Synthesis and calcium channel antagonist activity of new symmetrical and asymmetrical 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]- substituted 1,4-dihydropyridines

Article abstract of DOI:10.1007/s10593-011-0672-9

New symmetrical 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl] -substituted 1,4-di-hydropyridines were synthesized in moderate to good yields via the modified Hantzsch reaction of β-dicarbonyl compounds with (Z)-3-chloro-3-(4-chloro-6-methyl-

Full text of DOI:10.1007/s10593-011-0672-9

Chemistry of Heterocyclic Compounds, Vol. 46, No. 11, February, 2011 (Russian Original Vol. 46, No. 11, November, 2010)
SYNTHESIS AND CALCIUM CHANNEL ANTAGONIST
ACTIVITY OF NEW SYMMETRICAL AND ASYMMETRICAL
4-[2-CHLORO-2-(4-CHLORO-6-METHYL-2-OXO-2H-PYRAN-
3-YL)VINYL]-SUBSTITUTED 1,4-DIHYDROPYRIDINES
A. Shahrisa1*, M. Zirak1, A. R. Mehdipour2, R. Miri2
New symmetrical 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-substituted 1,4-di-
hydropyridines were synthesized in moderate to good yields via the modified Hantzsch reaction of
β-dicarbonyl compounds with (Z)-3-chloro-3-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)acrolein in the
presence of an excess amount of NH4OAc. Also, the reaction of β-dicarbonyl compounds with
(Z)-3-chloro-3-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)acrolein in the presence of enamino esters and
ketones was performed, and asymmetrical 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-
3-yl)vinyl]-substituted 1,4-dihydropyridines were obtained in moderate to good yields at room
temperature. The calcium channel blocking activity of these compounds was assessed. They
demonstrated moderate to weak effects, although one compound had a comparable effect
(IC50 =1.40×10-7 M) with respect to the reference drug Nifedipine.
Keywords: calcium channel antagonist, dihydropyridines, 2-pyrone derivatives, Hantzsch reaction.
The 4-aryl-substituted 1,4-dihydropyridines (1,4-DHPs) are among the most studied heterocyclic
compounds that present interesting pharmacological and biological properties [1-4]. They have been used as
organic calcium channel modulators [5-7], anticonvulsant [8], antidiabetic [9], antiviral [10], radioprotective
[11], antitumor [12], antioxidant [13], vasodilator [14], and anti-inflammatory agents [15]. It was proposed that
calcium channel modulation depends on the absolute configuration at C-4 and flexibility of both the ester group
of 1,4-DHPs and the C-4 aryl group of these compounds [16, 17]. Therefore, the development of new synthetic
methods leading to 1,4-DHPs with different substituents [18−20] or heterocycles [21-27] has attracted much
attention in organic synthesis. The Hantzsch synthesis is a classical method for the preparation of 1,4-DHPs [28]
and has been one of the most important basic reactions in organic chemistry for its use in pharmaceutical
synthesis. However, due to the drastic reaction conditions, long reaction times, and low yields, the classical
Hantzsch reaction was modified by several methods [29].
_______
*To whom correspondence should be addressed, e-mail: ashahrisa@yahoo.com.
1Department of Organic and Biochemistry, Faculty of Chemistry, University of Tabriz, Tabriz, Iran.
2Medicinal & Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1670-1680, November, 2010.
Original article received February 08, 2010.
1354
0009-3122/11/4611-1354©2011 Springer Science+Business Media, Inc.

On the other hand, 2H-pyran-2-ones and their analogues have been found to exhibit a wide range of
biological activities [30]. Due to the biological importance of 1,4-DHPs and pyrone derivatives, and as a
continuation of our work on the synthesis of new pyrone derivatives [31, 32], herein we report the synthesis of
4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-substituted 1,4-DHPs. The calcium channel
blocking activities of these compounds were also investigated.
The symmetrical 1,4-DHPs were synthesized by the modified Hantzsch reaction, which involves
condensation of an aldehyde, a β-dicarbonyl compound, and ammonium acetate. The asymmetrical 1,4-DHPs
were also obtained by the modified Hantzsch reaction, using an aldehyde, β-dicarbonyl compounds, and
enaminones.
Starting from commercially available 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one (dehydroacetic
acid) (1), (Z)-3-chloro-3-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)acrolein (2) was synthesized using the
Vilsmeier–Haack reaction [33] (Scheme 1).
Scheme 1
OH
O
Cl
H
O
CHO
POCl3, DMF
Me
Me
r.t.
45°C
69.4%
O
O
Me
Cl
O
2
1
Six examples of the conversion of aldehyde 2 to various 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-
2H-pyran-3-yl)vinyl]-substituted 1,4-DHPs 4a-f are listed in Table 1. The reactions were performed by adding
aldehyde 2 to a mixture of 2 eq. of β-dicarbonyl compounds 3a-f in ethanol in the presence of an excess amount
of NH4OAc at room temperature (Scheme 2). The reactions were completed within 0.5-1 h, and 1,4-DHPs 4a-f
1
were obtained in 39-61% yields. The structures of compounds 4a-f were established from FT-IR, H NMR,
13C NMR, mass spectra, and elemental analyses.
Scheme 2
Me
O
O
Cl
H
O
NH4OAc
R1
CO
2
+
Cl
R
COR1
R
EtOH, r. t.
