Synthesis and antiinflammatory activity of 4-amino-2-aryl-5-cyano-6-{3- and 4-(N-phthalimidophenyl)} pyrimidines

Article abstract of DOI:10.1016/j.ejmech.2005.09.009

Six new 4-amino-5-cyano-2,6-diarylpyrimidines 5a-h has been synthesized in a facile manner by reacting the appropriate arylamidines 4a-d with bisnitriles 3a-e. Reduction of the nitro group of 5a-e using Pd in ethyl acetate furnished 6a-e in good yields. R

Full text of DOI:10.1016/j.ejmech.2005.09.009

European Journal of Medicinal Chemistry 41 (2006) 276–282
http://france.elsevier.com/direct/ejmech
Laboratory note
Synthesis and antiinflammatory activity of 4-amino-2-
aryl-5-cyano-6-{3- and 4-(N-phthalimidophenyl)} pyrimidines1
Emerson Peter da S. Falcão a, Sebastião J. de Melo a,*, Rajendra M. Srivastava b,
Maria Tereza Jansen de A. Catanho c, Silene Carneiro Do Nascimento a
a
Departamento de Antibióticos, Universidade Federal de Pernambuco, 50.670-901 Recife, PE, Brazil
b
Departamento de Química Fundamental, Universidade Federal de Pernambuco, 50.670-901 Recife, PE, Brazil
c
Departamento de Biofísica, Universidade Federal de Pernambuco, 50.670-901 Recife, PE, Brazil
Received 4 November 2004; received in revised form 9 September 2005; accepted 14 September 2005
Available online 18 January 2006
Abstract
Six new 4-amino-5-cyano-2,6-diarylpyrimidines 5a–h has been synthesized in a facile manner by reacting the appropriate arylamidines 4a–d
with bisnitriles 3a–e. Reduction of the nitro group of 5a–e using Pd in ethyl acetate furnished 6a–e in good yields. Reaction of 6a–e individually
1
with phthalic anhydride yielded 7a–e in good to excellent yields. The newly synthesized heterocycles were characterized by IR, H-NMR and
mass spectral data. Compounds 5f–h and 7a–e were also evaluated against inflammation. Pyrimidines 5g, h exhibited better antiinflammatory
activity when compared with acetylsalicylic acid (ASA). Phthalimide derivatives 7a–e also presented antiinflammatory activity, and three of
them, viz., 7a–c have been found to be twice more active than aspirin. Cytotoxical evaluations of compounds 7a–e using neoplastic cells (NCI-
H292 and Hep-2) presented 41% of growth inhibition of neoplastic cells NCI-H292
© 2006 Elsevier SAS. All rights reserved.
.
Keywords: Pyrimidines; Bisnitriles; Antiinflammatory activity
1. Introduction
gaining importance due to their different and significant biolo-
gical activities [10]. Thalidomide is one of them, which was
once prohibited in the market is again being considered impor-
tant due to its activity as an antiinflammatory agent [10]. This
drug has been found to reduce tumor growth by blocking an-
giogenesis both in model systems and in clinical studies [11–
14]. Thalidomide and its analogs also slow down the replica-
tion rate of HIV-1 in vitro [15].
Pyrimidine derivatives comprise a diverse and interesting
group of drugs [1]. The subject has been discussed recently
[2]. Earlier, a comprehensive review concerning pyrimidines
has been published by Brown [3]. Pyrimidines in general are
extremely important for their biological activities. For example,
some are antiviral agents [4], the others are selective cholecys-
tokinin subtype 1 (CCK1) receptor antagonists [5], and a few
are antiinflammatory [6,7]. In fact, there are so many pyrimi-
dine derivatives with pharmacological activities that it is diffi-
cult to describe much about them in the present paper.
Since many phthalimide derivatives have presented hypoli-
pidemic activity [16] and antiinflammatory activities [loc. cit.],
we perceived that when two moieties, like phthalimide and
pyrimidine are joined the molecules might exhibit superior
antiinflammatory activity. It is with this idea in mind that the
present work was undertaken. Therefore, this paper describes
the synthesis of eight pyrimidine derivatives 5a–h where six of
them 5a–e, h have not yet been reported in the literature. Com-
pounds 5f–h and 7a–e have been tested for antiinflammatory
property with impressive results. In fact, 7a–e turned out to be
very active against inflammation.
