Synthesis and angiotensin II receptor antagonistic activities of benzimidazole derivatives bearing acidic heterocycles as novel tetrazole bioisosteres

Article abstract of DOI:10.1021/jm960547h

The design, synthesis, and biological activity of benzimidazole-7- carboxylic acids bearing 5-oxo-1,2,4-oxadiazole, 5-oxo-1,2,4-thiadiazole, 5- thioxo-1,2,4-oxadiazole, and 2-oxo-1,2,3,5-oxathiadiazole rings are described. These compounds were efficiently prepared from the key intermediates, the amidoximes 4. The synthesized compounds were evaluated for in vitro and in vivo angiotensin II (AII) receptor antagonistic activities. Most were found to have high affinity for the AT₁ receptor (IC₅₀ value, 10^-6-10^-7M) and to inhibit the AII-induced pressor response (more than 50% inhibition at 1 mg/kg po). The 5-oxo-1,2,4-oxadiazole, 5-oxo-1,2,4- thiadiazole, and 5-thioxo-1,2,4-oxadiazole derivatives showed stronger inhibitory effects than the corresponding tetrazole derivatives, while their binding affinities were weaker. This might be ascribed to their improved bioavailability by increased lipophilicity. The 5-oxo-1,2,4-oxadiazole derivative 2 (TAK-536) and 5-oxo-1,2,4-thiadiazole derivative 8f showed efficient oral bioavailability without prodrug formation. This study showed that the 5-oxo-1,2,4-oxadiazole ring and its thio analog, the 5-oxo-1,2,4- thiadiazole ring, could be lipophilic bioisosteres for the tetrazole ring in nonpeptide AII receptor antagonists.

Full text of DOI:10.1021/jm960547h

5228
J . Med. Chem. 1996, 39, 5228-5235
Syn th esis a n d An gioten sin II Recep tor An ta gon istic Activities of Ben zim id a zole
Der iva tives Bea r in g Acid ic Heter ocycles a s Novel Tetr a zole Bioisoster es1
Yasuhisa Kohara,* Keiji Kubo, Eiko Imamiya, Takeo Wada, Yoshiyuki Inada, and Takehiko Naka
Pharmaceutical Research Divisions, Pharmaceutical Group, Takeda Chemical Industries, Ltd., 17-85 J uso-honmachi 2-chome,
Yodogawa-ku, Osaka 532, J apan
Received J uly 26, 1996X
The design, synthesis, and biological activity of benzimidazole-7-carboxylic acids bearing 5-oxo-
1,2,4-oxadiazole, 5-oxo-1,2,4-thiadiazole, 5-thioxo-1,2,4-oxadiazole, and 2-oxo-1,2,3,5-oxathia-
diazole rings are described. These compounds were efficiently prepared from the key
intermediates, the amidoximes 4. The synthesized compounds were evaluated for in vitro and
in vivo angiotensin II (AII) receptor antagonistic activities. Most were found to have high
affinity for the AT1 receptor (IC50 value, 10-6-10-7M) and to inhibit the AII-induced pressor
response (more than 50% inhibition at 1 mg/kg po). The 5-oxo-1,2,4-oxadiazole, 5-oxo-1,2,4-
thiadiazole, and 5-thioxo-1,2,4-oxadiazole derivatives showed stronger inhibitory effects than
the corresponding tetrazole derivatives, while their binding affinities were weaker. This might
be ascribed to their improved bioavailability by increased lipophilicity. The 5-oxo-1,2,4-
oxadiazole derivative 2 (TAK-536) and 5-oxo-1,2,4-thiadiazole derivative 8f showed efficient
oral bioavailability without prodrug formation. This study showed that the 5-oxo-1,2,4-
oxadiazole ring and its thio analog, the 5-oxo-1,2,4-thiadiazole ring, could be lipophilic
bioisosteres for the tetrazole ring in nonpeptide AII receptor antagonists.
Ch a r t 1. Structures of CV-11974 (1a ), TCV-116 (1b),
and TAK-536 (2)
In tr od u ction
The renin-angiotensin system (RAS) is known to play
an important role in the regulation of blood pressure
and electrolyte balance.2 Inhibitors of the RAS would
be effective for the treatment of hypertension and
congestive heart failure. Although angiotensin-convert-
ing enzyme (ACE) inhibitors are highly effective and
their use has become well-established for the treatment
of hypertension and congestive heart failure, they suffer
from some side effects such as dry cough and an-
gioedema caused by the nonspecific action of ACE.3 On
the other hand, angiotensin II (AII) (the primary effector
component of the RAS) receptor antagonists block the
RAS at the AII receptor level and are expected to be
more specific and effective agents than ACE inhibitors.
We have already reported the synthesis of benzimi-
dazole-7-carboxylic acid derivatives such as 1a (CV-
11974, candesartan)4 (Chart 1), novel and potent non-
peptide AT1 selective AII receptor antagonists. The
prodrug of 1a , 1b (TCV-116, candesartan cilexetil)5
(Chart 1), is an orally active, highly effective, and long-
acting AII receptor antagonist, and it is now under
clinical trial as an antihypertensive agent. We have
also demonstrated that two acidic moieties are very
important for its highly potent AII receptor antagonistic
activities.6 Our research efforts have been focused on
modification of the heterocyclic moieties (part A)4-7
which are regarded as “templates” arranging three
essential components: a lipophilic substituent, a tetra-
zolylbiphenylmethyl group, and a carboxyl group (Chart
2). As a result, the benzimidazole ring was found to be
one of the most suitable templates.
synthetic, metabolic, and chemical disadvantages. The
synthesis of tetrazole derivatives could be dangerous
due to the use of toxic and explosive azide compounds
such as sodium azide or trialkyltin azide. Recently,
losartan has been reported to be metabolized by N-
glucuronidation on the tetrazole ring, which could
shorten its in vivo duration.8 Furthermore, some AII
receptor antagonists possessing two acidic groups, a
tetrazole ring and a carboxyl group, show low oral
bioavailability because of their highly polar character.
