Synthesis, analgesic, and antiparkinsonian profiles of some pyridine, pyrazoline, and thiopyrimidine derivatives

Article abstract of DOI:10.1007/s00706-007-0656-8

A series of substituted pyridine, pyrazoline, and thiopyrimidine derivatives were synthesized from 3-acetylpyridine, which was prepared from nicotinic acid as a naturally starting material. The pharmacological screening showed that many of these compounds

Full text of DOI:10.1007/s00706-007-0656-8

Monatshefte fu¨r Chemie 138, 715–724 (2007)
DOI 10.1007/s00706-007-0656-8
Printed in The Netherlands
Synthesis, Analgesic, and Antiparkinsonian Profiles of Some Pyridine,
Pyrazoline, and Thiopyrimidine Derivatives
Nehad A. Abdel-Latif1;ꢀ, Nermien M. Sabry2, Ashraf M. Mohamed2, and Mohamed M. Abdulla3
1
National Research Centre, Natural Compounds Chemistry Department, Dokki, Cairo, Egypt
2
National Research Centre, Applied Organic Chemistry Department, Dokki, Cairo, Egypt
3
Research Units, Hi-Care Pharmaceutical Co., Cairo, Egypt
Received January 18, 2007; accepted (revised) January 24, 2007; published online May 11, 2007
# Springer-Verlag 2007
Summary. A series of substituted pyridine, pyrazoline,
and thiopyrimidine derivatives were synthesized from 3-
acetylpyridine, which was prepared from nicotinic acid as
a naturally starting material. The pharmacological screen-
anti-inflammatory activity [13, 14] and are used as
potent antidiabetic agents [15, 16]. In addition, the
pharmacological and antitumor activities of many
compounds containing pyrazoline rings have been
ing showed that many of these compounds have good
reviewed [17–19]. Recently, these heterocyclic ni-
trogen derivatives have been shown to exhibit a gen-
eral ionophoric potency for divalent cations [20]
and have been used as a novel thiocyanate-selective
membrane sensor [21]. In view of these observations
and in continuation of our previous work in pyridine
and pyrimidine chemistry, we synthesized some new
heterocyclic compounds containing the pyridine, pyr-
azoline, or thiopyrimidine moiety and tested their an-
algesic and antiparkinsonian activities in comparison
to Voltarene+ and Benzatropine+ as reference drugs.
analgesic and antiparkinsonian activities comparable to
Voltarene+ and Benzatropine+ as reference drugs. The struc-
ture assignment of the new compounds is based on chemical
and spectroscopic evidence. The detailed synthesis, spectro-
scopic data, and pharmacological properties for synthesized
compounds are reported.
Keywords. Nicotinic acid; Pyrazolines; Thiopyrimidine;
Analgesic; Antiparkinsonian.
Introduction
Nicotinic acid and its derivatives constitute an im-
portant class of naturally occurring compounds, min-
ute amounts of nicotinic acid occur in all living cells
[1], and it exhibits a wide spectrum of biological
activities [2, 3]. Previous work reported that certain
substituted pyridines and their chiral macrocyclic
derivatives have antidepressant, antimacrobial, an-
ticancer, analgesic, and anticonvulsant activities
[4–10]. Pyrazolines present an interesting group
of compounds many of which possess wide-spread
pharmacological properties, such as analgesic, anti-
pyretic, and antirheumatic activities [11, 12]. These
derivatives are also well known for their pronounced
Results and Discussion
Synthesis
In the present work we report on the synthesis and
a preliminary biological activity screening of sev-
eral pyridine derivatives based on 3-ꢀ-[(p-methoxy-
phenyl)acryloyl]pyridine (2). 3-Acetylpyridine (1)
prepared from nicotinic acid according to Ref. [17]
was reacted with p-methoxybenzaldehyde in refluxing
ethanol in the presence of a mixture of triethylamine
and diethylamine as a catalyst to yield 3-ꢀ-[(p-me-
thoxyphenyl)acryloyl]pyridine (2). Condensation of
2 with hydroxylamine hydrochloride in refluxing
ꢀ
Corresponding author. E-mail: nehad_km@yahoo.com

716
N. A. Abdel-Latif et al.
Scheme 1
pyridine with stirring afforded the corresponding
3-ꢀ-(p-methoxyphenyl)acryloylpyridine oxime 3
(Scheme 1). The latter was cyclized with refluxing
acetic anhydride to the oxazole 4, which was also pre-
pared directly from 2 by reaction with hydroxylamine
hydrochloride in the presence of anhydrous sodium
acetate in refluxing acetic acid. Oxime 3 was treated
with phenyl isothiocyanate or toluene-3,5-diisocya-
nate in refluxing dioxane to afford the phenyl thio-
semicarbazide 5 and bissemicarbazide 6 (Scheme 1).
