Synthesis and Anti-inflammatory Screening of Some Mono and Bis-Alkoxyphthalimide Linked Benzimidazole and their Quinazoline and Pyrimidine Derivatives

Article abstract of DOI:10.1002/jhet.2471

In the present study, synthesis of some nonsymmetrical 2-(1H-benzimidazol-2-ylamino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6H)-one (3) and substituted-(1H-benzo[d]imidazol-2-yl)amino-pyrimidine derivatives (4a, 4b, 4c and 5a, 5b) is described as a three-component reaction of 2-guanidinobenzimidazole (2) with triethyl orthoformate and different reactive methylene compounds. Subsequent condensation of compounds 3, 4a, 4b, 4c, and 5a, 5b with bromoethoxyphthalimide (1) gave final compounds 6, 7a, 7b, 7c, and 8a, 8b. Synthesized final compounds have been screened for their in-vivo anti-inflammatory activity against carrageenan-induced paw edema in albino rats. Diclofenac was used as standard anti-inflammatory agents. Some of the compounds exhibited significant anti-inflammatory activity, as compared to standard drug. Structures of synthesized compounds have been confirmed on the basis of chemical tests and spectral studies.

Full text of DOI:10.1002/jhet.2471

Month 2015
Synthesis and Anti-inflammatory Screening of Some Mono and
Bis-Alkoxyphthalimide Linked Benzimidazole and their Quinazoline and
Pyrimidine Derivatives
*
Prakash Prajapat and Ganpat L. Talesara
Department of Chemistry, M. L. Sukhadia University, Udaipur 313001, India
*
E-mail: glntalesara@yahoo.com
Received March 13, 2015
DOI 10.1002/jhet.2471
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
In the present study, synthesis of some nonsymmetrical 2-(1H-benzimidazol-2-ylamino)-7,7-dimethyl-
7,8-dihydroquinazolin-5(6H)-one (3) and substituted-(1H-benzo[d]imidazol-2-yl)amino-pyrimidine deriva-
tives (4a-c and 5a-b) is described as a three-component reaction of 2-guanidinobenzimidazole (2) with
triethyl orthoformate and different reactive methylene compounds. Subsequent condensation of compounds
3, 4a-c, and 5a-b with bromoethoxyphthalimide (1) gave final compounds 6, 7a-c, and 8a-b. Synthesized
final compounds have been screened for their in-vivo anti-inflammatory activity against carrageenan-induced
paw edema in albino rats. Diclofenac was used as standard anti-inflammatory agents. Some of the
compounds exhibited significant anti-inflammatory activity, as compared to standard drug. Structures of
synthesized compounds have been confirmed on the basis of chemical tests and spectral studies.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
antimalarial [2], anticancer [3], anti-inflammatory [4,5],
anti-microbial [6,7], anticonvulsant [8], Hv1 proton
channel inhibitor [9], agonist neurotransmitter serotonin
receptors, 5-hydroxytryptamine (5-HT) antagonists, and
5-hydroxytryptamine type 3 (5-HT3), agents [10–14] etc.
Guanidinobenzimidazole and some of its derivatives are
biologically active compounds an example being the
blocking of skin sodium channels. In addition,
guanidinobenzimidazole diminishes gastric acid secretion
and also exhibit hypoglycemic and hypotensive properties
[15]. Some of the analogues of benzimidazole have been
used as active ingredients in major drugs like omeprazole,
Multicomponent reactions are of increasing importance
in organic and medicinal chemistry because the combina-
tion of three components to generate new products in a
single step is extremely economical and the synthesis of
complicated molecules can be achieved in a fast, efficient,
and time-saving manner without any separation of interme-
diate during the reaction process [1]. Benzimidazole sig-
nifies a key motif in heterocyclic chemistry and occupies
a major position in various synthetic pharmaceuticals
because of its wide range of biological activities such as
© 2015 HeteroCorporation

P. Prajapat and G. L. Talesara
Vol 000
as proton pump inhibitor; mebendazole, as antihelmintic;
enviradine, as antiviral; astemizole, as antihistaminic; and
telmisartan, as antihypertensive. A series of benzimidazole
and imidazopyridine derivatives were synthesized and
screened for anti-inflammatory activities, and the
imidazopyridine series showed excellent inhibition of
inflammatory cytokines in LPS-stimulated macrophages
(Fig. 1) [5].