In some cases, prodrug approaches have been used to
improve oral bioavailability.5,9 Replacement of the
tetrazole ring by other more lipophilic acidic groups has
also been used to improve oral bioavailability, which
would also solve the synthetic and metabolic problems.
While many acylsulfonamide moieties have been intro-
duced as bioisosteres of the tetrazole ring in AII receptor
antagonists,10 few heterocyclic moieties have been re-
ported.11 Thus, we started our investigation of replace-
ment of the tetrazole ring by other heterocyclic rings
We turned our attention to search for replacements
of the biphenyl tetrazole moiety, especially the tetrazole
ring (part B), because tetrazole derivatives have some
* Corresponding author: tel, +81-6-300-6120; fax, +81-6-300-6306;
e-mail, Kohara_Yasuhisa@takeda.co.jp.
X Abstract published in Advance ACS Abstracts, November 1, 1996.
S0022-2623(96)00547-X CCC: $12.00 © 1996 American Chemical Society

Synthesis and Activity of Benzimidazole Derivatives
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5229
Ch a r t 2. Our AII Receptor Antagonists
such as a thiazolidinedione ring, reported as a carboxylic
acid bioisostere,12 to find the 5-oxo-1,2,4-oxadiazole ring
(Chart 2).13 In our previous communication,13 we
described the synthesis and biological activities of a
series of 2-substituted benzimidazole-7-carboxylic acids
bearing the 5-oxo-1,2,4-oxadiazole ring which exhibited
AII receptor antagonistic activities comparable to those
of the tetrazole derivatives. The representative com-
pound 1-[[2′-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)-
biphenyl-4-yl]methyl]-2-ethoxy-1H-benzimidazole-7-car-
boxylic acid, 2 (TAK-536) (Chart 1), was as potent and
orally active as 1b (TCV-116). Further studies have
been conducted on the benzimidazole-7-carboxylic acids
with the thio analogs of the 5-oxo-1,2,4-oxadiazole ring
such as 5-oxo-1,2,4-thiadiazole ring, 5-thioxo-1,2,4-oxa-
diazole ring, and 2-oxo-1,2,3,5-oxathiadiazole ring. Here,
we describe the preparation, AII receptor antagonistic
activities, and structure-activity relationship (SAR) of
2-substituted benzimidazole-7-carboxylic acids possess-
ing the thio analogs of the 5-oxo-1,2,4-oxadiazole ring
as well as details of 5-oxo-1,2,4-oxadiazole derivatives.
were hydrolyzed to give the corresponding carboxylic
acids 11a -d ,f-h . In the case of the 2-ethoxy derivative
10e, the carboxylic acid could not be isolated in pure
state because it decomposed during purification.
The 2-oxo-1,2,3,5-oxathiadiazole series (12a ,b ) was
prepared in yields of 10% and 15%, respectively, by
condensation of 4d ,f with thionyl chloride in the pres-
ence of pyridine.16 The corresponding carboxylic acids
could not be obtained in pure state because of their
instability.
P h a r m a cologica l Resu lts a n d Discu ssion
The compounds reported in this paper were evaluated
for their binding affinity to the AII receptor with respect
to inhibition of [125I]AII (0.2 nM) binding to bovine
adrenal cortical membranes as described previously.7
The results are expressed as IC50 values and are listed
in Table 1 alongside some tetrazole derivatives as
references. Most carboxylic acids were found to have
IC50 values of the order of 10-7 M.17 With regard to the
heterocyclic ring (R3), the 5-oxo-1,2,4-thiadiazole (A),
5-thioxo-1,2,4-oxadiazole (B), and 5-oxo-1,2,4-oxadiazole
(D) derivatives were found to be as potent as the
tetrazole (E) derivatives (8d , 11d , 6 vs 15; 8f, 2 vs 1a ).
The effects of varying the side chain (R1) at the 2-posi-
tion of the benzimidazole ring on binding affinity were
also examined. The optimal length of R1 seemed to be
two or three atoms (C, N, O, S) regardless of the nature
of R1 and the heterocyclic rings (R3) (8a -l, 11a -d ,f-
h ). The binding affinities of the esters were generally
inferior to those of the corresponding carboxylic acids
(7d vs 8d ; 7f vs 8f; 10d vs 11d ). These SAR were
similar to those of the 5-oxo-1,2,4-oxadiazole13 and the
tetrazole derivatives previously reported.4,7
Ch em istr y
The compounds prepared for this study are shown in
Table 1, and the synthetic routes are outlined in Scheme
1. All compounds were synthesized from the common
intermediates, amidoximes 4a -l,13 which were prepared
by addition of hydroxylamine to the corresponding cyano
derivatives 3a -l.4,7 The 5-oxo-1,2,4-oxadiazole series
(2, 6) was obtained from 4a ,b by treatment with
2-ethylhexyl chloroformate and cyclization in refluxing
xylene followed by saponification. Compound 2 was
prepared in kilogram scale without column chromato-
graphic purification in this method.
The 5-oxo-1,2,4-thiadiazole series (7a -l) was synthe-
sized by reaction of 1,1′-thiocarbonyldiimidazole (TCDI)
with 4a -l followed by treatment with silica gel or boron
trifluoride diethyl etherate.14 The obtained esters 7a -l
were hydrolyzed to afford the respective carboxylic acids
8a -l.