Condensation of 2 with phenylhydrazine in reflux-
ing glacial acetic acid gave the N-phenylpyrazoline
7, while 2 was reacted with semicarbazide hydro-
chloride to give the N-aminocarbonylpyrazoline 8

Synthesis, Analgesic, and Antiparkinsonian Profiles
717
(Scheme 2). Compound 2 was condensed with hy-
drazine hydrate in refluxing propionic acid or glacial
acetic acid to afford the N-substituted pyrazolines 9
and 10, which were hydrolyzed by refluxing in al-
coholic potassium hydroxide to yield pyrazoline 11
(method A). The latter was obtained directly by con-
Scheme 2

718
N. A. Abdel-Latif et al.: Synthesis, Analgesic, and Antiparkinsonian Profiles
densation of acryloylpyridine 2 with hydrazine hy-
drate in refluxing ethanol (method B) (Scheme 2).
Several publications [22–24] have reported the re-
action of 1,2-diamines with ꢁ,ꢀ-unsaturated ketones
and the nature of the products varied according to
the experimental conditions. The present work re-
ports the reaction between 2 and o-phenylenediamine
under different conditions. The uncatalysed reaction
of 2 with o-phenylenediamine in refluxing butanol
afforded the diazepine 12. Formation of 12 was be-
lieved to proceed through the initial addition of the
diamine to the ethylenic double bond of 2 followed
by intramolecular condensation of the amino group
with the carbonyl function affording 12 as the sole
product (Scheme 3).
On the other hand, when equimolar amounts of 2
and o-phenylenediamine were fused together with-
out solvent at 200–220ꢁC, 2-(3-pyridyl)benzimid-
azole (13) was isolated as the main product along
with 2-(p-methoxyphenyl)benzimidazole (14) [25]
(Scheme 3). Moreover, thermolysis of the benzodia-
zipine derivative 12 at 200–220ꢁC afforded the same
Scheme 3

Scheme 4

720
N. A. Abdel-Latif et al.
benzimidazoles 13 and 14 as identified by TLC. In
addition, compound 13 was independently prepared
for TLC comparison by fusion of acetyl derivative 1
with o-phenylenediamine at the same temperature
(Scheme 3).
Pharmacological Screening
We tested two pharmacological activities namely,
analgesic and antiparkinsonian, despite of their dif-
ferent biological receptors. Yet both are of neurolog-
ical origin. Seven representative compounds 6, 8,
10, 12, 15, 17, and 21 were studied.
Condensation of 2 with diamines, namely, guani-
dine hydrochloride, urea, and thiourea in refluxing eth-
anolic potassium hydroxide afforded the 2-amino-,
2-carbonyl-, and 2-thiopyrimidines 15–17 (Scheme 4).
Compound 17 was condensed with 3-bromopropi-
onic acid, 2-bromopropionic acid, or chloroacetic
acid in a mixture of acetic acid=acetic anhydride in
the presence of anhydrous sodium acetate to yield
the corresponding thiazino-, methylthiazolo-, and thi-
azolopyrimidines 18–20. Compound 20 contains an
active methylene group. As such it condensed with
indole-3-carboxaldehyde in the presence of anhy-
drous sodium acetate and glacial acetic acid=acetic
anhydride mixture to yield the arylmethylene 21.
However, the latter was also prepared directly from
17 by the action of chloroacetic acid, indole-3-car-
boxaldehyde, and anhydrous sodium acetate in the
presence of acetic acid=acetic anhydride mixture
(Scheme 4).
Analgesic Activity
All tested compounds exhibited analgesic activities
(Table 1), the most potent one is 12 that showed
the same activity as Voltarene+ after 45 min and
it had even higher activity than Voltarene+ after
60, 90, and 120 min. Also the analgesic activities of
6 and 21 approached those of Voltarene+, and 8
had 31–47% activity as compared with Voltarene+
(Table 1).
Antiparkinsonian Activity
Compounds 6, 10, and 15 showed moderate activity
(relative potencies to Benzotropene+ 0.44, 0.60, and
0.40). Compounds 8 and 12 are the most potent anti-
parkinsonic agents (0.80 relative potency) (Table 2).
Table 1. Analgesic activity of several compounds as compared with Voltarene+ in mice
Comp. no.
Analgesic activity after:
45 min
10 min
20 min
30 min
60 min
90 min
120 min
Voltarene+
1
1
1
1
1
1
1
6
8
0.81
0.31
0.61
0.97
0.59
0.54
0.79
0.89
0.40
0.63
0.98
0.61
0.56
0.83
0.88
0.40
0.71
0.99
0.69
0.58
0.87
0.91
0.42
0.73
1.07
0.71
0.55
0.88
0.93
0.45
0.74
1.12
0.77
0.51
0.88
0.94
0.43
0.74
1.21
0.81
0.49
0.88
0.94
0.47
0.74
1.41
0.80
0.47
0.91
10
12
15
17
21
Table 2. Antiparkinsonian activity of several compounds as compared with Benzotropene+
Comp. no.
Salivation and
lacrimation score
Tremors score
% Decrease from
Oxotremerine+ rectal temp.
Relative potency
to Benzotropene+
Control
Benzotropene+
0
1
2
1
2
1
2
3
3
0
1
2
1
2
1
2
3
3
0
25
11
20
15
20
10
4
0
1
6
8
0.44
0.80
0.60
0.80
0.40
0.16
0.12
10
12
15
17
21
3

Synthesis, Analgesic, and Antiparkinsonian Profiles
721
Method B: A mixture of 0.24 g 2 (1mmol), ꢃ0.1 g hydrox-
ylamine hydrochloride (1mmol), and 0.082 g anhydrous
sodium acetate (1mmol) in 30cm3 glacial acetic acid was
heated under reflux for 6 h. The reaction mixture was cooled,
poured into ice, the obtained solid was collected by filtration,
washed with water, air dried, and crystallized to give 0.17 g
(66%) 4, as identified by m.p. and TLC in comparison with an
authentic sample from method A.
