Synthesis, structural elucidation and pharmacological properties of some 5-acetyl-3,4-dihydro-6-methyl-4-(substituted phenyl)-2(1H)-pyrimidinones

Article abstract of DOI:10.1016/S0014-827X(99)00042-7

In this study, the synthesis of some new 5-acetyl-3,4-dihydro-6-methyl-4-(substituted phenyl)-2(1H)-pyrimidimones has been reported. The compounds were prepared by the Biginelli reaction of acetylacetone with aromatic aldehydes and urea. The structures of

Full text of DOI:10.1016/S0014-827X(99)00042-7

www.elsevier.nl/locate/farmac
Il Farmaco 54 (1999) 359–363
Synthesis, structural elucidation and pharmacological properties of
some 5-acetyl-3,4-dihydro-6-methyl-4-(substituted
phenyl)-2(1H)-pyrimidinones
a
a,
a
b
b
8
M. Yarım , S. Sarac¸ *, M. Ertan , O. (Sarnıc¸) Batu , K. Erol
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe Uni6ersity, 06100 Ankara, Turkey
b Department of Pharmacology, Faculty of Medicine, Osmangazi Uni6ersity, Eskis¸ehir, Turkey
Received 27 July 1998; accepted 22 March 1999
Abstract
In this study, the synthesis of some new 5-acetyl-3,4-dihydro-6-methyl-4-(substituted phenyl)-2(1H)-pyrimidinones has been
reported. The compounds were prepared by the Biginelli reaction of acetylacetone with aromatic aldehydes and urea. The
structures of the compounds were characterized by UV, IR, 1H NMR, 13C NMR, mass spectra and elementary analysis. The
calcium antagonistic activity of these compounds was tested in vitro on rat ileum precontracted with 4×10−3 M barium chloride.
© 1999 Elsevier Science S.A. All rights reserved.
Keywords: Tetrahydropyrimidine-2-ones; Synthesis; UV, IR, 1H and 13C NMR, and mass spectra; Calcium antagonistic activity
1. Introduction
Calcium channel blockers have attained major sig-
nificance in the therapy for cardiovascular diseases
during the past few years [1,2]. It has been reported that
some 1,2,3,4-tetrahydro-, 2-oxo- or 2-thioxo-1,2,3,4-te-
trahydropyrimidine derivatives have vasodilator, anti-
hypertensive and calcium channel blocker activities
[3,4]. In our previous studies, the synthesis and calcium
antagonistic activities of some 1,2,3,4-tetrahydro-6-
methyl-4-(substituted
phenyl)-2-thioxo-5-pyrimidine-
carboxylic acid methyl esters (I) have been described
[5,6]. In order to acquire further information on the
structural characteristics enhancing calcium antagonis-
tic activity in this series of compounds, we aimed to
synthesize some new 5-acetyl-3,4-dihydro-6-methyl-4-
(substituted phenyl)-2(1H)-pyrimidinone derivatives
(II) and to test their calcium antagonistic activity.
2. Experimental
All chemicals used in this study were supplied by
Merck (Darmstadt, Germany). Melting points were
determined with a Thomas–Hoover capillary melting
point apparatus and were uncorrected. UV absorptions
were measured on a Shimadzu UV-160A UV–visible
spectrophotometer. The IR spectra were taken with a
Perkin–Elmer FT-IR spectrophotometer 1720x (KBr
disc). 1H NMR spectra were recorded on Bruker AC 80
and 200 MHz FT-NMR spectrometers using TMS as
internal standard. 13C NMR data were obtained with a
Bruker DPX400, 400 MHz high performance digital
ST-NMR spectrometer. All chemical shift values were
* Corresponding author.
0014-827X/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(99)00042-7