The 5-thioxo-1,2,4-oxadiazole series (10a -h ) was
prepared from the amidoximes 4a -d ,f,h -j via two
routes.14 According to Birr’s method,15 4a -d were
acetylated with acetic anhydride in the presence of
triethylamine followed by treatment with carbon dis-
ulfide and sodium hydride to give the 5-thioxo-1,2,4-
oxadiazoles 10a-d in yields of 24-55%. Direct 5-thioxo-
1,2,4-oxadiazole ring formation was accomplished in
50-59% yields (10a -h ) by treatment of amidoximes
4f,h -j with TCDI and base. The esters 10a -d ,f-h
Each compound was further evaluated in vivo for
inhibition of the pressor response induced by AII (100
ng/kg iv) in conscious rats,7 and the data are listed in
Table 1. With respect to the heterocyclic ring, the 5-oxo-
1,2,4-thiadiazole (A) derivatives and 5-thioxo-1,2,4-
oxadiazole (B) derivatives showed higher inhibitory
potencies than the tetrazole (E) derivatives (8d , 11d vs
15; 8f vs 1a ). The weaker in vivo activity of 2-oxo-
1,2,3,5-oxathiadiazole (C) derivatives 12a ,b might be
attributable to its instability in the body. Varying R1
had effects similar to those on binding affinity, and the
compounds with the chain length (R1) of two or three
atoms (C, N, O, S) displayed stronger potencies than
those with longer or shorter chains. 2-Alkylamino
derivatives 8k ,l clearly had less potent in vivo activity
than the others despite high binding affinity. The dose

5230 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26
Kohara et al.
Ta ble 1. Inhibitory Effects on the Specific Binding of [125I]AII-
and AII-Induced Pressor Responses in Rats
disturbance of pKa. The partition coefficient (log P)
19
between 1-octanol and water,13 pKa and oral bioavail-
ability5 were measured for the representative com-
pounds (1a , 2, 8f), and the results are shown in Table
2. Increasing pKa or percentage of neutral form leads
to higher lipophilicity (log P). It is worth noting that
compounds with higher lipophilicity (log P) show better
oral bioavailability. 2 and 8f were found to be absorbed
efficiently upon oral administration without prodrug
formation (BA ) 20% and 51%, respectively). The
acidity required for AII receptor antagonism seems to
have a large range (pKa ) 5.3-6.6); however 2 and 8f
(IC50 ) 4.2 × 10-7 and 2.5 × 10-7 M, respectively)
showed slightly lower binding affinity than 1a (IC50
)
receptor
1.1 × 10-7 M). Their improved BA could compensate
for the loss of binding affinity to enhance in vivo activity.
Replacement of the oxygen atom in the 5-oxo-1,2,4-
oxadiazole ring with a sulfur atom, which is softer than
the oxygen atom, caused not only higher lipophilicity
and bioavailability but also faintly shorter duration (8f
vs 2) which might have been due to the susceptibility
of the sulfur atom to metabolism. 1-[[2′-(2,5-Dihydro-
5-oxo-4H-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-
ethoxy-1H-benzimidazole-7-carboxylic acid (2, TAK-536)
was selected and is currently undergoing clinical trials.
affinity
% inhibitionb
3h/7h
compd
R1
Bu
EtO
Me
Et
Pr
Bu
MeO
EtO
R2 R3 IC50,10-7 Ma
7d
7f
Me
Me
H
H
H
H
H
H
A
A
A
A
A
A
A
A
>10
7.5
87/100 (10/35)c
100/100
80/71
100/100
100/100
92/83 (19/52)c
88/91
100/100
(100/100)c
83/100
100/100
100/100
100/100
32/29
8a
8b
8c
8d
8e
8f
9.7
0.69
3.6
7.2
3.6
2.5
8g
8h
8i
8j
8k
8l
10d
10e
11a
11b
11c
11d
11f
11g
11h
12a
12b
5a f
5bf
6f
PrO
MeS
EtS
PrS
MeNH
EtNH
Bu
EtO
Me
Et
H
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
A
A
A
A
A
A
B
B
B
B
B
B
B
B
B
C
C
D
D
D
D
E
9.2
5.0
4.7
Con clu sion
>10
In this study, it was demonstrated that the oral
bioavailability of 1a could be improved by increasing
its lipophilicity. The 5-oxo-1,2,4-oxadiazole ring and its
thio analogs were found to be lipophilic bioisosteric
replacements for the tetrazole ring in the potent AII
receptor antagonist 1a . The 5-oxo-1,2,4-oxadiazole (2,
TAK-536) and 5-oxo-1,2,4-thiadiazole (8f) derivatives
showed efficient oral BA and enhanced in vivo activity
without prodrug formation comparable to 1b (TCV-116).
We believe that these acidic bioisosteres can be applied
to modification of other acidic drugs.
5.4
1.3
70/71
>10
>10
>10
84/87 (7/20)c
83/93
57/50
91/89
96/94
3.4
3.9
7.6
Pr
Bu
82/100 (19/57)c
100/91
MeS
EtS
PrS
Bu
EtO
Bu
EtO
Bu
EtO
Bu
10
6.9
>10
>10
4.6
100/100
100/100
63/22d
Me
Me
Me
Me
H
35/29d
9.0
4.4
6.2
4.2
3.2
0.66
5.5
1.1
1.5
NTe
100/100d
68/64
Exp er im en ta l Section
All melting points were determined on
a Yanagimoto
2f (TAK-536)
H
100/100 (75/64)c
47/27
micromelting point apparatus and are uncorrected. The
infrared (IR) spectra were recorded on a Hitachi 215 or a
HORIBA FT-200 grating infrared spectrophotometer. The
proton nuclear magnetic resonance (1H NMR) spectra were
recorded on a Varian Gemini-200 (200 MHz) or an EM-390
(90 MHz) spectrometer. Chemical shifts are given in δ values
(ppm) using tetramethylsilane as the internal standard, and
coupling constants (J ) are given in hertz. Column chroma-
tography was performed using silica gel (Wakogel C-300,
Merck Art. 7734 or Merck Art. 9385). The biological assays
were performed as previously described.7
Met h yl 2-E t h oxy-1-[[2′-(h yd r oxya m id in o)bip h en yl-4-
yl]m eth yl]-1H-ben zim id a zole-7-ca r boxyla te (4f). Triethy-
lamine (6.18 g, 61.1 mmol) was added to a suspension of
hydroxylamine hydrochloride (4.24 g, 61.0 mmol) in DMSO (20
mL). An insoluble material was filtered off and washed with
THF. The filtrate was concentrated in vacuo to remove THF,
and methyl 1-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethoxy-1H-
benzimidazole-7-carboxylate (3f)4 (5.00 g, 12.2 mmol) was
added to the DMSO solution of hydroxylamine. After stirring
at 75 °C for 15 h, the reaction mixture was diluted with water
and extracted with EtOAc. The organic solution was extracted
with 1 N HCl (25 mL). The aqueous solution was adjusted to
pH 10 with 1 N NaOH and extracted with EtOAc. The organic
solution was washed with water and dried (Na2SO4). The
solvent was evaporated in vacuo, and the product was recrys-
tallized from EtOAc-MeOH-hexane to give 4f (2.97 g, 55%)
as colorless needles: mp 207-209 °C; 1H NMR (CDCl3) δ 1.49
(3H, t, J ) 7.1), 3.76 (3H, s), 4.35 (2H, brs), 4.68 (2H, q, J )
13g
14h
15g
Me
Me
H
EtO
Bu
E
E
E
100/90
49/53
1a h (CV-11974) EtO
losartan
H
100/92 (67/91)c
21/34
Inhibition of specific binding of [125I]AII (0.2 nM) to bovine
a
adrenal cortex. The IC50 value is the concentration of compound
b
which inhibits [125I]AII binding by 50%. Percent inhibition of AII
(0.1 µg/kg iv)-induced pressor response at
3 and 7 h after
administration of the test compounds (1 mg/kg po) in conscious
male Sprague-Dawley rats. c Inhibition at a dose of 0.1 mg/kg po.
