Evaluation of the anti-inflammatory activity of some pyrrolo[2,3-d] pyrimidine derivatives

Article abstract of DOI:10.1007/s00044-012-0217-5

A series of novel pyrrolo[2,3-d]pyrimidine and fused pyrrolo[2,3-d] pyrimidine derivatives were synthesized and their structures were characterized by elemental analysis, ¹H NMR, IR, and mass spectroscopy. Their in vivo anti-inflammatory activi

Full text of DOI:10.1007/s00044-012-0217-5

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:2244–2252
DOI 10.1007/s00044-012-0217-5
ORIGINAL RESEARCH
Evaluation of the anti-inflammatory activity of some
pyrrolo[2,3-d]pyrimidine derivatives
•
Mosaad S. Mohamed Rehab Kamel
•
Rania H. Abd El-hameed
Received: 1 March 2012 / Accepted: 24 August 2012 / Published online: 6 September 2012
Ó Springer Science+Business Media, LLC 2012
Abstract A series of novel pyrrolo[2,3-d]pyrimidine and
fused pyrrolo[2,3-d]pyrimidine derivatives were synthesized
and their structures were characterized by elemental analysis,
1H NMR, IR, and mass spectroscopy. Their in vivo anti-
inflammatory activities were evaluated, and the results indi-
cated that some of the title compounds compounds showed
significant activities. These compounds are 2b ((7-(4-
Methoxyphenyl)-5,6-diphenyl-7H-pyrrolo[2,3-d]pyrimidin-4-
yl)-hydrazine), 7b (4-(2-(Benzyl)hydrazinyl)-7-(4-methoxy-
phenyl)-5,6-diphenyl-7H-pyrrolo[2,3-d] pyrimidine), 7d (4-(2-
(Benzyl)hydrazinyl)-7-(4-methoxyphenyl)-5-phenyl-7H-pyr-
rolo[2,3-d]pyrimidine), and 9b (4-(3,5-Dimethyl-4H-pyrazol
-1-yl)-7-(4-Methoxyphenyl)-5,6-diphenyl-4,7dihydro-3H-pyr-
rolo[2,3-d]pyrimidine).
mediators from the injured tissue and migrating cells where
prostaglandins play a very important role as mediators in
the process of inflammation. Almost all classes of non-
steroidal ant-inflammatory drugs (NSAIDs) inhibit the
conversion of arachidonic acid to prostaglandins. The
carrageenin-induced rat hind paw edema test is a common
model for evaluation of anti-inflammatory agents; in this
model, cyclooxygenase-2 (COX-2) levels are raised and
this is accompanied with the increase in prostaglandin
production (Huslisson, 1983; Evans and Nigel, 1987).
Pyrrolo[2,3-d]pyrimidine derivatives have attracted a great
deal of interest owing to their medicinal activities as they
have wide variety of interesting biological activities such
as anti-microbial (Rao, 1968; Dang and Gomez-Galeno,
2002), analgesic (Danchev et al., 2006), anti-inflammatory
(Jarvis et al., 2002), antiviral (Gangjee et al., 2005), and
anti-cancer (Declercq et al., 1987; Krawczyk et al., 1995;
Finch et al., 1997). The rapid growth in the literature
dealing with the synthesis and anti-inflammatory activity of
the pyrrolo[2,3-d]pyrimidine derivatives prompted us to
synthesize new derivatives of pyrrolo[2,3-d]pyrimidine and
fused pyrrolopyrimidine derivatives and test their anti-
inflammatory activity as an extension to our previous work
(Mohamed et al., 2012).
Keywords Pyrrolo[2,3-d]pyrimidine ꢀ
Pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine ꢀ
Anti-inflammatory activity ꢀ Structure–activity relationship
Introduction
Inflammation is a normal protective response to tissue
injury caused by several causes (Mycek et al., 1987).
Inflammation is triggered by the release of chemical
Chemistry
M. S. Mohamed ꢀ R. H. Abd El-hameed (&)
Pharmaceutical Organic Chemistry Department,
Faculty of Pharmacy, Helwan University,
Ein Helwan, Cairo, Egypt
Compounds 1a–1d were prepared as we reported before
(Mohamed et al., 2011). These compounds were utilized for
the preparation of hydrazino-pyrrolo[2,3-d]pyrimidine
derivatives 2a–2d using hydrazine hydrate (Mohamed et al.,
2005). These hydrazino derivatives were the key compounds
for preparation of all the rest pyrrolopyrimidine derivatives.
Pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives
e-mail: zeiadomar@yahoo.com
R. Kamel
Toxicology and Pharmacology Department,
Faculty of Pharmacy, Helwan University,
Ein Helwan, Cairo, Egypt
123

Med Chem Res (2013) 22:2244–2252
2245
3–6 were synthesized via reaction of compounds 2a–2d with
formic acid, carbon disulfide, acetic anhydride, or ethyl
chloroformate (Abdel-Mohsen, 2005; Hossain and Bhuiyan,
2009; Fathalla et al., 2009) as revealed in Scheme 1.
Compound 9b exerted a stronger anti-inflammatory effect
than ibuprofen (63.24 and 74.6 % inhibition, respectively,
at 3 and 4 h interval postcarrageenan). Likewise, com-
pounds 2b and 7d showed a significantly higher inhibitory
action than ibuprofen at the 3 h interval (61.4 and 62.68 %
inhibition, respectively) but their activity at 4 h interval
postcarrageenan was lower than that of ibuprofen (62.38
and 66.19 %). Activity of compound 7b was lower than
that of ibuprofen at both 3 and 4 h interval postcarrageenan
(54.04 and 62.96 % inhibition, respectively). Compounds
2d, 9c, and 9d showed no significant anti-inflammatory
activity at 1, 2, and 3 h interval but their significant activity
only appeared at 4 h interval but less than that of ibuprofen
(50.26, 59.25, and 61.9 % respectively). The rest of the
tested compounds showed no activity.
