Synthesis, reactions, and pharmacological activities of some pyrimidines using (N-methylindolyl)acetic acid as synthon

Article abstract of DOI:10.1007/s00706-007-0781-4

A series of pyrimidinones, thienopyrimidines, and their derivatives were synthesized using N-methylindolyl acetic acid as a starting material. Sixteen new heterocyclics containing a pyrimidine ring were thus prepared. The pharmacological screening showed that many of these compounds have good analgesic and antiparkinsonian activities comparable to Voltarene and Benzatropine as reference drugs. The structure assignments of the new compounds based on chemical and spectroscopic evidence. The detailed synthesis, spectroscopic data, and pharmacological properties are reported.

Full text of DOI:10.1007/s00706-007-0781-4

Monatsh Chem 139, 281–287 (2008)
DOI 10.1007/s00706-007-0781-4
Printed in The Netherlands
Synthesis, Reactions, and Pharmacological Activities of Some Pyrimidines
Using (N-Methylindolyl)acetic Acid as Synthon
Nabil H. Ouf1, Abd El-Galil E. Amr2;ꢀ, and Ahmed A. Fayed2
1
Chemistry Department, Zagazig University, Zagazig, Egypt
2
National Research Center, Applied Organic Chemistry Department, Cairo, Dokki, Egypt
Received August 2, 2007; accepted August 6, 2007; published online February 12, 2008
# Springer-Verlag 2008
Summary. A series of pyrimidinones, thienopyrimidines,
and their derivatives were synthesized using N-methylindolyl
acetic acid as a starting material. Sixteen new heterocyclics
containing a pyrimidine ring were thus prepared. The pharma-
cological screening showed that many of these compounds
have good analgesic and antiparkinsonian activities compa-
rable to Voltarene+ and Benzatropine+ as reference drugs.
The structure assignments of the new compounds based on
chemical and spectroscopic evidence. The detailed synthe-
sis, spectroscopic data, and pharmacological properties are
reported.
of compounds many of which possess wide-spread
pharmacological properties such as analgesic, antiar-
rhythmic, and anticancer activities [14–16]. Recent-
ly, some new substituted pyrimidine derivatives have
been synthesized, which exhibit analgetic, antiin-
flammatory, antiparkinsonian, and androgenic-anabol-
ic activities [17–22]. In view of these observations
and as continuation of our previous work on pyrimi-
dine chemistry, we synthesized some new com-
pounds containing pyrimidine and indole moieties,
and tested their analgesic and antiparkinsonian ac-
tivities in comparison to Voltarene+ and Benzatro-
pine+ as reference drugs.
Keywords. Indole acetic acid; Pyrimidines; Thienopyrimi-
dines, Antimicrobial agents.
Introduction
Pyrimidines and fused pyrimidines, being an integral
part of DNA and RNA, play an essential role in sev-
eral biological processes and have considerable
chemical and pharmacological importance, particu-
larly, the pyrimidine ring can be found in nucleoside
antibiotics, antibacterials, cardio-vascular as well as
agro chemical and veterinarian products [1–9]. In
view of these observations and in continuation of
our interest in developing efficient syntheses of poly-
functionally substituted heterocycles we used the
readily obtainable pyrimidines as starting materials
[10–13]. Pyrimidines present an interesting group
Results and Discussion
Synthesis
In the present work we report the synthesis and a
preliminary biological activity screening of several
pyrimidine derivatives based on 2-[(N-methyl-
indolyl)methyl]-4-methyl-5-ethoxycarbonyl-6-mer-
captopyrimidine (4), which was prepared from
N-methylindolyl-3-acetic acid (1) according to Ref.
[23] (Scheme 1). The reaction of 6-mercaptopyrimi-
dine 4 with ethyl bromoacetate in the presence
of triethylamine (TEA) produced ethoxycarbonyl-
methyl-mercaptopyrimidine 5, which was refluxed
with ethanolic sodium ethoxide to yield the corre-
ꢀ
Corresponding author. E-mail: aamr1963@yahoo.com

282
N. H. Ouf et al.
Scheme 1
Scheme 2

Synthesis, Reactions, and Pharmacological Activities of Some Pyrimidines
283
sponding thieno[2,3-d]pyrimidine 6. However, the
latter was also prepared directly from 4 by refluxing
with ethyl bromoacetate in the presence of sodium
ethoxide (Scheme 1).
