Note: Descriptions are shown in the official language in which they were submitted.
20 6062
- 1 -
The present invention is concerned with
benzimidazole compounds, the isomers and salts thereof, which
are useful pharmaceutically and especially as angiotensin
antagonists.
The new benzimidazoles of the present invention are
suitable for the treatment of hypertension and cardiac
insufficiency and also for treating ischaemic peripheral
circulatory disorders, myocardial ischaemia (angina), for the
prevention of the progression of cardiac insufficiency after
myocardial infarction and for treating diabetic nephropathy,
glaucoma, gastrointestinal diseases and bladder diseases.
EP-A-0 392 317 has already described benzimidazoles
which are valuable as angiotensin antagonists.
It has now been found that the new benzimidazoles of
general formula
R1
N
R2 / ~R3
N
CH2
R4
which differ from the benzimidazoles described in the above-
mentioned published applications by the group R2, and the
compounds of general formula I wherein R2 denotes a pyridyl or
imidazolyl group, constitute a selection from EP-A-0,400,835,
27169-194
r
2o6ofi2~
- la -
are even more useful angiotensin-II antagonists than those
known from the literature.
The present invention thus relates to the new
benzimidazoles of the above general formula I and the salts
thereof, particularly, for pharmaceutical use, the
physiologically acceptable salts thereof with inorganic or
organic acids, pharmaceutical compositions containing these
compounds and processes for preparing them.
In general formula I above:
R1 represents a fluorine, chlorine or bromine atom,
an alkyl, cycloalkyl, fluoromethyl, difluoromethyl or
27169-194
2o sos24
- 2 -
trifluoromethyl group and
RZ represents a 5-, 6- or 7-membered alkyleneimino or
alkenyleneimino group, optionally substituted by one or
two alkyl groups or by a tetramethylene or
pentamethylene group, wherein a methylene group may be
replaced by a carbonyl or sulphonyl group,
a malefic acid imido group optionally mono- or
disubstituted by an alkyl or phenyl group, whilst the
substituents may be identical or different,
a benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-
2-yl group optionally substituted in the 1-position by
C1_6-alkyl or a cycloalkyl group, whilst the phenyl
nucleus of one of the abovementioned benzimidazole
groups may additionally be substituted by a fluorine
atom or by a methyl or trifluoromethyl group, RZ may
represent an imidazo[2,1-b]thiazol-6-yl,
imidazo[1,2-a]pyridin-2-yl, 5,6,7,8-tetrahydro-
imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-2-
yl, imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-
yl, imidazo[1,2-c]pyrimidin-2-yl, imidazo[1,2-a]pyrazin-
2-yl, imidazo[1,2-b]-pyridazin-2-yl, purin-8-yl,
imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl
or imidazo[4,5-d]pyridazin-2-yl group,
a pyridyl group or
a carbon attached imidazolyl group optionally
substituted in the 1-position by an alkyl or benzyl
group, and which may also be substituted in the carbon
skeleton by an alkyl group,
R3 represents a C1_5-alkyl group or a C3_S-cycloalkyl group
and
H
-~ 206062
- 3 -
R4 represents a carboxy or 1H-tetrazolyl group,
whilst, unless otherwise specified, an alkyl moiety
mentioned hereinbefore may contain 1 to 3 carbon atoms
in each case and a cycloalkyl moiety mentioned
hereinbefore may contain 3 to 7 carbon atoms in each
case.
As examples of the definitions of the groups R1 to R3
mentioned hereinbefore:
R1 may represent a fluorine, chlorine or bromine atom, a
methyl, ethyl, n-propyl, isopropyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
fluoromethyl, difluoromethyl or trifluoromethyl group,
Rz may represent a 2-oxo-pyrrolidino, 2-oxo-piperidino,
2-oxo-hexamethyleneimino, propanesultam-1-yl,
butanesultam-1-yl, pentanesultam-1-yl, malefic acid
imido, 2-methyl-malefic acid imido, 2-phenyl-malefic acid
imido, 2-methyl-3-phenyl-malefic acid imido, pyridin-2-
yl, 4-methyl-imidazol-2-yl, 1-methyl-imidazol-4-yl, 1-
methyl-imidazol-5-yl, 1-benzyl-imidazol-4-yl, 1-benzyl-
imidazol-5-yl, 1,2-dimethyl-imidazol-4-yl, 1,2-dimethyl-
imidazol-5-yl, 1-benzyl-2-methyl-imidazol-4-yl, 1-
benzyl-2-methyl-imidazol-5-yl, benzimidazol-2-yl, 1-
methyl-benzimidazol-2-yl, 1-ethyl-benzimidazol-2-yl, 1-
n-propyl-benzimidazol-2-yl, 1-isopropyl-benzimidazol-2-
yl, 1-n-butyl-benzimidazol-2-yl, 1-isobutyl-
benzimidazol-2-yl, 1-n-pentyl-benzimidazol-2-yl, 1-n-
hexyl-benzimidazol-2-yl, 1-cyclopropyl-benzimidazol-2-
yl, 1-cyclobutyl-benzimidazol-2-yl, 1-cyclopentyl-
benzimidazol-2-yl, 1-cyclohexyl-benzimidazol-2-yl, 5-
methyl-benzimidazol-2-yl, 1,5-dimethyl-benzimidazol-2-
yl, 1,6-dimethyl-benzimidazol-2-yl, 1,4-dimethyl-
benzimidazol-2-yl, 5-fluoro-1-methyl-benzimidazol-2-yl,
6-fluoro-1-methyl-benzimidazol-2-yl, 5-trifluoromethyl-
-4- 2060624
benzimidazol-2-yl, 5-trifluoromethyl-1-methyl-
benzimidazol-2-yl, 4,5,6,7-tetrahydro-benzimidazol-2-yl,
4,5,6,7-tetrahydro-1-methyl-benzimidazol-2-yl, 4,5,6,7-
tetrahydro-1-ethyl-benzimidazol-2-yl, 4,5,6,7-
tetrahydro-1-n-butyl-benzimidazol-2-yl, 4,5,6,7-
tetrahydro-1-n-hexyl-benzimidazol-2-yl, 4,5,6,7-
tetrahydro-1-cyclopropyl-benzimidazol-2-yl, 4,5,6,7-
tetrahydro-1-cyclohexyl-benzimidazol-2-yl, imidazo-
[1,2-a]pyrimidin-2-yl, 5,6,7,8-tetrahydro-
imidazo[1,2-a]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl,
imidazo[2,1-b]thiazol-6-yl, imidazo[1,2-c]pyrimidin-2-
yl, imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-b]pyridazin-
2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl, imidazo-
[4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin-2-yl
group and
R3 may represent a methyl, ethyl, n-propyl, isopropyl, n-
butyl, isobutyl, tert.butyl, n-pentyl, 1-methyl-butyl,
2-methyl-butyl, 3-methyl-butyl, cyclopropyl, cyclobutyl
or cyclopentyl group.
Preferred compounds of general formula I above are those
wherein
R1 represents a chlorine atom, or a C1-3-alkyl or a
trifluoromethyl group,
RZ represents a 5-, 6- or 7-membered alkyleneimino group
wherein a methylene group is replaced by a carbonyl or
sulphonyl group,
a malefic acid imido group optionally mono- or
disubstituted by a C1_3-alkyl or phenyl group, whilst the
substituents may be identical or different,
a benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol
2-yl group optionally substituted in the 1-position by a
2n 60624
- 5 -
C1_6-alkyl or by a cycloalkyl group, whilst the phenyl
nucleus of one of the abovementioned benzimidazole
groups may additionally be substituted by a fluorine
atom or by a methyl or trifluoromethyl group, or RZ may
represent an imidazo[2,1-b]thiazol-6-yl,
imidazo(1,2-a]pyridin-2-yl, 5,6,7,8-tetrahydro-
imidazo(1,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-2-
yl, imidazo[4,5-b]pyridin-2-yl, imidazo(4,5-c]pyridin-2-
yl, imidazo[1,2-c]pyrimidin-2-yl, imidazo(1,2-a]pyrazin-
2-yl, imidazo[1,2-b]-pyridazin-2-yl, purin-8-yl,
imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl
or imidazo(4,5-d]pyridazin-2-yl group,
a pyridyl group or
an imidazol-4-yl group substituted in the 1-position by
a C1_3 alkyl group or by a benzyl group which may also be
substituted in the carbon skeleton by a C1_3 alkyl group,
R3 represents a C1_5-alkyl group or a C3_5-cycloalkyl group
and
Rq represents a carboxy or 1H-tetrazolyl group,
and the salts thereof with inorganic or organic acids or
bases.
Particularly preferred compounds of general formula I
above are those wherein
R1 represents a methyl group or a chlorine atom and
R2 represents a 5-, 6- or 7-membered alkyleneimino group,
wherein a methylene group is replaced by a carbonyl or
sulphonyl group,
a malefic acid imido group optionally mono- or
_. 2o sos24
- 6 -
disubstituted by a C1_3-alkyl or phenyl group, whilst the
substituents may be identical or different,
a benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-
2-yl group optionally substituted in the 1-position by a
C1_3-alkyl group, whilst the phenyl nucleus of one of the
abovementioned benzimidazole groups may additionally be
substituted by a fluorine atom, or Rz may represent an
imidazo[1,2-a]-pyridin-2-yl group, 5,6,7,8-tetrahydro-
imidazo[1,2-a]-pyridin-2-yl, imidazo[1,2-a]pyrimidin-2-
yl or imidazo[2,1-b]thiazol-6-yl group,
an imidazol-4-yl group substituted in the 1-position by
a C1_3 alkyl group,
R3 represents a C1_5-alkyl group or a C3_5-cycloalkyl group
and
R4 represents a carboxy or 1H-tetrazolyl group,
and the salts thereof with inorganic or organic acids or
bases.