Refluxing of 2a–2d with the benzaldehyde in absolute
ethanol gave 4-(2-benzylhydrazinyl)pyrrolopyrimidine
derivatives 7a–7d (Hossain and Bhuiyan, 2009). Com-
pounds 2a and 2b were cyclized to pyrrolo[3,2-e]tetrazol-
o[1,5-c] pyrimidine 8a and 8b by stirring with sodium nitrite
in acetic acid (Dave and Shah, 2002). 4-Pyrazolyl-pyrrol-
o[2,3-d]pyrimidine 9b–9d were prepared by refluxing of
hydrazino-pyrrolopyrimidine 2b–2d with acetyl acetone
(Bhuiyan et al., 2005). Finally, pyrrolo[3,2-e][1,2,5]triazi-
no[5,6-c]pyrimidin-3-one 10a and 10b were produced when
compounds 2a and 2b were refluxed with chloro acetyl-
chloride (Fathalla et al., 2009) as revealed in Scheme 2.
In order to analyze structure–activity relationships, two
structural components were considered: the nature of the
heterocycle nucleus and the nature of the substituent on
positions 4 and 7 of pyrrolo[2,3-d]pyrimidine. First, regarding
the influence of the nature of the heterocycle nucleus, it is
generally observed that pyrrolo[2,3-d]pyrimidine derivatives
acquired significant anti-inflammatory activity as compounds
2b, 2d, 7b, 7d, and 9c–d over pyrrolo[3,2-e][1,2,4]triazol-
o[4,3-c]pyrimidine derivatives 3a–3d–6a–6d, pyrrolo[3,2-
e]tetrazolo[1,5-c]pyrimidine 8a and 8b, and pyrrolo[3,2-e]
[1,2,5]triazino[5,6-c]pyrimidine 10a and 10b which have no
Biological activity
All the synthesized compounds were tested for their anti-
inflammatory activity. As indicated in Table 1, compounds
2b, 7b, 7d, and 9b induced a good anti-inflammatory
activity at both 3 and 4-h interval postcarrageenan, com-
parable with that of ibuprofen and their activity profiles
were the same as ibuprofen (response increasing by time).
Scheme 1 Synthesis of
compounds 2–6
Cl
N
NHNH2
N
N
Ph
N
Ph
Ph
N
ii
I
N
X
N
R
N
N
X
X
N
R
N
R
2a-d
1a-d
3a-d
O
iii
V
H
H
N
iv
N
N
N
N
S
Ph
Ph
N
N
N
N
X
X
N
R
N
N
CH3
Ph
N
4a-d
6a,b
N
X
N
R
5a-d
R
X
R
CH3
Ph
a
Reagents: i=
NH2-NH2
ii=
HCOOH
b
Ph
H
OMe
CH3
c
d
iv=
v=
ClCOOEt
iii= CS2
(CH3CO)2O
OMe
H
123

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Med Chem Res (2013) 22:2244–2252
Scheme 2 Synthesis of
compounds 7–10
NHNH2
N
Ph
NHN=CHPh
N
H
O
N
X
N
R
Ph
N
I
N
iv
Ph
2a-d
N
N
X
N
R
N
X
N
iii
ii
7a-d
10a,b
CH3
R
N
N
N
N
Ph
N
N
H3C
N
Ph
N
X
N
R
N
X
N
R
8a,b
9b-d
R
X
CH3
Ph
a
Ph
H
b
OMe
CH3
Reagents: i=
iii=
PhCHO
ii=
NaNO2, CH3COOH
ClCH2COCl
c
d
OMe
H
(CH CO)CH
iv=
3
2
significant activity. Regarding the nature of the substituent,
the four 4-chloro-pyrrolo[2,3-d]pyrimidine derivatives 1a–1d
showednoactivityasanti-inflammatoryagents;byconverting
them to 4-hydrazino-pyrrolopyrimidine derivatives (2a–2d),
twoderivativesonlyshowedanti-inflammatoryactivitywhich
are 2b and 2d (both have 4-Methoxyphenyl group in position
7). Condensation of 4-hydrazino-pyrrolopyrimidines with
benzaldehyde producing 7a–7d, among them 7b and 7d
retained the anti-inflammatory activity. 4-Pyrazolyl-pyrrol-
o[2,3-d]pyrimidine derivatives 9b–9d have significant activ-
ity as anti-inflammatory agents (Table 1).
spectra were recorded as potassium bromide pellets on a
Perkin-Elmer 1650 spectrophotometer (USA), Faculty of
Science, Cairo University, Cairo, Egypt. 1H NMR spectra
were determined on a Varian Mercury (300 MHz) spec-
trometer (Varian UK) and chemical shifts were expressed as
ppm against TMS as internal reference (Faculty of Science,
Cairo University, Cairo, Egypt). Mass spectra were recorded
on 70 eV EI Ms-QP 1000 EX (Shimadzu, Japan), Faculty of
Science, Cairo University, Cairo, Egypt. Microanalyses were
operated using Vario, Elmentar apparatus (Shimadzu, Japan),
Organic Microanalysis Unit, Faculty of Science, Cairo Uni-
versity, Cairo, Egypt. Column Chromatography was per-
formedon(Merck) Silicagel 60(particlesize0.06–0.20 mm).
Compounds 1a–1d were prepared as reported in the literature
(Mohamed et al., 2011). All new compounds yielded spectral
data consistent with the proposed structure and microanalysis
within 0.4 % of the theoretical values.
Summary
In the present study, we described a straightforward and
efficient synthesis of novel pyrrolo[2,3-d]pyrimidine and
fused pyrrolo[2,3-d]pyrimidine derivatives as anti-inflam-
matory agents. Some of the synthesized pyrrolo[2,3-d]
pyrimidine compounds are promising anti-inflammatory
agents, while pyrrolopyrimidine derivatives fused with
third ring have no anti-inflammatory activity Fig. 1.