Reaction of 4 with chloro reagents, namely,
chloro-N-phenylacetamide, chloro-acetamide, and
phenacylchloride in refluxing ethanol containing tri-
ethylamine as a catalyst afforded the 2-(N-phenyl-
acetamido)mercapto-, 2-acetamidomercapto-, and
2-benzoylmethyl-mercaptopyrimidines 7–9. The
latter 7–9 undergo intramolecular cyclization using
sodium ethoxide affording the corresponding fused
thienopyrimidines 10–12 (Scheme 2).
acetic acid yielded 18 via the formation of 17 as
intermediate.
Treatment of 18 with sodium azide in refluxing
ethanol gave the corresponding tetrazolopyrimidine
20 via the formation of azide form 19. Compound
18 was reacted with thiourea, aniline, and hydrazine
hydrate in refluxing ethanol to afforded the corre-
sponding pyrimidopyrimidine 21, 6-phenylamino-
pyrimidine 22, and 6-hydrazinopyrimidine 23. The
latter compound was reacted with another molecule
of 18 to give the corresponding bis-pyrimidine de-
rivative 24.
The reaction of 4 with hydrogen peroxide in so-
dium hydroxide solution affording the 6-hydroxy-
pyrimidine 13. Michael addition of acrylonitrile in
refluxing ethanol gave the 6-mercaptoethyl carboni-
trile 14, which was treated with hydrazine hy-
drate to afford 3-hydroxypyrazolopyrimidine 15.
Oxidation of 4 with iodine in acetic acid gave the
disulfide 16. Chlorination of 4 with chlorine in
Pharmacological Screening
Two pharmacological activities namely, analgesic
and antiparkinsonism were tested despite their dif-
ferent biological receptors. Yet both are of neurolog-
ical origin. Seven representative compounds 6, 7, 11,
12, 15, 21, and 24 were studied with repect to their
analgesic and antiparkinsonian activities.
Scheme 3

284
N. H. Ouf et al.
Scheme 4
Table 1. Analgesic activity of several compounds as compared with Voltarene+ in mice
Comp. No.
Analgesic activity after:
10 min
20 min
30 min
45 min
60 min
90 min
120 min
Voltarene+
1
1
1
1
1
1
1
6
7
0.80
0.32
0.62
0.96
0.58
0.55
0.79
0.90
0.41
0.63
0.99
0.62
0.57
0.82
0.88
0.41
0.73
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
1.13
0.77
0.51
0.88
0.94
0.43
0.74
1.20
0.81
0.49
0.88
0.94
0.47
0.74
1.42
0.80
0.47
0.91
11
12
15
21
24
Analgesic Activity
approached those of Voltarene+, and 8 had 31–
47% activity (Table 1).
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 24
Antiparkinsonian Activity
Compounds 6, 11, and 15 showed moderate activity
(relative potencies to Benzotropene+ 0.44, 0.60, and

Synthesis, Reactions, and Pharmacological Activities of Some Pyrimidines
285
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
26
12
19
16
21
11
5
0
1
6
7
0.45
0.81
0.61
0.82
0.43
0.17
0.14
11
12
15
21
24
4
(s, N–CH3), 3.58 (s, CH2), 4.15 (q, J ¼ 7.15 Hz, CH2), 6.90–
7.95 (m, Ar–H), 12.20 (s, OH, exchangeable with D2O) ppm;
MS (EI, 70 eV): m=z (%) ¼ 381 (Mþ, 15) and at 336 (100,
base peak).
0.40). Compounds 7 and 12 are the most potent anti-
parkinsonic agents (0.80 relative potency) (Table 2).
Method B: A mixture of 0.34g 4 (1mmol), 0.17g ethyl
bromoacetate (1mmol) and ꢃ0.1 g sodium ethoxide (1mmol)
in 10 cm3 ethanol was refluxed for 2 h. After cooling, acidifi-
cation with 3 cm3 HCl (1N), the precipitate was collected and
crystallized from ethanol to give 0.23 g 6 (60%).
Experimental
Synthesis
All melting points were taken on Electrothermal IA 9000
series digital melting point apparatus. Elemental analytical
data were obtained from the microanalytical unit, Cairo
University, Cairo, Egypt; the results were in favorable agree-
ments with the calculated values. The IR spectra (KBr) were
recorded on a Perkin-Elmer model 1430 spectrophotometer.
