U.S. patent application number 10/012672 was filed with the patent office on 2002-06-27 for method of inhibiting neoplastic cells with benzimidazole derivatives.
Invention is credited to Ixkes, Ulrich, Pamukcu, Rifat, Piazza, Gary A., Sperl, Gerhard.
Application Number | 20020082280 10/012672 |
Document ID | / |
Family ID | 22736185 |
Filed Date | 2002-06-27 |
United States Patent
Application |
20020082280 |
Kind Code |
A1 |
Sperl, Gerhard ; et
al. |
June 27, 2002 |
Method of inhibiting neoplastic cells with benzimidazole
derivatives
Abstract
A method for inhibiting neoplasia, particularly cancerous and
precancerous lesions by exposing the affected cells to
benzimidazole derivatives.
Inventors: |
Sperl, Gerhard; (North
Wales, PA) ; Pamukcu, Rifat; (Spring House, PA)
; Ixkes, Ulrich; (Carluke, GB) ; Piazza, Gary
A.; (Doylestown, PA) |
Correspondence
Address: |
Cell Pathways, Inc.
702 Electronic Drive
Horsham
PA
19044
US
|
Family ID: |
22736185 |
Appl. No.: |
10/012672 |
Filed: |
November 5, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10012672 |
Nov 5, 2001 |
|
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09199094 |
Nov 23, 1998 |
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Current U.S.
Class: |
514/338 ;
514/394 |
Current CPC
Class: |
C07D 235/26 20130101;
C07D 405/12 20130101; C07D 235/10 20130101; C07D 235/06 20130101;
C07D 403/12 20130101; C07D 401/10 20130101; C07D 405/06 20130101;
C07D 401/12 20130101; C07D 417/14 20130101; C07D 417/06 20130101;
C07D 417/12 20130101; C07D 235/24 20130101; C07D 405/14 20130101;
C07D 235/30 20130101; C07D 401/06 20130101; C07D 235/08 20130101;
C07D 235/12 20130101 |
Class at
Publication: |
514/338 ;
514/394 |
International
Class: |
A61K 031/4439; A61K
031/4184 |
Claims
We claim
1. A method of treating a mammal having precancerous lesions
sensitive to the compounds of formula I comprising administering to
said mammal a pharmacologically effective amount of a compound of
formula I 10wherein R.sub.1 is selected from a group consisting of
substituted or unsubstituted pyridyl, dibenzofuranyl,
dioxymethylene benzyl, naphthyl, quinolinyl or isoquinolinyl and
wherein said substituents are one to three independently selected
from the group consisting of halogen, lower alkyl, lower alkoxy,
halo- or cyano-substituted or unsubstituted phenyloxy or benzyloxy,
lower haloalkyl, CN, amino, nitro, phenyl, thiadiazole, aryloxy,
arylsulfonyl methyl, arylsulfonyl amino, benzoyl, benzylamidyl,
benzenesulfonyl methyl, phenylethyl, and phenylethenyl, wherein
said aryl group is selected from the group consisting of phenyl,
benzyl and pyridyl; R.sub.2 is selected from a group consisting of
hydrogen, lower alkyl, haloalkyl and lower alkoxy, amino,
alkylamino, lower alkoxyalkyl, or carboxyl; R.sub.3 is selected
from a group consisting of halo, halo-carbonyl, carboxyl, haloalkyl
carbonyl, lower alkoxy carbonyl, carboxyalkenyl,
alkoxycarbonylalkenyl, aminosulfonyl, CN, --C(O)--NR.sub.4R.sub.5,
substituted or unsubstituted carbamoylalkyl, carbamoylalkenyl, or
aryloxy carbonyl, wherein said aryl group is selected from the
group consisting of benzyl, phenyl and pyridyl, and wherein said
substituents are one to three selected from the group consisting of
halogen, lower alkyl, lower alkoxy, CN, amino, and nitro, or said
substituent is one selected from the group consisting of phenyl,
benzyl, pyridyl, pyridylmethyl, benzenesulfonyl, alkyl sulfonyl,
and alkyl carbonyl. R.sub.4 and R.sub.5 are independently selected
from a group consisting of hydrogen, lower alkyl,
--SO.sub.2R.sub.6, substituted or unsubstituted aryl, wherein said
aryl group is selected from the group consisting of phenyl, benzyl
or pyridyl, pyridylmethyl, pyridinyl-oxide-2-methyl, piperonyl,
quinolinyl, thiazolyl, tetrazolyl, thiadiazolyl, and triazolyl, and
wherein said substituents are one to three selected from the group
consisting of halogen, lower alkyl, lower alkoxy, amino, and
dimethylamino; or R.sub.4 and R.sub.5 together form substituted or
unsubstituted morpholinyl, thiomorpholinyl, propansultamyl,
homopiperidyl, or pyrrolidyl, wherein said substituents are one to
three independently selected from the group consisting of halogen,
lower alkyl, lower alkoxy, or carboxyl; R.sub.6 is selected from a
group consisting of substituted or unsubstituted lower alkyl,
benzyl, phenyl, naphthyl and tolyl, wherein said substituents are
one to three selected from the group consisting of halogen, lower
alkyl, lower alkoxy, alkylmercapto, haloalkyl, trimethylsilyl,
nitro, phenyloxy, and benzyloxy; and y is 0, 1, or 2; and n is 0,
1, or 2.
2. A method for inhibiting the growth of neoplastic cells sensitive
to the compounds of formula I comprising exposing the cells to a
growth inhibiting effective amount of a compound of formula I
11wherein R.sub.1 is selected from a group consisting of
substituted or unsubstituted pyridyl, dibenzofuranyl,
dioxymethylene benzyl, naphthyl, quinolinyl or isoquinolinyl and
wherein said substituents are one to three independently selected
from the group consisting of halogen, lower alkyl, lower alkoxy,
halo- or cyano-substituted or unsubstituted phenyloxy or benzyloxy,
lower haloalkyl, CN, amino, nitro, phenyl, thiadiazole, aryloxy,
arylsulfonyl methyl, arylsulfonyl amino, benzoyl, benzylamidyl,
benzenesulfonyl methyl, phenylethyl, and phenylethenyl, wherein
said aryl group is selected from the group consisting of phenyl,
benzyl and pyridyl; R.sub.2 is selected from a group consisting of
hydrogen, lower alkyl, haloalkyl and lower alkoxy, amino,
alkylamino, lower alkoxyalkyl, or carboxyl; R.sub.3 is selected
from a group consisting of halo, halo-carbonyl, carboxyl, haloalkyl
carbonyl, lower alkoxy carbonyl, carboxyalkenyl,
alkoxycarbonylalkenyl, aminosulfonyl, CN, --C(O)--NR.sub.4R.sub.5,
substituted or unsubstituted carbamoylalkyl, carbamoylalkenyl, or
aryloxy carbonyl, wherein said aryl group is selected from the
group consisting of benzyl, phenyl and pyridyl, and wherein said
substituents are one to three selected from the group consisting of
halogen, lower alkyl, lower alkoxy, CN, amino, and nitro, or said
substituent is one selected from the group consisting of phenyl,
benzyl, pyridyl, pyridylmethyl, benzenesulfonyl, alkyl sulfonyl,
and alkyl carbonyl. R.sub.4 and R.sub.5 are independently selected
from a group consisting of hydrogen, lower alkyl,
--SO.sub.2R.sub.6, substituted or unsubstituted aryl, wherein said
aryl group is selected from the group consisting of phenyl, benzyl
or pyridyl, pyridylmethyl, pyridinyl-oxide-2-methyl, piperonyl,
quinolinyl, thiazolyl, tetrazolyl, thiadiazolyl, and triazolyl, and
wherein said substituents are one to three selected from the group
consisting of halogen, lower alkyl, lower alkoxy, amino, and
dimethylamino; or R.sub.4 and R.sub.5 together form substituted or
unsubstituted morpholinyl, thiomorpholinyl, propansultamyl,
homopiperidyl, or pyrrolidyl, wherein said substituents are one to
three independently selected from the group consisting of halogen,
lower alkyl, lower alkoxy, or carboxyl; R.sub.6 is selected from a
group consisting of substituted or unsubstituted lower alkyl,
benzyl, phenyl, naphthyl and tolyl, wherein said substituents are
one to three selected from the group consisting of halogen, lower
alkyl, lower alkoxy, alkylmercapto, haloalkyl, trimethylsilyl,
nitro, phenyloxy, and benzyloxy; and y is 0, 1, or 2; and n is 0,
1, or 2.
3. A method for regulating apoptosis in human cells comprising
exposing said cells to an effective amount of a compound of formula
I 12wherein R.sub.1 is selected from a group consisting of
hydrogen, lower alkyl, benzenesulfonyl, and substituted or
unsubstituted aryl, wherein said aryl group is selected from the
group consisting of phenyl, benzyl, pyridyl, dibenzofuranyl,
dioxymethylene benzyl, naphthyl, quinolinyl or isoquinolinyl and
wherein said substituents are one to three independently selected
from the group consisting of halogen, lower alkyl, lower alkoxy,
halo- or cyano-substituted or unsubstituted phenyloxy or benzyloxy,
lower haloalkyl, CN, amino, nitro, phenyl, thiadiazole, aryloxy,
arylsulfonyl methyl, arylsulfonyl amino, benzoyl, benzylamidyl,
benzenesulfonyl methyl, phenylethyl, and phenylethenyl, wherein
said aryl group is selected from the group consisting of phenyl,
benzyl and pyridyl; R.sub.2 is selected from a group consisting of
hydrogen, lower alkyl, haloalkyl, lower alkoxy, amino, alkylamino,
lower alkoxyalkyl, or carboxyl; R.sub.3 is selected from a group
consisting of halo-carbonyl, carboxyl, haloalkyl carbonyl, lower
alkoxy carbonyl, carboxyalkenyl, alkoxycarbonylalkenyl,
aminosulfonyl, CN, --C(O)--NR.sub.4R.sub.5, substituted or
unsubstituted carbamoylalkyl, carbamoylalkenyl, or aryloxy
carbonyl, wherein said aryl group is selected from the group
consisting of benzyl, phenyl and pyridyl, and wherein said
substituents are one to three selected from the group consisting of
halogen, lower alkyl, lower alkoxy, CN, amino, and nitro, or said
substituent is one selected from the group consisting of phenyl,
benzyl, pyridyl, pyridylmethyl, benzenesulfonyl, alkyl sulfonyl,
and alkyl carbonyl. R.sub.4 and R.sub.5 are independently selected
from a group consisting of hydrogen, lower alkyl,
--SO.sub.2R.sub.6, substituted or unsubstituted aryl, wherein said
aryl group is selected from the group consisting of phenyl, benzyl
or pyridyl, pyridylmethyl, pyridinyl-oxide-2-methyl, piperonyl,
quinolinyl, thiazolyl, tetrazolyl, thiadiazolyl, and triazolyl, and
wherein said substituents are one to three selected from the group
consisting of halogen, lower alkyl, lower alkoxy, amino, and
dimethylamino; or R.sub.4 and R.sub.5 together form substituted or
unsubstituted morpholinyl, thiomorpholinyl, propansultamyl,
homopiperidyl, or pyrrolidyl, wherein said substituents are one to
three independently selected from the group consisting of halogen,
lower alkyl, lower alkoxy, or carboxyl; R.sub.6 is selected from a
group consisting of substituted or unsubstituted lower alkyl,
benzyl, phenyl naphthyl and tolyl, wherein said substituents are
one to three selected from the group consisting of halogen, lower
alkyl, lower alkoxy, alkylmercapto, haloalkyl, trimethylsilyl,
nitro, phenyloxy, and benzyloxy; and y is 0, 1, or 2; and n is 0,
1, or 2.
Description
TECHNICAL FIELD
[0001] This invention relates to compounds and methods for inducing
or promoting apoptosis and for arresting uncontrolled neoplastic
cell proliferation, methods that are specifically useful in the
arresting and treatment of neoplasias, including precancerous and
cancerous lesions. This application is a division of prior U.S.
application Ser. No. 09/199,094 entitled "Method of Inhibiting
Neoplastic Cells with Benzimidazole Derivatives," which is
incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Pharmaceuticals that are effective against early stage
neoplasias comprise an emerging and expanding area of research and
potential commercial development. Such pharmaceuticals can delay or
arrest development of precancerous lesions into cancers. Each year
in the United States alone, untold numbers of people develop
precancerous lesions, which exhibit a strong statistically
significant tendency to develop into malignant tumors, or cancer.
Such lesions include lesions of the breast (that can develop into
breast cancer), lesions of the skin (that can develop into
malignant melanoma or basal cell carcinoma), colonic adenomatous
polyps (that can develop into colon cancer), cervical displasia
(cervical cancer) and other such neoplasms.
[0003] Such compounds and methods are particularly beneficial to
sub-populations of patients who repeatedly develop precancerous
lesions, and therefore have a statistically higher probability of
getting cancer. many cancer types (e.g., breast, colon, prostate
etc.) have such patient sub-populations.
[0004] The search for drugs useful for treating and preventing
neoplasias in their earliest stages is intensive because
chemotherapy and surgery on cancer itself is often not effective,
and current cancer chemotherapy has severe side effects. Such
cancer-preventative compounds are also envisaged for recovered
cancer patients who retain a risk of cancer reoccurrence, and even
for cancer patients who would benefit from compounds that
selectively induce apoptosis in neoplastic, but substantially not
in normal cells.
[0005] Because it is believed that chronic administration of
cancer-preventative pharmaceuticals is necessary to inhibit or
arrest the development of neoplasia, standard cancer
chemotherapeutic drugs are not considered appropriate drugs for
cancer chemoprevention because whatever cancer preventative (as
opposed to cancer-fighting) capabilities those drugs may possess do
not outweigh their severe side effects. most standard
chemotherapeutics are now believed to kill cancer cells by inducing
apoptosis (also sometimes referred to as "programmed cell death").
Apoptosis naturally occurs in many tissues in the body. Apoptosis
plays a critical role in tissue homeostasis, that is, it ensures
that the number of new cells produced are correspondingly offset by
an equal number of cells that die. Apoptosis is especially
pronounced in self-renewing tissues such as bone marrow, immune
cells, gut, and skin. For example, the cells in the intestinal
lining divide so rapidly that the body must eliminate cells after
only three days to protect and prevent the overgrowth of the
intestinal lining.
[0006] Standard chemotherapeutics promote apoptosis not only in
cancer cells, but also in normal human tissues, and therefore have
a particularly severe effect on tissues where apoptosis is
especially pronounced (e.g. hair, gut and skin). The results of
those effects include hair loss, weight loss, vomiting and bone
marrow immune suppression. Thus, standard chemotherapeutics are
inappropriate for cancer prevention, particularly if chronic
administration is indicated.
[0007] Several non-steroidal anti-inflammatory drugs ("NSAIDs"),
originally developed to treat arthritis, have shown effectiveness
in inhibiting and eliminating colonic polyps. Polyps virtually
disappear when the patients take the drug, particularly when the
NSAID sulindac is administered. However, the continued prophylactic
use of currently available NSAIDs, even in high colon cancer-risk
patients, is still marked by severe side reactions that include
gastrointestinal irritations, perforations, ulcerations and kidney
toxicity believed to be produced by inhibition of prostaglandin
synthetase activity ("PGE-2"). Such inhibition is a requirement for
the NSAIDs anti-inflammatory action since elevated levels of PGE-2
are associated with inflammation. PGE-2 plays a protective function
in the gastrointestinal tract, which is the reason such gastric
side effects arise with chronic NSAID therapy, which is rarely
indicated for arthritis sufferers, acute therapy being the norm for
them. However, chronic administration of sulindac is important for
high cancer-risk patients to eliminate and prevent future polyps
which causes gastric side effects in many such patients. Once NSAID
treatment is terminated due to such complications, the neoplasms
return, particularly in high risk patients.
[0008] Compounds such as those disclosed in U.S. Pat. No. 5,643,959
have exhibited advantages in the treatment of neoplastic lesions
since such compounds have been shown to induce apoptosis in
neoplastic cells but not in normal cells in humans. Thus, the
severe side effects due to induction of apoptosis in normal cells
by conventional chemotherapeutics are avoided by these novel
therapeutics (see, Van Stolk, et al., Gastroenterology 112 (4):
A673, 1997). In addition, such compounds do not exhibit the gastric
side effects associated with NSAIDs since such compounds do not
substantially inhibit PGE-2. more potent compounds with such
neoplasia specificity but without substantial PGE-2 activity are
desirable.
SUMMARY OF THE INVENTION
[0009] This invention represents potent compounds that induce
apoptosis in neoplastic cells (but not substantially in normal
cells), for treating patients with neoplastic lesions without
substantially inhibiting PGE-2. This invention also involves
methods for inducing such specific apoptosis in neoplastic cells by
exposing such cells to a pharmacologically effective amount of
those compounds described below to a patient in need of such
treatment. Such compositions are effective in modulating apoptosis
and modulating the growth of neoplasms, but are not suffering from
the side effects of conventional chemotherapeutics and NSAIDs.
DETAILED DESCRIPTION OF THE INVENTION
[0010] As discussed above, the present invention utilizes compounds
of Formula I below 1
[0011] Wherein
[0012] R.sub.1 is selected from a group consisting of hydrogen,
lower alkyl, benzenesulfonyl, and substituted or unsubstituted
aryl, wherein said aryl group is selected from the group consisting
of phenyl, benzyl, pyridyl, dibenzofuranyl, dioxymethylene benzyl,
naphthyl, quinolinyl or isoquinolinyl and wherein said substituents
are one to three independently selected from the group consisting
of halogen, lower alkyl, lower alkoxy, halo- or cyano-substituted
or unsubstituted phenyloxy or benzyloxy, lower haloalkyl, CN,
amino, nitro, phenyl, thiadiazole, aryloxy, arylsulfonyl methyl,
arylsulfonyl amino, benzoyl, benzylamidyl, benzenesulfonyl methyl,
phenylethyl, and phenylethenyl, wherein said aryl group is selected
from the group consisting of phenyl, benzyl and pyridyl;
[0013] R.sub.2 is selected from a group consisting of hydrogen,
lower alkyl, haloalkyl, lower alkoxy, amino, alkylamino, lower
alkoxyalkyl, or carboxyl;
[0014] R.sub.3 is selected from a group consisting of
halo-carbonyl, carboxyl, haloalkyl carbonyl, lower alkoxy carbonyl,
carboxyalkenyl, alkoxycarbonylalkenyl, aminosulfonyl, CN,
--C(O)--NR.sub.4R.sub.5, substituted or unsubstituted
carbamoylalkyl, carbamoylalkenyl, or aryloxy carbonyl, wherein said
aryl group is selected from the group consisting of benzyl, phenyl
and pyridyl, and wherein said substituents are one to three
selected from the group consisting of halogen, lower alkyl, lower
alkoxy, CN, amino, and nitro, or said substituent is one selected
from the group consisting of phenyl, benzyl, pyridyl,
pyridylmethyl, benzenesulfonyl, alkyl sulfonyl, and alkyl
carbonyl.
[0015] R.sub.4 and R.sub.5 are independently selected from a group
consisting of hydrogen, lower alkyl, --SO.sub.2R.sub.6, substituted
or unsubstituted aryl, wherein said aryl group is selected from the
group consisting of phenyl, benzyl or pyridyl, pyridylmethyl,
pyridinyl-oxide-2-methyl, piperonyl, quinolinyl, thiazolyl,
tetrazolyl, thiadiazolyl, and triazolyl, and wherein said
substituents are one to three selected from the group consisting of
halogen, lower alkyl, lower alkoxy, amino, and dimethylamino;
or
[0016] R.sub.4 and R.sub.5 together form substituted or
unsubstituted morpholinyl, thiomorpholinyl, propansultamyl,
homopiperidyl, or pyrrolidyl, wherein said substituents are one to
three independently selected from the group consisting of halogen,
lower alkyl, lower alkoxy, or carboxyl;
[0017] R.sub.6 is selected from a group consisting of substituted
or unsubstituted lower alkyl, benzyl, phenyl, naphthyl and tolyl,
wherein said substituents are one to three selected from the group
consisting of halogen, lower alkyl, lower alkoxy, alkylmercapto,
haloalkyl, trimethylsilyl, nitro, phenyloxy, and benzyloxy; and
[0018] y is 0, 1 or 2; and
[0019] n is 0, 1, or 2.
[0020] The present invention is also a method of treating
individuals with neoplastic lesions by administering a
pharmacologically effective amount of an enterically coated
pharmaceutical composition that includes compounds of this
invention.
[0021] Preferably, such compounds are administered without
therapeutic amounts of an NSAID.
[0022] Also, the present invention is a method of inhibiting the
growth of neoplastic cells by exposing the cells to an effective
amount of compounds of Formula I, wherein R.sub.1, R.sub.2,
R.sub.3, etc. are defined as above.
[0023] In still another form, the invention is a method of inducing
apoptosis in human cells by exposing those cells to an effective
amount of compounds of Formula I, wherein R.sub.1 etc. are defined
as above where such cells are sensitive to these compounds.
[0024] Additionally, in yet another form, the invention is a method
of treating a patient having a disease which would benefit from
regulation of apoptosis by treating the patient with an effective
amount of compounds of Formula I, wherein R.sub.1 through R.sub.7
etc. are defined as above. The regulation of apoptosis is believed
to play an important role in diseases associated with abnormalities
of cellular growth patterns such as benign prostatic hyperplasia,
neurodegenerative diseases such as Parkinson's disease, autoimmune
diseases including multiple sclerosis and rheumatoid arthritis,
infectious diseases such as AIDS, and other diseases, as well.
[0025] As used herein, the term "precancerous lesion" includes
syndromes represented by abnormal neoplastic, including dysplastic,
changes of tissue. Examples include dysplasic growths in colonic,
breast, bladder or lung tissues, or conditions such as dysplastic
nevus syndrome, a precursor to malignant melanoma of the skin.
Examples also include, in addition to dysplastic nevus syndromes,
polyposis syndromes, colonic polyps, precancerous lesions of the
cervix (i.e., cervical dysplasia), esophagus, prostatic dysplasia,
bronchial dysplasia, breast, bladder and/or skin and related
conditions (e.g., actinic keratosis), whether the lesions are
clinically identifiable or not.
[0026] As used herein, the term "cancerous" refers to lesions that
are malignant. Examples include malignant melanomas, breast cancer,
prostate cancer and colon cancer.
[0027] As used herein, the term "neoplasm" refers to both
precancerous and cancerous lesions and hyperplasia.
[0028] As used herein, the term "halo" or "halogen" refers to
chloro, bromo, fluoro and iodo groups, and the term "alkyl" refers
to straight, branched or cyclic alkyl groups and to substituted
aryl alkyl groups. The term "lower alkyl" refers to C1 to C8 alkyl
groups.
[0029] The term "lower alkoxy" refers to alkoxy groups having from
1 to 8 carbons, including straight, branched or cyclic
arrangements.
[0030] The term "pharmaceutically acceptable salt" refers to
non-toxic acid addition salts and alkaline earth metal salts of the
compounds of Formula I. The salts can be prepared in situ during
the final isolation and purification of such compounds, or
separately by reacting the free base or acid functions with a
suitable organic acid or base, for example. Representative acid
addition salts include the hydrochloride, hydrobromide, sulfate,
bisulfate, acetate, valerate, oleate, palmatate, stearate, laurate,
borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate,
maleate, fumarate, succinate, tartrate, glucoheptonate,
lactobionate, lauryl sulfate salts and the like. Representative
alkali and alkaline earth metal salts include the sodium, calcium,
potassium and magnesium salts.
[0031] Compounds of this invention may be formulated into
pharmaceutical compositions together with pharmaceutically
acceptable carriers for oral administration in solid or liquid
form, or for rectal or topical administration, although carriers
for oral administration are most preferred.
[0032] Pharmaceutically acceptable carriers for oral administration
include capsules, tablets, pills, powders, troches and granules. In
such solid dosage forms, the carrier can comprise at least one
inert diluent such as sucrose, lactose or starch. Such carriers can
also comprise, as is normal practice, additional substances other
than diluents, e.g., lubricating agents such as magnesium stearate.
In the case of capsules, tablets, troches and pills, the carriers
may also comprise buffering agents. Carriers such as tablets, pills
and granules can be prepared with enteric coatings on the surfaces
of the tablets, pills or granules. Alternatively, the enterically
coated compound can be pressed into a tablet, pill, or granule, and
the tablet, pill or granules for administration to the patient.
Preferred enteric coatings include those that dissolve or
disintegrate at colonic pH such as shellac or Eudraget S.
[0033] Pharmaceutically acceptable carriers include liquid dosage
forms for oral administration, e.g., pharmaceutically acceptable
emulsions, solutions, suspensions, syrups and elixirs containing
inert diluents commonly used in the art, such as water. Besides
such inert diluents, compositions can also include adjuvants such
as wetting agents, emulsifying and suspending agents, and
sweetening, flavoring and perfuming agents.
[0034] Pharmaceutically acceptable carriers for topical
administration include DMSO, alcohol or propylene glycol and the
like that can be employed with patches or other liquid-retaining
material to hold the medicament in place on the skin so that the
medicament will not dry out.
[0035] Pharmaceutically acceptable carriers for rectal
administration are preferably suppositories that may contain, in
addition to the compounds of this invention excipients such as
cocoa butter or a suppository wax, or gel.
[0036] The pharmaceutically acceptable carrier and compounds of
this invention are formulated into unit dosage forms for
administration to a patient. The dosage levels of active ingredient
(i.e., compounds of this invention) in the unit dosage may be
varied so as to obtain an amount of active ingredient effective to
achieve lesion-eliminating activity in accordance with the desired
method of administration (i.e., oral or rectal). The selected
dosage level therefore depends upon the nature of the active
compound administered, the route of administration, the desired
duration of treatment, and other factors. If desired, the unit
dosage may be such that the daily requirement for active compound
is in one dose, or divided among multiple doses for administration,
e.g., two to four tunes per day.
[0037] The pharmaceutical compositions of this invention are
preferably packaged in a container (e.g., a box or bottle, or both)
with suitable printed material (e.g., a package insert) containing
indications, directions for use, etc.
[0038] There are several general schemes for producing compounds
useful in this invention. 2
[0039] A substituted amide (a) is allowed to react with a base such
as sodium hydride, lithium diusopropylamide. Reaction with a
compound expressed by R.sub.2Z (Z represents a halogen atom or a
sulfonyl chloride) gives the tertiary amide (b). There are several
methods to obtain a compound of the formula (c). (A) Reduction with
iron or zinc under an acidic condition, (B) reduction with a
transition metal catalyst primarily exemplified by palladium,
platinum, ruthenium, and nickel under a hydrogen environment, (C)
reduction with a transition metal catalyst primarily exemplified by
palladium, platinum, ruthenium, and nickel under a presence of
formic acid, or (D) reduction with sodium hydrosulfite. In many
cases when method (A) is used, a compound of the formula (c) is
reduced within the reaction system to directly produce a compound
of the formula (d). Some compounds may partially produce a compound
of the formula (d) under any condition in the methods (A) through
(D). A compound of the formula (d) is produced from a compound of
the formula (c) with a carboxylic acid such as acetic acid,
p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, or
phosphoric acid, sulfonic acid, or an inorganic acid. 3
[0040] In scheme II, a compound of the formula (e) undergoes a
hydrolysis or solvolysis with a base such as lithium bicarbonate,
lithium carbonate, lithium hydroxide, sodium bicarbonate, sodium
carbonate, sodium hydroxide, potassium bicarbonate, potassium
carbonate, or potassium hydroxide, a carboxylic acid such as acetic
acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, or
phosphoric acid, sulfonic acid, or an inorganic acid and produces a
compound expressed by the formula (f). A compound of the formula
(f) is processed with a base such as sodium hydride, lithium
diisopropylamide, and is processed with a compound expressed by
R.sub.1bZ (Z represents a halogen or sulfonyl chloride) in order to
produce a compound of the formula (g). A compound of the formula
(g) can be altered to a compound of the formula (h) by a method
such as (A) reducing it with iron or zinc under an acidic
condition, (B) reducing it with a transition metal catalyst
primarily exemplified by palladium, platinum, ruthenium, and nickel
under a hydrogen environment, (C) reducing it with a transition
metal catalyst primarily exemplified by palladium, platinum,
ruthenium, and nickel under a presence of formic acid, and (D)
reducing it with sodium hydrosulfite. A compound of the formula (i)
is produced from a compound of the formula (h) and a corresponding
carboxylic acid, acid chloride, acid bromide, or acid anhydride.
4
[0041] In scheme III, a compound of the formula (k) is produced
from a compound of the formula (j) and a compound expressed by
R.sub.1NH.sub.2. The alteration of a compound of the formula (k) to
a compound of the formula (m) is the same as that of a compound of
the formula (g) to a compound of the formula (i) in scheme II.
5
[0042] In scheme IV, a compound of the formula (n) can be altered
to a compound of the formula (o) by a method such as (A) reducing
it with a transition metal catalyst primarily exemplified by
palladium, platinum, ruthenium, and nickel under a hydrogen
environment, and (B) reducing it with sodium hydrosulfite. A
compound of the formula (o) is processed with a base such as
lithium bicarbonate, lithium carbonate, lithium hydroxide, sodium
bicarbonate, sodium carbonate, sodium hydroxide, potassium
bicarbonate, potassium carbonate, or potassium hydroxide, and with
a compound expressed by R.sub.1Z (Z represents a halogen atom,, or
a sulfonyl chloride.) in order to produce a compound of the formula
(p). A compound of the formula (q) is produced from a compound of
the formula (p) with a carboxylic acid such as acetic acid,
p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, or
phosphoric acid, sulfonic acid, or an inorganic acid. 6
[0043] In scheme V, a compound of the formula (r) can be altered to
a compound of the formula (s) by a method such as (A) reducing it
with reduced iron or zinc under an acidic condition, (B) reducing
it with a transition metal catalyst primarily exemplified by
palladium, platinum, ruthenium, and nickel under a hydrogen
environment, (C) reducing it with a transition metal catalyst
primarily exemplified by palladium, platinum, ruthenium, and nickel
under a presence of formic acid, and (D) reducing it with sodium
hydrosulfite. A compound of the formula (t) is produced from a
compound of the formula (s) and a corresponding carboxylic acid,
acid anhydride, acid chloride, or acid bromide. A compound of the
formula (t) is processed with a base such as sodium hydride or
lithium diisopropylamide, and is processed with a compound
expressed by R.sub.1Z (Z represents a halogen atom, , or a sulfonyl
chloride.) in order to produce a compound of the formula (u).
[0044] These methods usually produce a compound of the formula (u)
having R.sub.3 at mixed substitution positions of the fifth and
sixth or of the fourth and seventh. The materials can be purified
by a means such as recrystallization, column chromatography, thin
film chromatography, or high speed liquid chromatography. 7
[0045] In scheme VI, a compound of the formula (v) can be altered
to a compound of the formula (w) by a method such as (A) reducing
it with reduced iron or zinc under an acidic condition, (B)
reducing it with a transition metal catalyst primarily exemplified
by palladium, platinum, ruthenium, and nickel under a hydrogen
environment, (C) reducing it with a transition metal catalyst
primarily exemplified by palladium, platinum, ruthenium, and nickel
under a presence of formic acid, and (D) reducing it with sodium
hydrosulfite. In many cases when the method (A) is used, a compound
of the formula (w) forms a ring within the reaction system to
directly produce a compound of the formula (x). Some compounds may
partially produce a compound of the formula (x) under any condition
in the methods (A) through (D). A compound of the formula (x) is
produced from a compound of the formula (w) with a carboxylic acid
such as acetic acid, p-toluenesulfonic acid, hydrochloric acid,
sulfuric acid, or phosphoric acid, sulfonic acid, or an inorganic
acid. A compound of the formula (x) can be altered to a
benzimidazole compound by using the alteration method from the
formula (t) to the formula (u) in scheme V. These methods usually
produce a compound of the formula (y) having R.sub.3 at mixed
substitution positions of the fifth and sixth or of the fourth and
seventh. The materials can be purified by a means such as
recrystallization, column chromatography, thin film chromatography,
or high speed liquid chromatography. 8
[0046] In scheme VII, a compound of the formula (A) undergoes a
hydrolysis with a base such as lithium hydroxide, sodium hydroxide,
and produces a compound of the formula (B). A compound of the
formula (B) is processed with carbonyldiimidazole and then is
processed with an amine or a sulfonamide under a presence of a base
to further produce benzimidazole derivatives.
[0047] A compound of the formula (B) can be altered to an acid
halide expressed by the formula (C) by thionyl chloride, thionyl
bromide, phosphorus trichloride, phosphorus pentachloride, or
phosphorus oxychloride. Benzimidazole derivatives can be further
produced by reacting a compound of the formula (C) with an amine or
a sulfonamide. 9
[0048] In scheme VIII, a compound of the formula (A) can be altered
by reduction to a compound of the formula (D). Furthermore, a
compound of the formula (D) can be altered to a compound of the
formula (E) by thionyl chloride, thionyl bromide, phosphorus
oxychloride, phosphorus oxybromide, phosphorus trichloride,
phosphorus pentachloride, methanesulfonyl chloride, or
toluenesulfonyl chloride.
[0049] The foregoing may be better understood from the following
examples that are presented for the purposes of illustration and
are not intended to limit the scope of the invention. As used in
the following examples, the references to substituents such as R1
Y, A, etc. refer to the corresponding substituents in Formula I
above.
EXAMPLES
Example 1
2-Methyl-1H-5-Methoxybenzimidazole
A.) 4-Methoxy-2-nitrophenyl-N-acetamide
[0050] 4-Methoxy-2-nitroaniline (50 mmole, 7.6 g) is added to a
solution of pyridine (75 mmole, 6.0 ml) in dichloromethane (120
ml). The mixture is charged slowly with acetylchloride (50 mmole,
3.6 ml) in dichloromethane (40 ml) and is stirred for 48 hours. The
reaction mixture is washed with water, the organic layer is dried
with Na.sub.2SO.sub.4, is filtered, evaporated and is dried in
vacuo (86%).
B.) 2-Methyl-1H-5-methoxybenzimidazole
[0051] A mixture of 4-methoxy-2-nitrophenyl-N-acetamide (21.41
mmole, 4.5 g) in acetic acid (100 ml) and iron (Fe) (0.1 mole, 5.57
g) is refluxed for three hours and is stirred at room temperature
over night. The solvent is evaporated, the residue is extracted
with ethylacetate (120 ml) and is washed with saturated
NaHCO.sub.3. The organic layer is washed with water (100 ml), dried
with MgSO.sub.4, is filtered and is evaporated. Recrystallisation
in ethylacetate gives the title compound (55%). .sup.1H-NMR
(CDCl.sub.3, .delta.): 2.60 (s, 3H, CH3), 3.81 (s, 3H, OCH3), 6.86
(dd, 1H, aromatic H, J=2.1 Hz und 8.7 Hz), 7.02 (d, 1H, aromatic H,
J=2.4 Hz), 7.43 (d, 1H, aromatic H, J=9 Hz).
[0052] (R.sub.1=H, R.sub.2=methyl, R.sub.3 =OCH.sub.3, n=1,
y=0)
Example 2
2-Methyl-5-Fluoro-1-(3,4,5-Trimethoxybenzyl)Benzimidazole
A.) 4-Fluoro-2-nitrophenyl-N-acetamide
[0053] 4-Fluoro-2-nitroaniline (50 mmole, 7.81 g) is added to a
solution of pyridine (75 mmole, 6.0 ml) in dichloromethane (125
ml). The mixture is charged slowly with acetylchloride (50 mmole,
3.56 ml) in dichloromethane (40 ml) and is stirred for 48 hours.
The reaction mixture is washed with 10% HCl and water, the organic
layer is dried with Na.sub.2SO.sub.4, is filtered and is
evaporated.
B.) 2-Methyl-5-fluorobenzimidazole
[0054] Iron (Fe) (176.75 mmole, 9.87 g) is added to a solution of
4-fluoro-2-nitrophenyl-N-acetamide (35.35 mmole, 7.5 g) in acetic
acid (160 ml) and the mixture is refluxed for one hour and is
stirred at room temperature over night. The solvent is evaporated.
The residue is extracted with ethylacetate and is washed with
saturated NaHCO.sub.3. The organic layer is washed with water,
dried with NaSO.sub.4, is filtered and evaporated.
Recrystallisation in ethylacetate gives the title compound
(80.4%).
C.) 2-Methyl-5-fluoro-1-(3,4,5-trimethoxybenzyl)benzimidazole
[0055] Sodium hydride (18.31 mmole, 0.44 g, 60% in mineral oil) is
added in small amounts under nitrogen to an ice cooled solution of
2-methyl-5-fluorobenzimidazole (16.64 mmole, 2.5 g) in dry DMA (9
ml). The mixture is stirred at the same temperature for 30 minutes.
Trimethoxybenzyl chloride (18.31 mmole, 3.97 g) in DMA (4 ml) is
added in several portions and the mixture is allowed to stir at
room temperature over night. The reaction mixture is poured on to
ice, the precipitate is collected and dissolved in dichloromethane.
The organic solution is washed several times with water, is dried
with Na.sub.2SO.sub.4, is filtered and is evaporated.
[0056] (R.sub.1=3,4,5-trimethoxybenzyl, R.sub.2=CH.sub.3,
R.sub.3=F, n=1, y=0)
Example 3
1-(2-Bromobenzyl)-6-Ethoxycarbonyl-2-n-Propylbenzimidazole
A.) 3-[N-(2-Bromobenzyl)butyrylamino]-4-nitro-ethylbenzoate
[0057] In a nitrogen environment and at room temperature, sodium
hydroxide (100 mg, 60% oil suspension) is added to an
N,N-dimethylformamide (10 ml) solution of
3-butyrylamino-4-nitro-ethylbenzoate (247 mg) in a number of
separate repetitions. The reaction suspension is stirred for 1 hour
at the same temperature. The N,N-dimethylformamide (2 ml) solution
of 2-bromobenzylbromide (244 mg) is gradually dripped over a 10
minute span. After the reaction mixture is stirred for 1 hour at
room temperature, it is then poured into ice water. Precipitated
oily material is extracted with methylene chloride . The organic
solvent layer is washed with water, dried, and then concentrated
under reduced pressure. The residue is developed through silica gel
flush column chromatography, and extraction is performed using 25%
ethyl acetate/n-hexane. Thus, yellow and oily
3-[N-(2-bromobenzyl)butyrylamino]-4-nitro-ethylbenzoate (540 mg) is
obtained. .sup.1H-NMR (CDCl.sub.3): 0.87 (3H, t, J=8 Hz), 1.48 (3H,
t, J=8 Hz), 1.68 (2H, sextet, J=8 Hz), 2.03 (2H, t, J=8 Hz),
4.30-4.46 (2H, m), 4.70 (1H, d, J=15 Hz), 5.40 (1H, d, J=15 Hz),
7.08-7.34 (2H, m), 7.43 (1H, dd, J=1, 8 Hz), 7.58 (1H, dd, J=1, 8
Hz), 7.66 (1H, d, J=1 Hz), 7.96 (1H, d, J=8 Hz), 8.16 ( 1H, dd,
J=1, 8 Hz).
B.) 1-(2-Bromobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole
[0058] 3-[N-(2-bromobenzyl)butyrylamino]-4-nitro-ethylbenzoate (390
mg) and reduced iron (210 mg) are added to the mixture solution of
acetic acid (1 ml) and ethanol (2 ml) , then the suspension is
refluxed for one hour while being stirred briskly. After the
reaction, the reaction solution is cooled, separated through
filtration using celite, and then the filtrate is concentrated
through evaporation under reduced pressure. Ethyl acetate and
sodium bicarbonate are added to the residue, and the mixture
separated into layers. After the organic layer is dried, the
solvent is removed through evaporation under reduced pressure, and
a brown residue is obtained. The residue is purified through flush
column chromatography, and yellow crystal of
1-(2-bromobenzyl)-6-ethoxycarbonyl-- 2-n-propylbenzimidazole (160
mg) is obtained. .sup.1H-NMR (CDCl.sub.3): 1.04 (3H, t, J=8 Hz),
1.40 (3H, t, J=8 Hz), 1.78-1.98 (2H, m), 2.34 (2H, t, J=8 Hz), 4.38
(2H, q, J=8 Hz), 5.45 (2H, s), 6.65 (1H, t, J=8 Hz), 7.00 (1H, t,
J=8 Hz), 7.13 (1H, t, J=8 Hz), 7.28 (1H, t, J=8 Hz), 7.78 (1H, d,
J=10 Hz), 7.99 (1H, d, J=10 Hz), 8.02 (1H, s).
[0059] mp=134-135.degree. C. (R.sub.1=2-bromobenzyl,
R.sub.2=2-n-propyl, R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 4
1-(2-Cyanobenzyl)-6-Ethoxycarbonyl-2-n-Propylbenzimidazole
A.) 3-[N-(2-Cyanobenzyl)butyrylamino]-4-nitro-ethylbenzoate
[0060] Potassium carbonate (296 mg) is added to an
N,N-dimethylformamide solution of
3-butyrylamino-4-nitro-ethylbenzoate (200 mg) and
2-cyanobenzylbromide (154 mg), and the solution is stirred for 3
hours at 20.degree. C. The reaction mixture is separated using
ethyl acetate and water. After washing the organic layer with water
and a saline solution, it is dried using magnesium sulfate. By
removing the solvent through evaporation under reduced pressure,
yellow and oily
3-[N-(2-cyanobenzyl)butyrylamino]-4-nitro-ethylbenzoate (330 mg) is
obtained. .sup.1H-NMR (CDCl.sub.3): 0.86 (3H, t, J=8 Hz), 1.49 (3H,
t, J=8 Hz), 1.67 (2H, sextet, J=8 Hz), 2.02 (2H, t, J=8 Hz),
4.28-4.52 (2H, m), 4.90 (1H, d, J=15 Hz), 5.28 (1H, d, J=15 Hz),
7.40 (1H, t, J=8 Hz), 7.61 (1H, dt, J=1, 8 Hz), 7.70 (1H, d, J=1
Hz), 7.74 (1H, dd, J=1, 8 Hz), 8.02 (1H, d, J=10 Hz), 8.22 (1H, dd,
J=1, 10 Hz).
B.) 1-(2-Cyanobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole
[0061] Colorless crystals of
1-(2-cyanobenzyl)-6-ethoxycarbonyl-2-n-propyl- benzimidazole (160
mg) are obtained from 3-[N-(2-cyanobenzyl)butyrylamino]-
-4-nitro-ethylbenzoate (390 mg) by using the same method as
described in Example 3.
[0062] .sup.1H-NMR (CDCl.sub.3): 1.04 (3H, t, J=8 Hz), 1.40 (3H, t,
J=8 Hz), 1.88 (2H, sextet, J=8 Hz), 2.80 (2H, t, J=8 Hz), 4.38 (2H,
q, J=8 Hz), 5.62 (2H, s), 6.57-6.63 (1H, m), 7.38-7.50 (2H, m),
7.78 (1H, dd, J=1, 8 Hz), 7.79 (1H, d, J=8 Hz), 7.94 (1H, d, J=1
Hz), 8.03 (1H, dd, J=1, 8 Hz).
[0063] mp=132-134.degree. C. (R.sub.1=2-cyanobenzyl,
R.sub.2=2-n-propyl, R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 5
6-Ethoxycarbonyl-1-(2-Fluorobenzyl)-2-n-Propylbenzimidazole
[0064] Colorless crystals of
6-ethoxycarbonyl-1-(2-fluorobenzyl)-2-n-propy- lbenzimidazole (160
mg) are obtained from 3-[N-(2-fluorobenzyl)butyrylamin-
o]-4-nitro-ethylbenzoate (390 mg) by using the same method as
described in example 3 (jap ex. 1).
[0065] .sup.1H-NMR (CDCl.sub.3): 1.04 (3H, t, J=8 Hz), 1.40 (3H, t,
J=8 Hz), 1.78-1.98 (2H, m), 2.34 (2H, t, J=8 Hz), 4.38 (2H, q, J=8
Hz), 5.45 (2H, s), 6.65 (1H, t, J=8 Hz), 7.00 (1H, t, J=8 Hz), 7.13
(1H, t, J=8 Hz), 7.28 (1H, t, J=8 Hz), 7.78 (1H, d, J=10 Hz), 7.99
(1H, d, J=10 Hz), 8.02 (1H, s).
[0066] mp=134-135.degree. C.
[0067] (R.sub.1=2-fluorobenzyl, R.sub.2=2-n-propyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 6
6-Ethoxycarbonyl-1-(4-Fluorobenzyl)-2-n-Propylbenzimidazole
[0068] Colorless crystals of
6-ethoxycarbonyl-1-(4-fluorobenzyl)-2-n-propy- lbenzimidazole (160
mg) are obtained from 3-[N-(4-fluorobenzyl)butyrylamin-
o]-4-nitro-ethylbenzoate (400 mg) by using the same method as
described in example 3 (jap. Ex 1).
[0069] .sup.1H-NMR (CDCl.sub.3): 1.04 (3H, t, J=8 Hz), 1.40 (3H, t,
J=8 Hz), 1.88 (2H, sextet, J=8 Hz), 2.82 (2H, t, J=8 Hz), 4.38 (2H,
q, J=8 Hz), 5.38 (2H, s), 7.00 (4H, d, J=7 Hz), 7.77 (1H, d, J=8
Hz), 7.98 (1H, d, J=1 Hz), 8.00 (1H, dd, J=1, 8 Hz).
[0070] mp=134-135.degree. C.
[0071] (R.sub.1=4-fluorobenzyl, R.sub.2=2-n-propyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
[0072] The following examples 7 to 14 are synthesized by using the
same method as described in Example 1.
Example 7
6-Ethoxycarbonyl-2-n-Propyl-1-(2-Pyridylmethyl)Benzimidazole
[0073] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.03 (3H, t, J=7.5 Hz),
1.39 (3H, t, J=7.5 Hz), 1.89 (2H, m), 2.86 (2H, t, J=7.5 Hz), 4.38
(2H, q, J=7.5 Hz), 5.50 (2H, s), 6.72 (1H, d, J=7.5 Hz), 7.24 (1H,
m), 7.58 (1H, dt, J=7.5, 1.5 Hz), 7.79 (1H, d, J=7.5 Hz), 7.96-8.02
(2H, m), 8.60 (1H, d, J=4 Hz).
[0074] mp=84-85.degree. C.
[0075] (R.sub.1=2-pyridylmethyl, R.sub.2=2-n-propyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 8
6-Ethoxycarbonyl-1-(3-Fluorobenzyl)-2-n-Propylbenzimidazole
[0076] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.04 (3H, t, J=7.5 Hz),
1.39 (3H, t, J=7.5 Hz), 1.90 (2H, m), 2.81 (2H, t, J=7.5 Hz), 4.39
(2H, q, J=7.5 Hz), 5.39 (2H, s), 6.70-6.84 (2H, m), 7.00 (1H, dt,
J=8.5 and 1.5 Hz), 7.78 (1H, d, J=8.5 Hz), 7.96 (1H, s), 8.00 (1H,
d, J=8.5 Hz).
[0077] mp=142-146.degree. C.
[0078] (R.sub.1=3-fluorobenzyl, R.sub.2=2-n-propyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 9
1-(2,6-Dichlorobenzyl)-6-Ethoxycarbonyl-2-n-Propylbenzimidazole
[0079] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.03 (3H, t, J=7.5 Hz),
1.38 (3H, t, J=7.5 Hz), 1.88 (2H, m), 2.93 (2H, t, J=7.5 Hz), 4.34
(2H, q, J=7.5 Hz), 5.61 (2H, s), 7.26 (1H, d, J=7.5 Hz), 7.39 (2H,
d, J=7.5 Hz), 7.68 (1H, d, J=7.5 Hz), 7.84 (1H, d, J=1.5 Hz), 7.91
(2, d, J=7.5 Hz).
[0080] mp=153-156.degree. C.
[0081] (R.sub.1=2,6-dichlorobenzyl, R.sub.2=2-n-propyl,
R.sub.3=ethoxycaxbonyl, n=1, y=0)
Example 10
1-(3-Methylbenzyl)-6-Ethoxycarbonyl-2-n-Propylbenzimidazole
[0082] Colorless solid
[0083] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.02 (3H, t, J=7.5 Hz),
1.41 (3H, t, J=7.5 Hz), 1.89 (2H, m), 2.29 (3H, s), 2.82 (2H, t,
J=7.5 Hz), 4.38 (2H, q, J=7.5 Hz), 5.35 (2H, s), 6.79-6.86 (2H, m),
7.09 (1H, d, J=7.5 Hz), 7.20 (1H, d,=7.5 Hz), 7.76 (1H, d, J=7.5
Hz), 7.95-8.02 (2H, m).
[0084] (R.sub.1=3-methylbenzyl, R.sub.2=2-n-propyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 11
2-Cyclopropyl-6-Ethoxycarbonyl-1-(2-Fluorobenzyl)Benzimidazole
[0085] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.10 (2H, m), 1.27 (2H,
m), 1.40 (3H, t, J=7.5 Hz), 1.95 (1H, m), 4.37 (2H, q, J=7.5 Hz),
5.56 (2H, s), 6.77 (1H, t, J=7.5 Hz), 7.03 (1H, t, J=7.5 Hz), 7.13
(1H, t, J=7.5 Hz), 7.29 (1H, m), 7.69 (1H, d, J=7.5 Hz), 7.96 (1H,
d, J=7.5 Hz), 8.02 (1H, d, J=2 Hz).
[0086] mp=122-126.degree. C.
[0087] (R.sub.1=2-fluorobenzyl, R.sub.2=2-cyclopropyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 12
1-(2-Chlorobenzyl)-6-Cyano-2-Cyclopropylbenzimidazole
[0088] .sup.1H-NMR (CDCl.sub.3, .delta.): 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=9 Hz), 7.16 (1H, td, J=9, 2 Hz), 7.22-7.38 (1H, m), 7.43-7.56
(3H, m), 7.74 (1H, dd, J=9, 2 Hz).
[0089] Mass (FAB): 308 (M+1)
[0090] IR (Nujol): 2210 cm.sup.-1
[0091] (R.sub.1=2-chlorobenzyl, R.sub.2=2-cyclopropyl,
R.sub.3=cyano, n=1, y=0)
Example 13
1-(2-Chlorobenzyl)-2-Cyclobutyl-6-Ethoxycarbonylbenzimidazole
[0092] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.38 (3H, t, J=7.5 Hz),
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=7.5 Hz), 5.39 (2H, s), 6.34 (1H, dd, J=9, 2
Hz), 7.06 (1H, td, J=9, 2 Hz), 7.23 (1H, td, J=9, 2 Hz), 7.46 (1H,
dd, J=9, 2 Hz), 7.83 (1H, d, J=9 Hz), 7.92 (1H, d, J=2 Hz) 8.01
(1H, dd, J=9, 2 Hz).
[0093] mp=111-113.degree. C.
[0094] (R.sub.1=2-chlorobenzyl, R.sub.2=2-cyclobutyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 14
1-(2-Chlorobenzyl)-6-Ethoxycarbonyl-2-n-Pentylbenzimidazole
[0095] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.87 (3H, t, J=7.5 Hz),
1.22-1.47 (7H, m), 1.74-1.93 (2H, m), 2.80 (2H, t, J=7.5 Hz), 4.37
(2H, q, J=7.5 Hz), 5.47 (2H, s), 6.39 (1H, dd, J=9, 2 Hz), 7.08
(1H, td, J=9, 2 Hz), 7.19-7.33 (1H, m), 7.48 (1H, dd, J=9, 2 Hz),
7.79 (1H, d, J=9 Hz), 7.94 (1H, d, J=2 Hz) 8.00 (1H, dd, J=9, 2
Hz).
[0096] (R.sub.1=2-chlorobenzyl, R.sub.2=2-n-pentyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 15
5-Carboxyl-1-(2-Chlorobenzyl)-2-n-Propylbenzimidazole
[0097] Ethanol (20 ml) and 10% sodium hydroxide aqueous solution
(10.4 g) are added to
1-(2-chlorobenzyl)-5-ethoxycarbonyl-2-n-propylbenzimidazole (2.8
g). The solution is then refluxed by heating for four hours. After
cooling the reaction solution, the acidity of the solution is
adjusted to pH 6 with 10% hydrochloric acid. Crystals are
collected, washed with water, dried through by evaporation under
reduced pressure, and colorless solids of
5-carboxyl-1-(2-chlorobenzyl)-2-n-propylbenzimidazole (2.46 g) are
obtained.
[0098] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.93 (3H, t, J=7.5 Hz),
1.75 (2H, m), 2.79 (2H, t, J=7.5 Hz), 5.61 (2H, s), 6.49 (1H, d,
J=7.5 Hz), 7.21 (1H, t, J=7.5 Hz), 7.33 (1H, t, J=7.5 Hz), 7.46
(1H, d, J=7.5 Hz), 7.56 (1H, d, J=7.5 Hz), 7.80 (1H, d, J=7.5 Hz)
8.20 (1H, s).
[0099] (R.sub.1=2-chlorobenzyl, R.sub.2=2-n-propyl,
R.sub.3=carboxyl, n=1, y=0)
[0100] The following examples 16 to 19 are synthesized by using the
same method as described in Example 15.
Example 16
6-Carboxy-1-(3-Methylbenzyl)-2-n-Propylbenzimidazole
[0101] Colorless solid. .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.97
(3H, t, J=7.5 Hz), 1.78 (2H, m), 2.23 (3H, s), 3.86 (2H, q, J=7.5
Hz), 5.53 (2H. s), 6.80 (1H, d, J=7.5 Hz), 6.91 (1H, s), 7.07 (1H,
d, J=7.5 Hz), 7.21 (1H, t, J=7.5 Hz), 7.65 (1H, d, J=7.5 Hz), 7.79
(1H, d, J=7.5 Hz), 8.04 (1H, s). (R.sub.1=3-methylbenzyl,
R.sub.2=2-n-propyl, R.sub.3=carboxyl, n=1, y=0)
Example 17
2-n-Butyl-7-Carboxy-1-(2-Chlorobenzyl)Benzimidazole
[0102] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.84 (3H, t, J=7.5 Hz),
1.34 (2H, m), 1.71 (2H, m), 2.80 (2H, t, J=7.5 Hz), 5.89 (2H. s),
6.03 (1H, d, J=7.5 Hz), 7.13 (1H, t, J=7.5 Hz), 7.27 (2H, t, J=7.5
Hz), 7.48 (1H, d, J=7.5 Hz), 7.63 (1H, d, J=7.5 Hz), 7.87 (1H, d,
J=7.5 Hz).
[0103] (R.sub.1=2-chlorobenzyl, R.sub.2=2-n-butyl,
R.sub.3=carboxyl, n=1, y=0)
Example 18
6-Carboxy-2-Cyclopropyl-1-(2-Fluorobenzyl)Benzimidazole
[0104] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.04-1.19 (4H, m), 2.37
(1H, m), 5.79 (2H, s), 7.00 (1H, t, J=7.5 Hz), 7.15 (1H, t, J=7.5
Hz), 7.27 (1H, t, J=10.5 Hz), 7.37 (1H, m), 7.60 (1H, d, J=7.5 Hz),
7.82 (1H, d, J=7.5 Hz), 8.11 (1H, s).