Anti-inflammatory activity
Animals
Young adult male Sprague–Dawley rats (5 rats per group),
weighing 140–170 g, were housed at cages in a temperature-
controlled (25 1 °C) environment and provided free access
to pelleted food and purified drinking water ad libitum. The
animal experiments described below comply with the ethical
Experimental section
All melting points were uncorrected and measured using
Electro-thermal IA 9100 apparatus (Shimadzu, Japan). IR
123

Med Chem Res (2013) 22:2244–2252
2247
Table 1 In vivo anti-inflammatory activity
Compounds
Edema induced by carrageenan (% edema inhibition relative to control)
1 h
2 h
3 h
4 h
Infl SE
% inh
Infl SE
% inh
Infl SE
% inh
Infl SE
% inh
1a
0.221 0.041
0.401 0.034
0.227 0.023
0.199 0.067
0.247 0.086
0.199 0.051
0.28 0.069
0.177 0.027
0.36 0.042
0.21 0.053
0.426 0.052
0.456 0.039
0.54 0.026
0.213 0.059
0.223 0.076
0.34 0.014
0.213 0.008
0.42 0.009
0.203 0.021
0.193 0.049
0.273 0.028
0.227 0.0419
0.41 0.078
0.19 0.019
0.313 0.034
0.177 0.037
0.217 0.027
0.54 0.016
0.293 0.037
0.21 0.038
0.212 0.027
0.19 0.051
0.41 0.028
0.216 0.034
0.23 0.033
3.92
0
0.234 0.043
0.398 0.072
0.255 0.083
0.215 0.075
0.34 0.034
0.216 0.042
0.373 0.013
0.237 0.062
0.365 0.037
0.219 0.057
0.401 0.067
0.415 0.064
0.233 0.0227
0.207 0.0109
0.21 0.017
0.352 0.074
0.234 0.083
0.406 0.034
0.211 0.027
0.217 0.036
0.3 0.089
10
0.373 0.013
0.361 0.078
0.374 0.063
0.365 0.042
0.383 0.017
0.21 0.017**
0.297 0.054
0.317 0.034
0.462 0.073
0.392 0.026
0.487 0.073
0.362 0.018
0.45 0.075
0.438 0.014
0.36 0.048
0.39 0.029
0.452 0.071
0.467 0.072
0.383 0.05
0.397 0.033
0.437 0.065
0.44 0.026
0.46 0.081
0.25 0.023**
0.393 0.012
0.203 0.013**
0.398 0.010
0.437 0.018
0.2 0.006**
0.373 0.022
0.35 0.054
0.39 0.025
0.46 0.082
0.214 0.024
0.544 0.081
31.43
33.64
31.25
32.9
0.452 0.083
0.344 0.027
0.515 0.061
0.511 0.012
0.513 0.043
0.237 0.043**
0.383 0.052
0.313 0.087*
0.35 0.029
0.33 0.025
0.45 0.009
0.402 0.025
0.48 0.021
0.412 0.04
0.383 0.035
0.33 0.027
0.48 0.084
0.452 0.004
0.423 0.017
0.403 0.048
0.36 0.0101
0.4 0.031
28.59
45.39
18.25
18.89
18.57
62.38
39.21
50.26
44.44
47.62
28.57
36.19
23.81
34.6
1b
0
1c
1.3
13.4
0
1.92
17.3
0
1d
2a
29.6
2b
13.48
0
16.92
0
61.4
2c
45.4
2d
23.04
0
8.85
0
41.73
15.07
27.94
10.48
33.46
17.27
19.49
33.8
3a
3b
8.69
0
15.77
0
3c
3d
0
0
4a
0
10.38
20.38
19.23
0
4b
7.39
3.04
0
4c
39.21
47.62
23.81
28.25
32.85
35.98
42.85
36.5
4d
28.31
16.91
14.15
29.5
5a
7.39
0
10
5b
0
5c
11.74
15.94
0
18.85
0.5416
0
5d
27.8
6a
19.7
6b
1.45
0
0.233 0.078
0.44 0.007
0.176 0.071
0.296 0.019
0.18 0.022
0.23 0.005
0.352 0.071
0.243 0.018
0.253 0.014
0.198 0.017
0.2 0.037
10.38
0
18.5
7a
15.44
54.04
27.7
0.423 0.037
0.233 0.005**
0.367 0.039
0.213 0.072**
0.431 0.04
0.383 0.002
0.16 0.044**
0.257 0.075*
0.24 0.033**
0.41 0.086
0.423 0.007
0192 0.012
0.63 0.037
32.8
7b
17.39
0
32.31
0
62.96
41.8
7c
7d
23.04
5.65
0
30.77
11.54
0
62.68
26.83
19.7
66.19
31.59
39.21
74.6
8a
8b
9b
0
6.41
2.56
23.85
23.08
0
63.24
31.37
35.66
28.31
15.44
60.66
9c
8.7
7.82
17.39
0
59.25
61.9
9d
10a
10b
Ibuprofen
Control
34.92
32.8
0.34 0.037
0.1425 0.031
0.26 0.049
6.08
45
69.52
infl mean difference in rat paw volume between right and left paw. SE, %inhibition (1 - rt/rc) 9 100 [rt infl. of tested group, rc infl. of control
group], Infl inflammation, SE Standard Error, %inh % inhibition
Significantly different from ibuprofen as indicated: * P \ 0.01; ** P \ 0.001
principles and guidelines for the care and use of laboratory
animals adopted by the National Egyptian Community.
Prepared compounds (equimolar to the reference drug)
were dissolved in DMSO and administrated subcutane-
ously. One hour later, paw edema was induced by subpl-
antar injection of 0.1 mL of 1 % carrageenan (Sigma-
Aldrich, St. Louis, USA) into the right hind paw. Paw
volume was measured using a water plethysmometer
(Basile, Comerio, Italy). The difference between the right
Assessment of anti-inflammatory activity
Rat paw edema assay was carried out according to Winter
et al. (Harrak et al., 2007).
123

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Med Chem Res (2013) 22:2244–2252
OCH3), 5.2 (br s, 2H, NH2, D2O exchangeable), 6.9–7.9
(m, 15H, Ar–H, NH, D2O exchangeable), 8.21 (s, 1H, C2-
H); Anal. Calcd for C25H21N5O (407.48): C, 73.69; H,
5.19; N, 17.19; O, 3.93 %. Found: C, 73.34; H, 4.96; N,
16.88; O, 4.08 %.