Inhibition at a dose of 3 mg/kg po. e NT means not tested. f 2,
d
g
5a ,b, and 6 are reported in ref 13. 13 and 15 are reported in ref
h
7. 1a and 14 are reported in ref 4.
dependency of the inhibitory effect on the pressor
response of the representative compound 5-oxo-1,2,4-
thiadiazole (A) derivative 8f was studied, and the results
are shown in Figure 1. At 0.01-1 mg/kg po, 8f produced
dose-dependent inhibition, which lasted for up to 24 h,
and its ID50 value was (ID50 ) 0.04 mg/kg) comparable
to that of 2 (ID50 ) 0.06 mg/kg).13
Lipophilicity, hydrophilicity, hydrogen bonding, and
pKa are likely to be important for the absorption,
transport, and excretion of compounds.18 In this study,
modifications were designed to increase the lipophilicity
of the tetrazole moiety in 1a , which might cause

Synthesis and Activity of Benzimidazole Derivatives
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5231
Sch em e 1a
a
(a)NH2OH‚HCl, Et3N; (b) pyridine, 2-ethylhexyl chloroformate; (c) xylene, reflux; (d) aq NaOH or aq LiOH; (e) TCDI; (f) silica gel or
BF3‚OEt2; (g) Ac2O, Et3N; (h) NaH, CS2; (i) DBU or DBN; (j) pyridine, SOCl2.
7.1), 5.63 (2H, s), 6.99 (2H, d, J ) 8.4), 7.16 (1H, t, J ) 7.9),
7.28-7.56 (7H, m), 7.73 (1H, dd, J ) 1.1, 7.9); IR (KBr) 3440,
prisms: mp 196-197 °C; 1H NMR (DMSO-d6) δ 1.40 (3H, t, J
) 6.9), 3.68 (3H, s), 4.61 (2H, q, J ) 7.0), 5.54 (2H, s), 7.00
(2H, d, J ) 8.4), 7.15-7.26 (3H, m), 7.45-7.71 (6H, m); IR
3345, 1715, 1640, 1545, 1435, 1275, 1040, 760 cm-1
(C25H24N4O4) C, H, N.
. Anal.
(Nujol) 1780, 1730, 1720, 1550, 1470, 1285, 1040, 760 cm-1
Anal. (C26H22N4O5) C, H, N.
.
Compounds 4c,e-l were prepared by a procedure similar
to that described above, and the results are shown in Table 3.
4a ,b,d ,l contaminated by amides were used for the next
reaction without further purification.
Meth yl 2-Bu tyl-1-[[2′-(2,5-d ih yd r o-5-oxo-4H-1,2,4-oxa -
d ia zol-3-yl)b ip h en yl-4-yl]m et h yl]-1H -b en zim id a zole-7-
ca r boxyla te (5a ). This compound was prepared from 4d by
a procedure similar to that described above in 48% yield as
colorless prisms: mp 232-233 °C; 1H NMR (CDCl3) δ 0.87 (3H,
t, J ) 7.2), 1.10-1.77 (4H, m), 2.47 (2H, t, J ) 7.8), 3.63 (3H,
s), 5.57 (2H, s), 6.57 (2H, d, J ) 8.1), 6.73-7.93 (9H, m); IR
(Nujol) 1770, 1720, 1260 cm-1. Anal. (C28H26N4O4) C, H, N.
1-[[2′-(2,5-Dih yd r o-5-oxo-4H-1,2,4-oxa d ia zol-3-yl)bip h e-
n yl-4-yl]m eth yl]-2-eth oxy-1H-ben zim id a zole-7-ca r boxy-
lic Acid (2, TAK-536). A mixture of 5b (32.0 g, 68.0 mmol)
and 0.4 N NaOH (500 mL, 0.20 mol) was stirred at 70 °C
for 1.5 h. The reaction mixture was adjusted to pH 3 with
2 N HCl. The precipitate was collected by filtration and
washed with EtOH to give 2 (29.2 g, 94%) as colorless prisms:
Meth yl 1-[[2′-(2,5-Dih yd r o-5-oxo-4H-1,2,4-oxa d ia zol-3-
yl)bip h en yl-4-yl]m et h yl]-2-et h oxy-1H-b en zim id a zole-7-
ca r boxyla te (5b). 2-Ethylhexyl chloroformate (25.3 g, 0.13
mol) was added dropwise to an ice-cooling mixture of 4f (58.5
g, 0.13 mol) and pyridine (11.1 g, 0.14 mol) in DMF (220 mL).