In our continuing work on pyrimidines [8,9], we became
interested to incorporate a phthalimido group in one of the phe-
nyl rings. The reason for this is that phthalimide derivatives are
* Corresponding author. Fax: +55 81 3271 8346.
E-mail address: melosj@ibest.com.br (S.J. de Melo).
Taken in part from the Ph.D. thesis (2003) of Emerson Peter da S. Falcão
1
0223-5234/$ - see front matter © 2006 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2005.09.009

E.P.d.S. Falcão et al. / European Journal of Medicinal Chemistry 41 (2006) 276–282
277
2. Chemistry
any toxicity symptoms when evaluated in five groups each
containing five animals under the same conditions described
above. The doses were from 100, 200, 400, 800,
1600 mg kg–1 of the body weight.
The starting benzaldehyde and 3- and 4- substituted benzal-
dehydes 1a–e were allowed to react with malononitrile 2 to
give unsaturated bisnitriles 3a–e. Condensation of these with
arylamidines 4a–d in the presence of piperidine furnished 4-
amino-5-cyano-2,6-diarylpirimidines 5a′–h′ in good yields [8,
17]. Reduction of compounds 5a–e using Pd/C provided their
respective amines 6a–e. Reaction of 6a–e individually with
phthalic anhydride yielded 7a–e in good to excellent yields. It
may be worthwhile to comment that only the amino group
either at meta or para positions of the phenyl ring suffered
selective reaction while the 4-amino group of the pyrimidine
ring did not take part in the reaction at all. The formation of
phthalimido-2-yl function at the meta and para positions in the
C-6 phenyl ring of the substituted pyrimidines 7a–e was veri-
fied by the 1H-NMR, infrared (IR) and mass spectral data. The
synthetic maneuvering leading to 7a–e has been presented in
Scheme 1.
Antiinflammatory tests have been performed for compounds
5f′–h′ and 7a–e using groups of 10 Swiss albino mice at the
dose of 250 mg kg–1. All of them exhibited such property
when compared with aspirin (acetylsalicylic acid, ASA) as well
as indomethacin (INDO). Both of these commercially available
antiinflammatory agents were also tested for comparative pur-
poses employing the same solution as described above. Com-
pound 5h′ showed the highest activity reducing the paw edema
by 47.8%. Pyrimidines 5g′ and 5f′ presented 38.7% and 20.7%
of inflammation reductions, respectively (Table 1).
Substances 7a–e also presented antiinflammatory activity,
but 7a–c were much better in terms of inflammation reduction
(Table 2). It is well known that INDO is stronger antiinflam-
matory drug than aspirin. A comparison of these two with
compounds 7a–c clearly demonstrate that compounds 7b and
7c are even superior in activity than INDO while 7a is compar-
able to INDO (Tables 1 and 2). Figs. 1 and 2 provide the per-
centage reduction of edema for compounds 5f′–h′ and 7a–e
and their comparison with ASA and INDO.
3. Results and discussion
All substituted pyrimidines are crystalline and stable com-
pounds with high melting points. These can be recrystallized
and are homogeneous by thin layer chromatography.
Figs. 1 and 2 represent the comparative analyses of the anti-
inflammatory activity of compounds 5f′–h′ and 7a–e.
3.1. Spectroscopy
4.2. Cytotoxical test evaluations
The IR and mass spectra of all compounds agreed with the
proposed structures. The series 5a′–h′ have the correct chemi-
cal shifts for the protons in the H-NMR spectra and it was
Initially, compounds 5g′–h′ were tested for cytotoxical
property but no significant activity was found. Next, phthalimi-
dopyrimidines (7a–e) were tested, which did not present cyto-
toxical activity against HEp-2 in the concentrations tested. All
compounds except 7e inhibited the growth of the neoplastic
cells NCI-H292. The most active one was 7d with 40.03% of
inhibition activity at the concentration of 10 μg ml–1 (Table 3).
1
easy to characterize them. Similarly, the amines 6a–e obtained
by the reduction of the nitro groups presented the expected
chemical shifts. The target compounds could also be character-
1
ized by H-NMR without any problem and the chemical shifts
of one of them, i.e. 7a are given: H2′ and H6′ (δ = 8.43 and
J = 9.0 Hz); H3″ and H5″ (δ = 8.12 and J = 8.7 Hz); δ 7.9
(b, 2H, NH2) H2″ and H6″ (δ = 7.69 and J = 8.1 Hz); H3′ and
H5′ (δ = 7.61 and J = 8.4Hz); H1′″ and H4′″ (δ = 8.02 m); H2′″
and H3′″ (δ = 7.94 m). δ 3.82 (s, 3H, CH3O) the chemical
shifts of all other compounds are given in Section 5.