The 1H NMR spectra were recorded at 270 MHz on a Perkin-
Elmer R12B Spectrometer using TMS as an internal standard.
The mass spectra were performed using VG 2AB-3F spec-
trometer (70 eV). All reactions were followed by TLC (silica
gel, aluminum sheets 60 F254, Merck)
Synthesis of Substituted Pyrimidines 7–9
A mixture of 0.34 g 4 (1mmol), 1 mmol appropriate chlorinat-
ing agent, and 3 drops of TEA in 25cm3 ethanol was refluxed
for 30min. The reaction mixture was cooled, poured into
water, the solid formed was filtered off, and crystallized to
give 0.34 g 7 (72%), 0.27g 8 (68%) and 0.26 g 9 (56%).
2-[(N-Methylindolyl)methyl]-4-methyl-5-ethoxycarbonyl-6-
mercapto-N-phenylacetamidopyrimidine (7, C26H26N4O3S)
Mp 245ꢁC (AcOH); IR (film): ꢀꢀ¼ 3397–3280 (NH), 1735
2-[(N-Methylindolyl)methyl]-4-methyl-5-ethoxycarbonyl-6-
ethoxycarbonylmethylmercaptopyrimidine (5, C22H25N3O4S)
A mixture of 0.34g 4 (1mmol) and 0.17 g ethyl bromoacetate
(1mmol) in the presence of 3 drops TEA as catalyst in 25cm3
absolute ethanol was refluxed for 30min. The reaction mix-
ture was cooled and poured into water, the obtained precipitate
was collected by filtration, and crystallized from methanol to
give 0.26g 5 (60%). Mp 110ꢁC; IR (film): ꢀꢀ¼ 1736 (C¼O,
1
(C¼O, ester), 1660 (C¼O, amide) cmꢂ1; H NMR (DMSO-
d6): ꢁ ¼ 1.30 (t, J ¼ 7.00Hz, CH3), 2.32 (s, CH3), 2.40 (s, N–
CH3), 3.54 (s, CH2), 3.74 (s, CH2), 4.16 (q, J ¼ 7.20Hz, CH2),
6.98–7.65 (m, Ar–H), 8.80 (s, NH, exchangeable with D2O)
ppm; MS (EI, 70eV): m=z (%) ¼ 474 (Mþ, 44) and at 263
[100, base peak].
2-[(N-Methylindolyl)methyl]-4-methyl-5-ethoxycarbonyl-
6-mercaptoacetamidopyrimidine (8, C20H22N4O3S)
Mp 233ꢁC (EtOH); IR (film): ꢀꢀ¼ 3360 (NH2), 1735 (C¼O,
ester), 1520 (C¼N) cmꢂ1
;
1H NMR (DMSO-d6): ꢁ ¼ 1.20,
1.24 (2t, J ¼ 7.05 Hz, 2 CH3), 2.30 (s, CH3), 2.38 (s, N–
CH3), 3.55 (s, CH2), 3.72 (s, CH2), 4.10 (q, J ¼ 7.18 Hz,
CH2), 4.30 (q, J ¼ 7.20Hz, CH2), 6.85–7.60 (m, Ar–H) ppm;
MS (EI, 70 eV): m=z (%) ¼ 427 (Mþ, 62) and at 337 (100,
base peak).
1
ester), 1705 (C¼O) cmꢂ1; H NMR (DMSO-d6): ꢁ ¼ 1.28 (t,
J ¼ 6.98 Hz, CH3), 2.35 (s, CH3), 2.42 (s, N–CH3), 3.56 (s,
CH2), 3.73 (s, CH2), 4.18 (q, J ¼ 7.16 Hz, CH2), 6.05 (s, NH2,
exchangeable with D2O), 6.94–7.60 (m, Ar–H) ppm; MS (EI,
70eV): m=z (%) ¼ 398 (Mþ, 48) and at 281 (100, base peak).