Bromoethoxyphthalimide (1) was prepared by literature
methods. In this method N-hydroxyphthalimide and 1,2
dibromoethane were kept overnight in dimethyl-
formamide medium using triethylamine as base (Scheme 1).
Ortho phenylenediamine on cyclocondensation with
dicyandiamide yielded guanidinobenzimidazole (2) in
more than 85% yield. IR spectra of compound 2 showed
new absorption band corresponding to NH and NH2 at
1
Quinazoline derivatives have occupied a prominent
place among various heterocyclic compounds by virtue of
their diverse medicinal values. Compounds containing
dihydroquinazolin-5(6H)-one moiety have been reported
to possess biological activity, especially central nervous
system (CNS) agents [16], heat-shock protein 90 (Hsp90)
inhibitor [17], negative allosteric modulator (NAM) of
the metabotropic glutamate receptor subtype 5(mGluR5),
and subtype mGluR1 [18]. Pyrimidine and their derivatives
occupy an extremely important role in the field of pharma-
ceutical and medicinal chemistry because they display a
fascinating array of pharmacological properties viz. antitu-
mor [19–24], antimicrobial [25–27], antihypertensive [28],
anti-inflammatory [29], antineoplastic [30], A2A and A3
Adenosine Receptors Antagonists [31], cardiovascular
[32,33], and diuretic [34,35]. Furthermore, pyrimidines
are compounds that in-vitro possess biological activity
against a wide spectrum of unrelated viruses, such as polio-
virus [36], herpes virus [37], and HIV [38–41]. Several
derivatives of alkoxyphthalimide have been synthesized
[42,43] by this research group and reported to demonstrate
a wide range of pharmacological activities such as antimalarial,
antihypertensive, CNS depressant, antimicrobial [44–48], etc.
Recent work in our laboratory has focused upon the synthe-
sis and biological evaluation of a series of oxygen substituted
hydroxylamine derivatives particularly containing heterocy-
cles, as potential anti-inflammatory agents. Led by above facts,
coupled with our desire of synthesizing alkoyphthalimide
derivatives, we report herein synthesis of some new heterocy-
cles incorporating above moieties together in order to prepare
the molecules having enhanced biological activity.
3456 and 3198 cmꢀ1. H-NMR spectra of compound 2
showed a broad signal at 11.14 δ corresponding to
exchangeable NH group while aromatic and NH group of
benzimidazole ring appeared at 6.91–7.18 δ. NH2 group
of guanidine site was observed at 3.40 δ. Compound 2 on
reaction with different reagents having reactive methylene
components viz: dimedone, acetylacetone, ethylacetoacetate,
methylacetoacetate, ethylcynoacetate, malanonitryle and
triethyl orthoformate yielded corresponding heterocyclic
moieties 3, 4a–c, and 5a–b. In the reaction mechanism
ethoxymethylene derivatives (new carbon–carbon bonds)
are formed by the reaction of triethylorthoformate with
compound having reactive methylene groups by electrophilic
addition and substitution reaction of dialkoxy carbonium
ions derived from triethyl orthoformate [49]. Addition of
amino group in 2-guanidinobenzimidazole to the activated
double bond in the ethoxymethylene derivatives to give
the non-ionizable acyclic intermediates, which undergoes
intramolecular cyclization and subsequent aromatization
via loss of ethanol and water molecules under the reaction
conditions. Structure of these compounds have been
confirmed by their analytical and spectral studies (Scheme
2). IR spectra of compounds 3 and 4a–c were elucidated
by disappearance of two absorption peaks of NH2 group
and appearance of absorption peaks at range between
1705 and 1737cmꢀ1 corresponding to C¼O group in
dihydroquinazolin-5(6H)-one and on pyrimidine ring. IR
spectra of compound 5a and 5b were elucidated by
appearance of two absorption peaks at a range between
3464 and 3154cmꢀ1 corresponding to NH2 group on
1
pyrimidine ring. H NMR spectra of compounds 3, 4a–c,
Scheme 1. Synthesis of bromeothoxy phthalimide.
RESULT AND DISCUSSION
Chemistry. In the present work effort has been made to
synthesize benzimidazole based quinazoline (3) and substituted
pyrimidines (4a–c and 5a–b) and their alkoxyphthalimide
derivatives (6, 7a–c, and 8a–b) using a multistep process.
