Synthesis of 4-aryl-3,4-dihydropyrimidin-2(1H)-thione derivatives as potential calcium channel blockers

Article abstract of DOI:10.1016/j.bmc.2006.08.031

Biginelli reaction which involves condensation of methyl 3-oxopentanoate, aromatic aldehydes and thiourea with a catalytic amount of HCl at reflux temperature has been used for the synthesis of 4-aryl-6-ethyl-5-(methoxycarbonyl)-3,4-dihydropyrimidin-2(1H)

Full text of DOI:10.1016/j.bmc.2006.08.031

Bioorganic & Medicinal Chemistry 14 (2006) 8582–8589
Synthesis of 4-aryl-3,4-dihydropyrimidin-2(1H)-thione derivatives
as potential calcium channel blockers
a
a,
b
b
_
*
Inci Selin Zorkun, Selma Sarac¸, Semra C¸ elebi and Kevser Erol
aDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sıhhiye-Ankara, Turkey
bDepartment of Pharmacology, Faculty of Medicine, Osmangazi University, 26480 Meßselik-Eskißsehir, Turkey
Received 22 May 2006; revised 17 August 2006; accepted 22 August 2006
Available online 12 September 2006
Abstract—Biginelli reaction which involves condensation of methyl 3-oxopentanoate, aromatic aldehydes and thiourea with a cat-
alytic amount of HCl at reflux temperature has been used for the synthesis of 4-aryl-6-ethyl-5-(methoxycarbonyl)-3,4-dihydropyr-
imidin-2(1H)-thiones (1–16). In addition, Lewis acids such as FeCl3Æ6 H2O and/or H3BO3 were also used as catalysts for one-pot
synthesis of the products. Compared to the classical Biginelli reaction conditions, the usage of Lewis acids has the advantage of
good yields and short reaction times. The calcium channel blocker activities of 1–16 were screened by the tests performed on isolated
rat ileum and thoracic aorta. Although product 11, 2-nitrophenyl-derivative, has potent antispasmodic activity on BaCl2-stimulated
rat ileum, it does not have vasodilator activity on KCl-stimulated rat thoracic aorta. Product 15, 2-ethoxyphenyl-derivative,
exhibited significant antispasmodic and vasodilator activities in both screening paradigms.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
The original procedure reported by Biginelli for the syn-
thesis of DHPMs involves one-pot condensation of
(thio)ureas, aldehydes, and b-oxoesters or 1,3-dicarbon-
yl compounds under strongly acidic conditions.15 The
main disadvantage of this procedure is low reaction
yields because of the side reactions particularly in the
case of some substituted aromatic and aliphatic alde-
hydes.2 This has led to the recent disclosure of several
improved reaction protocols for the synthesis of
DHPMs either by modification of the classical one-
pot, three-component condensation itself16–20 or by the
development of alternative multi-step strategies.21–24
Several combinatorial protocols based on the classical
Biginelli condensation have been advanced by using sol-
id phase or fluorous phase reaction conditions.25–30
Recently it has been reported that the Biginelli reaction
could be performed using different Lewis acids as well as
protic acids as promoters.31 This method makes it
possible to prepare a large number of DHPMs bearing
various substituents in the pyrimidine ring.
In recent years acid-catalyzed cyclocondensation of
b-oxoesters with aromatic aldehydes and (thio)ureas,
known as the Biginelli reaction, has attracted significant
attention.1,2 The resulting dihydropyrimidinones and
their sulfur analogs (DHPMs) have been reported to
have antibacterial, antiviral, antitumor, antiinflammato-
ry,3 and antihypertensive as well as calcium channel
blocker,4–6 a-1a-antagonist,7–9 and neuropeptide Y
(NPY) antagonist10 activities. Recently, structurally
simple DHPM derivative monastrol has emerged as a
mitotic kinesin Eg5 motor protein inhibitor for the
development of anticancer drugs.11,12 Furthermore, the
biological activity of several recently isolated marine
alkaloids has also been attributed to the dihydropyri-
midinone moiety in the structure.13 Among them the
batzelladine alkaloids A and B which inhibit the binding
of HIV envelope protein gp-120 to human CD4 cells are
potential compounds in AIDS therapy.14
In this study, we focused on the use of Lewis acids such
as ferric chloride hexahydrate and boric acid as activa-
tors of the Biginelli reaction for the preparation of
DHPM-2-thiones which are expected to have calcium
channel blocker activity. Reaction times and yields were
compared to the classical Biginelli reaction conditions
Keywords: Biginelli reaction; Dihydropyrimidin-2-thiones (DHPM-2-
thiones); Ferric chloride; Boric acid; Calcium channel blocker activity.
*
Corresponding author. Tel.: +90 312 3053 015; fax: +90 312 3114
777; e-mail: sesarac@hacettepe.edu.tr
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.08.031

_
I. Selin Zorkun et al. / Bioorg. Med. Chem. 14 (2006) 8582–8589
8583
and preliminary calcium channel blocker activity results
of the synthesized compounds were reported.
H3BO3 and FeCl3Æ6H2O as a catalyst were 245, 7, and
5 h, respectively.
The reaction yields of some of the products obtained
with Lewis acids were significantly better in comparison
with the classical Biginelli procedure. For example, 3-ni-
tro- 12 and 2-hydroxy-5-bromo- derivatives 16 were ob-
tained under classical Biginelli conditions in 16% and
26% yields. The yields of these DHPM derivatives were
extremely high in the boric acid-catalyzed Biginelli reac-
tion, 62% and 93%, respectively. Similarly, 3-bromo- 5,
2-methyl- 7, 3-fluoro- 14, and 2-hydroxy-5-bromo-
derivatives 16 were obtained in 21%, 16%, 9%, and
26% yields using HCl and in 69%, 78%, 77%, and 58%
yields using ferric chloride as catalyst, respectively. On
the other hand, the yields of 4-chloro- 4, 4-methyl- 9,
2-methoxy- 10, and 2-ethoxy- 15 derivatives obtained
by boric acid-catalyzed method, and 4-methyl- 9 and
3-nitro- derivatives 12 obtained by ferric chloride-cata-
lyzed method were lower than the classical Biginelli
method.
2. Results and discussion
In the present work, Biginelli-type cyclocondensation
reaction was studied for the preparation of 4-aryl-3,4-
dihydropyrimidin-2(1H)-thiones (1–16). Although the
synthesis of 2–8 and 10 has been reported in our previ-
ous studies,32,33 the synthesis and calcium channel
blocker activity of these compounds are included for
the examination of the reaction conditions and biologi-
cal activity.