6-[(N-Methylindolyl)methyl]-4-methyl-2-ethoxycarbonyl-
3-hydroxythienopyrimidine (6, C20H19N3O3S)
2-[(N-Methylindolyl)methyl]-4-methyl-5-ethoxycarbonyl-
6-mercaꢁptophenacylpyrimidine (9, C26H25N3O3S)
Mp 156 C (AcOH); IR (film): ꢀ ¼ 1736 (C¼O, ester), 1700
(C¼O), 1540 (C¼N) cmꢂ1; 1H NMR (DMSO-d6): ꢁ ¼ 1.32 (t,
J ¼ 7.00 Hz, CH3), 2.34 (s, CH3), 2.43 (s, N–CH3), 3.53 (s,
CH2), 3.76 (s, CH2), 4.14 (q, J ¼ 7.20 Hz, CH2), 6.84–7.70 (m,
Ar–H) ppm; MS (EI, 70eV): m=z (%) ¼ 459 (Mþ, 12) and at
308 (100, base peak).
Method A: A mixture of 0.42g 5 (1mmol) and ꢃ0.1 g sodium
ethoxide (1mmol) in 50cm3 ethanol was heated under reflux
for 30 min. The reaction mixture was cooled, acidified
with HCl, the formed solid was filtered off, and crystallized
from ethanol to give 0.22g 6 (58%). Mp 140ꢁC; IR (film):
ꢀ
1
ꢀꢀ¼ 3448–3250 (br, OH), 1732 (C¼O, ester) cmꢂ1; H NMR
(DMSO-d6): ꢁ ¼ 1.25 (t, J ¼ 7.10Hz, CH3), 2.36 (s, CH3), 2.41

286
N. H. Ouf et al.
tate obtained upon cooling was collected and crystallized from
ethanol to give 0.20 g 15 (67%). Mp 130ꢁC; IR (film): ꢀꢀ¼
Synthesis of Thienopyrimidines 10–12
A mixture of 7–9 (1mmol) and ꢃ0.1 g sodium ethoxide
(1mmol) in 25cm3 ethanol was heated under reflux for 1 h.
The reaction mixture was cooled, acidified with HCl, the solid
was filtered off and crystallized to give 0.3 g 10 (70%), 0.23g
11 (64%), and 0.24g 12 (58%).
3520, 3200, 3140 (NH, OH) cmꢂ1 1H NMR (DMSO-d6):
;
ꢁ ¼ 2.30 (s, CH3), 2.42 (s, N–CH3), 3.55 (s, CH2), 6.92–
7.75 (m, Ar–H), 11.10 (s, NH, exchangeable with D2O),
12.19 (s, OH, exchangeable with D2O) ppm; MS (EI, 70 eV):
m=z (%) ¼ 293 (Mþ, 22) and at 148 (100, base peak).
6-[(N-Methylindolyl)methyl]-4-methyl-2-(N-phenylamido)-
3-hydroxythienopyrimidine (10, C24H20N4O2S)
6,60-Bis-{2-[(N-methylindolyl)methyl]-4-methyl-5-ethoxy-
carbonylpyrimidino}sulfide (16, C36H36N6O4S2)
To a solution of 0.34 g 4 (1mmol) in 20cm3 acetic acid, 0.25 g
iodine (1mmol) was added portion-wise with stirring at room
temperature. The solid formed was collected by filtration and
crystallized from ethanol to give 0.37 g 16 (55%). Mp 220ꢁC;
Mp 218ꢁC (EtOH); IR (film): ꢀꢀ¼ 3440–3120 (NH, OH), 1707
1
(C¼O) cmꢂ1; H NMR (DMSO-d6): ꢁ ¼ 2.37 (s, CH3), 2.44
(s, N–CH3), 3.53 (s, CH2), 6.88–7.68 (m, Ar–H), 8.76 (s, NH,
exchangeable with D2O), 12.28 (s, OH, exchangeable with
D2O) ppm; MS (EI, 70 eV): m=z (%) ¼ 428 (Mþ, 36) and at
192 (100, base peak).
IR (film): ꢀꢀ¼ 1735, 1733 (2C¼O, ester) cmꢂ1
;
1H NMR
(DMSO-d6): ꢁ ¼ 1.24 (t, J ¼ 7.10 Hz, 2 CH3), 2.30 (s, 2CH3),
2.38 (s, 2N–CH3), 3.55 (s, 2CH2), 4.16 (q, J ¼ 7.20 Hz,
2CH2), 6.85–7.60 (m, Ar–H) ppm; MS (EI, 70eV): m=z
(%) ¼ 680 (Mþ, 42) and at 295 (100, base peak).