R1OC
3a–f
N
H
R
4a–f
3,4 a-c R = Me, a R1 = OMe, b R1 = OEt, c R1 = OBu-t;
d R = n-Pr, R1 = OEt; e, f R = Me, e R1 = Me, f R1 = Ph
Also, the reaction of aldehyde 2 with β-dicarbonyl compounds 3b-g in the presence of enamino esters
and ketones such as methyl 3-aminobut-2-enoate 5a, 4-aminopent-3-en-2-one 5b, and 3-amino-1-phenylbut-
2-en-1-one 5c was investigated and unsymmetrical 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-
3-yl)vinyl]-substituted 1,4-DHPs 6a-l were obtained in 21-46% yields (Scheme 3). The results are summarized
1
in Table 2. The structure of compounds 6a-l were established using FT-IR, H NMR, and 13C NMR spectra,
mass spectral data, and elemental analyses.
1355

TABLE 1. Reaction Conditions and Yields of 1,4-DHPs 4a-f
Entry
β-Dicarbonyl compound
Time, h
Product
Yield, %*
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
0.5
0.5
0.5
0.5
1
4a
4b
4c
4d
4e
4f
55
61
50
47
39
41
1
_______
* Yields refer to isolated products.
Scheme 3
Me
O
O
Cl
H
NH2
EtOH, r.t.
R2
CO
2
3b–g
+
+
Cl
Me
R1OC
5a–c
COR2
Me
N
R
H
6a–l
3g R = R1 = -CH2CMe2CH2-; 5 a R2 = OMe, b R2 = Me, c R2 = Ph;
6 a–f R2 = OMe, a R = Me, R1 = OEt, b R = Me, R1 = OBu-t; c R = n-Pr, R1 = OEt,
d R = R1 = Me, e R = Me, R1 = Ph, f R = R1 = -CH2CMe2CH2-; g-i R2 = Me, g R = Me,
R1 = OEt, h R = Me, R1 = OBu-t, i R = n-Pr, R1 = OEt; j-l R2 = Ph, j R = Me, R1 = OEt,
k R = Me, R1 = OBu-t, l R = n-Pr, R1 = OEt
TABLE 2. Reaction Conditions and Yields of 1,4-DHPs 6a-l
β-Dicarbonyl
compound
Entry
Enamine
Time, h
Product
Yield, %*
1
3b
3c
3d
3e
3f
5a
5a
5a
5a
5a
5a
5b
5b
5b
5c
5c
5c
3
6a
6b
6c
6d
6e
6f
45
41
46
41
38
36
32
26
32
23
21
21
2
5
3
5
4
12
12
2
5
6
3g
3b
3c
3d
3b
3c
3d
7
24
24
24
24
24
24
6g
6h
6i
8
9
10
11
12
6j
6k
6l
_______
* Yields refer to isolated products.
1356

TABLE 3. Calcium Channel Modulator Activity of Newly Synthesized
Compounds in Ileum of Guinea pigs
Compound
MW
(Mean ± S.E.*) IC50
(Mean ± S.E.) IC30
N
4a
428
456
512
512
396
520
442
470
470
412
474
452
426
454
454
488
516
516
346
(1.47± 0.78)×10-5
(1.35±1.27)×10-5
(1.40±0.28)×10-7
(9.40±2.48)×10-7
(4.00±2.00)×10-4
(5.81±1.53)×10-6
(8.28±1.04)×10-6
(2.28±1.37)×10-5
(3.15±1.43)×10-5
(3.00±0.20)×10-4
(2.51±0.20)×10-6
(3.46± 2.33)×10-6
(1.78±0.78)×10-6
(2.00±1.84)×10-4
(2.09±1.89)×10-6
(3.30±1.29)×10-6
(2.33±0.89)×10-6
(2.69±0.28)×10-5
(6.89±0.90)×10-8
(3.54±1.62)×10-6
(9.38±7.36)×10-7
(4.74±0.84)×10-9
(3.65±1.07)×10-7
(7.58±0.12)×10-6
(1.55±0.47)×10-6
(2.64±0.30)×10-6
(5.40±1.91)×10-6
(7.22±1.52)×10-6
(3.90±0.36)×10-5
(1.61±0.61)×10-7
(7.82±1.99)×10-7
(4.15±2.43)×10-7
(8.73±1.87)×10-7
(9.58±0.95)×10-7
(1.19±0.92)×10-6
(8.93±1.47)×10-7
(6.49±1.09)×10-6
(1.59±0.67)×10-8
3
4
4
4
4
4
4
4
4
4
3
4
4
4
4
4
4
4
3
4b
4c
4d
4e
4f
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
Nifedipine
_______
* S.E. - standard error.
The in vitro calcium channel antagonist activities (IC30 and IC50) of 18 compounds were determined as
the molar concentration of the test compounds required to produce 30% or 50% inhibition of guinea pig
longitudinal ileal smooth muscle (GPLISM). Results are summarized in the Table 3. These compounds
demonstrated moderate to weak calcium channel antagonist activity (10-5 to 10-7 M range) relative to the
reference drug Nifedipine (IC50 = 6.89×10-8 M). As seen in Table 3, the highest activity belongs to compound
4c, which is nearly 2 times weaker than Nifedipine as the reference drug, although, in the case of IC30, 4c
showed a lower value (IC30 = 4.74×10-9 M), which means that this compound has higher calcium channel
antagonist activity in a lower concentration compared to Nifedipine. On the other hand, 6d demonstrated the
least activity (IC50 = 3.00×10-4 M, IC30= 3.90×10-5 M), which is much lower than other compounds, and, in
addition, is nearly 1000 times weaker in comparison of Nifedipine. Furthermore, 4e and 6h have also weak
activity, similar to 6d. The interesting point about these compounds is the presence of the carbonyl group in one
or both sides in positions 3,5 instead of the carboxylate group. This is consistent with previous studies, which
showed the decreasing effect of the carbonyl group [34, 35].