[0105] mp: 224-229.degree. C. (R.sub.1=2-fluorobenzyl,
R.sub.2=2-cyclopropyl, R.sub.3=carboxyl, n=1, y=0)
Example 19
2-n-Butyl-6-Carboxy-1-(2-Fluorobenzyl)Benzimidazole
[0106] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.87 (3H, t, J=7.5 Hz),
1.26-1.48 (2H, m), 1.60-1.80 (2H, m), 2.90 (2H, t, J=7.5 Hz), 5.63
(2H. s), 6.89 (1H, td, J=9, 2Hz), 7.13 (1H, td, J=9, 2 Hz),
7.20-7.44 (2H, m), 7.64 (1H, d, J=9 Hz), 7.80 (1H, dd, J=9, 2 Hz),
8.08 (1H, d, J=2 Hz).
[0107] mp: 216-219.degree. C. (R.sub.1=2-fluorobenzyl,
R.sub.2=2-n-butyl, R.sub.3=carboxyl, n=1, y=0)
Example 20
1-(2-Chlorobenzyl)-6-Chlorocarbonyl-2-Cyclopropylbenzimidazole
Hydrochloride
[0108] A suspension is prepared by adding
6-carboxy-1-(2-chlorobenzyl)-2-c- yclopropylbenzimidazole (390 mg)
to methylene chloride (10 ml) which includes N,N-dimethylformamide
(one drop). Oxalyl chloride (0.208 ml) is dripped into the
suspension over a period of a few minutes at room temperature.
After stirring for two hours at the same temperature, the mixed
material is concentrated under reduced pressure. Isopropyl ether is
added to the residue, which is then turned into powder. Thus, white
powder of
1-(2-chlorobenzyl)-6-chlorocarbonyl-2-cyclopropylbenzimidazole
hydrochloride (450 mg) is obtained. Because this material is
unstable, it is used as a source material for the next process
without purification.
[0109] (R.sub.1=2-chlorobenzyl, R.sub.2=2-cyclopropyl,
R.sub.3=chloro-carbonyl, n=1, y=0)
Example 21
1-(2-Chlorobenzyl)-6-(4-Dimethylaminophenylmethylcarbamoyl)-2-n-Propylbenz-
imidazole
[0110] 6-Carboxy-1-(2-chlorobenzyl)-2-n-propylbenzimidazole (400
mg) is dissolved in methylene chloride (3 ml) to which one drop of
N,N-dimethylformamide has been added. Oxalyl chloride (0.208 ml) is
added to this solution at 5 C. After the obtained solution is
stirred for one hour at room temperature, the solution is
concentrated under reduced pressure. The residue is dissolved in
methylene chloride (3 ml), which is then added at room temperature
to a mixture solution prepared by adding 4-dimethylaminobenzylamine
hydrochloride (271 mg) and triethylamine (1 ml) to methylene
chloride (10 ml). The obtained reaction mixture is stirred for one
hour at the same temperature, washed with water, dried, and then
concentrated under reduced pressure. The residue is developed and
purified using thin film chromatography, and
1-(2-chlorobenzyl)-6-(4--
dimethylamino-phenylmethylcarbamoyl)-2-n-propylbenzimidazole (215
mg) is obtained. (Colorless crystal). .sup.1H-NMR (CDCl.sub.3):
1.01 (3H, t, J=7 Hz), 1.88 (2H, sextet, J=7 Hz), 2.76 (2H, t, J=7
Hz), 2.95 (6H, s), 4.50 (2H, d, J=5 Hz), 5.45 (2H, s), 6.32 (1H, d,
J=5 Hz), 6.36 (1H, d, J=7 Hz), 6.72 (2H, d, J=10 Hz), 7.07 (1H, dt,
J=1, 8 Hz), 7.20-7.25 (3H, m), 7.46 (1H, dd, J=1, 8 Hz), 7.58 (1H,
dd, J=1, 8 Hz), 7.76 (1H, d, J=8 Hz), 7.82 (1H, d, J=1 Hz).
[0111] mp: 155-156.degree. C. (R.sub.1=2-chlorobenzyl,
R.sub.2=2-n-propyl, R.sub.3=carbamoyl,
R.sub.4=4-dimethylamino-phenylmethyl, R.sub.5=H, n=1, y=0).
Example 22
1-(2-Chlorobenzyl)-6-Morpholinocarbamoyl-2-n-Propylbenzimidazole
[0112] By using the same method of example 21,
1-(2-chlorobenzyl)-6-morpho- linocarbamoyl-2-n-propylbenzimidazole
(205 mg) is obtained from
6-carboxy-1-(2-chlorobenzyl)-2-n-propylbenzimidazole (200 mg) and
4-aminomorpholine (124 mg). (Colorless crystal). .sup.1H-NMR
(CDCl.sub.3): 1.03 (3H, t, J=8 Hz), 1.88 (2H, sextet, J=8 Hz), 2.62
(4H, bs), 2.72 (2H, t, J=8 Hz), 3.85 (4H, bs), 5.42 (2H, s), 6.42
(1H, dd, J=1, 8 Hz), 7.08 (1H, dt, J=1, 8 Hz), 7.20-7.28 (3H, m),
7.47 (1H, dd, J=1, 8 Hz), 7.78 (1H, dd, J=1, 8 Hz).
[0113] mp: 195-197.degree. C. (R.sub.1=2-chlorobenzyl,
R.sub.2=2-n-propyl, R.sub.3=--C(O)--NR.sub.4R.sub.5, R.sub.4 and
R.sub.5=morpholino, n=1, y=0)
Example 23
1-(2-Chlorobenzyl)-2-n-Propyl-6-Thiomorpholinocarbonylbenzimidazole
[0114] By using the same method of example 21,
1-(2-chlorobenzyl)-2-n-prop-
yl-6-thiomorpholinocarbonylbenzimidazole (160 mg) is obtained from
6-carboxy-1-(2-chlorobenzyl)-2-n-propylbenzimidazole (200 mg) and
thiomorpholine (125 mg). (Colorless crystal). .sup.1H-NMR
(CDCl.sub.3): 1.03 (3H, t, J=8 Hz), 1.88 (2H, sextet, J=8 Hz), 2.78
(2H, t, J=8 Hz), 2.96 (4H, bt, J=5 Hz), 3.88 (4H, bt, J=5 Hz), 5.46
(2H, s), 6.34 (1H, dd, J=1, 8 Hz), 7.08 (1H, dt, J=1, 8 Hz), 7.26
(2H, dt, J=1, 8 Hz), 7.47 (1H, dd, J=1, 8 Hz), 7.58 (1H, bd, J=1, 8
Hz), 7.76 (1H, s), 7.78 (1H, d, J=8 Hz).
[0115] mp: 160-162.degree. C. (R.sub.1=2-chlorobenzyl,
R.sub.2=2-n-propyl, R.sub.3=carbamoyl, R.sub.4 and
R.sub.5=thiomorpholino, n=1, y=0)
Example 24
2-n-Butyl-1-(2-Chlorobenzyl)-6-[(2-Pyridylmethyl)carbamoyl]Benzimidazole
[0116] By using the same method of example 21,
2-n-butyl-1-(2-chlorobenzyl-
)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (230 mg) is obtained
from 6-carboxy-2-n-butyl-1-(2-chlorobenzyl)benzimidazole (200 mg)
and 2-aminomethyl-pyridine (126 mg). (Colorless crystal).
.sup.1H-NMR (CDCl3,): 0.92 (3H, t, J=8 Hz), 1.42 (2H, sextet, J=8
Hz), 1.82 (2H, quintet, J=8 Hz), 2.82 (2H, t, J=8 Hz), 4.76 (1H, d,
J=5 Hz), 5.46 (2H, s), 6.38 (1H, dd, J=1, 8 Hz), 7.08 (1H, dt, J=1,
8 Hz), 7.18-7.26 (2H, s), 7.32 (1H, d, J=8 Hz), 7.46 (1H, dd, J=1,
8 Hz), 7.62 (1H, dt, J=1, 8Hz), 7.72 (1H, dt, J=1, 8 Hz), 7.82 (1H,
d, J=8 Hz), 7.88 (1H, d, J=1 Hz), 8.56 (1H, dd, J=1, 8 Hz).
[0117] mp: 175-176.degree. C. (R.sub.1=2-chlorobenzyl,
R.sub.2=2-n-butyl, R.sub.3=--C(O)NR.sub.4R.sub.5,
R.sub.4=2-pyridylmethyl, R.sub.5=H, n=1, y=0)
Example 25
2-n-Butyl-5-Carbamoyl-1-(2-Chlorobenzyl)Benzimidazole
[0118] By using the same method of example 21,
2-n-butyl-5-carbamoyl-1-(2-- chlorobenzyl)benzimidazole (170 mg) is
obtained from 2-n-butyl-1-(2-chlorobenzyl)-5-carboxybenzimidazole
(100 mg). (Colorless crystal). .sup.1H-NMR (DMSO-d6,): 0.84 (3H, t,
J=8 Hz), 1.35 (2H, sextet, J=8 Hz), 1.68 (2H, quintet, J=8 Hz),
2.78 (2H, t, J=8 Hz), 5.58 (2H, s), 6.50 (1H, dd, J=1, 8 Hz), 7.25
(1H, dt, J=1, 8 Hz), 7.28 (1H, bs), 7.35 (1H, dt, J=1, 8 Hz), 7.42
(1H, d, J=10 Hz), 7.56 (1H, dd, J=1, 8 Hz), 7.74 (1H, dd, J=1, 10
Hz), 7.96 (1H, bs), 8.20 (1H, d, J=1 Hz).
[0119] mp: 195-198 C.
[0120] (R.sub.1=2-chlorobenzyl, R.sub.2=2-n-butyl,
R.sub.3=carbamoyl, n=1, y=0)
Example 26
1-(2-Chlorobenzyl)-2-Cyclopropyl-6-Morpholinocarbonylbenzimidazole
[0121]
1-(2-Chlorobenzyl)-6-chlorocarbonyl-2-cyclopropylbenzimidazole
hydrochloride (140 mg) is added at room temperature to a solution
which has been prepared by adding morpholine (298 mg, a 30%
methanol solution) to methylene chloride (10 ml) . After the
reaction mixture is stirred for one hour at the same temperature,
it is washed with water, dried and concentrated under reduced
pressure. The residue is recrystallized using ether and thus,
1-(2-chlorobenzyl)-2-cyclopropyl-6-morpholinocarbonylbenz-
imidazole (20 mg) is obtained. (Colorless crystal). .sup.1H-NMR
(CDCl3,): 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, 8 Hz), 7.13 (1H,
dt, J=1, 8 Hz), 7.22-7.29 (2H, m), 7.30 (1H, d, J=1 Hz), 7.46 (1H,
dd, J=1, 8 Hz), 7.77 (1H, d, J=8 Hz).
[0122] mp: 193-195.degree. C. (R.sub.1=2-chlorobenzyl,
R.sub.2=2-cyclopropyl, R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4 and
R.sub.5=morpholino, n=1, y=0)
Example 27
1-(2-Chlorobenzyl)-2-Cyclopropyl-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazo-
le
[0123] By using the same method of example 21,
1-(2-chlorobenzyl)-2-cyclop-
ropyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (95 mg) is
obtained from
1-(2-chlorobenzyl)-6-chlorobarbonyl-2-cyclopropylbenzimidazole
hydrochloride (150 mg) and 2-aminomethylpyridine (85 mg).
(Colorless crystal). .sup.1H-NMR (CDCl.sub.3): 1.02-1.13 (2H, m),
1.24-1.32 (2H, m), 1.82-1.95 (1H, m), 4.76 (2H, d, J=5 Hz), 5.5
(2H, s), 7.11 (1H, dt, J=1, 8 Hz), 7.20-7.26 (2H, m), 7.34 (1H, d,
J=8 Hz), 7.46 (1H, dd, J=1, 8 Hz), 7.60 (1H, t, J=5 Hz), 7.66 (1H,
dd, J=1, 8 Hz), 7.73 (1H, s), 7.88 (1H, s).
[0124] mp: 134-135 C.
[0125] (R.sub.1=2-chlorobenzyl, R.sub.2=2-cyclopropyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl, R.sub.5=H,
n=1, y=0)
[0126] The following examples 28 to 45 are synthesized by using the
same method as described in example 26.
Example 28
1-(2-Chlorobenzyl)-2-Cyclopropyl-6-(2-Pyridylcarbamoyl)Benzimidazole
[0127] .sup.1H-NMR (CDCl.sub.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 1.5 Hz), 7.15 (1H,
dt, J=7.5 and 1.5 Hz), 7.22-7.31 (2H, m), 7.48 (1H, dd, J=7.5 and
1.5 Hz), 7.77 (1H, d, J=9 Hz), 8.05 (2H, m).
[0128] mp: 206-209.degree. C. (R.sub.1=2-chlorobenzyl,
R.sub.2=2-cyclopropyl, R.sub.3=--C(O)NR.sub.4R.sub.5,
R.sub.4=2-pyridyl, R.sub.5=H, n=1, y=0)
Example 29
6-(2-Carboxy-1-Pyrrolidinocarbonyl)-1-(2-Chlorobenzyl)-2-n-Propylbenzimida-
zole
[0129] .sup.1H-NMR (DMSO-d.sub.6): 0.92 (3H, t, J=7.5 Hz),
1.65-1.99 (5H, m), 2.25 (1H, m), 2.77 (2H, t, J=7.5 Hz), 3.50 (2H,
m), 4.40 (1H, m), 5.52 (2H, s), 6.53 (1H, d, J=7.5 Hz), 7.21-7.71
(6H, m).
[0130] mp: 96.degree. C. (R.sub.1=2-chlorobenzyl,
R.sub.2=2-n-propyl, R.sub.3=R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4
and R.sub.5=pyrrolidino, n=1, y=0)
Example 30
1-(2-Chlorobenzyl)-2-Cyclobutyl-6-[(2-Pyridylmethyl)carbamoyl]Benzimidazol-
e
[0131] .sup.1H-NMR (CDCl.sub.3): 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=5 Hz), 5.39
(2H, s), 6.33 (1H, d, J=7.5 Hz), 7.05 (1H, t, J=7.5 Hz), 7.16-7.26
(2H, m), 7.33 (1H, d, J=7.5 Hz), 7.46 (1H, d, J=7.5 Hz), 7.69-7.76
(3H, m), 7.73 (1H, d, J=7.5 Hz), 7.86 (1H, s), 8.55 (1H, d, J=5
Hz).
[0132] mp: 183-185 C.
[0133] (R.sub.1=2-chlorobenzyl, R.sub.2=2-cyclobutyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl, R.sub.5=H,
n=1, y=0)
Example 31
(1-(2-Chlorobenzyl)-2-n-Propyl-5-[(2-Pyridylmethyl)carbamoyl]Benzimidazole
[0134] .sup.1H-NMR (CDCl.sub.3): 1.03 (3H, t, J=7.5 Hz), 1.90 (2H,
m), 2.80 (2H, t, J=7.5 Hz), 4.80 (2H, d, J=5 Hz), 5.44 (2H, s),
6.40 (1H, d, J=7.5 Hz), 7.09 (1H, t, J=7.5 Hz), 7.21-7.27 (3H, m),
7.34 (1H, d, J=7.5 Hz), 7.47 (1H, d, J=7.5 Hz), 7.64-7.72 (2H, m),
7.83 (1H, dd, J=7.5 and 2 Hz), 8.30 (1H, d, J=2 Hz), 8.56 (1H, d,
J=5 Hz).
[0135] mp: 115-116.degree. C. (R.sub.1=2-chlorobenzyl,
R.sub.2=2-n-propyl, R.sub.3=--C(O)NR.sub.4R.sub.5,
R.sub.4=2-pyridylmethyl, R.sub.5=H, n=1, y=0)
Example 32
1-(2-Chlorobenzyl)-6-[N-methyl-N-(2-Pyridylmethyl)carbamoyl]-2-n-Propylben-
zimidazole
[0136] .sup.1H-NMR (DMSO-d.sub.6): 1.03 (3H, t, J=7.5 Hz), 1.87
(2H, m), 2.79 (2H, t, J=7.5 Hz), 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).
[0137] mp: 99.degree. C. (R.sub.1=2-chlorobenzyl,
R.sub.2=2-n-propyl, R.sub.3=--C(O)NR.sub.4R.sub.5,
R.sub.4=2-pyridylmethyl, R.sub.5=methyl, n=1, y=0)
Example 33
1-(2-Chlorobenzyl)-6-Piperonylcarbamoyl-2-n-Propylbenzimidazole
[0138] .sup.1H-NMR (CDCl.sub.3): 1.01 (3H, t, J=7.5 Hz), 1.88 (2H,
m), 2.78 (2H, t, J=7.5 Hz), 4.54 (2H, d, J=5 Hz), 5.45 (2H, s),
5.95 (2H, s), 6.36 (1H, d, J=7.5 Hz), 6.44 (2H, t, J=5 Hz),
6.75-6.85 (3H, m), 7.08 (1H, t, J=7.5 Hz), 7.23 (1H, t, J=7.5 Hz),
7.4 (1H, d, J=7.5 Hz), 7.67 (1H, dd, J=7.5, 2 Hz), 7.78 (2H, d,
J=7.5 Hz), 7.83 (1H, s).
[0139] mp: 131-134 C.
[0140] (R.sub.1=2-chlorobenzyl, R.sub.2=2-n-propyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=piperonyl, R.sub.5=H, n=1,
y=0)
Example 34
1-(2-Chlorobenzyl)-6-Phenylcarbamoyl-2-n-Propylbenzimidazole
[0141] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.03 (3H, t, J=7.5 Hz),
1.90 (2H, m), 2.81 (2H, t, J=7.5 Hz), 5.47 (2H, s), 6.40 (1H, d,
J=7.5 Hz), 7.06-7.18 (2H, m), 7.26 (1H, t, J=7.5 Hz), 7.35 (2H, t,
J=7.5 Hz), 7.48 (1H, d, J=7.5 Hz), 7.64 (2H, d, J=7.5 Hz), 7.72
(1H, dd, J=7.5 and 2 Hz), 7.85-7.95 (3H, m).
[0142] mp: 168.degree. C.
[0143] (R.sub.1=2-chlorobenzyl, R.sub.2=2-n-propyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=phenyl, R.sub.5=H, n=1,
y=0)
Example 35
1-(2-Chlorobenzyl)-2-n-Propyl-6-[(4-Pyridylmethyl)carbamoyl]Benzimidazole
[0144] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.93 (3H, t, J=7.5 Hz),
1.76 (2H, m), 2.78 (2H, t, J=7.5 Hz), 4.49 (2H, d, J=5 Hz), 6.42
(1H, d, J=7.5 Hz), 7.22 (1H, t, J=7.5 Hz), 7.27 (2H, d, J=7.5 Hz),
7.34 (1H, t, J=7.5 Hz), 7.57 (1H, d, J=7.5 Hz), 7.69 (1H, d, J=7.5
Hz), 7.80 (1H, d, J=7.5 Hz), 7.97 (1H, s), 8.48 (2H, t, J=7.5 Hz),
9.03 (1H, t, J=5 Hz).
[0145] mp: 170-173.degree. C.
[0146] (R.sub.1=2-chlorobenzyl, R.sub.2=2-n-propyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=4-pyridylmethyl, R.sub.5=H,
n=1, y=0)
Example 36
1-(2-Chlorobenzyl)-2-n-Propyl-6-[(3-Pyridylmethyl)carbamoyl]Benzimidazole
[0147] .sup.1H-NMR (DMSO-d.sub.6): 0.95 (3H, t, J=7.5 Hz), 1.76
(2H, m), 2.80 (2H, t, J=7.5 Hz), 4.50 (2H, d, J=5 Hz), 5.60 (2H,
s), 6.42 (1H, d, J=7.5 Hz), 7.23 (1H, t, J=7.5 Hz), 7.30-7.58 (2H,
m), 7.57 (1H, d, J=7.5 Hz), 7.67-7.74 (2H, m), 7.75 (1H, d, J=7.5
Hz), 7.97 (1H, s), 8.46 (1H, d, J=5 Hz), 8.56 (1H, s), 9.0 (1H, t,
J=5 Hz).
[0148] mp: 193-195 C.
[0149] (R.sub.1=2-chlorobenzyl, R.sub.2=2-n-propyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=3-pyridylmethyl, R.sub.5=H,
n=1, y=0)
Example 37
1-(2-Chlorobenzyl)-6-[N-Methyl-N-(2-Pyridyl)carbamoyl]-2-n-Propylbenzimida-
zole
[0150] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.90 (3H, t, J=7.5 Hz),
1.70 (2H, m), 2.73 (2H, t, J=7.5 Hz), 3.40 (3H, s), 5.42 (2H, s),
6.23 (1H, d, J=7.5 Hz), 6.91 (1H, d, J=7.5 Hz), 6.98 (1H, m),
7.15-7.25 (3H, m), 7.36 (1H, t, J=7.5 Hz), 7.46-7.57 (3H, m), 8.23
(1H, m).
[0151] mp: 143-146.degree. C.
[0152] (R.sub.1=2-chlorobenzyl, R.sub.2=2-n-propyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl,
R.sub.5=methyl, n=1, y=0)
Example 38
1-(2-Chlorobenzyl)-6-(Homopiperidinocarbonyl)-2-n-Propylbenzimidazole
[0153] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.03 (3H, t, J=7.5 Hz),
1.46-1.94 (10H, m), 2.80 (2H, t, J=7.5 Hz), 3.32 (2H, brs), 3.64
(2H, t, J=7.5 Hz), 5.41 (2H, s), 6.42 (1H, d, J=7.5 Hz), 7.07 (1H,
t, J=7.5 Hz), 7.19-7.29 (3H, m), 7.45 (1H, t, J=7.5 Hz), 7.76 (1H,
d, J=7.5 Hz).
[0154] mp: 136-137.degree. C. (R.sub.1=2-chlorobenzyl,
R.sub.2=2-n-propyl, R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4 and
=homopiperidyl, n=1, y=0)
Example 39
1-(3-Methylbenzyl)-2-n-Propyl-6-[(2-Pyridylmethyl)carbamoyl]Benzimidazole
[0155] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.02 (3H, t, J=7.5 Hz),
1.88 (2H, m), 2.26 (3H, s), 2.81 (2H, t, J=7.5 Hz), 4.76 (2H, d,
J=5 Hz), 5.36 (2H, s), 6.78-6.84 (2H, m), 7.07 (1H, d, J=7.5 Hz),
7.13-7.22 (2H, m), 7.33 (1H, d, J=7.5 Hz), 7.57-7.72 (2H, m), 7.78
(1H, d, J=7.5 Hz), 7.94 (1H, s), 8.55 (1H, d, J=5 Hz).
[0156] mp: 129-131.degree. C. (R.sub.1=3-methylbenzyl,
R.sub.2=2-n-propyl, R.sub.3=2-pyridylmethylcarbamoyl, n=1, y=0)
Example 40
2-n-Butyl-1-(2-Fluorobenzyl)-6-[N-Methyl-N-(2-Pyridylmethyl)Carbamoyl]Benz-
imidazole
[0157] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.92 (3H, t, J=7.5 Hz),
1.45 (2H, m), 1.83 (2H, m), 2.86 (2H, t, J=7.5 Hz), 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=5 Hz).
[0158] mp: 97-100.degree. C.
[0159] (R.sub.1=2-fluorobenzyl, R.sub.2=2-n-propyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl,
R.sub.5=methyl, n=1, y=0)
Example 41
1-(2-Chlorobenzyl)-2-Ethyl-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
[0160] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.43 (3H, t, J=7.5 Hz),
2.84 (2H, q, J=7.5 Hz), 4.76 (2H, d, J=5 Hz), 5.45 (2H, s), 6.37
(1H, d, J=7.5 Hz), 7.07 (1H, t, J=7.5 Hz), 7.19-7.28 (2H, m), 7.33
(1H, d, J=7.5 Hz), 7.45 (1H, dd, J=7.5 and 2 Hz), 7.62-7.75 (3H,
m), 7.82 (1H, d, J=7.5 Hz), 7.89 (1H, d, J=2 Hz), 8.55 (1H, d, J=5
Hz).
[0161] mp: 167-168.degree. C. (R.sub.1=2-chlorobenzyl, R.sub.2
=ethyl, R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl,
R.sub.5=H, n=1, y=0)
Example 42
2-n-Butyl-1-(2-Chlorobenzyl)-7-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
[0162] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.93 (3H, t, J=7.5 Hz),
1.42 (2H, m), 1.83 (2H, m), 2.81 (2H, t, J=7.5 Hz), 4.44 (2H, d,
J=5 Hz), 5.70 (2H, s), 6.13 (1H, dd, J=7.5 and 2 Hz), 6.85-6.97
(3H, m), 7.12-7.28 (4H, m), 7.34 (1H, d, J=7.5 Hz), 7.62 (1H, dt,
J=7.5 and 2 Hz), 7.88 (1H, d, J=7.5 Hz), 8.40 (1H, d, J=5 Hz).
[0163] mp: 112-114.degree. C. (R.sub.1=2-chlorobenzyl,
R.sub.2=2-n-butyl, R.sub.3=--C(O)NR.sub.4R.sub.5,
R.sub.4=2-pyridylmethyl, R.sub.5=H, n=1, y=0)
Example 43
2-Cyclopropyl-1-(2-Fluorobenzyl)-6-(Piperonylcarbamoyl)Benzimidazole
[0164] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.05 (4H, m), 2.27 (1H,
m), 4.38 (2H, d, J=5 Hz), 5.71 (2H, s), 5.98 (2H, s), 6.73-6.91
(4H, m), 7.14 (1H, t, J=7.5 Hz), 7.27 (1H, t, J=7.5 Hz), 7.36 (1H,
m), 7.55 (1H, d, J=7.5 Hz), 7.73 (1H, dd, J=7.5 and 2 Hz), 8.04
(1H, s), 8.87 (1H, t, J=5 Hz).
[0165] mp: 170-173.degree. C.
[0166] (R.sub.1=2-fluorobenzyl, R.sub.2=cyclopropyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=piperonyl, R.sub.5=H, n=1,
y=0)
Example 44
2-[[1-(2-Chlorobenzyl)-2-ethylbenzimidazole-6-yl]carbonylaminomethyl]-Pyri-
dine 1-Oxide
[0167] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.42 (3H, t, J=7.5 Hz),
2.82 (2H, q, J=7.5 Hz), 4.81 (2H, d, J=7.5 Hz), 5.43 (2H, s), 6.31
(1H, d, J=7.5 Hz), 7.06 (1H, t, J=7.5 Hz), 7.20-7.31 (3H, m), 7.44
(1H, d, J=7.5 Hz), 7.52 (1H, dd, J=7.5 and 2 Hz), 7.65 (1H, dd,
J=7.5 and 2 Hz), 7.77-7.83 (2H, m), 7.96 (1H, t, J=7.5 Hz), 8.23
(1H, dd, J=7.5 and 2 Hz).
[0168] mp: 204-207.degree. C. (R.sub.1=2-chlorobenzyl,
R.sub.2=ethyl, R.sub.3=--C(O)--NR.sub.4R.sub.5,
R.sub.4=pyridyl-oxide-2-methyl, R.sub.5=H, n=1)
Example 45
2-n-Butyl-1-(2-Fluorobenzyl)-6-(2-Pyridylmethylcarbamoyl)Benzimidazole
[0169] .sup.1H-NMR (CDCl.sub.3, .delta.): 0.92 (3H, t, J=7.5 Hz),
1.38-1.49 (2H, m), 1.77-1.88 (2H, m), 2.86 (2H, t, J=7.5 Hz), 4.78
(2H, d, J=5 Hz), 5.46 (2H, s), 6.67 (1H, t, J=9 Hz), 7.00 (1H, t,
J=9 Hz), 7.13 (1H, t, J=9 Hz), 7.19-7.31 (2H, m), 7.33 (1H, d, J=9
Hz), 7.60 (1H, br peak), 7.65-7.74 (2H, m), 7.79 (1H, d, J=9 Hz),
7.97 (1H, d, J=2 Hz), 8.58 (1H, d, J=5 Hz).
[0170] mp: 154-155.degree. C. (R.sub.1=2-fluorobenzyl,
R.sub.2=n-butyl, R.sub.3=--C(O)NR.sub.4R.sub.5,
R.sub.4=2-pyridylmethyl, R.sub.5=H, n=1, y=0)
Example 46
1-(2-Chlorobenzyl)-6-Cyano-2-n-Propylbenzimidazole
[0171] Dichloromethane solution (1 molar, 0.14 ml) of titanium
tetrachloride and triethylamine (0.36 ml) are added to a
tetrahydrofuran solution (4 ml) of
6-carbamoyl-1-(2-chlorobenzyl)-2-n-propylbenzimidazole (200 mg) at
0.degree. C., and the solution is stirred for two hours at
20.degree. C. The reaction mixture is separated into layers using
ethyl acetate and water. The organic layer is washed with water,
dried and concentrated under reduced pressure. The residue is
developed and purified using column chromatography with ethyl
acetate/hexane (1/10.about.1/3). The material is re-crystallized
using ethyl acetate/hexane and
1-(2-chlorobenzyl)-6-cyano-2-n-propylbenzimidazole (140 mg) is
obtained. (Colorless crystal) .sup.1H-NMR (CDCl.sub.3, .delta.):
1.05 (3H, t, J=8 Hz), 1.90 (2H, sextet, J=8 Hz), 2.85 (2H, t, J=8
Hz), 5.45 (2H, s), 6.42, (1H, dd, J=1, 8 Hz), 7.15 (1H, dt, J=1, 8
Hz), 7.28 (1H, dt, J=1, 8 Hz), 7.48 (1H, s), 7.50 (1H, d, J=10 Hz),
7.54 (1H, dd, J=1, 8 Hz), 7.85 (1H, d, J=10 Hz).
[0172] mp: 124-126.degree. C. (R.sub.1=2-Chlorobenzyl,
R.sub.2=n-propyl, R.sub.3=cyano, n=1, y=0)
Example 47
1-(2-Chlorobenzyl)-6-Ethoxycarbonyl-2-Methylbenzimidazole
A.) 3-Acetylamino-4-nitro-ethylbenzoate
[0173] Acetyl chloride (9 ml) is added to a mixture of
3-amino-4-nitro-ethylbenzoate (18.4 g) and N,N-dimethylaniline (200
ml) under ice-chilled conditions, and the solution is stirred for 2
hours at room temperature. It is stirred for another 2 hours at
50.degree. C. The reaction solution is poured into the cold
1N-hydrochloric acid, and then extraction is performed with ethyl
acetate twice. After the organic layer is washed with
1N-hydrochloric acid, then with water, and dried, the solvent is
removed through evaporation under reduced pressure. The residue is
purified using silica gel column chromatography (eluate: ethyl
acetate/hexane=1/10.about.1/4) and thus,
3-acetylamino-4-nitro-ethylbenzo- ate (19.6 g) is obtained.
.sup.1H-NMR (CDCl.sub.3, .delta.): 1.42 (3H, t, J=7.1 Hz), 2.32
(3H, s), 4.43 (2H, q, J=7.1 Hz), 7.82 (1H, dd, J=1.8 and 8.7 Hz),
8.25 (1H, d, J=8.7 Hz), 9.35 (1H, d, J=1.8 Hz), 10.19 (1H, s).
B.) 3-[N-(2-Chlorobenzyl)acetylamino]-4-nitro-ethylbenzoate
[0174] 60% sodium hydride (0.406 g) is added to an
N,N-dimethylformamide (12 ml) solution of
3-acetylamino-4-nitro-ethylbenzoate (1.706 g) in an ice bath, and
the solution is stirred for 40 minutes at room temperature. Then an
N,N-dimethylformamide (10 ml) solution of 2-chlorobenzyl bromide
(1.806 g) is added and the solution is stirred for three hours at
room temperature. The reaction mixture is poured into cold
1N-hydrochloric acid, then extraction is performed using ethyl
acetate twice. The organic layer is washed with 1N-hydrochloric
acid, and then with water. After the solution is dried, the solvent
is removed through evaporation under reduced pressure. The residue
is purified using silica gel column chromatography (eluate: ethyl
acetate/hexane=1/10.about.1/4), and oily
3-[N-(2-chlorobenzyl)acetylamino]-4-nitro-ethylbenzoate (2.08 g) is
obtained. .sup.1H-NMR (CDCl.sub.3, .delta.): 1.38 (3H, t, J=7.1
Hz), 1.92 (3H, s), 4.28-4.45 (2H, m), 4.72 (1H, d, J=14.5 Hz), 5.34
(1H, d, J=14.5 Hz), 7.16-7.44 (4H, m), 7.69(1H, d, J=1.7 Hz), 7.94
(1H, d, J=8.4 Hz), 8.13 (1H, dd, J=1.7 and 8.4 Hz).
C.) 1-(2-Chlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole
[0175] Ethanol (20 ml), acetic acid (11 ml), and reduced iron (3.07
g) are added into
3-[N-(2-chlorobenzyl)acetylamino]-4-nitro-ethylbenzoate (2.07 g),
and the solution is refluxed for four hours. Solid are separated
through filtration, and washed with ethanol. After the filtrate is
concentrated, a sodium bicarbonate aqueous solution is added to the
residue, and extraction is performed with ethyl acetate. After it
is dried, the solvent is removed through evaporation under reduced
pressure. The residue is purified using silica gel column
chromatography (eluate: hexane/ethyl acetate=100/0.about.70/30) and
thus, 1-(2-chlorobenzyl)-6-et- hoxycarbonyl-2-methylbenzimidazole
(1.46 g) is obtained. .sup.1H-NMR (CDCl.sub.3, .delta.): 1.39 (3H,
t, J=7.1 Hz), 2.57 (3H, s), 4.37 (2H, q, J=7.1 Hz), 5.46 (2H, s),
6.41 (1H, d, J=7.8 Hz), 7.10 (1H, t, J=7.8 Hz), 7.25 (1H, t), 7.47
(1H, d, J=8.0 Hz), 7.75 (1H, d, J=8.4 Hz), 7.94 (1H, s), 8.00 (1H,
dd, J=1.5 and 8.4 Hz).
[0176] (R.sub.1=2-Chlorobenzyl, R.sub.2=methyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 48
6-Ethoxycarbonyl-1-Methyl-2-n-Propylbenzimidazole
[0177] By using the method of example 47, part A, a preliminarily
purified material of 3-(N-methylbutyrylamino)-4-nitro-ethylbenzoate
(1.00 g) is obtained from 3-butyrylamino-4-nitro-ethylbenzoate
(1.00 g) and methyl iodide (0.843 g). Subsequently, by using the
method of example 47, parts B and C,
6-ethoxycarbonyl-1-methyl-2-n-propylbenzimidazole (0.56 g) is
obtained. .sup.1H-NMR (CDCl.sub.3, .delta.): 1.08 (3H, t, J=7.4
Hz), 1.43 (3H, t, J=7.0 Hz), 1.89-1.97 (2H, m), 2.89 (2H, t, J=7.7
Hz), 3.79 (3H, s), 4.38-4.44 (2H, m), 7.71(1H, d, J=8.4 Hz), 7.96
(1H, dd, J=8.4 and 1.5 Hz,), 8.05 (1H, d, J=1.4 Hz).
[0178] (R.sub.1=methyl, R.sub.2=n-propyl, R.sub.3=ethoxycarbonyl,
n=1, y=0)
Example 49
1-n-Butyl-6-Ethoxycarbonyl-2-n-Propylbenzimidazole
[0179] Under room temperature, an N,N-dimethylformamide (10 ml)
solution of 3-butyrylamino-4-nitro-ethylbenzoate (1.86 g) is
dripped into a slurry of 60% sodium hydride (0.428 g) and
N,N-dimethylformamide (10 ml), and the solution is stirred for 30
minutes at room temperature. Then, an N,N-dimethylformamide (10 ml)
solution of n-butyl iodide (1.97 g) is dripped into the solution
and the solution is heated for 13 hours at 50.degree. C. The
reaction solution is poured into a mixture solution of diluted
hydrochloric acid (70 g) and ethyl acetate (70 g) and extraction is
performed. The obtained organic layer is washed with water (twice),
dried, concentrated under reduced pressure, and a preliminarily
purified material (2.59 g) of
3-(N-n-butylbutyrylamino)-4-nitro-ethylbenzoate is obtained.
Subsequently, by using the method of example 47,
1-n-butyl-6-ethoxycarbonyl-2-n-propylbenzimidazole (0.81 g) is
obtained. .sup.1H-NMR (CDCl.sub.3, .delta.): 0.98 (3H, t, J=7.4
Hz), 1.08 (3H, t, J=7.4 Hz), 1.43 (3H, t, J=7.1 Hz), 1.75-1.83 (2H,
m), 1.91-1.98 (2H, m), 2.88 (2H, t, J=7.6 Hz), 4.15 (2H, t, J=7.5
Hz), 4.42 (2H, q, J=7.2 Hz), 7.73 (1H, d, J=8.4 Hz), 7.96 (1H, dd,
J=8.5 and 1.5 Hz), 8.06 (1H, d, J=1.4 Hz).
[0180] (R.sub.1=n-butyl, R.sub.2=n-propyl, R.sub.3=ethoxycarbonyl,
n=1, y=0)
Example 50
1-(3-Chlorobenzyl)-6-Ethoxycarbonyl-2-n-Propylbenzimidazole
[0181] By using the method of example 47, part A, a preliminarily
purified material of
3-[N-(3-chlorobenzyl)butyrylamino]-4-nitro-ethylbenzoate isobtained
from 3-butyrylamino-4-nitro-ethylbenzoate (1.86 g) and
3-chlorobenzyl bromide (1.64 g). Without purification, this
material is changed to
1-(3-chlorobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole (0.57
g) by using the method of example 47, parts B and C. .sup.1H-NMR
(CDCl.sub.3, .delta.): 1.02 (3H, t, J=7.4 Hz), 1.39 (3H, t, J=7.1
Hz), 1.85-1.92 (2H, m), 2.80 (2H, t, J=7.5 Hz), 4.38 (2H, q, J=7.1
Hz), 5.37 (2H, s), 6.86 (1H, d, J=7.4 Hz), 7.04 (1H, s), 7.21-7.29
(2H, m), 7.77 (1H, d, J=8.4 Hz), 7.96 (1H, d, J=1.2 Hz), 7.99 (1H,
dd, J=8.5 and 1.5 Hz).
[0182] (R.sub.1=3-chlorbenzyl, R.sub.2=n-propyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 51
1-Benzyl-6-Ethoxycarbonyl-2-n-Propylbenzimidazole
[0183] By using the method of example 47, part A,
3-[N-benzylbutyrylamino]- -4-nitro-ethylbenzoate is obtained from
3-butyrylamino-4-nitro-ethylbenzoa- te (1.86 g) and benzyl bromide
(1.36 g). Without purification, this material is changed to
1-benzyl-6-ethoxycarbonyl-2-n-propylbenzimidazole (0.97 g) by using
the method of example 47, parts B and C.
[0184] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.01 (3H, t, J=7.4 Hz),
1.39 (3H, t, J=7.1 Hz), 1.83-1.91 (2H, m), 2.81 (2H, t, J=7.5 Hz),
4.37 (2H, q, J=7.1 Hz), 5.40 (2H, s), 7.03 (1H, d, J=6.4 Hz),
7.28-7.33 (3H, m), 7.76 (1H, d, J=8.4 Hz), 7.98 (1H, dd, J=8.4 and
1.2 Hz), 8.00 (1H, s). (R.sub.1=benzyl, R.sub.2=n-propyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 52
1-(4-Chlorobenzyl)-6-Ethoxycarbonyl-2-n-Propylbenzimidazole
[0185] By using the method of example 47, part A,
3-[N-(4-chlorobenzyl)but- yrylamino]-4-nitro-ethylbenzoate is
obtained from 3-butyrylamino-4-nitro-e- thylbenzoate (1.86 g) and
4-chlorobenzyl bromide (1.64 g). Without purification, this
material is changed to 1-(4-chlorobenzyl)-6-ethoxycarb-
onyl-2-n-propylbenzimidazole (1.06 g) by using the method of
example 47, parts B and C.
[0186] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.02 (3H, t, J=7.4 Hz),
1.39 (3H, t, J=7.1 Hz), 1.83-1.92 (2H, m), 2.80 (2H, t, J=7.8 Hz),
4.38 (2H, q, J=7.5 Hz), 5.36 (2H, s), 6.96 (2H, d, J=8.2 Hz), 7.29
(2H, d, J=8.3 Hz), 7.76 (1H, d, J=8.4 Hz), 7.96 (1H, d, J=1.2 Hz),
7.99 (1H, dd, J=8.3 and 1.2 Hz). (R.sub.1=4-chlorobenzyl,
R.sub.2=n-propyl, R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 53
6-Ethoxycarbonyl-2-Methyl-1-[2-(Trifluoromethyl)benzyl]Benzimidazole
[0187] By using the method of example 47, parts B and C,
6-ethoxycarbonyl-2-methyl-1-[2-(trifluoromethyl)benzyl]benzimidazole
(1.32 g) is obtained from
4-nitro-3-[N-[2-(trifluoromethyl)benzyl]acetyla- mino]ethylbenzoate
(1.82 g). .sup.1H-NMR (CDCl.sub.3, .delta.): 1.38 (3H, t, J=7.1
Hz), 2.53 (3H, s), 4.37 (2H, q, J=7.1 Hz), 5.58 (2H, s), 6.47 (1H,
d, J=7.1 Hz), 7.36 (1H, t, J=7.5 Hz), 7.41 (1H, t, J=7.5 Hz),
7.75-7.97 (2H, m), 7.94 (1H, d, J=1.0 Hz), 8.02 (1H, dd, J=1.6 and
8.6 Hz).
[0188] (R.sub.1=2-(trifluoromethyl)benzyl, R.sub.2=methyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 54
6-Ethoxycarbonyl-2-methyl-1-[4-(trifluoromethyl)benzyl]benzimidazole
[0189] By using the method of example 47, parts B and C,
6-ethoxycarbonyl-2-methyl-1-[4-(trifluoromethyl)benzyl]benzimidazole
(1.22 g) is obtained from
4-nitro-3-[N-[4-(trifluoromethyl)benzyl]acetyla- mino]ethylbenzoate
(1.52 g). .sup.1H-NMR (CDCl.sub.3, .delta.): 1.39 (3H, t, J=7.1
Hz), 2.58 (3H, s), 4.38 (2H, q, J=7.1 Hz), 5.44 (2H, s), 7.15 (2H,
d, J=8.2 Hz), 7.59 (2H, d, J=8.2 Hz), 7.75 (1H, d, J=8.3 Hz), 7.97
(1H, s), 8.00 (1H, dd, J=1.5 and 8.5 Hz).
[0190] (R.sub.1=4-(trifluoromethyl)benzyl, R.sub.2=methyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 55
1-(3,4-Dichlorobenzyl)-6-Ethoxycarbonyl-2-Methylbenzimidazole
[0191] By using the method of example 47, part A,
3-[N-(3,4-dichlorobenzyl- )acetylamino]-4-nitro-ethylbenzoate is
obtained from 3-acetylamino-4-nitro-ethylbenzoate (1.50 g) and
3,4-dichlorobenzyl bromide (1.74 g). Without purification, this
material is changed to
1-(3,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (0.76
g) by using the method of example 47, parts B and C. .sup.1H-NMR
(CDCl.sub.3, .delta.): 1.40 (3H, t, J=7.1 Hz), 2.58 (3H, s), 4.39
(2H, q, J=7.2 Hz), 5.33 (2H, s), 6.84 (1H, dd, J=8.4 and 2.3 Hz),
7.16 (2H, d, J=2.0 Hz), 7.39 (1H, d, J=8.3 Hz), 7.74 (1H, d, J=8.4
Hz), 7.96 (1H, d, J=1.2 Hz), 8.00 (1H, dd, J=8.4 and 1.5 Hz).
[0192] (R.sub.1=3,4-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 56
1-(Biphenyl-4-ylmethyl)-6-Ethoxycarbonyl-2-Methylbenzimidazole
[0193] By using the method of example 47, part A, a preliminarily
purified material (1.44 g) of
3-[N-(biphenyl-4-ylmethyl)acetylamino]-4-nitro-ethyl- benzoate is
obtained from 3-acetylamino-4-nitro-ethylbenzoate (1.51 g) and
4-chloromethylbiphenyl (1.46 g). Then by using the method of
example 47, parts B and C,
1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-methylbenzimida- zole
(1.13 g) is obtained. .sup.1H-NMR (CDCl.sub.3, .delta.): 1.39 (3H,
t, J=7.1 Hz), 2.62 (3H, s), 4.38 (2H, q, J=7.1 Hz), 5.42 (2H, s),
7.11 (2H, d, J=8.2 Hz), 7.34 (1H, m), 7.42 (2H, m), 7.54 (4H, m),
7.74 (1H, d, J=8.4 Hz), 7.99 (1H, dd J=1.5 and 8.4 Hz), 8.06 (1H,
d, J=1.5 Hz).
[0194] (R.sub.1=biphenyl-4-ylmethyl, R.sub.2=methyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 57
6-Ethoxycarbonyl-2-Methyl-1-(2-Methylbenzyl)Benzimidazole
[0195] By using the method of example 47, part A,
3-[N-(2-methylbenzyl)ace- tylamino]-4-nitro-ethylbenzoate is
obtained from 3-acetylamino-4-nitro-eth- ylbenzoate (1.50 g) and
2-methylbenzyl bromide (1.65 g). Without purification, this
material is changed to 6-ethoxycarbonyl-2-methyl-1-(2--
methylbenzyl)benzimidazole (0.81 g) by using the method of example
47, parts B and C. .sup.1H-NMR (CDCl.sub.3, .delta.): 1.38 (3H, t,
J=7.2 Hz), 2.43 (3H, s), 2.54 (3H, s), 4.36 (2H, q, J=7.2 Hz), 5.33
(2H, s), 6.35 (1H, d, J=7.7 Hz), 7.03 (1H, t, J=8.2 Hz), 7.18-7.25
(2H, m), 7.75 (1H, d, J=8.5 Hz), 7.91 (1H, d, J=1.2 Hz), 7.98 (1H,
dd, J=8.5 and 1.5 Hz).
[0196] (R.sub.1=2-methylbenzyl, R.sub.2=methyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 58
6-Ethoxycarbonyl-1-(2-Methoxybenzyl)-2-Methylbenzimidazole
[0197] By using the method of example 47, part A, a preliminarily
purified material of
3-[N-(2-methoxybenzyl)acetylamino]-4-nitro-ethylbenzoate is
obtained from 3-acetylamino-4-nitro-ethylbenzoate (1.16 g) and
2-methoxybenzyl chloride (1.44 g). Then by using the method of
example 47, parts B and C,
6-ethoxycarbonyl-1-(2-methoxybenzyl)-2-methylbenzimida- zole (1.18
g) is obtained. .sup.1H-NMR (CDCl.sub.3, .delta.): 1.39 (3H, t,
J=7.2 Hz), 2.60 (3H, s), 3.90 (3H, s), 4.37 (2H, q, 7.2 Hz), 5.36
(2H, s), 6.61 (1H, d, J=7.4 Hz), 6.82 (1H, t, J=7.5 Hz), 6.92 (1H,
d, J=8.3 Hz), 7.27 (1H, m), 7.71 (1H, d, J=8.4 Hz), 7.96 (1H, dd,
J=1.5 and 8.4 Hz), 8.03 (1H, d, J=1.3 Hz).
[0198] (R.sub.1=2-methoxybenzyl, R.sub.2=methyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 59
6-Ethoxycarbonyl-1-(4-Methoxybenzyl)-2-Methylbenzimidazole
[0199] By using the method of example 47, part A, a preliminarily
purified material of
3-[N-(4-methoxybenzyl)acetylamino]-4-nitro-ethylbenzoate is
obtained from 3-acetylamino-4-nitro-ethylbenzoate (1.60 g) and
4-methoxybenzyl chloride (1.49 g). Then by using the method of
example 47, parts B and C,
6-ethoxycarbonyl-1-(4-methoxybenzyl)-2-methylbenzimida- zole (1.27
g) is obtained. .sup.1H-NMR (CDCl.sub.3, .delta.): 1.40 (3H, t,
J=7.1 H), 2.59 (3H, s), 3.77 (3H, s), 4.38 (2H, q, J=7.1 Hz), 5.31
(2H, s), 6.84 (2H, m), 7.00 (2H, m), 7.71 (1H, d, J=8.4 Hz), 7.97
(1H, dd, J=1.4 and 8.4 Hz), 8.03 (1H, d, J=1.3 Hz).
[0200] (R.sub.1=4-methoxybenzyl, R.sub.2=methyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 60
1-[2-(Benzenesulfonylmethyl)benzyl]-6-Ethoxycarbonyl-2-Methylbenzimidazole
[0201] By using the method of example 47, part A,
3-[N-[2-(benzenesulfonyl-
methyl)benzyl]acetylamino]-4-nitro-ethylbenzoate is obtained from
3-acetylamino-4-nitro-ethylbenzoate (1.00 g) and
2-(benzenesulfonylmethyl- )benzyl bromide (1.93 g). Without
purification, this material is changed to
1-[2-(benzenesulfonylmethyl)benzyl]-6-ethoxycarbonyl-2-methylbenzimida-
zole (0.89 g) by using the method of example 47, parts B and C.
.sup.1H-NMR (CDCl.sub.3, .delta.): 1.37 (3H, t, J=7.1 Hz), 2.57
(3H, s), 4.36 (2H, q, J=7.1 Hz), 4.50 (2H, s), 5.60 (2H, s), 6.38
(1H, d, J=6.7 Hz), 6.88 (1H, dd, J=1.5 and 7.3 Hz), 7.10-7.18 (2H,
m), 7.57 (2H, t, J=7.6 Hz), 7.69-7.78 (2H, m), 7.79 (1H, dd, J=0.8
and 8.1 Hz), 7.92 (1H, d, J=1.2 Hz), 7.99 (1H, dd, J=1.5 and 8.4
Hz).
[0202] (R.sub.1=2-(benzenesulfonylmethyl)benzyl, R.sub.2=methyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 61
1-(2-Cyanobenzyl)-6-(2-Cyanobenzyloxycarbonyl)-2-Methylbenzimidazole
[0203] By using the method of example 47, parts B and C,
1-(2-cyanobenzyl)-6-(2-cyanobenzyloxycarbonyl)-2-methylbenzimidazole
(1.75 g) is obtained from
3-[N-(2-cyanobenzyl)acetylamino]-4-nitro-benzoi- c acid
2-cyanobenzyl ester (3.33 g). .sup.1H-NMR (CDCl.sub.3, .delta.):
2.60 (3H, s), 5.55 (2H, s), 5.60 (2H, s), 6.68 (1H, d, J=7.3 Hz),
7.41-7.48 (3H, m), 7.61 (2H, m), 7.72 (1H, d, J=7.6 Hz), 7.76(1H,
d, J=7.6 Hz), 7.77 (1H, d, J=8.6 Hz), 8.02 (1H, s), 8.05 (1H, dd,
J=8.4 and 1.5 Hz).
[0204] (R.sub.1=2-cyanobenzyl, R.sub.2=methyl,
R.sub.3=2-cyanobenzyloxycar- bonyl, n=1, y=0)
Example 62
1-(Biphenyl-2-ylmethyl)-6-Ethoxycarbonyl-2-Methylbenzimidazole
[0205] By using the method of example 47, part A,
3-[N-(biphenyl-2-ylmethy- l)acetylamino]-4-nitro-ethylbenzoate is
obtained from 3-acetylamino-4nitro-ethylbenzoate (1.00 g) and
2-bromomethylbiphenyl (1.47 g). Without purification, this material
is changed to
1-(biphenyl-2-ylmethyl)-6-ethoxycarbonyl-2-methylbenzimidazole
(1.31 g) by using the method of example 47, parts B and C.
.sup.1H-NMR (CDCl.sub.3, .delta.): 1.41 (3H, t, J=7.3 Hz), 2.39
(3H, s), 4.38 (2H, q, J=7.3 Hz), 5.27 (2H, s), 6.68 (1H, d, J=7.9
Hz), 7.21 (1H, dt, J=9.0 and 2.1 Hz), 7.32-7.39 (4H, m), 7.43 (1H,
dd, J=7.3 and 1.9 Hz), 7.46-7.51 (2H, m), 7.68 (1H, d, J=8.4 Hz),
7.87 (1H, d, J=1.3 Hz), 7.95 (1H, dd, J=8.4 and 1.6 Hz).
[0206] (R.sub.1=biphenyl-2-ylmethyl, R.sub.2=methyl,
R.sub.3=ethyoxycarbonyl, n=1, y=0)
Example 63
1-Benzyl-6-Ethoxycarbonyl-2-Methylbenzimidazole
[0207] By using the method of example 47, part A,
3-(N-benzylacetylamino)-- 4-nitro-ethylbenzoate is obtained from
3-acetylamino-4-nitro-ethylbenzoate (1.00 g) and benzyl bromide
(1.02 g). Without purification, this material is changed to
1-benzyl-6-ethoxycarbonyl-2-methylbenzimidazole (108) (0.71 g) by
using the method of example 47, parts B and C. .sup.1H-NMR
(CDCl.sub.3, .delta.): 1.39 (3H, t, J=7.1 Hz), 2.58 (3H, s), 4.38
(2H, q, J=7.1 Hz), 5.38 (2H, s), 7.05 (2H, dd, J=8.3 and 1.8 Hz),
7.28-7.33 (3H, m), 7.72 (1H, d, J=8.4 Hz), 7.98 (1H, dd, J=8.4 and
1.5 Hz), 8.02 (1H, d, J=1.2 Hz).
[0208] (R.sub.1=benzyl, R.sub.2=methyl, R.sub.3=ethyoxycarbonyl,
n=1, y=0)
Example 64
1-(4-t-Butylbenzyl)-6-Ethoxycarbonyl-2-Methylbenzimidazole
[0209] By using the method of example 47, part A,
3-[N-(4-t-butylbenzyl)ac- etylamino]-4-nitro-ethylbenzoate is
obtained from 3-acetylamino-4-nitro-et- hylbenzoate (1.00 g) and
4-t-butylbenzyl bromide (1.35 g). Without purification of this
material, a preliminarily purified material (1.60 g) of
1-(4-t-butylbenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole is
obtained by using the method of example 47, parts B and C.
[0210] (R.sub.1=4-t-butylbenzyl, R.sub.2=methyl,
R.sub.3=ethyoxycarbonyl, n=1, y=0)
Example 65
6-Ethoxycarbonyl-2-Methyl-1-(2-Naphthylmethyl)Benzimidazole
[0211] By using the method of example 47, part A,
3-[N-(2-naphthylmethyl)a- cetylamino]-4-nitro-ethylbenzoate is
obtained from 3-acetylamino-4-nitro-e- thylbenzoate (1.00 g) and
2-naphthylmethyl bromide (1.32 g). Without purification of this
material, a preliminarily purified material (1.28 g) of
6-ethoxycarbonyl-2-methyl-1-(2-naphthylmethyl)benzimidazole is
obtained by using the method of example 47, parts B and C.