Experimental
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, Centre of
Molecular and Macromolecular Studies, Polish Academy of
Science, Poland. The mass spectra were performed using a
VG 2AB-3F spectrometer (70 eV). All reactions were fol-
lowed by TLC (silica gel, aluminum sheets 60 F254, Merck).
Thiosemicarbazide and Bissemicarbazide 5 and 6
A mixture of 0.254 g 3 (1mmol) and phenyl isothiocyanate or
toluene-3,5-diisocyanate (1mmol) in 50cm3 dry dioxane con-
taining 1 cm3 triethylamine was heated under reflux for ꢃ8 h.
The solvent was evaporated under reduced pressure, and the
obtained residue was solidified with n-hexane. The obtained
solid was filtered off, washed with diethyl ether, air dried, and
crystallized to give 0.26 g (68%) thiosemicarbazide 5 and
0.37g (55%) biscarbazide 6.
3-[ꢀ-(p-Methoxyphenyl)acryloyl]pyridine (2, C15H13NO2)
A mixture of 0.12g 3-acetylpyridine (1) (1mmol), 0.14g
p-methoxybenzaldehyde (1mmol), and 3 cm3 triethylamine=
diethylamine in 50 cm3 absolute ethanol was heated under
reflux for 4 h. The reaction mixture was evaporated under re-
duced pressure to dryness. The obtained solid was triturated
with diethyl ether, filtered off, air-dried, and crystallized
to afford 0.18g (78%) 2. Mp 230–232ꢁC (AcOH=H2O);
3-[ꢀ-(p-Methoxyphenyl)acryloyl phenyl
thiosemicarbazide]pyridine (5, C22H19N3O2S)
Mp 213–215ꢁC (dioxane); IR (film): ꢂꢀ¼ 3336–3250 (NH),
1665 (C¼N), 1228 (C¼S) cmꢂ1
;
1H NMR (DMSO-d6):
IR (film): ꢂꢀ¼ 1682 (C¼O), 1610 (C¼C) cmꢂ1
;
1H NMR
ꢃ ¼ 3.60 (s, OCH3), 4.15–4.25 (bs, NH-CS, exchangeable with
D2O), 6.35 (d, J ¼ 14.60 Hz, CH-olefinic), 6.52 (d, J ¼
14.65 Hz, CH-olefinic), 6.95–7.35 (m, Ar-H), 7.88–8.42 (m,
pyrid-4,5,6), 8.86 (s, pyrid-2) ppm; MS (EI, 70eV): m=z
(%) ¼ 389 [Mþ, 32], 136 [100, base peak].
(DMSO-d6): ꢃ ¼ 3.65 (s, OCH3), 6.42 (d, J ¼ 14.65 Hz, CH-
olefinic), 6.85 (d, J ¼ 14.65 Hz, CH-olefinic), 7.10–7.45 (m,
Ar-H), 7.78–8.30 (m, pyrid-4,5,6), 8.70 (s, pyrid-2) ppm; MS
(EI, 70 eV): m=z (%) ¼ 239 [Mþ, 25], 161 [100, base peak].
3-[ꢀ-(p-Methoxyphenyl)acryloyl]pyridine oxime
(3, C15H14N2O2)
3,5-Bis{3-[ꢀ-(p-methoxyphenyl)acryloylsemicarbazide]
pyridine}toluene (6, C39H34N6O6)
A mixture of 0.24g 2 (1mmol) and ꢃ0.1 g hydroxylamine
hydrochloride (1mmol) in 30cm3 dry pyridine was refluxed
for 6 h. The reaction mixture was cooled, poured into ice, and
neutralized with 1 N HCl. The obtained solid was filtered,
dried (under vacuum), and crystallized to give 0.21 g (82%)
3. Mp 198–199ꢁC EtOH=H2O); IR (film): ꢂꢀ¼ 3540–3360
Mp 188–189ꢁC (dioxane); IR (film): ꢂꢀ¼ 3390–3260 (NH),
1705–1695 (C¼O), 1675–1665 (C¼N) cmꢂ1
;
1H NMR
(DMSO-d6): ꢃ ¼ 1.25 (s, CH3), 3.64 (s, OCH3), 6.25 (d, J ¼
14.60 Hz, 2CH-olefinic), 6.55 (d, J ¼ 14.65 Hz, 2CH-olefi-
nic), 6.85–7.40 (m, Ar-H), 7.82–8.40 (m, 2 pyrid-4,5,6),
8.65 (s, NHCO, exchangeable with D2O), 8.86 (s, 2 pyrid-2)
ppm; 13C NMR (DMSO-d6): ꢃ ¼ 18.65 (CH3), 55.90 (OCH3),
110.85, 114.65, 116.18, 127.32, 127.86, 135.80, 137.60,
158.76 (Ph-C), 122.75, 125.18, 136.32, 150.50, 150.95 (pyr-
idine-C), 137.28, 142.55 (CH¼CH), 152.80 (C¼O), 163.15
(C¼N) ppm; MS (EI, 70 eV): m=z (%) ¼ 682 [Mþ, 10], 237
[100, base peak].
