Synthesis, and analgesic and antiparkinsonian activities of thiopyrimidine, pyrane, pyrazoline, and thiazolopyrimidine derivatives from 2-chloro-6-ethoxy-4-acetylpyridine

Article abstract of DOI:10.1007/s00706-008-0937-x

A series of substituted pyridine derivatives were prepared from 2-chloro-6-ethoxy-4-acetylpyridine, which was prepared from the corresponding citrazinic acid as starting material. Reaction of acetylpyridine with thiophene-2-carboxaldehyde afforded the 2-chloro-6-ethoxy-4-β-(2-thienyl) acryloylpyridine, which was reacted with malononitrile in refluxing ethanol in the presence of piperidine as a catalyst to afford the cyanoaminopyrane derivative. Acryloylpyridine was treated with urea or guanidine hydrochloride in refluxing ethanolic potassium hydroxide to give the corresponding pyrimidinone and aminopyrimidine derivatives. The latter was condensed with hydrazine hydrate or phenyl hydrazine to give pyrazoline and N-phenylpyrazoline derivatives. Finally, cycloaddition reaction of acryloylpyridine with thiourea yielded thioxopyrimidine, which was treated with 2-bromopropionic acid, 3-bromopropionic acid, or bromoacetic acid to yield methylthiazolo-, thiazino-, and thiazolopyrimidine derivatives. The arylmethylene derivative was prepared by reacting thiazolopyrimidine with benzaldehyde or by reacting thioxopyrimidine with benzaldehyde and bromoacetic acid in one step. The pharmacological screening showed that many of these compounds have good analgesic and antiparkinsonian activities comparable to Valdecoxib and Benzatropine as reference drugs.

Full text of DOI:10.1007/s00706-008-0937-x

Monatsh Chem 139, 1409–1415 (2008)
DOI 10.1007/s00706-008-0937-x
Printed in The Netherlands
Synthesis, and analgesic and antiparkinsonian activities
of thiopyrimidine, pyrane, pyrazoline, and thiazolopyrimidine
derivatives from 2-chloro-6-ethoxy-4-acetylpyridine
Abd El-Galil E. Amr1, Soher S. Maigali2, Mohamed M. Abdulla3
1
National Research Center, Applied Organic Chemistry Department, Dokki, Cairo, Egypt
2
National Research Center, Organometallic and Organometalloid Chemistry Department, Dokki, Cairo, Egypt
3
Research Units, Hi-Care Pharmaceutical Co., Cairo, Egypt
Received 13 March 2008; Accepted 17 March 2008; Published online 2 June 2008
# Springer-Verlag 2008
Abstract A series of substituted pyridine derivatives
were prepared from 2-chloro-6-ethoxy-4-acetylpyri-
dine, which was prepared from the corresponding
citrazinic acid as starting material. Reaction of ace-
tylpyridine with thiophene-2-carboxaldehyde afforded
the 2-chloro-6-ethoxy-4-ꢀ-(2-thienyl)acryloylpyridine,
which was reacted with malononitrile in refluxing
ethanol in the presence of piperidine as a catalyst to
afford the cyanoaminopyrane derivative. Acryloylpyr-
idine was treated with urea or guanidine hydrochlo-
ride in refluxing ethanolic potassium hydroxide to give
the corresponding pyrimidinone and aminopyrimidine
derivatives. The latter was condensed with hydrazine
hydrate or phenyl hydrazine to give pyrazoline and
N-phenylpyrazoline derivatives. Finally, cycloaddition
reaction of acryloylpyridine with thiourea yielded
thioxopyrimidine, which was treated with 2-bromo-
propionic acid, 3-bromopropionic acid, or bromo-
acetic acid to yield methylthiazolo-, thiazino-, and
thiazolopyrimidine derivatives. The arylmethylene
derivative was prepared by reacting thiazolopyrimi-
dine with benzaldehyde or by reacting thioxopyrimi-
dine with benzaldehyde and bromoacetic acid in
one step. The pharmacological screening showed that
many of these compounds have good analgesic and
antiparkinsonian activities comparable to Valdecoxib+
and Benzatropine+ as reference drugs.
