Angiotensin II - AT1 receptor antagonists: Design, synthesis and evaluation of substituted carboxamido benzimidazole derivatives

Article abstract of DOI:10.1016/j.ejmech.2007.11.008

A series of 5-(alkyl and aryl)carboxamido benzimidazole derivatives had been designed, synthesized and evaluated for in vitro angiotensin II - AT₁ receptor antagonism and in vivo antihypertensive activities. The pharmacological activities were inversely related to the size of alkyl and aryl substituents. It can be suggested that compounds with lower alkyl groups at 5-position of benzimidazole nucleus demonstrated potent antihypertensive activity.

Full text of DOI:10.1016/j.ejmech.2007.11.008

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 43 (2008) 1808e1812
http://www.elsevier.com/locate/ejmech
Original article
Angiotensin II e AT1 receptor antagonists: Design, synthesis and
evaluation of substituted carboxamido benzimidazole derivatives
*
Dhvanit I. Shah, Manu Sharma, Yogita Bansal, Gulshan Bansal , Manjeet Singh
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, 147 002 Punjab, India
Received 22 February 2007; received in revised form 15 November 2007; accepted 16 November 2007
Available online 22 November 2007
Abstract
A series of 5-(alkyl and aryl)carboxamido benzimidazole derivatives had been designed, synthesized and evaluated for in vitro angiotensin II e
AT1 receptor antagonism and in vivo antihypertensive activities. The pharmacological activities were inversely related to the size of alkyl and aryl
substituents. It can be suggested that compounds with lower alkyl groups at 5-position of benzimidazole nucleus demonstrated potent antihyper-
tensive activity.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: Benzimidazole; Carboxamido; AT1 receptor antagonists; Receptor surface model; Antihypertensive
1. Introduction
demonstrated an increase in activity with appropriate substitu-
ent at 5-position [7]. Therefore, we hypothesized that exten-
sion of chemical group at 5-position may occupy either L3
pocket or some additional pocket in the receptor to increase
antihypertensive activity. We designed N-(alkyl and aryl)car-
bonyl derivatives 6 of 5 with expectations that alkyl or aryl
residues of 6 may not reach L3 pocket. A receptor surface
model generated for 1,2,4-triazol-3-one based AT1 antagonist
7 (Fig. 1) reveals that large lipophillic residue at 2-position
of the triazolone nucleus is responsible for binding through
van der Wal and electrostatic interactions with the pocket on
receptor surface [8]. A previous study has identified a similar
pocket in AT1 receptor (L4 in Fig. 2B) interacting with benzi-
midazolyl moiety of 2 in a GRID plot obtained by 3D-QSAR
correlation through GOLPE procedure [9]. The amino acids
responsible for interactions of different AT1 antagonists with
the receptor have been established by various homology mod-
eling and docking studies [10,11]. Therefore, we expected that
5-alkyl or aryl residues of 6 can be accommodated in L4 due
to lipophilic interactions with tyrosine, histidine, tryptophan
and leucine. Hence, the present study has been undertaken
to synthesize 5-(substituted carboxamido) benzimidazole de-
rivatives 6ae6g and evaluate their antihypertensive activities
taking 1 and 2 as reference compounds.
Angiotensin II (Ang II) AT1 receptor antagonists like losar-
tan 1 and candesartan 2 (Fig. 1) are preferred antihyperten-
sives due to their better therapeutic spectrum and fewer side
effects [1e3]. Sartans are appropriately substituted heterocy-
clic head coupled through a methylene linker to pendent
biphenyl system bearing an acidic function; viz. candesartan
is an effective competitive Ang II antagonist with benzimid-
azole nucleus as the heterocyclic head [4]. The substituent at
6-position on the nucleus increases the activity whereas small
substituent at 5-position decreases the activity [5]. Compounds
containing triazole nucleus are also reported as AT1 receptor
antagonists and their protypical derivative 3 exhibits non-com-
petitive antagonism [6]. The 5-substituted benzimidazole de-
rivatives 4 and 5 (Fig. 1) were designed and synthesized
earlier by our laboratory in which 5-nitro derivatives 4 were
found to be more potent than 2 whereas the corresponding
amino derivatives 5 were less potent than 2 but more potent
than 1 [7]. Further, extended binding profile (Fig. 2A)
* Corresponding author. Tel.: þ91 175 3046255; fax: þ91 175 2283073.