1
(OH), 1675 (C¼N), 1610 (C¼C) cmꢂ1; H NMR (DMSO-
d6): ꢃ ¼ 2.50 (s, OH, exchangeable with D2O), 3.62 (s, OCH3),
6.38 (d, J ¼ 14.58 Hz, CH-olefinic), 6.86 (d, J ¼ 14.60 Hz,
CH-olefinic), 6.95–7.35 (m, Ar-H), 7.75–8.25 (m, pyrid-
4,5,6), 8.72 (s, pyrid-2) ppm; MS (EI, 70 eV): m=z (%) ¼
254 [Mþ, 100, base peak].
2-(3-Pyridyl)-4-(p-methoxyphenyl)oxazole (4, C15H14N2O2)
Method A: A solution of 0.24 g 2 (1mmol) in 50 cm3 acetic
anhydride was refluxed for 10h. After cooling, the reaction
mixture was poured into ice, the obtained solid was filtered
off, washed with water, dried under reduced pressure, and
crystallized to give 0.19 g (74%) 4. Mp 176–178ꢁC (AcOH);
2-Phenyl-3-(p-methoxyphenyl)-3,4-dihydro-5-(3-pyridyl)
pyrazoline (7, C21H19N3O)
A mixture of 0.24g 2 (1 mmol) and 0.16 g phenylhydrazine
(1.5mmol) in 15cm3 glacial acetic acid was heated under
reflux for 5 h. The reaction mixture was poured into ice, the
obtained solid was filtered off, washed with water, dried under
reduced pressure, and crystallized to give 0.25 g (76%) 7. Mp
215–217ꢁC (MeOH=H2O); IR (film): ꢂꢀ¼ 1672 (C¼N), 1612
IR (film): ꢂꢀ¼ 1670 (C¼N), 1610 (C¼C) cmꢂ1
;
1H NMR
(DMSO-d6): ꢃ ¼ 1.50–1.85 (m, CH2-oxazole), 3.62 (s, OCH3),
4.20 (m, CH-oxazole), 6.92–7.45 (m, Ar-H), 7.82–8.32 (m,
pyrid-4,5,6), 8.72 (s, pyrid-2) ppm; 13C NMR (DMSO-d6):
ꢃ ¼ 55.90 (OCH3), 42.15, 77.75, 154.90 (oxazole-C), 114.30,
127.70, 134.86, 157.65 (Ph-C), 122.75, 125.10, 136.15,
149.50, 150.90 (pyridine-C) ppm; MS (EI, 70 eV): m=z
(%) ¼ 254 [Mþ, 35], 122 [100, base peak].
1
(C¼C) cmꢂ1; H NMR (DMSO-d6): ꢃ ¼ 1.70–2.05 (m, CH2-
pyrazoline), 3.60 (s, OCH3), 3.85 (m, CH-pyrazoline), 6.65–
7.35 (m, Ar-H), 7.66–8.652 (m, pyrid-4,5,6), 8.85 (s, pyrid-2)
ppm; MS (EI, 70eV): m=z (%) ¼ 329 [Mþ, 35], 221 [100,
base peak].

722
N. A. Abdel-Latif et al.
for ꢃ5 h. The solvent was evaporated under reduced pressure
to dryness, the residue was solidified with water, filtered off,
washed with water, dried, and crystallized to give 0.14g
(55%) 11, as identified by m.p. and Rf values in comparison
with authentic samples from the above method A.
2-Aminocarbonyl-3-(p-methoxyphenyl)-3,4-dihydro-5-
(3-pyridyl)pyrazoline (8, C16H16N4O2)
A solution of 0.24g 2 (1mmol) and 1.5 g semicarbazide
hydrochloride (1.5mmol) in sodium ethoxide [460 mg sodium
metal (20 mmol) in 25 cm3 absolute ethanol] was refluxed for
8 h. The reaction mixture was acidified with 1 N hydrochloric
acid. The obtained solid was filtered off, washed with water,
air dried, and crystallized to give 0.26 g (88%) 8. Mp 155–
157ꢁC (dioxane); IR (film): ꢂꢀ¼ 3340–3215 (NH2), 1670
2-(Pyridin-3-yl)-4-(p-methoxyphenyl)benzo[b]diazipene
(12, C21H19N3O)
A mixture of 0.24g 2 (1mmol) and 0.11 g o-phenylenedi-
amine (1mmol) in 30 cm3 dry butanol was heated under reflux
and followed up by TLC. The reaction was completed after
18h and the solvent was evaporated under reduced pressure to
dryness. The oily product was triturated with petroleum ether
(40–60ꢁC) and the separated solid was filtered off, washed
with petroleum ether (40–60ꢁC), dried, and crystallized to
give 0.24 g (74%) 12. Mp 165–167ꢁC (EtOH=n-hexane); IR
1
(C¼O), 1656 (C¼N) cmꢂ1; H NMR (DMSO-d6): ꢃ ¼ 1.80–
2.00 (m, CH2-pyrazoline), 3.62 (s, OCH3), 3.95 (m, CH-pyr-
azoline), 5.45 (s, NH2, exchangeable with D2O), 6.95–7.25
(m, Ar-H), 7.68–8.35 (m, pyrid-4,5,6), 8.86 (s, pyrid-2)
ppm; MS (EI, 70eV): m=z (%) ¼ 296 [Mþ, 15], 172 [100,
base peak].