6-[(N-Methylindolyl)methyl]-4-methyl-2-amido-3-hydroxy-
thienopyrimidine (11, C18H16N4O2S)
Mp 236ꢁC (MeOH); IR (film): ꢀꢀ¼ 3460–3210 (OH, NH2),
1
1704 (C¼O) cmꢂ1; H NMR (DMSO-d6): ꢁ ¼ 2.36 (s, CH3),
2.45 (s, N–CH3), 3.54 (s, CH2), 6.15 (s, NH2, exchangeable
with D2O), 6.85–7.65 (m, Ar–H), 12.32 (s, OH, exchangeable
with D2O) ppm; MS (EI, 70eV): m=z (%) ¼ 352 (Mþ, 35) and
at 320 (100, base peak).
2-[(N-Methylindolyl)methyl]-4-methyl-5-ethoxycarbonyl-
6-chloropyrimidine (18, C18H18ClN3O2)
Chlorine gas was bubbled through a suspension of 0.34 g 4
(1mmol) in 50cm3 acetic acid for about 3 h. The resulting
colorless precipitate was filtered off, washed with water, dried
and crystallized from ethanol to give 0.20g 18 (60%). Mp
6-[(N-Methylindolyl)methyl]-4-methyl-2-benzoyl-3-hydroxy-
thienopyrimidine (12, C24H19N3O2S)
125ꢁC; IR (film): ꢀꢀ¼ 1739 (C¼O, ester) cmꢂ1
;
1H NMR
Mp 256ꢁC (AcOH); IR (film): ꢀꢀ¼ 3418–1325 (OH), 1720
1
(C¼O) cmꢂ1; H NMR (DMSO-d6): ꢁ ¼ 2.35 (s, CH3), 2.43
(DMSO-d6): ꢁ ¼ 1.28 (t, J ¼ 7.02Hz, CH3), 2.32 (s, CH3),
2.40 (s, N–CH3), 3.56 (s, CH2), 4.15 (q, J ¼ 7.14 Hz, CH2),
6.87–7.68 (m, Ar–H) ppm; MS (EI, 70 eV): m=z (%) ¼ 344
(Mþ, 38) and at 298 (100, base peak).
(s, N–CH3), 3.58 (s, CH2), 6.90–7.74 (m, Ar–H), 12.28 (s,
OH, exchangeable with D2O) ppm; MS (EI, 70 eV): m=z
(%) ¼ 413 (Mþ, 46) and at 252 (100, base peak).
2-[(N-Methylindolyl)methyl]-4-methyl-5-ethoxycarbonyl-6-
hydroxypyrimidine (13, C18H19N3O3)
7-[(N-Methylindolyl)methyl]-5-methyl-4-ethoxycarbonyl-
tetrazolopyrimidine (20, C18H18N6O2)
A mixture of 0.34g 4 (1mmol), 60cm3 hydrogen peroxide
(30%), and 20cm3 sodium ethoxide (5%) was stirred for 1 h
at room temperature. The reaction mixture was cooled, acidi-
fied with HCl, the solid formed was filtered off, and crystallized
from ethanol to give 0.21 g 13 (65%). Mp 170ꢁC; IR (film): ꢀꢀ¼
A mixture of 0.34g 18 (1mmol) and ꢃ0.1 g sodium azide
(1.5mmol) in 30cm3 ethanol was refluxed for 4 h. The reac-
tion mixture was cooled, poured into water, the solid was
filtered off, and crystallized from ethanol to give 0.21g 20
(60%). Mp>300ꢁC; IR (film): ꢀꢀ¼ 1735 (C¼O, ester) cmꢂ1
;
1
3540–3350 (OH), 1695 (C¼O) cmꢂ1; H NMR (DMSO-d6):
1H NMR (DMSO-d6): ꢁ ¼ 1.30 (t, J ¼ 7.00Hz, CH3), 2.35 (s,
CH3), 2.39 (s, N–CH3), 3.54 (s, CH2), 4.12 (q, J ¼ 7.20 Hz,
CH2), 6.90–7.78 (m, Ar–H) ppm; MS (EI, 70eV): m=z
(%) ¼ 350 (Mþ, 100, base peak).
ꢁ ¼ 1.24 (t, J ¼ 7.04 Hz, CH3), 2.30 (s, CH3), 2.38 (s, N–CH3),
3.55 (s, CH2), 4.16 (q, J ¼ 7.21 Hz, CH2), 6.85–7.60 (m, Ar–H),
11.40 (s, OH, exchangeable with D2O) ppm; MS (EI, 70 eV):
m=z (%) ¼ 325 (Mþ, 75) and at 362 (100, base peak).
