The synthesis and characterization of new asymmetrical dihydropyridine derivatives containing a 2,4-dichloro-5-thiazolyl substituent

Article abstract of DOI:10.1080/10426500600732808

Dihydropyridines (DHP) having a heterocyclic aryl substituent at position-4 are calcium channel antagonists. In this report a new group of DHP derivatives with different esters at the C₃ and C₅ position (asymmetrical diesters) containing 2,4-dichloro-5-thiazolyl at position-4 were synthesized by a condensation reaction of alkyl, cycloalkyl, and aryl acetoacetate in the presence of ammonium acetate in a new shorter pathway. The structure of all compounds was confirmed by IR, ¹H NMR, and mass spectrometry. The calcium channel antagonist activity of compounds 6a-6f demonstrated that the compound 6a was the most active compound. Copyright Taylor & Francis Group, LLC.

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The Synthesis and
Characterization of New
Asymmetrical Dihydropyridine
Derivatives Containing a
2,4-Dichloro-5-Thiazolyl
Substituent
Shahram Ghodsi a , Eskandar Alipour a , Mohsen
Amini b , Ramin Miri c , Karim Masoud Tagi-Ganji
a , Marjan Hosseini a , Hossein Mirkhani d & Abbas
Shafiee b
a Faculty of Chemistry , Islamic Azad University ,
North Tehran Branch, Tehran, Iran
b Department of Chemistry, Faculty of Pharmacy and
Pharmaceutical Sciences Research Center , Tehran
University of Medical Sciences , Tehran, Iran
c Medicinal and Natural Products Chemistry Research
Center , Shiraz University of Medical Sciences ,
Shiraz, Iran
d Department of Pharmacology, Faculty of Medicine ,
Shiraz University of Medical Sciences , Shiraz, Iran
Published online: 22 Sep 2006.
To cite this article: Shahram Ghodsi , Eskandar Alipour , Mohsen Amini , Ramin Miri ,
Karim Masoud Tagi-Ganji , Marjan Hosseini , Hossein Mirkhani & Abbas Shafiee (2006)
The Synthesis and Characterization of New Asymmetrical Dihydropyridine Derivatives
Containing a 2,4-Dichloro-5-Thiazolyl Substituent, Phosphorus, Sulfur, and Silicon and
the Related Elements, 181:10, 2435-2444, DOI: 10.1080/10426500600732808

To link to this article: http://dx.doi.org/10.1080/10426500600732808
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Phosphorus, Sulfur, and Silicon, 181:2435–2444, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500600732808
The Synthesis and Characterization of New
Asymmetrical Dihydropyridine Derivatives Containing
a 2,4-Dichloro-5-Thiazolyl Substituent
Shahram Ghodsi
Eskandar Alipour
Faculty of Chemistry, Islamic Azad University, North Tehran Branch,
Tehran, Iran
Mohsen Amini
Department of Chemistry, Faculty of Pharmacy and Pharmaceutical
Sciences Research Center, Tehran University of Medical Sciences,
Tehran, Iran
Ramin Miri
Medicinal and Natural Products Chemistry Research Center, Shiraz
University of Medical Sciences, Shiraz, Iran
Karim Masoud Tagi-Ganji
Marjan Hosseini
Faculty of Chemistry, Islamic Azad University, North Tehran Branch,
Tehran, Iran
Hossein Mirkhani
Department of Pharmacology, Faculty of Medicine, Shiraz University
of Medical Sciences, Shiraz, Iran
Abbas Shafiee
Department of Chemistry, Faculty of Pharmacy and Pharmaceutical
Sciences Research Center, Tehran University of Medical Sciences,
Tehran, Iran
Dihydropyridines (DHP) having a heterocyclic aryl substituent at position-4 are
calcium channel antagonists. In this report a new group of DHP derivatives
Received November 10, 2005; accepted March 30, 2006.
This research was supported by grants from the research council of Tehran University
of Medical Sciences and Iran National Science Foundation (INSF), Tehran, Iran.
Address correspondence to Abbas Shafiee, Tehran University of Medical Sciences,
Department of Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, P.O. Box
14155-6451, Tehran, Iran. E-mail: ashafiee@ams.ac.ir
2435

