Note: Descriptions are shown in the official language in which they were submitted.
CA 02241186 1998-06-23
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s
BENZIMIDAZOLE DERIVATIVES
TECHNICAL FIELD
. The present invention relates to novel benzimidazole
derivatives, and, more precisely, to novel benzimidazole
derivatives and their pharmaceutically acceptable salts having
blood sugar level-depressing activity or PDE5-inhibiting
activity. The present invention also relates to pharmaceutical
compositions comprising, as an active ingredient, such
benzimidazole derivatives or their salts.
iURE OF THE INVENTION
The subject matter of the present invention is to provide
novel benzimidazole derivatives and their pharmaceutically
acceptable salts, and also pharmaceutical compositions which
comprise, as an active ingredient, such benzimidazole
derivatives or their pharmaceutically acceptable salts, and
which are useful for preventing and treating impaired glucose
tolerance, diabetes (type II diabetes), diabetic complications
(e. g., diabetic nephropathy, diabetic neuropathy, diabetic
retinopathy, etc.), syndrome of insulin resistance (e. g.,
insulin receptor disorders, Rabson-Mendenhall syndrome,
leprechaunism, Kobberling-Dunnigan syndrome, Seip syndrome,
Lawrence syndrome, Gushing syndrome, acromegaly, etc.),
hyperlipidemia, atherosclerosis, cardiovascular disorders (e. g.,
stenocardia, cardiac failure, etc.), hyperglycemia (e. g.,
abnormal saccharometabolism such as feeding disorders, etc.), or
hypertension; or stenocardia, hypertension, pulmonary
hypertension, congestive heart failure, glomerulopathy (e. g.,
diabetic glomerulosclerosis, etc.), tubulointerstitial disorders
(e. g., renopathy induced by FK506, cyclosporin, etc.), renal
failure, atherosclerosis, angiostenosis (e. g., after
percutaneous arterioplasty), distal angiopathy, cerebral
apoplexy, chronic reversible obstructions (e. g., bronchitis,
asthma (chronic asthma, allergic asthma), etc.), allergic
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rhinitis, urticaria, glaucoma, diseases characterized by
enteromotility disorders (e. g., hypersensitive enteropathy
syndrome, etc.), impotence (e. g., organic impotence, psychic
impotence, etc.), and diabetic complications (e. g., diabetic
gangrene, diabetic arthropathy, diabetic glomerulosclerosis,
diabetic dermatopathy, diabetic neuropathy, diabetic cataract,
diabetic retinopathy, etc.), nephritis, cancerous cachexia, or
restenosis after PTCA.
The present inventors provide pharmaceutical compositions
comprising, as an active ingredient, any of benzimidazole
derivatives of the following formulae (I) to (IV) and (VIII) to
(XIV), and their pharmaceutically acceptable salts, which is
usable for preventing and treating impaired glucose tolerance,
diabetes (type II diabetes), diabetic complications such as
diabetic nephropathy, diabetic neuropathy and diabetic
retinopathy, syndrome of insulin resistance (e. g., insulin
receptor disorders, Rabson-Mendenhall syndrome, leprechaunism,
Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence syndrome,
Gushing syndrome, acromegaly, etc.), hyperlipidemia,
atherosclerosis, cardiovascular disorders (e. g., stenocardia,
cardiac failure, etc.), hyperglycemia (e. g., abnormal
saccharometabolism such as feeding disorders, etc.), or
hypertension; or stenocardia, hypertension, pulmonary
hypertension, congestive heart failure, glomerulopathy (e. g.,
diabetic glomerulosclerosis, etc.), tubulointerstitial disorders
(e. g., renopathy induced by FK506, cyclosporin, etc.), renal
failure, atherosclerosis, angiostenosis (e. g., after
percutaneous arterioplasty), distal angiopathy, cerebral
apoplexy, chronic reversible obstructions (e. g., bronchitis,
asthma (chronic asthma, allergic asthma), etc.), allergic
rhinitis, urticaria, glaucoma, diseases characterized by
enteromotility disorders (e. g., hypersensitive enteropathy
syndrome, etc.), impotence (e. g., organic impotence, psychic
impotence, etc.), and diabetic complications (e. g., diabetic
gangrene, diabetic arthropathy, diabetic glomerulosclerosis,
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diabetic dermatopathy, diabetic neuropathy, diabetic cataract,
diabetic retinopathy, etc.), nephritis, cancerous cachexia, or
restenosis after PTCA.
N
\ ~ . ~~R2 C I )
N
R~
In formula (I);
R1 represents a hydrogen atom, an arylsulfonyl group, or a
lower alkyl group; said lower alkyl group may be substituted by
an aryl group or an aryl group substituted by one or two
substituents selected from a halogen atom, a haloaryl group, a
lower alkyl group, a halo-lower alkyl group, a lower alkoxy
group, a vitro group, an amino group, a cyano group, an aryl
group, an aryl-lower alkyl group, an aryl-lower alkyloxy group,
a haloaryl-lower alkyloxy group, an arylsulfonyl-lower alkyl
group, an arylsulfonylamino group, a cyanoaryl group, and a
heterocyclic group, or by a heterocyclic group;
Rz represents a hydrogen atom, a lower cycloalkyl group, a
hydroxyl group, a lower alkoxy .group, a mercapto group, a lower
alkylthio group, an amino group, a lower alkylamino group, a
carboxyl group, an aryl group, or a lower alkyl group; said
lower alkyl group may be substituted by a halogen atom, a lower
alkoxy group, a cyano group, a chlorocarbonyl group, an aryl
group, or a heterocyclic group;
R, represents a carboxyl group, an esterified carboxyl group,
an amidated carboxyl group, an amino group, an amido group, or a
sulfonyl group; said amino group and said amido group may be
substituted by an acyl group or a sulfonyl group; and a halogen
atom, an amino group, or an acylamino~group is bonded to said
sulfonyl group; or R, may be bonded to the skeleton via a lower
alkylene or alkenylene group;
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4
R, represents a neutral substituent; and
n means an integer from 0 to 3.
n CRa')
N
Rs w ~ ~ R~
\ N CII)
Rs
In formula (II);
R6 represents an aryl-lower alkyl group or an aryl-lower
alkyl group substituted by one or two substituents selected from
a halogen atom, a haloaryl group, a lower alkyl group, a halo-
lower alkyl group, a lower alkoxy group, a vitro group, an amino
group, a cyano group, an aryl group, a cyanoaryl group, an aryl-
lower alkyloxy group, an arylsulfonyl-lower alkyl group, an
arylsulfonylamino group, an aryl-lower alkyl group, and a
heterocyclic group;
R~ represents a lower alkyl group or a lower cycloalkyl
group;
RB represents a carbamoyl group,~which may be substituted by
a lower alkyl group, a lower alkyl group substituted by a
substituted or unsubstituted aryl group or a substituted or
unsubstituted heterocyclic group, an aryl group, a heterocyclic
group, or a group of:
R9wS
Cl la)
in which R9 represents an alkyl group having up to 8 carbon atoms,
a halo-lower alkyl group, an aryl-lower alkyl group, a hydroxy-
lower alkyl group, a tri-lower alkylsilyl-lower alkyl group, a
lower alkoxy-lower alkyl group, a lower alkylthio-lower alkyl
group, a heterocyclic group, or an aryl group; said aryl group
may be substituted by a halogen atom,' a lower alkyl group, a
halo-lower alkyl group, a lower alkoxy group, or a vitro group;
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or Re may be bonded to the skeleton via a lower alkylene or
alkenylene group;
R~' repxesents a hydrocarbon group or a halogenated
hydrocarbon group; and
n means an integer from 0 to 3.
n (R4')
N
R" I y R~
N (III
Rg
In formula (III);
R6 represents an aryl-lower alkyl group or an aryl-lower
alkyl group substituted by one or two substituents selected from _
a halogen atom, a lower alkyl group, a halo-lower alkyl group, a
lower alkoxy group, a vitro group, an amino group, a cyano group,
an aryl group, a haloaryl group, a cyanoaryl group, an aryl-
lower alkyloxy group, an arylsulfonyl-lower alkyl group, an
arylsulfonylamino group, an aryl-lower alkyl group, and a
heterocyclic group;
R, represents a lower alkyl group or a lower cycloalkyl
group;
R,1 represents a substitutent of a formula:
H
R,2 is'N
O O II (I l la)
O
in which Rlz represents an alkyl group having up to 8 carbon
atoms, a halo-lower alkyl group, an aryl-lower alkyl group, a
hydroxy-lower alkyl group, a tri-lower alkylsilyl-lower alkyl
group, a lower alkoxy-lower alkyl group, a lower alkylthio-lower
alkyl group, a heterocyclic group, or an aryl group; said aryl
group may be substituted by a halogen atom, a lower alkyl group,
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6
n ( R 4')
N
R,5 I ~~R,a
W N CIV~
Ri s
In formula (IV);
R1, represents an aryl-lower alkyl group or an aryl-lower
alkyl group substituted by one or two substituents selected from
a halogen atom, a lower alkyl group, a halo-lower alkyl group, a
lower alkoxy group, a vitro group, an amino group, a cyano group,
an aryl group, a haloaryl group, a cyanoaryl group, an aryl-
lower alkyl group, an arylsulfonyl-lower alkyl group, an
arylsulfonylamino group, and a heterocyclic group;
R14 represents a lower alkyl group;
Ris represents a substitutent of a formula:
H
R, g~S~N~
O' ~O CIVa)
O
in which R16 represents a lower alkyl group or an aryl group;
R9' represents a hydrocarbon group or a halogenated
hydrocarbon group; and
n means an integer from 0 to 3.
a halo-lower alkyl group, a lower alkoxy group, or a vitro
group;
or R11 may be bonded to the skeleton via a lower alkylene or
alkenylene group;
R4' represents a hydrocarbon group or a halogenated
hydrocarbon group; and
n mean$ an integer from 0 to 3.
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7
R2s n ~R4')
N
R2o~S b~Y-A I ~>--R2 (V I I I
N
In formula (VIII);
R1 represents a hydrogen atom, an arylsulfonyl group, or a
lower alkyl group; said lower alkyl group may be substituted by
an aryl group or an aryl group substituted by one or two
substituents selected from a halogen atom, a haloaryl group, a
lower alkyl group, a halo-lower alkyl group, a lower alkoxy
group, a nitro group, an amino group, a cyano group, an aryl
group, an aryl-lower alkyloxy group, an arylsulfonyl-lower alkyl
group, an aryl-lower alkyl group, a haloaryl-lower alkyloxy
group, an arylsulfonylamino group, an arylcarbonylamino group,
an arylcarbonyl group, an arylalkenyl group, a cyanoaryl group,
and a heterocyclic group, or by a heterocyclic group;
Ra represents a hydrogen atom, a lower cycloalkyl group, a
hydroxyl group, a hydroxy-lower alkyl group, a lower alkoxy
group, a mercapto group, a lower alkylthio group, an amino group,
a lower alkylamino group, a carboxyl group, an aryl group, or a
lower alkyl group; said lower alkyl group may be substituted by
a halogen atom, a lower alkoxy group, a cyano group, a
halocarbonyl group, an aryl group, or a heterocyclic group;
Ra5 represents an alkyl group having up to 8 carbon atoms, a
lower cycloalkyl group, a halo-lower alkyl group, a tri-lower
alkylsilyl-lower alkyl group, a lower alkoxy-lower alkyl group,
a lower alkylthio-lower alkyl group, an aryl group, a
heterocyclic group, an aryl-lower alkyl group, or a hydroxy-
lower alkyl group; said aryl group may be substituted by a
halogen atom, a lower alkyl group, a halo-lower alkyl group, a
lower alkoxy group, or a nitro group;
Rzs represents a hydrogen atom or a lower alkyl group;
provided that, when R25 and Rz6 are both ~ lower alkyl groups , they
may be bonded together to form a ring;
Y represents a carbonyl group or a lower alkylene group;
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A represents a single bond, or a lower alkylene or
alkenylene group;
R4' represents a hydrocarbon group or a halogenated
hydrocarbon group; and
n means an integer from 0 to 3.
R26 R2s
l N
R Ors b~Y'--A ~ I ~~--R Z S
N
"2 ~
In formula (IX);
RZ~ represents a hydrogen atom, an alkyl group having up to
7 carbon atoms, a halo-lower alkyl group, an arylsulfonyl group,
an aryl-lower alkyl group, a heterocyclic lower alkyl group, or
a halo-heterocyclic lower alkyl group; and the aromatic ring
moiety in said aryl-lower alkyl group may be substituted by one
or two substi~uen~s se' ecte~i trom a halogen atom, a lower °alkyl
group, a halo=lower alkyl group, a cyanoaryl group, an amino
group, a lower alkoxy group, a vitro group, a cyano group, an
aryl group, a haloaryl group, an arylsulfonyl-lower alkyl group,
an arylsulfonylamino group, an aryl-lower alkyloxy group, an
aryl-lower alkyl group, a heterocyclic group, an aryloxy group,
an arylcarbonyl group, an arylcarbonylamino group, and an aryl-
lower alkyloxy group substituted by one or two halogen atoms;
Rse represents a hydrogen atom, an alkyl group having up to
7 carbon atoms, a halo-lower alkyl group, a lower alkoxy-lower
alkyl group, a lower cycloalkyl group, an aryl group, an aryl-
lower alkyl group, a lower alkylamino group, a lower alkoxy
group, a lower alkylthio group, a hydroxyl group, a mercapto
group, an amino group, or a carboxyl group;
RZS represents an alkyl group having up to 8 carbon atoms, a
halo-lower alkyl group, a tri-lower alkylsilyl-lower alkyl group,
a lower alkoxy-lower alkyl group, a lower alkylthio-lower alkyl
group, an aryl group, a heterocyclic group, an aryl-lower alkyl
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w
group, or a hydroxy-lower alkyl group; and said aryl group may
be substituted by a halogen atom, a lower alkyl group, a halo-
lower alkyl group, a lower alkoxy group, or a vitro group;
Rz6 represents a hydrogen atom or a lower alkyl group;
provided that, when Ras and R26 are both lower alkyl groups , they
may be bonded together to form a ring;
Y represents a carbonyl group or a lower alkylene group;
A represents a single bond, or a lower alkylene or
alkenylene group; and
Rz9 represents a hydrogen atom or a lower alkyl group.
n (R4')
N
R33 A I \~R32
~ N Cx)
R3o
In formula (X);
R3o represents a hydrogen atom, a lower alkyl group, a
substituted or unsubstituted aryl-lower alkyl group of a
formula:
R3, ~ (Xa)
(xa)
in which R31 represents a hydrogen atom, a cyanoaryl group, an
amino group, a lower alkoxy group, a vitro group, a cyano group,
an aryl group, a haloaryl group, an arylsulfonyl-lower alkyl
group, an arylsulfonylamino group, an aryl-lower alkyloxy group,
an aryl-lower alkyl group, a heterocyclic group, or an aryloxy
group,
or represents an aryl-lower alkyloxy group or an aryl-lower
alkyloxy group substituted by one or two halogen atoms, an
arylsulfonyl group, a heterocyclic lower alkyl group, an
arylcarbonylamino group, an arylcarbonyl group, an arylalkenyl
group, or a lower alkylenedioxyaryl group; and the alkyl moiety
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in said aryl-lower alkyl group may be substituted by a lower
alkyl group;
R3z represents a hydrogen atom, a lower alkyl group, a halo-
lower alkyl group, a lower cycloalkyl group, an aryl group, an
aryl-lower alkyl group, a lower alkylamino group, a lower alkoxy
group, a lower alkylthio group, a lower alkoxy-lower alkyl group,
or a heterocyclic lower alkyl group;
R33 represents a carboxyl group, a lower alkoxycarbonyl
group, a (2-cyanoaryl).oxycarbonyl group, or a group of a
formula:
H
-
in which Y represents a carbonyl group or a lower alkylene
group; R34 represents a lower alkyl group or a lower alkyl group
substituted by a substituted or unsubstituted aryl or
heterocyclic group, or represents an aryl group or a
heterocyclic group;
A represents a single bond, or a lower alkylene or
alkenylene group;
Rs' represents a hydrocarbon group or a halogenated
hydrocarbon' group. Rq' may include an alkyl group, an aralkyl
group, an alkynyl group, and halogenated groups of these. R4'
may be either saturated or unsaturated, may be either linear or
cyclic, and may even be branched, as the case may be. For the
halogenated groups, the type of the halogen therein is not
specifically defined, and the number of the halogen substituents
therein is not also specifically defined. n means an integer
from 0 to 3. Therefore, one, two or three Rg's may be bonded to
the skeleton, or no R4' may be bonded thereto. The position of
R~' is not specifically defined and may be any of the ortho-
position, the meta-position and the para-position relative to
the other, substituent. However, when R3o is a hydrogen atom, n
is 0, or that is, no RQ' is bonded to the skeleton.
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11
V
R36 A ( Rss
\ CXI)
'W Rsa
In formula (XI);
R35 represents a hydrogen atom, an aryl group, a lower
alkoxy-lower alkyl group, a lower alkyl group, or an aryl-lower
alkyl group;
R36 represents a carboxyl group, a lower alkoxycarbonyl
group, a heterocyclic lower alkylamino group, or a heterocyclic
lower alkylcarbamoyl group;
Rj~ and R3$ each independently represent a hydrogen atom, a
halogen atom, a lower alkyl group, a halo-lower alkyl group, an
aryl group, an aryl-lower alkyl group, or an aryl-lower alkyloxy
group; and
A represents a single bond, or a lower alkylene or
alkenylene group; provided that, when R~5 is a lower alkyl group,
A is a lower alkylene group or a lower alkenylene group.
(X I I
R3s
R37
In formula (XII);
R3~ and R38 each independently represent a hydrogen atom, a
halogen atom, a lower alkyl group, a halo-lower alkyl group, an
aryl group, an aryl-lower alkyl group, or an. aryl-lower alkyloxy
group;
R39 represents a lower alkyl group; and
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la
R4a represents a hydrogen atom, a lower alkoxycarbonyl group,
a lower alkanoyl group, a lower alkanesulfonyl group, or a
carbamoyl group.
N
(X111)
Rss
Rs~
In formula (XIII);
R3~ and R38 each independently represent a hydrogen atom, a
halogen atom, a lower alkyl group, a halo-lower alkyl group, an
aryl group, an aryl-lower alkyl group, or an aryl-lower alkyloxy
group; and
R, represents a lower alkyl group or a lower cycloalkyl
group.
R29
R4,.
(XIV)
R3s
Rs~
In formula (XIV);
R3~ and R38 each independently represent a hydrogen atom, a
halogen atom, a lower alkyl group, a halo-lower alkyl group, an
aryl group, an aryl-lower alkyl group, or an aryl-lower alkyloxy
group;
R~ represents a lower alkyl group or a lower cycloalkyl
group;
R~1 represents a 2-pyridylcarbamoyl group, a 2-carboxy-1-
pyrrolidinocarbonyl group, an N-methyl-N-(2-
pyridylmethyl)carbamoyl group, a homopiperidinocarbonyl group, a
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13
[2-(N-oxo)-pyridylmethyl]carbamoyl group, a 4-
(dimethylamino)benzylcarbamoyl group, a piperonylcarbamoyl group,
an N-methyl-N-(2-pyridyl)carbamoyl group, a
thiomorpholinocarbonyl group, a halosulfonyl group, an
aminosulfonyl group, an acylaminosulfonyl group, a lower
alkoxycarbonyl group, or a carboxyl group;
Ra9 represents a hydrogen atom, or a lower alkyl group;
provided that, when R41 is a lower alkylcarbonyl group or a
carboxyl group, Rz9 is a.lower alkyl group.
The present invention also provides novel benzimidazole
derivatives of the above-mentioned (VIII) to (XIV) and their
salts.
Benzimidazole derivatives to be provided~by the present
invention can be produced according to the following reaction
formulae (a) to (f):
No2NOa NHZ
R3a \ ~ '-~ ~a \ ( , R3a \ ~ -..
NHCOR,a NOORaa NCORZa
~~a ~3) ~~a
-.~ R3 ~ ~ N~~a
(4~ Rya
NOZ N02 NOZ
R3 ' I ---. R3 \ ~ , R3
NHCOR~ NHZ NH
NH2 , N
R3 ~ ~ , R3 ~ ~ ~-Rz b
NH
Rib
t~,b
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1
NOz NOa NHZ
R3 w ( --~ R3 w I ~ R3c w ~ --
F NH NH
(10) . (11 ) ~'~ (12) k'~
.. Rs \ ~ ~~c
1V~
(13) Roc
Rid .
N02 ~ , NHZ ~. NHZ
R3d \ ~ --~ R~ ' I R~ \
NHCOR~ NHCOR~ NHCOR2
(14) (15) (16) . (d)
N
R3 \ ~ N~-I$d
(17) Rid
NOZ r NH2 R , N
R3 \ ~ -i R3 \ ~ ~, 3 ~ ~ ~~e
NHZ NH2 H
(18) (19) (20) (e)
N
i
R3~N~F$e
(21 ) Rye
NOZ NH2 ~ N
R3 f ~ ~ ~ R3 f ~ ~ ~ R3 f ~ ~F$ f --~
NHCO~f ~ NHCOR2f \ NH
(22) (23) (24) (f)
N
-~. R3 f \ ~ N~-R2f
(25) Ref
CA 02241186 1998-06-23
In the above-mentioned reaction formulae, Rla to Rif may be
selected from the above-mentioned Rl, R6, R13, Rl" Rz2, Ra3, Ra,. R3o,
or a substituted benzyl group of a formula:
Rsa
R3~
wherein R" and R,e have the same meanings as those mentioned
above. Raa to Rzf may be selected from the above-mentioned RZ, R"
R1" R18, Rze, R,z, R35 or R,9. The substituents R3a to R3f may be
selected from a substituent of a formula:
R2s
R O S b~Y.-A
with Ras, Rzs, Y and A having the same meanings as those mentioned
above, or from the above-mentioned R3, Rs, R11, Rls. R~s. Rz4. ~
AR,6, NHR4o, CN or R~1. The substituents that define R3a through R3t
can be mutually converted to each other. For example, as in the
step (g) or (h) mentioned below, the ester (26) can be converted
into the corresponding acid (27) or acid halide (28). The
desired benzimidazoles can be produced through the reaction of
these compounds with amines or sulfonamides. It is further
possible to give various derivatives, as in the step (i) or (j)
or (k) or (1) or (m) or (n) mentioned below. Such conversion of
the groups, R3a through R3f can be effected at any stage in the
steps (a) through (f), while depending on the stability of Rla to
Rlf as well as R2a to RZf in the compounds and even on the easiness
in the isolation of the products formed.
Rg02C / ~ n'~-R~ _ f ~ H02C / ~ N>--R2a_ f
N ~ N
~~a~f
Rya~f
(26) (27)
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16
In this reaction formula, R9 represents a lower alkyl group;
and Rla-f and Rza_f have the same meanings as those mentioned above.
N / N
H02C \ ~ N>--Rza-f ~ Z '0C \ ~ N~Rza -f
~t~a - f Rya-f
(2~) (2$)
In this reaction formula, Z' represents a chlorine atom or
a bromine atom; and Ria-f and Rza-f have the same meanings as those
mentioned above.
H2N r N / N
~R2a~f ~ NC \ ~ ~R2a-f (i)
O
N R~ a~f
R~ a~f
(29) (30)
In this reaction formula, Rla-f and Rsa-f have the same
meanings as those mentioned above.
O
N ~ / N
H02C ~ '~--Rza~f tBuO N ~ ~Rza-f
N H ~ N
R~ a~f (31 ) R~ a~f (.i)
(2~)
N R~4 , N
HzN I >---Rza-f ~ ~N ~ '>--Rza~f
N H ~ N
R~ a~~ R~ a~f
(32) (33)
In this reaction formula, Rla-f and R have the same
2 a-f
meanings as those mentioned above.
In the reaction step (a), a compound of formula (1) may be
reacted with a base, such as sodium hydride, lithium
diisopropylamide, lithium hydrogencarbonate, lithium carbonate,
CA 02241186 1998-06-23
17
lithium hydroxide, sodium hydrogencarbonate, sodium carbonate,
sodium hydroxide, potassium hydrogencarbonate, potassium
carbonate, potassium hydroxide or the like, and with a compound
to be represented by R1$Z (where Z represents a chlorine atom, a
bromine atom, a toluenesulfonyloxy group, or a
methanesulfonyloxy group) to give a compound of formula (2). The
compound of formula (2) may be 1) reduced with reduced iron or
zinc under an acidic condition, or 2) reduced with a transition
metal catalyst, such as typically palladium, platinum, ruthenium
or nickel, in a hydrogen atmosphere, or 3) reduced with a
transition metal catalyst, such as typically palladium, platinum,
ruthenium or nickel, in the presence of formic acid, or 4)
reduced with sodium hydrosulfite, to be converted into a
compound of formula (3). In the process 1), the compound of
formula (3) is often cyclized in the reaction system directly
into a compound of formula (4). Depending on the compound of
formula (2) being reduced, the compound of formula (4) may be
partly formed in any of the processes 1) to 4). The compound of
formula (3) may be processed with a carboxylic acid, a sulfonic
acid or an inorganic acid, such as acetic acid, p-
toluenesulfonic acid, hydrochloric acid, sulfuric acid,
phosphoric acid or the like, to give the compound of formula (4).
In the step (b), a compound of formula (5) is may be
hydrolyzed or solvolyzed with a base, such as lithium
hydrogencarbonate, lithium carbonate, lithium hydroxide, sodium
hydrogencarbonate, sodium carbonate, sodium hydroxide, potassium
hydrogencarbonate, potassium carbonate, potassium hydroxide or
the like, or with a carboxylic acid, a sulfonic acid or
inorganic acid, such as acetic acid, p-toluenesulfonic acid,
hydrochloric acid, sulfuric acid, phosphoric acid or the like,
into a compound of formula (6). The compound of formula (6) may
be reacted with a base, such as sodium hydride, lithium
diisopropylamide, lithium hydrogencarbonate, lithium carbonate,
lithium hydroxide, sodium hydrogencarbonate, sodium carbonate,
sodium hydroxide, potassium hydrogencarbonate, potassium
CA 02241186 1998-06-23
18
carbonate, potassium hydroxide or the like, and with a compound
to be represented by RlbZ (where Z represents a chlorine atom, a
bromine atom, a toluenesulfonyloxy group, or a
methanesulfonyloxy group) to give a compound of formula (7). The
compound of formula (7) may be 1) reduced with reduced iron or
zinc under an acidic condition, or 2) reduced with a transition
metal catalyst, such as typically palladium, platinum, ruthenium
or nickel, in a hydrogen atmosphere, or 3) reduced with a
transition metal catalyst, such as typically palladium, platinum,
ruthenium or nickel, in the presence of formic acid, or 4)
reduced with sodium hydrosulfite, to be converted into a
compound of formula (8). A compound of formula (9) can be
produced from the compound of formula (8) and the corresponding
carboxylic acid or acid chloride or acid bromide or acid
anhydride.
In the step (c), a compound of formula (11) can be produced
from a compound of formula (10) and a compound to be represented
by RlcNH2. The conversion of the compound of formula (11) to a
compound of formula ( 13 ) is the same as that of the compound of
formula (7) to the compound of formula (9) in the step (b).
In the step (d), a compound of formula (14) may be 1)
reduced with a transition metal catalyst such as typically
palladium, platinum, ruthenium or nickel in a hydrogen
atmosphere, or 2) reduced with sodium hydrosulfite to give a
compound of formula (15). The compound of formula (15) may be
reacted with a base, such as lithium hydrogencarbonate, lithium
carbonate, lithium hydroxide, sodium hydrogencarbonate, sodium
carbonate, sodium hydroxide, potassium hydrogencarbonate,
potassium carbonate, potassium hydroxide or the like, and with a
compound to be represented by RldZ (where Z represents a
chlorine atom, a bromine atom, a toluenesulfonyloxy group, or a
methanesulfonyloxy group) to give a compound of formula (16).
The compound of formula (16) may be treated with a carboxylic
acid, a sulfonic acid or an inorganic acid, such as acetic acid,
CA 02241186 1998-06-23
19
p-toluenesulfonic acid, hydrochloric acid, sulfuric acid,
phosphoric acid or the like, to give a compound of formula (17).
In the step (e), a compound of formula (18) may be (1)
reduced with reduced iron or zinc under an acidic condition, or
Z) reduced with a transition metal catalyst, such as typically
palladium, platinum, ruthenium or nickel, in a hydrogen
atmosphere, or 3) reduced with a transition metal catalyst, such
as typically palladium, platinum, ruthenium or nickel, in the
presence of formic acid, or 4) reduced with sodium hydrosulfite,
to be converted into a compound of formula (19). A compound of
formula (20) can be produced from the compound of formula (19)
and the corresponding carboxylic acid or acid anhydride or acid
chloride or acid bromide. The compound of formula (20) may be
reacted with a base, such as sodium hydride, lithium
diisopropylamide, lithium hydrogencarbonate, lithium carbonate,
lithium hydroxide, sodium hydrogencarbonate, sodium carbonate,
sodium hydroxide, potassium hydrogencarbonate, potassium
carbonate, potassium hydroxide or the like, and with a compound
to be represented by RiaZ (where Z represents a chlorine atom, a
bromine atom, a toluenesulfonyloxy group, or a
methanesulfonyloxy group) to give a compound of formula (21).
In the process comprising the above-mentioned step, in
general, the product may be obtained as a mixture comprising the
compound of formula (21) where R3o is positioned in the 5-
position and that where it is in the 6-position, or a mixture
comprising the compound of formula (21) where R3o is positioned
in the 4-position and that where it is in the 7-position. Each
compound of formula (21) can be purified from the mixture as the
single compound, for example, through recrystallization, column
chromatography, thin-layer chromatography, high-performance
liquid chromatography or the like.
In the step (f), a compound of formula (22) may be 1)
reduced with reduced iron or zinc under an acidic condition, or
2) reduced with a transition metal catalyst, such as typically
palladium, platinum, ruthenium or nickel, in a hydrogen
CA 02241186 1998-06-23
ao
atmosphere, or 3) reduced with a transition metal catalyst, such
as typically palladium, platinum, ruthenium or nickel, in the
presence of formic acid, or 4) reduced with sodium hydrosulfite,
to be converted into a compound of formula (23). In the process
1), the compound of formula (23) is often cyclized in the
reaction system directly into a compound of formula (24).
Depending on the compound of formula (22) being reduced, the
compound of formula (24) may be partly formed in any of the
processes 1) to 4). The compound of formula (23) may be
processed with a carboxylic acid, a sulfonic acid or an
inorganic acid, such as acetic acid, p-toluenesulfonic acid,
hydrochloric acid, sulfuric acid, phosphoric acid or the like,
to give the compound of formula (24). The compound of formula
(24) may be converted into a benzimidazole compound of formula
(25) in the same manner as in the step (e) of converting the
compound of formula (20) into the compound of formula (21). In
this step, in general, the product may be obtained as a mixture
comprising the compound of formula (25) where R3f a.s positioned
in the 5-position and that where a.t is in the 6-position, or a
mixture comprising the compound of formula (25) where R3f 1S
positioned in the 4-position and that where it is in the 7-
position. Each compound of formula (25) can be purified from the
mixture as the single compound, for example, through
recrystallization, column chromatography, thin-layer
chromatography, high-performance liquid chromatography or the
like.
In the step (g), a compound of formula (26) may be
hydrolyzed with a base, such as lithium ,hydroxide, sodium
hydroxide, potassium hydroxide or the like, to give a compound
of formula (27). The compound of formula (27) may be reacted
with a carbonyldiimidazole and then with amines or sulfonamides
in the presence of a base to give different benzimidazole
derivatives.
In the step (h), the compound of formula (27) may be
processed with thionyl chloride or thionyl bromide or phosphorus
CA 02241186 1998-06-23
21
trichloride or phosphorus pentachloride or phosphorus
oxychloride to be converted into its acid halide of formula (28).
The compound of formula (28) may be reacted with amines or
sulfonamides to give different benzimidazole derivatives.
In the step ( i ) , a compound of formula ( 29 ) may be reacted
with titanium tetrachloride to give a compound of formula (30).
In the step (j), the compound of formula (27) may be
reacted with an azide, such as typically diphenylphosphorylazide,
in the presence of an alcohol, such as typically t-butanol, to
give a compound of formula (31). The compound of formula (31)
may be decomposed with an acid to give a compound of formula
(32). The compound of formula (32) may be reacted with a
compound to be represented by RgoZ (where Z represents a chlorine
atom or a bromine atom) to give a compound of formula (33).
N / N
RgOzC ~ ')-R2a-f HOH2C ~ '>-R2a-f
\ N ~ \ N (k)
Rya -f Rya-f
(26) (34)
N
Z H2C \ ~ '~-R2a -f
N
Rya-f
(35)
wherein R , R , and R have the same meanings as those
g la-f 2a-f
mentioned above; and Z represents a chlorine atom, a bromine
atom, a toluenesulfonyloxy group, or a methanesulfonyloxy group.
N ~ N
ZH2C \ ( '>--R2a-f ~ NC H2C \ ~ N~R2a -f
N Rya-f
Rya-f
(35) (36)
N
H02C \ ~ '~Rza-f
N
~~a-f
(37)
CA 02241186 1998-06-23
22
wherein R1a-f, R2a-f and Z have the same meanings as those mentioned
above.
N
HOH2C ( . N?--R2a-f ~ OHC \ ( ~~--R2a -f
N
N
Rya _t Rya-f
(34) (38)
N
~ Rg ~ \ ( ~~--R2a -f ~ HO \ \ ( ~~-R2a -f
O N O N
Rya-f R~a-.f
(39) (40)
wherein Rla-t, Raa-f and R9 have the same meanings as those
mentioned above.
( )
Rg ~ ~ ( N>..-R2a -f ~ R9 _ / ( N~R2a -f
0 ~N
R~ a-f R~ a-f
(39) (41 )
wherein Rla-t, Rza-t and R9 have the same meanings as those
mentioned above.
In the step (k), the compound of formula (26) may be
reduced into a compound of formula (34), which may be then
treated with thionyl chloride, thionyl bromide, phosphorus
oxychloride, phosphorus oxybromide, phosphorus trichloride,
phosphorus pentachloride, methanesulfonyl chloride,
toluenesulfonyl chloride or the like to be converted into a
compound of formula (35).
In the step (1), the compound of formula (35) may be
reacted with sodium cyanide or potassium cyanide to give a
compound of formula (36), which may be then hydrolyzed with
lithium hydroxide or sodium hydroxide or potassium hydroxide to
give a carboxylic acid of formula (37).
CA 02241186 1998-06-23
23
In the step (m), a compound of formula (38) to be obtained
by oxidizing the compound of formula (34) may be reacted with an
alkyl (triphenylphosphoranilidene)acetate to give a compound of
formula (39), which may then be hydrolyzed with lithium
hydroxide or sodium hydroxide or potassium hydroxide to give a
carboxylic acid of formula (40). The compound of formula (35),
(37) or (40) may be reacted with amines or sulfonylamides to
give different benzimidazole compounds.
In the step (n),, the compound of formula (39) may be
reduced with palladium, platinum, ruthenium or the like
transition metal catalyst in a hydrogen atmosphere or in the
presence of formic acid to give a compound of formula (41).
The following compounds of:
R4a.-.f
R 3 a .-- f ~ N~R2a--f
N
R~ a-f .
where R , R and R have the same meanings as those
la-f 2a-f 3a-f
mentioned above; and R4a-f may be selected from the above-
mentioned R4, R~' and Rz9,
can be produced according to the steps (a) to (f) while starting
from the following compounds of:
R4a
Noz (2' )
Rsa
NHCOR~a
where Rla, Rza and R3a have the same meanings as those
mentioned above; and R4a may be selected from the above-
mentioned R6, R4' and R29;
R4b
No2 (3')
R3~
NHCORZb
CA 02241186 1998-06-23
24
where Rlb, Rzb and R3b have the same meanings as those
mentioned above; and Rab may be selected from the above-
mentioned R4, R~' and R29;
~NO2 (4' )
Rs I
F
where Rl~, Rz~ and R3~ have the same meanings as those
mentioned above; and R4~ may be selected from the above-
mentioned R4, Rg' and R2v;
N~ (5,)
Rya w I
NHCOR~
where Rld, Rza and R3d have the same meanings as those
mentioned above; and R4a may be selected from the above-
mentioned R~, R~' and R29;
R~~ Noa (fi')
R3 w I
NHZ
where Rlo, Rzo and R3Q have the same meanings as those
mentioned above; and Rg~ may be selected from the above-
mentioned Rs, R4' and R29;
R 4f
NOa (7' )
R3 f .~. I
NHCOF~ f
where Rl f, Rzf and R3f have the same meanings as those
mentioned above; and Raf may be selected from the above-
mentioned R~, R4' and RZ9.
If desired, the intermediates formed in the above-mentioned
steps may optionally be purified, prior to being subjected to
the next step, through any conventional purification including,
for example, recrystallization, column chromatography, thin-
CA 02241186 1998-06-23
layer chromatography, high-performance liquid chromatography and
the like. If also desired, the final products of the compounds
of the present invention may optionally be purified through any
conventional purification which is employed in the art of
purifying organic compounds and which includes, for example,
recrystallization, column chromatography, thin-layer
chromatography, high-performance liquid chromatography and the
like. To identify these compounds, employable is any of NMR
spectrography, mass spectrography, IR spectrography, elementary
analysis, measurement of melting point and others.
Preferred embodiments and their details of various
definitions as referred to herein to be within the scope of the
present invention are described below.
Unless otherwise specifically indicated herein, the
terminology "lower" indicates that the group has from 1 to 6
carbon atoms. As preferred examples of the lower alkyl group as
referred to herein, mentioned are linear or branched alkyl
groups including a methyl group, an ethyl group, an n-propyl
group, an i-propyl group, an n-butyl group, an i-butyl group, a
sec-butyl group, a t-butyl group, an n-pentyl group, an i-pentyl
group, a sec- pentyl group, a t- pentyl group, a 2-methylbutyl
group, an n-hexyl group, a 1-methylpentyl group, a 2-
methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl
group, a 1-ethylbutyl group, a 2-ethylbutyl group, a 1,1-
dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-
dimethylbutyl group, a 1-ethyl-1-methyl propyl groups, etc.
The alkyl group having up to 7 carbon atoms a.s a linear or
branched alkyl group, including a methyl group, an ethyl group,
an n-propyl group, an i-propyl group, an n-butyl group, an i-
butyl group, a sec-butyl group, a t-butyl group, an n-pentyl
group, an i-pentyl group, a sec-pentyl group, a t-pentyl group,
a 2-methylbutyl group, an n-hexyl group, a 1-methylpentyl group,
a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl
group, a 1-ethylbutyl group, a 2-ethylbutyl group, a 3-
ethylbutyl group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutyl
CA 02241186 1998-06-23
26
group, a 3,3-dimethylbutyl group, a 1-ethyl-1-methylpropyl group,
an n-heptyl group, a 1-methylhexyl group, a 2-methylhexyl group,
a 3-methylhexyl group, a 4-methylhexyl group, a 5-methylhexyl
group, a 1-ethylpentyl group, a 2-ethylpentyl group, a 3-
ethylpentyl group, a 4-ethylpentyl group, a 1,1-dimethylpentyl
group, a 2,2-dimethylpentyl group, a 3,3-dimethylpentyl group, a
4,4-dimethylpentyl group, a 1-propylbutyl group, etc.
The alkyl group having up to 8 carbon atoms is a linear or
branched alkyl group, including a methyl group, an ethyl group,
an n-propyl group, an i-propyl group, an n-butyl group, an i-
butyl group, a sec-butyl group, a t-butyl group, an n-pentyl
group, an i-pentyl group, a sec-pentyl group, a t-pentyl group,
a 2-methylbutyl group, an n-hexyl group, a 1-methylpentyl group,
a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl
group, a 1-ethylbutyl group, a 2-ethylbutyl group, a 3-
ethylbutyl group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutyl
group, a 3,3-dimethylbutyl group, a 1-ethyl-1-methylpropyl group,
an n-heptyl group, a 1-methylhexyl group, a 2-methylhexyl group,
a 3-methylhexyl group, a 4-methylhexyl group, a 5-methylhexyl
group, a 1-ethylpentyl group, a 2-ethylpentyl group, a 3-
ethylpentyl group, a 4-ethylpentyl group, a 1,1-dimethylpentyl
group, a 2,2-dimethylpentyl group, a 3,3-dimethylpentyl group, a
4,4-dimethylpentyl group, a 1-propylbutyl group, an n-octyl
group, a 1-methylheptyl group, a 2-methylheptyl group, a 3-
methylheptyl group, a 4-methylheptyl group, a 5-methylheptyl
group, a 6-methylheptyl group, a 1-ethylhexyl group, a 2-
ethylhexyl group, a 3-ethylhexyl group, a 4-ethylhexyl group, a
5-ethylhexyl group, a 1,1-dimethylhexyl group, a 2,2-
dimethylhexyl group, a 3,3-dimethylhexyl group, a 4,4-
dimethylhexyl group, a 5,5-dimethylhexyl group, a 1-propylpentyl
group, a 2-propylpentyl group, etc.
The lower alkylene group is an alkylene group having 6 or
less carbon atoms, including a methylene group, an ethylene
group, a propylene group, a butylene group, a pentylene group, a
hexylene group, etc. The lower alkenylene group is an alkenylene
CA 02241186 1998-06-23
2~
group having 6 or less carbon atoms, including an ethenylene
group, a 1-propenylene group, a 2-propenylene group, a 1-
butenylene group, a 2-butenylene group, a 3-butenylene group, a
1-pentenylene group, a 2-pentenylene group, a 3-pentenylene
group, a 4-pentenylene group, a 1-hexenylene group, a 2-
hexenylene group, a 3-hexenylene group, a 4-hexenylene group, a
5-hexenylene group, etc.
The halogen atom includes a fluorine atom, a chlorine atom,
a bromine atom and an iodine atom. Preferred are a fluorine atom,
a chlorine atom and a bromine atom.
The halo-lower alkyl group is a linear or branched alkyl
group having up to 8 carbon atoms, which is substituted with one
or more halogen atoms selected from fluorine, chlorine, bromine
and iodine atoms. Preferred is a linear or branched alkyl group
having up to 8 carbon atoms, which is substituted with one or
more halogen atoms selected from fluorine, chlorine and bromine
atoms. It includes, for example, a fluoromethyl group, a
difluoromethyl group, a trifluoromethyl group, a chloromethyl
group, a dichloromethyl group, a trichloromethyl group, a
bromomethyl group, a dibromomethyl group, a tribromomethyl group,
a 1-fluoroethyl group, a 1-chloroethyl group, a 1-bromoethyl
group, a 2-fluoroethyl group, a 2-chloroethyl group, a 2-
bromoethyl group, a 1,2-difluoroethyl group, a 1,2-dichloroethyl
group, a 1,2-dibromoethyl group, a 2,2,2-trifluoroethyl group, a
heptafluoroethyl group, a 1-fluoropropyl group, a 1-chloropropyl
group, a 1-bromopropyl group, a 2-fluoropropyl group, a 2-
chloropropyl group, a 2-bromopropyl group, a 3-fluoropropyl
group, a 3-chloropropyl group, a 3-bromopropyl group, a 1,2-
difluoropropyl group, a 1,2-dichloropropyl group, a 1,2-
dibromopropyl group, a 2,3-difluoropropyl group, a 2,3-
dichloropropyl group, a 2,3-dibromopropyl group, a 3,3,3-
trifluoropropyl group, a 2,2,3,3,3-pentafluoropropyl group, a 2-
fluorobutyl group, a 2-chlorobutyl group, a 2-bromobutyl group,
a 4-fluorobutyl group, a 4-chlorobutyl group, a 4-bromobutyl
group, a 4,4,4-trifluorobutyl group, a 2,2,3,3,4,4,4-
CA 02241186 1998-06-23
28
heptafluorobutyl group, a perfluorobutyl group, a 2-fluoropentyl
group, a 2-chloropentyl group, a 2-bromopentyl group, a 5-
fluoropentyl group, a 5-chloropentyl group, a 5-bromopentyl
group, a perfluoropentyl group, a 2-fluorohexyl group, a 2-
chlorohexyl group, a 2-bromohexyl group, a 6-fluorohexyl group,
a 6-chlorohexyl group, a 6-bromohexyl group, a perfluorohexyl
group, a 2-fluoroheptyl group, a 2-chloroheptyl group, a 2-
bromoheptyl group, a 7-fluoroheptyl group, a 7-chloroheptyl
group, a 7-bromoheptyl group, a perfluoroheptyl group, etc.
The lower alkoxy group is a linear or branched alkyloxy
group having up to 6 carbon atoms. It includes, for example, a
methoxy group, an ethoxy group, an n-propyloxy group, an i-
propyloxy group, an n-butyloxy group, an i-butyloxy group, a
sec-butyloxy group, a t-butyloxy group, an n-pentyloxy group, an
i-pentyloxy group, a sec-pentyloxy group, a t-pentyloxy group, a
2-methylbutoxy group, an n-hexyloxy group, an i-hexyloxy group,
a t-hexyloxy group, a sec-hexyloxy group, a 2-methylpentyloxy
group, a 3-methylpentyloxy group, a 1-ethylbutyloxy group, a 2-
ethylbutyloxy group, a 1,1-dimethylbutyloxy group, a 2,2-
dimethylbutyloxy group, a 3,3-dimethylbutyloxy group, a 1-ethyl-
1-methylpropyloxy group, etc. Preferred are a methoxy group, an
ethoxy group, an n-propyloxy group, an i-propyloxy group, an n-
butyloxy group, an i-butyloxy group, a sec-butyloxy group, a t-
butyloxy group, etc.
The lower cycloalkyl group is a cycloalkyl group having
from 3 to 7 carbon atoms, and preferably includes a cyclopropyl
group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl
group, a cycloheptyl group, etc. More preferred are a
cyclopropyl group, a cyclobutyl group, etc.
The lower alkoxy-lower alkyl group is a linear or branched
alkyl group having up to 8 carbon atoms, as substituted with a
linear or branched alkyloxy group having up to 8 carbon atoms.
For example, this includes a methoxymethyl group, a methoxyethyl
group, a methoxypropyl group, a methoxybutyl group, a
methoxypentyl group, a methoxyhexyl group, a methoxyheptyl group,
CA 02241186 1998-06-23
29
a methoxyoctyl group, an ethoxymethyl group, an ethoxyethyl
group, an ethoxybutyl group, an ehtoxypentyl group, an
ehtoxyhexyl group, an ethoxyheptyl group, a ethoxyoctyl group, a
propyloxymethyl group, a propyloxyethyl group, a propyloxypropyl
group, a propyloxybutyl group, a propyloxypentyl group, an i-
propyloxymethyl group, an i-propyloxyethyl group, an i-
propyloxypropyl group, an i-propyloxybutyl group, an i-
propyloxypentyl group, a butyloxymethyl group, a butyloxyethyl
group, a butyloxypropyl group, a butyloxybutyl group, an i-
butyloxymethyl group, an i-butyloxyethyl group, an i-
butyloxypropyl group, an i-butyloxybutyl group, a sec-
butyloxymethyl group, a sec-butyloxyethyl group, a sec-
butyloxypropyl group, a sec-butyloxybutyl group, a t-
butyloxymethyl group, a t-butyloxyethyl group, a t-
butyloxypropyl group, a t-butyloxybutyl group, a pentyloxymethyl
group, a pentyloxyethyl group, a pentyloxypropyl group, a
pentyloxybutyl group, a hexyloxymethyl group, a hexyloxyethyl
group, a hexyloxypropyl group, etc.
The tri-lower alkylsilyl-lower alkyl group is a lower alkyl
group, such as that mentioned hereinabove, to which is bonded a
trimethylsilyl group, a triethylsilyl group, a tripropylsilyl
group or the like.
The lower alkylamino group is a linear or branched
alkylamino group having up to 6 carbon atoms. This includes, for
example, a methylamino group, an ethylamino group, an n-
propylamino group, an i-propylamino group, an n-butylamino group,
an i-butylamino group, a sec-butylamino group, a t-butylamino
group, an n-pentylamino group, an i-pentylamino group, a sec-
pentylamino group, a t-pentylamino group, a 2-methylbutylamino
group, an n-hexylamino group, a 1-methylpentylamino group, a 2-
methylpentylamino group, a 3-methylpentylamino group, a 4-
methylpentylamino group, a 1-ethylbutylamino group, a 2-
ethylbutylamino group, a 3-ethylbutylamino group, a 1,1-
dimethylbutylamino group, a 2,2-dimethylbutylamino group, a 3,3-
dimethylbutylamino group, a 1-ethyl-1-methylpropylamino group,
CA 02241186 1998-06-23
etc. More preferred are a methylamino group, an ethylamino group,
an n-propylamino group, an i-propylamino group, an n-butylamino
group, an i-butylamino group, a sec-butylamino group, a t-
butylamino group, etc.
The lower alkylthio group is a linear or branched alkylthio
group having up to 6 carbon atoms. This includes, for example, a
methylthio group, an ethylthio group, an n-propylthio group, an
i-propylthio group, an n-butylthio group, an i-butylthio group,
a sec-butylthio group, a t-butylthio group, an n-pentylthio
group, an i-pentylthio group, a sec-pentylthio group, a t-
pentylthio group, a 2-methylbutylthio group, an n-hexylthio
group, an i-hexylthio group, a t-hexylthio group, a sec-
hexylthio group, a 2-methylpentylthio group, a 3-
methylpentylthio group, a 1-ethylbutylthio group, a 2-
ethylbutylthio group, a 1,1-dimethylbutylthio group, a 2,2-
dimethylbutylthio group, a 3,3-dimethylbutylthio group, a 1-
ethyl-1-methylpropylthio group, etc. More preferred are a
methylthio group, an ethylthio group, an n-propylthio group, an
i-propylthio group, an n-butylthio group, an i-butylthio group,
a sec-butylthio group, a t-butylthio group, etc.
The lower alkylthio-lower alkyl group is a linear or
branched alkyl group having up to 6 carbon atoms, such as that
mentioned hereinabove, as substituted with a linear or branched
alkylthio group having up to 6 carbon atoms, such as that
mentioned hereinabove.
The lower alkoxycarbonyl group is a linear or branched
alkyloxycarbonyl group with a alkyl moiety having up to 6 carbon
atoms. This includes, for example, a methoxycarbonyl group, an
ethoxycarbonyl group, an n-propyloxycarbonyl group, an i-
propyloxycarbonyl group, an n-butyloxycarbonyl group, an i-
butyloxycarbonyl group, a sec-butyloxycarbonyl group, a t-
butyloxycarbonyl group, an n-pentyloxycarbonyl group, an i-
pentyloxycarbonyl group, a sec-pentyloxycarbonyl group, a t-
pentyloxycarbonyl group, a 2-methylbutyloxycarbonyl group, an n-
hexyloxycarbonyl group, an i-hexyloxycarbonyl group, a t-
CA 02241186 1998-06-23
31
hexyloxycarbonyl group, a sec-hexyloxycarbonyl group, a 2-
methylpentyloxycarbonyl group, a 3-methylpentyloxycarbonyl group,
a 1-ethylbutyloxycarbonyl group, a 2-ethylbutyloxycarbonyl group,
a 1,1-dimethylbutyloxycarbonyl group, a 2,2-
dimethylbutyloxycarbonyl group, a 3,3-dimethylbutyloxycarbonyl
group, a 1-ethyl-1-methylpropyloxycarbonyl group, etc. More
preferred are a methoxycarbonyl group, an ethoxycarbonyl group,
an n-propyloxycarbonyl group, an i-propyloxycarbonyl group, an
n-butyloxycarbonyl group, an i-butyloxycarbonyl group, a sec-
butyloxycarbonyl group, a t-butyloxycarbonyl group.
The lower alkanoyl group is a linear or branched
alkylcarbonyl group having up to 6 carbon atoms. This includes,
for example, a methylcarbonyl group, an ethylcarbonyl group, an
n-propylcarbonyl group, an i-propylcarbonyl group, an n-
butylcarbonyl group, an i-butylcarbonyl group, a sec-
butylcarbonyl group, a t-butylcarbonyl group, an n-
pentylcarbonyl group, an i-pentylcarbonyl group, a sec-
pentylcarbonyl group, a t-pentylcarbonyl group, a 2-
methylbutylcarbonyl group, an n-hexylcarbonyl group, an i-
hexylcarbonyl group, a t-hexylcarbonyl group, a sec-
hexylcarbonyl group, a 2-methylpentylcarbonyl group, a 3-
methylpentylcarbonyl group, a 1-ethylbutylcarbonyl group, a 2-
ethylbutylcarbonyl group, an 1,1-dimethylbutylcarbonyl group, a
2,2-dimethylbutylcarbonyl group, a 3,3-dimethylbutylcarbonyl
group, a 1-ethyl-1-methylpropylcarbonyl group, etc. More
preferred are a methylcarbonyl group, an ethylcarbonyl group, an
n-propylcarbonyl group, an i-propylcarbonyl group, an n-
butylcarbonyl group, an i-butylcarbonyl group, a sec-
butylcarbonyl group, a t-butylcarbonyl group, etc.
The lower alkanesulfonyl group is a linear or branched
alkanesulfonyl group having up to 6 carbon atoms. This includes,
for example, a methanesulfonyl group, an ethanesulfonyl group, a
1-propanesulfonyl group, a 2-propanesulfonyl group, a 1-
butanesulfonyl group, a 2-butanesulfonyl group, a 1,1-
dimethylethanesulfonyl group, a 1-(2-methylpropane)sulfonyl
CA 02241186 1998-06-23
_ 32
group, a 1-pentanesulfonyl group, a 2-pentanesulfonyl group, a
3-pentanesulfonyl group, a 1-(3-methylbutane)sulfonyl group, a
1,1-dimethylpropanesulfonyl group, a 1-hexanesulfonyl group, a
2-hexanesulfonyl group, a 3-hexanesulfonyl group, a 1-(2-
methylpentane)sulfonyl group, a 1-(3-methylpentane)sulfonyl
group, a 1-(4-methylpentane)sulfonyl group, a 2-
ethylbuthanesulfonyl group, a 3-ethylbutanesulfonyl group, a
1,1-dimethylbutanesulfonyl group, a 2,2-dimethylbutanesulfonyl
group, a 3,3-dimethylbutanensulfonyl group, a 1-ethyl-1-
methylpropanesulfonyl group, etc.
The aryl group includes, for example, a phenyl group, a
naphthyl group, etc. The terminology "naphthyl" as referred to
herein includes 1-naphthyl and 2-naphthyl. The benzene ring or
the naphthalene ring in this group may optionally be substituted
by one or more substituents selected from a halogen atom, a
lower alkyl group, a cyano group, a nitro group, a
trifluoromethyl groups and the like, such as those mentioned
hereinabove.
The arylsulfonyl group is a sulfonyl group, to which a.s
bonded an aryl group such as that mentioned hereinabove, and
includes, for example, a benzenesulfonyl group, a
toluenesulfonyl group, a naphthalenesulfonyl group, etc.
The aryl-lower alkyl group is a lower alkyl group, such as
that mentioned hereinabove, to which is bonded an aryl group
such as that mentioned hereinabove, and includes, for example, a
benzyl group, a 1-phenylethyl group, a 2-phenylethyl group, a
phenylpropyl group, a phenylbutyl group, a phenylpentyl group, a
phenylhexyl group, a naphthylmethyl group, a naphthylethyl group,
a naphthylpropyl group, a naphthylbutyl group, a naphthylpentyl
group, a naphthylhexyl group, etc.
The aryl-lower alkyloxy group includes, for example, a
benzyloxy group, a 1-phenylethyloxy group, a 2-phenylethyloxy
group, a phenylpropyloxy group, a phenylbutyloxy group, a
phenylpentyloxy group, a phenylhexyloxy group, a
naphthylmethyloxy group, a naphthylethyloxy group, a
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naphthylpropyloxy group, a naphthylbutyloxy group, a
naphthylpentyloxy group, etc., in which the benzene ring or the
naphthalene ring may optionally be substituted.
The arylsulfonyl-lower alkyl group is a lower alkyl group,
such as that mentioned hereinabove, to which is bonded an
arylsulfonyl group such as that mentioned hereinabove, and
includes, for example, a benzenesulfonylmethyl group, a
toluenesulfonylmethyl group, a naphthalenesulfonylmethyl group,
etc.
The arylsulfonylamino group is an amino group to which is
bonded an arylsulfonyl group such as that mentioned hereinabove,
and this includes, for example, a benzenesulfonylamino group, a
toluenesulfonylamino group, a naphthalenesulfonylamino group,
etc.
The aryloxy group is an aryl group, such as that mentioned
hereinabove, to which is bonded an oxygen atom, and this
includes, for example, a phenoxy group, a 1-naphthoxy group, a
2-naphthoxy group, etc.
The arylcarbonyl group is a carbonyl group to which is
bonded an aryl group such as that mentioned hereinabove, and
this includes, for example, a phenylcarbonyl group, a
naphthylcarbonyl group, etc.
The arylcarbonylamino group is an amino group to which is
bonded an arylcarbonyl group such as that mentioned hereinabove,
and this includes, for example, a phenylcarbonylamino group, a
naphthylcarbonylamino group, etc.
The aryl-lower alkenyl group is an alkenyl group having 6
or less carbon atoms, which is substituted by an aryl group such
as that mentioned hereinabove, and this includes, for example, a
phenylethenyl group, a naphthylethenyl group, etc.
The heterocyclic group includes, for example, a pyridyl
group, a quinolyl group, an isoquinolyl group, a thiazolyl group,
a thiadiazolyl group, a benzofuranyl group, a dibenzofuranyl
group, a thianaphthalenyl group, a 1H-1,2,3-triazolyl group, a
1,2,4-triazolyl group, a tetrazolyl group, a furyl group, a
CA 02241186 1998-06-23
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thienyl group, a pyrrolyl group, an imidazolyl group, a
pyrimidinyl group, an indolyl group, a benzimidazolyl group, etc.
The heterocyclic group may optionally be substituted by one or
more substituents of halogen atoms and lower alkyl groups, such
as those mentioned hereinabove, and the substituted heterocyclic
group of that type includes, for example, a haloisoquinolyl
group, a methylisoquinolyl group, etc.
The heterocyclic lower alkyl group means a lower alkyl
group, such as that mentioned hereinabove, as substituted by a
heterocyclic group, such as that mentioned hereinabove. This
includes, for example, a pyridylmethyl group. The halo-
heterocyclic lower alkyl group is a heterocyclic lower alkyl
group, such as that mentioned hereinabove, in which the
heterocyclic moiety is substituted with one or more halogens.
The heterocyclic lower alkylamino group is an amino group
as substituted with a heterocyclic lower alkyl group, such as
that mentioned hereinabove, and this includes, for example, a
pyridylmethylamino group, etc. The heterocyclic lower
alkylcarbamoyl group is a carbamoyl group as substituted with a
heterocyclic lower alkyl group, such as that mentioned
hereinabove, and this includes, for example, a
pyridylmethylcarbamoyl group, etc.
The terminology "pyridyl" as referred to herein includes 2-
pyridyl, 3-pyridyl and 4-pyridyl, for which the bonding position
is not specifically defined. The same shall apply to the other
heterocyclic groups as referred to herein, or that is, the
bonding positions of the heterocyclic groups as referred to
herein are not specifically defined.
The lower alkylenedioxybenzyl group includes, for example,
a methylenedioxybenzyl group, an ethylenedioxybenzyl group, a
propylenedioxybenzyl group, etc.
A suitable heterocyclic group used herein means a saturated
or unsaturated mono- or polycyclic hetero ring containing at
least one hetero atom such as an oxygen atom, a sulfur atom, a
ni t rogen atom, etc.
CA 02241186 1998-06-23
Preferable examples thereof include the following
heterocyclic groups:
~ 7- to 12-membered, preferably 9- or 10-membered unsaturated
condensed heterocyclic group (preferably bicyclic group)
having 1 to 5 nitrogen atoms, such as indolyl, isoindolyl,
indolidinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl,
benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e. g.
tetrazolo[1,5-b]pyridazinyl, etc.),
dihydrotriazolopyridazinyl, or the like;
~ 7- to 12-membered, preferably 9- or 10-membered unsaturated
condensed heterocyclic group (preferably bicyclic group)
having 1 to 3 sulfur atoms or S,S-dioxide thereof, such as
dithianaphthalenyl (e. g. 4H-1,3-dithianaphthalenyl, 1,4-
dithianaphthalenyl, etc.), benzothiophenyl or S,S-dioxide
thereof (e. g. benzo[a]thiophenyl or S,S-dioxide thereof,
benzo[b]thiophenyl or S,S-dioxide thereof, etc.), or the
like;
~ 3- to 8-membered, preferably 5- or 6-membered unsaturated
hetero monocyclic group having 1 to 4 nitrogen atoms, such as
pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its
N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e. g.
4H-1,2,3-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl,
etc.), dihydrotriazinyl (e. g. 4,5-dihydro-1,2,4-triazinyl,
2,5-dihydro-1,2,4-triazinyl, etc.), or the like;
~ 3- to 8-membered, preferably 5- or 6-membered saturated
hetero monocyclic group having 1 to 4 nitrogen atoms, such as
azetydinyl, pyrrolidinyl, imidazolydinyl, piperidinyl,
pyrazolydinyl, piperadinyl, or the like;
~ 7- to 12-membered, preferably 9- or 10-membered unsaturated
condensed heterocyclic group (preferably bicyclic group)
having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as
benzooxazolyl, benzooxadiazolyl, or the like;
~ 3- to 8-membered, preferably 5- or 6-membered unsaturated
hetero monocyclic group having 1 to 2 oxygen atoms and 1 to 3
nitrogen atoms, such as oxazolyl, isooxazolyl, oxadiazolyl
CA 02241186 1998-06-23
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(e. g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl;
etc.), or the like;
~ 3- to 8-membered, preferably 5- or 6-membered saturated
hetero monocyclic group having 1 to 2 oxygen atoms and 1 to 3
nitrogen atoms, such as morpholinyl or the like;
~ 7- to 12-membered, preferably 9- or 10-membered unsaturated
condensed heterocyclic group (preferably bicyclic group)
having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as
benzothiazolyl, benzothiadiazolyl, or the like;
~ 3- to 8-membered,,preferably 5- or 6-membered unsaturated
hetero monocyclic group having 1 to 2 sulfur atoms and 1 to 3
nitrogen atoms, such as thiazolyl, 1,2-thiazolyl,
thiadiazolyl (e. g. 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, etc.), or the like;
~ 3- to 8-membered, preferably 5- or 6-membered saturated
hetero monocyclic group having 1 to 2 sulfur atoms and 1 to 3
nitrogen atoms, such as thiazolydinyl;
~ 3- to 8-membered, preferably 5- or 6-membered unsaturated
hetero monocyclic group having one sulfur atom, such as
thienyl or the like; etc.
Suitable ~~esterified carboxyl groups" are exemplified
below.
The ester portion of the esterified carboxyl group
suitably include a lower alkyl ester, such as methyl ester,
ethyl ester, propyl ester, isopropyl ester, butyl ester,
isobutyl ester, tertiary butyl ester, pentyl ester, or hexyl
ester, which may have at least one appropriate substituent.
Examples of the lower alkyl ester include lower
alkanoyloxy(lower)alkyl ester, such as acetoxymethyl ester,
propionyloxymethyl ester, butyryloxymethyl ester,
valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxy
methyl ester, 1-(or 2-)acetoxyethyl ester, 1-(2-, or 3-
)acetoxypropyl ester, 1-(2-, 3- or 4-)acetoxybutyl ester, 1-(or
2-)propionyloxyethyl ester, 1-(2-, or 3-)propionyloxypropyl
ester, 1-(or 2-)butyryloxyethyl ester, 1(or 2-
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)isobutyryloxyethyl ester, 1-(or 2-)pivaloyloxyethyl ester, 1-
(or 2-)hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-
ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester,
or 1-(or 2-)pentanoyloxyethyl ester, lower
alkanesulfonyl(lower)alkyl ester, such as 2-mesylethyl ester,
mono(di, or tri)halo(lower)alkyl ester, such as 2-iodoethyl
ester, 2,2,2-trichloroethyl ester, lower
alkoxycarbonyloxy(lower)alkyl ester, such as
methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester,
propoxycarbonyloxymethyl ester, tertiary-butoxycarbonyloxymethyl
ester, 1-(or 2-)methoxycarbonyloxyethyl ester, 1-(or 2-
)ethoxycarbonyloxyethyl ester, or 1-(or 2-
)isopropoxycarbonyloxyethyl ester, phthalizilidene(lower)alkyl
ester or (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester,
such as (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-ethyl-
2-oxo-1,3-dioxol-4-yl)methyl ester, or (5-propyl-2-oxo-1,3-
dioxol-4-yl)ethyl ester, lower alkenyl ester, such as vinyl
ester or allyl ester, lower alkynyl ester, such as ethynyl ester
or propinyl ester, ar(lower)alkyl ester which may have at least
one appropriate substituent, such as benzyl ester, 4-
methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester,
trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester,
3,4-dimethoxybenzyl ester, or 4-hydroxy-3,5-di-tertiary-
butylbenzyl ester, aryl ester which may have at least one
appropriate substituent, such as phenyl ester, 4-chlorophenyl
ester, tolyl ester, tertiary-butylphenyl ester, xylyl ester,
mesityl ester, or cumenyl ester, phthalidyl ester, etc.
Preferable examples of a carboxyl groups protected by
esterification include lower alkoxycarbonyl and phenyl(or
nitrophenyl)(C1-C~)alkoxycarbonyl. Most preferred are
methoxycarbonyl, ethoxycarbonyl, and benzyloxycarbonyl.
Suitable amidated carboxyl groups include the following:
~ a carbamoyl group;
~ a mono- or di-lower alkyl carbamoyl group (as a lower alkyl
group, those as described above can be used), such as
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38
methylcarbamoyl, dimethylcarbamoyl, isopropylcarbamoyl, n-
butylcarbamoyl, t-butylcarbamoyl, N-methyl-N-
(pyridylmethyl)carbamoyl, or the like;
~ an aryl(lower alkyl)carbamoyl (as an aryl group and a lower
alkyl group, those as described above can be used), such as
benzylcarbamoyl, 3,4-methylenedioxybenzylcarbamoyl,
diaminobenzylcarbamoyl, or phenethylcarbamoyl;
~ a cyclo(lower alkyl)carbamoyl having 3 to 7 carbon atoms (as
a cyclo lower alkyl group, those as described above can be
used), such as cyclopropylcarbamoyl, cyclobutylcarbamoyl,
cyclopentylcarbamoyl, cyclohexylcarbamoyl or the like;
~ an arylcabamoyl group (as an aryl group, those as described
above can be used), such as phenylcarbamoyl,
naphthylcarbamoyl, or the like;
~ a heterocyclic carbamoyl group (as a heterocyclic group,
those as described above can be used), such as
thiazolylcarbamoyl, thiadiazolylcarbamoyl, pyridyl-carbamoyl,
triazolylcarbamoyl, tetrazolylcarbamoyl, N-methyl-N-
pyridinecarbamoyl, morpholinocarbamoyl, or the like;
~ a heterocyclic(lower alkyl)carbamoyl group (as a heterocyclic
lower alkyl group, those as described above can be used),
such as morpholinoethylcarbamoyl, pyridylmethylcarbamoyl,
methylenedioxybenzylcarbamoyl, or the like;
~ an N-di-substituted carbamoyl group containing nitrogen as a
member of a nitrogen-containing heterocyclic ring, such as
morpholinocarbonyl, thiomorpholinocarbonyl, 1-
perhydroazepinylcarbonyl, l,l-dioxothiazolydinecarbonyl,
piperidinocarbonyl, 1-piperazinylcarbonyl, 4-(2-
hydroxyethyl)-1-piperazinylcarbonyl, 4-methyl-1-
piperazinylcarbonyl, carboxypyrrolidinocarbonyl, or the like;
~ a substituted sulfonylcarbomoyl group, etc.
The substituent for the substituted sulfonyl-carbamoyl
group includes the above-described groups such as the alkyl
group having carbon atoms up to 8, the halo lower alkyl group,
the aryl lower alkyl group, the hydroxy-lower alkyl group, the
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tri(lower alkyl)silyl(lower alkyl) group, the lower alkoxy-lower
alkyl group, the lower alkylthio-lower alkyl group, the
heterocyclic group, the aryl group, and the like. The aryl group
may be sutstituted by a halogen atom, a lower alkyl group a halo
lower alkyl group, a lower alkoxy group, a nitro group, or the
like. Specific examples of the substituted sulfonylcarbamoyl
group include naphthylsulfonylcarbamoyl, benzenesulfonyl-
carbamoyl, nitrobenzenesulfonylcarbamoyl, trihalobenzene-
sulfonylcarbamoyl, lower alkoxybenzenesulfonylcarbamoyl,
halobenzenesulfonylcarbamoyl, mono- or di-(lower alkyl)-
benzenesulfonylcarbamoyl, alkanesulfonylcarbamoyl having 1 to 8
carbon atoms, such as t-butylsulfonylcarbamoyl,
butylsulfonylcarbamoyl, propylsulfonylcarbamoyl, isopropyl-
sulfonylcarbamoyl, methylsulfonylcarbamoyl, octylsulfonyl-
carbamoyl, pentylsulfonylcarbamoyl, isopentylsulfonylcarbamoyl,
hexylsulfonylcarbamoyl, or the like, trihalo(lower) alkyl-
sulfonylcarbamoyl, phenyl(lower)alkylsulfonylcarbamoyl, tri-
(lower)alkylsulfonylcarbamoyl, lower alkylthio(lower) alkyl-
sulfonylcarbamoyl, lower alkoxy(lower)alkylsulfonylcarbamoyl,
quinolinesulfonylcarbamoyl, or the like.
Suitable acyl groups include aliphatic acyl, aromatic acyl,
heterocyclic acyl, and aliphatic aryl substituted with an
aromatic group or a heterocyclic group, which are derived from
carboxylic acid, carbonic acid, sulfonic acid, carbamic acid,
and the like.
Examples of the aliphatic acyl include saturated or
unsaturated non-cyclic or cyclic ones, for example, alkanoyl
such as lower alkanoyl (e. g. formyl, acetyl, propionyl, butyryl,
isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.),
alkylsulfonyl such as lower alkyl sulfonyl (e. g. mesyl,
ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl,
isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.),
carbamoyl, N-alkylcarbamoyl (e. g. methylcarbamoyl,
ethylcarbamoyl, etc.), alkoxycarbonyl such as lower alkoxy
carbonyl (e. g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
CA 02241186 1998-06-23
butoxycarbonyl, tertiary-butoxycarbonyl, etc.),
alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e. g.
vinyloxycarbonyl, allyloxycarbonyl, etc.), alkenoyl such as
lower alkenoyl (e. g. acryloyl, methacryloyl, chlotonoyl, etc.),
cycloalkanecarbonyl such as cyclo(lower)alkanecarbonyl (e. g.
cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,
etc.)~ and the like.
Examples of the aromatic acyl include C6-Clo aroyl (e. g.
benzoyl, toluoyl, xyloyl, etc.), N-(C6-Clo)arylcarbamoyl (e.g. N-
phenylcarbamoyl, N-tolylcarbamoyl, N-naphthylcarbamoyl, etc.),
Ce-Clo arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.), and the
like.
Examples of the heterocyclic acyl include heterocyclic
carbonyl, heherocyclic (lower)alkanoyl (e. g. heterocyclic acetyl,
heterocyclic propanoyl, heterocyclic butanoyl, heterocyclic
pentanoyl, heterocyclic hexanoyl, etc.), heterocyclic
(lower)alkenoyl (e. g. heterocyclic propenoyl, heterocyclic
butenoyl, heterocyclic pentenoyl, heterocyclic hexenoyl, etc.)
heterocyclic glyoxyloyl, heterocyclic sulfinyl, heterocyclic
sulfonyl, etc.
The aromatic group-bound aliphatic acyl includes
aralkoxycarbonyl such as phenyl(lower)alkoxycarbonyl (e. g.
benzyloxycarbonyl, phenethyloxycarbonyl, etc.).
These acyl groups may be substituted with one or more
appropriate substituent, such as a nitro group. An example
thereof is nitroaralkoxycarbonyl (e. g. nitrobenzyloxy-carbonyl,
etc.).
Preferred salts of the benzimidazole derivatives of the
present invention are non-toxic, ordinary pharmaceutically
acceptable salts thereof. For example, mentioned are salts of
the derivatives with bases as well as acid-addition salts of the
derivatives, which include, for example, salts thereof with
inorganic bases, such as salts with alkali metals (e. g., sodium,
potassium); salts with alkaline earth metals (e. g., calcium,
magnesium); ammonium salts; salts with organic amines (e. g.,
CA 02241186 1998-06-23
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triethylamine, pyridine, picoline, ethanolamine, triethanolamine,
dicyclohexylamine, N,N~-dibenzylethylenediamine); salts with
inorganic acids (e. g., hydrochloric acid, hydrobromic acid,
sulfuric acid, phosphoric acid); salts with organic carboxylic
acids (e. g., formic acid, acetic acid, trifluoroacetic acid,
malefic acid, tartaric acid); salts with sulfonic acids (e. g.,
methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic
acid); salts with basic or acidic amino acids (e. g., arginine,
aspartic acid, glutamic acid), etc.
The compounds of the invention could contain one or more
chiral centers, therefore they could be enantiomers or
diastereomers. Few of the compounds containing alkenyl group
could also be cis- or traps- isomers. In both cases, each of
such isomers as well as the mixture thereof are within the scope
of this invention.
The compounds of the invention can also exist as tautomers,
and individual of such tautmers and the mixture thereof are
within the scope of this invention.
The compounds of the invention and their salts can be
solvate, which are also within the invention. The solvent for
the solvate is preferably water or ethanol.