For comparison purposes, DHPM-2-thiones were pre-
pared using three different procedures (Scheme 1). Based
on comparison of melting points and spectral data we
assume that the identical materials have been obtained.
Our initial attempts focused on the classical Biginelli
reaction which involves condensation of methyl 3-oxo-
pentanoate with aromatic aldehydes and thiourea under
strongly acidic conditions.15 The reaction was carried
out simply by heating a mixture of the three components
dissolved in ethanol with a catalytic amount of HCl at
reflux temperature for long hours. The Biginelli conden-
sation is strongly dependent on the amount of acidic cat-
alyst present in the reaction medium. The main problem
of the classical synthesis was not only the low/moderate
reaction yields (8–36%) of the desired DHPM-2-thiones
1–16 but also long reaction times (35–245 h).
Among the products, 3-chloro- 3, 3-bromo- 5, 3-methyl-
8, and 3-fluoro- 14 derivatives using boric acid, and
4-chloro- 4, 4-bromo- 6, 2-nitro- 11, 2-fluoro- 13, and
2-ethoxy- 15 derivatives using ferric chloride could not
be isolated.
According to the mechanistic studies reported in the lit-
erature,2,46 in the first step of Biginelli reaction N-acyli-
minium ion is formed as the key intermediate by the
acid-catalyzed condensation of benzaldehyde and thio-
urea. Interception of this iminium ion by methyl 3-oxo-
pentanoate, possibly through its enol tautomer, results
in the formation of open-chain ureide, which then cycliz-
es to the DHPM derivative. The success of the Lewis
acid-catalyzed method may be the result of specifically
stabilization of the N-acyliminium ion intermediates.
A recent trend is to perform the condensation with a
Lewis acid such as BF3ÆOEt2 and CuCl,34 LaCl3,35
FeCl3,36,37 NiCl2,37 Yb(OTf)3,38 La(OTf)3,38 InCl3,39
InBr3,40 BiCl3,41 LiClO4,31 Mn(OAc)3,42 H3BO3,43
44
45
SmCl3 or ZrCl4 instead of protic acids to produce
higher yields of the DHPM-2-thione heterocycle and
to shorten reaction times. In continuation of our work
Lewis acid-catalyzed processes (such as H3BO3 and/or
FeCl3Æ6H2O) have been used for the one-pot synthesis
of 3,4-DHPM-2-thiones. A summary of the results
obtained is provided in Table 1.
Spectral examination and microanalysis data of the prod-
ucts 1–16 confirmed the formation of dihydropyrimidine
ring. The IR spectra of the products are characterized by
the presence of absorbtion bands at 3424–3270, 1701–
1662, and 1353–1311 cmÀ1 corresponding to the N–H,
5-C@O, and 2-C@S functions in the structure.
For all cases, the Lewis acid-catalyzed methods (Meth-
ods B and C) produced significantly shorter reaction
times (3–9 h) than the classical Biginelli reaction (35–
245 h) (Method A). For example, the reaction times in
the synthesis of 4-methyl-derivative 9 using HCl,
1
In the H NMR spectra of the products 1–6 and 8–15,
resonances of C-4 methine proton of the ring were seen
as a doublet due to N3–H proton at about d
S
Method A
HCl / EtOH
R
H2N
NH2
O
C
O
O
Method B
H3CO2C
H
N
H
H3BO3 / AcOH
H5C2
OCH3
R
H5C2
N
H
S
Method C
FeCl3 / HCl in EtOH
Scheme 1. Synthesis of DHPM-2-thione derivatives (1–16) by cyclocondensation of aromatic aldehyde, methyl 3-oxopentanoate and thiourea.

_
I. Selin Zorkun et al. / Bioorg. Med. Chem. 14 (2006) 8582–8589
8584
Table 1. Synthesis of 4-aryl-3,4-dihydropyrimidin-2(1H)-thione (DHPM-2-thione) derivatives using catalytic conditions versus classical Biginelli
conditions
R
O
H3COC
H
S
N
H5C2
N
H
Product
R
Method Aa
Refluxing time (h)
Method Bb
Method Cc
Refluxing time (h)
Yield (%)
Refluxing time (h)
Yield (%)
Yield (%)
1
2
H
2-Cl
63
105
175
112
154
105
140
133
245
35
30.40
11.69
35.90
25.87
21.39
12.37
15.91
23.57
35.38
17.44
11.17
16.06
8.27
6
8.5
62.37
29.82
—
5
37.69
26.13
42.26
—
5.5
5
d
3
3-Cl
4-Cl
—
d
4
9
—
12.44
—
—
5
d
5
3-Br
4-Br
69.43
—
d
6
8
6.5
21.02
15.39
—
—
6
7
2-CH3
3-CH3
4-CH3
2-OCH3
2-NO2
3-NO2
2-F
77.83
45.95
13.72
52.41
—
d
8
—
7
6
9
14.35
12.41
23.59
62.19
16.97
—
5
10
11
12
13
14
15
16
7.5
7
3
—
d
196
70
7.5
8.5
5.5
8.32
—
d
70
—
5
d
—
3-F
2-OC2H5
2-OH,5-Br
126
56
9.56
28.96
26.43
77.30
—
57.86
d
8.5
7.5
20.83
93.01
—
5
35
a Classical Biginelli conditions (cat. HCl in EtOH).
b Cat. H3BO3 in glacial acetic acid.
c Cat. FeCl3Æ6H2O in EtOH.
d Reaction product could not be isolated.
5.09–5.20 ppm. The signals of C-4 methine proton of 7
and 16 were apparent as two broad singlets at approxi-
mately d 4.70 and 5.39 ppm, respectively. All products
have a one-proton singlet at about d 10.20–10.42 ppm
assignable to the N1-H proton on the DHPM structure.
The signals of N3-H protons appeared as a singlet at
about d 9.52–9.73 ppm except product 14. In product
14 this proton was seen as a doublet at d 9.71 ppm
due to the C-4 methine proton of the DHPM ring.
were observed at about d 165.71–165.95 (C2) and d
175.17–175.53 (C10), respectively (Table 2).
