Synthesis and anti-inflammatory activities of some thiazolo[3,2-a]pyrimidine derivatives

Article abstract of DOI:10.1016/S0014-827X(99)00068-3

Sixteen new 2-benzylidene-7-methyl-3-oxo-5-(substituted phenyl)-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid methyl esters (1a-4d) have been synthesized by reacting 1,2,3,4-tetrahydropyrimidine-2-thiones (1-4) with chloroacetic acid and appropriate benzaldehydes in a single step. Their structures have been proved by IR, ¹H NMR, mass spectra and elemental analysis. The compounds were tested for their anti-inflammatory activities. Test results revealed that compounds 1b, 1c, 4a and 4c exerted moderate anti-inflammatory activity at the 100 mg/kg dose level compared with indomethacin. Copyright (C) 1999 Elsevier Science S.A.

Full text of DOI:10.1016/S0014-827X(99)00068-3

www.elsevier.nl/locate/farmac
Il Farmaco 54 (1999) 588–593
Synthesis and anti-inflammatory activities of some
thiazolo[3,2-a]pyrimidine derivatives
Birsen Tozkoparan a, Mevlu¨t Ertan a,*, Pelin Kelicen b, Ru¨meysa Demirdamar b
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe Uni6ersity, 06100, Ankara, Turkey
b Department of Pharmacology, Faculty of Pharmacy, Hacettepe Uni6ersity, 06100, Ankara, Turkey
Received 4 March 1999; accepted 10 June 1999
Abstract
Sixteen new 2-benzylidene-7-methyl-3-oxo-5-(substituted phenyl)-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid
methyl esters (1a–4d) have been synthesized by reacting 1,2,3,4-tetrahydropyrimidine-2-thiones (1–4) with chloroacetic acid and
appropriate benzaldehydes in a single step. Their structures have been proved by IR, 1H NMR, mass spectra and elemental
analysis. The compounds were tested for their anti-inflammatory activities. Test results revealed that compounds 1b, 1c, 4a and
4c exerted moderate anti-inflammatory activity at the 100 mg/kg dose level compared with indomethacin. © 1999 Elsevier Science
S.A. All rights reserved.
Keywords: 1,2,3,4-Tetrahydropyrimidine-2-thiones; Thiazolo[3,2-a]pyrimidines; Synthesis; Anti-inflammatory activity
In this study, synthesis, structural elucidation and
anti-inflammatory activities of a new series of thia-
zolo[3,2-a]pyrimidine having 4-bromo, 4-methoxy, 4-
methyl, 2-fluorophenyl at position 5 and 4-methyl,
4-methoxy, 4-chloro and non-substituted benzylidene at
position 2 are reported.
1. Introduction
The chemistry and the synthesis of 1,2,3,4-tetrahydro-
pyrimidine-2-ones(-thiones) have been attracting wide-
spread attention in recent years. The present popularity
of these tetrahydropyrimidines is mainly due to their
close structural relationship to the clinically important
dihydropyridine calcium channel blockers [1–6].
2. Experimental
1,2,3,4-Tetrahydropyrimidine-2-thiones are the key
intermediate for the synthesis of condensed pyrimidi-
nes. Their various condensed derivatives are reported to
possess calcium antagonist [7–9], anti-inflammatory
[10–12], analgesic [13], antitumor [14,15], antidepres-
sant [16], antibacterial and antifungal effects [17–19].
In our previous study, we synthesized some 2-ben-
zylidene-7-methyl-3-oxo-5-(substituted phenyl)-2,3-di-
hydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid
methyl esters and investigated their anti-inflammatory
activities [20]. Since few of them showed hopeful phar-
macological results, we decided to investigate the syn-
thesis and anti-inflammatory activities of new
condensed 1,2,3,4-tetrahydropyrimidine derivatives.
2.1. Chemistry
All chemicals were from Aldrich Chemical Co.