Keywords Citrazinic acid; 2-Chloro-6-ethoxy-4-acetylpyri-
dine; Thiazolopyrimidine; Analgesic; Antiparkinsonian.
Introduction
In previous work we have reported that certain
substituted pyridines and their chiral macrocyclic
derivatives have antimicrobial [1–5], anticancer [6,
7], analgesic, and anticonvulsant [8, 9] activities. In
addition, the biological and antiandrogenic activities
of many heterocyclic compounds have been reviewed
[10, 11]. On the other hand, thioxopyrimidine and
thiazolopyrimidine derivatives have promising bio-
logical activities, e.g., anticancer properties [12–16]
and androgenic anabolic activities [17]. Recently,
some new thienopyrimidinone derivatives have been
synthesized and tested for their analgesic, anticonvul-
sant, antiparkinsonian [18, 19], and antiinflammatory
[20–23] activity. In view of these observations and in
continuation of our previous work in heterocyclic
chemistry, we synthesized some new thiopyrimidine,
pyrane, pyrazoline, and thiazolopyrimidine deriva-
tives using citrazinic acid as starting material and
tested their analgesic and antiparkinsonian activities.
Correspondence: Abd El-Galil E. Amr, National Research
Center, Applied Organic Chemistry Department, Dokki,
Cairo, Egypt. E-mail: aamr1963@yahoo.com

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A. E.-G. E. Amr et al.
Scheme 1
Results and discussion
Synthesis
In previous work we have reported the synthesis and
a preliminary biological activity screening of several
pyridine derivatives based on 4-ꢀ-(2-thienyl)acry-
loylpyridine (6) [24], which was prepared as starting
material from the corresponding 2,6-dihydroxyisoni-
cotinic acid (citrazinic acid) (1) via 2,6-dichloroiso-
nicotinic acid ethyl ester (3) and the corresponding
2-chloro-6-ethoxy-4-acetylpyridine (5) according to
literature methods [4, 24] (Scheme 1).
Treatment of 6 with malononitrile in refluxing
ethanol with a small amount of piperidine gave the
cyanoaminopyrane 7, but, it was condensed with di-
amines, namely, urea or guanidine hydrochloride in
refluxing ethanolic potassium hydroxide to afford the
2-carbonyl- 8 and 2-aminopyrimidines 9 (Scheme 2).
Compound 6 was treated with hydrazine hydrate or
phenyl hydrazine in refluxing glacial acetic acid to
give N-acetylpyrazoline 10 and N-phenylpyrazoline
11 (Scheme 2).
Also, compound 6 was condensed with thiourea in
ethanol and dry HCl gas to give thioxopyrimidine
12, which was condensed with 2-propionic acid, 3-
propionic acid, or chloroacetic acid in a mixture of
acetic acid=acetic anhydride in the presence of an-
hydrous sodium acetate to yield the corresponding
methylthiazolo-, thiazino-, and thiazolopyrimidines
Scheme 2

2-Chloro-6-ethoxy-4-acetylpyridine derivatives
1411
Scheme 3
Table 1 Acute toxicity LD50 of the synthesized and starting
compounds
13–15. Compound 15 contains an active methylene
group. As such it condensed with benzaldehyde in
the presence of anhydrous sodium acetate and gla-
cial acetic acid=acetic anhydride mixture to yield the
arylmethylene 16. However, the latter was also pre-
pared directly from 12 by the action of chloroacetic
acid, benzaldehyde, and anhydrous sodium acetate
in the presence of an acetic acid=acetic anhydride
mixture (Scheme 3).
Compound no.