2436
S. Ghodsi et al.
with different esters at the C and C position (asymmetrical diesters) contain-
3
5
ing 2,4-dichloro-5-thiazolyl at position-4 were synthesized by a condensation reac-
tion of alkyl, cycloalkyl, and aryl acetoacetate in the presence of ammonium ac-
etate in a new shorter pathway. The structure of all compounds was confirmed
1
by IR, H NMR, and mass spectrometry. The calcium channel antagonist activ-
ity of compounds 6a–6f demonstrated that the compound 6a was the most active
compound.
Keywords 1,4-dihydropyridines; Ca2+-channel-antagonist; heterocyclic
compounds; thiazole
INTRODUCTION
The discovery that the 1,4-dihydropyridine class of calcium channel
antagonists inhibits the Ca2+ influx represented a major therapeutic
advance in the treatment of cardiovascular diseases, such as hyper-
tension, angina pectoris, and other spastic smooth muscle diseases.1
Dihydropyridine (DHP) derivatives substituted in position-4 are ana-
logues of nifedipine (CAS 218 29-25-4) and an important class of drugs.2
For example, amilodepine, nifedipine, and related dihydropyridine are
Ca2+ channel antagonists.
In the human body, it has been observed that these compounds
undergo oxidation to form pyridine derivatives. These oxidized com-
pounds are largely devoid of the pharmacological activity of the parent
compounds.3
Felodipine (Figure 1, having two chlorosubstituents) has high cal-
cium antagonist potency that is comparable to nifedipine.4 Therefore,
FIGURE 1 Two types of a calcium channel antagonist.

New Asymmetrical Dihydropyridine Derivatives
2437
chlorine substitution in the aryl rings on the C4 position can lead to po-
tent compounds. In addition, several papers illustrated that C4 hetero-
cycle substituents gave compounds as calcium channel antagonists.5−7
The esters structure in the 3 and 5 positions affect the type and
amount of DHP activity. DHPs having imidazole and its derivatives
as substituents in the 4-position are very active compounds as calcium
channels antagonist.8−10 Symmetrical diesters (with the same esters at
the C3 and C5-position) were synthesized by Hantzsch condensation,11
and asymmetrical derivatives with different esters at the C3 and C5-
position were prepared by the Meyer method.12
Memarian et al. illustrated that dihydropyridines having the aro-
matic ring substituent in position-4 in the presence of oxidizing
reagents and also light have been oxidized to related pyridines.13,14
This observation suggests that these compounds should be prepared in
darkness and in the absence of oxidizing materials.
In this report, a modified method for the synthesis of a novel group
of asymmetrical dialkyl, alkyl aryl, and alkyl cyclohexyl 1,4-dihydro-
2,6-dimethyl-4-(2,4-dichlorothiazol-5-yl)-3,5-pyridinecarboxylates is
described.
For the selection of this heterocyclic substituent in position-4, the
following reasons were considered.
1. Some heterocyclic rings were effective as 4-aryl in the dihydropyri-
dine structure.5,6
2. The substitution of chlorine instead of NO2 in the 4-aryl ring pro-
duced active compounds.4
3. A bulky substituent in the aryl group at the 4-position was tolerated
by a receptor.7,8
MATERIAL AND METHODS
Instrumentation and Chemistry
Melting points were determined using a Thomas-Hoover capillary ap-
1
paratus and were uncorrected. H NMR spectra were recorded on a
Bruker FT-80 spectrometer (Bruker, Rheinstetten, Germany). TMS was
used as an internal standard. Infrared spectra were acquired on a Nico-
let 550-FT spectrometer (Madison,WI, USA). Mass spectra were mea-
sured with a Finigan TSQ-70 spectrometer (Finnigan MAT, Bremen,
Germany) at 70 eV. Elemental analyses were carried out with a Perkin-
Elmer model 240-C apparatus (Perkin-Elmer, Norwalk, CT, USA). The
result of the elemental analyses (C, H, and N,) were within 0.4% of