5. Experimental protocols
5.1. Chemical analysis
4. Pharmacology
IR spectra were recorded with a Bruker spectrometer, model
IFS 66 (Fourier Transform) utilizing KBr pellets. EI mass spec-
tra were obtained with a Delsi-Nermag mass spectrometer,
coupled to GC (HP 5890) at an ionization potential of 70 eV.
1H-NMR spectra were recorded with a 300 MHz Varian spec-
trophotometer model UNITY plus. Melting points were ob-
tained with an Electrothermal digital melting point apparatus
(model 9100) and are uncorrected. Thin-layer chromatography
was carried out on plates coated with silica gel containing
fluorescent indicator F254 and the spots were detected under
ultraviolet light. The solvent system was ethyl acetate/hexane
(4:1) for compounds 5a–h and ethyl acetate/hexane (3:1) for
compounds 6a–e and 7a–e.
4.1. Preliminary toxicity and antiinflammatory tests
of 4-amino-5-cyano-2,6-diarylpyrimidines 5f′–h′ and 7a–e
The antiinflammatory assays were preceded by the acute
toxicity tests in mice. The pyrimidine derivatives 5f′–h′ were
dissolved individually in a 2.5% Tween 80 solution of 0.9%
saline water. Administration of this suspension (0.5 ml) intra-
peritonially to the animals in doses of 125, 250, 500,
1000 mg kg–1 of body weight followed by the waiting period
of 4–72 hours did not show any toxic effects. Pyrimidines con-
taining phthalimido-2-yl group on the C-6 phenyl function in
7a–e were also subjected to toxicity test which did not show

278
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Scheme 1.

E.P.d.S. Falcão et al. / European Journal of Medicinal Chemistry 41 (2006) 276–282
279
Table 1
left a solid mass, which was chromatographed over a silica gel
column. Elution with n-hexane/ethyl acetate (4:1) afforded the
desired compounds. The nitriles described in this work are
known and their melting points agreed with the literature [18,19].
Antiinflammatory test results of compounds 5f–h, ASA and INDO
Compound
Average difference in paw weights
(g); standard deviation (S.D.)
0.1045 0.007
Edema reduction
(%)
0.0
2.5% Tween 80
in 0.9% aqueous
NaCl
INDO
ASA
5f′
5g′
5h′
5.3. General method for the preparation of 4-amino-2,6-
diarilpyrimidines-5-cyano (5a–h)
0.5081 0.012
0.06680 0.001
0.08280 0.003
0.06432 0.002
0.05450 0.005
51.4
36.5
20.7
38.7
47.8
Bisnitrile 3 (5.36 mmol) and arylamidine 4 (5.36 mmol)
were dissolved in methanol (20 ml) and refluxed for 7 h. The
contents were cooled to room temperature and solvent evapo-
rated under reduced pressure to give a solid mass, which was
chromatographed over silica gel. The desired compound was
eluted using a mixture of n-hexane/ethyl acetate (8:2). The
fractions containing 5 were combined, solvent evaporated,
and the product crystallized from methanol in every case.
Table 2
Antiinflammatory test results of compounds 7a–e
Compound
Average difference in paw weights
(g); standard deviation (S.D.)
0.16487 0.005
Edema reduction
(%)
0.0
2.5% Tween 80
in 0.9%
Aqueous
NaCl INDO
ASA
7a
7b
7c
7d
7e
0.05081 0.012
69.2
5.3.1. 4-Amino-2-(p-anisyl)-5-cyano-6-(p-nitrophenyl)-
pyrimidine (5a)
0.10436 0.008
0.08454 0.010
0.05986 0.010
0.06066 0.007
0.11122 0.012115
0.116120 0.01494
36.7
65.7
73.6
73.2
32.53
29.54
This compound was obtained as colorless crystals in 32%
yield, m.p. 238–240 °C; Rf = 0.41 (n-hexane/ethyl acetate,
8:2); IR (KBr, γmax cm−1) 3446 (NH2), 3356 (NH2), 2209
1
(CN), 1648 (C=N); H-NMR: (DMSO-d6 300 MHz), δ 8.42
(d, 2H, J = 8.1Hz, H2′, H6′), δ 8.48 (d, 2H, J = 8.7 Hz, H3″,
H5″), δ 7.14 (l, 2H, NH2), δ 8.25 (d, 2H, J = 8.4 Hz, H2″,
H6″), δ 7.14 (d, 2H, J = 8.1 Hz, H3′, H5′), δ 3.65 (s, 3H,
CH3O), MS: m/z (rel. int.) 347 (M+, 100), 214 (35.5). Anal.
calculated for C18H13N5O2·1/4H2O: C, 61.44%; H, 3.86%; N,
19.90%. Found: C, 61.40%; H, 3.75%; N, 19.96%.