LD50=mg kgꢀ1
Valdecoxib+
6
7
8
1.68
1.80
2.05
1.79
2.53
3.62
2.45
1.77
1.81
2.97
2.45
2.35
9
10
11
12
13
14
15
16
Pharmacological screening
Initially, the acute toxicity of the compounds was as-
sayed by the determination of their LD50 (Table 1).

1412
A. E.-G. E. Amr et al.
Table 2 Analgesic activities of selected compounds in a hot plate assay
Compound
no.
Analgesic activity related to Valdecoxib+ after
10 min ꢁ SE
20 min ꢁ SE
30 min ꢁ SE
45 min ꢁ SE
60 min ꢁ SE
90 min ꢁ SE
120 min ꢁ SE
7
8
9
10
11
12
13
14
15
16
1.29 ꢁ 0.175 1.42 ꢁ 0.16
1.45 ꢁ 0.130 1.46 ꢁ 0.200 1.40 ꢁ 0.320 1.40 ꢁ 0.290 1.41 ꢁ 0.279
0.89 ꢁ 0.010 0.88 ꢁ 0.011 0.90 ꢁ 0.011 0.92 ꢁ 0.017 0.93 ꢁ 0.016 0.92 ꢁ 0.015 0.90 ꢁ 0.017
0.65 ꢁ 0.011 0.64 ꢁ 0.011 0.88 ꢁ 0.011 0.89 ꢁ 0.016 0.90 ꢁ 0.021 0.90 ꢁ 0.017 0.89 ꢁ 0.018
0.78 ꢁ 0.011 0.86 ꢁ 0.014 0.85 ꢁ 0.012 0.87 ꢁ 0.015 0.88 ꢁ 0.017 0.85 ꢁ 0.012 0.84 ꢁ 0.018
0.62 ꢁ 0.012 0.74 ꢁ 0.012 0.80 ꢁ 0.001 0.83 ꢁ 0.015 0.86 ꢁ 0.016 0.85 ꢁ 0.015 0.85 ꢁ 0.036
0.99 ꢁ 0.012 0.98 ꢁ 0.014 1.40 ꢁ 0.138 1.57 ꢁ 0.210 1.56 ꢁ 0.350 1.59 ꢁ 0.340 1.44 ꢁ 0.450
0.83 ꢁ 0.013 0.92 ꢁ 0.014 0.94 ꢁ 0.017 0.96 ꢁ 0.021 0.96 ꢁ 0.032 0.95 ꢁ 0.018 0.95 ꢁ 0.025
0.60 ꢁ 0.012 0.67 ꢁ 0.011 0.75 ꢁ 0.012 0.76 ꢁ 0.018 0.78 ꢁ 0.011 0.79 ꢁ 0.011 0.78 ꢁ 0.013
0.92 ꢁ 0.010 0.93 ꢁ 0.009 0.93 ꢁ 0.015 0.89 ꢁ 0.019 0.84 ꢁ 0.021 0.80 ꢁ 0.016 0.66 ꢁ 0.012
0.65 ꢁ 0.010 0.66 ꢁ 0.017 0.75 ꢁ 0.013 0.74 ꢁ 0.017 0.76 ꢁ 0.017 0.76 ꢁ 0.016 0.79 ꢁ 0.012
The tested two pharmacological activities name-
ly, analgesic and antiparkinsonian despite of their
different biological receptors yet all of a neuro-
logical. Ten representative compounds 7–16 were
studied with respect to analgesic and antiparkinso-
nian activities.
Antiparkinsonian activity
The muscarinic agonists Tremorine+ and
Oxotremorine+ induce parkinsonian signs, such
as tremor, ataxia, spasticity, salivation, lacrima-
tion, and hypothermia. Antiparkinsonian agents
antagonize these signs. The antiparkinsonian ac-
tivity measured by the ability of compounds to
protect animals against the parkinsonian like signs
induced by agonists. Compounds 8, 13, 14, and
15 showed nearly no antiparkinsonian activities.