According to the invention, the compounds are obtained
by the following processes:
a) Cyclising a compound of general formula
R1
X1
(II),
R2 w
Y1
wherein
R1 and RZ are defined as hereinbefore,
one of the groups X1 or Y1 represents a group of general
formula
,~y~
_.a.
20 6062
- NR8 - CH2 / ~ /
R4
and the other group X1 or Y1 represents a group of the
general formula
Zl /Zz
- NH - C - R3
wherein
R3 and R4 are defined as hereinbefore,
RB represents a hydrogen atom or an R3C0- group, wherein
R3 is defined as hereinbefore,
Z1 and Zz, which may be identical or different, represent
optionally substituted amino groups or hydroxy or
mercapto groups optionally substituted by lower alkyl
groups or
Z1 and Zz, together represent an oxygen or sulphur atom,
an optionally C1_3-alkyl substituted imino group, or a
Cz_3-alkylenedioxy or Cz_3-alkylenedithio group,
but one of the groups X1 or Y1 must represent a group of
general formula
- N(COR3) - CH2 /
R4
or
Z1~ /Zz
- NH - C - R3.
optionally with reduction of the corresponding N-oxide
=,s
20 60624
_8_
thus obtained.
The cyclisation is conveniently carried out in a solvent
or mixture of solvents such as ethanol, isopropanol,
glacial acetic acid, benzene, chlorobenzene, toluene,
xylene, glycol, glycolmonomethylether, diethyleneglycol-
dimethylether, sulpholane, dimethylformamide, tetraline
or in an excess of the acylating agent used to prepare
the compound of general formula II, e.g. in the
corresponding nitrile, anhydride, acid halide, ester or
amide, e.g. at temperatures between 0 and 250°C, but
preferably at the boiling temperature of the reaction
mixture, optionally in the presence of a condensing
agent such as phosphorusoxychloride, thionylchloride,
sulphurylchloride, sulphuric acid, p-toluenesulphonic
acid, methanesulphonic acid, hydrochloric acid,
phosphoric acid, polyphosphoric acid, acetic anhydride
or optionally in the presence of a base such as
potassium ethoxide or potassium tert.-butoxide.
However, cyclisation may also be carried out without a
solvent and/or condensing agent.
However, it is particularly advantageous to carry out
the reaction by preparing a compound of general formula
II in the reaction mixture by reducing a corresponding
o-nitro-amino compound, optionally in the presence of a
carboxylic acid of general formula R3COOH, or by
acylation of a corresponding o-diamino compound. When
the reduction of the nitro group is broken off at the
hydroxylamine stage, the N-oxide of a compound of
general formula I is obtained in the subsequent
cyclisation. The resulting N-oxide is then converted by
reduction into a corresponding compound of general
formula I.
The subsequent reduction of the N-oxide of formula I
obtained is preferably carried out in a solvent such as
2osos24
_ g _
water, water/ethanol, methanol, glacial acetic acid,
ethyl acetate or dimethylformamide with hydrogen in the
presence of a hydrogenation catalyst such as Raney
nickel, platinum or palladium/charcoal, with metals such
as iron, tin or zinc in the presence of an acid such as
acetic, hydrochloric or sulphuric acid, with salts such
as iron(II)sulphate, tin(II)chloride or sodium
dithionite, or with hydrazine in the presence of Raney
nickel at temperatures between 0 and 50°C, but
preferably at ambient temperature.
b) Reaction of a benzimidazole of general formula
R~
N
R2 / ~~R3 (III) ,
N
wherein
R1 to R3 are defined as hereinbefore, with a biphenyl
compound of general formula
Z3 _ CH2 / \ / \ (IV).
R4
wherein
RQ is defined as hereinbefore and
Z3 represents a nucleophilic leaving group such as a
halogen atom, e.g. a chlorine, bromine or iodine atom,
or a substituted sulphonyloxy group, e.g. a
methanesulphonyloxy, phenylsulphonyloxy or p-
toluenesulphonyloxy group.
The reaction is conveniently carried out in a solvent or
mixture of solvents such as methylene chloride,
B
... 20 60624
- 10 -
diethylether, tetrahydrofuran, dioxane, dimethyl-
sulphoxide, dimethylformamide or benzene, optionally in
the presence of an acid binding agent such as sodium
carbonate, potassium carbonate, sodium hydroxide,
potassium tert.-butoxide, triethylamine or pyridine,
whilst the latter two may simultaneously also be used as
solvent, preferably at temperatures between 0 and 100°C,
e.g. at temperatures between ambient temperature and
50°C.
In the reaction, a mixture of the 1- and 3- isomers is
preferably obtained which can if desired subsequently be
resolved into the corresponding 1- and 3- isomers,
preferably by chromatography using a substrate such as
silica gel or aluminium oxide.
c) In order to prepare a compound of general formula I
wherein RQ represents a carboxy group:
Converting a compound of general formula
R~
N
R2 / \~ R3
N (Zl)
/ ~ /
CHz
R '
4
wherein
R1 to R3 are defined as hereinbefore and
R9' represents a group which may be converted into a
carboxy group by hydrolysis, thermolysis or
hydrogenolysis.
For example, functional derivatives of the carboxy group
such as unsubstituted or substituted amides, esters,
2060s2~
- 11 -
thiolesters, orthoesters, iminoethers, amidines or
anhydrides, a nitrile group or a tetrazolyl group may be
converted into a carboxy group by hydrolysis, esters
with tertiary alcohols, e.g, tert.butylester, may be
converted into a carboxy group by thermolysis and esters
with aralkanols, e.g. benzylester, may be converted into
a carboxy group by hydrogenolysis.
The hydrolysis is conveniently carried out in the
presence of an acid such as hydrochloric, sulphuric,
phosphoric, trichloroacetic or trifluoroacetic acid in
the presence of a base such as sodium hydroxide or
potassium hydroxide in a suitable solvent such as water,
water/methanol, ethanol, water/ethanol,
water/isopropanol or water/dioxane at temperatures
between -10°C and 120°C, e.g. at temperatures between
ambient temperature and the boiling temperature of the
reaction mixture. When hydrolysis is carried out in the
presence of an organic acid such as trichloroacetic or
trifluoroacetic acid, any alcoholic hydroxy groups
present may optionally be simultaneously converted into
a corresponding acyloxy group such as a trifluoroacetoxy
group.
If R4' in a compound of general formula V represents a
cyano or aminocarbonyl group, these groups may also be
converted into a carboxy group with a nitrite, e.g.
sodium nitrite, in the presence of an acid such as
sulphuric acid, which may also be simultaneously used as
solvent, at temperatures between 0 and 50°C.
If R4' in a compound of general formula V represents, for
example, a tert.-butyloxycarbonyl group, the tert.-butyl
group may also be thermally cleaved, optionally in an
inert solvent such as methylene chloride, chloroform,
benzene, toluene, tetrahydrofuran or dioxane and
preferably in the presence of a catalytic amount of an
... 20 sOS24~
- 12 -
acid such as p-toluenesulphonic acid, sulphuric,
phosphoric or polyphosphoric acid, preferably at the
boiling temperature of the solvent used, e.g. at
temperatures between 40°C and 100°C.
If R4' in a compound of general formula V represents, for
example, a benzyloxycarbonyl group, the benzyl group may
also be hydrogenolytically cleaved in the presence of a
hydrogenation catalyst such as palladium/charcoal in a
suitable solvent such as methanol, ethanol,
ethanol/water, glacial acetic acid, ethyl acetate,
dioxane or dimethylformamide, preferably at temperatures
between 0 and 50°C, e.g. at ambient temperature, under a
hydrogen pressure of 1 to 5 bar. During hydrogenolysis,
other groups may be reduced at the same time, e.g. a
nitro group may be reduced to an amino group, a
benzyloxy group to a hydroxy group, a vinylidene group
to the corresponding alkylidene group or a cinnamic acid
group to the corresponding phenyl-propionic acid group,
or they may be replaced by hydrogen atoms, e.g. a
halogen may be replaced by a hydrogen atom.
d) In order to prepare a compound of general formula I
wherein RQ represents a 1H-tetrazolyl group:
Cleaving of a protective group from a compound of
general formula
R1
N
\~ R3
N (VI).
/ \ / \
CHz
R4 ~~
wherein
R1, RZ and R3 are defined as hereinbefore and
20 60624
- 13 -
R4" represents a 1H-tetrazolyl group protected in the f-
or 3-position by a protecting group.
Suitable protecting groups include, for example,
triphenylmethyl, tributyl tin or triphenyl tin groups.
The cleaving of a protective group used is preferably
carried out in the presence of a hydrohalic acid,
preferably in the presence of hydrochloric acid, in the
presence of a base such as sodium hydroxide or alcoholic
ammonia, in a suitable solvent such as methylene
chloride, methanol, methanol/ammonia, ethanol or
isopropanol at temperatures between 0 and 100°C, but
preferably at ambient temperature or, if the reaction is
carried out in the presence of alcoholic ammonia, at
elevated temperatures, e.g. at temperatures between 100
and 150°C, preferably at temperatures between 120 and
140°C.
e) In order to prepare a compound of general formula I
wherein R9 represents a 1H-tetrazolyl group:
Reaction of a compound of general formula
R1
N
RZ ~ N~ R3 (VII).