EI-Mass spectra of 1–16 showed the molecular ion [M+]
peaks of different intensity which confirmed their molec-
ular weights. In most of the products, the base peak fre-
quently resulted from loss of C6H4RÅ radical from the
molecular ion and appeared at m/e 199. In product 10
(2-methoxy derivative) the molecular peak was also the
base peak (m/e 306). In product 7 (2-methyl derivative)
The 13C NMR data of the products 1, 9, and 12 con-
firmed the proposed structure. Characteristic signals
loss of COOCH3 radical from the structure accounted
for the base peak at m/e 231. The base peak of product
Å
Table 2. 13C NMR spectral data (DMSO-d6, d ppm) of the products 1, 9, and 12
4'
3'
5'
6'
(C11
)
R
2'
1'
4
H3CO2C
5
3
2
N
H
9
10
H3CH2C
N
6
S
1
8
7
H
Product (R)
C–2
C–4
C–5
C–6
C–7
C–8
C–9
C–10
C–11
24.09
1 (H)
9 (4-CH3)
12 (3-NO2)
165.95
165.94
165.71
51.85
51.79
52.08
100.30
100.39
99.41
126.99
126.89
121.71
24.14
21.35
24.21
13.74
13.71
13.75
54.49
54.18
53.87
175.27
175.17
175.53

_
I. Selin Zorkun et al. / Bioorg. Med. Chem. 14 (2006) 8582–8589
8585
Table 3. The relaxant effects of nicardipine and products 1–16 on barium chloride (4 · 10À3 mol/l) contractions in isolated rat ileum and potassium
chloride (67 mmol/l) induced contraction in rat thoracic aorta (X SD) (n, the number of heads used)
Product
R
% inhibition of BaCl2
contractions in rat ileum
% inhibition of KCl contractions
in rat thoracic aorta
10À5 M
n
10À5 M
n
1
2
H
2-Cl
67.38 14.34
89.25 3.96
88.88 7.45
59.00 13.19
39.63 14.92
37.00 6.93
87.75 7.19
63.25 6.54
68.00 13.80
66.25 11.88
95.50 2.07
75.00 10.58
66.25 3.66
65.38 15.84
87.50 5.10
34.00 10.58
8
8
8
8
8
8
8
8
9
8
8
8
8
8
8
8
4.90 1.83
0
8
8
3
3-Cl
4-Cl
7.42 3.71
4.88 1.97
—
6
4
8
5
3-Br
4-Br
—
—
7
6
—
7
2-CH3
3-CH3
4-CH3
2-OCH3
2-NO2
3-NO2
2-F
2.50 1.02
0
8
8
9
6.50 2.14
8.50 4.21
0
8
10
11
12
13
14
15
16
8
8
6.77 0.77
6.69 2.83
10.38 2.56
19.33 6.59
—
6
8
3-F
2-OC2H5
2-OH,5-Br
8
6
—
Nicardipine
100.00
8
20.50 2.89
6
p < 0.05.
12 (2-nitro derivative) was probably formed by loss of
methoxy, ethyl, and nitro radicals [MÀ(OCH3 +
C2H5 + NO2)]. In all products prominent peaks resulted
from elimination of ÅCH3, ÅOCH3, and ÅCOOCH3
radicals.
did not display any inhibition of KCl contractions in
rat thoracic aorta. Product 15 (2-OC2H5) exhibited
significant activity (relaxant effect %: 19.33 6.59),
comparable to that of nicardipine (relaxant effect %:
20.50 2.89).
Regarding the fact that the biological activity could be
influenced by variety of substitution, series of 16 prod-
ucts has been investigated for their calcium channel
blocker activities by the tests performed on BaCl2-stim-
ulated rat ileum and KCl-stimulated rat thoracic aorta.
Nicardipine was included in all tests as the reference
drug47–52 (Table 3). Smooth muscles depend on calcium
influx for contraction. Although their underlying mech-
anism is somewhat different, inhibition of calcium chan-
nel influx into smooth muscles by calcium channel
blockers leads to relaxation.
3. Conclusion
In conclusion ferric chloride and boric acid efficiently
catalyze the three-component Biginelli reaction between
substituted benzaldehyde, methyl 3-oxopentanoate, and
thiourea to afford the corresponding DHPM-2-thiones.
The main advantages of these catalysts for the synthesis
of Biginelli-type DHPM-2-thiones are mild reaction
conditions, simple experimental workup procedure, high
yields, and short reaction times.
On the BaCl2-stimulated rat ileum products 2 (2-Cl), 3
(3-Cl), 7 (2-CH3), 11 (2-NO2), and 15 (2-OC2H5) were
found to be effective. Among these products, 3 was the
only m-substituted derivative. Product 11 having 2-
NO2 substituent on C-4 phenyl ring (relaxation effect
%: 95.50 2.07) was the most effective derivative com-
pared with the standard nicardipine (relaxation effect
%: 100). Products 2 (relaxation effect %: 89.25 3.96),
3 (relaxation effect %: 88.88 7.45), 7 (relaxation effect
%: 87.75 7.19), and 15 (relaxation effect %:
87.50 5.10), carrying 2-Cl, 3-Cl, 2-CH3, and
2-OC2H5 substituents on C-4 phenyl ring, exerted some-
what lower activity than nicardipine. Among the halo-
gen-substituted derivatives (2–6, 13, and 14) products
2 and 3 were the most effective derivatives which have
2- or 3-chloro substituents on the C-4 phenyl ring.
Considering the activity results of products 1–16 on the
BaCl2-stimulated rat ileum, we may conclude that o-sub-
stitution on C-4 phenyl group appears to be important
for the calcium channel blocker activity as it is reported
for 1,4-dihydropyridine (DHP) derivatives which have
structural similarities with 1,4-DHPMs.53–55 But no
relationship was found between the activity and the nat-
ure of the alkyl moiety such as electron-drawing or elec-
tron-releasing effects. While product 11, 2-NO2
derivative, has potent antispasmodic activity on isolated
rat ileum, it does not have vasodilator activity on isolat-
ed rat thoracic aorta. Product 15, 2-OC2H5 derivative,
showed antispasmodic activities on isolated rat ileum
and its vasodilatory activity on rat thoracic aorta was
as high as that of nicardipine. We had to use a high con-
centration (10À5 M) for compounds and nicardipine to
obtain a sufficient response on rat thoracic aorta, so
we used the same concentrations of compounds and
nicardipine on both rat ileum and thoracic aorta.
Introduction of 2-ethoxy substituent (15) instead of
Products 1–4 and 7–15 which have higher relaxant ef-
fects than 50% on the rat ileum were also evaluated on
rat thoracic aorta. Among these products 2, 8, and 11

_
I. Selin Zorkun et al. / Bioorg. Med. Chem. 14 (2006) 8582–8589
8586
2-methoxy substituent (10) on C-4 phenyl ring increased
both antispasmodic and vasodilator activities.
utes; the solid products were filtered, dried, and recrys-
tallized from appropriate solvent.