Specific examples of benzimidazole derivatives of formula
(IX) include 6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-
methylbenzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-
ylmethyl)-2-ethylbenzimidazole, 5-benzenesulfonylcarbamoyl-1-(2-
chlorobenzyl)-2-methylbenzimidazole, 5-(4-chlorobenzenesulfonyl-
carbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole, 1-(2-
chlorobenzyl)-2-methyl-5-(2-naphthalenesulfonylcarbamoyl)-
benzimidazole, 1-(2-chlorobenzyl)-6-methanesulfonylcarbamoyl-2-
methylbenzimidazole, 6-(1-butanesulfonylcarbamoyl)-1-(2-chloro-
benzyl)-2-methylbenzimidazole, 1-(2-chlorobenzyl)-2-methyl-6-(1-
octanesulfonylcarbamoyl)benzimidazole, 1-(2-chlorobenzyl)-2-
methyl-6-(2-propanesufonylcarbamoyl)benzimidazole, 1-(biphenyl-
4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole,
6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-
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methylbenzimidazole, 1-(biphenyl-4-ylmethyl)-6-(1-butane-
sulfonylcarbamoyl)-2-ethylbenzimidazole, 6-benzenesulfonyl-
carbamoyl-1-(biphenyl-4-ylmethyl)-2-trifluoromethylbenzimidazole,
5-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-trifluoro-
methylbenzimidazole, 6-benzenesulfonylcarbamoyl-2-cyclopropyl-1-
(2-fluorobenzyl)benzimidazole, N-benzenesulfonyl-3-[1-(2-chloro-
benzyl)-2-methylbenzimidazol-6-yl]acrylamide, N-benzenesulfonyl-
2-[1-(2-chlorobenzyl)-2-methylbenzimidazol-6-yl]acetamide,, 1-(2-
chlorobenzyl)-2-methyl-6-(2-naphthalenesulfonylcarbamoyl)-
benzimidazole, 1-(2-chlorobenzyl)-2-methyl-6-(1-naphthalene-
sulfonylcarbamoyl)benzimidazole, 6-(4-chlorobenzenesulfonyl-
carbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole, 6-(3-
chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methyl-
benzimidazole, 5-benzenesulfonylcarbamoyl-2-benzyl-1-(2-
chlorobenzyl)benzimidazole, 6-benzenesulfonylcarbamoyl-2-benzyl-
1-(2-chlorobenzyl)benzimidazole, 6-benzenesulfonylcarbamoyl-1-
(biphenyl-4-ylmethyl)-2-methylbenzimidazole, 1-(2-chlorobenzyl)-
2-methyl-6-trifluoromethanesulfonylcarbamoylbenzimidazole, 6-
benzenesulfonylcarbamoyl-1-(2,4-dichlorobenzyl)-2-methyl-
benzimidazole, 1-(2-chlorobenzyl)-6-(4-methoxybenzenesulfonyl-
carbamoyl)-2-methylbenzimidazole, 1-(2-chlorobenzyl)-2-methyl-6-
(a-toluenesulfonylcarbamoyl)benzimidazole, 1-(2-chlorobenzyl)-6-
(2,5-dimethylbenzenesulfonylcarbamoyl)-2-methylbenzimidazole, 1-
(2-chlorobenzyl)-2-methyl-6-(4-nitrobenzenesulfonylcarbamoyl)-
benzimidazole, 1-(2-chlorobenzyl)-2-methyl-6-[4-(trifluoro-
methyl)benzenesulfonylcarbamoyl]benzimidazole, 6-(2-chloro-
benzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methyl-
benzimidazole, 6-benzenesulfonylcarbamoyl-2-benzyl-1-(2,4-
dichlorobenzyl)benzimidazole, 5-benzenesulfonylcarbamoyl-2-
benzyl-1-(2,4-dichlorobenzyl)benzimidazole, 6-benzenesulfonyl-
carbamoyl-1-(biphenyl-4-ylmethyl)-2-hydroxybenzimidazole, 6-
benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-mercapto-
benzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-
ylmethyl)-2-methoxybenzimidazole, 6-benzenesulfonylcarbamoyl-1-
(biphenyl-4-ylmethyl)-2-carboxybenzimidazole, 6-benzenesulfonyl-
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carbamoyl-1-(biphenyl-4-ylmethyl)-2-methylaminobenzimidazole, 2-
amino-6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-
benzimidazole, 6-benzenesulfonylc.arbamoyl-1-(biphenyl-4-
ylmethyl)-2-n-propylbenzimidazole, 6-benzenesulfonylcarbamoyl-1-
(biphenyl-4-ylmethyl)-2-n-heptylbenzimidazole, 6-benzene-
sulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-chloromethyl-
benzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-
ylmethyl)-2-methoxymethylbenzimidazole, 6-benzenesulfonyl-
carbamoyl-1-(biphenyl-4-ylmethyl)-2-i-propylbenzimidazole, 6-
benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methylthio-
benzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-
ylmethyl)-2-ethylthiobenzimidazole, 6-benzenesulfonylcarbamoyl-
1-(biphenyl-4-ylmethyl)-2-n-propylthiobenzimidazole, 6-benzene-
sulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-hexylthio-
benzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-
ylmethyl)benzimidazole, 6-benzenesulfonylcarbamoyl-1-(2,4-
difluorobenzyl)-2-methylbenzimidazole, 6-benzenesulfonyl-
carbamoyl-1-(biphenyl-4-ylmethyl)-2-phenylbenzimidazole, 6-
benzenesulfonylcarbamoyl-2-methyl-1-(2-nitrobenzyl)-
benzimidazole, 6-benzenesulfonylcarbamoyl-2-methyl-1-benzyl-
benzimidazole, 6-benzenesulfonylcarbamoyl-2-methyl-1-(4-nitro-
benzyl)benzimidazole, 6-benzenesulfonyl-carbamoyl-1-(4-
benzyloxybenzyl)-2-methylbenzimidazole, 6-benzenesulfonylamino-
methyl-1-(2-chlorobenzyl)-2-methylbenzimidazole, N-
benzenesulfonyl-3-[1-(2-chlorobenzyl)-2-methylbenzimidazol-6-
yl]propionamide, 6-benzenesulfonylcarbamoyl-2-methyl-1-[4-
(1,2,3-thiadiazol-4-yl)benzyl]benzimidazole, 1-(2-chlorobenzyl)-
2-methyl-6-(8-quinolinesulfonylcarbamoyl)benzimidazole, 6-(4-t-
butylbenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methyl-
benzimidazole, 6-benzenesulfonylcarbamoyl-2-methyl-1-[4-
(trifluoromethyl)benzyl]benzimidazole, 5-benzenesulfonyl-
carbamoyl-2-methylbenzimidaozle, 1-(biphenyl-4-ylmethyl)-6-(1-
butanesulfonylcarbamoyl)-2-methoxymethylbenzimidazole, 1-(4-
benzyloxybenzyl)-6-(1-butanesulfonylcarbamoyl)-2-methoxymethyl-
benzimidazole, 6-(1-butanesulfonylcarbamoyl)-1-(2,4-
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dichlorobenzyl)-2-methoxymethylbenzimidazole, 1-(2-chloro-
benzyl)-2-methyl-6-(1-propanesulfonylcarbamoyl)benzimidazole, 6-
ethanesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazo1e,
6-(propanesultam-1-ylcarbonyl)-1-(2-chlorobenzyl)-2-methyl-
benzimidazole, 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-
ylmethyl)-2-cyclopropylbenzimidazole, 1-(2-chlorobenzyl)-2-
methyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole, 1-(2-
chlorobenzyl)-2-methyl-6-[(3-methylbutane)sulfonylcarbamoyl]-
benzimidazole, 1-(2-chlorobenzyl)-6-(1-hexanesulfonylcarbamoyl)-
2-methylbenzimidazole, 7-(1-butanesulfonylcarbamoyl)-1-(2,4-
dichlorobenzyl)-2-methylbenzimidazole, 1-(2-chlorobenzyl)-2-
methyl-6-[1-[3-(trimethylsilyl)propane]sulfonylcarbamoyl]-
benzimidazole, 4-(1-butanesulfonylcarbamoyl)-1-(2,4-
dichlorobenzyl)-2-methylbenzimidazole, 1-(4-benzyloxybenzyl)-6-
(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole, 6-(1-
butanesulfonylcarbamoyl)-1-[(2'-cyanobiphenyl-4-yl)methyl]-2-
methylbenzimidazole, 6-(1-ethanesulfonyl-carbamoyl)-1-[(2'-
fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole, 6-(1-
butanesulfonylcarbamoyl)-1-[(3-fluorobiphenyl-4-yl)methyl]-2-
methylbenzimidazole, 1-(2-chlorobenzyl)-6-[(2-methoxyethane)-
sulfonylcarbamoyl]-2-methylbenzimidazole, 1-(2-chlorobenzyl)-6-
(1-hexanesulfonylcarbamoyl)-2-methylbenzimidazole, 1-(2,4-
dichlorobenzyl)-2-methyl(1-pentanesulfonylcarbamoyl)-
benzimidazole, 1-(biphenyl-4-ylmethyl)-2-ethyl-6[1-[3-(methyl-
thio)propane]sulfonylcarbamoyl]benzimidazole, 1-(4-biphenyl-
methyl)-2-ethyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole, 6-
(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-ethyl-
benzimidazole, 1-(4-biphenylmethyl)-2-ethyl-6-[1-(3-methyl)-
butanesulfonylcarbamoyl]benzimidazole, 5-(1-butanesulfonyl-
carbamoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 1-(4-
biphenylmethyl)-5-(1-butanesulfonylcarbamoyl)-2-ethyl-
benzimidazole, 1-(4-biphenylmethyl)-2-ethyl-6-(2-methoxy-
ethanesulfonylcarbamoyl)benzimidazole, 6-(1-butanesulfonyl-
carbamoyl)-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole,
6-(1-butanesulfonylcarbamoyl)-1-[4-(3,4-dichlorobenzyloxy)-
CA 02241186 1998-06-23
benzyl]-2-ethylbenzimidazole, 6-(1-butanesulfonylcarbamoyl)-1-
[sec-(2,4-dichlorophenethyl)]-2-methylbenzimidazole, 6-(1-
butanesulfonylcarbamoyl)-1-[4-(2-pyridyl)benzyl]-2-methyl-
benzimidazole, 6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichloro-
benzyl)-2,4-dimethylbenzimidazole, 6-(1-butanesulfonyl-
carbamoyl)-2-methyl-1-(4-phenoxybenzyl)benzimidazole, 6-(butane-
sulfonylcarbamoyl)-2-methyl-1-(2-pyridylmethyl)benzimidazole, 1-
[(4-benzoylamino)benzyl]-6-(1-butanesulfonylcarbamoyl)-2-methyl-
benzimidazole, 6-(1-butanesulfonylcarbamoyl)-2-methyl-[4-(2-
phenylethyl)benzyl]benzimidazole, 1-[(4-benzoyl)benzyl]-6-(1-
butanesulfonylcarbamoyl)-2-methylbenzimidazole, 6-(1-butane-
sulfonylcarbamoyl)-2-methyl-[4-(2-phenylethenyl)benzyl]-
benzimidazole, 1-(dibenzofuran-2-ylmethyl)-6-(1-butanesulfonyl-
carbamoyl)-2-methylbenzimidazole, 6-(1-butanesulfonylcarbamoyl)-
1-(2,4-dichlorobenzyl)-2-hydroxybenzimidazole, 6-(1-butane-
sulfonylcarbamoyl)-2-methyl-1-(2-quinolylmethyl)benzimidazole,
and 6-(1-butanesulfonylcarbamoyl)-2-methyl-1-[3-(4-bromoiso-
quinolyl)methyl]benzimidazole, etc.
Specific examples of compounds of formula (X) include 1-(2-
cyanobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole, 6-ethoxy-
carbonyl-2-N-propyl-1-(2-pyridylmethyl)benzimidazole, 6-ethoxy-
carbonyl-1-methyl-2-n-propylbenzimidazole, 1-n-butyl-6-ethoxy-
carbonyl-2-n-propylbenzimidazole, 1-(biphenyl-4-ylmethyl)-6-
ethoxycarbonyl-2-methylbenzimidazole, 6-ethoxycarbonyl-1-(2-
methoxybenzyl)-2-methylbenzimidazole, 6-ethoxycarbonyl-1-(4-
methoxybenzyl)-2-methylbenzimidazole, 1-[2-(benzenesulfonyl-
methyl)benzyl]-6-ethoxycarbonyl-2-methylbenzimidazole, 1-(2-
cyanobenzyl)-6-(2-cyanobenzyloxycarbonyl)-2-methylbenzimidazole,
1-(biphenyl-2-ylmethyl)-6-ethoxycarbonyl-2-methyl-benzimidazole,
6-ethoxycarbonyl-2-methyl-1-(2-naphthylmethyl)benzimidazole, 1-
(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-ethylbenzimidazole, 6-
ethoxycarbonyl-2-n-propyl-1-i-propylbenzimidazole, 2-benzyl-6-
ethoxycarbonyl-1-methylbenzimidazole, 6-carboxy-1-methyl-2-n-
propylbenzimidazole, 6-carboxy-2-n-propyl-1-i-propyl-
benzimidazole, 1-n-butyl-6-carboxy-2-n-propylbenzimidazole, 6-
CA 02241186 1998-06-23
46
carboxy-2-methyl-1-(2-nitrobenzyl)benzimidazole, 1-(biphenyl-4-
ylmethyl)-6-carboxy-2-methylbenzimidazole, 6-carboxy-1-(2-
methoxybenzyl)-2-methylbenzimidazole, 6-carboxy-2-(4-
methoxybenzyl)-2-methylbenzimidazole, 6-carboxy-2-methyl-1-[2-
(benzenesulfonylmethyl)benzyl]benzimidazole, 6-carboxy-1-(2-
cyanobenzyl)-2-methylbenzimidazole, 6-carboxy-1-(biphenyl-2-
ylmethyl)-2-methylbenzimidazole, 6-carboxy-2-methyl-1-(2-
naphthylmethyl)benzimidazole, 1-(biphenyl-4-ylmethyl)-6-carboxy-
2-ethylbenzimidazole, 5-carbo.xy-2-methyl-1-(2-nitrobenzyl)-
benzimidazole, 1-(biphenyl-4-ylmethyl)-6-carboxy-2-trifluoro-
methylbenzimidazole, 1-(biphenyl-4-ylmethyl)-5-carboxy-2-
trifluoromethylbenzimidazole, 5-ethoxycarbonyl-2-methyl-
benzimidazole, 2-benzyl-5-ethoxycarbonylbenzimidazole, 6-
ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole, 5-
ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole, 5-
ethoxycarbonyl-2-trifluoromethylbenzimidazole, 1-(biphenyl-4-
ylmethyl)-6-ethoxycarbonyl-2-trifluoromethylbenzimidazole, 1-
(biphenyl-4-ylmethyl)-5-ethoxycarbonyl-2-trifluoromethyl-
benzimidazole, 1-methyl-2-n-propyl-6-[(2-pyridylmethyl)-
carbamoyl]benzimidazole, 2-n-propyl-1-i-propyl-6-[(2-pyridyl-
methyl)carbamoyl]benzimidazo1e, 1-n-butyl-2-n-propyl-6-[(2-
pyridylmethyl)carbamoyl]benzimidazole, 2-benzyl-1-methyl-6-[(2-
pyridylmethyl)carbamoyl]benzimidazole, 1-(2-methoxybenzyl)-2-
methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(4-
methoxybenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole, 1-[2-(benzenesulfonylmethyl)benzyl]-2-methyl-6-
[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(2-cyanobenzyl)-2-
methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(biphenyl-
2-ylmethyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,
2-methyl-1-(2-naphthylmethyl)-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole, 1-(biphenyl-4-ylmethyl)-2-ethyl-6-[(2-
pyridylmethyl)carbamoyl]benzimidazole, 2-methyl-1-(2-
nitrobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 2-
methyl-1-(2-nitrobenzyl)-5-[(2-pyridylmethyl)carbamoyl]-
benzimidazole, 1-(biphenyl-4-ylmethyl)-2-methyl-6-[(2-pyridyl-
CA 02241186 1998-06-23
47
methyl)carbamoyl]benzimidazole, 1-(4-benzyloxybenzyl)-2-methyl-
6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 2-methyl-1-(3,4-
methylenedioxybenzyl)-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole, 2-methyl-6-[(2-pyridylmethyl)carbamoyl]-1-[4-
(1,2,3-thiadiazol-4-yl)benzyl]benzimidazole, 2-methyl-5-[(2-
pyridylmethyl)carbamoyl]benzimidazole, 1-benzenesulfonyl-2-
methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-benzene-
sulfonyl-2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole,
2-methyl-1-(4-nitrobenzyl)-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole, 2-methyl-1-(4-nitrobenzyl)-5-[(2-pyridylmethyl)-
carbamoyl]benzimidazole, 2-methyl-1-(2-phenylethyl)-6-[(2-
pyridylmethyl)carbamoyl]benzimidazole, 2-methyl-1-(2-phenyl-
ethyl)-5-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(4-amino-
benzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-
(4-aminobenzyl)-2-methyl-5-[(2-pyridylmethyl)carbamoyl]-
benzimidazole, 1-[4-(benzenesulfonylamino)benzyl]-2-methyl-6-
[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(biphenyl-4-
ylmethyl)-2-methyl-6-[(2-pyridylmethyl)aminomethyl]-
benzimidazole, 2-benzyl-6-carboxy-1-methylbenzimidazole, 4-
ethoxycarbonyl-2-methylbenzimidazole, 1-(4-benzyloxybenzyl)-6-
ethoxycarbonyl-2-methylbenzimidazole, 1-(4-benzyloxybenzyl)-6-
carboxy-2-methylbenzimidazole, 6-ethoxycarbonyl-1-[(2'-cyano-
biphenyl-4-yl)methyl]-2-methylbenzimidazole, 6-carboxy-1-[(2'-
cyanobiphenyl-4-yl)methyl]-2-methylbenzimidazole, 6-ethoxy-
carbonyl-1-[(2'-fluorobiphenyl-4-yl)methyl]-2-methyl-
benzimidazole, 6-carboxy-1-[(2'-fluorobiphenyl-4-yl)methyl]-2-
methylbenzimidazo1e, 6-ethoxycarbonyl-1-[(3-fluorobiphenyl-4-
yl)methyl]-2-methylbenzimidazole, 6-carboxy-1-[(3-fluoro-
biphenyl-4-yl)methyl]-2-methylbenzimidazo1e, 1-(4-biphenyl-
methyl)-5-ethoxycarbonyl-2-ethylbenzimidazole, 1-(4-biphenyl-
methyl)-5-carboxy-2-ethylbenzimidazole, 6-ethoxycarbonyl-2-
ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole, 6-carboxy-2-
ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole, 1-[4-(3,4-
dichlorobenzyloxy)benzyl]-6-ethoxycarbonyl-2-ethylbenzimidazole,
6-carboxy-1-[4-(3,4-dichlorobenzyloxy)benzyl]-2-ethyl-
CA 02241186 1998-06-23
48
benzimidazole, 1-(4-biphenylmethyl)-6-(n-butylcarbamoyl)-2-
ethylbenzimidazole, 1-(4-biphenylmethyl)-2-ethyl-6-(thiazol-2-
ylcarbamoyl)benzimidazole, 1-(4-biphenylmethyl)-2-ethyl-6-(2-
pyridylcarbamoyl)benzimidazole, 1-[sec-(2,4-dichlorophenethyl)]-
6-ethoxycarbonyl-2-methylbenzimidazole, 6-carboxy-1-[sec-(2,4-
dichlorophenethyl)]-2-methylbenzimidazole, 1-(4-biphenylmethyl)-
2-ethyl-6-(phenylcarbamoyl)benzimidazole, 1-(4-biphenylmethyl)-
2-ethyl-6-(1,3,4-thiadiazol-2-ylcarbamoyl)benzimidazole, 1-(4-
biphenylmethyl)-2-ethyl-6-(tetrazol-5-ylcarbamoyl)benzimidazole,
1-(4-biphenylmethyl)-2-ethyl-6-(1,3,4-triazol-3-ylcarbamoyl)-
benzimidazole, 1-(4-biphenylmethyl)-2-ethyl-(1,3,4-triazol-2-
ylcarbamoyl)benzimidazole, 1-(4-biphenylmethyl)-2-ethyl-6-(3-
pyridylcarbamoyl)benzimidazole, 1-(4-biphenylmethyl)-2-ethyl-6-
(4-pyridylcarbamoyl)benzimidazole, 1-(2,4-dichlorobenzyl)-2,4-
dimethyl-6-methoxycarbonylbenzimidazo1e, 6-carboxy-1-(2,4-
dichlorobenzyl)-2,4-dimethylbenzimidazole, 6-ethoxycarbonyl-2-
methyl-1-(4-phenoxybenzyl)benzimidazole, 6-carboxy-2-methyl-1-
(4-phenoxybenzyl)benzimidazole, 6-ethoxycarbonyl-2-methyl-1-(2-
pyridylmethyl)benzimidazole, 6-carboxy-2-methyl-1-(2-pyridyl-
methyl)benzimidazole, 6-ethoxycarbonyl-2-methyl-1-(4-nitro-
benzyl)benzimidazole, 1-(4-aminobenzyl)-6-ethoxycarbonyl-2-
methylbenzimidazole, 1-[(4-benzoylamino)benzyl]-6-ethoxy-
carbonyl-2-methylbenzimidazo1e, 1-[(4-benzoylamino)benzyl]-6-
carboxy-2-methylbenzimidazole, 6-ethoxycarbonyl-2-methyl-1-[4-
(2-phenylethenyl)benzyl]benzimidazole, 6-ethoxycarbonyl-2-
methyl-1-[4-(2-phenylethyl)benzyl]benzimidazo1e, 6-carboxy-2-
methyl-1-[4-(2-phenylethyl)benzyl]benzimidazole, 1-[(4-benzoyl)-
benzyl]-6-ethoxycarbonyl-2-methylbenzimidazole, 1-[(4-benzoyl)-
benzyl]-6-carboxy-2-methylbenzimidazole, 6-carboxy-2-methyl-[4-
(2-phenylethenyl)benzyl]benzimidazole, 1-(dibenzofuran-2-
ylmethyl)-6-ethoxycarbonyl-2-methylbenzimidazo1e, 6-carboxy-1-
(dibenzofuran-2-ylmethyl)-2-methylbenzimidazole, 6-ethoxy-
carbonyl-2-methyl-1-(2-quinolylmethyl)benzimidazole, 6-carboxy-
2-methyl-(2-quinolylmethyl) -benzimidazole, 1-(2,4-dichloro-
benzyl)-2-hydroxy-6-ethoxycarbonylbenzimidazole, 6-
CA 02241186 1998-06-23
49
ethoxycarbonyl-2-methyl-1-[3-(4-bromoisoquinolyl)methyl]-
benzimidazole, and 6-carboxy-2-methyl-[3-(4-bromoisoquinolyl)-
methyl]benzimidazole, etc.
Specific examples of benzimidazole derivatives of formula
(XI) include 1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-
phenylbenzimidazole, 2-benzyl-5-carboxy-1-(2-chlorobenzyl)-
benzimidazole, 2-benzyl-6-carboxy-1-(2-chlorobenzyl)-
benzimidazole, 2-benzyl-5-carboxy-1-(2,4-dichlorobenzyl)-
benzimidazole, 2-benzyl-6-carboxy-1-(2,4-dichlorobenzyl)-
benzimidazole, 2-benzyl-1-(2-chlorobenzyl)-6-ethoxycarbonyl-
benzimidazole, 2-benzyl-1-(2-chlorobenzyl)-5-ethoxycarbonyl-
benzimidazole, 2-benzyl-1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-
benzimidazole, 2-benzyl-1-(2,4-dichlorobenzyl)-5-ethoxycarbonyl-
benzimidazole, 1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acetic
acid, methyl 1-(2-chlorobenzyl)-2-methyl-benzimidazole-6-
acrylate, 1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acrylic
acid, 1-(2-chlorobenzyl)-6-[2-(pyridylmethyl)carbamoyl]-
benzimidazole, 1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-
methoxymethylbenzimidazole, 1-(biphenyl-4-ylmethyl)-6-carboxy-2-
methoxymethyl-benzimidazole, 1-(4-benzyloxybenzyl)-6-
ethoxycarbonyl-2-methoxymethylbenzimidazole, 1-(4-
benzyloxybenzyl)-6-carboxy-2-methoxymethylbenzimidazole, 1-(2,4-
dichlorobenzyl)-6-ethoxycarbonyl-2-methoxymethyl-benzimidazole,
and 6-carboxy-1-(2,4-dichlorobenzyl)-2-methoxymethyl-
benzimidazole, etc.
Specific examples of benzimidazole derivatives of formula
(XII) include 6-t-butoxycarbonylamino-1-(2-chlorobenzyl)-2-n-
propylbenzimidazo1e, 1-(2-chlorobenzyl)-6-mesylamino-2-n-propyl-
benzimidazole, 6-acetylamino-1-(2-chlorobenzyl)-2-n-propyl-
benzimidazole, 6-amino-1-(2-chlorobenzyl)-2-n-propyl-
benza_midazole, 1-(2-chlorobenzyl)-2-n-propyl-6-ureido-
benzimidazole, 6-t-butoxycarbonylamino-1-(2-chlorobenzyl)-2-
methylbenzimidazole, 6-amino-1-(~2-chlorobenzyl)-2-methyl-
benzimidazole, and 6-(1-butanesulfonylamino)-1-(2-chlorobenzyl)-
2-methylbenzimidazo1e, etc.
CA 02241186 1998-06-23
, 50
Specific examples of benzimidazole derivatives of formula
(XIII) include 1-(2-chlorobenzyl)-6-cyano-2-cyclopropyl-
benzimidazole, and 1-(2-chlorobenzyl)-6-cyano-2-n-propyl-
benzimidazole, etc. Specific examples of benzimidazole
derivatives of formula (VI) include 1-(2-chlorobenzyl)-6-(4-
dimethylaminophenylmethylcarbamoyl)-2-n-propylbenzimidazole, 1-
(2-chlorobenzyl)-2-n-propyl-6-thiomorpholinocarbonyl-
benzimidazole, 1-(2-chlorobenzyl)-2-cyclopropyl-6-(2-pyridyl-
carbamoyl)benzimidazole, 6-(2-carboxy-1-pyrrolidinocarbonyl)-1-
(2-chlorobenzyl)-2-n-propylbenzimidazole, 1-(2-chlorobenzyl)-6-
[N-methyl-N-(2-pyridylmethyl)carbamoyl]-2-n-propylbenzimidazole,
1-(2-chlorobenzyl)-6-piperonylcarbamoyl-2-n-propylbenzimidazole,
1-(2-chlorobenzyl)-6-(homopiperidinocarbonyl)-2-n-propyl-
benzimidazole, 1-(2-chlorobenzyl)-6-[N-methyl-N-(2-
pyridyl)carbamoyl]-2-n-propylbenzimidazole, 2-n-butyl-1-(2-
(fluorobenzyl)-6-[N-methyl-N-(2-pyridylmethyl)carbamoyl]-
benzimidazole, 2-cyclopropyl-1-(2-fluorobenzyl)-6-(piperonyl-
carbamoyl)benzimidazole, 2-[[1-(2-chlorobenzyl)-2-ethyl-
benzimidazol-6-yl]carbonylaminomethyl]pyridine-1-oxide, and 1-
(2,4-dichlorobenzyl)-2-methyl-6-(2-pyridylcarbamoyl)-
benzimidazole, etc.
The present invention further includes, within its scope,
the following novel benzimidazole derivatives: 1-(2-
bromobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole, 6-ethoxy-
carbonyl-1-(2-fluorobenzyl)-2-n-propylbenzimidazole, 6-ethoxy-
carbonyl-1-(4-fluorobenzyl)-2-n-propylbenzimidazole, 6-ethoxy-
carbonyl-1-(3-fluorobenzyl)-2-n-propylbenzimidazole, 1-(2,6-
dichlorobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole, 1-(3-
methylbenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole, 2-
cyclopropyl-6-ethoxycarbonyl-1-(2-fluorobenzyl)-benzimidazole,
1-(2-chlorobenzyl)-2-cyclobutyl-6-ethoxycarbonylbenzimidazole,
1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-n-pentylbenzimidazole, 5-
carboxy-1-(2-chlorobenzyl)-2-n-propylbenzimidazole, 6-carboxy-1-
(3-methylbenzyl)-2-n-propylbenzimidazole, 2-n-butyl-7-carboxy-1-
(2-chlorobenzyl)benzimidazole, 6-carboxy-1-(2-fluorobenzyl)-2-
CA 02241186 1998-06-23
51
cyclopropylbenzimidazole, 2-n-butyl-6-carboxy-1-(2-fluoro-
benzyl)benzimidazole, 1-(2-chlorobenzyl)-6-chlorocarbonyl-2-
cyclopropylbenzimidazole, 1-(2-chlorobenzyl)-6-morpholino-
carbamoyl-2-n-propylbenzimidazole, 2-n-butyl-1-(2-chlorobenzyl)-
6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 2-n-butyl-5-
carbamoyl-1-(2-chlorobenzyl)benzimidazole, 1-(2-chlorobenzyl)-2-
cyclopropyl-6-morpholinocarbonylbenzimidazo1e, 1-(2-chloro-
benzyl)-2-cyclopropyl-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole, 1-(2-chlorobenzyl)-2-cyclobutyl-6-[(2-pyridyl-
methyl)carbamoyl]benzimidazole, 1-(2-chlorobenzyl)-2-n-propyl-5-
[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(2-chlorobenzyl)-6-
phenylcarbamoyl-2-n-propylbenzimidazole, 1-(2-chlorobenzyl)-2-n-
propyl-6-[(4-pyridylmethyl)carbamoyl]benzimidazole, I-(2-
chlorobenzyl)-2-n-propyl-6-[(3-pyridylmethyl)carbamoyl]-
benzimidazole, 1-(3-methylbenzyl)-2-n-propyl-6-[(2-pyridyl-
methyl)carbamoyl]benzimidazole, 1-(2-chlorobenzyl)-2-ethyl-6-
[(2-pyridylmethyl)carbamoyl]benzimidazole, 2-n-butyl-1-(2-
chlorobenzyl)-7-[(2-pyridylmethyl)carbamoyl]benzimidazole, 2-n-
butyl-1-(2-fluorobenzyl)-6-(2-pyridylmethylcarbamoyl)-
benzimidazole, 1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-methyl-
benzimidazole, 1-(3-chlorobenzyl)-6-ethoxycarbonyl-2-n-propyl-
benzimidazole, 1-benzyl-6-ethoxycarbonyl-2-n-propylbenzimidazole,
1-(4-chlorobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole, 6-
ethoxycarbonyl-2-methyl-1-[2-(trifluoromethyl)benzyl]-
benzimidazole, 6-ethoxycarbonyl-2-methyl-1-[4-(trifluoromethyl)-
benzyl]benzimidazole, 1-(3,4-dichlorobenzyl)-6-ethoxycarbonyl-2-
methylbenzimidazole, 6-ethoxycarbonyl-2-methyl-1-(2-methyl-
benzyl)benzimidazole, 1-benzyl-6-ethoxycarbonyl-2-methyl-
benzimidazole, 1-(4-t-butylbenzyl)-6-ethoxycarbonyl-2-methyl-
benzimidazole, 1-(2-chlorobenzyl)-5-ethoxycarbonyl-2-methyl-
benzimidazole, 1-(2,6-dichlorobenzyl)-6-ethoxycarbonyl-2-methyl-
benzimidazole, 1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methyl-
benzimidazole, 6-carboxy-1-(4-chlorobenzyl)-2-n-propyl-
benzimidazole, 6-carboxy-1-(2,6-dichlorobenzyl)-2-methyl-
benzimidazole, 6-carboxy-2-methyl-1-[2-(trifluoromethyl)benzyl]-
CA 02241186 1998-06-23
52
benzimidazole, 6-carboxy-2-methyl-1-[4-(trifluoromethyl)-
benzyl]benzimidazole, 6-carboxy-1-(3,4-dichlorobenzyl)-2-
methylbenzimidazole, 1-benzyl-6-carboxy-2-n-propylbenzimidazole,
6-carboxy-1-(3-chlorobenzyl)-2-n-propylbenzimidazole, 6-carboxy-
1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 1-(4-t-butyl-
benzyl)-6-carboxy-2-methylbenzimidazole, 6-carboxy-2-methyl-1-
(2-methylbenzyl)benzimidazole, 1-benzyl-6-carboxy-2-methyl-
benzimidazole, 5-carboxy-1-(2-chlorobenzyl)-2-methyl-
benzimidazole, 6-carboxy-1-(2-chlorobenzyl)-2-methyl-
benz.i.midazole, 1-(2,4-dichlorobenzyl)-2-methyl-6-[(2-pyridyl-
methyl)carbamoyl]benzimidazole, 1-(2-chlorobenzyl)-2-methyl-6-
[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(3-chlorobenzyl)-2-
n-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-benzyl-
2-n-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(4-
chlorobenzyl)-2-propyl-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole, 1-(2,6-dichlorobenzyl)-2-methyl-6-[(2-pyridyl-
methyl)carbamoyl]benzimidazole, 2-methyl-6-[(2-pyridylmethyl)-
carbamoyl]-.1-[2-(trifluoromethyl)benzyl]benzimidazole, 2-methyl-
6-[(2-pyridylmethyl)carbamoyl]-1-[4-(trifluoromethyl)benzyl]-
benzimidazole, 1-(3,4-dichlorobenzyl)-2-methyl-6-[(2-pyridyl-
methyl)carbamoyl]benzimidazole, 2-methyl-1-(2-methylbenzyl)-6-
[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-benzyl-2-methyl-6-
[(2-pyridylmethyl)carbamoyl]benzimidazole, 1-(4-t-butylbenzyl)-
2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole, 6-
carbamoyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 1-(2,4-
difluorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole, 1-(2,4-difluorobenzyl)-2-methyl-5-[(2-pyridyl-
methyl)carbamoyl]benzimidazole, 1-(2,4-dichlorobenzyl)-7-ethoxy-
carbonyl-2-methylbenzimidazole, 7-carboxy-1-(2,4-dichloro-
benzyl)-2-methylbenzimidazole, 1-(2,4-dichlorobenzyl)-4-ethoxy-
carbonyl-2-methylbenzimidazole, 4-carboxy-1-(2,4-dichloro-
benzyl)-2-methylbenzimidazole, 1-(2,4-dichlorobenzyl)-5-ethoxy-
carbonyl-2-methylbenzimidazole, 5-carboxy-1-(2,4-dichloro-
benzyl)-2-methylbenzimidazole, and 6-(n-butylcarbamoyl)-1-(2,4-
dichlorobenzyl)-2-methylbenzimidazole.
CA 02241186 1998-06-23
53
The benzimidazole derivatives and their pharmaceutically
acceptable salts of the present invention that are mentioned
hereinabove are effective for preventing and treating various
disorders of, for example, impaired glucose tolerance, diabetes
(type II diabetes), diabetic complications (e. g., diabetic
nephropathy, diabetic neuropathy, diabetic retinopathy, etc.),
syndrome of insulin resistance (e. g., insulin receptor disorders,
Rabson-Mendenhall syndrome, leprechaunism, Kobberling-Dunnigan
syndrome, Seip syndrome, Lawrence syndrome, Gushing syndrome,
acromegaly, etc.), hyperlipidemia, atherosclerosis,
cardiovascular disorders (e. g., stenocardia, cardiac failure,
etc.), hyperglycemia (e.g., abnormal saccharometabolism such as
feeding disorders, etc.), and hypertension based on their blood
sugar level-depressing activity, as well as stenocardia,
hypertension, pulmonary hypertension, congestive heart failure,
glomerulopathy (e. g., diabetic glomerulosclerosis, etc.),
tubulointerstitial disorders (e. g., renopathy induced by FK506,
cyclosporin, etc.), renal failure, atherosclerosis,
angiostenosis (e. g., after percutaneous arterioplasty), distal
angiopathy, cerebral apoplexy, chronic reversible obstructions
(e. g., bronchitis, asthma (chronic asthma, allergic asthma),
etc.), allergic rhinitis, urticaria, glaucoma, diseases
characterized by enteromotility disorders (e. g., hypersensitive
enteropathy syndrome, etc.), impotence (e. g., organic impotence,
psychic impotence, etc.), and diabetic complications (e. g.,
diabetic gangrene, diabetic arthropathy, diabetic
glomerulosclerosis, diabetic dermatopathy, diabetic neuropathy,
diabetic cataract, diabetic retinopathy, etc.), nephritis,
cancerous cachexia, and restenosis after PTCA based on their
cGMP-PDE (especially PDE-V)-inhibiting activity, smooth muscle
relaxing activity, bronchodilating activity, vasodilating
activity, smooth muscle cell suppressing activity, and
antiallergic activity.
In addition, we, the present inventors, have further found
that the benzimidazole derivatives which we have disclosed in
CA 02241186 1998-06-23
54
Japanese Patent Application Laid-Open No. 5-222000 as c-GMP
phosphodiesterase inhibitors also have the above-mentioned
activities, and have now confirmed that these benzimidazole
derivatives are also effective for preventing and treating the
above-mentioned diseases and disorders like the compounds
mentioned hereinabove.
Accordingly, the present invention further includes
pharmaceutical compositions comprising, as an active ingredient,
any of benzimidazole derivatives of the following formula (I)
and their pharmaceutically acceptable salts, which are effective
for preventing and treating impaired glucose tolerance, diabetes
(type II diabetes), diabetic complications (e. g., diabetic
nephropathy, diabetic neuropathy, diabetic retinopathy, etc.),
syndrome of insulin resistance (e. g., insulin receptor disorders,
Rabson-Mendenhall syndrome, leprechaunism, Kobberling-Dunnigan
syndrome, Seip syndrome, Lawrence syndrome, Gushing syndrome,
acromegaly, etc.), hyperlipidemia, atherosclerosis,
cardiovascular disorders (e. g., stenocardia, cardiac failure,
etc.), hyperglycemia (e.g., abnormal saccharometabolism such as
feeding disorders, etc.), or hypertension; or stenocardia,
hypertension, pulmonary hypertension, congestive heart failure,
glomerulopathy (e. g., diabetic glomerulosclerosis, etc.),
tubulointerstitial disorders (e. g., renopathy induced by FK506,
cyclosporin, etc.), renal failure, atherosclerosis,
angiostenosis (e. g., after percutaneous arterioplasty), distal
angiopathy, cerebral apoplexy, chronic reversible obstructions
(e. g., bronchitis, asthma (chronic asthma, allergic asthma),
etc.), allergic rhinitis, urticaria, glaucoma, diseases
characterized by enteromotility disorders (e. g., hypersensitive
enteropathy syndrome, etc.), impotence (e. g., organic impotence,
psychic impotence, etc.), and diabetic complications (e. g.,
diabetic gangrene, diabetic arthropathy, diabetic
glomerulosclerosis, diabetic dermatopathy, diabetic neuropathy,
diabetic cataract, diabetic retinopathy, etc.), nephritis,
cancerous cachexia, or restenosis after PTCA.
CA 02241186 1998-06-23
n (R4)
N
~'3 ~~ ~ . ~~R2
N
R1
In formula (I):
R1 represents a hydrogen atom, an arylsulfonyl group, or a
lower alkyl group; and said lower alkyl group may be substituted
by an aryl group or an aryl group substituted by one or two
substituents selected from a halogen atom, a haloaryl group, a
lower alkyl group, a halo-lower alkyl group, a lower alkoxy
group, a nitro group, an amino group, a cyano group, an aryl
group, an aryl-lower alkyl group, an aryl-lower alkyloxy group,
a haloaryl-lower alkyloxy group, an arylsulfonyl-lower alkyl
group, an arylsulfonylamino group, a cyanoaryl group, and a
heterocyclic group, or by a heterocyclic group;
Ra represents a hydrogen atom, a lower cycloalkyl group, a
hydroxyl group, a lower alkoxy group, a mercapto group, a lower
alkylthio group, an amino group, a lower alkylamino group, a
carboxyl group, an aryl group, or a lower alkyl group; and said
lower alkyl group may be substituted by a halogen atom, a lower
alkoxy group, a cyano group, a chlorocarbonyl group, an aryl
group, or a heterocyclic group;
R, represents a carboxyl group, an esterified carboxyl group,
an amidated carboxyl group, an amino group, an amido group, or a
sulfonyl group; and said amino group and said amido group may be
substituted by an acyl group or a sulfonyl group; and a halogen
atom, an amino group, or an acylamino group is bonded to said
sulfonyl group; or R, may be bonded to the skeleton via a lower
alkylene or alkenylene group; and
CA 02241186 1998-06-23
56
R~ represents a neutral substituent. R4 includes a halogen
atom, and a lower alkyl group, an aralkyl group, an alkynyl
group, a lower alkyloxy group, and halogen-substituted groups of
these. Where R4 is a hydrocarbon group, it may be either
saturated or unsaturated, or either linear or cyclic, or may
even be branched. For the halogen atom and the halogen-
substituted groups, the kind of the halogen is not specifically
defined. For the latter, the number of halogens substituted is
not specifically defined.
n means an integer from 0 to 3. Thus, one, two or three R4s
may be bonded to the skeleton, or no R, may be bonded thereto.
The position of RQ may be any of the ortho-position, the meta-
position and the para-position relative to the other substituent.
Specific examples of benzimidazole derivatives of formula
(I) include 2-butyl-1-(2-chlorobenzyl)-6-ethoxycarbonyl-
benzimidazole, 1-(4-bromo-2-fluorobenzyl)-2-butyl-6-ethoxy-
carbonylbenzimidazole, 2-butyl-1-(2,4-dichlorobenzyl)-6-ethoxy-
carbonylbenzimidazole, 2-butyl-6-ethoxycarbonyl-1-(4-methoxy-
carbonylbenzyl)benzimidazo1e, 2-butyl-6-ethoxycarbonyl-1-(2-
fluorobenzyl)benzimidazole, 2-butyl-6-ethoxycarbonyl-1-(2-
trifluoromethylbenzyl)benzimidazole, 1-(2-chlorobenzyl)-6-
ethoxycarbonyl-2-ethylbenzimidazole, 1-(2-chlorobenzyl)-6-
ethoxycarbonyl-2-propylbenzimidazole, 1-(2-chlorobenzyl)-2-
cyclopropyl-6-ethoxycarbonylbenzimidazole, 1-(2-chlorobenzyl)-6-
ethoxycarbonyl-2-isopropylbenzimidazole, 2-butyl-1-(2-chloro-
benzyl)-5-ethoxycarbonylbenzimidazole, 2-butyl-1-(2-chloro-
benzyl)-7-ethoxycarbonylbenzimidazole, 1-(2-chlorobenzyl)-5-
ethoxycarbonyl-2-propylbenzimidazole, 2-butyl-1-(2-chloro-
benzyl)-6-carboxybenzimidazole, 2-butyl-6-carboxy-1-(4-carboxy-
benzyl)benzimidazole, 6-carboxy-1-(2-chlorobenzyl)-2-ethyl-
benzimidazole, 6-carboxy-1-(2-chlorobenzyl)-2-propyl-
benzimidazole, 6-carboxy-1-(2-chlorobenzyl)-2-cyclopropyl-
benzimidazole, 2-butyl-5-carboxy-1-(2-chlorobenzyl)imidazole, 2-
butyl-1-(2-chlorobenzyl)-6-dimethylcarbamoylbenzimidazole, 6-
(benzylcarbamoyl)-2-butyl-1-(2-chlorobenzyl)benzimidazole, 2-
CA 02241186 1998-06-23
57
butyl-1-(2-chlorobenzyl)-6-morpholinocarbonylbenzimidazole, 2-
butyl-6-carbamoyl-(2-chlorobenzyl)-benzimidazole, 2-butyl-1-(2-
chlorobenzyl)-6-(4-methylpiperazinyl)carbonylbenzimidazole, 2-
butyl-1-(2-chlorobenzyl)-6-(methylcarbamoyl)benzimidazole, 6-
carbamoyl-1-(2-chlorobenzyl)-2-ethylbenzimidazole, 6-carbamoyl-
1-(2-chlorobenzyl)-2-propylbenzimidazole, 6-carbamoyl-1-(2-
chlorobenzyl)-2-cyclopropylbenzimidazole, 2-butyl-5-carbamoyl-1-
(2-chlorobenzyl)benzimidazole, 2-butyl-1-(2-chlorobenzyl)-6-
(isopropylcarbonyl)benzamidazole, 1-(2-chlorobenzyl)-6-chloro-
formyl-2-propylbenzimidazole, 1-(2-chlorobenzyl)-6-(methyl-
carbamoyl)-2-propylbenzimidazole, 1-(2-chlorobenzyl)-6-(ethyl-
carbamoyl)-2-propylbenzimidazole, 1-(2-chlorobenzyl)-6-
(isopropyl)carbamoyl-2-propylbenzimidazole, 1-(2-chlorobenzyl)-
6-(piperidinocarbonyl)-2-propylbenzimidazole, 1-(2-chloro-
benzyl)-6-(morpholinocarbonyl)-2-propylbenzimidazole, 1-(2-
chlorobenzyl)-6-(2-morpholinoethyl)carbamoyl-2-propyl-
benzimidazole, 1-(2-chlorobenzyl)-6-[4-(2-hydroxyethyl)-
piperazinyl]carbonyl-2-propylbenzimidazole, 1-(2-chlorobenzyl)-
2-propyl-6-(2-pyridylmethyl)carbamoylbenzimidazole, 1-(2-
chlorobenzyl)-2-propyl-6-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-
1-yl)butyl]carbamoylbenzimidazole, etc.
To use the benzimidazole derivatives of the present
invention for treating diseases or disorders such as those
mentioned hereinabove, they may be formulated into
pharmaceutical compositions of ordinary forms, which comprise,
as an active ingredient, any of the derivatives along with
pharmaceutically acceptable carriers, such as organic or
inorganic solid or liquid vehicles, and which are suitable for
peroral administration, parenteral administration or external
application. The pharmaceutical compositions may be of any solid
form of tablets, granules, powders, capsules, etc., or may be of
any liquid form of solutions, suspensions, syrups, emulsions,
lemonades, etc.
If desired, the pharmaceutical compositions may further
contain a pharmaceutical aid, a stabilizer, a wetting agent, and
CA 02241186 1998-06-23
58
also any ordinary additive of, for example, lactose, citric acid,
tartaric acid, stearic acid, magnesium stearate, terra alba,
sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil,
olive oil, cacao butter, ethylene glycol, etc.
The amount of the above-mentioned derivative of the present
invention to be used shall vary, depending on the age and the
condition of patients, the type and the condition~of diseases or
disorders, and the type of the derivative to be used. In general,
for peroral administration, the dose of the derivative may be
from 1 to 100 mg/kg; and for intramuscular injection or
intravenous injection, it may be from 0.1 to 10 mg/kg. Such a
unit dose may be applied to a patient once to four times a day.
$RTFF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows chemical formulae of compound (42) to compound
(47).
(53).
(59).
(65).
(71).
(77).
(83).
(89).
(95).
Fig. 2 shows chemical formulae of compound (48) to compound
Fig. 3 shows chemical formulae of compound (54) to compound
Fig. 4 shows chemical formulae of compound (60) to compound
Fig. 5 shows chemical formulae of compound (66) to compound
Fig. 6 shows chemical formulae of compound (72) to compound
Fig. 7 shows chemical formulae of compound (78) to compound
Fig. 8 shows chemical formulae of compound (84) to compound
Fig. 9 shows chemical formulae of compound (90) to compound
Fig. 10 shows chemical formulae of compound (96) to
compound (101).
CA 02241186 1998-06-23
59
Fig. 11 shows chemical formulae of compound (102) to
compound (107).
Fig. 12 shows chemical formulae of compound (108) to
compound (113).
Fig. 13 shows chemical formulae of compound (114) to
compound (119).
Fig. 14 shows chemical formulae of compound (120) to
compound (125).
Fig. 15 shows chemical formulae of compound (126) to
compound (131).
Fig. 16 shows chemical formulae of compound (132) to
compound (137).
Fig. 17 shows chemical formulae of compound (138) to
compound (143).
Fig. 18 shows chemical formulae of compound (144) to
compound (149).
Fig. 19 shows chemical formulae of compound (150) to
compound (155).
Fig. 20 shows chemical formulae of compound (156) to
compound (161).
Fig. 21 shows chemical formulae of compound (162) to
compound (167).
Fig. 22 shows chemical formulae of compound (168) to
compound (173).
Fig. 23 shows chemical formulae of compound (174) to
compound (179).
Fig. 24 shows chemical formulae of compound (180) to
compound (185).
Fig. 25 shows chemical formulae of compound (186) to
compound (191).
Fig. 26 shows chemical formulae of compound (192) to
compound (197).
Fig. 27 shows chemical formulae of compound (198) to
compound (203).
CA 02241186 1998-06-23
Fig. 28 shows chemical formulae of compound (204) to
compound (209).
Fig. 29 shows chemical formulae of compound (210) to
compound (215).
Fig. 30 shows chemical formulae of compound (216) to
compound (22I).
Fig. 31 shows chemical formulae of compound (222) to
compound (227).
Fig. 32 shows chemical formulae of compound (228) to
compound (233).
Fig. 33 shows chemical formulae of compound (234) to
compound (239).
Fig. 34 shows chemical formulae of compound (240) to
compound (245).
Fig. 35 shows chemical formulae of compound (246) to
compound (251).
Fig. 36 shows chemical formulae of compound (252) to
compound (257).
Fig. 37 shows chemical formulae of compound (258) to
compound (263).
Fig. 38 shows chemical formulae of compound (264) to
compound (269).
Fig. 39 shows chemical formulae of compound (270) to
compound (275).
Fig. 40 shows chemical formulae of compound (276) to
compound (281).
Fig. 41 shows chemical formulae of compound (282) to
compound (287).
Fig. 42 shows chemical formulae of compound (288) to
compound (293).
Fig. 43 shows chemical formulae of compound (294) to
compound (299).
Fig. 44 shows chemical formulae of compound (300) to
compound (305).
CA 02241186 1998-06-23
61
Fig. 45 shows chemical formulae of compound (306) to
compound (311).
Fig. 46 shows chemical formulae of compound (312} to
compound (316).
Fig. 47 shows chemical formulae of compound (317) to
compound (322).
Fig. 48 shows chemical formulae of compound (323) to
compound (328).
Fig. 49 shows chemical formulae of compound (329) to
compound (334).
Fig. 50 shows chemical formulae of compound (335) to
compound (340).
Fig. 51 shows chemical formulae of compound (341) to
compound (346).
Fig. 52 shows chemical formulae of compound (347) to
compound (352).
Fig. 53 shows chemical formulae of compound (353) to
compound (358).
Fig. 54 shows chemical formulae of compound (359) to
compound (364).
Fig. 55 shows chemical formulae of compound (365) to
compound (370).
Fig. 56 shows chemical formulae of compound (371) to
compound (376).
Fig. 57 shows chemical formulae of compound (377) to
compound (382).
Fig. 58 shows chemical formulae of compound (383) to
compound (386).
RPSt Mode or Ca yingr Out t_h_e Invention
The present invention is illustrated more specifically by
referring to the following Examples. However, the present
invention is not limited thereto.
Production Example 1
Production of ethyl 3-[N-(2-bromobenzyl)butyrylamino]-4-
CA 02241186 1998-06-23
62
nitrobenzoate
One-hundred milligrams of sodium hydride (60$ water-in-oil
suspension) were added to a solution of 247 mg of ethyl 3-
butyrylamino-4-nitrobenzoate in 10 ml of N,N-dimethylformamide
in a nitrogen atmosphere at room temperature in some divided
portions. The reaction suspension was stirred at the same
temperature for 1 hour, and a solution of 244 mg of 2-
bromobenzyl bromide in 2 ml of N,N-dimethylformamide was
gradually added dropwise thereto over a period of 10 minutes.
The reaction mixture was stirred at room temperature for 1 hour,
and was poured in ice water. The oily substance precipitated was
extracted with methylene chloride. The organic solvent layer was
washed with water, dried, and then concentrated under reduced
pressure. The residue was developed through silica-gel flash
column chromatography, and was eluted with a mixture of 25~
ethyl acetate and n-hexane to give 540 mg of yellow oil of ethyl
3-[N-(2-bromobenzyl)butyrylamino-4-nitrobenzoate.
Properties of the compound:
1 H-NMR. ( CDCl 3 , ~ ) . 0 . 87 ( 3H, t, J=8Hz ) , 1 .48 ( 3H, t, J=8Hz ) ,
1.68 (2H, sextet, J=8Hz), 2.03 (2H, t, J=8Hz), 4.30-4.46 (2H,
m), 4.70 (1H, d, J=lSHz), 5.40 (1H, d, J=l5Hz), 7.08-7.34 (2H,
m), 7.43 (1H, dd, J=1, 8Hz), 7.58 (1H, dd, J=1, 8Hz), 7.66 (1H,
d, J=1Hz), 7.96 (1H, d, J=8Hz 8.16 (1H, dd, J=1, 8Hz)
Production Examyle 2
Production of ethyl 3-[N-(2-chlorobenzyl)benzoylamino]-4-
nitrobenzoate
In the same manner as in Production Example 1, 480 mg of
yellow crystals of ethyl 3-[N-(2-chlorobenzyl)benzoylamino]-4-
nitrobenzoate were formed from 450 mg of ethyl 3-benzoylamino-4-
nitrobenzoate and 243 mg of 2-chlorobenzyl bromide.
Properties of the compound:
1H-NMR (CDC13, ~ ) . 1.35 (3H, t, J=8Hz), 4.35 (2H, q, J=8Hz),
4.76 (1H, bd, J=l5Hz), 5.82 (1H, bd, J=lSHz), 7.10-8.00 (12H,
m)
mp . 111-113°C
CA 02241186 1998-06-23
r
63
Production Exam~~l~ 3
Production of ethyl 3-[N-(2-fluorobenzyl)butyrylamino]-4-
nitrobenzoate
In the same manner as in Production Example 1, 394 mg of
yellow oil of ethyl 3-[N-(2-fluorobenzyl)butyrylamino]-4-
nitrobenzoate were formed from 300 mg of ethyl 3-butyrylamino-4-
nitrobenzoate and 243 mg of 2-fluorobenzyl bromide.
Properties of the compound:
1 H-NMR (CDCl 3 , ~ ) . 0 . 85 ( 3H, t, J=8Hz ) , 1 .40 ( 3H, t, J=8Hz ) ,
1.65 (2H, sextet, J=8Hz), 1.98 (2H, t, J=8Hz), 4.30-4.45 (2H, m),
4.60 (1H, d, J=lOHz), 5.25 (1H, d, J=lOHz), 6.88 (2H, t, J=8Hz),
7.08 (2H, dd, J=5, 8Hz), 7.24 (1H, dt, J=l, 8Hz), 7.41 (1H, dt,
J=1, 8Hz), 7.69 (1H, d, J=1Hz), 7.96 (1H, d, J=8Hz), 8.15 (1H,
dd, J=1, 8Hz)
prc~c3m~t,'_c~n Exam~l~ 4
Production of ethyl 3-[N-(4-fluorobenzyl)butyrylamino]-4-
nitrobenzoate
In the same manner as in Production Example l, 400 mg of
yellow oil of ethyl 3-[N-(4-fluorobenzyl)butyrylamino]-4-
nitrobenzoate were formed from 300 mg of ethyl 3-butyrylamino-4-
nitrobenzoate and 243 mg of 4-fluorobenzyl bromide.
Properties of the compound:
1 H-NMR (CDC1 3 , ~ ) . 0 . 86 ( 3H, t, J=8Hz ) , 1 . 37 ( 3H, t, J=8Hz ) ,
1.56-1.76 (2H, m), 1.96-2.04 (2H, m), 4.32-4.46 (2H, m), 4.40
(1H, d, J=l4Hz), 5.23(1H, d, J=l4Hz), 6.95 (2H, t, J=8Hz), 7.10
(2H, dd, J=5, 8Hz), 7.47 (1H, d, J=1Hz), 7.95 (1H, d, J=8Hz),
8.16 (1H, dd, J=1, 8Hz)
prodLCtion Example 5
Production of ethyl 3-[N-(2-cyanobenzyl)butyrylamino]-4-
nitrobenzoate
Potassium carbonate (296 mg) was added to a solution of
200 mg of ethyl 3-butyrylamino-4-nitrobenzoate and 154 mg of 2-
cyanobenzyl bromide in N,N-dimethylformamide, and the mixture
was stirred at 20°C for 3 hours. The reaction mixture was
extracted with ethyl acetate and with water. The organic layer
CA 02241186 1998-06-23
A
64
was washed with water and with a sodium chloride aqueous
solution, and was then dried over magnesium sulfate. The solvent
was distilled off under reduced pressure to give 330 mg of
yellow oil of ethyl 3-[N-(2-cyanobenzyl)butyrylamino]-4-
nitrobenzoate.
Properties of the compound:
1 H-NMR ( CDC1 3 , ~ ) . 0 . 86 ( 3H, t, J=8Hz ) , 1 . 49 ( 3H, t, J=8Hz ) ,
1.67 (2H, sextet, J=8Hz), 2.02 (2H, t, J=8Hz), 4.28-4.52 (2H, m),
4.90 (1H, d, J=l5Hz), 5.28 (1H, d, J=l5Hz), 7.40 (1H, t, J=8Hz),
7.61 (1H, dt, J=1, 8Hz), 7.70 (1H, d, J=1Hz), 7.74 (1H, dd, J=1,
8Hz), 8.02 (1H, d, J=lOHz), 8.22 (1H, dd, J=1, lOHz)
Production Examyle 6
The following compounds were produced in the same manner
as in Production Example 5.
Production Example 6-1
Ethyl 3-[N-(3-fluorobenzyl)butyrylamino]-4-nitrobenzoate
Properties of the compound:
yellow oil.
1H-NMR (CDC13, ~) . 0.86 (3H, t, J=7.5Hz), 1.35 (3H, t, J=7.5Hz),
1 . 68 ( 2H, m) , 2 . 00 ( 2H, t, J=7 . 5Hz ) , 4 . 36 ( 1H, d, J=lSHz ) , 4 .
40
(2H, m), 5.31 (1H, d, J=l5Hz), 6.85-7.28 (4H, m), 7.60 (1H, d,
J=l.5Hz), 7.97 (1H, d, J=lOHz), 8.16 (1H, dd, J=10,1.5Hz)
Production Example 6-2
Ethyl 4-nitro-3-[N-(2-pyridylmethyl)-n-butyrylamino] benzoate
This compound was used in the subsequent step at once.
Property of the compound:
yellow oil.
Production Examyle 6-3
Ethyl 3-[N-(2,6-dichlorobenzyl)butyrylamino]-4-nitrobenzoate
Properties of the compound:
1H-NMR (CDC13, ~) . 0.89 (3H, t, J=7.5Hz), 1.38 (3H, t, J=7.5Hz),
1. 70 ( 2H, m) , 2 . 03 ( 2H, t, J=7 .5Hz ) , 4 .36 ( 2H, m) , 4 . 96 ( 1H, d,
J=13.5Hz), 5.70(1H, d, J=13.5Hz), 7.10-7.28 (3H, m), 7.49 (1H, d,
J=l.5Hz), 8.03 (1H, d, J=7.5Hz), 8.14 (1H, dd, J=7.5 and l.5Hz)
mp . 85-89°C
CA 02241186 1998-06-23
Production Example 6-4
Ethyl 3-[N-(3-methylbenzyl)propionylamino]-4-nitrobenzoate
This compound was used in the subsequent step at once.
Property of the compound:
yellow oil.
Production Example 6-5
Ethyl 3-[N-(2-fluorobenzyl)cyclopropanecarbonylamino~-4-
nitrobenzoate
Properties of the compound:
yellow oil.
1H-NMR (CDC13, ~ ) . 0.60-0.71 (2H, m), 0.99-1.14 (3H, m), 1.38
( 3H, t, J=7 . 5Hz ) , 4 . 37 ( 2H, m) , 4 . 62 ( 1H, d, J=l2Hz ) , 5 . 3 0 (
1H,
d, J=l2Hz), 6.92 (1H, t, J=7.5Hz), 7.10 (1H, t, J=7.5Hz), 7.26
(1H, m), 7.42 (1H, t, J=7.5Hz), 7.80 (1H, s), 7.99 (1H, d,
J=7.5Hz), 8.14 (1H, dd, J=7.5 and 2Hz)
production Example 6-6
Ethyl 3-[N-(2-chlorobenzyl)cyclobutanecarbonylamino]-4-
nitrobenzoate
Properties of the compound:
1H-NMR (CDC13, 8 ) . 1.37 (3H, t, J=7.5Hz), 1.68-1.87 (4H, m),
2.22-2.58 (2H, m), 2.75-2.94 (1H, m), 4.23-4.46 (2H, m), 4.63
(1H, d, J=lSHz), 5.45 (1H, d, J=l5Hz), 7.14-7.24 (3H, m), 7.35-
7.45 (1H, m), 7.56 (1H, d, J=2Hz), 7.97 (1H, d, J=9Hz), 8.13 (1H,
dd, J=9, 2Hz)
p_r~c3LCt i on Exam~,le 6-7
Ethyl 3-cyclobutanecarbonylamino-4-nitrobenzoate
Properties of the compound:
1H-NMR (CDC13, ~ ) . 1.43 (3H, t, J=7.5Hz), 1.86-2.19 (2H, m),
2.22-2.54 (4H, m), 3.20-3.41 (1H, m), 4.43 (2H, q, J=7.5Hz),
7.80 (1H, dd, J=10, 2Hz), 8.26 (1H, d, J=lOHz), 9.45 (1H, d,
J=2Hz)
mp . 94-96°C
production Examp a 7
Production of 3-acetylamino-4-nitrobenzamide
Oxalyl chloride (3.91 ml) was added dropwise to a solution
CA 02241186 1998-06-23
66
of 7.00 g of 3-acetylamino-4-nitrobenzoic acid in 50 ml of
dichloromethane in a nitrogen atmosphere while being cooled with
ice, and the mixture was stirred for 1 hour while being cooled
with ice and then at room temperature for 2.5 hours. The
reaction solvent was distilled off under reduced pressure, and
the residue was then dissolved in 50 ml of tetrahydrofuran. The
solution was added dropwise to 28$ aqueous ammonia in a nitrogen
atmosphere while being cooled with ice. The reaction solution
was stirred for 1 hour, and water and ethyl acetate were added
thereto. Approximately 8 g of the solid material precipitated
were collected through filtration. After. the filtrate was
separated, the organic layer was washed with water, and dried
over magnesium sulfate. Then, the solvent was distilled off
under reduced pressure to obtain the residue. The solid material
precipitated and the residue were combined, washed with hot
ethyl acetate, and collected through filtration to give 4.94 g
of 3-acetylamino-4-nitrobenzamide.
Properties of the compound:
1H-NMR (DMSO-d6, ~ ) . 2.08 (3H, s), 7.68 (1H, br s), 7.78 (1H,
dd, J=9, 2Hz), 7.94-8.05 (2H, m), 8.23 (1H, brs)
Mass (FAB) . 224
Production Examyle 8
Production of 3-[N-(2-chlorobenzyl)acetylamino)-4-nitrobenzamide
3-[N-(2-chlorobenzyl)acetylamino~-4-riitrobenzamide was
produced from the compound in the same manner as in Production
Example 7.
Properties of the compound:
1 H-NMR (DMSO-d6, ~ ) . 1. 86 ( 3H, s ) , 4 . 64 ( 1H, d, J=l5Hz ) , 5. 06
(1H, d, J=l5Hz), 7.22-7.40 (4H, m), 7.73 (1H, br s), 7.84 (1H, d,
J=2Hz), 8.03 (1H, dd, J=9, 2Hz), 8.14 (1H, d, J=9Hz), 8.22 (1H,
br s)
Production Example 9
Production of 3-[N-(2-chlorobenzyl)acetylamino)-4-nitro-
benznitrile
Thirty milliliters of 1,4-dioxane were added dropwise to a
CA 02241186 1998-06-23
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solution of 1.70 ml of titanium tetrachloride in 4 ml of
dichloromethane in a nitrogen atmosphere while being cooled with
ice. Then, a solution of 2.70 g of 3-[N-(2-
chlorobenzyl)acetylamino]-4-nitrobenzamide in 65 ml of 1,4-
dioxane was added dropwise thereto. After the mixture was
stirred for 15 minutes, 3.14 g of triethylamine were added
thereto, and the mixture was stirred for 2 hours while being
cooled with ice. After the completion of the reaction, the
solvent was distilled off under reduced pressure, and the
residue was extracted with ethyl acetate and with water. The
organic layer was washed with water, and was dried over
magnesium sulfate. Subsequently, the solvent was distilled off
under reduced pressure. The residue was purified through column
chromatography [200 ml, a mixture of n-hexane and ethyl acetate
at a ratio of 4:1] to give 1.21 g of 3-[N-(2-
chlorobenzyl)acetylamino]-4-nitrobenznitrile.
Properties of the compound:
1H-NMR (CDC13, ~) . 1.92 (3H, s), 4.61 (1H, d, J=lSHz), 5.40 (1H,
d, J=lSHz), 7.18-7.50 (5H, m), 7.80 (1H, dd, J=9, 2Hz), 8.01 (1H,
d, J=9Hz) Mass (FAB) . 300
IR (Nujol) . 2250cm
Production Example 10
Production of 3-[N-(2-chlorobenzyl)amino]-4-nitrobenznitrile
One milliliter of 35~ hydrochloric acid was added to a
solution of 850 mg of 3-[N-(2-chlorobenzyl)acetylamino]-4-
nitrobenzamide in 10 ml of 1,4-dioxane, and the mixture was
heat-refluxed for 4 days. After the solvent was distilled off
from the reaction solution under reduced pressure, the residue
was separated by being poured in a mixture solution of water and
chloroform. The organic layer was washed with water, and was
dried over magnesium sulfate. The solvent was distilled off
under reduced pressure. The residue was purified through column
chromatography [50 ml, chloroform] to give 230 mg of 3-[N-(2-
chlorobenzyl)amino]-4-nitrobenznitrile.
Properties of the compound:
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1H-NMR (CDC13, ~) . 4.65 (2H, d, J=6Hz), 6.93 (1H, dd, J=9, 2Hz),
7.10 (1H, d, J=2Hz), 7.25-7.40 (3H, m), 7.40-7.54 (1H, m), 8.30
(1H, d, J=9Hz), 5.45 (1H, br s)
Mass (FAB) . 258
IR (Nujol) . 2220cm
Production Example 11
Production of 4-amino-3-[N-(2-chlorobenzyl)amino]-benznitrile
Fifty milligrams of 10~ palladium on carbon were added to
a mixed solution of 261 mg of 3-[N-(2-chlorobenzyl)amino~-4-
nitrobenznitrile, 15 ml of methanol and 3 ml of 1,4-dioxane to
conduct the catalytic reduction in a hydrogen atmosphere at 3
atm. After the completion of the reaction, the reaction solution
was filtered through celite, and the filtrate was distilled off
under reduced pressure. The resulting solid material was washed
with ether, and was collected through filtration to give 196 mg
of 4-amino-3-[N-(2-chlorobenzyl)amino]benznitrile.
Properties of the compound:
1H-NMR (DMSO-d6, C~) . 4.39 (2H, d, J=5Hz), 5.57 (1H, t, J=5Hz),
5.69 (2H, s), 6.46 (1H, d, J=2Hz), 6.61 (1H, d, J=9Hz), 6.88 (1H,
dd, J=9, 2Hz), 7.25- 7.41 (3H, m), 7.44-7.54 (1H, m)
xa ple 1
Synthesis of 1-(2-bromobenzyl)-6-ethoxycarbonyl-2-n-propyl-
benzimidazole (42)
A suspension obtained by adding 390 mg of ethyl 3-[N-(2-
bromobenzyl)butyrylamino~-4-nitrobenzoate and 210 mg of reduced
iron to a mixed solution of 1 ml of acetic acid and 2 ml of
ethanol was refluxed for 1 hour while being vigorously stirred.
After the completion of the reaction, the reaction solution was
cooled down and filtered through celite, and the filtrate was
then concentrated under reduced pressure. The residue was
separated with the addition of ethyl acetate and a sodium
hydrogencarbonate aqueous solution. After the organic solvent
layer was dried, the solvent was distilled off under reduced
pressure, and the brown residue was obtained. This residue was
purified through flash column chromatography to give 160 mg of
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yellow crystals of 1-(2-bromobenzyl)-6-ethoxycarbonyl-2-n-
propylbenzimidazole (42).
Properties of Compound (42):
1 H-NMR ( CDC1 3 , ~ ) . 1 . 04 ( 3H, t, J=8Hz ) , 1 . 4 0 ( 3H, t, J=8Hz ) ,
1.78-1.98 (2H, m), 2.34 (2H, t, J=8Hz), 4.38 (2H, q, J=8Hz),
5.45 (2H, s), 6.65 (1H, t, J=8Hz), 7.00 (1H, t, J=8Hz), 7.13 (1H,
t, J=8Hz ) , 7 . 28 ( 1H, t, J=8Hz ) , 7 . 78 ( 1H, d, J=lOHz ) , 7 . 99 ( 1H,
d, J=lOHz), 8.02 (1H, s)
mp . 134-135°C
Example 2
Synthesis of 1-(2-cyanobenzyl)-6-ethoxycarbonyl-2-n-
propylbenzimidazole (43)
In the same manner as in Example 1, 160 mg of colorless
crystals of 1-(2-cyanobenzyl)-6-ethoxycarbonyl-2-n-
propylbenzimidazole (43) were formed from 390 mg of ethyl 3-[N-
(2-cyanobenzyl)butyrylamino]-4-nitrobenzoate.
Properties of Compound (43):
1 H-NMR. ( CDC1 3 , ~ ) . 1. 04 ( 3H, t, J=8Hz ) , 1. 40 ( 3H, t, J=8Hz ) ,
1.88 (2H, sextet, J=8Hz), 2.80 (2H, t, J=8Hz), 4.38 (2H, q,
J=8Hz), 5.62 (2H, s), 6.57-6.63 (1H, m), 7.38-7.50 (2H, m), 7.78
(1H, dd, J=l, 8Hz), 7.79 (1H, d, J=8Hz), 7.94 (1H, d, J=1Hz),
8.03 (1H, dd, J=1, 8Hz)
mp . 132-134°C
Exam In a 3
Synthesis of 1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-phenyl-
benzimidazole (44)
In the same manner as in Example 1, 220 mg of yellow
crystals of 1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-phenyl-
benzimidazole (44) were obtained from 460 mg of ethyl 3-[N-(2-
chlorobenzyl)benzoylamino]-4-nitrobenzoate.
Properties of Compound (44):
1 H-NMR (CDCl 3 , ~ ) . 1 .40 ( 3H, t, J=8Hz ) , 4 . 38 ( 2H, q, J=8Hz ) ,
5.56 (2H, s), 6.72 (H, dd, J=1, 8Hz), 7.18 (1H, dt, J=1, 8Hz),
7.30 (1H, dt, J=l, 8Hz), 7.45-7.55 (4H, m), 7.64 (1H, d, J=1Hz),
7.68 (1H, d, J=1Hz), 7.90 (1H, d, J=lOHz), 7.95 (1H, s), 8.08
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s
(1H, dd, J=I, 8Hz)
mp . 140-142°C
Example 4
Synthesis of 6-ethoxycarbonyl-1-(2-fluorobenzyl)-2-n-propyl-
benzimidazole (45)
In the same manner as in Example 1, 160 mg of colorless
crystals of 6-ethoxycarbonyl-1-(2-fluorobenzyl)-2-n-propyl-
benzimidazole (45) were formed from 390 mg of ethyl 3-[N-(2-
fluorobenzyl)butyrylamino]-4-nitrobenzoate.
Properties of Compound (45):
1 H-NMR ( CDC1 3 , ~ ) . 1 . 04 ( 3H, t, J=8Hz ) , 1 . 40 ( 3H, t, J=8Hz ) ,
1.78-1.98 (2H, m), 2.34 (2H, t, J=8Hz), 4.38 (2H, q, J=8Hz),
5.45 (2H, s), 6.65 (1H, t, J=8Hz), 7.00 1H, t, J=8Hz), 7.13 (1H,
t, J=8Hz), 7.28 (1H, t, J=8Hz), 7.78 (1H, d, J=lOHz), 7.99 (1H,
d, J=lOHz); 8.02 (1H, s)
mp . 134-135°C
Examyle S
Synthesis of 6-ethoxycarbonyl-1-(4-fluorobenzyl)-2-n-propyl-
benzimidazole (46)
In the same manner as in Example 1, 160 mg of colorless
crystals of 6-ethoxycarbonyl-1-(4-fluorobenzyl)-2-nrpropyl-
benzimidazole (46) were formed from 400 mg of ethyl 3-[N-(4-
fluorobenzyl)butyryl)amino]-4-nitrobenzoate.
Properties of Compound (46):
1H-NMR (CDC13, ~ ) . 1.04 (3H, t, J=8Hz), 1.40 (3H, t, J=8Hz),
1.88 (2H, sextet, J=8Hz), 2.82 (2H, t, J=8Hz), 4.38 (2H, q,
J=8Hz), 5.38 (2H, s), 7.00 (4H, d, J=7Hz), 7.77 (1H, d, J=8Hz),
7.98 (1H, d, J=1Hz), 8.00 (1H, dd, J=1, 8Hz)
mp . 134 -135°C
Example 6
The following compounds were formed in the same manner as
in Example 1.
Example 6-1
6-Ethoxycarbonyl-2-n-propyl-1-(2-pyridylmethyl)benzimidazole
(47)
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71
Properties of Compound (47)
1H-NMR (CDC13, S) . 1.03 (3H, t, J=7.5Hz), 1.39 (3H, t, J=7.5Hz),
1.89 (2H, m), 2.86 (2H, t, J=7.5Hz), 4.38 (2H, q, J=7.5Hz), 5.50
(2H, s), 6.72 (1H, d, J=7.5Hz), 7.24 (1H, m), 7.58 (1H, dt,
J=7.5,1.5Hz), 7.79 (1H, d, J=7.5Hz), 7.96-8.02 (2H, m), 8.60 (1H,
d, J=4Hz)
mp . 84-85°C
Example 6-2
6-Ethoxycarbonyl-1-(3-fluorobenzyl)-2-n-propylbenzimidazole (48)
Properties of Compound (48)
1H-NMR (CDC13, ~) . 1.04 (3H, t, J=7.5Hz), 1.39 (3H, t, J=7.5Hz),
1.90 (2H, m), 2.81 (2H, t, J=7.5Hz), 4.39 (2H, q, J=7.5Hz), 5.39
(2H, s), 6.70-6.84 (2H, m), 7.00 (1H, dt, J=8.5 and l.5Hz), 7.78
(1H, d, J=8.5Hz), 7.96 (1H, s), 8.00 (1H, d, J=8.5Hz)
mp . 142-146°C
Example 6-3
1-(2,6-Dichlorobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole
(49)
Properties of Compound (49)
1H-NMR (CDC13, Cs) . 1.03 (3H, t, J=7.5Hz), 1.38 (3H, t, J=7.5Hz),
1.88 (2H, m), 2.93 (2H, t, J=7.5Hz), 4.34 (2H, q, J=7.5Hz), 5.61
(2H, s), 7.26 (1H, d, J=7.5Hz), 7.39 (2H, d, J=7.5Hz), 7.68 (1H,
d, J=7.5Hz), 7.84 (1H, d, J=l.5Hz), 7.91 (2H, d, J=7.5Hz)
mp . 153-156°C
Examt~le 6-4
1-(3-Methylbenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole (50)
Properties of Compound (50):
colorless solid.