1h
2h
3h
4h
80
60
40
20
0
(7-(4-Methylphenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-
4-yl)-hydrazine 2c Yield: 78 %; m.p.: 201–203 °C; IR
(KBr) t (cm-1): 3427, 3385 (NH2), 3217 (N–H), 1558
(C=N); MS (EI) m/z: 315 (M?, 16.2 %), 1H NMR (DMSO-
d6, 300 MHz) d (ppm): 2.2 (s, 3H, CH3), 5.18 (br s, 2H,
NH2, D2O exchangeable), 7.0-8.0 (m, 11H, Ar–H, NH,
D2O exchangeable), 8.34 (s, 1H, C2-H); Anal. Calcd for
C19H17N5 (315.38): C, 72.36; H, 5.43; N, 22.21 %. Found:
C, 72.51; H, 5.55; N, 21.94 %.
4h
3h
2h
1h
RF
2b
2d
7b
7d
9b
9c
9d
Fig. 1 Anti-inflammatory effect of active compound (% inhibition)
compared to ibuprofen as reference drug
and left paw volume was measured at 1, 2, 3, and 4 h after
induction of inflammation. Control group (five rats per
group) received DMSO subcutaneously and carrageenan in
subplantar region. Results were expressed as percentage
inhibition of inflammation. Ibuprofen (70 mg/kg) was used
as the reference drug (Winter et al., 1963).
(7-(4-Methoxyphenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimi-
din-4-yl)-hydrazine 2d Yield: 83 %; m.p.: 209–211 °C; IR
(KBr) t (cm-1): 3378, 3312 (NH2), 3167 (N–H), 1603
1
(C=N), 1233 (C–O); MS (EI) m/z: 331 (M?, 14.7 %), H
NMR (DMSO-d6, 300 MHz) d (ppm): 3.42 (s, 3H, OCH3),
4.78 (br s, 2H, NH2, D2O exchangeable), 6.8–7.7 (m, 11H,
Ar–H, NH, D2O exchangeable), 8.05 (s, 1H, C2-H); Anal.
Calcd for C19H17N5O (331.38): C, 68.87; H, 5.17; N, 21.13;
O, 4.83 %. Found: C, 69.15; H, 5.36; N, 20.86; O, 4.55 %.
Statistical analysis
Results are expressed as the mean SEM, and different
groups were compared using one-way analysis of variance
(ANOVA) followed by Tukey–Kramer test for multiple
comparisons.
Synthesis of 9-phenyl-7,8-disubstituted-7H-pyrrolo[3,
2-e][1,2,4]triazolo[4,3-c]pyrimidine (3a–3d)
Synthesis of (5-phenyl-6, 7-disubstituted-7H-
pyrrolo[2,3-d]pyrimidin-4-yl)-hydrazine (2a–2d)
The appropriate hydrazine 2a–2d (0.01 mol) was heated
under reflux for 8 h in formic acid (20 ml, 85 %), cooled,
poured onto ice water to give a precipitate which was fil-
tered off, dried, and recrystallized from ethanol to yield
compounds 3a–3d.
A mixture of 4-chloro pyrrolopyrimidine 1a–1d (0.01 mol)
and hydrazine hydrate (0.01 mol) was heated under reflux
in absolute ethanol for 8 h, cooled, poured onto ice water to
give precipitates which were filtered off, dried, and re-
crystallized from methanol to give compounds 2a–2d.
7-(4-Methylphenyl)-8,9-diphenyl-7H-pyrrolo[3,2-e][1,2,4]
triazolo[4,3-c]pyrimidine 3a Yield: 64 %; m.p.: 176–
178 °C; IR (KBr) t (cm-1): 1613 (C=N); MS (EI) m/z: 401
(7-(4-Methylphenyl)-5,6-diphenyl-7H-pyrrolo[2,3-d]pyrimi-
din-4-yl)-hydrazine 2a Yield: 82 %; m.p.: 204–206 °C;
IR (KBr) t (cm-1): 3412, 3320 (NH2), 3237 (N–H), 1533
1
(M?, 100 %), H NMR (DMSO-d6, 300 MHz) d (ppm):
2.34 (s, 3H, CH3), 6.94–7.96 (m, 14H, Ar–H), 8.0 (s, 1H,
C3-H), 8.9 (s, 1H, C5-H); Anal. Calcd for C26H19N5
(401.47): C, 77.79; H, 4.77; N, 17.44 %. Found: C, 78.03;
H, 5.02; N, 17.81 %.
1
(C=N); MS (EI) m/z: 391 (M?, 34 %), H NMR (DMSO-
d6, 300 MHz) d (ppm): 2.46 (s, 3H, CH3), 4.9 (br s, 2H,
NH2, D2O exchangeable), 6.7–7.9 (m, 15H, Ar–H, NH,
D2O exchangeable), 8.3 (s, 1H, C2-H); Anal. Calcd for
C25H21N5 (391.48): C, 76.70; H, 5.41; N, 17.89 %. Found:
C, 76.93; H, 5.12; N, 17.56 %.
7-(4-Methoxyphenyl)-8,9-diphenyl-7H-pyrrolo[3,2-e][1,2,4]
triazolo[4,3-c]pyrimidine 3b Yield: 73 %; m.p.: 192–
194 °C; IR (KBr) t (cm-1): 1598 (C=N), 1224 (C–O); MS
(EI) m/z: 417 (M?, 57 %), 1H NMR (DMSO-d6, 300 MHz)
d (ppm): 3.64 (s, 3H, OCH3), 6.8–7.4 (m, 14H, Ar–H), 7.91
(s, 1H, C3-H), 8.3 (s, 1H, C5-H); Anal. Calcd for
C26H19N5O (417.47): C, 74.80; H, 4.59; N, 16.78; O,
3.83 %. Found: C, 75.04; H, 4.91; N, 16.36; O, 3.66 %.