Although products 1–16 have an asymmetric center on
the fourth position, their resolutions have not been
done. Our next study will be concerned on the separa-
tion of enantiomers and comparison of the calcium
channel blocker activities of each enantiomer.
Melting points, spectral and analytical data for these
products are given below.
4.1.4. 6-Ethyl-4-phenyl–5-(methoxycarbonyl)-3,4-dihy-
dropyrimidin-2(1H)-thione (1). Mp 168–169 ꢁC; 1H
NMR: d = 1.15 (t, 3H, CH3), 2.45–3.00 (m, 2H, CH2),
3.55 (s, 3H, OCH3), 5.20 (d, 1H, H-4), 6.90–7.50 (m,
5H, C6H5), 9.60 (s, 1H, N3H), 10.35 (s, 1H, N1H); IR
(KBr): 3320, 3189, 3115, 2986, 1664, 1576, 1459, 1436,
1349, 1284, 1197, 1179, 1117, 763 cmÀ1; MS (70 eV,
EI): m/z (%): 276 (M+, 38.46), 261, 247, 217, 199 (MÀAr,
100), 167, 83; Anal. Calcd for C14H16N2O2S: C, 60.84; H,
5.83; N, 10.14. Found: C, 60.40; H, 5.64; N, 10.15.
4. Materials and methods
Melting points were determined using a Thomas Hoover
capillary melting point apparatus (Philadelphia, PA,
USA) and are uncorrected. UV absorptions were mea-
sured on a Agilent 8453 UV–visible spectrophotometer.
IR spectra were recorded on a Bruker Vector 22 IR
spectrophotometer (Opus Spectroscopic Software Ver-
4.1.5. 6-Ethyl–4-(2-chlorophenyl)-5-(methoxycarbonyl)-
3,4- dihydropyrimidin-2(1H)-thione (2). Mp 183–185 ꢁC,
lit.33 198–199 ꢁC; 1H NMR: d = 1.10 (t, 3H, CH3),
2.40–3.00 (m, 2H, CH2), 3.45 (s, 3H, OCH3), 5.60 (d,
1H, H–4), 7.20–7.50 (m, 4H, C6H4), 9.60 (s, 1H, N3H),
10.40 (s, 1H, N1H); IR (KBr): 3254, 3168, 3008, 2929,
1701, 1638, 1582, 1462, 1433, 1314, 1269, 1181, 1136,
1103, 776 cmÀ1; MS (70 eV, EI): m/z (%): 312 (M+2,
22.12), 310 (M+, 57.21), 295, 275, 251, 235, 213, 199
(MÀAr, 100), 183, 167.
1
sion 2,0). H NMR spectra were run on a Bruker AC
80 MHz FT NMR or Bruker Avance 400 MHz NMR
(XWIN-NMR Software) instruments in DMSO-d6 solu-
tions using TMS as the internal standard. 13C NMR
spectra were measured on a Bruker Avance 400 MHz
NMR (XWIN-NMR Software) using the same solvent
and internal standard. Mass (70 eV) spectra were taken
using a 73DIP–1 Direct Insertion Probe and Agilent
5973-Network Mass Selective Detector spectrometer.
Microanalysis data were performed on a Leco CHNS
932 analyzer. All chemicals used were of reagent grade.
Methyl 3-oxopentanoate was supplied from Ulkar
Chemistry (C¸ erkezko¨y, Tekirdag˘-Turkey). TLC was
performed on microplates coated with kieselgel 60 F254
(Merck).
4.1.6. 6-Ethyl–4-(3-chlorophenyl)-5-(methoxycarbonyl)-
3,4-dihydropyrimidin-2(1H)-thione (3). Mp 169–170 ꢁC,
lit.33 183–184 ꢁC; 1H NMR: d = 1.08 (t, 3H, CH3),
2.59–2.77 (m, 2H, CH2), 3.54 (s, 3H, OCH3), 5.16 (d,
1H, H–4), 7.14-7.39 (m, 4H, C6H4), 9.68 (s, 1H, N3H),
10.42 (s, 1H, N1H); IR (KBr): 3312, 3175, 3109, 2981,
1662, 1579, 1435, 1353, 1282, 1184, 1124, 760 cmÀ1
;
4.1. General procedures for the synthesis of DHPM-2-
thiones
MS (70 eV, EI): m/z (%): 312 (M+2, 22), 310 (M+,
56.94), 295, 279, 251, 213, 199 (MÀAr, 100), 183, 167.
4.1.1. Method A (classical Biginelli conditions). A mix-
ture of thiourea (0.025 mol), benzaldehyde or substituted
benzaldehyde (0.025 mol) and methyl 3-oxopentanoate
(0.0375 mol) in abs ethanol (20 ml) was treated with eight
drops of 37% HCl as catalyst and then refluxed for an
appropriate period. The crude product which precipitat-
ed on cooling was filtered and washed with 50% ethanol.
Then it was recrystallized from appropriate solvent.
4.1.7. 6-Ethyl-4-(4-chlorophenyl)-5-(methoxycarbonyl)-
3,4-dihydropyrimidin-2(1H)-thione (4). Mp 161–163 ꢁC,
lit.33 166–167 ꢁC; 1H NMR: d = 1.07 (t, 3H, CH3),
2.60–2.76 (m, 2H, CH2), 3.54 (s, 3H, OCH3), 5.14 (d,
1H, H-4), 7.20–7.39 (m, 4H, C6H4), 9.64 (s, 1H, N3H),
10.37 (s, 1H, N1H); IR (KBr): 3424, 3176, 2976, 1684,
1589, 1462, 1343, 1197, 1111, 1013, 855, 765 cmÀ1; MS
(70 eV, EI): m/z (%): 312 (M+2, 21.63), 310 (M+,
55.29), 295, 281, 251, 213, 199 (MÀAr, 100), 167.
4.1.2. Method B (catalyst: H3BO3).43 A solution of aro-
matic aldehyde (3 mmol), methyl 3-oxopentanoate
(3 mmol), thiourea (3.6 mmol), and H3BO3 (0.6 mmol),
in glacial acetic acid (10 ml) is heated at 100 ꢁC, while
stirring for 6–9 h. Then it is cooled to room temperature
and poured into 50 ml ice-water. The solid products are
filtered, washed with ice-water and ethanol (95%), dried,
and recrystallized from appropriate solvent.