(Steinheim, Germany). Melting points were detected
with a Thomas Hoover capillary melting point appara-
tus (Philadelphia, PA, USA) and are uncorrected. IR
spectra (KBr) were recorded on a Perkin–Elmer 1720X
FT-IR spectrometer (Beaconsfield, UK). 1H NMR
spectra were obtained using a Bruker 200 MHz FT
NMR instrument (Karlsruhe, Germany) using CDCl3
or DMSO-d6 and tetramethylsilane as an internal stan-
dard. All chemical shift values were recorded as l
(ppm). Mass spectra were taken on a VG Analytical
70-250S or Finnigan MAT GCQ mass spectrometer
with electron ionization (EI) (University of Regensburg
or Westfa¨lische Wilhelms–University of Mu¨nster, Ger-
* Corresponding author. Fax: +90-312-311-4777.
0014-827X/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(99)00068-3

B. Tozkoparan et al. / Il Farmaco 54 (1999) 588–593
589
which appeared as a precipitate, was filtered off
and washed with 50% ethanol. It was then recrystallized
from ethanol. The synthesis and the structural data
of compounds 1–3 were reported previously [5,6].
Compound 4 was newly synthesized and its struc-
ture was proved by IR, 1H NMR and elementary
analysis.
2.1.2. Methyl 6-methyl-4-(2-fluorophenyl)-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4)
M.p. 215–216°C (EtOH). IR (KBr): w=3186 cm−1
(NH), 1665 (CꢀO), 1573, 1490, 1456 (CꢀC), 1347, 1285,
1
1271 (CꢁO, CꢁN), 1196 (CꢀS). H NMR (DMSO-d6):
l=2.30 (s, 3H, ꢁCH3), 3.50 (s, 3H, ꢁOCH3), 5.50 (d,
J=3.68 Hz, 1H, H-4), 6.90–7.40 (m, 4H, arom. H),
9.60 (s, 1H, N1ꢁH), 10.40 (s, 1H, N3ꢁH). Anal.
(C13H13FN2O2S) C, H, N.
Scheme 1.
many). The purity of the compounds was controlled by
2.1.3. Methyl 2-benzylidene-7-methyl-3-oxo-5-phenyl-
2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxy-
lates (1a–4d)
These were obtained by reacting 1,2,3,4-tetra-
hydropyrimidine-2-thiones (1–4) with chloroacetic acid
and the appropriate benzaldehydes as reported in Ref.
[20].
thin layer chromatography (Merck, silicagel, HF254–361
,
type 60, 0.25 mm, Darmstadt, Germany). The elemen-
tary analyses were performed by Westfa¨lische Wil-
helms–University of Mu¨nster, Germany. Elementary
analyses for C, H, N were within 90.4% of theoretical
values.
2.1.1. Methyl 6-methyl-4-(substituted phenyl)-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylates (1–4)
A mixture of thiourea (0.05 mol), substituted benz-
aldehyde (0.05 mol), methyl acetoacetate (0.075 mol),
dry ethanol (20 ml) and 37% HCl (eight drops) was
heated under reflux for an appropriate period and
the reaction solution was allowed to cool. The product,
2.2. Pharmacology
Local breed albino mice of both sexes (Refik Saydam
Hıfzıssıhha Institute, Animal Care Unit, Ankara,
Turkey) weighing approximately 20–25 g were used.
Six randomly chosen mice were housed for 2 days
for acclimatization to room conditions and were main-
Table 1
Some characteristics of the compounds 1a–4d
Comp. no.