360
M. Yarım et al. / Il Farmaco 54 (1999) 359–363
recorded as l (ppm). Mass spectra were taken on VG
analytical 70-250 S and Finnigan MAT-GCQ mass
spectrometers with electron ionization (EI) (Mu¨nster,
Germany). The purity of the compounds was checked
by thin-layer chromatography (Merck, silica gel,
HF254–361, type 60, 0.25 mm). Elemental analysis of the
compounds was performed on a Leco CHNS 932 ana-
lyzer at the Scientific and Technical Research Council
of Turkey, Instrumental Analysis Laboratory at
Ankara.
2.2. Determination of calcium antagonist acti6ity
Male and female albino rats weighing between 200
and 220 g were used in this study. Animals entering the
test fasted overnight. After the animals had been sac-
rificed by cervical dislocation, the ileum (10–15 cm
terminal portion) was immediately removed, discarding
the 5–8 cm segment proximal to the ilio–caecal junc-
tion. 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.
2.1. Preparation of 5-acetyl-3,4-dihydro-6-methyl-4-
(substituted phenyl)-2(1H)-pyrimidinones
A mixture of 1.50 g (0.015 mol) of acetylacetone,
0.60 g (0.01 mol) of urea and 0.01 mol of substituted
benzaldehyde in 20 ml abs. ethanol was treated with
four drops of 37% HCl as catalyst and then stirred at
room temperature for a few hours. The crude product
precipitated on cooling was filtered and washed with
50% ethanol, then it was recrystallized several times
from ethanol.
A tension of 2 g was applied and isometric recording
was done by using an isometric transducer (T-FDT10-
A). Responses were recorded through a MAY TDA95
transducer data acquisition system.
The preparations were allowed to equilibrate for 60
min with regular washes every 15 min. In order to
check for antagonistic activity, contractions were in-
duced with barium chloride (4×10−3 M, bath concen-
tration). After thorough washing, this process was
repeated until the amplitude of the contraction became
constant.
The empirical formula of the compounds, melting
points, reaction yields and elemental analysis data are
shown in Table 1. Their structures were elucidated by
1
spectral methods. UV, IR, and H and 13C NMR data
Investigation of the substances to be tested was per-
formed using the single-dose technique. The barium
of the compounds are shown in Tables 2 and 3.
Table 1
Melting points, yields, empirical formula and elemental analyses of the synthesized compounds
Comp.
R
M.p. (°C)
Yield (%)
Empirical formula
Elemental analysis
Calc. (%)
Found (%)
C
H
N
C
H
N
IIa a
IIb
IIc
–H
2-Cl
3-Cl
4-Cl
2-Br
3-Br
2-CH3
3-CH3
4-CH3
2-OCH3
3-OCH3
234–235
257–258
284–285
215–216
222–223
220–221
218–219
253–254
228–229
251–252
245–246
35.70
32.11
31.36
36.64
24.58
28.46
33.57
39.30
37.66
29.58
29.19
C13H14N2O2
72.87
58.99
58.99
58.99
50.51
50.51
68.83
68.83
68.83
64.60
64.60
6.59
4.95
4.95
4.95
4.24
4.24
6.60
6.60
6.60
6.20
6.20
13.07
10.58
10.58
10.58
9.06
72.95
58.80
58.99
58.82
50.50
51.12
69.41
68.64
70.08
64.36
64.27
6.46
4.48
4.02
4.65
4.76
4.41
7.03
6.77
7.07
6.12
5.59
12.93
10.51
10.54
10.47
9.38
C13H13ClN2O2
C13H13ClN2O2
C13H13ClN2O2
C13H13BrN2O2
IId a
IIe
IIf
C13H13BrN2O2
9.06
9.47
IIg
IIh
IIi
C14H16N2O2
C14H16N2O2
C14H16N2O2
C14H16N2O3
C14H16N2O3
11.47
11.47
11.47
10.76
10.76
11.55
11.40
11.82
10.47
10.66
IIj a
IIk
a Compounds IIa, IId and IIj have been reported in the literature [7,8].