2438
S. Ghodsi et al.
the calculated amounts. Some of the alkyl acetoacetates (3-oxobutanoic
acid esters) were prepared according to the literature procedure.15,16
Synthesis
Asymmetrical diester analogues 6a–f of nifedipine were synthesized
according to Scheme 1. These compounds were synthesized in a shorter
modified pathway. Since these compounds undergo oxidation13,14 during
synthesis, the preparation, collection, and purification of the product
SCHEME 1 The synthesis of 1,4-dihydropyridines with different ester groups
in the 3- and 5-position.

New Asymmetrical Dihydropyridine Derivatives
2439
should be carried out in the absence of oxidizing materials and in
darkness. 2,4-dichlorothiazole-5-carboxaldehyde 2 was prepared in two
steps. First chloroacetic acid and thiourea were refluxed for a desired
time to give 1,3-thiazolidine-2,4-diones 1.17 The reaction of 1 with
POCl3 and DMF gave the desired aldehyde 2.18
The asymmetrical analogues were prepared by the condensation of
2 with 3-oxobutanoic acid ester 3 and ammonium acetate in a new
modified shorter pathway. Alkyl acetoacetates 3 were synthesized by
known methods15,16 in which 2,2,6- trimethyl-4H-1,3-dioxine-4-one was
used as starting material.
The structure of all compounds was confirmed by elemental analyses,
IR, H NMR, and mass spectroscopy.
EXPERIMENTAL
The Preparation of 1,3-Thiazolidine-2,4-dione (1)
To stirring solution of thiourea (10.13 g, 0.133 mol) in 100 mL of water
was added chloroacetic acid (12.613 g, 0.133 mol) in the presence of
conc. HCl and was refluxed for 7 h.17 The precipitate was collected and
crystallized from water to give 13 g (83%) of 1, m.p. (123–125)◦C; IR
(KBr, cm−1): 1736, 1666 (CO); 1H NMR (DMSO-d6), δ: 1.59 (s, 2H, CH2),
4.03 (s, 1H, NH); MS, m/z (%): 117 (M+, 85), 89 (50), 74 (65), 46 (100);
Anal. calcd. for C3H3O2NS: C, 30.76; H, 2.58; N, 11.96. Found: C, 30.70;
H, 2.63; N, 12.05.
The Preparation of 2,4-Dichlorothiazole-5-carbaldehyde (2)
A mixture of compound 1 (10 g, 0.0584 mol) and POCl3 (78.6 g, 0.51 mol)
in 6.8 mL of DMF was refluxed for 6 h18 and cooled to r.t. The product
was purified by column chromatography (silica gel) and was crystallized
in methanol to give 8.7 g (56%) of 2, m.p. 45–46◦C; IR (KBr, cm−1): 1690
1
(CO); H NMR(CDCl3), δ: 9.96 (s, CHO); MS, m/z (%): 185 (M+, 80),
182 (100), 154 (37), 152 (43), 91 (53), 79 (32), 57 (30). Anal. calcd. for
C4H1Cl2NOS: C, 26.39; H, 0.55; N, 7.69. Found: C, 26.43; H, 0.54; N,
7.72.
The Preparation of Methyl Benzyl 1,4-Dihydro-2,6-dimethyl-4-
(2,4-dichlorothiazole-5-yl)-3,5-pyridinedicarboxylate (6a)
A solution of compound 2 (500 mg, 2.7 mmol) and methyl 3-
oxobutanoate 3 (321 mg, 2.77 mmol) in the presence of 0.1 mL of piperi-
dine and 0.25 mL of glacial acetic acid in 50 mL of benzene was refluxed