While compounds 9, 10, and 11 showed moder-
ate antiparkinsonian activities (relative potencies
to Benzatropine+ (¼ 1.0) are 0.64, 0.60, and 0.40).
Compounds 7, 12, and 16 are the most potent
antiparkinsonian agents (0.80 relative potencies)
(Table 3).
Analgesic activity
All compounds tested exhibited analgesic activities
in a hot plate assay (Table 2). The most potent are
compounds 7 and 12 showing higher activity than
Voldecoxib+ by nearly 140–160% (compound 7
showed the most pronounced effect). Also, the anal-
gesic activities of 8–11 and 13–16 approached those
of Valdecoxib+, and showed 62–84% activity as
compared to Valdecoxib+ (¼100%) (Table 2).
Table 3 Antiparkinsonian activities of synthesized compounds as compared with Benzatropine+
Compound
no.
Salivation and
lacrimation score
Tremors
score
Decrease from oxotremorine
rectal temperature=% ꢁSE
Relative potency compared to
benzatropine mesilate ꢁSE
Control
Benzatropine+
7
8
9
10
11
12
13
14
15
16
0
1
1
3
2
2
1
1
3
3
3
1
0
1
1
3
2
2
1
1
3
3
3
1
0
0
25.0 ꢁ 0.400
21.0 ꢁ 0.370
5.0 ꢁ 0.012
16.0 ꢁ 0.290
11.0 ꢁ 0.100
17.0 ꢁ 0.300
21.0 ꢁ 0.140
4.0 ꢁ 0.011
4.0 ꢁ 0.015
5.0 ꢁ 0.010
21.0 ꢁ 0.480
1.00 ꢁ 0.09
0.80 ꢁ 0.075
0.17 ꢁ 0.012
0.59 ꢁ 0.059
0.41 ꢁ 0.031
0.65 ꢁ 0.07
0.80 ꢁ 0.06
0.13 ꢁ 0.013
0.13 ꢁ 0.011
0.15 ꢁ 0.014
0.80 ꢁ 0.071

2-Chloro-6-ethoxy-4-acetylpyridine derivatives
1413
N-substituted pyrazolines 10 and 11
Experimental
A mixture of 0.293 g 6 (1mmol) and 0.4cm3 hydrazine hy-
drate (8mmol) or 1.6 g phenyl hydrazine (1.5mmol) in 15cm3
glacial acetic acid was heated under reflux for 5 h. The reac-
tion mixture was poured into ice, the obtained solid was fil-
tered off, washed with water, dried under pressure, and
crystallized to give 0.25g (72%) 10 and 0.26 g (68%) 11.
All melting points were taken on Electrothermal IA 9000
series digital melting point apparatus. Elemental analytical
data (in accord with the calculated values) were obtained from
the microanalytical unit, Cairo University, Cairo, Egypt. The
IR spectra (KBr) were recorded on a Pye Unicam SP-1000
spectrophotometer. The 1H NMR spectra were recorded at
270 MHz on Varian EM-360 Spectrometer using TMS as
an internal standard. The Central Services Laboratory, Cairo
University, Egypt. The mass spectra were performed using VG
2AB-3F spectrometer (70 eV). All reactions were followed by
TLC (silica gel, aluminum sheets 60 F254, Merck). Starting
materials 2–6 were prepared from citrazinic acid (1) according
to published procedures [4, 24].
2-Acetyl-3-(2-thienyl)-3,4-dihydro-5-[(2-chloro-6-ethoxy-
pyridin-4-yl)pyrazoline (10, C16H16ClN3O2S)
Mp 186–188ꢂC (MeOH=H2O); IR (film): ꢁꢀ¼ 1718 (C¼O),
1
1668 (C¼N) cmꢀ1; H NMR (DMSO-d6): ꢂ ¼ 1.29 (t, CH3,
J ¼ 6.96 Hz), 1.90–2.10 (m, CH2-pyrazoline), 3.65 (s,
COCH3), 3.81 (q, CH2, J ¼ 6.96 Hz), 3.86–3.88 (m, CH-pyr-
azoline), 6.98–7.20 (m, 3 thiophene-H), 8.10–8.22 (m, 2 pyr-
H) ppm; MS (EI, 70eV): m=z ¼ 350 [Mþ, 16], and at 179
[100, base peak].