(7-(4-Methoxyphenyl)-5,6-diphenyl-7H-pyrrolo[2,3-d]pyr-
imidin-4-yl)-hydrazine 2b Yield: 91 %; m.p.: 224–226
°C; IR (KBr) t (cm-1): 3430, 3414 (NH2), 3212 (N–H),
1612 (C=N), 1227 (C–O); MS (EI) m/z: 407 (M?, 5.6 %),
1H NMR (DMSO-d6, 300 MHz) d (ppm): 3.39 (s, 3H,
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Med Chem Res (2013) 22:2244–2252
2249
7-(4-Methylphenyl)-9-phenyl-7H-pyrrolo[3,2-e][1,2,4]triaz-
olo[4,3-c]pyrimidine 3c Yield: 79 %; m.p.: 188–190 °C;
IR (KBr) t (cm-1): 1609 (C=N); MS (EI) m/z: 325 (M?,
43.6 %), 1H NMR (DMSO-d6, 300 MHz) d (ppm): 2.25 (s,
3H, CH3), 6.9–7.8 (m, 10H, Ar–H), 8.11 (s, 1H, C3-H),
8.47 (s, 1H, C5-H); Anal. Calcd for C20H15N5 (325.38): C,
73.83; H, 4.65; N, 21.25 %. Found: C, 74.05; H, 4.59; N,
21.56 %.
exchangeable); Anal. Calcd for C20H15N5S (357.44): C,
67.21; H, 4.23; N, 19.59; S, 8.97 %. Found: C, 67.48; H,
4.57; N, 19.23; S, 9.13 %.
7-(4-Methoxyphenyl)-9-phenyl-7H-pyrrolo[3,2-e][1,2,4]triaz-
olo[4,3-c]pyrimidin-3-thione 4d Yield: 64 %; m.p.: 179–
181 °C; IR (KBr) t (cm-1): 3325 (N–H), 1663 (C=S), 1618
1
(C=N), 1248 (C–O); MS (EI) m/z: 373 (M?, 23.6 %), H
NMR (DMSO-d6, 300 MHz) d (ppm): 3.43(s, 3H, OCH3),
6.9–7.9 (m, 10H, Ar–H), 8.32(s, 1H, C5-H), 8.5 (s, 1H,
NH, D2O exchangeable); Anal. Calcd for C20H15N5OS
(373.44): C, 64.33; H, 4.05; N, 18.75; O, 4.28; S, 8.59 %.
Found: C, 64.71; H, 4.37; N, 19.02; O, 4.54; S, 8.47 %.
7-(4-Methoxyphenyl)-9-phenyl-7H-pyrrolo[3,2-e][1,2,4]
triazolo[4,3-c]pyrimidine 3d Yield: 82 %; m.p.: 187–
189 °C; IR (KBr) t (cm-1): 1573 (C=N), 1218 (C–O); MS
(EI) m/z: 341 (M?, 12.8 %), 1H NMR (DMSO-d6,
300 MHz) d (ppm): 3.49 (s, 3H, OCH3), 7.0–7.9 (m, 10H,
Ar–H), 8.13 (s, 1H, C3-H), 8.4 (s, 1H, C5-H); Anal. Calcd
for C20H15N5O (341.38): C, 70.37; H, 4.43; N, 20.52; O,
4.69 %. Found: C, 69.95; H, 4.17; N, 20.86; O, 4.34 %.
Synthesis of 3-methyl-9-phenyl-7,8-disubstituted-7H-
pyrrolo[3,2-e][1,2,4] triazolo[4,3-c]pyrimidine (5a–5d)
The appropriate hydrazine 2a–2d (0.01 mol) was heated
under reflux for 5 h in acetic anhydride (30 ml), cooled,
poured onto ice water and neutralize with ammonia to give
a precipitate which was filtered off, dried, and recrystal-
lized from ethanol to yield compounds 5a–5d.
Synthesis of 9-phenyl-7,8-disubstituted-7H-pyrrolo
[3,2-e][1,2,4]triazolo[4,3-c]pyrimidin-3-thione (4a–4d)
A mixture of the appropriate hydrazine 2a–2d (0.01 mol)
and carbon disulfide (0.01 mol) was heated under reflux for
3 h in absolute ethanol (30 ml), cooled, poured onto ice
water to give a precipitate which was filtered off, dried, and
recrystallized from ethanol to yield compounds 4a–4d.
3-Methyl-7-(4-methylphenyl)-8,9-diphenyl-7H-pyrrolo[3,2
-e][1,2,4]triazolo[4,3-c]pyrimidine 5a Yield: 59 %;
m.p.: 185–187 °C; IR (KBr) t (cm-1): 1598 (C=N); MS
(EI) m/z: 415 (M?, 6.49 %), 1H NMR (DMSO-d6,
300 MHz) d (ppm): 2.21 (s, 3H, C3-CH3), 2.32 (s, 3H, Ar-
CH3), 6.98–7.6 (m, 14H, Ar–H), 8.2 (s, 1H, C5-H); Anal.
Calcd for C27H21N5 (415.50): C, 78.05; H, 5.09; N,
16.86 %. Found: C, 78.35; H, 5.24; N, 17.03 %.
7-(4-Methylphenyl)-8,9-diphenyl-7H-pyrrolo[3,2-e][1,2,4]
triazolo[4,3-c]pyramid in-3-thione 4a Yield: 52 %; m.p.:
190–192 °C; IR (KBr) t (cm-1): 3314 (N–H), 1652 (C=S),
1567 (C=N); MS (EI) m/z: 433 (M?, 13 %), 1H NMR
(DMSO-d6, 300 MHz) d (ppm): 2.36 (s, 3H, CH3), 6.8–7.5
(m, 14H, Ar–H), 8.89 (s, 1H, C5-H), 8.98 (br s,1H, NH,
D2O exchangeable); Anal. Calcd for C26H19N5S (433.54):
C, 72.03; H, 4.42; N, 16.15; S, 7.40 %. Found: C, 71.85; H,
4.78; N, 15.83; S, 7.14 %.