CH.,
CN
wherein
R1 to R3 are defined as hereinbefore, with hydrazoic acid
or the salts thereof.
The reaction is preferably carried out in a solvent such
as benzene, toluene or dimethylformamide at temperatures
.,
_~.. 206062
- 14 -
between 80 and 150°C, preferably at 125°C. Conveniently,
either the hydrazoic acid is liberated during the
reaction from an alkali metal azide, e.g. sodium azide,
in the presence of a weak acid such as ammonium chloride
or a tetrazolide salt obtained in the reaction mixture
during the reaction with a salt of hydrazoic acid,
preferably with aluminium azide or tributyl tin azide,
which is also preferably produced in the reaction
mixture by reacting aluminium chloride or tributyl tin
chloride with an alkali metal azide such as sodium
azide, is subsequently liberated by acidification with a
dilute acid such as 2N hydrochloric or 2N sulphuric
acid.
f) In order to prepare compounds of general formula I
wherein RZ represents one of the above-mentioned
imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-
2-yl, imidazo[1,2-c]pyrimidin-2-yl,
imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-b]pyridazin-2-yl
or imidazo[2,1-b]-thiazol-6-yl groups:
Reaction of a compound of general formula
B'A~N
(VIII) ,
~2
wherein
one of the groups A, B, C or D represents an optionally
methyl-substituted methine group or a nitrogen atom and
the remaining groups A, B, C or D represent methine
groups or A and B each represent a methine group and the
-C=D- group represents a sulphur atom,
with a compound of general formula
... 20 60624
- 15 -
R1
N
Z4 - CH2 - CC , \~ R3 (IX).
N
\ /
CH.,
wherein . R4
R1, R3 and R4 are defined as hereinbefore and
Z9 represents a nucleophilic leaving group such as a
halogen atom, e.g. a chlorine or bromine atom.
The reaction is expediently carried out in a solvent or
mixture of solvents such as ethanol, isopropanol,
benzene, glycol, glycolmonomethylether, dimethyl-
formamide or dioxane, e.g. at temperatures between 0 and
150°C, preferably at temperatures between 20 and 100°C.
However, the reaction may also be carried out without
solvents.
g) In order to prepare compounds of general formula I
wherein RZ represents one of the above-mentioned
benzimidazol-2-yl, imidazo[4,5-b]pyridin-2-yl,
imidazo[4,5-c]pyridin-2-yl, imidazo[4,5-b]pyrazin-2-yl,
imidazo[4,5-c]pyridazin-2-yl, imidazo[4,5-d]pyridazin-2-
yl or purin-8-yl groups:
Cyclisation of a compound of general formula
R11
~A, X2
(X) ,
Clb
Y2
wherein
none, one or two of the groups Al, B1, C1 or D1 represent
a nitrogen atom and
Zo sos2~
- 16 -
the remaining groups Al, B1, C1 or D1 represent methine
groups,
R11 represents a hydrogen or fluorine atom or a methyl or
trifluoromethyl group,
one of the groups Xz or Y2 represents an R13-NH- group and
the other XZ or Yz group represents a group of general
formula
R1
N
_ NR14 _ C ~ R3
N
/ \ /
CH.,
R4
wherein Rl, R3 and R4 are defined as he reinbefore,
one of the groups R13 or R14 represents a hydrogen atom
and the other R,3 or R19 group represents a hydrogen atom,
a C1_6-alkyl group or a C3_~-cycloalkyl group,
ZS and Z6, which may be identical or different, represent
optionally substituted amino groups or hydroxy or
mercapto groups optionally substituted by lower alkyl
groups or
ZS and Z6 together represent an oxygen or sulphur atom,
an optionally C1_3-alkyl substituted imino group, or an
alkylenedioxy or alkylenedithio group each having 2 or 3
carbon atoms, optionally followed by reduction of an N-
oxide thus obtained and optional hydrolysis.
The cyclisation is conveniently carried out in a solvent
or mixture of solvents such as ethanol, isopropanol,
glacial acetic acid, benzene, chlorobenzene, toluene,
xylene, glycol, glycolmonomethylether, diethyleneglycol-
dimethylether, sulpholan, dimethylformamide, tetralin or
in an excess of the acylating agent used to prepare the
compound of general formula X, e.g. in the corresponding
J,i
20 ~os24
-1~-
nitrile, anhydride, acid halide, ester or amide, e.g. at
temperatures between 0 and 250°C, but preferably at the
boiling temperature of the reaction mixture, optionally
in the presence of a condensing agent such as phosphorus
oxychloride, thionylchloride, sulphurylchloride,
sulphuric acid, p-toluenesulphonic acid,
methanesulphonic acid, hydrochloric acid, phosphoric
acid, polyphosphoric acid, acetic acid anhydride or
optionally in the presence of a base such as potassium
ethoxide or potassium tert.-butoxide. However, the
cyclisation may also be carried out without a solvent
and/or condensing agent.
However, it is particularly advantageous to perform the
reaction by preparing a compound of general formula X in
the reaction mixture by reducing a corresponding o-
nitro-amino compound, optionally in the presence of a
carboxylic acid of general formula
R1
N
HOOC ~~ R3
N , (XI)
/ \ / \
CHz
wherein R4
R1, R3 and R9 are defined as hereinbefore, or by
acylating a corresponding o-diamino compound with a
carboxylic acid of general formula XI.
When the reduction of the nitro group is broken off at
the hydroxylamine stage, subsequent cyclisation produces
the N-oxide of a compound of general formula I. The N-
oxide thus obtained is then converted by reduction into
a corresponding compound of general formula I.
The subsequent reduction of an N-oxide thus obtained is
20 60624
- 18 -
preferably carried out in a solvent such as water,
water/ethanol, methanol, glacial acetic acid, ethyl
acetate or dimethylformamide with hydrogen in the
presence of a hydrogenation catalyst such as Raney
nickel, platinum or palladium/charcoal, with metals such
as iron, tin or zinc in the presence of an acid such as
acetic, hydrochloric or sulphuric acid, with salts such
as iron(II)sulphate, tin(II)chloride or sodium
dithionite, or with hydrazine in the presence of Raney
nickel at temperatures between 0 and 50°C, but
preferably at ambient temperature.
The subsequent hydrolysis is conveniently carried out
either in the presence of an acid such as hydrochloric,
sulphuric, phosphoric, trichloroacetic or
trifluoroacetic acid in the presence of a base such as
sodium hydroxide or potassium hydroxide in a suitable
solvent such as water, water/methanol, ethanol,
water/ethanol, water/isopropanol or water/dioxane at
temperatures between -10°C and 120°C, e.g. at
temperatures between ambient temperature and the boiling
temperature of the reaction mixture. When hydrolysis is
carried out in the presence of an organic acid such as
trichloroacetic or trifluoroacetic acid, any alcoholic
hydroxy groups present may simultaneously be converted
into a corresponding acyloxy group such as the
trifluoroacetoxy group.
In the reactions described hereinbefore, any reactive
groups present such as hydroxy, amino or alkylamino
groups may be protected during the reaction by
conventional protecting groups which are split off again
after the reaction.
Examples of protecting groups for a hydroxy group are
trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.-
butyl, benzyl and tetrahydropyranyl groups and
~r
2o sos24
- 19 -
protecting groups for an amino, alkylamino or imino
group include the acetyl, benzoyl, ethoxycarbonyl and
benzyl groups.
The optional subsequent cleaving of a protecting group
is preferably carried out by hydrolysis in an aqueous
solvent, e.g. in water, isopropanol/water,
tetrahydrofuran/water or dioxane/water, in the presence
of an acid such as hydrochloric or sulphuric acid or in
the presence of an alkali metal base such as sodium
hydroxide or potassium hydroxide at temperatures between
0 and 100°C, preferably at the boiling temperature of
the reaction mixture. However, a benzyl group is
preferably split off by hydrogenolysis, e.g. with
hydrogen in the presence of a catalyst such as
palladium/charcoal in a solvent such as methanol,
ethanol, ethyl acetate or glacial acetic acid,
optionally with the addition of an acid such as
hydrochloric acid at temperatures between 0 and 50°C,
but preferably at ambient temperature, under a hydrogen
pressure of 1 to 7 bar, preferably 3 to 5 bar.
An isomer mixture of a compound of general formula I
thus obtained may if desired be resolved by
chromatography using a substrate such as silica gel or
aluminium oxide.
Moreover, the compounds of general formula I obtained
may be converted into the acid addition salts thereof,
more particularly for pharmaceutical use the
physiologically acceptable salts thereof with inorganic
or organic acids. Suitable acids for this purpose
include hydrochloric, hydrobromic, sulphuric,
phosphoric, fumaric, succinic, lactic, citric, tartaric
or malefic acid.
Furthermore, the new compounds of general formula I thus
;r t
2osos24
- 20 -
obtained, if they contain a carboxy or 1H-tetrazolyl
group, may if desired subsequently be converted into the
salts thereof with inorganic or organic bases, more
particularly for pharmaceutical use into the
physiologically acceptable addition salts thereof.
Suitable bases include for example sodium hydroxide,
potassium hydroxide, cyclohexylamine, ethanolamine,
diethanolamine and triethanolamine.
The compounds of general formulae II to XI used as
starting materials are known from the literature in some
cases or may be obtained by methods known from the
literature.