2-Amino-4-(2-thienyl)-6-[4-(20-chloro-60-ethoxypyridinyl)]-
3-carbonitrile (7, C17H14ClN3O2S)
A solution of 0.293 g 6 (1mmol), and 0.06 g malononitrile
(1 mmol) in 30 cm3 absolute ethanol in the presence of
2 cm3 piperidine was stirred at room temperature for 3 h.
The solvent was concentrated under reduced pressure, the
formed product was collected by filtration, washed with water,
dried, and crystallized to give 0.27g (76%) 7. Mp 214–216ꢂC
2-Phenyl-3-(2-thienyl)-3,4-dihydro-5-[(2-chloro-6-ethoxy-
pyridin-4-yl)pyrazoline (11, C20H18ClN3OS)
Mp 176–178ꢂC (MeOH=H2O); IR (film): ꢁꢀ¼ 1674 (C¼N),
1
1616 (C¼C) cmꢀ1; H NMR (DMSO-d6): ꢂ ¼ 1.31 (t, CH3,
J ¼ 6.98 Hz), 1.88–2.12 (m, CH2-pyrazoline), 3.79 (q, CH2,
J ¼ 6.98 Hz), 3.84–3.87 (m, CH-pyrazoline), 6.94–7.36 (m, 3
thiophene-H þ Ph-H), 8.09–8.24 (m, 2 pyr-H) ppm; MS (EI,
70eV): m=z ¼ 384 [Mþ, 24], and at 226 [100, base peak].
(EtOH); IR (film): ꢁꢀ¼ 3405–3345 (NH2), 2226 (CN) cmꢀ1
;
1H NMR (DMSO-d6): ꢂ ¼ 1.32 (t, CH3, J ¼ 6.95 Hz), 3.78 (q,
CH2, J ¼ 6.95Hz), 4.46 (d, H-a pyrane), 4.72 (s, NH2 ex-
changeable with D2O), 6.95–7.18 (m, 3 thiophene-H þ H-
b pyrane), 8.12–8.26 (m, 2 pyr-H) ppm; MS (EI, 70 eV):
m=z ¼ 360 [Mþ, 18] and at 161 [100, base peak].
6-[(2-Chloro-6-ethoxypyridin-4-yl)-1,2,3,4-tetrahydro-2-
thioxo-4-(2-thienyl)pyrimidine (12, C15H14ClN3OS2)
Dry hydrogen chloride gas was passed through a mixture of
0.293 g 6 (1mmol) and 0.076g thiourea (1mmol) in 25 cm3
absolute ethanol at room temperature for 6 h. The reaction mix-
ture was poured gradually with stirring onto cold water. The
solid formed was filtered off, washed with water, dried under
pressure, and crystallized to give 0.3 g (85%) 12. Mp>265ꢂC
(AcOH=H2O); IR (film): ꢁꢀ¼ 3376–3265 (NH), 1218 (C¼S)
Substituted pyrimidines 8 and 9
Diamino compounds, namely, urea or guanidine hydrochloride
(1 mmol) were added to 0.293 g 6 (1mmol) in 100 cm3 etha-
nolic sodium hydroxide (1%). The reaction mixture was
refluxed for 4–6 h and then poured gradually with stirring onto
cold water. The solid formed was filtered off, washed with
H2O, and crystallized to give 8 and 9.