Figure 1. Some benzimidazole and imidazole containing anti-inflammatory agents.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Anti-inflammatory Effects of Benzimidazole Based Quinazoline and Substituted
Pyrimidines Containing Alkoxyphthalimide Derivatives
Scheme 2. Synthesis of benzimidazole-based quinazoline and pyrimidine derivatives.
1
and 5a–b appeared as a singlet peak between 9.61 and
12.11 δ for NH group while methine (¼CH) group of
pyrimidine rings was observed between 4.36 and 6.91 δ
as a singlet peak for these compounds. Compounds 3,
4a–c, and 5a–b have a poor solubility in most of organic
solvents. It was not dissolved in common solvents such as
methanol, ethanol, acetone, or chloroform, but it could be
dissolved in polar nonproton solvents such as DMSO and
DMF. All these compounds possess replaceable reactive
hydrogen in their structures. Replacement of reactive
hydrogen takes place by nucleophilic substitution of
alkoxyphthalimide group in the presence of base in a mixture
of DMSO and DMF (1:2) media using phthalimidoxy
ethyl bromide to obtain targeted products 6, 7a–c, and
8a–b (Scheme 3). Structures of these compounds have
been confirmed by the analytical and spectral studies.
8a–b. H NMR spectra of compounds 6, 7a–c, and 8a–b
appeared as triplet at between 3.15 and 3.53 δ and 2.39 and
2.84 δ for O―CH2 and N―CH2 of ethoxyphthalimide
moiety. The mass spectrum also supports the proposed
structure by viewing molecular ion peaks of all compounds.
Addition confirmation of phthalimidoxyl group attachment
was achieved by usual chemical test including fluorescence
formation.
CONCLUSION
A new series of alkoxyphthalimide containing benz-
imidazole bearing a biologically active quinazoline and
substituted pyrimidine derivatives have been synthesized
and screened for their biological activity with the aim of
discovering innovative structure leads serving as potent
anti-inflammatory agents. The synthesized derivatives 6,
7a–c, and 8a–b showed significant anti-inflammatory ac-
tivity against carrageenan-induced rat paw edema. On
screening, compounds 6, 7a, and 8a exhibited good anti-
inflammatory activity whereas compounds 7b, 7c, and 8b
exhibited moderate anti-inflammatory activity when com-
pared to reference diclofenac. It was concluded that the
1
New IR bands for CH str. as well as new H NMR signals
for proton of methine (¼CH) group were observed for final
products. Condensation of bromoethoxyphthalimide (1) at
the N-atom was confirmed by IR spectroscopy. The new
strong str. vibration bands at 1292–1156cmꢀ1 and
1355–1385cmꢀ1 for the CH2―N―CO and N―O group
confirming the formation of final compounds 6, 7a–c, and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

P. Prajapat and G. L. Talesara
Vol 000
Scheme 3. Synthesis of alkoxyphthalimide linked derivatives.
compounds 6 and 8a showed stronger anti-inflammatory
activity than the other compounds and they can be devel-
oped as potent chemotherapeutic agents.
filtered off, washed with water, dried, and recrystallized
from ethanol [50].
Synthesis of 1-(1H-benzimidazol-2-yl)guanidine 2. Ortho
phenylenediamine (5.40g, 0.05 mol) were dissolved on
heating in 50mL of 10% sulfuric acid and dicyandiamide
(6.30 g, 0.075 mol) was added. The reaction mixture was
refluxed for 1 h, and then 10mL of 50% NaOH solution
was added and heated for further 15min. The reaction
mixture was cooled, and the obtained solid was collected
by filtration, washed with water, dried, and recrystallized
from ethanol [11]. IR (KBr): 3456, 3247, 3198, 3065,
1606, 1445cmꢀ1; 1H NMR (400MHz, DMSO-d6): δ 6.92
(s, 1H, NH), 3.40 (s, 2H, NH2), 7.0–7.19 (m, 4H, Ar-H),
11.14(s, 2H, br exchangeable NH); MS: m/z 175 [M+].