In summary, new symmetrical and unsymmetrical 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-
yl)vinyl]-substituted 1,4-DHPs were synthesized in moderate to good yields via the modified Hantzsch reaction
of β-dicarbonyl compounds with (Z)-3-chloro-3-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)acrolein in the presence
of an excess amount of NH4OAc and enamino esters or ketones respectively.
The calcium channel blocking activity of these compounds was evaluated. They demonstrated moderate
to weak effects, although one compound, 4c, had an effect (IC50 = 1.40×10-7 M) comparable to the reference
drug nifedipine. Some derivatives, however, exhibited very weak activity (4e, 6d, and 6h), which may be
attributed to the conversion of the carboxylate group into the carbonyl moiety in positions 3 and 5.
1357

EXPERIMENTAL
All chemicals were purchased and used without any further purification. Melting points were determined
on a Electrothermal MEL-TEMP apparatus (model 1202D) and are uncorrected. FT-IR spectra were obtained
with a Bruker Tensor 27 spectrometer in KBr. NMR spectra were recorded with a Bruker spectrometer operating
at 400 or 500 MHz for protons and at 100 or 125 MHz for carbon nuclei. TMS was used as an internal standard.
1H and 13C NMR spectra were recorded for compounds 4a-f, 6a-c (at 400 and 100 MHz respectively in CDCl3),
6d, 6e, 6g-l (at 500 and 125 MHz respectively in CDCl3), and 6f (at 500 and 125 MHz respectively in
CDCl3/DMSO-d6). Mass spectra were taken with a Shimadzu (70 eV) mass spectrometer. Elemental analyses
were done on an Elementar Vario EL III instrument. The products were purified by PLC on silica gel using
hexane–acetone mixture as eluent.
Synthesis of Symmetrical 1,4-DHPs (General Method). To a solution of compound 2 (1 mmol) in
ethanol (3 ml), β-dicarbonyl compound (2 mmol) and NH4OAc (excess amount) were added successively at
room temperature (20-25°C), and the mixture was stirred for the appropriate time (0.5-1 h). After completion of
the reaction, ethanol was evaporated under reduced pressure. The crude mixture was purified by PLC on silica
gel using hexane–acetone, 4:1, to afford the final product.
Dimethyl
4-[(Z)-2-Chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-2,6-dimethyl-1,4-di-
hydropyridine-3,5-dicarboxylate (4a). Pale-yellow solid, 55% yield; mp 182-184°C. FT-IR, , cm-1: 3303
(NH), 3093, 2989, 2941, 2842, 1732, 1694, 1625, 1550, 1496, 1295, 1108, 850, 776, 737. 1H NMR spectrum, δ,
ppm (J, Hz): 6.06 (1H, d, 4J = 0.8, CH α-pyrone); 5.72 (1H, s, NH); 5.60 (1H, d, 3J = 9.7, CH vinyl); 5.06 (1H,
d, 3J = 9.7, CH dihydropyridine); 3.74 (6H, s, OCH3); 2.27 (6H, s, CH3 dihydropyridine); 2.22 (3H, d, 4J = 0.4,
CH3 α-pyrone). 13C NMR spectrum, δ, ppm: 166.8, 160.4, 158.3, 148.3, 144.4, 134.2, 120.9, 118.5, 105.4, 99.1,
50.0, 33.8, 18.7, 18.1. Mass spectrum (EI), m/z (Irel, %): 427 [M]+ (15), [M+2]+ (9); 392 (85), 368 (87), 300 (65),
224 (100). Found, %: C 52.91; H 4.63; N 3.30. C19H19Cl2NO6. Calculated, %: C 53.29; H 4.47; N 3.27.
Diethyl 4-[(Z)-2-Chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-2,6-dimethyl-1,4-dihydro-
pyridine-3,5-dicarboxylate (4b). Pale-yellow solid, 61% yield; mp 76-78°C. FT-IR, , cm-1: 3340 (NH), 3095,
2974, 1739, 1694, 1626, 1550, 1487, 1207, 1101, 794, 739. 1H NMR spectrum, δ, ppm (J, Hz): 6.06 (1H, s, CH
3
3
α-pyrone); 5.90 (1H, s, NH); 5.59 (1H, d, J = 9.7, CH vinyl); 5.05 (1H, d, J = 9.7, CH dihydropyridine);
4.14-4.23 (4H, m, CH2 ethyl); 2.27 (6H, s, CH3 dihydropyridine); 2.21 (3H, s, CH3 α-pyrone); 1.32 (6H, t,
13
3J = 7.1, CH3 ethyl). C NMR spectrum, δ, ppm: 166.4, 160.3, 158.3, 148.3, 144.5, 134.1, 120.9, 117.8, 105.4,
99.1, 58.9, 33.4, 18.6, 18.1, 13.4. Mass spectrum (EI), m/z (Irel, %): 455 [M]+ (75), [M+2]+ (35); 43 (100).
Found, %: C 55.11; H 5.16; N 3.13. C21H23Cl2NO6. Calculated, %: C 55.27; H 5.08; N 3.07.