1
cmꢀ1; H NMR (DMSO-d6): ꢂ ¼ 1.33 (t, CH3, J ¼ 6.95 Hz),
3.80 (q, CH2, J ¼ 6.95 Hz), 5.35 (d, H-a, pyrimidine), 6.94–
7.28 (m, 3 thiophene-H þ H-b pyrimidine), 8.16–8.22 (m,
2 pyr-H), 8.35 and 8.49 (2s, 2 NH exchangeable with D2O)
ppm; MS (EI, 70 eV): m=z ¼ 352 [Mþ, 100, base peak].
6-[(2-Chloro-6-ethoxypyridin-4-yl)]-1,2,3,4-tetrahydro-2-
oxo-4-(2-thienyl)pyrimidine (8, C15H14ClN3O2S)
Yield 0.22 g (65%); mp 146–148ꢂC (EtOH=H2O); IR (film):
1
ꢁꢀ¼ 3338–3268 (NH), 1670 (C¼O) cmꢀ1; H NMR (DMSO-
d6): ꢂ ¼ 1.30 (t, CH3, J ¼ 6.98 Hz), 3.80 (q, CH2, J ¼ 6.98Hz),
5.36 (d, H-a, pyrimidine), 6.98–7.22 (m, 3 thiophene-H þ H-b
pyrimidine), 8.06–8.24 (m, 2 pyr-H), 8.34 and 8.48 (2s, 2 NH-
exchangeable with D2O) ppm; MS (EI, 70 eV): m=z ¼ 336
[Mþ, 12], and at 290 [100, base peak].
Methylthiazolo-, thiazino-, and thiazolopyrimidines 13–15
A mixture of 0.352 g 12 (1mmol) and halo compounds, name-
ly, 2-bromopropionic acid, 3-bromopropionic acid, or bromo-
acetic acid (1mmol) was dissolved in 40cm3 of a mixture of
AcOH=Ac2O (1=3) in the presence 3 g anhydrous sodium ace-
tate was refluxed for 6–7 h. The reaction mixture was cooled
and poured onto cold water with stirring, the solid formed was
filtered off and crystallized to give 0.27g (66%) 13, 0.28 g
(70%) 14, and 0.3 g (75%) 15.
2-Amino-6-[(2-chloro-6-ethoxypyridin-4-yl)-3,4-dihydro-4-
(2-thienyl)pyrimidine (9, C15H15ClN4OS)
Yield 0.24 g (75%); mp 232–234ꢂC (AcOH=H2O); IR (film):
ꢁꢀ¼ 3444–3318 (NH, NH2) cmꢀ1
;
1H NMR (DMSO-d6):
ꢂ ¼ 1.33 (t, CH3, J ¼ 6.95 Hz), 3.79 (q, CH2, J ¼ 6.95 Hz), 4.52
(s, NH2 exchangeable with D2O), 5.26 (d, H-a, pyrimidine),
6.95–7.16 (m, 3 thiophene-Hþ H-b pyrimidine), 8.10–8.18
(m, 2 pyr-H), 8.49 (s, NH- exchangeable with D2O) ppm; MS
(EI, 70eV): m=z ¼ 335 [Mþ, 24], and at 273 [100, base peak].
7-[(2-Chloro-6-ethoxypyridin-4-yl)-5-(2-thienyl)-2,3-dihydro-
5H-3-methylthiazolo[3,2-a]-pyrimidine (13, C18H16ClN3O2S2)
Mp 198–200ꢂC (AcOH=H2O); IR (film): ꢁꢀ¼ 1715 (C¼O)
1
cmꢀ1; H NMR (DMSO-d6): ꢂ ¼ 1.32 (t, CH3, J ¼ 7.05Hz),

1414
A. E.-G. E. Amr et al.
1.36 (d, CH3), 3.55 (m, CH-thiazole), 3.80 (q, CH2, J ¼
7.05 Hz), 5.45 (d, H-a, pyrimidine), 6.88–7.28 (m, 3 thio-
phene-H þ H-b pyrimidine), 8.10–8.23 (m, 2 pyr-H) ppm;
MS (EI, 70 eV): m=z ¼ 406 [Mþ, 14], and at 310 [100, base
peak].