4.1.8. 6-Ethyl–4-(3-bromophenyl)-5-(methoxycarbonyl)-
3,4-dihydropyrimidin-2(1H)-thione (5). Mp 185–187 ꢁC,
lit.33 195–196 ꢁC; 1H NMR: d = 1.15 (t, 3H, CH3),
2.45–2.95 (m, 2H, CH2), 3.55 (s, 3H, OCH3), 5.25 (s,
1H, H–4), 7.05–7.65 (m, 4H, C6H4), 9.75 (d, 1H,
N3H), 10.45 (s, 1H, N1H); IR (KBr): 3317, 3173, 3108,
2980, 2930, 1661, 1579, 1460, 1435, 1353, 1282, 1196,
1183, 1123, 792 cmÀ1; MS (70 eV, EI): m/z (%): 358
(M+2, 62.98), 356 (M+, 62.98), 339, 325, 309, 295, 279,
213, 199 (MÀAr, 100), 183, 167, 151.
4.1.3. Method C (catalyst: FeCl3Æ6H2O).20 A solution of
thiourea (75 mmol), methyl 3-oxopentanoate (50 mmol),
the appropriate aldehyde (50 mmol), FeCl3Æ6H2O
(30 mmol), and concd. HCl (2–3 drops) in ethanol
(40 ml) was heated under reflux for 5–6 h. The solution
was cooled to room temperature and poured onto 200 g
of crushed ice. Stirring was continued for several min-
4.1.9. 6-Ethyl-4-(4-bromophenyl)-5-(methoxycarbonyl)-
3,4-dihydropyrimidin-2(1H)-thione (6). Mp 181–183 ꢁC,
lit.33 174–175 ꢁC; 1H NMR: d = 1.10 (t, 3H, CH3),
2.35–2.90 (m, 2H, CH2), 3.55 (s, 3H, OCH3), 5.20 (d,

_
I. Selin Zorkun et al. / Bioorg. Med. Chem. 14 (2006) 8582–8589
8587
1H, H-4), 7.20–7.60 (m, 4H, C6H4), 9.75 (s, 1H, N3H),
10.45 (s, 1H, N1H); IR (KBr): 3168, 2976, 1684, 1588,
1462, 1435, 1342, 1274, 1196, 1108, 764 cmÀ1; MS
(70 eV, EI): m/z (%): 358 (M+2, 55.29), 356 (M+,
55.29), 341, 325, 295, 275, 213, 199 (MÀAr, 100), 167.
4.1.15. 6-Ethyl-4-(3-nitrophenyl)-5-(methoxycarbonyl)-
3,4-dihydropyrimidin-2(1H)-thione (12). Mp 201–
203 ꢁC; 1H NMR: d = 1.10 (t, 3H, CH3), 2.40–2.95
(m, 2H, CH2), 3.55 (s, 3H, OCH3), 5.35 (d, 1H, H-
4), 7.70–8.10 (m, 4H, C6H4), 9.80 (s, 1H, N3H),
10.50 (s, 1H, N1H); IR (KBr): 3317, 3215, 2925,
1660, 1579, 1529, 1461, 1439, 1348, 1283, 1188,
1126, 758, 741, 693 cmÀ1; MS (70 eV, EI): m/z (%):
321 (M+, 74.52), 304, 288, 274, 262, 216, 199 (MÀAr,
100), 183, 167; Anal. Calcd for C14H15N3O4S: C,
52.33; H, 4.71; N, 13.08. Found: C, 53.40; H, 5.16;
N, 12.47.
4.1.10. 6-Ethyl-4-(2-methylphenyl)-5-(methoxycarbonyl)-
3,4- dihydropyrimidin-2(1H)-thione (7). Mp 181–183 ꢁC,
lit.32 192–193 ꢁC; 1H NMR: d = 1.13 (t, 3H, CH3),
2.48 (s, 3H, Ar-CH3), 2.48 (m, 2H, CH2), 3.46 (s, 3H,
OCH3), 5.39 (d, 1H, H-4), 7.12-7.17 (m, 4H, C6H4),
9.52 (s, 1H, N3H), 10.29 (s, 1H, N1H); IR (KBr):
3270, 3169, 3009, 2972, 1690, 1631, 1580, 1461, 1434,
1311, 1187, 1136, 1101, 755 cmÀ1; MS (70 eV, EI): m/z
(%): 290 (M+, 59.13), 275, 259, 231 (MÀCOOCH3,
100), 213, 199, 185, 167.
4.1.16. 6-Ethyl-4-(2-fluorophenyl)-5-(methoxycarbonyl)-
3,4-dihydropyrimidin-2(1H)-thione (13). Mp 183–
1
185 ꢁC; H NMR: d = 1.10 (t, 3H, CH3), 2.67–2.73 (m,
2H, CH2), 3.49 (s, 3H, OCH3), 5.43 (d, 1H, H-4),
7.14–7.22 (m, 4H, C6H4), 9.56 (s, 1H, N3H), 10.39 (s,
1H, N1H); IR (KBr): 3265, 3179, 2934, 1699, 1642,
1576, 1485, 1462, 1436, 1313, 1273, 1225, 1189, 1149,
1132, 1105, 759 cmÀ1; MS (70 eV, EI): m/z (%): 294
(M+, 51.44), 279, 265, 235, 216, 199 (MÀAr, 100), 167;
Anal. Calcd for C14H15N2O2SF: C, 57.13; H, 5.14; N,
9.52. Found: C, 56.59; H, 4.47; N, 9.47.
4.1.11. 6-Ethyl-4-(3-methylphenyl)-5-(methoxycarbonyl)-
3,4-dihydropyrimidin-2(1H)-thione (8). Mp 170–171 ꢁC,
lit.32 178–179 ꢁC; 1H NMR: d = 1.08 (t, 3H, CH3),
2.25 (s, 3H, Ar-CH3), 2.63–2.75 (m, 2H, CH2), 3.53 (s,
3H, OCH3), 5.09 (d, 1H, H-4), 6.96–7.22 (m, 4H,
C6H5), 9.61 (s, 1H, N3H), 10.32 (s, 1H, N1H); IR
(KBr): 3333, 3180, 3112, 2980, 1664, 1578, 1460, 1437,
1348, 1283, 1187, 1116, 757, 704 cmÀ1; MS (70 eV,
EI): m/z (%): 290 (M+, 91.35), 275, 259, 231, 213, 199
(MÀAr, 100), 185, 167.