1H-NMR (CDC13, CS) . 1.02 (3H, t, J=7.5Hz), 1.41 (3H, t, J=7.5Hz),
1. 89 ( 2H, m) , 2 . 29 ( 3H, s ) , 2 . 82 ( 2H, t, J=7 . 5Hz ) , 4 .38 ( 2H,
q,
J=7.5Hz), 5.35 (2H, s), 6.79-6.86 (2H, m), 7.09 (1H, d, J=7.5Hz),
7.20 (1H, t, J=7.5Hz), 7.76 (1H, d, J=7.5Hz), 7.95-8.02 (2H, m)
xa ~,le 6-5
2-Cyclopropyl-6-ethoxycarbonyl-1-(2-fluorobenzyl)benzimidazole
(51)
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a
72
Properties of Compound (51):
1H-NMR (CDC13, ~ ) . 1.10 (2H, m), 1.27 (2H, m), 1.40 (3H, t,
J=7.5Hz), 1.95 (1H, m), 4.37 (2H, q, J=7.5Hz), 5.56 (2H, s),
6.77 (1H, t, J=7.5Hz), 7.03 (1H, t, J=7.5Hz), 7.13 (1H, t,
J=7.5Hz), 7.29 (1H, m), 7.69 (1H, d, J=7.5Hz), 7.96 (1H, d,
J=7.5Hz), 8.02 (1H, d, J=2Hz)
mp . 122-126°C
E~yle 6-6
1-(2-Chlorobenzyl)-6-cyano-2-cyclopropylbenzimidazole (52)
Properties of Compound (52):
iH-NMR (CDC13, S ) . 1.04-1.24 (2H, m), 1.24-1.39 (2H, m), 1.83-
2.01 (1H, m), 5.58 (2H, s), 6.54 (1H, d, J=9Hz), 7.16 (1H, td,
J=9, 2Hz), 7.22-7.38 (1H, m), 7.43-7.56 (3H, m), 7.74 (1H, dd,
J=9, 2Hz)
Mass (FAB) . 308 (M+1)
IR (Nujol) . 2210ciri
Exam~,,le 6-7
1-(2-Chlorobenzyl)-2-cyclobutyl-6-ethoxycarbonylbenzimidazole
(53)
Properties of Compound (53):
1H-NMR (CDC13, ~ ) . 1.38 (3H, t, J=7.5Hz), 1.90-2.21 (2H, m),
2.21-2.24 (2H, m), 2.46-2.70 (2H, m), 3.52-3.73 (1H, m), 4.37
(2H, q, J=7.5Hz), 5.39 (2H, s), 6.34 (1H, dd, J=9, 2Hz), 7.06
( 1H, td, J=9, 2Hz ) , 7 . 23 ( 1H, td, J=9, 2Hz ) , 7 .46 ( 1H, dd, J=9,
2Hz), 7.83 (1H, d, J=9Hz), 7.92 (1H, d, J=2Hz), 8.0I (1H, dd,
J=9, 2Hz)
mp . 111-113°C
Exam~,,le 6-8
1-(2-Chlorobenzyl)-6-ethoxycarbonyl-2-n-pentylbenzimidazole (54)
Properties of Compound (54):
1H-NMR (CDC13, ~ ) . 0.87 (3H, t, J=7.5Hz), 1.22-1.47 (7H, m),
1.74-1.93 (2H, m), 2.80 (2H, t, J=7.5Hz), 4.37 (2H, q, J=7.5Hz),
.47 ( 2H, s ) , 6 .39 ( 1H, dd, J=9, 2Hz ) , 7 . 08 ( 1H, td, J=9, 2Hz ) ,
7.19-7.33 (1H, m), 7.48 (1H, dd, J=9, 2Hz), 7.79 (1H, d, J=9Hz),
7.94 (1H, d, J=2Hz), 8.00 (lH,dd, J=9, 2Hz)
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r
73
Exam~~le 7
5-Carboxy-1-(2-chlorobenzyl)-2-n-propylbenzimidazole (55)
Twenty milliliters of ethanol and 10.4 g of a 10~ sodium
hydroxide aqueous solution were added to 2.8 g of 1-(2-
chlorobenzyl)-5-ethoxycarbonyl-2-n-propylbenzimidazole, and the
mixture was heat-refluxed for 4 hours. The reaction solution was
cooled, and was then adjusted to a pH of 6 with 10~ hydrochloric
acid. The crystals were collected, washed with water, and dried
under reduced pressure to give 2.46 g of a colorless solid of 5-
carboxy-1-(2-chlorobenzyl)-2-n-propylbenzimidazole (55).
Properties of Compound (55):
1H-NMR (DMSO-d6, ~ ) . 0.93 (3H, t, J=7.5Hz), 1.75 (2H, m), 2.79
(2H,t, J=7.5Hz), 5.61 (2H, s), 6.49 (1H, d, J=7.5Hz), 7.21 (1H,
t, J=7.5Hz),7.33 (1H, t, J=7.5Hz), 7.46 (1H, d, J=7.5Hz), 7.56
(1H, d, J=7.5Hz), 7.80 (1H, d, J=7.5Hz), 8.20 (1H, s)
Example 8
The following compounds were formed in the same manner as
in Example 7.
Examt-~le 8-1
6-Carboxy-1-(3-methylbenzyl)-2-n-propylbenzimidazole (56)
Properties of Compound (56):
colorless solid.
1 H-NMR (DMSO-d6, ~ ) . 0. 97 ( 3H, t, J=7 .5Hz ) , 1. 78 ( 2H, m) , 2 .23
(3H, s), 3.86 (2H, q, J=7.5Hz), 5.53 (2H, s), 6.80 (1H, d,
J=7.5Hz), 6.91 (lH,s), 7.07 (1H, d, J=7.5Hz), 7.21 (1H, t,
J=7.5Hz), 7.65 (1H, d, J=7.5Hz),7.79 (1H, d, J=7.5Hz), 8.04 (1H,
s)
2-n-Butyl-7-carboxy-1-(2-chlorobenzyl)benzimidazole (57)
Properties of Compound (57):
1H-NMR (DMSO-d6, ~ ) . 0.84 (3H, t, J=7.5Hz), 1.34 (2H, m), 1.71
(2H, m), 2.80 (2H, t, J=7.5Hz), 5.89 (2H, s), 6.03 (1H, d,
J=7.5Hz), 7.13 (1H, t, J=7.5Hz), 7.27 (2H, t, J=7.5Hz), 7.48 (1H,
d, J=7.5Hz), 7.63 (1H, d, J=7.5Hz), 7.87 (1H, d, J=7.5Hz)
Example 8-3
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74
6-Carboxy-2-cyclopropyl-1-(2-fluorobenzyl)benzimidazole (58)
Properties of Compound (58):
1H-NMR (DMSO-d6, ~) . 1.04-1.19 (4H, m), 2.37 (1H, m), 5.79 (2H,
s), 7.00 (1H, t, J=7.5Hz), 7.15 (1H, t, J=7.5Hz), 7.27 (1H, t,
J=10.5Hz), 7.37 (1H, m), 7.60 (1H, d, J=7.5Hz), 7.82 (1H, d,
J=7.5Hz), 8.11 (1H, s)
mp . 224-229°C
Eagle 8-4
2-n-Butyl-6-carboxy-1-(2-fluorobenzyl)benzimidazole (59)
Properties of Compound (59):
1H-NMR (DMSO-d6, (S) . 0.87 (3H, t, J=7.5Hz), 1.26-1.48 (2H, m),
1.60-1.80 (2H, m), 2.90 (2H, t, J=7.5Hz), 5.63 (2H, s), 6.89 (1H,
td, J=9, 2Hz), 7.13 (1H, td, J=9, 2Hz), 7.20-7.44 (2H, m), 7.64
(1H, d, J=9Hz), 7.80 (1H, dd, J=9, 2Hz), 8.08 (1H, d, J=2Hz)
mp . 216-219°C
E~yle 9
Synthesis of 1-(2-chlorobenzyl)-6-chlorocarbonyl-2-cyclopropyl-
benzimidazole hydrochloride (60)
Oxalyl chloride (0.208 ml) was added dropwise to a
suspension prepared by adding 390 mg of 6-carboxy-1-(2-
chlorobenzyl)-2-cyclopropylbenzimidazole to 10 ml of methylene
chloride containing 1 drop of N,N-dimethylformamide at room
temperature over a period of several minutes. The mixture was
stirred at the same temperature for 2 hours, and was then
concentrated under reduced pressure. Isopropyl ether was added
to the residue, and the mixture was pulverized to give 450 mg of
1-(2-chlorobenzyl)-6-chlorocarbonyl-2-cyclopropylbenzimidazole
hydrochloride (60) as a white powder. Since this product was
unstable, it was used as a starting material in the subsequent
step without being purified.
Example 10
Synthesis of 1-(2-chlorobenzyl)-6-(4-dimethylaminophenylmethyl-
carbamoyl)-2-n-propylbenzimidazole (61)
Four-hundred milligrams of 6-carboxy-1-(2-chlorobenzyl)-2-
n-propylbenzimidazole were dissolved in 3 ml of methylene
CA 02241186 1998-06-23
chloride containing 1 drop of N,N-dimethylformamide. Oxalyl
chloride ( 28 mg ) was added to this solution at 5 °C . The thus-
obtained solution was stirred at room temperature for 1 hour,
and was then concentrated under reduced pressure. The residue
was dissolved in 3 ml of methylene chloride, and the mixture was
added to a mixed solution prepared by adding 271 mg of 4-
dimethylaminobenzylamine hydrochloride and 1 ml of triethylamine
to 10 ml of methylene chloride at room temperature. The
resulting reaction mixture was stirred at the same temperature
for 1 hour, washed with water, dried and then concentrated under
reduced pressure. The residue was developed and purified through
thin-layer chromatography to give 215 mg of 1-(2-chlorobenzyl)-
6-(4-dimethylaminophenylmethylcarbamoyl)-2-n-propylbenzimidazole
(61).
Properties of Compound (61):
colorless crystal.
1H-NMR (CDC13 , ~ ) . 1.01 (3H, t, J=7Hz), 1.88 (2H, sextet,
J=7Hz ) , 2 . 76 ( 2H, t, J=7Hz ) , 2 . 95 ( 6H, s ) , 4 . 50 ( 2H, d, J=5Hz )
,
5.45 (2H, s), 6.32 (1H, d, J=5Hz), 6.36 (1H, d, J=7Hz), 6.72 (2H,
d, J=lOHz), 7.07 (1H, dt, J=1, 8Hz), 7.20-7.25 (3H, m), 7.46 (1H,
dd, J=1, 8Hz), 7.58 (1H, dd, J=1, 8Hz), 7.76 (1H, d, J=8Hz),
7.82 (1H, d, J=1Hz)
mp . 155-156°C
Example 11
Synthesis of 1-(2-chlorobenzyl)-6-morpholino-carbamoyl-2-n-
propylbenzimidazole (62)
In the same manner as in Example 10, 205 mg of 1-(2-
chlorobenzyl)-6-morpholinocarbamoyl-2-n-propylbenzimidazole (62)
were formed from 200 mg of 6-carboxy-1-(2-chlorobenzyl)-2-n-
propylbenzimidazole and 124 mg of 4-aminomorpholine.
Properties of Compound (62):
colorless crystal.
1H-NMR (CDC13 , ~ ) . 1.03 (3H, t, J=8Hz), 1.88 (2H, sextet,
J=8Hz ) , 2 . 62 ( 4H, bs ) , 2 . 72 ( 2H, t, J=8Hz ) , 3 . 85 ( 4H, bs ) , 5
. 42
(2H, s), 6.42 (1H, dd, J=1, 8Hz), 7.08 (1H, dt, J=1, 8Hz), 7.20-
CA 02241186 1998-06-23
76
7.28 (3H, m), 7.47 (1H, dd, J=1, 8Hz), 7.78 (1H, dd, J=1, 8Hz)
mp . 195-197°C
Examlale 1212
Synthesis of 1-(2-chlorobenzyl)-2-n-propyl-6-thiomorpholino-
carbonylbenzimidazole (63)
In the same manner as in Example 10, 160 mg of 1-(2-
chlorobenzyl-2-n-propyl-6-thiomorpholinocarbonyl-benzimidazole
(63) were formed from 200 mg of 6-carboxy-1-(2-chlorobenzyl)-2-
n-propylbenzimidazole and 125 mg of thiomorpholine.
Properties of Compound (63):
colorless crystal.
1H-NMR (CDC13, ~ ) . 1.03 (3H, t, J=8Hz), 1.88 (2H, sextet,
J=8Hz), 2.78 (2H, t, J=8Hz), 2.96 (4H, bt, J=5Hz), 3.88 (4H, bt,
J=5Hz), 5.46 (2H, s), 6.34 (1H, dd, J=1, 8Hz), 7.08 (1H, dt, J=1,
8Hz), 7.26 (2H, dt, J=1, 8Hz), 7.47 (1H, dd, J=1, 8Hz), 7.58 (1H,
bd, J=8Hz), 7.76 (1H, s), 7.78 (1H, d, J=8Hz)
mp . 160-162°C
Example 13
Synthesis of 2-n-butyl-1-(2-chlorobenzyl)-6-[(2-pyridylmethyl)-
carbamoyl]benzimidazole (64)
In the same manner as in Example 10, 230 mg of 2-n-butyl-
1-(2-chlorobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole
(64) were formed from 200 mg of 6-carboxy-2-n-butyl-1-(2-
chlorobenzyl)-benzimidazole and 126 mg of 2-aminomethylpyridine.
Properties of Compound (64):
colorless crystal.
1H-NMR (CDC13, ~ ) . 0.92 (3H, t, J=8Hz), 1.42 (2H, sextet,
J=8Hz), 1.82 (2H, quintet, J=8Hz), 2.82 (2H, t, J=8Hz), 4.76 (1H,
d, J=5Hz ) , 5 . 46 ( 2H, s ) , 6 . 38 ( 1H, dd, J=1, 8Hz ) , 7 . 08 ( 1H, dt,
J=1, 8Hz), 7.18-7.26 (2H, m), 7.32 (1H, d, J=8Hz), 7.46 (1H, dd,
J=1, 8Hz), 7.62 (1H, dt, J=l, 8Hz), 7.72 (1H, dt, J=1, 8Hz),
7.82 (1H, d, J=8Hz), 7.88 (1H, d, J=1Hz), 8.56 (1H, dd, J=1,
8Hz)
mp . 175-176°C
E~ple 14
CA 02241186 1998-06-23
77
Synthesis of 2-n-butyl-5-carbamoyl-1-(2-chlorobenzyl)-
benzimidazole (65)
In the same manner as in Example 10, 170 mg of 2-n-butyl-
5-carbamoyl-1-(2-chlorobenzyl)benzimidazole (65) were formed
from 100 mg of 2-n-butyl-1-(2-chlorobenzyl)-5-carboxy-
benzimidazole.
Properties of Compound (65):
colorless crystal.
1H-NMR (DMSO-d6, ~ ) . 0.84 (3H, t, J=8Hz), 1.35 (2H, sextet,
J=8Hz), 1.68 (2H, quintet, J=8Hz), 2.78 (2H, t, J=8Hz), 5.58 (2H,
s ) , 6. 50 ( 1H, dd, J=1, 8Hz ) , 7 .25 ( 1H, dt, J=1, 8Hz ) , 7 .28 ( 1H,
bs), 7.35 (1H, dt, J=1, 8Hz), 7.42 (1H, d, J=lOHz), 7.56 (1H, dd,
J=1, 8Hz), 7.74 (1H, dd, J=1, lOHz), 7.96 (1H, bs), 8.20 (1H, d,
J=1Hz)
mp . 195-198°C
Example 15
Synthesis of 1-(2-chlorobenzyl)-2-cyclopropyl-6-morpholino-
carbonylbenzimidazole (66)
1-(2-Chlorobenzyl)-6-chlorocarbonyl-2-cyclopropyl-
benzimidazole hydrochloride (140 mg) was added to a solution
prepared by adding 298 mg of morpholine (30$ methanol solution)
to 10 ml of methylene chloride at room temperature. The reaction
mixture was stirred at the same temperature for 1 hour, then
washed with water, dried, and concentrated under reduced
pressure. The residue was recrystallized with ether to give 20
mg of 1-(2-chlorobenzyl)-2-cyclopropyl-6-morpholinocarbonyl-
benzimidazole (66).
Properties of Compound (66):
colorless crystal.
1H-NMR (CDC13, S) . 1.04-1.12 (2H, m), 1.25-1.32 (2H, m), 1.82-
1.96 (1H, m), 3.68 (8H, bs), 5.56 (2H, s), 6.55 (1H, dd, J=1,
8Hz), 7.13 (1H, dt, J=I, 8Hz), 7.22-7.29 (2H, m), 7.30 (1H, d,
J=1Hz), 7.46 (1H, dd, J=1, 8Hz), 7.77 (1H, d, J=8Hz)
mp . 193-195°C
Exam~,,le 16
CA 02241186 1998-06-23
78
Synthesis of 1-(2-chlorobenzyl)-2-cyclopropyl-6-[(2-pyridyl-
methyl)carbamoyl]benzimidazole (67)
In the same manner as in Example 15, 95 mg of 1-(2-
chlorobenzyl)-2-cyclopropyl-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole (67) were formed from 150 mg of 1-(2-
chlorobenzyl)-6-chlorocarbonyl-2-cyclopropylbenzimidazole
hydrochloride and 85 mg of 2-aminomethylpyridine.
Properties of Compound (67):
colorless crystal.
1H-NMR (CDC13, ~) . 1.02-1.13 (2H, m), 1.24-1.32 (2H, m), 1.82-
1.95 (1H, m), 4.76 (2H, d, J=5Hz), 5.59 (2H, s), 7.11 (1H, dt,
J=1, 8Hz), 7.20-7.26 (2H, m), 7.34 (1H, d, J=8Hz), 7.46 (1H, dd,
J=1, 8Hz), 7.60 (1H, t, J=5Hz), 7.66 (1H, dd, J=1, 8Hz), 7.73
(1H, s), 7.88 (1H, s)
mp . 134-135°C
Example 17
The following compounds were formed in the same manner as
in Example 15.
Example 17-1
1-(2-Chlorobenzyl)-2-cyclopropyl-6-(2-pyridylcarbamoyl)-
benzimidazole (68)
Properties of Compound (68):
1 H-NMR (CDC1 3 , ~ ) . 1 . 16 ( 2H, m) , 1. 32 ( 2H, m) , 1 . 92 ( 1H, m) ,
5.61 (2H, s), 6.57 (1H, d, J=7.5 and l.5Hz), 7.15 (1H, dt, J=7.5
and l.5Hz), 7.22-7.31 (2H, m), 7.48 (1H, dd, J=7.5 and l.5Hz),
7.77 (1H, d, J=9Hz), 8.05 (2H, m).
mp . 206-209°C
Exam~,le 17-2
6-(2-Carboxy-1-pyrrolidinocarbonyl)-1-(2-chlorobenzyl)-2-n-
propylbenzimidazole (69)
Properties of Compound (69):
1H -NMR (DMSO-d6, S) . 0.92 (3H, t, J=7.5Hz), 1.65-1.99 (5H, m),
2.25 (1H, m), 2.77 (2H, t, J=7.5Hz), 3.50 (2H, m), 4.40 (1H, m),
5.52 (2H, s), 6.53 (1H, d, J=7.5Hz), 7.21-7.71 (6H, m).
mp . 9 6 °C
CA 02241186 1998-06-23
79
Example 17-3
1-(2-Chlorobenzyl)-2-cyclobutyl-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole (70)
Properties of Compound (70):
1H -NMR (CDC13, ~) . 1.90-2.21 (2H, m), 2.25-2.37 (2H, m), 2.40-
2.65 (2H, m), 3.64 (1H, m), 4.76 (2H, d, J=5Hz), 5.39 (2H, s),
6.33 (1H, d, J=7.5Hz), 7.05 (1H, t, J=7.5Hz), 7.16-7.26 (2H, m),
7.33 (1H, d, J=7.5Hz), 7.46 (1H, d, J=7.5Hz), 7.69-7.76 (3H, m),
7.73 (1H, d, J=7.5Hz), 7.86 (1H, s), 8.55 (1H, d, J=5Hz).
mp . 183-185°C.
Example 17-4
(1-(2-Chlorobenzyl)-2-n-propyl-5-[(2-pyridylmethyl)carbamoyl]-
benzimidazole (71)
Properties of Compound (71)
1 H -NMR ( CDC1 3 , ~ ) . 1 . 03 ( 3H, t, J=7 . 5Hz ) , 1 . 90 ( 2H, m) , 2 .
80
(2H, t, J=7.5Hz), 4.80 (2H, d, J=5Hz), 5.44 (2H, s), 6.40 (1H, d,
J=7.5Hz), 7.09 (1H, t, J=7.5Hz), 7.21-7.27 (3H, m), 7.34 (1H, d,
J=7.5Hz), 7.47 (1H, d, J=7.5Hz), 7.64-7.72 (2H, m), 7.83 (1H, dd,
J=7.5 and 2Hz), 8.30 (1H, d, J=2Hz), 8.56 (1H, d, J=5Hz).
mp . 115 -116 °C
Example 17-5
1-(2-Chlorobenzyl)-6-[N-methyl-N-(2-pyridylmethyl)carbamoyl]-2-
n-propylbenzimidazole (72)
Properties of Compound (72):
1H -NMR (DMSO-d6, S) . 1.03 (3H, t, J=7.5Hz), 1.87 (2H, m), 2.79
(2H, t, J=7.5Hz), 3.05 (3H, brs), 4.60 (1H, brs), 4.87 (1H, brs),
5.40 (2H, d, J=unknown), 6.38 (1H, d, J=unknown), 7.05 (1H, brs),
7.20 (3H, m), 7.35-7.49 (3H, m), 7.60-7.81 (2H, m), 8.54 (1H,
brs).
mp . 99°C.
Example 17-6
1-(2-Chlorobenzyl)-6-piperonylcarbamoyl-2-n-propylbenzimidazole
(73)
Properties of Compound (73):
1 H -NMR (CDC13, S ) . 1 . O1 ( 3H, t, J=7 . 5Hz ) , 1 . 88 ( 2H, m) , 2 . 78
CA 02241186 1998-06-23
(2H, t, J=7.5Hz), 4.54 (2H, d, J=5Hz), 5.45 (2H, s), 5.95 (2H,
s), 6.36 (1H, d, J=7.5Hz), 6.44 (1H, t, J=5Hz), 6.75-6.85 (3H,
m), 7.08 (1H, t, J=7.5Hz), 7.23 (1H, t, J=7.5Hz), 7.45 (1H, d,
J=7.5Hz), 7.67 (1H, dd, J=7.5 , 2Hz), 7.78 (1H, d, J=7.5Hz),
7.83 (1H, s).
mp . 131-134°C.
Examp 1e 17-7
1-(2-chlorobenzyl)-6-phenylcarbamoyl-2-n-propylbenzimidazole
(74)
Properties of Compound (74):
1H -NMR (CDC13, ~ ) . 1.03 (3H, t, J=7.5Hz), 1.90 (2H, m), 2.81
(2H, t, J=7.5Hz), 5.47 (2H, s), 6.40 (1H, d, J=7.5Hz), 7.06-7.18
(2H, m), 7.26 (1H, t, J=7.5Hz), 7.35 (2H, t, J=7.5Hz), 7.48 (1H,
d, J=7.5Hz), 7.64 (2H, d, J=7.5Hz), 7.72 (1H, dd, J=7.5 and 2Hz),
7.85-7.95 (3H, m).
mp . 168°C.
Example 17-g-
1-(2-Chlorobenzyl)-2-n-propyl-6-[(4-pyridylmethyl)carbamoyl]-
benzimidazole (75)
Properties of Compound (75):
1H -NMR (DMSO-d6, ~) . 0.93 (3H, t, J=7.5Hz), 1.76 (2H, m), 2.78
(2H, t, J=7.5Hz), 4.49 (2H, d, J=5Hz), 6.42 (1H, d, J=7.5Hz),
7.22 (1H, t, J=7.5Hz), 7.27 (2H, d, J=7.5Hz), 7.34 (1H, t,
J=7.5Hz), 7.57 (1H, d, J=7.5Hz), 7.69 (1H, d, J=7.5Hz), 7.80 (1H,
d, J=7.5Hz), 7.97 (1H, s), 8.48 (2H, d, J=7.5Hz), 9.03 (1H, t,
J=5Hz).
mp . 170-173°C.
Exam~,,le 17-9
1-(2-Chlorobenzyl)-2-n-propyl-6-[(3-pyridylmethyl)carbamoyl]-
benzimidazole (76)
Properties of Compound (76):
1H -NMR (DMSO-d6, ~) . 0.95 (3H, t, J=7.5Hz), 1.76 (2H, m), 2.80
(2H, t, J=7.5Hz), 4.50 (2H, d, J=5Hz), 5.60 (2H, s), 6.42 (1H, d,
J=7.5Hz), 7.23 (1H, t, J=7.5Hz), 7.30-7.58 (2H, m), 7.57 (1H, d,
J=7.5Hz), 7.67-7.74 (2H, m), 7.75 (1H, d, J=7.5Hz), 7.97 (1H, s),
CA 02241186 1998-06-23
81
8.46 (1H, d, J=5Hz), 8.56 (1H, s), 9.0 (1H, t, J=5Hz).
mp . 193-195°C.
Exam~,,le 17-10
1-(2-Chlorobenzyl)-6-[N-methyl-N-(2-pyridyl)carbamoyl]-2-n-
propylbenzimidazole (77)
Properties of Compound (77):
1H -NMR (DMSO-d6, ~) . 0.90 (3H, t, J=7.5Hz), 1.70 (2H, m), 2.73
(2H, t, J=7.5Hz), 3.40 (3H, s), 5.42 (2H, s), 6.23 (1H, d,
J=7.5Hz), 6.91 (1H, d, J=7.5Hz), 6.98 (1H, m), 7.15-7.25 (3H, m),
7.36 (1H, t, J=7.5Hz), 7.46-7.57 (3H, m), 8.23 (1H, m).
mp . 143-146°C.
Exam=le 17-11
1-(2-Chlorobenzyl)-6-(homopiperidinocarbonyl)-2-n-propyl-
benzimidazole (78)
Properties of Compound (78):
1 H-NMR ( CDCl 3 , ~ ) . 1 . 03 ( 3H, t, J=7 . 5Hz ) , 1 . 46-1. 94 ( 10H, m)
,
2.80 (2H, t, J=7.5Hz), 3.32 (2H, brs), 3.64 (2H, t, J=7.5Hz),
5.41 (2H, s), 6.42 (1H, d, J=7.5Hz), 7.07 (1H, t, J=7.5Hz),
7.19-7.29 (3H, m), 7.45 (1H, d, J=7.5Hz), 7.76 (1H, d, J=7.5Hz).
mp . 136-137°C.
Example 17-12
1-(3-Methylbenzyl)-2-n-propyl-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole (79)
Properties of Compound (79):
1 H-NMR (CDCl 3 , c~ ) . 1 . 02 ( 3H, t, J=7 . 5Hz ) , 1 . 88 ( 2H, m) , 2 .26
(3H, s), 2.81 (2H, t, J=7.5Hz), 4.76 (2H, d, J=5Hz), 5.36 (2H,
s), 6.78-6.84 (2H, m), 7.07 (1H, d, J=7.5Hz), 7.13-7.22 (2H, m),
7.33 (1H, d, J=7.5Hz), 7.57-7.72 (2H, m), 7.78 (1H, d, J=7.5Hz),
7.94 (1H, s), 8.55 (1H, d, J=5Hz).
mp . 129-131°C.
Example 17-13
2-n-Butyl-1-(2-fluorobenzyl)-6-[N-methyl-N-(2-pyridylmethyl)-
carbamoyl]benzimidazole (80)
Properties of Compound (80):
1 H-NMR (CDC1 3 , CS ) . 0. 92 ( 3H, t, J=7 . 5Hz ) , 1 . 45 ( 2H, m) , 1 . 83
CA 02241186 1998-06-23
82
( 2H, m) , 2 . 86 ( 2H, t, J=7 . 5Hz ) , 3 . 06 ( 3H, brs ) , 4 . 61 ( 1H, brs
) ,
4 . 86 ( 1H, brs ) , 5.37 ( 2H, brd) , 6. 62 ( 1H, brd) , 6. 97 ( 1H, brs ) ,
7.07-7.85 (8H, m), 8.57 (1H, d, J=5Hz).
mp . 97-100°C.
Example 17-14
1-(2-Chlorobenzyl)-2-ethyl-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole (81)
Properties of Compound (81):
1H-NMR (CDC13, c~) . 1.43 (3H, t, J=7.5Hz), 2.84 (2H, q, J=7.5Hz),
4.76 (2H, d, J=5Hz), 5.45 (2H, s), 6.37 (1H, d, J=7.5Hz), 7.07
(1H, t, J=7.5Hz), 7.19-7.28 (2H, m), 7.33 (1H, d, J=7.5Hz), 7.45
(1H, dd, J=7.5 and 2Hz), 7.62-7.75 (3H, m), 7.82 (1H, d,
J=7.5Hz), 7.89 (1H, d, J=2Hz), 8.55 (1H, d, J=5Hz).
mp . 167-168°C.
Example 17-15
2-n-Butyl-1-(2-chlorobenzyl)-7-[(2-pyridylmethyl)carbamoyl]-
benzimidazole-(g2~
Properties of Compound (82):
1H-NMR (CDC13, 8 ) . 0.93 (3H, t, J=7.5Hz), 1.42 (2H, m), 1.83
(2H, m), 2.81 (2H, t, J=7.5Hz), 4.44 (2H, d, J=5Hz), 5.70 (2H,
s), 6.13.(1H, dd, J=7.5 and 2Hz), 6.85-6.97 (3H, m), 7.12-7.28
(4H, m), 7.34 (1H, d, J=7.5Hz), 7.62 (1H, dt, J=7.5 and 2Hz),
7.88 (1H, d, J=7.5Hz), 8.40 (1H, d, J=5Hz).
mp . 112-114°C.
Example 17-16
2-Cyclopropyl-1-(2-fluorobenzyl)-6-(piperonylcarbamoyl)-
benzimidazole (83)
Properties of Compound (83):
1 H-NMR (DMSO-d6, ~ ) . 1 . 05 ( 4H, m) , 2 .27 ( 1H, m) , 4 . 38 ( 2H, d,
J=5Hz), 5.71 (2H, s), 5.98 (2H, s), 6.73-6.91 (4H, m), 7.14 (1H,
t, J=7.5Hz), 7.27 (1H, t, J=7.5Hz), 7.36 (1H, m), 7.55 (1H, d,
J=7 . 5Hz ) , 7 . 73 ( 1H, dd, J=7 . 5 and 2Hz ) , 8 . 04 ( 1H, s ) , 8 . 87 (
1H,
t, J=5Hz).
mp . 170-173°C.
Example 17-17
CA 02241186 1998-06-23
83
2-[[1-(2-chlorobenzyl)-2-ethylbenzimidazol-6-yl]carbonylamino-
methyl]-pyridine-1-oxide (84)
Properties of Compound (84):
1H-NMR (CDC13, ~) . 1.42 (3H, t, J=7.5Hz), 2.82 (2H, q, J=7.5Hz),
4.81 (2H, d, J=7.5Hz), 5.43 (2H, s), 6.31 (1H, d, J=7.5Hz), 7.06
(1H, t, J=7.5Hz), 7.20-7.31 (3H, m), 7.44 (1H, d, J=7.5Hz), 7.52
(1H, dd, J=7.5 and 2Hz), 7.65 (1H, dd, J=7.5 and 2Hz), 7.77-7.83
(2H, m), 7.96 (1H, t, J=7.5Hz), 8.23 (1H, dd, J=7.5 and 2Hz).
mp . 204-207°C
Example 17-18
2-n-Butyl-1-(2-fluorobenzyl)-6-(2-pyridylmethylcarbamoyl)-
benzimidazole (85)
Properties of Compound (85):
1H-NMR (CDC13, ~ ) . 0.92 (3H, t, J=7.5Hz), 1.38-1.49 (2H, m),
1.77-1.88 (2H, m), 2:86 (2H, t, J=7.5Hz), 4.78 (2H, d, J=5Hz),
5.46 (2H, s), 6.67 (1H, t, J=9Hz), 7.00 (1H, t, J=9Hz), 7.13 (1H,
t, J=9Hz ) , 7 . 19-7 . 31 ( 2H, m) , 7 . 33 ( 1H, d, J=9Hz ) , 7 . 60 ( 1H,
br
peak), 7.65-7.74 (2H, m), 7.79 (1H, d, J=9Hz), 7.97 (1H, d,
J=2Hz), 8.58 (1H, d, J=5Hz).
mp . 154-155°C
Example 18
Synthesis of 6-tert-buthoxycabonylamino-1-(2-chlorobenzyl)-2-n-
propylbenzimidazole (86)
Two-hundred milligrams of 6-carboxy-1-(2-chlorobenzyl)-2-
n-propylbenzimidazole were suspended in 5 ml of tert-butyl
alcohol, and 0.19 ml of diphenylphosphorylazide and 0.21 ml of
diisopropylethylamine were added thereto at room temperature.
The reaction mixture was refluxed for 4 hours, and was then
separated with ethyl acetate and with water. The organic layer
was washed with water, dried, and then concentrated under
reduced pressure. The residue was developed and purified through
column chromatography using a mixture of ethyl acetate and
hexane (at a ratio of from 1:10 to 1:3), and was further
recrystallized from a mixture of ethyl acetate and hexane to
give 165 mg of 6-tert-buthoxycabonylamino-1-(2-chlorobenzyl)-2-
CA 02241186 1998-06-23
84
n-propylbenzimidazole (86).
Properties of Compound (86):
colorless crystal.
1H-NMR (CDC13, ~) . 0.98 (3H, t, J=8Hz), 1.50 (9H, s), 1.86 (2H,
sextet, J=8Hz), 2.72 (2H, t, J=8Hz), 5.38 (2H, s), 6.40 (1H, dd,
J=1, 8Hz), 6.95 (1H, dd, J=1, lOHz), 7.08 (1H, dt, J=1, 8Hz),
7.24 (1H, dt, J=1, 8Hz), 7.28 (1H, d, J=1Hz), 7.45 (1H, dd, J=1,
8Hz), 7.66 (1H, d, J=lOHz).
mp . 166-168°C.
Example 19
Synthesis of 1-(2-chlorobenzyl)-6-cyano-2-n-propylbenzimidazole
(87)
A solution of 1 mol of titanium tetrachloride in 0.14 ml
of dichloromethane and 0 . 3 6 ml of triethylamine were added to a
solution of 200 mg of 6-carbamoyl-1-(2-chlorobenzyl)-2-n-
propylbenzimidazole in 4 ml of tetrahydrofuran at 0°C, and the
mixture was stirred at 20°C for 2 hours. The reaction mixture
was separated with ethyl acetate and with water. The organic
layer was washed with water, dried, and then concentrated under
reduced pressure. The residue was developed and purified through
column chromatography using a mixture of ethyl acetate and
hexane (at a ratio of from 1:10 to 1:3), and was further
recrystallized from a mixture of ethyl acetate and hexane to
give 140 mg of 1-(2-chlorobenzyl)-6-cyano-2-n-
propylbenzimidazole (87).
Properties of Compound (87):
colorless crystal.
1H-NMR (CDC13 , ~ ) . 1.05 (3H, t, J=8Hz), 1.90 (2H, sextet,
J=8Hz), 2.85 (2H, t, J=8Hz), 5.45 (2H, s), 6.42 (1H, dd, J=1,
8Hz), 7.15 (1H, dt, J=l, 8Hz), 7.28 (1H, dt, J=1, 8Hz), 7.48 (1H,
s ) , 7 . 50 ( 1H, d, J=l OHz ) , 7 . 54 ( 1H, dd, J=1, 8Hz ) , 7 . 85 ( 1H,
d,
J=lOHz).
mp . 124-126°C.
Synthesis of 1-(2-chlorobenzyl)-6-mesylamino-2-n-propyl-
CA 02241186 1998-06-23
benzimidazole (88)
1-(2-Chlorobenzyl)-2-n-propylbenzimidazole (150 mg) and 61
mg of triethylamine were dissolved in 3 ml of methylene chloride,
and 70 mg of methanesulfonyl chloride were added thereto at room
temperature. The mixture was stirred for 1 hour, then washed
with dilute hydrochloric acid, washed with water, and dried. The
solvent was distilled off under reduced pressure. The residual
solid was collected with ether through filtration to give 124 mg
of 1-(2-chlorobenzyl)-6-mesylamino-2-n-propylbenzimidazole (88).
Properties of Compound (88):
1H-NMR (CDC13-CD 3 OD, ~ ) . 0.94 (3H, t, J=7.5Hz), 1.76 (2H, m),
2.71 (2H, t, J=7.5Hz), 2.81 (3H, s), 5.36 (2H, s), 6.40 (1H, d,
J=7.5Hz), 6.98-7.22 (4H, m), 7.40 (1H, d, J=7.5Hz), 7.59 (1H, d,
J=7.5Hz).
mp . 191-193°C.
F-xample 21
Synthesis of 6-acetylamino-1-(2-chlorobenzyl)-2-n-propyl-
benzimidazole (89)
Acetic anhydride (62 mg) was added to a solution of 150 mg
of 6-amino-1-(2-chlorobenzyl)-2-n-propylbenzimidazole and 61 mg
of triethylamine in 3 ml of methylene chloride at room
temperature, and the mixture was stirred for 1 hour. The
reaction mixture was washed with water, and was then dried. The
solvent was distilled off under reduced pressure. The residue
was crystallized with ether to give 143 mg of 6-acetylamino-1-
(2-chlorobenzyl)-2-n-propylbenzimidazole (89).
Properties of Compound (89):
1 H-NMR (CDC1 3 , cS ) . 1 . 00 ( 3H, t, J=7 . 5Hz ) , 1 . 86 ( 2H, m) , 2 .
17
(3H, s), 2.73 (2H, t, J=7.5Hz), 5.39 (2H, s), 6.43 (1H, d,
J=7.5Hz), 6.98-7.11 (2H, m), 7.22 (1H, t, J=7.5Hz), 7.45 (1H, d,
J=7.5Hz), 7.59 (1H, brs), 7.68 (1H, d, J=7.5Hz), 7.84 (1H, d,
J=l.5Hz).
mp . 180-182°C.
Synthesis of 6-amino-1-(2-chlorobenzyl)-2-n-propylbenzimidazole
CA 02241186 1998-06-23
86
(90)
Seven-hundred milligrams of 6-tert-butoxycarbonylamino-1-
(2-chlorobenzyl)-2-n-propylbenzimidazole were dissolved in a
mixed solvent of 10 ml of methylene chloride and 1 ml of
trifluoroacetic acid, and the mixture was stirred at room
temperature for 5 hours. A small amount of methylene chloride
was added to the reaction solution. The mixture was washed with
a sodium carbonate aqueous solution, and was dried. The solvent
was then distilled off. The residue was crystallized from a
mixed solvent of n-hexane and ether to give 455 mg of 6-amino-1-
(2-chlorobenzyl)-2-n-propylbenzimidazole (90).
Properties of Compound (90):
1 H-NMR ( CDCl 3 , ~ ) . 1 . O1 ( 3H, t, J=7 . 5Hz ) , 1 . 86 ( 2H, m) , 2 .
73
(2H, t, J=7.5Hz), 5.30 (2H, s), 6.41 (1H, d, J=l.5Hz), 6.48 (1H,
d, J=7.5Hz), 6.66 (1H, dd, J=7.5 and l.SHz), 7.10 (1H, t,
J=7.5Hz), 7.25 (1H, t, J=7.5Hz), 7.46 (1H, d, J=7.5Hz), 7.57 (1H,
d, J=7.5Hz).
mp . 121-122°C.
F-xam~,l ~ 23
Synthesis of 1-(2-chlorobenzyl)-2-n-propyl-6-ureidobenzimidazole
(91)
1-(2-Chlorobenzyl)-2-n-propyl-6-ureidobenzimidazole (91)
was formed in the same manner as in Example 21.
Properties of Compound (9I):
1H-NMR (DMSO-d6, S ) . 0.93 (3H, t, J=7.5Hz), 1.72 (2H, m), 2.73
(2H, t, J=7.5Hz), 5.43 (2H, s), 5.73 (2H, s), 6.42 (1H, dd,
J=7.5 and l.5Hz), 7.05 (1H, dd, J=7.5 and l.5Hz), 7.22 (1H, dt,
J=7.5 and l.5Hz), 7.33 (1H, dt, J=7.5 and l.5Hz), 7.45 (1H, d,
J=7.5Hz), 7.50 (1H, s), 7.57 (1H, dd, J=7.5 and l.SHz), 8.50 (1H,
s).
mp . 198°C
production Example
Production of ethyl 3-acetylamino-4-nitrobenzoate
Nine milliliters of acetyl chloride were added to a
mixture of 18.4 g of ethyl 3-amino-4-nitrobenzoate and 200 ml of
CA 02241186 1998-06-23
87
N,N-dimethylaniline while being cooled with ice. The mixture was
stirred at room temperature for 2 hours and then at 50°C for 2
hours. The reaction solution was poured into cold 1-N
hydrochloric acid, and the mixture was extracted twice with
ethyl acetate. The organic layer was washed with 1-N
hydrochloric acid and then with water, and was dried. The
solvent was then distilled off under reduced pressure. The
residue was purified through silica-gel column chromatography
(eluent: a mixture of ethyl acetate and hexane at a ratio of
from 1:10 to 1:4) to give 19.6 g of ethyl 3-acetylamino-4-
nitrobenzoate.
Properties of the compound:
1H-NMR(CDC13, ~) . 1.42(3H, t, J=7.lHz), 2.32(3H, s), 4.43(2H, q,
J=7.lHz), 7.82(1H, dd, J=1.8 and 8.7Hz), 8.25(1H, d, J=8.7Hz),
9.35(1H, d, J=l.8Hz), 10.19(1H, s).
prOduGt~on Example 13
Production of ethyl 4-nitro-3-phenylacetylaminobenzoate
In the same manner as in Production Example 12, 3.30 g of
ethyl 4-nitro-3-phenylacetylaminobenzoate were formed from 2.02
g of ethyl 3-amino-4-nitrobenzoate and 1.87 g of phenylacetyl
chloride.
Properties of the compound:
1H-NMR(CDC13, ~) . 1.41(3H, t, J=7.2Hz), 3.85(2H, s), 4.42(2H, q,
J=7.2Hz), 7.34-7.49(5H, m), 7.79(1H, m), 8.19(1H, d, J=8.7Hz),
9.39(1H, d, J=l.6Hz), 10.15(1H, s).
production Example 74
Production of ethyl 3-[N-(2-chlorobenzyl)acetylamino]-4-
nitrobenzoate
A solution of 1.706 g of ethyl 3-acetylamino-4-
nitrobenzoate in 12 ml of N,N-dimethylformamide were added 0.406
g of 60 % sodium hydride while being cooled with ice, and the
mixture was stirred at room temperature for 40 minutes. A
solution of 1.806 g of 2-chlorobenzyl bromide in 10 ml of N,N-
dimethylformamide was added thereto, and the mixture was stirred
at room temperature for 3 hours. The reaction mixture was poured
CA 02241186 1998-06-23
88
into cold 1-N hydrochloric acid, and the mixed solution was
extracted twice with ethyl acetate. The organic layer was washed
with 1-N hydrochloric acid and then with water, and was dried.
The solvent was distilled off under reduced pressure. The
residue was purified through silica-gel column chromatography
(eluent: a mixture of ethyl acetate and hexane at a ratio of
from 1:10 to 1:4) to give 2.08 g of oily ethyl 3-[N-(2-
chlorobenzyl)acetylamino]-4-nitrobenzoate.
Properties of the compound:
iH-NMR(CDC13, ~ ) . 1.38(3H, t, J=7.lHz), 1.92(3H, s), 4.28-
4.45(2H, m), 4.72(1H, d, J=14.5Hz), 5.34(1H, d, J=14.5Hz), 7.16-
7.44(4H, m), 7.69(1H, d, J=l.7Hz), 7.94(1H, d, J=8.4Hz), 8.13(1H,
dd, J=1.7 and 8.4Hz).
~_roduction Example 15
Production of ethyl 4-nitro-3-[N-[2-(trifluoromethyl)benzyl]-
acetylamino]benzoate
In the same manner as in Production Example 14, 1.82 g of
ethyl 4-nitro-3-[N-[2-(trifluoromethyl)-benzyl]acetylamino]
benzoate were formed from 1.49 g of ethyl 3-acetylamino-4-
nitrobenzoate and 1.69 g of 2-(trifluoromethyl)benzyl bromide.
Properties of the compound:
1H-NMR(CDC13, ~ ) . 1.37(3H, t, J=7.lHz), 1.96(3H, s), 4.29-
4.42(2H, m), 4.78(1H, d, J=15.4Hz), 5.40(1H, d, J=15.4Hz),
7.38(1H, t, J=7.6Hz), 7.51-7.58(2H, m), 7.61(1H, d, J=l.7Hz),
7.67(1H, d, J=7.8Hz), 7.92(1H, d, J=8.4Hz), 8.13(1H, dd, J=1.7
and 8.4Hz).
mp . 153.5-158.0°C.
pr~r3LC-t; on Example 1 6
Production of ethyl 4-nitro-3-[N-[4-(trifluoromethyl)benzyl]-
acetylaminobenzoate
In the same manner as in Production Example 14, 1.52 g of
ethyl 4-nitro-3-[N-[4-(trifluoromethyl)-benzyl]acetylamino-
benzoate were formed from 1.50 g of ethyl 3-acetylamino-4-
nitrobenzoate and 1.71 g of 4-(trifluoromethyl)benzyl bromide.
Properties of the compound:
CA 02241186 1998-06-23
89
1H-NMR(CDC13, S ) . 1.36(3H, t, J=7.lHz), 1.91(3H, s), 4.32-
4.43(2H, m), 4.42(1H, d, J=14.6Hz), 5.33(1H, d, J=14.6Hz),
7.30(2H, d, J=8.lHz), 7.54(2H, d, J=8.lHz), 7.61(1H, d, J=l.8Hz),
7.96(1H, d, J=8.4Hz), 8.12(1H, dd, J=1.8 and 8.4Hz).
p"rn~7n~t; nn .xampl~ 17
Production of 2-cyanobenzyl 3-[N-(2-cyanobenzyl)acetylamino]-4-
nitrobenzoate
A solution of 1.50 g of 3-acetylamino-4-nitrobenzoic acid
in 10 ml of N,N-dimethylformamide was added dropwise to a slurry
of 0.802 g of 60 % sodium hydride and 10 ml of N,N-
dimethylformamide at room temperature, and the mixture was
stirred for 30 minutes. Subsequently, a solution of 3.93 g of 2-
cyanobenzyl bromide in 10 ml of N,N-dimethylformamide was added
dropwise thereto, and the mixture was stirred for 30 minutes.
Ethyl acetate was poured into the reaction solution, and the
crystals precipitated were separated through filtration. The
crystals obtained were washed with ethyl acetate, and were
further dissolved in chloroform. The filtrate from which the
solid component was removed was concentrated to give 1.96 g of
yellow crystals of 2-cyanobenzyl 3-[N-(2-cyanobenzyl)acetyl-
amino]-4-nitrobenzoate.
Properties of the compound:
1H-NMR(CDC13, 8) . 1.92(3H, s), 4.92(1H, d, J=4.8Hz), 5.24(2H, d,
J=4.9Hz), 5.44(2H, dd, J=7.9 and 2.9Hz), 7.36(1H, t, J=7.5Hz),
7.47(1H, d, J=7.7Hz), 7.52(1H, t, J=7.7Hz), 7.56-7.62(2H, m),
7.63-7.71(2H, m), 7.76(1H, d, J=7.8Hz), 7.80(1H, d, J=l.7Hz),
7.99(1H, d, J=8.4Hz), 8.25(1H, dd, J=8.4 and l.8Hz).
prodLCtion Example 18
Production of ethyl 4-amino-3-(N-i-propylbutyrylamino)benzoate
A solution of 2.00 g of ethyl 3-butyrylamino-4-
nitrobenzoate in 10 ml of N,N-dimethylformamide was added
dropwise to a slurry of 0.428 g of 60% sodium hydride and 10 ml
of N,N-dimethylformamide at room temperature, and the mixture
was stirred for 30 minutes. A solution of 1.46 g of isopropyl
iodide in 10 ml of N,N-dimethylformamide was then added dropwise
CA 02241186 1998-06-23
thereto, and the mixture was stirred at 100°C for 5 days. The
reaction solution was poured into a mixed solution of 80 g of
dilute hydrochloric acid and 80 g of ethyl acetate for
separation. The resulting organic layer was washed with 50 g of
water, and was then concentrated under reduced pressure. The
residue was purified through silica-gel column chromatography
(eluent: a mixture of hexane and ethyl acetate at a ratio of
4:1) to obtain 0.260 g of crude ethyl 4-vitro-3-(N-i-
propylbutyrylamino)benzoate. Subsequently, 3 ml of ethanol and 2
ml of acetic acid were added to 0.260 g of ethyl 4-vitro-3-(N-i-
propylbutyrylamino)benzoate at room temperature, and 0.519 g of
reduced iron were further added thereto. The mixture was heat-
refluxed for 4 hours. The solid material was removed using a
filtration aid, and the filtrate was concentrated. The residue
were added 30 ml of ethyl acetate and 30 ml of dilute
hydrochloric acid for separation. The organic layer was washed
with 30 ml of water, and was then concentrated under reduced
pressure. The residue was purified through preparative thin-
layer silica-gel chromatography (developing eluent: a mixture of
hexane and ethyl acetate at a ratio of 1:1) to give 0.06 g of
ethyl 4-amino-3-(N-i-propylbutyrylamino)benzoate.
Properties of the compound:
1H-NMR(CDC13, ~ ) . 0.82(3H, t, J=7.4Hz), 1.01(3H, d, J=6.9Hz),
1.24(3H, d, J=6.6Hz), 1.38(3H, t, J=7.OHz), 1.54-1.62(2H, m),
1.87-2.04(2H, m), 4.34(2H, q, J=7.OHz), 4.45(2H, s), 4.88-
4.96(1H, m), 6.78(1H, d, J=8.4Hz), 7.64(1H, d, J=l.9Hz), 7.87(1H,
dd, J=8.4 and l.9Hz).
production examp~
Production of ethyl 3-vitro-4-phenylacetylaminobenzoate
In the same manner as in Production example 12, 6.00 g of
ethyl 3-vitro-4-phenylacetylaminobenzoate were formed from 4.04
g of ethyl 4-amino-3-nitrobenzoate and 3.74 g of phenylacetyl
chloride.
Production of N-benzenesulfonyl-3-amino-4-nitrobenzamide
CA 02241186 1998-06-23
91
N,N'-carbonyldiimidazole (28.9 g) was added to a solution
of 20.0 g of 3-acetylamino-4-nitrobenzoic acid in 300 ml of N,N-
dimethylformamide, and the mixture was stirred at. room
temperature for 1 hour. Further, 28.00 g of benzenesulfonamide
and 27.16 g of diazabicycloundecene were added thereto, and the
mixture was stirred at 100 °C for 4 days. The solvent was
distilled off under reduced pressure. Chloroform and a 10
sodium hydroxide aqueous solution were added to the residue, and
the mixture was vigorously stirred. The aqueous layer was
neutralized with 10 % hydrochloric acid, and the mixture was
vigorously stirred with the addition of chloroform. The crystals
precipitated were separated through filtration, and were dried
to 14.4 g of N-benzenesulfonyl-3-amino-4-nitrobenzamide.
Properties of the compound:
1H-NMR(DMSO-d6, ~ ) . 6.93(1H, dd, J=1.8 and 9.OHz), 7.43(1H, d,
J=l.8Hz), 7.52(2H, br s), 7.65(2H, t, J=7.5Hz), 7.74(1H, t,
J=7.5Hz), 7.98-7.82(3H, m), 12.74(1H, s).
Prc~c3nnti ~n Example 21
Production of N-benzenesulfonyl-3-(biphenyl-4-ylmethylamino)-4-
nitrobenzamide potassium salt
A solution of 10.0 g of N-benzenesulfonyl-3-amino-4-
nitrobenzamide in 150 ml of methanol were added 56.5 g of a 20%
potassium hydrogencarbonate aqueous solution and 11.5 g of 4-
bromomethylbiphenyl, and the mixture was stirred at 70°C for 3
hours. The mixture was cooled, and the crystals precipitated
were collected through filtration, and were dried to give 4.27 g
of N-benzenesulfonyl-3-(biphenyl-4-ylmethylamino)-4-nitro-
benzamide potassium salt.
Properties of the compound:
1H-NMR(DMSO-d6, S) . 4.65(2H, d, J=5.8Hz), 7.19(1H, d, J=8.9Hz),
7.33-7.42(4H, m), 7.57-7.71(4H, m), 7.75-7.81(2H, m), 8.02(1H, d,
J=8.9Hz), 8.61(1H, br t).
IR(Nujol) . 1598cm 1.
Production of N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethyl-
CA 02241186 1998-06-23
92
amino)benzamide potassium salt
Five-percent palladium on carbon (0.64 g) was added to a
mixture containing 4.27 g of N-benzenesulfonyl-3-(biphenyl-4-
ylmethylamino)-4-nitrobenzamide potassium salt, 10.7 g of a 20%
potassium hydrogencarbonate aqueous solution and 200 ml of
methanol, and the mixture was stirred in a hydrogen atmosphere
at 35°C for 14 hours. The crystals precipitated were dissolved
in 400 ml of a mixed solution of acetone and water (at a ratio
of 5:2). The solid material was separated through filtration.
The filtrate was concentrated, and the crystals precipitated
were separated through filtration, and were dried to give 3.15 g
of N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)-
benzamide potassium salt.
Properties of the compound:
1H-NMR(DMSO-d6, ~) . 4.31(2H, d, J=5.7Hz), 4.85(2H, s), 4.91(1H,
br t, J=5.7Hz), 6.45(1H, d, J=7.9Hz), 7.07(1H, s), 7.13(1H, d,
J=7.9Hz), 7.29-7.36(4H, m), 7.43-7.47(4H, m), 7.60(2H, d,
J=8.lHz), 7.65(2H, d, J=7.6Hz), 7.73-7.76(2H, m).
IR(Nujol) . 1574cm 1.
prodLCtion Example 23
Production of N-(2-pyridylmethyl)-4-acetylamino-3-nitrobenzamide
Oxalyl chloride (1.25 g) was added dropwise to a solution
of 1.00 g of 4-acetylamino-3-nitrobenzoic acid and 0.20 g of
N,N-dimethylformamide in 15 ml of methylene chloride while being
cooled with ice. The mixture was further stirred at room
temperature for 1 hour. The reaction solution was concentrated,
and diisopropyl ether was added thereto for crystallization. The
crystals were added to a solution of 0.483 g of 2
aminomethylpyridine and 0.35 g of triethylamine in 15 ml of
methylene chloride. After the mixture was stirred at room
temperature for 1 hour, the organic layer was washed twice with
water (100 ml x 2) and then with 100 ml of a sodium
hydrogencarbonate aqueous solution. The organic layer was
concentrated to give 0.99 g of N-(2-pyridylmethyl)-4
acetylamino-3-nitrobenzamide.
CA 02241186 1998-06-23
93
Properties of the compound:
1H-NMR(CDC13, ~ ) . 2.33(3H, s), 4.76(2H, d, J=4.8Hz), 7.25(1H,
dd, J=5.0 and 7.2Hz), 7.34(1H, d, J=7.9Hz), 7.71(1H, dt, J=1.8
and 7.8Hz), 7.84(1H, s), 8.14(1H, dd, J=2.1 and 8.8Hz), 8.58(1H,
d, J=4.9Hz), 8.77(1H, d, J=2.lHz), 8.90(1H, d, J=8.OHz),
10.47(1H, s).
prnclm~t-i can Example 24
Production of N-(2-pyridylmethyl)-4-acetylamino-3-aminobenzamide
Five-percent palladium on carbon (2.53 g) was added to a
solution of 10.0 g of N-(2-pyridylmethyl)-4-acetylamino-3
nitrobenzamide in 150 ml of methanol, and the mixture was
stirred in a hydrogen atmosphere at 60°C for 15 hours. The solid
material was separated through filtration, and the filtrate was
concentrated. The resulting residue was purified through silica
gel column chromatography (eluent: a mixture of ethyl acetate
and methanol at a ratio of 7:3) to give 8.02 g of N-(2
pyridylmethyl)-4-acetylamino-3-aminobenzamide.
Properties of the compound:
1H-NMR(DMSO-d6, S) . 2.06(3H, s), 4.52(2H, d, J=5.9Hz), 5.09(2H,
s), 7.10(1H, dd, J=1.9 and 8.2Hz), 7.22-7.30(3H, m), 7.38(1H, d,
J=8.2Hz), 7.75(1H, dt, J=1.7 and 7.6Hz), 8.50(1H, d, J=4.6Hz),
8.84(1H, t, J=5.8Hz), 9.19(1H, s).
~,_rncim~_t i cm Example 2 5
Production of N-(2-pyridylmethyl)-4-acetylamino-3-(4-benzyloxy-
benzylamino)benzamide
A solution of 0.80 g of N-(2-pyridylmethyl)-4-acetylamino
3-aminobenzamide in 10 ml of N,N-dimethylformamide were added
1.31 g of 4-benzyloxybenzyl chloride and 1.18 g of sodium
hydrogencarbonate, and the mixture was stirred at 90°C for 2
hours. Chloroform and water were added to the reaction solution,
and the chloroform extraction was conducted. The organic layer
was washed with water, concentrated, and purified through
silica-gel column chromatography to give 0.434 g of N-(2
pyridylmethyl)-4-acetylamino-3-(4-benzyloxybenzylamino)benzamide.
Properties of the compound:
CA 02241186 1998-06-23
94
1H-NMR(DMSO-d6, ~) . 2.07(3H, s), 4.30(2H, d, J=5.6Hz), 4.51(2H,
d, J=5.9Hz), 5.07(2H, s), 5.68(1H, t, J=5.6Hz), 6.97(2H, d,
J=8.6Hz), 7.14(2H, m), 7.25(2H, dd, J=3.4 and 7.4Hz), 7.32(4H, t,
7.5Hz), 7.38(2H, t, J=7.lHz), 7.44(2H, d, J=7.2Hz), 7.72(1H, dt,
J=1.8 and 7.7Hz), 8.49(1H, dd, J=1.9 and 5.3Hz), 8.89(1H, t,
J=5.9Hz), 9.28(1H, s).
production Example 26
Production of N-(2-pyridylmethyl)-4-acetylamino-3-(3,4-
methylenedioxybenzylamino)benzamide
A solution of 0.80 g of N-(2-pyridylmethyl)-4-acetylamino-
3-aminobenzamide in lOml of N,N-dimethylformamide were added
0.962 g of 3,4-methylenedioxybenzyl chloride and 0.710 g of
sodium hydrogencarbonate, and the mixture was stirred at 80°C for
4 hours. Chloroform and water were added to the reaction
solution, and the chloroform extraction was conducted. The
organic layer was washed with water, concentrated, and purified
through silica-gel column chromatography (eluent: a mixture of
ethyl acetate and methanol at a ratio of 9:1) to give 0.49 g of
N-(2-pyridylmethyl)-4-acetylamino-3-(3,4-methylenedioxybenzyl-
amino)benzamide.
Properties of the compound:
1 H-NMR(DMSO-d6, ~ ) . 2.08(3H, s), 4.29(2H, s), 4.52(2H, d,
J=5.9Hz), 5.27(1H, s), 5.97(2H, s), 6.84-6.88(2H, m), 6.96(1H,
s), 7.10(1H, d, J=l.3Hz), 7.13(1H, dd, J=1.6 and 8.2Hz), 7.25-
7.32(3H, m), 7.76(1H, dt, J=1.2 and 7.6Hz), 8.51(1H, d, J=4.8Hz),
8.90(1H, t, J=5.8Hz), 9.28(1H, s)..
prc~r3ncti on Exam~~l~ 27
Production of N-(2-pyridylmethyl)-4-acetylamino-3-[4-(1,2,3-
thiadiazol-4-yl)benzylamino]benzamide
A solution of 0.800 g of N-(2-pyridylmethyl)-4-
acetylamino-3-aminobenzamide in 10 ml of methanol were added
1.08 g of 4-(4-bromomethylphenyl)-1,2,3-thiadiazole and 0.710 g
of sodium hydrogencarbonate, and the mixture was stirred at 70°C
for 1 hour. The reaction solution was concentrated, and was
purified through silica-gel column chromatography (eluent: a
CA 02241186 1998-06-23
mixture of ethyl acetate and methanol at a ratio of 9:1) to give
0.830 g of N-(2-pyridylmethyl)-4-acetylamino-3-[4-(1,2,3-
thiadiazol-4-yl)benzylamino~benzamide
Properties of the compound:
1 H-NMR( CDCl 3 , ~ ) . 2 . 11 ( 3H, s ) , 4 . 43-5 . 56 ( 2H, m) , 5 . 92 (
1H, t,
J=5.9Hz), 7.51(1H, d, J=l.4Hz), 7.15(1H, dd, J=1.6 and 8.lHz),
7.22(2H, dd, J=1.9 and 8.lHz), 7.33(1H, d, J=8.lHz), 7.57(2H, d,
J=8.lHz), 7.69(1H, dt, J=1.8 and 7.7Hz), 8.09(2H, d, J=8.2Hz),
8.47(1H, dd, J=1.9 and 5.2Hz), 8.89(1H, t, J=5.9Hz), 9.34(1H, s),
9.58(1H, s).
Prc~c3mc!i-inn Fxam~l~ 28
Production of N-benzenesulfonyl-4-acetylamino-3-nitrobenzamide
N,N'-carbonyldiimidazole (14.45 g) was added to a solution
of 10.00 g of 4-acetylamino-3-nitrobenzoic acid in 300 ml of
N,N-dimethylformamide, and the mixture was stirred at room
temperature for 1 hour. Subsequently, 14.03 g of
benzenesulfonamide and 13.58 g of diazabicycloundecene were
added thereto, and the mixture was stirred at 100°C for 72 hours.
The reaction mixture was separated with the addition of
chloroform and water. The organic layer was then concentrated,
and the resulting residue was purified through silica-gel column
chromatography (eluent: a mixture of ethyl acetate and methanol
at a ratio of 4:1) to give 12.67 g of N-benzenesulfonyl-4-
acetylamino-3-nitrobenzamide.
Properties of the compound:
1H-NMR(DMSO-d6, ~ ) . 2.08(3H, s), 7.39-7.47(3H, m), 7.65(1H, d,
J=8.5Hz), 7.84(2H, dd, J=1.4 and 7.7Hz), 8.11(1H, dd, J=1.9 and
8.4Hz), 8.38(1H, d, J=l.9Hz), 10.34(1H, s).
prc~cinn_~t-_ic~n Example 29
Production of N-benzenesulfonyl-4-acetylamino-3-aminobenzamide
N-benzenesulfonyl-4-acetylamino-3-nitrobenzamide (12.67 g)
was dissolved in 200 ml of methanol and 30 ml of water, and 7.59
g of potassium hydrogencarbonate were further added thereto. The
mixture was hydrogenated in a hydrogen atmosphere using 2.53 g
of 5 % palladium on carbon as catalyst at 40°C for 24 hours. The
CA 02241186 1998-06-23
96
solid material was separated through filtration, and the
filtrate was concentrated. The resulting residue was purified
through silica-gel column chromatography (eluent: a mixture of
ethyl acetate and methanol at a ratio of 4 :1 ) to give 6. 72 g of
N-benzenesulfonyl-4-acetylamino-3-aminobenzamide.
Properties of the compound:
1H-NMR(DMSO-d6, ~) . 2.06(3H, s), 7.07(1H, dd, J=1.8 and 8.3Hz),
7.17(1H, d, J=l.8Hz), 7.44(1H, d, J=8.3Hz), 7.61(2H, t), 7.68(1H,
t), 7.96(2H, d, J=7.5Hz), 9.19(1H, s).
IR(Nujol) . 1682ciri 1.
production Fxampl~ 30
Production of N-benzenesulfonyl-4-acetylamino-3-(2-nitrobenzyl-
amino)benzamide
In the same manner as in Production Example~32, 0.79 g of
N-benzenesulfonyl-4-acetylamino-3-(2-nitrobenzylamino)benzamide
were formed from 0.60 g of N-benzenesulfonyl-4-acetylamino-3-
aminobenzamide and 0.52 g of 2-nitrobenzyl bromide.
Properties of the compound:
1H-NMR(DMSO-d6, ~) . 2.08(3H, s), 4.72(2H, d, J=5.OHz), 5.92(1H,
s), 6.86(1H, s), 7.13(1H, d, J=8.lHz), 7.31(1H, d, J=8.OHz),
7.49-7.58(3H, m), 7.60(2H, d, J=7.6Hz), 7.66(1H, t, J=7.4Hz),
7.86(2H, d, J=7.7Hz), 8.11(1H, d, J=8.3Hz), 9.37(1H, s).
P_rodLCtion Examt~l~ 31
Production of N-benzenesulfonyl-4-acetylamino-3-benzylamino-
benzamide
In the same manner as in Production Example 32, 0.38 g of
N-benzenesulfonyl-4-acetylamino-3-benzylaminobenzamide were
formed from 0.60 g of N-benzenesulfonyl-4-acetylamino-3-
aminobenzamide and 0.47 g of benzyl bromide.
Properties of the compound:
1 H-NMR ( DMSO-d6, S ) . 2.07 ( 3H, S), 4.35(2H, d, J=5.5Hz),
5.73(1H, s), 7.06(1H, s), 7.14(1H, d, J=8.3Hz), 7.21-7.28(2H, m),
7.32(2H, t, J=7.3Hz), 7.37(2H, d, J=7.6Hz), 7.53(2H, t, J=7.4Hz),
7.59(1H, t, J=7.OHz), 7.88(2H, d, J=7.7Hz), 9.29(1H, s),
12.34(1H, s)
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Production Example 32_
Production of N-benzenesulfonyl-4-acetylamino-3-(2,4-difluoro-
benzylamino)benzamide
A solution of 7m1 of methanol containing 0.60 g of N-
benzenesulfonyl-4-acetylamino-3-aminobenzamide, 0.656 g of 2,4-
difluorobenzyl bromide and 0.423 g of potassium
hydrogencarbonate was stirred at 60°C for 1 hour. The reaction
solution was concentrated, and the residue was purified through
silica-gel column chromatography (eluent: a mixture of ethyl
acetate and methanol at a ratio of 9:1) to give 0.370 g of N-
benzenesulfonyl-4-acetylamino-3-(2,4-difluorobenzylamino)-
benzamide.
Properties of the compound:
1H-NMR(DMSO-d6, ~) . 2.05(3H, s), 4.34(2H, d, J=5.5Hz), 5.60(1H,
s), 7.02(1H, t, J=8.OHz), 7.06(1H, s), 7.16-7.27(3H, m), 7.38-
7.51(4H, m), 7.82(2H, d, J=7.2Hz), 9.27(1H, s), 12.35(1H, s)
P_roducti on Exam.~2.7 a 33
Production of N-benzenesulfonyl-4-acetylamino-3-(4-nitrobenzyl-
amino)benzamide
In the same manner as in Production Example 32, 0.52 g of
N-benzenesulfonyl-4-acetylamino-3-(4-nitrobenzylamino)benzamide
were formed from 0.50 g of N-benzenesulfonyl-4-acetylamino-3-
aminobenzamide and 0.436 g of 4-nitrobenzyl bromide.
Properties of the compound:
1H-NMR(DMSO-d6, ~) . 2.09(3H, s), 4.54(2H, d, J=5.OHz), 6.10(1H,
s), 6.89(1H, d, J=l.8Hz), 7.14(1H, dd, J=1.8 and 8.2Hz), 7.39(1H,
d, J=8.2Hz), 7.58-7.65(4H, m), 7.68(1H, t, J=7.6Hz), 7.92(2H, dd,
J=1.4 and 7.4Hz), 8.20(2H, d, J=8.7Hz), 9.36(1H, s), 12.28(1H,
s)
Production of N-benzenesulfonyl-4-acetylamino-3-[4-(1,2,3-
thiadiazol-4-yl)benzylamino]benzamide
In the same manner as in Production Example 32, 0.38 g of
N-benzenesulfonyl-4-acetylamino-3-[4-(1,2,3-thiadiazol-4-
yl)benzylamino]benzamide were formed from 0.50 g of N-
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benzenesulfonyl-4-acetylamino-3-aminobenzamide and 0.45 g of 4-
(4-bromomethylphenyl)-1,2,3-thiadiazole.
Properties of the compound:
1H-NMR(DMSO-d6, ~) . 2.10(3H, s), 4.46(2H, d, J=5.3Hz). 5.96(1H,
s), 7.03(1H, s), 7.14(1H, dd, J=1.7 and 8.2Hz), 7.40(1H, d,
J=8.OHz), 7.52-7.61(4H, m), 7.65(1H, t, J=7.lHz), 7.93(2H, d,
J=7.6Hz), 8.10(2H, d, J=8.2Hz), 9.35(1H, s), 9.58(1H, s),
12.31(1H, s)
Production Exam~rle 35
Production of ethyl 3-amino-2-nitrobenzoate
A mixture of 20.2 g of 3-acetylamino-2-nitrobenzoic acid,
11.4 g of 97 % sulfuric acid and 300 ml of ethanol was stirred
for 23 hours while being heat-refluxed. One-hundred milliliters
of ethanol were distilled off under reduced pressure, and the
residue was cooled to room temperature. Subsequently, the
reaction.solution was poured into 200 ml of ice water containing
19.5 g of sodium hydrogencarbonate. The crystals precipitated
were separated through filtration, and were washed with water.
Further, these crystals were dispersed in 30 ml of a mixed
solution of ethyl acetate and hexane at a ratio of 1:2. The
crystals were separated through filtration, washed with hexane,
and then dried to give 18.0 g of ethyl 3-amino-2-nitrobenzoate.
Properties of the compound:
1H-NMR(CDC13, ~ ) . 1.39(3H, t, J=7.lHz), 4.37(2H, q, J=7.lHz),
6.41(2H, br s), 6.83(1H, d, J=8.7Hz), 8.00(1H, dd, J=1.8 and
8.7Hz), 8.85(1H, d, J=l.8Hz)
Production Example 36
Production of ethyl 3-acetylamino-2-nitrobenzoate
Acetyl chloride (13 ml) was added dropwise to a solution
of 2.98 g of ethyl 3-amino-2-nitrobenzoate and 20 ml of N,N-
dimethylaniline in an ice bath. The mixture was stirred at room
temperature for 48 hours. The reaction solution was acidified
with 10 % hydrochloric acid, and was extracted twice with ethyl
acetate. The organic layer was washed three times with water.
The solvent was distilled off under reduced pressure, and the
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resulting residue was crystallized with hexane. The crystals
were separated through filtration, washed with hexane, and dried
to give 3.30 g of ethyl 3-acetylamino-2-nitrobenzoate.
Properties of the compound:
1 H-NMR(CDC1 3 , ~ ) . 1.42(3H, t), 2.33(3H, s), 4.42(2H, q),
8.27(1H, dd, J=1.9 and 8.9Hz), 8.89(1H, d, J=l.9Hz), 8.91(1H, d,
J=8.9Hz), 10.54(1H, br s)
Prc~du~ti on E_x_amp~e 37
Production of ethyl 4-acetylamino-3-aminobenzoate
A mixture of 149.4 g of ethyl 3-acetylamino-2-
nitrobenzoate, 14 . 9g of 5 % palladium on carbon and 1, 500 ml of
ethanol was stirred in a hydrogen atmosphere for 15 hours. The
solid material was separated though filtration, and the ffiltrate
was concentrated. The resulting residue was dissolved in a small
amount of ethanol, and diisopropyl ether was added thereto. The
crystals precipitated were separated through filtration, and
were dried to give 114.4 g of ethyl 4-acetylamino-3-
aminobenzoate.
Properties of the compound:
1 H-NMR(DMSO-d6, cS ) . 1.27(3H, t), 2.05(3H, s), 4.23(2H, q),
5.19(2H, s), 7.13(1H, d, J=8.2Hz), 7.35(1H, s), 7.47(1H, d,
J=8.2Hz), 9.19(1H, s)
F-xamnl~ 24
Synthesis of 1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-methyl-
benzimidazole (92)
Twenty milliliters of ethanol, 11 ml of acetic acid and
3.07 g of reduced iron were added to 2.07 g of ethyl 3-[N-(2-
chlorobenzyl)acetylamino]-4-nitrobenzoate, and the mixture was
refluxed for 4 hours. The solid material was separated through
filtration, and was washed with ethanol. The filtrate was
concentrated, and a sodium hydrogencarbonate aqueous solution
was added to the residue. The mixture was extracted with ethyl
acetate. The organic layer was dried, and the solvent was then
distilled off under reduced pressure. The residue was purified
through silica-gel column chromatography (eluent: a mixture of
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hexane and ethyl acetate at a ratio of from 100/0 to 70:30) to
give 1.46 g of 1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-
methylbenzimidazole (92).
Properties of Compound (92):
1H-NMR(CDC13, ~) . 1.39(3H, t, J=7.lHz), 2.57(3H, s), 4.37(2H, q,
J=7.lHz), 5.46(2H, s), 6.41(1H, d, J=7.8Hz), 7.10(IH, t,
J=7.8Hz), 7.25(1H, t), 7.47(1H, d, J=B.OHz), 7.75(1H, d,
J=8.4Hz), 7.94(1H, s), 8.00(1H, dd, J=1.5 and 8.4Hz)
Example 25
Synthesis of 6-ethoxycarbonyl-1-methyl-2-n-propylbenzimidazole
(93)
In the same manner as in Production Example 14, 1.00 g of
crude ethyl 3-(N-methylbutyrylamino)-4-nitrobenzoate was
obtained from 1.00 g of ethyl 3-butyrylamino-4-nitrobenzoate and
0.843 g of methyl iodide. Subsequently, 0.56 g of 6-
ethoxycarbonyl-1-methyl-2-n-propylbenzimidazole (93) were formed
in the same manner as in Example 24.
Properties of Compound (93):
1H-NMR(CDC13, ~ ) . 1.08(3H, t, J=7.4Hz), 1.43(3H, t, J=7.OHz),
1.89-1.97(2H, m), 2.89(2H, t, J=7.7Hz), 3.79(3H, s), 4.38-
4.44(2H, m), 7.71(1H, d, J=8.4Hz), 7.96(1H, dd, J=8.4 and
l.5Hz, ), 8.05(1H, d, J=l.4Hz)
Exam~,,l a 2 6
Synthesis of 1-n-butyl-6-ethoxycarbonyl-2-n-propylbenzimidazole
(94)
A solution of 1.86 g of ethyl 3-butyrylamino-4-
nitrobenzoate in 10 ml of N,N-dimethylformamide was added
dropwise to a slurry of 0.428 g of 60% sodium hydride and 10 ml
of N,N-dimethylformamide at room temperature, and the mixture
was stirred at room temperature for 30 minutes. Subsequently, a
solution of 1.97 g of n-butyl iodide in 10 ml of N,N-
dimethylformamide was added dropwise thereto, and the mixture
was heated at 50°C for 13 hours. The reaction solution was
poured into a mixed solution of 70 g of dilute hydrochloric acid
and 70 g of ethyl acetate for extraction. The resulting organic
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layer was washed twice with water, dried, and then concentrated
under reduced pressure to obtain 2.59 g of crude ethyl. 3-(N-n-
butylbutyrylamino)-4-nitrobenzoate. Then, 0.81 g of 1-n-butyl-6-
ethoxycarbonyl-2-n-propylbenzimidazole (94) were formed in the
same manner as in Example 24.