3-Methyl-7-(4-methoxyphenyl)-8,9-diphenyl-7H-pyrrolo[3,2
-e][1,2,4]triazolo[4,3-c]pyrimidine 5b Yield: 47 %; m.p.:
199–201 °C; IR (KBr) t (cm-1): 1614 (C=N), 1243 (C–O);
MS (EI) m/z: 431 (M?, 22 %), 1H NMR (DMSO-d6,
300 MHz) d (ppm): 2.04 (s, 3H, C3-CH3), 3.7 (s, 3H,
OCH3), 6.8–7.9, m, 14H, Ar–H), 8.15 (s, 1H, C5-H); Anal.
Calcd for C27H21N5O (431.50): C, 75.16; H, 4.91; N, 16.23;
O, 3.71 %. Found: C, 75.01; H, 5.11; N, 16.39; O, 3.99 %.
7-(4-Methoxyphenyl)-8,9-diphenyl-7H-pyrrolo[3,2-e][1,2,4]
triazolo[4,3-c]pyrimid in-3-thione 4b Yield: 63 %; m.p.:
209–211 °C; IR (KBr) t (cm-1): 3278 (N–H), 1649 (C=S),
1598 (C=N), 1253 (C–O); MS (EI) m/z: 449 (M?, 8.5 %),
1H NMR (DMSO-d6, 300 MHz) d (ppm): 3.6(s, 3H,
OCH3), 6.8–8.0 (m, 14H, Ar–H), 8.2(s, 1H, C5-H), 8.4 (s,
1H, NH, D2O exchangeable); Anal. Calcd for C26H19N5OS
(449.54): C, 69.47; H, 4.26; N, 15.58; O, 3.56; S, 7.13 %.
Found: C, 69.13; H, 4.52; N, 15.27; O, 3.84; S, 6.82 %.
3-Methyl-7-(4-Methylphenyl)-9-phenyl-7H-pyrrolo[3,2-e]
[1,2,4]triazolo[4,3-c]pyrimidine 5c Yield: 52 %; m.p.:
181–183 °C; IR (KBr) t (cm-1): 1620 (C=N); MS (EI)
1
m/z: 339 (M?, 46 %), H NMR (DMSO-d6, 300 MHz) d
(ppm): 2.2 (s, 3H, C3-CH3), 2.29(s, 3H, CH3), 6.8–7.8, m,
10H, Ar–H), 8.03(s, 1H, C5-H); Anal. Calcd for C21H17N5
(339.40): C, 74.32; H, 5.05; N, 20.63 %. Found: C, 74.65;
H, 5.42; N, 21.02 %.
7-(4-Methylphenyl)-9-phenyl-7H-pyrrolo[3,2-e][1,2,4]triaz-
olo[4,3-c]pyrimidin-3-thione 4c Yield: 68 %; m.p.:
185–187 °C; IR (KBr) t (cm-1): 3301 (N–H), 1658(C=S),
1602 (C=N); MS (EI) m/z: 357 (M?, 17 %), 1H NMR
(DMSO-d6, 300 MHz) d (ppm): 2.6(s, 3H, CH3), 6.8–7.7
(m, 10H, Ar–H), 8.1(s, 1H, C5-H), 8.29(s, 1H, NH, D2O
3-Methyl-7-(4-methoxyphenyl)-9-phenyl-7H-pyrrolo[3,
2-e][1,2,4]triazolo[4,3-c]pyrimidine 5d Yield: 66 %;
123

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Med Chem Res (2013) 22:2244–2252
m.p.: 194–196 °C; IR (KBr) t (cm-1): 1583 (C=N), 1222
(C–O); MS (EI) m/z: 355 (M?, 19.8 %), 1H NMR (DMSO-
d6, 300 MHz) d (ppm): 2.3 (s, 3H, C3-CH3), 3.68 (s, 3H,
OCH3), 7.0–7.9, m, 10H, Ar–H), 8.21 (s, 1H, C5-H); Anal.
Calcd for C21H17N5O (355.40): C, 70.97; H, 4.82; N,
19.71; O, 4.50 %. Found: C, 71.16; H, 4.53; N, 20.05; O,
4.39 %.
exchangeable), 7.0–7.9 (m, 19H, Ar–H), 8.26(s, 1H, C2-H),
8.32(s, 1H, CH).; Anal. Calcd for C32H25N5 (479.59): C,
80.14; H, 5.25; N, 14.60 %. Found: C, 79.82; H, 5.61; N,
14.36 %.
4-(2-(Benzyl)hydrazinyl)-7-(4-methoxyphenyl)-5,6-diphenyl
-7H-pyrrolo[2,3-d]pyrimidine 7b Yield: 45 %; m.p.:
239–241 °C; IR (KBr) t (cm-1): 3338(N–H), 1591 (C=N),
1
1213 (C–O); MS (EI) m/z: 495 (M?, 7.3 %), H NMR
Synthesis of 9-phenyl-7,8-disubstituted-7H-pyrrolo[3,2-
e][1,2,4]triazolo[4,3-c]pyrimidin-3-one (6a, 6b)
(DMSO-d6, 300 MHz) d (ppm): 3.5(s, 3H, OCH3), 4.5(s,
1H, NH, D2O exchangeable), 6.7–7.8 (m, 19H, Ar–H),
8.0(s, 1H, C2-H), 8.2(s, 1H, CH); Anal. Calcd for
C32H25N5O (495.59): C, 77.57; H, 5.05; N, 14.14; O,
3.23 %. Found: C, 77.79; H, 4.81; N, 14.47; O, 3.51 %.
A solution of the appropriate hydrazine 2a, 2b (0.01 mol)
in pyridine (10 ml) was cooled in ice bath and equimolar
amount (0.01 mol) of ethyl chloroformate was added por-
tion wise. Then the mixture was heated under reflux for
3 h, cooled, poured onto ice water and neutralize with HCl
to give a precipitate which was filtered off, dried, and
recrystallized from ethanol to yield compounds 6a, 6b.