R
R%
M.p. (°C)
Yield (%)
Formula (MW)
22H17BrN2O3S
C23H19BrN2O3S
C23H19BrN2O4S
C22H16BrClN2O3S
Analysis a
1a
1b
1c
1d
4-Br
-H
143–144
204–205
161–162
197–198
63.10
53.79
66.88
58.55
C
C, H, N
C, H, N
C, H, N
C, H, N
4-CH3
4-OCH3
4-Cl
2a
2b
2c
2d
4-OCH3
4-CH3
2-F
-H
171–172
194–195
184–186
217–218
62.43
63.29
61.60
50.56
C23H20N2O4S
C24H22N2O4S
C24H22N2O5S
C23H19ClN2O4S
C, H, N
C, H, N
C, H, N
C, H, N
4-CH3
4-OCH3
4-Cl
3a
3b
3c
3d
-H
167–168
218–219
167–168
198–199
50.20
39.13
44.13
55.93
C23H20N2O3S
C24H22N2O3S
C24H22N2O4S
C23H19ClN2O3S
C, H, N
C, H, N
C, H, N
C, H, N
4-CH3
4-OCH3
4-Cl
4a
4b
4c
4d
-H
192–193
132–133
213–214
133–134
52.64
74.56
45.61
62.09
C22H17FN2O3S
C23H19FN2O3S
C23H19FN2O4S
C22H16ClFN2O3S
C, H, N
C, H, N
C, H, N
C, H, N
4-CH3
4-OCH3
4-Cl
a Analytical results for C, H, N were within 90.4% of the calculated values.

590
B. Tozkoparan et al. / Il Farmaco 54 (1999) 588–593
Table 2
IR and 1H NMR data of the compounds 1a–4d
Comp. no. IR (KBr): w (cm−1
)
1H NMR (CDCl3): l (ppm) (J in Hz)
1a
1b
1c
1708 (CꢀO), 1603 (CꢀN) 2.50 (s, 3H, ꢁCH3), 3.65 (s, 3H, ꢁOCH3), 6.15 (s, 1H, H-5), 7.20–7.50
(m, 9H, arom.H), 7.70 (s, 1H, ꢀCꢁH)
1708, (CꢀO), 1598 (CꢀN) 2.40 (s, 3H, ꢀCHꢁC6H4ꢁCH3), 2.55 (s, 3H, ꢁCH3), 3.65 (s, 3H, ꢁOCH3), 6.15
(s, 1H, H-5), 7.20–7.50 (m, 8H, arom.H), 7.75 (s, 1H, ꢀCꢁH)
1714 (CꢀO), 1588 (CꢀN) 2.50 (s, 3H, ꢁCH3), 3.65 (s, 3H, ꢁOCH3), 3.85 (s, 3H, ꢀCHꢁC6H4ꢁOCH3), 6.15
(s, 1H, H-5), 6.95 (d, J=8.70 Hz, 2H, arom.H), 7.30 (d, J=8.70 Hz, 2H, arom.H),
7.40–7.50 (m, 4H, arom.H), 7.70 (s, 1H, ꢀCꢁH)
1717 (CꢀO), 1608 (CꢀN) 2.50 (s, 3H, ꢁCH3), 3.65 (s, 3H, ꢁOCH3), 6.15 (s, 1H, H-5), 7.20–7.50 (m, 9H, arom.H),
7.70 (s, 1H, ꢀCꢁH)
1d
2a
2b
1706 (CꢀO), 1622 (CꢀN) 2.50 (s, 3H, ꢁCH3), 3.65 (s, 3H, ꢁOCH3), 3.80 (s, 3H, ꢁC6H4ꢁOCH3), 6.15 (s, 1H, H-5),
6.82 (d, J=8.50 Hz, 2H, arom.H), 7.25–7.50 (m, 7H, arom.H), 7.75 (s, 1H, ꢀCꢁH)
1703 (CꢀO), 1599 (CꢀN). 2.40 (s, 3H, ꢀCHꢁC6H4ꢁCH3), 2.55 (s, 3H, ꢁCH3), 3.65 (s, 3H, ꢁOCH3), 3.75
(s, 3H, ꢁC6H4ꢁOCH3), 6.15 (s, 1H, H-5), 6.80 (d, J=8.50 Hz, 2H, arom.H), 7.20–7.40
(m, 6H, arom.H), 7.75 (s, 1H, ꢀCꢁH)
2c
2d
1710 (CꢀO), 1596 (CꢀN) 2.55 (s, 3H, ꢁCH3), 3.65 (s, 3H, ꢁOCH3), 3.75 (s, 3H, ꢁC6H4ꢁOCH3), 3.85