2440
S. Ghodsi et al.
for 72 h. After removing the solvent, the reaction mixture was added to
benzyl 3-oxobutanoate 5 (532 mg, 2.77 mmol) and ammonium acetate
(231 mg, 3 mmol) in 30 mL of methanol and then refluxed for 12 h.
The solvent was removed under reduced pressure, and the residue was
poured into 100 mL of water; the emulsion was extracted with ethyl ac-
etate. The solvent was removed, and the residue was purified by a silica
gel column using CH2Cl2: ethanol = 98:2 as eluent. The product was
crystallized from methanol-water to give 373 mg (30%) of 6a m.p. 151–
1
152◦C; IR (KBr, cm−1): 3324, 3240 (NH), 1696 (CO); H NMR (CDCl3,
80 MHz):δ, 2.32 (s, 6H, C2, C6-CH3), 3.66 (s, 3H, COOCH3), 5.35 (s, 1H,
H4- DHP), 5.15 (s, 2H, COOCH2Ph) 5.90 (bs, 1H, NH-DHP), 7.31 (s, 5H,
Phenyl); MS, m/z (%): 452 (M+, 32), 393 (12), 361 (32), 300 (97), 267 (32),
165 (70), 150 (37), 91 (100), 67 (45). Anal. calcd. for C20H18Cl2N2O4S:
C, 52.99; H, 4.00; N, 6.18. Found: C, 52.72; H, 4.02; N, 6.16.
Compounds 6b–c (Table I) were prepared similarly.
6b, m.p. 165–166◦C; yield = 47%; IR (KBr, cm−1): 3306, 3240
(NH), 1705 (CO); 1H NMR (CDCl3): δ, 1.24 (dd, J = 6.4 Hz, 6H,
COOCH(CH ) ), 2.32 (s, 6H, C2, C6-CH3), 3.70 (s, 3H, COOCH3), 4.85–
3 2
5.2 (m, 1H, CH(CH3)2), 5.32 (s, 1H, H4- DHP), 5.92 (bs, 1H, NH- DHP);
TABLE I Physical and Calcium Channel Modulation Data for
Compounds 6a–f
Calcium Channel
Compound
No.
M.P. Yield
(◦C)
(%)
Antagonist Activity
(IC50 SEM)
R1
CH3
CH3
CH3
CH(CH3)2 C6H11
CH(CH3)2 CH2CH3
R2
Formula
6a
6b
6c
6d
6e
6f
CH2C6H5
CH(CH3)2
CH2C6H11
151–152 30 C20H18Cl2N2O4S 2.1 0.84 × 10−7
165–166 47 C16H18Cl2N2O4S 1.1 0.24 × 10−6
Oil
28 C20H24Cl2N2O4S 5.9 0.99 × 10−6
119–120 40 C21H26Cl2N2O4S 2.2 0.3 × 10−6
Oil
39 C17H20Cl2N2O4S 9.5 3.8 × 10−7
CH(CH3)2 CH2CH2C6H5 107–108 42 C23H24Cl2N2O4S 8.0 2.9 × 10−7
Nifedipine
1.1 0.4 × 10−8