[0212] (R.sub.1=2-naphthylmethyl, R.sub.2=methyl,
R.sub.3=ethyoxycarbonyl, n=1, y=0)
Example 66
1-(Biphenyl-4-ylmethyl)-6-Ethoxycarbonyl-2-Ethylbenzimidazole
[0213] By using the method of example 47, part A,
3-[N-(biphenyl-4-ylmethy- l)propionylamino]-4-nitro-ethylbenzoate
is obtained from 4-nitro-3-propionylamino-ethylbenzoate (2.00 g)
and 4-chloromethylbiphenyl (2.28 g). Without purification, this
material is changed to
1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-ethylbenzimidazole (2.07
g) by using the method of example 47, parts B and C. .sup.1H-MNR
(CDCl.sub.3, .delta.): 1.39 (3H, t, J=7.2 Hz), 1.45 (3H, t, J=7.5
Hz), 2.90 (2H, q, J=7.5 Hz), 4.38 (2H, q, J=7.2 Hz), 5.43 (2H, s),
7.10 (2H, d, J=8.3 Hz), 7.33-7.36 (1H, m), 7.43 (2H, t, J=7.4 Hz),
7.51-7.56 (4H, m), 7.79 (1H, d, J=8.5 Hz), 7.80 (1H, dd, J=1.5 and
8.4 Hz), 8.05 (1H, d, J=1.3 Hz). (R.sub.1=biphenyl-4-ylmethyl,
R.sub.2=ethyl, R.sub.3=ethyoxycarbonyl, n=1, y=0)
Example 67
1-(2-Chlorobenzyl)-5-ethoxycarbonyl-2-methylbenzimidazole
[0214] By using the method of example 47, part A,
4-[N-(2-chlorobenzyl)ace- tylamino]-3-nitro-ethylbenzoate is
obtained from 4-acetylamino-3-nitro-eth- ylbenzoate (3.15 g) and
2-chlorobenzyl bromide (3.85 g). Without purification, this
material is changed to 1-(2-chlorobenzyl)-5-ethoxycarb-
onyl-2-methyl-benzimidazole (2.54 g) by using the method of example
47, parts B and C. .sup.1H-NMR (CDCl.sub.3, .delta.): 1.41 (3H, t,
J=7.1 Hz), 2.59 (3H, s), 4.40 (2H, q, J=7.1 Hz), 5.43 (1H, s), 6.43
(1H, d, J=7.8 Hz), 7.10 (1H, t, J=7.5 Hz), 7.19 (1H, d, J=8.5 Hz),
7.25 (1H, m), 7.46 (1H, d, J=8.1 Hz), 7.95 (1H, dd, J=1.4 and 8.4
Hz), 8.47 (1H,s). (R.sub.1=2-chloro-benzyl, R.sub.2=methyl,
R.sub.3=ethyoxycarbonyl, n=1, y=0)
Example 68
1-(2,6-Dichlorobenzyl)-6-Ethoxycarbonyl-2-Methylbenzimidazole
[0215] By using the method of example 47, part A,
3-[N-(2,6-dichlorobenzyl- )acetylamino]-4-nitro-ethylbenzoate is
obtained from 3-acetylamino-4-nitro-ethylbenzoate (1.50 g) and
2,6-dichlorobenzyl bromide (2.14 g). Without purification, this
material is changed to
1-(2,6-dichlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (0.91
g) by using the method of example 47, parts B and C. .sup.1H-NMR
(CDCl.sub.3, .delta.): 1.38 (3H, t, J=7.1 Hz), 2.64 (3H, s), 4.34
(2H, q, J=7.1 Hz), 5.61 (2H, s), 7.30 (1H, dd, J=7.6, and 8.5 Hz),
7.40 (2H, d, J=8.0 Hz), 7.66 (1H, d, J=8.4 Hz), 7.87 (1H, d, J=1.1
Hz), 7.91 (1H, dd, J=8.4 and 1.5 Hz). (R.sub.1=2,6-dichlorobenzyl,
R.sub.2=methyl, R.sub.3=ethyoxycarbonyl, n=1, y=0)
Example 69
6-Ethoxycarbonyl-2-n-Propyl-1-i-Propylbenzimidazole
A.) 4-Amino-3-(N-i-propylbutyrylamino)-ethylbenzoate
[0216] At room temperature, an N,N-dimethylformamide (10 ml)
solution of3-butyrylamino-4-nitro-ethylbenzoate (2.00 g) is dripped
into a slurry of 60% sodium hydride (0.428 g) and
N,N-dimethylformamide (10 ml) , and the mixture is stirred for 30
minutes. Then, an N,N-dimethylformamide (10 ml) solution of
isopropyl iodide (1.46 g) is dripped into the solution, and the
solution is stirred for 5 days at 100.degree. C. The reaction
solution is poured into a mixture solution of diluted hydrochloric
acid (80 g) and ethyl acetate (80 g), then separated into layers.
The obtained organic layer is washed with water (50 g), and
concentrated under reduced pressure. The residue is purified using
silica gel column chromatography (eluate: hexane/ethyl acetate=4/1)
and a preliminarily purified material (0.260 g) of
4-nitro-3-(N-i-propylbutyrylamino)-ethylbenzoate is obtained.
Subsequently, under room temperature, ethanol (3 ml) and acetic
acid (2 ml) are added to the
3-(N-i-propylbutyrylamino)-4-nitro-ethylbenz- oate (0.260 g).
Further, reduced iron (0.519 g) is added to the solution, and the
solution is refluxed by heating for four hours. Using filter aid,
solids are removed, and the filtrate is concentrated. Ethyl acetate
(30 ml) and diluted hydrochloric acid (30 ml) are added to the
residue, and the solution is separated into layers. Its organic
layer is washed with water and concentrated under reduced pressure.
The residue is purified using fractional thin film silica gel
column chromatography (developing solvent: hexane/ethyl
acetate=1/1), and 4-amino-3-(N-i-propyl-butyrylamin-
o)ethylbenzoate (0.06 g) is obtained. .sup.1H-NMR (CDCl.sub.3,
.delta.): 0.82 (3H, t, J=7.4 Hz), 1.01 (3H, d, J=6.9 Hz), 1.24 (3H,
d, J=6.6 Hz), 1.38 (3H, t, J=7.0 Hz), 1.54-1.62 (2H, m), 1.87-2.04
(2H, m), 4.34 (2H, q, J=7.0 Hz), 4.45 (2H, s), 4.88-4.96 (1H, m),
6.78 (1H, d, J=8.4 Hz), 7.64 (1H, d, J=1.9 Hz), 7.87 (1H, dd, J=8.4
and 1.9 Hz).
B.) 6-Ethoxycarbonyl-2-n-propyl-1-i-propylbenzimidazole
[0217] Acetic acid (2 ml) is added to
4-amino-3-(N-i-propylbutyrylamino)-e- thylbehzoate (0.06 g), and
the solution is stirred for 14 hours at 90.degree. C. The reaction
solution is concentrated under reduced pressure, and
6-ethoxycarbonyl-2-n-propyl-1-i-propylbenzimidazole (0.05 g) is
obtained. .sup.1H-NMR (CDCl.sub.3, .delta.): 1.07 (3H, t, J=7.4
Hz), 1.43 (3H, t, J=7.0 Hz), 1.69 (6H, d, J=6.9 Hz), 1.85-1.92 (2H,
m), 2.91 (2H, t, J=7.7 Hz), 4.41 (2H, q, J=7.3 Hz), 4.67-4.76 (1H,
m), 7.72 (1H, d, J=8.3 Hz), 7.94 (1H, dd, J=8.7 and 1.5 Hz), 8.25
(1H, d, J=1.2 Hz).
[0218] (R.sub.1=isopropyl, R.sub.2=n-propyl,
R.sub.3=ethyoxycarbonyl, n=1, y=0)
Example 70
1-(2,4-Dichlorobenzyl)-6-Ethoxycarbonyl-2-Methylbenzimidazole>
[0219] Under room temperature, an N,N-dimethylformamide (8 ml)
solution of 3-acetylamido-4-nitro-ethylbenzoate (1.50 g) is dripped
into the slurry of 60% sodium hydride (0.357 g) and
N,N-dimethylformamide (8 ml), and the solution is stirred for 30
minutes. Next, an N,N-dimethylformamide (8 ml) solution of
2,4-dichlorobenzyl chloride (1.74 g) is dripped into the solution,
and the solution is stirred for 30 minutes. The reaction solution
is poured into the mixture solution of diluted hydrochloric acid
(50 g) and ethyl acetate (60 g), and its layers are separated.
Obtained organic layer is washed with water (50 g) twice. The
organic layer is concentrated under reduced pressure, and
preliminarily purified material of
3-[N-(2,4-dichlorobenzyl)acetylamino]-4-nitro-ethylbenzoate (3.5 g)
is obtained. Without purification, this material is dissolved with
ethanol (23 ml) and acetic acid (12 ml) , then reduced iron (3.32
g) is added to the solution, and the solution is refluxed by
heating for 6 hours. Using filter aid, the solids are removed, and
the filtrate is concentrated under reduced pressure. Ethyl acetate
(60 ml) and diluted hydrochloric acid (50 ml) are added to the
obtained residue, and its layers are separated. The organic layer
is washed with saturated sodium bicarbonate aqueous solution (50
g), then washed with water (50 g) twice, and concentrated under
reduced pressure. The obtained residue is purified using silica gel
column chromatography (eluate: hexane/ethyl acetate 4/1.about.1/1)
and, 1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methylbenzi-
midazole (0.94 g) is obtained. .sup.1H-NMR(CDCl.sub.3, .delta.):
1.40 (3H, t, J=7.1 Hz), 2.56 (3H, s), 4.38 (2H, q, J=7.1 Hz), 5.41
(2H, s), 6.34 (1H, d, J=8.4 Hz), 7.09 (1H, dd, J=8.4 and 2.0 Hz),
7.49 (1H, d, J=2.0 Hz), 7.75 (1H, d, J=8.4 Hz), 7.92 (1H, s), 8.00
(1H, dd, J=8.5 and 1.4 Hz)
[0220] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=ethyoxycarbonyl, n=1, y=0)
Example 71
6-Carboxy-1-(4-Chlorobenzyl)-2-n-Propylbenzimidazole
[0221] 10% sodium hydroxide aqueous solution (3.57 g), ethanol (5
mnl) and water (3.57 g) are added to
1-(4-chlorobenzyl)-6-ethoxycarbonyl-2-n-propy- lbenzimidazole (1.06
g) (example 51), and the solution is refluxed by heating for 1
hour. The acidity of the reaction solution is adjusted to pH 6 with
10% hydrochloric acid. The solution is concentrated under reduced
pressure, ethanol is added to its obtained residue, and the
inorganic acid (MU KI ENN) is separated through filtration. The
filtrate is concentrated under reduced pressure, and residue (0.80
g) is obtained. The residue is purified with silica gel column
chromatography (eluate: ethyl acetate/methanol=4/1), and
6-carboxy-1-(4-chlorobenzyl)-2-n-propylb- enzimidazole (0.63 g) is
obtained. .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.96 (3H, t, J=7.3
Hz), 1.76-1.88 (2H, m), 3.10-3.23 (2H, m), 5.83 (2H, s), 7.27 (2H,
d, J=8.4 Hz), 7.44 (2H, d, J=8.4 Hz), 7.89 (1H, d, J=8.4 Hz), 7.89
(1H, d, J=8.5 Hz), 8.28 (1H, s)
[0222] (R.sub.1=4-chlorobenzyl, R.sub.2=n-propyl, R.sub.3=carboxyl,
n=1, y=0)
Example 72
6-Carboxy-1-Methyl-2-n-Propylbenzimidazole
[0223] By using the method of example 71,
6-carboxy-1-methyl-2-n-propylben- zimidazole (0.46 g) is obtained
from 6-ethoxycarbonyl-1-methyl-2-n-propylc- arbonylbenzimidazole
(0.56 g). .sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.00 (3H, t, J=7.3
Hz), 1.79-1.93 (2H, m), 3.06 (3H, t, J=7.4 Hz), 3.92 (3H, s), 7.76
(1H, d, J=8.4 Hz), 7.97 (1H, d, J=8.4 Hz), 8.31 (1H, s).
[0224] (R.sub.1=methyl, R.sub.2=n-propyl, R.sub.3=carboxyl, n=1,
y=0)
Example 73
6-Carboxy-2-n-Propyl-1-i-Propylbenzimidazole
[0225] By using the method of example 71,
6-carboxy-2-n-propyl-1-i-propylb- enzimidazole (0.045 g) is
obtained from 6-ethoxycarbonyl-2-n-propyl-1-i-pr- opylbenzimidazole
(0.045 g). .sup.1H-NMR (CD.sub.3OD, .delta.): 0.98 (3H, t, J=7.4
Hz), 1.61 (6H, d, J=6.9 Hz), 1.74-1.82 (2H, m), 2.89 (2H, t, J=7.5
Hz), 3.21-3.24 (2H, m), 4.78-4.83 (1H, m), 7.51 (1H, d, J=8.3 Hz),
7.84 (1H, dd, J=8.4 and 1.5 Hz), 8.26 (1, s).
[0226] (R.sub.1=i-propyl, R.sub.2=n-propyl, R.sub.3=carboxyl, n=1,
y=0)
Example 74
1-n-Butyl-6-Carboxy-2-n-Propylbenzimidazole
[0227] By using the method of example 71,
1-n-butyl-6-carboxy-2-n-propylbe- nzimidazole (0.60 g) is obtained
from 1-n-butyl-6-ethoxycarbonyl-2-n-propy- lbenzimidazole (0.81 g).
.sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.02 (3H, t, J=7.3 Hz), 1.17
(3H, t, J=7.3 Hz), 1.33-1.41 (2H, m), 1.70-1.77 (2H, m), 1.85-1.93
(2H, m), 3.07 (2H, t, J=7.6 Hz), 4.42 (2H, t, J=7.4 Hz), 7.78 (1H,
d, J=8.5 Hz), 7.99 (1H, dd, J=8.5 and 1.0 Hz), 8.35 (1H, s), 13.13
(1H, s).
[0228] (R.sub.1=n-butyl, R.sub.2=n-propyl, R.sub.3=carboxyl, n=1,
y=0)
Example 75
6-Carboxy-1-(2-Chlorobenzyl)-2-Methylbenzimidazole
[0229] Ethanol (80 ml) and 10% sodium hydroxide aqueous solution
(37 g) are added to
1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (10.0 g)
(example 47), and the solution is refluxed for 4 hours. After the
reaction solution is cooled, its acidity is adjusted to pH 6 with
10% hydrochloric acid. The sediment is gathered, washed with water,
dried under reduced pressure, and thus, (8.30 g) is obtained.
[0230] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl, R.sub.3=carboxyl,
n=1, y=0)
Example 76
6-Carboxy-1-(2,6-Dichlorobenzyl)-2-Methylbenzimidazole
[0231] By using the method of example 75,
6-carboxy-1-(2,6-dichlorobenzyl)- -2-methylbenzimidazole (0.72 g)
is obtained from 1-(2,6-dichlorobenzyl)-6--
ethoxycarbonyl-2-methylbenzimidazole (0.90 g) (example 67).
.sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.60 (3H, s), 5.71 (2H, s),
7.46 (1H, t, J=7.9 Hz), 7.57 (3H, t, J=8.2 Hz), 7.73 (2H, m), 12.57
(1H, s).
[0232] (R.sub.1=2,6-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=carboxyl, n=1, y=0)
Example 77
6-Carboxy-2-Methyl-1-[2-(Trifluoromethyl)Benzyl]Benzimidazole
[0233] By using the method of example 75,
6-carboxy-2-methyl-1-[2-(trifluo- romethyl)benzyl]benzimidazole
(0.98 g) is obtained from
6-ethoxycarbonyl-2-methyl-1-[2-(trifluoromethyl)benzyl]benzimidazole
(1.17 g) (example 53). .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.49
(3H, s), 5.70 (2H, s), 6.46-6.51 (1H, m), 7.51 (2H, m), 7.65 (1H,
d, J=8.4 Hz), 7.81 (1H, dd, J=1.4 and 8.4 Hz), 7.82-7.87 (1H, m),
7.91 (1H, s).
[0234] (R.sub.1=2-(trifluoromethyl)benzyl, R.sub.2=methyl,
R.sub.3=carboxyl, n=1, y=0)
Example 78
6-Carboxy-2-Methyl-1-[4-(Trifluoromethyl)Benzyl]Benzimidazole
[0235] By using the method of example 75,
6-carboxy-2-methyl-1-[4-(trifluo- romethyl)benzyl]benzimidazole
(1.07 g) is obtained from
6-ethoxycarbonyl-2-methyl-1-[4-(trifluoromethyl)benzyl]benzimidazole
(1.22 g) (example 54).
[0236] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.85 (3H, s), 5.92 (2H,
s), 7.50 (2H, d, J=8.1 Hz), 7.74 (2H, d, J=8.1 Hz), 7.88 (1H, d,
J=8.5 Hz), 8.07 (1H, d, J=8.5Hz), 8.31 (1H, s), 13.3 (1H, br
s).
[0237] (R.sub.1=4-(trifluoromethyl)benzyl, R.sub.2=methyl,
R.sub.3=carboxyl, n=1, y=0)
Example 79
6-Carboxy-1-(3,4-Dichlorobenzyl)-2-Methylbenzimidazole
[0238] By using the method of example 75,
6-carboxy-1-(3,4-dichlorobenzyl)- -2-methylbenzimidazole (0.55 g)
is obtained from 1-(3,4-dichlorobenzyl)-6--
ethoxycarbonyl-2-methylbenzimidazole (0.76 g) (example 55.
.sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.56 (3H, s), 5.61 (2H, s),
6.98 (1H, dd, J=8.4 and 1.9 Hz), 7.46 (1H, d, J=1.9 Hz), 7.59 (1H,
d, J=8.3 Hz), 7.63 (1H, d, J=8.4 Hz), 7.81 (1H, dd, J=8.4 and 1.4
Hz), 8.07 (1H, s), 12.76 (1H, s).
[0239] (R.sub.1=3,4-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=carboxyl, n=1, y=0)
Example 80
1-Benzyl-6-Carboxy-2-n-Propylbenzimidazole
[0240] 10% sodium hydroxide aqueous solution (3.61 g), ethanol (5
ml), and water (3 ml) are added to
1-benzyl-6-ethoxycarbonyl-2-n-propylbenzimidazo- le (0.97 g)
(example 51), and the solution is refluxed by heating for one hour.
The acidity of the reaction solution is adjusted to pH 6 with 10%
hydrochloric acid. The solution is concentrated under reduced
pressure, ethanol is added to the obtained residue, and the
inorganic salt is separated through filtration. The filtrate is
concentrated under reduced pressure, and
1-benzyl-6-carboxy-2-n-propylbenzimidazole (0.85 g) (example 80) is
obtained. .sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.94 (3H, t, J=7.4
Hz), 1.73-1.81 (2H, m), 2.85 (2H, t, J=7.3 Hz), 5.59 (2H, s), 7.07
(2H, dd, J=1.1 and 8.3 Hz), 7.27 (1H, t, J=7.3 Hz), 7.33 (2H, t,
J=7.4 Hz), 7.65 (1H, d, J=8.4 Hz), 7.79 (1H, dd, J=1.5 and 8.4 Hz),
8.04 (1H, s).
[0241] (R.sub.1=benzyl, R.sub.2=n-propyl, R.sub.3=carboxyl, n=1,
y=0)
Example 81
6-Carboxy-1-(3-Chlorobenzyl)-2-n-Propylbenzimidazole
[0242] By using the method of example 80,
6-carboxy-1-(3-chlorobenzyl)-2-n- -propylbenzimidazole (0.35 g) is
obtained from 1-(3-chlorobenzyl)-6-ethoxy-
carbonyl-2-n-propylbenzimidazole (0.57 g) (example 50). .sup.1H-NMR
(DMSO-d.sub.6, .delta.): 0.94 (3H, t, J=7.3 Hz), 1.70-1.79 (2H, m),
2.83 (2H, t, J=7.4 Hz), 5.59 (2H, s), 6.94 (1H, s), 7.15 (1H, s),
7.34 (2H, d, J=4.4 Hz), 7.59 (1H, d, J=8.4 Hz), 7.81 (1H, d, J=8.1
Hz), 8.02 (1H, s).
[0243] (R.sub.1=3-chlorobenzyl, R.sub.2=n-propyl, R.sub.3=carboxyl,
n=1, y=0)
Example 82
5-Ethoxycarbonyl-2-methylbenzimidazole
[0244] Reduced iron (6.64 g), ethanol (48 ml) and acetic acid (24
ml) are added to 3-acetylamino-4-nitro-ethylbenzoate (3.00 g), and
the solution is refluxed by heating for 12 hours. Solid materials
are removed using filter aid, and the filtrate is concentrated
under reduced pressure. Ethanol (100 ml) and 35% hydrochloric acid
(5.2 g) are added to the residue and the solution is refluxed by
heating for five hours. The reaction solution is neutralized with
sodium bicarbonate (6.3 g). The filtrate obtained through
filtration is concentrated under reduced pressure. Ethyl acetate
(70 ml) and water (70 ml) are added to the obtained residue, and
the solution is separated. The organic layer is washed with water
three times and extraction is performed on the aqueous layer using
ethyl acetate three times. By concentrating the obtained organic
layer under reduced pressure, 5-ethoxycarbonyl-2-methylbenzimidaz-
ole (1.53 g ) powder is obtained. .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.41 (3H, t, J=6.9 Hz), 2.67 (3H, s), 4.40 (2H, q, J=7.1
Hz), 7.55 (1H, d, J=8.4 Hz), 7.96 (1H, dd, J=8.4 and 1.5 Hz), 8.27
(1H, d, J=1.4 Hz).
[0245] (R.sub.2=methyl, R.sub.3=ethoxycarbonyl, n=1, y=0)
Examples 83 and 84
6-Ethoxycarbonyl-2-Methyl-1-(2-Nitrobenzyl)Benzimidazole and
5-Ethoxycarbonyl-2-Methyl-1-(2-Nitrobenzyl)Benzimidazole
[0246] N,N-dimethylformamide (15 ml), 2-nitrobenzyl bromide (1.59
g) and sodium bicarbonate (1.23 g) are added to
5-ethoxycarbonyl-2-methylbenzimi- dazole (1.00 g) and the solution
is heated for one hour at 60.degree. C. After adding ethyl acetate
(70 ml) and water (70 ml) and separating the solution, the organic
layer is washed with water three times and extraction is performed
on the aqueous layer using ethyl acetate three times. By
concentrating the obtained organic layer under reduced pressure, a
mixture of 6-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimi-
dazole and 5-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole
is obtained. Purification using medium pressure silica gel column
chromatography (eluate: hexane/ethyl acetate=1/4.about.0/100)
produced 6-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole
(83) (0.614 g) and
5-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole (84)
(0.259 g). .sup.1H-NMR (CDCl.sub.3, .delta.): 1.38 (3H, t, J=7.2
Hz), 2.56 (3H, s), 4.37 (2H, q, J=7.1 Hz), 5.84 (2H, s), 6.41 (1H,
d, J=6.8 Hz), 7.44-7.53 (2H, m), 7.78 (1H, d, J=8.6 Hz), 7.88 (1H,
s), 8.02 (1H, dd, J=8.3 and 1.5 Hz), 8.30 (1H, dd, J=7.9 and 1.5
Hz).
[0247] (R.sub.1=2-nitrobenzyl, R.sub.2=methyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
[0248] Example 84: .sup.1H-NMR (CDCl.sub.3, .delta.): 1.42 (3H, t,
J=7.0 Hz), 2.56 (3H, s), 4.40 (2H, q, J=7.0 Hz), 5.80 (2H, s), 6.43
(1H, dd, J=7.6 and 1.0 Hz), 7.14 (1H, d, J=8.3 Hz), 7.45-7.53 (2H,
m), 7.95 (1H, dd, J=8.4 and 1.5 Hz), 8.27 (1H, dd, J=8.0 and 1.7
Hz), 8.48 (1H, d, J=1.2 Hz).
[0249] (R.sub.1=2-nitrobenzyl, R.sub.2=methyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 85
6-Carboxy-2-Methyl-1-(2-Nitrobenzyl)Benzimidazole
[0250] By using the method of example 80,
6-carboxy-2-methyl-1-(2-nitroben- zyl)benzimidazole (0.35 g) is
obtained from 6-ethoxycarbonyl-2-methyl-1-(2-
-nitrobenzyl)benzimidazole (0.61 g). .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 2.51 (3H, s), 5.96 (2H, s), 6.33 (1H, d, J=7.0 Hz),
7.55-7.62 (2H, m), 7.66 (1H, d, J=8.3 Hz), 7.81 (1H, d, J=8.4 Hz),
8.06 (1H, s), 8.24 (1H, d, J=7.0 Hz), 12.66 (1H, s).
[0251] (R.sub.1=2-nitrobenzyl, R.sub.2=methyl, R.sub.3=carboxyl,
n=1, y=0)
Example 86
6-Carboxy-1-(2-Chlorobenzyl)-2-Methylbenzimidazole
[0252] Ethanol (15 ml) and 5% sodium hydroxide aqueous solution
(10.6 g) are added to
1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (1.456 g)
(example 47), and the solution is refluxed for 1 hour. After the
reaction solution is cooled, its acidity is adjusted to pH 6 with
10% hydrochloric acid. The sediment is gathered, washed with water,
dried under reduced pressure, and thus,
6-carboxy-1-(2-chlorobenzyl)-2-methylbe- nzimidazole (0.645 g) is
obtained.
[0253] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl, R.sub.3=carboxyl,
n=1, y=0)
Example 87
6-Carboxy-1-(2,4-Dichlorobenzyl)-2-Methylbenzimidazole
[0254] 10% sodium hydroxide aqueous solution (3.10 g) and ethanol
(10 ml) are added to
1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazol- e
(0.94 g) (example 70), and the solution is refluxed by heating for
1 hour. Its acidity is adjusted to pH 6 with 10% hydrochloric acid.
The precipitated crystals are separated through filtration, dried,
and thus, 6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole
(0.68 g) is obtained.
[0255] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.52 (3H, s), 5.61 (2H,
s), 6.54 (1H, d, J=8.4 Hz), 7.33 (1H, dd, J=8.4 and 2.1 Hz), 7.64
(1H, d, J=8.4 Hz), 7.74 (1H, d, J=2.1 Hz), 7.81 (1H, dd, J=8.4 and
1.5 Hz), 7.98 (1H, s), 12.72 (1H, s).
[0256] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=carboxyl, n=1, y=0)
Example 88
1-(Biphenyl-4-ylmethyl)-6-Carboxy-2-Methylbenzimidazole
[0257] By using the method of example 75,
1-(biphenyl-4-ylmethyl)-6-carbox- y-2-methylbenzimidazole (0.83 g)
is obtained from 1-(biphenyl-4-ylmethyl)--
6-ethoxycarbonyl-2-methylbenzimidazole (1.10 g) (example
56)..sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.53 (3H, s), 5.61 (2H,
s), 7.18 (2H, d, J=8.2 Hz), 7.34 (1H, m), 7.43 (2H, m), 7.62 (5H,
m), 7.79 (1H, dd, J=1.6 and 8.5 Hz), 8.09 (1H, d, J=1.0 Hz), 12.72
(1H, br s).
[0258] (R.sub.1=4-biphenyl, R.sub.2=methyl, R.sub.3=carboxyl, n=1,
y=1)
Example 89
1-(4-t-Butylbenzyl)-6-Carboxy-2-Methylbenzimidazole
[0259] By using the method of example 75,
1-(4-t-butylbenzyl)-6-carboxy-2-- methylbenzimidazole (0.55 g) is
obtained from 1-(4-t-butylbenzyl)-6-ethoxy-
carbonyl-2-methylbenzimidazole (1.34 g) (example 63). .sup.1H-NMR
(DMSO-d.sub.6, .delta.):1.22 (9H, s), 2.57 (3H, s), 5.52 (2H, s),
7.03 (2H, d, J=8.2 Hz), 7.35 (1H, d, J=8.3 Hz), 7.60 (1H, d, J=8.4
Hz), 7.78 (1H, dd, J=8.4 and 1.5 Hz), 8.06 (1H, s), 12.71 (1H,
s).
[0260] (R.sub.1=4-t-butylbenzyl, R.sub.2=methyl, R.sub.3=carboxyl,
n=1, y=0)
Example 90
6-Carboxy-2-Methyl-1-(2-Methylbenzyl)Benzimidazole
[0261] By using the method of example 75,
6-carboxy-2-methyl-1-(2-methylbe- nzyl)benzimidazole (0.49 g) is
obtained from 6-ethoxycarbonyl-2-methyl-1-(-
2-methylbenzyl)benzimidazole (0.81 g) (example 57). .sup.1H-NMR
(DMSO-d.sub.6, .delta.): 2.41 (3H, s), 2.48 (3H, s), 5.55 (2H, s),
6.14 (1H, d, J=7.6 Hz), 7.02 (1H, t, J=7.4 Hz), 7.17 (1H, t, J=7.3
Hz), 7.26 (1H, d, J=7.4 Hz), 7.65 (1H, d, J=8.4 Hz), 7.81 (1H, dd,
J=8.4 and 1.4 Hz), 7.97 (1H, d, J=1.1 Hz), 12.71 (1H, s).
[0262] (R.sub.1=2-methylbenzyl, R.sub.2=methyl, R.sub.3=carboxyl,
n=1, y=0)
Example 91
6-Carboxy-1-(2-Methoxybenzyl)-2-Methylbenzimidazole
[0263] By using the method of example 75,
6-carboxy-1-(2-methoxybenzyl)-2-- methylbenzimidazole (1.00 g) is
obtained from 6-ethoxycarbonyl-1-(2-methox-
ybenzyl)-2-methylbenzimidazole (1.63 g) (example 58). .sup.1H-NMR
(DMSO-d.sub.6, .delta.): 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).
[0264] (R.sub.1=2-methoxybenzyl, R.sub.2=methyl, R.sub.3=carboxyl,
n=1, y=0)
Example 92
6-Carboxy-1-(4-Methoxybenzyl)-2-Methylbenzimidazole
[0265] By using the method of example 75,
6-carboxy-1-(4-methoxybenzyl)-2-- methylbenzimidazole (0.99 g) is
obtained from 6-ethoxycarbonyl-1-(4-methox-
ybenzyl)-2-methylbenzimidazole (1.27 g) (example 59). .sup.1H-NMR
(DMSO-d.sub.6, .delta.): 2.86 (3H, s), 3.71 (3H, s), 5.69 (2H, s),
6.92 (2H, d, J=8.4 Hz), 7.27 (2H, d, J=8.4 Hz), 7.84 (1H, d, J=8.5
Hz), 8.04 (1H, d, J=8.5 Hz), 8.33 (1H, s), 13.25 (1H, br t).
[0266] (R.sub.1=4-methoxybenzyl, R.sub.2=methyl, R.sub.3=carboxyl,
n=1, y=0)
Example 93
6-Carboxy-2-Methyl-1-[2-(Benzenesulfonylmethyl)Benzyl]Benzimidazole
[0267] By using the method of example 75,
6-carboxy-2-methyl-1-[2-(benzene-
sulfonylmethyl)benzyl]benzimidazole (0.74 g) is obtained from
6-ethoxycarbonyl-2-methyl-1-[2-(benzenesulfonylmethyl)benzyl]benzimidazol-
e (0.89 g).
[0268] .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.44 (3H, s), 4.99 (2H,
s), 5.71 (2H, s), 6.08 (1H, d, J=6.5 Hz), 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).
[0269] (R.sub.1=2-(benzenesulfonylmethyl)benzyl, R.sub.2=methyl,
R.sub.3=carboxyl, n=1, y=0)
Example 94
6-Carboxy-1-(2-Cyanobenzyl)-2-Methylbenzimidazole
[0270] By using the method of example 75,
6-carboxy-1-(2-cyanobenzyl)-2-me- thylbenzimidazole (1.14 g) is
obtained from 1-(2-cyanobenzyl)-6-(2-cyanobe-
nzyloxycarbonyl)-2-methylbenzimidazole (2.04 g) (example 61).
.sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.54 (3H, s), 5.80 (2H, s),
6.78 (1H, d, J=7.8 Hz), 7.51 (1H, t, J=7.4 Hz), 7.61 (1H, dt, J=7.8
and 1.2 Hz), 7.64 (1H, d, J=8.4 Hz), 7.80 (1H, dd, J=8.4 and 1.5
Hz), 7.94 (1H, d, J=6.7 Hz), 8.00 (1H, d, J=1.1 Hz), 12.70 (1H,
s).
[0271] (R.sub.1=2-cyanobenzyl, R.sub.2=methyl, R.sub.3=carboxyl,
n=1, y=0)
Example 95
6-Carboxy-1-(Biphenyl-2-ylmethyl)-2-Methylbenzimidazole
[0272] By using the method of example 75,
6-carboxy-1-(biphenyl-2-ylmethyl- )-2-methylbenzimidazole (1.07 g)
is obtained from 1-(biphenyl-2-ylmethyl)--
6-ethoxycarbonyl-2-methylbenzimidazole (1.31 g) (example 62).
.sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.32 (3H, s), 5.45 (2H, s),
6.61 (1H, d, J=7.7 Hz), 7.26 (1H, dt, J=7.7 and 1.4 Hz), 7.31 (1H,
dd, J=7.5 and 1.3 Hz), 7.36 (1H, dt, J=7.5 and 0.7 Hz), 7.40-7.46
(1H, m), 7.46-7.52 (4H, m), 7.57 (1H, d, J=8.4 Hz), 7.76 (1H, dd,
J=7.9 and 1.5 Hz), 7.86 (1H, d, J=1.2 Hz), 12.72 (1H, s).
[0273] (R.sub.1=2-biphenyl, R.sub.2=methyl, R.sub.3=carboxyl, n=1,
y=1)
Example 96
1-Benzyl-6-Carboxy-2-Methylbenzimidazole
[0274] By using the method of example 75,
1-benzyl-6-carboxy-2-methylbenzi- midazole (0.59 g) is obtained
from 1-benzyl-6-ethoxycarbonyl-2-methylbenzi- midazole (0.71 g)
(example 63). .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.56 (3H, s),
5.57 (2H, s), 7.11 (1H, d, J=8.0 Hz), 7.27 (1H, t, J=7.2 Hz),
7.32-7.35 (2H, m), 7.61 (1H, d, J=8.3 Hz), 7.79 (1H, dd, J=8.4 and
1.3 Hz), 8.06 (1H, s), 12.75 (1H, s).
[0275] (R.sub.1=benzyl, R.sub.2=methyl, R.sub.3=carboxyl, n=1,
y=0)
Example 97
6-Carboxy-2-Methyl-1-(2-Naphthylmethyl)Benzimidazole
[0276] By using the method of example 75,
6-carboxy-2-methyl-1-(2-naphthyl- methyl)benzimidazole (0.80 g) is
obtained from 6-ethoxycarbonyl-2-methyl-1-
-(2-naphthylmethyl)benzimidazole (1.28 g) (example 65). .sup.1H-NMR
(DMSO-d.sub.6, .delta.): 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 (1H, d, J=8.3 Hz),
7.78-7.92 (4H, m), 8.09 (1H, s), 12.68 (1H, s).
[0277] (R.sub.1=2-naphthyl, R.sub.2=methyl, R.sub.3=carboxyl, n=1,
y=1)
Example 98
1-(Biphenyl-4-ylmethyl)-6-Carboxy-2-Ethylbenzimidazole
[0278] By using the method of example 75,
1-(biphenyl-4-ylmethyl)-6-carbox- y-2-ethylbenzimidazole (1.70 g)
is obtained from 1-(biphenyl-4-ylmethyl)-6-
-ethoxycarbonyl-2-ethylbenzimidazole (2.07 g) (example 66).
.sup.1H-NMR (DMSO-d.sub.6, .delta.): 1.32 (3H, t, J=7.4 Hz), 2.94
(2H, q, J=7.5 Hz), 5.63 (2H, s), 7.16 (2H, d, J=8.2 Hz), 7.34 (1H,
t, J=7.4 Hz), 7.44 (2H, t, J=7.5 Hz), 7.60-7.78 (5H, m), 7.81 (1H,
dd, J=1.4 and 8.4 Hz), 8.10 (1H, d, J=1.2 Hz), 12.73 (1H, s).
[0279] (R.sub.1=4-biphenyl, R.sub.2=ethyl, R.sub.3=carboxyl, n=1,
y=1)
Example 99
5-Carboxy-1-(2-Chlorobenzyl)-2-Methylbenzimidazole
[0280] By using the method of example 75,
5-carboxy-1-(2-chlorobenzyl)-2-m- ethylbenzimidazole (2.48 g) is
obtained from 1-(2-chloro-benzyl)-5-ethoxyc-
arbonyl-2-methylbenzimidazole (3.70 g) (example 67)..sup.1H-NMR
(DMSO-d.sub.6, .delta.): 2.49 (3H, s), 5.57 (2H, s), 6.53 (1H, d,
J=7.8 Hz), 7.22 (1H, d, J=7.6 Hz), 7.33 (1H, t, J=7.6 Hz), 7.44
(1H, d, J=8.4 Hz), 7.54 (1H, d, J=8.0 Hz), 7.77 (1H, dd, J=1.6 and
8.5 Hz), 8.16 (1H, d, J=1.3 Hz), 12.71 (1H, br s).
[0281] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl, R.sub.3=carboxyl,
n=1, y=0)
Example 100
5-Carboxy-2-methyl-1-(2-nitrobenzyl)benzimidazole
[0282] By using the method of example 75,
5-carboxy-2-methyl-1-(2-nitroben- zyl)benzimidazole (0.15 g) is
obtained from 5-ethoxycarbonyl-2-methyl-1-(2-
-nitrobenzyl)benzimidazole (0.26 g)(example 84). .sup.1H-NMR
(DMSO-d.sub.6, .delta.): 2.49 (3H, s), 5.91 (2H. s), 6.36 (1H, dd,
J=7.2 and 1.8 Hz), 7.52 (1H, d, J=8.5 Hz), 7.55-7.62 (2H, m), 7.77
(1H, dd, J=8.5 and 1.5 Hz), 8.18 (1H, d, J=1.3 Hz), 8.24 (1H, dd,
J=7.4 and 1.6 Hz), 12.69 (1H, s).
[0283] (R.sub.1=2-nitrobenzyl, R.sub.2=methyl, R.sub.3=carboxyl,
n=1, y=0)
Example 101
2-Benzyl-5-Carboxy-1-(2-Chlorobenzyl)Benzimidazole
A.) 3-Acetylamino-4-nitro-ethylbenzoate
[0284] Phenylacetyl chloride (3.74 g) is added to a mixture of
4-amino-3-nitro-ethylbenzoate (4.04 g) and N,N-dimethylaniline (200
ml) under ice-chilled conditions, and the solution is stirred for 2
hours at room temperature. It is stirred for another 2 hours at
50.degree. C. The reaction solution is poured into the cold
1N-hydrochloric acid, and then extraction is performed with ethyl
acetate twice. After the organic layer is washed with
1N-hydrochloric acid, then with water, and dried, the solvent is
removed through evaporation under reduced pressure. The residue is
purified using silica gel column chromatography (eluate: ethyl
acetate/hexane=1/10.about.1/4) and thus
3-nitro-4-phenylacetylamino-ethyl- benzoate (6.00 g) is
obtained.
B.) 2-Benzyl-5-ethoxycarbonylbenzimidazole
[0285] A mixture of 3-nitro-4-phenylacetylamino-ethylbenzoate (3.60
g), ethanol (47 ml), acetic acid (23 ml) and iron (6.4 g) is
refluxed by heating for four hours. Solids are separated through
filtration and the filtrate is concentrated. Ethanol (50 ml) and
35% hydrochloric acid (5 g) are added to the residue and the
solution is stirred for 40 hours as it is refluxed by heating. The
solution is neutralized with sodium bicarbonate and chloroform
extraction is performed. The organic layer is concentrated under
reduced pressure and then purified using silica gel column
chromatography. Thus, 2-benzyl-5-ethoxycarbonylbenzimidazole (2.30
g) is obtained. .sup.1H-NMR (CDCl.sub.6, .delta.): 1.39 (3H, t,
J=7.1 Hz), 4.26 (2H, s), 4.37 (2H, q, J=7.1 Hz), 7.22-7.36 (5H, m),
7.50 (1H, d, J=8.6 Hz), 7.94 (1H, dd, J=1.5 and 8.6 Hz), 8.23 (1H,
d, J=1.3 Hz).
C.) 2-Benzyl-1-(2-chlorobenzyl)-6-ethoxycarbonylbenzimidazole and
2-Benzyl-1-(2-chlorobenzyl)-5-ethoxycarbonylbenzimidazole
[0286] By using the method of examples 83 and 84,
2-benzyl-1-(2-chlorobenz- yl)-6-ethoxycarbonylbenzimidazole (1.06
g) and 2-benzyl-1-(2-chlorobenzyl)- -5-ethoxycarbonylbenzimidazole
(0.640 g) are obtained from 2-benzyl-5-ethoxycarbonylbenzimidazole
(2.37 g) and 2-chlorobenzyl bromide (3.94 g). .sup.1H-NMR
(CDCl.sub.3, .delta.): 1.83 (3H, t, J=7.1 Hz), 4.23 (2H, s), 4.35
(2H, q, J=7.1 Hz), 5.36 (2H, s), 6.23 (1H, d, J=7.8 Hz), 6.97 (1H,
d, J=7.6 Hz), 7.11-7.45 (7H, m), 7.85 (1H, d, J=8.5 Hz), 7.91 (1H,
s), 8.02 (1H, dd, J=1.2 and 8.6 Hz).
[0287] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.41 (3H, t, J=7.1 Hz),
4.25 (2H, s), 4.41 (2H, q, J=7.1 Hz), 5.33 (2H, s), 6.22 (1H, d,
J=6.9 Hz), 6.97 (1H, t, J=7.6 Hz), 7.12-7.28 (7H, m), 7.40 (1H, d,
J=8.0 Hz), 7.95 (1H, dd, J=1.6 and 8.6 Hz), 8.60 (1H, d, J=1.4
Hz).
D.) 2-Benzyl-5-carboxy-1-(2-chlorobenzyl)benzimidazole
[0288] By using the method of example 75,
2-benzyl-5-carboxy-1-(2-chlorobe- nzyl)benzimidazole (0.488 g) is
obtained from 2-benzyl-1-(2-chlorobenzyl)--
5-ethoxycarbonylbenzimidazole (0.635 g). .sup.1H-NMR (DMSO-d.sub.6,
.delta.): 4.27 (2H, s), 5.57 (2H, s), 6.27 (1H, d, J=7.1 Hz), 7.06
(1H, t), 7.10-7.29 (6H, m), 7.39 (1H, d, J=8.6 Hz), 7.47 (1H, d,
J=7.9 Hz), 7.78 (1H, dd, J=1.4 and 8.6 Hz), 8.21 (1H, d, J=1.2 Hz),
12.71 (1H, br s).
[0289] (R.sub.1=2-chlorobenzyl, R.sub.2=benzyl, R.sub.3=carboxyl,
n=1, y=0)
Example 102
2-Benzyl-6-carboxy-1-(2-chlorobenzyl)benzimidazole
[0290] By using the method of example 75,
2-benzyl-6-carboxy-1-(2-chlorobe- nzyl)benzimidazole (0.780 g) is
obtained from 2-benzyl-1-(2-chlorobenzyl)--
6-ethoxycarbonylbenzimidazole (1.00 g) (example 101, part C).
.sup.1H-NMR (DMSO-d.sub.6, .delta.): 4.29 (2H, s), 5.63 (2H, s),
6.28 (1H, d, J=7.8 Hz), 7.07 (1H, t, J=7.6 Hz), 7.15 (1H, m),
7.19-7.29 (5H, m), 7.49 (1H, d, J=7.4 Hz), 7.70 (1H, d, J=8.4 Hz),
7.81 (1H, d, J=8.4 Hz), 7.91 (1H, s), 12.73 (1H, br s).
[0291] (R.sub.1=2-chlorobenzyl, R.sub.2=benzyl, R.sub.3=carboxyl,
n=1, y=0)
Example 103
5-Ethoxycarbonyl-2-Trifluoromethylbenzimidazole
[0292] To a methanol (100 ml) solution of
3-amino-4-nitro-ethylbenzoate (4.00 g), 5% palladium/carbon (0.50
g) is added, and the solution is stirred for 12 hours at 50.degree.
C. under a nitrogen environment. Solids are separated through
filtration. Concentration of the filtrate produced
3,4-diamino-ethylbenzoate. Trifluoroacetic acid (20 ml) is added to
this material, and the solution is stirred for two hours at
60.degree. C. The reaction solution is concentrated and chloroform
is added. Precipitated crystals are separated through filtration
and dried. Thus, 5-ethoxycarbonyl-2-trifluoromethylbenzimidazole
(4.46 g) (157) is obtained. .sup.1H-NMR (DMSO-d.sub.6, .delta.):
1.36 (3H, t, J=7.0 Hz), 4.36 (2H, q, J=7.0 Hz), 7.82 (1H, d, J=8.5
Hz), 7.99 (1H, dd, J=1.5 and 8.7 Hz), 8.33 (1H, s).
[0293] (R.sub.1=H, R.sub.2=trifluoromethyl, R.sub.3=ethoxycarbonyl,
n=1, y=0)
Examples 104 and 105
1-(Biphenyl-4-ylmethyl)-6-Ethoxycarbonyl-2-Trifluoromethylbenzimidazole
and
1-(Biphenyl-4-ylmethyl)-5-Ethoxycarbonyl-2-Trifluoromethylbenzimidazo-
le
[0294] By using the method of examples 83 and 84,
1-(biphenyl-4-ylmethyl)--
6-ethoxycarbonyl-2-trifluoromethylbenzimidazole (104) (0.69 g) and
1-(biphenyl-4-ylmethyl)-5-ethoxycarbonyl-2-trifluoromethylbenzimidazole
(105) (0.38 g) are obtained from
5-ethoxycarbonyl-2-trifluoromethylbenzim- idazole (2.00 g) and
4-bromomethylbiphenyl (10.08 g). .sup.1H-NMR (CDCl.sub.3, .delta.):
1.39 (3H, t), 4.38 (2H, q), 5.64 (2H, s), 7.18 (2H, d, J=8.2 Hz),
7.34 (1H, t, J=7.4 Hz), 7.42 (2H, t, J=7.4 Hz), 7.52-7.57 (4H, m),
7.95 (1H, d, J=8.8 Hz), 8.09 (2H, dd, J=1.4 and 8.8 Hz), 8.14 (1H,
d, J=1.1 Hz).
[0295] (R.sub.1=4-biphenyl, R.sub.2=trifluoromethyl,
R.sub.3=ethoxycarbonyl, n=1, y=1)
[0296] Example 105: .sup.1H-NMR (CDCl.sub.3, .delta.): 1.40 (3H,
t), 4.40 (2H, q), 5.59 (2H, s), 7.16 (2H, d, J=8.1 Hz), 7.34 (2H,
t, J=6.2 Hz), 7.41 (2H, t, J=7.5 Hz), 7.53 (4H, m), 8.08 (1H, dd,
J=1.3 and 9.1 Hz), 8.65 (1H, s).
[0297] (R.sub.1=4-biphenyl, R.sub.2=trifluoromethyl,
R.sub.3=ethoxycarbonyl, n=1, y=1)
Example 106
1-(Biphenyl-4-ylmethyl)-6-Carboxy-2-Trifluoromethylbenzimidazole
[0298] By using the method of example 75,
1-(biphenyl-4-ylmethyl)-6-carbox- y-2-trifluoromethylbenzimidazole
(0.483 g) is obtained from
1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-trifluoromethylbenzimidazole
(0.690 g) (example 104). .sup.1H-NMR (DMSO-d.sub.6, .delta.): 5.87
(2H, s), 7.18 (2H, d, J=8.2 Hz), 7.35 (1H, t, J=7.4 Hz), 7.44 (2H,
t, J=7.5 Hz), 7.60-7.67 (4H, m), 7.98 (2H, d, J=0.7 Hz), 8.32 (1H,
s), 13.15 (1H, s).
[0299] (R.sub.1=4-biphenyl, R.sub.2=trifluoromethyl,
R.sub.3=carboxyl, n=1, y=1)
Example 107
1-(Biphenyl-4-ylmethyl)-5-Carboxy-2-Trifluoromethylbenzimidazole
[0300] By using the method of example 75,
1-(biphenyl-4-ylmethyl)-5-carbox- y-2-trifluoromethylbenzimidazole
(0.270 g) is obtained from
1-(biphenyl-4-ylmethyl)-5-ethoxycarbonyl-2-trifluoromethylbenzimidazole
(0.38 g) (example 105). .sup.1H-NNR (DMSO-d.sub.6, .delta.): 5.80
(2H, s), 7.19 (2H, d, J=6.3 Hz), 7.35 (1H, t, J=7.2 Hz), 7.43 (2H,
t, J=7.3 Hz), 7.82 (1H, d, J=8.7 Hz), 8.04 (1H, d, J=8.7 Hz), 8.45
(1H, s).
[0301] (R.sub.1=4-biphenyl, R.sub.2=trifluoromethyl,
R.sub.3=carboxyl, n=1, y=1)
Example 108
1-(2-Chlorobenzyl)-2-Methylbenzimidazole-6-Acetic Acid
[0302] To 1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acetonitrile
(0.500 g), 10% hydrochloric acid is added, and the solution is
refluxed by heating for 15 hours. It is neutralized with a
saturated sodium bicarbonate aqueous solution, and chloroform
extraction is performed. The organic layer is concentrated and
purified using silica gel column chromatography (eluate:
chloroform/ethanol=9/1.about.4/1). Thus,
1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acetic acid (0.170 g) is
obtained. .sup.1H-NMR (CDCl.sub.3, .delta.): 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=7.9 Hz), 7.62 (1H, d), 8.90 (1H, br
s).
[0303] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=carboxymethyl, n=1, y=0)
Example 109
1-(2-Chlorobenzyl)-2-Methylbenzimidazole-6-Methyl Acrylate
[0304] Triphenylphosphoranyl-methyl acetate (4.49 g) is added to a
1,4-dioxane (50 ml) solution of
1-(2-chlorobenzyl)-6-formyl-2-methylbenzi- midazole (2.73 g), and
the solution is stirred for six hours as it is refluxed by heating.
After the reaction solution is cooled, the solvent is removed
through evaporation under reduced pressure and the residue is
purified using silica gel chromatography (eluate:
chloroform/methanol=9/1- ). Thus a preliminarily purified material
of 1-(2-chlorobenzyl)-2-methylbe- nzimidazole-6-methyl acrylate
(7.43 g) is obtained. This preliminarily purified material is
immediately used for the following reaction.
[0305] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=methoxycarbonyl-2-- ethenyl, n=1, y=0)
Example 110
1-(2-Chlorobenzyl)-2-Methylbenzimidazole-6-Acrylic Acid
[0306] The above-mentioned (example 109) preliminarily purified
material, 1-(2-chlorobenzyl)-2-methylbenzimidazole-6-methyl
acrylate (3.29 g) is dissolved in ethanol (20 ml), 5% sodium
hydroxide aqueous solution (10.1 g) is added, and the solution is
refluxed for two hours. The reaction solution is neutralized with a
hydrochloric acid aqueous solution, and a residue is obtained by
concentrating the solvent under reduced pressure. The residue is
purified using silica gel chromatography (eluate:
chloroform/methanol=9/1.about.6/1), and thus,
1-(2-chlorobenzyl)-2-methyl- benzimidazole-6-acrylic acid (1.10 g)
is obtained. .sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.56 (3H, s),
5.65 (2H, s), 6.54 (1H, d, J=15.9 Hz), 6.62 (1H, d, J=7.6 Hz), 7.25
(1H, t), 7.35 (1H, t), 7.56 (1H, d, J=8.1 Hz), 7.60-7.70 (3H, m),
7.99 (1H, s), 12.35 (1H, br s).
[0307] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=carboxyl-2-ethenyl- , n=1, y=0)
Example 111
6-Benzenesulfonylcarbamoyl-1-(2-Chlorobenzyl)-2-Methylbenzimidazole
[0308] N,N'-carbonyldiimidazole (45.8 g) is added all at once to an
N,N-dimethylformamide (950 ml) solution of
6-carboxy-1-(2-chlorobenzyl)-2- -methylbenzimidazole (45.0 g)
(example 75), and the solution is stirred for one hour at room
temperature. Subsequently, benzenesulfonamide (47.1 g) and
diazabicycloundecene (35.0 g) are added, and the solution is
stirred for 70 hours at 100.degree. C. The reaction solution is
cooled and the solvent is removed through evaporation under reduced
pressure. Water (300 ml) and methanol (200 ml) are added to the
residue, and moreover, 35% hydrochloric acid is added to adjust the
acidity of the solution to pH 5.5. Precipitated crystals are
separated through filtration, washed with a mixture solution (200
ml) of methanol and water (1/1), dried and thus,
6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-me-
thylbenzimidazole (38.4 g) is obtained. In addition, water is added
to filtrates and crystals precipitated. The crystals are separated
through filtration, washed with water, dried and thus, of the
material (13.3 g) is obtained. Both sets of crystals are gathered
and dissolved by adding acetone (3300 ml) and water (900 ml) and by
heating. The solvent is removed through evaporation as this
solution is heated. Then the solution is cooled. Precipitated
crystals are separated through filtration, dried, and thus, of
6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzim-
idazole (33.8 g) is obtained. .sup.1H-NMR (DMSO-d6, .delta.): 2.53
(3H, s), 5.46 (2H, s), 6.34 (1H, d, J=7.8 Hz), 7.11 (1H, m), 7.27
(1H, m), 7.48 (1H, m), 7.52 (2H, m), 7.60 (1H, m), 7.69 (1H, d,
J=8.6 Hz), 7.90 (1H, m), 8.09 (2H, m), 8.11 (1H, s), 11.84 (1H, br
s).
[0309] IR(KBr): 1684, 1448 cm.sup.-1.
[0310] Mass(FAB): m/e 440(M+1).
[0311] mp: 273.5-274.3.degree. C.
[0312] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6, R=H,
R.sub.6=phenyl, n=1, y=0)
Example 112
6-Benzenesulfonylcarbamoyl-1-(Biphenyl-4-ylmethyl)-2-Methylbenzimidazole
[0313] By using the method of example 111,
6-benzenesulfonyl-carbamoyl-1-(-
biphenyl-4-ylmethyl)-2-methylbenzimidazole (0.473 g) is obtained
from 1-(biphenyl-4-ylmethyl)-2-ethyl-6-carboxybenzimidazole (0.600
g), N,N'-carbonyldiimidazole (0.546 g), benzenesulfonamide (0.529
g) and diazabicycloundecene (0.512 g). .sup.1H-NMR (DMSO-d6,
.delta.): 1.29 (3H, t, J=7.4 Hz), 2.88 (2H, q, J=7.4 Hz), 5.59 (2H,
s), 7.16 (2H, d, J=8.2 Hz), 7.33-7.37 (1H, m), 7.44 (2H, t, J=7.5
Hz), 7.59-7.71 (8H, m), 7.74 (1H, dd, J=8.4 and 1.4 Hz), 7.98-8.02
(2H, m), 8.21 (1H, s), 12.43 (1H, br s).