Properties of Compound (94):
1H-NMR(CDC13, ~ ) . 0.98(3H, t, J=7.4Hz), 1.08(3H, t, J=7.4Hz),
1.43(3H, t, J=7.lHz), 1.75-1.83(2H, m), 1.91-1.98(2H, m),
2.88(2H, t, J=7.6Hz), 4.15(2H, t, J=7.5Hz), 4.42(2H, q, J=7.2Hz),
7.73(1H, d, J=8.4Hz), 7.96(1H, dd, J=8.5 and l.5Hz), 8.06(1H, d,
J=l.4Hz)
Example 27
Synthesis of 1-(3-chlorobenzyl)-6-ethoxycarbonyl-2-n-propyl-
benzimidazole (95)
In the same manner as in Production Example 14, crude
ethyl 3-[N-(3-chlorobenzyl)butyrylamino]-4-nitrobenzoate was
obtained from 1.86 g of ethyl 3-butyrylamino-4-nitrobenzoate and
1.64 g of 3-chlorobenzyl bromide. This compound was converted to
1-(3-chlorobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole
[(95), 0.57 g] in the same manner as in Example 24 without being
purified .
Properties of Compound (95):
1H-NMR(CDC13, S ) . 1.02(3H, t, J=7.4Hz), 1.39(3H, t, J=7.lHz),
1.85-1.92(2H, m), 2.80(2H, t, J=7.5Hz), 4.38(2H, q, J=7.lHz),
5.37(2H, s), 6.86(1H, d, J=7.4Hz), 7.04(1H, s), 7.21-7.29(2H, m),
7.77(1H, d, J=8.4Hz), 7.96(1H, d, J=l.2Hz), 7.99(1H, dd, J=8.5
and l.5Hz)
Examt~le 28
Synthesis of 1-benzyl-6-ethoxycarbonyl-2-n-propylbenzimidazole
(96)
In the same manner as in Production Example 14, ethyl 3-
[N-benzylbutyrylamino]-4-nitrobenzoate was obtained from 1.86 g
of ethyl 3-butyrylamino-4-nitrobenzoate and 1.36 g of benzyl
bromide. This compound was converted to 1-benzyl-6-
ethoxycarbonyl-2-n-propylbenzimidazole [(96), 0.97 g] in the
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102
same manner as in Example 24 without being purified.
Properties of Compound (96):
iH-NMR(CDC13, ~ ) . 1.01(3H, t, J=7.4Hz), 1.39(3H, t, J=7.lHz),
1.83-1.91(2H, m), 2.81(2H, t, J=7.5Hz), 4.37(2H, q, J=7.lHz),
5.40(2H, s), 7.03(1H, d, J=6.4Hz), 7.28-7.33(3H, m), 7.76(1H, d,
J=8.4Hz), 7.98(1H, dd, J=8.4 and l.2Hz), 8.00(1H, s)
Example 29
Synthesis of 1-(4-chlorobenzyl)-6-ethoxycarbonyl-2-n-propyl-
benzimidazole (97)
In the same manner as in Production Example 14, ethyl 3-
[N-(4-chlorobenzyl)butyrylamino]-4-nitrobenzoate was obtained
from 1.86 g of ethyl 3-butyrylamino-4-nitrobenzoate and 1.64 g -
of 4-chlorobenzyl bromide. This compound was converted to 1-(4-
chlorobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole ((97),
1.06 g] in the same manner as in Example 24 without being
purified.
Properties of Compound (97):
1.H-NMR(CDC13, ~ ) . 1.02(3H, t, J=7.4Hz), 1.39(3H, t, J=7.IHz),
1.83-1.92(2H, m), 2.80(2H, t, J=7.8Hz), 4.38(2H, q, J=7.5Hz),
5.36(2H, s), 6.96(2H, d, J=8.2Hz), 7.29(2H, d, J=8.3Hz), 7.76(1H,
d, J=8.4Hz), 7.96(1H, d, J=l.2Hz), 7.99(1H, dd, J=8.3 and l.2Hz)
Example 30
Synthesis of 6-ethoxycarbonyl-2-methyl-1-[2-(trifluoromethyl)-
benzyl]benzimidazole (98)
In the same manner as in Example 24, 1.32 g of 6-
ethoxycarbonyl-2-methyl-1-[2-(trifluoromethyl)benzyl]-
benzimidazole (98) were formed from 1.82 g of ethyl 4-nitro-3-
[N-[2-(trifluoromethyl)benzyl]acetylamino]benzoate.
Properties of Compound (98):
1H-NMR(CDC13, ~) . 1.38(3H, t, J=7.lHz), 2.53(3H, s), 4.37(2H, q,
J=7.lHz), 5.58(2H, s), 6.47(1H, d, J=7.7Hz), 7.36(1H, t,
J=7.5Hz), 7.41(1H, t, J=7.5Hz), 7.75-7.97(2H, m), 7.94(1H, d,
J=l.OHz), 8.02(1H, dd, J=1.6 and 8.6Hz).
Exa ple 31
Synthesis of 6-ethoxycarbonyl-2-methyl-1-[4-(trifluoromethyl)-
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benzyl]benzimidazole (99)
In the same manner as in Example 24, 1.22 g of 6-
ethoxycarbonyl-2-methyl-1-[4-(trifluoromethyl)benzyl]-
benzimidazole (99) were formed from 1.52 g of ethyl 4-nitro-3-
[N-[4-(trifluoromethyl)benzyl]acetylamino]benzoate.
Properties of Compound (99):
1H-NMR(CDC13, ~) . 1.39(3H, t, J=7.lHz), 2.58(3H, s), 4.38(2H, q,
J=7.lHz), 5.44(2H, s), 7.15(2H, d, J=8.2Hz), 7.59(2H, d,
J=8.2Hz), 7.75(1H, d, J=8.3Hz), 7.97(1H, s), 8.00(1H, dd, J=1.5
and 8.5Hz)
Example 32
Synthesis of 1-(3,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methyl-
benzimidazole (100)
In the same manner as in Production Example 14, ethyl 3-
[N-(3,4-dichlorobenzyl)acetylamino]-4-nitrobenzoate was obtained
from 1.50 g of ethyl 3-acetylamino-4-nitrobenzoate and 1.74 g of
3,4-dichlorobenzyl bromide. This compound was converted to 1-
(3,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole
[(100), 0.76 g] in the same manner as in Example 24 without
being purified.
Properties of Compound (100):
1H-NMR(CDC13, ~) . 1.40(3H, t, J=7.lHz), 2.58(3H, s), 4.39(2H, q,
J=7.2Hz), 5.33(2H, s), 6.84(1H, dd, J=8.4 and 2.3Hz), 7.16(2H, d,
J=2.OHz), 7.39(1H, d, J=8.3Hz), 7.74(1H, d, J=8.4Hz), 7.96(1H, d,
J=l.2Hz), 8.00(1H, dd, J=8.4 and l.5Hz)
Example 33
Synthesis of 1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-methyl-
benzimidazole (101)
In the same manner as in Production Example 14, 1.44 g of
crude ethyl 3-[N-biphenyl-4-ylmethyl)acetylamino]-4-nitro-
benzoate were obtained from 1.51 g of ethyl 3-acetylamino-4-
nitrobenzoate and 1.46 g of 4-chloromethylbiphenyl. Subsequently,
1.13 g of 1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-
methylbenzimidazole (101) were formed in the same manner as in
Example 24.
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Properties of Compound (101):
1H-NMR(CDC13, ~) . 1.39(3H, t, J=7.lHz), 2.62(3H, s), 4.38(2H, q,
J=7.lHz), 5.42(2H, s), 7.11(2H, d, J=8.2Hz), 7.34(1H, m),
7.42(2H, m), 7.54(4H, m), 7.74(1H, d, J=8.4Hz), 7.99(1H, dd,
J=1.5 and 8.4Hz), 8.06(1H, d, J=l.5Hz)
Fxamt~le 34
Synthesis of 6-ethoxycarbonyl-2-methyl-1-(2-methylbenzyl)-
benzimidazole (102)
In the same manner as in Production Example 14, ethyl 3-
[N-(2-methylbenzyl)acetylamino]-4-nitrobenzoate was obtained
from 1.50 g of ethyl 3-acetylamino-4-nitrobenzoate and 1.65 g of
2-methylbenzyl bromide. This compound was converted to 6-
ethoxycarbonyl-2-methyl-1-(2-methylbenzyl)benzimidazole [(102),
0.81 g] in the same manner as in Example 24 without being
purified.
Properties of Compound (102):
1H-NMR(CDC13, ~ ) . 1.38(3H, t, J=7.2Hz), 2.43(3H, s), 2.54(3H,
s), 4.36(2H, q, J=7.2Hz), 5.33(2H, s), 6.35(1H, d, J=7.7Hz),
7.03(1H, t, J=8.2Hz), 7.18-7.25(2H, m), 7.75(1H, d, J=8.5Hz),
7.91(1H, d, J=l.2Hz), 7.98(1H, dd, J=8.5 and l.5Hz)
Example 35
Synthesis of 6-ethoxycarbonyl-1-(2-methoxybenzyl)-2-methyl-
benzimidazole (103)
In the same manner as in Production example 14, crude
ethyl 3-[N-(2-methoxybenzyl)acetylamino]-4-nitrobenzoate was
obtained from 1.16 g of ethyl 3-acetylamino-4-nitrobenzoate and
1.44 g of 2-methoxybenzyl chloride. Subsequently, 1.18 g of 6-
ethoxycarbonyl-1-(2-methoxybenzyl)-2-methylbenzimidazole (103)
were formed in the same manner as in Example 24.
Properties of Compound (103):
1H-NMR(CDC13, ~ ) . 1.39(3H, t, J=7.2Hz), 2.60(3H, s), 3.90(3H,
s), 4.37(2H, q, J=7.2Hz), 5.36(2H, s), 6.61(1H, d, J=7.4Hz),,
6.82(1H, t, J=7.5Hz), 6.92(1H, d, J=8.3Hz), 7.27(1H, m), 7.71(1H,
d, J=8.4Hz), 7.96(1H, dd, J=1.5 and 8.4Hz), 8.03(1H, d, J=l.3Hz).
Example 36
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Synthesis of 6-ethoxycarbonyl-1-(4-methoxybenzyl)-2-methyl-
benzimidazole (104)
In the same manner as in Production Example 14, crude
ethyl 3-[N-(4-methoxybenzyl)acetylamino]-4-nitrobenzoate was
obtained from 1.60 g of ethyl 3-acetylamino-4-nitrobenzoate and
1.49 g of 4-methoxybenzyl chloride. Subsequently, 1.27 g of 6-
ethoxycarbonyl-1-(4-methoxybenzyl)-2-methylbenzimidazole (104)
were formed in the same manner as in Example 24.
Properties of Compound (104):
1H-NMR(CDC13,~) . 1.40(3H, t, J=7.lHz), 2.59(3H, s), 3.77(3H, s),
4.38(2H, q, J=7.lHz), 5.31(2H, s), 6.84(2H, m), 7.00(2H, m),
7.71(1H, d, J=8.4Hz), 7.97(1H, dd, J=1.4 and 8.4Hz), 8.03(1H, d,
J=l.3Hz)
Example 37
Synthesis of 1-[2-(benzenesulfonylmethyl)benzyl]-6-ethoxy-
carbonyl-2-methylbenzimidazole (105)
In the same manner as in Production Example 14, ethyl 3-
[N-[2-(benzenesulfonylmethyl)benzyl]acetylamino]-4-nitrobenzoate
was obtained from 1.00 g of ethyl 3-acetylamino-4-nitrobenzoate
and 1.93 g of 2-(benzenesulfonylmethyl)benzyl bromide. This
compound was converted to 1-[2-benzenesulfonylmethyl)benzyl]-6-
ethoxycarbonyl-2-methylbenzimidazole [(105), 0.89 g] in the same
manner as in Example 24 without being purified.
Properties of Compound (105):
1H-NMR(CDC13, c~) . 1.37(3H, t, J=7.lHz), 2.57(3H, s), 4.36(2H, q,
J=7.lHz), 4.50(2H, s), 5.60(2H, s), 6.38(1H, d, J=6.7Hz),
6.88(1H, dd, J=1.5 and 7.3Hz), 7.10-7.18(2H, m), 7.57(2H, t,
J=7.6Hz), 7.69-7.78(2H, m), 7.79(1H, dd, J=0.8 and 8.lHz),
7.92(1H, d, J=l.2Hz), 7.99(1H, dd, J=1.5 and 8.4Hz)
Example 38
Synthesis of 1-(2-cyanobenzyl)-6-(2-cyanobenzyloxycarbonyl)-2-
methylbenzimidazole (106)
In the same manner as in Example 24, 1.75 g of 1-(2-
cyanobenzyl)-6-(2-cyanobenzyloxycarbonyl)-2-methylbenzimidazole
(106) were formed from 3.33 g of 2-cyanobenzyl 3-[N-(2-
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cyanobenzyl.)acetylamino]-4-nitrobenzoate.
Properties of Compound (106):
1 H-NMR(CDC1 3 , ~ ) . 2.60(3H, s), 5.55(2H, s), 5.60(2H, s),
6.68(1H, d, J=7.3Hz), 7.41-7.48(3H, m), 7.61(2H, m), 7.72(1H, d,
J=7.6Hz), 7.76(1H, d, J=7.6Hz), 7.77(1H, d, J=8.6Hz), 8.02(1H,
s), 8.05(1H, dd, J=8.4 andl.5Hz).
Example 39
Synthesis of 1-(biphenyl-2-ylmethyl)-6-ethoxycarbonyl-2-methyl-
benzimidazole (107)
In the same manner as in Production Example 14 , ethyl 3-
[N-(biphenyl-2-ylmethyl)acetylamino]-4-nitrobenzoate was
obtained from 1.00 g of ethyl 3-acetylamino-4-nitrobenzoate and
1.47 g of 2-bromomethylbiphenyl. This compound was converted to
1-(biphenyl-2-ylmethyl)-6-ethoxycarbonyl-2-methylbenzimidazole
[(107), 1.31 g] in the same manner as in Example 24 without
being purified.
Properties of Compound (107):
1H-NMR(CDC13, ~) . 1.41(3H, t, J=7.3Hz), 2.39(3H, s), 4.38(2H, q,
J=7.3Hz), 5.27(2H, s), 6.68(1H, d, J=7.9Hz), 7.21(1H, dt, J=9.0
and 2.lHz), 7.32-7.39(4H, m), 7.43(1H, dd, J=7.3 and I.9Hz),
7.46-7.51(2H, m), 7.68(1H, d, J=8.4Hz), 7.87(1H, d, J=l.3Hz),
7.95(1H, dd, J=8.4 and 1.5H
Examrale 40
Synthesis of 1-benzyl-6-ethoxycarbonyl-2-methylbenzimidazole
(108)
In the same manner as in Production Example 14, ethyl 3-
(N-benzylacetylamino)-4-nitrobenzoate was obtained from 1.00 g
of ethyl 3-acetylamino-4-nitrobenzoate and 1.02 g of benzyl
bromide. This compound was converted to 1-benzyl-6-
ethoxycarbonyl-2-methylbenzimidazole [(108), 0.71 g] in the same
manner as in Example 24 without being purified.
Properties of Compound (108):
1H-NMR(CDC13, ~) . 1.39(3H, t, J=7.lHz), 2.58(3H, s), 4.38(2H, q,
J=7.lHz), 5.38(2H, s), 7.05(2H, dd, J=8.3 and l.8Hz), 7.28-
7.33(3H, m), 7.72(1H, d, J=8.4Hz), 7.98(1H, dd, J=8.4 and l.5Hz),
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8.02(1H, d, J=l.2Hz)
Synthesis of 1-(4-tert-butylbenzyl)-6-ethoxycarbonyl-2-methyl-
benzimidazole (109)
In the same manner as in Production Example 14, ethyl 3-
[N-(4-tert-butylbenzyl)acetylamino]-4-nitrobenzoate was obtained
from 1.00 g of ethyl 3-acetylamino-4-nitrobenzoate and 1.35 g of
4-tert-butylbenzyl bromide. This compound was converted to crude
1-(4-tent-butylbenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole
[(109), 1.60 g] in the same manner as in Example 24 without
being purified.
Example 42
Synthesis of 6-ethoxycarbonyl-2-methyl-1-(2-naphthylmethyl)-
benzimidazole (110)
In the same manner as in Production example 14, ethyl 3-
[N-(2-naphthylmethyl)acetylamino]-4-nitrobenzoate was obtained
from 1.00 g of ethyl 3-acetylamino-4-nitrobenzoate and 1.32 g of
2-naphthylmethyl bromide. This compound was converted to crude
6-ethoxycarbonyl-2-methyl-1-(2-naphthylmethyl)benzimidazole
[(110), 1.28 g] in the same manner as in Example 24 without
being purified .
Example 43
Synthesis of 1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-ethyl-
benzimidazole (111)
In the same manner as in Production Example 14 , ethyl 3-
[N-(biphenyl-4-ylmethyl)propionylamino]-4-nitrobenzoate was
obtained from 2.00 g of ethyl 4-nitro-3-propionylaminobenzoate
and 2.28 g of 4-chloromethylbiphenyl. This compound was
converted to 1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-
ethylbenzimidazole [(111), 2.07 g)] in the same manner as in
Example 24 without being purified.
Properties of Compound (111):
1H-NMR(CDC13, ~ ) . 1.39(3H, t, J=7.2Hz), 1.45(3H, t, J=7.5Hz),
2.90(2H, q, J=7.5Hz), 4.38(2H, q, J=7.2Hz), 5.43(2H, s), 7.10(2H,
d, J=8.3Hz), 7.33-7.36(1H, m), 7.43(2H, t, J=7.4Hz), 7.51-
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7.56(4H, m), 7.79(1H, d, J=8.5Hz), 7.80(1H, dd, J=1.5 and 8.4Hz),
8.05(1H, d, J=l.3Hz)
Example 44
Synthesis of 1-(2-chlorobenzyl)-5-ethoxycarbonyl-2-methyl-
benzimidazole (112)
In the same manner as in Production Example 14, ethyl 4-
[N-(2-chlorobenzyl)acetylamino]-3-nitrobenzoate was obtained
from 3.15 g of ethyl 4-acetylamino-3-nitrobenzoate and 3.85 g of
2-chlorobenzyl bromide. This compound was converted to 1-(2-
chlorobenzyl)-5-ethoxycarbonyl-2-methylbenzimidazole [(112),
2.54 g] in the same manner as in Example 24 without being
purified .
Properties of Compound (112):
1H-NMR(CDC13, ~) . 1.41(3H, t, J=7.lHz), 2.59(3H, s), 4.40(2H, q,
J=7.lHz), 5.43(1H, s), 6.43(1H, d, J=7.8Hz), 7.10(1H, t,
J=7.5Hz), 7.19(1H, d, J=8.5Hz}, 7.25(1H, m), 7.46(1H, d,
J=8.lHz), 7.95(1H, dd, J=1.4 and 8.4Hz), 8.47(1H, s).
Example 45
Synthesis of 1-(2,6-dichlorobenzyl)-6-ethoxycarbonyl-2-methyl-
benzimidazole (113)
In the same manner as in Production Example 14 , ethyl 3-
[N-(2,6-dichlorobenzyl)acetylamino]-4-nitrobenzoate was obtained
from 1.50 g of ethyl 3-acetylamino-4-nitrobenzoate and 2.14 g of
2,6-dichlorobenzyl bromide. This compound was converted to 1-
(2,6-dichlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole
[(113), 0.91 g] in the same -manner as in Example 24 without
being purified.
Properties of Compound (113):
1H - NMR(CDC13, ~ ) . 1.38(3H, t, J=7.lHz), 2.64(3H, s}, 4.34(2H,
q, J=7.lHz), 5.61(2H, s), 7.30(1H, dd, J=7.6 and 8.5Hz), 7.40(2H,
d, J=8.OHz), 7.66(1H, d, J=8.4Hz), 7.87(1H, d, J=l.lHz), 7.91(1H,
dd, J=8.4 and l.5Hz).
Example 46
Synthesis of 6-ethoxycarbonyl-2-n-propyl-1-i-propylbenzimidazole
(114)
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Two milliliters of acetic acid were added to 0.06 g of
ethyl 4-amino-3-(N-i-propylbutyrylamino)benzoate, and the
mixture was stirred at 90°C for 14 hours. The reaction solution
was concentrated under reduced pressure to give 0.05 g of 6-
ethoxycarbonyl-2-n-propyl-1-i-propylbenzimidazole (114).
Properties of Compound (114)
1H-NMR(CDC13, 8 ) . 1.07(3H, t, J=7.4Hz), 1.43(3H, t, J=7.OHz),
1.69(6H, d, J=6.9Hz), 1.85-1.92(2H, m), 2.91(2H, t, J=7.7Hz),
4.41(2H, q, J=7.3Hz), 4.67-4.76(1H, m), 7.72(1H, d, J=8.3Hz),
7.94(1H, dd, J=8.7 and l.5Hz), 8.25(1H, d, J=l.2Hz)
Examfile 47
Synthesis of 2-benzyl-6-ethoxycarbonyl-1-methylbenzimidazole
(115)
A solution of 0.924 g of ethyl 4-nitro-3-
phenylacetylaminobenzoate in 10 ml of N,N-dimethylformamide were
added 0.166 g of 60% sodium hydride while being cooled with ice,
and the mixture was stirred at room temperature for 1 hour.
Methyl iodide (0.50 ml) was added thereto, and the resulting
mixture was stirred at room temperature for 1 hour. The reaction
solution was poured into cold 1-N hydrochloric acid, and the
mixture was extracted twice with ethyl acetate. The organic
layer was washed with 1-N hydrochloric acid and then with water,
and was dried. The solvent was distilled off under reduced
pressure. The residue was purified through silica-gel column
chromatography (developing eluent: a mixture of ethyl acetate
and hexane at a ratio of from 1 : 10 to 1:4 ) to obtain 0.510 g of
ethyl 4-nitro-3-[N-(methyl)phenylacetylamino] benzoate. To 0.148
g of this compound were added 2 ml of ethanol, 1 ml of acetic
acid and 0.240 g of reduced iron, and the mixture was refluxed
for 2 hours. The solid material was separated through filtration.
The filtrate was concentrated, and was then purified through
preparative thin-layer silica-gel chromatography (eluent: a
mixture of chloroform and ethyl acetate at a ratio of 2:1) to
give 0.090 g of 2-benzyl-6-ethoxycarbonyl-1-methylbenzimidazole
(115).
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Properties of Compound (115):
1 H-NMR( CDC1 3 , ~ ) . 1 . 41 ( 3H, t, J=7 . 1Hz ) , 3 . 63 ( 3H, s ) , 4 .
32 ( 2H,
s), 4.40(2H, q, J=7.lHz), 7.21-7.26(3H, m), 7.27-7.32(2H, m),
7.72(1H, d, J=8.4Hz), 7.98(1H, dd, J=1.5 and 8.4Hz), 8.03(1H, d,
J=l.3Hz).
Exam~yle 48
Synthesis of 1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methyl-
benzimidazole (116)
A solution of 1.50 g of ethyl 3-acetylamido-4-
nitrobenzoate in 8 ml of N,N-dimethylformamide was added
dropwise to a slurry of 0 . 357 g of 60 % sodium hydride and 8 ml
of N,N-dimethylformamide at room temperature, and the mixture
was stirred for 30 minutes. Subsequently, a solution of 1.74 g
of 2,4-dichlorobenzyl chloride in 8 ml of N,N-dimethylformamide
was added dropwise thereto, and the mixture was stirred for 30
minutes. The reaction solution was poured into a mixed solution
of 50 g of dilute hydrochloric acid and 60 g of ethyl acetate
for separation. The resulting organic layer was washed twice
with 50g of water. This organic layer was concentrated under
reduced pressure to obtain 3.5 g of crude ethyl 3-[N-(2,4-
dichlorobenzyl)acetylamino]-4-nitrobenzoate. This compound
without being purified was dissolved in 23 ml of ethanol and 12
ml of acetic acid, and then 3.32 g of reduced iron were added
thereto. The mixture was heat-refluxed for 6 hours. The solid
material was removed using a filtration aid, and the filtrate
was concentrated under reduced pressure. The resulting residue
was separated with the addition of 60 ml of ethyl acetate and 50
ml of dilute hydrochloric acid. The organic layer was washed
with 50 g of a saturated aqueous solution of sodium
hydrogencarbonate and then twice with 50 g of water, and was
concentrated under reduced pressure. The resulting residue was
purified through silica-gel column chromatography (eluent: a
mixture of hexane and ethyl acetate at a ratio of from 4:1 to
1:1) to give 0.94 g of 1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-
2-methylbenzimidazole (116).
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y 1 1 1
Properties of Compound (116):
1H-NMR(CDC13, S) . 1.40(3H, t, J=7.lHz), 2.56(3H, s), 4.38(2H, q,
J=7.lHz), 5.41(2H, s), 6.34(1H, d, J=8.4Hz), 7.09(1H, dd, J=8.4
and 2.OHz), 7.49(1H, d, J=2.OHz), 7.75(1H, d, J=8.4Hz), 7.92(1H,
s), 8.00(1H, dd, J=8.5 and l.4Hz)
Examale 49
Synthesis of 6-carboxy-1-(4-chlorobenzyl)-2-n-propyl-
benzimidazole (117)
1.06 g of 1-(4-chlorobenzyl)-6-ethoxycarbonyl-2-n-
propylbenzimidazole were added 3.57 g of a 10% sodium hydroxide
aqueous solution, 5 ml of ethanol and 3.57 g of water, and the
mixture was heat-refluxed for 1 hour. The reaction solution was
adjusted to a pH of 6 with 10 % hydrochloric acid, and was
concentrated under reduced pressure. Ethanol was added to the
resulting residue, and the inorganic salt was separated through
filtration. The filtrate was concentrated under reduced pressure
to obtain 0.80 g of the residue. This residue was purified
through silica-gel column chromatography (eluent: a mixture of
ethyl acetate and methanol at a ratio of 4 : 1 ) to give 0. 63 g of
6-carboxy-1-(4-chlorobenzyl)-2-n-propylbenzimidazole (117).
Properties of Compound (117)
1H-NMR(DMSO-d6, C~ ) . 0.96(3H, t, J=7.3Hz), 1.76-1.88(2H, m),
3.10-3.23(2H, m), 5.83(2H, s), 7.27(2H, d, J=8.4Hz), 7.44(2H, d,
J=8.4Hz), 7.89(1H, d, J=8.4Hz), 7.89(1H, d, J=8.5Hz), 8.28(1H,
s)
Example 50
Synthesis of 6-carboxy-1-methyl-2-n-propylbenzimidazole (118)
In the same manner as in Example 49, 0.46 g of 6-carboxy-
1-methyl-2-n-propylbenzimidazole (118) were formed from 0.56 g
of 6-ethoxycarbonyl-1-methyl-2-n-propylcarbonylbenzimidazole.
Properties of Compound (118):
1H-NMR(DMSO-d6, ~ ) . 1.00(3H, t, J=7.3Hz), 1.79-1.93(2H, m),
3.06(3H, t, J=7.4Hz), 3.92(3H, s), 7.76(1H, d, J=8.4Hz), 7.97(1H,
d, J=8.4Hz), 8.31(1H, s).
E~ple 51
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Synthesis of 6-carboxy-2-n-propyl-1-i-propylbenzimidazole (119)
In the same manner as in Example 49, 0.045 g of 6-carboxy-
2-n-propyl-1-i-propylbenzimidazole (119) were formed from 0.045
g of 6-ethoxycarbonyl-2-n-propyl-1-i-propylbenzimidazole.
Properties of Compound (119):
1 H-NMR(CD 3 OD, ~ ) . 0 . 98 ( 3H, t, J=7 .4Hz ) , 1 . 61 ( 6H, d, J=6 . 9Hz
) ,
1.74-1.82(2H, m), 2.89(2H, t, J=7.5Hz), 3.21-3.24(2H, m), 4.78-
4.83(1H, m), 7.51(1H, d, J=8.3Hz), 7.84(1H, dd, J=8.4 and l.5Hz),
8.26(1H, s).
Example 52
Synthesis of 1-n-butyl-6-carboxy-2-n-propylbenzimidazole (120)
In the same manner as in Example 49, 0.60 g of 1-n-butyl-
6-carboxy-2-n-propylbenzimidazole (120) were formed from 0.81 g
of 1-n-butyl-6-ethoxycarbonyl-2-n-propylbenzimidazole.
Properties of Compound (120):
1H-NMR(DMSO-d6, ~) . 1.02(3H, t, J=7.3Hz), 1.17(3H, t, J=7.3Hz),
1.33-1.41(2H, m), 1.70-1.77(2H, m), 1.85-1.93(2H, m), 3.07(2H, t,
J=7.6Hz), 4.42(2H, t, J=7.4Hz), 7.78(1H, d, J=8.5Hz), 7.99(1H,
dd, J=8.5 and I.OHz), 8.35(1H, s), 13.13(1H, s)
Example 53
Synthesis of 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole
(121)
Eighty milliliters of ethanol and 37 g of a 10 % sodium
hydroxide aqueous solution were added to 10.0 g of 1-(2-
chlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole, and the
mixture was refluxed for 4 hours. The reaction solution was
cooled, and was then adjusted to a pH of 6 with 10% hydrochloric
acid. The precipitate was collected, washed with water, and
dried under reduced pressure to give 8.30 g of 6-carboxy-1-(2-
chlorobenzyl)-2-methylbenzimidazole (121).
Example 54
Synthesis of 6-carboxy-1-(2,6-dichlorobenzyl)-2-methyl-
benzimidazole (122)
In the same manner as in Example 53, 0.72 g of 6-carboxy-
1-(2,6-dichlorobenzyl)-2-methylbenzimidazole (122) were formed
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from 0.90 g of 1-(2,6-dichlorobenzyl)-6-ethoxycarbonyl-2-
methylbenzimidazole.
Properties of Compound (122):
1 H-NMR(DMSO-d6, cS ) . 2.60(3H, s), 5.71(2H, s), 7.46(1H, t,
J=7.9Hz), 7.57(3H, t, J=8.2Hz), 7.73(2H, m), 12.57(1H, s).
7~,xample 55
Synthesis of 6-carboxy-2-methyl-1-[2-(trifluoromethyl)benzyl]-
benzimidazole (123)
In the same manner as in Example 53, 0.98 g of 6-carboxy-
2-methyl-1-[2-(trifluoromethyl)benzyl]benzimidazole (123) were
formed from 1.17 g of 6-ethoxycarbonyl-2-methyl-1-[2-
(trifluoromethyl)benzyl]benzimidazole.
Properties of Compound (123):
1H-NMR(DMSO-d6, ~) . 2.49(3H, s), 5.70(2H, s), 6.46-6.51(1H, m),
7.51(2H, m), 7.65(1H, d, J=8.4Hz), 7.81(1H, dd, J=1.4 and 8.4Hz),
7.82-7.87(1H, m), 7.91(1H, s).
xample 56
Synthesis of 6-carboxy-2-methyl-1-[4-(trifluoromethyl)benzyl]-
benzimidazole (124)
In the same manner as in Example 53, 1.07 g of 6-carboxy-
2-methyl-1-[4-(trifluoromethyl)benzyl]-benzimidazole (124) were
formed from 1.22 g of 6-ethoxycarbonyl-2-methyl-1-[4-
(trifluoromethyl)benzyl]-benzimidazole.
Properties of Compound (124):
1 H-NMR(DMSO-d6, ~ ) . 2.85(3H, s), 5.92(2H, s), 7.50(2H, d,
J=8.lHz), 7.74(2H, d, J=8.lHz), 7.88(1H, d, J=8.5Hz), 8.07(1H, d,
J=8.5Hz), 8.31(1H, s), 13.3(1H, br s).
Example 57
Synthesis of 6-carboxy-1-(3,4-dichlorobenzyl)-2-methyl-
benzimidazole (125)
In the same manner as in Example 53, 0.55 g of 6-carboxy-
1-(3,4-dichlorobenzyl)-2-methylbenzimidazole (125) were formed
from 0.76 g of 1-(3,4-dichlorobenzyl)-6-ethoxycarbonyl-2-
methylbenzimidazole.
Properties of Compound (125):
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114
1H-NMR(DMSO-d6, S ) . 2.56(3H, s), 5.61(2H, s), 6.98(1H, dd,
J=8.4 and l.9Hz), 7.46(1H, d, J=l.9Hz), 7.59(1H, d, J=8.3Hz),
7.63(1H, d, J=8.4Hz), 7.81(1H, dd, J=8.4 and l.4Hz), 8.07(1H, s),
12.76(1H, s)
F-xample 58
Synthesis of 1-benzyl-6-carboxy-2-n-propylbenzimidazole (126)
A 10% sodium hydroxide aqueous solution (3.61 g), 5 ml of
ethanol and 3 ml of water were added to 0.97 g of 1-benzyl-6-
ethoxycarbonyl-2-n-propylbenzimidazole, and the mixture was
heat-refluxed for 1 hour. The reaction solution was adjusted to
a pH of 6 with 10% hydrochloric acid, and was concentrated under
reduced pressure. Ethanol was added to the residue, and the
inorganic salt was separated through filtration. The filtrate
was concentrated under reduced pressure to give 0.85 g of 1-
benzyl-6-carboxy-2-n-propylbenzimidazole (126).
Properties of Compound (126):
1H-NMR(DMSO-d6, ~ ) . 0.94(3H, t, J=7.4Hz), 1.73-1.81(2H, m),
2.85(2H, t, J=7.3Hz), 5.59(2H, s), 7.07(2H, dd, J=1.1 and 8.3Hz),
7.27(1H, t, J =7.3Hz), 7.33(2H, t, J=7.4Hz), 7.65(1H, d,
J=8.4Hz), 7.79(1H, dd, J=1.5 and 8.4Hz), 8.04(1H, s)
Example 59
Synthesis of 6-carboxy-1-(3-chlorobenzyl)-2-n-propyl-
benzimidazole (127)
In the same manner as a.n Example 58, 0.35 g of 6-carboxy-
1-(3-chlorobenzyl)-2-n-propylbenzimidazole (127) were formed
from 0.57 g of 1-(3-chlorobenzyl)-6-ethoxycarbonyl-2-n-
propylbenzimidazole.
Properties of Compound (127):
1H-NMR(DMSO-d6, ~ ) . 0.94(3H, t, J=7.3Hz), 1.70-1.79(2H, m),
2.83(2H, t, J=7.4Hz), 5.59(2H, s), 6.94(1H, s), 7.15(1H, s),
7.34(2H, d, J=4.4Hz), 7.59(1H, d, J=8.4Hz), 7.81(1H, d, J=8.lHz),
8.02(1H, s)
Examgle 60
Synthesis of 6-carboxy-2-methyl-1-(2-nitrobenzyl)benzimidazole
(128)
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115
In the same manner as in Example 58, 0.35 g of 6-carboxy-
2-methyl-1-(2-nitrobenzyl)benzimidazole (128) were formed from
0.61 g of 6-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)-
benzimidazole.
Properties of Compound (128):
1 H-NMR(DMSO-d6, (S ) . 2.51(3H, s), 5.96(2H, s), 6.33(1H, d,
J=7.OHz), 7.55-7.62(2H, m), 7.66(1H, d, J=8.3Hz), 7.81(1H, d,
J=8.4Hz), 8.06(1H, s), 8.24(1H, d, J=7.OHz), 12.66(1H, s)
Example 61
Synthesis of 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole
(121)
Ethanol (15 ml) and 10.6 g of a 5 % sodium hydroxide
aqueous solution were added to 1.456 g of 1-(2-chlorobenzyl)-6-
ethoxycarbonyl-2-methylbenzimidazole, and the mixture was
refluxed for 1 hour. The reaction solution was cooled, and was
then adjusted to a pH of 6 with 10 % hydrochloric acid. The
precipitate was collected, washed with water, and dried under
reduced pressure to give 0.645 g of 6-carboxy-1-(2-
chlorobenzyl)-2-methylbenzimidazole (121).
Example 62
Synthesis of 6-carboxy-1-(2,4-dichlorobenzyl)-2-methyl-
benzimidazole (129)
A 10 % sodium hydroxide aqueous solution (3.10 g) and 10
ml of ethanol were added to 0.94 g of 1-(2,4-dichlorobenzyl)-6-
ethoxycarbonyl-2-methylbenzimidazole, and the mixture was heat-
refluxed for 1 hour. The reaction solution was adjusted to a pH
of 6 with 10% hydrochloric acid. The crystals precipitated were
separated through filtration, and were dried to give 0.68 g of
6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (129).
Properties of Compound (129):
1 H-NMR(DMSO-d6, S ) . 2.52(3H, s), 5.61(2H, s), 6.54(1H, d,
J=8.4Hz), 7.33(1H, dd, J=8.4 and 2.lHz), 7.64(1H, d, J=8.4Hz),
7.74(1H, d, J=2.lHz), 7.81(1H, dd, J=8.4 and l.5Hz), 7.98(1H, s),
12.72(1H, s).
Example 63
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rr ~ ~ 116
Synthesis of 1-(biphenyl-4-ylmethyl)-6-carboxy-2-methyl-
benzimidazole (130)
In the same manner as in Example 53, 0.83 g of 1-
(biphenyl-4-ylmethyl)-6-carboxy-2-methylbenzimidazole (130) were
formed from 1.10 g of 1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-
2-methylbenzimidazole.
Properties of Compound (130):
1 H-NMR(DMSO-d6, S ) . 2.53(3H, s), 5.61(2H, s), 7.18(2H, d,
J=8.2Hz), 7.34(1H, m), 7.43(2H, m), 7.62(5H, m), 7.79(1H, dd,
J=1.6 and 8.5Hz), 8.09(1H, d, J=l.OHz), 12.72(1H, br s)
Fop
Synthesis of 1-(4-tert-butylbenzyl)-6-carboxy-2-methyl-
benzimidazole (131)
In the same manner as in Example 53, 0.55 g of 1-(4-tert-
butylbenzyl)-6-carboxy-2-methylbenzimidazole (131) were formed
from 1.34 g of 1-(4-tert-butylbenzyl)-6-ethoxycarbonyl-2-
methylbenzimidazole.
Properties of Compound (131):
1H-NMR(DMSO-d6, ~ ) . 1.22(9H, s), 2.57(3H, s), 5.52(2H, s),
7.03(2H, d, J=8.2Hz), 7.35(1H, d, J=8.3Hz), 7.60(1H, d, J=8.4Hz),
7.78(1H, dd, J=8.4 and l.5Hz), 8.06(1H, s), 12.71(1H, s)
Rxam~l_e 65
Synthesis of 6-carboxy-2-methyl-1-(2-methylbenzyl)benzimidazole
(132)
In the same manner as in Example 53, 0.49 g of 6-carboxy-
2-methyl-1-(2-methylbenzyl)benzimidazole (132) were formed from
0.81 g of 6-ethoxycarbonyl-2-methyl-1-(2-methylbenzyl)-
benzimidazole.
Properties of Compound (132):
1H-NMR(DMSO-d6, ~ ) . 2.41(3H, s), 2.48(3H, s), 5.55(2H, s),
6.14(1H, d, J=7.6Hz), 7.02(1H, t, J=7.4Hz), 7.I7(1H, t, J=7.3Hz),
7.26(1H, d, J=7.4Hz), 7.65(1H, d, J=8.4Hz), 7.81(1H, dd, J=8.4
and l.4Hz), 7.97(1H, d, J=l.lHz), 12.71(1H, s)
Synthesis of 6-carboxy-1-(2-methoxybenzyl)-2-methylbenzimidazole
CA 02241186 1998-06-23
117
(133)
In the same manner as in Example 53, 1.00 g of 6-carboxy-
1-(2-methoxybenzyl)-2-methylbenzimidazole (133) was formed from
1.63 g of 6-ethoxycarbonyl-1-(2-methoxybenzyl)-2-methyl-
benzimidazole.
Properties of Compound (133):
1 H-NMR(DMSO-d6, ~ ) . 2.55(3H, s), 3.81(3H, s), 5.42(2H, s),
6.77(1H, m), 6.85(1H, m), 7.05(1H, m), 7.28(1H, m), 7.58(1H, m),
7.76(1H, m), 7.99(1H, s), 12.65(1H, br s).
Example 67
Synthesis of 6-carboxy-1-(4-methoxybenzyl)-2-methylbenzimidazole
(134)
In the same manner as in Example 53, 0.99 g of 6-carboxy-
1-(4-methoxybenzyl)-2-methylbenzimidazole (134) were formed from
1.27 g of 6-ethoxycarbonyl-1-(4-methoxybenzyl)-2-methyl-
benzimidazole.
Properties of Compound (134):
iH-NMR(DMSO-d6, S ) . 2.86(3H, s), 3.71(3H, s), 5.69(2H, s),
6.92(2H, d, J=8.4Hz), 7.27(2H, d, J=8.4Hz), 7.84(1H, d, J=8.5Hz),
8.04(1H, d, J=8.5Hz), 8.33(1H, s), 13.25(1H, br t)
Example 68
Synthesis of 6-carboxy-2-methyl-1-[2-(benzenesulfonylmethyl)-
benzyl]benzimidazole (135)
In the same manner as in Example 53, 0.74 g of 6-carboxy-
2-methyl-1-[2-(benzenesulfonylmethyl)benzyl]-benzimidazole (135)
were formed from 0.89 g of 6-ethoxycarbonyl-2-methyl-1-[2-
(benzenesulfonylmethyl)benzyl]benzimidazole.
Properties of Compound (135):
1H-NMR(DMSO-d6, ~ ) . 2.44(3H, s), 4.99(2H, s), 5.71(2H, s),
6.08(1H, d, J=6.5Hz), 7.12-7.20(3H, m), 7.64-7.70(3H, m), 7.77-
7.83(2H, m), 7.89(2H, s), 7.90(1H, s), 12.71(1H, s)
~p1_e 69
Synthesis of 6-carboxy-1-(2-cyanobenzyl)-2-methylbenzimidazole
(136)
In the same manner as in Example 53, 1.14 g of 6-carboxy-
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1-(2-cyanobenzyl)-2-methylbenzimidazole (136) were formed from
2.04 g of 1-(2-cyanobenzyl)-6-(2-cyanobenzyloxycarbonyl)-2-
methylbenzimidazole.
Properties of Compound (136):
1 H-NMR(DMSO-d6, 8 ) . 2.54(3H, s), 5.80(2H, s), 6.78(1H, d,
J=7.8Hz), 7.51(1H, t, J=7.4Hz), 7.61(1H, dt, J=7.8 and l.2Hz),
7.64(1H, d, J=8.4Hz), 7.80(1H, dd, J=8.4 and l.SHz), 7.94(1H, d,
J=6.7Hz), 8.00(1H, d, J=l.lHz), 12.70(1H, s)
E~~?le 70
Synthesis of 6-carboxy-1-(biphenyl-2-ylmethyl)-2-methyl-
benzimidazole (137)
In the same manner as in Example 53, 1.07 g of 6-carboxy-
1-(biphenyl-2-ylmethyl)-2-methylbenzimidazole (137) were formed
from 1.31 g of 1-(biphenyl-2-ylmethyl}-6-ethoxycarbonyl-2-
methylbenzimidazole.
Properties of Compound (137):
1 H-NMR(DMSO-d6, ~ ) . 2.32(3H, s), 5.45(2H, s), 6.61(1H, d,
J=7.7Hz}, 7.26(1H, dt, J=7.7 and l.4Hz), 7.31(1H, dd, J=7.5 and
l.3Hz), 7.36(1H, dt, J=7.5 and 0.7Hz), 7.40-7.46(1H, m), 7.46-
7.52(4H, m), 7.57(1H, d, J=8.4Hz), 7.76(1H, dd, J=7.9 andl.5Hz),
7.86(1H, d, J=l.2Hz), 12.72(1H, s)
Example 71
Synthesis of 1-benzyl-6-carboxy-2-methylbenzimidazole (138)
In the same manner as in Example 53, 0.59 g of 1-benzyl-6-
carboxy-2-methylbenzimidazole(138) were formed from 0.71 g of 1-
benzyl-6-ethoxycarbonyl-2-methylbenzimidazole.
Properties of Compound (138):
1 H-NMR(DMSO-d6, ~ ) . 2.56(3H, s), 5.57(2H, s), 7.11(1H, d,
J=8.OHz), 7.27(1H, t, J=7.2Hz), 7.32-7.35(2H, m), 7.61(1H, d,
J=8.3Hz), 7.79(1H, dd, J=8.4 and l.3Hz), 8.06(1H, s), 12.75(1H,
s)
F;xample 72
Synthesis of 6-carboxy-2-methyl-1-(2-naphthylmethyl)-
benzimidazole (139)
In the same manner as in Example 53, 0.80 g of 6-carboxy-
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2-methyl-1-(2-naphthylmethyl)benzimidazole (139) were formed
from 1.28 g of 6-ethoxycarbonyl-2-methyl-1-(2-naphthyl-
methyl)benzimidazole.
Properties of Compound (139):
1 H-NMR(DMSO-d6, ~ ) . 2.61(3H, s), 5.74(2H, s), 7.29(1H, d,
J=8.6Hz), 7.46-7.52(2H, m), 7.59(1H, s), 7.63(IH, d, J=8.3Hz),
7.78-7.92(4H, m), 8.09(1H, s), 12.68(1H, s).
Example 73
Synthesis of 1-(biphenyl-4-ylmethyl)-6-carboxy-2-ethyl-
benzimidazole (140)
In the same manner as in Example 53, 1.70 g of 1-
(biphenyl-4-ylmethyl)-6-carboxy-2-ethylbenzimidazole (140) were
formed from 2.07 g of 1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-
2-ethylbenzimidazole.
Properties of Compound (140):
1H-NMR(DMSO-d6, ~) . 1.32(3H, t, J=7.4Hz), 2.94(2H, q, J=7.5Hz),
5.63(2H, s), 7.16(2H, d, J=8.2Hz), 7.34(1H, t, J=7.4Hz), 7.44(2H,
t, J=7.5Hz), 7.60-7.78(5H, m), 7.81(1H, dd, J=1.4 and 8.4Hz),
8.10(1H, d, J=l.2Hz), 12.73(1H, s).
Example 74
Synthesis of 5-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole
(141)
In the same manner as in Example 53, 2.48 g of 5-carboxy-
1-(2-chlorobenzyl)-2-methylbenzimidazole (141) were formed from
3.70 g of 1-(2-chlorobenzyl)-5-ethoxycarbonyl-2-methyl-
benzimidazole.
Properties of Compound (141):
1 H-NMR(DMSO-d6, ~ ) . 2.49(3H, s), 5.57(2H, s), 6.53(1H, d,
J=7.8Hz), 7.22(1H, t, J=7.6Hz), 7.33(1H, t, J=7.6Hz), 7.44(1H, d,
J=8.4Hz), 7.54(1H, d, J=8.OHz), 7.77(1H, dd, J=1.6 and 8.5Hz),
8.16(1H, d, J=l.3Hz), 12.71(1H, br s).
Exa ple 75
Synthesis of 5-carboxy-2-methyl-1-(2-nitrobenzyl)benzimidazole
(142)
In the same manner as in Example 53, 0.15 g of 5-carboxy-
t
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2-methyl-1-(2-nitrobenzyl)benzimidazole (142) were formed from
0.26 g of 5-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)-
benzimidazole.
Properties of Compound (142):
1H-NMR(DMSO-d6, S ) . 2.49(3H, s), 5.91(2H, s), 6.36(1H, dd,
J=7.2 and l.8Hz), 7.52(1H, d, J=8.5Hz), 7.55-7.62(2H, m),
7.77(1H, dd, J=8.5 andl.5Hz), 8.18(1H, d, J=l.3Hz), 8.24(1H, dd,
J=7.4 and l.6Hz), 12.69(1H, s).
Example 76
Synthesis of 2-benzyl-5-carboxy-1-(2-chlorobenzyl)benzimidazole
(143)
In the same manner as in Example 53, 0.488 g of 2-benzyl-
5-carboxy-1-(2-chlorobenzyl)benzimidazole (143) were formed from
0.635 g of 2-benzyl-1-(2-chlorobenzyl)-5-ethoxycarbonyl-
benzimidazole.
Properties of Compound (143):
1 H-NMR(DMSO-d6, ~ ) . 4.27(2H, s), 5.57(2H, s), 6.27(1H, d,
J=7.lHz), 7.06(1H, t), 7.10-7.29(6H, m), 7.39(1H, d, J=8.6Hz),
7.47(1H, d, J=7.9Hz), 7.78(1H, dd, J=1.4 and 8.6Hz), 8.21(1H, d,
J=l.2Hz), I2.71(1H, br s).
Example 77
Synthesis of 2-benzyl-6-carboxy-1-(2-chlorobenzyl)benzimidazole
(144)
In the same manner as in Example 53, 0.780 g of 2-benzyl-
6-carboxy-1-(2-chlorobenzyl)benzimidazole (144) were formed from
1.00 g of 2-benzyl-1-(2-chlorobenzyl)-6-ethoxycarbonyl-
benzimidazole.
Properties of Compound (144):
1 H-NMR(DMSO-d6, ~ ) . 4.29(2H, s), 5.63(2H, s), 6.28(1H, d,
J=7.8Hz), 7.07(1H, t, J=7.6Hz), 7.15(1H, m), 7.19-7.29(5H, m),
7.49(1H, d, J=7.4Hz), 7.70(1H, d, J=8.4Hz), 7.81(1H, d, J=8.4Hz),
7.91(1H, s), 12.73(1H, br s).
Example 78
Synthesis of 2-benzyl-5-carboxy-1-(2,4-dichlorobenzyl)-
benzimidazole (145)
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In the same manner as in Example 53, 0.40 g of 2-benzyl-5-
carboxy-1-(2,4-dichlorobenzyl)benzimidazole (145) were formed
from 0.50 g of 2-benzyl-1-(2,4-dichlorobenzyl)-5-ethoxy-
carbonylbenzimidazole.
Properties of Compound (145):
1 H-NMR(DMSO-d6, ~ ) . 4.28(2H, s), 5.55(2H, s), 6.19(1H, d,
J=8.4Hz), 7.08-7.22(6H, m), 7.41(1H, d, J=8.4Hz), 7.62(1H, d,
J=2.2Hz), 7.79(1H, dd, J=1.5 and 8.6Hz), 8.22(1H, s), 12.72(1H,
br s)
Examgle 79
Synthesis of 2-benzyl-6-carboxy-1-(2,4-dichlorobenzyl)-
benzimidazole (146)
In the same manner as in Example 53, 0.35 g of 2-benzyl-6-
carboxy-1-(2,4-dichlorobenzyl)benzimidazole (146) were formed
from 0.48 g of 2-benzyl-1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-
benzimidazole.
Properties of Compound (146):
1 H-NMR(DMSO-d6, ~ ) . 4.30(2H, s), 5.61(2H, s), 6.19(1H, d,
J=8.4Hz), 7.09-7.22(6H, m), 7.64(1H, d, J=2.lHz), 7.71(1H, d,
J=8.4Hz), 7.82(1H, dd, J=1.5 and 8.4Hz), 7.94(1H, d, J=l.2Hz),
12.78(1H, br s)
Example 80
Synthesis of 1-(biphenyl-4-ylmethyl)-6-carboxy-2-trifluoro-
methylbenzimidazole (147)
In the same manner as in Example 53, 0.483 g of 1-
(biphenyl-4-ylmethyl)-6-carboxy-2-trifluoromethylbenzimidazole
(147) were formed from 0.690 g of 1-(biphenyl-4-ylmethyl)-6-
ethoxycarbonyl-2-trifluoromethylbenzimidazole.
Properties of Compound (147):
1H-NMR(DMSO-d6, ~) . 5.87(2H, s), 7.18(2H, d, J=8.2Hz), 7.35(1H,
t, J=7.4Hz), 7.44(2H, t, J=7.5Hz), 7.60-7.67(4H, m), 7.98(2H, d,
J=0.7Hz), 8.32(1H, s), 13.15(1H, s).
E~ple 81
Synthesis of 1-(biphenyl-4-ylmethyl)-5-carboxy-2-trifluoro-
methylbenzimidazole (148)
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In the same manner as in Example 53, 0.270 g of 1-
(biphenyl-4-ylmethyl)-5-carboxy-2-trifluoromethylbenzimidazole
(148) were formed from 0.38 g of 1-(biphenyl-4-ylmethyl)-5-
ethoxycarbonyl-2-trifluoromethylbenzimidazole.
Properties of Compound (148):
iH-NMR(DMSO-d6, ~) . 5.80(2H, s), 7.19(2H, d, J=6.3Hz), 7.35(1H,
t, J=7.2Hz), 7.43(2H, t, J=7.3Hz), 7.82(1H, d, J=8.7Hz), 8.04(1H,
d, J=8.7Hz), 8.45(1H, s)
F_xampl~ 82
Synthesis of 5-ethoxycarbonyl-2-methylbenzimidazole (149)
Reduced iron (6.46 g), 48 ml of ethanol and 24 ml of
acetic acid were added to 3.00 g of ethyl 3-acetylamino-4-
nitrobenzoate, and the mixture was heat-refluxed for 12 hours.
The solid material was removed using a filtration aid, and the
filtrate was concentrated under reduced pressure,. To the residue
were added 100 ml of ethanol and 5.2 g of 35% hydrochloric acid,
and the mixture was heat-refluxed for 5 hours. The reaction
solution was neutralized with 6.3 g of sodium hydrogencarbonate,
and was filtrated. The filtrate was concentrated under reduced
pressure. The residue was separated with the addition of 70 ml
of ethyl acetate and 70 ml of water. The organic layer was
washed three times with water, and the aqueous layer was
extracted three times with ethyl acetate. The resulting organic
layer was concentrated under reduced pressure to give 1.53 g of
a powder of 5-ethoxycarbonyl-2-methylbenzimidazole (149).
Properties of Compound (149):
1H-NMR(CDC13, ~) . 1.41(3H, t, J=6.9Hz), 2.67(3H, s), 4.40(2H, q,
J=7.lHz), 7.55(1H, d, J=8.4Hz), 7.96(1H, dd, J=8.4 and l.5Hz),
8.27(1H, d, J=l.4Hz)
.xample 83
Synthesis of 2-benzyl-5-ethoxycarbonylbenzimidazole (150)
A mixture of 3.60 g of ethyl 3-nitro-4-
phenylacetylaminobenzoate, 47 ml of ethanol, 23 ml of acetic
acid and 6.4 g of reduced iron was heat-refluxed for 4 hours.
The solid material was separated through filtration, and the
i
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filtrate was concentrated. To the residue were added 50 ml of
ethanol and 5 g of 35 % hydrochloric acid. The mixture was
stirred for 40 hours while being heat-refluxed. The reaction
solution was neutralized with sodium hydrogencarbonate, and was
extracted with chloroform. The organic layer was concentrated
under reduced pressure, and was purified through silica-gel
column chromatography to give 2.30 g of 2-benzyl-5-
ethoxycarbonylbenzimidazole (150).
Properties of Compound (150):
1H-NMR(CDC13, ~) . 1.39(3H, t, J=7.lHz), 4.26(2H, s), 4.37(2H, q,
J=7.lHz), 7.22-7.36(5H, m), 7.50(1H, d, J=8.6Hz), 7.94(1H, dd,
J=1.5 and 8.6Hz), 8.23(1H, d, J=l.3Hz)
Examples 84 and 85
Synthesis of 6-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)-
benzimidazole (151) and 5-ethoxycarbonyl-2-methyl-1-(2-
nitrobenzyl)benzimidazole (152)
To 1.00 g of 5-ethoxycarbonyl-2-methylbenzimidazole were
added 15 ml of N,N-dimethylformamide, 1.59 g of 2-nitrobenzyl
bromide and 1.23 g of sodium hydrogencarbonate, and the mixture
was heated at 60 °C for 1 hour. The reaction solution was
separated with the addition of 70 ml of ethyl acetate and 70 ml
of water. The organic layer was then washed three times with
water, and the aqueous layer was extracted three times with
ethyl acetate. The resulting organic layer was concentrated
under reduced pressure to obtain a mixture of 6-ethoxycarbonyl-
2-methyl-1-(2-nitrobenzyl)benzimidazole and 5-ethoxycarbonyl-2-
methyl-1-(2-nitrobenzyl)benzimidazole. The mixture was purified
through medium-pressure silica-gel column chromatography
(eluent: a mixture of hexane and ethyl acetate at a ratio of
from 1:4 to 0:100) to give 0.614 g of 6-ethoxycarbonyl-2-methyl-
1-(2-nitrobenzyl)benzimidazole (151) and 0.259 g of 5-
ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole (152).
Properties of Compound (151):
1H-NMR(CDC13, ~) . 1.38(3H, t, J=7.2Hz), 2.56(3H, s), 4.37(2H, q,
J=7.lHz), 5.84(2H, s), 6.41(1H, d, J=6.SHz), 7.44-7.53(2H, m),
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r 124
7.78(1H, d, J=8.6Hz), 7.88(1H, s), 8.02(1H, dd, J=8.3 and l.5Hz),
8.30(1H, dd, J=7.9 and l.5Hz)
Properties of Compound (152):
1H-NMR(CDC13, ~) . 1.42(3H, t, J=7.OHz), 2.56(3H, s), 4.40(2H, q,
J=7.OHz), 5.80(2H, s), 6.43(1H, dd, J=7.6 and l.OHz), 7.14(1H, d,
J=8.3Hz), 7.45-7.53(2H, m), 7.95(1H, dd, J=8.4 and l.5Hz),
8.27(1H, dd, J=8.0 and l.7Hz), 8.48(1H, d, J=l.2Hz)
ExamAles 86 and 87
Synthesis of 2-benzyl-1-(2-chlorobenzyl)-6-ethoxycarbonyl-
benzimidazole (153) and 2-benzyl-1-(2-chlorobenzyl)-5-
ethoxycarbonylbenzimidazole (154)
In the same manner as in Examples 84 and 85, 1.06 g of 2
benzyl-1-(2-chlorobenzyl)-6-ethoxycarbonylbenzimidazole (153)
and 0.640 g of 2-benzyl-1-(2-chlorobenzyl)-5-ethoxycarbonyl
benzimidazole (154) were formed from 2.37 g of 2-benzyl-5
ethoxycarbonylbenzimidazole and 3.94 g of 2-chlorobenzyl bromide.
Properties of Compound (153):
1H-NMR(CDC13, ~) . 1.83(3H, t, J=7.lHz), 4.23(2H, s), 4.35(,2H, q,
J=7.lHz), 5.36(2H, s), 6.23(1H, d, J=7.8Hz), 6.97(1H, t,
J=7.6Hz), 7.11-7.45(7H, m), 7.85(1H, d, J=8.5Hz), 7.91(1H, s),
8.02(1H, dd, J=1.2 and 8.6Hz).
Properties of Compound (154):
1H-NMR(CDC13, 8) . 1.41(3H, t, J=7.IHz), 4.25(2H, s), 4.41(2H, q,
J=7.lHz), 5.33(2H, s), 6.22(1H, d, J=6.9Hz), 6.97(1H, t,
J=7.6Hz), 7.12-7.28(7H, m), 7.40(1H, d, J=S.OHz), 7.95(1H, dd,
J=1.6 and 8.6Hz), 8.60(1H, d, J=l.4Hz)
Examples 88 and 89
Synthesis of 2-benzyl-1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-
benzimidazole (155) and 2-benzyl-1-(2,4-dichlorobenzyl)-5-
ethoxycarbonylbenzimidazole (156)
In the same manner as in Examples 84 and 85, 0.49 g of 2-
benzyl-1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-benzimidazole and
0.52 g of 2-benzyl-1-(2,4-dichlorobenzyl)-5-ethoxycarbonyl-
benzimidazole (156) were formed from 2.37 g of 2-benzyl-5-
ethoxycarbonyl-benzimidazole and 4.45 g of 2,4-dichlorobenzyl
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r 125
bromide.
Properties of Compound (155):
1 H-NMR(CDCl 3 , 8 ) . 1.39(3H, t), 4.24(2H, s), 4.37(2H, q),
5.32(2H, s), 6.08(1H, d, J=8.3Hz), 6.90(1H, d, J=8.4Hz), 7.12-
7.24(5H, m), 7.41(1H, s), 7.84(1H, d, J=8.4Hz), 7.88(1H, s),
8.03(1H, d, J=8.4Hz)
Properties of Compound (156):
1H-NMR(CDC13, ~) . 1.42(3H, t, J=7.lHz), 4.25(2H, s), 4.41(2H, q,
J=7.lHz), 5.28(2H, s), 6.07(1H, d, J=8.4Hz), 6.90(1H, dd, J=1.9
and 8.4Hz), 7.08-7.28(6H, m), 7.40(1H, d, J=2.lHz), 7.96(1H, dd,
J=1.3 and 8.3Hz), 8.56(1H, d, J=0.9Hz)
Example 90
Synthesis of 5-ethoxycarbonyl-2-trifluoromethylbenzimidazole
(157)
Five-percent palladium on carbon ( 0 . 50 g ) was added to a
solution of 4.00 g of ethyl 3-amino-4-nitro-benzoate in 100 ml
of methanol, and the mixture was stirred in a hydrogen
atmosphere at 50 °C for 16 hours. The solid material was
separated through filtration, and the filtrate was concentrated
to obtain ethyl 3,4-diaminobenzoate. Twenty milliliters of
trifluoroacetic acid were added thereto, and the mixture was
stirred at 60 °C for 2 hours. The reaction solution was
concentrated, and chloroform was added thereto. The crystals
precipitated were separated through filtration, and were dried
to give 4.46 g of 5-ethoxycarbonyl-2-trifluoromethyl-
benzimidazole (157).
Properties of Compound (157):
1H-NMR(DMSO-d6, S) . 1.36(3H, t, J=7.OHz), 4.36(2H, q, J=7.OHz),
7.82(1H, d, J=8.5Hz), 7.99(1H, dd, J=1.5 and 8.7Hz), 8.33(1H, s)
F-xamples 91 and 92
Synthesis of 1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-
trifluoromethylbenzimidazole (158) and 1-(biphenyl-4-ylmethyl)-
5-ethoxycarbonyl-2-trifluoromethylbenzimidazole (159)
In the same manner as in Examples 84 and 85, 0.69 g of 1-
(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-trifluoromethyl-
t
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126
benzimidazole (158) and 0.38 g of 1-(biphenyl-4-ylmethyl)-5-
ethoxycarbonyl-2-trifluoromethylbenzimidazole (159) were formed
from 2.00 g of 5-ethoxycarbonyl-2-trifluoromethylbenzimidazole
and 10.08 g of 4-bromomethylbiphenyl.
Properties of Compound (158):
1 H-NMR(CDCl 3 , ~ ) . 1.39(3H, t), 4.38(2H, q), 5.64(2H, s),
7.18(2H, d, J=8.2Hz), 7.34(1H, t, J=7.4Hz), 7.42(2H, t, J=7.4Hz),
7.52-7.57(4H, m), 7.95(1H, d, J=8.8Hz), 8.09(2H, dd, J=1.4 and
8.8Hz), 8.14(1H, d, J=l.lHz)
Properties of Compound (159):
1 H-NMR(CDC1 3 , ~ ) . 1.40(3H, t), 4.40(2H, q), 5.59(2H, s),
7.16(2H, d, J=8.lHz), 7.34(2H, t, J=6.2Hz), 7.41(2H, t, J=7.5Hz),
7.53(4H, m), 8.08(1H, dd, J=1.3 and 9.lHz), 8.65(1H, s)
Production Example 38
Production of 1-(2-chlorobenzyl)-6-hydroxymethyl-2-methyl-
benzimidazole
A solution of 2.66 g of 1-(2-chlorobenzyl)-6-
ethoxycarbonyl-2-methylbenzimidazole in 20 ml of tetrahydrofuran
was slowly added to a solution of 1.54 g of lithium aluminum
hydride in 20 ml of tetrahydrofuran at a temperature of from 20
to 25°C. Further, the mixture was stirred at room temperature for
1 hour. Thirty milliliters of tetrahydrofuran were added thereto
to dilute the reaction solution. Lithium ammonium hydride was
decomposed and solidified with a saturated aqueous solution of
sodium sulfate, and the tetrahydrofuran layer was separated. The
solvent was distilled off, and the residue was purified through
silica-gel column chromatography (eluent: a mixture of
chloroform and methanol at a ratio of 9 : 1 ) to give 1 .45 g of 1-
(2-chlorobenzyl)-6-hydroxymethyl-2-methylbenzimidazole.
Properties of the compound:
1 H-NMR(CDC1 3 , ~ ) . 2.53(3H, s), 4.77(2H, s), 5.39(2H, s),
6.40(1H, d, J=7.7Hz), 7.08(1H, t, J=7.7Hz), 7.20-7.28(3H, m),
7.45(1H, d, J=7.9Hz), 7.70(1H, d, JH=8.2Hz)
Production of 1-(biphenyl-4-ylmethyl)-6-hydroxymethyl-2-methyl-
t
CA 02241186 1998-06-23
127
benzimidazole
In the same manner as in Production Example 38, 3.72 g of
1-(biphenyl-4-ylmethyl)-6-hydroxymethyl-2-methylbenzimidazole
were formed from 5.30 g of 1-(biphenyl-4-ylmethyl)-6-
ethoxycarbonyl-2-methylbenzimidazole and 2.17 g of lithium
aluminum hydride.
Properties of the compound:
1 H-NMR(CDCl 3 , ~ ) . 2.59(3H, s), 4.78(2H, s), 5.37(2H, s),
7.11(2H, d, J=8.3Hz), 7.24(1H, d, J=8.3Hz), 7.30-7.37(2H, m),
7.42(2H, t), 7.51-7.56(4H, m), 7.70(1H, d, J=8.2Hz).
Production Example 40
Production of 1-(2-chlorobenzyl)-6-chloromethyl-2-methyl-
benzimidazole hydrochloride
Five milliliters of thionyl chloride were added to 3.56 g
of 1-(2-chlorobenzyl)-6-hydroxymethyl-2-methylbenzimidazole, and
the mixture was stirred at room temperature for 20 minutes and
then at 80°C for 20 minutes. After excess thionyl chloride was
distilled off under reduced pressure, the residue was dissolved
in 10 ml of chloroform, and the solution was crystallized from
hexane. The crystals were separated through filtration, washed
with hexane, and dried to give 4.07 g of 1-(2-chlorobenzyl)-6-
chloromethyl-2-methylbenzimidazole hydrochloride.
Properties of the compound:
1 H-NMR(CDC1 3 , 8 ) . 3.01(3H, s), 4.68(2H, s), 5.61(2H, s),
6.71(1H, d, J=7.5Hz), 7.24-7.29(1H, m), 7.38(1H, t, J=7.7Hz),
7.44(1H, s), 7.52(2H, d, J=8.2Hz), 7.92(1H, d, J=8.4Hz).
Pr~dLGt~on Example 41
Production of 1-(biphenyl-4-ylmethyl)-6-chloromethyl-2-methyl-
benzimidazole
Two milliliters of thionyl chloride were added to a
solution of 3.62 g of 1-(biphenyl-4-ylmethyl)-6-hydoroxymethyl-
2-methylbenzimidazole in 30 ml of chloroform at room temperature,
and the mixture was stirred at 60°C for 1 hour. A sodium
hydrogencarbonate aqueous solution was added thereto to stop the
reaction. The chloroform layer was washed with water, and was
4
CA 02241186 1998-06-23
128
dried. The solvent was distilled off under reduced pressure, and
the residue was crystallized from ethyl acetate. The crystals
were separated through filtration, washed with ethyl acetate,
and then dried to give 2.04 g of 1-(biphenyl-4-ylmethyl)-6-
chloromethyl-2-methylbenzimidazole.
Properties of the compound:
1 H-NMR(CDCl 3 , ~ ) . 2.67(3H, s), 4.71(2H, s), 5.40(2H, s),
7.12(2H, d, J=8.2Hz), 7.31-7.38(3H, m), 7.43(2H, t), 7.52-
7.58(4H, m), 7.75(1H, d, J=8.2Hz).
prOdLGtion example 42
Production of 1-(2-chlorobenzyl)-6-formyl-2-methylbenzimidazole
Manganese dioxide (3.46 g) was added to a solution of 3.46
g of 1-(2-chlorobenzyl)-6-hydroxymethyl-2-methylbenzimidazole in
100 ml of toluene, and toluene was heat-refluxed for 3.5 hours
while the mixture was dehydrated using a molecular sieve 4A. The
solid material was separated through filtration, and was washed
with chloroform. The filtrate was concentrated to give 3.35 g of
1-(2-chlorobenzyl)-6-formyl-2-methylbenzimidazole.
Properties of the compound:
1 H-NMR(CDCl 3 , ~ ) . 2.61(3H, s), 5.48(2H, s), 6.42(1H, d,
J=7.8Hz), 7.11(1H, t, J=7.6Hz), 7.27(1H, t), 7.48(1H, d,
J=8.OHz), 7.76(1H, s), 7.81(1H, dd, J=1.4 and 8.3Hz), 7.86(1H, d,
J=8.3Hz), 10.02(1H, s).
IR(KBr) . 1676cm 1.
mp . 124.1-125.2°C
p_rnc_3LGti on Example 43
Production of 1-(2-chlorobenzyl)-2-methylbenzimidazole-6-
acetonitrile
Potassium cyanate (0.450 g) and 0.450 g of 18-crown-6 were
added to a solution of 1.20 g of 1-(2-chlorobenzyl)-6-
chloromethyl-2-methylbenzimidazole in 10 ml of dimethylsulfoxide,
and the mixture was stirred at room temperature for 18 hours.
The reaction mixture was extracted with the addition of
chloroform, water and a small amount of aqueous ammonia. The
organic layer was concentrated, and the residue was purified
A
CA 02241186 1998-06-23
129
through silica-gel column chromatography (eluent: a mixture of
chloroform and methanol at a ratio of 20:1) to give 0.500 g of
1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acetonitrile.
Properties of the compound:
1 H-NMR(CDC1 3 , 8 ) . 2.52(3H, s), 3.80(2H, s), 5.37(2H, s),
6.40(1H, d, J=7.6Hz), 7.09(1H, t), 7.10-7.19(2H, m), 7.23(1H, t),
7.44(1H, d, J=7.9Hz), 7.70(1H, d, J=8.2Hz).
producti on Examp.~ 44
Production of 6-carboxy-1-(2-chlorobenzyl)benzimidazole
To 0.490 g of 4-amino-3-(2-chlorobenzyl)aminobenzoic acid
formed by the method described in U. S. Patent No. 5,294,631
were added 0.5 ml of 98 % formic acid, and the mixture was
refluxed for 1 hour. The solid material precipitated was
collected, washed with water, and dried to give 0.468 g of 6-
carboxy-1-(2-chlorobenzyl)benzimidazole.
Properties of the compound:
1H-NMR(DMSO-d6, ~) . 5.69(2H, s), 7.02(1H, dct; J=1.5 and 7.7Hz),
7.30(1H, t, J=7.5Hz), 7.36(1H, dt, J=1.7 and 7.5Hz), 7.53(1H, dd,
J=1.3 and 7.9Hz), 7.75(1H, d, J=8.4Hz), 7.83(1H, dd, J=1.5 and
8.4Hz), 8.09(1H, s), 8.54(1H, s), 12.8(1H, br s)
Example 93
Synthesis of 1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-methyl-
benzimidazole (92)
One-hundred grams of 2-chlorobenzyl bromide were added to
a solution of 86.0 g of ethyl 4-acetylamino-3-aminobenzoate and
37.3 g of potassium carbonate in 750 ml of ethanol, and the
mixture was stirred at 60°C for 14 hours. The solid material was
separated through filtration, and the filtrate was concentrated
to 500 ml under reduced pressure. Then, 38.7 g of 35
hydrochloric acid were added thereto, and the mixture was
stirred at 60°C for 2 hours. The solid material was separated
through filtration, and the residue was neutralized with sodium
hydrogencarbonate. Ethanol was distilled off under reduced
pressure. The residue was extracted three times with ethyl
acetate and with water. The organic layer was washed with water,
CA 02241186 1998-06-23
130
and was dried. The solvent was distilled off until the amount of
the organic layer reached 300 ml. The crystals precipitated were
separated through filtration, and were recrystallized from
ethanol to obtain 54.3 g of 1-(2-chlorobenzyl)-6-ethoxycarbonyl-
2-methylbenzimidazole(192). The filtrate was also all collected,
and was concentrated. The resulting crystals were recrystallized
from ethanol to give 18.1 g of 1-(2-chlorobenzyl)-6-
ethoxycarbonyl-2-methylbenzimidazole (92).
Properties of Compound (92):
1H-NMR(CDC13, ~) . 1.39(3H, t, J=7.lHz), 2.57(3H, s), 4.37(2H, q,
J=7.lHz), 5.46(2H, s), 6.41(1H, d, J=7.8Hz), 7.10(1H, t,
J=7.8Hz), 7.25(1H, t), 7.47(1H, d, J=8.OHz), 7.75(1H, d,
J=8.4Hz), 7.94(1H, s), 8.00(1H, dd, J=1.5 and 8.4Hz)
mp . 126.0-127.0°C.
Example 94
Synthesis of 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole
(121)
To 60.0 g of 1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-
methylbenzimidazole were added 240 g of a 10 % sodium hydroxide
aqueous solution and 200 ml of ethanol, and the mixture was
heat-refluxed for 2 hours. The reaction solution was cooled, and
was then adjusted to a pH of 6 with 10% hydrochloric acid. The
crystals precipitated were separated through filtration, and
were dried to give 54.7 g of 6-carboxy-1-(2-chlorobenzyl)-2-
methylbenzimidazole (121).
Properties of Compound (121):
1 H-NMR(DMSO-d6, ~ ) . 2.51(3H, s), 5.62(2H, s), 6.54(1H, d,
J=7.7Hz), 7.23(1H, t, J=7.5Hz), 7.33(1H, t, J=7.7Hz), 7.55(1H, d,
J=8.OHz), 7.63(1H, d, J=8.4Hz), 7.79(1H, d, J=8.4Hz), 7.95(1H,
s).
mp . 300.8-303.0°C.
~,xa~pl a 95
Synthesis of 1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acetic
acid (160)
To 0.500 g of 1-(2-chlorobenzyl)-2-methylbenzimidazole-6-
w
CA 02241186 1998-06-23
131
acetonitrile was added 10 % hydrochloric acid, and the mixture
was heat-refluxed for 15 hours. The reaction mixture was
neutralized with a saturated aqueous solution of sodium
hydrogencarbonate, and was extracted with chloroform. The
organic layer was concentrated, and was purified through silica-
gel column chromatography (eluent: a mixture of chloroform and
methanol at a ratio of 9:1 to 4:1) to give 0.170 g of 1-(2-
chlorobenzyl)-2-methylbenzimidazole-6-acetic acid (160).
Properties of Compound (160):
1 H-NMR(CDC1 3 , S ) . 2.42(3H, s), 3.56(2H, s), 5.15(2H, s),
6.33(1H, d), 6.96(1H, t), 7.03(1H, s), 7.13(2H, m), 7.35(1H, d,
J=7.9Hz), 7.62(1H, d), 8.90(1H, br s)
.xample 96
Synthesis of methyl 1-(2-chlorobenzyl)-2-methylbenzimidazole-6-
acrylate
Methyl trifluorophosphoranilacetate (4.49 g) was added to
a solution of 2.73 g of 1-(2-chlorobenzyl)-6-formyl-2-
methylbenzimidazole in 50 ml of 1,4-dioxane, and the mixture was
stirred for 6 hours while being heat-refluxed. After the
reaction solution was cooled, the solvent was distilled off
under reduced pressure, and the residue was purified through
silica-gel chromatography (eluent: a mixture of chloroform and
methanol at a ratio of 9: 1 ) to obtain 7 .43 g of crude methyl 1-
(2-chlorobenzyl)-2-methylbenzimidazole-6-acrylate (161). This
crude product was used in the subsequent reaction at once.