Di-tert-butyl 4-[(Z)-2-Chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-2,6-dimethy-1,4-di-
hydrolpyridine-3,5-dicarboxylate (4c). Pale-yellow solid, 50% yield; mp 208-210°C. FT-IR, , cm-1: 3332
(NH), 3095, 2974, 2928, 1739, 1690, 1647, 1554, 1486, 1232, 1161, 1110, 856, 777, 743. 1H NMR spectrum, δ,
3
ppm (J, Hz): 6.05 (1H, s, CH α-pyrone); 5.60 (1H, s, NH); 5.59 (1H, d, J = 9.6, CH vinyl); 5.07 (1H, d,
3J = 9.6, CH dihydropyridine); 2.23 (6H, s, CH3 dihydropyridine); 2.21 (3H, s, CH3 α-pyrone); 1.52 (18H, s, CH3
tert-butyl). 13C NMR spectrum, δ, ppm: 165.8, 160.3, 158.2, 148.2, 143.1, 134.6, 121.0, 117.5, 105.4, 100.7,
79.0, 33.8, 27.3, 18.7, 18.2. Mass spectrum (EI), m/z (Irel, %): 511 [M]+ (20), [M+2]+ (17); 454 (25), 196 (100).
Found, %: C 58.33; H 6.16; N 2.88. C25H31Cl2NO6. Calculated, %: C 58.60; H 6.10; N 2.73.
Diethyl 4-[(Z)-2-Chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-2,6-dipropyl-1,4-dihydro-
pyridine-3,5-dicarboxylate (4d). Pale-yellow solid, 47% yield; mp 136-138°C. FT-IR, , cm-1: 3340 (NH),
3098, 2966, 2932, 2870, 1717, 1692, 1635, 1559, 1488, 1366, 1278, 1110, 769, 719. 1H NMR spectrum, δ, ppm
4
3
(J, Hz): 6.05 (1H, d, J = 0.7, CH α-pyrone); 5.72 (1H, s, NH); 5.57 (1H, d, J = 9.7, CH vinyl); 5.09 (1H, d,
3J =9.7, CH dihydropyridine); 4.12-4.24 (4H, m, CH2CH3); 2.72-2.80 (2H, m, CH2 propyl); 2.48-2.55 (2H, m,
CH2 propyl); 2.21 (3H, s, CH3 α-pyrone); 1.51-1.63 (4H, m, CH2 propyl); 1.33 (6H, t, J = 7.1, CH2CH3); 0.95
3
1358

(6H, t, 3J = 7.3, CH3 propyl). 13C NMR spectrum, δ, ppm: 165.9, 160.3, 158.2, 148.7, 148.2, 133.9, 120.9, 117.8,
105.4, 98.9, 58.9, 33.5, 33.1, 20.8, 18.7, 13.4, 12.8. Mass spectrum (EI), m/z (Irel, %): 511 [M]+ (55), [M+2]+
(40), [M+4]+ (10); 476 (90), 308 (100). Found: C 58.53; H 6.17; N 2.84. C25H31Cl2NO6. Calculated, %: C 58.60;
H 6.10; N 2.73.
4-Chloro-3-[(Z)-1-chloro-2-(3,5-diacetyl-2,6-dimethyl-1,4-dihydropyridin-4-yl)ethenyl]-6-methyl-
2H-pyran-2-one (4e). Yellow solid, 39% yield; mp 208-210°C. FT-IR, , cm-1: 3336 (NH), 3092, 2990, 2925,
1718, 1660, 1627, 1588, 1555, 1464, 1357, 1220, 781, 748, 714. 1H NMR spectrum, δ, ppm (J, Hz): 6.44 (1H, s,
3
3
NH); 6.10 (1H, s, CH α-pyrone); 5.65 (1H, d, J = 9.8, CH vinyl); 4.93 (1H, d, J = 9.8, CH dihydropyridine);
2.43 (6H, s, CH3 acetyl); 2.26 (6H, s, CH3); 2.24 (3H, s, CH3). 13C NMR, δ, ppm: 197.1 (C=O ketone), 160.9,
158.3, 149.1, 144.0, 133.5, 120.1, 117.2, 107.9, 105.5, 35.1, 29.0, 18.9, 18.7. Mass spectrum (EI), m/z (Irel, %):
396 [M+H]+ (15), [M+H+2]+ (7); 360 (90), 316 (80), 43 (100). Found, %: C 57.25; H 4.66; N 3.77.
C19H19Cl2NO4. Calculated, %: C 57.59; H 4.83; N 3.53.
4-Chloro-3-[(Z)-1-chloro-2-(3,5-dibenzoyl-2,6-dimethyl-1,4-dihydropyridin-4-yl)ethenyl]-6-methyl-
2H-pyran-2-one (4f). Yellow solid, 41% yield; mp 190-192°C. FT-IR, , cm-1: 3306 (NH), 3058, 2963, 2923,
1
1735, 1694, 1626, 1549, 1478, 1230, 855, 730, 700. H NMR spectrum, δ, ppm (J, Hz): 7.71-7.73 (4H, m,
CH Ph); 7.36-7.43 (6H, m, CH Ph); 6.20 (1H, s, NH); 6.02 (1H, d, 4J = 0.5, CH α-pyrone); 5.74 (1H, d, 3J = 9.2,
CH vinyl); 5.06 (1H, d, 3J = 9.2, CH dihydropyridine); 2.19 (3H, s, CH3 α-pyrone ); 2.01 (6H, s, CH3). 13C NMR
spectrum, δ, ppm: 196.5 (C=O ketone), 160.5, 158.2, 148.7, 141.3, 138.8, 134.4, 130.5, 127.4, 127.3, 120.1,
118.9, 108.6, 105.4, 37.8, 18.7, 17.8. Mass spectrum (EI), m/z (Irel, %): 520 [M+H]+ (20), [M+H+2]+ (12); 77
(100). Found, %: C 66.63; H 4.57; N 2.60. C29H23Cl2NO4. Calculated, %: C 66.93; H 4.45; N 2.69.