E-mail address: gulshanbansal@rediffmail.com (G. Bansal).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.11.008

D.I. Shah et al. / European Journal of Medicinal Chemistry 43 (2008) 1808e1812
1809
Fig. 1. Angiotensin II e AT1 receptor antagonists.
2. Results and discussion
acylating reagents was performed to synthesize target com-
pounds. Compounds 6a and 6b were prepared by reaction of
5 with acetic anhydride and propionic anhydride, respectively,
whereas compounds 6ce6g were prepared by reacting 5 with
butanoyl chloride, pentanoyl chloride, benzoyl chloride, 2-
chloro benzoyl chloride and 4-chloro benzoyl chloride, respec-
tively. Each compound was purified by crystallization and
purity was ascertained by chromatographic techniques. The
compounds were characterized on the basis of spectral
evidences.
2.1. Chemistry
The synthetic route described in Fig. 3 was employed to
synthesize the target compounds 6ae6g. The key intermediate
5 was prepared by coupling of 2-n-butyl benzimidazole nu-
cleus (II) with pendent biphenyl moiety (V) followed by nitra-
tion, and subsequent reduction of the nitro group as reported
earlier [7]. Further, acylation of amino group with different
Fig. 2. Extended binding profile (A) where L3 can accommodate a bulky substituent at 6-position, B/H acts either as a basic or H-bond donor site for 5-substituent
while Ar/R may find another pocket and a drug-receptor interaction model (B) showing accommodation of 5-substituent of 6 in L4.

1810
D.I. Shah et al. / European Journal of Medicinal Chemistry 43 (2008) 1808e1812
Fig. 3. Synthetic scheme (i) pentanoic acid, reflux, 6 h; (ii) H2SO4, HNO3, 0e5 ꢁC, 10 h; (iii) KOH, 180e200 ꢁC, dil. HCl; (iv) acetamide, paraformaldehyde,
H2SO4, heat, stirring; (v) POCl3, xylene, DMF, reflux; (vi) pyridine; (vii) Zn/NaOH, reflux, 3 h (viii) Method A or Method B as in Section 4.
2.2. Pharmacological evaluation
lipophillic group (methyl) can be accommodated without af-
fecting interaction of eNHe of 5-substituent with L4 pocket
which is limited mainly by Tyr292, His256, Try253 and Leu112
(Fig. 2B). The gradual decrease in activity from compound
6c to 6g can be attributed to overfilling and/or unfavorable ste-
ric interactions of lipophilic and bulky tyrosine, histidine and
tryptophan residues of L4 with longer alkyl groups.
2.2.1. Antagonism of angiotensin II receptor
The antagonistic activity of compounds 6ae6g was deter-
mined on isolated rat aortic ring using force transducers and
BIOPAC four channel recorder systems (BIOPAC systems
INC., Santa Barbara, CA, USA). Linear regression was em-
ployed to plot the dose response curve between the developed
tension and negative molar concentration of angiotensin II.
Paired student’s ‘t’ test was employed for statistical analysis.