5.3.2. 4-Amino-5-cyano-6-(p-nitrophenyl)-2-(phenyl)-
pyrimidine (5b)
Fig. 1. Comparative analyses of the antiinflammatory activity of compounds
5f–h, ASA and INDO.
This compound was obtained as colorless crystals in 33%
yield, m.p. 265–266 °C; Rf = 0.45 (n-hexane/ethyl acetate,
8:2); IR (KBr, γmax cm−1): 3421 (NH2 symm), 3339 (NH2
asymm), 2218 (CN), 1639 (C=N); 1H-NMR (DMSO-d6
300 MHz); δ 8.42 (2H, d, J = 8.7 Hz, H2′ and H6′), δ 8.43
(2H, d, J = 8.7 Hz, H3″, H5″) δ 8.09 (2H, b, NH2), δ 7.37
(3H), m, H3′, H4′ and H5′, δ 8.21 (2H, d, J = 8.7 Hz, H2″,
H6″). MS: m/z (rel. int.) 317 (M+, 100), 318 (49.66), 214
(25.9), 303 (12.41), 270 (10.44). Anal. calculated for
C17H11N5O2: C, 64.35%; H, 3.49%; N, 22.07%. Found: C,
64.24%; H, 3.47%; N, 22.01%.
5.3.3. 4-Amino-2-(p-chlorophenyl)-5-cyano-6-
(p-nitrophenyl)-pyrimidine (5c′)
Fig. 2. Comparative analyses of the antiinflammatory activity of compounds
7a–e, ASA and INDO.
This compound was obtained as colorless crystals in a yield
of 55%; m.p. 319–320 °C; Rf = 0.17 (n-hexane/ethyl acetate,
8:2); (KBr, νmax cm−1): 3469 (NH2 asymm), 3346 (NH2 symm),
1
5.2. General method for the preparation of bisnitriles (3)
2220 (CN), 1645 (C=N), H-NMR (DMSO-d6 300 MHz), δ
8.42 (2H, d, J = 8.7 Hz, H2′, H6′), δ 8.39 (2H, d, J = 8.7 Hz,
H3″, H5″), δ 8.13 (2H, b, NH2), δ 8.21 (2H, d, J = 8.7 Hz, H2″,
H6′’), δ 7.61 (2H, d, J = 8.7 Hz, H3′, H5′). Anal. calculated for
C17H10N5O2Cl·1/4H2O: C, 57.31%; H, 2.97%; N, 19.65%.
Found: C, 57.54%; H, 2.67%; N, 19.73%.
An appropriate aldehyde 1 (24 mmol) and malononitrile 2
(24 mmol) were dissolved in methanol under stirring, and the
contents stirred for 4 h at room temperature. The reaction was
monitored by thin layer chromatography. Solvent evaporation

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Table 3
Cytotoxic activity in vitro of 4-amino-2-aryl-5-cyano-6-{3- and 4-(N-phthalimidophenyl)} pyrimidines 7a–e
Growth inhibition (%)
NCI-H292
2.50
Concentration (μg ml–1
)
1.25
5.0
10.0
Compound 7a
9.31 0.023
7.09 0.006
8.22 0.016
8.07 0.016
–
16.55 0.011
9.55 0.032
17.30 0.034
24.39 0.034
–
24.38 0.042
10.55 0.016
28.17 0.035
27.51 0.035
–
26.69 0.020
18.78 0.029
30.97 0.036
40.03 0.036
–
7b
7c
7d
7e
5.3.4. 4-Amino-5-cyano-2-(p-fluorophenyl)-6-
(p-nitrorophenyl)-pyrimidine (5d′)
added to it. The contents were stirred at room temperature for
2 h under hydrogen atmosphere, and filtered to remove the
catalyst followed by the solvent removal and crystallization
from ethyl acetate.