[0314] IR(KBr): 1684 cm.sup.-1.
[0315] mp: 149.5-157.0.degree. C.
[0316] (R.sub.1=4-biphenyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=phenyl, n=1, y=1)
Example 113
5-Benzenesulfonylcarbamoyl-1-(2-Chlorobenzyl)-2-Methylbenzimidazole
[0317] By using the method of example 111,
5-benzenesulfonyl-carbamoyl-1-(-
2-chlorobenzyl)-2-methylbenzimidazole (0.480 g) is obtained from
5-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (0.450 g)
(example 99), N,N'-carbonyldiimidazole (0.485 g),
benzenesulfonamide (0.470 g) and diazabicycloundecene (0.456 g).
.sup.1H-NMR (DMSO-d6, .delta.): 2.53 (3H, s), 5.61 (2H, s), 6.57
(1H, d, J=7.4 Hz), 7.22 (1H, t), 7.33 (1H, t), 7.50 (1H, d, J=8.6
Hz), 7.54 (1H, dd, J=7.9 and 0.9 Hz), 7.63 (2H, t), 7.71 (2H, m),
8.00 (2H, d, J=7.3 Hz), 8.21 (1H, d, J=1.4 Hz), 12.50 (1H, br
s).
[0318] IR(KBr): 1685 cm.sup.-1.
[0319] mp: 137.0-138.5.degree. C.
[0320] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=phenyl, n=1, y=0)
Example 114
5-(4-Chlorobenzenesulfonylcarbamoyl)-1-(2-Chlorobenzyl)-2-Methylbenzimidaz-
ole
[0321] By using the method of example 111,
5-(4-benzenesulfonyl-carbamoyl)-
-1-(2-chlorobenzyl)-2-methylbenzimidazole (0.520 g) is obtained
from 5-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (0.450 g)
(example 99, N,N'-carbonyldiimidazole (0.485 g),
4-chlorobenzenesulfonamide (0.573 g) and diazabicycloundecene
(0.456 g). .sup.1H-NM (DMSO-d6, .delta.): 2.49 (3H, s), 5.58 (2H,
s), 6.51 (1H, d, J=7.6 Hz), 7.21 (1H, t), 7.32 (1H, t), 7.45 (1H,
d, J=8.6 Hz), 7.53 (1H, d, J=7.8 Hz), 7.69 (3H, d, J=8.6 Hz), 7.99
(2H, d, J=8.6 Hz), 8.18 (1H, s), 12.58 (1H, br s).
[0322] IR(KBr): 1619 cm.sup.-1.
[0323] mp: 261.5-263.0.degree. C.
[0324] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=S.sub.2R.sub.6, R.sub.5=H,
R.sub.6=4-chlorophenyl, n=1, y=0)
Example 115
1-(2-Chlorobenzyl)-2-Methyl-5-(2-Naphthalenesulfonylcarbamoyl)Benzimidazol-
e
[0325] By using the method of example 111,
1-(2-chlorobenzyl)-2-methyl-5-(-
2-naphthalenesulfonylcarbamoyl)benzimidazole (0.352 g) is obtained
from 5-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (0.450 g)
(example 99), N,N'-carbonyldiimidazole (0.485 g),
2-naphthalenesulfonamide (0.620 g) and diazabicyclo-undecene (0.456
g). .sup.1H-NMR (DMSO-d6, .delta.): 2.48 (3H, s), 5.56 (2H, s),
6.49 (1H, d, J=7.7 Hz), 7.20 (1H, t, J=7.6 Hz), 7.31 (1H, t, J=7.7
Hz), 7.44 (1H, d, J=8.6 Hz), 7.52 (1H, d, J=8.0 Hz), 7.66-7.75 (3H,
m), 7.97 (1H, d, J=8.8 Hz), 8.04 (1H, d, J=8.0 Hz), 8.14 (1H, d,
J=8.8 Hz), 8.19 (1H, s), 8.23 (1H, d, J=8.0 Hz), 8.68 (1H, s),
12.55 (1H, br s).
[0326] IR(KBr): 1685 cm.sup.-1.
[0327] mp: 236.5-238.0.degree. C.
[0328] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=2-naphthyl, n=1, y=0)
Example 116
1-(2-Chlorobenzyl)-6-Methanesulfonylcarbamoyl-2-Methylbenzimidazole
[0329] By using the method of example 111 ,
1-(2-chlorobenzyl1)-6-methanes-
ulfonylcarbamoyl-2-methylbenzimidazole (0.564 g) is obtained from
6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (0.500 g)
(example 75), N,N'-carbonyldiimidazole (0.539 g),
methanesulfonamide (0.316 g) and diazabicyclo-undecene (0.506 g).
.sup.1H-NMR (DMSO-d6, .delta.): 2.49 (3H, s), 3.35 (3H, s), 5.60
(2H, s), 6.43 (1H, d, J=7.8 Hz), 7.23 (1H, t), 7.34 (1H, t, J=7.7
Hz), 7.57 (1H, d, J=8.0 Hz), 7.68 (1H, d, J=8.5 Hz), 7.81 (1H, dd,
J=1.7 and 8.5 Hz), 8.13 (1H, d, J=1.5 Hz), 11.94 (1H, br s).
[0330] IR(KBr): 1670 cm.sup.-1.
[0331] mp: 302.0-303.0.degree. C.
[0332] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=methyl, n=1, y=0)
Example 117
6-(Butanesulfonylcarbamoyl)-1-(2-Chlorobenzyl)-2-Methylbenzimidazole
[0333] By using the method of example 111,
6-(butanesulfonyl-carbamoyl)-1--
(2-chlorobenzyl)-2-methylbenzimidazole (0.595 g) is obtained from
6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (0.500 g)
(example 75), N,N'-carbonyldiimidazole (0.539 g),
1-butanesulfonamide (0.456 g) and diaza-bicycloundecene (0.506 g).
.sup.1H-NMR (DMSO-d6, .delta.): 0.84 (3H, t, J=7.4 Hz), 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=7.6 Hz), 7.23 (1H, t, J=7.6 Hz), 7.35 (1H, t), 7.56 (1H,
d, J=8.0 Hz), 7.68 (1H, d, J=8.4 Hz), 7.80 (1H, dd, J=1.6 and 8.4
Hz), 8.11 (1H, d, J=1.4 Hz), 11.86 (1H, br s).
[0334] IR(KBr): 1684 cm.sup.-1.
[0335] mp: 214-217.0.degree. C.
[0336] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=butyl, n=1, y=0)
Example 105
1-(2-Chlorobenzyl)-2-Methyl-6-(1-Octanesulfonylcarbamoyl)Benzimidazole
[0337] By using the method of example 111,
1-(2-chlorobenzyl)-2-methyl-6-(-
1-octanesulfonylcarbamoyl)benzimidazole (0.309 g) is obtained from
6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (0.400 g)
(example 75), N,N'-carbonyldiimidazole (0.431 g),
1-octanesulfonamide (0.406 g) and diazabicyclo-undecene (0.404 g).
.sup.1H-NMR (DMSO-d6, .delta.): 0.82 (3H, t, J=7.3 Hz), 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=8.5 Hz), 5.61 (2H, s), 6.45 (1H, d, J=7.7 Hz), 7.24 (1H,
t, J=7.5 Hz), 7.35 (1H, t, J=7.5 Hz), 7.58 (1H, d, J=8.0 Hz), 7.69
(1H, d, J=8.4 Hz), 7.81 (1H, d, J=8.5 Hz), 8.12 (1H, s), 11.86 (1H,
s).
[0338] IR(KBr): 1674 cm.sup.-1.
[0339] mp: 180.0-183.0.degree. C.
[0340] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=octyl, n=1, y=0)
Example 119
1-(2-Chlorobenzyl)-2-Methyl-6-(2-Propanesulfonylcarbamoyl)Benzimidazole
[0341] By using the method of example 111,
1-(2-chlorobenzyl)-2-methyl-6-(-
2-propanesulfonylcarbamoyl)benzimidazole (0.417 g) is obtained from
6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (0.400 g)
(example 75), N,N'-carbonyldiimidazole (0.431 g),
1-propanesulfonamide (0.328 g) and diazabicycloundecene (0.404 g).
.sup.1H-NMR (DMSO-d6, .delta.): 1.30 (6H, d, J=6.9 Hz), 2.50 (3H,
s), 3.81-3.87 (1H, m), 5.62 (2H, s), 6.46 (1H, d, J=7.7 Hz), 7.25
(1H, t, J=7.5 Hz), 7.35 (1H, t, J=7.5 Hz), 7.62 (1H, d, J=7.9 Hz),
7.69 (1H, d, J=8.5 Hz), 7.81 (1H, d, J=8.6 Hz), 8.12 (1H, s), 11.83
(1H, s).
[0342] IR(KBr): 1670 cm.sup.-1.
[0343] mp: 215.0-217.5.degree. C.
[0344] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=propyl, n=1, y=0)
Example 120
1-(Biphenyl-4-ylmethyl)-6-(1-Butanesulfonulcarbamoyl)-2-Methylbenzimidazol-
e
[0345] By using the method of example 111,
1-(biphenyl-4-ylmethyl)-6-(1-bu-
tanesulfonylcarbamoyl)-2-methylbenzimidazole (0.349 g) is obtained
from 1-(biphenyl-4-ylmethyl)-6-carboxy-2-methylbenzimidazole (0.300
g) (example 88), N,N'-carbonyldiimidazole (0.323 g),
1-butanesulfonamide (0.273 g) and diazabicyclo-undecene (0.303 g).
.sup.1H-NMR (DMSO-d.sub.6, .delta.): 0.85 (3H, t, J=7.4 Hz),
1.36-1.43 (2H, m), 1.63-1.72 (2H, m), 2.57 (3H, s), 3.52 (2H, t,
J=7.7 Hz), 5.60 (2H, s), 7.21 (2H, d, J=8.2 Hz), 7.35 (1H, t, J=7.3
Hz), 7.44 (2H, t, J=7.5 Hz), 7.60-7.68 (5H, m), 7.81 (1H, dd, J=1.6
and 8.4 Hz), 8.26 (1H, d, J=1.4 Hz), 11.97 (1H, s).
[0346] IR(KBr): 1676 cm.sup.-1.
[0347] mp: 219.5-222.5.degree. C.
[0348] (R.sub.1=4-biphenyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=butyl, n=1, y=1)
Example 121
6-(1-Butanesulfonylcarbamoyl)-1-(2,4-Dichlorobenzyl)-2-Methylbenzimidazole
[0349] By using the method of example 111,
6-(1-butanesulfony-lcabarmoyl)--
1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (0.459 g) is obtained
from 6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (0.400
g) (example 87), N,N'-carbonyldiimidazole (0.431 g),
1-butanesulfonamide (0.364 g) and diazabicycloundecene (0.404 g).
.sup.1H-NMR (DMSO-d6, .delta.): 0.85 (3H, t, J=7.3 Hz), 1.36-1.42
(2H, m), 1.63-1.70 (2H, m), 2.50 (3H, s), 3.51 (2H, t, J=7.7 Hz),
5.59 (2H, s), 6.45 (1H, d, J=8.4 Hz), 7.33 (1H, dd, J=2.1 and 8.4
Hz), 7.69 (1H, t, J=8.4 Hz), 7.76 (1H, d, J=2.0 Hz), 7.81 (1H, dd,
J=1.7 and 8.5 Hz), 8.11 (1H, d, J=1.3 Hz), 11.90 (1H, s).
[0350] IR(KBr): 1670 cm.sup.-1.
[0351] mp: 222.0-223.0.degree. C.
[0352] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=butyl, n=1, y=0)
Example 122
1-Biphenyl-4-ylmethyl)-6-(1-Butanesulfonylcarbamoyl)-2-Ethylbenzimidazole
[0353] By using the method of example 111,
1-(biphenyl-4-ylmethyl)-6-(1-bu-
tanesulfonylcarbamoyl)-2-ethylbenzimidazole (0.300 g) is obtained
from 1-(biphenyl-4-ylmethyl)-6-carboxy-2-ethylbenzimidazole (0.300
g) (example 98), N,N'-carbonyldiimidazole (0.340 g),
1-butanesulfonamide (0.300 g) and diazabicycloundecene (0.320 g).
.sup.1H-NMR (DMSO-d6, .delta.): 0.85 (3H, t, J=7.3 Hz), 1.30 (3H,
t, J=7.5 Hz), 1.35-1.44 (2H, m), 1.64-1.72 (2H, m), 2.90 (2H, q,
J=7.4 Hz), 3.52 (2H, t, J=7.7 Hz), 5.61 (2H, s), 7.19 (2H, d, J=8.3
Hz), 7.35 (1H, t, J=7.3 Hz), 7.44 (2H, t, J=7.5 Hz), 7.61-7.67(4H,
m), 7.71 (1H, d, J=8.5 Hz), 7.82 (1H, dd, J=1.6 and 8.5 Hz), 8.27
(1H, d, J=1.3 Hz), 12.01 (1H, s).
[0354] IR(Nujol): 1687, 1682 cm.sup.-1.
[0355] mp: 171.8-173.0.degree. C.
[0356] (R.sub.1=4-biphenyl, R.sub.2=ethyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=butyl, n=1, y=1)
Example 123
6-Benzenesulfonylcarbamoyl-1-(Biphenyl-4-ylmethyl)-2-Trifluoromethylbenzim-
idazole
[0357] By using the method of example 111,
6-benzenesulfonyl-carbamoyl-1-(-
biphenyl-4-ylmethyl)-2-trifluoromethylbenzimidazole (0.508 g) is
obtained from
1-(biphenyl-4-ylmethyl)-6-carboxy-2-trifluoromethylbenzimidazole
(0.483 g) (example 106), N,N'-carbonyldiimidazole (0.396 g),
benzenesulfonamide (0.383 g) and diazabicyclo-undecene (0.371 g).
.sup.1H-NMR (DMSO-d6, .delta.): 5.81 (2H, s), 7.15 (2H, d, J=8.3
Hz), 7.35 (1H, t, J=7.5 Hz), 7.44 (2H, t, J=7.5 Hz), 7.60-7.66 (6H,
m), 7.70 (1H, t, J=7.4 Hz), 7.91 (1H, dd, J=8.7 and 1.4 Hz),
7.96-8.01 (3H, m), 8.42 (1H, s), 12.65 (1H, s).
[0358] IR(KBr): 1685 cm.sup.-1.
[0359] mp: 164.5-167.0.degree. C.
[0360] (R.sub.1=4-biphenyl, R.sub.2=trifluoromethyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=phenyl, n=1, y=1)
Example 124
5-Benzenesulfonylcarbamoyl-1-(Biphenyl-4-ylmethyl)-2-Trifluoromethylbenzim-
idazole
[0361] By using the method of example 111,
5-benzenesulfonyl-carbamoyl-1-(-
biphenyl-4-ylmethyl)-2-trifluoromethylbenzimidazole (0.286 g) is
obtained from
1-(biphenyl-4-ylmethyl)-5-carboxy-2-trifluoromethylbenzimidazole
(0.270 g) (example 107), N,N'-carbonyldiimidazole (0.221 g),
benzenesulfonamide (0.214 g) and diazabicycloundecene (0.207 g).
.sup.1H-NMR (DMSO-d6, .delta.): 5.79 (2H, s), 7.15 (2H, d, J=8.1
Hz), 7.35 (1H, t, J=7.5 Hz), 7.43 (2H, t, J=7.5 Hz), 7.59-7.67 (6H,
m), 7.72 (1H, t, J=7.6 Hz), 7.83 (1H, d, J=8.8 Hz), 7.94 (1H, d,
J=8.9 Hz), 8.02 (2H, d, J=7.4 Hz), 8.49 (1H, s), 12.69 (1H, s).
[0362] IR(KBr): 1699 cm.sup.-1.
[0363] mp: 248.5-251.0.degree. C.
[0364] (R.sub.1=4-biphenyl, R.sub.2=trifluoromethyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=phenyl, n=1, y=1)
Example 125
6-Benzenesulfonylcarbamoyl-2-Cyclopropyl-1-(2-Fluorobenzyl)Benzimidazole
[0365] By using the method of example 111,
6-benzenesulfonylcarbamoyl-2-cy-
clopropyl-1-(2-fluorobenzyl)benzimidazole (0.730 g) is obtained
from 6-carboxy-2-cyclopropyl-1-(2-fluorobenzyl)benzimidazole (0.930
g) (example 18), N,N'-carbonyldiimidazole (0.972 g),
benzenesulfonamide (0.942 g) and diazabicycloundecene (0.906 g).
.sup.1H-NMR (DMSO-d6, .delta.): 1.04 (4H, m), 2.15 (1H, m), 5.70
(2H, s), 6.85 (1H, t, J=7.5 Hz), 7.12 (1H, t, J=7.5 Hz), 7.22-7.38
(2H, m), 7.54-7.70 (5H, m), 7.99 (2H, d, J=7.5 Hz), 8.11 (1H,
s).
[0366] White Powder
[0367] (R.sub.1=2-fluorobenzyl, R.sub.2=cyclopropyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=phenyl, n=1, y=0)
Example 126
N-Benzenesulfonyl-3-[1-(2-Chlorobenzyl)-2-Methylbenzimidazole-6-yl]Acrylam-
ide
[0368] By using the method of example 111,
N-benzenesulfonyl-3-[1-(2-chlor-
obenzyl)-2-methylbenzimidazole-6-yl]acrylamide (1.05 g) is obtained
from 1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acrylic acid (1.10
g) (example 110), N,N'-carbonyldiimidazole (1.09 g),
benzenesulfonamide (1.06 g) and diazabicycloundecene (1.02 g).
.sup.1H-NMR (DMSO-d.sub.6, .delta.): 2.47 (3H, s), 5.55 (2H, s),
6.46-6.55 (2H, m), 7.22 (1H, t, J=7.6 Hz), 7.32 (1H, t, J=7.7 Hz),
7.40 (1H, d, J=8.4 Hz), 7.52-7.66 (6H, m), 7.69 (1H, t), 7.93 (2H,
d, J=7.9 Hz), 12.17 (1H, br s).
[0369] IR(KBr): 1687 cm.sup.-1.
[0370] Mass(FAB): m/e 466(M+1).
[0371] mp: 243.1-244.3.degree. C.
[0372] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=benzenesulfonylcar- bamoylethenyl, n=1, y=0)
Example 127
1-(2,4-Dichlorobenzyl)-2-Methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazol-
e
[0373] Dichloromethane (150 ml) and a few drops of
N-dimethylformamide are added to
6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (9.00 g)
(example 87), and the solution is chilled with ice. Oxalyl chloride
(6.84 g) is dripped into the solution, which is then stirred for a
few minutes. After the solution is further stirred for 1.5 hours at
room temperature, the solution is concentrated under reduced
pressure to a third of its original volume. Precipitants are
collected and added to a dichloromethane (200 ml) solution of
2-aminomethylpyridine (2.69 g) and triethylamine (7.34 g) over a
few doses while it is chilled with ice. After the solution is
stirred for 15 hours, the reaction solution is washed with water
three times, and is further washed with a saturated sodium
bicarbonate aqueous solution. The organic layer is concentrated
under reduced pressure, and crystals are formed using ethyl
acetate. When crystals are separated through filtration and dried,
1-(2,4-dichlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazo-
le (4.35 g) is obtained. .sup.1H-NMR (CDCl.sub.3, .delta.): 2.56
(3H, s), 4.76 (2H, d, J=4.8 Hz), 5.40 (2H, s), 6.33 (1H, d, J=8.4
Hz), 7.07 (1H, dd, J=8.4 and 2.0 Hz), 7.22 (1H, dd, J=7.4 and 4.9
Hz), 7.33 (1H, d, J=7.9 Hz), 7.48 (1H, d, J=2.1 Hz), 7.62-7.79 (4H,
m), 7.86 (1H, d, J=1.1 Hz), 8.57 (1H, d, J=4.9 Hz).
[0374] IR(KBr): 1645 cm.sup.-1.
[0375] mp: 204.5-206.5.degree. C.
[0376] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=cyclopropyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl, R.sub.5=H,
n=1, y=0)
Example 128
1-Methyl-2-n-Propyl-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
[0377] By using the method of example 127,
1-methyl-2-n-propyl-6-[(2-pyrid- ylmethyl)carbamoyl]benzimidazole
(0.213 g) is obtained from
6-carboxy-1-methyl-2-n-propylbenzimidazole (0.402 g), oxalyl
chloride (0.468 g), 2-aminomethylpyridine (0.199 g) and
triethylamine (0.559 g). .sup.1H-NMR (CDCl.sub.3, .delta.): 1.08
(3H, t, J=7.4 Hz), 1.92 (2H, m), 2.88 (2H, m), 3.76 (3H, s), 4.80
(2H, d, J=4.8 Hz), 7.22 (1H, dd, J=2.5 and 7.5 Hz), 7.35 (1H, d,
J=7.8 Hz), 7.67-7.77 (4H, m), 7.80 (1H, s), 8.58 (1H, dd, J=4.9 and
0.9 Hz).
[0378] IR(KBr): 1647 cm.sup.-1.
[0379] mp: 140.5-141.5.degree. C.
[0380] (R.sub.1=methyl, R.sub.2=n-propyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl, R.sub.5=H,
n=1, y=0)
Example 129
1-(2-Chlorobenzyl)-2-Methyl-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
[0381] By using the method of example 127,
1-(2-chlorobenzyl)-2-methyl-6-[-
(2-pyridylmethyl)carbamoyl]benzimidazole (0.164 g) is obtained from
6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (0.300 g)
(example 75), oxalyl chloride (0.253 g), 2-aminomethylpyridine
(0.108 g) and triethylamine (0.302 g). .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.56 (3H, s), 4.76 (2H, d, J=4.8 Hz), 5.45 (2H, s), 6.40
(1H, d, J=7.8 Hz), 7.08 (1H, t, J=7.6 Hz), 7.20-7.27 (2H, m), 7.33
(1H, d, J=7.8 Hz), 7.45 (1H, dd, J=0.9 and 8.1 Hz), 7.64 (1H, s),
7.65-7.69 (1H, m), 7.72 (1H, dd, J=1.5 and 8.4 Hz), 7.77 (1H, d,
J=8.4 Hz), 7.88 (1H, d, J=1.2 Hz), 8.56 (1H, d, J=4.7 Hz).
[0382] IR(KBr): 1646 cm.sup.-1.
[0383] mp: 156.5-157.5.degree. C.
[0384] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=2-pyridylmethyl,
R.sub.5=H, n=1, y=0)
Example 130
2-n-Propyl-1-i-Propyl-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
[0385] By using the method of example 127,
2-n-propyl-1-i-propyl-6-[(2-pyr- idylmethyl)carbamoyl]benzimidazole
(0.020 g) is obtained from
6-carboxy-2-n-propyl-1-i-propylbenzimidazole (0.095 g) (example
73), oxalyl chloride (0.100 g), 2-aminomethylpyridine (0.039 g) and
triethylamine (0.097 g). .sup.1H-NMR (CDCl.sub.3, .delta.): 1.08
(3H, t, J=7.4 Hz), 1.69 (6H, d, J=7.1 Hz), 1.87-1.93 (2H, m), 2.90
(2H, t, J=7.8 Hz), 4.69-4.75 (1H, m), 4.80 (2H, d, J=4.9 Hz), 7.23
(1H, dd, J=7.3 and 2.1 Hz), 7.37 (1H, d, J=7.7 Hz), 7.62-7.77 (4H,
m), 8.21 (1H, s), 8.58 (1H, d, J=4.5 Hz).
[0386] IR(KBr): 1631 cm.sup.-1.
[0387] mp: 155.0-156.9.degree. C.
[0388] (R.sub.1=i-propyl, R.sub.2=n-propyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl, R.sub.5=H,
n=1, y=0)
Example 131
1-n-Butyl-2-n-Propyl-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
[0389] By using the method of example 127,
1-n-butyl-2-n-propyl-6-[(2-pyri- dylmethyl)carbamoyl]benzimidazole
(0.283 g) is obtained from
1-n-butyl-6-carboxy-2-n-propylbenzimidazole (0.500 g), oxalyl
chloride (0.487 g), 2-aminomethylpyridine (0.208 g) and
triethylamine (0.582 g). .sup.1H-NMR (CDCl.sub.3, .delta.): 0.97
(3H, t, J=7.3 Hz), 1.08 (3H, t, J=7.4 Hz), 1.37-1.46 (2H, m),
1.76-1.83 (2H, m), 1.92-2.0 (2H, m), 2.86 (2H, t, J=7.8 Hz), 4.15
(2H, t, J=7.6 Hz), 4.81 (2H, d, J=4.8 Hz), 7.23 (1H, dd, J=7.3 and
2.4 Hz), 7.36 (1H, d, J=7.8 Hz), 7.63-7.76 (4H, m), 8.02 (1H, s),
8.58 (1H, d, J=4.7 Hz).
[0390] IR(KBr): 1631 cm.sup.-1.
[0391] mp: 105.8-107.2.degree. C.
[0392] (R.sub.1=n-butyl, R.sub.2=n-propyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl, R.sub.5=H,
n=1, y=0)
Example 132
1-(3-Chlorobenzyl)-2-n-Propyl-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
[0393] By using the method of example 127),
1-(3-chlorobenzyl)-2-n-propyl--
6-[(2-pyridylmethyl)carbamoyl]benzimidazole (0.311 g) is obtained
from 6-carboxy-1-(3-chlorobenzyl)-2-n-propylbenzimidazole (0.580 g)
(example 81), oxalyl chloride (0.407 g), 2-aminomethylpyridine
(0.173 g) and triethylamine (0.486 g). .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.03 (3H, t, J=7.4 Hz), 1.85-1.93 (2H, m), 2.80 (2H, t,
J=7.5 Hz), 4.77 (2H, d, J=4.8 Hz), 5.36 (2H, s), 6.86 (1H, d, J=7.4
Hz), 7.02 (1H, s), 7.20-7.28 (3H, m), 7.33 (1H, d, J=7.8 Hz),
7.63-7.73 (3H, m), 7.79 (1H, d, J=8.4 Hz), 7.91 (1H, d, J=1.3 Hz),
8.57 (1H, d, J=4.7 Hz).
[0394] IR(KBr): 1643 cm.sup.-1.
[0395] mp: 157.7-158.8.degree. C.
[0396] (R.sub.1=3-chlorobenzyl, R.sub.2=n-propyl,
R.sub.3=--C(O)NR.sub.4R.- sub.5, R.sub.4=2-pyridylmethyl,
R.sub.5=H, n=1, y=0)
Example 133
1-Benzyl-2-n-Propyl-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
[0397] By using the method of example 127,
1-benzyl-2-n-propyl-6-[(2-pyrid- ylmethyl)carbamoyl]benzimidazole
(0.350 g) is obtained from
1-benzyl-6-carboxy-2-n-propylbenzimidazole (0.850 g) (example 80),
oxalyl chloride (0.949 g), 2-aminomethylpyridine (0.404 g) and
triethylamine (1.132 g). .sup.1H-NMR (CDCl.sub.3, .delta.): 1.01
(3H, t, J=7.4 Hz), 1.83-1.92 (2H, m), 2.82 (2H, t, J=7.6 Hz), 4.77
(2H, d, J=4.8 Hz), 5.40 (2H, s), 7.03 (2H, d, J=6.5 Hz), 7.21 (1H,
dd, J=7.1 and 2.1 Hz), 7.18-7.34 (4H, m), 7.60 (1H, s), 7.65-7.72
(2H, m), 7.78 (1H, d, J=8.4 Hz), 7.94 (1H, d, J=1.2 Hz), 8.56 (1H,
d, J=4.2 Hz).
[0398] IR(KBr): 1642 cm.sup.-1.
[0399] mp: 121.9-123.1.degree. C.
[0400] (R.sub.1=benzyl, R.sub.2=n-propyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl, R.sub.5=H,
n=1, y=0)
Example 134
2-Benzyl-6-Carboxy-1-Methylbenzimidazole Hydrochloride
[0401] To an ethanol (4 ml) solution of
2-benzyl-6-ethoxycarbonyl-1-methyl- benzimidazole (0.340 g), 5%
sodium hydroxide aqueous solution (2.8 g) is added, and the
solution is refluxed by heating for 1.5 hours. The solution is made
acidic using 1N hydrochloric acid and concentrated under reduced
pressure. Ethanol is added to the residue and organic materials are
extracted. The ethanol is removed under reduced pressure and thus,
2-benzyl-6-carboxy-1-methylbenzimidazole hydrochloride (0.300 g) is
obtained. .sup.1H-NMR (DMSO-d6, .delta.): 4.00 (3H, s), 4.62 (2H,
s), 7.33 (1H, m), 7.35-7.45 (4H, m), 7.83 (1H, d, J=8.4 Hz), 8.06
(1H, d, J=8.4 Hz), 8.42 (1s), 13.3 (1H, br s).
[0402] (R.sub.1=benzyl, R.sub.2=methyl, R.sub.3=carboxyl, n=1,
y=0)
Example 135
1-(4-Chlorobenzyl)-2-Propyl-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
[0403] By using the method of example 127,
1-(4-chlorobenzyl)-2-propyl-6-[-
(2-pyridylmethyl)carbamoyl]benzimidazole (0.089 g) is obtained from
6-carboxy-1-(4-chlorobenzyl)-2-propylbenzimidazole (0.547 g)
(example 71), oxalyl chloride (0.384 g), 2-aminomethylpyridine
(0.163 g) and triethylamine (0.458 g). .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.02 (3H, t, J=7.4 Hz), 1.84-1.92 (2H, m), 2.77-2.83 (2H,
m), 4.76 (2H, d, J=4.8 Hz), 5.36 (2H, s), 6.96 (2H, d, J=8.3 Hz),
7.22 (1H, dd, J=6.4 and 0.4 Hz), 7.27 (2H, dd, J=8.3 and 1.3 Hz),
7.33 (1H, d, J=7.8 Hz), 7.62-7.73 (3H, m), 7.78 (1H, d, J=8.4 Hz),
7.91 (1H, d, J=0.9 Hz), 8.56 (1H, dd, J=4.9 and 0.8 Hz).
[0404] IR(KBr): 1643 cm.sup.-1.
[0405] mp: 158.8-161.0.degree. C.
[0406] (R.sub.1=3-chlorobenzyl, R.sub.2=propyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=2-pyridylmethyl,
R.sub.5=H, n=1,y=0)
Example 136
1-(2,6-Dichlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazol-
e
[0407] By using the method of example 127,
1-(2,6-dichlorobenzyl)-2-methyl-
-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (0.040 g) is obtained
from 6-carboxy-1-(2,6-dichlorobenzyl)-2-methylbenzimidazole (0.600
g) (example 76), oxalyl chloride (0.472 g), 2-aminomethylpyridine
(0.201 g) and triethylamine (0.188 g). .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.62 (3H, s), 4.76 (2H, d, J=4.7 Hz), 5.62 (2H, s), 7.23
(1H, dd, J=7.1 and 2.2 Hz), 7.28 (1H, d, J=7.8 Hz), 7.32 (1H, d,
J=7.9 Hz), 7.39 (2H, d, J=8.1 Hz), 7.54 (1H, s), 7.66-7.71 (3H, m),
7.78 (1H, s), 8.60 (1H, d, J=4.6 Hz).
[0408] IR(KBr): 1635 cm.sup.-1.
[0409] mp: 225.7-226.9.degree. C.
[0410] (R.sub.1=2,6-dichlorobenzyl, R.sub.2=propyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl, R.sub.5=H,
n=1, y=0)
Example 137
2-Methyl-6-[(2-Pyridylmethyl)Carbamoyl]-1-[2-(Trifluoromethyl)Benzyl]Benzi-
midazole
[0411] By using the method of example 127,
2-methyl-6-[(2-pyridylmethyl)ca-
rbamoyl]-1-[2-(trifluoromethyl)benzyl]benzimidazole (0.713 g) is
obtained from
6-carboxy-2-methyl-1-[2-(trifluoromethyl)benzyl]benzimidazole
(0.970 g) (example 77), oxalyl chloride (0.736 g),
2-aminomethylpyridine (0.261 g) and triethylamine (0.726 g).
.sup.1H-NMR (CDCl.sub.3, .delta.): 2.54 (3H, s), 4.76 (2H, d, J=4.8
Hz), 5.59 (2H, s), 6.45 (1H, d, J=7.9 Hz), 7.22 (1H, d, J=5.8 Hz),
7.34 (2H, t, J=8.8 Hz), 7.40 (1H, t, J=7.5 Hz), 7.62 (1H, br s),
7.68 (1H, dt, J=1.7 and 7.7 Hz), 7.72-7.82 (3H, m), 7.87 (1H, s),
8.56 (1H, d, J=4.9 Hz).
[0412] IR(KBr): 1648 cm.sup.-1.
[0413] mp: 172-174.degree. C.
[0414] (R.sub.1=2-trifluoromethylbenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl, R.sub.5=H,
n=1, y=0)
Example 138
2-Methyl-6-[(2-Pyridylmethyl)Carbamoyl]-1-[4-(Trifluoromethyl)benzyl]Benzi-
midazole
[0415] By using the method of example 127,
2-methyl-6-[(2-pyridylmethyl)ca-
rbamoyl]-1-[4-(trifluoromethyl)benzyl]benzimidazole (0.194 g) is
obtained from
6-carboxy-2-methyl-1-[4-(trifluoromethyl)benzyl]benzimidazole
(0.970 g) (example 78), oxalyl chloride (0.736 g),
2-aminomethylpyridine (0.261 g) and triethylamine (0.726 g).
.sup.1H-NMR (CDCl.sub.3, .delta.): 2.59 (3H, s), 4.77 (2H, d, J=4.7
Hz), 5.45 (2H, s), 7.15 (2H, d, J=8.2 Hz), 7.23 (1H, m), 7.33 (1H,
d, J=7.9 Hz), 7.58 (2H, d, J=8.2 Hz), 7.63 (1H, br s), 7.67-7.74
(2H, m), 7.77 (1H, d, J=8.3 Hz), 7.93 (1H, s), 8.57 (1H, d, J=4.9
Hz).
[0416] IR(KBr): 1637 cm.sup.-1.
[0417] mp: 188.5-190.0.degree. C.
[0418] (R.sub.1=2-trifluoromethylbenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl, R.sub.5=H,
n=1, y=0)
Example 139
1-(3,4-Dichlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazol-
e
[0419] By using the method of example 127,
1-(3,4-dichlorobenzyl)-2-methyl-
-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (0.264 g) is obtained
from 6-carboxy-1-(3,4-dichlorobenzyl)-2-methylbenzimidazole (0.500
g) (example 79), oxalyl chloride (0.393 g), 2-aminomethylpyridine
(0.167 g) and triethylamine (0.469 g). .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.58 (3H, s), 4.77 (2H, d, J=4.8 Hz), 5.33 (2H, s), 6.85
(1H, dd, J=8.3 and 2.2 Hz), 7.14 (1H, d, J=2.1 Hz), 7.22 (1H, dd,
J=7.3 and 5.6 Hz), 7.33 (1H, d, J=7.8 Hz), 7.38 (1H, d, J=8.3 Hz),
7.65-7.77 (4H, m), 7.92 (1H, d, J=1.2 Hz), 8.57 (1H, d, J=4.8
Hz).
[0420] IR(KBr): 1638 cm.sup.-1.
[0421] mp: 219.0-220.7.degree. C.
[0422] (R.sub.1=3,4-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl, R.sub.5=H,
n=1, y=0)
Example 140
2-Methyl-1-(2-Methylbenzyl)-6-[(2-pyridylmethyl)Carbamoyl]Benzimidazole
[0423] By using the method of example 127,
2-methyl-1-(2-methylbenzyl)-6-[-
(2-pyridylmethyl)carbamoyl]benzimidazole (0.100 g) is obtained from
6-carboxy-2-methyl-1-(2-methylbenzyl)benzimidazole (0.453 g)
(example 90), oxalyl chloride (0.41 1 g), 2-aminomethylpyridine
(0.175 g) and triethylamine (0.490 g). .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.42 (3H, s), 2.54 (3H, s), 4.75 (2H, d, J=4.9 Hz), 5.32
(2H, s), 6.33 (1H, d, J=7.8 Hz), 7.01 (1H, t, J=7.8 Hz), 7.17-7.24
(3H, m), 7.33 (1H, d, J=7.8 Hz), 7.60 (1H, s), 7.63-7.73 (2H, m),
7.76 (1H, d, J=8.4 Hz), 7.84 (1H, d, J=1.4 Hz), 8.56 (1H, d, J=4.9
Hz).
[0424] IR(KBr): 1635 cm.sup.-1.
[0425] mp: 154.0-157.0.degree. C.
[0426] (R.sub.1=2-methylbenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=2-pyridylmethyl,
R.sub.5=H, n=1, y 0)
Example 141
1-(2-Methoxybenzyl)-2-Methyl-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
[0427] By using the method of example 127,
1-(2-methoxybenzyl)-2-methyl-6--
[(2-pyridylmethyl)carbamoyl]benzimidazole (0.918 g) is obtained
from 6-carboxy-1-(2-methoxybenzyl)-2-methylbenzimidazole (0.997 g)
(example 91), oxalyl chloride (0.858 g), 2-aminomethylpyridine
(0.309 g) and triethylamine (1.02 g). .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.60 (3H, s), 3.89 (3H, s), 4.77 (2H, d, J=4.8 Hz), 5.36
(2H, s), 6.60 (1H, d, J=7.4 Hz), 6.79 (1H, dt, J=0.8 and 7.4 Hz),
6.91 (1H, d, J=7.4 Hz), 7.20-7.28 (2H, m), 7.34 (1H, d, J=7.9 Hz),
7.56 (1H, br t), 7.66-7.75 (3H, m), 7.95 (1H, m), 8.57 (1H, d,
J=4.9 Hz).
[0428] IR(KBr): 1652 cm.sup.-1.
[0429] mp: 136-138.5.degree. C.
[0430] (R.sub.1=2-methoxybenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.s- ub.5, R.sub.4=2-pyridylmethyl,
R.sub.5=H, n=1, y=0)
Example 142
1-(4-Methoxybenzyl)-2-Methyl-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
[0431] By using the method of example 127,
1-(4-methoxybenzyl)-2-methyl-6--
[(2-pyridylmethyl)carbamoyl]benzimidazole (0.697 g) is obtained
from 6-carboxy-1-(4-methoxybenzyl)-2-methylbenzimidazole (0.985 g)
(example 92), oxalyl chloride (0.858 g), 2-aminomethylpyridine
(0.309 g) and triethylamine (1.02 g). .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.59 (3H, s), 3.76 (3H, s), 4.78 (2H, d, J=4.8 Hz), 5.32
(2H, s), 6.83 (2H, m), 7.00 (2H, m), 7.22 (1H, dd, J=5.1 and 6.8
Hz), 7.34 (1H, d, J=7.8 Hz), 7.60 (1H, br t), 7.67-7.76 (3H, m),
7.97 (1H, d, J=1.2 Hz), 8.57 (1H, d, J=4.9 Hz).
[0432] IR(KBr): 1652 cm.sup.-1.
[0433] mp: 191.5-192.2.degree. C.
[0434] (R=4-methoxybenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl, R.sub.5=H,
n=1, y=0)
Example 143
1-[2-(Benzenesulfonylmethyl)Benzyl]-2-Methyl-6-[(2-Pyridylmethyl)Carbamoyl-
]Benzimidazole
[0435] By using the method of example 127,
1-[2-(benzenesulfonylmethyl)ben-
zyl]-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (0.64 g)
is obtained from
1-[2-(benzenesulfonylmethyl)benzyl]-6-carboxy-2-methylbenzi-
midazole (0.74 g), oxalyl chloride (0.45 g), 2-aminomethylpyridine
(0.19 g) and triethylamine (0.53 g). .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.57 (3H, s), 4.50 (2H, s), 4.74 (2H, d, J=4.9 Hz), 5.59
(2H, s), 6.63 (1H, d, J=7.7 Hz), 6.87 (1H, d, J=7.4 and 1.5 Hz),
7.09-7.19 (3H, m), 7.31 (1H, d, J=7.8 Hz), 7.53-7.61 (3H, m), 7.64
(1H, dt, J=7.6 and 1.6 Hz), 7.68-7.79 (5H, m), 7.84 (1H, s), 8.52
(1H, d, J=4.8 Hz).
[0436] IR(neat): 1646 cm.sup.-1.
[0437] Liquid.
[0438] (R.sub.1=2-(benzenesulfonylmethyl)benzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl, R.sub.5=H,
n=1, y=0)
Example 144
1-(2-Cyanobenzyl)-2-Methyl-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
[0439] By using the method of example 127,
1-(2-cyanobenzyl)-2-methyl-6-[(-
2-pyridylmethyl)carbamoyl]benzimidazole (1.03 g) is obtained from
6-carboxy-1-(2-cyanobenzyl)-2-methylbenzimidazole (1.14 g) (example
94), oxalyl chloride (0.998 g), 2-aminomethylpyridine (0.425 g) and
triethylamine (1.19 g). .sup.1H-NMR (CDCl.sub.3, .delta.): 2.58
(3H, s), 4.76 (2H, d, J=4.8 Hz), 5.59 (2H, s), 6.64 (1H, d, J=7.4
Hz), 7.21 (1H, dt, J=5.6 and 1.8 Hz), 7.33 (1H, d, J=7.9 Hz),
7.39-7.47 (2H, m), 7.65-7.79 (5H, m), 7.89 (1H, s), 8.56 (1H, dd,
J=4.9 and 0.9 Hz).
[0440] IR(KBr): 2223, 1642 cm.sup.-1.
[0441] mp: 150.5-151.4.degree. C.
[0442] (R.sub.1=2-cyanobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub- .5, R.sub.4=2-pyridylmethyl,
R.sub.5=H, n=1, y=0)
Example 145
1-(Biphenyl-2-ylmethyl)-2-Methyl-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazo-
le
[0443] By using the method of example 127,
1-(biphenyl-2-ylmethyl)-2-methy-
l-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (0.672 g) is obtained
from 1-(biphenyl-2-ylmethyl)-6-carboxy-2-methylbenzimidazole (1.07
g), oxalyl chloride (0.796 g), 2-aminomethylpyridine (0.339 g) and
triethylamine (0.950 g).
[0444] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.38 (3H, s), 4.78 (2H,
d, J=4.8 Hz), 5.27 (2H, s), 6.64 (1H, d, J=8.0 Hz), 7.17-7.24 (2H,
m), 7.29-7.43 (6H, m), 7.48 (2H, t, J=5.5 Hz), 7.49 (1H, s),
7.57-7.73 (3H, m), 7.80 (1H, d, J=1.0 Hz), 8.58 (1H, d, J=4.9
Hz).
[0445] IR(KBr): 1630, 1619 cm.sup.-1.
[0446] mp: 179.8-180.8.degree. C.
[0447] (R.sub.1=2-biphenyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl, R.sub.5=H,
n=1, y=1)
Example 146
1-Benzyl-2-methyl-6-[(2-pyridylmethylcarbamoyl]benzimidazole
[0448] By using the method of example 127,
1-benzyl-2-methyl-6-[(2-pyridyl- methyl)carbamoyl]benzimidazole
(0.66 g) is obtained from 1-benzyl-6-carboxy-2-methylbenzimidazole
(0.59 g) (example 96), oxalyl chloride (0.56 g),
2-aminomethylpyridine (0.24 g) and triethylamine (0.67 g).
.sup.1H-NMR (CDCl.sub.3, .delta.): 2.58 (3H, s), 4.76 (2H, d, J=4.9
Hz), 5.36 (2H, s), 7.02-7.06 (2H, m), 7.21 (1H, dd, J=6.9 and 5.0
Hz), 7.27-7.35 (4H, m), 7.65-7.75 (4H, m), 7.96 (1H, d, J=0.8 Hz),
8.56 (1H, d, J=4.8 Hz).
[0449] IR(KBr): 1640 cm.sup.-1.
[0450] mp: 124.0-124.9.degree. C.
[0451] (R.sub.1=benzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl, R.sub.5=H,
n=1, y=0)
Example 147
1-(4-t-Butylbenzyl)-2-Methyl-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
[0452] By using the method of example 127,
1-(4-t-butylbenzyl)-2-methyl-6--
[(2-pyridylmethyl)carbamoyl]benzimidazole (0.477 g) is obtained
from 1-(4-t-butylbenzyl)-6-carboxy-2-methylbenzimidazole (0.544 g)
(example 89), oxalyl chloride (0.428 g), 2-aminomethylpyridine
(0.183 g) and triethylamine (0.511 g). .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.27 (9H, s), 2.60 (3H, s), 4.77 (2H, d, J=4.9 Hz), 5.34
(2H, s), 6.98 (2H, d, J=8.3 Hz), 7.21 (1H, dd, J=7.3 and 5.1 Hz),
7.29-7.35 (3H, m), 7.62 (1H, br.s), 7.65-7.75 (3H, m), 7.96 (1H, d,
J=1.1 Hz), 8.57 (1H, d, J=4.7 Hz).
[0453] IR(KBr): 1646 cm.sup.-1.
[0454] mp: 140.4-142.8.degree. C.
[0455] (R.sub.1=4-t-butylbenzyl, R.sub.2=methyl, R.sub.3=-carboxyl,
n=1, y=0)
Example 148
2-Methyl-1-(2-Naphthylmethyl)-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
[0456] By using the method of example 127,
2-methyl-1-(2-naphthylmethyl)-6-
-[(2-pyridylmethyl)carbamoyl]benzimidazole (0.47 g) is obtained
from 6-carboxy-2-methyl-1-(2-naphthylmethyl)benzimidazole (0.80 g)
(example 97), oxalyl chloride (0.64 g), 2-aminomethylpyridine (0.27
g) and triethylamine (0.77 g). .sup.1H-NMR (CDCl.sub.3, .delta.):
2.60 (3H, s), 4.75 (2H, d, J=4.9 Hz), 5.52 (2H, s), 7.17-7.23 (2H,
m), 7.31 (1H, d, J=7.8 Hz), 7.38 (1H, s), 7.43-7.48 (2H, m),
7.60-7.82 (7H, m), 8.00 (1H, d, J=1.0 Hz), 8.53 (1H, d, J=4.7
Hz).
[0457] IR(KBr): 1640 cm.sup.-1.
[0458] mp: 143.0-144.5.degree. C.
[0459] (R.sub.1=2-naphthylmethyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.- sub.5, R.sub.4=2-pyridylmethyl,
R.sub.5=H, n=1, y=0)
Example 149
1-(Biphenyl-4-ylmethyl)-2-Ethyl-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazol-
e
[0460] By using the method of example 127,
1-(biphenyl-4-ylmethyl)-2-ethyl-
-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (0.410 g) is obtained
from 1-(biphenyl-4-ylmethyl)-6-carboxy-2-ethylbenzimidazole (0.500
g) (example 98), oxalyl chloride (0.356 g), 2-aminomethylpyridine
(0.151 g) and triethylamine (0.424 g). .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.45 (3H, t, J=7.7 Hz), 2.90 (2H, q, J=7.4 Hz), 4.77 (2H,
d, J=4.7 Hz), 5.43 (2H, s), 7.10 (2H, d, J=8.2 Hz), 7.20 (1H, dt,
J=4.9 and 7.7 Hz), 7.33 (2H, t, J=7.4 Hz), 7.42 (2H, t, J=7.5 Hz),
7.49-7.55 (4H, m), 7.61 (1H, br t), 7.67 (1H, dt, J=7.8 and 1.8
Hz), 7.72 (1H, d, J=8.4 Hz), 7.81 (1H, d, J=8.4 Hz), 7.99 (1H, s),
8.56 (1H, d, J=4.9 Hz).
[0461] IR(KBr): 1640 cm.sup.-1.
[0462] mp: 123.0-124.0.degree. C.
[0463] (R.sub.1=4-biphenyl, R.sub.2=ethyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl, R.sub.5=H,
n=1, y=1)
Example 150
1-(2-Chlorobenzyl)-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
[0464] By using the method of example 127,
1-(2-chlorobenzyl)-6-[(2-pyridy- lmethyl)carbamoyl]benzimidazole
(0.110 g) is obtained from
6-carboxy-1-(2-chlorobenzyl)benzimidazole (0.461 g), oxalyl
chloride (0.728 g), 2-aminomethylpyridine (0.174 g) and
triethylamine (0.486 g). .sup.1H-NMR (CDCl.sub.3, .delta.): 4.78
(2H, t, J=4.8 Hz), 5.51 (2H, s), 6.92 (1H, d, J=6.5 Hz), 7.17-7.31
(3H, m), 7.34 (1H, d, J=7.8 Hz), 7.45 (1H, dd, J=1.1 and 8.0 Hz),
7.69 (1H, dt, J=1.8 and 7.7 Hz), 7.67-7.73 (1H, br s), 7.76 (1H,
dd, J=1.5 and 8.4 Hz), 7.87 (1H, d, J=8.4 Hz), 8.05 (2H, s), 8.57
(1H, d, J=4.9 Hz).
[0465] IR(KBr): 1646 cm.sup.-1.
[0466] mp: 144.0-145.0.degree. C.
[0467] (R.sub.1=2-chlorobenzyl, R.sub.2=H,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl, R.sub.5=H,
n=1, y=0)
Example 151
2-Methyl-1-(2-Nitrobenzyl)-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
[0468] By using the method of example 127,
2-methyl-1-(2-nitrobenzyl)-6-[(-
2-pyridylmethyl)carbamoyl]benzimidazole (0.241 g) is obtained from
6-carboxy-2-methyl-1-(2-nitrobenzyl)benzimidazole (0.367 g)
(example 85), oxalyl chloride (0.299 g), 2-aminomethylpyridine
(0.217 g) and triethylamine (0.360 g). .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.56 (3H, s), 4.75 (2H, t, J=4.8 Hz), 5.83 (2H, s), 6.41
(1H, d, J=7.8 and 1.2 Hz), 7.22 (1H, dt, J=5.0 and 1.7 Hz), 7.32
(1H, d, J=7.9 Hz), 7.43-7.52 (2H, m), 7.64 (1H, s), 7.68 (1H, dt,
J=7.6 and 1.7 Hz), 7.75 (1H, dd, J=8.4 and 1.5 Hz), 7.80 (1H, d,
J=8.4 Hz), 7.82 (1H, d, J=1.3 Hz), 8.28 (1H, dd, J=8.0 and 1.7 Hz),
8.56 (1H, d, J=4.9 Hz).
[0469] IR(KBr): 1645 cm.sup.-1.
[0470] mp: 194.8-196.7.degree. C.
[0471] (R.sub.1=2-nitrobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub- .5, R.sub.4=2-pyridylmethyl,
R.sub.5=H, n=1, y=0)
Example 152
2-Methyl-1-(2-nitrobenzyl)-5-[(2-pyridylmethyl)carbamoyl]benzimidazole
[0472] By using the method of example 127,
2-methyl-1-(2-nitrobenzyl)-5-[(-
2-pyridylmethyl)carbamoyl]benzimidazole (0.079 g) is obtained from
5-carboxy-2-methyl-1-(2-nitrobenzyl)benzimidazole (0.096 g), oxalyl
chloride (0.078 g), 2-aminomethylpyridine (0.048 g) and
triethylamine (0.093 g). .sup.1H-NMR (CDCl.sub.3, .delta.): 2.57
(3H, s), 4.80 (2H, d, J=4.7 Hz), 5.80 (2H, s), 6.43 (1H, d, J=7.4
and 0.8 Hz), 7.17 (1H, d, J=8.4 Hz), 7.22 (1H, dt, J=5.5 and 1.8
Hz), 7.35 (1H, d, J=7.8 Hz), 7.44-7.52 (2H, m), 7.67 (1H, s), 7.69
(1H, dt, J=7.8 and 1.9 Hz), 7.82 (1H, dd, J=8.4 and 1.5 Hz), 8.27
(1H, dd, J=8.0 and 1.6 Hz), 8.28 (1H, d, J=1.4 Hz), 8.56 (1H, d,
J=4.9 Hz).
[0473] IR(KBr): 1645 cm.sup.-1.
[0474] mp: .about.96.degree. C. (accompanied with
decomposition).
[0475] (R.sub.1=2-nitrobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub- .5, R.sub.4=2-pyridylmethyl,
R.sub.5=H, n=1, y=0)
Example 153
1-(2-Chlorobenzyl)-2-Methyl-6-(2-Naphthalenesulfonylcarbamoyl]Benzimidazol-
e Sodium Salt
[0476] N,N'-carbonyldiimidazole (0.541 g) is added all at once to
an N,N-dimethylformamide (20 ml) solution of
6-carboxy-1-(2-chlorobenzyl)-2-- methylbenzimidazole (0.500 g)
(example 75), and the solution is stirred for one hour at room
temperature. Subsequently, an N,N-dimethylformamide (5 ml) solution
of 2-naphthalenesulfonamide (0.689 g) and diazabicycloundecene
(0.506 g) is added, and the solution is stirred for 48 hours at
100.degree. C. The reaction solution is cooled and the solvent is
removed through evaporation under reduced pressure. Water and
chloroform are added to the residue. 10% hydrochloric acid is added
until the aqueous layer became acidic. Chloroform extraction is
performed (twice) and to the resultant organic layer, a saturated
sodium bicarbonate aqueous solution is added. The solution is
stirred. Precipitated crystals are separated through filtration and
are dissolved in a small amount of methanol. Further, ethyl acetate
is added and crystallization is performed. The crystals are
separated through filtration, dried, and thus,
1-(2-chlorobenzyl)-2-methyl-6-(2-naphthalene-
sulfonylcarbamoyl]benzimidazole sodium salt (206) (0.508 g) is
obtained.
[0477] .sup.1H-NMR (DMSO-d6, .delta.): 2.46 (3H, s), 5.51 (2H, s),
6.38 (1H, d, J=7.9 Hz), 7.17 (1H, t, J=7.5 Hz), 7.30 (1H, t), 7.45
(1H, d, J=8.5 Hz), 7.51-7.57 (3H, m), 7.77-7.93 (5H, m), 7.99 (1H,
m), 8.35 (1H, s).
[0478] IR(KBr): 1594 cm.sup.-1.
[0479] Mass(FAB): m/e 512(M+1).
[0480] mp: 352.0-354.5.degree. C.