1
2-Substituted Pyrazolines 9 and 10
(film): ꢂꢀ¼ 3380–3342 (NH), 1605 (C¼N) cmꢂ1; H NMR
A mixture of 0.24 g 2 (1 mmol) and 0.4 cm3 hydrazine hy-
drate (8 mmol) in 15 cm3 propionic acid or glacial acetic
acid was heated under reflux for ꢃ7 h. The reaction mixture
was poured onto ice, then neutralized with sodium bicar-
bonate. The formed precipitate was collected by filtration,
washed with water, air dried, and crystallized to give 0.2 g
(65%) 9 and 0.22 g (75%) 10.
(DMSO-d6): ꢃ ¼ 3.15 (d, CH2-diazepine), 3.68 (s, OCH3),
4.05 (m, CH-diazepine), 6.78–7.60 (m, Ar-H), 7.76-8.45 (m,
pyrid-4,5,6), 8.65 (s, pyrid-2), 10.15 (s, NH-diazepine, ex-
changeable with D2O) ppm; 13C NMR (DMSO-d6): ꢃ ¼
42.30 (CH2), 55.80 (OCH3), 58.25 (CH), 113.80, 113.95,
117.65, 122.10, 125.68, 127.10, 129.75, 137.54, 144.25
162.40, (Ar-C), 122.75, 126.65, 136.48, 149.75, 151.05 (pyri-
dine-C), 161.05 (C¼N) ppm; MS (EI, 70eV): m=z (%) ¼ 329
[Mþ, 15], 312 [100, base peak].
2-Acetyl-3-(p-methoxyphenyl)-3,4-dihydro-5-(3-pyridyl)
pyrazoline (9, C18H19N3O2)
Mp 245–246ꢁC (EtOH=H2O); IR (film): ꢂꢀ¼ 1715 (C¼O),
Formation of Benzimidazoles 13 and 14
1
1660 (C¼N) cmꢂ1; H NMR (DMSO-d6): ꢃ ¼ 1.15 (t, CH3),
Equimolar amounts of 0.24g 2 (1mmol) and 0.11 g o-phenyl-
enediamine (1mmol) were fused together in an oil bath at
200–220ꢁC for 6 h. The obtained solid was crushed and ex-
tracted with hot benzene. The benzene extract was evaporated
under reduced pressure to dryness and the residue was solid-
ified with petroleum ether (40–60ꢁC) to give 0.07g (36%)
2-(3-pyridyl)benzimidazole (13), mp 133–135ꢁC. The undis-
solved residue left after extraction with benzene was dissolved
in a mixture of ethanol=methanol. The solution was evap-
orated under reduced pressure, and the obtained residue was
solidified with n-hexane to give 0.1 g (45%) 2-(p-methoxy-
phenyl)benzimidazole (14), mp 215–217ꢁC (Lit. mp 214–
216ꢁC) [25].
1.75–2.05 (m, CH2-pyrazoline), 2.15 (m, CH2), 3.65 (s,
OCH3), 3.88 (m, CH-pyrazoline), 7.05–7.30 (m, Ar-H),
7.70–8.25 (m, pyrid-4,5,6), 8.85 (s, pyrid-2) ppm; MS (EI,
70eV): m=z (%) ¼ 309 [Mþ, 10], 172 [100, base peak].
2-Ethylcarbonyl-3-(p-methoxyphenyl)-3,4-dihydro-5-
(3-pyridyl)pyrazoline (10, C17H17N3O2)
Mp 186–188ꢁC (MeOH=H2O); IR (film): ꢂꢀ¼ 1718 (C¼O),
1
1662 (C¼N) cmꢂ1; H NMR (DMSO-d6): ꢃ ¼ 1.80 (s, CH3),
1.90–2.15 (m, CH2-pyrazoline), 3.66 (s, OCH3), 3.86 (m, CH-
pyrazoline), 7.00–7.35 (m, Ar-H), 7.68–8.15 (m, pyrid-4,5,6),
8.84 (s, pyrid-2) ppm; MS (EI, 70eV): m=z (%) ¼ 295 [Mþ,
45], 174 [100, base peak].
Thermolysis of Benzodiazipine 12
Benzodiazipine 12 (0.33 g, 1 mmol) was heated in an oil bath at
200–220ꢁC for 6 h. The dark mass was crushed and extracted
with boiling benzene. The benzene extract was evaporated to
dryness and crystallized from benzene=petroleum ether (40–
60ꢁC) to give 0.05 g (28%) 13. The residue left after extraction
with benzene was dissolved in ethanol=methanol. The solution
was evaporated under reduced pressure, and the obtained resi-
due was crystallized from ethanol=petroleum ether (40–60ꢁC)
to give 0.08g (35%) 14. The obtained products were identified
by m.p. and Rf values in comparison with authentic samples
from the above method.