Analgesic activity
Sixty Webster mice of both sexes weighting from 20–25g
were divided into 10 groups. One group was kept as control
(received saline), the second group received vehicle (Gum
acacia), and the third one received Valdecoxib+ as a reference
drug, whereas the other groups received tested compounds
(SC administration). Mice were dropped gently in a dry glass
beaker of one-liter capacity maintained at 55–55.5ꢂC. Normal
reaction time in seconds for all animals was determined at
time intervals of 10, 20, 30, 45, 60, 90, and 120 min. This is
the interval extending from the instant the mouse reaches the
hot beaker till the animals licks its feet or jump out of the
beaker (dose 5 mg=kg) [26], relative potencies to Valdecoxib+
were determined (Table 2).
2-Chloro-6-ethoxy-4-[6-(2-thienyl)-2,3-dihydro-6H-thiazino-
[3,2-a]pyrimidin-4-one-8-yl)]pyridine (14, C18H16ClN3O2S2)
Mp 215–217ꢂC (AcOH=H2O); IR (film): ꢁꢀ¼ 1718 (C¼O)
1
cmꢀ1; H NMR (DMSO-d6): ꢂ ¼ 1.30 (t, CH3, J ¼ 6.96 Hz),
3.40–3.55 (m, 2 CH2-thiazine ring), 3.81 (q, CH2, J ¼
6.96 Hz), 5.36 (d, H-a, pyrimidine), 6.78–7.16 (m, 3 thiophene-
H þ H-b pyrimidine), 8.14–8.26 (m, 2 pyr-H) ppm; MS (EI,
70eV): m=z ¼ 406 [Mþ, 32], and at 249 [100, base peak].
Antiparkinsonian activity
7-[(2-Chloro-6-ethoxypyridin-4-yl)-5-(2-thienyl)-2,3-dihydro-
5H-thiazolo[3,2-a]pyrimidine (15, C17H14ClN3O2S2)
Groups of eight mail mice (18–20g) were used. They were
dosed orally with the tested compounds (5mg=kg) or the
standard (Benzatropine+, 5 mg=kg) [27] 1 h prior to the
administration of 0.5 mg=kg of Oxotremorine+ S.C. Rectal
temperature was measured before administration of the com-
pounds and 1 h after Oxotremorine+ dosage. The score for the
recorded signs are zero (absent), one (slight), two (mediums),
and three (highs) (Table 3).
Mp 218–220ꢂC (AcOH=H2O); IR (film): ꢁꢀ¼ 1709 (C¼O)
1
cmꢀ1; H NMR (DMSO-d6): ꢂ ¼ 1.34 (t, CH3, J ¼ 6.95 Hz),
3.74 (s, CH2-thiazole), 3.78 (q, CH2, J ¼ 6.95Hz), 5.38 (d, H-
a, pyrimidine), 6.82–7.18 (m, 3 thiophene-H þ H-b pyrimi-
dine), 8.11–8.24 (m, 2 pyr-H) ppm; MS (EI, 70 eV): m=z ¼
392 [Mþ, 5], and at 152 [100, base peak].
7-[(2-Chloro-6-ethoxypyridin-4-yl)-2-(phenylmethylene)-5-
(2-thienyl)-2,3-dihydro-5-thiazolo[3,2-a]pyrimidine
(16, C24H18ClN3O2S2)
Acknowledgement
The kind helps of Dr. M. M. Abdalla, Research Unit, Hi-Care,
Pharmaceutical Co., Cairo, Egypt, for carrying out the phar-
macological screening are acknowledged.