4.1.17. 6-Ethyl-4-(3-fluorophenyl)-5-(methoxycarbonyl)-
3,4-dihydropyrimidin-2(1H)-thione (14). Mp 150–
152 ꢁC; 1H NMR: d = 1.09 (t, 3H, CH3), 2.62–2.78
(m, 2H, CH2), 3.56 (s, 3H, OCH3), 5.17 (d, 1H,
H-4), 7.38–7.43 (m, 4H, C6H4), 9.71 (d, 1H, N3H),
10.45 (s, 1H, N1H); IR (KBr): 3321, 2925, 1663,
1572, 1461, 1350, 1280, 1189, 1117, 786 cmÀ1; MS
(70 eV, EI): m/z (%): 294 (M+, 82.21), 279, 263, 235,
213, 199 (MÀAr, 100), 167; Anal. Calcd for
C14H15N2O2SF: C, 57.13; H, 5.14; N, 9.52. Found:
C, 57.38; H, 5.60; N, 9.43.
4.1.12. 6-Ethyl-4-(4-methylphenyl)-5-(methoxycarbonyl)-
3,4- dihydropyrimidin-2(1H)-thione (9). Mp 176–178 ꢁC;
1H NMR: d = 1.08 (t, 3H, CH3), 2.25 (s, 3H, Ar-CH3),
2.62–2.75 (m, 2H, CH2), 3.53 (s, 3H, OCH3), 5.10 (d,
1H, H-4), 7.06–7.14 (m, 4H, C6H4), 9.61 (s, 1H, N3H),
10.33 (s, 1H, N1H); IR (KBr): 3168, 2978, 1688, 1647,
1590, 1511, 1462, 1343, 1275, 1196, 1111, 769 cmÀ1
;
MS (70 eV, EI): m/z (%): 290 (M+, 88.03), 275, 261,
231, 213, 199 (MÀAr, 100), 167. Anal. Calcd for
C15H18N2O2S: C, 62.04; H, 6.24; N, 9.64. Found: C,
62.31; H, 6.19; N, 9.47.
4.1.18. 6-Ethyl-4-(2-ethoxyphenyl)-5-(methoxycarbonyl)-
3,4-dihydropyrimidin-2(1H)-thione (15). Mp 204–206 ꢁC;
1H NMR: d = 1.09 (t, 3H, CH3), 1.37 (t, 3H, Ar-CH3),
2.63–2.68 (m, 2H, CH2), 3.33 (s, 3H, OCH3), 3.96–4.04
(m, 2H, Ar-OCH2), 5.41 (d, 1H, H-4), 6.82–7.23 (m,
4H, C6H4), 9.12 (s, 1H, N3H), 10.22 (s, 1H, N1H); IR
(KBr): 3309, 3177, 3105, 2975, 2932, 1711, 1650, 1579,
1484, 1433, 1338, 1299, 1258, 1233, 1181, 1131, 1101,
1034, 758 cmÀ1; MS (70 eV, EI): m/z (%): 320 (M+,
100), 305, 291, 275, 261, 242, 231, 216, 199, 185, 167;
Anal. Calcd for C16H20N2O3S: C, 59.98; H, 6.29; N,
8.74. Found: C, 59.32; H, 6.81; N, 8.64.
4.1.13. 6-Ethyl-4-(2-methoxyphenyl)-5-(methoxycarbon-
yl)-3,4-dihydropyrimidin-2(1H)-thione (10). Mp 231 ꢁC,
lit.32 235–236 ꢁC; 1H NMR: d = 1.10 (t, 3H, CH3),
2.40–3.00 (m, 2H, CH2), 3.50 (s, 3H, Ar-OCH3), 3.75
(s, 3H, OCH3), 5.50 (d, 1H, H-4), 6.60–7.50 (m, 4H,
C6H4), 9.25 (s, 1H, N3H), 10.25 (s, 1H, N1H); IR
(KBr): 3194, 2972, 2931, 1713, 1661, 1571, 1487, 1470,
1428, 1277, 1245, 1177, 1132, 1102, 758 cmÀ1; MS
(70 eV, EI): m/z (%): 306 (M+, 100), 291, 273, 247,
231, 216, 199, 167.
4.1.19.
6-Ethyl-4-(5-bromo-2-hydroxyphenyl)-5-(meth-
(16).
4.1.14. 6-Ethyl-4-(2-nitrophenyl)-5-(methoxycarbonyl)-
3,4-dihydropyrimidin-2(1H)-thione (11). Mp 159–
161 ꢁC; H NMR: d = 1.18 (t, 3H, CH3), 2.75–2.77 (m,
oxycarbonyl)-3,4-dihydropyrimidin-2(1H)-thione
Mp 209–211 ꢁC; 1H NMR: d = 1.00 (t, 3H, CH3),
1.95–2.40 (m, 2H, CH2), 3.35 (s, 3H, OCH3), 3.75 (s,
H, OH), 4.70 (s, 1H, H-4), 6.90–7.40 (m, 3H, C6H3),
9.05 (s, 1H, N3H), 10.02 (s, 1H, N1H); IR (KBr):
3309, 3177, 3105, 2975, 2932, 1711, 1650, 1579, 1484,
1433, 1338, 1299, 1258, 1233, 1181, 1131, 1101, 1034,
758 cmÀ1; MS (70 eV, EI): m/z (%): 374 (M+2,
85.17), 372 (M+, 85.17), 355, 339, 311, 295, 280, 199
(MÀAr, 100), 167; Anal. Calcd for C14H16N2O3SBr:
C, 45.17; H, 4.33; N, 7.52. Found: C, 45.59; H, 4.46;
N, 7.59.
1
2H, CH2), 3.39 (s, 3H, OCH3), 5.56 (d, 1H, H-4),
7.46–7.55 (m, 4H, C6H4), 9.68 (s, 1H, N3H), 10.52 (s,
1H, N1H); IR (KBr): 3275, 3173, 2974, 2949, 1718,
1654, 1558, 1523, 1470, 1438, 1351, 1309, 1270, 1200,
1180, 1127, 1101, 750 cmÀ1; MS (70 eV, EI): m/z (%):
321 (M+, 9.62), 303, 273, 244, 228, 216 (MÀOCH3,
–C2H5, –NO2, 100), 199, 128; Anal. Calcd for
C14H15N3O4S: C, 52.33; H, 4.71; N, 13.07. Found: C,
52.87; H, 4.74; N, 12.99.