M. Yarım et al. / Il Farmaco 54 (1999) 359–363
361
Table 2
UV, IR and 1H NMR spectral data of the compounds
Comp. UVmax (MeOH)
IR (KBr) w (cm−1
)
1H NMR (DMSO-d6) l (ppm)
(log m)
IIa
IIb
IIc
IId
IIe
IIf
300.5 (4.02),
218.0 (3.85)
3257 (N–H), 1703 (CꢀO, acetyl), 1675 (CꢀO, ring),
2.05 (3H, s, CH3–CO), 2.28 (3H, s, CH3), 5.26 (1H, d,
J 3.41 Hz, H-4), 7.07–7.49 (5H, m, hydrogens of
phenyl ring), 7.82 (1H, s, N1–H), 9.16 (1H, s, N3–H)
2.18 (3H, s, CH3–CO), 2.29 (3H, s, CH3), 5.63 (1H, d,
J 3.43 Hz, H-4), 7.06–7.55 (4H, m, hydrogens of
phenyl ring), 7.74 (1H, s, N1–H), 9.28 (1H, s, N3–H)
2.07 (3H, s, CH3–CO), 2.30 (3H, s, CH3), 5.23 (1H, d,
J 3.41 Hz, H-4), 6.99–7.54 (4H, m, hydrogens of
phenyl ring), 7.89 (1H, s, N1–H), 9.24 (1H, s, N3–H)
2.15 (3H, s, CH3–CO), 2.30 (3H, s, CH3), 5.30 (1H, d,
J 3.50 Hz, H-4), 7.10–7.50 (4H, m, hydrogens of
phenyl ring), 7.85 (1H, s, N1–H), 9.20 (1H, s, N3–H)
2.15 (3H, s, CH3–CO), 2.30 (3H, s, CH3), 5.25 (1H, d,
J 3.50 Hz, H-4), 7.10–7.50 (4H, m, hydrogens of
phenyl ring), 7.80 (1H, s, N1–H), 9.20 (1H, s, N3–H)
2.05 (3H, s, CH3–CO), 2.30 (3H, s, CH3), 5.60 (1H, d,
J 3.40 Hz, H-4), 7.00–7.55 (4H, m, hydrogens of
phenyl ring), 7.65 (1H, s, N1–H), 9.20 (1H, s, N3–H)
2.10 (3H, s, CH3–CO), 2.26 (3H, s, CH3), 2.50 (3H, s,
Ar–CH3), 5.25 (1H, d, J 3.50 Hz, H-4), 6.80–7.50 (4H,
m, hydrogens of phenyl ring), 7.80 (1H, s, N1–H), 9.15
(1H, s, N3–H)
769, 706 (mono subst. benzene)
300.5 (3.87),
235.5 (3.69)
3247 (N–H), 1704 (CꢀO, acetyl), 1623 (CꢀO, ring),
757 (1,2-disubst. benzene)
300.5 (3.96),
234.5 (3.64)
3273 (N–H), 1703 (CꢀO, acetyl), 1615 (CꢀO, ring),
873, 800 (1,3-disubst. benzene)
300.5 (4.03),
221.0 (4.04)
3288 (N–H), 1702 (CꢀO, acetyl), 1619 (CꢀO, ring),
839 (1,4-disubst. benzene)
300.2 (3.70),
235.0 (3.48)
3235 (N–H), 1704 (CꢀO, acetyl), 1624 (CꢀO, ring),
755 (1,2-disubst. benzene)
300.0 (3.66),
226.0 (3.51)
3281 (N–H), 1703 (CꢀO, acetyl), 1614 (CꢀO, ring),
876, 799 (1,3-disubst. benzene)
IIg
302.0 (3.96),
234.5 (3.73)
3241 (N–H), 1704 (CꢀO, acetyl), 1625 (CꢀO, ring),
752 (1,2-disubst. benzene)
IIh
IIi
300.5 (3.98),
233.5 (3.69)
3226 (N–H), 1702 (CꢀO, acetyl), 1594 (CꢀO, ring),
2.08 (3H, s, CH3–CO), 2.27 (6H, s, CH3 and Ar–CH3),
5.22 (1H, d, J 3.36 Hz, H-4), 6.81–7.38 (4H, m, hydro-
gens of phenyl ring), 7.77 (1H, s, N1–H), 9.14 (1H, s,
N3–H)
2.00 (3H, s, CH3–CO), 2.26 (3H, s, CH3), 2.55 (3H, s,
Ar–CH3), 5.21 (1H, d, J 3.51 Hz, H-4), 6.87–7.37 (4H,
m, hydrogens of phenyl ring), 7.76 (1H, s, N1–H), 9.15
(1H, s, N3–H)
883, 785 (1,3-disubst. benzene)
299.0 (3.17),
218.4 (3.15)
3290 (N–H), 1700 (CꢀO, acetyl), 1619 (CꢀO, ring),
823 (1,4-disubst. benzene)
IIj
300.5 (3.98),
220.0 (4.00)
3274 (N–H), 1702 (CꢀO, acetyl), 1682 (CꢀO, ring),
762 (1,2-disubst. benzene)
2.01 (3H, s, CH3–CO), 2.27 (3H, s, CH3), 3.82 (3H, s,
OCH3), 5.57 (1H, d, J 3.30 Hz, H-4), 6.71–7.12 (4H,
m, hydrogens of phenyl ring), 7.28 (1H, s, N1–H), 9.13
(1H, s, N3–H)
IIk
299.4 (3.36),
223.4 (3.39)
3273 (N–H), 1716 (CꢀO, acetyl), 1681 (CꢀO, ring),
757 (1,3-disubst. benzene)
2.04 (3H, s, CH3–CO), 2.28 (3H, s, CH3), 3.73 (3H, s,
OCH3), 5.22 (1H, d, J 3.39 Hz, H-4), 6.65–7.00 (3H,
m, H-4, H-5 and H-6 of phenyl ring), 7.09–7.38 (1H,
m, H-2 of phenyl ring), 7.76 (1H, s, N1–H), 9.18 (1H,
s, N3–H)
Table 3
13C NMR (DMSO-d6) spectral data of compounds IIb and IIh
Comp.
C2
C4
C5
C6
C7
C8
C9
C1’
C2’
C3’
C4’
C5’
C6’
C7’
IIb
IIh
149.55
152.94
49.64
54.76
106.50
110.40
125.92
124.36
192.03
195.18
16.90
19.73
28.13
22.02
138.88
145.10
146.80
129.30
129.89
148.81
127.36
128.85
126.57
138.40
127.69
127.89
–
31.11