.xa yl~ 97
Synthesis of 1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acrylic
acid
The above-mentioned crude methyl 1-(2-chlorobenzyl)-2-
methylbenzimidazole-6-acrylate (3.29 g) was dissolved in 20 ml
of ethanol, and 10.1 g of a 5% sodium hydroxide aqueous solution
were added thereto . The mixture was refluxed for 2 hours . The
reaction solution was neutralized with a hydrochloric acid
aqueous solution. The solvent was distilled off under reduced
pressure, and the residue was purified through silica-gel
CA 02241186 1998-06-23
r 132
chromatography (eluent: a mixture of chloroform and methanol at
a ratio of from 9:1 to 6:1) to give 1.10 g of 1-(2-
chlorobenzyl)-2-methylbenzimidazole-6-acrylic acid.
Properties of Compound (162):
1 H-NMR(DMSO-d6, ~ ) . 2.56(3H, s), 5.65(2H, s), 6.54(1H, d,
J=15.9Hz), 6.62(1H, d, J=7.6Hz), 7.25(1H, t), 7.35(1H, t),
7.56(1H, d, J=8.lHz), 7.60-7.70(3H, m), 7.99(1H, s), 12.35(1H,
br s)
Example 98
Synthesis of 6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-
methylbenzimidazole (163)
N,N'-carbonyldiimidazole (45.8 g) was added at a time to a
solution of 45.0 g of 6-carboxy-1-(2-chlorobenzyl)-2-
methylbenzimidazole in 950 ml of N,N-dimethylformamide, and the
mixture was stirred at room temperature for 1 hour. Subsequently,
47.1 g of benzenesulfonamide and 35.0 g of diazabicycloundecene
were added thereto, and the mixture was stirred at 100°C for 70
hours. The reaction solution was cooled, and the solvent was
distilled off under reduced pressure. To the residue were added
300 ml of water and 200 ml of methanol. Further, 60.7 g of 35
hydrochloric acid were added thereto to adjust the solution to a
pH of 5.5. The crystals precipitated were separated through
filtration, washed with 200 ml of a mixed solution of methanol
and water ( at a ratio of 1 : 1 ) , and dried to obtain 38.4 g of 6-
benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methyl-
benzimidazole. Water was added to the filtrate. The crystals
precipitated were separated through filtration, washed with
water, and dried. The amount of the crystals was 13.3 g. The
crystals were combined, and were dissolved by being heated with
the addition of 3300 ml of acetone and 900 ml of water. From
this solution, 200 ml of the solvent were distilled off while
being heated, and the residue was cooled. The crystals
precipitated were separated through filtration, and were dried
to give 33.8 g of 6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-
2-methylbenzimidazole (163).
CA 02241186 1998-06-23
133
Properties of Compound (163):
1 H-NMR(DMSO-d6, ~ ) . 2.53(3H, s), 5.46(2H, s), 6.34(1H, d,
J=7.8Hz), 7.11(1H, m), 7.27(1H, m), 7.48(1H, m), 7.52(2H, m),
7.60(1H, m), 7.69(lH,d, J=8.6Hz), 7.90(1H, m), 8.09(2H, m),
8.11(1H, s), 11.84(1H, br s).
IR(KBr) . 1684, 1448cm 1.
Mass(FAB) . m/e 440(M+1).
mp . 273.5-274.3°C.
Example 99
Synthesis of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-
2-ethylbenzimidazole (164)
In the same manner as in Example 98, 0.473 g of 6-
benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-ethyl-
benzimidazole (164) were formed from 0.600 g of 1-(biphenyl-4-
ylmethyl)-2-ethyl-6-carboxybenzimidazole, 0.546 g of N,N'-
carbonyldiimidazole, 0.529 g of benzenesulfonamide and 0.512 g
of diazabicycloundecene.
Properties of Compound (164):
1H-NMR(DMSO-d6, ~) . 1.29(3H, t, J=7.4Hz), 2.88(2H, q, J=7.4Hz),
5.59(2H, s), 7.16(2H, d, J=8.2Hz), 7.33-7.37(1H, m), 7.44(2H, t,
J=7.5Hz), 7.59-7.71(8H, m), 7.74(1H, dd, J=8.4 and l.4Hz), 7.98-
8.02(2H, m), 8.21(1H, s), 12.43(1H, s).
IR(KBr) . 1684cm-1.
mp . 149.5-157.0°C
Example 100
Synthesis of 5-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-
methylbenzimidazole (165)
In the same manner as in Example 98, 0.480 g of 5-
benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methyl-
benzimidazole (165) were formed from 0.450 g of 5-carboxy-1-(2-
chlorobenzyl)-2-methylbenzimidazole, 0.485 g of N,N'-
carbonyldiimidazole, 0.470 g of benzenesulfonamide and 0.456 g
of diazabicycloundecene.
Properties of Compound (165):
1 H-NMR(DMSO-d6, 8 ) . 2.53(3H, s), 5.61(2H, s), 6.57(1H, d,
CA 02241186 1998-06-23
134
J=7.4Hz), 7.22(1H, t), 7.33(1H, t), 7.50(1H, d, J=8.6Hz),
7.54(1H, dd, J=7.9 and 0.9Hz), 7.63(2H, t), 7.71(2H, m), 8.00(2H,
d, J=7.3Hz), 8.21(1H, d, J=l.4Hz), 12.50(1H, br s).
IR(KBr) . 1685cm 1.
mp . 137.0-138.5°C.
E~ple 101
Synthesis of 5-(4-chlorobenzenesulfonylcarbamoyl)-1-(2-chloro-
benzyl)-2-methylbenzimidazole (166)
In the same manner as in Example 98, 0.520 g of 5-(4-
chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methyl-
benzimidazole (166) were formed from 0.450 g of 5-carboxy-1-(2-
chlorobenzyl)-2-methylbenzimidazole, 0.485 g of N,N'-
carbonyldiimidazole, 0.573 g of 4-chlorobenzenesulfonamide and
0.456 g of diazabicycloundecene.
Properties of Compound (166):
1 H-NMR(DMSO-d6, ~ ) . 2.49(3H, s), 5.58(2H, s), 6.51(1H, d,
J=7.6Hz), 7.21(1H, t), 7.32(1H, t), 7.45(1H, d, J=8.6Hz),
7.53(1H, d, J=7.8Hz), 7.69(3H, d, J=8.6Hz), 7.99(2H, d, J=8.6Hz),
8.18(1H, s), 12.58(IH, br s).
IR(KBr) . 1619cm 1.
mp . 261.5-263.0°C
Exa ple 102
Synthesis of 1-(2-chlorobenzyl)-2-methyl-5-(2-naphthalene-
sulfonylcarbamoyl)benzimidazole (167)
In .the same manner as in Example 98, 0.352 g of 1-(2-
chlorobenzyl)-2-methyl-5-(2-naphthalenesulfonylcarbamoyl)-
benzimidazole (167) were formed from 0.450 g of 5-carboxy-1-(2-
chlorobenzyl)-2-methylbenzimidazole, 0.485 g of N,N'-
carbonyldiimidazole, 0.620 g of 2-naphthalenesulfonamide and
0.456 g of diazabicycloundecene.
Properties of Compound (167):
1 H-NMR(DMSO-d6, S ) . 2.48(3H, s), 5.56(2H, s), 6.49(1H, d,
J=7.7Hz), 7.20(1H, t, J=7.6Hz), 7.31(1H, t, J=7.7Hz), 7.44(1H, d,
J=8.6Hz), 7.52(1H, d, J=8.OHz), 7.66-7.75(3H, m), 7.97(1H, d,
J=8.8Hz), 8.04(1H, d, J=8.OHz), 8.14(1H, d, J=8.8Hz), 8.19(1H,
CA 02241186 1998-06-23
135
s), 8.23(1H, d, J=8.OHz), 8.68(1H, s), 12.55(1H, br s).
IR(KBr) . 1685ciri 1.
mp . 236.5-238.0°C
Example 103
Synthesis of 1-(2-chlorobenzyl)-6-methanesulfonylcarbamoyl-2-
methylbenzimidazole (168)
In the same manner as in Example 98, 0.564 g of 1-(2-
chlorobenzyl)-6-methanesulfonylcarbamoyl-2-methylbenzimidazole
(168) were formed from 0.500 g of 6-carboxy-1-(2-chlorobenzyl)-
2-methylbenzimidazole, 0.539 g of N,N'-carbonyldiimidazole,
0.316 g of methanesulfonamide and 0.506 g of
diazabicycloundecene.
Properties of Compound (168):
1H-NMR(DMSO-d6, ~ ) . 2.49(3H, s), 3.35(3H, s), 5.60(2H, s),
6.43(1H, d, J=7.8Hz), 7.23(1H, t), 7.34(1H, t, J=7.7Hz), 7.57(1H,
d, J=8.OHz), 7.68(1H, d, J=8.5Hz), 7.81(1H, dd, J=1.7 and 8.5Hz),
8.13(1H, d, J=l.5Hz), 11.94(1H, br s).
IR(KBr) . 1670cn1 1.
mp . 302.0-303.0°C
F'.xa p1 a 104
Synthesis of 6-(1-butanesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-
methylbenzimidazole (169)
In the same manner as in Example 98, 0.595 g of 6-(1-
butanesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methyl-
benzimidazole (169) were formed from 0.500 g of 6-carboxy-1-(2-
chlorobenzyl)-2-methylbenzimidazole, 0.539 g of N,N'-
carbonyldiimidazole, 0.456 g of 1-butanesulfonamide and 0.506 g
of diazabicycloundecene.
Properties of Compound (169):
1H-NMR(DMSO-d6, ~) . 0.84(3H, t, J=7.4Hz), 1.38(2H, m), 1.65(2H,
m), 2.49(3H, s), 3.49(2H, m), 5.60(2H, s), 6.44(1H, d, J=7.6Hz),
7.23(1H, t, J=7.6Hz), 7.35(1H, t), 7.56(1H, d, J=8.OHz), 7.68(1H,
d, J=8.4Hz), 7.80(1H, dd, J=1.6 and 8.4Hz), 8.11(1H, d, J=l.4Hz),
11.86(1H, br s).
IR(KBr) . 1684cra 1.
CA 02241186 1998-06-23
136
mp . 214.0-217.0°C
Synthesis of 1-(2-chlorobenzyl)-2-methyl-6-(1-octanesulfonyl-
carbamoyl)benzimidazole (170)
In the same manner as in Example 98, 0.309 g of 1-(2-
chlorobenzyl)-2-methyl-6-(1-octanesulfonylcarbamoyl)-
benzimidazole (170) were formed from 0.400 g of 6-carboxy-1-(2-
chlorobenzyl)-2-methylbenzimidazole, 0.431 g of N,N'-
carbonyldiimidazole, 406 g of 1-octanesulfonamide and 0.404 g of
diazabicycloundecene.
Properties of Compound (170):
1H-NMR(DMSO-d6, ~ ) . 0.82(3H, t, J=7.3Hz), 1.13-1.28(8H, m),
1.32-1.41(2H, m), 1.62-1.71(2H, m), 2.50(3H, s), 3.50(2H, t,
J=8.5Hz), 5.61(2H, s), 6.45(1H, d, J=7.7Hz), 7.24(1H, t,
J=7.5Hz), 7.35(1H, t, J=7.5Hz), 7.58(1H, d, J=8.OHz), 7.69(1H, d,
J=8.4Hz), 7.81(1H, d, J=8.5Hz), 8.12(1H, s), 11.86(1H ,s).
IR(KBr) . 1674cm 1.
mp . 180.0-183.0°C
Example 106
Synthesis of 1-(2-chlorobenzyl)-2-methyl-6-(2-propanesulfonyl-
carbamoyl)benzimidazole (171)
In the same manner as in Example 98, 0.417 g of 1-(2-
chlorobenzyl)-2-methyl-6-(2-propanesulfonylcarbamoyl)-
benzimidazole (171) were formed from 0.400 g of 6-carboxy-1-(2-
chlorobenzyl)-2-methylbenzimidazole, 0.431 g of N,N'-
carbonyldiimidazole, 0.328 g of 2-propanesulfonamide and 0.404 g
of diazabicycloundecene.
Properties of Compound (171):
1H-NMR(DMSO-d6, (S ) . 1.30(6H, d, J=6.9Hz), 2.50(3H, s), 3.81-
3.87(1H, m), 5.62(2H, s), 6.46(1H, d, J=7.7Hz), 7.25(1H, t,
J=7.5Hz), 7.35(1H, t, J=7.5Hz), 7.62(1H, d, J=7.9Hz), 7.69(1H, d,
J=8.5Hz), 7.81(1H, d, J=8.6Hz), 8.12(1H, s), 11.83(1H, s).
IR(KBr) . 1670cm 1.
mp . 215.0-217.5°C.
Example 107
CA 02241186 1998-06-23
137
Synthesis of 1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonyl-
carbamoyl)-2-methylbenzimidazole (172)
In the same manner as in Example 98, 0.349 g of 1-
(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-methyl-
benzimidazole (172) were formed from 0.300 g of 1-(biphenyl-4-
ylmethyl)-6-carboxy-2-methylbenzimidazole, 0.323 g of N,N'-
carbonyldiimidazole, 0.273 g of 1-butanesulfonamide and 0.303 g
of diazabicycloundecene.
Properties of Compound (172)
1H-NMR(DMSO-d6, ~ ) . 0.85(3H, t, J=7.4Hz), 1.36-1.43(2H, m),
1.63-1.72(2H, m), 2.57(3H, s), 3.52(2H, t, J=7.7Hz), 5.60(2H, s),
7.21(2H, d, J=8.2Hz), 7.35(1H, t, J=7.3Hz), 7.44(2H, t, J=7.5Hz),
7.60-7.68(5H, m), 7.81(1H, dd, J=1.6 and 8.4Hz), 8.26(1H, d,
J=l.4Hz), 11.97(1H, s).
IR(KBr) . 1676ciri 1.
mp . 219.5-222.5°C
Example 108
Synthesis of 6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichloro-
benzyl)-2-methylbenzimidazole (173)
In the same manner as in Example 98, 0.459 g of 6-(1-
butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methyl-
benzimidazole (173) were formed from 0.400 g of 6-carboxy-1-
(2,4-dichlorobenzyl)-2-methylbenzimidazole, 0.431 g of N,N'-
carbonyldiimidazole, 0.364 g of 1-butanesulfonamide and 0.404 g
of diazabicycloundecene.
Properties of Compound (173):
1H-NMR(DMSO-d6, ~ ) . 0.85(3H, t, J=7.3Hz), 1.36-1.42(2H, m),
1.63-1.70(2H, m), 2.50(3H, s), 3.51(2H, t, J=7.7Hz), 5.59(2H, s),
6.45(1H, d, J=8.4Hz), 7.33(1H, dd, J=2.1 and 8.4Hz), 7.69(1H, d,
J=8.4Hz), 7.76(IH, d, J=2.OHz), 7.81(1H, dd, J=1.7 and 8.5Hz),
8.11(1H, d, J=l.3Hz), 11.90(1H, s).
IR(KBr) . 1670cm-1
mp . 222.0-223.0°C
Synthesis of 1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonyl-
CA 02241186 1998-06-23
138
carbamoyl)-2-ethylbenzimidazole (174)
In the same manner as in Example 98, 0.300 g of 1-
(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-
ethylbenzimidazole (174) were formed from 0.300 g of 1-
(biphenyl-4-ylmethyl)-6-carboxy-2-ethylbenzimidazole, 0.340 g of
N,N'-carbonyldiimidazole, 0.300 g of butanesulfonamide and 0.320
g of diazabicycloundecene.
Properties of Compound (174):
1H-NMR(DMSO-d6, ~) . 0.85(3H, t, J=7.3Hz), 1.30(3H, t, J=7.5Hz),
1.35-1.44(2H, m), 1.64-1.72(2H, m), 2.90(2H, q, J=7.4Hz),
3.52(2H, t, J=7.7Hz), 5.6I(2H, s), 7.19(2H, d, J=8.3Hz), 7.35(1H,
t, J=7.3Hz), 7.44(2H, t, J=7.5Hz), 7.61-7.67(4H, m), 7.71(IH, d,
J=8.5Hz), 7.82(1H, dd, J=1.6 and 8.5Hz), 8.27(1H, d, J=l.3Hz),
12.01(1H, s).IR(Nujol) . 1687,1682cm-1
mp . 171.8-173.0°C
Example 110
Synthesis of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-
2-trifluoromethylbenzimidazole (175)
In the same manner as in Example 98, 0.508 g of 6-
benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-trifluoro-
methylbenzimidazole (175) were formed. from 0.483 g of 1-
(biphenyl-4-ylmethyl)-6-carboxy-2-trifluoromethylbenzimidazole,
0.396 g of N,N'-carbonyldiimidazole, 0.383 g of
benzenesulfonamide and 0.371 g of diazabicycloundecene.
Properties of Compound (175):
1H-NMR(DMSO-d6, ~) . 5.81(2H, s), 7.15(2H, d, J=8.3Hz), 7.35(1H,
t, J=7.5Hz), 7.44(2H, t, J=7.5Hz), 7.60-7.66(6H, m), 7.70(1H, t,
J=7.4Hz), 7.91(1H, dd, J=8.7 and l.4Hz), 7.96-8.01(3H, m),
8.42(1H, s), 12.65(1H, s).
IR(KBr) . 1685cm 1.
mp . 164.5-167.0°C
Example 111
Synthesis of 5-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-
2-trifluoromethylbenzimidazole (176)
In the same manner as in Example 98, 0.286 g of 5-
CA 02241186 1998-06-23
139
benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-trifluoro-
methylbenzimidazole (176) were formed from 0.270 g of 1-
(biphenyl-4-ylmethyl)-5-carboxy-2-trifluoromethylbenzimidazole,
0.221 g of N,N'-carbonyldiimidazole, 0.214 g of
benzenesulfonamide and 0.207 g of diazabicycloundecene.
Properties of Compound (176):
1H-NMR(DMSO-d6, ~) . 5.79(2H, s), 7.15(2H, d, J=8.lHz), 7.35(1H,
t, J=7.5Hz), 7.43(2H, t, J=7.5Hz), 7.59-7.67(6H, m), 7.72(1H, t,
J=7.6Hz), 7.83(1H, d, J=8.8Hz), 7.94(1H, d, J=8.9Hz), 8.02(2H, d,
J=7.4Hz), 8.49(1H, s), 12.69(1H, s).
IR(KBr) . 1699cm
mp . 248.5-251.0°C
Example 112
Synthesis of 6-benzenesulfonylcarbamoyl-2-cyclopropyl-1-(2-
fluorobenzyl)benzimidazole (177)
In the same manner as in Example 98, 0.730 g of 6-
benzenesulfonylcarbamoyl-2-cyclopropyl-1-(2-fluorobenzyl)-
benzimidazole (177) were formed from 0.930 g of 6-carboxy-2-
cyclopropyl-1-(2-fluorobenzyl)benzimidazole, 0.972 g of N,N'-
carbonyldiimidazole, 0.942 g of benzenesulfonamide and 0.906 g
of diazabicycloundecene.
Properties of Compound (177):
1H-NMR (DMSO-d6, ~) . 1.04 (4H, m), 2.15 (1H, m), 5.70 (2H, s),
6.85 (1H, t, J=7.5Hz), 7.12 (1H, t, J=7.5Hz), 7.22-7.38 (2H, m),
7.54-7.70 (5H, m), 7.99 (2H, d, J=7.5Hz), 8.11 (1H, s)
white powder.
Examgle 113
Synthesis of N-benzenesulfonyl-3-[1-(2-chlorobenzyl)-2-methyl-
benzimidazol-6-yl]acrylamide (178)
In the same manner as in Example 98, 1.05 g of N-
benzenesulfonyl-3-[1-(2-chlorobenzyl)-2-methylbenzimidazol-6-
yl]acrylamide (178) were formed from 1.10 g of 1-(2-
chlorobenzyl)-2-methylbenzimidazole-6-acrylic acid, 1.09 g of
N,N'-carbonyldiimidazole, 1.06 g of benzenesulfonamide and 1.02
g of diazabicycloundecene.
CA 02241186 1998-06-23
140
Properties of Compound (178):
1H-NMR(DMSO-d6, ~) . 2.47(3H ,s), 5.55(2H, s), 6.46-6.55(2H, m),
7.22(1H, t, J=7.6Hz), 7.32(1H, t, J=7.7Hz), 7.40(1H, d, J=8.4Hz),
7.52-7.66(6H, m), 7.69(1H, t), 7.93(2H, d, J=7.9Hz), 12.17(1H,
br s).
IR(KBr) . 1687ctn 1.
Mass(FAB) . m/e 466(M+1).
mp . 243.1-244.3°C
Example 114
Synthesis of N-benzenesulfonyl-2-[1-(2-chlorobenzyl)-2-methyl-
benzimidazol-6-yl]acetamide (179)
In the same manner as in Example 98, 0.09 g of N-
benzenesulfonyl-2-[1-(2-chlorobenzyl)-2-methylbenzimidazol-6-
yl]acetamide (179) were formed from 0.170 g of 1-(2-
chlorobenzyl)-2-methylbenzimidazole-6-acetic acid, 0.175 g of
N,N~-carbonyldiimidazole, 0.170 g of benzenesulfonamide and
0.164 g of diazabicycloundecene.
Properties of Compound (179):
1H-NMR(DMSO-d6, ~ ) . 2.44(3H, s), 3.57(2H, s), 5.46(2H, s),
6.41(1H, d, J=7.7Hz), 6.96(1H, d, J=7.OHz), 7.16(1H, s), 7.20(1H,
t), 7.32(1H, t), 7.47(1H, d, J=8.2Hz), 7.52-7.59(3H, m), 7.67(1H,
t, J=7.5Hz), 7.84(2H, d, J=7.4Hz), 12.28(1H, br s).
IR(KBr) 1719cm 1.
mp . 236.2-237.8°C
Example 115
Synthesis of 1-(2,4-dichlorobenzyl)-2-methyl-6-[(2-pyridyl-
methyl)carbamoyl]benzimidazole (180)
Dichloromethane (150 ml) and some drops of N,N-
dimethylformamide were added to 9.00 g of 6-carboxy-1-(2,4-
dichlorobenzyl)-2-methylbenzimidazole, and the mixture was
cooled with ice. Oxalyl chloride (6.84 g) were added dropwise
thereto, and the mixed solution was stirred for some minutes.
Further, this solution was stirred at room temperature for 1.5
hours, and was then concentrated to a volume of approximately
1/3 of the original volume under reduced pressure. The solid
CA 02241186 1998-06-23
141
material precipitated was collected, and was added to a solution
of 2.69 g of 2-aminomethylpyridine and 7.34 g of triethylamine
in 200 ml of dichloromethane in some divided portions. After the
mixture was stirred for 15 hours, the reaction solution was
washed three times with water and then with a saturated aqueous
solution of sodium hydrogencarbonate. The organic layer was
concentrated under reduced pressure, and was crystallized from
ethyl acetate. The crystals were separated through filtration,
and were dried to give 4.35 g of 1-(2,4-dichlorobenzyl)-2-
methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (180).
Properties of Compound (180):
1H-NMR(CDC13, ~ ) . 2.56(3H, s), 4.76(2H, d, J=4.8Hz), 5.40(2H,
s), 6.33(1H, d, J=8.4Hz), 7.07(1H, dd, J=8.4 and 2.OHz), 7.22(1H,
dd, J=7.4 and 4.9Hz), 7.33(1H, d, J=7.9Hz), 7.48(1H, d, J=2.lHz),
7.62-7.79(4H, m), 7.86(1H, d, J=l.lHz)8.57, (1H, d, J=4.9Hz).
IR(KBr) . 1645ciri
mp . 204.5-206.5°C
Example 116
Synthesis of 1-methyl-2-n-propyl-6-[(2-pyridylmethyl)-
carbamoyl]benzimidazole (181)
In the same manner as in Example 115, 0.213 g of 1-methyl-
2-n-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (181)
were formed from 0.402 g of 6-carboxy-1-methyl-2-n-
propylbenzimidazole, 0.468 g of oxalyl chloride, 0.199 g of 2-
aminomethylpyridine and 0.559 g of triethylamine.
Properties of Compound (181):
1H-NMR(CDC13, 8 ) . 1.08(3H, t, J=7.4Hz) 1.92(2H, m) 2.88(2H,
m) 3.76(3H, s) 4.80(2H, d, J=4.8Hz), 7.22(1H, dd, J=2.5 and
7.5Hz), 7.35(1H, d, J=7.8Hz), 7.67-7.77(4H, m), 7.80(1H, s),
8.58(1H, dd, J=4.9 and 0.9Hz).
IR(KBr) . 1647cm 1.
mp . 140.5-141.5°C
Example 117
Synthesis of 1-(2-chlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)-
carbamoyl]benzimidazole (182)
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142
In the same manner as in Example 115, 0.164 g of 1-(2-
chlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole (182) were formed from 0.300 g of 6-carboxy-1-(2-
chlorobenzyl)-2-methylbenzimidazole, 0.253 g of oxalyl chloride,
0.108 g of 2-aminomethylpyridine and 0.302 g of triethylamine.
Properties of Compound (182):
1H-NMR(CDC13, S ) . 2.56(3H, s), 4.76(2H, d, J=4.8Hz), 5.45(2H,
s), 6.40(1H, d, J=7.8Hz), 7.08(1H, t, J=7.6Hz), 7.20-7.27(2H, m),
7.33(1H, d, J=7.8Hz), 7.45(1H, dd, J=0.9 and 8.lHz), 7.64(1H, s),
7.65-7.69(1H, m), 7.72(1H, dd, J=1.5 and 8.4Hz), 7.77(1H, d,
J=8.4Hz), 7.88(1H, d, J=l.2Hz), 8.56(1H, d, J=4.7Hz).
IR(KBr) . 1646cm 1.
mp . 156.5-157.5°C
Example 118
Synthesis of 2-n-propyl-1-i-propyl-6-[(2-pyridylmethyl)-
carbamoyl]benzimidazo1e (183)
In the same manner as in Example 115, 0.020 g of 2-n-
propyl-1-i-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole
(183) were formed from 0.095 g of 6-carboxy-2-n-propyl-1-i-
propylbenzimidazole, 0.100 g of oxalyl chloride, 0.039 g of 2-
aminomethylpyridine and 0.097 g of triethylamine.
Properties of Compound (183):
iH-NMR(CDC13, ~ ) . 1.08(3H, t, J=7.4Hz), 1.69(6H, d, J=7.lHz),
1.87-1.93(2H, m), 2.90(2H, t, J=7.8Hz), 4.69-4.75(1H, m),
4.80(2H, d, J=4.9Hz), 7.23(1H, dd, J=7.3 and 2.lHz), 7.37(1H, d,
J=7.7Hz), 7.62-7.77(4H, m), 8.21(1H, s), 8.58(1H, d, J=4.5Hz).
IR(KBr) . 1631cm-1.
mp . 155.0-156.9°C
Example 119
Synthesis of 1-n-butyl-2-n-propyl-6-[(2-pyridylmethyl)-
carbamoyl]benzimidazole (184)
In the same manner as in Example 115, 0.283 g of 1-n-
butyl-2-n-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole
(184) were formed from 0.500 g of 1-n-butyl-6-carboxy-2-n-
propylbenzimidazole, 0.487 g of oxalyl chloride, 0.208 g of 2-
CA 02241186 1998-06-23
' 143
aminomethylpyridine and 0.582 g of triethylamine.
Properties of Compound (184):
1 H-NMR(CDC1 3 , ~ ) . 0 . 97 ( 3H, t, J=7 . 3Hz ) , 1 . 08 ( 3H, t, J=7 . 4Hz
) ,
1.37-1.46(2H, m), 1.76-1.83(2H, m), 1.92-2.00(2H, m), 2.86(2H, t,
J=7.8Hz), 4.15(2H, t, J=7.6Hz), 4.81(2H, d, J=4.8Hz), 7.23(1H,
dd, J=7.3 and 2.4Hz), 7.36(1H, d, J=7.8Hz), 7.63-7.76(4H, m),
8.02(1H, s), 8.58(1H, d, J=4.7Hz).
IR(KBr) . I631cm-1.
mp . 105.8-107.2°C
Example 120
Synthesis of 1-(3-chlorobenzyl)-2-n-propyl-6-[2-pyridylmethyl)-
carbamoyl]benzimidazole (185)
In the same manner as in Example 115, 0.311 g of 1-(3-
chlorobenzyl)-2-n-propyl-6-[2-
pyridylmethyl)carbamoyl]benzimidazole (185) were formed from
0.580 g of 6-carboxy-1-(3-chlorobenzyl)-2-n-propylbenzimidazole,
0.407 g of oxalyl chloride, 0.173 g of 2-aminomethylpyridine and
0.486 g of triethylamine.
Properties of Compound (185):
1 H-NMR(CDC1 3 , ~ ) . 1.03(3H, t, J=7.4Hz), 1.85-1.93(2H, m),
2.80(2H, t, J=7.5Hz), 4.77(2H, d, J=4.8Hz), 5.36(2H, s), 6.86(1H,
d, J=7.4Hz), 7.02(1H, s), 7.20-7.28(3H, m), 7.33(1H, d, J=7.8Hz),
7.63-7.73(3H, m), 7.79(1H, d, J=8.4Hz), 7.91(1H, d, J=l.3Hz),
8.57(1H, d, J=4.7Hz).
IR(KBr) . 1643ciri 1.
mp . 157.7-158.8°C
Fxa ~1_e 1_21_
Synthesis of 1-benzyl-2-n-propyl-6-[(2-pyridylmethyl)-
carbamoyl]benzimidazole (186)
In the same manner as in Example 115, 0.350 g of 1-benzyl-
2-n-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (186)
were formed from 0.850 g of 1-benzyl-6-carboxy-2-n-
propylbenzimidazole, 0.949 g of oxalyl chloride, 0.404 g of 2-
aminomethylpyridine and 1.132 g of triethylamine.
Properties of Compound (186):
CA 02241186 1998-06-23
144
1 H-NMR(CDC1 3 , S ) . 1.01(3H, t, J=7.4Hz), 1.83-1.92(2H, m),
2.82(2H, t, J=7.6Hz), 4.77(2H, d, J=4.8Hz), 5.40(2H, s), 7.03(2H,
d, J=6.5Hz), 7.21(1H, dd, J=7.1 and 2.lHz), 7.18-7.34(4H, m),
7.60(1H, s), 7.65-7.72(2H, m), 7.78(1H, d, J=8.4Hz), 7.94(1H, d,
J=l.2Hz), 8.56(lH,d,J=4.2Hz).
IR(KBr) . 1642cm
mp . 121.9-123.1°C
Example 122
Synthesis of 1-(4-chlorobenzyl)-2-propyl-6-[(2-pyridylmethyl)-
carbamoyl]benzimidazole (187)
In the same manner as in Example 115, 0.089 g of 1-(4-
chlorobenzyl)-2-propyl-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole (187) were formed from 0.547 g of 6-carboxy-1-(4-
chlorobenzyl)-2-propylbenzimidazole, 0.384 g of oxalyl chloride,
0.163 g of 2-aminomethylpyridine and 0.458 g of triethylamine.
Properties of Compound (187):
1H-NMR(CDC13, ~) . 1.02(3H, t, J=7.4Hz), 1.84-1.92(2H, m), 2.77-
2.83(2H, m), 4.76(2H, d, J=4.8Hz), 5.36(2H, s), 6.96(2H, d,
J=8.3Hz), 7.22(1H, dd, J=6.4 and 0.4Hz), 7.27(2H, dd, J=8.3 and
l.3Hz), 7.33(1H, d, J=7.8Hz), 7.62-7.73(3H, m), 7.78(1H, d,
J=8.4Hz), 7.91(1H, d, J=0.9Hz), 8.56(1H, dd, J=4.9 and 0.8Hz).
IR(KBr) . 1643cm 1.
mp . 158.8-161.0°C
Exa ple 123
Synthesis of 2-benzyl-1-methyl-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole (188)
In the same manner as in Example 115, 0.171 g of 2-benzyl-
1-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (188) were
formed from 0.310 g of 2-benzyl-6-carboxy-1-methylbenzimidazole,
0.295 g of oxalyl chloride, 0.108 g of 2-aminomethylpyridine and
0.303 g of triethylamine.
Properties of Compound (188):
1 H-NMR(CDC1 3 , ~ ) . 3.66(3H, s), 4.35(2H, s), 4,80(2H, d,
J=4.8Hz), 7.21-7.37(7H, m), 7.66(1H, br t), 7.67-7.73(2H, m),
7.78(1H, d, J=8.4Hz), 7.98(1H, s), 8.58(1H, d, J=4.9Hz)
CA 02241186 1998-06-23
' 145
IR(KBr) . 1632ciri 1.
mp . 168.5-169.5°C.
Example I24
Synthesis of 1-(2,6-dichlorobenzyl)-2-methyl-6-[(2-pyridyl-
methyl)carbamoyl]benzimidazole (189)
In the same manner as in Example 115, 0.040 g of 1-(2,6-
dichlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole (189) were formed from 0.600 g of 6-carboxy-1-
(2,6-dichlorobenzyl)-2-methylbenzimidazole, 0.472 g of oxalyl
chloride, 0.201 g of 2-aminomethylpyridine and 0.188 g of
triethylamine.
Properties of Compound (189):
1H-NMR(CDC13, ~ ) . 2.62(3H, s), 4.76(2H, d, J=4.7Hz), 5.62(2H,
s), 7.23(1H, dd, J=7.1 and 2.2Hz), 7.28(1H, d, J=7.8Hz), 7.32(1H,
d, J=7.9Hz), 7.39(2H, d, J=8.lHz), 7.54(1H, s), 7.66-7.71(3H, m),
7.78(1H, s), 8.60(1H, d, J=4.6Hz).
IR(KBr) . 1635cm-1.
mp . 225.7-226.9°C.
Rxample 1_25
Synthesis of 2-methyl-6-[(2-pyridylmethyl)carbamoyl]-1-[2-
(trifluoromethyl)benzyl]benzimidazole (190)
In the same manner as in Example 115, 0.713 g of 2-methyl-
6-[(2-pyridylmethyl)carbamoyl]-1-[2-(trifluoromethyl)benzyl]-
benzimidazole (190) were formed from 0.970 g of 6-carboxy-2-
methyl-1-[2-(trifluoromethyl)benzyl]benzimidazole, 0.736 g of
oxalyl chloride, 0.261 g of 2-aminomethylpyridine and 0.726 g of
triethylamine.
Properties of Compound (190):
1H-NMR(CDC13, ~ ) . 2.54(3H, s), 4.76(2H, d, J=4.8Hz), 5.59(2H,
s), 6.45(1H, d, J=7.9Hz), 7.22(1H, t, J=5.8Hz), 7.34(2H, t,
J=8.8Hz), 7.40(1H, t, J=7.5Hz), 7.62(1H, br s), 7.68(1H, dt,
J=1.7 and 7.7Hz), 7.72-7.82(3H, m), 7.87(1H, s), 8.56(1H, d,
J=4.9Hz).
IR(KBr) . 1648cm 1
mp . 172-174°C
CA 02241186 1998-06-23
' 146
Example 126
Synthesis of 2-methyl-6-[(2-pyridylmethyl)carbamoyl]-1-[4-
(trifluoromethyl)benzyl]benzimidazole (191)
In the same manner as in Example 115, 0.194 g of 2-methyl-
6-[(2-pyridylmethyl)carbamoyl]-1-[4-(trifluoromethyl)benzyl]-
benzimidazole (191) were formed from 0.970 g of 6-carboxy-2-
methyl-1-[4-(trifluoromethyl)benzyl]benzimidazole, 0.736 g of
oxalyl chloride, 0.261 g of 2-aminomethylpyridine and 0.726 g of
triethylamine.
Properties of Compound (191):
1H-NMR(CDC13, ~ ) .-2.59(3H, s), 4.77(2H, d, J=4.7Hz), 5.45(2H,
s), 7.15(2H, d, J=8.2Hz), 7.23(1H, m), 7.33(1H, d, J=7.9Hz),
7.58(2H, d, J=8.2Hz), 7.63(1H, br s), 7.67-7.74(2H, m), 7.77(1H,
d, J=8.3Hz), 7.93(1H, s), 8.57(1H, d, J=4.9Hz).
IR(KBr) . 1637cm
mp . 188.5-190.0°C
Fxa ple 127
Synthesis of 1-(3,4-dichlorobenzyl)-2-methyl-6-[(2-pyridyl-
methyl)carbamoyl]benzimidazole (192)
In the same manner as in Example 115 , 0 . 264 g of 1- ( 3 , 4-
dichlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole (192) were formed from 0.500 g of 6-carboxy-1-
(3,4-dichlorobenzyl)-2-methylbenzimidazole, 0.393 g of oxalyl
chloride, 0.167 g of 2-aminomethylpyridine and 0.469 g of
triethylamine.
Properties of Compound (192):
1 H-NMR.( CDC1 3 , ~ ) . 2 . 58 ( 3H, s ) , 4 . 77 ( 2H, d, J=4 . 8Hz ) , 5 .
33 ( 2H,
s), 6.85(1H, dd, J=8.3 and 2.2Hz), 7.14(1H, d, J=2.lHz), 7.22(1H,
dd, J=7.3 and 5.6Hz), 7.33(1H, d, J=7.8Hz), 7.38(1H, d, J=8.3Hz),
7.65-7.77(4H, m), 7.92(1H, d, J=l.2Hz), 8.57(1H, d, J=4.8Hz).
IR(KBr) . 1638cm 1.
mp . 219.0-220.7°C
F-xample 128
Synthesis of 2-methyl-1-(2-methylbenzyl)-6-[(2-pyridylmethyl)-
carbamoyl]benzimidazole (193)
CA 02241186 1998-06-23
147
In the same manner as in Example 115, 0.100 g of 2-methyl-
1-(2-methylbenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole
(193) were formed fromm 0.453 g of 6-carboxy-2-methyl-1-(2-
methylbenzyl)benzimidazole, 0.411 g of oxalyl chloride, 0.175 g
of 2-aminomethylpyridine and 0.490 g of triethylamine.
Properties of Compound (193):
1 H-NMR(CDC1 3 , ~ ) . 2.42(3H, s), 2.54(3H, s), 4.75(2H, d,
J=4.9Hz), 5.32(2H, s), 6.33(1H, d, J=7.8Hz), 7.01(1H, t,
J=7.8Hz), 7.17-7.24(3H, m), 7.33(1H, d, J=7.8Hz), 7.60(1H, s),
7.63-7.73(2H, m), 7.76(1H, d, J=8.4Hz), 7.84(1H, d, J=l.4Hz),
8.56(1H, d, J=4.9Hz).
IR(KBr) . 1635cm 1.
mp . 154.0-157.0°C
F_xam~~e 129
Synthesis of 1-(2-methoxybenzyl)-2-methyl-6-[(2-pyridylmethyl)-
carbamoyl]benzimidazole (194)
In the same manner as in Example 115, 0.918 g of 1-(2-
methoxybenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole (194) were formed from 0.997 g of 6-carboxy-1-(2-
methoxybenzyl)-2-methylbenzimidazole, 0.858 g of oxalyl chloride,
0.309 g of 2-aminomethylpyridine and 1.02 g of triethylamine.
Properties of Compound (194):
1 H-NMR(CDC1 3 , ~ ) . 2.60(3H, s), 3.89(3H, s), 4.77(2H, d,
J=4.8Hz), 5.36(2H, s), 6.60(1H, d, J=7.4Hz), 6.79(1H, dt, J=0.8
and 7.4Hz), 6.91(1H,~ d, J=7.4Hz), 7.20-7.28(2H, m), 7.34(1H, d,
J=7.9Hz), 7.56(1H, br t), 7.66-7.75(3H, m), 7.95(1H, m), 8.57(1H,
d, J=4.9Hz).
IR(KBr) . 1652cm 1.
mp . 136-138.5°C
Fxa pla 130
Synthesis of 1-(4-methoxybenzyl)-2-methyl-6-[(2-pyridylmethyl)-
carbamoyl]benzimidazole (195)
In the same manner as in Example 115, 0.697 g of 1-(4-
methoxybenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole (195) were formed from 0.985 g of 6-carboxy-1-(4-
CA 02241186 1998-06-23
148
methoxybenzyl)-2-methylbenzimidazole, 0.858 g of oxalyl chloride,
0.309 g of 2-aminomethylpyridine and 1.02 g of triethylamine.
Properties of Compound (195):
1 H-NMR(CDC1 3 , ~ ) . 2.59(3H, s), 3.76(3H, s), 4.78(2H, d,
J=4.8Hz), 5.32(2H, s), 6.83(2H, m), 7.00(2H, m), 7.22(1H, dd,
J=5.1 and 6.8Hz), 7.34(1H, d, J=7.8Hz), 7.60(1H, br t), 7.67-
7.76(3H, m), 7.97(1H, d, J=l.2Hz), 8.57(1H, d, J=4.9Hz).
IR(KBr) . 1652cm 1.
mp _ 191.5-192.2°C
F_xamt~le 131
Synthesis of 1-[2-(benzenesulfonylmethyl)benzyl]-2-methyl-6-[(2-
pyridylmethyl)carbamoyl]benzimidazole (196)
In the same manner as in Example 115, 0.64 g of 1-[2-
(benzenesulfonylmethyl)benzyl]-2-methyl-6-[(2-
pyridylmethyl)carbamoyl]benzimidazole (196) were formed from
0.74 g of 1-[2-(benzenesulfonylmethyl)benzyl]-6-carboxy-2-
methylbenzimidazole, 0.45 g of oxalyl chloride, 0.19 g of 2-
aminomethylpyridine and 0.53 g of triethylamine.
Properties of Compound (196):
1 H-NMR(CDC1 3 , 8 ) _ 2.57(3H, s), 4.50(2H, s), 4.74(2H, d,
J=4.9Hz), 5.59(2H, s), 6.63(1H, d, J=7.7Hz), 6_87(1H, d, J=7.4
and l.5Hz), 7.09-7.19(3H, m), 7.31(1H, d, J=7.8Hz), 7.53-7.61(3H,
m), 7.64(1H, dt, J=7.6 and l.6Hz), 7.68-7.79(5H, m), 7.84(1H, s),
8.52(1H, d, J=4.8Hz).
IR(neat) 1646cm-1
liquid.
xample 132
Synthesis of 1-(2-cyanobenzyl)-2-methyl-6-[(2-pyridylmethyl)-
carbamoyl]benzimidazole (197)
In the same manner as in Example 115, 1.03 g of 1-(2-
cyanobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole (197) were formed from 1.14 g of 6-carboxy-1-(2-
cyanobenzyl)-2-methylbenzimidazole, 0.998 g of oxalyl chloride,
0.425 g of 2-aminomethylpyridine and 1.19 g of triethylamine.
Properties of Compound (197):
CA 02241186 1998-06-23
149
1H-NMR(CDC13, ~ ) . 2.58(3H, s), 4.76(2H, d, J=4.8Hz), 5.59(2H,
s), 6.64(1H, d, J=7.4Hz), 7.21(1H, dt, J=5.6 and l.8Hz), 7.33(1H,
d, J=7.9Hz), 7.39-7.47(2H, m), 7.65-7.79(5H, m), 7.89(1H, s),
8.56(1H, dd, J=4.9 and 0.9Hz).
IR(KBr) . 2223, 1642cm 1
mp : 150.5-151.4°C
F~xam~.~-a i 3 3
Synthesis of 1-(biphenyl-2-ylmethyl)-2-methyl-6-[(2-pyridyl-
methyl)carbamoyl]benzimidazole (198)
In the same manner as in Example 115, 0.672 g of 1-
(biphenyl-2-ylmethyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole (198) were formed from 1.07 g of 1-(biphenyl-2-
ylmethyl)-6-carboxy-2-methylbenzimidazole, 0.796 g of oxalyl
chloride, 0.339 g of 2-aminomethylpyridine and 0.950 g of
triethylamine.
Properties of Compound (198):
1H-NMR(CDC13, ~ ) . 2.38(3H, s), 4.78(2H, d, J=4.8Hz), 5.27(2H,
s), 6.64(1H, d, J=8.OHz), 7.17-7.24(2H, m), 7.29-7.43(6H, m),
7.48(2H, t, J=5.5Hz), 7.49(1H, s), 7.57-7.73(3H, m), 7.80(1H, d,
J=l.OHz), 8.58(1H, d, J=4.9Hz).
IR(KBr) . 1630, 1619cm
mp . 179.8-180.8°C
F-xamp~e 134
Synthesis of 1-benzyl-2-methyl-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole (199)
In the same manner as in Example 115, 0.66 g of 1-benzyl-
2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (199) were
formed from 0.59 g of 1-benzyl-6-carboxy-2-methylbenzimidazole,
0.56 g of oxalyl chloride, 0.24 g of 2-aminomethylpyridine and
0.67 g of triethylamine.
Properties of Compound (199):
1H-NMR(CDC13, ~ ) . 2.58(3H, s), 4.76(2H, d, J=4.9Hz), 5.36(2H,
s), 7.02-7.06(2H, m), 7.21(1H, dd, J=6.9 and 5.OHz), 7.27-
7.35(4H, m), 7.65-7.75(4H, m), 7.96(1H, d, J=0.8Hz), 8.56(1H, d,
J=4.8Hz).
CA 02241186 1998-06-23
' 150
IR(KBr) . 1640cm 1.
mp . 124.0-124.9°C
Example 135
Synthesis of 1-(4-tert-butylbenzyl)-2-methyl-6-[(2-pyridyl-
methyl)carbamoyl]benzimidazole (200)
In the same manner as in Example 115, 0.477 g of 1-(4-
tert-butylbenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole (200) were formed from 0.544 g of 1-(4-tert-
butylbenzyl)-6-carboxy-2-methylbenzimidazole, 0.428 g of oxalyl
chloride, 0.183 g of 2-aminomethylpyridine and 0.511 g of
triethylamine.
Properties of Compound (200):
1 H-NMR(CDC1 3 , ~ ) . 1.27(9H, s), 2.60(3H, s), 4.77(2H, d,
J=4.9Hz), 5.34(2H, s), 6.98(2H, d, J=8.3Hz), 7.21(1H, dd, J=7.3
and 5.lHz), 7.29-7.35(3H, m), 7.62(1H, br s), 7.65-7.75(3H, m),
7.96(1H, d, J=l.lHz), 8.57(1H, d, J =4.7Hz).
IR(KBr) . 1646cm 1.
mp . 140.4-142.8°C
Example 136_
Synthesis of 2-methyl-1-(2-naphthylmethyl)-6-[(2-pyridyl-
methyl)carbamoyl]benzimidazole (201)
In the same manner as in Example 115, 0.47 g of 2-methyl-
1-(2-naphthylmethyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole
(201) were formed from 0.80 g of 6-carboxy-2-methyl-1-(2-
naphthylmethyl)benzimidazole, 0.64 g of oxalyl chloride, 0.27 g
of 2-aminomethylpyridine and 0.77 g of triethylamine.
Properties of Compound (201):
1 H-NMR( CDC1 3 , ~ ) . 2 . 60 ( 3H, s ) , 4 . 75 ( 2H, d, J=4 . 9Hz ) , 5 .
52 ( 2H,
s), 7.17-7.23(2H, m), 7.31(1H, d, J=7.8Hz), 7.38(1H, s), 7.43-
7.48(2H, m), 7.60-7.82(7H, m), 8.00(1H, d, J=l.OHz), 8.53(1H, d,
J =4.7Hz).
IR(KBr) . 1640cm 1.
mp . 143.0-144.5°C.
Synthesis of 1-(biphenyl-4-ylmethyl)-2-ethyl-6-[(2-pyridyl-
CA 02241186 1998-06-23
151
methyl)carbamoyl]benzimidazole (202)
In the same manner as in Example 115, 0.410 g of 1-
(biphenyl-4-ylmethyl)-2-ethyl-6-[(2-
pyridylmethyl)carbamoyl]benzimidazole (202) were formed from
0.500 g of 1-(biphenyl-4-ylmethyl)-6-carboxy-2-ethyl-
benzimidazole, 0.356 g of oxalyl chloride, 0.151 g of 2-
aminomethylpyridine and 0.424 g of triethylamine.
Properties of Compound (202):
1H-NMR(CDC13, ~ ) . 1.45(3H, t, J=7.7Hz), 2.90(2H, q, J=7.4Hz),
4.77(2H, d, J=4.7Hz), 5.43(2H, s), 7.10(2H, d, J=8.2Hz), 7.20(1H,
dt, J=4.9 and 7.7Hz), 7.33(2H, t, J=7.4Hz), 7.42(2H, t, J=7.5Hz),
7.49-7.55(4H, m), 7.61(1H, br t), 7.67(1H, dt, J=7.8 and l.8Hz),
7.72(1H, d, J=8.4Hz), 7.81(1H, d, J=8.4Hz), 7.99(1H, s), 8.56(1H,
d, J=4.9Hz).
IR(KBr) . 1640cm 1.
mp . 123.0-124.0°C
Fxa X71 a 13 8
Synthesis of 1-(2-chlorobenzyl)-6-[2-(pyridylmethyl)-
carbamoyl]benzimidazole (203)
In the same manner as in Example 115, 0.110 g of 1-(2-
chlorobenzyl)-6-[2-(pyridylmethyl)carbamoyl]benzimidazole (203)
were formed from 0.461 g of 6-carboxy-1-(2-
chlorobenzyl)benzimidazole, 0.728 g of oxalyl chloride, 0.174 g
of 2-aminomethylpyridine and 0.486 g of triethylamine.
Properties of Compound (203):
1H-NMR(CDC13, ~) . 4.78(2H, d, J=4.8Hz), 5.5I(2H, s), 6.92(1H, d,
J=6.5Hz), 7.17-7.31(3H, m), 7.34(1H, d, J=7.8Hz), 7.45(1H, dd,
J=1.1 and 8.OHz), 7.69(1H, dt, J=1.8 and 7.7Hz), 7.67-7.73(1H,
br s), 7.76(1H, dd, J=1.5 and 8.4Hz), 7.87(1H, d, J=8.4Hz),
8.05(2H, s), 8.57(1H, d, J =4.9Hz).
IR(KBr) . 1646cnz 1.
mp . 144.0-145.0°C.
Fxamyle 139
Synthesis of 2-methyl-1-(2-nitrobenzyl)-6-[(2-pyridylmethyl)-
carbamoyl]benzimidazole (204)
CA 02241186 1998-06-23
a
152
In the same manner as in Example 115, 0.241 g of 2-methyl-
1-(2-nitrobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole
(204) were formed from 0.367 g of 6-carboxy-2-methyl-1-(2-
nitrobenzyl)benzimidazole, 0.299 g of oxalyl chloride, 0.217 g
of 2-aminomethylpyridine and 0.360 g of triethylamine.
Properties of Compound (204):
1H-NMR(CDC13, ~ ) . 2.56(3H, s), 4.75(2H, d, J=4.8Hz), 5.83(2H,
s), 6.41(1H, d, J=7.8 and l.2Hz), 7.22(1H, dt, J=5.0 and l.7Hz),
7.32(1H, d, J=7.9Hz), 7.43-7.52(2H, m), 7.64(1H, s), 7.68(1H, dt,
J=7.6 and l.7Hz),7.75(1H, dd, J=8.4 and l.5Hz), 7.80(1H, d,
J=8.4Hz), 7.82(1H, d, J=l.3Hz), 8.28(1H, dd, J=8.0 and l.7Hz),
8.56(1H, d, J=4.9Hz).
IR(KBr) . 1645cm-1.
mp . 194.8-196.7°C
F:xa p1 a 1 40
Synthesis of 2-methyl-1-(2-nitrobenzyl)-5-[(2-pyridylmethyl)-
carbamoyl]benzimidazole (205)
In the same manner as in Example 115, 0.079 g of 2-methyl-
1-(2-nitrobenzyl)-5-[(2-pyridylmethyl)carbamoyl]benzimidazole
(205) were formed from 0.096 g of 5-carboxy-2-methyl-1-(2-
nitrobenzyl)benzimidazole, 0.078 g of oxalyl chloride, 0.048 g
of 2-aminomethylpyridine and 0.093 g of triethylamine.
Properties of Compound (205):
1 H-NMR(CDC1 3 , S ) . 2 . 57 ( 3H, s ) , 4 . 80 ( 2H, d, J=4 .7Hz ) , 5 . 80
( 2H,
s), 6.43(1H, d, J=7.4 and 0.8Hz), 7.17(1H, d, J=8.4Hz), 7.22(1H,
dt, J=5.5 and l.8Hz), 7.35(1H, d, J=7.8Hz), 7.44-7.52(2H, m),
7.67(1H, s), 7.69(1H, dt, J=7.8 and l.9Hz), 7.82(1H, dd, J=8.4
and l.SHz), 8.27(1H, dd, J=8.0 and l.6Hz), 8.28(1H, d, J=l.4Hz),
8.56(1H, d, J=4.9Hz).
IR(KBr) . 1645cm 1.
mp . ~-96°C ( decomp. )
~~'-xampl a 141
Synthesis of 1-(2-chlorobenzyl)-2-methyl-6-(2-naphthalene-
sulfonylcarbamoyl)benzimidazole sodium salt (206)
N,N'-carbonyldiimidazole (0.541 g) was added at a time to
CA 02241186 1998-06-23
153
a solution of 0.500 g of 6-carboxy-1-(2-chlorobenzyl)-2
methylbenzimidazole in 20 ml of N,N-dimethylformamide, and the
mixture was stirred at room temperature for 1 hour. Subsequently,
a solution of 0.689 g of 2-naphthalenesulfonamide and 0.506 g of
diazabicycloundecene in 5 ml of N,N-dimethylformamide were added
thereto, and the mixture was stirred at 100°C for 48 hours. The
reaction solution was cooled, and the solvent was distilled off
under reduced pressure. Water and chloroform were added to the
residue, and 10 % hydrochloric acid was added thereto until the
aqueous layer was acidified. The mixture was extracted twice
with chloroform. A saturated aqueous solution of sodium
hydrogencarbonate was added to the resulting organic layer, and
the mixed solution was stirred. The crystals precipitated were
separated through filtration, and were dissolved in a small
amount of methanol. Further, ethyl acetate was added thereto for
crystallization. The crystals were separated through filtration,
and were dried to give 0.508 g of 1-(2-chlorobenzyl)-2-methyl-6
(2-naphthalenesulfonylcarbamoyl)benzimidazole sodium salt (206).
Properties of Compound (206):
_ 1 H-NMR(DMSO-d6, ~ ) . 2.46(3H, s), 5.51(2H, s), 6.38(1H, d,
J=7.9Hz), 7.17(1H, t, J=7.5Hz), 7.30(1H, t), 7.45(1H, d,
J=8.5Hz), 7.51-7.57(3H, m), 7.77-7.93(5H, m), 7.99(1H, m),
8.35(1H, s).
IR(KBr) . 1594cm 1.
Mass(FAB) . m/e 512(M+1).
mp . 352.0-354.5°C
F-xam~,,l a 142
Synthesis of 1-(2-chlorobenzyl)-2-methyl-6-(1-naphthalene-
sulfonylcarbamoyl)benzimidazole sodium salt (207)
In the same manner as in Example 141, 0.390 g of 1-(2-
chlorobenzyl)-2-methyl-6-(1-naphthalenesulfonylcarbamoyl)-
benzimidazole sodium salt (207) were formed from 0.600 g of 6-
carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.647 g of
N,N'-carbonyldiimidazole, 0.829 g of 1-naphthalenesulfonamide
and 0.608 g of diazabicycloundecene.
CA 02241186 1998-06-23
154
Properties of Compound (207):
1 H-NMR(DMSO-d6, (S ) . 2.46(3H, s), 5.49(2H, s), 6.39(1H, d,
J=7.8Hz), 7.16(1H, t, J=7.5Hz), 7.31(1H, t, J=7.3Hz), 7.36(1H,
t), 7.40-7.45(2H, m), 7.50(1H, t, J=7.7Hz), 7.54(1H, d, J=8.OHz),
7.75-7.81(2H, m), 7.87(1H, d, J=7.9Hz), 7.93(1H, d, J=8.2Hz),
8.09(1H, d, J=7.3Hz), 8.86(1H, d, J=8.5Hz).
IR(KBr) . 1633cm 1.
Mass(FAB) . m/e 512(M+1).
mp . ~-265°C (decomp. )
Fx_am~pl_e 143
Synthesis of 6-(4-chlorobenzenesulfonylcarbamoyl)-1-(2-
chlorobenzyl)-2-methylbenzimidazole sodium salt (208)
In the same manner as in Example 141, 0.270 g of 6-(4-
chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methyl-
benzimidazole sodium salt (208) were formed from 0.400 g of 6-
carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.432 g of
N,N'-carbonyldiimidazole, 0.510 g of 4-chlorobenzenesulfonamide
and 0.404 g of diazabicycloundecene.
Properties of Compound (208):
1 H-NMR(DMSO-d6, ~ ) . 2.46(3H, s), 5.52(2H, s), 6.38(1H, d,
J=7.4Hz), 7.19(1H, t, J=7.6Hz), 7.31(1H, t, J=7.6Hz), 7.39(2H, d,
J=8.5Hz), 7.45(1H, d, J=8.9Hz), 7.54(1H, d, J=8.OHz), 7.76-
7.82(4H, m).
IR(KBr) . 1592cm 1.
Mass(FAB) . m/e 496(M+1).
mp . 360-362°C(decomp. )
f.xa ~1 a 1 44
Synthesis of 6-(3-chlorobenzenesulfonylcarbamoyl)-1-(2-chloro-
benzyl)-2-methylbenzimidazole (209)
In the same manner as in Example 141, 6-(3-
chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methyl-
benzimidazole sodium salt was obtained from 0.450 g of 6-
carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.486 g of
N,N'-carbonyldiimidazole, 0.573 g of 3-chlorobenzenesulfonamide
and 0.456 g of diazabicycloundecene. This salt was dissolved in
CA 02241186 1998-06-23
155
a mixed solution of methanol and water, and was adjusted to a pH
of from 5 to 6 with 10 % hydrochloric acid. The crystals
precipitated were separated through filtration, and were dried
to give 0.420 g of 6-(3-chlorobenzenesulfonylcarbamoyl)-1-(2-
chlorobenzyl)-2-methylbenzimidazole (209).
Properties of Compound (209):
1 H-NMR(DMSO-d6, ~ ) . 2.51(3H, s), 5.63(2H, s), 6.48(1H, d,
J=7.7Hz), 7.22(1H, t, J=7.6Hz), 7.34(1H, t, J=7.7Hz), 7.56(1H, t,
J=8.OHz), 7.64(1H, t, J=8.OHz), 7.68(1H, d, J=8.5Hz), 7.78(2H, t,
J=8.6Hz), 7.91(1H, d, J=7.6Hz), 7.95(1H, d, J=l.6Hz), 8.10(1H,
s).
IR(KBr) . 1687cm 1.
Mass(FAB) . m/e 474(M+1).
mp . 254.5-257.5°C(decomp. )
~t~1_e 145
Synthesis of 5-benzenesulfonylcarbamoyl-2-benzyl-1-(2-chloro-
benzyl)benzimidazole (210)
In the same manner as in Example 144, 0.447 g of 5-
benzenesulfonylcarbamoyl-2-benzyl-1-(2-chlorobenzyl)-
benzimidazole (210) were formed from 0.466 g of 2-benzyl-5-
carboxy-1-(2-chlorobenzyl)benzimidazole, 0.401 g of N,N'-
carbonyldiimidazole, 0.389 g of benzenesulfonamide and 0.377 g
of diazabicycloundecene.
Properties of Compound (210):
1 H-NMR(DMSO-d6, ~ ) . 4.28(2H, s), 5.57(2H, s), 6.23(1H, d,
J=7.6Hz), 7.04(1H, t, J=7.6Hz), 7.10-7.26(6H, m), 7.40(1H, d,
J=8.6Hz), 7.46(IH, d, J=8.OHz), 7.61-7.73(4H, m), 8.00(2H, d,
J=7.6Hz), 8.23(1H, s), 12.43(1H, br s).
IR(KBr) . 1685ciri 1.
mp . 152.0-155.0°C
Example 146
Synthesis of 6-benzenesulfonylcarbamoyl-2-benzyl-1-(2-chloro-
benzyl)benzimidazole (211)
In the same manner as in Example 144, 0.803 g of 6-
benzenesulfonylcarbamoyl-2-benzyl-1-(2-
CA 02241186 1998-06-23
156
chlorobenzyl)benzimidazole (211) were formed from 0.760 g of 2-
benzyl-6-carboxy-1-(2-chlorobenzyl)benzimidazole, 0.654 g of
N,N'-carbonyldiimidazole, 0.634 g of benzenesulfonamide and
0.614 g of diazabicycloundecene.
Properties of Compound (211):
1 H-NMR(DMSO-d6, ~ ) . 4.41(2H, s), 5.71(2H, s), 6.32(1H, d,
J=7.7Hz), 7.06(1H, t, J=7.7Hz), 7.14-7.30(6H, m), 7.50(1H, d,
J=B.OHz), 7.62(2H, t), 7.70(1H, t), 7.81(1H, d, J=8.6Hz),
7.87(1H, d, J=8.5Hz), 7.97(2H, d, J=8.2Hz), 8.16(1H, s),
12.60(1H, br s).
IR(KBr) . 1704cm 1.
mp . 143.0-144.5°C.
F-xam~tl_e 1 4 7
Synthesis of 1-(2,4-dichlorobenzyl)-2-methyl-6-[(2-pyridyl-
methyl)carbamoyl~benzimidazole (180)
Ten milliliters of dichloromethane and 1 drop of N,N-
dimethylformamide were added to 0.627 g of 6-carboxy-1-(2,4-
dichlorobenzyl)-2-methylbenzimidazole, and the mixture was
cooled with ice. Oxalyl chloride (0.493 g) was added dropwise
thereto, and the mixture was stirred for several minutes.
Further, the mixture was stirred at room temperature for 1 hour,
and was then concentrated under reduced pressure to remove
oxalyl chloride. The residue was dissolved in 10 ml of
dichloromethane. This solution was added dropwise to a solution
of 0.167 g of 2-aminomethylpyridine and 0.469 g of triethylamine
in 5 ml of methylene chloride while being cooled with ice. After
the mixture was stirred for 1 hour, the reaction solution was
washed three times with water and further with a saturated
aqueous solution of sodium hydrogencarbonate. The organic layer
was concentrated under reduced pressure, and was purified
through preparative thin-layer silica-gel chromatography
(eluent: a mixture of acetone and diethyl ether at a ratio of
1:1). The resulting product was further dissolved in 5 ml of
ethyl acetate, and 2 ml of hexane were added thereto for
crystallization. The crystals were separated through filtration,
CA 02241186 1998-06-23
157
and were dried to give 0.359 g of 1-(2,4-dichlorobenzyl)-2-
methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (180).
Properties of Compound (180):
1H-NMR(CDC13, 8 ) . 2.56(3H, s), 4.76(2H, d, J=4.8Hz), 5.40(2H,
s), 6.33(1H, d, J=8.4Hz), 7.07(1H, dd, J=8.4 and 2.OHz), 7.22(1H,
dd, J=7.4 and 4.9Hz), 7.33(1H, d, J=7.9Hz), 7.48(1H, d, J=2.lHz),
7.62-7.79(4H, m), 7.86(1H, d, J=l.lHz), 8.57, (1H, d, J=4.9Hz).
IR(KBr) . 1645cm 1.
mp . 204.1-206.3°C
.xample 1_48
Synthesis of 1-(biphenyl-4-ylmethyl)-2-methyl-6-[(2-pyridyl-
methyl)carbamoyl]benzimidazole (212)
Oxalyl chloride (0.655 g) was added to a solution of 0.886
g of 1-(biphenyl-4-ylmethyl)-6-carboxy-2-methylbenzimidazole and
1 drop of N,N-dimethylformamide in 13 ml of dichloromethane
while being cooled with ice, and the mixture was stirred at room
temperature for 15 hours. The crystals precipitated were
separated through filtration, washed with methylene chloride,
and dried under reduced pressure. The crystals were added to a
solution of 0.235 g of 2-aminomethylpyridine and 0.653 g of
triethylamine in 15 ml of dichloromethane while being cooled,
and the mixture was stirred for 1 hour. Water was added to the
reaction solution to stop the reaction. The reaction solution
was washed twice with water and further with a saturated aqueous
solution of sodium hydrogencarbonate. The organic layer was then
dried, and the solvent was concentrated under reduced pressure.
The residue was recrystallized from a mixed solvent of ethyl
acetate and ethanol to give 0.774 g of 1-(biphenyl-4-ylmethyl)-
2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (212).
Properties of Compound (212):
1H-NMR(CDC13, ~ ) . 2.62(3H, s), 4.77(2H, d, J=4.8Hz), 5.42(2H,
s), 7.12(2H, d, J=8.5Hz), 7.21(1H, m), 7.34(2H, m), 7.42(2H, m),
7.51-7.55(4H, m),7.62(1H, br t), 7.67(1H, dt, J=1.7 and 7.7Hz),
7.71(1H, dd, J=1.6 and 8.4Hz), 7.76(1H, d, J=8.4Hz), 8.00(1H, d,
J=l.2Hz), 8.56(1H, d, J=4.8Hz).
CA 02241186 1998-06-23
158
IR(KBr) . 1642ciri 1.
mp . 205.0-206.5°C
FXamp~e 149
Synthesis of 6-benzenesulfonylcarbamoyl-1-(2-chloroben:zyl)-2-
methylbenzimidazole (163)
N,N'-carbonyldiimidazole (0.973 g) was added to a solution
of 0.902 g of 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole
in 20 ml of N,N-dimethylformamide, and the mixture was stirred
at room temperature for 1 hour. Subsequently, a solution of
0.943 g of benzenesulfonamide and 0.913 g of
diazabicycloundecene in 5 ml of N,N-dimethylformamide was added
thereto, and the mixture was stirred at 100°C for 70 hours. The
reaction solution was cooled, and the solvent was distilled off
under reduced pressure. Water and chloroform were added to the
residue, and 10% hydrochloric acid was added thereto while being
stirred until the aqueous layer was acidified. The mixed
solution was extracted twice with chloroform. The resulting
organic layer was washed with a saturated aqueous solution of
sodium hydrogencarbonate, and the solvent was distilled off
under reduced pressure. The residue was dissolved a.n a small
amount of chloroform, and ethyl acetate was added to the
solution for crystallization. The crystals were separated
through filtration, and were dried to give 0.667 g of 6-
benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-
methylbenzimidazole (163).
~~._xampl a 150
Synthesis of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-
2-methylbenzimidazole sodium salt (213)
In the same manner as in Example 141, 0.365 g of 6-
benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methyl-
benzimidazole sodium salt (213) were formed from 0.637 g of 6-
carboxy-1-(biphenyl-4-ylmethyl)-2-methylbenzimidazole, 0.533 g
of N,N'-carbonyldiimidazole, 0.516 g of benzenesulfonamide and
0.500 g of diazabicycloundecene.
Properties of Compound (213):
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159
l H-NMR(DMSO-d6, ~ ) . 2.52(3H, s), 5.52(2H, s), 7.13(2H, d,
J=8.lHz), 7.31-7.37(4H, m), 7.39-7.45(3H, m), 7.58-7.63(4H, m),
7.78-7.82(3H, m), 7.97(1H, s).
IR(Nujol) . 1591ciri 1.
mp . 289.0-290.0°C (decomp. )
Fxampl_e 1_51_
Synthesis of 6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-
methylbenzimidazole (163)
N,N'-carbonyldiimidazole (5.41 g) was added at a time to a
solution of 5.02 g of 6-carboxy-1-(2-chlorobenzyl)-2-
methylbenzimidazole in 110 ml of N,N-dimethylformamide, and the
mixture was stirred at room temperature for 1 hour. Subsequently,
a solution of 5.24 g of benzenesulfonamide and 5.08 g of
diazabicycloundecene in 20 ml of N,N-dimethylformamide was added
thereto, and the mixed solution was stirred at 100°C for 70 hours.
The reaction solution was cooled, and the solvent was distilled
off under reduced pressure. Water and chloroform were added to
the residue, and 10 % hydrochloric acid was added thereto while
being stirred until the aqueous layer was acidified. The
solution was extracted twice with chloroform. The organic layer
was washed with a saturated aqueous solution of sodium
hydrogencarbonate, and a part of the solvent was distilled off
under reduced pressure. The crystals precipitated were separated
through filtration, and were dried to give 4.96 g of 6-
benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-
methylbenzimidazole (163).
F_xampla 152
Synthesis of 1-(2-chlorobenzyl)-2-methyl-6-trifluoromethane-
sulfonylcarbamoylbenzimidazole hydrochloride (214)
N,N'-carbonyldiimidazole (0.647 g) was added at a time to
a solution of 0.600 g of 6-carboxy-1-(2-chlorobenzyl)-2-
methylbenzimidazole in 20 ml of N,N-dimethylformamide, and the
mixture was stirred at room temperature for 1 hour. Subsequently,
a solution of 0.596 g of trifluoromethanesulfonamide and 0.609 g
of diazabicycloundecene in 5 ml of N,N-dimethylformamide was
r
CA 02241186 1998-06-23
160
added thereto, and the mixture was stirred at 100°C for 72 hours.
The reaction solution was cooled, and the solvent was distilled
off under reduced pressure. Water and ethyl acetate were added
to the residue, and 10 % hydrochloric acid was added thereto
while being stirred until the aqueous layer was acidified. The
crystals precipitated were washed with a mixed solvent of 25 ml
of ethanol and 25 ml of methanol. The crystals were dried to
give 0.420 g of 1-(2-chlorobenzyl)-2-methyl-6-
trifluoromethanesulfonylcarbamoylbenzimidazole hydrochloride
(214).
Properties of Compound (214):
1 H-NMR(DMSO-d6, S ) . 2.84(3H, s), 5.82(2H, s), 7.08(1H, d,
J=7.5Hz), 7.30(1H, t), 7.40(1H, t, J=7.7Hz), 7.58(1H, d,
J=8.OHz), 7.79(1H, d, J=8.6Hz), 8.07-8.13(2H, m).
IR(KBr) . 1634cm 1.
Mass(CI) . m/e 432(M+1-HC1).
mp . 332-335°C(decomp. )
F-xamp~P 153 and 154
Synthesis of 6-benzenesulfonylcarbamoyl-1-(2,4-dichlorobenzyl)-
2-methylbenzimidazole hydrochloride (215) and 6-
benzenesulfonylcarbamoyl-1-(2,4-dichlorobenzyl)-2-methyl-
benzimidazole (216)
In the same manner as in Example 152, 0.540 g of 6-
benzenesulfonylcarbamoyl-1-(2,4-dichlorobenzyl)-2-
methylbenzimidazole hydrochloride (215) were formed from 0.460 g
of 6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 0.455
g of N,N'-carbonyldiimidazole, 0.431 g of benzenesulfonamide and
0.418 g of diazabicycloundecene.
Properties of Compound (215):
1 H-NMR(DMSO-d6, ~ ) . 2.71(3H, s), 5.74(2H, s), 6.83(1H, 'd,
J=8.4Hz), 7.33(1H, dd, J=2.0 and 8.4Hz), 7.63(2H, t), 7.71(1H,
t), 7.78(1H, d, J=2.OHz), 7.86(1H, d, J=8.7Hz), 7.95(1H, dd,
J=1.4 and 8.7Hz), 7.99(2H, m), 8.29(1H, s).
IR(KBr) . 1686ciri 1.
mp . 236.0-238.0°C
CA 02241186 1998-06-23
161
This compound was dissolved in a mixed solvent of a
potassium hydrogencarbonate and methanol, and the solution was
adjusted to a pH of from 5 to 6 with 10% hydrochloric acid. The
crystals precipitated were collected, washed with water and with
methanol, and dried to give 6-benzenesulfonylcarbamoyl-1-(2,4-
dichlorobenzyl)-2-methylbenzimidazole (216).
Properties of Compound (216):
1 H-NMR(DMSO-d6, S ) . 2.48(3H, s), 5.58(2H, s), 6.42(1H, d,
J=8.4Hz), 7.31(1H, dd, J=2.2 and 8.4Hz), 7.60-7.75(6H, m),
7.99(2H, d, J=7.4Hz), 8.06(1H, s), 12.40(1H, s).
IR(KBr) . 1540cn1 1.
mp : 238.2 . -239. 9°C
Example 155
Synthesis of 1-(2-chlorobenzyl)-6-(4-methoxybenzenesulfonyl-
carbamoyl)-2-methylbenzimidazole (217)
N,N'-carbodiimidazole (0.431 g) was added at a time to a
solution of 0.400 g of 6-carboxy-1-(2-chlorobenzyl)-2-
methylbenzimidazole in 15 ml of N,N-dimethylformamide, and the
mixture was stirred at room temperature for 1 hour. Subsequently,
a solution of 0.498 g of 4-methoxybenzenesulfonamide and 0.405 g
of diazabicycloundecene in 5 ml of N,N-dimethylformamide was
added thereto, and the mixed solution was stirred at 100°C for 67
hours. The reaction solution was cooled, and the solvent was
distilled off under reduced pressure. Water and chloroform were
added to the residue, and 10 % hydrochloric acid was added
thereto while being cooled until the aqueous layer was acidified.
The resulting mixture was extracted twice with chloroform. The
organic layer was washed with a saturated aqueous solution of
sodium hydrogencarbonate, and the solvent was distilled off
under reduced pressure. The residue was purified through silica-
gel column chromatography (eluent: a mixture of chloroform and
methanol at a ratio of 100:2 to 100:10). The resulting product
was concentrated, and was crystallized from a mixed solution of
ethyl acetate and diethyl ether. The crystals were separated
through filtration, and were dried to give 0.450 g of 1-(2-
CA 02241186 1998-06-23
' 162
chlorobenzyl)-6-(4-methoxybenzenesulfonylcarbamoyl)-2-
methylbenzimidazole (217).
Properties of Compound (217):
1H-NMR(DMSO-d6, ~ ) . 2.46(3H, s), 3.83(3H, s), 5.58(2H, s),
7.12(2H, d, J=9.OHz), 7.21(1H, t, J=7.3Hz), 7.33(1H, t), 7.56(1H,
d, J=7.OHz), 7.63(1H, d, J=8.5Hz), 7.71(1H, dd, J=1.6 and 8.5Hz),
7.91(2H, d, J=9.OHz), 8.05(1H, d, J=l.3Hz).
IR(KBr) . 1683ciri 1.
Mass(FAB) . m/e 470(M+1).
mp . 271.0-274.0°C
Example 156
Synthesis of 1-(2-chlorobenzyl)-2-methyl-6-(a-toluenesulfonyl-
carbamoyl)benzimidazole (218)
In the same manner as in Example 155, 0.350 g of 1-(2-
chlorobenzyl)-2-methyl-6-(a-toluenesulfonylcarbamoyl)-
benzimidazole (218) were formed from 0.450 g of 6-carboxy-1-(2-
chlorobenzyl)-2-methylbenzimidazole, 0.485 g of N,N-
carbonyldiimidazole, 0.512 g of a -toluenesulfonamide and 0.456 g
of diazabicycloundecene.