The antagonistic activity was expressed as pA2 values
(Table 1). The pA10 values were also determined to establish
the mode of antagonism [12]. Comparison of the pA2 and
pA10 values indicates that 6ae6d are non-competitive antago-
nists (pA2 ꢀ pA10 > 1) whereas the other compounds are com-
petitive antagonists (pA2 ꢀ pA10 < 1). The antagonistic
potential of targeted compounds 6ae6g was wide ranging
(6a > 6b [ 6c > 6e > 6f > 6d > 6g). Compounds 6a and 6b
are more potent whereas 6ce6g are less potent in comparison
to 1 and 2. The activity of 6a was superior to 1 and 5 but
equivalent to 2 whereas the activity of 6b is better than 1
but equivalent to 5. However, the activity decreases with in-
crease in bulk of the alkyl/aryl residues. It suggests that a small
Table 1
Pharmacological activity of the target and the reference compounds
Compound pA2
(mg kgꢀ1
pA10
Decrease in MABP pA2 ꢀ Mode of
)
(mm of Hg)
pA10
antagonism
6a (3)
6b (3)
6c (3)
6d (3)
6e (3)
6f (3)
6g (3)
5 (3)
8.0 ꢂ 0.31 5.9 ꢂ 0.27 33.5 ꢂ 1.4*,**,*** 2.1
NC
NC
NC
NC
C
7.7 ꢂ 0.26 4.7 ꢂ 0.19 36.2 ꢂ 1.9
7.1 ꢂ 0.24 4.4 ꢂ 0.21 26.4 ꢂ 0.8
6.4 ꢂ 0.25 3.7 ꢂ 0.12 21.7 ꢂ 0.7
6.6 ꢂ 0.29 6.0 ꢂ 0.31 19.8 ꢂ 0.6
6.5 ꢂ 0.25 5.8 ꢂ 0.28 20.3 ꢂ 0.9
6.2 ꢂ 0.28 5.4 ꢂ 0.23 12.0 ꢂ 0.4
7.8 ꢂ 0.22 7.0 ꢂ 0.25 33.3 ꢂ 1.2
7.4 ꢂ 0.34 6.5 ꢂ 0.30 29.7 ꢂ 1.1
8.0 ꢂ 0.29 7.1 ꢂ 0.26 31.8 ꢂ 1.3
3.0
2.7
2.7
0.6
0.7
0.8
0.8
0.9
0.9
C
C
C
1 (5)
2 (5)
C
C
All values (n ¼ 6) represent mean ꢂ SEM; NC, non-competitive; C, competi-
tive; *p < 0.05 vs 5; **p < 0.05 vs 1; ***p < 0.05 vs 2.

D.I. Shah et al. / European Journal of Medicinal Chemistry 43 (2008) 1808e1812
1811
2.2.2. Antihypertensive activity
compounds (6ae6g) were prepared by acylation using one of
the two following methods.
Hypertension in rats was induced by desoxycortisone ace-
tate (40 mg kgꢀ1, s.c.) and mean arterial blood pressure
(MABP) was measured by cannulating carotid artery [13] to
pressure transducer attached to BIOPAC systems. The stan-
dardization of in vivo dose was done by administering com-
pound 5 in dose range of 0.1, 0.3, 1.0, 3.0, 10.0 and
30.0 mg kgꢀ1 intraperitonealy. The plateau effect was produced
at doses of 3.0, 10.0 and 30.0 mg kgꢀ1, and hence the other
compounds (6) were evaluated at doses of 1.0, 3.0 and
10.0 mg kgꢀ1. The antihypertensive activity was measured as
a decrease in MABP (mm of Hg) taking 1 and 2 as reference
compounds (Table 1). The data were statistically analyzed by
performing one way analysis of variance followed by tukey’s
multiple range test and p < 0.05 was considered to be statistical
significant. The antihypertensive activity is found to correspond
to the in vitro activity for each compound except for 6a and 6b.
The antihypertensive activity of 6a is equivalent to that of 5.
Though antagonistic activity of 6b is less than that of 6a, but
decrease in MABP is found to be the maximum with 6b. This
deviation may be attributed to minor increase in bulk due to
ethyl group. The latter may decrease the drugereceptor interac-
tion due to steric hindrance leading to decreased in vitro activ-
ity but on the other hand it can be favorable to optimum
partitioning in body fluids leading to better in vivo activity.
Method A: Acetylating agent (0.1 M) was added to a mix-
ture of 5 (0.015 M) and 1 ml of conc. H2SO4 in a round bottom
flask (RBF). The reaction mixture was refluxed for 45 min and
subsequently boiled to remove excess of the acetylating agent.
The contents were cooled to room temperature and poured in
ice chilled water. The product was separated as white lumps
which were recrystallized from ethanol to produce the product
as white crystals.