[0481] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=2-naphthyl, n=1, y=0)
Example 154
1-(2-Chlorobenzyl)-2-Methyl-6-(1-Naphthalenesulfonylcarbamoyl]Benzimidazol-
e Sodium Salt
[0482] By using the method of example 153,
1-(2-chlorobenzyl)-2-methyl-6-(-
1-naphthalenesulfonylcarbamoyl]benzimidazole sodium salt (0.390 g)
is obtained from 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole
(0.600 g) (example 75), N,N'-carbonyldiimidazole (0.647 g),
1-naphthalenesulfonamide (0.829 g) and diazabicycloundecene (0.608
g). .sup.1H-NMR (DMSO-d6, .delta.): 2.46 (3H, s), 5.49 (2H, s),
6.39 (1H, d, J=7.8 Hz), 7.16 (1H, t, J=7.5 Hz), 7.31 (1H, t, J=7.3
Hz), 7.36 (1H, t), 7.40-7.45 (2H, m), 7.50 (1H, t, J=7.7 Hz), 7.54
(1H, d, J=8.0 Hz), 7.75-7.81 (2H, m), 7.87 (1H, d, J=7.9 Hz), 7.93
(1H, d, J=8.2 Hz), 8.09 (1H, d, J=7.3 Hz), 8.86 (1H, d, J=8.5
Hz).
[0483] IR(KBr): 1633 cm.sup.-1.
[0484] Mass(FAB): m/e 512(M+1).
[0485] mp: .about.265.degree. C. (accompanied with
decomposition).
[0486] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=2-naphthyl, n=1, y=0)
Example 155
6-(4-Chlorobenzenesulfonylcarbamoyl)-1-(2-Chlorobenzyl)-2-Methylbenzimidaz-
ole Sodium Salt
[0487] By using the method of example 153,
6-(4-chlorobenzenesulfonylcarba-
moyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole sodium salt (0.270
g) is obtained from
6-carboxy-1-(2-chlorobenzyl)-2-methyl-benzimidazole (0.400 g)
(example 75), N,N'-carbonyldiimidazole (0.432 g),
4-chlorobenzenesulfonamide (0.510 g) and diazabicycloundecene
(0.404 g). .sup.1H-NMR (DMSO-d6, .delta.): 2.46 (3H, s), 5.52 (2H,
s), 6.38 (1H, d, J=7.4 Hz), 7.19 (1H, t, J=7.6 Hz), 7.31 (1H, t,
J=7.6 Hz), 7.39 (2H, d, J=8.5 Hz), 7.45 (1H, d, J=8.9 Hz), 7.54
(1H, d, J=8.0 Hz), 7.76-7.82 (4H, m).
[0488] IR(KBr): 1592 cm.sup.-1.
[0489] Mass(FAB): m/e 496(M+1).
[0490] mp: 360-362.degree. C. (decomposition).
[0491] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=4-chlorophenyl, n=1, y=0)
Example 156
6-(3-Chlorobenzenesulfonylcarbamoyl)-1-(2-Chlorobenzyl)-2-Methylbenzimidaz-
ole
[0492] By using the method of example 153,
6-(3-chlorobenzenesulfonylcarba-
moyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole sodium salt is
obtained from 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole
(0.450 g) (example 75), N,N'-carbonyldiimidazole (0.486 g),
3-chlorobenzene-sulfona- mide (0.573 g) and diazabicycloundecene
(0.456 g). This material is dissolved in a mixture solution of
methanol and water. Its acidity is adjusted to pH5.about.6 using
10% hydrochloric acid. Precipitated crystals are separated through
filtration, dried and thus,
6-(3-chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimida-
zole (0.420 g) is obtained. .sup.1H-NMR (DMSO-d6, .delta.): 2.51
(3H, s), 5.63 (2H, s), 6.48 (1H, d, J=7.7 Hz), 7.22 (1H, t, J=7.6
Hz), 7.34 (1H, t, J=7.7 Hz), 7.56 (1H, t, J=8.0 Hz), 7.64 (1H, t,
J=8.0 Hz), 7.68 (1H, d, J=8.5 Hz), 7.78 (2H, t, J=8.6 Hz), 7.91
(1H, d, J=7.6 Hz), 7.95 (1H, d, J=1.6 Hz), 8.10 (1H, s).
[0493] IR(KBr): 1687 cm.sup.-1.
[0494] Mass(FAB): m/e 474(M+1).
[0495] mp: 254.5-257.5.degree. C. (accompanied with
decomposition).
[0496] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=2-chlorophenyl, n=1, y=0)
Example 157
1-(Biphenyl-4-ylmethyl)-2-Methyl-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazo-
le
[0497] Oxalyl chloride (0.655 g) is added to a dichloromethane (13
ml) solution of
1-(biphenyl-4-ylmethyl)-6-carboxy-2-methylbenzimidazole (0.886 g)
(example 88), and N,N-dimethylformamide (one drop) under
ice-chilled conditions, and the solution is stirred for 15 hours at
room temperature. Precipitated crystals are separated through
filtration, washed with methylene chloride and dried under reduced
pressure. These crystals are added to a dichloromethane (15 ml)
solution of 2-aminomethylpyridine (0.235 g) and triethylamine
(0.653 g) under ice-chilled conditions, and the solution is stirred
for one hour. Water is added to the reaction solution and the
reaction is halted. After the solution is washed with water (twice)
and washed with a saturated sodium bicarbonate aqueous solution,
the organic layer is dried. Then, the solvent is concentrated under
reduced pressure. Recrystallization of the residue in a mixed
solvent of ethyl acetate and ethanol produced
1-(biphenyl-4-ylmethyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidaz-
ole (0.774 g). .sup.1H-NMR (CDCl.sub.3, .delta.): 2.62 (3H, s),
4.77 (2H, d, J=4.8 Hz), 5.42 (2H, s), 7.12 (2H, d, J=8.5 Hz), 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 7.7 Hz), 7.71 (1H, dd, J=1.6 and 8.4
Hz), 7.76 (1H, d, J=8.4 Hz), 8.00, (1H, d, J=1.2 Hz), 8.56 (1H, d,
J=4.8 Hz).
[0498] IR(KBr): 1642 cm.sup.-1.
[0499] mp: 205.0-206.5.degree. C.
[0500] (R.sub.1=4-biphenyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=pyridylmethyl, R.sub.5=H,
n=1, y=1)
Example 158
6-Benzenesulfonylcarbamoyl-1-(Biphenyl-4-ylmethyl)-2-Methylbenzimidazole
Sodium Salt
[0501] By using the method of example 153,
6-benzenesulfonyl-carbamoyl-1-(-
biphenyl-4-ylmethyl)-2-methylbenzimidazole sodium salt (0.365 g) is
obtained from
6-carboxy-1-(biphenyl-4-ylmethyl)-2-methylbenzimidazole (0.637 g),
N,N'-carbonyldiimidazole (0.533 g), benzenesulfonamide (0.516 g)
and diazabicycloundecene (0.500 g). .sup.1H-NMR (DMSO-d6, .delta.):
2.52 (3H, s), 5.52 (2H, s), 7.13 (2H, d, J=8.1 Hz), 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).
[0502] IR(KBr): 1591 cm.sup.-1.
[0503] mp: 289.0-290.0.degree. C. (accompanied with
decomposition).
[0504] (R.sub.1=4-biphenyl, R.sub.2=methyl,
R.sub.3=benzenesulfonylcarbamo- yl, n=1, y=1)
Example 159
1-(2-Chlorobenzyl)-2-Methyl-6-Trifluoromethanesulfonylcarbamoyl-Benzimidaz-
ole Hydrochloride
[0505] N,N'-carbonyldiimidazole (0.647 g) is added all at once to
an N,N-dimethylformamide (20 ml) solution of
6-carboxy-1-(2-chlorobenzyl)-2-- methylbenzimidazole (0.600 g)
(example 75), and the solution is stirred for one hour at room
temperature. Subsequently, an N,N-dimethylformamide (5 ml) solution
of trifluoromethanesulfonamide (0.596 g) and diazabicycloundecene
(0.609 g) is added, and the solution is stirred for 72 hours at
100.degree. C. The reaction solution is cooled and the solvent is
removed through evaporation under reduced pressure. Water and ethyl
acetate are added to the residue. While being stirred, 10%
hydrochloric acid is added until the aqueous layer became acidic.
Precipitated crystals are washed with a mixture solvent of ethanol
(25 ml) and methanol (25 ml). The crystals are dried and thus,
1-(2-chlorobenzyl)-2-methyl-6-trifluoromethanesulfonylcarbamoylbenzimidaz-
ole hydrochloride (214) (0.420 g) is obtained. .sup.1H-MR (DMSO-d6,
.delta.): 2.84 (3H, s), 5.82 (2H, s), 7.08 (1H, d, J=7.5 Hz), 7.30
(1H, t), 7.40 (1H, t, J=7.7 Hz), 7.58 (1H, d, J=8.0 Hz), 7.79 (1H,
d, J=8.6 Hz), 8.07-8.13 (2H, m).
[0506] IR(KBr): 1634 cm.sup.-1.
[0507] Mass(CI): m/e 432(M+1-HCl).
[0508] mp: 332-335.degree. C. (accompanied with decomposition).
[0509] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=trifluoromethyl, n=1, y=0)
Examples 160 and 161
6-Benzenesulfonylcarbamoyl-1-(2,4-Dichlorobenzyl)-2-Methylbenzimidazole
Hydrochloride and
6-Benzenesulfonylcarbamoyl-1-(2,4-Dichlorobenzyl)-2-Met-
hylbenzimidazole
[0510] By using the method of example 159,
6-benzenesulfonylcarbamoyl-1-(2-
,4-dichlorobenzyl)-2-methylbenzimidazole hydrochloride (0.540 g) is
obtained from
6-carboxy-1-(2,4-dichlorobenzyl)-2-methyl-benzimidazole (0.460 g),
N,N'-carbonyldiimidazole (0.445 g), benzenesulfonamide (0.431 g)
and diazabicycloundecene (0.418 g). .sup.1H-NMR (DMSO-d6, .delta.):
2.71 (3H, s), 5.74 (2H, s), 6.83 (1H, d, J=8.4 Hz), 7.33 (1H, dd,
J=2.0 and 8.4 Hz), 7.63 (2H, t), 7.71 (1H, t), 7.78 (1H, d, J=2.0
Hz), 7.86 (1H, d, J=8.7 Hz), 7.95 (1H, dd, J=1.4 and 8.7 Hz), 7.99
(2H, m), 8.29 (1H, s).
[0511] IR(KBr): 1686 cm.sup.-1.
[0512] mp: 236.0-238.0.degree. C.
[0513] This material is dissolved in a mixture solvent of a
potassium bicarbonate aqueous solution and methanol, and its
acidity is adjusted to pH5.about.6 with 10% hydrochloric acid.
Precipitated crystals are collected, washed with water, washed with
methanol, and then dried. Thus,
6-benzenesulfonylcarbamoyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole
(216). .sup.1H-NMR (DMSO-d6, .delta.): 2.48 (3H, s), 5.58 (2H, s),
6.42 (1H, d, J=8.4 Hz), 7.31 (1H, dd, J=2.2 and 8.4 Hz), 7.60-7.75
(6H, m), 7.99 (2H, d, J=7.4 Hz), 8.06 (1H, s), 12.40 (1H, s).
[0514] IR(KBr): 1540 cm.sup.-1.
[0515] mp: 238.2-239.9.degree. C.
[0516] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4 SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=phenyl, n=1, y=0)
Example 162
1-(2-Chlorobenzyl)-6-(4-Methoxybenzenesulfonylcarbamoyl)-2-Methylbenzimida-
zole
[0517] N,N'-carbonyldiimidazole (0.431 g) is added all at once to
an N,N-dimethylformamide (15 ml) solution of
6-carboxy-1-(2-chlorobenzyl)-2-- methylbenzimidazole (0.400 g)
(example 75), and the solution is stirred for one hour at room
temperature. Subsequently, an N,N-dimethylformamide (5 ml) solution
of 4-methoxybenzenesulfonamide (0.498 g) and diazabicycloundecene
(0.405 g) is added, and the solution is stirred for 67 hours at
100.degree. C. The reaction solution is cooled and the solvent is
removed through evaporation under reduced pressure. Water and
chloroform are added to the residue. While being stirred, 10%
hydrochloric acid is added until the aqueous layer became acidic.
The organic layer, which is obtained through chloroform extraction
(twice), is washed with a saturated sodium bicarbonate aqueous
solution, and the solvent is removed through evaporation under
reduced pressure. After purification using silica gel column
chromatography (eluate: chloroform/methanol=100/2.about.100/10) and
then concentration, crystals are formed in a mixture solution of
ethyl acetate and diethylether. The crystals are separated through
filtration, dried, and thus,
1-(2-chlorobenzyl)-6-(4-methoxybenzenesulfonylcarbamoyl)-2-methylbenzimid-
azole (0.450 g) is obtained.
[0518] .sup.1H-NMR (DMSO-d6, .delta.): 2.46 (3H, s), 3.83 (2H, s),
5.58 (2H, s), 7.12 (2H, d, J=9.0 Hz), 7.21 (1H, t, J=7.3 Hz), 7.33
(1H, t), 7.56 (1H, d, J=7.0 Hz), 7.63 (1H, d, J=8.5 Hz), 7.71 (1H,
dd, J=1.6 and 8.5 Hz), 7.91 (2H, d, J=9.0 Hz), 8.05 (1H, d, J=1.3
Hz).
[0519] IR(KBr): 1683 cm.sup.-1.
[0520] Mass(FAB): m/e 470(M+1).
[0521] mp: 271.0-274.0.degree. C.
[0522] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=4-methoxyphenyl, n=1, y=0)
Example 163
1-(2-Chlorobenzyl)-2-Methyl-6-(.alpha.-Toluenesulfonylcarbamoyl)Benzimidaz-
ole
[0523] By using the method of example 162,
1-(2-chlorobenzyl)-2-methyl-6-(-
.alpha.-toluenesulfonylcarbamoyl)benzimidazole (0.350 g) is
obtained from 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole
(0.450 g) (example 75), N,N'-carbonyldiimidazole (0.485 g),
.alpha.-toluenesulfonamide (0.512 g) and diazabicycloundecene
(0.456 g). .sup.1H-NMR (DMSO-d6, .delta.): 2.48 (3H, s), 4.36 (2H,
s), 5.53 (2H, s), 6.40 (1H, d, J=6.8 Hz), 7.15-7.28 (6H, t), 7.32
(1H, t), 7.49 (1H, d, J=8.3 Hz), 7.55 (1H, d), 7.83-7.87 (2H,
m).
[0524] IR(KBr): 1593 cm.sup.-1.
[0525] Mass(FAB): m/e 454(M+1).
[0526] mp: 193-196.degree. C. (foam).
[0527] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=2-toluene, n=1, y=0)
Example 164
1-(2-Chlorobenzyl)-6-(2,5-Dimethylbenzenesulfonylcarbamoyl)-2-Methylbenzim-
idazole
[0528] By using the method of example 162,
1-(2-chlorobenzyl)-6-(2,5-dimet-
hylbenzenesulfonylcarbamoyl)-2-methylbenzimidazole (0.490 g) is
obtained from 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole
(0.500 g) (example 75), N,N'-carbonyldiimidazole (0.539 g),
2,5-xylenesulfonamide (0.616 g) and diazabicycloundecene (0.506 g).
.sup.1H-NMR (DMSO-d6, .delta.): 2.35 (3H, s), 2.48 (3H, s), 2.51
(3H, s), 5.58 (2H, s), 6.45 (1H, d, J=7.5 Hz), 7.20-7.27 (2H, m),
7.31-7.39 (2H, m), 7.56 (1H, d, J=8.0 Hz), 7.64 (1H, d, J=8.5 Hz),
7.75 (1H, d, J=8.5 Hz), 7.82 (2H, s), 8.06 (1H, s), 12.45 (1H, br
s).
[0529] IR(KBr): 1690 cm.sup.-1.
[0530] Mass(FAB): m/e 468(M+1).
[0531] mp: 266.5-267.5.degree. C.
[0532] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=2,5-dimethylphenyl, n=1, y=0)
Example 165
1-(2-Chlorobenzyl)-2-Methyl-6-(4-Nitrobenzenesulfonylcarbamoyl)Benzimidazo-
le
[0533] N,N'-carbonyldiimidazole (0.432 g) is added all at once to
an N,N-dimethylformamide (15 ml) solution of
6-carboxy-1-(2-chlorobenzyl)-2-- methylbenzimidazole (0.432 g)
(example 75), and the solution is stirred for one hour at room
temperature. Subsequently, an N,N-dimethylformamide (5 ml) solution
of 4-nitrobenzenesulfonamide (0.538 g) and diazabicycloundecene
(0.405 g) is added, and the solution is stirred for 84 hours at
100.degree. C. The reaction solution is cooled and the solvent is
removed through evaporation under reduced pressure. When chloroform
and hydrochloric acid are added to the residue and the solution is
stirred, crystals precipitated. The crystals are separated through
filtration, dried, and thus, 1-(2-chlorobenzyl)-2-methyl-6-(4-nit-
robenzenesulfonylcarbamoyl)benzimidazole (0.300 g) is obtained.
[0534] .sup.1H-NMR (DMSO-d6, .delta.): 2.56 (3H, s), 5.65 (2H, s),
6.54 (1H, d, J=7.6 Hz), 7.23 (1H, t, J=7.6 Hz), 7.34 (1H, t, J=7.6
Hz), 7.56 (1H, t, J=8.0 Hz), 7.68 (1H, d, J=8.5 Hz), 7.83 (1H, d,
J=8.3 Hz), 8.07 (1H, s), 8.16 (2H, d, J=8.7 Hz), 8.37 (2H, d, J=8.7
Hz).
[0535] IR(KBr): 1621 cm.sup.-1.
[0536] Mass(FAB): m/e 485(M+1).
[0537] mp: 330-332.degree. C.
[0538] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=4-nitrophenyl, n=1, y=0)
Example 166
1-(2-Chlorobenzyl)-2-Methyl-6-[4(Trifluoromethyl)Benzenesulfonylcarbamoyl]-
Benzimidazole
[0539] By using the method of example 162,
1-(2-chlorobenzyl)-2-methyl-6-[-
4-(trifluoromethyl)benzenesulfonylcarbamoyl]benzimidazole (0.390 g)
is obtained from 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole
(0.450 g) (example 75), N,N'-carbonyldiimidazole (0.486 g),
4-(trifluoromethyl)benzenesulfonamide (0.676 g) and
diazabicycloundecene (0.457 g). .sup.1H-NMR (DMSO-d6, .delta.):
2.52 (3H, s), 5.62 (2H, s), 6.47 (1H, d, J=7.2 Hz), 7.22 (1H, t,
J=7.5 Hz), 7.34 (1H, t), 7.56 (1H, d, J=8.0 Hz), 7.66 (1H, d, J=8.5
Hz), 7.78 (1H, d), 7.97 (2H, d, J=8.3 Hz), 8.06 (1H, s), 8.15 (2H,
d, J=8.3 Hz).
[0540] IR(KBr): 1620 cm.sup.-1.
[0541] Mass(FAB): m/e 508(M+1).
[0542] mp: 288.0-292.0.degree. C.
[0543] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=4-trifluoromethylphenyl, n=1, y=0)
Example 167
6-(2-Chlorobenzenesulfonylcarbamoyl)-1-(2-Chlorobenzyl)-2-Methylbenzimidaz-
ole Ammonium Salt
[0544] N,N'-carbonyldiimidazole (0.485 g) is added all at once to
an N,N-dimethylformamide (15 ml) solution of
6-carboxy-1-(2-chlorobenzyl)-2-- methylbenzimidazole (0.450 g)
(example 75), and the solution is stirred for one hour at room
temperature. Subsequently, an N,N-dimethylformamide (5 ml) solution
of trifluoromethanesulfonamide (0.575 g) and diazabicycloundecene
(0.457 g) is added, and the solution is stirred for 72 hours at
100.degree. C. The reaction solution is cooled and the solvent is
removed under reduced pressure. Water and ethyl acetate are added
to the residue. As it is being stirred, 10% hydrochloric acid is
added until the water layer became acidic. Precipitated crystals
are separated through filtration. The crystals are then dissolved
in ethanol and then aqueous ammonia is added to adjust the acidity
to pH 7. Furthermore, diisopropyl ether is added. Precipitated
crystals are separated through filtration, then dried and thus,
6-(2-chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)2-methylbenzimidaz-
ole ammonium salt (0.360 g) is obtained. .sup.1H-NNR (DMSO-d6,
.delta.): 2.47 (3H, s), 5.51 (2H, s), 6.43 (1H, d, J=7.5 Hz), 7.12
(4H, br s), 7.19 (1H, t, J=7.6 Hz), 7.28-7.38 (4H, m), 7.46 (1H, d,
J=8.3 Hz), 7.53 (1H, d, J=7.9 Hz), 7.78-7.82 (2H, m), 7.97 (1H,
m).
[0545] IR(KBr): 1590 cm.sup.-1.
[0546] Mass (FAB): m/e474(M+1-NH3).
[0547] mp: 264.0-267.0.degree. C.
[0548] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4.sub- .5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=2-chlorophenyl, n=1, y=0)
Example 168
6-Carbamoyl-1-(2,4-Dichlorobenzyl)-2-Methylbenzimidazole
[0549] Oxylyl chloride (0.437 g) is added to a methylene chloride
(8 ml) solution of
6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (0.490 g)
and N,N-dimethylformamide (1 drop) under ice-chilled conditions,
and the solution is stirred for 1.5 hours at room temperature.
Then, 28% aqueous ammonia (4 ml) is added and the solution is
stirred for 12 hours at room temperature. Water and methylene
chloride are added to the reaction solution for extraction. After
the organic layer is concentrated, precipitated crystals are
collected, dried and
6-carbamoyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (0.240 g)
is obtained. .sup.1H-NMR (DMSO-d6, .delta.): 2.48 (3H, s), 5.54
(2H, s), 6.41 (1H, d, J=8.4 Hz), 7.21-8.02 (3H, m), 7.31 (1H, dd,
J=2.2 and 8.4 Hz), 7.60 (1H, d, J=8.4 Hz), 7.75 (1H, m), 7.93 (1H,
s).
[0550] IR(KBr): 1666 cm.sup.-1.
[0551] mp: 112.0-114.0.degree. C.
[0552] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methyl, R.sub.3
carbamoyl, n=1, y=0)
Example 169
6-Benzenesulfonylcarbamoyl-1-(Biphenyl-4-ylmethyl)-2-Methoxybenzimidazole
A.) N-Benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide
Potassium Salt
[0553] 5% Palladium/carbon (0.64 g) is added to a mixture of
N-benzenesulfonyl-3-(biphenyl-4-ylmethylamino)-4-nitrobenzamide
potassium salt (4.27 g), 20% potassium bicarbonate aqueous solution
(10.7 g), and methanol (200 ml). The solution is then stirred for
14 hours at 35.degree. C. under a hydrogen environment. The
precipitated crystals are dissolved when a mixture solution of
acetone and water (acetone/water=5/2, 400 ml) is added and its
solids are separated through filtration. The filtrate is
concentrated, the precipitated crystals are separated through
filtration and dried, and thus, N-benzenesulfonyl-4-ami-
no-3-(biphenyl-4-ylmethylamino)benzamide potassium salt (3.15 g) is
obtained. .sup.1H-NMR (DMSO-d6, .delta.): 4.31 (2H, d, J=5.7 Hz),
4.85 (2H, s), 4.91 (1H, br t, J=5.7 Hz), 6.45 (1H, d, J=7.9 Hz),
7.07 (1H, s), 7.13 (1H, d, J=7.9 Hz), 7.29-7.36 (4H, m), 7.43-7.47
(4H, m), 7.60 (2H, d, J=8.1 Hz), 7.65 (2H, d, J=7.6 Hz), 7.73-7.76
(2H, m).
[0554] IR (Nujol): 1574 cm.sup.-1
B.)
6-Benzenesulfonylcarbamoyl-1-(Biphenyl-4-ylmethyl)-2-Methoxybenzimidaz-
ole
[0555] Tetramethoxymethane (0.250 g) is added to an acetic acid
solution (3 ml) of
N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide
(0.400 g), and the solution is stirred for two hours at 80.degree.
C. Methanol is added to the reaction solution, and precipitated
crystals are collected. The crystals are washed in a mixture
solvent of acetone (1 ml) and methanol (8 ml), separated through
filtration, dried and thus,
6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methoxybenzimidazole
(0.280 g) is obtained. .sup.1H-NMR (DMSO-d6, .delta.): 4.17 (3H,
s), 5.33 (2H, s), 7.30 (2H, d, J=8.2 Hz), 7.35 (1H, t, J=7.4 Hz),
7.44 (2H, t, J=7.5 Hz), 7.50 (1H, d, J=8.4 Hz), 7.60-7.65 (6H, m),
7.68-7.72 (2H, m), 7.98-8.01 (2H, m), 8.05 (1H, d, J=1.5 Hz), 8.18
(1H, s), 12.50 (1H, s).
[0556] IR(KBr): 1690 cm.sup.-1.
[0557] mp: 136.0-138.5.degree. C.
[0558] (R.sub.1=4-biphenyl, R.sub.2=methoxy,
R.sub.3=--C(O)NR.sub.4R.sub.5- , R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=phenyl, n=1, y=1)
Example 170
6-Benzenesulfonylcarbamoyl-1-(Biphenyl-4-ylmethyl)-2-carboxybenzimidazole
[0559] Triethylamine (0.080 g) and methyloxalyl chloride (0.148 g)
are added to an N,N-dimethylformamide (3 ml) solution of
N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide
(0.400 g) (example 169, part A), and the solution is stirred for
two hours at room temperature. The reaction solution is
concentrated and the residue is purified using silica gel column
chromatography (eluate: ethyl acetate/methanol=9/1) and
preliminarily purified 6-benzenesulfonylcarbamo-
yl-1-(biphenyl-4-ylmethyl)-2-carboxybenzimidazole is obtained. This
is dissolved in acetic acid (1 ml) and methanol (5 ml) and the
solution is stirred for 15 hours at 60.degree. C. The solution is
neutralized with a potassium hydroxide aqueous solution.
Precipitated crystals are separated through filtration, dried and
thus, 6-benzenesulfonylcarbamoyl-1-(bipheny-
l-4-ylmethyl)-2-carboxybenzimidazole (0.245 g) is obtained.
.sup.1H-NMR (DMSO-d6, .delta.): 5.44 (2H, s), 7.23 (1H, d, J=8.4
Hz), 7.36 (1H, t, J=7.6 Hz), 7.41 (2H, d, J=8.1 Hz), 7.45 (2H, t,
J=7.5 Hz), 7.58 (2H, t, J=7.8 Hz), 7.60-7.71 (7H, m), 7.94 (2H, d,
J=8.3 Hz), 12.38 (1H, s), 12.52 (1H, s).
[0560] IR(KBr): 1670 cm.sup.-1.
[0561] mp: 247.5-250.0.degree. C.
[0562] (R.sub.1=4-biphenyl, R.sub.2=carboxyl,
R.sub.3=--C(O)NR.sub.4R.sub.- 5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=phenyl, n=1, y=1)
Example 171
6-Benzenesulfonylcarbamoyl-1-(Biphenyl-4-ylmethyl)-2-Methylaminobenzimidaz-
ole
[0563] A mixture of
N-benzenesulfonylcarbamoyl-4-amino-3-(biphenyl-4-ylmet-
hylamino)benzamide (0.300 g), methylisothiocyanate (0.200 g),
methanol (5 ml) and acetone (5 ml) is stirred for twelve hours at
room temperature. Furthermore, 97% sulfuric acid (1 ml) is added
and the solution is stirred for 43 hours at room temperature. After
the reaction solution is made basic by adding 20% potassium
bicarbonate aqueous solution, the solution is concentrated and the
residue is extracted with ethyl acetate and water. An organic layer
is concentrated and dissolved in chloroform. Hexane is added to the
solution. Precipitated crystals are separated through filtration,
dried and thus, 6-benzenesulfonylcarbamoyl-1-(bipheny-
l-4-ylmethyl)-2-methylaminobenzimidazole 0.140 g) is obtained.
.sup.1H-NMR (DMSO-d6, .delta.): 2.98 (3H, d, J=4.4 Hz), 5.34 (2H,
s), 7.22 (2H, d, J=8.2 Hz), 7.26 (1H, d, J=8.4 Hz), 7.34 (1H, t,
J=7.3 Hz), 7.44 (2H, t, J=7.5 Hz), 7.57 (2H, t, J=7.6 Hz),
7.59-7.68 (6H, m), 7.76 (1H, s), 7.95 (2H, d, J=7.4 Hz), 12.28 (1H,
s).
[0564] IR(KBr): 1672 cm.sup.-1.
[0565] mp: 225.0-228.0.degree. C.
[0566] (R.sub.1=4-biphenyl, R.sub.2=methylamino,
R.sub.3=--C(O)NR.sub.4R.s- ub.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=phenyl, n=1, y=1)
Example 172
2-Amino-6-Benzenesulfonylcarbamoyl-1-(Biphenyl-4-ylmethyl)Benzimidazole
[0567] Methanol (10 ml), acetone (10 ml), and bromocyanogen (0.395
g) are added to
N-benzenesulfonylcarbamoyl-4-amino-3-(biphenyl-4-ylmethylamino)b-
enzamide (0.395 g). The solution is stirred for 100 hours at room
temperature and 30 hours at 50.degree. C. Chloroform and water are
added and an extraction is performed. An organic layer is washed
with water (6 times), and concentrated. The residue is purified
using silica gel column chromatography (eluate: ethyl
acetate/methanol=9/1) and thus,
2-amino-6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)benzimidazole
(0.135 g) is obtained.
[0568] .sup.1H-NMR (DMSO-d6, .delta.): 5.32 (2H, s), 6.77 (2H, s),
7.05 (1H, d, J=8.8 Hz), 7.21 (2H, d, J=8.3 Hz), 7.31-7.38 (4H, m),
7.43 (2H, t, J=7.5 Hz), 7.58-7.65 (6H, m), 7.79-7.82 (2H, m).
[0569] IR(KBr): 1684 cm.sup.-1.
[0570] Mass(FAB): m/e 483(M+1).
[0571] mp: 352.5-355.0.degree. C.
[0572] (R.sub.1=4-biphenyl, R.sub.2=amino,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=phenyl, n=1, y=1)
Example 173
6-Benzenesulfonylcarbamoyl-1-(Biphenyl-4-ylmethyl)-2-n-Propylbenzimidazole
Potassium Salt
[0573] Triethylamine (0.060 g) and butyryl chloride (0.084 g) are
added to an N,N-dimethylformamide (2 ml) solution of
N-benzenesulfonyl-4-amino-3-(- biphenyl-4-ylmethylamino)benzamide
(0.300 g). The solution is stirred for 1.5 hours at room
temperature. The reaction solution is purified of itself using
silica gel column chromatography Chloroform and
N-benzenesulfonyl-3-(biphenyl-4-ylmethylamino)-4-butyrylaminobenzamide
(0.250 g) is obtained. Methanol (5 ml) and 35% hydrochloric acid
(0.50 g) are added to this and the solution is stirred for three
hours at 60.degree. C. The reaction is halted by adding 20%
potassium bicarbonate. Extraction is performed with ethyl acetate
and water. An organic layer is concentrated and the formed material
is dissolved in a small amount of chloroform. By adding ether,
crystallization is performed. The crystals are separated through
filtration, dried and thus, 6-benzenesulfonyl-carba-
moyl-1-(biphenyl-4-ylmethyl)-2-n-propylbenzimidazole Potassium Salt
(0.157 g) is obtained. .sup.1H-NMR (DMSO-d6, .delta.): 0.95 (3H, t,
J=7.4 Hz), 1.77 (2H, q, J=7.5 Hz), 2.82 (2H, t, J=7.5 Hz), 5.55
(2H, s), 7.11 (2H, d, J=8.2 Hz), 7.32-7.38 (4H, m), 7.43 (2H, t,
J=7.5 Hz), 7.47 (1H, d, J=8.4 Hz), 7.58-7.64 (4H, m), 7.79-7.83
(3H, m), 7.96 (1H, s).
[0574] IR(Nujol): 1592 cm.sup.-1.
[0575] Mass(FAB): m/e 548(M+1).
[0576] mp: 279.0-282.0.degree. C.
[0577] (R.sub.1=4-biphenyl, R.sub.2=n-propyl,
R.sub.3=--C(O)NR.sub.4R.sub.- 5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=phenyl, n=1, y=1)
Example 174
6-Benzenesulfonylcarbamoyl-1-(Biphenyl-4-ylmethyl)-2-n-Butylbenzimidazole
[0578] By using the method of example 173,
6-benzenesulfonylcarbamoyl-1-(b-
iphenyl-4-ylmethyl)-2-n-butylbenzimidazole (0.232 g) is obtained
from
N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide
(0.400 g), triethylamine (0.080 g), and oxtanoyl chloride (0.170
g). .sup.1H-NMR (DMSO-d6, .delta.): 0.79 (3H, t, J=7.3 Hz),
1.12-1.24 (6H, m), 1.24-1.31 (2H, m), 1.66-1.73 (2H, m), 2.84 (2H,
t, J=7.6 Hz), 5.58 (2H, s), 7.14 (2H, d, J=8.1 Hz), 7.34 (2H, t,
J=7.6 Hz), 7.43 (2H, t, J=7.4 Hz), 7.52-7.66 (7H, m), 7.75 (1H, d,
J=8.8 Hz), 7.95 (2H, d, J=7.6 Hz), 8.15 (1H, s), 12.45 (1H, s).
[0579] IR(KBr): 1688 cm.sup.-1.
[0580] mp: 112.0-117.5.degree. C.
[0581] (R.sub.1=4-biphenyl, R.sub.2=n-butyl,
R.sub.3=--C(O)NR.sub.4R.sub.5- , R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=phenyl, n=1, y=1)
Example 175
6-Benzenesulfonylcarbamoyl-1-(Biphenyl-4-ylmethyl)-2-Chloromethylbenzimida-
zole
[0582] By using the method of of example 173,
6-benzenesulfonylcarbamoyl-1-
-(biphenyl-4-ylmethyl)-2-chloromethylbenzimidazole (0.193 g) is
obtained from
N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide
(0.300 g), triethylamine (0.060 g), and chloroacetyl chloride
(0.102 g). .sup.1H-NMR (DMSO-d6, .delta.): 5.10 (2H, s), 5.71 (2H,
s), 7.23 (2H, d, J=8.3 Hz), 7.23 (2H, d, J=8.3 Hz), 7.35 (1H, t,
J=7.3 Hz), 7.44 (2H, t, J=7.5 Hz), 7.60-7.66 (6H, m), 7.69 (1H, t,
J=7.5 Hz), 7.75-7.81 (2H, m), 7.98-8.01 (2H, m), 8.16 (1H, s),
12.52 (1H, s).
[0583] IR(KBr): 1700 cm.sup.-1.
[0584] mp: 220.5-223.5.degree. C.
[0585] (R.sub.1=4-biphenyl, R.sub.2=chloromethyl,
R.sub.3=--C(O)NR.sub.4R.- sub.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=phenyl, n=1, y=1)
Example 176
6-Benzenesulfonylcarbamoyl-1-(Biphenyl-4-ylmethyl)-2-Methoxymethylbenzimid-
azole
[0586] By using the method of of example 173,
6-benzenesulfonylcarbamoyl-1-
-(biphenyl-4-ylmethyl)-2-methoxymethylbenzimidazole (0.183 g) is
obtained from
N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide
(0.400 g), triethylamine (0.115 g), and methoxyacetyl chloride
(0.131 g). .sup.1H-NMR (DMSO-d6, .delta.): 3.31 (3H, s), 4.72 (2H,
s), 5.63 (2H, s), 7.23 (2H, d, J=8.3 Hz), 7.35 (1H, t, J=7.4 Hz),
7.44 (2H, t, J=7.5 Hz), 7.60-7.65 (6H, m), 7.70 (1H, t, J=7.5 Hz),
7.72-7.79 Hz), (2H, m), 7.98-8.01 (2H, m), 8.18 (1H, s), 12.50 (1H,
s).
[0587] IR(KBr): 1690 cm.sup.-1.
[0588] mp: 195.0-198.0.degree. C.
[0589] (R.sub.1=4-biphenyl, R.sub.2=methoxymethyl,
R.sub.3=--C(O)NR.sub.4R- .sub.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=phenyl, n=1, y=1)
Example 177
6-Benzenesulfonylcarbamoyl-1-(Biphenyl-4-ylmethyl)-2-i-Propylbenzimidazole
Potassium Salt
[0590] By using the method of of example 173,
N-benzenesulfonyl-4-amino-3-- (biphenyl-4-ylmethylamino)benzamide
(0.400 g), triethylamine (0.080 g), and isobutyryl chloride (0.121
g) are reacted as source materials. The preliminarily purified
material is dissolved in a mixture solvent of methanol and 20%
potassium bicarbonate aqueous solution. The solution's acidity is
adjusted to pH 7 with 10% hydrochloric acid. Precipitated crystals
are found to be 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethy-
l)-2-i-propylbenzimidazole Potassium Salt (0.167 g). .sup.1H-NMR
(DMSO-d6, .delta.): 1.26 (6H, d, J=6.8 Hz), 3.25-3.40 (1H, m), 5.58
(2H, s), 7.09 (2H, d, J=8.3 Hz), 7.32-7.37 (4H, m), 7.43 (2H, t,
J=7.5 Hz), 7.48 (1H, d, J=8.4 Hz), 7.58-7.64 (4H, m), 7.79-7.83
(3H, m), 7.95 (1H, s).
[0591] IR(Nujol): 1592 cm.sup.-1.
[0592] Mass(FAB): m/e 548(M+1).
[0593] mp: 310.1-312.7.degree. C.
[0594] (R.sub.1=4-biphenyl, R.sub.2=i-propyl,
R.sub.3=--C(O)NR.sub.4R.sub.- 5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=phenyl, n=1, y=1)
Example 178
6-Benzenesulfonylcarbamoyl-1-(Biphenyl-4-ylmethyl)Benzimidazole
[0595] A mixture of
N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)- benzamide
(0.400 g) and formic acid (2 ml) is stirred for three hours at
90.degree. C. The reaction solution is concentrated. The crystals
which precipitated by adding methanol are separated through
filtration, dried and thus,
6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)benzimidazole
(0.243 g) is obtained. .sup.1H-NMR (DMSO-d6, .delta.): 5.60 (2H,
s), 7.35 (1H, t, J=7.2 Hz), 7.39 (2H, d, J=8.2 Hz), 7.44 (2H, t,
J=7.6 Hz), 7.61-7.77 (9H, m), 8.00 (2H, d, J=7.7 Hz), 8.26 (1H, s),
8.66 (1H, s), 12.5 (1H, s).
[0596] IR(KBr): 1683 cm.sup.-1.
[0597] mp: 141.5-143.6.degree. C.
[0598] (R.sub.1=4-biphenyl, R.sub.2=H,
R.sub.3--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=phenyl, n=1, y=1)
Example 179
1-(4-Benzyloxybenzyl)-2-Methyl-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
[0599] Acetic acid (4 ml) and ethanol (8 ml) are added to an
N-(2-pyridylmethyl)-4-acetylamino-3-(4-benzyloxybenzylamino)benzamide
(0.434 g) and the solution is stirred for seven hours at 90.degree.
C. Residue is obtained by reduced pressure condensation. By adding
ethyl acetate and ether to the residue, crystallization is
performed. The crystals are separated through filtration, dried and
thus,
1-(4-benzyloxybenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazol-
e (0.375 g) is obtained. .sup.1H-NMR (DMSO-d6, .delta.): 2.59 (3H,
s), 4.78 (2H, d, J=4.8 Hz), 5.01 (2H, s), 5.31 (2H, s), 6.89 (2H,
d, J=8.7 Hz), 6.99 (2H, d, J=8.6 Hz), 7.21 (1H, dd, J=5.1 and 7.4
Hz), 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=4.1 Hz).
[0600] IR(KBr): 1640 cm.sup.-1.
[0601] mp: 169.0-170.0.degree. C.
[0602] (R.sub.1=4-benzyloxybenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R- .sub.5, R.sub.4=pyridylmethyl, R.sub.5=H,
n=1, y=0)
Example 180
2-Methyl-1-(3,4-Methylenedioxybenzyl)-6-[(2-Pyridylmethyl)Carbamoyl]Benzim-
idazole
[0603] Acetic acid (2 ml) and ethanol (5 ml) are added to an
N-(2-pyridylmethyl)-4-acetylamino-3-(3,4-methylenedioxybenzylamino)benzam-
ide (0.490 g) and the solution is stirred for eight hours at
70.degree. C. The residue obtained by reduced pressure condensation
is purified using silica gel column chromatography (eluate: ethyl
acetate/methanol=9/1), and crystallization is performed in ethyl
acetate. The crystals are separated through filtration, dried and
thus, 2-methyl-1-(3,4-methylenedi-
oxybenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (0.270 g) is
obtained. .sup.1H-NMR (CDCl.sub.3, .delta.): 2.59 (3H, s), 4.78
(2H, d, J=4.8 Hz), 5.28 (2H, s), 5.93 (2H, s), 6.51 (1H, d, J=1.6
Hz), 6.55 (1H, dd, J=1.4 and 7.9 Hz), 6.72 (2H, d, J=8.0 Hz), 7.22
(1H, dd, J=6.7 and 5.0 Hz), 7.34 (1H, d, J=7.7 Hz), 7.62 (1H, br
t), 7.67-7.75 (3H, m), 7.96 (1H, d, J=1.1 Hz), 8.58 (1H, d, J=4.9
Hz).
[0604] IR(KBr): 1637 cm.sup.-1.
[0605] mp: 190.5-192.0.degree. C.
[0606] (R.sub.1=3,4-methylenedioxybenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl, R.sub.5=H,
n=1, y=0)
Example 181
2-Methyl-6-[(2-Pyridylmethyl)Carbamoyl]-1-[4-(1,2,3-Thiadiazole-4-yl)Benzy-
l]Benzimidazole
[0607] By using the method of example 179,
2-methyl-6-[(2-pyridylmethyl)ca-
rbamoyl]-1-[4-(1,2,3-thiadiazole-4-yl)benzyl]benzimidazole (0.33 g)
is obtained from
N-(2-pyridylmethyl)-4-acetylamino-3-[4-(1,2,3-thiadiazole-4-
-yl)benzylamino]benzamide (0.50 g). .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.58 (3H, s), 4.58 (2H, d, J=5.9 Hz), 5.62 (2H, s), 7.24
(1H, dd, J=7.3 and 5.0 Hz), 7.28-7.33 (3H, m), 7.64 (1H, d, J=8.4
Hz), 7.73 (1H, dd, J=7.7 and 1.6 Hz), 7.81 (1H, dd, J=8.4 and 1.3
Hz), 8.10 (1H, d, J=8.2 Hz), 8.13 (1H, s), 8.49 (1H, d, J=4.2 Hz),
9.04 (1H, t, J=5.9 Hz), 9.58 (1H, s).
[0608] IR(KBr): 1642 cm.sup.-1.
[0609] mp: 216.0-217.0.degree. C.
[0610] (R.sub.1=4-(1,2,3-thiadiazole-4-yl)benzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl, R.sub.5=H,
n=1, y=0)
Example 182
6-Benzenesulfonylcarbamoyl-1-(2,4-Difluorobenzyl)-2-Methylbenzimidazole
[0611]
N-benzenesulfonyl-4-acetylamino-3-(2,4-difluorobenzylamino)benzamid-
e (0.370 g) is added to a mixture solvent of 10% hydrochloric acid
(3.3 g), methanol (6 ml), and water (4 ml). Furthermore, 35%
hydrochloric acid (0.5 g) is added and the solution is stirred for
three hours at 60.degree. C. After 20% potassium bicarbonate
aqueous solution is added to turn the reaction solution into a
basic, its acidity is adjusted to pH 5.about.6 with 10%
hydrochloric acid. Precipitated crystals are separated through
filtration, dried and thus, 0.182 g of 6-benzenesulfonylcarbamoyl-
-1-(2,4-difluorobenzyl)-2-methyl-benzimidazole is obtained.
.sup.1H-NMR (DMSO-d6, .delta.): 2.53 (3H, s), 5.56 (2H, s),
6.95-7.01 (1H, m), 7.04 (1H, dt, J=8.7 and 1.4 Hz), 7.32 (1H, dt,
J=10.7 and 2.1 Hz), 7.59-7.66 (3H, m), 7.68-7.74 (2H, m), 8.00 (2H,
d, J=8.1 Hz), 8.13 (1H, s), 12.43 (1H, s).
[0612] IR(KBr): 1686 cm.sup.-1.
[0613] mp: 234.5-235.5.degree. C. (accompanied by
decomposition).
[0614] (R.sub.1=2,4-difluorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=phenyl, n=1, y=0)
Example 183
6-Benzenesulfonylcarbamoyl-2-Methyl-1-(2-Nitrobenzyl)Benzimidazole
[0615] By using the method of example 182,
6-benzenesulfonyl-carbamoyl-2-m-
ethyl-1-(2-nitrobenzyl)benzimidazole (0.237 g) is obtained from
N-benzenesulfonyl-4-acetylamino-3-(2-nitrobenzylamino)benzamide
(0.79 g). .sup.1H-NMR (DMSO-d6, .delta.): 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=8.0 Hz), 8.10 (1H, s), 8.22-8.28 (1H, m),
12.39 (1H, s).
[0616] IR(KBr): 1686 cm.sup.-1.
[0617] mp: 269.5-272.5.degree. C. (accompanied by
decomposition).
[0618] (R.sub.1=2-nitrobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub- .5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=phenyl, n=1, y=0)
Example 184
6-Benzenesulfonylcarbamoyl-2-Methyl-1-Benzylbenzimidazole
[0619] By using the method of example 182,
6-benzenesulfonyl-carbamoyl-2-m- ethyl-1-benzylbenzimidazole (0.222
g) is obtained from
N-benzenesulfonyl-4-acetylamino-3-benzylaminobenzamide (0.38 g).
.sup.1H-NMR (DMSO-d6, .delta.): 2.54 (3H, s), 5.55 (2H, s), 7.12
(2H, d, J=7.9 Hz), 7.28 (1H, t, J=7.3 Hz), 7.34 (2H, t, J=7.0 Hz),
7.61-7.66 (3H, m), 7.69-7.76 (2H, m), 8.00 (2H, d, J=7.9 Hz), 8.18
(1H, s), 12.43 (1H, s).
[0620] IR(KBr): 1695 cm.sup.-1.
[0621] mp: 260.0-262.0.degree. C. (accompanied by
decomposition).
[0622] (R.sub.1=benzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=phenyl, n=1, y=0)
Examples 185 and 186
6-Benzenesulfonylcarbamoyl-2-Methyl-1-(4-Nitrobenzyl)Benzimidazole
and
6-Benzenesulfonylcarbamoyl-2-Methyl-1-(4-Nitrobenzyl)Benzimidazole
Potassium Salt
[0623] By using the method of example,
6-benzenesulfonyl-carbamoyl-2-methy-
l-1-(4-nitrobenzyl)benzimidazole (0.255 g) (185) is obtained in a
crystal from from
N-benzenesulfonyl-4-acetylamino-3-(4-nitrobenzylamino)benzamide
(0.505 g). Furthermore, the filtrate is concentrated and thus,
crystals of
6-benzenesulfonylcarbamoyl-2-methyl-1(4-nitrobenzyl)benzimidazole
potassium salt (250) (0.136 g) (186) are obtained. .sup.1H-NMR
(DMSO-d6, .delta.): 2.50 (3H, s), 5.70 (2H, s), 7.30 (2H, d, J=8.7
Hz), 7.52 (2H, t, J=7.6 Hz), 7.57 (2H, d, J=8.3 Hz), 7.76 (1H, dd,
J=8.4 and 1.4 Hz), 7.92 (2H, d, J=7.3 Hz), 8.05 (1H, s), 8.20 (2H,
d, J=8.7 Hz), 12.43 (1H, s).
[0624] IR(KBr): 1686 cm.sup.-1.
[0625] mp: 164.5-167.0.degree. C.
[0626] example 186: .sup.1H-NMR (DMSO-d6, .delta.): 2.51 (3H, s),
5.68 (2H, s), 7.28 (2H, d, J=8.5 Hz), 7.32-7.41 (3H, m), 7.46 (1H,
d, J=8.4 Hz), 7.78-7.86 (3H, m), 7.91 (1H, s), 8.20 (2H, d, J=8.5
Hz).
[0627] IR(KBr): 1594 cm.sup.-1.
[0628] mp: 326.0-328.0.degree. C. (accompanied by
decomposition).
[0629] (R.sub.1=4-nitrobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub- .5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=phenyl, n=1, y=0)
Example 187
6-Benzenesulfonylcarbamoyl-1-(4-Benzyloxybenzyl)-2-Methylbenzimidazole
[0630] A mixture of
N-benzenesulfonyl-3-amino-4-acetylaminobenzamide potassium salt
(0.500 g), 4-benzyloxybenzyl bromide (0.470 g), 20% potassium
bicarbonate aqueous solution (0.925 g) and N,N-dimethylformamide (3
ml) is stirred for one hour at 90.degree. C. The reaction solution
is concentrated and purified through silica gel column
chromatography (eluate: ethyl acetate/methanol=9/1) to obtain
preliminarily purified
N-benzenesulfonyl-4-acetylamino-3-(4-benzyloxybenz-
ylamino)benzamide. This material underwent cyclization and thus,
6-benzenesulfonylcarbamoyl-1-(4-benzyloxybenzyl)-2-methylbenzimidazole
(0.160 g) is obtained. .sup.1H-NMR (DMSO-d6, .delta.): 2.54 (3H,
s), 5.05 (2H, s), 5.44 (2H, s). 7.09 (2H, d, J=8.7 Hz), 7.32 (2H,
d, J=7.0 Hz), 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).
[0631] IR(KBr): 1685 cm.sup.-1.
[0632] mp: 111.0-114.0.degree. C.
[0633] (R.sub.1=4-benzyloxybenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R- .sub.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=phenyl, n=1, y=0)
Example 188
2-Methyl-5-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
[0634] 5% palladium/carbon (0.10 g) is added to a mixture of
preliminarily purified
N-(pyridylmethyl)-4-acetylamino-3-nitrobenzamide (1.00 g), acetic
acid (8 ml), and ethanol (12 ml), and then solution is stirred for
seven hours at 80.degree. C. under a nitrogen environment. The
solids are separated through filtration and the filtrate is then
concentrated. Ethyl acetate is added to the residue and crystals
are formed. The crystals are separated through filtration, then
dried and thus,
2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole (0.57 g) is
obtained. .sup.1H-NMR (CDCl.sub.3, .delta.): 2.52 (3H, s), 4.59
(2H, d, J=5.9 Hz), 7.26 (1H, dd, J=7.1 and 5.1 Hz), 7.33 (1H, d,
J=7.8 Hz), 7.50 (1H, d, J=8.4 Hz), 7.72-7.78 (2H, m), 8.08(1H, s),
8.51 (1H, d, J=4.8 Hz), 9.04 (1H, t, J=5.8 Hz), 12.44 (1H, s).
[0635] IR(KBr): 1641 cm.sup.-1.
[0636] mp: 212.0-215.0.degree. C.
[0637] (R.sub.1=H, R.sub.2=methyl, R.sub.3=--C(O)NR.sub.4R.sub.5,
R.sub.4=SO.sub.2R.sub.6, R.sub.5=H, R.sub.6=phenyl, n=1, y=0)
Examples 189 and 190
1-Benzenesulfonyl-2-Methyl-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
and
1-Benzenesulfonyl-2-Methyl-5-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
[0638] Dichloromethane (10 ml) and triethylamine (0.760 g) are
added to 1-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole (1.00
g). Furthermore, benzenesulfonyl chloride (0.994 g) is dripped into
the solution. After stirring for three hours, the reaction solution
is washed with water three times, and once more washed with a
sodium bicarbonate aqueous solution. An organic layer is
concentrated under reduced pressure, purified through silica gel
column chromatography (eluate: ethyl acetate/ethanol=9/1) and thus,
a mixture of 1-benzenesulfonyl-2-met-
hyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole and
1-benzenesulfonyl-2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole
(1.38 g) is obtained. Further, this mixture is purified through
medium pressure silica gel column chromatography (eluate: ethyl
acetate/methanol=100/3) and thus, 0.550 g of oily
1-benzenesulfonyl-2-Met-
hyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (189) and 0.540 g
of oily
1-benzenesulfonyl-2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole
(190) are obtained. The oily materials are dissolved using
methylene chloride (1.5 ml), and then crystallized by adding
diethylether.
[0639] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.84 (3H, s), 4.81 (2H,
d, J=4.8 Hz), 7.24 (1H, dd, J=5.1 and 7.3 Hz), 7.37 (1H, d, J=7.7
Hz), 7.53 (2H, dd, J=7.9 and 7.5 Hz), 7.63-7.74 (2H, m), 7.85 (1H,
dd, J=8.4 and 1.2 Hz), 7.97 (2H, dd, J=9.6 and 1.1 Hz), 8.58-8.61
(2H, m).
[0640] IR(KBr): 1636 cm.sup.-1.
[0641] mp: 163.4-164.3.degree. C.
[0642] (R.sub.1=benzenesulfonyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.s- ub.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=phenyl, n=1, y=0)
[0643] example 190: .sup.1H-NMR (CDCl.sub.3, .delta.): 2.83 (3H,
s), 4.78 (2H, d, J=4.7 Hz), 7.23 (1H, dd, J=4.9 and 8.6 Hz), 7.34
(1H, d, J=7.9 Hz), 7.53 (2H, dd, J=7.5 and 8.4 Hz), 7.64-7.75 (3H,
m), 7.91-7.96 (3H, m), 8.10 (1H, d, J=9.1 Hz), 8.14 (1H, d, J=1.3
Hz), 8.56 (1H, dd, J=4.9 and 1.0 Hz).
[0644] IR(KBr): 1657 cm.sup.-1.
[0645] mp: 88.3-91.3.degree. C.
[0646] (R.sub.1=benzenesulfonyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.s- ub.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=phenyl, n=1, y=0)
Examples 191 and 192
2-Methyl-1-(4-Nitrobenzyl)-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
and
2-Methyl-1-(4-Nitrobenzyl)-5-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
[0647] N,N-dimethylformamide (10 ml), 4-nitrobenzyl bromide (3.24
g), and sodium bicarbonate (2.52 g) are added to
2-methyl-5-[(2-pyridylmethyl)car- bamoyl]benzimidazole (3.56 g),
and the solution is heated for two hours at 80.degree. C.
Chloroform and water are added to the reaction solution and layers
are separated. After the organic layer is concentrated under
reduced pressure, it is purified through silica gel column
chromatography (eluate: ethyl acetate/methanol=4/1), and a mixture
of
2-methyl-1-(4-nitrobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole
and
2-methyl-1-(4-nitrobenzyl)-5-[(2-pyridylmethyl)carbamoyl]benzimidazol-
e is obtained. Further, the position isomers in this mixture are
separated through medium pressure silica gel column chromatography
(eluate: ethyl acetate/methanol 85/15). Each is recrystallized in a
mixed solvent of chloroform and diethylether, and thus,
2-methyl-1-(4-nitrobenzyl)-6-[(2-p-
yridylmethyl)carbamoyl]benzimidazole (1.37 g) (191) and
2-methyl-1-(4-nitrobenzyl)-5-[(2-pyridylmethyl)carbamoyl]benzimidazole
(1.19 g) (192) are obtained.