The resulting mixture was stirred at 0 °C for 30 min, diluted
with water, and extracted with EtOAc. The extract was
washed with water and dried (Na2SO4). The solvent was
evaporated in vacuo, and the residue was dissolved in xylene
(800 mL). The solution was heated under reflux for 2 h. The
reaction mixture was concentrated in vacuo, diluted with
CHCl3-EtOAc (3:1) (200 mL), and allowed to stand at room
temperature. The precipitate was collected by filtration and
washed with MeOH to give 5b (32.2 g, 52%) as colorless
1
mp 212-214 °C; H NMR (DMSO-d6) δ 1.47 (3H, t, J ) 7.0),
4.67 (2H, q, J ) 7.0), 5.77 (2H, s), 7.07-7.70 (11H, m); IR

5232 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26
Kohara et al.
2-Bu tyl-1-[[2′-(2,5-d ih yd r o-5-oxo-4H-1,2,4-oxa d ia zol-3-
yl)bip h en yl-4-yl]m eth yl]-1H-ben zim id a zole-7-ca r boxyl-
ic Acid (6). This compound was prepared from 8a by a
procedure similar to that described above in 64% yield as
colorless prisms: mp 165-167 °C; 1H NMR (DMSO-d6) δ 0.90
(3H, t, J ) 7.2), 1.13-2.00 (4H, m), 2.83 (2H, t, J ) 7.0), 5.93
(2H, s), 6.93 (2H, d, J ) 8.0), 7.13-7.90 (9H, m); IR (Nujol)
1770, 1700, 1440, 1420, 1250, 765 cm-1. Anal. (C27H24N4O4‚
0.3CHCl3) C, H, N.
Meth yl 1-[[2′-(2,5-Dih yd r o-5-oxo-4H-1,2,4-th ia d ia zol-3-
yl)biph en yl-4-yl]m eth yl]-2-eth yl-1H-ben zim idazole-7-car -
boxyla te (7b). A mixture of 4b (0.40 g, 0.93 mmol) and TCDI
(90%, 0.20 g, 1.01 mmol) in THF (5 mL) was stirred at room
temperature for 1 h. After a suspension of silica gel (Merck
Art. 9385) (4.0 g) in CHCl3-MeOH (5:1) (50 mL) was added,
the resulting mixture was stirred at room temperature for 23
h. Silica gel was filtered off and washed with CHCl3-MeOH.
The filtrate was concentrated in vacuo, and the residue was
purified by flash column chromatography (EtOAc-hexane )
2:1 and then 3:1). The product was recrystallized from
CHCl3-Et2O to give 7b (0.11 g, 38%) as colorless crystals: mp
203-205 °C; 1H NMR (CDCl3) δ 1.13 (3H, t, J ) 7.4), 2.62
(2H, q, J ) 7.4), 3.53 (3H, s), 5.62 (2H, s), 6.60 (2H, d, J )
8.2), 6.87 (2H, d, J ) 8.2), 6.80-7.90 (7H, m); IR (KBr) 1715,
1690, 1600, 1520 cm-1. Anal. (C26H22N4O3S‚0.5H2O) C, H, N.
Compounds 7c,d ,k ,l were prepared by a procedure similar
to that described above, and the results are shown in Table 4.
Meth yl 1-[[2′-(2,5-Dih yd r o-5-oxo-4H-1,2,4-th ia d ia zol-3-
yl)bip h en yl-4-yl]m et h yl]-2-et h oxy-1H-b en zim id a zole-7-
ca r boxyla te (7f). A mixture of 4f (7.50 g, 16.9 mmol) and
TCDI (90%, 4.01 g, 20.3 mmol) in THF (100 mL) was stirred
at room temperature for 30 min. The mixture was diluted with
water and extracted with EtOAc. The extract was washed
with water and dried (MgSO4). The solvent was evaporated
in vacuo, and the residue was dissolved with THF (100 mL).
After addition of boron trifluoride diethyl etherate (12.0 g, 84.5
mmol) to the solution, the resulting mixture was stirred at
room temperature for 1 h. The reaction mixture was diluted
with water and extracted with EtOAc. The extract was
washed with 1 N HCl and dried (MgSO4). The solvent was
evaporated in vacuo, and the residue was purified by flash
column chromatography (EtOAc-hexane ) 1:2 and then 1:1).
The product was recrystallized from EtOAc-hexane to give
7f (2.90 g, 35%) as colorless needles: mp 209-211 °C; 1H NMR
(CDCl3) δ 1.46 (3H, t, J ) 6.9), 3.73 (3H, s), 4.57 (2H, q, J )
7.1), 5.67 (2H, s), 7.00-7.18 (5H, m), 7.28-7.33 (1H, m), 7.44-
7.57 (4H, m), 7.82-7.86 (1H, m), 9.03 (1H, brs); IR (KBr) 1710,
F igu r e 1. Inhibitory effects of 8f and TAK-536 (2) on AII (100
ng/kg iv)-induced pressor response in conscious normotensive
rats.
Ta ble 2. pKa, log P, and BA Values of the Acidic Heterocycles
in AII Receptor Antagonists
1660, 1550, 1430, 1280, 1250, 1130, 1040, 745 cm-1
(C26H22N4O4S) C, H, N.
. Anal.
Compounds 7a ,e,g-j were prepared by a procedure similar
to that described above, and the results are shown in Table 4.