Synthesis of Asymmetrical 1,4-DHPs (General Method). To a solution of compound 2 (1 mmol) in
ethanol (3 ml), enamino ester or ketone (1 mmol), and β-dicarbonyl (1 mmol) were added successively at room
temperature (20-25°C), and the mixture was stirred for the appropriate time. After completion of the reaction,
ethanol was evaporated under reduced pressure. The crude mixture was purified by PLC on silica gel using
hexane–acetone, 5:1, to afford the final product.
(Z)-3-Ethyl 5-Methyl 4-[2-Chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-2,6-dimethyl-
1,4-dihydropyridine-3,5-dicarboxylate (6a). Pale-yellow solid, 45% yield; mp 60-62°C. FT-IR, , cm-1: 3335
(NH), 3095, 2983, 2946, 1736, 1695, 1626, 1550, 1491, 1303, 1241, 1105, 858, 777, 738. 1H NMR spectrum, δ,
3
ppm (J, Hz): 6.06 (1H, s, CH α-pyrone); 6.01 (1H, s, NH); 5.59 (1H, d, J = 9.6, CH vinyl); 5.04 (1H, d,
3J = 9.6, CH dihydropyridine); 4.16-4.21 (2H, m, CH2 ethyl); 3.72 (3H, s, OCH3); 2.25 (6H, s, CH3); 2.21 (3H, s,
CH3 α-pyrone); 1.32 (3H, t, 3J = 6.8, CH3 ethyl). 13C NMR spectrum, δ, ppm: 166.8, 166.4, 160.3, 158.3, 148.3,
144.7, 144.5, 134.2, 120.9, 118.1, 105.4, 99.2, 98.7, 58.9, 49.9, 33.6, 18.6, 18.0, 17.9, 13.4. Mass spectrum (EI),
m/z (Irel, %): 441 [M]+ (37), [M+2]+ (26), [M+4]+ (12), 406 (80), 368 (80), 43 (100). Found, %: C 54.01; H 4.73;
N 3.34. C20H21Cl2NO6. Calculated, %: C 54.31; H 4.79; N 3.17.
(Z)-3-tert-Butyl 5-Methyl 4-[2-Chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-2,6-dimethyl-
1,4-dihydropyridine-3,5-dicarboxylate (6b). Pale-yellow solid, 41% yield; mp 80-82°C. FT-IR, , cm-1: 3326
1
(NH), 3095, 2973, 1737, 1689, 1624, 1554, 1492, 1308, 1221, 1107, 855, 781, 740. H NMR spectrum, δ, ppm
(J, Hz): 6.08 (1H, s, CH α-pyrone); 5.75 (1H, s, NH); 5.61 (1H, d, 3J = 9.6, CH vinyl); 5.04 (1H, d, 3J = 9.6, CH
dihydropyridine); 3.75 (3H, s, OCH3); 2.28 (3H, s, CH3); 2.24 (3H, s, CH3); 2.23 (3H, s, CH3 α-pyrone); 1.54
(9H, s, CH3 tert-butyl). 13C NMR spectrum, δ, ppm: 166.9, 165.8, 160.3, 158.3, 148.3, 144.7, 142.9, 134.4,
120.9, 117.9, 105.4, 101.1, 98.6, 79.3, 49.9, 33.7, 27.4, 18.7, 18.3, 18.2. Mass spectrum (EI), m/z (Irel, %): 469
[M]+ (15), [M+2]+ (10), 412 (80), 368 (85), 267 (80), 210 (100). Found, %: C 56.01; H 5.53; N 3.22.
C22H25Cl2NO6. Calculated, %: C 56.18; H 5.36; N 2.98.
(Z)-3-Ethyl 5-Methyl 4-[2-Chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-6-methyl-
2-propyl-1,4-dihydropyridine-3,5-dicarboxylate (6c). Pale-yellow solid, 46% yield; mp 52-54°C; FT-IR, ,
1
cm-1: 3340 (NH), 3095, 2961, 2871, 1737, 1695, 1627, 1550, 1490, 1300, 1201, 1106, 859, 777. H NMR, δ,
3
ppm (J, Hz): 6.08 (1H, s, CH α-pyrone); 5.76 (1H, s, NH); 5.60 (1H, d, J = 9.7, CH vinyl); 5.08 (1H, d,
1359

3J = 9.7, CH dihydropyridine); 4.16-4.25 (2H, m, CH2 ethyl); 3.76 (3H, s, OCH3); 2.60-2.68 (2H, m, CH2
propyl); 2.29 (3H, s, CH3); 2.23 (3H, s, CH3); 1.55-1.63 (2H, m, CH2 propyl); 1.34 (3H, t, 3J = 7.1, CH3 ethyl);
3
13
0.97 (3H, t, J = 7.3, CH3 propyl). C NMR spectrum, δ, ppm: 166.8, 165.9, 160.3, 158.3, 148.5, 148.3, 144.6,
134.1, 120.9, 118.2, 105.4, 99.1, 98.7, 58.9, 50.0, 33.6, 33.1, 20.8, 18.7, 18.1, 13.4, 12.8. Mass spectrum (EI),
m/z (Irel, %): 468 [M-H]+ (35), [M-H+2]+ (30), [M-H+4]+ (7), 432 (85), 372 (85), 266 (80), 165 (85), 43 (100).