4-(2-(Benzyl)hydrazinyl)-7-(4-methylphenyl)-5-phenyl-7H-
pyrrolo[2,3-d]pyrimidine 7c Yield: 39 %; m.p.: 224–
226 °C; IR (KBr) t (cm-1): 3315(N–H), 1569 (C=N); MS
(EI) m/z: 403 (M?, 24 %), 1H NMR (DMSO-d6, 300 MHz)
d (ppm): 2.35(s, 3H, CH3), 4.85 (s, 1H, NH, D2O
exchangeable), 6.8–7.9 (m, 15H, Ar–H), 8.1(s, 1H, C2-H),
8.36(s, 1H, CH).; Anal. Calcd for C26H21N5 (403.49): C,
77.40; H, 5.25; N, 17.36 %. Found: C, 77.73; H, 5.61; N,
17.02 %.
7-(4-Methylphenyl)-8,9-diphenyl-7H-pyrrolo[3,2-e][1,2,4]
triazolo[4,3-c]pyrimid in-3-one 6a Yield: 54 %; m.p.:
226–228 °C; IR (KBr) t (cm-1): 3402 (N–H), 1624 (C=O),
1
1512 (C=N); MS (EI) m/z: 417 (M?, 2.8 %), H NMR
(DMSO-d6, 300 MHz) d (ppm): 2.28(s, 3H, CH3), 6.8–7.89
(m, 14H, Ar–H), 8.2(s, 1H, C5-H), 8.53(s, 1H, NH, D2O
exchangeable); Anal. Calcd for C26H19N5O (417.47): C,
74.80; H, 4.59; N, 16.78 %. Found: C, 74.61; H, 4.35; N,
16.85 %.
4-(2-(Benzyl)hydrazinyl)-7-(4-methoxyphenyl)-5-phenyl-7H-
pyrrolo[2,3-d]pyrimidine 7d Yield: 41 %; m.p.: 175–
177 °C; IR (KBr) t (cm-1): 3352(N–H), 1623 (C=N), 1236
1
(C–O); MS (EI) m/z: 419 (M?, 12 %), H NMR (DMSO-
d6, 300 MHz) d (ppm): 3.62(s, 3H, OCH3), 5.2 (s, 1H, NH,
D2O exchangeable), 7.0–7.9 (m, 15H, Ar–H), 8.2(s, 1H,
C2-H), 8.4(s, 1H, CH); Anal. Calcd for C26H21N5O
(419.49): C, 74.46; H, 5.01; N, 16.71; O, 3.82 %. Found:
C, 74.12; H, 4.77; N, 16.98; O, 3.98 %.
7-(4-Methoxyphenyl)-8,9-diphenyl-7H-pyrrolo[3,2-e][1,2,4]
triazolo[4,3-c]pyrimid in-3-one 6b Yield: 60 %; m.p.:
239–241 °C; IR (KBr) t (cm-1): 3394(N–H), 1657 (C=O),
1602 (C=N), 1231 (C–O); MS (EI) m/z: 433 (M?, 17 %),
1H NMR (DMSO-d6, 300 MHz) d (ppm): 3.54(s, 3H,
OCH3), 6.8–8.0 (m, 14H, Ar–H), 8.31(s, 1H, C5-H), 8.54(s,
1H, NH, D2O exchangeable); Anal. Calcd for C26H19N5O2
(433.47): C, 72.04; H, 4.42; N, 16.16; O, 7.38 %. Found:
C, 71.85; H, 4.74; N, 16.42; O, 7.69 %.
Synthesis of 9-phenyl-7, 8-disubstituted-7H-pyrrolo[3,
2-e]tetrazolo[1,5-c]pyrimidine (8a, 8b)
A mixture of the appropriate hydrazine 2a, 2b (0.01 mol)
and sodium nitrite (0.69 gm, 0.01 mol dissolved in 5 ml
H2O) was stirred in glacial acetic acid (20 mL) at 40 °C for
8 h. The reaction mixture was poured onto ice water to
give precipitates which were filtered, dried, and recrystal-
lized from ethanol to yield compounds 8a, 8b.
Synthesis of 4-(2-(Benzyl)hydrazinyl)-5-phenyl-6,
7-disubstituted-7H-pyrrolo[2,3-d]pyrimidine(7a–7d)
A mixture of the appropriate hydrazine 2a–2d (0.01 mol)
and benzaldehyde (0.01 mol) was heated under reflux in
absolute ethanol for 8 h, cooled, poured onto ice water to
give precipitates which were filtered off, dried, and re-
crystallized from methanol to give compounds 7a–7d.
7-(4-Methylphenyl)-8,9-diphenyl-7H-pyrrolo[3,2-e]tetraz-
olo[1,5-c]pyrimidine 8a Yield: 37 %; m.p.: 219–221 °C;
IR (KBr) t (cm-1): 3312 (N–H), 1623 (C=N); MS (EI)
m/z: 402 (M?, 26.9 %), 1H NMR (DMSO-d6, 300 MHz) d
(ppm): 2.36(s, 3H, CH3), 6.7–7.9 (m, 14H, Ar–H), 8.2(s,
1H, C5-H); Anal. Calcd for C25H18N6 (402.46): C, 74.61;
H, 4.51; N, 20.88 %. Found: C, 74.99; H, 4.25; N,
20.54 %.
4-(2-(Benzyl)hydrazinyl)-7-(4-methylphenyl)-5,6-diphenyl-
7H-pyrrolo[2,3-d]pyrimidine 7a Yield: 32 %; m.p.:
187–189 °C; IR (KBr) t (cm-1): 3323(N–H), 1608 (C=N);
MS (EI) m/z: 479 (M?, 37.9 %), 1H NMR (DMSO-d6,
300 MHz) d (ppm): 2.54(s, 3H, CH3), 5.12(s, 1H, NH, D2O
123

Med Chem Res (2013) 22:2244–2252
2251
7-(4-Methoxyphenyl)-8,9-diphenyl-7H-pyrrolo[3,2-e]tetraz-
olo[1,5-c]pyrimidine 8b Yield: 42 %; m.p.: 236–238 °C;
IR (KBr) t (cm-1): 3279 (N–H), 1598 (C=N), 1253 (C–O);
MS (EI) m/z: 418 (M?, 19.5 %), 1H NMR (DMSO-d6,
300 MHz) d (ppm): 3.62(s, 3H, OCH3), 6.8–8.0 (m, 14H,
Ar–H), 8.36(s, 1H, C5-H); Anal. Calcd for C25H18N6O
(418.46): C, 71.76; H, 4.34; N, 20.08 %. Found: C, 71.52; H,
4.73; N, 19.86 %.
absolute ethanol (20 mL) for 8 h. The reaction mixture was
cooled, poured onto ice water to give precipitates which
were filtered, dried, and recrystallized from ethanol to yield
compounds 10a and 10b.