Synthesis of Pyrimidopyrimidine 21 and Substituted
Pyrimidines 22 and 23
2-[(N-Methylindolyl)methyl]-4-methyl-5-ethoxycarbonyl-6-
mercaptoethylcarbonitrilepyrimidine (14, C21H22N4O2S)
A mixture of 0.34g 4 (1mmol), ꢃ0.1 g acrylonitrile
(1.9mmol), and 3 drops of TEA in 10 cm3 ethanol was heated
under reflux for 1 h. After cooling the precipitate was collected
and crystallized from ethanol to give 0.27g 14 (68%). Mp
115ꢁC; IR (film): ꢀꢀ¼ 2218 (CꢄN), 1734 (C¼O, ester),
1595 (C¼N) cmꢂ1; MS (EI, 70 eV): m=z (%) ¼ 394 (Mþ,
16) and at 362 (100, base peak).
A mixture of 0.34 g 18 (1mmol) and amino reagents, namely,
thiourea, aniline (1mmol) or hydrazine hydrate (8mmol) in
30cm3 ethanol in the presence of 3 drops TEA was refluxed
for 3 h. The reaction mixture was poured into water, the sepa-
rated solid was collected and crystallized to give 0.28g 21
(82%), 0.24 g 22 (60%), and 0.25g 23 (75%).
7-[(N-Methylindolyl)methyl]-5-methyl-4-oxo-2-mercapto-
pyrimidopyrimidine (21, C17H14N5O5)
Mp 130ꢁC (EtOH); IR (film): ꢀꢀ¼ 3465 (NH), 1705 (C¼O),
1230 (C ¼ S) cmꢂ1; 1H NMR (DMSO-d6): ꢁ ¼ 2.31 (s, CH3),
2.38 (s, N–CH3), 3.57 (s, CH2), 6.89–7.80 (m, Ar–H), 8.45,
6-[(N-Methylindolyl)methyl]-4-methyl-3-hydroxypyrazolo-
pyrimidine (15, C16H15N5O)
A mixture of 0.4 g 14 (1mmol) and 0.5 cm3 hydrazine hydrate
(8mmol) in 20cm3 ethanol was refluxed for 2 h. The precipi-

Synthesis, Reactions, and Pharmacological Activities of Some Pyrimidines
287
9.70 (2s, 2NH, exchangeable with D2O) ppm; MS (EI,
70 eV): m=z (%) ¼ 336 (Mþ, 18) and at 192 (100, base peak).
temperature was measured before administration of the com-
pounds and 1 h after Oxotremerine+ dosage. The scores for the
recorded signs are zero (absent), one (slight), two (medium),
and three (high) (Table 2).
2-[(N-Methylindolyl)methyl]-4-methyl-5-ethoxycarbonyl-
6-phenylaminopyrimidine (22, C24H24N4O2)
Acknowledgement
Mp 214 (EtOH); IR (film): ꢀꢀ¼ 3455 (NH), 1734 (C¼O,
ester) cmꢂ1
;
1H NMR (DMSO-d6): ꢁ ¼ 1.32 (t, J ¼
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.
7.02 Hz, CH3), 2.33 (s, CH3), 2.39 (s, N–CH3), 3.57 (s,
CH2), 4.16 (q, J ¼ 7.20 Hz, CH2), 6.45 (s, NH, exchange-
able with D2O), 6.84–7.66 (m, Ar–H) ppm; MS (EI, 70 eV):
m=z (%) ¼ 400 (Mþ, 8) and at 235 (100, base peak).
References
2-[(N-Methylindolyl)methyl]-4-methyl-5-ethoxycarbonyl-
6-hydrazinopyrimidine (23, C18H21N5O2)
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Mp 224ꢁC (EtOH); IR (film): ꢀꢀ¼ 3455–3265 (NH, NH2),
1
1736 (C¼O, ester) cmꢂ1; H NMR (DMSO-d6): ꢁ ¼ 1.29 (t,
J ¼ 7.00Hz, CH3), 2.30 (s, CH3), 2.36 (s, N–CH3), 3.54 (s,
CH2), 4.12 (q, J ¼ 7.22 Hz, CH2), 6.25 (s, NH2, exchangeable
with D2O), 6.92–7.76 (m, Ar–H), 9.45 (s, NH, exchangeable
with D2O) ppm; MS (EI, 70eV): m=z (%) ¼ 339 (Mþ, 100,
base peak).