EXPERIMENTAL
Material and methods. All chemicals were commercially
procured and were used without further purification. Melting
points were determined in an open capillary tube and are
therefore uncorrected. Purity of synthesized compounds
was checked by TLC using silica gel-G plates, n-hexane-
ethyl acetate as developing solvent, and the spots were
exposed in an UV light or iodine chamber. Fourier
transform infrared (FT-IR) spectra were recorded with a
Perkin-Elmer BX spectrum on KBr pellets, and NMR was
recorded on a Bruker DRX-400-MHz spectrometer with
dimethylsulfoxide DMSO-d6/CDCl3 as solvent using
tetramethylsilane (TMS) as an internal standard. The mass
spectra were recorded on Joel SX-102 (EI) model with
60-eV ionizing energy. Elemental analysis was done on
“Heraeus Rapid Analyser.” Structures of all synthesized
compounds were characterized by using IR, NMR, Mass,
General procedure for the synthesis of compounds 3–5.
A
solution of compound 2 (1.75g, 0.01 mol) and an
equivalent molar ratio of the dimedone, acetylacetone,
ethylacetoacetate, methylacetoacetate, ethylcynoacetate,
or malanonitryle in triethyl orthoformate (20 mL), in the
presence of few drops of piperidine were heated under
stirred reflux for 1–2 h. The excess solvent was removed
by distillation under reduced pressure, and the residue was
left to cool. The precipitated solid product was collected
and Elemental analysis.
Synthesis of 2-(2-bromoethoxy)-1H-isoindole-1,3(2H)-dione
1. A solution of N-hydroxy phthalimide (1.63g, 1.72mL,
0.02mole) and triethylamine (2.02g, 2.8mL, 0.02 mol) was
added to it. This was allowed to stand at room temperature
with occasional stirring, until the red color of the reaction
mixture turned colorless (17–22h). Solid precipitate was
by filtration, washed with ethanol, and dried.
2-(1H-benzimidazol-2-ylamino)-7,7-dimethyl-7,8-dihydroquinazolin-
5(6H)-one (3). IR (KBr): 3329, 3054, 2874, 1730, 1625,
1464cmꢀ1; 1H NMR (400MHz, DMSO-d6): δ 1.09 (s, 6H,
CH3), 1.92 (s, 2H, COCH2), 7.01–7.23 (m, 4H, Ar―H),
8.94 (s, 1H, Ar―H), 11.82 (s, 2H, br exchangeable NH);
Journal of Heterocyclic Chemistry
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Month 2015
Anti-inflammatory Effects of Benzimidazole Based Quinazoline and Substituted
Pyrimidines Containing Alkoxyphthalimide Derivatives
MS: m/z 307 [M+]; Anal. calcd. for C17H17N5O: C, 66.43; H,
5.58; N, 22.79; Found: C, 66.29; H, 5.38; N, 22.67.
1-[2-(1H-benzimidazol-2-ylamino)-4-methylpyrimidin-5-yl]
ethanone (4a). IR (KBr): 3347, 3014, 2889, 1715, 1620,
251 [M+]; Anal. calcd. For C12H9N7: C, 57.37; H, 3.61;
N, 39.02; Found: C, 57.48; 3.79; N, 38.92.
Synthesis of compound 6. Compound 3 (0.92g, 0.003 mol)
and bromoethoxyphthalimide (0.81 g, 0.003mol) were
dissolved in a mixture of DMSO (5mL) and DMF (10mL).
Pyridine was added to this solution as a base. The reaction
mixture was refluxed for 17h in a round bottom flask.
Excess of solvent was distilled of under reduced pressure.
The reaction mixture was cooled to room temperature and
poured into crushed ice. Products were filtered, washed with
cold water, dried, and recrystallized from ethanol.
1449cmꢀ1; 1H NMR (400MHz, DMSO-d6): δ 1.36 (s, 3H,
CH3), 2.39 (s, 3H, COCH3), 6.82 (s, 1H, CH), 7.09–7.16
(m, 4H, Ar―H), 9.09 (s, 1H, Ar―H), 12.11 (s, 2H, br
exchangeable NH); MS: m/z 267 [M+]; Anal. calcd. For
C14H13N5O: C, 62.91; H, 4.90; N, 26.20; Found: C, 63.01;
4.82; N, 26.35.
Ethyl 2-(1H-benzimidazol-2-ylamino)-4-methylpyrimidine-5-
carboxylate (4b).
1609, 1460cmꢀ1
IR (KBr): 3364, 3030, 2859, 1735,
1H NMR (400 MHz, DMSO-d6): δ
Compounds 7a–c and 8a–b were prepared in similar
way with minor change in reflux time and mole ratio.