[0648] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.59 (3H, s), 4.77 (2H,
d, J=4.8 Hz), 5.48 (2H, s), 7.09 (2H, d, J=8.7 Hz), 7.22 (1H, dd,
J=7.2 and 4.9 Hz), 7.33 (1H, d, J=7.8 Hz), 7.66-7.70 (2H, m), 7.73
(1H, dd, J=8.4 and 1.5 Hz), 7.78 (1H, d, J=8.4 Hz), 7.91 (1H, d,
J=1.2 Hz), 8.15-8.19 (2H, m), 8.56 (1H, d, J=4.6 Hz).
[0649] IR(KBr): 1652 cm.sup.-1.
[0650] mp: 116.1-119.1.degree. C.
[0651] (R.sub.1=4-nitrobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub- .5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=phenyl, n=1, y=0)
[0652] example 192: .sup.1H-NMR (CDCl.sub.3, .delta.): 2.59 (3H,
s), 4.79 (2H, d, J=4.8 Hz), 5.46 (2H, s), 7.17-7.24 (4H, m), 7.35
(1H, d, J=7.8 Hz), 7.69 (2H, dt, J=7.6 and 1.7 Hz), 7.83 (1H, d,
J=8.4 Hz), 8.19 (2H, d, J=8.6 Hz), 8.26 (1H, d, J=1.3 Hz), 8.57
(1H, d, J=4.8 Hz).
[0653] IR(KBr): 1634 cm.sup.-1.
[0654] mp: 203.7-206.3.degree. C.
[0655] (R.sub.1=4-nitrobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub- .5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=phenyl, n=1, y=0)
Examples 193 and 194
2-Methyl-1-(2-Phenylethyl)-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
and
2-Methyl-1-(2-Phenylethyl)-5-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
[0656] By using the method of examples 191 and 192,
2-methyl-1-(2-phenylethyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole
(0.30 g) (193) and
2-methyl-1-(2-phenylethyl)-5-[(2-pyridylmethyl)carbamo-
yl]benzimidazole (0.23 g) (194) are obtained from
2-methyl-5-[(2-pyridylme- thyl)carbamoyl]benzimidazole (2.00 g) and
phenylethyl iodide (15.0 g). .sup.1H-NMR (CDCl.sub.3, .delta.):
2.17 (3H, s), 3.10 (2H, t, J=6.8 Hz), 4.35 (2H, t, J=6.8 Hz), 4.82
(2H, d, J=4.8 Hz), 6.92-6.97 (2H, m), 7.21-7.28 (4H, m), 7.38 (1H,
d, J=7.8 Hz), 7.78 (1H, d, J=7.8 Hz), 7.78 (1H, br t), 7.68-7.73
(3H, m), 7.98 (1H, d, J=0.9 Hz), 8.60 (1H, dd, J=1.0 and 4.9
Hz).
[0657] IR(neat): 1633 cm.sup.-1.
[0658] Liquid.
[0659] (R.sub.1=2-phenylethyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub- .5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=phenyl, n=1, y=0)
[0660] Example 194: .sup.1H-NMR (CDCl.sub.3, .delta.): 2.19 (3H,
s), 3.08 (2H, t, J=6.8 Hz), 4.35 (2H, t, J=6.8 Hz), 4.81 (2H, d,
J=4.8 Hz), 6.91-6.96 (2H, m), 7.19-7.26 (4H, m), 7.31 (1H, d, J=8.4
Hz), 7.36 (1H, d, J=7.8 Hz), 7.64-7.73 (2H, m), 7.85 (1H, dd, J=1.7
and 8.4 Hz), 8.19 (1H, d, J=1.3 Hz), 8.58 (1H, d, J=4.0 Hz).
[0661] IR(neat): 1643 cm.sup.-1.
[0662] Liquid.
[0663] (R.sub.1=2-phenylethyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub- .5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=phenyl, n=1, y=0)
Examples 195 and 196
1-(2,4-Difluorobenzyl)-2-Methyl-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazol-
e and
1-(2,4-Difluorobenzyl)-2-Methyl-5-[(2-Pyridylmethyl)Carbamoyl]Benzim-
idazole
[0664] By using the method of examples 191 and 192,
1-(2,4-difluorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazo-
le (0.25 g) (195) and
1-(2,4-difluorobenzyl)-2-methyl-5-[(2-pyridylmethyl)-
carbamoyl]benzimidazole (0.25 g) (196) are obtained from
2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole (1.00 g) and
2,4-difluorobenzyl bromide (1.0 g). .sup.1H-NMR (CDCl.sub.3,
.delta.): 2.62 (3H, s), 4.78 (2H, d, J=4.7 Hz), 5.38 (2H, s),
6.73-6.79 (2H, m), 6.88 (1H, t, J=10.0 Hz), 7.24 (1H, dd, J=7.3 and
5.1 Hz), 7.35(1H, d, J=7.8 Hz), 7.67-7.76 (4H, m), 7.97 (1H, s),
8.58 (1H, d, J=4.4 Hz).
[0665] IR(KBr): 1642 cm.sup.-1.
[0666] mp: 98.0-104.0.degree. C.
[0667] (R.sub.1=2,4-difluorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl, R.sub.5=H,
n=1, y=0)
[0668] .sup.1H-NMR (CDCl.sub.3, .delta.): 2.62 (3H, s), 4.79 (2H,
d, J=4.7 Hz), 5.35 (2H, s), 6.72-6.81 (2H, m), 6.89 (1H, t, J=9.8
Hz), 7.22 (1H, t, J=6.2 Hz), 7.28 (1H, d, J=8.4 Hz), 7.34 (1H, d,
J=7.8 Hz), 7.63-7.71 (2H, m), 7.83 (1H, d, J=8.4 Hz), 7.97 (1H, s),
8.57 (1H, d, J=4.7 Hz).
[0669] IR(KBr): 1647 cm.sup.-1.
[0670] mp: 143.5-144.0.degree. C.
[0671] (R.sub.1=2,4-difluorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl, R.sub.5=H,
n=1, y=0)
Examples 197 and 198
1-(4-Aminobenzyl)-2-Methyl-6-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
and
1-(4-Aminobenzyl)-2-Methyl-5-[(2-Pyridylmethyl)Carbamoyl]Benzimidazole
[0672] Methanol (30 ml) and 5% palladium/carbon (0.20 g) are added
to a mixture (2.32 g) of
2-methyl-1-(4-nitrobenzyl)-6-[(2-pyridylmethyl)carbam-
oyl]benzimidazole and
2-methyl-1-(4-nitrobenzyl)-5-[(2-pyridylmethyl)carba-
moyl]benzimidazole, and the solution is stirred at room temperature
under a nitrogen environment until the raw materials dissolved.
Solid materials are separated through filtration. The filtrate is
concentrated and a residue is obtained. The residue is purified
through medium pressure silica gel column chromatography (eluate:
ethyl acetate/methanol=85/15), and
1-(4-aminobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazol-
e and
1-(4-aminobenzyl)-2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazo-
le are separated. These materials are crystallized in mixed
solvents of chloroform and diethylether. The crystals are separated
through filtration, dried and thus,
1-(4-aminobenzyl)-2-methyl-6-[(2-pyridylmethy-
l)carbamoyl]benzimidazole (0.354 g) (197) and
1-(4-aminobenzyl)-2-methyl-5-
-[(2-pyridylmethyl)carbamoyl]benzimidazole (0.33 0 g) (198) are
obtained. .sup.1H-NMR (CDCl.sub.3, .delta.): 3.00 (3H, s), 4.98
(2H, s), 5.88 (2H, s), 7.55 (2H, d, J=8.6 Hz), 7.69 (2H, d, J=8.6
Hz), 7.90 (1H, d, J=8.6 Hz), 7.96 (1H, dt, J=7.1 and 0.6 Hz), 8.12
(1H, J=8.0 Hz), 8.18 (1H, dd, J=8.5 and 1.4 Hz), 8.55 (1H, dt,
J=8.0 and 1.7 Hz), 8.62 (1H, d, J=1.1 Hz), 8.77 (1H, dd, J=5.9 and
1.1 Hz).
[0673] IR(KBr): 1643 cm.sup.-1.
[0674] mp: 180.0-181.0.degree. C.
[0675] (R.sub.1=4-aminobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub- .5, R.sub.4=2-pyridylmethyl,
R.sub.5=H, n=1, y=0)
[0676] example 198: .sup.1H-NMR (CDCl.sub.3, .delta.): 3.00 (3H,
s), 5.01 (2H, s), 5.83 (2H, s), 7.47 (2H, d, J=8.5 Hz), 7.78 (2H,
d, J=8.5 Hz), 7.78 (1H, d, J=8.9 Hz), 7.97 (1H, dt, J=7.2 and 0.7
Hz), 8.13 (1H, J=8.1 Hz), 8.15 (1H, d, J=8.9 Hz), 8.15 (1H, s),
8.55 (1H, dt, J=7.9 and 1.6 Hz), 8.77 (1H, d, J=5.8 Hz).
[0677] IR(KBr): 1639, 1612 cm.sup.-1.
[0678] mp: 168.0-171.0.degree. C.
[0679] (R.sub.1=4-aminobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub- .5, R.sub.4=2-pyridylmethyl,
R.sub.5=H, n=1, y=0)
Example 199
1-[4-(Benzenesulfonylamino)Benzyl]-2-Methyl-6-[(2-Pyridylmethyl)Carbamoyl]-
Benzimidazole
[0680] Triethylamine (0.185 g) and benzenesulfonyl chloride (0.210
g) are added to a chloroform (10 ml) solution of
1-(4-aminobenzyl)-2-methyl-6-[(-
2-pyridylmethyl)carbamoyl]benzimidazole (0.340 g), and the solution
is stirred for eight hours at room temperature. Water is added and
the reaction is halted. A chloroform extraction is performed. An
organic layer is washed with water (three times), and dried. After
concentration, the residue is purified through silica gel column
chromatography (eluate: ethyl acetate/methanol=100/0.about.4/1),
and thus,
1-[4-(benzenesulfonylamino)benzyl]-2-methyl-6-[(2-pyridylmethyl)carbamoyl-
]benzimidazole (263) (0.300 g) is obtained. .sup.1H-NMR
(CDCl.sub.3, .delta.): 2.53 (3H, s), 4.78 (2H, d, J=4.8 Hz), 5.28
(2H, s), 6.90 (2H, t, J=8.6 Hz), 6.99 (2H, d, J=8.5 Hz), 7.11 (1H,
s), 7.23 (1H, dd, J=5.5 and 7.2 Hz), 7.34 (1H, d, J=7.7 Hz), 7.40
(2H, t, J=8.1 Hz), 7.50 (1H, t, J=7.5 Hz), 7.66-7.74 (6H, m), 7.92
(1H, s), 8.56 (1H, d, J=4.8 Hz).
[0681] IR(KBr): 1642 cm.sup.-1.
[0682] mp: 204.4-206.5.degree. C.
[0683] (R.sub.1=4-(benzenesulfonylamino)benzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=2-pyridylmethyl, R.sub.5=H,
n=1, y=0)
Example 200
N-Benzenesulfonyl-3-[1-(2-chlorobenzyl)-2-methylbenzimidazole-6-yl]propion-
amide
[0684] To an ethanol (150 ml) solution of
N-benzenesulfonyl-1-(2-chloroben-
zyl)-2-methylbenzimidazole-6-acrylamide (0.607 g), 5%
palladium/carbon (0.500 g) is added, and the solution is stirred
for 43 hours at room temperature under a hydrogen environment.
Solid materials are separated through filtration. The filtrate is
concentrated and then dissolved in a mixture solution of 20%
potassium bicarbonate aqueous solution and methanol. The solution's
acidity is adjusted to pH 5.about.6 with 10% hydrochloric acid.
Precipitated crystals are separated through filtration and thus,
N-benzenesulfonyl-3-[1-(2-chlorobenzyl)-2-methylbenzimidazole-6-
-yl]propionamide (0.250 g) is obtained. .sup.1H-NMR (DMSO-d6,
.delta.): 2.45 (3H, s), 2.52 (2H, t), 2.78 (2H, t), 5.37 (2H, s),
6.88 (1H, d, J=8.4 Hz), 7.08 (2H, d, J=7.4 Hz), 7.22-7.34 (3H, m)
7.36 (1H, t, J=8.1 Hz), 7.55 (2H, t), 7.67 (1H, t), 7.84 (2H, d,
J=7.6 Hz), 12.04 (1H, br s).
[0685] IR(KBr): 1715 cm.sup.-1.
[0686] Mass(FAB): m/e 468(M+1)
[0687] mp: 229.8-233.0.degree. C.
[0688] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=phenyl, n=1, y=0)
Example 201
6-Benzenesulfonylcarbamoyl-2-Methyl-1-[4-(1,2,3-Thiadiazole-4-yl)Benzyl]Be-
nzimidazole
[0689] By using the method of example 182, 6-benzenesulfonyl
carbamoyl-2-methyl-1-[4-(1,2,3-thiadiazole-4-yl)benzyl]benzimidazole
(0.279 g) is obtained from
N-benzenesulfonyl-4-acetylamino-3-[4-(1,2,3-th-
adiazole-4-yl)benzylamino]benzimidazole (0.382 g). .sup.1H-NMR
(DMSO-d6, .delta.): 2.56 (3H, s), 5.62 (2H, s), 7.28 (2H, d, J=8.2
Hz), 7.58-7.63 (3H, m), 7.67 (1H, t, J=7.3 Hz), 7.74 (1H, dd, J=8.5
and 1.2 Hz), 7.99 (2H, dd, J=8.4 and 1.2 Hz) 8.10 (2H, d, J=8.2
Hz), 8.19 (1H, s), 9.58 (1H, s), 12.47 (1H, s).
[0690] IR(KBr): 1617, 1556 cm.sup.-1.
[0691] mp: 258.5-260.0.degree. C. (accompanied by
decomposition).
[0692] (R.sub.1=4-(1,2,3-thiadiazole-4-yl)benzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=phenyl, n=1, y=0)
Example 202
1-(2-Chlorobenzyl)-2-Methyl-6-(8-Quinolinesulfonylcarbamoyl)Benzimidazole
Sodium Salt
[0693] By using the method of example 153,
1-(2-chlorobenzyl)-2-methyl-6-(-
8-quinolinesulfonylcarbamoyl)benzimidazole sodium salt (0.400 g) is
obtained from 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole
(0.450 g) (example 75), N,N'-carbonyldiimidazole (0.485 g),
8-quinolinesulfonamide (0.625 g) and diazabicycloundecene (0.457
g). .sup.1H-NMR (DMSO-d6, .delta.): 2.42 (3H, s), 5.48 (2H, s),
6.32 (1H, d, J=7.7 Hz), 7.17 (1H, t, J=7.5 Hz), 7.30 (1H, t, J=7.7
Hz), 7.42 (1H, d, J=8.4 Hz), 7.48 (1H, dd, J=4.2 and 8.2 Hz) 7.53
(1H, d, J=8.0 Hz), 7.64 (1H, t, J=7.7 Hz), 7.79 (1H, d, J=8.5 Hz),
7.88 (1H, s), 8.04 (1H, d, J=8.1 Hz), 8.33-8.37 (2H, m), 8.85 (1H,
dd).
[0694] IR(KBr): 1594 cm.sup.-1.
[0695] Mass(FAB): m/e 513(M+1).
[0696] mp: 348-352.degree. C. (accompanied by decomposition).
[0697] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=8-quinoline, n=1, y=0)
Example 203
6-(4-t-Butylbenzenesulfonylcarbamoyl)-1-(2-Chlorobenzyl)-2-Methylbenzimida-
zole Sodium Salt
[0698] By using the method of example 153,
6-(4-t-butylbenzenesulfonylcarb-
amoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole sodium salt (0.280
g) is obtained from
6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (0.450 g)
(example 75), N,N'-carbonyldiimidazole (0.486 g),
2-t-benzenesulfonamide (0.640 g) and diazabicycloundecene (0.657
g). .sup.1H-NMR (DMSO-d6, .delta.): 1.25 (9H, s), 2.46 (3H, s),
5.51 (2H, s), 6.37 (1H, d, J=7.7 Hz), 7.18 (1H, t), 7.31 (1H, t),
7.34 (2H, d, J=8.4 Hz), 7.44 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=8.0
Hz), 7.69 (2H, d, J=8.5 Hz), 7.78-7.82 (2H, m).
[0699] IR(KBr): 1596 cm.sup.-1.
[0700] Mass(FAB): m/e 518(M+1).
[0701] mp: 359.5-362.degree. C.
[0702] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=4-t-butylphenyl, n=1, y=0)
Example 204
6-Benzenesulfonylcarbamoyl-2-Methyl-1-[4-(Trifluoromethyl)Benzyl]Benzimida-
zole
[0703] A methanol (7 ml) solution of
N-benzenesulfonyl-4-acetylamino-3-ami- nobenzamide (0.50 g),
4-(trifluoromethyl)benzyl bromide (0.418 g) and potassium
bicarbonate (0.423 g) is stirred for 1 hour at 60.degree. C. to
give preliminarily purified
N-benzenesulfonyl-4-acetylamino-3-[4-(tifluor-
omethyl)benzylamino]benzamide (0.30 g). This is dissolved in
methanol. When it is left undisturbed crystals precipitated. The
crystals are separated through filtration, dried and thus,
6-benzenesulfonylcarbamoyl--
2-methyl-1-[4-(trifluoromethyl)benzyl]benzimidazole (0.160 g)is
obtained
[0704] .sup.1H-NMR (DMSO-d6, .delta.): 2.51 (3H, s), 5.66 (2H, s),
7.28 (2H, d, J=8.1 Hz), 7.59-7.65 (3H, m), 7.67-7.75 (4H, m), 7.99
(2H, d, J=7.5 Hz), 8.14 (1H, d, J=1.0 Hz), 12.43 (1H, s).
[0705] IR(KBr): 1618, 1550 cm.sup.-1.
[0706] mp: 278.5-280.0.degree. C.
[0707] (R.sub.1=4-trifluoromethylbenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=phenyl, n=1, y=0)
Example 205
5-Benzenesulfonylcarbamoyl-2-Methylbenzimidazole
[0708] A mixture of
N-benzenesulfonyl-4-acetylamino-3-aminobenzamide (0.500 g), 35%
hydrochloric acid (3.9 g), methanol (15 ml), and water (12 ml) is
stirred for one hour at 60.degree. C. The solution is neutralized
with a potassium bicarbonate aqueous solution. Precipitated
crystals are separated through filtration, dried, and thus,
5-benzenesulfonyl-carbamoy- l-2-methylbenzimidazole (0.404 g) is
obtained. .sup.1H-NMR (DMSO-d6, .delta.): 2.79 (3H, s), 7.64-7.68
(2H, m), 7.72-7.76 (1H, m), 7.81 (1H, d, J=8.7 Hz), 7.94 (1H, dd,
J=1.6 and 8.7 Hz), 8.02-8.05 (2H, m), 8.30 (1H, s).
[0709] IR(KBr): 1701 cm.sup.-1.
[0710] mp: 223.0-227.5.degree. C.
[0711] (R.sub.1=H, R.sub.2=methyl, R.sub.3=--C(O)NR.sub.4R.sub.5,
R.sub.4=SO.sub.2R.sub.6, R.sub.5=H, R.sub.6=phenyl, n=1, y=0)
Example 206
1-(Biphenyl-4-ylmethyl)-6-Ethoxycarbonyl-2-Methoxymethylbenzimidazole
[0712] By using the method of example 47, part B, preliminarily
purified
3-[N-(biphenyl-4-ylmethyl)methoxyacetylamino]-4-nitro-ethylbenzoate
(2.02 g) is obtained from
3-methoxyacetylamino-4-nitro-ethylbenzoate (2.00 g) and
4-biphenylmethyl bromide (2.98 g). Subsequently, by using the
method of example 47, preliminarily purified
1-(biphenyl-4-ylmethyl)-6-ethoxycar-
bonyl-2-methoxymethylbenzimidazole (1.44 g) is obtained.
[0713] (R.sub.1=4-biphenyl, R.sub.2=methoxymethyl,
R.sub.3=ethoxycarbonyl, n=1, y=1)
Example 207
1-(Biphenyl-4-ylmethyl)-6-Carboxy-2-Methoxymethylbenzimidazole
[0714] By using the method of example 75,
1-(biphenyl-4-ylmethyl)-6-carbox- y-2-methoxymethylbenzimidazole
(0.864 g) is obtained from the preliminarily purified
1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-methoxy-
methyl-benzimidazole (1.44 g). .sup.1H-NMR (DMSO-d6, .delta.): 3.35
(3H, s), 4.77 (2H. s), 5.68 (2H, s), 7.25 (2H, d, J=8.3 Hz), 7.35
(1H, t, J=7.4 Hz), 7.44 (2H, t, J=7.5 Hz), 7.61-7.66 (4H, m), 7.74
(1H, d, J=8.6 Hz), 7.83 (1H, dd, J=1.6 and 8.5 Hz), 8.08 (1H, d,
J=1.2 Hz), 12.83 (1H, s).
[0715] (R.sub.1=4-biphenyl, R.sub.2=methoxymethyl,
R.sub.3=-carboxyl, n=1, y=1)
Example 208
1-(Biphenyl-4-ylmethyl)-6-(Butanesulfonylcarbamoyl)-2-Methoxymethylbenzimi-
dazole
[0716] By using the method of example 111,
1-(biphenyl-4-ylmethyl)-6-(buta-
nesulfonylcarbamoyl)-2-methoxymethylbenzimidazole (0.429 g) is
obtained from
1-(biphenyl-4-ylmethyl)-6-carboxy-2-methoxymethylbenzimidazole
(0.400 g), N,N'-carbonyldiimidazole (0.348 g), 1-butanesulfonamide
(0.294 g) and diazabicycloundecene (0.327 g). .sup.1H-NMR (DMSO-d6,
.delta.): 0.84 (3H, t, J=7.4 Hz), 1.35-1.42 (2H. m), 1.62-1.70 (2H,
m), 3.33(3H, s), 3.51 (2H, t, J=7.6 Hz), 4.74 (2H, s), 5.65 (2H,
s), 7.26 (2H, d, J=8.3 Hz), 7.35 (1H, t, J=7.3 Hz), 7.44 (2H, t,
J=7.5 Hz), 7.62-7.67 (4H, m), 7.78 (1H, d, J=8.6 Hz), 7.84 (1H, dd,
J=1.5 and 8.4 Hz), 8.24 (1H, d, J=1.5 Hz), 12.10 (1H, s).
[0717] IR(KBr): 1684 cm.sup.-1.
[0718] mp: 176.0-178.5.degree. C.
[0719] (R.sub.1=4-biphenyl, R.sub.2=methoxymethyl,
R.sub.3=--C(O)NR.sub.4R- .sub.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=butyl, n=1, y=1)
Example 209
1-(4-Benzyloxybenzyl)-6-ethoxycarbonyl-2-methoxymethylbenzimidazole
[0720] By using the method of example 47, part B, preliminarily
purified
3-[N-(4-benzyloxybenzyl)methoxyacetylamino]-4-nitro-ethylbenzoate
(2.14 g) is obtained from
3-methoxyacetylamino-4-nitro-ethylbenzoate (2.00 g) and
4-benzyloxybenzyl chloride (3.30 g). Subsequently, by using the
method of Example 24, preliminarily purified
1-(4-benzyloxybenzyl)-6-etho-
xycarbonyl-2-methoxymethylbenzimidazole (1.66 g) is obtained.
[0721] (R.sub.1=4-benzyloxybenzyl, R.sub.2=methoxymethyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 210
1-(4-Benzyloxybenzyl)-6-Carboxy-2-Methoxymethylbenzimidazole
[0722] By using the method of example 75,
1-(4-benzyloxybenzyl)-6-carboxy-- 2-methoxymethylbenzimidazole
(2.64 g) is obtained from the preliminarily purified
1-(4-benzyloxybenzyl)-6-ethoxycarbonyl-2-methoxymethyl-benzimida-
zole (3.75 g). .sup.1H-NMR (DMSO-d6, .delta.): 3.34 (3H, s), 4.74
(2H. s), 5.05 (2H, s), 5.53 (2H, s), 6.97 (2H, d, J=8.7 Hz), 7.15
(2H, d, J=8.7 Hz), 7.31 (1H, t, J=7.2 Hz), 7.41 (2H, d, J=7.2 Hz),
7.71 (1H, d, J=8.4 Hz), 7.81 (1H, dd, J=1.5 and 7.4 Hz), 8.04 (1H,
d, J=1.1 Hz), 12.81 (1H, s).
[0723] (R.sub.1=4-benzyloxybenzyl, R.sub.2=methoxymethyl,
R.sub.3=carboxyl, n=1, y=0)
Example 211
1-(4-Benzyloxybenzyl)-6-(1-Butanesulfonylcarbamoyl)-2-Methoxymethylbenzimi-
dazole
[0724] By using the method of example 162,
1-(4-benzyloxybenzyl)-6-(1-buta-
nesulfonylcarbamoyl)-2-methoxymethylbenzimidazole (0.321 g) is
obtained from
1-(4-benzyloxybenzyl)-6-carboxy-2-methoxymethyl-benzimidazole
(0.400 g), N,N'-carbonyldiimidazole (0.322 g), 1-butanesulfonamide
(0.272 g) and diazabicycloundecene (0.302 g). .sup.1H-NMR (DMSO-d6,
.delta.): 0.86 (3H, t, J=7.4 Hz), 1.37-1.44 (2H. m), 1.65-1.71 (2H,
m), 3.32 (3H, s), 3.52 (2H, t, J=7.6 Hz), 4.71 (2H, s), 5.05 (2H,
s), 5.51 (2H, s), 6.98 (2H, d, J=8.7 Hz), 7.15 (2H, d, J=8.3 Hz),
7.31 (1H, t, J=7.2 Hz), 7.37 (2H, t, J=7.2 Hz), 7.41 (2H, d, J=7.1
Hz), 7.74, (1H, d, J=8.5 Hz), 7.82 (1H, dd, J=1.5 and 8.5 Hz), 8.21
(1H, s), 11.98 (1H, s).
[0725] IR(KBr): 1685 cm.sup.-1.
[0726] mp: 72.0-74.0.degree. C.
[0727] (R.sub.1=4-benzyloxybenzyl, R.sub.2=methoxymethyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=butyl, n=1, y=1)
Example 212
1-(2,4-Dichlorobenzyl)-6-Ethoxycarbonyl-2-Methoxymethylbenzimidazole
[0728] By using the method of example 47, part B, preliminarily
purified
3-[N-(2,4-dichlorobenzyl)methoxyacetylamino]-4-nitro-ethylbenzoate
is obtained from 3-methoxyacetylamino-4-nitro-ethylbenzoate (2.00
g) and 2,4-dichlorobenzyl chloride (2.08 g). Subsequently, by using
the method of example 47, preliminarily purified
1-(2,4-dichlorobenzyl)-6-ethoxycarb-
onyl-2-methoxymethylbenzimidazole (3.15 g) is obtained.
[0729] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methoxymethyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 213
6-Carboxy-1-(2,4-Dichlorobenzyl)-2-Methoxymethylbenzimidazole
[0730] By using the method of example 75,
6-carboxy-1-(2,4-dichlorobenzyl)- -2-methoxymethylbenzimidazole
(1.46 g) is obtained from the preliminarily purified
1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methoxymethyl-benzimid-
azole (3.15 g) (example 212). .sup.1H-NMR (DMSO-d6, .delta.): 3.23
(3H, s), 4.70 (2H. s), 5.68 (2H, s), 6.54 (1H, d, J=8.5 Hz), 7.31
(1H, dd, J=2.2 and 8.5 Hz), 7.73 (1H, d, J=2.1 Hz), 7.76 (1H, d,
J=8.5 Hz), 7.86 (1H, dd, J=1.5 and 8.5 Hz), 8.00 (1H, d, J=1.1 Hz),
12.85 (1H, s).
[0731] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methoxymethyl,
R.sub.3=carboxyl, n=1, y=0)
Example 214
6-(1-Butanesulfonylcarbamoyl)-1-(2,4-Dichlorobenzyl)-2-Methoxymethylbenzim-
idazole
[0732] By using the method of example 111,
6-(1-butanesulfonyl-carbamoyl)--
1-(2,4-dichlorobenzyl)-2-methoxymethylbenzimidazole (0.430 g) is
obtained from
6-carboxy-1-(2,4-dichlorobenzyl)-2-methoxymethylbenzimidazole
(0.400 g), N,N'-carbonyldiimidazole (0.355 g), 1-butanesulfonamide
(0.300 g) and diazabicycloundecene (0.333 g). .sup.1H-NMR (DMSO-d6,
.delta.): 0.85 (3H, t, J=7.3 Hz), 1.37-1.42 (2H. m), 1.63-1.69 (2H,
m), 3.21 (3H, s), 3.51 (2H, t, J=7.6 Hz), 4.68 (2H, s), 5.65 (2H,
s), 6.46 (1H, d, J=8.5 Hz), 7.31 (1H, dd, J=2.0 and 8.4 Hz), 7.75
(1H, d, J=2.1 Hz), 7.80 (1H, d, J=8.5 Hz), 7.86 (1H, dd, J=1.7 and
8.6 Hz), 8.14 (1H, d, J=1.2 Hz), 12.00 (1H, s).
[0733] IR(KBr): 1694 cm.sup.-1.
[0734] mp: 168.5-170.5.degree. C.
[0735] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methoxymethyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=butyl, n=1, y=0)
Example 215
1-(2-Chlorobenzyl-2-Methyl-6-(1-Propanesulfonylcarbamoyl)Benzimidazole
[0736] By using the method of example 111,
1-(2-chlorobenzyl)-2-methyl-6-(-
1-propanesulfonylcarbamoyl)benzimidazole (0.459 g) is obtained from
6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (0.400 g),
N,N'-carbonyl-diimidazole (0.43 1 g), 1-propanesulfonamide (0.328
g) and diazabicycloundecene (0.404 g). .sup.1H-NMR (DMSO-d6,
.delta.): 0.98 (3H, t, J=7.4 Hz), 1.67-1.75 (2H. m), 2.50 (3H, s),
3.49 (2H, t, J=7.7 Hz), 5.61 (2H, s), 6.45 (1H, d, J=7.0 Hz), 7.24
(1H, dt, J=0.8 and 7.8 Hz), 7.35 (1H, dt, J=1.4 and 7.4 Hz), 7.63
(1H, dd, J=0.9 and 7.9 Hz), 7.69 (1H, d, J=8.5 Hz), 7.81 (1H, dd,
J=1.6 and 8.5 Hz), 8.12 (1H, d, J=1.6 Hz), 11.90 (1H, s).
[0737] IR(KBr): 1676 cm.sup.1.
[0738] mp: 217.5-218.5.degree. C.
[0739] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=propyl, n=1, y=0)
Example 216
6-Ethanesulfonylcarbamoyl-1-(2-Chlorobenzyl)-2-Methylbenzimidazole
[0740] By using the method of example 111,
6-ethanesulfonyl-carbamoyl-1-(2-
-chlorobenzyl)-2-methylbenzimidazole (0.459 g) is obtained from
6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (0.400 g),
N,N'-carbonyldiimidazole (0.431 g), ethanesulfonamide (0.290 g) and
diazabicycloundecene (0.404 g). .sup.1H-NMR (DMSO-d6, .delta.):
1.23 (3H, t, J=7.3 Hz), 2.50 (3H. s), 3.50 (2H, q, J=7.3 Hz), 5.61
(2H, s), 6.45 (1H, d, J=6.7 Hz), 7.24 (1H, dt, J=0.9 and 7.5 Hz),
7.35 (1H, dt, J=1.4 and 7.5 Hz), 7.58 (1H, dd, J=1.0 and 8.0 Hz),
7.69 (1H, d, J=8.5 Hz), 7.81 (1H, dd, J=1.6 and 8.4 Hz), 8.13 (1H,
d, J=1.5 Hz), 11.86 (1H, s).
[0741] IR(KBr): 1673 cm.sup.-1.
[0742] mp: 256.5-258.5.degree. C.
[0743] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=ethyl, n=1, y=0)
Example 217
6-(Propanesultam-1-ylcarbonyl)-1-(2-Chlorobenzyl)-2-Methylbenzimidazole
[0744] By using the method of example 111,
6-(propanesultam-1-ylcarbonyl)--
1-(2-chlorobenzyl)-2-methylbenzimidazole (0.323 g) is obtained from
6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (0.400 g),
N,N'-carbonyldiimidazole (0.431 g), 1-(3-chloropropane)sulfonamide
(0.420 g) and diazabicycloundecene (0.404 g). .sup.1H-NMR (DMSO-d6,
.delta.): 2.27-2.33 (2H, m), 2.52 (3H. s), 3.52 (2H, t, J=7.0 Hz),
3.87 (2H, t, J=6.6 Hz), 5.59 (2H, s), 6.57 (1H, d, J=7.7 Hz), 7.23
(1H, t, J=7.6 Hz), 7.34 (1H, t, J=6.4 Hz), 7.53-7.58 (2H, m), 7.67
(1H, d, J=8.4 Hz), 7.79 (1H, d, J=1.1 Hz).
[0745] IR(KBr): 1648 cm.sup.-1.
[0746] mp: 165.5-166.6.degree. C.
[0747] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4 and
R.sub.5=propansultamyl, n=1, y=0)
Example 218
6-Benzenesulfonylcarbamoyl-1-(Biphenyl-4-ylmethyl)-2-Cyclopropylbenzimidaz-
ole
[0748] By using the method of example 173, from
N-benzenesulfonyl-4-amino-- 3-(biphenyl-4-ylmethylamino)benzamide
(0.400 g) and cyclopropanecarbonyl chloride (0.101 g), first
N-benzenesulfonyl-3-(biphenyl-4-ylmethylamino)--
4-cyclopropanecarbonylaminobenzamide is obtained and then
6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-cyclopropylbenzimida-
zole (0.196 g) is obtained. .sup.1H-NNR (DMSO-d6, .delta.):
1.00-1.15 (4H, m), 2.23-2.31 (1H. m), 5.66 (2H, s), 7.21 (2H, m,
J=9.1 Hz), 7.32-7.45 (7H, m), 7.59-7.63 (4H, m), 7.78-7.83 (3H, m),
7.97 (1H, s).
[0749] IR(Nujol): 1540 cm.sup.-1.
[0750] Mass(FAB): m/e 546(M+1).
[0751] mp: 220.8-224.8.degree. C.
[0752] (R.sub.1=4-biphenyl, R.sub.2=cyclopropyl,
R.sub.3=--C(O)NR.sub.4R.s- ub.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=phenyl, n=1, y=1)
Example 219
1-(2-Chlorobenzyl)-2-Methyl-6-(1-Pentanesulfonylcarbamoyl)Benzimidazole
[0753] By using the method of example 111,
1-(2-chlorobenzyl)-2-methyl-6-(-
1-pentanesulfonylcarbamoyl)benzimidazole (0.491 g) is obtained from
6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (0.400 g),
N,N'-carbonyldiimidazole (0.431 g), 1-pentanesulfonamide (0.402 g)
and diazabicyclo-undecene (0.404 g). .sup.1H-NMR (DMSO-d6,
.delta.): 0.81 (3H, t, J=7.2 Hz), 1.23-1.28 (2H, m), 1.32-1.37 (2H.
m), 1.65-1.69 (2H, m), 3.50 (2H, t, J=7.8 Hz), 5.61 (2H, s), 6.45
(1H, d, J=7.5 Hz), 7.24 (1H, t, J=7.6 Hz), 7.35 (1H, t, J=7.5 Hz),
7.57 (1H, d, J=7.9 Hz), 7.69 (1H, d, J=8.5 Hz), 7.81 (1H, dd, J=1.7
and 8.4 Hz), 8.12 (1H, d, J=1.2 Hz), 12.25 (1H, s).
[0754] IR(KBr): 1684 cm.sup.-1.
[0755] mp: 173.3-179.8.degree. C.
[0756] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=pentyl, n=1, y=0)
Example 220
1-(2-Chlorobenzyl)-2-Methyl-6-[(3-Methylbutane)Sulfonylcarbamoyl]Benzimida-
zole
[0757] By using te method of example 111,
1-(2-chlorobenzyl)-2-methyl-6-[(-
3-methylbutane)sulfonylcarbamoyl]benzimidazole (0.284 g) is
obtained from 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole
(0.300 g), N,N'-carbonyldiimidazole (0.323 g),
1-(3-methyl)butanesulfonamide (0.302 g) and diazabicycloundecene
(0.303 g). .sup.1H-NMR (DMSO-d6, .delta.): 0.84 (6H, d, J=6.5 Hz),
1.52-1.59 (2H, m), 1.61-1.70 (1H. m), 3.44 (2H, t, J=7.9 Hz), 5.60
(2H, s), 6.45 (1H, d, J=7.8 Hz), 7.24 (1H, t, J=7.6 Hz), 7.35 (1H,
t, J=7.4 Hz), 7.57 (1H, d, J=7.9 Hz), 7.66 (1H, d, J=8.5 Hz), 7.81
(1H, dd, J=1.6 and 8.6 Hz), 8.09 (1H, s), 11.87 (1H, s).
[0758] IR(KBr): 1682 cm.sup.-1.
[0759] mp: 201.0-204.1.degree. C.
[0760] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=3-methylbutyl, n=1, y=0)
Example 221
1-(2-Chlorobenzyl)-6-(1-Hexanesulfonylcarbamoyl)-2-Methylbenzimidazole
[0761] By using the method of example 111,
1-(2-chlorobenzyl)-6-(1-hexanes-
ulfonylcarbamoyl)-2-methylbenzimidazole (0.379 g) is obtained from
6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (0.300 g),
N,N'-carbonyldiimidazole (0.323 g), 1-hexanesulfonamide (0.335 g)
and diazabicycloundecene (0.303 g). .sup.1H-NMR (DMSO-d6, .delta.):
0.81 (3H, t, J=7.0 Hz), 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=7.7 Hz), 5.64 (2h,
s), 6.51 (1H, d, J=7.7 Hz), 7.25 (1H, dt, J=1.2 and 7.8 Hz), 7.36
(1H, dt, J=1.4 and 7.7 Hz), 7.58 (1H, dd, J=1.0 and 8.0 Hz), 7.72
(1H, d, J=8.5 Hz), 7.84 (1H, dd, J=1.6 and 8.5 Hz), 8.15 (1H, d,
J=1.3 Hz), 11.87 (1H, s).
[0762] IR(KBr): 1682 cm.sup.-1.
[0763] mp: 141.2-143.5.degree. C.
[0764] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=hexyl, n=1, y=0)
Example 222
1-(2,4-Dichlorobenzyl)-7-Ethoxycarbonyl-2-Methylbenzimidazole
A.)
2-[N-(2,4-Dichlorobenzyl)acetylamino]-3-nitro-methylbenzoate
[0765] By using the method of example 47, part B,
2-[N-(2,4-dichlorobenzyl- )acetylamino]-3-nitro-methylbenzoate
(0.250 g) is obtained from 2-acetylamino-3-nitro-methylbenzoate
(1.00 g) and 2,4-dichlorobenzyl chloride (0.985 g).
[0766] .sup.1H-NMR (CDCl.sub.3, .delta.): 1.99 (3H, s), 3.71 (3H,
s), 4.85 (1H, d, J=4.5 Hz), 4.98 (1H, d, J==4.5 Hz), 7.17-7.22 (2H,
m), 7.46 (1H, d, J=7.9 Hz), 7.63 (1H, t, J=7.9 Hz), 7.98 (1H, d,
J=8.0 Hz), 8.09 (1H, d, J=7.9 Hz).
B.)
1-(2,4-Dichlorobenzyl)-7-ethoxycarbonyl-2-methylbenzimidazole
[0767] By using the method of example 47,
1-(2,4-dichlorobenzyl)-7-ethoxyc- arbonyl-2-methylbenzimidazole
(5.15 g) is obtained from
2-[N-(2,4-dichlorobenzyl)acetylamino]-3-nitro-methylbenzoate (6.50
g). .sup.1H-NMR (CDCl.sub.3, .delta.): 2.53 (3H, s), 3.70 (3H, s),
5.72 (2H, s), 6.26 (1H, d, J=8.4 Hz), 7.04 (1H, dd, J=2.0 and 8.4
Hz), 7.28 (1H, t, J=7.9 Hz), 7.45 (1H, d, J=2.0 Hz), 7.75 (1H, d,
J=7.8 Hz), 7.93 (1H, d, J=7.9 Hz).
[0768] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 223
7-Carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole
[0769] By using the method of example 75,
7-carboxy-1-(2,4-dichlorobenzyl)- -2-methylbenzimidazole (1.76 g)
is obtained from 1-(2,4-dichlorobenzyl)-7--
ethoxycarbonyl-2-methylbenzimidazole (2.00 g). .sup.1H-NMR(DMSO-d6,
.delta.): 2.49 (3H, s), 5.81 (2H, s), 6.09 (1H, d, J=8.4 Hz),
7.21-7.28 (2H, m), 7.62 (1H, d, J=7.8Hz), 7.67 (1H, d, J=2.2 Hz),
7.83 (1H, d, J=8.0 Hz), 13.04 (1H, br s).
[0770] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=carboxyl, n=1, y=0)
Example 224
7-(1-Butanesulfonylcarbamoyl)-1-(2,4-Dichlorobenzyl)-2-Methylbenzimidazole
[0771] By using the method of example 111,
7-(1-butanesulfonylcarbamoyl)-1-
-(2,4-dichlorobenzyl)-2-methylbenzimidazole (0.325 g) is obtained
from 7-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (0.463
g), N,N'-carbonyldiimidazole (0.448 g), 1-butanesulfonamide (0.379
g) and diazabicycloundecene (0.421 g). .sup.1H-NM (DMSO-d6,
.delta.): 0.84 (3H, t, J=7.3 Hz), 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=8.4 Hz), 7.25
(1H, dd, J=2.1 and 8.4 Hz), 7.30 (1H, t, J=7.8 Hz), 7.44 (1H, d,
J=7.4 Hz), 7.68 (1H, d, J=2.1 Hz), 7.87 (1H, d, J=7.8 Hz), 12.18
(1H, br s).
[0772] IR(KBr): 1690 cm.sup.-1.
[0773] mp: 98.5-102.0.degree. C.
[0774] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=butyl, n=1, y=0)
Example 225
1-(2-Chlorobenzyl)-2-Methyl-6-[1-[3-(Trimethylsilyl)Propane]Sulfonylcarbam-
oyl]Benzimidazole
[0775] By using the method of example 111,
1-(2-chlorobenzyl)-2-methyl-6-[-
1-[3-(trimethylsilyl)propanel]sulfonylcarbamoyl]benzimidazole
(0.604 g) is obtained from
6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (0.400 g),
N,N'-carbonyldiimidazole (0.431 g),
1-[3-(trimethylsilyl)propane]sulf- onamide (0.520 g), and
diazabicycloundecene (0.404 g).
[0776] .sup.1H-NMR (DMSO-d6, .delta.): -0.06 (9H, s), 0.61 (2H, t,
J=8.6 Hz), 1.66-1.73 (2H, m), 2.50 (3H, s), 3.51 (2H, t, J=7.7 Hz),
5.61 (2H, s), 6.46 (1H, d, J=7.8 Hz), 7.24 (1H, t, J=7.6 Hz), 7.35
(1H, t, J=7.6 Hz), 7.57 (1H, dd, J=7.9 and 0.9 Hz), 7.70 (1H, d,
J=8.5 Hz), 7.81 (1H, dd, J=1.5 and 8.5 Hz), 8.12 (1H, d, J=1.4 Hz),
11.98 (1H, s).
[0777] IR(KBr): 1688 cm.sup.-1.
[0778] mp: 197.0-203.9.degree. C.
[0779] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=3-trimethylsilyl-propyl, n=1, y=0)
Example 226
4-Ethoxycarbonyl-2-Methylbenzimidazole
[0780] A mixture of 2-acetylamino-3nitromethylzenzoate (8.03 g),
reduced iron (18.8 g), acetic acid (20 ml), and ethanol (40 ml) is
refluxed by heating for 18 hours. After the solvent is
concentrated, chloroform and 10% hydrochloric acid is added to the
residue and extraction is performed. After a saturated sodium
bicarbonate aqueous solution is added to the water layer to turn it
basic, chloroform extraction is performed. The chloroform is
removed under reduced pressure and thus,
4-ethoxycarbonyl-2-methylbenzimidazole (1.61 g) is obtained.
.sup.1H-NMR (CDCl.sub.3, .delta.): 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).
[0781] (R.sub.1=H, R.sub.2=methyl, R.sub.3=-ethoxycarbonyl, n=1,
y=0)
Example 227
1-(2,4-Dichlorobenzyl)-4-Ethoxycarbonyl-2-Methylbenzimidazole
[0782] A mixture of 4-ethoxycarbonyl-2-methylbenzimidazole (1.61
g), 2,4-dichlorobenzyl chloride (3.08 g), potassium iodide (1.51
g), potassium carbonate (1.05 g) and N,N-dimethylformamide (4 ml)
is stirred for 16 hours at 80.degree. C. Chloroform and water are
added and extraction is performed. The chloroform layer is washed
with water, dried, and concentrated. The residue is purified using
silica gel column chromatography (eluate: hexane/ethyl acetate=2/8)
and thus,
1-(2,4-dichlorobenzyl)-4-ethoxycarbonyl-2-methylbenzimidazole
(0.730 g) is obtained. .sup.1H-NMR (CDCl.sub.3, .delta.): 1.47 (3H,
t, J=7.1 Hz), 2.63 (3H, s), 4.52 (2H, q, J=7.1 Hz), 5.39 (2H, s),
6.30 (1H, d, J=8.4 Hz), 7.06 (1H, dd, J=2.1 and 8.4 Hz), 7.25 (1H,
t, J=7.9 Hz), 7.32 (1H, dd, J=1.0 and 7.9 Hz), 7.48 (1H, d, J=2.0
Hz), 7.93 (1H, dd, J=1.0 and 7.7 Hz).
[0783] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=-ethoxycarbonyl, n=1, y=0)
Example 228
4-Carboxy-1-(2,4-Dichlorobenzyl)-2-Methylbenzimidazole
[0784] By using the method of example 75,
4-carboxy-1-(2,4-dichlorobenzyl)- -2-methylbenzimidazole (0.575 g)
is obtained from 1-(2,4-dichlorobenzyl)-4-
-ethoxycarbonyl-2-methylbenzimidazole (0.730 g). .sup.1H-NMR
(DMSO-d6, .delta.): 2.65 (3H, s), 5.67 (2H, s), 6.73 (1H, d, J=8.3
Hz), 7.33 (1H, dd, J=2.2 and 8.4 Hz), 7.39 (1H, t, J=7.9 Hz), 7.74
(1H, d, J=2.2 Hz), 7.76 (1H, d, J=8.2 7.7 Hz), 7.85 (1H, d, J=7.5
Hz).
[0785] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=carboxyl, n=1, y=0)
Example 229
4-(1-Butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole
[0786] By using the method of example 111,
4-(1-butanesulfonyl-carbamoyl)--
1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (0.275 g) is obtained
from 4-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (0.350
g), N,N'-carbonyldiimidazole (0.339 g), 1-butanesulfonamide (0.287
g) and diazabicycloundecene (0.318 g). .sup.1H-NMR (DMSO-d6,
.delta.): 0.86 (3H, t, J=7.3 Hz), 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=8.4 Hz), 7.32
(1H, dd, J=2.1 and 8.4 Hz), 7.39 (1H, t, J=7.9 Hz), 7.73 (1H, d,
J=2.1 Hz), 7.78 (1H, d, J=8.0 Hz), 7.91 (1H, d, J=7.7 Hz), 12.66
(1H, br s).
[0787] IR(KBr): 1699 cm.sup.-1.
[0788] mp: 180.7-183.6.degree. C.
[0789] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=butyl, n=1, y=0)
Example 230
1-(4-Benzyloxybenzyl)-6-Ethoxycarbonyl-2-Methylbenzimidazole
[0790] By using the method of example 47, part B, preliminarily
purified 3-[N-(4-benzyloxybenzyl)acetylamino]-4-nitroethylzenzoate
is obtained from 3-acetylamino-4-nitro-ethylbenzoate (2.00 g) and
4-chlorobenzyl chloride (3.69 g). Subsequently, by using the method
of example 47, part C, preliminarily purified
1-(4-benzyloxybenzyl)-6-ethoxycarbonyl-2-methyl- benzimidazole
(4.09 g) is obtained.
[0791] (R.sub.1=4-benzyloxybenzyl, R.sub.2=methyl,
R.sub.3=-ethoxycarbonyl- , n=1, y=0)
Example 231
1-(4-Benzyloxybenzyl)-6-Carboxy-2-Methylbenzimidazole
[0792] By using the method of example 75,
1-(4-benzyloxybenzyl)-6-carboxy-- 2-methylbenzimidazole (1.13 g) is
obtained from 1-(4-benzyloxy-benzyl)-6-e-
thoxycarbonyl-2-methylbenzimidazole (4.09 g)..sup.1H-NMR (DMSO-d6,
.delta.): 2.57 (3H, s), 5.05 (2H, s), 5.48 (2H, s), 6.97 (2H, d,
J=8.6 Hz), 7.08 (2H, d, J=8.5 Hz), 7.28-7.43 (5H, m), 7.60 (1H, d,
J=8.3 Hz), 7.78 (1H, d, J=7.5 Hz), 8.07 (1H, s), 12.72 (1H, s).
[0793] (R.sub.1=4-benzyloxybenzyl, R.sub.2=methyl,
R.sub.3=-carboxyl, n=1, y=0)
Example 232
1-(4-Benzyloxybenzyl)-6-(1-Butanesulfonylcarbamoyl)-2-Methylbenzimidazole
[0794] By using the method of example 111,
1-(4-benzyloxybenzyl)-6-(1-buta-
nesulfonylcarbamoyl)-2-methylbenzimidazole (0.206 g) is obtained
from 6-carboxy-1-(2-benzyloxybenzyl)-2-methylbenzimidazole (0.300
g), N,N'-carbonyldiimidazole (0.242 g), 1-butanesulfonamide (0.204
), and diazabicyclo-undecene (0.227 g). .sup.1H-NMR (DMSO-d6,
.delta.): 0.87 (3H, t, J=7.3 Hz), 1.38-1.43 (2H, m), 1.64-1.71 (2H,
m), 2.54 (3H, s), 3.49 (2H, t, J=6.8 Hz), 5.05 (2H, s), 5.45 (2H,
s), 6.98 (2H, d, J=8.7 Hz), 7.10 (2H, d, J=8.7 Hz), 7.31 (1H, t,
J=7.2 Hz), 7.37 (2H, t, J=7.2 Hz), 7.41 (2H, d, J=7.3 Hz), 7.62
(1H, d, 8.5 Hz), 7.79 (1H, dd, J-1.5 and 8.4 Hz), 8.23 (1H, s),
11.93 (1H, s).
[0795] IR(KBr): 1684 cm.sup.-1.
[0796] mp 132.4-137.7.degree. C.
[0797] (R.sub.1=4-benzyloxybenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R- .sub.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=butyl, n=1, y=0)
Example 233
6-Ethoxycarbonyl-1-[(2'-Cyanobiphenyl-4-yl)Methyl]-2-Methylbenzimidazole
[0798] By using the method of example 47, part B, preliminarily
purified
3-[N-[(2'-cyanobiphenyl-4-yl)methyl]acetylamino]-4-nitroethyl-benzoate
(0.750 g) is obtained from 3-acetylamino-4-nitro-ethylbenzoate
(1.00 g) and 4'-bromomethyl-2-cyanobiphenyl (1.30 g). Subsequently,
by using the method of example 47, part C,
6-ethoxycarbonyl-1-[(2'-cyanobiphenyl-4-yl)-
methyl]-2-methylbenzimidazole (0.410 g) is obtained. .sup.1H-NMR
(CDCl.sub.3, .delta.): 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 8.5 Hz), 8.05 (1H, d, J=1.2 Hz).
[0799] (R.sub.1=2'-cyano-4-biphenyl, R.sub.2=methyl,
R.sub.3=-ethoxycarbonyl, n=1, y=1)
Example 234
6-Carboxy-1-[(2'-Cyanobiphenyl-4-yl)Methyl]-2-Methylbenzimidazole
[0800] By using the method of example 75,
6-carboxy-1-[(2'-cyanobiphenyl-4- -yl)methyl]-2-methylbenzimidazole
(0.190 g) is obtained from
6-ethoxycarbonyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-2-methylbenzimidazole
(0.410 g).
[0801] .sup.1H-NMR (DMSO-d6, .delta.): 2.59 (3H, s), 5.67 (2H, s),
7.24 (2H, d, J=8.1 Hz), 7.53-7.64 (5H, m), 7.75 (1H, t, J=7.7 Hz),
7.80 (1H, d), 7.92 (1H, d, J=7.7 Hz), 8.12 (1H, s), 12.74 (1H, br
s).
[0802] (R.sub.1=2'-cyano-4-biphenyl, R.sub.2=methyl,
R.sub.3=-carboxyl, n=1, y=1)
Example 235
6-(1-Butanesulfonylcarbamoyl-1-[(2'-Cyanobiphenyl-4-yl)Methyl]-2-Methyl-Be-
nzimidazole
[0803] By using the method of example 162,
6-(1-butanesulfonyl-carbamoyl-1-
-[(2'-cyanobiphenyl-4-yl)methyl]-2-methylbenzimidazole (0.155 g) is
obtained from
6-carboxy-1-[(2'-cyanobiphenyl-4-yl)methyl]-2-methylbenzimi- dazole
(0.187 g), N,N'-carbonyldiimidazole (0.160 g), 1-butanesulfonamide
(0.135 g) and diazabicycloundecene (0.150 g) through purification
using silica gel column chromatography (eluate:
chloroform/methanol=20/1). .sup.1H-NMR (DMSO-d6, .delta.): 0.83
(3H, t, J=7.4 hz), 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=8.2 Hz), 7.53-7.57 (4H, m),
7.60 (1H, d, J=7.8 Hz), 7.75 (1H, dt, J=1.0 and 7.8 Hz), 7.83 (1H,
dd, J=1.5 and 8.4 Hz), 7.92 (1H. d), 8.13 (1H, s), 11.92 (1H, br
s).
[0804] IR(KBr): 2223 cm.sup.-1.
[0805] mp: 115-118.degree. C.