3-(p-Methoxyphenyl)-3,4-dihydro-5-(3-pyridyl)pyrazoline
(11, C15H15N3O)
Method A: A solution of 9 or 10 (1mmol) in 15cm3 ethanolic
potassium hydroxide (5%) was refluxed for 4–6 h. The reac-
tion mixture was acidified with 1 N HCl, the obtained solid
was filtered off, washed with water, dried, and crystallized to
give 0.22 g (88%) 11. Mp 156–158ꢁC MeOH); IR (film):
1
ꢂꢀ¼ 3335–3225 (NH), 1665 (C¼O), 1658 (C¼N) cmꢂ1; H
NMR (DMSO-d6): ꢃ ¼ 1.78–2.05 (m, CH2-pyrazoline), 3.63
(s, OCH3), 3.86 (m, CH-pyrazoline), 6.55 (s, NH, exchange-
able with D2O), 6.98–7.35 (m, Ar-H), 7.78–8.25 (m, pyrid-
4,5,6), 8.96 (s, pyrid-2) ppm; MS (EI, 70 eV): m=z (%) ¼ 253
[Mþ, 25], 121 [100, base peak].
2-(3-Pyridyl)benzimidazole (13, C12H9N3)
A mixture of 0.12g 1 (1mmol) and 0.11 g o-phenylenedi-
amine (1mmol) was fused in an oil bath at 200–220ꢁC for
Method B: A mixture of 0.24 g 2 (1mmol) and 0.4 cm3
hydrazine hydrate (8mmol) in 25 cm3 ethanol was refluxed

Synthesis, Analgesic, and Antiparkinsonian Profiles
723
6 h. The obtained residue was solidified with methanol, filtered
off, and crystallized to give 0.1 g (55%) 13. The product was
identified by its mp and Rf value in comparison with an au-
thentic sample. Mp 133–135ꢁC (EtOH=pet. ether]; IR (film):
solid formed was filtered off and crystallized to give 0.24 g
(68%) 18, 0.29 g (82%) 19, and 0.27g (80%) 20.
3-(6-p-Methoxyphenyl-2,3-dihydro-6H-thiazino[3,2-a]pyrimidin-4-
one-8-yl)pyridine (18, C19H17N3O2S)
1
ꢂꢀ¼ 3380–3342 (NH), 1610 (C¼N) cmꢂ1; H NMR (DMSO-
Mp 235–237ꢁC (AcOH=H2O); IR (film): ꢂꢀ¼ 1725 (C¼O)
cmꢂ1; 1H NMR (DMSO-d6): ꢃ ¼ 3.40–3.55 (m, 2CH2 thiazine
ring), 3.64 (s, OCH3), 5.36 (d, H-a, pyrimidine), 6.72–7.15
(m, Ar-Hþ H-b pyrimidine), 7.79–8.48 (m, pyrid-4,5,6), 8.84
(s, pyrid-2) ppm; MS (EI, 70eV): m=z (%) ¼ 351 [Mþ, 12],
166 [100, base peak].
d6): ꢃ ¼ 7.15–7.65 (m, Ar-H), 7.75–8.55 (m, pyrid-4,5,6), 8.76
(s, pyrid-2), 8.62 (s, NH-imidazole, exchangeable with D2O)
ppm; MS (EI, 70eV): m=z (%) ¼ 195 [Mþ, 100, base peak].
Substituted Pyrimidines 15–17
General Procedure
Diamino compounds, namely, guanidine hydrochloride, urea,
and thiourea (1mmol) were added to 0.24 g 2 (1mmol) in
100 cm3 ethanolic potassium hydroxide (1%). The reaction
mixture was refluxed for 4–6 h and then poured gradually with
stirring into cold water. The solid formed was filtered off,
washed with H2O, and crystallized to give 15–17.
7-(Pyridin-3-yl)-5-(p-methoxyphenyl)-2,3-dihydro-5H-3-
methylthiazolo[3,2-a]pyrimidine (19, C19H17N3O2S)
Mp 224–246ꢁC (DMF=H2O); IR (film): ꢂꢀ¼ 1705 (C¼O)
1
cmꢂ1; H NMR (DMSO-d6): ꢃ ¼ 1.36 (s, 3H, CH3), 3.55 (m,
1H, thiazole), 3.64 (s, OCH3), 5.45 (d, H-a, pyrimidine), 6.82–
7.18 (m, Ar-Hþ H-b pyrimidine), 7.84–8.65 (m, pyrid-4,5,6),
8.82 (s, pyrid-2) ppm; MS (EI, 70eV): m=z (%) ¼ 351 [Mþ,
10], 152 [100, base peak].
2-Amino-6-(pyridin-3-yl)-3,4-dihydro-4-(p-methoxyphenyl)
pyrimidine (15, C16H16N4O)
Yield 0.19 g (68%); mp 240–242ꢁC (AcOH=H2O); IR (film):
7-(Pyridin-3-yl)-5-(p-methoxyphenyl)-2,3-dihydro-5H-thiazolo[3,2-
a]pyrimidine (20, C18H15N3O2S)
ꢂꢀ¼ 3440–3320 (NH, NH2) cmꢂ1
;
1H NMR (DMSO-d6):
ꢃ ¼ 3.62 (s, OCH3), 4.55 (s, NH-pyrimidine, exchangeable
with D2O), 5.15 (d, H-a, pyrimidine), 6.75–7.25 (m, Ar-
H þ H-b pyrimidine), 6.60 (bs, NH2, exchangeable with D2O),
7.76–8.45 (m, pyrid-4,5,6), 8.74 (s, pyrid-2) ppm; MS (EI,
70eV): m=z (%) ¼ 280 [Mþ, 15], and at 233 [100, base peak].