Thus, for example, a compound of general formula II is
obtained by alkylation of a corresponding o-amino-nitro
compound and subsequent reduction of the nitro group.
A compound of general formula III, V, VI, VII, IX or X
used as starting material is obtained by acylation of a
corresponding o-phenylenediamine or a corresponding o-
amino-nitro compound, followed by reduction of the nitro
group and subsequent cyclisation of an o-diamino-phenyl
compound thus obtained, optionally followed by the
cleaving of any protecting group used or by cyclisation
of a correspondingly substituted benzimidazole with a
corresponding amine or by NH-alkylation of a
corresponding 1H-benzimidazole, whilst the isomer
mixture thus obtained may subsequently be resolved by
conventional methods, e.g. chromatography. Some of the
starting compounds mentioned above are described in
EP-A-0 392 317.
For example, 2-n-butyl-5-(imidazo[1,2-a]pyridin-2-yl)-
3H-benzimidazole is obtained by reacting p-amino-
acetophenone with butyric acid chloride, followed by
nitration, bromination, cyclisation with 2-aminopyridine
... 2o sos2~
- 21 -
to form the 6-n-butanoylamido-3-(imidazo[1,2-a]pyridin-
2-yl)-nitrobenzene, which is subsequently converted into
the desired compound by cyclisation, after reduction of
the nitro group, or
2-n-butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-1H-
benzimidazole may be obtained by nitration of methyl 3-
methyl-4-n-butanoylamido-benzoate, subsequent reduction
of the nitro group and cyclisation to yield 2-n-butyl-4-
methyl-6-methoxycarbonyl-1H-benzimidazole, which is then
converted into the desired compound using 2-methylamino-
aniline with cyclisation.
The new compounds of general formula I and the
physiologically acceptable salts thereof have valuable
pharmacological properties. They are angiotensin
antagonists, particularly angiotensin-II-antagonists.
By way of example, the following compounds were tested
for their biological effects as described hereinafter:
A = 4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-
yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-
carboxylic acid,
B = 4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-
yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-
yl)-biphenyl,
C = 4'-[[2-n-propyl-4-methyl-6-(butanesultam-1-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-
biphenyl,
D = 4'-[[2-n-butyl-6-(2,3-dimethylmaleic acid imino)-4-
methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-
carboxylic acid semihydrate,
,~~ '.,
.. 20 60624
- 22 -
E = 4'-[(2-cyclopropyl-4-methyl-6-(1-
methylbenzimidazol-2-yl)-benzimidazol-1-yl)-
methyl]-biphenyl-2-carboxylic acid,
F = 4'-[(2-n-propyl-4-methyl-6-(1-methyl-5-fluoro-
benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-
biphenyl-2-carboxylic acid,
G = 4'-[(2-n-propyl-4-methyl-6-
(imidazo[1,2-a]pyrimidin-2-yl)-benzimidazol-1-yl)-
methyl]-2-(1H-tetrazol-5-yl)-biphenyl,
H = 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-
imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-
methyl]-biphenyl-2-carboxylic acid,
I - 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-
imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-
methyl]-2-(1H-tetrazol-5-yl)-biphenyl,
J = 4'-[(2-n-propyl-4-chloro-6-(1-methylbenzimidazol-2-
yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-
yl)-biphenyl-hydrochloride and
K = 4'-[[2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-
6-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-
carboxylic acid
Descr~prion of method:Angiotensin II-recet~tor bondina
The tissue (rats lung) is homogenised in Tris-buffer
(50 mMol Tris, 150 mMol NaCl, 5 mMol EDTA, pH 7.40) and
centrifuged twice for 20 minutes at 20,000 x g. The
finished pellets are resuspended in incubating buffer
(50 mMol Tris, 5 mMol MgCl2, 0.2% BSA, pH 7.40) 1:75,
based on the moist weight of the tissue. Each 0.1 ml of
homogenate is incubated for 60 minutes at 37°C with
50 pM [lzsI] -antiotensin II (NEN, Dreieich, FRG) with
a
.... 20 60x24
- 23 -
increasing concentrations of the test substance in a
total volume of 0.25 ml. Incubation is ended by rapid
filtration through glass fibre filter mats. The filters
are each washed with 4 ml of ice cold buffer (25 mMol
Tris, 2.5 mMol MgCl2, 0.1% BSA, pH 7.40). The bound
radioactivity is measured using a gamma-counter. The
corresponding ICso value is obtained from the dose-
activity curve.
In the test described, substances A to K show the
following ICso values
Substance ICso [nM]
A 3.7
B 14.0
C 1.2
D 20.0
E 12.0
F 26.0
G 3.4
H 1.2
I 1.7
J 20.0
K 7.8
In addition, compounds A, B, C, D, E and G were tested
on conscious renally hypertensive rats for their effect
after oral administration using methods known from the
literature. At a dosage of 10 mg/kg these compounds
exhibited a hypotensive effect.
Moreover, when the above-mentioned compounds were
administered in a dose of 30 mg/kg i.v. no toxic side
effects, e.g. negative inotropic effects or disorders in
heart rhythm, were observed. The compounds are
therefore well tolerated.
2osos2~
- 24 -
In view of their pharmacological properties, the new
compounds and the physiologically acceptable addition
salts thereof are suitable for the treatment of
hypertension and cardiac insufficiency and also for
treating ischaemic peripheral circulatory disorders,
myocardial ischaemia (angina), for the prevention of the
progression of cardiac insufficiency after myocardial
infarction and for treating diabetic nephropathy,
glaucoma, gastrointestinal diseases and bladder
diseases.
The new compounds and the physiologically acceptable
addition salts thereof are also suitable for treating
pulmonary diseases, e.g. lung oedema and chronic
bronchitis, for preventing arterial re-stenosis after
angioplasty, for preventing thickening of blood vessel
walls after vascular operations, and for preventing
arteriosclerosis and diabetic angiopathy. In view of
the effects of angiotensin on the release of acetyl-
choline and dopamine in the brain, the new angiotensin
antagonists are also suitable for alleviating central
nervous system disorders, e.g. depression, Alzheimer's
disease, Parkinson syndrome, bulimia and disorders of
cognitive function.
The dosage required to achieve these effects in adults
is appropriately, when administered intravenously, 20 to
100 mg, preferably 30 to 70 mg, and, when administered
orally, 50 to 200 mg, preferably 75 to 150 mg, 1 to 3
times a day. For this purpose, the compounds of general
formula I prepared according to the invention,
optionally in conjunction with other active substances,
such as hypotensives, diuretics and/or calcium
antagonists, may be incorporated together with one or
more inert conventional carriers and/or diluents, e.g.
with corn starch, lactose, glucose, microcrystalline
cellulose, magnesium stearate, polyvinylpyrrolidone,
20 60624
- 25 -
citric acid, tartaric acid, water, water/ethanol,
water/glycerol, water/sorbitol, water/polyethylene-
glycol, propylene-glycol, cetylstearyl alcohol,
carboxymethylcellulose or fatty substances such as hard
fat or suitable mixtures thereof, in conventional
galenic preparations such as plain or coated tablets,
capsules, powders, suspensions or suppositories.
Additional active substances which may be included in
the combinations mentioned above might be, for example,
bendroflumethiazide, chlorothiazide, hydrochloro-
thiazide, spironolactone, benzothiazide, cyclothiazide,
ethacrinic acid, furosemide, metoprolol, prazosine,
atenolol, propranolol, (di)hydralazine-hydrochloride,
diltiazem, felodipin, nicardipin, nifedipin, nisoldipin
and nitrendipin. The dosage for these active substances
is appropriately one fifth of the lowest recommended
dose up to 1/1 of the normally recommended dose, i.e.,
for example, 15 to 200 mg of hydrochlorothiazide, 125 to
2000 mg of chlorothiazide, 15 to 200 mg of ethacrinic
acid, 5 to 80 mg of furosemide, 20 to 480 mg of
propranolol, 5 to 60 mg of felodipine, 5 to 60 mg of
nifedipin or 5 to 60 mg of nitrendipin.
The Examples which follow are intended to illustrate the
invention:
_.. 20 60624
- 26 -
4'-[[2-n-Butyl-7-[5-(imidazol-1-yl)-pentyloxy]-4-methyl-
benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid
hydrate
0.7 g (1.15 mMol) of tert.-butyl 4'-[[2-n-butyl-7-[5-
(imidazol-1-yl)-pentyloxy]-4-methyl-benzimidazol-1-yl]-
methyl]-biphenyl-2-carboxylate are dissolved in 35 ml of
methylene chloride, 5 ml of trifluoroacetic acid are
added and the mixture is stirred for 12 hours at ambient
temperature. It is diluted with methylene chloride and
extracted with water and with saturated sodium
bicarbonate solution. The organic phase is dried over
sodium sulphate and evaporated down ~ vacuo. The crude
product thus obtained is purified over a silica gel
column (particle size: 0.063-0.02 mm, ethyl
acetate/ethanol/ammonia - 90:10:0.1) and crystallised
from acetone.
Yield: 0.19 g (29.9% of theory),
Melting point: 185-187°C
C39H38N9O3 X H20 (550.70)
Calculated: C 71.81 H 7.09 N 9.85
Found: 72.03 7.19 9.71
Mass spectrum: m/e = M+ 550
4'-[[2-n-Propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid
Prepared analogously to Example A from tert.-butyl 4'-
[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and
trifluoroacetic acid in dimethylformamide.