Properties of Compound (218):
1H-NMR(DM50-d6, ~ ) . 2.48(3H, s), 4.36(2H, s), 5.53(2H, s),
6.40(1H, d, J=6.8Hz), 7.15-7.28(6H, m), 7.32(1H, t), 7.49(1H, d,
J=8.3Hz), 7.55(1H, d), 7.83-7.87(2H, m).
IR(KBr) . 1593cm 1.
Mass(FAB) . m/e 454(M+1).
mp . 193-196°C(foamed)
F,xample 157
Synthesis of 1-(2-chlorobenzyl)-6-(2,5-dimethylbenzenesulfonyl-
carbamoyl)-2-methylbenzimidazole (219)
In the same manner as in Example 155, 0.490 g of 1-(2-
chlorobenzyl)-6-(2,5-dimethylbenzenesulfonylcarbamoyl)-2-
methylbenzimidazole (219) were formed from 0.500 g of 6-carboxy-
1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.539 g of N,N'-
carbonyldiimidazole, 0.616 g of 2,5-xylenesulfonamide and 0.506
g of diazabicycloundecene.
CA 02241186 1998-06-23
163
Properties of Compound (219):
1H-NMR(DMSO-d6, ~ ) . 2.35(3H, s), 2.48(3H, s), 2.51(3H, s),
5.58(2H, s), 6.45(1H, d, J=7.5Hz), 7.20-7.27(2H, m), 7.31-
7.39(2H, m), 7.56(1H, d, J=8.OHz), 7.64(1H, d, J=8.5Hz), 7.75(1H,
d, J=8.5Hz), 7.82(1H, s), 8.06(1H, s), 12.45(1H, br s).
IR(KBr) . 1690cm 1.
Mass(FAB) . m/e 468(M+1).
mp . 266.5-267.5°C
F-xwmpl_e 158
Synthesis of 1-(2-chlorobenzyl)-2-methyl-6-(4-nitrobenzene-
sulfonylcarbamoyl)benzimidazole (220)
N,N'-carbodiimidazole (0.432 g) was added at a time to a
solution of 0.400 g of 6-carboxy-1-(2-chlorobenzyl)-2-
methylbenzimidazole in 15 ml of N,N-dimethylformamide, and the
solution was stirred at room temperature for 1 hour.
Subsequently, a solution of 0.538 g of 4-nitrobenzenesulfonamide
and 0.405 g of diazabicycloundecene in 5 ml of N,N-
dimethylformamide, and the mixture was stirred at 100°C for 84
hours. The reaction solution was cooled, and the solvent was
distilled off under reduced pressure. Chloroform and
hydrochloric acid were added to the residue, and the mixture was
stirred to precipitate the crystals. The crystals precipitated
were separated through filtration, and were dried to give 0.300
g of 1-(2-chlorobenzyl)-2-methyl-6-(4-nitrobenzenesulfonyl-
carbamoyl)benzimidazole (220).
Properties of Compound (220):
I H-NMR(DMSO-d6, S ) . 2.56(3H, s), 5.65(2H, s), 6.54(1H, d,
J=7.6Hz), 7.23(1H, t, J=7.6Hz), 7.34(1H, t, J=7.6Hz), 7.56(1H, t,
J=8.OHz), 7.68(1H, d, J=8.5Hz), 7.83(1H, d, J=8.3Hz), 8.07(1H,
s), 8.16(2H,d,J=8.7Hz), 8.37(2H, d, J=8.7Hz).
IR(KBr) . 1621cm-1.
Mass(FAB) . m/e 485(M+1).
mp . 330-332°C
Synthesis of 1-(2-chlorobenzyl)-2-methyl-6-[4-(trifluoromethyl)-
CA 02241186 1998-06-23
164
benzenesulfonylcarbamoyl]benzimidazole (221)
In the same manner as in Example 158, 0.390 g of 1-(2-
chlorobenzyl)-2-methyl-6-[4-(trifluoromethyl)benzenesulfonyl-
carbamoyl]benzimidazole (221) were formed from 0.450 g of 6-
carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.486 g of
N,N'-carbonyldiimidazole, 0.676 g of 4-(trifluoromethyl)-
benzenesulfonamide and 0.457 g of diazabicycloundecene.
Properties of Compound (221):
1 H-NMR(DMSO-d6, 8 ) . 2.52(3H, s), 5.62(2H, s), 6.47(1H, d,
J=7.2Hz), 7.22(1H, t, J=7.5Hz), 7.34(1H, t), 7.56(1H, d,
H=8.OHz), 7.66(1H, d, 8.5Hz), 7.78(1H, d), 7.97(2H, d, J=8.3Hz),
8.06(1H, s), 8.15(2H, d, J=8.3Hz) .
IR(KBr) . 1620cm 1.
Mass(FAB) . m/e 508(M+1).
mp . 288.0-292.0°C
Exam~Lle 160
Synthesis of 6-(2-chlorobenzenesulfonylcarbamoyl)-1-(2-chloro-
benzyl)-2-methylbenzimidazole ammonium salt (222)
N,N'-carbodiimidazole (0.485 g) was added at a time to a
solution of 0.450 g of 6-carboxy-1-(2-chlorobenzyl)-2-
methylbenzimidazole in 15 ml of N,N-dimethylformamide and the
mixture was stirred at room temperature for 1 hour. Subsequently,
a solution of 0.575 g of trifluoromethanesulfonamide and 0.457 g
of diazabicycloundecene in 5 ml of N,N-dimethylformamide was
added thereto, and the mixture was stirred at 100°C for 72 hours.
The reaction solution was cooled, and the solvent was distilled
off under reduced pressure. Water and ethyl acetate were added
to the residue, and 10 % hydrochloric acid was added thereto
while being mixed until the aqueous layer was acidified. The
crystals precipitated were separated through filtration. The
crystals were dissolved in ethanol, and the solution was
adjusted to a pH of 7 with aqueous ammonia. Further, diisopropyl
ether was added thereto. The crystals precipitated were
separated through filtration, and were dried to give 0.360 g of
6-(2-chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-
CA 02241186 1998-06-23
165
methylbenzimidazole ammonium salt (222).
Properties of Compound (222):
1 H-NMR(DMSO-d6, ~ ) . 2.47(3H, s), 5.51(2H, s), 6.43(1H, d,
J=7.5Hz), 7.12(4H, br s), 7.19(1H, t, J=7.6Hz), 7.28-7.38(4H, m),
7.46(1H, d, J=8.3Hz), 7.53(1H, d, J=7.9Hz), 7.78-7.82(2H, m),
7.97(1H, m).
IR(KBr) . 1590cm 1.
Mass(FAB) . m/e 474(M+1-NH3).
mp . 264.0-267.0°C
F-xam,Fl_e 161
Synthesis of 6-carbamoyl-1-(2,4-dichlorobenzyl)-2-methyl-
benzimidazole (223)
Oxalyl chloride (0.437 g) was added to a solution of 0.490
g of 6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole and
1 drop of N,N-dimethylformamide in 8 ml of methylene chloride
while being cooled with ice, and the mixture was stirred at room
temperature for 1.5 hours. Four milliliters of 28 % aqueous
ammonia were added thereto, and the solution was stirred at room
temperature for 12 hours. The reaction solution was extracted
with the addition of water and methylene chloride. The organic
layer was concentrated, and the crystals precipitated were then
collected, and were dried to give 0.240 g of 6-carbamoyl-1-(2,4-
dichlorobenzyl)-2-methylbenzimidazole (223).
Properties of Compound (223):
1 H-NMR(DMSO-d6, ~ ) . 2.48(3H, s), 5.54(2H, s), 6.41(1H, d,
J=8.4Hz), 7.21-8.02(3H, m), 7.31(1H, dd, J=2.2 and 8.4Hz),
7.60(1H, d, J=8.4Hz), 7.75(1H, m), 7.93(1H, s).
IR(KBr) . 1666cm I.
mp . 112.0-114.0°C
Exa ple 162
Synthesis of 6-benzensulfonylcarbamoyl-2-benzyl-1-(2,4-dichloro-
benzyl)benzimidazole (224)
N,N'-carbonyldiimidazole (0.248 g) was added at a time to
a solution of 0.315 g of 2-benzyl-6-carboxy-1-(2,4-dichloro-
benzyl)benzimidazole in 5 ml of N,N-dimethylformamide, and the
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mixture was stirred at room temperature for 1 hour. Subsequently,
a solution of 0.240 g of benzenesulfonamide and 0.233 g of
diazabicycloundecene in 4 ml of N,N-dimethylformamide was added
thereto, and the mixture was stirred at 100°C for 62 hours. The
reaction solution was cooled, and the solvent was distilled off
under reduced pressure. Water and chloroform were added to the
residue, and 10% hydrochloric acid was added thereto while being
mixed until the aqueous layer was acidified. The solution was
extracted twice with chloroform. The resulting organic layer was
washed with a saturated aqueous solution of sodium
hydrogencarbonate, and a part of the solvent was distilled off
under reduced pressure. To the residue were added 4 ml of
methanol and 4 ml of a 20 % potassium hydrogencarbonate aqueous
solution to form a uniform solution. This solution was then
adjusted to a pH of from 5 to 6 with 10% hydrochloric acid. The
crystals precipitated were separated through filtration, and
were dried to give 0.310 g of 6-benzenesulfonylcarbamoyl-2-
benzyl-1-(2,4-dichlorobenzyl)benzimidazole (244).
Properties of Compound (224):
1 H-NMR(DMSO-d6, ~ ) . 4.32(1H, s), 5.61(2H, s), 6.16(1H, d,
J=8.4Hz), 7.09(1H, dd, J=8.4 and l.9Hz), 7.18-7.10(5H, m), 7.82-
7.58(6H, m), 7.97(2H, d, J=7.6Hz), 8.10(1H, s), 12.43(1H, br s).
IR(KBr) . 1703cm 1.
mp . 236.0-238.0°C
F-F-xample 163
Synthesis of 5-benzenesulfonylcarbamoyl-2-benzyl-1-(2,4-
dichlorobenzyl)benzimidazole (225)
In the same manner as in Example 152, 0.270 g of 5-
benzenesulfonylcarbamoyl-2-benzyl-1-(2,4-dichlorobenzyl)-
benzimidazole (225) were formed from 0.385 g of 2-benzyl-5-
carboxy-1-(2,4-dichlorobenzyl)benzimidazole, 0.304 g of N,N'-
carbonyldiimidazole, 0.294 g of benzenesulfonamide and 0.285 g
of diazabicycloundecene.
Properties of Compound (225):
1 H-NMR(DMSO-d6, S ) . 4.28(2H, s), 5.52(2H, s), 6.14(1H, d,
CA 02241186 1998-06-23
167
J=8.4Hz), 7.21-7.06(6H, m), 7.42(1H, d, J=8.6Hz), 7.76-7.57(5H,
m), 8.05-7.95(2H, m), 8.24(1H, s), 12.43(1H, br s).
IR(KBr) . 1691cm 1.
mp . 107.0-110.0°C.
Example 164
Synthesis of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl-
2-hydroxybenzimidazole (226)
Tetramethoxymethane (0.220 g) was added to a solution of
0.400 g of N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethyl-
amino)benzamide in 5 ml of acetic acid, and the mixture was
stirred at 80 °C for 2 hours. The reaction solution was
concentrated, and a 20 % potassium hydrogencarbonate aqueous
solution was added to this reaction solution to render it basic.
This solution was then adjusted to a pH of from 5 to 6 with 10%
hydrochloric acid. The crystals precipitated were collected, and
ml of methanol, 0.50 g of 10 % hydrochloric acid and 0.35
hydrochloric acid were added thereto. The mixture was stirred at
60°C for 15 hours. A 20 % potassium hydrogencarbonate aqueous
solution was added to the solution to render it alkaline. This
solution was then adjusted to a pH of from 5 to 6 with 10
hydrochloric acid. The crystals precipitated were separated
through filtration, and were dried to give 0.219 g of 6-
benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl-2-hydroxy-
benzimidazole (226).
Properties of Compound (226):
1H-NMR(DMSO-d6, ~ ) . 5.07(2H, s), 7.08(1H, d, J=8.2Hz), 7.33-
7.39(3H, m), 7.44(2H, t, J=7.5Hz), 7.60-7.65(7H, m), 7.66-
7.72(2H, m), 7.96-7.80(2H, m), 11.46(1H, s), 12.34(1H, s).
IR(KBr) . 1704, 1686cm 1.
Mass(FD) . m/e 483(M).
mp . 268.7-273.9°C
E~ple 165
Synthesis of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-
2-mercaptobenzimidazole (227)
Two milliliters of carbon disulfide were added to a
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168
solution of 0.800 g of N-benzenesulfonylcarbamoyl-4-amino-3-
(biphenyl-4-ylmethylamino)benzamide, and the mixture was stirred
at 50°C for 70 hours. Chloroform and water were added thereto.
The crystals precipitated were separated through filtration, and
were dried to give 0.719 g of 6-benzenesulfonylcarbamoyl-1-
(biphenyl-4-ylmethyl)-2-mercaptobenzimidazole (227).
Properties of Compound (227):
1H-NMR(DMSO-d6, S) . 5.55(2H, s), 7.28(1H, d, J=8.4Hz), 7.35(1H,
t, J=6.3Hz), 7.39-7.47(4H, m), 7.61-7.65(6H, m), 7.69(1H, t,
J=7.4Hz), 7.78(1H, dd, J=8.4 and l.4Hz), 7.87(1H, s), 7.81-
7.98(2H, m), 12.51(1H, s), 13.29(1H, s).
IR(KBr) . 1701cm-1.
mp . 320.0-321.0°C
Example 166
Synthesis of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-
2-methoxybenzimidazole (228)
Tetramethoxymethane (0.250 g) was added to a solution of
0.400 g of N-benzenesulfonyl-4-amino-3-(biphenyl-4-
ylmethylamino)benzamide in 3 ml of acetic acid, and the mixture
was stirred at 80°C for 2 hours. Methanol was added to the
reaction solution, and the crystals precipitated were collected.
The crystals were washed with a mixed solvent of 1 ml of acetone
and 8 ml of methanol, separated through filtration, and dried to
give 0.280 g of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-
ylmethyl)-2-methoxybenzimidazole (228).
Properties of Compound (228):
1 H-NMR(DMSO-d6, ~ ) . 4.17(3H, s), 5.33(2H, s), 7.30(2H, d,
J=8.2Hz), 7.35(1H, t, J=7.4Hz), 7.44(2H, t, J=7.5Hz), 7.50(1H, d,
J=8.4Hz), 7.60-7.65(6H, m), 7.68-7.72(2H, m), 7.98-8.01(2H, m),
8.05(1H, d, J=l.5Hz), 8.18(1H, s), 12.50(1H, s).
IR(KBr) . 1690cm 1.
mp . 136.0-138.5°C
Fxa ple 167
Synthesis of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-
2-carboxybenzimidazole (229)
CA 02241186 1998-06-23
169
Triethylamine (0.080 g) and 0.148 g of methyloxalyl
chloride were added to a solution of 0.400 g of N-
benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide in
3 ml of N,N-dimethylformamide, and the mixture was stirred at
room temperature for 2 hours. The reaction solution was
concentrated, and the residue was purified through silica-gel
column chromatography (eluent: a mixture of ethyl acetate and
methanol at a ratio of 9:1) to obtain crude 6-
benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-carboxy-
benzimidazole. This compound was dissolved in 1 ml of acetic
acid and 5 ml of methanol, and the mixture was stirred at 60°C
for 15 hours. The reaction solution was neutralized with a
potassium hydroxide aqueous solution. The crystals precipitated
were separated through filtration, and were dried to give 0.245
g of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-
carboxybenzimidazole (229).
Properties of Compound (229):
iH-NMR(DMSO-d6, S) . 5.44(2H, s), 7.23(1H, d, J=8.4Hz), 7.36(1H,
t, J=7.6Hz), 7.41(2H, d, J=8.lHz), 7.45(2H, t, J=7.5Hz), 7.58(2H,
t, J=7.8Hz), 7.60-7.71(7H, m), 7.94(2H, d, J=8.3Hz), 12.38(1H,
s), 12.52(1H, s).
IR(KBr) . 1670cm 1.
mp . 247.5-250.0°C
F_xample 168
Synthesis of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-
2-methylaminobenzimidazole (230)
A mixture containing 0.300 g of N-benzene-
sulfonylcarbamoyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide,
0.200 g of methyl isothiocyanate, 5 ml of methanol and 5 ml of
acetone was stirred at room temperature for 12 hours. Further, 1
ml of 97 % sulfuric acid was added thereto, and the mixture was
stirred at room temperature for 43 hours. A 20 % potassium
hydrogencarbonate aqueous solution was added to the reaction
solution to render it basic. This reaction solution was then
concentrated, and the residue was extracted with ethyl acetate
CA 02241186 1998-06-23
170
and with water. The organic layer was concentrated, dissolved in
chloroform, and precipitated with hexane. The crystals
precipitated were separated through filtration, and were dried
to give 0.140 g of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-
ylmethyl)-2-methylaminobenzimidazole (230).
Properties of Compound (230): ,
1H-NMR(DMSO-d6, ~) . 2.98(3H, d, J=4.4Hz), 5.34(2H, s), 7.22(2H,
d, J=8.2Hz), 7.26(1H, d, J=8.4Hz), 7.34(1H, t, J=7.3Hz), 7.44(2H,
t, J=7.5Hz), 7.57(2H, t, J=7.6Hz), 7.59-7.68(6H, m), 7.76(1H, s),
7.95(2H, d, J=7.4Hz), 12.28(1H, s).
IR(KBr) . 1672cm 1.
Mass(FAB) . m/e 497(M+1).
mp . 225.0-228.0°C
Example 169
Synthesis of 2-amino-6-benzenesulfonylcarbamoyl-1-(biphenyl-4-
ylmethyl)benzimidazole (231)
Ten milliliters of methanol, 10 ml of acetone and 0.395 g
of cyanogen bromide were added to 1.500 g of N-
benzenesulfonylcarbamoyl-4-amino-3-(biphenyl-4-ylmethylamino)-
benzamide, and the mixture was stirred at room temperature for
100 hours and then at 50 °C for 30 hours . The reaction solution
was extracted with chloroform and with water. The organic layer
was washed six times with water, and was concentrated. The
residue was purified through silica-gel column chromatography
(eluent: a mixture of ethyl acetate and methanol at a ratio of
9:1) to give 0.135 g of 2-amino-6-benzenesulfonylcarbamoyl-1-
(biphenyl-4-ylmethyl)benzimidazole (231).
Properties of Compound (231):
1 H-NMR(DMSO-d6, ~ ) . 5.32(2H, s), 6.77(2H, s), 7.05(1H, d,
J=8.8Hz), 7.21(2H, d, J=8.3Hz), 7.31-7.38(4H, m), 7.43(2H, t,
J=7.5Hz), 7.58-7.65(6H, m), 7.79-7.82(2H, m).
IR(KBr) . 1684cm 1.
Mass(FAB) . m/e 483(M+1).
mp . 352.5-355.0°C
F-xwmpl_e 170
CA 02241186 1998-06-23
171
Synthesis of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-
2-n-propylbenzimidazole potassium salt (232)
Triethylamine (0.060 g) and 0.084 g of butyryl chloride
were added to a solution of 0.300 g of N-benzenesulfonyl-4-
amino-3-(biphenyl-4-ylmethylamino)benzamide in 2 ml of N,N-
dimethylformamide, and the mixture was stirred at room
temperature for 1.5 hours. The reaction solution was directly
purified through silica-gel column chromatography to obtain
0.250 g of N-benzenesulfonyl-3-(biphenyl-4-ylmethylamino)-4-
butyrylaminobenzamide. To this compound were added 5 ml of
methanol and 0.50 g of 35 % hydrochloric acid, and the mixture
was stirred at 60 °C for 3 hours. Then, 20 % potassium
hydrogencarbonate was added thereto to stop the reaction, and
the reaction solution was extracted with ethyl acetate and with
water. The organic layer was concentrated, and the product was
dissolved in a small amount of chloroform. Ether was added
thereto for crystallization. The crystals precipitated were
separated through filtration, and were dried to give 0.157 g of
6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-
propylbenzimidazole potassium salt (232).
Properties of Compound (232):
1H-NMR(DMSO-d6, ~) . 0.95(3H, t, J=7.4Hz), 1.77(2H, q, J=7.5Hz),
2.82(2H, t, J=7.5Hz), 5.55(2H, s), 7.11(2H, d, J=8.2Hz), 7.32-
7.38(4H, m), 7.43(2H, t, J=7.5Hz), 7.47(1H, d, J=8.4Hz), 7.58-
7.64(4H, m), 7.79-7.83(3H, m), 7.96(1H, s).
IR(Nujol) . 1592cm 1.
Mass(FAB) . m/e 548(M+1).
mp . 279.0-282.0°C
E~ple 171
Synthesis of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-
2-n-heptylbenzimidazole (233)
In the same manner as in Example 170, 0.232 g of 6-
benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-heptyl-
benzimidazole (233) were formed from 0.400 g of N-
benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide,
CA 02241186 1998-06-23
172
0.080 g of triethylamine and 0.170 g of octanoyl chloride.
Properties of Compound (233):
1H-NMR(DMSO-d6, c~ ) . 0.79(3H, t, J=7.3Hz), 1.12-1.24(6H, m),
1.24-1.31(2H, m), 1.66-1.73(2H, m), 2.84(2H, t, J=7.6Hz),
5.58(2H, s), 7.14(2H, d, J=8.lHz), 7.34(2H, t, J=7.6Hz), 7.43(2H,
t, J=7.4Hz), 7.52-7.66(7H, m), 7.75(1H, d, J=8.8Hz), 7.95(2H, d,
J=7.6Hz), 8.15(1H, s), 12.45(1H, s).IR(KBr) . 1688cm 1.
mp . 112 . 0 -117 . 5 °C
Fxamsle 172
Synthesis of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-
2-chloromethylbenzimidazole (234)
In the same manner as in Example 170, 0.913 g of 6-
benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-chloromethyl-
benzimidazole (234) were formed from 0.300 g of N-
benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide,
0.060 g of triethylamine and 0.102 of chloroacetyl chloride.
Properties of Compound (234):
1 H-NMR(DMSO-d6, ~ ) . 5.10(2H, s), 5.71(2H, s), 7.23(2H, d,
J=8.3Hz), 7.35(1H, t, J=7.3Hz), 7.44(2H, t, J=7.5Hz), 7.60-
7.66(6H, m), 7.69(1H, t, J=7.5Hz), 7.75-7.81(2H, m), 7.98-
8.01(2H, m), 8.16(1H, s), 12.52(1H, s).
IR(KBr) . 1700cm 1.
mp . 220.5-223.5°C.
Example 1_73
Synthesis of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-
2-methoxymethylbenzimidazole (235)
In the same manner as in Example 170, 0.183 g of 6-
benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methoxy-
methylbenzimidazole (235) were formed from 0.400 g of N-
benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide,
0.115 g of triethylamine and 0.131 g of methoxyacetyl chloride.
Properties of Compound (235):
1 H-NMR(DMSO-d6, ~ ) . 3.31(3H, s), 4.72(2H, s), 5.63(2H, s),
7.23(2H, d, J=8.3Hz), 7.35(IH, t, J=7.4Hz), 7.44(2H, t, J=7.5Hz),
7.60-7.65(6H, m), 7.70(1H, t, J=7.5Hz), 7.72-7.79(2H, m), 7.98-
CA 02241186 1998-06-23
173
8.01(2H, m), 8.18(1H, s), 12.50(1H, s).
IR(KBr) . 1690cn1 1.
mp . 195.0-198.0°C.
F.xamy a 1_74
Synthesis of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-
2-i-propylbenzimidazole potassium salt (236)
In the same manner as in Example 170, 0.400 g of N-
benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide,
0.080 g of triethylamine and 0.112 g of isobutyryl chloride were
reacted as starting materials. The crude product was dissolved
in a mixed solvent of methanol and a 20 % potassium
hydrogencarbonate aqueous solution, and the pH was adjusted to 7
with 10 % hydrochloric acid. The crystals precipitated were
crystals of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-
2-i-propylbenzimidazole potassium salt [(236), 0.167 g].
Properties of Compound (236):
1H-NMR(DMSO-d6, (S ) . 1.26(6H, d, J=6.8Hz), 3.25-3.40(1H, m),
5.58(2H, s), 7.09(2H, d, J=8.3Hz), 7.32-7.37(4H, m), 7.43(2H, t,
J=7.5Hz), 7.48(1H, d, J=8.4Hz), 7.58-7.64(4H, m), 7.79-7.83(3H,
m), 7.95(1H, s).
IR(Nujol) . 1592cm-1.
Mass(FAB) . m/e 548(M+1).
mp . 310.1-312.7°C.
Example 175
Synthesis of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl-
2-methylthiobenzimidazole (237)
A 20 % potassium hydroxide aqueous solution (0.323 g), 2
ml of water and 0.123 g of methyl iodide were added to a
solution of 0.310 g of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-
ylmethyl)-2-mercaptobenzimidazole in 5 ml of methanol in this
order, and the mixture was stirred at room temperature for 2
hours. The reaction solution was adjusted to a pH of from 5 to 6
with 10 % hydrochloric acid. The crystals precipitated were
separated through filtration, and were dried to give 0.281 g of
6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methylthio-
CA 02241186 1998-06-23
174
benzimidazole (237).
Properties of Compound (237):
1 H-NMR(DMSO-d6, S ) . 2.75(3H, s), 5.48(2H, s), 7.25(2H, d,
J=8.3Hz), 7.35(1H, t, J=7.4Hz), 7.44(2H, t, J=7.5Hz), 7.60-
7.66(7H, m), 7.68-7.75(2H, m), 7.82-7.99(2H, m), 8.19(1H, d,
J=l.6Hz), 12.43(1H, s).
IR(KBr) . 1685ciri 1.
mp . 218.8-220.4°C.
Examyle 176
Synthesis of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-
2-ethylthiobenzimidazole (238)
In the same manner as in Example 175, 0.225 g of 6-
benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-ethylthio-
benzimidazole (238) were formed from 0.240 g of 6-
benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-mercapto-
benzimidazole and 0.117 g of ethyl iodide.
Properties of Compound (238):
1H-NMR(DMSO-d6, ~) . 1.39(3H, t, J=7.3Hz), 3.37(2H, q, J=7.3Hz),
5.47(2H, s), 7.24(2H, d, J=8.lHz), 7.35(1H, t, J=7.lHz), 7.44(2H,
t, J=7.6Hz), 7.57-7.68(8H, m), 7.75(1H, d, J=8.4Hz), 7.98(2H, d,
J=7.5Hz), 8.15(1H, s), 12.43(1H, s).
IR(KBr) . 1686cm 1.
mp . 125.5-129.5°C.
E~ple 177
Synthesis of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-
2-n-propylthiobenzimidazole (239)
In the same manner as in Example 175, 0.156 g of 6-
benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-propylthio-
benzimidazole (239) were formed from 0.220 g of 6-
benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-mercapto-
benzimidazole and 0.117 g of n-propyl iodide.
Properties of Compound (239):
1H-NMR(DMSO-d6, c~) . 0.97(3H, t, J=7.4Hz), 1.76(2H, q, J=7.2Hz),
3.29-3.36(2H, m), 5.48(2H, s), 7.24(2H, d, J=8.3Hz), 7.35(1H, t,
J=7.3Hz), 7.44(2H, t, J=7.4Hz), 7.58-7.71(8H, m), 7.74(1H, dd,
CA 02241186 1998-06-23
175
J=8.5 and l.7Hz), 7.99(2H, d, J=7.7Hz), 8.17(1H, s), 12.43(1H,
s).
IR(KBr) . 1690cm 1.
mp . 106.0-111.5°C.
E~ple 178
Synthesis of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-
2-n-hexylthiobenzimidazole (240)
In the same manner as in Example 175, 0.212 g of 6-
benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-hexylthio-
benzimidazole (240) were formed from 0.250 g of 6-
benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-mercapto-
benzimidazole and 0.166 g of n-hexyl iodide.
Properties of Compound (240):
1H-NMR(DMSO-d6, ~ ) . 0.82(3H, t, J=7.9Hz), 1.19-1.33(4H, m),
1.33-1.44(2H, m), 1.68-1.75(2H, m), 3.30-3.43(2H, m), 5.48(2H,
s), 7.23(2H, d, J=8.2Hz),. 7.35(1H, t, J=7.lHz), 7.44(2H, t,
J=7.6Hz), 7.60-7.75(9H, m), 8.00(2H, d, J=7.7Hz), 8.19(1H, s),
12.44(1H, s).
IR(KBr) . 1688cm 1.
mp . 139.5-141 .0°C (decomp. )
F_xampl a 179
Synthesis of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-
benzimidazole (241)
A mixture of 0.400 g of N-benzenesulfonyl-4-amino-3-
(biphenyl-4-ylmethylamino)benzamide and 2 ml of formic acid was
stirred at 90 °C for 3 hours. The reaction solution was
concentrated, and was precipitated with methanol. The crystals
precipitated were separated through filtration, and were dried
to give 0.243 g of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-
ylmethyl)benzimidazole (241).
Properties of Compound (241):
1H-NMR(DMSO-d6, ~) . 5.60(2H, s), 7.35(1H, t, J=7.2Hz), 7.39(2H,
d, J=8.2Hz), 7.44(2H, t, J=7.6Hz), 7.61-7.77(9H, m), 8.00(2H, d,
J=7.7Hz), 8.26(1H, s), 8.66(1H, s), 12.5(1H, s).
IR(KBr) . 1683cm 1.
CA 02241186 1998-06-23
176
mp . 141.5-143.6°C.
Synthesis of 1-(4-benzyloxybenzyl)-2-methyl-6-[(2-pyridyl-
methyl)carbamoyl]benzimidazole (242)
Four milliliters of acetic acid and 8 ml of ethanol were
added to 0.434 g of N-(2-pyridylmethyl)-4-acetylamino-3-(4-
benzyloxybenzylamino)benzamide, and the mixture was stirred at
90°C for 7 hours. The reaction solution was concentrated under
reduced pressure. Ethyl acetate and ether were added to the
residue for crystallization. The crystals were separated through
filtration, and were dried to give 0.375 g of 1-(4-
benzyloxybenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole (242).
Properties of Compound (242):
1H-NMR(CDC13, ~ ) . 2.59(3H, s), 4.78(2H, d, J=4.8Hz), 5.01(2H,
s), 5.31(2H, s), 6.89(2H, d, J=8.7Hz), 6.99(2H, d, J=8.6Hz),
7.21(1H, dd, J=5.1 and 7.4Hz), 7.29-7.42(6H, m), 7.62(1H, br t),
7.65-7.75(3H, m), 7.98(1H, s), 8.57(1H, d, J =4.lHz).
IR(KBr) . 1640cm 1.
mp . 169.0-170.0°C.
Example 181
Synthesis of 2-methyl-1-(3,4-methylenedioxybenzyl)-6-[(2-
pyridylmethyl)carbamoyl]benzimidazole (243)
Two milliliters of acetic acid and 5 ml of methanol were
added to 0.490 g of N-(2-pyridylmethyl)-4-acetylamino-3-(3,4-
methylenedioxybenzylamino)benzamide, and the mixture was stirred
at 70°C for 8 hours. The reaction solution was concentrated
under reduced pressure. The residue was purified through silica-
gel column chromatography (eluent: a mixture of ethyl acetate
and methanol at a ratio of 9 : 1 ) , and was then crystallized from
ethyl acetate. The crystals were separated through filtration,
and were dried to give 0.270 g of 2-methyl-1-(3,4-
methylenedioxybenzyl)-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole (243).
Properties of Compound (243):
CA 02241186 1998-06-23
177
1 H-NMR(CDC1 3 , (~ ) . 2 .59 ( 3H, s ) , 4 . 78 ( 2H, d, J=4 . 8Hz ) , 5.28 (
2H,
s), 5.93(2H, s), 6.51(1H, d, J=l.6Hz), 6.55(1H, dd, J=1.4 and
7.9Hz), 6.72(2H, d, J=8.OHz), 7.22(1H, dd, J=6.7 and 5.OHz),
7.34(1H, d, J=7.7Hz), 7.62(1H, br t), 7.67-7.75(3H, m), 7.96(1H,
d, J=l.lHz), 8.58(1H, d, J=4.9Hz).
IR(KBr) . 1637cm 1.
mp . 190.5-192.0°C.
Example 182
Synthesis of 2-methyl-6-[(2-pyridylmethyl)carbamoyl]-1-[4-
(1,2,3-thiadiazol-4-yl)benzyl]benzimidazole (244)
In the same manner as in Example 180, 0.33 g of 2-methyl-
6-[(2-pyridylmethyl)carbamoyl]-1-[4-(1,2,3-thiadiazol-4-
yl)benzyl]benzimidazole (244) were formed from 0.50 g of N-(2-
pyridylmethyl)-4-acetylamino-3-[4-(1,2,3-thiadiazol-4-
yl)benzylamino]benzamide.
Properties of Compound (244):
1H-NMR(CDC13, ~ ) . 2.58(3H, s), 4.58(2H, d, J=5.9Hz), 5.62(2H,
s), 7.24(1H, dd, J=7.3 and 5.OHz), 7.28-7.33(3H, m), 7.64(1H, d,
J=8.4Hz), 7.73(1H, dt, J=7.7 and l.6Hz), 7.81(1H, dd, J=8.4 and
l.3Hz), 8.10(1H, d, J=8.2Hz), 8.13(1H, s), 8.49(1H, d, J=4.2Hz),
9.04(1H, t, J=5.9Hz), 9.58(1H, s).
IR(.KBr) . 1642cm-1.
mp . 216 . 0 - 217 . 0 °C .
Example 183
Synthesis of 6-benzenesulfonylcarbamoyl-1-(2,4-difluorobenzyl-2-
methylbenzimidazole (245)
N-benzenesulfanyl-4-acetylamino-3-(2,4-difluorobenzyl-
amino)benzamide (0.370 g) was dissolved in a mixed solvent of
3.3 g of 10 % hydrochloric acid, 6 ml of methanol and 4 ml of
water, and 0.5 g of 35 % hydrochloric acid were further added
thereto. The mixture was stirred at 60°C for 3 hours. A 20
potassium hydrogencarbonate aqueous solution was added to the
reaction solution to render it basic. Then, this solution was
adjusted to a pH of from 5 to 6 with 10% hydrochloric acid. The
crystals precipitated were separated through filtration, and
CA 02241186 1998-06-23
178
were dried to give 0.182 g of 6-benzenesulfonylcarbamoyl-1-(2,4-
difluorobenzyl-2-methylbenzimidazole (245).
Properties of Compound (245):
1H-NMR(DMSO-d6, ~) . 2.53(3H, s), 5.56(2H, s), 6.95-7.01(1H, m),
7.04(1H, dt, J=8.7 and l.4Hz), 7.32(1H, dt, J=10.7 and 2.lHz),
7.59-7.66(3H, m), 7.68-7.74(2H, m), 8.00(2H, d, J=8.lHz),
8.13(1H, s), 12.43(1H, s).IR(KBr) . 1686cm 1.
mp . 234.5-235.5°C(decomp. )
Example 184
Synthesis of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-
2-phenylbenzimidazole (246)
Triethylamine (0.115g) and 0.200 g of benzoyl chloride
were added to a solution of 0.500 g of N-benzenesulfonyl-4-
amino-3-(biphenyl-4-ylmethylamino)benzamide in 5 ml of N,N-
dimethylformamide. The mixture was stirred at room temperature
for 15 hours. A potassium hydrogencarbonate aqueous solution was
added thereto to stop the reaction. The solvent was distilled
off under reduced pressure. The residue was dissolved in a
mixture of water and methanol, and the solution was adjusted to
a pH of from 5 to 6 with 10 % hydrochloric acid. The crystals
precipitated were collected, and were dried to obtain 0.393 g of
crude N-benzenesulfonyl-4-benzoylamino-3-(biphenyl-4-ylmethyl-
amino)benzamide. This crude product was converted to 6-
benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-phenyl-
benzimidazole [(246), 0.270 g] in the same manner as in Example
183.
Properties of Compound (246):
1H-NMR(DMSO-d6, (~ ) . 5.70(2H, s), 7.07(2H, d, J=8.2Hz), 7.32-
7.37(1H, m), 7.43(2H, t, J=5.7Hz), 7.53-7.58(2H, m), 7.58-
7.65(7H, m), 7.68-7.72(1H, m), 7.77(2H, dd, J=7.5 and l.5Hz),
7.81-7.83(2H, m), 7.98-8.02(2H, m), 8.22(1H, s), 12.47(1H, s).
IR(KBr) . 1690cm 1.
mp . 138.5-139.5°C.
Synthesis of 6-benzenesulfonylcarbamoyl-2-methyl-1-(2-nitro-
CA 02241186 1998-06-23
' 179
benzyl)benzimidazole (247)
In the same manner as in Example 183, 0.237 g of 6-
benzenesulfonylcarbamoyl-2-methyl-1-(2-nitrobenzyl)benzimidazo1e
(247) were formed from 0.79 g of N-benzenesulfonyl-4-
acetylamino-3-(2-nitrobenzylamino)benzamide.
Properties of Compound (247):
1H-NMR(DMSO-d6, ~ ) . 2.48(3H, s), 5.01(2H, s), 5.93(2H, s),
6.28-6.30(1H, m), 7.55-7.62(4H, m), 7.64-7.74(3H, m), 7.97(2H, d,
J=8.OHz), 8.10(1H, s), 8.22-8.28(1H, m), 12.39(1H, s).
IR(KBr) . 1686cW 1.
mp . 269.5-272.5(decomp.)
F, .xam~,1_e 186
Synthesis of 6-benzenesulfonylcarbamoyl-2-methyl-1-benzyl-
benzimidazole (248)
In the same manner as in Example 183, 0.222 g of 6-
benzenesulfonylcarbamoyl-2-methyl-1-benzylbenzimidazole (248)
were formed from 0.38 g of N-benzenesulfonyl-4-acetylamino-3-
benzylaminobenzamide.
Properties of Compound (248):
1 H-NMR(DMSO-d6, S ) . 2.54(3H, s), 5.55(2H, s), 7.12(2H, d,
J=7.9Hz), 7.28(IH, t, J=7.3Hz), 7.34(2H, t, J=7.OHz), 7.61-
7.66(3H, m), 7.69-7.76(2H, m), 8.00(2H, d, J=7.9Hz), 8.18(1H, s),
12.43(1H, s).
IR(KBr) . 1695ciri 1 .
mp . 260.0-262.0°C(decomp. )
~,,les 187 and 188
Synthesis of 6-benzenesulfonylcarbamoyl-2-methyl-1-(4-nitro-
benzyl)benzimidazole (249) and 6-benzenesulfonylcarbamoyl-2-
methyl-1-(4-nitrobenzyl)benzimidazo1e potassium salt (250)
In the same manner as in Example 183, 0.255 g of 6-
benzenesulfonylcarbamoyl-2-methyl-1-(4-nitrobenzyl)benzimidazo1e
(249) were formed as a crystal from 0.505 g of N-
benzenesulfonyl-4-acetylamino-3-(4-nitrobenzylamino)benzamide.
Further, the filtrate was concentrated to form 0.136 g of 6-
benzenesulfonylcarbamoyl-2-methyl-1-(4-nitrobenzyl)benzimidazo1e
CA 02241186 1998-06-23
180
potassium salt (250) as a crystal.
Properties of Compound (249):
1 H-NMR(DMSO-d6, S ) . 2.50(3H, s), 5.70(2H, s), 7.30(2H, d,
J=8.7Hz), 7.52(2H, t, J=7.6Hz), 7.57(2H, d, J=8.3Hz), 7.76(1H,
dd, J=8.4 and l.4Hz), 7.92(2H, d, J=7.3Hz), 8.05(1H, s), 8.20(2H,
d, J=8.7Hz), 12.43(1H, s).
IR(KBr) . 1686cm.
mp . 164.5-167.0°C.
Properties of Compound (250):
1H-NMR(DMSO-d6, ~ ) . 2.51(3H, s), 5.68(2H, s), 7.28(2H, d, J
=8.5Hz), 7.32-7.41(3H, m), 7.46(1H, d, J=8.4Hz), 7.78-7.86(3H,
m), 7.91(1H, s), 8.20(2H, d, J=8.5Hz).
IR(KBr) . 1594cm-1.
mp . 326.0-328.0°C(decomp. )
Example 189
Synthesis of 6-benzenesulfonylcarbamoyl-1-(4-benzyloxybenzyl)-2-
methylbenzimidazole (251)
A mixture containing 0.500 g of N-benzenesulfonyl-3-amino-
4-acetylaminobenzamide potassium salt, 0.470 g of 4-
benzyloxybenzyl bromide, 0.925 g of a 20 % potassium
hydrogencarbonate aqueous solution and 3 ml of N,N-
dimethylformamide was stirred at 90°C for I hour. The reaction
solution was concentrated, and was purified through silica-gel
column chromatography (eluent: a mixture of ethyl acetate and
methanol at a ratio of 9:1) to obtain crude N-benzenesulfonyl-4-
acetylamino-3-(4-benzyloxybenzylamino)benzamide. This crude
product was cyclized in the same manner as in Example 183 to
give 0.160 g of 6-benzenesulfonylcarbamoyl-1-(4-
benzyloxybenzyl)-2-methylbenzimidazole (251).
Properties of Compound (251):
1H-NMR(DMSO-d6, ~ ) . 2.54(3H, s), 5.05(2H, s), 5.44(2H, s),
7.09(2H, d, J=8.7Hz), 7.32(2H, d, J=7.OHz), 7.29-7.44(5H, m),
7.58-7.67(3H, m), 7.68-7.75(2H, m), 7.79-8.02(2H, m), 8.18(1H,
s), 12.46(1H, s).
IR(KBr) . 1685cm-1.
CA 02241186 1998-06-23
' 181
mp . 111.0-114.0°C.
Synthesis of 2-methyl-5-[(2-pyridylmethyl)carbamoyl]-
benzimidazole (252)
Five-percent palladium on carbon (0.10 g) was added to a
mixture of 1.00 g of crude N-(2-pyridylmethyl)-4-acetylamino-3-
nitrobenzamide, 8 ml of acetic acid and 12 ml of ethanol, and
the solution was stirred in a hydrogen atmosphere at 80 °C for 7
hours. The solid material was separated through filtration, and
the filtrate was concentrated. Ethyl acetate was added to the
residue for crystallization. The crystals were separated through
filtration, and were dried to give 0.57 g of 2-methyl-5-[(2-
pyridylmethyl)carbamoyl]benzimidazole (252).
Properties of Compound (252):
1H-NMR(CDC13, ~ ) . 2.52(3H, s), 4.59(2H, d, J=5.9Hz), 7.26(1H,
dd, J=7.1 and 5.lHz), 7.33(1H, d, J=7.8Hz), 7.50(1H, d, J=8.4Hz),
7.72-7.78(2H, m), 8.08(1H, s), 8.51(1H, d, J=4.8Hz), 9.04(1H, t,
J=5.8Hz), 12.44(1H, s).
IR(KBr) . 1641cm-1.
mp . 212.0-215.0°C.
Examr~les 191 and 192
Synthesis of 1-benzenesulfonyl-2-methyl-6-[(2-pyridylmethyl)-
carbamoyl]benzimidazole (253) and 1-benzenesulfonyl-2-methyl-5-
[2-pyridylmethyl)carbamoyl]benzimidazole (254)
Ten milliliters of dichloromethane and 0.760 g of
triethylamine were added to 1.00 g of 1-methyl-5-[(2-
pyridylmethyl)carbamoyl]benzimidazole, and 0.994 g of
benzenesulfonyl chloride were added dropwise thereto. The
mixture was stirred for 3 hours, and the reaction solution was
washed three times with water and then with a sodium
hydrogencarbonate aqueous solution. The organic layer was
concentrated under reduced pressure, and was purified through
silica-gel column chromatography (eluent: a mixture of ethyl
acetate and methanol at a ratio of 9:1) to obtain 1.380 g of a
mixture of 1-benzenesulfonyl-2-methyl-6-[(2-pyridylmethyl)-
CA 02241186 1998-06-23
' 182
carbamoyl]benzimidazole and 1-benzenesulfonyl-2-methyl-5-[2-
pyridylmethyl)carbamoyl]benzimidazole. This mixture was further
purified through medium-pressure silica-gel column
chromatography (eluent: a mixture of ethyl acetate and methanol
at a ratio of 100 : 3 ) to give 0 . 550 g of oily 1-benzenesulfonyl-
2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (253) and
0.540 g of oily 1-benzenesulfonyl-2-methyl-5-[2-
pyridylmethyl)carbamoyl]benzimidazole (254). These oily products
were dissolved in 1.5 ml of methylene chloride, and were
crystallized from diethyl ether.
Properties of Compound (253):
1H-NMR(CDC13, ~ ) . 2.84(3H, s), 4.81(2H, d, J=4.8Hz), 7.24(1H,
dd, J=5.1 and 7.3Hz), 7.37(1H, d, J=7.7Hz), 7.53(2H, dd, J=7.9
and 7.5Hz), 7.63-7.74(2H, m), 7.85(1H, dd, J=8.4 and l.2Hz),
7.97(2H, dd, J=9.6 and l.lHz), 8.58-8.61(2H, m).
IR(KBr) . 1636cm 1. -
mp . 163.4-164.3°C.
Properties of Compound (254):
1H-NMR(CDC13, 8):2.83(3H, s), 4.78(2H, d, J=4.7Hz), 7.23(1H, dd,
J=4.9 and 8.6Hz), 7.34(1H, d, J=7.9Hz), 7.53(2H, dd, J=7.5 and
8.4Hz), 7.64-7.75(3H, m), 7.91-7.96(3H, m),8.10(1H, d, J=9.lHz),
8.14(1H, d, J=l.3Hz), 8.56(1H, dd, J=4.9 and l.OHz).
IR(KBr) . 1657cm 1.
mp . 88.3-91.3°C.
E~ples 193 and 194
Synthesis of 2-methyl-1-(4-nitrobenzyl)-6-[(2-pyridylmethyl)-
carbamoyl]benzimidazole (255) and 2-methyl-1-(4-nitrobenzyl)-5-
[(2-pyridylmethyl)carbamoyl]benzimidazole (256)
Ten milliliters of N,N-dimethylformamide, 3.24 g of 4-
nitrobenzyl bromide and 2.52 g of sodium hydrogencarbonate were
added to 3.56 g of 2-methyl-5-[2-pyridylmethyl)-
carbamoyl]benzimidazole, and the mixture was heated at 80°C for 2
hours. The reaction solution was separated with the addition of
chloroform and water. The organic layer was concentrated under
reduced pressure, and was purified through silica-gel column
CA 02241186 1998-06-23
- 183
chromatography (eluent: a mixture of ethyl acetate and methanol
at a ratio of 4:1) to obtain a mixture of 2-methyl-1-(4-
nitrobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole and 2-
methyl-1-(4-nitrobenzyl)-5-[(2-pyridylmethyl)carbamoyl]-
benzimidazole. This mixture was further separated into position
isomers through medium-pressure silica-gel column chromatography
(eluent: a mixture of ethyl acetate and methanol at a ratio of
85:15). Each of the position isomers was recrystallized from a
mixed solvent of chloroform and diethyl ether to give 1.37 g of
2-methyl-1-(4-nitrobenzyl)-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole (255) and 1.19 g of 2-methyl-1-(4-nitrobenzyl)-5-
[(2-pyridylmethyl)carbamoyl]benzimidazole (256).
Properties of Compound (255):
1H-NMR(CDC13, ~ ) . 2.59(3H, s), 4.77(2H, d, J=4.8Hz), 5.48(2H,
s), 7.09(2H, d, J=8.7Hz), 7.22(1H, dd, J=7.2 and 4.9Hz), 7.33(1H,
d, J=7.8Hz), 7.66-7.70(2H, m), 7.73(1H, dd, J=8.4 and l.5Hz),
7.78(1H, d, J=8.4Hz), 7.91(1H, d, J=l.2Hz), 8.15-8.19(2H, m),
8.56(1H, d, J=4.6Hz)
IR(KBr) . 1652cm
mp . 116 . 1-119 . 1 °C
Properties of Compound (256):
1H-NMR(CDC13, ~ ) . 2.59(3H, s), 4.79(2H, d, J=4.8Hz), 5.46(2H,
s), 7.17-7.24(4H, m), 7.35(1H, d, J=7.8Hz), 7.69(2H, dt, J=7.6
and l.7Hz), 7.83(1H, d, J=8.4Hz), 8.19(2H, d, J=8.6Hz), 8.26(1H,
d, J=l.3Hz), 8.57(lI~, d, J=4.8Hz)
IR(KBr) . 1634cm- 1
mp . 203.7-206.3°C
Examples 195 and 196
Synthesis of 2-methyl-1-(2-phenylethyl)-6-[(2-pyridylmethyl)-
carbamoyl]benzimidazole (257) and 2-methyl-1-(2-phenylethyl)-5-
[(2-pyridylmethyl)carbamoyl]benzimidazole (258)
In the same manner as in Examples 193 and 194, 0.30 g of
2-Methyl-1-(2-phenylethyl)-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole (257) and 0.23 g of 2-methyl-1-(2-phenylethyl)-5-
[(2-pyridylmethyl)carbamoyl]benzimidazole (258) were formed from
CA 02241186 1998-06-23
' 184
2.00 g of 2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole
and 15.0 g of phenetyl iodide.
Properties of Compound (257):
1H-NMR(CDC13, ~) . 2.17(3H, s), 3.10(2H, t, J=6.8Hz), 4.35(2H, t,
J=6.8Hz), 4.82(2H, d, J=4.8Hz), 6.92-6.97(2H, m), 7.21-7.28(4H,
m), 7.38(1H, d, J=7.8Hz), 7.78(1H, br t), 7.68-7.73(3H, m),
7.98(1H, d, J=0.9Hz), 8.60(1H, dd, J=1.0 and 4.9Hz)
IR(neat) . 1633cm 1
liquid.
Properties of Compound (258):
1H-NMR(CDC13, ~) . 2.19(3H, s), 3.08(2H, t, J=6.8Hz), 4.35(2H, t,
J=6.8Hz), 4.81(2H, d, J=4.8Hz), 6.91-6.96(2H, m), 7.19-7.26(4H,
m), 7.31(1H, d, J=8.4Hz), 7.36(1H, d, J=7.8Hz), 7.64-7.73(2H, m),
7.85(1H, dd, J=1.7 and 8.4Hz), 8.19(1H, d, J=l.3Hz), 8.58(1H, d,
J=4.OHz)
IR(neat) . 1643cm 1
liquid.
Examples 197 and 198
Synthesis of 1-(2,4-difluorobenzyl)-2-methyl-6-[(2-pyridyl-
methyl)carbamoyl]benzimidazole (259) and 1-(2,4-difluorobenzyl)-
2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole (260)
In the same manner as in Examples 193 and 194, 0.25 g of
1-(2,4-difluorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole (259) and 0.25 g of 1-(2,4-difluorobenzyl)-2-
methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole (260) were
formed from 1.00 g of 2-methyl-5-[(2-pyridylmethyl)-
carbamoyl]benzimidazole and 1.00 g of 2,4-difluorobenzyl bromide.
Properties of Compound (259):
1H-NMR(CDC13, ~ ) . 2.62(3H, s), .4.78(2H, d, J=4.7Hz), 5.38(2H,
s), 6.73-6.79(2H, m), 6.88(1H, t, J=lO.OHz), 7.24(1H, dd, J=7.3
and 5.lHz), 7.35(1H, d, J=7.8Hz), 7.67-7.76(4H, m), 7.97(1H, s),
8.58(1H, d, J=4.4Hz).IR(KBr) . 1642cm
mp . 98.0-104.0°C
Properties of Compound (260):
1H-NMR(CDC13, ~ ) . 2.62(3H, s), 4.79(2H, d, J=4.7Hz), 5.35(2H,
CA 02241186 1998-06-23
185
s), 6.72-6.81(2H, m), 6.89(1H, t, J=9.8Hz), 7.22(1H, t, J=6.2Hz),
7.28(1H, d, J=8.4Hz), 7.34(1H, d, J=7.8Hz), 7.63-7.71(2H, m),
7.83(1H, d, J=8.4Hz), 7.97(1H, s), 8.57(1H, d, J=4.7Hz)
IR(KBr) . 1647cm-1
mp . 143.5-144.0°C
Examples 199 and 200
Synthesis of 1-(4-aminobenzyl)-2-methyl-6-[(2-pyridylmethyl)-
carbamoyl]benzimidazole (261) and 1-(4-aminobenzyl)-2-methyl-5-
[(2-pyridylmethyl)carbamoyl]benzimidazole (262)
Thirty milliliters of methanol and 0.20 g of 5~ palladium
on carbon were added to 2.32 g of a mixture of 2-methyl-1-(4-
nitrobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole and 2-
methyl-1-(4-nitrobenzyl)-5-[(2-pyridylmethyl)carbamoyl]-
benzimidazole, and the mixture was stirred in a hydrogen
atmosphere at room temperature until the starting material
disappeared. The solid material was separated through filtration,
and the filtrate was concentrated. The resulting residue was
purified through medium-pressure silica-gel column
chromatography (eluent: a mixture of ethyl acetate and methanol
at a ratio of 85:15) to separate 1-(4-aminobenzyl)-2-methyl-6-
[(2-pyridylmethyl)carbamoyl]benzimidazole and 1-(4-aminobenzyl)-
2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole. Each of
these compounds was crystallized from a mixed solvent of
chloroform and diethyl ether. The crystals were separated
through filtration, and were dried to give 0.354 g of 1-(4-
aminobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole (261) and 0.330 g of 1-(4-aminobenzyl)-2-methyl-5-
[(2-pyridylmethyl)carbamoyl]benzimidazole (262).
Properties of Compound (261):
1 H-NMR(CDCl 3 , ~ ) . 3.00(3H, s), 4.98(2H, s), 5.88(2H, s),
7.55(2H, d, J=8.6Hz), 7.69(2H, d, J=8.6Hz), 7.90(1H, d, J=8.6Hz),
7.96(1H, dt, J=7.1 and 0.6Hz), 8.12(1H, J=8.OHz), 8.18(1H, dd,
J=8.5 and l.4Hz), 8.55(1H, dt, J=8.0 and l.7Hz), 8.62(1H, d,
J=l.lHz), 8.77(1H, dd, J=5.9 and l.lHz)
IR(KBr) . 1643cm
CA 02241186 1998-06-23
' 186
mp . 180.0-181.0°C
Properties of Compound (262):
1 H-NMR(CDC1 3 , ~ ) . 3.00(3H, s), 5.01(2H, s), 5.83(2H, s),
7.47(2H, d, J=8.5Hz), 7.78(2H, d, J=8.5Hz), 7.78(1H, d, J=8.9Hz),
7.97(1H, dt, J=7.2 and 0.7Hz), 8.13(1H, J=8.lHz), 8.15(IH, d,
J=8.9Hz), 8.51(1H, s), 8.55(1H, dt, J=7.9 and l.6Hz), 8.77(1H, d,
J=5.8Hz)
IR(KBr) . 1639, 1612ciri 1
mp . 168.0-171.0°C
Examgle 201
Synthesis of 1-[4-(benzenesulfonylamino)benzyl]-2-methyl-6-[(2-
pyridylmethyl)carbamoyl]benzimidazole (263)
Triethylamine (0.185 g) and benzenesulfonyl chloride
(0.210 g) were added to a solution of 0.340 g of 1-(4-
aminobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]-
benzimidazole in 10 ml of chloroform, and the mixture was
stirred at room temperature for 8 hours. Water was added thereto
to stop the reaction, and the reaction mixture was extracted
with chloroform. The organic layer was washed three times with
water, dried, and concentrated. The residue was then purified
through silica-gel column chromatography (eluent: a mixture of
ethyl acetate and methanol at a ratio of 100:1 to 4:1) to give
0.300 g of 1-[4-(benzenesulfonylamino)benzyl]-2-methyl-6-[(2-
pyridylmethyl)carbamoyl]benzimidazole (263).
Properties of Compound (263):
1 H-NMR( CDC1 3 , ~ ) . 2 . 53 ( 3H, s ) , 4 . 78 ( 2H, d, J=4 . 8Hz ) , 5 .
28 ( 2H,
s), 6.90(2H, t, J=8.6Hz), 6.99(2H, d, J=8.5Hz), 7.11(1H, s),
7.23(1H, dd, J=5.5 and 7.2Hz), 7.34(1H, d, J=7.7Hz), 7.40(2H, t,
J=8.lHz), 7.50(1H, t, J=7.5Hz), 7.66-7.74(6H, m), 7.92(1H, s),
8.56(1H, d, J=4.8Hz)
IR(KBr) . 1642cm-1
mp . 204.4-206.5°C
Exa ple 202
Synthesis of 6-benzenesulfonylaminomethyl-1-(2-chlorobenzyl)-2-
methylbenzimidazole (264)
CA 02241186 1998-06-23
' 187
To a solution of 0.667 g of benzenesulfonic acid amide in
ml of N,N-dimethylformamide were added 0.127 g of 60~ sodium
hydride at room temperature, and the mixture was stirred for 1
hour. Further, 0.648 g of 1-(2-chlorobenzyl)-6-chloromethyl-2-
methylbenzimidazole hydrochloride were added thereto, and the
mixture was stirred at room temperature for 18 hours. Water was
added to the reaction solution to stop the reaction, and the
solvent was distilled off under reduced pressure. The residue
was extracted with ethyl acetate and with water. The organic
layer was concentrated, and was purified through silica-gel
column chromatography (eluent: ethyl acetate) to give 0.240 g of
6-benzenesulfonylaminomethyl-1-(2-chlorobenzyl)-2-methyl-
benzimidazole (264).
Properties of Compound (264):
1H-NMR(DMSO-d6, ~ ) . 2.42(3H, s), 4.02(2H, m), 4.02(2H, m),
5.44(2H, s), 6.36(1H, d, J=7.7Hz), 7.03(1H, d, J=8.4Hz), 7.18(1H,
s), 7.21(1H, t), 7.33(1H, t), 7.59-7.43(5H, m), 7.73(2H, d,
J=7.5Hz), 8.08(1H, s)
IR(KBr) . 1522cm
mp . 164.5-167.0°C
F,xamyles 203
Synthesis of 1-(biphenyl-4-ylmethyl)-2-methyl-6-[(2-pyridyl-
methyl)aminomethyl]benzimidazole (265)
2-Aminomethylpyridine (0.372 g) was added to a solution of
0.597 g of 1-(biphenyl-4-ylmethyl)-6-chloromethyl-2-methyl-
benzimidazole and 0.350 g of potassium carbonate in 3 ml of N,N-
dimethylformamide, and the mixture was stirred at 60°C for 2
hours. The reaction mixture was extracted with water and with
ethyl acetate. The organic layer was washed twice with water,
and the solvent was distilled off under reduced pressure. The
resulting residue was purified through silica-gel column
chromatography (eluent: a mixture of chloroform and methanol at
a ratio of 9:1), and was recrystallized from a mixed solvent of
ethyl acetate and hexane to give 0.300 g of 1-(biphenyl-4-
ylmethyl)-2-methyl-6-[2-pyridylmethyl)aminomethyl]benzimidazole
S
CA 02241186 1998-06-23
188
(265).
Properties of Compound (265):
1 H-NMR(CDC1 3 , ~ ) . 2.57(3H, s), 3.91(2H, s), 3.93(2H, s),
5.35(2H, s), 7.08-7.14(3H, m), 7.23(2H, d, J=7.3Hz), 7.30-
7.35(2H, m), 7.41(2H, t), 7.50-7.55(4H, m), 7.57(1H, dt, J=1.8
and 7.6Hz), 7.68(1H, d, J=8.lHz), 8.53(1H, d, J=4.9Hz)
IR(KBr) . 1618cm-1
mp . 104.5-106.0°C
Exalgnle 204
Synthesis of N-benzenesulfonyl-3-[1-(2-chlorobenzyl)-2-methyl-
benzimidazole-6-yl]propionamide (266)
5~ Palladium on carbon (0.500 g) was added to a solution
of 0.607 g of N-benzenesulfonyl-1-(2-chlorobenzyl)-2-methyl-
benzimidazole-6-acrylamide in 150 ml of ethanol, and the mixture
was stirred in a hydrogen atmosphere at room temperature for 43
hours. The solid material was separated through filtration, and
the filtrate was concentrated. The residue was dissolved in a
mixed solution of a 20~ potassium hydrogencarbonate aqueous
solution and methanol, and was adjusted to a pH of from 5 to 6
with 10~ hydrochloric acid. The crystals precipitated were
separated through filtration, and was dried to give 0.250 g of
N-benzenesulfonyl-3-[1-(2-chlorobenzyl)-2-methylbenzimidazol-6-
yl]propionamide (266).
Properties of Compound (266):
1H-NMR(DMSO-d6, ~ ) . 2.45(3H, s), 2.52(2H, t), 2.78(2H, t),
5.37(2H, s), 6.88(1H, d, J=8.4Hz), 7.08(2H, d, J=7.4Hz), 7.22-
7.34(3H, m), 7.36(1H, t, J=8.lHz), 7.55(2H, t), 7.67(1H, t),
7.84(2H, d, J=7.6Hz), 12.04(1H, br s)
IR(KBr) . 1715ciri
Mass(FAB) . m/e 468(M+1)
mp . 229.8-233.0°C
Example 205
Synthesis of 6-benzenesulfonylcarbamoyl-2-methyl-1-[4-(1,2,3-
thiadiazol-4-yl)benzyl]benzimidazole (267)
In the same manner as in Example 183, 0.279 g of 6-
CA 02241186 1998-06-23
- 189
benzenesulfonylcarbamoyl-2-methyl-1-[4-(1,2,3-thiadiazol-4-yl)-
benzyl]benzimidazole (267) were formed from 0.382 g of N-
benzenesulfonyl-4-acetylamino-3-[4-(1,2,3-thiadiazol-4-yl)-
benzylamino]benzamide.
Properties of Compound (267):
1 H-NMR(DMSO-d6, ~ ) . 2.56(3H, s), 5.62(2H, s), 7.28(2H, d,
J=8.2Hz), 7.58-7.63(3H, m), 7.67(1H, t, J=7.3Hz), 7.74(1H, dd,
J=8.5 and l.2Hz), 7.99(2H, dd, J=8.4 and l.2Hz), 8.10(2H, d,
J=8.2Hz), 8.19(1H, s), 9.58(1H, s), 12.47(1H, s)
IR(KBr) . 1617, 1556cm 1
mp . 258.5-260. 0°C (decomp. )
Exam~,le 206
Synthesis of 1-(2-chlorobenzyl)-2-methyl-6-(8-quinolinesulfonyl-
carbamoyl)benzimidazole sodium salt (268)
In the same manner as in Example 141, 0.400 g of 1-(2-
chlorobenzyl)-2-methyl-6-(8-quinolinesulfonylcarbamoyl)-
benzimidazole sodium salt (268) were formed from 0.450 g of 6-
carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.485 g of
N,N'-carbonyldiimidazole, 0.625 g of 8-quinolinesulfonamide and
0.457 g of diazabicycloundecene.
Properties of Compound (268):
1 H-NMR(DMSO-d6, ~ ) . 2.42(3H, s), 5.48(2H, s), 6.32(1H, d,
J=7.7Hz), 7.17(1H, t, J=7.5Hz), 7.30(1H, t, J=7.7Hz), 7.42(1H, d,
J=8.4Hz), 7.48(1H, dd, J=4.2 and 8.2Hz), 7.53(1H, d, J=8.OHz),
7.64(1H, t, J=7.7Hz), 7.79(1H, d, J=8.5Hz), 7.88(1H, s), 8.04(1H,
d, J=8.lHz), 8.33-8.37(2H, m), 8.85(1H, dd)
IR(KBr) . 1594cm
Mass(FAB) . m/e 513(M+1)
mp . 348-352°C (decomp. )
E~ple 207
Synthesis of 6-(4-tert-butylbenzenesulfonylcarbamoyl)-1-(2-
chlorobenzyl)-2-methylbenzimidazole sodium salt (269)
In the same manner as in Example 141, 0.280 g of 6-(4-
tert-butylbenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methyl-
benzimidazole sodium salt (269) were obtained from 0.450 g of 6-
CA 02241186 1998-06-23
190
carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.486 g of
N,N'-carbonyldiimidazole, 0.640 g of 2-tert-benzenesulfonamide
and 0.657 g of diazabicycloundecene.
Properties of Compound (269):
1 H-NMR(DMSO-d6, ~ ) 1.25(9H, s), 2.46(3H, s), 5.51(2H, s),
6.37(1H, d, J=7.7Hz), 7.18(1H, t), 7.31(1H, t), 7.34(2H, d,
J=8.4Hz), 7.44(1H, d, J=8.4Hz), 7.54(1H, d, J=8.OHz), 7.69(2H, d,
J=8.5Hz), 7.78-7.82(2H, m)
IR(KBr) . 1596cm-1
Mass(FAB) . m/e 518(M+1)
mp . 359.5-362°C
Example 208
Synthesis of 6-benzenesulfonylcarbamoyl-2-methyl-1-[4-
(trifluoromethyl)benzyl]benzimidazole (270)
In the same manner as in Production Example 32, 0.30 g of
crude N-benzenesulfonyl-4-acetylamino-3-[4-(trifluoromethyl)-
benzylamino]benzamide were obtained from 0.50 g of N-
benzenesulfonyl-4-acetylamino-3-aminobenzamide and 0.418 g of 4-
(trifluoromethyl)benzyl bromide. When this crude product was
dissolved in methanol and was allowed to stand, the crystals
were precipitated. The crystals were separated through
filtration, and were dried to give 0.160 g of 6-
benzenesulfonylcarbamoyl-2-methyl-1-[4-(trifluoromethyl)benzyl]-
benzimidazole (270).
Properties of Compound (270):
1 H-NMR(DMSO-d6, ~ ) . 2.51(3H, s), 5.66(2H, s), 7.28(2H, d,
J=8.lHz), 7.59-7.65(3H, m), 7.67-7.75(4H, m), 7.99(2H, d,
J=7.5Hz), 8.14(1H, d, J=l.OHz), 12.43(1H, s)
IR(KBr) . 1618, 1550cm 1
mp . 278.5-280.0°C
E~~le 209
Synthesis of 2-benzyl-6-carboxy-1-methylbenzimidazole
hydrochloride (271)
A 5~ sodium hydroxide aqueous solution (2.8 g) was added
to a solution of 0.340 g of 2-benzyl-6-ethoxycarbonyl-1-
i
CA 02241186 1998-06-23
191
methylbenzimidazole in 4 ml of ethanol, and the mixture was
heat-refluxed for 1.5 hours. The reaction mixture was acidified
with 1-N hydrochloric acid, and was concentrated under reduced
pressure. Ethanol was added to the residue to extract the
organic substance. Ethanol was distilled off under reduced
pressure to give 0.300 g of 2-benzyl-6-carboxy-1-methyl-
benzimidazole hydrochloride (271).
Properties of Compound (271):
1H-NMR(DMSO-d6, ~ ) . 4.00(3H, s), 4.62(2H, s), 7.33(1H, m),
7.35-7.45(4H, m), 7.83(1H, d, J=8.4Hz), 8.06(1H, d, J=8.4Hz),
8.42(1H, s), 13.3(1H, br s)
Example 210
Synthesis of 5-benzenesulfonylcarbamoyl-2-methylbenzimidazole
(272)
A mixture of 0.500 g of N-benzenesulfonyl-4-acetylamino-3-
aminobenzamide, 3.9 g of 35~ hydrochloric acid, 15 ml of
methanol and 12 ml of water was stirred at 60°C for 1 hour. The
reaction mixture was neutralized with a potassium
hydrogencarbonate aqueous solution. The crystals precipitated
were separated through filtration, and were dried to give 0.404
g of 5-benzenesulfonylcarbamoyl-2-methylbenzimidazole (272).
Properties of Compound (272):
1H-NMR(DMSO-d6, ~) . 2.79(3H, s), 7.64-7.68(2H, m), 7.72-7.76(1H,
m), 7.81(1H, d, J=8.7Hz), 7.94(1H, dd, J=1.6 and 8.7Hz), 8.02-
8.05(2H, m), 8.30(1H, s)
IR(KBr) . 1701cm
mp . 223.0-227.5°C
Production Example 45
Production of ethyl 3-methoxyacetylamino-4-nitrobenzoate
Ethyl 3-methoxyacetylamino-4-nitrobenzoate (18.7 g) was
obtained from 15.0 g of ethyl 3-amino-4-nitrobenzoate and 15.0 g
of methoxyacetyl chloride in the same manner as in Production
Example 12.
Properties of the compound:
1H-NMR(CDC13, ~ ) . 1.42(3H, t, J=7.2Hz), 3.58(3H, s), 4.11(2H,
CA 02241186 1998-06-23
'- 19 2
s), 4.43(2H, q, J=7.2Hz), 7.85(1H, dd, J=1.6 and 8.7Hz), 8.27(1H,
d, J=8.7Hz), 9.44(1H, d, J=l.6Hz), 11.15(1H, s)
Example 211
Synthesis of 1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-methoxy-
methylbenzimidazole (273)
Crude ethyl 3-[N-(biphenyl-4-ylmethyl)methoxyacetylamino)-
4-nitrobenzoate (2.02 g) was obtained from 2.00 g of ethyl 3-
methoxyacetylamino-4-nitrobenzoate and 2.98 g of 4-
biphenylmethyl bromide in the same manner as in Production
Example 14. Subsequently, 1.44 g of crude 1-(biphenyl-4-
ylmethyl)-6-ethoxycarbonyl-2-methoxymethylbenzimidazole (273)
were obtained in the same manner as in Example 24.
F~xample 212
Synthesis of 1-(biphenyl-4-ylmethyl)-6-carboxy-2-methoxy-
methylbenzimidazole (274)
In the same manner as in Example 53, 0.864 g of 1-
(biphenyl-4-ylmethyl)-6-carboxy-2-methoxymethylbenzimidazole
(274) were formed from 1.44 g of crude 1-(biphenyl-4-ylmethyl)-
6-ethoxycarbonyl-2-methoxymethylbenzimidazole.
Properties of Compound (274):
1H-NMR(DMSO-d6, ~ ) . 3.35(3H, s), 4.77(2H, s), 5.68(2H, s),
7.25(2H, d, J=8.3Hz), 7.35(1H, t, J=7.4Hz), 7.44(2H, t, J=7.5Hz),
7.61-7.66(4H, m), 7.74(1H, d, J=8.6Hz), 7.83(1H, dd, J=1.6 and
8.5Hz), 8.08(1H, d, J=l.2Hz), 12.83(1H, s)
Example 213
Synthesis of 1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonyl-
carbamoyl)-2-methoxymethylbenzimidazole (275)
In the same manner as in Example 98, 0.429 g of 1-
(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-
methoxymethylbenzimidazole (275) were formed from 0.400 g of 1-
(biphenyl-4-ylmethyl)-6-carboxy-2-methoxymethylbenzimidazole,
0.348 g of N,N'-carbonyldiimidazole, 0.294 g of 1-
butanesulfonamide and 0.327 g of diazabicycloundecene.
Properties of Compound (275):
1H-NMR(DMSO-d6, ~ ) . 0.84(3H, t, J=7.4Hz), 1.35-1.42(2H, m),
CA 02241186 1998-06-23
193
1.62-1.70(2H, m), 3.33(3H, s), 3.51(2H, t, J=7.6Hz), 4.74(2H, s),
5.65(2H, s), 7.26(2H, d, J=8.3Hz), 7.35(1H, t, J=7.3Hz), 7.44(2H,
t, J=7.5Hz), 7.62-7.67(4H, m), 7.78(1H, d, J=8.6Hz), 7.84(1H, dd,
J=1.5 and 8.4Hz), 8.24(1H, d, J=l.5Hz), 12.01(1H, s)
IR(KBr) . 1684cm
mp . 176.0-178.5°C
Example 214
Synthesis of 1-(4-benzyloxybenzyl)-6-ethoxycarbonyl-2-methoxy-
methylbenzimidazole (276)
Crude ethyl 3-[N-4-benzyloxybenzyl)methoxyacetylamino]-4-
nitrobenzoate (2.14 g) was obtained from 2.00 g of ethyl 3-
methoxyacetylamino-4-nitrobenzoate and 3.30 g of 4-
benzyloxybenzyl chloride in the same manner as in Production
Example 14. Subsequently, 1.66 g of crude 1-(4-benzyloxybenzyl)-
6-ethoxycarbonyl-2-methoxymethylbenzimidazole (276) were
obtained in the same manner as in Example 24.
Example 215
Synthesis of 1-(4-benzyloxybenzyl)-6-carboxy-2-methoxymethyl-
benzimidazole (277)
In the same manner as in Example 53, 2.64 g of 1-(4-
benzyloxybenzyl)-6-carboxy-2-methoxymethylbenzimidazole (277)
were formed from 3.75 g of crude 1-(4-benzyloxybenzyl)-6-
ethoxycarbonyl-2-methoxymethylbenzimidazole.
Properties of Compound (277):
1H-NMR(DMSO-d6, ~ ) . 3.34(3H, s), 4:74(2H, s), 5.05(2H, s),
5.53(2H, s), 6.97(2H, d, J=8.7Hz), 7.15(2H, d, J=8.7Hz), 7.31(1H,
t, J=7.2Hz), 7.41(2H, d, J=7.2Hz), 7.71(1H, d, J=8.4Hz), 7.81(1H,
dd, J=1.5 and 7.4Hz), 8.04(1H, d, J=l.lHz), 12.81(1H, s)
F.~ple 216
Synthesis of 1-(4-benzyloxybenzyl)-6-(1-butanesulfonyl-
carbamoyl)-2-methoxymethylbenzimidazole (278)
In the same manner as in Example 155, 0.321 g of
1-(4-benzyloxybenzyl)-6-(1-butanesulfonylcarbamoyl)-2-
methoxymethylbenzimidazole (278) were formed from 0.400 g of 1-
(4-benzyloxybenzyl)-6-carboxy-2-methoxymethylbenzimidazole,
CA 02241186 1998-06-23
' 194
0.322 g of N,N'-carbonyldiimidazole, 0.272 g of 1-
butanesulfonamide and 0.302 g of diazabicycloundecene.
Properties of Compound (278):
1 H-NMR(DMSO-d6, ~ ) . 0.86(3H, t, J=7.4Hz), 1.37-1.44(2H,
m),1.65-1.71(2H, m), 3.32(3H, s), 3.52(2H, t, J=7.6Hz), 4.71(2H,
s), 5.05(2H, s), 5.51(2H, s), 6.98(2H, d, J=8.7Hz), 7.15(2H, d,
J=8.3Hz), 7.31(1H, t, J=7.2Hz), 7.37(2H, t, J=7.2Hz), 7.41(2H, d,
J=7.lHz), 7.74(1H, d, J=8.5Hz), 7.82(1H, dd, J=1.5 and 8.5Hz),
8.21(1H, s), 11.98(1H, s)
IR(KBr) . 1685cm
mp . 72.0-74.0°C
Example 217
Synthesis of 1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-2-
methoxymethylbenzimidazole (279)
Crude ethyl 3-[N-2,4-dichlorobenzyl)methoxyacetylamino]-4-
nitrobenzoate was obtained from 2.00 g of ethyl 3-
methoxyacetylamino-4-nitrobenzoate and 2.08 g of 2,4-
dichlorobenzyl chloride in the same manner as in Production
Example 14. Subsequently, 3.15 g of crude 1-(2,4-
dichlorobenzyl)-6-ethoxycarbonyl-2-methoxymethylbenzimidazole
(279) were obtained in the same manner as in Example 24.