New Asymmetrical Dihydropyridine Derivatives
2441
MS, m/z (%): 404 (M+, 22), 369 (23), 317 (62), 210 (100), 150 (27), 67 (15).
Anal. calcd. for C16H18Cl2 N2O4S: C, 47.42; H, 4.48; N, 6.91. Found: C,
47.59; H, 4.46; N, 6.97.
6c, oil; yield = 28%; IR (KBr, cm−1): 3411, 3296 (NH), 1701(CO); 1H
NMR (CDCl3): δ, 0.6–2 (m, 13H, Cyclohexyl-CH2), 2.17 and 2.34 (2s, C2,
C6-CH3), 3.70 (s, 3H, COO CH3), 3.95–4.5 (m, 2H, COOCH2 ), 5.16 (s,
1H, H4- DHP), 5.95(bs, 1H, NH-DHP); MS, m/z (%): 472 (M+, 472, 63),
437 (97), 317 (100), 279 (40), 269 (18), 210 (87), 167 (25), 149 (32), 93
(12), 59 (10). Anal. calcd. for C20H24Cl2 N2O4S: C, 52.29; H, 5.23; N,
6.10. Found: C, 52.39; H, 5.45; N, 6.26.
The Preparation of Isopropyl Cyclohexyl
1,4-Dihydro-2,6-dimethyl-4-(2,4-dichlorothiazole-5-yl)-3,5-
pyridinedicarboxylate (6d)
A solution of compound 2 (500 mg, 2.7 mmol) and isopropyl 3-
oxobutanoate 3 (393 mg, 2.77 mmol) in the presence of 0.1 mL of piperi-
dine and 0.25 mL of glacial acetic acid in 50 mL of benzene was refluxed
for 48 h. After removing the solvent, the reaction mixture was added to
cyclohexyl 3-oxobutanoate 5 (510 mg, 2.77 mmol) and ammonium ac-
etate (231 mg, 3 mmol) in 30 mL of methanol and then refluxed for 12 h.
The solvent was removed under reduced pressure, and the residue was
poured into 100 mL of water; the emulsion was extracted with ethyl
acetate, and the solvent was removed. The residue was purified by a
silica gel column using CH2Cl2: ethanol = 99:1 as aneluent. The prod-
uct was crystallized from methanol-water to give 520 mg (40%) of 6d
m.p. 119–120◦C; IR (KBr, cm−1): 3240, 3293 (NH), 1699 (CO); 1H NMR
(CDCl3): δ, 1.2–1.85 (m, 16H, cyclohexyl, CH(CH ) ), 2.33 (s, 6H, C2,
3 2
C6-CH3), 5.04 (m, 2H, COOCH ), 5.35 (s, 1H, H4−DHP), 5.92 (bs, 1H,
NH-DHP); MS, m/z (%): 472 (M+, 22), 437 (40), 347 (42), 303 (59), 267
(22), 196 (100), 150 (15), 83 (21). Anal. calcd. for C21H26Cl2 N2O4S: C,
53.28; H, 5.54; N, 5.92. Found: C, 53.42; H, 5.53; N, 5.91.
Compounds 6e–f (Table I) were prepared similarly.
6e, oil; yield = 39%; IR (KBr, cm−1): 3475, 3408 (NH), 1702 (CO); 1H
NMR (CDCl3): δ, 1.17–1.379 (m, 9H, COOCH2CH and COOCH(CH ) ),
3
3 2
2.34 (s, 6H, C2, C6-CH3), 4.12 (q, J = 6.4 HZ, 2H, COOCH CH3), 5.08
2
(m, 1H, CH(CH3)2), 5.34 (s, 1H, H4-DHP), 5.83 (bs, 1H, NH-DHP); MS,
m/z (%): 418 (M+, 57), 331 (100), 266 (95), 224 (98), 196 (96), 150 (52),
106 (18). Anal. calcd. for C17H20Cl2 N2O4S: C, 48.69; H, 4.81; N, 6.68.
Found: C, 48.45; H, 4.84; N, 6.73.
6f, m.p. 107–108◦C; yield = 42%; IR (KBr, cm−1): 3417, 3294(NH),
1
1699(CO); H NMR (CDCl3): δ, 1.24 (dd, J = 6.4 HZ, 6H, CH(CH ) ),
3 2