Yield: 63.9% of theory,
Melting point: 261-263°C
C33H30N902 ( 514 . 6 0 )
B
2p 80624
- 27 -
Calculated: C 77.02 H 5.87 N 10.89
Found: 76.90 5.85 10.99
The following compounds are obtained analogously to
Example 1:
4'-[[2-n-propyl-4-methyl-6-(1-n-propylbenzimidazol-2-
yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic
acid
4'-[[2-n-propyl-4-methyl-6-(1-n-hexylbenzimidazol-2-yl)-
benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid
4'-[[2-n-propyl-4-methyl-6-(1-cyclopropylbenzimidazol-2-
yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic
acid
4'-[[2-n-propyl-4-methyl-6-(1-cyclohexylbenzimidazol-2-
yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic
acid
4'-[[2-n-Propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
4.3 g (66 mMol) of sodium azide and 3.5 g (66 mMol) of
ammonium chloride are added to a solution of 1.60 g
(3.3 mMol) of 4'-[[2-n-propyl-4-methyl-6-(1-
methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-
cyano-biphenyl in 50 ml of dimethylformamide and the
mixture is stirred for 24 hours at 140°C. Then water is
added and the precipitate is removed by suction
filtering. The crude product thus obtained is purified
by chromatography over silica gel (300 g of silica gel,
methylene chloride + 6% ethanol).
Yield: 900 mg (51% of theory),
Melting point: 228-230°C
;r,
r
..: 206062
- 28 -
C33H30N8 (538.70)
Calculated: C 73.58 H 5.61 N 20.80
Found: 73.48 5.55 20.70
The following compounds are obtained analogously to
Example 2:
4'-[[2-n-propyl-4-methyl-6-(1-n-hexylbenzimidazol-2-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
4'-[[2-n-propyl-4-methyl-6-(1-cyclobutylbenzimidazol-2-
yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-
biphenyl
4'-[[2-n-propyl-4-methyl-6-(1-cyclohexylbenzimidazol-2-
yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-
biphenyl
4'-[[2-n-Propyl-4-methyl-6-(butanesultam-1-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 2 from 4'-[[2-n-propyl-
4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-
methyl]-2-cyano-biphenyl and sodium azide in
dimethylformamide.
Yield: 49.0% of theory,
Melting point: Sintering from 186°C
CZ9H31N.,OZS ( 541 . 70 )
Calculated: C 64.30 H 5.77 N 18.10 S 5.92
Found: 64.10 5.39 18.01 5.98
... 2060624
- 29 -
4'-[[2-Ethyl-4-methyl-6-(butanesultam-1-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 2 from 4'-[[2-ethyl-4-
methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-
2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 60.0% of theory,
Melting point: amorphous, sintering from 194°C
CZBHZ9N~O2S ( 527 . 70 )
Calculated: C 63.74 H 5.54 N 18.58 S 6.08
Found: 63.83 5.66 18.41 5.82
4'-[[2-n-Butyl-4-methyl-6-(butanesultam-'1-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 2 from 4'-[[2-n-butyl-4-
methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-
2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 48.0% of theory,
Melting point: amorphous, sintering from 183°C
C3aH33N-,OzS (555.70)
Calculated: C 64.84 H 5.99 N 17.64 S 5.77
Found: 64.53 5.66 17.63 5.55
4'-[[2-n-Propyl-4-ethyl-6-(butanesultam-1-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 2 from 4'-[[2-n-propyl-
4-ethyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-
methyl]-2-cyano-biphenyl and sodium azide in
dimethylformamide.
Yield: 27.0% of theory,
._ 20 60624
- 30 -
Melting point: amorphous, sintering from 189°C
C30H33N702'S ( 555 . 70 )
Calculated: C 64.84 H 5.99 N 17.64 S 5.77
Found: 64.81 5.68 17.87 5.31
4'-[[2-Ethyl-4-ethyl-6-(butanesultam-1-yl)-benzimidazol-
1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 2 from 4'-[[2-ethyl-4-
ethyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-
2-cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 39.0% of theory,
Melting point: amorphous, sintering from 212°C
Cz9H31N~O2S ( 541. 70 )
Calculated: C 64.30 H 5.77 N 18.10 S 5.92
Found: 64.30 5.51 17.99 5.59
4'-[[2-n-Propyl-4-isopropyl-6-(butanesultam-1-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 2 from 4'-[[2-n-propyl-
4-isopropyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-
methyl]-2-cyano-biphenyl and sodium azide in dimethyl-
formamide.
Yield: 22.0% of theory,
Melting point: amorphous
C31H3sN~O2S (569.70)
Calculated: C 65.35 H 6.19 N 17.21 S 5.63
Found: 65.13 6.10 17.54 5.40
20 fi0~24
- 31 -
4'-[[2-Ethyl-4-isopropyl-6-(butanesultam-1-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 2 from 4'-[[2-ethyl-4-
isopropyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-
methyl]-2-cyano-biphenyl and sodium azide in dimethyl-
formamide.
Yield: 24.0% of theory,
Melting point: amorphous, sintering from 209°C
C30H33N7~2S ( 555 . 70 )
Calculated: C 64.84 H 5.99 N 17.64 S 5.77
Found: 64.99 5.71 17.43 5.71
4'-[[2-n-Propyl-4-trifluoromethyl-6-(butanesultam-1-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 2 from 4'-[[2-n-propyl-
4-trifluoromethyl-6-(butanesultam-1-yl)-benzimidazol-1-
yl]-methyl]-2-cyano-biphenyl and sodium azide in
dimethyl-formamide.
Yield: 17.0% of theory,
Melting point: 199-203°C
CZ9HZ8F3N~OZS ( 595 . 70 )
Calculated: C 58.48 H 4.74 N 16.46
Found: 58.28 4.43 16.22
4'-[[2-n-Butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid
Prepared analogously to Example A from tert.-butyl 4'-
[[2-n-butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and
20 60624
- 32 -
trifluoroacetic acid in methylene chloride.
Yield: 48.0% of theory,
Melting point: 233-235°C
C39H32N4~2 ( 528 . 70 )
Calculated: C 77.25 H 6.10 N 10.60
Found: 77.10 5.98 10.46
4'-[[2-n-Butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 2 from 4'-[[2-n-butyl-4-
methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-
methyl]-2-cyano-biphenyl and sodium azide in
dimethylformamide.
Yield: 41.0% of theory,
Melting point: 235-237°C
C34H32N8 (552.70)
Calculated: C 73.89 H 5.84 N 20.28
Found: 73.67 5.81 19.93
The following compounds are obtained analogously to
Example 12:
4'-[[2-n-butyl-4-methyl-6-(1-ethylbenzimidazol-2-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
4'-[[2-n-butyl-4-methyl-6-(1-cyclopropylbenzimidazol-2-
yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-
biphenyl
4'-[[2-n-butyl-4-methyl-6-(1-n-pentylbenzimidazol-2-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
4'-[[2-n-butyl-4-methyl-6-(1-cyclopentylbenzimidazol-2-
yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-
biphenyl
H
2o sos2~
- 33 -
4'-[[2-n-Propyl-4-methyl-6-(2-oxo-piperidin-1-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 2 from 4'-[[2-n-propyl-
4-methyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-
methyl]-2-cyano-biphenyl and sodium azide in dimethyl-
formamide.
Yield: 51.0% of theory,
Melting point: amorphous, from 140°C (sintering)
C3oH31N~0 ( 505 . 60 )
Calculated: C 71.26 H 6.18 N 19.39
Found: 71.08 6.22 19.47
4'-[[2-n-Butyl-4-methyl-6-(2-oxo-piperidin-1-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 2 from 4'-[[2-n-butyl-4-
methyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-
methyl]-2-cyano-biphenyl and sodium azide in dimethyl-
formamide.
Yield: 39.0% of theory,
Melting point: amorphous, from 128°C (sintering)
C31H33N70 ( 519 . 7 0 )
Calculated: C 71.65 H 6.40 N 18.87
Found: 71.44 6.23 18.59
4'-[[2-n-Propyl-4-methyl-6-(2-oxo-piperidin-1-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared from 4'-[[2-n-propyl-4-methyl-6-(2-oxo-
piperidin-1-yl)-benzimidazol-1-yl]-methyl]-2-(2-
triphenylmethyl-tetrazol-5-yl)biphenyl by cleaving the
2osos24
- 34 -
triphenylmethyl group with methanolic hydrochloric acid.
Yield: 51.0% of theory,
Melting point: amorphous, sintering from 115°C
C3oH31N~0 (505.60)
Calculated: C 71.26 H 6.18 N 19.39
Found: 71.51 6.39 19.09
4'-[[2-n-Propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-
benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid
Prepared analogously to Example A from tert.-butyl 4'-
[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-
benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 38.0% of theory,
Melting point: 195-197°C (after evaporation and without
recrystallisation)
Melting point: 299-303°C (methylene chloride/ethanol =
20:1)
C32HZgN4O2 ( 5 0 0 . 6 0 )
Calculated: C 76.78 H 5.64 N 11.19
Found: 76.55 5.61 10.87
4' - [ [2-n-Propyl-4-methyl-6- (imidazo [1, 2-a] pyridin-2-yl) -
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 2 from 4'-[[2-n-propyl-
4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-
yl]-methyl]-2-cyano-biphenyl and sodium azide in
dimethylformamide.