Found, %: C 56.13; H 5.74; N 3.04. C22H25Cl2NO6. Calculated, %: C 56.18; H 5.36; N 2.98.
(Z)-Methyl 5-Acetyl-4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-2,6-dimethyl-1,4-di-
hydropyridine-3-carboxylate (6d). Yellow solid, 41% yield; mp 94-96°C; FT-IR, , cm-1: 3313 (NH), 3084,
2998, 2944, 1725, 1696, 1671, 1629, 1550, 1488, 1304, 1211, 850, 750. 1H NMR spectrum, δ, ppm (J, Hz): 6.12
3
3
(1H, s, CH α-pyrone); 6.02 (1H, s, NH); 5.67 (1H, d, J = 9.7, CH vinyl); 5.04 (1H, d, J = 9.7, CH
dihydropyridine); 3.80 (3H, s, OCH3); 2.43 (3H, s, CH3 acetyl); 2.32 (3H, s, CH3 α-pyrone); 2.27 (6H, s, CH3).
13C NMR spectrum, δ, ppm: 199.4 (C=O ketone), 167.9, 162.2, 159.8, 150.2, 146.0, 145.3, 135.2, 122.0, 119.4,
108.7, 106.9, 100.8, 51.6, 35.9, 30.2, 20.6, 20.2, 19.5. Mass spectrum (EI), m/z (Irel, %): 411 [M]+ (35), [M+2]+
(26), 208 (100). Found, %: C 55.30; H 4.88; N 3.55. C19H19Cl2NO5. Calculated, %: C 55.35; H 4.65; N 3.40.
(Z)-Methyl 5-Benzoyl-4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-2,6-dimethyl-
1,4-dihydropyridine-3-carboxylate (6e). Yellow solid, 38% yield; mp 180-182°C. FT-IR, , cm-1: 3290 (NH),
3085, 2996, 2949, 1732, 1703, 1632, 1598, 1554, 1434, 1300, 1224, 1052, 857, 777, 746. 1H NMR spectrum, δ,
ppm (J, Hz): 7.79 (2H, d, 3J = 7.4, CH Ph); 7.50-7.53 (1H, m, CH Ph); 7.43-7.46 (2H, m, CH Ph); 6.08 (1H, s,
3
3
CH α-pyrone); 5.91 (1H, s, NH); 5.72 (1H, d, J = 9.4, CH vinyl); 5.18 (1H, d, J = 9.4, CH dihydropyridine);
3.73 (3H, s, OCH3); 2.37 (3H, s, CH3); 2.24 (3H, s, CH3); 1.91 (3H, s, CH3). 13C NMR spectrum, δ, ppm: 198.1
(C=O ketone), 168.2, 161.9, 159.7, 149.9, 146.7, 140.7, 140.1, 135.9, 132.2, 129.2, 128.8, 121.9, 120.2, 110.7,
106.8, 99.8, 51.5, 37.3, 20.1, 19.7, 18.9. Mass spectrum (EI), m/z (Irel, %): 473 [M]+ (20), [M+2]+ (18), 458 (30),
270 (100). Found, %: C 60.99; H 4.42; N 3.23. C24H21Cl2NO5. Calculated, %: C 60.77; H 4.46; N 2.95.
(Z)-Methyl
4-[2-Chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-2,7,7-trimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (6f). Pale-yellow solid, 36% yield; mp 214-216°C. FT-IR, ,
1
cm-1: 3278 (NH), 3100, 3067, 2953, 1741, 1694, 1618, 1551, 1472, 1381, 1217, 855, 808, 777, 743. H NMR
3
spectrum, δ, ppm (J, Hz): 7.90 (1H, s, CH α-pyrone); 5.99 (1H, s, NH); 5.69 (1H, d, J = 9.2, CH vinyl); 4.87
3
(1H, d, J = 9.2, CH dihydropyridine); 3.62 (3H, s, OCH3); 2.24 (2H, s, CH2); 2.21 (2H, s, CH2); 2.13 (3H, s,
CH3); 2.11 (3H, s, CH3); 0.96-0.98 (6H, 2s, CH3). 13C NMR spectrum, δ, ppm: 195.2 (C=O ketone), 168.2,
161.6, 159.6, 150.7, 149.6, 146.5, 137.1, 122.4, 120.9, 108.3, 106.8, 101.6, 51.2, 51.0, 32.6, 31.8, 30.0, 27.2,
20.0, 18.9. Mass spectrum (EI), m/z (Irel, %): 452 [M+H]+ (35), [M+H+2]+ (18), 248 (100). Found, %: C 58.15;
H 5.40; N 3.14. C22H23Cl2NO5. Calculated, %: C 58.42; H 5.13; N 3.10.
(Z)-Ethyl 5-Acetyl-4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-2,6-dimethyl-1,4-di-
hydropyridine-3-carboxylate (6g). Yellow solid, 32% yield; mp 60-62°C. FT-IR, , cm-1: 3318 (NH), 3093,
2980, 2929, 1737, 1696, 1670, 1628, 1550, 1476, 1303, 1212, 859, 778, 748. 1H NMR spectrum, δ, ppm (J, Hz):
3
3
6.11 (1H, s, CH α-pyrone); 5.88 (1H, s, NH); 5.66 (1H, d, J = 9.8, CH vinyl); 5.06 (1H, d, J = 9.8, CH
dihydropyridine); 4.24-4.31 (2H, m, CH2 ethyl); 2.45 (3H, s, CH3 acetyl); 2.33 (3H, s, CH3 α-pyrone); 2.26-2.28
(6H, 2s, CH3); 1.38 (3H, t, 3J = 7.0, CH3 ethyl). 13C NMR spectrum, δ, ppm: 199.3 (C=O ketone), 167.4, 162.1,
159.7, 150.1, 145.7, 145.2, 135.2, 122.0, 119.1, 108.8, 106.8, 101.2, 60.6, 35.8, 30.3, 20.6, 20.2, 19.7, 14.9.