8-(4-Methylphenyl)-9,10-diphenyl-8H-pyrrolo[3,2-e][1,2,5]
triazino[5,6-c]pyrimidin-3-one (10a) Yield: 35 %; m.p.:
216–218 °C; IR (KBr) t (cm-1): 3394 (N–H), 1635 (C=O),
1512 (C=N); MS (EI) m/z: 431 (M?, 10 %), 1H NMR
(DMSO-d6, 300 MHz) d (ppm): 2.2(s, 3H, CH3), 2.6 (s,
2H, CH2-C=O), 6.8–7.9 (m, 14H, Ar–H), 8.13 (s, 1H, NH),
8.34(s, 1H, C6-H); Anal. Calcd for C27H21N5O (431.50):
C, 75.16; H, 4.91; N, 16.23; O, 3.71 %. Found: C, 75.38;
H, 5.22; N, 16.46; O, 3.95 %.
Synthesis of 4-(3,5-dimethyl-4H-pyrazol-1-yl)-5-phenyl-
6,7-disubstituted-4,7dihydro-3H-pyrrolo [2,3-d]
pyrimidine (9b–9d)
A Mixture of the appropriate hydrazine 2b–2d (0.01 mol)
and acetyl acetone (0.01 mol) in absolute ethanol was
heated under reflux for 3 h, cooled, poured onto ice water
to give a precipitate which was filtered off, dried, and
recrystallized from ethanol to yield compounds 9b–9d.
8-(4-Methoxyphenyl)-9,10-diphenyl-8H-pyrrolo[3,2-e][1,2,5]
triazino[5,6-c]pyrimidin-3-one (10b) Yield: 42 %; m.p.:
241–243 °C; IR (KBr) t (cm-1): 3418 (N–H), 1659 (C=O),
1588 (C=N), 1213 (C–O); MS (EI) m/z: 447 (M?, 24.3 %),
1H NMR (DMSO-d6, 300 MHz) d (ppm): 2.52 (s, 2H,
CH2-C=O), 3.46(s, 3H, OCH3), 6.8–7.85 (m, 14H, Ar–H),
8.06 (s, 1H, NH), 8.26(s, 1H, C6-H); Anal. Calcd for
C27H21N5O2 (447.50): C, 72.47; H, 4.73; N, 15.65; O,
7.15 %. Found: C, 72.71; H, 5.03; N, 15.79; O, 6.93 %.
4-(3,5-Dimethyl-4H-pyrazol-1-yl)-7-(4-methoxyphenyl)-5,
6-diphenyl-4,7dihydro-3H-pyrrolo[2,3-d]pyrimidine (9b)
Yield: 38 %; m.p.: 196–198 °C; IR (KBr) t (cm-1): 1608
1
(C=N), 1231 (C–O); MS (EI) m/z: 471 (M?, 5.57 %), H
NMR (DMSO-d6, 300 MHz) d (ppm): 2.2(s, 3H, CH3),
2.32(s, 3H, CH3), 3.4(s, 3H, OCH3), 6.7 (s, 1H, pyrazole),
6.9–7.8 (m, 14H, Ar–H), 8.3(s, 1H, C2-H); Anal. Calcd for
C30H25N5O (471.57): C, 76.41; H, 5.34; N, 14.85; O,
3.39 %. Found: C, 76.20; H, 5.67; N, 15.15; O, 3.67 %.
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phenyl-4,7dihydro-3H-pyrrolo[2,3-d]pyrimidine
(9c)
Yield: 31 %; m.p.: 179–181 °C; IR (KBr) t (cm-1): 1583
(C=N), MS (EI) m/z: 379 (M?, 13.8 %), 1H NMR (DMSO-
d6, 300 MHz) d (ppm): 2.2(s, 3H, CH3), 2.34(s, 3H, CH3),
2.47(s, 3H, CH3), 6.73 (s, 1H, pyrazole), 6.97–7.9 (m, 10H,
Ar–H), 8.2(s, 1H, C2-H); Anal. Calcd for C24H21N5
(379.57): C, 75.99; H, 5.54; N, 18.47 %. Found: C, 76.24;
H, 5.77; N, 18.38 %.
4-(3,5-Dimethyl-4H-pyrazol-1-yl)-7-(4-methoxyphenyl)-5-
phenyl-4,7dihydro-3H-pyrrolo[2,3-d]pyrimidine
(9d)
Yield: 37 %; m.p.: 188–190 °C; IR (KBr) t (cm-1): 1602
1
(C=N), 1227 (C–O); MS (EI) m/z: 395 (M?, 26 %), H
NMR (DMSO-d6, 300 MHz) d (ppm): 2.23(s, 3H, CH3),
2.4(s, 3H, CH3), 3.51(s, 3H, OCH3), 6.8 (s, 1H, pyrazole),
7.0–7.9 (m, 10H, Ar–H), 8.32(s, 1H, C2-H); Anal. Calcd
for C24H21N5O (395.57): C, 72.89; H, 5.35; N, 17.71; O,
4.05 %. Found: C, 73.14; H, 5.11; N, 17.98; O, 3.89 %.
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2-e][1,2,5]triazino[5,6-c]pyrimidin-3-one (10a, 10b)
A mixture of the appropriate hydrazine 2a, b (0.01 mol)
and chloro-acetyl chloride (0.01 mol) was refluxed in
123

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