Yield: 21.0% of theory,
Melting point: sintering from 181°C
C32HZBN8 (524.60)
Calculated: C 73.26 H 5.38 N 21.36
2osos24
- 35 -
Found: 73.10 5.24 21.13
The following compound may be prepared analogously to
Example 17:
4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-
yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-
biphenyl
4' - [ [2-n-Butyl-4-methyl-6- (imidazo [1, 2-a] pyridin-2-yl) -
benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid
Prepared analogously to Example A from tert.-butyl 4'-
[[2-n-butyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-
benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 51.0% of theory,
Melting point: 194-197°C
C33H30N9O2 ( 514 . 6 0 )
Calculated: C 77.02 H 5.88 N 10.89
Found: 76.81 5.78 10.64
4'-[[2-n-Butyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 2 from 4'-[[2-n-butyl-4-
methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-
yl]-methyl]-2-cyano-biphenyl and sodium azide in
dimethylformamide.
Yield: 26.0% of theory,
C33H30N8 ( 53 8 . 6 0 )
Calculated: C 73.58 H 5.61 N 20.80
Found: 73.39 5.40 20.92
.~ .,
..
__ 20 60624
- 36 -
4'-[[2-n-Propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-
yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic
acid
Prepared analogously to Example A from tert.-butyl 4'-
[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)-
benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 47% of theory,
Melting point: 224-226°C (after evaporation and without
recrystallisation)
Melting point: 294-297°C (methylene chloride/ethanol =
20:1)
C31HZ~NSO2 ( 5 O l . 6 0 )
Calculated: C 74.23 H 5.43 N 13.96
Found: 74.10 5.31 13.66
4'-[[2-n-Propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-
benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid
Prepared analogously to Example A from tert.-butyl 4'-
[[2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-
benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 43% of theory,
Melting point: 192-195°C (after evaporation and without
recrystallisation)
Melting point: >300°C (methylene chloride/ethanol -
20:1)
C3pH26NqO2S (506.64)
Calculated: C 71.12 H 5.17 N 11.06 S 6.33
Found: 70.97 5.19 10.88 6.09
- 37 _ 20 6062
4'-[[2-n-Propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 2 from 4'-[[2-n-propyl-
4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-
yl]-methyl]-2-cyano-biphenyl and sodium azide in
dimethylformamide.
Yield: 21% of theory,
Melting point: amorphous, sintering from 196°C
C30H26N8S (530. 67)
Calculated: C 67.90 H 4.94 N 21.12 S 6.04
Found: 67.77 4.84 21.00 5.87
4'-[[2-n-Propyl-4-methyl-6-(benzimidazol-2-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 2 from 4'-[[2-n-propyl-
4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-
methyl]-2-cyano-biphenyl and sodium azide in dimethyl-
formamide.
Yield: 28% of theory,
Melting point: 202-205°C
C32H28N8 ( 524 . 64 )
Calculated: C 73.26 H 5.38 N 21.36
Found: 73.01 5.22 21.56
The following compounds are obtained analogously to
Example 23:
4'-[[2-ethyl-4-methyl-6-(benzimidazol-2-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
4'-[[2-n-butyl-4-methyl-6-(benzimidazol-2-yl)-
benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
.. 20 60624
- 38 -
4'-[[2-n-propyl-4-methyl-6-(1-n-hexyl-benzimidazol-2-
yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-
biphenyl
4'-[[2-n-propyl-4-methyl-6-(1-cyclopropyl-benzimidazol-
2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-
biphenyl
4'-[[2-n-propyl-4-methyl-6-(1-cyclohexyl-benzimidazol-2-
yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-
biphenyl
4'-[[2-n-Propyl-4-methyl-6-(benzimidazol-2-yl)-
benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid
Prepared analogously to Example A from tert.-butyl 4'-
[[2-n-propyl-4-methyl-6-(benzimidazol-2-yl)-
benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 43% of theory,
Melting point: 239-242°C
C32HzaN902 ( 5 0 0 . 61 )
Calculated: C 76.78 H 5.64 N 11.19
Found: 76.55 5.60 11.41
The following compounds are obtained analogously to
Example 24:
4'-[[2-ethyl-4-methyl-6-(benzimidazol-2-yl)-
benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid
4'-[[2-n-butyl-4-methyl-6-(benzimidazol-2-yl)-
benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid
4'-[[2-n-propyl-4-methyl-6-(1-n-hexyl-benzimidazol-2-
yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic
20 60624
- 39 -
acid
4'-[[2-n-propyl-4-methyl-6-(1-cyclopropyl-benzimidazol-
2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic
acid
4'-[[2-n-propyl-4-methyl-6-(1-cyclohexyl-benzimidazol-2-
yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic
acid
4'-[[2-n-Butyl-6-(2,3-dimethylmaleic acid imino)-4-
methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic
acid-semihydrate
Prepared analogously to Example A from tert.butyl 4'-
[[2-n-butyl-6-(2,3-dimethylmaleic acid imino)-4-methyl-
benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 88.9% of theory,
Melting point: 321-322°C
C'32H31NgOq x 0 . 5 H20 ( 53 0 . 62 )
Calculated: C 72.43 H 6.08 N 7.92
Found: 72.89 6.16 7.89
4'-[[6-(2,3-Dimethylmaleic acid imino)-2-n-propyl-4-
methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic
acid semihydrate
Prepared analogously to Example A from tert.butyl 4'-
[[6-(2,3-dimethylmaleic acid imino)-2-n-propyl-4-methyl-
benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 75.4% of theory,
Melting point: 329-331°C
C31Hz9N3O4 x 0 . 5 Hz0 ( 516 . 6 0 )
20 sos24 .
- 40 -
Calculated: C 72.08 H 5.85 N 8.13
Found: 72.04 5.84 7.96
a 2 7
4'-[(2-n-Propyl-4-ethyl-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid
Prepared analogously to Example A from tert.butyl 4'-
[(2-n-propyl-4-ethyl-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 64% of theory,
Melting point: 217-219°C
C39H32N9O2 ( 52 8 . 7 0 )
Calculated: C 77.24 H 6.10 N 10.60
Found: 77.12 6.09 10.75
4'-[(2-n-Propyl-4-ethyl-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 2 from 4'-[(2-n-propyl-
4-ethyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-
yl)-methyl]-2-cyano-biphenyl and sodium azide in
dimethylformamide.
Yield: 15% of theory,
Melting point: 215-217°C
C39H32N8 (552.70)
Calculated: C 73.89 H 5.84 N 20.28
Found: 73.66 6.02 20.56
4'-[(2-Cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-
yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic
acid
Prepared analogously to Example A from tert.butyl 4'-
B
20 60624
- 41 -
[(2-cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 52% of theory,
Melting point: 244-246°C
C33H28N9O2 ( 512 . 6 0 )
Calculated: C 77.32 H 5.51 N 10.93
Found: 77.75 5.71 10.94
4'-[(2-Cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-
yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-
biphenyl
Prepared analogously to Example 2 from 4'-[(2-
cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium
azide in dimethylformamide.
Yield: 59% of theory,
Melting point: 245-247°C
C33H2eNa (536.65)
Calculated: C 73.86 H 5.26 N 20.88
Found: 73.95 5.42 20.90
4'-[(2-Cyclobutyl-4-methyl-6-(1-methylbenzimidazol-2-
yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic
acid
Prepared analogously to Example A from tert.butyl 4'-
[(2-cyclobutyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 63% of theory,
Melting point: 189-191°C
C39H3oN9O2 (526.60)
Calculated: C 77.55 H 5.74 N 10.64
- 42 - 2o sos2~
Found: 77.35 5.92 10.40
4'-f(2-Cyclobutyl-4-methyl-6-(1-methylbenzimidazol-2-
yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-
biphenyl
Prepared analogously to Example 2 from 4'-f(2-
cyclobutyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium
azide in dimethylformamide.
Yield: 61% of theory,
Melting point: 197-199°C
C34H3oNe (550.70)
Calculated: C 74.16 H 5.49 N 20.35
Found: 74.12 5.74 20.67
4'-f(2-n-Propyl-4-methyl-6-(1-methyl-5-fluoro-
benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-
2-carboxylic acid
Prepared analogously to Example A from tert.butyl 4'-
f(2-n-propyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-
2-yl)-benzimidazol-1-y)-methyl]-biphenyl-2-carboxylate
and trifluoroacetic acid in methylene chloride.
Yield: 34% of theory,
Melting point: 250-252°C
C33HZgFNqO2 (532.60)
Calculated: C 74.42 H 5.49 N 10.52
Found: 74.14 5.64 10.54
The following compound is obtained analogously to
Example 33:
4'-f(2-n-propyl-4-methyl-6-(pyridin-2-yl)-benzimidazol-
1-yl)-methyl]-biphenyl-2-carboxylic acid
2osos2~ a
- 43 -
4'-[(2-n-Propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-
yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-
biphenyl
Prepared analogously to Example 2 from 4'-[(2-n-propyl-
4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)-benzimidazol-
1-yl)-methyl]-2-cyano-biphenyl and sodium azide in
dimethylformamide.
Yield: 16.5% of theory,
Melting point: from 275°C (decomp.)
C31H2-,N9 x H20 (543.65)
Calculated: C 68.49 H 5.38 N 23.19
Found: 68.25 5.50 23.37
The following compound is obtained analogously to
Example 34:
4'-[(2-n-propyl-4-methyl-6-(pyridin-2-yl)-benzimidazol-
1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
4'-[(2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-
imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-
biphenyl-2-carboxylic acid
Prepared analogously to Example A from tert.butyl 4'-
[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-
[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-
biphenyl-2-carboxylate and trifluoroacetic acid in
methylene chloride.