Mass spectrum (EI), m/z (Irel, %): 425 [M]+ (15), [M+2]+ (12), 43 (100). Found, %: C 56.26; H 4.85; N 3.33.
C20H21Cl2NO5. Calculated, %: C 56.35; H 4.97; N 3.29.
tert-Butyl 5-Acetyl-4-[(1Z)-2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-2,6-dimethyl-
1,4-dihydropyridine-3-carboxylate (6h). Yellow solid, 26% yield; mp 74-76°C. FT-IR, , cm-1: 3337 (NH), 3096,
1
2971, 2926, 2855, 1738, 1694, 1665, 1628, 1551, 1475, 1381, 1223, 1166, 859, 843, 782. H NMR spectrum, δ,
ppm (J, Hz): 6.33 (1H, s, NH); 6.12 (1H, s, CH α-pyrone); 5.63 (1H, d, 3J = 9.8, CH vinyl); 5.05 (1H, d, 3J = 9.8,
CH dihydropyridine); 2.43 (3H, s, CH3 acetyl); 2.28 (3H, s, CH3); 2.27 (3H, s, CH3); 2.25 (3H, s, CH3); 1.56 (9H, s,
CH3 tert-butyl). 13C NMR spectrum, δ, ppm: 199.2 (C=O ketone), 166.9, 162.1, 159.8, 150.2, 146.0, 144.5,
1360

135.3, 122.0, 118.6, 108.2, 106.9, 102.7, 80.8, 35.9, 30.3, 28.8, 20.5, 20.2, 19.5. Mass spectrum (EI), m/z (Irel,
%): 453 [M]+ (35), [M+2]+ (18), 194 (100). Found, %: C 58.10; H 5.78; N 2.92. C22H25Cl2NO5. Calculated, %: C
58.16; H 5.55; N 3.08.
Ethyl 5-Acetyl-4-[(1Z)-2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-6-methyl-2-propyl-
1,4-dihydropyridine-3-carboxylate (6i). Yellow solid, 32% yield; mp 54-56°C. FT-IR, , cm-1: 3322 (NH),
1
3094, 2964, 2929, 2870, 1737, 1697, 1664, 1628, 1591, 1550, 1477, 1301, 1204, 859, 777. H NMR spectrum,
4
3
δ, ppm (J, Hz): 6.11 (1H, d, J = 0.6, CH α-pyrone); 5.90 (1H, s, NH); 5.65 (1H, d, J = 9.8, CH vinyl); 5.06
3
(1H, d, J = 9.8, CH dihydropyridine); 4.21-4.30 (2H, m, CH2 ethyl); 2.66-2.71 (2H, m, CH2 propyl); 2.45 (3H,
3
s, CH3 acetyl); 2.29 (3H, s, CH3); 2.26 (3H, s, CH3); 1.57-1.66 (2H, m, CH2 propyl); 1.37 (3H, t, J = 7.1, CH3
ethyl); 0.99 (3H, t, 3J = 7.3, CH3 propyl). 13C NMR spectrum, δ, ppm: 199.2 (C=O ketone), 167.1, 162.1, 159.7,
150.1, 150.0, 145.5, 135.1, 122.0, 119.1, 108.6, 106.9, 100.9, 60.5, 35.8, 34.6, 30.3, 22.4, 20.5, 20.2, 14.9, 14.2.
Mass spectrum (EI), m/z (Irel, %): 453 [M]+ (18), [M+2]+ (12), 43 (100). Found, % C 57.99; H 5.85; N 3.33.
C22H25Cl2NO5. Calculated, %: C 58.16; H 5.55; N 3.08.
(Z)-Ethyl 5-Benzoyl-4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-2,6-dimethyl-1,4-di-
hydropyridine-3-carboxylate (6j). Yellow solid, 23% yield; mp 166-168°C. FT-IR, , cm-1: 3324 (NH), 3089,
2977, 2925, 1735, 1695, 1627, 1549, 1484, 1300, 1218, 1107, 855, 776, 733, 700. 1H NMR spectrum, δ, ppm (J,
3
Hz): 7.80 (2H, d, J = 7.0, CH Ph); 7.50-7.51 (1H, m, CH Ph); 7.44-7.46 (2H, m, CH Ph); 6.07 (1H, s, CH
3
3
α-pyrone); 5.91 (1H, s, NH); 5.70 (1H, d, J = 9.4, CH vinyl); 5.21 (1H, d, J = 9.3, CH dihydropyridine);
4.18-4.21 (2H, m, CH2 ethyl); 2.39 (3H, s, CH3); 2.23 (3H, s, CH3); 1.93 (3H, s, CH3); 1.30 (3H, t, 3J = 6.8, CH3
ethyl). 13C NMR spectrum, δ, ppm: 198.1 (C=O ketone), 167.7, 161.8, 159.7, 150.0, 146.6, 140.9, 140.2, 135.9,
132.2, 129.3, 128.7, 121.9, 119.9, 110.6, 106.9, 100.1, 60.4, 37.2, 20.1, 19.7, 18.9, 14.8. Mass spectrum (EI),
m/z (Irel, %): 487 [M]+ (35), [M+2]+ (23), 77 (100). Found, %: C 61.25; H 4.42; N 3.01. C25H23Cl2NO5.