;
1.34 (s, 3H, CH3), 2.09(t, 3H, CH3), 6.91(s, 1H, CH),
4.32 (q, 2H, OCH2), 7.12–7.54 (m, 4H, Ar―H), 8.98
(s, 1H, Ar―H), 12.05 (s, 2H, br exchangeable NH);
MS: m/z 297 [M+]; Anal. calcd. For C15H15N5O2: C,
60.61; H, 5.09; N, 23.56; Found: C, 59.92; H, 5.17; N, 22.64.
Methyl 2-(1H-benzimidazol-2-ylamino)-4-methylpyrimidine-
The observed physical properties are presented in Table 1.
2-{2-[2-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinazolin-
2-ylamino)-benzoimidazol-1-yl]-ethoxy}-isoindole-1,3-dione
(6). IR (KBr): 3425, 3000, 2870, 1715, 1690, 1625,
1360, 1205, 1055, 1450 cmꢀ1 1H NMR (400 MHz,
;
CDCl3): δ 7.44–7.86 (m, 8H, Ar―H), 5.35 (s, NH),
0.96 (s, 6H, CH3), 1.26 ( s, 2H, CH2), 2.20 (s, 2H,
COCH2), 3.32(t, 2H, OCH2), 2.84(t, 2H, NCH2),
2.33(q, 4H, CH2―CH2); 13C NMR (400 MHz,
CDCl3): δ 13.82, 26.78, 28.11, 29.33, 42.31, 58.02,
74.32, 122.01, 122.15, 128.05, 129.13, 130.44, 132.14,
132.73, 133.24 134.67, 134.86, 136.22, 136.14,
138.59, 148.44, 161.25, 163.14, 167.25, 170.10; MS:
5-carboxylate (4c).
IR (KBr): 3386, 3012, 2829, 1745,
1642, 1454cmꢀ1
;
1H NMR (400 MHz, DMSO-d6): δ
1.37 (s, 3H, CH3), 3.46(s, 3H, CH3), 6.85(s, 1H, CH),
7.08–7.31 (m, 4H, Ar―H), 8.69 (s, 1H, Ar―H), 12.18
(s, 2H, br exchangeable NH); MS m/z 283 [M+]; Anal.
calcd. For C14H13N5O2: C, 59.36; H, 4.63; N, 24.72;
Found: C, 59.28; H, 4.74; N, 24.63.
Ethyl 4-amino-2-(1H-benzimidazol-2-ylamino)pyrimidine-5-
m/z 496 [M+]; Anal. calcd. For C27H24N6O4: C, 65.31;
H, 4.87; N, 16.93; Found: C, 65.24; H, 4.76; N, 17.02.
2-{2-[2-(5-Acetyl-4-methyl-pyrimidine-2-ylamino)-benzoimidazol-
carboxylate (5a).
IR (KBr): 3485, 3328, 3154, 3042,
2856, 1737, 1614, 1416, 1046 cmꢀ1; H NMR (400MHz,
DMSO-d6): δ 3.56 (s, 2H, NH2), 1.28 (t, 3H, CH3), 4.26
(q, 2H, OCH2), 6.45 (s, 1H, CH), 7.07–7.52 (m, 4H, Ar―H),
8.90 (s, 1H, Ar―H), 9.61 (s, 2H, br exchangeable NH);
MS: m/z 298 [M+]; Anal. calcd. For C14H14N6O2: C,
1
1-yl]-ethoxy}-isoindole-1,3-dione (7a). IR (KBr): 3445, 3026,
1
2866, 1717, 1695, 1615, 1365, 1223, 1045, 1442cmꢀ1; H
NMR (400MHz, CDCl3): δ 7.22–7.85 (m, 8H, Ar―H), 5.94
(s, NH), 1.25 (s, 3H, CH3), 2.85 (s, 3H, COCH3), 6.68
(s, 1H, CH), 3.22(t, 2H, OCH2), 2.50(t, 2H, NCH2), 2.30(q,
4H, CH2―CH2); 13C NMR (400MHz, CDCl3): δ 23.92,
26.78, 28.11, 29.33, 40.31, 58.02, 70.24, 74.32, 120.02,
123.15, 127.05, 127.05, 127.38, 128.54, 128.93, 133.24
134.70, 134.86, 136.22, 136.71, 138.89, 147.44, 161.22,
56.37; H, 4.73; N, 28.17; Found: C, 56.29; H, 4.83; N, 28.23.