Yield: 67% of theory,
Melting point: from 240°C (sinters)
C32H32NqO2 ( 5 04 . 64 )
Calculated: C 76.16 H 6.39 N 11.10
Found: 75.94 6.46 11.20
a. 2060fi24
- 44 -
The following compounds are obtained analogously to
Example 35:
4'-[(2-n-butyl-4-methyl-6-(5,6,7,8-tetrahydro-
imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-
biphenyl-2-carboxylic acid
4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-
imidazo [1, 2-a] pyridin-2-yl) -benzimidazol-1-yl) -methyl] -
biphenyl-2-carboxylic acid
4'-[(2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-
[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-
tetrazol-5-yl)-biphenyl
Prepared analogously to Example 2 from 4'-[(2-n-propyl-
4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-
yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and
sodium azide in dimethylformamide.
Yield: 73.5% of theory,
Melting point: from 275°C (decomp.)
C32H32N8 ( 5 2 8 . 6 7 )
Calculated: C 72.70 H 6.10 N 21.20
Found: 72.40 6.07 21.48
The following compounds are obtained analogously to
Example 36:
4'-[(2-n-butyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-
[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-
tetrazol-5-yl)-biphenyl
4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-
[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-
tetrazol-5-yl)-biphenyl
__ 2060624
- 45 -
4'-[(2-n-Propyl-4-methyl-6-(1-methyl-6-fluoro-
benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-
2-carboxylic acid
Prepared analogously to Example A from tert.butyl 4'-
[(2-n-propyl-4-methyl-6-(1-methyl-6-fluoro-benzimidazol-
2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate
and trifluoroacetic acid in methylene chloride.
Yield: 76% of theory,
Melting point: 243-245°C
C33Hz9FN902 ( 53 2 . 6 0 )
Calculated: 74.42 H 5.49 N 10.52
Found: 74.74 5.52 10.77
Mass spectrum: m/e = 532
4'-[(2-n-Propyl-4-chloro-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid
Prepared analogously to Example A from tert.butyl 4'-
[(2-n-propyl-4-chloro-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 52.7% of theory,
Melting point: 292-295°C
C32HZ~CN402 ( 53 5 . 06 )
Rf value: 0.30 (silica gel; methylene chloride/ethanol =
19:1)
Calculated: C 71.90 H 5.08 N 10.45 C1 6.63
Found: 71.29 5.21 10.40 6.76
20 60624
- 46 -
4'-[(2-n-Propyl-4-chloro-6-(1-methylbenzimidazol-2-yl)-
benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
hydrochloride
Prepared analogously to Example 2 from 4'-[(2-n-propyl-
4-chloro-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-
yl)-methyl]-2-cyano-biphenyl and sodium azide in
dimethylformamide.
Yield: 54.8% of theory,
Melting point: sintering from 204°C
C32HZ~C1N8 x HC1 (595.55)
Rf value: 0.20 (silica gel; petroleum ether/ethyl acetate
- 1:1 and 1% glacial acetic acid)
Calculated: C 62.55 H 4.71 N 18.85 C1 11.85
Found: 62.34 4.97 18.84 11.57
4'-[(2-n-Propyl-4-methyl-6-(1-methyl-imidazol-4-yl)
benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid
a) ~-MethX,l-4-butyr~lamino-5-nitro-acetop non
32.6 g (148 mmol) of 3-methyl-4-butyrylamino-
acetophenone are added in batches at -15°C to 300 ml of
fuming nitric acid with stirring, and stirred for a
further 30 minutes at -15°C. The reaction mixture is
then poured onto 3 litres of ice, with stirring, the
crude product precipitated is suction filtered, washed
with 400 ml of water, dried and purified by
recrystallisation from ethanol/diethylether (1:1).
Yield: 23.8 g (61.0% of theory),
Rf value: 0.32 (silica gel; methylene chloride),
Rf value: 0.48 (silica gel; methylene chloride/methanol
- 50:1) .
2osos24
- 47 -
b) 3-Methyl-4-butyrylamino-5-nitro-1-bromoacetophenone
A solution of 16.0 g (200 mmol) of bromine in 140 ml of
dioxane is added dropwise to a solution of 23.8 g (90
mmol) of 3-methyl-4-butyrylamino-5-nitro-acetophenone in
900 ml of dichloromethane at ambient temperature, with
stirring, so slowly that total decolorisation of the
reaction mixture occurs constantly. The mixture is then
stirred for a further two hours, then the reaction
mixture is evaporated to dryness in vacuo, the residue
obtained is triturated with about 20 ml of
dichloromethane/diethylether (1:1), suction filtered and
then dried. 23g (74% of theory) of 3-methyl-4-
butyrylamino-5-nitro-Z~-bromoacetophenone are thus
obtained, still containing about 10% starting material.
The product is further reacted without any more
purification.
Rf value: 0.69 (silica gel; methylene chloride/methanol
- 50:1)
Rf value: 0.84 (silica gel; methylene chloride/methanol
- 9:1) .
c) ~-Butvrvlamino-3-nitro-5-(imidazo-4-yl)-toluene
A solution of 6.8 g (20 mmol) of 3-methyl-4-
butyrylamino-5-nitro-~a-bromoacetophenone in 20 ml of
formamide is heated to 140°C for two hours. The cooled
solution is then poured into about 50 ml of 1N ammonia
and stirred for about 15 minutes. The crude product
precipitated is suction filtered, washed with about 50
ml of water and dried. In this way, 4.4 g (75% of
theory) of the product are obtained, which is further
reacted without any more purification.
Rf value: 0.29 (silica gel; methylene chloride/methanol
- 9:1)
d) 2-Bud,vrylamino-3-nitro-5-(1-methyl-imidazol-4-yl)-
toluene
1.3 g (9.5 mmol) of methyliodide are added dropwise at
20 6062
- 48 -
ambient temperature to a solution of 2.5 g (8.7 mmol) of
2-butyrylamino-3-nitro-5-(imidazol-4-yl)-toluene and 5.2
g (30 mmol) of potassium carbonate dehydrate in 30 ml of
dimethylsulfoxide and the mixture is then stirred for
two hours. The reaction mixture is then stirred into
about 150 ml of water and extracted four times with 25
ml of ethylacetate. The organic extracts are washed
with about 30 ml of water, dried and evaporated down.
The crude product thus obtained is purified by column
chromatography (300 g of silica gel, eluant: methylene
chloride/methanol = 30:1).
Yield: 640 mg (24% of theory),
Rf value: 0.54 (silica gel; methylene chloride/methanol
- 9:1)
e)
640 mg (2.1 mmol) of 2-butyrylamino-3-nitro-5-(1-methyl-
imidazol-4-yl)-toluene are hydrogenated in 30 ml of
methanol after the addition of about 200 mg of
palladium/charcoal (20%) at ambient temperature under a
hydrogen pressure of 5 bar. After all the hydrogen has
been absorbed the catalyst is removed by filtering and
the filtrate is evaporated down. The crude product
obtained is further reacted without any more
purification.
Yield: 600 mg (100% of theory),
Rf value: 0.23 (silica gel; methylene chloride/methanol
- 9:1)
f)
600 mg (2.1 mmol) of 2-butyrylamino-3-amino-5-(1-methyl-
imidazol-4-yl)-toluene are refluxed for one hour in 10
ml of glacial acetic acid. Then the mixture is
evaporated to dryness in vacuo, the residue is mixed
with about 15 ml of water, made alkaline with ammonia
20 60624
- 49 -
and extracted four times with about 10 ml of
ethylacetate. The organic extracts are washed with
about 15 ml of water, dried and finally evaporated down.
The crude product thus obtained is further reacted
without any more purification.
Yield: 420 mg (79% of theory),
Rf value: 0.37 (silica gel; methylene chloride/methanol
- 9:1)
g) TPrr.buty -4'-
280 mg (0.8 mmol) of tert.butyl-4'-bromomethyl-biphenyl-
2-carboxylate are added to a solution of 200 mg (0.79
mmol) of 2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-
benzimidazole and 90 mg (0.8 mmol) of potassium
tert.butoxide in 5 ml of dimethylsulfoxide and the
mixture is stirred for 90 minutes at ambient
temperature, then stirred into about 40 ml of water,
extracted four times with about 10 ml of ethylacetate,
then the organic extracts are washed with 10 ml of
water, dried and evaporated to dryness. The crude
product thus obtained is purified by column
chromatography (100 g silica gel, eluant:
dichloromethane/methanol = 30:1).
Yield: 230 mg (56% of theory),
Rf value: 0.61 (silica gel; methylene chloride/methanol
- 9:1)
h)
A solution of 230 mg (0.44 mmol) of tert.butyl-4'-[(2-n-
propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-
1-yl)-methyl]-biphenyl-2-carboxylate and 2 ml of
trifluoroacetic acid in 10 ml of dichloromethane was
stirred overnight at ambient temperature and then
evaporated to dryness. The residue was dissolved in
f'l
20 60624
- 50 -
about 5 ml of dilute sodium hydroxide solution, the
solution was neutralised with acetic acid, the
precipitate was suction filtered, washed with water and
dried.