_
I. Selin Zorkun et al. / Bioorg. Med. Chem. 14 (2006) 8582–8589
8588
4.2. Calcium channel blocker activity
had been reestablished and the potassium chloride con-
tractions were induced. The contractions were enrolled
by MAY TDA95 transducer data acquisition system.
4.2.1. Studies on isolated rat ileum. Male and female albi-
no rats weighing between 200 and 220 g were used in this
study. Animals entered the test having fasted overnight.
After the animals had been sacrified by cervical disloca-
tion, the ileum (10–15 cm terminal portion) was immedi-
ately removed, discarding the 5–8 cm segment proximal
to the ilio-caecal junction. Segments 1.5–2 cm long were
mounted vertically in a 10 ml organ bath containing
Tyrode solution of the following composition (mM):
NaCl, 136.87; KCl, 2.68; CaCl2, 1.80; MgSO4, 0.81;
NaH2PO4, 4.16; NaHCO3, 11.9; glucose, 11.1. The bath
contents were maintained at 37 ꢁC and aerated by 95%
O2 and 5% CO2.
Acknowledgment
The authors thank Professor M. Ertan from Hacettepe
University (Ankara, Turkey) for his helpful comments.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmc.2006.08.031.
A tension of 2 g was applied and isomeric recording was
done using an isometric transducer (T-FDT10-A).
Responses were recorded with a MAY TDA95 trans-
ducer data acquisition system.
References and notes
1. Kappe, C. O. Tetrahedron 1993, 49, 6937.
The preparations were allowed to equilibrate for 60 min
with regular washes every 15 min. In order to check for
antagonistic effects, contractions were induced with bar-
ium chloride (4 · 10À3 mol/l, bath concentration). After
thorough washing out, this process was repeated until
the amplitude of the contraction became constant. The
substances to be tested were investigated using the sin-
gle-dose technique. Barium chloride contractions were
induced after addition of the test substances at the differ-
ent concentrations (10À6, 10À5, and 10À4 M) and 5 min
exposure time. Only one compound was tested in each
preparation. Because of solubility problems, the com-
pounds were dissolved in dimethylsulfoxide (DMSO)
and the control responses were taken after the addition
of 0.1 ml DMSO.
2. Kappe, C. O. Acc. Chem. Res. 2000, 33, 879.
3. Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043.
4. Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D. M.;
Moreland, S.; Hedberg, A.; O’Reilly, B. C. J. Med. Chem.
1991, 34, 806.
5. Rovnyak, G. C.; Atwal, K. S.; Hedberg, A.; Kimball, S.
D.; Moreland, S.; Gougoutas, J. Z.; O’Reilly, B. C.;
Schwartz, J.; Malley, M. F. J. Med. Chem. 1992, 35, 3254.
6. Grover, G. J.; Dzwonczyk, S.; McMullen, D. M.;
Normandin, D. E.; Parham, C. S.; Sleph, P. G.; Moreland,
S. J. Cardiovasc. Pharmacol. 1995, 26, 289.
7. Nagarathnam, D.; Miao, S. W.; Lagu, B.; Chiu, G.; Fang,
J.; Dhar, T. G. M.; Zhang, J.; Tyagarajan, S.; Marzabadi,
M. R.; Zhang, F. Q.; Wong, W. C.; Sun, W. Y.; Tian, D.;
Wetzel, J. M.; Forray, C.; Chang, R. S. L.; Broten, T. P.;
Ransom, R. W.; Schorn, T. W.; Chen, T. B.; O’Malley, S.;
Kling, P.; Schneck, K.; Benedesky, R.; Harrell, C. M.;
Vyas, K. P.; Gluchowski, C. J. Med. Chem. 1999, 42, 4764.
8. Murali Dhar, T. G.; Nagarathnam, D.; Marzabadi, M. R.;
Lagu, B.; Wong, W. C.; Chiu, G.; Tyagarajan, S.; Miao, S.
W.; Zhang, F.; Sun, W.; Tian, D.; Shen, Q.; Zhang, J.;
Wetzel, J. M.; Forray, C.; Chang, R. S. L.; Broten, T. P.;
Schorn, T. W.; Chen, T. B.; O’Malley, S.; Ransom, R.;
Schneck, K.; Bendesky, R.; Harrell, C. M.; Vyas, K. P.;
Zhang, K.; Gilbert, J.; Pettibone, D. J.; Patane, M. A.;
Bock, M. G.; Freidinger, R. M.; Gluchowski, C. J. Med.
Chem. 1999, 42, 4778.
9. Barrow, J. C.; Nantermet, P. G.; Selnick, H. G.; Glass, K.
L.; Rittle, K. E.; Gilbert, K. F.; Steele, T. G.; Homnick, C.
F.; Freidinger, R. M.; Ransom, R. W.; Kling, P.; Reis, D.;
Broten, T. P.; Schorn, T. W.; Chang, R. S. L.; O’Malley,
S. S.; Olah, T. V.; Ellis, J. D.; Barrish, A.; Kassahun, K.;
Leppert, P.; Nagarathnam, D.; Forray, C. J. Med. Chem.
2000, 43, 2703.
Results were expressed as the percentage of the maxi-
mum relaxation of the contractions of the compounds.
The responses of the compounds were compared to
those of nicardipine. The data were expressed as
means SD. Student’s t test was used for statistical
analysis. P values <0.05 were considered to be statisti-
cally significant.
4.2.2. Studies on rat thoracic aorta. The thoracic aortas
taken from rats were cut in spirals and 0.3 cm long strips
were fastened in organ bath of 10 ml capacity which
contains Tyrode solution in a gas of 95% O2/5% CO2
and a tension of 2 g was applied. The preparations were
allowed to equilibrate for 60 min with regular washes
every 15 min.
10. Bruce, M.A.; Pointdexter, G.S.; Johnson, G. PCT Int.
Appl. WO 99 07695.
11. Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R.
W.; Schreiber, S. L.; Mitchison, T. J. Science 1999, 286,
971.
12. Haggarty, S. J.; Mayer, T. U.; Miyamoto, D. T.; Fathi, R.;
King, R. W.; Mitchison, T. J.; Schreiber, S. L. Chem. Biol.
2000, 7, 275.
13. Heys, L.; Moore, C. G.; Murphy, P. J. Chem. Soc. Rev.
2000, 29, 57.
In order to check for antagonistic effects, contractions
were induced with potassium chloride (67 mmol/l). After
thorough washing out, this process was repeated until
the amplitude of the contraction became constant. The
substances to be tested were investigated using the sin-
gle-dose technique. Potassium chloride contractions
were induced after addition of the substances at
10À4 M concentration and 10 min exposure time.
