Synthesis and analgesic activity of 1-(1- piperidinyl)methyl-2-(4-substituted styryl)-5-chlorobenzimidazole derivatives

Article abstract of DOI:10.1211/146080899128734532

Seven 1-(1-piperidinyl)methyl-2-(4-substituted styryl)-5-chlorobenzimidazole derivatives were synthesized by the reaction of 2-(p-substituted styryl)-5-chlorobenzimidazoles with formaldehyde and piperidine in methanol. Analgesic activity of the 1-(1-piperidinyl)-methyl-2-(4-substituted styryl)-5-chlorobenzimidazole derivatives was investigated by the modified Koster test in mice. No obvious relationships between analgesic activity and the nature of the substituent on the styryl group was found.

Full text of DOI:10.1211/146080899128734532

Pharm. Pharmacol. Commun. 1999, 5: 103±106
Received September 14, 1998
Accepted November 3, 1998
# 1999 Pharm. Pharmacol. Commun.
Synthesis and Analgesic Activity of 1-(1-Piperidinyl)methyl-2-
(4-substituted styryl)-5-chlorobenzimidazole Derivatives
BILGE CAKIR, SERMIN UZUNOGLU, ALI ULVI TOSUN AND M. FETHI SAHIN
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey
Abstract
Seven 1-(1-piperidinyl)methyl-2-(4-substituted styryl)-5-chlorobenzimidazole derivatives
were synthesized by the reaction of 2-(p-substituted styryl)-5-chlorobenzimidazoles with
formaldehyde and piperidine in methanol. Analgesic activity of the 1-(1-piperidinyl)-
methyl-2-(4-substituted styryl)-5-chlorobenzimidazole derivatives was investigated by the
modi®ed Koster test in mice. No obvious relationships between analgesic activity and the
nature of the substituent on the styryl group was found.
Benzimidazoles bearing an o- or p-substituted
phenyl moiety at position 2 have a wide spectrum
of biological activity including antihelmintic, anti-
fungal, antituberculous and anti-in¯ammatory
with formaldehyde (formalin 35%) and piperidine
in methanol at 30±35ꢀC (Bahadur et al 1976). The
synthetic route is shown in Figure 1.
activity (Dandegaonker
& Daulatabad 1967;
Fuveau 1972; Garuti et al 1987; Vishnevskii 1987).
It is well known that alkylaminoalkyl groups at
Materials and Methods
position
1 of 2-benzylbenzimidazoles confer
analgesic activity to these derivatives (Hunger et al
1960). It was reported that some 1-substituted-2-
styrylbenzimidazole derivatives also had signi®cant
analgesic, anti-in¯ammatory and antispasmodic
activity (Hoffmann & Hunger 1962; Kamissarov et
al 1982). These ®ndings have prompted us to syn-
Chemistry
4-Chloro-o-phenylenediamine, p-substituted ben-
zaldehydes, acetic anhydride, glacial acetic acid,
ammonia, hydrochloric acid, piperidine and for-
maldehyde were all from Merck.
Melting points were determined on an Electro-
thermal-9200 Digital Melting Point Apparatus and
are uncorrected.
thesize
1-(1-piperidinyl)methyl-2-(4-substituted
styryl)-5-chlorobenzimidazole derivatives, and
investigate their analgesic activity.
The classic Phillips method was used to prepare
5-chloro-2-methylbenzimidazole (1). As 4 M
hydrochloric acid was used, the yield increased
signi®cantly. This ®nding is also in accordance
with the literature (Weidenhagen 1936; Isikdag et
al 1989).
The synthesis of 5-chloro-2-styrylbenzimida-
zoles, 2a±g was achieved by re¯uxing 1 and p-
substituted benzaldehydes in acetic anhydride for
30 h. The reaction mixture was then poured into
ice-water and neutralized with concentrated
ammonia (Sullivan 1970; Tosun et al 1996). Man-
nich derivatives were prepared by stirring 2a±g
IR spectra were recorded on Perkin Elmer 1330 IR
SpectrophotometerusingtheKBrdiscmethodand1H
NMR spectra were recorded on Bruker 400 MHz
Spectrometer in d6-DMSO:CDCl3 (1:2) using tetra-
methylsilane as an internal standard. Elemental ana-
lyses were made with Leco Model-932 Elemental
Analyzer (Microanalytical Unit, Tubitak Research
Center, Ankara, Turkey). Where analyses are indi-
cated by symbols, the analytical results were within
the range of Æ 0Á4% of the theoretical values.
Synthesis
2-Methyl-5-chlorobenzimidazole (1) (Isikdag et al
1989). A mixture of 4-chloro-o-phenylenediamine
(5Á7 g; 0Á04 mol) and glacial acetic acid (3Á6 g;
0Á06 mol) in 50 mL 4 M hydrochloric acid solution
was re¯uxed for 6 h, cooled and neutralized with
Correspondence: B. Cakir, Department of Pharmaceutical
Chemistry, Faculty of Pharmacy, Gazi University, 06330
Ankara, Turkey.