Yield: 120 mg (59% of theory);
Melting point: 293-295°C
Rf value: 0.39 (silica gel; methylene chloride/methanol
- 9:1)
The following compounds are obtained analogously to
Example 40:
4'-[(2-n-propyl-4-methyl-6-(1-ethyl-imidazol-4-yl)-
benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid
4'-[(2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)
benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid
4'-[(2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-
benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid
4'-[(2-n-Propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-
benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 2 from 4'-[(2-n-propyl-
4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)-
methyl]-2-cyano-biphenyl and sodium azide in
dimethylformamide.
Yield: 24% of theory,
Melting point: 255-257°C
Rf value: 0.24 (silica gel, methylene chloride/methanol =
9:1)
CZ9HZ8N8 x H20 (506.62)
Calculated: C 68.75 H 5.97 N 22.12
Found: 68.90 5.97 22.03
ri
2o sos24
- 51 -
The following compounds are obtained analogously to
Example 41:
4'-[(2-n-propyl-4-methyl-6-(1-ethyl-imidazol-4-yl)-
benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
4'-[(2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)
benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid
4'-[(2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-
benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
4'-[2-Ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-
a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-
tetrazol-5-vl)-bi~henyl
Prepared analogously to Example 2 from 4'-[(2-ethyl-4-
methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-
yl)-benzimidazol-1-yl)methyl]-2-cyano-biphenyl and
sodium azide in dimethylformamide.
Yield: 21% of theory,
Melting point: amorphous
Rf value: 0.27(silica gel, methylene chloride/ethanol =
9:1)
CsiH3oNe ( 514 . 64 )
Calculated: C 72.35 H 5.88 N 21.78
Found: 72.01 5.82 21.44
4'-[(2-n-Propyl-4-methyl-6-(8-methyl-imidazo-[1,2-a]-
pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-
carboxylic acid
Prepared analogously to Example A from tert.butyl 4'-
[(2-n-propyl-4-methyl-6-(8-methyl-imidazo-[1,2-a]-
20 60624
- 52 -
pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-
carboxylate and trifluoroacetic acid in methylene
chloride.
Yield: 87% of theory,
Melting point: 295-297°C
Rf value: 0.34 (silica gel, methylene chloride/ethanol =
9:1)
C33H30N9O2 x H20 ( 5 3 2 . 6 5 )
Calculated: C 74.41 H 6.06 N 10.52
Found: 74.81 6.05 10.43
4'-[(2-n-Propyl-4-methyl-6-(2-pyridyl)-benzimidazol-1-
yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl
Prepared analogously to Example 2 from 4'-[(2-n-propyl-
4-methyl-6-(2-pyridyl)-benzimidazol-1-yl)-methyl]-2-
cyano-biphenyl and sodium azide in dimethylformamide.
Yield: 56% of theory,
Melting point: from 136°C (decomp.)
C3oH2-,N7 x 0 . 5 H20 ( 4 94 . 6 0 )
Calculated: C 72.85 H 5.71 N 19.83
Found: 72.45 6.01 19.83
4'-((2-n-Propyl-4-methyl-6-(8-methyl-imidazo[1,2-
a] pyridin-2-yl) -benzimidazol-1-yl) -methyl] -2- (1H-
tetrazol-5-yl)-biahenyl
Prepared analogously to Example 2 from 4'-[(2-n-propyl-
4-methyl-6-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-
benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium
azide in dimethylformamide.
Yield: 19% of theory,
Melting point: amorphous
Rf value: 0.36 (silica gel, methylene chloride/ethanol =
9:1)
., 2060624
- 53 -
C33H30N8 ( 5 3 8 . 61 )
Mass spectrum: m/e = 538
4'-[(2-Ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-
a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-
r~arhnxyl i c~ ari r3
Prepared analogously to Example A from tert.butyl 4'-[2-
ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-
a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-
carboxylate and trifluoroacetic acid in methylene
chloride.
Yield: 50% of theory,
Melting point: > 300°C
Rf value: 0.16 (silica gel, methylene chloride/ethanol =
9:1)
4'-[(2-n-Propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-
Prepared analogously to Example A from tert.butyl 4'-
[(2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-
benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and
trifluoroacetic acid in methylene chloride.
Yield: 84% of theory,
Melting point: 285-286°C
Rf value: 0.55 (silica gel, methylene chloride/methanol =
9:1)
4'-[(2-n-Propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-
hcn~imi ~aa~~i -1 girl) -methyll -2- (1H-tetrazol-5-yl) -bi~henvl
Prepared analogously to Example 2 from 4'-[(2-n-propyl-
4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-
- 54 -
yl)-methyl]-2-cyano-biphenyl and sodium azide in
dimethylformamide.
Yield: 18% of theory,
Melting point: amorphous
Rf value: 0.29 (silica gel, methylene chloride/methanol =
9:1)
CsiH3zNs ( 516 . 66 )
Mass spectrum: m/e = 516
4'-[(2-n-Propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)
hPn~im~~a~n1-1-girl)-methyll-biphenyl-2-carboxylic acid
Prepared analogously to Example A from tert.butyl 4'-
[(2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-
benzimidazol-1-yl)-methyl]-biphenyl and trifluoroacetic
acid in methylene chloride.
4'-[(2-n-Propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-
~'1P1'l7~mi ~a~~1 -1 =yl) -methyll -2- (1H-tetrazol-5-yl) -biphenvl
Prepared analogously to Example 2 from 4'-[(2-n-propyl-
4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl)-
methyl]-2-cyano-biphenyl and sodium azide in
dimethylformamide.
Ampoules containing 50 mg of active substance per 5 ml
Active substance 50 mg
KH2P09 2 mg
Na2HP04 x 2H20 50 mg
NaCl 12 mg
Water for injections ~ 5 ml
a
2060624 -
- 55 -
The buffer substances and isotonic substance are
dissolved in some of the water. The active substance is
added and, once it has been completely dissolved, water
is added to make up the required volume.
Ampoules containing 100 mg of active substance per 5 ml
Active substance 100 mg
Methyl glucamine 35 mg
Glycofurol 1000 mg
Polyethyleneglycol-polypropylene-
glycol block polymer 250 mg
Water for injections ~ 5 ml
Methyl glucamine is dissolved in some of the water and
the active substance is dissolved with stirring and
heating. After the addition of solvents, water is added
to make up the desired volume.
Tablets containing 50 mg of active substance
Active substance 50.0 mg
Calcium phosphate 70.0 mg
Lactose 40.0 mg
Corn starch 35.0 mg
Polyvinylpyrrolidone 3.5 mg
Magnesium stearate 1.5 ma
200.0 mg
w. 2o sos24
- 56 -
The active substance, CaHP04, lactose and corn starch are
uniformly moistened with an aqueous PVP solution. The
mass is passed through a 2 mm screen, dried at 50°C in a
circulating air dryer and screened again.
After the lubricant has been added, the granules are
compressed in a tablet making machine.
Coated tablets containing 50 mg of active substance
Active substance 50.0 mg
Lysine 25.0 mg
Lactose 60.0 mg
Corn starch 34.0 g
Gelatin 10.0 mg
Magnesium stearate 1.0 mg'
180.0 mg
The active substance is mixed with the excipients and
moistened with an aqueous gelatin solution. After
screening and drying the granules are mixed with
magnesium stearate and compressed to form tablet cores.
The cores thus produced are covered with a coating by
known methods. A colouring may be added to the coating
suspension or solution.
i?
20 60624
- 57 -
Coated tablets containing 100 mg of active substance
Active substance 100.0 mg
Lysine 50.0 mg
Lactose 86.0 mg
Corn starch 50.0 mg
Polyvinylpyrrolidone 2.8 mg
Microcrystalline cellulose 60.0 mg
Magnesium stearate 1.2 ma
350.0 mg
The active substance is mixed with the excipients and
moistened with an aqueous PVP solution. The moist mass
is passed through a 1.5 mm screen and dried at 45°C.
After drying, it is screened again and the magnesium
stearate is added. This mixture is compressed into
cores.
The cores thus produced are covered with a coating by
known methods. Colourings may be added to the coating
suspension or solution.
Capsules containing 250 mg of active substance
Active substance 250.0 mg
Corn starch 68.5 mg
Magnesium stearate 1.5 ma
320.0 mg
20 60624
- 58 -
The active substance and corn starch are mixed together
and moistened with water. The moist mass is screened
and dried. The dry granules are screened and mixed with
magnesium stearate. The final mixture is packed into
size 1 hard gelatine capsules.
Example 57
Oral suspension containing 50 mg of active substance per
ml
Active substance 50.0 mg
Hydroxyethylcellulose 50.0 mg
Sorbic acid 5.0 mg
70% sorbitol 600.0 mg
Glycerol 200.0 mg
Flavouring 15.0 mg
Water ~ 5.0 ml
Distilled water is heated to 70°C. Hydroxyethyl-
cellulose is dissolved therein with stirring. With the
addition of sorbitol solution and glycerol the mixture
is cooled to ambient temperature. At ambient
temperature, sorbic acid, flavouring and active
substance are added. The suspension is evacuated with
stirring to remove any air. One dose of 50 mg is
contained in 5.0 ml.
2o sos24
- 59 -
Suppositories containing 100 mg of active substance
Active substance 100.0 mg
Solid fat 1600.0 ma
1700.0 mg
The hard fat is melted. At 40°C the ground active
substance is homogeneously dispersed in the melt. It is
cooled to 38°C and poured into slightly chilled
suppository moulds.
;4F