Method B: Acyl chloride (0.1 M) was added drop wise from
a dropping funnel over 15 min with stirring to a solution of 5
(0.015 M) and 50 ml of 20% NaOH in 250 ml RBF. The stir-
ring was continued at 60 ꢁC for another 30 minutes and the re-
sulting solid product was recrystallized from hot ethanol to
produce white needle shaped crystals.
4.1. 40-(5-Acetylamino-2-butyl-benzoimidazol-1-
ylmethyl)-biphenyl-2-carboxylic acid (6a)
The compound was prepared by Method A using acetic anhy-
dride as acetylating agent. Yield 48%, m.p. 168e170 ꢁC, IR
(KBr): 3600e2900 (OeH and NeH); 1702 (CaO); 1578 (Am-
ide II). Anal. Calcd for C27H27N3O3: C, 73.45; H, 6.16; N, 9.52.
Found: C, 72.61; H, 6.11; N, 8.65. dH (300 MHz, CDCl3) 0.95
(t, 3H, J ¼ 8 Hz, CH2CH2CH2CH3); 1.46 (sx, 2H, J ¼ 8 Hz,
CH2CH2CH2CH3); 2.01 (qv, 2H, J ¼ 8 Hz, CH2CH2CH2CH3);
2.16 (s, 2H, CH2); 2.41 (s, 3H, NHCOCH3); 3.38 (t, 2H,
J ¼ 8 Hz, CH2CH2CH2CH3); 7.39e7.42 (m, 3H, ArH); 7.46
(d, 2H, J ¼ 6 Hz, ArH); 7.92 (d, 1H, J ¼ 6 Hz, ArH); 8.04e
8.17 (m, 3H, ArH); 8.38 (dd, 1H, J ¼ 8 Hz; 2 Hz, ArH); 8.72
(d, 1H, J ¼ 2 Hz, ArH); 9.41 (b, 1H, COOH ); 9.12 (b, 1H,
CONH ). MS (ESI): 442 (M þ 1).
3. Conclusion
Substitution at 5-amino group on benzimidazole nucleus
with diverse alkylcarbonyl chains produced AT1 antagonists
with wide-ranging activities. An alkyl group, not longer than
methyl, can be accommodated in the L4 pocket. The antihy-
pertensive activity can be increased by selecting an appropri-
ate alkyl group so that optimum in vivo partitioning of the
molecule is achieved without significant effect on the H-bond-
ing interaction of eNHe with L4 pocket. In the present study,
compound 6b bearing ethyl group exhibits better antihyperten-
sive activity than the in vitro AT1 receptor antagonism.
4.2. 40-(2-Butyl-5-propionylamino-benzoimidazol-1-
ylmethyl)-biphenyl-2-carboxylic acid (6b)
The compound was prepared by Method A using propionic
anhydride as acetylating agent. Yield 47%, m.p. 171e173 ꢁC,
IR (KBr): 3600e2900 (OeH and NeH); 1706 (CaO); 1576
(Amide II). Anal. Calcd for C28H29N3O3: C, 73.82; H, 6.42;
N, 9.22. Found: C, 72.88; H, 6.29; N, 8.89. dH (300 MHz,
CDCl3) 0.95 (t, 3H, J ¼ 8 Hz, CH2CH2CH2CH3); 1.46 (sx,
2H, J ¼ 8 Hz, CH2CH2CH2CH3); 2.01 (qv, 2H, J ¼ 8 Hz,
CH2CH2CH2CH3); 2.06 (s, 2H, CH2); 2.41 (q, 2H, J ¼ 7 Hz,
NHCOCH2CH3); 2.45 (t, 3H, J ¼ 7 Hz, NHCOCH2CH3); 3.38
(t, 2H, J ¼ 8 Hz, CH2CH2CH2CH3); 7.39e7.42 (m, 3H, ArH);
7.45 (d, 2H, J ¼ 6 Hz, ArH); 7.95 (d, 1H, J ¼ 6 Hz, ArH);
8.04e8.15 (m, 3H, ArH); 8.35 (dd, 1H, J ¼ 8 Hz; 2 Hz, ArH);
8.77 (d, 1H, J ¼ 2 Hz, ArH); 9.41 (b, 1H, COOH ); 9.19 (b,
1H, CONH ). MS (ESI): 456 (M þ 1).