(s, 3H, ꢀCHꢁC6H4ꢁOCH3), 6.15 (s, 1H, H-5), 6.80 (d, J=8.50 Hz, 2H, arom.H), 6.95
(d, J=8.50 Hz, 2H, arom.H), 7.25–7.45 (m, 4H, arom.H), 7.70 (s, 1H, ꢀCꢁH)
1704 (CꢀO), 1625 (CꢀN) 2.50 (s, 3H, ꢁCH3), 3.65 (s, 3H, ꢁOCH3), 3.75 (s, 3H, ꢁC6H4ꢁOCH3), 6.15 (s, 1H, H-5),
6.80 (d, J=8.30 Hz, 2H, arom.H), 7.25–7.50 (m, 6H, arom.H), 7.70 (s, 1H, ꢀCꢁH)
3a
3b
3c
1710 (CꢀO), 1604 (CꢀN) 2.30 (s, 3H, ꢁC6H4ꢁCH3), 2.50 (s, 3H, ꢁCH3), 3.65 (s, 3H, ꢁOCH3), 6.15 (s, 1H, H-5),
7.10–7.50 (m, 9H, arom.H), 7.70 (s, 1H, ꢀCꢁH)
1714 (CꢀO), 1601 (CꢀN) 2.30 (s, 3H, ꢁC6H4ꢁCH3), 2.40 (s, 3H, ꢀCHꢁC6H4ꢁCH3), 2.55 (s, 3H, ꢁCH3), 3.65
(s, 3H, ꢁOCH3), 6.15 (s, 1H, H-5), 7.05–7.40 (m, 8H, arom.H), 7.70 (s, 1H, ꢀC–H)
1708 (CꢀO), 1595 (CꢀN) 2.30 (s, 3H, ꢁC6H4ꢁCH3), 2.55 (s, 3H, ꢁCH3), 3.65 (s, 3H, ꢁOCH3), 3.85
(s, 3H, ꢀCHꢁC6H4ꢁOCH3), 6.15 (s, 1H, H-5), 6.95 (d, J=8.20 Hz, 2H, arom.H), 7.10
(d, J=8.20 Hz, 2H, arom.H), 7.30 (d, J=8.20, 2H, arom.H), 7.40 (d, J=8.20 Hz, 2H, arom.H),
7.70 (s, 1H, ꢀCꢁH)
1715 (CꢀO), 1621 (CꢀN) 2.30 (s, 3H, ꢁC6H4ꢁCH3), 2.50 (s, 3H, ꢁCH3), 3.65 (s, 3H, ꢁOCH3), 6.15 (s, 1H, H-5), 7.10
(d, J=8.50 Hz, 2H, arom.H), 7.30 (d, J=8.50 Hz, 2H, arom.H), 7.35–7.50 (m, 4H, arom.H),
7.65 (s, 1H, ꢀCꢁH)
3d
4a
4b
4c
4d
1718 (CꢀO), 1604 (CꢀN) 2.50 (s, 3H, ꢁCH3), 3.65 (s, 3H, ꢁOCH3), 6.40 (s, 1H, H-5), 6.95–7.50 (m, 9H, arom.H), 7.75
(s, 1H, ꢀCꢁH)
1714 (CꢀO), 1602 (CꢀN) 2.40 (s, 3H, ꢀCHꢁC6H4ꢁCH3), 2.50 (s, 3H, ꢁCH3), 3.65 (s, 3H, ꢁOCH3), 6.40 (s, 1H, H-5),
6.95–7.45 (m, 8H, arom.H), 7.70 (s, 1H, ꢀCꢁH)
1713 (CꢀO), 1595 (CꢀN) 2.50 (s, 3H, ꢁCH3), 3.65 (s, 3H, ꢁOCH3), 3.85 (s, 3H, ꢀCHꢁC6H4ꢁOCH3), 6.40 (s, 1H, H-5),
6.90–7.45 (m, 8H, arom.H), 7.70 (s, 1H, ꢀCꢁH)
1713 (CꢀO), 1607 (CꢀN) 2.50 (s, 3H, ꢁCH3), 3.65 (s, 3H, ꢁOCH3), 6.40 (s, 1H, H-5), 6.95–7.50 (m, 8H, arom.H), 7.65
(s, 1H, ꢀCꢁH)
tained on a standard diet and water ad libitum. The
food was withdrawn on the day before the experiment,
but free access to water was allowed. Mice used in the
present study were cared in accordance with the direc-
tory of the Refik Saydam Hıfzıssıhha Institute’s Animal
Care Unit, which applies the guidelines of the National
Institutes of Health on laboratory animal welfare.