2442
S. Ghodsi et al.
2.26 and 2.32 (2s, 6H, C2, C6-CH3), 2.98 (t, 2H, COOCH2CH Ph), 4.35
2
(m, 3H, COOCH2 , COOCH), 5.30 (s, 1H, H4-DHP), 5.85 (bs, 1H, NH-
DHP); MS, m/z (%): 494 (M+, 46), 459 (40), 342 (42), 303 (45), 267 (20),
196 (100), 150 (23), 105 (97), 79 (17). Anal. calcd. for C23H24Cl2 N2O4S:
C, 55.76; H, 4.88; N, 5.65. Found: C, 55.53; H, 4.83; N, 5.66.
PHARMACOLOGY
Male guinea pigs weighing 300–400 g were killed by a blow on the head.
The animals were deprived from food 18 h before sacrifice but had free
access to water. The non-terminal part of the ileum was removed and
cut into segments of 10–15 mm in length. Each ileal segment was sus-
pended in an organ bath and connected to an isometric transducer (K30,
Hugo Sachs Electronic, Germany). The organ bath contained 20 mL of
physiological solution of the following composition (in mM): NaCl, 119;
KCl, 2.7; CaCl2, MgCl2, 0.88; NaH2PO4, 0.36; NaHCO3, 12; glucose 5.5.
The physiologic salt solution was continuously gassed with a mixture of
95% O2 and 5% CO2, and its temperature was held at 37◦C. 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 Electronic, Germany) and a recorder (Graphtec,
model WR3320).
In order to study the effects of synthesized dihydropyridines on a
KCl-induced contraction of ileum, at the first step, several contrac-
tions with KCl (40 mM) were made. No significant differences between
KCl-induced contractions were considered as the stability of tissue,
and thereafter the main experiments were started. At this step, a KCl
(40 mM)-induced contraction was recorded again, and the peak of the
first phase (phasic contraction) was considered as the control. Then,
tissues were pre-incubated with one certain concentration of each com-
pound (for 15 min), and then the effect of KCl (40 mM) was assessed
once again. Each segment was treated with only one compound. From
concentration-response curves, the pIC50(-log IC50) value of each com-
pound was calculated. Nifedipine was used as a reference compound.
Statistical Methods
Results are expressed as means
s. e. Comparing pEC130s of com-
pounds on an isolated guinea-pig atrium and pIC50s of them on isolated
guinea were performed using one-way ANOVA followed by a Dunnet
test. A P value <0.05 was considered to be significant.

New Asymmetrical Dihydropyridine Derivatives
2443
RESULTS AND DISCUSSION
Asymmetrical DHPs were often prepared according to the reported
procedure12 in which the compounds were synthesized by three steps. In
the first step, aldehyde 2 was reacted with alkyl acetoacetates 3 to give
intermediate 4; the product was synthesized by a reaction of 4 and alkyl
aminocrotonate (with different alkyl or aryl). Some aminocrotonates,
such as methyl, ethyl, and isopropyl, were commercially available but
others had to be prepared. Therefore, an extra synthesis procedure was
used to prepare the other alkyl aminocrotonates. In the present method
according to Scheme 1, DHP 6 was synthesized in a shorter pathway
because alkyl acetoacetate was used instead of alkyl aminocrotonate. In
the presence of ammonium acetate, the aminocrotonate was formed in
situ. The structure of the synthesized compounds was confirmed by IR,
H NMR, and mass spectroscopy. The yields of the product in comparison
to asymmetrical DHPs containing imidazole substituents were almost
the same.7,8 A trace amount of symmetrical DHPs was produced dur-
ing the preparation of our desired compounds. Therefore, this method
is applicable to synthesize some asymmetrical DHPs in a shorter pro-
cedure.
The Ca2+ channel antagonist activities of compounds 6a–f deter-
mined as the concentration needed to produce 50% inhibition of the
guinea-pig ileal longitudinal smooth muscle contractility are summa-
rized in Table I. As it can be seen from Table I, the most active compound
was compound 6a, which had comparable activity with nifedipine as
a reference drug. The structure activity data indicate that 4-(2,4-
dichloro-5-thiazolyl moiety is a bioisoester of the o-nitrophenyl group
of nifedipine.
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