362
M. Yarım et al. / Il Farmaco 54 (1999) 359–363
Scheme 1.
Scheme 2. Fragmentation pathway of the compounds (IIa, IIc, IIh–k).
chloride contractions were induced after addition of
pounds were dissolved in dimethylsulfoxide and the
control responses were taken after the addition of
0.1 ml DMSO. Results are expressed as the per-
cent of maximum relaxation of the contractions
(Table 4).
the test substances at different concentrations (10−6
10−5 and 10−4 M) and 5 min of exposure time.
,
Only one compound was tested in each prepara-
tion. Because of the solubility problems, the com-

M. Yarım et al. / Il Farmaco 54 (1999) 359–363
363
Table 4
The reported mass spectra data are in full agree-
ment with the proposed structures (Scheme 2). The
elemental analysis results of the compounds also sup-
ported the postulated structure.
The relaxant effects of nicardipine and the compounds for relaxant
response on isolated rat ileum (n=number of experiments)
Comp.
R
Concentration Relaxant effects (%)
The calcium antagonistic activity of the compounds
IIa–k was evaluated in vitro by preventing BaCl2-in-
duced contractions in rat ileum [10,11] and then com-
paring with results of nicardipine activity under the
same experimental conditions. As can be seen in
Table 4, the maximum relaxation values of all these
compounds were negligible when compared to those
of nicardipine. Compound IIe, with a 2-bromo sub-
stituent, is the most active with 23.7593.26% of
maximum relaxation. Compounds IIi and IId, carry-
ing 4-methyl and 4-chloro substituents on the aro-
matic ring, respectively, have almost the same
activity.
IIa
IIb
IIc
IId
IIe
IIf
IIg
IIh
–H
2-Cl
3-Cl
4-Cl
2-Br
3-Br
2-CH3
3-CH3
4-CH3
2-OCH3
3-OCH3
10−4 (n=6)
10−4 (n=8)
10−4 (n=8)
10−4 (n=8)
10−4 (n=8)
10−4 (n=8)
10−4 (n=8)
10−4 (n=8)
10−4 (n=8)
10−4 (n=6)
10−4 (n=8)
10−8 (n=6)
16.1794.69
11.5092.97
13.8893.39
19.7594.91
23.7593.26
16.3892.65
17.5092.99
11.5092.94
19.1393.52
10.0094.26
11.1391.31
71.5095.54
IIi
IIj
IIk
Nicardipine
3. Results and discussion
References
The synthetic pathway employed in the preparation of
5-acetyl-3,4-dihydro-6-methyl-4-(substituted phenyl)-
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new 2-thioxo-1,2,3,4-tetrahydropyrimidine derivatives, Arch.
Pharm. (Weinheim) 324 (1991) 135–139.
2(1H)-pyrimidinones is outlined in Scheme 1. The con-
densation of acetylacetone, substituted benzaldehyde
and urea in abs. ethanol, catalyzed by HCl, proceeded
according to the Biginelli reaction (Scheme 1) [9].
Compounds IIa, IId and IIj have been reported in the
literature [7,8]. Since there were no pharmacological data
available on these compounds, they have been synthe-
sized to test their calcium antagonistic activity.
Although the compounds have an asymmetric center
on the fourth position, their resolutions have not been
done. The purity of the compounds was checked by
thin-layer chromatography (silica gel HF254+366, Merck).
The structures of the compounds were confir-
med by spectral data. All UV spectra showed two
absorption maxima in the 218–235 and 299–302 nm
regions, respectively. In the IR spectra all the compounds
displayed strong absorption bands at 3290–3226 cm−1
(N–H), 1716–1700 cm−1 (CꢀO, acetyl) and 1682–1594
cm−1 (CꢀO, ring), respectively. Additionally, disubsti-
tuted benzene deformation bands were observed in the
[6] M. Ertan, A. Balkan, S. Sarac¸, S. Uma, K. Ru¨bseman, J.F.
Renaud, Synthesis and biological evaluations of some 2-
thioxo-1,2,3,4-tetrahydropyrimidine
derivatives,
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1
expected wave number regions. In the H NMR spectra
of the compounds the protons of the acetyl and methyl
groups appeared as two singlets at about 2.00–2.18 and
2.26–2.30 ppm, respectively. The doublet appearing in
the range 5.21–5.63 ppm confirmed the ring closure. The
signals of the N1–H and N3–H protons appeared as a
singlet at about 7.28–7.89 and 9.13–9.28 ppm. The
phenyl protons were seen at the expected chemical shifts
and integral values. In the 13C NMR spectra of the
compounds IIb and IIh the most shielded carbons are C7
and C2 (Table 3). The chemical shifts of C7 and C2 are
192.03 and 149.55 ppm for compound IIb, and 195.18
and 152.94 ppm for compound IIh, respectively.
.