2.2.1. Anti-inflammatory acti6ity: carrageenan induced
edema
The method of Winter et al. [21] was employed with
some modifications. All test samples were administered
to animals at a 100 mg/kg dosage, as a suspension in
0.5% carboxymethyl cellulose using gastric lavage ap-
paratus. One hour after the oral administration of the
test sample, each mouse was injected with 0.01 ml of
Fig. 1. A view of methyl 2-(4-metylbenzylidene)-7-methyl-3-oxo-5-(3-
methoxyphenyl)-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxy-
late [20].

B. Tozkoparan et al. / Il Farmaco 54 (1999) 588–593
591
Scheme 2.
2% carrageenan solution into subplantar tissue of the
right hind paw. The volume of the paw was measured
immediately and again 2 h after the carrageenan injec-
tion with a Peacock thickness gauge. The animals in the
control group received appropriate volumes of the dos-
ing vehicle only. The percent of inhibitory effects of
drugs was calculated according to the following equa-
tion:
Indomethacin was compared to control groups as a
positive control for gastric ulceration.
3. Chemistry
The synthesis of 1,2,3,4-tetrahydropyrimidines (1–4)
was achieved in a one-pot condensation reaction of
aromatic aldehyde, thiourea and methyl acetoacetate in
ethanolic solution, commonly known as the Biginelli
reaction. Reaction of 1–4 with chloroacetic acid and
appropriate benzaldehydes under the previously given
conditions yielded thiazolo[3,2-a]pyrimidines (1a–4d)
(Scheme 1). The melting points, % yields and formulas
of the synthesized compounds are given in Table 1. The
Anti-inflammatory activity (%)=[(n−n%)/n]×100
where n is the difference in thickness between the first
and second measure of the paw in the control group
and n% is the difference in thickness between the first
and second measure of the paw in the group treated
with the test sample.
1
structures of the compounds were elucidated by IR, H
Indomethacin (10 mg/kg) was used as a reference
compound.
NMR, mass spectra and elemental analysis and all
spectral data were in accordance with the assigned
structures (Table 2).
The experiment was repeated at two different dose
levels (25 and 50 mg/kg) for the compounds which
showed significant statistical differences between the
treatments and the control group. ED50 values were
calculated by using the Lichtfield–Wilcoxon method.
Two-way analysis of variance (ANOVA) was em-
ployed as the statistical method.
4. Results and discussion
In the IR spectra no absorption band was detected at
about 3152–3380 cm−1 and 1187–1196 cm−1. The
lack of bands attributable to the NꢁH and CꢀS groups,
respectively, was the evidence of the ring closure. The
lactam CꢀO and ester CꢀO stretching bands were seen
at the same region (at about 1703–1718 cm−1).
2.2.2. Gastrointestinal ulceration studies [22]
Mice were fasted for 24 h (with water ad libitum).