Between administrations of the individual substances,
the preparation was washed until the initial situation
14. Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.;
Freyer, A. J.; De Brosse, C.; Mai, S.; Truneh, A.;

_
I. Selin Zorkun et al. / Bioorg. Med. Chem. 14 (2006) 8582–8589
8589
Faulkner, D. J.; Carte, B.; Breen, A. L.; Hertzberg, R. P.;
Johnson, R. K.; Westley, J. W.; Potts, B. C. M. J.Org.
Chem. 1995, 60, 1182.
34. Hu, E. H.; Sidler, D. R.; Dolling, U.-H. J. Org. Chem.
1998, 63, 3454.
35. Lu, J.; Bai, Y. J.; Wang, Z. J.; Yang, B.; Ma, H. R.
Tetrahedron Lett. 2000, 41, 9075.
36. Lu, J.; Ma, H. Synlett 2000, 63.
37. Lu, J.; Bai, Y. Synthesis 2002, 466.
38. Ma, Y.; Qian, C.; Wang, L.; Yang, M. J. Org. Chem. 2000,
65, 3864.
39. Ranu, C. B.; Hajra, A.; Jana, U. J. Org. Chem. 2000, 65,
6270.
15. Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.
16. Hu, E. H.; Sidler, D. R.; Dolling, U.-H. J. Org. Chem.
1998, 63, 3454.
17. Kappe, C. O.; Falsone, S. F. Synlett 1998, 718.
18. Bigi, F.; Carloni, S.; Frullanti, B.; Maggi, R.; Sartori, G.
Tetrahedron Lett. 1999, 40, 3465.
19. Singh, K.; Singh, J.; Deb, P. K.; Singh, H. Tetrahedron
1999, 55, 12873.
20. Lu, J.; Ma, H. Synlett 2000, 63.
21. O’Reilly, B. C.; Atwal, K. S. Heterocycles 1987, 26,
1185.
40. Fu, N.-Y.; Yuan, Y.-F.; Cao, Z.; Wang, S.-W.; Wang,
J.-T.; Peppe, C. Tetrahedron 2002, 58, 4801.
41. Ramalinga, K.; Vijayalakshmi, P.; Kaimal, T. N. B.
Synlett 2001, 863.
22. Atwal, K. S.; O’Reilly, B. C.; Gougoutas, J. Z.; Malley,
M. F. Heterocycles 1987, 26, 1189.
42. Kumar, K. A.; Kasthuraiah, M.; Reddy, C. S.; Reddy, C.
D. Tetrahedron Lett. 2001, 42, 7873.
23. Atwal, K. S.; Rovnyak, G. C.; O’Reilly, B. C.; Schwartz,
J. J. Org. Chem. 1989, 54, 5898.
24. Shutalev, A. D.; Kishko, E. A.; Sivova, N.; Kuznetsov, A.
Y. Molecules 1998, 3, 100.
43. Tu, S.; Fang, F.; Miao, C.; Jiang, H.; Feng, Y.; Shi, D.;
Wang, X. Tetrahedron Lett. 2003, 44, 6153.
44. Fan, Xuesen; Zhang, X.; Zhang, Y. J. Chem. Res. (S)
2002, 436.
25. Wipf, P.; Cunningham, A. Tetrahedron Lett. 1995, 36,
7819.
26. Studer, A.; Jeger, P.; Wipf, P.; Curan, D. P. J. Org. Chem.
1997, 62, 2917.
27. Studer, A.; Hadida, S.; Ferritto, R.; Kim, S. Y.; Jeger, P.;
Wipf, P.; Curan, D. P. Science 1997, 275, 823.
´
28. Lewandowski, K.; Murer, P.; Svec, F.; Frechet, J. M. J.
45. Reddy, C. V.; Mahesh, M.; Raju, P. V. K.; Babu, T. R.;
Reddy, V. V. N. Tetrahedron Lett. 2002, 43, 2657.
46. Kappe, C. J. Org. Chem. 1997, 62, 7201.
47. Sarac¸, S.; Yarım, M.; Ertan, M.; Erol, K.; Aktan, Y. Boll.
Chim. Farmaceutico. 1997, 136, 657.
48. Sarac¸, S.; Yarım, M.; Ertan, M.; Boydag˘, S.; Erol, K.
Pharmazie 1998, 53, 91.
¨
49. Yarım, M.; Sarac¸, S.; Ertan, M.; Batu, O. S.; Erol, K. Il
Farmaco 1999, 54, 359.
50. Sarac¸, S.; Yarım, M.; Ertan, M.; Kılıc¸, F. S.; Erol, K.
Pharmazie 2001, 56, 298.
51. Yarım, M.; Sarac¸, S.; Ertan, M.; Kılıc¸, F. S.; Erol, K.
Arzneim. Forsch./Drug Res. 2002, 52, 27.
52. Yarım, M.; Sarac¸, S.; Kılıc¸, F. S.; Erol, K. Il Farmaco
2003, 58, 17.
53. Loev, B.; Goodman, M. M.; Shader, K. M.; Tedesch, R.;
Macko, E. J. Med. Chem. 1974, 17, 956.
Chem. Commun. 1998, 2237.
29. Lewandowski, K.; Murer, P.; Svec, F.; Frechet, J. M.
´
J. J. Comb. Chem. 1999, 1, 105.
30. Dondoni, A.; Massi, A. Tetrahedron Lett. 2001, 42,
7975.
31. Cappe, C. O.; Stadler, A. In Organic Reactions, The
Biginelli dihydropyrimidine synthesis; Overman, L. E., Ed.;
John Wiley& Sons: New York, 2004; pp 1–116.
32. Tozkoparan, B.; Yarım, M.; Sarac¸, S.; Ertan, M.; Kelicen,
P.; Altınok, G.; Demirdamar, R. Arch. Pharm. Pharm.
Med. Chem. 2000, 333, 415.
54. Ohtsuka, M.; Yokota, M.; Kodama, I.; Yamada, K.;
Shibata, S. Gen. Pharmac. 1989, 20, 539.
55. Triggle, D. J. Stroke 1990, 21(Suppl. IV), 49.
¨
33. Yarım, M.; Tozkoparan, B.; Sarac¸, S.; Ertan, M.; Ozc¸elik,
B.; Abbasog˘lu, U. FABAD J. Pharm. Sci. 2002, 27, 65.