104
BILGE CAKIR ET AL
dride and the ®nal solution was re¯uxed for 30 h.
The reaction mixture was poured into ice-water and
neutralized with ammonia. The crude precipitate
was ®ltered and crystallized from ethanol.
1-(1-Piperidinyl)methyl-2-(4-substituted styryl)-5-
chlorobenzimidazole hydrochlorides 3a±g. Com-
pound 2 (0Á002 mol), formaldehyde (0Á006
mol) and piperidine (0Á004 mol) were dissolved in
30 mL methanol and the mixture was stirred for 2 h
at 30±35ꢀC. The solvent was removed in a rotatory
evaporator. The residue was treated with metha-
nolic hydrochloride. The precipitate was ®ltered
and crystallized from methanol. The yields, melting
points and elemental analyses of title compounds
are given in Table 1.
Biology
Analgesic activity. Albino mice (local strain), 20±
25 g, were used. Eight animals were used in each
group. The animals were allowed to acclimatize to
the room conditions for two days, and were main-
tained on standard pellet diet and water. Food was
withdrawn on the day before the experiment but
free access to water was maintained.
Figure 1. Synthesis of 1-(1-piperidinyl)methyl-2-(4-substi-
tuted styryl)-5-chlorobenzimidazole derivatives.
ammonia. The brown precipitate was ®ltered and
crystallized from ethanol.
The modi®ed Koster test (Boisser & Simon 1966;
Gyires & Torma 1984) was used. Aspirin was used
as the reference drug. Each compound was sus-
pended in 0Á5% aqueous carboxymethyl cellulose
2-(4-Substituted styryl)-5-chlorobenzimidazoles
2a±g (Uzunoglu et al 1997). Compound 1 (1 g;
0Á006 mol) and an appropriate benzaldehyde
(0Á006 mol) were dissolved in 20 mL acetic anhy-
1
and given orally to mice at 100 mg kg dose. One
hour after administration, pain was induced by
intraperitoneal injection of a 3% solution of acetic
Table 1. Yield, melting points and elemental analysis of 1-(1-piperidinyl)methyl-2-(4-substituted styryl)-5-chlorobenzimidazole
hydrochloride derivatives.
Elemental analysis
Compound
R
Yield (%)
Mp (ꢀC)
Calculated
H
Found
H
C
N
C
N
3a (C21H23N3Cl2)
3b (C21H23N3Cl2O)
3c (C21H22N3Cl3)
3d (C21H22N4Cl2O2)
3e (C22H25N3Cl2)
3f (C22H25N3Cl2O)
3g (C23H27N3Cl2O)
H
OH
Cl
NO2
CH3
OCH3
OC2H5
57
63
70
85
68
75
78
245±246
256±258
222±224
212±213
234±236
192±194
142±144
64Á95
62Á38
59Á65
58Á20
65Á67
63Á15
63Á88
5Á97
5Á73
5Á24
5Á11
6Á28
6Á02
6Á29
10Á82
10Á39
9Á94
65Á04
62Á24
59Á53
58Á36
65Á81
63Á27
64Á03
5Á88
5Á67
5Á37
5Á19
6Á31
5Á93
6Á18
10Á76
10Á46
10Á02
12Á89
10Á33
9Á92
12Á92
10Á44
10Á04
9Á71
9Á65