This compound was obtained as colorless crystals in a yield
of 44%; m.p. 254–256 °C; Rf = 0.57 (n-hexane/ethyl acetate,
8:2); (KBr, γmax cm−1): 3417 (NH2 asymm), 3334 (NH2 symm),
1
2219 (CN), 1640 (C=N); H-NMR (DMSO-d6, 300 MHz): δ
5.4.1. 4-Amino-6-(p-aminophenyl)-2-(p-anisyl)-5-cyano-
pyrimidine (6a)
8.42 (4H, d, J = 8.7 Hz, H2′, H6′, H3″, H5″), δ 8.16 (2H, b,
NH2), δ 7.36 (2H, t, H3′, H5′), δ 8.21 (2H, d, J = 8.7 Hz, H2″,
H6″). Anal. calculated for C17H10N5O2F·1/4H2O: C, 60.59%;
H, 3.00%; N, 20.88%. Found: C, 60.59%; H, 2.94%; N,
20.45%.
This compound was obtained as yellow crystals in a yield of
90%; m.p. 177–178 °C; Rf = 0.53 (n-hexane/ethyl acetate, 8:2);
(KBr, γmax cm−1): 3442 (NH2 asymm), 3344 (NH2 symm), 2203
(CN), 1610 (C=N); 1H-NMR: (DMSO-d6 300 MHz), δ 8.34 (d,
2H, J = 9.0 Hz, H2′, H6′), δ 7.85 (d, 2H, J = 9.0 Hz, H2″, H6″),
δ 7.75 (b, 2H, C4-NH2), δ 7.04 (d, 2H, J = 9.0 Hz, H3′, H5′), δ
6.68 (d, 2H, J = 8.7 Hz, H3″, H5″), δ 5.65 (s, 2H, 4′′-NH2), the
NH2 signals disappeared after addition of D2O; 3.65 (3H, s,
CH3O); MS: m/z (rel. int.) 347 (M+, 100), 348 (24.31), 214
(36.43).
5.3.5. 4-Amino-5-cyano-2-(p-chlorophenyl)-6-(m-nitrophenyl)-
pyrimidine (5e′)
This compound was obtained as colorless crystals in a yield
of 53%; m.p. 295–296 °C; Rf = 0.29 (n-hexane/ethyl acetate,
8:2); (KBr, γmax cm−1): 3486 (NH2′ asymm), 3331 (NH2 symm),
1
2216 (CN), 1630 (C=N); H-NMR (DMSO-d6 300 MHz), δ
8.38 (2H, d, J = 8.7 Hz, H2′, H6′), δ 8.42 (1H, d, J = 8.7 Hz,
H2″), δ 8.39 (2H, b, NH2), δ 7.62 (2H, d, J = 8.4 Hz, H3′, H5′),
δ 8.76 (1H, t, J = 1.8 Hz, J = 2.1Hz, H6″), δ 8.47 (1H, t,
J = 8.7 Hz, J = 1.8 Hz, H4″), δ 7.9 (1H, t, J = 7.8 Hz,
J = 8.1 Hz, H5″). Anal. calculated for C17H10N5O2Cl·1/4H2O:
C, 57.47%; H, 2.97%; N, 19.71%. Found: C, 57.68%; H,
2.76%; N, 19.74%.
5.4.2. 4-Amino-6-(p-aminophenyl)-5-cyano-2-(phenyl)-
pyrimidine (6b)
This compound was obtained as yellow crystals in a yield of
76%; m.p. 185–186 °C; Rf = 0.27 (n-hexane/ethyl acetate, 8:2);
(KBr, νmax cm−1): 3323 (NH2 asymm), 3212 (NH2 symm), 2201
1
(CN), 1611 (C=N); H-NMR: (DMSO-d6, 300 MHz), δ 8.40
(dd, 2H, J = 8.0 Hz; J = 2.0 Hz, H2′, H6′), δ 7.90 (d, 2H,
J = 8.7 Hz, H2″, H6″), δ 7.69 (b, 2H, 4′′-NH2), 7.53 (m, 3H,
H3′, H4′, H5′); 6.69 (d, 2H, J = 8.7Hz, H3″, H5″); δ 5.89 (s, 2H,
C6-NH2), the NH2 signals disappeared after addition of D2O;
MS: m/z (rel. int.) 317 (M+, 100), 318 (49.66), 214 (25.89).
5f′ and 5g′: The melting points and spectroscopic data of
these compounds agreed with the reported data in [17].