Meth yl 1-[[2′-(Acetoxya m id in o)bip h en yl-4-yl]m eth yl]-
2-m eth yl-1H-ben zim id a zole-7-ca r boxyla te (9a ). A mix-
ture of 4a (2.00 g, 4.83 mmol), acetic anhydride (0.49 g, 4.80
mmol), and triethylamine (0.49 g, 4.84 mmol) in CH2Cl2 (20
mL) was stirred at room temperature for 2 h. The mixture
was washed with water and dried (MgSO4). The solvent was
evaporated in vacuo, and the residue was purified by flash
column chromatography (EtOAc-hexane ) 5:1, EtOAc, and
then EtOAc-MeOH ) 20:1) to give 9a (1.26 g, 57%) as
1
colorless crystals: mp 183-184 °C; H NMR (CDCl3) δ 2.14
(3H, s), 2.65 (3H, s), 3.76 (3H, s), 4.60 (2H, brs), 5.77 (2H, s),
6.91 (2H, d, J ) 8.0), 7.20-7.70 (8H, m), 7.90 (1H, dd, J )
1.0, 8.0); IR (KBr) 1730, 1725, 1620, 1595, 1585, 1520 cm-1
.
Anal. (C26H24N4O4‚0.3H2O) C, H, N.
Compounds 9b-d were prepared by a procedure similar to
that described above, and the results are shown in Table 6.
Meth yl 1-[[2′-(2,5-Dih yd r o-5-th ioxo-4H-1,2,4-oxa d ia zol-
3-yl)bip h en yl-4-yl]m eth yl]-2-m eth yl-1H-ben zim id a zole-
7-ca r boxyla te (10a ). To an ice-cooling mixture of 9a (0.60
g, 1.31 mmol) and carbon disulfide (0.38 g, 4.99 mmol) in DMF
(8 mL) was added sodium hydride (60% in oil, 0.16 g, 4.00
mmol), and the resulting mixture was stirred at 0 °C for 50
min. The reaction mixture was diluted with 1 N HCl and
extracted with EtOAc. The extract was washed with water
and dried (MgSO4). The solvent was evaporated in vacuo, and
a
A pKa value was estimated using the corresponding methyl
ester. All the pKa’s were determined in DMSO-H2O (2:3) at 26
°C by potentiometric titration with standardized 0.1 N NaOH.b log
P indicates the observed partition coefficient between 1-octanol
and water.13 c The bioavailability (BA) was determined as de-
scribed previously.5
(Nujol) 1780, 1700, 1555, 1470, 1440, 1290, 1050, 765 cm-1
Anal. (C25H20N4O4) C, H, N.
.

Synthesis and Activity of Benzimidazole Derivatives
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5233
Ta ble 3. Physicochemical Data of 1-[[2′-(Hydroxyamidino)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylates
compd
R
yield, %
recryst solvent
mp, °C
formulaa
4a
4b
4c
4d
4e
4f
Me
Et
Pr
Bu
MeO
EtO
68b
61b
41
EtOAc-hexane
187-189
C26H26N4O3‚0.3H2O
61b
26
CHCl3-EtOAc
EtOAc-MeOH-
hexane
203-204
207-209
C24H22N4O4
C25H24N4O4
55
4g
4h
4i
4j
4k
4l
PrO
MeS
EtS
PrS
MeNH
EtNH
61
54
58
52
58
66b
EtOAc
175-176
204-205
137-139
158-160
153-158
C26H26N4O4
C24H22N4O3S‚0.5H2O
EtOAc-hexane
EtOAc-hexane
EtOAc-hexane
EtOAc-hexane
C
C
C
25H24N4O3S‚0.4H2O
26H26N4O3S
24H23N5O3‚0.5H2O
a
b
4c,e-k gave satisfactory analyses (C, H, N). Crude yields. These were used for the next reaction without purification.
Ta ble 4. Physicochemical Data of 1-[[2′-(2,5-Dihydro-5-oxo-4H-1,2,4-thiadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-
carboxylates and 1-[[2′-(2,5-Dihydro-5-thioxo-4H-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylates
compd
R
X
synthetic methoda
yield, %
recryst solvent
mp, °C
formulac
C25H20N4O3S
7a
7b
7c
7d
7e
7f
7g
7h
7i
Me
A
A
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
B
B
A
A
A
B
B
B
B
B
B
A
A
C
C
C
C
D
E
8
38
14
44
45
35
45
45
42
51
11
12
55
24
29
32
58
50
59
53
CHCl3-hexane
CHCl3-ether
EtOAc-hexane
EtOAc-hexane
CHCl3-EtOAc
EtOAc
240-242 dec
203-205
Et
Pr
C26H22N4O3S‚0.5H2O
225-227 dec
178-179
C
C
27H24N4O3S‚0.2H2O
28H26N4O3S
Bu
MeO
EtO
PrO
MeS
EtS
PrS
MeNH
EtNH
Me
222-223
C25H20N4O4S
211-212
C
C
C
26H22N4O4S
27H24N4O4S
25H20N4O3S2‚0.5H2O
EtOAc
195-196
EtOAc-MeOH
CHCl3-ether
CHCl3-ether
CHCl3
226-229 dec
232-233 dec
229-230 dec
147-149
C26H22N4O3S2‚0.1H2O
C27H24N4O3S2
7j
7k
7l
C25H21N5O3S‚0.3CHCl3
C26H23N5O3S‚0.4CH2Cl2
C25H20N4O3S‚0.5H2O
C26H22N4O3S‚H2O
amorphous
127-133
10a
10b
10c
10d
10e
10f
10g
10h
EtOAc-hexane
CHCl3-ether
EtOAc-hexane
EtOAc-hexane
b
EtOAc
EtOAc-hexane
EtOAc-hexane
192-194
Et
Pr
187-188
206-209 dec
180-181
C
C
C
C
27H24N4O3S‚0.2H2O
28H26N4O3S
26H22N4O4S‚EtOAc
25H20N4O3S2
Bu
EtO
MeS
EtS
PrS
128-130 dec
185-187 dec
160-162
E
E
C26H22N4O3S2
C27H24N4O3S2
161-163
a
Method A: (1) 4, TCDI; (2) silica gel, CHCl3-MeOH (5:1). Method B: (1) 4, TCDI; (2) BF3‚OEt2. Method C: 9, CS2, NaH, DMF.