[5] Santagati M, Modica M, Santagati A, Russo F,
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6,60-Bis-{2-[(N-methylindolyl)methyl]-4-methyl-5-ethoxy-
carbonylpyrimidino}imide (24, C36H38N8O4)
A mixture of 0.34 g 18 (1mmol) and 0.33 g of 23 (1mmol) in
50cm3 ethanol in the presence of 3 drops TEAwas refluxed for
5 h. The separated solid was collected and crystallized from
ethanol to give 0.49 g 24 (62%). Mp 132–134ꢁC; IR (film):
1
ꢀꢀ¼ 3446 NH, 1750 (C¼O) cmꢂ1; H NMR (DMSO-d6): ꢁ ¼
1.35 (t, J ¼ 7.04 Hz, 2 CH3), 2.34 (s, 2 CH3), 2.42 (s, 2 N–CH3),
3.54 (s, 2 CH2), 4.18 (q, J ¼ 7.20 Hz, 2 CH2), 6.87–7.70 (m,
Ar–H), 10.10 (s, 2 NH, exchangeable with D2O) ppm; MS (EI,
70eV): m=z (%) ¼ 646 (Mþ, 100, base peak).
[9] Danel K, Pedersen EB, Nielsen CJ (1998) Med Chem
41: 191
[10] Yvette AI, Aly AA (2003) Z Naturforsch 58b: 1227
[11] Aly AA, Nassar SA (2004) Heteroatom Chem 15: 2
[12] Aly AA (2003) Phosphorus Sulfur Silicon 178: 2415
[13] Aly AA (2004) Chi Chem 51: 1381
[14] Nehad AA, Nermien MS, Ashraf MM, Abdulla MM
(2007) Monatsh Chem 138: 715
Pharmacology Screening
Analgesic Activity
Sixty mice of both sexes weighting from 20 to 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 Voltarene+ as a reference drug, whereas the other
groups received 6, 7, 11, 12, 15, 21, and 24 (SC administration).
Mice were dropped gently in a dry glass beaker of 1 dm3 ca-
pacity maintained at 55–55.5ꢁC, Normal reaction time in sec-
onds 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 ani-
mal licks its feet or jamb out of the beaker (dose 5 mg=kg) [24].
Relative potencies to Voltarene+ were determined (Table 1).
[15] Ahmed FAS, Abdulla MM, Amr AE, Azza AH (2007)
Monatsh Chem 138: accepted 20-4-2007
[16] Hammam AG, Fahmy AFM, Amr AE, Mohamed AM
(2003) Ind J Chem 42B: 1985
[17] Amr AE, Hegab MI, Ibrahim AA, Abdalah MM (2003)
Monatsh Chem 134: 1395
[18] Amr AE, Abdulla MM (2002) Ind J Heterocycl Chem
12: 129
[19] Nehad AA, Amr AE, Alhusien AI (2007) Monatsh
Chem 138: 559
[20] Amr AE, Nermien MS, Abdulla MM (2007) Monatsh
Chem 138: 699
[21] Amr AE, Ashraf MM, Salwa FM, Nagla AA, Hammam
AG (2006) Bioorg Med Chem 14: 5481
[22] Amr AE, Sayed HH, Abdulla MM (2005) Arch Pharm
Chem Life Sci 338: 433
[23] Saad HA, Mostafa HY, Assy MG, Sayed MA (2001)
Bull Korean Chem Soc 22: 311
Antiparkinsonian Activity
The muscarinic agonists Tremorine+ and Oxotremorine+ in-
duce parkinisonisin-like signs such as tremor, ataxia, spastici-
ty, salivation, lacrimation, and hypothermia. These signs are
antagonized by antiparkinsonian agents.
Groups of eight mail mice (18–20 g) were used. They
were dosed orally with the tested compounds (5mg=kg) or
the standard (Benzotropene+ mesilate, 5 mg=kg) [25] 1 h prior
the administration of 0.5mg=kg of Oxotremerine+ S.C. Rectal
[24] Tgolsen A, Rofland GH, Berge OG, Hole K (1991)
J Pharmacol Ther 25: 241
[25] Vieweg H, Leistner S, Wagner G (1988) Pharmazie
43: 358