61.
5-(4)-Chloro-2-ethylimidazole-4(5)-carboxaldehyde (3)
A suspension of 2 (12.79 g, 0.079 mol) and manganese dioxide
(21.5 g, 0.24 mol) in CH2Cl2 (175 mL) and 1,4-dioxane (175 mL)
was heated at reflux for 9 h. The hot mixture was filtered and
washed with warm CHCl3. The solvent was removed under
reduced pressure. The residue was crystallized from CCl4 to give
the title compound (12.4 g, 98%) as white crystals: m.p. 107–
1108C. IR (KBr): m cm– 1 1670 (CO). 1H-NMR (CDCl3): d = 1.4 (t, 3H,
CH3), 2.9 (q, 2H, CH2), 9.65 (s, 1H, CHO), 11.45 (s, 1H, NH). Anal.
Calcd. for C6H7ClN2O: C, 45.44; H, 4.45; N, 17.66, found C, 45.29;
H, 4.27; N, 17.49.
Compounds 4a-4j was prepared similarly (Table 1).
General procedure for the preparation unsymmetrical
dialkyl-1,4-dihydro-2,6-dimethyl-4-[4-(5)-chloro-2-ethyl-
5-(4)-imidazolyl]-3,5-pyridinedicarboxylate (5a–5m)
A solution of compound 3 (0.2 g, 1.26 mmol), alkyl 3-aminocro-
tonate (0.16 g, 1.24 mmol) and alkyl 3-oxobutanoate (1.29 mmol)
in methanol (3 mL) was reflux for several hours. The reaction
mixture was purified with preparative TLC (silica gel, chloro-
form:methanol 20:1). The crude product was crystallized from
ether to give the desired compound.
General procedure for the preparation of dialkyl-1,4-
dihydro-2,6-dimethyl-4-[-4(5)-chloro-2-ethyl-5-(4)-
imidazolyl]-3,5-pyridinedicarboxylate (4a–4l)
A solution of compound 3 (0.3 g, 1.893 mmol), ammonium acet-
ate (0.14 g, 1.89 mmol) and alkyl 3-oxobutanoate (3.78 mmol) in
methanol (3 mL) was refluxed for several hours. The solvent was
removed under reduced pressure and the residue was crystal-
lized from ethyl acetate to give the title compound.
Methyl-phenethyl-1,4-dihydro-2,6-dimethyl-4-[4-(5)-
chloro-2-ethyl-5-(4)-imidazolyl]-3,5-pyridinedicarboxylate
(5g)
Using the general procedure, methyl 3-aminocrotonate and phe-
nethyl 3-oxobutanoate afford the title compound after 35 h
reflux: White crystals, yield 50%; m.p. 177–1808C (ether). IR
(KBr): m cm– 1 3339 (NH), 1711 (CO). 1H-NMR (CDCl3): d = 1.21 (t, J =
7.6 Hz, 3H, CH3-imidazole), 2.21 and 2.28 (2s, 6H, C2, C6-CH3,
DHP), 2.54 (q, J = 7.6 Hz, 2H, CH2-imidazole), 2.98 (m, 2H, CH2–
Ph), 3.72 (s, 3H, –O–CH3), 4.27 (m, 1H, –O–CH2–CH2–Ph), 4.38 (m,
1H, OCH2–CH2–Ph), 5.00 (s, 1H, H4–DHP), 6.80 (s, 1H, NH, DHP),
7.27 (m, 3H, phenyl), 7.35 (m, 2H, phenyl), 9.06 (s, 1H, NH-imida-
zole). 13C-NMR (CDCl3): d = 168.91 (C=O) 167.90 (CO), 146.38 and
146.31 (C2, C6, DHP), 146.12 (C2-imidazole), 138.84 (C1, phenyl),
129.33 (C4, imidazole), 129.26 (C3, C5, phenyl), 128.98 (C2, C6, phe-
nyl), 126.91 (C4, phenyl), 125.06 (C5, imidazole), 99.92 (C3, C5,
DHP), 64.86 (–O-CH2–), 51.55 (–O–CH3), 35.70 (–CH2–Ph), 31.53
(CH2-imidazole), 22.23 (C4-DHP), 19.66 and 19.61 (C2, C6, CH3-
DHP), 12.53 (CH3, imidazole). – MS: m/z (%), 443 (4), 408 (64), 294
(50), 210 (30), 165 (44), 104 (100), 91 (67), 77 (40), 56 (25), 42 (10).
Anal. Calcd. for C23H26ClN3O4: C, 62.23; H, 5.90; N, 9.47, found C,
62.47; H, 5.71; N, 9.21.