SYNTHESIS OF NEW CHLOROBENZIMIDAZOLE DERIVATIVES
1
105
1-(1-Piperidinyl)methyl-2-(4-methylstyryl)-5-chloro-
benzimidazole hydrochloride (3e)
acid at a dose of 300 mg kg . The control group
received carboxymethyl cellulose 1 h before injec-
tion of acetic acid. Each animal was placed in a
separate cage 5 min after acetic acid injection and
the number of abdominal constrictions per animal
was recorded during the following 10-min period.
Percent analgesic activity was calculated using the
formula:
1
‡
IR n (cm ): 3390 (N -H); 1H NMR d (ppm): 9Á45
‡
(s, 1H, N -H), 7Á83±7Á32 (m, 9H, Ar-H), 3Á07 (s,
2H, N-CH2 -N), 2Á58 (t, 4H, piperidine C2,6 -H),
2Á14 (s, 3H, Ar -CH3), 1Á87 (m, 4H, piperidine C3,5
-H), 1Á65 (m, 2H, piperidine C4 -H).
analgesic activity ꢁ%† ˆ ꢁꢁn n1†=n†  100
where n ˆ average number of constrictions of
control group n1 ˆ average number of constrictions
of test group.
Acetylsalicylic acid was used as the reference
compound and administered according to the test
protocol.
1-(1-Piperidinyl)methyl-2-(4-methoxystyryl)-5-
chlorobenzimidazole hydrochloride (3f)
1
‡
IR n (cm ): 3370 (N -H); 1H NMR d (ppm): 9Á32
‡
(s, 1H, N -H), 7Á88±7Á38 (m, 9H, Ar-H), 3Á72 (s,
3H, Ar -OCH3), 3Á09 (s, 2H, N-CH2 -N), 2Á62 (t,
4H, piperidine C2,6 -H), 1Á83 (m, 4H, piperidine
C3,5 -H), 1Á68 (m, 2H, piperidine C4 -H).
1-(1-Piperidinyl)methyl-2-(4-ethoxystyryl)-5-chloro-
benzimidazole hydrochloride (3g)
Results and Discussion
1
‡
1
Spectral data of the compounds synthesized are
given.
IR n (cm ): 3335 (N -H); H NMR d (ppm):
1
‡
10Á08 (s, H, N -H), 8Á12±7Á36 (m, 9H, Ar-H),
4Á32 (q, 2H, Ar -O-CH2 -CH3), 3Á28 (s, 2H, N-CH2
-N), 2Á64 (t, 4H, piperidine C2,6 -H), 1Á86 (m, 4H,
piperidine C3,5 -H), 1Á61 (m, 2H, piperidine C4 -H),
1Á37 (t, 3H, Ar -O-CH2 -CH3).
1-(1-Piperidinyl)methyl-2-styryl-5-chlorobenzimi-
dazole hydrochloride (3a)
1
‡
IR n (cm ): 3300 (N -H); 1H NMR d (ppm): 9Á38
‡
(s, 1H, N -H), 7Á92±7Á05 (m, 10H, Ar-H), 3Á12 (s,
2H, N-CH2 -N), 2Á66 (t, 4H, piperidine C2,6 -H),
1Á84 (m, 4H, piperidine C3,5 -H), 1Á63 (m, 2H,
piperidine C4 -H).
Results of the analgesic activity test are given as
the percentage inhibition of abdominal constriction
in Table 2.
Compounds 3a, 3b and 3e exhibited lower
analgesic activity than aspirin, compounds 3d and
3f were almost as potent and compounds 3c and 3g
had higher analgesic activity. Compounds 3a, 3c,
3d and 3g also caused drowsiness in the experi-
mental animals. This could provide evidence for
their mode of antinociceptive activity which is not
known at present. Further investigation of these
derivatives is therefore necessary. No obvious
relationships between analgesic activity and the
nature of the substituent on the styryl group was
found.
1-(1-Piperidinyl)methyl-2-(4-hydroxystyryl)-5-
chlorobenzimidazole hydrochloride (3b)
1
‡
1
IR n (cm ): 3320 (N -H); H NMR d (ppm):
‡
12Á83 (s, 1H, OH), 9Á27 (s, 1H, N -H), 7Á78±6Á93
(m, 9H, Ar-H), 3Á18 (s, 2H, N-CH2 -N), 2Á54 (m,
4H, piperidine C2,6 -H), 1Á81 (m, 4H, piperidine
C3,5 -H), 1Á64 (m, 2H, piperidine C4 -H).
1-(1-Piperidinyl)methyl-2-(4-chlorostyryl)-5-chloro-
benzimidazole hydrochloride (3c)
1
‡
IR n (cm ): 3380 (N -H); 1H NMR d (ppm): 9Á18
‡
(s, 1H, N -H), 8Á21±7Á23 (m, 9H, Ar-H), 3Á09 (s,
1
Table 2. Analgesic activity of 100 mg kg 1-
(1-piperidinyl)methyl-2-(4-substituted styryl)-5-
chlorobenzimidazole hydrochloride derivatives.
2H, N-CH2 -N), 2Á57 (t, 4H, piperidine C2,6 -H),
1Á78 (m, 4H, piperidine C3,5 -H), 1Á62 (m, 2H,
piperidine C4 -H).
Compound
Activity (%)
1-(1-Piperidinyl)methyl-2-(4-nitrostyryl)-5-chloro-
benzimidazole hydrochloride (3d)
3a
3b
3c
3d
3e
3f
3g
25Á6
24Á2
78Á1
37Á3
11Á3
41Á7
77Á5
40Á8
1
‡
IR n (cm ): 3310 (N -H); 1H NMR d (ppm): 9Á18
‡
(s, 1H, N -H), 7Á92±7Á21 (m, 9H, Ar-H), 3Á09 (s,
2H, N-CH2 -N), 2Á61 (t, 4H, piperidine C2,6 -H),
1Á81 (m, 4H, piperidine C3,5 -H), 1Á65 (m, 2H,
piperidine C4 -H).
Aspirin

106
BILGE CAKIR ET AL
Hoffmann, K., Hunger, A. (1962) Analgesic and anti-in¯am-
Acknowledgements
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This study was ®nancially supported by the Turkish
Scienti®c and Technical Research Institute,
Ankara, Turkey . Soc. (SBAG-AYD=117)
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