[0806] (R.sub.1=2'-cyano-4-biphenyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=butyl, n=1, y=1)
Example 236
6-Ethoxycarbonyl-1-[(2'-Fluorobiphenyl-4-yl)Methyl]-2-Methylbenzimidazole
A.) 2-Fluoro-4'-methylbiphenyl
[0807] 1.6M-n-Butyllithiumhexane solution (30 ml) is added to
tetrahydrofuran (30 ml), the tetrahydrofuran is chilled to
-78.degree. C. under a nitrogen environment beforehand. Subsequent
to this addition, a tetrahydrofuran (30 ml) solution of
4-bromotoluene (8.33 g) is added. Then, the solution is stirred for
one hour at -78.degree. C. A tetrahydrofuran (30 ml) solution of
zinc chloride (6.64 g), which had been heat-dissolved and
dehydrated under reduced pressure, is added to the solution at
-78.degree. C. and the solution is stirred for one hour at room
temperature. This solution is added to a tetrahydrofuran (30 ml)
solution of 2-fluoroiodobenzene (7.22 g) and
tetrakis(triphenylphosphyne)- palladium, (0.52 g) at room
temperature, and the solution is stirred for a day and a night. The
reaction solution is diluted with ethyl acetate (300 ml), 10%
hydrochloric acid is added, and extraction is performed. After the
organic layer is washed with a saturated saline solution and dried,
it is concentrated. The residue is purified using silica gel column
chromatography (eluate: hexane) and thus, oily
2-fluoro-4'-methylbiphenyl (6.05 g) is obtained. .sup.1H-NMR
(CDCl.sub.3, .delta.): 2.39 (3H, s), 7.10-7.30 (5H, m), 7.39-7.49
(3H, m).
B.) 2-Fluoro-4'-bromomethylbiphenyl
[0808] A mixture of 2-fluoro-4'-methylbiphenyl (8.70 g),
N-bromosuccinimide (8.32 g), 2,2'-azobisisobutyronitrile (0.10 g)
and carbon tetrachloride (150 ml) is refluxed by heating for five
hours. The reaction solution is washed with water. The residue,
which is obtained by concentrating the organic layer, is purified
using silica gel column chromatography (eluate: hexane/ethyl
acetate=9/1) and thus, preliminarily purified
2-fluoro-4'-bromomethylbiphenyl is obtained. Furthermore,
crystallization using hexane produced
2-fluoro-4'-bromomethylbiphenyl (4.93 g). .sup.1H-NMR (CDCl.sub.3,
.delta.): 4.55 (2H, s), 7.13-7.23 (2H, m), 7.33 (1H, m), 7.43 (1H,
m), 7.47 (2H, d, J=8.1 Hz), 7.54 (2H, d, J=8.1 Hz).
C.)
3-[N-[(2'-Fluorobiphenyl-4-yl)methyl]acetylamino]-4-nitro-ethylbenzoat-
e
[0809] By using the method of example 47, part B,
3-[N-[(2'-fluorobiphenyl-
-4-yl)methyl]acetylamino]-4-nitro-ethylbenzoate (1.90 g) is
obtained from 3-acetylamino-4-niro-ethylbenzoate (1.54 g) and
2-fluoro-4'-bromomethylbi- phenyl (2.26 g). .sup.1H-NMR
(CDCl.sub.3, .delta.): 1.33 (3H, t, J=7.1 Hz), 1.92 (3H, s), 4.36
(2H, m), 4.44 (1H, d, J=4.4 Hz), 5.32 (1H, d, J=4.4 Hz), 7.13 (1H,
m), 7.18-7.22 (3H, m), 7.31 (1H, m), 7.40 (1H, dt, J=1.6 and 7.7
Hz), 7.44 (2H, d), 7.67 (1H, d, J=1.6 Hz), 7.94 (1H, d, J=8.4 Hz),
8.15 (1H, dd, J=1.8 and 8.4 Hz).
D.)
6-Ethoxycarbonyl-1-[(2'-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidaz-
ole
[0810] By using the method of example 47, part C,
6-ethoxycarbonyl-1-[(2'--
fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole (1.53 g) is
obtained from
3-[N-[(2'-fluorobiphenyl-4-yl)methyl]acetylamino]-4-nitro-ethylbenzo-
ate (1.90 g). .sup.1H-NMR (CDCl.sub.3, .delta.): 1.40 (3H, t, J=7.1
Hz), 2.62 (3H, s), 4.38 (2H, q, J=7.1 Hz), 5.43 (2H, s), 7.10-7.17
(3H, m), 7.19 (1H, dt, J=1.0 and 7.5 Hz), 7.31 (1H, m), 7.38 (1H,
dt, J=1.8 and 7.8 Hz), 7.50 (2H, dd), 7.74 (1H, d, J=8.5 Hz), 8.00
(1H, dd, J=1.4 and 8.4 Hz), 8.06 (1H, s).
[0811] (R.sub.1=2'-fluoro-4-biphenyl, R.sub.2=methyl,
R.sub.3=ethoxycarbonyl, n=1, y=1)
Example 237
6-Carboxy-1-[(2'-Fluorobiphenyl-4-yl)Methyl]-2-Methylbenzimidazole
[0812] By using the method of example 75,
6-carboxy-1-[(2'-fluorobiphenyl--
4-yl)methyl]-2-methylbenzimidazole (1.24 g) is obtained from
6-ethoxycarbonyl-1-[(2'-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole
(1.50 g).
[0813] .sup.1H-NMR (DMSO-d6, .delta.): 2.59 (3H, s), 5.63 (2H, s),
7.19 (2H, d, J=8.1 Hz), 7.24-7.31 (2H, m), 7.39 (1H, m), 7.46-7.53
(3H, m), 7.62 (1H, d, J=8.4 Hz), 7.80 (1H, dd, J=1.3 and 8.4 Hz),
8.10 (1H, s).
[0814] (R.sub.1=2'-fluoro-4-biphenyl, R.sub.2 methyl, R.sub.3
ethoxycarbonyl, n=1, y=1)
Example 238
6-(1-Ethanesulfonylcarbamoyl)-1-[(2'-Fluorobiphenyl-4-yl)Methyl]-2-Methyl--
Benzimidazole
[0815] By using the method of example 111,
6-(1-ethanesulfonyl-carbamoyl)--
1-[(2'-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole (0.340 g)
is obtained from
6-carboxy-1-[(2'-fluorobiphenyl-4-yl)methyl]-2-methylbenzim-
idazole (0.455 g), N,N'-carbonyldiimidazole (0.409 g),
1-butanesulfonamide (0.346 g) and diazabicycloundecene (0.384 g).
.sup.1H-NMR (DMSO-d6, .delta.): 0.84 (3H, t, J=7.3 Hz), 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=8.0 Hz), 7.24-7.30 (2H, m), 7.39 (1H, m), 7.48 (1H, t),
7.52 (2H, d, J=8.0 Hz), 7.66 (1H, d, J=8.5 Hz), 7.80 (1H, d, J=8.5
Hz), 8.25 (1H.s), 11.93 (1H, br s).
[0816] (R.sub.1=2'-fluoro-4-biphenyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=ethyl, n=1, y=1)
Example 239
6-Ethoxycarbonyl-1-[(3-Fluorobiphenyl-4-yl)Methyl]-2-Methylbenzimidazole
A.) 3-Fluoro-4-methylbiphenyl
[0817] 1.6M-n-Butyllithiumhexane solution (30 ml) is added to
tetrahydrofuran (30 ml), the tetrahydrofuiran is chilled to
-78.degree. C. under a nitrogen environment beforehand. Subsequent
to this addition, a tetrahydrofuran (30 ml) solution of
4-bromo-2-fluorotoluene (9.21 g) is added. Then, the solution is
stirred for one hour at -78.degree. C. A tetrahydrofuran (30 ml)
solution of zinc chloride (6.64 g), which had been heat-dissolved
and dehydrated under reduced pressure, is added to the solution at
-78.degree. C. and the solution is stirred for one hour at room
temperature. This solution is added to a tetrahydrofuran (30 ml)
solution of iodobenezen (6.63 g) and
tetrakis(triphenylphosphyne)palladiu- m, (0.52 g) at room
temperature, and the solution is stirred for a day and a night. The
reaction solution is diluted with ethyl acetate (300 ml), 10%
hydrochloric acid is added, and extraction is performed. After the
organic layer is washed with a saturated saline solution and dried,
it is concentrated. The residue is purified using silica gel column
chromatography (eluate: hexane) and thus, oily
3-fluoro-4-methylbiphenyl (6.00 g) is obtained. .sup.1H-NMR
(CDCl.sub.3, .delta.): 2.31 (3H, d, J=1.8 Hz), 7.20-7.28 (3H, m),
7.34 (1H, m), 7.43 (2H, t), 7.55 (2H, d).
B.) 4-Bromomethyl-3-fluorobiphenyl
[0818] A mixture of 3-fluoro-4-methylbiphenyl (6.00 g),
N-bromosuccinimide (5.73 g), 2,2'-azobisisobutyronitrile (0.075 g)
and carbon tetrachloride (120 ml) is refluxed by heating for five
hours. The reaction solution is washed with water. The residue,
which is obtained by concentrating the organic layer, is purified
using silica gel column chromatography (eluate: hexane/ethyl
acetate=9/1) and thus, oily 4-bromomethyl-3-fluorob- iphenyl (8.30
g) is obtained. .sup.1H-NMR (CDCl.sub.3, .delta.): 4.57 (2H, s),
7.30 (1H, d, J=11.0 Hz), 7.34-7.40 (2H, m), 7.45 (3H, m), 7.56 (2H,
d).
C.)
3-[N-[(3-Fluorobiphenyl-4-yl)methyl]acetylamino]-4-nitro-ethylbenzoate
[0819] By using the method of example 47, part B, 2.68 g of a
preliminarily purified material of
3-[N-[(3-fluorobiphenyl-4-yl)methyl]ac-
etylamino]-4-nitro-ethylbenzoate is obtained from
3-acetylamino-4-nitro-et- hylbenzoate (1.54 g) and
3-fluoro-4-bromomethylbiphenyl (2.26 g).
D.)
6-Ethoxycarbonyl-1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazo-
le
[0820] By using the method of example 47, part C,
6-ethoxycarbonyl-1-[(3-f-
luorobiphenyl-4-yl)methyl]-2-methylbenzimidazole (1.34 g) is
obtained from the preliminarily purified material (2.68 g) of
3-[N-[(3-fluorobiphenyl-4-
-yl)methyl]acetylamino]-4-nitro-ethylbenzoate. .sup.1H-NMR
(CDCl.sub.3, .delta.): 1.40 (3H, t, J=7.1 Hz), 2.65 (3H, s), 4.39
(2H, q, J=7.1 Hz), 5.46 (2H, s), 6.79 (1H, t, J=8.0 Hz), 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=8.5 Hz), 7.99 (1H, dd, J=1.5 and 8.4 Hz), 8.07 (1H, d,
J=1.3 Hz).
[0821] (R.sub.1=2'-fluoro-4-biphenyl, R.sub.2=methyl,
R.sub.3=-ethoxycarbonyl, n=1, y=1)
Example 240
6-Carboxy-1-[(3-Fluorobiphenyl-4-yl)Methyl]-2-Methylbenzimidazole
[0822] By using the method of example 75,
6-carboxy-1-[(3-fluorobiphenyl-4- -yl)methyl]-2-methylbenzimidazole
(1.15 g) is obtained from
6-ethoxycarbonyl-1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole
(1.34 g).
[0823] .sup.1H-NMR (DMSO-d6, .delta.): 2.59 (3H, s), 5.64 (2H, s),
7.03 (1H, t, J=8.0 Hz), 7.37 (1H, t, J=7.3 Hz), 7.42-7.48 (3H, m),
7.56-7.68 (4H, m), 7.79 (1H, dd, J=1.4 and 8.4 Hz), 8.11 (1H, s),
12.7 (1H, br s).
[0824] (R.sub.1=2'-fluoro-4-biphenyl, R.sub.2=methyl,
R.sub.3=-carboxyl, n=1, y=1)
Example 241
6-(1-Butanesulfonylcarbamoyl)-1-[(3-Fluorobiphenyl-4-yl)Methyl]-2-Methyl-B-
enzimidazole
[0825] By using the method of example 111,
6-(1-butanesulfonyl-carbamoyl)--
1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole (0.236 g)
is obtained from
6-carboxy-1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimi- dazole
(0.390 g), N,N'-carbonyldiimidazole (0.351 g), 1-butanesulfonamide
(0.297 g) and diazabicycloundecene (0.329 g). .sup.1H-NMR (DMSO-d6,
.delta.): 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=8.1 Hz), 7.37 (1H, m),
7.42-7.47 (3H, m), 7.60 (1H, dd, J=1.7 and 11.8 Hz), 7.62-7.68 (3H,
m), 7.80 (1H, dd, J=1.5 and 8.4 Hz), 8.21 (1H, d, J=1.3 Hz), 11.90
(1H, br s).
[0826] IR(Nujol): 1681 cm.sup.-1.
[0827] mp: 227-230.degree. C.
[0828] (R.sub.1=3-fluoro-4-biphenyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=butyl, n=1, y=1)
Example 242
1-(2-Chlorobenzyl)-6-[(2-Methoxyethane)Sulfonylcarbamoyl]-2-Methylbenzimid-
azote
[0829] By using the method of example 111,
1-(2-chlorobenzyl)-6-[(2-methox-
yethane)sulfonylcarbamoyl]-2-methylbenzimidazole (0.149 g) is
obtained from
1-(biphenyl-4-ylmethyl)-6-carboxy-2-ethylbenzimidazole (0.300 g),
N,N'-carbonyldiimidazole (0.272 g), (2-ethoxyethane)sulfonamide
(0.258 g) and diazabicycloundecene (0.256 g). .sup.1H-NMR (DMSO-d6,
.delta.): 0.87 (3H, t, J=6.9 Hz), 1.30 (3H, t, J=8.0 Hz), 2.89 (2H,
q, J=7.6 Hz), 3.25-3.35 (2H, m), 3.63-3.74 (2H, m), 5.59 (2H, s),
7.17 (2H, d, J=8.1 Hz), 7.34 (1H, t, J=7.0 Hz), 7.44 (2H, t, J=7.6
Hz), 7.58-7.68 (5H, m), 7.82 (1H, d, J=8.4 Hz), 8.23 (1H, s), 11.88
(1H, s).
[0830] IR(Nujol): 1681 cm.sup.-1.
[0831] mp: 78-81.degree. C.
[0832] (R.sub.1=2-chlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.su- b.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=2-methoxyethyl, n=1, y=0)
Example 243
1-(2,4-Dichlorobenzyl)-2-Methyl-6-(1-Pentanesulfonylcarbamoyl)Benzimidazol-
e
[0833] By using the method of example 111,
1-(2,4-dichlorobenzyl)-2-methyl-
-6-(1-pentanesulfonylcarbamoyl)benzimidazole (0.196 g) is obtained
from 6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (0.300
g), N,N'-carbonyldiimidazole (0.323 g), 1-pentanesulfonamide (0.301
g) and diazabicyclo-undecene (0.303 g). .sup.1H-NMR (DMSO-d6,
.delta.): 0.81 (3H, t, J=7.3 Hz), 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=7.8 Hz), 5.59
(2H, s), 6.45 (1H, d, J=8.4 Hz), 7.33 (1H, dd, J=2.2 and 8.5 Hz),
7.69 (1H, t, J=8.5 Hz), 7.76 (1H, d, J=2.1 Hz), 7.80 (1H, dd, J=1.6
and 8.5 Hz), 8.10 (1H, s), 11.89 (1H, s).
[0834] IR(Nujol): 1682 cm.sup.-1.
[0835] mp: 213.2-214.6.degree. C.
[0836] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=pentyl, n=1, y=0)
Example 244
1-(Biphenyl-4-ylmethyl)-2-Ethyl-6-[1-[3-(Methylthio)Propane]Sulfonylcarbam-
oyl]Benzimidazole
[0837] By using the method of example 111,
1-(biphenyl-4-ylmethyl)-2-ethyl-
-6-[1-[3-(methylthio)propane]sulfonylcarbamoyl]benzimidazole (0.178
g) is obtained from
6-carboxy-1-(biphenyl-4-ylmethyl)-2-ethylbenzimidazole (0.300 g),
N,N'-carbonyldiimidazole (0.272 g), 1-[(3-methylthio)propane]s-
ulfonamide (0.285 g) and diazabicycloundecene (0.256 g).
.sup.1H-NMR (DMSO-d6, .delta.): 1.30 (3H, t, J=7.5 Hz), 1.91-1.99
(2H, m), 1.97 (3H, s), 2.58 (2H, t, J=7.2 Hz), 2.90 (2H, q, J=7.6
Hz), 3.55-3.61 (2H, m), 5.60 (2H, s), 7.18 (2H, d, J=8.2 Hz), 7.35
(1H, t, J=7.3 Hz), 7.44 (2H, t, J=7.5 Hz), 7.60-7.66 (4H, m), 7.69
(1H, d, J=8.5 Hz), 7.82 (1H, dd, J=1.8 and 8.5 Hz), 8.24 (1H, s),
11.98 (1H, s).
[0838] IR(Nujol): 1671 cm.sup.-1.
[0839] mp: 89.9-91.2.degree. C.
[0840] (R.sub.1=4-biphenyl, R.sub.2=ethyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=3-methylthiopropyl, n=1, y=1)
Example 245
1-(4-Biphenylmethyl)-2-Ethyl-6-(1-Pentanesulfonylcarbamoyl)Benzimidazole
[0841] By using the method of example 111,
1-(4-biphenylmethyl)-2-ethyl-6--
(1-pentanesulfonylcarbamoyl)benzimidazole (0.258 g) is obtained
from 6-carboxy-1-(4-biphenylmethyl)-2-ethylbenzimidazole (0.300 g),
N,N'-carbonyldiimidazole (0.272 g), 1-pentanesulfonamide (0.254 g)
and diazabicyclo-undecene (0.256 g). .sup.1H-NMR (DMSO-d6,
.delta.): 0.87 (3H, t, J=7.2 Hz), 1.22-1.39 (4H, m), 1.30 (3H, t,
J=7.5 Hz), 1.66-1.73 (2H, m), 2.90 (2H, q, J=7.4 Hz), 3.51 (2H, t,
J=7.7 Hz), 5.60 (2H, s), 7.18 (2H, d, J=8.2 Hz), 7.34 (1H, t, J=7.4
Hz), 7.44 (2H, t, J=7.6 Hz), 7.60-7.67 (4H, m), 7.71 (1H, d, J=8.4
Hz), 7.81 (1H, dd, J=1.6 and 8.4 Hz), 8.27 (1H, d, J=1.1 Hz), 11.92
(1H, s).
[0842] IR(Nujol): 1682 cm.sup.-1.
[0843] mp: 175.3-178.4.degree. C.
[0844] (R.sub.1=4-biphenyl, R.sub.2=ethyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=3-pentyl, n=1, y=1)
Example 246
6-(1-Butanesulfonylcarbamoyl)-1-(2,4-Dichlorobenzyl)-2-Ethylbenzimidazole
[0845] By using the method of example 111,
6-(1-butanesulfonyl-carbamoyl)--
1-(2,4-dichlorobenzyl)-2-ethylbenzimidazole (0.253 g) is obtained
from 6-carboxy-1-(2,4-dichlorobenzyl)-2-ethylbenzimidazole (0.300
g), N,N'-carbonyldiimidazole (0.258 g), 1-butanesulfonamide (0.217
g) and diazabicycloundecene (0.262 g). .sup.1H-NMR (DMSO-d6,
.delta.): 0.85 (3H, t, J=7.4 Hz), 1.27 (3H, t, J=7.4 Hz), 1.35-1.43
(2H, m), 1.63-1.70 (2H, m), 2.81 (2H, q, J=7.4 Hz), 3.51 (2H, t,
J=7.7 Hz), 5.59 (2H, s), 6.41 (1H, d, J=8.4 Hz), 7.32 (1H, dd,
J=2.0 and 8.4 Hz), 7.73 (1H, d, J=8.4 Hz), 7.76 (1H, d, J=2.0 Hz),
7.81 (1H, dd, J=1.5 and 8.5 Hz), 8.12 (1H, d, J=1.6 Hz), 11.87 (1H,
s).
[0846] IR(Nujol): 1694 cm.sup.-1.
[0847] mp: 175.7-176.9.degree. C.
[0848] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=ethyl,
R.sub.3=--C(O)NR.sub.4R- .sub.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=butyl, n=1, y=0)
Example 247
1-(4-Biphenylmethyl)-2-Ethyl-6-[1-(3-Methyl)Butanesulfonylcarbamoyl]Benzim-
idazole
[0849] By using the method of example 111,
1-(4-biphenylmethyl)-2-ethyl-6--
[1-(3-methyl)butanesulfonylcarbamoyl]benzimidazole (0.273 g) is
obtained from 1-(4-biphenylmethyl)-6-carboxy-2-ethylbenzimidazole
(0.300 g), N,N'-carbonyldiimidazole (0.272 g),
1-(3-methyl)butanesulfonamide (0.254 g) and diazabicycloundecene
(0.256 g).
[0850] .sup.1H-NMR (DMSO-d6, .delta.): 0.85 (6H, d, J=6.5 Hz), 1.30
(3H, t, J=7.4 Hz), 1.55-1.62 (2H, m), 1.63-1.70 (1H, m), 2.90 (2H,
q, J=7.4 Hz), 3.52 (2H, t, J=7.9 Hz), 5.61 (2H, s), 7.19 (2H, d,
J=8.3 Hz), 7.35 (1H, t, J=7.4 Hz), 7.44 (2H, t, J=7.5 Hz),
7.61-7.66 (4H, m), 7.71 (1H, d, J=8.5 Hz), 7.81 (1H, dd, J=1.6 and
8.4 Hz), 8.27 (1H, s), 11.95 (1H, s).
[0851] IR(Nujol): 1682 cm.sup.-1.
[0852] mp: 102.8-104.50.degree. C.
[0853] (R.sub.1=4-biphenyl, R.sub.2=ethyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=3-methylbutyl, n=1, y=1)
Example 248
1-(2,4-Dichlorobenzyl)-5-Ethoxycarbonyl-2-Methylbenzimidazole
[0854] By using the method of example 47, part B,
4-[N-((2,4-dichlorobenzy- l)acetylamino]-3-nitro-ethylbenzoate is
obtained from 4-acetylamino-3-nitro-ethylbenzoate (1.525 g) and
2,4-dichlorobenzyl chloride (1.42 g). By using the method of
example 47, part C, without purification, this material is altered
to 1-(2,4-dichlorobenzyl)-5-ethoxy- carbonyl-2-methylbenzimidazole
(1.476 g). .sup.1H-NMR (CDCl.sub.3, .delta.): 1.42 (3H, t, J=7.1
Hz), 2.57 (3H, s), 4.41 (2H, q, J=7.1 Hz), 5.38 (2H, s), 6.35 (1H,
d, J=8.4 Hz), 7.09 (1H, dd, J=2.0 and 8.4 Hz), 7.16 (1H, d, J=8.9
Hz), 7.49 (1H, d, J=2.0 Hz), 7.96 (1H, dd, J=1.5 and 8.5 Hz), 8.46
(1H, s).
[0855] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=-ethoxycarbonyl, n=1, y=0)
Example 249
5-Carboxy-1-(2,4-Dichlorobenzyl)-2-Methylbenzimidazole
[0856] By using the method of example 75,
5-carboxy-1-(2,4-dichlorobenzyl)- -2-methylbenzimidazole (1.195 g)
is obtained from 1-(2,4-dichlorobenzyl)-5-
-ethoxycarbonyl-2-methylbenzimidazole (1.465 g). .sup.1H-NMR
(DMSO-d6, .delta.): 2.48 (3H, s), 5.56 (2H, s), 6.53 (1H, d, J=8.4
Hz), 7.32 (1H, dd, J=2.1 and 8.4 Hz), 7.44 (1H, d, J=8.4 Hz), 7.73
(1H, d, J=2.2 Hz), 7.78 (1H, dd, J=1.5 and 8.4 Hz), 8.15 (1H, d,
J=1.3 Hz).
[0857] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=-carboxyl, n=1, y=0)
Example 250
5-(1-Butanesulfonylcarbamoyl)-1-(2,4-Dichlorobenzyl)-2-Methylbenzimidazole
[0858] By using the method of example 111,
5-(1-butanesulfonyl-carbamoyl)--
1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (0.690 g) is obtained
from 5-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (0.565
g), N,N'-carbonyldiimidazole (0.504 g), 1-butanesulfonamide (0.427
g) and diazabicycloundecene (0.473 g). .sup.1H-NMR (DMSO-d6,
.delta.): 0.87 (3H, t, J=7.3 Hz), 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=8.4 Hz), 7.33
(1H, dd, J=2.1 and 8.4 Hz), 7.50 (1H, d, J=8.5 Hz), 7.73 (1H, d,
J=2.1 Hz), 7.78 (1H, dd, J=1.5 and 8.5 Hz), 8.24 (1H, s), 11.97
(1H, br s).
[0859] IR(Nujol): 1674 cm.sup.-1.
[0860] mp: 135.4-139.2.degree. C.
[0861] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=butyl,n=1, y=0)
Example 251
1-(4-Biphenylmethyl)-5-Ethoxycarbonyl-2-Ethylbenzimidazole
[0862] By using the method of example 47, part B,
4-[N-[(4-biphenylmethyl)- propionylamino]-3-nitro-ethylbenzoate is
obtained from 4-propionylamino-3-nitro-ethylbenzoate (1.50 g) and
4-bromomethylbiphenyl (1.67 g). By using the method of example 47,
part C, without purification, this material is altered to
1-(4-biphenylmethyl)-5-ethoxyca- rbonyl-2-ethylbenzimidazole (1.23
g). .sup.1H-NMR (CDCl.sub.3, .delta.): 1.40 (3H, t, J=7.1 Hz), 1.45
(3H, t, J=7.6 Hz), 2.90 (2H, q, J=7.6 Hz), 4.39 (2H, q, J=7.1 Hz),
5.40 (2H, s), 7.09 (2H, d, J=8.2 Hz), 7.27 (1H, d, J=8.8 Hz), 7.34
(1H, m), 7.42 (2H, t), 7.55-7.51 (4H, m), 7.97 (1H, dd, J=1.5 and
8.4 Hz), 8.52 (1H, d, J=1.2 Hz).
[0863] (R.sub.1=4-biphenyl, R.sub.2=ethyl, R.sub.3=-ethoxycarbonyl,
n=1, y=1)
Example 260
1-(4-Biphenylmethyl)-5-Carboxy-2-Ethylbenzimidazole
[0864] By using the method of example 75,
1-(4-biphenylmethyl)-5-carboxy-2- -ethylbenzimidazole (0.870 g) is
obtained from 1-(4-biphenylmethyl)-5-etho-
xycarbonyl-2-ethylbenzimidazole (1.00 g). .sup.1H-NMR (DMSO-d6,
.delta.): 1.30 (3H, t, J=7.4 Hz), 2.90 (2H, q, J=7.4 Hz), 5.57 (2H,
s), 7.17 (2H, d, J=8.3 Hz), 7.33 (1H, m), 7.42 (2H, t), 7.63-7.57
(5H, m), 7.81 (1H, dd, J=1.6 and 8.6 Hz), 8.18 (1H, d, J=1.3 Hz),
12.67(1H, br s).
[0865] (R.sub.1=4-biphenyl, R.sub.2=ethyl, R.sub.3=-carboxyl, n=1,
y=1)
Example 261
1-(4-Biphenylmethyl)-5-(1-Butanesulfonylcarbamoyl)-2-Ethylbenzimidazole
[0866] By using the method of example 111,
1-(4-biphenylmethyl)-5-(1-butan-
esulfonylcarbamoyl)-2-ethylbenzimidazole (0.305 g) is obtained from
1-(4-biphenylmethyl)-5-carboxy-2-ethylbenzimidazole (0.400 g),
N,N'-carbonyl-diimidazole (0.364 g), 1-butanesulfonamide (0.308 g)
and diazabicycloundecene (0.342 g). .sup.1H-NMR (DMSO-d6, .delta.):
0.86 (3H, t, J=7.4 Hz), 1.30 (3H, t, J=7.5 Hz), 1.41 (2H, m), 1.68
(2H, m), 2.91 (2H, q, J=7.4 Hz), 3.52 (2H, m), 5.59 (2H, s), 7.16
(2H, d, J=8.2 Hz), 7.34 (1H, t, J=7.4 Hz), 7.43 (2H, t), 7.59-7.65
(5H, m), 7.80 (1H, dd, J=1.6 and 8.6 Hz), 8.24 (1H, d, J=1.6 Hz),
11.97 (1H, br s).
[0867] IR(Nujol): 1682 cm.sup.-1.
[0868] mp: 142.9-144.4.degree. C.
[0869] (R.sub.1=4-biphenyl, R.sub.2=ethyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=butyl, n=1, y=1)
Example 254
1-(4-Biphenylmethyl)-2-Ethyl-6-(2-Methoxyethanesulfonylcarbamoyl)Benzimida-
zole
[0870] By using the method of example 111,
1-(4-biphenylmethyl)-2-ethyl-6--
(2-methoxyethanesulfonylcarbamoylbenzimidazole (0.487 g)is obtained
from benzimidazole (0.513 g), N,N'-carbonyldiimidazole (0.464 g),
2-methoxyethanesulfonamide (0.420 g) and diazabicycloundecene
(0.438 g). .sup.1H-NMR (DMSO-d6, .delta.): 1.30 (3H, t, J=7.5 Hz),
2.90 (2H, 1, J=7.4 Hz), 3.13 (3H, s), 3.70-3.77 (4H, m), 5.60 (2H,
s), 7.18 (2H, d, J=8.2 Hz), 7.35 (1H, t, J=7.1 Hz), 7.44 (2H, t,
J=7.5 Hz), 7.60-7.67 (4H, m), 7.70 (1H, d, J=8.5 Hz), 7.80 (1H, dd,
J=7.4 and 1.3 Hz), 8.25 (1H, s), 11.97 (1H, s).
[0871] IR(Nujol): 1684 cm.sup.-1.
[0872] mp: 94.6-97.25.degree. C.
[0873] (R.sub.1=4-biphenyl, R.sub.2=ethyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=2-methoxyethayl, n=1, y=1)
Example 255
6-Ethoxycarbonyl-2-Ethyl-1-[4-(4-Fluorobenzyloxy)Benzyl]Benzimidazole
[0874] A mixture of 4-propionylamino-3-amino-ethylbenzoate (0.534
g), potassium carbonate (0.374 g), 4-(4-fluorobenzyloxy)benzyl
bromide (0.800 g), ethyl acetate (5 ml) and water (3 ml) is stirred
for 16 hours at 75.degree. C. The organic layer is concentrated,
and ethanol and 36% hydrochloric acid (0.46 g) are added to the
obtained residue. The residue is stirred for two hours as it is
refluxed by heating. After neutralizing it by adding potassium
carbonate, the solvent is concentrated under reduced pressure.
Ethyl acetate and water are added and extraction is performed. The
organic layer is concentrated under reduced pressure, purified
using silica gel column chromatography (eluate: hexane/ethyl
acetate=1/1), and thus,
6-ethoxycarbonyl-2-ethyl-1-[4-(4-fluorobenzyloxy)-
benzyl]benzimidazole (0.228 g) is obtained. .sup.1H-NR (CDCl.sub.3,
.delta.): 1.40 (3H, t, J=7.1 Hz), 1.42 (3H, t, J=7.5 Hz), 2.86 (2H,
q, J=7.5 Hz), 4.38 (2H, q, J=7.1 Hz), 4.97 (2H, s), 5.32 (2H, s),
6.88 (2H, q, J=8.7 Hz), 6.98 (2H, d, J=8.7 Hz), 7.05 (2H, t, J=8.7
Hz), 7.37 (2H, m), 7.76 (2H, d, J=8.4 Hz), 7.98 (1H, dd, J=1.5 and
8.5 Hz), 8.02 (1H, s).
[0875] (R.sub.1=4-(4-fluorobenzyloxy)benzyl, R.sub.2=ethyl,
R.sub.3=-ethoxycarbonyl, n=1, y=0)
Example 264
6-Carboxy-2-Ethyl-1-[4-(4-Fluorobenzyloxy)benzyl]Benzimidazole
[0876] By using the method of example 75,
6-carboxy-2-ethyl-1-[4-(4-fluoro- benzyloxy)benzyl]benzimidazole
(0.175 g) is obtained from
6-ethoxycarbonyl-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole
(0.225 g). .sup.1H-NMR (DMSO-d6, .delta.): 1.28 (3H, t, J=7.4 Hz),
2.89 (2H, q, J=7.4 Hz), 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=8.4 Hz),
7.77 (1H, d, J=8.4 Hz), 8.05 (1H, s).
[0877] (R.sub.1=4-(4-fluorobenzyloxy)benzyl, R.sub.2=ethyl,
R.sub.3=-carboxyl, n=1, y=0)
Example 257
6-(1-Butanesulfonylcarbamoyl)-2-Ethyl-1-[4-(4-Fluorobenzyloxy)benzyl]Benzi-
midazole Ammonium Salt
[0878] By using the method of example 111, oily
6-(1-butanesulfonylcarbamo-
yl)-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole is
obtained from
6-carboxy-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole
(0.171 g), N,N'-carbonyldiimidazole (0.137 g), butanesulfonamide
(0.116 g) and diazabicycloundecene (0.129 g). This is dissolved in
ethyl acetate, and aqueous ammonia is added. Precipitated solids
are separated through filtration, dried, and thus,
6-(1-Butanesulfonylcarbamoyl)-2-ethyl-1-[4-(-
4-fluorobenzyloxy)benzyl]benzimidazole Ammonium Salt (0. 140 g) is
obtained. .sup.1H-NMR (DMSO-d6, .delta.): 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=7.8 Hz), 7.02 (2H, d, J=7.8
Hz), 7.17 (2H, t), 7.44 (2H, m), 7.57 (1H, d, J=8.1 Hz), 7.82 (1H,
d, J=8.1 Hz), 8.12 (1H, s).
[0879] IR(Nujol): 1614 cm.sup.-1.
[0880] mp: 105-115.degree. C.
[0881] (R.sub.1=4-(4-fluorobenzyloxy)benzyl, R.sub.2=ethyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=butyl, n=1, y=0)
Example 258
1-[4-(3,4-Dichlorobenzyloxy)Benzyl]-6-Ethoxycarbonyl-2-Ethylbenzimidazole
[0882] By using the method of example 255,
1-[4-(3,4-dichlorobenzyloxy)ben-
zyl]-6-ethoxycarbonyl-2-ethylbenzimidazole (2.01 g) is obtained
from 4-propionylamino-3-amino-ethylbenzoate (1.81 g) and
4-(3,4-dichlorobenzyloxy)benzyl bromide (3.18 g). .sup.1H-NMR
(CDCl.sub.3, .delta.): 1.40 (3H, t, J=7.1 Hz), 1.42 (3H, t, J=7.5
Hz), 2.86 (2H, q, J=7.5 Hz), 4.38 (2H, q, J=7.1 Hz), 4.97 (2H, s),
5.33 (2H, s), 6.87 (2H, m), 6.98 (2H, m), 7.22 (1H, dd, J=2.0 and
8.3 Hz), 7.44 (1H, d, J=8.3 Hz), 7.50 (1H, d, J=2.0 Hz), 7.76 (1H,
d, J=8.6 Hz), 7.97 (1H, dd, J=1.6 and 8.6 Hz), 8.02 (1H, d, J=1.3
Hz).
[0883] (R.sub.1=4-(3,4-dichlorobenzyloxy)benzyl, R.sub.2=ethyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 259
6-Carboxy-1-[4-(3,4-Dichlorobenzyloxy)benzyl]-2-Ethylbenzimidazole
[0884] By using the method of example 75,
6-carboxy-1-[4-(3,4-dichlorobenz-
yloxy)benzyl]-2-ethylbenzimidazole (1.82 g) is obtained from
6-ethoxycarbonyl-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole
(2.01 g).
[0885] .sup.1H-NMR (DMSO-d6, .delta.): 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=8.4 Hz), 8.06 (1H, s).
[0886] (R.sub.1=4-(3,4-dichlorobenzyloxy)benzyl, R.sub.2=ethyl,
R.sub.3=carboxyl, n=1, y=0)
Example 260
6-(1-Butanesulfonylcarbamoyl)-1-[4-(3,4-Dichlorobenzyloxy)benzyl]-2-Ethylb-
enzimidazole Ammonium Salt
[0887] By using the method of example 111, oily
6-(1-butanesulfonylcarbamo-
yl)-1-[4-(3,4-dichlorobenzyloxy)benzyl]-2-ethylbenzimidazole is
obtained from
6-carboxy-1-[4-(3,4-dichlorobenzyloxy)benzyl]-2-ethylbenzimidazole
(0.500 g), N,N'-carbonyldiimidazole (0.356 g), butanesufonamide
(0.301 g) and diazabicycloundecene (0.334 g). This is dissolved in
ethyl acetate, and aqueous ammonia is added. Precipitated solids
are separated through filtration, dried, and thus,
6-(1-butanesulfonylcarbamoyl)-1-[4-(3,4-dich-
lorobenzyloxy)benzyl]-2-ethylbenzimidazole ammonium salt (0.51 g)
is obtained. .sup.1H-NMR (DMSO-d6, .delta.): 0.82 (3H, t, J=7.3
Hz), 1.26 (3H, t, J=7.4 Hz), 1.31 (2H, m), 1.54 (2H, m), 2.84 (2H,
q, J=7.4 Hz), 3.07 (2H, m), 5.05 (2H, s) 5,41 (2H, s), 6.95 (2H, d,
J=8.7 Hz), 7.00 (2H, d, J=8.7 Hz), 7.41 (2H, d, J=8,2 Hz), 7.46
(2H, d, J=8.4 Hz), 7.62 (1H, d, J=8.2 Hz), 7.68 (1H, s), 7.81 (1H,
d, J=8.4 Hz), 7.97 (1H, s).
[0888] IR(Nujol): 1540 cm.sup.-1.
[0889] mp: 99.5-101.5.degree. C.
[0890] (R.sub.1=4-(3,4-dichlorobenzyloxy)benzyl, R.sub.2=ethyl,
R.sub.3=--C(O)--NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, n=1, y=0)
Example 261
1-(4-Biphenylmethyl)-6-(n-Butylcarbamoyl)-2-Ethylbenzimidazole
[0891] By using the method of example 26,
1-(4-biphenylmethyl)-6-(n-butylc- arbamoyl)-2-ethylbenzimidazole
(0.295 g) is obtained from
1-(4-biphenylmethyl)-6-chlorocarbonyl-2-ethylbenzimidazole
hydrochloride (0. 400 g), n-butylamine (0.233 g) and triethylamine
(0.215 g). .sup.1H-NMR (DMSO-d6, .delta.): 0.95 (3H, t, J=7.3 Hz),
1.37-1.48 (2H, m), 1.45 (3H, t, J=7.4 Hz), 1.57-1.63 (2H, m), 2.90
(2H, q, J=7.5 Hz), 3.46 (2H, q, J=7.1 Hz), 5.42 (2H, s), 6.16 (1H,
br s), 7.10 (2H, d, J=8.1 Hz), 7.34 (1H, t, J=7.5 Hz), 7.42 (2H, t,
J=7.5 Hz), 7.48-7.57 (5H, m), 7.87 (1H, d, J=8.4 Hz), 7.91 (1H,
s).
[0892] IR(Nujol): 1621 cm.sup.-1.
[0893] mp: 170.5-173.0.degree. C.
[0894] (R.sub.1=4-biphenyl, R.sub.2=ethyl,
R.sub.3=--C(O)--NR.sub.4R.sub.5- , R.sub.4=n-butyl, R.sub.5=H, n=1,
y=1)
Example 262
1-(4-Biphenylmethyl)-2-Ethyl-6-(Thiazole-2-ylcarbamoyl)Benzimidazole
[0895] By using the method of example 26,
1-(4-biphenylmethyl)-2-ethyl-6-(-
thiazole-2-ylcarbamoyl)benzimidazole (0.179 g) is obtained from
1-(4-biphenylmethyl)-6-chlorocarbonyl-2-ethylbenzimidazole
hydrochloride (0.400 g), 2-aminothiazole (0.318 g) and
triethylamine (0.215 g). .sup.1H-NMR (DMSO-d6, .delta.): 1.48 (3H,
t, J=7.5 Hz), 2.95 (2H, q, J=7.5 Hz), 5.41 (2H, s), 6.94 (1H, d,
J=3.6 Hz), 7.06 (2H, d, J=8.1 Hz), 7.26 (1H, d, J=3.6 Hz), 7.32
(1H, t, J=7.4 Hz), 7.39 (2H, t, J=7.3 Hz), 7.47-7.51 (4H, m), 7.87
(2H, s), 8.03 (1H, s), 11.15 (1H, s).
[0896] IR(Nujol): 1652 cm.sup.-1.
[0897] mp: 225.2-227.7.degree. C.
[0898] (R.sub.1=4-biphenyl, R.sub.2=ethyl,
R.sub.3=--C(O)--NR.sub.4R.sub.5- , R.sub.4=2-thiazolyl, R.sub.5=H,
n=1, y=1)
Example 263
1-(4-Biphenylmethyl)-2-Ethyl-6-(2-Pyridylcarbamoyl)Benzimidazole
[0899] By using the method of example 111,
1-(4-biphenylmethyl)-2-ethyl-6-- (2-pyridylcarbamoyl)benzimidazole
(0.11 6 g) is obtained from
1-(4-biphenylmethyl)-6-carboxy-2-ethylbenzimidazole (0.300 g),
N,N'-carbonyldiimidazole (0.272 g), 2-aminopyridine (0.158 g) and
diazabicycloundecene (0.256 g). .sup.1H-NMR (CDCl.sub.3, .delta.):
1.47 (3H, t, J=7.6 Hz), 2.93 (2H, q, J=7.4 Hz), 5.45 (2H, s), 7.06
(1H, dd, J=7.4 and 4.9 Hz), 7.10 (2H, d, J=8.1 Hz), 7.34 (1H, t,
J=7.4 Hz), 7.42 (2H, t, J=7.6 Hz), 7.50-7.55 (4H, m), 7.75 (1H, t,
J=7.9 Hz), 7.79 (1H, d, J=8.4 Hz), 7.86 (1H, d, J=8.4 Hz), 7.98
(1H, s), 8.30 (1H, d, J=6.2 Hz), 8.38 (1H, d, J=8.4 Hz), 8.62 (1H,
s).
[0900] IR(Nujol): 1661 cm.sup.-1.
[0901] mp: 160.9-164.5.degree. C.
[0902] (R.sub.1=4-biphenyl, R.sub.2=ethyl,
R.sub.3=--C(O)--NR.sub.4R.sub.5- , R.sub.4=2-pyridyl, R.sub.5=H,
n=1, y=1)
Example 264
6-(n-Butylcarbamoyl)-1-(2,4-Dichlorobenzyl)-2-Methylbenzimidazole
[0903] By using the method of example 26,
6-(n-butylcarbamoyl)-1-(2,4-dich- lorobenzyl)-2-methylbenzimidazole
(0.156 g) is obtained from
6-chlorocarbonyl-1-(2,4-dichlorobenzyl)-2-ethylbenzimidazole
hydrochloride (0.300 g), triethylamine (0.181 g) and n-butylamine
(0.196 g). .sup.1H-NMR (CDCl.sub.3, .delta.): 0.96 (3H, t, J=7.3
Hz), 1.37-1.43 (2H, m), 1.55-1.62 (2H, m), 2.56 (3H, s), 3.46 (2H,
q, J=7.0 Hz), 5.40 (2H, s), 6.15 (1H, br s), 6.32 (1H, d, J=8.5
Hz), 7.07 (1H, d, J=8.4 Hz), 7.48 (1H, d, J=2.0 Hz), 7.55 (1H, d,
J=8.4 Hz), 7.74 (1H, d, J=8.4 Hz), 7.79 (1H, s).
[0904] IR(Nujol): 1636 cm.sup.-1.
[0905] mp: 146.6-147.5.degree. C.
[0906] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)--NR.sub.4R.sub.5, R.sub.4=n-butyl, R.sub.5=H, n =1,
y=0)
Example 265
1-[sec-(2,4-Dichlorophenethyl)]-6-Ethoxycarbonyl-2-Methylbenzimidazole
A.) 3-[sec-(2,4-Dichlorophenethyl)amino]-4-nitro-ethylbenzoate
[0907] A toluene (5 ml) solution of 3-fluoro-4-nitro-benzoic acid
(0.877 g) and sec-(2,4-dichlorophenethyl)amine (2.25 g) is refluxed
by heating for 15 hours. After the solvent is removed by
evaporation, the residue is purified using silica gel column
chromatography and thus, a preliminarily purified material of
3-[sec-(2,4-dichlorophenethyl)amino]-4-nitro-benzoic acid is
obtained. Ethanol (80 ml) and 97% sulfuric acid (3.0 g) are added
to this, and the solution is refluxed by heating for 4.5 hours.
After removing the ethanol by evaporation under reduced pressure,
chloroform and a saturated sodium bicarbonate aqueous solution are
added and extraction is performed. After drying the organic layer,
a residue is obtained through concentration under reduced pressure.
The residue is purified using silica gel column chromatography
(eluate: hexane/ethyl acetate=2/1) and thus,
3-[sec-(2,4-dichlorophenethyl)amino]-4-nitro-ethyl- benzoate (1.16
g) is obtained. .sup.1H-NMR (CDCl.sub.3, .delta.): 1.35 (3H, t,
J=7.1 Hz), 1.64 (3H, d, J=6.6 Hz), 4.30 (2H, q, J=7.1 Hz), 5.16
(1H, m), 7.18-7.31 (4H, m), 7.43 (1H, d, J=2.0 Hz), 8.21 (1H, d,
J=8.8 Hz), 8.34 (1H, d, J=5 Hz).
B.) 4-Amino-3-[sec-(2,4-dichlorophenethyl)amino]ethylbenzoate
[0908] A mixture of
3-[sec-(2,4-dichlorophenethyl)amino]-4-nitro-ethylbenz- oate (1.14
g), reduced iron (1.60 g), ethanol (10 ml) and acetic acid (5 ml)
is refluxed by heating for three hours. Solids are separated
through filtration. The filtrate is concentrated and a residue is
formed. Extraction is performed on the residue with chloroform and
10% hydrochloric acid. The organic layer is washed with a saturated
sodium bicarbonate aqueous solution and the solvent is removed by
evaporation under reduced pressure. The obtained residue is
purified using silica gel column chromatography (eluate:
hexane/ethyl acetate=2/1) and thus,
4-amino-3-[sec-(2,4-dichlorophenethyl)amino]ethylbenzoate (0.920 g)
is obtained. .sup.1H-NMR (CDCl.sub.3, .delta.): 1.31 (3H, t, J=7.1
Hz), 1.52 (3H, d, J=6.7 Hz), 3.56 (1H, br s), 3.79 (2H, br s), 4.23
(2H, q, J=7.1 Hz), 4.96 (1H, q, J=6.7 Hz), 6.68 (1H, d, J=8.0 Hz),
7.03 (1H, d, J=1.7 Hz), 7.15 (1H, dd, J=2.1 and 8.4 Hz), 7.35 (1H,
d, J=8.4 Hz), 7.39-7.43 (2H, m).
C.)
1-[sec-(2,4-Dichlorophenethyl)]-6-ethoxycarbonyl-2-methylbenzimidazole
[0909] Acetyl chloride (0.243 g) is dripped into a pyridine (2.0
ml) solution of
4-amino-3-[sec-(2,4-dichlorophenethyl)amino]ethylbenzoate (0.900 g)
at room temperature. After the solution is stirred for one hour at
room temperature, ethyl acetate and excessive 10% hydrochloric acid
are added and extraction is performed. The organic layer is washed
with a saturated sodium bicarbonate aqueous solution. Removal of
the solvent through evaporation under reduced pressure produced a
preliminarily purified material of
4-4-acetylamino-3-[sec-(2,4-dichlorophenethyl)amino]-
ethylbenzoate. This is immediately dissolved in ethanol (20 ml).
36% hydrochloric acid (0.4 ml) is added and the solution is
refluxed by heating for two hours. Sodium bicarbonate is added and
it is neutralized. The solvent is removed through evaporation under
reduced pressure. Ethyl acetate and water are added to the residue
and extraction is performed. The organic layer is concentrated,
purified using silica gel column chromatography (eluate: ethyl
acetate/methanol=20/1) and thus,
1-[sec-(2,4-dichlorophenethyl)]-6-ethoxycarbonyl-2-methylbenzimidazole
(0.700 g) is obtained. .sup.1H-NMR (CDCl.sub.3, .delta.): 1.38 (3H,
t, J=7.2 Hz), 2.01 (3H, d, J=7.2 Hz), 2.63 (3H, s), 4.29-4.40 (2H,
m), 5.89 (1H, q, J=7.2 Hz), 7.37 (1H, dd J=2.2 and 8.4 Hz), 7.40
(1H, d, J=2.0 Hz), 7.52 (1H, d, J=8.4 Hz), 7.67 (1H, d, J=8.4 Hz),
7.86 (1H, s), 7.91 (1H, dd, J=1.4 and 8.4 Hz).
[0910] (R.sub.1=sec-(2,4-dichlorophenethyl), R.sub.2=methyl,
R.sub.3=-ethoxycarbonyl, n=1, y=0)
Example 266
6-Carboxy-1'-[sec-(2,4-Dichlorophenethyl)-2-Methylbenzimidazole
[0911] By using the method of example 75,
6-carboxy-1-[sec-(2,4-dichloroph- enethyl)]-2-methylbenzimidazole
(0.447 g) is obtained from
1-[sec-(2,4-dichlorophenethyl)]-6-ethoxycarbonyl-2-methylbenzimidazole
(0.690 g). .sup.1H-NMR (DMSO-d6, .delta.): 1.88 (3H, d, J=6.8 Hz),
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).
[0912] (R.sub.1=sec-(2,4-dichlorophenethyl), R.sub.2=methyl,
R.sub.3=-carboxyl, n=1, y=0)
Example 267
6-(1-Butanesulfonylcarbamoyl)-1-[sec-(2,4-Dichlorophenethyl)]-2-Methylbenz-
imidazole
[0913] By using the method of example 111,
6-(1-butanesulfonyl-carbamoyl)--
1-[sec-(2,4-dichlorophenethyl)]-2-methylbenzimidazole is obtained
from
6-carboxy-1-[sec-(2,4-dichlorophenethyl)]-2-methylbenzimidazole
(0.433 g), N,N'-carbonyldiimidazole (0.412 g), butanesulfonamide
(0.348 g), and diazabicycloundecene (0.386 g). .sup.1H-NMR
(DMSO-d6, .delta.): 0.84 (3H, d, J=7.3 Hz), 1.34 (2H, m), 1.57 (2H,
m), 1.89 (3H, d, J=7.0 Hz), 2.49 (3H, s), 3.07 (2H, m), 5.954 (1H,
q, J=7.0 Hz), 7.41 (1H, d, J=8.7 Hz), 7.56 (1H, dd, J=2.1 and 8.5
Hz), 7.61 (1H, d, J=2.1 Hz), 7.74-7.79 (3H, m).
[0914] (R.sub.1=sec-(2,4-dichlorophenethyl), R.sub.2=methyl,
R.sub.3=--C(O)--NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=butyl, n=1, y=0)
Example 268
1-(4-Biphenylmethyl)-2-Ethyl-6-(Phenylcarbamoyl)Benzimidazole
[0915] By using the method of example 26,
1-(4-biphenylmethyl)-2-ethyl-6-(- phenylcarbamoyl)benzimidazole
(0.195 g) is obtained from
1-(4-biphenylmethyl)-6-chlorocarbamoyl-2-ethylbenzimidazole
hydrochloride (0.300 g), triethylamine (0.243 g) and aniline (0.224
g). .sup.1H-NMR (CDCl.sub.3, .delta.): 1.47 (3H, d, J=7.5 Hz), 2.93
(2H, q, J=7.5 Hz), 5.44 (2H, s), 7.11 (2H, d, J=8.2 Hz), 7.14 (1H,
t, J=7.4 Hz), 7.32-7.38 (3H, m), 7.42 (2H, t, J=7.4 Hz), 7.51-7.54
(4H, m), 7.63 (2H, d, J=7.8 Hz), 7.69 (1H, dd, J=8.4 and 1.6 Hz),
7.84 (1H, d, J=8.4 Hz), 7.88 (1H, br s), 7.97 (1H, d, J=1.5
Hz).
[0916] IR(Nujol): 1647 cm.sup.-1.
[0917] mp: 171.7-172.1.degree. C.
[0918] (R.sub.1=4-biphenyl, R.sub.2=ethyl,
R.sub.3=--C(O)--NR.sub.4.sub.5, R.sub.4=phenyl, R.sub.5=H, n=1,
y=1)
Example 269
1-(4-Biphenylmethyl)-2-Ethyl-6-(1,3,4-Thiadiazole-2-ylcarbamoyl)Benzimidaz-
ole
[0919] By using the method of example 111,
1-(4-biphenylmethyl)-2-ethyl-6--
(1,3,4-thiadiazole-2-ylcarbamoyl)benzimidazole (339) (0.234 g) is
obtained from 1-(4-biphenylmethyl)-6-carboxy-2-ethylbenzimidazole
(0.300 g), N,N'-carbonyldiimidazole (0.272 g),
2-amino-1,3,4-thiadiazole (0.170 g) and diazabicyclo-undecene
(0.256 g). .sup.1H-NMR (CDCl.sub.3, .delta.): 1.45 (3H, d, J=7.5
Hz), 2.90 (2H, q, J=7.5 Hz), 5.53 (2H, s), 7.07 (2H, d, J=8.3 Hz),
7.33 (1H, t, J=7.5 Hz), 7.40 (2H, t, J=7.3 Hz), 7.52 (4H, d, J=8.2
Hz), 7.89 (1H, d, J=8.5 Hz), 8.08 (1H, dd, J=8.5 and 1.6 Hz), 8.34
(1H, d, J=1.2 Hz), 7.60 (1H, s), 12.26 (1H, s).
[0920] IR(Nujol): 1654 cm.sup.-1.
[0921] mp: 230.1-233.4.degree. C.
[0922] (R.sub.1=4-biphenyl, R.sub.2=ethyl,
R.sub.3=--C(O)--NR.sub.4R.sub.5- , R.sub.4=2-(1,3,4-thiadiazolyl),
R.sub.5=H, n=1, y=1)
Example 270
1-(4-Biphenylmethyl)-2-Ethyl-6-(Tetrazole-5-ylcarbamoyl)Benzimidazole
[0923] By using the method of example 111,
1-(4-biphenylmethyl)-2-ethyl-6--
(tetrazole-5-ylcarbamoyl)benzimidazole (340) (0.135 g) is obtained
from 1-(4-biphenylmethyl)-6-carboxy-2-ethylbenzimidazole (0.300 g),
N,N'-carbonyldiimidazole (0.272 g), 5-aminotetrazole (0.143 g) and
diazabicycloundecene (0.256 g). .sup.1H-NMR (DMSO-d6, .delta.):
1.32 (3H, t, J=7.5 Hz), 2.93 (2H, q, J=7.5 Hz), 5.61 (2H, s), 7.23
(2H, d, J=8.1 Hz), 7.34 (1H, t, J=7.4 Hz), 7.44 (2H, t, J=7.6 Hz),
7.60-7.67 (4H, m), 7.76 (1H, d, J=8.5 Hz), 7.98 (1H, d, J=8.6 Hz),
8.46 (1H, s), 12.30 (1H, s), 15.95 (1H, s).