Diphenethyl-1,4-dihydro-2,6-dimethyl-4-[4-(5)-chloro-2-
ethyl-5-(4)-imidazolyl]-3,5-pyridinedicarboxylate (4k)
Using the general procedure and phenethyl 3-oxobutanoate pro-
vides the title compound after 31 h reflux: White crystals, yield
88%; m.p. 186–1898C (ethyl acetate). IR (KBr): m cm– 1 3411, 3263
1
(NH), 1690 (CO). H-NMR (CDCl3): d = 1.22 (t, J = 7.5 Hz, 3H, CH3,
imidazole), 2.17 (s, 6H, C2, C6-CH3), 2.50 (q, J = 7.55 Hz, 2H, CH2-
imidazole), 2.91 (t, J = 6.83 Hz, 4H, CH2-Ph), 4.26 (m, 2H, -O-CH2),
4.41 (m, 2H, -O-CH2), 4.95 (s, 1H, H4-DHP), 6.75 (s, 1H, NH, DHP),
7.28 (m, 6H, phenyl), 7.37 (m, 4H, phenyl), 9.05 (s, 1H, NH-imida-
zole). 13C-NMR (CDCl3): d = 168.67 (CO), 146.39 (C2, imidazole),
146.31 (C2, C6-DHP), 138.85 (C1, phenyl), 129.33 (C3, C5, phenyl),
129.27 (C4, imidazole), 128.99 (C2, C6, phenyl), 126.93 (C4, phe-
nyl), 125.07 (C5, imidazole), 99.93 (C3, C5, DHP), 64.86 (OCH2),
35.72 (CH2-Ph), 31.53 (CH2-imidazole), 22.23 (C4, DHP), 19.67 (C2,
C6-CH3, DHP), 12.54 (CH3, imidazole). MS: m/z (%) 533 [M+] (3), 498
(87), 426 (15), 384 (30), 376 (10), 318 (30), 262 (35), 255 (10), 196
(45), 130 (10), 104 (100), 79 (17). Anal. Calcd. for C30H32ClN3O4: C,
67.47; H, 6.04; N, 7.87, found C, 67.59; H, 6.25; N, 7.71.
Ethyl-phenethyl-1,4-dihydro-2,6-dimethyl-4-[4-(5)-chloro-
2-ethyl-5-(4)-imidazolyl]-3,5-pyridinedicarboxylate (5m)
Using the general procedure, ethyl 3-aminocrotonate and phe-
nethyl 3-oxobutanoate afford the title compound after 36 h
reflux: White crystals, yield 26%; m.p. 153–1578C (ether). IR
(KBr): m cm– 1 3345 (NH), 1701 (CO). 1H-NMR (CDCl3): d = 1.17 (m,
6H, CH3-imidazole-O–CH2–CH3), 2.19 and 2.24 (2s, 6H, C2, C6-
CH3,DHP), 2.55 (q, J = 7.55 Hz, 2H, CH3-CH2-imidazole), 2.96 (m,
2H, CH2-Ph), 4.14 (m, 2H, O-CH2-CH3), 4.26 (m, 1H, O–CH2–CH2–
Ph), 4.38 (m, 1H, –O–CH2–CH2–Ph), 5.00 (s, 1H, H4-DHP), 6.80 (s,
1H, NH-DHP), 7.27 (m, 3H, phenyl), 7.35 (m, 2H, phenyl), 9.10 (s,
1H, NH-imidazole). 13C-NMR (CDCl3): d = 168.40 (C=O), 167.89
(CO), 146.51 and 146.46 (C2, C6-DHP), 146.21 (C2-imidazole),
139.01 (C1, phenyl), 129.35 (C4-imidazole), 129.20 (C3, C5 phenyl),
128.98 (C2, C6 phenyl), 126.89 (C4, phenyl), 125.12 (C5-imidazole),
99.89 and 99.72 (C3, C4, DHP), 64.59 (-O-CH2-) 59.75 (–O–CH2–CH3),
35.73 (O–CH2–CH2–Ph) 31.43 (CH2-imidazole), 22.19 (C4-DHP),
Diphenpropyl-1,4-dihydro-2,6-dimethyl-4-[4-(5)-chloro-2-
ethyl-5-(4)-imidazolyl]-3,5-pyridinedicarboxylate (4l)
Using the general procedure and phenpropyl 3-oxobutanoate
provides the title compound after 30 h reflux: White crystals,
yield 49%; m.p. 162–1648C (ethyl acetate). IR (KBr): m cm– 1 3411,
3263 (NH), 1696 (CO). 1H-NMR (CDCl3 + DMSO-d6): d = 1.20 (t, J =
7.62 Hz, 3H, CH3, imidazole), 2.01 (m, 4H, CH2–CH2–Ph), 2.29 (s,
6H, C2, C6-CH3, DHP), 2.58 (q, J = 7.6 Hz, 2H, CH2-imidazole), 2.68
(t, J = 7.4 Hz, 4H, CH2-Ph), 4.17 (m, 4H, –O–CH2), 5.13 (s, 1H, H4-
DHP), 7.17 (d, J = 7.28 Hz, 4H, H2,6-phenyl), 7.21 (m, 3H, 4-H, phe-
nyl, NH-DHP), 7.30 (t, J = 7.28 Hz, 4H, H3,5), 9.77 (s, 1H, NH-imida-
zole). 13C-NMR (CDCl3): d = 168.34 (C=O), 146.61 (C2, imidazole),
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304
A. Davood et al.
Arch. Pharm. Chem. Life Sci. 2006, 339, 299–304
19.59 and 19.39 (C2, C6–CH3–DHP), 12.36 (O–CH2–CH3), 12.49 (CH3-
imidazole). MS: m/z (%) 457 [M+] (4), 408 (64), 294 (50), 210 (30),
165 (44), 104 (100), 91 (67), 77(40), 56 (25), 42 (10). Anal. Calcd. for
C24H28ClN3O4: C, 62.95; H, 6.16; N, 9.18, found C, 62.63; H, 6.47;
N, 9.50.
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www.archpharm.com