5.3.6. 4-Amino-2-(p-anisyl)-6-(p-anisyl)-5-cyano-pyrimidine
(5h′)
This compound was obtained as colorless crystals in a yield
of 84%; m.p. 191–192 °C; Rf = 0.28 (n-hexane/ethyl acetate,
8:2); (KBr, γmax cm−1): 3446 (NH2 asymm), 3356 (NH2 symm),
5.4.3. 4-Amino-6-(p-aminophenyl)-5-cyano-2-
(p-chlorophenyl)-pyrimidine (6c)
This compound was obtained as yellow crystals in a yield of
55%; m.p. 240–245 °C; Rf = 0.23 (n-hexane/ethyl acetate, 8:2);
(KBr, γmax cm−1): 3464 (NH2), 3418 (NH2), 2202 (CN), 1618
(C=N); 1H-NMR: (DMSO-d6, 300 MHz), δ 8.46 (d, 2H,
J = 9.0 Hz; H2′, H6′), δ 7.95 (d, 2H, J = 9.0 Hz, H2″, H6″), δ
7.81 (b, 2H, C4-NH2), 7.66 (d, 2H, J = 9.0 Hz; H3′, H5′); 6.75
(d, 2H, J = 9.0 Hz, H3″, H5″); δ 5.97 (b, 2H, 4′′-NH2), the NH2
signals disappeared after the addition of D2O.
1
2209 (CN), 1648 (C=N); H-NMR (DMSO-d6, 500 MHz); δ
8.37 (2H, d, J = 5.1 Hz, H2′, H6′), δ 8.02 (2H, d, J = 5.4 Hz,
H2″, H6″), δ 7.76 (2H, L, NH2), δ 7.14 (2H, d, J = 5.4 Hz, H3′,
H5′), δ 7.09 (2H, d, J = 5.4 Hz, H3″, H5″), δ 3.86 (6H, s,
CH3O), MS: m/z (rel. int.) 332 (M+, 100), 331 (65.2), 199
(24.9). Anal. calculated for C19H16N4O2·1/4H2O C, 68.66%;
H, 4.85%; N, 16.86%. Found: C, 68.99%; H, 4.76%; N,
17.19%.
5.4.4. 4-Amino-6-(p-aminophenyl)-5-cyano-2-(p-fluorophenyl)-
pyrimidine (6d)
5.4. General method for the preparation of compounds (6a–e)
This compound was obtained as yellow crystals in a yield of
69%; m.p. 262–263 °C; Rf = 0.22 (n-hexane/ethyl acetate, 8:2);
(KBr, γmax cm−1): 3465 (NH2), 3412 (NH2), 2203 (CN), 1605
Nitro pyrimidines (5a′–e′) (5.36 mmol) were dissolved in
ethyl acetate and 5% Pd on charcoal (20% by weight) was

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281
(C=N); 1H-NMR: (DMSO-d6, 300 MHz), δ 8.44 (q, 2H,
J = 8.7 Hz; J = 5.0 Hz, H2′, H6′); 7.90 (d, 2H, J = 8.70 Hz,
H2″, H6″); 7.65 (b, 2H, C4-NH2); 7.34 (m, 2′′H, H3′, H5′);
6.69 (d, 2H, J = 9.0 Hz, H5″, H3″), 5.85 (s, 2H, 4′′-NH2), the
NH2 signals disappeared after addition of D2O).
116.45, 84.58; MS: m/z (int. rel.) 417 (M+, 100), 418 (18.75),
314 (62.13). Anal. calculated for C26H17N5O3·1/2H2O: C,
68.41%; H, 3.75%; N, 15.34%. Found: C, 68.62%; H,
3.52%; N, 15.30%.
5.5.3. 4-Amino-5-cyano-2-(4-chlorophenyl)-6-{4-(N-
phthalimidophenyl)}pyrimidine (7c)
5.4.5. 4-Amino-6-(m-aminophenyl)-5-cyano-2-(p-
chlorophenyl)-pyrimidine (6e)
This compound was obtained in a yield of 61%; m.p. 312–
313 °C; Rf = 0.26 (n-hexane/ethyl acetate 8:2); (KBr, γmax
cm−1): 3471 (NH2 asymm), 3445 (NH2 symm), 2250 (CN), 1730
(C=N), 1611 (C=O); 1H-NMR: (DMSO-d6 300 MHz/δ ppm), δ
8.43 (d, 2H, J = 9.0 Hz, H2′, H6′), δ 8.12 (d, 2H, J = 8.7 Hz,
H3″, H5″), δ 8.02 (m, 2H, H1′″, H4′″), δ 7.94 (2H, m, H2′″,
H3′″), δ 7.69 (d, 2H, J = 8.1 Hz, H2″, H6″), δ 7.61 (d, 2H,
J = 8.4 Hz, H3′, H5′); It was not possible to locate the -NH2
protons 13C-NMR (DMSO-d6): δ 167.59, 166.86, 164.56,
163.08, 136.57, 135.86, 135.38, 134.88, 134.24, 131.59,
130.25, 129.28, 128.75, 127.23, 123.61, 116.32, 84.80. Anal.