4. Experimental
The melting points were recorded in open sulfuric acid bath
1
and uncorrected. H NMR spectra were recorded on Bruker
AC 30 NMR Spectrometer (300 MHz), mass spectra were re-
corded on Vg Micro Mass 7070F spectrometer and GCeMS
(Gcq) Spectrometer and FT-IR spectra were recorded on FT-
IR Perkin-Elmer 1710 series. In 1H NMR, chemical shifts
were reported in d values using tetramethylsilane as internal
standard with multiplicities (br-broad, s-singlet, d-doublet, t-
triplet, q-quartet, m-multiplet, dd-double doublet) and number
of protons in the solvent indicated. The coupling constants (J )
were expressed in Hz. IR spectra were recorded as KBr pellets.
The elemental analyses were performed on Heraus CHNeO
rapid elemental analyzer. When necessary, solvents and re-
agents were dried prior to use over KOH or anhydrous
Na2SO4 or fused CaCl2. The intermediates IeV, 4 and 5
were prepared as described in our earlier report [7]. The target
4.3. 40-(2-Butyl-5-butyrylamino-benzoimidazol-1-
ylmethyl)-biphenyl-2-carboxylic acid (6c)
The compound was prepared by Method B using butanoyl
chloride. Yield 44%, m.p. 174e176 ꢁC, IR (KBr): 3600e2900

1812
D.I. Shah et al. / European Journal of Medicinal Chemistry 43 (2008) 1808e1812
(OeH and NeH); 1705 (CaO); 1577 (Amide II). Anal. Calcd
for C29H31N3O3: C, 74.18; H, 6.65; N, 8.95. Found: C, 73.08;
H, 6.54; N, 8.72. dH (300 MHz, CDCl3) 0.94e0.98 (m, 6H,
CH2CH2CH2CH3 and NHCOCH2CH2CH3); 1.46 (sx, 2H,
J ¼ 8 Hz, CH2CH2CH2CH3); 1.88 (sx, 2H, J ¼ 7 Hz,
NHCOCH2CH2CH3); 2.01 (qv, 2H, J ¼ 8 Hz, CH2CH2
CH2CH3); 2.06 (s, 2H, CH2); 2.47 (t, 2H, J ¼ 7 Hz,
NHCOCH2CH2CH3); 3.38 (t, 2H, J ¼ 8 Hz, CH2CH2CH2CH3);
7.37e7.41 (m, 3H, ArH); 7.43 (d, 2H, J ¼ 6 Hz, ArH); 7.94 (d,
1H, J ¼ 6 Hz, ArH); 8.05e8.14 (m, 3H, ArH); 8.33 (dd, 1H,
J ¼ 8 Hz; 2 Hz, ArH); 8.74 (d, 1H, J ¼ 2 Hz, ArH); 9.56 (b,
1H, COOH ); 9.21 (b, 1H, CONH ). MS (ESI): 470 (M þ 1).
CDCl3) 0.95 (t, 3H, J ¼ 8 Hz, CH2CH2CH2CH3); 1.46 (sx,
2H, J ¼ 8 Hz, CH2CH2CH2CH3); 2.01 (qv, 2H, J ¼ 8 Hz,
CH2CH2CH2CH3); 2.09 (s, 2H, CH2); 3.38 (t, 2H, J ¼ 8 Hz,
CH2CH2CH2CH3); 7.35e7.39 (m, 5H, ArH); 7.53e7.56 (m,
2H, ArH); 8.00 (d, 2H, J ¼ 7 Hz, ArH); 8.09 (d, 4H,
J ¼ 7 Hz, ArH); 8.35 (dd, 1H, J ¼ 8 Hz; 3 Hz, ArH); 8.76 (d,
1H, J ¼ 3 Hz, ArH); 9.43 (b, 1H, COOH ); 9.19 (b, 1H,
CONH ). MS (ESI): 538 (M þ 1).