4-Amino-2-(1H-benzimidazol-2-ylamino)pyrimidine-5-carbonitrile
(5b). IR (KBr): 3464, 3343, 3186, 3026, 2154, 1618, 1454,
1190 cmꢀ1; 1H NMR (400 MHz, DMSO-d6): δ 3.39(s, 2H,
NH2), 6.9 (s, 1H, CH), 7.12–7.50 (m, 4H, Ar―H), 8.53 (s,
1H, Ar―H), 11.98 (s, 2H, br exchangeable NH); MS: m/z
Table 1
The physical properties of synthesized compounds.
Compounds
Mol. formula
17H17N5O
C14H13N5O
C15H15N5O2
C14H13N5O2
C14H14N6O2
C12H9N7
C27H24N6O4
C24H22N6O4
C25H22N6O5
C25H22N6O5
C34H28N8O8
C32H23N9O6
Mol. weight
Reflux time (h)
mp (°C)
Yield (%)
3
C
307.35
267.28
297.31
283.28
298.29
251.24
496.51
456.45
486.48
472.45
676.63
629.58
2
1
1.5
1
1.5
1
17
19
17
15
18
16
298
>300
228
256
166
>300
186
207
252
220
80
78
86
82
68
64
59
60
62
56
59
54
4a
4b
4c
5a
5b
6
7a
7b
7c
8a
8b
169
212
Journal of Heterocyclic Chemistry
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P. Prajapat and G. L. Talesara
163.11, 167.18; MS: m/z 456 [M+]; Anal. calcd. For
Vol 000
C24H22N6O4: C, 63.15; H, 4.42; N, 18.41; Found: C, 63.23;
H, 4.52; N, 18.36.
2-{1-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yloxy)-ethyl]-1H-
benzoimidazol-2-ylamino}-4-methyl-pyrimidine-5-carboxylic
acid ethyl ester (7b). IR (KBr): 3422, 3015, 2852, 1739,
1708, 1606, 1385, 1218, 1057, 1453 cmꢀ1 1H NMR
;
( 400 MHz, CDCl3): δ 7.16–7.54 (m, 8H, Ar―H), 6.01
(s, NH), 1.26 (s, 3H, CH3), 3.98 (q, 2H, OCH2 ester),
1.92(t, 3H, CH3), 6.83 (s, 1H, CH), 3.53(t, 2H, OCH2),
2.71(t, 2H, NCH2), 2.45(q, 4H, CH2―CH2); 13C NMR
(400 MHz, CDCl3): δ 24.95, 26.78, 28.12, 29.33,
38.22, 58.12, 70.26, 72.22 74.32, 121.22, 123.15,
126.05, 127.05, 128.38, 128.54, 128.93, 134.24 134.70,
135.26, 136.22, 136.19, 138.20, 140.41, 162.11,
163.11, 169.67; MS: m/z 486 [M+]; Anal. calcd. For
C25H22N6O5: C, 60.70; H, 4.31; N, 16.33; Found: C,
60.79; H, 4.24; N, 16.29.
2-{1-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yloxy)-ethyl]-1H-
benzoimidazol-2-ylamino}-4-methyl-pyrimidine-5-carboxylic
acid methyl ester (7c). IR (KBr): 3382, 3018, 2862, 1741, 1712,
1
1619, 1355, 1223, 1059, 1461 cmꢀ1; H NMR (400MHz,
CDCl3): δ 7.18–7.52 (m, 8H, Ar―H), 5.84(s, NH), 1.26
(s, 3H, CH3), 3.86 (s, 2H, OCH3 ester), 6.87(s, 1H, CH),
3.23(t, 2H, OCH2), 2.61(t, 2H, NCH2), 2.55(q, 4H,
CH2―CH2); 13C NMR (400 MHz, CDCl3): δ 26.72,
28.12, 29.34, 38.22, 58.12, 70.24, 71.67, 75.36, 121.14,
123.15, 127.55, 128.15, 128.28, 129.52, 130.93, 134.24
134.70, 136.10, 140.21, 141.18, 144.20, 150.21, 165.22,
163.13, 168.52; MS: m/z 472 [M+]; Anal. calcd. For
C25H22N6O5: C, 61.01; H, 4.27; N, 17.79; Found: C,
59.92; H, 4.32; N, 17.82.