Calculated, %: C 61.48; H 4.75; N 2.87.
(Z)-tert-Butyl 5-Benzoyl-4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)-vinyl]-2,6-dimethyl-
1,4-dihydropyridine-3-carboxylate (6k). Yellow solid, 21% yield; mp 70-72°C. FT-IR, , cm-1: 3347 (NH),
3091, 2964, 2926, 2857, 1737, 1693, 1628, 1550, 1479, 1261, 1100, 1023, 801, 730. 1H NMR spectrum, δ, ppm
3
(J, Hz): 7.81 (2H, d, J = 7.2, CH Ph); 7.50-7.52 (1H, m, CH Ph); 7.43-7.46 (2H, m, CH Ph); 6.08 (1H, s, CH
α-pyrone); 5.88 (1H, s, NH); 5.67 (1H, d, 3J = 9.3, CH vinyl); 5.20 (1H, d, 3J = 9.2, CH dihydropyridine); 2.38
(3H, s, CH3); 2.24 (3H, s, CH3); 1.99 (3H, s, CH3); 1.52 (9H, s, CH3 tert-butyl). 13C NMR spectrum, δ, ppm:
197.9 (C=O ketone), 167.0, 161.8, 159.6, 149.9, 145.5, 141.4, 140.2, 135.9, 132.0, 129.3, 128.6, 121.9, 119.5,
110.2, 106.9, 101.7, 80.5, 37.5, 28.7, 20.1, 19.6, 18.9. Mass spectrum (EI), m/z (Irel, %): 515 [M]+ (35), [M+2]+
(10), 256 (100). Found, %: C 62.75; H 5.44; N 2.75. C27H27Cl2NO5. Calculated, %: C 62.80; H 5.27; N 2.71.
(Z)-Ethyl 5-Benzoyl-4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-6-methyl-2-propyl-
1,4-dihydropyridine-3-carboxylate (6l). Yellow solid, 21% yield; mp 56-58°C; FT-IR, , cm-1: 3322 (NH),
3089, 2962, 2926, 2867, 1737, 1695, 1627, 1549, 1484, 1301, 1215, 1107, 859, 776, 700.; 1H NMR spectrum, δ,
ppm (J, Hz): 7.80 (2H, d, 3J = 7.2, CH Ph); 7.50-7.53 (1H, m, CH Ph); 7.44-7.47 (2H, m, CH Ph); 6.08 (1H, s,
3
3
CH α-pyrone); 5.95 (1H, s, NH); 5.69 (1H, d, J = 9.4, CH vinyl); 5.23 (1H, d, J = 9.4, CH dihydropyridine);
3
4.20 (2H, q, J = 7.1, CH2 ethyl); 2.73-2.78 (2H, m, CH2 propyl); 2.24 (3H, s, CH3); 1.95 (3H, s, CH3);
3
3
13
1.62-1.71 (2H, m, CH2 propyl); 1.30 (3H, t, J = 7.1, CH3 ethyl); 1.03 (3H, t, J = 7.3, CH3 propyl). C NMR
spectrum, δ, ppm: 198.0 (C=O ketone), 167.3, 161.8, 159.6, 150.8, 149.9, 141.3, 140.3, 135.9, 132.1, 129.2,
128.7, 121.9, 119.9, 110.4, 106.9, 99.9, 60.3, 37.2, 34.5, 22.4, 20.1, 19.0, 14.7, 14.3. Mass spectrum (EI), m/z
(Irel, %): 515 [M]+ (21), [M+2]+ (15), 105 (100). Found, %: C 62.66; H 5.30; N 3.01. C27H27Cl2NO5. Calculated,
%: C 62.80; H 5.27; N 2.71.
Pharmacology. Male albino guinea pigs were purchased from the Shiraz University Animal House
Department. They had free access to standard rodent chow and tap water at all times. The animals were housed
in a room maintained at 23±2ºC temperature, 55±10% humidity, and on a 12-hour dark ⁄ light cycle. The feeding
was disrupted one day before starting in vitro tests. Guinea pigs (300–450 g) were killed and their intestine
1361

removed above the ileocecal junction. Smooth muscle segments of about 1 cm length were mounted under a
resting tension of 500 mg and were maintained at 37ºC in a 20-ml jacketed organ bath containing an oxygenated
(95% O2 and 5% CO2) physiological saline solution of the following composition: NaCl 137 mM; CaCl2 1.8
mM; KCl 2.7 mM; MgSO4 1.1 mM; NaH2PO4 0.4 mM; NaHCO3 12 mM, and glucose 5 mM. The muscle was
equilibrated for 1 h with a solution change every 15 min. The contractions were recorded with a forced
displacement transducer (Hugo Sachs, March-Hugstetten, Germany) on a physiograph (Hugo Sachs). All
compounds were dissolved in DMSO, and the same volume of solvent was used as the negative control.
Nifedipine was used as the positive control. The contraction was elicited with 80 mM KCl. The contractile
response was taken as the 100% value for the tonic (slow) component of the response. Test compounds were
added in accumulation increment after the dose response for KCl. Test compound-induced relaxation of the
contracted muscle was expressed as percent of control. The IC50 values were graphically determined from the
contraction–response curve [36-38].
We thank research affairs of University of Tabriz for financial support.
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