4.7. 40-[2-Butyl-5-(4-chloro-benzoylamino)-benzoimidazol-
1-ylmethyl]-biphenyl-2-carboxylic acid (6g)
4.4. 40-(2-Butyl-5-pentanoylamino-benzoimidazol-1-
ylmethyl)-biphenyl-2-carboxylic acid (6d)
The compound was prepared by Method B using 4-chloro-
benzoyl chloride. Yield 49%, m.p. 175e177 ꢁC, IR (KBr):
3600e2900 (OeH and NeH); 1687 (CaO); 1538 (Amide
II). Anal. Calcd for C32H28ClN3O3: C, 71.43; H, 5.25; N,
7.81. Found: C, 70.26; H, 5.09; N, 7.67. dH (300 MHz,
CDCl3) 0.94 (t, 3H, J ¼ 8 Hz, CH2CH2CH2CH3); 1.45 (sx,
2H, J ¼ 8 Hz, CH2CH2CH2CH3); 2.04 (qv, 2H, J ¼ 8 Hz,
CH2CH2CH2CH3); 2.12 (s, 2H, CH2); 3.39 (t, 2H, J ¼ 8 Hz,
CH2CH2CH2CH3); 7.36e7.39 (m, 4H, ArH); 7.46e7.53 (m,
2H, ArH); 7.97e8.06 (m, 4H, ArH); 8.14e8.17 (m, 3H,
ArH); 8.48 (dd, 1H, J ¼ 8 Hz; 3 Hz, ArH); 8.72 (d, 1H,
J ¼ 3 Hz, ArH); 9.43 (b, 1H, COOH ); 9.21 (b, 1H, CONH ).
MS (ESI): 538 (M þ 1).
The compound was prepared by Method B using pentanoyl
chloride. Yield 46%, m.p. 176e178 ꢁC, IR (KBr): 3600e2850
(OeH and NeH); 1707 (CaO); 1576 (Amide II). Anal. Calcd
for C30H33N3O3: C, 74.51; H, 6.88; N, 8.69. Found: C, 73.18;
H, 6.76; N, 8.52. dH (300 MHz, CDCl3) 0.97e1.02 (m, 6H,
CH2CH2CH2CH3 and NHCOCH2CH2CH2CH3); 1.44e1.51
(m, 4H, CH2CH2CH2CH3 and NHCOCH2CH2CH2CH3);
1.97 (qv, 2H, J ¼ 8 Hz, CH2CH2CH2CH3); 2.08 (qv, 2H,
J ¼ 7 Hz, NHCOCH2CH2CH2CH3); 2.13 (s, 2H, CH2); 2.51
(t, 2H, J ¼ 7 Hz, NHCOCH2CH2CH2CH3); 3.38 (t, 2H,
J ¼ 8 Hz, CH2CH2CH2CH3); 7.35e7.42 (m, 3H, ArH); 7.44
(d, 2H, J ¼ 6 Hz, ArH); 7.96 (d, 1H, J ¼ 6 Hz, ArH); 8.04e
8.12 (m, 3H, ArH); 8.31 (dd, 1H, J ¼ 8 Hz; 2 Hz, ArH);
8.72 (d, 1H, J ¼ 2 Hz, ArH); 9.49 (b, 1H, COOH ); 9.22 (b,
1H, CONH ). MS (ESI): 484 (M þ 1).
References
[1] J.V. Duncia, A.T. Chiu, D.J. Carini, G.B. Gregory, A.L. Johnson,
P.B.M.W.M. Timmermans, J. Med. Chem. 33 (1990) 1312e1329.
[2] D.J. Carini, J.V. Duncia, P.E. Aldrich, A.T. Chiu, A.L. Johnson,
M.E. Pierc, W.A. Price, J.B. Santella III, J. Wells, R. Wexler,
C. Wong, S.E. Yoo, P.B.M.W.M. Timmermans, J. Med. Chem. 34
(1991) 2525e2547.
4.5. 40-(5-Benzoylamino-2-butyl-benzoimidazol-1-
ylmethyl)-biphenyl-2-carboxylic acid (6e)
[3] R.R. Wexler, W.J. Greenleen, J.D. Irvin, M.R. Goldberg, K. Prendergast,
R.D. Smith, P.B.M.W.M. Timmermans, J. Med. Chem. 39 (1996) 625e665.