Method A: A mixture of 0.352 g 12 (1mmol), 0.138 g bromoa-
cetic acid (1mmol), 1.5 g anhydrous sodium acetate in 40cm3
a mixture of AcOH=Ac2O (1=3) and 0.106 g benzaldehye
(1 mmol) was refluxed for 6 h. The reaction mixture was
cooled and poured onto ice–water, the obtained solid was
collected by filtration and crystallized to give 0.4 g (82%)
16. Mp 242–244ꢂC (AcOH=H2O); IR (film): ꢁꢀ¼ 3365–3298
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(NH), 1712 (C¼O) cmꢀ1; H NMR (DMSO-d6): ꢂ ¼ 1.32 (t,
CH3, J ¼ 6.98Hz), 3.80 (q, CH2, J ¼ 6.98Hz), 5.42 (d, H-a,
pyrimidine), 6.78–7.44 (m, 3 thiophene-Hþ H-b pyrimidi-
neþ benzylic-Hþ Ph-H), 8.12–8.24 (m, 2 pyr-H) ppm; MS
(EI, 70 eV): m=z ¼ 478 [Mþ, 100, base peak].
Method B: A mixture of 0.292 g 15 (1mmol) and 0.106g
benzaldehyde (1mmol) in 40cm3 a mixture of AcOH=Ac2O
(1=3) was refluxed for 5 h, allowed to cool, then poured onto
water the solid formed was collected by filtration and crystal-
lized to yield 0.35g (74%) 16, as identified by its mp; mixed
mp and Rf value on TLC by comparison with authentic sample
from method A.
Pharmacological screening
All animals were obtained from Animal House Colony,
Research Institute of Ophthalmology, Giza, Egypt.
10. Amr AE, Abdel-Latif NA, Abdalla MM (2006) Acta
Pharm 56:203
11. Amr AE, Abdel-Latif NA, Abdalla MM (2006) Bioorg
Med Chem 14:273
Determination of acute toxicity (LD50)
The LD50 for compounds were determined by injected dif-
ferent gradual increased doses of the tested compounds to
adult mail albino rats, then calculate the dose cause 50%
animal death, according to Austen and Brocklehurst [25]
(Table 1).
12. Hammam AG, Fahmy AF, Amr AE, Mohamed AM
(2003) Ind J Chem Sec B 42B:1985
13. Hammam AG, Naglaa AA, Wanda MH, Marian M (2000)
Z Naturforsch 55b:417
14. Ali MI, Hammam AG (1981) J Chem Eng Data 26:352

2-Chloro-6-ethoxy-4-acetylpyridine derivatives
1415
15. Hammam AG, Mohie AS, Naglaa AA (2001) Ind J Chem
Sec B 40B:213
16. Hammam AG, Hussain SM, Kotob IR (1990) Phosphorus
Sulfur Silicon 47:47
17. Amr AE, Abdulla MM (2002) Ind J Heterocycl Chem
12:129
18. Amr AE, Hegab MI, Ibrahim AA, Abdulla MM (2003)
Monatsh Chem 134:1395
21. Amr AE, Abdalla MM (2006) Bioorg Med Chem 14:4341
22. Amr AE, Abdalla MM (2006) Arch Pharm Chem Life Sci
339:88
23. Amr AE, Nermien MS, Mohamed MA (2007) Monatsh
Chem 138:699
24. Attia A, Abdel-Salam OI, Abou-GHalia MH, Amr AE
(1995) Egypt J Chem 38:543
25. Austen KF, Brocklehurst WE (1961) J Exp Med 113:521
26. Tgolsen A, Rofland GH, Berge OG, Hole K (1991) J
Pharmacol Ther 25:241
19. Amr AE, Sayed HH, Abdulla MM (2005) Arch Pharm
Chem Life Sci 338:433
20. Abo-Ghalia MH, Amr AE, Abdulla MM (2003) Z Nat-
urforsch 58b:903
27. Tyahr MD (1976) The Basal Ganginia. Raven Press, New
York, p 293
¨
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