b
Method D: 4, TCDI, DBN, CH3CN. Method E: 4, TCDI, DBU, CH3CN. 10e was not recrystallized because it decomposed during the
process. c All compounds gave satisfactory analyses (C, H, N).
the residue was purified by flash column chromatography
(CHCl3-MeOH ) 50:1 and then 30:1) to give 10a (0.33 g,
55%) as colorless crystals: mp 192-194 °C; 1H NMR (DMSO-
d6) δ 2.59 (3H, s), 3.66 (3H, s), 5.72 (2H, s), 6.93 (2H, d, J )
8.0), 7.21 (2H, d, J ) 8.0), 7.20-7.70 (6H, m), 7.85 (1H, dd,
Meth yl 1-[[2′-(2,5-Dih yd r o-5-th ioxo-4H-1,2,4-oxa d ia zol-
3-yl)b ip h en yl-4-yl]m et h yl]-2-et h oxy-1H-b en zim id a zole-
7-ca r boxyla te (10e). A mixture of 4f (1.00 g, 2.25 mmol),
TCDI (90%, 0.49 g, 2.47 mmol), and DBN (1.10 g, 8.86 mmol)
in acetonitrile (20 mL) was stirred at room temperature for 4
h. The mixture was concentrated in vacuo, diluted with water,
adjusted to pH 4-5 with 1 N HCl, and extracted with EtOAc.
After the extract was concentrated in vacuo, the residue was
dissolved with 1 N NaOH and washed with ether. The
J
) 1.2, 8.2); IR (KBr) 1720, 1600, 1520 cm-1
.
Anal.
(C25H20N4O3S‚0.5H2O) C, H, N.
Compounds 10b-d were prepared by a procedure similar
to that described above, and the results are shown in Table 4.

5234 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26
Kohara et al.
Ta ble 5. Physicochemical Data of 1-[[2′-(2,5-Dihydro-5-oxo-4H-1,2,4-thiadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-
carboxylic Acids and 1-[[2′-(2,5-Dihydro-5-thioxo-4H-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic Acids
compd
R
X
synthetic methoda
yield, %
recyrst solvent
EtOAc-MeOH
mp, °C
formulab
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
11a
11b
11c
11d
11f
11g
11h
Me
A
F
G
F
60
58
66
82
73
87
88
88
90
75
91
80
85
90
76
42
68
64
81
237-240 dec
204-207
228-230 dec
238-239 dec
203-205
C24H18N4O3S‚0.5EtOAc
C25H20N4O3S‚0.5CHCl3
C26H22N4O3S‚0.2H2O
27H24N4O3S‚0.3H2O
24H18N4O4S
25H20N4O4S
26H22N4O4S
24H18N4O3S2
C25H20N4O3S2
Et
Pr
A
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
MeOH-CHCl3-ether
MeOH-EtOAc-hexane
EtOAc-MeOH
EtOAc-MeOH
EtOAc-MeOH
EtOAc-MeOH
MeOH-EtOAc-ether
EtOAc-hexane
EtOAc-hexane
EtOH
EtOAc-EtOH
CHCl3-MeOH
CHCl3-MeOH
CHCl3-MeOH
EtOH
Bu
G
H
H
H
H
H
H
I
I
F
J
H
J
C
C
C
C
C
MeO
EtO
PrO
MeS
EtS
PrS
MeNH
EtNH
Me
213-214
204-206
215-218 dec
210-212 dec
135-140
320-321 dec
281-283 dec
249-255 edc
240-245 dec
187-191 dec
178-180
186-190 dec
163-165 dec
147-150 dec
C26H22N4O3S2
C24H19N5O3S‚0.6H2O
C25H21N5O3S‚0.3H2O
C24H18N4O3S
Et
Pr
C25H20N4O3S‚0.5H2O
C26H22N4O3S‚0.9H2O
Bu
C
C
27H24N4O3S
24H18N4O3S2
MeS
EtS
PrS
H
H
H
EtOAc-hexane
EtOAc-hexane
EtOAc-hexane
C25H20N4O3S2‚0.8H2O
26H22N4O3S2
C
a
Method F: 7 or 10, LiOH‚H2O, MeOH-H2O. Method G: 7, 1 N NaOH, MeOH. Method H: 7 or 10, LiOH‚H2O, THF-H2O. Method
b
I: 7, 0.1 N NaOH, MeOH. Method J : 10, 2N NaOH, MeOH. All compounds gave satisfactory analyses (C, H, N).
Ta ble 6. Physicochemical Data of 1-[[2′-(Acetoxyamidino)-
biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylates
evaporated in vacuo, and the residue was purified by flash
column chromatography (EtOAc-hexane ) 5:1). The product
was recrystallized from EtOAc to give 10f (0.31 g, 50%) as
colorless crystals: mp 185-187 °C dec; 1H NMR (CDCl3) δ 2.67
(3H, s), 3.78 (3H, s), 5.76 (2H, s), 7.03 (2H, d, J ) 8.0), 7.15
(1H, t, J ) 7.9), 7.17 (2H, d, J ) 8.0), 7.38 (1H, dd, J ) 1.3,
7.5), 7.49-7.68 (4H, m), 7.84 (1H, dd, J ) 1.7, 7.5); IR (KBr)
1715, 1485, 1470, 1460, 1450, 1415, 1280, 1255, 1180, 1140,
755, 740 cm-1. Anal. (C25H20N4O3S2) C, H, N.
Compounds 10g,h were prepared by a procedure similar to
that for the preparation of 10f, and the results are shown in
Table 4.