[4] K. Kubo, Y. Kohara, E. Imamiya, Y. Sugiura, Y. Inada, Y. Furukawa,
K. Nishikawa, T. Naka, J. Med. Chem. 36 (1993) 2182e2195.
[5] U.J. Ries, G. Mihm, B. Narr, K.M. Hasselbach, H. Wittneben,
M. Entzreoth, J.C.A. Van Meel, M. Wienen, N.H. Hauel, J. Med.
Chem. 36 (1993) 4040e4051.
The compound was prepared by Method B using benzoyl
chloride. Yield 56%, m.p. 171e173 ꢁC, IR (KBr): 3600e
2900 (OeH and NeH); 1690 (CaO); 1578 (Amide II).
Anal. Calcd for C32H29N3O3: C, 76.32; H, 5.80; N, 8.34.
Found: C, 75.28; H, 5.70; N, 8.19. dH (300 MHz, CDCl3)
0.96 (t, 3H, J ¼ 8 Hz, CH2CH2CH2CH3); 1.49 (sx, 2H,
J ¼ 8 Hz, CH2CH2CH2CH3); 2.02 (qv, 2H, J ¼ 8 Hz,
CH2CH2CH2CH3); 2.13 (s, 2H, CH2); 3.39 (t, 2H, J ¼ 8 Hz,
CH2CH2CH2CH3); 7.33e7.36 (m, 6H, ArH); 7.43 (dd, 2H,
J ¼ 8 Hz; 1 Hz, ArH); 7.96e8.02 (m, 3H, ArH); 8.02e8.09
(m, 4H, ArH); 8.35 (dd, 1H, J ¼ 8 Hz; 1 Hz, ArH); 8.76 (d,
1H, J ¼ 1 Hz, ArH); 9.56 (b, 1H, COOH ); 9.24 (b, 1H,
CONH ). MS (ESI): 504 (M þ 1).
[6] W.T. Ashton, C.L. Cantone, L.L. Chang, S.M. Hutchins, R.A. Strelitz,
M. Maccoss, R.S.L. Chang, V.J. Lotti, K.A. Faust, T. Chen, P. Bunting,
T.W. Schorn, S.D. Kivlighn, P.K.S. Siegel, J. Med. Chem. 36 (1993)
591e609.
[7] A. Bali, Y. Bansal, M. Sugumaran, J.S. Saggu, P. Balakumar, G. Kaur,
G. Bansal, A. Sharma, M. Singh, Bioorg. Med. Chem. Lett. 15 (2005)
3962e3965.
[8] P.A. Datar, P.V. Desai, E.C. Coutinho, J. Chem. Inf. Comput. Sci. 44
(2004) 210e220.
[9] G. Berrllini, G. Cruciani, R. Mannhold, J. Med. Chem. 48 (2005) 4389e
4399.
4.6. 40-[2-Butyl-5-(2-chloro-benzoylamino)-
benzoimidazol-1-ylmethyl]-biphenyl-2-carboxylic acid (6f)
[10] T. Tuccinardi, V. Calderone, S. Rapposelli, A. Martinelli, J. Med. Chem.
49 (2006) 4305e4316.
[11] P. Zoumpoulakis, I. Daliani, M. Zervou, I. Kyrikou, E. Siapi,
G. Lamprindis, E. Mikros, T. Mavromoustakos, Chem. Phys. Lipids
125 (2003) 13e25.
[12] H.O. Schild, Br. J. Pharmacol. Chemother. 2 (1947) 189.
[13] H.C. Stanton, in: A. Schwartz (Ed.), Methods in Pharmacology, vol. 1,
Appleton-Century-Crafts, Meredith Corporation, New York, 1971, pp.
125e150.
The compound was prepared by Method B using 2-chloro-
benzoyl chloride. Yield 49%, m.p. 175e177 ꢁC, IR (KBr):
3600e2900 (OeH and NeH); 1695 (CaO); 1577 (Amide
II). Anal. Calcd for C32H28ClN3O3: C, 71.43; H, 5.25; N,
7.81. Found: C, 70.29; H, 5.14; N, 7.69. dH (300 MHz,