The compounds were suspended in a carboxymethyl
cellulose vehicle and administered orally by lavage at
100 mg/kg/day dose for 5 days in a volume of 0.5
ml/100 g of body weight. The animals were sacrificed
with diethyl ether inhalation 4 h after the last dose and
their stomachs were removed, opened by cutting along
the greater curvature and examined for lesions in the
gastrointestinal mucosa under a dissecting microscope.
Because of the thiourea moiety, there is a possibility
of obtaining two isomeric cyclization products (5H or
7H isomers) in this reaction. The identity of the isolated
1
product has been determined from the H NMR data.
The signal for the C-4 proton in compounds 1–4
appeared at 5.10–5.70 ppm as a doublet. Due to the
electronegative effect of the CꢀO group in position 3 a

592
B. Tozkoparan et al. / Il Farmaco 54 (1999) 588–593
Table 3
Anti-inflammatory activity of 1a–4d
b
Comp.
no.
R
R%
Anti-inflammatory
activity (%)a
ED50
Ulcer incidence
(No./gp.)
1a
1b
1c
1d
4-Br
-H
7
41
38
0
4-CH3
4-OCH3
4-Cl
18.36
18.36
6/8
6/8
2a
2b
2c
2d
4-OCH3
4-CH3
2-F
-H
5
0
0
0
4-CH3
4-OCH3
4-Cl
3a
3b
3c
3d
-H
8
0
6
0
4-CH3
4-OCH3
4-Cl
4a
4b
4c
4d
-H
16
0
28
0
39.68
39.68
6/8
6/8
4-CH3
4-OCH3
4-Cl
Indomethacinc
32
1.98
8/8
a 100 mg/kg p.o. (n=6).
b Since the result was not significant compared to control (P\0.05) ED50 values were not calculated.
c 10 mg/kg p.o.
downfield shift of the C-4 proton was observed when the
ring closure occurred. Therefore, the fused products
1a–4d were identified as 5H-thiazolo[3,2-a]pyrimidine
and not as 7H-thiazolo[3,2-a]pyrimidine. In our previous
study [20], we confirmed the structure of the cyclization
product as 5H-thiazolo[3,2-a]pyrimidine for this type of
compounds by X-ray crystallographic analysis as illus-
trated in Fig. 1.
activity at the 100 mg/kg dose, when ED50 values were
taken into consideration these compounds showed less
anti-inflammatory activity than that of indomethacin. It
is well known that anti-inflammatory compounds can
exhibite ulcerogenic properties. Therefore, the com-
pounds 1b, 1c, 4a and 4c were screened for their
ulcerogenic properties and gastric mucosal erosions
were observed at the 100 mg/kg dose level.
EI-MS spectra of all examined compounds showed
molecular ion peaks as expected. The fragmentation
patterns (Scheme 2) confirmed the suggested structure.
The base peaks were seen at m/e=313 (R%=-H), m/
e=327 (R%=4-CH3), m/e=343 (R%=4-OCH3), m/e=
347 (R%=4-Cl) resulting from cleavage of the CꢁC bond
adjacent to nitrogen (N-3).
Acknowledgements
The authors gratefully acknowledge the financial sup-
port of the Government Planning Office through the
grant 96.K.120930.
Anti-inflammatory activities of the compounds were
screened by the carrageenan induced edema test using
indomethacin as a reference compound. The pharmaco-
logical results indicated that none of the compounds
showed noticeable anti-inflammatory activity (except
1b, 1c, 4a and 4c) at the 100 mg/kg dose level. Although
it has been reported that [20] the introduction of a
chlorine atom into the benzylidene group in position 2
of the ring causes an increase in activity, any significant
activity for compounds carrying chlorine was not ob-
served. As seen in Table 3, the compounds 1b, 1c, 4a
and 4c, which bear 4-bromo- and 2-fluorophenyl at
position 5 of the condensed ring, exhibited some anti-
inflammatory activity. On the other hand, whereas the
compounds 1b and 1c had moderate anti-inflammatory
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