4-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yloxy)-ethylamino]-
2-{1-[2-(1,3-dioxo-1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-ethyl]-
1H-benzimidazol-2-ylamino}-pyrimidine-5-carboxylic acid ethyl
ester (8a). IR (KBr): 3456, 3025, 2890, 1734, 1698, 1612,
1378, 1219, 1066, 1453 cmꢀ1; 1H NMR (400 MHz, CDCl3):
δ 7.22–7.85(12H, m, Ar―H), 9.12(s, NH), 5.29(t, 1H,
NHCH2), 4.28(q, 2H, OCH2 ester), 1.86(t, 3H, CH3),
5.96 (s, 1H, CH), 3.15(t, 4H, OCH2), 2.39(t, 4H, NCH2),
2.92(q, 8H, CH2―CH2); 13C NMR (400MHz, CDCl3): δ
25.85, 26.78, 28.12, 30.13, 38.22, 48.25, 58.12, 70.34,
72.43, 76.11, 116.22, 116.25, 118.08, 120.06, 124.45,
128.33, 128.68, 133.24 133.55, 135.22, 136.51, 137.20,
140.41, 144.86, 147.22, 148.74, 150.22, 155.67, 155.85,
162.18, 163.19, 165.22, 168.11, 169.67; MS: m/z 676 [M+];
Anal. calcd. For C34H28N8O8: C, 16.35; H, 4.17; N, 16.56;
Found: C, 16.29; H, 4.21; N, 16.43.
4-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yloxy)-ethylamino]-
2-{1-[2-(1,3-dioxo-1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-ethyl]-
1H-benzimidazol-2-ylamino}-pyrimidine-5-carbonitrile (8b). IR
(KBr): 3426, 3044, 2842, 2235, 1702, 1616, 1359, 1292,
1066, 1483cmꢀ1; 1H NMR (400MHz, CDCl3): δ 7.51–8.46
(12H, m, ArH), 8.73(s, NH), 5.34(t, 1H, NHCH2), 5.77
(s, 1H, CH), 3.40(t, 4H, OCH2), 2.41(t, 4H, NCH2), 2.62(q,
8H, CH2―CH2); 13C NMR (400MHz, CDCl3): δ 26.55,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Anti-inflammatory Effects of Benzimidazole Based Quinazoline and Substituted
Pyrimidines Containing Alkoxyphthalimide Derivatives
[4] Prasad, A. T.; Sudhir, G. W.; Chandrabhan, T. C.
Pharmacologyonline 2007, 1, 314.
27.28, 28.15, 30.12, 38.25, 48.27, 58.22, 70.34, 116.25,
116.29, 119.28, 120.12, 125.33, 126.32, 128.81, 133.22
133.53, 135.19, 137.52, 137.18, 140.44, 142.58, 144.82,
146.25, 151.25, 154.12, 155.85, 162.15, 164.13, 164.24,
168.19, 169.34; MS: m/z 629[M+]; Anal. calcd. For
C32H23N9O6: C, 61.05; H, 3.68; N, 20.02; Found: C, 61.13;
H, 3.71; N, 20.10.
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BIOLOGICAL ACTIVITY
In-vivo anti-inflammatory activity.
Anti-inflammatory
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activity was evaluated by the method described by
(Winter et al., 1962) [51]. Albino rats of either sex
weighing 160–220g were divided into eight groups
containing six rats each. Group-1 received 0.5% CMC
suspension (control), Group-2 accustomed accepted
biologic Diclofenac (50 mg/kg, p.o) respectively. Group
3–8 received test compounds through the same route.
Rats were treated with drugs by oral route. Thirty
minutes later 0.1 mL of 1% freshly prepared carrageenan
suspension in 0.9% NaCl solution was injected
subcutaneously into the planter aponeurosis of the hind
paw. The paw volume is measured by using
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The difference between the initial and subsequent values
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% Anti ꢀ inflammatory activity ¼ ½ 1 – Vt= Vcꢁ ꢂ 100
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Vt and Vc are paw volumes of edema in tested and con-
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inhibit the paw edema in albino rats. The outcome of this
investigation is presented in Table 2.
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Acknowledgments. The authors are thankful to the Head, De-
partment of Chemistry, M. L. Sukhadia University, Udaipur
(Rajasthan) for providing laboratory facilities, the Director,
NFDD Rajkot, India for providing spectral and analytical data,
and B. N. Institute of Pharmaceutical Science, Udaipur, India
for providing anti-inflammatory results. One of the authors
Mr Prakash Prajapat (JRF-NET) is thankful to UGC, New Delhi,
for financial assistance.
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