Mp 210–212ꢁC (AcOH=H2O); IR (film): ꢂꢀ¼ 1712 (C¼O)
cmꢂ1
;
1H NMR (DMSO-d6): ꢃ ¼ 3.66 (s, OCH3), 3.74 (s,
CH2-thiazole), 5.24 (d, H-a, pyrimidine), 6.80–7.15 (m, Ar-
H þ H-b pyrimidine), 7.78–8.52 (m, pyrid-4,5,6), 8.81 (s,
pyrid-2) ppm; MS (EI, 70eV): m=z (%) ¼ 337 [Mþ, 5], 152
[100, base peak].
6-(Pyridin-3-yl)-1,2,3,4-tetrahydro-2-oxo-4-(p-methoxyphenyl)
pyrimidine (16, C16H15N3O2)
7-(Pyridin-3-yl)-2-(indolylmethylene)-5-(p-methoxyphenyl)-
2,3-dihydro-5-thiazolo[3,2-a]pyrimidine (21, C27H20N4O2S)
Method A: A mixture of 0.297 g 17 (1mmol), 0.094g chloro-
acetic acid (1mmol), 1.5g anhydrous sodium acetate in
40cm3 of a mixture of AcOH=Ac2O (1=3) and 0.145g indole-
3-carboxaldehyde (1mmol) was refluxed for 6 h. The reaction
mixture was cooled and poured into ice-water, the obtained
solid was collected by filtration and crystallized to give 0.39 g
(84%) 21. Mp 232–234ꢁC (EtOH=H2O); IR (film): ꢂꢀ¼ 3355–
Yield 0.18 (66%); mp 246–248ꢁC (DMF=H2O); IR (film):
1
ꢂꢀ¼ 3348–3265 (NH), 1668 (C¼O) cmꢂ1; H NMR (DMSO-
d6): ꢃ ¼ 3.66 (s, OCH3), 5.35 (d, H-a, pyrimidine), 6.80–7.20
(m, Ar-Hþ H-b pyrimidine), 7.86–8.64 (m, pyrid-4,5,6), 8.30
and 8.55 (2s, 2NH-pyrimidine, exchangeable with D2O), 8.78
(s, pyrid-2) ppm; MS (EI, 70 eV): m=z (%) ¼ 281 [Mþ, 100,
base peak].
6-(Pyridin-3-yl)-1,2,3,4-tetrahydro-2-thioxo-4-(p-methoxyphenyl)
pyrimidine (17, C16H15N3OS)
3325 (NH), 1716 (C¼O) cmꢂ1
;
1H NMR (DMSO-d6):
ꢃ ¼ 3.64 (s, OCH3), 5.55 (d, H-a, pyrimidine ring), 6.70–
7.45 (m, indole-Hþ H-b pyrimidine ringþ Ar-Hþ benzylic
proton), 7.80–8.45 (m, pyrid-4,5,6), 8.72 (s, pyrid-2), 9.68
(s, NH-indole, exchangeable with D2O) ppm; 13C NMR
(DMSO-d6): ꢃ ¼ 45.05 (C-a), 55.86 (OCH3), 119.65 (C-b),
110.15, 111.35, 118.10, 119.22, 121.34, 122.94, 126.15,
135.80 (indole-C), 113.65, 127.12, 134.67, 157.26 (Ph-C),
141.10, 162.20 (pyrimidine-C), 141.38 (CH-benzylic-C),
120.85 (thiazole-C), 122.86, 126.32, 130.12, 149.58, 150.81
(pyridine-C), 165.65 (C¼O) ppm; MS (EI, 70eV): m=z (%) ¼
464 [Mþ, 100, base peak].
Yield 0.23 (79%); mp >250ꢁC (AcOH=H2O); IR (film):
1
ꢂꢀ¼ 3368–3255 (NH), 1665 (C¼O), 1215 (C¼S) cmꢂ1; H
NMR (DMSO-d6): ꢃ ¼ 3.63 (s, OCH3), 5.18 (d, H-a, pyrimi-
dine), 6.85–7.26 (m, Ar-Hþ H-b pyrimidine), 7.82–8.46 (m,
pyrid-4,5,6), 8.28 and 8.45 (2s, 2NH-pyrimidine, exchange-
able with D2O), 8.76 (s, pyrid-2) ppm; MS (EI, 70eV): m=z
(%) ¼ 297 [Mþ, 5], and at 112 [100, base peak].
Thiazino- and Thiazolopyrimidines 18–20
General Procedure
Method B: A mixture of 0.337 g 20 (1mmol) and 0.145g
indole-3-carboxaldehyde (1mmol) in 40 cm3 of a mixture of
AcOH=Ac2O (1=3) was refluxed for 5 h, allowed to cool, then
poured into water, and the solid formed was collected by
filtration and crystallized to yield 0.33g (72%) 21, as identi-
fied by its m.p., mixed m.p., and Rf value on TLC by compar-
ison with an authentic sample from method A.