[0924] IR(Nujol): 1667 cm.sup.-1.
[0925] mp: 273.1-276.0.degree. C.
[0926] (R.sub.1=4-biphenyl, R.sub.2=ethyl,
R.sub.3=--C(O)--NR.sub.4R.sub.5- , R.sub.4=5-tetrazolyl, R.sub.5=H,
n=1, y=1)
Example 271
1-(4-Biphenylmethyl)-2-Ethyl-6-(1,3,4-Triazole-3-ylcarbamoyl)Benzimidazole
[0927] By using the method of example 111,
1-(4-biphenylmethyl)-2-ethyl-6--
(1,3,4-triazole-3-ylcarbamoyl)benzimidazole (341) (0.224 g) is
obtained from 1-(4-biphenylmethyl)-6-carboxy-2-ethylbenzimidazole
(0.300 g), N,N'-carbonyldiimidazole (0.272 g),
3-amino-1,3,4-triazole (0.141 g) and diazabicycloundecene (0.256
g). .sup.1H-NMR (DMSO-d6, .delta.): 1.33 (3H, t, J=7.4 Hz), 2.93
(2H, q, J=7.4 Hz), 5.63 (2H, s), 7.17 (2H, d, J=8.3 Hz), 7.35 (1H,
t, J=7.4 Hz), 7.44 (2H, t, J=7.5 Hz), 7.60-7.65 (4H, m), 7.78 (1H,
d, J=7.4 Hz), 7.83 (1H, dd, J=8.4 and 1.5 Hz), 8.17 (1H, s), 8.77
(2H, s), 12.04 (1H, s).
[0928] IR(Nujol): 1675 cm.sup.-1.
[0929] mp: 263.4-266.2.degree. C.
[0930] (R.sub.1=4-biphenyl, R.sub.2=ethyl,
R.sub.3=--C(O)--NR.sub.4R.sub.5- , R.sub.4=3-(1,3,4-triazolyl),
R.sub.5=H, n=1, y=1)
Example 272
1-(4-Biphenylmethyl)-2-Ethyl-6-(1,3.4-Triazole-2-ylcarbamoyl)Benzimidazole
[0931] By using the method of example 111,
1-(4-biphenylmethyl)-2-ethyl-6--
(1,3,4-triazole-2-ylcarbamoyl)benzimidazole (342) (0.215 g) is
obtained from 1-(4-biphenylmethyl)-6-carboxy-2-ethylbenzimidazole
(0.300 g), N,N'-carbonyldiimidazole (0.272 g),
2-amino-1,3,4-triazole (0.141 g) and diazabicycloundecene (0.256
g). .sup.1H-NMR (DMSO-d6, .delta.): 1.31 (3H, t, J=7.4 Hz), 2.92
(2H, q, J=7.4 Hz), 5.60 (2H, s), 7.23 (2H, d, J=7.8 Hz), 7.34 (1H,
t, J=7.2 Hz), 7.44 (2H, t, J=7.6 Hz), 7.60-7.66 (4H, m), 7.72 (1H,
d, J=8.3 Hz), 7.78 (1H, s), 7.95 (1H, d, J=8.3 Hz), 8.43 (1H, s),
11.85 (1H, s), 13.57 (1H, s).
[0932] IR(Nujol): 1659 cm.sup.-1.
[0933] mp: 306.degree. C. (decomposition).
[0934] (R.sub.1=4-biphenyl, R.sub.2=ethyl,
R.sub.3=--C(O)--NR.sub.4R.sub.5- , R.sub.4=3-(1,3,4-triazolyl),
R.sub.5=H, n=1, y=1)
Example 273
1-(4-Biphenylmethyl-2-Ethyl-6-(3-Pyridylcarbamoyl)Benzimidazole
[0935] By using the method of example 111,
1-(4-biphenylmethyl)-2-ethyl-6-- (3-pyridylcarbamoyl)benzimidazole
(0.229 g) is obtained from
1-(4-biphenylmethyl)-6-carboxy-2-ethylbenzimidazole (0.300 g),
N,N'-carbonyldiimidazole (0.272 g), 3-aminopyridine (0.158 g) and
diazabicycloundecene (0.256 g). .sup.1H-NMR (CDCl.sub.3, .delta.):
1.47 (3H, t, J=7.6 Hz), 2.93 (2H, q, J=7.4 Hz), 5.45 (2H, s), 7.10
(2H, d, J=8.1 Hz), 7.29-7.36 (2H, m), 7.42 (2H, t, J=7.4 Hz), 7.53
(4H, d, J=8.0 Hz), 7.71 (1H, d, J=8.5 Hz), 7.86 (1H, d, J=8.4 Hz),
7.97 (1H, s), 7.98 (1H, s), 8.27 (1H, d, J=8.4 Hz), 8.38 (1H, d,
J=4.7 Hz), 8.68 (1H, d, J=2.5 Hz).
[0936] IR(Nujol): 1644 cm.sup.-1.
[0937] mp: 124.4-125.6.degree. C.
[0938] (R.sub.1=4-biphenyl, R.sub.2=ethyl,
R.sub.3=--C(O)--NR.sub.4R.sub.5- , R.sub.4=3-pyridyl, R.sub.5=H,
n=1, y=1)
Example 274
1-(2,4-Dichlorobenzyl)-2-Ethyl-6-(2-Pyridylcarbamoyl)Benzimidazole
[0939] By using the method of example 111,
1-(2,4-dichlorobenzyl)-2-ethyl--
6-(2-pyridylcarbamoyl)benzimidazole (0.152 g) is obtained from
6-carboxy-1-(2,4-dichlorobenzyl)-2-ethylbenzimidazole (0.300 g),
N,N'-carbonyldiimidazole (0.290 g), 2-aminopyridine (0.168 g) and
diazabicycloundecene (0.273 g). .sup.1H-NMR (CDCl.sub.3, .delta.):
2.59 (3H, s), 5.43 (2H, s), 6.33 (1H, d, J=8.4 Hz), 7.06-7.10 (2H,
m), 7.50 (1H, d, J=2.1 Hz), 7.77 (1H, dt, J=7.8 and 1.9 Hz), 7.83
(2H, s), 7.88 (1H, s), 8.30 (1H, d, J=3.7 Hz), 8.39 (1H, d, J=8.3
Hz), 8.78 (1H, s).
[0940] IR(Nujol): 1666 cm.sup.-1.
[0941] mp: 157.4-159.2.degree. C.
[0942] (R.sub.1=2,4-dichlorbenzyl, R.sub.2=ethyl,
R.sub.3=--C(O)--NR.sub.4- R.sub.5, R.sub.4=2-pyridyl, R.sub.5=H,
n=1, y=0)
Example 275
1-(4-Biphenylmethyl)-2-Ethyl-6-(4-Pyridylcarbamoyl)Benzimidazole
[0943] By using the method of example 111,
1-(4-biphenylmethyl)-2-ethyl-6-- (4-pyridylcarbamoyl)benzimidazole
(0.153 g) is obtained from
1-(4-biphenylmethyl)-6-carboxy-2-ethylbenzimidazole (0.300 g),
N,N'-carbonyldiimidazole (0.272 g), 4-aminopyridine (0.158 g) and
diazabicycloundecene (0.256 g). .sup.1H-NMR (CDCl.sub.3, .delta.):
1.48 (3H, t, J=7.4 Hz), 2.94 (2H, q, J=7.4 Hz), 5.45 (2H, s), 7.10
(2H, d, J=8.1 Hz), 7.35 (1H, d, J=7.4 Hz), 7.42 (2H, t, J=7.4 Hz),
7.50-7.60 (6H, m), 7.691 (1H, d, J=7.8 Hz), 7.86 (1H, d, J=8.3 Hz),
7.95 (1H, s), 7.99 (1H, br s), 8.54 (2H, dd, J=1.5 and 4.7 Hz).
[0944] IR(Nujol): 1663 cm.sup.-1.
[0945] mp: 123.8-124.7.degree. C.
[0946] (R.sub.1=4-biphenyl, R.sub.2=ethyl,
R.sub.3=--C(O)--NR.sub.4R.sub.5- , R.sub.4=4-pyridyl, R.sub.5=H,
n=1, y=1)
Example 276
6-(1-Butanesulfonylcarbamoyl)-1-[4-(2-Pyridyl)benzyl]-2-Methylbenzimidazol-
e
A.) N-(1-Butanesulfonyl)-4-acetylamino-3-nitrobenzamide
[0947] N,N'-carbonyldiimidazole (9.40 g) is added to an
N,N-dimethylformamide (300 ml) solution of
4-acetylamino-3-nitro-benzoic acid (10.0 g), and the solution is
stirred for 1 hour at room temperature. Then, 1-butanesulfonamide
(7.92 g) and diazabicycloundecene (8.83 g) are added into the
solution, and the solution is stirred for 72 hours at 100.degree.
C. After chloroform and water are added into the solution and the
solution is separated into layers, the residue, which is obtained
by concentrating the organic layer, is purified using silica gel
column chromatography (eluate: ethyl acetate/methanol=4/1), and
thus, N-(1-butanesulfonyl)-4-acetylamino-3-nitrobenzamide (10.75 g)
is obtained..sup.1H-NMR (DMSO-d6, .delta.): 0.87 (3H, t, J=7.4 Hz),
1.37-1.44 (2H, m), 1.64-1.71 (2H, m), 2.12 (3H, s), 3.52 (2H, t,
J=7.7 Hz), 7.83 (1H, d, J=8.6 Hz), 8.21 (1H, dd, J=8.6 and 2.1 Hz),
8.54 (1H, d, J=2.2 Hz), 10.56 (1H, s), 12.32 (1H, s).
B.) N-(1-butanesulfonyl)-3-amino-4-acetylaminobenzamide
[0948] N-(1-butanesulfonyl)-4-acetylamino-3-nitrobenzamide (10.75
g) is dissolved with methanol (200 ml) and water (30 ml), and
potassium bicarbonate (7.59 g) is added. The solution is
hydrogenated with a 5% palladium/carbon (2.53 g) catalyst under a
hydrogen environment for 24 hours at 40.degree. C. The solids are
separated through filtration, the residue, which is obtained by
concentrating the filtrate, is purified using silica gel column
chromatography (eluate: ethyl acetate/methanol=4/1), and 6.72 g of
N-1-butylsulfonyl-4-acetylamino-3-am- inobenzamide is obtained.
.sup.1H-NMR (DMSO-d6, .delta.): 0.86 (3H, t, J=7.3 Hz), 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), 7.13 (1H, dd, J=8.2 and 2.0 Hz), 7.28 (1H, d, J=1.9
Hz), 7.40 (1H, d, J=8.3 Hz), 9.09 (1H, s).
C.) Production
Example 57; Production of
N-(1-Butanesulfonyl)-4-acetylamino-3-[4-(2-pyrid-
yl)benzylamino]benzamide
[0949] By using the method of example 204, a crude product material
of
N-(1-butanesulfonyl)-4-acetylamino-3-[4-(2-pyridyl)benzylamino]benzamide
is obtained from
N-(1-butanesulfonyl)-3-amino-4-acetylaminobenzamide (0.400 g) and
2-[(4-brommethyl)phenyl]pyridine (0.477 g). This material is
immediately used for the following reaction.
D.)
6-(1-Butanesulfonylcarbamoyl)-1-[4-(2-pyridyl)benzyl]-2-methylbenzimid-
azole
[0950] By using the method of example 182,
6-(1-butanesulfonylcarbamoyl)-1-
-[4-(2-pyridyl)benzyl]-2-methylbenzimidazole (0.330 g) is obtained
from the above-described crude product material of
N-(1-butanesulfonyl)-4-acet-
ylamino-3-[4-(2-pyridyl)benzylamino]benzamide.
[0951] .sup.1H-NMR (DMSO-d6, .delta.): 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=7.8 Hz), 5.57
(2H, s), 7.19 (2H, t, J=7.5 Hz), 7.33 (1H, t, J=5.2 Hz), 7.49 (1H,
d, J=8.4 Hz), 7.82-7.87 (2H, m), 7.90 (1H, d, J=8.0 Hz), 8.01-8.04
(3H, m), 8.63 (1H, d, J=4.2 Hz).
[0952] IR(Nujol): 1722 cm.sup.-1.
[0953] mp: 292.4-298.4.degree. C.
[0954] (R.sub.1=4-(2-pyridyl)-benzyl, R.sub.2=methyl,
R.sub.3=--C(O)--NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=butyl, n=1, y=0)
Example 277
5-Chlorosulfonyl-1-(2,4-Dichlorobenzyl)-2-Methylbenzimidazole and
6-Chlorosulfonyl-1-(2,4-Dichlorobenzyl)-2-Methylbenzimidazole
[0955] In an ice bath, 1-(2,4-dichlorobenzyl)-2-methylbenzimidazole
(4.00 g) is added to chlorosulfonic acid (20 ml) and the solution
is stirred for 24 hours at room temperature and at 1.5 hours at
80.degree. C. The reaction solution is poured into ice water,
precipitated gummy solids are separated through filtration, and
thus, a mixture of
5-chlorosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole and
6-chlorosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole is
obtained. This material is immediately used for the following
reaction.
[0956] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=chlorosulfonyl, n=1, y=1)
Example 278
5-Aminosulfonyl-1-(2,4-Dichlorobenzyl)-2-Methylbenzimidazole and
6-Aminosulfonyl-1-(2,4-Dichlorobenzyl)-2-Methylbenzimidazole
[0957] The mixture of
5-chlorosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenz- imidazole and
6-chlorosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazol- e,
which is obtained in Example 285, is immediately processed with a
25% aqueous ammonia (100 ml) for one hour at room temperature.
Separation of solids through filtration produced a 1/1 mixture
(2.68 g) of
5-aminosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole and
6-aminosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole.
.sup.1H-NMR (CD.sub.3OD, .delta.): 2.52 (3/2H, s), 2.54 (3/2H, s),
5.54 (2H, s), 6.55 (1H, d, J=6.9 Hz), 7.17 (1H, d, J=8.0 Hz), 7.52
(1H, s), 7.65-7.78 (2H, m), 7.82 (1/2H, s), 8.11 (1/2H, s).
[0958] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=-aminosulfonyl, n=1, y=0)
Example 287
6-(n-Valerylaminosulfonyl)-1-(2,4-Dichlorobenzyl)-2-Methylbenzimidazole
and
5-(n-Valerylaminosulfonyl)-1-(2,4-Dichlorobenzyl)-2-Methylbenzimidazo-
le
[0959] Chloroform (1 ml), triethylamine (0.56 ml) and n-valeryl
chloride (0.500 g) are added to the mixture (0.500 g) of
5-aminosulfonyl-1-(2,4-di- chlorobenzyl)-2-methylbenzimidazole and
6-aminosulfonyl-1-(2,4-dichloroben- zyl)-2-methylbenzimidazole, and
the solution is stirred for 48 hours at room temperature. Water is
added, the reaction is halted, and chloroform extraction is
performed. The organic layer is dried, concentrated and purified
using silica gel column chromatography (eluate:
chloroform/methanol=95/5). Thus, a mixture (0.360 g) of
5-(n-valerylaminosulfonyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole
and
6-(n-valerylaminosulfonyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazo-
le is obtained. Further, purification of the material using medium
pressure silica gel column chromatography (eluate: hexane/ethyl
acetate=1/1.about.1/4) produced
6-(n-valerylaminosulfonyl)-1-(2,4-dichlor-
obenzyl)-2-methylbenzimidazole (0.95 g) and
5-(n-valerylaminosulfonyl)-1-(-
2,4-dichlorobenzyl)-2-methylbenzimidazole (0.45 g). .sup.1H-NMR
(DMSO-d6, .delta.): 0.74 (3H, t, J=7.3 Hz), 1.09 (2H, m), 1.31 (2H,
m), 2.10 (2H, t, J=7.3 Hz), 2.53 (3H, s), 5.63 (2H, s), 6.60 (1H,
d, J=8.4 Hz), 7.32 (1H, d, J=8.3 Hz), 7.67-7.77 (3H, m), 7.93 (1H,
s).
[0960] IR(KBr): 1726 cm.sup.-1.
[0961] mp: 207.5-210.0.degree. C.
[0962] Mass(FD): m/e 454(M+1).
[0963] .sup.1H-NMR (DMSO-d6, .delta.): 0.75 (3H, t, J=7.3 Hz), 1.11
(2H, m), 1.34 (2H, m), 2.13 (2H, t, J=7.4 Hz), 2.51 (3H, s), 5.59
(2H, s), 6.57 (1H, d, J=8.5 Hz), 7.32 (1H, dd, J=2.2 and 8.4 Hz),
7.57 (1H, d, J=8.6 Hz), 7.67 (1H, dd, J=1.6 and 8.6 Hz), 7.73 (1H,
d, J=2.1 Hz), 8.08 (1H, d, J=1.6 Hz).
[0964] IR(KBr): 1706 cm.sup.-1.
[0965] mp: 213.0-216.0.degree. C.
[0966] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=-valerylaminosulfonyl, n=1, y=0)
Example 280
1-(2,4-Dichlorobenzyl)-2,4-Dimethyl-6-Methoxycarbonylbenzimidazole
[0967] A mixture of 2,4-dimethyl-6-methoxycarbonylbenzimidazole
(0.900 g), 2,4-dichlorobenzyl chloride (1.20 g), sodium iodide
(0.200 g), potassium carbonate (0.610 g) and N,N-dimethylformamide
(4 ml) is stirred for 16 hours at 80.degree. C. After removing the
organic solvent through evaporation under reduced pressure, ethyl
acetate and water are added and extraction is performed. The
organic layer is concentrated, hexane is added and it is
crystallized. The crystals are separated through filtration, dried
and thus, 1-(2,4-dichlorobenzyl)-2,4-dimethyl-6-methoxy-
carbonylbenzimidazole (1.08 g) is obtained. .sup.1H-NMR
(CDCl.sub.3, .delta.): 2.58 (3H, s), 2.71 (3H, s), 3.90 (3H, s),
5.39 (2H, s), 6.30 (1H, d, J=8.4 Hz), 7.07 (1H, dd, J=8.4 and 2.0
Hz), 7.49 (1H, d, J=2.0 Hz), 7.75 (1H, s), 7.81 (1H, s).
[0968] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=-methoxycarbonyl, methyl, n=2, y=0)
Example 281
6-Carboxy-1-(2,4-dichlorobenzyl)-2,4-dimethylbenzimidazole
[0969] By using the method of example 75,
6-carboxy-1-(2,4-dichlorobenzyl)- -2,4-dimethylbenzimidazole (0.435
g) is obtained from
1-(2,4-dichlorobenzyl)-2,4-dimethyl-6-methoxycarbonylbenzimidazole
(0.510 g). .sup.1H-NMR (DMSO-d6, .delta.): 2.51 (3H, s), 2.55 (3H,
s), 5.57 (2H, s), 6.49 (1H, d, J=8.4 Hz), 7.31 (1H, dd, J=8.4 and
2.2 Hz), 7.62 (1H, s), 7.72 (1H, d, J=2.0 Hz), 7.78 (1H, s), 12.64
(1H, br s).
[0970] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=-methoxycarbonyl, methyl, n=2, y=0)
Example 282
6-(1-Butanesulfonylcarbamoyl)-1-(2,4-Dichlorobenzyl)-2,4-Dimethylbenzimida-
zole
[0971] By using the method of example 111,
6-(1-butanesulfonylcarbamoyl)-1-
-(2,4-dichlorobenzyl)-2,4-dimethylbenzimidazole (0.468 g) is
obtained from
6-carboxy-1-(2,4-dichlorobenzyl)-2,4-dimethylbenzimidazole (0.417
g), N,N'-carbonyldiimidazole (0.290 g), 1-butanesulfonamide (0.246
g) and diazabicycloundecene (0.273 g). .sup.1H-NMR (DMSO-d6,
.delta.): 0.84 (3H, t, J=7.4 Hz), 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=8.5 Hz), 7.31 (1H, dd, J=2.1 and 8.4 Hz), 7.64 (1H, s), 7.75 (1H,
d, J=2.1 Hz), 7.90 (1H, s), 11.79 (1H, br s).
[0972] IR(Nujol): 1682 cm.sup.-1.
[0973] mp: 180.0-181.5.degree. C.
[0974] (R.sub.1=2,4-dichlorobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, methyl, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=butyl, n=2, y=0)
Example 283
6-Ethoxycarbonyl-2-Methyl-1-(4-Phenoxybenzyl)Benzimidazole
[0975] By using the method of example 255,
4-acetylamino-3-[(4-phenoxy)ben- zylamino]ethylbenzoate (0.49 g) is
obtained from 4-acetylamino-3-amino-eth- ylbenzoate (0.56 g),
sodium carbonate (0.33 g), sodium iodide (0.12 g) and
4-phenoxybenzyl chloride (0.66 g). Subsequently, this material is
altered to
6-ethoxycarbonyl-2-methyl-1-(4-phenoxybenzyl)benzimidazole (0.44
g). .sup.1H-NMR (CDCl.sub.3, .delta.): 1.40 (3H, t, J=7.1 Hz), 2.61
(3H, s), 4.39 (2H, q, J=7.1 Hz), 5.35 (2H, s), 6.92-6.95 (2H, m),
6.97-7.00 (2H, m), 7.02 (2H, d, J=8.7 Hz), 7.09-7.13 (1H, m),
7.31-7.34 (2H, m), 7.72 (1H, d, J=8.6 Hz), 7.98 (1H, dd, J=1.5 and
8.4 Hz), 8.04 (1H, d, J=1.2 Hz).
[0976] (R.sub.1=4-phenoxybenzyl, R.sub.2=methyl,
R.sub.3=-ethoxycarbonyl, n=1, y=0)
Example 284
6-Carboxy-2-methyl-1-(4-phenoxybenzyl)benzimidazole
[0977] By using the method of example 75,
6-carboxy-2-methyl-1-(4-phenoxyb- enzyl)benzimidazole (0.37 g) is
obtained from 6-ethoxycarbonyl-2-methyl-1--
(4-phenoxy)benzylbenzimidazole (0.44 g). .sup.1H-NMR (DMSO-d6,
.delta.): 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=8.4 Hz), 7.78 (1H, d,
J=8.4 Hz), 8.07 (1H, s), 12.72 (1H, br s).
[0978] (R.sub.1=4-phenoxybenzyl, R.sub.2=methyl, R.sub.3=-carboxyl,
n=1, y=0)
Example 285
6-(1-Butanesulfonylcarbamoyl)-2-Methyl-1-(4-Phenoxybenzyl)Benzimidazole
[0979] By using the method of example 111,
6-(1-butanesulfonylcarbamoyl)-2-
-methyl-1-(4-phenoxybenzyl)benzimidazole (0.19 g) is obtained from
6-carboxy-2-methyl-1-(4-phenoxybenzyl)benzimidazole (0.3 6 g),
N,N'-carbonyldiimidazole (0.24 g), 1-butanesulfonamide (0.21 g) and
diazabicycloundecene (0.23 g). .sup.1H-NMR (DMSO-d6, .delta.): 0.85
(3H, t, J=7.4 Hz), 1.40 (2H, m), 1.68 (2H, m), 2.54 (3H, s), 3.52
(2H, t, J=7.8 Hz), 5.51 (2H, s), 6.96-6.98 (4H, m), 7.11 (1H, t,
J=7.4Hz), 7.17 (2H, d, J=8.6 Hz), 7.34-7.37 (2H, m), 7.64 (1H, d,
J=8.5 Hz), 7.79 (1H, dd, J=1.5 and 8.5 Hz), 8.24 (1H, s), 11.92
(1H, br s).
[0980] IR(Nujol): 1632 cm.sup.-1.
[0981] mp: 183.4-184.4.degree. C.
[0982] (R.sub.1=4-phenoxybenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.s- ub.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=butyl, n=1, y=0)
Example 286
6-Ethoxycarbonyl-2-Methyl-1-(2-Pyridylmethyl)Benzimidazole
[0983] By using the method of example 255,
6-ethoxycarbonyl-2-methyl-1-(2-- pyridylmethyl)benzimidazole (0.656
g) is obtained from 4-acetylamino-3-amino-ethylbenzoate (0.600 g),
potassium carbonate (0.450 g), sodium iodide (0.121 g) and
2-chloromethylpyridine (0.413 g). This material is immediately used
for the following reaction.
[0984] (R.sub.1=2-pyridylmethyl, R.sub.2=methyl,
R.sub.3=-ethoxycarbonyl, n=1, y=0)
Example 287
6-Carboxy-2-Methyl-1-(2-Pyridylmethyl)Benzimidazole
[0985] By using the method of example 75,
6-carboxy-2-methyl-1-(2-pyridylm- ethyl)benzimidazole (0.532 g) is
obtained from 6-ethoxycarbonyl-2-methyl-1-
-(2-pyridylmethyl)benzimidazole (0.656 g). .sup.1H-NMR (DMSO-d6,
.delta.): 2.56 (3H, s), 5.56 (2H, s), 7.22 (1H, d, J=7.9 Hz), 7.28
(1H, dd, J=5.0 and 7.1 Hz), 7.45 (1H, d, J=8.3 Hz), 7.74-7.79 (2H,
m), 7.95 (1H, s), 8.48 (1H, d, J=8.5 Hz).
[0986] (R.sub.1=2-pyridylmethyl, R.sub.2=methyl, R.sub.3=-carboxyl,
n=1, y=0)
Example 289
1-(Butanesulfonylcarbamoyl)-2-Methyl-1-(2-Pyridylmethyl)Benzimidazole
[0987] By using the method of example 111,
1-(butanesulfonyl-carbamoyl)-2--
methyl-1-(2-pyridylmethyl)benzimidazole (0.142 g) is obtained from
6-carboxy-2-methyl-1-(2-pyridylmethyl)benzimidazole (0.500 g),
N,N'-carbonyldiimidazole (0.394 g), 1-butanesulfonamide (0.334 g)
and diazabicyclouridecene (0.370 g). .sup.1H-NMR (DMSO-d6,
.delta.): 0.83 (3H, t, J=7.3 Hz), 1.28-1.36 (2H, m), 1.52-1.58 (2H,
m), 2.55 (3H, s), 3.06 (2H, t, J=7.9 Hz), 5.56 (2H, s), 7.17 (1H,
t, J=7.8 Hz), 7.29 (1H, dd, J=4.2 and 7.3 Hz), 7.43 (1H, d, J=8.4
Hz), 7.77 (1H, dt, J=1.8 and 7.7 Hz), 7.81 (1H, dd, J=1.4 and 8.4
Hz), 7.96 (1H, s), 8.50 (1H, d, J=4.7 Hz).
[0988] IR(Nujol): 1674 cm.sup.-1.
[0989] mp: 139.degree. C. (decomposition).
[0990] (R.sub.1=2-pyridylmethyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.s- ub.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=butyl, n=1, y=0)
Example 289
6-Ethoxycarbonyl-2-Methyl-1-(4-Nitrobenzyl)Benzimidazole
[0991] By using the method of example 255,
6-ethoxycarbonyl-2-methyl-1-(4-- nitrobenzyl)benzimidazole (0.51 g)
is obtained from 4-acetylamino-3-amino-ethylbenzoate (0.67 g),
sodium carbonate (0.39 g), sodium iodide (0.14 g) and 4-nitrobenzyl
bromide (0.78 g). .sup.1H-NMR (CDCl.sub.3, .delta.): 1.39 (3H, t,
J=7.1 Hz), 2.59 (1H, s), 4.38 (2H, q, J=7.1 Hz), 5.49 (2H, s), 7.20
(2H, d, J=8.6 Hz), 7.76 (1H, d, J=8.5 Hz), 7.94 (1H, d, J=1.1 Hz),
8.01 (1H, dd, J=1.4 and 8.5 Hz), 8.20 (2H, d, J=8.6 Hz).
[0992] (R.sub.1=4-nitrobenzyl, R.sub.2=methyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 290
1-(4-Aminobenzyl)-6-Ethoxycarbonyl-2-Methylbenzimidazole
[0993] Ethanol (6 ml) and acetic acid (0.8 ml) are added to
1-(4-nitorbenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (0.50 g)
and reduced iron (0.47 g), and the solution is refluxed for 4.5
hours. Water and ethyl acetate are added and extraction is
performed. After the organic layer is washed with water and dried,
it is concentrated under reduced pressure, and
1-(4-aminobenzyl)-6-ethoxycarbonyl-2-methylbenzimid- azole (0.46 g)
is obtained. .sup.1H-NMR (CDCl.sub.3, .delta.): 1.40 (3H, t, J=7.2
Hz), 2.59 (3H, s), 4.38 (2H, q, J=7.2 Hz), 5.25 (2H, s), 6.61 (2H,
d, J=8.6 Hz), 6.87 (2H, d, J=8.6 Hz), 7.71 (1H, d, J=8.3 Hz), 7.96
(1H, dd, J=1.5 and 8.4 Hz), 8.05 (1H, d, J=1.3 Hz).
[0994] (R.sub.1=4-aminobenzyl, R.sub.2=methyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 291
1-[(4-Benzoylamino)Benzyl]-6-Ethoxycarbonyl-2-Methylbenzimidazole
[0995] A chloroform (4 ml) solution of benzoyl chloride (0.25 g) is
added to a chloroform (8 ml) solution of
1-(4-aminobenzyl)-6-ethoxycarbonyl-2-m- ethylbenzimidazole (0.45 g)
and pyridine (0.1 5 g), and the solution is stirred for 16 hours at
room temperature. After water is added, chloroform extraction is
performed. The organic layer is concentrated under reduced
pressure, and 1-[(4-benzoylamino)benzyl]-6-ethoxycarbonyl-2-
-methylbenzimidazole (0.33 g) is obtained. .sup.1H-NM (CDCl.sub.3,
.delta.): 1.40 (3H, t, J=7.1 Hz), 2.59 (3H, s), 4.38 (2H, q, J=7.1
Hz), 5.37 (2H, s), 7.06 (2H, d, J=8.5 Hz), 7.46-7.50 (2H, m),
7.53-7.57 (1H, m), 7.61 (2H, d, J=8.5 Hz), 7.72 (1H, d, J=8.4 Hz),
7.84-7.86 (2H, m), 7.89 (1H, br s), 7.98 (1H, dd, J=1.5 and 8.5
Hz), 8.03 (1H, s).
[0996] (R.sub.1=4-benzoylaminobenzyl, R.sub.2=methyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 292
1-[(4-Benzoylamino)Benzyl]-6-Carboxy-2-Methylbenzimidazole
[0997] By using the method of example 75,
1-[(4-benzoylamino)benzyl]-6-car- boxy-2-methylbenzimidazole (365)
(0.28 g) is obtained from
1-[(4-benzoylamino)benzyl]-6-ethoxycarbonyl-2-methylbenzimidazole
(0.31 g). .sup.1H-NMR (DIMSO-d6, .delta.): 2.58 (3H, s), 5.52 (2H,
s), 7.12 (2H, d, J=8.5 Hz), 7.48-7.52 (2H, m), 7.54-7.58 (1H, m),
7.61 (1H, d, J=8.4 Hz), 7.73 (2H, d, J=8.6 Hz), 7.79 (1H, dd, 1.5
and 8.4 Hz), 7.90-7.92 (2H, m), 8.07 (1H, d, J=1.2 Hz), 10.26 (2H,
s), 12.73 (1H, br s).
[0998] (R.sub.1=4-benzoylaminobenzyl, R.sub.2 methyl,
R.sub.3=carboxyl, n=1, y=0)
Example 293
1-[(4-Benzoylamino)Benzyl]-6-(1-Butanesulfonyl)carbamoyl-2-Methylbenzimida-
zole
[0999] By using the method of example 111,
1-[(4-benzoylamino)benzyl]-6-(1-
-butanesulfonylcarbamoyl-2-methylbenzimidazole (366) (0.14 g) is
obtained from
1-[(4-benzoylamino)benzyl]-6-carboxy-2-methylbenzimidazole (0.26
g), N,N'-carbonyldiimidazole (0.17 g), 1-butanesulfonamide (0.14 g)
and diazabicycloundecene (0.16 g). .sup.1H-NMR (DMSO-d6, .delta.):
0.85 (3H, t, J=7.4 Hz), 1.40 (2H, m), 1.68 (2H, m), 2.56 (3H, s),
3.52 (2H, t, J=7.8 Hz), 5.50 (2H, s), 7.15 (2H, d, J=8.6 Hz), 7.50
(2H, t, J=7.5 Hz), 7.55-7.59 (1H, m), 7.64 (1H, d, J=8.5 Hz), 7.74
(2H, d, J=8.6 Hz), 7.79 (1H, dd, J=1.6 and 8.5 Hz), 7.90-7.92 (2H,
m), 8.24 (1H, d, J=1.3 Hz), 10.27 (1H, s), 11.92 (1H, br s).
[1000] IR(Nujol): 1693 cm.sup.-1.
[1001] mp: 267.5-268.1.degree. C.
[1002] (R.sub.1=4-benzoylaminobenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=butyl, n=1, y=0)
Example 294
6-Ethoxycarbonyl-2-Methyl-1-[4-(2-Phenylethenyl)benzyl]Benzimidazole
[1003] By using the method of example 255,
6-ethoxycarbonyl-2-methyl-1-[4--
(2-phenylethenyl)benzyl]benzimidazole (0.320 g) is obtained from
4-acetylamino-3-amino-ethylbenzoate (0.405 g), potassium carbonate
(0.253 g), sodium iodide (0.082 g) and 4-chloromethylstilbene
(0.500 g). .sup.1H-NMR (CDCl.sub.3, .delta.): 1.40 (3H, t, J=7.2
Hz), 2.6 (3H, s), 4.38 (2H, q, J=7.1 Hz), 5.38 (2H, s), 7.01-7.09
(4H, m), 7.26 (1H, t, J=7.4 Hz), 7.35 (2H, t, J=7.5 Hz), 7.45 (2H,
d, J=8.2 Hz), 7.49 (2H, d, J=7.5 Hz), 7.73 (1H, d, J=8.5 Hz), 7.99
(1H, dd, J=1.5 and 8.4 Hz), 8.30 (1H, d, J=1.2 Hz).
[1004] (R.sub.1=4-(2-phenylethenyl)benzyl, R.sub.2=methyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 295
6-Ethoxycarbonyl-2-Methyl-1-[4-(2-Phenylethyl)benzyl]-Benzimidazole
[1005] In a nitrogen environment, 5% palladium-carbon is added to
an ethanol (910 ml) solution of
6-ethoxycarbonyl-2-methyl-1-[4-(2-phenylethe-
nyl)benzyl]benzimidazole (0.320 g),. The solution is stirred for 23
hours under a nitrogen environment. Solids are separated through
filtration, the filtrate is concentrated, and thus,
6-ethoxycarbonyl-2-methyl-1-[4-(2-
-phenylethyl)benzyl]-benzimidazole is obtained. This material is
immediately used for the following reaction.
[1006] (R.sub.1=4-(2-phenylethyl)benzyl, R.sub.2=methyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 296
6-Carboxy-2-methyl-1-[4-(2-phenylethyl)benzyl]-benzimidazole
[1007] By using the method of example 75,
6-carboxy-2-methyl-1-[4-(2-pheny- lethyl)benzyl]-benzimidazole
(0.242 g) is obtained from
6-ethoxycarbonyl-2-methyl-1-[4-(2-phenylethyl)benzyl]-benzimidazole
(0.283 g). .sup.1H-NMR (DMSO-d6, .delta.): 2.56 (3H, s), 2.82 (4H,
s), 5.51 (2H, s), 7.02 (2H, d, J=8.1 Hz), 7.11-7.27 (7H, m), 7.61
(1H, d, J=8.4 Hz), 7.78 (1H, dd, 1.5 and 8.04(1H, s), 12.72 (1H,
s).
[1008] (R.sub.1=4-(2-phenylethyl)benzyl, R.sub.2=methyl,
R.sub.3=carboxyl, n=1, y=0)
Example 297
6-(1-Butanesulfonylcarbamoyl)-2-Methyl-[4-(2-Phenylethyl)benzyl]Benzimidaz-
ole
[1009] By using the method of Example 111,
6-(1-butanesulfonylcarbamoyl)-2-
-methyl-[4-(2-phenylethyl)benzyl]benzimidazole (370) (0.249 g) is
obtained from
6-carboxy-2-methyl-1-[4-(2-phenylethyl)benzyl]-benzimidazole (0.225
g), N,N'-carbonyldiimidazole (1.214 g), 1-butanesulfonamide (0.1 67
g) and diazabicycloundecene (0.185 g). .sup.1H-NMR (DMSO-d6,
.delta.): 0.86 (3H, t, J=7.4 Hz), 1.35-1.42 (2H, m), 1.63-1.71 (2H,
m), 2.53 (3H, s), 2.83 (4H, s), 3.52 (2H, t, J=7.7 Hz), 5.49 (2H,
s), 7.04 (2H, d, J=8.0 Hz), 7.12-7.25 (7H, m), 7.64 (1H, d, J=8.4
Hz), 7.79 (1H, dd, 1.7 and 8.5 Hz), 8.22 (1H, d, J=1.3 Hz), 11.92
(1H, s).
[1010] IR(Nujol): 1682 cm.sup.-1.
[1011] mp: 95.4-99.0.degree. C.
[1012] (R.sub.1=4-(2-phenylethyl)benzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=butyl, n=1, y=0)
Example 298
1-[(4-Benzoyl)benzyl]-6-ethoxycarbonyl-2-methylbenzimidazole
[1013] By using the method of example 255,
1-[(4-benzoyl)benzyl]-6-ethoxyc- arbonyl-2-methylbenzimidazole
(371) (0.70 g) is obtained from 4-acetylamino-3-amino-ethylbenzoate
(0.56 g), sodium carbonate (0.33 g), sodium iodide (0.11 g) and
4-benzoylbenzyl bromide (0.83 g). .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.40 (3H, t, J=7.2 Hz), 2.61 (3H, s), 4.39 (2H, q, J=7.2
Hz), 5.47 (2H, s), 7.14 (2H, d, J=8.2 Hz), 7.45-7.48 (2H, m),
7.56-7.60 (1H, m), 7.74-7.77 (5H, m), 7.99-8.02 (2H, m).
[1014] (R.sub.1=4-benzoylbenzyl, R.sub.2=methyl,
R.sub.3=ethoxycarbonyl, n=1, y=0)
Example 299
1-[(4-Benzoyl)benzyl]-6-Carboxy-2-Methylbenzimidazole
[1015] By using the method of example 75,
1-[(4-benzoyl)benzyl]-6-carboxy-- 2-methylbenzimidazole (372) (0.55
g) is obtained from
1-[(4-benzoyl)benzyl]-6-ethoxycarbonyl]-2-methylbenzimidazole (0.68
g). .sup.1H-NMR (DMSO-d6, .delta.): 2.57 (3H, s), 5.71 (2H, s),
7.25 (2H, d, J=8.2 Hz), 7.52 (2H, t, J=7.7 Hz), 7.62-7.66 (2H, m),
7.68-7.72 (4H, m), 7.80 (1H, dd, J=1.3 and 8.4 Hz), 8.08 (1H, d,
J=1.1 Hz), 12.72 (1H, br s).
[1016] (R.sub.1=4-benzoylbenzyl, R.sub.2=methyl, R.sub.3=carboxyl,
n=1, y=0)
Example 300
1-[(4-Benzoyl)benzyl]-6-(1-Butanesulfonylcarbamoyl)-2-Methylbenzimidazole
[1017] By using the method of example 111,
1-[(4-benzoyl)benzyl]-6-(1-buta-
nesulfonylcarbamoyl)-2-methylbenzimidazole (0.13 g) is obtained
from 1-[(4-benzoyl)benzyl]-6-carboxy-2-methylbenzimidazole (0.52
g), N,N'-carbonyldiimidazole (0.34 g), 1-butanesulfonamide (0.29 g)
and diazabicycloundecene (0.32 g). .sup.1H-NMR (DMSO-d6, .delta.):
0.84 (3H, t, J=7.4 Hz), 1.38 (2H, m), 1.66 (2H, m), 2.54 (3H, s),
3.48 (2H, t, J=7.7 Hz), 5.67 (2H, s), 7.27 (2H, d, J=8.2 Hz),
7.51-7.55 (2H, m), 7.63-7.73 (6H, m), 7.81 (1H, dd, J=1.6 and 8.5
Hz), 8.21 (1H, d, J=1.4 Hz).
[1018] IR(Nujol): 1660 cm.sup.-1.
[1019] mp: 111.0-112.4.degree. C.
[1020] Mass(FAB): m/e 490(M+1).
[1021] (R.sub.1=4-benzoylbenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.s- ub.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=butyl, n=1, y=0)
Example 301
6-Carboxy-2-Methyl-[4-(2-Phenylethenyl)Benzyl]Benzimidazole
[1022] By using the method of example 75,
6-carboxy-2-methyl-[4-(2-phenyle- thenyl)benzyl]benzimidazole
(0.237 g) is obtained from
6-ethoxycarbonyl-2-methyl-1-[4-(2-phenylethenyl)benzyl]benzimidazole
(0.500 g). .sup.1H-NMR (DMSO-d6, .delta.): 2.59 (3H, s), 5.58 (2H,
s), 7.12 (2H, d, J=8.2 Hz), 7.21 (2H, s), 7.26 (1H, t, J=7.4 Hz),
7.36 (2H, t, J=7.6 Hz), 7.57 (4H, d, J=8.0 Hz), 7.62 (1H, d, J=8.4
Hz), 7.79 (1H, dd, J=1.5 and 8.4 Hz), 8.07 (1H, d, J=1.2 Hz), 12.73
(1H, s).
[1023] (R.sub.1=4-benzoylbenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.s- ub.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=butyl, n=1, y=0)
Example 302
6-(1-Butanesulfonylcarbamoyl)-2-Methyl-[4-(2-Phenylethenyl)Benzyl]Benzimid-
azole
[1024] By using the method of example 111,
6-(1-butanesulfonylcarbamoyl)-2-
-methyl-[4-(2-phenylethenyl)benzyl]benzimidazole (0.239 g) is
obtained from
6-carboxy-2-methyl-[4-(2-phenylethenyl)benzyl]benzimidazole (0.237
g), N,N'-carbonyldiimidazole (0.209,), 1-butanesulfonamide (0.176
g) and diazabicycloundecene (0.195 g). .sup.1H-NMR (DMSO-d6,
.delta.): 0.86 (3H, t, J=7.4 Hz), 1.35-1.43 (2H, m), 1.63-1.70 (2H,
m), 2.56 (3H, s), 3.52 (2H, t, J=7.6 Hz), 5.55 (2H, s), 7.15 (2H,
d, J=8.2 Hz), 7.22 (2H, s), 7.26 (1H, t, J=7.4 Hz), 7.36 (2H, t,
J=7.6 Hz), 7.57 (1H, d, J=7.3 Hz), 7.58 (1H, d, J=8.2 Hz), 7.66
(1H, d, J=8.5 Hz), 7.80 (1H, d, J=8.4 Hz), 8.24 (1H, s), 11.93 (1H,
brs).
[1025] IR(Nujol): 1680 cm.sup.-1.
[1026] mp: 140.3-143.40.degree. C.
[1027] (R.sub.1=2-phenylethenylbenzyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=butyl, n=1, y=0)
Example 303
1-(Dibenzofuran-2-ylmethyl)-6-Ethoxycarbonyl-2-Methylbenzimidazole
[1028] By using the method of example 255,
1-(dibenzofuran-2-ylmethyl)-6-e-
thoxycarbonyl-2-methylbenzimidazole (0.47 g) is obtained from
4-acetylamino-3-amino-ethylbenzoate (0.480 g), sodium carbonate
(0.274 g), sodium iodide (0.097 g) and 2-bromomethyldibenzofuran
(0.56 g). .sup.1H-NMR (CDCl.sub.3, .delta.): 1.38 (3H, t, J=7.1
Hz), 2.62 (3H, s), 4.36 (2H, q, J=7.1 Hz), 5.54 (2H, s), 7.19 (2H,
dd, J=1.6 and 8.5 Hz), 7.32 (1H, t, J=7.6 Hz), 7.43-7.59 (4H, m),
7.76 (1H, d, J=8.4 Hz), 7.85 (1H, d, J=7.1 Hz), 8.00 (1H, dd, J=1.3
and 8.4 Hz), 8.07 (1H, d, J=1.2 Hz).
[1029] (R.sub.1=2-dibenzofuranyl, R.sub.2=methyl,
R.sub.3=ethoxycarbonyl, n=1, y=1)
Example 304
6-Carboxy-1-(Dibenzofuran-2-ylmethyl)-2-Methylbenzimidazole
[1030] By using the method of example 75,
6-carboxy-1-(dibenzofuran-2-ylme- thyl)-2-methylbenzimidazole
(0.336 g) is obtained from 6-ethoxycarbonyl-2-methylbenzimidazole
(0.46 g). .sup.1H-NMR (DMSO-d6, .delta.): 2.63 (3H, s), 5.71 (2H,
s), 7.27 (1H, d, J=8.5 Hz), 7.36 (1H, t, J=7.5 Hz), 7.50 (1H, t),
7.61-7.68 (3H, m), 7.78 (1H, d, J=8.3 Hz), 7.97 (1H, s), 7.07-8.11
(2H, m).
[1031] (R.sub.1=2-dibenzofuranyl, R.sub.2=methyl,
R.sub.3=-carboxyl, n=1, y=1)
Example 305
1-(Dibenzofuran-2-ylmethyl)-6-(1-Butanesulfonylcarbamoyl)-2-Methylbenzimid-
azole
[1032] By using the method of example 111,
1-(dibenzofuran-2-ylmethyl)-6-(-
1-butanesulfonylcarbamoyl)-2-methylbenzimidazole (0.249 g) is
obtained from
6-carboxy-1-(dibenzofuran-2-ylmethyl)-2-methylbenzimidazole (0.255
g), N,N'-carbonyldiimidazole (0.197 g), 1-butanesulfonamide (0.167
g) and diazabicycloundecene (0.185 g). .sup.1H-NMR (DMSO-d6,
.delta.): 0.81 (3H, t, J=7.4 Hz), 1.36 (2H, m), 1.65 (2H, m), 2.60
(3H, s), 3.50 (2H, t, J=7.7 Hz), 5.69 (2H, s), 7.29 (1H, dd, J=1.96
and 8.7 Hz), 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 8.5 Hz), 8.00 (1H, d, J=1.4 Hz), 8.94
(1H, d, J=7.1 Hz), 8.28 (1H, d, J=1.4 Hz), 12.70 (1H, br s).
[1033] IR(Nujol): 1682 cm.sup.-1.
[1034] mp: 224.1-229.8.degree. C.
[1035] (R.sub.1=2-dibenzofuranyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.- sub.5, R.sub.4=SO.sub.2R.sub.6,
R.sub.5=H, R.sub.6=butyl, n=1, y=1)
Example 306
6-Ethoxycarbonyl-2-Methyl-1-(2-Quinolylmethyl)Benzimidazole
[1036] By using the method of example 255,
6-ethoxycarbonyl-2-methyl-1-(2-- quinolylmethyl)benzimidazole (0.87
g) is obtained from 4-acetylamino-3-amino-ethylbenzoate (2.22 g),
sodium carbonate (1.27 g), sodium iodide (0.45 g) and
2-bromomethylquinoline (0.56 g). .sup.1H-NMR (DMSO-d6, .delta.):
1.27 (3H, t, J=7.1 Hz), 2.62 (3H, s), 4.26 (2H, q, J=7.1 Hz), 5.85
(2H, s), 7.35 (1H, d, J=8.5 Hz), 7.58 (1H, m), 7.63 (1H, d, J=8.4
Hz), 7.73 (1H, m), 7.78 (1H, dd, J=1.3 and 8.4 Hz), 7.86 (1H, d,
J=8.4 Hz), 7.95 (1H, d, J=8.0 Hz), 8.14 (1H, s), 8.36 (1H, d, J=8.5
Hz).
[1037] (R.sub.1=4-quinolyl, R.sub.2=methyl, R.sub.3=ethoxycarbonyl,
n=1, y=1)
Example 307
6-Carboxy-2-Methyl-(2-Ouinolylmethyl)Benzimidazole
[1038] By using the method of example 75,
6-carboxy-2-methyl-(2-quinolylme- thyl)benzimidazole (381) (0.46 g)
is obtained from 6-ethoxycarbonyl-2-meth-
yl-1-(2-quinolylmethyl)benzimidazole (0.85 g) .sup.1H-NMR (DMSO-d6,
.delta.): 2.62 (3H, s), 5.83 (2H, s), 7.35 (1H, d, J=8.5 Hz), 7.57
(1H, m), 7.60 (1H, d, J=8.5 Hz), 7.72 (1H, t, J=7.6 Hz), 7.77 (1H,
d, J=8.4 Hz), 7.86 (1H, d, J=8.4 Hz), 7.94 (1H, d, J=8.1 Hz), 8.11
(1H, s), 8.35 (1H, d, J=8.5 Hz).
[1039] (R.sub.1=4-quinolyl, R.sub.2=methyl, R.sub.3=carboxyl, n=1,
y=1)
Example 308
6-(1-Butanesulfonylcarbamoyl)-2-methyl-1-(2-quinolylmethyl)benzimidazole
[1040] By using the method of example 111,
6-(1-butanesulfonylcarbamoyl)-2-
-methyl-1-(2-quinolylmethyl)benzimidazole (0.088 g) is obtained
from 6-carboxy-2-methyl-1-(2-quinolylmethyl)benzimidazole (0.222
g), N,N'-carbonyldiimidazole (0.195 g), 1-butanesulfonamide (0.165
g) and diazabicycloundecene (0.183 g). .sup.1H-NMR (DMSO-d6,
.delta.): 0.82 (3H, t, J=7.3 Hz), 1.36 (2H, m), 1.64 (2H, m), 2.61
(3H, s), 3.48 (2H, t, J=7.4 Hz), 5.82 (2H, s), 7.32 (1H, d, J=8.5
Hz), 7.58 (1H, m), 7.65 (1H, d, J=8.5 Hz), 7.73 (1H, t, J=7.6 Hz),
7.78 (1H, m), 7.87 (1H, d, J=8.5 Hz), 7.95 (1H, d, J=8.1 Hz), 8.23
(1H, s), 8.37 (1H, d, J=8.5 Hz), 11.86 (1H, brs).
[1041] IR(Nujol): 1684 cm.sup.-1.
[1042] mp: 185.5-187.5.degree. C.
[1043] (R.sub.1=quinolyl, R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=butyl, n=1, y=1)
Example 309
6-Ethoxycarbonyl-2-Methyl-1-[3-(4-Bromoisoquinolyl)Methyl]Benzimidazole
[1044] By using the method of example 255,
6-ethoxycarbonyl-2-methyl-1-[3--
(4-bromoisoquinolyl)methyl]benzimidazole (0.30 g) is obtained from
4-acetylamino-3-amino-ethylbenzoate (0.87 g), sodium carbonate
(0.53 g), sodium iodide (0.18 g) and
4-bromo-3-bromomethylisoquinoline (0.87 g). .sup.1H-NMR (DMSO-d6,
.delta.): 1.26 (3H, t, J=7.0 Hz), 2.59 (3H, s), 4.24 (2H, q, J=7.0
Hz), 5.93 (2H, s), 7.61 (1H, d, J=8.4 Hz), 7.75-7.80 (2H, m), 7.99
(1H, m), 8.03 (1H, s), 8.13 (1H, d, J=8.1 Hz), 8.23 (1H, d, J=8.5
Hz), 9.12 (1H, s).
[1045] (R.sub.1=3-(4-bromoisoquinolyl), R.sub.2=methyl,
R.sub.3=ethoxycarbonyl, n=1, y=1)
Example 310
6-Carboxy-2-Methyl-[3-(4-Bromoisoquinolyl)Methyl]Benzimidazole
[1046] By using the method of example 75,
6-carboxy-2-methyl-[3-(4-bromois- oquinolyl)methyl]benzimidazole
(0.11 8 g) is obtained from
6-ethoxycarbonyl-2-methyl-1-[3-(4-bromoisoquinolyl)methyl]benzimidazole
(0.290 g). This material is immediately used for the following
reaction.
[1047] (R.sub.1=3-(4-bromoisoquinolyl), R.sub.2=methyl,
R.sub.3=carboxyl, n=1, y=1)
Example 311
6-(1-Butanesulfonylcarbamoyl)-2-Methyl-1-[3-(4-Bromoisoquinolyl)Methyl]Ben-
zimidazole
[1048] By using the method of example 111,
6-(1-butanesulfonylcarbamoyl)-2-
-methyl-1-[3-(4-bromoisoquinolyl)methyl]benzimidazole (0.075 g) is
obtained from
6-carboxy-2-methyl-1-[3-(4-bromoisoquinolyl)methyl]benzimid- azole
(0.111 g), N,N'-carbonyldiimidazole (0.097 g), 1-butanesulfonamide
(0.082 g) and diazabicycloundecene (0.091 g). .sup.1H-NMR (DMSO-d6,
.delta.): 0.81 (3H, t, J=7.4 Hz), 1.35 (2H, m), 1.62 (2H, m), 2.54
(3H, s), 3.46 (2H, t, J=7.5 Hz), 5.91 (2H, s), 7.63 (1H, d, J=8.5
Hz), 7.76 (1H, dd, J=8.5 and 1.4 Hz), 7.79 (1H, t, J=7.6 Hz), 8.00
(1H, t, J=7.9 Hz), 8.08 (1H, t, J=1.1 Hz), 8.13 (1H, d, J=8.2 Hz),
8.24 (1H, d, J=8.5 Hz), 9.11 (1H, s), 11.81 (1H, brs).
[1049] IR(Nujol): 1678 cm.sup.-1.
[1050] mp: 258-259.degree. C.
[1051] Mass(FAB): m/e 515, 517(M+1).
[1052] (R.sub.1=3-(4-bromoisoquinolyl), R.sub.2=methyl,
R.sub.3=--C(O)NR.sub.4R.sub.5, R.sub.4=SO.sub.2R.sub.6, R.sub.5=H,
R.sub.6=butyl, n=1, y=1)
[1053] The compounds of this invention can be formulated with
pharmaceutically acceptable carriers into unit dosage forms in a
conventional manner so that the patient in need of therapy for
precancerous lesions can periodically (e.g., once or more per day)
take a compound according to the methods of this invention. The
exact initial dose of the compounds of this invention can be
determined with reasonable experimentation. For compounds of this
invention, a dosage of from about 0.12 to about 400 mg/day of such
compounds for intravenous administration to achieve a systemic
circulatory therapeutic concentration.
[1054] It will be understood that various changes and modifications
can be made in the details of procedure, formulation and use
without departing from the spirit of the invention, especially as
defined in the following claims.
* * * * *