Example 218
Synthesis of 6-carboxy-1-(2,4-dichlorobenzyl)-2-methoxy-
methylbenzimidazole (280)
In the same manner as in Example 53, 1.46 g of 6-carboxy-
1-(2,4-dichlorobenzyl)-2-methoxymethylbenzimidazole (280) were
formed from 3.15 g of crude 1-(2,4-dichlorobenzyl)-6-
ethoxycarbonyl-2-methoxymethylbenzimidazole.
Properties of Compound (280):
1H-NMR(DMSO-d6, ~ ) . 3.23(3H, s), 4.70(2H, s), 5.68(2H, s),
6.54(1H, d, J=8.5Hz), 7.31(1H, dd, J=2.2 and 8.5Hz), 7.73(1H, d,
J=2.lHz), 7.76(1H, d, J=8.5Hz), 7.86(1H, dd, J=1.5 and 8.5Hz),
8.00(1H, d, J=l.lHz), 12.85(1H, s)
Synthesis of 6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichloro-
CA 02241186 1998-06-23
v
0
195
benzyl)-2-methoxymethylbenzimidazole (281)
In the same manner as in Example 98, 0.430 g of 6-(1-
butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-
methoxymethylbenzimidazole (281) were formed from 0.400 g of 6-
carboxy-1-(2,4-dichlorobenzyl)-2-methoxymethylbenzimidazole,
0.355 g of N,N'-carbonyldiimidazole, 0.300 g of 1-
butanesulfonamide and 0.333 g of diazabicycloundecene.
Properties of Compound (281):
1H-NMR(DMSO-d6, ~ ) . 0.85(3H, t, J=7.3Hz), 1.37-1.42(2H, m),
1.63-1.69(2H, m), 3.21(3H, s), 3.51(2H, t, J=7.6Hz), 4.68(2H, s),
5.65(2H, s), 6.46(1H, d, J=8.5Hz), 7.31(1H, dd, J=2.0 and 8.4Hz),
7.75(1H, d, J=2.lHz), 7.80(1H, d, J=8.5Hz), 7.86(1H, dd, J=1.7
and 8.6Hz), 8.14(1H, d, J=l.2Hz), 12.00(1H, s)
IR(KBr) . 1694cm-1
mp . 168.5-170.5°C
Example 220
Synthesis of 1-(2-chlorobenzyl)-2-methyl-6-(1-propane-
sulfonylcarbamoyl)benzimidazole (282)
In the same manner as in Example 98, 0.459 g of 1-(2-
chlorobenzyl)-2-methyl-6-(1-propanesulfonylcarbamoyl)-
benzimidazole (282) were formed from 0.400 g of 6-carboxy-1-(2-
chlorobenzyl)-2-methylbenzimidazole, 0.431 g of N,N'-
carbonyldiimidazole, 0.328 g of 1-propanesulfonamide and 0.404 g
of diazabicycloundecene.
Properties of Compound (282):
1H-NMR(DMSO-d6, (~ ) . 0.98(3H, t, J=7.4Hz), 1.67-1.75(2H, m),
2.50(3H, s), 3.49(2H, t, J=7.7Hz), 5.61(2H, s), 6.45(1H, d,
J=7.OHz), 7.24(1H, dt, J=0.8 and 7.8Hz), 7.35(1H, dt, J=1.4 and
7.4Hz), 7.63(1H, dd, J=0.9 and 7.9Hz), 7.69(IH, d, J=8.5Hz),
7.81(1H, dd, J=1.6 and 8.5Hz), 8.12(1H, d, J=l.6Hz), 11.90(1H,
s)
IR(KBr) . 1676cm-I
mp . 217.5-218.5°C
Synthesis of 6-ethanesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-
CA 02241186 1998-06-23
'l~
196
methylbenzimidazole (283)
In the same manner as in Example 98, 0.459 g of 6
ethanesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazo1e
(283) were formed from 0.400 g of 6-carboxy-1-(2-chlorobenzyl)
2-methylbenzimidazole, 0.431 g of N,N'-carbonyldiimidazole,
0.290 g of ethanesulfonamide and 0.404 g of diazabicycloundecene.
Properties of Compound (283):
1H-NMR(DMSO-d6, ~) . 1.23(3H, t, J=7.3Hz), 2.50(3H, s), 3.50(2H,
q, J=7.3Hz), 5.61(2H, s), 6.45(1H, d, J=6.7Hz), 7.24(1H, dt,
J=0.9 and 7.5Hz), 7.35(1H, dt, J=1.4 and 7.5Hz), 7.58(1H, dd,
J=1.0 and 8.OHz), 7.69(1H, d, J=8.5Hz), 7.81(1H, dd, J=1.6 and
8.4Hz), 8.13(1H, d, J=l.5Hz), 11.86(1H, s)
IR(KBr) . 1673cia
mp . 256.5-258.5°C
Example 222
Synthesis of 6-(propanesultam-1-ylcarbonyl)-1-(2-chlorobenzyl)-
2-methylbenzimidazole (284)
In the same manner as in Example 98, 0.323 g of 6-
(propanesultam-1-ylcarbonyl)-1-(2-chlorobenzyl)-2-methyl-
benzimidazole (284) were formed from 0.400 g of 6-carboxy-1-(2-
chlorobenzyl)-2-methylbenzimidazole, 0.431 g of N,N'-
carbonyldiimidazole, 0.420 g of 1-(3-chloropropane)sulfonamide
and 0.404 g of diazabicycloundecene.
Properties of Compound (284):
1H-NMR(DMSO-d6, ~ ) . 2.27-2.33(2H, m), 2.52(3H, s), 3.52(2H, t,
J=7.OHz), 3.87(2H, t, J=6.6Hz), 5.59(2H, s), 6.57(1H, d,
J=7.7Hz), 7.23(1H, t, J=7.6Hz), 7.34(1H, t, J=6.4Hz), 7.53-
7.58(2H, m), 7.67(1H, d, J=8.4Hz), 7.79(1H, d, J=l.lHz)
IR(KBr) . 1648cm
mp . 165.5-166.6°C
Example 223
Synthesis of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-
2-cyclopropylbenzimidazole potassium salt (285)
In the same manner as in Example 170, 0.196 g of 6-
benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-cyclopropyl-
CA 02241186 1998-06-23
'~4
197
benzimidazole potassium salt (285) were obtained from 0.400 g of
N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide
and 0.101 g of cyclopropanecarbonyl chloride via N-
benzenesulfonyl-3-(biphenyl-4-ylmethylamino)-4-cyclopropane-
carbonylaminobenzamide.
Properties of Compound (285):
1H-NMR(DMSO-d6, S ):1.00-1.15(4H, m), 2.23-2.31(1H, m), 5.66(2H,
s), 7.21(2H, m, J=9.lHz), 7.32-7.45(7H, m), 7.59-7.63(4H, m),
7.78-7.83(3H, m), 7.97(1H, s).
IR(Nujol) . 1540cm 1
Mass(FAB) . m/e 546(M+1)
mp . 220.8-224.8°C
Example 224
Synthesis of 1-(2-chlorobenzyl)-2-methyl-6-(1-pentanesulfonyl-
carbamoyl)benzimidazole (286)
In the same manner as in Example 98, 0.491 g of
1-(2-chlorobenzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)-
benzimidazole (286) were formed from 0.400 g of 6-carboxy-1-(2-
chlorobenzyl)-2-methylbenzimidazole, 0.431 g of N,N'-
carbonyldiimidazole, 0.402 g of 1-pentanesulfonamide and 0.404 g
of diazabicycloundecene.
Properties of Compound (286):
1H-NMR(DMSO-d6, ~ ) . 0.81(3H, t, J=7.2Hz), 1.23-1.28(2H, m),
1.32-1.37(2H, m), 1.65-1.69(2H, m), 3.50(2H, t, J=7.8Hz),
5.61(2H, s), 6.45(1H, d, J=7.5Hz), 7.24(1H, t, J=7.6Hz), 7.35(1H,
t, J=7.5Hz), 7.57(1H, d, J=7.9Hz), 7.69(1H, d, J=8.5Hz), 7.81(1H,
dd, J=1.7 and 8.4Hz), 8.12(1H, d, J=l.2Hz), 12.25(1H, s)
IR(KBr) . 1684ciri
mp . 173.3-179.8°C
E~ple 225
Synthesis of 1-(2-chlorobenzyl)-2-methyl-6-[(3-methylbutane)-
sulfonylcarbamoyl]benzimidazole (287)
In the same manner as in Example 98, 0.284 g of 1-(2-
chlorobenzyl)-2-methyl-6-[(3-methylbutane)sulfonylcarbamoyl]-
benzimidazole (287) were formed from 0.300 g of 6-carboxy-1-(2-
CA 02241186 1998-06-23
198
chlorobenzyl)-2-methylbenzimidazole, 0.323 g of N,N'-
carbonyldiimidazole, 0.302 g of 1-(3-methyl)butanesulfonamide
and 0.303 g of diazabicycloundecene.
Properties of Compound (287): .
1H-NMR(DMSO-d6, S ) . 0.84(6H, d, J=6.5Hz), 1.52-1.59(2H, m),
1.61-1.70(1H, m), 3.44(2H, t, J=7.9Hz), 5.60(2H, s), 6.45(1H, d,
J=7.8Hz), 7.24(1H, t, J=7.6Hz), 7.35(1H, t, J=7.4Hz), 7.57(1H, d,
J=7.9Hz), 7.66(1H, d, J=8.5Hz), 7.81(1H, dd, J=1.6 and 8.6Hz),
8.09(1H, s), 11.87(1H, s)
IR(KBr) . 1682cm
mp . 201.0-204.1°C
E~ple 226
Synthesis of 1-(2-chlorobenzyl)-6-(1-hexanesulfonylcarbamoyl)-2-
methylbenzimidazole (288)
In the same manner as in Example 98, 0.379 g of 1-(2-
chlorobenzyl)-6-(1-hexanesulfonylcarbamoyl)-2-methyl-
benzimidazole (288) were formed from 0.300 g of 6-carboxy-1-(2-
chlorobenzyl)-2-methylbenzimidazole, 0.323 g of N,N'-
carbonyldiimidazole, 0.335 g of 1-hexanesulfonamide and 0.303 g
of diazabicycloundecene.
Properties of Compound (288):
1H-NMR(DMSO-d6, S ) . 0.81(3H, t, J=7.OHz), 1.18-1.28(4H, m),
1.32-1.41(2H, m), 1.63-1.71(2H, m), 2.53(3H, s), 3.50(2H, t,
J=7.7Hz), 5.64(2H, s), 6.51(1H, d, J=7.7Hz), 7.25(1H, dt, J=1.2
and 7.8Hz), 7.36(1H, dt, J=1.4 and 7.7Hz), 7.58(1H, dd, J=1.0
and 8.OHz), 7.72(1H, d, J=8.5Hz), 7.84(1H, dd, J=1.6 and 8.5Hz),
8.15(1H, d, J=l.3Hz), 11.87(1H, s)
IR(KBr) . 1682cm
mp . 141.2-143.5°C
Example 227
Synthesis of 6-tert-butoxycarbonylamino-1-(2-chlorobenzyl)-2-
methylbenzimidazole (289)
In the same manner as in Example 18, 0.760 g of 6-tert-
butoxycarbonylamino-1-(2-chlorobenzyl)-2-methylbenzimidazole
(289) were formed from 1.01 g of 6-carboxy-1-(2-chlorobenzyl)-2-
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methylbenzimidazole, 1 ml of diphenylphosphorylazide, 1 ml of
diisopropylethylamine and 25 ml of tert-butyl alcohol.
Properties of Compound (289):
1 H-NMR(CDC1 3 , ~ ) . 1.49(9H, s), 2.47(3H, s), 5.37(2H, s),
6.41(1H, d, J=7.5Hz), 6.55(1H, br s), 6.93(1H, dd, J=1.9 and
8.6Hz), 7.08(1H, t, J=7.5Hz), 7.22(1H, t), 7.44(1H, d, J=B.OHz),
7.62(2H, d, J=8.6Hz)
E~ple 228
Synthesis of 6-amino-1-(2-chlorobenzyl)-2-methylbenzimidazole
(290)
In the same manner as in Example 22, 0.420 g of 6-amino-1-
(2-chlorobenzyl)-2-methylbenzimidazole (290) were formed from
0.760 g of 6-tert-butoxycarbonylamino-1-(2-chlorobenzyl)-2-
methylbenzimidazole.
Properties of Compound (290):
iH-NMR(DMSO-d6, ~ ) . 2.37(3H, s), 4.83(2H, br s), 5.32(2H, s),
6.33(1H, d, J=l.9Hz), 6.42(1H, d, J=7.7Hz), 6.46(1H, dd, J=1.9
and 8.5Hz), 7.19-7.24(2H, m), 7.31(1H, t), 7.53(1H, d, J=7.9Hz)
Example 229
Synthesis of 6-(1-butanesulfonylamino)-1-(2-chlorobenzyl)-2-
methylbenzimidazo1e (291)
In the same manner as in Example 20, 0.230 g of 6-(1-
butanesulfonylamino)-1-(2-chlorobenzyl)-2-methylbenzimidazo1e
(291) were formed from 0.300 g of 6-amino-1-(2-chlorobenzyl)-2-
methylbenzimidazole, 0.216 g of 1-butanesulfonyl chloride and
0.130 g of triethylamine_
Properties of Compound (291):
1 H-NMR(DMSO-d6, ~ ) . 0.74(3H, m), 1.23(2H, m), 1.55(2H, m),
2.50(3H, s), 2.89(2H, m), 5.47(2H, s), 6.58(1H, d, J=7.4Hz)
7.02(1H, d, J=8.5Hz), 7.10(1H, s), 7.23(1H, t), 7.33(1H, t),
7.52(2H, m), 9.55(1H, s)
IR(KBr) . 1629ciri
mp . 149.5-151.0°C
Production of methyl 2-[N-(2,4-dichlorobenzyl)acetylamino]-3-
4
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nitrobenzoate
In the same manner as in Production Example 14, 0.250 g of
methyl 2-[N-(2,4-dichlorobenzyl)acetylamino]-3-nitrobenzoate
were formed from 1.00 g of methyl 2-acetylamino-3-nitrobenzoate
and 0.985 g of 2,4-dichlorobenzyl chloride.
Properties of the compound:
1 H-NMR(CDCl 3 , ~ ) . 1.99(3H, s), 3.71(3H, s), 4.85(1H, d,
J=4.5Hz), 4.98(1H, d, J=4.5Hz), 7.17-7.22(2H, m), 7.46(1H, d,
J=7.9Hz), 7.63(1H, t, J=7.9Hz), 7.98(1H, d, J=B.OHz), 8.09(1H, d,
J=7.9Hz)
Example 230
Synthesis of 1-(2,4-dichlorobenzyl)-7-ethoxycarbonyl-2-
methylbenzimidazole (292)
In the same manner as in Example 24, 5.15 g of 1-(2,4-
dichlorobenzyl)-7-ethoxycarbonyl-2-methylbenzimidazole (292)
were formed from 6.50 g of methyl 2-[N-(2,4-
dichlorobenzyl)acetylamino]-3-nitrobenzoate.
Properties of Compound (292):
1 H-NMR(CDC1 3 , ~ ) . 2.53(3H, s), 3.70(3H, s), 5.72(2H, s),
6.26(1H, d, J=8.4Hz), 7.04(1H, dd, J=2.0 and 8.4Hz), 7.28(1H, t,
J=7.9Hz), 7.45(1H, d, J=2.OHz), 7.75(1H, d, J=7.8Hz), 7.93(1H, d,
J=7.9Hz)
Example 231
Synthesis of 7-carboxy-1-(2,4-dichlorobenzyl)-2-methyl-
benzimidazole (293)
In the same manner as in Example 53, 1.76 g of 7-carboxy-
1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (293) were formed
from 2.00 g of 1-(2,4-dichlorobenzyl)-7-ethoxycarbonyl-2-
methylbenzimidazole.
Properties of Compound (293):
1 H-NMR(DMSO-d6, S ) . 2.49(3H, s), 5.81(2H, s), 6.09(1H, d,
J=8.4Hz), 7.21-7.28(2H, m), 7.62(1H, d, J=7.8Hz), 7.67(1H, d,
J=2.2Hz), 7.83(1H, d, J=8.OHz), 13.04(1H, br s)
Synthesis of 7-(1-butanesulfonylcarbamoyl)-1-(2,4-dichloro-
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benzyl)-2-methylbenzimidazole (294)
In the same manner as in Example 98, 0.325 g of 7-(1-
butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-
methylbenzimidazole (294) were formed from 0.463 g of 7-carboxy-
1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 0.448 g of N,N'-
carbonyldiimidazole, 0.379 g of 1-butanesulfonamide and 0.421 g
of diazabicycloundecene.
Properties of Compound (294):
1H-NMR(DM50-d6, S) . 0.84(3H, t, J=7.3Hz), 1.33(2H, m), 1.44(2H,
m), 2.53(3H, s), 3.16(2H, m), 5.64(2H, s), 6.03(1H, d, J=8.4Hz),
7.25(1H, dd, J=2.1 and 8.4Hz), 7.30(1H, t, J=7.8Hz), 7.44(1H, d,
J=7.4Hz), 7.68(1H, d, J=2.lHz), 7.87(1H, d, J=7.8Hz), 12.18(1H,
br s)
IR(KHr) . 1690cm 1
mp . 98.5-102.0°C
Example 233
Synthesis of 1-(2-chlorobenzyl)-2-methyl-6-[1-[3-(trimethyl-
silyl)propane]sulfonylcarbamoyl]benzimidazole (295)
In the same manner as in Example 149, 0.604 g of 1-(2-
chlorobenzyl)-2-methyl-6-[1-[3-(trimethylsilyl)propane]sulfonyl-
carbamoyl]benzimidazole (295) were formed from 0.400 g of 6-
carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.431 g of
N,N'-carbonyldiimidazole, 0.520 g of 1-[3-(trimethyl-
silyl)propane]sulfonamide and 0.404 g of diazabicycloundecene.
Properties of Compound (295):
iH-NMR(DMSO-d6, ~ ) . -0.06(9H, s), 0.61(2H, t, J=8.6Hz), 1.66-
1.73(2H, m), 2.50(3H, s), 3.51(2H, t, J=7.7Hz), 5.61(2H, s),
6.46(1H, d, J=7.8Hz), 7.24(1H, t, J=7.6Hz), 7.35(1H, t, J=7.6Hz),
7.57(1H, dd, J=7.9 and 0.9Hz), 7.70(1H, d, J=8.5Hz), 7.81(1H, dd,
J=1.5 and 8.5Hz), 8.12(1H, d, J=l.4Hz), 11.98(1H, s)
IR(KBr) . 1688cm
mp . 197.0-203.9°C
Example 234
Synthesis of 4-ethoxycarbonyl-2-methylbenzimidazole (296)
A mixture of 8.03 g of methyl 2-acetylamino-3-
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202
r
nitrobenzoate, 18.8 g of reduced iron, 20 ml of acetic acid and
40 ml of ethanol was heat-refluxed for 18 hours. After the
solvent was concentrated, chloroform and 10~ hydrochloric acid
were added to the residue for extraction. The aqueous layer was
acidified with a saturated aqueous solution of sodium
hydrogencarbonate, and was extracted with chloroform. Chloroform
was then distilled off under reduced pressure to give 1.61 g of
4-ethoxycarbonyl-2-methylbenzimidazole (296).
Properties of Compound (296):
1H-NMR(CDC13, 8 ) . 1.43(3H, t), 2.66(3H, s), 4.45(2H, q), 7.24-
7.28(1H, m), 7.84-7.89(2H, m), 10.26(1H, br s)
Example 235
Synthesis of 1-(2,4-dichlorobenzyl)-4-ethoxycarbonyl-2-methyl-
benzimidazole (297)
A mixture of 1.61 g of 4-ethoxycarbonyl-2-
methylbenzimidazole, 3.08 g of 2,4-dichlorobenzyl chloride, 1.51
g of potassium iodide, 1.05 g of potassium carbonate and 4 ml of
N,N-dimethylformamide was stirred at 80°C for 16 hours. The
reaction mixture was extracted with chloroform and with water.
The chloroform layer was washed with water, dried, and
concentrated. The residue was purified through silica-gel column
chromatography (eluent: a mixture of hexane and ethyl acetate at
a ratio of 2:8) to give 0.730 g of 1-(2,4-dichlorobenzyl)-4-
ethoxycarbonyl-2-methylbenzimidazole (297).
Properties of Compound (297):
1H-NMR(CDC13, S) . 1.47(3H, t, J=7.lHz), 2.63(3H, s), 4.52(2H, q,
J=7.lHz), 5.39(2H, s), 6.30(1H, d, J=8.4Hz), 7.06(1H, dd, J=2.1
and 8.4Hz), 7.25(1H, t, J=7.9Hz), 7.32(1H, dd, J=1.0 and 7.9Hz),
7.48(1H, d, J=2.OHz), 7.93(1H, dd, J=1.0 and 7.7Hz)
Example 236
Synthesis of 4-carboxy-1-(2,4-dichlorobenzyl)-2-methyl-
benzimidazole (298)
In the same manner as in Example 53, 0.575 g of 4-carboxy-
1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (298) were formed
from 0.730 g of 1-(2,4-dichlorobenzyl)-4-ethoxycarbonyl-2-
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203
methylbenzimidazole.
Properties of Compound (298):
1 H-NMR(DMSO-d6, ~ ) . 2.65(3H, s), 5.67(2H, s), 6.73(1H, d,
J=8.3Hz), 7.33(1H, dd, J=2.2 and 8.4Hz), 7.39(1H, t, J=7.9Hz),
7.74(1H, d, J=2.2Hz), 7.76(1H, d, J=8.2Hz), 7.85(1H, d, J=7.5Hz)
Exam=le 237
Synthesis of 4-(1-butanesulfonylcarbamoyl)-1-(2,4-dichloro-
benzyl)-2-methylbenzimidazole (299)
In the same manner as in Example 98, 0.275 g of 4-(1-
butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methyl-
benzimidazole (299) were formed from 0.350 g of 4-carboxy-1-
(2,4-dichlorobenzyl)-2-methylbenzimidazole, 0.339 g of N,N'-
carbonyldiimidazole, 0.287 g of 1-butanesulfonamide and 0.318 g
of diazabicycloundecene.
Properties of Compound (299):
1H-NMR(DMSO-d6, ~) . 0.86(3H, t, J=7.3Hz), 1.42(2H, m), 1.73(2H,
m), 2.61(3H, s), 3.61(2H, m), 5.65(2H, s), 6.67(1H, d, J=8.4Hz),
7.32(1H, dd, J=2.1 and 8.4Hz), 7.39(1H, t, J=7.9Hz), 7.73(1H, d,
J=2.lHz), 7.78(1H, d, J=8.OHz), 7.91(1H, d, J=7.7Hz), 12.66(1H,
br s)
IR(KBr) . 1699cm-1
mp . 180.7-183.6°C
Example 238
Synthesis of 1-(4-benzyloxybenzyl)-6-ethoxycarbonyl-2-methyl-
benzimidazole (300)
In the same manner as in Production Example 14, crude
ethyl 3-[N-(4-benzyloxybenzyl)acetylamino]-4-nitrobenzoate was
obtained from 2.00 g of ethyl 3-acetylamino-4-nitrobenzoate and
3.69 g of 4-benzyloxybenzyl chloride. Subsequently, 4.09 g of
crude 1-(4-benzyloxybenzyl)-6-ethoxycarbonyl-2-methyl-
benzimidazole (300) were formed in the same manner as in Example
24.
Example 239
Synthesis of 1-(4-benzyloxybenzyl)-6-carboxy-2-methyl-
benzimidazole (301)
CA 02241186 1998-06-23
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In the same manner as in Example 53, 1.13 g of 1-(4-
benzyloxybenzyl)-6-carboxy-2-methylbenzimidazole (301) were
formed from 4.09 g of 1-(4-benzyloxybenzyl)-6-ethoxycarbonyl-2-
methylbenzimidazole.
Properties of Compound (301):
iH-NMR(DMSO-d6, ~ ) . 2.57(3H, s), 5.05(2H, s), 5.48(2H, s),
6.97(2H, d, J=8.6Hz), 7.08(2H, d, J=8.5Hz), 7.28-7.43(5H, m),
7.60(1H, d, J=8.3Hz), 7.78(1H, d, J=7.5Hz), 8.07(1H, s),
12.72(1H, s)
ExamFle 240
Synthesis of 1-(4-benzyloxybenzyl)-6-(1-butanesulfonyl-
carbamoyl)-2-methylbenzimidazole (302)
In the same manner as in Example 149, 0.206 g of 1-(4-
benzyloxybenzyl)-6-(1-butanesulfonylcarbamoyl}-2-methyl-
benzimidazole (302) were formed from 0.300 g of 6-carboxy-1-(4-
benzyloxybenzyl)-2-methylbenzimidazole, 0.242 g of N,N'-
carbonyldiimidazole, 0.204 g of 1-butanesulfonamide and 0.227 g
of diazabicycloundecene.
Properties of Compound (302):
1H-NMR(DMSO-d6, ~ ) . 0.87(3H, t, J=7.3Hz), 1.38-1.43(2H, m),
1.64-1.71(2H, m), 2.54(3H, s), 3.49(2H, t, J=6.8Hz), 5.05(2H, s),
5.45(2H, s), 6.98(2H, d, J=8.7Hz), 7.10(2H, d, J=8.7Hz), 7.31(1H,
t, J=7.2Hz), 7.37(2H, t, J=7.2Hz), 7.41(2H, d, J=7.3Hz), 7.62(1H,
d, J=8.5Hz), 7.79(1H, dd, J=1.5 and 8.4Hz), 8.23(1H, s),
11.93(1H, s)
IR(KBr) . 1684cm
mp . 132.4-137.7°C
Example 241
Synthesis of 6-ethoxycarbonyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-
2-methylbenzimidazole (303)
In the same manner as in Production Example 14, 0.750 g of
crude ethyl 3-[N-[(2'-cyanobiphenyl-4-yl)methyl]acetylamino]-4-
nitrobenzoate were obtained from 1.00 g of ethyl 3-acetylamino-
4-nitrobenzoate and 1.30 g of 4'-bromomethyl-2-cyanobiphenyl.
Subsequently, 0.410 g of 6-ethoxycarbonyl-1-[(2'-cyanobiphenyl-
CA 02241186 1998-06-23
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205
4-yl)methyl]-2-methylbenzimicazole (303) were formed in the same
manner as in Example 24.
Properties of Compound (303):
1 H-NMR(CDC1 3 , ~ ) . 1.40(3H, t), 2.63(3H, s), 4.39(2H, q),
5.46(2H, s), 7.17(2H, d), 7.40-7.66(5H, m), 7.73-7.78(2H, m),
8.00(1H, dd, J=1.5 and 8.5Hz), 8.05(1H, d, J=l.2Hz)
E~ple 242
Synthesis of 6-carboxy-1-[(2'-cyanobiphenyl-4-yl)methyl]-2-
methylbenzimidazole (304)
In the same manner as in Example 53, 0.190 g of 6-carboxy-
1-[(2'-cyanobiphenyl-4-yl)methyl]-2-methylbenzimidazole (304)
were formed from 0.410 g of 6-ethoxycarbonyl-1-[(2'-
cyanobiphenyl-4-yl)methyl]-2-methylbenzimidazole.
Properties of Compound (304):
1 H-NMR(DMSO-d6, ~ ) . 2.59(3H, s), 5.67(2H, s), 7.24(2H, d,
J=8.lHz), 7.53-7.64(5H, m), 7.75(1H, t, J=7.7Hz), 7.80(1H, d),
7.92(1H, d, J=7.7Hz), 8.12(1H, s), 12.74(1H, br s)
Example 243___
Synthesis of 6-(1-butanesulfonylcarbamoyl)-1-[(2'-cyanobiphenyl-
4-yl)methyl]-2-methylbenzimidazole (305)
In the same manner as in Example 155, 0.155 g of 6-(1-
butanesulfonylcarbamoyl)-1-[(2'-cyanobiphenyl-4-yl)methyl]-2-
methylbenzimidazole (305) were formed from 0.187 g of 6-carboxy-
1-[(2'-biphenyl-4-yl)methyl]-2-methylbenzimidazole, 0.160 g of
N,N'-carbonyldiimidazole, 0.135 g of 1-butanesulfonamide and
0.150 g of diazabicycloundecene by being purified through
silica-gel column chromatography (eluent: a mixture of
chloroform and methanol at a ratio of 20:1).
Properties of Compound (305):
1H-NMR(DMSO-d6, ~) . 0.83(3H, t, J=7.4Hz), 1.34(2H, m), 1.60(2H,
m),2.56(3H, s), 3.27(2H, m), 5.62(2H, s), 7.23(2H, d, J=8.2Hz),
7.53-7.57(4H, m), 7.60(1H, d, J=7.8Hz), 7.75(1H, dt, J=1.0 and
7.8Hz), 7.83(1H, dd, J=1.5 and 8.4Hz), 7.92(1H, d), 8.13(1H,
s), 11.92(1H, br s).
IR(KBr) . 2223ciri 1.
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206
mp . 115-118°C
Production of 2-fluoro-4'-methylbiphenyl
Thirty milliliters of a 1.6-M-n-butyllithium hexane
solution and a solution of 8.33 g of 4-bromotoluene in 30 ml of
tetrahydrofuran were added in this order to 30 ml of
tetrahydrofuran which had been cooled to -78°C in a nitrogen
atmosphere, and the mixture was then stirred at -78°C for 1 hour.
A solution containing 6.64 g of zinc chloride which had been
dehydrated through heat-melting under reduced pressure in 30 ml
of tetrahydrofuran was added thereto at -78°C, and the mixture
was stirred at room temperature for 1 hour. This solution was
added to a solution of 7.22 g of 2-fluoroiodobenzene and 0.52 g
of tetrakis(trifluorophosphine)palladium (O) in 30 ml of
tetrahydrofuran at room temperature, and the mixed solution was
stirred for 24 hours. The reaction solution was diluted with 300
ml of ethyl acetate, and the dilute solution was extracted with
the addition of 10~ hydrochloric acid. The organic layer was
washed with a saturated aqueous solution of sodium chloride,
dried, and then concentrated. The residue was purified through
silica-gel column chromatography (eluent: hexane) to give 6.05 g
of oily 2-fluoro-4'-methylbiphenyl.
Properties of the compound:
1H-NMR(CDC13, 8) . 2.39(3H, s), 7.10-7.30(5H, m), 7.39-7.49(3H,
m)
Production Example 48
Production of 2-fluoro-4'-bromomethylbiphenyl
A mixture of 8.70 g of 2-fluoro-4'-methylbiphenyl, 8.32 g
of N-bromosuccinimide, 0.10 g of 2,2'-azobisisobutylonitrile and
150 ml of carbon tetrachloride was heat-refluxed for 5 hours.
The reaction solution was washed with water, and the organic
layer was concentrated. The resulting residue was purified
through silica-gel column chromatography (eluent: a mixture of
hexane and ethyl acetate at a ratio of 9:1) to obtain crude 2-
fluoro-4'-bromomethylbiphenyl. Further, this compound was
CA 02241186 1998-06-23
207
crystallized from hexane to give 4.93 g of 2-fluoro-4'-
bromomethylbiphenyl.
Properties of the compound:
1H-NMR(CDC13, ~ ) . 4.55(2H, s), 7.13-7.23(2H, m), 7.33(1H, m),
7.43(1H, m), 7.47(2H, d, J=8.lHz), 7.54(2H, d, J=8.lHz}
Production Example 49
Production of ethyl 3-[N-[(2'-fluorobiphenyl-4-yl)methyl]-
acetylamino]-4-nitrobenzoate
Ethyl 3-[N-[2'-fluorobiphenyl-4-yl)methyl]acetylamino]-4-
nitrobenzoate (1.90 g) was formed from 1.54 g of ethyl 3-
acetylamino-4-nitrobenzoate and 2.26 g of 2-fluoro-4'-
bromomethylbiphenyl in the same manner as in Production Example
14 .
Properties of the compound:
1H-NMR(CDC13, ~ ) . 1.33(3H, t, J=7.lHz), 1.92(3H, s), 4.36(2H,
m), 4.44(1H, d, J=4.4Hz), 5.32(1H, d, J=4.4Hz), 7.13(1H, m),
7.18-7.22(3H, m), 7.31(1H, m), 7.40(1H, dt, J=1.6 and 7.7Hz),
7.44(2H, d), 7.67(1H, d, J=l.6Hz), 7.94(1H, d, J=8.4Hz), 8.15(1H,
dd, J=1.8 and 8.4Hz)
E~yle 244
Synthesis of 6-ethoxycarbonyl-1-[(2'-fluorobiphenyl-4-yl)-
methyl]-2-methylbenzimidazole (306)
In the same manner as in Example 24, 1.53 g of 6-
ethoxycarbonyl-1-[(2'-fluorobiphenyl-4-yl)methyl]-2-methyl-
benzimidazole (306) were formed from 1.90 g of ethyl 3-[N-[2'-
fluorobiphenyl-4-yl)methyl]acetylamino]-4-nitrobenzoate.
Properties of Compound (306):
1H-NMR(CDC13, 8) . 1.40(3H, t, J=7.lHz), 2.62(3H, s), 4.38(2H, q,
J=7.lHz), 5.43(2H, s), 7.10-7.17(3H, m), 7.19(1H, dt, J=1.0 and
7.5Hz), 7.31(1H, m), 7.38(1H, dt, J=1.8 and 7.8Hz), 7.50(2H, dd),
7.74(1H, d, J=8.5Hz), 8.00(1H, dd, J=1.4 and 8.4Hz), 8.06(1H, s)
Example 245
Synthesis of 6-carboxy-1-[(2'-fluorobiphenyl-4-yl)methyl]-2-
methylbenzimidazo1e (307)
In the same manner as in Example 53, 1.24 g of 6-carboxy-
CA 02241186 1998-06-23
!T
t
208
1-[(2'-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole (307)
were formed from 1.50 g of 6-ethoxycarbonyl-1-[(2'-
fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole.
Properties of Compound (307):
1 H-NMR(DMSO-d6, ~ ) . 2.59(3H, s), 5.63(2H, s), 7.19(2H, d,
J=8.lHz), 7.24-7.31(2H, m), 7.39(1H, m), 7.46-7.53(3H, m),
7.62(1H, d, J=8.4Hz), 7.80(1H, dd, J=1.3 and 8.4Hz), 8.10(1H, s)
xa ple 246
Synthesis of 6-(1-ethanesulfonylcarbamoyl)-1-[(2'-fluoro-
biphenyl-4-yl)methyl]-2-methylbenzimidazole (308)
In the same manner as in Example 98, 0.340 g of 6-(1-
ethanesulfonylcarbamoyl)-1-((2'-fluorobiphenyl-4-yl)methyl]-2-
methylbenzimidazole (308) were formed from 0.455 g of 6-carboxy-
1-[(2'-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazo1e, 0.409
g of N,N'-carbonyldiimidazole, 0.346 g of 1-butanesulfonamide
and 0.384 g of diazabicycloundecene.
Properties of Compound (308):
1H-NMR(DMSO-d6, ~) . 0.84(3H, t, J=7.3Hz), 1.39(1H, m), 1.67(1H,
m), 2.57(3H, s), 3.51(1H, t), 5.60(2H, s), 7.21(2H, d, J=8.OHz),
7.24-7.30(2H, m), 7.39(1H, m), 7.48(1H, t), 7.52(2H, d, J=8.OHz),
7.66(1H, d, J=8.5Hz), 7.80(1H, d, J=8.5Hz), 8.25(1H, s),
11.93(1H, br s)
Production Example 50
Production of 3-fluoro-4-methylbiphenyl
Thirty milliliters of a 1.6-M-n-butyllithium hexane
solution and a solution of 9.21 g of 4-bromo-2-fluorotoluene in
30 ml of tetrahydrofuran were added in this order to 30 ml of
tetrahydrofuran which had been cooled to -78°C in a nitrogen
atmosphere, and the mixture was then stirred at -78°C for 1 hour.
A solution containing 6.64 g of zinc chloride which had been
dehydrated through heat-melting under reduced pressure in 30 ml
of tetrahydrofuran was added thereto at -78°C, and the mixture
was stirred at room temperature for 1 hour. The reaction
solution was added to ~a solution of 6.63 g of iodobenzene and
0.52 g of tetrakis(triphenylphosphine)palladium (0) in 30 ml of
CA 02241186 1998-06-23
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tetrahydrofuran at room temperature, and the mixed solution was
stirred for 24 hours. The reaction solution was diluted with 300
ml of ethyl acetate, and the dilute solution was extracted with
the addition of 10~ hydrochloric acid. The organic layer was
washed with a saturated aqueous solution of sodium chloride,
dried, and then concentrated. The residue was purified through
silica-gel column chromatography (eluent: hexane) to give 6.00 g
of oily 3-fluoro-4-methylbiphenyl.
Properties of the compound:
1 H-NMR(CDC1 3 , ~ ) . 2.31(3H, d, J=l.8Hz), 7.20-7.28(3H, m),
7.34(1H, m), 7.43(2H, t), 7.55(2H, d)
Prc~dLGti on Example 51
Production of 4-bromomethyl-3-fluorobiphenyl
A mixture of 6.00 g of 3-fluoro-4-methylbiphenyl, 5.73 g
of N-bromosuccinimide, 0.075 g of 2,2'-azobisisobutylonitrile
and 120 ml of carbon tetrachloride was heat-refluxed for 5 hours.
The reaction solution was washed with water, and the organic
layer was concentrated. The resulting residue was purified
through silica-gel column chromatography (eluent: a mixture of
hexane and ethyl acetate at a ratio of 9:1) to give 8.30 g of
oily 4-bromomethyl-3-fluorobiphenyl.
Properties of the compound:
1H-NMR(CDC13, ~ ) . 4.57(2H, s), 7.30(1H, d, J=1l.OHz), 7.34-
7.40(2H, m), 7.45(3H, m), 7.56(2H, d)
prodLCtion Example 52
Production of ethyl 3-[N-[(3-fluorobiphenyl-4-yl)methyl]-
acetylamino]-4-nitrobenzoate
In the same manner as in Production Example 14, 2.68 g of
crude ethyl 3-[N-[3-fluorobiphenyl-4-yl)methyl]acetylamino]-4-
nitrobenzoate were obtained from 1.54 g of ethyl 3-acetylamino-
4-nitrobenzoate and 2.26 g of 3-fluoro-4-bromomethylbiphenyl.
Example 247
Synthesis of 6-ethoxycarbonyl-1-[(3-fluorobiphenyl-4-yl)methyl]-
2-methylbenzimidazole (309)
In the same manner as in Example 24, 1.34 g of 6-
CA 02241186 1998-06-23
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ethoxycarbonyl-1-[(3-fluorobiphenyl-4-yl)methyl]-2-
methylbenzimidazole (309) were formed from 2.68 g of crude ethyl
3-[N-[3-fluorobiphenyl-4-yl)methyl]acetylamino]-4-nitrobenzoate.
Properties of Compound (309):
1H-NMR(CDC13, (S) . 1.40(3H, t, J=7.lHz), 2.65(3H, s), 4.39(2H, q,
J=7.lHz), 5.46(2H, s), 6.79(1H, t, J=8.OHz), 7.25(1H, m), 7.34-
7.40(2H, m), 7.41-7.47(2H, m), 7.50-7.54(2H, m), 7.74(1H, d,
J=8.5Hz), 7.99(1H, dd, J=1.5 and 8.4Hz), 8.07(1H, d, J=l.3Hz)
Example 248
Synthesis of 6-carboxy-1-[(3-fluorobiphenyl-4-yl)methyl]-2-
methylbenzimidazole (310)
In the same manner as in Example 53, 1.15 g of 6-carboxy-
1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole (310)
were formed from 1.34 g of 6-ethoxycarbonyl-1-[(3-
fluorobiphenyl-4-yl)methyl]'-2-methylbenzimidazole.
Properties of Compound 310:
1 H-NMR(DMSO-d6, ~ ) . 2.59(3H, s), 5.64(2H, s), 7.03(1H, t,
J=8.OHz), 7.37(1H, t, J=7.3Hz), 7.42-7.48(3H, m), 7.56-7.68(4H,
m), 7.79(1H, dd, J=1.4 and 8.4Hz), 8.11(1H, s), 12.7(1H, br s)
Example 249
Synthesis of 6-(1-butanesulfonylcarbamoyl)-1-[(3-fluorobiphenyl-
4-yl)methyl]-2-methylbenzimidazole (311)
In the same manner as in Example 98, 0.236 g of 6-(1-
butanesulfonylcarbamoyl)-1-[(3-fluorobiphenyl-4-yl)methyl]-2-
methylbenzimidazole (311) were formed from 0.390 g of 6-carboxy-
1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole, 0.351 g
of N,N'-carbonyldiimidazole, 0.297 g of 1-butanesulfonamide and
0.329 g of diazabicycloundecene.
Properties of Compound (311):
1H-NMR(DMSO-d6, ~ ) . 0.84(3H, t), 1.38(2H, m), 1.65(2H, m),
2.57(3H, s), 3.48(2H, m), 5.63(2H, s), 6.93(1H, t, J=8.lHz),
7.37(1H, m), 7.42-7.47(3H, m), 7.60(1H, dd, J=1.7 and 11.8Hz),
7.62-7.68(3H, m), 7.80(1H, dd, J=1.5 and 8.4Hz), 8.21(1H, d,
J=l.3Hz), 11.90(1H, br s).
IR(Nujol) . 1681cm 1
CA 02241186 1998-06-23
211
mp . 227-230°C
Synthesis of 1-(2-chlorobenzyl)-6-[(2-methoxyethane)sulfonyl-
carbamoyl]-2-methylbenzimidazole (312)
In the same manner as in Example 98, 0.149 g of 1-(2-
chlorobenzyl)-6-[(2-methoxyethane)sulfonylcarbamoyl]-2-methyl-
benzimidazole (312) were formed from 0.300 g of 1-(biphenyl-4-
ylmethyl)-6-carboxy-2-ethylbenzimidazole, 0.272 g of N,N'-
carbonyldiimidazole, 0.258 g of (2-ethoxyethane)sulfonamide and
0.256 g of diazabicycloundecene.
Properties of Compound (312):
1H-NMR(DMSO-d6, ~) . 0.87(3H, t, J=6.9Hz), 1.30(3H, t, J=8.OHz),
2.89(2H, q, J=7.6Hz), 3.25-3.35(2H, m), 3.63-3.74(2H, m),
5.59(2H, s), 7.17(2H, d, J=8.lHz), 7.34(1H, t, J=7.OHz), 7.44(2H,
t, J=7.6Hz), 7.58-7.68(5H, m), 7.82(1H, d, J=8.4Hz), 8.23(1H, s),
11.88(1H, s).
IR(Nujol) . 1681cm I.
mp . 78-81°C
Example 251'
Synthesis of 1-(2,4-dichlorobenzyl)-2-methyl-6-(1-pentane-
sulfonylcarbamoyl)benzimidazole (313)
In the same manner as in Example 98, 0.196 g of 1-(2,4-
dichlorobenzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)-
benzimidazole (313) were formed from 0.300 g of 6-carboxy-1-
(2,4-dichlorobenzyl)-2-methylbenzimidazole, 0.323 g of N,N'-
carbonyldiimidazole, 0.301 g of 1-pentanesulfonamide and 0.303 g
of diazabicycloundecene.
Properties of Compound (313):
1H-NMR(DMSO-d6, ~ ) . 0.81(3H, t, J=7.3Hz), 1.22-1.30(2H, m),
1.32-1.39(2H, m), 1.64-1.71(2H, m), 2.50(3H, s), 3.50(2H, t,
J=7.8Hz), 5.59(2H, s), 6.45(1H, d, J=8.4Hz), 7.33(1H, dd, J=2.2
and 8.5Hz), 7.69(1H, d, J=8.5Hz), 7.76(1H, d, J=2.lHz), 7.80(1H,
dd, J=1.6 and 8.5Hz), 8.10(1H, s), 11.89(1H, s).
IR(Nujol) . 1682cm-1.
mp . 213.2-214.6°C
CA 02241186 1998-06-23
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Y
Example 252
Synthesis of 1-(biphenyl-4-ylmethyl)-2-ethyl-6-[1-[3-(methyl-
thio)propane]sulfonylcarbamoyl]benzimidazole (314)
In the same manner as in Example 98, 0.178 g of 1-
(biphenyl-4-ylmethyl)-2-ethyl-6-[1-[3-(methylthio)propane]-
sulfonylcarbamoyl]benzimidazole (314) were formed from 0.300 g
of 6-carboxy-1-(biphenyl-4-ylmethyl)-2-ethylbenzimidazole, 0.272
g of N,N'-carbonyldiimidazole, 0.285 g of 1-[(3-
methylthio)propane]sulfonamide and 0.256 g of
diazabicycloundecene.
Properties of Compound (314):
1H-NMR(DMSO-d6, ~ ) . 1.30(3H, t, J=7.5Hz), 1.91-1.99(2H, m),
1.97(3H, s), 2.58(2H, t, J=7.2Hz), 2.90(2H, q, J=7.6Hz), 3.55-
3.61(2H, m), 5.60(2H, s), 7.18(2H, d, J=8.2Hz), 7.35(1H, t,
J=7.3Hz), 7.44(2H, t, J=7.5Hz), 7.60-7.66(4H, m), 7.69(1H, d,
J=8.5Hz), 7.82(1H, dd, J=1.8 and 8.5Hz), 8.24(1H, s), 11.98(1H,
s).
IR(Nujol) . 1671cm '.
mp . 89.9-91.2°C
Ex~mt~le 253 -
Synthesis of 1-(4-biphenylmethyl)-2-ethyl-6-(1-pentanesulfonyl-
carbamoyl)benzimidazole (315)
In the same manner as in Example 98, 0.258 g of 1-(4-
biphenylmethyl)-2-ethyl-6-(1-pentanesulfonylcarbamoyl)-
benzimidazole (315) were formed from 0.300 g of 6-carboxy-1-(4-
biphenylmethyl)-2-ethylbenzimidazole, 0.272 g of N,N'-
carbonyldiimidazole, 0.254 g of 1-pentanesulfonamide and 0.256 g
of diazabicycloundecene.
Properties of Compound (315):
1H-NMR(DMSO-d6, ~ ) . 0.87(3H, t, J=7.2Hz), 1.22-1.39(4H, m),
1.30(3H, t, J=7.5Hz), 1.66-1.73(2H, m), 2.90(2H, q, J=7.4Hz),
3.51(2H, t, J=7.7Hz), 5.60(2H, s), 7.18(2H, d, J=8.2Hz), 7.34(1H,
t, J=7.4Hz), 7.44(2H, t, J=7.6Hz), 7.60-7.67(4H, m), 7.71(1H, d,
J=8.4Hz), 7.81(1H, dd, J=1.6 and 8.4Hz), 8.27(1H, d, J=l.lHz),
11.92(1H, s).
CA 02241186 1998-06-23
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213
IR(Nujol) . 1682cm-1.
mp . 175.3-178.4°C
Example 254
Synthesis of 6-(1-butanesulfonylcarbamoyl)-1-(2,4-dicyclo-
benzyl)-2-ethylbenzimidazole (316)
In the same manner as in Example 98, 0.253 g of 6-(1-
butanesulfonylcarbamoyl)-1-(2,4-dicyclobenzyl)-2-ethyl-
benzimidazole (316) were formed from 0.300 g of 6-carboxy-1-
(2,4-dichlorobenzyl)-2-ethylbenzimidazole, 0.258 g of N,N'-
carbonyldiimidazole, 0.217 g of 1-butanesulfonamide and 0.262 g
of diazabicycloundecene.
Properties of Compound (316):
1H-NMR(DMSO-d6, ~) . 0.85(3H, t, J=7.4Hz), 1.27(3H, t, J=7.4Hz),
1.35-1.43(2H, m), 1.63-1.70(2H, m), 2.81(2H, q, J=7.4Hz),
3.51(2H, t, J=7.7Hz), 5.59(2H, s), 6.41(1H, d, J=8.4Hz), 7.32(1H,
dd, J=2.0 and 8.4Hz), 7.73(1H, d, J=8.4Hz), 7.76(1H, d, J=2.OHz),
7.81(1H, dd, J=1.5 and 8.5Hz), 8.12(1H, d, J=l.6Hz), 11.87(1H,
s).
IR(Nujol) . 1694cm 1.
mp . 175.7-176.9°C
~ple 255
Synthesis of I-(4-biphenylmethyl)-2-ethyl-6-[1-(3-methyl)butane-
sulfonylcarbamoyl]benzimidazole (317)
In the same manner as in Example 98, 0.273 g of 1-(4-
biphenylmethyl)-2-ethyl-6-[1-(3-methyl)butanesulfonyl-
carbamoyl]benzimidazole (317) were formed from 0.300 g of 1-(4-
biphenylmethyl)-6-carboxy-2-ethylbenzimidazole, 0.272 g of N,N'-
carbonyldiimidazole, 0.254 g of 1-(3-methyl)butanesulfonamide
and 0.256 g of diazabicycloundecene.
Properties of Compound (317):
1H-NMR(DMSO-d6, ~) . 0.85(6H, d, J=6.5Hz), 1.30(3H, t, J=7.4Hz),
1.55-1.62(2H, m), 1.63-1.70(1H, m), 2.90(2H, q, J=7.4Hz),
3.52(2H, t, J=7.9Hz), 5.61(2H, s), 7.19(2H, d, J=8.3Hz), 7.35(1H,
t, J=7.4Hz), 7.44(2H, t, J=7.5Hz), 7.61-7.66(4H, m), 7.71(1H, d,
J=8.5Hz), 7.81(1H, dd, J=1.6 and 8.4Hz), 8.27(1H, s), 11.95(1H,
CA 02241186 1998-06-23
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214
s).
IR(Nujol) . 1682cm-1.
mp . 102.8-104.5°C
Example 256
Synthesis of 1-(2,4-dichlorobenzyl)-5-ethoxycarbonyl-2-methyl-
benzimidazole (318)
In the same manner as in Production Example 14, ethyl 4-
[N-(2,4-dichlorobenzyl)acetylamino]-3-nitrobenzoate was formed
from 1.525 g of ethyl 4-acetylamino-3-nitrobenzoate and 1.42 g
of 2,4-dichlorobenzyl chloride. This compound was converted into
1-(2,4-dichlorobenzyl)-5-ethoxycarbonyl-2-methylbenzimidazole
[(318), 1.476 g] in the same manner as in Example 24 without
being purif ied .
Properties of Compound (318):
1H-NMR(CDC13, CS) . 1.42(3H, t, J=7.lHz), 2.57(3H, s), 4.41(2H, q,
J=7.lHz), 5.38(2H, s), 6.35(1H, d, J=8.4Hz), 7.09(1H, dd, J=2.0
and 8.4Hz), 7.16(1H, d, J=8.9Hz), 7.49(1H, d, J=2.OHz), 7.96(1H,
dd, J=1.5 and 8.5Hz), 8.46(1H, s)
Exan~le 257
Synthesis of 5-carboxy-1-(2,4-dichlorobenzyl)-2-methyl-
benzimidazole (319)
In the same manner as in Example 53, 1.195 g of 5-carboxy-
1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (319) were formed
from 1.465 g of 1-(2,4-dichlorobenzyl)-5-ethoxycarbonyl-2-
methylbenzimidazole.
Properties of Compound (319):
1 H-NMR(DMSO-d6, ~ ) . 2.48(3H, s), 5.56(2H, s), 6.53(1H, d,
J=8.4Hz), 7.32(1H, dd, J=2.1 and 8.4Hz), 7.44(1H, d, J=8.4Hz),
7.73(1H, d, J=2.2Hz), 7.78(1H, dd, J=1.5 and 8.4Hz), 8.15(1H, d,
J=l.3Hz)
Example 258
Synthesis of 5-(1-butanesulfonylcarbamoyl)-1-(2,4-dichloro-
benzyl)-2-methylbenzimidazole (320)
In the same manner as in Example 98, 0.690 g of 5-(1-
butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methyl-
CA 02241186 1998-06-23
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r
benzimidazole (320) were formed from 0.565 g of 5-carboxy-1-
(2,4-dichlorobenzyl)-2-methylbenzimidazole, 0.504 g of N,N'-
carbonyldiimidazole, 0.427 g of 1-butanesulfonamide and 0.473 g
of diazabicycloundecene.
Properties of Compound (320):
1H-NMR(DMSO-d6, ~) . 0.87(3H, t, J=7.3Hz), 1.41(2H, m), 1.68(2H,
m), 2.49(3H, s), 3.52(2H, m), 5.58(2H, s), 6.53(1H, d, J=8.4Hz),
7.33(1H, dd, J=2.1 and 8.4Hz), 7.50(1H, d, J=8.5Hz), 7.73(1H, d,
J=2.lHz), 7.78(1H, dd, J=1.5 and 8.5Hz), 8.24(1H, s), 11.97(1H,
br s).
IR(Nujol) . 1674ciri 1.
mp . 135.4-139.2°C
F.xampl a 259
Synthesis of 1-(4-biphenylmethyl)-5-ethoxycarbonyl-2-ethyl-
benzimidazole (321)
In the same manner as in Production Example 14, ethyl 4-
[N-(4-biphenylmethyl)propionylamino]-3-nitrobenzoate was formed
from 1.50 g of 4-propionylamino-3-nitrobenzoate and 1.67 g of 4-
bromomethylbiphenyl. This compound was converted into 1-(4-
biphenylmethyl)-5-ethoxycarbonyl-2-ethylbenzimidazole [(321),
1.23 g] in the same manner as in Example 24 without being
purified.
Properties of Compound (321):
1H-NMR(CDC13, ~ ) . 1.40(3H, t, J=7.lHz), 1.45(3H, t, J=7.6Hz),
2.90(2H, q, J=7.6Hz), 4.39(2H, q, J=7.lHz), 5.40(2H, s), 7.09(2H,
d, J=8.2Hz), 7.27(1H, d, J=8.8Hz), 7.34(1H, m), 7.42(2H, t),
7.55-7.51(4H, m), 7.97(1H, dd, J=1.5 and 8.4Hz), 8.52(1H, d,
J=l.2Hz)
Example 260
Synthesis of 1-(4-biphenylmethyl)-5-carboxy-2-ethylbenzimidazole
(322)
In the same manner as in Example 53, 0.870 g of 1-(4-
biphenylmethyl)-5-carboxy-2-ethylbenzimidazole (322) were formed
from 1.00 g of 1-(4-biphenylmethyl)-5-ethoxycarbonyl-2-
ethylbenzimidazole.
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t
Properties of Compound (322):
1H-NMR(DMSO-d6, ~) . 1.30(3H, t, J=7.4Hz), 2.90(2H, q, J=7.4Hz),
5.57(2H, s), 7.17(2H, d, J=8.3Hz), 7.33(1H, m), 7.42(2H, t),
7.63-7.57(5H, m), 7.81(1H, dd, J=1.6 and 8.6Hz), 8.18(1H, d,
J=l.3Hz), 12.67(1H, br s)
Example 261
Synthesis of 1-(4-biphenylmethyl)-5-(1-butanesulfonylcarbamoyl)-
2-ethylbenzimidazole (323)
In the same manner as in Example 98, 0.305 g of 1-(4-
biphenylmethyl)-5-(1-butanesulfonylcarbamoyl)-2-ethyl-
benzimidazole (323) were formed from 0.400 g of 1-(4-
biphenylmethyl)-5-carboxy-2-ethylbenzimidazole, 0.364 g of N,N'-
carbonyldiimidazole, 0.308 g of 1-butanesulfonamide and 0.342 g
of diazabicycloundecene.
Properties of Compound (323):
1H-NMR(DMSO-d6, ~) . 0.86(3H, t, J=7.4Hz), 1.30(3H, t, J=7.5Hz),
1.41(2H, m), 1.68(2H, m), 2.91(2H, q, J=7.4Hz), 3.52(2H, m),
5.59(2H, s), 7.16(2H, d, J=8.2Hz), 7.34(1H, t, J=7.4Hz), 7.43(2H,
t), 7.59-7.65(5H, m), 7.80(1H, dd, J=1.6 and 8.6Hz), 8.24(1H, d,
J=l.6Hz), 11.97(1H, br s).
IR(Nujol) . 1682ciri 1.
mp . 142.9-144.4°C
Example 262
Synthesis of 1-(4-biphenylmethyl)-2-ethyl-6-(2-methoxyethane-
sulfonylcarbamoyl)benzimidazole (324)
In the same manner as in Example 98, 0.487 g of 1-(4-
biphenylmethyl)-2-ethyl-6-(2-methoxyethanesulfonylcarbamoyl)-
benzimidazole (324) were formed from 0.513 g of benzimidazole,
0.464 g of N,N'-carbonyldiimidazole, 0.420 g of 2-
methoxyethanesulfonamide and 0.438 g of diazabicycloundecene.
Properties of Compound (324):
1H-NMR(DMSO-d6, ~) . 1.30(3H, t, J=7.5Hz), 2.90(2H, q, J=7.4H2),
3.13(3H, s), 3.70-3.77(4H, m), 5.60(2H, s) 7.18(2H, d, J=8.2Hz),
7.35(1H, t, J=7.lHz), 7.44(2H, t, J=7.5Hz), 7.60-7.67(4H, m),
7.70(1H, d, J=8.5Hz), 7.80(1H, dd, J=7.4 and l.3Hz), 8.25(1H, s),
CA 02241186 1998-06-23
217
11.97(1H, s).
IR(Nujol) . 1684cm 1.
mp . 94.6-97.2°C
Example 263
Synthesis of 6-ethoxycarbonyl-2-ethyl-1-[4-(4-fluoro-
benzyloxy)benzyl]benzimidazole (325)
A mixture of 0.534 g of ethyl 4-propionylamino-3-
aminobenzoate, 0.374 g of potassium carbonate, 0.800 g of 4-(4-
fluorobenzyloxy)benzyl bromide, 5 ml of ethyl acetate and 3 ml
of water was stirred at 75°C for 16 hours. The organic layer was
concentrated, and ethanol and 0.46 g of 36~ hydrochloric acid
were added to the residue. The mixture was stirred for 2 hours
while being heat-refluxed. The reaction mixture was neutralized
with potassium carbonate, and the solvent was then concentrated
under reduced pressure. The residue was extracted with ethyl
acetate and with water. The organic layer was concentrated under
reduced pressure, and was purified through silica-gel column
chromatography (eluent: a mixture of hexane and ethyl acetate at
a ratio of 1:1) to give 0.228 g of 6-ethoxycarbonyl-2-ethyl-1-
[4-(4-fluorobenzyloxy)benzyl]benzimidazole (325).
Properties of Compound (325):
iH-NMR(CDC13, S ) . 1.40(3H, t, J=7.lHz), 1.42(3H, t, J=7.5Hz),
2.86(2H, q, J=7.5Hz), 4.38(2H, q, J=7.lHz), 4.97(2H, s), 5.32(2H,
s), 6.88(2H, d, J=8.7Hz), 6.98(2H, d, J=8.7Hz), 7.05(2H, t,
J=8.7Hz), 7.37(2H, m), 7.76(2H, d, J=8.4Hz), 7.98(1H, dd, J=1.5
and 8.5Hz), 8.02(1H, s)
Exa ple 264
Synthesis of 6-carboxy-2-ethyl-1-[4-(4-fluorobenzyloxy)-
benzyl]benzimidazole (326)
In the same manner as in Example 53, 0.175 g of 6-carboxy-
2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole (326) were
formed from 0.225 g of 6-ethoxycarbonyl-2-ethyl-1-[4-(4-
fluorobenzyloxy)benzyl]benzimidazole.
Properties of Compound (326):
1H-NMR(DMSO-d6, ~) . 1.28(3H, t, J=7.4Hz), 2.89(2H, q, J=7.4Hz),
CA 02241186 1998-06-23
218
T
5.01(2H, s), 5.47(2H, s), 6.95(2H, d), 7.03(2H, d), 7.18(2H, t),
7.45(2H, m), 7.62(1H, d, J=8.4Hz), 7.77(1H, d, J=8.4Hz), 8.05(1H,
s)
Example 265
Synthesis of 6-(1-butanesulfonylcarbamoyl)-2-ethyl-1-[4-(4-
fluorobenzyloxy)benzyl]benzimidazole ammonium salt (327)
In the same manner as in Example 98, oily 6-(1-
butanesulfonylcarbamoyl)-2-ethyl-1-[4-(4-fluorobenzyloxy)-
benzyl]benzimidazole was obtained from 0.171 g of 6-carboxy-2-
ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole, 0.137 g of
N,N'-carbonyldiimidazole, 0.116 g of butanesulfonamide and 0.129
g of diazabicycloundecene. This compound was dissolved in ethyl
acetate, and aqueous ammonia was added thereto. The solid
material precipitated was separated through filtration, and was
dried to give 0.140 g of 6-(1-butanesulfonylcarbamoyl)-2-ethyl-
1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole ammonium salt (327).
Properties of Compound (327):
1 H-NMR(DMSO-d6, ~ ) . 0.83(3H, t), 1.25(3H, t), 1.35(2H,
m),1.61(2H, m), 2.84(2H, q), 3.27(2H, m), 5.01(2H, s), 5.42(2H,
s), 6.95(2H, d, J=7.8Hz), 7.02(2H, d, J=7.8Hz), 7.17(2H, t),
7.44(2H, m), 7.57(1H, d, J=8.lHz), 7.82(1H, d, J=8.lHz), 8.12(1H,
s).
IR(Nujol) . 1614cm 1.
mp . 105-115°C
Example 266
Synthesis of 1-[4-(3,4-dichlorobenzyloxy)benzyl]-6-ethoxy-
carbonyl-2-ethylbenzimidazole (328)
In the same manner as in Example 263, 2.01 g of I-[4-(3,4-
dichlorobenzyloxy)benzyl]-6-ethoxycarbonyl-2-ethylbenzimidazole
(328) were formed from 1.81 g of ethyl 4-propionylamino-3-
aminobenzoate and 3.18 g of 4-(3,4-dichlorobenzyloxy)benzyl
bromide.
Properties of Compound (328):
1H-NMR(CDC13, ~ ) . 1.40(3H, t, J=7.lHz), I.42(3H, t, J=7.5Hz),
2.86(2H, q, J=7.5Hz), 4.38(2H, q, J=7.lHz), 4.97(2H, s), 5.33(2H,
CA 02241186 1998-06-23
219
s), 6.87(2H, m), 6.98(2H, m), 7.22(1H, dd, J=2.0 and 8.3Hz),
7.44(1H, d, J=8.3Hz), 7.50(1H, d, J=2.OHz), 7.76(1H, d, J=8.6Hz),
7.97(1H, dd, J=1.6 and 8.6Hz), 8.02(1H, d, J=l.3Hz)
Example 267
Synthesis of 6-carboxy-1-[4-(3,4-dichlorobenzyloxy)benzyl]-2-
ethylbenzimidazo1e (329)
In the same manner as in Example 53, 1.82 g of 6-carboxy-
1-[4-(3,4-dichlorobenzyloxy)benzyl]-2-ethylbenzimidazo1e (329)
were formed from 2.01 g of 6-ethoxycarbonyl-2-ethyl-1-[4-(4-
fluorobenzyloxy)benzyl]benzimidazole.
Properties of Compound (329):
1H-NMR(DMSO-d6, ~ ) . 1.28(3H, t), 2.88(2H, q), 5.05(2H, s),
5.47(2H, s), 6.96(2H, d), 7.04(2H, d), 7.39(1H, m), 7.68-7.59(3H,
m), 7.78(1H, d, J=8.4Hz), 8.06(1H, s)
F;xample 268
Synthesis of 6-(1-butanesulfonylcarbamoyl)-1-[4-(3,4-dichloro-
benzyloxy)benzyl]-2-ethylbenzimidazole ammonium salt (330)
Oily 6-(1-butanesulfonylcarbamoyl)-1-[4-(3,4-dichloro-
benzyloxy)benzyl]-2-ethylbenzimidazole was obtained from 0.500 g
of 6-carboxy-1-[4-(3,4-dichlorobenzyloxy)benzyl]-2-ethyl-
benzimidazole, 0.356 g of N,N'-carbonyldiimidazole, 0.301 g of
butanesulfonamide and 0.334 g of diazabicycloundecene in the
same manner as in Example 98. This compound was dissolved in
ethyl acetate, and aqueous ammonia was added thereto. The solid
material precipitated was separated through filtration, and was
dried to give 0.51 g of 6-(1-butanesulfonylcarbamoyl)-1-[4-(3,4-
dichlorobenzyloxy)benzyl]-2-ethylbenzimidazole ammonium salt
(330).
Properties of Compound (330)
1H-NMR(DMSO-d6, ~) . 0.82(3H, t, J=7.3Hz), 1.26(3H, t, J=7.4Hz),
1.31(2H, m), 1.54(2H, m), 2.84(2H, q, J=7.4Hz), 3.07(2H, m),
5.05(2H, s), 5.41(2H, s), 6.95(2H, d, J=8.7Hz), 7.00(2H, d,
J=8.7Hz), 7.41(1H, d, J=8.2Hz), 7.46(1H, d, J=8.4Hz), 7.62(1H, d,
J=8.2Hz), 7.68(1H, s), 7.81(1H, d, J=8.4Hz), 7.97(1H, s).
IR(Nujol) . 1540cm 1.
CA 02241186 1998-06-23
a
220
mp . 99.5-101.5°C
Synthesis of 1-(4-biphenylmethyl)-6-(n-butylcarbamoyl)-2-ethyl-
benzimidazole (331)
In the same manner as in Example 15, 0.295 g of 1-(4-
biphenylmethyl)-6-(n-butylcarbamoyl)-2-ethylbenzimidazole (331)
were formed from 0.400 g of 1-(4-biphenylmethyl)-6-
chlorocarbonyl-2-ethylbenzimidazole hydrochloride, 0.233 g of n-
butylamine and 0.215 g of triethylamine.
Properties of Compound (331):
1H-NMR(DMSO-d6, ~ ) . 0.95(3H, t, J=7.3Hz), 1.37-1.48(2H, m),
1.45(3H, t, J=7.4Hz), 1.57-1.63(2H, m), 2.90(2H, q, J=7.5Hz),
3.46(2H, q, J=7.lHz), 5.42(2H, s), 6.16(1H, br s), 7.10(2H, d,
J=8.lHz), 7.34(1H, t, J=7.5Hz), 7.42(2H, t, J=7.5Hz), 7.48-
7.57(5H, m), 7.87(1H, d, J=8.4Hz), 7.91(1H, s).
IR(Nujol) . 1621cm 1.
mp . 170.5-173.0°C
Example 270
Synthesis of 1-(4-biphenylmethyl)-2-ethyl-6-(thiazol-2-yl-
carbamoyl)benzimidazole (332)
In the same manner as in Example 15, 0.179 g of 1-(4-
biphenylmethyl)-2-ethyl-6-(thiazol-2-ylcarbamoyl)benzimidazole
(332) were obtained from 0.400 g of 1-(4-biphenylmethyl)-6-
chlorocarbonyl-2-ethylbenzimidazole hydrochloride, 0.318 g of 2-
aminothiazole and 0.215 g of triethylamine.
Properties of Compound (332):
1H-NMR(DMSO-d6, ~) . 1.48(3H, t, J=7.5Hz), 2.95(2H, q, J=7.5Hz),
5.41(2H, s), 6.94(1H, d, J=3.6Hz), 7.06(2H, d, J=8.lHz), 7.26(1H,
d, J=3.6Hz), 7.32(1H, t, J=7.4Hz), 7.39(2H, t, J=7.3Hz), 7.47-
7.51(4H, m), 7.87(2H, s), 8.03(1H, s), 11.15(1H, s).
IR(Nujol) . 1652cm 1.
mp . 225.5-227.7°C
Example 271
Synthesis of 1-(4-biphenylmethyl)-2-ethyl-6-(2-pyridyl-
carbamoyl)benzimidazole (333)
CA 02241186 1998-06-23
221
In the same manner as in Example 98, 0.116 g of 1-(4-
biphenylmethyl)-2-ethyl-6-(2-pyridylcarbamoyl)benzimidazole
(333) were formed from 0.300 g of 1-(4-biphenylmethyl)-6-
carboxy-2-ethylbenzimidazole, 0.272 g of N,N~-
carbonyldiimidazole, 0.158 g of 2-aminopyridine and 0.256 g of
diazabicycloundecene.
Properties of Compound (333):
1 H-NMR.( CDCl 3 , ~ ) . 1. 47 ( 3H, t, J=7 . 6Hz ) , 2 . 93 ( 2H, q, J=7 .
4Hz ) ,
5.45(2H, s), 7.06(1H, dd, J=7.4 and 4.9Hz), 7.10(2H, d, J=8.lHz),
7.34(1H, t, J=7.4Hz), 7.42(2H, t, J=7.6Hz), 7.50-7.55(4H, m),
7.75(1H, t, J=7.9Hz), 7.79(1H, d, J=8.4Hz), 7.86(1H, d, J=8.4Hz),
7.98(1H, s), 8.30(1H, d, J=6.2Hz), 8.38(1H, d, J=8.4Hz),
8.62(lH,s).
IR(Nujol) . 1661cm 1.
mp . 160.9-164.5°C
Example 272
Synthesis of 6-(n-butylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-
methyl-benzimidazo1e (334)
In the same manner as in Example 15, 0.156 g of 6-(n-
butylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole
(334) were formed from 0.300 g of 6-chlorocarbonyl-1-(2,4-
dichlorobenzyl)-2-ethylbenzimidazole hydrochloride, 0.181 g of
tr.i.ethylamine and 0.196 g of n-butylamine.
Properties of Compound (334):
1H-NMR(CDC13, ~) . 0.96(3H, t, J=7.3Hz), 1.37-1.43(2H, m), 1.55-
1.62(2H, m), 2.56(3H, s), 3.46(2H, q, J=7.OHz), 5.40(2H, s),
6.15(1H, br s), 6.32(1H, d, J=8.5Hz), 7.07(1H, d, J=8.4Hz),
7.48(1H, d, J=2.OHz), 7.55(1H, d, J=8.4Hz), 7.74(1H, d, J=8.4Hz),
7.79(lH,s).
IR(Nujol) . 1636ciri 1.
mp . 146.6-147.5°C
Production Example 53
Production of ethyl 3-[sec-(2,4-dichlorophenetyl)amino]-4-
nitrobenzoate
A solution of 0.877 g of 3-fluoro-4-nitrobenzoic acid and
CA 02241186 1998-06-23
222
2.25 g of sec-(2,4-dichlorophenetyl)amine in 5m1 of toluene was
heat-refluxed for 15 hours. After the solvent was distilled off,
the residue was purified through silica-gel column
chromatography to obtain crude 3-[sec-(2,4-dichloro-
phenetyl)amino]-4-nitrobenzoic acid. To this compound were added
80 ml of ethanol and 3.0 g of 97~ sulfuric acid, and the mixture
was heat-refluxed for 4.5 hours. After ethanol was distilled off
under reduced pressure, the residue was extracted with
chloroform and with a saturated aqueous solution of sodium
hydrogencarbonate. The organic layer was dried, and was then
concentrated under reduced pressure. The residue was purified
through silica-gel column chromatography (eluent: a mixture of
hexane and ethyl acetate at a ratio of 2:1) to give 1.16 g of
ethyl 3-[sec-(2,4-dichlorophenetyl)amino]-4-nitrobenzoate.
Properties of the compound:
1H-NMR(CDC13, ~ ) . 1.35(3H, t, J=7.lHz), 1.64(3H, d, J=6.6Hz),
4.30(2H, q, J=7.lHz), 5.16(1H, m), 7.18-7.31(4H, m), 7.43(1H, d,
J=2.OHz), 8.21(1H, d, J=8.8Hz), 8.34(1H, d, J=5Hz)
prodLCti_on Example 54
Production of ethyl 4-amino-3-[sec-(2,4-dichlorophenetyl)-
amino]benzoate
A mixture of 1.14 g of ethyl 3-[sec-(2,4-
dichlorophenetyl)amino]-4-nitrobenzoate, 1.60 g of reduced iron,
ml of ethanol and 5 ml of acetic acid was heat-refluxed for 3
hours. The solid material was separated through filtration, and
the filtrate was concentrated. The residue was extracted with
chloroform and with 10~ hydrochloric acid. The organic layer was
washed with a saturated aqueous solution of sodium
hydrogencarbonate, and the solvent was distilled off under
reduced pressure. The residue was purified through silica-gel
column chromatography (eluent: a mixture of hexane and ethyl
acetate at a ratio of 2:1) to give 0.920 g of ethyl 4-amino-3-
[sec-(2,4-dichlorophenetyl)amino]benzoate.
Properties of the compound:
1 H-NMR(CDC1 3 , Cs ) . 1 .31 ( 3H, t, J=7 . 1Hz ) , 1 . 52 ( 3H, d, J=6 . 7Hz
) ,
CA 02241186 1998-06-23
223
3.56(1H, br s), 3.79(2H, br s), 4.23(2H, q, J=7.lHz), 4.96(1H, q,
J=6.7Hz), 6.68(1H, d, J=8.OHz), 7.03(1H, d, J=l.7Hz), 7.15(1H,
dd, J=2.1 and 8.4Hz), 7.35(1H, d, J=8.4Hz), 7.39-7.43(2H, m)
Example 273
Synthesis of 1-[sec-(2,4-dichlorophenetyl)]-6-ethoxycarbonyl-2-
methylbenzimidazole (335)
Acetyl chloride (0.243 g) was added dropwise to a
solution of 0.900 g of ethyl 4-amino-3-[sec-2,4-
dichlophenetyl)amino]benzoate in 2.0 ml of pyridine at room
temperature. Further, the mixture was stirred at room
temperature for 1 hour, and the reaction mixture was then
extracted with the addition of ethyl acetate and excess 10~
hydrochloric acid. The organic layer was washed with a saturated
aqueous solution of sodium hydrogencarbonate, and the solvent
was distilled off under reduced pressure to obtain crude ethyl
4-4-acetylamino-3-[sec-(2,4-dichlorophenetyl)amino]benzoate.
This crude product was immediately dissolved in 20 ml of ethanol,
and 0.4 ml of 36~ hydrochloric acid were added to the solution.
The mixture was heat-refluxed for 2 hours. The reaction solution
was neutralized with sodium hydrogencarbonate, and the solvent
was distilled off under reduced pressure. The residue was
extracted with ethyl acetate and with water. The organic layer
was concentrated, and the residue was purified through silica
gel column chromatography (eluent: a mixture of ethyl acetate
and methanol at a ratio of 20:1) to give 0.700 g of 1-[sec-(2,4
dichlorophenetyl)]-6-ethoxycarbonyl-2-methylbenzimidazole (335).