A mixture of 0.297 g 17 (1mmol) and halo compounds,
namely 3-bromopropionic acid, 2-bromopropionic acid, and
chloroacetic acid (1mmol), was dissolved in 40cm3 of a mix-
ture of AcOH=Ac2O (1=3) in the presence 3 g anhydrous
sodium acetate and then refluxed for 6–7 h. The reaction mix-
ture was cooled and poured into cold water with stirring, the

724
N. A. Abdel-Latif et al.: Synthesis, Analgesic, and Antiparkinsonian Profiles
[5] Amr AE, Abdel-Latif NA, Abdalla MM (2006) Acta
Pharm 56: 203
[6] Amr AE, Abdel-Latif NA, Abdalla MM (2006) Bioorg
Pharmacology Screening
Analgesic Activity
Sixty mice of both sexes weighting from 20 to 25g were di-
vided into 10 groups. One group was kept as control (received
saline), the second group received vehicle (Gumacaccia), and
the third one received Voltarene+ as a reference drug, whereas
the other groups received 6, 8, 10, 12, 15, 17, and 21 (SC
administration). Mice were dropped gently in a dry glass bea-
ker of one liter capacity maintained at 55–55.5ꢁC. Normal
reaction times in seconds for all animals were 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 jamb out of the
beaker (dose 5 mg=kg) [26]. Relative potencies to Voltarene+
were determined (Table 1).
Med Chem 14: 273
[7] Amr AE (2005) Z Naturforsch 60b: 990
[8] Amr AE, Sayed HH, Abdulla MM (2005) Arch Pharm
Chem Life Sci 338: 433
[9] Abo-Ghalia MH, Amr AE (2004) Amino Acids 26: 283
[10] Hammam AG, Fahmy AFM, Amr AE, Mohamed AM
(2003) Ind J Chem 42B: 1985
[11] Hukki J, Laitinen P, Alberty JE (1968) Pharm Acta Helv
43: 704
[12] Jung JC, Watkins EB, Avery MA (2005) Heterocycles
65: 77
[13] Bansal E, Srivastava VK, Kumar A (2001) Eur J Med
Chem 36: 81
[14] Udupi RH, Rao SN, Bhat AR (1998) Ind J Heterocycl
Chem 7: 217
Antiparkinsonian Activity
[15] Ahn JH, Kim HM, Jung SH, Kang SK, Kim KR, Rhee
SD, Yong SD, Cheon HG, Kim SS (2004) Bioorg Med
Chem Lett 14: 4461
Purpose and Rationale
The muscarinic agonists Tremorine+ and Oxotremorine+ in-
duce parkinisonisin-like signs such as tremor, attaxia, spastic-
ity, salivation, lacrimation, and hypothermia. These signs are
antagonized by antiparkinsonian agents.
[16] Villhauer EB, Brinkman JA, Naderi CB, Dunning BE,
Mangold BL, Mone MD, Russell ME, Weldon SC,
Hughes TE (2002) J Med Chem 45: 2362
[17] Amr AE (2000) Ind J Heterocycl Chem 10: 49
[18] Amr AE, Mohamed AM, Salwa FM, Abdel Hafez NA,
Hammam AG (2006) Bioorg Med Chem 14: 5481
[19] Hammam AG, Abdel Hafez NA, Midura WH,
Mikolajczyk M (2000) Z Naturforsch 55b: 417
[20] Hassan SSM, Abou-Ghalia MH, Amr AE, Mohamed
AHK (2003) Talanta 60: 81
Procedure
Groups of eight male mice (18–20 g) were used. They were
dosed orally with the tested compounds (5mg=kg) or the
standard (Benzotropene+ mesilate, 5 mg=kg) [27] 1 h prior
the administration of 0.5 mg=kg of Oxotremerine+ SC. Rectal
temperature was measured before administration of the com-
pounds and one hour after Oxotremerine+ dosage. The scores
for the recorded signs are zero (absent), one (slight), two
(medium), and three (high) (Table 2).
[21] Hassan SSM, Abou-Ghalia MH, Amr AE, Mohamed
AHK (2003) Analytica Chemica Acta 482: 9
[22] Attia A, Michael M (1983) Acta Chimica Hungarica
114: 337
[23] Salmula K, Ewa JK (1974) Bocz Chem 48: 2287; C.A.
1975, 43: 79207t
References
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[2] Abo Ghalia MH, Salem EMS (1980) Ind J Chem 19B:
135
[3] Abo Ghalia MH, Salem EMS, Shoeb S, Zedan M (1979)
Polish J Chem 53: 2239
[24] Ried W, Staphlofen P (1954) Chem Ber 87: 1814
[25] Pushkina LN, Mazalov SA, Dostovskii I Ya (1962) Zh
Obshck Khim 32: 2617; C A 1963, 58: 9050a
[26] Tgolsen A, Rofland GH, Berge OG, Hole K (1991) J
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[27] Vieweg H, Leistner S, Wagner G (1988) Pharmazie 43:
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[4] Abdel-Latif NA (2005) Scientia Pharmaceutica 74:
193
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¨
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