calculated for C26H17N5O3·1/2H2O: C, 68.41%; H, 3.75%; N,
15.34%. Found: C, 68.62%; H, 3.52%; N, 15.30%.
This compound was obtained as yellow crystals in a yield of
55%; m.p. 237–238 °C; Rf = 0.21 (n-hexane/ethyl acetate, 8:2);
(KBr, γmax cm−1): 3423 (NH2), 3342 (NH2), 2208 (CN), 1650
(C=O); 1H-NMR: (DMSO-d6, 300 MHz), δ 8.38 (d, 2H,
J = 9.0 Hz; H2′, H6′), δ 7.13 (2H, m, H2″, H5″), δ 7.07 (d,
1H, J = 9.0 Hz, H6″), δ 7.88 (b, 2H, 4′′-NH2), 7.60 (d, 2H,
J = 9.0 Hz, H3′, H5′); 6.76 (d, 1H, J = 9.0 Hz, H4″), δ 5.35
(s, 2H, 4′′-NH2) the NH2 signals disappeared after addition of
D2O.
5.5. General procedure for the synthesis of compounds (7a–e)
Compound 6 was dissolved in nitrobenzene with phthalic
anhydride. The contents were refluxed and stirred for 30 min.
The solid mass was precipitated using cyclohexane and the de-
sired compound 7 was crystallized from acetic acid.
5.5.4. 4-Amino-5-cyano-2-(4-fluorophenyl)-6-{4-
(N-phthalimidophenyl)}pyrimidine (7d)
This compound was obtained in a yield of 68%; m.p.
314.5–315 °C; Rf = 0.28 (n-hexane/ethyl acetate 8:2); (KBr,
γmax cm−1): 3466 (NH2 asymm), 3317 (NH2 symm), 2187 (CN),
5.5.1. 4-Amino-2-(p-anisyl)-5-cyano-6-{4-
(N-phthalimidophenyl)} pyrimidine (7a)
1
This compound was obtained in a yield of 67%; m.p. 335–
340 °C; Rf = 0.60 (n-hexane/ethyl acetate 8:2); (KBr, γmax
cm−1): 3459 (NH2 asymm), 3361 (NH2 symm), 2212 (CN), 1750
(C=N), 1644 (C=O); 1H-NMR: (DMSO-d6 300 MHz/δ ppm), δ
8.4 (2H, d, J = 9.0 Hz, H2′, H6′), δ 8.11 (d, 2H, J = 8.4 Hz,
H3″, H5″), δ 8,02 (m, 2H, H1′″ H4′″), δ 7.9 (b, 2H, NH2, after
addition of D2O the signal disappeared), δ 7.94 (m, 2H, H2′″,
H3′″), δ 7.68 (d, 2H, J = 8.4Hz, H2″, H6″), δ 7.08 (d, 2H,
J = 8.7 Hz, H3′, H5′), δ 3.82 (s, 3H, CH3O); 13C-NMR
(DMSO-d6): δ 167.41, 166.86, 164.46, 163.84, 162.23,
136.15, 134.85, 134.10, 131.60, 130.41, 129.20, 128.89,
127.22, 123.59, 116.56, 113.94, 83.75, 55.42; MS: m/z (int.
rel.) 317 (M+, 100), 403 (44.2), 316 (81.6). Anal. calculated for
C26H17N5O3·1/2H2O: C, 68.41%; H, 3.75%; N, 15.34%.
Found: C, 68.62%; H, 3.52%; N, 15.30%.