Properties of Compound (335):
1H-NMR(CDC13, ~ ) . 1.38(3H, t, J=7.2Hz), 2.01(3H, d, J=7.2Hz),
2.63(3H, s), 4.29-4.40(2H, m), 5.89(1H, q, J=7.2Hz), 7.37(1H, dd,
J=2.2 and 8.4Hz), 7.40(1H, d, J=2.OHz), 7.52(1H, d, J=8.4Hz),
7.67(1H, d, J=8.4Hz), 7.86(1H, s), 7.91(1H, dd, J=1.4 and 8.4Hz)
Example 274
Synthesis of 6-carboxy-1-[sec-(2,4-dichlorophenetyl)]-2-methyl-
benzimidazole (336)
In the same manner as in Example 53, 0.447 g of 6-carboxy-
CA 02241186 1998-06-23
224
1-[sec-(2,4-dichlorophenetyl)]-2-methylbenzimidazole (336) were
formed from 0.690 g of 1-[sec-(2,4-dichlorophenetyl)]-6-
ethoxycarbonyl-2-xnethylbenzimidazole.
Properties of Compound (336):
1H-NMR(DMSO-d6, ~) . 1.88(3H, d, J=6.8Hz), 2.57(3H, s), 6.01(1H,
q), 7.55(1H, d), 7.60-7.67(3H, m), 7.71(1H, d), 7.89(1H, d),
12.65(1H, br s)
Example 275
Synthesis of 6-(1-butanesulfonylcarbamoyl)-1-[sec-(2,4-dichloro-
phenetyl)]-2-methylbenzimidazole (337)
In the same manner as in Example 98, 6-(1-
butanesulfonylcarbamoyl)-1-[sec-(2,4-dichlorophenetyl)]-2-
methylbenzimidazole (336) was formed from 0.433 g of 6-carboxy-
1-[sec-(2,4-dichlorophenetyl)]-2-methylbenzimidazole, 0.412 g of
N,N'-carbonyldiimidazole, 0.348 g of butanesulfonamide and 0.386
g of diazabicycloundecene.
Properties of Compound (337)
1H-NMR(DMSO-d6, ~) . 0.84(3H, t, J=7.3Hz), I.34(2H, m), 1.57(2H,
m), 1.89(3H, d, J=7.OHz), 2.49(3H, s), 3.07(2H, m), 5.954(1H, q,
J=7.OHz), 7.41(1H, d, J=8.7Hz), 7.56(1H, dd, J=2.1 and 8.5Hz),
7.61(1H, d, J=2.lHz), 7.74-7.79(3H, m)
Example 276
Synthesis of 1-(4-biphenylmethyl)-2-ethyl-6-(phenylcarbamoyl)-
benzimidazole (338)
In the same manner as in Example 15, 0.195 g of 1-(4-
biphenylmethyl)-2-ethyl-6-(phenylcarbamoyl)benzimidazole (338)
were formed from 0.300 g of 1-(4-biphenylmethyl)-6-
chlorocarbonyl-2-ethylbenzimidazole hydrochloride, 0.243 g of
triethylamine and 0.224 g of aniline.
Properties of Compound (338):
1 H-NMR( CDC1 3 , S ) . 1 . 47 ( 3H, t, J=7 . 5Hz ) , 2 . 93 ( 2H, q, J=7 .
5Hz ) ,
5.44(2H, s), 7.11(2H, d, J=8.2Hz), 7.14(1H, t, J=7.4Hz), 7.32-
7.38(3H, m), 7.42(2H, t, J=7.4Hz), 7.51-7.54(4H, m), 7.63(2H, d,
J=7.8Hz), 7.69(1H, dd, J=8.4 and l.6Hz), 7.84(1H, d, J=8.4Hz),
7.88(1H, br s), 7.97(lH,d,J=l.5Hz).
CA 02241186 1998-06-23
225
IR(Nujol) . 1647cm 1.
mp . 171.7-172.1°C
gxamtle 277
Synthesis of 1-(4-biphenylmethyl)-2-ethyl-6-(1,3,4-thiadiazol-2-
ylcarbamoyl)benzimidazole (339)
In the same manner as in Example 98, 0.234 g of 1-(4-
biphenylmethyl)-2-ethyl-6-(1,3,4-thiadiazol-2-ylcarbamoyl)-
benzimidazole (339) were formed from 0.300 g of 1-(4-
biphenylmethyl)-6-carboxy-2-ethylbenzimidazole, 0.272 g of N,N'-
carbonyldiimidazole, 0.170 g of 2-amino-1,3,4-thiadiazole and
0.256 g of diazabicycloundecene.
Properties of Compound (339):
1H-NMR(CDC13, ~ ) . 1.45(3H, t, J=7.5Hz), 2.90(2H, q, J=7.5Hz),
5.53(2H,s), 7.07(2H, d, J=8.3Hz), 7.33(1H, t, J=7.5Hz), 7.40(2H,
t, J=7.3Hz), 7.52(4H, d, J=8.2Hz), 7.89(1H, d, J=8.5Hz), 8.08(1H,
dd, J=8.5 and l.6Hz), 8.34(1H, d, J=l.2Hz), 7.60(1H, s),
12.26(1H, s).
IR(Nujol) . 1654cm 1.
mp . 230.1-233.4°C
Example 278
Synthesis of 1-(4-biphenylmethyl)-2-ethyl-6-(tetrazol-5-
ylcarbamoyl)benzimidazole (340)
In the same manner as in Example 98, 0.135 g of 1-(4-
biphenylmethyl)-2-ethyl-6-(tetrazol-5-ylcarbamoyl)benzimidazole
(340) were formed from 0.300 g of 1-(4-biphenylmethyl)-6-
carboxy-2-ethylbenzimidazole, 0.272 g of N,N'-carbonyl-
diimidazole, 0.143 g of 5-aminotetrazole and 0.256 g of
diazabicycloundecene.
Properties of Compound (340)
1H-NMR(DMSO-d6, ~ ) . 1.32(3H, t, J=7.5Hz), 2.93(2H, q, J=7.5Hz),
5.61(2H, s), 7.23(2H, d, J=8.lHz), 7.34(1H, t, J=7.4Hz), 7.44(2H,
t, J=7.6Hz), 7.60-7.67(4H, m), 7.76(1H, d, J=8.5Hz), 7.98(1H, d,
J=8.6Hz), 8.46(1H, s), 12.30(1H, s), 15.95(1H, s).
IR(Nujol) . 1667cm 1.
mp . 273.1-276.0°C
CA 02241186 1998-06-23
226
Example 279
Synthesis of 1-(4-biphenylmethyl)-2-ethyl-6-(1,3,4-triazol-3-
ylcarbamoyl)benzimidazole (341)
In the same manner as in Example 98, 0.224 g of 1-(4-
biphenylmethyl)-2-ethyl-6-(1,3',4-triazol-3-ylcarbamoyl)-
benzimidazole (341) were formed from 0.300 g of 1-(4-
biphenylmethyl)-6-carboxy-2-ethylbenzimidazole, 0.272 g of N,N'-
carbonyldiimidazole, 0.141 g of 3-amino-1,3,4-triazole and 0.256
g of diazabicycloundecene.
Properties of Compound (341):
1H-NMR(DMSO-d6, ~ ) . 1.33(3H, t, J=7.4Hz), 2.93(2H, q, J=7.4Hz),
5.63(2H, s), 7.17(2H, d, J=8.3Hz), 7.35(1H, t, J=7.4Hz), 7.44(2H,
t, J=7.5Hz), 7.60-7.65(4H, m), 7.78(1H, d, J=7.4Hz), 7.83(1H, dd,
J=8.4 and l.5Hz), 8.17(1H, s), 8.77(2H, s), 12.04(1H, s).
IR(Nujol ) . 1675ciri 1 .
mp . 263.4-266.2°C
Example 280
Synthesis of 1-(4-biphenylmethyl)-2-ethyl-6-(1,3,4-triazol-2-
ylcarbamoyl)benzimidazole (342)
In the same manner as in Example 98, 0.215 g of 1-(4-
biphenylmethyl)-2-ethyl-6-(1,3,4-triazol-2-ylcarbamoyl)-
benzimidazole (342) were formed from 0.300 g of 1-(4-
biphenylmethyl)-6-carboxy-2-ethylbenzimidazole, 0.272 g of N,N'-
carbonyldiimidazole, 0.141 g of 2-amino-1,3,4-triazole and 0.256
g of diazabicycloundecene.
Properties of Compound (342):
1H-NMR(DMSO-d6, ~) . 1.31(3H, t, J=7.4Hz), 2.92(2H, q, J=7.4Hz),
5.60(2H, s), 7.23(2H, d, J=7.8Hz), 7.34(1H, t, J=7.2Hz), 7.44(2H,
t, J=7.6Hz), 7.60-7.66(4H, m), 7.72(1H, d, J=8.3Hz), 7.78(1H, s),
7.95(1H, d, J=8.3Hz), 8.43(1H, s), 11.85(1H, s), 13.57(1H, s).
IR(Nujol) . 1659cm-1.
mp . 306.0°C(decomp.)
Example 281
Synthesis of 1-(4-biphenylmethyl)-2-ethyl-6-(3-pyridyl-
carbamoyl)benzimidazole (343)
CA 02241186 1998-06-23
227
In the same manner as in Example 98, 0.229 g of 1-(4-
biphenylmethyl)-2-ethyl-6-(3-pyridylcarbamoyl)benzimidazole
(343) were formed from 0.300 g of 1-(4-biphenylmethyl)-6-
carboxy-2-ethylbenzimidazole, 0.272 g of N,N'-
carbonyldiimidazole, 0.158 g of 3-aminopyridine and 0.256 g of
diazabicycloundecene.
Properties of Compound (343):
1 H-NMR( CDC1 3 , ~ ) . 1 . 47 ( 3H, t, J=7 . 6Hz ) , 2 . 93 ( 2H, q, J=7 .
4Hz ) ,
5.45(2H, s), 7.10(2H, d, J=8.lHz), 7.29-7.36(2H, m), 7.42(2H, t,
J=7.4Hz), 7.53(4H, d, J=8.OHz), 7.71(1H, d, J=8.5Hz), 7.86(1H, d,
J=8.4Hz), 7.97(1H, s), 7.98(1H, s), 8.27(1H, d, J=8.4Hz),
8.38(1H, d, J=4.7Hz), 8.68(1H, d, J=2.5Hz).
IR(Nujol) . 1644ciri 1.
mp . 124.4-125.6°C
Example 282
Synthesis of 1-(2,4-dichlorobenzyl)-2-methyl-6-(2-pyridyl-
carbamoyl)benzimidazole (344)
In the same manner as in Example 98, 0.152 g of 1-(2,4-
dichlorobenzyl)-2-methyl-6-(2-pyridylcarbamoyl)benzimidazole
(344) were formed from 0.300 g of 6-carboxy-1-(2,4-
dichlorobenzyl)-2-methylbenzimidazole, 0.290 g of N,N'-
carbonyldiimidazole, 0.168 g of 2-aminopyridine and 0.273 g of
diazabicycloundecene.
Properties of Compound (344):
1 H-NMR(CDC1 3 , S ) . 2.59(3H, s), 5.43(2H, s), 6.33(1H, d,
J=8.4Hz), 7.06-7.10(2H, m), 7.50(1H, d, J=2.lHz), 7.77(1H, dt,
J=7.8 and l.9Hz), 7.83(2H, s), 7.88(1H, s), 8.30(1H, d, J=3.7Hz),
8.39(1H, d, J=8.3Hz), 8.78(1H, s).
IR(Nujol) . 1666ciri 1.
mp . 157.4-159.2°C
Example 283
Synthesis of 1-(4-biphenylmethyl)-2-ethyl-6-(4-pyridyl-
carbamoyl)benzimidazole (345)
In the same manner as in Example 98, 0.153 g of 1-(4-
biphenylmethyl)-2-ethyl-6-(4-pyridylcarbamoyl)benzimidazole
CA 02241186 1998-06-23
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(345) were formed from 0.300 g of 1-(4-biphenylmethyl)-6-
carboxy-2-ethylbenzimidazole, 0.272 g of N,N'-
carbonyldiimidazole, 0.158 g of 4-aminopyridine and 0.256 g of
diazabicycloundecene.
Properties of Compound (345):
iH-NMR(CDC13, ~ ) . 1.48(3H, t, J=7.4Hz), 2.94(2H, q, J=7.4Hz),
5.45(2H, s), 7.10(2H, d, J=8.lHz), 7.35(1H, t, J=7.4Hz), 7.42(2H,
t, J=7.4Hz), 7.50-7.60(6H, m), 7.691(1H, d, J=7.8Hz), 7.86(1H, d,
J=8.3Hz), 7.95(1H, s), 7.99(1H, br s), 8.54(2H, dd, J=1.5 and
4.7Hz).
IR(Nujol) . 1663cm 1.
mp . 123.8-124.7°C
production Example 55
Production of N-(1-butanesulfonyl)-4-acetylamino-3-nitro-
benzamide
In the same manner as in Production Example 28, 10.75 g of
N-(1-butanesulfonyl)-4-acetylamino-3-nitrobenzamide were formed
from 10.0 g of 4-acetylamino-3-nitrobenzoic acid, 9.40 g of
N,N'-carbonyldiimidazole, 7.92 g of 1-butanesulfonamide and 8.83
g of diazabicycloundecene.
Properties of the compound:
1H-NMR(DMSO-d6, ~ ) . 0.87(3H, t, J=7.4Hz), 1.37-1.44(2H, m),
1.64-1.71(2H, m), 2.12(3H, s), 3.52(2H, t, J=7.7Hz), 7.83(1H, d,
J=8.6Hz), 8.21(1H, dd, J=8.6 and 2.lHz), 8.54(1H, d, J=2.2Hz),
10.56(1H, s), 12.32(1H, s)
production Examgl~ 56
Production of N-(1-butanesulfonyl)-3-amino-4-acetylamino-
benzamide
In the same manner as in Production Example 29, 3.04 g of
N-(1-butanesulfonyl)-3-amino-4-acetylaminobenzamide were formed
from 10.75 g of N-(1-butanesulfonyl)-4-acetylamino-3-
nitrobenzamide.
Properties of the compound:
1H-NMR(DMSO-d6, S ) . 0.86(3H, t, J=7.3Hz), 1.33-1.43(2H, m),
1.59-1.67(2H, m), 2.07(3H, s), 3.37-3.43(2H, t), 5.12(2H, br s),
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7.13(1H, dd, J=8.2 and 2.OHz), 7.28(1H, d, J=l.9Hz), 7.40(1H, d,
J=8.3Hz), 9.09(1H, s)
Production Example 57
Production of N-(1-butanesulfonyl)-4-acetylamino-3-[4-(2-
pyridyl)benzylamino]benzamide
In the same manner as in Production Example 32, crude N-
(1-butanesulfonyl)-4-acetylamino-3-[4-(2-pyridyl)benzylamino]-
benzamide was obtained from 0.400 g of N-(1-butanesulfonyl)-3-
amino-4-acetylaminobenzamide and 0.477 g of 2-[(4-
bromomethyl)phenyl]pyridine. This product was used in the
subsequent reaction at once.
Example 284
Synthesis of 6-(1-butanesulfonylcarbamoyl)-1-[4-(2-pyridyl)-
benzyl]-2-methylbenzimidazole ('346)
In the same manner as in Example 183, 0.330 g of 6=(1-
butanesulfonylcarbamoyl)-1-[4-(2-pyridyl)benzyl]-2-methyl-
benzimidazole (346) were obtained from the above-mentioned crude
N-(1-butanesulfonyl)-4-acetylamino-3-[4-(2-pyridyl)benzylamino]-
benzamide.
Properties of Compound (346):
1H-NMR(DMSO-d6, 8) . 0.82(3H, t), 1.37-1.46(2H, m), 1.54-1.61(2H,
m), 2.54(3H, s), 3.10(2H, t, J=7.8Hz), 5.57(2H, s), 7.19(2H, d,
J=7.5Hz), 7.33(1H, t, J=5.2Hz), 7.49(1H, d, J=8.4Hz), 7.82-
7.87(2H, m), 7.90(1H, d, J=8.OHz), 8.01-8.04(3H, m), 8.63(1H, d,
J=4.2Hz).
IR(Nujol) . 1722cm 1.
mp . 292.4-298.4°C
Example 285
Synthesis of 5-chlorosulfonyl-1-(2,4-dichlorobenzyl)-2-
methylbenzimidazole (347) and 6-chlorosulfonyl-1-(2,4-
dichlorobenzyl)-2-methylbenzimidazole (348)
Four grams of 1-(2,4-dichlorobenzyl)-2-methylbenzimidazole
were added to 20 ml of chlorosulfonic acid in an ice bath, and
the mixture was stirred at room temperature for 24 hours and
then at 80°C for 1.5 hours. The reaction solution was poured
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into ice water, and the gum solid material precipitated was
separated through filtration to obtain a mixture of 5-
chlorosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole
(347) and 6-chlorosulfonyl-1-(2,4-dichlorobenzyl)-2-
methylbenzimidazole (348). This mixture was used in the
subsequent reaction at once.
Example 286
Synthesis of 5-aminosulfonyl-1-(2,4-dichlorobenzyl)-2-
methylbenzimidazole (349) and 6-aminosulfonyl-1-(2,4-
dichlorobenzyl)-2-methylbenzimidazole (350)
The mixture of 5-chlorosulfonyl-1-(2,4-dichlorobenzyl)-2-
methylbenzimidazole and 6-chlorosulfonyl-1-(2,4-dichlorobenzyl)-
2-methylbenzimidazole obtained in Example 285 was immediately
treated with 100 ml of 25~ aqueous ammonia at room temperature
for 1 hour. The solid material was separated through filtration
to give 2.68 g of a mixture of 5-aminosulfonyl-1-(2,4-
dichlorobenzyl)-2-methylbenzimidazole (349) and 6-
aminosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (350)
at a ratio of 1:1.
Properties of the mixture of Compound (349) and Compound (350):
1H-NMR(CD30D, ~) . 2.52(3/2H, s), 2.54(3/2H, s), 5.54(2H, s),
6.55(1H, d, J=6.9Hz), 7.17(1H, d, J=B.OHz), 7.52(1H, s), 7.65-
7.78(2H, m), 7.82(1/2H, s), 8.11(1/2H, s)
Examt~le 287
Synthesis of 6-(n-valerylaminosulfonyl)-1-(2,4-dichlorobenzyl)-
2-methylbenzimidazole (351) and 5-(n-valerylaminosulfonyl)-1-
(2,4-dichlorobenzyl)-2-methylbenzimidazole (352)
One milliliter of chloroform, 0.56 ml of triethylamine and
0.326 g of n-valeryl chloride were added to 0.500 g of a mixture
of 5-aminosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole
and 6-aminosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole
at a ratio of 1:1, and the mixture was stirred at room
temperature for 48 hours. water was added thereto to stop the
reaction, and the reaction solution was extracted with
chloroform. The organic layer was dried, concentrated, and
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purified through silica-gel column chromatography (eluent: a
mixture of chloroform and methanol at a ratio of 95:5) to obtain
0.360 g of a mixture of 5-(n-valerylaminosulfonyl)-I-(2,4-
dichlorobenzyl)-2-methylbenzimidazole and 6-(n-valerylamino-
sulfonyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole. Further,
this mixture was purified through medium-pressure silica-gel
column chromatography (eluent: a mixture of hexane and ethyl
acetate at a ratio of from 1 : 1 to 1 : 4 ) to give 0 . 95 g of 6- ( n-
valerylaminosulfonyl)-1-(2,4-dichlorobenzyl)-2-methyl-
benzimidazole (351) and 0.45 g of 5-(n-valerylaminosulfonyl)-1-
(2,4-dichlorobenzyl)-2-methylbenzimidazole (352).
Properties of Compound (351):
iH-NMR(DMSO-d6, ~) . 0.74(3H, t, J=7.3Hz), 1.09(2H, m), 1.31(2H,
m), 2.10(2H, t, J=7.3Hz), 2.53(3H, s), 5.63(2H, s), 6.60(1H, d,
J=8.4Hz), 7.32(1H, d, J=8.3Hz), 7.67-7.77(3H, m), 7.93(1H, s).
IR(KBr) . 1726cm 1.
mp . 207.5-210.0°C.
Mass(FD) . m/e 454(M+1)
Properties of Compound (352):
1H-NMR(DMSO-d6, ~) . 0.75(3H, t, J=7.3Hz), 1.11(2H, m), 1.34(2H,
m), 2.13(2H, t, J=7.4Hz), 2.51(3H, s), 5.59(2H, s), 6.57(1H, d,
J=8.5Hz), 7.32(1H, dd, J=2.2 and 8.4Hz), 7.57(1H, d, J=8.6Hz),
7.67(1H, dd, J=1.6 and 8.6Hz), 7.73(1H, d, J=2.lHz), 8.08(1H, d,
J=l.6Hz).
IR(KBr) . 1706em 1.
mp . 213.0-216.0°C
Example 288
Synthesis of 2,4-dimethyl-6-methoxycarbonylbenzimidazole
Methyl 4-acetylamino-5-amino-3-methylbenzoate was obtained
from methyl 4-amino-3-methylbenzoate by the method described in
Journal of Medicinal Chemistry, 1993, 36, 4040 - 4051.
Subsequently, this compound was heat-refluxed in acetic acid for
2 hours to give 2,4-dimethyl-6-methoxycarbonylbenzimidazole.
Properties of the compound:
1 H-NMR(CDC1 3 , l~ ) . 2.55(3H, s), 2.62(3H, s), 3.91(3H, s),
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7.74(1H, s), 8.07(1H, s), 10.65(1H, br s)
Synthesis of 1-(2,4-dichlorobenzyl)-2,4-dimethyl-6-methoxy-
carbonylbenzimidazole (353)
A mixture containing 0.900 g of 2,4-dimethyl-6-
methoxycarbonylbenzimidazole, 1.20 g of 2,4-dichlorobenzyl
chloride, 0.200 g of sodium iodide, 0.610 g of potassium
carbonate and 4 ml of N,N-dimethylformamide was stirred at 80°C
for 16 hours. After the organic solvent was distilled off under
reduced pressure, the residue was extracted with ethyl acetate
and with water. The organic layer was concentrated, and was
crystallized with the addition of hexane. The crystals were
separated through filtration, and were dried to give 1.08 g of
1-(2,4-dichlorobenzyl)-2,4-dimethyl-6-
methoxycarbonylbenzimidazo1e (353).
Properties of Compound (353):
1 H-NMR(CDC1 3 , ~ ) . 2.58(3H, s), 2.71(3H, s), 3.90(3H, S),
5.39(2H, s), 6.30(1H, d, J=8.4Hz), 7.07(1H, dd, J=8.4 and 2.OHz),
7.49(1H, d, J=2.OHz), 7.75(1H, s), 7.81(lH,s)
Example 290
Synthesis of 6-carboxy-1-(2,4-dichlorobenzyl)-2,4-dimethyl-
benzimidazole (354)
In the same manner as in Example 53, 0.435 g of 6-carboxy-
1-(2,4-dichlorobenzyl)-2,4-dimethylbenzimidazole (354) were
formed from 0.510 g of 1-(2,4-dichlorobenzyl)-2,4-dimethyl-6-
methoxycarbonylbenzimidazo1e.
Properties of Compound (354):
1H-NMR(DM5a-d6, ~ ) . 2.51(3H, s), 2.55(3H, s), 5.57(2H, s),
6.49(1H, d, J=8.4Hz), 7.31(1H, dd, J=8.4 and 2.2Hz), 7.62(1H, s),
7.72(1H, d, J=2.OHz), 7.78(1H, s), 12.64(1H, br s)
Example 291
Synthesis of 6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichloro-
benzyl)-2,4-dimethylbenzimidazole (355)
In the same manner as in Example 98, 0.468 g of 6-(1-
butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2,4-
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dimethylbenzimidazole (355) were formed from 0.417 g of 6-
carboxy-1-(2,4-dichlorobenzyl)-2,4-dimethylbenzimidazole, 0.290
g of N,N'-carbonyldiimidazole, 0.246 g of 1-butenesulfonamide
and 0.273 g of diazabicycloundecene.
Properties of Compound (355):
1H-NMR(DMSO-d6, ~) . 0.84(3H, t, J=7.4Hz), 1.38(2H, m), 1.64(2H,
m), 2.49(3H, s), 2.56(3H, s), 3.48(2H, t), 5.55(2H, s), 6.40(1H,
d, J=8.5Hz), 7.31(1H, dd, J=2.1 and 8.4Hz), 7.64(1H, s), 7.75(1H,
d, J=2.lHz), 7.90(1H, s), 11.79(1H, br s).
IR(Nujol) . 1682cni 1.
mp . 180.0-181.5°C
Production Example 58
Production of 4-phenoxybenzyl alcohol
Sodium borohydride (0.48 g) was added to a solution of
4.96 g of 4-phenoxybenzaldehyde in 20 ml of ethanol, and the
mixture was stirred at room temperature for 1.5 hours. After the
completion of the concentration, the residue was extracted with
tert-butylmethyl ether and with water. The organic layer was
concentrated to give 4.84 g of 4-phenoxybenzyl alcohol.
Properties of the compound:
1H-NMR(CDCl 3 , ~ ) . 4..67(2H, d, J=5.7Hz), 6.99-7.01(4H, m),
7.10(1H, t, J=7.4Hz), 7.32-7.35(4H, m)
Production Example 59
Production of 4-phenoxybenzyl chloride
Thionyl chloride (13.34 g) was added to 4.06 g of 4-
phenoxybenzyl alcohol, and the mixture was stirred at 80°C for
3.5 hours. After the completion of the concentration, the
reaction mixture was extracted with ethyl acetate and with water.
The organic layer was concentrated to give 4.31 g of 4-
phenoxybenzyl chloride.
Properties of the compound:
1H-NMR(CDC13, ~) . 4..58(2H, s), 6.96-7.03(4H, m), 7.11-7.14(1H,
m), 7.32-7.37(4H, m)
Synthesis of 6-ethoxycarbonyl-2-methyl-1-(4-phenoxybenzyl)-
CA 02241186 1998-06-23
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benzimidazole (356)
In the same manner as in Example 263, 0.49 g of ethyl 4-
acetylamino-3-[(4-phenoxy)benzylamino]benzoate were obtained
from 0.56 g of ethyl 4-acetylamino-3-aminobenzoate, 0.33 g of
sodium carbonate, 0.12 g of sodium iodide and 0.66 g of 4-
phenoxybenzyl chloride. Subsequently, this compound was
converted into 6-ethoxycarbonyl-2-methyl-1-(4-phenoxybenzyl)-
benzimidazole [(356), 0.44 g].
Properties of ethyl 4-acetylamino-3-[(4-phenoxy)-
benzylamino]benzoate:
1H-NMR(CDC13, ~ ) . 1.37(3H, t, J=7.lHz), 2.04(3H, s), 4.18(1H,
br s), 4.31-4.36(4H, m), 6.98-7.02(4H, m), 7.09-7.12(1H, m),
7.27-7.51(8H, m)
Properties of Compound (356):
1H-NMR(CDC13, ~) . 1.40(3H, t, J=7.lHz), 2.61(3H, s), 4.39(2H, q,
J=7.lHz), 5.35(2H, s), 6.92-6.95(2H, m), 6.97-7.00(2H, m),
7.02(2H, d, J=8.7Hz), 7.09-7.13(1H, m), 7.31-7.34(2H, m),
7.72(1H, d, J=8.6Hz), 7.98(1H, dd, J=1.5 and 8.4Hz), 8.04(1H, d,
J=l.2Hz)
Example 293
Synthesis of 6-carboxy-2-methyl-1-(4-phenoxybenzyl)benzimidazole
(357)
In the same manner as in Example 53, 0.37 g of 6-carboxy-
2-methyl-1-(4-phenoxybenzyl)benzimidazole (357) were formed from
0.44 g of 6-ethoxycarbonyl-2-methyl-1-(4-phenoxy)benzyl-
benzimidazole.
Properties of Compound (357):
iH-NMR(DMSO-d6, ~) . 2.57(3H, s), 5.54(2H, s), 6.95-6.97(4H, m),
7.09-7.13(3H, m), 7.33-7.37(2H, m), 7.60(1H, d, J=8.4Hz),
7.78(1H, d, J=8.4Hz), 8.07(1H, s), 12.72(1H, br s)
Example 294
Synthesis of 6-(1-butanesulfonylcarbamoyl)-2-methyl-1-(4-
phenoxybenzyl)benzimidazole (358)
In the same manner as in Example 98, 0.19 g of 6-(1-
butanesulfonylcarbamoyl)-2-methyl-1-(4-phenoxybenzyl)-
CA 02241186 1998-06-23
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a
benzimidazole (358) were obtained from 0.36 g of 6-carboxy-2-
methyl-1-(4-phenoxybenzyl)benzimidazole, 0.24 g of N,N'-
carbonyldiimidazole, 0.21 g of 1-butanesulfonamide and 0.23 g of
diazabicycloundecene.
Properties of Compound (358):
1H-NMR(DMSO-d6, ~) . 0.85(3H, t, J=7.4Hz), 1.40(2H, m), 1.68(2H,
m), 2.54(3H, s), 3.52(2H, t, J=7.8Hz), 5.51(2H, s), 6.96-6.98(4H,
m), 7.11(1H, t, J=7.4Hz), 7.17(2H, d, J=8.6Hz), 7.34-7.37(2H, m),
7.64(1H, d, J=8.5Hz), 7.79(1H, dd, J=1.5 and 8.5Hz), 8.24(1H, s),
11.92(1H, br s).
IR(Nujol) . 1632cm 1.
mp . 183.4-184.4°C
Example 295
Synthesis of 6-ethoxycarbonyl-2-methyl-1-(2-pyridylmethyl)-
benzimidazole (359)
In the same manner as in Example 263, 0.656 g of 6-
ethoxycarbonyl-2-methyl-1-(2-pyridylmethyl)benzimidazole (359)
were formed from 0.600 g of ethyl 4-acetylamino-3-aminobenzoate,
0.450 g of potassium carbonate, 0.122 g of sodium iodide and
0.413 g of 2-chloromethylpyridine. This compound was used in the
subsequent reaction at once.
Example 296
Synthesis of 6-carboxy-2-methyl-1-(2-pyridylmethyl)benzimidazole
(360)
In the same manner as in Example 53, 0.532 g of 6-carboxy-
2-methyl-1-(2-pyridylmethyl)benzimidazole (360) were formed from
0.656 g of 6-ethoxycarbonyl-2-methyl-1-(2-pyridylmethyl)-
benzimidazole.
Properties of Compound (360):
1H-NMR(DMSO-d6, ~ ) . 2.56(3H, s), 5.56(2H, s), 7.22(1H, d,
J=7.9Hz), 7.28(1H, dd, J=5.0 and 7.lHz), 7.45(1H, d, J=8.3Hz),
7.74-7.79(2H, m), 7.95(1H, s), 8.48(1H, d, J=8.5Hz).
F-xample 297
Synthesis of 1-(butanesulfonylcarbamoyl)-2-methyl-1-(2-pyridyl-
methyl)benzimidazole (361)
CA 02241186 1998-06-23
236
r
In the same manner as in Example 98, 0.142 g of 1-
(butanesulfonylcarbamoyl)-2-methyl-1-(2-pyridylmethyl)-
benzimidazole (361) were formed from 0.500 g of 6-carboxy-2-
methyl-1-(2-pyridylmethyl)benzimidazole, 0.394 g of N,N~-
carbonyldiimidazole, 0.334 g of 1-butanesulfonamide and 0.370 g
of diazabicycloundecene.
Properties of Compound (361):
1H-NMR(DMSO-d6, ~ ) . 0.83(3H, t, J=7.3Hz), 1.28-1.36(2H, m),
1.52-1.58(2H, m), 2.55(3H, s), 3.06(2H, t, J=7.9Hz), 5.56(2H, s),
7.17(1H, d, J=7.8Hz), 7.29(1H, dd, J=4.2 and 7.3Hz), 7.43(1H, d,
J=8.4Hz), 7.77(1H, dt, J=1.8 and 7.7Hz), 7.81(1H, dd, J=1.4 and
8.4Hz), 7.96(1H, s), 8.50(1H, d, J=4.7Hz)
IR(Nujol) . 1674cm1.
mp 13 9 °C ( decomp . )
Example 298
Synthesis of 6-ethoxycarbonyl-2-methyl-1-(4-nitrobenzyl)-
benzimidazole (362)
In the same manner as in Example 263, 0.51 g of 6-
ethoxycarbonyl-2-methyl-1-(4-nitrobenzyl)benzimidazole (362)
were formed from 0.67 g of ethyl 4-acetylamino-3-aminobenzoate,
0.39 g of sodium carbonate, 0.14 g of sodium iodide and 0.78 g
of 4-nitrodibenzyl bromide.
Properties of Compound (362):
1H-NMR(CDC13, ~) . 1.39(3H, t, J=7.lHz), 2.59(3H, s), 4.38(2H, q,
J=7.lHz), 5.49(2H, s), 7.20(2H, d, J=8.6Hz), 7.76(1H, d,
J=8.5Hz), 7.94(1H, d, J=l.lHz), 8.01(1H, dd, J=1.4 and 8.5Hz),
8.20(2H, d, J=8.6Hz).
Example 299
Synthesis of 1-(4-aminobenzyl)-6-ethoxycarbonyl-2-methyl-
benzimidazole (363)
Six milliliters of ethanol and 0.8 ml of acetic acid were
added to 0.50 g of 1-(4-nitrobenzyl)-6-ethoxycarbonyl-2-
methylbenzimidazole and 0.47 g of reduced iron, and the mixture
was refluxed for 4.5 hours. The reaction mixture was extracted
with water and with ethyl acetate. The organic layer was washed
CA 02241186 1998-06-23
237
with water, dried, and then concentrated under reduced pressure
to give 0.46 g of 1-(4-aminobenzyl)-6-ethoxycarbonyl-2-
methylbenzimidazole (363).
Properties of Compound (363):
1H-NMR(CDC13, ~) . 1.40(3H, t, J=7.2Hz), 2.59(3H, s), 4.38(2H, q,
J=7.2Hz), 5.25(2H, s), 6.61(2H, d, J=8.6Hz), 6.87(2H, d,
J=8.6Hz), 7.71(1H, d, J=8.3Hz), 7.96(1H, dd, J=1.5 and 8.4Hz),
8.05(1H, d, J=l.3Hz).
Example 300
Synthesis of 1-[(4-benzoylamino)benzyl]-6-ethoxycarbonyl-2-
methylbenzimidazole (364)
A solution of 0.25 g of benzoyl chloride in 4 ml of
chloroform was added to a solution of 0.45 g of 1-(4-
aminobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole and 0.15 g
of pyridine in 8 ml of chloroform, and the mixture was stirred
at room temperature for 16 hours. The reaction mixture was
extracted with water and then with chloroform. The organic layer
was concentrated under reduced pressure to give 0.33 g of 1-[(4-
benzoylamino)benzyl]-6-ethoxycarbonyl-2-methylbenzimidazole
(364).
Properties of Compound (364)
1H-NMR(CDC13, (~) . 1.40(3H, t, J=7.lHz), 2.59(3H, s), 4.38(2H, q,
J=7.lHz), 5.37(2H, s), 7.06(2H, d, J=8.5Hz), 7.46-7.50(2H, m),
7.53-7.57(1H, m), 7.61(2H, d, J=8.5Hz), 7.72(1H, d, J=8.4Hz),
7.84-7.86(2H, m), 7.89(1H, br s), 7.98(1H, dd, J=1.5 and 8.5Hz),
8.03(1H, s).
Example 3O1
Synthesis of 1-[(4-benzoylamino)benzyl]-6-carboxy-2-methyl-
benzimidazole (365)
In the same manner as in Example 53, 0.28 g of 1-[(4-
benzoylamino)benzyl]-6-carboxy-2-methylbenzimidazole (365) were
formed from 0.31 g of 1-[(4-benzoylamino)benzyl]-6-ethoxy-
carbonyl-2-methylbenzimidazo1e.
Properties of the compound (365):
1H-NMR(DMSO-d6, ~ ) . 2.58(3H, s), 5.52(2H, s), 7.12(2H, d,
CA 02241186 1998-06-23
238
J=8.5Hz), 7.48-7.52(2H, m), 7.54-7.58(1H, m), 7.61(1H, d,
J=8.4Hz), 7.73(2H, d, J=8.6Hz), 7.79(1H, dd, J=1.5 and 8.4Hz),
7.90-7.92(2H, m), 8.07(1H, d, J=l.2Hz), 10.26(1H, s), 12.73(1H,
br s).
Example 302
Synthesis of 1-[(4-benzoylamino)benzyl]-6-(1-butanesulfonyl-
carbamoyl)-2-methylbenzimidazole (366)
In the same manner as in Example 98, 0.14 g of 1-((4-
benzoylamino)benzyl]-6-(1-butanesulfonylcarbamoyl)-2-methyl-
benzimidazole (366) were obtained from 0.26 g of 1-[(4-
benzoylamino)benzyl]-6-carboxy-2-methylbenzimidazole, 0.17 g of
N,N~-carbonyldiimidazole, 0.14 g of 1-butanesulfonamide and 0.16
g of diazabicycloundecene.
Properties of Compound (366):
1H-NMR(DMSO-d6, ~) . 0.85(3H, t, J=7.4Hz), 1.40(2H, m), 1.68(2H,
m), 2.56(3H, s), 3.52(2H, t, J=7.8Hz), 5.50(2H, s), 7.15(2H, d,
J=8.6Hz), 7.50(2H, t, J=7.5Hz), 7.55-7.59(1H, m), 7.64(1H, d,
J=8.5Hz), 7.74(2H, d, J=8.6Hz), 7.79(1H, dd, J=1.6 and 8.5Hz),
7.90-7.92(2H, m), 8.24(1H, d, J=l.3Hz), 10.27(1H, s), 11.92(1H,
br s).
IR(Nujol ) . 1693ciri 1.
mp . 267.5-268.1°C.
Example 303
Synthesis of 6-ethoxycarbonyl-2-methyl-1-(4-(2-phenylethenyl)-
benzyl]benzimidazole (367)
In the same manner as in Example 263, 0.320 g of 6-
ethoxycarbonyl-2-methyl-1-[4-(2-phenylethenyl)benzyl]-
benzimidazole (367) were formed from 0.405 g of ethyl 4-
acetylamino-3-aminobenzoate, 0.253 g of potassium carbonate,
0.082 g of sodium iodide and 0.500 g of 4-chloromethylstilbene.
Properties of Compound (367):
1H-NMR(CDC13, ~) . 1.40(3H, t, J=7.2HJz), 2.6(3H, s), 4.38(2H, q,
J=7.lHz), 5.38(2H, s), 7.01-7.09(4H, m), 7.26(1H, t, J=7.4Hz),
7.35(2H, t, J=7.5Hz), 7.45(2H, d, J=8.2Hz), 7.49(2H, d, J=7.5Hz),
7.73(1H, d, J=8.5Hz), 7.99(1H, dd, J=1.5 and 8.4Hz), 8.30(1H, d,
CA 02241186 1998-06-23
239
J=l.2Hz).
Synthesis of 6-ethoxycarbonyl-2-methyl-1-[4-(2-phenylethyl)-
benzyl]-benzimidazole (368)
Five-percent palladium on carbon was added to a solution
of 0.320 g of 6-ethoxycarbonyl-2-methyl-1-[4-(2-phenyl-
ethenyl)benzyl]benzimidazole in 10 ml of ethanol in a nitrogen
atmosphere, and the mixture was stirred in a hydrogen atmosphere
for 23 hours. The solid material was separated through
filtration, and the filtrate was concentrated to give 6-
ethoxycarbonyl-2-methyl-1-[4-(2-phenylethyl)benzyl]-
benzimidazole (368). This compound was used in the subsequent
reaction at once.
Example 305
Synthesis of 6-carboxy-2-methyl-1-[4-(2-phenylethyl)benzyl]-
benzimidazole (369)
In the same manner as in Example 53, 0.242 g of 6-carboxy-
2-methyl-1-[4-(2-phenylethyl)benzyl]-benzimidazole (369) were
formed from 0.283 g of 6-ethoxycarbonyl-2-methyl-1-[4-(2-
phenylethyl)benzyl]-benzimidazole.
Properties of Compound (369)
1H-NMR(DMSO-d6, ~ ) . 2.56(3H, s), 2.82(4H, s), 5.51(2H, s),
7.02(2H, d, J=8.lHz), 7.11-7.27(7H, m), 7.61(1H, d, J=8.4Hz),
7.78(1H, dd, J=1.5 and 8.04(1H, s), 12.72(1H, s).
Exa nle 306
Synthesis of 6-(1-butanesulfonylcarbamoyl)-2-methyl-[4-(2-
phenylethyl)benzyl]benzimidazole (370)
In the same manner as in Example 98, 0.249 g of 6-(1-
butanesulfonylcarbamoyl)-2-methyl-[4-(2-phenylethyl)benzyl]-
benzimidazole (370) were formed from 0.225 g of 6-carboxy-2-
methyl-1-[4-(2-phenylethyl)benzyl]-benzimidazole, 1.214 g of
N,N'-carbonyldW midazole, 0.167 g of 1-butanesulfonamide and
0.185 g of diazabicycloundecene.
Properties of Compound (370):
1H-NMR(DMSO-d6, ~ ) . 0.86(3H, t, J=7.4Hz), 1.35-1.42(2H, m),
CA 02241186 1998-06-23
240
1.63-1.71(2H, m), 2.53(3H, s), 2.83(4H, s), 3.52(2H, t, J=7.7Hz),
5.49(2H, s), 7.04(2H, d, J=8.OHz), 7.12-7.25(7H, m), 7.64(1H, d,
J=8.4Hz), 7.79(1H, dd, J=1.7 and 8.5Hz), 8.22(1H, d, J=l.3Hz),
11.92(IH, s).
IR(Nujol) . 1682ciri 1.
mp . 95.4-99.0°C.
Production Example 60
Production of 4-benzoylbenzyl bromide
In the same manner as in Production Example 48, 5.28 g of
4-benzoylbenzyl bromide were formed from 3.92 g of 4-
methylbenzophenone, 4.28 g of N-bromosuccinimide and 0.40 g of
2,2'-azobisisobutylonitrile.
Properties of the compound:
1H-NMR(CDC13, ~ ) . 4.54(2H, s), 7.47-7.52(4H, m), 7.58-7.62(1H,
m), 7.77-7.82(4H, m).
Example 307
Synthesis of 1-[(4-benzoyl)benzyl]-6-ethoxycarbonyl-2-methyl-
benzimidazole (371)
In the same manner as in Example 263, 0.70 g of 1-[(4-
benzoyl)benzyl]-6-ethoxycarbonyl-2-methylbenzimidazole (371)
were formed from 0.56 g of ethyl 4-acetylamino-3-aminobenzoate,
0.33 g of sodium carbonate, 0.11 g of sodium iodide and 0.83 g
of 4-benzoylbenzyl bromide.
Properties of Compound (371):
1H-NMR(CDC13, ~) . 1.40(3H, t, J=7.2Hz), 2.61(3H, s), 4.39(2H, q,
J=7.2Hz), 5.47(2H, s), 7.14(2H, d, J=8.2Hz), 7.45-7.48(2H, m),
7.56-7.60(1H, m), 7.74-7.77(5H, m), 7.99-8.02(2H, m).
E~ple 308
Synthesis of 1-[(4-benzoyl)benzyl]-6-carboxy-2-methyl-
benzimidazole (372)
In the same manner as in Example 53, 0.55 g of 1-[(4-
benzoyl)benzyl]-6-carboxy-2-methylbenzimidazole (372) were
formed from 0.68 g of 1-[(4-benzoyl)benzyl]-6-ethoxycarbonyl]-2-
methylbenzimidazole.
Properties of Compound (372):
CA 02241186 1998-06-23
241
1H-NMR(DMSO-d6, 8 ) . 2.57(3H, s), 5.71(2H, s), 7.25(2H, d,
J=8.2Hz), 7.52(2H, t, J=7.7Hz), 7.62-7.66(2H, m), 7.68-7.72(4H,
m), 7.80(1H, dd, J=1.3 and 8.4Hz), 8.08(1H, d, J=l.lHz),
12.72(1H, br s).
E~yle 309
Synthesis of 1-[(4-benzoyl)benzyl]-6-(1-butanesulfonyl-
carbamoyl)-2-methylbenzimidazole (373)
In the same manner as in Example 98, 0.13 g of 1-[(4-
benzoyl)benzyl]-6-(1-butanesulfonylcarbamoyl)-2-methyl-
benzimidazole (373) were formed from 0.52 g of 1-[(4-
benzoyl)benzyl]-6-carboxy-2-methylbenzimidazole, 0.34 g of N,N'-
carbonyldiimidazole, 0.29 g of 1-butanesulfonamide and 0.32 g of
diazabicycloundecene.
Properties of Compound (373):
1H-NMR(DMSO-d6, ~) . 0.84(3H, t, J=7.4Hz), 1.38(2H, m), 1.66(2H,
m), 2.54(3H, s), 3.48(2H, t, J=7.7Hz), 5.67(2H, s), 7.27(2H, d,
J=8.2Hz), 7.51-7.55(2H, m), 7.63-7.73(6H, m), 7.81(1H, dd, J=1.6
and 8.5Hz), 8.21(1H, d, J=l.4Hz).
IR(Nujol ) . 1660ciri 1.
mp . 111.0-112.4°C.
Mass(FAB) . m/e 490(M+1).
Example 310
Synthesis of 6-carboxy-2-methyl-[4-(2-phenylethenyl)benzyl]-
benzimidazole (374)
In the same manner as in Example 53, 0.237 g of 6-carboxy-
2-methyl-[4-(2-phenylethenyl)benzyl]benzimidazole (374) were
formed from 0.500 g of 6-ethoxycarbonyl-2-methyl-1-[4-(2-
phenylethenyl)benzyl]benzimidazole.
Properties of Compound (374):
1H-NMR(DMSO-d6, ~ ) . 2.59(3H, s), 5.58(2H, s), 7.12(2H, d,
J=8.2Hz), 7.21(2H, s), 7.26(1H, t, J=7.4Hz), 7.36(2H, t,
J=7.6Hz), 7.57(4H, d, J=8.OHz), 7.62(1H, d, J=8.4Hz), 7.79(1H,
dd, J=1.5 and 8.4Hz), 8.07(1H, d, J=l.2Hz), 12.73(1H, s).
Synthesis of 6-(1-butanesulfonylcarbamoyl)-2-methyl-[4-(2-
CA 02241186 1998-06-23
242
phenylethenyl)benzyl]benzimidazole (375)
In the same manner as in Example 98, 0.239 g of 6-(1-
butanesulfonylcarbamoyl)-2-methyl-(4-(2-phenylethenyl)benzyl]-
benzimidazole (375) were formed from 0.237 g of 6-carboxy-2-
methyl-[4-(2-phenylethenyl)benzyl]benzimidazole, 0.209 g of
N,N'-carbonyldiimidazole, 0.176 g of 1-butanesulfonamide and
0.195 g of diazabicycloundecene.
Properties of Compound (375):
1H-NMR(DMSO-d6, ~ ) . 0.86(3H, t, J=7.4Hz), 1.35-1.43(2H, m),
1.63-1.70(2H, m), 2.56(3H, s), 3.52(2H, t, J=7.6Hz), 5.55(2H, s),
7.15(2H, d, J=8.2Hz), 7.22(2H, s), 7.26(1H, t, J=7.4Hz), 7.36(2H,
t, J=7.6Hz), 7.57(1H, d, J=7.3Hz), 7.58(1H, d, J=8.2Hz), 7.66(1H,
d, J=8.5Hz), 7.80(1H, d, J=8.4Hz), 8.24(1H, s), 11.93(1H, brs).
IR(Nujol) . 1680cm1.
mp . 140.3-143.4°C.
Example 312
Synthesis of 1-(dibenzofuran-2-ylmethyl)-6-ethoxycarbonyl-2-
methylbenzimidazo1e (376)
In the same manner as in Example 263, 0.47 g of 1-
(dibenzofuran-2-ylmethyl)-6-ethoxycarbonyl-2-methylbenzimidazo1e
(376) were formed from 0.480 g of ethyl 4-acetylamino-3-
aminobenzoate, 0.274 g of sodium carbonate, 0.097 g of sodium
iodide and 0.56 g of 2-bromomethyldibenzofuran.
Properties of Compound (376):
1H-NMR(CDC13, ~) . 1.38(3H, t, J=7.lHz), 2.62(3H, s), 4.36(2H, q,
J=7.lHz), 5.54(2H, s), 7.19(1H, dd, J=1.6 and 8.5Hz), 7.32(1H, t,
J=7.6Hz), 7.43-7.59(4H, m), 7.76(1H, d, J=8.4Hz), 7.85(1H, d,
J=7.lHz), 8.00(1H, dd, J=1.3 and 8.4Hz), 8.07(1H, d, J=l.2Hz).
Example 313
Synthesis of 6-carboxy-1-(dibenzofuran-2-ylmethyl)-2-
methylbenzimidazole (377)
In the same manner as in Example 53, 0.336 g of 6-carboxy-
1-(dibenzofuran-2-ylmethyl)-2-methylbenzimidazole (377) were
formed from 0.46 g of 6-ethoxycarbonyl-2-methylbenzimidazole.
Properties of Compound (377):
CA 02241186 1998-06-23
243
iH-NMR(DMSO-d6, ~ ) . 2.63(3H, s), 5.71(2H, s), 7.27(1H, d,
J=8.5Hz), 7.36(1H, t, J=7.5Hz), 7.50(1H, t), 7.61-7.68(3H, m),
7.78(1H, d, J=8.3Hz), 7.97(1H, s), 7.07-8.11(2H, m).
Example 314
Synthesis of 1-(dibenzofuran-2-ylmethyl)-6-(1-butanesulfonyl-
carbamoyl)-2-methylbenzimidazole (378)
In the same manner as in Example 98, 0.249 g of 1-
(dibenzofuran-2-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-
methylbenzimidazole (378) were formed from 0.255 g of 6-carboxy-
1-(dibenzofuran-2-ylmethyl)-2-methylbenzimidazole, 0.197 g of
N,N'-carbonyldiimidazole, 0.167 g of 1-butanesulfonamide and
0.185 g of diazabicycloundecene.
Properties of Compound (378):
1H-NMR(DMSO-d6, ~) . 0.81(3H, t, J=7.4Hz), 1.36(2H, m), 1.65(2H,
m), 2.60(3H, s), 3.50(2H, t, J=7.7Hz), 5.69(2H, s), 7.29(1H, dd,
J=1.96 and 8.7Hz), 7.34-7.38(1H, m), 7.48-7.52(1H, m), 7.63-
7.68(3H, m), 7.81(1H, dd, J=1.7 and 8.5Hz), 8.00(1H, d, J=l.4Hz),
8.94(1H, d, J=7.lHz), 8.28(1H, d, J=l.4Hz), 12.70(1H, br s).
IR(Nujol) . 1682ciri 1.
mp . 224.1-229.8°C.
Production Examgle 61
Production of N-1-butanesulfonyl-3-acetylamino-4-nitrobenzamide
In the same manner as in Production Example 28, 6.30 g of
N-1-butanesulfonyl-3-acetylamino-4-nitrobenzamide were obtained
from 5.15 g of 3-acetylamino-4-nitrobenzoic acid, 5.59 g of
N,N'-carbonyldiimidazole, 4.73 g of 1-butanesulfonamide and 5.25
g of diazabicycloundecene.
Properties of the compound:
1H-NMR(DMSO-d6, ~) . 0.87(3H, t, J=7.4Hz), 1.40(2H, m), 1.68(2H,
m), 2.07(3H, s), 3.51(2H, t), 7.83(1H, dd, J=1.8 and 8.5Hz),
8.03(1H, d, J=8.5Hz), 8.07(1H, d, J=l.8Hz), 10.43(1H, s),
12.64(1H, br s).
Production Example 62
Production of N-1-butanesulfonyl-3-amino-4-nitrobenzamide
A mixture containing 6.30 g of N-1-butanesulfonyl-3-
CA 02241186 1998-06-23
244
acetylamino-4-nitrobenzamide, a 10~ sodium hydroxide aqueous
solution, 300 ml of ethanol and 200 ml of water was stirred at
room temperature for 4 hours and then at 50 °C for 3 hours . The
solvent was distilled off to approximately a half volume, and
the residue was adjusted to a pH of 2 with 10~ hydrochloric acid.
The crystals precipitated were collected, and were dried under
reduced pressure to give 5.22 g of N-1-butanesulfonyl-3-amino-4-
nitrobenzamide.
Properties of the compound:
iH-NMR(DMSO-d6, ~) . 0.87(3H, t, J=7.4Hz), 1.40(2H, m), 1.66(2H,
m), 3.49(2H, m), 6.99(1H, dd, J=1.8 and 9.OHz), 7.49(1H, d,
J=l.8Hz), 7.55(2H, br s), 8.04(1H, d, J=9.OHz), 12.28(1H, br s).
Production Example 63
Production of N-1-butanesulfonyl-3-(2,4-dichlorobenzylamino)-4-
nitrobenzamide
A solution containing 1.10 g of N-1-butanesulfonyl-3-
amino-4-nitrobenzamide, 0.273 g of sodium iodide, 1.54 g of
potassium carbonate, 2.17 g of 2,4-dichlorobenzyl chloride and
ml of methanol was stirred at 60°C for 24 hours. Further,
2.00 g of 2,4-dichlorobenzyl chloride were added thereto, and
the mixture was heated at 60°C for 36 hours. To the reaction
solution were added ethyl acetate and a saturated aqueous
solution of sodium hydrogencarbonate, and N-1-butanesulfonyl-3-
(2,4-dichlorobenzylamino)-4-nitrobenzamide was extracted in the
aqueous layer. The organic layer was concentrated to give 0.885
g of N-1-butanesulfonyl-3-(2,4-dichlorobenzylamino)-4-nitro-
benzamide.
Properties of the compound:
1H-NMR(DMSO-d6, ~) . 0.81(3H, t, J=7.3Hz), 1.29(2H, m), 1.49(2H,
m), 2.97(2H, m), 4.66(2H, d, J=6.OHz), 7.22(1H, d, J=8.9Hz),
7.27(1H, s), 7.31(1H, d, J=8.4Hz), 7.37(1H, d, J=8.3Hz), 7.65(1H,
s), 8.04(1H, d, J=8.9Hz), 8.57(1H, t).
production Example 64
Production of N-1-butanesulfonyl-4-amino-3-(2,4-dichloro-
benzylamino)benzamide
CA 02241186 1998-06-23
245
N-1-butanesulfonyl-3-(2,4-dichlorobenzylamino)-4-nitro-
benzamide (0.505 g) was added to a mixture of 1.32 g of sodium
hydrosulfite, 1 ml of ethanol, 1 ml of tetrahydrofuran and 1 ml
of water at room temperature. The mixture was heat-refluxed for
40 minutes. The solvent was distilled off under reduced pressure,
and water was added to the residue. The solid material
precipitated was collected, and was dried. Further, the
resulting material was washed with a mixed solution of 10 ml of
methanol and 3 ml of water, and was dried to give 0.220 g of N-
1-butanesulfonyl-4-amino-3-(2,4-dichlorobenzylamino)benzamide.
Properties of the compound:
1H-NMR(DMSO-d6, ~) . 0.93(3H, t, J=7.4Hz), 1.45(2H, m), 1.83(2H,
m), 3.57(2H, m), 5.45(2H, s), 6.36(1H, d, J=8.2Hz), 7.11(1H, d,
J=8.3Hz), 7.51(1H, s), 7.75(1H, d), 7.79(1H, d), 7.88(1H, s).
Example 315
Synthesis of 6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichloro-
benzyl)-2-hydroxybenzimidazole (379)
A mixture of 0.220 mg of N-1-butanesulfonyl-4-amino-3-
(2,4-dichlorobenzylamino)benzamide, 0.3 ml of tetramethoxy-
methane and 2.0 ml of acetic acid was stirred at 60°C for 4 hours.
Acetic acid was distilled off under reduced pressure, and the
residue was extracted with chloroform and with water. The
chloroform layer was concentrated, and 4.0 ml of methanol and
36~ hydrochloric acid (4 drops) were added to the residue. The
mixture was stirred at 60°C for 2 hours. The reaction solution
was neutralized with a saturated aqueous solution of sodium
hydrogencarbonate. The crystals precipitated were washed with
water, and were dried to give 0.207 g of 6-(1-butane-
sulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-hydroxybenzimidazole
(379).
Properties of Compound (379):
1H-NMR(DMSO-d6, S) . 0.83(3H, t, J=7.3Hz), 1.36(2H, m), 1.61(2H,
m), 3.40(2H, m), 5.08(2H, s), 6.94(1H, d, J=8.3Hz), 7.11(1H, d,
J=8.2Hz), 7.36(1H, dd, J=2.0 and 8.4Hz), 7.58(1H, s), 7.68-
7.73(2H, m), 11.47(1H, br s), 11.77(1H, br s).
CA 02241186 1998-06-23
246
IR(Nujol) . 1689ciri 1.
mp . 254-256°C.
Mass(FD) . m/e 455(M).
Example 316
Synthesis of 6-ethoxycarbonyl-2-methyl-1-(2-quinolylmethyl)-
benzimidazole (380)
In accordance with Example 263, 0.87 g of 6-
ethoxycarbonyl-2-methyl-1-(2-quinolylmethyl)benzimidazole (380)
were formed from 2.22 g of ethyl 4-acetylamino-3-aminobenzoate,
1.27 g of sodium carbonate, 0.45 g of sodium iodide and 2.28 g
of 2-bromomethylquinoline.
Properties of the compound (380):
1H-NMR(DMSO-d6, (S) . 1.27(3H, t, J=7.lHz), 2.62(3H, s), 4.26(2H,
q, J=7.lHz), 5.85(2H, s), 7.35(1H, d, J=8.5Hz), 7.58(1H, m),
7.63(1H, d, J=8.4Hz), 7.73(1H, m), 7.78(1H, dd, J=1.3 and 8.4Hz),
7.86(1H, d, J=8.4Hz), 7.95(1H, d, J=8.OHz), 8.14(1H, s), 8.36(1H,
d, J=8.5Hz).
Eagle 317
Synthesis of 6-carboxy-2-methyl-(2-quinolylmethyl)benzimidazole
(381)
In the same manner as in Example 53, 0.46 g of 6-carboxy-
2-methyl-(2-quinolylmethyl)benzimidazole (381) were formed from
0.85 g of 6-ethoxycarbonyl-2-methyl-1-(2-quinolylmethyl)-
benzimidazole.
Properties of Compound (381):
1H-NMR(DMSO-d6, ~ ) . 2.62(3H, s), 5.83(2H, s), 7.35(1H, d,
J=8.5Hz), 7.57(1H, m), 7.60(1H, d, J=8.5Hz), 7.72(1H, t,
J=7.6Hz), 7.77(1H, d, J=8.4Hz), 7.86(1H, d, J=8.4Hz), 7.94(1H, d,
J=8.lHz), 8.11(1H, s), 8.35(1H, d, J=8.5Hz).
F,xample 31_8
Synthesis of 6-(1-butanesulfonylcarbamoyl)-2-methyl-1-(2-
quinolylmethyl)benzimidazole (382)
In the same manner as in Example 98, 0.088 g of 6-(1-
butanesulfonylcarbamoyl)-2-methyl-1-(2-quinolylmethyl)-
benzimidazole (382) were formed from 0.222 g of 6-carboxy-2-
CA 02241186 1998-06-23
247
methyl-1-(2-quinolylmethyl)benzimidazole, 0.195 g of N,N'-
carbonyldiimidazole, 0.165 g of 1-butanesulfonamide and 0.183 g
of diazabicycloundecene.
Properties of Compound (382):
1H-NMR(DMSO-d6, ~ ) . 0.82(3H, t, J=7.3Hz), 1.36(2H, m), 1.64(2H,
m), 2.61(3H, s), 3.48(2H, t, J=7.4Hz), 5.82(2H,s), 7.32(lH,d,
J=8.5Hz), 7.58(1H, m), 7.65(1H, d, J=8.5Hz), 7.73(1H, t,
J=7.6Hz), 7.78(1H, m), 7.87(1H, d, J=8.5Hz), 7.95(lH,d, J=8.lHz),
8.23(1H, s), 8.37(1H, d, J=8.5Hz), 11.86(lH,brs).
IR(Nujol) . 1684cm1.
mp . 185.5-187.5°C.
prodLCtion Example 65
Production of ethyl 4-amino-3-(2,4-dichlorobenzylamino)benzoate
Crude ethyl 4-amino-3-(2,4-dichlorobenzylamino)benzoate
was formed from 1.40 g of 3-(2,4-dichlorobenzylamino)-4-
nitrobenzoate and 4.50 g of sodium hydrosulf ite in the same
manner as in Production Example 64. This compound was used in
the subsequent reaction at once.
Exa~~2le 319
Synthesis of 1-(2,4-dichlorobenzylamino)-2-hydroxy-6-ethoxy-
carbonylbenzimidazole (383)
In the same manner as in Example 315 , 0 . 400 g of 1- ( 2 , 4-
dichlorobenzylamino)-2-hydroxy-6-ethoxycarbonylbenzimidazole
(383) were formed from ethyl 4-amino-3-(2,4-
dichlorobenzylamino)benzoate obtained in the above-mentioned
Production Example 63 and 2.60 g of tetramethoxymethane.
Properties of Compound (383):
1H-NMR(DMSO-d6, ~) . 1.27(3H, t, J=7.lHz), 4.24(2H, q, J=7.lHz),
5.12(2H, s), 7.04(1H, d, J=8.4Hz), 7.12(1H, d, J=8.2Hz), 7.37(1H,
dd, J=2.1 and 8.4Hz), 7.51(1H, s), 7.67-7.72(2H, m), 11.37(1H,
br s)
Example 320
Synthesis of 6-ethoxycarbonyl-2-methyl-1-[3-(4-bromoiso-
quinolyl)methyl]benzimidazole (384)
In the same manner as in Example 263, 0.30 g of 6-
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ethoxycarbonyl-2-methyl-1-[3-(4-bromoisoquinolyl)methyl]-
benzimidazole (384) were formed from 0.87 g of ethyl 4-
acetylamino-3-aminobenzoate, 0.53 g of sodium carbonate, 0.18 g
of sodium iodide and 0.87 g of 4-bromo-3-bromomethylisoquinoline.
Properties of Compound (384):
1H-NMR(DMSO-d6, ~) . 1.26(3H, t, J=7.OHz), 2.59(3H, s), 4.24(2H,
q, J=7.OHz), 5.93(2H, s), 7.61(1H, d, J=8.4Hz), 7.75-7.80(2H, m).
7.99(1H, m), 8.03(1H, s), 8.13(1H, d, J=8.lHz), 8.23(1H, d,
J=8.5Hz), 9.12(1H, s).
Example 321
Synthesis of 6-carboxy-2-methyl-[3-(4-bromoisoquinolyl)methyl]-
benzimidazole (385)
In the same manner as in Example 53, 0.118 g of 6-carboxy-
2-methyl-[3-(4-bromoisoquinolyl)methyl]benzimidazole (385) were
formed from 0.290 g of 6-ethoxycarbonyl-2-methyl-1-[3-(4-
bromoisoquinolyl)methyl]benzimidazole. This compound was used in
the subsequent reaction at once.
~~,xample 322
Synthesis of 6-(1-butanesulfonylcarbamoyl)-2-methyl-1-[3-(4-
bromoisoquinolyl)methyl]benzimidazole (386)
In the same manner as in Example 98, 0.075 g of 6-(1-
butanesulfonylcarbamoyl)-2-methyl-1-[3-(4-bromoisoquinolyl)-
methyl]benzimidazole (386) were formed from 0.111 g of 6-
carboxy-2-methyl-1-[3-(4-bromoisoquinolyl)-methyl]benzimidazole,
0.097 g of N,N'-carbonyldiimidazole, 0.082 g of 1-
butanesulfonamide and 0.091 g of diazabicycloundecene.
Properties of Compound (386):
1H-NMR(DMSO-d6, ~) . 0.81(3H, t, J=7.4Hz), 1.35(2H, m), 1.62(2H,
m), 2.54(3H, s), 3.46(2H, t, J=7.5Hz), 5.91(2H, s), 7.63(1H, d,
J=8.5Hz), 7.76(1H, dd, J=8.5 and l.4Hz), 7.79(1H, t, J=7.6Hz),
8.00(1H, t, J=7.9Hz), 8.08(1H, t, J=l.lHz), 8.13(1H, d, J=8.2Hz),
8.24(1H, d, J=8.5Hz), 9.11(lH,s), 11.81(1H, brs).
IR(Nujol) . 1678ciri 1.
mp . 258-259°C.
Mass(FAB) . m/e 515, 517(M+1).
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From among the compounds of the present invention, the
typical compounds were selected, and were tested for
pharmacological properties.
Test Example 1
Stimulatory activity of triglyceride (TG) accumulation in 3T3-L 1
cells (pre-adipocytes)
Test com on and
6-benzylsulfonylcarbamoyl-2-cyclopropyl-1-(2-
fluorobenzyl)benzimidazole
Devices used
1. Centrifuge: TOMY LC-122
2. Incubator: ESPEC BNA-121D
3. Mixer: Automatic Labo-Mixer
4. Water bath: TAITEC PERSONAL-11
5. Spectrophotometer: Shimadzu UV Visible Spectro-
photometer UV-160A
6. 24-well plate: IWAKI GLASS CORNING
Reac~~ents used
1. Medium: Dulbecco minimum essential medium (MEM) + 5~
fetal calf serum (FCS)
2. PBS (-): solution having the following composition
NaCl 0.8 g/liter
KC1 0.2
NaaHP04 1 . 15
KH2P04 0.2
3. Solution of EDTA and trypsin:
0.02 EDTA + 0.25 trypsin/PBS(-)
4. Dexamethasone: made by Sigma
5. IBMX (3-isobutyl-1-methylxanthine): made by Sigma
6. Insulin: made by Sigma
7. DMSO (dimethylsulfoxide):
made by Wako Pure Chemical Industries, Ltd.
8. TG measuring kit:
Triglyceride-Test Wako (acetyl-acetone method): made
by Wako Pure Chemical Industries, Ltd.
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9. 0.1-N NaOH solution:
prepared by diluting a 1N NaOH solution to 10 times
with distilled water.
10. Bio-Rad Protein Assay Reagent: made by Bio-Rad.
11. Bovine albumin: made by Sigma
Test method
preparat;on of 3T3-L1 cells
3T3-L1 cells just before a confluent state were prepared
in an F75 flask. The medium was removed, and the residue was
washed twice with 5 ml of PBS (-). The cells were detached using
a solution of EDTA and trypsin. Ten milliliters of the medium
were added thereto to form a suspension. This suspension was
collected in a 50-milliliter centrifuge tube, and was subjected
to centrifugation at 1,000 rpm for 5 minutes. Thus, the cells
were precipitated, and the supernatant was removed. The cells
were re-suspended in 20 ml of the medium, and the number of
cells was counted. The suspension was adjusted such that the
concentration of the cells reached 6 x 104 cells/ml, and was
inoculated into a 24-well plate in an amount of 1 ml/well. In
this state, the incubation was conducted in an incubator at 37°C
in 5~ C02 for 2 days.
prP~,a_rat;nn and addition of dexamethasone and IBMX
A solution of 1-mM dexamethasone and 500-mM IBMX was
prepared in DMSO. Further, this solution was diluted to 1,000
times with the medium to form a solution of 1~M dexamethasone
and 0.5mM IBMX. At the same time, DMSO was diluted with the
medium to form a 0.1~ DMSO solution as well.
Subsequently, the 24-well plate containing the incubated
3T3-L1 cells was withdrawn from the incubator. It was identified
using a microscope that the cells became confluent, and the
medium was removed through suction. The 2 wells of the 24-well
plate were charged with the 0.1~ DMSO solution in an amount of 1
ml/well, and the remaining 22 wells were charged with the
solution of 1-uM dexamethasone and 0.5mM IBMX in an amount of 1
ml/well. In this state, the incubation was conducted in an
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incubator at 37°C in 5~ C02 for 1 day.
A test chemical agent was diluted with DMSO to 1 x 10-2 M,
1 x 10-3 M and 1 x 10-4 M. The dilute solutions were further
diluted to 500 times, and were adjusted to 2 X 10-5 M, 2 x 10-6 M
and 2 x 10-~ M respectively. At the same time, a 0.2~ DMSO
solution was also prepared. Insulin which had been adjusted to
100 uM (in 0.2~ bovine serum albumin (BSA) and 3-mM HC1) and had
been stored at -80°C was naturally thawed, diluted to 50,000
times with the medium, and adjusted to 2-nM.
Subsequently, the 24-well plate to which dexamethasone and
IBMX had been added the preceding day was withdrawn from the
incubator. It was identified using a microscope that the shape
of the cells was changed with the addition of dexamethasone and
IBMX. Then, the medium was removed through suction. The 2 wells
to which the 0.1~ DMSO solution had been added the preceding day
were charged with the 0.2$ DMSO solution in an amount of 500
ul/well and the medium (this was required to check the cell
state at that time). The remaining 22 wells (containing the
solution of dexamethasone and IBMX) were charged with the 0.2$
DMSO solution (2 wells) or the test chemical agent (20 wells) in
an amount of 500 ul/well and then with the insulin solution in
an amount of 500 ~.tl/well. In this state, the incubation was
conducted in an incubator at 37°C in 5~ C02 for from 4 to 5 days.
MPa~nrPment of triglyceride (TG) and protein
Four to five days after the addition of the test chemical
agent and the insulin solution, the 24-well plate was withdrawn
from the incubator. The medium was discarded by decantation, and
the remaining medium was then absorbed in a paper towel to
completely remove the medium. Subsequently, the residue was
extracted twice with isopropyl alcohol, and TG was measured at a
wavelength of 410 nm using a TG-measuring kit (acetyl-acetone
method). Subsequently, isopropyl alcohol was completely
vaporized from the plate in which the extraction with isopropyl
alcohol was completed. This plate was then charged with a 0.1-N
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NaOH solution in an amount of 400 ul/well, and was allowed to
stand at room temperature for 30 minutes to dissolve the cells.
This solution was sampled into a tube in an amountof 50 u1.
Further, a solution obtained by diluting a Bio-Rad protein assay
reagent to 5 times with distilled water was added to the tube in
an amount of 2.5 ml. The mixture was stirred well, and protein
was measured at a measurement wavelength of 595 nm using a
spectrophotometer.
Results
The stimulatory activity of the test compound for TG
accumulation was calculated, when 1 x 10-6 M of a control
compound, pioglitazone, was defined as 100 and insulin (+)
without the chemical agent was defined as 0~. The result is
shown following.
Table 1
Concentration (M) Stimulatory activity of
TG accumulation ~
--
1 x 10-5 38. 2~
rest Example 2
Test for activity of decreasing plasma glucose using db/db
mice
Test compounds
6-benzenesulfonylcarbamoyl-2-cyclopropyl-1-(2-fluoro-
benzyl)benzimidazole (177)
6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methyl-
benzimidazole (163)
1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-
methylbenzimidazole (172)
Animal used
Five-week-old female mice (C57BL/KsJ-dbm db+/db+,
C57BL/KsJ-dbm +m/+m (Jackson Laboratory) were purchased, and
were kept for 2 to 3 weeks . Then, these mice were used in the
test.
PreFaratiOri Of an a5~ent
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A test compound was mixed with a powdered chow (CE-2, made
by Nippon Clea) using a mortar. According to the amount of food
intake of the mouse, the mixing ratios, 0.1$, 0.03$, and 0.01
corresponded to 100, 30, and 10 mg/kg body weight, respectively.
The mixed chow was changed twice a week. The feed amount and the
remaining amount were recorded, and the intake was calculated
from the difference therebetween.
Test schedule
The female db/db mice were grouped according to the body
weight, the plasma glucose and the plasma triglyceride
concentrations. Then, the mixture containing the test compound
was administered to the mice for 14 days (from 8 to 10 weeks
old). In the morning on day 7 and day 14, the blood was
collected from the orbital venous plexus using heparinized glass
capillary tubes (Chase Heparinized Capillary Tubes), and a
plasma fraction was obtained through centrifugal separation.
Plasma glucose, triglyceride, and insulin concentrations were
measured on day 0 and day 14 as well as plasma glucose and
triglyceride concentrations on day 7. The body weight was
measured on day 0, day 7, and day 14. After the final collection
of the blood, the mice were killed using CO~ gas.
Measurement method
The plasma glucose was measured by a glucose oxidase
method (Glucose CII-Test Wako made by Wako Pure Chemical
Industries, Ltd.) using from 10 to 15 p1 of plasma. The plasma
triglyceride concentration was measured by a GPO-p-chlorophenol
method (Triglyceride G-Test Wako made by Wako Pure Chemical
Industries, Ltd.) or a GPO-DADS method (Triglyceride E-Test
Wako) using from 10 to 15 u1 of plasma. The above-mentioned
measurements were conducted immediately after the blood
collection. The plasma insulin concentration was measured by
radio immuno assay method (Phadesef Insulin RIA Kit made by Cabi
Pharmacia) using 20 p1 of plasma (which can be stored at -20°C).
The difference in the plasma glucose and the plasma
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triglyceride concentrations betweeen the db/db mouse and the +/+
mouse was defined as 100, and the rate ($) of decrease in the
plasma glucose and the plasma triglyceride concentrations of the
group to which the test compound was administered was calculated.
The results were shown in Table 2.
Table 2
Activity of
Compound Dose (mg/kg) decreasing
No. plasma glucose
(177) 30 34.5
(163) 30 72
172 10 70 - 80
TNDU~'T'RTAT, ~PpLIGARIT,TT'V
Herein provided are novel benzimidazole derivatives and
their pharmaceutically acceptable salts. These compounds and
their salts have blood sugar level-depressing activity or pDES-
inhibiting activity, and are useful for preventing and treating
impaired glucose tolerance, diabetes (type II diabetes),
diabetic complications such as diabetic nephropathy, diabetic
neuropathy and diabetic retinopathy, syndrome of insulin
resistance (e. g., insulin receptor disorders, Rabson-Mendenhall
syndrome, leprechaunism, Kobberling-Dunnigan syndrome, Seip
syndrome, Lawrence syndrome, Gushing syndrome, acromegaly, etc.),
hyperlipidemia, atherosclerosis, cardiovascular disorders (e. g.,
stenocardia, cardiac failure, etc.), hyperglycemia(e.g.,
abnormal saccharometabolism such as feeding disorders, etc.), or
hypertension; or stenocardia, hypertension, pulmonary
hypertension, congestive heart failure, glomerulopathy (e. g.,
diabetic glomerulosclerosis, etc.), tubulointerstitial disorders
(e. g., renopathy induced by FK506, cyclosporin, etc.), renal
failure, atherosclerosis, angiostenosis (e. g., after
percutaneous arterioplasty), distal angiopathy, cerebral
apoplexy, chronic reversible obstructions (e. g., bronchitis,
asthma (chronic asthma, allergic asthma), etc.), allergic
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255
rhinitis, urticaria, glaucoma, diseases characterized by
enteromotility disorders (e. g., hypersensitive enteropathy
syndrome, etc.), impotence (e. g., organic impotence, psychic
impotence, etc.), and diabetic complications (e. g., diabetic
gangrene, diabetic arthropathy, diabetic glomerulosclerosis,
diabetic dermatopathy, diabetic neuropathy, diabetic cataract,
diabetic retinopathy, etc.), nephritis, cancerous cachexia, or
restenosis after PTCA.