Meth yl 2-Eth oxy-1-[[2′-(2-oxo-3H-1,2,3,5-oxa th ia d ia zol-
4-yl)bip h en yl-4-yl]m eth yl]-1H-ben zim id a zole-7-ca r boxy-
la te (12b). To an ice-cooling mixture of 4f (2.00 g, 4.50 mmol)
and pyridine (0.71 g, 8.98 mmol) in THF (100 mL) was added
dropwise a solution of thionyl chloride (0.54 g, 4.54 mmol) in
CH2Cl2 (20 mL), and the resulting mixture was stirred at the
same temperature for 45 min. The reaction mixture was
concentrated in vacuo, diluted with water, and extracted with
CHCl3. The extract was washed with water and dried (Mg-
SO4). The solvent was evaporated in vacuo, and the residue
was purified by flash column chromatography (CHCl3-EtOAc-
MeOH ) 60:10:1 and then 30:1:2). The product was recrystal-
lized from EtOAc to give 12b (0.35 g, 16%) as colorless
yield,
compd
R
%
recryst solvent
EtOAc-hexane 183-184 C26H24N4O4‚0.3H2O
EtOAc-hexane 187-188 27H26N4O4
EtOAc-hexane 177-178 C28H28N4O4‚0.1H2O
EtOAc-hexane 170-173 29H30N4O4
mp, °C
formulaa
9a
9b
9c
9d
Me
Et
Pr
57
80
86
98
C
Bu
C
a
All compounds gave satisfactory analyses (C, H, N).
aqueous solution was adjusted to pH 4 with 1 N HCl, and
extracted with EtOAc. The extract was washed with water
and dried (MgSO4). The solvent was evaporated in vacuo, and
the residue was washed with EtOAc to give 10e (0.57 g, 65%)
as pale yellow crystals: mp 121-123 °C dec; 1H NMR (CDCl3)
δ 1.42 (3H, t, J ) 6.9), 3.66 (3H, s), 4.39 (2H, q, J ) 7.0), 5.65
(2H, s), 6.90-7.11 (6H, m), 7.29-7.33 (1H, m), 7.50 (1H, dd, J
) 1.4, 7.4), 7.53-7.61 (2H, m), 7.81-7.86 (1H, m); IR (KBr)
1
prisms: mp 109-110.5 °C; H NMR (CDCl3) δ 1.50 (3H, t, J
) 7.0), 3.78 (3H, s), 4.62 (2H, q, J ) 7.0), 5.60 (2H, s), 6.99
(2H, d, J ) 8.2), 7.11-7.66 (8H, m), 7.90 (1H, dd, J ) 1.3,
7.5); IR (KBr) 1720, 1550, 1430, 1280, 1040, 755 cm-1. Anal.
(C25H22N4O5S‚0.2H2O) C, H, N.
1720, 1545, 1480, 1470, 1435, 1280, 1250, 1040, 780 cm-1
Anal. (C26H22N4O4S‚EtOAc) C, H, N.
.
Meth yl 2-Bu tyl-1-[[2′-(2-oxo-3H-1,2,3,5-oxa th ia d ia zol-
4-yl)bip h en yl-4-yl]m eth yl]-1H-ben zim id a zole-7-ca r boxy-
la te (12a ). This compound was prepared from 4d by a
procedure similar to that described above in 18% yield as
colorless prisms: mp 124-125 °C; 1H NMR (CDCl3) δ 0.93 (3H,
t, J ) 7.2), 1.30-1.49 (2H, m), 1.62-1.79 (2H, m), 2.64 (2H, t,
J ) 7.8), 3.70 (3H, s), 5.64 (2H, s), 6.74 (2H, d, J ) 8.1), 7.09-
7.62 (8H, m), 7.89 (1H, dd, J ) 1.7, 7.4); IR (KBr) 1720, 1520,
Meth yl 1-[[2′-(2,5-Dih yd r o-5-th ioxo-4H-1,2,4-oxa d ia zol-
3-yl)bip h en yl-4-yl]m eth yl]-2-(m eth ylth io)-1H-ben zim id a -
zole-7-ca r boxyla te (10f). A mixture of 4h (0.57 g, 1.25
mmol), TCDI (90%, 0.37 g, 1.87 mmol), and DBU (0.76 g, 4.99
mmol) in acetonitrile (10 mL) was stirred at room temperature
for 1 h. The mixture was diluted with water, adjusted to pH
4 with 1 N HCl, and extracted with EtOAc. The extract was
washed with water and dried (Na2SO4). The solvent was
1450, 1435, 1410, 1285, 1185, 1120, 760 cm-1
.
Anal.
(C27H26N4O4S‚0.2iPr2O‚0.2H2O) C, H, N.

Synthesis and Activity of Benzimidazole Derivatives
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 26 5235
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Potent Orally Active (Imidazolylbiphenyl)sulfonylureas (HR
720). J . Med. Chem. 1995, 38, 2357-2377.
1-[[2′-(2,5-Dih yd r o-5-oxo-4H -1,2,4-t h ia d ia zol-3-yl)b i-
p h en yl-4-yl]m et h yl]-2-et h oxy-1H -b en zim id a zole-7-ca r -
boxylic Acid (8f). A mixture of 10f (2.40 g, 4.93 mmol) and
LiOH‚H2O (0.52 g, 12.4 mmol) in THF (25 mL)-H2O (15 mL)
was stirred at room temperature for 19 h. The reaction
mixture was diluted with water and acidified with 1 N HCl.
The precipitate was collected by filtration and recrystallized
from CHCl3-MeOH to give 8f (2.04 g, 87%) as colorless
1
needles: mp 213-214 °C; H NMR (DMSO-d6) δ 1.39 (3H, t,
J ) 7.0), 4.58 (2H, q, J ) 7.0), 5.66 (2H, s), 7.02 (2H, d,
J ) 8.2), 7.14-7.22 (3H, m), 7.43-7.69 (6H, m); IR (KBr)
1700, 1660, 1550, 1280, 1240, 1040, 765, 750 cm-1
(C25H20N4O3S) C, H, N.
. Anal.
The compounds 8a -e,g-l and 11a -d ,f-h were prepared
by a procedure similar to that described above, and the results
are shown in Table 5.
Ack n ow led gm en t. We wish to thank Dr. K. Nish-
ikawa for his encouragement and helpful discussion
throughout this work and Ms. M. Ojima for her techni-
cal assistance.
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J M960547H