1734 (C=N), 1644 (C=O); H-NMR: (DMSO-d6 300 MHz/δ
ppm), δ 8.48 (d, 2H, J = 9.0 Hz, H2′, H6′), δ 8.13 (d, 2H,
J = 7.8 Hz, H3″, H5″), δ 8.0 (m, 2H, H1′″, H4′″), δ 7.7 (d,
2H, J = 7.8 Hz, H2″, H6″), δ 7.94 (m, 2H, H2′″, H3′″), δ 7.35
(t, 2H, J = 8.1 Hz, J = 8.4 Hz, H3′, H5′); the -NH2 protons pre-
sumably appeared 7.20 ppm 13C-NMR (DMSO-d6): δ 167.53,
166.85, 164.56, 163.11, 135.92, 135.34, 134.87, 134.21,
133.04, 131.56, 131.09, 129.89, 129.28, 127.21, 123.60,
116.38, 84.51. Anal. calculated for C25H14N5FO2·H2O: C,
66.22%; H, 3.56%; N, 15.45%. Found: C, 66.22%; H,
3.31%; N, 15.21%.
5.5.5. 4-Amino-2-(4-chlorophenyl)-5-cyano-6-{3-
(N-phthalimidophenyl)}pyrimidine (7e)
This compound was obtained in a yield of 50%; m.p. 309–
310 °C; Rf = 0.34 (n-hexane/ethyl acetate 8:2); (KBr, γmax
cm−1): 3460 (NH2 asymm), 3351 (NH2 symm), 2187 (CN), 1727
(C=N), 1642 (C=O); 1H-NMR: (DMSO-d6 300 MHz/δ ppm), δ
8.4 (d, 2H, J = 8.7 Hz, H2′, H6′), δ 8.07 (m, 2H, H4″, H6″), δ
8.01 (m, 2H, H1′″, H4′″), δ 7.93 (m, 2H, H2′″, H3′″), δ 7.74 (d,
1H, J = 8.4 Hz, H2″), δ 7.72 (bs, 1H, H5″), δ 7.59 (2H,
J = 8.4 Hz, H3′, H5′); The -NH2 protons could not be located
13C-NMR (DMSO-d6): δ 173.06, 167.36, 167.10, 164.71,
163.24, 137.27, 136.74, 135.40, 134.99, 132.46, 131.67,
130.35, 130.04, 129.25, 128.81, 128.33, 127.69, 123.69,
116.21. Anal. calculated for C25H14N5ClO2·1/2H2O: C,
65.15%; H, 3.28%; N, 15.26%. Found: C, 64.86%; H,
3.33%; N, 15.61%.
5.5.2. 4-Amino-5-cyano-2-(phenyl)-6-{4-
(N-phthalimidophenyl)}-pyrimidine (7b)
This compound was obtained in a yield of 64%; m.p. 327–
328 °C; Rf = 0.29 (n-hexane/ethyl acetate 8:2); (KBr, γmax
cm−1): 3404 (NH2 asymm), 3355 (NH2 symm), 2210 (CN), 1718
(C=N), 1609 (C=O), 1H-NMR: (DMSO-d6 300 MHz/δ ppm), δ
8.44 (2H, d, J = 7.5 Hz, H2′, H6′), δ 8.13 (d, 2H, J = 8.7 Hz,
H3″, H5″), δ 8.02 (m, 2H, H1′″, H4′″), δ 7.9 (2H, b, NH2, after
addition of D2O the signal disappeared), δ 7.94 (m, 2H, H2′″,
H3′″), δ 7.76 (2H, d, J = 8.4 Hz, H2″, H6″), δ 7.55 (d, 3H,
J = 7.5 Hz, H3′, H4′, H5′), 13C-NMR (DMSO-d6): δ 167.50,
166.85, 164.61, 164.10, 136.51, 136.01, 134.85, 134.18,
131.57, 129.88, 129.28, 128.58, 127.21, 123.59, 123.34,

282
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5.6. The antiinflammatory activity of the compounds 5 and 7
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We have achieved an efficient and simple synthesis of 5a–
h. The transformation of these to 6a–e followed by the pre-
paration of phthalimidoyl pyrimidines 7a–e has also been ac-
complished. The discovery that these final phthalimidopyrimi-
dines are antiinflammatory without any toxic effects is
exciting. This finding is quite satisfactory. Hence, this study
has widened the scope for evolving the new and promising
antiinflammatory drugs.
Acknowledgments
One of us (E.P.d.S.F.) is thankful to the Ministry of Educa-
tion (CAPES) for a Research Fellowship from 1999 to 2002.
Our thanks are also due to Conselho Nacional de Desenvolvi-
mento Científico e Tecnológico (CNPq) for financial help.